Traceless Benzylic C−H Amination via BifunctionalN‐Aminopyridinium Intermediates

Abstract

CÀ H amination reactions provide the opportunity to streamline the synthesis of nitrogen-containing organic small molecules. The impact of intermolecular CÀ H amination methods, however, is currently limited the frequent requirement for the amine precursors to bear activating groups, such as N-sulfonyl substituents, that are both challenging to remove and not useful synthetic handles for subsequent derivatization. Here, we introduce traceless nitrogen activation for CÀ H amination-which enables application of selective CÀ H amination chemistry to the preparation of diverse Nfunctionalized products-via sequential benzylic CÀ H N-aminopyridylation followed by Ni-catalyzed CÀ N cross-coupling with aryl boronic acids. Unlike many CÀ H amination reactions that provide access to protected amines, the current method installs an easily diversifiable synthetic handle that serves as a lynchpin for CÀ H amination, deaminative NÀ N functionalization sequences.

Diversification of Amidyl Radical Intermediates Derived from C–H Aminopyridylation

“…We recently introduced N -aminopyridinium salts as bifunctional reagents in C–H amination chemistry . The combination of a nucleophilic N -amino group and a reductively activatable N–N bond provided a platform to couple C–H amination with C–N cross-coupling to achieve formal nitrene transfer to benzylic C–H bonds.…”

“…During our initial studies of C–H aminopyridylation, we developed conditions that promoted selective benzylic C–H functionalization of a variety of ethyl and alkylbenzene derivatives . We envisioned that oxidative quenching of the excited state of an appropriate photoredox mediator would promote reductive cleavage of the N–N bonds of these compounds to release pyridine and unveil an electrophilic aminyl radical.…”

Electrochemical Benzylic C–H Amination via N-Aminopyridinium

“…6, 143.5, 130.6, 128.5, 128.2, 114.6, 63.7, 55.3, 20.1; HRMS (ESI-TOF) m/z: [M + ] calcd for C 14 H 17 N 2 O, 229.1335O, 229. , found 229.1334ethyl)amino)pyridin-1-ium Trifluoromethanesulfonate (3f). 18 The residue was purified by column chromatography on silica gel with DCM/MeOH (10:1) to afford 3f (28 mg, 34% yield) as a white solid; 1 H NMR (500 MHz, CDCl 3 ) δ 8.74 (d, J = 6.0 Hz, 2H), 8.46 (s, 1H), 8.22 (t, J = 7.8 Hz, 1H), 7.80 (t, J = 7.0 Hz, 2H), 7.29 (d, J = 8.1 Hz, 2H), 7.00 (d, J = 8.1 Hz, 2H), 4.60 (q, J = 6.8 Hz, 1H), 2.26 (s, 3H), 1.61 (d, J = 6.5 Hz, 3H); 13 C{ 1 H} NMR (100 MHz, CDCl 3 ) δ 169. 5,151.0,143.7,143.6,136.6,128.5,128.3,122.6,63.4,21.2,-4-yl)ethyl)amino)pyridin-1-ium Trifluoromethanesulfonate (3g).…”

“…5,151.0,143.7,143.6,136.6,128.5,128.3,122.6,63.4,21.2,-4-yl)ethyl)amino)pyridin-1-ium Trifluoromethanesulfonate (3g). 18 The residue was purified by column chromatography on silica gel with DCM/MeOH (10:1) to afford 3g (61 mg, 72% yield) as a brown oil; 1 H NMR (500 MHz, CDCl 3 ) δ 8.74 (d,J = 6.2 Hz,2H),2H), 7.80 (t, J = 7.2 Hz, 2H), 7.49 (d, J = 4.5 Hz, 4H), 7.40−7.30 (m, 5H), 4.64 (q, J = 7.0 Hz, 1H), 1.65 (d, J = 6.5 Hz, 3H); 13 C{ 1 H} NMR (125 MHz, CDCl 3 ) δ 143. 5,143.4,141.7,140.0,137.8,129.0,128.3,127.82,127.78,127.7,127.0,63.6,ethyl)amino)pyridin-1-ium Trifluoromethanesulfonate (3h).…”

“…17 Recently, Powers and co-workers reported a benzylic C−H N-aminopyridylation under thermolysis or photolysis conditions in the presence of superstoichiometric oxidant DDQ or NIS (Scheme 1b). 18 Inspired by these works, we envisioned that the benzylic carbocations generated by anodic oxidation could be trapped by N-aminopyridiniums to produce the corresponding benzylaminopyridiniums. In light of our continued interest in Naminopyridinums 19 and electrochemical benzylic C−H functionalization, 20 we report herein an electrochemical benzylic C(sp 3 )−H amination via direct C−H/N−H crosscoupling.…”