Baylis-Hillman Reaction
The Baylis-Hillman reaction, sometimes referred to as the Morita-Baylis-Hillman reaction, is a C–C bond-forming reaction between the α-position of an activated alkene and the carbonyl of an aldehyde. It is usually catalyzed by a tertiary amine such as DABCO or phosphine derivatives.
General features:
1. The asymmetric version can be mediated by chiral amines or even with catalytic amounts of BINAP. 2. The main drawback is a slow reaction rate and a limited scope of substrates.
Baylis-Hillman Reaction
Reaction Mechanism
The mechanism involves a Michael addition of the catalyst at the β-position of the activated alkene leading to an enolate that reacts with the carbonyl of the aldehyde to give a zwitterion that is subsequently deprotonated. The final product is obtained upon release of the catalyst and proton transfer.
1. 1,4-addition of the amine catalyst to the activated alkene. 2. Aldol addition (the enolate adds to the aldehyde). 3. Elimination of the catalyst affords the final product.
Experimental Procedure
To a stirred solution of the enone (76.6 mmol, 1.0 eq) and 37% formaldehyde (8.0 eq) in chloroform (270 mL) was added dropwise tributylphosphine (1.3 eq) at 0 °C under nitrogen. The resulting mixture was allowed to warm to room temperature and stirred for 4 h before it was quenched with ice water and extracted with dichloromethane. The combined organic phases were washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by column chromatography on silica gel to give the corresponding product (80% yield).
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