Science of Synthesis

Lishchynskyi, A.; Novák, P.; Grushin, V. V., Science of Synthesis: C-1 Building Blocks in Organic Synthesis, (2014) 2, 367.

General Introduction

The trifluoromethyl group (CF3) occupies a special place among other C-1 building blocks in synthetic organic chemistry for at least two reasons. First, trifluoromethylated compounds play an important role as intermediates and building blocks for the preparation of pharmaceuticals, agrochemicals, monomers, and specialty materials (for selected examples, see ‌Scheme 1‌). Second, in most cases, traditional methods for carbon—alkyl bond formation are not applicable to trifluoromethylation. In particular, trifluoroiodomethane, bromotrifluoromethane, and chlorotrifluoromethane are reluctant to undergo nucleophilic displacement of the heavier halogen. Furthermore, trifluoromethyl derivatives of active metals that are widely used in synthesis (e.g., Mg, Li) are unstable or nonexistent because of facile α-fluoro-elimination reactions leading to metal fluorides and difluorocarbene. Finally, widely used palladium- and nickel-catalyzed cross-coupling reactions are inapplicable to analogous trifluoromethylation processes because of the exceptional strength and inertness of the late-transition-metal–trifluoromethyl bonds. It follows that the development of synthetic methods for the selective trifluoromethylation of various organic molecules is not only important, but also challenging.

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References