Synthesis Of Small Heterocyclic Compounds Using Multicomponent Reaction

Multicomponent reaction (MCR) is regarded as one of the most widely studied and applied synthetic methodologies in chemistry and related areas in recent years. It is also one of the main routes of achieving diversity oriented synthesis. The focus research described in this dissertation is developing novel multicomponent reactions for the synthesis of small heterocyclic molecules that contain the central skeletons of natural products or clinical drugs/lead compounds.Firstly, the synthesis of 3-unsubstituted isoindolinones and 3-substituted isoindolinones has been investigated. At first, the one-pot tandem reactions of o-phthalaldehyde and (thio)ureas/amides furnishing 3-unsubstituted isoindolinones has been established. The reaction process was administrated with ESI/ESI-MS2 and characterized with deuterium labeling experiments. The results indicated that the products were formed via the key isoindolinone-like nucleophilic intermediate. Based on these findings, we designed the multicomponent reactions to synthesize 3-substituted isoindolinones. By employing an additional aldehyde to react with urea, the electrophilic imine intermediate was generated in situ, and the incorporation of imine intermediate with isoindolinone nucleophile directly furnished 3-alkylated isoindolinones. The reactions were performed at room temperature and the protocol exhibited good reactant tolerance to N-substituted ureas and aromatic aldehydes. In addition, most entries afforded products as one pair of enantiomers regardless the formation of 2 new chiral centers, which implied the excellent diastereoselectivity of the reaction.Secondly, we have developed the three-component synthetic method towards unsymmetrical 1,4-dihydropyridines (1,4-DHPs). The one-pot reactions of enaminone, a,(3-unsaturated aldehyde and primary amine furnished structurally unsymmetrical 1,4-DHPs in one step. Interestingly, by employing aromatic amines with strong electron withdrawing groups or sterically bulky groups, the regio-selectivity of the reaction could be altered to yield 1,2-DHPs as major products. This is the first observation of 1,2-DHPs formation in this kind of synthetic methodology. By using enaminone as a starting materials, we have also established the three-component methodology for synthesizing 6-unsubstituted 3,4-dihydropyrimidin-ones (DHPMs). Through the three-component reactions of enaminone, aldehyde and (thio)urea, a number of 6-unsubstituted DHPMs have been synthesized. This synthetic approach bears broad reactants compatibility, a variety of substituted enaminones, aromatic and aliphatic aldehydes, (thio)ureas were able to undergo this transformation to yield corresponding DHPMs. What is more, it has been discovered that the chemo-and regio-selectivity of the reaction could be manipulated by employing reactants with particular functional groups. When N-substituted thiourea was used, 1,3-thiazine compound was afforded as the main product; when 2-hydroxyphenyl enaminone was applied, totally different chemo-selectivity was observed in the reaction and 3-substituted chromones have been obtained as the major products.At last, we constructed the water mediated three-component reaction for the selective synthesis of 1,2-disubstituted benzimidazoles. By employing water as the solvent, o-phenylenediamine reacts with 2 equiv mole of aldehydes to produce 1,2-disubstituted benzimidazoles via the tandem condensation, cyclization and redox amination process. This reaction displayed excellent chemo-selectivity as the other potential side product 2-substituted benzimidazoles furnished by two-component reaction was not observed in our experiments. Further more, this green catalysis system had been successfully applied in the two-component synthesis of quinoxalines using o-phenylenediamine and a-bromoketones. The reaction tolerates various substrates and the transformations were completed under mild conditions.Based on systematical research, several novel multicomponent reaction protocols have been developed, the application of these reactions focuses on the synthesis of diverse small heterocyclic molecules. Totally 168 compounds have been synthesized in our reaserch and 138 of which have been obtained as new compounds.