Modular Access to Chiral α-(Hetero)aryl Amines via Ni/Photoredox-Catalyzed Enantioselective Cross-Coupling

Abstract

Chiral α-aryl N-heterocycles are commonly found in natural products, pharmaceutical agents, and chiral catalysts but remain challenging to access via asymmetric catalysis. Herein, we report a general and modular approach for the direct enantioselective α-arylation of saturated azacycles and acyclic N-alkyl benzamides via nickel/photoredox dual catalysis. This process exploits the hydrogen atom transfer ability of photoeliminated chlorine radicals to convert azacycles to the corresponding α-amino alkyl radicals that then are coupled with ubiquitous and inexpensive (hetero)­aryl chlorides. These coupling reactions require no oxidants or organometallic reagents, feature feedstock starting materials, a broad substrate scope, and high enantioselectivities, and are applicable to late-stage diversification of medicinally relevant complex molecules. Mechanistic studies suggest that the nickel catalyst uncommonly plays multiple roles, accomplishing chlorine radical generation, α-amino radical capture, cross-coupling, and asymmetric induction.

Electrophoto-catalytic decoupled radical relay enables highly efficient and enantioselective benzylic C-H functionalization

“…It is worth-noted that all these substrates (2, 10-18) provided poor reactivity under our previous coupled radical relay conditions with NFSI as terminal oxidant. Moreover, comparable yields and enantioselectivity were also observed for a number of substrates (9,(19)(20)(21)(22) that worked well using the previous method 18 .…”

“…Metal-catalyzed radical relay has been introduced for the asymmetric C-H functionalization by integrating HAT for sp 3 C-H cleavage and unique stereo-control of transition metal catalysis (Figure 1A-i) [16][17] . Many asymmetric functionalization reactions of C-H bonds were explored in the last decade [18][19][20][21][22] . For instance, the copper-catalyzed asymmetric benzylic C-H functionalization, such as cyanation 18 , arylation 19 and alkynylation 20 reactions, were discovered by using electrophilic N-F reagents, where metal-bounded radicals L*Cu-N radicals are disclosed as the key intermediate for the HAT process 23 and L*Cu(II)-FG for the asymmetric radical functionalization.…”

Ligand‐to‐Metal Charge Transfer (LMCT) Photochemistry at 3d‐Metal Complexes: An Emerging Tool for Sustainable Organic Synthesis

“…This strategy for C−H arylation based on metallaphotoredox catalysis was very recently applied to the enantioselectiveα‐arylation of protected amines (Scheme 28). [145] Based on the above‐described reactivity mode, Huo and coworkers not only enabled the use of slight excess (3.0–4.0 equiv.) of the C−H coupling partner with respect to the aryl chloride, but also succeeded in the asymmetric induction through the use of chiral bis(imidazoline) ligands to access valuable enantioenriched α‐aryl N‐heterocycles.…”

Enantioselective Single and Dual a-C–H Bond Functionalization of Cyclic Amines via Enzymatic Carbene Transfer

“…[4][5][6][7][8][9] Other notable approaches involve the use of oxidative -C-H functionalization to generate an intermediate iminium ion, which is captured by carbon-based nucleophiles (Figure 2b); [10][11][12][13][14] , directing group mediated C(sp 3 )-H functionalization [15][16][17] , and photoredox strategies strategies (Figure 2c). [18][19][20][21][22] Despite this progress, these protocols require multistep sequences, rare transition metals, and/or lack of stereoselectivity. Enzymes are attractive alternatives for C-H functionalization because of their inherent chemoselectivity, sustainability, and potential to be optimized via protein engineering for tuning activity and stereoselectivity.…”