A Modified System for the Synthesis of Enantioenriched N‐Arylamines through Copper‐Catalyzed Hydroamination

Abstract

Despite significant recent progress in copper-catalyzed enantioselective hydroamination chemistry, the synthesis of chiral N-arylamines, which are frequently found in natural products and pharmaceuticals, has not been realized. Initial experiments with N-arylhydroxylamine ester electrophiles were unsuccessful and, instead, their reduction in the presence of copper hydride (CuH) catalysts was observed. Herein, we report key modifications to our previously reported hydroamination methods that lead to broadly applicable conditions for the enantioselective net addition of secondary anilines across the double bond of styrenes, 1,1-disubstituted olefins, and terminal alkenes. NMR studies suggest that suppression of the undesired reduction pathway is the basis for the dramatic improvements in yield under the reported method.

Design, scope and mechanism of highly active and selective chiral NHC–iridium catalysts for the intramolecular hydroamination of a variety of unactivated aminoalkenes

“…3 . 8,9 Progress has been made in this field over the last few years through discoveries pioneered by Miura and Buchwald, 10,11 who were able to overcome some of these limitations by introducing formal intermolecular HA reactions that use electrophilic aminating reagents and rely on the use of an exogenous hydrogen source. These advances though come at a price, as these processes employ superstoichiometric amounts of additives and are thus moving away from the concept of atom economy epitomized by the classical HA reaction.…”

Copper‐Catalyzed Ring Opening of Benzofurans and an Enantioselective Hydroamination Cascade

“…and 49 % yield with greater than 19:1 d.r., respectively, suggesting that the catalyst control is dominant. To our disappointment, N,N‐alkylaryl and dialkyl hydroxylamine esters only gave undesired amines resulting from the side reactions between more‐reactive electrophilic amination reagents and copper hydride ,. In addition, 2‐methylbenzofuran turned out to be a poor substrate (<5 % yield), and might be attributed to unfavorable sterically hindrance encountered with the hydrocupration process.…”

Earth-Abundant 3d Transition Metal Catalysts for Hydroalkoxylation and Hydroamination of Unactivated Alkenes

“…Additionally, the nature of the protecting group on the nitrogen or oxygen functionality attached at the (homo)allylic position of the internal alkenes significantly improves the reaction efficiency by either enabling the hydrocupration, preventing the detrimental β-H elimination or electronically controlling the regioselectivity [147,152]. In some cases, the addition of a stoichiometric amount of t-BuOH and/or catalytic amount of PPh 3 to the reaction medium could enhance the reaction rate and improve the yield of C-N bond formation product, as is the case in the formation of enantioenriched N-arylamines [158], by suppression undesired reduction pathways [147,152]. This methodology could also be impressively extended to the asymmetric synthesis of three and five-membered N-heterocycles, such as aziridines or α-(hetero)arylpyrrolidines or sixto nine membered benzo-fused analogues by intramolecular cyclization of hydroxylamine ester derivatives (not shown in Figure 25) [159,160].…”