An efficient method for the preparation of 1,3,4,5-tetrasubstituted pyrazoles promoted by butyllithium and palladium(0) cross-coupling reactions is described. Advantages of this new method include high yields and mild reaction conditions, which tolerate functional groups such as esters.Numerous syntheses of 1,3,4,5-tetrasubstituted pyrazoles have been developed to obtain biological compounds such as estrogen receptor antagonists 1 and endothelin antagonists 2 or in agrochemistry to obtain pesticides 3 and herbicides. 4Previously, 1,3,4,5-tetrasubstituted pyrazoles were synthesized from selected 1,3-dicarbonyl compounds by condensation with hydrazine or its derivatives. This process generally leads to a mixture of N1 and N2 substituted pyrazoles. 5 When pyrazoles are previously N1, C3, C4 substituted and more particularly with a carboxylate group at C4, a C5 metallation by lithium diisopropylamine at -78°C is possible but, under these conditions, the bis-pyrazolyl ketone is obtained as by-product in significant yields. 6In this paper, we present a convenient synthesis of polysubstituted derivatives from ethyl 3-methoxy-1-methyl-1H-pyrazol-4-carboxylate 1 6 without formation of by-products.First, C5 metallation of 1 was optimised by the use of butyllithium in THF at -45°C, leading to quantitative lithiation, permitting the synthesis of a large variety of pyrazoles 2 9 (Scheme, Table 1). Compounds 2a-e can be used in situ or isolated to realise cross-coupling reactions ( Table 2).In a subsequent investigation combining transmetallation and palladium catalysed cross-coupling reaction, 7 we report a convenient general approach to 5-aryl and 5-heteroaryl substituted pyrazoles. A recent paper, 8 has disclosed that 1-methyl-3-trifluoromethyl-1H-pyrazol-5-trin-butyltin reacts in better yields than 1-methyl-3-Table 1 Direct Synthesis of 1,3,4,5-Tetrasubstituted Pyrazoles Reagents Compounds Yield (%) Br 2 2a 86 I 2 2b 72 ZnCl 2 2c -a B(O-i-Pr) 3 2d 51 Sn(Bu) 3 Cl 2e 99 (CH 3 ) 2 CCHCH 2 Br 2f 62 (CH 3 ) 2 NC 6 H 4 CHO 2g 83 2,3,4-(OCH 3 ) 3 C 6 H 2 CHO 2h 74 DMF 2i 80 CO 2 2j 95 a Compound not isolated. Scheme Downloaded by: Collections and Technical Services Department. Copyrighted material.
