Regioselective Scalable Approaches to Trifluoromethylated Pyrazoles

Key words

pyrazoles - trifluoromethylation - flow chemistry - lithiation - halogen–metal exchange - direct ortho-metalation

Significance

The regioselective scalable synthesis of 3/5-trifluoromethyl pyrazole derivatives represents an important challenge, given the prominence of these motifs in both agrochemicals and pharmaceuticals. The current report details a kilogram synthesis and efficient distillation-based separation of 1-methyl-(3-trifluoromethyl)-1H-pyrazole (4) and 1-methyl-(5-trifluoromethyl)-1H-pyrazole (3), and their subsequent regioselective elaboration in either batch or flow mode through a series of strategies based on lithiation/electrophilic trapping chemistries (M. Schlosser et al. Eur. J. Org. Chem. 2002, 2913).

Comment

Several approaches for the synthesis of the parent pyrazoles were evaluated, and the ­reaction of 4-ethoxy-1,1,1-trifluorobut-3-en-2-one (1) with methyl hydrazine hydrochloride (2) was scaled to provide access to the desired compounds. Functionalization of the 5-position was achieved by lithiation in flow followed by trapping in batch with a series of electrophiles (for example, 5). Judicious control of the concentration in flow proved important in avoiding precipitation. Bromination with NBS cleanly afforded the 4-bromopyrazoles 6, which could be subsequently elaborated either through halogen–metal exchange followed by functionalization (see 7) or by direct ortho-lithiation, functionalization, and debromination (for example, 9), although in the latter sequence control of temperature proved critical to avoid the formation of isomers through a ‘halogen-dance’ reaction (see Review below).

Review

M. Schnürch, M. Spina, A. F. Khan, M. D. Mihovilovic, P. Stanetty Chem. Soc. Rev. 2007, 36, 1046–1057.