Nickel-Catalyzed Reductive Cross-Coupling of Aryl Halides with Alkyl Halides

Introduction of alkyl chains into aromatic rings catalyzed by Nickel.

Transition-metal (Pd, Ni, Fe)-catalyzed methods to form alkylated aromatic compounds are of obvious importance and a part of the typical toolkit of the medicinal chemist. However, most of the every day methods available require the use of an organometallic reagent [RB(OH)2, RBF3K, RZnI, RMgBr] in conjunction with an organohalide. The preparation of the organometallic partner is sometimes more complicated than the coupling itself, so any advance in eliminating that step is worthwhile.

The group of Weix (Rochester, NY, USA) has published a very interesting paper on the Nickel catalyzed alkylation of aryl moieties using only halides as starting materials. According to the authors the new method seems to be the best invention since the striped toothpaste (all jokes aside, is a very interesting invention itself): Equimolar amounts of the halides, high yields, highly functional-group-tolerant [hydroxy groups, amines, ketones, esters, nitriles…) and easy to perform (uses only benchtop-stable reagents, tolerates small amounts of water and oxygen, changes color when completed, and uses filtration workup).

In a typical reaction one equivalent of each halide are mixed along with NiI2·xH2O (10 mol%), 4,4′-di-tert-butyl-2,2′-bipyridine (5 mol%), 1,2-bis(diphenylphosphino)benzene (5 mol%) and pyridine (10 mol%) and Mn (2 eq) in DMPU at 60 °C for several hours. Only one example with a heterocycle (a protected indole) is included, but the type of alkyl branches introduced is really intriguing, including butyl chains with terminal functionalization.

J. Am. Chem. Soc., 2010, 132 (3), pp 920–921. See: 10.1021/ja9093956