Morita-Baylis-Hillman (MBH) reaction is one of the most prominent carbon-carbon bond-forming processes in synthetic organic chemistry, with enormous synthetic utility, promise, and potential. The catalytic activation of electron-poor olefins offers the opportunity to reach beyond the standard aldehyde and imine electrophiles used in the original MBH reaction. In this context, we have turned our attention to pyridinium salts, the dearomatization of which constitutes a straightforward way to obtain partially or fully saturated heterocycles, such as hydroquinolines, hydropyridines, and piperidines, which have been discovered in many biologically important natural products and are the most common azaheterocycles in FDA-approved drugs.<br/>We have developed a general and efficient dearomatization of pyridinium salts under the MBH conditions for the first time. The reaction is promoted by DBU, which acts both at the catalyst activating the olefin as well as a base. Depending on the substrate substitution pattern the addition takes place regioselctively either at 2- or 4-position. The method allows for the construction of a functional group-rich vinylhydropyridine scaffold from a variety of activated pyridines and quinolines, providing access to diverse building blocks for, for instance, medicinal chemistry applications.

Pyridinium salts as electrophiles in Morita-Baylis-Hillman reaction: The synthesis of vinylhydropyridines via regioselective dearomatization

ACS Spring 2022

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