Electrophilic Trifluoromethylation

18 March, 2015 / by SK / in Reactions

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General Characteristics

Fluorine and hydrogen are about the same size, but are electronically very different. The substitution of hydrogen atoms with fluorine atoms is a common way of tuning the electronic property of molecules without substantially affecting their size. In particular, trifluoromethyl (CF₃) group is an important functional group in drug development.

The introduction of CF₃ group is roughly divided into two approaches: nucleophilic conditions (the Ruppert-Prakash method) and electrophilic/free radical conditions.

For the latter, many new useful reagents have been developed in the past few years. Representative examples are shown below.

General References

Umemoto T. Chem. Rev. 1996,96, 1757. DOI: 10.1021/cr941149u
Ma, J.-A.; Cahard, D. Chem. Rev. 2004, 104, 6119. DOI: 10.1021/cr030143e
Ma, J.-A.; Cahard, D. J. Fluor. Chem. 2007, 128, 975. doi:10.1016/j.jfluchem.2007.04.026
Shibata, N.; Matsnev, A.; Cahard, D. Beil. J. Org. Chem. 2010, 6, 65. doi:10.3762/bjoc.6.65

<Umemoto’s reagent>

Umemoto T, Ishihara S. Tetrahedron Lett. 1990, 31, 3579. doi:10.1016/S0040-4039(00)94447-2
Umemoto T, Ishihara S. J. Am. Chem. Soc. 1993, 115, 2156. DOI: 10.1021/ja00059a009
Umemoto, T.; Adachi, K.; Ishihara, S. J. Org. Chem. 2007, 72, 6905. DOI: 10.1021/jo070896r
Li, H. Synlett 2012, 2289. DOI: 10.1055/s-0032-1317176

<Togni’s reagent>

Eisenberger, P.; Gischig, S.; Togni, A. Chem. Eur. J. 2006, 12, 2579. DOI: 10.1002/chem.200501052
Kieltsch, I,; Eisenberger, P.; Togni, A. Angew. Chem. Int. Ed. 2007, 46, 754. DOI: 10.1002/anie.200603497
Eisenberger, P.; Kieltsch, I.; Armanino, N.; Togni, A. Chem. Commun. 2008, 1575. DOI: 10.1039/B801424H
Stanek, K.; Koller, R.; Togni, A. J. Org. Chem. 2008, 73, 7678. DOI: 10.1021/jo8014825
Koller, R.; Stanek, K.; Stolz, D.; Aardoom, R.; Niedermann, K.; Togni, A. Angew. Chem. Int. Ed. 2009, 48, 4332. DOI: 10.1002/anie.200900974
Eisenberger, P.; Kiltsch, I.; Koller, R.; Stanek, K.; Togni, A. Org. Synth. 2011, 88, 168. [PDF]

<Shibata-Johnson reagent>

Noritake, S.; Shibata, N.; Nakamura, S.; Toru, T.; Shiro, M. Eur. J. Org. Chem. 2008, 3465. DOI: 10.1002/ejoc.200800419

Langlois, B. R.; Laurent, E.; Roidot, N. Tetrahedron Lett. 1991, 32, 7525. doi:10.1016/0040-4039(91)80524-A
Ji, Y.; Bruecki, T.; Baxter, R. D.; Fujiwara, Y.; Seiple, I. B.; Su, S.; Blackmond, D. G.; Baran, P. S. Proc. Natl. Acad. Sci. USA 2011, 108, 14411. doi: 10.1073/pnas.1109059108
Fujiwara, Y.; Dixon, J.A.; Rodriguez, R.A.; Baxter, R.D.; Dixon, D.D.; Collins, M.R.; Blackmond, D.G.; Baran, P.S. J. Am. Chem. Soc. 2012, 134, 1494. DOI: 10.1021/ja211422g
Fujiwara, Y.; Dixon, J.A.; O’Hara, F.; Daa Funder, E.; Dixon, D.D.; Rodriguez, R.A.; Baxter, R.D.; Herle, B.; Sach, N.; Collins, M.R.; Ishihara, Y.; Baran, P.S. Nature 2012, 492, 95. doi:10.1038/nature11680
Ye, Y.; Kunzi, S. A.; Sanford, M. S. Org. Lett. 2012, 14, 4979. DOI: 10.1021/ol3022726

Reaction Mechanism

Since the carbon atom of CF₃ group is surrounded by electronegative fluorine atoms, it is not particularly reactive towards substitution via backside attack (S_N2 reaction).

Examples
Experimental Procedure
Experimental Tips
References
Related Reactions

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Nucleophilic Fluoroalkylation

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Electrophilic Fluorination Reagent

Balz-Schiemann Reaction

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