Synthesis of 3,5-Diphenyl-1H-pyrazoles by Mechanochemical Ball Milling

Significance

The pyrazole scaffold is generally made by 1) condensation of 1,3-diketones with hydrazines, 2) 1,3-dipolar cycloaddition of terminal alkynes with diazo compounds, or 3) reaction of α,β-unsaturated carbonyl compounds with hydrazine. Although all three methods have their pros and cons, the latter is the most suitable one for diversity-oriented synthesis, avoids toxic and potentially explosive diazo compounds, and does not give a mixture of condensation products. This report provides yet another improvement of the method, shortening the reaction time, improving yields, and avoiding the use of solvent with the proviso that ball-milling equipment is available.

Comment

Mechanical ball milling has been one of the emerging solvent-free techniques, contributing to promotion of various organic reactions in a ‘greener’ way (see Review below). For the present reaction, a chalcone derivative is introduced into a metal jar together with hydrazine and stainless balls and vibrated at a high frequency for 30 minutes, then the oxidant is added and the procedure is repeated. Following the optimization studies, Na₂S₂O₈ and Ce(NH₄)₂(NO₃)₆ emerged as oxidants of choice, the former being superior from the view of cost and atom economy. The workup involves simple dispersion of the reaction mixture in water and filtration. As expected, considerable tolerance of the reaction for chalcone substituents was observed. Parallel experiments in various organic solvents were conducted, which typically gave lower yields, required longer reaction times and elevated temperatures, and often gave undesired by-products. The authors present a ‘green’ alternative of a well-known transformation, employing inexpensive reagents and avoiding tedious work-up.

Review

S.-E Zhu, F. Lei, G.-W. Wang and co-workers Chem. Soc. Rev. 2013, 42, 7535–7570.