Influence of Michael Acceptor Stereochemistry on Intramolecular Morita−Baylis−Hillman Reactions

Abstract

[reaction: see text] A study of the effect of Michael acceptor stereochemistry on the efficiency of intramolecular Morita-Baylis-Hillman (MBH) reactions has been performed. The reactions were catalyzed by a phosphine, and the reaction substrates studied were enones containing a pendant aldehyde moiety attached at the beta-position of the alkene group. In all cases examined with PPh3 as the catalyst, cyclization substrates possessing (Z)-alkene stereochemistry afforded a much higher yield of the desired product than did the E isomeric substrates under identical reaction conditions. This was also true when a polymer-supported phosphine catalyst was used. While both alkene isomers afforded the same product, in parallel reactions, the Z isomer afforded 2.5-8.5 times higher yield than did the corresponding E isomer. It is proposed that steric effects are a possible source of this dramatic difference in reactivity. Substrates where the beta-substituent is cis to the electron-withdrawing substituent are relatively more accessible to react with the nucleophile catalyst than are their trans counterparts. These findings are expected to be useful in the design of synthetic intermediates, as intramolecular MBH reactions are being increasingly used in the preparation of complex synthetic targets.

The Morita-Baylis-Hillman Reaction: Insights into Asymmetry and Reaction Mechanisms by Electrospray Ionization Mass Spectrometry

“…In all studied cases, the same product was obtained using both isomers. However, the ( Z )-alkene afforded 2.5–8.5 times higher yield than the E isomer [ 18 ]. The authors rationalized the data due to steric hindrance, as depicted in Figure 2 .…”

Reactions of Aldehydes and Ketones and their Derivatives

“…164 Using triphenylphosphine as catalyst, the Zisomer consistently gave 2.5-8.5 times higher yield of the product (55), using reaction times of 1-3 days. It is unclear whether this is due to the relative accessibility of the β-positions of the isomers to the nucleophilic catalyst, or differential stability in the enolate intermediates.…”

Remarkable Enhancement of the Rate of the Intramolecular Morita–Baylis–Hillman Reaction by the Combination of a Nucleophilic Catalyst and 1,3‐Diphenyl‐2‐thiourea

“…However, the stereochemistry of the Michael accepter ( E or Z olefin) significantly affects the efficiency of the intramolecular triphenylphosphine‐mediated MBH reaction. Reactions of Z isomers give the desired products in 2.5 to 8.5‐fold higher yields than the corresponding E isomers 7. This rate acceleration of intramolecular MBH reactions8 has not been well studied compared with the corresponding intermolecular reactions 9…”