Heterocycles from 1,3-dicarbonyls: 8a isoxazoles and pyrazoles Retrosynthetic analysis R HOR HR R R R R mA OR ry HN—N oO ° a pyrazole + Hj,N—NH2, R H oR HR “yt = Wie = 1 O-N (7 Oo 0 an isoxazole + HO—NH2 Synthesis of 3,5-dimethylisoxazole and 3,5-dimethylpyrazole from pentane-2-,4-dione NOH NH,-NH3 <—o ————_ oe 2,4 roMechanism for isoxazole / pyrazole synthesis 8b The chemistry involved here is very similar to the Paal-Knorr pyrrole synthesis. oO oO HO CH; H3C: 7 —= fa N Ve proton {} tanstor of H~g CH; Hc y —— X—N :NH)XH ©nnxn He te HNN ts oO OW oO ou ~H proton {} transfer H ‘NXH sy oS Hs => —— © HC UN Hye OS 3) HX~ 3) \" compare this intermediate with the first enol in the Paal-Knorr (slide 3a) H mono —— He CH \ J | an XN isoxazole X pyrazole XIsoxazoles and pyrazoles: Unsymmetrical 1,3-diketones 9a The reaction of unsymmetrical 1,3-diketones with hydroxylamine (NH,OH) may lead to mixtures of isoxzoles, but with hydrazine (NHjNHz) this is not an issue as the two "products" are in fact tautomers. Rt R? NH>-OH ——> 0 0 Rt R? NH>-NH2, ——_— o 0 N-alkyl or aryl subsitutued hydrazines can give two products which cannot tautomerise, and so the same question of selectivity seen with hydroxylamine arises (above) “NA Me-NH-NH2 — oO OExamples of isoxazoles and pyrazoles made from 9b unsymmetrical 1,3-diketones The reaction of unsymmetrical 1,3 diketones may however lead to single isoxzoles or pyrazoles if one carbonyl group is more reactive than the other. starting material intermediate product 0 A Cay CO2Et —-Me-NH,-NH, -H,0 \ 0 Oo ! Me Me Me, NH,-OH Pm i -H,0 } 1, 0 0 Ph So” Ar = 4-NO,CgH,- Ar Ph. Ar Me-NH,-NH2 -H,0 i Oo ——_> ae N 0 0 N