New Methodologies for the Catalytic Enantioselective Addition of Organometallic Reagents to Carbonyl Compounds
New methodologies for the catalytic enantioselective addition of organometallic reagents to carbonyl compounds
Emilio Fernández Mateos
Instituto de Síntesis Orgánica (ISO)
New methodologies for the catalytic enantioselective addition of organometallic reagents to carbonyl compounds
Memoria para optar al Título de Doctor Internacional por la Universidad de Alicante presentada por el licenciado:
EMILIO FERNÁNDEZ MATEOS
Alicante, junio de 2015
V.º B.º de la Directora:
Fdo.: Dra. Beatriz Maciá Ruiz Lecturer in Organic Chemistry (Manchester Metropolitan University)
Instituto de Síntesis Orgánica (ISO), Facultad de Ciencias, Fase I, Universidad de Alicante Campus de Sant Vicent del Raspeig, Apdo. 99, E-03080 Alicante, España Tel. +34 965903400, ext. 2121; +34 965903549; Fax +34 965903549 http://iso.ua.es; [email protected]
A mis padres
Table of contents
Table of contents
Resumen ...... 11
Preface ...... 33
General objectives ...... 37
Chapter I ...... 41
1. Introduction ...... 41 1.1. History of Ar-BINMOL ligands ...... 41 1.2. Applications of Ar-BINMOL ligands ...... 43 2. Results and discussion ...... 45 3. Experimental part ...... 45 3.1. Synthesis of monobenzylated (S)-BINOL derivatives I1-10 ...... 45 3.2. Data of hydroxyethers (S)-I1 and (S)-I10 ...... 50 3.3. Synthesis of chiral Ar-BINMOL ligands L1-10 ...... 51 3.4. Data of chiral Ar-BINMOL ligands L1-10 ...... 52
3.5. Synthesis of chiral Ar-BINMOL ligand (Sa,S)-L1 ...... 58
3.6. Data of chiral Ar-BINMOL ligand (Sa,S)-L1 ...... 58
Chapter II ...... 63
1. Introduction ...... 63 1.1. Stoichiometric and superstochiometric enantioselective addition of organolithium reagents to aldehydes ...... 64 1.2. Catalytic enantioselective addition of organolithium reagents to aldehydes ...... 74 2. Results and discussion ...... 79 2.1. Optimization of the catalytic enantioselective addition of organolithium reagents to aldehydes ...... 79 2.2. Scope of the reaction ...... 83 3. Experimental part ...... 89 3.1. General procedure for the enantioselective addition of organolithium reagents to aldehydes ...... 89 3.2. Data of chira secondary alcohols prepared from organolithium reagents ...... 89
Table of contents
Chapter III ...... 103
1. Introduction...... 103 1.1. Stoichiometric and superstoichiometric enantioselective addition of organomagnesium reagents to aldehydes ...... 105 1.2. Catalytic enantioselective addition of Grignard reagents to aldehydes ...... 110 1.3. Catalytic enantioselective addition of Grignard reagents to ketones ...... 113 2. Results and discussion ...... 117 2.1. Optimization of the catalytic enantioselective addition of Grignard reagents to aromatic aldehydes ...... 117 2.2. Scope of the reaction ...... 121 2.3. Application of the methodology: Synthesis of 2-substituted chiral tetrahydropyranes .. 125 3. Experimental part ...... 129 3.1. General procedure for the enantioselective addition of Grignard reagents to aromatic aldehydes ...... 129 3.2. Data of chiral secondary alcohols prepared from Grignard reagents...... 129 3.3. General procedure for the intramolecular cyclization of 4-chlorobutyl alcohols into 2- substituted chiral tetrahydropyrans ...... 136 3.4. Data of 2-substituted chiral tetrahydropyrans ...... 136 4. Results and discussion ...... 139 4.1. Optimization of the catalytic enantioselective addition of Grignard reagents to aliphatic aldehydes ...... 139 4.2. Scope of the reaction ...... 142 4.3. Mechanistic aspects ...... 144 5. Experimental part ...... 149 5.1. General procedure for the enantioselective addition of Grignard reagents to aliphatic aldehydes ...... 149 5.2. Data of chiral secondary aliphatic alcohols ...... 149 5.3. Procedure for the derivatization of chiral secondary aliphatic alcohols into the corresponding esters ...... 154 5.4. Data of chiral esters...... 155 6. Results and discussion ...... 159 6.1. Catalytic enantioselective arylation of ketones with Grignard reagents ...... 159 6.2. Scope of the reaction ...... 162 7. Experimental part ...... 167 7.1. General procedure for the enantioselective arylation of ketones with Grignard reagents167 7.2. Data of chiral tertiary alcohols ...... 167
Table of contents
Chapter IV ...... 179
1. Introduction...... 179 1.1. Catalytic enantioselective addition of organoaluminum reagents to aldehydes ...... 180 2. Results and discussion ...... 187 2.1. Optim. of the cat. enantioselec. addition of organoaluminum reagents to aldehydes ... 187 2.2. Scope of the reaction ...... 191 3. Experimental part ...... 195 3.1. General procedure for the enantioselective addition of organoaluminum reagents to aldehydes ...... 195 3.2. Data of chiral secondary alcohol prepared from organoaluminum reagents...... 195
General conclusions ...... 203
Experimental part (General information) ...... 207
RESUMEN
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1. Introducción general
1.1. Síntesis de alcoholes quirales
La adición nucleófila de reactivos organometálicos a compuestos carbonílicos es un método versátil y eficiente para generar enlaces C–C. Desde el punto de vista sintético, es una metodología especialmente atractiva, pues el producto generado en la reacción es un alcohol secundario o terciario que contiene un nuevo centro estereogénico, fragmento presente en numerosos productos naturales y/o con actividad biológica. (Esquema 1).
Esquema 1. Adición enantioselectiva de reactivos organometálicos a compuestos carbonílicos.
La adición enantioselectiva de reactivos organozíncicos y de alquilaluminio a aldehídos ha sido extensamente estudiada tanto en su versión estequiométrica como catalítica. Sin embargo, para compuestos organometálicos más reactivos, como organomagnesianos y organolíticos, el desarrollo ha sido menor y actualmente, su versión catalítica está siendo estudiada con resultados incipientes para reactivos de Grignard y organolíticos.
La principal desventaja de los reactivos organomagnesianos y organolíticos frente a organozíncicos, es su elevada reactividad debido a la mayor polaridad del enlace carbono-metal: 1.55 (C–Li), 1.24 (C–Mg) y 0.65 (C–Zn). La alta reactividad de los compuestos de litio y magnesio dificulta el control de la estereoselectividad en procesos de adición y además los hacen incompatibles con ciertos grupos funcionales. Por ello, la investigación en las últimas décadas ha estado enfocada hacia el estudio de otros compuestos organometálicos menos reactivos, como los compuestos organozíncicos. No obstante, una protección adecuada de los grupos funcionales más sensibles puede solucionar el problema de incompatibilidad con
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reactivos organomagnesianos y organolíticos, pudiéndose así aprovechar las ventajas que los mismos presentan, como su precio asequible y la simple y eficaz metodología para sintetizarlos.
La transmetalación de compuestos organolíticos y organomagnesianos con metales menos reactivos como zinc, titanio o cobre, supone una solución eficaz al problema de trabajar con compuestos organometálicos muy reactivos. De esta forma se consigue disminuir in situ la reactividad de dichos compuestos. Sin embargo, este procedimiento supone un problema añadido, y es la generación de sales inorgánicas que favorecen la reacción no catalizada (ausencia de estereocontrol). Además, la eliminación de dichas sales resulta un procedimiento tedioso.
1.2. Subunidad metil carbinol
La subunidad de metil carbinol está presente en numerosos productos naturales y de interés farmacéutico como la Batzelladina F, ácido (S)-mincuartinóico, ácido (E)- 15,16-dihidromincuartinóico y Zearalenona (Esquema 2). Un posible método eficiente para la preparación de esta subunidad, consiste en la adición enantioselectiva de una fuente organometálica de metilo a un aldehído precursor del producto natural deseado.
La fuente de metilo utilizada con más frecuencia en síntesis asimétrica es Me2Zn, debido a la amplia gama de ligandos quirales disponibles para reactivos organozíncicos. Aunque, Me2Zn es un compuesto organometálico poco reactivo y tan solo unos pocos ligandos de los existentes son capaces de activarlo y hacerlo reaccionar de forma selectiva con aldehídos.
Una manera de evitar el uso de Me2Zn (poco reactivo y de coste elevado), es mediante la utilización de otros reactivos organometálicos más reactivos como MeLi,
MeMgBr o Me3Al. Desafortunadamente, la ventaja del menor coste de estos reactivos organometálicos está contrarrestada por la cantidad de ligando quiral requerida en las metodologías no catalíticas.
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Esquema 2. Productos naturales que contienen la subunidad metil carbinol en su estructura.
Con los inicios de la adición 1,2 enantioselectiva catalítica a compuestos carbonílicos con reactivos de Grignard y organolíticos, se abren nuevas posibilidades para la síntesis asimétrica de alcoholes secundarios y terciarios presentes en numerosos productos naturales de forma directa o derivatizados.
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2. Resumen
2.1. Síntesis de ligandos Ar-BINMOL
Se decidió sintetizar ligandos derivados de (S)-BINOL para su utilización en catálisis asimétrica en la adición de reactivos de Grignard a aldehídos. La estructura binaftílica proporciona restricción en la rotación del eje biarílico debido al impedimento estérico ejercido por los dos naftilos. Por otra parte, la sencilla modificación de la estructura de este tipo de ligandos permite modular la actividad catalítica e incluso sus aplicaciones químicas en catálisis asimétrica.
Los ligandos empleados para el propósito de esta memoria son conocidos como Ar- BINMOLs (1,1´-binaftalen-2--arilmetan-2-oles) y han sido descritos en 2011 por Xu. La metodología empleada por nuestro grupo de investigación para la síntesis de estos ligandos consiste en dos pasos de reacción (Esquema 3), mediante una ligera modificación del procedimiento original del grupo de investigación de Xu.
Esquema 3. Síntesis de los ligandos Ar-BINMOL L1-10.
En el primer paso de la síntesis de los ligandos L1-10 (Esquema 3), se hizo reaccionar
(S)-BINOL en presencia de 1.5 eq. K2CO3 y 1 eq. ArCH2Br a reflujo de acetona durante 6 h. Sin embargo, cuando se utilizó bromuro de 4-bromometilpiridinio como electrófilo (I9-10) las condiciones de reacción tuvieron que ser ligeramente
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modificadas para solucionar los problemas de solubilidad de dicho compuesto, utilizando para ello una mezcla 9:1 acetona/H2O como disolvente y 3 eq. K2CO3 durante 12 horas de reacción.
El crudo de la reacción de la síntesis de los intermedios monobencilados (S)-I se utilizó en el siguiente paso de reacción sin necesidad de aislar dichos intermedios. A continuación, los intermedios (S)-I se trataron con 2.5 eq. n-BuLi en THF anhidro, a – 78 ᵒC durante 2 h para obtener los ligandos L1-8 a través de una transposición de
Wittig [1,2] asímetrica (Esquema 3). Por otra parte, los ligandos H8-(Sa,R)-L1 y L9-10 se sintetizaron mediante unas condiciones de reacción más agresivas, empleando 5 eq. n-BuLi en THF anhidro como disolvente, a 70 ᵒC durante 12 horas. Los ligandos Ar-BINMOL se obtuvieron con buenos rendimientos después de dos pasos de reacción y una sola purificación mediante columna cromatográfica, aunque los productos L9-10 se obtuvieron con rendimientos bajos, 40% y 33%, respectivamente, debido a que en la transposición de Wittig [1,2] se produjo (S)-BINOL como subproducto mayoritario de la reacción procedente de la ruptura homolítica del éter bencílico sin dar lugar a la etapa de recombinación de radicales. A pesar de esto, todos los dioles quirales se obtuvieron con excelentes diastereoselectividades en todos los casos (>99%).
Esquema 4. Epimerización del diol (Sa,R)-L1 a (Sa,S)-L1.
Debido al excelente diastereocontrol de la transposición de Wittig [1,2] asimétrica de éteres bencílicos derivados de (S)-BINOL resultó complicado preparar el diasteroisómero opuesto del ligando (Sa,R)-L1 obtenido mediante dicha ruta sintética. Tras varios procedimiento probados, la epimerización del centro
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esterogénico del ligando (Sa,R)-L1 utilizando una mezcla 1:1 THF/HCl(ac) 6 M a 25 ᵒC durante 3 horas resulto la ruta sintética más corta y eficiente (Esquema 4). Así se obtuvo el ligando (Sa,S)-L1 en un solo paso de reacción con un 20% de rendimiento y el correspondiente subproducto de ciclación intramolecular C1 como una mezcla diastereomérica (26% rto., r.d. 6:1).
2.2. Adición enantioselectiva de reactivos organolíticos a aldehídos
Se decido emplear dichos ligandos en diferentes reacciones de adición 1,2. En primer lugar, se probó la alquilación enantioselectiva de aldehídos utilizando reactivos organolíticos.
Los reactivos organolíticos han sido empleados en multitud de reacciones en química orgánica, pero no suelen estar relacionados con la síntesis asimétrica debido su alta reactividad y como consecuencia directa de esto, a su baja tolerancia a ciertos grupos funcionales sensibles. El principal problema de este tipo de reactivos es que la reacción de fondo o no catalizada es mucho más rápida que la reacción catalizada. Para solucionar este problema, varios grupos de investigación han desarrollado diferentes metodologías que consiguen modificar el transcurso de la reacción como por ejemplo: i) utilizar agentes de transmetalación para reducir la reactividad del reactivo organolítico original, ii) empleo de cantidades estequiométricas o superestequiométricas de ligandos quirales para evitar que no haya ninguna especie organolítica libre y pueda atacar directamente al electrófilo en ausencia del ligando, iii) empleo de temperaturas extremadamente (–100 ᵒC) para aumentar los niveles de selectividad, iv) adición lenta del nucleófilo sobre una disolución del correspondiente complejo quiral para disminuir de forma prácticamente total la reacción de fondo o no catalizada.
En nuestro grupo de investigación, se probaron diferentes ligandos Ar-BINMOL sintetizados previamente para la adición enantioselectiva de MeLi a benzaldehído (1a), esta fue la reacción modelo durante todo el proceso de optimización. También se probaron diferentes temperaturas de reacción, metodologías de adición: lenta o
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rápida, disolventes apróticos de distinta polaridad y diferentes proporciones Ti(Oi-
Pr)4/MeLi. La etapa clave de la optimización fue la determinación de la proporción
óptima Ti(Oi-Pr)4/MeLi, ya que pequeñas variaciones en dicha relación entre el nucleófilo y el agente de transmetalación afectaban de forma drástica al ee. Finalmente, la proporción adecuada para este sistema catalítico fue 1.9:1.
Otra peculiaridad de este sistema a destacar, es la necesidad de adicionar el electrófilo rápidamente (aproximadamente 20 s) previa adición del nucleófilo, ya que en caso contrario se obtenían conversiones inferiores al 20% aunque el exceso enantiomérico permanecía constante. Por tanto, se deduce de esto que las especies activas de alquiltitanio resultantes de la transmetalación tienen una vida media corta y además cabe la posibilidad de que no todas las especies generadas in situ sean activas en el proceso catalítico.
Las condiciones óptimas para la alquilación enantioselectiva de aldehídos con reactivos organolíticos fueron: 3.2 eq. RLi, 6 eq. Ti(Oi-Pr)4, 20% mol (Sa,R)-L1, tolueno como disolvente, –40 ᵒC de temperatura de reacción y durante 1 hora. Con las condiciones de reacción optimizadas se consiguió la adición enantioselectiva de MeLi a una gran variedad de aldehídos aromáticos con excesos enantioméricos comprendidos entre 62% y 90% y muy buenos rendimientos (Esquema 5). El sistema presentó algunas limitaciones como el uso de aldehídos aromáticos con sustituyentes en posición orto-, ya que la enantioselectividad disminuyó notablemente cuando se utilizó este tipo de aldehídos (62% ee, o-metilbenzaldehído). El uso de aldehídos alifáticos también produjo una disminución en el exceso enantiomérico de los correspondientes alcoholes quirales metilados.
Esquema 5. Adición enantioselectiva de EtLi y n-BuLi a aldehídos aromáticos catalizada por (Sa,R)-L1.
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También se utilizaron otros nucleófilos alifáticos como EtLi o n-BuLi ofreciendo los correspondientes productos de adición a aldehídos aromáticos con excelentes excesos enantioméricos comprendidos entre 90% y 96% y rendimientos de buenos a excelentes (Esquema 6). Cabe destacar, que bajo las condiciones de reacción previamente descritas fue posible la utilización de sustratos con grupos sensibles a reactivos organolíticos, como un carbamato (1p).
Esquema 6. Adición enantioselectiva de EtLi y n-BuLi a aldehídos aromáticos catalizada por (Sa,R)-L1.
Una limitación adicional de la metodología fue la imposibilidad de adicionar i-BuLi, probablemente debido a ser voluminoso y tampoco se obtuvieron resultados buenos cuando se utilizó en nucleófilo sp2 PhLi. En este caso, los rendimientos fueron excelentes (>92%), pero las enantioselectividades fueron inferiores a 39% en todas las pruebas realizadas.
2.3. Adición enantioselectiva de reactivos de Grignard a aldehídos aromáticos
Los ligandos Ar-BINMOL también se utilizaron en la alquilación enantioselectiva de aldehídos aromáticos utilizando reactivos de Grignard como nucleófilos.
Los reactivos de Grignard han sido empleados en química orgánica en muchos procesos sintéticos, pero su aplicación a la síntesis asimétrica y más concretamente a la catálisis está en pleno proceso de evolución debido al surgimiento de nuevos ligandos y metodologías que permiten trabajar con dichos compuestos organometálicos. Y es que la principal desventaja es su elevada reactividad y como consecuencia de esto, presentan una baja tolerancia a ciertos grupos funcionales sensibles. Al igual que los reactivos organolíticos, los reactivos de Grignard debido a
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su elevada reactividad, la reacción de fondo o no catalizada es mucho más rápida que la reacción catalizada. Para solucionar este problema, existen diferentes metodologías que consiguen modificar el transcurso de la reacción mediante: i) el uso de agentes de transmetalación para reducir la reactividad del reactivo organolítico original, ii) empleo de cantidades estequiométricas o superestequiométricas de ligandos quirales para evitar que no haya ninguna especie organolítica libre y pueda atacar directamente al electrófilo en ausencia del ligando, iii) empleo de temperaturas extremadamente (–100 ᵒC) para aumentar los niveles de selectividad, iv) adición lenta del nucleófilo sobre una disolución del correspondiente complejo quiral para disminuir de forma prácticamente total la reacción de fondo o no catalizada.
Sin embargo, este tipo de reactivos presentan varias ventajas a tener muy en cuenta: (i) son fáciles de sintetizar mediante reacción directa del correspondiente haluro de alquilo o arilo y limaduras de magnesio o haciéndolo reaccionar con otro reactivo de Grignard, (ii) son altamente estables a temperatura ambiente y pueden ser almacenados, (iii) tienen un precio asequible comparado con los reactivos organozíncicos que son los más utilizados en catálisis asimétrica, (iv) la adición de dioxano a una disolución etérea de un reactivo de Grignard causa la precipitación del dihaluro de magnesio (MgX2) y esto causa el desplazamiento del equilibrio de Schlenk hacia la formación de otro tipo de reactivos organomagnesianos (R2Mg).
En nuestro grupo de investigación, se probaron diferentes ligandos Ar-BINMOL sintetizados previamente para la adición enantioselectiva de MeMgBr a benzaldehído (1a), esta fue la reacción modelo durante todo el proceso de optimización. También se probaron diferentes temperaturas de reacción, metodologías de adición: lenta o rápida, disolventes apróticos de distinta polaridad, distintas fuentes de titanio y diferentes proporciones Ti(Oi-Pr)4/MeMgBr. La etapa clave de la optimización fue la determinación de la proporción óptima Ti(Oi-Pr)4/MeMgBr ya que pequeñas variaciones en dicha relación entre el nucleófilo y el agente de transmetalación afectaban de forma drástica al exceso enantiomérico. Finalmente, la proporción
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adecuada para este sistema catalítico fue 4:1. Para el caso particular de los reactivos de Grignard, se añadió el electrófilo 15 min después de haber adicionado el correspondiente RMgBr sin observar ningún efecto sobre el rendimiento del producto deseado.
Las condiciones óptimas para la alquilación enantioselectiva de aldehídos aromáticos con reactivos de Grignard fueron: 3.8 eq. RMgBr, 15 eq. Ti(Oi-Pr)4, 20% mol (Sa,R)-L1, tolueno como disolvente, –40 ᵒC de temperatura de reacción y durante 4 horas.
Con las condiciones de reacción optimizadas se consiguió la adición enantioselectiva de MeMgBr a una amplia variedad de aldehídos aromáticos con excesos enantioméricos comprendidos entre 53% y 90% y muy buenos rendimientos (Esquema 7). El sistema presentó algunas limitaciones como el uso de aldehídos aromáticos con sustituyentes en posición orto-, es decir, cercanos al centro reactivo, causando una disminución del exceso enantiomérico notable cuando se empleó este tipo de aldehídos (53% ee, o-metilbenzaldehído). El uso de aldehídos alifáticos (cinamaldehído y 2-fenilacetaldehído) y heterocíclicos (2-tiofenocarbaldehído) también produjeron una disminución en el exceso enantiomérico de los correspondientes alcoholes quirales metilados.
Esquema 7. Adición enantioselectiva de MeMgBr a aldehídos aromáticos catalizada por (Sa,R)-L1.
También se utilizaron otros nucleófilos alifáticos como EtMgBr o n-BuMgBr ofreciendo los correspondientes productos de alquilación de aldehídos aromáticos con excesos enantioméricos de buenos a excelentes, comprendidos entre 72% y 96% y rendimientos excelentes (Esquema 8). En este caso, el uso de i-BuMgBr como nucleófilo, a pesar de ser voluminoso, fue posible en la adición a benzaldehído (1a) obteniendo un 86% ee y 91% de rendimiento.
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Esquema 8. Adición enantioselectiva de EtMgBr, n-BuMgBr y i-BuMgBr a aldehídos aromáticos
catalizada por (Sa,R)-L1.
Como aplicación de esta metodología, se propuso la síntesis de tetrahidropiranos quirales sustituidos en posición 2, mediante dos pasos de síntesis (Esquema 9). El primer paso de reacción, consistió en la adición enantioselectiva de (4- clorobutil)MgBr a diferentes aldehídos aromáticos con sustituyentes en posición meta y para con excelentes selectividades (92%-98% ee) y rendimientos moderados, debido a la aparición de un subproducto derivado de la adición de butilo. En el segundo paso de reacción se hicieron reaccionar los alcoholes cloroalquílicos (2) con terc-butóxido de potasio en THF a 25 ᵒC para producir la correspondiente ciclación intramolecular y obtener así los productos deseados (3) con conversión completa en la mayoría de los casos sin observar perdida de exceso enantiomérico durante el proceso.
Esquema 9. Síntesis de tetrahidropiranos quirales sustituidos en posición 2.
Como limitaciones de la metodología fue la imposibilidad de adicionar nucleófilos secundarios (isopropilo o ciclohexilo), terciarios (terc-butilo), sp2 (fenilo, vinilo), conjugados (alilo y bencilo). Los nucleófilos secundarios y terciarios al ser voluminosos produjeron conversiones muy bajas o nulas y el producto racémico. Sin embargo, la adición de nucleófilos sp2 a benzaldehído fue racémica, pero con rendimientos buenos.
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2.4. Adición enantioselectiva de reactivos de Grignard a aldehídos alifáticos
Una de las limitaciones que presentaba la metodología de adición de reactivos de Grignard a aldehídos y es que la alquilación de ciclohexanocarbaldehído con n- BuMgBr solo se pudo obtener con un máximo de 50% ee y 98% de rendimiento.
Por eso, se decidió mejorar la metodología para intentar conseguir la alquilación enantioselectiva de aldehídos alifáticos. Los alcoholes alifáticos secundarios resultantes de la adición son muy interesantes desde el punto de vista sintético ya que están presentes en la estructura de numerosos productos naturales y farmacéuticos. Además, la síntesis de este tipo de alcoholes a través de otras metodologías no ha sido estudiada en profundidad, ni siquiera con los reactivos organozíncicos que son los más empleados en las adiciones 1,2 a carbonilos, debido a una serie de particularidades que presentan este tipo de sustratos: (i) tienen múltiples conformaciones y por tanto esto dificulta la aproximación selectiva del complejo quiral por una las caras del carbonilo, (ii) al no poseer ningún grupo aromático, este tipo de sustratos no tienen interacción – con el ligando, (iii) tienen un alto carácter enolizable debido a la presencia de hidrógenos ácidos en posición alfa al carbonilo.
Tomando como reacción modelo la adición de n-BuMgBr a ciclohexanocarboxaldehído, se procedió a la optimización y para ello se probaron diferentes ligandos Ar-BINMOL. También se probaron diferentes temperaturas de reacción, metodologías de adición: lenta o rápida, disolventes apróticos de distinta polaridad y diferentes proporciones Ti(Oi-Pr)4/n-BuMgBr. La etapa clave de la optimización fue la determinación de la proporción óptima Ti(Oi-Pr)4/n-BuMgBr ya que pequeñas variaciones en dicha relación entre el nucleófilo y el agente de transmetalación afectaban de forma drástica al exceso enantiomérico. Como se vio en el apartado anterior, la proporción correcta entre tetraisopropóxido de titanio y los reactivos de Grignard para este sistema catalítico también fue 4:1.
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Las condiciones óptimas para la alquilación enantioselectiva de aldehídos alifáticos con reactivos de Grignard fueron: 2.5 eq. RMgBr, 10 eq. Ti(Oi-Pr)4, 20% mol (Sa,R)-
L10, Et2O como disolvente, –20 ᵒC de temperatura de reacción y durante 3 horas. Las nuevas condiciones de reacción que son mucho más suaves que las anteriormente descritas y además emplea menos cantidad de nucleófilo, Ti(Oi-Pr)4 y mayor temperatura de reacción. Esto fue posible gracias a la utilización del nuevo ligando
(Sa,R)-L10 que posee un anillo de piridina en su estructura y que afecta de forma positiva a la enantioselectividad del producto, aunque todavía se desconoce su función en el mecanismo de la reacción.
Con las condiciones de reacción optimizadas se consiguió la adición enantioselectiva de n-BuMgBr y EtMgBr a diferentes aldehídos alifáticos lineales, cíclicos y de pequeño tamaño (como acroleina) con excesos enantioméricos comprendidos entre 77% y 96% y muy buenos rendimientos (Esquema 10). Cabe destacar el uso de 2- metilpentanal como electrófilo, ya que se obtuvo el alcohol derivado de la adición de etilo con poca diastereoselectividad (1:1.3 r.d.), pero con muy buena enantioselectividad (77% y 87% ee, respectivamente).
Esquema 10. Adición enantioselectiva de EtMgBr, n-BuMgBr a aldehídos alifáticos catalizada por (Sa,R)- L10.
Por otra parte, también fue posible la adición de MeMgBr a una amplia variedad de sustratos alifáticos lineales, cíclicos y -sustituidos y se obtuvieron los correspondientes alcoholes ópticamente activos con excesos enantioméricos comprendidos entre 60% y 99% con rendimientos de moderados a buenos (Esquema 11). Curiosamente el sustrato más rígido (fenilpropinal) debido a la presencia del triple en la estructura produjo un descenso en el exceso enantiomérico (60% ee) comparado con análogos estructurales como cinamaldehído o 3-fenilpropanal. El
Resumen
aldehído más voluminoso de todos, pivalaldehído, resulto ser positivo ya que se obtuvo el mejor exceso enantiomérico (>99% ee) de toda la serie de productos.
Esquema 11. Adición enantioselectiva de MeMgBr a aldehídos alifáticos catalizada por (Sa,R)-L10. 2.5. Arilación enantioselectiva de reactivos de Grignard a cetonas
Las cetonas son sustratos muy interesantes desde el punto de vista sintético ya que permiten la adición de diferentes nucleófilos para obtener los correspondientes alcoholes terciarios, pero la principal desventaja que presentan es su baja reactividad comparadas con los aldehídos. Este tipo de alcoholes son muy valiosos en química orgánica, ya que están presentes en numerosos productos naturales y farmacéuticos, además no existen muchos procedimientos efectivos que permitan la síntesis de forma enantioselectiva.
La adición de reactivos organometálicos a cetonas ha sido ampliamente estudiada con compuestos organozíncicos obteniendo buenos resultados tanto para la adición de nucleófilos sp3 como sp2. Sin embargo, hasta hace 3 años, no existía ningún procedimiento catalítico que permitiera la adición de reactivos de Grignard alifáticos a cetonas empleando un complejo Josiphos-Cu y una metodología de adición lenta del nucleófilo. Hasta la actualidad, no existe ninguna metodología que permita la adición de nucleófilos sp2 organomagnesianos.
Nuevamente, se emplearon los ligandos Ar-BINMOL en la arilación asimétrica de cetonas con reactivos de Grignard. Para ello, se tomo como reacción modelo para todo el proceso de optimización la adición de PhMgBr a acetofenona. En la optimización, se ajustaron diferentes parámetros de la reacción como: temperatura de reacción, ligandos Ar-BINMOL, metodologías de adición: lenta o rápida,
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disolventes apróticos de distinta polaridad y diferentes proporciones Ti(Oi-
Pr)4/PhMgBr. Una vez más, la etapa clave de la optimización fue la determinación de la proporción óptima Ti(Oi-Pr)4/PhMgBr, ya que pequeñas variaciones en dicha relación entre el nucleófilo y el agente de transmetalación afectaban de forma drástica al exceso enantiomérico del producto. Como ya se ha descrito en apartados anteriores, la proporción óptima entre Ti(Oi-Pr)4 y cualquier reactivo de Grignard en nuestro sistema catalítico es siempre 4:1.
Las condiciones óptimas para la arilación enantioselectiva de aril aquil cetonas con reactivos de Grignard fueron: 2.5 eq. ArMgBr, 10 eq. Ti(Oi-Pr)4, 20% mol (Sa,R)-L7,
Et2O como disolvente, 0 ᵒC de temperatura de reacción y durante 12 horas. Esto fue posible gracias a la utilización del nuevo ligando (Sa,R)-L10 que posee un naftilo unido por la posición 1 al carbono bencílico en su estructura y que ofreció las enantioselectividades más altas de toda la serie de ligandos probados, probablemente debido a que era el más voluminoso.
Con las condiciones de reacción optimizadas se consiguió la adición enantioselectiva de PhMgBr a una amplia variedad de aril metil cetonas con excesos enantioméricos comprendidos entre 46% y 80% y rendimientos de bajos a moderados (Esquema 12), debido a la baja reactividad de las cetonas. El sistema presentó algunas limitaciones como el uso de cetonas aromáticas con sustituyentes en posición orto-, es decir, cercanos al centro reactivo, causando una disminución brusca del rendimiento (12% conv., o-metilacetofenona). La adición de PhMgBr a cetonas donde el grupo alquilo es voluminoso produce un efecto positivo en la enantiodiscrimianción de las caras del carbonilo, pero el aumento del impedimento estérico por la presencia de un grupo voluminoso causa una disminución del rendimiento (35 rto., 84% ee, 4j). Por otra parte, las cetonas cíclicas benzofusionadas al poseer una estructura más rígida favorecen el aumento del exceso enantiomerio comparado con las cetonas acíclicas.
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Esquema 12. Adición enantioselectiva de PhMgBr a alquil aril cetonas catalizada por (Sa,R)-L7.
Esta metodología también permitió el uso de otros reactivos de Grignard aromáticos con sustituyentes electrondonores (-OMe), electronatractores (-F) y neutros (-Me) en posición para del anillo aromático del nucleófilo (Esquema 13). Los excesos enantioméricos obtenidos estuvieron comprendidos entre 64% y 82% y, en general, los rendimientos fueron superiores al análogo PhMgBr.
Esquema 13. Adición enantioselectiva de PhMgBr a aril alquil cetonas catalizada por (Sa,R)-L7.
La limitación de esta metodología es el empleo de sustratos totalmente alifáticos, como ciclohexil metil cetona, ya que a la temperatura óptima de la reacción (0 ᵒC) no se produjo reacción.
2.6. Adición enantioselectiva de reactivos de organoaluminio a aldehídos
Los reactivos de organoaluminio han sido utilizados en química orgánica en gran variedad de reacciones, incluida las adiciones enantioselectivas a aldehídos y cetonas. En cuanto a catálisis asimétrica, existen varios complejos quirales de aluminio que son empleados en síntesis enantioselectiva, pero la reacción en si no implica transferencia de un grupo alquilo o arilo procedente del reactivo de organoaluminio a un electrófilo, normalmente son empleados como ácidos de Lewis quirales.
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Una de las principales ventajas que presentan este tipo de reactivos es que son comercialmente asequibles, pueden sintetizarse a gran escala y además es posible su empleo en reacciones a escala industrial. Otra ventaja adicional es que los compuestos de organoaluminio son muy estables a temperatura ambiente, por lo que se pueden almacenar fácilmente y además presentan una baja toxicidad.
Se decidió probar la adición enantioselectiva de reactivos organometálicos a aldehídos. Como reacción modelo para optimizar se escogió, la adición de Me3Al a benzaldehído (1a). Durante el proceso de optimización se variaron diferentes parámetros de la reacción como: temperaturas de reacción, metodologías de adición: lenta o rápida, disolventes apróticos de distinta polaridad, distintos ligandos Ar-
BINMOL y diferentes proporciones Ti(Oi-Pr)4/Me3Al. El sistema catalítico se mostro bastante robusto y pequeñas variaciones en las proporciones de Ti(Oi-Pr)4/Me3Al no causaron variaciones significativas en la enantioselectividad, aunque la proporción óptima para reactivos de organoalumnio fue 2.7:1.
Las condiciones óptimas para la alquilación enantioselectiva de aldehídos con reactivos de organoaluminio fueron: 1.5 eq. R3Al, 4 eq. Ti(Oi-Pr)4, 10% mol (Sa,R)-L1, tolueno como disolvente, 0 ᵒC de temperatura de reacción y durante 1-3 horas. Con las condiciones de reacción previamente descritas, se consiguió la adición enantioselectiva de Me3Al a una amplia variedad de aldehídos con excesos enantioméricos comprendidos entre 62% y 98% y muy buenos rendimientos
(Esquema 14). La adición de Me3Al aldehídos heteroaromáticos y alifáticos de pequeño tamaño (1n) se produjo con muy buenas enantioselectividades, pero rendimientos bajos debido a la volatilidad de los productos durante el proceso de purificación. Cabe destacar, que se puede utilizar aldehídos aromaticos con sustituyentes en posición orto-, aunque se observó un descenso en el ee.
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Esquema 14. Adición enantioselectiva de Me3Al a aldehídos catalizada por (Sa,R)-L1.
También fue posible la adición a aldehídos de otros reactivos de organoaluminio alifáticos como: Et3Al y n-Pr3Al (Esquema 15). La etilación de aldehídos aromáticos se produjo con excelentes excesos enantioméricos (87%-92%), pero con moderados rendimientos comparado con los alcoholes metilados. Sin embargo, mejores enantioselectividades (92%-94%) se obtuvieron para la adición de n-Pr3Ar a aldehídos aromáticos e incluso alifáticos (1q), a costa de unos rendimientos muy bajos.
Esquema 15. Adición enantioselectiva de Et3Al y n-Pr3Al a aldehídos catalizada por (Sa,R)-L1.
Una limitación de esta metodología desarrollada en nuestro grupo de investigación, 2 fue la adición de nucleófilos sp (Ph3Al) y voluminosos como i-Bu3Al. En el caso de
Ph3Al, los correspondientes productos de arilación se obtuvieron con excesos enantioméricos <20%, excepto para la adición a pivalaldehído (1n) donde se obtuvo el producto con un 72% ee. Por último, cuando se utilizó i-Bu3Al como nucleófilo, no se observo la formación de ningún producto bajo las condiciones óptimas de reacción.
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3. Conclusiones generales
Se han sintetizado una serie de ligandos quirales (L1-L10) derivados de (S)-BINOL, conocidos como Ar-BINMOL, que presentan dos tipos diferentes de quiralidad: (i) quiralidad axial, procedente del binaftilo y (ii) un centro sp3 generado mediante una transposición de Wittig [1,2] asímetrica del correspondiente éter monobencílico de (S)-BINOL. Estos ligandos previamente mencionados, se utilizaron en la adición enantioselectiva de reactivos organolíticos, Grignard y organoaluminio a aldehídos y también en la arilación enantioselectiva de cetonas con reactivos de Grignard.
Se ha desarrollado una metodología simple y eficaz para la adición enantioselectiva de reactivos organolíticos a aldehídos aromáticos empleando 3.2 eq. RLi, 6 eq. Ti(Oi-
Pr)4, 20% mol del ligando quiral (Sa,R)-L1, tolueno como disolvente a 40 °C durante 1 hora. Esta metodología permite la síntesis de alcoholes secundarios ópticamente activos con enanioselectividades de moderadas a excelentes para la metilación de aldehídos (62-90% ee) y rendimientos muy buenos. En el caso de la adición de EtLi y n-BuLi se consiguieron rendimientos similares pero excesos enantiomericos comprendidos entre 90% y 96%.
También se han desarrollado dos metodologías similares para la adición enantioselectiva de reactivos de Grignard a aldehídos aromáticos y alifáticos, respectivamente. La alquilación enantioselectiva de aldehídos aromáticos implicó el uso de condiciones de reacción más drásticas: 3.8 eq. RMgBr, 15 eq. Ti(Oi-Pr)4, 20% mol (Sa,R)-L1, tolueno como disolvente a 40 °C durante 3 horas. Sin embargo, la alquilación asimétrica de aldehidos alifáticos son sustratos que presentan mayor dificultad, gracias a la utilización de un nuevo ligando, se consiguío mediante el empleo de unas condiciones de reacción más suaves: 2.5 eq. RMgBr, 10 eq. Ti(Oi-Pr)4,
20% mol (Sa,R)-L10, Et2O como disolvente a 20 °C durante 3 horas. En ambos casos, los correspondientes alcoholes secundarios quirales se obtuvieron con excesos enantiomericos de moderados a excelentes (53-99% ee) y rendimientos muy buenos.
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Por otra parte, se consiguió por primera vez la arilación enantioselectiva de cetonas empleando reactivos de Grignard como nucleófilos. La utilización de un nuevo ligando desarrollado en nuestro grupo de investigación fue la clave de la nueva metodología que se desarrollo, empleando: 2.5 eq. RMgBr, 10 eq. Ti(Oi-Pr)4, 20% mol
(Sa,R)-L7, Et2O como disolvente a 0 °C durante 12 horas. Sin embargo, con estas condiciones suaves de reacción solo se pudieron alcanzaron excesos enantioméricos de moderados a buenos (46-84% ee). Aunque en el caso particular de 1-tetralona se alcanzo un 92% ee. En general, los rendimientos obtenidos para la arilacion de cetonas mediante este procedimiento fueron bajos debido a la poca reactividad de estos electrófilos.
Por último, se desarrolló una metodología para la alquilación enantioselectiva de aldehídos mediante el uso de reactivos de organoaluminio como nucleófilos. Para ello se utilizó: 1.5 eq. R3Al, 4 eq. Ti(Oi-Pr)4, 10% mol (Sa,R)-L1, Et2O como disolvente a
0 °C durante 3 horas. La adición de Me3Al a aldehídos aromáticos no voluminosos ofreció las mayores selectividades (80-94% ee) y muy buenos rendimientos. Por otra parte, la adición de Et3Al y n-Pr3Al mantuvo los excesos enantioméricos de los derivados metilados, pero a costa de una disminución considerable del rendimiento.
PREFACE
Preface
Preface
The present thesis has been developed in the Department of Organic Chemistry and Organic Synthesis Institute of the University of Alicante. As a result of the work developed during my PhD who began in September 2011 and during this period of time, I have published the following articles:
(1) Fernández-Mateos, E.; Maciá, B.; Yus, M. Eur. J. Org. Chem. 2014, 6519–6526.
(2) Fernández-Mateos, E.; Maciá, B.; Yus, M. Adv. Synth. Catal. 2013, 355, 1249–1254.
(3) Fernández-Mateos, E.; Maciá, B.; Yus, M. Tetrahedron: Asymmetry 2012, 23, 789– 794.
(4) Fernández-Mateos, E.; Maciá, B.; Yus, M. Eur. J. Org. Chem. 2012, 3732–3736.
(5) Fernández-Mateos, E.; Maciá, B.; Ramón, D. J.; Yus, M. Eur. J. Org. Chem. 2011, 6851–6855.
The author acknowledge financial support from the Spanish Ministerio de Ciencia y Tecnología (MCYT) project numbers CTQ2007-65218/BQU and CTQ2011-24151), Consolider Ingenio 2010 (grant number CSD2007-00006), Generalitat Valenciana (G. V. PROMETEO/2009/039 and FEDER) and also to the Ministerio de Educación, Cultura y Deporte (MECD) for the concession of a FPU predoctoral fellowship (AP-2010- 2926).
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GENERAL OBJECTIVES
General objectives
General objectives
The objectives of this thesis consist on the development of new chiral ligands (Ar- BINMOLs) and the study of their applications in asymmetric catalysis. In particular, we will focus on the enantioselective addition of different challenging organometallic reagents to carbonyl compounds and the study of the mechanistic aspects related to the corresponding reaction.
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CHAPTER I
Chapter I – Introduction
1. Introduction
1.1. History of Ar-BINMOLs ligands
The synthesis of the chiral ligands used in this thesis, known as Ar-BINMOL ligands, dates from 1996, when Kiyooka´s group tested, for the first time, the [1,2]-Wittig rearrangement on a (S)-BINOL derivative,1 provided of a MOM protecting group in one of the hydroxyl groups and a benzyl group in the other (I, Scheme 1), affording intermediates II with excellent diastereoselectivities and moderate yields. Chiral diols III are obtained after deprotection of MOM group with a mixture THF/HCl.
Scheme 1. Synthesis of chiral Ar-BINMOL´s ligands (III) by Kiyooka´s methodology.
In 2011, Xu and his group, as part of their study on neighboring lithium alcoxides as promoters of [1,2]-Wittig rearrangements on benzylic ethers, improved the synthetic route for the synthesis of Ar-BINMOLs.2 Their strategy consisted on modifying the (S)- BINOL substrate (by removing the MOM protecting group) and reoptimizing Kiyooka´s reaction conditions for the [1,2]-Wittig rearrangement2 (Scheme 2).
This new methodology allows the synthesis of chiral Ar-BINMOL´s ligands in only two reaction steps (Scheme 2), starting from commercially available (S)-BINOL (IV). In the first step, IV is monobenzylated using the corresponding benzyl bromide (1 eq.),
K2CO3 (1 eq.) as a base, in acetone as solvent, at 60 °C during 6 hours. The crude of the reaction was used in the next step without further purification. In the second step, the hydroxyether binaphtyl derivative (V) is treated with 2.5 eq. of i-BuLi in
1 Kiyooka, S-I. Tsutsui, T. Kira, T. Tetrahedron Lett. 1996, 37, 8903–8904. 2 Gao, G. Gu, F-L.; Jiang, J-X.; Jiang, K.; Sheng, C-Q.; Lai, G-Q.; Xu, L-W. Chem. Eur. J. 2011, 17, 2698–2703.
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Chapter I – Introduction
anhydrous THF at 78 °C during 1.5 hours, affording the chiral diol ligands (III) in high yields and perfect diastereocontrol (>99%) in all cases, after purification on flash silica gel chromatography.
Scheme 2. Synthesis of chiral Ar-BINMOL´s ligands (III) by Xu´s methodology
The transformation of the intermediate V into the corresponding chiral Ar-BINMOL ligand (III) involves a neighboring lithium-assisted [1,2]-Wittig rearrangement, which is explained in the mechanism below, proposed by Xu Li-Wen´s group.
Scheme 3. Mechanism lithium-assisted [1,2]-Wittig rearrangement of V.
The [1,2]-Wittig rearrangement takes place via a well known radical mechanism,3 which, in this case, is facilitated by the effect of a lithium phenolate group close to the reactive site (Scheme 3).2 In the first step of the mechanism, the first equivalent of i-BuLi deprotonates the most acidic proton which is the phenol (OH) to form the
3 Wittig, G.; Löhmann, L. Liebigs. Ann. Chem. 1942, 550, 260–262.
42
Chapter I – Introduction
corresponding lithium phenoxide V-A. Then, the second equivalent of i-BuLi selectively deprotonate the pro-S benzylic proton, generating dilithiated specie V-B.
After that, an homolitic dissociation of CAr-O bond takes place and intermediate V-C is formed, which immediately suffers a [1,2]-Wittig rearrangement and finally a radical recombination happens in a enantioselective way through a five member ring transition state (V-D), obtaining chiral diol Ar-BINMOL´s ligands III with high diastereomeric excess (>99%). The axial chirality of hydroxyether intermediate (V) is the responsible for the estereoselective generation of the new asymmetric center.
1.2. Applications of Ar-BINMOLs ligands
Ar-BINMOL ligands are relatively new compounds, although a few applications in asymmetric catalysis have been already described in the literature. For example, Xu Li-Wen´s group have employed these type of ligands (in particular, dimer VI, 10 mol%) for the enantioselective alkylation of aromatic aldehydes with Et2Zn, in the 4 presence of Ti(Oi-Pr)4 and using Et2O as solvent at room temperature. Excellent yields and enantioselectivities (from 97% to >99%) were achieved for all the examples described (Scheme 4).
Scheme 4. Asymmetric addition of Et2Zn to different aldehydes catalyzed by ligand VI.
A similar methodology has also been developed by the same research group for the methylation and arylation of aldehydes with Grignard reagents with an Ar-BINMOL ligand (see introduction of chapter 3, section 1.2 for further details).
4 Gao, Guang.; Bai, X-F.; Yang, H-M.; Jiang, J-X.; Lai, G-Q.; Xu L-W. Eur. J. Org. Chem. 2011, 5039–5046.
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Chapter I – Introduction
In addition, Ar-BINMOLs have been also tested, by Xu Li-Wen´s group, as organocatalysts in the enantioselective conjugate addition of anthrone to (E)-- nitrostyrene. The use of chiral diol VII (10 mol%), in THF as solvent at room temperature during 24 hours,4 provided only 25% ee of the corresponding Michael adduct (Scheme 5).
Scheme 5. Asymmetric addition of anthrone to (E)--nitrostyrene organocatalyzed by VII.
Successful modifications in the structure of Ar-BINMOLs have been developed by Xu´s group, in order to expand the applications in asymmetric catalysis for this new type of chiral ligands.5
5 a) Zheng, L-S.; Wei, Y-L.; Jiang, K-Z.; Deng, Y.; Zheng, Z-J.; Xu, L-W. Adv. Synth. Catal. 2014, 356, 3769–3776; b) Wei, Y-L.; Yang, K-F.; Li, F.; Zheng, Z-J.; Xu, Z.; Xu, L-W. RSC Adv., 2014, 4, 37859–37867; c) Li, F.; Zhou, W.; Zheng, L-S.; Li, L.; Zheng, Z-J.; Xu, L-W. Synthetic Communications 2014, 44, 2861–2869; d) Song, T.; Zheng, L-S.; Ye, F.; Deng, W-H.; Wei, Y-L.; Jiang, K-Z.; Xu, L-W. Adv. Synth. Catal. 2014, 356, 1708–1718; e) Zheng, L-S.; Li, L.; Yang, K-F.; Zheng, Z-J.; Xiao, X-Q.; Xu, L-W. Tetrahedron 2013, 69, 8777–8784; f) Li, F.; Li, L.; Yang, W.; Zheng, L-S.; Zheng, Z-J.; Jiang, K.; Lu, Y.; Xu, L-W. Tetrahedron Lett. 2013, 54, 1584–1588.
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Chapter I – Results and discussion
2. Results and discussion
In this section, the synthesis of the ligands employed in this thesis will be explained. Ligands L1-L8 were prepared via [1,2]-Wittig rearrangement of the corresponding benzylic hydroxyethers of (S)-BINOL, following a modified procedure from Xu´s synthesis. In the first step of the synthesis, the corresponding benzyl bromide (1 eq.) was refluxed in acetone at 65 °C for 6 hours, using. of K2CO3 (1.5 eq) as base. The corresponding monobenzylated (S)-BINOLs I1-8 were obtained in good yields (65- 83%), Procedure A, Scheme 6) and used in the next reaction step without further purification. The hydroxyether I1 was isolated by flash silica gel chromatography
(83% yield) and fully characterized. When the partially hydrogenated H8-(S)-BINOL was used as starting material, the desired product H8-(S)-I1 was also obtained in high conversion (74%) using the same reaction condition.
The preparation of the pyridine containing intermediates I-9 and I-10 followed a slightly modified procedure, to overcome the solubility problems associated to the
(bromomethyl)pyridinium bromide used as a reagent. Thus, a mixture acetone/H2O
(9:1) was used as solvent together with 3 eq. of K2CO3 and longer reaction times (12 h) (Procedure B, Scheme 6). The desired products I-9 and I-10 were obtained in 48% and 66 % yield, respectively. The hydroxyether I-9 was used in the next reaction step without further purification, however compound I-10 was isolated by flash silica gel chromatography (66% yield) and fully characterized.
Scheme 6. Synthesis of hydroxyethers intermediates derived from (S)-BINOL. Conversions of hydroxyethers I1-10 were determined by 1H-NMR.
45
Chapter I – Results and discussion
In the second step of the synthesis, hydroxyethers I1-8 were treated with 2.5 eq. of n-BuLi in anhydrous THF at –78 °C during 2 hours (Procedure A, Scheme 7). The desired chiral diol ligands L1-8 were obtained after flash silica gel purification with moderate to very good yields (Table 1, entries 1, 3 and 4-8), except (Sa,S)-L3 which was obtained with only 20% yield (Table 1, entry 4), probably due to bulky methoxy group close to the reactive site, that hampers the [1,2]-Wittig rearrangement.
The synthesis of the more challenging H8-(Sa,R)-L1 and L9-10 was achieved under more forcing reaction conditions from the corresponding hydroxyethers H8-(S)-I1 and I9-10. The [1,2]-Wittig rearrangement took place with 5 eq. of n-BuLi in anhydrous THF at 70 °C during 12 hours (Procedure B, Scheme 7); at lower temperatures the reaction did not proceed. Under this harsh conditions, the chiral diol H8-(Sa,R)-L1 was obtained in moderate yield (53% , Table 1, entry 2) and L9-10 were obtained in low 3 yields (Table 1, entry 10-11), due to homolitic dissociation of Csp -O bond of corresponding hydroxyethers and a consequent not effective radical recombination, which led to the formation of (S)-BINOL instead the desired product. For all chiral diol synthesized, excellent diastereomeric excess (>99%) were achieved in the [1,2]-Wittig rearrangement.
Scheme 7. Synthesis of Ar-BINMOLs ligands through [1,2]-Wittig rearrangement.
46
Chapter I – Results and discussion
Table 1. Ar-BINMOLs synthesis[a] Entry Ligand Yield[c] (%) de[d] (%)
1 82[a] >99
2 53[b] >99
3 80[a] >99
4 20[a] >99
5 86[a] >99
6 81[a] >99
7 83[a] >99
8 72[a] >99
9 60[a] >99
10 27[b],[e] >99
11 33[b],[e] >99
[a] Conditions A: I (4 mmol, 0.12 M), n-BuLi (2.5 M in n-hexane, 2.5 eq.), THF (30 mL), –78 °C, 2 h. [b] Conditions B: I (4 mmol, 0.08 M), n-BuLi (2.5 M in n-hexane, 5 eq.), THF (40 mL), 70 °C, 12 h. [c] Isolated yield after flash silica gel chromatography. [d] Absolute configuration of chiral ligands was determined by correlation of optical rotation with known compounds. [e] 65% of (S)-BINOL was generated as byproduct in the reaction.
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Chapter I – Results and discussion
Due to the perfect stereoelectivity of the lithium-assisted [1,2]-Wittig rearrangement of benzylic ethers derived from (S)-BINOL, the synthesis of the corresponding diastereoisomer (Sa,S)-L1 resulted not trivial. After many attempts trying to prepared 3 desired (Sa,S)-L1 by different synthetic routes, we decided to epimerize the sp benzylic alcohol, by treating (Sa,R)-L1 with a 1:1 mixture of THF/HCl 6 M during 3 hours (Scheme 8). The desired diol (Sa,S)-L1 was obtained with only 20% yield, together with the cyclic ether C1 and some unidentified side products. The rest was starting material (Sa,R)-L1 (42% yield).
Scheme 8. Epimerization of chiral diol (Sa,R)-L1 to (Sa,S)-L1.
Chiral ligand (Sa,S)-L1 will be used in following chapters to determine the effect of the configuration of the chiral benzylic alcohol of the ligand in the asymmetric addition of different organometallic reagents to aldehydes.
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Chapter I – Experimental part
3. Experimental part
3.1. Synthesis of monobenzylated (S)-BINOL hydroxyethers I1-10
The intermediates (S)-I1-7 and H8-(S)-I1 were prepared starting from commercially available (S)-BINOL or (S)-H8-BINOL according to two different procedures (Scheme 9):
Scheme 9. Synthesis of hydroxyethers intermediates (I) derived from (S)-BINOL
Procedure A: Synthesis of hydroxyethers (S)-I1-8
(S)-BINOL (2 g, 7 mmol) or (S)-H8-BINOL (2.1 g, 7 mmol) was dissolved in acetone (40 mL) in a round bottom flask, then K2CO3 (1.5 g, 10.5 mmol, 1.5 eq.) and the corresponding benzyl bromide derivative (ArCH2Br, 7 mmol, 1 eq.) were added and the mixture was heated at 65 °C during 6 h. After cooling down the reaction to room temperature, acetone was evaporated in the rotary evaporator under reduced pressure. Then the reaction crude was extracted with EtOAc (3 × 15 mL) and water (30 mL). The combined organic layers were dried over magnesium sulfate and concentrated under vacuum. Synthetic intermediates (S)-I2–8 were used in the next step without further purification. The hydroxyether (S)-I1 was purified by flash silica gel chromatography as a white foamy solid and then was recrystallized in a n- hexane/EtOAc (9:1) mixture at room temperature. Data of all known products were in accordance with the literature.
49
Chapter I – Experimental part
Procedure B: Synthesis of hydroxyethers (S)-I9 and (S)-I10.
(S)-BINOL (2 g, 7 mmol) was dissolved in acetone (40 mL) in a round bottom flask and then a solution of K2CO3 (2.9 g, 21 mmol, 3 eq.) in water (4 mL) was added. Next, the corresponding (bromomethyl)pyridinium bromide (7 mmol, 1 eq.) was added and the mixture was heated at 65 °C during 12 h. The dark brown reaction crude was filtered under vacuum over celite and the residue was washed with EtOAc (3 × 50 mL). Then, flash silica gel was directly added to the previous solution and the solvent was evaporated under vacuum. The hydroxyether (S)-I10 was purified by flash silica gel chromatography as white powder and then recrystallized in n-hexane/EtOAc (20:1) mixture at room temperature. Intermediate (S)-I9 was used in the next step without further purification.
3.2. Data of hydroxyethers (S)-I1 and (S)-I10
(S)-2'-(Benzyloxy)-(1,1'-binaphthalen)-2-ol [(S)-I1]:6 Compound (S)-I1 was obtained after purification on flash silica gel chromatography from 100:0 till 92:8 (n- hexane/EtOAc) as colorless crystals after recrystallization in 25 20:1 n-hexane/EtOAc (83% yield); m.p. 120.5 – 123.5 °C, []D = +5.2 (c 1.2, CHCl3). 1 H NMR (300 MHz, CDCl3) 7.91 (t, J = 8.6 Hz, 2H), 7.85 (dd, J = 8.0, 4.1 Hz, 2H), 7.41 (d, J = 9.1 Hz, 1H), 7.38 – 7.33 (m, 2H), 7.33 – 7.29 (m, 1H), 7.29 – 7.24 (m, 1H), 7.24 – 7.19 (m, 2H), 7.19 – 7.11 (m, 3H), 7.11 – 7.05 (m, 1H), 7.01 (dd, J = 6.4, 3.0 Hz, 2H), 5.07 (d, J = 12.6 Hz, 1H), 5.02 (d, J = 12.7 Hz, 1H), 4.95 (s, 1H). 13C NMR (75 MHz,
CDCl3) 154.9, 151.3, 136.9, 134.0, 133.8, 130.8, 129.8, 129.6, 129.1, 128.3, 128.1, 127.6, 127.3, 126.8, 126.4, 125.0, 124.9, 124.4, 123.2, 117.5, 116.8, 115.9, 115.1, 71.1. IR (ATR): (cm-1): 3515, 3058, 1620, 1591, 1506, 1463, 1261, 1210, 1040. LRMS (EI-DIP): m/z (%): 378 [M++2] (4), 377 [M++1] (24), 376 [M+] (84), 286 (22), 285 (100), 268 (22), 257 (12), 239 (23), 229 (16), 228 (22), 226 (24), 91 (55), 65 (6).
6 Bremmer, J. B.; Keller, P. A.; Pyne, S. G.; Boyle, T. P.; Brkic, Z.; Morgan, J.; Rhodes, D. I. Bioorgan. Med. Chem. 2010, 18, 4793-4800.
50
Chapter I – Experimental part
(S)-2'-(Pyridin-4-ylmethoxy)-(1,1'-binaphthalen)-2-ol [(S)- I10]: Compound (S)-I10 was obtained after purification on flash silica gel chromatography from 100:0 till 0:100 (n- hexane/EtOAc) as colorless cubic crystals after 25 recrystallization in 10:1 n-hexane/EtOAc (66% yield); m.p. 182 – 184 °C, []D = -17.5 1 (c 1.0, CHCl3). H NMR (400 MHz, CDCl3) 8.26 (br d, J = 4.5 Hz, 2H), 7.97 (d, J = 9.0 Hz, 1H), 7.91 (d, J = 8.9 Hz, 1H), 7.87 (d, J = 7.8 Hz, 2H), 7.42 – 7.34 (m, 3H), 7.34 – 7.26 (m, 3H), 7.21 (ddd, J = 8.1, 6.8, 1.3 Hz, 1H), 7.06 (d, J = 8.4 Hz, 1H), 6.85 (br d, J = 5.2 Hz, 2H), 5.08 (d, J = 13.9 Hz, 1H), 5.03 (d, J = 13.8 Hz, 1H), 3.18 (br s, 1H). 13C NMR
(101 MHz, CDCl3) 154.3, 151.6, 148.9, 146.9, 134.0, 133.8, 130.9, 129.9, 129.1, 128.2, 127.5, 126.5, 125.2, 124.7, 123.3, 121.2, 117.7, 115.4, 114.8, 69.4. IR (ATR): (cm-1): 3064, 1610, 1504, 1325, 1264, 1044, 798. LRMS (EI-DIP): m/z (%): 379 [M++2] (5), 378 [M++1] (28), 377 [M+] (100), 286 (14), 285 (47), 284 (10), 269 (11), 268 (38), 257 (15), 255 (19), 240 (17), 239 (42), 229 (28), 228 (37), 227 (20), 226 (37), 93 (22), + 80 (49). HRMS (EI): m/z: 377.1416 calculated for C26H19NO2 [M ], found 377.1404.
3.3. Synthesis of chiral Ar-BINMOL ligands L1-10
Two different procedures were employed to synthesize compounds L1-10 through a [1,2]-Wittig rearrangement from the corresponding hydroxyethers (S)-I1-10 (Scheme 10).
Scheme 10. Synthesis of Ar-BINMOL ligands L1-10 through [1,2]-Wittig rearrangement.
51
Chapter I – Experimental part
Procedure A: Synthesis of compounds L1-8 n-BuLi (2.5 M in n-hexane, 2.5 eq.) was slowly added to a solution of the corresponding hydroxyether (S)-I1-8 (4 mmol) in anhydrous THF (30 mL) at –78 °C. The mixture was stirred for 2 h at –78 °C and then quenched with water at 0 °C. The resulting mixture was extracted with EtOAc (3 × 10 mL), and the combined organic layers were washed with brine, dried over magnesium sulfate and concentrated under vacuum. The crude product was purified by flash silica gel chromatography to give the desired products L1-8. Data of known products were in accordance with the previously reported in the literature.
Procedure B: Synthesis of compounds L9-10 and H8-(Sa,R)-L1 n-BuLi (2.5 M in n-hexane, 5 eq.) was slowly added to a solution of the corresponding hydroxyether (S)-I9-10 or (S)-H8-I1 (4 mmol) in anhydrous THF (40 mL) at room temperature. The mixture was stirred for 12 h at 70 °C and then the reaction was quenched with water at 0 °C. The resulting mixture was extracted with EtOAc (3 × 15 mL) and the combined organic layers were dried over magnesium sulfate and concentrated under vacuum. The crude product was purified by flash silica gel chromatography to give the desired products L9-10 and (Sa,R)-H8-L1. Data of known products were in accordance with the previously reported in the literature.
3.4 Data of chiral Ar-BINMOL ligands L1-10
(Sa)-2'-[(R)-Hydroxy(phenyl)methyl]-(1,1'-binaphthalen)-2-ol 2 [(Sa,R)-L1]: Compound (Sa,R)-L1 was obtained after purification on flash silica gel chromatography from 100:0 till 85:15 (n- hexane/EtOAc) as a white foamy solid (85% yield); m.p. 72 – 75 25 1 °C, []D = +264.7 (c 1.0, CHCl3). H RMN (400 MHz, CDCl3) 7.90 (ddd, J = 21.8, 13.0, 8.5 Hz, 4H), 7.60 (d, J = 8.7 Hz, 1H), 7.47 (ddd, J = 8.0, 6.8, 1.1 Hz, 1H), 7.33 (d, J = 8.8 Hz, 1H), 7.29 (d, J = 7.9 Hz, 1H), 7.27 – 7.24 (m, 1H), 7.20 – 7.08 (m, 5H), 7.06 – 6.98 (m, 2H), 6.83 (d, J = 8.4 Hz, 1H), 5.69 (s, 1H), 5.61 (br s, 1H), 2.64 (br s, 1H). 13C NMR
(101 MHz, CDCl3) 151.2, 142.5, 141.4, 134.0, 133.4, 132.9, 130.2, 129.9, 129.7,
52
Chapter I – Experimental part
129.1, 128.1, 127.1, 126.8, 126.7, 126.5, 126.0, 125.1, 125.0, 123.6, 117.9, 117.2, 73.4. IR (ATR): (cm-1): 3276, 3058, 2926, 2850, 1620, 1595, 1341, 1268, 1027, 1012. LRMS (EI-DIP): m/z (%): 376 [M+] (2), 359 (27), 358 (100), 357 (29), 330 (12), 282 (11), 281 (51), 279 (22), 252 (18), 239 (15), 140 (12), 77 (9). HRMS (EI): m/z (%): 376.1463 + calculated for C27H20O2 [M ], found 376.1436.
(Sa)-2'-[(R)-Hydroxy(phenyl)methyl]-5,5',6,6',7,7',8,8'-
octahydro-(1,1'-binaphthalen)-2-ol [H8-(Sa,R)-L1]: Compound
(Sa,R)-H8-L1 was obtained after purification on flash silica gel chromatography from 100:0 till 80:20 (n-hexane/EtOAc) as a 25 1 yellow foamy solid (53% yield); m.p. 74 – 77 °C, []D = +90 (c 1.0, CHCl3). H NMR
(400 MHz, CDCl3) 7.30 (d, J = 8.0 Hz, 1H), 7.24 – 7.17 (m, 3H), 7.14 (d, J = 8.0 Hz, 1H), 7.11 – 7.06 (m, 2H), 7.01 (d, J = 8.3 Hz, 1H), 6.81 (d, J = 8.3 Hz, 1H), 5.43 (s, 1H), 4.96 (br s, 1H), 2.80 (t, J = 6.0 Hz, 3H), 2.69 (dd, J = 13.3, 6.7 Hz, 2H), 2.19 (dd, J = 13 14.2, 6.1 Hz, 2H), 1.99 – 1.89 (m, 1H), 1.80 – 1.50 (m, 9H). C NMR (101 MHz, CDCl3) 149. 8, 142.7, 139.9, 137.8, 136.5, 136.1, 133.6, 129.8, 129.7, 129.6, 128.1, 127.3, 126.8, 124.7, 124.3, 113.1, 73.5, 29.9, 29.2, 27.4, 27.2, 23.2, 22.9, 22.8, 22.7. IR (ATR): (cm-1): 3337, 2927, 1591, 1448, 1018, 808, 698. LRMS (EI-DIP): m/z (%): 384 [M+] (<1), 367 (28), 366 (100), 365 (11), 338 (9), 289 (36), 275 (27), 235 (8), 105 (11), + 77 (7). HRMS (EI): m/z: 384.2089 calculated for C27H28O2 [M ], found 384.2057.
(Sa)-2'-[(R)-Hydroxy(o-tolyl)methyl]-(1,1'-binaphthalen)-2-ol 2 [(Sa,R)-L2]: Compound (Sa,R)-L2 was obtained after purification on flash silica gel chromatography from 100:0 till 80:20 (hexane/EtOAc) as a white foamy solid (80% yield); m.p. 77.7 – 25 1 80.0 °C, []D = +165.5 (c 1.0, CHCl3). H NMR (300 MHz, CDCl3) 7.90 (d, J = 8.7 Hz, 3H), 7.85 (d, J = 8.1 Hz, 1H), 7.55 (d, J = 7.6 Hz, 1H), 7.47 (ddd, J = 8.1, 6.8, 1.2 Hz, 1H), 7.38 (d, J = 8.7 Hz, 1H), 7.32 (d, J = 8.9 Hz, 1H), 7.26 (m, 2H), 7.10 (m, 4H), 6.88 (d, J = 7.3 Hz, 1H), 6.82 (d, J = 8.2 Hz, 1H), 6.32 (br s, 1H), 5.84 (s, 1H), 2.91 (br s, 1H), 1.58 (s, 13 3H). C NMR (75 MHz, CDCl3) 151.6, 140.0, 139.8, 135.1, 133.6, 133.5, 133.2, 131.5, 130.1, 129.3, 129.2, 128.1, 127.9, 127.3, 126.7, 126.5, 126.4, 126.2, 126.0,
53
Chapter I – Experimental part
125.9, 125.4, 124.7, 123.6, 118.5, 118.1, 71.4, 19.3. IR (ATR): (cm-1): 3212, 2923, 1621, 1594, 1210, 815, 742. LRMS (EI-DIP): m/z (%): 390 [M+] (1), 373 (28), 372 (100), 371 (18), 344 (15), 329 (12), 282 (13), 281 (54), 279 (18), 252 (17), 245 (14), 239 (14), + 228 (6), 140 (7), 91 (8). HRMS (EI): m/z: 372.1514 calculated for C28H20O [M–H2O] , found 372.1541.
(Sa)-2'-[(S)-Hydroxy(2-methoxyphenyl)methyl]-(1,1'- 2 binaphthalen)-2-ol [(Sa,S)-L3]: Compound (Sa,S)-L3 was obtained after purification on flash silica gel chromatography from 100:0 till 80:20 (n-hexane/EtOAc) as a white foamy solid 25 1 (20% yield); m.p. 77 – 80 °C, []D = +173.8 (c 1.0, CHCl3). H RMN (300 MHz, CDCl3) 7.91 – 7.77 (m, 4H), 7.44 (dd, J = 16.0, 7.8 Hz, 2H), 7.31 – 7.17 (m, 4H), 7.17 – 7.04 (m, 3H), 6.85 (dd, J = 16.8, 8.3 Hz, 2H), 6.54 (d, J = 8.2 Hz, 1H), 6.32 (br s, 1H), 5.89 (s, 13 1H), 3.23 (s, 3H), 3.22 (br s, 1H). C NMR (75 MHz, CDCl3) 156.1, 151.5, 140.6, 134.1, 133.4, 133.2, 130.8, 130.3, 129.8, 129.0, 128.3, 128.0, 127.7, 127.2, 126.5, 126.1, 125.9, 125.8, 124.8, 123.3, 120.2, 118.4, 118.1, 110.0, 69.8, 54.5. IR (ATR): (cm-1): 3255, 3057, 1491, 1461, 1240, 1027, 815. LRMS (EI-DIP): m/z (%): 406 [M+] (<1), 389 (28), 388 (100), 387 (24), 371 (11), 282 (12), 281 (47), 279 (16), 261 (10), 252 (14), 239 (14), 194 (8), 177 (7), 135 (9), 77 (5). HRMS (EI): m/z: 406.1569 + calculated for C28H22O3 [M ], found 406.1542.
(Sa)-2'-[(R)-Hydroxy(3-methoxyphenyl)methyl]-(1,1'- 2 binaphthalen)-2-ol [(Sa,R)-L4]: Compound (Sa,R)-L4 was obtained after purification on flash silica gel chromatography from 100:0 till 82:18 (n-hexane/EtOAc) as a white foamy solid 25 1 (86% yield); m.p. 74 – 78 °C, []D = +267.0 (c 1.0, CHCl3). H
RMN (300 MHz, CDCl3) 7.92 (d, J = 8.7 Hz, 1H), 7.86 (t, J = 9.4 Hz, 3H), 7.59 (d, J = 8.7 Hz, 1H), 7.46 (ddd, J = 8.0, 6.6, 1.3 Hz), 1H), 7.33 – 7.21 (m, 3H), 7.19 – 7.08 (m, 2H), 7.02 (t, J = 7.9 Hz, 1H), 6.84 (d, J = 8.4 Hz, 1H), 6.62 (d, J = 8.2 Hz, 2H), 6.51 (s, 1H), 13 5.78 (br s, 1H), 5.64 (s, 1H), 3.55 (s, 3H), 2.80 (br s, 1H). C NMR (75 MHz, CDCl3) 159.3, 151.2, 144.2, 141.3, 134.1, 133.4, 132.9, 130.2, 129.9, 129.6, 129.1, 129.0,
54
Chapter I – Experimental part
128.1, 128.1, 126.8, 126.6, 126.5, 125.1, 125.0, 123.5, 118.3, 117.9, 117.1, 113.0, 111.3, 73.3, 55.0. IR (ATR): (cm-1): 3316, 3057, 1595, 1258, 1144, 1029, 816. LRMS (EI-DIP): m/z (%): 406 [M+] (2), 389 (28), 388 (100), 387 (14), 360 (13), 282 (9), 281 (40), 280 (8), 279 (22), 261 (13), 252 (17), 239 (14), 135 (6), 77 (5). HRMS (EI): m/z: + 406.1569 calculated for C28H22O3 [M ], found 406.1558.
(Sa)-2'-[(R)-Hydroxy(4-methoxyphenyl)methyl]-(1,1'- 2 binaphthalen)-2-ol [(Sa,R)-L5]: Compound (Sa,R)-L5 was obtained after purification on flash silica gel chromatography from 100:0 till 80:20 (n-hexane/EtOAc) 25 as a white foamy solid (81% yield); m.p. 173 – 175 °C, []D = +241.0 (c 0.5, CHCl3). 1 H RMN (300 MHz, CDCl3) 7.91 (ddd, J = 20.0, 16.1, 8.4 Hz, 4H), 7.68 (d, J = 8.7 Hz, 1H), 7.47 (t, J = 7.4 Hz, 1H), 7.34 (d, J = 8.9 Hz, 1H), 7.32 – 7.21 (m, 2H), 7.16 (d, J = 8.5 Hz, 1H), 7.09 (t, J = 7.6 Hz, 1H), 6.88 (d, J = 8.5 Hz, 2H), 6.75 (d, J = 8.5 Hz, 1H), 6.62 (d, J = 8.7 Hz, 2H), 5.64 (s, 1H), 5.52 (br s, 1H), 3.70 (s, 3H) ,2.52 (br s, 1H). 13C NMR (75
MHz, CDCl3) 158.6, 151.1, 141.7, 134.7, 134.0, 133.4, 133.0, 130.2, 129.6, 129.5, 129.0, 128.1, 128.0, 127.3, 126.8, 126.6, 126.4, 126.4, 125.0, 124.9, 123.5, 117.9, 117.1, 113.4, 73.1, 55.2. IR (ATR): (cm-1): 3563, 3285, 3064, 2964, 1508, 1300, 1236, 1172, 1030, 1017, 822. LRMS (EI-DIP) m/z (%): 406 [M+], (<1), 404 (6), 389 (29), 388 (100), 387 (22), 360 (13), 329 (8), 281 (28), 279 (20), 261 (21), 252 (15), 239 (14), 135 + (17), 77 (6). HRMS (EI): m/z: 406.1569 calculated for C28H22O3 [M ], found 406.1550.
(Sa)-2'-[(R)-(4-Fluorophenyl)(hydroxy)methyl]-(1,1'- 2 binaphthalen)-2-ol [(Sa,R)-L6]: Compound (Sa,R)-L6 was obtained after purification on flash silica gel chromatography from 100:0 till 87:13 (n-hexane/EtOAc) as a white foamy 25 1 solid (83% yield); m.p. 53 – 56 °C, []D = +245.0 (c 1.0, CHCl3). H RMN (400 MHz,
CDCl3) 7.88 (ddd, J = 17.3, 16.2, 8.4 Hz, 4H), 7.57 (d, J = 8.7 Hz, 1H), 7.46 (ddd, J = 8.1, 6.8, 1.1 Hz, 1H), 7.32 – 7.21 (m, 3H), 7.16 (d, J = 8.4 Hz, 1H), 7.09 (ddd, J = 8.2, 6.9, 1.2 Hz, 1H), 6.91 – 6.82 (m, 2H), 6.77 – 6.67 (m, 3H), 5.82 (br s, 1H), 5.61 (s, 1H), 13 2.88 (br s, 1H). C NMR (101 MHz, CDCl3) 163.0, 160.6, 151.1, 141.1, 138.2, 133.9,
55
Chapter I – Experimental part
133.4, 132.9, 130.2, 129.9, 129.6, 129.0, 128.1, 128.0, 127.8, 127.7, 126.9, 126.7, 126.5, 126.4, 124.8, 124.7, 123.6, 117.8, 117.0, 114.9, 114.7, 72.8. 19F NMR (376 -1 MHz, CDCl3) -115.57. IR (ATR): (cm ): 3303, 3058, 1597, 1507, 1220, 1030, 1013, 817. LRMS (EI-DIP): m/z (%): 394 [M+] (1), 377 (27), 376 (100), 375 (35), 348 (9), 282 (10), 281 (47), 279 (22), 252 (18), 239 (15), 140 (12), 123 (13), 95 (7). HRMS (EI): m/z: + 394.1369 calculated for C27H19FO2 [M ], found 394.1393.
(Sa)-2'-[(R)-Hydroxy(naphthalen-1-yl)methyl]-(1,1'-
binaphthalen)-2-ol [(Sa,R)-L7]: Compound (Sa,R)-L7 was obtained after purification on flash silica gel chromatography from 100:0 till 80:20 (n-hexane/EtOAc) as a yellow foamy solid 25 1 (72% yield); m.p. 105 – 108 °C, []D = +330 (c 1.0, CHCl3). H
NMR (400 MHz, CDCl3) 7.87 (t, J = 6.8 Hz, 2H), 7.81 (t, J = 6.9 Hz, 2H), 7.75 (d, J = 8.7 Hz, 1H), 7.69 (d, J = 8.2 Hz, 2H), 7.48 – 7.41 (m, 2H), 7.37 (ddd, J = 8.1, 6.9, 1.1 Hz, 1H), 7.34 – 7.27 (m, 3H), 7.27 – 7.21 (m, 4H), 7.13 (d, J = 8.3 Hz, 1H), 6.91 (ddd, J = 8.3, 6.9, 1.1 Hz, 1H), 6.40 (s, 1H), 3.45 (br s, 1H), 1.60 (br s, 1H). 13C NMR (101 MHz,
CDCl3) 151.9, 140.1, 137.5, 133.8, 133.6, 133.4, 133.2, 131.4, 130.4, 129.8, 129.4, 128.4, 128.3, 128.1, 127.9, 126.8, 126.7, 126.5, 126.4, 125.6, 125.4, 125.3, 125.2, 124.9, 123.8, 123.7, 123.4, 118.6, 118.1, 71.6. IR (ATR): (cm-1): 3227, 3051, 1621, 1508, 1268, 783, 748. LRMS (EI-DIP): m/z (%): 426 [M+] (2), 409 (33), 408 (100), 407 (15), 380 (27), 379 (14), 282 (18), 281 (80), 280 (10), 279 (18), 252 (19), 239 (16), 127 + (14). HRMS (EI): m/z: 426.1620 calculated for C31H22O2 [M ], found 426,1609.
(Sa)-2'-[(R)-Hydroxy(naphthalen-2-yl)methyl]-(1,1'- 2 binaphthalen)-2-ol [(Sa,R)-L8]: Compound (Sa,R)-L8 was obtained after purification on flash silica gel chromatography from 100:0 till 80:20 (n-hexane/EtOAc) as 26 1 a white foamy solid (60% yield); m.p. 86.5 – 90.0 °C, []D = +376 (c 1.0, CHCl3). H
NMR (300 MHz, CDCl3) 7.94 – 7.80 (m, 4H), 7.72 – 7.64 (m, 1H), 7.62 – 7.49 (m, 3H), 7.49 – 7.41 (m, 2H), 7.41 – 7.33 (m, 2H), 7.33 – 7.15 (m, 4H), 7.12 – 6.99 (m, 2H), 6.84 (d, J = 8.3 Hz, 1H), 5.94 (s, 1H), 5.82 (br s, 1H), 3.00 (br s, 1H). 13C NMR (75 MHz,
56
Chapter I – Experimental part
CDCl3) 151.3, 141.2, 139.8, 134.1, 133.4, 133.0, 132.9, 132.5, 130.2, 130.1, 129.6, 129.1, 128.10, 128.05, 128.0, 127.8, 127.4, 126.8, 126.6, 126.5, 125.9, 125.7, 125.1, 125.0, 124.6, 124.3, 123.6, 117.9, 117.2, 73.5. IR (ATR): (cm-1): 3266, 3055, 1620, 1595, 1507. LRMS (EI-DIP): m/z (%): 426 [M+] (2), 409 (33), 408 (100), 407 (22), 380 (11), 282 (10), 281 (45), 280 (12), 279 (23), 252 (16), 239 (11), 127 (10). HRMS (ESI): + m/z: 409.1592 calculated for C31H21O [M–OH] , found 409.1597.
(Sa)-2'-[(S)-Hydroxy(pyridin-2-yl)methyl]-(1,1'-binaphthalen)-
2-ol [(Sa,S)-L9]: Compound (Sa,S)-L9 was obtained after purification on flash silica gel chromatography from 100:0 till 20:80 (n-hexane/EtOAc) as a yellow foamy solid (40% yield); 25 1 m.p. 83 – 85 °C, []D = +251 (c 1.0, CHCl3). H NMR (400 MHz, CDCl3) 8.50 (br d, J = 4.6 Hz, 1H), 7.96 – 7.84 (m, 4H), 7.45 (m, 3H), 7.39 – 7.30 (m, 2H), 7.29 – 7.16 (m, 3H), 7.15 – 7.09 (m, 1H), 6.99 (d, J = 8.4 Hz, 1H), 6.68 (d, J = 7.9 Hz, 1H), 5.66 (s, 1H). 13C
NMR (101 MHz, CDCl3) 159.5, 152.1, 147.2, 140.7, 137.0, 134.2, 133.5, 133.0, 130.8, 130.2, 129.7, 129.0, 128.3, 128.1, 126.9, 126.7, 126.6, 125.2, 124.9, 123.4, 122.5, 122.0, 118.8, 116.9, 71.7. IR (ATR): (cm-1): 3248, 3057, 1594, 1434, 1038, 816, 746. LRMS (EI-DIP): m/z (%): 378 [M++1] (26), 377 [M+] (90), 360 (16), 359 (54), 358 (11), 332 (22), 331 (96), 330 (100), 329 (11), 328 (16), 282 (19), 281 (79), 280 (11), 279 (30), 268 (15), 254 (14), 253 (45), 252 (53), 250 (19), 240 (11), 239 (36), 237 (11), 164 (10), 109 (14), 80 (24), 79 (12), 78 (19). HRMS (EI): m/z: 377.1416 calculated for + C26H19NO2 [M ], found 377.1441.
(Sa)-2'-[(R)-Hydroxy(pyridin-4-yl)methyl]-(1,1'-binaphthalen)-
2-ol [(Sa,R)-L10]: Compound (Sa,R)-L10 was obtained after purification on flash silica gel chromatography from 100:0 till 20:80 (n-hexane/EtOAc) as a yellow foamy solid (48% yield); 25 1 m.p. 100 – 103 °C, []D = +252 (c 1.0, CHCl3). H NMR (300 MHz, CDCl3) 8.20 (br d, J = 6.1 Hz, 2H), 7.93 – 7.78 (m, 4H), 7.44 (ddd, J = 8.1, 6.6, 1.4 Hz, 1H), 7.39 – 7.23 (m, 4H), 7.23 – 7.15 (m, 2H), 6.99 (br d, J = 5.8 Hz, 2H), 6.89 (d, J = 8.4 Hz, 1H), 5.65 (s, 13 1H), 3.56 (br s, 2H). C NMR (75 MHz, CDCl3) 152.9, 151.8, 148.3, 139.9, 134.2,
57
Chapter I – Experimental part
133.5, 132.9, 131.5, 130.3, 129.6, 128.9, 128.2, 128.1, 126.9, 126.7, 126.6, 125.0, 124.7, 123.7, 121.5, 118.2, 117.2, 72.1. IR (ATR): (cm-1): 3297, 3055, 1606, 1506, 1342, 813, 747. LRMS (EI-DIP) m/z (%): 378 [M++1] (3), 377 [M+] (9), 360 (27), 359 (100), 358 (36), 282 (21), 281 (91), 279 (25), 252 (25), 239 (16), 140 (9), 78 (5). HRMS + (EI): m/z: 377.1416 calculated for C26H19NO2 [M ], found 377.1386.
3.5 Synthesis of chiral Ar-BINMOL ligand (Sa,S)-L1
The following procedure was used to epimerized benzylic alcohol present in compound (Sa,R)-L1 (Scheme 11).
Scheme 11. Methodology for the epimerization of chiral diol (Sa,R)-L1 to (Sa,S)-L1.
(Sa,R)-L1 (300 mg, 0.8 mmol) was dissolved with anhydrous THF (10 mL) in a round bottom flask, HCl 6 M (10 mL) was then added and the mixture was stirred during 3 hours at 25 °C. The resulting solution was extracted with EtOAc (3 × 10 mL) and the combined organic layers were washed with brine, dried over magnesium sulfate and concentrated in vacuum. The crude product was purified by flash silica gel chromatography to give the desired product (Sa,S)-L1 in 20% yield.
3.6 Data of chiral Ar-BINMOL ligand (Sa,S)-L1
(Sa)-2'-[(S)-hydroxy(phenyl)methyl]-(1,1'-binaphthalen)-2-ol
[(Sa,S)-L1]: Compound (Sa,S)-L1 was obtained after purification on flash silica gel chromatography from 100:0 till 89:11 (n- hexane/EtOAc) as a white foamy solid (20% yield), m.p. 56 – 20 1 58 °C, []D = –246.2 (c 1.0, CHCl3). H RMN (400 MHz, CDCl3) 8.02 (d, J = 8.7 Hz, 1H), 7.94 (d, J = 3.8 Hz, 1H), 7.93 – 7.86 (m, 3H), 7.47 (td, J = 8.0, 1.7 Hz, 1H), 7.35 (td,
58
Chapter I – Experimental part
J = 8.0, 1.2 Hz, 1H), 7.32 – 7.25 (m, 3H), 7.24 (d, J = 2.9 Hz, 1H), 7.22 – 7.14 (m, 3H), 13 7.14 – 7.08 (m, 3H), 5.53 (s, 1H), 4.49 (s, 1H), 2.08 (s, 1H). C NMR (101 MHz, CDCl3) 151.6, 143.0, 142.5, 133.5, 133.4, 132.5, 130.3, 129.9, 129.1, 128.3, 128.2, 127.4, 127.2, 127.1, 126.6, 126.2, 125.7, 124.8, 124.1, 123.7, 117.7, 116.5, 73.2. IR (ATR): (cm-1): 3392, 3058, 2925, 1619, 1596, 1143, 1034, 814. LRMS (EI-DIP) m/z (%): 377 [M++1] (3), 376 [M+] (11), 359 (27), 358 (100), 357 (34), 330 (14), 329 (11), 282 (13), 281 (59), 279 (23), 252 (21), 239 (20), 231 (10), 140 (10), 105 (12), 77 (13).
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CHAPTER II
Chapter II – Introduction
1. Introduction
Organolithium compounds, which were discovered in 1917 by Wilhelm Schlenk,7 are common bench reagents that can be found in any organic synthetic laboratory and are widely used in industry to produce numerous materials from pharmaceutical to polymers.8 For catalytic applications, the low price and good availability of organolithium reagents make them desirable but their high reactivity often precludes their use in complex procedures, such as asymmetric C-C bond formation; (super) stoichiometric amounts of a chiral modifier and extremely low temperatures are usually required to obtain high enantioselectivity9 Only a few examples of asymmetric deprotonations,10 addition to imines,11 and allylic alkylation reactions12 have been described in the literature as catalytic processes for organolithium reagents.
In the next few pages, it will be summarized the methodologies that have been described over the years for the asymmetric addition of organolithium reagents to aldehydes using stoichiometric and catalytic loadings of a chiral ligand.
7 Tidwell, T. T. Angew. Chem. Int. Ed. 2001, 40, 331–337. 8 a) Rappoport, Z.; Marek, I. The Chemistry of Organolithium Compounds, Wiley-VCH, 2004; b) Najera, C.; Yus, Y. Curr. Org. Chem. 2003, 867926. 9 a) Luderer, M. R.; Bailey, W. F.; Luderer,M. R.; Fair, J. D.; Dancer, R. J.; Sommer, M. B. Tetrahedron: Asymmetry 2009, 20, 981998; b) Wu, G.; Huang, M. Chem. Rev. 2006, 106, 25962616; c) Wu, G. G.; Huang, M. in Topics in Organometallic Chemistry, Vol. 6, 2004, 135; d) Hodgson, D. M. Organolithiums in Enantioselective Chemistry, Springer-Verlag, 2003. 10 a) Beng, T. K.; Gawley, R. E. J. Am. Chem. Soc. 2010, 132, 1221612217; b) Bilke, J. L.; Moore, S. P.; O’Brien, P.; Gilday, J. Org. Lett. 2009, 11, 19351938. 11 a) Alexakis, A.; Amiot, F. Tetrahedron: Asymmetry 2002, 13, 21172122; b) Denmark, S. E.; Nicaise, O. J.-C. Chem. Commun. 1996, 9991004; c) Denmark, S. E.; Nakajima, N.; Nicaise, O. J.-C. J. Am. Chem. Soc. 1994, 116, 87988798; d) Inoue, I.; Mitsuru, I.; Kenji, S.; Koga, K.; Tomioka, K. Tetrahedron 1994, 50, 44294438; e) Tomioka, K.; Inoue, I.; Mitsuru, I.; Kenji, S.; Koga, K. Tetrahedron Lett. 1991, 32, 30953098. 12 a) Perez, M.; Fañanás-Mastral, M.; Hornillos, V.; Rudolph, A.; Bos, P. H.; Harutyunyan, S.R.; Feringa, B. L.; Chem. Eur. J. 2012, 18, 11880–11883; b) Fañanás-Mastral, M.; Pérez, M.; Bos, P. H.; Rudolph, A.; Harutyunyan, S. R.; Feringa, B. L. Angew. Chem. Int. Ed. 2012, 51, 1922–1925; c) Pérez, M.; Fañanás-Mastral, M.; Bos, P. H.; Rudolph, A.; Harutyunyan, S. R.; Feringa, B. L. Nature Chem. 2011, 3, 377381; d) Gao, F.; Lee, Y.; Mandai, K.; Hoveyda, A. H. Angew. Chem. Int. Ed. 2010, 49, 83708374; e) Tanaka, K.; Matsuui, J.; Suzuki, H. J. Chem. Soc. Perkin Trans. 1993, 1, 153157.
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1.1. Stoichiometric and superstoichiometric enantioselective addition of organolithium reagents to aldehydes
In 1968, Nozaki et al. investigated the ability of (–)-sparteine (VIII) to promote asymmetric addition of organolithium reagents to aldehydes and ketones.13 The reaction of benzaldehyde with n-BuLi in anhydrous n-hexane as solvent at –70 ᵒC gave (R)-1-phenyl-1-pentanol in 90% yield and only 6% ee (Scheme 12).
Scheme 12. Asymmetric addition of n-BuLi to benzaldehyde promoted by (–)-sparteine (VIII).
A few years later, Seebach et al. continued the studies in asymmetric addition of organolithium reagents to aldehydes. His group performed the first comprehensive investigation of addition of organolithium nucleophiles in the presence of various chiral ligands prepared from diethyl tartrate (IX).14 Ligands were screened in the reaction of n-BuLi with benzaldehyde in n-pentane as solvent at –78 ᵒC. Amongst the variety of chiral ligands that were tested, the authors observed that C2 symmetric ligands which contained three or four heteroatoms provided the lowest selectivity.
On the contrary, C2 symmetric ligands with six heteroatoms in their structure, displayed the highest performance (Scheme 13).
13 a) Nozaki, H.; Aratini, T.; Toraya, T. Tetrahedron Lett. 1968, 9, 4097–4098; b) Nozaki, H.; Aratini, T.; Toraya, T.; Noyori, R. Tetrahedron 1971, 27, 905–913. 14 a) Seebach, D.; Oei, H.-A.; Daum, H. Chem. Ber. 1977, 110, 2316–2333; b) Seebach, D.; Dörr, H.; Bastani, B.; Ehrig, V. Angew. Chem., Int. Ed. Engl. 1969, 8, 982–983; c) Seebach, D.; Kalinowski, H.-O.; Bastani, B.; Crass, G.; Daum, H.; Dörr, H.; DuPreez, N. P.; Ehrig, V.; Langer, W.; Nüssler, C.; Oei, H.-A.; Schmidt, M. Helv. Chim. Acta 1977, 60, 301–325; d) Seebach, D.; Langer, W. Helv. Chim. Acta 1979, 62, 1710–1722; e) Seebach, D.; Crass, G.; Wilka, E.-M.; Hilvert, D.; Brunner, E. Helv. Chim. Acta 1979, 62, 2695–2698.
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Chapter II – Introduction
Scheme 13. Asymmetric addition of n-BuLi to benzaldehyde promoted by chiral ligands IX.
In 1978, Mukaiyama´s group found that pyrrolidine ligand X was very effective as a chiral medium for the asymmetric addition of alkyllithiums to aldehydes.15 Long chain aliphatic nucleophiles afforded the best enantioselectivities in the addition to benzaldehyde, such as n-BuLi, which gave the best result with 72% ee. The lowest enantiomeric excess was achieved with PhLi (11%). A significant solvent effect was observed by the authors; non-coordinating solvents exhibited the lowest selectivity (up to 20% ee), while coordinanting solvents displayed better enantioselectivities (up to 72%). In all cases, extremely low temperature (–123 ᵒC) was required to obtain moderate enantioselectivities (Scheme 14).
Scheme 14. Asymmetric addition of alkyllithium reagents to benzaldehyde promoted by ligand X.
15 a) Mukaiyama, T.; Soai, K.; Kobayashi, S. Chem. Lett. 1978, 219–222; b) Mukaiyama, T.; Soai, K.; Sato, T.; Shimizu, H.; Suzuki, K. J. Am. Chem. Soc. 1979, 101, 1455–1460; c) Soai, K.; Mukaiyama, T. Chem. Lett. 1978, 491–492; d) Sato, T.; Soai, K.; Suzuki, K.; Mukaiyama, T. Chem. Lett. 1978, 601–604.
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Chapter II – Introduction
Mukaiyama et al. also used the previous ligand X to prepare optically active alkynyl alcohols.16 Using lithium trimethylsilylacetylide as nucleophiles and benzaldehyde as electrophile, in Et2O at –123 ᵒC, afforded (S)-1-phenyl-2-propyn-1-ol in 87% yield and 92% ee (Scheme 14).
In 1981, Mazaleyrat and Cram observed an important effect in the reaction of alkyllithium reagents with aldehydes in the presence of a chiral C2-symmetric binaphtyl based diamines XI and XII (Scheme 15),17 the rate of the catalyzed addition exceeded the rate of the non-catalyzed addition reaction. Treatment of benzaldehyde with n-BuLi in the presence of the dimeric binaphtyl diamine ligand XI, in Et2O at –120 ᵒC, afforded the corresponding (R)-1-phenylpentan-1-ol in 73% yield and excellent enantioselectivity (95% ee). The monomeric binaphtyl diamine ligand XII gave a similar yield (71%), but only 58% enantiomeric excess when is used under the same conditions.
Scheme 15. Asymmetric addition of n-BuLi to benzaldehyde promoted by chiral binaphtyl diamines
16 Mukaiyama, T.; Suzuki, K.; Soai, K.; Sato, T. Chem. Lett. 1979, 447–448. 17 Mazazleyrat, J.-P.; Cram, D. J. J. Am. Chem. Soc. 1981, 103, 4585–4586.
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In 1982, Colombo et al. studied the (S)-(–)-proline-based ligands XIII and XIV in the addition of n-BuLi to benzaldehyde at –85 ᵒC.18 The highest enantioselectivity observed in this study was 36%, using proline lithium alcoxide ligand in dimethoxyethane (DMM) as solvent (Scheme 16). The authors observed that the lithium salts (LiI or LiClO4) present in n-BuLi affected the enantioselectivity of the reaction and gave the racemic product.
Scheme 16. Asymmetric addition of n-BuLi to benzaldehyde promoted by ligands XIII and XIV.
Eleveld and Hogeveen were the first to investigate the ability of chiral lithium amides XV to effect the asymmetric addition of n-BuLi to benzaldehyde.19 Several (S)-- methylbenzylamine-based ligands were examined using a 1:2.7:4 ratio of benzaldehyde /n-BuLi/L* at –120 ᵒC (Scheme 17). They observed an important effect based on the structure of the chiral ligand, when the structural rigidity and bulkiness of the ligand was increased, an improvement in the enantiomeric excess of the product was observed.
Scheme 17. Asymmetric addition of n-BuLi to benzaldehyde promoted by ligands XV.
18 Colombo, L.; Gennari, C.; Scolastico, P. C. Tetrahedron 1982, 38, 2725–2727. 19 Eleveld, M. B.; Hogeven, H. Tetrahedron Lett. 1984, 25, 5187–5190.
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In 1988, Kanoh et al. studied the use of chiral biphenyl diamines XVI and XVII in the enantioselective addition of phenyl lithium to butyryaldehyde.20 Comparable results were obtained to those reported by Cram,17 due to the ligand structure similarity.
However, when the reaction was cooled down to –120 ᵒC in Et2O an outstanding 99% ee was achieved (Scheme 18).
Scheme 18. Enantioselective arylation of butyraldehyde promoted by diamine ligands XVI and XVII.
With the rise of organolithium reagents, the first autoinduction studies in the enantioselective addition to aldehydes were carried out by Alberts and Wynberg.21 They found that the lithium alcoxide XVIII generated in the reaction had an asymmetric inducting effect on the addition of EtLi to benzaldehyde. The formation of mixed aggregates containing both product and starting material fragments influenced the stereochemistry of subsequent C-C bond formation (Scheme 19).
Scheme 19. Autoinduction effect observed by deuterated lithium alcoxide XVIII.
20 Kanoh, S.; Muramoto, H.; Maeda, K.; Kawaguchi, N.; Motoi, M.; Suda, H. Bull. Chem. Soc. Jpn. 1988, 61, 2244–2246. 21 Alberts, A. H.; Wynberg, H. J. Am. Chem. Soc. 1989, 111, 7265–7266.
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The previous study inspired Jackman et al. to investigate the addition of MeLi to benzaldehyde in the presence of various chiral lithium alcoxides as ligands (XIX).22 Unfortunately, poor results were obtained for all the ligands that were tested (Scheme 20).
Scheme 20. Ligand screening of chiral lithium alcoxides (XIX) in the methylation of benzaldehyde.
An interesting secondary nucleophile (2-lithio-1,3-dithiane) was chosen by Kang et al. to study the enantioselective addition to aldehydes in the presence of (–)- isosparteine (XX).23 The enantioselectivities obtained were moderated for aromatic aldehydes and poor to aliphatic ones (Scheme 21).
Scheme 21. Asymmetric addition of 2-lithio-1,3-dithiane to aldehydes using ligand XX.
22 Ye, M.; Logaraj, S.; Jackman, L. M.; Hiilegass, K.; Hirsh, K. A.; Bollinger, A. M.; Grosz, A. L. Tetrahedron 1994, 50, 6109–6116. 23 Kang, J.; Kim, J. I.; Lee, J. H. Bull. Korean Chem. Soc. 1994, 15, 865–868.
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Chapter II – Introduction
In the late 90s, many groups were interested in the alkylation of aldehydes using organolithium reagents as nucleophiles. Corruble et al. studied lithium amides (XXI), derived from substituted 3-aminopyrrolidines, as chiral ligands in the addition of n- BuLi to a selection of aldehydes.24 The enantioselectivities of the reaction varied from poor to moderate. Also, the authors studied the mechanistic pathway of the reaction and presented spectroscopic evidence for the formation of a hemiaminal-like intermediate (Scheme 22).
Scheme 22. Asymmetric addition of n-BuLi to aldehydes promoted by lithium diamines XXI.
Schön tested aminoalcohol XXII as a ligand which derive from 1-amino-1,2- diphenylethanols. Those type of ligands were tested in the addition of linear aliphatic nucleophiles to benzaldehyde providing very good yields and ee (75%-86%).25 For the first time, a very promising result was obtained for sp2 lithium nucleophiles (75% ee) (Scheme 23).
Scheme 23. Asymmetric addition of alkyllithium reagents promoted aminoalcohol XXII.
24 a) Corruble, A.; Valnot, J.-Y.; Maddaluno, J.; Duhamel, P. Tetrahedron: Asymmetry 1997, 8, 1519–1523; b) Flinois, K.; Yuan, Y.; Bastide, C.; Harrison-Marchand, A.; Maddaluno, J. Tetrahedron 2002, 58, 4707–4716. 25 Schön, M.; Naef, R. Tetrahedron: Asymmetry 1999, 10, 169–176.
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In 1999, Aspinall et al. investigated the ability of chiral lanthanide binaphtolate
Li3[Ln(S-BINOL)3] (XXIII) to induce chirality in the asymmetric addition of MeLi and n- BuLi to aromatic aldehydes.26 Enantiomeric excesses in the range 28%-84% were obtained (Scheme 24). The variation in the ee is attributed to changes in the ionic radius of the lanthanide.
Scheme 24. Asymmetric addition of MeLi and n-BuLi promoted by Li3[Ln(S-BINOL)3] complex XXIII.
Hilmersson et al. studied the use chiral aminoethers (XXIV) as effective ligands in the alkylation of aromatic and aliphatic aldehydes using n-BuLi as nucleophile.27 The authors observed that the process showed a strong dependence on the substrate and also on the reactive species present in solution, which consisted of three complexes in equilibrium:28 (i) homoaggregated n-BuLi; (ii) lithium amide dimers; and (iii) mixed 1:1 complex between n-BuLi and lithium amide. Excellent enantioselectivities (up to 91% ee) were achieved at –116 ᵒC with this methodology (Scheme 25).
Scheme 25. Asymmetric addition of n-BuLi to aldehydes promoted by chiral aminoethers XXIV.
26 Aspinall, H. C.; Dwyer, J. L. M.; Greeves, N.; Steiner, A. Organometallics 1999, 18, 1366–1368. 27 Arvidsson, P. I.; Davidsson, Ö.; Hilmersson, G. Tetrahedron: Asymmetry 1999, 10, 527–534. 28 a) Hilmersson, G.; Davidsson, Ö. J. Organomet. Chem. 1995, 489, 175–179; b) Arvidsson, P. I.; Hilmersson, G.; Davidsson, Ö. Chem. Eur. J. 1999, 5, 2348–2355.
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The studies with lithium amides continued with Davidsson, who synthesized new types of chiral ligands derived form aminoethers and aminosulfides (XXV).29 He found that aminosulfide ligands gave better ee (75%-97%) than structurally identical aminoethers in the asymmetric addition of n-BuLi to benzaldehyde, under optimal conditions for each ligand respectively (Scheme 26). This fact suggests that the stronger chelation between lithium and oxygen it is not important to lead higher enantioselectivities.
Scheme 26. Asymmetric addition of n-BuLi to aldehydes promoted by lithium amides XXV.
Tobe et al. employed a new type of C2 symmetric chiral ligands derived from the dimethyl ether of cis-1-phenylcyclohexane-1,2-diol (XXVI).30 This ligand only gave a modest enantiomeric excess (52%) in THF at 0 ᵒC (Scheme 27).
Scheme 27. Asymmetric addition of n-BuLi to benzaldehyde promoted by ligand XXVI.
29 a) Arvidsson, P. I.; Hilmersson, G.; Davidsson, Ö. Chem. Eur. J. 1999, 5, 2348–2355; b) Granander, J.; Scott, R.; Hilmersson, G. Tetrahedron 2002, 58, 4717–4725; c) Granander, J.; Scott, R.; Hilmersson, G. Tetrahedron: Asymmetry 2003, 14, 439–447. 30 Tobe, Y.; Iketani, H.; Tsuchiya, Y.; Konishi, M.; Naemura, K. Tetrahedron: Asymmetry 1997, 8, 3735–3744.
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In 2000, Nishiyama et al. investigated the addition of PhLi to acrolein using a chiral ruthenium-bis(oxazolidinyl)pyridine complex (XXVII).31 The activation mode for this chiral complex is relatively novel for this type of reaction because there is a interaction between the ruthenium complex and double bond of acrolein. This methodology is quite limited, because it is only effective for ,-unsaturated substrates. The corresponding allylic alcohols were obtained in moderate to very good enantioselectivities (Scheme 28).
Scheme 28. Asymmetric addition of PhLi to acrolein promoted by ruthenium complex XXVII.
Maddaluno used chiral lithium amides derived from 3-aminopyrrolidines (XXVIII) in the enantioselective vinylation of aldehydes. Modest to good enantioselectivities (up to 61%) were observed (Scheme 29).32 This is the first effective enantioselective addition of lithium sp2 nucleophiles to aldehydes.
Scheme 29. Asymmetric addition of vinylation of aldehydes promoted by 3-aminopyrrolidines XXVIII.
31 Motoyama, Y.; Kurihara, O.; Murata, K.; Aoki, K.; Nishiyama, H. Organometallics 2000, 19, 1025–1034. 32 Yuan, Y.; Marchand-Harrison, A.; Maddaluno, J. Synlett 2005, 1555–1558.
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Hilmersson et al. improved the methodology previously developed by Davidsson and himself28, 29 through the inclusion of a soft donor group such as diphenylphosphino or phenylthio in the ligand structure (XXIX).33 Very good to excellent enantiomeric excess are obtained with this kind of chiral ligands (Scheme 30).
Scheme 30. Asymmetric addition of n-BuLi to aldehydes promoted by chiral lithium amides XXIX. 1.2. Catalytic enantioselective additions of organolithium reagents to aldehydes
Several factors complicate the control of the stereochemistry in the enantioselective addition of organolithium reagents to aldehydes and cause unpredictable behavior; this includes the high reactivity of organolithium reagents, which often leads to uncatalyzed reactions, and the presence of the aggregates,34 common to organolithium reagents.
In 1996, Seebach´s group performed the first enantioselective addition of already titanium-transmetallated organolithium reagents (alkyl and aryl) to aldehydes using chiral titanium TADDOLate XXX (10 mol%), in toluene as solvent at –78 ᵒC (Scheme 31). When n-BuLi was added to benzaldehyde without remove the LiCl generated after transmetallation with ClTi(Oi-Pr)3 (1.2 eq.) 60% ee is obtained, but when LiCl is removed an excellent 98% of enantiomeric excess is achieved, demonstrating that lithium salts are the responsible of the decrease in the enantioselectivity.
33 Rönnholm, P.; Södergren, M.; Hilmerson, G. Org. Lett. 2007, 9, 3781–3783. 34 Gessner, V. H.; Däschlein, C.; Strohmann, C. Chem. Eur. J. 2009, 15, 3320–3334.
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Chapter II – Introduction
Scheme 31. Catalytic enantioselective addition of RLi to aldehydes catalyzed by TADDOLate XXX.
In 2009, Walsh´s group developed an effective methodology for the arylation of aldehydes with in situ generated organolithium reagents to broad variety of aldehydes using ZnCl2 as transmetallating agent and ligand XXXI (Scheme 32). The methodology also includes the addition of TEEDA (0.8 eq.) to chelate lithium salts generated during the transmetallation process that allows the synthesis of active specie Ar(n-Bu)Zn. Chiral diarylmethanols, prepared from the addition of aryl and heteroaryl nucleophiles, are synthesized with excellent levels of enantioselectivities (up to 95%) and very good yields under this novel methodology.
Scheme 32. Catalytic enantioselective addition of ArLi to aldehydes catalyzed by (–)-MIB (XXXI).
In 2010, Harada developed a methodology to prepare enantioenriched secondary alcohols through asymmetric arylation of aldehydes using organolithium reagents as nucleophile, prepared by lithiation with n-BuLi of the corresponding aryl bromide. Prior to the reaction with the aldehyde, the organolithium reagent is treated with
MgBr2, (to transmetallate to the corresponding Grignard reagent), followed by the addition of Ti(Oi-Pr)4 in excess, to generate the corresponding organotitanium
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Chapter II – Introduction
compound.35 The reaction is carried out in DCM at 0 ᵒC, using 2 mol% of 3-(3,5- diphenylphenyl)-H8-(R)-BINOL (XXXII) and excellent yields and enantioselectivities are achieved with this methodology (Scheme 33).
Scheme 33. Catalytic enantioselective addition of ArLi to aldehydes catalyzed by diol XXXII.
Organolithium reagents are highly reactive organometallic nucleophiles and achieve the asymmetric direct addition to aldehydes without a metal salt to transmetallate into a less reactive organometallic specie it is not easy. In 2011, Maddaluno and Marchand achieved the first substoichiometric direct addition of MeLi to o- methylbenzaldehyde using 33 mol% of chiral ligand XXXIII and 33 mol% of LiCl (Scheme 34). The methylated alcohol was generated in 80% yield and 80% ee.
Scheme 34. Subtoichiometric enantioselective addition of MeLi to o-methylbenzaldehyde catalyzed by diol XXXIII.
In 2014, Da reported a double transmetallation methodology for the arylation of aldehydes with organolithium reagents, but in this case the first transmetallation 36 takes place with AlCl3. The reaction is carried out in a THF/n-hexane mixture at 40 ᵒC using TMEDA to chelate lithium salts generated during the transmetallation
35 Nakagawa, Y.; Muramatsu, Y.; Harada, T. Eur. J. Org. Chem. 2010, 6535–6538. 36 Yang, Y-X.; Liu, Y.; Zhang, L.; Jia, Y-E.; Wang, P.; Zhuo, F-F.; An, X-T.; Da, C-S. J. Org. Chem. 2014, 79, 10696−10702.
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process (Scheme 35). These salts catalyze the background reaction and are the responsible of racemic products. The ligand used in this transformation is the readily commercial available H8-(S)-BINOL (XXXIV) offering excellent results concerning yield and ee for a wide variety of aromatic aldehydes.
Scheme 35. Catalytic enantioselective addition of ArLi to aldehydes catalyzed by H8-(S)-BINOL XXXIV.
As has been shown in previous works, it is difficult to perform the enantioselective addition of organolithium reagents to aldehydes using catalytic amounts of a chiral ligand and without employing metal salts as transmetallating reactant.
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Chapter II – Results and discussion
2. Results and discussion
2.1 Optimization of the catalytic enantioselective addition of organolithium reagents to aldehydes
As a starting point of the optimization process, MeLi was chosen as nucleophile for the asymmetric addition to benzaldehyde (1a) as the model reaction. The parameters that were taken into account for the optimization are: solvent, temperature, Ti(Oi-
Pr)4/MeLi ratio and ligand screening.
Preliminary tests for the addition of MeLi to the model substrate benzaldehyde (1a) provided very promising results (Table 2). (S)-1-Phenylethanol (2a) was obtained with 90% enantioselectivity and 40% conversion when 1a was added immediately after the addition of 1.5 eq. of MeLi into a toluene solution containing 10 mol% of (Sa,R)-L1 and 4.5 eq. of Ti(Oi-Pr)4 at 40 °C (Table 2, entry 1). Both conversion and enantioselectivity could be improved (63% conv., 93% ee) by increasing the catalyst loading up to 20 mol% (Table 2, entry 2). However, changing the reaction temperature did not provide any better results; higher temperatures (20 °C) led to lower enantioselectivity (Table 2, entry 3) whilst lower temperatures (60 °C) gave lower conversions (Table 2, entry 4).
It should be noted that the addition protocol had a significant influence in the outcome of the process. When MeLi was added last to the reaction mixture, the enantioselectivity dropped to 74% (Table 2, entry 5). More interestingly, when substrate 1a was added 15 min after the addition of the MeLi to the reaction mixture containing the ligand and the titanium tetraisopropoxide, the conversion drastically diminished to 19% (Table 2, entry 6), which indicates that the active species formed upon addition of MeLi to complex (Sa,R)-L1-Ti(Oi-Pr)4 has a short life time at 40 °C.
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Chapter II – Results and discussion
Table 2. Influence of catalyst loading, temperature and addition protocol[a]
[b] [b] Entry (Sa,R)-L1 (mol%) T (°C) Conv. (%) ee (%) 1 10 40 40 90 2 20 40 63 93 3 20 20 50 66 4 20 60 20 84 5[c] 20 40 63 74 6[d] 20 40 19 86
[a] Conditions: 1a (0.1 mmol, 0.07 M), MeLi (1.6 M in Et2O, 1.5 eq.), (Sa,R)-L1, Ti(Oi-Pr)4 (4.5 eq.), toluene (1.5 mL), 40 °C, 1 h. [b] Determined by chiral GC analysis. [c] MeLi was added the last. [d] 1a was added 15 min after the addition of MeLi.
In a second stage of the optimization process, the amounts of Ti(Oi-Pr)4 and MeLi were adjusted, which was a crucial step in this process to get good results. The reaction in the presence of chiral ligand (Sa,R)-L1 but no Ti(Oi-Pr)4, was checked and gave the desired product 2a with full conversion, but racemic (Table 3, entry 1). This means that there is probably no coordination between the free organometallic species and the ligand, indicating that the active species in the reaction are the organotitanium species generated in situ by transmetallation of the organolithium reagent with the excess of Ti(Oi-Pr)4.
The presence of substoichiometric amount (0.2 eq.) of Ti(Oi-Pr)4 respect to the nucleophile provided the same result (Table 3, entry 1 vs 2). The presence of, at least, equimolar Ti(Oi-Pr)4/MeLi amounts were necessary to get high enantioselectivities of 89 and 90% (Table 3, entries 3-4). The conversion of the reaction was optimized, preserving good enantioselectivities, by increasing the amount of nucleophile from
1.5 eq. to 3 eq. keeping the same Ti(Oi-Pr)4/MeLi ratio (Table 3, entries 3-4).
In order to improve the previous results, different superstoichiometric Ti(Oi-
Pr)4/MeLi amounts were tested (Table 3, entries 5-12). As shown in Table 3, there is not a strong correlation between Ti(Oi-Pr)4/MeLi ratio and enantiomeric excess, so after several attempts, the best results concerning ee and conversion were achieved
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Chapter II – Results and discussion
with a ratio 2:1 Ti(Oi-Pr)4/MeLi (Table 3, entries 5-8). Then, different combinations were tested keeping the 2:1 Ti(Oi-Pr)4/MeLi ratio constant (Table 3, entries 5-8). The optimal combination found was 3.2 eq. MeLi and 6 eq. Ti(Oi-Pr)4 (Table 3, entry 7), which allowed the reaction to reach very good levels of conversion and 94% enantioselectivity in only 1 hour at 40 oC.
[a] Table 3. Optimization Ti(Oi-Pr)4/MeLi ratio
[b] [b] Entry Ti(Oi-Pr)4 (eq.) MeLi (eq.) Ti:Li ratio Conv. (%) ee (%) 1 - 1.5 - >99 0 2 0.2 1.5 0.1:1 >99 0 3 1.5 1.5 1:1 23 89 4 3 3 1:1 55 90 5 3 1.5 2:1 59 96 6 5 2.5 2:1 73 94 7 6 3.2 1.9:1 85 94 8 7 3.5 2:1 88 94 9 3.8 1.5 2.5:1 52 96 10 4.5 1.5 3:1 63 93 11 9 3 3:1 88 90 12 6 1.5 4:1 41 92
[a] Conditions: 1a (0.1 mmol, 0.07 M), MeLi (1.6 M in Et2O, x eq.), Ti(Oi-Pr)4 (y eq.), (Sa,R)-L1 (20 mol%), toluene (1.5 mL), 40 °C, 1 h. [b] Determined by chiral GC analysis.
With the previous optimized conditions in hand, diverse anhydrous solvents with different polarity and coordination ability were also evaluated for the model reaction. In polar solvents, the reaction did not work properly and very low conversions and ee were obtained (Table 4, entries 1-4), except when DCM was used as solvent an 88% ee was achieved, but with 35% conversion (Table 4, entry 2). However, when more apolar solvents were used, the reaction proceeded with excellent levels of enantioselectivity and moderate to very good conversions (Table 4, entries 5-7). In particular, toluene and n-hexane provided the best results (Table 4, entries 6-7), but the use of n-hexane was discarded to avoid possible solubility problems with other substrates.
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Table 4. Solvent optimization[a]
Entry Solvent Conv.[b] (%) ee[b] (%) 1 Acetonitrile 10 0 2 DCM 35 88 3 DME 0 - 4 THF 4 36 5 Et2O 46 88 6 Toluene 85 94 7 n-Hexane 86 94
[a] Conditions: 1a (0.1 mmol, 0.07 M), MeLi (1.6 M en Et2O, 3.2 eq.), Ti(Oi-Pr)4 (6 eq.), (Sa,R)-L1 (20 mol%), solvent (1.5 mL), 40 °C, 1 h. [b] Determined by chiral GC analysis.
Under these optimized conditions, a small library of chiral diols was screened as ligands (Figure 1) for the addition of MeLi to benzaldehyde (1a). The results suggest that the configuration of the sp3 stereogenic center of the ligand is of crucial importance (Table 5, entry 1 vs 2). Variation of the aromatic substituents (L1-L6) on that sp3 stereogenic center did not have a significant effect on either conversion or enantioselectivity (Table 5, entry 1 vs 3-7), with the exception of the ortho-methoxy substituted (Sa,S)-L3 which provided lower conversion (Table 5, entry 3), probably due to steric effects. (Sa,R)-L1 and (Sa,R)-L6 provided the best results (Table 5, entry 1 and 7), but (Sa,R)-L1 was chosen for the rest of these studies for being structurally simpler and easier to synthetize.
Figure 1. Chiral diol ligands screened in this study
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Chapter II – Results and discussion
Table 5. Ligand optimization[a]
Entry L* Conv.[b] (%) ee[b] (%)
1 (Sa,R)-L1 85 94 [c] 2 (Sa,S)-L1 60 0 3 (Sa,R)-L2 79 94 4 (Sa,S)-L3 15 93 5 (Sa,R)-L4 81 90 6 (Sa,R)-L5 84 86 7 (Sa,R)-L6 87 94 [a] Conditions: 1a (0.1 mmol, 0.07 M), MeLi (1.6 M in Et2O, 3.2 eq.), Ti(Oi-Pr)4 (6 eq.), L* (20 mol%), toluene (1.5 mL), 40 °C, 1 h. (b) Determined by chiral GC analysis. [c] Same axial chirality as (Sa,R)-L1 but oppositte configuration at the sp3 stereogenic center.
2.2. Scope of the reaction
With the best optimized conditions in hands, the scope of the addition of MeLi was then examined with different aldehydes (Table 6). The new catalytic system described above proved to be remarkably efficient; a versatile range of methyl carbinol units were prepared in good yield (74% to 91%) and enantioselectivity (72% to 90%) from a wide range of substrates bearing electron-poor or electron-rich substituents at the meta and para position (Table 6, entries 1 and 3-8). The lower yield and selectivity of o-methylbenzaldehyde (1b, Table 6, entry 2) might be ascribed to higher steric hindrance around the reactive site.
The tolerance of this methodology towards functionalized substrates should be emphasized: chloro- (1g) and cyano- (1h) functionalities showed resistance to the very reactive lithium reagents when used under these reaction conditions (Table 6, entries 7-8). The reactions with 2-naphthaldehyde (1i) and the heteroaromatic substrates: 2-thiophenecarboxaldehyde (1j) and 2-furaldehyde (1k) gave 90%, 88% and 72% ee respectively along with very good yields (Table 6, entries 9-11), whereas cinnam aldehyde (1l) provided a moderate enantioselectivity (Table 6, entry 12). Remarkably, all reactions were finished in less than 1 h without by-product formation. Moreover, the unreacted starting material and ligand could be easily
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Chapter II – Results and discussion
recovered and the latter, recycled and reused with any loss of activity. Regarding aliphatic substrates, phenylacetaldehyde (1m, Table 6, entry 13) gave low conversion and moderate enantioselectivity while the addition of MeLi to pivaldehyde (1n, Table 6, entry 14) proceeded in less than 2% conversion. In general, the use of aliphatic aldehydes as electrophiles for 1,2 addition is a challenge because this type of substrates have several drawbacks which disfavoured the asymmetric addition such as: i) multiple conformations, ii) hydrogens in to the carbonyl, with highly enolyzable character and iii) absence of – stacking with the ligand.
Table 6. Asymmetric addition of MeLi to aldehydes[a]
Entry Aldehyde Product Yield[b] (%) ee[c] (%)
1 87 90 (S)
2 78 62 (S)
3 87 82 (S)
4 81 88 (S)
5 91 89 (S)
6 82 88 (S)
7 74 84 (S)
8 84 82 (S)
9 85 90 (S)
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Chapter II – Results and discussion
10 57 (90)[d] 88 (S)
11 56 (86)[d] 72 (S)
12 84 68 (S)
13 23 62 (S)
14 2 n.d.[e]
[a] Conditions: 1 (0.3 mmol, 0.12 M), MeLi (1.6 M in Et2O, 3.2 eq.), (Sa,R)-L1 (20 mol%),
Ti(Oi-Pr)4 (6 eq.), toluene (2.5 mL), 40 °C, 1 h. [b] Isolated yield after flash silica gel chromatography. [c] Determined by chiral GC analysis. Absolute configuration of chiral alcohols was determined by correlation of optical rotation with known compounds. [d] Volatile products, conversions based on GC data in brackets. [e] Not determined.
Finally, other common alkyllithium reagents were also tested (Table 7). Gratifyingly, the addition of other linear reagents like EtLi and n-BuLi proceeded with good yield (62% to 90%) and enantioselectivity (90% to 96%) for a wide range of aromatic aldehydes bearing electron donating or withdrawing groups (Table 7, entries 1-8). It was also noted that: i) the increase in the size of the nucleophile meant an improvement in the enantioselectivity (Table 7, entries 1-3 vs 4-8); ii) no evidence of common lithium-halogen exchange was found when halogenated aldehydes were used as substrates (Table 7, entries 5-6); iii) labile functionalities like carbonates were tolerated as demonstrated by the addition of n-BuLi to 1p (Table 7, entry 8).
Table 7. Asymmetric addition of EtLi and n-BuLi reagents to aldehydes[a]
Entry Aldehyde Product Yield[b] (%) ee[c] (%)
1 78 92 (S)
2 66 90 (S)
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Chapter II – Results and discussion
3 62 92 (S)
4 90 96 (S)
5 89 94 ()
6 85 92 (S)
7 89 94 (S)
8 90 96 ()
[a] Conditions: 1 (0.3 mmol, 0.12 M), RLi (3.2 eq.), (Sa,R)-L1 (20 mol%), Ti(Oi-Pr)4 (6 eq.), toluene (2.5 mL), 40 °C, 1 h. [b] Isolated yield after flash silica gel chromatography. [c] Determined by chiral GC or HPLC analysis. Absolute configuration of chiral alcohols was determined by correlation of optical rotation with known compounds.
A limitation of this methodology is highlighted by the reaction of the bulky i-BuLi with benzaldehyde (1a), that gave 40% conversion into the reduction product phenylmethanol while the desired alcohol 2w was only formed in 8% yield with 62% ee (Figure 2).
Figure 2. Chiral secondary alcohols derived from addition of i-BuLi and PhLi to aldehydes
Interestingly, the use of the sp2-hybridized phenyllithium reagent provided very good yield but low and moderated enantioselectivities in the addition to 2-naphthaldehyde (1i) and cyclohexanecarboxaldehyde (1q), respectively (Figure 2). Aryllithium reagents are more reactive than alkyllithium due to the negative charge is localized 2 on a sp carbon. Also the lower aggregation state in solution (tetramer-dimer in Et2O) compared to alkyllithium (tetramer, hexamer) makes them much more reactive. We
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Chapter II – Results and discussion
believe this high reactivity was the reason why we were unable to suppress/minimize the uncatalyzed background reaction and low enantioselectivities (2x and 2y, Figure 2).
In conclusion, a methodology has been developed for the first efficient enantioselective catalytic system for the addition of alkyllithium reagents to aromatic aldehydes using an excess of titanium tetraisopropoxide. This methodology allows the preparation of highly valuable optically active alcohols from economical and commercially available lithium reagents. Reactions are performed in a simple and fast one-pot procedure and no salt exclusion is needed. Moreover, the potential problems associated with the high reactivity of organolithium compounds are overcome under these reaction conditions since this methodology proves to be compatible with functionalized substrates.
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Chapter II – Experimental part
3. Experimental part
3.1 General procedure for the enantioselective addition of organolithium reagents to aldehydes
In a flame dried Schlenk tube, (Sa,R)-L1 (22.6 mg, 0.06 mmol, 20 mol%) was dissolved in anhydrous toluene (2.5 mL) under argon atmosphere. The solution was cooled down to 40 °C and Ti(Oi-Pr)4 (550 L, 1.8 mmol, 6 eq.) was then added. Five minutes later, RLi (0.96 mmol, 3.2 eq.) was added followed by the immediate addition of the corresponding aldehyde (0.3 mmol) previously distilled. The reaction was quenched with water (5 mL) and then HCl 2 M (5 mL) to eliminate the titanium oxides generated by the addition of water. The crude was extracted with EtOAc (3 × 10 mL), and the combined organic layers were neutralized with a saturated NaHCO3 aqueous solution (15 mL), dried over magnesium sulfate and concentrated under vacuum. The crude product was purified by flash silica gel chromatography to give the desired products.
3.2 Data of chiral secondary alcohols prepared from organolithium reagents
(S)-1-Phenylethanol (2a):37 Compound 2a was obtained after purification on flash silica gel chromatography from 100:0 till 86:14 (n- 25 hexane/EtOAc) as a colorless oil (87% yield, 90% ee); []D = 54.0 (c Lit. 20 1 1.0, CHCl3) { []D = 39.6 (c 2.5, CHCl3) for 82% ee}. H NMR (300 MHz, CDCl3) 7.39 – 7.21 (m, 5H), 4.86 (q, J = 6.5 Hz, 1H), 2.10 (br s, 1H), 1.47 (d, J = 6.5 Hz, 3H). 13C
NMR (75 MHz, CDCl3) 145.8, 128.4, 127.4, 125.3, 70.3, 25.1. LRMS (EI): m/z (%): 122 [M+] (12), 107 (39), 105 (15), 104 (100), 103 (47), 79 (41), 78 (50), 77 (42), 51 (24), 50 (13). Ee determination by chiral GC analysis, HP-CHIRAL-20 column, T = 120 °C, P =
14.3 psi, retention times: tr(R) = 13.1 min, tr(S) = 13.5 min (major enantiomer).
37 Kantam, M. L.; Laha, S.; Yadav, J.; Likhar, P.R.; Sreedhar, B.; Jha, S.; Bhargava, S.; Udayakiran, M.; Jagadeesh, B. Org. Lett. 2008, 10, 2979–2982.
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Chapter II – Experimental part
(S)-1-(o-Tolyl)ethanol (2b):38 Compound 2b was obtained after purification on flash silica gel chromatography from 100:0 till 86:14 (n- 25 hexane/EtOAc) as a yellow oil (78% yield, 62% ee); []D = 47.0 (c 1.0, Lit. 20 1 CHCl3) { []D = 72.5 (c 1.0, CHCl3) for 96% ee}. H NMR (300 MHz, CDCl3) 7.49 (d, J = 7.4 Hz, 1H), 7.26 – 7.08 (m, 3H), 5.09 (q, J = 6.4 Hz, 1H), 2.32 (s, 3H), 1.99 (br s, 13 1H), 1.44 (d, J = 6.4 Hz, 3H). C NMR (75 MHz, CDCl3) 143.8, 134.1, 130.3, 127.1, 126.3, 124.4, 66.7, 23.9, 18.9. LRMS (EI): m/z (%): 136 [M+] (2), 121 (16), 119 (10), 118 (80), 117 (100), 115 (44), 103 (10), 93 (16), 91 (44), 77 (15), 65 (12), 63 (11). Ee determination by chiral GC analysis, HP-CHIRAL-20 column, T = 120 °C, P = 14.3 psi, retention times: tr(R) = 24.2 min, tr(S) = 27.4 min (major enantiomer).
(S)-1-(m-Tolyl)ethanol (2c):39 Compound 2c was obtained after purification on flash silica gel chromatography from 100:0 till 86:14 25 (n-hexane/EtOAc) as a yellow oil (87% yield, 82% ee); []D = 43.0 (c Lit. 16 1 1.0, CHCl3) { []D = 47.3 (c 0.8, CHCl3) for 90% ee}. H NMR (300 MHz, CDCl3) 7.23 (dd, J = 7.2, 3.7 Hz, 1H), 7.20 – 7.13 (m, 2H), 7.08 (d, J = 7.3 Hz, 1H), 4.85 (q, J = 6.4 Hz, 1H), 2.36 (s, 3H), 1.92 (br s, 1H), 1.48 (d, J = 6.5 Hz, 3H). 13C NMR (75 MHz,
CDCl3) 145.8, 138.1, 128.4, 128.2, 126.1, 122.4, 70.4, 25.1, 21.4. LRMS (EI): m/z (%): 136 [M+] (11), 121 (23), 119 (16), 118 (93), 117 (100), 115 (40), 103 (13), 93 (27), 92 (11), 91 (53), 77 (17), 65 (13), 51 (9). Ee determination by chiral GC analysis, HP-
CHIRAL-20 column, T = 120 °C, P = 14.3 psi, retention times: tr(R) = 20.1 min, tr(S) = 20.8 min (major enantiomer).
(S)-1-(p-Tolyl)ethanol (2d):40 Compound 2d was obtained after purification on flash silica gel chromatography from 100:0 till 86:14 25 (n-hexane/EtOAc) as a colorless oil (81% yield, 88% ee); []D = 55.0 Lit. 20 1 (c 1.0, CHCl3) { []D = 53.7 (c 0.4, CHCl3) for 96% ee}. H NMR (400 MHz, CDCl3) 7.26 (d, J = 8.2 Hz, 2H), 7.15 (d, J = 7.6 Hz, 2H), 4.86 (q, J = 6.4 Hz, 1H), 2.34 (s, 3H),
38 Li, Y.; Zhou, Y.; Shi, Q.; Ding, K.; Sandoval, C. A.; Noyori, R. Adv. Synth. Catal. 2011, 353, 495–500. 39 Wang, W.; Wang, Q. Chem.Commun. 2010, 46, 4616–4618. 40 Zhu, Q-M.; Shi, D-J.; Xia, C-G.; Huang, H-M. Chem. Eur. J. 2011, 17, 7760–7763.
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Chapter II – Experimental part
13 2.03 (br s, 1H), 1.48 (d, J = 6.5 Hz, 3H). C NMR (101 MHz, CDCl3) 142.8, 137.1, 129.1, 125.3, 70.2, 25.0, 21.1. LRMS (EI): m/z (%): 136 [M+] (9), 121 (27), 119 (13), 118 (84), 117 (100), 115 (38), 103 (11), 93 (19), 91 (48), 77 (15), 65 (12). Ee determination by chiral GC analysis, HP-CHIRAL-20 column, T= 120 °C, P= 14.3 psi, retention times: tr(R) = 19.3 min, tr(S) = 20.2 min (major enantiomer).
(S)-1-(4-Methoxyphenyl)ethanol (2e):41 Compound 2e was obtained after purification on flash silica gel chromatography from 100:0 till 83:17 (n-hexane/EtOAc) as a yellow oil (91% yield, 89% 25 Lit. 20 1 ee); []D = 42.0 (c 1.0, CHCl3) { []D = 51.9 (c 1.0, CHCl3) for 97% ee}. H NMR
(300 MHz, CDCl3) 7.30 (d, J = 8.7 Hz, 2H), 6.88 (d, J = 8.7 Hz, 2H), 4.85 (q, J = 6.4 Hz, 13 1H), 3.80 (s, 3H), 1.85 (br s, 1H), 1.47 (d, J = 6.4 Hz, 3H). C NMR (75 MHz, CDCl3) 159.0, 138.0, 126.6, 113.8, 70.0, 55.3, 25.0. LRMS (EI): m/z (%): 152 [M+] (6), 137 (23), 135 (14), 134 (100), 119 (50), 109 (9), 91 (54), 77 (12), 65 (23), 63 (10), 51 (6). Ee determination by chiral GC analysis, HP-CHIRAL-20 column, T = 120 °C, P = 14.3 psi, retention times: tr(R) = 53.8 min, tr(S) = 55.3 min (major enantiomer).
(S)-1-[4-(Trifluoromethyl)phenyl]ethanol (2f):37 Compound 2f was obtained after purification on flash silica gel chromatography from 100:0 till 86:14 (n-hexane/EtOAc) as a yellow oil (82% yield, 88% 25 Lit. 20 1 ee); []D = 41.0 (c 1.0, CHCl3) { []D = 33.7 (c 5.5, CHCl3) for 97% ee}. H NMR
(300 MHz, CDCl3) 7.60 (d, J = 8.2 Hz, 2H), 7.47 (d, J = 8.6 Hz, 2H), 4.95 (q, J = 6.5 Hz, 13 1H), 2.16 (br s, 1H), 1.49 (d, J = 6.5 Hz, 3H). C NMR (75 MHz, CDCl3) 149.7, 129.8, 129.4, 125.6, 125.4, 125.4, 122.3, 69.8, 25.3. LRMS (EI): m/z (%): 190 [M+] (7), 175 (100), 173 (18), 172 (40), 171 (14), 151 (13), 145 (22), 127 (93), 103 (16), 77 (12). Ee determination by chiral GC analysis, HP-CHIRAL-20 column, T = 130 °C, P = 14.3 psi, retention times: tr(R) = 11.1 min, tr(S) = 11.8 min (major enantiomer).
41 Fujii, A.; Hashiguchi, S.; Uematsu, N.; Ikariya, T.; Noyori, R. J. Am.Chem. Soc. 1996, 118, 2521–2522.
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(S)-1-(4-Chlorophenyl)ethanol (2g):42 Compound 2g was obtained after purification on flash silica gel chromatography from 100:0 till 25 86:14 (n-hexane/EtOAc) as a yellow oil (74% yield, 84% ee); []D = Lit. 20 1 38.0 (c 1.0, CHCl3) { []D = 43.6 (c 1.0, CHCl3) for 97% ee}. H NMR (400 MHz,
CDCl3) 7.31 (d, J = 9.0 Hz, 2H), 7.28 (d, J = 8.9 Hz, 2H), 4.86 (q, J = 6.5 Hz, 1H), 2.40 13 (br s, 1H), 1.46 (d, J = 6.5 Hz, 3H). C NMR (101 MHz, CDCl3) 144.2, 133.0, 128.5, 126.8, 69.7, 25.2. LRMS (EI): m/z (%): 156 [M+] (11), 143 (13), 141 (46), 140 (34), 139 (23), 138 (100), 113 (14), 112 (13), 103 (72), 102 (22), 101 (12), 77 (60), 75 (22), 74 (12), 51 (23), 50 (14). Ee determination by chiral GC analysis, HP-CHIRAL-20 column,
T = 125 °C, P = 14.3 psi, retention times: tr(R) = 35.8 min, tr(S) = 38.0 min (major enantiomer).
(S)-4-(1-Hydroxyethyl)benzonitrile (2h):43 Compound 2h was obtained after purification on flash silica gel chromatography from 100:0 till 80:20 (n-hexane/EtOAc) as a yellow oil (84% yield, 82% 25 Lit. 20 1 ee); []D = 27.0 (c 0.7, CHCl3) { []D = 62.7 (c 2.1, CHCl3) for 72% ee}. H NMR
(300 MHz, CDCl3) 7.63 (d, J = 8.3 Hz, 2H), 7.49 (d, J = 8.1 Hz, 2H), 4.96 (q, J = 6.5 Hz, 13 1H), 2.22 (br s, 1H), 1.49 (d, J = 6.5 Hz, 3H). C NMR (75 MHz, CDCl3) 151.1, 132.3, 126.0, 118.8, 111.0, 69.6, 25.4. LRMS (EI): m/z (%): 147 [M+] (8), 132 (100), 130 (25), 129 (53), 128 (17), 104 (85), 103 (19), 102 (32), 77 (27), 76 (16), 75 (14), 51 (13). Ee determination by chiral GC analysis, HP-CHIRAL-20 column, T = 150 °C, P = 14.3 psi, retention times: tr(R) = 43.0 min, tr(S) = 46.2 min (major enantiomer).
(S)-1-(Naphthalen-2-yl)ethanol (2i):40 Compound 2i was obtained after purification on flash silica gel chromatography from 100:0 till 86:14 (n-hexane/EtOAc) as a white powder (85% yield, 90% ee); 25 Lit. 20 m.p. 56 – 58 °C, []D = 36.7 (c 1.0, CHCl3) { []D = 48.1 (c 1.5, CHCl3) for 92% 1 ee}. H NMR (300 MHz, CDCl3) 7.84 – 7.70 (m, 4H), 7.50 – 7.39 (m, 3H), 4.98 (q, J = 13 6.4 Hz, 1H), 2.39 (br s, 1H), 1.52 (d, J = 6.5 Hz, 3H). C NMR (75 MHz, CDCl3) 143.1,
42 Xie, J-H.; Liu, X-Y.; Xie, J-B.; Wang, L-X.; Zhou, Q-L. Angew. Chem., Int. Ed. Engl. 2011, 50, 7329–7332. 43 Kantam, M. L.; Yadav, J.; Laha, S.; Srinivas, P.; Sreedhar, B.; Figueras, F. J. Org. Chem.2009, 74, 4608–4611.
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133.2, 132.8, 128.2, 127.9, 127.6, 126.0, 125.7, 123.8, 123.7, 70.4, 25.0. LRMS (EI): m/z (%): 172 [M+] (6), 155 (16), 154 (100), 153 (56), 152 (37), 151 (12), 129 (27), 128 (18), 127 (12), 76 (18), 63 (6). Ee determination by chiral GC analysis, CP-Chirasil-DEX
CB column, T = 150 °C, P = 14.3 psi, retention times: tr(R) = 25.6 min, tr(S) = 26.5 min (major enantiomer).
(S)-1-(Thiophen-2-yl)ethanol (2j):40 Compound 2j was obtained after purification on flash silica gel chromatography from 100:0 till 82:18 (n- 25 hexane/EtOAc) as a volatile brown oil (57% yield, 88% ee); []D = 21.0 Lit. 20 1 (c 1.0, CHCl3) { []D = 27.6 (c 1.0, CHCl3) for 94% ee}. H NMR (400 MHz, CDCl3) 7.24 (dd, J = 4.8, 1.4 Hz, 1H), 7.00 – 6.94 (m, 2H), 5.13 (q, J = 6.4 Hz, 1H), 2.09 (br s, 13 1H), 1.60 (d, J = 6.4 Hz, 3H). C NMR (101 MHz, CDCl3) 149.83, 126.62, 124.40, 123.15, 66.22, 25.23. LRMS (EI): m/z (%): 128 [M+] (11), 113 (22), 111 (18), 110 (100), 109 (43), 85 (32), 84 (26), 66 (24), 65 (10), 58 (10). Ee determination by chiral GC analysis, HP-CHIRAL-20 column, T = 120 °C, P = 14.3 psi, retention times: tr(R) = 14.3 min, tr(S) = 14.7 min (major enantiomer).
(S)-1-(Furan-2-yl)ethanol (2k):40 Compound 2k was obtained after purification on flash silica gel chromatography from 100:0 till 82:18 (n- 25 hexane/EtOAc) as a very volatile yellow oil (56% yield, 72% ee); []D = Lit. 20 1 7.0 (c 0.8, CHCl3) { []D = 19.8 (c 0.9, CHCl3) for 98% ee}. H NMR (300 MHz,
CDCl3) 7.38 (dd, J = 1.8, 0.7 Hz, 1H), 6.33 (dd, J = 3.2, 1.8 Hz, 1H), 6.23 (d, J = 3.2 Hz, 13 1H), 4.89 (q, J = 6.6 Hz, 1H), 1.55 (d, J = 6.6 Hz, 3H). C NMR (75 MHz, CDCl3) 157.5, 141.9, 110.1, 105.1, 63.6, 21.2. LRMS (EI): m/z (%): 113 [M++1] (3), 112 [M+] (47), 111 (6), 97 (100), 95 (23), 84 (10), 69 (21), 67 (7), 65 (6), 55 (6). Ee determination by chiral
GC analysis, HP-CHIRAL-20 column, T = 80 °C, P = 14.3 psi, retention times: tr(R) =
21.7 min, tr(S) = 22.4 min (major enantiomer).
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(S,E)-4-Phenylbut-3-en-2-ol (2l):44 Compound 2l was obtained after purification on flash silica gel chromatography from 100:0 till 85:15 25 (n-hexane/EtOAc) as a yellow oil (84% yield, 68% ee); []D = 20.3 Lit. 20 1 (c 1.0, CHCl3) { []D = 14.6 (c 1.0, CHCl3) for 60% ee}. H NMR (400 MHz, CDCl3) 7.37 (dd, J = 5.3, 3.2 Hz, 2H), 7.34 – 7.27 (m, 2H), 7.27 – 7.20 (m, 1H), 6.55 (d, J = 15.9 Hz, 1H), 6.25 (dd, J = 15.9, 6.4 Hz, 1H), 4.47 (p, J = 6.3 Hz, 1H), 1.99 (br s, 1H), 1.36 (d, 13 J = 6.4 Hz, 3H). C NMR (101 MHz, CDCl3) 136.6, 133.5, 129.3, 128.5, 127.6, 126.4, 68.8, 23.3. LRMS (EI): m/z (%): 149 [M++1] (1), 148 [M+] (9), 131 (11), 130 (87), 129 (100), 128 (63), 127 (25), 115 (63), 105 (14), 91 (11), 77 (15), 51 (13). Ee determination by chiral GC analysis, CP-Chirasil-DEX CB column, T = 110 °C, P = 10.0 psi, retention times: tr(R) = 62.4 min, tr(S) = 63.7 min (major enantiomer).
(S)-1-Phenylpropan-2-ol (2m):45 Compound 2m was obtained after purification on flash silica gel chromatography from 100:0 till 86:14 25 Lit. (n-hexane/EtOAc) as a colorless oil (23% yield, 62% ee); []D = +4.5 (c 0.8, CHCl3) { 25 1 []D = +42.2 (c 1.0, CHCl3) for 99% ee}. H NMR (300 MHz, CDCl3) 7.35 – 7.26 (m, 2H), 7.26 – 7.16 (m, 3H), 4.08 – 3.90 (m, 1H), 2.75 (dd, J = 28.1, 6.4 Hz, 1H), 2.70 (dd, J 13 = 28.1, 6.4 Hz, 1H), 1.66 (br s, 1H), 1.23 (d, J = 6.2 Hz, 3H). C NMR (75 MHz, CDCl3) 138.5, 129.4, 128.5, 126.4, 68.8, 45.8, 22.7. LRMS (EI): m/z (%): 136 [M+] (1), 118 (23), 117 (35), 115 (15), 92 (100), 91 (94), 65 (19), 51 (9). Ee determination by chiral GC analysis, CP-Chirasil-DEX CB column, T = 100 °C, P = 14.3 psi, retention times: tr(R) =
24.7 min, tr(S) = 26.0 min (major enantiomer).
(S)-1-Phenylpropan-1-ol (2o):40 Compound 2o was obtained after purification on flash silica gel chromatography from 100:0 till 88:12 (n- 25 hexane/EtOAc) as a yellow oil (75% yield, 92% ee); []D = 39.8 (c Lit. 20 1 1.0, CHCl3) { []D = 49.6 (c 0.5, CHCl3) for 98% ee}. H NMR (400 MHz, CDCl3) 7.38 – 7.26 (m, 5H), 4.60 (t, J = 6.6 Hz, 1H), 1.91 – 1.69 (m, 2H), 1.60 (br s, 1H), 0.92 (t,
44 Inagaki, T.; Ito, A.; Ito, J.; Nishiyama, H. Angew. Chem., Int. Ed. Engl. 2010, 49, 9384–9387. 45 Erdélyi, B.; Szabó, A.; Seres, G.; Birincsik, L.; Ivanics, J.; Szatzker, G.; Poppe,L. Tetrahedron: Asymmetry 2006, 17, 268–274.
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13 J = 7.4 Hz, 3H). C NMR (101 MHz, CDCl3) 144.6, 128.4, 127.5, 126.0, 76.0, 31.9, 10.1. LRMS (EI): m/z (%): 136 [M+] (4), 118 (73), 117 (100), 115 (45), 107 (38), 103 (10), 91 (34), 79 (28), 78 (10), 77 (25), 51 (14). Ee determination by chiral GC analysis,
HP-CHIRAL-20 column, T = 120 °C, P = 6.0 psi, retention times: tr(R) = 49.3 min, tr(S) = 50.5 min (major enantiomer).
(S)-1-(p-Tolyl)propan-1-ol (2p):46 Compound 2p was obtained after purification on flash silica gel chromatography from 100:0 till 88:12 25 (n-hexane/EtOAc) as a brown oil (66% yield, 90% ee); []D = 41.0 Lit. 20 1 (c 1.0, CHCl3) { []D = 36.1 (c 1.0, CHCl3) for 84% ee}. H NMR (400 MHz, CDCl3) 7.20 (d, J = 8.1 Hz, 2H), 7.13 (d, J = 8.2 Hz, 2H), 4.50 (t, J = 6.6 Hz, 1H), 2.33 (s, 3H), 13 2.08 (br s, 1H), 1.85 – 1.62 (m, 2H), 0.88 (t, J = 7.4 Hz, 3H). C NMR (101 MHz, CDCl3) 141.6, 137.0, 129.0, 125.9, 75.8, 31.7, 21.0, 10.1. LRMS (EI): m/z (%): 150 [M+] (3), 132 (71), 131 (19), 121 (35), 118 (10), 117 (100), 116 (16), 115 (47), 105 (11), 93 (15), 91 (40), 77 (16), 65 (13). Ee determination by chiral GC analysis, HP-CHIRAL-20 column, T = 120 °C, P = 14.3 psi, retention times: tr(R) = 30.5 min, tr(S) = 31.8 min (major enantiomer).
(S)-1-(4-Chlorophenyl)propan-1-ol (2q):47 Compound 2q was obtained after purification on flash silica gel chromatography from 100:0 till 88:12 (n-hexane/EtOAc) as a yellow oil (62% yield, 92% 25 Lit. 25 1 ee); []D = 35.5 (c 1.0, CHCl3) { []D = 38.4 (c 1.1, CHCl3) for 95% ee}. H NMR
(400 MHz, CDCl3) 7.31 (d, J = 8.6 Hz, 2H), 7.26 (d, J = 8.6 Hz, 2H), 4.57 (t, J = 6.6 Hz, 1H), 2.05 (br s, 1H), 1.85 – 1.64 (m, 2H), 0.89 (t, J = 7.4 Hz, 3H). 13C NMR (101 MHz, + CDCl3) 143.0, 133.0, 128.5, 127.3, 75.2, 31.9, 9.9. LRMS (EI): m/z (%): 172 [M +2] (2), 170 [M+] (5), 154 (19), 152 (58), 143 (17), 141 (55), 139 (14), 125 (13), 118 (10), 117 (100), 116 (24), 115 (75), 113 (12), 91 (13), 89 (12), 77 (33), 75 (13). Ee determination by chiral GC analysis, HP-CHIRAL-20 column, T = 125 °C, P = 14.3 psi, retention times: tr(R) = 57.3 min, tr(S) = 60.3 min (major enantiomer).
46 Touati, R. J. Soc. Chim. Tun. 2008, 10, 127–139. 47 Salvi, N.A. Tetrahedron: Asymmetry 2008, 19, 1992–1997.
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(S)-1-Phenylpentan-1-ol (2r):48 Compound 2r was obtained after purification on flash silica gel chromatography from 100:0 till 91:9 (n-hexane/EtOAc) as colorless needles crystals (90% yield, 96% 25 Lit 20 ee); m.p. 35 – 37 °C, []D = 37.2 (c 1.0, CHCl3) { []D = 13.6 (c 0.5, CHCl3) for 1 80% ee}. H NMR (300 MHz, CDCl3) 7.43 – 7.21 (m, 5H), 4.64 (t, J = 6.6 Hz, 1H), 1.99 (br s, 1H), 1.87 – 1.61 (m, 2H), 1.48 – 1.16 (m, 4H), 0.88 (t, J = 7.0 Hz, 3H). 13C NMR
(75 MHz, CDCl3) 144.9, 128.4, 127.4, 125.9, 74.6, 38.8, 28.0, 22.6, 14.0. LRMS (EI): m/z (%): 164 [M+] (8), 107 (100), 105 (5), 79 (40), 77 (19). Ee determination by chiral
GC analysis, Cyclosil- column, T = 150 °C, P = 14.3 psi, retention times: tr(S) = 13.5 min (major enantiomer), tr(R) = 14.4 min.
()-1-(4-Bromophenyl)pentan-1-ol (2s):49 Compound 2s was obtained after purification on flash silica gel chromatography from 100:0 till 92:8 (n-hexane/EtOAc) as a colorless crystals 25 1 (89% yield, 94% ee); m.p. 36.5 – 38.5 °C, []D = 25.8 (c 1.0, CHCl3). H NMR (300
MHz, CDCl3) 7.46 (m, 2H), 7.21 (m, 2H), 4.62 (t, J = 6.6 Hz, 1H), 1.92 (s, 1H), 1.72 (m, 13 2H), 1.28 (m, 4H), 0.88 (t, J = 7.0 Hz, 3H). C NMR (75 MHz, CDCl3) 143.8, 131.5, 127.6, 121.1, 74.0, 38.8, 27.8, 22.5, 14.0. IR (ATR): (cm-1): 3280, 2956, 2932, 2871, 2856, 1591, 1007, 824. LRMS (EI): m/z (%): 244 [M++2] (12), 242 [M+] (12), 188 (9), 187 (100), 186 (11), 185 (100), 159 (19), 157 (24), 78 (33), 77 (65), 51 (8). HRMS (EI): + m/z: 242.0306 calculated for C11H15BrO [M ], found 242.0299. Ee determination by chiral HPLC analysis, Chiralcel OJ column, n-hexane/i-PrOH 99:1, flow rate = 0.5 mL/min, = 210 nm, retention times: tr(S) = 45.3 min (major enantiomer), tr(R) = 48.2 min.
48 Glynn, D.; Shannon, J.; Woodward, S. Chem. Eur. J. 2010, 16, 1053–1060. 49 Fukushima, T.; Takachi, K.; Tsuchihara, K. Macromolecules. 2008, 41, 6599–6601.
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(S)-1-(4-Chlorophenyl)pentan-1-ol (2t):50 Compound 2t was obtained after purification on flash silica gel chromatography from 100:0 till 91:9 (n-hexane/EtOAc) as a colorless needles 25 Lit. 20 crystals (85% yield, 92% ee); m.p. 31.0 – 33.2 °C, []D = 37.6 (c 1.0, CHCl3) { []D 1 = 33.0 (c 1.0, CHCl3) for 96% ee}. H NMR (300 MHz, CDCl3) 7.31 (d, J = 8.6 Hz, 2H), 7.25 (d, J = 8.6 Hz, 2H), 4.67 – 4.57 (t, J = 6.8 Hz, 1H), 2.05 (br s, 1H), 1.84 – 1.57 (m, 13 2H), 1.43 – 1.21 (m, 4H), 0.88 (t, J = 7.0 Hz, 2H). C NMR (75 MHz, CDCl3) 143.3, 133.0, 128.5, 127.3, 73.9, 38.8, 27.8, 22.5, 13.9. LRMS (EI): m/z (%): 198 [M+] (4), 180 (24), 153 (17), 151 (53), 143 (32), 141 (100), 138 (22), 116 (35), 115 (52), 113 (15), 77 (41). Ee determination by chiral HPLC analysis, Chiralcel® OD-H column, n-hexane/i-
PrOH 99:1, flow rate = 0.5 mL/min, = 215 nm, retention times: tr(S) = 37.2 min
(major enantiomer), tr(R) = 40.7 min.
(S)-1-(4-Methoxyphenyl)pentan-1-ol (2u):48 Compound 2u was obtained after purification on flash silica gel chromatography from 100:0 till 87:13 (n-hexane/EtOAc) as 25 Lit. 20 a yellow oil (89% yield, 94% ee); []D = 35.3 (c 1.0, CHCl3) { []D = 24.2 (c 0.5, 1 CHCl3) for 82% ee}. H NMR (300 MHz, CDCl3) 7.25 (d, J = 8.7 Hz, 2H), 6.86 (d, J = 8.6 Hz, 2H), 4.58 (t, J = 6.7 Hz, 1H), 3.79 (s, 3H), 2.02 (br s, 1H), 1.88 – 1.58 (m, 2H), 1.43 – 13 1.18 (m, 4H), 0.87 (t, J = 7.0 Hz, 3H). C NMR (75 MHz, CDCl3) 158.9, 137.1, 127.1, 113.7, 74.2, 55.2, 38.6, 28.0, 22.6, 14.0. LRMS (EI): m/z (%): 194 [M+] (1), 176 (41), 147 (100), 137 (20), 115 (21), 103 (10), 91 (26), 77 (9). Ee determination by chiral HPLC analysis, Chiralcel® OD-H column, n-hexane/i-PrOH 99:1, flow rate = 0.5 mL/min, = 210 nm, retention times: tr(R) = 50.6 min, tr(S) = 59.8 min (major enantiomer).
50 Nakagawa, Y.; Muramatsu, Y.; Harada, T. J. Org. Chem. 2010, 34, 6535–6538.
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Chapter II – Experimental part
()-4-(1-Hydroxypentyl)phenyl methyl carbonate (2v): Compound 2v was obtained after purification on basic alumina chromatography from 100:0 till 77:23 (n- 25 hexane/EtOAc) as a dark yellow oil (90% yield, 96% ee); []D = 26.7 (c 1.2, CHCl3). 1 H NMR (300 MHz, CDCl3) 7.36 (d, J = 8.5 Hz, 2H), 7.15 (d, J = 8.6 Hz, 2H), 4.67 (t, J = 6.6 Hz, 1H), 3.90 (s, 3H), 1.92 (br s, 1H), 1.74 (m, 2H), 1.32 (m, 4H), 0.89 (t, J = 7.0 Hz, 13 3H). C NMR (75 MHz, CDCl3) 154.3, 150.3, 142. 8, 127.0, 120.9, 74.0, 55.4, 38.8, 27.9, 22.5, 14.0. IR (ATR): (cm-1): 3395, 2956, 2930, 1763, 1440, 1255, 1214, 1063, 1015. LRMS (EI): m/z (%): 238 [M+] (5), 182 (18), 181 (100), 137 (6), 135 (5), 122 (5), 109 (37), 94 (26), 77 (19), 66 (7), 59 (7). HRMS (EI): m/z: 238.1205 calculated for + C13H18O4 [M ], found 238.1210. Ee determination by chiral HPLC analysis, Chiralpak® AD-H column, n-hexane/i-PrOH 97:3, flow rate = 0.5 mL/min, = 220 nm, retention times: tr(S) = 23.5 min (major enantiomer), tr(R) = 25.7 min.
(S)-Naphthalen-2-yl(phenyl)methanol (2x):51 Compound 2x was obtained after purification on flash silica gel chromatography from 100:0 till 90:10 (n-hexane/EtOAc) as a 25 Lit. white powder (96% yield, 17% ee); m.p. 81 – 82 °C, []D = +2.3 (c 1.0, CHCl3) { 20 1 []D = +11.2 (c 0.8, CHCl3) for 95% ee}. H NMR (300 MHz, CDCl3) 7.83 – 7.61 (m, 4H), 7.47 – 7.36 (m, 2H), 7.36 – 7.15 (m, 6H), 5.81 (s, 1H), 2.87 (br s, 1H). 13C NMR (75
MHz, CDCl3) 143.5, 141.0, 133.1, 132.8, 128.4, 128.2, 128.0, 127.6, 127.5, 126.6, 126.1, 125.9, 125.0, 124.7, 76.2. LRMS (EI): m/z (%): 235 [M++1] (17), 234 [M+] (100), 233 (12), 217 (12), 215 (28), 202 (16), 155 (41), 129 (94), 128 (82), 127 (40), 105 (90), 77 (32). Ee determination by chiral HPLC analysis, Chiralcel® OD-H column, n- hexane/i-PrOH 90:10, flow rate = 1.0 mL/min, = 220 nm, retention times: tr(R) =
15.6 min (major enantiomer), tr(S) = 18.0 min.
51 Tjosaas, F. Arkivoc 2008, 6, 81–90.
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(R)-Cyclohexyl(phenyl)methanol (2y):52 Compound 2y was obtained after purification on flash silica gel chromatography from 100:0 till 25 90:10 (n-hexane/EtOAc) as a yellow oil (92% yield, 39% ee); []D = Lit. 20 1 +22.0 (c 1.0, CHCl3) { []D = +39.5 (c 0.2, CHCl3) for 94% ee}. H NMR (300 MHz,
CDCl3) 7.30 (m, 5H), 4.35 (d, J = 7.2 Hz, 1H), 1.98 (m, 1H), 1.85 (br s, 1H), 1.67 (m, 13 4H), 1.36 (m, 1H), 1.08 (m, 5H). C NMR (75 MHz, CDCl3) 143.6, 128.2, 127.4, 126.6, 79.4, 44.9, 29.3, 28.8, 26.4, 26.1, 26.0. LRMS (EI): m/z (%): 190 [M+] (8), 108 (10), 107 (100), 79 (29), 77 (14), 55 (7). Ee determination by chiral HPLC analysis, Chiralpak® AS-H column, n-hexane/i-PrOH 99:1, flow rate = 1.0 mL/min, = 210 nm, retention times: tr(R) = 7.5 min (major enantiomer), tr(S) = 8.3 min.
52 Yamamoto, Y.; Shirai, T.; Watanabe, M.; Kurihara, K.; Miyaura, N. Molecules 2011, 16, 50205034.
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Chapter III – Introduction
1. Introduction
An organomagnesium reagent is an organometallic compound that contains a C-Mg bond. Under this description, organomagnesium can be classified into two different categories: complete compounds, such as dialkyl or diarylmagnesium with general formula R2Mg; and mixed compounds, such as alkyl or arylmagnesium halides with general formula RMgX (where X = Cl, Br or I), also known as Grignard reagents. An important characteristic of Grignard reagents is that, in solution, they are in equilibrium with the corresponding R2Mg and MgX2 (Scheme 36, Schlenck equilibrium).53 The position of the equilibrium is greatly influenced by the solvent. For example, in diethyl ether or THF, alkyl- or arylmagnesium halide species are favored. The addition of dioxane to such solutions, however, leads to selective precipitation of dihalide MgX2, driving the equilibrium completely to the right side of the equation (Le Châtelier´s principle).54
Scheme 36. Schlenck equilibrium
The preparation of a Grignard reagent is one of the most famous and important reactions in organic chemistry. It was discovered in 1900 by Françoise Auguste Victor Grignard who was awarded, in 1912, with the Nobel Prize for this work.55 The reaction consists on the transformation of an alkyl or aryl halide (electrophilic species by nature), into the corresponding alkyl or arylmagnesium halide, respectively (nucleophilic species) by using magnesium turnings in an appropriate solvent. The overall reaction, which involves an inversion in the polarity at the ipso carbon, occurs via a single electron transfer mechanism.56
53 Schlenk, W.; Schlenk Jr., W. Chem. Ber. 1929, 62, 920–924. 54 Andersen, R. A.; Wilkinson, G. Inorg. Synth. 1979, 19, 262–265. 55 Grignard, V. Compt. Rend. 1900, 130, 1322–1325. 56 Richey, H. G. Grignard Reagents: New Developments, Wiley: New York, 1999.
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Grignard compounds are common reagents that can be found in any organic laboratory. A wide variety of Grignard reagents are commercially available in good price, depending on their complexity.56
Grignard reagents have been extensively employed in C-C bond formation reactions, normally with carbonyl substrates, but their use in asymmetric catalysis has been limited, due to the high reactivity. Only in the last decade, some examples have been reported on the use of Grignard reagents in enantioselective catalytic processes, such as: conjugate addition to ,-unsaturated substrates,57 allylic substitution,58 cross- coupling reactions59 and very recently, addition to carbonyl compounds, which will be described in sections 1.2 and 1.3.
This thesis focuses in the development of novel catalytic methodologies for the enantioselective addition of Grignard reagents to carbonyl compounds. At the beginning of our investigation, most of the methodologies described in the literature, involved the use of stoichiometric or superstoichiometric amounts of a chiral ligand, and very low temperatures, and only a few methodologies were known for the catalytic version of this reaction, using mainly aldehydes as electrophiles (see section 1.2 for further details).
In the following sections, the most relevant examples reported in the literature on both stoichiometric and catalytic enantioselective additions of Grignard reagents to aldehydes and ketones will be summarized.
57 a) Kehrli, S.; Martin, D.; Rix, D.; Mauduit, M.; Alexakis, A. Chem. Eur. J. 2010, 16, 9890–9904; b) Harutyunyan, S. R.; den Hartog, T.; Geurts, K.; Minnaard, A. J.; Feringa, B. L. Chem. Rev. 2008, 108, 2824–2852; c) Martin, D.; Kehrli, S.; D'Augustin, M.; Clavier, H.; Mauduit, M.; Alexakis, A. J. Am. Chem. Soc. 2006, 128, 8416–8417; d) Lopez, F.; Harutyunyan, S. R.; Meetsma, A.; Minnaard, A. J.; Feringa, B. L. Angew. Chem., Int. Ed. Engl. 2005, 44, 2752–2756; e) Lopez, F.; Harutyunyan, S. R.; Minnaard, A. J.; Feringa, B. L. J. Am. Chem. Soc. 2004, 126, 12784–12785. 58 a) Hornillos, V.; van Zijl, A. W.; Feringa, B.L. Chem. Comm. 2012, 48, 3712–3714; b) Lopez, F.; Van Zijl, A. W.; Minnaard, A. J.; Feringa, B.L. Chem. Comm. 2006, 4, 409–411; c) Fañanás-Mastral, M.; Feringa, B.L. J. Am. Chem. Soc. 2010, 132, 13152–13153; d) Alexakis, A.; Malan, C.; Lea, L.; Benhaim, C.; Fournioux, X. Synlett 2001, SI, 927–930. 59 Swift, E. C.; Jarvo, E. R. Tetrahedron 2013, 69, 5799–5817.
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1.1. Stoichiometric and superstoichiometric enantioselective addition of organomagnesium reagents to carbonyl compounds
The first example on the asymmetric alkylation of aldehydes using organomagnesium reagents was reported by Wright in 1964, who achieved the addition of Me2Mg to benzaldehyde using stoichiometric amounts of the chiral promoter XXXV (1 eq.).60 The corresponding alcohol was obtained in 67% yield and 20% ee (Scheme 37). Similar results were described by Bloomberg and Coops, which confirmed that bidentate chiral ethers were better ligands than monodentate chiral ethers in the 1,2 addition of Grignard reagents to benzaldehyde.61
Scheme 37. First enantioselective addition of Me2Mg to benzaldehyde promoted by XXXV.
A few years later, in 1968, Nozaki checked the ability of (–)-sparteine (1 eq., VIII) as a chiral ligand in the asymmetric addition of EtMgBr to benzaldehyde in toluene at –70 °C.62 The alcohol was obtained with poor enantioselectivity (22%) and yield (15%) using stoichiometric amounts of the chiral alkaloid VIII (Scheme 38).
Scheme 38. Asymmetric addition of EtMgBr to benzaldehyde promoted by (–)-sparteine (VIII).
60 French, W.; Wright, G. F. Can. J. Chem. 1964, 42, 2474–2479. 61 a) Vink, P.; Bloomberg, C.; Vreugdenhil, A. D.; Bickelhaupt, F. Tetrahedron Lett. 1966, 7, 6419–6423; b) Bloombler, C.; Coops, J. Recl. Trav. Chim. Pays-Bas 1964, 83, 1083–1095. 62 a) Toraya, T.; Aratini, T.; Nozaki, H. Tetrahedron Lett. 1968, 9, 4097–4098; b) Toraya, T.; Aratini, T.; Nozaki, H.; Noyori, R. Tetrahedron 1971, 27, 905–913.
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Nature is an excellent source of chiral molecules that can be used as ligands in asymmetric synthesis and catalysis. In this context, Battioni and Chodkiewicz, for example, employed chiral amino alcohols derived from ephedrine, N- methylephedrine and (+)-cinchona for the ethylation of aldehydes with Et2Mg at room temperature, achieving enantioselectivities up to 20%.63
Chiral solvents have been used in the asymmetric addition of Grignard reagents to aldehydes. Ifflandis and Davis employed the (R)-2-methyltetrahydrofurane (XXXVI) as a source of chirality for the arylation of aldehydes.64 This methodology proved not effective enough; the best result was obtained for the addition of PhMgBr to pivalaldehyde, which gave the corresponding alcohol in only 11% ee and 57% yield (Scheme 39).
Scheme 39. Asymmetric addition of PhMgBr promoted by a chiral solvent XXXVI.
In 1978, Mukaiyama´s group achieved moderate to excellent enantioselectivities in the addition of different R2Mg to benzaldehyde in toluene at –110 °C, with superstoichiometric amounts of the lithium alkoxide X as chiral ligand.65 The authors observed that non-coordinating solvents, such as toluene, allowed better enantioselectivities in the reaction, in contrast with the more commonly used, ethereal solvents (Scheme 40).
63 Battioni, J. P.; Chodkiewicz, W. Bull. Chim. Soc. Fr. 1972, 5, 2068–2069. 64 Iffland, D.C.; Davis, J. E. J. Org. Chem. 1977, 42, 4150–4151. 65 a) Mukaiyama, T.; Soai, K.; Sato, T.; Shimizu, H.; Suzuki, K. J. Am. Chem. Soc. 1979, 101, 1455–1460; b) Soai, K.; Mukaiyama, T. Chem. Lett. 1978, 5, 491–492; c) Sato, T.; Soai, K.; Suzuki, K.; Mukaiyama, T. Chem. Lett. 1978, 6, 601– 604.
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Esquema 40. Asymmetric addition of R2Mg to benzaldehyde promoted by lithium alkoxide X.
In 1987, Tomioka synthesized a new type of chiral ligands, XXXVII and XXXVIII (4 eq.), derived from 3,4-diarylpirrolidine, which were tested in the alkylation and arylation of aromatic aldehydes using Grignard reagents as nucleophiles.66 The authors employed 3 eq. of the chiral ligands and phenoxymetal halides derived from magnesium or aluminum as additives to improve the enantioseletivities in some particular cases. In general, moderate to good ee’s were obtained (Scheme 41).
Scheme 41. Asymmetric addition of Grignard reagents to aldehydes promoted by diamines XXXVII and XXXVIII.
At the same time, Noyori achieved the first effective addition of an organomagnesium reagent to an aldehyde with high levels of enantioselectivity employing 1 eq. of a chiral Li-Mg bimetallic (S)-BINOL complex (XXXIX) stabilized with 67 coordinating solvents. The chiral alcohols from the addition of R2Mg to aldehydes, performed in a THF/DME (1:1) mixture at –100 °C, were obtained in good yields and ee’s (Scheme 42).
66 a) Nakajima, M.; Tomioka, K.; Koga, K. Tetrahedron 1993, 49, 9751–9758; b) Tomioka, K.; Nakajima, M.; Koga, K. Chem. Lett. 1987, 1, 65–68; c) Tomioka, K.; Nakajima, M.; Koga, K. Tetrahedron Lett. 1987, 28, 1291–1292. 67 Noyori, R.; Suga, S.; Kawai, K.; Okada, S.; Kitamura, M. Pure Appl. Chem. 1988, 60, 1597–1606.
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Scheme 42. Asymmetric addition of R2Mg to aldehyde promoted by Li-Mg bimetallic complex XXXIX.
In 1992, Seebach reported the use of stoichiometric amounts of the chiral TADDOL derivatives XL and XLI (1 eq.) developed in his research group, for the successful enantioselective addition of RMgBr to ketones.68 The reaction was carried out in THF, which was crucial, at –100 °C, and excellent enantioselectivities were achieved for linear aliphatic Grignard reagents and aryl methyl ketones as electrophiles (Scheme 43). Also this group performed the first substoichiometric attempt in the addition of n-BuMgBr to acetophenone using only 25 mol% of chiral ligand XL, but the results were not completely satisfactory (84% ee and 55% yield being the best results obtained in THF at –100 °C).
Scheme 43. Asymmetric addition of RMgBr to ketones promoted by TADDOL ligands (XL and XLI).
Markó reported the use of stoichiometric amounts of the chiral diamine XLII for the addition of primary and secondary Grignard reagents to an aliphatic aldehyde, cyclohexanecarboxaldehyde.69 Although the levels of enantioselectivity for this process were not impressive, the reaction deserves to be highlighted because: i) it was carried out at 20 °C, a temperature not very common for this type of asymmetric
68 a) Pellisier, H. Tetrahedron 2008, 64, 10279–10317; b) Weber, B.; Seebach, D. Tetrahedron 1994, 50, 6117–6128; c) Weber, B.; Seebach, D. Angew. Chem., Int. Ed. Engl. 1992, 31, 84–86. 69 Markó, I. E.; Chesney, A.; Hollinshead, D.M. Tetrahedron: Asymmetry 1994, 5, 569–572.
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transformations and ii) it involved the use of aliphatic substrates, which are, in general more challenging (Scheme 44). A slightly improvement in the enantioselectivity of the product was detected when increasing the size of the nucleophile, but in general poor selectivities were achieved (up to 34% ee).
Scheme 44. Asymmetric addition of RMgBr to CyCHO promoted by diamine ligand XLII.
In 2002, Yong continued the studies on chiral diamine ligands for the asymmetric addition of dialkylmagnesium compounds to aromatic aldehydes.70 Different linear aliphatic nucleophiles were screened in the addition to benzaldehyde using 2.4 eq. of chiral ligand XLIII in Et2O as solvent at –78 °C. The enantiomeric excess obtained with this methodology varied from moderate to good (up to 82%, Scheme 45).
Scheme 45. Asymmetric addition of R2Mg to aromatic aldehydes promoted by diamine ligand XLIII.
It can be concluded from all these examples, that the enantioselective addition of RMgX to carbonyls represents an important challenge in organic synthesis since the origins. The limited amount of ligands that can be employed for this type of transformation and the extreme reaction conditions (temperatures below –100 °C and super- or stoichiometric amounts of chiral ligands) that are required to get good results, are indicative that many improvements can be done in the area.
70 Yong, K. H.; Taylor, N. J.; Chong, J. M. Org. Lett. 2002, 4, 3553–3556.
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1.2. Catalytic enantioselective addition of Grignard reagents to aldehydes
In the last years, various enantioselective catalyzed additions of Grignard reagents to aldehydes have been developed by a few research groups, all based on the use of catalytic amounts of BINOL derivatives as chiral ligands and excess of Ti(Oi-Pr)4.
Harada´s group was the first to achieve the enantioselective alkylation of aldehydes with Grignard reagents with high levels of enantioselectivity using catalytic amounts of a chiral 3-modified BINOL ligand XLIV (2 mol%) and DCM as solvent at 0 °C.71 The key step of the methodology consists on the slow addition (over 2 h) of the Grignard reagent and Ti(Oi-Pr)4 (1.4 eq.) over a solution containing the aldehyde, the ligand and Ti(Oi-Pr)4 (4.4 eq.). No tedious procedures for salts exclusion are needed in this process. The addition of linear nucleophiles to different aromatic aldehydes takes place with excellent yields and ee (Scheme 46), except for the addition of MeMgBr, which provides low levels of enantioselectivity (up to 28%).
Scheme 46. Asymmetric alkylation and arylation of aldehydes with Grignard reagents catalyzed by XXXII and XLIV.
71 Muramatsu, Y.; Harada, T. Angew. Chem. Int. Ed. 2008, 47, 1088–1090.
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An extension of the previous methodology includes the arylation of aldehydes, which was carried out under very similar reaction conditions using the 3-substituted partially hydrogenated binaftol XXXII.72b This methodology allows the addition of previously prepared aromatic Grignard reagents, but also Grignard reagents that are generated in situ by reaction between the corresponding aryl bromide and Knochel´s turbo Grignard (i-PrMgCl·LiCl).72a In both cases, comparable results and very high enantioselectivities and yields were obtained for the synthesis of chiral diarylmethanols from the corresponding aromatic aldehydes (Scheme 46).
Scheme 47. Use of BDMAEE as chelating agent to remove magnesium salts from solution.
Da´s group focused the attention in the use of external additives to improve the enantioselectivity in the alkylation and arylation of aldehydes with Grignard reagents 73 using (S)-BINOL (IV) or (S)-H8-BINOL (XXXIV), as chiral ligands. bis[2-(N,N´- dimethylamino)ethyl]ether (BDMAEE) was used as chelating or “trapping” agent for the magnesium salts, such as MgBr2 or Mg(Oi-Pr)Br, generated in either the Schlenck equilibrium and/or the transmetallation process with titanium tetraisopropoxide. The
72 a) Itakura, D.; Harada, T. Synlett 2011, 2875−2879; b) Muramatsu, Y.; Harada, T. Chem. Eur. J. 2008, 14, 10560– 10563. 73 a) Fan, X-Y.; Yang, Y-X.; Zhuo, F-F.; Yu, S-L.; Li, X.; Guo, Q-P.; Du, Z-X.; Da C-S. Chem. Eur. J. 2010, 16, 7988–7991; b) Liu, Y.; Da, C.-S.; Liu, S.-L.; Yin, X.-Y.; J.-R. Wang.; X.-Y. Fan.; Li, J.-R.; Wang, R. J. Org. Chem. 2010, 75, 6869–6878; c) Da, C.-S.; Wang, J.-R.; Yin, X.-G.; Fan, X.-Y.; Liu, Y.; Yu, S.-L. Org. Lett. 2009, 11, 5578–5581.
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chelation of the magnesium salts with this additive diminishes its Lewis acid character, therefore lowering the chances of undesired non-stereoselective addition processes (Scheme 47).74
The use of BDMAEE as additive (1:1 with respect to the RMgBr) allowed a considerable reduction in the amount of Ti(Oi-Pr)4 necessary in the reaction (down to 0.9-1.7 eq.), compared to Harada´s methodology. In this case, the best enantioselectivities were reached with aryl (77-97% ee) and bulky aliphatic (87-98% ee) Grignard reagents. However, when small nucleophiles were employed the yield and ee of the reaction dropped. The addition of MeMgBr to benzaldehyde, for example, only provided 33% yield and 35% ee.
In 2011, after the publication of our results related to the asymmetric addition of Grignard reagents to aldehydes (which will be discussed later in section 2 of this chapter), Xu Li-Wen´s group applied the same methodology for the methylation and arylation of aromatic aldehydes with Grignard reagents using the binaftol derivative XLV as a chiral ligand.75 Very good enantioselectivities and excellent yields were obtained for the addition of MeMgBr at –40 °C in toluene. On the contrary, the arylation of aldehydes was carried out at –20 °C in DCM and only gave the corresponding alcohols with moderate to good ee (Scheme 48).
Scheme 48. Asymmetric addition of MeMgBr and ArMgBr to aldehydes with ligand XLV.
74 Balsells, J.; Davis, T. J.; Carroll, P.; Walsh, P. J. J. Am. Chem. Soc. 2002, 124, 10336–10348. 75 Zheng, L-S.; Jiang, K-Z.; Deng, Y.; Bai, X-F.; Gao, G.; Gu, F-L.; Xu, L-W. Eur. J. Org. Chem. 2013, 4, 748–755.
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5.1.3 Catalytic enantioselective addition of Grignard reagents to ketones
Ketones are interesting electrophiles for the synthesis of valuable chiral tertiary alcohols through the enantioselective addition of organometallic reagents. The lower reactivity of the ketone and the higher steric hindrance around the carbonyl center hampers their use as successful substrates in 1,2-addition reactions with organometallic reagents. The catalytic asymmetric addition of Grignard reagents to ketones is in early development and only one research group has performed this challenging addition.76-79
Harutyunyan´s group recently developed the first efficient catalytic enantioselective addition of Grignard reagents to ketones. The catalytic system is based on the copper complexes formed between a chiral Josiphos-type diphosphine ligand XLVI or XLVII,76 . and CuBr2 Me2S. The slow addition (over 2 to 3 h) of the nucleophile over a solution of the corresponding ketone and the preformed copper complex (5 mol%), in TBME at low temperature, is essential to achieve good yields and enantiomeric excess. The authors propose a -interaction between the carbonyl and the chiral cuprate as the responsible for the high levels of selectivity. -Branched aliphatic Grignard reagents provide the best results for the alkylation of different ketones, affording the desired tertiary alcohols with excellent enantioselectivities and yields in the case of aryl methyl ketones77 and moderate to good for aryl heteroaryl ketones78 (Scheme 49). Linear aliphatic Grignard reagents provide lower enantioselectivities (22-72%) compared with -branched nucleophiles (76-98%).
76 Caprioli, F.; Lutz, M.; Meetsma, A.; Minaard, A. J.; Harutyunyan, S. R. Synlett 2013, 24, 2419–2422. 77 Madduri, A. V. R.; Harutyunyan, S. R.; Minaard, A. J. Angew. Chem. Int. Ed. 2012, 51, 3164–3167. 78 Ortiz, P.; del Hoyo, A. M.; Harutyunyan, S. R. Eur. J. Org. Chem. 2015, 72–76.
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Scheme 49. Asymmetric alkylation of ketones with -branched aliphatic Grignard reagents.
This methodology has also been successfully applied to the addition of Grignard reagents to -substituted-,-unsaturated ketones.79 Surprisingly, the expected 1,4- addition reaction did not take place (process that, till date, was known as favored for all copper catalyzed nucleophilic additions with organometallic reagents) and only the chiral tertiary alcohol (coming from the 1,2-addition of the Grignard reagent to the carbonyl) was obtained when ligand XLVI was used at –78 °C or –60 °C in TBME. It is believed that the substituent (Me or Br) at the alpha position of the ,- unsaturated system distorts the possible interaction between the copper complex and the double bond, hampering the 1,4-addition process. The catalytic system is again more effective when -branched Grignard reagents, instead linear, are used as nucleophiles and when a bulky substituent is at the alpha position in the electrophile; i. e. -bromo substituted ,-unsaturated ketones provide better results than their -methyl substituted analogs (Scheme 50).
79 a) Madduri, A. V. R.; Harutyunyan, S. R.; Minaard, A. J. Chem. Comm. 2012, 48, 1478–1480; b) Madduri, A. V. R.; Harutyunyan, S. R.; Minaard, A. J. Org. Biomol. Chem. 2012, 10, 2878–2884.
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Scheme 50. Asymmetric alkylation of ,-unsaturated -substituted ketones with Grignard reagents.
A broad range of possibilities have been opened in the research field of 1,2 asymmetric addition of Grignard reagents to carbonyls with the design of new ligands and catalytic systems and/or methodologies. The use of new types of nucleophiles and ketones to prepare more complex chiral tertiary alcohols is a challenge that could be achieved in a near future.
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2. Results and discussion
2.1. Optimization of the catalytic enantioselective addition of Grignard reagents to aromatic aldehydes
The addition of MeMgBr to benzaldehyde (1a) or o-methylbenzaldehyde (1b) were taken as a model reaction for this study. The optimization process began with a solvent screening carried out at 0 °C with 10 mol% of the ligand (Sa,R)-L1. DCM, THF, or TBME were evaluated in the reaction (Table 8, entries 1-3), but very low enantioselectivities were achieved. Promising results were obtained with diethyl ether and toluene which gave 20 and 35% ee respectively (Table 8, entries 4-5).
The effect of the temperature was then analysed to improve the previous results. Lowering the temperature to 20 °C produced a drastic decrease in both conversion and selectivity when the reaction was carried out in Et2O (Table 8, entry 6), probably due to solubility problems. Fortunately, the use of toluene at 40 °C provided an increase in the enantioselectivity up to 51% (Table 8, entry 5 vs 7), preserving the full conversion. Lower temperatures (60 °C) led to a significant decrease in the rate of the reaction (Table 8, entry 8), although the ee was found to be slightly higher (54%).
Table 8. Influence of solvent and temperature[a]
Entry T (°C) Solvent Conv.[b] (%) ee[b] (%) 1 0 DCM 99 16 2 0 THF 70 8 3 0 TBME 99 0 4 0 Et2O 98 35 5 0 Toluene 99 20 6 20 Et2O 20 5 7 40 Toluene 99 51 8 60 Toluene 60 54
[a] Conditions: 1b (0.1 mmol, 0.07 M), MeMgBr (3 M in Et2O, 2.5 eq.), (Sa,R)-L1 (10 mol%), Ti(Oi-Pr)4 (10 eq.), solvent (1.5 mL), T (°C), 4 h. [b] Determined by chiral GC analysis.
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The titanium source was studied as a possible effective parameter to improve the enantioselectivity in the reaction. Therefore, six titanium (IV) reagents with different alkyl substituents were evaluated under the previous optimized conditions using benzaldehyde (1a) as electrophile. Surprisingly, when linear substituents at the alkoxy group attached to titanium were employed, the addition product was detected with very low conversion and racemic (Table 9, entries 1-3). With the most common and inexpensive titanium source, Ti(Oi-Pr)4 the best result was achieved, 90% conv. and 80% ee (Table 9, entry 4). Also, chlorotriisopropoxytitanium (IV), which has different electronic properties than Ti(Oi-Pr)4, was tested, but gave the corresponding alcohol 2a in a racemic form (Table 9, entry 5). It seems that titanium sources with bulky alkoxy groups are crucial for this process, so the bulkiest commercially available Ti(Ot-Bu)4 was also tested; unfortunately, only 2% of conversion was achieved (Table 9, entry 6).
Table 9. Titanium (IV) source screening[a]
Entry Ti source Conv.[b] (%) ee[b] (%)
1 Ti(OMe)4 10 0 2 Ti(OEt)4 30 0 3 Ti(On-Pr)4 30 0 4 Ti(OiPr)4 90 80 5 TiCl(Oi-Pr)3 99 0 6 Ti(Ot-Bu)4 2 34 [a] Conditions: 1a (0.1 mmol, 0.07 M), MeMgBr (3 M in Et2O, 2.5 eq.), Ti source (10 eq.), (Sa,R)-L1 (10 mol%), toluene (1.5 mL), 40 °C, 4 h. [b] Determined by chiral GC analysis.
With these preliminary conditions, a small library of chiral diols (Figure 3) was screened as ligands for the addition of MeMgBr to 1a (Table 10). The corresponding diastereoisomer of (Sa,R)-L1, with same axial chirality but oppositte configuration at the sp3 center provided no enantioselectivity in the alkylation reaction with benzaldehyde (Table 10, entry 2). Methoxy substituted chiral diols gave lower enantioselectivities (Table 10, entries 3-5) than the simplest ligand (Sa,R)-L1 (Table
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10, entry 1). Moreover, lower conversion was observed in the case of the meta- methoxy substituted (Sa,R)-L4. Probably, too bulky ligands did not give good enantioselectivities due to steric hindrance cause a distortion in the titanium complex. The para-fluoro substituted ligand (Sa,R)-L6 proved equally effective as
(Sa,R)-L1 (Table 3, entry 1 vs 6), but (Sa,R)-L1 was chosen for the rest of the study because it is simpler and easier to synthetize.
Figure 3. Chiral diol ligands screened in this study
Table 10. Ligand optimization[a]
Entry L* Conv.[b] (%) ee[b] (%)
1 (Sa,R)-L1 90 80 2 (Sa,S)-L1 71 0 3 (Sa,S)-L3 86 48 4 (Sa,R)-L4 25 74 5 (Sa,R)-L5 89 70 6 (Sa,R)-L6 89 83 [a] Conditions: 1a (0.1 mmol, 0.07 M), MeMgBr (3 M in Et2O, 2.5 eq.), Ti(Oi-Pr)4 (x eq.), (Sa,R)-L1 (10 mol%), toluene (1.5 mL), 40 °C, 4 h. [b] Determined by chiral GC analysis.
In the next step of the optimization process, the amount of titanium tetraisopropoxide respect to the nucleophile was adjusted carefully because it was found crucial to get high enantioselectivity. For this study, the bulky ortho-methyl substituted benzaldehyde (1b) was used as model substrate (Table 11). We soon noticed that a large excess of the Lewis acid Ti(Oi-Pr)4 was necessary to reach good results. For substoichiometric amounts of Ti(Oi-Pr)4 (respect to MeMgBr) or absence of this reagent, the desired product 2b was obtained racemic (Table 11, entries 1-3).
As the amount of Ti(Oi-Pr)4 was increased, keeping the amount of nucleophile at 2.5
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eq. (Table 11, entries 4-7), the results improved. A thoroughly screening of different titanium-magnesium ratios allowed us to establish the optimal ratio Ti(Oi-
Pr)4:MeMgBr as 4:1.
In order to improve the previous results, the slow addition of MeMgBr (2.5 eq.) and the slow addition of a toluene solution containing MeMgBr (2.5 eq.) and Ti(Oi-Pr)4
(2.5 eq.) over a solution of 1a, Ti(Oi-Pr)4 (7.5 eq.) and ligand (Sa,R)-L1 (10 mol%) at 40 °C were also attempted. The slow addition strategy did not improve the previous results and in both cases, we obtained 90% conv. and only 44% ee.
[a] Table 11. Optimization Ti(Oi-Pr)4/MeLi ratio
[b] [b] Entry Ti(Oi-Pr)4 (eq.) MeMgBr (eq.) Ti:Mg ratio Conv. (%) ee (%) 1 0 2.5 - 90 0 2 2.5 2.5 - 99 0 3 2.5 2.5 1:1 99 0 4 5 2.5 2:1 89 30 5 7.5 2.5 3:1 90 44 6 10 2.5 4:1 99 51 7 12.5 2.5 5:1 90 40
[a] Conditions: 1b (0.1 mmol, 0.07 M), MeMgBr (3 M in Et2O, 2.5 eq.), Ti(Oi-Pr)4 (x eq.), (Sa,R)-L1 (10 mol%), toluene (1.5 mL), 40 °C, 4 h. [b] Determined by chiral GC analysis.
In a last effort to improve the methodology, the influence of the catalyst loading and amount of MeMgBr in the reaction with benzaldehyde (1a) was then examined (Table 12). Higher ligand loadings improved both conversion and enantioselectivity of the reaction (Table 12, entries 1-3) up to 79% conv. and 85% ee when using 20 mol% of (Sa,R)-L1 (Table 12, entry 3). In order to reach full conversion, the equivalents of MeMgBr were increased up to 3.75. Under these last adjustments, enantioselectivity slightly increased up to 88% (Table 12, entry 4).
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Table 12. Effect of catalyst loading[a]
[b] [b] Entry (Sa,R)-L1 (mol%) Ti(Oi-Pr)4 (eq.) MeMgBr (eq.) Conv. (%) ee (%) 1 5 1.25 5 60 78 2 10 1.25 5 73 83 3 20 1.25 5 79 85 4 20 3.75 15 98 88
[a] Conditions: 1a (0.1 mmol, 0.07 M), MeMgBr (3 M in Et2O, x eq.), Ti(Oi-Pr)4 (y eq.), (Sa,R)-L1 (z mol%), toluene (1.5 mL), 40 °C, 4 h. [b] Determined by chiral GC analysis.
2.2. Scope of the reaction
With the optimized conditions in hand (Table 12, entry 4), the addition of MeMgBr to different aldehydes was screened (Table 13). The highly desirable addition of the low reactive MeMgBr was achieved with high yields and enantioselectivities from 80% to 90% for a wide variety of aromatic aldehydes with electron-poor and electron-rich substituents at the meta and para position (Table 13, entries 4-10). The alkylation of o-methylbenzaldehyde (1b) proceeded with lower enantioselectivity 53% (Table 13, entry 2), probably due to steric hindrance close to the reactive site. The use of 2- thiophenecarboxaldehyde (1j) or cinnamaldehyde (1l) prompted a decrease in the enantioselectivity values (Table 13, entries 11-12). Moreover, volatile product 2j was obtained in low yield (53%) in spite of 98% conversion, due to problems during the isolation. The reaction with phenylacetaldehyde (1m) proceeded with moderated enantioselectivity (68%) and poor yield (43%) at 40 °C (Table 13 entry 13); gratifyingly, yield could be improved up to 70% increasing the temperature to 20 °C without observing any loss of enantioselectivity (Table 13, entry 14).
Full conversion was achieved in almost all the cases and no by-products were formed under the optimized conditions. Only phenylacetaldehyde (1m) did not react completely (probably due to the high acidity of the benzylic hydrogen atoms) (Table
13, entries 13-14). Moreover, the ligand (Sa,R)-L1 could also be recovered and reused without observing any loss of catalytic activity in product 2a (Table 13, entry 2).
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Table 13. Asymmetric addition of MeMgBr to aldehydes[a]
Entry Aldehyde Product Yield[b] (%) ee[c] (%) 1 92 88 (S) 2 90[d] 87 (S)
3 85 53 (S)
4 99 88 (S)
5 98 87 (S)
6 95 80 (S)
7 88 88 (S)
8 98 84 (S)
9 89 85 (S)
10 92 90 (S)
11 53 (98)[e] 58 (S)
12 90 68
13 43 68 14 70[f] 70
[a] Conditions: 1 (0.3 mmol, 0.12 M), MeMgBr (3 M in Et2O, 3.8 eq.), (Sa,R)-L1 (20 mol%),
Ti(Oi-Pr)4 (15 eq.), toluene (2.5 mL), 40 °C, 4 h. [b] Isolated yield after flash silica gel chromatography. [c] Determined by chiral GC analysis. Absolute configuration of chiral alcohols was determined by correlation of optical rotation with known compounds. [d]
Result after recovery of (Sa,R)-L1 and reused in the addition of MeMgBr to 1a. [e] Volatile product, conversion based on GC data in brackets. [f] Reaction performed at 40 °C.
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Encouraged by the excellent results in the addition of the challenging MeMgBr reagent, the attention was turned to the use of other Grignard reagents (Table 14). The addition of linear Grignard reagents like EtMgBr and n-BuMgBr proceeded with good yields and enantioselectivities up to 96% for a wide range of aromatic aldehydes with electron donating or electron withdrawing groups (Table 14, entries 2-3 and 6-7). The use of n-BuMgCl in the alkylation of benzaldehyde provided the same enantioselectivity as its bromide derived counterpart (Table 14, entry 4); however, conversion only reached moderated levels and 19% of benzyl alcohol was formed as by-product during the reaction (Table 14, entry 5). It seems that, -hydride elimination of alkylmagnesium chloride derivatives is favoured under this reaction conditions, confirmed by the generation of benzyl alcohol from 1a.
Moreover, n-BuMgBr could be added at 20 °C to an aliphatic aldehyde with moderated enantioselectivity 50% (Table 14, entry 8) and good yield. The bulky i- BuMgBr gave excellent enantioselectivity (96%) but poor yield (41%) in the reaction with benzaldehyde (Table 14, entry 9) and the formation of 5% of benzyl alcohol was detected, which could be generated from the reduction of 1a via -hydride elimination from i-BuMgBr and/or through Meerwein-Ponndorf-Verley reduction from in situ generated RxMg(Oi-Pr)2-x species. In this case, an improvement of the yield could be achieved at higher temperatures (20 °C), but at the expense of the enantioselectivity (Table 14, entry 10).
Table 14. Asymmetric addition EtMgBr, n-BuMgBr and i-BuMgBr to aldehydes[a]
Entry Aldehyde Product Yield[b] (%) ee[c] (%)
1 95 86 (S)
2 80 78 (S)
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3 85 72 (S)
4 90 96 (S) 5 41[d][e] 96 (S)
6 89 93 (S)
7 81 92 (S)
8 98[f] 50 (S)
9 41[g] 96 (S) 10 91[f][g] 86 (S)
[a] Conditions: 1 (0.3 mmol, 0.12 M), RMgBr (3.8 eq.), (Sa,R)-L1 (20 mol%), Ti(Oi-Pr)4 (15 eq.), toluene (2.5 mL), 40 °C, 4 h. [b] Isolated yield after flash silica gel chromatography. [c] Determined by chiral GC analysis. Absolute configuration of chiral alcohols was determined by correlation of optical rotation with
known compounds. [d] n-BuMgCl (4.1 M in Et2O) was used as nucleophile. [e] 40% of unreacted 1a and 19% of benzyl alcohol were isolated. [f] Reaction performed at 20 °C. [g] 5% of benzyl alcohol was isolated.
A limitation of this methodology is the use of secondary and tertiary Grignard reagents such as i-PrMgBr, CyMgBr and t-BuMgBr, which provided very low conversion to the corresponding racemic alcohol in the reaction with benzaldehyde (2aa, 2y and 2ab, Figure 4). Secondary and tertiary nucleophiles are more reactive and bulky than primary, so that can explain low yields and racemic products. Also, the addition of allylmagnesium bromide to 1a provided 79% of conversion but 0% ee when the reaction was carried out under the optimized previous conditions (2ad, Figure 4). Moreover, the addition of sp2 hybridized Grignard reagents, such as vinylMgBr and PhMgBr, to aromatic aldehydes proceeded in good yield, but low enantioselectivity was observed in the case of arylation (2x, Figure 4) and no enantioselectivity was achieved for the vinylation reaction (2ae, Figure 4).
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Figure 4. Chiral secondary alcohols derived from the addition of RMgBr to aldehydes. Limitations of the methodology. 2.3. Application of the methodology: Synthesis of 2-substituted chiral tetrahydropyrans
The synthesis of 2-substituted chiral tetrahydropyrans was carried out as an application of the developed methodology for the enantioselective alkylation of aldehydes with Grignard reagents. Those compounds can be found in the structure of natural products and pharmaceutical compounds.
The synthesis of these valuable building blocks was envisioned in two steps (Figure 5). We decided to apply our developed methodology to carry out the enantioselective addition of 4-chlorobutylmagnesium bromide to different aromatic aldehydes. The corresponding chloroalkyl alcohols could be subsequently cyclised to provide the desired 2-substituted chiral tetrahydropyrans.
Figure 5. Retrosynthesis of 2-substituted chiral tetrahydropyrans.
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The alkylation step proceeded with moderate to good yields and excellent enantioselectivities for non-substituted aromatic aldehydes, such as benzaldehyde (1a) and 2-naphtylaldehyde (Table 15, entries 1-2), para substituted aromatic aldehydes (Table 15, entries 3-4) and also bulky trisubstituted and heteroaromatic aldehydes (Table 15, entries 5-6). However, in all cases, the corresponding n-butyl alkylated adduct was observed as by-product (yield of this by-product have been presented in brackets in Table 15 for each entry) and its formation could not be avoided even a separately optimization process was attempted for this kind of substrates. The formation of this by-product can be explained by two possible pathways: i) chloro-magnesium exchange during the formation of the Grignard reagent and/or ii) in situ reduction of the desired product.
Table 15. Asymmetric addition of (4-chlorobutyl)MgBr to aromatic aldehydes[a]
Entry Aldehyde Product Yield[b] (%) ee[c] (%)
1 63 (34) 97 (S)
2 56 (35) 94 ()
3 40 (51) 92 ()
4 53 (45) 94 ()
5 55 (41) 98 ()
6 67 (30) 94 ()
[a] Conditions: 1 (0.5 mmol, 0.06 M), (4-clorobutyl)MgBr (1.6 M in Et2O, 3.8 eq.), (Sa,R)-L1 (20 mol%),
Ti(Oi-Pr)4 (15 eq.), toluene (6 mL), 40 °C, 4 h. [b] Isolated yield after flash silica gel chromatography. Yield in brackets corresponding to n-butyl addition [c] Determined by chiral HPLC analysis. Absolute configuration of chiral alcohols was determined by correlation of optical rotation with known compounds.
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Chapter III – Results and discussion
In the following step, the intramolecular cyclization of chloroalkyl alcohols took place under mild reaction conditions using KOt-Bu as base in anhydrous THF during 3 hours at 25 °C. The corresponding 2-substituted chiral tetrahydropyrans were obtained in high purity (>99%) and in excellent yields and enantiomeric excess for a wide varity of alcohols with different substituents at the meta- and para- position of the aromatic ring (Table 16). It is important to highlight that no byproduct were observed during the cyclization reaction, which indicates that this methodology is useful and fast for the synthesis of this type of heterocycles.
Table 16. Cyclization of alcohols to 2-substituted tetrahydropyrans[a]
Entry Alcohol Product Yield[b] (%) ee [c] (%)
1 >99 97 (S)
2 >99 94 (S)
3 90 92 ()
4 99 94 ()
5 96 98 ()
6 80 94 ()
[a] Conditions: 2 (0.2 mmol, 0.1 M), KOt-Bu (2 eq.), THF (2 mL), 25 °C, 3 h. [b] Isolated yield after standard work up. [c] Determined by chiral HPLC analysis of the starting material. Absolute configuration of chiral tetrahydropyrans was determined by correlation of optical rotation with known compounds.
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Chapter III – Results and discussion
In conclusion, an efficient enantioselective catalytic system has been developed for the addition of MeMgBr and other Grignard reagents to aldehydes. This methodology allows the preparation of the very versatile optically active methyl carbinol motif in a simple one-pot procedure and using an economical and commercially available source of the methyl group. A readily available binaphthyl derivative (Sa,R)-L1 is used as a chiral ligand and an excess of titanium tetraisopropoxide was found to be crucial to achieve high enantioselectivities. Moreover, the addition of longer chain Grignard reagents to aromatic and aliphatic aldehydes could be also achieved with high yields and enantioselectivities with the here presented catalytic system. Also, an application of the methodology has been developed for the synthesis of 2- substituted chiral tetrahydropyrans in two reaction steps with excellent enantiomeric excess and moderate yields.
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Chapter III – Experimental part
3 Experimental part
3.1 General procedure for the enantioselective addition of Grignard reagents to aromatic aldehydes
In a flame dried Schlenk tube, (Sa,R)-L1 (22.6 mg, 0.06 mmol, 20 mol%) was dissolved in anhydrous toluene (2.5 mL) under argon atmosphere. The solution was cooled down to 40 °C and Ti(Oi-Pr)4 (1.33 mL, 4.5 mmol, 15 eq.) was then added. Five minutes later, RMgBr (1.14 mmol, 3.8 eq.) was added. After stirring the mixture for additional 15 min, the corresponding freshly distilled aromatic aldehyde (0.3 mmol) was added and the reaction mixture was stirred at 40 °C for 4 h. The reaction was quenched with water (5 mL) and then HCl 2 M (5 mL) to eliminate the titanium oxides generated by the addition of water. The crude was extracted with EtOAc (3 × 10 mL), and the combined organic layers were neutralized with a saturated NaHCO3 aqueous solution (15 mL), dried over magnesium sulfate and concentrated under vacuum. The crude product was purified by flash silica gel chromatography to give the desired products.
3.2 Data of chiral secondary alcohols prepared from Grignard reagents
1H NMR and 13C NMR, LRMS, HRMS, m.p., IR data and conditions for the chromatographic separation of enantiomers for some of the compounds listed below has been already reported in Chapter I section 3.2. In these cases, only the yield, optical rotation and ee obtained in the addition reaction with organomagnesium reagents will be reported.
25 (S)-1-Phenylethanol (2a): Colorless oil (92% yield, 88% ee); []D = Lit. 20 37.5 (c 2.8, CHCl3) { []D = 39.6 (c 2.5, CHCl3) for 82% ee}.
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Chapter III – Experimental part
25 (S)-1-(o-Tolyl)ethanol (2b): Yellow oil (85% yield, 53% ee); []D = Lit. 20 35.0 (c 3.4, CHCl3) { []D = 72.5 (c 1.0, CHCl3) for 96% ee}.
25 (S)-1-(m-Tolyl)ethanol (2c): Yellow oil (98% yield, 88% ee); []D = Lit. 16 26.0 (c 2.0, CHCl3) { []D = 47.3 (c 0.8, CHCl3) for 90% ee}.
25 (S)-1-(p-Tolyl)ethanol (2d): Colorless oil (98% yield, 87% ee); []D Lit. 20 = 37.5 (c 2.0, CHCl3). { []D = 53.7 (c 0.4, CHCl3) for 96% ee}.
(S)-1-(4-Methoxyphenyl)ethanol (2e): Yellow oil (95% yield, 80% 25 Lit. 20 ee); []D = 34.0 (c 2.3, CHCl3) { []D = 51.9 (c 1.0, CHCl3) for 97% ee}.
(S)-1-[4-(Trifluoromethyl)phenyl]ethanol (2f): Yellow oil (88% yield, 25 Lit. 20 88% ee); []D = 29.0 (c 2.0, CHCl3) { []D = 33.7 (c 5.5, CHCl3) for 97% ee}.
(S)-1-(4-Chlorophenyl)ethanol (2g): Yellow oil (98% yield, 84% ee); 25 Lit. 20 []D = 32.0 (c 4.0, CHCl3) { []D = 43.6 (c 1.0, CHCl3) for 97% ee}.
(S)-4-(1-Hydroxyethyl)benzonitrile (2h): Yellow oil (89% yield, 85% 25 Lit. 20 ee); []D = 29.2 (c 2.1, CHCl3) { []D = 62.7 (c 2.1, CHCl3) for 72% ee}.
(S)-1-(Naphthalen-2-yl)ethanol (2i): White powder (92% yield, 90% 25 Lit. 20 ee); []D = 41.0 (c 1.0, CHCl3) { []D = 48.1 (c 1.5, CHCl3) for 92% ee}.
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Chapter III – Experimental part
(S)-1-(Thiophen-2-yl)ethanol (2j): Volatile brown oil (53% yield, 58% ee); 25 Lit. 20 []D = 9.8 (c 2.0, CHCl3) { []D = 27.6 (c 1.0, CHCl3) for 94% ee}.
(S,E)-4-Phenylbut-3-en-2-ol (2l): Yellow oil (90% yield, 68% ee); 25 Lit. 20 []D = 23.0 (c 3.6, CHCl3) { []D = 14.6 (c 1.0, CHCl3) for 60% ee}.
25 (S)-1-Phenylpropan-2-ol (2m): Colorless oil (70% yield, 70% ee); []D Lit. 25 = +13.2 (c 1.7, CHCl3) { []D = +42.2 (c 1.0, CHCl3) for 99% ee}.
25 (S)-1-Phenylpropan-1-ol (2o): Yellow oil (95% yield, 86% ee); []D = Lit. 20 33.5 (c 2.3, CHCl3) { []D = 49.6 (c 0.5, CHCl3) for 98% ee}.
25 (S)-1-(p-Tolyl)propan-1-ol (2p): Brown oil (80% yield, 78% ee); []D Lit. 20 = 24.8 (c 1.1, CHCl3) { []D = 36.1 (c 1.0, CHCl3) for 84% ee}.
(S)-1-(4-Chlorophenyl)propan-1-ol (2q): Yellow oil (85% yield, 72% 25 Lit. 25 ee); []D = 25.5 (c 2.0, CHCl3) { []D = 38.4 (c 1.1, CHCl3) for 95% ee}.
(S)-1-Phenylpentan-1-ol (2r): Colorless needles crystals (90% 25 Lit 20 yield, 96% ee), []D = 39.0 (c 2.0, CHCl3) { []D = 13.6 (c 0.5,
CHCl3) for 80% ee}.
(S)-1-(4-Chlorophenyl)pentan-1-ol (2t): Colorless needles 25 Lit. 20 (89% yield, 93% ee), []D = 31.0 (c 2.0, CHCl3) { []D =
33.0 (c 1.0, CHCl3) for 96% ee}.
(S)-1-(4-Methoxyphenyl)pentan-1-ol (2u): Yellow oil (83% 25 Lit. 20 yield, 92% ee); []D = 32.0 (c 2.0, CHCl3) { []D = 24.2
(c 0.5, CHCl3) for 82% ee}.
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Chapter III – Experimental part
(S)-1-Cyclohexylpentan-1-ol (2z):80 Compound 2s was obtained after purification on flash silica gel chromatography from 100:0 till 92:8 (n-Hexane/EtOAc) as a volatile yellow oil (98% yield, 50% 25 Lit. 20 ee); []D = 10.0 (c 2.0, CHCl3) { []D = +14.3 (c 1.9, CHCl3) for 90% ee of R 1 enantiomer}. H NMR (300 MHz, CDCl3) 3.41 – 3.29 (m, 1H), 1.86 – 1.71 (m, 3H), 1.71 – 1.57 (m, 3H), 1.55 – 0.96 (m, 12H), 0.91 (t, J = 7.0 Hz, 3H). 13C NMR (75 MHz,
CDCl3) 76.2, 43.5, 33.8, 29.3, 28.1, 27.7, 26.6, 26.4, 26.2, 22.8, 14.1. LRMS (EI): m/z (%): 170 [M+] (<1), 152 (8), 113 (44), 95 (100), 87 (45), 82 (17), 69 (90), 67 (19), 57 (13), 55 (22). Ee determination by chiral GC analysis, CP-Chirasil-DEX CB column, T =
120 °C, P = 14.3 psi, retention times: tr(S) = 23.3 min (major enantiomer), tr(R) = 24.6 min.
(S)-3-Methyl-1-phenylbutan-1-ol (2w):81 Compound 2t was obtained after purification on flash silica gel chromatography from 100:0 till 91:9 (n-hexane/EtOAc) as a white needles (41% yield, 96% 25 1 ee); m.p. 39 – 43 °C, []D = 39.4 (c 1.8, CHCl3). H NMR (300 MHz, CDCl3) 7.34 (d, J = 4.4 Hz, 4H), 7.31 – 7.26 (m, 1H), 4.79 – 4.70 (m, 1H), 1.85 (br s, 1H), 1.78 – 1.63 (m, 2H), 1.57 – 1.44 (m, 1H), 0.96 (d, J = 1.4 Hz, 3H), 0.94 (d, J = 1.5 Hz, 3H). 13C NMR
(75 MHz, CDCl3) 145.2, 128.5, 127.5, 125.8, 72.8, 48.3, 24.8, 23.1, 22.2. LRMS (EI): m/z (%): 165 [M++1] (2), 164 [M+] (17), 131 (4), 108 (16), 107 (100), 105 (10), 79 (84), 77 (38). Ee determination by chiral GC analysis, CP-Chirasil-DEX CB column, T = 125
°C, P = 14.3 psi, retention times: tr(S) = 18.9 min (major enantiomer), tr(R) = 20.6 min.
(S)-Naphthalen-2-yl(phenyl)methanol (2x): White powder 25 Lit. 20 (98% yield, 15% ee), []D = +2.5 (c 2.1, CHCl3) { []D = +11.2
(c 0.8, CHCl3) for 95% ee}.
80 Behrendt, L.; Felix. D.; Seebach, D. Angew. Chem., Int. Ed. Engl. 1991, 30, 1008-1009. 81 V. Bussche-Huennefeld, J. L.; Seebach, D. Tetrahedron 1992, 48, 5719-5730.
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(S)-5-chloro-1-phenylpentan-1-ol (2af):82 Compound 2af was obtained after purification on flash silica gel chromatography from 100:0 till 92:8 (n-hexane/EtOAc) as a yellow oil (63% 29 Lit. 25 yield, 97% ee); []D = 27.8 (c 1.0, CHCl3) { []D = 16.1 (c 1.0, CHCl3) for 92% ee}. 1 H NMR (400 MHz, CDCl3) 7.38 – 7.30 (m, 4H), 7.30 – 7.24 (m, 1H), 4.65 (td, J = 7.4, 5.8 Hz, 1H), 3.50 (t, J = 6.7 Hz, 2H), 2.03 (br s, 1H), 1.86 – 1.65 (m, 4H), 1.63 – 1.49 (m, 13 1H), 1.48 – 1.35 (m, 1H). C NMR (101 MHz, CDCl3) 144.5, 128.5, 127.6, 125.8, 74.4, 44.8, 38.2, 32.4, 23.2. LRMS (EI): m/z (%): 200 [M++2] (3), 198 [M+] (8), 108 (14), 107 (100), 105 (9), 79 (60), 77 (29). Ee determination by chiral HPLC analysis, Chiralcel® OJ column, n-hexane/i-PrOH 99:1, flow rate = 1.0 mL/min, = 220 nm, retention times: tR(R) = 38.4 min, tR(S) = 43.2 min (major enantiomer).
(S)-5-chloro-1-(naphthalen-2-yl)pentan-1-ol (2ag): Compound 2ag was obtained after purification on flash silica gel chromatography from 100:0 till 89:11 (n- 28 hexane/EtOAc) as a white waxy solid (56% yield, 94% ee); m.p. 61.5 – 63.3 °C, []D = 1 23.5 (c 1.0, CHCl3). H NMR (300 MHz, CDCl3) 7.84 (dd, J = 8.9, 3.3 Hz, 3H), 7.78 (s, 1H), 7.55 – 7.40 (m, 3H), 4.85 (t, J = 6.4 Hz, 1H), 3.51 (t, J = 6.7 Hz, 2H), 1.96 (br s, 1H), 1.94 – 1.72 (m, 4H), 1.69 – 1.54 (m, 1H), 1.52 – 1.37 (m, 1H). 13C NMR (101 MHz,
CDCl3) 141.9, 133.2, 133.0, 128.3, 127.9, 127.7, 126.2, 125.8, 124.6, 123.9, 74.5, 44.8, 38.0, 32.4, 23.2. IR (ATR): (cm-1): 3240, 2940, 2866, 1314, 1066, 1025. LRMS (EI): m/z (%): 250 [M++2] (5), 248 [M+] (14), 230 (12), 212 (32), 211 (16), 167 (36), 165 (23), 158 (13), 157 (100), 156 (16), 155 (36), 153 (10), 152 (18), 141 (14), 129 (62), + 128 (47), 127 (32). HRMS (ESI): m/z: 248.0968 calculated for C15H17ClO [M ], found 248.0960. Ee determination by chiral HPLC analysis, Chiralcel® OD-H column, n- hexane/i-PrOH 95:5, flow rate = 1.0 mL/min, = 220 nm, retention times: tR(S) = 23.7 min (major enantiomer), tR(R) = 26.0 min.
82
133
Chapter III – Experimental part
(S)-5-chloro-1-[4-(methylthio)phenyl]pentan-1-ol (2ah): Compound 2ah was obtained after purification on flash silica gel chromatography from 100:0 till 89:11 (n- 27 hexane/EtOAc) as a white waxy solid (40% yield, 92% ee); m.p. 48.5 – 50.0 °C, []D = 1 22.7 (c 1.0, CHCl3). H NMR (300 MHz, CDCl3) 7.30 – 7.20 (m, 4H), 4.64 (t, J = 6.5 Hz, 1H), 3.52 (t, J = 6.7 Hz, 2H), 2.48 (s, 3H), 1.88 – 1.63 (m, 5H), 1.61 – 1.51 (m, 1H), 13 1.50 – 1.35 (m, 1H). C NMR (101 MHz, CDCl3) 141.4, 137.6, 126.7, 126.4, 73.9, 44.8, 38.1, 32.4, 23.1, 15.9. IR (ATR): (cm-1): 3264, 2933, 2863, 1598, 1429, 1088. LRMS (EI): m/z (%): 246 [M++2] (4), 245 [M++1] (2), 244 [M+] (10), 154 (10), 153 (100), + 109 (18). HRMS (ESI): m/z: 244.0689 calculated for C12H17ClOS [M ], found 244.0686. Ee determination by chiral HPLC analysis, Chiralpak® AS-H column, n-hexane/i-PrOH
99:1, flow rate = 1.0 mL/min, = 254 nm, retention times: tR(R) = 26.8 min, tR(S) = 29.3 min (major enantiomer).
(S)-5-chloro-1-(4-chlorophenyl)pentan-1-ol (2ai): Compound 2ai was obtained after purification on flash silica gel chromatography from 100:0 till 92:8 (n- 28 1 hexane/EtOAc) as a colorless oil (53% yield, 94% ee); []D = 20.2 (c 1.0, CHCl3). H
NMR (400 MHz, CDCl3) 7.31 (d, J = 8.6 Hz, 2H), 7.26 (d, J = 8.6 Hz, 2H), 4.64 (td, J = 7.3, 5.7 Hz, 1H), 3.51 (t, J = 6.7 Hz, 2H), 2.06 (br s, 1H), 1.83 – 1.72 (m, 3H), 1.72 – 13 1.62 (m, 1H), 1.62 – 1.48 (m, 1H), 1.47 – 1.36 (m, 1H). C NMR (101 MHz, CDCl3) 143.0, 133.2, 128.6, 127.2, 73.7, 44.8, 38.2, 32.3, 23.0. IR (ATR): (cm-1): 3369, 2932, 2863, 1490, 1088, 1013. LRMS (EI): m/z (%): 234 [M++1] (2), 232 (2), 196 (10), 161 (18), 151 (10), 143 (32), 142 (10), 141 (100), 140 (10), 139 (35), 115 (11), 113 (11), 77 + (25). HRMS (ESI): m/z: 214.0316 calculated for C11H12Cl2 [M–H2O] , found 214.0324. Ee determination by chiral HPLC analysis, Chiralcel® OD-H column, n-hexane/i-PrOH
99:1, flow rate = 1.0 mL/min, = 220 nm, retention times: tR(S) = 25.3 min (major enantiomer), tR(R) = 27.3 min.
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Chapter III – Experimental part
(S)-5-chloro-1-(3-iodo-4,5-dimethoxyphenyl)pentan-1-ol (2aj): Compound 2aj was obtained after purification on flash silica gel chromatography from 100:0 till 88:12 (n- hexane/EtOAc) as a pale yellow viscous oil (55% yield, 27 1 98% ee); []D = 11.6 (c 1.0, CHCl3). H NMR (400 MHz, CDCl3) 7.27 (d, J = 1.9 Hz, 1H), 6.87 (d, J = 1.9 Hz, 1H), 4.57 (td, J = 7.6, 5.3 Hz, 1H), 3.86 (s, 3H), 3.81 (s, 3H), 3.53 (t, J = 6.6 Hz, 2H), 2.10 (br s, 1H), 1.85 – 1.72 (m, 3H), 1.70 – 1.55 (m, 2H), 1.51 – 13 1.39 (m, 1H). C NMR (101 MHz, CDCl3) 152.6, 148.0, 142.7, 127.6, 110.2, 92.2, 73.4, 60.4, 56.0, 44.8, 38.2, 32.3, 23.2. IR (ATR): (cm-1): 3418, 2934, 2866, 1562, 1478, 1269, 1040. LRMS (EI): m/z (%): 386 [M++2] (6), 384 [M+] (18), 368 (10), 366 (28), 348 (22), 294 (10), 293 (100), 277 (11), 176 (20), 165 (11), 138 (24). HRMS (ESI): + m/z: 383.9989 calculated for C13H18ClIO3 [M ], found 383.9983. Ee determination by chiral HPLC analysis, Chiralcel® OD-H column, n-hexane/i-PrOH 99:11, flow rate = 1.0 mL/min, = 220 nm, retention times: tR(S) = 52.5 min (major enantiomer), tR(R) = 68.3 min.
(S)-5-chloro-1-(thiophen-2-yl)pentan-1-ol (2ak): Compound 2ak was obtained after purification on flash silica gel chromatography from 100:0 till 93:7 (n-hexane/EtOAc) as a 27 1 yellow oil (67% yield, 94% ee); []D = 12.5 (c 1.0, CHCl3). H NMR (400 MHz, CDCl3) 7.24 (dd, J = 4.2, 2.0 Hz, 1H), 6.99 – 6.94 (m, 2H), 4.91 (t, J = 6.7 Hz, 1H), 3.52 (t, J = 6.7 Hz, 2H), 2.17 (br s, 1H), 1.97 – 1.75 (m, 4H), 1.69 – 1.54 (m, 1H), 1.54 – 1.41 (m, 13 1H). C NMR (101 MHz, CDCl3) 148.5, 126.6, 124.6, 123.8, 70.0, 44.8, 38.4, 32.3, 23.2. IR (ATR): (cm-1): 3370, 2927, 2861, 1444, 1013. LRMS (EI): m/z (%): 206 [M++2] (2), 204 [M+] (6), 188 (11), 186 (31), 124 (10), 123 (100), 113 (96), 111 (13), 97 (15), + 85 (20). HRMS (ESI): m/z: 186.0270 calculated for C9H11ClS [M–H2O] , found 186.0277. Ee determination by chiral HPLC analysis, Chiralcel® OJ column, n- hexane/i-PrOH 99:1, flow rate = 1.0 mL/min, = 230 nm, retention times: tR(S) = 47.6 min (major enantiomer), tR(R) = 50.3 min.
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Chapter III – Experimental part
3.3. General procedure for the intramolecular cyclization of 4- chlorobutyl alcohols into 2-substituted chiral tetrahydropyrans
In a flame dried Schlenk tube, the corresponding chiral 4-chlorobutyl alcohol (0.2 mmol) was dissolved in anhydrous THF (2 mL). Then, KOt-Bu (45 mg, 2 eq.) was added to the previous solution and the suspension was stirred at 25 °C for 3 hours. After that, the reaction was quenched with water (1 mL) and then 4 drops of HCl 2 M were added to eliminate potassium salts. The crude was extracted with EtOAc (3 × 5 mL), and the combined organic layers were neutralized with a saturated NaHCO3 aqueous solution (10 mL), dried over magnesium sulfate and concentrated under vacuum. The crude product was purified by flash silica gel chromatography to give the desired tetrahydropyrans.
3.4. Data of 2-substituted chiral tetrahydropyrans
(S)-2-phenyltetrahydro-2H-pyran (3a):83 Compound 3a was obtained without further purification as a yellow oil (>99% yield, 97% ee); 27 Lit. 25 []D = 49.5 (c 1.0, CHCl3) { []D = -16.1 (c 1.0, CHCl3) for 92% ee}. 1 H NMR (300 MHz, CDCl3) 7.40 – 7.28 (m, 4H), 7.28 – 7.19 (m, 1H), 4.32 (dd, J = 10.5, 2.2 Hz, 1H), 4.20 – 4.08 (m, 1H), 3.61 (td, J = 11.4, 2.6 Hz, 1H), 1.99 – 1.89 (m, 13 1H), 1.87 – 1.77 (m, 1H), 1.76 – 1.48 (m, 4H). C NMR (75 MHz, CDCl3) 143.3, 128.2, 127.2, 125.8, 80.1, 69.0, 34.0, 25.9, 24.0. LRMS (EI): m/z (%): 163 [M++1] (12), 162 [M+] (100), 161 (90), 106 (16), 105 (75), 104 (12), 91 (16), 79 (11), 78 (13), 77 (21).
(S)-2-(naphthalen-2-yl)tetrahydro-2H-pyran (3b): Compound 3b was obtained without further purification as a yellow waxy solid 30 (>99% yield, 94% ee); m.p. 40.0 – 44.0 °C, []D = 40.3 (c 1.0, 1 CHCl3). H NMR (400 MHz, CDCl3) 7.87 – 7.75 (m, 4H), 7.50 – 7.39 (m, 3H), 4.48 (dd, J = 10.6, 2.2 Hz, 1H), 4.23 – 4.15 (m, 1H), 3.67 (td, J = 11.5, 2.5 Hz, 1H), 2.02 – 1.83 (m, 13 2H), 1.82 – 1.52 (m, 4H). C NMR (101 MHz, CDCl3) 140.8, 133.3, 132.8, 128.0,
83
136
Chapter III – Experimental part
127.90, 127.6, 125.9, 125.5, 124.3, 124.2, 80.1, 69.0, 34.1, 25.9, 24.0. IR (ATR): (cm- 1): 2934, 2847, 1202, 1083, 1038, 823, 744. LRMS (EI): m/z (%): 213 [M++1] (16), 212 [M+] (100), 211 (55), 156 (36), 155 (71), 154 (13), 153 (13), 152 (14), 142 (14), 141
(23), 129 (10), 128 (44), 127 (36). HRMS (ESI): m/z: 212.1201 calculated for C15H16O [M+], found 212.1193.
(S)-2-[(4-(methylthio)phenyl]tetrahydro-2H-pyran (3c): Compound 3c was obtained without further purification as a 31 1 colorless oil (90% yield, 92% ee); []D = 45.7 (c 1.0, CHCl3). H
NMR (400 MHz, CDCl3) 7.27 (d, J = 8.5 Hz, 2H), 7.23 (d, J = 8.5 Hz, 2H), 4.28 (dd, J = 10.7, 2.1 Hz, 1H), 4.16 – 4.09 (m, 1H), 3.60 (td, J = 11.6, 2.6 Hz, 1H), 2.46 (s, 3H), 1.97 13 – 1.89 (m, 1H), 1.85 – 1.75 (m, 1H), 1.72 – 1.53 (m, 4H). C NMR (101 MHz, CDCl3) 140.5, 137.1, 126.8, 126.4, 79.7, 69.0, 33.9, 25.9, 24.0, 16.1. IR (ATR): (cm-1): 2933, 2845, 1085, 1040, 815. LRMS (EI): m/z (%): 210 [M++2] (5), 209 [M++1] (15), 208 [M+] (100), 207 (24), 193 (16), 161 (29), 153 (10), 152 (49), 151 (74), 150 (16), 137 (24), + 135 (10), 124 (15), 105 (12). HRMS (ESI): m/z: 208.0922 calculated for C12H16OS [M ], found 208.0916.
(S)-2-(4-chlorophenyl)tetrahydro-2H-pyran (3d): Compound 3d was obtained without further purification as a colorless oil (99% 30 1 yield, 94% ee); []D = 37.6 (c 1.0, CHCl3). H NMR (300 MHz,
CDCl3) 7.28 (s, 4H), 4.29 (dd, J = 10.8, 2.2 Hz, 1H), 4.18 – 4.08 (m, 1H), 3.60 (td, J = 11.3, 2.9 Hz, 1H), 1.98 – 1.87 (m, 1H), 1.85 – 1.75 (m, 1H), 1.72 – 1.52 (m, 4H). 13C
NMR (75 MHz, CDCl3) 141.9, 132.8, 128.4, 127.2, 79.3, 69.0, 34.1, 29.7, 25.8, 23.9. IR (ATR): (cm-1): 2932, 2849, 1492, 1086, 1043, 819. LRMS (EI): m/z (%): 198 [M++2] (15), 197 [M++1] (16), 196 [M+] (45), 195 (32), 161 (76), 142 (11), 141 (42), 140 (34), 139 (100), 138 (14), 125 (21), 115 (10), 112 (24), 111 (14), 77 (15). HRMS (ESI): m/z: + 196.0655 calculated for C11H13ClO [M ], found 196.0637.
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Chapter III – Experimental part
(S)-2-(3-iodo-4,5-dimethoxyphenyl)tetrahydro-2H-pyran (3e): Compound 3e was obtained without further purification as a 30 1 colorless oil (96% yield, 98% ee); []D = 28.4 (c 1.0, CHCl3). H
NMR (400 MHz, CDCl3) 7.31 (d, J = 1.8 Hz, 1H), 6.91 (d, J = 1.8 Hz, 1H), 4.22 (dd, J = 10.8, 2.0 Hz, 1H), 4.16 – 4.08 (m, 1H), 3.86 (s, 3H), 3.80 (s, 3H), 3.58 (td, J = 11.5, 2.6 Hz, 1H), 1.99 – 1.88 (m, 1H), 1.86 – 1.75 (m, 1H), 1.72 – 1.51 (m, 13 4H). C NMR (101 MHz, CDCl3) 152.5, 148.0, 141.3, 127.8, 110.6, 92.1, 79.0, 69.0, 60.3, 56.0, 33.9, 25.7, 23.9. IR (ATR): (cm-1): 2933, 2845, 1561, 1270, 1086, 1043, 1003. LRMS (EI): m/z (%): 349 [M++1] (15), 348 [M+] (100), 292 (25), 291 (22), 277
(35), 221 (24), 177 (11), 165 (27). HRMS (ESI): m/z: 348.0222 calculated for C13H17IO3 [M+], found 348.0224.
(S)-2-(thiophen-2-yl)tetrahydro-2H-pyran (3f): Compound 3f was obtained without further purification as a yellow oil (80% yield, 94% 33 1 ee); []D = 11.8 (c 1.0, CHCl3). H NMR (300 MHz, CDCl3) 7.23 (dd, J = 7.4, 4.4 Hz, 1H), 6.97 – 6.94 (m, 2H), 4.59 (dd, J = 10.4, 2.2 Hz, 1H), 4.17 – 4.04 (m, 1H), 3.62 (td, J = 11.4, 2.7 Hz, 1H), 2.06 – 1.89 (m, 2H), 1.82 – 1.54 (m, 4H). 13C NMR
(75 MHz, CDCl3) 146.5, 126.3, 124.3, 123.2, 75.7, 68.9, 33.8, 25.7, 23.6. IR (ATR): (cm-1): 2934, 2849, 1085, 1036, 695. LRMS (EI): m/z (%): 170 [M++2] (6), 169 [M++1] (15), 168 (100), 167 (35), 113 (16), 112 (45), 111 (83), 110 (28), 97 (22), 84 (16), 55 + (10). HRMS (ESI): m/z: 168.0609 calculated for C9H12OS [M ], found 168.0603.
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Chapter III – Results and discussion
4 Results and discussion
4.1 Optimization of the catalytic enantioselective addition of Grignard reagents to aliphatic aldehydes
As it has been shown in the first part of this chapter, the described methodology for the enantioselective alkylation of aromatic aldehydes works well for this type of substrates, but when an aliphatic aldehyde is used as electrophile, moderate enantioselectivity was generally obtained. For example, the addition of n-BuMgBr to cyclohexanecarboxaldehyde (1q) at –20 ᵒC in toluene provided product 2z (Table 17, entry 1) in only 50% ee. We decided to optimize our methodology further to broaden the substrate scope and allow the use of aliphatic substrates as electrophiles. As a model reaction for our study we chose the addition of n-BuMgBr to cyclohexanecarboxaldehyde (1q) (Table 17).
Based on the previous experience about the behavior of this catalytic system, we attempted our model reaction in Et2O as solvent at –20 ᵒC (Table 17, entry 2). Under these conditions, a positive increase in the enantioselectivity (65% ee) was observed, although the conversion of the reaction dropped till 27%.
Different ligands were next tested in the model reaction. A systematic and extensive study on the electronic, steric and chelating properties of different diol ligands (see further discussion on Figure 6 and Table 3 of this section), brought us to pyridine- substituted ligands (Sa,S)-L9 and (Sa,R)-L10 (Figure 6). Ligand (Sa,R)-L10 gave very promising results in the alkylation reaction of 1q (89% ee and 89% conversion, Table
17, entry 3). Interestingly, (Sa,S)-L9, where the nitrogen of the pyridine ring is at the two position, and therefore closer to the coordination site of the ligand, showed lower catalytic activity, perhaps due to unfavourable coordination effects (Table 17, entry 4).
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Table 17. Initial tests[a]
Entry L* Solvent Conv.[b] (%) ee[b] (%)
1 (Sa,R)-L1 Toluene 98 50 2 (Sa,R)-L1 Et2O 27 65 3 (Sa,R)-L10 Et2O 89 89 4 (Sa,S)-L9 Et2O 84 55 [a] Conditions: Conditions: 1q (0.1 mmol, 0.05 M), n-BuMgBr (3 M in Et2O, 3.8 eq.), Ti(Oi-Pr)4 (15 eq.), (Sa,R)-L* (20 mol%), solvent (1.5 mL), 20 °C, 3 h. [b] Determined by chiral GC analysis.
With the best ligand (Sa,R)-L10 in hand, different Ti(Oi-Pr)4/n-BuMgBr ratio were next tested (Table 18, entries 1-5) in order to find the best ratio between both reagents. As it was observed in the first part of this chapter, for the alkylation reaction of aromatic aldehydes, the optimal ratio Ti(Oi-Pr)4/n-BuMgBr in this case was also 4:1
(Table 11, entry 6). Gratifyingly, the new ligand (Sa,R)-L10 allowed a reduction in the equivalents of both Ti(i-PrO)4 and n-BuMgBr compared to the alkylation reaction of aromatic aldehydes with (Sa,R)-L1, without affecting the enantioselectivity or conversion of the process (Table 18, entry 5). Unfortunately, both conversion and enantioselectivity on the desired alcohol 2z dropped till 33 and 70%, respectively, when the ligand loading was reduced to 10 mol% (Table 18, entry 6). Higher temperatures (0 ᵒC), did not produce any improvement in the conversion of the reaction and, as expected, lower enantioselectivity was obtained (Table 18, entry 7).
[a] Table 18. Optimization Ti(Oi-Pr)4/n-BuMgBr ratio
[b] [b] Entry Ti(Oi-Pr)4 (eq.) n-BuMgBr (eq.) Ti:Mg ratio Conv. (%) ee (%) 1 6 3 2:1 34 40 2 9 3 3:1 59 62 3 12 3 4:1 97 48 4 13.5 3 4.5:1 91 45 5 10 2.5 4:1 89 89 6 10 2.5 4:1 33[c] 70 7 10 2.5 4:1 82[d] 82
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[a] Conditions: 1q (0.1 mmol, 0.05 M), n-BuMgBr (3 M in Et2O, x eq.), Ti(Oi-Pr)4 (y eq.), (Sa,R)-L10 (20 mol%), Et2O (1.5 mL), 20 °C, 3 h. [b] Determined by chiral GC analysis. [c] Performed with 10 mol% of (Sa,R)-L10. [c] Reaction carried out at 0 °C.
Other chiral diol ligands (Figure 6) were also evaluated under the optimized conditions, but results were inferior in all cases (Table 19, entries 1-7). It is interesting to note that the octahydro-binaphtyl derivative H8-(Sa,R)-L1 provided the product 2z in lower enantioselectivity than the corresponding binaphtyl derivative (Sa,R)-L1. A control experiment was performed, whereby 20 mol% of pyridine was added to the reaction mixture containing the ligand (Sa,R)-L1 (Table 19, entry 8). The desired product 2z was obtained with lower enantiomeric excess (78%) and conversion
(50%), proving the efficacy of the ligand (Sa,R)-L10 in the process.
Figure 6. Chiral diol ligands screened in this study.
Table 19. Ligand optimization[a]
Entry L* Conv.[b] (%) ee[b] (%)
1 H8-(Sa,R)-L1 38 13 2 (Sa,R)-L3 64 23 3 (Sa,R)-L4 66 11 4 (Sa,R)-L5 68 16 5 (Sa,R)-L7 84 46 6 (Sa,S)-L9 84 84 7 (Sa,R)-L10 85 90 [c] 8 (Sa,R)-L1 50 78 [a] Conditions: 1q (0.1 mmol, 0.05 M), n-BuMgBr (3 M in Et2O, 2.5 eq.), Ti(Oi-Pr)4 (10 eq.), (Sa,R)-L* (20 mol%), Et2O (1.5 mL), 20 °C, 3 h. [b] Determined by chiral GC analysis. [c] 20 mol% of pyridine was added.
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4.2 Scope of the reaction
To investigate the scope of the catalytic system, both substrate and nucleophile were systematically varied. The addition of n-BuMgBr to cyclic (1q) and -branched (1t) aliphatic aldehydes proceeded with very good yields and enantioselectivities (Table 20, entries 1-2). Moreover, ,-unsaturated aldehydes, such as acrolein (1u, Table 20, entry 3), also provided satisfactory results. The range of nucleophiles examined in this work included EtMgBr (Table 20, entries 4-5), which afforded good yields and enantioselectivities in the reaction with -branched aliphatic substrates. The addition of EtMgBr to 2-methylpentanal (1w, Table 20, entry 5) gave a 1:1.3 mixture of diastereoisomers (S,S)/(S,R), with 77% and 87% enantioselectivities respectively.
Table 20. Asymmetric addition of n-BuMgBr and EtMgBr to aldehydes[a]
Entry Aldehyde Product Yield[b] (%) ee[c] (%)
1 97 90 (S)
2 97 80 ()[d]
3 53 96 (S)
4 80 86 (+)[e]
77 (S,S) 5 78[f] 87 (S,R)[e]
[a] Conditions: 1 (0.3 mmol, 0.05 M), RMgBr (3 M in Et2O, 2.5 eq.), Ti(Oi-Pr)4 (10 eq.),
(Sa,R)-L10 (20 mol%), Et2O (2.5 mL), 20 °C, 3 h. [b] Isolated yield after flash silica gel chromatography. [c] Determined by chiral GC or HPLC analysis. [d] Determined on the corresponding p-nitrobenzoate derivative 4. [e] Determined on the corresponding acetate derivative. [f] Diastereomeric ratio (S,S)/(S,R) : 43/57, determined by GC analysis.
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Finally, the attention was focused on the addition of MeMgBr to varying aliphatic aldehydes (Table 21). Methyl carbinol units are especially interesting since they are present in a large number of natural products and biologically active compounds; however, its construction via addition to a carbonyl moiety is hampered by the low reactivity of methyl derived organometallic reagents as nucleophiles. Gratifyingly, under the optimized conditions, the newly developed catalytic system proved to be effective for the addition of MeMgBr to various aliphatic aldehydes. Both linear and -branched aliphatic substrates were suitable substrates for the reaction, giving high enantioselectivities along with good yields (Table 21, entries 1-7). Moreover, ,- unsaturated aldehydes like cinnamaldehyde (1l, Table 21, entry 8) and phenylpropargyl aldehyde (1aa, Table 21, entry 9) afforded the corresponding chiral alcohols in good yield with 82% and 60% ee, respectively; this demonstrates the robustness and applicability of this methodology.
Table 21. Asymmetric addition of MeMgBr to aldehydes[a]
Entry Aldehyde Product Yield[b] (%) ee[c] (%)
1 98 88 (S)[d]
2 81 86 (S) 3 77[e] 84 (S)
4 99 83 (+)
5 61 92 (S)[d]
6[f] (58)[g] 99 (S)
7 60 98(S)[d]
8 >99 82 (S)
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Chapter III – Results and discussion
9 80 60 (S)
[a] Conditions: 1 (0.3 mmol, 0.05 M), MeMgBr (3 M in Et2O, 2.5 eq.), Ti(Oi-Pr)4 (10 eq.), (Sa,R)-L10 (20
mol%), Et2O (2.5 mL), 20 °C, 3 h. [b] Isolated yield after flash silica gel chromatography. [c] Determined by chiral GC or HPLC analysis. [d] Determined on the corresponding acetate derivative
4. [e] Result after recovery of (Sa,R)-L10 and reused in the addition of MeMgBr to 1y. [f] 1 (0.3
mmol, 0.07 M), MeMgBr (3 M en Et2O, 3.8 eq.), Ti(Oi-Pr)4 (15 eq.), (Sa,R)-L10 (20 mol%), Et2O (2.5 mL), 20 °C, 3 h. [g] Volatile product. Conversion determined by GC in brackets.
Most of the chiral secondary alcohols here presented have been identified as natural products with biological function and/or have applications in the fragrance/cosmetic industry.84 This work represents a convenient procedure for the use of Grignard reagents as inexpensive and readily accessible nucleophiles for the preparation of these valuable building blocks. Further advantages of this methodology include the recovery of the chiral ligand (Sa,R)-L10 from the reaction mixture by simple acid base extraction (60% recovery yield) which, at the same time, facilitates the isolation and purification of the corresponding products. The recovered ligand (Sa,R)-L10 can be reused in subsequent reactions without any loss of activity (Table 21, entry 3).
4.3 Mechanistic aspects
Some mechanistic aspects about the asymmetric alkylation of aliphatic aldehydes with Grignard reagents catalyzed by (Sa,R)-L10 has been studied to clarified the pathway of the reaction, such as: non-linear effect, autocatalysis and kinetic profiles.
Non-linear effect studies were carried out using the addition of MeMgBr to 3- phenylpropanal (1y) as model reaction. Ligand (Sa,R)-L10, in different enantiomeric purities, was chosen for the purpose of this investigation. The reaction was carried out under the previously optimized conditions: Et2O, 20 °C, 10 eq. of Ti(Oi-Pr)4 and
2.5 eq. of MeMgBr. The linear plot of the ee values for (Sa,R)-L10 vs the ee values of
84 a) Mozga, T.; Prokop, Z.; Chaloupková, R.; Damborský, J. Collect. Czech. Chem. Commun. 2009, 74, 11951278; b) Keinan, E.; Sinha, S. C.; Singh, S. P. Tetrahedron 1991, 47, 46314638; c) Keinan, E.; Seth, K. K.; Lamed, R. J. Am. Chem. Soc. 1986, 108, 34743480.
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the corresponding reaction product 2aq (Figure 7) suggested that only one molecule of chiral ligand is involved in the active metallic species.85
Non-linear effect
100
80
60 2aq (%) 2aq 40 ee 20
0 0 20 40 60 80 100
ee (Sa,R)-L10 (%)
Figure 7. Linear plot of ee values of 2aq vs ee values of (Sa,R)-L10
By analogy with previous reports on the asymmetric addition of alkyl groups to aldehydes catalyzed by titanium-BINOLate86 and titanium-TADDOLate87 ligands, we believe that monomeric bimetallic species like (Sa,R)-L10-A or (Sa,R)-L10-B could be present at the optimized reaction conditions (Figure 8) and that intermediates like
(Sa,R)-L10-C or (Sa,R)-L10-D are possibly responsible for both conversion and asymmetric induction in our system.
85 Guillaneux, D.; Zhao, S.-H.; Samuel, O.; Rainford, D.; Kagan, H. B. J. Am. Chem. Soc. 1994, 116, 94309439. 86 Balsells, J.; Davis, T. J.; Carroll, P.; Walsh, P. J. J. Am. Chem. Soc. 2002, 124, 1033610348. 87 Ito, Y. N.; Ariza, X.; Beck, A. K.; Boháč, A.; Ganter, C.; Gawley, R. E.; Kühnle, F. N. M.; Tuleja, J.; Wang, Y. M.; Seebach, D. Helv. Chim. Acta 1994, 77, 20712110.
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Chapter III – Results and discussion
Figure 8. Possible intermediates involved in the catalysis.
The possibility of autocatalytic effect in the system was also examined. The reaction of 3-phenylpropanal (1y) with MeMgBr (2.5 eq.) in the presence of 40 mol% of enantiomerically pure (S)-2aq and 10 eq. of Ti(Oi-Pr)4 in Et2O at –20 ᵒC for 5 h, allowed the generation of product 2aq in 54% ee, indicating that there is some autocatalysis effect (Scheme 51).
Scheme 51. Autocatalytic effect observed in the addition of MeMgBr to 3-phenylpropanal (2aq)
The same reaction was carried out in the presence of 20 mol% of pyridine (together with the 40 mol% of enantiomerically pure (S)-2aq) and, in a similar way, the newly form 2aq was obtained with 54% ee, indicating that pyridine does not perform any role separately. However, both reactions showed very low conversions (30% and
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Chapter III – Results and discussion
27%, respectively) and much slower rate than when the reaction was carried out in the presence of (Sa,R)-L10, so we conclude that the autocatalysis of the chiral alcohol 88 product is negligible compared with the (Sa,R)-L10 catalyzed reaction.
Kinetic experiments 100
80
60
40 (Sa,R)-L2 Conversion (%) Conversion Without ligand 20 (S)-BINOL
0 0 30 60 90 120 150 180 Time (min)
Figure 9. Comparative curves on the rate of the reaction with (Sa,R)-L10, (S)-BINOL and without ligand.
Finally, three kinetic analysis were conducted to determine the effect of the chiral ligand (Sa,R)-L10 in the rate of the addition of MeMgBr (2.5 eq.) to 3-phenylpropanal
(1y), in the presence of 10 eq. of Ti(Oi-Pr)4, Et2O as solvent at –20 ᵒC. As it is shown in the kinetic profiles above (Figure 10), the reaction catalyzed by ligand (Sa,R)-L10 (blue profile) was much faster than the reaction in the absence of ligand (green profile) or in the presence of (S)-BINOL as chiral diol (red profile). The corresponding alcohol 2aq was generated with only 7% of enantiomeric excess when (S)-BINOL was used as a ligand and racemic when no ligand was employed in the reaction. So, this indicates that chiral ligand (Sa,R)-L10 is the responsible of the catalysis and the chirality induced in the product.
88 a) Wu, K.-H.; Kuo, Y.-Y.; Chen, C.-A.; Huang, Y.-L.; Gau, H.-M. Adv. Synth. Catal. 2013, 335, 10011008; b) Wu, K.-H.; Zhou, S.; Chen, C.-A.; Yang, M.-C.; Chiang, R.-T.; Chen, C.-R.; Gau, H.-M. Chem. Commun. 2011, 47, 1166811670.
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Chapter III – Results and discussion
In conclusion, an efficient enantioselective catalytic system has been developed for the addition of alkyl Grignard reagents to aliphatic aldehydes that allows the preparation of chiral aliphatic secondary alcohols in a simple one-pot procedure under mild reaction conditions. This methodology overcomes the main problems associated with the use of aliphatic substrates: their multiple conformations, the absence of possible – stacking interactions with the catalyst and/or their highly- enolizable character. A readily available binaphthyl derivative is used as a chiral ligand and an excess of titanium tetraisopropoxide was found to be crucial to achieve high enantioselectivities. Moreover, the addition of the challenging MeMgBr to aliphatic aldehydes could also be achieved for the first time with high yields and enantioselectivities, allowing the construction of the versatile and optically active aliphatic methyl carbinol motif.
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Chapter III – Experimental part
5. Experimental part
5.1 General procedure for the enantioselective addition of Grignard reagents to aliphatic aldehydes
In a flame dried Schlenk tube, (Sa,R)-L10 (22.6 mg, 0.06 mmol, 10 mol%) was dissolved in anhydrous Et2O (2.5 mL) under argon atmosphere. The solution was cooled down to 20 °C and Ti(Oi-Pr)4 (915 L, 3 mmol, 10 eq.) was then added. Five minutes later, RMgBr (0.75 mmol, 2.5 eq.) was added. After stirring the mixture for additional 15 min, the corresponding freshly distilled aliphatic aldehyde (0.3 mmol) was added and the reaction mixture was stirred at 20 °C for 3 h. The reaction was quenched with water (5 mL) and then HCl 2 M (5 mL) to eliminate the titanium oxides generated by the addition of water. The crude was extracted with Et2O (3 × 10 mL), and the combined organic layers were neutralized with a saturated NaHCO3 aqueous solution (15 mL), dried over magnesium sulfate and concentrated under vacuum. The crude product was purified by flash silica gel chromatography to give the desired products.
5.2 Data of chiral secondary aliphatic alcohols
(S)-1-Cyclohexylpentan-1-ol (2z): Yellow oil (97% yield, 90% ee); 25 Lit. 20 []D = 15.4 (c 1.0, CHCl3) { []D = +14.3 (c 1.9, CHCl3) for 90% ee of R enantiomer}.
()-3-Ethyloctan-4-ol (2al):89 Compound 2al was obtained after purification on flash silica gel chromatography from 100:0 till 94:6 25 (n-hexane/EtOAc) as a colorless oil (97% yield, 80% ee); []D = 1 10.6 (c 1.0, CHCl3). H NMR (400 MHz, CDCl3) 3.61 (dt, J = 8.1, 4.0 Hz, 1H), 1.44 (m, 6H), 1.38 – 1.24 (m, 5H), 1.23 – 1.14 (m, 1H), 0.96 – 0.86 (m, 9H). 13C NMR (101 MHz,
CDCl3) 73.2, 46.8, 33.7, 28.5, 22.8, 22.1, 21.1, 14.1, 11.9, 11.8. LRMS (EI): m/z (%):
89 Zhang, X.; Lu, Z.; Fu, C.; Ma, S. Org. Biomol. Chem. 2009, 7, 3258–3263.
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Chapter III – Experimental part
158 [M+] (<1), 101 (17), 87 (47), 86 (15), 83 (11), 70 (17), 69 (100), 59 (18), 57 (15), 55 (15). Ee was determined by chiral HPLC analysis on the derivative 4a.
(S)-Hept-1-en-3-ol (2am):90 Compound 2am was obtained after purification on flash silica gel chromatography from 100:0 till 90:10 25 Lit. (n-pentane/Et2O) as a colorless oil (53% yield, 96% ee); []D = +14.2 (c 0.9, CHCl3) { 20 1 []D = +9.0 (c 1.0, CHCl3) for 99% ee}. H NMR (300 MHz, CDCl3) 5.94 – 5.80 (ddd, J = 16.7, 10.4, 6.3 Hz, 1H), 5.21 (dd, J = 17.2, 1.5 Hz, 1H), 5.13 – 5.06 (dd, J = 10.4, 1.4 Hz, 1H), 4.14 – 4.04 (qt, J = 6.3, 1.1 Hz, 1H), 1.90 (br s, 1H), 1.65 – 1.43 (m, 2H), 1.43 – 13 1.24 (m, 4H), 0.98 – 0.83 (t, J = 7.1 Hz, 3H). C NMR (75 MHz, CDCl3) 141.3, 114.5, 73.2, 36.7, 27.5, 22.6, 14.0. LRMS (EI): m/z (%): 114 [M+] (<1), 85 (9), 81 (7), 72 (21), 58 (6), 57 (100), 55 (8). Ee determination by chiral GC analysis, CP-Chirasil-DEX CB column, T = 70 °C, P = 14.3 psi, retention times: tr(S) = 18.1 min (major enantiomer), tr(R) = 19.7 min.
(+)-1-Cyclopentylpropan-1-ol (2an):91 Compound 2an was obtained after purification on flash silica gel chromatography from 100:0 till 25 90:10 (n-pentane/Et2O) as a colorless oil (80% yield, 86% ee); []D = 1 +3.7 (c 1.2, CHCl3). H NMR (300 MHz, CDCl3) 3.40 – 3.30 (td, J = 8.0, 3.5 Hz, 1H), 1.99 – 1.75 (m, 2H), 1.73 – 1.49 (m, 8H), 1.48 – 1.32 (m, 2H), 0.98 (t, J = 7.4 Hz, 3H). 13 C NMR (75 MHz, CDCl3) 77.4, 45.9, 29.1, 28.9, 28.5, 25.7, 25.6, 10.0. LRMS (EI): m/z (%): 128 [M+] (<1), 99 (42), 82 (8), 81 (100), 79 (10), 69 (10), 68 (20), 67 (14), 59 (81), 58 (21), 57 (13), 55 (9). Ee was determined by chiral GC analysis on the derivative 4b.
90 Gawas, D.; Kazmaier, U. Org. Biomol. Chem. 2010, 8, 457–462. 91 Xin, S.; Harrod, J. F. Can. J. Chemistry 1995, 73, 999–1002.
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Chapter III – Experimental part
(3S,4R)-4-Methylheptan-3-ol and (3S,4S)-4-Methylheptan-3-ol (2ao):92 Compounds 2ao were obtained as a diastereomeric mixture 43/57 after purification on flash silica gel chromatography from
100:0 till 90:10 (n-pentane/Et2O) as a colorless oil {78% yield, 77% 1 ee (anti) and 87% ee (syn)}. H NMR (400 MHz, CDCl3) 3.42 (m, 1H), 3.35 (m, 1H), 1.05 – 1.60 (m, 16H), 0.87– 0.97 (m, 18H). 13C NMR (101 MHz,
CDCl3) 78.3, 77.6, 38.5, 35.5, 35.6, 34.1, 27.2, 26.2, 20.4, 20.3, 14.4, 14.3, 13.9, 13.5, 10.6, 10.4. LRMS (EI): m/z (%): 130 [M+] (<1), 101 (16), 83 (22), 70 (8), 59 (100), 58 (21), 57 (11), 55 (18). Ee was determined by chiral GC analysis on the derivatives 4c.
(S)-Decan-2-ol (2ap):93 Compound 2ap was obtained after purification on flash silica gel chromatography from 100:0 till 25 94:6 (n-hexane/EtOAc) as a colorless oil (98% yield, 88% ee); []D = +6.2 (c 1.0, Lit. 20 1 CHCl3) { []D = +6.1 (c 1.0, CHCl3) for 99% ee}. H NMR (400 MHz, CDCl3) 3.86 – 3.73 (sext, J = 6.2 Hz, 1H), 1.72 (s, 1H), 1.53 – 1.37 (m, 3H), 1.36 – 1.22 (m, 11H), 1.19 13 (d, J = 6.2 Hz, 3H), 0.88 (t, J = 6.8 Hz, 3H). C NMR (101 MHz, CDCl3) 68.2, 39.3, 31.9, 29.6, 29.5, 29.3, 25.8, 23.4, 22.6, 14.1. LRMS (EI): m/z (%): 158 [M+] (<1), 143 (24), 140 (23), 112 (47), 111 (31), 98 (22), 97 (41), 85 (26), 84 (35), 83 (72), 82 (15), 71 (28), 70 (51), 69 (100), 67 (10), 57 (58), 56 (45), 55 (80). Ee was determined by chiral GC analysis on the derivative 4d.
(S)-4-Phenylbutan-2-ol (2aq):94 Compound 2aq was obtained after purification on flash silica gel chromatography from 100:0 till 90:10 25 (n-Hexane/EtOAc) as a colorless oil (81% yield, 86% ee); []D = Lit. 20 1 +13.5 (c 1.0, CHCl3) { []D = +13.8 (c 1.7, CHCl3) for 79% ee}. H NMR (300 MHz,
CDCl3) 7.33 – 7.13 (m, 5H), 3.88 – 3.75 (sext, J = 6.2 Hz, 1H), 2.83 – 2.59 (m, 2H), 13 1.83 – 1.72 (m, 2H), 1.70 (s, 1H), 1.22 (d, J = 6.2 Hz, 3H). C NMR (75 MHz, CDCl3) 142.0, 128.4, 125.8, 67.4, 40.8, 32.1, 23.6. LRMS (EI): m/z (%): 151 [M++1] (1), 150
92 Zada, A.; Ben-Yehuda, S.; Dunkelblum, E.; Harel, M.; Assael, F.; Mendel, Z. J. Chem. Ecol. 2004, 30, 631–641. 93 Keinan, E.; Hafeli, E. K.; Seth, K. K.; Lamed, R. J. Am. Chem. Soc. 1986, 108, 162–169. 94 Li, D. R.; He, A.; Falck, J.R. Org. Lett. 2010, 12, 1756–1759.
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[M+] (10), 132 (52), 131 (9), 118 (10), 117 (100), 115 (9), 105 (10), 92 (34), 91 (75), 78 (20), 77 (13), 65 (12), 51 (7). Ee determination by chiral GC analysis, CP-Chirasil-DEX
CB column, T = 110 °C, P = 14.3 psi, retention times: tr(S) = 27.0 min (major enantiomer), tr(R) = 29.7 min.
(+)-3-Ethylpentan-2-ol (2ar):95 Compound 2ar was obtained after purification on flash silica gel chromatography from 100:0 till 90:10 (n- 25 pentane/Et2O) as a colorless oil (99% yield, 83% ee); []D = +2.6 (c 1.0, 1 CHCl3). H NMR (300 MHz, CDCl3) 3.84 (qd, J = 6.4, 5.1 Hz, 1H), 1.93 (br s, 1H), 1.48 – 1.19 (m, 5H), 1.15 (d, J = 6.4 Hz, 3H), 0.91 (t, J = 7.4 Hz, 6H). 13C NMR (75 MHz, + CDCl3) 69.3, 48.1, 21.6, 21.5, 20.0, 11.7, 11.6. LRMS (EI): m/z (%): 116 [M ] (<1), 101 (10), 83 (9), 71 (16), 70 (100), 69 (14), 59 (17), 57 (13), 55 (42), 53 (6). Ee determination by chiral GC analysis, CP-Chirasil-DEX CB column, T = 70 °C, P = 14.3 psi, retention times: tr(R) = 20.4 min, tr(S) = 21.0 min (major enantiomer).
(S)-1-Cyclohexylethanol (2as):96 Compound 2as was obtained after purification on flash silica gel chromatography from 100:0 till 94:6 (n- 25 hexane/EtOAc) as a yellow oil (61% yield, 92% ee); []D = +2.8 (c 1.0, Lit. 20 1 CHCl3) { []D = +3.5 (c 3.1, CHCl3) for 95% ee}. H NMR (300 MHz, CDCl3) 3.54 (quin, J = 6.2 Hz, 1H), 1.92 – 1.59 (m, 6H), 1.34 – 1.09 (m, 7H), 1.09 – 0.87 (m, 2H). 13C
NMR (75 MHz, CDCl3) 72.2, 45.1, 28.6, 28.3, 26.5, 26.2, 26.1, 20.3. LRMS (EI): m/z (%): 128 [M+] (<1), 113 (16), 110 (37), 95 (42), 84 (24), 83 (35), 82 (100), 81 (18), 69 (16), 67 (61), 56 (25), 55 (76), 54 (14), 53 (9). Ee was determined by chiral GC analysis on the derivative 4e.
(S)-3,3-Dimethylbutan-2-ol (2n):97 Compound 2n was obtained after purification on flash silica gel chromatography from 100:0 till 90:10 (n- 25 pentane/Et2O) as a colorless oil (58% yield, 99% ee); []D = 8.0 (c 1.7,
95 Rawson. D.; Meyers, A. I. J. Chem. Soc., Chem. Commun. 1992, 6, 494–496. 96 Li, G.; Kabalka, G. W. J. Organomet. Chem., 1999, 581, 66–69. 97 Gilmore, N. J.; Jones, S.; Muldowney, M. P. Org. Lett. 2004, 6, 2805–2808.
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Lit. 20 1 EtOAc) { []D = +31.0 (c 1.0, CHCl3) for 60% ee}. H NMR (300 MHz, CDCl3) 3.47 (q, J = 6.4 Hz, 1H), 1.76 (br s, 1H), 1.12 (d, J = 6.4 Hz, 3H), 0.89 (s, 9H). 13C NMR (75 + MHz, CDCl3) 75.6, 34.8, 25.4, 17.8. LRMS (EI): m/z (%): 136 [M ] (1), 118 (23), 117 (35), 115 (15), 92 (100), 91 (94), 65 (19), 51 (9). Ee determination by chiral GC analysis, HP-CHIRAL-20 column, T = 60 °C, P = 6.0 psi, retention time: tr(S) = 29.8 min
(major enantiomer), tr(R) = 31.9 min.
(S)-3,3-Dimethylhex-5-en-2-ol (2at):98 Compound 2at was obtained after purification on flash silica gel chromatography from 100:0 till 25 92:8 (n-pentane/Et2O) as a colorless oil (60% yield, 98% ee); []D = Lit. 20 1 +2.8 (c 1.0, CHCl3) { []D = 7.2 (c 1.1, CHCl3) for 76% ee of R enantiomer}. H NMR
(300 MHz, CDCl3) 5.95 – 5.79 (dddd, J = 15.0, 12.6, 9.4, 7.5 Hz, 1H), 5.10 – 5.05 (m, 1H), 5.05 – 5.01 (m, 1H), 3.55 (q, J = 6.1 Hz, 1H), 2.11 (ddt, J = 13.6, 7.6, 1.1 Hz, 1H), 1.99 (ddt, J = 13.6, 7.4, 1.1 Hz, 1H)., 1.70 (br s, 1H), 1.13 (d, J = 6.4 Hz, 3H), 0.88 (s, 13 3H), 0.86 (s, 3H). C NMR (75 MHz, CDCl3) 135.5, 117.0, 74.2, 43.5, 37.8, 22.9, 22.1, 17.6. LRMS (EI): m/z (%): 128 [M+] (<1), 110 (16), 95 (16), 87 (70), 86 (10), 84 (44), 83 (22), 82 (14), 71 (12), 69 (100), 67 (28), 56 (11), 55 (79), 53 (9). Ee was determined by chiral GC analysis on the derivative 4f.
(S,E)-4-Phenylbut-3-en-2-ol (2l): Yellow oil (>99% yield, 82% ee); 25 Lit. 20 []D = 25.4 (c 1.0, CHCl3) { []D = 14.6 (c 1.0, CHCl3) for 60% ee}.
(S)-4-Phenylbut-3-yn-2-ol (2au):89 Compound 2au was obtained after purification on a flash silica gel chromatography from 100:0 till 25 90:10 (n-hexane/EtOAc) as a colorless oil (80% yield, 60% ee); []D Lit. 20 1 = 21.5 (c 1.0, CHCl3) { []D = 33.0 (c 0.9, CHCl3) for 98% ee}. H
NMR (300 MHz, CDCl3) 7.43 (m, 2H), 7.31 (m, 3H), 4.76 (m, 1H), 2.14 (br s, 1H), 1.56 13 (d, J = 6.6 Hz, 3H). C NMR (75 MHz, CDCl3) 131.6, 128.3, 128.2, 122.5, 90.9, 84.0,
98 Cozzi, P. G.; Kotrusz, P. J. Am. Chem. Soc. 2006, 128, 4940–4941.
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Chapter III – Experimental part
58.8, 24.4. LRMS (EI): m/z (%): 147 [M++1] (3), 146 [M+] (33), 145 (50), 132 (10), 131 (100), 129 (11), 128 (12), 127 (10), 103 (65), 102 (14), 77 (32), 51 (11). Ee determination by chiral HPLC analysis, Chiralcel® OJ column, n-hexane/i-PrOH 97:3, flow rate = 1.0 mL/min, = 210 nm, retention times: tr(R) = 15.6 min, tr(S) = 18.0 min (major enantiomer).
5.3 Procedure for derivatization of chiral secondary aliphatic alcohols into the corresponding esters
Two different procedures were used to derivatize chiral aliphatic alcohols into the corresponding p-nitrobenzoate (Procedure A) and acetate (Procedure B) products.
Procedure A: Synthesis of (S)-3-ethyloctan-4-yl p-nitrobenzoate (4a)
In a flame dried Schlenk tube, the corresponding aliphatic alcohol 2al (31.7 mg, 0.2 mmol) was dissolved in anhydrous DCM (1 mL) at 0 °C and Et3N (56 L, 0.4 mmol, 2 eq.), DMAP (2.5 mg, 0.02 mmols, 10 mol%) and p-nitrobenzoyl chloride (55.7 mg, 0.3 mmol, 1.5 eq.) were added sequentially. The reaction mixture was stirred at room temperature for 12 h. The reaction was quenched with water (1 mL), extracted with
Et2O (3 × 5 mL) and the combined organic layers were dried over magnesium sulfate and concentrated under vacuum. The crude product was purified by flash silica gel chromatography to give the desired product 4a.
Procedure B: Synthesis of acetates 4b, 4c, 4d, 4e and 4f
In a flame dried Schlenk tube, the corresponding aliphatic alcohol [2an, 2ao, 2ap, 2as or 2at] (0.1 mmol) was dissolved in anhydrous DCM (1 mL) at 0 °C and Et3N (28 L, 0.2 mmol, 2 eq.), DMAP (1.3 mg, 0.01 mmol, 10 mol%) and acetic anhydride (22 L, 0.2 mmol, 2 eq.) were added sequentially. The reaction mixture was stirred at room temperature for 12 h. The reaction was quenched with water (1 mL), extracted with
Et2O (3 × 5 mL) and the combined organic layers were dried over magnesium sulfate and concentrated under vacuum. The crude product was purified by Kugelrohr distillation to give the desired products 4b, 4c, 4d, 4e and 4f.
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5.4 Data of chiral esters
(S)-3-Ethyloctan-4-yl p-nitrobenzoate (4a): Compound 4a was obtained after purification on flash silica gel chromatography from 100:0 till 98:2 (n-hexane/EtOAc) as a yellow viscous oil 1 (>99% yield). H NMR (400 MHz, CDCl3) 8.29 (d, J = 9.0 Hz, 2H), 8.21 (d, J = 9.0 Hz, 2H), 5.27 (dt, J = 8.5, 4.2 Hz, 1H), 1.80 – 1.58 (m, 2H), 1.58 – 1.46 (m, 2H), 1.45 – 1.21 (m, 7H), 0.97 (t, J = 7.0 13 Hz, 3H), 0.94 (t, J = 7.4 Hz, 3H), 0.89 (t, J = 6.9 Hz, 3H). C NMR (101 MHz, CDCl3) 164.4, 150.4, 136.2, 130.6, 123.5, 77.8, 44.5, 30.7, 28.0, 22.6, 22.2, 21.93, 14.0, 11.8, 11.7. IR (ATR): (cm-1): 2960, 1719, 1527, 1271, 1101, 718. LRMS (EI) m/z (%): 307 [M+] (<1), 236 (9), 151 (13), 150 (100), 140 (7), 104 (13), 92 (5), 76 (6), 55 (4). HRMS + (EI): m/z: 250.1079 calculated for C13H16NO4 [M–n-Bu] , found 250.1119. Ee determination by chiral HPLC analysis, Chiralpak® AS-H column, n-hexane/i-PrOH
99:1, flow rate = 0.8 mL/min, = 254 nm, retention times: tr(R) = 7.5 min, tr(S) = 8.7 min (major enantiomer).
(S)-1-Cyclopentylpropyl acetate (4b): Compound 4b was obtained after purification by Kugelrohr distillation as a colorless oil (>99% 1 yield). H NMR (300 MHz, CDCl3) 4.77 (td, J = 7.8, 4.1 Hz, 1H), 2.06 (s, 3H), 1.76 – 1.41 (m, 9H), 1.36 – 1.11 (m, 2H), 0.88 (t, J = 7.4 Hz, 4H). 13C
NMR (75 MHz, CDCl3) 171.1, 78.8, 43.3, 29.0, 28.6, 26.2, 25.5, 25.2, 21.2, 9.6. LRMS (EI): m/z (%): 170 [M+] (<1), 141 (17), 112 (33), 110 (35), 101 (69), 97 (11), 95 (14), 82 (17), 81 (100), 71 (16), 68 (16), 67 (39), 55 (11). Ee determination by chiral GC analysis, CP-Chirasil-DEX CB column, T = 110 °C, P = 14.3 psi, retention time: tr(S) = 6.6 min (major enantiomer), tr(R) = 7.3 min.
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(3S,4R)-4-Methylheptan-3-yl acetate (3S,4S)-4-Methylheptan-3-yl acetate (4c): Compounds 4c were obtained after Kugelrohr distillation as a colorless oil (>99% yield). LRMS (EI): m/z (%): 172 [M+] (<1), 143 (9), 130 (9), 112 (22), 101 (100), 83 (47), 72 (50), 71 (14), 70 (26), 69 (25), 57 (13), 55 (29). Ee determination by chiral GC analysis, HP-CHIRAL-20 column, T = 70 °C, P = 14.3 psi, retention time for anti diastereoisomers: tr(3S,4R) = 27.9 min (major enantiomer), tr(3R,4S) =
31.2 min, and for syn diastereoisomers: tr(3S,4S) = 29.4 min (major enantiomer), tr(3R,4R) = 32.3 min.
(S)-Decan-2-yl acetate (4d): Compound 4d was obtained after purification by Kugelrohr distillation as a colorless oil 1 (>99% yield). H NMR (300 MHz, CDCl3) 4.95 – 4.79 (sext, J = 6.3 Hz, 1H), 2.04 – 1.95 (s, 3H), 1.66 – 1.36 (m, 2H), 1.35 – 1.21 (m, 11H), 1.18 (d, J 13 = 6.3 Hz, 3H), 0.86 (t, J = 6.7 Hz, 3H). C NMR (75 MHz, CDCl3) 170.8, 71.1, 35.9, 31.8, 29.5, 29.4, 29.2, 25.4, 22.6, 21.3, 19.9, 14.0. LRMS (EI): m/z (%): 200 [M+] (<1), 140 (43), 112 (16), 111 (26), 102 (12), 98 (22), 97 (34), 96 (11), 87 (100), 85 (11), 84 (21), 83 (24), 82 (10), 71 (16), 70 (36), 69 (37), 58 (16), 57 (24), 56 (37), 55 (42). Ee determination by chiral GC analysis, Chirasil-DEX CB column, T = 130 °C, P = 14.3 psi, retention time: tr(S) = 6.5 min (major enantiomer), tr(R) = 7.4 min.
(S)-1-Cyclohexylethyl acetate (4e): Compound 4e was obtained after purification by Kugelrohr distillation as a colorless oil (>99% yield). 1H
NMR (400 MHz, CDCl3) δ 4.72 (quin, J = 6.4 Hz, 1H), 2.04 (s, 3H), 1.80 – 1.61 (m, 5H), 1.43 (m, 1H), 1.27 – 1.09 (m, 3H), 1.16 (d, J = 6.4 Hz, 3H), 13 1.07 – 0.90 (m, 2H). C NMR (101 MHz, CDCl3) δ 171.0, 74.7, 42.5, 28.4, 26.3, 26.0, 25.9, 20.92, 17.0. LRMS (EI): m/z (%): 128 [M+] (<1), 113 (16), 110 (37), 95 (42), 84 (24), 83 (35), 82 (100), 81 (18), 69 (16), 67 (61), 56 (25), 55 (76), 54 (14), 53 (9). Ee determination by chiral GC analysis, HP-CHIRAL-20 column, T = 130 °C, P = 14.3 psi, retention time: tr(S) = 8.1 min (major enantiomer), tr(R) = 8.5 min.
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Chapter III – Experimental part
(S)-3,3-Dimethylhex-5-en-2-yl acetate (4f): Compound 4f was obtained after purification by Kugelrohr distillation as a colorless oil 1 (>99% yield). H NMR (300 MHz, CDCl3) 5.80 (ddt, J = 17.6, 10.2, 7.5 Hz, 1H), 5.10 – 4.95 (m, 2H), 4.72 (q, J = 6.4 Hz, 1H), 2.04 (s, 3H), 13 1.14 (d, J = 6.4 Hz, 3H), 0.88 (d, J = 7.9 Hz, 6H). C NMR (75 MHz, CDCl3) 170.7, 134.6, 117.4, 76.4, 43.3, 36.8, 22.8, 22.5, 21.2, 14.5. LRMS (EI): m/z (%): 170 [M+] (<1), 129 (27), 110 (17), 95 (19), 87 (100), 83 (20), 69 (29), 67 (13), 55 (29). Ee determination by chiral GC analysis, Chirasil-DEX CB column, T = 90 °C, P = 14.3 psi, retention time: tr(S) = 7.2 min (major enantiomer), tr(R) = 8.5 min.
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Chapter III – Results and discussion
6. Results and discussion
6.1. Catalytic enantioselective arylation of ketones with Grignard reagents
In this section of this chapter, a catalytic approach for the asymmetric arylation of aryl alkyl ketones with Grignard reagents will be described, to afford highly valuable diarylmethanols.99 The challenging formation of the new quaternary stereocenter herein achieved, takes place with good levels of enantioselection, despite the fact that both substrate and nucleophile have similar steric and electronic properties. The use of readily accessible and inexpensive aryl Grignard reagents as nucleophiles is a strong advantage of the methodology, compared with the more expensive diarylzinc or organoboron reagents.
As a model reaction for this study, we chose the addition of PhMgBr to 2- acetylnaphthalene (5a) due to the simplicity of both, nucleophile and substrate. At the beginning of the investigation, four different solvents (DCM, TBME, toluene and
Et2O) were screened at 0 and 20 °C in the addition of PhMgBr to 2-acetylnaphtalene
(5a), catalyzed by (Sa,R)-L10, under the previously reported optimized conditions for the alkylation of aliphatic aldehydes (see section 4.1 in this chapter). Both, Et2O and toluene gave the best enantioselectivities (Table 22, entries 3-4 and 7-8) at 0 and 20 °C, although with poor conversions. Conversions were higher at 0 °C, and ee’s were only slightly lower at this temperature. For this reason, Et2O at 0 °C was chosen as the best solvent/temperature system, because it provided the best combination between ee and conversion (Table 22, entry 8). It was observed that this reaction was strongly temperature dependent; when the temperature was increased up to 25 °C, full conversion and only 8% ee was achieved for the alcohol product 6a (Table 22, entry 9).
99 a) Caprio, V.; Williams, J. M. J. Catalysis in Asymmetric Synthesis, 2nd Ed., Wiley: United Kingdom, 2009; b) Walsh, P. J.; Kozlowski, M. C. Fundamentals of Asymmetric Catalysis, University Science Books, California, 2009; c) Jacobsen, E. N.; Pfaltz, A.; Yamamoto, H. Comprehensive Asymmetric Catalysis: Suppl. 2, Springer-Verlag, Berlin, 2004.
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Table 22. Solvent and temperature screening[a]
Entry T (°C) Solvent Conv.[b] (%) ee[c] (%) 1 20 DCM 10 36 2 20 TBME 0 - 3 20 Toluene 20 55 4 20 Et2O 27 24 5 0 DCM 70 10 6 0 TBME 0 - 7 0 Toluene 56 44 8 0 Et2O 68 46 9 25 Et2O >99 8 [a] Conditions: 5a (0.1 mmol, 0.05 M), PhMgBr (3 M in Et2O, 2.5 eq.), Ti(Oi-Pr)4 (10 eq.), (Sa,R)-L10 (20 mol%), Et2O (1.5 mL), 0 °C, 12 h. [b] Determined by GC-MS analysis [c] Determined by chiral HPLC analysis.
In the next step of the optimization process, the influence of the ligand was studied, comprising a selection of chiral diol ligands (Figure 10) with different electronic and steric properties (Table 2). The use of (Sa,R)-L1 and the partially hydrogenated version
H8-(Sa,R)-L1 provided low conversions and enantiomeric excesses (Table 23, entries 1- 2). Methoxy substituted ligands L3-5 were also evaluated (Table 23, entries 3-5), but proved to be inferior ligands than (Sa,R)-L10 under the tested conditions. The arylation reaction of the model substrate 5a could be improved up to 74% ee and
50% conversion (Table 23, entry 6) with the bulky 1-naphtyl-substituted diol (Sa,R)-L7.
Interestingly, when the 1-naphtyl-substituted diol (Sa,R)-L8 was employed, both conversion and enantioselectivity dropped to 27 and 40%, respectively (Table 23, entry 7). To conclude the ligand secreening, commercially available (S)-BINOL was tested in the same reaction and surprisingly no conversion was obtained (Table 23, entry 9).
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Chapter III – Results and discussion
Figure 10. Chiral diol ligands screened in this study
Table 23. Ligand optimization[a]
Entry L* Conv.[b] (%) ee[c] (%)
1 (Sa,R)-L1 32 36 2 H8-(Sa,R)-L1 28 10 3 (Sa,S)-L3 30 46 4 (Sa,R)-L4 32 26 5 (Sa,R)-L5 41 20 6 (Sa,R)-L7 50 74 7 (Sa,R)-L8 27 40 8 (Sa,R)-L10 68 46 9 (S)-BINOL 0 -
[a] Conditions: 5a (0.1 mmol, 0.05 M), PhMgBr (3 M in Et2O, 2.5 eq.), Ti(Oi-Pr)4 (10 eq.), (Sa,R)-L* (20 mol%), Et2O (1.5 mL), 0 °C, 12 h. [b] Determined by GC-MS analysis [c] Determined by chiral HPLC analysis.
From the previous work performed on the enantioselective addition of Grignard reagents to aldehydes, we were well aware that the relative stoichiometries of Ti(Oi-
Pr)4 and Grignard reagent play a very important role in the enantioselectivity of the reaction and a careful optimization of this parameter must be done to achieve good results. For our model reaction, when less than 2.5 eq. of PhMgBr were employed as nucleophile, poor conversions were obtained. For this reason, the amount of nucleophile was set to this value and different amounts of the titanium source were screened (Table 24, entries 1-4). Our tests revealed that a 4:1 ratio between the
Ti(Oi-Pr)4 and the Grignard reagent was optimal for the process (Table 24, entry 3).
The use of less than 10 eq. of Ti(Oi-Pr)4 led to a detrimental drop in enantioselectivity
(Table 24, entries 1-2), while a large excess of Ti(Oi-Pr)4 (12 eq.) impaired the
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Chapter III – Results and discussion
conversion of the reaction (Table 24, entry 4). Increasing both nucleophile and Ti(Oi-
Pr)4 at a fixed optimal ratio of 4:1 slightly improved the conversion, but caused an small decrease in the enantioselectivity of the reaction (Table 24, entry 5).
[a] Table 24. Optimization Ti(Oi-Pr)4/PhMgBr ratio
[b] [c] Entry Ti(Oi-Pr)4 (eq.) PhMgBr (eq.) Ti:Mg ratio Conv. (%) ee (%) 1 3 2.5 1.2:1 43 14 2 7.5 2.5 3:1 21 28 3 10 2.5 4:1 50 74 4 12 2.5 4.8:1 22 70 5 15 3.8 4:1 66 70
[a] Conditions: 5a (0.1 mmol, 0.05 M), PhMgBr (3 M in Et2O, x eq.), Ti(Oi-Pr)4 (y eq.), (Sa,R)-L7 (20 mol%), Et2O (1.5 mL), 0 °C, 12 h. [b] Determined by GC-MS analysis [c] Determined by chiral HPLC analysis.
6.2. Scope of the reaction
With the optimized conditions in hands, the addition of PhMgBr to different aryl alkyl ketones was performed (Table 25). The arylation reaction was achieved in moderate yields and good enantioselectivities (68-80%) for a wide variety of aryl methyl ketones, with both electron-poor and electron-rich substituents at the meta and para position (Table 25, entries 1-7). The arylation of o-methylacetophenone (5b) was an exception and proceeded with very low yield, 12% (Table 25, entry 2), which did not improve with longer reaction times (i.e. 24 h); this is probably due to steric hindrance close to the reactive site.
The scope of this methodology includes heteroaryl and ,-unsaturated ketones, that, although in moderate enantioselectivities, provided very good yields in the addition of PhMgBr (Table 25, entries 8-9). For both substrates, the temperature was decreased up to 20 °C in an attempt to improve the enantioselectivity, but the reaction did not take place. Other alkyl aryl ketones were also examined. As expected, increasing the size of the aliphatic substituent of the ketone (ethyl instead of methyl) afforded better enantioselectivity but lower yields (Table 25, entry 10).
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Chapter III – Results and discussion
Benzo-fused cyclic ketones, such as 5-methyl-1-indanone (5k) and 1-tetralone (5l), were also tested under the optimized conditions. The addition of PhMgBr to the more rigid indanone derivative (Table 25, entry 11) proceeded with good enantioselectivity (76%) and in very high yield (92%). When the larger six membered ring tetralone was employed, the best enantioselectivity of the series was reached, 92% (Table 25, entry 12) at the expense of a decrease in the yield of the reaction (60%).
Table 25. Asymmetric addition of PhMgBr to ketones[a]
Entry Ketone Product Yield[b] (%) ee[c] (%)
1 50 76 (S)
2 (12)[d] n.d.
3 40 76 (S)
4 45 76 (S)
5 43 72 (S)
6 50 80 (S)
7 42 68 (S)
8 78 46 (S)
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Chapter III – Results and discussion
9 88 59 (R)
10 35 84 (S)
11 92 76 (S)
12 60 92 (S)
[a] Conditions: 5 (0.5 mmol, 0.06 M), PhMgBr (3 M in Et2O, 2.5 eq.), (Sa,R)-L7 (20 mol%), Ti(Oi-
Pr)4 (10 eq.), toluene (6 mL), 0 °C, 12 h. [b] Isolated yield after flash silica gel chromatography. [c] Determined by chiral HPLC analysis. Absolute configuration of chiral alcohols was determined by correlation of optical rotation with known compounds. [d] Conversion in brackets was determined by GC-MS analysis.
The study was supplemented with the evaluation of different aryl Grignard reagents as nucleophiles. The synthesis of chiral diaryl tertiary alcohols using Grignard reagents as the aryl source is a very attractive and interesting strategy due to the ready availability, facile synthesis and inexpensive character of these organometallic species.
The addition of p-tolyl, p-methoxy and p-fluorophenylmagnesium bromide to different acetophenone derivatives allowed the synthesis of alcohols 6d and 6m-p (Table 26, entries 1-5) with enantioselectivities at the same levels as when PhMgBr was employed as nucleophile. It is worth noting that the addition of p- tolylmagnesium bromide to acetophenone allowed the formation of (R)-6d with opposite stereochemistry from the addition of phenylmagnesium bromide to p- methylacetophenone (Table 26, entry 1 vs Table 25, entry 4), using the same chiral ligand (Sa,R)-L7. Furthermore, the use of the p-methoxy substituted Grignard reagent provided very good yields; the highest on the series of experiments performed in this study (Table 26, entries 3-4), probably due to electronic effect of methoxy group at the Grignard reagent which confers more nucleophilic character. The addition of p-
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Chapter III – Results and discussion
fluorophenylmagnesium bromide to 5-methyl-1-indanone (5k) provided the corresponding alcohol 6q in good yield and enantioselectivity (Table 26, entry 6).
Table 26. Asymmetric addition of ArMgBr to ketones[a]
Entry Ketone Product Yield[b] (%) ee[c] (%)
1 54 66 (R)
2 40 77 (+)
3 96 82 (+)
4 >99 66 (+)
5 38 64 ()
6 82 80 (+)
[a] Conditions: 5 (0.5 mmol, 0.06 M), ArMgBr (3 M in Et2O, 2.5 eq.), (Sa,R)-L7 (20 mol%), Ti(Oi-Pr)4 (10 eq.), toluene (6 mL), 0 °C, 12 h. [b] Isolated yield after flash silica gel chromatography. [c] Determined by chiral HPLC analysis. Absolute configuration of chiral alcohols was determined by correlation of optical rotation with known compounds.
In conclusion, the first catalytic system for the addition of aryl Grignard reagents to ketones has been developed. This methodology allows the preparation of challenging optically active diaryl tertiary alcohols in a simple one-pot procedure and using economical and readily available organometallic reagents. A bulky 1-naphthyl- substituted ligand (Sa,R)-L7 and excess of titanium tetraisopropoxide were found to be crucial in achieving good enantioselectivities. This work, together with the
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Chapter III – Results and discussion
developments achieved on the enantioselective addition of Grignard reagents to aldehydes, points toward the versatility of chiral diols L1-10 as catalysts for asymmetric addition reactions to carbonyl compounds.
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Chapter III – Experimental part
7. Experimental part
7.1. General procedure for the enantioselective arylation of ketones with Grignard reagents
In a flame dried Schlenk tube, (Sa,R)-L7 (42.7 mg, 0.1 mmol, 20 mol%) was dissolved in anhydrous Et2O (6 mL) under argon atmosphere. The solution was cooled down to
0 °C and Ti(Oi-Pr)4 (1.53 mL, 5.0 mmol, 10 eq.) was then added. Five minutes later, the corresponding ArMgBr (1.25 mmol, 2.5 eq.) was added. After stirring the mixture for additional 15 min, the corresponding ketone (0.5 mmol) was added and the reaction mixture was stirred at 0 °C for 12 h. The reaction was quenched with water (5 mL) and then HCl 1 M (3 mL) to eliminate the titanium oxides generated by the addition of water. The crude was extracted with EtOAc (3 × 10 mL), and the combined organic layers were neutralized with a saturated NaHCO3 aqueous solution (2 × 10 mL), dried over magnesium sulfate and concentrated under vacuum. The crude product was purified by flash silica gel chromatography to give the desired products.
7.2. Data of chiral tertiary alcohols
(S)-1-(Naphthalen-2-yl)-1-phenylethanol (6a):100 Compound 6a was obtained after purification on flash silica gel chromatography from 100:0 till 96:4 (n-hexane/EtOAc) as a 25 Lit. 25 colorless viscous oil (50% yield, 76% ee); []D = -9.7 (c 1.0, CH2Cl2) { []D = -16.1 1 (c 1.0, CH2Cl2) for 92% ee}. H NMR (300 MHz, CDCl3) 7.96 (s, 1H), 7.87 – 7.77 (m, 2H), 7.75 (d, J = 8.7 Hz, 1H), 7.49 – 7.37 (m, 5H), 7.36 – 7.18 (m, 3H), 2.32 (br s, 1H), 13 2.04 (s, 3H). C NMR (75 MHz, CDCl3) 147.7, 145.2, 133.0, 132.4, 129.6, 128.23, 128.20, 127.9, 127.5, 127.0, 126.1, 125.9, 124.9, 123.7, 115.3, 76.4, 30.7. LRMS (EI- DIP): m/z (%): 249 [M++1] (10), 248 [M+] (52), 234 (18), 233 (100), 205 (11), 155 (15), 128 (11), 127 (23), 105 (74), 77 (20), 43 (19). Ee determination by chiral HPLC
100 Chen, C-A.; Wu, K-H.; Gau, H-M. Adv. Synth. Catal. 2008, 350, 1626–1634.
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analysis, Chiralcel® OJ column, n-hexane/i-PrOH 80:20, flow rate = 1.0 mL/min, =
220 nm, retention times: t1(S) = 14.7 min (major enantiomer), t2(R) = 18.5 min.
(S)-1-Phenyl-1-(m-tolyl)ethanol (6c):101 Compound 6c was obtained after purification on flash silica gel chromatography from 100:0 till 97:3 (n-hexane/EtOAc) as a pale yellow oil (40% 27 Lit. 25 yield, 76% ee); []D = 4.6 (c 1.0, CH2Cl2) { []D = 14.3 (c 1.2, CH2Cl2) for 86% 1 ee}. H NMR (300 MHz, CDCl3) 7.45 – 7.38 (m, 2H), 7.35 – 7.26 (m, 2H), 7.27 – 7.22 (m, 2H), 7.18 (m, 2H), 7.09 – 7.02 (m, 1H), 2.32 (s, 3H), 2.19 (br s, 1H), 1.93 (s, 3H). 13C
NMR (75 MHz, CDCl3) 148.1, 147.9, 137.7, 128.1, 128.0, 127.7, 126.9, 126.5, 125.8, 122.9, 76.2, 30.9, 21.6. LRMS (EI): m/z (%): 212 [M+] (7), 198 (16), 197 (100), 194 (10), 179 (14), 178 (11), 119 (16), 105 (42), 91 (14), 77 (13). Ee determination by chiral HPLC analysis, Chiralpak® IA column, n-hexane/i-PrOH 99:1, flow rate = 0.5 mL/min,
= 210 nm, retention times: t1(S) = 38.8 min (major enantiomer), t2(R) = 45.6 min.
(S)-1-Phenyl-1-(p-tolyl)ethanol (6d):101 Compound 6d was obtained after purification on flash silica gel chromatography from 100:0 till 95:5 (n-hexane/EtOAc) as a pale yellow oil (45% 25 Lit. 25 yield, 76% ee); []D = 7.5 (c 1.0, CH2Cl2) { []D = +16.0 (c 1.2, CH2Cl2) for 96% ee 1 for the (R) enantiomer}. H NMR (300 MHz, CDCl3) 7.45 – 7.36 (m, 2H), 7.34 – 7.19 (m with a d at 7.29, J = 8.0 Hz, 5H), 7.11 (d, J = 8.0 Hz, 2H), 2.32 (s, 3H), 2.21 (br s, 1H), 13 1.92 (s, 3H). C NMR (75 MHz, CDCl3) 148.2, 145.1, 136.6, 128.8, 128.1, 126.8, 125.8, 76.1, 30.8, 21.0. LRMS (EI): m/z (%): 212 [M+] (7), 198 (16), 197 (100), 194 (11), 179 (14), 178 (11), 119 (22), 105 (35), 91 (14), 77 (13). Ee determination by chiral HPLC analysis, Chiralpak® AD-H column, n-hexane/i-PrOH 99:1, flow rate = 0.5 mL/min, = 210 nm, retention times: t1(R) = 46.1 min, t2(S) = 48.7 min (major enantiomer).
101 Forrat, V. J.; Prieto, O.; Ramón, D. J.; Yus, M. Chem. Eur. J. 2006, 12, 4431–4445.
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(S)-1-(4-Methoxyphenyl)-1-phenylethanol (6e):100 Compound 6e was obtained after purification on flash silica gel chromatography from 100:0 till 94:6 (n-hexane/EtOAc) as a 28 Lit. 25 pale yellow oil (43% yield, 72% ee); []D = 12.3 (c 1.0, CH2Cl2) { []D = 14.6 (c 1 0.7, CH2Cl2) for 90% ee}. H NMR (300 MHz, CDCl3) 7.44 – 7.36 (m, 2H), 7.35 – 7.27 (m with a d at 7.32, J = 8.9 Hz, 4H), 7.27 – 7.18 (m, 1H), 6.83 (d, J = 8.9 Hz, 2H), 3.78 13 (s, 3H), 2.18 (br s, 1H), 1.92 (s, 3H). C NMR (75 MHz, CDCl3) 158.5, 148.3, 140.3, 128.1, 127.1, 126.8, 125.7, 113.4, 75.9, 55.2, 31.0. LRMS (EI): m/z (%): 228 [M+] (7), 213 (46), 211 (17), 210 (100), 209 (12), 195 (52), 179 (12), 178 (11), 167 (15), 166 (11), 165 (33), 152 (23), 151 (10), 135 (12), 105 (16), 77 (10). Ee determination by chiral HPLC analysis, Chiralcel® OJ column, n-hexane/i-PrOH 80:20, flow rate = 1.0 mL/min, = 210 nm, retention times: t1(R) = 17.0 min, t2(S) = 20.7 min (major enantiomer).
(S)-1-Phenyl-1-[3-(trifluoromethyl)phenyl]ethanol (6f):100 Compound 6f was obtained after purification on flash silica gel chromatography from 100:0 till 94:6 (n-hexane/EtOAc) as a 24 Lit. 25 yellow viscous oil (50% yield, 80% ee); []D = +18.5 (c 1.0, CH2Cl2) { []D = +24.8 1 (c 4.5, CH2Cl2) for 93% ee}. H NMR (300 MHz, CDCl3) 7.76 (s, 1H), 7.54 (d, J = 7.8 Hz, 1H), 7.50 (d, J = 7.8 Hz, 1H), 7.44 – 7.21 (m, 6H), 2.26 (br s, 1H), 1.96 (s, 3H). 13C NMR
(75 MHz, CDCl3) 149.0, 147.0, 130.4 (q, JC–F = 32.1 Hz), 129.4, 128.6, 128.4, 127.4,
125.8, 124.3 (q, JC–F = 272.0 Hz), 123.7 (q, JC–F = 3.6 Hz), 122.4 (q, JC–F = 3.5 Hz), 76.0, 19 + 30.8. F NMR (282 MHz, CDCl3) -62.5. LRMS (EI): m/z (%): 266 [M ] (3), 252 (16), 251 (100), 173 (49), 145 (17), 105 (9), 77 (9). Ee determination by chiral HPLC analysis, Chiralcel® OD-H column, n-hexane/i-PrOH 96:4, flow rate = 1.0 mL/min, =
220 nm, retention times: t1(R) = 9.6 min, t2(S) = 11.2 min (major enantiomer).
(S)-1-(4-Chlorophenyl)-1-phenylethanol (6g):100 Compound 6g was obtained after purification on flash silica gel chromatography from 100:0 till 97:3 (n-hexane/EtOAc) as a 28 Lit. 25 colorless oil (42% yield, 68% ee); []D = +6.3 (c 1.0, CH2Cl2) { []D = +8.8 (c 3.2,
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1 CH2Cl2) for 92% ee}. H NMR (300 MHz, CDCl3) 7.42 – 7.30 (m with a d at 7.33, J = 8.9 Hz, 5H), 7.30 – 7.19 (m with a d at 7.26, J = 8.9 Hz, 4H), 2.24 (br s, 1H), 1.92 (s, 13 3H). C NMR (75 MHz, CDCl3) 147.4, 146.5, 132.7, 128.3, 128.2, 127.3, 127.2, 125.7, 75.9, 30.8. LRMS (EI): m/z (%): 232 [M+] (7), 219 (33), 218 (15), 217 (100), 141 (12), 139 (38), 111 (10), 105 (19), 77 (13). Ee determination by chiral HPLC analysis, Chiralpak® AD-H column, n-hexane/i-PrOH 99:1, flow rate = 1.0 mL/min, = 230 nm, retention times: t1(R) = 16.5 min, t2(S) = 17.8 min (major enantiomer).
(S)-1-(Furan-2-yl)-1-phenylethanol (6h):102 Compound 6h was obtained after purification on flash silica gel chromatography from 100:0 till 95:5 (n-hexane/EtOAc) as a yellow oil (78% yield, 46% ee); 29 Lit. 22 1 []D = 16.5 (c 1.0, CH2Cl2) { []D = 34.1 (c 5.4, CH2Cl2) for 96% ee}. H NMR
(300 MHz, CDCl3) 7.43 – 7.22 (m, 6H), 6.33 (dd, J = 3.2, 1.8 Hz, 1H), 6.24 (dd, J = 3.2, 13 0.8 Hz, 1H), 2.54 (br s, 1H), 1.87 (s, 3H). C NMR (75 MHz, CDCl3) 158.9, 145.8, 142.1, 128.1, 127.3, 125.2, 110.0, 106.2, 73.0, 29.2. LRMS (EI): m/z (%): 188 [M+] (32), 174 (12), 173 (100), 171 (12), 170 (36), 169 (12), 141 (28), 115 (23), 111 (15), 105 (16), 95 (65), 77 (17). Ee determination by chiral HPLC analysis, Chiralcel® OD-H column, n-hexane/i-PrOH 99:1, flow rate = 0.5 mL/min, = 220 nm, retention times: t1(R) = 30.1 min, t2(S) = 33.4 min (major enantiomer).
(R,E)-2,4-Diphenylbut-3-en-2-ol (6i):103 Compound 6i was obtained after purification on flash silica gel chromatography from 100:0 till 95:5 (n-hexane/EtOAc) as a pale yellow oil (88% 26 Lit. 22 yield, 59% ee); []D = 9.7 (c 1.0, CHCl3) { []D = 12.7 (c 2.5, CHCl3) for 81% ee}. 1 H NMR (300 MHz, CDCl3) 7.51 (d, J = 8.2 Hz, 2H), 7.41 – 7.17 (m, 8H), 6.64 (d, J = 16.1 Hz, 1H), 6.50 (d, J = 16.1 Hz, 1H), 2.06 (br s, 1H), 1.75 (s, 3H). 13C NMR (75 MHz,
CDCl3) 146.6, 136.7, 136.3, 128.5, 128.3, 127.7, 127.6, 127.1, 126.5, 125.2, 74.7, 29.8. LRMS (EI): m/z (%): 224 [M+] (14), 209 (12), 206 (48), 205 (24), 203 (12), 202 (10), 191 (21), 182 (17), 181 (100), 178 (10), 166 (12), 165 (15), 131 (15), 129 (12),
102 Stymiest, J. L.; Bagutski, V.; French R. M.; Aggarwal, V. K. Nature 2008, 456, 778–782. 103 Ueda, T.; Tanaka, K.; Ichibakase, T.; Orito, Y.; Nakajima, M. Tetrahedron 2010, 66, 7726–7731.
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128 (18), 105 (20), 103 (22), 91 (29), 77 (21). Ee determination by chiral HPLC analysis, Chiralpak® AS-H column, n-hexane/i-PrOH 99:1, flow rate = 0.5 mL/min, =
230 nm, retention times: t1(S) = 20.0 min, t2(R) = 21.9 min (major enantiomer).
(S)-1-(4-Bromophenyl)-1-phenylpropan-1-ol (6j):101 Compound 6j was obtained after purification on flash silica gel chromatography from 100:0 till 98:2 (n-hexane/EtOAc) as a pale 29 Lit. 25 yellow oil (35% yield, 84% ee); []D = +8.7 (c 1.0, CH2Cl2) { []D = +9.9 (c 1.7, 1 CH2Cl2) for 80% ee}. H NMR (300 MHz, CDCl3) 7.41 (d, J = 8.8 Hz, 2H), 7.38 (d, J = 8.8 Hz, 2H), 7.35 – 7.17 (m, 5H), 2.28 (q, J = 7.3 Hz, 2H), 2.05 (s, 1H), 0.87 (t, J = 7.3 Hz, 13 3H). C NMR (75 MHz, CDCl3) 146.4, 145.9, 131.1, 128.3, 128.0, 127.0, 126.0, 120.7, 78.2, 34.3, 8.0. LRMS (EI): m/z (%): 291 [M+] (<1), 264 (14), 263 (97), 262 (15), 261 (100), 185 (32), 183 (33), 105 (30), 77 (16). Ee determination by chiral HPLC analysis, Chiralpak® IA column, n-hexane/i-PrOH 99:1, flow rate = 0.5 mL/min, =
230 nm, retention times: t1(R) = 48.6 min, t2(S) = 53.7 min (major enantiomer).
(+)-5-Methyl-1-phenyl-2,3-dihydro-1H-inden-1-ol (6k): Compound 6k was obtained after purification on flash silica gel chromatography from 100:0 till 95:5 (n-hexane/EtOAc) as a yellow viscous oil (92% 29 1 yield, 76% ee); []D = +13.6 (c 1.0, CH2Cl2). H NMR (300 MHz,
CDCl3) 7.43 – 7.19 (m, 5H), 7.13 (s, 1H), 7.02 (d, J = 7.7 Hz, 1H), 6.96 (d, J = 7.7 Hz, 1H), 3.21 – 3.04 (dt, J = 16.0, 7.3 Hz, 1H), 2.98 – 2.81 (dt, J = 16.0, 6.4 Hz, 1H), 2.51 – 13 2.41 (m, 2H), 2.36 (s, 3H), 2.11 (s, 1H). C NMR (75 MHz, CDCl3) 146.5, 145.2, 144.3, 138.3, 128.0, 127.9, 126.8, 125.7, 125.5, 123.7, 85.2, 45.0, 29.8, 21.4. IR (ATR): (cm- 1): 3381, 2938, 1612, 1492, 1446, 1047. LRMS (EI): m/z (%): 224 [M+] (<1), 222 (15), 194 (44), 193 (30), 180 (20), 179 (100), 178 (55), 165 (8), 89 (11). HRMS (ESI): m/z: + 207.1174 calculated for C16H15 [M–OH] , found 207.1183. Ee determination by chiral HPLC analysis, Chiralcel® OD-H column, n-hexane/i-PrOH 96:4, flow rate = 1.0 mL/min, = 220 nm, retention times: t1(R) = 7.8 min, t2(S) = 10.3 min (major enantiomer).
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Chapter III – Experimental part
(S)-1-Phenyl-1,2,3,4-tetrahydronaphthalen-1-ol (6l):104 Compound 6l was obtained after purification on flash silica gel chromatography from 100:0 till 97:3 (n-hexane/EtOAc) as a yellow viscous oil (60% yield, 92% 27 Lit. 22 ee); []D = -29.5 (c 1.0, CHCl3) { []D = -32.0 (c 4.2, CHCl3) for >99% 1 ee}. H NMR (300 MHz, CDCl3) 7.40 – 6.99 (m, 9H), 2.94 – 2.84 (m, 2H), 2.19 (br s, 1H), 2.16 – 2.09 (m, 2H), 2.05 – 1.91 (m, 1H), 1.86 – 1.70 (m, 1H). 13C NMR (75 MHz,
CDCl3) 148.9, 142.0, 137.6, 128.9, 128.8, 127.7, 127.5, 126.6, 126.44, 126.38, 75.3, 41.4, 29.9, 19.6. LRMS (EI): m/z (%): 224 [M+] (22), 207 (14), 206 (75), 205 (11), 196 (22), 195 (100), 191 (16), 178 (14), 165 (12), 147 (59), 146 (15), 129 (11), 128 (11), 105 (10), 91 (26), 77 (15). Ee determination by chiral HPLC analysis, Chiralcel® OD-H column, n-hexane/i-PrOH 99:1, flow rate = 1.0 mL/min, = 220 nm, retention times: t1(R) = 9.7 min, t2(S) = 13.2 min (major enantiomer).
(+)-1-(3-Methoxyphenyl)-1-(p-tolyl)ethanol (6m): Compound 6m was obtained after purification on flash silica gel chromatography from 100:0 till 96:4 (n-hexane/EtOAc)
29 1 as a yellow oil (40% yield, 77% ee); []D = +15.8 (c 1.0, CH2Cl2). H NMR (300 MHz,
CDCl3) 7.29 (d, J = 8.2 Hz, 2H), 7.21 (dd, J = 8.2, 7.8, 1H), 7.11 (d, J = 8.2 Hz, 2H), 7.01 (dd, J = 2.6, 1.7, 1H), 6.94 (ddd, J = 7.8, 1.7, 0.9 Hz, 1H), 6.76 (ddd, J = 8.2, 2.6, 0.9 Hz,
13 1H), 3.77 (s, 3H), 2.31 (s, 3H), 2.21 (br s, 1H), 1.91 (s, 3H). C NMR (75 MHz, CDCl3) 159.4, 149.9, 144.9, 136.6, 129.1, 128.8, 125.7, 118.3, 111.9, 76.0, 55.2, 30.8, 21.0. IR (ATR): (cm-1): 3452, 2925, 1600, 1485, 1432, 1253. LRMS (EI): m/z (%): 242 [M+] (37), 228 (17), 227 (100), 224 (12), 135 (31), 119 (57), 91 (15). HRMS (ESI): m/z:
+ 225.1279 calculated for C16H17O [M–OH] , found 225.1290. Ee determination by chiral HPLC analysis, Chiralcel® OJ column, n-hexane/i-PrOH 90:10, flow rate = 1.0 mL/min, = 210 nm, retention times: t1(S) = 22.1 min (major enantiomer), t2(R) = 27.3 min.
104 Jaouen, G.; Meyer, A. J. Am. Chem. Soc. 1975, 97, 4667–4672
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Chapter III – Experimental part
(+)-1-(4-Methoxyphenyl)-1-[3- (trifluoromethyl)phenyl]ethanol (6n): Compound 6n was obtained after purification on flash silica gel chromatography from 100:0 till 91:9 (n-hexane/EtOAc) as a yellow viscous oil (96%
29 1 yield, 82% ee); []D = +32.5 (c 1.0, CH2Cl2). H NMR (300 MHz, CDCl3) 7.75 (s, 1H), 7.53 (d, J = 7.7 Hz, 1H), 7.49 (d, J = 7.7 Hz, 1H), 7.40 (t, J = 7.7 Hz, 1H), 7.31 (d, J = 8.9 Hz, 2H), 6.85 (d, J = 8.9 Hz, 2H), 3.79 (s, 3H), 2.22 (br s, 1H), 1.94 (s, 3H). 13C NMR (75
MHz, CDCl3) 158.8, 149.4, 139.3, 130.4 (q, JC–F = 32.1 Hz), 129.3, 128.5, 127.2, 124.2
(q, JC–F = 272.3 Hz), 123.6 (q, JC–F = 3.8 Hz), 122.3 (q, JC–F = 3.8 Hz), 113.7, 75.7, 55.3,
19 -1 31.0. F NMR (282 MHz, CDCl3) -62.4. IR (ATR): (cm ): 3456, 2962, 1611, 1510, 1327, 1254, 1162, 1119. LRMS (EI): m/z (%): 296 [M+] (19), 282 (17), 281 (100), 278 (15), 173 (56), 151 (19), 145 (18), 135 (10). HRMS (ESI): m/z: 279.0997 calculated for
+ C16H14F3O [M–OH] , found 279.0995. Ee determination by chiral HPLC analysis, Chiralcel® OD-H column, n-hexane/i-PrOH 99:1, flow rate = 1.0 mL/min, = 220 nm, retention times: t1(R) = 18.9 min, t2(S) = 19.9 min (major enantiomer).
(+)-1-(4-Bromophenyl)-1-(4-methoxyphenyl)ethanol (6o): Compound 6o was obtained after purification on flash silica gel chromatography from 100:0 till 90:10 (n-
29 hexane/EtOAc) as a yellow viscous oil (>99% yield, 66% ee); []D = +15.8 (c 1.0,
1 CH2Cl2). H NMR (300 MHz, CDCl3) 7.41 (d, J = 8.8 Hz, 2H), 7.28 (d, J = 7.2 Hz, 2H), 7.25 (d, J = 7.2 Hz, 2H), 6.83 (d, J = 8.8 Hz, 2H), 3.77 (s, 3H), 2.26 (br s, 1H), 1.88 (s,
13 3H). C NMR (75 MHz, CDCl3) 158.6, 147.4, 139.6, 131.1, 127.6, 127.1, 120.7, 113.5, 75.6, 55.2, 30.8. IR (ATR): (cm-1): 3449, 2974, 1608, 1509, 1509, 1248, 1176. LRMS (EI): m/z (%): 308 [M++1] (17), 307 [M+] (3), 306 (17), 294 (14), 293 (92), 292 (16), 291 (100), 290 (34), 288 (34), 185 (32), 183 (33), 166 (17), 165 (25), 151 (18),
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Chapter III – Experimental part
+ 135 (26). HRMS (ESI): m/z: 289.0228 calculated for C15H14BrO [M–OH] , found 289.0227. Ee determination by chiral HPLC analysis, Chiralcel® OJ column, n- hexane/i-PrOH 97:3, flow rate = 1.0 mL/min, = 230 nm, retention times: t1(S) = 58.0 min (major enantiomer), t2(R) = 63.0 min.
(-)-1-(3,4-Dimethoxyphenyl)-1-(4-fluorophenyl)ethanol (6p): Compound 6p was obtained after purification on flash silica gel chromatography from 100:0 till 75:25 (n-
29 hexane/EtOAc) as a yellow viscous oil (38% yield, 64% ee); []D = 4.8 (c 1.0,
1 3 3 CH2Cl2). H NMR (300 MHz, CDCl3) 7.36 (dd, J = 9.0, JH–F = 5.4 Hz, 2H), 6.98 (t, J ≈
JH–F = 9.0 Hz, 2H), 6.94 (d, J = 2.1 Hz, 1H), 6.89 (dd, J = 8.4, 2.1 Hz, 1H), 6.79 (d, J = 8.4 Hz, 1H), 3.86 (s, 3H), 3.81 (s, 3H), 2.28 (br s, 1H), 1.91 (s, 3H). 13C NMR (75 MHz,
CDCl3) 161.6 (d, JC–F = 245.4 Hz), 148.6, 148.0, 143.9 (d, JC–F = 2.9 Hz), 140.5, 127.5 19 (d, JC–F = 8.0 Hz), 117.9, 114.7 (d, JC–F = 21.2 Hz), 110.4, 109.5, 75.7, 55.8, 31.2. F
-1 NMR (282 MHz, CDCl3) -116.2. IR (ATR): (cm ): 3505, 2933, 1735, 1601, 1505, 1255, 1222, 1143. LRMS (EI): m/z (%): 276 [M+] (38), 261 (50), 259 (19), 258 (100), 243 (13), 183 (19), 171 (13), 170 (11), 123 (75), 121 (14). HRMS (ESI): m/z: 259.1134
+ calculated for C16H16FO2 [M–OH] , found 259.1126. Ee determination by chiral HPLC analysis, Chiralcel® OJ column, n-hexane/i-PrOH 85:15, flow rate = 1.0 mL/min, =
210 nm, retention times: t1(R) = 21.6 min, t2(S) = 37.5 min (major enantiomer).
(+)-1-(4-Fluorophenyl)-5-methyl-2,3-dihydro-1H-inden-1-ol (6q): Compound 6q was obtained after purification on flash silica gel chromatography from 100:0 till 96:4 (n-hexane/EtOAc) as a yellow 29 1 viscous oil (82% yield, 80% ee); []D = +17.5 (c 1.0, CH2Cl2). H NMR 3 (300 MHz, CDCl3) 7.35 (dd, J = 9.0, JH–F = 5.4 Hz, 2H), 7.14 (s, 1H), 3 7.04 (d, J = 7.7 Hz, 1H), 6.98 (t, J ≈ JH–F = 9.0 Hz, 2H), 6.95 (d, J = 7.7 Hz, 1H), 3.12 (dt, J = 16.0, 7.2 Hz, 1H), 2.88 (dt, J = 16.0, 6.4 Hz, 1H), 2.43 (dd, J = 7.2, 6.4 Hz, 2H), 2.37 (s,
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Chapter III – Experimental part
13 3H), 2.06 (br s, 1H). C NMR (75 MHz, CDCl3) 161.8 (d, JC–F = 245.0 Hz), 145.0,
144.3, 142.2 (d, JC–F = 3.0 Hz), 138.6, 128.0, 127.4 (d, JC–F = 8.0 Hz), 125.6, 123.6, 114.7 19 (d, JC–F = 21.2 Hz), 84.9, 45.1, 29.7, 21.4. F NMR (282 MHz, CDCl3) -116.6. IR (ATR): (cm-1): 3384, 2940, 1602, 1506, 1221, 1157. LRMS (EI-DIP): m/z (%): 243 [M++1] (17), 242 [M+] (100), 241 (50), 228 (11), 227 (68), 226 (30), 225 (50), 224 (21), 212 (12), 210 (11), 209 (16), 207 (10), 183 (14), 148 (11), 147 (99), 133 (11), 123 (15), 105 + (11), 95 (17), 91 (11). HRMS (ESI): m/z: 225.1080 calculated for C16H14F [M–OH] , found 225.1078. Ee determination by chiral HPLC analysis, Chiralcel® OD-H column, n-hexane/i-PrOH 96:4, flow rate = 1.0 mL/min, = 220 nm, retention times: t1(R) =
7.1 min, t2(S) = 9.5 min (major enantiomer).
175
CHAPTER IV
Chapter IV – Introduction
1. Introduction
Organoaluminum reagents are organometallic compounds with, at least, one C-Al bond in chemical structure. The most common organoaluminum reagents described in the literature are R3Al, R2AlX and RAlX2, where R are alkyl or aryl moieties and X halogens.
The first organoaluminium compound, Et3Al2I3, was discovered and isolated in 1859.105 However, organoaluminum compounds were known since 1953, when Karl Ziegler and Giulio Natta discovered the direct synthesis of trialkylaluminium compounds and applied them to catalytic olefin polymerization. Ziegler and Natta were awarded Nobel Prize in 1963 for their research in this area.
Amongst the most common organometallic species, organoaluminum reagents stand out for practical applications, since they can be economically obtained on an industrial scale.106 Additional advantages of organoaluminum compounds include low toxicities and considerable stabilities.
Scheme 52. Methods for the synthesis of organoaluminum reagents
On the other hand, the straightforward synthesis of R3Al makes them valuable compounds for organic chemistry. The most common methods for the preparation of organoaluminum compounds are: direct reaction between RLi or RMgX and AlCl3 (A,
Scheme 52), hydroalumination of akynes with R2AlH (B, Scheme 52), carboalumination of alkynes with R3Al (C, Scheme 52) and another method for the
105 Hallwachs, W.; Schafarik, A. Liebigs Ann. Chem. 1859, 109, 206–209. 106 Cotton, F. A.; Wilkinson, G. Advanced Inorganic Chemistry, 5th ed.; Wiley: New York, 1988.
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preparation of these compounds, although less used due to the toxicity of the procedure, is the transmetallation of organomercury compounds with pure aluminum metal (D, Scheme 52).
1.1. Catalytic enantioselective addition of organoaluminum reagents to aldehydes
In 1986, the first enantioselective alkylation of aldehydes with organoaluminum reagents was developed by Mukaiyama´s group.107 The allylation of different aldehydes was carried out at –78 ᵒC in DCM as solvent using Allyl(i-Bu)2Al as nucleophile, Sn(OTf)2 as additive and the chiral diamine XLVII (1.9 eq.) as ligand. The enantioselectivities of the corresponding homoallylic alcohols varied from good to very good for aromatic aldehydes and moderate for aliphatic aldehydes (Scheme 53).
Scheme 53. First enantioselective addition of Allyl(i-Bu)2Al to aldehydes promoted by XLVII.
In 1997, Chan´s group achieved the first catalytic enantioselective addition of Et3Al to aromatic aldehydes catalyzed by 20 mol% of (S)-BINOL (IV) or H8-(S)-BINOL (XXXIV) 108 and an excess of Ti(Oi-Pr)4 (1.4 eq.) under very mild reaction condition. Ligand (S)- XXXIV provides better enantiomeric excess for the corresponding secondary alcohols (90-96%) compared to the non-hydrogenated analogous (R)-IV ligand (Scheme 54).
107 Mukaiyama, T.; Minowa, N.; Oriyama, T.; Narasaka, K. Chem. Lett. 1986, 97–100. 108 Chan, A. S. C.; Zhang, F.-Y.; Yip, C.-W. J. Am. Chem. Soc. 1997, 119, 40804081.
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Scheme 54. First catalytic enantioselective addition of Et3Al to aldehydes catalyzed by IV and XXXIV.
Very interesting studies were carried out by Carreira´s group in 1988, on the enantioselective addition of Me3Al to different aldehydes, employing, for the first time, a catalytic amount of a transmetallating agent such as TiF4 (14 mol%) and a 109 chiral diol XLVIII (15 mol%) as ligand. The excess of Me3Al (1.4 eq.) is necessary to deprotonate the chiral diol and form the corresponding aluminum alcoxide, which transmetallates in situ to the real active catalyst, dialcoxide-TiF2 (XLIX). Moderate to very good enantioselectivities can be achieved with this methodology for the methylation of different aldehydes (Scheme 55).
Scheme 55. Asymmetric addition of Me3Al to aldehydes catalyzed by chiral diol XLVIII.
In 2005, Bauer´s group tested different commercially available chiral -hydroxy carboxylic acids as chiral ligands in the ethylation reaction of different aldehydes with 110 Et3Al (1.5 eq.) as nucleophile. The best results (up to 92% ee) were achieved with 20 mol% of (S)-mandelic acid (L) and 1.4 eq. of titanium tetraisopropoxide in THF from 0 ᵒC to room temperature (Scheme 56).
109 Pagenkopf, B. L.; Carreira, E. M. Tetrahedron Lett. 1998, 39, 9593–9596. 110 Bauer, T.; Gajewiak, J. Tetrahedron: Asymmetry 2005, 16, 851–855.
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Scheme 56. Asymmetric addition of Me3Al to aldehydes catalyzed by -hydroxy carboxilic acid L.
In the same year, Woodward´s group designed two ingenious catalytic systems for the methylation and ethylation of aldehydes with organoaluminum reagents,111 out of the classical titanium-diol systems (Scheme 57). Both methodologies are based on the use of only 2 mol% of a chiral phosphoramidite (LI) and 1 mol% of Ni(acac)2.
When highly stable (R3Al)2·DABCO complex is used as nucleophile, milder reaction conditions can be employed (5 ᵒC), due to its lower reactivity compared to the free
R3Al nucleophiles, which require much lower temperatures (–20 ᵒC). Moreover, the use of (R3Al)2·DABCO complex gives, in general, better enantiomeric excess in the corresponding addition products than the free organoaluminum reagents. Both methodologies, however, give moderate selectivities when aliphatic aldehydes (R1 = alkyl) are used as substrates.
Scheme 57. Asymmetric addition of R3Al and (R3Al)2·DABCO to aldehydes catalyzed by phosphoramidite LI.
111 Biswas, K.; Prieto, Oscar.; Goldsmith, P. J.; Woodward, S. Angew. Chem. Int. Ed. 2005, 44, 2232 –2234.
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In collaboration with Prof. Woodward, Pamies and Diéguez´s group reported new chiral sugar phosphite-oxazoline ligands (1 mol%, LII, Scheme 58) for the addition of 112 Me3Al and (Me3Al)2·DABCO to different aldehydes, using Ni(acac)2 (1 mol%). Poor yields and enantioselectivities were achieved for this initial catalytic system, but a second generation of sugar monophosphite ligands (LIII), under the same reaction conditions, provided much satisfactory results (ee´s up to 84% and yields up to 99%).113
Scheme 58. Asymmetric addition of organoaluminum reagents to aldehydes catalyzed by sugar phosphites LII and LIII.
In 2006, Gau´s group developed the first catalytic enantioselective arylation of aldehydes with organoaluminum reagents.114 The reaction was carried out in THF at 0
ᵒC, using 1.2 eq. of Ar3Al·(THF), 1.3 eq. of Ti(Oi-Pr)4 and in only 10 min the corresponding chiral diaryl alcohols were obtained with excellent levels of selectivity and yield, employing (R)-H8-Tinanium BINOLate (LIV, 10 mol%) as ligand (Scheme 59).
In addition, the use of ArEt2Al·(THF) in the selective arylation of aldehydes, using ligand LIV and Ti(Oi-Pr)4, provided the corresponding chiral alcohols with high ee and yields, even for aliphatic substrates (Scheme 59).115
112 Mata, Y.; Diéguez, M.; Pàmies, O.; Woodward, S. Inorg. Chim. Acta 2008, 361, 1381–1384. 113 Alegre, S.; Diéguez, M.; Pàmies, O. Tetrahedron: Asymmetry 2011, 22, 834–839 114 Wu, K-H.; Gau, H-M. J. Am. Chem. Soc. 2006, 128, 14808–14809. 115 Zhou, S.; Wu, K-H.; Chen, C-A.; Gau, H-M. J. Org. Chem. 2009, 74, 3500–3505.
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Scheme 59. Asymmetric arylation of aldehydes with Ar3Al·(THF) and ArEt2Al·(THF) catalyzed by LIV.
The group of Gau also reported the phenylation reaction of different aldehydes using 116 the chiral hydroxysulfonamide LV as ligand and Ar3Al·(THF) as nucleophiles.
Interestingly, higher amounts of chiral ligand, nucleophile and Ti(Oi-Pr)4 are required for this catalytic system, in order to achieve comparable results to previous work (Scheme 60). On the other hand, complex LVI (5 mol%) provided better results (ee > 90%), with shorter reaction times, in the enantioselective arylation of aldehydes 117 using Ar3Al·(THF) as nucleophile (Scheme 60).
Scheme 60. Asymmetric arylation of aldehydes with Ar3Al·(THF) catalyzed by ligands LV and LVI.
In 2013, Harada´s group reported the first catalytic enantioselective vinylation of aldehydes with organoaluminum reagents.118 The corresponding nucleophiles were prepared through hydroalumination of the corresponding alkyne. Different allylic alcohols were prepared with this methodology using the chiral binaphtol XXXII as ligand, under mild reaction conditions. High enantioselectivities were achieved for a
116 Hsieh, S-H.; Chen, C-A.; Chuang, D-W.; Yang, M-C.; Yang, H-T.; Gau, H-M. Chirality 2008, 20, 924–929. 117 Zhou, S.; Chuang, D-W.; Chang, S-J.; Gau, H-M. Tetrahedron: Asymmetry 2009, 20, 1407–1412. 118 Kumar, R.; Kawasaki, H.; Harada, T. Chem. Eur. J. 2013, 19, 17707–17710.
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wide variety of (vinyl)Me2Al nucleophiles, although yields were moderated (Scheme 61).
Scheme 61. Asymmetric vinylation of aldehydes organoaluminum reagents catalyzed by binaphtol XXXII.
Not many examples of catalytic enantioselective additions of organoluminium reagents to aldehydes have been described in the literature, in spite of the many advantages that this type of organometallic compounds offers.
So, by the previous reason, we decided to explore the use of organoaluminum as nucleophiles in the enantioselective addition to aldehydes that will be described in the next section.
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2. Results and discussion
2.1. Optimization of the catalytic enantioselective addition of organoaluminum reagents to aldehydes
The optimization process for the asymmetric alkylation of aldehydes with organoaluminium reagents was conducted with the addition of Me3Al, as nucleophile, to benzaldehyde (1a). The first tests carried out with Ar-BINMOL ligands, provided very promising results (Table 1); the desired alcohol 2a was obtained with 95% enantioselectivity and 82% conversion when 1a was added into a toluene solution containing 20 mol% of (Sa,R)-L1, 3 eq. of Me3Al and 4 eq. of Ti(Oi-Pr)4 at 20 °C (Table 27, entry 1). In order to increase the conversion, the temperature was raised to 0 °C, which meant a severe drop in enantioselectivity (Table 27, entry 2). Based on our previous knowledge on the solvent suitability for this catalytic system,
Et2O was chosen as an alternative to toluene. Three different temperatures were tested with Et2O as solvent (Table 27, entries 3-5) and only when the reaction was carried out at 0 °C, full conversion was achieved, preserving the enantioselectivity at 96% (Table 27, entry 4).
Table 27. Influence of catalyst loading and temperature[a]
[b] [b] Entry (Sa,R)-L1 (mol%) Solvent T (°C) Conv. (%) ee (%) 1 20 Toluene 20 82 96 2 20 Toluene 0 >99 20
3 20 Et2O 20 55 95 4 20 Et2O 0 >99 96 5 20 Et2O 20 99 68 6 10 Et2O 0 >99 94 7 5 Et2O 0 >99 86 [a] Conditions: 1a (0.1 mmol, 0.07 M), Me3Al (2 M in toluene, 3 eq.), (Sa,R)-L1 (x mol%), Ti(Oi-Pr)4 (4 eq.), toluene or Et2O (1.5 mL), T (°C), 3 h. [b] Determined by chiral GC analysis.
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Moreover, under these conditions, the catalyst loading could be reduced to 10 mol% without any significant loss of enantioselectivity (Table 27, entry 6). However, when 5 mol% of ligand (Sa,R)-L1 was employed, a small decrease in the enantioselectivity was observed without affecting the conversion (Table 27, entry 7).
Different solvents were also evaluated (Table 28), to confirm that diethyl ether was the best choice for this reaction. For polar and apolar non-coordinant solvents, full conversion was achieved with very low yield (Table 28, entries 1 and 5). When more coordinant solvents were employed, such as THF or Et2O, higher enantioselectivities were obtained (Table 28, entries 2 and 4). In the case of using tert-butyl methyl ether (TBME) as solvent, only phenylmethanol was obtained as product (full conversion, Table 28, entry 3). We believe phenylmethanol is generated through a Meerwein- Ponndorf-Verley reduction of benzaldehyde (1a); the hydride source coming from the isopropoxide group present in the in situ generated RxAl(Oi-Pr)3-x species, which is oxidized to acetone in the process.
Table 28. Solvent optimization[a]
Entry Solvent Conv.[b] (%) ee[b] (%) 1 DCM 99 36 2 THF 97 76 3 TBME >99[c] - 4 Et2O >99 94 5 n-Hexane 99 24
[a] Conditions: 1a (0.1 mmol, 0.07 M), Me3Al (2 M in toluene, 3 eq.), (Sa,R)-L1 (10 mol%), Ti(Oi-Pr)4 (4 eq.), toluene or Et2O (1.5 mL), 0 °C, 3 h. [b] Determined by chiral GC analysis. [c] Phenylmethanol was obtained instead 2a.
In the next optimization step, a survey of chiral diol ligands (Figure 11) revealed the simplest (Sa,R)-L1 as the best ligand for the addition of Me3Al to benzaldehyde (Table 29). Substituted derivatives L2-5 provided, in general, lower conversions and enantioselectivities (Table 29, entries 2-5 vs 1), especially in the case of the ortho- methoxy substituted (Sa,S)-L3, probably due to steric factors (Table 29, entry 2).
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Figure 1. Chiral diol ligands screened in this study
Table 29. Ligand screening[a]
Entry L* Conv.[b] (%) ee[b] (%)
1 (Sa,R)-L1 >99 94 2 (Sa,S)-L3 87 54 3 (Sa,R)-L4 98 80 4 (Sa,S)-L5 95 88 5 (Sa,R)-L6 >99 92 [a] Conditions: 1a (0.1 mmol, 0.07 M), Me3Al (2 M in toluene, 3 eq.), L* (10 mol%), Ti(Oi-Pr)4 (4 eq.), Et2O (1.5 mL), 0 °C, 3 h. [b] Determined by chiral GC analysis.
In the final stage of the optimization process, the amounts of Me3Al and Ti(Oi-Pr)4 were adjusted. The reaction in the presence of chiral ligand (Sa,R)-L1 but no titanium isopropoxide, gave racemic alcohol 2a with full conversion (Table 30, entry 1). We believe that, although there is probably some coordination between the organoaluminum species and the ligand, due to a deprotonation, the catalysis is not effective. This is indicative that the active catalytic complex in the reaction is an organotitanium species, and possibly, an in situ transmetallation of R3Al with the excess of Ti(Oi-Pr)4 has to occur in order to achieve good results.
A low excess of Ti(Oi-Pr)4 (1.5 eq.) respect to the nucleophile was not enough to induce an asymmetric addition to substrate 1a and product 2a was obtained in a racemic form under this conditions (Table 30, entry 2 vs 1). Equimolar amounts of
Ti(Oi-Pr)4 and Me3Al provided low enantioselectivity and moderate conversion (Table 30, entry 3). Further tests demonstrated that a higher excess of titanium tetraisopropoxide was necessary to get good enantiomeric excess (Table 30, entries
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Chapter IV – Results and discussion
4-10). A 1.3:1 ratio Ti(Oi-Pr)4/Me3Al, which had provided good levels of enantioselectivity in previous screenings (Table 27-29) was our starting point for the further optimization process. The equivalents of nucleophile and Ti(Oi-Pr)4 were modified (trying to minimize the amount of each one) to observe the effect on enantioselectivity, but always keeping the 1.3:1 ratio constant (Table 30, entries 4-7). In general, very good to full conversions were obtained and the highest enantiomeric excess (94%) was reached with 3 eq. of trimethylaluminum and 4 eq. of Ti(Oi-Pr)4
(Table 30, entry 7). In order to improve this last result, other Ti(Oi-Pr)4/Me3Al ratios were also evaluated (Table 30, entries 8-10). A ratio Ti(Oi-Pr)4/Me3Al 2:1 gave similar results concerning ee and conversion, using less equivalents of both reagents (Table
30, entry 8) or just decreasing the amount of Me3Al (Table 30, entry 9). When the amount of nucleophile was minimized to 1.5 eq., and the Ti(Oi-Pr)4/Me3Al ratio slightly adjusted to 2.7:1, alcohol 2a was generated with 94% ee and full conversion (Table 30, entry 10 vs 7).
[a] Table 30. Optimization Ti(Oi-Pr)4/Me3Al ratio
[b] [b] Entry Ti(Oi-Pr)4 (eq.) Me3Al (eq.) Ti:Al ratio Conv. (%) ee (%) 1 0 1.5 - >99 0 2 1.5 3 0.5:1 81 2 3 1.5 1.5 1:1 59[c] 18 4 2 1.5 1.3:1 90 60 5 2.7 2 1.3:1 75 60 6 3.3 2.5 1.3:1 99 85 7 4 3 1.3:1 >99 94 8 3 1.5 2:1 85 94 9 4 2 2:1 99 94 10 4 1.5 2.7:1 >99 94
[a] Conditions: 1a (0.1 mmol, 0.07 M), Me3Al (2 M in toluene, x eq.), (Sa,R)-L1 (10 mol%), Ti(Oi-Pr)4 (y eq.), Et2O (1.5 mL), 0 °C, 3 h. [b] Determined by chiral GC analysis. [c] 1% of phenylmethanol was detected by GC analysis.
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2.2. Scope of the reaction
Under the optimized conditions, the scope of the addition of Me3Al was examined with different aldehydes (Table 31). The system proved to be remarkably efficient for a variety of aromatic substrates and a wide range of methyl carbinol units were prepared in good yield (87 to 99%) and enantioselectivity 80 to 94% (Table 31, entries 1-10). The lower selectivity for the o-methylbenzaldehyde (1b) and the fact that 4% of reduction product [1-(o-tolyl)methanol] was also obtained along with the desired 2b (Table 31, entry 2), could be attributed to higher steric hindrance around the reactive site.
Enantioselectivities ranging from 80-88% and very good yields were recorded for the heteroaromatic substrates 2-thiophenecarboxaldehyde (1j) and 2-furaldehyde (1k) (Table 31, entries 11-12). The reaction with cinnamaldehyde (1l) gave good enantioselectivity as well (Table 31, entry 13), whereas phenylpropargyl aldehyde (1aa) provided moderate yield and enantiomeric excess (Table 31, entry 14). The substrate generality was also examined for aliphatic aldehydes; good yield and moderate enantioselectivity were achieved in the reaction with 1m (Table 31, entry 15) and, outstandingly, the bulky pivaldehyde (1n) provided the highest enantioselectivity of the series (Table 31, entry 16). As a general feature, it should be mentioned that all reactions were finished in less than 1 hour without by-product formation and the unreacted starting material and ligand could be easily recovered.
Moreover, the addition of Me3Al to benzaldehyde (1a) was scaled up to 1 mmol of substrate without any loss of enantiomeric excess (94%) or yield (>99%).
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Chapter IV – Results and discussion
[a] Table 31. Asymmetric addition of Me3Al to aldehydes
Entry Aldehyde Product Yield[b] (%) ee[c] (%)
1 >99 94 (S)
2 92[d] 80 (S)
3 98 94 (S)
4 99 94 (S)
5 87 94 (S)
6 >99 94 (S)
7 92 94 (S)
8 99 94 (S)
9 99 94 (S)
10 99 94 (S)
11 68 (95)[e] 80 (S)
12 75 (91)[e] 88 (S)
13 98 90 (S)
14 80 62 (S)
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Chapter IV – Results and discussion
15 92 84 (S)
16 (55)[e] 98 (S)
[a] Conditions: 1 (0.3 mmol, 0.12 M), Me3Al (2 M in toluene, 1.5 eq.), (Sa,R)-L1 (10 mol%),
Ti(Oi-Pr)4 (4 eq.), Et2O (2.5 mL), 0 °C, 1 h. [b] Isolated yield after distillation or flash silica gel chromatography. [c] Determined by chiral GC or HPLC analysis. Absolute configuration of chiral alcohols was determined by correlation of optical rotation with known compounds. [d] o-Tolylmethanol (4%) was detected by GC analysis. [e] Volatile products, conversions based on GC data in brackets.
Finally, we turned our attention to other commercially available organoaluminum reagents (Table 32). Regarding the enantioselectivities, the system worked well for the addition of the linear Et3Al and (n-Pr)3Al to a variety of aromatic and aliphatic aldehydes, although lower yields were obtained compared to the addition of Me3Al
(Table 32, entries 1-6). In particular, the use of (n-Pr)3Al led to the formation of significant amounts of the by-product derived from the reduction of the corresponding aldehyde via -hydride elimination from the organoaluminum reagent species and/or through Meerwein-Ponndorf-Verley reduction from in situ generated
RxAl(Oi-Pr)3-x species (Table 32, entries 4-6).
[a] Table 32. Asymmetric addition of Et3Al and (n-Pr)3Al to aldehydes
Entry Aldehyde Product Yield[b] (%) ee[c] (%)
1 77 90 (S)
2 65 87 (S)
3 70 92 (S)
4 35[d] 94 ()
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Chapter IV – Results and discussion
5 26[e] 92 ()
6 34[f] 94 ()
[a] Conditions: 1 (0.3 mmol, 0.12 M), R3Al (1.5 eq.), (Sa,R)-L1 (10 mol%), Ti(Oi-Pr)4 (4 eq.), Et2O (2.5 mL), 0 °C, 1 h. [b] Isolated yield after distillation or flash silica gel chromatography. [c] Determined by chiral GC analysis. Absolute configuration of chiral alcohols was determined by correlation of optical rotation with known compounds. [d] 9% (4-chlorophenyl)methanol was detected by GC analysis. [e] 8% (4-methoxyphenyl)methanol was detected by GC analysis. [f] 23% 1-cyclohexylmethanol was detected by GC analysis.
An intriguing characteristic of this catalytic system is its incompatibility with the branched i-butyl moiety; no products were formed when (i-Bu)3Al was used as nucleophile or when isovaleraldehyde was used as substrate (2w, Figure 12). The use 2 of sp -hybridized aluminum reagents was also studied. For example, Ph3Al could be added to 2-naphthaldehyde (1i) with very good yield but low enantioselectivity (2x, Figure 12), in contrast to the higher enantioselectivity and lower yield that resulted from the addition to 1n (2ab, Figure 12).
Figure 12. Chiral secondary alcohols derived from the addition of (i-Bu)3Al or Ph3Al to aldehydes.
In conclusion, an efficient catalytic system has been developed for the enantioselective addition of organoaluminum reagents to aldehydes. The asymmetric methylation, ethylation and propylation of a wide variety of aromatic and aliphatic aldehydes proceeded with good yields and high enantioselectivities in a simple one- pot procedure and under mild conditions using economical and commercially available reagents.
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Chapter IV – Experimental part
3. Experimental part
3.1. General procedure for the asymmetric alkylation of aromatic aldehydes with organoaluminum reagents
In a flame dried Schlenk tube, (Sa,R)-L1 (11.4 mg, 0.03 mmol, 10 mol%) was dissolved in anhydrous Et2O (2.5 mL) under argon atmosphere. The solution was cooled down to 0 °C and Ti(Oi-Pr)4 (370 µL, 1.2 mmol, 4 eq.) was then added. Five minutes later,
R3Al (0.45 mmol, 1.5 eq.) was added followed by the addition of the corresponding aldehyde (0.3 mmol) previously distilled. The reaction mixture was stirred at 0 °C for
1 h (for Me3Al) or 3 h (for the rest of organoaluminum reagents) and then quenched with water (5 mL) and HCl 2 M (5 mL). The crude was extracted with EtOAc (3 × 10 mL), and the combined organic layers were neutralized with a saturated NaHCO3 aqueous solution (15 mL), dried over magnesium sulfate and concentrated under vacuum. The crude product was purified by flash silica gel chromatography or/and distillation on Kugelrohr to give the desired products.
3.2 Data of chiral secondary alcohols prepared from organoaluminum reagents
1H NMR and 13C NMR, LRMS, HRMS, m.p., IR data and conditions for the chromatographic separation of enantiomers for some of the compounds listed below has been already reported in Chapter II section 3.2 and/or Chapter III section 5.2. In these cases, only the yield, optical rotation and ee obtained in the addition reaction with organoaluminium reagents will be reported.
(S)-1-Phenylethanol (2a): Compound 2a was obtained after purification 25 by Kugelrohr distillation as a colorless oil (>99% yield, 94% ee); []D = Lit. 20 57.0 (c 1.0, CHCl3) { []D = 39.6 (c 2.5, CHCl3) for 82% ee}.
(S)-1-(o-Tolyl)ethanol (2b): Compound 2b was obtained after purification by Kugelrohr distillation as a colorless oil (92% yield, 80%
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Chapter IV – Experimental part
25 Lit. 20 ee); []D = 73.0 (c 1.0, CHCl3) { []D = 72.5 (c 1.0, CHCl3) for 96% ee}.
(S)-1-(m-Tolyl)ethanol (2c): Compound 2c was obtained after purification by Kugelrohr distillation as a colorless oil (98% yield, 94% 25 Lit. 16 ee); []D = 51.0 (c 1.0, CHCl3) { []D = 47.3 (c 0.8, CHCl3) for 90% ee}.
(S)-1-(p-Tolyl)ethanol (2d): Compound 2d was obtained after purification by Kugelrohr distillation as a colorless oil (99% yield, 94% 25 Lit. 20 ee); []D = 54.5 (c 1.0, CHCl3) { []D = 53.7 (c 0.4, CHCl3) for 96% ee}.
(S)-1-(4-Methoxyphenyl)ethanol (2e): Compound 2e was obtained after purification by Kugelrohr distillation as a colorless oil (87% 25 Lit. 20 yield, 94% ee); []D = 44.0 (c 1.0, CHCl3) { []D = 51.9 (c 1.0,
CHCl3) for 97% ee}.
(S)-1-[4-(Trifluoromethyl)phenyl]ethanol (2f): Compound 2f was obtained after purification by Kugelrohr distillation as a colorless oil 25 Lit. 20 (>99% yield, 94% ee); []D = 37.0 (c 1.0, CHCl3) { []D = 33.7
(c 5.5, CHCl3) for 97% ee}.
(S)-1-(4-Chlorophenyl)ethanol (2g): Compound 2g was obtained after purification by Kugelrohr distillation as a colorless oil (92% 25 Lit. 20 yield, 94% ee); []D = 43.0 (c 1.0, CHCl3) { []D = 43.6 (c 1.0,
CHCl3) for 97% ee}.
(S)-4-(1-Hydroxyethyl)benzonitrile (2h): Compound 2h was obtained after purification by Kugelrohr distillation as a colorless oil 25 Lit. 20 (99% yield, 94% ee); []D = 49.0 (c 1.0, CHCl3) { []D = 62.7 (c
2.1, CHCl3) for 72% ee}.
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Chapter IV – Experimental part
(S)-1-[4-(1-Hydroxyethyl)phenyl]ethanone (2av):119 Compound 2i was obtained after purification by Kugelrohr distillation as a 25 Lit. colorless oil (99% yield, 94% ee); []D = 42.6 (c 1.0, CHCl3) { 25 1 []D = 44.9 (c 1.2, CHCl3) for 98% ee}. H NMR (300 MHz, CDCl3) 7.88 (d, J = 8.3 Hz, 2H), 7.42 (d, J = 8.4 Hz, 2H), 4.92 (q, J = 6.5 Hz, 1H), 2.61 (br s, 1H), 13 2.55 (s, 3H), 1.47 (d, J = 6.5 Hz, 3H). C NMR (75 MHz, CDCl3) 198.0, 151.3, 136.1, 128.5, 125.4, 69.7, 26.5, 25.2. LRMS (EI): m/z (%): 164 [M+] (6), 150 (10), 149 (97), 122 (10), 121 (100), 106 (8), 105 (10), 103 (18), 91 (10), 78 (9), 77 (30), 51 (13). Ee determination by chiral GC analysis, CP-Chirasil-DEX CB column, T = 150 °C, P = 14.3 psi, retention times: tr(R) = 20.0 min, tr(S) = 20.6 min (major enantiomer).
(S)-1-(Naphthalen-2-yl)ethanol (2i): Compound 2i was obtained after purification by Kugelrohr distillation as a white powder (99% 25 Lit. 20 yield, 94% ee); []D = 46.0 (c 1.0, CHCl3) { []D = 48.1 (c 1.5,
CHCl3) for 92% ee}.
(S)-1-(Thiophen-2-yl)ethanol (2j): Compound 2j was obtained after purification by Kugelrohr distillation as a colorless oil (68% yield, 80% 25 Lit. 20 ee); []D = 30.0 (c 1.0, CHCl3) { []D = 27.6 (c 1.0, CHCl3) for 94% ee}.
(S)-1-(Furan-2-yl)ethanol (2k): Compound 2k was obtained after purification by Kugelrohr distillation as a colorless oil (75% yield, 88% 25 Lit. 20 ee); []D = 22.6 (c 1.0, CHCl3) { []D = 19.8 (c 0.9, CHCl3) for 98% ee}.
(S,E)-4-Phenylbut-3-en-2-ol (2l): Compound 2l was obtained after purification by Kugelrohr distillation as a colorless oil (98% yield, 25 Lit. 20 90% ee); []D = 29.0 (c 1.0, CHCl3) { []D = 14.6 (c 1.0, CHCl3) for 60% ee}.
119
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Chapter IV – Experimental part
(S)-4-Phenylbut-3-yn-2-ol (2au): Compound 2au was obtained after purification by Kugelrohr distillation followed by a flash silica gel chromatography from 100:0 till 90:10 (hexane/EtOAc) as a colorless 25 Lit. 20 oil (80% yield, 62% ee); []D = 28.0 (c 1.0, CHCl3) { []D = 33.0
(c 0.9, CHCl3) for 98% ee}.
(S)-1-Phenylpropan-2-ol (2m): Compound 2m was obtained after purification by Kugelrohr distillation as a colorless oil (92% yield, 84% 25 Lit. 25 ee); []D = +44.0 (c 1.0, CHCl3) { []D = +42.2 (c 1.0, CHCl3) for 99% ee}.
(-)-3,3-Dimethylbutan-2-ol (2n): Compound 2n was obtained after 25 purification by Kugelrohr distillation (55% yield, >99% ee); []D = 8.0 (c Lit. 20 1.7, EtOAc) { []D = +31.0 (c 1.0, CHCl3) for 60% ee}
(S)-1-Phenylpropan-1-ol (2o): Compound 2o was obtained after purification by Kugelrohr distillation as a colorless oil (77% yield, 90% 25 Lit. 20 ee); []D = 38.0 (c 1.0, CHCl3) { []D = 49.6 (c 0.5, CHCl3) for 98% ee}.
(S)-1-(p-Tolyl)propan-1-ol (2p): Compound 2p was obtained after purification by Kugelrohr distillation as a colorless oil (65% yield, 25 Lit. 20 87% ee); []D = 40.0 (c 1.0, CHCl3) { []D = 36.1 (c 1.0, CHCl3) for 84% ee}.
(S)-1-(4-Chlorophenyl)propan-1-ol (2q): Compound 2q was obtained after purification by Kugelrohr distillation as a colorless 25 Lit. 25 oil (70% yield, 92% ee); []D = 35.7 (c 1.0, CHCl3) { []D =
38.4 (c 1.1, CHCl3) for 95% ee}.
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Chapter IV – Experimental part
(-)-1-(4-Chlorophenyl)butan-1-ol (2aw):120 Compound 2aw was obtained after purification on flash silica gel chromatography from 100:0 till 95:5 (n-hexane/EtOAc) as a yellow oil (35% yield, 25 1 94% ee); []D = 41.6 (c 1.3, CHCl3). H NMR (500 MHz, CDCl3) 7.24 (d, J = 8.5 Hz, 2H), 7.20 (d, J = 8.6 Hz, 2H), 4.59 (t, J = 6.8 Hz, 1H), 1.83 (br s, 1H), 1.68 (m, 1H), 1.57 13 (m, 1H), 1.34 (m, 1H), 1.22 (m, 1H), 0.85 (t, J = 7.4 Hz, 3H). C NMR (126 MHz, CDCl3) 143.3, 133.0, 128.5, 127.3, 73.7, 41.3, 18.9, 13.9. LRMS (EI): m/z (%): 186 [M++2] (3), 185 [M++1] (1), 184 [M+] (8), 143 (32), 141 (100), 113 (17), 77 (48), 51 (6). Ee determination by chiral GC analysis, CP-Chirasil-DEX CB column, T = 130 °C, P = 14.3 psi, retention times: tr(R) = 36.3 min, tr(S) = 36.9 min (major enantiomer).
(-)-1-(4-Methoxyphenyl)butan-1-ol (2ax):121 Compound 2ax was obtained after purification on flash silica gel chromatography from 100:0 till 94:6 (n-hexane/EtOAc) as a 25 1 yellow oil (26% yield, 92% ee); []D = 35.0 (c 1.0, CHCl3). H NMR (500 MHz, CDCl3) 7.19 (d, J = 8.6 Hz, 2H), 6.80 (d, J = 8.6 Hz, 2H), 4.55 (t, J = 6.7 Hz, 1H), 3.73 (s, 3H), 1.79 (br s, 1H), 1.72 (m, 1H), 1.58 (m, 1H), 1.33 (m, 1H), 1.21 (m, 1H), 0.85 (t, J = 7.4 13 Hz, 3H). C NMR (126 MHz, CDCl3) 159.0, 137.0, 127.1, 113.8, 74.0, 55.3, 41.1, 19.1, 13.9. LRMS (EI): m/z (%): 180 [M+] (10), 138 (9), 137 (100), 109 (23), 94 (14), 77 (12). Ee determination by chiral GC analysis, CP-Chirasil-DEX CB column, T = 130 °C, P
= 14.3 psi, retention times: tr(R) = 36.4 min, tr(S) = 36.8 min (major enantiomer).
(-)-1-Cyclohexylbutan-1-ol (2ay):122 Compound 2ay was obtained after purification on flash silica gel chromatography from 100:0 till 25 95:5 (n-hexane/EtOAc) as a yellow oil (34% yield, 94% ee); []D = 1 11.3 (c 0.9, CHCl3). H NMR (300 MHz, CDCl3) 3.36 (m, 1H), 1.28 (m, 16H), 0.92 (t, J 13 = 6.5 Hz, 3H). C NMR (75 MHz, CDCl3) 76.0, 43.6, 36.3, 29.7, 29.3, 27.7, 26.6, 26.4, + 26.2, 19.1, 14.2. LRMS (EI): m/z (%): 138 [M–H2O] (5), 113 (44), 96 (9), 95 (100), 82
120 For racemic mixture see: Kuhlmann, B.; Arnett, E. M.; Siskin, M. J. Org. Chem. 1994, 59, 3098–3101. 121 For racemic mixture see: Pearson, W. H.; Fang, W-K. J. Org. Chem. 1995, 60, 4960–4961. 122 For racemic mixture see: Yeh, M. C. P.; Knochel, P.; Santa, L. E. Tetrahedron Lett. 1988, 29, 3887–3890.
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Chapter IV – Experimental part
(18), 73 (52), 72 (22), 67 (21), 57 (11), 55 (69). Ee determination by chiral GC analysis,
Cyclosil- column, T = 120 °C, P = 14.3 psi, retention times: tr(S) = 23.6 min (major enantiomer), tr(R) = 24.9 min.
(S)-Naphthalen-2-yl(phenyl)methanol (2x): Compound 2x was obtained after purification on flash silica gel chromatography from 100:0 till 90:10 (n-hexane/EtOAc) as a white powder (90% 25 Lit. 20 yield, 20% ee); []D = +3.0 (c 1.0, CHCl3) { []D = +11.2 (c 0.8, CHCl3) for 95% ee}.
(S)-2,2-Dimethyl-1-phenylpropan-1-ol (2ab):123 Compound 2ab was obtained after purification on flash silica gel chromatography from 100:0 till 92:8 (n-hexane/EtOAc) as a white powder (61% yield, 72% 25 Lit. 20 ee); m.p. 56 – 58 °C, []D = 26.0 (c 1.0, CHCl3) { []D = 15.5 (c 1.7, CHCl3) for 1 95% ee}. H NMR (300 MHz, CDCl3) 7.30 (m, 5H), 4.42 (s, 1H), 1.90 (br s, 1H), 0.94 (s, 13 9H). C NMR (75 MHz, CDCl3) 142.2, 127.6, 127.5, 127.3, 82.4, 35.6, 25.9. LRMS (EI): m/z (%): 164 [M+] (4), 108 (10), 107 (100), 79 (40), 77 (19), 57 (9). Ee determination by chiral GC analysis, CP-Chirasil-DEX CB column, T = 115 °C, P = 14.3 psi, retention times: tr(R) = 35.5 min, tr(S) = 37.3 min (major enantiomer).
123 Kasai, M.; Froussios, C.; Ziffer, H. J. Org. Chem. 1983, 48, 459–64.
200
GENERAL CONCLUSIONS
General conclusions
General conclusions
A new class of chiral binaphtyl diol ligands (Ar-BINMOLs), containing both axial chirality and a sp3 stereogenic center, have been prepared in two reaction steps, starting from (S)-BINOL, through a lithium-assisted [1,2]-Wittig rearrangement with very good yields and perfect diastereocontrol.
Ligand (Sa,R)-L1 has been used in the enantioselective 1,2 addition of different organometallic reagents, such as organolithium, Grignard and organoaluminum compounds, to aromatic aldehydes, in combination with an excess of Ti(Oi-Pr)4. Chiral secondary alcohols have been obtained with very good yields and enantioselectivities from a wide variety of aromatic aldehydes. It is important to mention that better yields were achieved when the less reactive organoaluminum reagents were used as nucleophiles, compared with the highly reactive Grignard and organolithium reagents. Moreover, mechanistic studies carried out with the organolithium and Grignard reagents in the alkylation of aldehydes, concluded that there is no linear effect in the reaction and no autocatalytic effect was observed.
In addition, the asymmetric alkylation of challenging aliphatic aldehydes with
Grignard reagents has been possible by the use of a novel Ar-BINMOL ligand, (Sa,R)- L10, synthesized in our research by a new synthetic procedure. With the new ligand, new reaction conditions were found to achieve valuable chiral secondary aliphatic alcohols in high yields and very good enantioselectivities.
The synthesis of chiral tertiary diarylmethanols has been achieved through an enantioselective addition of aryl Grignard reagents to variety of aryl alkyl ketones using our catalytic system and ligand (Sa,R)-L7. The corresponding products were obtained in moderate yield, due to the low reactivity of ketones, and good enantiomeric excesses.
Important limitations of our catalytic system include the addition of secondary, tertiary, allylic and aryl nucleophiles to aldehydes, which provided low yields and
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General conclusions
enantioselectivities under the conditions tested. The addition of alkyl organometallic reagents to ketones also remains a challenge; the desired addition product was not observed and only pinacol coupling and/or aldol product was detected in the reaction crude.
However, the catalytic system developed by our research group is very versatile in the asymmetric 1,2 addition of organometallic reagents to aldehydes, considering that was possible the addition of organolithium, Grignard and organoaluminum reagents with the same ligand (Sa,R)-L1. Those compounds have been employed in the catalytic enantioselective alkylation of a wide variety of aldehydes with electrondonor and electrowithdrawing substituents, even some sensitive functional groups are tolerated.
204
EXPERIMENTAL PART (GENERAL INFORMATION)
Experimental part (General information)
Experimental part (General information)
1. Solvents and reagents
Here are described in detail the technical characteristics of most common solvents and reagents that were used for the development of this thesis.
Solvents: Not anhydrous solvents: n-hexane (absolute for analysis quality), EtOAc (for analysis quality), Et2O (for analysis quality) were purchased from Merck®. Not anhydrous n-pentane (95% PS), DCM (99%), CHCl3 (99% stabilized with ethanol) and acetone (for analysis quality) were purchased from Panreac®.
THF (HPLC grade), Toluene (HPLC grade) and DCM (HPLC grade, stabilized with 50 ppm of amylene), purchased from Scharlau®, were dried in a PureSolv® MD 3 apparatus and concentration of water was determined by Karl-Fischer analysis following standard procedures. Et2O anhydrous (≥99.7%, with 1 ppm of BHT as inhibitor) was purchased from Sigma-Aldrich®.
Reagents: Grignard reagents were prepared from the corresponding alkyl or aryl halide and magnesium turnings in Et2O following standard procedures, except
MeMgBr (3.0 M in Et2O) and EtMgBr (3.0 M in Et2O) which were purchased from Sigma-Aldrich®. The Grignard reagents that were prepared are: i-PrMgBr (2.6 M in
Et2O), n-BuMgBr (3.0 M in Et2O), n-BuMgCl (4.1 M in Et2O), i-BuMgBr (2.6 M in Et2O), t-
BuMgBr (2.0 M in Et2O), (4-chlorobutyl)MgBr (1.6 M in Et2O), CyMgBr (2.0 M in Et2O),
AllylMgBr (1.0 M in Et2O), BnMgBr (2.0 M in Et2O), VinylMgBr (1.0 M in THF/Et2O),
PhMgBr (3.0 M in Et2O), (4-anisyl)MgBr (1.9 M in Et2O), (4-tolyl)MgBr (1.9 M in Et2O),
(4-fluorophenyl)MgBr (2.0 M in Et2O). All Grignard reagents were titrated using 2- butanol and catalytic amounts of 1,10-phenanthroline in anhydrous THF and were stored under argon and used within 2-3 weeks.
Organolithium reagents: MeLi (1.6 M in Et2O) and EtLi (0.5 M in Benzene/Cyclohexane) were purchased from Sigma-Aldrich®. n-BuLi (2.5 M in hexane) was purchased from Chemetall® and PhLi (1.9 M in n-Bu2O) was purchased
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Experimental part (General information)
from Alfa Aesar®. Organolithium reagents were titrated by Gilman double titration method and were used without purification.
Organoaluminum reagents: Me3Al (2.0 M in toluene), Et3Al (1.0 M in n-hexane), i-
Bu3Al (1.0 M in n-hexane) and Ph3Al (1.0 M in n-Bu2O) were purchased from Sigma-
Aldrich® and n-Pr3Al (0.7 M in n-heptane) was purchased from Acros Organics®. Organoaluminum reagents were used without purification.
Ti(Oi-Pr)4 ≥97% was purchased from Sigma-Aldrich® and kept under argon atmosphere with a rubber septum once opened.
Liquid aldehydes and ketones were purified by distillation in a Büchi® Glass Oven B- 585 Kugelrohr and used immediately. Solid aldehydes and ketones were bought from the highest purity available and used without further purification.
Chromatography: Crude mixtures were purified in a glass chromatography column, using flash silica gel Panreac® 60, 40-63 m as stationary phase, using, as mobile phase (eluent) n-hexane/EtOAc or pentane/Et2O mixtures, increasing the polarity till product elution. The purification process was monitored by Machery-Nagel® TLC silica gel (0.2 mm thickness, 60 m particle size), which contains an ultraviolet (254 nm) sensitive indicator. All components were visualized by UV and/or phosphomolybdic acid (1 g/24 mL EtOH absolute) staining.
2. Analytical equipment
The following instruments have been employed for full characterization of the different compounds. Herein, is described the technical characteristics of each apparatus.
Melting points: Melting points were measured in a Reichtert® Thermovar hot plate apparatus and are corrected.
Optical rotation: Optical rotations were measured at room temperature on a Jasco® P-1030 or Perkin Elmer® instruments Model 341 Polarimeter with a 5 cm quartz cell
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Experimental part (General information)
(c is given in g/100 mL). Depending on each compound, the solvent employed for measurement was CHCl3 or CH2Cl2.
NMR: 1H NMR, 13C NMR and 19F NMR were recorded on a Bruker® AV300 Oxford (300, 75 and 282 MHz, respectively) or Bruker® AV400 (400, 101 and 376 MHz, respectively) using CDCl3 as solvent. Chemical shift values are reported in ppm with 1 13 TMS as internal standard (CDCl3: 7.26 for H NMR, 77.0 for C NMR). Data are reported as follows: chemical shifts, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, quin = quintuplet, sextuplet = sext, m = multiplet, br = broad), coupling constants (Hz), and integration.
IR: IR spectra were recorded on Jasco® FT/IR – 4100 Fourier Transform Infrared Spectrometer.
LRMS: Low resolution mass spectra were recorded on Agilent Technologies® 6890N Network GC System equipped with a HP-5MS column (Agilent Technologies®, 30 m × 0.25 mm), connected to an Agilent Technologies® 5973 Network Mass Selective Detector. Also, some analyses were recorded out on a mass spectrometer (Agilent Technologies® 5973 Network) with a direct insertion probe (73DIP-1), equipped with a transmission quadrupole analyzer. In both equipments the samples were ionized by an electronic impact source (70 eV).
HRMS: High resolution mass spectra were obtained on a Waters® LCT Premier XE apparatus equipped with a time of flight (TOF) analyzer and the samples were ionized by ESI techniques and introduced through an ultra-high pressure liquid chromatography (UPLC) model Waters® ACQUITY H CLASS.
Chiral GC: Enantioselectivities were determined by chiral GC Agilent Technologies® 7820A equipped with a FID detector. Nitrogen was used as carrier gas (7 mL/min), the injector and detector were kept at 250 °C. Specific isothermal programs were employed for optimal enantiomeric separation and different columns were also used for this purpose for each compound: Varian® CP-Chiralsil-DEX CB (25 m × 0.25 mm),
209
Experimental part (General information)
Agilent Technologies® Cyclosil- (30 m × 0.25 mm) and Agilent Technologies® HP- CHIRAL-20 (30 m × 0.25 mm).
Chiral HPLC: Enantioselectivities were determined by HPLC analysis (Agilent Technologies® 1100 Series HPLC) equipped with a G1315B diode array detector and a Quat Pump G1311A. The following chiral HPLC columns were employed to determine the enantioselectivities of all chiral compounds: Daicel Chiralcel® ODH (5 m, 0.46 cm Ø × 25 cm), Daicel Chiralpak® ADH (5 m, 0.46 cm Ø × 25 cm), Daicel Chiralpak® ASH (5 m, 0.46 cm Ø × 25 cm), Daicel Chiralcel® OJ (10 m, 0.46 cm Ø × 25 cm) and Daicel Chiralpak® IA (5 m, 0.46 cm Ø × 25 cm). Mixtures of n-hexane (HPLC grade) and i-PrOH (HPLC grade), were purchased from VWR Chemicals Prolabo® and Panreac®, respectively and were used as eluent.
210