Enantioselective Direct α-Amination of Aromatic Ketones Catalyzed by Binaphthyl-Modified Primary Amine

Abstract

Optically active α-aminated carbonyl compounds are important synthetic building blocks for the synthesis of a large number of biologically active compounds. The enantioselective electrophilic amination of carbonyl compounds represents a powerful and the simplest procedures to generate α-amino carbonyl compounds possessing a nitrogen moiety attached to a stereogenic center. The catalytic enantioselective direct α-amination of active methine compounds such as 1,3-dicarbonyl compounds, β-keto phosphonates and α-cyano carbonyl compounds has been extensively studied. Since the first report for proline-catalyzed α-amination of aldehydes, a number of organocatalytic electrophilic α-aminations of simple aliphatic aldehydes and ketones have been reported. Recently, a organocatalytic enantioselective direct α-amination of aromatic ketones has been reported by Chen et al. However, this synthetic method suffered some drawbacks such as the high catalyst loading and long reaction time. To overcome these drawbacks, the development of alternative catalysts for the organocatalytic enantioselective direct α-amination of aromatic ketones is highly desirable. As part of our effort to demonstrate the development of catalytic synthetic methods for the enantioselective construction of stereogenic carbon centers, we recently reported the catalytic enantioselective Michael-type reactions using chiral primary amine organocatalysts. In this letter, we wish to report the catalytic enantioseletive electrophilic α-amination of aromatic ketones in the presence of chiral binaphthylmodified organocatalysts. A survey of some reaction parameters was performed, and some representative results are presented in Table 1. Our investigation began with the catalytic enantioselective electrophilic amination of propiophenone (1a) with ethyl azodicarboxylates (2) as the electrophilic aminating reagent in ethanol at room temperature in the presence of 20 mol % of catalysts and 40 mol % of p-TsOH as additive. We surveyed binaphthyl-modified chiral primary amines I and II as catalysts (Figure 1). Catalyst I exhibited better enantioselectivity (75% ee, entry 1). Among the solvents probed, the best results were achieved when the reaction was conducted in iPrOH (entry 3). We examined our investigations by examining the reactivity and selectivity with organocatalyst I in the presence of different acids, such as formic acid and various sulfonic acid derivatives as additives (entries 3 and 9-12). Among the additives probed, the best results were achieved when the reaction was conducted in trifluoromethanesulfonic acid (75% yield and 97% ee, entry 12). The present catalytic system tolerates catalyst loading down to 10, 5, or 2.5 mol % without compromising the yield or the enantioselectivity (entries 13-15). To examine the generality of the catalytic enantioselective direct α-amination of aromatic ketones 1 by using binaph-