COMMUNICATION DOI: 10.1002/asia.201402510
Copper-Promoted Site-Selective Acyloxylation of Unactivated CACHTUNGRE(sp3) H Bonds Xuesong Wu,[a] Yan Zhao,[a, b] and Haibo Ge*[a, b]
ligand-directed CACHTUNGRE(sp3) H bond functionalization via palladium catalysis,[12] herein we report the direct acyloxylation of aliphatic amides on unactivated sp3 carbons. Our investigation began with the direct acetoxylation of N-(quinolin-8-yl)pivalamide (1 a) with catalytic CuACHTUNGRE(OAc)2 in the presence of 1.5 equivalents of K2HPO4 as the base and 3.0 equivalents of AgOAc as the oxidant and additional acetate source at 170 8C (Table 1). After an initial solvent
Abstract: The site-selective acyloxylation of aliphatic amides was achieved via a copper-promoted CACHTUNGRE(sp3) H bond functionalization process directed by a bidentate ligand. The reaction showed a great preference for activating C H bonds of b-methyl groups over those of g-methyl and unactivated methylene groups.
Direct functionalization of unactivated C H bonds is of current research interest in organic chemistry, and significant progress has been achieved in the last couple of decades.[1] Within this reaction category, the copper-catalyzed bidentate ligand-directed process has attracted great attention in recent years.[2] Inspired by the report on copper-catalyzed functionalization of CACHTUNGRE(sp2) H bonds by the group of Yu,[3] Daugulis and co-workers reported the first example of copper-promoted bidentate ligand-directed C H functionalization reactions on sp2 carbons in 2012: the sulfenylation of benzoic acid and benzylamine derivatives.[4] Following this discovery, copper-catalyzed direct amination,[5] amidation,[5b] arylation,[6] chlorination,[7] etherification,[8] and fluorination[9] of arenes were rapidly established. Mechanistically, either an organometallic C H activation/functionalization or a single-electron-transfer pathway is believed to be involved in the process.[5b, 10] In comparison with the well-established CACHTUNGRE(sp2) H bond functionalization process, copper-catalyzed direct functionalization of unactivated CACHTUNGRE(sp3) H bonds is underdeveloped. Very recently, the intramolecular dehydrogenative cyclization of aliphatic amides by a copper-catalyzed CACHTUNGRE(sp3) H bond functionalization process was realized in the group of Kanai and in our laboratory.[11] It is believed that cyclic CuIII complexes are formed in both cases and provide the b-lactam products via reductive elimination. Encouraged by these results and the success of bidentate
Table 1. Optimization of reaction conditions[a]
Base
Solvent
Yield [%][b]
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19[c] 20[e]
CuACHTUNGRE(OAc)2 CuACHTUNGRE(OAc)2 CuACHTUNGRE(OAc)2 CuACHTUNGRE(OAc)2 CuACHTUNGRE(OAc)2 CuACHTUNGRE(OAc)2 CuACHTUNGRE(OAc)2 CuACHTUNGRE(OAc)2 CuACHTUNGRE(OAc)2 CuACHTUNGRE(OAc)2 CuACHTUNGRE(OAc)2 CuACHTUNGRE(OAc)2 CuACHTUNGRE(OAc)2 CuACHTUNGRE(OTf)2 CuBr2 CuCl2 CuOAc CuI CuACHTUNGRE(OAc)2 CuACHTUNGRE(OAc)2
K2HPO4 K2HPO4 K2HPO4 K2HPO4 K2HPO4 K2HPO4 K2HPO4 Na2HPO4 K3PO4 K2CO3 Na2CO3 Li2CO3 PhCO2Na K2HPO4 K2HPO4 K2HPO4 K2HPO4 K2HPO4 K2HPO4 K2HPO4
o-xylene toluene DMF DMA DMSO diglyme NMP NMP NMP NMP NMP NMP NMP NMP NMP NMP NMP NMP NMP NMP
Copper-Promoted Site-Selective Acyloxylation of Unactivated CACHTUNGRE(sp3) H Bonds Xuesong Wu,[a] Yan Zhao,[a, b] and Haibo Ge*[a, b]
ligand-directed CACHTUNGRE(sp3) H bond functionalization via palladium catalysis,[12] herein we report the direct acyloxylation of aliphatic amides on unactivated sp3 carbons. Our investigation began with the direct acetoxylation of N-(quinolin-8-yl)pivalamide (1 a) with catalytic CuACHTUNGRE(OAc)2 in the presence of 1.5 equivalents of K2HPO4 as the base and 3.0 equivalents of AgOAc as the oxidant and additional acetate source at 170 8C (Table 1). After an initial solvent
Abstract: The site-selective acyloxylation of aliphatic amides was achieved via a copper-promoted CACHTUNGRE(sp3) H bond functionalization process directed by a bidentate ligand. The reaction showed a great preference for activating C H bonds of b-methyl groups over those of g-methyl and unactivated methylene groups.
Direct functionalization of unactivated C H bonds is of current research interest in organic chemistry, and significant progress has been achieved in the last couple of decades.[1] Within this reaction category, the copper-catalyzed bidentate ligand-directed process has attracted great attention in recent years.[2] Inspired by the report on copper-catalyzed functionalization of CACHTUNGRE(sp2) H bonds by the group of Yu,[3] Daugulis and co-workers reported the first example of copper-promoted bidentate ligand-directed C H functionalization reactions on sp2 carbons in 2012: the sulfenylation of benzoic acid and benzylamine derivatives.[4] Following this discovery, copper-catalyzed direct amination,[5] amidation,[5b] arylation,[6] chlorination,[7] etherification,[8] and fluorination[9] of arenes were rapidly established. Mechanistically, either an organometallic C H activation/functionalization or a single-electron-transfer pathway is believed to be involved in the process.[5b, 10] In comparison with the well-established CACHTUNGRE(sp2) H bond functionalization process, copper-catalyzed direct functionalization of unactivated CACHTUNGRE(sp3) H bonds is underdeveloped. Very recently, the intramolecular dehydrogenative cyclization of aliphatic amides by a copper-catalyzed CACHTUNGRE(sp3) H bond functionalization process was realized in the group of Kanai and in our laboratory.[11] It is believed that cyclic CuIII complexes are formed in both cases and provide the b-lactam products via reductive elimination. Encouraged by these results and the success of bidentate
Table 1. Optimization of reaction conditions[a]
Base
Solvent
Yield [%][b]
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19[c] 20[e]
CuACHTUNGRE(OAc)2 CuACHTUNGRE(OAc)2 CuACHTUNGRE(OAc)2 CuACHTUNGRE(OAc)2 CuACHTUNGRE(OAc)2 CuACHTUNGRE(OAc)2 CuACHTUNGRE(OAc)2 CuACHTUNGRE(OAc)2 CuACHTUNGRE(OAc)2 CuACHTUNGRE(OAc)2 CuACHTUNGRE(OAc)2 CuACHTUNGRE(OAc)2 CuACHTUNGRE(OAc)2 CuACHTUNGRE(OTf)2 CuBr2 CuCl2 CuOAc CuI CuACHTUNGRE(OAc)2 CuACHTUNGRE(OAc)2
K2HPO4 K2HPO4 K2HPO4 K2HPO4 K2HPO4 K2HPO4 K2HPO4 Na2HPO4 K3PO4 K2CO3 Na2CO3 Li2CO3 PhCO2Na K2HPO4 K2HPO4 K2HPO4 K2HPO4 K2HPO4 K2HPO4 K2HPO4
o-xylene toluene DMF DMA DMSO diglyme NMP NMP NMP NMP NMP NMP NMP NMP NMP NMP NMP NMP NMP NMP
