Oxidant-Triggered C₁-Benzylation of Isoquinoline by Iodine-­Catalyzed Cross-Dehydrogenative-Coupling with Methylarenes

Abstract

A practical iodine-catalyzed oxidative functionalization of isoquinolines with methylarenes is developed, which can be triggered by the selected oxidants to produce C₁- or N-benzyl-substituted products selectively. This method utilizes readily available isoquinolines and methylarenes as starting materials and proceeds under metal-free conditions with broad substrate scope with respect to methylarenes, avoiding the usage of expensive metal catalysts and generation of halide and metal wastes.

Key words

benzylation - Minisci reaction - iodine - isoquinoline - isoquinolinone

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• 11 A general experimental procedure for this CDC is described as following: an oven-dried reaction vessel was charged with isoquinoline (1a, 0.4 mmol, 1 equiv), I₂ (0.02 mmol, 5.2 mg, 5 mol%), DTBP (di-tert-butyl peroxide, 1.2 mmol, 3 equiv) in p-xylene (1 mL) under air. The vessel was sealed and heated at 130 °C for 12 h, then cooled to r.t. The resulting mixture was transferred to a silica gel column and eluted with hexanes and EtOAc (12:1) to give 1-(4-methylbenzyl)isoquinoline (3a) in 71% yield as a yellow oil. ¹H NMR (400 MHz, CDCl₃): δ = 8.49 (d, J = 5.6 Hz, 1 H), 8.15 (d, J = 8.0 Hz, 1 H), 7.80 (d, J = 8.0 Hz, 1 H), 7.62 (t, J = 7.4 Hz, 1 H), 7.50–7.55 (m, 2 H), 7.17 (d, J = 7.3 Hz, 2 H), 7.05 (d, J = 7.4 Hz, 2 H), 4.63 (s, 2 H), 2.27 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 160.48, 142.11, 136.67, 136.49, 135.81, 129.88, 129.30, 128.59, 127.41, 127.28, 127.25, 125.94, 119.82, 41.76, 21.07.