Enantioselective Synthesis of N-Alkylamines through β-Amino C–H Functionalization Promoted by Cooperative Actions of B(C₆F₅)₃ and a Chiral Lewis Acid Co-Catalyst

Abstract

We disclose a catalytic method for β-C(sp 3 )−H functionalization of N-alkylamines for the synthesis of enantiomerically enriched βsubstituted amines, entities prevalent in pharmaceutical compounds and used to generate different families of chiral catalysts. We demonstrate that a catalyst system comprising of seemingly competitive Lewis acids, B(C 6 F 5 ) 3 , and a chiral Mg-or Sc-based complex, promotes the highly enantioselective union of N-alkylamines and α,β-unsaturated compounds. An array of δamino carbonyl compounds was synthesized under redox-neutral conditions by enantioselective reaction of a N-alkylamine-derived enamine and an electrophile activated by the chiral Lewis acid co-catalyst. The utility of the approach is highlighted by late-stage β-C−H functionalization of bioactive amines. Investigations in regard to the mechanistic nuances of the catalytic processes are described.

Non-Directed β- or γ-C(sp3)–H Functionalization of Saturated Nitrogen-Containing Heterocycles

“…In addition, Wasa demonstrated the late-stage functionalization of bioactive compounds [cloperastine (108b) and raloxifene derivative 108c], which possess a nitrogen-containing heterocycle (Scheme 33). 38 As a result, the C-H functionalized products 110b and 110c were obtained. The reason that products 110b and 110c, containing an unsaturated bond in the heterocycle, are obtained, is probably due to protonation of only the enolate in the zwitterionic intermediate (cf.…”

“…37 Moreover, Wasa reported the B(C 6 F 5 ) 3 and chiral Lewis acid co-catalyzed enantioselective -C(sp 3 )-H functionalization of N-alkyl amines. 38 This report presents several different sets of optimized reaction conditions, one set of which is described below (Scheme 31). Under these conditions, -functionalized pyrrolidine 110a was obtained by the 1,4-addition of 108a to ,-unsaturated compound 109a in 80% yield, 2.0:1 dr, and 97:3 to 98:2 er.…”

Synthetic applications of hydride abstraction reactions by organic oxidants

“…The hydride borrowing approach can also be used for functionalizing the β-carbons of amines. 223 Raloxifene derivative 371 can be coupled to diisopropyl fumarate to form 372 . The route proceeds through hydride abstraction from 371 and proton loss from the resulting iminium ion to generate enamine 373 .…”

Boron-Based Lewis Acid Catalysis: Challenges and Perspectives

“…Another elegantly designed approach has been recently developed to obtain the β-C(sp 3 )−H functionalization of N-alkylamines 79 reacting with α,β-unsaturated compounds 80. This cutting-edge methodology allows the enantioselective late-stage β-C−H functionalization of bioactive amines which revealed itself to be a powerful strategy to access key building blocks of N-based natural products and drugs [53]. Wasa et al fine-tuned a synthetic approach which exploits the cooperation of two different catalysts which in appearance could act competitively: a Lewis acid, BCF, and a chiral Mg-or Sc-based complex.…”