Deep Eutectic Solvents: platform for asymmetric catalysis...alternativa sostenible a los disolventes convencionales en Química Orgánica An. Quím., 2018, 114, 79-87 ... Esta se encarga

Deep Eutectic Solvents: platform for asymmetric catalysis

Diego Ros Ñíguez

https://www.ua.es/

http://www.eltallerdigital.com/es/index.html

Organic Synthesis Institute (ISO)

Deep Eutectic Solvents: platform for

asymmetric catalysis

Manuscript thesis submitted to apply for the PhD degree with International

Mention at the University of Alicante by:

DIEGO ROS ÑÍGUEZ

Alicante, September 2019

Doctoral Programme: Organic Synthesis

Scientific advisors:

Prof. Diego A. Alonso Velasco Prof. Gabriela Guillena Townley

Organic Chemistry Department, Organic Synthesis Institute, Science Faculty University of Alicante, San Vicente del Raspeig, 99, E-03080 Alicante, Spain

Tel. +34 965903400, ext. 2121; +34 965903549; Fax +34 965903549 [email protected]; [email protected]

Agradecimientos

Llega a su fin esta etapa de 3 años en las que ha habido ilusión, satisfacción, trabajo,

risas y algún que otro momento de sufrimiento. De esta etapa me llevo conocimientos

de química, pero sobre todo amigos que han hecho que este periodo sea especial. Por

ello, quiero agradecer a todas esas personas que han ido apareciendo en mi vida durante

estos años.

En primer lugar, dar las gracias a mis directores de tesis, Diego Alonso y Gabriela por

darme la oportunidad de realizar esta Tesis Doctoral. Durante estos casi 5 años

(contando el máster) hemos pasado por buenos y malos momentos juntos y quiero

agradecer que no perdierais la paciencia cuándo realizaba mis experimentos locos

(aunque alguno salió bien).

En segundo lugar, me gustaría dar las gracias a mi familia del laboratorio (que casi he

visto más que a mi propia familia). Iris, María, Bea, Xavi, Edu, Marcos, Aitor, Lahosa,

Natalia, Melania y Patri por hacerme la vida más fácil y hacerme sentir como en casa

cada día. Me gustaría agradecer especialmente a Patri su ayuda tanto en el laboratorio

como fuera de él, ya que sin su consejo y conocimiento no habría entregado un papel a

tiempo y en algún momento el laboratorio estaría en llamas. También merece especial

mención Melania que me ayudó a dar mis primeros pasos en química orgánica y siempre

me sirvió de apoyo en los buenos y en los malos momentos (no pude sacar el

Angewandte pero todo el trabajo de estos años fue gracias a ti). También dar las gracias

Alberto Cuezva por incluirme en su grupo de trabajo, permitiéndome rozar el JACS por

momentos.

En cuanto a mi club de las cervezas, Llorenç, Óscar, Catalá, Manu, Yara, Martín y

Mauricio gracias por las interminables horas en la bodeguita. El máster y el doctorado

no hubieran sido lo mismo sin esos momentos de cervezas hablando de cosas sin

sentido y olvidando todos los males de la semana. Poca gente habrá que este tan fatal

de la cabeza como vosotros.

Por supuesto, no me puedo olvidar de mis grandes amigos, los de toda la vida. Los que

me hacéis desconectar los fines de semana con muchas locuras y me hacéis volver a

empezar la semana con energía. Rodri, Damián, Valero y David gracias por el mejunje.

El Doctorado también me ha dado una gran experiencia. Mi estancia en Groningen

fueron 3 meses inolvidables, reencontrándome con Juani, la cual me hizo la vida

Agradecimientos

facilísima tanto dentro como fuera del laboratorio y al conocer a Paula, Nacho, Jorge,

Simone y Takuya. Siempre sabías como empezaba un borrel o una barbacoa, pero nunca

sabías ni dónde ni cuando ibas a acabar. También a María Ronda por hacer de gruía

turística por Ámsterdam los fines de semana Todo esto gracias a Syuzi por permitirme

trabajar en su grupo de investigación y hacer enseñarme una química tan interesante y

distinta a la mía.

Aunque ha pasado bastante tiempo este seguramente sea mi último trabajo en la

Universidad y me gustaría agradecer a Josevi, Adolfo, Inés, Curro, Aaron todos esos años

de clases, fiestas, paellas y risas. Gente que no hubiera conocido si no me hubiera

inspirado mi profesor de instituto Sergio Menargues al cual admiro profundamente.

Y como no, dar las gracias a esa persona que ha compartido de cerca esta etapa conmigo.

Elisabeth, gracias por estar conmigo todo este tiempo porque sin tu ayuda no habría

terminado este proceso. No puedo ponerme a enumerar todas las cosas en las que me

has ayudado porque me faltarían hojas para agradecértelo.

Finalmente, quiero agradecer profundamente a mi familia. Principalmente a mis padres,

por siempre estar tan pendientes de mí y darme la mejor educación posible. A mi

hermano Pablo, por ayudarme en todo lo que ha podido y hacerme luchar para llegar a

mis metas.

Y como todos sabéis, suelo ser un poco olvidadizo así que voy a rematar este apartado

con algo que leí en otra tesis, aunque no lo recuerdo exactamente: “Gracias a todos

porque sin vuestra ayuda esto no hubiera sido posible”.

PREFACE

Preface

During the last years, the research group “Stereoselective Catalysis in Organic Synthesis

(CESO)” of the Organic Chemistry Department and the Organic Synthesis Institute (ISO)

at the University of Alicante, has focused its research activity in the development of new

asymmetric catalytic methodologies using sustainable and green conditions. In

particular, novel and efficient organocatalyzed asymmetric transformations have been

developed employing Deep Eutectic Solvents as alternative reaction medium.

The order for the present thesis has been established as follows.

GENERAL INTRODUCTION

1.1. Green Chemistry

1.2. Deep Eutectic Solvents

1.3. Asymmetric Organocatalysis

1.4. Supported Asymmetric Organocatalysis

CHAPTER 1. Asymmetric Organocatalyzed Michael Addition in Deep Eutectic

Solvents

1.1. Background

1.2. Objectives

1.3. Discussion of Results

1.4. Experimental Part

1.5. Conclusions

CHAPTER 2. Asymmetric Organocatalyzed Electrophilic α-aminations in Deep

Eutectic Solvents

2.1. Background

2.2. Objectives



2.5. Conclusions

Preface

CHAPTER 3. Chiral Deep Eutectic Solvents

3.1. Background

3.2. Objectives



3.5. Conclusions

ABBREVIATIONS

Preface

Part of the results described in this thesis has been reported in the following

publications:

➢ Ñíguez, D. R.; Guillena, G.; Alonso, D. A. “Chiral 2-Aminobenzimidazoles in Deep

Eutectic Mixtures: Recyclable Organocatalysts for the Enantioselective Michael

Addition of 1,3-Dicarbonyl Compounds to β-Nitroalkenes”. ACS Sustain. Chem.

Eng. 2017, 5, 10649-10656.

➢ Ñíguez, D. R.; Khazaeli, P.; Alonso, D. A.; Guillena, G. "Deep Eutectic Mixtures as

Reaction Media for the Enantioselective Organocatalyzed α-Amination of 1,3-

Dicarbonyl Compounds". Catalysts 2018, 8, 217-228.

➢ Ñíguez, D. R.; Guillena, G.; Alonso, D. A. “Rational Design of Chiral Deep Eutectic

Solvents”. Manuscript in preparation.

Other publications related to the topics presented in this thesis:

➢ Alonso, D. A.; Baeza, A.; Chinchilla, R.; Gómez, C.; Guillena, G.; Marset, X.; Pastor,

I. M.; Ramón, D. J.; Ñíguez, D. R.; Saavedra, B. “Mezclas eutécticas como

alternativa sostenible a los disolventes convencionales en Química Orgánica”

An. Quím., 2018, 114, 79-87.

➢ Martínez-Cuezva, A.; Marín-Luna, M.; Alonso, D. A.; Ñíguez, D. R.; Alajarin, M.;

Berná, J.; "Ringing the Catalyst: Thread versus Rotaxane-Mediated

Enantiodivergent Michael Addition of Ketones to β-Nitrostyrene" Org. Lett.

2019, accepted manuscript.

The present work has been possible thanks to the funding from the Ministerio de

Economía y Competitividad (CTQ2015-66624-P), the University of Alicante (UAUSTI16-

03, UAUSTI16-10, VIGROB-173). Additionally, I would like to thank the Vicerrectorado

de Investigación y Transferencia del Conocimiento at the University of Alicante for a

grant for a three-month stay in the University of Groningen, which has allowed me to

apply for the title of International Doctor in the doctoral degree. Finally, the Institute of

Organic Synthesis from the University of Alicante (ISO) is also acknowledged for the

financial support.

RESUMEN

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Química sostenible

Desde el siglo XX la química ha cambiado nuestra sociedad, transformándola en

moderna y tecnológica, teniendo un gran impacto en nuestra vida diaria (energía, me-

dicamentos, alimentos, nuevos materiales, etc.).

Debido al importante papel que juega esta disciplina en la sociedad actual se han

tomado una serie de medidas con el objetivo de "satisfacer las necesidades de esta ge-

neración sin comprometer la capacidad de satisfacer las necesidades de las generacio-

nes futuras". Para llegar a esta sostenibilidad se ha tomado el camino de la “Química

verde”. Esta se encarga de la conversión de los antiguos métodos de síntesis en otros

más ecológicos mediante el diseño de nuevos procesos y reactivos químicos que produ-

cen y utilizan pequeñas cantidades (o incluso eliminan) los materiales tóxicos y peligro-

sos para el ser humano y el medio ambiente.

Esta serie de medidas de resume en los doce principios de la “Química Verde”

definidos por Anastas en el año 2000 (Figura 1). Estos son:

Figura 1. Doce principios de la química verde.

1 •Prevention en la formación de residuos

2 • Economía atómica

3 •Evitar intermedios tóxicos

4 • Productos finales seguros

5 •Reducción del uso de sustancias auxiliares

6 •Reducción de la energía consumida

7 •Uso de materias renovables

8 •Reducción de la derivatización

9 •Uso de catalizadores

10 •Diseño para la degradación

11 •Monitorización en tiempo real

12 •Minimización del riesgo de accidentes

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En esta línea de trabajo el uso de nuevos disolventes provenientes de fuentes re-

novables como los líquidos eutécticos pueden ser de gran utilidad al sustituir a los di-

solventes volátiles convencionales.

Líquidos Eutécticos

Una mezcla eutéctica es una composición única de dos o más componentes, los

cuales sufren un cambio de fase a una temperatura precisa (Figura 2). En general, las

mezclas eutécticas tienen puntos de fusión menores que cada uno de los componentes

sólidos por separado. Dichas mezclas en estado líquido presentan propiedades muy in-

teresantes, tales como una alta polaridad y baja miscibilidad con disolventes orgánicos

como acetato de etilo, heptano, éter dietílico, etc. La depresión del punto de fusión de la

mezcla eutéctica depende en gran medida del tipo de interacción que existe entre los

componentes de esta. Así, existen mezclas eutécticas con puntos de fusión cercanos o

por debajo de la temperatura ambiente. Este punto de fusión tan bajo se debe principal-

mente a la formación de una extensa red tridimensional mediante enlace de hidrógeno

a partir de los componentes de la mezcla. Este tipo de líquidos eutécticos se forman a

partir de una molécula donante y otra aceptora de enlace de hidrógeno.

Figura 2. Diagrama de fases.

Debido a su estructura, los líquidos eutécticos pueden ser utilizados como so-

porte para catalizadores por medio de enlaces no covalentes. Sin embargo, han sido más

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utilizados como medio de reacción ecológico y reutilizable. Esto es debido a sus ventajas

con respecto a los disolventes orgánicos clásicos como: su nula presión de vapor, su

origen renovable, su baja o nula toxicidad, son extremadamente biodegradables, pre-

sentan una alta economía atómica (ya que todos los átomos se conservan en la mezcla),

alta solubilidad en agua y su posibilidad de reciclaje. Teniendo en cuenta estas ventajas

se han utilizado un gran número de disolventes eutécticos en reacciones muy diversas.

En concreto el uso de líquidos eutécticos como soporte de organocatalizadores y medio

de reacción presenta ventajas añadidas como la activación tanto del catalizador como

de los reactivos. Así esta metodología está experimentando un creciente desarrollo.

Organocatálisis asimétrica

Los materiales derivados de productos naturales con capacidad catalítica, y más

concretamente los organocatalizadores, pueden ser de gran utilidad debido a su capa-

cidad de sustituir a los catalizadores metálicos reduciendo así los costes de producción

y la toxicidad de los productos e intermedios.

La organocatálisis se define como el uso de moléculas orgánicas de bajo pesos

molecular capaces de acelerar las reacciones varios cientos o miles de veces. Los oríge-

nes de la organocatálisis se remontan a 1896, cuando Emil Knoevenagel demostró la

capacidad de ciertas aminas primarias y secundarias para catalizar la condensación al-

dólica de α-cetoésteres y malonatos con aldehídos y cetonas.

La primera reacción organocatalizada asimétrica data de 1904, cuando Mar-

ckwald llevó a cabo la descarboxilación del ácido 2-etil-2-metilmalónico en presencia

de brucina para dar el ácido 2-metilbutírico con un 10% de exceso enantiomérico (Es-

quema 1).

Esquema 1. Descarboxilación del ácido 2-etil-2-metilmalónico en presencia de brucina.

Uno de los hechos más importantes en la historia de la organocatálisis es el des-

cubrimiento de la L-prolina como catalizador, molécula capaz de catalizar una reacción

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aldólica intramolecular asimétrica (reacción de Hajos-Parrish-Eder-Sauer-Wiechert)

(Esquema 2). Los derivados de este aminoácido han sido muy estudiados en este campo,

suponiendo una gran herramienta para la obtención de nuevos organocatalizadores.

Esquema 2. Reacción de Hajos-Parrish-Eder-Sauer-Wiechert.

En el año 2000, los trabajos de Barbas, List y MacMillan, publicados de manera

casi simultánea, dieron inicio a la organocatálisis asimétrica tal y como la conocemos

hoy en día. La reacción estudiada por MacMillan fue la cicloadición de Diels-Alder entre

aldehídos α,β-insaturados y dienos catalizada por imidazolidinonas quirales. Esta reac-

ción implica la activación del electrófilo mediante la formación de la correspondiente

sal de iminio quiral con el catalizador (Esquema 3).

Esquema 3. Reacción de Diels-Alder entre aldehídos α,β-insaturados y ciclopentadieno catalizada por imida-zolidinonas quirales.

Por otro lado, List y Barbas desarrollaron la primera reacción aldólica directa y

enantioselectiva entre la acetona y aldehídos catalizada por L-prolina (Esquema 4). En

este trabajo se propuso un mecanismo que involucraba como intermedio una enamina

quiral formada entre el catalizador y la acetona. Además, para el estado de transición

los autores postularon una interacción entre el aldehído y el grupo ácido del catalizador

mediante enlaces de hidrógeno que favorecía una determinada estereoquímica (Es-

quema 4).

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Esquema 4. Reacción aldólica enantioselectiva entre acetona y aldehídos catalizada por L-Prolina.

Fue a partir de los trabajos de MacMillan, Barbas y List, cuando la organocatá-

lisis logró un reconocimiento por parte de la comunidad científica como una importante

herramienta en síntesis de compuestos enantioméricamente enriquecidos y se potenció

el estudio y desarrollo de nuevas reacciones y catalizadores, siendo actualmente esen-

cial dentro de la síntesis orgánica. Así, especialmente en los últimos años, la organoca-

tálisis asimétrica ha experimentado un crecimiento exponencial tal y como se muestra

en la Figura 3 para la metodología en general y para algunas de las reacciones más es-

tudiadas en particular.

Figura 3. Número de publicaciones relacionadas con la organocatálisis asimétrica (2000−2019). Fuente Sci-finder.

Diversos factores han sido responsables del desarrollo tan importante que la or-

ganocatálisis asimétrica ha experimentado durante los últimos diez años. Por un lado, y

principalmente con la ayuda de cálculos computacionales, se ha avanzado mucho en el

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conocimiento de los mecanismos a través de los cuales transcurren las reacciones. Ade-

más, la organocatálisis es una técnica de fácil manejo, ya que generalmente no es nece-

sario modificar los componentes de reacción o preactivarlos en etapas separadas. Por

otro lado, los organocatalizadores no suelen ser tóxicos y un gran número de ellos son

fáciles de preparar o comercialmente asequibles en ambas formas enantioméricas en-

contrándolos, en muchas ocasiones, directamente a partir de fuentes naturales como

aminoácidos, alcaloides, etc. Además, suelen ser estables al aire y la humedad, de forma

que normalmente no requieren condiciones especiales de reacción, tales como el uso de

atmósfera inerte o disolventes secos, y pueden ser empleados en pequeñas cantidades

(<3% molar), o inmovilizados (y por tanto recuperados) en diversos soportes inorgáni-

cos y orgánicos, lo que ha acentuado el carácter “verde” de esta metodología. Por último,

hay que destacar el desarrollo y puesta a punto de un gran número de reacciones mul-

ticomponente y “one-pot” organocatalizadas y asimétricas, lo que ha posibilitado la sín-

tesis de complejas moléculas quirales de manera enantioselectiva.

La primera reacción organocatalizada en líquidos eutécticos fue llevada a cabo

en el año 2014 y consistió en la transformación biocatalizada, mediante una lipasa in-

movilizada, de acetato de vinilo en acetaldehído para ser combinado con la reacción al-

dólica catalizada por prolinol (Esquema 5).

Esquema 5. Combinación entre biocatálisis y organocatálisis en líquidos eutécticos.

Paralelamente nuestro grupo de investigación llevó a cabo reacciones aldólicas

organocatalizadas por L-prolina en diferentes líquidos eutécticos, obteniendo los mejo-

res resultados de conversión y exceso enantiomérico en la mezcla d-glucosa/(L/D)-

ácido málico (Esquema 6).

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Esquema 6. Reacción aldólica organocatalizada en líquido eutéctico.

Siguiendo este trabajo, el grupo de Del Amo desarrolló un sistema catalítico for-

mado por cloruro de colina etilenglicol (ChCl:EG 1:2) y L-leucina para la adición de ce-

tonas a aldehídos aromáticos. Bajo estas condiciones la adición resultó satisfactoria, ob-

teniendo rendimientos de hasta el 80%, diastereoselectividades de hasta el 90% y enan-

tioselectividades de hasta el 99% ee. Adicionalmente el mismo sistema catalítico fue

empleado cinco veces sin pérdida de la actividad ni erosión de la selectividad (Esquema

7).

Esquema 7. Reacción aldólica orgnocaalizada por L-leuicina.

En cuanto a la adición de tipo Michael, los grupos de Capriati y Chinchilla descri-

bieron la primera adición enantioselective en DES. El grupo de Capriati diseñó la adición

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de iso-butaraldehido a nitroestireno catalizado por 9-amino-9-deoxi-epi-quinina en tres

DES diferentes; cloruro de colina:urea (1:2), cloruro de colina:fructosa:agua (1:1:1) y

cloruro de colina:glicerol (1:2). En todos los casos ácido benzoico fue empleado como

aditivo, obteniendo selectividades mayores del 60% ee siendo la mayor 95% ee en el

DES colina:fructosa:agua (1:1:1). Finalmente, la reacción llevada a cabo en condiciones

óptimas dio lugar al producto con un 95% ee y una conversión del 98% en 5 horas (Es-

quema 8). La reciclabilidad del catalizador se estudió durante 3 ciclos observando una

selectividad constante a lo largo de los ciclos, sin embargo, la conversión decae ostensi-

blemente después del segundo ciclo.

Esquema 8. Adición Michael enentioselectiva entre isobutiraldehido y nitroestireno en NADES.

Para demostrar la utilidad de esta metodología el anticoagulante Warfarina se

sintetizó empleando como disolvente cloruro de colina:urea (1:2) obteniendo este pro-

ducto con un 70% de rendimiento y un 87% de exceso enantiomérico (Esquema 9).

Esquema 9. Síntesis enantioselectiva de Warfarina

Finalmente, el grupo de Chinchilla realizó la síntesis de succinimidas sustituidas

por mediante la adición de aldehídos a maleimidas en la mezcla Ph3MePBr:Gli (1:2) (Es-

quema 10). El proceso, catalizado por un organocatalizador no natural derivado de ci-

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clohexanodiamina y ácido 3,4-dimetoxibenzoico, permitió la obtención de los corres-

pondientes aductos conjugados en tiempos de reacción cortos y altos rendimientos

(hasta un 97%) y enantioselectividades (hasta 94% ee) (Esquema 10). El sistema cata-

lítico fue reutilizado cinco veces con una ligera disminución en la conversión después

del tercer ciclo, observándose una disminución en la selectividad después del cuarto

uso.

Esquema 10. Síntesis de succiniminas quirales mediante adición Michael asimétrica.

Objetivos

Teniendo en cuenta estos antecedentes se planteó como objetivo el uso de or-

ganocatalizadores derivados de benzimidazol y ciclohexanodiamina en reacciones de

tipo Michael en DES. Así mismo, se pensó en el estudio de las interacciones del organo-

catalizador con la estructura del DES, el escalado del proceso y la recuperación y reuti-

lización del sistema catalítico formado por el DES y el organocatalizador (Capítulos 1 y

2). Finalmente, la síntesis de un líquido eutéctico quiral se marcó como objetivo debido

a los escasos antecedentes previos tanto en la síntesis como en el uso de estos sistemas

como catalizadores bifásicos reutilizables (Capítulo 3).

Capítulo 1. Reacción Michael organocatalizada en líquidos eutecticos

En primer lugar, se llevó a cabo la síntesis de organocatalizadores derivados de

benzimidazoles (Figura 4).

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Figura 4. Benzimidazoles quirales empleados como catalizadores.

Los organocatalizadores 1 y 3 se sintetizaron directamente mediante una susti-

tución nucleofílica aromática entre (1R,2R)-ciclohexano-1,2-diamina y 2-cloro-1H-

benzo[d]imidazol a 200 °C utilizando trietilamina como disolvente y base, obteniéndose

ambos catalizadores con un rendimiento del 65% y 40%, respectivamente (Esquema

11). Posteriomente, la aminación reductora (reacción Eschweiler-Clarke) del cataliza-

dor 1 se llevó a cabo utilizando formaldehído y ácido fórmico, obteniendo del cataliza-

dor 2 con un rendimiento del 46% (Esquema 11).

Esquema 11. Síntesis de los catalizadores 1, 2 y 3.

El catalizador 4 se obtuvo con un rendimiento del 74% por nitración aromática

del catalizador 2, empleando una mezcla de ácido sulfúrico y ácido nítrico (Esquema

12). Para la obtención del catalizador 5 se realizó la mononitración del catalizador 2

utilizando 1,2 equivalentes de ácido nítrico en ácido sulfúrico, obteniendo una mezcla

de los intermedios 4 y 6. Esta mezcla se redujo utilizando SnCl2 en el HCl concentrado a

100 °C para obtener el catalizador 5 con un rendimiento del 83% (Esquema 12).

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Esquema 12. Síntesis de los catalizadores 4 y 5.

Una vez obtenidos los catalizadores derivados de benzimidazol se llevó a cabo la

optimización de los disolventes en la reacción Michael entre compuestos 1,3-dicarbo-

nilicos y nitroestireno. Teniendo en cuenta la alta selectividad del catalizador 2 presente

en los antecedentes bibliográficos este fue empleado en la optimización. En primer lu-

gar se utilizaron los DES formados por cloruro de colina:urea (1:2) y cloruro de co-

lina:glicerol (1:2) empleando diferentes concentraciones de catalizador. Los mejores re-

sultados (conversión completa y excesos enantioméricos del 60% y 65% respectiva-

mente) se obtuvieron empleando un 10% a temperatura ambiente. También se obtu-

vieron buenos resultados empleando NADES formados por cloruro de colina:ácido má-

lico (1:2) y ChCl:Glucosa. Con la intención de aumentar la selectividad en la reacción

modelo las disoluciones fueron llevadas a 0 °C, obteniendo los mejores resultados de

conversión (>95%) y selectividad (80%) con el DES formado por ChCl:glicerol (1:2) por

lo que fue seleccionado como medio de reacción (Esquema 13).

Esquema 13. Adición Michael asimétrica catalizada por 2.

Los catalizadores anteriormente sintetizados se probaron en la adición Michael

modelo entre malonato de dietilo y nitroestireno bajo las condiciones óptimas de disol-

vente y temperatura obteniendo con todos ellos conversión completa pero distintas

enantiselectividades. En primer lugar, mediante el uso del catalizador 1 se obtuvo el

Resumen

aducto Michael con una enantiselectividad del 40%. En el caso del catalizador 4 con dos

grupos electrón atractores en el anillo de benzimidazol la selectividad alcanzo un 91%

mientras que empleando el catalizador 5 con un grupo electrón donante en el anillo de

benzimidazol la selectividad disminuyó hasta un 67% ee. Finalmente, el catalizador 3

con dos anillos de benzimidazol unidos a la ciclohexanodiamina fue empleado en la rea-

ción, sin embargo, se obtuvo nula selectividad en este proceso (Esquema, 14).

Esquema 14. Adición Michael de malonato de dietilo a nitrestireno catalizada por benimidazoles quirales.

Teniendo en cuenta estas selectividades se estudiaron los efectos electrónicos de

los diferentes grupos en el anillo de benzimidazol considerando la constante de Ham-

mett y su correlación entre las enantioselectividades logradas en la adición conjugada.

Utilizando la ecuación de Hammett (ln([R]/[S]) = ρ σ + c) el gráfico muestra que existe

una correlación lineal entre la relación enantiomérica[ln([R]/[S])] con la constante de

Hammett de la posición para de los grupos (ρ = 0,9483 y R2 = 0,9606) (Figura).

Resumen

Figura 5. Relación entre la selectividad y el carácter electrónico de los grupos unidos al anillo de benzimidazol del catalizador.

Bajo las condiciones óptimas se realizó la reacción Michael empleando el catali-

zador 4, diferentes electrófilos y nucleófilos. Inicialmente, se demostró que el tamaño

del grupo de ésteres del nucleófilo tenía un ligero efecto sobre la selectividad de la adi-

ción (Tabla 1, entradas 1-3). Sin embargo, los malonatos más impedidos, como el malo-

nato de iso-propilo, causaron una disminución en la formación del aducto Michael, dis-

minuyendo el rendimiento (Tabla 1, entrada 3). En este punto se probaron diferentes

electrofilos empleando como nucleófilo el malonato de dietilo, obteniendo en todos los

casos altos rendimientos y enantioselectividades (Tabla 1, entradas 4-7). Como se

muestra, no hay efecto en la selectividad después de cambiar las propiedades electróni-

cas del β-nitroalqueno (Tabla 1, entradas 4-6), obteniendo en estas reacciones buenas

enantioselectividades (80-90% ee). Finalmente, se realizó la adición de malonato de

dietilo al (E)-2-(2-nitrovinil)tiofeno, obteniéndose el aducto de Michael con excelente

rendimiento y enantioselectividad (Tabla 1, entrada 7).

Tabla 1. Adición conjugada de dialquil malonatos a nitroalquenos.

Entrada R Ar No. Rto. (%)b ee (%)c

y = 0,9483x + 2,3567R² = 0,9606

0,00

0,50

1,00

1,50

2,00

2,50

3,00

3,50

-0,80 -0,60 -0,40 -0,20 0,00 0,20 0,40 0,60 0,80 1,00

ln (R

/S)

p-NO2

Hp-NH2

s

Resumen

1 Et Ph 6a 83 91

2 Me Ph 6b 88 91

3 iPr Ph 6c 63 90

4 Et 4-ClC6H4 6d 84 80

5 Et 2,4-(Cl)2C6H3 6e 86 90

6 Et 4-MeC6H4 6f 87 85

7 Et 2-Thienil 6g 85 90

Para una evaluación adicional de la eficiencia de orgacatalizador 4 en la síntesis

de los aductos Michael, se evaluaron diferentes compuestos de 1,3-dicarbonicos y ni-

troalquenos (Tabla 2). Inicialmente, la acetilacetona se empleó como nucleófilo en la

adición a β-nitrostireno y (E)-4-fenil-1-nitro-1-buteno, para obtener los compuestos 6a

y 6b con rendimientos de moderados a buenos y enantioselectividades moderadas (Ta-

bla 2, entradas 1 y 2). Además, se probaron 1,3-dicetonas asimétricas, como la 1-fenil-

butilbutano-1-3-diona, en la reacción con β-nitrostyrene, lo que produjo el producto sin

diastereoselectividad (1/1) y con una enantioselectividad moderada para ambos dias-

tereoisómeros (65% ee, Tabla 2, entrada 3).

Utilizando acil β-betacetoesteres como el etil 3-oxobutenoato en la adición a β-

nitrostyrene, se obtuvieron buenas enantioselectividades para ambos diastereoisóme-

ros (79% y 81% ee, Tabla 2, entrada 4), lo que muestra una pequeña influencia sobre la

selectividad de la fracción de éster. Finalmente, β-ketoesters α-sustituido también fue

empleados en la adición conjugada a β-nitrostyrene, para ofrecer los productos 6l y 6m

con rendimientos moderados y enantioselectividades de bajas a moderadas (Tabla 2

entradas 5 y 6).

Tabla 2. Adición conjugada de compuestos 1,3-dicarbonilicos a nitroalquenos cataliada por 4.

Entrada Estructura No. Rto. (%)b dr (%)b ee (%)d

Resumen

1

6h 91 - 77

2

6i 46 - 67

3

6j 96 57/43 65/65

4

6k 85 55/45 79/81

5

6l 66 58/42 <5/69

6

6m 52e 65/35 55/73

A continuación, se estudió la reciclabilidad del sistema catalítico en la adición

modelo de malonato de dietilo a β-nitrostyrene en las condiciones óptimas de reacción.

Con este objetivo, se probó la capacidad de extracción de diferentes disolventes, como

el 2-metiltetrahidrofurano (2-MeTHF), terc-butil metil éter (TBME), éter dietílico y he-

xano, para eliminar los reactivos y los productos de la mezcla de DES/organocataliza-

dor. Se observaron buenas conversiones y enantioselectividades para los dos primeros

ciclos con todos los disolventes (Figura 6). Sin embargo, la conversión disminuyó en el

tercer y cuarto ciclos de reacción cuando se emplearon disolventes etéreos como me-

dios de extracción (Figura 6a-c). Tras el análisis por 1H-RMN de las fracciones etéreas

recogidas en el segundo y tercer ciclo, se detectó la presencia de trazas de organocata-

lizador 4. Este hecho explica la reducción de la conversión a lo largo de los ciclos. Afor-

tunadamente, cuando el hexano se usó como solvente para el reciclaje del sistema cata-

lítico, se logró una alta conversión y selectividad en los cuatro ciclos de reacción estu-

diados (Figura 6d).

Resumen

Figura 6. Estudios de reciclado.

Además, se llevó a cabo un experimento de escalada para empleando un gramo

de aceptador Michael (6.7 mmol) para demostrar la utilidad de esta metodología para

la síntesis verde de los productos Michael. Esta síntesis se realizó obteniendo alto ren-

dimiento (96%) y enantioselectividad (90%, Esquema 15).

Esquema 15. Escalado de la reacción modelo.

Para buscar las interacciones entre el catalizador y el DES que favorece la reci-

clabilidad del sistema, se realizaron estudios de RMN. Inicialmente los espectros 1H-

NMR del catalizador y el DES se llevaron a cabo en DMSO-d6 para asignar los protones

relevantes involucrados en las interacciones. Luego se disolvió una mezcla de 40 mg de

organocatalítico 4 (0.11 mmol) y 0.1 mL de ChCl:Gly¡i (1:2) en DMSO-d6 y se analizó

mediante 1H-NMR. Este espectro no mostró cambios relevantes en los desplazamientos

químicos de los protones del catalizador. Sin embargo, la ampliación de los protones en

el espectro reveló intercambios de protones y formación de enlaces de hidrógeno entre

el catalizador y el disolvente.

a) b)

c) d)

Resumen

Para aclarar las interacciones entre el disolvente y el organocatalizador, se reali-

zaron experimentos de 2D-RMN y experimentos selectivos de NOE. Estos experimentos

mostraron un fuerte efecto NOE entre los dos grupos metilo del catalizador 4 (NMe2) y

los tres grupos metilo del cloruro de colina (NMe3), así como la interacción entre el

NMe3 y el protón H3 del organocatalizador (Figura 7). Estas interacciones pueden des-

cribirse como enlace iónico de hidrógeno entre el catalizador y el DES (Figura 7). Ade-

más, el grupo metileno de la fracción de amonio (NMe3) mostró un efecto NOE con los

protones H5, H6 y H8 del glicerol (Figura 7). Por lo tanto, este enlace de hidrógeno-iónico

entre los componentes del medio de reacción y el catalizador favorece que el catalizador

4 no sea extraído por disolventes no polares.

Figura 7. Estudio de las interacciones DES-4.

En conclusión, la adición de Michael entre compuestos de 1,3-dicarbonilicos a ni-

troalquenos se ha realizado en disolventes eutécticos, obteniendo altos rendimientos y

selectividades empleando el organocatalizador 4 en la mezcla cloruro de colina:glicerol

(1:2). Los procedimientos son limpios, simples, baratos, escalables y seguros. Además,

el sistema catalítico puede ser recuperado y reutilizado al menos cuatro veces sin per-

der conversión o selectividad. Finalmente, los estudios de RMN revelan una interacción

no covalente (enlace iónico-hidrógeno) entre el catalizador y el disolvente.

Capítulo 2. α-aminación electrofílica asimétrica en líquidos eutécticos bajo irra-

diación con ultrasonidos.

Para realizar la α-aminación asimétrica de compuestos dicarbonílicos se tuvieron

en cuenta las condiciones óptimas del trabajo realizado anteriormente, así tras una

breve optimización para comprobar la eficiencia del catalizador 4 en la aminación asi-

métrica en el líquido eutéctico formado por cloruro de colina:glicerol (1:2).

Resumen

Para incrementar la actividad catalítica de este sistema se empleó irradiación mediante

ultrasonidos. Este factor hizo aumentar la velocidad de la reacción pasando de cinco

horas a una hora, consiguiendo alta selectividad (82% ee) en la reacción modelo adición

de 2-oxociclopentano-1-carboxilato de etilo a azodircarboxilato de ditectbutilo (Es-

quema 16).

Esquema 16. Aminación organocatalitica de 2-oxociclopentano-1-carboxilato de etilo.

La reciclabilidad del organocatalizador 4 y del líquido eutéctico se realizó para

reacción modelo bajo las condiciones de reacción optimizadas. Con este fin, se probó la

capacidad de extracción del hexano y del ciclopentil metil éter con el objetivo de separar

los reactivos y productos de reacción de la mezcla 4/DES. Como se muestra en la Figura

8, el catalizador recuperado se utilizó en cinco ciclos consecutivos, manteniendo una

elevada enantioselectividad, pero con una actividad reducida. Además, es necesaria una

agitación vigorosa al realizar la extracción de los productos para obtener un buen resul-

tado de reciclabilidad. Por ejemplo, en el segundo ciclo de la secuencia de recuperación

del ciclopentil metil éter se utilizó un agitador estándar y, por lo tanto, se observó una

disminución de la conversión al quedar el producto retenido en el DES.

Figura 8. Estudios de reciclado.

Resumen

La eficiencia y la utilidad sintética del sistema 4 en ChCl:glicerol se evaluó me-

diante el escalado de la reacción a un gramo (4.3 mmol de 2-oxociclopentano-1-carbo-

xilato de etilo) para la síntesis del correspondiente aducto, que se obtuvo en un 95% de

rendimiento y 85% de ee.

Por último, se evaluó la influencia de diferentes electrofílicos y nucleófilos en el ámbito

de la reacción. Para ello, las diferentes reacciones se realizaron en las condiciones opti-

mizadas utilizando ChCl:glicerol como disolvente (Tabla 3). En cuanto al electrofilo, se

observó un importante efecto estérico, siendo el compuesto obtenido el de mayor enan-

tioselectividad al utilizar azodicarboxilato de di-terc-butilo (DBAB) como electrofilo

(Tabla 3, entrada 3). Este electrofilo se utilizó para estudios adicionales.

También se evaluó la aminación de otros cetoésteres como 1-oxo-2,3-dihidro-1H-in-

dano-2-carboxilato de etilo, 1-oxo-2,3-dihidro-1H-indano-2-carboxilato de metilo, 1-

oxo-1,2,3,4-tetrahidronaftaleno-2-carboxilato de metilo y 3-acetildihidrofurano-2(3H)-

ona (Tabla 3, entradas 5-7). En general, se obtuvieron buenos rendimientos aislados

con enantioselectividades bajas (de 13 a 36% ee). Se observó una mejor enantioselecti-

vidad en la aminación con DBAB de 1,3-dicetonas, especialmente en el caso del 2-acetil-

ciclopentano-1-ona (Tabla 3, entrada 9), que permitió la obtención del compuesto 14

en un 75% de rendimiento aislado y un 53% de exceso enantiomérico.

Table 3. Aminación de compuestos dicarbonílicos. Alcance de la reacción-

En-

trada Nucleófilo Azodicarboxilate No. Rto. (%)a

ee

(%)b

1

BocN=NBoc 8 78 85

2 iPrO2CN=NCO2iPr 9 52 60

3 EtO2CN=NCO2Et 10 76 65

4 BnO2CN=NCO2Bn 11 0 Nd

Resumen

5

BocN=NBoc 12 66 36

6

BocN=NBoc 13 65 35

7

BocN=NBoc 14 65 13

8

BocN=NBoc 15 68 25

9

BocN=NBoc 16 75 53

Debido a la accesibilidad y a consideraciones ecológicas, la organocatalisis enan-

tioselectiva ha demostrado ser uno de los métodos más eficaces para la síntesis de fár-

macos y productos naturales. En particular, la funcionalización organocatalítica de los

oxindoles ha sido estudiada recientemente ya que este tipo de heterociclos se encuen-

tran comúnmente en un amplio rango de alcaloides naturales biológicamente activos.

Como se muestra en el Esquema 17 (Eq. a), la aminación electrofílica catalizada de 1-

acetil-3-oxoindolin-2-carboxilato de metilo en ChCl:glicerol (1:2) como disolvente en

las condiciones de reacción optimizadas dio lugar a compuestos de 17 con excelentes

rendimientos y enantioselectividades moderadas (17a: R = iPr, 30% ee; 17b: R = tBu,

45% ee).

Por otra parte, el oxindole 18 2,2-disustituido, precursor de moléculas biológicamente

activas que contienen indolin-3-ona con un estereocentro cuaternario en la posición 2,

como Brevianamide A, Austamide, entre otras, ha sido preparado con excelente rendi-

miento y diastereoselectividad y un 57% de ee mediante la adición conjugada de 1-ace-

til-3-oxoindoline-2-carboxilato de metilo a β-nitrostireno (Esquema 17, Eq. b).

Resumen

Esquema 17. Formación de precursores de productos naturales y farmacéuticos organocatalizada por 4.

Capítulo 3. Líquidos Eutécicos Quirales.

Debido a la gran utilidad y carácter verde tanto de organocatalizadores como de

líquidos eutécticos la combinación de estos dos campos puede producir un gran avance

en el desarrollo de procesos químicos sostenibles. Sin embargo, el uso de líquidos eu-

técticos formados por organocatalizadores no ha sido prácticamente explorado. Un

ejemplo de este tipo de sistemas es el líquido eutéctico quiral (CDES) desarrollado por

Tiecco y colaboradores, el cual es un derivado de la feniletilamina combinado con ácido

canforsulfónico. La síntesis del CDES se completó en dos etapas, la primera de ellas con-

sistente en la formación de la sal cuaternaria mediante una metilación empleando me-

tanosulfonato de metilo mientras que la segunda consistió en la adción ácido camfor-

sulfonico, produciendo un líquido eutéctico a 70 °C (Esquema 18).

Resumen

Esquema 18. Síntesis de líquidos eutécticos quirales derivados de feniletilamina.

Posteriormente estos dos CDES fueron utilizados en la adición asimétrica de in-

dol a chalcona, obteniendo un 11% de ee y un 5% de ee, respectivamente (Esquema 19).

Estos resultados son comparables con los resultados obtenidos empleando +CSA en ace-

tonitrilo en las mismas condiciones de reacción (10% ee, Esquema 19).

Esquema 19. Adición asimétrica de indol a chalcona catalizada por líqudos eutécticos quirales y CSA.

Teniendo en cuenta estos antecedentes, nuestro grupo de investigación se centro

en la formación de líquidos eutécticos basados en L-prolina como fuente de quiralidad,

ya que este aminoácido ha sido fundamental durante el desarrollo de la organocatálisis

al ser muy selectivo en las reacciones aldólicas y reacciones de adición de tipo Michael.

Así, dos derivados diferentes de la L-prolina (Figura 9) surgen como una buena estrate-

gia para mejorar la selectividad del sistema catalítico eliminando la fracción ácida y se-

parando la parte quiral de la molécula de la parte responsable de la formación de los

enlaces de hidrógeno.

Resumen

Figura 9. Moléculas objetivo para la formación del CDES.

Para la síntesis de los derivados catiónicos de prolina, se aplicó la metodología

desarrollada por Chen y sus colaboradores. El aminoácido natural L-prolina se empleó

como precursor debido a su disponibilidad. La reducción del aminoácido se realizó uti-

lizando como agente reductor hidruro de litio y aluminio, obteniendo el correspon-

diente L-prolinol con un alto rendimiento (99%, Esquema 20). Después de este proceso

la amina fue protegida con cloroformiato de bencilo, obteniendo el producto 23 en un

77% de rendimiento y el crudo fue tratada con cloruro de metanosulfonilo, logrando el

producto 24 con un 52% de rendimiento (Esquema 20).

El producto aislado 24 fue tratado de dos maneras diferentes para obtener el cataliza-

dor 27 y 30. Para obtener el derivado catiónico de prolina 27, el intermedio 24 se di-

solvió en THF y se llevío a reflujo en presencia de bromuro de litio, proporcionando el

producto 25 con un 55% de rendimiento aislado. Para realizar la síntesis de la sal deri-

vada protegida de prolina 26, se burbujeó trimetilamina a una solución de 25 en acetato

de etilo a 0 °C y se agitó a temperatura ambiente durante tres días. Después de este

período el producto 26 se obtuvo como precipitado blanco, proporcionando la pirroli-

dina 26 con un rendimiento del 25% (Esquema 20). Finalmente, se empleó un proceso

de hidrogenación del intermedio 26 para desproteger la fracción amínica, obteniendo

el derivado catiónico de prolina en un 99% de rendimiento.

Se empleó una segunda vía para sintetizar el derivado de prolina a partir del producto

mesilado 24 (Esquema 20). El precursor 24 se disolvió en THF y se llevó a reflujo en

presencia de pirrolidina obteniendo el intermedio 28 con rendimiento moderado

(32%). A continuación, el producto aislado 28 se agitó con 2-bromoetanol, obteniendo

la pirrolidina protegida 29 en forma de aceite marrón con impurezas (Esquema 20).

Para eliminar las impurezas, se llevó la hidrogenación y posterior precipitación de la sal

deseada. Así, el producto 29 fue tratado con hidrógeno en presencia de hidróxido de

paladio logrando la sal de pirrolidina desprotegida en buena conversión (Esquema 20),

Parte quiral Parte quiral HBA HBA/HBD

Resumen

sin embargo, el producto 30 fue obtenido como un aceite rojizo con presencia de impu-

rezas el cual no fue posible purificar.

Esquema 20. Síntesis de sales de amonio cuaternarias para la formación del CDES.

Después de la síntesis del derivado de la L-prolina 27, se realizó la formación de

un líquido eutéctico quiral. En primer lugar, se mezclaron dos equivalentes de la sal de

amonia con urea y se calentaron una hora aumentando la temperatura de cinco en cinco

grados hasta llegar a ochenta grados, pero no se detectó la formación de una mezcla

líquida (Tabla 5, entrada 1). El mismo experimento se llevó a cabo disminuyendo los

equivalentes del compuesto 27 a un equivalente, pero la mezcla permaneció como dos

sólidos (Tabla 5, entrada 2). Los equivalentes de urea se incrementaron a dos y tres

formando una disolución líquida clara a 60 °C (Tabla 5, entradas 3 y 4). Finalmente, se

emplearon dos equivalentes de glicerol como donantes de enlace de hidrógeno combi-

nados con un equivalente de 27 en la formación del CDES obteniendo una solución lí-

quida a 45 °C (Tabla 5, entrada 5).

Resumen

Tabla 5. Síntesis de líquidos eutécticos quirales.

Entrada 27 (equiv.) HBD (equiv.) Tformación (°C)

1 2 Urea (1) Nd

2 1 Urea (1) Nd

3 1 Urea (2) 60

4 1 Urea (3) 60

5 1 Gli (2) 45

Estos tres líquidos eutécticos se utilizaron en la adición Michael de ciclohexanona

a nitrostireno. Mediante el uso de los CDES basados en urea, se logró una diastereosele-

cividad y enantioselectividad moderadas en la síntesis del producto en un día, sin em-

bargo, se lograron bajas conversiones (Tabla 6, entradas 1 y 2). Usando el CDES basado

en 27/Glicerol (1:2) se obtuvieron mejores resultados en la reacción modelo, obte-

niendo el aducto 31 con alta conversión, diastereoselectividad moderada y enantiose-

lectividad moderada (Tabla 6, entrada 3). El mismo CDES de 27/Gli se reutilizó a 0 °C

para aumentar la selectividad del producto, pero se obtubo conversión nula (Tabla 6,

entrada 4). Finalmente, el 10% del derivado de prolina 27 se empleó como catalizador

usando glicerol como disolvente para estudiar la eficiencia de la molécula disuelta, pero

se logró una baja conversión y una selectividad moderada (Tabla 6, entrada 5).

Table 6. Empleo de líquidos eutecticos quirales en catálisis.

Entrada CDES Conv. (%) dr ee

Resumen

1 27:Urea (1:2) 62 75:25 70/50

2 27:Urea (1:3) 33 75:25 65/50

3 27:Gli (1:2) >95 70:30 67/60

4 27:Gli (1:2) - Nd Nd

5 27(10% molar):Gli <10 70:30 65/60

La reciclabilidad del sistema catalítico en 27:Gli (1:2) fue probada en la reacción

modelo (Figura 10). Para lograr este objetivo, se empleó acetato de etilo como medio

de extracción para separar los reactivos y los productos del CDES. Como se muestra en

el gráfico, la mezcla eutéctica fue recuperada y reutilizada en cuatro reacciones conse-

cutivas, sin perder actividad manteniendo una buena diastereoselectividad y una enan-

tioselectvidad moderada.

Figura 10. Estudios de reciclado

Finalmente, se estudió el ámbito de aplicación del nuevo disolvente eutéctico qui-

ral. En primer lugar, se probaron dos nitroalquenos con un grupo donor de electrones

y un grupo atractor de electrones, obteniendo en ambos casos una alta conversión y una

0

20

40

60

80

100

1 2 3 4

%

nº cIclos

Reciclado

conv

de

ee major

ee minor

Resumen

diastereoselectividad moderada (Tabla 7, entradas 2 y 3). Además, se lograron buenas

enantioselectividades del producto en ambos enantiómeros (Tabla 7, entrada 2). Sin

embargo, en el caso del producto 33 el diastereómero mayor se obtuvo con buena enan-

tioselectividad, mientras que el enantiómero menor se obtuvo con baja enantioselecti-

vidad (Tabla 7 entrada 3). Posteriormete, se probaron dos nucleófilos diferentes en la

adición de Michael a nitroestireno catalizado por la mezcla 27:Gly obteniendo un ren-

dimiento moderado pero enantioselectividades nulas (Tabla 14, entradas 4 y 5).

Tabla 7. Adicón Michael catalizada por el líquido eutectic 27/Gli. Alcance de la reacción.

Entrada Producto R1 R2 R3 Conv

% dr ee

1 31 -(CH2CH2CH2)- H 75 75:25 67/60

2 32 -(CH2CH2CH2)- MeO 42 74:26 60/55

3 33 -(CH2CH2CH2)- Cl 53 75:25 70/22

4 34 -(CH2CH2)- H 63 rac/rac

5 35 H H H 71 - rac

Conclusiones

Se ha demostrado la utilidad de los líquidos eutécticos como disolventes para la

catálisis asimétrica, obteniendo buenos rendimientos, enantioselectividades y diaste-

reoselectividades mediante el uso de organocatalizadores derivados de benzimidazol.

Además, se han realizado reciclados de los sistemas catalíticos con leves perdidas de

selectividad a partir del tercer ciclo en algunos casos. También ha sido posible realizar

el escalado de la reacción en el caso de la reacción Michael entre compuestos 1,3-dicar-

bonílicos y nitroalquenos y en la reacción de α-aminación de compuestos 1,3-dicarboí-

licos. Finalmente se realizó la síntesis de diferentes mezclar eutécticas quirales y se em-

plearon el la adición Michael de cetonas a alkenos obteniendo buenos rendimientos y

moderadas selectividades y pudiendo reciclar el complejo catalítico un total de cuatro

veces sin perdidas de selectividad ni conversión.

Resumen

SUMMARY

Summary

Chapter 1. Asymmetric Organocatalyzed Michael Addition in Deep Eutectic

Solvents.

Following the principles of “Green Chemistry” a catalytic system based on deep eutectic

solvents and chiral 2-amino benzimidazole organocatalysts was used to promote the

enantioselective addition of 1,3-dicarbonyl compounds to β-nitrostyrenes. This

procedure avoids the use of toxic volatile organic compounds as reaction medium,

providing access to highly functionalized chiral molecules in a selective and efficient

way. Furthermore, the reaction can be performed a gram scale and the recyclability of

the catalytic system is possible at least for four, reaction cycles leading to a clean, cheap,

simple and scalable procedure that meets most of the criteria required to be a green and

sustainable process. Moreover, NMR studies have confirmed the key role of the

hydrogen-bonding interactions between the deep eutectic solvent and the chiral

organocatalyst, which allows their recovery and the recyclability of the system

Chapter 2. Asymmetric Organocatalyzed Electrophilic α-amination in Deep

Eutectic Solvents.

The enantioselective α-amination of 1,3-dicarbonyl compounds has been performed

using deep eutectic solvents as a reaction media and chiral 2-amino benzimidazole-

derived compounds as catalysts. With this procedure, the use of toxic volatile organic

compounds as reaction medium was avoided. Therefore, highly functionalized chiral

molecules, which are important intermediates towards natural product synthesis, were

Summary

prepared by an efficient and stereoselective protocol. Moreover, the reaction can be

done on gram scale, with the recycling of the catalytic system being possible for at least

five consecutive reaction runs. This procedure represents a cheap, simple, clean, and

scalable method that meets most of the principles to be considered a green and

sustainable process.

Chapter 3. Chiral Deep Eutectic Solvents.

Different proline based eutectic mixtures were used in the asymmetric Michael addition

of ketones to nitroalkenes. In view of the results and the 1H-RMN studies carried out, a

relationship between the conversion and selectivity with the association constant of the

components of the eutectic mixture was confirmed. With these data, a novel chiral deep

eutectic solvent base on a quaternarium proline derivative (S)-N,N,N-trimethyl-1-

(pyrrolidin-2-yl)methanaminium bromide and glycerol was prepared. This system was

an efficient catalytic system for the Michael addition of carbonyl compounds to β-

nitrostyrenes, obtaining moderate selectivities under mild conditions. Moreover, the

catalyst could be easily recovered and recycled five times in the addition of

cyclohexanone to β-nitrostyrene without significant loss of catalytic activity.

INDEX

INDEX:

GENERAL INTRODUCTION ......................................................................................................................... 1

1. Green Chemistry .................................................................................................................................... 3

1.1. Alternative solvents .................................................................................................................. 4

2. Deep Eutectic Solvents ........................................................................................................................ 6

2.1. Active DES ..................................................................................................................................... 9

2.2. Innocent DES ............................................................................................................................. 10

3. Asymmetric Organocatalysis .................................................................................................. 12

3.1. Enamine Catalysis ................................................................................................................... 17

3.2. Iminium Catalysis ................................................................................................................... 18

3.3. SOMO Activation ..................................................................................................................... 20

3.4. Hydrogen-Bonding Catalysis ............................................................................................. 22

3.5. Counterion Catalysis.............................................................................................................. 24

4. Supported Organocatalysis ...................................................................................................... 25

4.1. Covalently Supported Chiral Organocatalysts ........................................................... 26

4.2. Non-Covalently Supported Chiral Organocatalyst ................................................... 28

4.3. Biphasic Catalysis ................................................................................................................... 30

CHAPTER 1 ...................................................................................................................................................... 33

1.1. Background ............................................................................................................................... 35

1.1.1. Asymmetric Organocatalysis in Deep Eutectic Solvents .................................. 35

1.1.2. Benzimidazole Derivatives in Asymmetric Organocatalysis.......................... 39

1.2. Objectives ................................................................................................................................... 47

1.3. Discussion of Results ............................................................................................................. 49

1.3.1. Synthesis of Chiral Organocatalysts for the Michael Addition ...................... 49

1.3.2. Michael Addition of 1,3-Dicarbonyl Compounds to Nitroolefines in DES 50

1.4. Experimental Data .................................................................................................................. 63

1.4.1. General ................................................................................................................................... 63

1.4.2. Synthesis and Spectroscopic Data of Chiral Organocatalysts ........................ 63

1.4.3. Experimental Procedure ................................................................................................ 67

1.4.4. Recycling Experiment ...................................................................................................... 67

1.4.5. Physical and Spectroscopic Data for Compounds 26 ........................................ 68

1.5. Conclusions................................................................................................................................ 75

CHAPTER 2 ...................................................................................................................................................... 77

2.1. Background ............................................................................................................................... 79

2.1.1. Asymmetric Electrophilic α-Amination of Carbonyl Compounds ............... 79

2.1.2. Ultrasounds in Asymmetric Organocatalysis ........................................................ 83

2.2. Objetives ..................................................................................................................................... 87

2.3. Discussion of Results ............................................................................................................. 89

2.4. Experimental Data .................................................................................................................. 99

2.4.1. General ................................................................................................................................... 99

2.4.2. Synthesis and Spectroscopic Data of Chiral Organocatalysts. ....................... 99

2.4.3. Experimental Procedure ..............................................................................................102

2.4.4. Recycling Experiment ....................................................................................................102

2.4.5. Physical and Spectroscopic Data for Compounds 33 ......................................103

2.5. Conclusions..............................................................................................................................107

CHAPTER 3 ....................................................................................................................................................109

3.1. Background .............................................................................................................................111

3.1.1. Non-Natural Deep Eutectic Solvents .......................................................................111

3.2 Objectives .................................................................................................................................117

3.3. Discussion of Results ...........................................................................................................119

3.4. Experimental Data ................................................................................................................129

3.4.1. General .................................................................................................................................129

3.4.2. Synthesis and Spectroscopic Data of Chiral Organocatalysts ......................129

3.4.3. Experimental Procedure ..............................................................................................133

3.4.4. Recycling Experiment ....................................................................................................133

3.4.5. Physical and Spectroscopic Data for Compounds 52 ......................................134

3.5. Conclusions..............................................................................................................................137

GENERAL INTRODUCTION

General Introduction

3

1. Green Chemistry

Nowadays, our society faces great challenges such as global warming, the

generation of waste and the scarcity of resources, all of them related to humankind. Due

to these problems, the United Nations (UN) signed the Millennium Declaration in 2000,

which supports the "Protection of our common environment".1 In this context, in 1998

Anastas published the twelve principles of Green Chemistry devoted to increase the

sustainability and ecological efficiency of chemical processes (Figure 1).2 These twelve

principles are:

Figure 1. The twelve principles of the Green Chemistry.

Considering these principles, switching for current processes to a more

environmentally friendly ones becomes quite difficult since the achievement of all the

required principles is almost an impossible task. This thesis focuses on the following

1 http://www.un.org/millennium/declaration/ares552e.pdf. 2 Anastas, P. T.; Warner, J. C. Green Chemistry : Theory and Practice Oxford, 1998.

•Prevention in the formation of waste

• Atomic economy

•Less toxic intermediates

• Safer end products

•Reduction of the use of auxiliary substances

•Reduction of energy consumption

•Use of renewable raw materials

•Reduction of unnecessary derivatization

•Use of catalysts

•Design for degradation

•Real-time monitoring

•Minimization of the risk of accidents


4

principles: using renewable solvents and catalysts, recycling the catalytic system and

developing reactions with high atomic economy.

1.1. Alternative solvents

One of the most complicated principles of Green Chemistry to accomplish is the

reduction (even elimination) of the auxiliary substances employed in the processes,

such as the solvent. Volatile Organic Solvents (VOCs) improve the reactivity of the

reactants, especially when they are in the same phase. However, VOCs have important

disadvantages such as: accumulation in the atmosphere due to their low boiling points,

high flammability, high toxicity and very low biodegradability. On the other hand, the

annual industrial-scale production of organic solvents has been estimated at almost 20

million kilograms only in the pharmaceutical industry,3 amount which continues

growing with the industrial development of the countries.

Some alternatives have emerged trying to replace VOCs as reaction medium

(Figure 2). These alternatives attempt to follow the principles of Green or Sustainable

Chemistry and can also be applied at industrial level; however, all of them present some

disadvantages, hampering in most cases their general use.

3 Constable, D. J. C.; Jimenez-Gonzalez, C.; Henderson, R. K. Org. Process Res. Dev. 2007,

11, 133-137.


5

Figure 2. Alternative solvents.

The first alternative solvent that emerges when thinking about an ideal solvent

is water, since it is safe, both for human beings and for the environment, abundant and

renewable.4 Unfortunately, the low solubility of the organic compounds in this solvent

limits its use. The nucleophilic properties of this solvent and the complex purification of

water residues during the work-up procedures strongly decreases its chances to be use

as alternative to VOCs in most organic processes.

One of the oldest alternatives to VOCs are supercritical fluids, developed and

applied in the food-processing industry.5 Supercritical fluids are substances that have

hybrid properties between liquid and gas, such as the ability to dissolve substances and

the possibility of spreading. These solvents allow to perform heterogeneous processes

due to their biphasic character and they are easily tuneable just modifying the pressure

or the temperature. However, its use in general is quite limited due to the high cost of

the necessary equipment, the low solubility of the organic reagents and the high

reactivity of the molecules that usually compose these fluids.

4 Li, C. J.; Chen, L. Chem. Soc. Rev. 2006, 35, 68-82. 5 Herrero, M.; Mendiola, J. A.; Cifuentes, A.; Ibáñez, E. J. Chromatogr. A 2010, 1217, 2495-

2511.

Alternative

Solvents

Water

Super-critic

Fluids

Ionic liquids

Deep Eutectic Solvetns

Biomass

Waste


6

Due to the new trend towards the circular economy, the recycling of agricultural

waste has gained importance as source of renewable energy and basic chemical

products.6 A large number of biochemical and thermal processes offer the possibility of

converting waste into solvents such as ethanol, glycerol, limonene, ethyl lactate or

2-methyltetrahydrofuran. Although these solvents have a green character and origin, it

is not possible to modulate their properties (such as polarity) and some of them display

flammability problems, making their general application difficult.

Ionic liquids (IL) are two-component salts, an organic cation and an inorganic

anion (Figure 3), which are usually liquids at temperatures under hundred degrees.7

These compounds have been studied as green solvents due to their null vapor pressure,

low flammability, high thermal stability, immiscibility with many organic solvents and

catalytic activity. Despite these properties, there are some drawbacks that should be

consider. For instance, their synthesis usually requires organic solvents decreasing the

atom economy of this process. Also, ILs display low biodegradability and generally have

an unknown toxicity.

Figure 3. Components of Ionic Liquids.

2. Deep Eutectic Solvents

Due to the above-mentioned reasons, deep eutectic solvents have appeared on

the scene as a new class of green solvents. This kind of solvents was firstly reported in

6 Zuin, V. G.; Ramin, L. Z. Top. Curr. Chem. 2018, 376, 3-57. 7 Welton, T. Chem. Rev. 1999, 99, 2071-2084.


7

2001 by Abbott et al. as a sub-category of ionic liquids due to their similar properties.

However, DES show great differences with ILs.8

DES are mixtures of two or more components, which undergo a phase change at

a precise temperature. In general, eutectic mixtures have lower melting points than

each of the pure components. These eutectic mixtures have very interesting properties,

such as high polarity and low miscibility with certain organic solvents such as ethyl

acetate, heptane, etc. The depression of the melting point of the eutectic mixture

depends on the type of interaction between its components (Figure 4).

Figure 4. Phase diagram for Deep Eutectic Solvents.

There are eutectic mixtures with melting points near or below room temperature

due to the formation of an extensive three-dimensional hydrogen bonding network by

the components of the mixture. According to the nature of the components of the

eutectic mixture, DES can be classified into four different families (Table 1).9

8 Abbott, A. P.; Capper, G.; Davies, D. L.; Munro, H. L.; Rasheed, R. K.; Tambyrajah, V. Chem.

Commun. 2001, 2010-2011. 9 Smith, E. L.; Abbott, A. P.; Ryder, K. S. Chem. Rev. 2014, 114, 11060-11082.

Eutectic mixture


8

Table 1. General formula for the classification of Deep Eutectic Solvents.

Type General Formula Terms

Type I Cat+X−zMClx M = Zn, Sn, Fe, Al, Ga, In

Type II Cat+X−

zMClx·yH2O M = Cr, Co, Cu, Ni, Fe

Type III Cat+X−zRZ Z = CONH2, COOH, OH

Type IV MClx + RZ = MClx−1+·RZ + MClx+1

− M = Al, Zn and Z = CONH2, OH

Eutectic liquids have been applied in a variety of fields such as CO2

sequestration,10 extraction and separation of compounds,11 purification of biodiesel and

as solvent for organic synthesis (Figure 5).12

Figure 5. Applications of Deep Eutectic Solvents, Source: Scifinder, 2019.

Type III DESs are particularly interesting considering the ability to fine-tune the

properties of the solvent, just by changing its composition. In addition, the formation of

these DESs with alcohols and carboxylic acids allows the use of the solvent as reactant

or even catalyst. This type of eutectic liquids is formed by a hydrogen bond donor

molecule (HBD) and hydrogen bonding acceptor (HBA). The structure of the DES

formed by choline chloride:Urea (1:2) is the only one directly measured by neutron

diffraction, showing the hydrogen bond formation between two urea molecules with

10 García, G.; Aparicio, S.; Ullah, R.; Atilhan, M. Energ. Fuel 2015, 29, 2616-2644. 11 Cunha, S. C.; Fernandes, J. O. TrAc-Trend. Anal. Chem. 2018, 105, 225-239. 12 Alonso, D. A.; Baeza, A.; Chinchilla, R.; Guillena, G.; Pastor, I. M.; Ramón, D. J. Eur. J. Org.

Chem. 2016, 612-632.

Biology and biotechnology

Properties

Organic synthesis

Preparation

Analysis

Extraction

Separation

Electrochemistry CO2

Sequestration


9

one molecule of choline chloride, to afford the corresponding DES interaction (Figure

6).13

Figure 6. Interaction between the components of the Deep Eutectic Solvent obtained from choline chloride and urea.

Eutectic mixtures are prepared through a clean one-step synthesis under atom-

economy conditions by just mixing components usually obtained from natural sources

(citric acid, malic acid, lactic acid,…) and industrial side-product components (glycerol,

urea, ethylene glycol, choline chloride). Regarding applications, eutectic mixtures can

be use as reaction solvents, either being part of the chemical reaction, with DES acting

as solvent and as reagent (Active DES) or being used as an inert organic solvent (Non-

Active DES).

2.1. Active DES

Deep eutectic solvents are able to pre-activate reagents and thus catalyse organic

reactions by hydrogen bond or acid-base interactions. The great majority of active DES

are those formed by biomass-derived carboxylic acids such as, tartaric acid, citric acid

or malic acid. This type of acidic solvents can change both the polarity of the solvent

(thereby increasing the reactivity) and can perform as acid catalysts. One of the most

reported use of active DES is related with the synthesis of hydroxymethylfurfural

(HMF), which can be used as a building block for the preparation of polyesters or

converted to bioethanol, through degradation of fructose, also present in biomass

(Scheme 1).14

13 Hammond, O. S.; Bowron, D. T.; Edler, K. J. Green Chem. 2016, 18, 2736-2744. 14 Hu, S.; Zhang, Z.; Zhou, Y.; Han, B.; Fan, H.; Li, W.; Song, J.; Xie, Y. Green Chem. 2008, 10,

1280-1283.


10

Scheme 1. Synthesis of hydroxymethylfurfural and derivatives using Deep Eutectic Solvents.

Besides from catalysing organic reactions, active DESs can also work as reagents,

decreasing the required reaction times due to their excess with respect to the other

reagents and therefore using fewer resources in the synthesis. In this line, Koening’s

group has achieved an efficient synthesis of 3,4-dihydropyrimidin-2-ones (DHPMs)

employing the mixture tartaric acid:dimethyl urea (DMU, 3:7) as solvent (Scheme 2).15

In this example the mixture works as catalyst, reactant and solvent, promoting the

formation of the Biginelli product. The tartaric acid-catalysed formation of the dimethyl

urea imine is followed by the nucleophilic attack of the ketone, obtaining the final

product by condensation of the resulting ketone.

Scheme 2. Synthesis of 3,4-dihydropyrimidin-2-ones from various carbonyl compounds.

2.2. Innocent DES

Innocent deep eutectic solvents are those that participate only as a reaction

medium, however, these solvents are also capable of decreasing the reaction times or

15 Gore, S.; Baskaran, S.; Koenig, B. Green Chem. 2011, 13, 1009-1013.


11

the energy necessary to carry out the process.16 One of the most important advantages

of these solvents is the possibility to recover and recycle the system, leading to less

waste generation.

One of the most surprising reactions carried out using innocent DES is the

addition of organometallic reagents to ketones17 and imines.18 It is well known that dry

conditions are usually mandatory to avoid the decomposition of the organometallic

compounds. In this case, the reaction was accomplished with different deep eutectic

solvents, including the mixture formed by choline chloride and water [ChCl:H2O (1:2)].

Aromatic and aliphatic ketones were employed as electrophiles achieving the

corresponding tertiary alcohols from moderate to good yields at room temperature

(Scheme 3).

Scheme 3. Addition of organometallic compounds to ketones in different Deep Eutectic Solvents.

Applying the same protocol, organolithium derivatives were added to different

imines and quinolines in aerobic conditions at room temperature using choline

chloride:glycerol (1:2) as reaction medium. Using this methodology, 23 amines were

synthesised, in just 3 to 5 seconds of reaction time, obtaining high and moderate yields

in the addition to imines and quinolines, respectively (Scheme 4).

16 Sonawane, Y. A.; Phadtare, S. B.; Borse, B. N.; Jagtap, A. R.; Shankarling, G. S. Org. Lett.

2010, 12, 1456-1459. 17 Vidal, C.; García-Álvarez, J.; Hernán-Gómez, A.; Kennedy, A. R.; Hevia, E. Angew. Chem.

Int. Ed. 2014, 53, 5969-5973. 18 Vidal, C.; García-Álvarez, J.; Hernán-Gómez, A.; Kennedy, A. R.; Hevia, E. Angew. Chem.

Int. Ed. 2016, 55, 16145-16148.


12

Scheme 4. Addition of orgalithium reagents to imines in Deep Eutectic Solvents under aerobic conditions.

On the other hand, organocatalytic multicomponent reactions have been tested

in DESs in order to obtain cyclohexa-1,3-dienamines, employing mild conditions and

short reaction times (Scheme 5).19 In this case, the DES is the reaction medium and plays

an important role in the activation, via hydrogen bond, of the carbonyl groups of the

reactants increasing the rate of the reaction. This reaction medium can be recovered for

five times in the model reaction between benzaldehyde, cyclohexanone and

malononitrile, observing a slightly decrease in the yield of the product in subsequent

cycles.

Scheme 5. Synthesis of cyclohexa-1,3-dienamines via multicomponent reaction in Deep Eutectic Solvents.

3. Asymmetric Organocatalysis

The use of catalyst and the employment of less toxic substances in the synthetic

processes are two of the twelve principles of Green Chemistry. Both of them can be

accomplished by using organocatalysis.

19 Azizi, N.; Ahooie, T. S.; Hashemi, M. M. J. Mol. Liq. 2017, 246, 221-224.


13

In 2000, David MacMillan defined the term “Organocatalysis” as the use of

organic molecules with low molecular weight as catalyst in organic reactions.20 After

this definition, the asymmetric organocatalysis field was developed very fast, achieving

an exponential growth, as depicted in Figure 7. However, the origins of organocatalysis

date back to 1896, when Emil Knoevenagel demonstrated the ability of certain primary

and secondary amines to catalyse the aldol condensation of α-ketoesters and malonates

with aldehydes and ketones.21 Currently, this transformation is considered as the origin

of organocatalysis, more specifically, of aminocatalysis

. 22

Figure 7. Asymmetric organocatalysed reactions. Source: Scifinder. 2019.

The first asymmetric organocatalysed reaction dates from 1904, when

Marckwald performed the decarboxylation of 2-ethyl-2-methylmalonic acid in the

presence of brucine to obtain 2-methylbutyric acid with 10% enantiomeric excess

(Scheme 6).23

20 Ahrendt, K. A.; Borths, C. J.; MacMillan, D. W. C. J. Am. Chem. Soc. 2000, 122, 4243-4244. 21 Knoevenagel, E. Ber. Dtsch. Chem. Ges. 1898, 31, 730-737. 22 List, B. Angew. Chem. Int. Ed. 2010, 49, 1730-1734. 23 Marckwald, W. Ber. Dtsch. Chem. Ges. 1904, 37, 349-354.

0

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Publications


14

Scheme 6. Asymmetric decarboxylation of 2-ethyl-2-methylmalonic acid catalysed by brucine.

One of the most important events in the history of asymmetric organocatalysis is

the discovery of L-proline as a catalyst. This amino acid was capable to catalyse an

intramolecular asymmetric aldol reaction (

Scheme 7).24 After this work the use of L-proline derivatives as chiral

organocatalysts has been well studied,25 becoming a great tool to obtain a wide variety

of chiral compounds.

Scheme 7. Asymmetric aldol condensation.

In the year 2000, the works of Barbas, List and MacMillan were published almost

simultaneously, being the beginning of the asymmetric organocatalysis as research field

just as it is known today. List and Barbas developed the first direct and enantioselective

aldol reaction between acetone and different aldehydes catalysed by L-proline (Scheme

8), proposing a chiral enamine formed between the catalyst and acetone as reaction

intermediate.26 In addition, the postulated transition state involved a hydrogen bond

interaction between the aldehyde and the carboxylic acid of the catalyst that favoured

a chiral environment.

24 Hajos, Z. G.; Parrish, D. R. J. Org. Chem. 1974, 39, 1615-1621. 25 (a) List, B.; Lerner, R. A.; Barbas, C. F. J. Am. Chem. Soc. 2000, 122, 2395-2396; (b) Liu,

J.; Wang, L. Synthesis 2017, 49, 960-972; (c) Agirre, M.; Arrieta, A.; Arrastia, I.; Cossío, F. P. Chem. Asian J. 2019, 14, 44-66.

26 List, B. Tetrahedron 2002, 58, 5573-5590.


15

Scheme 8. Enantioselective aldol reaction via enamine formation.

On the other hand, MacMillan studied the Diels-Alder cycloaddition between α,β-

unsaturated aldehydes and dienes catalysed by chiral imidazolidinones. In this case, the

activation of the electrophile was achieved by forming the corresponding chiral

iminium salt with the organocatalyst (Scheme 9).20

Scheme 9. Asymmetric Diels-Alder reaction via chiral iminium salt intermediate.

After the works of MacMillan, Barbas and List, asymmetric organocatalysis

achieved recognition by the scientific community as a fundamental tool in the synthesis

of enantiomerically enriched compounds,27 at the same level as catalysis with metal

27 (a) Dalko, P. I.; Moisan, L. Angew. Chem. Int. Ed. 2001, 40, 3726-3748; (b) Houk, K. N.;

List, B. Accounts Chem. Res. 2004, 37, 487-487; (c) Dalko, P. I.; Moisan, L. Angew. Chem. Int. Ed. 2004, 43, 5138-5175; (d) Berkessel, A.; Gröger, H. Asymmetric Organocatalysis: From Biomimetic Concepts to Applications in Asymmetric Synthesis; Wiley-VCH: Weinheim, 2005; (e) Pellissier, H. Tetrahedron 2007, 63, 9267-9331; (f) List, B. Chem. Rev. 2007, 107, 5413-5415; (g) Dalko, P. I. Enantioselective Organocatalysis, Reactions and Experimental Procedures; Wiley-VCH: Weinheim, 2007; (h) Jaroch, S.; List, B.; Reetz, M. T.; Weinmann, H. Organocatalysis; Springer: Berlin, 2007; (i) Dondoni, A.; Massi, A. Angew. Chem. Int. Ed. 2008, 47, 4638-4660; (j) Mahrwald, R. Enantioselective


16

catalysis and biocatalysis being these three, the pillars of asymmetric catalysis (Figure

8).28

Figure 8. Pillars of asymmetric catalysis.

Several factors have been responsible for the development of the asymmetric

organocatalysis during the last twenty years such as, the advances in computational

chemistry and mechanistic studies and the advantages of chiral organocatalysts: readily

available, non-toxic and stable molecules, which are easily functionalized enabling their

immobilization into inorganic and organic supports. It is possible to distinguish

between different activation modes depending on the catalyst structure and the

substrates involved in the reaction. These catalytic activation modes, established by

MacMillan in 2008, are: enamine, iminium, Singly Occupied Molecular Orbital (SOMO),

and counterion and hydrogen-bonding catalysis (Figure 9).29

Organocatalyzed Reactions; Springer: Heidelberg, 2011; (k) List, B. Science of Synthesis: Asymmetric Organocatalysis Thieme: Stuttgart, 2012; (l) Maruoka, K. Science of Synthesis: Asymmetric Organocatalysis; Thieme: Stuttgart, 2012.

28 (a) Giacalone, F.; Gruttadauria, M.; Agrigento, P.; Noto, R. Chem. Soc. Rev. 2012, 41, 2406-2447;(b) Seayad, J.; List, B. Org. Biomol. Chem. 2005, 3, 719-724.

29 MacMillan, D. W. C. Nature 2008, 455, 304-308.


17

Figure 9. Activation modes in asymmetric organocatalysis.

3.1. Enamine Catalysis

As mentioned above, the first successful asymmetric organocatalytic reactions

that employed enamine catalysis were reported by the groups of Parrish24 and Barbas

25 involving an asymmetric aldol reaction. The activation of the Highest Occupied

Molecular Orbital (HOMO) of the carbonyl nucleophile by forming the corresponding

enamine favours the nucleophilic addition to the electrophile in wide range of

asymmetric reactions such as, Mannich30, Michael31 and α-functionalizations (Figure

10).32

30(a) Hoekman, S.; Verkade, J. M. M.; Rutjes, F. P. J. T. Organocatalized Asymmetric

Mannich Reactions, In Organocatalyzed reactions II. Asymmetric C-C Bond Formation Processes; Mahrwald, R., Ed.; Springer: Heidelberg, 2011; (b) Yliniemelä-Sipari, S. M.; Piisola, A.; Pihko, P. M. Enamine Catalysis of Intermolecular Aldol Reactions, In Science of Synthesis, Asymmetric Organocatalysis I; List, B., Ed.; Thieme: Stuttgart, 2012; (c) Benohoud, M.; Hayashi, Y. Enamine Catalysis of Mannich Reactions, In Science of Synthesis, Asymmetric Organocatalysis I; List, B., Ed.; Thieme: Stuttgart, 2012.

31 Mase, N. Enamine Catalysis of Michael Reactions, In Science of Synthesis, Asymmetric Organocatalysis I; List, B., Ed.; Thieme: Stuttgart, 2012.

32 (a) Mukherjee, S. Enamine Catalysis of -Functionalizations and Alkylations, In Science of Synthesis, Asymmetric Organocatalysis I; List, B., Ed.; Thieme: Stuttgart, 2012; (b) Ramón, D. J.; Guillena, G. Enantioselective -Heterofunctionalization of Carbonyl Compounds, In Organocatalyzed Reactions I. Enantioselective Oxidation, reduction,


18

Figure 10. Nucleophilic additions via chiral enamine.

3.2. Iminium Catalysis

The catalysis via iminium salt formation was born with the idea of achieving the

same mechanistic activation mode showed by using Lewis acids, activating the Lowest

Unoccupied Molecular Orbital (LUMO) of the electrophile, thus generating an electronic

demand in the compound (Figure 11).

Figure 11. a) Carbonyl activation by a Lewis acid. b) Carbonyl activation by iminium salt formation.

Functionalization and Desymmetrization; Mahrwald, R., Ed.; Springer: Heidelberg, 2011.


19

The first work in the field of the asymmetric catalysis via chiral iminium salt was

the asymmetric synthesis of Diels-Alder adducts employing a chiral imidazolidinone as

organocatalysts by MacMillan.20 After this pioneering work, the chiral iminium

activation become very useful33 in the synthesis of natural products and chiral

molecules in general supported by the development of new chiral organocatalysts

(usually primary and secondary amines) and the corresponding structure/activity

studies (Figure 12).34

Figure 12. Examples of non-natural chiral organocatalyst.

An example of the synthetic usefulness of the iminium activation mode is the

obtention of the precursor of (−)-Paroxetine (antidepressant) by conjugate addition of

malonates to α,β-unsaturated aldehydes catalysed by Jørgensen’s organocatalyst at 0 °C

in ethanol.35 Following this methodology, 15 products were synthesized with high

yields and enantioselectivity (Scheme 10).

33(a) Mlynarski, J.; Gut, B. Chem. Soc. Rev. 2012, 41, 587-596; (b) Marson, C. M. Chem. Soc.

Rev. 2012, 41, 7712-7722; (c) Dalpozzo, R.; Bartoli, G.; Bencivenni, G. Chem. Soc. Rev. 2012, 41, 7247-7290; (d) Abbasov, M. E.; Romo, D. Nat. Prod. Rep. 2014, 31, 1318-1327; (e) Chauhan, P.; Mahajan, S.; Enders, D. Chem. Rev. 2014, 114, 8807-8864; (f) Xie, X.; Huang, W.; Peng, C.; Han, B. Adv. Synth. Catal. 2018, 360, 194-228; (g) Chanda, T.; Zhao, J. C.-G. Adv. Synth. Catal. 2018, 360, 2-79.

34 Erkkilä, A.; Majander, I.; Pihko, P. M. Chem. Rev. 2007, 107, 5416-5470. 35 Brandau, S.; Landa, A.; Franzén, J.; Marigo, M.; Jørgensen, K. A. Angew. Chem. Int. Ed.

2006, 45, 4305-4309.


20

Scheme 10. Organocatalytic conjugate addition of malonates to α,β-unsaturated aldehydes.

3.3. SOMO Activation

In the year 2007, chiral organocatalysis by activation of the Singly Occupied

Molecular Orbital (SOMO) was developed. This new methodology allowed to discover

unknown transformations such as direct α-alkylations of ketones and aldehydes

emoplying simple olefins as coupling partners.36 This activation mode consists of the

generation of a reactive radical cation after the formation of the enamine between the

organocatalyst and the aldehyde. This three π-electron specie, in which one of the

electrons occupies the SOMO orbital, is able to react with weak nucleophiles

(‘SOMOphiles’) that cannot react with the typical enamine. The first example of SOMO

activation was reported by MacMillan ad co-workers as a new and highly asymmetric

synthesis of α-allylated aldehydes. This transformation with high selectivity was

accomplished by the oxidation of the enamine form between the organocatalyst and the

aldehyde. This three-electron specie reacts with the electrondeficien olefin that

functions effectively SOMO nucleophile to provide the corresponding alkylated adduct.

(Scheme 11).

36 Beeson, T. D.; Mastracchio, A.; Hong, J.-B.; Ashton, K.; MacMillan, D. W. C. Science 2007,

316, 582-585.


21

Scheme 11. Enantioselective α-allylation via SOMO-activated aldehydes.

SOMO activation has been also used combining organocatalysis and photoredox

catalysis.37 A representative example of this methodology, developed by MacMillan and

co-workers, is shown in Scheme 1238 where Jørgensen’s catalyst was used in

combination with an iridium catalyst as oxidant were used to -alkylate aldehydes with

styrene via SOMO-activation.

37 Zhu, L.; Wang, D.; Jia, Z.; Lin, Q.; Huang, M.; Luo, S. ACS Catal. 2018, 8, 5466-5484. 38 Capacci, A. G.; Malinowski, J. T.; McAlpine, N. J.; Kuhne, J.; MacMillan, D. W. C. Nat. Chem.

2017, 9, 1073-1077.


22

Scheme 12. Enantioselective intermolecular α-alkylation.

3.4. Hydrogen-Bonding Catalysis

The activation via hydrogen-bonding was not considered as an activation mode

in the early 80s.39 The formation of strong hydrogen bonds was studied by Etter’s group

who described the rapid formation of co-crystals between electron-poor diarylureas

with several proton acceptors, including carbonyl compounds. After this work, Curran’s

group developed urea-derived catalysts that were employed to carry out allylations of

sulfoxides and Claisen rearrangements of allyl vinyl ethers.40 The use of this powerful

interaction between the substrate and the catalyst acquired importance after the work

of Jacobsen41 and Corey42 who used chiral thiourea and chiral guanidine catalysts,

respectively (Figure 13).

39 (a) Hiemstra, H.; Wynberg, H. J. Am. Chem. Soc. 1981, 103, 417-430. Oku, J.; Inoue, S. J.

Chem. Soc. Comm. 1981, 229-230; (b) Dolling, U. H.; Davis, P.; Grabowski, E. J. J. Am. Chem. Soc. 1984, 106, 446-447.

40 Curran, D. P.; Kuo, L. H. J. Org. Chem. 1994, 59, 3259-3261. 41 Sigman, M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 1998, 120, 4901-4902. 42 Corey, E. J.; Grogan, M. J. Org. Lett. 1999, 1, 157-160.


23

Figure 13. Chiral thiourea and guanidine base organocatalyst.

In the following years, the group of Takemoto developed cyclohexane1,2-

diamine-derived chiral urea and thiourea organocatalysts that were employed in a large

number of organocatalysed asymmetric reactions43 such as Michael,44 the Mannich

reaction45 and the aza-Henry reaction.46 One example of this reactions is the addition of

malonates to nitrostyrene performed in toluene and involving an activation of the

nucleophile and electrophile by a Takemoto’s type organocatalyst (Scheme 13).

Scheme 13. Enantioselective Michael addition catalysed by a chiral thiourea.

43 Hideto, M.; Yoshiji, T. B. Chem. Soc. Jpn. 2008, 81, 785-795. 44 Okino, T.; Hoashi, Y.; Takemoto, Y. J. Am. Chem. Soc. 2003, 125, 12672-12673. 45 Okino, T.; Nakamura, S.; Furukawa, T.; Takemoto, Y. Org. Lett. 2004, 6, 625-627. 46 Yamaoka, Y.; Miyabe, H.; Yasui, Y.; Takemoto, Y. Synthesis 2007, 2571-2575.


24

Nowadays, this activation mode is fundamental in asymmetric catalysis47 being

even effective and selective in hydrogen-bonding solvents, such as water48 and DES.49

3.5. Counterion Catalysis

Counterion catalysis was initially reported by Jacobsen´s group during the

development of new asymmetric methodologies for the synthesis of chiral heterocycles,

through the generation of N-acyl-iminium and oxocarbenium ions employing α-

haloimines and α-haloethers.50 This activation mode presents some similarities with the

hydrogen bond activation mode, being its fundamental pathway the formation of a

strong hydrogen-ionic bond between the catalyst (usually a chiral urea or thiourea

moiety) and the corresponding halogen. This transient ion pair with the catalyst is

stable enough to favour the approach of the nucleophile. This methodology has been

scarcely studied,51 however, highly efficient catalysts have been developed showing

their activity in sub-ppm levels.52

47 (a) Schreiner, P. R. Chem. Soc. Rev. 2003, 32, 289-296; (b) Akiyama, T.; Itoh, J.; Fuchibe,

K. Adv. Synth. Catal. 2006, 348, 999-1010; (c) Yu, X.; Wang, W. Chem. Asian J. 2008, 3, 516-532; (d) Zhang, Z.; Schreiner, P. R. Chem. Soc. Rev. 2009, 38, 1187-1198; (e) Alemán, J.; Parra, A.; Jiang, H.; Jørgensen, K. A. Chem. Eur. J. 2011, 17, 6890-6899.; (f) Freckleton, M.; Baeza, A.; Benavent, L.; Chinchilla, R. Asian J. Org. Chem. 2018, 7, 1006-1014; (g) Martín-Sómer, A.; Arpa, E. M.; Díaz-Tendero, S.; Alemán, J. Eur. J. Org. Chem. 2019, 574-581.

48 (a) Schreiner, P. R. Chem. Soc. Rev. 2003, 32, 289-296; (b) Gruttadauria, M.; Giacalone, F.; Noto, R. Adv. Synth. Catal. 2009, 351, 33-57; (c) Yu, J.; Shi, F.; Gong, L.-Z. Accounts Chem. Res. 2011, 44, 1156-1171.

49 (a) Ñíguez, D. R.; Guillena, G.; Alonso, D. A. ACS Sustain. Chem. Eng. 2017, 5, 10649-10656; (b) Ñíguez, D. R.; Khazaeli, P.; Alonso, D. A.; Guillena, G. Catalysts 2018, 8, 217-228.

50 (a) Raheem, I. T.; Thiara, P. S.; Peterson, E. A.; Jacobsen, E. N. J. Am. Chem. Soc. 2007, 129, 13404-13405; (b) Reisman, S. E.; Doyle, A. G.; Jacobsen, E. N. J. Am. Chem. Soc. 2008, 130, 7198-7199.

51 Mahlau, M.; List, B. Angew. Chem. Int. Ed. 2013, 52, 518-533. 52 Bae, H. Y.; Höfler, D.; Kaib, P. S. J.; Kasaplar, P.; De, C. K.; Döhring, A.; Lee, S.; Kaupmees,

K.; Leito, I.; List, B. Nat. Chem. 2018, 10, 888-894.


25

Scheme 14. Enantioselective thiourea-catalysed additions to oxocarbenium ions.

4. Supported Organocatalysis

Very often, the price of a given catalysed process depends largely on the price of

the corresponding catalyst. Generally, chiral organocatalysts are cheaper than chiral

metallic catalysts, and anchoring these organocatalysts to a support makes possible the

recycling and reuse of them.53 In general, supported organocatalysts are reused more

conveniently than the organometallic/bioorganic analogues. Supported

organocatalysts can be classified based either on the bond between the catalyst and the

support or on the nature of the support. In the first case, it is possible to distinguish

between covalent bond immobilization, non-covalent bond immobilization and

biphasic catalysis (Figure 14).53

53 Gruttadauria, M.; Giacalone, F.; Noto, R. Chem. Soc. Rev. 2008, 37, 1666-1688.


26

Figure 14. Classification of support organocatalyst attending to the type of interaction with the support.

4.1. Covalently Supported Chiral Organocatalysts

One of the main advantages of the use of covalent bonds to support chiral

organocatalysts is their higher mechanical and thermal stability when compare to non-

covalently supported catalysts. However, some problems have been detected in the

selectivity of the heterogeneous process due to the plausible activation of the reactants

by the corresponding supports, which may catalyse the racemic background reaction.

In order to avoid this problem, Pericàs’s group has shown that is possible to increase

the selectivity of the reaction enlarging the separation between the support and the

catalyst.54 Thus, two proline supported derivatives have been prepared through a click

reaction to form the corresponding covalent bond with a modified Merrifield resin

(Scheme 15).

54 Alza, E.; Cambeiro, X. C.; Jimeno, C.; Pericàs, M. A. Org. Lett. 2007, 9, 3717-3720.


27

Scheme 15. Synthesis of L-proline support derivatives.

After the synthesis of supported chiral organocatalyst 1 and 2, the Michael

addition between cyclohexanone and nitrostyrene was studied employing

trifluoroacetic acid (TFA) as co-catalyst and water as solvent. In both cases high

diastereomeric ratio was achieved. However, better conversion and selectivity was

obtained with catalyst 2 due to the longer distance between the catalyst and the matrix

(Scheme 16). Also, catalyst 2 was reused for three cycles without losing selectivity or

conversion.

Scheme 16. Michael addition of cyclohexanone to nitrostyrene catalysed by supported L-prolines 1 and 2.

Following a similar approach, the synthesis of the quinine supported derivative

3 was achieved by derivatization of Wang resin with terephthaloyl dichloride and

subsequent esterification of quinine (Scheme 17a). Catalyst 4 has been used in the

asymmetric chlorination of acid chlorides with 2,2,3,4,5,6-hexachloro-3,5-

cyclohexadien-1-one as chlorinating agent under continuous flow conditions obtaining


28

the corresponding chlorinated product with moderate yield and high enantioselectivity

(Scheme 17b).55

Scheme 17. a) Synthesis of Wang resin anchored quinine. b) Asymmetric α-chlorination in continuous flow.

4.2. Non-Covalently Supported Chiral Organocatalyst

The immobilization of chiral organocatalysts can be also performed through non-

covalent interactions such as hydrogen bonding or electrostatic with the support. The

simplicity of non-covalent methodologies to support chiral organocatalysts lies in the

absence of a post-functionalization process of the catalyst. On the other hand, the main

disadvantage of this technique is the challenging control of the multiple and different

potential interactions involving not only the catalyst and the support, but also the

solvents and the reagents. Furthermore, the leaching of the chiral organocatalysts to the

reaction medium is also a problem since it is not anchored by strong links to the support

55 Bernstein, D.; France, S.; Wolfer, J.; Lectka, T. Tetrahedron: Asymmetry 2005, 16, 3481-

3483.


29

The first attempts to use non-covalent supported chiral organocatalysts were

performed by the groups of Toma56 and Yang57, using ionic liquids as reaction medium.

Toma´s group, employed substequiometric L-proline loadings in the aldol reaction

between p-trifluoromethylbenzaldehyde and acetone using 1-n-butyl-3-

methylimidazolium hexafluorophosphate as reaction medium. The product was

extracted using ethyl ether, obtaining high yield and good selectivity in the first run.

Subsequent runs showed a slight decrease in the selectivity of the process (Scheme 18).

Scheme 18. Aldol reaction using 1-n-butyl-3-methylimidazolium hexafluorophosphate as reaction media.

On the other hand, Tan’s group has used graphene oxide as non-covalent support

for L-proline through hydrogen bond and acid-base interactions between the oxygen-

functional groups of the graphene derivative (such as acids, alcohols, and epoxides) and

the chiral organocatalysts (Scheme 19). The carbonaceous catalyst (Pro-GO) was

successfully used in the aldol reaction between acetone and different substituted

benzaldehydes to afford the corresponding aldol adducts in moderate to excellent yields

(up to 96%) and good selectivities (up to 79% ee).58 Furthermore, the catalyst was

easily recovered, without observing an appreciable decrease in the reactivity or

enantioselectivity until the 7th reaction cycle in the aldol reaction between p-

nitrobenzaldehyde and acetone (Scheme 20). Elementary analysis of the recovered

catalyst was used for determining the L-proline leaching in terms of nitrogen element

percentage, and there were no significant changes in the nitrogen element percentage

compared with the fresh catalyst indicating the stability of the system.

56 Kotrusz, P.; Kmentová, I.; Gotov, B.; Toma, Š.; Solčániová, E. Chem. Commun. 2002,

2510-2511. 57 Loh, T.-P.; Feng, L.-C.; Yang, H.-Y.; Yang, J.-Y. Tetrahedron Lett. 2002, 43, 8741-8743. 58 Tan, R.; Li, C.; Luo, J.; Kong, Y.; Zheng, W.; Yin, D. J. Catal. 2013, 298, 138-147.


30

Scheme 19. Pro-GO synthesis.

Scheme 20. Aldol reaction catalyse by graphene oxide supported proline.

4.3. Biphasic Catalysis

Biphasic catalysis consists of two non-miscible phases (usually two solvents) one

of them capturing the catalyst being the reactants delivered in the second phase. The

reaction takes place in the interphase of both solvents and, after completion, the

product can be removed from the mixture without removing the catalyst. The main

restriction of this type of catalysis is the identification of the corresponding solvent pair

to perform a perfect separation between the catalyst and products, avoiding cross-

contamination and thus providing an efficient catalyst recycling. In this field, the use of

chiral organocatalysts anchored to ionic liquids has been widely explored.53,59 Based on

the previous studies using non-covalent supported L-proline in ionic liquids base on

imidazolium salts, Chan and coworkers have developed the first IL-anchored L-proline

organocatalysts.60 These proline-anchored organocatalysts were synthetized in a two

steps reaction sequence as depicted in Scheme 21.

59 (a) Hernández, J. G.; Juaristi, E. Chem. Commun. 2012, 48, 5396-5409; (b) Durand, J.;

Teuma, E.; Gómez, M. CR. Chim. 2007, 10, 152-177. 60 Miao, W.; Chan, T. H. Adv. Synth. Catal. 2006, 348, 1711-1718.


31

Scheme 21. Synthesis of ionic liquid anchored proline derivatives 5 and 6.

The synthesised chiral ionic liquids (CIL) were employed in the aldol reaction

between aromatic aldehydes and acetone using either the nucleophile or DMSO as

solvent, obtaining the corresponding adducts with low to high yields (10-92%) and low

to high enantioselectivity (11-87% ee, Scheme 22). Interestingly, L-proline was tested

under homogeneous conditions affording similar or lower selectivities when compared

with the supported catalyst 6 (up to 28% ee difference when 2-naphthaldehyde was

employed as electrophile). Furthermore, recycling studies of ionic-liquid-supported

proline 6 base on imidazolium salts were carried out using the aldol reaction between

4-nitrobenzaldehyde and acetone as model, achieving moderate yields (64-68%) and

high enantioselectivities (82-85% ee), without observing a decrease in the catalytic

activity and selectivity after four cycles.

Scheme 22. Aldol reaction between acetone and 4-Cyanobenzaldehyde.


32

On the other hand, Zlotin’s group has synthetised different C2-symmetric ionic

liquids with a very poor solubility in water to facilitate their recovery.61 These catalysts

were employed in the aldol reaction between cyclohexanone and p-nitrobezaldehyde

obtaining moderate to full conversion with the catalyst 7a (47-99%) and full conversion

with the catalyst 7b after fifteen cycles (Scheme 23). Moreover, the diastereo- and

enantioselectivities remained very high after the recycling process for both catalysts:

up to 96% ee and 92:8 dr.

Scheme 23. Aldol reaction catalysed by Chiral Ionic Liquids 7a and 7b in water.

61 Kochetkov, S. V.; Kucherenko, A. S.; Kryshtal, G. V.; Zhdankina, G. M.; Zlotin, S. G. Eur. J.

Org. Chem. 2012, 7129-7134.

33

CHAPTER 1

Asymmetric Organocatalyzed

Michael Addition in Deep Eutectic

Solvents

Chapter 1 Background

35

1.1. Background

1.1.1. Asymmetric Organocatalysis in Deep Eutectic Solvents

The development of new synthetic methodologies devoted to improve chemical

processes using greener solvents, catalysts efficiencies and selectivities is needed.

However, the use of deep eutectic solvents in organocatalysed processes has been

scarcely studied.62

The first asymmetric organocatalytic reaction in DES was carried out by the

group of Domínguez de María.62a The combination of enzymatic catalysis and

organocatalysis in the aldol reaction between aromatic aldehydes and acetaldehyde,

catalysed by prolinol derivative 8 and the immobilized enzyme Candida Antarctica

(CAL-B) to promoted the transesterification of vinyl acetate with isopropanol was

studied (Scheme 24). The DES used as solvent in this process could be reused up to six

cycles without observing any loss of enzymatic or organocatalytic activity and obtaining

excellent enantioselectivity (99% ee).

Scheme 24. First asymmetric organocatalyzed aldol reaction in deep eutectic solvents.

62 (a) Müller, C. R.; Meiners, I.; Domínguez de María, P. RSC Adv. 2014, 4, 46097-46101;

(b) Guajardo, N.; Müller, C. R.; Schrebler, R.; Carlesi, C.; Domínguez de María, P. ChemCatChem 2016, 8, 1020-1027; (c) Müller, C. R.; Rosen, A.; Domínguez de María, P. Sust. Chem. Process. 2015, 3, 12-20; (d) Martínez, R.; Berbegal, L.; Guillena, G.; Ramón, D. J. Green Chem. 2016, 18, 1724-1730; (e) Brenna, D.; Massolo, E.; Puglisi, A.; Rossi, S.; Celentano, G.; Benaglia, M.; Capriati, V. Beilstein J. Org. Chem. 2016, 12, 2620-2626; (f) Flores-Ferrándiz, J.; Chinchilla, R. Tetrahedron: Asymmetry 2017, 28, 302-306; (g) Massolo, E.; Palmieri, S.; Benaglia, M.; Capriati, V.; Perna, F. M. Green Chem. 2016, 18, 792-797; (h) Palomba, T.; Ciancaleoni, G.; Del Giacco, T.; Germani, R.; Ianni, F.; Tiecco, M. J. Mol. Liq. 2018, 262, 285-294; (i) Fanjul-Mosteirín, N.; Concellón, C.; del Amo, V. Org. Lett. 2016, 18, 4266-4269.


36

Meanwhile, our research group focused the attention on the L-proline-catalysed

aldol reaction using DES and natural deep eutectic solvents (NADES).62d Thus, the

organocatalysed aldol reaction between acetone and benzaldehyde was chosen as

model process obtaining the best selectivity using the mixture choline chloride:glycerol

(1:2) (54% ee) and choline chloride:resorcinol (1:2) (59% ee). To complete this study,

NADES were also tested as reaction medium, observing an increase in the selectivity of

the process when the mixture D-Glucose/(D/L)-malic acid (1:1) was employed (70% ee).

Finally, under the optimized reaction conditions, cyclic ketones and aromatic aldehydes

with neutral and electron-withdrawing substituents were used as substrates, affording

the corresponding aldol adducts in high yields and moderate to high selectivities

(Scheme 25)

Scheme 25. Asymmetric aldol reaction in D-glucose/(D/L)-Malic acid.

In this case, the recyclability of the catalytic system was studied after using water

to separate the reaction product from the water-soluble DES+catalyst mixture, avoiding

completely the use of volatile organic solvents. After the addition of water, the organic

layer was separated and evaporated under vacuum obtaining the desired product, while

removal of the water, allowed the recovery of eutectic mixture and the catalyst. This


37

DES+catalyst mixture was used two more times without observing a decrease in the

selectivity of the reaction.

Later, Del Amo’s group developed a highly selective catalytic system formed by

choline chloride:ethylene glycol (ChCl:EG, 1:2) and L-leucine for the addition of ketones

to aromatic aldehydes using water as additive (Scheme 26).62i Under these conditions,

high yields (up to 80%), diastereo- (90%) and enantioselectivities (up to 99% ee) were

accomplished. Moreover, the catalytic system was recovered and reuse for five cycles

with no activity or selectivity erosion.

Scheme 26. Asymmetric aldol reaction catalysed by L-Isoleucine.

Regarding conjugate additions, the groups of Capriati and Chinchilla reported the

first organocatalyzed enantioselective reactions in DES.62f,g Thus, Capriati’s group

designed the addition of iso-butyraldehyde to nitrostyrene catalysed by 9-amino-9-

deoxy-epi-quinine (9) in three different DES, choline chloride:Urea (1:2), choline

chloride:fructose:water (1:1:1) and choline chloride:glycerol (1:2), obtaining the

highest selectivity (95% ee) and high concersion (89%) using the NADES choline

chloride:fructose:water (1:1:1) after 5 hours (Scheme 27). Furthermore, the

recyclability of the catalyst and DES was also tested during 3 runs, with the

enantioselectivity being observed constant for all runs but with an important loss of the

reaction conversion after the second cycle.

Scheme 27. Enantioselective Michael addition between isobutyraldehyde and nitrostyrene in NADES.


38

To demonstrate the utility of this procedure, the anticoagulant drug Warfarin

was synthesised using ChCl:urea (1:2) as solvent and TFA as additive (40 mol%),

obtaining 70% of yield and 87% of ee (Scheme 28).

Scheme 28. Enantioselective synthesis of Warfarin in DES.

Finally, Chinchilla’s group carried out the synthesis of chiral substituted

succinimides by the addition of aldehydes to maleimides in the DES mixture

Ph3MePBr:Gly (1:2) (Scheme 29).62f The process, catalysed by a non-natural chiral

cyclohexanediamine-derived organocatalyst (10) and 3,4-dimethoxybenzoic acid as co-

catalyst, afforded the corresponding conjugate addition adducts in short reaction times

and high yields (up to 97%) and enantioselectivities (up to 94% ee) (Scheme 29). The

catalytic system was reused five times with a slight decrease in the conversion after the

third cycle and in the selectivity after the fourth run.

Scheme 29. Synthesis of chiral succinimides by asymmetric Michael addition.


39

1.1.2. Benzimidazole Derivatives in Asymmetric Organocatalysis

Benzimidazoles are organic heterocycles present in a wide range of fields such

as, pharmaceutical industry,63 ionic liquids,64 carbenes,65 molecules with biological

activity66 and organocatalysts.67 The interesting properties of benzimidazole

derivatives, such as their easy synthesis, as well as their easy structural and electronic

modification, their basicity ([pKa (BzImH2+) = 5.4]) and the possibility of hydrogen bond

formation, makes these molecules ideal candidates to be used as chiral organocatalyst

as in the case of guanidine, urea and thiourea derivatives. Figure 15 shows some of the

most active and selective chiral benzimidazoles reported so far.68

63 (a) Horton, D. A.; Bourne, G. T.; Smythe, M. L. Chem. Rev. 2003, 103, 893-930; (b)

Sørensen, U. S.; Strøbæk, D.; Christophersen, P.; Hougaard, C.; Jensen, M. L.; Nielsen, E. Ø.; Peters, D.; Teuber, L. J. Med. Chem. 2008, 51, 7625-7634.

64 Holbrey, J. D.; Rogers, R. D.; Mantz, R. A.; Trulove, P. C.; Cocalia, V. A.; Visser, A. E.; Anderson, J. L.; Anthony, J. L.; Brennecke, J. F.; Maginn, E. J.; Welton, T.; Mantz, R. A. Physicochemical Properties, In Ionic Liquids in Synthesis; Wasserscheid, P., Welton, T., Eds.; Wiley-VCH: Weinheim, 2007.

65 Dove, A. P.; Pratt, R. C.; Lohmeijer, B. G.; Li, H.; Hagberg, E. C.; Waymouth, R. M.; Hedrick, J. L. N-Heterocyclic Carbenes as Organic Catalysts, In N‐Heterocyclic Carbenes in Synthesis; Nolan, S. P., Ed.; Wiley-VCH: Weinheim, 2006.

66 Preston, P. N. Chem. Rev. 1974, 74, 279-314. 67 Nájera, C.; Yus, M. Tetrahedron Lett. 2015, 56, 2623-2633. 68 (a) Zhang, Z.; Schreiner, P. R. Chem. Soc. Rev. 2009, 38, 1187-1198; (b) Connon, S. J.

Chem. Commun. 2008, 2499-2510; (c) Dong, S.; Feng, X.; Liu, X. Chem. Soc. Rev. 2018, 47, 8525-8540; (d) Nájera, C.; Yus, M. Chiral Guanidines in Michael Reactions, In Guanidines as Reagents and Catalysts I; Selig, P., Ed.; Springer International Publishing: Cham, 2017,95-128.


40

Figure 15. Chiral benzimidazole derivatives used as organocatalyst.69

The first report using chiral benzimidazoles as organocatalysts was described by

Vincent in 2004.69a Catalyst 11 was employed in the addition of ketones to aromatic

aldehydes with equimolar quantities of both reagents in THF as solvent. Later, the same

group performed mechanistic studies showing the bifunctional properties of the

catalyst (Scheme 30).70

69 (a) Lacoste, E.; Landais, Y.; Schenk, K.; Verlhac, J.-B.; Vincent, J.-M. Tetrahedron Lett.

2004, 45, 8035-8038; (b) Reddy, K. R.; Krishna, G. G.; Rajasekhar, C. V. Synth. Commun. 2007, 37, 4289-4299; (c) Zheng, J.-F.; Li, Y.-X.; Zhang, S.-Q.; Yang, S.-T.; Wang, X.-M.; Wang, Y.-Z.; Bai, J.; Liu, F.-A. Tetrahedron Lett. 2006, 47, 7793-7796; (d) Tang, G.; Gün, Ü.; Altenbach, H.-J. Tetrahedron 2012, 68, 10230-10235; (e) Zhang, L.; Lee, M.; Lee, S.; Lee, J.; Cheng, M.; Jeong, B.; Park, H.; Jew, S. Adv. Synth. Catal. 2009, 351, 3063-3066; (f) Almaşi, D.; Alonso, D. A.; Gómez-Bengoa, E.; Nájera, C. J. Org. Chem. 2009, 74, 6163-6168; (g) Gómez-Torres, E.; Alonso, D. A.; Gómez-Bengoa, E.; Nájera, C. Eur. J. Org. Chem. 2013, 1434-1440; (h) Benavent, L.; Puccetti, F.; Baeza, A.; Gómez-Martínez, M. Molecules 2017, 22, 1333-1344.

70 Lacoste, E.; Vaique, E.; Berlande, M.; Pianet, I.; Vincent, J.-M.; Landais, Y. Eur. J. Org. Chem. 2007, 167-177.


41

Scheme 30. Mechanistic studies of the iminium intermediate.

The bifunctional activation mode of chiral benzimidazoles (enamine and

hydrogen bond) was later employed by Tang’s group using catalyst 14 in the aldol

reaction between aromatic aldehydes and ketones, obtaining a significant improvement

of the enantio- and diastereoselectivity of the reaction (98% ee, 98:2 de, Scheme 31).69d

Scheme 31. Aldol reaction catalysed by chiral benzimidazole 14.

Regarding the Michael addition, Zhang’s group carried out the addition of

ketones to nitrostyrene obtaining the corresponding adducts, with high yields and

selectivities, when employing benzimidazole 15 (10 mol%) as bifunctional

organocatalyst (Scheme 32).69e

Scheme 32. Michael addition of cyclohexanone to trans-nitrostyrenes catalysed by 15.

The addition of 1,3-dicarbonyl compounds to nitroolefins has been studied using

organocatalyst 18 obtaining the corresponding products in high selectivity.69f

Interestingly, catalyst 18 derived from (1R,2R)-cyclohexane-1,2-diamine has resulted a


42

high selective system in the conjugate addition of 1,3-diketones, β-ketoesters and

malonates to aromatic and aliphatic nitroolefins in the presence of trifluoroacetic acid

as co-catalyst (Scheme 33). In addition, it is possible to recover the catalyst by

acid/basic extraction and reused it subsequently in at least five cycles without loss of

catalytic activity or selectivity.

Scheme 33. Conjugate addition of 1,3-dicarbonyl compounds to nitroolefins catalysed by 18.

Computational studies confirmed the activation of the electrophile by hydrogen

bond formation with the protonated secondary amine of the catalyst (Figure 16, A),

rather than the activation of the nucleophile by the tertiary amine (Figure 16, B).

Figure 16. Plausible activation mechanism of the 18-catalysed conjugate addition of 1,3-dicarbonyl compounds to nitrostyrenes.


43

Moreover, C2-symmetric organocatalyst 19 has been studied in the Michael

addition of 1,3-dicarbonyl compounds to maleimides, obtaining the corresponding

succinimides in moderate to high yields and high selectivity (Scheme 34).69g

Scheme 34. Michael addition of 1,3-dicarbonyl compounds to maleimides catalysed by 19.

DFT computational studies showed a complex transition state, where a triple

hydrogen-bond formation between the benzimidazole moiety of the organocatalyst and

the co-catalyst resulted in the formation of a fixed structure (Figure 17). Then, a double

hydrogen-bond interaction between the substrates and the previously activated

organocatalyst allows the approaching of the reactants in the space to obtain the

product with a well-defined stereochemistry.

Figure 17. Proposed transition state for the Michael addition of 1,3-dycarbonyl compounds to malonates.

Our research group has also developed the α-chlorination of 1,3-dicarbonyl

compounds catalysed by chiral benzimidazole derivatives 20 and 21.71 Two sources of

chlorine, N-chlorosuccinimide (NCS) or 2,3,4,4,5,6-hexachloro-2,5-cyclohexadien-1-

one, were used to synthesize the corresponding chlorinated adducts in excellent yields

and moderate to good enantioselectivities in toluene at -50 °C (Scheme 35). Based on

previous studies the proposed mechanism involves the bifunctional character of the

71 Sánchez, D. S.; Baeza, A.; Alonso, D. A. Symmetry 2016, 8, 3-13.


44

benzimidazole derivatives that would act as a Brønsted base (deprotonating the 1,3-

dicarbonyl compound) generating the corresponding enolate which could be

coordinated through a dual hydrogen bond as shown in intermediates I and III (Scheme

35). Next, the chlorinating agent would be activated by hydrogen bond either with the

ammonium moiety or with the second benzimidazole moiety avoiding a tight transition

state which would render the final product, regenerating the catalyst (Scheme 35).

Scheme 35. α-Chlorination of β-ketoesters and 1,3-diketones catalysed by 20 or 21.

Recently catalyst 18 was evaluated in the -amination of unprotected 3-

substituted oxindoles. This reaction was carried out using di-tert-butyl


45

azodicarboxylate (DBAB) as nitrogen source in toluene for 9 different oxindoles,

achieving high yields and selectivities (Scheme 36).72

Scheme 36. Enantioselective α-amination of unprotected oxindoles.

72 Benavent, L.; Baeza, A.; Freckleton, M. Molecules 2018, 23, 1374-1384.

Chapter 1 Objectives

47

1.2. Objectives

Based on the above exposed literature background, the following objectives were

stablished:

To study the catalytic activity and recyclability of chiral benzimidazole

derivatives in the asymmetric Michael addition of 1,3-dicarbonyl compounds

to nitroolefins in DES.

Chapter 1 Discussion of Results

49


1.3.1. Synthesis of Chiral Organocatalysts for the Michael Addition

The synthesis of chiral 2-amimobenzimidazole derivatives 17-19, 23 and 24 was

achieved (Figure 18).

Figure 18. Chiral benzimidazole derivatives used as organocatalysts.

Chiral organocatalysts 17 and 19 were directly synthesized by an aromatic

nucleophilic substitution of (1R,2R)-cyclohexane-1,2-diamine over 2-chloro-1H-

benzo[d]imidazole at 200 °C using triethylamine as solvent and base, obtaining both

catalyst in 65% and 40% yield, respectively (Scheme 37). Then, the reductive amination

(Eschweiler-Clarke reaction)73 of catalyst 17 using formaldehyde and formic acid led to

catalyst 18 in 46% yield (Scheme 37). The catalyst 19 was obtained by adding 2

equivalents of cyclohexanediamine 2-chloro-1H-benzo[d]imidazole at 200 °C. After a

period of one day the reaction was quenched and the crude mixture was purified by

flash column chromatography obtaining 40% isolated yield.

Scheme 37. Synthesis of catalysts 17, 18 and 19.

73 Eschweiler, W. Ber. Dtsch. Chem. Ges. 1905, 38, 880-882. Clarke, H. T.; Gillespie, H. B.;

Weisshaus, S. Z. J. Am. Chem. Soc. 1933, 55, 4571-4587.


50

Catalyst 23 was obtained 74% yield by an electrophilic aromatic nitration of catalyst

18, employing a mixture of sulfuric and nitric acids (Scheme 38). On the other hand, for

the synthesis of catalyst 24, mononitration of the catalyst 18 through an aromatic

electrophilic substitution was carried out using just 1.2 equivalents of nitric acid in

sulfuric acid, affording a mixture of 23 and intermediate 25 This mixture was reduced

using SnCl2 in concentrated HCl at 100 °C to obtain the catalyst 24 in 83% overall yield

(the presence of the double reduction of 23 was not detected because this compound

decomposes at 100 °C) (Scheme 38).

Scheme 38. Synthesis of catalysts 23 and 24.

1.3.2. Michael Addition of 1,3-Dicarbonyl Compounds to Nitroolefines in DES

Based on previous studies developed by our research group, it is well known that

chiral benzimidazole derivative 18 efficiently catalyses the Michael addition of 1,3-

dicarbonyl compounds to nitroolefins in toluene through a bifunctional Brønsted-

base/hydrogen bonding activation.69f We thought about the possibility of replacing

toluene by deep eutectic mixtures in the model conjugate addition of diethyl malonate

to β-nitrostyrene, catalysed by 18 (Table 2). Initially, the reaction was carried out under

catalyst-free conditions in two different DES [ChCl:Gly (1:2) and ChCl:Urea (1:2)]

obtaining in both cases null conversion (Table 2, entries 1 and 2). Then, the reaction

was performed using different catalyst 18 loadings (1-20 mol%) at different

concentrations in these two mixtures (Table 2, entries 3-8). Excellent conversions

towards 26a were achieved in all the studied reactions (>95%) with

enantioselectivities between 50 and 65% ee, with the highest being obtained with 10

mol% of catalyst loading in ChCl:Gly (1:2) (entry 5). With these conditions in hand, the

model conjugate addition was carried out in different DES, (Table 2, entries 9-15)


51

glycerol (entry 16) and toluene (entry 17). As depicted, complete conversions were

achieved for the conjugate addition, after four days with the eutectic mixtures

ChCl:Malic acid, ChCl:Glu, Glu:Malic acid, as well as in organic solvents glycerol and

toluene. The best enantioselectivity for compound 26a (75% ee) was obtained with

ChCl:Malic acid (1:2), ChCl:Glu (1:1), and Glu:Malic acid (1:1)(Table 2, entries 9, 11, and

12). Then, the most selective deep eutectic mixtures were chosen to perform the

addition at lower temperature (0 °C) leading an improvement in the enantioselectivity

(80-83% ee) in all the tested eutectic solvents (Table 2, entries 18-22) However, only

the mixtures ChCl:Gly (1:2) and ChCl:Urea (1:2) afforded complete reaction conversion

(entries 18 and 19). Finally, lower catalyst loadings (1 mol%) were tested at 0°C in these

two solvents, but the reaction did not take place (Table 2, entries 23 and 24).

Table 2. 18-Catalysed conjugate addition of diethyl malonate to β-nitrostyrene. Reaction conditions optimization.

Entry 18

(mol%)/[M] DES (molar ratio) T (°C)

Conv.

(%)a ee (%)b

1 (0)/[0] ChCl:Gly (1:2) 25 0 0

2 (0)/[0] ChCl:Urea (1:2) 25 0 0

3 (20)/[0.150] ChCl:Gly (1:2) 25 >95 55

4 (20)/[0.150] ChCl:Urea (1:2) 25 >95 50

5 (10)/[0.075] ChCl:Gly (1:2) 25 >95 65

6 (10)/[0.075] ChCl:Urea (1:2) 25 >95 60

7 (1)/[0.0075] ChCl:Gly (1:2) 25 >95 60

8 (1)/[0.0075] ChCl:Urea (1:2) 25 >95 60

9 (10)/[0.075] ChCl:Malic acid (1:2) 25 >95 75


52

10 (10)/[0.075] ChCl:Malonic acid (1:1) 25 >95 0

11 (10)/[0.075] ChCl:Glucose (1:1) 25 >95 75

12 (10)/[0.075] Glucose:Malic acid (1:1) 25 >95 75

13 (10)/[0.075] ChCl:Resorcinol (1:1) 25 >95 20

14 (10)/[0.075] AcCh:Urea (1:2) 25 >95 53

15 (10)/[0.075] ChCl:H2O (1:2) 25 >95 63

16 (10)/[0.075] Gly 25 >95 73

17 (10)/[0.075] Toluene 25 >95 75

18 (10)/[0.075] ChCl:Gly (1:2) 0 >95 80

19 (10)/[0.075] ChCl:Urea (1:2) 0 >95 80

20 (10)/[0.075] ChCl:Malic acid (1:2) 0 50 83

21 (10)/[0.075] ChCl:Glucose (1:1) 0 88 80

22 (10)/[0.075] Glucose:Malic acid (1:1) 0 20 82

23 (1)/[0.0075] ChCl:Gly (1:2) 0 - -

24 (1)/[0.0075] ChCl:Urea (1:2) 0 - -

aDetermined by 1H-NMR analysis of the crude reaction mixture. bDetermined by chiral HPLC analysis of the crude reaction mixture mixture (Chiralpack AD, hexane/iPrOH: 90/10, 1 mL/min).

After the solvent optimization, it was necessary to explore the influence of the

organocatalyst structure in the process. Thus, chiral benzimidazole derivatives 17, 18

and 23-25 (10 mol%, 0.075 M) were tested in the model conjugate addition of diethyl

malonate to nitrostyrene using ChCl:Gly (1:2) and ChCl:Urea (1:2) as solvents at 0 °C.

First catalyst 18 was used in the Michael addition affording full conversion and 80% ee

in both solvents (Table 3, entries 1 and 2). On the other hand, catalyst 17 with a free

primary amine provided lower selectivity for the model reaction (40 and 60% ee, Table

3, entries 3 and 4), compared to the catalysts bearing a tertiary amine in the structure

(18, 23 and 24), highlighting the importance of the basicity of the catalysts. The best

results (90 and 91% ee) were achieved with benzimidazole derivative 22 with two

strong electron-withdrawing groups in the aromatic catalyst moiety (Table 3, entries 5-

6), demonstrating the importance of the steric and electronic properties of the catalyst.


53

This effect could be due to the increase of the hydrogen-bonding ability of the catalyst

that strongly interacts with the reagents. Thus, catalyst 23 with an electron-donating

amino group in the benzimidazole ring was tested in the model reaction, obtaining

moderate selectivity (67% ee, Table 3, entries 7 and 8). Then, the electronic effects of

the different groups in the benzimidazole ring were studied considering the Hammett

constant and its correlation with the enantioselectivities in the model asymmetric

conjugated addition. Using the Hammett equation (ln([R]/[S]) = ρ σ + c),74 Figure 19

shows a linear correlation between the enantiomeric ratio [ln([R]/[S])] with the

Hammett constant of the para position of the groups (been ρ = 0.9483 and R2 = 0.9606)

(Figure 19).

Figure 19. Hammett plots for the asymmetric conjugate addition catalysed by chiral benzimidazoles.

Also, steric factors were considered employing the C2-symmetric chiral

benzimidazole 19 in the conjugate addition, showing less selectivity than the non-

sterically hindered catalysts (Table 3, entries 9 and 10).

After the catalyst study, some co-catalysts were tested in the model addition.

First, TFA was employed as co-catalyst based on its synergistic effect observed in our

previous works.69f However, no reaction was observed when using TFA (10 mol%)

(Table 3, entry 11). Water and benzoic acid were also tested as co-catalysts, but in both

cases no improvement on the selectivity was observed (Table 3, entries 12 and 13).

74 Hansch, C.; Leo, A.; Taft, R. W. Chem. Rev. 1991, 91, 165-195.

y = 0,9483x + 2,3567R² = 0,9606

-0,80 -0,60 -0,40 -0,20 0,00 0,20 0,40 0,60 0,80 1,00

0,00

1,00

2,00

3,00

4,00

ln (

R/S

)

p-NO2

H p-NH2

s


54

Table 3. Conjugate addition between diethyl malonate and -nitroestyrene. Catalyst study.

Entry Organocat DES (molar ratio) Conv. (%)a ee (%)b

1 18 ChCl:Gly (1:2) >95 80

2 18 ChCl:Urea (1:2) >95 80

3 17 ChCl:Gly (1:2) >95 40

4 17 ChCl:Urea (1:2) >95 60

5 23 ChCl:Gly (1:2) >95 91

6 23 ChCl:Urea (1:2) >95 90

7 24 ChCl:Gly (1:2) >95 67

8 24 ChCl:Urea (1:2) >95 67

9 19 ChCl:Gly (1:2) >95 0

10 19 ChCl:Urea (1:2) >95 30

11 23c ChCl:Gly (1:2) - -

12 23d ChCl:Gly (1:2) >95 91

13 23e ChCl:Gly (1:2) >95 91

aDetermined by 1H-NMR analysis of the crude reaction mixture. bDetermined by chiral HPLC analysis of the crude reaction mixture (Chiralpack AD, hexane/iPrOH: 90/10, 1 mL/min). cThe reaction was performed in the presence of TFA (10 mol%) as co-catalyst. dThe reaction was performed in the presence of PhCO2H (10 mol%) as co-catalyst. eThe reaction was performed in the presence of H2O (10 mol%) as co-catalyst.


55

Under the optimized reaction conditions (Table 3, entry 5), the scope of the 23-

catalysed Michael addition was then studied (Table 4). Initially, it was shown that the

bulkiness of the ester group of the malonate had no effect on the selectivity of the

addition neither in the reaction conversion as demonstrated when using isopropyl

malonate (Table 4, entries 1-3). At this point, different electrophiles were tested

employing diethyl malonate as nucleophile, obtaining in all the cases high yields and

enantioselectivities (Table 4, entries 4-7). As shown, there was not effect in the

selectivity of the reaction, regardless of electron properties of the Michael acceptor

(Table 4, entries 4-6), obtaining in all the studied reactions good enantioselectivities

(80-90% ee). Finally, the addition of diethyl malonate to (E)-2-(2-nitrovinyl)thiophene

was also carried out, yielding Michael adduct 26g in excellent yield and

enantioselectivity (Table 4, entry 7).

Table 4. Conjugate addition of dialkyl malonates to nitroalkenes catalysed by 23.a

Entry R Ar No. Yield (%)b ee (%)c

1 Et Ph 26a 83 91

2 Me Ph 26b 88 91

3 iPr Ph 26c 63 90

4 Et 4-ClC6H4 26d 84 80

5 Et 2,4-(Cl)2C6H3 26e 86 90

6 Et 4-MeC6H4 26f 87 85

7 Et 2-Thienyl 26g 85 90

aReaction conditions: nitroolefin (0.15 mmol), dialkyl malonate (0.30 mmol), catalyst 23 (0.015 mmol), ChCl:Gly (1:2 molar ratio, 0.2 mL), 0 °C, 4 days. bIsolated yield after purification by flash column chromatography. cDetermined by chiral HPLC analysis of the crude reaction mixture.

For a further evaluation of the efficiency of orgacatalyst 23 in the synthesis of

Michael adducts, different 1,3-dicarbonyl compounds and nitroalkenes were evaluated

(Table 5). Initially, acetylacetone was employed as nucleophile in the addition to β-


56

nitrostyrene and (E)-4-phenyl-1-nitro-1-butene, to obtain compounds 26h and 26i in

moderate to good yields and moderate enantioselectivities (Table 5, entries 1 and 2). In

addition, non-symmetric 1,3-diketones, such as 1-phenylbutane-1-3-diones, were

tested in the reaction with β-nitrostyrene, affording product 26j as a 1/1 mixture of

diastereoisomers and moderate selectivity for both of them (65% ee, Table 5, entry 3).

Using acyclic β-ketoesters such as ethyl 3-oxobutenoate in the addition to β-

nitrostyrene, good enantioselectivities for both diastereoisomers were obtained (79%

and 81% ee, Table 5, entry 4). Finally, α-substituted β-ketoesters were also tested in the

conjugate addition to β-nitrostyrene, such as ethyl 2-oxocyclopentane-1-carboxylate

and methyl 1-oxo-2,3-dihydro-1H-indene-2-carboxylate to afford products 26l and

26m with moderate yields and low to moderate enantioselectivities (Table 5, entries 5

and 6).

Table 5. Conjugate addition of 1,3-dicarbonyl compounds to nitroalkenes catalysed by 23.a

Entry Product structure No. Yield (%)b dr (%)b ee (%)d

1

26h 91 - 77

2

26i 46 - 67

3

26j 96 57/43 65/65

4

26k 85 55/45 79/81

5

26l 66 58/42 <5/69


57

6

26m 52e 65/35 55/73

a Reaction conditions: nitroolefin (0.15 mmol), dialkyl malonate (0.30 mmol), 23 (0.015 mmol), ChCl:Gly (1:2 molar ratio, 0.2 mL), 0 °C, 4 days. b Isolated yield after flash column chromatography. c Determined by 1H-NMR analysis of the crude reaction mixture. d Determined by chiral HPLC analysis of the crude reaction mixture. Diastereomeric mixtures were not separated when isolating the reaction product. e 1 equiv. of nucleophile was used.

Next, the recyclability of the catalytic system was studied in the model conjugate

addition of diethyl malonate to β-nitrostyrene under the optimal reaction conditions

(Table 3, entry 5). With this objective, the extraction ability of different solvents, such

as of 2-methyltetrahydrofuran (2-MeTHF), tert-butyl methyl ether (TBME), diethyl

ether and hexane, were tested to extract the unreactive reagents and the reaction

products from the DES/chiral organocatalyst mixture. As depicted in Figure 20, good

conversions and enantioselectivities were observed for the first two runs with all the

tested extracting solvents (Figure 20). However, the conversion decreased in the third

and the forth reaction cycles when ethereal solvents were employed as extraction

medium (Figure 20a-c). The 1H-NMR analysis of the ethereal fractions collected after

the second and third runs showed the presence of traces of organocatalyst 23. This

result would explain the reduction of catalytic activity over the cycles when using

ethereal solvents for the extractions. Fortunately, when hexane was used as solvent for

the recycling of the catalytic system, high conversion and selectivity were achieved in

the four reaction cycles (Figure 20d).


58

Figure 20. Recycling studies.

In addition, a gram-scale experiment (6.7 mmol of the Michael acceptor, 5 mol%

of 23) was carried out to demonstrate the utility of this methodology for the green

synthesis of Michael products. This synthesis was accomplished in high yield (96%) and

enantioselectivity (90%, Scheme 39).

Scheme 39. Gram-scale experiment.

To evaluate the advantages of the methodology in economic terms, comparison

between catalysts 18 and 23 was carried out considering the recently reported “Cost of

Academic Methodologies” (Equation 1).75 In this sense, the higher the CAM, the more

expensive the methodology. However, the price of the final synthesis depends on the

recovery capacity of the catalytic system (as the number of cycles increases, the price of

the methodology decreases each time the catalyst is reused).

75 Berger, O.; Winters, K. R.; Sabourin, A.; Dzyuba, S. V.; Montchamp, J. L. Org. Chem. Front.

2019, 6, 2095-2108.

a) b)

c) d)


59

CAM = ∑(𝑏B + 𝑐C) (

€mol

)

yield

Equation 1. Cost of Academic Methodologies.

The similarities in the reaction conversion and selectivity as well as in the

synthesis of the catalysts allowed a quick study about the economic viability of the two

processes. As it is shown in Table 6, the CAM in the first cycle using catalyst 18 is lower

than using catalyst 23 but, since benzimidazole-derivative 23 can be recovered, further

uses of the catalyst decreases the cost of the methodology with each run (Table 6).

Table 6. CAM €/mol (conv. %)

Cycle 1 2 3 4

18 73 (99) - - -

23 100 (99) 50 (99) 33 (99) 22.5 (90)

Finally, in order to study the plausible interactions between the catalyst and the

DES that favors the recyclability of the system, NMR studies were conducted (Figure

21). Initially the 1H-NMR spectra of the catalyst (Figure 21a) and the DES (Figure 21b)

were carried out in DMSO-d6 to assign the relevant protons involved in the


60

interactions.76 Then a mixture of 40 mg of organocatalyst 23 (0.11 mmol) and 0.1 mL of

ChCl:Gly (1:2) was dissolved in DMSO-d6 and analyzed by 1H-NMR (Figure 21c). The

resulting spectrum showed no relevant changes in the chemical shifts of the protons of

the catalyst. However, the broadening of the absorptions in the spectrum revealed

exchanges of protons and hydrogen bond formation between the catalyst and the

solvent.

To clarify the interactions between the solvent and the organocatalyst, 2D-NMR

experiments and selective NOE experiments were performed.76 These experiments

showed strong NOE effect between the two methyl groups of catalyst 23 (NMe2) and the

three methyl groups of the choline chloride (NMe3), as well as the interaction between

NMe3 and proton H3 of the organocatalyst (Figure 22). These interactions can be

explained by the formation of a hydrogen-ionic bond between the catalyst and the DES

(Figure 22). Moreover, the methyl groups of the ammonium moiety (NMe3) showed

NOE effect with protons H5, H6 and H8 of glycerol (Figure 22). Therefore, this hydrogen-

ionic bond between the reaction media and 23 favours the immobilization of the chiral

organocatalyst in the eutectic solvent.

76 (a) Hadj-Kali, M. K.; Al-khidir, K. E.; Wazeer, I.; El-blidi, L.; Mulyono, S.; AlNashef, I. M.

Colloid. Surface. A. 2015, 487, 221-231; (b) Dai, Y.; van Spronsen, J.; Witkamp, G.-J.; Verpoorte, R.; Choi, Y. H. Anal. Chim. Acta 2013, 766, 61-68.


61

Figure 21. 1H-NMR spectra (300 MHz, DMSO-d6) of: a) 23; b) DES: ChCl:Gly (1:2); c) 23 + DES.


62

Figure 22. Proposed interactions of chiral organocatalyst 23 with the eutectic mixture. Arrows are used for the observed NOE correlations.

Chapter 1 Experimental Data

63

1.4. Experimental Data

1.4.1. General

Unless otherwise noted, all commercial reagents and solvents were used without

further purification. Reactions under argon atmosphere were carried out in oven-dried

glassware sealed with a rubber septum using anhydrous solvents. Melting points were

determined with a hot plate apparatus and are uncorrected. 1H-NMR (300 or 400 MHz)

and 13C-NMR (75 or 101 MHz) spectra were obtained on a Bruker AC-300 or AC-400,

using CDCl3 as solvent and TMS (0.003%) as reference, unless otherwise stated.

Chemical shifts () are reported in ppm values relative to TMS and coupling constants

(J) in Hz. Low-resolution mass spectra (MS) were recorded in the electron impact mode

(EI, 70 eV, He as carrier phase) using an Agilent 5973 Network Mass Selective Detector

spectrometer, being the samples introduced through a GC chromatograph Agilent

6890N equipped with a HP-5MS column [(5%-phenyl)-methylpolysiloxane; length 30

m; ID 0.25 mm; film 0.25 mm]. IR spectra were obtained using a JASCO FT/IR 4100

spectrophotometer equipped with an ATR component; wavenumbers are given in cm-1.

Analytical TLC was performed on Merck aluminium sheets with silica gel 60 F254.

Analytical TLC was visualized with UV light at 254 nm Silica gel 60 (0.04-0.06 mm) was

employed for flash column chromatography whereas P/UV254 silica gel with CaSO4

(28-32%) supported on glass plates was employed for preparative TLC. Chiral HPLC

analyses were performed on an Agilent 1100 Series (Quat Pump G1311A, DAD G1315B

detector and automatic injector) equipped with chiral columns using mixtures of

hexane/isopropanol as mobile phase, at 25 °C.

1.4.2. Synthesis and Spectroscopic Data of Chiral Organocatalysts

(1R,2R)-N1-(1H-benzo[d]imidazol-2-yl)cyclohexane-1,2-diamine (17).69f

Scheme 40. Synthesis of chiral organocatalyst 17.

A mixture of 2-chloro-1H-benzo[d]imidazole (233 mg, 1.53 mmol, 1 equiv.), (1R,2R)-

cyclohexane-1,2-diamine (698 mg, 6.12 mmol, 4 equiv.), and TEA (213 μL, 1.53 mmol, 1

equiv.) was heated at 190-200 °C during 24 h in a sealed pressure tube. Then, the


64

reaction mixture was allowed to reach ~50 °C, and water (20 mL) was added. The

obtained mixture was quickly extracted with CH2Cl2 (3 × 20 mL) before the temperature

of the reaction reached rt in order to avoid solubility problems. The collected organic

phases were dried over MgSO4. After filtration, the organic solvents were evaporated

under reduced pressure to give a crude mixture, which was purified by precipitation in

CH2Cl2 to obtain 17 (229 mg, 65%, 1 mmol) as a pale yellow solid: mp 235-240 °C

(CH2Cl2); IR 2929, 2855, 1700, 1644, 1606, 1580, 1468, 1270, 1116, 1030; δH (300 MHz,

CD3OD) 1.19-1.49 (m, 4H, 2×CH2), 1.74-1.77 (m, 2H, CH2), 1.98-2.11 (m, 2H, CH2), 2.50-

2.58 (m, 1H, CH, CHNH2), 3.34-3.40 (m, 1H, CHNH), 6.93-6.97 (m, 2H, ArH), 7.15-7.18

(m, 2H, ArH); m/z 230 [M+, 10%], 160 (24), 134 (100), 133 (59), 97 (28).

(1R,2R)-N1-(1H-benzo[d]imidazol-2-yl)-N2,N2-dimethylcyclohexane-1,2-diamine (18).69f


A mixture of 18 (168 mg, 0.7 mmol, 1 equiv.), 80% HCO2H (3.5 mL), and 36% aqueous

solution of HCHO (127 μL, 1.6 mmol, 2.2 equiv.) was stirred at 120 °C for 24 h. Then, the

solvent was removed under reduced pressure. Saturated NaHCO3 solution (15 mL) and

10% NaOH solution (until pH = 8) were added in this order, and the resulting mixture

was extracted with CH2Cl2 (3×15 mL). The organic phases were dried over MgSO4. After

filtration, the organic solvent was evaporated under reduced pressure to give a crude

mixture, which was purified by precipitation in CH3CN to afford pure 18 (87 mg, 46%,

0.3 mmol) as a white solid; mp 248-250 °C (CH3CN); IR 2923, 2856, 2818, 2775, 1700,

1633, 1576, 1499, 1461, 1375, 12653, 1064; δH (300 MHz, CDCl3) 1.09-1.42 (m, 4H,

2×CH2), 1.65-1.70 (m, 1H, CH), 1.82-1.87 (m, 2H, CH2), 2.22 (s, 6H, CH3), 2.33 (td, J = 10.9,

3.2 Hz, 1H, CHCNMe2), 2.65-2.69 (m, 1H, CH), 3.44 (td, J = 10.4, 4.0 Hz, 1H, CHNH), 5.46

(br. s, 1H, NH), 6.91-6.96 (m, 2H, ArH), 7.14-7.20 (m, 2H, ArH); m/z 258 [M+, 1.5%], 133

(30), 125 (100), 84 (20).

(1R,2R)-N1,N2-bis(1H-benzo[d]imidazol-2-yl)cyclohexane-1,2-diamine (19).69g


65


2-chloro-1H-benzo[d]imidazole (2.0 g, 13.2 mmol) was added to (1R,2R)-cyclohexane-

1,2-diamine (3 g, 26.4 mmol, 2 equiv.) and the resulting mixture was stirred at 195-200

°C for 20 h. After this time, the reaction mixture was allowed to reach 50 °C and water

(40 mL) was added. Then, the reaction was basified until pH = 8 with a saturated

aqueous solution of NaHCO3 and the obtained mixture was extracted with CH2Cl2 (5×20

mL). The combined organic phases were dried over MgSO4. After filtration, the organic

solvent was evaporated under reduced pressure to give the corresponding crude

product which was purified by flash column chromatography (EtOAc/MeOH) to give

pure 19 as a white solid (1.70 g, 40%, 5.3 mmol); mp 193-196 °C (Et2O); IR 2944, 2916,

2847, 1630, 1603, 1580, 1461,1410, 1259, 1112, 1047; δH (300 MHz, CD3OD,) 1.35-1.47

(m, 4H, 2×CH2), 1.76 (br. s, 2H, CH2), 2.18-2.23 (m, 2H, CH2), 3.71-3.74 (m, 2H, 2×CHNH),

6.9-6.95 (m, 4H, ArH), 7.11-7.15 (m, 4H, ArH); m/z 346 [M+, 33%], 214 (64), 213 (100),

212 (36), 184 (16), 173 (19), 172 (15), 170 (10), 160 (14), 159 (21), 158 (11), 146 (11),

145 (16), 134 (32), 133 (37), 132 (16).

(1R,2R)-N1-(5,6-dinitro-1H-benzo[d]imidazol-2-yl)-N2,N2-dimethylcyclohexane-1,2-

diamine (23).49


Catalyst 18 (50 mg, 0.2 mmol, 1 equiv.) was dissolved in concentrated H2SO4 (0.2 mL,

98%) and stirred vigorously for 5 minutes; after this time concentrated HNO3 (0.4 mL,

65%) was carefully added to the mixture at -20 °C. Then, the reaction was stirred at

room temperature for 16 hours. After this period, the mixture was treated with cold

water and basified until pH = 8 with 25% aqueous solution of NH3. Finally, the aqueous

phase was extracted with EtOAc (3×20 mL). The collected organic phases were dried

over anhydrous MgSO4. After filtration, the organic solvent was removed under reduced


66

pressure to give catalyst 23 without further purification as a red solid (52 mg, 74%, ,

0.15 mmol); mp 100-105 °C (CH2Cl2, decompose); δH (300 MHz, CDCl3) 1.19-1.49 (m,

4H, 2×CH2), 1.63-1.98 (m, 4H, 2×CH2), 2.37 (s, 6H, 2×Me), 2.51 (m, 1H, CHNMe2), 3.66

(br s, 1H, CHNH),7.49 (s, 2H, ArH); δC (75 MHz, CDCl3) 21.7, 24.4, 24.6, 33.2, 39.8, 53.8,

67.8, 108.3, 136.8, 142.0, 161.8; m/z 348 [M+, <1%] 128 (10), 126 (11), 125 (100), 124

(25), 84 (64), 71 (24), 58 (20), 44 (10); HRMS calcd. for C13H13N5O4 [M+-NHMe2]

303.0968, found 303.0964.

N2-((1R,2R)-2-(dimethylamino)cyclohexyl)-1H-benzo[d]imidazole-2,6-diamine (24).49


Catalyst 18 (50 mg, 0.2 mmol) was dissolved in concentrated H2SO4 98% (0.2 mL) and

stirred vigorously for 5 minutes; after this time, concentrated HNO3 65% (20 µL, 0.24

mmol, 1.2 equiv.) was added to the mixture carefully at -20 °C. The reaction was then

stirred at 0 °C for 5 minutes. After this period, the mixture was treated with cold water

(15 mL) and basified until pH = 8 with 25% aqueous solution of NH3 (25%). The aqueous

phase was extracted with EtOAc (3×20 mL) and the collected organic phases were dried

over anhydrous MgSO4. After filtration, the organic solvent was evaporated under

reduced pressure to give a yellow oil. The yellow solid was introduced in a round

bottom flask with SnCl2 (95 mg, 0,5 mmol, 3,5 equiv.) and then a concentrated HCl

solution (400 µL, 12 M) was added. The resulting mixture was stirred for 24 hours. After

this time, the reaction was quenched with cold water (5 mL) and the solution was

basified until pH = 8 with NaOH (6M). The aqueous phase was extracted with EtOAc

(3×20 mL) and the collected organic phases were dried over anhydrous MgSO4. After

filtration, the solvent was evaporated under reduced pressure to give catalyst 24 as a

white solid (45.4 mg, 83%, 0.16 mmol); δH (300 MHz, CDCl3) 1.27-0.93 (m, 4H, 2×CH2),

1.62-1.38 (m, 1H, CH), 1.84-1.62 (m, 2H, CH2), 2.17 (s, 6H, 2×Me), 2.41-2.20 (m, 1H, CH),

2.69-2.48 (m, 1H, CHNMe2), 3.48 (td, J = 10.5, 3.9 Hz, 1H, CHCNH), 5.60 (br. s, 1H, NH),

6.37 (dd, J = 8.2, 2.1 Hz, 1H, ArH), 6.54 (d, J = 1.9 Hz, 1H, ArH), 7.00 (d, J = 8.2 Hz, 1H,

ArH); δC (75 MHz, CDCl3) 21.3, 24.3, 25.1, 29.6, 33.2, 39.7, 53.6, 66.9, 99.6, 108.8, 112.5,

131.7, 138.8, 140.2, 155.3; m/z 274 (M++1, 4%), 273 (M+, 19), 228 (32), 227 (10), 215


67

(11), 201 (13), 189 (11), 188 (18), 173 (11), 149 (28), 148 (62), 147(15), 126 (21), 125

(100),124 (34), 97 (12), 84 (23), 71 (20), 70 (13), 58 (13), 57 (11), 44 (30), 43 (48), 42

(11), 41 (11); HRMS calcd. for C15H23N5 (M+): 273.1953; found: 273.1936.

1.4.3. Experimental Procedure

Scheme 45. Model reaction for the synthesis of the compound 26.

Catalyst 23 (5.22 mg, 0.015 mmol, 10 mol%) and β-nitrostyrene (22.4 mg, 0.15 mmol)

were dissolved in a mixture of ChCl:Gly (1:2 molar ratio, 0.2 mL) and kept under stirring

for 10 minutes at room temperature Then, the mixture was cooled-down to 0 °C and

diethyl malonate (50 µL, 0.30 mmol) was added. The reaction was vigorously stirred

during 4 days at 0 °C. After this period, water (3 mL) was added to the mixture and the

reaction product was extracted with EtOAc (3×5 mL). The collected organic phases

were dried over anhydrous MgSO4 and, after filtration, the solvent was evaporated

under reduced pressure to give crude 26. Purification by flash column chromatography

on silica gel (hexane/EtOAc: 4/1) afforded pure 26 (38.2 mg, 83%, 0.12 mmol). δH (300

MHz, CDCl3) 1.04, 1.26 (2t, J = 7.1, 6H), 3.82 (d, J = 9.4 Hz, 1H), 4.00 (q, J = 7.1 Hz, 2H),

4.18-4.28 (m, 3H), 4.86 (dd, J = 13.1, 9.0 Hz, 1H), 4.93 (dd, J = 13.1, 5.2 Hz, 1H), 7.22-7.37

(m, 5H); m/z 263,[M+ - NO2, 25%], 189 (100), 171 (44), 161 (43), 115 (54), 104 (26),

103 (28), 102 (26), 91 (29), 76 (37). The enantiomeric excess of 26 was determined by

chiral HPLC analysis (Chiralpack AD, hexane/iPrOH: 90/10, 1 mL/min).

1.4.4. Recycling Experiment

A mixture of catalyst 23 (5.22 mg, 0.015 mmol) and β-nitrostyrene (22.4 mg, 0.15

mmol) in ChCl:Gly (1:2 molar ratio, 0.2 mL) was stirred for 10 minutes at room

temperature. Then, the mixture was cooled-down to 0 °C and diethyl malonate (50 µL,

0.30 mmol) was added. The reaction was vigorously stirred for 4 days at 0 °C. After this

period, the corresponding organic solvent was added (3 mL) and the mixture was

stirred for 10 minutes at room temperature. The stirring was stopped to allow phase


68

separation and the upper organic layer was removed. This extractive procedure was

repeated two more times and the combined organic extracts were washed with water

(3×5 mL), dried (MgSO4), filtered, and evaporated under reduced pressure to afford the

reaction product. The residual volatile organic solvent present in the DES/catalyst

phase was removed under vacuum evaporation. Then, the next reaction cycle was

performed with the obtained DES/23 mixture, adding fresh β-nitroestyrene and diethyl

malonate. This reaction mixture was subjected again to the above-described procedure

and further reaction cycles were repeated using the recycled deep eutectic solvent

phase.

1.4.5. Physical and Spectroscopic Data for Compounds 26

Dimethyl (R)-2-(2-nitro-1-phenylethyl)malonate (26b).77

Yield 88%, white solid; mp 58-61 °C; δH (400 MHz, CDCl3) 3.57, 3.78 (2s, 6H, 2×CH3),

3.88 [d, J = 9.1 Hz, 1H, CH(CO2Me)2], 4.26 (td, J = 9.0, 5.2 Hz, 1H, CHCH2), 4.89 (dd, J =

13.2, 8.9 Hz, 1H, CHHNO2), 4.95 (dd, J = 13.2, 5.2 Hz, 1H, CHHNO2), 7.20-7.37 (m, 5H,

ArH); m/z 281 [M+, <1%], 176 (12), 175 (100), 171 (26), 116 (10), 115 (38), 104 (19),

103 (11), 91 (10).

(R)-Diisopropyl 2-(2-nitro-1-phenylethyl)malonate (26c).77

Yield 63%, white solid; mp 53-55 °C; δH (300 MHz, CDCl3) 1.01, 1.07 (2d, J = 6.3 Hz, 6H,

2×CH3), 1.25 (d, J = 6.2 Hz, 6H, 2×CH3), 3.76 [d, J = 9.6 Hz, 1H, CH(CO2iPr)2], 4.21 (td, J =

9.4, 4.8 Hz, 1H, CHCH2), 4.79-4.87 [m, 2H, CH(CH3)2, CHHNO2], 4.92 (dd, J = 12.9, 4.8 Hz,

1H, CHHNO2), 5.09 [sept, J = 6.3 Hz, 1H, CH(CH3)2], 7.23-7.34 (m, 5H, ArH); m/z 338 [M+

77 Evans, D. A.; Mito, S.; Seidel, D. J. Am. Chem. Soc. 2007, 129, 11583-11592.


69

+1, <1%], 291 (10), 218 (29), 207 (100), 205 (39), 203(43), 171 (26), 163 (63), 161

(98), 145 (30), 131 (29), 117 (24), 105 (28), 104 (25), 103 (32), 77 (27).

(R)-Diethyl 2-[1-(4-chlorophenyl)-2-nitroethyl]malonate (26d).78

Yield 84%, colourless oil; δH (300 MHz, CDCl3) 1.08, 1.26 (2t, J = 7.1, 6H, 2×CH3), 3.78 [d,

J = 9.3 Hz, 1H, CH(CO2Et)2], 4.03 (q, J = 7.1 Hz, 2H, CH2CH3), 4.17-4.29 (m, 3H, CHCH2,

CH2CH3), 4.83 (dd, J = 13.2, 9.2 Hz, 1H, CHHNO2), 4.91 (dd, J = 13.2, 4.9 Hz, 1H, CHHNO2),

7.18-7.21, 7.27-7.32 (2m, 4H, 4×ArH); m/z 343 [M+, <1%], 297 (16), 281 (13), 252 (11),

235 (10), 225 (28), 197 (14), 195 (36), 179 (18), 167 (12), 165 (21), 151 (11), 150 (11),

149 (10), 144 (10), 140 (13), 139 (15), 138 (34), 136 (11), 116 (14), 115 (32), 103 (14),

102 (12), 77 (12).

(R)-Diethyl 2-[1-(2,4-dichlorophenyl]-2-nitroethyl)malonate (26e).69f

Yield 86%, colourless oil; δH (300 MHz, CDCl3) 1.15, 1.25 (2t, J = 7.1, 6H, 2×CH3), 4.04 [d,

J = 8.7 Hz, 1H, CH(CO2Et)2], 4.10 (q, J = 7.1 Hz, 2H, CH2CH3), 4.15-4.27 (m, 2H, CH2CH3),

4.69 (td, J = 8.6, 4.3 Hz, 1H, CHCH2), 4.92 (dd, J = 13.6, 4.3 Hz, 1H, CHHNO2), 5.09 (dd, J =

13.6, 8.6 Hz, 1H, CHHNO2), 7.21-7.23 (m, 2H, 2×ArH), 7.43-7.44 (m, 1H, ArH); m/z 377

[M+, <1%], 344 (38), 343 (20), 342 (94), 333 (12), 331 (18), 286 (11), 285 (16), 281

(14), 273 (13), 272 (10), 271 (18), 261 (14), 259 (62), 258 (14), 257 (100), 253 (28),

244 (12), 242 (17), 241 (44), 239 (60), 234 (16), 231 (42), 229 (59), 217 (12), 215 (13),

213 (20), 209 (20), 201 (24), 199 (16), 186 (11), 185 (20), 184 (12), 183 (29), 174 (32),

78 Okino, T.; Hoashi, Y.; Furukawa, T.; Xu, X.; Takemoto, Y. J. Am. Chem. Soc. 2005, 127,

119-125.


70

173 (26), 172 (54) 171 (17), 161 (12), 159 (17), 151 (14), 150 (18), 149 (27), 137 (19),

136 (15), 135 (13), 115 (43), 102 (13), 101 (12).

(R)-Diethyl 2-(2-nitro-1-p-tolylethyl)malonate (26f).77

Yield 87%, colourless oil; δH (300 MHz, CDCl3) 1.07 (t, J = 7.1, 3H, CH3CH2), 1.26 (t, J =

7.1, 3H, CH3CH2), 2.30 (s, 3H, CH3Ar), 3.80 [d, J = 9.4 Hz, 1H, CH(CO2Et)2], 4.02 (q, J = 7.1

Hz, 2H, CH2CH3), 4.15-4.28 (m, 3H, CHCH2, CH2CH3), 4.83 (dd, J = 13.0, 9.0 Hz, 1H,

CHHNO2), 4.90 (dd, J = 13.0, 5.1 Hz, 1H, CHHNO2), 7.11 (s, 4H, ArH); m/z 323 [M+, <1%],

277 (11), 232 (12), 215 (11), 204 (17), 203 (100), 185 (36), 175 (39), 159 (18), 145

(15), 131 (11), 130 (12), 129 (21), 118 (28), 117 (28), 116 (13), 115 (26), 91 (16).

(S)-Diethyl 2-[2-nitro-1-(thiophen-2-yl)ethyl]malonate (26g).78

Yield 85%, yellow oil; δH (300 MHz, CDCl3) 1.16, 1.27 (2t, J = 7.1, 6H, 2×CH3), 3.87 [d, J =

8.1 Hz, 1H, CH(CO2Et)2], 4.12 (q, J = 7.1 Hz, 2H, CH2CH3), 4.17-4.28 (m, 2H, CH2CH3), 4.56

(td, J = 8.0, 5.6 Hz, 1H, CHCH2), 4.89 (dd, J = 11.5, 6.1Hz, 1H, CHHNO2), 4.95 (dd, J = 11.5,

3.7 Hz, 1H, CHHNO2), 6.93 (dd, J = 5.0, 3.6 Hz, 1H, ArH), 6.96 (dd, J = 3.5, 0.9 Hz, 1H, ArH),

7.23 (dd, J = 5.0, 1.3 Hz, 1H, ArH); m/z 315 [M+, <1%], 269 (11), 268 (20), 196 (12), 195

(100), 177 (23), 167 (41), 137 (10), 110 (30), 109 (11).

(R)-3-(2-Nitro-1-phenylethyl)pentane-2,4-dione (26h).77

Yield 88%, white solid; mp 124-126 °C; δH (300 MHz, CDCl3) 1.93, 2.28 (2s, 6H, 2×CH3),

4.20-4.28 (m, 1H, CHCH2), 4.38 [d, J = 10.8 Hz, 1H, CH(COMe)2], 4.17-4.28 (m, 2H,

CH2CH3), 4.61 (dd, J = 12.5, 5.0 Hz, 1H, CHHNO2), 4.66 (dd, J = 12.5, 7.5 Hz, 1H, CHHNO2),


71

7.17-7.22 (m, 2H, ArH), 7.29-7.37 (m, 3H, ArH); m/z 203 [M+ -NO2 , 3%], 162 (11), 161

(80), 160 (27), 159 (100), 158 (14), 147 (12), 145 (28), 143 (21), 131 (18), 129 (11),

128 (17), 117 (22), 115 (32), 204 (18), 103 (22), 78 (10) , 77 (18).

(S)-3-(1-Nitro-4-phenylbutan-2-yl)pentane-2,4-dione (26i).69f

Yield 46%,white solid; mp 40-42 °C; δH (400 MHz, CDCl3) 1.56-1.65, 1.71-1.84 (2m, 2H,

PhCH2CH2), 2.15, 2.22 (2s, 6H, 2×CH3), 2.56-2.63, 2.78-2.87 (2m, 3H, CHCH2, PhCH2),

3.98 [d, J = 8.4 Hz, 1H, CH(COMe)2], 4.54 (dd, J =S15 12.6, 5.1 Hz, 1H, CHHNO2), 4.59 (dd,

J = 12.6, 4.6 Hz, 1H, CHHNO2), 7.14 (d, J = 6.9 Hz, 1H, ArH), 7.20-7.23 (m, 1H, ArH), 7.26-

7.32 (m, 2H, ArH); m/z 263 [M+, >1%], 216 (16), 169 (17), 143 (10), 131 (23), 130 (31),

129 (32), 125 (10), 105 (15), 104 (22), 91 (100), 84 (13), 83 (11), 65 (15).

2-[(R)-2-Nitro-1-phenylethyl]-1-phenylbutane-1,3-dione (26j).79

Yield 96%, white solid, mp 132-134 °C; δH (400 MHz, CDCl3) (1.02:1 mixture of

diastereomers) 1.93 (s, 3H, CH3), 4.49-4.57 (m, 1H, CHPh), 4.63-4.76 (m, 2H, CH2NO2),

5.17 (d, J = 9.9 Hz, 1H, CHCO), 7.25-7.35 (m, 5H, ArH), 7.46-7.50 (m, 2H, ArH), 7.51- 7.54

(m, 1H, ArH), 7.81 (m, 2H, ArH); m/z 265 [M+ -NO2, 2%], 223 (24), 221 (15), 207 (30),

117 (10), 105 (100), 103 (10), 77 (34).

(3R)-Ethyl 2-acetyl-4-nitro-3-phenylbutanoate (24k).69f

Yield 85%, colourless oil; δH (300 MHz, CDCl3) 0.99 (t, J = 7.1 Hz, 2.4H, CH3CH2), 1.28 (t,

J = 7.1 Hz, 3H, CH3CH2), 2.05 (s, 2.6H, CH3CO), 2.30 (s, 3H, CH3CO), 3.96 (q, J = 7.1 Hz, 2H,

CH2CH3), 4.02 (d, J = 9.7 Hz, 0.85H, CHCO), 4.11 (d, J = 9.9 Hz, 1H, CHCO) 4.17-4.26 (m,

3.5H, CH2CH3, CHCH2, CHCH2), 4.71-4.78 (m, 2H, CH2NO2), 4.81 (dd, J = 12.9, 8.6 Hz,

79 Ballini, R.; Maggi, R.; Palmieri, A.; Sartori, G. Synthesis 2007, 3017-3020.


72

0.85H, CHHNO2), 4.85 (dd, J = 12.9, 5.1 Hz, 0.85H, CHHNO2), 7.19-7.34 (m, 9.25H, ArH);

m/z 233 [M+-NO2, 2%], 192 (11), 191 (90), 190 (29), 189 (100), 161 (24), (159 (70),

146 (11), 145 (95), 144 (27), 131 (37), 118 (10), 117 (31), 116 (16), 115 (51), 105 (15),

104 (30), 103 (29), 91 (34), 78 (11), 77 (22), 51 (10).

Ethyl 1-[(S)-2-nitro-1-phenylethyl]-2-oxocyclopentanecarboxylate (24l).80

Yield 66%, colourless oil; δH (400 MHz, CDCl3) 1.27 (t, J = 7.2 Hz, 3.5H, CH3), 1.75-2.07

(m, 4.5H, CH2CH2CH2C=O), 2.26-2.47 (m, 2.4H, CH2C=O), 4.08 (dd, J = 10.8, 4.0 Hz, 1H,

CHPh), 4.15-4.28 (m, 2.5H, CHPh, CH2CH3), 4.83 (dd, J = 13.5, 3.4 Hz, 0.16H, CHHNO2),

5.01 (dd, J = 13.6, 10.8 Hz, 1H, CHHNO2), 5.18 (dd, J = 13.6, 4.0 Hz, 1H, CHHNO2), 5.29

(dd, J = 13.5, 11.1 Hz, 0.15H, CHHNO2), 7.18-7.33 (m, 5.8H, ArH); 259 [M+-NO2, 1%], 230

(25), 229 (42), 213 (22), 211 (30), 207 (43), 202 (25), 201 (18), 1853 , 184 (59), 183

(58), 182 (18), 171 (22), 170 (21), 169 (20), 167 (21), 159 (12), 158 (53), 157 (53), 156

(17), 155 (20), 154 (13), 143 (75), 142 (31), 141 (15), 131 (14), 130 (28), 129 (100),

128 (70), 127 (33), 115 (79), 105 (23), 104 (79), 103 (47), 102 (12), 91 (66), 78 (31),

77 (40), 55 (36).

Ethyl 1-[(S)-2-nitro-1-phenylethyl]-2-oxocyclopentanecarboxylate (24m).77

Yield 52%, yellow oil; δH (400 MHz, CDCl3) 3.18 (d, J = 17.7 Hz, 2H×CH2), 3.22 (d, J = 17.7

Hz, 1H×CH2C), 3.49 (d, J = 17.4 Hz, 2H×CH2C), 3.64 (d, J = 17.4, 1H×CH2C), 3.70 (s, 6H,

CH3), 3.74 (s, 3H, CH3), 4.22 (dd, J = 11.0, 3.4 Hz, 1H, CHPh), 4.48 (dd, J = 11.3, 3.4 Hz, 2H,

CHPh), 5.07 (dd, J = 13.4, 3.5 Hz, 2H, CHHNO2), 5.17-5.23 (m, 3H, 1×CHHNO2,

2×CHHNO2), 5.43 (dd, J = 13.6, 3.5 Hz, 1H, CHHNO2), 7.11-7.15 (m, 9H, ArH), 7.18-7.26

(m, 6H, ArH), 7.32-7.39 (m, 5H, ArH), 7.47-7,49 (m, 1H, ArH) 7.49-7.52 (m, 2H, ArH),

7.53 7.60 (m, 1H, ArH), 7.67 (d, J = 7.7 Hz, 1H, ArH), 7.76 (d, J = 7.7 Hz, 2H, ArH); m/z

80 Luo, J.; Xu, L.-W.; Hay, R. A. S.; Lu, Y. Org. Lett. 2009, 11, 437-440.


73

293 [M+-NO2, >1%], 261 (16), 233 (38), 232 (23), 231 (20), 215 (28), 207 (11), 105 (17),

203 (16), 202 (15), 191 (14), 190 (28), 189 (100), 161 (16), 158 (11), 157 (72), 131

(10), 130 (20), 104 (32), 103 (18), 102 (14), 101 (11), 91 (23), 89 (11), 77 (19).

Chapter 1 Conclusions

75

1.5. Conclusions

The Michael addition between 1,3-dicarbonyl compounds and nitroalkenes has

been performed in deep eutectic solvents, obtaining high yields and selectivities

employing the organocatalyst 23 (10 mol%) in the mixture choline chloride:glycerol

(1:2). The procedure is clean, simple, cheap, scalable and safe. In addition, the catalytic

system can be recovered and reuse at least four times without lost of conversion or

selectivity. Finally, NMR studies have shown a non-covalent interaction (ionic-hydrogen

bond) between the catalyst and the eutectic solvent.

77

CHAPTER 2

Asymmetric Organocatalyzed

Electrophilic α-Aminations in

Deep Eutectic Solvent


79

2.1. Background

2.1.1. Asymmetric Electrophilic α-Amination of Carbonyl Compounds

The asymmetric electrophilic α-amination of carbonyl compounds has been

widely studied32,81 due to the potential use of this methodology towards the synthesis

of natural products and pharmaceutical active compounds (Figure 23).82

Figure 23. Examples of the most prescribed pharmaceutical products.

In this field, the α-amination of prochiral carbonyl compounds with

azodicarboxylates was first explored by the groups of Jørgensen83 and List.84 Thus,

Jørgensen’s group used L-proline as organocatalyst in the amination of aldehydes with

electrophilic azodicarboxylates (Scheme 46). The mechanism of this reaction involves a

very stable six-member transition state formed by the nucleophilic enamine and a

81 (a) Janey, J. M. Angew. Chem. Int. Ed. 2005, 44, 4292-4300; (b) Smith, A. M. R.; Hii, K.

K. Chem. Rev. 2011, 111, 1637-1656. 82 (a) Kricheldorf, H. R. Angew. Chem. Int. Ed. 2006, 45, 5752-5784. Gröger, H. Chem. Rev.

2003, 103, 2795-2828; (b) Das, P.; Delost, M. D.; Qureshi, M. H.; Smith, D. T.; Njardarson, J. T. J. Med. Chem. 2018, 62, 4265-4311.

83 (a) Bøgevig, A.; Juhl, K.; Kumaragurubaran, N.; Zhuang, W.; Jørgensen, K. A. Angew. Chem. Int. Ed. 2002, 41, 1790-1793; (b) Kumaragurubaran, N.; Juhl, K.; Zhuang, W.; Bøgevig, A.; Jørgensen, K. A. J. Am. Chem. Soc. 2002, 124, 6254-6255; (c) Marigo, M.; Juhl, K.; Jørgensen, K. A. Angew. Chem. Int. Ed. 2003, 42, 1367-1369.

84 List, B. J. Am. Chem. Soc. 2002, 124, 5656-5657.


80

hydrogen bond between the proline-enamine intermediate and the electrophile

(Scheme 46). After reduction of the carbonyl moiety and cyclization, under basic

conditions, the corresponding N-amino oxazolidinones were synthesized in high yields

and enantioselectivities (Scheme 46).

Scheme 46. Organocatalytic synthesis of N-amino oxazolidinones via asymmetric α-amination.

Simultaneously, List’s group used the same catalyst (L-proline) in the addition of

aldehydes to benzyl azodicarboxylate (DBAD) in acetonitrile, obtaining higher

selectivities (>95%) in only 3 hours (Scheme 47).

Scheme 47. Enantioselective addition of aldehydes to benzyl azodicarboxylate.

Years later, Jørgensen’s group performed the α-amination of α-substituted

cyanoacetates (Scheme 48a) and β-dicarbonyl compounds (Scheme 48b) employing di-

tert-butyl azodicarboxylate (DBAB) as amination agent and using β-isocupreidine as

chiral organocatalyst in toluene.85 This asymmetric process was carried out taking

advantage of the hydrogen bond formation between the catalyst and the carbonyl

compounds, transferring the chirality to the products to obtain high selectivities.

85 Saaby, S.; Bella, M.; Jørgensen, K. A. J. Am. Chem. Soc. 2004, 126, 8120-8121.


81

Scheme 48. a) Synthesis of chiral α-aminated cyanoacetates catalysed by β-isocupreidine. b) Synthesis of chiral funcionalised1,3-dycarbonyl compounds catalysed by β-isocupreidine.

After this work, different chiral organocatalysts were synthesized (Figure 24) in

order to perform the new α-functionalizations of 1,3-dicarbonyl compounds.86 Our

research group has recently developed different chiral benzimidazole organocatalysts

(Figure 24, 18, 20 and 21) that have shown high activity and selectivity in the α-

amination of 1,3-dicarbonyl compounds using volatile organic solvents. For instance,

the benzimidazole derivative 18 has been successfully employed under low loading

conditions (1 mol%) in the amination of cyclic 1,3-dicarbonyl compounds with

azodicarboxylates in diethyl ether to afford the corresponding functionalized products

in moderate to high yields (66-99%) and enantioselectivities (20-95%) (Scheme 49).87

86 (a) Vallribera, A.; Maria Sebastian, R.; Shafir, A. Curr. Org. Chem. 2011, 15, 1539-1577;

(b) Vilaivan, T.; Bhanthumnavin, W. Molecules 2010, 15, 917-958; (c) Greck, C.; Drouillat, B.; Thomassigny, C. Eur. J. Org. Chem. 2004, 1377-1385.

87 Trillo, P.; Gómez-Martínez, M.; Alonso, D. A.; Baeza, A. Synlett 2015, 26, 95-100.


82

Figure 24. Molecules employed as chiral organocatalyst in the α-amination of 1,3-dicarbonyl compounds mediated via hydrogen bond interactions.

Scheme 49. Asymmetric amination of cyclic 1,3-dicarbonlyl compounds catalysed by 18.

Baeza and co-workers have synthesised the chiral 2-aminobenzimidazole

derivatives 20 and 21, that show to be able to perform the α-amination of carbonyl

compounds in toluene at room temperature, obtaining the corresponding

functionalised adducts in moderate to high yields (61-99%) and moderate to high

enantioselectivities (15-91%) (Scheme 50).69h


83

Scheme 50. α-Amination of 1,3-dicarbonyl compounds catalysed by 20 and 21.

Regarding the reaction mechanism, it has been proposed that 20 and 21 could

act as bifunctional catalyst. First the enolate formed by the basic part of the catalyst

could be coordinated with the organocatalyst through hydrogen bonding, as depicted in

intermediate I. A possible π–π stacking interaction would explain the good results

observed in the benzocondensed-keto esters and could not be ruled out. Afterwards, the

protonated guanidine group can activate the azodicarboxylate and hence facilitate the

enantioselective attack of the enolate (intermediate B) (Figure 25).

Figure 25. Catalytic cycle for the amination of 1,3-dicarbonyl compounds catalysed by 20 or 21.

2.1.2. Ultrasounds in Asymmetric Organocatalysis

The use of ultrasounds in chemical reactions provides specific activation and has

taken relevance in the last years in order to develop greener processes and to perform

non-common reactions.88 The driving force of the positive effort of sonochemistry is

88 (a) Mason, T. J. Chem. Soc. Rev. 1997, 26, 443-451; (b) Bruckmann, A.; Krebs, A.; Bolm,

C. Green Chem. 2008, 10, 1131-1141; (c) Branco, L. C. F. P., A.M.; Marques, M.M.; Gago,


84

cavitation, which implicates the formation and destruction of bubbles, causing

mechanical effects in the solvent and the increase in the temperature of some points

(“hot-spots”). This “hot spots” can act as micro-reactors decreasing reaction times and

energies. However, the energy contribution can activate the non-catalyse reaction by

reducing the selectivity of the process.

Maruoka’s group has developed a chiral phase-transfer alkylation of glycinate

benzophenone using ultrasounds irradiation.89 In terms of selectivity and yield, the

results obtained under natural stirring90 and ultrasounds were similar, but the reaction

time decreased from 8 to 1 hour under ultrasound irradiation (Scheme 51).

Scheme 51. Enantioselective ultrasound-assisted asymmetric PTC alkylation of glycinate esters.

After this work, Choudary and co-workers tested this methodology in the

Mannich reaction between substituted ketones and imines in a two-component and

three-component reaction catalysed by L-proline.91 After one hour, the Mannich

products were obtained in high yields (90-98%), high enantioselectivities (81-99%)

and excellent diastereoselectivities (Scheme 52).

S.; Branco, P.S. Recent advances in sustainable organocatalysis., In Recent Advances in Organocatalysis; Karame, I., Srour, H., Ed.; InTech: Rijeka, Croatia, 2016, 141-182.

89 Ooi, T.; Tayama, E.; Doda, K.; Takeuchi, M.; Maruoka, K. Synlett 2000, 1500-1502. 90 Ooi, T.; Kameda, M.; Maruoka, K. J. Am. Chem. Soc. 2003, 125, 5139-5151. 91 Kantam, M. L.; Rajasekhar, C. V.; Gopikrishna, G.; Rajender Reddy, K.; Choudary, B. M.

Tetrahedron Lett. 2006, 47, 5965-5967.


85

Scheme 52. Ultrasound mediated asymmetric Mannich reaction catalysed by L-proline.

Furthermore, in the context of sustainable chemistry Mlynarski’s group have

developed a green “on water” synthesis of warfarin catalysed by a chiral primary amine

(31) achieving moderate yield (61%) and very high enantioselectivity (>99% ee) in a

preparative scale (Scheme 53).92

Scheme 53. Enantioselective synthesis of warfarin on water employing ultrasounds.

92 Rogozińska, M.; Adamkiewicz, A.; Mlynarski, J. Green Chem. 2011, 13, 1155-1157.


87

2.2. Objetives

Based on the above exposed bibliographical background, the following objectives

were stablished:

The study of the asymmetric α-amination of 1,3-dicarbonyl compounds

catalysed by chiral 2-aminobenzimidazoles in deep eutectic solvents and the

recovery and reuse of the catalytic system.


89


The synthesis of chiral 2-amimobenzimidazole derivatives ent-17-19, ent-23

and ent-24 was initially attempted employing the conditions already reported in

Chapter 1 (Scheme 37 and Scheme 38), just by changing the chiral source to (1S,2S)-

cyclohexane-1,2-diamine, obtaining the corresponding enantiomers.

Figure 26. Chiral benzimidazole derivatives used as organocatalysts.

Moreover, a new organocatalyst (32) was synthesised by an aromatic

nucleophilic substitution of (1S,2S)-cyclohexane-1,2-diamine over 2-chloro-1-methyl-

1H-benzo[d]imidazole at 200 °C using triethylamine as solvent and base, obtaining the

product in 43% yield (Scheme 54).

Scheme 54. Synthesis of catalysts 32.

To begin with the study, the conditions reported in the Chapter 1 were selected

in order to perform the addition of ethyl 2-oxocyclopentane-1-carboxylate to di-tert-

butyl azodicarboxylate employing ent-18 as organocatalyst (ent-18, 10 mol%) in

different DES (Table 7). First, using catalyst ent-18 in urea-base DES [ChCl:Urea (1:2)

and AcCh:Urea (1:2)] moderate to good conversion (55-94%) an good selectivity was

observed at 0 °C and 25 °C after 5 hours (Table 7, entries 1-4). Then, polyalcohols as

ethylene glycol and glycerol were tested in the model reaction of addition of ethyl 2-

oxocyclopentane-1-carboxylate to di-tert-butyl azodicarboxylate (Table 7, entries 5-8)

Under these conditions the product 33a was obtained in good to excellent conversion

in both solvents at 0 °C and 25 °C, achieving between 70% ee to 80% ee (Table 7, entries


90

5-8). Using DES base on carboxylic acids such as malic and tartaric acid (Table 7, entries

9-11) the conversion of the model reaction decreased, probably due to the high viscosity

of the mixture. In the mixture ChCl:Malic the formation of the product was not detect at

room temperature (Table 7, entries 9) so the reaction was not further tested at lower

temperature. When ChCl:Tartaric acid was used as solvent at room temperature

moderate conversion (64%) and good selectivity (76% ee) were observed (Table 7,

entries). At 0 °C the conversion decreased to 58% maintaining the selectivity ( 77% ee).

Finally, the mixtures in which the best results were obtained [ChCl:Urea (1:2) and

ChCl:Gly(1:2)]. Table 7, entries 2 and 6 were used under ultrasound irradiation. Taking

into consideration the similarities in the physical-chemical properties between DES and

ionic liquids, ultrasounds were considered in order to decrease the reaction times.93 The

model amination reaction was performed under ultrasound irradiation (360 W) at 25

°C in ChCl:Urea (1:2) and ChCl:Gly (1:2), obtaining similar conversions (92% and 80%)

and selectivities (76% ee and 80% ee) than using standard conditions but in only 1 hour

(Table 7, entries 12 and 13).

Table 7. Asymmetric α-amination of ethyl 2-oxocyclopentane-1-carboxylate with DBAB. DES study.

Entry DES T (°C) t (h) Conv. (%)a ee (%)b

1 ChCl:Urea (1:2) 25 5 61 77

2 ChCl:Urea (1:2) 0 5 94 78

3 AcChCl:Urea (1:2) 25 5 64 72

4 AcChCl:Urea (1:2) 0 5 55 75

5 ChCl:Gly (1:2) 25 5 94 73

6 ChCl:Gly (1:2) 0 5 94 80

93 Chatel, G.; MacFarlane, D. R. Chem. Soc. Rev. 2014, 43, 8132-8149.


91

7 ChCl:EG (1:2) 25 5 78 72

8 ChCl:EG (1:2) 0 5 84 70

9 ChCl:Malic acid (1:1) 25 5 <5 Nd

10 ChCl:Tartaric acid (1:1) 25 5 64 76

11 ChCl:Tartaric acid (1:1) 0 5 58 77

12 ChCl:Urea (1:2) 25c 1 92 76

13 ChCl:Gly (1:2) 25c 1 80 80

a Reaction conversion towards 33a determined by 1H-NMR. b Enantiomeric excess determined by chiral HPLC analysis (Chiralpack IA, hexane/EtOH: 96/04, 0.7 mL/min). c Reaction performed under ultrasounds irradiation (360 W).

After the optimization of the reaction medium, the influence of the structural and

electronic properties of the catalyst in the selectivity of the process was studied. Then,

chiral benzimidazole-derived organocatalysts ent-18, ent-19, ent-17, ent and 32 were

tested in the model α-amination reaction under the optimized reaction conditions

(Table 8). First, ent-18 was tested in the α-amination of ethyl 2-oxocyclopentane-1-

carboxylate with DBAB using ChCl:Urea (1:2) and ChCl:Gly (1:2) under ultrasound

irradiation (Table 8, entries 1 and 2). In both solvents the catalyst showed good activity

obtaining product 33a in high conversion (92% and 80%) and good selectivity (76% ee

and 80% ee) after 1 hour (Table 8, entries 1 and 2). Chiral benzimidazole ent-23,

showed the best results, obtaining the adduct 33a in 84% ee in ChCl:Urea and 82% ee

in ChCl:Gly (Table 8, entries 3 and 4). As it has been demonstrated in previous works49

the presence of two nitro groups on the benzimidazole ring increases the solubility of

the catalyst in the eutectic mixture and its hydrogen-bonding ability favouring the

interaction with the reactants, thus, leading to an improvement of the selectivity of the

heterofunctionalization. On the other hand, employing the less basic catalyst ent-17

high yields (70-95%) were achieved in both solvents, although the selectivities in the

synthesis of the product 33a were lower than using catalyst ent-23 under the best

reaction conditions (Table 8, entries 5 and 6). Finally, the use of chiral C2-symmetric

organocatalysts ent-19 and 32, led to a strong decrease in the enantioselectivity of the

process affording compound 33a with an enantiomeric excess ranging from 33 to 44%

(Table 8, entries 7-10).


92

Table 8. Asymmetric α-amination of ethyl 2-oxocyclopentane-1-carboxylate with DBAB. Catalyst study.

Entry Catalyst DES Conv.(%)a ee (%)b

1 ent-18 ChCl:Urea (1:2) 92 76

2 ent-18 ChCl:Gly (1:2) 80 80

3 ent-23 ChCl:Urea (1:2) 85 84

4 ent-23 ChCl:Gly (1:2) 90 82

5 ent-17 ChCl:Urea (1:2) 95 74

6 ent-17 ChCl:Gly (1:2) 70 78

7 ent-19 ChCl:Urea (1:2) 90 40

8 ent-19 ChCl:Gly (1:2) 95 44

9 32 ChCl:Urea (1:2) 92

10 32 ChCl:Gly (1:2) 91 33

a Reaction conversion towards 33a determined by 1H-NMR analysis on the crude reaction mixture. b

Enantiomeric excess determined by chiral HPLC analysis (Chiralpack IA, hexane/EtOH: 96/04, 0.7 mL/min).

The recyclability of the catalytic system ent-23/DES [ChChl:Gly (1:2)] was

tested in the model reaction (Figure 27). To achieve this goal, hexane and cyclopentyl

methyl ether were employed as extraction media in order to separate the unreactive

reagents and the products from the DES, with the catalyst remaining in the eutectic

mixture. As it is shown in Figure 27, the chiral organocatalyst and the DES were

recovered and reused with hexane in five consecutive reaction runs, maintaining high

enantioselectivity, but with a slight decrease of the yield along the runs. In the case of


93

using cyclopentyl methyl ether, it was not observed a decrease in the selectivity after

the cycles. However, a significant decrease in the conversion was detected in the second

cycle, probably due, in this particular case, to an inefficient reaction stirring. After this

cycle, the conversion increased again but without achieving full conversion (Figure 27).

Figure 27. Recycling studies.

To compare the economic viability of the process, the model α-amination

reaction catalysed by ent-23 was compared with the same reaction using diethyl ether

as solvent89,69h using the Cost of Academic Methodologies (Equation 1). In these three

catalytic methodologies, different issues must be considered. First, the reusability of

catalysts 18 and 20 have not been studied in the considered heterofunctionalization

reaction. Second, catalyst 18 only needed 1 mol% loading to catalysed the process. As it

is shown in the Table 9, the high efficiency of the catalyst 18 resulted in a very economic

synthesis. A less expensive process was accomplished by Baeza and co-workers

employing the inexpensive catalyst 20 obtaining a 0.74 €/mol cost for the preparation

of the desired product. Finally, it is worthy to mention that although the use of the

catalytic system based on ent-23 resulted in a more expensive synthetic pathway, non-

volatile organic solvents were employed achieving better results in terms of

environmental footprint.


94

Table 9. CAM €/mol (conv. %).

Cycle 1 2 3 4 5

18 7.5 (99) - - - -

20 0.4 (95) - - - -

ent-23 124 (80) 66 (75) 43 (75) 33 (74) 39(50)

To demonstrate the efficiency and utility of the catalytic system ent-23/DES, a

gram experiment (4.3 mmol of ethyl 2-oxocyclopentane-1-carboxylate) was carried out,

obtaining the desired product 33a in 95% yield and 85% ee (Scheme 55).

Scheme 55. Gram-scale α-amination of ethyl 2-oxocyclopentane-1-carboxylate catalysed by ent-23.

Finally, different electrophiles and nucleophiles were tested in the α-amination

of 1,3-dicarbonyl compounds catalysed by ent-23 in ChCl:Gly (1:2) under ultrasound

irradiation (Table 10). Regarding the electrophile, an important steric effect was

observed in the -amination of ethyl 2-oxocyclopentane-1-carboxylate (Table 10,

entries 1-4), obtaining compound 33a with the best enantioselectivity when di-tert-

butyl azodicarboxylate was used as electrophile (Table 10, entry 1). This electrophile

was used for further studies.


95

Table 10. Asymmetric α-amination catalysed by ent-23. Reaction scope.

Entry Nucleophile Azodicarboxylate Product Yield

(%)a

ee

(%)b

1

BocN=NBoc 33a 78 85

2 iPrO2CN=NCO2iPr 33b 52 60

3 EtO2CN=NCO2Et 33c 76 65

4 BnO2CN=NCO2Bn 33d 0 Nd

5

BocN=NBoc 33e 66 36

6

BocN=NBoc 33f 65 35

7

BocN=NBoc 33g 65 13

8

BocN=NBoc 33h 68 25

9

BocN=NBoc 33i 75 53

aIsolated yield after flash column chromatography. bEnantiomeric excess determined by chiral HPLC analysis.

The -amination of other -ketoesters such as, ethyl 1-oxo-2,3-dihydro-1H-

indene-2-carboxylate, methyl 1-oxo-2,3-dihydro-1H-indene-2-carboxylate, methyl 1-

oxo-1,2,3,4-tetrahydronaphthalene-2-carboxylate, and 3-acetyldihydrofuran-2(3H)-

one was also evaluated. As observed, (Table 10, entries 5-7), good isolated yields (65-

66%) were generally obtained, along with low enantioselectivities (13 to 36% ee). In

the case of 1,3-diketones, better enantioselectivity was observed using as amination

agent DBAB, especially in the case of 2-acetylcyclopentan-1-one (Table 10, entry 9). In


96

this case, the -amination of this nucleophile gave 75% isolated yield and 53%

enantiomeric excess.

The combination of DES an organocatalysis has been proved to be an accessible

and green methodology in the synthesis of drugs.62f Particularly interesting results have

been observed in the synthesis of chiral indolin-3-ones, derivatives, usually present in

diverse biologically active natural alkaloids.94 Moreover, 1-acetyl-3-oxoindoline-2-

carboxylate derivatives have been synthesized employing asymmetric organocatalysis

in VOCs in high yield and selectivity.95 With these considerations, we focused our

attention in the synthesis of 1-acetyl-3-oxoindoline-2-carboxylate and its derivatization

employing the catalytic system form by ent-23/DES [ChCl:Gly (1:2)]. First, the synthesis

of methyl 1-acetyl-3-oxoindoline-2-carboxylate was carried out in three steps (Scheme

56). Thus, methyl 2-aminobenzoate was alkylated with methyl 2-bromoacetate in DMF

at 80 °C to obtain intermediated 34 with 95% yield. Then, the aniline was acetylated

with acetic anhydride at reflux and sulfuric acid as catalyst, affording intermediate 35

in 83% yield. Finally, the cyclization of this intermediate with potassium tert-butoxide

in THF afforded the target compound in 64% yield (Scheme 56).

94 (a) Abbasov, M. E.; Romo, D. Nat. Prod. Rep. 2014, 31, 1318-1327; (b) Yu, J.; Zhou, Y.;

Chen, D.-F.; Gong, L.-Z. Pure Appl. Chem. 2014, 86, 1217-1226; (c) Sun, B.-F. Tetrahedron Lett. 2015, 56, 2133-2140; (d) Estefania, D.; Daniela, G.; Gustavo, S. Curr. Organocatal. 2015, 2, 124-149; (e) Merad, J.; Lalli, C.; Bernadat, G.; Maury, J.; Masson, G. Chem. Eur. J. 2018, 24, 3925-3943.

95 (a) Jin, C.-Y.; Wang, Y.; Liu, Y.-Z.; Shen, C.; Xu, P.-F. J. Org. Chem. 2012, 77, 11307-11312; (b) Yarlagadda, S.; Ramesh, B.; Ravikumar Reddy, C.; Srinivas, L.; Sridhar, B.; Subba Reddy, B. V. Org. Lett. 2017, 19, 170-173.


97

Scheme 56. Synthesis of methyl 1-acetyl-3-oxoindoline-2-carboxylate (36).

Compound 36 was then submitted to the ent-23-catalysed -amination reaction

employing DBAB and diisopropyl azodicarboxylate (DIAD) as electrophiles in ChCl:Gly

(1:2) as solvent (Scheme 57, Eq. a). The two α-aminated products were obtained in

excellent yields (>95%) but moderate selectivity (30-45% ee). On the other hand,

compound 36 was also functionalized, using similar reaction conditions via Michael

addition to -nitrostyrene to afford the 2,2-disubstituted oxindole 37 in excellent yield

and diastereoselectivity and 57% ee (Scheme 57, Eq. b). Compound 38 is a precursor of

biologically active molecules containing indolin-3-ones with a quaternary stereocenter

at the 2-position, such as, Brevianamide A and Austamide.


98

Scheme 57. Asymmetric organocatalysed functionalization of methyl 1-acetyl-3-indol-2-carboxylate in DES.


99


2.4.1. General





















2.4.2. Synthesis and Spectroscopic Data of Chiral Organocatalysts.

(1S,2S)-N1-(1H-benzo[d]imidazol-2-yl)cyclohexane-1,2-diamine (ent-17).69f

Scheme 58. Synthesis of chiral organocatalyst ent-17.

A mixture of 2-chloro-1H-benzo[d]imidazole (233 mg, 1.53 mmol, 1 equiv.), (1S,2S)-

cyclohexane-1,2-diamine (698 mg, 6.12 mmol, 4 equiv.), and TEA (213 μL, 1.53 mmol, 1

equiv.) was heated at 190-200 °C during 16 h in a sealed pressure tube. Then, the


100

reaction mixture was allowed to reach ~50 °C, and water (20 mL) was added. The

obtained mixture was quickly extracted with CH2Cl2 (3×20 mL) before the temperature

of the reaction reached rt in order to avoid solubility problems. The collected organic

phases were dried over MgSO4. After filtration, the organic solvents were evaporated

under reduced pressure to give a crude mixture, which was purified by precipitation in

CH2Cl2 to obtain ent-17 (229 mg, 65%) as a pale yellow solid: mp 235-240 °C (CH2Cl2);

IR 2929, 2855, 1700, 1644, 1606, 1580, 1468, 1270, 1116, 1030; δH (300 MHz, CD3OD)

1.19-1.49 (m, 4H, 2×CH2), 1.74-1.77 (m, 2H, CH2), 1.98-2.11 (m, 2H, CH2), 2.50-2.58 (m,

1H, CH, CHNH2), 3.34-3.40 (m, 1H, CHNH), 6.93-6.97 (m, 2H, ArH), 7.15-7.18 (m, 2H,

ArH); m/z 230 [M+, 10%], 160 (24), 134 (100), 133 (59), 97 (28).

(1S,2S)-N1-(1H-benzo[d]imidazol-2-yl)-N2,N2-dimethylcyclohexane-1,2-diamine (ent-

18).69f


A mixture of ent-18 (168 mg, 0.73 mmol, 1 equiv.), 80% HCO2H (3.5 mL), and a 36%

aqueous solution of HCHO (127 μL, 1.61 mmol, 2.2 equiv.) was stirred at 120 °C for 16

h. Then, the solvent was removed under reduced pressure. Saturated NaHCO3 solution

(15 mL) and 10% NaOH solution (until pH = 8) were added in this order, and the

resulting mixture was extracted with CH2Cl2 (3×15 mL). The organic phases were dried

over MgSO4. After filtration, the organic solvent was evaporated under reduced pressure

to give a crude mixture, which was purified by precipitation in CH3CN to afford pure

ent-18 (87 mg, 46%) as a white solid; mp 248-250 °C (CH3CN); IR 2923, 2856, 2818,

2775, 1700, 1633, 1576, 1499, 1461, 1375, 1265, 1064; δH (300 MHz, CDCl3) 1.09-1.42

(m, 4H, 2×CH2), 1.65-1.70 (m, 1H, CH), 1.82-1.87 (m, 2H, CH2), 2.22 (s, 6H, CH3), 2.33 (td,

J = 10.9, 3.2 Hz, 1H, CHCNMe2), 2.65-2.69 (m, 1H, CH), 3.44 (td, J = 10.4, 4.0 Hz, 1H,

CHNH), 5.46 (br. s, 1H, NH), 6.91-6.96 (m, 2H, ArH), 7.14-7.20 (m, 2H, ArH); m/z 258

[M+, 1.5%], 133 (30), 125 (100), 84 (20).

(1R,2R)-N1,N2-bis(1H-benzo[d]imidazol-2-yl)cyclohexane-1,2-diamine (ent-19). 73


101


2-chloro-1H-benzo[d]imidazole (2.064 g, 13.56 mmol) was added to (1R,2R)-

cyclohexane-1,2-diamine (773.9 mg, 6.78 mmol) and the resulting mixture was stirred

at 195-200 °C for 20 h. After this time, the reaction mixture was allowed to reach 50 °C

and water (40 mL) was added. Then, the reaction was basified until pH = 8 with a

saturated aqueous solution of NaHCO3 and the obtained mixture was extracted with

CH2Cl2 (5×50 mL). The combined organic phases were dried over MgSO4. After filtration,

the organic solvent was evaporated under reduced pressure to give the corresponding

crude product which was purified by flash column chromatography (EtOAc/MeOH) to

give pure ent-19 as a white solid (1.87 g, 40% yield); mp 193-196 °C (Et2O); IR 2944,

2916, 2847, 1630, 1603, 1580, 1461,1410, 1259, 1112, 1047; δH (300 MHz, CD3OD,)

1.35-1.47 (m, 4H, 2×CH2), 1.76 (br. s, 2H, CH2), 2.18-2.23 (m, 2H, CH2), 3.71-3.74 (m, 2H,

2×CHNH), 6.9-6.95 (m, 4H, ArH), 7.11-7.15 (m, 4H, ArH); m/z 346 [M+, 33%], 214 (64),

213 (100), 212 (36), 184 (16), 173 (19), 172 (15), 170 (10), 160 (14), 159 (21), 158

(11), 146 (11), 145 (16), 134 (32), 133 (37), 132 (16).

(1S,2S)-N1-(5,6-dinitro-1H-benzo[d]imidazol-2-yl)-N2,N2-dimethylcyclohexane-1,2-

diamine (ent-23) 50


Catalyst ent-23 (50 mg, 0.2 mmol, 1 equiv.) was dissolved in concentrated H2SO4 (0.2

mL, 98%) and stirred vigorously for 5 minutes; after this time concentrated HNO3 (0.4

mL, 65%) was carefully added to the mixture at -20 °C. Then, the reaction was stirred at

room temperature for 16 hours. After this period, the mixture was treated with cold

water and basified until pH = 8 with 25% aqueous solution of NH3. Finally, the aqueous

phase was extracted with EtOAc (3×20 mL). The collected organic phases were dried


102

over anhydrous MgSO4. After filtration, the organic solvent was removed under reduced

pressure to give catalyst ent-23 without further purification as a red solid (74% yield,

52 mg, 0.15 mmol) ; mp 100-105 °C (CH2Cl2, decompose); δH (300 MHz, CDCl3) 1.19-

1.49 (m, 4H, 2×CH2), 1.63-1.98 (m, 4H, 2×CH2), 2.37 (s, 6H, 2×Me), 2.51 (m, 1H, CHNMe2),

3.66 (br s, 1H, CHNH),7.49 (s, 2H, ArH); δC (75 MHz, CDCl3) 21.7, 24.4, 24.6, 33.2, 39.8,

53.8, 67.8, 108.3, 136.8, 142.0, 161.8; m/z 348 [M+, <1%] 128 (10), 126 (11), 125 (100),

124 (25), 84 (64), 71 (24), 58 (20), 44 (10); HRMS calcd. for C13H13N5O4 [M+-NHMe2]

303.0968, found 303.0964.


Scheme 62. Model reaction for the synthesis of the compound 32.

Catalyst ent-23 (5.22 mg, 0.015 mmol, 10 mol%) and ethyl 2-oxocyclopentane-1-

carboxylate (23.4 mg, 0.15 mmol) were dissolved in a mixture of ChCl:Gly (1:2 molar

ratio, 0.2 mL) and kept under stirring for 10 minutes at room temperature. Then, di-

tert-butylazodicarboxylate (36.8 mg, 0.16 mmol) was added. The reaction was

vigorously stirred with ultrasounds 1 hour. After this period, water (3 mL) was added

to the mixture and the reaction product was extracted with EtOAc (3×5 mL). The

collected organic phases were dried over anhydrous MgSO4 and, after filtration, the

solvent was evaporated under reduced pressure to give crude 33a. Purification by flash

column chromatography on silica gel (hexane/EtOAc: 7/3) afforded pure 33a (45.2 mg,

78%, 0.11 mmol). δH (300 MHz, CDCl3) 1.28 (t, J = 7.1 Hz, 3H), 1.59–1.36 (m, 18H), 2.98–

1.75 (m, 6H), 4.24 (m, 2H), 6.53 (br s, 1H). The enantiomeric excess of 33a was

determined by chiral HPLC analysis (Chiralpack IA, hexane/EtOH: 96/04, 0.7 mL/min).


A mixture of catalyst ent-23 (5.22 mg, 0.015 mmol, 10 mol%) and ethyl 2-

oxocyclopentane-1-carboxylate (23.4 mg, 0.15 mmol) in ChCl:Gly (1:2 molar ratio, 0.2


103

mL) was stirred for 10 minutes at room temperature. Then, di-tert-

butylazodicarboxylate (38.8 mg, 0.16 mmol) was added. The reaction was vigorously

stirred with ultrasounds 1 hour. After this period, the corresponding organic solvent

was added (3 mL) and the mixture was stirred for 10 minutes at room temperature. The

stirring was stopped to allow phase separation and the upper organic layer was

removed. This extractive procedure was repeated two more times and the combined

organic extracts were washed with water (3×5 mL), dried (MgSO4), filtered, and

evaporated under reduced pressure. Then, the next reaction cycle was performed with

the obtained DES/ent-23 mixture, adding fresh ethyl 2-oxocyclopentane-1-carboxylate

and di-tert-butylazodicarboxylate. This reaction mixture was subjected again to the

above-described procedure and further reaction cycles were repeated using the

recycled deep eutectic solvent phase.


(R)-Di-tert-butyl-1-[1-(ethoxycarbonyl)-2-oxocyclopentyl]hydrazine-1,2-dicarboxylate

(33b)96

Yield 78%, colourless oil; H (300 MHz, CDCl3) 1.27-1.32 (t, J = 7.0 Hz, 3H), 1.45 -1.47

(m, 18H), 1.95-2.64 (m, 6H), 4.25 (m, 2H), 6.28-6.56 (br s, 1H).

(R)-Diisopropyl-1-[1-(ethoxycarbonyl)-2-oxocyclopentyl]hydrazine-1,2-dicarboxylate

(33c)96

Yield 52%, colourless oil; H (300 MHz, CDCl3) 1.24-1.29 (m, 15H), 1.69 - 2.68 (m, 6H),

4.21-4.24 (m, 2H) 4.93-4.99 (m, 2H), 6.35 -6.66 (br s, 1H).

96 Tang, S.; Wang, Z.; Liu, B.; Dong, C. E. Chin. Chem. Lett. 2015, 26, 744-748.


104

(R)-Diethyl-1-[1-(ethoxycarbonyl)-2-oxocyclopentyl]hydrazine-1,2-dicarboxylate (3d)96

Yield 76%, colourless oil; H (300 MHz, CDCl3) 1.24-1.31 (m, 9H), 2.01-2.68 (m, 6H),

4.18-4.26 (m, 6H), 6.46-6.77 (br s, 1H).

(R)-Di-tert-butyl-1-[2-(ethoxycarbonyl)-1-oxo-2,3-dihydro-1H-inden-2-yl]hydrazine-1,2-

dicarboxylate (33e)97

Yield 66%, colourless oil; H (300 MHz, CDCl3) 1.17-1.49 (m, 21H), 3.83 (d, J = 20.4 Hz,

1H), 4.25 (m, 3H), 6.37-6.74 (br s, 1H), 7.37 (t, J = 7.3 Hz, 1H), 7.51 (d, J = 7.5 Hz, 1H),

7.64 (t, J = 7.4 Hz, 1H), 7.78 (d, J = 9.9 Hz, 1H).

(R)-Di-tert-butyl-1-[2-(methoxycarbonyl)-1-oxo-2,3-dihydro-1H-inden-2-yl]hydrazine-

1,2-dicarboxylate (33f)97

Yield 65%, slightly yellow oil; H (300 MHz, CDCl3) 1.27-1.55 (m, 18H), 3.78-4.26 (m,

5H), 6.41-6.72 (m, 1H), 7.38 (t, J = 7.4 Hz, 1H), 7.51 (d, J = 6.9 Hz, 1H), 7.64 (t, J = 7.1 Hz,

1H), 7.79 (d, J = 8.8 Hz, 1H).

97 Konishi, H.; Lam, T. Y.; Malerich, J. P.; Rawal, V. H. Org. Lett. 2010, 12, 2028-2031.


105

(R)-Di-tert-butyl1-(3-acetyl-2-oxotetrahydrofuran-3-yl)hydrazine-1,2-dicarboxylate

(33g)

Yield 65%, colourless oil; H (300 MHz, CDCl3) 1.47 (d, J = 2.0 Hz, 18H), 2.36 (m, 3H),

2.80 (br s, 1H), 3.2 (d, J = 43.5 Hz, 1H), 4.39 (br s, 2H) 6.57 (d, J = 159.6 Hz, 1H).

(R)-Di-tert-butyl-1-(2-acetyl-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)hydrazine-1,2-

dicarboxylate (33h)

Yield 68%, brown oil; H (300 MHz, CDCl3) 1.46-1.54 (m, 18H), 2.42 (m, 3H), 2.71 (br s,

2H), 2.92-3.04 (m, 2H), 6.21 (s, 1H), 7.20 (d, J = 7.6 Hz, 1H), 7.33 (d, J = 3.7 Hz, 1H), 7.47

(t, J = 7.4 Hz, 1H), 7.99 (d, J = 7.7 Hz, 1H).

(R)-Di-tert-butyl 1-(1-acetyl-2-oxocyclopentyl)hydrazine-1,2-dicarboxylate (33i)

Yield 75%, colourless oil; H (300 MHz, CDCl3) 1.47 (d, J = 7.0 Hz, 18H), 1.56-2.09 (m,

3H), 2.20-2.51 (m, 5H), 2.51-2.84 (m, 1H), 6.24-6.48 (br s, 1H).

(R)-Diisopropyl-1-(1-acetyl-2-(methoxycarbonyl)-3-oxoindolin-2-yl)hydrazine-1,2-

dicarboxylate (37a)99b

Yield 67%, brown oil; H (300 MHz, CDCl3) 1.10-1.42 (m, 12H), 2.51 (s, 1H) 2.61 (d, J =

5.3 Hz, 2H), 3.63-3.83 (m, 3H), 4.81-5.16 (m, 2H), 7.22-7.24 (m, 1H), 7.52-7.72 (m, 2H),

7.83 (d, J = 7.3 Hz, 1H).


106

(R)-Di-tert-butyl1-(1-acetyl-2-(methoxycarbonyl)-3-oxoindolin-2-yl)hydrazine-1,2-

dicarboxylate (37b)99b

Yield 95%, colourless oil; H (300 MHz, CDCl3) 1.03-1.76 (m, 18H), 2.37-2.70 (m, 3H),

3.75 (d, J = 18.3 Hz, 3H), 7.23 (t, J = 7.7 Hz, 1H), 7.67 (t, J = 7.2 Hz, 1H), 7.82 (d, J = 7.2 Hz,

1H).

(S)-Methyl 1-acetyl-2-((S)-2-nitro-1-phenylethyl)-3-oxoindoline-2-carboxylate (38)99a

Yield 95%, colourless oil, H (300 MHz, CDCl3) 2.30 (s, 3H), 3.73 (s, 3H), 5.06 (d, J = 10.9

Hz, 2H), 5.90 (m, 1H), 6.89 (d, J = 6.8 Hz, 2H) 6.95 − 7.10 (m, 4H), 7.17 (t, J = 7.2 Hz, 1H),

7.50 (ddd, J = 8.6, 7.3, 1.5 Hz, 1H), 7.77 (d, J = 7.2 Hz, 1H).


107

2.5. Conclusions

The α-amination reaction of 1,3-dicarbonyl compounds with azodicarboxylates

has been performed in deep eutectic solvents, obtaining moderate to high yields and

selectivities catalyzed by chiral 2-aminobenzimidazole ent-23 in the mixture choline

chloride:glycerol (1:2). The procedure is fast, clean, simple, cheap, scalable and safe.

Regarding recovery and recyclability of the catalytic system, cyclopentyl methyl ether

afforded the best results.

109

CHAPTER 3

Chiral Deep Eutectic Solvents


111

3.1. Background

3.1.1. Non-Natural Deep Eutectic Solvents

The green behaviour of deep eutectic solvents makes these mixtures the ideal

reaction medium for organic synthesis. However, some problems associated with some

of these mixtures such as their high viscosity and high melting points have emerged as

important drawbacks. In this context, the synthesis of new tailor-made deep eutectic

solvents makes possible the tuning of the properties of the system.98

One of the first designed DES was synthesised by Zhao’s group to employ

supported TEMPO as catalyst in the oxidation of alcohols.99 TEMPO’s salt was

synthesised in two steps employing 4-hydroxy-TEMPO as precursor (Scheme 63). First,

deprotonated 4-hydroxy-TEMPO was alkylated with 1,4-dibromobutane to afford the

intermediate 39, which after reaction with N,N-dimethyldodecylamine led to the final

quaternary ammonium-TEMPO salt 40 (Scheme 63).

Scheme 63. Synthesis of Quaternium-TEMPO salt.

Pure Quarternium-TEMPO salt was then mixed with urea and heated at 60 °C to

obtain the DES-supported TEMPO with a total atom economy and 100% yield (Scheme

64).

98 Tang, B.; Row, K. H. Monatsh. Chem. 2013, 144, 1427-1454. 99 Zhang, Y.; Lü, F.; Cao, X.; Zhao, J. RSC Adv. 2014, 4, 40161-40169.


112

Scheme 64. Formation of the DES-supported TEMPO.

This tailor-made DES was employed in the oxidation of 21 alcohols giving

excellent yields (94-99%). Moreover, the system was recovered and reused for 5 cycles

without losing activity in the oxidation with molecular oxygen of benzyl alcohol

(Scheme 65).

Scheme 65. Recycling of DES–TEMPO in the aerobic oxidation of benzyl alcohol.

Simultaneously, room temperature deep eutectic solvents of camphorsulfonic

acid (CSA)-sulfobetaines have been developed by Germani and co-workers.100 Twelve

examples of different sulfobetaines were synthesized in a single step employing

acetonitrile as solvent in a brief period of time (2-10 hours) leading to high yields by

ring opening of 1,3-propanesultone. One representative example of this methodology is

the use of N,N-dimethylcyclohexanamine in order to synthetize the corresponding

tertiary amine (Scheme 66). After this first step, 0.7 mmol of (+)-CSA were combined

with the tertiary amine and heated to obtain a liquid mixture at room temperature

(Scheme 66).

100 Cardellini, F.; Germani, R.; Cardinali, G.; Corte, L.; Roscini, L.; Spreti, N.; Tiecco, M. RSC

Adv. 2015, 5, 31772-31786.


113

Scheme 66. Synthesis of sulfobetaine salts.

After full characterization of the novel DES, the mixture 42 was employed as

reaction medium and catalyst in the Claisen–Schmidt condensation of benzaldehyde

with acetophenone (Scheme 67). The corresponding chalcone was obtained in good

yield (70%) and the DES was recovered for four times without losing activity.

Scheme 67. Claisen-Schmidt condensation employing DES as catalyst and reaction media.

Moreover, novel chiral choline-chloride-based deep-eutectic-solvents have been

formulated using bio-based and biodegradable molecules such as xylitol, D-sorbitol or

L-tartaric acid mixed with choline chloride.101 The viscosity and the melting points of

these solvents have been evaluated taking in account the addition of stoichiometric

amounts of glycerol and the absorption of water. Finally, the solubility of these novel

mixtures was tested in aprotic solvents (ethyl acetate, 2-metyltetrahydrofurane and

acetone) observing two phases without alterations in the structure of the DES, with the

exception of the mixture formed by choline chloride:levulinic acid (1:2). The addition of

acetone to this mixture results in a quantitative precipitation of the choline chloride

(Figure 28) making possible the formation of a new the DES by adding levulinic acid.

101 Maugeri, Z.; Domínguez de María, P. RSC Adv. 2012, 2, 421-425.


114

Figure 28. Precipitation of choline chloride by the addition of different amount of acetone.

Furthermore, the combination hydrophobic and hydrophilic deep eutectic

solvents have been studied in the enantioselective extraction of threonine.102 After a

brief optimization, the combination between (-)-menthol: L-(+)-lactic acid (M:LA) with

molar ratios 1:1 and ChCl:Urea (1:2) was chosen as the phase-forming component for

the studies. The factors studied in this work were the effect of the phase volume ratio,

the concentration of the chiral selector, the concentration of threonine, the pH, the

temperature and the water content in the hydrophilic phase. Under the optimal

conditions [mixture of M:LA (1:1) and ChCl:Urea (1:2) phase volume ratio of 2:1, 35 °C,

pH = 6 and water content of 20 wt%] 31.6% ee was obtained.

Tiecco and co-workers have developed the first chiral deep eutectic solvent

(CDES) base on N,N,N-trimethyl-(1-phenylethyl)ammonium methanesulfonate.103 The

two enantiomers of this salt were synthesized in one step by addition of methyl-

methanesulfonate to 1-phenylethylamine in acetonitrile obtaining the desired product

in good yields (Scheme 68). After the synthesis of the corresponding ammonium salts,

(+)-CSA was added and the mixtures were heated at 70 °C for three hours to obtain the

DES in excellent yields (Scheme 68).

102 Wang, R.; Sun, D.; Wang, C.; Liu, L.; Li, F.; Tan, Z. Sep. Purif. Technol. 2019, 215, 102-

107. 103 Palomba, T.; Ciancaleoni, G.; Del Giacco, T.; Germani, R.; Ianni, F.; Tiecco, M. J. Mol. Liq.

2018, 262, 285-294.

Acetone (equivalents)


115

Scheme 68. Synthesis of CDES base on N,N,N-trimethyl-(1-phenylethyl)ammonium methanesulfonates and CSA.

CDES 44 and 46 were tested in the asymmetric addition of indole to chalcone

obtaining 11% ee and 5% ee, respectively (Scheme 69). These results are comparable

with the results obtained employing (+)-CSA in acetonitrile under the same reaction

conditions (10% ee).104

Scheme 69. Enantioselective addition of indole to chalcone catalyse by (+)-CSA, CDES 44 and CDES 46.

Moreover, the variation in enantiomeric excess was attributed to the difference

in interactions between the components of the DES. The relationship between the

solvent molecules was analysed by 1H-NMR, showing a different behaviour at the time

of forming the mixture. Figure 29 shows the interactions of the protons, the most

intense in red and the least intense appearing in green.

104 Zhou, W.; Xu, L.-W.; Li, L.; Yang, L.; Xia, C.-G. Eur. J. Org. Chem. 2006, 5225-5227.


116

Figure 29. NMR analysis of the interactions between the components of the DES.

As demonstrated with the above described bibliographic background, no

efficient chiral deep eutectic solvents have been efficiently employed in asymmetric

catalysis so far.


117

3.2 Objectives

Based on the above exposed bibliographical background, the following objectives

were established

1. The synthesis of proline based Deep Eutectic Solvents and its use in the Michael

addition of ketones to nitroalkenes.

2. The synthesis of cationic proline derivatives as hydrogen bond-acceptors for

the formation of a chiral deep eutectic solvent.

3. The study of the selectivity of the new chiral deep eutectic solvents in the

Michael addition of ketones to nitroalkenes.


119


The use of chiral deep eutectic solvents as biphasic catalytic system has been

scarcely survey, for this reason we begin with the study of different L-proline base deep

eutectic solvents as reaction medium and catalyst in asymmetric conjugate additions.

First, the formation of the DES was accomplished in one step with total atom economy

employing different hydrogen-bond donors (Table 11). When p-toluensulfonic acid was

used as HBD, a low temperature melting eutectic mixture was obtained (Table 11, entry

1). Then, one equivalent of proline was mixed with one and two equivalents of malonic

acid producing a eutectic mixture at eighty degrees (Table 11, entries 2 and 3). In

addition, when oxalic acid was employed for the formation of the liquid solution this

transformation takes place at sixty degrees (Table 11, entry 4). Finally, using different

alcohols as HBD the eutectic point was achieved at forty degrees (Table 11, entries 5-8).

Table 11. Synthesis of Chiral Deep Eutectic Solvents employing L-proline.

Entry HBD (equiv.) Tformation (°C)

1 p-Toluensulfonic

acid·H2O (2)

50

2 Malonic acid (1) 80

3 Malonic acid (2) 80

4 Oxalic acid (1) 60

5 Glycolic acid (3) 40

6 Glycerol (3) 40

7 Diethylenglyco (3) 40

8 1,4-butanediol (3) 40


120

These CDES (0.5 grams) were used in the model Michael addition of butanone to

nitrostyrene (Table 12, entries 1-5), and in the Michael addition of cyclohexanone to

nitrostyrene (Table 12, entries 6-13) at room temperature, observing similar results

regardless the composition of the CDES. When acidic mixtures were employed as

reaction media (Table 12, entries 1-2 and 6-10) low or null conversion were obtained,

showing the importance of the pH in the addition. Using butanone as nucleophile and

the CDES formed by glycolic acid:L-proline (Table 12, entry 2), the blank reaction was

avoided and the formation of the product took place through the organocatalyzed

pathway, obtaining low conversion (15%) but good selectivities for both

diastereoisomers (73% ee in the major diastereoisomer and 87% ee in the minor).

Using the same CDES in the addition of cyclohexanone to nitrostyrene (Table 12, entry

10), although a low conversion was achieved, the diastereoselectivity increased to

20>1, with low enantioselectivity being achieved for the major diastereoisomer (23%

ee). Finally, the mixtures formed by polyalcohols and proline were tested, obtaining

high conversions in all the cases (Table 12, entries 3-5 and 11-13) but low

enantioselectivities.

Table 12. Michael addition using L-proline base deep eutectic solvents

Entry R1 R2 DES Conv

(%)a dra ee (%)b

1 H Me p-toluensulfonic acid·H2O:

L-Pro (2:1) 0 Nd Nd

2 H Me glycolic acid: L-Pro (3:1) 15 60/40 73/87

3 H Me glycerol: L-Pro (3:1) >95 80/20 rac/rac

4 H Me diethylenglycol: L-Pro (3:1) 92 85/15 26/rac

5 H Me 1,4-butanediol: L-Pro (3:1) >95 75/25 13/rac

6 -(CH2CH2CH2)- p-toluensulfonic acid·H2O:

L-Pro (2:1) 0 Nd Nd


121

7 -(CH2CH2CH2)- Malonic acid: L-Pro (1:1) 0 Nd Nd

8 -(CH2CH2CH2)- Malonic acid: L-Pro (2:1) 0 Nd Nd

9 -(CH2CH2CH2)- Oxalic acid: L-Pro (1:1) 0 Nd Nd

10 -(CH2CH2CH2)- glycolic acid: L-Pro (3:1) 9 >20/1 23/Nd

11 -(CH2CH2CH2)- glycerol: L-Pro (3:1) 94 >20/1 20/Nd

12 -(CH2CH2CH2)- diethylenglycol: L-Pro (3:1) 89 >20/1 20/Nd

13 -(CH2CH2CH2)- 1,4-butanediol: L-Pro (3:1) 92 >20/1 32/Nd

a Determined by 1H-NMR analysis of the crude reaction mixture. b Enantiomeric excess determined by chiral HPLC analysis.

Based on these results of the Michael addition of butanone to β-nitrostyrene

(Table 12, entries 10-13) and the analysis of the association constant between the

components of the mixture, a semi-quantitative analysis was carried out. First, 1H-NMR

analysis of changes in the molecular shifts (DD) for proline indicates the level of

association between the two molecules that are forming the CDES. In all the cases the

movement in chemical shift was low due to the deuterated solvent employed

(CDCl3/CD3OD). As it is shown in the Table 13 entry 1, when the association between

the two components of the CDES is high (high DD), the conversion decreases, probably

due to the higher difficulty of the substrate to arrive to the catalytic centre. However,

the enantioselectivity increases because all the molecules that are involved in catalysing

the blank reaction are present in the formation of the DES network. The opposite effect

occurs when DD is low (Table 13, entry 4), obtaining full conversion but null selectivity.

Table 13. Semi-quantitative analysis of association constant-conversion and association constant-selectivity

Entry Counter part DD

ppm Conv. (%)

ee major (%) ee minor (%) De

1 Glycolic acid 0.0356 15 73 87 20

2 Diethylengycol 0.0209 92 26 0 70

3 1,4-butanediol 0.0137 >95 13 0 50

4 Glycerol 0.0102 >95 0 0 60

In order to improve the selectivity of the reaction employing CDES and obtaining

more data about the relationship between the structure and the activity, the synthesis

of a cationic proline derivative was performed (Figure 30).


122

Figure 30. Target L-proline derivatives for the CDES formation.

For the synthesis of the cationic proline derivative, the reduction of the L-proline

was carried out using lithium aluminium hydride, obtaining the corresponding L-

prolinol in high yield (99%, Scheme 70). After this process the amino moiety was

protected with benzyl chloroformate, obtaining product 47 in 77% of yield as a pure

compound by 1HNMR. Then, compound 47 was treated with methanesulfonyl chloride,

achieving product 48 with 52% of yield after isolation by chromatographic column

(Scheme 70).

Compound 48 was dissolved in THF and reflux in the presence of lithium

bromide, affording the corresponding product 49 with 55% of isolated yield. To

perform the synthesis of the protected proline derivative salt 50, trimethyl amine was

bubbled to a solution of 49 in ethyl acetate at 0 °C and stirred at room temperature for

three days. After this period the product 50 was obtained as a white precipitated,

affording the pyrrolidine 50 with 25% yield (Scheme 70). Finally, a hydrogenation

process of the intermediate 50 was employed to deprotect the amine moiety, obtaining

the cationic proline derivative 51 in 99% yield.

Chiral moiety HBA


123

Scheme 70. Synthesis of cationic proline derivatives.

After the synthesis of the L-proline derivative 51, the formation of a chiral deep

eutectic solvent was performed. First, two equivalents of the ammonium salt 51 were

mixed with urea and heated one hour increasing the temperature slowly up to eighty

degrees, but the formation of a liquid mixture was not detected (Table 14, entry 1).

Then, the same experiment was carried out decreasing the equivalents of the compound

51 to one equivalent, but the mixture remained as two solids (Table 14, entry 2). When

the equivalents of urea were increased to two and three both mixtures formed a clear

liquid solution at 60 °C (Table 14, entries 3 and 4). Finally, two equivalents of glycerol

were also employed as hydrogen bond donors combined with one equivalent of 51 in

the formation of the CDES, obtaining a liquid solution at 45 °C (Table 14, entry 5).

Table 14. Synthesis of Chiral Deep Eutectic Solvents.

Entry 51 (equiv.) HBD (equiv.) Tformation (°C)


124

1 2 Urea (1) Nd

2 1 Urea (1) Nd

3 1 Urea (2) 60

4 1 Urea (3) 60

5 1 Gly (2) 45

In order to determine with accuracy, the eutectic temperature for the mixture

51:Gly a Differential Scanning Calorimetry (DSC) experiment was carried out (Figure

31). In the experiment the mixture of 51 and glycerol (1:2) was heated (temperature

ramp: 5 °C), from -90 °C to 160 °C. This procedure was repeated two times, observing

and absorption of 3.736 J/g at 54 °C between the two cycles. This difference suggests

the formation of the corresponding hydrogen-bond network between the HBD

(glycerol) and the HBA (51) at this temperature.

Figure 31. Differential Scanning Calorimetry experiment of the mixture 51Gly (1:2).

Next, these three chiral deep eutectic solvents [51:Urea (1:2), 51:Urea (1:3) and

51:Gly (1:2)] were used in the model Michael addition of cyclohexanone to nitrostyrene

(Table 15, entries 1-4). When using urea-based deep eutectic solvents, good diastereo-

and enantioselectivity were obtained after one day. However, low conversions were


125

achieved (Table 15, entries 1 and 2). On the other hand, when using the CDES 51:Gly

(1:2), better results were achieved in the conjugate addition reaction, obtaining adduct

52a in high conversion, good diastereo- and enantioselectivity (Table 15, entry 3). The

same CDES formed by 51:Gly was reused at 0 °C in order to increase the selectivity of

the product but null conversion was afforded at this temperature (Table 15, entry 4).

Finally, 10 mol% of the proline derivative 51 was employed as organocatalyst using

glycerol as solvent to study the efficiency of this molecule in the process obtaining

similar results in terms of selectivity but with a very low conversion (Table 15, entry 5).

Table 15. Chiral Deep Eutectic Solvents. Catalytic studies.

Entry CDES Conv. (%)a dr eeb

1 51:Urea (1:2) 62 75/25 70/50

2 51:Urea (1:3) 33 75/25 65/50

3 51:Gly (1:2) >95 70/30 67/60

4 51:Gly (1:2)c - Nd Nd

5 51:Glyd <10 70/30 65/60

a Reaction conversion towards 52a determined by 1H-NMR. b Enantiomeric excess determined by chiral HPLC analysis. c The reaction was performed at 0 °C. d10% of 56 was used as catalyst in 0.1 g of glycerol

The recyclability of the catalytic eutectic mixture 51:Gly (1:2) was tested in the

model reaction (Figure 32). To achieve this goal, ethyl acetate was employed as

extraction media in order to separate the unreactive reagents and the products from

the CDES. As shown, the mixture was recovered and reused in four consecutive reaction

runs, without losing activity and maintaining good diastereo- and enantioselectivity.


126

Figure 32. Recycling study.

Finally, a brief scope was carried out with the freshly prepared chiral deep

eutectic solvent 51:Gly (1:2). First, the product of the addition of cyclohexanone to β-

nytrostyrene 52a was obtained in good yield (75%) moderate diastereoselectivity

(75/25) and moderate enantioselectivity for both diastereoisomers (67% ee major

diastereoisomer and 60% minor diastereoisomer, Table 16, entry 1). When 4-methoxy-

β-nitrostyrene was used as electrophile in the Michael addition with cyclohexanone at

room temperature, the Michael adduct was achieved in moderate yield,

disateroselectivity (74/26) and enantioselectivity (60% ee major diastereoisomer and

55% minor diastereoisomer, Table 16, entry 2). Using 4-chloro-β-nitrostyrene, similar

results in terms of yield and diastereoselectivity were obtained (53% yield, 75/25).

However, 70% of enantiomeric excess was reached for the major diastereoisomer

(Table 16, entry 3). Then, cyclopentanone and acetone were used as nucleophiles in the

Michael addition to nitrostyrene catalysed by the mixture 51:Gly. In both cases

moderate yields were obtained, but null selectivities were observed (Table 16, entries

4 and 5).

1 2 3 40

20

40

60

80

100

nº cycles

%

Recycling

conv

de

ee major

ee minor


127

Table 16. Asymmetric Michael addition catalysed by 51:Gly (1:2). Reaction scope.

Entry Product R1 R2 R3 yield (%)a drb ee (%)c

1 52a -(CH2CH2CH2)- H 75 75/25 67/60

2 52b -(CH2CH2CH2)- MeO 42 74/26 60/55

3 52c -(CH2CH2CH2)- Cl 53 75/25 70/22

4 52d -(CH2CH2)- H 63 60/40 rac:rac

5 52e H H H 71 - rac

a Isolated yield after flash column chromatography. b Determined by 1H-NMR analysis of the crude reaction mixture. c Determined by chiral HPLC analysis of the crude reaction mixture. Diastereomeric mixtures were not separated when isolating the reaction product.


129


3.4.1. General





















3.4.2. Synthesis and Spectroscopic Data of Chiral Organocatalysts

(S)-pyrrolidin-2-ylmethanol.105

Scheme 71. Synthesis of prolinol.

In a three-neck flask under argon atmosphere, lithium aluminium hydride (10.0 g, 264

mmol) was place. Then, THF (130 mL) was slowly added to the powder at 0 °C, to form

105 Nouch, R.; Cini, M.; Magre, M.; Abid, M.; Diéguez, M.; Pàmies, O.; Woodward, S.; Lewis,

W. Chem. Eur. J. 2017, 23, 17195-17198.


130

a suspension to which solid L-proline (10.1 g, 87.7 mmol) was added over 30 minutes.

The resulting mixture was heated at reflux for 16 h. After this, the mixture was cooled

down to 0 °C and quenched via dropwise addition of water (10 mL) over an hour,

followed by the careful addition of aqueous sodium hydroxide (5% w/v, 10 mL) and

water (30 mL). The resulting mixture was filtered to remove the aluminium oxide

formed, washed with dichloromethane and dried over anhydrous sodium sulphate. The

mixture was filtrated, and the organic solvent was concentrated at reduced pressure to

give the product (8.79 g, 98%, 86.9 mmol) as a yellow oil.

Benzyl (S)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (47).106

Scheme 72 Synthesis of 47.

To a solution of L-prolinol (5.0 g, 50 mmol) in CH2Cl2 (165 mL) was added dropwise

benzyl chloroformate (10.6 g, 60 mmol, 1.2 equiv.) at 0 °C, followed by Et3N (25.3 g, 250

mmol, 5 equiv.). The resulting mixture was stirred at room temperature overnight. The

resulting solution was washed with brine (3×100 mL) and dried over anhydrous

sodium sulphate. The mixture was filtrated, and the organic solvent was concentrated

at reduced pressure to give the pure N-Cbz amino alcohol 47 (9.1 g, 77%, 38 .5 mmol)

as a yellowish oil; δH (300 MHz, CDCl3): 1.67 (br s, 1H, -CHHCH2-) 1.74-1.94 (m, 2H, -

CHHCH2-), 1.97-2.06 (m, 1H, -CHHCH2-), 3.37-3.45 (m, 1H, CHHNH ), 3.51-3.59 (m, 1H,

CHHNH), 3.64-3.66 (m, 3H, CH2OH and CHNH), 3.97-4.05 (m, 1H, OH), 5.16 (d, J= 1,3 Hz,

2H, CH2Ph) 7.30-7.40 (m, 5H, ArH); δC (75 MHz, CDCl3): 24.02, 28.58, 47.34, 60.68, 66.89,

67.22, 127.93, 128.08, 128.52, 136.51, 157.12.

Benzyl (S)-2-(((methylsulfonyl)oxy)methyl)pyrrolidine-1-carboxylate (48)107

Scheme 73. Synthesis of 48.

106 Meng, F.; Chen, N.; Xu, J. Sci. China Chem. 2012, 55, 2548-2553. 107 Wang, G.; Sun, H.; Cao, X.; Chen, L. Catal. Lett. 2011, 141, 1324-1331.


131

To a stirred solution of compound 47 (5.5 g, 23 mmol) in CH2Cl2 (60 mL), NEt3 (3.0 mL,

30 mmol, 1.3 equiv.) was added at 0 °C. Then a solution of methanesulfonyl chloride (3.2

mL, 28 mmol, 1.2 equiv.) in CH2Cl2 (20 mL) was added. After letting the reaction

temperature increase to room temperature, the reaction mixture was stirred for 18 h.

The mixture was diluted with water (50 mL), and then, the resulted mixture was

extracted with CH2Cl2 (3×10 mL). The combined organic layer was washed with 1 M HCl

solution (25 mL) and brine (20 mL), then dried over anhydrous Na2SO4 and

concentrated in vacuo to give the compound 48 as colourless oil (3.8 g, 52%, 12.0

mmol); δH (300 MHz, CDCl3): 1.86-2.11 (m, 4H, -CH2CH2-), 2.84-2,94 (m, 3H, SCH3), 3.45-

3.49 (m, 3H, CH2NHCH), 4.09-4.22 (m, 1H, m), 4.27-4.38 (2H, m), 5.10-5.23 (m, 2H,

CH2Ph), 7.30-7.40 (m, 5H, ArH); δC (75 MHz, CDCl3): 23.81, 27.76, 36.91, 46.86, 56.29,

66.91, 69.37, 127.92, 128.33, 128.53, 136.62, 155.00.

Benzyl (S)-2-(bromomethyl)pyrrolidine-1-carboxylate (49).107


Under argon atmosphere, compound 48 (3.8 g, 12 mol) and THF (30 mL) were added

to 100 mL single neck bottle. Then, LiBr·H2O (3.2 g, 30 mmol, 2.5 equiv.) was added to

the solution. The reaction mixture was stirred for 16 h at reflux and THF was removed

under vacuo. The mixture was diluted with water (10 mL), and the resulted mixture was

extracted with CH2Cl2 (3×10 mL). The combined organic layer was washed with water

(10 mL) and brine (20 mL), then dried over anhydrous MgSO4 and concentrated in

vacuo. The residue was purified by flash column chromatography (EtOAc:PE = 1:4) on

silica gel to give the compound 49 as a colourless oil (2.0 g, 55%, 6.6 mmol); δH(300

MHz, CDCl3): 1.83-2.09 (m, 4H, -CH2CH2-), 3.28-3.71 (m, 4H, CH2NH and CH2Br), 4.13 (br

s, 1H, CHNH), 5.11-5.23 (m, 2H, CH2Ph), 7.32–7.37 (m, 5H, ArH); δC (75 MHz, CDCl3):

23.61, 29.36, 34.66, 47.20, 56.29, 58.18, 66.82, 127.86, 128.00, 128.50, 136.73, 154.85;

m/z 299.1 [M+, <1%], 204.1 (27), 160.2 (25), 92.1 (11), 91.1 (100).

(S)-1-(1-(Benzyloxycarbonyl)pyrrolidin-2-yl)-N,N,Ntrimethylmethanaminium bromide

(50).107


132

Scheme 75. Synhesis of 50.

A gas flow of NMe3 was generated by adding a solution of NaOH (6.6 g, 165 mmol, 25

equiv.) in water (12 mL) through a dropping funnel connected to a two-neck flask where

NMe3·HCl (12.1 g, 132 mmol, 20 equiv.) was placed . The generated NMe3 was bubbled

to a solution of compound 49 (2.0 g, 6.6 mmol) in EtOAc (20 mL) at 0 °C. After 10

minutes of bubbling, the reaction mixture was sealed by a rubber plug and stirred at

room temperature for 72 h. The mixture was filtrated, and the filter cake was washed

with EtOAc (20 mL) to give the product 50 as a white solid (589.5 mg, 25%, 1.65 mmol);

mp 233-243 °C (EtOAc); δH (300 MHz, CD3OD): 2.03 (br s, 3H, -CHHCH2-), 2.22-2.31 (m,

1H, -CHHCH2- ), 3.08 (br s, 3H, Me), 3.29 (br s, 6H, 2×Me), 3.46-3.60 (m, 4H, CH2NH and

CH2NMe3), 4.43 (br s, 1H, CHNH ), 5.20 (br s, 2H, CH2Ph), 7.35-7.51 (m, 5H, ArH); δC (75

MHz, CD3OD): 23.41, 31.30, 45.81, 52.88, 66.91, 67.72, 69.16, 127.46, 127.76, 128.17,

128.65, 155.51; m/z 277.2 (positive ion).

(S)-N,N,N-Trimethyl-1-(pyrrolidin-2-yl)methanaminium bromide (51).107


To the solution of corresponding compound 50 (589.5 mg, 1.65 mmol) in EtOH (30 mL),

20% Pd(OH)2/C (4.77 mg, 0.17 mmol, 0.1 equiv.) was added. The reaction mixture was

stirred under 1 atm H2 at room temperature overnight. After filtrating the Pd(OH)2/C,

the solution was concentrated in vacuo to give the crude product. Adding EtOAc (5 mL)

to the crude product and submitting the flask to ultrasounds, the product was solidified.

The corresponding catalyst 51 was obtained by filtration) as a white powder (380.6 mg,

99%, 1.63 mmol); mp 180-185 °C (EtOAc); δH (300 MHz, CD3OD): 1.12-1.47 (m, 1H, -

CHHCH2-), 1.58-1.86 (m, 2H, -CHHCH2-), 1.98-2.31 (m, 1H, -CHHCH2-), 2.68-3.07 (m, 2H,

CH2NH), 3.26 (s, 9H, 3×Me), 3.36 (dd, J = 13.4, 9.0 Hz, 1H, CHNH), 3.50 (dd, J = 13.4, 3.3

Hz, 1H, CHHNMe3), 3.57-3.71 (m, 1H, CHHNMe3); δC (300 MHz, CD3OD): 24.85, 31.06,

46.43, 53.18, 53.38, 70.04; m/z 143.1 (positive ion).


133


Scheme 77. Model reaction for the synthesis of the compound 52a.

β-nitrostyrene (15 mg, 0.10 mmol) was dissolved in a mixture of 51:Gly (1:2 molar ratio,

0.1 g) and kept under stirring for 10 minutes at room temperature. Then, the

cyclohexanone (20 µL, 0.20 mmol) was added. The reaction was vigorously stirred for

1 day. After this period, ethyl acetate (1 mL) was added to the mixture and the reaction

sonicated for 1 minute. Then, the organic phase was collected, and the mixture was

extracted again two times with 1 mL of ethyl acetate under ultrasound irradiation. The

combination of organic solvents was evaporated under reduced pressure to give the

crude product. Purification by flash column chromatography on silica gel

(hexane/EtOAc: 4/1) afforded pure (18.5 mg, 75%, 0.08 mmol). The enantiomeric

excess 52a was determined by chiral HPLC analysis (Chiralpack AD, hexane/iPrOH:

90/10, 1 mL/min).


β-nitrostyrene (15 mg, 0.10 mmol) was dissolved in a mixture of 51:Gly (1:2 molar ratio,

0.1 g) and kept under stirring for 10 minutes at room temperature. Then, the

cyclohexanone (20 µL, 0.20 mmol) was added. The reaction was vigorously stirred for

1 day. After this period, ethyl acetate (1 mL) was added to the mixture and the reaction

sonicated for 1 minute. After this period, the organic phase was collected, and the

mixture was extracted again two times with 1 mL of ethyl acetate under ultrasound

irradiation. The combination of organic solvent was evaporated under reduced

pressure to give crude product. Then, the next reaction cycle was performed with the

obtained 51:Gly mixture, adding fresh β-nitrostyrene and cyclohexanone. This reaction

mixture was subjected again to the above-described procedure and further reaction

cycles were repeated using the recycled deep eutectic solvent phase.


134


(S)-2-((R)-2-Nitro-1-phenylethyl)cyclohexanone (52a)108

Yield 75%, yellow solid; mp 122-130 °C, H (300 MHz, CDCl3): 1.23-1.31 (m, 2H), 1.60-

1.78 (m, 3H), 2.07-2.12 (m, 1H), 2.40-2.48 (m, 2H), 2.70-2.75 (m, 1H), 3.74-3.82 (td, J =

9.9, 4.6 Hz, 1H), 4.62-4.69 (dd, J = 12.5, 9.9 Hz, 1H), 4.89-4.99 ((dd, J = 12.5, 4.5 Hz, 1H),

7.16-7.20 (m, 2H), 7,28-87,37 (m, 3H).

(S)-2-((R)-1-(4-Methoxyphenyl)-2-nitroethyl)cyclohexanone (52b)108

Yield 42%, white solid; mp 133-134 °C, H (300 MHz, CDCl3): 1.22–1.34 (m, 2H), 1.64-

1.74 (m, 4H), 2.07-2.12 (m, 1H), 2.36-2.52 (m, 1H), 2.62-2.68 (m, 1H), 3.69-3.74 (m, 1H),

3.79 (s, 3H), 4.57-4.61 (m, 1H), 4.90-4.93 (dd, J = 12.3, 4.6 Hz, 1H), 6.84 (d, J = 8.7 Hz,

1H), 7.06 (d, J = 8.7 Hz, 2H).

(S)-2-((R)-1-(4-Chlorophenyl)-2-nitroethyl)cyclohexanone (52c)108

Yield 53%, white solid; mp 132-137 °C, H (300 MHz, CDCl3): 1.19-1.28 (m, 1H), 1.57-

1.83 (m, 4H), 2.08-2.13 (m, 1H), 2.35-2.42 (m, 1H), 2.46-2.51 (m, 1H), 2.63-2.68 (m, 1H,

108 Yu, C.; Qiu, J.; Zheng, F.; Zhong, W. Tetrahedron Lett. 2011, 52, 3298-3302.


135

m), 3.74-3.79 (m, 1H), 4.59-4.63 (m, 1H), 4.92-4.96 (m, 1H), 7.11-7.14 (m, 2H), 7.29-

7.32 (m, 2H).

(S)-2-((R)-2-nitro-1-phenylethyl)cyclopentanone (52d)108

Yield 63%, white solid, mp 115-118 °C, H (300 MHz, CDCl3):1.43-1.54 (m, 2H), 1.61-

1.76 (m, 1H), 1.82-1.96 (m, 2H), 2.06-2.18 (m, 1H), 2.31-2.43 (m, 2H), 3.66-3.73 (m, 1H),

4.73 (dd, J = 10.0, 12.9 Hz, 1H), 5.35 (dd, J = 5.6, 12.9 Hz, 1H), 7.15-7.20 (m, 2H), 7.24-

7.34 (m, 3H)

(R)-5-Nitro-4-phenylpentan-2-one (52e)108

Yield 71%, white solid; mp 120-122°C, H (300 MHz, CDCl3): 2.11 (s, 3H), 2.91 (d, J = 7.6

Hz, 2H), 3.92-4.07 (m, 1H), 4.59 (dd, J = 12.3 Hz and 7.6 Hz, 1H), 4.69 (dd, J = 12.3 Hz

and 7.0 Hz, 1H), 7.14-7.19 (m, 2H), 7.26-7.38 (m, 3H).

(3R,4R)-3-methyl-5-nitro-4-phenylpentan-2-one108

Yield %, colourless oil; H (300 MHz, CDCl3): 0.99 (d, J = 7.4 Hz, 3H), 2.23 (s, 3H), 2.92-

3.00 (m, 1H), 3.67 (td, J = 9.2, 5.4 Hz, 1H), 4.70-4-61 (m, 2H), 7.12-7.15 (m, 2H), 7.24-

7.32 (m,·H).


137

3.5. Conclusions

The first efficient Chiral Deep Eutectic Solvents have been developed in an easy

manner employing non-expensive reactants. Moreover, the CDES have been used a

biphasic catalytic system in the Michael addition of ketones to nitroalkenes obtaining

moderate yields and selectivities. Finally, a recovery study of the catalytic system has

been carried out using ethyl acetate as extraction agent in four catalytic cycles,

achieving excellent conversion and moderate selectivity in all the experiments.

139

ABBREVIATIONS

Abbreviations

141

1H-NMR Proton nuclear magnetic resonance

13C-NMR Carbon nuclear magnetic resonance

2D-NMR Two dimensional nuclear magnetic resonance

2Me-THF 2-Methyl tetrahydrofuran

Ac Acetyl group

aq. Aqueous

Ar Aromatic

β-CD β-Cyclodextrin

Boc Tert-butoxycarbonyl protecting group

br s Broad signal

Bn Benzyl group

CAL-B Candida Antarticia

calcd. Calculated

CAM Cost of Academic Methodologies

CAN Cerium ammonium nitrate

cat. Catalyst

Cbz Benzyl chloroformate

CDES Chiral deep eutectic solvents

ChCl Choline chloride

conc. Concentrated

Conv. Reaction conversion

CSA Camphorsulfonic acid

d Doublet

DBAB Di-tert-butyl azodicarboxylate

DBAD Benzyl azodicarboxylate

DCC N,N'-Dicyclohexylcarbodiimide

DCE 1,2-Dichloroethane

DCM Dichloromethane

DD Sum of the changes in the molecular shift

DEAD Diethyl azodicarboxylate

DES Deep Eutectic Solvents

DFT Density functional theory

DHPM 3,4-dihydropyrimidin-2-one

DIAD Diisopropyl azodicarboxylate

Abbreviations

142

DIP Direct injection process

DMA Dimethylacetamide

DMAP 4-(Dimethylamino)pyridine

DME 1,2-Dimethoxyethane

DMF N,N-dimethylformamide

DMSO Dimethyl sulfoxide

DMU Dimethylurea

DIPEA N,N-Diisopropylethylamine

DSC Differential Scanning Calorimetry

de Diastereomeric excess

dr Diastereomeric ratio

ee Enantiomeric excess

EG Ethylene glycol

EI Electron impact mode

equiv. Equivalents

EWG Electron-withdrawing group

FT Fourier transform

GC Gas chromatography

Gly Glycerol

GO Graphene oxide

h Hours

HBA Hydrogen bond acceptor

HBD Hydrogen bond donor

HMF Hydroxymethylfurfural

HOMO Highest energy occupied molecular orbital

HPLC High performance liquid chromatography

HRMS High resolution mass spectrometry

iBu Isobutyl

IL Ionic liquid

IPA 2-Propanol

IR Infrared

LA Lewis acid

LED Light-emitting diode

LUMO Lowest energy unoccupied molecular orbital

Abbreviations

143

m Multiplet

m- Meta-substitution

mCPBA m-Chloroperbenzoic acid

M Molarity

MHz Megahertz

min Minutes

MS Mass spectrometry or molecular sieves

mp Melting point

MTBE Methyl tert-butyl ether

MW Microwave

NADES Natural deep eutectic solvents

NCS N-Chlorosuccinimide

NOE Nuclear Overhauser effect

NOESY Nuclear Overhauser effect spectroscopy

o- Ortho-substitution

OAc Acetate group

OBz Benzoate group

OMs Mesylate group

p- Para-substitution

p-TSA p-Toluenesulfonic acid

PEG Polyethylene glycol

PG Protecting group

Ph Phenyl

pKa Negative decadic logarithm of the dissociation constant K of an

acid (pKa = –logKa)

PMP p-Methoxyphenyl

Pro L-Proline

q Quartet

quant. Quantitative

RT Room temperature

s Singlet or seconds

sat. Saturated

SET Single electron transfer

SOMO Singly occupied molecular orbital

Abbreviations

144

t Time and also triplet

T Temperature

TBME Tert-butyl methyl ether

Tf Trifluoromethanesulfonic group (triflic group)

TEA Trimethylamine

TFA Trifluoroacetic acid

THF Tetrahydrofuran

TLC Thin layer chromatography

TMS Tetramethylsilane

Ts Tosyl group

UN United Nations

UV Ultraviolet

VOC Volatile organic solvents

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