Enantioselective Oxidative Cross‐Dehydrogenative Coupling of Tertiary Amines to Aldehydes

Abstract

The direct oxidative cross-dehydrogenative coupling (CDC) of two C H bonds can be an efficient and relatively clean strategy in organic synthesis. Various sp C Hbonds, such as benzylic and allylic C H bonds, the a-C H bonds of amines and ethers, and the C H bonds of alkanes can be oxidized for direct reaction with carbon nucleophiles. Among these reactions, the oxidation of tertiary amines to generate iminium intermediates, as pioneered by Murahashi et al., Li et al. and others, has received considerable attention. Carbonyl compounds, such as 1,3-dicarbonyls, 10b,g] a,bunsaturated ketones, and simple ketones have been successfully coupled with tertiary amines by using metal catalysis, acid catalysis, metal/organic cooperative catalysis, or photoredox catalysis. In all of these reactions, the development of enantioselective catalysis remains a challenge. Very recently, Wang and co-workers used metals together with chiral bisoxazoline ligands to realize enantioselective reactions of activated carbonyl nucleophiles (such as 1,3dicarbonyls and acetyl phosphates) to oxidatively generate iminiums or their analogues. However, this approach with chiral ligands was found to be unsuccessful for reactions starting with simple ketone nucleophiles, as reported by Klussmann and co-workers as well as Xie and Huang. Approaches that use asymmetric enamine catalysis for the activation of carbonyl compounds have led to disappointing results (for example, less than 20% ee) as well . As part of a larger program for developing sustainable oxidation chemistry, we herein report an enantioselective oxidative coupling reaction of aldehydes and tertiary amines under cooperative amine and metal catalysis. The racemic version of this reaction was also realized by using metal catalysts alone (without amine catalysts), on account of its potential utility and the very different optimized conditions, relative to the enantioselective reactions. We examined metal-catalyzed oxidative coupling reactions between N-phenyltetrahydroisoquinoline (1a) and propionaldehyde (2a) in the presence of tBuOOH without an amine catalyst. An initial survey of solvents and catalysts indicated that DMF is a good solvent and CuBr2 is an effective metal catalyst (Table 1, entries 1–3, see also the Supporting Information). The amino aldehyde product 3a is unstable and, thus, was isolated as the corresponding amino alcohol product 4a in 72% yield after reduction with NaBH4 in situ, albeit with no diastereoselectivity (Table 1, entry 3). Under these conditions, various amines, such as N-aryl tetrahydroisoquinolines 1 and N,N-dialkyl anilines, and aldehydes 2 were used to obtain the corresponding racemic amino alcohols 4 in acceptable yields. Aldehydes with longer carbon chains required elevated reaction temperatures. N,Ndialkyl anilines gave the corresponding products in lower yields (Table S6 and Scheme S3 in the Supporting Information).