Cu~0Promoted Cross-coupling Reactionof2-(Bromodifluoromethyl) Benzo-1,3-diazole With Aryl/Alkenyl Halides

Introduction of gem-difluoromethylene unit to organic compounds cansignificantly enhance biological activities of thecompounds.Therefore,gem-difluoromethylenecontaining compounds have beenwidespread concerned. In this paper, the cross-coupling of2-（bromodifluoromethyl）benzo-1,3-diazole building blockwith aryl/alkenyl halidesin thepromotion of copper was studied, the gem-difluoromethylene linkedbenzo-1,3-diazole-containingcompounds which have potential biological activitieswere successfully synthesized, and mechanism of this cross-coupling reaction wasalso explored.The reaction conditions of2-（bromodifluoromethyl）benzo-1,3-oxazole withethyl-4-iodobenzoate and methyl-2-iodobenzoate wereoptimized: the reaction toprovide the best yield at room temperature in DMSO under the molar ratio ofgem-difluoromethylene-containing block: methyl-2-iodobenzoate: copper was1.2:1:2.5, whilethe optimal condition of the cross-coupling reaction ofethyl-4-iodobenzoate with2-（bromodifluoromethyl）-benzo-1,3-oxazole at roomtemperature was observed under the molar ratio ofgem-difluoromethylene-containing block: ethyl-4-iodobenzoate: copper=3:1:6.9.Under these optimal conditions, more than30gem-difluoromethylenelinkedcompounds were obtained which were confirmed by means of1H NMR,¹⁹FNMR,¹³C NMR and IR etc. Not only halogenated aromatics but also halogenatedolefinscould be successfully carried out with good yields in the cross-couplingreactions. And the neighboring group effect was shown in the cross-couplingreactions. In addition, reactive groups （such as–COOEt,-COOMe,-OMe,-CH₂OMe,-NO₂, X） have a good tolerability to this cross-coupling conditions. Othergem-difluoromethylene-containing blocks such as2-（bromodifluoromethyl）benzo-1,3-thiazole, 2-（bromodifluoromethyl）-1-butyl-1,3-benzoimidazole and2-（bromo-difluoromethyl）-4-butyl-6-methyl-quinoline can also participate in thecross-coupling reaction.After studing the effectof the feeding sequence and the amount of copper in thereaction,discussion on the effect of neighboring group, the influence of ligands, andtheconsumption of the excess fluorine-containing substrates, as well as structure ofthe fluorine-containing substrates in the cross-coupling reaction, the reactionmechanism was proposed. A single electron transfer process between CF2Brsubstitutedbenzo-1,3-diazole building block and copper powder gave a RCF2-Cuintermediate, which reacted with various aryl/alkenyl halides and providedcross-coupling products.And neighboring group can play a stabilizing roleonintermediates in oxidative additionprocess.