| Benzimidazoles are a class of aromatic heterocycle containing nitrogen, comprised by benzene ring and imidazole ring. In medicinal chemistry, benzimidazole is important pharmacophore and building block all the time. Derivatives containing benzimidazole have extensive applications as such antibacterial, antiulcer, antihypertension, antiviral, antifungal, anticancer, antiparasite and antihistamines, etc. Therefore, synthesis study on benzimidazoles is profoundly significant. Especially nowadays microbial appearing with the widespread development of resistance to traditional antimicrobial agents(β-lactam antibiotics, macrolides, quinolones, and vancomycin), as new type antibacterial agent, benzimidazoles is much valuable in medicinal chemistry.Here we developed one pot synthesis of 2-arylbenzimidazoles from benzyl halides and o-phenylenediamines catalyzed by cheap cuprous salt. We used benzyl bromide and o-phenylenediamine as material templet to examine reaction factors, mainly including cuprous salt catalyst, base, solvent, temperature and approximate reaction time. After experimental study, we found the reaction proceeds well with CuBr as catalyst, rate of charge of materials benzyl bromide and o-phenylenediamine 1:3, NaHCO3 as base(1.2equiv.), DMSO as solvent in 120 ℃ for 24 h to give the highest yield 83%.Under this best reaction condition, derivatives of benzyl halogens and o-phenylenediamines react well in 53-90% yield. Also cinnamyl bromide can be used in the method(yield 46%). The result of experiment shows that: first, the reaction system is well compatiable with lots of functional group such as halo(F, Cl, Br), trifluoromethyl, nitro, ester group, nitrile group and so on; second, the type of halogen of the benzyl halides nearly make no diffierence to the reaction, for example, m-trifluoromethylbenzyl chloride reacted with o-phenylenediamine in 83% yield while m-nitrilebenzyl bromide reacted with o-phenylenediamine in 82% yield; third, electron-withdrawing group on the ortho-position and para-position of benzyl halides would reduce the reaction yield in proportion to strength of the electron-withdrawing group, for example, p-trifluoromethylbenzyl bromide in 70% yield, p-nitrobenzyl bromide in 71% yield,p-brooethyl ethyl benzoate in 74%, p-chlobenzyl chloride in76% yield; forth, either electron-withdrawing group or electron-donating group on the ortho-position of o-phenylenediamine make for the reaction yield, for example, 4-methoxy-1, 2-diaminobenzene reacted with benzyl bromide in 87% yield, 4-trifluoromethylbenzyl bromide reacted with benzyl bromide in 90% yield.At last, we roughly deduced the mechanism of reaction catalyzed by CuBr. First of all, the SN2 nucleophilic substitution promoted by weak base between benzyl bromide and o-phenylenediamine produced N-benzyl-1, 2-diaminobenzene, which was oxidated to N-benzylidene-1,2-diaminobenzene by air catalyzed by CuBr. Then the N-benzylidene-1, 2-diaminobenzene converted to 2-phenyl-2, 3-dihydronbenzimidazole via intramolecular cyclization, which translate to the ultimate product, 2-phenylbenzimidazoles.This process is highly efficient, cost saving and simple with good universality. It contains potencial value for application. What a pity, it’s nonideal for halogenated aliphatic hydrocarbon in the reaction system.The pollution caused by traditional chemical industry to the environment is very serious. In recent years, although organic synthetic chemistry developed rapidly providing various synthetic medicines for human, it’s no doubt that most of these organic synthetic methods are builded on complicated transition metal catalytic system. What’ more, these transition metal catalysts are always toxic, expensive and difficult to deal with. In this era troubled by serious industrial pollution, it’s positive and significant to explore greener synthetic methods to reduce or eliminate pollution to the environment in the source as well as improve atom economy.4-(3H)-quinazolinones is a class of important heterocycle containing nitrogen, with a broad spectrum of bioactivities. So it’s meaningful to develop synthetic methods for quinazolinones.So far there are many methods for the synthesis of quizazolinones. These methods involves diverse materials, such as o-nitrobenzamides, anthranilamides, isatoic anhydrides, o-halogen benzoic acids, aldehydes, carboxylic acids, amidines and halides; also various catalysts, such as Pd, Ir, Cu, Va. Although some methods are relatively mature, there still exist drawbacks unavoidly such as using transition metals or downstream products. In fact, there are only a few green syntheses of quizazolinones. Especially recently in unwonted reports for the synthesis of quizazolinones from alcohols and aminobenzamides it’s a pity that transition metals are essential. Therefore, it’s relatively novel and unique to develop the synthesis of quizazolinones from alcohols.Complying with green chemistry, we developed one pot synthesis of quizazolinones from low industrial material Aryl alcohols and o-aminobenzamides promoted by KOH in toluene in 90 ℃ for 24 h under air in 99% yield.In the reaction condition, various derivatives of benzyl alcohol and aminobenzamide are tested and all of them reacted well(80-98%). Also cinnamyl alcohol performed well in the reaction(90%). A series of experiments shows: first, Ortho- substituents of benzyl alcohol would reduce the reaction yield by stereospecific blockade effect, for example, o-methylbenzyl alcohol reacted with o-aminobenzamide in just 84% yield while the corresponding yield of m-methylbenzyl alcohol and p-methylbenzyl alcohol is 98% and 97% respectively; second, neither electron-withdrawing groups or electron-donating groups go against the reaction, for example, p-trifluoromethylbenzyl alcohol reacted with o-aminobenzamide in 84% yield, 2-fluobenzyl alcohol in 86% yield, p-methoxylbenzyl alcohol in 80% while benzyl alcohol reacted with o-aminobenzamide in 99% yield; third, electron-withdrawing group on the 4-position and 6-position of o-aminobenzamide make against the reaction, such as 6-fluo-2-aminobenzamide reacted with m-methyl benzyl alcohol in 80% yield, 2-amino-4-chlobenzamide reacted with benzyl alcohol in 89% yield, which were lower than the reaction yield between o-aminobenzamide and benzyl alcohol obviously.At last, we roughly proposed the mechanism of the synthesis of 2-aryl-4(3H)-quizazolinones from benzyl alcohol via oxidation promoted by KOH. At beginning, benzyl alcohol converted to benzyl alcohol potassium effected by KOH, then the benzyl alcohol potassium was slowly oxidated to trace benzaldehyde, which immediately reacted with o-aminobenzamide to give corresponding imine. Then the imine changed into 1, 2-dihydro-4(3H)-quinazolinone via intramolecular cyclization. In the end, it was oxidated to the final product, 2-phenyl-4(3H)-quinazolinone by air forced by aromatization.The protocol will have wide applicationis because it’s simple, practical, cost saving and green, with a good yield(82%) even if ten times magnificated. It’s a pity that this method is not applicable to the synthesis of other types quinazolinones. |
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