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New methodologies for the catalytic enantioselective addition of organometallic reagents to carbonyl compounds Emilio Fernández Mateos

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Page 1: New methodologies for the catalytic enantioselective ... · New methodologies for the catalytic enantioselective addition of organometallic reagents to carbonyl compounds Emilio Fernández

New methodologies for the catalytic enantioselective addition of organometallic reagents to carbonyl compounds

Emilio Fernández Mateos

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Instituto de Síntesis Orgánica (ISO) New methodologies for the catalytic enantioselective addition

of organometallic reagents to carbonyl compounds

Memoria para optar al Título de Doctor Internacional por la Universidad de Alicante presentada por el licenciado:

EMILIO FERNÁNDEZ MATEOS

Alicante, junio de 2015

V.º B.º de la Directora:

Fdo.: Dra. Beatriz Maciá Ruiz Lecturer in Organic Chemistry (Manchester Metropolitan University)

Instituto de Síntesis Orgánica (ISO), Facultad de Ciencias, Fase I, Universidad de Alicante

Campus de Sant Vicent del Raspeig, Apdo. 99, E-03080 Alicante, España Tel. +34 965903400, ext. 2121; +34 965903549; Fax +34 965903549

http://iso.ua.es; [email protected]

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A mis padres

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Table of contents

Table of contents

Resumen ...................................................................................................................... 11

Preface ......................................................................................................................... 33

General objectives .............................................................................................. 37

Chapter I ............................................................................................................ 41

1. Introduction .......................................................................................................... 41

1.1. History of Ar-BINMOL ligands .......................................................................................... 41

1.2. Applications of Ar-BINMOL ligands ................................................................................. 43

2. Results and discussion ........................................................................................... 45

3. Experimental part ................................................................................................. 45

3.1. Synthesis of monobenzylated (S)-BINOL derivatives I1-10 .............................................. 45

3.2. Data of hydroxyethers (S)-I1 and (S)-I10 ......................................................................... 50

3.3. Synthesis of chiral Ar-BINMOL ligands L1-10 ................................................................... 51

3.4. Data of chiral Ar-BINMOL ligands L1-10 .......................................................................... 52

3.5. Synthesis of chiral Ar-BINMOL ligand (Sa,S)-L1 ................................................................ 58

3.6. Data of chiral Ar-BINMOL ligand (Sa,S)-L1 ....................................................................... 58

Chapter II ........................................................................................................... 63

1. Introduction .............................................................................................. 63

1.1. Stoichiometric and superstochiometric enantioselective addition of organolithium

reagents to aldehydes ................................................................................................... 64

1.2. Catalytic enantioselective addition of organolithium reagents to aldehydes ................. 74

2. Results and discussion ........................................................................................... 79

2.1. Optimization of the catalytic enantioselective addition of organolithium reagents to

aldehydes ...................................................................................................................... 79

2.2. Scope of the reaction ...................................................................................................... 83

3. Experimental part .................................................................................................. 89

3.1. General procedure for the enantioselective addition of organolithium reagents to

aldehydes ...................................................................................................................... 89

3.2. Data of chira secondary alcohols prepared from organolithium reagents ...................... 89

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Table of contents

Chapter III ....................................................................................................... 103

1. Introduction........................................................................................................... 103

1.1. Stoichiometric and superstoichiometric enantioselective addition of organomagnesium

reagents to aldehydes ................................................................................................... 105

1.2. Catalytic enantioselective addition of Grignard reagents to aldehydes .......................... 110

1.3. Catalytic enantioselective addition of Grignard reagents to ketones ............................. 113

2. Results and discussion ........................................................................................... 117

2.1. Optimization of the catalytic enantioselective addition of Grignard reagents to aromatic

aldehydes ...................................................................................................................... 117

2.2. Scope of the reaction ...................................................................................................... 121

2.3. Application of the methodology: Synthesis of 2-substituted chiral tetrahydropyranes .. 125

3. Experimental part .................................................................................................. 129

3.1. General procedure for the enantioselective addition of Grignard reagents to aromatic

aldehydes ...................................................................................................................... 129

3.2. Data of chiral secondary alcohols prepared from Grignard reagents.............................. 129

3.3. General procedure for the intramolecular cyclization of 4-chlorobutyl alcohols into 2-

substituted chiral tetrahydropyrans ............................................................................. 136

3.4. Data of 2-substituted chiral tetrahydropyrans ................................................................ 136

4. Results and discussion ........................................................................................... 139

4.1. Optimization of the catalytic enantioselective addition of Grignard reagents to aliphatic

aldehydes ...................................................................................................................... 139

4.2. Scope of the reaction ...................................................................................................... 142

4.3. Mechanistic aspects ........................................................................................................ 144

5. Experimental part .................................................................................................. 149

5.1. General procedure for the enantioselective addition of Grignard reagents to aliphatic

aldehydes ...................................................................................................................... 149

5.2. Data of chiral secondary aliphatic alcohols ..................................................................... 149

5.3. Procedure for the derivatization of chiral secondary aliphatic alcohols into the

corresponding esters .................................................................................................... 154

5.4. Data of chiral esters......................................................................................................... 155

6. Results and discussion ........................................................................................... 159

6.1. Catalytic enantioselective arylation of ketones with Grignard reagents ......................... 159

6.2. Scope of the reaction ...................................................................................................... 162

7. Experimental part .................................................................................................. 167

7.1. General procedure for the enantioselective arylation of ketones with Grignard reagents167

7.2. Data of chiral tertiary alcohols ........................................................................................ 167

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Table of contents

Chapter IV ......................................................................................................... 179

1. Introduction........................................................................................................... 179

1.1. Catalytic enantioselective addition of organoaluminum reagents to aldehydes ............ 180

2. Results and discussion ........................................................................................... 187

2.1. Optim. of the cat. enantioselec. addition of organoaluminum reagents to aldehydes ... 187

2.2. Scope of the reaction ...................................................................................................... 191

3. Experimental part .................................................................................................. 195

3.1. General procedure for the enantioselective addition of organoaluminum reagents to

aldehydes ...................................................................................................................... 195

3.2. Data of chiral secondary alcohol prepared from organoaluminum reagents.................. 195

General conclusions ........................................................................................... 203

Experimental part (General information) ........................................................... 207

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RESUMEN

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1. Introducción general

1.1. Síntesis de alcoholes quirales

La adición nucleófila de reactivos organometálicos a compuestos carbonílicos es un

método versátil y eficiente para generar enlaces C–C. Desde el punto de vista

sintético, es una metodología especialmente atractiva, pues el producto generado en

la reacción es un alcohol secundario o terciario que contiene un nuevo centro

estereogénico, fragmento presente en numerosos productos naturales y/o con

actividad biológica. (Esquema 1).

Esquema 1. Adición enantioselectiva de reactivos organometálicos a compuestos carbonílicos.

La adición enantioselectiva de reactivos organozíncicos y de alquilaluminio a

aldehídos ha sido extensamente estudiada tanto en su versión estequiométrica como

catalítica. Sin embargo, para compuestos organometálicos más reactivos, como

organomagnesianos y organolíticos, el desarrollo ha sido menor y actualmente, su

versión catalítica está siendo estudiada con resultados incipientes para reactivos de

Grignard y organolíticos.

La principal desventaja de los reactivos organomagnesianos y organolíticos frente a

organozíncicos, es su elevada reactividad debido a la mayor polaridad del enlace

carbono-metal: 1.55 (C–Li), 1.24 (C–Mg) y 0.65 (C–Zn). La alta reactividad de los

compuestos de litio y magnesio dificulta el control de la estereoselectividad en

procesos de adición y además los hacen incompatibles con ciertos grupos

funcionales. Por ello, la investigación en las últimas décadas ha estado enfocada

hacia el estudio de otros compuestos organometálicos menos reactivos, como los

compuestos organozíncicos. No obstante, una protección adecuada de los grupos

funcionales más sensibles puede solucionar el problema de incompatibilidad con

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reactivos organomagnesianos y organolíticos, pudiéndose así aprovechar las ventajas

que los mismos presentan, como su precio asequible y la simple y eficaz metodología

para sintetizarlos.

La transmetalación de compuestos organolíticos y organomagnesianos con metales

menos reactivos como zinc, titanio o cobre, supone una solución eficaz al problema

de trabajar con compuestos organometálicos muy reactivos. De esta forma se

consigue disminuir in situ la reactividad de dichos compuestos. Sin embargo, este

procedimiento supone un problema añadido, y es la generación de sales inorgánicas

que favorecen la reacción no catalizada (ausencia de estereocontrol). Además, la

eliminación de dichas sales resulta un procedimiento tedioso.

1.2. Subunidad metil carbinol

La subunidad de metil carbinol está presente en numerosos productos naturales y de

interés farmacéutico como la Batzelladina F, ácido (S)-mincuartinóico, ácido (E)-

15,16-dihidromincuartinóico y Zearalenona (Esquema 2). Un posible método

eficiente para la preparación de esta subunidad, consiste en la adición

enantioselectiva de una fuente organometálica de metilo a un aldehído precursor del

producto natural deseado.

La fuente de metilo utilizada con más frecuencia en síntesis asimétrica es Me2Zn,

debido a la amplia gama de ligandos quirales disponibles para reactivos

organozíncicos. Aunque, Me2Zn es un compuesto organometálico poco reactivo y tan

solo unos pocos ligandos de los existentes son capaces de activarlo y hacerlo

reaccionar de forma selectiva con aldehídos.

Una manera de evitar el uso de Me2Zn (poco reactivo y de coste elevado), es

mediante la utilización de otros reactivos organometálicos más reactivos como MeLi,

MeMgBr o Me3Al. Desafortunadamente, la ventaja del menor coste de estos

reactivos organometálicos está contrarrestada por la cantidad de ligando quiral

requerida en las metodologías no catalíticas.

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Esquema 2. Productos naturales que contienen la subunidad metil carbinol en su estructura.

Con los inicios de la adición 1,2 enantioselectiva catalítica a compuestos carbonílicos

con reactivos de Grignard y organolíticos, se abren nuevas posibilidades para la

síntesis asimétrica de alcoholes secundarios y terciarios presentes en numerosos

productos naturales de forma directa o derivatizados.

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2. Resumen

2.1. Síntesis de ligandos Ar-BINMOL

Se decidió sintetizar ligandos derivados de (S)-BINOL para su utilización en catálisis

asimétrica en la adición de reactivos de Grignard a aldehídos. La estructura binaftílica

proporciona restricción en la rotación del eje biarílico debido al impedimento

estérico ejercido por los dos naftilos. Por otra parte, la sencilla modificación de la

estructura de este tipo de ligandos permite modular la actividad catalítica e incluso

sus aplicaciones químicas en catálisis asimétrica.

Los ligandos empleados para el propósito de esta memoria son conocidos como Ar-

BINMOLs (1,1´-binaftalen-2--arilmetan-2-oles) y han sido descritos en 2011 por Xu.

La metodología empleada por nuestro grupo de investigación para la síntesis de estos

ligandos consiste en dos pasos de reacción (Esquema 3), mediante una ligera

modificación del procedimiento original del grupo de investigación de Xu.

Esquema 3. Síntesis de los ligandos Ar-BINMOL L1-10.

En el primer paso de la síntesis de los ligandos L1-10 (Esquema 3), se hizo reaccionar

(S)-BINOL en presencia de 1.5 eq. K2CO3 y 1 eq. ArCH2Br a reflujo de acetona durante

6 h. Sin embargo, cuando se utilizó bromuro de 4-bromometilpiridinio como

electrófilo (I9-10) las condiciones de reacción tuvieron que ser ligeramente

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modificadas para solucionar los problemas de solubilidad de dicho compuesto,

utilizando para ello una mezcla 9:1 acetona/H2O como disolvente y 3 eq. K2CO3

durante 12 horas de reacción.

El crudo de la reacción de la síntesis de los intermedios monobencilados (S)-I se

utilizó en el siguiente paso de reacción sin necesidad de aislar dichos intermedios. A

continuación, los intermedios (S)-I se trataron con 2.5 eq. n-BuLi en THF anhidro, a –

78 ᵒC durante 2 h para obtener los ligandos L1-8 a través de una transposición de

Wittig [1,2] asímetrica (Esquema 3). Por otra parte, los ligandos H8-(Sa,R)-L1 y L9-10

se sintetizaron mediante unas condiciones de reacción más agresivas, empleando 5

eq. n-BuLi en THF anhidro como disolvente, a 70 ᵒC durante 12 horas. Los ligandos

Ar-BINMOL se obtuvieron con buenos rendimientos después de dos pasos de

reacción y una sola purificación mediante columna cromatográfica, aunque los

productos L9-10 se obtuvieron con rendimientos bajos, 40% y 33%, respectivamente,

debido a que en la transposición de Wittig [1,2] se produjo (S)-BINOL como

subproducto mayoritario de la reacción procedente de la ruptura homolítica del éter

bencílico sin dar lugar a la etapa de recombinación de radicales. A pesar de esto,

todos los dioles quirales se obtuvieron con excelentes diastereoselectividades en

todos los casos (>99%).

Esquema 4. Epimerización del diol (Sa,R)-L1 a (Sa,S)-L1.

Debido al excelente diastereocontrol de la transposición de Wittig [1,2] asimétrica de

éteres bencílicos derivados de (S)-BINOL resultó complicado preparar el

diasteroisómero opuesto del ligando (Sa,R)-L1 obtenido mediante dicha ruta

sintética. Tras varios procedimiento probados, la epimerización del centro

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esterogénico del ligando (Sa,R)-L1 utilizando una mezcla 1:1 THF/HCl(ac) 6 M a 25 ᵒC

durante 3 horas resulto la ruta sintética más corta y eficiente (Esquema 4). Así se

obtuvo el ligando (Sa,S)-L1 en un solo paso de reacción con un 20% de rendimiento y

el correspondiente subproducto de ciclación intramolecular C1 como una mezcla

diastereomérica (26% rto., r.d. 6:1).

2.2. Adición enantioselectiva de reactivos organolíticos a aldehídos

Se decido emplear dichos ligandos en diferentes reacciones de adición 1,2. En primer

lugar, se probó la alquilación enantioselectiva de aldehídos utilizando reactivos

organolíticos.

Los reactivos organolíticos han sido empleados en multitud de reacciones en química

orgánica, pero no suelen estar relacionados con la síntesis asimétrica debido su alta

reactividad y como consecuencia directa de esto, a su baja tolerancia a ciertos grupos

funcionales sensibles. El principal problema de este tipo de reactivos es que la

reacción de fondo o no catalizada es mucho más rápida que la reacción catalizada.

Para solucionar este problema, varios grupos de investigación han desarrollado

diferentes metodologías que consiguen modificar el transcurso de la reacción como

por ejemplo: i) utilizar agentes de transmetalación para reducir la reactividad del

reactivo organolítico original, ii) empleo de cantidades estequiométricas o

superestequiométricas de ligandos quirales para evitar que no haya ninguna especie

organolítica libre y pueda atacar directamente al electrófilo en ausencia del ligando,

iii) empleo de temperaturas extremadamente (–100 ᵒC) para aumentar los niveles de

selectividad, iv) adición lenta del nucleófilo sobre una disolución del correspondiente

complejo quiral para disminuir de forma prácticamente total la reacción de fondo o

no catalizada.

En nuestro grupo de investigación, se probaron diferentes ligandos Ar-BINMOL

sintetizados previamente para la adición enantioselectiva de MeLi a benzaldehído

(1a), esta fue la reacción modelo durante todo el proceso de optimización. También

se probaron diferentes temperaturas de reacción, metodologías de adición: lenta o

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rápida, disolventes apróticos de distinta polaridad y diferentes proporciones Ti(Oi-

Pr)4/MeLi. La etapa clave de la optimización fue la determinación de la proporción

óptima Ti(Oi-Pr)4/MeLi, ya que pequeñas variaciones en dicha relación entre el

nucleófilo y el agente de transmetalación afectaban de forma drástica al ee.

Finalmente, la proporción adecuada para este sistema catalítico fue 1.9:1.

Otra peculiaridad de este sistema a destacar, es la necesidad de adicionar el

electrófilo rápidamente (aproximadamente 20 s) previa adición del nucleófilo, ya que

en caso contrario se obtenían conversiones inferiores al 20% aunque el exceso

enantiomérico permanecía constante. Por tanto, se deduce de esto que las especies

activas de alquiltitanio resultantes de la transmetalación tienen una vida media corta

y además cabe la posibilidad de que no todas las especies generadas in situ sean

activas en el proceso catalítico.

Las condiciones óptimas para la alquilación enantioselectiva de aldehídos con

reactivos organolíticos fueron: 3.2 eq. RLi, 6 eq. Ti(Oi-Pr)4, 20% mol (Sa,R)-L1, tolueno

como disolvente, –40 ᵒC de temperatura de reacción y durante 1 hora. Con las

condiciones de reacción optimizadas se consiguió la adición enantioselectiva de MeLi

a una gran variedad de aldehídos aromáticos con excesos enantioméricos

comprendidos entre 62% y 90% y muy buenos rendimientos (Esquema 5). El sistema

presentó algunas limitaciones como el uso de aldehídos aromáticos con sustituyentes

en posición orto-, ya que la enantioselectividad disminuyó notablemente cuando se

utilizó este tipo de aldehídos (62% ee, o-metilbenzaldehído). El uso de aldehídos

alifáticos también produjo una disminución en el exceso enantiomérico de los

correspondientes alcoholes quirales metilados.

Esquema 5. Adición enantioselectiva de EtLi y n-BuLi a aldehídos aromáticos catalizada por (Sa,R)-L1.

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También se utilizaron otros nucleófilos alifáticos como EtLi o n-BuLi ofreciendo los

correspondientes productos de adición a aldehídos aromáticos con excelentes

excesos enantioméricos comprendidos entre 90% y 96% y rendimientos de buenos a

excelentes (Esquema 6). Cabe destacar, que bajo las condiciones de reacción

previamente descritas fue posible la utilización de sustratos con grupos sensibles a

reactivos organolíticos, como un carbamato (1p).

Esquema 6. Adición enantioselectiva de EtLi y n-BuLi a aldehídos aromáticos catalizada por (Sa,R)-L1.

Una limitación adicional de la metodología fue la imposibilidad de adicionar i-BuLi,

probablemente debido a ser voluminoso y tampoco se obtuvieron resultados buenos

cuando se utilizó en nucleófilo sp2 PhLi. En este caso, los rendimientos fueron

excelentes (>92%), pero las enantioselectividades fueron inferiores a 39% en todas

las pruebas realizadas.

2.3. Adición enantioselectiva de reactivos de Grignard a aldehídos

aromáticos

Los ligandos Ar-BINMOL también se utilizaron en la alquilación enantioselectiva de

aldehídos aromáticos utilizando reactivos de Grignard como nucleófilos.

Los reactivos de Grignard han sido empleados en química orgánica en muchos

procesos sintéticos, pero su aplicación a la síntesis asimétrica y más concretamente a

la catálisis está en pleno proceso de evolución debido al surgimiento de nuevos

ligandos y metodologías que permiten trabajar con dichos compuestos

organometálicos. Y es que la principal desventaja es su elevada reactividad y como

consecuencia de esto, presentan una baja tolerancia a ciertos grupos funcionales

sensibles. Al igual que los reactivos organolíticos, los reactivos de Grignard debido a

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su elevada reactividad, la reacción de fondo o no catalizada es mucho más rápida que

la reacción catalizada. Para solucionar este problema, existen diferentes

metodologías que consiguen modificar el transcurso de la reacción mediante: i) el

uso de agentes de transmetalación para reducir la reactividad del reactivo

organolítico original, ii) empleo de cantidades estequiométricas o

superestequiométricas de ligandos quirales para evitar que no haya ninguna especie

organolítica libre y pueda atacar directamente al electrófilo en ausencia del ligando,

iii) empleo de temperaturas extremadamente (–100 ᵒC) para aumentar los niveles de

selectividad, iv) adición lenta del nucleófilo sobre una disolución del correspondiente

complejo quiral para disminuir de forma prácticamente total la reacción de fondo o

no catalizada.

Sin embargo, este tipo de reactivos presentan varias ventajas a tener muy en cuenta:

(i) son fáciles de sintetizar mediante reacción directa del correspondiente haluro de

alquilo o arilo y limaduras de magnesio o haciéndolo reaccionar con otro reactivo de

Grignard, (ii) son altamente estables a temperatura ambiente y pueden ser

almacenados, (iii) tienen un precio asequible comparado con los reactivos

organozíncicos que son los más utilizados en catálisis asimétrica, (iv) la adición de

dioxano a una disolución etérea de un reactivo de Grignard causa la precipitación del

dihaluro de magnesio (MgX2) y esto causa el desplazamiento del equilibrio de Schlenk

hacia la formación de otro tipo de reactivos organomagnesianos (R2Mg).

En nuestro grupo de investigación, se probaron diferentes ligandos Ar-BINMOL

sintetizados previamente para la adición enantioselectiva de MeMgBr a benzaldehído

(1a), esta fue la reacción modelo durante todo el proceso de optimización. También

se probaron diferentes temperaturas de reacción, metodologías de adición: lenta o

rápida, disolventes apróticos de distinta polaridad, distintas fuentes de titanio y

diferentes proporciones Ti(Oi-Pr)4/MeMgBr. La etapa clave de la optimización fue la

determinación de la proporción óptima Ti(Oi-Pr)4/MeMgBr ya que pequeñas

variaciones en dicha relación entre el nucleófilo y el agente de transmetalación

afectaban de forma drástica al exceso enantiomérico. Finalmente, la proporción

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adecuada para este sistema catalítico fue 4:1. Para el caso particular de los reactivos

de Grignard, se añadió el electrófilo 15 min después de haber adicionado el

correspondiente RMgBr sin observar ningún efecto sobre el rendimiento del

producto deseado.

Las condiciones óptimas para la alquilación enantioselectiva de aldehídos aromáticos

con reactivos de Grignard fueron: 3.8 eq. RMgBr, 15 eq. Ti(Oi-Pr)4, 20% mol (Sa,R)-L1,

tolueno como disolvente, –40 ᵒC de temperatura de reacción y durante 4 horas.

Con las condiciones de reacción optimizadas se consiguió la adición enantioselectiva

de MeMgBr a una amplia variedad de aldehídos aromáticos con excesos

enantioméricos comprendidos entre 53% y 90% y muy buenos rendimientos

(Esquema 7). El sistema presentó algunas limitaciones como el uso de aldehídos

aromáticos con sustituyentes en posición orto-, es decir, cercanos al centro reactivo,

causando una disminución del exceso enantiomérico notable cuando se empleó este

tipo de aldehídos (53% ee, o-metilbenzaldehído). El uso de aldehídos alifáticos

(cinamaldehído y 2-fenilacetaldehído) y heterocíclicos (2-tiofenocarbaldehído)

también produjeron una disminución en el exceso enantiomérico de los

correspondientes alcoholes quirales metilados.

Esquema 7. Adición enantioselectiva de MeMgBr a aldehídos aromáticos catalizada por (Sa,R)-L1.

También se utilizaron otros nucleófilos alifáticos como EtMgBr o n-BuMgBr

ofreciendo los correspondientes productos de alquilación de aldehídos aromáticos

con excesos enantioméricos de buenos a excelentes, comprendidos entre 72% y 96%

y rendimientos excelentes (Esquema 8). En este caso, el uso de i-BuMgBr como

nucleófilo, a pesar de ser voluminoso, fue posible en la adición a benzaldehído (1a)

obteniendo un 86% ee y 91% de rendimiento.

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Esquema 8. Adición enantioselectiva de EtMgBr, n-BuMgBr y i-BuMgBr a aldehídos aromáticos

catalizada por (Sa,R)-L1.

Como aplicación de esta metodología, se propuso la síntesis de tetrahidropiranos

quirales sustituidos en posición 2, mediante dos pasos de síntesis (Esquema 9). El

primer paso de reacción, consistió en la adición enantioselectiva de (4-

clorobutil)MgBr a diferentes aldehídos aromáticos con sustituyentes en posición

meta y para con excelentes selectividades (92%-98% ee) y rendimientos moderados,

debido a la aparición de un subproducto derivado de la adición de butilo. En el

segundo paso de reacción se hicieron reaccionar los alcoholes cloroalquílicos (2) con

terc-butóxido de potasio en THF a 25 ᵒC para producir la correspondiente ciclación

intramolecular y obtener así los productos deseados (3) con conversión completa en

la mayoría de los casos sin observar perdida de exceso enantiomérico durante el

proceso.

Esquema 9. Síntesis de tetrahidropiranos quirales sustituidos en posición 2.

Como limitaciones de la metodología fue la imposibilidad de adicionar nucleófilos

secundarios (isopropilo o ciclohexilo), terciarios (terc-butilo), sp2 (fenilo, vinilo),

conjugados (alilo y bencilo). Los nucleófilos secundarios y terciarios al ser

voluminosos produjeron conversiones muy bajas o nulas y el producto racémico. Sin

embargo, la adición de nucleófilos sp2 a benzaldehído fue racémica, pero con

rendimientos buenos.

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2.4. Adición enantioselectiva de reactivos de Grignard a aldehídos

alifáticos

Una de las limitaciones que presentaba la metodología de adición de reactivos de

Grignard a aldehídos y es que la alquilación de ciclohexanocarbaldehído con n-

BuMgBr solo se pudo obtener con un máximo de 50% ee y 98% de rendimiento.

Por eso, se decidió mejorar la metodología para intentar conseguir la alquilación

enantioselectiva de aldehídos alifáticos. Los alcoholes alifáticos secundarios

resultantes de la adición son muy interesantes desde el punto de vista sintético ya

que están presentes en la estructura de numerosos productos naturales y

farmacéuticos. Además, la síntesis de este tipo de alcoholes a través de otras

metodologías no ha sido estudiada en profundidad, ni siquiera con los reactivos

organozíncicos que son los más empleados en las adiciones 1,2 a carbonilos, debido a

una serie de particularidades que presentan este tipo de sustratos: (i) tienen

múltiples conformaciones y por tanto esto dificulta la aproximación selectiva del

complejo quiral por una las caras del carbonilo, (ii) al no poseer ningún grupo

aromático, este tipo de sustratos no tienen interacción – con el ligando, (iii) tienen

un alto carácter enolizable debido a la presencia de hidrógenos ácidos en posición

alfa al carbonilo.

Tomando como reacción modelo la adición de n-BuMgBr a

ciclohexanocarboxaldehído, se procedió a la optimización y para ello se probaron

diferentes ligandos Ar-BINMOL. También se probaron diferentes temperaturas de

reacción, metodologías de adición: lenta o rápida, disolventes apróticos de distinta

polaridad y diferentes proporciones Ti(Oi-Pr)4/n-BuMgBr. La etapa clave de la

optimización fue la determinación de la proporción óptima Ti(Oi-Pr)4/n-BuMgBr ya

que pequeñas variaciones en dicha relación entre el nucleófilo y el agente de

transmetalación afectaban de forma drástica al exceso enantiomérico. Como se vio

en el apartado anterior, la proporción correcta entre tetraisopropóxido de titanio y

los reactivos de Grignard para este sistema catalítico también fue 4:1.

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Las condiciones óptimas para la alquilación enantioselectiva de aldehídos alifáticos

con reactivos de Grignard fueron: 2.5 eq. RMgBr, 10 eq. Ti(Oi-Pr)4, 20% mol (Sa,R)-

L10, Et2O como disolvente, –20 ᵒC de temperatura de reacción y durante 3 horas. Las

nuevas condiciones de reacción que son mucho más suaves que las anteriormente

descritas y además emplea menos cantidad de nucleófilo, Ti(Oi-Pr)4 y mayor

temperatura de reacción. Esto fue posible gracias a la utilización del nuevo ligando

(Sa,R)-L10 que posee un anillo de piridina en su estructura y que afecta de forma

positiva a la enantioselectividad del producto, aunque todavía se desconoce su

función en el mecanismo de la reacción.

Con las condiciones de reacción optimizadas se consiguió la adición enantioselectiva

de n-BuMgBr y EtMgBr a diferentes aldehídos alifáticos lineales, cíclicos y de

pequeño tamaño (como acroleina) con excesos enantioméricos comprendidos entre

77% y 96% y muy buenos rendimientos (Esquema 10). Cabe destacar el uso de 2-

metilpentanal como electrófilo, ya que se obtuvo el alcohol derivado de la adición de

etilo con poca diastereoselectividad (1:1.3 r.d.), pero con muy buena

enantioselectividad (77% y 87% ee, respectivamente).

Esquema 10. Adición enantioselectiva de EtMgBr, n-BuMgBr a aldehídos alifáticos catalizada por (Sa,R)-

L10.

Por otra parte, también fue posible la adición de MeMgBr a una amplia variedad de

sustratos alifáticos lineales, cíclicos y -sustituidos y se obtuvieron los

correspondientes alcoholes ópticamente activos con excesos enantioméricos

comprendidos entre 60% y 99% con rendimientos de moderados a buenos (Esquema

11). Curiosamente el sustrato más rígido (fenilpropinal) debido a la presencia del

triple en la estructura produjo un descenso en el exceso enantiomérico (60% ee)

comparado con análogos estructurales como cinamaldehído o 3-fenilpropanal. El

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aldehído más voluminoso de todos, pivalaldehído, resulto ser positivo ya que se

obtuvo el mejor exceso enantiomérico (>99% ee) de toda la serie de productos.

Esquema 11. Adición enantioselectiva de MeMgBr a aldehídos alifáticos catalizada por (Sa,R)-L10.

2.5. Arilación enantioselectiva de reactivos de Grignard a cetonas

Las cetonas son sustratos muy interesantes desde el punto de vista sintético ya que

permiten la adición de diferentes nucleófilos para obtener los correspondientes

alcoholes terciarios, pero la principal desventaja que presentan es su baja reactividad

comparadas con los aldehídos. Este tipo de alcoholes son muy valiosos en química

orgánica, ya que están presentes en numerosos productos naturales y farmacéuticos,

además no existen muchos procedimientos efectivos que permitan la síntesis de

forma enantioselectiva.

La adición de reactivos organometálicos a cetonas ha sido ampliamente estudiada

con compuestos organozíncicos obteniendo buenos resultados tanto para la adición

de nucleófilos sp3 como sp2. Sin embargo, hasta hace 3 años, no existía ningún

procedimiento catalítico que permitiera la adición de reactivos de Grignard alifáticos

a cetonas empleando un complejo Josiphos-Cu y una metodología de adición lenta

del nucleófilo. Hasta la actualidad, no existe ninguna metodología que permita la

adición de nucleófilos sp2 organomagnesianos.

Nuevamente, se emplearon los ligandos Ar-BINMOL en la arilación asimétrica de

cetonas con reactivos de Grignard. Para ello, se tomo como reacción modelo para

todo el proceso de optimización la adición de PhMgBr a acetofenona. En la

optimización, se ajustaron diferentes parámetros de la reacción como: temperatura

de reacción, ligandos Ar-BINMOL, metodologías de adición: lenta o rápida,

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disolventes apróticos de distinta polaridad y diferentes proporciones Ti(Oi-

Pr)4/PhMgBr. Una vez más, la etapa clave de la optimización fue la determinación de

la proporción óptima Ti(Oi-Pr)4/PhMgBr, ya que pequeñas variaciones en dicha

relación entre el nucleófilo y el agente de transmetalación afectaban de forma

drástica al exceso enantiomérico del producto. Como ya se ha descrito en apartados

anteriores, la proporción óptima entre Ti(Oi-Pr)4 y cualquier reactivo de Grignard en

nuestro sistema catalítico es siempre 4:1.

Las condiciones óptimas para la arilación enantioselectiva de aril aquil cetonas con

reactivos de Grignard fueron: 2.5 eq. ArMgBr, 10 eq. Ti(Oi-Pr)4, 20% mol (Sa,R)-L7,

Et2O como disolvente, 0 ᵒC de temperatura de reacción y durante 12 horas. Esto fue

posible gracias a la utilización del nuevo ligando (Sa,R)-L10 que posee un naftilo unido

por la posición 1 al carbono bencílico en su estructura y que ofreció las

enantioselectividades más altas de toda la serie de ligandos probados,

probablemente debido a que era el más voluminoso.

Con las condiciones de reacción optimizadas se consiguió la adición enantioselectiva

de PhMgBr a una amplia variedad de aril metil cetonas con excesos enantioméricos

comprendidos entre 46% y 80% y rendimientos de bajos a moderados (Esquema 12),

debido a la baja reactividad de las cetonas. El sistema presentó algunas limitaciones

como el uso de cetonas aromáticas con sustituyentes en posición orto-, es decir,

cercanos al centro reactivo, causando una disminución brusca del rendimiento (12%

conv., o-metilacetofenona). La adición de PhMgBr a cetonas donde el grupo alquilo

es voluminoso produce un efecto positivo en la enantiodiscrimianción de las caras

del carbonilo, pero el aumento del impedimento estérico por la presencia de un

grupo voluminoso causa una disminución del rendimiento (35 rto., 84% ee, 4j). Por

otra parte, las cetonas cíclicas benzofusionadas al poseer una estructura más rígida

favorecen el aumento del exceso enantiomerio comparado con las cetonas acíclicas.

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Esquema 12. Adición enantioselectiva de PhMgBr a alquil aril cetonas catalizada por (Sa,R)-L7.

Esta metodología también permitió el uso de otros reactivos de Grignard aromáticos

con sustituyentes electrondonores (-OMe), electronatractores (-F) y neutros (-Me) en

posición para del anillo aromático del nucleófilo (Esquema 13). Los excesos

enantioméricos obtenidos estuvieron comprendidos entre 64% y 82% y, en general,

los rendimientos fueron superiores al análogo PhMgBr.

Esquema 13. Adición enantioselectiva de PhMgBr a aril alquil cetonas catalizada por (Sa,R)-L7.

La limitación de esta metodología es el empleo de sustratos totalmente alifáticos,

como ciclohexil metil cetona, ya que a la temperatura óptima de la reacción (0 ᵒC) no

se produjo reacción.

2.6. Adición enantioselectiva de reactivos de organoaluminio a

aldehídos

Los reactivos de organoaluminio han sido utilizados en química orgánica en gran

variedad de reacciones, incluida las adiciones enantioselectivas a aldehídos y

cetonas. En cuanto a catálisis asimétrica, existen varios complejos quirales de

aluminio que son empleados en síntesis enantioselectiva, pero la reacción en si no

implica transferencia de un grupo alquilo o arilo procedente del reactivo de

organoaluminio a un electrófilo, normalmente son empleados como ácidos de Lewis

quirales.

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Una de las principales ventajas que presentan este tipo de reactivos es que son

comercialmente asequibles, pueden sintetizarse a gran escala y además es posible su

empleo en reacciones a escala industrial. Otra ventaja adicional es que los

compuestos de organoaluminio son muy estables a temperatura ambiente, por lo

que se pueden almacenar fácilmente y además presentan una baja toxicidad.

Se decidió probar la adición enantioselectiva de reactivos organometálicos a

aldehídos. Como reacción modelo para optimizar se escogió, la adición de Me3Al a

benzaldehído (1a). Durante el proceso de optimización se variaron diferentes

parámetros de la reacción como: temperaturas de reacción, metodologías de adición:

lenta o rápida, disolventes apróticos de distinta polaridad, distintos ligandos Ar-

BINMOL y diferentes proporciones Ti(Oi-Pr)4/Me3Al. El sistema catalítico se mostro

bastante robusto y pequeñas variaciones en las proporciones de Ti(Oi-Pr)4/Me3Al no

causaron variaciones significativas en la enantioselectividad, aunque la proporción

óptima para reactivos de organoalumnio fue 2.7:1.

Las condiciones óptimas para la alquilación enantioselectiva de aldehídos con

reactivos de organoaluminio fueron: 1.5 eq. R3Al, 4 eq. Ti(Oi-Pr)4, 10% mol (Sa,R)-L1,

tolueno como disolvente, 0 ᵒC de temperatura de reacción y durante 1-3 horas. Con

las condiciones de reacción previamente descritas, se consiguió la adición

enantioselectiva de Me3Al a una amplia variedad de aldehídos con excesos

enantioméricos comprendidos entre 62% y 98% y muy buenos rendimientos

(Esquema 14). La adición de Me3Al aldehídos heteroaromáticos y alifáticos de

pequeño tamaño (1n) se produjo con muy buenas enantioselectividades, pero

rendimientos bajos debido a la volatilidad de los productos durante el proceso de

purificación. Cabe destacar, que se puede utilizar aldehídos aromaticos con

sustituyentes en posición orto-, aunque se observó un descenso en el ee.

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Esquema 14. Adición enantioselectiva de Me3Al a aldehídos catalizada por (Sa,R)-L1.

También fue posible la adición a aldehídos de otros reactivos de organoaluminio

alifáticos como: Et3Al y n-Pr3Al (Esquema 15). La etilación de aldehídos aromáticos se

produjo con excelentes excesos enantioméricos (87%-92%), pero con moderados

rendimientos comparado con los alcoholes metilados. Sin embargo, mejores

enantioselectividades (92%-94%) se obtuvieron para la adición de n-Pr3Ar a aldehídos

aromáticos e incluso alifáticos (1q), a costa de unos rendimientos muy bajos.

Esquema 15. Adición enantioselectiva de Et3Al y n-Pr3Al a aldehídos catalizada por (Sa,R)-L1.

Una limitación de esta metodología desarrollada en nuestro grupo de investigación,

fue la adición de nucleófilos sp2 (Ph3Al) y voluminosos como i-Bu3Al. En el caso de

Ph3Al, los correspondientes productos de arilación se obtuvieron con excesos

enantioméricos <20%, excepto para la adición a pivalaldehído (1n) donde se obtuvo

el producto con un 72% ee. Por último, cuando se utilizó i-Bu3Al como nucleófilo, no

se observo la formación de ningún producto bajo las condiciones óptimas de

reacción.

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3. Conclusiones generales

Se han sintetizado una serie de ligandos quirales (L1-L10) derivados de (S)-BINOL,

conocidos como Ar-BINMOL, que presentan dos tipos diferentes de quiralidad: (i)

quiralidad axial, procedente del binaftilo y (ii) un centro sp3 generado mediante una

transposición de Wittig [1,2] asímetrica del correspondiente éter monobencílico de

(S)-BINOL. Estos ligandos previamente mencionados, se utilizaron en la adición

enantioselectiva de reactivos organolíticos, Grignard y organoaluminio a aldehídos y

también en la arilación enantioselectiva de cetonas con reactivos de Grignard.

Se ha desarrollado una metodología simple y eficaz para la adición enantioselectiva

de reactivos organolíticos a aldehídos aromáticos empleando 3.2 eq. RLi, 6 eq. Ti(Oi-

Pr)4, 20% mol del ligando quiral (Sa,R)-L1, tolueno como disolvente a 40 °C durante 1

hora. Esta metodología permite la síntesis de alcoholes secundarios ópticamente

activos con enanioselectividades de moderadas a excelentes para la metilación de

aldehídos (62-90% ee) y rendimientos muy buenos. En el caso de la adición de EtLi y

n-BuLi se consiguieron rendimientos similares pero excesos enantiomericos

comprendidos entre 90% y 96%.

También se han desarrollado dos metodologías similares para la adición

enantioselectiva de reactivos de Grignard a aldehídos aromáticos y alifáticos,

respectivamente. La alquilación enantioselectiva de aldehídos aromáticos implicó el

uso de condiciones de reacción más drásticas: 3.8 eq. RMgBr, 15 eq. Ti(Oi-Pr)4, 20%

mol (Sa,R)-L1, tolueno como disolvente a 40 °C durante 3 horas. Sin embargo, la

alquilación asimétrica de aldehidos alifáticos son sustratos que presentan mayor

dificultad, gracias a la utilización de un nuevo ligando, se consiguío mediante el

empleo de unas condiciones de reacción más suaves: 2.5 eq. RMgBr, 10 eq. Ti(Oi-Pr)4,

20% mol (Sa,R)-L10, Et2O como disolvente a 20 °C durante 3 horas. En ambos casos,

los correspondientes alcoholes secundarios quirales se obtuvieron con excesos

enantiomericos de moderados a excelentes (53-99% ee) y rendimientos muy buenos.

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Por otra parte, se consiguió por primera vez la arilación enantioselectiva de cetonas

empleando reactivos de Grignard como nucleófilos. La utilización de un nuevo

ligando desarrollado en nuestro grupo de investigación fue la clave de la nueva

metodología que se desarrollo, empleando: 2.5 eq. RMgBr, 10 eq. Ti(Oi-Pr)4, 20% mol

(Sa,R)-L7, Et2O como disolvente a 0 °C durante 12 horas. Sin embargo, con estas

condiciones suaves de reacción solo se pudieron alcanzaron excesos enantioméricos

de moderados a buenos (46-84% ee). Aunque en el caso particular de 1-tetralona se

alcanzo un 92% ee. En general, los rendimientos obtenidos para la arilacion de

cetonas mediante este procedimiento fueron bajos debido a la poca reactividad de

estos electrófilos.

Por último, se desarrolló una metodología para la alquilación enantioselectiva de

aldehídos mediante el uso de reactivos de organoaluminio como nucleófilos. Para

ello se utilizó: 1.5 eq. R3Al, 4 eq. Ti(Oi-Pr)4, 10% mol (Sa,R)-L1, Et2O como disolvente a

0 °C durante 3 horas. La adición de Me3Al a aldehídos aromáticos no voluminosos

ofreció las mayores selectividades (80-94% ee) y muy buenos rendimientos. Por otra

parte, la adición de Et3Al y n-Pr3Al mantuvo los excesos enantioméricos de los

derivados metilados, pero a costa de una disminución considerable del rendimiento.

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PREFACE

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Preface

33

Preface

The present thesis has been developed in the Department of Organic Chemistry and

Organic Synthesis Institute of the University of Alicante. As a result of the work

developed during my PhD who began in September 2011 and during this period of

time, I have published the following articles:

(1) Fernández-Mateos, E.; Maciá, B.; Yus, M. Eur. J. Org. Chem. 2014, 6519–6526.

(2) Fernández-Mateos, E.; Maciá, B.; Yus, M. Adv. Synth. Catal. 2013, 355, 1249–1254.

(3) Fernández-Mateos, E.; Maciá, B.; Yus, M. Tetrahedron: Asymmetry 2012, 23, 789–

794.

(4) Fernández-Mateos, E.; Maciá, B.; Yus, M. Eur. J. Org. Chem. 2012, 3732–3736.

(5) Fernández-Mateos, E.; Maciá, B.; Ramón, D. J.; Yus, M. Eur. J. Org. Chem. 2011,

6851–6855.

The author acknowledge financial support from the Spanish Ministerio de Ciencia y

Tecnología (MCYT) project numbers CTQ2007-65218/BQU and CTQ2011-24151),

Consolider Ingenio 2010 (grant number CSD2007-00006), Generalitat Valenciana (G.

V. PROMETEO/2009/039 and FEDER) and also to the Ministerio de Educación, Cultura

y Deporte (MECD) for the concession of a FPU predoctoral fellowship (AP-2010-

2926).

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GENERAL OBJECTIVES

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General objectives

37

General objectives

The objectives of this thesis consist on the development of new chiral ligands (Ar-

BINMOLs) and the study of their applications in asymmetric catalysis. In particular,

we will focus on the enantioselective addition of different challenging organometallic

reagents to carbonyl compounds and the study of the mechanistic aspects related to

the corresponding reaction.

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CHAPTER I

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Chapter I – Introduction

41

1. Introduction

1.1. History of Ar-BINMOLs ligands

The synthesis of the chiral ligands used in this thesis, known as Ar-BINMOL ligands,

dates from 1996, when Kiyooka´s group tested, for the first time, the [1,2]-Wittig

rearrangement on a (S)-BINOL derivative,1 provided of a MOM protecting group in

one of the hydroxyl groups and a benzyl group in the other (I, Scheme 1), affording

intermediates II with excellent diastereoselectivities and moderate yields. Chiral diols

III are obtained after deprotection of MOM group with a mixture THF/HCl.

Scheme 1. Synthesis of chiral Ar-BINMOL´s ligands (III) by Kiyooka´s methodology.

In 2011, Xu and his group, as part of their study on neighboring lithium alcoxides as

promoters of [1,2]-Wittig rearrangements on benzylic ethers, improved the synthetic

route for the synthesis of Ar-BINMOLs.2 Their strategy consisted on modifying the (S)-

BINOL substrate (by removing the MOM protecting group) and reoptimizing

Kiyooka´s reaction conditions for the [1,2]-Wittig rearrangement2 (Scheme 2).

This new methodology allows the synthesis of chiral Ar-BINMOL´s ligands in only two

reaction steps (Scheme 2), starting from commercially available (S)-BINOL (IV). In the

first step, IV is monobenzylated using the corresponding benzyl bromide (1 eq.),

K2CO3 (1 eq.) as a base, in acetone as solvent, at 60 °C during 6 hours. The crude of

the reaction was used in the next step without further purification. In the second

step, the hydroxyether binaphtyl derivative (V) is treated with 2.5 eq. of i-BuLi in

1 Kiyooka, S-I. Tsutsui, T. Kira, T. Tetrahedron Lett. 1996, 37, 8903–8904. 2 Gao, G. Gu, F-L.; Jiang, J-X.; Jiang, K.; Sheng, C-Q.; Lai, G-Q.; Xu, L-W. Chem. Eur. J. 2011, 17, 2698–2703.

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Chapter I – Introduction

42

anhydrous THF at 78 °C during 1.5 hours, affording the chiral diol ligands (III) in high

yields and perfect diastereocontrol (>99%) in all cases, after purification on flash

silica gel chromatography.

Scheme 2. Synthesis of chiral Ar-BINMOL´s ligands (III) by Xu´s methodology

The transformation of the intermediate V into the corresponding chiral Ar-BINMOL

ligand (III) involves a neighboring lithium-assisted [1,2]-Wittig rearrangement, which

is explained in the mechanism below, proposed by Xu Li-Wen´s group.

Scheme 3. Mechanism lithium-assisted [1,2]-Wittig rearrangement of V.

The [1,2]-Wittig rearrangement takes place via a well known radical mechanism,3

which, in this case, is facilitated by the effect of a lithium phenolate group close to

the reactive site (Scheme 3).2 In the first step of the mechanism, the first equivalent

of i-BuLi deprotonates the most acidic proton which is the phenol (OH) to form the

3 Wittig, G.; Löhmann, L. Liebigs. Ann. Chem. 1942, 550, 260–262.

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Chapter I – Introduction

43

corresponding lithium phenoxide V-A. Then, the second equivalent of i-BuLi

selectively deprotonate the pro-S benzylic proton, generating dilithiated specie V-B.

After that, an homolitic dissociation of CAr-O bond takes place and intermediate V-C is

formed, which immediately suffers a [1,2]-Wittig rearrangement and finally a radical

recombination happens in a enantioselective way through a five member ring

transition state (V-D), obtaining chiral diol Ar-BINMOL´s ligands III with high

diastereomeric excess (>99%). The axial chirality of hydroxyether intermediate (V) is

the responsible for the estereoselective generation of the new asymmetric center.

1.2. Applications of Ar-BINMOLs ligands

Ar-BINMOL ligands are relatively new compounds, although a few applications in

asymmetric catalysis have been already described in the literature. For example, Xu

Li-Wen´s group have employed these type of ligands (in particular, dimer VI, 10

mol%) for the enantioselective alkylation of aromatic aldehydes with Et2Zn, in the

presence of Ti(Oi-Pr)4 and using Et2O as solvent at room temperature.4 Excellent

yields and enantioselectivities (from 97% to >99%) were achieved for all the

examples described (Scheme 4).

Scheme 4. Asymmetric addition of Et2Zn to different aldehydes catalyzed by ligand VI.

A similar methodology has also been developed by the same research group for the

methylation and arylation of aldehydes with Grignard reagents with an Ar-BINMOL

ligand (see introduction of chapter 3, section 1.2 for further details).

4 Gao, Guang.; Bai, X-F.; Yang, H-M.; Jiang, J-X.; Lai, G-Q.; Xu L-W. Eur. J. Org. Chem. 2011, 5039–5046.

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Chapter I – Introduction

44

In addition, Ar-BINMOLs have been also tested, by Xu Li-Wen´s group, as

organocatalysts in the enantioselective conjugate addition of anthrone to (E)--

nitrostyrene. The use of chiral diol VII (10 mol%), in THF as solvent at room

temperature during 24 hours,4 provided only 25% ee of the corresponding Michael

adduct (Scheme 5).

Scheme 5. Asymmetric addition of anthrone to (E)--nitrostyrene organocatalyzed by VII.

Successful modifications in the structure of Ar-BINMOLs have been developed by

Xu´s group, in order to expand the applications in asymmetric catalysis for this new

type of chiral ligands.5

5 a) Zheng, L-S.; Wei, Y-L.; Jiang, K-Z.; Deng, Y.; Zheng, Z-J.; Xu, L-W. Adv. Synth. Catal. 2014, 356, 3769–3776; b) Wei,

Y-L.; Yang, K-F.; Li, F.; Zheng, Z-J.; Xu, Z.; Xu, L-W. RSC Adv., 2014, 4, 37859–37867; c) Li, F.; Zhou, W.; Zheng, L-S.; Li,

L.; Zheng, Z-J.; Xu, L-W. Synthetic Communications 2014, 44, 2861–2869; d) Song, T.; Zheng, L-S.; Ye, F.; Deng, W-H.;

Wei, Y-L.; Jiang, K-Z.; Xu, L-W. Adv. Synth. Catal. 2014, 356, 1708–1718; e) Zheng, L-S.; Li, L.; Yang, K-F.; Zheng, Z-J.;

Xiao, X-Q.; Xu, L-W. Tetrahedron 2013, 69, 8777–8784; f) Li, F.; Li, L.; Yang, W.; Zheng, L-S.; Zheng, Z-J.; Jiang, K.; Lu, Y.;

Xu, L-W. Tetrahedron Lett. 2013, 54, 1584–1588.

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Chapter I – Results and discussion

45

2. Results and discussion

In this section, the synthesis of the ligands employed in this thesis will be explained.

Ligands L1-L8 were prepared via [1,2]-Wittig rearrangement of the corresponding

benzylic hydroxyethers of (S)-BINOL, following a modified procedure from Xu´s

synthesis. In the first step of the synthesis, the corresponding benzyl bromide (1 eq.)

was refluxed in acetone at 65 °C for 6 hours, using. of K2CO3 (1.5 eq) as base. The

corresponding monobenzylated (S)-BINOLs I1-8 were obtained in good yields (65-

83%), Procedure A, Scheme 6) and used in the next reaction step without further

purification. The hydroxyether I1 was isolated by flash silica gel chromatography

(83% yield) and fully characterized. When the partially hydrogenated H8-(S)-BINOL

was used as starting material, the desired product H8-(S)-I1 was also obtained in high

conversion (74%) using the same reaction condition.

The preparation of the pyridine containing intermediates I-9 and I-10 followed a

slightly modified procedure, to overcome the solubility problems associated to the

(bromomethyl)pyridinium bromide used as a reagent. Thus, a mixture acetone/H2O

(9:1) was used as solvent together with 3 eq. of K2CO3 and longer reaction times (12

h) (Procedure B, Scheme 6). The desired products I-9 and I-10 were obtained in 48%

and 66 % yield, respectively. The hydroxyether I-9 was used in the next reaction step

without further purification, however compound I-10 was isolated by flash silica gel

chromatography (66% yield) and fully characterized.

Scheme 6. Synthesis of hydroxyethers intermediates derived from (S)-BINOL. Conversions of

hydroxyethers I1-10 were determined by 1H-NMR.

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Chapter I – Results and discussion

46

In the second step of the synthesis, hydroxyethers I1-8 were treated with 2.5 eq. of

n-BuLi in anhydrous THF at –78 °C during 2 hours (Procedure A, Scheme 7). The

desired chiral diol ligands L1-8 were obtained after flash silica gel purification with

moderate to very good yields (Table 1, entries 1, 3 and 4-8), except (Sa,S)-L3 which

was obtained with only 20% yield (Table 1, entry 4), probably due to bulky methoxy

group close to the reactive site, that hampers the [1,2]-Wittig rearrangement.

The synthesis of the more challenging H8-(Sa,R)-L1 and L9-10 was achieved under

more forcing reaction conditions from the corresponding hydroxyethers H8-(S)-I1 and

I9-10. The [1,2]-Wittig rearrangement took place with 5 eq. of n-BuLi in anhydrous

THF at 70 °C during 12 hours (Procedure B, Scheme 7); at lower temperatures the

reaction did not proceed. Under this harsh conditions, the chiral diol H8-(Sa,R)-L1 was

obtained in moderate yield (53% , Table 1, entry 2) and L9-10 were obtained in low

yields (Table 1, entry 10-11), due to homolitic dissociation of Csp3-O bond of

corresponding hydroxyethers and a consequent not effective radical recombination,

which led to the formation of (S)-BINOL instead the desired product. For all chiral diol

synthesized, excellent diastereomeric excess (>99%) were achieved in the [1,2]-Wittig

rearrangement.

Scheme 7. Synthesis of Ar-BINMOLs ligands through [1,2]-Wittig rearrangement.

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Chapter I – Results and discussion

47

Table 1. Ar-BINMOLs synthesis[a]

Entry Ligand Yield[c]

(%) de[d]

(%)

1

82[a]

>99

2

53[b]

>99

3

80[a]

>99

4

20[a]

>99

5

86[a]

>99

6

81[a]

>99

7

83[a]

>99

8

72[a]

>99

9

60[a]

>99

10

27[b],[e]

>99

11

33[b],[e]

>99

[a] Conditions A: I (4 mmol, 0.12 M), n-BuLi (2.5 M in n-hexane, 2.5 eq.), THF (30 mL), –78 °C, 2 h. [b] Conditions B: I (4 mmol, 0.08 M), n-BuLi (2.5 M in n-hexane, 5 eq.), THF (40 mL), 70 °C, 12 h. [c] Isolated yield after flash silica gel chromatography. [d] Absolute configuration of chiral ligands was determined by correlation of optical rotation with known compounds. [e] 65% of (S)-BINOL was generated as byproduct in the reaction.

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Chapter I – Results and discussion

48

Due to the perfect stereoelectivity of the lithium-assisted [1,2]-Wittig rearrangement

of benzylic ethers derived from (S)-BINOL, the synthesis of the corresponding

diastereoisomer (Sa,S)-L1 resulted not trivial. After many attempts trying to prepared

desired (Sa,S)-L1 by different synthetic routes, we decided to epimerize the sp3

benzylic alcohol, by treating (Sa,R)-L1 with a 1:1 mixture of THF/HCl 6 M during 3

hours (Scheme 8). The desired diol (Sa,S)-L1 was obtained with only 20% yield,

together with the cyclic ether C1 and some unidentified side products. The rest was

starting material (Sa,R)-L1 (42% yield).

Scheme 8. Epimerization of chiral diol (Sa,R)-L1 to (Sa,S)-L1.

Chiral ligand (Sa,S)-L1 will be used in following chapters to determine the effect of the

configuration of the chiral benzylic alcohol of the ligand in the asymmetric addition of

different organometallic reagents to aldehydes.

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Chapter I – Experimental part

49

3. Experimental part

3.1. Synthesis of monobenzylated (S)-BINOL hydroxyethers I1-10

The intermediates (S)-I1-7 and H8-(S)-I1 were prepared starting from commercially

available (S)-BINOL or (S)-H8-BINOL according to two different procedures (Scheme

9):

Scheme 9. Synthesis of hydroxyethers intermediates (I) derived from (S)-BINOL

Procedure A: Synthesis of hydroxyethers (S)-I1-8

(S)-BINOL (2 g, 7 mmol) or (S)-H8-BINOL (2.1 g, 7 mmol) was dissolved in acetone (40

mL) in a round bottom flask, then K2CO3 (1.5 g, 10.5 mmol, 1.5 eq.) and the

corresponding benzyl bromide derivative (ArCH2Br, 7 mmol, 1 eq.) were added and

the mixture was heated at 65 °C during 6 h. After cooling down the reaction to room

temperature, acetone was evaporated in the rotary evaporator under reduced

pressure. Then the reaction crude was extracted with EtOAc (3 × 15 mL) and water

(30 mL). The combined organic layers were dried over magnesium sulfate and

concentrated under vacuum. Synthetic intermediates (S)-I2–8 were used in the next

step without further purification. The hydroxyether (S)-I1 was purified by flash silica

gel chromatography as a white foamy solid and then was recrystallized in a n-

hexane/EtOAc (9:1) mixture at room temperature. Data of all known products were

in accordance with the literature.

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Chapter I – Experimental part

50

Procedure B: Synthesis of hydroxyethers (S)-I9 and (S)-I10.

(S)-BINOL (2 g, 7 mmol) was dissolved in acetone (40 mL) in a round bottom flask and

then a solution of K2CO3 (2.9 g, 21 mmol, 3 eq.) in water (4 mL) was added. Next, the

corresponding (bromomethyl)pyridinium bromide (7 mmol, 1 eq.) was added and the

mixture was heated at 65 °C during 12 h. The dark brown reaction crude was filtered

under vacuum over celite and the residue was washed with EtOAc (3 × 50 mL). Then,

flash silica gel was directly added to the previous solution and the solvent was

evaporated under vacuum. The hydroxyether (S)-I10 was purified by flash silica gel

chromatography as white powder and then recrystallized in n-hexane/EtOAc (20:1)

mixture at room temperature. Intermediate (S)-I9 was used in the next step without

further purification.

3.2. Data of hydroxyethers (S)-I1 and (S)-I10

(S)-2'-(Benzyloxy)-(1,1'-binaphthalen)-2-ol [(S)-I1]:6

Compound (S)-I1 was obtained after purification on flash

silica gel chromatography from 100:0 till 92:8 (n-

hexane/EtOAc) as colorless crystals after recrystallization in

20:1 n-hexane/EtOAc (83% yield); m.p. 120.5 – 123.5 °C, []D25 = +5.2 (c 1.2, CHCl3).

1H NMR (300 MHz, CDCl3) 7.91 (t, J = 8.6 Hz, 2H), 7.85 (dd, J = 8.0, 4.1 Hz, 2H), 7.41

(d, J = 9.1 Hz, 1H), 7.38 – 7.33 (m, 2H), 7.33 – 7.29 (m, 1H), 7.29 – 7.24 (m, 1H), 7.24 –

7.19 (m, 2H), 7.19 – 7.11 (m, 3H), 7.11 – 7.05 (m, 1H), 7.01 (dd, J = 6.4, 3.0 Hz, 2H),

5.07 (d, J = 12.6 Hz, 1H), 5.02 (d, J = 12.7 Hz, 1H), 4.95 (s, 1H). 13C NMR (75 MHz,

CDCl3) 154.9, 151.3, 136.9, 134.0, 133.8, 130.8, 129.8, 129.6, 129.1, 128.3, 128.1,

127.6, 127.3, 126.8, 126.4, 125.0, 124.9, 124.4, 123.2, 117.5, 116.8, 115.9, 115.1,

71.1. IR (ATR): (cm-1): 3515, 3058, 1620, 1591, 1506, 1463, 1261, 1210, 1040. LRMS

(EI-DIP): m/z (%): 378 [M++2] (4), 377 [M++1] (24), 376 [M+] (84), 286 (22), 285 (100),

268 (22), 257 (12), 239 (23), 229 (16), 228 (22), 226 (24), 91 (55), 65 (6).

6 Bremmer, J. B.; Keller, P. A.; Pyne, S. G.; Boyle, T. P.; Brkic, Z.; Morgan, J.; Rhodes, D. I. Bioorgan. Med. Chem. 2010,

18, 4793-4800.

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Chapter I – Experimental part

51

(S)-2'-(Pyridin-4-ylmethoxy)-(1,1'-binaphthalen)-2-ol [(S)-

I10]: Compound (S)-I10 was obtained after purification on

flash silica gel chromatography from 100:0 till 0:100 (n-

hexane/EtOAc) as colorless cubic crystals after

recrystallization in 10:1 n-hexane/EtOAc (66% yield); m.p. 182 – 184 °C, []D25 = -17.5

(c 1.0, CHCl3). 1H NMR (400 MHz, CDCl3) 8.26 (br d, J = 4.5 Hz, 2H), 7.97 (d, J = 9.0

Hz, 1H), 7.91 (d, J = 8.9 Hz, 1H), 7.87 (d, J = 7.8 Hz, 2H), 7.42 – 7.34 (m, 3H), 7.34 –

7.26 (m, 3H), 7.21 (ddd, J = 8.1, 6.8, 1.3 Hz, 1H), 7.06 (d, J = 8.4 Hz, 1H), 6.85 (br d, J =

5.2 Hz, 2H), 5.08 (d, J = 13.9 Hz, 1H), 5.03 (d, J = 13.8 Hz, 1H), 3.18 (br s, 1H). 13C NMR

(101 MHz, CDCl3) 154.3, 151.6, 148.9, 146.9, 134.0, 133.8, 130.9, 129.9, 129.1,

128.2, 127.5, 126.5, 125.2, 124.7, 123.3, 121.2, 117.7, 115.4, 114.8, 69.4. IR (ATR):

(cm-1): 3064, 1610, 1504, 1325, 1264, 1044, 798. LRMS (EI-DIP): m/z (%): 379 [M++2]

(5), 378 [M++1] (28), 377 [M+] (100), 286 (14), 285 (47), 284 (10), 269 (11), 268 (38),

257 (15), 255 (19), 240 (17), 239 (42), 229 (28), 228 (37), 227 (20), 226 (37), 93 (22),

80 (49). HRMS (EI): m/z: 377.1416 calculated for C26H19NO2 [M+], found 377.1404.

3.3. Synthesis of chiral Ar-BINMOL ligands L1-10

Two different procedures were employed to synthesize compounds L1-10 through a

[1,2]-Wittig rearrangement from the corresponding hydroxyethers (S)-I1-10 (Scheme

10).

Scheme 10. Synthesis of Ar-BINMOL ligands L1-10 through [1,2]-Wittig rearrangement.

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Chapter I – Experimental part

52

Procedure A: Synthesis of compounds L1-8

n-BuLi (2.5 M in n-hexane, 2.5 eq.) was slowly added to a solution of the

corresponding hydroxyether (S)-I1-8 (4 mmol) in anhydrous THF (30 mL) at –78 °C.

The mixture was stirred for 2 h at –78 °C and then quenched with water at 0 °C. The

resulting mixture was extracted with EtOAc (3 × 10 mL), and the combined organic

layers were washed with brine, dried over magnesium sulfate and concentrated

under vacuum. The crude product was purified by flash silica gel chromatography to

give the desired products L1-8. Data of known products were in accordance with the

previously reported in the literature.

Procedure B: Synthesis of compounds L9-10 and H8-(Sa,R)-L1

n-BuLi (2.5 M in n-hexane, 5 eq.) was slowly added to a solution of the corresponding

hydroxyether (S)-I9-10 or (S)-H8-I1 (4 mmol) in anhydrous THF (40 mL) at room

temperature. The mixture was stirred for 12 h at 70 °C and then the reaction was

quenched with water at 0 °C. The resulting mixture was extracted with EtOAc (3 × 15

mL) and the combined organic layers were dried over magnesium sulfate and

concentrated under vacuum. The crude product was purified by flash silica gel

chromatography to give the desired products L9-10 and (Sa,R)-H8-L1. Data of known

products were in accordance with the previously reported in the literature.

3.4 Data of chiral Ar-BINMOL ligands L1-10

(Sa)-2'-[(R)-Hydroxy(phenyl)methyl]-(1,1'-binaphthalen)-2-ol

[(Sa,R)-L1]:2 Compound (Sa,R)-L1 was obtained after purification

on flash silica gel chromatography from 100:0 till 85:15 (n-

hexane/EtOAc) as a white foamy solid (85% yield); m.p. 72 – 75

°C, []D25 = +264.7 (c 1.0, CHCl3).

1H RMN (400 MHz, CDCl3) 7.90 (ddd, J = 21.8, 13.0,

8.5 Hz, 4H), 7.60 (d, J = 8.7 Hz, 1H), 7.47 (ddd, J = 8.0, 6.8, 1.1 Hz, 1H), 7.33 (d, J = 8.8

Hz, 1H), 7.29 (d, J = 7.9 Hz, 1H), 7.27 – 7.24 (m, 1H), 7.20 – 7.08 (m, 5H), 7.06 – 6.98

(m, 2H), 6.83 (d, J = 8.4 Hz, 1H), 5.69 (s, 1H), 5.61 (br s, 1H), 2.64 (br s, 1H). 13C NMR

(101 MHz, CDCl3) 151.2, 142.5, 141.4, 134.0, 133.4, 132.9, 130.2, 129.9, 129.7,

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Chapter I – Experimental part

53

129.1, 128.1, 127.1, 126.8, 126.7, 126.5, 126.0, 125.1, 125.0, 123.6, 117.9, 117.2,

73.4. IR (ATR): (cm-1): 3276, 3058, 2926, 2850, 1620, 1595, 1341, 1268, 1027, 1012.

LRMS (EI-DIP): m/z (%): 376 [M+] (2), 359 (27), 358 (100), 357 (29), 330 (12), 282 (11),

281 (51), 279 (22), 252 (18), 239 (15), 140 (12), 77 (9). HRMS (EI): m/z (%): 376.1463

calculated for C27H20O2 [M+], found 376.1436.

(Sa)-2'-[(R)-Hydroxy(phenyl)methyl]-5,5',6,6',7,7',8,8'-

octahydro-(1,1'-binaphthalen)-2-ol [H8-(Sa,R)-L1]: Compound

(Sa,R)-H8-L1 was obtained after purification on flash silica gel

chromatography from 100:0 till 80:20 (n-hexane/EtOAc) as a

yellow foamy solid (53% yield); m.p. 74 – 77 °C, []D25 = +90 (c 1.0, CHCl3).

1H NMR

(400 MHz, CDCl3) 7.30 (d, J = 8.0 Hz, 1H), 7.24 – 7.17 (m, 3H), 7.14 (d, J = 8.0 Hz,

1H), 7.11 – 7.06 (m, 2H), 7.01 (d, J = 8.3 Hz, 1H), 6.81 (d, J = 8.3 Hz, 1H), 5.43 (s, 1H),

4.96 (br s, 1H), 2.80 (t, J = 6.0 Hz, 3H), 2.69 (dd, J = 13.3, 6.7 Hz, 2H), 2.19 (dd, J =

14.2, 6.1 Hz, 2H), 1.99 – 1.89 (m, 1H), 1.80 – 1.50 (m, 9H). 13C NMR (101 MHz, CDCl3)

149. 8, 142.7, 139.9, 137.8, 136.5, 136.1, 133.6, 129.8, 129.7, 129.6, 128.1, 127.3,

126.8, 124.7, 124.3, 113.1, 73.5, 29.9, 29.2, 27.4, 27.2, 23.2, 22.9, 22.8, 22.7. IR

(ATR): (cm-1): 3337, 2927, 1591, 1448, 1018, 808, 698. LRMS (EI-DIP): m/z (%): 384

[M+] (<1), 367 (28), 366 (100), 365 (11), 338 (9), 289 (36), 275 (27), 235 (8), 105 (11),

77 (7). HRMS (EI): m/z: 384.2089 calculated for C27H28O2 [M+], found 384.2057.

(Sa)-2'-[(R)-Hydroxy(o-tolyl)methyl]-(1,1'-binaphthalen)-2-ol

[(Sa,R)-L2]:2 Compound (Sa,R)-L2 was obtained after purification

on flash silica gel chromatography from 100:0 till 80:20

(hexane/EtOAc) as a white foamy solid (80% yield); m.p. 77.7 –

80.0 °C, []D25 = +165.5 (c 1.0, CHCl3).

1H NMR (300 MHz, CDCl3) 7.90 (d, J = 8.7 Hz,

3H), 7.85 (d, J = 8.1 Hz, 1H), 7.55 (d, J = 7.6 Hz, 1H), 7.47 (ddd, J = 8.1, 6.8, 1.2 Hz, 1H),

7.38 (d, J = 8.7 Hz, 1H), 7.32 (d, J = 8.9 Hz, 1H), 7.26 (m, 2H), 7.10 (m, 4H), 6.88 (d, J =

7.3 Hz, 1H), 6.82 (d, J = 8.2 Hz, 1H), 6.32 (br s, 1H), 5.84 (s, 1H), 2.91 (br s, 1H), 1.58 (s,

3H). 13C NMR (75 MHz, CDCl3) 151.6, 140.0, 139.8, 135.1, 133.6, 133.5, 133.2,

131.5, 130.1, 129.3, 129.2, 128.1, 127.9, 127.3, 126.7, 126.5, 126.4, 126.2, 126.0,

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Chapter I – Experimental part

54

125.9, 125.4, 124.7, 123.6, 118.5, 118.1, 71.4, 19.3. IR (ATR): (cm-1): 3212, 2923,

1621, 1594, 1210, 815, 742. LRMS (EI-DIP): m/z (%): 390 [M+] (1), 373 (28), 372 (100),

371 (18), 344 (15), 329 (12), 282 (13), 281 (54), 279 (18), 252 (17), 245 (14), 239 (14),

228 (6), 140 (7), 91 (8). HRMS (EI): m/z: 372.1514 calculated for C28H20O [M–H2O]+,

found 372.1541.

(Sa)-2'-[(S)-Hydroxy(2-methoxyphenyl)methyl]-(1,1'-

binaphthalen)-2-ol [(Sa,S)-L3]:2 Compound (Sa,S)-L3 was

obtained after purification on flash silica gel chromatography

from 100:0 till 80:20 (n-hexane/EtOAc) as a white foamy solid

(20% yield); m.p. 77 – 80 °C, []D25 = +173.8 (c 1.0, CHCl3).

1H RMN (300 MHz, CDCl3)

7.91 – 7.77 (m, 4H), 7.44 (dd, J = 16.0, 7.8 Hz, 2H), 7.31 – 7.17 (m, 4H), 7.17 – 7.04

(m, 3H), 6.85 (dd, J = 16.8, 8.3 Hz, 2H), 6.54 (d, J = 8.2 Hz, 1H), 6.32 (br s, 1H), 5.89 (s,

1H), 3.23 (s, 3H), 3.22 (br s, 1H). 13C NMR (75 MHz, CDCl3) 156.1, 151.5, 140.6,

134.1, 133.4, 133.2, 130.8, 130.3, 129.8, 129.0, 128.3, 128.0, 127.7, 127.2, 126.5,

126.1, 125.9, 125.8, 124.8, 123.3, 120.2, 118.4, 118.1, 110.0, 69.8, 54.5. IR (ATR):

(cm-1): 3255, 3057, 1491, 1461, 1240, 1027, 815. LRMS (EI-DIP): m/z (%): 406 [M+]

(<1), 389 (28), 388 (100), 387 (24), 371 (11), 282 (12), 281 (47), 279 (16), 261 (10),

252 (14), 239 (14), 194 (8), 177 (7), 135 (9), 77 (5). HRMS (EI): m/z: 406.1569

calculated for C28H22O3 [M+], found 406.1542.

(Sa)-2'-[(R)-Hydroxy(3-methoxyphenyl)methyl]-(1,1'-

binaphthalen)-2-ol [(Sa,R)-L4]:2 Compound (Sa,R)-L4 was

obtained after purification on flash silica gel chromatography

from 100:0 till 82:18 (n-hexane/EtOAc) as a white foamy solid

(86% yield); m.p. 74 – 78 °C, []D25 = +267.0 (c 1.0, CHCl3).

1H

RMN (300 MHz, CDCl3) 7.92 (d, J = 8.7 Hz, 1H), 7.86 (t, J = 9.4 Hz, 3H), 7.59 (d, J = 8.7

Hz, 1H), 7.46 (ddd, J = 8.0, 6.6, 1.3 Hz), 1H), 7.33 – 7.21 (m, 3H), 7.19 – 7.08 (m, 2H),

7.02 (t, J = 7.9 Hz, 1H), 6.84 (d, J = 8.4 Hz, 1H), 6.62 (d, J = 8.2 Hz, 2H), 6.51 (s, 1H),

5.78 (br s, 1H), 5.64 (s, 1H), 3.55 (s, 3H), 2.80 (br s, 1H). 13C NMR (75 MHz, CDCl3)

159.3, 151.2, 144.2, 141.3, 134.1, 133.4, 132.9, 130.2, 129.9, 129.6, 129.1, 129.0,

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128.1, 128.1, 126.8, 126.6, 126.5, 125.1, 125.0, 123.5, 118.3, 117.9, 117.1, 113.0,

111.3, 73.3, 55.0. IR (ATR): (cm-1): 3316, 3057, 1595, 1258, 1144, 1029, 816. LRMS

(EI-DIP): m/z (%): 406 [M+] (2), 389 (28), 388 (100), 387 (14), 360 (13), 282 (9), 281

(40), 280 (8), 279 (22), 261 (13), 252 (17), 239 (14), 135 (6), 77 (5). HRMS (EI): m/z:

406.1569 calculated for C28H22O3 [M+], found 406.1558.

(Sa)-2'-[(R)-Hydroxy(4-methoxyphenyl)methyl]-(1,1'-

binaphthalen)-2-ol [(Sa,R)-L5]:2 Compound (Sa,R)-L5 was

obtained after purification on flash silica gel

chromatography from 100:0 till 80:20 (n-hexane/EtOAc)

as a white foamy solid (81% yield); m.p. 173 – 175 °C, []D25 = +241.0 (c 0.5, CHCl3).

1H RMN (300 MHz, CDCl3) 7.91 (ddd, J = 20.0, 16.1, 8.4 Hz, 4H), 7.68 (d, J = 8.7 Hz,

1H), 7.47 (t, J = 7.4 Hz, 1H), 7.34 (d, J = 8.9 Hz, 1H), 7.32 – 7.21 (m, 2H), 7.16 (d, J = 8.5

Hz, 1H), 7.09 (t, J = 7.6 Hz, 1H), 6.88 (d, J = 8.5 Hz, 2H), 6.75 (d, J = 8.5 Hz, 1H), 6.62 (d,

J = 8.7 Hz, 2H), 5.64 (s, 1H), 5.52 (br s, 1H), 3.70 (s, 3H) ,2.52 (br s, 1H). 13C NMR (75

MHz, CDCl3) 158.6, 151.1, 141.7, 134.7, 134.0, 133.4, 133.0, 130.2, 129.6, 129.5,

129.0, 128.1, 128.0, 127.3, 126.8, 126.6, 126.4, 126.4, 125.0, 124.9, 123.5, 117.9,

117.1, 113.4, 73.1, 55.2. IR (ATR): (cm-1): 3563, 3285, 3064, 2964, 1508, 1300, 1236,

1172, 1030, 1017, 822. LRMS (EI-DIP) m/z (%): 406 [M+], (<1), 404 (6), 389 (29), 388

(100), 387 (22), 360 (13), 329 (8), 281 (28), 279 (20), 261 (21), 252 (15), 239 (14), 135

(17), 77 (6). HRMS (EI): m/z: 406.1569 calculated for C28H22O3 [M+], found 406.1550.

(Sa)-2'-[(R)-(4-Fluorophenyl)(hydroxy)methyl]-(1,1'-

binaphthalen)-2-ol [(Sa,R)-L6]:2 Compound (Sa,R)-L6 was

obtained after purification on flash silica gel chromatography

from 100:0 till 87:13 (n-hexane/EtOAc) as a white foamy

solid (83% yield); m.p. 53 – 56 °C, []D25 = +245.0 (c 1.0, CHCl3).

1H RMN (400 MHz,

CDCl3) 7.88 (ddd, J = 17.3, 16.2, 8.4 Hz, 4H), 7.57 (d, J = 8.7 Hz, 1H), 7.46 (ddd, J =

8.1, 6.8, 1.1 Hz, 1H), 7.32 – 7.21 (m, 3H), 7.16 (d, J = 8.4 Hz, 1H), 7.09 (ddd, J = 8.2,

6.9, 1.2 Hz, 1H), 6.91 – 6.82 (m, 2H), 6.77 – 6.67 (m, 3H), 5.82 (br s, 1H), 5.61 (s, 1H),

2.88 (br s, 1H). 13C NMR (101 MHz, CDCl3) 163.0, 160.6, 151.1, 141.1, 138.2, 133.9,

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133.4, 132.9, 130.2, 129.9, 129.6, 129.0, 128.1, 128.0, 127.8, 127.7, 126.9, 126.7,

126.5, 126.4, 124.8, 124.7, 123.6, 117.8, 117.0, 114.9, 114.7, 72.8. 19F NMR (376

MHz, CDCl3) -115.57. IR (ATR): (cm-1): 3303, 3058, 1597, 1507, 1220, 1030, 1013,

817. LRMS (EI-DIP): m/z (%): 394 [M+] (1), 377 (27), 376 (100), 375 (35), 348 (9), 282

(10), 281 (47), 279 (22), 252 (18), 239 (15), 140 (12), 123 (13), 95 (7). HRMS (EI): m/z:

394.1369 calculated for C27H19FO2 [M+], found 394.1393.

(Sa)-2'-[(R)-Hydroxy(naphthalen-1-yl)methyl]-(1,1'-

binaphthalen)-2-ol [(Sa,R)-L7]: Compound (Sa,R)-L7 was

obtained after purification on flash silica gel chromatography

from 100:0 till 80:20 (n-hexane/EtOAc) as a yellow foamy solid

(72% yield); m.p. 105 – 108 °C, []D25 = +330 (c 1.0, CHCl3).

1H

NMR (400 MHz, CDCl3) 7.87 (t, J = 6.8 Hz, 2H), 7.81 (t, J = 6.9 Hz, 2H), 7.75 (d, J = 8.7

Hz, 1H), 7.69 (d, J = 8.2 Hz, 2H), 7.48 – 7.41 (m, 2H), 7.37 (ddd, J = 8.1, 6.9, 1.1 Hz,

1H), 7.34 – 7.27 (m, 3H), 7.27 – 7.21 (m, 4H), 7.13 (d, J = 8.3 Hz, 1H), 6.91 (ddd, J =

8.3, 6.9, 1.1 Hz, 1H), 6.40 (s, 1H), 3.45 (br s, 1H), 1.60 (br s, 1H). 13C NMR (101 MHz,

CDCl3) 151.9, 140.1, 137.5, 133.8, 133.6, 133.4, 133.2, 131.4, 130.4, 129.8, 129.4,

128.4, 128.3, 128.1, 127.9, 126.8, 126.7, 126.5, 126.4, 125.6, 125.4, 125.3, 125.2,

124.9, 123.8, 123.7, 123.4, 118.6, 118.1, 71.6. IR (ATR): (cm-1): 3227, 3051, 1621,

1508, 1268, 783, 748. LRMS (EI-DIP): m/z (%): 426 [M+] (2), 409 (33), 408 (100), 407

(15), 380 (27), 379 (14), 282 (18), 281 (80), 280 (10), 279 (18), 252 (19), 239 (16), 127

(14). HRMS (EI): m/z: 426.1620 calculated for C31H22O2 [M+], found 426,1609.

(Sa)-2'-[(R)-Hydroxy(naphthalen-2-yl)methyl]-(1,1'-

binaphthalen)-2-ol [(Sa,R)-L8]:2 Compound (Sa,R)-L8 was

obtained after purification on flash silica gel

chromatography from 100:0 till 80:20 (n-hexane/EtOAc) as

a white foamy solid (60% yield); m.p. 86.5 – 90.0 °C, []D26 = +376 (c 1.0, CHCl3).

1H

NMR (300 MHz, CDCl3) 7.94 – 7.80 (m, 4H), 7.72 – 7.64 (m, 1H), 7.62 – 7.49 (m, 3H),

7.49 – 7.41 (m, 2H), 7.41 – 7.33 (m, 2H), 7.33 – 7.15 (m, 4H), 7.12 – 6.99 (m, 2H), 6.84

(d, J = 8.3 Hz, 1H), 5.94 (s, 1H), 5.82 (br s, 1H), 3.00 (br s, 1H). 13C NMR (75 MHz,

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CDCl3) 151.3, 141.2, 139.8, 134.1, 133.4, 133.0, 132.9, 132.5, 130.2, 130.1, 129.6,

129.1, 128.10, 128.05, 128.0, 127.8, 127.4, 126.8, 126.6, 126.5, 125.9, 125.7, 125.1,

125.0, 124.6, 124.3, 123.6, 117.9, 117.2, 73.5. IR (ATR): (cm-1): 3266, 3055, 1620,

1595, 1507. LRMS (EI-DIP): m/z (%): 426 [M+] (2), 409 (33), 408 (100), 407 (22), 380

(11), 282 (10), 281 (45), 280 (12), 279 (23), 252 (16), 239 (11), 127 (10). HRMS (ESI):

m/z: 409.1592 calculated for C31H21O [M–OH]+, found 409.1597.

(Sa)-2'-[(S)-Hydroxy(pyridin-2-yl)methyl]-(1,1'-binaphthalen)-

2-ol [(Sa,S)-L9]: Compound (Sa,S)-L9 was obtained after

purification on flash silica gel chromatography from 100:0 till

20:80 (n-hexane/EtOAc) as a yellow foamy solid (40% yield);

m.p. 83 – 85 °C, []D25 = +251 (c 1.0, CHCl3).

1H NMR (400 MHz, CDCl3) 8.50 (br d, J =

4.6 Hz, 1H), 7.96 – 7.84 (m, 4H), 7.45 (m, 3H), 7.39 – 7.30 (m, 2H), 7.29 – 7.16 (m, 3H),

7.15 – 7.09 (m, 1H), 6.99 (d, J = 8.4 Hz, 1H), 6.68 (d, J = 7.9 Hz, 1H), 5.66 (s, 1H). 13C

NMR (101 MHz, CDCl3) 159.5, 152.1, 147.2, 140.7, 137.0, 134.2, 133.5, 133.0, 130.8,

130.2, 129.7, 129.0, 128.3, 128.1, 126.9, 126.7, 126.6, 125.2, 124.9, 123.4, 122.5,

122.0, 118.8, 116.9, 71.7. IR (ATR): (cm-1): 3248, 3057, 1594, 1434, 1038, 816, 746.

LRMS (EI-DIP): m/z (%): 378 [M++1] (26), 377 [M+] (90), 360 (16), 359 (54), 358 (11),

332 (22), 331 (96), 330 (100), 329 (11), 328 (16), 282 (19), 281 (79), 280 (11), 279

(30), 268 (15), 254 (14), 253 (45), 252 (53), 250 (19), 240 (11), 239 (36), 237 (11), 164

(10), 109 (14), 80 (24), 79 (12), 78 (19). HRMS (EI): m/z: 377.1416 calculated for

C26H19NO2 [M+], found 377.1441.

(Sa)-2'-[(R)-Hydroxy(pyridin-4-yl)methyl]-(1,1'-binaphthalen)-

2-ol [(Sa,R)-L10]: Compound (Sa,R)-L10 was obtained after

purification on flash silica gel chromatography from 100:0 till

20:80 (n-hexane/EtOAc) as a yellow foamy solid (48% yield);

m.p. 100 – 103 °C, []D25 = +252 (c 1.0, CHCl3).

1H NMR (300 MHz, CDCl3) 8.20 (br d,

J = 6.1 Hz, 2H), 7.93 – 7.78 (m, 4H), 7.44 (ddd, J = 8.1, 6.6, 1.4 Hz, 1H), 7.39 – 7.23 (m,

4H), 7.23 – 7.15 (m, 2H), 6.99 (br d, J = 5.8 Hz, 2H), 6.89 (d, J = 8.4 Hz, 1H), 5.65 (s,

1H), 3.56 (br s, 2H). 13C NMR (75 MHz, CDCl3) 152.9, 151.8, 148.3, 139.9, 134.2,

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133.5, 132.9, 131.5, 130.3, 129.6, 128.9, 128.2, 128.1, 126.9, 126.7, 126.6, 125.0,

124.7, 123.7, 121.5, 118.2, 117.2, 72.1. IR (ATR): (cm-1): 3297, 3055, 1606, 1506,

1342, 813, 747. LRMS (EI-DIP) m/z (%): 378 [M++1] (3), 377 [M+] (9), 360 (27), 359

(100), 358 (36), 282 (21), 281 (91), 279 (25), 252 (25), 239 (16), 140 (9), 78 (5). HRMS

(EI): m/z: 377.1416 calculated for C26H19NO2 [M+], found 377.1386.

3.5 Synthesis of chiral Ar-BINMOL ligand (Sa,S)-L1

The following procedure was used to epimerized benzylic alcohol present in

compound (Sa,R)-L1 (Scheme 11).

Scheme 11. Methodology for the epimerization of chiral diol (Sa,R)-L1 to (Sa,S)-L1.

(Sa,R)-L1 (300 mg, 0.8 mmol) was dissolved with anhydrous THF (10 mL) in a round

bottom flask, HCl 6 M (10 mL) was then added and the mixture was stirred during 3

hours at 25 °C. The resulting solution was extracted with EtOAc (3 × 10 mL) and the

combined organic layers were washed with brine, dried over magnesium sulfate and

concentrated in vacuum. The crude product was purified by flash silica gel

chromatography to give the desired product (Sa,S)-L1 in 20% yield.

3.6 Data of chiral Ar-BINMOL ligand (Sa,S)-L1

(Sa)-2'-[(S)-hydroxy(phenyl)methyl]-(1,1'-binaphthalen)-2-ol [(Sa,S)-L1]: Compound (Sa,S)-L1 was obtained after purification

on flash silica gel chromatography from 100:0 till 89:11 (n-

hexane/EtOAc) as a white foamy solid (20% yield), m.p. 56 –

58 °C, []D20 = –246.2 (c 1.0, CHCl3).

1H RMN (400 MHz, CDCl3) 8.02 (d, J = 8.7 Hz,

1H), 7.94 (d, J = 3.8 Hz, 1H), 7.93 – 7.86 (m, 3H), 7.47 (td, J = 8.0, 1.7 Hz, 1H), 7.35 (td,

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J = 8.0, 1.2 Hz, 1H), 7.32 – 7.25 (m, 3H), 7.24 (d, J = 2.9 Hz, 1H), 7.22 – 7.14 (m, 3H),

7.14 – 7.08 (m, 3H), 5.53 (s, 1H), 4.49 (s, 1H), 2.08 (s, 1H). 13C NMR (101 MHz, CDCl3)

151.6, 143.0, 142.5, 133.5, 133.4, 132.5, 130.3, 129.9, 129.1, 128.3, 128.2, 127.4,

127.2, 127.1, 126.6, 126.2, 125.7, 124.8, 124.1, 123.7, 117.7, 116.5, 73.2. IR (ATR):

(cm-1): 3392, 3058, 2925, 1619, 1596, 1143, 1034, 814. LRMS (EI-DIP) m/z (%): 377

[M++1] (3), 376 [M+] (11), 359 (27), 358 (100), 357 (34), 330 (14), 329 (11), 282 (13),

281 (59), 279 (23), 252 (21), 239 (20), 231 (10), 140 (10), 105 (12), 77 (13).

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CHAPTER II

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1. Introduction

Organolithium compounds, which were discovered in 1917 by Wilhelm Schlenk,7 are

common bench reagents that can be found in any organic synthetic laboratory and

are widely used in industry to produce numerous materials from pharmaceutical to

polymers.8 For catalytic applications, the low price and good availability of

organolithium reagents make them desirable but their high reactivity often precludes

their use in complex procedures, such as asymmetric C-C bond formation; (super)

stoichiometric amounts of a chiral modifier and extremely low temperatures are

usually required to obtain high enantioselectivity9 Only a few examples of

asymmetric deprotonations,10 addition to imines,11 and allylic alkylation reactions12

have been described in the literature as catalytic processes for organolithium

reagents.

In the next few pages, it will be summarized the methodologies that have been

described over the years for the asymmetric addition of organolithium reagents to

aldehydes using stoichiometric and catalytic loadings of a chiral ligand.

7 Tidwell, T. T. Angew. Chem. Int. Ed. 2001, 40, 331–337. 8 a) Rappoport, Z.; Marek, I. The Chemistry of Organolithium Compounds, Wiley-VCH, 2004; b) Najera, C.; Yus, Y. Curr.

Org. Chem. 2003, 867926. 9 a) Luderer, M. R.; Bailey, W. F.; Luderer,M. R.; Fair, J. D.; Dancer, R. J.; Sommer, M. B. Tetrahedron: Asymmetry 2009,

20, 981998; b) Wu, G.; Huang, M. Chem. Rev. 2006, 106, 25962616; c) Wu, G. G.; Huang, M. in Topics in

Organometallic Chemistry, Vol. 6, 2004, 135; d) Hodgson, D. M. Organolithiums in Enantioselective Chemistry,

Springer-Verlag, 2003. 10 a) Beng, T. K.; Gawley, R. E. J. Am. Chem. Soc. 2010, 132, 1221612217; b) Bilke, J. L.; Moore, S. P.; O’Brien, P.;

Gilday, J. Org. Lett. 2009, 11, 19351938. 11 a) Alexakis, A.; Amiot, F. Tetrahedron: Asymmetry 2002, 13, 21172122; b) Denmark, S. E.; Nicaise, O. J.-C. Chem.

Commun. 1996, 9991004; c) Denmark, S. E.; Nakajima, N.; Nicaise, O. J.-C. J. Am. Chem. Soc. 1994, 116, 87988798;

d) Inoue, I.; Mitsuru, I.; Kenji, S.; Koga, K.; Tomioka, K. Tetrahedron 1994, 50, 44294438; e) Tomioka, K.; Inoue, I.;

Mitsuru, I.; Kenji, S.; Koga, K. Tetrahedron Lett. 1991, 32, 30953098. 12 a) Perez, M.; Fañanás-Mastral, M.; Hornillos, V.; Rudolph, A.; Bos, P. H.; Harutyunyan, S.R.; Feringa, B. L.; Chem. Eur.

J. 2012, 18, 11880–11883; b) Fañanás-Mastral, M.; Pérez, M.; Bos, P. H.; Rudolph, A.; Harutyunyan, S. R.; Feringa, B. L.

Angew. Chem. Int. Ed. 2012, 51, 1922–1925; c) Pérez, M.; Fañanás-Mastral, M.; Bos, P. H.; Rudolph, A.; Harutyunyan,

S. R.; Feringa, B. L. Nature Chem. 2011, 3, 377381; d) Gao, F.; Lee, Y.; Mandai, K.; Hoveyda, A. H. Angew. Chem. Int.

Ed. 2010, 49, 83708374; e) Tanaka, K.; Matsuui, J.; Suzuki, H. J. Chem. Soc. Perkin Trans. 1993, 1, 153157.

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1.1. Stoichiometric and superstoichiometric enantioselective addition

of organolithium reagents to aldehydes

In 1968, Nozaki et al. investigated the ability of (–)-sparteine (VIII) to promote

asymmetric addition of organolithium reagents to aldehydes and ketones.13 The

reaction of benzaldehyde with n-BuLi in anhydrous n-hexane as solvent at –70 ᵒC

gave (R)-1-phenyl-1-pentanol in 90% yield and only 6% ee (Scheme 12).

Scheme 12. Asymmetric addition of n-BuLi to benzaldehyde promoted by (–)-sparteine (VIII).

A few years later, Seebach et al. continued the studies in asymmetric addition of

organolithium reagents to aldehydes. His group performed the first comprehensive

investigation of addition of organolithium nucleophiles in the presence of various

chiral ligands prepared from diethyl tartrate (IX).14 Ligands were screened in the

reaction of n-BuLi with benzaldehyde in n-pentane as solvent at –78 ᵒC. Amongst the

variety of chiral ligands that were tested, the authors observed that C2 symmetric

ligands which contained three or four heteroatoms provided the lowest selectivity.

On the contrary, C2 symmetric ligands with six heteroatoms in their structure,

displayed the highest performance (Scheme 13).

13 a) Nozaki, H.; Aratini, T.; Toraya, T. Tetrahedron Lett. 1968, 9, 4097–4098; b) Nozaki, H.; Aratini, T.; Toraya, T.;

Noyori, R. Tetrahedron 1971, 27, 905–913. 14 a) Seebach, D.; Oei, H.-A.; Daum, H. Chem. Ber. 1977, 110, 2316–2333; b) Seebach, D.; Dörr, H.; Bastani, B.; Ehrig, V.

Angew. Chem., Int. Ed. Engl. 1969, 8, 982–983; c) Seebach, D.; Kalinowski, H.-O.; Bastani, B.; Crass, G.; Daum, H.; Dörr,

H.; DuPreez, N. P.; Ehrig, V.; Langer, W.; Nüssler, C.; Oei, H.-A.; Schmidt, M. Helv. Chim. Acta 1977, 60, 301–325; d)

Seebach, D.; Langer, W. Helv. Chim. Acta 1979, 62, 1710–1722; e) Seebach, D.; Crass, G.; Wilka, E.-M.; Hilvert, D.;

Brunner, E. Helv. Chim. Acta 1979, 62, 2695–2698.

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Scheme 13. Asymmetric addition of n-BuLi to benzaldehyde promoted by chiral ligands IX.

In 1978, Mukaiyama´s group found that pyrrolidine ligand X was very effective as a

chiral medium for the asymmetric addition of alkyllithiums to aldehydes.15 Long chain

aliphatic nucleophiles afforded the best enantioselectivities in the addition to

benzaldehyde, such as n-BuLi, which gave the best result with 72% ee. The lowest

enantiomeric excess was achieved with PhLi (11%). A significant solvent effect was

observed by the authors; non-coordinating solvents exhibited the lowest selectivity

(up to 20% ee), while coordinanting solvents displayed better enantioselectivities (up

to 72%). In all cases, extremely low temperature (–123 ᵒC) was required to obtain

moderate enantioselectivities (Scheme 14).

Scheme 14. Asymmetric addition of alkyllithium reagents to benzaldehyde promoted by ligand X.

15 a) Mukaiyama, T.; Soai, K.; Kobayashi, S. Chem. Lett. 1978, 219–222; b) Mukaiyama, T.; Soai, K.; Sato, T.; Shimizu,

H.; Suzuki, K. J. Am. Chem. Soc. 1979, 101, 1455–1460; c) Soai, K.; Mukaiyama, T. Chem. Lett. 1978, 491–492; d) Sato,

T.; Soai, K.; Suzuki, K.; Mukaiyama, T. Chem. Lett. 1978, 601–604.

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Mukaiyama et al. also used the previous ligand X to prepare optically active alkynyl

alcohols.16 Using lithium trimethylsilylacetylide as nucleophiles and benzaldehyde as

electrophile, in Et2O at –123 ᵒC, afforded (S)-1-phenyl-2-propyn-1-ol in 87% yield and

92% ee (Scheme 14).

In 1981, Mazaleyrat and Cram observed an important effect in the reaction of

alkyllithium reagents with aldehydes in the presence of a chiral C2-symmetric

binaphtyl based diamines XI and XII (Scheme 15),17 the rate of the catalyzed addition

exceeded the rate of the non-catalyzed addition reaction. Treatment of

benzaldehyde with n-BuLi in the presence of the dimeric binaphtyl diamine ligand XI,

in Et2O at –120 ᵒC, afforded the corresponding (R)-1-phenylpentan-1-ol in 73% yield

and excellent enantioselectivity (95% ee). The monomeric binaphtyl diamine ligand

XII gave a similar yield (71%), but only 58% enantiomeric excess when is used under

the same conditions.

Scheme 15. Asymmetric addition of n-BuLi to benzaldehyde promoted by chiral binaphtyl diamines

16 Mukaiyama, T.; Suzuki, K.; Soai, K.; Sato, T. Chem. Lett. 1979, 447–448. 17 Mazazleyrat, J.-P.; Cram, D. J. J. Am. Chem. Soc. 1981, 103, 4585–4586.

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In 1982, Colombo et al. studied the (S)-(–)-proline-based ligands XIII and XIV in the

addition of n-BuLi to benzaldehyde at –85 ᵒC.18 The highest enantioselectivity

observed in this study was 36%, using proline lithium alcoxide ligand in

dimethoxyethane (DMM) as solvent (Scheme 16). The authors observed that the

lithium salts (LiI or LiClO4) present in n-BuLi affected the enantioselectivity of the

reaction and gave the racemic product.

Scheme 16. Asymmetric addition of n-BuLi to benzaldehyde promoted by ligands XIII and XIV.

Eleveld and Hogeveen were the first to investigate the ability of chiral lithium amides

XV to effect the asymmetric addition of n-BuLi to benzaldehyde.19 Several (S)--

methylbenzylamine-based ligands were examined using a 1:2.7:4 ratio of

benzaldehyde /n-BuLi/L* at –120 ᵒC (Scheme 17). They observed an important effect

based on the structure of the chiral ligand, when the structural rigidity and bulkiness

of the ligand was increased, an improvement in the enantiomeric excess of the

product was observed.

Scheme 17. Asymmetric addition of n-BuLi to benzaldehyde promoted by ligands XV.

18 Colombo, L.; Gennari, C.; Scolastico, P. C. Tetrahedron 1982, 38, 2725–2727. 19 Eleveld, M. B.; Hogeven, H. Tetrahedron Lett. 1984, 25, 5187–5190.

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In 1988, Kanoh et al. studied the use of chiral biphenyl diamines XVI and XVII in the

enantioselective addition of phenyl lithium to butyryaldehyde.20 Comparable results

were obtained to those reported by Cram,17 due to the ligand structure similarity.

However, when the reaction was cooled down to –120 ᵒC in Et2O an outstanding 99%

ee was achieved (Scheme 18).

Scheme 18. Enantioselective arylation of butyraldehyde promoted by diamine ligands XVI and XVII.

With the rise of organolithium reagents, the first autoinduction studies in the

enantioselective addition to aldehydes were carried out by Alberts and Wynberg.21

They found that the lithium alcoxide XVIII generated in the reaction had an

asymmetric inducting effect on the addition of EtLi to benzaldehyde. The formation

of mixed aggregates containing both product and starting material fragments

influenced the stereochemistry of subsequent C-C bond formation (Scheme 19).

Scheme 19. Autoinduction effect observed by deuterated lithium alcoxide XVIII.

20 Kanoh, S.; Muramoto, H.; Maeda, K.; Kawaguchi, N.; Motoi, M.; Suda, H. Bull. Chem. Soc. Jpn. 1988, 61, 2244–2246. 21 Alberts, A. H.; Wynberg, H. J. Am. Chem. Soc. 1989, 111, 7265–7266.

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The previous study inspired Jackman et al. to investigate the addition of MeLi to

benzaldehyde in the presence of various chiral lithium alcoxides as ligands (XIX).22

Unfortunately, poor results were obtained for all the ligands that were tested

(Scheme 20).

Scheme 20. Ligand screening of chiral lithium alcoxides (XIX) in the methylation of benzaldehyde.

An interesting secondary nucleophile (2-lithio-1,3-dithiane) was chosen by Kang et al.

to study the enantioselective addition to aldehydes in the presence of (–)-

isosparteine (XX).23 The enantioselectivities obtained were moderated for aromatic

aldehydes and poor to aliphatic ones (Scheme 21).

Scheme 21. Asymmetric addition of 2-lithio-1,3-dithiane to aldehydes using ligand XX.

22 Ye, M.; Logaraj, S.; Jackman, L. M.; Hiilegass, K.; Hirsh, K. A.; Bollinger, A. M.; Grosz, A. L. Tetrahedron 1994, 50,

6109–6116. 23 Kang, J.; Kim, J. I.; Lee, J. H. Bull. Korean Chem. Soc. 1994, 15, 865–868.

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In the late 90s, many groups were interested in the alkylation of aldehydes using

organolithium reagents as nucleophiles. Corruble et al. studied lithium amides (XXI),

derived from substituted 3-aminopyrrolidines, as chiral ligands in the addition of n-

BuLi to a selection of aldehydes.24 The enantioselectivities of the reaction varied from

poor to moderate. Also, the authors studied the mechanistic pathway of the reaction

and presented spectroscopic evidence for the formation of a hemiaminal-like

intermediate (Scheme 22).

Scheme 22. Asymmetric addition of n-BuLi to aldehydes promoted by lithium diamines XXI.

Schön tested aminoalcohol XXII as a ligand which derive from 1-amino-1,2-

diphenylethanols. Those type of ligands were tested in the addition of linear aliphatic

nucleophiles to benzaldehyde providing very good yields and ee (75%-86%).25 For the

first time, a very promising result was obtained for sp2 lithium nucleophiles (75% ee)

(Scheme 23).

Scheme 23. Asymmetric addition of alkyllithium reagents promoted aminoalcohol XXII.

24 a) Corruble, A.; Valnot, J.-Y.; Maddaluno, J.; Duhamel, P. Tetrahedron: Asymmetry 1997, 8, 1519–1523; b) Flinois,

K.; Yuan, Y.; Bastide, C.; Harrison-Marchand, A.; Maddaluno, J. Tetrahedron 2002, 58, 4707–4716. 25 Schön, M.; Naef, R. Tetrahedron: Asymmetry 1999, 10, 169–176.

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In 1999, Aspinall et al. investigated the ability of chiral lanthanide binaphtolate

Li3[Ln(S-BINOL)3] (XXIII) to induce chirality in the asymmetric addition of MeLi and n-

BuLi to aromatic aldehydes.26 Enantiomeric excesses in the range 28%-84% were

obtained (Scheme 24). The variation in the ee is attributed to changes in the ionic

radius of the lanthanide.

Scheme 24. Asymmetric addition of MeLi and n-BuLi promoted by Li3[Ln(S-BINOL)3] complex XXIII.

Hilmersson et al. studied the use chiral aminoethers (XXIV) as effective ligands in the

alkylation of aromatic and aliphatic aldehydes using n-BuLi as nucleophile.27 The

authors observed that the process showed a strong dependence on the substrate

and also on the reactive species present in solution, which consisted of three

complexes in equilibrium:28 (i) homoaggregated n-BuLi; (ii) lithium amide dimers; and

(iii) mixed 1:1 complex between n-BuLi and lithium amide. Excellent

enantioselectivities (up to 91% ee) were achieved at –116 ᵒC with this methodology

(Scheme 25).

Scheme 25. Asymmetric addition of n-BuLi to aldehydes promoted by chiral aminoethers XXIV.

26 Aspinall, H. C.; Dwyer, J. L. M.; Greeves, N.; Steiner, A. Organometallics 1999, 18, 1366–1368. 27 Arvidsson, P. I.; Davidsson, Ö.; Hilmersson, G. Tetrahedron: Asymmetry 1999, 10, 527–534. 28 a) Hilmersson, G.; Davidsson, Ö. J. Organomet. Chem. 1995, 489, 175–179; b) Arvidsson, P. I.; Hilmersson, G.;

Davidsson, Ö. Chem. Eur. J. 1999, 5, 2348–2355.

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The studies with lithium amides continued with Davidsson, who synthesized new

types of chiral ligands derived form aminoethers and aminosulfides (XXV).29 He found

that aminosulfide ligands gave better ee (75%-97%) than structurally identical

aminoethers in the asymmetric addition of n-BuLi to benzaldehyde, under optimal

conditions for each ligand respectively (Scheme 26). This fact suggests that the

stronger chelation between lithium and oxygen it is not important to lead higher

enantioselectivities.

Scheme 26. Asymmetric addition of n-BuLi to aldehydes promoted by lithium amides XXV.

Tobe et al. employed a new type of C2 symmetric chiral ligands derived from the

dimethyl ether of cis-1-phenylcyclohexane-1,2-diol (XXVI).30 This ligand only gave a

modest enantiomeric excess (52%) in THF at 0 ᵒC (Scheme 27).

Scheme 27. Asymmetric addition of n-BuLi to benzaldehyde promoted by ligand XXVI.

29 a) Arvidsson, P. I.; Hilmersson, G.; Davidsson, Ö. Chem. Eur. J. 1999, 5, 2348–2355; b) Granander, J.; Scott, R.;

Hilmersson, G. Tetrahedron 2002, 58, 4717–4725; c) Granander, J.; Scott, R.; Hilmersson, G. Tetrahedron: Asymmetry

2003, 14, 439–447. 30 Tobe, Y.; Iketani, H.; Tsuchiya, Y.; Konishi, M.; Naemura, K. Tetrahedron: Asymmetry 1997, 8, 3735–3744.

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In 2000, Nishiyama et al. investigated the addition of PhLi to acrolein using a chiral

ruthenium-bis(oxazolidinyl)pyridine complex (XXVII).31 The activation mode for this

chiral complex is relatively novel for this type of reaction because there is a

interaction between the ruthenium complex and double bond of acrolein. This

methodology is quite limited, because it is only effective for ,-unsaturated

substrates. The corresponding allylic alcohols were obtained in moderate to very

good enantioselectivities (Scheme 28).

Scheme 28. Asymmetric addition of PhLi to acrolein promoted by ruthenium complex XXVII.

Maddaluno used chiral lithium amides derived from 3-aminopyrrolidines (XXVIII) in

the enantioselective vinylation of aldehydes. Modest to good enantioselectivities (up

to 61%) were observed (Scheme 29).32 This is the first effective enantioselective

addition of lithium sp2 nucleophiles to aldehydes.

Scheme 29. Asymmetric addition of vinylation of aldehydes promoted by 3-aminopyrrolidines XXVIII.

31 Motoyama, Y.; Kurihara, O.; Murata, K.; Aoki, K.; Nishiyama, H. Organometallics 2000, 19, 1025–1034. 32 Yuan, Y.; Marchand-Harrison, A.; Maddaluno, J. Synlett 2005, 1555–1558.

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Hilmersson et al. improved the methodology previously developed by Davidsson and

himself28, 29 through the inclusion of a soft donor group such as diphenylphosphino or

phenylthio in the ligand structure (XXIX).33 Very good to excellent enantiomeric

excess are obtained with this kind of chiral ligands (Scheme 30).

Scheme 30. Asymmetric addition of n-BuLi to aldehydes promoted by chiral lithium amides XXIX.

1.2. Catalytic enantioselective additions of organolithium reagents to

aldehydes

Several factors complicate the control of the stereochemistry in the enantioselective

addition of organolithium reagents to aldehydes and cause unpredictable behavior;

this includes the high reactivity of organolithium reagents, which often leads to

uncatalyzed reactions, and the presence of the aggregates,34 common to

organolithium reagents.

In 1996, Seebach´s group performed the first enantioselective addition of already

titanium-transmetallated organolithium reagents (alkyl and aryl) to aldehydes using

chiral titanium TADDOLate XXX (10 mol%), in toluene as solvent at –78 ᵒC (Scheme

31). When n-BuLi was added to benzaldehyde without remove the LiCl generated

after transmetallation with ClTi(Oi-Pr)3 (1.2 eq.) 60% ee is obtained, but when LiCl is

removed an excellent 98% of enantiomeric excess is achieved, demonstrating that

lithium salts are the responsible of the decrease in the enantioselectivity.

33 Rönnholm, P.; Södergren, M.; Hilmerson, G. Org. Lett. 2007, 9, 3781–3783. 34 Gessner, V. H.; Däschlein, C.; Strohmann, C. Chem. Eur. J. 2009, 15, 3320–3334.

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Scheme 31. Catalytic enantioselective addition of RLi to aldehydes catalyzed by TADDOLate XXX.

In 2009, Walsh´s group developed an effective methodology for the arylation of

aldehydes with in situ generated organolithium reagents to broad variety of

aldehydes using ZnCl2 as transmetallating agent and ligand XXXI (Scheme 32). The

methodology also includes the addition of TEEDA (0.8 eq.) to chelate lithium salts

generated during the transmetallation process that allows the synthesis of active

specie Ar(n-Bu)Zn. Chiral diarylmethanols, prepared from the addition of aryl and

heteroaryl nucleophiles, are synthesized with excellent levels of enantioselectivities

(up to 95%) and very good yields under this novel methodology.

Scheme 32. Catalytic enantioselective addition of ArLi to aldehydes catalyzed by (–)-MIB (XXXI).

In 2010, Harada developed a methodology to prepare enantioenriched secondary

alcohols through asymmetric arylation of aldehydes using organolithium reagents as

nucleophile, prepared by lithiation with n-BuLi of the corresponding aryl bromide.

Prior to the reaction with the aldehyde, the organolithium reagent is treated with

MgBr2, (to transmetallate to the corresponding Grignard reagent), followed by the

addition of Ti(Oi-Pr)4 in excess, to generate the corresponding organotitanium

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76

compound.35 The reaction is carried out in DCM at 0 ᵒC, using 2 mol% of 3-(3,5-

diphenylphenyl)-H8-(R)-BINOL (XXXII) and excellent yields and enantioselectivities are

achieved with this methodology (Scheme 33).

Scheme 33. Catalytic enantioselective addition of ArLi to aldehydes catalyzed by diol XXXII.

Organolithium reagents are highly reactive organometallic nucleophiles and achieve

the asymmetric direct addition to aldehydes without a metal salt to transmetallate

into a less reactive organometallic specie it is not easy. In 2011, Maddaluno and

Marchand achieved the first substoichiometric direct addition of MeLi to o-

methylbenzaldehyde using 33 mol% of chiral ligand XXXIII and 33 mol% of LiCl

(Scheme 34). The methylated alcohol was generated in 80% yield and 80% ee.

Scheme 34. Subtoichiometric enantioselective addition of MeLi to o-methylbenzaldehyde catalyzed by

diol XXXIII.

In 2014, Da reported a double transmetallation methodology for the arylation of

aldehydes with organolithium reagents, but in this case the first transmetallation

takes place with AlCl3.36 The reaction is carried out in a THF/n-hexane mixture at 40

ᵒC using TMEDA to chelate lithium salts generated during the transmetallation

35 Nakagawa, Y.; Muramatsu, Y.; Harada, T. Eur. J. Org. Chem. 2010, 6535–6538. 36 Yang, Y-X.; Liu, Y.; Zhang, L.; Jia, Y-E.; Wang, P.; Zhuo, F-F.; An, X-T.; Da, C-S. J. Org. Chem. 2014, 79, 10696−10702.

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77

process (Scheme 35). These salts catalyze the background reaction and are the

responsible of racemic products. The ligand used in this transformation is the readily

commercial available H8-(S)-BINOL (XXXIV) offering excellent results concerning yield

and ee for a wide variety of aromatic aldehydes.

Scheme 35. Catalytic enantioselective addition of ArLi to aldehydes catalyzed by H8-(S)-BINOL XXXIV.

As has been shown in previous works, it is difficult to perform the enantioselective

addition of organolithium reagents to aldehydes using catalytic amounts of a chiral

ligand and without employing metal salts as transmetallating reactant.

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79

2. Results and discussion

2.1 Optimization of the catalytic enantioselective addition of

organolithium reagents to aldehydes

As a starting point of the optimization process, MeLi was chosen as nucleophile for

the asymmetric addition to benzaldehyde (1a) as the model reaction. The parameters

that were taken into account for the optimization are: solvent, temperature, Ti(Oi-

Pr)4/MeLi ratio and ligand screening.

Preliminary tests for the addition of MeLi to the model substrate benzaldehyde (1a)

provided very promising results (Table 2). (S)-1-Phenylethanol (2a) was obtained with

90% enantioselectivity and 40% conversion when 1a was added immediately after

the addition of 1.5 eq. of MeLi into a toluene solution containing 10 mol% of (Sa,R)-L1

and 4.5 eq. of Ti(Oi-Pr)4 at 40 °C (Table 2, entry 1). Both conversion and

enantioselectivity could be improved (63% conv., 93% ee) by increasing the catalyst

loading up to 20 mol% (Table 2, entry 2). However, changing the reaction

temperature did not provide any better results; higher temperatures (20 °C) led to

lower enantioselectivity (Table 2, entry 3) whilst lower temperatures (60 °C) gave

lower conversions (Table 2, entry 4).

It should be noted that the addition protocol had a significant influence in the

outcome of the process. When MeLi was added last to the reaction mixture, the

enantioselectivity dropped to 74% (Table 2, entry 5). More interestingly, when

substrate 1a was added 15 min after the addition of the MeLi to the reaction mixture

containing the ligand and the titanium tetraisopropoxide, the conversion drastically

diminished to 19% (Table 2, entry 6), which indicates that the active species formed

upon addition of MeLi to complex (Sa,R)-L1-Ti(Oi-Pr)4 has a short life time at 40 °C.

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80

Table 2. Influence of catalyst loading, temperature and addition protocol

[a]

Entry (Sa,R)-L1 (mol%) T (°C) Conv.

[b] (%) ee

[b] (%)

1 10 40 40 90 2 20 40 63 93 3 20 20 50 66 4 20 60 20 84

5[c]

20 40 63 74 6

[d] 20 40 19 86

[a] Conditions: 1a (0.1 mmol, 0.07 M), MeLi (1.6 M in Et2O, 1.5 eq.), (Sa,R)-L1,

Ti(Oi-Pr)4 (4.5 eq.), toluene (1.5 mL), 40 °C, 1 h. [b] Determined by chiral GC analysis. [c] MeLi was added the last. [d] 1a was added 15 min after the addition of MeLi.

In a second stage of the optimization process, the amounts of Ti(Oi-Pr)4 and MeLi

were adjusted, which was a crucial step in this process to get good results. The

reaction in the presence of chiral ligand (Sa,R)-L1 but no Ti(Oi-Pr)4, was checked and

gave the desired product 2a with full conversion, but racemic (Table 3, entry 1). This

means that there is probably no coordination between the free organometallic

species and the ligand, indicating that the active species in the reaction are the

organotitanium species generated in situ by transmetallation of the organolithium

reagent with the excess of Ti(Oi-Pr)4.

The presence of substoichiometric amount (0.2 eq.) of Ti(Oi-Pr)4 respect to the

nucleophile provided the same result (Table 3, entry 1 vs 2). The presence of, at least,

equimolar Ti(Oi-Pr)4/MeLi amounts were necessary to get high enantioselectivities of

89 and 90% (Table 3, entries 3-4). The conversion of the reaction was optimized,

preserving good enantioselectivities, by increasing the amount of nucleophile from

1.5 eq. to 3 eq. keeping the same Ti(Oi-Pr)4/MeLi ratio (Table 3, entries 3-4).

In order to improve the previous results, different superstoichiometric Ti(Oi-

Pr)4/MeLi amounts were tested (Table 3, entries 5-12). As shown in Table 3, there is

not a strong correlation between Ti(Oi-Pr)4/MeLi ratio and enantiomeric excess, so

after several attempts, the best results concerning ee and conversion were achieved

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81

with a ratio 2:1 Ti(Oi-Pr)4/MeLi (Table 3, entries 5-8). Then, different combinations

were tested keeping the 2:1 Ti(Oi-Pr)4/MeLi ratio constant (Table 3, entries 5-8). The

optimal combination found was 3.2 eq. MeLi and 6 eq. Ti(Oi-Pr)4 (Table 3, entry 7),

which allowed the reaction to reach very good levels of conversion and 94%

enantioselectivity in only 1 hour at 40 oC.

Table 3. Optimization Ti(Oi-Pr)4/MeLi ratio[a]

Entry Ti(Oi-Pr)4 (eq.) MeLi (eq.) Ti:Li ratio Conv.

[b] (%) ee

[b] (%)

1 - 1.5 - >99 0 2 0.2 1.5 0.1:1 >99 0 3 1.5 1.5 1:1 23 89 4 3 3 1:1 55 90 5 3 1.5 2:1 59 96 6 5 2.5 2:1 73 94 7 6 3.2 1.9:1 85 94 8 7 3.5 2:1 88 94 9 3.8 1.5 2.5:1 52 96

10 4.5 1.5 3:1 63 93 11 9 3 3:1 88 90 12 6 1.5 4:1 41 92

[a] Conditions: 1a (0.1 mmol, 0.07 M), MeLi (1.6 M in Et2O, x eq.), Ti(Oi-Pr)4 (y eq.), (Sa,R)-L1 (20 mol%),

toluene (1.5 mL), 40 °C, 1 h. [b] Determined by chiral GC analysis.

With the previous optimized conditions in hand, diverse anhydrous solvents with

different polarity and coordination ability were also evaluated for the model

reaction. In polar solvents, the reaction did not work properly and very low

conversions and ee were obtained (Table 4, entries 1-4), except when DCM was used

as solvent an 88% ee was achieved, but with 35% conversion (Table 4, entry 2).

However, when more apolar solvents were used, the reaction proceeded with

excellent levels of enantioselectivity and moderate to very good conversions (Table

4, entries 5-7). In particular, toluene and n-hexane provided the best results (Table 4,

entries 6-7), but the use of n-hexane was discarded to avoid possible solubility

problems with other substrates.

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Table 4. Solvent optimization[a]

Entry Solvent Conv.

[b] (%) ee

[b] (%)

1 Acetonitrile 10 0 2 DCM 35 88 3 DME 0 - 4 THF 4 36 5 Et2O 46 88 6 Toluene 85 94 7 n-Hexane 86 94

[a] Conditions: 1a (0.1 mmol, 0.07 M), MeLi (1.6 M en Et2O, 3.2 eq.), Ti(Oi-Pr)4 (6

eq.), (Sa,R)-L1 (20 mol%), solvent (1.5 mL), 40 °C, 1 h. [b] Determined by chiral GC analysis.

Under these optimized conditions, a small library of chiral diols was screened as

ligands (Figure 1) for the addition of MeLi to benzaldehyde (1a). The results suggest

that the configuration of the sp3 stereogenic center of the ligand is of crucial

importance (Table 5, entry 1 vs 2). Variation of the aromatic substituents (L1-L6) on

that sp3 stereogenic center did not have a significant effect on either conversion or

enantioselectivity (Table 5, entry 1 vs 3-7), with the exception of the ortho-methoxy

substituted (Sa,S)-L3 which provided lower conversion (Table 5, entry 3), probably

due to steric effects. (Sa,R)-L1 and (Sa,R)-L6 provided the best results (Table 5, entry 1

and 7), but (Sa,R)-L1 was chosen for the rest of these studies for being structurally

simpler and easier to synthetize.

Figure 1. Chiral diol ligands screened in this study

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Chapter II – Results and discussion

83

Table 5. Ligand optimization[a]

Entry L* Conv.

[b] (%) ee

[b] (%)

1 (Sa,R)-L1 85 94 2 (Sa,S)-L1

[c] 60 0

3 (Sa,R)-L2 79 94 4 (Sa,S)-L3 15 93 5 (Sa,R)-L4 81 90 6 (Sa,R)-L5 84 86 7 (Sa,R)-L6 87 94

[a] Conditions: 1a (0.1 mmol, 0.07 M), MeLi (1.6 M in Et2O, 3.2 eq.), Ti(Oi-Pr)4 (6

eq.), L* (20 mol%), toluene (1.5 mL), 40 °C, 1 h. (b) Determined by chiral GC analysis. [c] Same axial chirality as (Sa,R)-L1 but oppositte configuration at the sp3 stereogenic center.

2.2. Scope of the reaction

With the best optimized conditions in hands, the scope of the addition of MeLi was

then examined with different aldehydes (Table 6). The new catalytic system

described above proved to be remarkably efficient; a versatile range of methyl

carbinol units were prepared in good yield (74% to 91%) and enantioselectivity (72%

to 90%) from a wide range of substrates bearing electron-poor or electron-rich

substituents at the meta and para position (Table 6, entries 1 and 3-8). The lower

yield and selectivity of o-methylbenzaldehyde (1b, Table 6, entry 2) might be ascribed

to higher steric hindrance around the reactive site.

The tolerance of this methodology towards functionalized substrates should be

emphasized: chloro- (1g) and cyano- (1h) functionalities showed resistance to the

very reactive lithium reagents when used under these reaction conditions (Table 6,

entries 7-8). The reactions with 2-naphthaldehyde (1i) and the heteroaromatic

substrates: 2-thiophenecarboxaldehyde (1j) and 2-furaldehyde (1k) gave 90%, 88%

and 72% ee respectively along with very good yields (Table 6, entries 9-11), whereas

cinnam aldehyde (1l) provided a moderate enantioselectivity (Table 6, entry 12).

Remarkably, all reactions were finished in less than 1 h without by-product

formation. Moreover, the unreacted starting material and ligand could be easily

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Chapter II – Results and discussion

84

recovered and the latter, recycled and reused with any loss of activity. Regarding

aliphatic substrates, phenylacetaldehyde (1m, Table 6, entry 13) gave low conversion

and moderate enantioselectivity while the addition of MeLi to pivaldehyde (1n, Table

6, entry 14) proceeded in less than 2% conversion. In general, the use of aliphatic

aldehydes as electrophiles for 1,2 addition is a challenge because this type of

substrates have several drawbacks which disfavoured the asymmetric addition such

as: i) multiple conformations, ii) hydrogens in to the carbonyl, with highly

enolyzable character and iii) absence of – stacking with the ligand.

Table 6. Asymmetric addition of MeLi to aldehydes[a]

Entry Aldehyde Product Yield

[b] (%) ee

[c] (%)

1

87 90 (S)

2

78 62 (S)

3

87 82 (S)

4

81 88 (S)

5

91 89 (S)

6

82 88 (S)

7

74 84 (S)

8

84 82 (S)

9

85 90 (S)

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85

10

57 (90)[d]

88 (S)

11

56 (86)[d]

72 (S)

12

84 68 (S)

13

23 62 (S)

14

2 n.d.[e]

[a] Conditions: 1 (0.3 mmol, 0.12 M), MeLi (1.6 M in Et2O, 3.2 eq.), (Sa,R)-L1 (20 mol%),

Ti(Oi-Pr)4 (6 eq.), toluene (2.5 mL), 40 °C, 1 h. [b] Isolated yield after flash silica gel

chromatography. [c] Determined by chiral GC analysis. Absolute configuration of chiral

alcohols was determined by correlation of optical rotation with known compounds. [d]

Volatile products, conversions based on GC data in brackets. [e] Not determined.

Finally, other common alkyllithium reagents were also tested (Table 7). Gratifyingly,

the addition of other linear reagents like EtLi and n-BuLi proceeded with good yield

(62% to 90%) and enantioselectivity (90% to 96%) for a wide range of aromatic

aldehydes bearing electron donating or withdrawing groups (Table 7, entries 1-8). It

was also noted that: i) the increase in the size of the nucleophile meant an

improvement in the enantioselectivity (Table 7, entries 1-3 vs 4-8); ii) no evidence of

common lithium-halogen exchange was found when halogenated aldehydes were

used as substrates (Table 7, entries 5-6); iii) labile functionalities like carbonates were

tolerated as demonstrated by the addition of n-BuLi to 1p (Table 7, entry 8).

Table 7. Asymmetric addition of EtLi and n-BuLi reagents to aldehydes[a]

Entry Aldehyde Product Yield

[b] (%) ee

[c] (%)

1

78 92 (S)

2

66 90 (S)

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Chapter II – Results and discussion

86

3

62 92 (S)

4

90 96 (S)

5

89 94 ()

6

85 92 (S)

7

89 94 (S)

8

90 96 ()

[a] Conditions: 1 (0.3 mmol, 0.12 M), RLi (3.2 eq.), (Sa,R)-L1 (20 mol%), Ti(Oi-Pr)4 (6 eq.), toluene (2.5 mL),

40 °C, 1 h. [b] Isolated yield after flash silica gel chromatography. [c] Determined by chiral GC or HPLC

analysis. Absolute configuration of chiral alcohols was determined by correlation of optical rotation with

known compounds.

A limitation of this methodology is highlighted by the reaction of the bulky i-BuLi with

benzaldehyde (1a), that gave 40% conversion into the reduction product

phenylmethanol while the desired alcohol 2w was only formed in 8% yield with 62%

ee (Figure 2).

Figure 2. Chiral secondary alcohols derived from addition of i-BuLi and PhLi to aldehydes

Interestingly, the use of the sp2-hybridized phenyllithium reagent provided very good

yield but low and moderated enantioselectivities in the addition to 2-naphthaldehyde

(1i) and cyclohexanecarboxaldehyde (1q), respectively (Figure 2). Aryllithium

reagents are more reactive than alkyllithium due to the negative charge is localized

on a sp2 carbon. Also the lower aggregation state in solution (tetramer-dimer in Et2O)

compared to alkyllithium (tetramer, hexamer) makes them much more reactive. We

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87

believe this high reactivity was the reason why we were unable to suppress/minimize

the uncatalyzed background reaction and low enantioselectivities (2x and 2y, Figure

2).

In conclusion, a methodology has been developed for the first efficient

enantioselective catalytic system for the addition of alkyllithium reagents to aromatic

aldehydes using an excess of titanium tetraisopropoxide. This methodology allows

the preparation of highly valuable optically active alcohols from economical and

commercially available lithium reagents. Reactions are performed in a simple and fast

one-pot procedure and no salt exclusion is needed. Moreover, the potential

problems associated with the high reactivity of organolithium compounds are

overcome under these reaction conditions since this methodology proves to be

compatible with functionalized substrates.

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89

3. Experimental part

3.1 General procedure for the enantioselective addition of

organolithium reagents to aldehydes

In a flame dried Schlenk tube, (Sa,R)-L1 (22.6 mg, 0.06 mmol, 20 mol%) was dissolved

in anhydrous toluene (2.5 mL) under argon atmosphere. The solution was cooled

down to 40 °C and Ti(Oi-Pr)4 (550 L, 1.8 mmol, 6 eq.) was then added. Five minutes

later, RLi (0.96 mmol, 3.2 eq.) was added followed by the immediate addition of the

corresponding aldehyde (0.3 mmol) previously distilled. The reaction was quenched

with water (5 mL) and then HCl 2 M (5 mL) to eliminate the titanium oxides generated

by the addition of water. The crude was extracted with EtOAc (3 × 10 mL), and the

combined organic layers were neutralized with a saturated NaHCO3 aqueous solution

(15 mL), dried over magnesium sulfate and concentrated under vacuum. The crude

product was purified by flash silica gel chromatography to give the desired products.

3.2 Data of chiral secondary alcohols prepared from organolithium

reagents

(S)-1-Phenylethanol (2a):37 Compound 2a was obtained after

purification on flash silica gel chromatography from 100:0 till 86:14 (n-

hexane/EtOAc) as a colorless oil (87% yield, 90% ee); []D25 = 54.0 (c

1.0, CHCl3) {Lit. []D

20 = 39.6 (c 2.5, CHCl3) for 82% ee}. 1H NMR (300 MHz, CDCl3)

7.39 – 7.21 (m, 5H), 4.86 (q, J = 6.5 Hz, 1H), 2.10 (br s, 1H), 1.47 (d, J = 6.5 Hz, 3H). 13C

NMR (75 MHz, CDCl3) 145.8, 128.4, 127.4, 125.3, 70.3, 25.1. LRMS (EI): m/z (%): 122

[M+] (12), 107 (39), 105 (15), 104 (100), 103 (47), 79 (41), 78 (50), 77 (42), 51 (24), 50

(13). Ee determination by chiral GC analysis, HP-CHIRAL-20 column, T = 120 °C, P =

14.3 psi, retention times: tr(R) = 13.1 min, tr(S) = 13.5 min (major enantiomer).

37 Kantam, M. L.; Laha, S.; Yadav, J.; Likhar, P.R.; Sreedhar, B.; Jha, S.; Bhargava, S.; Udayakiran, M.; Jagadeesh, B. Org.

Lett. 2008, 10, 2979–2982.

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90

(S)-1-(o-Tolyl)ethanol (2b):38 Compound 2b was obtained after

purification on flash silica gel chromatography from 100:0 till 86:14 (n-

hexane/EtOAc) as a yellow oil (78% yield, 62% ee); []D25 = 47.0 (c 1.0,

CHCl3) {Lit. []D

20 = 72.5 (c 1.0, CHCl3) for 96% ee}. 1H NMR (300 MHz, CDCl3) 7.49

(d, J = 7.4 Hz, 1H), 7.26 – 7.08 (m, 3H), 5.09 (q, J = 6.4 Hz, 1H), 2.32 (s, 3H), 1.99 (br s,

1H), 1.44 (d, J = 6.4 Hz, 3H). 13C NMR (75 MHz, CDCl3) 143.8, 134.1, 130.3, 127.1,

126.3, 124.4, 66.7, 23.9, 18.9. LRMS (EI): m/z (%): 136 [M+] (2), 121 (16), 119 (10),

118 (80), 117 (100), 115 (44), 103 (10), 93 (16), 91 (44), 77 (15), 65 (12), 63 (11). Ee

determination by chiral GC analysis, HP-CHIRAL-20 column, T = 120 °C, P = 14.3 psi,

retention times: tr(R) = 24.2 min, tr(S) = 27.4 min (major enantiomer).

(S)-1-(m-Tolyl)ethanol (2c):39 Compound 2c was obtained after

purification on flash silica gel chromatography from 100:0 till 86:14

(n-hexane/EtOAc) as a yellow oil (87% yield, 82% ee); []D25 = 43.0 (c

1.0, CHCl3) {Lit. []D

16 = 47.3 (c 0.8, CHCl3) for 90% ee}. 1H NMR (300 MHz, CDCl3)

7.23 (dd, J = 7.2, 3.7 Hz, 1H), 7.20 – 7.13 (m, 2H), 7.08 (d, J = 7.3 Hz, 1H), 4.85 (q, J =

6.4 Hz, 1H), 2.36 (s, 3H), 1.92 (br s, 1H), 1.48 (d, J = 6.5 Hz, 3H). 13C NMR (75 MHz,

CDCl3) 145.8, 138.1, 128.4, 128.2, 126.1, 122.4, 70.4, 25.1, 21.4. LRMS (EI): m/z (%):

136 [M+] (11), 121 (23), 119 (16), 118 (93), 117 (100), 115 (40), 103 (13), 93 (27), 92

(11), 91 (53), 77 (17), 65 (13), 51 (9). Ee determination by chiral GC analysis, HP-

CHIRAL-20 column, T = 120 °C, P = 14.3 psi, retention times: tr(R) = 20.1 min, tr(S) =

20.8 min (major enantiomer).

(S)-1-(p-Tolyl)ethanol (2d):40 Compound 2d was obtained after

purification on flash silica gel chromatography from 100:0 till 86:14

(n-hexane/EtOAc) as a colorless oil (81% yield, 88% ee); []D25 = 55.0

(c 1.0, CHCl3) {Lit. []D

20 = 53.7 (c 0.4, CHCl3) for 96% ee}. 1H NMR (400 MHz, CDCl3)

7.26 (d, J = 8.2 Hz, 2H), 7.15 (d, J = 7.6 Hz, 2H), 4.86 (q, J = 6.4 Hz, 1H), 2.34 (s, 3H),

38 Li, Y.; Zhou, Y.; Shi, Q.; Ding, K.; Sandoval, C. A.; Noyori, R. Adv. Synth. Catal. 2011, 353, 495–500. 39 Wang, W.; Wang, Q. Chem.Commun. 2010, 46, 4616–4618. 40 Zhu, Q-M.; Shi, D-J.; Xia, C-G.; Huang, H-M. Chem. Eur. J. 2011, 17, 7760–7763.

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91

2.03 (br s, 1H), 1.48 (d, J = 6.5 Hz, 3H). 13C NMR (101 MHz, CDCl3) 142.8, 137.1,

129.1, 125.3, 70.2, 25.0, 21.1. LRMS (EI): m/z (%): 136 [M+] (9), 121 (27), 119 (13),

118 (84), 117 (100), 115 (38), 103 (11), 93 (19), 91 (48), 77 (15), 65 (12). Ee

determination by chiral GC analysis, HP-CHIRAL-20 column, T= 120 °C, P= 14.3 psi,

retention times: tr(R) = 19.3 min, tr(S) = 20.2 min (major enantiomer).

(S)-1-(4-Methoxyphenyl)ethanol (2e):41 Compound 2e was

obtained after purification on flash silica gel chromatography from

100:0 till 83:17 (n-hexane/EtOAc) as a yellow oil (91% yield, 89%

ee); []D25 = 42.0 (c 1.0, CHCl3) {

Lit. []D20 = 51.9 (c 1.0, CHCl3) for 97% ee}. 1H NMR

(300 MHz, CDCl3) 7.30 (d, J = 8.7 Hz, 2H), 6.88 (d, J = 8.7 Hz, 2H), 4.85 (q, J = 6.4 Hz,

1H), 3.80 (s, 3H), 1.85 (br s, 1H), 1.47 (d, J = 6.4 Hz, 3H). 13C NMR (75 MHz, CDCl3)

159.0, 138.0, 126.6, 113.8, 70.0, 55.3, 25.0. LRMS (EI): m/z (%): 152 [M+] (6), 137 (23),

135 (14), 134 (100), 119 (50), 109 (9), 91 (54), 77 (12), 65 (23), 63 (10), 51 (6). Ee

determination by chiral GC analysis, HP-CHIRAL-20 column, T = 120 °C, P = 14.3 psi,

retention times: tr(R) = 53.8 min, tr(S) = 55.3 min (major enantiomer).

(S)-1-[4-(Trifluoromethyl)phenyl]ethanol (2f):37 Compound 2f was

obtained after purification on flash silica gel chromatography from

100:0 till 86:14 (n-hexane/EtOAc) as a yellow oil (82% yield, 88%

ee); []D25 = 41.0 (c 1.0, CHCl3) {

Lit. []D20 = 33.7 (c 5.5, CHCl3) for 97% ee}. 1H NMR

(300 MHz, CDCl3) 7.60 (d, J = 8.2 Hz, 2H), 7.47 (d, J = 8.6 Hz, 2H), 4.95 (q, J = 6.5 Hz,

1H), 2.16 (br s, 1H), 1.49 (d, J = 6.5 Hz, 3H). 13C NMR (75 MHz, CDCl3) 149.7, 129.8,

129.4, 125.6, 125.4, 125.4, 122.3, 69.8, 25.3. LRMS (EI): m/z (%): 190 [M+] (7), 175

(100), 173 (18), 172 (40), 171 (14), 151 (13), 145 (22), 127 (93), 103 (16), 77 (12). Ee

determination by chiral GC analysis, HP-CHIRAL-20 column, T = 130 °C, P = 14.3 psi,

retention times: tr(R) = 11.1 min, tr(S) = 11.8 min (major enantiomer).

41 Fujii, A.; Hashiguchi, S.; Uematsu, N.; Ikariya, T.; Noyori, R. J. Am.Chem. Soc. 1996, 118, 2521–2522.

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(S)-1-(4-Chlorophenyl)ethanol (2g):42 Compound 2g was obtained

after purification on flash silica gel chromatography from 100:0 till

86:14 (n-hexane/EtOAc) as a yellow oil (74% yield, 84% ee); []D25 =

38.0 (c 1.0, CHCl3) {Lit. []D

20 = 43.6 (c 1.0, CHCl3) for 97% ee}. 1H NMR (400 MHz,

CDCl3) 7.31 (d, J = 9.0 Hz, 2H), 7.28 (d, J = 8.9 Hz, 2H), 4.86 (q, J = 6.5 Hz, 1H), 2.40

(br s, 1H), 1.46 (d, J = 6.5 Hz, 3H). 13C NMR (101 MHz, CDCl3) 144.2, 133.0, 128.5,

126.8, 69.7, 25.2. LRMS (EI): m/z (%): 156 [M+] (11), 143 (13), 141 (46), 140 (34), 139

(23), 138 (100), 113 (14), 112 (13), 103 (72), 102 (22), 101 (12), 77 (60), 75 (22), 74

(12), 51 (23), 50 (14). Ee determination by chiral GC analysis, HP-CHIRAL-20 column,

T = 125 °C, P = 14.3 psi, retention times: tr(R) = 35.8 min, tr(S) = 38.0 min (major

enantiomer).

(S)-4-(1-Hydroxyethyl)benzonitrile (2h):43 Compound 2h was

obtained after purification on flash silica gel chromatography from

100:0 till 80:20 (n-hexane/EtOAc) as a yellow oil (84% yield, 82%

ee); []D25 = 27.0 (c 0.7, CHCl3) {

Lit. []D20 = 62.7 (c 2.1, CHCl3) for 72% ee}. 1H NMR

(300 MHz, CDCl3) 7.63 (d, J = 8.3 Hz, 2H), 7.49 (d, J = 8.1 Hz, 2H), 4.96 (q, J = 6.5 Hz,

1H), 2.22 (br s, 1H), 1.49 (d, J = 6.5 Hz, 3H). 13C NMR (75 MHz, CDCl3) 151.1, 132.3,

126.0, 118.8, 111.0, 69.6, 25.4. LRMS (EI): m/z (%): 147 [M+] (8), 132 (100), 130 (25),

129 (53), 128 (17), 104 (85), 103 (19), 102 (32), 77 (27), 76 (16), 75 (14), 51 (13). Ee

determination by chiral GC analysis, HP-CHIRAL-20 column, T = 150 °C, P = 14.3 psi,

retention times: tr(R) = 43.0 min, tr(S) = 46.2 min (major enantiomer).

(S)-1-(Naphthalen-2-yl)ethanol (2i):40 Compound 2i was obtained

after purification on flash silica gel chromatography from 100:0 till

86:14 (n-hexane/EtOAc) as a white powder (85% yield, 90% ee);

m.p. 56 – 58 °C, []D25 = 36.7 (c 1.0, CHCl3) {

Lit. []D20 = 48.1 (c 1.5, CHCl3) for 92%

ee}. 1H NMR (300 MHz, CDCl3) 7.84 – 7.70 (m, 4H), 7.50 – 7.39 (m, 3H), 4.98 (q, J =

6.4 Hz, 1H), 2.39 (br s, 1H), 1.52 (d, J = 6.5 Hz, 3H). 13C NMR (75 MHz, CDCl3) 143.1,

42 Xie, J-H.; Liu, X-Y.; Xie, J-B.; Wang, L-X.; Zhou, Q-L. Angew. Chem., Int. Ed. Engl. 2011, 50, 7329–7332. 43 Kantam, M. L.; Yadav, J.; Laha, S.; Srinivas, P.; Sreedhar, B.; Figueras, F. J. Org. Chem.2009, 74, 4608–4611.

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133.2, 132.8, 128.2, 127.9, 127.6, 126.0, 125.7, 123.8, 123.7, 70.4, 25.0. LRMS (EI):

m/z (%): 172 [M+] (6), 155 (16), 154 (100), 153 (56), 152 (37), 151 (12), 129 (27), 128

(18), 127 (12), 76 (18), 63 (6). Ee determination by chiral GC analysis, CP-Chirasil-DEX

CB column, T = 150 °C, P = 14.3 psi, retention times: tr(R) = 25.6 min, tr(S) = 26.5 min

(major enantiomer).

(S)-1-(Thiophen-2-yl)ethanol (2j):40 Compound 2j was obtained after

purification on flash silica gel chromatography from 100:0 till 82:18 (n-

hexane/EtOAc) as a volatile brown oil (57% yield, 88% ee); []D25 = 21.0

(c 1.0, CHCl3) {Lit. []D

20 = 27.6 (c 1.0, CHCl3) for 94% ee}. 1H NMR (400 MHz, CDCl3)

7.24 (dd, J = 4.8, 1.4 Hz, 1H), 7.00 – 6.94 (m, 2H), 5.13 (q, J = 6.4 Hz, 1H), 2.09 (br s,

1H), 1.60 (d, J = 6.4 Hz, 3H). 13C NMR (101 MHz, CDCl3) 149.83, 126.62, 124.40,

123.15, 66.22, 25.23. LRMS (EI): m/z (%): 128 [M+] (11), 113 (22), 111 (18), 110 (100),

109 (43), 85 (32), 84 (26), 66 (24), 65 (10), 58 (10). Ee determination by chiral GC

analysis, HP-CHIRAL-20 column, T = 120 °C, P = 14.3 psi, retention times: tr(R) = 14.3

min, tr(S) = 14.7 min (major enantiomer).

(S)-1-(Furan-2-yl)ethanol (2k):40 Compound 2k was obtained after

purification on flash silica gel chromatography from 100:0 till 82:18 (n-

hexane/EtOAc) as a very volatile yellow oil (56% yield, 72% ee); []D25 =

7.0 (c 0.8, CHCl3) {Lit. []D20 = 19.8 (c 0.9, CHCl3) for 98% ee}. 1H NMR (300 MHz,

CDCl3) 7.38 (dd, J = 1.8, 0.7 Hz, 1H), 6.33 (dd, J = 3.2, 1.8 Hz, 1H), 6.23 (d, J = 3.2 Hz,

1H), 4.89 (q, J = 6.6 Hz, 1H), 1.55 (d, J = 6.6 Hz, 3H).13C NMR (75 MHz, CDCl3) 157.5,

141.9, 110.1, 105.1, 63.6, 21.2. LRMS (EI): m/z (%): 113 [M++1] (3), 112 [M+] (47), 111

(6), 97 (100), 95 (23), 84 (10), 69 (21), 67 (7), 65 (6), 55 (6). Ee determination by chiral

GC analysis, HP-CHIRAL-20 column, T = 80 °C, P = 14.3 psi, retention times: tr(R) =

21.7 min, tr(S) = 22.4 min (major enantiomer).

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(S,E)-4-Phenylbut-3-en-2-ol (2l):44 Compound 2l was obtained after

purification on flash silica gel chromatography from 100:0 till 85:15

(n-hexane/EtOAc) as a yellow oil (84% yield, 68% ee); []D25 = 20.3

(c 1.0, CHCl3) {Lit. []D

20 = 14.6 (c 1.0, CHCl3) for 60% ee}. 1H NMR (400 MHz, CDCl3)

7.37 (dd, J = 5.3, 3.2 Hz, 2H), 7.34 – 7.27 (m, 2H), 7.27 – 7.20 (m, 1H), 6.55 (d, J = 15.9

Hz, 1H), 6.25 (dd, J = 15.9, 6.4 Hz, 1H), 4.47 (p, J = 6.3 Hz, 1H), 1.99 (br s, 1H), 1.36 (d,

J = 6.4 Hz, 3H). 13C NMR (101 MHz, CDCl3) 136.6, 133.5, 129.3, 128.5, 127.6, 126.4,

68.8, 23.3. LRMS (EI): m/z (%): 149 [M++1] (1), 148 [M+] (9), 131 (11), 130 (87), 129

(100), 128 (63), 127 (25), 115 (63), 105 (14), 91 (11), 77 (15), 51 (13). Ee

determination by chiral GC analysis, CP-Chirasil-DEX CB column, T = 110 °C, P = 10.0

psi, retention times: tr(R) = 62.4 min, tr(S) = 63.7 min (major enantiomer).

(S)-1-Phenylpropan-2-ol (2m):45 Compound 2m was obtained after

purification on flash silica gel chromatography from 100:0 till 86:14

(n-hexane/EtOAc) as a colorless oil (23% yield, 62% ee); []D25 = +4.5 (c 0.8, CHCl3) {

Lit.

[]D25 = +42.2 (c 1.0, CHCl3) for 99% ee}. 1H NMR (300 MHz, CDCl3) 7.35 – 7.26 (m,

2H), 7.26 – 7.16 (m, 3H), 4.08 – 3.90 (m, 1H), 2.75 (dd, J = 28.1, 6.4 Hz, 1H), 2.70 (dd, J

= 28.1, 6.4 Hz, 1H), 1.66 (br s, 1H), 1.23 (d, J = 6.2 Hz, 3H). 13C NMR (75 MHz, CDCl3)

138.5, 129.4, 128.5, 126.4, 68.8, 45.8, 22.7. LRMS (EI): m/z (%): 136 [M+] (1), 118 (23),

117 (35), 115 (15), 92 (100), 91 (94), 65 (19), 51 (9). Ee determination by chiral GC

analysis, CP-Chirasil-DEX CB column, T = 100 °C, P = 14.3 psi, retention times: tr(R) =

24.7 min, tr(S) = 26.0 min (major enantiomer).

(S)-1-Phenylpropan-1-ol (2o):40 Compound 2o was obtained after

purification on flash silica gel chromatography from 100:0 till 88:12 (n-

hexane/EtOAc) as a yellow oil (75% yield, 92% ee); []D25 = 39.8 (c

1.0, CHCl3) {Lit. []D

20 = 49.6 (c 0.5, CHCl3) for 98% ee}. 1H NMR (400 MHz, CDCl3)

7.38 – 7.26 (m, 5H), 4.60 (t, J = 6.6 Hz, 1H), 1.91 – 1.69 (m, 2H), 1.60 (br s, 1H), 0.92 (t,

44 Inagaki, T.; Ito, A.; Ito, J.; Nishiyama, H. Angew. Chem., Int. Ed. Engl. 2010, 49, 9384–9387. 45 Erdélyi, B.; Szabó, A.; Seres, G.; Birincsik, L.; Ivanics, J.; Szatzker, G.; Poppe,L. Tetrahedron: Asymmetry 2006, 17,

268–274.

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95

J = 7.4 Hz, 3H). 13C NMR (101 MHz, CDCl3) 144.6, 128.4, 127.5, 126.0, 76.0, 31.9,

10.1. LRMS (EI): m/z (%): 136 [M+] (4), 118 (73), 117 (100), 115 (45), 107 (38), 103

(10), 91 (34), 79 (28), 78 (10), 77 (25), 51 (14). Ee determination by chiral GC analysis,

HP-CHIRAL-20 column, T = 120 °C, P = 6.0 psi, retention times: tr(R) = 49.3 min, tr(S)

= 50.5 min (major enantiomer).

(S)-1-(p-Tolyl)propan-1-ol (2p):46 Compound 2p was obtained after

purification on flash silica gel chromatography from 100:0 till 88:12

(n-hexane/EtOAc) as a brown oil (66% yield, 90% ee); []D25 = 41.0

(c 1.0, CHCl3) {Lit. []D

20 = 36.1 (c 1.0, CHCl3) for 84% ee}. 1H NMR (400 MHz, CDCl3)

7.20 (d, J = 8.1 Hz, 2H), 7.13 (d, J = 8.2 Hz, 2H), 4.50 (t, J = 6.6 Hz, 1H), 2.33 (s, 3H),

2.08 (br s, 1H), 1.85 – 1.62 (m, 2H), 0.88 (t, J = 7.4 Hz, 3H). 13C NMR (101 MHz, CDCl3)

141.6, 137.0, 129.0, 125.9, 75.8, 31.7, 21.0, 10.1. LRMS (EI): m/z (%): 150 [M+] (3),

132 (71), 131 (19), 121 (35), 118 (10), 117 (100), 116 (16), 115 (47), 105 (11), 93 (15),

91 (40), 77 (16), 65 (13). Ee determination by chiral GC analysis, HP-CHIRAL-20

column, T = 120 °C, P = 14.3 psi, retention times: tr(R) = 30.5 min, tr(S) = 31.8 min

(major enantiomer).

(S)-1-(4-Chlorophenyl)propan-1-ol (2q):47 Compound 2q was

obtained after purification on flash silica gel chromatography from

100:0 till 88:12 (n-hexane/EtOAc) as a yellow oil (62% yield, 92%

ee); []D25 = 35.5 (c 1.0, CHCl3) {

Lit. []D25 = 38.4 (c 1.1, CHCl3) for 95% ee}.1H NMR

(400 MHz, CDCl3) 7.31 (d, J = 8.6 Hz, 2H), 7.26 (d, J = 8.6 Hz, 2H), 4.57 (t, J = 6.6 Hz,

1H), 2.05 (br s, 1H), 1.85 – 1.64 (m, 2H), 0.89 (t, J = 7.4 Hz, 3H). 13C NMR (101 MHz,

CDCl3) 143.0, 133.0, 128.5, 127.3, 75.2, 31.9, 9.9. LRMS (EI): m/z (%): 172 [M++2]

(2), 170 [M+] (5), 154 (19), 152 (58), 143 (17), 141 (55), 139 (14), 125 (13), 118 (10),

117 (100), 116 (24), 115 (75), 113 (12), 91 (13), 89 (12), 77 (33), 75 (13). Ee

determination by chiral GC analysis, HP-CHIRAL-20 column, T = 125 °C, P = 14.3 psi,

retention times: tr(R) = 57.3 min, tr(S) = 60.3 min (major enantiomer).

46 Touati, R. J. Soc. Chim. Tun. 2008, 10, 127–139. 47 Salvi, N.A. Tetrahedron: Asymmetry 2008, 19, 1992–1997.

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(S)-1-Phenylpentan-1-ol (2r):48 Compound 2r was obtained after

purification on flash silica gel chromatography from 100:0 till 91:9

(n-hexane/EtOAc) as colorless needles crystals (90% yield, 96%

ee); m.p. 35 – 37 °C, []D25 = 37.2 (c 1.0, CHCl3) {

Lit []D20 = 13.6 (c 0.5, CHCl3) for

80% ee}. 1H NMR (300 MHz, CDCl3) 7.43 – 7.21 (m, 5H), 4.64 (t, J = 6.6 Hz, 1H), 1.99

(br s, 1H), 1.87 – 1.61 (m, 2H), 1.48 – 1.16 (m, 4H), 0.88 (t, J = 7.0 Hz, 3H). 13C NMR

(75 MHz, CDCl3) 144.9, 128.4, 127.4, 125.9, 74.6, 38.8, 28.0, 22.6, 14.0. LRMS (EI):

m/z (%): 164 [M+] (8), 107 (100), 105 (5), 79 (40), 77 (19). Ee determination by chiral

GC analysis, Cyclosil- column, T = 150 °C, P = 14.3 psi, retention times: tr(S) = 13.5

min (major enantiomer), tr(R) = 14.4 min.

()-1-(4-Bromophenyl)pentan-1-ol (2s):49 Compound 2s was

obtained after purification on flash silica gel chromatography

from 100:0 till 92:8 (n-hexane/EtOAc) as a colorless crystals

(89% yield, 94% ee); m.p. 36.5 – 38.5 °C, []D25 = 25.8 (c 1.0, CHCl3).

1H NMR (300

MHz, CDCl3) 7.46 (m, 2H), 7.21 (m, 2H), 4.62 (t, J = 6.6 Hz, 1H), 1.92 (s, 1H), 1.72 (m,

2H), 1.28 (m, 4H), 0.88 (t, J = 7.0 Hz, 3H). 13C NMR (75 MHz, CDCl3) 143.8, 131.5,

127.6, 121.1, 74.0, 38.8, 27.8, 22.5, 14.0. IR (ATR): (cm-1): 3280, 2956, 2932, 2871,

2856, 1591, 1007, 824. LRMS (EI): m/z (%): 244 [M++2] (12), 242 [M+] (12), 188 (9),

187 (100), 186 (11), 185 (100), 159 (19), 157 (24), 78 (33), 77 (65), 51 (8). HRMS (EI):

m/z: 242.0306 calculated for C11H15BrO [M+], found 242.0299. Ee determination by

chiral HPLC analysis, Chiralcel OJ column, n-hexane/i-PrOH 99:1, flow rate = 0.5

mL/min, = 210 nm, retention times: tr(S) = 45.3 min (major enantiomer), tr(R) = 48.2

min.

48 Glynn, D.; Shannon, J.; Woodward, S. Chem. Eur. J. 2010, 16, 1053–1060. 49 Fukushima, T.; Takachi, K.; Tsuchihara, K. Macromolecules. 2008, 41, 6599–6601.

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(S)-1-(4-Chlorophenyl)pentan-1-ol (2t):50 Compound 2t was

obtained after purification on flash silica gel chromatography

from 100:0 till 91:9 (n-hexane/EtOAc) as a colorless needles

crystals (85% yield, 92% ee); m.p. 31.0 – 33.2 °C, []D25 = 37.6 (c 1.0, CHCl3) {

Lit. []D20

= 33.0 (c 1.0, CHCl3) for 96% ee}. 1H NMR (300 MHz, CDCl3) 7.31 (d, J = 8.6 Hz, 2H),

7.25 (d, J = 8.6 Hz, 2H), 4.67 – 4.57 (t, J = 6.8 Hz, 1H), 2.05 (br s, 1H), 1.84 – 1.57 (m,

2H), 1.43 – 1.21 (m, 4H), 0.88 (t, J = 7.0 Hz, 2H). 13C NMR (75 MHz, CDCl3) 143.3,

133.0, 128.5, 127.3, 73.9, 38.8, 27.8, 22.5, 13.9. LRMS (EI): m/z (%): 198 [M+] (4), 180

(24), 153 (17), 151 (53), 143 (32), 141 (100), 138 (22), 116 (35), 115 (52), 113 (15), 77

(41). Ee determination by chiral HPLC analysis, Chiralcel® OD-H column, n-hexane/i-

PrOH 99:1, flow rate = 0.5 mL/min, = 215 nm, retention times: tr(S) = 37.2 min

(major enantiomer), tr(R) = 40.7 min.

(S)-1-(4-Methoxyphenyl)pentan-1-ol (2u):48 Compound 2u

was obtained after purification on flash silica gel

chromatography from 100:0 till 87:13 (n-hexane/EtOAc) as

a yellow oil (89% yield, 94% ee); []D25 = 35.3 (c 1.0, CHCl3) {

Lit. []D20 = 24.2 (c 0.5,

CHCl3) for 82% ee}. 1H NMR (300 MHz, CDCl3) 7.25 (d, J = 8.7 Hz, 2H), 6.86 (d, J = 8.6

Hz, 2H), 4.58 (t, J = 6.7 Hz, 1H), 3.79 (s, 3H), 2.02 (br s, 1H), 1.88 – 1.58 (m, 2H), 1.43 –

1.18 (m, 4H), 0.87 (t, J = 7.0 Hz, 3H). 13C NMR (75 MHz, CDCl3) 158.9, 137.1, 127.1,

113.7, 74.2, 55.2, 38.6, 28.0, 22.6, 14.0. LRMS (EI): m/z (%): 194 [M+] (1), 176 (41),

147 (100), 137 (20), 115 (21), 103 (10), 91 (26), 77 (9). Ee determination by chiral

HPLC analysis, Chiralcel® OD-H column, n-hexane/i-PrOH 99:1, flow rate = 0.5

mL/min, = 210 nm, retention times: tr(R) = 50.6 min, tr(S) = 59.8 min (major

enantiomer).

50

Nakagawa, Y.; Muramatsu, Y.; Harada, T. J. Org. Chem. 2010, 34, 6535–6538.

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()-4-(1-Hydroxypentyl)phenyl methyl carbonate (2v):

Compound 2v was obtained after purification on basic

alumina chromatography from 100:0 till 77:23 (n-

hexane/EtOAc) as a dark yellow oil (90% yield, 96% ee); []D25 = 26.7 (c 1.2, CHCl3).

1H NMR (300 MHz, CDCl3) 7.36 (d, J = 8.5 Hz, 2H), 7.15 (d, J = 8.6 Hz, 2H), 4.67 (t, J =

6.6 Hz, 1H), 3.90 (s, 3H), 1.92 (br s, 1H), 1.74 (m, 2H), 1.32 (m, 4H), 0.89 (t, J = 7.0 Hz,

3H). 13C NMR (75 MHz, CDCl3) 154.3, 150.3, 142. 8, 127.0, 120.9, 74.0, 55.4, 38.8,

27.9, 22.5, 14.0. IR (ATR): (cm-1): 3395, 2956, 2930, 1763, 1440, 1255, 1214, 1063,

1015. LRMS (EI): m/z (%): 238 [M+] (5), 182 (18), 181 (100), 137 (6), 135 (5), 122 (5),

109 (37), 94 (26), 77 (19), 66 (7), 59 (7). HRMS (EI): m/z: 238.1205 calculated for

C13H18O4 [M+], found 238.1210. Ee determination by chiral HPLC analysis, Chiralpak®

AD-H column, n-hexane/i-PrOH 97:3, flow rate = 0.5 mL/min, = 220 nm, retention

times: tr(S) = 23.5 min (major enantiomer), tr(R) = 25.7 min.

(S)-Naphthalen-2-yl(phenyl)methanol (2x):51 Compound 2x

was obtained after purification on flash silica gel

chromatography from 100:0 till 90:10 (n-hexane/EtOAc) as a

white powder (96% yield, 17% ee); m.p. 81 – 82 °C, []D25 = +2.3 (c 1.0, CHCl3) {Lit.

[]D20 = +11.2 (c 0.8, CHCl3) for 95% ee}. 1H NMR (300 MHz, CDCl3) 7.83 – 7.61 (m,

4H), 7.47 – 7.36 (m, 2H), 7.36 – 7.15 (m, 6H), 5.81 (s, 1H), 2.87 (br s, 1H). 13C NMR (75

MHz, CDCl3) 143.5, 141.0, 133.1, 132.8, 128.4, 128.2, 128.0, 127.6, 127.5, 126.6,

126.1, 125.9, 125.0, 124.7, 76.2. LRMS (EI): m/z (%): 235 [M++1] (17), 234 [M+] (100),

233 (12), 217 (12), 215 (28), 202 (16), 155 (41), 129 (94), 128 (82), 127 (40), 105 (90),

77 (32). Ee determination by chiral HPLC analysis, Chiralcel® OD-H column, n-

hexane/i-PrOH 90:10, flow rate = 1.0 mL/min, = 220 nm, retention times: tr(R) =

15.6 min (major enantiomer), tr(S) = 18.0 min.

51 Tjosaas, F. Arkivoc 2008, 6, 81–90.

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(R)-Cyclohexyl(phenyl)methanol (2y):52 Compound 2y was obtained

after purification on flash silica gel chromatography from 100:0 till

90:10 (n-hexane/EtOAc) as a yellow oil (92% yield, 39% ee); []D25 =

+22.0 (c 1.0, CHCl3) {Lit. []D

20 = +39.5 (c 0.2, CHCl3) for 94% ee}. 1H NMR (300 MHz,

CDCl3) 7.30 (m, 5H), 4.35 (d, J = 7.2 Hz, 1H), 1.98 (m, 1H), 1.85 (br s, 1H), 1.67 (m,

4H), 1.36 (m, 1H), 1.08 (m, 5H). 13C NMR (75 MHz, CDCl3) 143.6, 128.2, 127.4, 126.6,

79.4, 44.9, 29.3, 28.8, 26.4, 26.1, 26.0. LRMS (EI): m/z (%): 190 [M+] (8), 108 (10), 107

(100), 79 (29), 77 (14), 55 (7). Ee determination by chiral HPLC analysis, Chiralpak®

AS-H column, n-hexane/i-PrOH 99:1, flow rate = 1.0 mL/min, = 210 nm, retention

times: tr(R) = 7.5 min (major enantiomer), tr(S) = 8.3 min.

52 Yamamoto, Y.; Shirai, T.; Watanabe, M.; Kurihara, K.; Miyaura, N. Molecules 2011, 16, 50205034.

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CHAPTER III

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1. Introduction

An organomagnesium reagent is an organometallic compound that contains a C-Mg

bond. Under this description, organomagnesium can be classified into two different

categories: complete compounds, such as dialkyl or diarylmagnesium with general

formula R2Mg; and mixed compounds, such as alkyl or arylmagnesium halides with

general formula RMgX (where X = Cl, Br or I), also known as Grignard reagents. An

important characteristic of Grignard reagents is that, in solution, they are in

equilibrium with the corresponding R2Mg and MgX2 (Scheme 36, Schlenck

equilibrium).53 The position of the equilibrium is greatly influenced by the solvent.

For example, in diethyl ether or THF, alkyl- or arylmagnesium halide species are

favored. The addition of dioxane to such solutions, however, leads to selective

precipitation of dihalide MgX2, driving the equilibrium completely to the right side of

the equation (Le Châtelier´s principle).54

Scheme 36. Schlenck equilibrium

The preparation of a Grignard reagent is one of the most famous and important

reactions in organic chemistry. It was discovered in 1900 by Françoise Auguste Victor

Grignard who was awarded, in 1912, with the Nobel Prize for this work.55 The

reaction consists on the transformation of an alkyl or aryl halide (electrophilic species

by nature), into the corresponding alkyl or arylmagnesium halide, respectively

(nucleophilic species) by using magnesium turnings in an appropriate solvent. The

overall reaction, which involves an inversion in the polarity at the ipso carbon, occurs

via a single electron transfer mechanism.56

53 Schlenk, W.; Schlenk Jr., W. Chem. Ber. 1929, 62, 920–924. 54 Andersen, R. A.; Wilkinson, G. Inorg. Synth. 1979, 19, 262–265. 55 Grignard, V. Compt. Rend. 1900, 130, 1322–1325. 56 Richey, H. G. Grignard Reagents: New Developments, Wiley: New York, 1999.

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Grignard compounds are common reagents that can be found in any organic

laboratory. A wide variety of Grignard reagents are commercially available in good

price, depending on their complexity.56

Grignard reagents have been extensively employed in C-C bond formation reactions,

normally with carbonyl substrates, but their use in asymmetric catalysis has been

limited, due to the high reactivity. Only in the last decade, some examples have been

reported on the use of Grignard reagents in enantioselective catalytic processes, such

as: conjugate addition to ,-unsaturated substrates,57 allylic substitution,58 cross-

coupling reactions59 and very recently, addition to carbonyl compounds, which will

be described in sections 1.2 and 1.3.

This thesis focuses in the development of novel catalytic methodologies for the

enantioselective addition of Grignard reagents to carbonyl compounds. At the

beginning of our investigation, most of the methodologies described in the literature,

involved the use of stoichiometric or superstoichiometric amounts of a chiral ligand,

and very low temperatures, and only a few methodologies were known for the

catalytic version of this reaction, using mainly aldehydes as electrophiles (see section

1.2 for further details).

In the following sections, the most relevant examples reported in the literature on

both stoichiometric and catalytic enantioselective additions of Grignard reagents to

aldehydes and ketones will be summarized.

57 a) Kehrli, S.; Martin, D.; Rix, D.; Mauduit, M.; Alexakis, A. Chem. Eur. J. 2010, 16, 9890–9904; b) Harutyunyan, S. R.;

den Hartog, T.; Geurts, K.; Minnaard, A. J.; Feringa, B. L. Chem. Rev. 2008, 108, 2824–2852; c) Martin, D.; Kehrli, S.;

D'Augustin, M.; Clavier, H.; Mauduit, M.; Alexakis, A. J. Am. Chem. Soc. 2006, 128, 8416–8417; d) Lopez, F.;

Harutyunyan, S. R.; Meetsma, A.; Minnaard, A. J.; Feringa, B. L. Angew. Chem., Int. Ed. Engl. 2005, 44, 2752–2756; e)

Lopez, F.; Harutyunyan, S. R.; Minnaard, A. J.; Feringa, B. L. J. Am. Chem. Soc. 2004, 126, 12784–12785. 58 a) Hornillos, V.; van Zijl, A. W.; Feringa, B.L. Chem. Comm. 2012, 48, 3712–3714; b) Lopez, F.; Van Zijl, A. W.;

Minnaard, A. J.; Feringa, B.L. Chem. Comm. 2006, 4, 409–411; c) Fañanás-Mastral, M.; Feringa, B.L. J. Am. Chem. Soc.

2010, 132, 13152–13153; d) Alexakis, A.; Malan, C.; Lea, L.; Benhaim, C.; Fournioux, X. Synlett 2001, SI, 927–930. 59 Swift, E. C.; Jarvo, E. R. Tetrahedron 2013, 69, 5799–5817.

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1.1. Stoichiometric and superstoichiometric enantioselective addition

of organomagnesium reagents to carbonyl compounds

The first example on the asymmetric alkylation of aldehydes using organomagnesium

reagents was reported by Wright in 1964, who achieved the addition of Me2Mg to

benzaldehyde using stoichiometric amounts of the chiral promoter XXXV (1 eq.).60

The corresponding alcohol was obtained in 67% yield and 20% ee (Scheme 37).

Similar results were described by Bloomberg and Coops, which confirmed that

bidentate chiral ethers were better ligands than monodentate chiral ethers in the 1,2

addition of Grignard reagents to benzaldehyde.61

Scheme 37. First enantioselective addition of Me2Mg to benzaldehyde promoted by XXXV.

A few years later, in 1968, Nozaki checked the ability of (–)-sparteine (1 eq., VIII) as a

chiral ligand in the asymmetric addition of EtMgBr to benzaldehyde in toluene at –70

°C.62 The alcohol was obtained with poor enantioselectivity (22%) and yield (15%)

using stoichiometric amounts of the chiral alkaloid VIII (Scheme 38).

Scheme 38. Asymmetric addition of EtMgBr to benzaldehyde promoted by (–)-sparteine (VIII).

60 French, W.; Wright, G. F. Can. J. Chem. 1964, 42, 2474–2479. 61 a) Vink, P.; Bloomberg, C.; Vreugdenhil, A. D.; Bickelhaupt, F. Tetrahedron Lett. 1966, 7, 6419–6423; b) Bloombler,

C.; Coops, J. Recl. Trav. Chim. Pays-Bas 1964, 83, 1083–1095. 62 a) Toraya, T.; Aratini, T.; Nozaki, H. Tetrahedron Lett. 1968, 9, 4097–4098; b) Toraya, T.; Aratini, T.; Nozaki, H.;

Noyori, R. Tetrahedron 1971, 27, 905–913.

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Nature is an excellent source of chiral molecules that can be used as ligands in

asymmetric synthesis and catalysis. In this context, Battioni and Chodkiewicz, for

example, employed chiral amino alcohols derived from ephedrine, N-

methylephedrine and (+)-cinchona for the ethylation of aldehydes with Et2Mg at

room temperature, achieving enantioselectivities up to 20%.63

Chiral solvents have been used in the asymmetric addition of Grignard reagents to

aldehydes. Ifflandis and Davis employed the (R)-2-methyltetrahydrofurane (XXXVI) as

a source of chirality for the arylation of aldehydes.64 This methodology proved not

effective enough; the best result was obtained for the addition of PhMgBr to

pivalaldehyde, which gave the corresponding alcohol in only 11% ee and 57% yield

(Scheme 39).

Scheme 39. Asymmetric addition of PhMgBr promoted by a chiral solvent XXXVI.

In 1978, Mukaiyama´s group achieved moderate to excellent enantioselectivities in

the addition of different R2Mg to benzaldehyde in toluene at –110 °C, with

superstoichiometric amounts of the lithium alkoxide X as chiral ligand.65 The authors

observed that non-coordinating solvents, such as toluene, allowed better

enantioselectivities in the reaction, in contrast with the more commonly used,

ethereal solvents (Scheme 40).

63 Battioni, J. P.; Chodkiewicz, W. Bull. Chim. Soc. Fr. 1972, 5, 2068–2069. 64 Iffland, D.C.; Davis, J. E. J. Org. Chem. 1977, 42, 4150–4151. 65 a) Mukaiyama, T.; Soai, K.; Sato, T.; Shimizu, H.; Suzuki, K. J. Am. Chem. Soc. 1979, 101, 1455–1460; b) Soai, K.;

Mukaiyama, T. Chem. Lett. 1978, 5, 491–492; c) Sato, T.; Soai, K.; Suzuki, K.; Mukaiyama, T. Chem. Lett. 1978, 6, 601–

604.

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Esquema 40. Asymmetric addition of R2Mg to benzaldehyde promoted by lithium alkoxide X.

In 1987, Tomioka synthesized a new type of chiral ligands, XXXVII and XXXVIII (4 eq.),

derived from 3,4-diarylpirrolidine, which were tested in the alkylation and arylation

of aromatic aldehydes using Grignard reagents as nucleophiles.66 The authors

employed 3 eq. of the chiral ligands and phenoxymetal halides derived from

magnesium or aluminum as additives to improve the enantioseletivities in some

particular cases. In general, moderate to good ee’s were obtained (Scheme 41).

Scheme 41. Asymmetric addition of Grignard reagents to aldehydes promoted by diamines XXXVII and

XXXVIII.

At the same time, Noyori achieved the first effective addition of an

organomagnesium reagent to an aldehyde with high levels of enantioselectivity

employing 1 eq. of a chiral Li-Mg bimetallic (S)-BINOL complex (XXXIX) stabilized with

coordinating solvents.67 The chiral alcohols from the addition of R2Mg to aldehydes,

performed in a THF/DME (1:1) mixture at –100 °C, were obtained in good yields and

ee’s (Scheme 42).

66 a) Nakajima, M.; Tomioka, K.; Koga, K. Tetrahedron 1993, 49, 9751–9758; b) Tomioka, K.; Nakajima, M.; Koga, K.

Chem. Lett. 1987, 1, 65–68; c) Tomioka, K.; Nakajima, M.; Koga, K. Tetrahedron Lett. 1987, 28, 1291–1292. 67 Noyori, R.; Suga, S.; Kawai, K.; Okada, S.; Kitamura, M. Pure Appl. Chem. 1988, 60, 1597–1606.

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Scheme 42. Asymmetric addition of R2Mg to aldehyde promoted by Li-Mg bimetallic complex XXXIX.

In 1992, Seebach reported the use of stoichiometric amounts of the chiral TADDOL

derivatives XL and XLI (1 eq.) developed in his research group, for the successful

enantioselective addition of RMgBr to ketones.68 The reaction was carried out in THF,

which was crucial, at –100 °C, and excellent enantioselectivities were achieved for

linear aliphatic Grignard reagents and aryl methyl ketones as electrophiles (Scheme

43). Also this group performed the first substoichiometric attempt in the addition of

n-BuMgBr to acetophenone using only 25 mol% of chiral ligand XL, but the results

were not completely satisfactory (84% ee and 55% yield being the best results

obtained in THF at –100 °C).

Scheme 43. Asymmetric addition of RMgBr to ketones promoted by TADDOL ligands (XL and XLI).

Markó reported the use of stoichiometric amounts of the chiral diamine XLII for the

addition of primary and secondary Grignard reagents to an aliphatic aldehyde,

cyclohexanecarboxaldehyde.69 Although the levels of enantioselectivity for this

process were not impressive, the reaction deserves to be highlighted because: i) it

was carried out at 20 °C, a temperature not very common for this type of asymmetric

68 a) Pellisier, H. Tetrahedron 2008, 64, 10279–10317; b) Weber, B.; Seebach, D. Tetrahedron 1994, 50, 6117–6128; c)

Weber, B.; Seebach, D. Angew. Chem., Int. Ed. Engl. 1992, 31, 84–86. 69 Markó, I. E.; Chesney, A.; Hollinshead, D.M. Tetrahedron: Asymmetry 1994, 5, 569–572.

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transformations and ii) it involved the use of aliphatic substrates, which are, in

general more challenging (Scheme 44). A slightly improvement in the

enantioselectivity of the product was detected when increasing the size of the

nucleophile, but in general poor selectivities were achieved (up to 34% ee).

Scheme 44. Asymmetric addition of RMgBr to CyCHO promoted by diamine ligand XLII.

In 2002, Yong continued the studies on chiral diamine ligands for the asymmetric

addition of dialkylmagnesium compounds to aromatic aldehydes.70 Different linear

aliphatic nucleophiles were screened in the addition to benzaldehyde using 2.4 eq. of

chiral ligand XLIII in Et2O as solvent at –78 °C. The enantiomeric excess obtained with

this methodology varied from moderate to good (up to 82%, Scheme 45).

Scheme 45. Asymmetric addition of R2Mg to aromatic aldehydes promoted by diamine ligand XLIII.

It can be concluded from all these examples, that the enantioselective addition of

RMgX to carbonyls represents an important challenge in organic synthesis since the

origins. The limited amount of ligands that can be employed for this type of

transformation and the extreme reaction conditions (temperatures below –100 °C

and super- or stoichiometric amounts of chiral ligands) that are required to get good

results, are indicative that many improvements can be done in the area.

70 Yong, K. H.; Taylor, N. J.; Chong, J. M. Org. Lett. 2002, 4, 3553–3556.

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1.2. Catalytic enantioselective addition of Grignard reagents to

aldehydes

In the last years, various enantioselective catalyzed additions of Grignard reagents to

aldehydes have been developed by a few research groups, all based on the use of

catalytic amounts of BINOL derivatives as chiral ligands and excess of Ti(Oi-Pr)4.

Harada´s group was the first to achieve the enantioselective alkylation of aldehydes

with Grignard reagents with high levels of enantioselectivity using catalytic amounts

of a chiral 3-modified BINOL ligand XLIV (2 mol%) and DCM as solvent at 0 °C.71 The

key step of the methodology consists on the slow addition (over 2 h) of the Grignard

reagent and Ti(Oi-Pr)4 (1.4 eq.) over a solution containing the aldehyde, the ligand

and Ti(Oi-Pr)4 (4.4 eq.). No tedious procedures for salts exclusion are needed in this

process. The addition of linear nucleophiles to different aromatic aldehydes takes

place with excellent yields and ee (Scheme 46), except for the addition of MeMgBr,

which provides low levels of enantioselectivity (up to 28%).

Scheme 46. Asymmetric alkylation and arylation of aldehydes with Grignard reagents catalyzed by XXXII

and XLIV.

71 Muramatsu, Y.; Harada, T. Angew. Chem. Int. Ed. 2008, 47, 1088–1090.

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An extension of the previous methodology includes the arylation of aldehydes, which

was carried out under very similar reaction conditions using the 3-substituted

partially hydrogenated binaftol XXXII.72b This methodology allows the addition of

previously prepared aromatic Grignard reagents, but also Grignard reagents that are

generated in situ by reaction between the corresponding aryl bromide and Knochel´s

turbo Grignard (i-PrMgCl·LiCl).72a In both cases, comparable results and very high

enantioselectivities and yields were obtained for the synthesis of chiral

diarylmethanols from the corresponding aromatic aldehydes (Scheme 46).

Scheme 47. Use of BDMAEE as chelating agent to remove magnesium salts from solution.

Da´s group focused the attention in the use of external additives to improve the

enantioselectivity in the alkylation and arylation of aldehydes with Grignard reagents

using (S)-BINOL (IV) or (S)-H8-BINOL (XXXIV), as chiral ligands.73 bis[2-(N,N´-

dimethylamino)ethyl]ether (BDMAEE) was used as chelating or “trapping” agent for

the magnesium salts, such as MgBr2 or Mg(Oi-Pr)Br, generated in either the Schlenck

equilibrium and/or the transmetallation process with titanium tetraisopropoxide. The

72 a) Itakura, D.; Harada, T. Synlett 2011, 2875−2879; b) Muramatsu, Y.; Harada, T. Chem. Eur. J. 2008, 14, 10560–

10563. 73 a) Fan, X-Y.; Yang, Y-X.; Zhuo, F-F.; Yu, S-L.; Li, X.; Guo, Q-P.; Du, Z-X.; Da C-S. Chem. Eur. J. 2010, 16, 7988–7991; b)

Liu, Y.; Da, C.-S.; Liu, S.-L.; Yin, X.-Y.; J.-R. Wang.; X.-Y. Fan.; Li, J.-R.; Wang, R. J. Org. Chem. 2010, 75, 6869–6878; c)

Da, C.-S.; Wang, J.-R.; Yin, X.-G.; Fan, X.-Y.; Liu, Y.; Yu, S.-L. Org. Lett. 2009, 11, 5578–5581.

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112

chelation of the magnesium salts with this additive diminishes its Lewis acid

character, therefore lowering the chances of undesired non-stereoselective addition

processes (Scheme 47).74

The use of BDMAEE as additive (1:1 with respect to the RMgBr) allowed a

considerable reduction in the amount of Ti(Oi-Pr)4 necessary in the reaction (down to

0.9-1.7 eq.), compared to Harada´s methodology. In this case, the best

enantioselectivities were reached with aryl (77-97% ee) and bulky aliphatic (87-98%

ee) Grignard reagents. However, when small nucleophiles were employed the yield

and ee of the reaction dropped. The addition of MeMgBr to benzaldehyde, for

example, only provided 33% yield and 35% ee.

In 2011, after the publication of our results related to the asymmetric addition of

Grignard reagents to aldehydes (which will be discussed later in section 2 of this

chapter), Xu Li-Wen´s group applied the same methodology for the methylation and

arylation of aromatic aldehydes with Grignard reagents using the binaftol derivative

XLV as a chiral ligand.75 Very good enantioselectivities and excellent yields were

obtained for the addition of MeMgBr at –40 °C in toluene. On the contrary, the

arylation of aldehydes was carried out at –20 °C in DCM and only gave the

corresponding alcohols with moderate to good ee (Scheme 48).

Scheme 48. Asymmetric addition of MeMgBr and ArMgBr to aldehydes with ligand XLV.

74 Balsells, J.; Davis, T. J.; Carroll, P.; Walsh, P. J. J. Am. Chem. Soc. 2002, 124, 10336–10348. 75 Zheng, L-S.; Jiang, K-Z.; Deng, Y.; Bai, X-F.; Gao, G.; Gu, F-L.; Xu, L-W. Eur. J. Org. Chem. 2013, 4, 748–755.

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5.1.3 Catalytic enantioselective addition of Grignard reagents to

ketones

Ketones are interesting electrophiles for the synthesis of valuable chiral tertiary

alcohols through the enantioselective addition of organometallic reagents. The lower

reactivity of the ketone and the higher steric hindrance around the carbonyl center

hampers their use as successful substrates in 1,2-addition reactions with

organometallic reagents. The catalytic asymmetric addition of Grignard reagents to

ketones is in early development and only one research group has performed this

challenging addition.76-79

Harutyunyan´s group recently developed the first efficient catalytic enantioselective

addition of Grignard reagents to ketones. The catalytic system is based on the copper

complexes formed between a chiral Josiphos-type diphosphine ligand XLVI or XLVII,76

and CuBr2.Me2S. The slow addition (over 2 to 3 h) of the nucleophile over a solution

of the corresponding ketone and the preformed copper complex (5 mol%), in TBME

at low temperature, is essential to achieve good yields and enantiomeric excess. The

authors propose a -interaction between the carbonyl and the chiral cuprate as the

responsible for the high levels of selectivity. -Branched aliphatic Grignard reagents

provide the best results for the alkylation of different ketones, affording the desired

tertiary alcohols with excellent enantioselectivities and yields in the case of aryl

methyl ketones77 and moderate to good for aryl heteroaryl ketones78 (Scheme 49).

Linear aliphatic Grignard reagents provide lower enantioselectivities (22-72%)

compared with -branched nucleophiles (76-98%).

76 Caprioli, F.; Lutz, M.; Meetsma, A.; Minaard, A. J.; Harutyunyan, S. R. Synlett 2013, 24, 2419–2422. 77 Madduri, A. V. R.; Harutyunyan, S. R.; Minaard, A. J. Angew. Chem. Int. Ed. 2012, 51, 3164–3167. 78 Ortiz, P.; del Hoyo, A. M.; Harutyunyan, S. R. Eur. J. Org. Chem. 2015, 72–76.

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Scheme 49. Asymmetric alkylation of ketones with -branched aliphatic Grignard reagents.

This methodology has also been successfully applied to the addition of Grignard

reagents to -substituted-,-unsaturated ketones.79 Surprisingly, the expected 1,4-

addition reaction did not take place (process that, till date, was known as favored for

all copper catalyzed nucleophilic additions with organometallic reagents) and only

the chiral tertiary alcohol (coming from the 1,2-addition of the Grignard reagent to

the carbonyl) was obtained when ligand XLVI was used at –78 °C or –60 °C in TBME. It

is believed that the substituent (Me or Br) at the alpha position of the ,-

unsaturated system distorts the possible interaction between the copper complex

and the double bond, hampering the 1,4-addition process. The catalytic system is

again more effective when -branched Grignard reagents, instead linear, are used as

nucleophiles and when a bulky substituent is at the alpha position in the electrophile;

i. e. -bromo substituted ,-unsaturated ketones provide better results than their

-methyl substituted analogs (Scheme 50).

79 a) Madduri, A. V. R.; Harutyunyan, S. R.; Minaard, A. J. Chem. Comm. 2012, 48, 1478–1480; b) Madduri, A. V. R.;

Harutyunyan, S. R.; Minaard, A. J. Org. Biomol. Chem. 2012, 10, 2878–2884.

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Scheme 50. Asymmetric alkylation of ,-unsaturated -substituted ketones with Grignard reagents.

A broad range of possibilities have been opened in the research field of 1,2

asymmetric addition of Grignard reagents to carbonyls with the design of new ligands

and catalytic systems and/or methodologies. The use of new types of nucleophiles

and ketones to prepare more complex chiral tertiary alcohols is a challenge that

could be achieved in a near future.

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2. Results and discussion

2.1. Optimization of the catalytic enantioselective addition of Grignard

reagents to aromatic aldehydes

The addition of MeMgBr to benzaldehyde (1a) or o-methylbenzaldehyde (1b) were

taken as a model reaction for this study. The optimization process began with a

solvent screening carried out at 0 °C with 10 mol% of the ligand (Sa,R)-L1. DCM, THF,

or TBME were evaluated in the reaction (Table 8, entries 1-3), but very low

enantioselectivities were achieved. Promising results were obtained with diethyl

ether and toluene which gave 20 and 35% ee respectively (Table 8, entries 4-5).

The effect of the temperature was then analysed to improve the previous results.

Lowering the temperature to 20 °C produced a drastic decrease in both conversion

and selectivity when the reaction was carried out in Et2O (Table 8, entry 6), probably

due to solubility problems. Fortunately, the use of toluene at 40 °C provided an

increase in the enantioselectivity up to 51% (Table 8, entry 5 vs 7), preserving the full

conversion. Lower temperatures (60 °C) led to a significant decrease in the rate of

the reaction (Table 8, entry 8), although the ee was found to be slightly higher (54%).

Table 8. Influence of solvent and temperature[a]

Entry T (°C) Solvent Conv.

[b] (%) ee

[b] (%)

1 0 DCM 99 16 2 0 THF 70 8 3 0 TBME 99 0 4 0 Et2O 98 35 5 0 Toluene 99 20 6 20 Et2O 20 5

7 40 Toluene 99 51

8 60 Toluene 60 54 [a] Conditions: 1b (0.1 mmol, 0.07 M), MeMgBr (3 M in Et2O, 2.5 eq.), (Sa,R)-L1 (10 mol%), Ti(Oi-Pr)4 (10 eq.), solvent (1.5 mL), T (°C), 4 h. [b] Determined by chiral GC analysis.

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The titanium source was studied as a possible effective parameter to improve the

enantioselectivity in the reaction. Therefore, six titanium (IV) reagents with different

alkyl substituents were evaluated under the previous optimized conditions using

benzaldehyde (1a) as electrophile. Surprisingly, when linear substituents at the

alkoxy group attached to titanium were employed, the addition product was

detected with very low conversion and racemic (Table 9, entries 1-3). With the most

common and inexpensive titanium source, Ti(Oi-Pr)4 the best result was achieved,

90% conv. and 80% ee (Table 9, entry 4). Also, chlorotriisopropoxytitanium (IV),

which has different electronic properties than Ti(Oi-Pr)4, was tested, but gave the

corresponding alcohol 2a in a racemic form (Table 9, entry 5). It seems that titanium

sources with bulky alkoxy groups are crucial for this process, so the bulkiest

commercially available Ti(Ot-Bu)4 was also tested; unfortunately, only 2% of

conversion was achieved (Table 9, entry 6).

Table 9. Titanium (IV) source screening[a]

Entry Ti source Conv.

[b] (%) ee

[b] (%)

1 Ti(OMe)4 10 0 2 Ti(OEt)4 30 0 3 Ti(On-Pr)4 30 0 4 Ti(OiPr)4 90 80 5 TiCl(Oi-Pr)3 99 0 6 Ti(Ot-Bu)4 2 34

[a] Conditions: 1a (0.1 mmol, 0.07 M), MeMgBr (3 M in Et2O, 2.5 eq.), Ti source (10

eq.), (Sa,R)-L1 (10 mol%), toluene (1.5 mL), 40 °C, 4 h. [b] Determined by chiral GC analysis.

With these preliminary conditions, a small library of chiral diols (Figure 3) was

screened as ligands for the addition of MeMgBr to 1a (Table 10). The corresponding

diastereoisomer of (Sa,R)-L1, with same axial chirality but oppositte configuration at

the sp3 center provided no enantioselectivity in the alkylation reaction with

benzaldehyde (Table 10, entry 2). Methoxy substituted chiral diols gave lower

enantioselectivities (Table 10, entries 3-5) than the simplest ligand (Sa,R)-L1 (Table

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119

10, entry 1). Moreover, lower conversion was observed in the case of the meta-

methoxy substituted (Sa,R)-L4. Probably, too bulky ligands did not give good

enantioselectivities due to steric hindrance cause a distortion in the titanium

complex. The para-fluoro substituted ligand (Sa,R)-L6 proved equally effective as

(Sa,R)-L1 (Table 3, entry 1 vs 6), but (Sa,R)-L1 was chosen for the rest of the study

because it is simpler and easier to synthetize.

Figure 3. Chiral diol ligands screened in this study

Table 10. Ligand optimization[a]

Entry L* Conv.

[b] (%) ee

[b] (%)

1 (Sa,R)-L1 90 80 2 (Sa,S)-L1 71 0 3 (Sa,S)-L3 86 48 4 (Sa,R)-L4 25 74 5 (Sa,R)-L5 89 70 6 (Sa,R)-L6 89 83

[a] Conditions: 1a (0.1 mmol, 0.07 M), MeMgBr (3 M in Et2O, 2.5 eq.), Ti(Oi-Pr)4 (x

eq.), (Sa,R)-L1 (10 mol%), toluene (1.5 mL), 40 °C, 4 h. [b] Determined by chiral GC analysis.

In the next step of the optimization process, the amount of titanium

tetraisopropoxide respect to the nucleophile was adjusted carefully because it was

found crucial to get high enantioselectivity. For this study, the bulky ortho-methyl

substituted benzaldehyde (1b) was used as model substrate (Table 11). We soon

noticed that a large excess of the Lewis acid Ti(Oi-Pr)4 was necessary to reach good

results. For substoichiometric amounts of Ti(Oi-Pr)4 (respect to MeMgBr) or absence

of this reagent, the desired product 2b was obtained racemic (Table 11, entries 1-3).

As the amount of Ti(Oi-Pr)4 was increased, keeping the amount of nucleophile at 2.5

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Chapter III – Results and discussion

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eq. (Table 11, entries 4-7), the results improved. A thoroughly screening of different

titanium-magnesium ratios allowed us to establish the optimal ratio Ti(Oi-

Pr)4:MeMgBr as 4:1.

In order to improve the previous results, the slow addition of MeMgBr (2.5 eq.) and

the slow addition of a toluene solution containing MeMgBr (2.5 eq.) and Ti(Oi-Pr)4

(2.5 eq.) over a solution of 1a, Ti(Oi-Pr)4 (7.5 eq.) and ligand (Sa,R)-L1 (10 mol%) at

40 °C were also attempted. The slow addition strategy did not improve the previous

results and in both cases, we obtained 90% conv. and only 44% ee.

Table 11. Optimization Ti(Oi-Pr)4/MeLi ratio[a]

Entry Ti(Oi-Pr)4 (eq.) MeMgBr (eq.) Ti:Mg ratio Conv.

[b] (%) ee

[b] (%)

1 0 2.5 - 90 0 2 2.5 2.5 - 99 0 3 2.5 2.5 1:1 99 0 4 5 2.5 2:1 89 30 5 7.5 2.5 3:1 90 44 6 10 2.5 4:1 99 51 7 12.5 2.5 5:1 90 40

[a] Conditions: 1b (0.1 mmol, 0.07 M), MeMgBr (3 M in Et2O, 2.5 eq.), Ti(Oi-Pr)4 (x eq.), (Sa,R)-L1 (10 mol%),

toluene (1.5 mL), 40 °C, 4 h. [b] Determined by chiral GC analysis.

In a last effort to improve the methodology, the influence of the catalyst loading and

amount of MeMgBr in the reaction with benzaldehyde (1a) was then examined

(Table 12). Higher ligand loadings improved both conversion and enantioselectivity of

the reaction (Table 12, entries 1-3) up to 79% conv. and 85% ee when using 20 mol%

of (Sa,R)-L1 (Table 12, entry 3). In order to reach full conversion, the equivalents of

MeMgBr were increased up to 3.75. Under these last adjustments, enantioselectivity

slightly increased up to 88% (Table 12, entry 4).

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Table 12. Effect of catalyst loading[a]

Entry (Sa,R)-L1 (mol%) Ti(Oi-Pr)4 (eq.) MeMgBr (eq.) Conv.

[b] (%) ee

[b] (%)

1 5 1.25 5 60 78 2 10 1.25 5 73 83 3 20 1.25 5 79 85 4 20 3.75 15 98 88

[a] Conditions: 1a (0.1 mmol, 0.07 M), MeMgBr (3 M in Et2O, x eq.), Ti(Oi-Pr)4 (y eq.), (Sa,R)-L1 (z mol%), toluene (1.5

mL), 40 °C, 4 h. [b] Determined by chiral GC analysis.

2.2. Scope of the reaction

With the optimized conditions in hand (Table 12, entry 4), the addition of MeMgBr to

different aldehydes was screened (Table 13). The highly desirable addition of the low

reactive MeMgBr was achieved with high yields and enantioselectivities from 80% to

90% for a wide variety of aromatic aldehydes with electron-poor and electron-rich

substituents at the meta and para position (Table 13, entries 4-10). The alkylation of

o-methylbenzaldehyde (1b) proceeded with lower enantioselectivity 53% (Table 13,

entry 2), probably due to steric hindrance close to the reactive site. The use of 2-

thiophenecarboxaldehyde (1j) or cinnamaldehyde (1l) prompted a decrease in the

enantioselectivity values (Table 13, entries 11-12). Moreover, volatile product 2j was

obtained in low yield (53%) in spite of 98% conversion, due to problems during the

isolation. The reaction with phenylacetaldehyde (1m) proceeded with moderated

enantioselectivity (68%) and poor yield (43%) at 40 °C (Table 13 entry 13);

gratifyingly, yield could be improved up to 70% increasing the temperature to 20 °C

without observing any loss of enantioselectivity (Table 13, entry 14).

Full conversion was achieved in almost all the cases and no by-products were formed

under the optimized conditions. Only phenylacetaldehyde (1m) did not react

completely (probably due to the high acidity of the benzylic hydrogen atoms) (Table

13, entries 13-14). Moreover, the ligand (Sa,R)-L1 could also be recovered and reused

without observing any loss of catalytic activity in product 2a (Table 13, entry 2).

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122

Table 13. Asymmetric addition of MeMgBr to aldehydes[a]

Entry Aldehyde Product Yield

[b] (%) ee

[c] (%)

1 2

92 90

[d]

88 (S) 87 (S)

3

85 53 (S)

4

99 88 (S)

5

98 87 (S)

6

95 80 (S)

7

88 88 (S)

8

98 84 (S)

9

89 85 (S)

10

92 90 (S)

11

53 (98)[e]

58 (S)

12

90 68

13

43 68

14 70[f]

70

[a] Conditions: 1 (0.3 mmol, 0.12 M), MeMgBr (3 M in Et2O, 3.8 eq.), (Sa,R)-L1 (20 mol%),

Ti(Oi-Pr)4 (15 eq.), toluene (2.5 mL), 40 °C, 4 h. [b] Isolated yield after flash silica gel

chromatography. [c] Determined by chiral GC analysis. Absolute configuration of chiral

alcohols was determined by correlation of optical rotation with known compounds. [d]

Result after recovery of (Sa,R)-L1 and reused in the addition of MeMgBr to 1a. [e] Volatile

product, conversion based on GC data in brackets. [f] Reaction performed at 40 °C.

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Chapter III – Results and discussion

123

Encouraged by the excellent results in the addition of the challenging MeMgBr

reagent, the attention was turned to the use of other Grignard reagents (Table 14).

The addition of linear Grignard reagents like EtMgBr and n-BuMgBr proceeded with

good yields and enantioselectivities up to 96% for a wide range of aromatic

aldehydes with electron donating or electron withdrawing groups (Table 14, entries

2-3 and 6-7). The use of n-BuMgCl in the alkylation of benzaldehyde provided the

same enantioselectivity as its bromide derived counterpart (Table 14, entry 4);

however, conversion only reached moderated levels and 19% of benzyl alcohol was

formed as by-product during the reaction (Table 14, entry 5). It seems that, -hydride

elimination of alkylmagnesium chloride derivatives is favoured under this reaction

conditions, confirmed by the generation of benzyl alcohol from 1a.

Moreover, n-BuMgBr could be added at 20 °C to an aliphatic aldehyde with

moderated enantioselectivity 50% (Table 14, entry 8) and good yield. The bulky i-

BuMgBr gave excellent enantioselectivity (96%) but poor yield (41%) in the reaction

with benzaldehyde (Table 14, entry 9) and the formation of 5% of benzyl alcohol was

detected, which could be generated from the reduction of 1a via -hydride

elimination from i-BuMgBr and/or through Meerwein-Ponndorf-Verley reduction

from in situ generated RxMg(Oi-Pr)2-x species. In this case, an improvement of the

yield could be achieved at higher temperatures (20 °C), but at the expense of the

enantioselectivity (Table 14, entry 10).

Table 14. Asymmetric addition EtMgBr, n-BuMgBr and i-BuMgBr to aldehydes[a]

Entry Aldehyde Product Yield

[b] (%) ee

[c] (%)

1

95 86 (S)

2

80 78 (S)

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Chapter III – Results and discussion

124

3

85 72 (S)

4

90 96 (S)

5 41[d][e]

96 (S)

6

89 93 (S)

7

81 92 (S)

8

98[f]

50 (S)

9

41[g]

96 (S)

10 91[f][g]

86 (S)

[a] Conditions: 1 (0.3 mmol, 0.12 M), RMgBr (3.8 eq.), (Sa,R)-L1 (20 mol%), Ti(Oi-Pr)4 (15 eq.), toluene (2.5

mL), 40 °C, 4 h. [b] Isolated yield after flash silica gel chromatography. [c] Determined by chiral GC

analysis. Absolute configuration of chiral alcohols was determined by correlation of optical rotation with

known compounds. [d] n-BuMgCl (4.1 M in Et2O) was used as nucleophile. [e] 40% of unreacted 1a and

19% of benzyl alcohol were isolated. [f] Reaction performed at 20 °C. [g] 5% of benzyl alcohol was

isolated.

A limitation of this methodology is the use of secondary and tertiary Grignard

reagents such as i-PrMgBr, CyMgBr and t-BuMgBr, which provided very low

conversion to the corresponding racemic alcohol in the reaction with benzaldehyde

(2aa, 2y and 2ab, Figure 4). Secondary and tertiary nucleophiles are more reactive

and bulky than primary, so that can explain low yields and racemic products. Also,

the addition of allylmagnesium bromide to 1a provided 79% of conversion but 0% ee

when the reaction was carried out under the optimized previous conditions (2ad,

Figure 4). Moreover, the addition of sp2 hybridized Grignard reagents, such as

vinylMgBr and PhMgBr, to aromatic aldehydes proceeded in good yield, but low

enantioselectivity was observed in the case of arylation (2x, Figure 4) and no

enantioselectivity was achieved for the vinylation reaction (2ae, Figure 4).

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Chapter III – Results and discussion

125

Figure 4. Chiral secondary alcohols derived from the addition of RMgBr to aldehydes. Limitations of the

methodology.

2.3. Application of the methodology: Synthesis of 2-substituted chiral

tetrahydropyrans

The synthesis of 2-substituted chiral tetrahydropyrans was carried out as an

application of the developed methodology for the enantioselective alkylation of

aldehydes with Grignard reagents. Those compounds can be found in the structure of

natural products and pharmaceutical compounds.

The synthesis of these valuable building blocks was envisioned in two steps (Figure

5). We decided to apply our developed methodology to carry out the

enantioselective addition of 4-chlorobutylmagnesium bromide to different aromatic

aldehydes. The corresponding chloroalkyl alcohols could be subsequently cyclised to

provide the desired 2-substituted chiral tetrahydropyrans.

Figure 5. Retrosynthesis of 2-substituted chiral tetrahydropyrans.

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126

The alkylation step proceeded with moderate to good yields and excellent

enantioselectivities for non-substituted aromatic aldehydes, such as benzaldehyde

(1a) and 2-naphtylaldehyde (Table 15, entries 1-2), para substituted aromatic

aldehydes (Table 15, entries 3-4) and also bulky trisubstituted and heteroaromatic

aldehydes (Table 15, entries 5-6). However, in all cases, the corresponding n-butyl

alkylated adduct was observed as by-product (yield of this by-product have been

presented in brackets in Table 15 for each entry) and its formation could not be

avoided even a separately optimization process was attempted for this kind of

substrates. The formation of this by-product can be explained by two possible

pathways: i) chloro-magnesium exchange during the formation of the Grignard

reagent and/or ii) in situ reduction of the desired product.

Table 15. Asymmetric addition of (4-chlorobutyl)MgBr to aromatic aldehydes[a]

Entry Aldehyde Product Yield

[b] (%) ee

[c] (%)

1

63 (34) 97 (S)

2

56 (35) 94 ()

3

40 (51) 92 ()

4

53 (45) 94 ()

5

55 (41) 98 ()

6

67 (30) 94 ()

[a] Conditions: 1 (0.5 mmol, 0.06 M), (4-clorobutyl)MgBr (1.6 M in Et2O, 3.8 eq.), (Sa,R)-L1 (20 mol%),

Ti(Oi-Pr)4 (15 eq.), toluene (6 mL), 40 °C, 4 h. [b] Isolated yield after flash silica gel chromatography.

Yield in brackets corresponding to n-butyl addition [c] Determined by chiral HPLC analysis. Absolute

configuration of chiral alcohols was determined by correlation of optical rotation with known

compounds.

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Chapter III – Results and discussion

127

In the following step, the intramolecular cyclization of chloroalkyl alcohols took place

under mild reaction conditions using KOt-Bu as base in anhydrous THF during 3 hours

at 25 °C. The corresponding 2-substituted chiral tetrahydropyrans were obtained in

high purity (>99%) and in excellent yields and enantiomeric excess for a wide varity of

alcohols with different substituents at the meta- and para- position of the aromatic

ring (Table 16). It is important to highlight that no byproduct were observed during

the cyclization reaction, which indicates that this methodology is useful and fast for

the synthesis of this type of heterocycles.

Table 16. Cyclization of alcohols to 2-substituted tetrahydropyrans[a]

Entry Alcohol Product Yield

[b] (%) ee

[c] (%)

1

>99 97 (S)

2

>99 94 (S)

3

90 92 ()

4

99 94 ()

5

96 98 ()

6

80 94 ()

[a] Conditions: 2 (0.2 mmol, 0.1 M), KOt-Bu (2 eq.), THF (2 mL), 25 °C, 3 h. [b] Isolated yield after

standard work up. [c] Determined by chiral HPLC analysis of the starting material. Absolute

configuration of chiral tetrahydropyrans was determined by correlation of optical rotation with

known compounds.

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Chapter III – Results and discussion

128

In conclusion, an efficient enantioselective catalytic system has been developed for

the addition of MeMgBr and other Grignard reagents to aldehydes. This methodology

allows the preparation of the very versatile optically active methyl carbinol motif in a

simple one-pot procedure and using an economical and commercially available

source of the methyl group. A readily available binaphthyl derivative (Sa,R)-L1 is used

as a chiral ligand and an excess of titanium tetraisopropoxide was found to be crucial

to achieve high enantioselectivities. Moreover, the addition of longer chain Grignard

reagents to aromatic and aliphatic aldehydes could be also achieved with high yields

and enantioselectivities with the here presented catalytic system. Also, an

application of the methodology has been developed for the synthesis of 2-

substituted chiral tetrahydropyrans in two reaction steps with excellent enantiomeric

excess and moderate yields.

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Chapter III – Experimental part

129

3 Experimental part

3.1 General procedure for the enantioselective addition of Grignard

reagents to aromatic aldehydes

In a flame dried Schlenk tube, (Sa,R)-L1 (22.6 mg, 0.06 mmol, 20 mol%) was dissolved

in anhydrous toluene (2.5 mL) under argon atmosphere. The solution was cooled

down to 40 °C and Ti(Oi-Pr)4 (1.33 mL, 4.5 mmol, 15 eq.) was then added. Five

minutes later, RMgBr (1.14 mmol, 3.8 eq.) was added. After stirring the mixture for

additional 15 min, the corresponding freshly distilled aromatic aldehyde (0.3 mmol)

was added and the reaction mixture was stirred at 40 °C for 4 h. The reaction was

quenched with water (5 mL) and then HCl 2 M (5 mL) to eliminate the titanium oxides

generated by the addition of water. The crude was extracted with EtOAc (3 × 10 mL),

and the combined organic layers were neutralized with a saturated NaHCO3 aqueous

solution (15 mL), dried over magnesium sulfate and concentrated under vacuum. The

crude product was purified by flash silica gel chromatography to give the desired

products.

3.2 Data of chiral secondary alcohols prepared from Grignard reagents

1H NMR and 13C NMR, LRMS, HRMS, m.p., IR data and conditions for the

chromatographic separation of enantiomers for some of the compounds listed below

has been already reported in Chapter I section 3.2. In these cases, only the yield,

optical rotation and ee obtained in the addition reaction with organomagnesium

reagents will be reported.

(S)-1-Phenylethanol (2a): Colorless oil (92% yield, 88% ee); []D25 =

37.5 (c 2.8, CHCl3) {Lit. []D

20 = 39.6 (c 2.5, CHCl3) for 82% ee}.

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Chapter III – Experimental part

130

(S)-1-(o-Tolyl)ethanol (2b): Yellow oil (85% yield, 53% ee); []D25 =

35.0 (c 3.4, CHCl3) {Lit. []D

20 = 72.5 (c 1.0, CHCl3) for 96% ee}.

(S)-1-(m-Tolyl)ethanol (2c): Yellow oil (98% yield, 88% ee); []D25 =

26.0 (c 2.0, CHCl3) {Lit. []D

16 = 47.3 (c 0.8, CHCl3) for 90% ee}.

(S)-1-(p-Tolyl)ethanol (2d): Colorless oil (98% yield, 87% ee); []D25

= 37.5 (c 2.0, CHCl3). {Lit. []D

20 = 53.7 (c 0.4, CHCl3) for 96% ee}.

(S)-1-(4-Methoxyphenyl)ethanol (2e): Yellow oil (95% yield, 80%

ee); []D25 = 34.0 (c 2.3, CHCl3) {

Lit. []D20 = 51.9 (c 1.0, CHCl3) for

97% ee}.

(S)-1-[4-(Trifluoromethyl)phenyl]ethanol (2f): Yellow oil (88% yield,

88% ee); []D25 = 29.0 (c 2.0, CHCl3) {

Lit. []D20 = 33.7 (c 5.5, CHCl3)

for 97% ee}.

(S)-1-(4-Chlorophenyl)ethanol (2g): Yellow oil (98% yield, 84% ee);

[]D25 = 32.0 (c 4.0, CHCl3) {

Lit. []D20 = 43.6 (c 1.0, CHCl3) for 97%

ee}.

(S)-4-(1-Hydroxyethyl)benzonitrile (2h): Yellow oil (89% yield, 85%

ee); []D25 = 29.2 (c 2.1, CHCl3) {

Lit. []D20 = 62.7 (c 2.1, CHCl3) for

72% ee}.

(S)-1-(Naphthalen-2-yl)ethanol (2i): White powder (92% yield, 90%

ee); []D25 = 41.0 (c 1.0, CHCl3) {

Lit. []D20 = 48.1 (c 1.5, CHCl3) for

92% ee}.

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Chapter III – Experimental part

131

(S)-1-(Thiophen-2-yl)ethanol (2j): Volatile brown oil (53% yield, 58% ee);

[]D25 = 9.8 (c 2.0, CHCl3) {

Lit. []D20 = 27.6 (c 1.0, CHCl3) for 94% ee}.

(S,E)-4-Phenylbut-3-en-2-ol (2l): Yellow oil (90% yield, 68% ee);

[]D25 = 23.0 (c 3.6, CHCl3) {

Lit. []D20 = 14.6 (c 1.0, CHCl3) for 60%

ee}.

(S)-1-Phenylpropan-2-ol (2m): Colorless oil (70% yield, 70% ee); []D25

= +13.2 (c 1.7, CHCl3) {Lit. []D

25 = +42.2 (c 1.0, CHCl3) for 99% ee}.

(S)-1-Phenylpropan-1-ol (2o): Yellow oil (95% yield, 86% ee); []D25 =

33.5 (c 2.3, CHCl3) {Lit. []D

20 = 49.6 (c 0.5, CHCl3) for 98% ee}.

(S)-1-(p-Tolyl)propan-1-ol (2p): Brown oil (80% yield, 78% ee); []D25

= 24.8 (c 1.1, CHCl3) {Lit. []D

20 = 36.1 (c 1.0, CHCl3) for 84% ee}.

(S)-1-(4-Chlorophenyl)propan-1-ol (2q): Yellow oil (85% yield, 72%

ee); []D25 = 25.5 (c 2.0, CHCl3) {

Lit. []D25 = 38.4 (c 1.1, CHCl3) for

95% ee}.

(S)-1-Phenylpentan-1-ol (2r): Colorless needles crystals (90%

yield, 96% ee), []D25 = 39.0 (c 2.0, CHCl3) {

Lit []D20 = 13.6 (c 0.5,

CHCl3) for 80% ee}.

(S)-1-(4-Chlorophenyl)pentan-1-ol (2t): Colorless needles

(89% yield, 93% ee), []D25 = 31.0 (c 2.0, CHCl3) {

Lit. []D20 =

33.0 (c 1.0, CHCl3) for 96% ee}.

(S)-1-(4-Methoxyphenyl)pentan-1-ol (2u): Yellow oil (83%

yield, 92% ee); []D25 = 32.0 (c 2.0, CHCl3) {

Lit. []D20 = 24.2

(c 0.5, CHCl3) for 82% ee}.

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132

(S)-1-Cyclohexylpentan-1-ol (2z):80 Compound 2s was obtained

after purification on flash silica gel chromatography from 100:0

till 92:8 (n-Hexane/EtOAc) as a volatile yellow oil (98% yield, 50%

ee); []D25 = 10.0 (c 2.0, CHCl3) {Lit. []D

20 = +14.3 (c 1.9, CHCl3) for 90% ee of R

enantiomer}. 1H NMR (300 MHz, CDCl3) 3.41 – 3.29 (m, 1H), 1.86 – 1.71 (m, 3H),

1.71 – 1.57 (m, 3H), 1.55 – 0.96 (m, 12H), 0.91 (t, J = 7.0 Hz, 3H). 13C NMR (75 MHz,

CDCl3) 76.2, 43.5, 33.8, 29.3, 28.1, 27.7, 26.6, 26.4, 26.2, 22.8, 14.1. LRMS (EI): m/z

(%): 170 [M+] (<1), 152 (8), 113 (44), 95 (100), 87 (45), 82 (17), 69 (90), 67 (19), 57

(13), 55 (22). Ee determination by chiral GC analysis, CP-Chirasil-DEX CB column, T =

120 °C, P = 14.3 psi, retention times: tr(S) = 23.3 min (major enantiomer), tr(R) = 24.6

min.

(S)-3-Methyl-1-phenylbutan-1-ol (2w):81 Compound 2t was

obtained after purification on flash silica gel chromatography from

100:0 till 91:9 (n-hexane/EtOAc) as a white needles (41% yield, 96%

ee); m.p. 39 – 43 °C, []D25 = 39.4 (c 1.8, CHCl3).

1H NMR (300 MHz, CDCl3) 7.34 (d,

J = 4.4 Hz, 4H), 7.31 – 7.26 (m, 1H), 4.79 – 4.70 (m, 1H), 1.85 (br s, 1H), 1.78 – 1.63

(m, 2H), 1.57 – 1.44 (m, 1H), 0.96 (d, J = 1.4 Hz, 3H), 0.94 (d, J = 1.5 Hz, 3H). 13C NMR

(75 MHz, CDCl3) 145.2, 128.5, 127.5, 125.8, 72.8, 48.3, 24.8, 23.1, 22.2. LRMS (EI):

m/z (%): 165 [M++1] (2), 164 [M+] (17), 131 (4), 108 (16), 107 (100), 105 (10), 79 (84),

77 (38). Ee determination by chiral GC analysis, CP-Chirasil-DEX CB column, T = 125

°C, P = 14.3 psi, retention times: tr(S) = 18.9 min (major enantiomer), tr(R) = 20.6 min.

(S)-Naphthalen-2-yl(phenyl)methanol (2x): White powder

(98% yield, 15% ee), []D25 = +2.5 (c 2.1, CHCl3) {

Lit. []D20 = +11.2

(c 0.8, CHCl3) for 95% ee}.

80 Behrendt, L.; Felix. D.; Seebach, D. Angew. Chem., Int. Ed. Engl. 1991, 30, 1008-1009. 81 V. Bussche-Huennefeld, J. L.; Seebach, D. Tetrahedron 1992, 48, 5719-5730.

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(S)-5-chloro-1-phenylpentan-1-ol (2af):82 Compound 2af was

obtained after purification on flash silica gel chromatography

from 100:0 till 92:8 (n-hexane/EtOAc) as a yellow oil (63%

yield, 97% ee); []D29 = 27.8 (c 1.0, CHCl3) {

Lit. []D25 = 16.1 (c 1.0, CHCl3) for 92% ee}.

1H NMR (400 MHz, CDCl3) 7.38 – 7.30 (m, 4H), 7.30 – 7.24 (m, 1H), 4.65 (td, J = 7.4,

5.8 Hz, 1H), 3.50 (t, J = 6.7 Hz, 2H), 2.03 (br s, 1H), 1.86 – 1.65 (m, 4H), 1.63 – 1.49 (m,

1H), 1.48 – 1.35 (m, 1H). 13C NMR (101 MHz, CDCl3) 144.5, 128.5, 127.6, 125.8, 74.4,

44.8, 38.2, 32.4, 23.2. LRMS (EI): m/z (%): 200 [M++2] (3), 198 [M+] (8), 108 (14), 107

(100), 105 (9), 79 (60), 77 (29). Ee determination by chiral HPLC analysis, Chiralcel® OJ

column, n-hexane/i-PrOH 99:1, flow rate = 1.0 mL/min, = 220 nm, retention times:

tR(R) = 38.4 min, tR(S) = 43.2 min (major enantiomer).

(S)-5-chloro-1-(naphthalen-2-yl)pentan-1-ol (2ag):

Compound 2ag was obtained after purification on flash

silica gel chromatography from 100:0 till 89:11 (n-

hexane/EtOAc) as a white waxy solid (56% yield, 94% ee); m.p. 61.5 – 63.3 °C, []D28 =

23.5 (c 1.0, CHCl3). 1H NMR (300 MHz, CDCl3) 7.84 (dd, J = 8.9, 3.3 Hz, 3H), 7.78 (s,

1H), 7.55 – 7.40 (m, 3H), 4.85 (t, J = 6.4 Hz, 1H), 3.51 (t, J = 6.7 Hz, 2H), 1.96 (br s, 1H),

1.94 – 1.72 (m, 4H), 1.69 – 1.54 (m, 1H), 1.52 – 1.37 (m, 1H). 13C NMR (101 MHz,

CDCl3) 141.9, 133.2, 133.0, 128.3, 127.9, 127.7, 126.2, 125.8, 124.6, 123.9, 74.5,

44.8, 38.0, 32.4, 23.2. IR (ATR): (cm-1): 3240, 2940, 2866, 1314, 1066, 1025. LRMS

(EI): m/z (%): 250 [M++2] (5), 248 [M+] (14), 230 (12), 212 (32), 211 (16), 167 (36), 165

(23), 158 (13), 157 (100), 156 (16), 155 (36), 153 (10), 152 (18), 141 (14), 129 (62),

128 (47), 127 (32). HRMS (ESI): m/z: 248.0968 calculated for C15H17ClO [M+], found

248.0960. Ee determination by chiral HPLC analysis, Chiralcel® OD-H column, n-

hexane/i-PrOH 95:5, flow rate = 1.0 mL/min, = 220 nm, retention times: tR(S) = 23.7

min (major enantiomer), tR(R) = 26.0 min.

82

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(S)-5-chloro-1-[4-(methylthio)phenyl]pentan-1-ol (2ah):

Compound 2ah was obtained after purification on flash

silica gel chromatography from 100:0 till 89:11 (n-

hexane/EtOAc) as a white waxy solid (40% yield, 92% ee); m.p. 48.5 – 50.0 °C, []D27 =

22.7 (c 1.0, CHCl3). 1H NMR (300 MHz, CDCl3) 7.30 – 7.20 (m, 4H), 4.64 (t, J = 6.5

Hz, 1H), 3.52 (t, J = 6.7 Hz, 2H), 2.48 (s, 3H), 1.88 – 1.63 (m, 5H), 1.61 – 1.51 (m, 1H),

1.50 – 1.35 (m, 1H). 13C NMR (101 MHz, CDCl3) 141.4, 137.6, 126.7, 126.4, 73.9,

44.8, 38.1, 32.4, 23.1, 15.9. IR (ATR): (cm-1): 3264, 2933, 2863, 1598, 1429, 1088.

LRMS (EI): m/z (%): 246 [M++2] (4), 245 [M++1] (2), 244 [M+] (10), 154 (10), 153 (100),

109 (18). HRMS (ESI): m/z: 244.0689 calculated for C12H17ClOS [M+], found 244.0686.

Ee determination by chiral HPLC analysis, Chiralpak® AS-H column, n-hexane/i-PrOH

99:1, flow rate = 1.0 mL/min, = 254 nm, retention times: tR(R) = 26.8 min, tR(S) =

29.3 min (major enantiomer).

(S)-5-chloro-1-(4-chlorophenyl)pentan-1-ol (2ai):

Compound 2ai was obtained after purification on flash

silica gel chromatography from 100:0 till 92:8 (n-

hexane/EtOAc) as a colorless oil (53% yield, 94% ee); []D28 = 20.2 (c 1.0, CHCl3).

1H

NMR (400 MHz, CDCl3) 7.31 (d, J = 8.6 Hz, 2H), 7.26 (d, J = 8.6 Hz, 2H), 4.64 (td, J =

7.3, 5.7 Hz, 1H), 3.51 (t, J = 6.7 Hz, 2H), 2.06 (br s, 1H), 1.83 – 1.72 (m, 3H), 1.72 –

1.62 (m, 1H), 1.62 – 1.48 (m, 1H), 1.47 – 1.36 (m, 1H). 13C NMR (101 MHz, CDCl3)

143.0, 133.2, 128.6, 127.2, 73.7, 44.8, 38.2, 32.3, 23.0. IR (ATR): (cm-1): 3369, 2932,

2863, 1490, 1088, 1013. LRMS (EI): m/z (%): 234 [M++1] (2), 232 (2), 196 (10), 161

(18), 151 (10), 143 (32), 142 (10), 141 (100), 140 (10), 139 (35), 115 (11), 113 (11), 77

(25). HRMS (ESI): m/z: 214.0316 calculated for C11H12Cl2 [M–H2O]+, found 214.0324.

Ee determination by chiral HPLC analysis, Chiralcel® OD-H column, n-hexane/i-PrOH

99:1, flow rate = 1.0 mL/min, = 220 nm, retention times: tR(S) = 25.3 min (major

enantiomer), tR(R) = 27.3 min.

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(S)-5-chloro-1-(3-iodo-4,5-dimethoxyphenyl)pentan-1-ol

(2aj): Compound 2aj was obtained after purification on

flash silica gel chromatography from 100:0 till 88:12 (n-

hexane/EtOAc) as a pale yellow viscous oil (55% yield,

98% ee); []D27 = 11.6 (c 1.0, CHCl3).

1H NMR (400 MHz, CDCl3) 7.27 (d, J = 1.9 Hz,

1H), 6.87 (d, J = 1.9 Hz, 1H), 4.57 (td, J = 7.6, 5.3 Hz, 1H), 3.86 (s, 3H), 3.81 (s, 3H),

3.53 (t, J = 6.6 Hz, 2H), 2.10 (br s, 1H), 1.85 – 1.72 (m, 3H), 1.70 – 1.55 (m, 2H), 1.51 –

1.39 (m, 1H). 13C NMR (101 MHz, CDCl3) 152.6, 148.0, 142.7, 127.6, 110.2, 92.2,

73.4, 60.4, 56.0, 44.8, 38.2, 32.3, 23.2. IR (ATR): (cm-1): 3418, 2934, 2866, 1562,

1478, 1269, 1040. LRMS (EI): m/z (%): 386 [M++2] (6), 384 [M+] (18), 368 (10), 366

(28), 348 (22), 294 (10), 293 (100), 277 (11), 176 (20), 165 (11), 138 (24). HRMS (ESI):

m/z: 383.9989 calculated for C13H18ClIO3 [M+], found 383.9983. Ee determination by

chiral HPLC analysis, Chiralcel® OD-H column, n-hexane/i-PrOH 99:11, flow rate = 1.0

mL/min, = 220 nm, retention times: tR(S) = 52.5 min (major enantiomer), tR(R) =

68.3 min.

(S)-5-chloro-1-(thiophen-2-yl)pentan-1-ol (2ak): Compound

2ak was obtained after purification on flash silica gel

chromatography from 100:0 till 93:7 (n-hexane/EtOAc) as a

yellow oil (67% yield, 94% ee); []D27 = 12.5 (c 1.0, CHCl3).

1H NMR (400 MHz, CDCl3)

7.24 (dd, J = 4.2, 2.0 Hz, 1H), 6.99 – 6.94 (m, 2H), 4.91 (t, J = 6.7 Hz, 1H), 3.52 (t, J =

6.7 Hz, 2H), 2.17 (br s, 1H), 1.97 – 1.75 (m, 4H), 1.69 – 1.54 (m, 1H), 1.54 – 1.41 (m,

1H). 13C NMR (101 MHz, CDCl3) 148.5, 126.6, 124.6, 123.8, 70.0, 44.8, 38.4, 32.3,

23.2. IR (ATR): (cm-1): 3370, 2927, 2861, 1444, 1013. LRMS (EI): m/z (%): 206 [M++2]

(2), 204 [M+] (6), 188 (11), 186 (31), 124 (10), 123 (100), 113 (96), 111 (13), 97 (15),

85 (20). HRMS (ESI): m/z: 186.0270 calculated for C9H11ClS [M–H2O]+, found

186.0277. Ee determination by chiral HPLC analysis, Chiralcel® OJ column, n-

hexane/i-PrOH 99:1, flow rate = 1.0 mL/min, = 230 nm, retention times: tR(S) = 47.6

min (major enantiomer), tR(R) = 50.3 min.

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3.3. General procedure for the intramolecular cyclization of 4-

chlorobutyl alcohols into 2-substituted chiral tetrahydropyrans

In a flame dried Schlenk tube, the corresponding chiral 4-chlorobutyl alcohol (0.2

mmol) was dissolved in anhydrous THF (2 mL). Then, KOt-Bu (45 mg, 2 eq.) was

added to the previous solution and the suspension was stirred at 25 °C for 3 hours.

After that, the reaction was quenched with water (1 mL) and then 4 drops of HCl 2 M

were added to eliminate potassium salts. The crude was extracted with EtOAc (3 × 5

mL), and the combined organic layers were neutralized with a saturated NaHCO3

aqueous solution (10 mL), dried over magnesium sulfate and concentrated under

vacuum. The crude product was purified by flash silica gel chromatography to give

the desired tetrahydropyrans.

3.4. Data of 2-substituted chiral tetrahydropyrans

(S)-2-phenyltetrahydro-2H-pyran (3a):83 Compound 3a was obtained

without further purification as a yellow oil (>99% yield, 97% ee);

[]D27 = 49.5 (c 1.0, CHCl3) {

Lit. []D25 = -16.1 (c 1.0, CHCl3) for 92% ee}.

1H NMR (300 MHz, CDCl3) 7.40 – 7.28 (m, 4H), 7.28 – 7.19 (m, 1H), 4.32 (dd, J =

10.5, 2.2 Hz, 1H), 4.20 – 4.08 (m, 1H), 3.61 (td, J = 11.4, 2.6 Hz, 1H), 1.99 – 1.89 (m,

1H), 1.87 – 1.77 (m, 1H), 1.76 – 1.48 (m, 4H). 13C NMR (75 MHz, CDCl3) 143.3, 128.2,

127.2, 125.8, 80.1, 69.0, 34.0, 25.9, 24.0. LRMS (EI): m/z (%): 163 [M++1] (12), 162

[M+] (100), 161 (90), 106 (16), 105 (75), 104 (12), 91 (16), 79 (11), 78 (13), 77 (21).

(S)-2-(naphthalen-2-yl)tetrahydro-2H-pyran (3b): Compound 3b

was obtained without further purification as a yellow waxy solid

(>99% yield, 94% ee); m.p. 40.0 – 44.0 °C, []D30 = 40.3 (c 1.0,

CHCl3). 1H NMR (400 MHz, CDCl3) 7.87 – 7.75 (m, 4H), 7.50 – 7.39 (m, 3H), 4.48 (dd,

J = 10.6, 2.2 Hz, 1H), 4.23 – 4.15 (m, 1H), 3.67 (td, J = 11.5, 2.5 Hz, 1H), 2.02 – 1.83 (m,

2H), 1.82 – 1.52 (m, 4H). 13C NMR (101 MHz, CDCl3) 140.8, 133.3, 132.8, 128.0,

83

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127.90, 127.6, 125.9, 125.5, 124.3, 124.2, 80.1, 69.0, 34.1, 25.9, 24.0. IR (ATR): (cm-

1): 2934, 2847, 1202, 1083, 1038, 823, 744. LRMS (EI): m/z (%): 213 [M++1] (16), 212

[M+] (100), 211 (55), 156 (36), 155 (71), 154 (13), 153 (13), 152 (14), 142 (14), 141

(23), 129 (10), 128 (44), 127 (36). HRMS (ESI): m/z: 212.1201 calculated for C15H16O

[M+], found 212.1193.

(S)-2-[(4-(methylthio)phenyl]tetrahydro-2H-pyran (3c):

Compound 3c was obtained without further purification as a

colorless oil (90% yield, 92% ee); []D31 = 45.7 (c 1.0, CHCl3).

1H

NMR (400 MHz, CDCl3) 7.27 (d, J = 8.5 Hz, 2H), 7.23 (d, J = 8.5 Hz, 2H), 4.28 (dd, J =

10.7, 2.1 Hz, 1H), 4.16 – 4.09 (m, 1H), 3.60 (td, J = 11.6, 2.6 Hz, 1H), 2.46 (s, 3H), 1.97

– 1.89 (m, 1H), 1.85 – 1.75 (m, 1H), 1.72 – 1.53 (m, 4H). 13C NMR (101 MHz, CDCl3)

140.5, 137.1, 126.8, 126.4, 79.7, 69.0, 33.9, 25.9, 24.0, 16.1. IR (ATR): (cm-1): 2933,

2845, 1085, 1040, 815. LRMS (EI): m/z (%): 210 [M++2] (5), 209 [M++1] (15), 208 [M+]

(100), 207 (24), 193 (16), 161 (29), 153 (10), 152 (49), 151 (74), 150 (16), 137 (24),

135 (10), 124 (15), 105 (12). HRMS (ESI): m/z: 208.0922 calculated for C12H16OS [M+],

found 208.0916.

(S)-2-(4-chlorophenyl)tetrahydro-2H-pyran (3d): Compound 3d

was obtained without further purification as a colorless oil (99%

yield, 94% ee); []D30 = 37.6 (c 1.0, CHCl3).

1H NMR (300 MHz,

CDCl3) 7.28 (s, 4H), 4.29 (dd, J = 10.8, 2.2 Hz, 1H), 4.18 – 4.08 (m, 1H), 3.60 (td, J =

11.3, 2.9 Hz, 1H), 1.98 – 1.87 (m, 1H), 1.85 – 1.75 (m, 1H), 1.72 – 1.52 (m, 4H). 13C

NMR (75 MHz, CDCl3) 141.9, 132.8, 128.4, 127.2, 79.3, 69.0, 34.1, 29.7, 25.8, 23.9.

IR (ATR): (cm-1): 2932, 2849, 1492, 1086, 1043, 819. LRMS (EI): m/z (%): 198 [M++2]

(15), 197 [M++1] (16), 196 [M+] (45), 195 (32), 161 (76), 142 (11), 141 (42), 140 (34),

139 (100), 138 (14), 125 (21), 115 (10), 112 (24), 111 (14), 77 (15). HRMS (ESI): m/z:

196.0655 calculated for C11H13ClO [M+], found 196.0637.

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138

(S)-2-(3-iodo-4,5-dimethoxyphenyl)tetrahydro-2H-pyran (3e):

Compound 3e was obtained without further purification as a

colorless oil (96% yield, 98% ee); []D30 = 28.4 (c 1.0, CHCl3).

1H

NMR (400 MHz, CDCl3) 7.31 (d, J = 1.8 Hz, 1H), 6.91 (d, J = 1.8

Hz, 1H), 4.22 (dd, J = 10.8, 2.0 Hz, 1H), 4.16 – 4.08 (m, 1H), 3.86 (s, 3H), 3.80 (s, 3H),

3.58 (td, J = 11.5, 2.6 Hz, 1H), 1.99 – 1.88 (m, 1H), 1.86 – 1.75 (m, 1H), 1.72 – 1.51 (m,

4H). 13C NMR (101 MHz, CDCl3) 152.5, 148.0, 141.3, 127.8, 110.6, 92.1, 79.0, 69.0,

60.3, 56.0, 33.9, 25.7, 23.9. IR (ATR): (cm-1): 2933, 2845, 1561, 1270, 1086, 1043,

1003. LRMS (EI): m/z (%): 349 [M++1] (15), 348 [M+] (100), 292 (25), 291 (22), 277

(35), 221 (24), 177 (11), 165 (27). HRMS (ESI): m/z: 348.0222 calculated for C13H17IO3

[M+], found 348.0224.

(S)-2-(thiophen-2-yl)tetrahydro-2H-pyran (3f): Compound 3f was

obtained without further purification as a yellow oil (80% yield, 94%

ee); []D33 = 11.8 (c 1.0, CHCl3).

1H NMR (300 MHz, CDCl3) 7.23 (dd,

J = 7.4, 4.4 Hz, 1H), 6.97 – 6.94 (m, 2H), 4.59 (dd, J = 10.4, 2.2 Hz, 1H), 4.17 – 4.04 (m,

1H), 3.62 (td, J = 11.4, 2.7 Hz, 1H), 2.06 – 1.89 (m, 2H), 1.82 – 1.54 (m, 4H). 13C NMR

(75 MHz, CDCl3) 146.5, 126.3, 124.3, 123.2, 75.7, 68.9, 33.8, 25.7, 23.6. IR (ATR):

(cm-1): 2934, 2849, 1085, 1036, 695. LRMS (EI): m/z (%): 170 [M++2] (6), 169 [M++1]

(15), 168 (100), 167 (35), 113 (16), 112 (45), 111 (83), 110 (28), 97 (22), 84 (16), 55

(10). HRMS (ESI): m/z: 168.0609 calculated for C9H12OS [M+], found 168.0603.

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139

4 Results and discussion

4.1 Optimization of the catalytic enantioselective addition of Grignard

reagents to aliphatic aldehydes

As it has been shown in the first part of this chapter, the described methodology for

the enantioselective alkylation of aromatic aldehydes works well for this type of

substrates, but when an aliphatic aldehyde is used as electrophile, moderate

enantioselectivity was generally obtained. For example, the addition of n-BuMgBr to

cyclohexanecarboxaldehyde (1q) at –20 ᵒC in toluene provided product 2z (Table 17,

entry 1) in only 50% ee. We decided to optimize our methodology further to broaden

the substrate scope and allow the use of aliphatic substrates as electrophiles. As a

model reaction for our study we chose the addition of n-BuMgBr to

cyclohexanecarboxaldehyde (1q) (Table 17).

Based on the previous experience about the behavior of this catalytic system, we

attempted our model reaction in Et2O as solvent at –20 ᵒC (Table 17, entry 2). Under

these conditions, a positive increase in the enantioselectivity (65% ee) was observed,

although the conversion of the reaction dropped till 27%.

Different ligands were next tested in the model reaction. A systematic and extensive

study on the electronic, steric and chelating properties of different diol ligands (see

further discussion on Figure 6 and Table 3 of this section), brought us to pyridine-

substituted ligands (Sa,S)-L9 and (Sa,R)-L10 (Figure 6). Ligand (Sa,R)-L10 gave very

promising results in the alkylation reaction of 1q (89% ee and 89% conversion, Table

17, entry 3). Interestingly, (Sa,S)-L9, where the nitrogen of the pyridine ring is at the

two position, and therefore closer to the coordination site of the ligand, showed

lower catalytic activity, perhaps due to unfavourable coordination effects (Table 17,

entry 4).

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Chapter III – Results and discussion

140

Table 17. Initial tests[a]

Entry L* Solvent Conv.

[b] (%) ee

[b] (%)

1 (Sa,R)-L1 Toluene 98 50 2 (Sa,R)-L1 Et2O 27 65 3 (Sa,R)-L10 Et2O 89 89 4 (Sa,S)-L9 Et2O 84 55

[a] Conditions: Conditions: 1q (0.1 mmol, 0.05 M), n-BuMgBr (3 M in Et2O, 3.8 eq.), Ti(Oi-Pr)4

(15 eq.), (Sa,R)-L* (20 mol%), solvent (1.5 mL), 20 °C, 3 h. [b] Determined by chiral GC analysis.

With the best ligand (Sa,R)-L10 in hand, different Ti(Oi-Pr)4/n-BuMgBr ratio were next

tested (Table 18, entries 1-5) in order to find the best ratio between both reagents.

As it was observed in the first part of this chapter, for the alkylation reaction of

aromatic aldehydes, the optimal ratio Ti(Oi-Pr)4/n-BuMgBr in this case was also 4:1

(Table 11, entry 6). Gratifyingly, the new ligand (Sa,R)-L10 allowed a reduction in the

equivalents of both Ti(i-PrO)4 and n-BuMgBr compared to the alkylation reaction of

aromatic aldehydes with (Sa,R)-L1, without affecting the enantioselectivity or

conversion of the process (Table 18, entry 5). Unfortunately, both conversion and

enantioselectivity on the desired alcohol 2z dropped till 33 and 70%, respectively,

when the ligand loading was reduced to 10 mol% (Table 18, entry 6). Higher

temperatures (0 ᵒC), did not produce any improvement in the conversion of the

reaction and, as expected, lower enantioselectivity was obtained (Table 18, entry 7).

Table 18. Optimization Ti(Oi-Pr)4/n-BuMgBr ratio[a]

Entry Ti(Oi-Pr)4 (eq.) n-BuMgBr (eq.) Ti:Mg ratio Conv.

[b] (%) ee

[b] (%)

1 6 3 2:1 34 40 2 9 3 3:1 59 62 3 12 3 4:1 97 48 4 13.5 3 4.5:1 91 45 5 10 2.5 4:1 89 89 6 10 2.5 4:1 33

[c] 70

7 10 2.5 4:1 82[d]

82

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Chapter III – Results and discussion

141

[a] Conditions: 1q (0.1 mmol, 0.05 M), n-BuMgBr (3 M in Et2O, x eq.), Ti(Oi-Pr)4 (y eq.), (Sa,R)-L10 (20 mol%), Et2O

(1.5 mL), 20 °C, 3 h. [b] Determined by chiral GC analysis. [c] Performed with 10 mol% of (Sa,R)-L10. [c] Reaction carried out at 0 °C.

Other chiral diol ligands (Figure 6) were also evaluated under the optimized

conditions, but results were inferior in all cases (Table 19, entries 1-7). It is interesting

to note that the octahydro-binaphtyl derivative H8-(Sa,R)-L1 provided the product 2z

in lower enantioselectivity than the corresponding binaphtyl derivative (Sa,R)-L1. A

control experiment was performed, whereby 20 mol% of pyridine was added to the

reaction mixture containing the ligand (Sa,R)-L1 (Table 19, entry 8). The desired

product 2z was obtained with lower enantiomeric excess (78%) and conversion

(50%), proving the efficacy of the ligand (Sa,R)-L10 in the process.

Figure 6. Chiral diol ligands screened in this study.

Table 19. Ligand optimization[a]

Entry L* Conv.

[b] (%) ee

[b] (%)

1 H8-(Sa,R)-L1 38 13 2 (Sa,R)-L3 64 23 3 (Sa,R)-L4 66 11 4 (Sa,R)-L5 68 16 5 (Sa,R)-L7 84 46 6 (Sa,S)-L9 84 84 7 (Sa,R)-L10 85 90 8 (Sa,R)-L1

[c] 50 78

[a] Conditions: 1q (0.1 mmol, 0.05 M), n-BuMgBr (3 M in Et2O, 2.5 eq.), Ti(Oi-Pr)4 (10 eq.),

(Sa,R)-L* (20 mol%), Et2O (1.5 mL), 20 °C, 3 h. [b] Determined by chiral GC analysis. [c] 20 mol% of pyridine was added.

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Chapter III – Results and discussion

142

4.2 Scope of the reaction

To investigate the scope of the catalytic system, both substrate and nucleophile were

systematically varied. The addition of n-BuMgBr to cyclic (1q) and -branched (1t)

aliphatic aldehydes proceeded with very good yields and enantioselectivities (Table

20, entries 1-2). Moreover, ,-unsaturated aldehydes, such as acrolein (1u, Table

20, entry 3), also provided satisfactory results. The range of nucleophiles examined in

this work included EtMgBr (Table 20, entries 4-5), which afforded good yields and

enantioselectivities in the reaction with -branched aliphatic substrates. The addition

of EtMgBr to 2-methylpentanal (1w, Table 20, entry 5) gave a 1:1.3 mixture of

diastereoisomers (S,S)/(S,R), with 77% and 87% enantioselectivities respectively.

Table 20. Asymmetric addition of n-BuMgBr and EtMgBr to aldehydes

[a]

Entry Aldehyde Product Yield

[b] (%) ee

[c] (%)

1

97 90 (S)

2

97 80 ()[d]

3

53 96 (S)

4

80 86 (+)[e]

5

78[f]

77 (S,S)

87 (S,R)[e]

[a] Conditions: 1 (0.3 mmol, 0.05 M), RMgBr (3 M in Et2O, 2.5 eq.), Ti(Oi-Pr)4 (10 eq.),

(Sa,R)-L10 (20 mol%), Et2O (2.5 mL), 20 °C, 3 h. [b] Isolated yield after flash silica gel

chromatography. [c] Determined by chiral GC or HPLC analysis. [d] Determined on the

corresponding p-nitrobenzoate derivative 4. [e] Determined on the corresponding

acetate derivative. [f] Diastereomeric ratio (S,S)/(S,R) : 43/57, determined by GC analysis.

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Chapter III – Results and discussion

143

Finally, the attention was focused on the addition of MeMgBr to varying aliphatic

aldehydes (Table 21). Methyl carbinol units are especially interesting since they are

present in a large number of natural products and biologically active compounds;

however, its construction via addition to a carbonyl moiety is hampered by the low

reactivity of methyl derived organometallic reagents as nucleophiles. Gratifyingly,

under the optimized conditions, the newly developed catalytic system proved to be

effective for the addition of MeMgBr to various aliphatic aldehydes. Both linear and

-branched aliphatic substrates were suitable substrates for the reaction, giving high

enantioselectivities along with good yields (Table 21, entries 1-7). Moreover, ,-

unsaturated aldehydes like cinnamaldehyde (1l, Table 21, entry 8) and

phenylpropargyl aldehyde (1aa, Table 21, entry 9) afforded the corresponding chiral

alcohols in good yield with 82% and 60% ee, respectively; this demonstrates the

robustness and applicability of this methodology.

Table 21. Asymmetric addition of MeMgBr to aldehydes[a]

Entry Aldehyde Product Yield

[b] (%) ee

[c] (%)

1

98 88 (S)[d]

2 3

81 77

[e]

86 (S) 84 (S)

4

99 83 (+)

5

61 92 (S)[d]

6[f]

(58)[g]

99 (S)

7

60 98(S)[d]

8

>99 82 (S)

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Chapter III – Results and discussion

144

9

80 60 (S)

[a] Conditions: 1 (0.3 mmol, 0.05 M), MeMgBr (3 M in Et2O, 2.5 eq.), Ti(Oi-Pr)4 (10 eq.), (Sa,R)-L10 (20

mol%), Et2O (2.5 mL), 20 °C, 3 h. [b] Isolated yield after flash silica gel chromatography. [c]

Determined by chiral GC or HPLC analysis. [d] Determined on the corresponding acetate derivative

4. [e] Result after recovery of (Sa,R)-L10 and reused in the addition of MeMgBr to 1y. [f] 1 (0.3

mmol, 0.07 M), MeMgBr (3 M en Et2O, 3.8 eq.), Ti(Oi-Pr)4 (15 eq.), (Sa,R)-L10 (20 mol%), Et2O (2.5

mL), 20 °C, 3 h. [g] Volatile product. Conversion determined by GC in brackets.

Most of the chiral secondary alcohols here presented have been identified as natural

products with biological function and/or have applications in the fragrance/cosmetic

industry.84 This work represents a convenient procedure for the use of Grignard

reagents as inexpensive and readily accessible nucleophiles for the preparation of

these valuable building blocks. Further advantages of this methodology include the

recovery of the chiral ligand (Sa,R)-L10 from the reaction mixture by simple acid base

extraction (60% recovery yield) which, at the same time, facilitates the isolation and

purification of the corresponding products. The recovered ligand (Sa,R)-L10 can be

reused in subsequent reactions without any loss of activity (Table 21, entry 3).

4.3 Mechanistic aspects

Some mechanistic aspects about the asymmetric alkylation of aliphatic aldehydes

with Grignard reagents catalyzed by (Sa,R)-L10 has been studied to clarified the

pathway of the reaction, such as: non-linear effect, autocatalysis and kinetic profiles.

Non-linear effect studies were carried out using the addition of MeMgBr to 3-

phenylpropanal (1y) as model reaction. Ligand (Sa,R)-L10, in different enantiomeric

purities, was chosen for the purpose of this investigation. The reaction was carried

out under the previously optimized conditions: Et2O, 20 °C, 10 eq. of Ti(Oi-Pr)4 and

2.5 eq. of MeMgBr. The linear plot of the ee values for (Sa,R)-L10 vs the ee values of

84 a) Mozga, T.; Prokop, Z.; Chaloupková, R.; Damborský, J. Collect. Czech. Chem. Commun. 2009, 74, 11951278; b)

Keinan, E.; Sinha, S. C.; Singh, S. P. Tetrahedron 1991, 47, 46314638; c) Keinan, E.; Seth, K. K.; Lamed, R. J. Am. Chem.

Soc. 1986, 108, 34743480.

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Chapter III – Results and discussion

145

the corresponding reaction product 2aq (Figure 7) suggested that only one molecule

of chiral ligand is involved in the active metallic species.85

Figure 7. Linear plot of ee values of 2aq vs ee values of (Sa,R)-L10

By analogy with previous reports on the asymmetric addition of alkyl groups to

aldehydes catalyzed by titanium-BINOLate86 and titanium-TADDOLate87 ligands, we

believe that monomeric bimetallic species like (Sa,R)-L10-A or (Sa,R)-L10-B could be

present at the optimized reaction conditions (Figure 8) and that intermediates like

(Sa,R)-L10-C or (Sa,R)-L10-D are possibly responsible for both conversion and

asymmetric induction in our system.

85 Guillaneux, D.; Zhao, S.-H.; Samuel, O.; Rainford, D.; Kagan, H. B. J. Am. Chem. Soc. 1994, 116, 94309439. 86 Balsells, J.; Davis, T. J.; Carroll, P.; Walsh, P. J. J. Am. Chem. Soc. 2002, 124, 1033610348. 87 Ito, Y. N.; Ariza, X.; Beck, A. K.; Boháč, A.; Ganter, C.; Gawley, R. E.; Kühnle, F. N. M.; Tuleja, J.; Wang, Y. M.;

Seebach, D. Helv. Chim. Acta 1994, 77, 20712110.

0

20

40

60

80

100

0 20 40 60 80 100

ee 2

aq (

%)

ee (Sa,R)-L10 (%)

Non-linear effect

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Chapter III – Results and discussion

146

Figure 8. Possible intermediates involved in the catalysis.

The possibility of autocatalytic effect in the system was also examined. The reaction

of 3-phenylpropanal (1y) with MeMgBr (2.5 eq.) in the presence of 40 mol% of

enantiomerically pure (S)-2aq and 10 eq. of Ti(Oi-Pr)4 in Et2O at –20 ᵒC for 5 h,

allowed the generation of product 2aq in 54% ee, indicating that there is some

autocatalysis effect (Scheme 51).

Scheme 51. Autocatalytic effect observed in the addition of MeMgBr to 3-phenylpropanal (2aq)

The same reaction was carried out in the presence of 20 mol% of pyridine (together

with the 40 mol% of enantiomerically pure (S)-2aq) and, in a similar way, the newly

form 2aq was obtained with 54% ee, indicating that pyridine does not perform any

role separately. However, both reactions showed very low conversions (30% and

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Chapter III – Results and discussion

147

27%, respectively) and much slower rate than when the reaction was carried out in

the presence of (Sa,R)-L10, so we conclude that the autocatalysis of the chiral alcohol

product is negligible compared with the (Sa,R)-L10 catalyzed reaction.88

Figure 9. Comparative curves on the rate of the reaction with (Sa,R)-L10, (S)-BINOL and without ligand.

Finally, three kinetic analysis were conducted to determine the effect of the chiral

ligand (Sa,R)-L10 in the rate of the addition of MeMgBr (2.5 eq.) to 3-phenylpropanal

(1y), in the presence of 10 eq. of Ti(Oi-Pr)4, Et2O as solvent at –20 ᵒC. As it is shown in

the kinetic profiles above (Figure 10), the reaction catalyzed by ligand (Sa,R)-L10 (blue

profile) was much faster than the reaction in the absence of ligand (green profile) or

in the presence of (S)-BINOL as chiral diol (red profile). The corresponding alcohol

2aq was generated with only 7% of enantiomeric excess when (S)-BINOL was used as

a ligand and racemic when no ligand was employed in the reaction. So, this indicates

that chiral ligand (Sa,R)-L10 is the responsible of the catalysis and the chirality

induced in the product.

88 a) Wu, K.-H.; Kuo, Y.-Y.; Chen, C.-A.; Huang, Y.-L.; Gau, H.-M. Adv. Synth. Catal. 2013, 335, 10011008; b) Wu, K.-H.;

Zhou, S.; Chen, C.-A.; Yang, M.-C.; Chiang, R.-T.; Chen, C.-R.; Gau, H.-M. Chem. Commun. 2011, 47, 1166811670.

0

20

40

60

80

100

0 30 60 90 120 150 180

Co

nve

rsio

n (%

)

Time (min)

Kinetic experiments

(Sa,R)-L2

Without ligand

(S)-BINOL

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Chapter III – Results and discussion

148

In conclusion, an efficient enantioselective catalytic system has been developed for

the addition of alkyl Grignard reagents to aliphatic aldehydes that allows the

preparation of chiral aliphatic secondary alcohols in a simple one-pot procedure

under mild reaction conditions. This methodology overcomes the main problems

associated with the use of aliphatic substrates: their multiple conformations, the

absence of possible – stacking interactions with the catalyst and/or their highly-

enolizable character. A readily available binaphthyl derivative is used as a chiral

ligand and an excess of titanium tetraisopropoxide was found to be crucial to achieve

high enantioselectivities. Moreover, the addition of the challenging MeMgBr to

aliphatic aldehydes could also be achieved for the first time with high yields and

enantioselectivities, allowing the construction of the versatile and optically active

aliphatic methyl carbinol motif.

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Chapter III – Experimental part

149

5. Experimental part

5.1 General procedure for the enantioselective addition of Grignard

reagents to aliphatic aldehydes

In a flame dried Schlenk tube, (Sa,R)-L10 (22.6 mg, 0.06 mmol, 10 mol%) was

dissolved in anhydrous Et2O (2.5 mL) under argon atmosphere. The solution was

cooled down to 20 °C and Ti(Oi-Pr)4 (915 L, 3 mmol, 10 eq.) was then added. Five

minutes later, RMgBr (0.75 mmol, 2.5 eq.) was added. After stirring the mixture for

additional 15 min, the corresponding freshly distilled aliphatic aldehyde (0.3 mmol)

was added and the reaction mixture was stirred at 20 °C for 3 h. The reaction was

quenched with water (5 mL) and then HCl 2 M (5 mL) to eliminate the titanium oxides

generated by the addition of water. The crude was extracted with Et2O (3 × 10 mL),

and the combined organic layers were neutralized with a saturated NaHCO3 aqueous

solution (15 mL), dried over magnesium sulfate and concentrated under vacuum. The

crude product was purified by flash silica gel chromatography to give the desired

products.

5.2 Data of chiral secondary aliphatic alcohols

(S)-1-Cyclohexylpentan-1-ol (2z): Yellow oil (97% yield, 90% ee);

[]D25 = 15.4 (c 1.0, CHCl3) {Lit. []D

20 = +14.3 (c 1.9, CHCl3) for

90% ee of R enantiomer}.

()-3-Ethyloctan-4-ol (2al):89 Compound 2al was obtained after

purification on flash silica gel chromatography from 100:0 till 94:6

(n-hexane/EtOAc) as a colorless oil (97% yield, 80% ee); []D25 =

10.6 (c 1.0, CHCl3). 1H NMR (400 MHz, CDCl3) 3.61 (dt, J = 8.1, 4.0 Hz, 1H), 1.44 (m,

6H), 1.38 – 1.24 (m, 5H), 1.23 – 1.14 (m, 1H), 0.96 – 0.86 (m, 9H). 13C NMR (101 MHz,

CDCl3) 73.2, 46.8, 33.7, 28.5, 22.8, 22.1, 21.1, 14.1, 11.9, 11.8. LRMS (EI): m/z (%):

89 Zhang, X.; Lu, Z.; Fu, C.; Ma, S. Org. Biomol. Chem. 2009, 7, 3258–3263.

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Chapter III – Experimental part

150

158 [M+] (<1), 101 (17), 87 (47), 86 (15), 83 (11), 70 (17), 69 (100), 59 (18), 57 (15), 55

(15). Ee was determined by chiral HPLC analysis on the derivative 4a.

(S)-Hept-1-en-3-ol (2am):90 Compound 2am was obtained after

purification on flash silica gel chromatography from 100:0 till 90:10

(n-pentane/Et2O) as a colorless oil (53% yield, 96% ee); []D25 = +14.2 (c 0.9, CHCl3) {

Lit.

[]D20 = +9.0 (c 1.0, CHCl3) for 99% ee}. 1H NMR (300 MHz, CDCl3) 5.94 – 5.80 (ddd, J

= 16.7, 10.4, 6.3 Hz, 1H), 5.21 (dd, J = 17.2, 1.5 Hz, 1H), 5.13 – 5.06 (dd, J = 10.4, 1.4

Hz, 1H), 4.14 – 4.04 (qt, J = 6.3, 1.1 Hz, 1H), 1.90 (br s, 1H), 1.65 – 1.43 (m, 2H), 1.43 –

1.24 (m, 4H), 0.98 – 0.83 (t, J = 7.1 Hz, 3H). 13C NMR (75 MHz, CDCl3) 141.3, 114.5,

73.2, 36.7, 27.5, 22.6, 14.0. LRMS (EI): m/z (%): 114 [M+] (<1), 85 (9), 81 (7), 72 (21),

58 (6), 57 (100), 55 (8). Ee determination by chiral GC analysis, CP-Chirasil-DEX CB

column, T = 70 °C, P = 14.3 psi, retention times: tr(S) = 18.1 min (major enantiomer),

tr(R) = 19.7 min.

(+)-1-Cyclopentylpropan-1-ol (2an):91 Compound 2an was obtained

after purification on flash silica gel chromatography from 100:0 till

90:10 (n-pentane/Et2O) as a colorless oil (80% yield, 86% ee); []D25 =

+3.7 (c 1.2, CHCl3). 1H NMR (300 MHz, CDCl3) 3.40 – 3.30 (td, J = 8.0, 3.5 Hz, 1H),

1.99 – 1.75 (m, 2H), 1.73 – 1.49 (m, 8H), 1.48 – 1.32 (m, 2H), 0.98 (t, J = 7.4 Hz, 3H). 13C NMR (75 MHz, CDCl3) 77.4, 45.9, 29.1, 28.9, 28.5, 25.7, 25.6, 10.0. LRMS (EI):

m/z (%): 128 [M+] (<1), 99 (42), 82 (8), 81 (100), 79 (10), 69 (10), 68 (20), 67 (14), 59

(81), 58 (21), 57 (13), 55 (9). Ee was determined by chiral GC analysis on the

derivative 4b.

90 Gawas, D.; Kazmaier, U. Org. Biomol. Chem. 2010, 8, 457–462. 91 Xin, S.; Harrod, J. F. Can. J. Chemistry 1995, 73, 999–1002.

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(3S,4R)-4-Methylheptan-3-ol and (3S,4S)-4-Methylheptan-3-ol

(2ao):92 Compounds 2ao were obtained as a diastereomeric mixture

43/57 after purification on flash silica gel chromatography from

100:0 till 90:10 (n-pentane/Et2O) as a colorless oil {78% yield, 77%

ee (anti) and 87% ee (syn)}. 1H NMR (400 MHz, CDCl3) 3.42 (m,

1H), 3.35 (m, 1H), 1.05 – 1.60 (m, 16H), 0.87– 0.97 (m, 18H). 13C NMR (101 MHz,

CDCl3) 78.3, 77.6, 38.5, 35.5, 35.6, 34.1, 27.2, 26.2, 20.4, 20.3, 14.4, 14.3, 13.9, 13.5,

10.6, 10.4. LRMS (EI): m/z (%): 130 [M+] (<1), 101 (16), 83 (22), 70 (8), 59 (100), 58

(21), 57 (11), 55 (18). Ee was determined by chiral GC analysis on the derivatives 4c.

(S)-Decan-2-ol (2ap):93 Compound 2ap was obtained after

purification on flash silica gel chromatography from 100:0 till

94:6 (n-hexane/EtOAc) as a colorless oil (98% yield, 88% ee); []D25 = +6.2 (c 1.0,

CHCl3) {Lit. []D

20 = +6.1 (c 1.0, CHCl3) for 99% ee}. 1H NMR (400 MHz, CDCl3) 3.86 –

3.73 (sext, J = 6.2 Hz, 1H), 1.72 (s, 1H), 1.53 – 1.37 (m, 3H), 1.36 – 1.22 (m, 11H), 1.19

(d, J = 6.2 Hz, 3H), 0.88 (t, J = 6.8 Hz, 3H). 13C NMR (101 MHz, CDCl3) 68.2, 39.3,

31.9, 29.6, 29.5, 29.3, 25.8, 23.4, 22.6, 14.1. LRMS (EI): m/z (%): 158 [M+] (<1), 143

(24), 140 (23), 112 (47), 111 (31), 98 (22), 97 (41), 85 (26), 84 (35), 83 (72), 82 (15), 71

(28), 70 (51), 69 (100), 67 (10), 57 (58), 56 (45), 55 (80). Ee was determined by chiral

GC analysis on the derivative 4d.

(S)-4-Phenylbutan-2-ol (2aq):94 Compound 2aq was obtained after

purification on flash silica gel chromatography from 100:0 till 90:10

(n-Hexane/EtOAc) as a colorless oil (81% yield, 86% ee); []D25 =

+13.5 (c 1.0, CHCl3) {Lit. []D

20 = +13.8 (c 1.7, CHCl3) for 79% ee}. 1H NMR (300 MHz,

CDCl3) 7.33 – 7.13 (m, 5H), 3.88 – 3.75 (sext, J = 6.2 Hz, 1H), 2.83 – 2.59 (m, 2H),

1.83 – 1.72 (m, 2H), 1.70 (s, 1H), 1.22 (d, J = 6.2 Hz, 3H). 13C NMR (75 MHz, CDCl3)

142.0, 128.4, 125.8, 67.4, 40.8, 32.1, 23.6. LRMS (EI): m/z (%): 151 [M++1] (1), 150

92 Zada, A.; Ben-Yehuda, S.; Dunkelblum, E.; Harel, M.; Assael, F.; Mendel, Z. J. Chem. Ecol. 2004, 30, 631–641. 93 Keinan, E.; Hafeli, E. K.; Seth, K. K.; Lamed, R. J. Am. Chem. Soc. 1986, 108, 162–169. 94 Li, D. R.; He, A.; Falck, J.R. Org. Lett. 2010, 12, 1756–1759.

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[M+] (10), 132 (52), 131 (9), 118 (10), 117 (100), 115 (9), 105 (10), 92 (34), 91 (75), 78

(20), 77 (13), 65 (12), 51 (7). Ee determination by chiral GC analysis, CP-Chirasil-DEX

CB column, T = 110 °C, P = 14.3 psi, retention times: tr(S) = 27.0 min (major

enantiomer), tr(R) = 29.7 min.

(+)-3-Ethylpentan-2-ol (2ar):95 Compound 2ar was obtained after

purification on flash silica gel chromatography from 100:0 till 90:10 (n-

pentane/Et2O) as a colorless oil (99% yield, 83% ee); []D25 = +2.6 (c 1.0,

CHCl3). 1H NMR (300 MHz, CDCl3) 3.84 (qd, J = 6.4, 5.1 Hz, 1H), 1.93 (br s, 1H), 1.48

– 1.19 (m, 5H), 1.15 (d, J = 6.4 Hz, 3H), 0.91 (t, J = 7.4 Hz, 6H). 13C NMR (75 MHz,

CDCl3) 69.3, 48.1, 21.6, 21.5, 20.0, 11.7, 11.6. LRMS (EI): m/z (%): 116 [M+] (<1), 101

(10), 83 (9), 71 (16), 70 (100), 69 (14), 59 (17), 57 (13), 55 (42), 53 (6). Ee

determination by chiral GC analysis, CP-Chirasil-DEX CB column, T = 70 °C, P = 14.3

psi, retention times: tr(R) = 20.4 min, tr(S) = 21.0 min (major enantiomer).

(S)-1-Cyclohexylethanol (2as):96 Compound 2as was obtained after

purification on flash silica gel chromatography from 100:0 till 94:6 (n-

hexane/EtOAc) as a yellow oil (61% yield, 92% ee); []D25 = +2.8 (c 1.0,

CHCl3) {Lit. []D

20 = +3.5 (c 3.1, CHCl3) for 95% ee}. 1H NMR (300 MHz, CDCl3) 3.54

(quin, J = 6.2 Hz, 1H), 1.92 – 1.59 (m, 6H), 1.34 – 1.09 (m, 7H), 1.09 – 0.87 (m, 2H). 13C

NMR (75 MHz, CDCl3) 72.2, 45.1, 28.6, 28.3, 26.5, 26.2, 26.1, 20.3. LRMS (EI): m/z

(%): 128 [M+] (<1), 113 (16), 110 (37), 95 (42), 84 (24), 83 (35), 82 (100), 81 (18), 69

(16), 67 (61), 56 (25), 55 (76), 54 (14), 53 (9). Ee was determined by chiral GC analysis

on the derivative 4e.

(S)-3,3-Dimethylbutan-2-ol (2n):97 Compound 2n was obtained after

purification on flash silica gel chromatography from 100:0 till 90:10 (n-

pentane/Et2O) as a colorless oil (58% yield, 99% ee); []D25 = 8.0 (c 1.7,

95 Rawson. D.; Meyers, A. I. J. Chem. Soc., Chem. Commun. 1992, 6, 494–496. 96 Li, G.; Kabalka, G. W. J. Organomet. Chem., 1999, 581, 66–69. 97 Gilmore, N. J.; Jones, S.; Muldowney, M. P. Org. Lett. 2004, 6, 2805–2808.

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153

EtOAc) {Lit. []D20 = +31.0 (c 1.0, CHCl3) for 60% ee}. 1H NMR (300 MHz, CDCl3) 3.47

(q, J = 6.4 Hz, 1H), 1.76 (br s, 1H), 1.12 (d, J = 6.4 Hz, 3H), 0.89 (s, 9H). 13C NMR (75

MHz, CDCl3) 75.6, 34.8, 25.4, 17.8. LRMS (EI): m/z (%): 136 [M+] (1), 118 (23), 117

(35), 115 (15), 92 (100), 91 (94), 65 (19), 51 (9). Ee determination by chiral GC

analysis, HP-CHIRAL-20 column, T = 60 °C, P = 6.0 psi, retention time: tr(S) = 29.8 min

(major enantiomer), tr(R) = 31.9 min.

(S)-3,3-Dimethylhex-5-en-2-ol (2at):98 Compound 2at was obtained

after purification on flash silica gel chromatography from 100:0 till

92:8 (n-pentane/Et2O) as a colorless oil (60% yield, 98% ee); []D25 =

+2.8 (c 1.0, CHCl3) {Lit. []D

20 = 7.2 (c 1.1, CHCl3) for 76% ee of R enantiomer}. 1H NMR

(300 MHz, CDCl3) 5.95 – 5.79 (dddd, J = 15.0, 12.6, 9.4, 7.5 Hz, 1H), 5.10 – 5.05 (m,

1H), 5.05 – 5.01 (m, 1H), 3.55 (q, J = 6.1 Hz, 1H), 2.11 (ddt, J = 13.6, 7.6, 1.1 Hz, 1H),

1.99 (ddt, J = 13.6, 7.4, 1.1 Hz, 1H)., 1.70 (br s, 1H), 1.13 (d, J = 6.4 Hz, 3H), 0.88 (s,

3H), 0.86 (s, 3H). 13C NMR (75 MHz, CDCl3) 135.5, 117.0, 74.2, 43.5, 37.8, 22.9, 22.1,

17.6. LRMS (EI): m/z (%): 128 [M+] (<1), 110 (16), 95 (16), 87 (70), 86 (10), 84 (44), 83

(22), 82 (14), 71 (12), 69 (100), 67 (28), 56 (11), 55 (79), 53 (9). Ee was determined by

chiral GC analysis on the derivative 4f.

(S,E)-4-Phenylbut-3-en-2-ol (2l): Yellow oil (>99% yield, 82% ee);

[]D25 = 25.4 (c 1.0, CHCl3) {

Lit. []D20 = 14.6 (c 1.0, CHCl3) for 60%

ee}.

(S)-4-Phenylbut-3-yn-2-ol (2au):89 Compound 2au was obtained

after purification on a flash silica gel chromatography from 100:0 till

90:10 (n-hexane/EtOAc) as a colorless oil (80% yield, 60% ee); []D25

= 21.5 (c 1.0, CHCl3) {Lit. []D

20 = 33.0 (c 0.9, CHCl3) for 98% ee}. 1H

NMR (300 MHz, CDCl3) 7.43 (m, 2H), 7.31 (m, 3H), 4.76 (m, 1H), 2.14 (br s, 1H), 1.56

(d, J = 6.6 Hz, 3H). 13C NMR (75 MHz, CDCl3) 131.6, 128.3, 128.2, 122.5, 90.9, 84.0,

98 Cozzi, P. G.; Kotrusz, P. J. Am. Chem. Soc. 2006, 128, 4940–4941.

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58.8, 24.4. LRMS (EI): m/z (%): 147 [M++1] (3), 146 [M+] (33), 145 (50), 132 (10), 131

(100), 129 (11), 128 (12), 127 (10), 103 (65), 102 (14), 77 (32), 51 (11). Ee

determination by chiral HPLC analysis, Chiralcel® OJ column, n-hexane/i-PrOH 97:3,

flow rate = 1.0 mL/min, = 210 nm, retention times: tr(R) = 15.6 min, tr(S) = 18.0 min

(major enantiomer).

5.3 Procedure for derivatization of chiral secondary aliphatic alcohols

into the corresponding esters

Two different procedures were used to derivatize chiral aliphatic alcohols into the

corresponding p-nitrobenzoate (Procedure A) and acetate (Procedure B) products.

Procedure A: Synthesis of (S)-3-ethyloctan-4-yl p-nitrobenzoate (4a)

In a flame dried Schlenk tube, the corresponding aliphatic alcohol 2al (31.7 mg, 0.2

mmol) was dissolved in anhydrous DCM (1 mL) at 0 °C and Et3N (56 L, 0.4 mmol, 2

eq.), DMAP (2.5 mg, 0.02 mmols, 10 mol%) and p-nitrobenzoyl chloride (55.7 mg, 0.3

mmol, 1.5 eq.) were added sequentially. The reaction mixture was stirred at room

temperature for 12 h. The reaction was quenched with water (1 mL), extracted with

Et2O (3 × 5 mL) and the combined organic layers were dried over magnesium sulfate

and concentrated under vacuum. The crude product was purified by flash silica gel

chromatography to give the desired product 4a.

Procedure B: Synthesis of acetates 4b, 4c, 4d, 4e and 4f

In a flame dried Schlenk tube, the corresponding aliphatic alcohol [2an, 2ao, 2ap, 2as

or 2at] (0.1 mmol) was dissolved in anhydrous DCM (1 mL) at 0 °C and Et3N (28 L,

0.2 mmol, 2 eq.), DMAP (1.3 mg, 0.01 mmol, 10 mol%) and acetic anhydride (22 L,

0.2 mmol, 2 eq.) were added sequentially. The reaction mixture was stirred at room

temperature for 12 h. The reaction was quenched with water (1 mL), extracted with

Et2O (3 × 5 mL) and the combined organic layers were dried over magnesium sulfate

and concentrated under vacuum. The crude product was purified by Kugelrohr

distillation to give the desired products 4b, 4c, 4d, 4e and 4f.

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5.4 Data of chiral esters

(S)-3-Ethyloctan-4-yl p-nitrobenzoate (4a): Compound 4a was

obtained after purification on flash silica gel chromatography

from 100:0 till 98:2 (n-hexane/EtOAc) as a yellow viscous oil

(>99% yield). 1H NMR (400 MHz, CDCl3) 8.29 (d, J = 9.0 Hz, 2H),

8.21 (d, J = 9.0 Hz, 2H), 5.27 (dt, J = 8.5, 4.2 Hz, 1H), 1.80 – 1.58

(m, 2H), 1.58 – 1.46 (m, 2H), 1.45 – 1.21 (m, 7H), 0.97 (t, J = 7.0

Hz, 3H), 0.94 (t, J = 7.4 Hz, 3H), 0.89 (t, J = 6.9 Hz, 3H). 13C NMR (101 MHz, CDCl3)

164.4, 150.4, 136.2, 130.6, 123.5, 77.8, 44.5, 30.7, 28.0, 22.6, 22.2, 21.93, 14.0, 11.8,

11.7. IR (ATR): (cm-1): 2960, 1719, 1527, 1271, 1101, 718. LRMS (EI) m/z (%): 307

[M+] (<1), 236 (9), 151 (13), 150 (100), 140 (7), 104 (13), 92 (5), 76 (6), 55 (4). HRMS

(EI): m/z: 250.1079 calculated for C13H16NO4 [M–n-Bu]+, found 250.1119. Ee

determination by chiral HPLC analysis, Chiralpak® AS-H column, n-hexane/i-PrOH

99:1, flow rate = 0.8 mL/min, = 254 nm, retention times: tr(R) = 7.5 min, tr(S) = 8.7

min (major enantiomer).

(S)-1-Cyclopentylpropyl acetate (4b): Compound 4b was obtained

after purification by Kugelrohr distillation as a colorless oil (>99%

yield). 1H NMR (300 MHz, CDCl3) 4.77 (td, J = 7.8, 4.1 Hz, 1H), 2.06 (s,

3H), 1.76 – 1.41 (m, 9H), 1.36 – 1.11 (m, 2H), 0.88 (t, J = 7.4 Hz, 4H). 13C

NMR (75 MHz, CDCl3) 171.1, 78.8, 43.3, 29.0, 28.6, 26.2, 25.5, 25.2, 21.2, 9.6. LRMS

(EI): m/z (%): 170 [M+] (<1), 141 (17), 112 (33), 110 (35), 101 (69), 97 (11), 95 (14), 82

(17), 81 (100), 71 (16), 68 (16), 67 (39), 55 (11). Ee determination by chiral GC

analysis, CP-Chirasil-DEX CB column, T = 110 °C, P = 14.3 psi, retention time: tr(S) = 6.6

min (major enantiomer), tr(R) = 7.3 min.

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(3S,4R)-4-Methylheptan-3-yl acetate (3S,4S)-4-Methylheptan-3-yl

acetate (4c): Compounds 4c were obtained after Kugelrohr

distillation as a colorless oil (>99% yield). LRMS (EI): m/z (%): 172

[M+] (<1), 143 (9), 130 (9), 112 (22), 101 (100), 83 (47), 72 (50), 71

(14), 70 (26), 69 (25), 57 (13), 55 (29). Ee determination by chiral GC

analysis, HP-CHIRAL-20 column, T = 70 °C, P = 14.3 psi, retention

time for anti diastereoisomers: tr(3S,4R) = 27.9 min (major enantiomer), tr(3R,4S) =

31.2 min, and for syn diastereoisomers: tr(3S,4S) = 29.4 min (major enantiomer),

tr(3R,4R) = 32.3 min.

(S)-Decan-2-yl acetate (4d): Compound 4d was obtained

after purification by Kugelrohr distillation as a colorless oil

(>99% yield). 1H NMR (300 MHz, CDCl3) 4.95 – 4.79 (sext,

J = 6.3 Hz, 1H), 2.04 – 1.95 (s, 3H), 1.66 – 1.36 (m, 2H), 1.35 – 1.21 (m, 11H), 1.18 (d, J

= 6.3 Hz, 3H), 0.86 (t, J = 6.7 Hz, 3H). 13C NMR (75 MHz, CDCl3) 170.8, 71.1, 35.9,

31.8, 29.5, 29.4, 29.2, 25.4, 22.6, 21.3, 19.9, 14.0. LRMS (EI): m/z (%): 200 [M+] (<1),

140 (43), 112 (16), 111 (26), 102 (12), 98 (22), 97 (34), 96 (11), 87 (100), 85 (11), 84

(21), 83 (24), 82 (10), 71 (16), 70 (36), 69 (37), 58 (16), 57 (24), 56 (37), 55 (42). Ee

determination by chiral GC analysis, Chirasil-DEX CB column, T = 130 °C, P = 14.3 psi,

retention time: tr(S) = 6.5 min (major enantiomer), tr(R) = 7.4 min.

(S)-1-Cyclohexylethyl acetate (4e): Compound 4e was obtained after

purification by Kugelrohr distillation as a colorless oil (>99% yield). 1H

NMR (400 MHz, CDCl3) δ 4.72 (quin, J = 6.4 Hz, 1H), 2.04 (s, 3H), 1.80 –

1.61 (m, 5H), 1.43 (m, 1H), 1.27 – 1.09 (m, 3H), 1.16 (d, J = 6.4 Hz, 3H),

1.07 – 0.90 (m, 2H). 13C NMR (101 MHz, CDCl3) δ 171.0, 74.7, 42.5, 28.4, 26.3, 26.0,

25.9, 20.92, 17.0. LRMS (EI): m/z (%): 128 [M+] (<1), 113 (16), 110 (37), 95 (42), 84

(24), 83 (35), 82 (100), 81 (18), 69 (16), 67 (61), 56 (25), 55 (76), 54 (14), 53 (9). Ee

determination by chiral GC analysis, HP-CHIRAL-20 column, T = 130 °C, P = 14.3 psi,

retention time: tr(S) = 8.1 min (major enantiomer), tr(R) = 8.5 min.

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(S)-3,3-Dimethylhex-5-en-2-yl acetate (4f): Compound 4f was

obtained after purification by Kugelrohr distillation as a colorless oil

(>99% yield). 1H NMR (300 MHz, CDCl3) 5.80 (ddt, J = 17.6, 10.2,

7.5 Hz, 1H), 5.10 – 4.95 (m, 2H), 4.72 (q, J = 6.4 Hz, 1H), 2.04 (s, 3H),

1.14 (d, J = 6.4 Hz, 3H), 0.88 (d, J = 7.9 Hz, 6H). 13C NMR (75 MHz, CDCl3) 170.7,

134.6, 117.4, 76.4, 43.3, 36.8, 22.8, 22.5, 21.2, 14.5. LRMS (EI): m/z (%): 170 [M+]

(<1), 129 (27), 110 (17), 95 (19), 87 (100), 83 (20), 69 (29), 67 (13), 55 (29). Ee

determination by chiral GC analysis, Chirasil-DEX CB column, T = 90 °C, P = 14.3 psi,

retention time: tr(S) = 7.2 min (major enantiomer), tr(R) = 8.5 min.

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6. Results and discussion

6.1. Catalytic enantioselective arylation of ketones with Grignard

reagents

In this section of this chapter, a catalytic approach for the asymmetric arylation of

aryl alkyl ketones with Grignard reagents will be described, to afford highly valuable

diarylmethanols.99 The challenging formation of the new quaternary stereocenter

herein achieved, takes place with good levels of enantioselection, despite the fact

that both substrate and nucleophile have similar steric and electronic properties. The

use of readily accessible and inexpensive aryl Grignard reagents as nucleophiles is a

strong advantage of the methodology, compared with the more expensive diarylzinc

or organoboron reagents.

As a model reaction for this study, we chose the addition of PhMgBr to 2-

acetylnaphthalene (5a) due to the simplicity of both, nucleophile and substrate. At

the beginning of the investigation, four different solvents (DCM, TBME, toluene and

Et2O) were screened at 0 and 20 °C in the addition of PhMgBr to 2-acetylnaphtalene

(5a), catalyzed by (Sa,R)-L10, under the previously reported optimized conditions for

the alkylation of aliphatic aldehydes (see section 4.1 in this chapter). Both, Et2O and

toluene gave the best enantioselectivities (Table 22, entries 3-4 and 7-8) at 0 and 20

°C, although with poor conversions. Conversions were higher at 0 °C, and ee’s were

only slightly lower at this temperature. For this reason, Et2O at 0 °C was chosen as the

best solvent/temperature system, because it provided the best combination

between ee and conversion (Table 22, entry 8). It was observed that this reaction was

strongly temperature dependent; when the temperature was increased up to 25 °C,

full conversion and only 8% ee was achieved for the alcohol product 6a (Table 22,

entry 9).

99 a) Caprio, V.; Williams, J. M. J. Catalysis in Asymmetric Synthesis, 2nd Ed., Wiley: United Kingdom, 2009; b) Walsh,

P. J.; Kozlowski, M. C. Fundamentals of Asymmetric Catalysis, University Science Books, California, 2009; c) Jacobsen,

E. N.; Pfaltz, A.; Yamamoto, H. Comprehensive Asymmetric Catalysis: Suppl. 2, Springer-Verlag, Berlin, 2004.

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160

Table 22. Solvent and temperature screening[a]

Entry T (°C) Solvent Conv.

[b] (%) ee

[c] (%)

1 20 DCM 10 36

2 20 TBME 0 -

3 20 Toluene 20 55

4 20 Et2O 27 24

5 0 DCM 70 10 6 0 TBME 0 - 7 0 Toluene 56 44 8 0 Et2O 68 46 9 25 Et2O >99 8

[a] Conditions: 5a (0.1 mmol, 0.05 M), PhMgBr (3 M in Et2O, 2.5 eq.), Ti(Oi-Pr)4 (10 eq.), (Sa,R)-L10 (20 mol%), Et2O (1.5 mL), 0 °C, 12 h. [b] Determined by GC-MS analysis [c] Determined by chiral HPLC analysis.

In the next step of the optimization process, the influence of the ligand was studied,

comprising a selection of chiral diol ligands (Figure 10) with different electronic and

steric properties (Table 2). The use of (Sa,R)-L1 and the partially hydrogenated version

H8-(Sa,R)-L1 provided low conversions and enantiomeric excesses (Table 23, entries 1-

2). Methoxy substituted ligands L3-5 were also evaluated (Table 23, entries 3-5), but

proved to be inferior ligands than (Sa,R)-L10 under the tested conditions. The

arylation reaction of the model substrate 5a could be improved up to 74% ee and

50% conversion (Table 23, entry 6) with the bulky 1-naphtyl-substituted diol (Sa,R)-L7.

Interestingly, when the 1-naphtyl-substituted diol (Sa,R)-L8 was employed, both

conversion and enantioselectivity dropped to 27 and 40%, respectively (Table 23,

entry 7). To conclude the ligand secreening, commercially available (S)-BINOL was

tested in the same reaction and surprisingly no conversion was obtained (Table 23,

entry 9).

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161

Figure 10. Chiral diol ligands screened in this study

Table 23. Ligand optimization[a]

Entry L* Conv.

[b] (%) ee

[c] (%)

1 (Sa,R)-L1 32 36 2 H8-(Sa,R)-L1 28 10 3 (Sa,S)-L3 30 46 4 (Sa,R)-L4 32 26 5 (Sa,R)-L5 41 20 6 (Sa,R)-L7 50 74 7 (Sa,R)-L8 27 40 8 (Sa,R)-L10 68 46 9 (S)-BINOL 0 -

[a] Conditions: 5a (0.1 mmol, 0.05 M), PhMgBr (3 M in Et2O, 2.5 eq.), Ti(Oi-Pr)4 (10 eq.), (Sa,R)-L* (20 mol%), Et2O (1.5 mL), 0 °C, 12 h. [b] Determined by GC-MS analysis [c] Determined by chiral HPLC analysis.

From the previous work performed on the enantioselective addition of Grignard

reagents to aldehydes, we were well aware that the relative stoichiometries of Ti(Oi-

Pr)4 and Grignard reagent play a very important role in the enantioselectivity of the

reaction and a careful optimization of this parameter must be done to achieve good

results. For our model reaction, when less than 2.5 eq. of PhMgBr were employed as

nucleophile, poor conversions were obtained. For this reason, the amount of

nucleophile was set to this value and different amounts of the titanium source were

screened (Table 24, entries 1-4). Our tests revealed that a 4:1 ratio between the

Ti(Oi-Pr)4 and the Grignard reagent was optimal for the process (Table 24, entry 3).

The use of less than 10 eq. of Ti(Oi-Pr)4 led to a detrimental drop in enantioselectivity

(Table 24, entries 1-2), while a large excess of Ti(Oi-Pr)4 (12 eq.) impaired the

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conversion of the reaction (Table 24, entry 4). Increasing both nucleophile and Ti(Oi-

Pr)4 at a fixed optimal ratio of 4:1 slightly improved the conversion, but caused an

small decrease in the enantioselectivity of the reaction (Table 24, entry 5).

Table 24. Optimization Ti(Oi-Pr)4/PhMgBr ratio[a]

Entry Ti(Oi-Pr)4 (eq.) PhMgBr (eq.) Ti:Mg ratio Conv.

[b] (%) ee

[c] (%)

1 3 2.5 1.2:1 43 14 2 7.5 2.5 3:1 21 28 3 10 2.5 4:1 50 74 4 12 2.5 4.8:1 22 70 5 15 3.8 4:1 66 70

[a] Conditions: 5a (0.1 mmol, 0.05 M), PhMgBr (3 M in Et2O, x eq.), Ti(Oi-Pr)4 (y eq.), (Sa,R)-L7 (20 mol%), Et2O (1.5 mL), 0 °C, 12 h. [b] Determined by GC-MS analysis [c] Determined by chiral HPLC analysis.

6.2. Scope of the reaction

With the optimized conditions in hands, the addition of PhMgBr to different aryl alkyl

ketones was performed (Table 25). The arylation reaction was achieved in moderate

yields and good enantioselectivities (68-80%) for a wide variety of aryl methyl

ketones, with both electron-poor and electron-rich substituents at the meta and para

position (Table 25, entries 1-7). The arylation of o-methylacetophenone (5b) was an

exception and proceeded with very low yield, 12% (Table 25, entry 2), which did not

improve with longer reaction times (i.e. 24 h); this is probably due to steric hindrance

close to the reactive site.

The scope of this methodology includes heteroaryl and ,-unsaturated ketones,

that, although in moderate enantioselectivities, provided very good yields in the

addition of PhMgBr (Table 25, entries 8-9). For both substrates, the temperature was

decreased up to 20 °C in an attempt to improve the enantioselectivity, but the

reaction did not take place. Other alkyl aryl ketones were also examined. As

expected, increasing the size of the aliphatic substituent of the ketone (ethyl instead

of methyl) afforded better enantioselectivity but lower yields (Table 25, entry 10).

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Benzo-fused cyclic ketones, such as 5-methyl-1-indanone (5k) and 1-tetralone (5l),

were also tested under the optimized conditions. The addition of PhMgBr to the

more rigid indanone derivative (Table 25, entry 11) proceeded with good

enantioselectivity (76%) and in very high yield (92%). When the larger six membered

ring tetralone was employed, the best enantioselectivity of the series was reached,

92% (Table 25, entry 12) at the expense of a decrease in the yield of the reaction

(60%).

Table 25. Asymmetric addition of PhMgBr to ketones[a]

Entry Ketone Product Yield

[b] (%) ee

[c] (%)

1

50 76 (S)

2

(12)[d]

n.d.

3

40 76 (S)

4

45 76 (S)

5

43 72 (S)

6

50 80 (S)

7

42 68 (S)

8

78 46 (S)

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9

88 59 (R)

10

35 84 (S)

11

92 76 (S)

12

60 92 (S)

[a] Conditions: 5 (0.5 mmol, 0.06 M), PhMgBr (3 M in Et2O, 2.5 eq.), (Sa,R)-L7 (20 mol%), Ti(Oi-

Pr)4 (10 eq.), toluene (6 mL), 0 °C, 12 h. [b] Isolated yield after flash silica gel

chromatography. [c] Determined by chiral HPLC analysis. Absolute configuration of chiral

alcohols was determined by correlation of optical rotation with known compounds. [d]

Conversion in brackets was determined by GC-MS analysis.

The study was supplemented with the evaluation of different aryl Grignard reagents

as nucleophiles. The synthesis of chiral diaryl tertiary alcohols using Grignard

reagents as the aryl source is a very attractive and interesting strategy due to the

ready availability, facile synthesis and inexpensive character of these organometallic

species.

The addition of p-tolyl, p-methoxy and p-fluorophenylmagnesium bromide to

different acetophenone derivatives allowed the synthesis of alcohols 6d and 6m-p

(Table 26, entries 1-5) with enantioselectivities at the same levels as when PhMgBr

was employed as nucleophile. It is worth noting that the addition of p-

tolylmagnesium bromide to acetophenone allowed the formation of (R)-6d with

opposite stereochemistry from the addition of phenylmagnesium bromide to p-

methylacetophenone (Table 26, entry 1 vs Table 25, entry 4), using the same chiral

ligand (Sa,R)-L7. Furthermore, the use of the p-methoxy substituted Grignard reagent

provided very good yields; the highest on the series of experiments performed in this

study (Table 26, entries 3-4), probably due to electronic effect of methoxy group at

the Grignard reagent which confers more nucleophilic character. The addition of p-

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fluorophenylmagnesium bromide to 5-methyl-1-indanone (5k) provided the

corresponding alcohol 6q in good yield and enantioselectivity (Table 26, entry 6).

Table 26. Asymmetric addition of ArMgBr to ketones[a]

Entry Ketone Product Yield

[b] (%) ee

[c] (%)

1

54 66 (R)

2

40 77 (+)

3

96 82 (+)

4

>99 66 (+)

5

38 64 ()

6

82 80 (+)

[a] Conditions: 5 (0.5 mmol, 0.06 M), ArMgBr (3 M in Et2O, 2.5 eq.), (Sa,R)-L7 (20 mol%), Ti(Oi-Pr)4

(10 eq.), toluene (6 mL), 0 °C, 12 h. [b] Isolated yield after flash silica gel chromatography. [c]

Determined by chiral HPLC analysis. Absolute configuration of chiral alcohols was determined by

correlation of optical rotation with known compounds.

In conclusion, the first catalytic system for the addition of aryl Grignard reagents to

ketones has been developed. This methodology allows the preparation of challenging

optically active diaryl tertiary alcohols in a simple one-pot procedure and using

economical and readily available organometallic reagents. A bulky 1-naphthyl-

substituted ligand (Sa,R)-L7 and excess of titanium tetraisopropoxide were found to

be crucial in achieving good enantioselectivities. This work, together with the

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developments achieved on the enantioselective addition of Grignard reagents to

aldehydes, points toward the versatility of chiral diols L1-10 as catalysts for

asymmetric addition reactions to carbonyl compounds.

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7. Experimental part

7.1. General procedure for the enantioselective arylation of ketones

with Grignard reagents

In a flame dried Schlenk tube, (Sa,R)-L7 (42.7 mg, 0.1 mmol, 20 mol%) was dissolved

in anhydrous Et2O (6 mL) under argon atmosphere. The solution was cooled down to

0 °C and Ti(Oi-Pr)4 (1.53 mL, 5.0 mmol, 10 eq.) was then added. Five minutes later,

the corresponding ArMgBr (1.25 mmol, 2.5 eq.) was added. After stirring the mixture

for additional 15 min, the corresponding ketone (0.5 mmol) was added and the

reaction mixture was stirred at 0 °C for 12 h. The reaction was quenched with water

(5 mL) and then HCl 1 M (3 mL) to eliminate the titanium oxides generated by the

addition of water. The crude was extracted with EtOAc (3 × 10 mL), and the

combined organic layers were neutralized with a saturated NaHCO3 aqueous solution

(2 × 10 mL), dried over magnesium sulfate and concentrated under vacuum. The

crude product was purified by flash silica gel chromatography to give the desired

products.

7.2. Data of chiral tertiary alcohols

(S)-1-(Naphthalen-2-yl)-1-phenylethanol (6a):100 Compound 6a

was obtained after purification on flash silica gel

chromatography from 100:0 till 96:4 (n-hexane/EtOAc) as a

colorless viscous oil (50% yield, 76% ee); []D25 = -9.7 (c 1.0, CH2Cl2) {

Lit. []D25 = -16.1

(c 1.0, CH2Cl2) for 92% ee}. 1H NMR (300 MHz, CDCl3) 7.96 (s, 1H), 7.87 – 7.77 (m,

2H), 7.75 (d, J = 8.7 Hz, 1H), 7.49 – 7.37 (m, 5H), 7.36 – 7.18 (m, 3H), 2.32 (br s, 1H),

2.04 (s, 3H). 13C NMR (75 MHz, CDCl3) 147.7, 145.2, 133.0, 132.4, 129.6, 128.23,

128.20, 127.9, 127.5, 127.0, 126.1, 125.9, 124.9, 123.7, 115.3, 76.4, 30.7. LRMS (EI-

DIP): m/z (%): 249 [M++1] (10), 248 [M+] (52), 234 (18), 233 (100), 205 (11), 155 (15),

128 (11), 127 (23), 105 (74), 77 (20), 43 (19). Ee determination by chiral HPLC

100 Chen, C-A.; Wu, K-H.; Gau, H-M. Adv. Synth. Catal. 2008, 350, 1626–1634.

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analysis, Chiralcel® OJ column, n-hexane/i-PrOH 80:20, flow rate = 1.0 mL/min, =

220 nm, retention times: t1(S) = 14.7 min (major enantiomer), t2(R) = 18.5 min.

(S)-1-Phenyl-1-(m-tolyl)ethanol (6c):101 Compound 6c was

obtained after purification on flash silica gel chromatography

from 100:0 till 97:3 (n-hexane/EtOAc) as a pale yellow oil (40%

yield, 76% ee); []D27 = 4.6 (c 1.0, CH2Cl2) {

Lit. []D25 = 14.3 (c 1.2, CH2Cl2) for 86%

ee}. 1H NMR (300 MHz, CDCl3) 7.45 – 7.38 (m, 2H), 7.35 – 7.26 (m, 2H), 7.27 – 7.22

(m, 2H), 7.18 (m, 2H), 7.09 – 7.02 (m, 1H), 2.32 (s, 3H), 2.19 (br s, 1H), 1.93 (s, 3H). 13C

NMR (75 MHz, CDCl3) 148.1, 147.9, 137.7, 128.1, 128.0, 127.7, 126.9, 126.5, 125.8,

122.9, 76.2, 30.9, 21.6. LRMS (EI): m/z (%): 212 [M+] (7), 198 (16), 197 (100), 194 (10),

179 (14), 178 (11), 119 (16), 105 (42), 91 (14), 77 (13). Ee determination by chiral

HPLC analysis, Chiralpak® IA column, n-hexane/i-PrOH 99:1, flow rate = 0.5 mL/min,

= 210 nm, retention times: t1(S) = 38.8 min (major enantiomer), t2(R) = 45.6 min.

(S)-1-Phenyl-1-(p-tolyl)ethanol (6d):101 Compound 6d was

obtained after purification on flash silica gel chromatography

from 100:0 till 95:5 (n-hexane/EtOAc) as a pale yellow oil (45%

yield, 76% ee); []D25 = 7.5 (c 1.0, CH2Cl2) {

Lit. []D25 = +16.0 (c 1.2, CH2Cl2) for 96% ee

for the (R) enantiomer}. 1H NMR (300 MHz, CDCl3) 7.45 – 7.36 (m, 2H), 7.34 – 7.19

(m with a d at 7.29, J = 8.0 Hz, 5H), 7.11 (d, J = 8.0 Hz, 2H), 2.32 (s, 3H), 2.21 (br s, 1H),

1.92 (s, 3H). 13C NMR (75 MHz, CDCl3) 148.2, 145.1, 136.6, 128.8, 128.1, 126.8,

125.8, 76.1, 30.8, 21.0. LRMS (EI): m/z (%): 212 [M+] (7), 198 (16), 197 (100), 194 (11),

179 (14), 178 (11), 119 (22), 105 (35), 91 (14), 77 (13). Ee determination by chiral

HPLC analysis, Chiralpak® AD-H column, n-hexane/i-PrOH 99:1, flow rate = 0.5

mL/min, = 210 nm, retention times: t1(R) = 46.1 min, t2(S) = 48.7 min (major

enantiomer).

101 Forrat, V. J.; Prieto, O.; Ramón, D. J.; Yus, M. Chem. Eur. J. 2006, 12, 4431–4445.

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(S)-1-(4-Methoxyphenyl)-1-phenylethanol (6e):100 Compound

6e was obtained after purification on flash silica gel

chromatography from 100:0 till 94:6 (n-hexane/EtOAc) as a

pale yellow oil (43% yield, 72% ee); []D28 = 12.3 (c 1.0, CH2Cl2) {

Lit. []D25 = 14.6 (c

0.7, CH2Cl2) for 90% ee}. 1H NMR (300 MHz, CDCl3) 7.44 – 7.36 (m, 2H), 7.35 – 7.27

(m with a d at 7.32, J = 8.9 Hz, 4H), 7.27 – 7.18 (m, 1H), 6.83 (d, J = 8.9 Hz, 2H), 3.78

(s, 3H), 2.18 (br s, 1H), 1.92 (s, 3H). 13C NMR (75 MHz, CDCl3) 158.5, 148.3, 140.3,

128.1, 127.1, 126.8, 125.7, 113.4, 75.9, 55.2, 31.0. LRMS (EI): m/z (%): 228 [M+] (7),

213 (46), 211 (17), 210 (100), 209 (12), 195 (52), 179 (12), 178 (11), 167 (15), 166

(11), 165 (33), 152 (23), 151 (10), 135 (12), 105 (16), 77 (10). Ee determination by

chiral HPLC analysis, Chiralcel® OJ column, n-hexane/i-PrOH 80:20, flow rate = 1.0

mL/min, = 210 nm, retention times: t1(R) = 17.0 min, t2(S) = 20.7 min (major

enantiomer).

(S)-1-Phenyl-1-[3-(trifluoromethyl)phenyl]ethanol (6f):100

Compound 6f was obtained after purification on flash silica gel

chromatography from 100:0 till 94:6 (n-hexane/EtOAc) as a

yellow viscous oil (50% yield, 80% ee); []D24 = +18.5 (c 1.0, CH2Cl2) {

Lit. []D25 = +24.8

(c 4.5, CH2Cl2) for 93% ee}. 1H NMR (300 MHz, CDCl3) 7.76 (s, 1H), 7.54 (d, J = 7.8 Hz,

1H), 7.50 (d, J = 7.8 Hz, 1H), 7.44 – 7.21 (m, 6H), 2.26 (br s, 1H), 1.96 (s, 3H). 13C NMR

(75 MHz, CDCl3) 149.0, 147.0, 130.4 (q, JC–F = 32.1 Hz), 129.4, 128.6, 128.4, 127.4,

125.8, 124.3 (q, JC–F = 272.0 Hz), 123.7 (q, JC–F = 3.6 Hz), 122.4 (q, JC–F = 3.5 Hz), 76.0,

30.8. 19F NMR (282 MHz, CDCl3) -62.5. LRMS (EI): m/z (%): 266 [M+] (3), 252 (16),

251 (100), 173 (49), 145 (17), 105 (9), 77 (9). Ee determination by chiral HPLC

analysis, Chiralcel® OD-H column, n-hexane/i-PrOH 96:4, flow rate = 1.0 mL/min, =

220 nm, retention times: t1(R) = 9.6 min, t2(S) = 11.2 min (major enantiomer).

(S)-1-(4-Chlorophenyl)-1-phenylethanol (6g):100 Compound 6g

was obtained after purification on flash silica gel

chromatography from 100:0 till 97:3 (n-hexane/EtOAc) as a

colorless oil (42% yield, 68% ee); []D28 = +6.3 (c 1.0, CH2Cl2) {

Lit. []D25 = +8.8 (c 3.2,

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CH2Cl2) for 92% ee}. 1H NMR (300 MHz, CDCl3) 7.42 – 7.30 (m with a d at 7.33, J =

8.9 Hz, 5H), 7.30 – 7.19 (m with a d at 7.26, J = 8.9 Hz, 4H), 2.24 (br s, 1H), 1.92 (s,

3H). 13C NMR (75 MHz, CDCl3) 147.4, 146.5, 132.7, 128.3, 128.2, 127.3, 127.2,

125.7, 75.9, 30.8. LRMS (EI): m/z (%): 232 [M+] (7), 219 (33), 218 (15), 217 (100), 141

(12), 139 (38), 111 (10), 105 (19), 77 (13). Ee determination by chiral HPLC analysis,

Chiralpak® AD-H column, n-hexane/i-PrOH 99:1, flow rate = 1.0 mL/min, = 230 nm,

retention times: t1(R) = 16.5 min, t2(S) = 17.8 min (major enantiomer).

(S)-1-(Furan-2-yl)-1-phenylethanol (6h):102 Compound 6h was

obtained after purification on flash silica gel chromatography from

100:0 till 95:5 (n-hexane/EtOAc) as a yellow oil (78% yield, 46% ee);

[]D29 = 16.5 (c 1.0, CH2Cl2) {

Lit. []D22 = 34.1 (c 5.4, CH2Cl2) for 96% ee}. 1H NMR

(300 MHz, CDCl3) 7.43 – 7.22 (m, 6H), 6.33 (dd, J = 3.2, 1.8 Hz, 1H), 6.24 (dd, J = 3.2,

0.8 Hz, 1H), 2.54 (br s, 1H), 1.87 (s, 3H). 13C NMR (75 MHz, CDCl3) 158.9, 145.8,

142.1, 128.1, 127.3, 125.2, 110.0, 106.2, 73.0, 29.2. LRMS (EI): m/z (%): 188 [M+] (32),

174 (12), 173 (100), 171 (12), 170 (36), 169 (12), 141 (28), 115 (23), 111 (15), 105

(16), 95 (65), 77 (17). Ee determination by chiral HPLC analysis, Chiralcel® OD-H

column, n-hexane/i-PrOH 99:1, flow rate = 0.5 mL/min, = 220 nm, retention times:

t1(R) = 30.1 min, t2(S) = 33.4 min (major enantiomer).

(R,E)-2,4-Diphenylbut-3-en-2-ol (6i):103 Compound 6i was

obtained after purification on flash silica gel chromatography

from 100:0 till 95:5 (n-hexane/EtOAc) as a pale yellow oil (88%

yield, 59% ee); []D26 = 9.7 (c 1.0, CHCl3) {

Lit. []D22 = 12.7 (c 2.5, CHCl3) for 81% ee}.

1H NMR (300 MHz, CDCl3) 7.51 (d, J = 8.2 Hz, 2H), 7.41 – 7.17 (m, 8H), 6.64 (d, J =

16.1 Hz, 1H), 6.50 (d, J = 16.1 Hz, 1H), 2.06 (br s, 1H), 1.75 (s, 3H). 13C NMR (75 MHz,

CDCl3) 146.6, 136.7, 136.3, 128.5, 128.3, 127.7, 127.6, 127.1, 126.5, 125.2, 74.7,

29.8. LRMS (EI): m/z (%): 224 [M+] (14), 209 (12), 206 (48), 205 (24), 203 (12), 202

(10), 191 (21), 182 (17), 181 (100), 178 (10), 166 (12), 165 (15), 131 (15), 129 (12),

102 Stymiest, J. L.; Bagutski, V.; French R. M.; Aggarwal, V. K. Nature 2008, 456, 778–782. 103 Ueda, T.; Tanaka, K.; Ichibakase, T.; Orito, Y.; Nakajima, M. Tetrahedron 2010, 66, 7726–7731.

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128 (18), 105 (20), 103 (22), 91 (29), 77 (21). Ee determination by chiral HPLC

analysis, Chiralpak® AS-H column, n-hexane/i-PrOH 99:1, flow rate = 0.5 mL/min, =

230 nm, retention times: t1(S) = 20.0 min, t2(R) = 21.9 min (major enantiomer).

(S)-1-(4-Bromophenyl)-1-phenylpropan-1-ol (6j):101 Compound

6j was obtained after purification on flash silica gel

chromatography from 100:0 till 98:2 (n-hexane/EtOAc) as a pale

yellow oil (35% yield, 84% ee); []D29 = +8.7 (c 1.0, CH2Cl2) {Lit. []D

25 = +9.9 (c 1.7,

CH2Cl2) for 80% ee}. 1H NMR (300 MHz, CDCl3) 7.41 (d, J = 8.8 Hz, 2H), 7.38 (d, J =

8.8 Hz, 2H), 7.35 – 7.17 (m, 5H), 2.28 (q, J = 7.3 Hz, 2H), 2.05 (s, 1H), 0.87 (t, J = 7.3 Hz,

3H). 13C NMR (75 MHz, CDCl3) 146.4, 145.9, 131.1, 128.3, 128.0, 127.0, 126.0,

120.7, 78.2, 34.3, 8.0. LRMS (EI): m/z (%): 291 [M+] (<1), 264 (14), 263 (97), 262 (15),

261 (100), 185 (32), 183 (33), 105 (30), 77 (16). Ee determination by chiral HPLC

analysis, Chiralpak® IA column, n-hexane/i-PrOH 99:1, flow rate = 0.5 mL/min, =

230 nm, retention times: t1(R) = 48.6 min, t2(S) = 53.7 min (major enantiomer).

(+)-5-Methyl-1-phenyl-2,3-dihydro-1H-inden-1-ol (6k): Compound

6k was obtained after purification on flash silica gel chromatography

from 100:0 till 95:5 (n-hexane/EtOAc) as a yellow viscous oil (92%

yield, 76% ee); []D29 = +13.6 (c 1.0, CH2Cl2).

1H NMR (300 MHz,

CDCl3) 7.43 – 7.19 (m, 5H), 7.13 (s, 1H), 7.02 (d, J = 7.7 Hz, 1H), 6.96 (d, J = 7.7 Hz,

1H), 3.21 – 3.04 (dt, J = 16.0, 7.3 Hz, 1H), 2.98 – 2.81 (dt, J = 16.0, 6.4 Hz, 1H), 2.51 –

2.41 (m, 2H), 2.36 (s, 3H), 2.11 (s, 1H). 13C NMR (75 MHz, CDCl3) 146.5, 145.2, 144.3,

138.3, 128.0, 127.9, 126.8, 125.7, 125.5, 123.7, 85.2, 45.0, 29.8, 21.4. IR (ATR): (cm-

1): 3381, 2938, 1612, 1492, 1446, 1047. LRMS (EI): m/z (%): 224 [M+] (<1), 222 (15),

194 (44), 193 (30), 180 (20), 179 (100), 178 (55), 165 (8), 89 (11). HRMS (ESI): m/z:

207.1174 calculated for C16H15 [M–OH]+, found 207.1183. Ee determination by chiral

HPLC analysis, Chiralcel® OD-H column, n-hexane/i-PrOH 96:4, flow rate = 1.0

mL/min, = 220 nm, retention times: t1(R) = 7.8 min, t2(S) = 10.3 min (major

enantiomer).

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(S)-1-Phenyl-1,2,3,4-tetrahydronaphthalen-1-ol (6l):104 Compound 6l

was obtained after purification on flash silica gel chromatography from

100:0 till 97:3 (n-hexane/EtOAc) as a yellow viscous oil (60% yield, 92%

ee); []D27 = -29.5 (c 1.0, CHCl3) {

Lit. []D22 = -32.0 (c 4.2, CHCl3) for >99%

ee}. 1H NMR (300 MHz, CDCl3) 7.40 – 6.99 (m, 9H), 2.94 – 2.84 (m, 2H), 2.19 (br s,

1H), 2.16 – 2.09 (m, 2H), 2.05 – 1.91 (m, 1H), 1.86 – 1.70 (m, 1H). 13C NMR (75 MHz,

CDCl3) 148.9, 142.0, 137.6, 128.9, 128.8, 127.7, 127.5, 126.6, 126.44, 126.38, 75.3,

41.4, 29.9, 19.6. LRMS (EI): m/z (%): 224 [M+] (22), 207 (14), 206 (75), 205 (11), 196

(22), 195 (100), 191 (16), 178 (14), 165 (12), 147 (59), 146 (15), 129 (11), 128 (11),

105 (10), 91 (26), 77 (15). Ee determination by chiral HPLC analysis, Chiralcel® OD-H

column, n-hexane/i-PrOH 99:1, flow rate = 1.0 mL/min, = 220 nm, retention times:

t1(R) = 9.7 min, t2(S) = 13.2 min (major enantiomer).

(+)-1-(3-Methoxyphenyl)-1-(p-tolyl)ethanol (6m):

Compound 6m was obtained after purification on flash silica

gel chromatography from 100:0 till 96:4 (n-hexane/EtOAc)

as a yellow oil (40% yield, 77% ee); []D29 = +15.8 (c 1.0, CH2Cl2).

1H NMR (300 MHz,

CDCl3) 7.29 (d, J = 8.2 Hz, 2H), 7.21 (dd, J = 8.2, 7.8, 1H), 7.11 (d, J = 8.2 Hz, 2H), 7.01

(dd, J = 2.6, 1.7, 1H), 6.94 (ddd, J = 7.8, 1.7, 0.9 Hz, 1H), 6.76 (ddd, J = 8.2, 2.6, 0.9 Hz,

1H), 3.77 (s, 3H), 2.31 (s, 3H), 2.21 (br s, 1H), 1.91 (s, 3H). 13C NMR (75 MHz, CDCl3)

159.4, 149.9, 144.9, 136.6, 129.1, 128.8, 125.7, 118.3, 111.9, 76.0, 55.2, 30.8, 21.0. IR

(ATR): (cm-1): 3452, 2925, 1600, 1485, 1432, 1253. LRMS (EI): m/z (%): 242 [M+]

(37), 228 (17), 227 (100), 224 (12), 135 (31), 119 (57), 91 (15). HRMS (ESI): m/z:

225.1279 calculated for C16H17O [M–OH]+, found 225.1290. Ee determination by

chiral HPLC analysis, Chiralcel® OJ column, n-hexane/i-PrOH 90:10, flow rate = 1.0

mL/min, = 210 nm, retention times: t1(S) = 22.1 min (major enantiomer), t2(R) =

27.3 min.

104 Jaouen, G.; Meyer, A. J. Am. Chem. Soc. 1975, 97, 4667–4672

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(+)-1-(4-Methoxyphenyl)-1-[3-

(trifluoromethyl)phenyl]ethanol (6n): Compound 6n was

obtained after purification on flash silica gel

chromatography from 100:0 till 91:9 (n-hexane/EtOAc) as a yellow viscous oil (96%

yield, 82% ee); []D29 = +32.5 (c 1.0, CH2Cl2).

1H NMR (300 MHz, CDCl3) 7.75 (s, 1H),

7.53 (d, J = 7.7 Hz, 1H), 7.49 (d, J = 7.7 Hz, 1H), 7.40 (t, J = 7.7 Hz, 1H), 7.31 (d, J = 8.9

Hz, 2H), 6.85 (d, J = 8.9 Hz, 2H), 3.79 (s, 3H), 2.22 (br s, 1H), 1.94 (s, 3H). 13C NMR (75

MHz, CDCl3) 158.8, 149.4, 139.3, 130.4 (q, JC–F = 32.1 Hz), 129.3, 128.5, 127.2, 124.2

(q, JC–F = 272.3 Hz), 123.6 (q, JC–F = 3.8 Hz), 122.3 (q, JC–F = 3.8 Hz), 113.7, 75.7, 55.3,

31.0. 19F NMR (282 MHz, CDCl3) -62.4. IR (ATR): (cm-1): 3456, 2962, 1611, 1510,

1327, 1254, 1162, 1119. LRMS (EI): m/z (%): 296 [M+] (19), 282 (17), 281 (100), 278

(15), 173 (56), 151 (19), 145 (18), 135 (10). HRMS (ESI): m/z: 279.0997 calculated for

C16H14F3O [M–OH]+, found 279.0995. Ee determination by chiral HPLC analysis,

Chiralcel® OD-H column, n-hexane/i-PrOH 99:1, flow rate = 1.0 mL/min, = 220 nm,

retention times: t1(R) = 18.9 min, t2(S) = 19.9 min (major enantiomer).

(+)-1-(4-Bromophenyl)-1-(4-methoxyphenyl)ethanol (6o):

Compound 6o was obtained after purification on flash

silica gel chromatography from 100:0 till 90:10 (n-

hexane/EtOAc) as a yellow viscous oil (>99% yield, 66% ee); []D29 = +15.8 (c 1.0,

CH2Cl2). 1H NMR (300 MHz, CDCl3) 7.41 (d, J = 8.8 Hz, 2H), 7.28 (d, J = 7.2 Hz, 2H),

7.25 (d, J = 7.2 Hz, 2H), 6.83 (d, J = 8.8 Hz, 2H), 3.77 (s, 3H), 2.26 (br s, 1H), 1.88 (s,

3H). 13C NMR (75 MHz, CDCl3) 158.6, 147.4, 139.6, 131.1, 127.6, 127.1, 120.7,

113.5, 75.6, 55.2, 30.8. IR (ATR): (cm-1): 3449, 2974, 1608, 1509, 1509, 1248, 1176.

LRMS (EI): m/z (%): 308 [M++1] (17), 307 [M+] (3), 306 (17), 294 (14), 293 (92), 292

(16), 291 (100), 290 (34), 288 (34), 185 (32), 183 (33), 166 (17), 165 (25), 151 (18),

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135 (26). HRMS (ESI): m/z: 289.0228 calculated for C15H14BrO [M–OH]+, found

289.0227. Ee determination by chiral HPLC analysis, Chiralcel® OJ column, n-

hexane/i-PrOH 97:3, flow rate = 1.0 mL/min, = 230 nm, retention times: t1(S) = 58.0

min (major enantiomer), t2(R) = 63.0 min.

(-)-1-(3,4-Dimethoxyphenyl)-1-(4-fluorophenyl)ethanol

(6p): Compound 6p was obtained after purification on

flash silica gel chromatography from 100:0 till 75:25 (n-

hexane/EtOAc) as a yellow viscous oil (38% yield, 64% ee); []D29 = 4.8 (c 1.0,

CH2Cl2). 1H NMR (300 MHz, CDCl3) 7.36 (dd, 3J = 9.0, JH–F = 5.4 Hz, 2H), 6.98 (t, 3J ≈

JH–F = 9.0 Hz, 2H), 6.94 (d, J = 2.1 Hz, 1H), 6.89 (dd, J = 8.4, 2.1 Hz, 1H), 6.79 (d, J = 8.4

Hz, 1H), 3.86 (s, 3H), 3.81 (s, 3H), 2.28 (br s, 1H), 1.91 (s, 3H). 13C NMR (75 MHz,

CDCl3) 161.6 (d, JC–F = 245.4 Hz), 148.6, 148.0, 143.9 (d, JC–F = 2.9 Hz), 140.5, 127.5

(d, JC–F = 8.0 Hz), 117.9, 114.7 (d, JC–F = 21.2 Hz), 110.4, 109.5, 75.7, 55.8, 31.2. 19F

NMR (282 MHz, CDCl3) -116.2. IR (ATR): (cm-1): 3505, 2933, 1735, 1601, 1505,

1255, 1222, 1143. LRMS (EI): m/z (%): 276 [M+] (38), 261 (50), 259 (19), 258 (100),

243 (13), 183 (19), 171 (13), 170 (11), 123 (75), 121 (14). HRMS (ESI): m/z: 259.1134

calculated for C16H16FO2 [M–OH]+, found 259.1126. Ee determination by chiral HPLC

analysis, Chiralcel® OJ column, n-hexane/i-PrOH 85:15, flow rate = 1.0 mL/min, =

210 nm, retention times: t1(R) = 21.6 min, t2(S) = 37.5 min (major enantiomer).

(+)-1-(4-Fluorophenyl)-5-methyl-2,3-dihydro-1H-inden-1-ol (6q):

Compound 6q was obtained after purification on flash silica gel

chromatography from 100:0 till 96:4 (n-hexane/EtOAc) as a yellow

viscous oil (82% yield, 80% ee); []D29 = +17.5 (c 1.0, CH2Cl2).

1H NMR

(300 MHz, CDCl3) 7.35 (dd, 3J = 9.0, JH–F = 5.4 Hz, 2H), 7.14 (s, 1H),

7.04 (d, J = 7.7 Hz, 1H), 6.98 (t, 3J ≈ JH–F = 9.0 Hz, 2H), 6.95 (d, J = 7.7 Hz, 1H), 3.12 (dt, J

= 16.0, 7.2 Hz, 1H), 2.88 (dt, J = 16.0, 6.4 Hz, 1H), 2.43 (dd, J = 7.2, 6.4 Hz, 2H), 2.37 (s,

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3H), 2.06 (br s, 1H). 13C NMR (75 MHz, CDCl3) 161.8 (d, JC–F = 245.0 Hz), 145.0,

144.3, 142.2 (d, JC–F = 3.0 Hz), 138.6, 128.0, 127.4 (d, JC–F = 8.0 Hz), 125.6, 123.6, 114.7

(d, JC–F = 21.2 Hz), 84.9, 45.1, 29.7, 21.4. 19F NMR (282 MHz, CDCl3) -116.6. IR (ATR):

(cm-1): 3384, 2940, 1602, 1506, 1221, 1157. LRMS (EI-DIP): m/z (%): 243 [M++1]

(17), 242 [M+] (100), 241 (50), 228 (11), 227 (68), 226 (30), 225 (50), 224 (21), 212

(12), 210 (11), 209 (16), 207 (10), 183 (14), 148 (11), 147 (99), 133 (11), 123 (15), 105

(11), 95 (17), 91 (11). HRMS (ESI): m/z: 225.1080 calculated for C16H14F [M–OH]+,

found 225.1078. Ee determination by chiral HPLC analysis, Chiralcel® OD-H column,

n-hexane/i-PrOH 96:4, flow rate = 1.0 mL/min, = 220 nm, retention times: t1(R) =

7.1 min, t2(S) = 9.5 min (major enantiomer).

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CHAPTER IV

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1. Introduction

Organoaluminum reagents are organometallic compounds with, at least, one C-Al

bond in chemical structure. The most common organoaluminum reagents described

in the literature are R3Al, R2AlX and RAlX2, where R are alkyl or aryl moieties and X

halogens.

The first organoaluminium compound, Et3Al2I3, was discovered and isolated in

1859.105 However, organoaluminum compounds were known since 1953, when Karl

Ziegler and Giulio Natta discovered the direct synthesis of trialkylaluminium

compounds and applied them to catalytic olefin polymerization. Ziegler and Natta

were awarded Nobel Prize in 1963 for their research in this area.

Amongst the most common organometallic species, organoaluminum reagents stand

out for practical applications, since they can be economically obtained on an

industrial scale.106 Additional advantages of organoaluminum compounds include low

toxicities and considerable stabilities.

Scheme 52. Methods for the synthesis of organoaluminum reagents

On the other hand, the straightforward synthesis of R3Al makes them valuable

compounds for organic chemistry. The most common methods for the preparation of

organoaluminum compounds are: direct reaction between RLi or RMgX and AlCl3 (A,

Scheme 52), hydroalumination of akynes with R2AlH (B, Scheme 52),

carboalumination of alkynes with R3Al (C, Scheme 52) and another method for the

105 Hallwachs, W.; Schafarik, A. Liebigs Ann. Chem. 1859, 109, 206–209. 106 Cotton, F. A.; Wilkinson, G. Advanced Inorganic Chemistry, 5th ed.; Wiley: New York, 1988.

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preparation of these compounds, although less used due to the toxicity of the

procedure, is the transmetallation of organomercury compounds with pure

aluminum metal (D, Scheme 52).

1.1. Catalytic enantioselective addition of organoaluminum reagents

to aldehydes

In 1986, the first enantioselective alkylation of aldehydes with organoaluminum

reagents was developed by Mukaiyama´s group.107 The allylation of different

aldehydes was carried out at –78 ᵒC in DCM as solvent using Allyl(i-Bu)2Al as

nucleophile, Sn(OTf)2 as additive and the chiral diamine XLVII (1.9 eq.) as ligand. The

enantioselectivities of the corresponding homoallylic alcohols varied from good to

very good for aromatic aldehydes and moderate for aliphatic aldehydes (Scheme 53).

Scheme 53. First enantioselective addition of Allyl(i-Bu)2Al to aldehydes promoted by XLVII.

In 1997, Chan´s group achieved the first catalytic enantioselective addition of Et3Al to

aromatic aldehydes catalyzed by 20 mol% of (S)-BINOL (IV) or H8-(S)-BINOL (XXXIV)

and an excess of Ti(Oi-Pr)4 (1.4 eq.) under very mild reaction condition.108 Ligand (S)-

XXXIV provides better enantiomeric excess for the corresponding secondary alcohols

(90-96%) compared to the non-hydrogenated analogous (R)-IV ligand (Scheme 54).

107 Mukaiyama, T.; Minowa, N.; Oriyama, T.; Narasaka, K. Chem. Lett. 1986, 97–100. 108 Chan, A. S. C.; Zhang, F.-Y.; Yip, C.-W. J. Am. Chem. Soc. 1997, 119, 40804081.

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Scheme 54. First catalytic enantioselective addition of Et3Al to aldehydes catalyzed by IV and XXXIV.

Very interesting studies were carried out by Carreira´s group in 1988, on the

enantioselective addition of Me3Al to different aldehydes, employing, for the first

time, a catalytic amount of a transmetallating agent such as TiF4 (14 mol%) and a

chiral diol XLVIII (15 mol%) as ligand.109 The excess of Me3Al (1.4 eq.) is necessary to

deprotonate the chiral diol and form the corresponding aluminum alcoxide, which

transmetallates in situ to the real active catalyst, dialcoxide-TiF2 (XLIX). Moderate to

very good enantioselectivities can be achieved with this methodology for the

methylation of different aldehydes (Scheme 55).

Scheme 55. Asymmetric addition of Me3Al to aldehydes catalyzed by chiral diol XLVIII.

In 2005, Bauer´s group tested different commercially available chiral -hydroxy

carboxylic acids as chiral ligands in the ethylation reaction of different aldehydes with

Et3Al (1.5 eq.) as nucleophile.110 The best results (up to 92% ee) were achieved with

20 mol% of (S)-mandelic acid (L) and 1.4 eq. of titanium tetraisopropoxide in THF

from 0 ᵒC to room temperature (Scheme 56).

109 Pagenkopf, B. L.; Carreira, E. M. Tetrahedron Lett. 1998, 39, 9593–9596. 110 Bauer, T.; Gajewiak, J. Tetrahedron: Asymmetry 2005, 16, 851–855.

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182

Scheme 56. Asymmetric addition of Me3Al to aldehydes catalyzed by -hydroxy carboxilic acid L.

In the same year, Woodward´s group designed two ingenious catalytic systems for

the methylation and ethylation of aldehydes with organoaluminum reagents,111 out

of the classical titanium-diol systems (Scheme 57). Both methodologies are based on

the use of only 2 mol% of a chiral phosphoramidite (LI) and 1 mol% of Ni(acac)2.

When highly stable (R3Al)2·DABCO complex is used as nucleophile, milder reaction

conditions can be employed (5 ᵒC), due to its lower reactivity compared to the free

R3Al nucleophiles, which require much lower temperatures (–20 ᵒC). Moreover, the

use of (R3Al)2·DABCO complex gives, in general, better enantiomeric excess in the

corresponding addition products than the free organoaluminum reagents. Both

methodologies, however, give moderate selectivities when aliphatic aldehydes (R1 =

alkyl) are used as substrates.

Scheme 57. Asymmetric addition of R3Al and (R3Al)2·DABCO to aldehydes catalyzed by phosphoramidite

LI.

111 Biswas, K.; Prieto, Oscar.; Goldsmith, P. J.; Woodward, S. Angew. Chem. Int. Ed. 2005, 44, 2232 –2234.

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183

In collaboration with Prof. Woodward, Pamies and Diéguez´s group reported new

chiral sugar phosphite-oxazoline ligands (1 mol%, LII, Scheme 58) for the addition of

Me3Al and (Me3Al)2·DABCO to different aldehydes, using Ni(acac)2 (1 mol%).112 Poor

yields and enantioselectivities were achieved for this initial catalytic system, but a

second generation of sugar monophosphite ligands (LIII), under the same reaction

conditions, provided much satisfactory results (ee´s up to 84% and yields up to

99%).113

Scheme 58. Asymmetric addition of organoaluminum reagents to aldehydes catalyzed by sugar

phosphites LII and LIII.

In 2006, Gau´s group developed the first catalytic enantioselective arylation of

aldehydes with organoaluminum reagents.114 The reaction was carried out in THF at 0

ᵒC, using 1.2 eq. of Ar3Al·(THF), 1.3 eq. of Ti(Oi-Pr)4 and in only 10 min the

corresponding chiral diaryl alcohols were obtained with excellent levels of selectivity

and yield, employing (R)-H8-Tinanium BINOLate (LIV, 10 mol%) as ligand (Scheme 59).

In addition, the use of ArEt2Al·(THF) in the selective arylation of aldehydes, using

ligand LIV and Ti(Oi-Pr)4, provided the corresponding chiral alcohols with high ee and

yields, even for aliphatic substrates (Scheme 59).115

112 Mata, Y.; Diéguez, M.; Pàmies, O.; Woodward, S. Inorg. Chim. Acta 2008, 361, 1381–1384. 113 Alegre, S.; Diéguez, M.; Pàmies, O. Tetrahedron: Asymmetry 2011, 22, 834–839 114 Wu, K-H.; Gau, H-M. J. Am. Chem. Soc. 2006, 128, 14808–14809. 115 Zhou, S.; Wu, K-H.; Chen, C-A.; Gau, H-M. J. Org. Chem. 2009, 74, 3500–3505.

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Scheme 59. Asymmetric arylation of aldehydes with Ar3Al·(THF) and ArEt2Al·(THF) catalyzed by LIV.

The group of Gau also reported the phenylation reaction of different aldehydes using

the chiral hydroxysulfonamide LV as ligand and Ar3Al·(THF) as nucleophiles.116

Interestingly, higher amounts of chiral ligand, nucleophile and Ti(Oi-Pr)4 are required

for this catalytic system, in order to achieve comparable results to previous work

(Scheme 60). On the other hand, complex LVI (5 mol%) provided better results (ee >

90%), with shorter reaction times, in the enantioselective arylation of aldehydes

using Ar3Al·(THF) as nucleophile (Scheme 60).117

Scheme 60. Asymmetric arylation of aldehydes with Ar3Al·(THF) catalyzed by ligands LV and LVI.

In 2013, Harada´s group reported the first catalytic enantioselective vinylation of

aldehydes with organoaluminum reagents.118 The corresponding nucleophiles were

prepared through hydroalumination of the corresponding alkyne. Different allylic

alcohols were prepared with this methodology using the chiral binaphtol XXXII as

ligand, under mild reaction conditions. High enantioselectivities were achieved for a

116 Hsieh, S-H.; Chen, C-A.; Chuang, D-W.; Yang, M-C.; Yang, H-T.; Gau, H-M. Chirality 2008, 20, 924–929. 117 Zhou, S.; Chuang, D-W.; Chang, S-J.; Gau, H-M. Tetrahedron: Asymmetry 2009, 20, 1407–1412. 118 Kumar, R.; Kawasaki, H.; Harada, T. Chem. Eur. J. 2013, 19, 17707–17710.

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185

wide variety of (vinyl)Me2Al nucleophiles, although yields were moderated (Scheme

61).

Scheme 61. Asymmetric vinylation of aldehydes organoaluminum reagents catalyzed by binaphtol XXXII.

Not many examples of catalytic enantioselective additions of organoluminium

reagents to aldehydes have been described in the literature, in spite of the many

advantages that this type of organometallic compounds offers.

So, by the previous reason, we decided to explore the use of organoaluminum as

nucleophiles in the enantioselective addition to aldehydes that will be described in

the next section.

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2. Results and discussion

2.1. Optimization of the catalytic enantioselective addition of

organoaluminum reagents to aldehydes

The optimization process for the asymmetric alkylation of aldehydes with

organoaluminium reagents was conducted with the addition of Me3Al, as

nucleophile, to benzaldehyde (1a). The first tests carried out with Ar-BINMOL ligands,

provided very promising results (Table 1); the desired alcohol 2a was obtained with

95% enantioselectivity and 82% conversion when 1a was added into a toluene

solution containing 20 mol% of (Sa,R)-L1, 3 eq. of Me3Al and 4 eq. of Ti(Oi-Pr)4 at 20

°C (Table 27, entry 1). In order to increase the conversion, the temperature was

raised to 0 °C, which meant a severe drop in enantioselectivity (Table 27, entry 2).

Based on our previous knowledge on the solvent suitability for this catalytic system,

Et2O was chosen as an alternative to toluene. Three different temperatures were

tested with Et2O as solvent (Table 27, entries 3-5) and only when the reaction was

carried out at 0 °C, full conversion was achieved, preserving the enantioselectivity at

96% (Table 27, entry 4).

Table 27. Influence of catalyst loading and temperature[a]

Entry (Sa,R)-L1 (mol%) Solvent T (°C) Conv.

[b] (%) ee

[b] (%)

1 20 Toluene 20 82 96

2 20 Toluene 0 >99 20

3 20 Et2O 20 55 95 4 20 Et2O 0 >99 96 5 20 Et2O 20 99 68 6 10 Et2O 0 >99 94 7 5 Et2O 0 >99 86

[a] Conditions: 1a (0.1 mmol, 0.07 M), Me3Al (2 M in toluene, 3 eq.), (Sa,R)-L1 (x mol%), Ti(Oi-Pr)4 (4 eq.), toluene or Et2O (1.5 mL), T (°C), 3 h. [b] Determined by chiral GC analysis.

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Moreover, under these conditions, the catalyst loading could be reduced to 10 mol%

without any significant loss of enantioselectivity (Table 27, entry 6). However, when 5

mol% of ligand (Sa,R)-L1 was employed, a small decrease in the enantioselectivity was

observed without affecting the conversion (Table 27, entry 7).

Different solvents were also evaluated (Table 28), to confirm that diethyl ether was

the best choice for this reaction. For polar and apolar non-coordinant solvents, full

conversion was achieved with very low yield (Table 28, entries 1 and 5). When more

coordinant solvents were employed, such as THF or Et2O, higher enantioselectivities

were obtained (Table 28, entries 2 and 4). In the case of using tert-butyl methyl ether

(TBME) as solvent, only phenylmethanol was obtained as product (full conversion,

Table 28, entry 3). We believe phenylmethanol is generated through a Meerwein-

Ponndorf-Verley reduction of benzaldehyde (1a); the hydride source coming from the

isopropoxide group present in the in situ generated RxAl(Oi-Pr)3-x species, which is

oxidized to acetone in the process.

Table 28. Solvent optimization[a]

Entry Solvent Conv.

[b] (%) ee

[b] (%)

1 DCM 99 36 2 THF 97 76 3 TBME >99

[c] -

4 Et2O >99 94 5 n-Hexane 99 24

[a] Conditions: 1a (0.1 mmol, 0.07 M), Me3Al (2 M in toluene, 3 eq.), (Sa,R)-L1 (10 mol%), Ti(Oi-Pr)4 (4 eq.), toluene or Et2O (1.5 mL), 0 °C, 3 h. [b] Determined by chiral GC analysis. [c] Phenylmethanol was obtained instead 2a.

In the next optimization step, a survey of chiral diol ligands (Figure 11) revealed the

simplest (Sa,R)-L1 as the best ligand for the addition of Me3Al to benzaldehyde (Table

29). Substituted derivatives L2-5 provided, in general, lower conversions and

enantioselectivities (Table 29, entries 2-5 vs 1), especially in the case of the ortho-

methoxy substituted (Sa,S)-L3, probably due to steric factors (Table 29, entry 2).

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Figure 1. Chiral diol ligands screened in this study

Table 29. Ligand screening[a]

Entry L* Conv.

[b] (%) ee

[b] (%)

1 (Sa,R)-L1 >99 94 2 (Sa,S)-L3 87 54 3 (Sa,R)-L4 98 80 4 (Sa,S)-L5 95 88 5 (Sa,R)-L6 >99 92

[a] Conditions: 1a (0.1 mmol, 0.07 M), Me3Al (2 M in toluene, 3 eq.), L* (10 mol%), Ti(Oi-Pr)4 (4 eq.), Et2O (1.5 mL), 0 °C, 3 h. [b] Determined by chiral GC analysis.

In the final stage of the optimization process, the amounts of Me3Al and Ti(Oi-Pr)4

were adjusted. The reaction in the presence of chiral ligand (Sa,R)-L1 but no titanium

isopropoxide, gave racemic alcohol 2a with full conversion (Table 30, entry 1). We

believe that, although there is probably some coordination between the

organoaluminum species and the ligand, due to a deprotonation, the catalysis is not

effective. This is indicative that the active catalytic complex in the reaction is an

organotitanium species, and possibly, an in situ transmetallation of R3Al with the

excess of Ti(Oi-Pr)4 has to occur in order to achieve good results.

A low excess of Ti(Oi-Pr)4 (1.5 eq.) respect to the nucleophile was not enough to

induce an asymmetric addition to substrate 1a and product 2a was obtained in a

racemic form under this conditions (Table 30, entry 2 vs 1). Equimolar amounts of

Ti(Oi-Pr)4 and Me3Al provided low enantioselectivity and moderate conversion (Table

30, entry 3). Further tests demonstrated that a higher excess of titanium

tetraisopropoxide was necessary to get good enantiomeric excess (Table 30, entries

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4-10). A 1.3:1 ratio Ti(Oi-Pr)4/Me3Al, which had provided good levels of

enantioselectivity in previous screenings (Table 27-29) was our starting point for the

further optimization process. The equivalents of nucleophile and Ti(Oi-Pr)4 were

modified (trying to minimize the amount of each one) to observe the effect on

enantioselectivity, but always keeping the 1.3:1 ratio constant (Table 30, entries 4-7).

In general, very good to full conversions were obtained and the highest enantiomeric

excess (94%) was reached with 3 eq. of trimethylaluminum and 4 eq. of Ti(Oi-Pr)4

(Table 30, entry 7). In order to improve this last result, other Ti(Oi-Pr)4/Me3Al ratios

were also evaluated (Table 30, entries 8-10). A ratio Ti(Oi-Pr)4/Me3Al 2:1 gave similar

results concerning ee and conversion, using less equivalents of both reagents (Table

30, entry 8) or just decreasing the amount of Me3Al (Table 30, entry 9). When the

amount of nucleophile was minimized to 1.5 eq., and the Ti(Oi-Pr)4/Me3Al ratio

slightly adjusted to 2.7:1, alcohol 2a was generated with 94% ee and full conversion

(Table 30, entry 10 vs 7).

Table 30. Optimization Ti(Oi-Pr)4/Me3Al ratio[a]

Entry Ti(Oi-Pr)4 (eq.) Me3Al (eq.) Ti:Al ratio Conv.

[b] (%) ee

[b] (%)

1 0 1.5 - >99 0 2 1.5 3 0.5:1 81 2 3 1.5 1.5 1:1 59

[c] 18

4 2 1.5 1.3:1 90 60 5 2.7 2 1.3:1 75 60 6 3.3 2.5 1.3:1 99 85 7 4 3 1.3:1 >99 94 8 3 1.5 2:1 85 94 9 4 2 2:1 99 94

10 4 1.5 2.7:1 >99 94 [a] Conditions: 1a (0.1 mmol, 0.07 M), Me3Al (2 M in toluene, x eq.), (Sa,R)-L1 (10 mol%), Ti(Oi-Pr)4 (y eq.), Et2O (1.5 mL), 0 °C, 3 h. [b] Determined by chiral GC analysis. [c] 1% of phenylmethanol was detected by GC analysis.

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Chapter IV – Results and discussion

191

2.2. Scope of the reaction

Under the optimized conditions, the scope of the addition of Me3Al was examined

with different aldehydes (Table 31). The system proved to be remarkably efficient for

a variety of aromatic substrates and a wide range of methyl carbinol units were

prepared in good yield (87 to 99%) and enantioselectivity 80 to 94% (Table 31,

entries 1-10). The lower selectivity for the o-methylbenzaldehyde (1b) and the fact

that 4% of reduction product [1-(o-tolyl)methanol] was also obtained along with the

desired 2b (Table 31, entry 2), could be attributed to higher steric hindrance around

the reactive site.

Enantioselectivities ranging from 80-88% and very good yields were recorded for the

heteroaromatic substrates 2-thiophenecarboxaldehyde (1j) and 2-furaldehyde (1k)

(Table 31, entries 11-12). The reaction with cinnamaldehyde (1l) gave good

enantioselectivity as well (Table 31, entry 13), whereas phenylpropargyl aldehyde

(1aa) provided moderate yield and enantiomeric excess (Table 31, entry 14). The

substrate generality was also examined for aliphatic aldehydes; good yield and

moderate enantioselectivity were achieved in the reaction with 1m (Table 31, entry

15) and, outstandingly, the bulky pivaldehyde (1n) provided the highest

enantioselectivity of the series (Table 31, entry 16). As a general feature, it should be

mentioned that all reactions were finished in less than 1 hour without by-product

formation and the unreacted starting material and ligand could be easily recovered.

Moreover, the addition of Me3Al to benzaldehyde (1a) was scaled up to 1 mmol of

substrate without any loss of enantiomeric excess (94%) or yield (>99%).

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Chapter IV – Results and discussion

192

Table 31. Asymmetric addition of Me3Al to aldehydes[a]

Entry Aldehyde Product Yield

[b] (%) ee

[c] (%)

1

>99 94 (S)

2

92[d]

80 (S)

3

98 94 (S)

4

99 94 (S)

5

87 94 (S)

6

>99 94 (S)

7

92 94 (S)

8

99 94 (S)

9

99 94 (S)

10

99 94 (S)

11

68 (95)[e]

80 (S)

12

75 (91)[e]

88 (S)

13

98 90 (S)

14

80 62 (S)

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Chapter IV – Results and discussion

193

15

92 84 (S)

16

(55)[e]

98 (S)

[a] Conditions: 1 (0.3 mmol, 0.12 M), Me3Al (2 M in toluene, 1.5 eq.), (Sa,R)-L1 (10 mol%),

Ti(Oi-Pr)4 (4 eq.), Et2O (2.5 mL), 0 °C, 1 h. [b] Isolated yield after distillation or flash silica

gel chromatography. [c] Determined by chiral GC or HPLC analysis. Absolute configuration

of chiral alcohols was determined by correlation of optical rotation with known

compounds. [d] o-Tolylmethanol (4%) was detected by GC analysis. [e] Volatile products,

conversions based on GC data in brackets.

Finally, we turned our attention to other commercially available organoaluminum

reagents (Table 32). Regarding the enantioselectivities, the system worked well for

the addition of the linear Et3Al and (n-Pr)3Al to a variety of aromatic and aliphatic

aldehydes, although lower yields were obtained compared to the addition of Me3Al

(Table 32, entries 1-6). In particular, the use of (n-Pr)3Al led to the formation of

significant amounts of the by-product derived from the reduction of the

corresponding aldehyde via -hydride elimination from the organoaluminum reagent

species and/or through Meerwein-Ponndorf-Verley reduction from in situ generated

RxAl(Oi-Pr)3-x species (Table 32, entries 4-6).

Table 32. Asymmetric addition of Et3Al and (n-Pr)3Al to aldehydes[a]

Entry Aldehyde Product Yield

[b] (%) ee

[c] (%)

1

77 90 (S)

2

65 87 (S)

3

70 92 (S)

4

35[d]

94 ()

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Chapter IV – Results and discussion

194

5

26[e]

92 ()

6

34[f]

94 ()

[a] Conditions: 1 (0.3 mmol, 0.12 M), R3Al (1.5 eq.), (Sa,R)-L1 (10 mol%), Ti(Oi-Pr)4 (4 eq.), Et2O

(2.5 mL), 0 °C, 1 h. [b] Isolated yield after distillation or flash silica gel chromatography. [c]

Determined by chiral GC analysis. Absolute configuration of chiral alcohols was determined by

correlation of optical rotation with known compounds. [d] 9% (4-chlorophenyl)methanol was

detected by GC analysis. [e] 8% (4-methoxyphenyl)methanol was detected by GC analysis. [f]

23% 1-cyclohexylmethanol was detected by GC analysis.

An intriguing characteristic of this catalytic system is its incompatibility with the

branched i-butyl moiety; no products were formed when (i-Bu)3Al was used as

nucleophile or when isovaleraldehyde was used as substrate (2w, Figure 12). The use

of sp2-hybridized aluminum reagents was also studied. For example, Ph3Al could be

added to 2-naphthaldehyde (1i) with very good yield but low enantioselectivity (2x,

Figure 12), in contrast to the higher enantioselectivity and lower yield that resulted

from the addition to 1n (2ab, Figure 12).

Figure 12. Chiral secondary alcohols derived from the addition of (i-Bu)3Al or Ph3Al to aldehydes.

In conclusion, an efficient catalytic system has been developed for the

enantioselective addition of organoaluminum reagents to aldehydes. The asymmetric

methylation, ethylation and propylation of a wide variety of aromatic and aliphatic

aldehydes proceeded with good yields and high enantioselectivities in a simple one-

pot procedure and under mild conditions using economical and commercially

available reagents.

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Chapter IV – Experimental part

195

3. Experimental part

3.1. General procedure for the asymmetric alkylation of aromatic

aldehydes with organoaluminum reagents

In a flame dried Schlenk tube, (Sa,R)-L1 (11.4 mg, 0.03 mmol, 10 mol%) was dissolved

in anhydrous Et2O (2.5 mL) under argon atmosphere. The solution was cooled down

to 0 °C and Ti(Oi-Pr)4 (370 µL, 1.2 mmol, 4 eq.) was then added. Five minutes later,

R3Al (0.45 mmol, 1.5 eq.) was added followed by the addition of the corresponding

aldehyde (0.3 mmol) previously distilled. The reaction mixture was stirred at 0 °C for

1 h (for Me3Al) or 3 h (for the rest of organoaluminum reagents) and then quenched

with water (5 mL) and HCl 2 M (5 mL). The crude was extracted with EtOAc (3 × 10

mL), and the combined organic layers were neutralized with a saturated NaHCO3

aqueous solution (15 mL), dried over magnesium sulfate and concentrated under

vacuum. The crude product was purified by flash silica gel chromatography or/and

distillation on Kugelrohr to give the desired products.

3.2 Data of chiral secondary alcohols prepared from organoaluminum

reagents

1H NMR and 13C NMR, LRMS, HRMS, m.p., IR data and conditions for the

chromatographic separation of enantiomers for some of the compounds listed below

has been already reported in Chapter II section 3.2 and/or Chapter III section 5.2. In

these cases, only the yield, optical rotation and ee obtained in the addition reaction

with organoaluminium reagents will be reported.

(S)-1-Phenylethanol (2a): Compound 2a was obtained after purification

by Kugelrohr distillation as a colorless oil (>99% yield, 94% ee); []D25 =

57.0 (c 1.0, CHCl3) {Lit. []D

20 = 39.6 (c 2.5, CHCl3) for 82% ee}.

(S)-1-(o-Tolyl)ethanol (2b): Compound 2b was obtained after

purification by Kugelrohr distillation as a colorless oil (92% yield, 80%

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Chapter IV – Experimental part

196

ee); []D25 = 73.0 (c 1.0, CHCl3) {

Lit. []D20 = 72.5 (c 1.0, CHCl3) for 96% ee}.

(S)-1-(m-Tolyl)ethanol (2c): Compound 2c was obtained after

purification by Kugelrohr distillation as a colorless oil (98% yield, 94%

ee); []D25 = 51.0 (c 1.0, CHCl3) {Lit. []D

16 = 47.3 (c 0.8, CHCl3) for

90% ee}.

(S)-1-(p-Tolyl)ethanol (2d): Compound 2d was obtained after

purification by Kugelrohr distillation as a colorless oil (99% yield, 94%

ee); []D25 = 54.5 (c 1.0, CHCl3) {Lit. []D

20 = 53.7 (c 0.4, CHCl3) for

96% ee}.

(S)-1-(4-Methoxyphenyl)ethanol (2e): Compound 2e was obtained

after purification by Kugelrohr distillation as a colorless oil (87%

yield, 94% ee); []D25 = 44.0 (c 1.0, CHCl3) {

Lit. []D20 = 51.9 (c 1.0,

CHCl3) for 97% ee}.

(S)-1-[4-(Trifluoromethyl)phenyl]ethanol (2f): Compound 2f was

obtained after purification by Kugelrohr distillation as a colorless oil

(>99% yield, 94% ee); []D25 = 37.0 (c 1.0, CHCl3) {

Lit. []D20 = 33.7

(c 5.5, CHCl3) for 97% ee}.

(S)-1-(4-Chlorophenyl)ethanol (2g): Compound 2g was obtained

after purification by Kugelrohr distillation as a colorless oil (92%

yield, 94% ee); []D25 = 43.0 (c 1.0, CHCl3) {

Lit. []D20 = 43.6 (c 1.0,

CHCl3) for 97% ee}.

(S)-4-(1-Hydroxyethyl)benzonitrile (2h): Compound 2h was

obtained after purification by Kugelrohr distillation as a colorless oil

(99% yield, 94% ee); []D25 = 49.0 (c 1.0, CHCl3) {

Lit. []D20 = 62.7 (c

2.1, CHCl3) for 72% ee}.

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Chapter IV – Experimental part

197

(S)-1-[4-(1-Hydroxyethyl)phenyl]ethanone (2av):119 Compound 2i

was obtained after purification by Kugelrohr distillation as a

colorless oil (99% yield, 94% ee); []D25 = 42.6 (c 1.0, CHCl3) {Lit.

[]D25 = 44.9 (c 1.2, CHCl3) for 98% ee}. 1H NMR (300 MHz, CDCl3)

7.88 (d, J = 8.3 Hz, 2H), 7.42 (d, J = 8.4 Hz, 2H), 4.92 (q, J = 6.5 Hz, 1H), 2.61 (br s, 1H),

2.55 (s, 3H), 1.47 (d, J = 6.5 Hz, 3H).13C NMR (75 MHz, CDCl3) 198.0, 151.3, 136.1,

128.5, 125.4, 69.7, 26.5, 25.2. LRMS (EI): m/z (%): 164 [M+] (6), 150 (10), 149 (97),

122 (10), 121 (100), 106 (8), 105 (10), 103 (18), 91 (10), 78 (9), 77 (30), 51 (13). Ee

determination by chiral GC analysis, CP-Chirasil-DEX CB column, T = 150 °C, P = 14.3

psi, retention times: tr(R) = 20.0 min, tr(S) = 20.6 min (major enantiomer).

(S)-1-(Naphthalen-2-yl)ethanol (2i): Compound 2i was obtained

after purification by Kugelrohr distillation as a white powder (99%

yield, 94% ee); []D25 = 46.0 (c 1.0, CHCl3) {

Lit. []D20 = 48.1 (c 1.5,

CHCl3) for 92% ee}.

(S)-1-(Thiophen-2-yl)ethanol (2j): Compound 2j was obtained after

purification by Kugelrohr distillation as a colorless oil (68% yield, 80%

ee); []D25 = 30.0 (c 1.0, CHCl3) {

Lit. []D20 = 27.6 (c 1.0, CHCl3) for 94%

ee}.

(S)-1-(Furan-2-yl)ethanol (2k): Compound 2k was obtained after

purification by Kugelrohr distillation as a colorless oil (75% yield, 88%

ee); []D25 = 22.6 (c 1.0, CHCl3) {

Lit. []D20 = 19.8 (c 0.9, CHCl3) for 98%

ee}.

(S,E)-4-Phenylbut-3-en-2-ol (2l): Compound 2l was obtained after

purification by Kugelrohr distillation as a colorless oil (98% yield,

90% ee); []D25 = 29.0 (c 1.0, CHCl3) {

Lit. []D20 = 14.6 (c 1.0, CHCl3)

for 60% ee}.

119

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Chapter IV – Experimental part

198

(S)-4-Phenylbut-3-yn-2-ol (2au): Compound 2au was obtained after

purification by Kugelrohr distillation followed by a flash silica gel

chromatography from 100:0 till 90:10 (hexane/EtOAc) as a colorless

oil (80% yield, 62% ee); []D25 = 28.0 (c 1.0, CHCl3) {

Lit. []D20 = 33.0

(c 0.9, CHCl3) for 98% ee}.

(S)-1-Phenylpropan-2-ol (2m): Compound 2m was obtained after

purification by Kugelrohr distillation as a colorless oil (92% yield, 84%

ee); []D25 = +44.0 (c 1.0, CHCl3) {

Lit. []D25 = +42.2 (c 1.0, CHCl3) for 99% ee}.

(-)-3,3-Dimethylbutan-2-ol (2n): Compound 2n was obtained after

purification by Kugelrohr distillation (55% yield, >99% ee); []D25 = 8.0 (c

1.7, EtOAc) {Lit. []D20 = +31.0 (c 1.0, CHCl3) for 60% ee}

(S)-1-Phenylpropan-1-ol (2o): Compound 2o was obtained after

purification by Kugelrohr distillation as a colorless oil (77% yield, 90%

ee); []D25 = 38.0 (c 1.0, CHCl3) {

Lit. []D20 = 49.6 (c 0.5, CHCl3) for 98%

ee}.

(S)-1-(p-Tolyl)propan-1-ol (2p): Compound 2p was obtained after

purification by Kugelrohr distillation as a colorless oil (65% yield,

87% ee); []D25 = 40.0 (c 1.0, CHCl3) {

Lit. []D20 = 36.1 (c 1.0, CHCl3)

for 84% ee}.

(S)-1-(4-Chlorophenyl)propan-1-ol (2q): Compound 2q was

obtained after purification by Kugelrohr distillation as a colorless

oil (70% yield, 92% ee); []D25 = 35.7 (c 1.0, CHCl3) {Lit. []D

25 =

38.4 (c 1.1, CHCl3) for 95% ee}.

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Chapter IV – Experimental part

199

(-)-1-(4-Chlorophenyl)butan-1-ol (2aw):120 Compound 2aw was

obtained after purification on flash silica gel chromatography

from 100:0 till 95:5 (n-hexane/EtOAc) as a yellow oil (35% yield,

94% ee); []D25 = 41.6 (c 1.3, CHCl3).

1H NMR (500 MHz, CDCl3) 7.24 (d, J = 8.5 Hz,

2H), 7.20 (d, J = 8.6 Hz, 2H), 4.59 (t, J = 6.8 Hz, 1H), 1.83 (br s, 1H), 1.68 (m, 1H), 1.57

(m, 1H), 1.34 (m, 1H), 1.22 (m, 1H), 0.85 (t, J = 7.4 Hz, 3H). 13C NMR (126 MHz, CDCl3)

143.3, 133.0, 128.5, 127.3, 73.7, 41.3, 18.9, 13.9. LRMS (EI): m/z (%): 186 [M++2]

(3), 185 [M++1] (1), 184 [M+] (8), 143 (32), 141 (100), 113 (17), 77 (48), 51 (6). Ee

determination by chiral GC analysis, CP-Chirasil-DEX CB column, T = 130 °C, P = 14.3

psi, retention times: tr(R) = 36.3 min, tr(S) = 36.9 min (major enantiomer).

(-)-1-(4-Methoxyphenyl)butan-1-ol (2ax):121 Compound 2ax

was obtained after purification on flash silica gel

chromatography from 100:0 till 94:6 (n-hexane/EtOAc) as a

yellow oil (26% yield, 92% ee); []D25 = 35.0 (c 1.0, CHCl3).

1H NMR (500 MHz, CDCl3)

7.19 (d, J = 8.6 Hz, 2H), 6.80 (d, J = 8.6 Hz, 2H), 4.55 (t, J = 6.7 Hz, 1H), 3.73 (s, 3H),

1.79 (br s, 1H), 1.72 (m, 1H), 1.58 (m, 1H), 1.33 (m, 1H), 1.21 (m, 1H), 0.85 (t, J = 7.4

Hz, 3H). 13C NMR (126 MHz, CDCl3) 159.0, 137.0, 127.1, 113.8, 74.0, 55.3, 41.1,

19.1, 13.9. LRMS (EI): m/z (%): 180 [M+] (10), 138 (9), 137 (100), 109 (23), 94 (14), 77

(12). Ee determination by chiral GC analysis, CP-Chirasil-DEX CB column, T = 130 °C, P

= 14.3 psi, retention times: tr(R) = 36.4 min, tr(S) = 36.8 min (major enantiomer).

(-)-1-Cyclohexylbutan-1-ol (2ay):122 Compound 2ay was obtained

after purification on flash silica gel chromatography from 100:0 till

95:5 (n-hexane/EtOAc) as a yellow oil (34% yield, 94% ee); []D25 =

11.3 (c 0.9, CHCl3). 1H NMR (300 MHz, CDCl3) 3.36 (m, 1H), 1.28 (m, 16H), 0.92 (t, J

= 6.5 Hz, 3H).13C NMR (75 MHz, CDCl3) 76.0, 43.6, 36.3, 29.7, 29.3, 27.7, 26.6, 26.4,

26.2, 19.1, 14.2. LRMS (EI): m/z (%): 138 [M–H2O]+ (5), 113 (44), 96 (9), 95 (100), 82

120 For racemic mixture see: Kuhlmann, B.; Arnett, E. M.; Siskin, M. J. Org. Chem. 1994, 59, 3098–3101. 121 For racemic mixture see: Pearson, W. H.; Fang, W-K. J. Org. Chem. 1995, 60, 4960–4961. 122 For racemic mixture see: Yeh, M. C. P.; Knochel, P.; Santa, L. E. Tetrahedron Lett. 1988, 29, 3887–3890.

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Chapter IV – Experimental part

200

(18), 73 (52), 72 (22), 67 (21), 57 (11), 55 (69). Ee determination by chiral GC analysis,

Cyclosil- column, T = 120 °C, P = 14.3 psi, retention times: tr(S) = 23.6 min (major

enantiomer), tr(R) = 24.9 min.

(S)-Naphthalen-2-yl(phenyl)methanol (2x): Compound 2x was

obtained after purification on flash silica gel chromatography

from 100:0 till 90:10 (n-hexane/EtOAc) as a white powder (90%

yield, 20% ee); []D25 = +3.0 (c 1.0, CHCl3) {

Lit. []D20 = +11.2 (c 0.8, CHCl3) for 95% ee}.

(S)-2,2-Dimethyl-1-phenylpropan-1-ol (2ab):123 Compound 2ab was

obtained after purification on flash silica gel chromatography from

100:0 till 92:8 (n-hexane/EtOAc) as a white powder (61% yield, 72%

ee); m.p. 56 – 58 °C, []D25 = 26.0 (c 1.0, CHCl3) {

Lit. []D20 = 15.5 (c 1.7, CHCl3) for

95% ee}. 1H NMR (300 MHz, CDCl3) 7.30 (m, 5H), 4.42 (s, 1H), 1.90 (br s, 1H), 0.94 (s,

9H). 13C NMR (75 MHz, CDCl3) 142.2, 127.6, 127.5, 127.3, 82.4, 35.6, 25.9. LRMS

(EI): m/z (%): 164 [M+] (4), 108 (10), 107 (100), 79 (40), 77 (19), 57 (9). Ee

determination by chiral GC analysis, CP-Chirasil-DEX CB column, T = 115 °C, P = 14.3

psi, retention times: tr(R) = 35.5 min, tr(S) = 37.3 min (major enantiomer).

123 Kasai, M.; Froussios, C.; Ziffer, H. J. Org. Chem. 1983, 48, 459–64.

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GENERAL CONCLUSIONS

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General conclusions

203

General conclusions

A new class of chiral binaphtyl diol ligands (Ar-BINMOLs), containing both axial

chirality and a sp3 stereogenic center, have been prepared in two reaction steps,

starting from (S)-BINOL, through a lithium-assisted [1,2]-Wittig rearrangement with

very good yields and perfect diastereocontrol.

Ligand (Sa,R)-L1 has been used in the enantioselective 1,2 addition of different

organometallic reagents, such as organolithium, Grignard and organoaluminum

compounds, to aromatic aldehydes, in combination with an excess of Ti(Oi-Pr)4.

Chiral secondary alcohols have been obtained with very good yields and

enantioselectivities from a wide variety of aromatic aldehydes. It is important to

mention that better yields were achieved when the less reactive organoaluminum

reagents were used as nucleophiles, compared with the highly reactive Grignard and

organolithium reagents. Moreover, mechanistic studies carried out with the

organolithium and Grignard reagents in the alkylation of aldehydes, concluded that

there is no linear effect in the reaction and no autocatalytic effect was observed.

In addition, the asymmetric alkylation of challenging aliphatic aldehydes with

Grignard reagents has been possible by the use of a novel Ar-BINMOL ligand, (Sa,R)-

L10, synthesized in our research by a new synthetic procedure. With the new ligand,

new reaction conditions were found to achieve valuable chiral secondary aliphatic

alcohols in high yields and very good enantioselectivities.

The synthesis of chiral tertiary diarylmethanols has been achieved through an

enantioselective addition of aryl Grignard reagents to variety of aryl alkyl ketones

using our catalytic system and ligand (Sa,R)-L7. The corresponding products were

obtained in moderate yield, due to the low reactivity of ketones, and good

enantiomeric excesses.

Important limitations of our catalytic system include the addition of secondary,

tertiary, allylic and aryl nucleophiles to aldehydes, which provided low yields and

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General conclusions

204

enantioselectivities under the conditions tested. The addition of alkyl organometallic

reagents to ketones also remains a challenge; the desired addition product was not

observed and only pinacol coupling and/or aldol product was detected in the

reaction crude.

However, the catalytic system developed by our research group is very versatile in

the asymmetric 1,2 addition of organometallic reagents to aldehydes, considering

that was possible the addition of organolithium, Grignard and organoaluminum

reagents with the same ligand (Sa,R)-L1. Those compounds have been employed in

the catalytic enantioselective alkylation of a wide variety of aldehydes with

electrondonor and electrowithdrawing substituents, even some sensitive functional

groups are tolerated.

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EXPERIMENTAL PART (GENERAL INFORMATION)

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Experimental part (General information)

207

Experimental part (General information)

1. Solvents and reagents

Here are described in detail the technical characteristics of most common solvents

and reagents that were used for the development of this thesis.

Solvents: Not anhydrous solvents: n-hexane (absolute for analysis quality), EtOAc (for

analysis quality), Et2O (for analysis quality) were purchased from Merck®. Not

anhydrous n-pentane (95% PS), DCM (99%), CHCl3 (99% stabilized with ethanol) and

acetone (for analysis quality) were purchased from Panreac®.

THF (HPLC grade), Toluene (HPLC grade) and DCM (HPLC grade, stabilized with 50

ppm of amylene), purchased from Scharlau®, were dried in a PureSolv® MD 3

apparatus and concentration of water was determined by Karl-Fischer analysis

following standard procedures. Et2O anhydrous (≥99.7%, with 1 ppm of BHT as

inhibitor) was purchased from Sigma-Aldrich®.

Reagents: Grignard reagents were prepared from the corresponding alkyl or aryl

halide and magnesium turnings in Et2O following standard procedures, except

MeMgBr (3.0 M in Et2O) and EtMgBr (3.0 M in Et2O) which were purchased from

Sigma-Aldrich®. The Grignard reagents that were prepared are: i-PrMgBr (2.6 M in

Et2O), n-BuMgBr (3.0 M in Et2O), n-BuMgCl (4.1 M in Et2O), i-BuMgBr (2.6 M in Et2O), t-

BuMgBr (2.0 M in Et2O), (4-chlorobutyl)MgBr (1.6 M in Et2O), CyMgBr (2.0 M in Et2O),

AllylMgBr (1.0 M in Et2O), BnMgBr (2.0 M in Et2O), VinylMgBr (1.0 M in THF/Et2O),

PhMgBr (3.0 M in Et2O), (4-anisyl)MgBr (1.9 M in Et2O), (4-tolyl)MgBr (1.9 M in Et2O),

(4-fluorophenyl)MgBr (2.0 M in Et2O). All Grignard reagents were titrated using 2-

butanol and catalytic amounts of 1,10-phenanthroline in anhydrous THF and were

stored under argon and used within 2-3 weeks.

Organolithium reagents: MeLi (1.6 M in Et2O) and EtLi (0.5 M in

Benzene/Cyclohexane) were purchased from Sigma-Aldrich®. n-BuLi (2.5 M in

hexane) was purchased from Chemetall® and PhLi (1.9 M in n-Bu2O) was purchased

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from Alfa Aesar®. Organolithium reagents were titrated by Gilman double titration

method and were used without purification.

Organoaluminum reagents: Me3Al (2.0 M in toluene), Et3Al (1.0 M in n-hexane), i-

Bu3Al (1.0 M in n-hexane) and Ph3Al (1.0 M in n-Bu2O) were purchased from Sigma-

Aldrich® and n-Pr3Al (0.7 M in n-heptane) was purchased from Acros Organics®.

Organoaluminum reagents were used without purification.

Ti(Oi-Pr)4 ≥97% was purchased from Sigma-Aldrich® and kept under argon

atmosphere with a rubber septum once opened.

Liquid aldehydes and ketones were purified by distillation in a Büchi® Glass Oven B-

585 Kugelrohr and used immediately. Solid aldehydes and ketones were bought from

the highest purity available and used without further purification.

Chromatography: Crude mixtures were purified in a glass chromatography column,

using flash silica gel Panreac® 60, 40-63 m as stationary phase, using, as mobile

phase (eluent) n-hexane/EtOAc or pentane/Et2O mixtures, increasing the polarity till

product elution. The purification process was monitored by Machery-Nagel® TLC

silica gel (0.2 mm thickness, 60 m particle size), which contains an ultraviolet (254

nm) sensitive indicator. All components were visualized by UV and/or

phosphomolybdic acid (1 g/24 mL EtOH absolute) staining.

2. Analytical equipment

The following instruments have been employed for full characterization of the

different compounds. Herein, is described the technical characteristics of each

apparatus.

Melting points: Melting points were measured in a Reichtert® Thermovar hot plate

apparatus and are corrected.

Optical rotation: Optical rotations were measured at room temperature on a Jasco®

P-1030 or Perkin Elmer® instruments Model 341 Polarimeter with a 5 cm quartz cell

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(c is given in g/100 mL). Depending on each compound, the solvent employed for

measurement was CHCl3 or CH2Cl2.

NMR: 1H NMR, 13C NMR and 19F NMR were recorded on a Bruker® AV300 Oxford

(300, 75 and 282 MHz, respectively) or Bruker® AV400 (400, 101 and 376 MHz,

respectively) using CDCl3 as solvent. Chemical shift values are reported in ppm with

TMS as internal standard (CDCl3: 7.26 for 1H NMR, 77.0 for 13C NMR). Data are

reported as follows: chemical shifts, multiplicity (s = singlet, d = doublet, t = triplet, q

= quartet, quin = quintuplet, sextuplet = sext, m = multiplet, br = broad), coupling

constants (Hz), and integration.

IR: IR spectra were recorded on Jasco® FT/IR – 4100 Fourier Transform Infrared

Spectrometer.

LRMS: Low resolution mass spectra were recorded on Agilent Technologies® 6890N

Network GC System equipped with a HP-5MS column (Agilent Technologies®, 30 m ×

0.25 mm), connected to an Agilent Technologies® 5973 Network Mass Selective

Detector. Also, some analyses were recorded out on a mass spectrometer (Agilent

Technologies® 5973 Network) with a direct insertion probe (73DIP-1), equipped with

a transmission quadrupole analyzer. In both equipments the samples were ionized by

an electronic impact source (70 eV).

HRMS: High resolution mass spectra were obtained on a Waters® LCT Premier XE

apparatus equipped with a time of flight (TOF) analyzer and the samples were ionized

by ESI techniques and introduced through an ultra-high pressure liquid

chromatography (UPLC) model Waters® ACQUITY H CLASS.

Chiral GC: Enantioselectivities were determined by chiral GC Agilent Technologies®

7820A equipped with a FID detector. Nitrogen was used as carrier gas (7 mL/min),

the injector and detector were kept at 250 °C. Specific isothermal programs were

employed for optimal enantiomeric separation and different columns were also used

for this purpose for each compound: Varian® CP-Chiralsil-DEX CB (25 m × 0.25 mm),

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Experimental part (General information)

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Agilent Technologies® Cyclosil- (30 m × 0.25 mm) and Agilent Technologies® HP-

CHIRAL-20 (30 m × 0.25 mm).

Chiral HPLC: Enantioselectivities were determined by HPLC analysis (Agilent

Technologies® 1100 Series HPLC) equipped with a G1315B diode array detector and a

Quat Pump G1311A. The following chiral HPLC columns were employed to determine

the enantioselectivities of all chiral compounds: Daicel Chiralcel® ODH (5 m, 0.46 cm

Ø × 25 cm), Daicel Chiralpak® ADH (5 m, 0.46 cm Ø × 25 cm), Daicel Chiralpak® ASH

(5 m, 0.46 cm Ø × 25 cm), Daicel Chiralcel® OJ (10 m, 0.46 cm Ø × 25 cm) and

Daicel Chiralpak® IA (5 m, 0.46 cm Ø × 25 cm). Mixtures of n-hexane (HPLC grade)

and i-PrOH (HPLC grade), were purchased from VWR Chemicals Prolabo® and

Panreac®, respectively and were used as eluent.