Palladium-Catalyzed anti-Michael-Type (Hetero)arylation of Acrylamides

Abstract

This paper reports a direct α-(hetero)­arylation of acrylamides through an inverse electron-demand nucleophilic addition, specifically an anti-Michael-type addition. The introduction of a quinolyl directing group facilitates the nucleophilic addition of (hetero)­arenes to the α-position of acrylamides. The quinolyl directing group effectively suppresses undesired β-hydrogen elimination and is removable for subsequent derivatization. The presented method provides an atom economical synthesis of α-(hetero)­arylamide with a high degree of functional group tolerance.

Palladium-Catalyzed anti-Michael-Type Hydroamination of N-(Quinolin-8-yl)acrylamide with 2-Pyridones

“…Conversely, achieving the less common α-addition requires an inverse electron-demand nucleophilic addition process. Recently, we successfully established the anti -Michael-type addition reaction in a palladium-catalyzed α-(hetero)­arylation of acrylamides, assisted by a quinolyl directing group . Given the recent progress in the hydroamination of 2-pyridones to electronically unbiased alkenes as reported by Widenhoefer’s and Engle’s groups − and the pivotal role of N -substituted 2-pyridone carboxylic acids, we embarked on exploring the anti -Michael-type addition of 2-pyridones, building upon the principles outlined in our previous report.…”

“…Our study was initiated using N -(quinolin-8-yl)­acrylamide ( 1a ) and 2-pyridone ( 2a ) as model substrates, based on our previous work on an anti -Michael-type (hetero)­arylation (Table ). In the initial experiment, Pd­(OCOCF 3 ) 2 (10 mol %) was employed in the presence of benzoic acid (50 mol %) in CH 3 CN (1.0 M) at 80 °C for 18 h, resulting in 2-[2-oxopyridin-1­(2 H )-yl]­propanamide 3a in 77% yield, although a small amount of the β-adduct 4a was formed (entry 1). The exclusion of benzoic acid from the reaction marginally reduced the yield (entry 2).…”

“…Based on our previous research and preliminary mechanistic investigations, we proposed a reaction mechanism for this transformation (Scheme ). The process initiates with the coordination of the quinolyl directing group of acrylamide 1a to palladium­(II) catalyst A .…”