Organocatalytic Asymmetric Three-Component Povarov Reactions of Anilines and Aldehydes

Abstract

We report the first highly enantio-and diastereoselective three-component Povarov reaction between anilines and aldehydes catalyzed by a chiral amine catalyst. A wide variety of substituted tetrahydroquinolines were obtained with moderate to good yields and excellent enantioselectivity and diastereoselectivity (up to 99% ee and >95:5 dr) under the reaction conditions. Furthermore, the reaction intermediates could be efficiently converted to other valuable building blocks. Letter pubs.acs.org/OrgLett

Theoretical investigation on the mechanism and enantioselectivity of organocatalytic asymmetric Povarov reactions of anilines and aldehydes

“…From the perspective of exergonic energy, rss path is more preferential than sss one owing to the more stable of rss‐int8 (−47.20 kcal mol −1 ) than sss‐int8 . This outcome agrees with experiment since the absolute configuration of THQ alcohol was detected to be 1R2S3S by the single X‐ray analysis of main product [13]. Whereas, an inconsistent partiality is drawn from the comparison of energy barriers of ring‐opening/cyclization.…”

“…The relative energies of all stationary points in four paths are listed in Table S1 and the optimized structure of TSs are shown in Figure S1. According to the energy barrier of ts1 relative to int4 (Table 1), ss path is not superior to other three from kinetics, which is in contradiction to the dominant 2S3S configuration of product THQ ketone in experiment [13]. From the stability of int5 point of view, the order of superiority for four paths should be ss > rr > rs > sr in light of exergonic energy.…”

“…As int3 approaches int1 , a pre‐reactive complex ss‐int4 is formed, which is 3.77 kcal mol −1 lower in energy than the sum of initial reactants 1a , 2* 2a , and cat after the removal of two water molecules. The proposed nucleophilic addition product is a structure with positive charge center on iminium N1 of cat and negative one on arylimine N2 of int1 [13]. This process proceeds via transition state ss‐ts1‐ip (246i) forming the desired intermediate ss‐int5‐ip (Figure S1) with new C2C3 single bond and separate charge centers (2.63 Å).…”

“…In terms of catalyst selection, besides transition metal [7], Lewis acids [8], and chiral Brønsted acids [9], a series of organocatalysts have been reported including bifunctional phosphoric acid and chiral urea for asymmetric Povarov reaction [10, 11]. There is also a recent boost in research such as one‐pot protocol in a tandem Polonovski–Povarov sequence activated with di‐tert‐butyl dicarbonate and highly enantio‐ and diastereoselective three‐component Povarov reaction catalyzed by a chiral amine [12, 13].…”

“…In this field, of special interest to us is the breakthrough of Xiong's experimental work, who has provided asymmetric three‐component Povarov reaction where the aldehydes were applied directly for the first time and gave THQ scaffold in good yield, high ee, and excellent dr [13]. As one of the most versatile synthon, aldehyde could be tautomerized to olefin under the chiral amine catalyst.…”