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

Synthesis of trifluoromethyl arenes


Recent Literature

Fluoride ions induce a cross-coupling reaction of organic halides with trifluoromethyltrialkylsilanes in the presence of Cu(I) salts under mild reaction conditions to provide the corresponding trifluoromethylated products in good yields.
M. Oishi, H. Kondo, H. Amii, Chem. Commun., 2009, 86, 1909-1911.

An efficient and broadly applicable copper-catalyzed trifluoromethylation of aromatic iodides with TMSCF3 was achieved in the presence of borate. Trimethylborate anchors in situ generated trifluoromethyl anion and suppress its rapid decomposition.
Z. Gonda, S. Kovács, C. Wéber, T. Gáti, A. Mészáros, A. Kotschy, Z. Novák, Org. Lett., 2014, 16, 4268-4271.

Fluoride ions induce a cross-coupling reaction of organic halides with trifluoromethyltrialkylsilanes in the presence of Cu(I) salts under mild reaction conditions to provide the corresponding trifluoromethylated products in good yields.
H. Urata, T. Fuchikami, Tetrahedron Lett., 1991, 32, 91-94.

A highly efficient Rh-catalyzed carbenoid addition to trifluoromethylthioether enables the formation of a trifluoromethyl-substituted sulfonium ylide. This ylide can act as an electrophilic trifluoromethylation reagent, as demonstrated by trifluoromethylation of β-ketoesters and aryl iodides.
S. Liu, X. Shao, P. Zhang, L. Lu, Q. Shen, Org. Lett., 2015, 17, 2752-2755.

Trifluoromethylcopper (“CuCF3”) species can be generated from readily available phenyl trifluoromethyl sulfoxide. The reagent can be applied in efficient trifluoromethylations of aryl iodides and activated aryl bromides in the absence of additional ligands. Furthermore, the “CuCF3” species can also undergo oxidative cross-coupling with terminal alkynes and arylboronic acids.
X. Li, J. Zhao, L. Zhang, M. Hu, L. Wang, J. Hu, Org. Lett., 2015, 17, 298-301.

A mild, copper-catalyzed cross-coupling of Ruppert-Prakash type reagents (TMSCF3, TMSC2F5, and TMSC3F7) with aryl and alkyl bromides provides a diverse array of trifluoromethyl, pentafluoroethyl, and heptafluoropropyl adducts. This light-mediated transformation enables also the late-stage functionalization of several drug analogues.
X. Zhao, D. W. C. MacMillan, J. Am. Chem. Soc., 2020, 142, 19480-19486.

A copper-catalyzed trifluoromethylation of aryl- and alkenylboronic acids with Togni’s reagent proceeded in good to excellent yields for a range of different substrates including heteroarylboronic acids and substrates with a variety of functional groups under mild reaction conditions.
T. Liu, Q. Shen, Org. Lett., 2011, 13, 2342-2345.

A mild and practical protocol for the copper-mediated trifluoromethylation of aryl and heteroaryl boronic acids using NaSO2CF3 (Langlois’ reagent) and TBHP proceeds at room temperature under ambient conditions. The products can be readily purified by extraction or column chromatography.
Y. Ye, S. A. Künzi, M. S. Sanford, Org. Lett., 2012, 14, 4979-7981.

A mild method for the trifluoromethylation of arylboronic acids has been developed via the merger of photoredox and Cu catalysis with CF3I. This approach allows trifluoromethylation of electronically diverse aromatic and heteroaromatic substrates, and tolerates many common functional groups.
Y. Ye, M. S. Sanford, J. Am. Chem. Soc., 2012, 134, 9034-9037.

A mild copper-catalyzed trifluoromethylation of (hetero)arylboronic acid pinacol esters with YlideFluor provides trifluoromethylated (hetero)arenes in high yields. The reaction conditions are compatible with a broad range of functional groups.
J. Liu, Y. Xiao, J. Hao, Q. Shen, Org. Lett., 2023, 25, 1204-1208.

Catalytic trifluoromethylation of aryl- and vinylboronic acids by 2-cyclopropyl-1-(trifluoromethyl)benzo[b]thiophenium proceeded in good yields for various substrates in the presence of a catalytic amount of CuOAc and 2,4,6-collidine in ethyl acetate under mild reaction conditions at room temperature.
S. Arimori, N. Shibata, Org. Lett., 2015, 17, 1632-1635.

Fluoroform-derived CuCF3 exhibits remarkably high reactivity toward aryl and heteroaryl halides. A broad variety of iodoarenes undergo smooth trifluoromethylation with the ligandless CuCF3 to give the corresponding benzotrifluorides in nearly quantitative yield. A number of much less reactive aromatic bromides also have been trifluoromethylated.
A. Lishchynskyi, M. A. Novikov, E. Martin, E. C. Escudero-Adán, P. Novák, V. V. Grushin, J. Org. Chem., 2013, 78, 11126-11146.

Difluorocarbene derived from various carbene precursors could be effectively decomposed by 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) into a fluoride ion and carbon monoxide. This decomposition process was successfully combined with a trifluoromethylation of various (hetero)aryl iodides without the addition of an external fluoride ion.
J. Zheng, J.-H. Lin, X.-Y. Deng, J.-C. Xiao, Org. Lett., 2015, 17, 532-535.

A range of benzotrifluorides are conveniently accessible in high yields from diazonium salts and the inexpensive trifluoromethylating agent TMSCF3 through a copper-mediated Sandmeyer trifluoromethylation reaction. The combination of diazotization and trifluoromethylation in a one-pot procedure enables the trifluoromethylation of widely available (hetero)aromatic amines.
G. Danoun, B. Bayermagnai, M. F. Grünberg, C. Matheis, E. Risto, L. J. Gooßen, Synthesis, 2014, 46, 2283-2286.

A mild, copper-promoted Sandmeyer trifluoromethylation of aromatic amines proceeds smoothly and exhibits good tolerance of many synthetically relevant functional groups. The reaction provides an alternative approach for the synthesis of trifluoromethylated arenes and heteroarenes.
J.-J. Dai, C. Fang, B. Xiao, J. Yi, J. Xu, Z.-J. Liu, X. Lu, L. Liu, Y. Fu, J. Am. Chem. Soc., 2013, 135, 8436-8439.

A metal-free, cascade regio- and stereoselective trifluormethyloximation, cyclization, and elimination strategy of readily available α,β-unsaturated carbonyl compounds with CF3SO2Na and tBuONO provides a wide variety of 4-(trifluoromethyl)isoxazoles. Mechanistic studies revealed a radical pathway for the reaction.
P. Pattanayak, T. Chatterjee, J. Org. Chem., 2023, 88, 5420-5430.

A copper-mediated remarkable domino sequence of cyclization, trifluoromethylation, and detosylation provides 4-(trifluoromethyl)pyrazoles from readily accessible α,β-alkynic tosylhydrazones and commercially available trifluoromethyltrimethylsilane as the CF3 source. The reaction conditions are mild and convenient with good functional group compatibility, at room temperature in air.
Q. Wang, L. He, K. K. Li, G. C. Tsui, Org. Lett., 2017, 19, 658-661.

The use of the well-established fluoroform-derived CuCF3 reagent enables the synthesis of 2-(trifluoromethyl)indoles from easily accessible 2-alkynylanilines via a domino trifluoromethylation/cyclization strategy. 3-formyl-2-(trifluoromethyl)indoles can also be synthesized, which are useful intermediates for the preparation of trifluoromethylated drug analogues.
Y. Ye, K. P. S. Cheung, L. He, G. C. Tsui, Org. Lett., 2018, 20, 1676-1679.