Synthesis of 2,4,6‐Trisubstituted Pyrimidines via Iron‐Catalyzed Homocoupling of α,β‐Unsaturated Ketoximes

Abstract

A FeCl2‐catalyzed homocoupling of α,β‐unsaturated ketoximes in batch and flow is reported. This protocol demonstrates broad substrate scope and functional group tolerance, providing an alternate route toward the synthesis of 2,4,6‐trisubstituted pyrimidines under mild conditions. Also a gram‐scale reaction has been performed to evaluate the applicability of this method.

Synthesis of 2,4,6-Trisubstituted Pyrimidines through Copper-Catalyzed [4 + 2] Annulation of α,β-Unsaturated Ketoximes with Activated Nitriles

“…Consequently, various synthetic methods for the assembly of 2,4,6-trisubstituted pyrimidines have been developed, such as the transition-metal or base-catalyzed reaction of amidines with carbonyls, multicomponent dehydrogenative coupling reaction of amidines with two different alcohols, [2 + 2 + 2] annulation of ketones or alkynes with two molecules of nitriles, and one-pot condensation of aldehydes, ketones with NH 4 OAc . Our group has a longstanding interest in the nitrogen-containing heterocycle construction from α,β-unsaturated ketoximes, and recently, we successively disclosed the FeCl 2 -catalyzed synthesis of 2,4,6-trisubstituted pyrimidines . As a continuation, herein, we report the first copper-catalyzed annulations of α,β-unsaturated ketoximes with activated nitriles, which enables the efficient synthesis of novel 2,4,6-trisubstituted pyrimidines (Scheme b).…”