Synthesis of trifluoromethyl alkanes
The combination of Et3SiH and K2S2O8 initiates radical reactions of primary and secondary alkyl bromides or iodides with BPyCu(CF3)3 (BPy = 2,2′-bipyridine) in aqueous acetone at room temperature to provide trifluoromethylated products in good yield. The protocol exhibits wide functional group compatibility.
H. Shen, Z. Liu, P. Zhang, X. Tan, Z. Zhang, C. Li, J. Am. Chem. Soc., 2017, 139, 9843-9846.
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.
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 40°C 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.
Organocopper(III) complexes with well-defined structures can undergo reductive elimination for the formation of Csp3-Csp3 bonds. A general method for the synthesis of a series of [alkyl-CuIII-(CF3)3]− complexes followed by reductive elimination provides alkyl-CF3 products with good yields.
M. Paeth, S. B. Tyndall, L.-Y. Chen, J.-C. Hong, W. P. Carson, X. Liu, X. Sun, J. Liu, K. Yang, E. M. Hale, D. L. Tierney, B. Liu, Z. Cao, M.-J. Cheng, W. A. Goddard III, W. Liu, J. Am. Chem. Soc., 2019, 141, 3153-3159.
Trifluoromethyl thianthrenium triflate is a conveniently accessible trifluoromethylating reagent, that can be used in electrophilic, radical, and nucleophilic trifluoromethylation reactions.
H. Jia, A. P. Häring, F. Berger, L. Zhang, T. Ritter, J. Am. Chem. Soc., 2021, 143, 7623-7628.
A single electron oxidation of the commercially available CF3SO2Na (Langlois' reagent) using Mn(OAc)3·2H2O as the oxidant enables a simple and efficient method for hydrotrifluoromethylation of unactivated alkenes. The reaction proceeds readily under mild conditions and tolerates various functional groups.
B. Cui, H. Sun, Y. Xu, L. Li, L. Duan, Y.-M. Li, J. Org. Chem., 2018, 83, 6015-6024.
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.
Sodium trifluoromethanesulfinate and iodine pentoxide as safe solid reagents enable a scalable, selective, and convenient iodotrifluoromethylation of a wide range of alkenes and alkynes in aqueous medium. Mechanistic studies confirm a free-radical processes, in which key radical intermediates such as CF3 and β-CF3 alkyl radicals have been detected by spin trapping and electron spin resonance.
Z. Hang, Z. Li, Z.-Q. Liu, Org. Lett., 2014, 16, 3648-3651.
A trifluoromethylation of alkenes or alkynes using trifluoromethanesulfonic anhydride (Tf2O) as a trifluoromethylating reagent in the presence of CuX2 (X = Br, Cl), Zn powder, and 2,2'-bipyridine affords bromo(chloro)trifluoromethylated products in good yields. CuX2 plays a dual role as the catalyst and halide source, whereas 2,2′-bipyridine acts as both the activation reagent and ligand.
Y. Ouyang, C.-L. Tong, X.-H. Xu, F.-L. Qing, Org. Lett., 2021, 23, 346-350.
In a photoredox vicinal chlorotrifluoromethylation in the presence of Ru(Phen)3Cl2 as catalyst, various terminal and internal alkenes can be transformed to their vicinal chlorotrifluoromethylated derivatives using CF3SO2Cl as a source for CF3 radicals and chloride ions.
S. H. Oh, Y. R. Malpani, N. Ha, Y.-S. Jung, S. B. Han, Org. Lett., 2014, 16, 1310-1313.
The use of NaSO2CF3 and NaBrO3 enables a free-radical bromotrifluoromethylation of olefins. Sodium bromate acts not only as a single-electron oxidant but also as a bromine source.
Z.-Q. Liu, D. Liu, J. Org. Chem., 2017, 82, 1649-1656.
Trifluoromethylsulfonyl-pyridinium salt (TFSP) is an efficient, solid trifluoromethylation reagent, which can be readily prepared from cheap and easily available bulk industrial feedstocks. TFSP can generate a trifluoromethyl radical under photocatalysis, that can be used for azido- or cyano-trifluoromethylation reactions of alkenes.
M. Zhang, J.-H. Lin, J.-C. Xiao, Org. Lett., 2021, 23, 6079-6083.
A convenient Fe-catalyzed A-D-A-T-type radical-dual-difunctionalization and cross-coupling of two different alkenes provides chain elongated and trifluoromethylated aromatic alkenes.
J. Zhao, R.-X. Liu, C.-P. Luo, L. Yang, Org. Lett., 2020, 22, 6776-6779.
2,4,6-Trimethylpyridine catalyzes a trifluoromethylalkynylation of unactivated alkenes with alkynyl sulfones and Togni's reagent to provide various β-trifluoromethylated alkynes under metal-free conditions with a broad substrate scope and wide functional group compatibility. A mechanism involving catalytic nonchain radical processes is proposed.
S. Zhou, T. Song, H. Chen, Z. Liu, H. Shen, C. Li, Org. Lett., 2017, 19, 698-701.
A carbene-catalyzed radical trifluoromethylation of olefins with aldehydes in the presence of Togni reagent provides β-trifluoromethyl-α-substituted ketones with a broad scope and good yields.
B. Zhang, Q. Peng, D. Guo, J. Wang, Org. Lett., 2020, 22, 443-447.
A constant current electrolysis synergizing with a Lewis-acid catalysis protocol enables an external oxidant-free oxytrifluoromethylation and aminotrifluoromethylation of styrene derivatives using sodium trifluoromethanesulfinate as the trifluoromethyl source.
L. Zhang, G. Zhang, P. Wang, Y. Li, A. Lei, Org. Lett., 2018, 20, 7396-7399.
An enantioselective copper-catalyzed trifluoromethylalkynylation of styrenes affords structurally diverse CF3-containing propargylic compounds in good yield with excellent enantioselectivities under very mild conditions via a radical relay process. The reaction offers wide substrate scope and good functional group tolerance. The trifluoromethylalkynylated products can be converted into synthetically useful chiral terminal alkynes, allenes, and Z-alkenes.
L. Fu, S. Zhou, X. Wan, P. Chen, G. Liu, J. Am. Chem. Soc., 2018, 140, 10965-10969.
A copper-catalyzed intermolecular cyanotrifluoromethylation of alkenes provides various CF3-containing alkylnitriles with excellent enantiomeric excess. The reaction is initiated by a SET process between activated Togni’s CF3+ reagent and a Cu(I) catalyst. The released CF3 radical readily added to styrene to provide a benzylic radical, which is then trapped by a chiral Cu(II) cyanide species.
F. Wang, D. Wang, X. Wan, L. Wu, P. Chen, G. Liu, J. Am. Chem. Soc., 2016, 138, 15547-15550.
A highly practical copper-catalyzed intermolecular cyanotrifluoromethylation of alkenes provides a general and straightforward way to synthesize various useful CF3-containing nitriles, which can be used for the preparation of pharmaceutically and agrochemically important compounds.
Y.-T. He, L.-H. Li, Y.-F. Yang, Z.-Z. Zhou, H.-L. Hua, X.-Y. Liu, Y.-M. Liang, Org. Lett., 2014, 16, 270-273.
A highly regioselective cyanotrifluoromethylation of electron-deficient styrenes with a trifluoromethylated hypervalent iodine reagent proceeds under mild conditions in the presence of a bulky phosphine and CuCN. The process involves the consecutive formation of two C-C bonds in a single addition reaction. In the presence of a p-methoxy substituent in the styrene, oxytrifluoromethylation occurs instead of the cyanotrifluoromethylation.
N. O. Ilchenko, P. G. Janson, K. J. Szabó, J. Org. Chem., 2013, 78, 11087-11091.
A photoredox-catalyzed azidotrifluoromethylation of substituted styrenes as well as various activated and nonactivated alkenes using [Ru(bpy)3(PF6)2] as the photocatalyst and Umemoto’s reagent as the CF3 source delivers a wide range β-trifluoromethylated azides or amines in good yields.
G. Dagousset, A. Carboni, E. Magnier, G. Masson, Org. Lett., 2014, 16, 4340-4343.
The use of a commercially available Umemoto’s reagent enables a metal-free trifluoromethylation of nitroalkanes. This method provides quaternary α-(trifluoromethyl)nitroalkanes, that can be elaborated to various complex nitrogen-containing molecules, including α-(trifluoromethyl)amines.
A. S. Gietter-Burch, V. Devannah, D. A. Watson, Org. Lett., 2017, 19, 2957-2960.