Reductive amination/aza-Michael

The high performance of 64 compared to Hantzsch ester 39 was demonstrated by Akiyama and coworkers in the asymmetric transfer hydrogenation of trifluor-omethylacetophenone derivatives (Scheme 11.17a) [31]. Benzothiazoline 64c afforded 68 in 89% yield with 96% ee. In contrast, a significant reduction of reactivity and enantioselectivity was observed when 39 was used (4% yield, 45% ee). Enders and coworkers also reported the superiority of benzothiazoline over Hantzsch ester in a symmetric synthesis of tetrahydroisoquinolines via the reductive amination/aza-Michael addition sequence (Scheme 11.17b) [32]. Benzothiazoline 64d had a beneficial effect on both chemical yield and selectivity (98% yield,... 

In 2010, Enders et al. reported on an organocatalytic, one-pot, three-component reductive amination/aza-Michael sequence. They used bis(2,4,6-triisopropyl-phenyl)-l,l -binaphthyl-2,2 -diyl hydrogenphosphate (TRIP) 319 as the organocatalyst and 2-binaphthyl substituted benzathioazole derivatives 320 as the reducing agent and t-BuOH was used as the base. After alkylative cyclization, substituted tetrahydroisoquinoline derivatives 318 were formed in high yields with excellent stereoselectivity (Scheme 40.69). 

SCHEME 40.69. Three-component reductive amination/aza-Michael sequence. 

FIGURE 40.19. Transition state model of the reductive amination/aza-Michael sequence. (Reprinted with permission from Reference 181. Copyright 2010, Wiley-VCH Verlag GmbH Co. KGaA.)... 

Enders D, Liebich JX, Raabe G. Organocatalytic asymmetric s3mthesis of tra j-l,3-disubstituted tetrahydroisoquinolines via a reductive amination/aza-Michael sequence. Chem. Eur. J. 2010 16(32) 9763 9766. 

Indium chloride is known to have little water sensitivity and this has led to the discovery of a novel multicomponent synthesis of monocyclic 1,4-diazepines from aldehyde, amine, and a,p-xmsaturated ketone [89]. The initial step was the bimolecular reductive coupling of the aldimine formed in situ leading to the formation of N, N -diphenyl-l,2-diaryl-l,2-diamino ethane, which underwent aza-Michael addition to the a,p-xmsaturated ketone. The product 129 (Scheme 26) was isolated by simple recrystallization and obtained in very good yield witir excellent diastereose-lectivity favoring the trans-isomer. In the dimerization of tire radical Zn anion of aldimine, the repulsion of the lone pair on nitrogen and steric hindrance between the aryl groups seemed to have contributed toward frans-selectivity. 

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