Radical Chlorination of Non-Resonant Heterobenzylic C-H Bonds and High-Throughput Diversification of Heterocycles

Abstract

Site-selective functionalization of the heterobenzylic C(sp³)-H bonds of pyridines and related heteroaromatic compounds presents challenges associated with the basic nitrogen atom and the variable reactivity among different positions on the heteroaromatic ring. Methods for functionalization of 2- and 4-alkylpyridines are increasingly available through polar pathways that leverage resonance stabilization of charge build-up at these positions. In contrast, functionalization of 3-alkylpyridines is largely inaccessible. Here, we report a photochemically promoted method for chlorination of non-resonant heterobenzylic C(sp³)-H sites in 3-alkylpyridines and related alkylheteroaromatics. Density functional theory calculations show that the optimal reactivity reflects a balance between the energetics of the two radical-chain propagation steps, with the preferred reagent consisting of an N-chlorosulfonamide. The operationally simple chlorination protocol enables access to heterobenzylic chlorides which serve as versatile intermediates in C-H cross-coupling reactions between heteroaromatic building blocks and diverse oxidatively sensitive nucleophiles using high-throughput experimentation.

Keywords: Chlorination; C–H functionalization; high-throughput experimentation; photochemistry.

Figure 1.. Functionalization of heterobenzylic C(sp³)–H bonds in alkylpyridines.

(A) Bioactive molecules with 3-alkylpyridine fragments. (B) General reactivity trends associated with (hetero)benzylic reactivity.

Figure 2.

Strategy for sequential chlorination/diversification of non-resonant heterobenzylic C–H bonds, such as those in 3-alkylpyridines.

Figure 3.. Applications of various C–H chlorination methods on ethylbenzene, 2-ethylpyridine, and 3-ethylpyridine.

Yields determined by ¹H NMR spectroscopy (ext. std. = mesitylene). NFSI = N-fluorobenzensulfonimide, NCS = N-chlorosuccinimide, TCCA = trichloroisocyanuric acid, TfCl = trifluoromethanesulfonyl chloride, pipNH = cis-2,6-dimethylpiperidine, Acr⁺Mes = 9-mesityl-10-methylacridinium, NCl-amide = N-(tert-butyl)-N-chloro-3,5-bis(trifluoromethyl)benzamide.

Figure 4.. Energetic analysis of propagation steps and correlation with C–H chlorination yields.

Yields determined by ¹H NMR spectroscopy (ext. std. = mesitylene). ^aYield reported using AIBN initiation (see Table S6 for more information).

Figure 5.. Chlorination reactions with acid/base effects on heterobenzylic selectivity.

(A) Chlorination reactions with N-chlorosulfonamide (G). (B) Acid/base effects on heterobenzylic selectivity. Regioselectivity determined by ¹H NMR analysis of crude product mixture. (C) Computational analysis of acid/base effects on heterobenzylic selectivity. Yields determined by ¹H NMR spectroscopy (ext. std. = mesitylene). ^aYield obtained under conditions from ref. 15. ^bIsolated yield.

Figure 6.. Assessment of non-resonant heteroaromatic C–H substrates.

Reported as isolated yield unless otherwise specified. ^{a 1}H NMR yield (ext. std. = mesitylene) ^b 0.5 mmol scale ^c 0.05 mmol scale ^d Reaction time 8 h

Figure 7.. t-SNE analysis and HTE 96-well plate assessment of amine, carboxylic acid and alcohol nucleophilic coupling partners with isolated chloride 2c.

HTE yields reported based on liquid chromatography area percent (LCAP), accounting for all observed analytes. Hit rate defined as percent of nucleophiles with LCAP ≥ 10%. Isolated yields were reported for 6 examples. See section 7 in the Supplemental Information for details.

Figure 8.. Sequential chlorination/ nucleophilic displacement of two C–H substrates with amine, phenol and carboxylic acid coupling partners.

LCAP reported over 2 steps. Representative examples reported as isolated yield over two steps.