Modified reaction conditions to achieve high regioselectivity in the two component synthesis of 1,5-diarylpyrazoles.

JESICA PEROTTI AND MARCELO C. MURGUÍA

Los Cocos. Córdoba. Argentina.

Conferencia; 9th Latin American Conference on Physical Organic Chemistry (CLAFQO-9); 2007

9a Conferencia Latinoamericana de Físico-Química Orgánica

The pyrazole ring is present in many pharmacologically important compounds. Although many methods are known for the construction of this ring system, the search for novel synthetic methodology addressing the necessity for a particular regioisomer is always desirable. Recently, 1,5-diarylpyrazoles gained further importance after the introduction of celecoxib 1 (Fig.1), a COX-2 inhibitor for the treatment of chronic inflammatory diseases like rheumatoid and osteoarthritis. The widely accepted synthetic method for this class of compounds comprises of the coupling of an appropriate phenylhydrazine hydrochloride with a suitable 1-phenyl-1,3-diketone in hot ethanol. Although it is an excellent method in terms of yield, it suffers from poor regioselectivity in many cases depending on the nature of the 1,3-diketone. Figure 1. In a discovery project, we were interested in the practical synthesis of 1,5-diarylpyrazoles 2 (Fig. 1) with alkyl and heteroaryl groups at C-3. While the reported regiospecific syntheses of this class of compounds involves low yielding steps, it was anticipated that the high yielding coupling method described above would yield a mixture of regioisomers. Previously, the two component synthesis has been conducted in acidic medium and the suitability of the 1,3-diketone has generally been emphasized for the synthesis of 1,5-diarylpyrazoles, but, to our knowledge, no systematic study has correlated the control of regiochemistry with reaction conditions and the electronic/steric factors of the 1,3-diketone and phenylhydrazine. We present here the outcome of our study of the effect of substituents on both of the components on the formation of regioisomers. We found that by employing simple methods we could achieve excellent regioisomeric excesses.