Polar Heterobenzylic C(sp3)-H Chlorination Pathway Enabling Efficient Diversification of Aromatic Nitrogen Heterocycles

Abstract

Site-selective radical reactions of benzylic C-H bonds are now highly effective methods for C(sp³-H) functionalization and cross-coupling. The existing methods, however, are often ineffective with heterobenzylic C-H bonds in alkyl-substituted pyridines and related aromatic heterocycles that are prominently featured in pharmaceuticals and agrochemicals. Here, we report new synthetic methods that leverage polar, rather than radical, reaction pathways to enable the selective heterobenzylic C-H chlorination of 2- and 4-alkyl-substituted pyridines and other heterocycles. Catalytic activation of the substrate with trifluoromethanesulfonyl chloride promotes the formation of enamine tautomers that react readily with electrophilic chlorination reagents. The resulting heterobenzyl chlorides can be used without isolation or purification in nucleophilic coupling reactions. This chlorination-diversification sequence provides an efficient strategy to achieve heterobenzylic C-H cross-coupling with aliphatic amines and a diverse collection of azoles, among other coupling partners.

Figure 1.

Effective C–H functionalization methods at heterobenzylic sites face key challenges relative to benzylic C–H positions (A). Substituted heterobenzylic structures are common in bioactive molecules (B), and selective heterobenzylic chlorination/diversification (C) provide a key strategy to access such target structures.

Figure 2.

Precedent for heterobenzylic fluorination with NFSI, involving in situ formation of an alkylidene dihydropyridine intermediate (A) and strategy to expand on this concept through in situ pyridine activation of chlorination via a polar reaction pathway (B).

Figure 3.

Relative free energies among 2-, 3-, and 4-ethylpyridines (EP) and their corresponding alkylidene dihydropyridine isomers (EP′) (A) and among deprotonated N-triflyl derivatives of 2-, 3-, and 4-ethylpyridine (EP′-Tf).

Figure 4.

Precedent for polar chlorination of 7,8-dihydroquinolin-5(6H)-one with trichloroisocyanuric acid (TCCA) (A), and preliminary assessment of optimized TCCA conditions to other substrates (B). Reactions conducted 0.05 mmol scale. Yields determined by ¹H NMR spectroscopy (ext. std. = dibromoethane).

Figure 5.

Heterobenzylic C–H chlorination data obtained with different polar and radical chlorination methods a – i to access 3 and 4. Yields determined by ¹H NMR spectroscopy (ext. std. = dibromoethane) and or UPLC area percentages of chloride products.

Figure 6.

Scope of heterobenzylic polar chlorination reactions. Reactions were typically conducted on a 0.05 mmol scale, with 1 and 3 mmol examples specifically noted. Yields determined by ¹H NMR spectroscopy (ext. std. = dibromoethane). ^a Reactions run at 70 °C. ^b Reaction run at 45 °C ^c Reaction run at 65 °C. See Section 6 in the Supporting Information Section for deviation from standard conditions.

Figure 7.

Diversification of heterobenzylic C–H bonds through tandem C–H chlorination/functionalization, including C–H chlorination and coupling with amine nucleophiles (A), azole nucleophiles (B), in addition to other nucleophiles (C). For full experiment details, see Sections 8 and 9 in the Supporting Information.