Morita Baylis Hillman Reaction Aaron C. Smith 11/10/04
Outline 1. Background 2. Development of Asymmetric Variants 3. Aza-Baylis Hillman Reaction 4. Applications of Baylis Hillman Adducts
Outline 1. Background 1. Mechanism, Scope of Reaction 2. Advancements in Rate 2. Development of Asymmetric Variants 3. Aza-Baylis Hillman Reaction 4. Applications of Baylis Hillman Adducts
Basic Baylis Hillman Reaction
Background Reported by Morita and coworkers in 1968 used PCy 3 as nucleophilic catalyst Mortia, K., Suzuki, Z., Hirose, H. Bull. Chem. Soc. Jap. 1968, 41, 2815. Baylis and Hillman in 1972 used tertiary amines (DABCO) as nucleophilic catalyst. Baylis, A. B., Hillman, M. E. D. German Patent 2155113, 1972, Chem. Abstr. 1972, 77, 34147q. Applications in complex systems limited by low rates of conversion and substrate dependence of reaction Led to underdevelopment of reaction until 1980 s when 3 o amine variant was further studied Majority of reactions require days-weeks for reasonable conversions Basavaiah, D. et al. Chem. Rev. 2003, 103, 811.
Basavaiah, D. et al. Chem. Rev. 2003, 103, 811. Versatility of Nucleophiles
Basavaiah, D. et al. Chem. Rev. 2003, 103, 811. Versatility of Electrophiles
Basavaiah, D. et al. Chem. Rev. 2003, 103, 811. Mechanism
Temperature Dependence on Rate at rt, reactions takes many days for a variety of different aldehydes in this system at 0 o C, reactions complete in hours proposed explanation: at 0 o C, a greater population of one enolate is formed, leading to more rapid reaction with aldehyde Leahy, J. W. et al. JOC 1997, 62, 1521. Leahy, J. W. et al. Tetrahedron 1997, 53, 16423.
Other Examples of Rate Acceleration Aggarwal, V. K., et al. Chem. Comm. 1996, 2713. Aggarwal, V. K., et al. JOC 1998, 63, 7183. Yu, C. et al. JOC, 2001, 66, 5413. Aggarwal, V. K., et al. Chem. Comm. 1999, 2311.
Rate vs pk a more acidic the catalyst, the slower the rate Aggarwal, V. K., et al. JOC, 2003, 68, 692.
Ikegami, S., et al. TL 2000, 41, 2165. Use of Bronsted Acids
Efficient Catalyst with Titanium Activation Verkade, J. G., et al. ACIEE 2003, 42, 5054.
Conjugate Acids of Phosphines Problems with trialkylphosphines regarding air stability, solved through protection as phosphonium salts: Baylis Hillman reaction proceeds smoothly with the salt Fu, G. et al. Org. Lett. 2001, 3, 4295.
Outline 1. Background 2. Development of Asymmetric Variants 1. Use of Chiral Auxiliaries 2. Chiral Bronsted Acids 3. Chiral Amines 3. Aza-Baylis Hillman Reaction 4. Applications of Baylis Hillman Adducts
Early Examples Gilbert, et. al. Tet: Asymm. 1991, 2, 969. Leahy, et al. Tet. 1997, 53, 16423.
Use of Chiral Sultam Auxiliary yields 33-98%, ee's >99%, reaction times <1 day Works only for aliphatic aldehydes Sultam is expelled from the reaction upon formation of dioxinone leading to recoverable auxiliary. ~ 15 eq. aldehyde are required, however Leahy, J.W. JACS 1997, 119, 4317
Leahy, J.W. JACS 1997, 119, 4317 Proposed Mechanism
Use of Chiral Lewis Acids
Use of Chiral Bronsted Acids
Use of Proline Derivatives in Catalysis
Nagasawa, K., et al. TL 2004, 45, 5589. Use of Bis-thiourea in Catalysis
Use of Chiral Amines
Proposed Mechanism
Outline 1. Background 2. Development of Asymmetric Variants 3. Asymmetric Aza-Baylis Hillman Reaction 4. Applications of Baylis Hillman Adducts
Asymmetric Aza-Baylis Hillman * with methyl acrylate: yields <72%, ee's <83% yields <78 %, ee's < 93% proposed mechanism: proposed H-bonding providing rigid T. S. Shi, M., Xu, Y-M. ACIEE 2002, 41, 4507.
Hatakeyama, S. et al. Org. Lett. 2003, 5, 3103. Asymmetric Aza-Baylis Hillman
Hatakeyama, S. et al. Org. Lett. 2003, 5, 3103. Proposed Mechanism
Asymmetric Aza Baylis Hillman proposed that phosphine utilized as lewis base with phenolic proton utilized as bronsted acid
Outline 1. Background 2. Development of Asymmetric Variants 3. Aza-Baylis Hillman Reaction 4. Applications of Baylis Hillman Adducts
Applications of Baylis Hillman Adducts Leahy, J. W., et al. JACS 1997, 119, 4317. Leahy, J. W. et al. Tetrahedron 1997, 53, 16423.
Application to Total Synthesis Krishna, P. R., et al. TL, 2004, 45, 4773.
Application to Total Synthesis
Application to Total Synthesis Furaquinocin E Trost, B. M., et al. JACS 2002, 124, 11616.
Summary Achievements made in reducing the time of reaction Changing solvents, temperature, use of Bronsted acids, Several approaches to achieving enantioselective Baylis Hillman: Use of chiral auxiliaries Use of chiral Bronsted acids Use of chiral amines Development of Aza Baylis Hillman Reaction use of chiral bases to provide induction in the reaction Reaction applied to several total syntheses
References For Reviews see: Baylis Hillman: Basavaiah, D. et al. Tetrahydron 1996, 52, 8001. Basavaiah, D. et al. Chem. Rev. 2003, 103, 811. Nucleophilic Phosphine Organocatalysis: Roush, W. R. et al. Adv. Synth. Catal. 2004, 346, 1035.