Synthesis of α-Trifluoromethylamines by Cu-Catalyzed Regio- and Enantioselective Hydroamination of 1-Trifluoromethylalkenes

Abstract

A copper-catalyzed regioselective net hydroamination of 1-trifluoromethylalkenes with hydrosilanes and hydroxylamines has been developed. The judicious choice of ligand and additive suppresses the conceivable but undesired β-F elimination of an α-CF 3 -substituted organocopper intermediate, leading to targeted α-trifluoromethylamines in good yields with excellent regioselectivity. Additionally, with an appropriate chiral bisphosphine ligand, the enantioselective reaction is also possible to deliver optically active α-trifluoromethylamines of high potential in medicinal and pharmaceutical chemistry.

Copper-Catalyzed Asymmetric Hydroamination: A Unified Strategy for the Synthesis of Chiral β-Amino Acid and Its Derivatives

“…Moreover, without any racemization, the chiral center in 5a was observed under harsh conditions [e.g., in the presence of NaOH or trifluoroacetic acid (TFA)], indicating that these types of chiral compounds might have the capacity to transfer into more complicated chiral compounds while maintaining the enantioselectivity. According to previous reports, [40][41][42][43][44][45][46][47][48][49][50][51][52][53][54][55][56]62,63 a mechanism involving a regio-and enantioselective insertion of CuH into C-C double bond in a Michael acceptor to form benzylcopper intermediate, followed by an amination process with hydroxylamine 4 to provide expected chiral β-amino carbonyls, might be possible. Other mechanisms cannot be excluded, and further studies need to be carried out to illuminate the origin of this unusual regio-and enantionselectivity.…”

“…Transition-metal-catalyzed asymmetric hydroamination of unsaturated hydrocarbons is a straightforward and powerful approach for rapid assembly of a variety of biologically active chiral amines. [36][37][38][39] In this context, asymmetric hydroamination of various alkenes and alkynes [40][41][42][43][44][45][46][47][48][49][50][51][52][53][54][55][56] with in situ generated CuH catalysts [56][57][58][59][60][61] has attracted much attention since the pioneering reports by Buchwald 62 and Hirano, and Miura in 2013. 63 Besides, an array of electronically matched CuH-catalyzed asymmetric transformations of Michael acceptors, namely undergoing the 1,4-hydrocupration process, have also been disclosed in past decades (Scheme 1b).…”

Cobalt-Catalyzed Hydroamination of Alkenes with 5-Substituted Tetrazoles: Facile Access to 2,5-Disubstituted Tetrazoles and Asymmetric Intermolecular Hydroaminations

“…In particular, the asymmetric intermolecular hydroamination of nonactivated olefins still remains one of the unsolved challenges in modern synthetic organic chemistry, 19) with reported reactions resulting in low enantioselectivity 20) or requiring activated olefin substrates, such as styrenes, 20-28) allenes, 5) dienes, 29,30) allylamines, [31][32][33] etc. [6][7][8][9][10][11][34][35][36][37][38][39][40][41][42] We chose 1a, 1g, and 1l as test substrates for the asymmetric reaction. Although the asymmetric induction on 1a did not improve beyond 20% enantiomeric excess (ee) with any of the tested catalysts, 1g with (S,S)-Co5 and 1l with (S,S)-Co6 gave (−)-3g and (+)-3l with a moderate enantioselectivity 46% ee and 39% ee, respectively (entries 4 and 5).…”

Ligand‐Promoted, Enantioconvergent Synthesis of Aliphatic Alkanes Bearing Trifluoromethylated Stereocenters via Hydrotrifluoroalkylation of Unactivated Alkenes

“…[ 3 ] However, while drug chirality has seen its importance and thus emerged as one major theme in drug research and development in the past decades, the utility of chiral fluorine‐containing compounds featuring a trifluoromethylated stereogenic carbon center is still underdeveloped due to lack of feasible methods for enantioselective syntheses of such chiral molecules. Moreover, the precedented protocols for asymmetric construction of trifluoromethylated stereogenic carbon centers usually relies on skeletal divergence at bond‐ forming site, resulting in positioning of this CF 3 ‐substituted carbon at specific spots [ 8,13 ] like benzyl, [ 4,6,11 ] allylic, [ 12 ] or ɑ‐position of heteroatoms, [ 5,9‐10 ] etc . [ 7 ] A general, highly efficient and enantioselective strategy for diverse synthesis of enantiopure alkanes featuring trifluoromethyl‐substituted stereocenters remains elusive but extremely desired.…”