A Study On Synthesis Of 4(5)-Substituted Imidazole Derivatives

The imidazoles existing widely in nature, are of great importance in the biological building blocks, such as histidine, and the related hormone histamine. Imidazole derivatives are widely used in agricultural pesticide, pharmaceuticals, dyes and fine chemicals and so on. 4(5)-substituted imidazole are vital intermediates in organic chemistry. For example, 4-nitroimidazole is a good intermediate product of explosives synthesis; 4(5)-hydroxymethylimidazole is an important intermediate in medicine, pesticide and resin.Based on many purposes and potential application prospects of 4(5)-substituted imidazole, these compounds were synthesized as follows: 4(5)-bromoimidazole, 4-nitroimidazole, 4(5)-hydroxymethylimidazole hydrochloride, imidazole-4(5)- carboxaldehyde, 1H-Imidazole-4(5)-carbonitrile, 4(5)-methylimidazole. Moreover, their synthesis conditions were optimized as follows:First, The effect of the amount of bromine and sodium acetate on the product yield of 4(5)-bromoimidazole was discussed. The results indicated that the yield is higher when 0.02 mol of imidazole, 0.06 mol of bromine and 20～25 g of sodium acetate were added.Second, 4-nitroimidazole was synthesized from imidazole using mixed acid as nitrating agent. The effect of the ratio of mixed acid on the yield was investigated adopting the theory of Nitronium by Lv Chun-xu in this experiment. The synthesis conditions were better than any others. An optimal production condition has been obtained: the molar ratio of imidazole and nitric acid is 1:1.2, the molar ratio of fuming sulfuric acid and nitric acid is 3:1, reaction temperature is 55～60℃and reaction time is 1.5 h.Third, A synthesis condition of Hydroxymethylimidazole picrate was optimized from cheap D-Fructose as the material using sodium sulfide nonahydrate as the precipitant of copper ion. This operation is easy to control, less contaminative and is apt to realize industrial production. An optimal production condition has been obtained: the molar ratio of fructose, ammonia, formaldehyde and basic cupric carbonate is 1:25:3:2.25, reaction temperature is 95～100℃and reaction time is 3 h. Moreover, the pH of solution was 7 before adding picric acid.Fourth, imidazole-4(5)-carboxaldehyde was prepared from 4(5)-hydroxymethyl- imidazole hydrochloride using manganese dioxide as oxidant. In this experiment, water was used for solution. It is very simple, fast synthesis, high yield and pollution-free. The results showed that the yield was higher when 0.01 mol of 4(5)-hydroxymethylimidazole hydrochloride at 90～95℃for 40 min via Oxidation by adding 4.5 g of manganese dioxide and 15 mL water.In the end, 1H-imidazole-4(5)-carbonitrile was synthesized from imidazole-4(5)- carboxaldehyde using hydroxylamine hydrochloride as a cyanation reagent in a one-pot process. It is very cheap, mild condition, high yield and easy to realize industrial production. An optimal production condition has been obtained: 0.05 mol of imidazole-4(5)-carboxaldehyde, 0.06 mol of hydroxylamine hydrochloride, reaction temperature is 95～100℃and reaction time is 1.5 h.The investigation had laid a well foundation for further study of the complex imidazole derivative. The structures of the as-synthesized compounds are all confirmed by 1H NMR, 13C NMR. All characterization results of these compounds are consistent with the reported literature data.