Heterocycles from 1,4- retro-synthetic analysis iketones: pyridazines 4b i 2 2 ‘ 2 R’ R? —> R RS RI PR’ N=N HN—NH N—N pyridazine 2x enamines 2 x imines (or bis-hydrazone) Synthesis of the first hydrazone intermediate 9 ® NH, H2N eo —— HC CH; NH2NH2 proton Sn transfer He pai HN’ > ~«—— uc ==— Hc CH3 @NH 0° HN’ H OHMechanism of pyridazine synthesis (cont.) 5a 9° CH ® H CH; ne 3 +H _ 4 ] © UN N | HN’ H3C’ y proton transfer CH H CH ~ CHs 3 i 3 [ —- == 120 if -NH H3C HC 7 N H Air oxidation of the dihydropyridazine is favourable ~ CH; due to the formation of the stable aromatic pyridazine ring. The oxidation can be achieved by simply N heating in air for a hour or so, or else achieved c N7 pyridazine chemically with a suitable oxidising agent.By-product formation: 1-aminopyrroles 5b Synthesis of pyridazines from 1,4-diketones by this method may be accompanied by a 1-aminopyrrole by-product arising from a Paal-Knorr type mechanism. 4. NH2NH2 wn 2 air 0] mi LN oo N= | HN. HN. HOT NHe SNH? SNH, protonated hydrazone see slide 4b +H proton LN tt \ transfer oN H3C N CH3 ~ H3C N’ ‘CH; ~«———_—-H3;C N ‘CH3 1 420 | HO |*H NH, ® NH, NH,