Enantioselective Synthesis of Propargylamines by Copper-Catalyzed Addition of Alkynes to Enamines

Abstract

Propargylamines are important as both synthetic intermediates for the preparation of polyfunctional amino derivatives and as biologically active compounds. [1] Their preparation in enantiomerically enriched form is therefore of great importance. Although several diastereo-and enantioselective syntheses have been developed, [2] until now no metal-catalyzed enantioselective synthesis of propargylamines is known. [3] We report herein a new copper(i)-catalyzed enantioselective addition of alkynes [4] to enamines. First, we examined the racemic synthesis of propargylamines by metal-complex catalysis. Various metal salts, including Sc(OTf) 3 , Zn(OTf) 2 , Yb(OTf) 3 , and Cu I and Cu II salts, [5] were tested as catalysts. Copper(i) and copper(ii) bromide proved to give the fastest conversions. We chose test enamines [6] with readily removable protecting groups such as an allyl or a benzyl group. Enamines 1 a ± h (1.2 ± 1.5 equiv) reacted readily with terminal alkynes 2 a ± k in toluene in the presence of copper(i) bromide (5 mol %) to give propargylic amines of type 3 (Scheme 1, Table 1) under mild reaction conditions. R 1 N R 2 R 4 R 3 R 5 R 1 N R 4 R 3 R 2 R 5 CuBr (5 mol%) toluene RT or 60 °C 3 -24 h + 1a-h 2a-k 3a-r 66 -98 % Scheme 1. Synthesis of propargylamines by the addition of alkynes to enamines.

Cu-catalyzed cross-dehydrogenative coupling: A versatile strategy for C–C bond formations via the oxidative activation of sp 3 C–H bonds

“…For examples, we (61) and others (62-65) have described the direct addition of a terminal alkyne to aldehyde and imines to afford propargyl alcohols and propargyl amines. With Cu(I)-pybox as a chiral catalyst, a highly enantioselective alkyne-imine addition in either water or toluene also was reported by us (66,67). We also developed the coupling of alkynes with N-acylimines and N-acyliminium ions by using a CuBr catalyst, and the gold-or silver-catalyzed coupling reactions of alkyne, aldehyde, and amine in water (68)(69)(70)(71)(72)(73)(74)(75).…”

Synthesis, copper(II) complexes and catalytic activity of substituted 6-(1,3-oxazolin-2-yl)pyridine-2-carboxylates

“…This reaction belongs among C-C couplings producing chiral propargylamines which represent important intermediates in synthesis of various chiral nitrogen compounds (heterocyclic, in particular) [32][33][34][35][36]. It is well known [37] that Cu(I) complexes are highly efficient catalysts in this reaction.…”

Catalytic asymmetric alkynylation of α-imino ester: A versatile approach to optically active unnatural α-amino acid derivatives

“…We then switched our efforts to other transition metals, such as Zn(II), Cu(I)͞(II), Ir(I), and Sc(III) ( Table 1), some of which have been reported to lead the formation of metal alkynilides (33)(34)(35)(36)(37)(38)(39)(40)(41). In the investigation of 4-phenyl-1-butyne 2a addition to ␣-imino ester 1, none of the target was essentially detected in the presence of IrCl⅐2COD, Zn(OTf) 2 , ZnCl 2 , and Sc(OTf) 3 (entry 1).…”