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New methodologies for the catalytic enantioselective addition of organometallic reagents to carbonyl compounds
Emilio Fernández Mateos
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]
A mis padres
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
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
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
RESUMEN
Resumen
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.
Resumen
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.
Resumen
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.
Resumen
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
Resumen
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,
Resumen
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.
Resumen
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.
Resumen
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.
Resumen
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.
Resumen
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.
Resumen
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.
PREFACE
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).
GENERAL OBJECTIVES
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.
CHAPTER I
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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,
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,
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,
Chapter I – Experimental part
55
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,
Chapter I – Experimental part
56
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,
Chapter I – Experimental part
57
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,
Chapter I – Experimental part
58
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,
Chapter I – Experimental part
59
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).
CHAPTER II
Chapter II – Introduction
63
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.
Chapter II – Introduction
64
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.
Chapter II – Introduction
65
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.
Chapter II – Introduction
66
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.
Chapter II – Introduction
67
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.
Chapter II – Introduction
68
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.
Chapter II – Introduction
69
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.
Chapter II – Introduction
70
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.
Chapter II – Introduction
71
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.
Chapter II – Introduction
72
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.
Chapter II – Introduction
73
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.
Chapter II – Introduction
74
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.
Chapter II – Introduction
75
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
Chapter II – Introduction
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.
Chapter II – Introduction
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.
Chapter II – Results and discussion
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.
Chapter II – Results and discussion
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
Chapter II – Results and discussion
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.
Chapter II – Results and discussion
82
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
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
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)
Chapter II – Results and discussion
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)
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
Chapter II – Results and discussion
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.
Chapter II – Experimental part
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.
Chapter II – Experimental part
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.
Chapter II – Experimental part
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.
Chapter II – Experimental part
92
(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.
Chapter II – Experimental part
93
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).
Chapter II – Experimental part
94
(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.
Chapter II – Experimental part
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.
Chapter II – Experimental part
96
(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.
Chapter II – Experimental part
97
(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.
Chapter II – Experimental part
98
()-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.
Chapter II – Experimental part
99
(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.
CHAPTER III
Chapter III – Introduction
103
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.
Chapter III – Introduction
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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.
Chapter III – Introduction
105
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.
Chapter III – Introduction
106
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.
Chapter III – Introduction
107
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.
Chapter III – Introduction
108
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.
Chapter III – Introduction
109
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.
Chapter III – Introduction
110
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.
Chapter III – Introduction
111
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.
Chapter III – Introduction
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.
Chapter III – Introduction
113
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.
Chapter III – Introduction
114
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.
Chapter III – Introduction
115
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.
Chapter III – Results and discussion
117
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.
Chapter III – Results and discussion
118
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
Chapter III – Results and discussion
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
Chapter III – Results and discussion
120
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).
Chapter III – Results and discussion
121
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).
Chapter III – Results and discussion
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.
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)
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).
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.
Chapter III – Results and discussion
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.
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.
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.
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}.
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}.
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}.
Chapter III – Experimental part
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.
Chapter III – Experimental part
133
(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
Chapter III – Experimental part
134
(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.
Chapter III – Experimental part
135
(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.
Chapter III – Experimental part
136
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
Chapter III – Experimental part
137
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.
Chapter III – Experimental part
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.
Chapter III – Results and discussion
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).
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
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.
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.
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)
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.
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
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
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
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.
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.
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.
Chapter III – Experimental part
151
(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.
Chapter III – Experimental part
152
[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.
Chapter III – Experimental part
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.
Chapter III – Experimental part
154
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.
Chapter III – Experimental part
155
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.
Chapter III – Experimental part
156
(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.
Chapter III – Experimental part
157
(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.
Chapter III – Results and discussion
159
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.
Chapter III – Results and discussion
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).
Chapter III – Results and discussion
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
Chapter III – Results and discussion
162
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).
Chapter III – Results and discussion
163
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)
Chapter III – Results and discussion
164
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-
Chapter III – Results and discussion
165
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
Chapter III – Results and discussion
166
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.
Chapter III – Experimental part
167
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.
Chapter III – Experimental part
168
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.
Chapter III – Experimental part
169
(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,
Chapter III – Experimental part
170
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.
Chapter III – Experimental part
171
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).
Chapter III – Experimental part
172
(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
Chapter III – Experimental part
173
(+)-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),
Chapter III – Experimental part
174
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,
Chapter III – Experimental part
175
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).
CHAPTER IV
Chapter IV – Introduction
179
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.
Chapter IV – Introduction
180
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.
Chapter IV – Introduction
181
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.
Chapter IV – Introduction
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.
Chapter IV – Introduction
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.
Chapter IV – Introduction
184
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.
Chapter IV – Introduction
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.
Chapter IV – Results and discussion
187
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.
Chapter IV – Results and discussion
188
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).
Chapter IV – Results and discussion
189
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
Chapter IV – Results and discussion
190
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.
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%).
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)
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 ()
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.
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%
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}.
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
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}.
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.
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.
GENERAL CONCLUSIONS
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
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.
EXPERIMENTAL PART (GENERAL INFORMATION)
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
Experimental part (General information)
208
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
Experimental part (General information)
209
(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),
Experimental part (General information)
210
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.