Cimetidine과 Halopyrrole유도체의 합성
Synthesis of cimetidine derivative. Thermal and photochemical isomerization of N-benzyl-2-halopyrroles:syntheses of N-benzyl-3-halopyrrole
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There are biologically many important heterocyclic compounds which containimidazole. Especially cimetidine which contain the imidazole ring is a drug for treatment of peptic ulcers. Thus, we hope to synthesize some derivatives of cimetidine. The synthesis of cimetidine derivative will be accomplished by the substituted reaction of chlorinated 5H-imidazo[5,1-a]isoindole with cyanoguanizine derivative. The synthesis of chlorinated 5H-imidazo[5,1-a]isoindole will be achieving by halogenation of 5H-imidazo [5,1-a]isoindole, which was prepared by photocyclization of N-(o-bromobenzyl)imidazole. Pyrrole derivatives are very important classes of compounds due to their presence in a variety of biologically important heterocycles. The synthetic methods of 3-substituted pyrroles are important because the synthetic method of 3-substituted pyrrole derivatives are less. We easily synthesized N-benzyl-3-halopyrrole from its 2-halo analogue by the thermal reaction as well as photochemical reaction. The isomerization is main reaction in the thermal reaction whereas disproportionation and isomerization reactions are primary reactions in the photochemical reaction. However, the reaction mechanisms are not clear. In order to clear the mechanisms, some kinetic and isotope (deuterium) labeling studies have been accomplished. The thermal isomerization is acid-catalized reaction. We prepared 5-deutrio-substituted N-benzyl-2-bromopyrrole. In the thermal reaction, the deuterium is retained at the 5-position of the product formed whereas in the photochemical reaction, this deuterium is shifted to 2-position of the product. In the thermal reaction, a proton is attached to 2-position of N-benzyl-2-bromopyrrole to give a protonated N-benzyl-2-bromopyrrole, the lone pair electrons on the bromine attached to the carbon 2 position of the pyrrole attacks carbon 3 to form a cyclic bromonium ion between carbon 2 and carbon 3, and then 1,2-bromine shift of the bromonium ion to give N-benzyl-3-bromopyrrole. In the photochemical reaction, a bond between carbon 2 and carbon 5 of the pyrrole is formed via 4π-electrocyclic reaction followed by 1,3-sigmatropic and a rearomatization resulted in the product, N-benzyl-3-bromopyrrole.