Baylis-Hillman reaction
| Baylis-Hillman reaction | |
|---|---|
| Named after | Anthony B. Baylis Melville E. D. Hillman |
| Reaction type | Coupling reaction |
| Identifiers | |
| Organic Chemistry Portal | baylis-hillman-reaction |
| RSC ontology ID | RXNO:0000076 |
The Baylis–Hillman reaction is a carbon-carbon bond forming reaction between the α-position of an activated alkene and an aldehyde, or generally a carbon electrophile. Employing a nucleophilic catalyst, such as tertiary amine and phosphine, this reaction provides a densely functionalized product (e.g. functionalized allyl alcohol in the case of aldehyde as the electrophile). This reaction is also known as the Morita–Baylis–Hillman reaction or MBH reaction. It is named for the Japanese chemist Ken-ichi Morita, the British chemist Anthony B. Baylis, and the German chemist Melville E. D. Hillman.
DABCO is one of the most frequently used tertiary amine catalysts for this reaction. In addition, nucleophilic amines such as DMAP and DBU as well as phosphines have been found to successfully catalyze this reaction.
MBH reaction has several advantages as a useful synthetic method: 1) It is an atom-economic coupling of easily prepared starting materials. 2) Reaction of a pro-chiral electrophile generates a chiral center, therefore an asymmetric synthesis is possible. 3) Reaction products usually contain multiple functionalities in a proximity so that a variety of further transformations are possible. 4) It can employ a nucleophilic organo-catalytic system without the use of heavy metal under mild conditions.
Several reviews have been written.
Hoffmann first proposed a mechanism for the MBH reaction. The first reaction step involves 1,4-addition of the catalytic tertiary amine to the activated alkene to generate the zwitterionic aza-enolate. In the second step, this enolate adds to an aldehyde via an aldol addition. The third step involves intramolecular proton shift, which subsequently generates the final MBH adduct and releases the catalyst via E2 or E1cb elimination in the last step. Hill and Isaacs performed kinetic experiments to probe the mechanistic details. The rate of reaction between acrylonitrile and acetaldehyde was first order in concentrations of acrylonitrile, acetaldehyde, and DABCO. Hill and Isaacs proposed that the aldol addition step, which involves all three reactants, thus is the rate determining step. That they did not observe kinetic isotope effect using α-deutrated acrylonitrile also supported this statement.
However, this initial mechanistic proposal had been criticized because of several points. The rate of MBH reaction was accelerated by the build-up of product (autocatalytic effect), which could not be rationalized by the mechanism. Also the formation of a considerable amount of ‘unusual’ dioxanone byproduct in the MBH reaction of aryl aldehydes with acrylates was not expected.
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