Aryl Radical Activation of C-O Bonds: Copper-Catalyzed Deoxygenative Difluoromethylation of Alcohols

被引:57
作者
Cai, Aijie [1 ]
Yan, Wenhao [1 ]
Liu, Wei [1 ]
机构
[1] Univ Cincinnati, Dept Chem, Cincinnati, OH 45221 USA
关键词
MEDIATED DIFLUOROMETHYLATION; EASY ACCESS; HALIDES; GENERATION; TRIFLUOROMETHYLATION; ISOTHIOCYANATES; OXALATES; IODIDES;
D O I
10.1021/jacs.1c04254
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
Given their ubiquity in natural products and pharmaceuticals, alcohols represent one of the most attractive starting materials for the construction of C-C bonds. We report herein the first catalytic strategy to harness the reactivity of aryl radicals for the activation of C-O bonds in alcohol-derived xanthate esters, allowing for the discovery of the first catalytic deoxygenative difluoromethylation reaction. Under copper-catalyzed conditions, a wide variety of alkyl xanthate esters, readily synthesized from alcohol feedstocks, were activated by catalytically generated aryl radicals and were converted to the alkyl-difluoromethane products via alkyl radical intermediates. This scalable protocol exhibits a broad substrate scope and functional group tolerance, enabling late-stage modification of complex pharmaceutical agents. A one-pot protocol has been developed that allows for the direct use of free alcohols without purification of the xanthate esters. Mechanistic studies are consistent with the hypothesis of aryl radicals being formed and initiating the cleavage of the C-O bonds of xanthate esters, to generate alkyl radicals as the key intermediates. This aryl radical activation approach represents a new strategy for the activation of alcohols as cross-coupling partners.
引用
收藏
页码:9952 / 9960
页数:9
相关论文
共 72 条
[1]   Copper-catalyzed allylic difluoromethylation of allyl carbonates with (difluoromethyl)zinc reagent [J].
Aikawa, Kohsuke ;
Ishii, Koki ;
Endo, Yu ;
Mikami, Koichi .
JOURNAL OF FLUORINE CHEMISTRY, 2017, 203 :122-129
[2]   Palladium-Catalyzed Negishi Cross-Coupling Reaction of Aryl Halides with (Difluoromethyl)zinc Reagent [J].
Aikawa, Kohsuke ;
Serizawa, Hiroki ;
Ishii, Koki ;
Mikami, Koichi .
ORGANIC LETTERS, 2016, 18 (15) :3690-3693
[3]   Selective Cross-Coupling of Organic Halides with Allylic Acetates [J].
Anka-Lufford, Lukiana L. ;
Prinsell, Michael R. ;
Weix, Daniel J. .
JOURNAL OF ORGANIC CHEMISTRY, 2012, 77 (22) :9989-10000
[4]   NEW METHOD FOR DEOXYGENATION OF SECONDARY ALCOHOLS [J].
BARTON, DHR ;
MCCOMBIE, SW .
JOURNAL OF THE CHEMICAL SOCIETY-PERKIN TRANSACTIONS 1, 1975, (16) :1574-1585
[5]   Recent Progress toward the Introduction of Functionalized Difluoromethylated Building Blocks onto C(sp2) and C(sp) Centers [J].
Belhomme, Marie-Charlotte ;
Besset, Tatiana ;
Poisson, Thomas ;
Pannecoucke, Xavier .
CHEMISTRY-A EUROPEAN JOURNAL, 2015, 21 (37) :12836-12865
[6]   Cascade radical reactions via α-(arylsulfanyl)imidoyl radicals:: Competitive [4+2] and [4+1] radical annulations of alkynyl isothiocyanates with aryl radicals [J].
Benati, L ;
Calestani, G ;
Leardini, R ;
Minozzi, M ;
Nanni, D ;
Spagnolo, P ;
Strazzari, S ;
Zanardi, G .
JOURNAL OF ORGANIC CHEMISTRY, 2003, 68 (09) :3454-3464
[7]   Synthesis, Reactivity, and Catalytic Applications of Isolable (NHC)Cu(CHF2) Complexes [J].
Bour, James R. ;
Kariofillis, Stavros K. ;
Sanford, Melanie S. .
ORGANOMETALLICS, 2017, 36 (07) :1220-1223
[8]   Recent Applications of the (TMS)3SiH Radical-Based Reagent [J].
Chatgilialoglu, Chryssostomos ;
Lalevee, Jacques .
MOLECULES, 2012, 17 (01) :527-555
[9]   A Systematic Review of the Safety of Lisdexamfetamine Dimesylate [J].
Coghill, David R. ;
Caballero, Beatriz ;
Sorooshian, Shaw ;
Civil, Richard .
CNS DRUGS, 2014, 28 (06) :497-511
[10]  
Colucci Philippe, 2013, Eur Endocrinol, V9, P40, DOI 10.17925/EE.2013.09.01.40