Categories: C-F Bond Formation >
Synthesis of 1,1-difluoroalkanes
Bis(2-methoxyethyl)aminosulfur trifluoride (Deoxo-Fluor reagent) is a new deoxofluorinating agent that is much more thermally stable than DAST (C2H5)2NSF3. It is effective for the conversion of alcohols to alkyl fluorides, aldehydes and ketones to the corresponding gem-difluorides, and carboxylic acids to the trifluoromethyl derivatives with, in some cases, superior performance compared to DAST.
G. S. Lal, G. P. Pez, R. J. Pesaresi, F. M. Prozonic, H. Cheng, J. Org. Chem., 1999, 7048-7054.
Aminodifluorosulfinium tetrafluoroborate salts act as efficient deoxofluorinating reagents when promoted by an exogenous fluoride source and, in most cases, exhibited greater selectivity by providing less elimination byproduct as compared to DAST and Deoxo-Fluor. Aminodifluorosulfinium tetrafluoroborates are storage-stable, and unlike DAST and Deoxo-Fluor do not react violently with water.
F. Beaulieu, L.-P. Beauregard, G. Courchesne, M. Couturier, F. LaFlamme, A. L'Heureux, Org. Lett., 2009, 11, 5050-5053.
Easily prepared 2-alkyl-1,3-dithiane derivatives were reacted with BrF3 to form the corresponding 1,1-difluoromethyl alkanes in good yield. The reaction proceeds well with primary alkyl halides. The limiting step for secondary alkyl halides is the relatively low yield of the dithiane preparation.
R. Sasson, A. Hagooly, S. Rozen, Org. Lett., 2003, 59, 3635-3641.
A Ag-catalyzed decarboxylative fluorination reaction provides an unprecedented route to either gem-difluoroalkanes or α-fluorocarboxylic acids from malonic acid derivatives by the judicious selection of base and solvent. This reaction features the use of readily available starting materials, tunable chemoselectivity and good functional group compatibility.
Z. Wang, C.-Y. Guo, C. Yang, J.-P. Chen, J. Am. Chem. Soc., 2019, 141, 5617-5622.
Fluorination of styrene derivatives with a reagent system composed of μ-oxo-bis[trifluoroacetato(phenyl)iodine] or PhI(OCOCF3)2 and a pyridine·HF complex gave the corresponding (2,2-difluoroethyl)arenes in good yields. Catalytic conditions using 4-iodotoluene as a catalyst and m-CPBA as a terminal oxidant are possible.
T. Kitamura, K. Muta, J. Oyamada, J. Org. Chem., 2015, 80, 10431-10436.
The nucleophilic fluorination reagent DMPU/HF offers high acidity and is compatible with cationic metal catalysts. Gold-catalyzed mono- and dihydrofluorination of alkynes using this stable complex yields synthetically important fluoroalkenes and gem-difluoromethlylene compounds regioselectively.
O. E. Okoromoba, J. Han, G. B. Hammond, B. Xu, J. Am. Chem. Soc., 2014, 136, 14381-14384.
The combination of sulfuryl fluoride and Me4NF enables a room temperature deoxyfluorination of a broad range of benzaldehydes and α-ketoesters.
P. R. Melvin, D. M. Ferguson, S. D. Schimler, D. C. Bland, M. S. Sanford, Org. Lett., 2019, 21, 1350-1353.
A desulfurizing difluorination reaction of benzyl sulfides having an electron-withdrawing group such as an ester, a ketone, a nitrile, or an amide in the presence of IF5 gave gem-difluoro compounds in good yield.
T. Fukuhara, S. Hara, Synlett, 2009, 198-200.
The combination of PhIO and HF·py enables fluorination of functionalized aromatic olefins bearing synthetically important carbonyl and hydroxyl groups. Fluorination of for example 1,3-diphenyl-2-propen-1-one with PhIO/HF·py reagent gave 3,3-difluoro-1,2-diphenyl-1-propanone in high yield. The fluorination of cinnamyl alcohol derivatives proceeded smoothly to afford 2-aryl-3,3-difluoro-1-propanols in moderate yields.
T. Kitamura, K. Yoshida, S. Mizuno, A. Miyake, J. Oyamada, J. Org. Chem., 2018, 83, 14834-14841.
Various thiocarbonyl derivatives (thioketones, thioesters, thioamides, dithioesters, and dithiocarbamates) were converted to the corresponding gem-difluorides in excellent yields on reaction with bis(2-methoxyethyl)aminosulfur trifluoride as fluorinating reagent in the presence of SbCl3.
G. S. Lal, E. Lobach, A. Evans, J. Org. Chem., 2000, 65, 4830-4832.
Peri-xanthenoxanthene mediates a reaction of an iododifluoromethylphosphonium salt with unactivated alkenes under blue-light irradiation. This iododifluoromethylation proceeds via activation of the carbon-iodine bond to generate a (phosphonio)difluoromethyl radical cation, which attacks the double bond with subsequent quenching by the iodine.
A. L. Trifonov, L. I. Panferova, V. V. Levin, V. A. Kokorekin, A. D. Dilman, Org. Lett., 2020, 22, 2409-2413.
A MW-based protocol enables a rapid preparation of 1,1-difluorocyclopropanes, using fluorinated acetate salts. The new procedure is not only considerably faster than conventional methods, but it also employs easily removed, low boiling-point solvents and avoids the use of highly toxic or ozone-depleting substances.
D. M. Gill, N. McLay, M. J. Waring, C. T. Wilkinson, J. B. Sweeney, Synlett, 2014, 25, 1756-1758.
Sodium bromodifluoroacetate (BrCF2CO2Na) is an effective difluorocarbene source for high-yielding synthesis of gem-difluorocyclopropanes and gem-difluorocyclopropenes under mild conditions.
K. Oshiro, Y. Morimoto, H. Amii, Synthesis, 2010, 2080-2084.