Baylis-Hillman reaction, protocol

In 2005, Wang and coworkers reported a new bifunctional binaphthyl-derived amine thiourea 16 as an efficient organocatalyst for the Morita-Baylis-Hillman reaction of cyclohexenone with aliphatic, aromatic and sterically hindered aldehydes. The design of the catalyst follows Takemoto s design of a bifunctional motif. This catalytic protocol provided access to useful chiral allylic alcohol building blocks in high yields and high enan-tioselectivities (Scheme 19.21). 

Phosphonium salts may be intermediates in different reactions. The Morita-Baylis-Hillman reaction follows such a protocol. In a typical reaction sequence, a,P-unsaturated carbonyl compounds react with aldehydes in the presence of nucleophiles, such as a trialkylphosphine, to afford aldol-like products (Scheme 75/1), while in another example, unsaturated carbonyl compounds with bromo atom at the end of the chain are cyclized to cycloalkene derivatives (Scheme 75/2). In both... 

Very recently, Verkade and coworkers developed a highly active and selective catalyst system by combining TiCU with proazaphosphatrane sulfide in a molar ratio of 1 0.05 for Baylis-Hillman reaction. It was found that proazaphosphatrane sulfide can significantly enhance the rate and selectivity of the reactions mediated by TiCU [250]. The reaction can be completed within 10 minutes. This protocol is applicable to activated alkenes such as enones, acrylonitrile, and acrylates (Scheme 14.107). 

Conditions for a highly enantioselective Baylis-Hillman reaction (142) + (143) (144) have been developed (Scheme 20). The new protocol relies on the use of 1,1,1,3,3,3-hexafluoroisopropyl acrylate (144) as an activated alkene and (3R,8R,9S)-10,ll-dihydro-3,9-epoxy-6 -hydroxycinchonane (145) as a chiral amine catalyst. The highest enantioselectivity (99% ee) was obtained for R = cyclohexyl. A mechanism has been proposed that highlights an important synergism of the tertiary nitrogen and the phenolic OH of the alkaloid (143) + (145) —> (146) + (147). 9 However, the reviewer feels that the proposed mechanism would be disfavoured by the entropy factor. 

Ab initio calculations also confirm that the use of an allyl magnesium alkoxide in place of the alcohol functionality will lead to high or complete stereoselectivity (138). When homoallylic alcohols are used, the Kanemasa protocol afforded the respective isoxazolines with poor stereoselectivity ( 55 45) in the case of terminal aUcenes, but with very high diastereoselectivity (up to 96 4) in the reaction of cis-1,2-disubstituted olefins (136). Extension of this concept to the reaction of a-silyl allyl alcohols also proved feasible and produced the syn (threo) adducts as nearly pure diastereomers (>94 6) (137). Thus, the normal stereoselectivity of the cycloaddition to the Morita-Baylis-Hillman adducts (anti > syn, see above) can be reversed by prior addition of a Grignard reagent (176,177). Both this reversal... 

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