The Green Synthesis Involving Aza-Michael Addition And Michael Addition/retro-Claisenaddition Condensation Cascade Reaction Of α,β-Unsaturated Carbonyl Compounds

The green chemistry with the advantages of economy, environmental friendliness, as well as synthetic efficiency is the hot area of current research. The aza-Michael reaction and Michael reaction are classic methods to build C-N and C- C bond, respectively. However, the conventional methods still suffering the harsh conditions are hard to agree with the viewpoint of green chemistry. The exploration of green and convenient synthetic strategies for preparing target compound is still of current interest. Based on the green synthesis, we developed the aza-Michael addition of 1H-benzimidazoles to α,β-unsaturated compounds in water, and the sequential processes of Michael addition and retro-Claisen condensations starting from α,β-unsaturated carbonyl compounds and aromatic β-diketones.Benzimidazoles, which are an important class of nitrogen-containing heterocycles, display broad potential applications as medicinal agents, supramolecular blocks as well as functional materials and so on. Recently, the research on the construction and functionalization of the benzimidazole scaffold has attracted enormous interest and produced a large number of exciting findings. However, the exploration of green and convenient synthetic strategies for preparing novel benzimidazole derivatives under mild conditions is pendent. The aza-Michael addition reaction is one of effective methods to construct the benzimidazole scaffold. Nevertheless, the aza-Michael addition reaction of the 1H-benzimidazole, as a benzene-fused imidazole, is very difficult to occur, which makes their application still suffer from many limitations.We have developed the green synthesis of novel N-alkylated benzimidazole derivatives via the aza-Michael addition of 1H-benzimidazoles to α,β-unsaturated compounds in water and had the evaluation of their antimicrobial activity. Particularly noteworthy is that our strategy is suitable for various α,β-unsaturated compounds. The reaction conditions were also compatible with the presence of functional groups, which may be subject to further synthetic transformations. However, the methyl group presenting at α- and β-position of ethyl acrylate afforded corresponding products in low to moderate yields, which illustrated that steric hindrance of alkene had side effect on the step of Michael addition. Further antimicrobial activity studies showed that: the prepared new benzimidazoles showed superior bioactivity against tested strains to the comparator clinical drugs. Butyl 3-(5,6-dimethyl-1H-benzo[d]imidazol-1-yl)propanoate, for example, exhibited 2- and 4-fold higher inhibitory activity against B. subtilis(MIC = 16 mg/mL) and B. proteus(MIC = 8 mg/mL), respectively. Above all, we offered a green synthetic method to successfully prepare various bioactive or functional compounds containing the benzimidazole scaffold.1,5-Dicarbonyl compounds are versatile scaffolds in chemical drugs, functional materials and natural products. They, for instance, usually furnished heterocyclic and aromatic compounds as well as precursors of chiral building blocks. However, the conventional methods having access to 1,5-dicarbonyl compounds still suffer from the harsh conditions. There has been an increasing number of pioneering reports concerningthe efficient methods of synthesizing them.The cascade process, agreeing with the principle of atom economy and environmental friendliness, notably showed the superiority of synthetic methodology. Especially, Michael sequential reactions improved the elegance of synthesis. Herein, we are interested in the synthesis of 1,5-ketoesters starting from the α,β-unsaturated carbonyl compounds and aromatic β-diketones as phenacyl donors, via sequential processes of C-C formations and retro-Claisen condensations.We have disclosed a cascade process involving Michael addition and retro-Claisen condensation in one pot. Aromatic β-diketones with α,β-unsaturated carbonyl compounds could smoothly access to 1,5-ketoesters in the presence of K2CO3 in alcohol solutions. In addition, we have developed the NEt3/NaCl co-promoted cascade reaction including Michael addition and retro-Claisen condensation reaction, further studied the different roles of base and alkali metal ion. The study disclosed that NaCl assisted in activating the carbonyl of 1,3-diphenylpropane-1,3-dione(1a), and well promoted the Michael addition and retro-Claisen condensation reactions catalyzed by trimethylamine to synthesize 1,5- ketoesters. Especially, the C-C bond cleavage of aromatic β-diketones supplying the phenacyl group differentiated from reported 1,3-diketones as an acylation reagent. Further mechanical studies showed that:(1) though the aromatic β-diketones in the standard condition could produce little retro-Claisen condensation product, the Michael addition reactions take precedence of the retro-Claisen condensation reactions;(2) EtOH played an unprecedented role, which assisted the cleavages of both C-C and C-O bonds in one pot. This method provides a convenient and practical green mothod to 1,5-dicarbonyl compounds using economical reagents.