Selective Synthesis of Z-Michael Acceptors via Hydroalkylation of Conjugated Alkynes

Abstract

Hydroalkylation of terminal alkynes is a powerful approach to the synthesis of disubstituted alkenes. However, its application is largely unexplored in the synthesis of α,β-unsaturated carbonyls, which are common among synthetic intermediates and biologically active molecules. The thermodynamically less stable Z-isomers of activated alkenes have been particularly challenging to access because of their propensity for isomerization and the paucity of reliable Z-selective hydroalkylation methods. We developed a highly Z-selective silver-catalyzed hydroalkylation of terminal conjugated alkynes using alkyl boranes as coupling partners. The reaction allows access to (Z)-α,β-unsaturated esters, secondary and tertiary alkyl amides, aryl amides, and alkyl and aryl ketones and tolerates a wide range of functional groups. The reaction can be performed successfully in the presence of alkyl and aryl halides, esters, protected alcohols, and amines. The hydroalkylation involves the formation of an alkynylboronate complex followed by a 1,2-metalate shift. This sequence of steps mechanistically constrains the stereochemical outcome, which, together with mild reaction conditions, ensures high Z-selectivity.