SYNTHESIS OF NEW PYRAZOLES AND THE PHYSICO-CHEMICAL STUDIES ON THEIR PRECURSORS

Abstract

The chemistry of heterocyclic compounds in general and pyrazoles in particular now forms one of the most extensively investigated branches of chemistry. The major developments in this field are due largely to the discovery of naturally occurlng physiologically active substances having at least one nitrogen in their skeleton. For over a hundred years, chemists and pharmacologists have been intriqued by observed changes in biological effects of chemical congeners as a result of minor alterations in their molecular structure. Following many success es and failures since the initiation of such studies, this interest continues to increase as the level of sophistication of the methods for studying these substituent effects in drug design improves. In recent years, the development of newer methods of synthesis and a better appreciation of their chemical nature have sufficiently strengthened the fabric of heterocyclic compounds. Further, in collaboration with physical methods which are at present perhaps the most effective tools in the hands of chemists, many astounding developments are expected in the near future. Diabetes is a serious health problem arising from the modern way of life. Despite the best efforts put in by the medicinal chemists all over the world towards the discovery of effective drugs for the treatment of this disease, very little seems to have been achieved in this direction. Although several classes of compounds - the salicylates , guanidines , . 9-11 1 p Ik sulphonamides7 , sulphonyl ureas and five membered 15-17 heterocycles ' ' have given rise to a few antidiabetic agents, still no effective hypoglycemic agent with negligible side effects has yet been found. During the last six or seven years, novel approaches have been innovated in the heterocyclic field to enhance potency and hopefully to reduce side effects. Progress in the field of pyrazoles and ifoxazoles as antidiabetic agents '5-'7 ^as Deen particularly im pressive, because these have provided much relief to sufferers of this disorder. Nevertheless, a more effective 'cur»> with minimum toxicity is yet to be discovered. A programme was therefore undertaken with a view to search for pyrazole deri vatives ( effective as potential antidiabetics) by altering the substituents at positions 1,3,*f and 5 of the pyrazole nucleus. One of the simplest methods of building up a pyrazole molecule is to react hydrazine or substituted hydrazine with #- diketones. This procedure permits variation in position 1 by taking different hydrazines, and positions 3 and 5 "by using different 0- diketones. In the present study, acetyl hydrazine, hippur; 1 hydrazin e, semi carbazide hydrochloride, p-sulphamoyl benzoyl hydrazine and other aryl substituted sulphonyl hydra zines have been used to give different substituents at position 1. Using 2,it—pentanedione, 1- phenylbutane 1,3-dione and 1,3- diphenyl propane 1,3- dionej positions 3 and 5 have been varied. Position h is prone to electrophilic substitution reactions. It is known to couple with various diazonium chlorides to give ^f-arylazo pyrazoles. Alternative3.y, the same derivatives have been obtained by first subjecting the f> -diketone to coupling reaction with substituted aryl diazonium chlorides and subsequen tly using these coupled products (pyrazole precursors) as substraotes in pyrazole synthesis. The biological testing results of a few series are reported, but testing of the others is under progress in various laboratories abroad. The structure ( in the ground state) of the coupled products of /3-keto esters and j9-diketones with aryl diazonium 1 ft oo chlorides has been the subject of investigation for a long time. The most well studied reaction is that of aryl 21 diazonium chlorides with phenols. Zincke , as early as 188*4-, showed that identical products are obtained by the coupling of phenols with aryl diazonium chlorides and by the reaction of the corresponding quinone with phenyl hydrazine. Thus, 1-naphthol and benzene diazonium chloride give the same product as 1,1+- naphthoquinone and phenyl hydrazine. This compound can be formulated either as the true hydroxy azo derivative or as the hydrazone, the method of preparation in no way permitting conclusions to be drawn about the constitution of the product. In the following years, a large number of workers tried to clarify the structure on the basis of chemical reactions. However, no fruitful results could be obtained, as reactions of both the possible functional groups, -C=0 and -OH were 22 2.~\ observed. This dual behaviour was explained • J by them on the basis of the existence of a rapid equilibrium between the two tautomeric forms. In order to determine which side of the azo hydrazone equilibrium is favoured under given conditions 4 the aid of physico chemical methods was sought. Following investigations of the spectra of 2-phenylazophenols »2' and of sulphonated o-phenylazonaphthols » " such as Orange II, it was found that whereas the former are essentially true azo compounds, the latter exist largely as hydrazones. In recent years, the polarographic method has also gained immense importance, since the various functional groups reduce at different applied potentials, depending on the electron density around the bonds undergoing reduction. During the course of the present investigations, it was considered worthwhile to testify the above view point by sub jecting some of the precursors of pyrazoles to polarographic reduction and NMR and IR studies. Interestingly enough, pre cise information regarding their structural characteristics could be obtained on the basis of polarographic work and further experimental evidence was available from IR and NMR studies. In the case of the coupled products of /}- keto esters and B -diketones with aryl diazonium chlorides, it has been realised that the following four structures are possible