palavras-chave Catálise assimétrica, ferrocenilfosfinas, Fesulphos, ligandos quirais suportados, adicão conjugada, nitrometano, cinamilidenoacetofenonas, sulfoniliminas.
resumo A presente dissertação centrou-se em duas areas de investigação distintas: o estudo de novas aplicações de ferrocenilfosfinas e a adição conjugada de nitrometano a substratos conjugados.
Tendo em conta êxito do grupo do Prof. Carretero no desenvolvimento e uso de 1-fosfino-2-sulfenilferrocenos (ligandos Fesulphos) enquanto catalizadores quirais, propusemo-nos estudar a possibilidade de as ferrocenil dialquilfosfinas, compostos estáveis ao ar e ricos em electrões graças à sua estrutura
ferrocénica, constituírem bons catalizadores para a reacção de Morita-Baylis-Hillman (RMBH). Adicionalmente, a elevada estabilidade destes sólidos cristalinos também constitui uma grande vantagem sobre as trialquilfosfinas comerciais, conhecidas pela sua elevada sensibilidade à oxidação pelo contacto com o ar e, nalguns casos, carácter pirofórico.
Esta reacção geradora de ligações C-C entre alquenos activados e nucleófilos de carbono contendo um átomo de carbono sp2 deficiente em electrões tem frequentemente associados problemas de baixa reactividade e rendimentos dependentes do tipo de substracto utilizado. Durante o nosso estudo
confirmámos que as ferrocenil diarilfosfinas e as ferrocenil dialquilfosfinas são, de facto, mais eficientes do que as fosfinas comerciais PPh3 e PCy3. Também,
de acordo com o aumento de nucleofilicidade com a variação dos substituintes alquílicos, as ferrocenildialquilfosfinas demonstraram ser mais eficientes e, em especial, a dietilfosfina, menos estericamente impedida, permitiu obter
conversões totais em 1h, gerando o aducto de MBH com um rendimento excelente. Em seguida explorámos o alcance estrutural da reacção usando a ferrocenildietilfosfina como catalizador e verificámosque as condições de reacção podiam ser aplicadas a outros aldeídos aromáticos, bem como a aldeídos alifáticos lineares e ramificados.
Durante a reacção de Morita-Baylis-Hillman formam-se dois esterocentros, um dos quais permanece no produto da RMBH. Dado que, até onde nos foi possível averiguar, não existem relatos do uso de ferrrocenilfosfinas quirais na reacção de MBH, um conjunto de ferrocenildialquilfosfinas de fácil preparação e outras comerciais foram testas em reacções assimétricas de MBH. Os melhores resultados de enantioselectividade foram obtidos utilizando o catalizador quiral Mandyphos (até 65% ee).
Na sequência do nosso estudo sobre as aplicação de ferrocenilfosfinas, o nosso objective seguinte consistiu na imobilização do ligado quiral Fesulphos num suporte sólido e sua utilização em catálise assimétrica de reacções organometálicas. Este ligando tem sido aplicado numa variedade de importantes reacções assimétricas com excelentes resultados, tanto em termos de reactividade como de enantioselectividade, comprovando assim a sua aplicabilidade generalizada. A imobilização sobre um suporte sólido permitiria a sua fácil recuperação da mistura reaccional, sem contaminação do produto, e facilitaria a sua reciclagem.
Para imobilizar o Fesulphos sobre um suporte poliestirénico foi necessário introduzir na estrutura ferrocénica um terceiro substituinte, capaz de ligar o ligando ao suporte. Para minimizar as interacções estéricas que poderiam resultar num decréscimo da reactividade e/ou selectividade do catalizador, optámos por ligar o polímero ao anel Cp inferior que não contém os grupos coordenantes tioéter e fosfina. Foram preparados dois ligandos de Fesulphos imobilizados (diferentes extensores de ligação ao suporte) que, após a
formação de complexos com sais de cobre (I), funcionaram como catalizadores eficientes na reacção de cicloadição 1,3-dipolar de iletos de azometino com uma variedade de dipolarófilos, proporcionando os produtos com excelentes enantioselectividades. Os produtos da reacção foram isolados da mistura reaccional por filtração do catalizador. Um dos ligandos quirais imobilizado pode ser reciclado até três vezes na reacção de cicloadição 1,3-dipolar, sem necessidade de adicionar mais cobre, e sem perda de reactividade ou enantioselectividade.
A segunda linha de trabalho explorada durante este projecto de doutoramento consistiu no estudo da adição conjugada de nitrometano a dienos activados. O trabalho previamente realizado pelo grupo do Prof. Silva sobre a adição de nitrometano a (E,E)-cinamilidenoacetofenonas havia confirmado que apenas tem lugar a formação dos produtos de adição-1,4. Uma vez que estas
estruturas poderiam constituir interessantes materiais quirais de partida para a síntese de compostos com potencial actividade biológica, decidimos tentar obter a versão assimétrica desta reacção. No entanto, não obtivemos quaisquer resultados usando aminas quirais, ácidos de Lewis ou uma estratégia de dupla activação.
Curiosamente, durante o nosso estudo também preparámos derivados
sulfonilimínicos de (E,E)-cinamilidenoacetofenonas e verificámos que, no caso destes substratos, a regioselectividade da reacção se alterava completamente. Observámos, pela primeira vez, a adição-1,6 de um nucleófilo de carbono (nitrometano) a iminas conjugadas. Foi estudada a optimização das condições de reacção, nomeadamente em termos das propriedades electrónicas destes sistemas altamente conjugados. Porém, os produtos de adição-1,6 apenas puderam ser obtidos com rendimentos modestos (até 49%) devido à formação simultânea de outros três compostos: um produto de adição-1,2 com perda do grupo sulfonamida, um produto de dupla adição 1,2/1,4 e a (E)-1,5-diaril-3-nitrometil-4-penten-1-ona. Longe de estar concluído, este estudo conduziu a novas questões, ainda por responder, sobre os factores controladores da regioselectividade em reacções de adição em sistemas altamente conjugados.
keywords Asymmetric catalysis, ferrocenylphosphines, Fesulphos, immobilized chiral ligands, conjugate addition, nitromethane, cinnamylideneacetophenones, sulfonylimines.
abstract This dissertation focused on two distinct areas of research: the study of new applications for ferrocenylphosphines and, secondly, the conjugate addition of nitromethane to conjugated substrates.
Considering Prof. Carretero’s group successful background on the use of 1-phosphino-2-sulfenylferrocenes (Fesulphos ligands) as chiral catalysts, we envisaged that, due to the electron-rich character of the ferrocene moiety, air-stable ferrocenyl dialkylphosphines could be interesting catalysts for the Morita-Baylis-Hillman reaction (MBHR). Also, the high stability of these solid crystalline solids also constitutes a great advantage over trialkylphosphines, which are highly sensitive to air oxidation and, in some cases, have a pyrophoric character.
This C-C bond forming reaction between activated alkenes and carbon electrophiles containing an electron-deficient sp2 carbon atom is often hampered by low reaction rates and highly substrate-dependent chemical yields. We confirmed that ferrocenyl diarylphosphines and ferrocenyl
dialkylphosphines are more efficient than the commercially available PPh3 and
PCy3. Also, in agreement with the increase in nucleophilicity with the alkyl
substitution, ferrocenyl dialkylphosphines proved more effective and, particularly, the less hindered diethylphosphine promoted a complete conversion within 1h, providing the MBH adduct with an excellent yield. We next explored the reaction’s scope using ferrocenyl diethylphosphine as catalyst and found that the reaction conditions could also be successfully applied to other aromatic aldehydes, as well as both branched and linear aliphatic aldehydes.
During the course of the Morita-Baylis-Hillman reaction two stereocenters are formed, one of which remains in the MBHR product. Since, to the best of our knowledge, there were no reports of the use of chiral ferrocenylphosphines in the MBH reaction, a set of readily accessible chiral ferrocenyldialkylphosphines have been tested in asymmetric Baylis-Hillman reactions. The best
enantioselectivities were obtained using Mandyphos as chiral catalyst (up to 65% ee).
Proceeding with our work on the applications of ferrocenyphosphines, our next goal was to attempt the immobilization of fesulphos on a solid polymeric support and its application on organometallic asymmetric reactions. This ligand has been applied to a variety of synthetically important asymmetric reactions giving excellent results, both in terms of reactivity and enantioselectiviy, thus proving their generalized applicability. It’s immobilization on a solid support would allow its easy recovery from the reaction mixture by simple filtration, without contamination of the product solution, and easy recyclability.
To immobilize fesulphos on a polystyrene support it was necessary to introduce into the ferrocene structure a third substituent able to anchor the ligands to the polymeric support. In order to minimize steric interactions that could result in a lower reactivity and/or selectivity in the catalytic reaction, we chose to attach the polymer to the Cp ring that does not contain the coordinating phosphine and tioether groups. Two new supported-fesulphos ligands were successfully prepared and, after forming complexes with copper (I) salts, acted as very efficient catalysts in 1,3-dipolar cycloaddition azomethine ylides with a variety of dipolarophiles, providing the products with excellent enantioselectivities. Filtration of the catalysts from the reaction mixture allowed simple product isolation. One of the polymer-supported chiral ligands was recycled up to three times in the 1,3-dipolar cycloaddition reaction, with no need for additional copper, and without loss of reactivity or enantioselectivity.
The second line of work followed during this PhD thesis consisted in the conjugate addition of nitromethane to activated α,β,γ,δ-dienes. Prof. Silva’s group previous work on the conjugate addition of nitromethane to (E,E)-cinnamylideneacetophenones had confirmed that only 1,4-addition products were obtained. Since these compounds could be interesting chiral starting materials to synthesize compounds with potential biological activity, we attempted to achieve the asymmetric version of this reaction. Nevertheless, no results were obtained using chiral amines, Lewis acids or a double activation strategy.
Interestingly, during our study we also prepared sulfonylimine derivatives of (E,E)-cinnamylideneacetophenones and found that, in the case of these
substrates, the reaction’s regioselectivity was completely altered. We observed, for the first time, the formation of 1,6-addition products of a nucleophile
(nitromethane) to conjugated imines. The reaction conditions were further optimized, namely in terms of the electronic properties of these extended unsaturated systems. Nevertheless, the 1,6-addition products were still obtained in modest yields (up to 49%) due to the simultaneous formation of three other compounds: a 1,2-addition product with loss of the sulfonamide group, a double 1,2/1,4-addition product and (E)-1,5-diaryl-3-nitromethyl-4-penten-1-one. Far from being complete, this study led to new questions still to be answered with respect to the factors controlling the regioselectivity in conjugate addition reactions of carbon nucleophiles to highly conjugated systems.
palabras-clave Catálisis asimétrica, ferrocenilfosfinas, Fesulphos, ligandos quirales soportados, adicion conjugada, nitrometano, cinamilidenoacetofenonas, sulfoniliminas.
resumen La presente tesis doctoral se ha centrado en dos áreas de investigación distintas: el estudio de nuevas aplicaciones de ferrocenilfosfinas y la adición conjugada de nitrometano a sustratos conjugados.
Teniendo en cuenta el éxito que el grupo del Prof. Carretero había tenido en el desarrollo y utilización de 1-fosfino-2-sulfenilferrocenos (ligandos Fesulphos) en cuanto catalizadores quirales, nos propusimos averiguar la posibilidad de que las ferrocenildialquilfosfinas, compuestos estables al aire y ricos en electrones gracias a su estructura ferrocénica, pudiesen ser catalizadores eficientes para a la reacción de Morita-Baylis-Hillman (RMBH). Asi mismo, la elevada estabilidad de estos sólidos cristalinos también constituye una gran ventaja frente a las trialquilfosfinas comerciales, conocidas por su sensibilidad a la oxidación cuando en contacto con el aire e, en algunos casos, su carácter pirofórico.
Esta reacción generadora de enlaces C-C entre alquenos activados y nucleófilos de carbono conteniendo un átomo de carbono sp2 pobre en electrones está frecuentemente asociada a problemas de baja reactividad y rendimientos dependientes del tipo de sustratos utilizados. En nuestro estudio hemos comprobado que las ferrocenil diarilfosfinas y las ferrocenil
dialquilfosfinas son, efectivamente, más eficientes que las fosfinas comerciales PPh3 y PCy3. También, según el aumento del carácter nucleofílico con la
variación de los sustituyentes alquílicos, las ferrocenildialquilfosfinas han demostrado ser más eficientes y, en especial, la dietilfosfina, menos
estericamente impedida, ha permitido obtener conversiones totales en 1h de reacción, generando el aducto de MBH con un rendimiento excelente. A continuación evaluamos el alcance estructural de la reacción utilizando la ferrocenildietilfosfina como catalizador y verificamos que las condiciones de reacción eran aplicables a otros aldehídos aromáticos, bien como a aldehídos alifáticos lineales y ramificados.
En la reacción de Morita-Baylis-Hillman se forman dos estereocentros, uno de los cuales permanece en el producto de la RMBH. Una vez que, hasta donde hemos podido comprobar, no existían datos relativos al uso de
ferrrocenilfosfinas quirales en la reacción de MBH, un conjunto de
ferrocenildialquilfosfinas, de fácil preparación o comerciales fueron testadas en reacciones asimétricas de MBH. Los mejores resultados de
enantioselectividade se obtuvieron utilizando como catalizador quiral el ligando Mandyphos (hasta un 65% ee).
En la secuencia de nuestro estudio sobre nuevas aplicaciones de
ferrocenilfosfinas, el objetivo siguiente consistió en la inmovilización del ligando quiral Fesulphos en un soporte sólido y su utilización en catálisis asimétrica de reacciones organometálicas. Este ligando ha sido utilizado en una gran variedad de importantes reacciones asimétricas con excelentes resultados, tanto de reactividad como de enantioselectividad, poniendo así de manifiesto su amplia aplicabilidad.
La inmovilización en un soporte sólido permitiría su fácil recuperación de la mezcla de reacción, sin contaminar el producto, y facilitaría su reciclaje. Con el fin de inmovilizar el Fesulphos sobre un soporte poliestirénico ha sido necesario introducir en la estructura ferrocénica un tercer sustituyente, capaz de anclar el ligando al soporte. Para minimizar las interacciones estéricas que podrían afectar la reactividad y/o selectividad del catalizador, elegimos anclar el polímero al anillo Cp inferior, que no contiene los grupos coordinantes tioéter y fosfina. Fueron preparados dos ligandos de Fesulphos inmovilizados
(diferentes alargadores de anclaje al soporte) que, después la formación de complejos con sales de cobre (I), funcionaron como catalizadores eficientes en la reacción de cicloadición 1,3-dipolar de ilusos de azometino con una variedad de dipolarófilos, proporcionando los productos con excelentes
enantioselectividades. Los productos han sido aislados de la mezcla de reacción por simple filtración del catalizador. Uno de los ligandos quirales inmovilizado pudo ser reciclado hasta tres veces en la reacción de cicloadición 1,3-dipolar, sin necesitar añadir mas cobre, y sin pérdida de reactividad o enantioselectividad.
La segunda línea de trabajo seguida en este proyecto de doctorado ha sido el estudio de la adición conjugada de nitrometano a dienos activados. El trabajo previamente realizado por el grupo del Prof. Silva sobre la adición de
nitrometano a (E,E)-cinamilidenoacetofenonas había confirmado que solamente tiene lugar la formación del producto de adición-1,4. Una vez que estas estructuras podrían constituir interesantes materiales quirales de partida para la síntesis de compuestos con potencial actividad biológica, decidimos intentar obtener la versión asimétrica de esta reacción. No obstante, no obtuvimos cualquier resultado empleando aminas quirales, ácidos de Lewis e, incluso, una estrategia de doble activación.
Curiosamente, descubrimos que, al emplear derivados sulfonilimínicos de (E,E)-cinamilidenoacetofenonas como sustratos, la regioselectividad de la reacción sufría un cambio drástico. Para nuestra grata sorpresa, obtuvimos, por primera vez en adiciones conjugadas, el producto de adición-1,6 de un nucleófilo a iminas conjugadas. A continuación se intentó la optimización de las condiciones de reacción. No obstante, los productos de adición-1,6 apenas pudieron ser obtenidos con rendimientos bajos a moderados (hasta el 49%) debido a la formación en simultáneo de otros tres compuestos: un producto de adición-1,2 con pérdida del grupo sulfonamida, un producto de doble adición 1,2/1,4 y la (E)-1,5-diaril-3-nitrometil-4-penten-1-ona. Lejos de estar terminado, este estudio ha llevado a nuevas cuestiones, todavía por contestar, sobre los factores que controlan la regioselectividad en reacciones de adición en sistemas altamente conjugados.
BINAP – 2,2´-Bis(diarylphosphino)-1,1´-binaphthyl BINOL - 1,1′-Bi(2-naphthol)
BOX - Bisoxazolines
CAMP - (S)-Cyclohexyl(2-methoxyphenyl)(methyl)phosphine CLPB - Chiral phosphine Lewis base
COSY – 1H/1H Correlation spectroscopy
Cp - Cyclopentadienyl
CuTC – Copper(I) thiophene carboxylate DABCO – Diaza[2.2.2]bicyclooctane DBU - Diaza(1,3)bicyclo[5.4.0]undecane DDQ – 2,3-Dichloro-5,6-dicyano-p-benzoquinone DIPEA - Diisopropylethylamine DMAP - Dimethylaminopyridine DMD - Dimethyldioxirane DMF – N,N-Dimethylformamide
DPPBA – 2-(Diphenylphosphino)benzoic acid dppf – 1,1´-Bis(diphenylphosphino)ferrocene DVB – Divinylbenzene
Ee – Enantiomeric excess
EI – Electron impact (mass spectrometry technique) Eq. - Equivalent
ESI - Electrospray (mass spectrometry technique) EWG – Electron withdrawing group
FAB - Fast atom bombardment (mass spectrometry technique) Fc - Ferrocene
HMG-CoA – 3-Hydroxy-3-methyl-glutaryl-Coenzime A HPLC – High pressure liquid Chromatography
HRMS – High resolution mass spectrometry
HSQC - 1H/13C Heteronuclear single quantum coherente spectroscopy
KHDMS - Potassium hexamethyldisilazide
MAS NMR - 1H Magic-Angle Spinning Nuclear Magnetic Resonance
MBH – Morita-Baylis-Hillman
MBHR - Morita-Baylis-Hillman reaction
m-CPBA - meta-Chloroperbenzoic acid
Me - Methyl Mp – Melting point MS – Molecular sieves
NMR – Nuclear magnetic resonance NOE – Nuclear overhauser effect
NOESY - 1H/1H Nuclear overhauser effect spectroscopy
OTf – Triflate (trifluoromethanesulfonate) PCy3 - Tricyclohexylphosphine PPh3 - Triphenylphosphine PS – polymer supported PTA – 1,3,5-triaza-7-phosphaadamantene QD – Quinidine derivative rac – Racemic (R)-LPB – (R)-LaK3trisbinaphthoxide (R,R)-DBFOX/Ph – (R,R)-4,6-Dibenzofurandiyl-2,2´-bis(4-phenyloxazoline) Rt – Room temperature
t-Bu – tert-Butyl
THF – Tetrahydrofuran TIPS – Triisopropylsilyl
TIPSCl – Triisopropylsilyl chloride TLC – Thin layer chromatography
TMP - 2,2,6,6-Tetramethylpiperidin-4-ylamine VO(acac)2 – Vanadyl acetylacetonate
1. INTRODUCTION TO PhD THESIS
1
1.1 PhD thesis general approach 3
1.1.1 Asymmetric catalysis 3
1.1.2 Chemistry of heterocyclic compounds 7
2. FERROCENYLPHOSPHINES AS CATALYSTS FOR THE
MORITA-BAYLIS-HILLMAN REACTION
11
2.1 Introduction: The Morita-Baylis-Hillman reaction 13
2.1.1 General aspects 13
2.1.2 Reaction’s limitations vs chemical and physical solutions 15
2.1.3 Chemical parameters 16 Substrate structure 16 Hydrogen bonding 17 Salt effects 20 Co-catalysis 21 2.1.4 Physical parameters 22 Pressure 22 Microwaves 23 Ultrasound radiation 23 Temperature 24 2.1.5 Phosphines as catalysts 24
2.1.7 Enantioselective Morita-Baylis-Hillman reaction 32
2.2 Objectives 36
2.3 Ferrocenylphosphines as catalysts for the Morita-Baylis-Hillman reaction 39
2.3.1 Synthesis of ferrocenylphosphines 39
2.3.2 Reaction conditions 39
2.3.3 Reaction scope 41
2.3.4 Enantioselective approach 44
2.4 Conclusions 50
3. POLYMER-SUPPORTED FESULPHOS LIGANDS AND THEIR
APPLICATION IN ASYMMETRIC CATALYSIS
51
3.1 Introduction: Heterogeneous asymmetric catalysis 53
3.1.1 Synthesis of enantiomerically pure compounds 53
3.1.2 Strategies for heterogeneous asymmetric catalysis 55
3.1.3 Immobilization of chiral homogeneous catalysts 57
3.1.4 Immobilization of privileged chiral catalysts 58 3.1.5 Immobilized chiral ferrocene homogeneous catalysts 62
3.2 Fesulphos chiral ligands 65
3.2.1 Synthesis of Fesulphos ligands 66
3.2.2 Application of Fesulphos ligands in asymmetric catalysis 68
Pd-catalyzed allylic substitution 68
Diels-Alder reaction catalyzed by Pd(II) and Cu(I) Lewis acids 69 Aza-Diels-Alder reaction catalyzed by Pd(II) and Cu(I) Lewis acids 70
Ring-opening of meso-heterobicyclic alkenes 71 Mannich-type reactions of N-sulfonylimines catalyzed by Fesulphos-Cu(I)
complexes 71
1,3-Dipolar cycloaddition of azomethine ylides 72
3.3 Objectives 74
3.4 Polymer-supported Fesulphos ligands and their application in asymmetric
catalysis 76
3.4.1 Synthesis of functionalized Fesulphos ligands and immobilization on polymeric
resins 76
3.4.2 Application of immobilized Fesulphos to 1,3-dipolar cycloaddition 90
3.4.3 Recovery and reuse of PS-54 94
3.5 Conclusions 98
4. NITROMETHANE ADDITION TO CONJUGATED SYSTEMS
101
4.1 Introduction: Asymmetric conjugate addition 103
4.1.1 Nitroalkane enantioselective conjugate addition 103
Chiral amine catalysts 104
Lewis acid and double activation catalysis 108
Other chiral catalysts 110
4.2 Activated dienes 112
4.2.1 Organocatalytic 1,6-conjugate addition 112
4.2.2 Organometallic 1,6-conjugate addition 116
4.3 Group precedents 118
4.3.2 Nitromethane addition to (E)-cinnamylideneacetophenones 120
4.4 Objectives 122
4.5 Nitromethane addition to polyconjugated systems 124
4.5.1 Synthesis of (E,E)-cinnamylideneacetophenones 124
4.5.2 Nitromethane conjugate addition to (E,E)-cinnamylideneacetophenones 125 4.5.3 Asymmetric nitromethane addition to (E,E)-cinnamylideneacetophenones 127
Basic chiral organocatalysts 127
Use of double catalysis: Chiral Lewis acid and amine catalysts 128 4.5.4 Synthesis of sulfonylimine derivatives of cinnamylideneacetophenones 132 4.5.5 Conjugate additions of nitromethane to sulfonylimine derivatives of
(E,E)-cinnamylideneacetophenones 134
Optimization of reaction parameters: influence on regioselectivity 126 4.6 Structural characterization of conjugate addition products 144
4.7 Conclusions 148
5. EXPERIMENTAL DETAILS
151
5.1 Experimental 153
General techniques 153
Solvents and reagents 154
5.2 Ferrocenylphosphines as catalysts for the Morita-Baylis-Hillman reaction 156
Synthesis of ferrocenyl phosphines (26a-c) 156
Synthesis of Fesulphos ligands (1a-c) 157
5.3 Synthesis of polymer-supported Fesulphos ligands and their application in
asymmetric catalysis 168
Synthesis of polymer-supported Fesulphos ligands 168
Synthesis of aryliminoesters (52) 176
1,3-Dipolar cycloaddition catalyzed by PS-54 and PS-69 177
Recycling experiments 180
5.4 Nitromethane conjugate addition 181
Synthesis of cinnamaldehyde derivatives 181
Synthesis of cinnamylideneacetophenone derivatives 182 Synthesis of α,β,γ,δ-unsaturated ketimines 186 Conjugate addition of nitromethane to cinnamylideneacetophenone and its
derivatives 191
Conjugate addition of nitromethane to sulfonylimine derivatives of
cinnamylideneacetophenone 193
CHAPTER 1:
1.1
PhD THESIS GENERAL APPROACH
The present PhD thesis resulted from my working experience in two different research groups:
Professor Juan Carlos Carretero’s group, at the Organic Chemistry Department of the Universidad Autónoma de Madrid, whose field of expertise consists in the study of asymmetric catalytic systems;
Professor Artur M. S. Silva’s group, at the Chemistry Department of the
Universidade de Aveiro, whose main area of research is the chemistry of heterocyclic
compounds.
The opportunity to work in groups with such different scientific backgrounds has greatly contributed to expand my scientific formation in two important areas of organic chemistry and also to gradually complement the knowledge obtained from each research area. In order to understand the general approach chosen for the current PhD thesis we will briefly illustrate the main research areas of both groups.
1.1.1 Asymmetric catalysis
The long experience of Prof. Carretero’s group on asymmetric catalysis started with the application of sulfoxides as chiral auxiliaries in asymmetric reactions, such as the intramolecular Heck reaction1 and the intramolecular Pauson-Khand reaction (Scheme 1.1).2
1. a) Buezo, N. D.; Mancheño, O. G.; Carretero, J. C. Org. Lett. 2000, 2, 1451. b) Buezo, N. D.; de la Rosa, J. C.; Priego, J.; Alonso, I.; Carretero, J. C. Chem. Eur. J. 2001, 7, 3890. c) Alonso, I.; Carretero, J. C. J. Org. Chem. 2001, 66, 4453.
2. a) Carretero, J. C.; Adrio, J. Synthesis, 2001, 12, 1888. b) Rivero, M. R.; de la Rosa, J. C.; Carretero, J. C. J. Am. Chem. Soc. 2003, 125, 14992. c) Rivero, M. R.; Alonso, I.; Carretero, J. C. Chem. Eur. J. 2004, 10, 5443. d) Rivero, M. R.; Adrio, J.; Carretero, J. C. Synlett, 2005, 1, 26.
Me E I E n S O Pd(OAc)2 Ag2CO3 E E n S O NMe2 n = 1,2 ee > 95% Heck Reaction NMO CH3CN, rt up to >98:<2 in A:B ratio Pauson Khand Reaction
nBu Co2(CO)6 + S Ar O Bun O S H O Ar Bun O S H + A B Ar O NMe2 Scheme 1.1
Encouraged by the good results obtained, other electron-poor sulfur groups, such as sulfones, were also tested as stereochemical controllers and found to be as effective, in both Heck3 and Pauson-Khand reactions (Scheme 1.2).2d,4
Ag2CO3 DMF, 120oC PhI Pd(OAc)2 SO2 NMe2 R O2 S N Me2 Pd R Ph R H SO2 Ph β-H elimination R = iPr, 85% R = nPent, 70% Heck reaction SO2Ph R1 R3O R2 R2 a) [Co2(CO)8] CH2Cl2, rt b) Me3NO CH2Cl2, rt O O R2 R2 R2 R2 SO2Ph SO2Ph H R3O H R3O R1 R1 + endo exo Pauson-Khand reaction up to >98:<2 in endo:exo ratio NMe2 Scheme 1.2
2. d) Rivero, M. R.; Adrio, J.; Carretero, J. C. Synlett, 2005, 1, 26.
3. a) Mauleón P.; Alonso, I.; Carretero, J. C. Angew. Chem. Int. Ed. 2001, 40, 1291.
4. a) Adrio, J.; Rivero, M. R.; Carretero, J. C. Angew. Chem. Int. Ed. 2000, 39, 2906. b) Adrio, J.; Rivero, M. R.; Carretero, J. C. Chem. Eur. J. 2001, 7, 2435.
Being vinyl sulfones such interesting substrates other lines of research were also explored, namely as activated alkenes in enantioselective organometallic conjugate addition of boronic acids (Scheme 1.3)5 and 1,3-dipolar cycloadditions of azomethine ylides.6 R SO2Py + ArB(OH)2 Rh(acac)(C2H4)2 (3 mol%) Dioxane:H2O, 100oC (3 mol%) PPh2 PPh2 R SO2Py Ar KHDMS R'CHO R Ar R' 84-98% yield 76-92% ee > 90% yield major or only E Scheme 1.3
The high reactivity of these vinyl sulfones in catalytic asymmetric organometallic reactions heavily relies on the presence of a metal-coordinating group in the sulfone moiety, namely a pyridyl ring. Since the coordinating sulfonyl groups were also electron-deficient their introduction on imines was also studied, confirming their activating effect on these poor Michael acceptors. 2-Pyridyl and (8-quinolyl)sulfonylimines proved to be very effective as substrates for the enantioselective conjugate addition of dialkylzinc reagents (Scheme 1.4),7 the Aza-Friedel-Crafts reaction,8 the inverse-electron-demand Diels Alder reaction9 and the addition of bromoalkylzinc reagents.10
Ar1 Ar2 Ar1 Ar2 NH S O O N Me 72-91% yield 70-80% ee Me2Zn +
(2.0 eq.) CuTC (10 mol%) Toluene, -20oC (10 mol%) O O P N Me Me Ph Ph N S O O N Scheme 1.4
5. a) Mauleón, P.; Carretero, J. C. Org. Lett. 2004, 6, 3195. b) Mauleón, P.; Carretero, J. C. Chem. Commun. 2005, 4961.
6. Llamas, T.; Arrayás, R. G.; Carretero, J. C. Org. Lett. 2006, 8, 1795. 7. Esquivias, J.; Arrayás, R. G.; Carretero, J. C. J. Org. Chem. 2005, 70, 7451. 8. Esquivias, J.; Arrayás, R. G.; Carretero, J. C. Angew. Chem. Int. Ed. 2006, 45, 629. 9. Esquivias, J.; Arrayás, R. G.; Carretero, J. C. J. Am. Chem. Soc. 2007, 129, 1480. 10. Esquivias, J.; Arrayás, R. G.; Carretero, J. C. Angew. Chem. Int. Ed. 2007, in press.
Another important area of research in Prof. Carretero’s group has been the development of new chiral catalysts. Therefore, in the last few years, a great deal of attention has been given to the synthesis of a family of chiral ferrocene ligands, the 1-phosphino-2-sulfenylferrocenes,11 generally known as Fesulphos ligands (1), that later proved to be very effective and of generalized application (Figure 1.1). These bidentate ligands, with P,S coordination, have exclusively planar chirality and have been applied successfully to a number of important enantioselective organometallic reactions such as: enantioselective palladium and copper-catalyzed reactions, allylic substitution, Diels-Alder and formal aza-Diels-Alder reactions of N-sulfonylimines, ring-opening of meso-heterobicyclic alkenes, 1,3-cycloaddition of azomethine ylides, and Mannich-type reactions of N-sulfonylimines.11,12 The Fesulphos ligands and their application will be further detailed in Chapter 3 of this dissertation.
Other ferrocene-based ligands were also developed and applied in asymmetric catalysis such as a family of ligands with N,S coordination, the 2-amino-substituted 1-sulfinyllferrocenes (2),13 as well as planar chiral bisferrocenes bearing sulfur 3 or nitrogen substituents 4.14 Another metallocene ligand, based on a (η5-cyclopentadienyl)( η4 -cyclobutadiene) cobalt backbone and with P,S-coordination, Cosulphos (5), was also prepared and used with efficiency in enantioselective palladium-catalyzed allylic substitutions15 (Figure 1.1).
11. a) Priego, J.; García Mancheño, O.; Cabrera, S.; Gómez Arrayás, R.; Llamas, T.; Carretero, J. C. Chem. Commun. 2002, 2512. b) García Mancheño, O.; Priego, J.; Cabrera, S.; Gómez Arrayás, R.; Llamas, T.; Carretero, J. C. J. Org. Chem. 2003, 68, 3679.
12. a) García Mancheño O.; Gómez-Arrayás, R.; Carretero, J. C. J. Am. Chem. Soc. 2004, 126, 456. b) Cabrera, S.; Gómez-Arrayás, R.; Carretero, J. C. Angew. Chem. Int. Ed. 2004, 43, 3944. c) García Mancheño, O.; Gómez Arrayás, R.; Carretero J. C. Organometallics 2005, 24, 557. d) Cabrera, S.; Arrayás, R.; Carretero, J. C. J. Am. Chem. Soc. 2005, 127, 16394. e) Cabrera, S.; Arrayás, R.; Alonso, I.; Carretero, J. C. J. Am. Chem. Soc. 2005, 127, 17938. f) Salvador, A.; Gómez-Arrayás, R.; Carretero, J. C. Org. Lett., 2006, 8, 2977.
13. a) Priego, J.; García Mancheño, O.; Cabrera, S.; Carretero, J. C. Chem. Commun. 2001, 2026. b) Priego, J.; García Mancheño, O.; Cabrera, S.; Carretero, J. C. J. Org. Chem. 2002, 67, 1346.
14. Arrayás, R. G.; Alonso, I.; Familiar, O.; Carretero, J. C. Organometallics, 2004, 23, 1991. 15. Arrayás, R. G.; Mancheño, O. G.; Carretero, J. C. Chem. Commun. 2004, 1654.
Fe S-t-Bu PR2 Fesulphos (1) Co S-t-Bu PR2 Ph Ph Ph Ph Cosulphos (5) Fe Fe S S O O t-Bu t-Bu HO H Fe Fe HO Ph N O N O t-Bu t-Bu Bisferrocene 3 Bisferrocene 4 Fe S-t-Bu NHR 1-Sulfenyl-2-aminoferrocenes (2) Figure 1.1
1.1.2 Chemistry of heterocyclic compounds
Prof. Silva’s research activity has focused on the synthesis, chemical transformation and biological activity evaluation of heterocyclic compounds from three main structural groups: chromones (2-styrylchromones 6 and 3-styrylchromones 7), xanthones 8 and pyrazoles 9, as well as compounds derived from some of the previously mentioned structural groups (Figure 1.2).
O O N H N Pyrazoles 9 (E)-2-Styrylchromones 6 A B 2 3 4 5 10 6 7 8 9 α β 1' 2' 3' 4' 5' 6' (E)-3-Styrylchromones 7 O O A 2 3 4 5 10 6 7 8 9 α β 1' 2' 3' 4' 5' 6' B O O Xanthones 8 OH Figure 1.2
Among the scientific reports published by Prof. Silva’s group on efficient synthetic routes we can refer, for example, the synthesis of benzo[b]xanthones,16
diarylxanthones,17 hydroxy-2-styrylchromones,18 3-styrylchromones,19 pyrazoles,20 bis(pyrazoles),21 or styrylpyrazoles.22
In the last few years the group has also explored the application of new synthetic methodologies such as the microwave-assisted organic synthesis.23 The use of microwave radiation has been reported to increase the rate of organic reactions and, in some cases, change the reaction’s selectivity.
An example of the successful use of microwave is the synthesis of xanthones from 3-styrylchromones 10 acting as dienes in Diels-Alder reactions with N-phenylmaleimide 11. After initial results indicating that under classical heating conditions 3-styrylchromones are reluctant to react in Diels-Alder reactions,24 the use of microwave radiation proved to be a very effective alternative for introducing energy into these reactions, and thus achieve the synthesis of xanthones (Scheme 1.5).23a
17. Santos, C. M. M.; Silva, A. M. S.; Cavaleiro, J. A. S. Synlett, 2005, 20, 3095. 18. Santos, C. M. M.; Silva, A. M. S.; Cavaleiro, J. A. S. Eur. J. Org. Chem. 2003, 4575.
19. a) Sandulache, A.; Silva, A. M. S.; Pinto, D. C. G. A.; Almeida, L. M. P. M.; Cavaleiro, J. A. S. New. J. Chem. 2003, 1592. b) Silva, V. L. M.; Silva, A. M. S.; Pinto, D. C. G. A.; Cavaleiro, J. A. S.; Patonay, T. Synlett, 2004, 2717.
20. a) Pinto, D. C. G. A.; Silva, A. M. S.; Lévai, A.; Cavaleiro, J. A. S.; Patonay, T.; Elguero, J. Eur. J. Org. Chem. 2000, 2593. b) Lévai, A.; Silva, A. M. S.; Cavaleiro, J. A. S.; Alkorta, I.; Elguero, J.; Jekő, J. Eur. J. Org. Chem. 2006, 2825.
21. Lévai, A.; Silva, A. M. S.; Pinto, D. C. G. A.; Cavaleiro, J. A. S.; Alkorta, I.; Elguero, J.; Jekő, J. Eur. J. Org. Chem. 2004, 4672.
22. a) Silva, V. L. M.; Silva, A. M. S.; Pinto, D. C. G. A.; Cavaleiro, J. A. S.; Elguero, J. Eur. J. Org. Chem. 2004, 4348. b) Silva, V. L. M.; Silva, A. M. S.; Pinto, D. C. G. A.; Cavaleiro, J. A. S.; Elguero, J. Eur. J. Org. Chem. 2007, 3859.
23. a) Pinto, D. C. G. A.; Silva, A. M. S.; Brito, C. M.; Sandaluche, A.; Carrillo, J. R.; Prieto, P.; Díaz-Ortiz, A.; de la Hoz, A.; Cavaleiro, J. A. S. Eur. J. Org. Chem. 2005, 2973. b) Pinto, D. C. G. A.; Silva, A. M. S.; Cavaleiro, J. A. S. Synlett, 2007, 12, 1897.
24. Pinto, D. C. G. A.; Silva, A. M. S.; Almeida, L. M. P. M.; Carrillo, J. R.; Díaz-Ortiz, A.; de la Hoz, A.; Cavaleiro, J. A. S. Synlett, 2003, 1415.
O O R R = H (a), Cl (b), OEt (c) O O + NMe O O A: 1,2,4-trichlorobenzene, reflux, N2 B: DDQ, 1,2,4-trichlorobenzene NMe O O R 10 O O NMe O O R 12, 40-41% + O O NMe O O R O O NMe O O R 13, up to 47% A, 18-24 h MW B, MW MW = microwave 30 mins 12, 75-77% 13, 67-74% 11 Scheme 1.5
Another important area of work of Prof. Silva’s group consists in the evaluation of the biological activity some of these heterocyclic compounds present, through structure/activity studies (commonly designated SAR). In order to do so, collaborations have been established with several research groups in the areas of biology and medicinal chemistry. 2-Styrylchromones, for example, of which several analogues have been synthesized and tested in different biological systems, showing different activities with potential therapeutic application, have been the subject of Prof. Silva’s SAR studies. Polyhydroxylated 2-styrylchromones (14) have been confirmed to have hepatoprotective activity against tert-butylhydroperoxide-induced toxicity in freshly isolated rat hepatocytes.25 The hydroxylation pattern of 2-styrylchromones was also found to be important in the modulation of these compounds function as scavengers for reactive oxygen species (ROS) and reactive nitrogen species (RNS),26 such as the known free radicals (Figure 1.3).
25. Fernandes, E.; Carvalho, M.; Carvalho, F.; Silva. A. M. S.; Santos, C. M. M.; Pinto, D. C. G. A.; Cavaleiro, J. A. S.; Bastos, M. L. Arch. Toxicol. 2003, 77, 500.
26. Gomes, A.; Fernandes, E.; Silva. A. M. S.; Santos, C. M. M.; Pinto, D. C. G. A.; Cavaleiro, J. A. S.; Lima, J. L. F. C. Bioorg. Med. Chem. 2007, 17, 6027.
O
O
Hydroxylated positions in 2-styrylchromones (14)
Figure 1.3
Prof. Silva’s study of natural compounds has also extended to the full characterization, through spectroscopic techniques, of compounds isolated from plant material.27 The use of NMR experiments, in particular, is one of the group’s strongest points, and has been applied in spectroscopic studies of heterocyclic structures such as the aminoflavones (Figure 1.4).28
O O H R1 R2 R3 H R7 R6 R5 R4 H R4, R5, R6 or R7 = NH 2 R1, R2 or R3 = OMe
Figure 1.4 – Typical connectivities found in flavones HMBC spectra.
27. Kijjoa, A.; Gonzalez, M. J.; Pinto, M. M. M.; Silva, A. M. S.; Anantachoke, C.; Herz, W. Phytochemistry, 2000, 55, 833.
CHAPTER 2:
FERROCENYLPHOSPHINES AS CATALYSTS FOR THE MORITA-BAYLIS-HILLMAN REACTION
2.1
INTRODUCTION: THE MORITA-BAYLIS-HILLMAN REACTION
2.1.1 General aspects
The Morita-Baylis-Hillman reaction (MBHR) is a C-C bond forming reaction that allows the direct preparation of multifunctional molecules and may be generally defined as a “reaction between the α-position of activated alkenes and carbon electrophiles containing an electron-deficient sp2 carbon atom under the influence of a suitable catalyst, particularly a tertiary amine”.29
The reaction, as it is commonly known, was considered to have its origin in a patent granted to Baylis and Hillman,30 of the Celanese Corporation of New York, in 1972. According to the review of Drewes and Roos,31 the authors describe the reaction between α,β-unsaturated esters, nitriles, amides or ketones with a broad spectrum of aldehydes, using cyclic tertiary amines, like the widely used diaza[2.2.2]bicyclooctane (DABCO), as catalysts (Scheme 2.1).
H R1
+ Base
O
H R
R1=ester, nitrile, amide, ketone
R R
1 OH
Scheme 2.1
Nevertheless, and in spite of the fact that this reaction is attributed to Baylis and Hillman, there is a report from Oda,32 dating as far back as 1964, of the reaction of acrylics and benzaldehyde catalyzed by triphenylphosphine, in equimolar proportions, yielding “Wittig-type” products (Scheme 2.2).
H R2 + PPh3 (equimolar) O H R1 R 1 R1= Alkyl, Ph, substituted Ph 130 to 140oC, 6h R2 R2= CO2R,CN 9-45% yield Scheme 2.2
29. Basavaiah, D.; Rao, P. D.; Hyma, R. S. Tetrahedron, 1996, 52, 8001.
30. Baylis, A. B.; Hillman, M. E. D. German Patent 2155113, Chem. Abs. 1972, 77, 34174q. 31. Drewes, S. E.; Roos, G. H. P. Tetrahedron, 1988, 44, 4653.
Later, in 1968, Morita33 employed a catalytic amount of tricyclohexylphoshine to catalyze the same reaction, reporting for the first time the isolation of 2-hydroxyalkyl derivatives of acrylate and related systems (Scheme 2.3).
H R2 + PCy3 (catalytic) O H R1 R1 R1= Alkyl, Ph, substituted Ph 120 to 130oC, 2h R2 R2= CO2R,CN up to 85% yield OH Scheme 2.3
The currently known as Morita-Baylis-Hillman reaction (MBHR) may be considered a three component reaction and the most widely accepted mechanism for the amine-catalyzed reaction is believed to proceed through a Michael-initiated addition-elimination sequence.34,35 Considering a model case reaction between an acrylic ester (activated olefin) and an aldehyde (electrophile), catalyzed by DABCO, two steps seem to be involved (Scheme 2.4):
Michael-type nucleophilic addition of the tertiary amine to the activated alkene 16 to produce a zwitterionic36 enolate 17, which then performs an aldolic-type nucleophilic attack on the aldehyde 15 to generate zwitterion 18.
Subsequent proton migration and release of the catalyst provide the multifunctional molecule 20. N N N N OR2 O N N OR2 O H R1 O N N OR2 O H H R1 O N N O OR2 H OH R1 + R1 CO2R 2 OH K1 K2 STEP 2 STEP 3 15 16 17 18 19 20 R2 = alkyl, aryl R1 = alkyl, aryl Scheme 2.4
33. Morita, K.; Suzuki, Z.; Hirose, H. Bull. Chem. Soc. Jpn. 1968, 41, 2815. 34. Hill, J. S.; Isaacs, N. S. J. Phys. Org. Chem. 1990, 285.
35. Basavaiah, D.; Rao, A. J.; Styanarayana, T. Chem. Rev. 2003, 103, 811.
36. Zwitterion (from German “Zwitter”- “hybrid”) is a chemical compound that is electrically neutral but carries formal positive and negative charges on different atoms.
Although the MBHR has been broadly described as a condensation of an electron-deficient alkene and an aldehyde catalyzed by a tertiary amine or phosphine, imines can also participate in the reaction if they are adequately activated. In this case the process is commonly referred to as the aza-Morita-Baylis-Hillman reaction.37
2.1.2 Reaction’s limitations vs chemical and physical solutions
Being a reaction with three different components it has developed into an ever growing multitude of possible reactions, some of which are summarized in the following scheme (Scheme 2.5).35 + DABCO (catalyst) R 1= H EW G= C ON H2 RCHO EWG R1 • COOMe R OH EW G= SO 3 Ph SO3Ph R OH R1= H R1= H EW G= C N CN R OH EWG= COOMe EWG= COOR2 R1= H 9-10 K bar EW G= SO Ph COOR2 R OH EW G= COR 2 R1 = H COR2 R OH R1 = H EW G = CH O CHO R OH R 1 = H E W G = S O 2P h SO2Ph R OH COOMe Me OH CN Me OH SOPh R OH CONH2 Me OH PO(OEt)2 R OH R 1= H R=R 1= Me 9-10 K bar EWG= COOM e R=R1= Me 9-10 Kbar EWG= CN R1 = H E W G = P O (O E t) 2 R= P h, M e: R1 = H Scheme 2.5
However, this reaction is still often hampered by low reaction rates (reactions lasting a week or more are common) and chemical yields highly sensitive to the
35. Basavaiah, D.; Rao, A. J.; Styanarayana, T. Chem. Rev. 2003, 103, 811. 37. Shi, Y. -L.; Shi, M. Eur. J. Org. Chem. 2007, 18, 2905.
substitution at both the aldehyde and Michael acceptor partners. As illustrated on Scheme 2.5, activated alkenes with β-substituents such as crotononitrile, crotonic acid esters, less reactive alkenes such as phenyl vinyl sulfoxide or even electrophiles like simple ketones, require high pressure to undergo this reaction.
Therefore, the applicability of the MBHR is very often limited and for this reason several of the reaction determining parameters (chemical and physical) have been studied and modified in an attempt to overcome these limitations.
2.1.3 Chemical parameters
The use of higher catalyst loadings has been reported by several authors in an attempt to improve yields and reaction rates.29-31. Since this strategy was not always successful, attention was focused on the effect of other factors such as substrate structure, hydrogen bonding (solvent effect, bifunctional catalysts, protic additives), salt effects, co-catalysis by Lewis acids.
Substrate structure
The Morita-Baylis-Hillman reaction is known to be highly substrate-dependent. Namely, the electrophilicity of the electrophilic component is of obvious importance. Therefore, as should be expected, aldehydes undergo the reaction more readily than aldimines, ketones or ketoesters.29
Some authors also consider that the electronic and steric characteristics of the ester part of the activated vinylic system must play an important role in the reactivity of acrylic esters.38 According to the generally accepted mechanism proposed by Hill and Isaacs,34 electron-withdrawing properties of the ester group (CO2R) would increase the impoverishment of the unsaturation and favor the formation of zwiterionic intermediate 17 (Scheme 2.4).
Fort et al.38 found that functionalized alkyl acrylates react faster than simple alkyl acrylates, and aryl acrylates react more readily than alkyl acrylates.
29. Basavaiah, D.; Rao, P. D.; Hyma, R. S. Tetrahedron, 1996, 52, 8001.
30. Baylis, A. B.; Hillman, M. E. D. German Patent 2155113, Chem. Abs. 1972, 77, 34174q. 31. Drewes, S. E.; Roos, G. H. P. Tetrahedron, 1988, 44, 4653.
34. Hill, J. S.; Isaacs, N. S. J. Phys. Org. Chem. 1990, 285.
The presence of an aromatic group may reduce substantially the reaction rate, generating products in less time and higher yields,39 as observed by Lee et al. when using naphthyl acrylate (Scheme 2.6).40
PhCHO, CH3CN rt CO2R DABCO (50 mol%) CO2R Ph OH R Time Yield (%) Me 48h 62 Ph 2h 86 α-Naphthyl 20 min 88 Scheme 2.6
Similar results were also published by Bode and Kaye,41 who reported that methyl acrylate reacts faster than ethyl or isopropyl acrylate and attributed this fact to an electron-releasing inductive effect.
Hydrogen bonding
Some enhancements in the reaction rate are also attributed to the involvement of hydrogen bonding and, once again, these assumptions are based on the mechanism proposed by Hill and Isaacs.34 It is assumed that, since the nucleophilic attack of the dipolar enolate 17 (Scheme 2.4) to the aldehyde is the rate determining step, the hydrogen bonding can be responsible for the rate enhancement in two ways: 1) by stabilizing the tertiary amine alkene adduct, which would increase the zwitterionic adduct 17 concentration; 2) and/or by activating the aldehyde.
A good example is the introduction of a hydroxyl group at the terminal position of alkyl acrylates in their reaction with benzaldehyde, using DABCO as catalyst.42 It was shown that hydroxyalkyl acrylates react faster than the non-hydroxylated counterparts (Scheme 2.7).
39. Perlmutter, P.; Puniani, E.; Westman, G. Tetrahedron Lett. 1996, 37, 1715. 40. Lee, W. B.; Yang, K. S.; Chen, K. Chem. Commun. 2001, 1612.
41. Bode, M. L; Kaye, P. T. Tetrahedron Lett. 1991, 32, 5611. 42. Basavaiah, D; Sarma, P. K. S. Synth. Commun. 1990, 20, 1611.
PhCHO + PhCHO + O O CH2OH 8 O O CH3 8 OH O O CH3 8 OH O O CH2OH 8 DABCO DABCO 12 days 6 days reaction incomplete 78% yield (only 70% conversion) Scheme 2.7
The presence of the hydroxyl group would probably play a role in the stabilization of enolate 21 or the activation of aldehyde 22, as illustrated in Figure 2.1.
Me3N O O H O n Me3N O O O n 21 22 H O R H Figure 2.1
A similar effect was observed when the hydroxyl group was present on the catalyst. For example, the α-hydroxyalkylations of methyl acrylate with different aldehydes were approximately three times faster when 3-hydroxyquinuclidine was used instead of DABCO.31,43,44
This hydrogen bonding interaction may also be the explanation for the rate accelerating effect of protic solvents like methanol,45 ethylene glycol or water.46 As solvents, they may be responsible for a higher solvation of both the enolate and the ammonium cation, displacing the addition of the tertiary amine to the Michael acceptor
31. Drewes, S. E.; Roos, G. H. P. Tetrahedron, 1988, 44, 4653.
43. Ameer, F.; Drewes, S. E.; Freese, S.; Kaye, P. T. Synth. Commun. 1988, 8, 495. 44. Structures of DABCO, quinuclidine and 3-hydroxyquinuclidine:
N OH 3-hydroxyquinuclidine N quinuclidine N N DABCO
45. Luo, S.; Mi, X.; Xu, H.; Wang, P. G.; Cheng, J. P. J. Org. Chem. 2004, 69, 8413.
46. a) Yu, C.; Liu, B.; Hu, L. J. Org. Chem. 2001, 66, 5413. b) Cai, J.; Zhou, Z.; Zhao, G.; Tang, C. Org. Lett. 2002, 4, 4723. c) Aggarwal, V. K; Dean, D.K.; Mereu, A.; Williams, R. J. Org. Chem. 2002, 67, 510.
(reversible) in the direction of the zwitterionic intermediate. Therefore, strongly polar solvents should provide such solvation and thereby increase reaction rates.
According to Yu et al.,46a. since the reaction sequence involves charged transition states and intermediates, these could be stabilized by polar solvents, such as water, either through intermolecular charge-dipole interactions as well as hydrogen bonding interactions.
In the case of methanol, Luo et al.45 propose a methoxide anion catalysis to explain the good results obtained when using DBU in methanol. In fact, when sodium methoxide was used as catalyst (also in methanol) the reaction proceeded slightly faster when compared with the DBU-promoted reaction, affording the desired product with 98% yield, after 3h (Scheme 2.8).
Catalyst Solvent, rt +
Catalyst (mol%) Solvent Time (h) Yield (%)
DBU (100) neat 24 Traces
DBU (50) MeOH 6 99
DBU (50) MeCN 16 No reaction DBU (50) + MeOH (50) MeCN 24 No reaction
MeONa MeOH 3 98 O Cl CHO O Cl OH Scheme 2.8
Aggarwal et al.46c focused on slower reacting substrates like β-substituted enones and acrylates, as the tert-butyl acrylate (a notoriously slow partner in the Morita-Baylis-Hillman reaction). They found that the rate acceleration observed with water, formamide and N-methylformamide is associated with hydrogen bonding and smaller contributions from hydrophobic effects (with water) and solvent polarity.
Finally, the use of imidazolium-based ionic liquids was also reported as being an effective way of improving the MBHR yield and rate.47 It was thought that this type of stable, inert organic solvents, with their high polarity and ability to solubilise both inorganic
45. Luo, S.; Mi, X.; Xu, H.; Wang, P. G.; Cheng, J. P. J. Org. Chem. 2004, 69, 8413.
46. a) Yu, C.; Liu, B.; Hu, L. J. Org. Chem. 2001, 66, 5413. c) Aggarwal, V. K; Dean, D.K.; Mereu, A.; Williams, R. J. Org. Chem. 2002, 67, 510.
and organic materials, could result in enhanced rates of chemical processes like the MBHR, with higher/different selectivities compared to conventional solvents. Besides they are recyclable.
However, the work of Aggarwal et al.48 later proved that not only the imidazolium salts are not inert, but under mild basic conditions they are deprotonated thus generating reactive nucleophiles which consume the aldehyde (electrophile) leading to lower yields (Scheme 2.9). N N Cl NR3 NR3 = N N N N OH N N PhCHO N N Ph OH Cl Scheme 2.9 Salt effects
A small raise in reaction rates was also observed when either salting-in (GnCl) or salting-out salts (LiCl) were added to water. The indiscriminate effect of both types of salt indicates that hydrophobic effects are not the primary cause for the acceleration, which could be due to the solvation of the ammonium cation, by an increase of the hydrogen bond donor ability of water.46c
The same rate improvement was also obtained when LiClO4 was used as co-catalyst in the reaction of a variety of aldehydes (aromatic and aliphatic) and activated alkenes (vinyl esters, ketones and aldehydes, cyclic enones) catalyzed by DABCO in ethyl ether.49
The rate enhancement or inhibition resulting from salt addition is also attributed by Kumar and Pawar50 to salting-out and salting–in phenomena. However, this salting effect does not conform with conventional definitions as observed in other reactions. Although
46. c) Aggarwal, V. K; Dean, D.K.; Mereu, A.; Williams, R. J. Org. Chem. 2002, 67, 510. 48. Agarwal, V. K; Emme, I.; Mereu, A. Chem. Commun. 2002, 1612.
49. Kawamura, M.; Kobayashi, S. Tetrahedron Lett. 1999, 40, 1539. 50. Kumar, A.; Pawar, S. S. Tetrahedron, 2003, 59, 5019.
the MBHR has negative activation volumes, suggesting that the rate variation in these reactions should be related to hydrophobic or solvophobic effects, their results do not fully agree with the literature. It seems that the cation, anion, nature of solvent and of reactants together define whether a salt will enhance or retard the Morita-Baylis-Hillman reaction.
Co-catalysis
Another parameter of the reaction whose variation has been subject of several studies is the catalyst system. There are several examples illustrating the useful combination of bases and co-catalysts like Lewis acids, or even the use of catalysts having both functions (basic and acidic).
A first attempt to use Lewis acids,51 as activating agents of the aldehyde towards the nucleophilic attack by the zwitterionic intermediate, was performed using the model reaction between benzaldehyde and tert-butyl acrylate catalyzed by DABCO, that under neat conditions took 28 days to reach completion.38
The essays revealed that standard Lewis acids (TiCl4, BF3.OEt2) resulted in deceleration of the reaction. A possible explanation could be the formation of an amine-Lewis acid complex that sequesters the amine, preventing it from acting as a nucleophilic catalyst, and renders the Lewis acid inactive.
The solution, according to Aggarwal et al.,51,52 was to use a harder Lewis acid (more oxophilic), that could weaken the Lewis acid-amine complex, and bind multiple ligands in order to retain the Lewis acid ability. Lanthanides fulfilled the criteria.
The reaction only took place after DABCO reached 10 mol%, at which point the base could start to perform its role as a nucleophilic catalyst and Ln(OTf)y(DABCO)2 24 presumably acted as a Lewis acid, with the reaction occurring via 25 (Scheme 2.10).
38. Fort, Y.; Berthe, M. C.; Caubere, P. Tetrahedron, 1992, 48, 6371. 51. Aggarwal, V. K.; Tarver, G.J.; McCague, R. Chem. Commun. 1996, 2713.
La(OTf)3 La(OTf)x(DABCO) La(OTf)y(DABCO)2 N N N N R O O O N N tBu La (OTf)y(DABCO)2 23 24 25 Scheme 2.10
2.1.4 Physical parameters
PressureBeing a process that involves bond formation and charge separation, MBHR has a very large and negative volume of reaction. Therefore some reports indicate that the Morita-Baylis-Hillman reaction can be accelerated under high pressureconditions.
For example, Hill and Isaacs53 found that the addition of acetone to acrylonitrile, in presence of DABCO (equimolar quantities) and without solvent, proceeded at 25oC, in good yield, after 4-5 days. However, the same result could be achieved by maintaining the reagents at 2-3 Kbar for 1h (Scheme 2.11).
1 atm 4-5 days 2-3 Kbar 1h (Me)2CO + DABCO + CN OH CN OH CN Scheme 2.11
These conditions were also applied to reactions of various acrylate esters and amides with aldehydes and ketones. The most important outcome of these studies was that substrates like ketones an crotonic derivatives were finally brought into the scope of the reaction by applying pressures of 10 Kbar.54
53. Hill, J. S.; Isaacs, N. S. Tetrahedron Lett. 1986, 27, 5007. 54. Hill, J. S.; Isaacs, N. S. J. Chem. Res. 1988, 330.
Other authors also refer the positive effect of high pressure on yields and reaction times of Morita-Baylis-Hillman reactions with other substrates.55
Microwaves
The use of microwaves is also reported as an efficient method to increase reaction rates. A good example is the one of acrylamides that under normal circumstances were usually considered inert substrates for the Morita-Baylis-Hillman reaction, 56 unlike other commonly used substrates like methyl acrylate or acrylonitrile. However, Kundu et al.57 were also able to perform the reaction between acrylamide and 3,4,5-trimethoxybenzaldehyde with a 40% yield under microwave irradiation (Scheme 2.12), although with a lower reaction rate than in the case of the other two acrylic esters used.
RCHO +
Microwaves
(DABCO) R X
OH X
Room Temp. Microwaves
R X Time
(days) Yield (%) Time (min) Yield (%)
2-OHC6H4 CO2CH3 3 10 10 70
4-NO2C6H4 CN 3 45 10 95
3,4,5-(CH3O)3C6H2 CONH2 3 0 25 40
Scheme 2.12
Ultrasound radiation
Ultrasound radiation is still another technique applied to MBHR in an attempt to overcome its limitations. Roos and Rampershad58 reported a rate acceleration in the DABCO-catalyzed α-hydroalkylation of methyl acrylate due to sonication. Another recent study59 also found improvements in the reaction of aromatic aldehydes with different types
55. Schuurman, R. J. W.; Linden, A. V. D.; Grimbergen, R. P. F.; Nolte, R.J.M.; Scheeren, H.W. Tetrahedron, 1996, 52, 8307.
56. Bode, M. L.; Kaye, P. T. J. Chem. Soc., Perkin Trans. I, 1993, 1809.
57. Kundu, M. K.; Mukherjee, S. B.; Balu, N.; Padmakumar, R.; Bhat, S. V. Synlett, 1994, 444. 58. Roos, G. H. P.; Rampershad, P. Synth. Commun. 1993, 23, 1261.
59. Coelho, F.; Almeida, W. P.; Veronese, D.; Mateus, C. R.; Lopes, E. C. S.; Rossi, R. C.; Silveira, G. P. C.; Pavam, C. H. Tetrahedron, 2002, 58, 7437.
of α,β-unsaturated reactants, including some which are prone to polymerize, like acrylonitrile and methyl vinyl ketone.
However, and in spite of the improvements observed when applying pressure, microwave radiation or ultrasounds, these methods require sophisticated and specific equipments, not always available, which effectively reduces their applicability.
Temperature
Finally, temperature is also described as being an important factor when trying to achieve better reaction rates and yields. However, no pattern seems to exist in these variations since either slight increases (43oC)58 and lower temperatures (0oC)60 are referred as being effective.
2.1.5 Phosphines as catalysts
The reaction originally described by Baylis and Hillman is catalyzed by tertiary amine bases, being DABCO one of the most widely used, and the majority of the studies reported from then on have also used amines as catalyst nucleophiles. However, other types of catalysts have also been used: quinidine-derived amines,61,62 azoles,63 imidazolines,64 and L-proline.65
Recently, enzymes were also applied to the catalysis of Morita-Baylis-Hillman reactions, taking advantage of the several types of nucleophilic moieties in the side chains of amino acids present in proteins that could function as catalytical active centres.66 Nevertheless, only low conversions (<35%) were obtained.
An alternative, proposed by some authors, to achieve better results in nucleophilic catalysis is the use of phosphines as catalysts, since their chemistry is also centered on a
58. Roos, G. H. P.; Rampershad, P. Synth. Commun. 1993, 23, 1261. 60. Rafel, S.; Leahy, J. W. J. Org. Chem. 1997, 62, 1521.
61. Iwabuchi, Y.; Nakatani, M.; Yokoyama, N.; Hatakeyama, S. J. Am. Chem. Soc. 1999, 121, 10219. 62. Shi, M.; Jiang, J. -K. Tetrahedron: Asymmetry, 2002, 13, 1941.
63. Luo, S.; Mi, X.; Wang, P. G.; Cheng, J. -P. Tetrahedron Lett. 2004, 45, 5171. 64. Xu, J.; Guan, Y.; Yang, S.; Ng, Y.; Peh, G.; Tan, C.-H. Chem. Asian J. 2006, 724. 65. Tomkinson, N. C. O.; Ruda, A. M.; Davies, H. J. Tetrahedron Lett. 2007, 48, 1461. 66. Reetz, M. T.; Mondière, R.; Carballeira, J. D. Tetrahedron Lett. 2007, 48, 1679.
non-bonded pair of electrons, as in the case of amines, which gives them a nucleophilic character.67
Phosphines are generally less basic and more nucleophilic than similarly substituted amines.68 Nucleophilicity is strongest in trialkylphosphines and decreases with aryl substitution since the buildup of negative charge on phosporus increases with the nucleophilicity of the free electron pair.69
After the first version of this reaction, reported by Morita,33 that used tricyclohexylphosphine as catalyst, and in spite of the rate and yield improvements generally observed, the phosphine-catalyzed variant was explored only sporadically.
Rafel and Leahy60 found that tributylphosphine was the ideal catalyst not only to promote the Morita-Baylis-Hillman reaction in high yields but also to avoid the formation of undesired self-aldol products from the initial aldehyde, especially in cases where aliphatic aldehydes having α-protons were used (Scheme 2.13).
CHO CO2Me + Catalyst Dioxane, rt OH CO2Me
Catalyst Time (days) Yield (%)
DABCO 10 84
Bu3P 2 80
Scheme 2.13
Tributylphosphine was also successfully used in cooperative catalysis with phenols, like BINOL, to give α-methylene-β-hydroxyalkanones in high yields (52% to quantitative).70 Similar results (up to 98% yields) were obtained in the reaction of aldehydes with methyl vinyl ketone using triphenylphosphine as a Lewis base (16 mol%) but only when catalytic amounts of phenols (24 mol%) were added.71
33. Morita, K.; Suzuki, Z.; Hirose, H. Bull. Chem. Soc. Jpn. 1968, 41, 2815. 60. Rafel, S.; Leahy, J. W. J. Org. Chem. 1997, 62, 1521.
67. Methot, J. L.; Roush, W. R. Adv. Synth. Catal. 2004, 346, 1035. 68. Henderson, W. A.; Streuli, C. A. J. Am. Chem. Soc. 1960, 82, 5791. 69. Henderson, W. A.; Buckler, S. A. J. Am. Chem. Soc. 1960, 82, 5794. 70. Yamada, Y. M. A.; Ikegami, S. Tetrahedron Lett. 2000, 41, 2165. 71. Shi, M.; Liu, Y. H. Org. Biomol. Chem. 2006, 4, 1468.
A possible explanation for the lack of reports on the use of phosphines, and especially the highly nucleophilic trialkylphosphines, may be the need to use them under careful experimental conditions. Unlike tertiary amines, trialkylphosphines are highly sensitive to air oxidation and, in some cases, have a pyrophoric character.72
Some strategies were developed to allow an easier handling of trialkylphosphines as catalysts, such as the one reported by Netherton and Fu,72 where phosphines were protected as their conjugate acids (Scheme 2.14).
According to this approach, an oxidation stable, easily handled phosphonium salt was employed as catalyst/reagent precursor, and a weak base [e.g., (i-Pr)2NEt] was used to liberate the desired phosphine through simple acid-base chemistry. Special care was taken so that the chemistry of the phosphonium salts would mimic that of the free phosphine, and so they chose to investigate salts for which the counterion was non-coordinating.
The MBH reaction between cyclopentenone and cinnamaldehyde catalyzed by [(n-Bu)3PH]BF4/PhONa (1:1) afforded the desired product with an isolated yield comparable to that furnished by Ikegami’s procedure using (n-Bu)3P (Scheme 2.14).70
O H O + Catalyst (20 mol%) THF, rt, 1h O OH Catalyst Yield (%) (n-Bu)3P/PhOH (1:1) 96 [(n-Bu)3P]BF4/PhONa (1:1) 94 Scheme 2.14
Later, in 2006, was reported the use of PTA (1,3,5-triaza-7-phosphaadamantane),73 a cage-like water-soluble phosphine, in a MBH reaction of aromatic aldehydes with ethyl (and n-butyl) acrylates and methyl vinyl ketone with moderate to good yields (57-96%).74
70. Yamada, Y. M. A.; Ikegami, S. Tetrahedron Lett. 2000, 41, 2165. 72. Netherton, M. R.; Fu, G. C. Org. Lett. 2001, 3, 4295.
73. Comparative structures of PTA and DABCO:
N N P N PTA N N DABCO
PTA’s nucleophilicity is comparable to other pure trialkylphosphines and its air stability is higher even than triphenylphosphine, when comparing their kinetic constants of oxidation.
Curiously, most of the examples of MBHR catalyzed by nucleophiles, such as phosphines, are of intramolecular reactions. The intramolecular variant of the Morita-Baylis-Hillman reaction was first reported by Fráter, in 1992,75 who described the formation of a five-member ring starting from an α,β-unsaturated-ε-keto-ester and, contrary to the N-bases, phosphines turned out to be useful in this reaction (Scheme 2.15). COOC2H5 O COOC2H5 OH (n-Bu)3P (25 mol%) 1 day, rt 75% yield Scheme 2.15
These results were further investigated and improved by other authors thus allowing the synthesis of functionalized cyclopentenes76 and cyclohexenes,76a or even ring expansion to seven-member rings,76b using either trialkyl or triarylphosphines alone, as nucleophilic catalysts, or as co-catalysts.
2.1.6 Recent mechanistic insights
As previously mentioned, the currently accepted mechanism for the MBH reaction was first proposed by Hill and Isaacs34 and later found consistent with the experimental data of Bode and Kaye.41 According to these authors, the reaction showed pseudo-second order kinetics and sensitivity to variation of both aldehyde 15 substituent (R1) and the alkyl substituent (R2) of acrylate 16.77 For example, a reduction in rate constant (Kobs=K1.K2) was observed with an increasing electron-donating inductive effect of the alkyl substituent (R2). According to the authors this may be due to a destabilisation of the dipolar enolate 17 and consequent decrease in the equilibrium constant K1.77 These electronic effects, as
34. Hill, J. S.; Isaacs, N. S. J. Phys. Org. Chem. 1990, 285. 41. Bode, M. L; Kaye, P. T. Tetrahedron Lett. 1991, 32, 5611. 75. Roth, F.; Gygax, P.; Fráter, G. Tetrahedron Lett. 1992, 33, 1045.
76. a) Frank, S. A.; Mergott, D. J.; Roush, W. R. J. Am. Chem. Soc. 2002, 124, 2404. b) Yeo, J. E.; Yang, X.; Kim, H. J.; Koo, S. Chem. Commun. 2004, 236. c) Krafft, M. E.; Haxel, T. F. N. S. J. Am. Chem. Soc. 2005, 127, 10168. d) Teng, W. -D.; Huang, R.; Kwong, C. K. -W.; Shi, M.; Toy, P. H. J. Org. Chem. 2006, 71, 368. e) Krafft, M. E.; Seibert, K. A. Synlett, 2006, 3334.
