title: Room-temperature Negishi cross-coupling of unactivated alkyl bromides with alkyl organozinc reagents utilizing a Pd/N-heterocyclic carbene catalyst.
abstract: A high-yielding cross-coupling reaction of unactivated alkyl bromides possessing beta-hydrogens with alkylzinc halides utilizing a Pd/N-heterocyclic carbene (NHC) catalyst at room temperature is described. A variety of Pd sources, Pd2(dba)3, Pd(OAc)2, or PdBr2, with the commercially available ligand precursor 1,3-bis(2,6-diisopropylphenyl)imidazolium chloride (IPr.HCl) successfully coupled 1-bromo-3-phenylpropane with n-butylzinc bromide in THF/NMP. An investigation of different NHC precursors showed that the bulky 2,6-diisopropylphenyl moiety was necessary to achieve high coupling yields (75-85%). The corresponding ethyl analogue was moderately active (11%). A range of unsymmetrical NHC precursors were prepared and evaluated. The ligand precursor containing one 2,6-diisopropylphenyl and one 2,6-diethylphenyl afforded the coupling product in 47% yield, clearly suggesting a direct relationship between the steric topography created by the flanking N-substituents and catalyst activity. Under optimal conditions, a number of alkyl bromides and alkylzinc halides possessing common functional groups (amide, nitrile, ester, acetal, and alkyne) were effectively coupled (61-92%). It is noteworthy that beta-substituted alkyl bromides and alkylzinc halides successfully underwent cross-coupling. Also, under these conditions alkyl chlorides were unaffected.
authors.affiliation: Department of Chemistry, York University, 4700 Keele Street Toronto, ON, Canada M3J 1P3.
authors.forename: Niloufar
authors.initials: N
authors.lastname: Hadei
authors.forename: Eric Assen B
authors.initials: EA
authors.lastname: Kantchev
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: O'Brien
authors.forename: Michael G
authors.initials: MG
authors.lastname: Organ