Azolation of Benzylic C–H Bonds via Photoredox-Catalyzed Carbocation Generation

Abstract

A visible-light photoredox-catalyzed method is reported that enables the coupling between benzylic C−H substrates and N−H azoles. Classically, medicinally relevant N-benzyl azoles are produced via harsh substitution conditions between the azole and a benzyl electrophile in the presence of strong bases at high temperatures. Use of C−H bonds as the alkylating partner streamlines the preparation of these important motifs. In this work, we report the use of N-alkoxypyridinium salts as a critically enabling reagent for the development of a general C(sp 3 )−H azolation. The platform enables the alkylation of electron-deficient, -neutral, and -rich azoles with a range of C−H bonds, most notably secondary and tertiary partners. Moreover, the protocol is mild enough to tolerate benzyl electrophiles, thus offering an orthogonal approach to existing S N 2 and cross-coupling methods.

Copper-Catalyzed Hydroamination: Enantioselective Addition of Pyrazoles to Cyclopropenes

“…In the case of unsymmetric pyrazoles, 65–90% yield, 92:8–99:1 er , and nitrogen regioselectivity (N 2 :N 1 > 20:1) were observed ( 3j – 3o ). X-ray crystallographic analysis of 3j confirmed the coupling of cyclopropene with the more sterically hindered nitrogen of the pyrazole; this regioselectivity is rare in pyrazole functionalization. ,, Further NOE experiments confirmed similar regiocontrol for related pyrazole substrates (see the SI). Despite the presence of a competing amino group, 3l was isolated exclusively, showing a highly chemoselective cyclopropylation for pyrazole nitrogens.…”

A General Photocatalytic Strategy for Nucleophilic Amination of Primary and Secondary Benzylic C–H Bonds

“…Despite these important advances, expansion of N -nucleophile identity beyond nitriles in solvent quantity has been comparatively less explored. Copper-catalyzed platforms, including variants of the original Karasch–Sosnocky reaction as well as more recent developments by Stahl, Liu, and others, have proven most versatile, enabling C–H (sulfonyl)­amidation, − azolation, and azidation. , Alternatively, transition-metal-free platforms for C­(sp 3 )–H (sulfonyl)­amidation − and C­(sp 3 )–H azolation − exist, but each method and set of reaction conditions is confined to a single nucleophile class (amides, sulfonamides, or azoles, but never all three within one protocol) (Figure B). Moreover, many still require stoichiometric oxidants such as Selectfluor, NFSI, or DDQ.…”

A general photocatalytic strategy for nucleophilic amination of primary and secondary benzylic C–H bonds

“…Copper-catalyzed platforms, including variants of the original Karasch-Sosnocky reaction 6 as well as more recent developments by Stahl, Liu, and others have proven most versatile, enabling C-H (sulfonyl)amidation, [7][8][9][10][11][12][13] azolation, 14 and azidation. 15,16 Alternatively, transition metal-free platforms for C(sp 3 )-H (sulfonyl)amidation [17][18][19] and C(sp 3 )-H azolation [20][21][22][23] exist, but each method and reaction conditions is confined to a single nucleophile class (amides, sulfonamides, or azoles, but never all three within one protocol). Moreover, many still require stoichiometric strong oxidants such as Selectfluor, NFSI, or DDQ, which limit the scope of the methods.…”

“…Likewise, Musacchio and coworkers reported only a single example of C-N bond formation using a pyrazole derivative; 25 they have since expanded this catalyst platform to include secondary benzylic and tertiary benzylic and aliphatic C(sp 3 )-H azolations. 23 In our original report, inclusion of NEt3•3HF was necessary in order to obtain high yields of C(sp 3 )-H functionalization (even for non-fluoride nucleophiles), likely because this additive accelerated single-electron reduction and decarboxylation of N-acyloxyphthalimide with excited-state Ir(p-F-ppy)3, affording higher concentrations of the HAT reagent (methyl radical). However, we found that NH-nucleophiles such as sulfonamides and amides were deactivated by competitive hydrogen bonding with the NEt3•3HF additive.…”