Pd-catalyzed difluoromethylation of di-, tri- or tetra-substituted vinyl bromides, triflates, tosylates and nonaflates under mild conditions is described. The reaction tolerates a wide range of functional groups, such as bromide, chloride, fluoride, ester, amine, nitrile, and protected carbonyl, thus providing a general route for the preparation of difluoromethylated alkenes.
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Org Lett
October 2024
Key Laboratory of the Ministry of Education for Advanced Catalysis Materials, College of Chemistry and Materials Science, Zhejiang Normal University, Jinhua 321004, China.
We report a visible-light-driven, palladium-catalyzed 1,4-difluoromethylative functionalization of conjugated dienes using chlorodifluoromethane (ClCFH, Freon-22) as a cost-effective difluoromethyl source. The excited palladium catalyst efficiently reduces the C-Cl bond, which generates a CFH radical, followed by regioselective S2' substitution to afford 1,4-difunctionalized products. This versatile, redox-neutral method accommodates diverse nucleophiles and exhibits broad functional group compatibility, making it suitable for late-stage functionalization in drug discovery and offering a direct route to difluoromethylated molecules.
View Article and Find Full Text PDFChemistry
June 2022
Carbon Dioxide Activation Center (CADIAC), The Interdisciplinary Nanoscience Center (iNANO) and, Department of Chemistry, Aarhus University, Gustav Wieds Vej 14, 8000, Aarhus C, Denmark.
An expedient ex-situ generation of difluoroiodomethane (DFIM) and its immediate use in a Pd-catalyzed difluoromethylation of aryl boronic acids and ester derivatives in a two-chamber reactor is reported. Heating a solution of bromodifluoroacetic acid with sodium iodide in sulfolane proved to be effective for the generation of near stoichiometric amounts of DFIM for the ensuing catalytic coupling step. A two-step difluoromethylation of aryl (pseudo)halides with tetrahydroxydiboron as a low-cost reducing agent, both promoted by Pd catalysis, proved effective to install this fluorine-containing C group onto several pharmaceutically relevant molecules.
View Article and Find Full Text PDFJ Am Chem Soc
November 2021
Department of Chemistry, University of Michigan, 930 North University Avenue, Ann Arbor, Michigan 48109, United States.
This Article describes the development of a decarbonylative Pd-catalyzed aryl-fluoroalkyl bond-forming reaction that couples fluoroalkylcarboxylic acid-derived electrophiles [RC(O)X] with aryl organometallics (Ar-M'). This reaction was optimized by interrogating the individual steps of the catalytic cycle (oxidative addition, carbonyl de-insertion, transmetalation, and reductive elimination) to identify a compatible pair of coupling partners and an appropriate Pd catalyst. These stoichiometric organometallic studies revealed several critical elements for reaction design.
View Article and Find Full Text PDFOrg Biomol Chem
May 2019
Division of Chemistry, Faculty of Pure and Applied Sciences, University of Tsukuba, Tsukuba, Ibaraki 305-8571, Japan.
The insertion of 1,1-difluoroallenes was carried out to form a C-C bond exclusively on their central carbon. o-Bromophenyl-bearing 1,1-difluoroallenes underwent intramolecular insertion in the presence of a palladium catalyst. Regioselective C-C bond formation occurred to form a six-membered carbocycle, leading to pharmaceutically and agrochemically promising difluoromethylated naphthalenes.
View Article and Find Full Text PDFAngew Chem Int Ed Engl
March 2019
Leibniz-Institut für Katalyse an der, Universität Rostock, Albert-Einstein-Straße 29a, 18059, Rostock, Germany.
The first catalyst for the alkoxycarbonylation of gem-difluoroalkenes is described. This novel catalytic transformation proceeds in the presence of Pd(acac) /1,2-bis((di-tert-butylphosphan-yl)methyl)benzene (btbpx) (L4) and allows for an efficient and straightforward access to a range of difluoromethylated esters in high yields and regioselectivities. The synthetic utility of the protocol is showcased in the practical synthesis of a Cyclandelate analogue using this methodology as the key step.
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