C(sp3)–heteroatom bond formation by iron-catalyzed soft couplings
Julius Semenya, Yuan-Jie Yang, Hye Joon Lee, Kimberly A. Giannantonio, Rikhil Manduva, Elias Picazo
Abstract
Carbon–heteroatom bonds are of great importance due to their prevalence in pharmaceuticals, agrochemicals, materials, and natural products. Despite the effective use of metal-catalyzed cross-coupling reactions between sp2-hybridized organohalides and soft heteroatomic nucleophiles for carbon–heteroatom bond formation, the use of sp3-hybridized organohalides remain limited and the coupling with thiols remains elusive. Here, we report the coupling of sp3-hybridized benzyl or tertiary halides with soft thiol nucleophiles catalyzed by iron and extend the utility to alcohol and amine nucleophiles. The reaction is broad in substrate scope for both coupling partners and applicable in the construction of congested tri- and tetrasubstituted carbon centers as well as β-quaternary heteroatomic products. The synthetic utility is further emphasized by gram-scale synthesis and rapid herbicide library synthesis. Overall, we provide an efficient method to prepare pharmaceutically and materially relevant carbon–heteroatom bonds by expanding iron-catalyzed cross-coupling reactions to the coupling of sp3-hybridized organohalides with soft nucleophiles. Carbon–heteroatom bonds are of great importance in organic chemistry, however, synthetic approaches to access broad substrates remain limited. Here, the authors report an iron-catalyzed soft coupling of sp3-hybridized benzyl or tertiary halides with soft thiol, alcohol and amine nucleophiles.