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Categories: C-C Bond Formation > Heteroatom-containing Molecules, Chains > Trifluoromethylation

Synthesis of benzylic trifluoromethanes

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A one-pot metal-free decarboxylative procedure for accessing β,β,β-trifluoroethylarenes and -heteroarenes from readily available ketones and aldehydes features several benefits, including ease of operation, readily available reagents, mild reaction conditions, high functional-group compatibility, and scalability.
Y. Qiao, T. Si, M.-H. Yang, R. A. Altman, J. Org. Chem., 2014, 79, 7122-7131.


A general, copper-mediated chemoselective trifluoromethylation at the benzylic position of a wide variety of benzyl bromides facilitates the rapid creation of structurally diverse medicinal candidates in drug discovery in good yields under mild conditions by the use of a shelf-stable electrophilic trifluoromethylating reagent.
H. Kawai, T. Furukawa, Y. Nomura, E. Tokunaga, N. Shibata, Org. Lett., 2011, 13, 3596-3599.


Trifluoroethylarenes can be directly accessed via nucleophilic trifluoromethylation of benzylic electrophiles, but current catalytic methods fail to transform electron-deficient substrates and heterocycles. A Cu-catalyzed decarboxylative trifluoromethylation of benzylic bromodifluoroacetates effectively provides a wide range of trifluoroethylarenes.
B. R. Ambler, L. Zhu, R. A. Altman, J. Org. Chem., 2015, 80, 8449-8457.


A light-driven, copper-mediated trifluoromethylation of O-alkyl thiocarbonates offers broad functional group tolerance (e.g., alkyne, alkene, phenol, free alcohol, electron-rich and -deficient arenes), orthogonality and practicality. A radical organometallic mechanism is proposed.
Z.-Y. Liu, S. P. Cook, Org. Lett., 2021, 23, 739-744.


In the presence of AgNO3 as the catalyst and K2S2O8 as the oxidant, reactions of aliphatic carboxylic acids with (bpy)Cu(CF3)3 and ZnMe2 in aqueous acetonitrile at 40C provide the corresponding decarboxylative trifluoromethylation products in good yield. The protocol is applicable to various primary and secondary alkyl carboxylic acids and exhibits wide functional group compatibility.
X. Tan, Z. Liu, H. Shen, P. Zhang, Z. Zhang, C. Li, J. Am. Chem. Soc., 2017, 139, 12430-12433.


The copper-catalyzed ring-opening of arylcyclopropanes in the presence of N-fluorobis(arenesulfonyl)imides and (2,2′-bipyridine)Zn(CF3)2 affords γ-trifluoromethylated amines in good yields at room temperature.
H. Zhang, H. Xiao, F. Jiang, Y. Fang, L. Zhu, C. Li, Org. Lett., 2021, 23, 2268-2272.

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A nickel-catalyzed reductive cross-coupling between industrial chemical CF3CH2Cl and (hetero)aryl bromides and chlorides is synthetically simple, avoids the preparation of arylmetals, and exhibits high functional group tolerance.
X. Li, X. Gao, C.-Y. He, X. Zhang, Org. Lett., 2021, 23, 1400-1405.


A readily available nickel/bis(oxazoline) catalyst effectively distinguishes between a CF3 and an alkyl group and accomplishes a wide array of enantioconvergent cross-couplings of arylzinc reagents with CF3-substituted racemic secondary alkyl halides. This method can also be applied without modification to the asymmetric synthesis of other families of fluorinated organic compounds.
Y. Liang, G. C. Fu, J. Am. Chem. Soc., 2015, 137, 9523-9526.


A nickel-catalyzed enantioselective cross-coupling reaction of aryl titanates with α-CF3-benzyl bromides enables the synthesis of chiral α-CF3-substituted benzhydryls in good yields and excellent enantioselectivities. The use of commercially available anesthetic halothane as a cheap fluorinated building block in a sequential one-pot reaction with two different aryl titanates is also described.
A. Varenikov, E. Shapiro, M. Gandelman, Org. Lett., 2020, 22, 9386-9391.