Research On The Multi-component Reactions Synthesis Of Aza-Heterocyclics And Their Application As Fluorescent Probes

Multi-component reactions (MCRs) refer to the reactions containing three or more reactants and their products containing the fragments of all reactants. Because MCRs can lead to the formation of several and even more than ten chemical bonds, MCRs have the advantages of atom economy, high efficiency, high yield and the diversity and complexity structural of product. So, MCRs are ideal reaction mode which is consistent with the concept of green chemistry. This thesis focuses on the synthesis of aza-heterocyclics via MCRs, and their application as fluorescent probes for the determination of the critical micelle concentrations (CMC) of surfactants. This thesis includes five chapters:chapter one is about the introductions of the development of MCRs and the fluorescent probes for CMC, and the research significance and objection of this thesis; chapter two is on the synthesis of pentasubstituted dihydropyrrole; chapter three describes the synthesis of pentasubstituted tetrahydropyrimidines and as their application as fluorescent probes for CMC; chapter four is on the synthesis of 1-alky-3-aryl-maleimides and their application as fluorescent probes for CMC; chapter five is a conclusion of the experimental resulta and significances of the thesis.Part I:Synthesis of Pentasubstituted DihydropyrrolesBackground:Pyrroles are a kind of important heterocyclics widely existing in natural products and show important biological activities.They are also important chemicals widely used in medicine, textile, dye, paint, cosmetics and other fields. Therefore, the development of convenient and efficienct protocols for the synthesis of novel pyrroles have attracted great interest in wide areas. Our research group developed convenient MCRs for the synthesis of novel series of tetra-and pentasubstituted dihydropyrroles and found that they can be used as the inhibitors of caspase-3 (cysteinyl aspartate specific proteinase). However, the reactants of two primary amines for the MCRs are limited to the combinations of aromatic/aliphatic and aliphatic/aliphatic primary amines. Therefore, dedicated efforts were made to widen the range of these MCRs. We found that using copper (II) as catalyst, the MCRs can afford pyrroles with various substituent by free combinations of the reactants of aromatic and aliphatic primary amines.Methods:Dimethyl/diethyl acetylenedicarboxylate and aromatic/aliphatic primary amine were added into test tube A with 3 mL MeOH and kept at room temperature for 30 min; primary amine, aldehyde, salicylic acid and Cu(OAc)2·H2O were added into test tube B with 3 mL MeOH; then the mixture in tube B was added into tube A, and stirred at room temperature for desired time. After the reaction completed, the target products were separated and purified by thin layer chromatography (TLC) with petroleum ether-ethyl acetate (6:1-1:1) as eluent.Results:(1) Copper (Ⅱ) was found to be an efficient catalyst for widening the range of the four-component reaction (4CR) for the synthesis of pentasubstituted dihydropyrroles.(2) 20 pentasubstituted dihydropyrroles were successfully synthesized via the copper-catalyzied 4CR.(3) Structural characteristics were determned by ESI-MS, 1H 和 13C NMR, elemental analysis and IR.(4) The possible mechanism of the 4CR was proposed.Conclusions:(1) We found an efficient catalyst (copper) for widening the range of the 4CR for the synthesis of pentasubstituted dihydropyrroles with the advantages of high efficiency, low toxicity, low cost, and friendly to environment.(2) Salicylic was found to be beneficial to activate the catalytic activity of copper.(3) Compared with the previous reported 4CR for the synthesis of pentasubstituted dihydropyrroles, the copper-catalyzed 4CR can carry out under milder conditions and using wider reactants.Part II. Synthesis of Pentasubstituted Tetrahydropyrimidines and Their Application as Fluorescent Probes for CMCBackground:Organic fluorophores are used in wide areas for their advantages of low cost, very high sensitivity and easily detection. The traditional organic fluorophores usually havehigh fluorescence efficiency in dilute solution, but become weak or even no emissive in the concentrated solution or solid state, this phenomemon is called aggregation caused quenching (ACQ) that greatly restrict their application range. In 2001, Ben-Zhong Tang group found that silole shows no emission in solution but strong emission in aggregates. They described this unsual phenomenon as aggregation induced emission (AIE).Pyrimidines are very important nitrogen heterocyclic compounds with extensive biological activities. Different molecular structures and substituents often influence the proterites and biological activities of a compound. Therefore, the synthesis of pyrimidines with different substitents is interested from organic chemistry and pharmaceutical chemistry. Our resear group recently developed a convenient five-component reaction (5CR) for the selective synthesis of a novel series of C6-unsubstituted tetrahydropyrimides (THPs) and found that THPs possess strong AIE because they show practically no emission in solutions but strong emission in aggregates with fluorescene quantum yields up to 93%.Surfactants refer to that the properties of their solutions can get the obvious changes in the interfaceby adding a small amount of them. Surfactants can be usually divided into ionic surfactants (anionic, cationic and amphoteric surfactant) and nonionic surfactants. With the increase of surfactant concentration, some physical and chemical properties (such as density, conductivity, surface tension, osmotic pressure, interfacial tension) in a certain concentration or within a very narrow concentration range qualitative change will happen, the concentration is known as the critical micelle concentration (CMC). The reported methods for determining CMC include conductivity method, surface applanation tonometry method, light scattering method and fluorescence spectrometry. Among them, the fluorescence spectrometry has attracted great interste owing to it advantange of high sensitivity, simple operation, low cost.Methods:Pentasubstituted tetrahydropyrimidines (THPs) were synthesized via the five-component reaction of dimethyl/diethyl acetylenedicarboxylate, amine 1, formaldehyde, amine 2 and aromatic aldehyde that we rencently depveloped. They were used to determine the CMC of sodium dodecyl sulfate (SDS), cetyl trimethyl ammonium bromide (CTAB) and 3-[(3-cholamidopropy) dimethylammonio] propanesulfonate (CHAPS).Results:(1) We have synthetized 16 pentasubstituted tetrahydropyrimidines (THPs) via the multi-component reations that we developed.(2) Structural characteristics of new THPs were determined by ESI-MS,1H 和 13C NMR, elemental analysis and IR.(3) The pentasubstituted tetrahydropyrimidines were used to determine the CMC of sodium dodecyl sulfate, cetyl trimethyl ammonium bromide and 3-[(3-cholamidopropy) dimethylammonio] propanesulfonate.Conclusions:(1) All synthesized sixteen THPs can be used as fluorescence-turn-on probes for the CMC determination of SDS, CTAB and CHAPS.(2) The structures of THPs show no significant influences on the CMC values of these ionic surfactants but strong influence on their fluorescent sensitivities to the concentrations of these surfanctants.(3) The 4-CF3 group was found to be an effectent moiety improving the sensitivities of THPs. The concentrations detecting CMC of THPs with 4-CF3 group are low to 0.7 μM.Part III. Synthesis of 1-Alkyl-3-arylmaleimides and Their Use as Fluorescent Probes for CMCBackground:Maleimides are a class of important nitrogen heterocyclic compounds widely existing in many natural products and possessing different biological activities. In addition to the application in the biomedical field, maleimides are effective fluorophores and can be used as intermidiates for preparing functional fluorescent materials. Therefore, maleimides have attracted great interest from wide areas. In the process of developing multi-component reactions for the synthesis of hetereocycles, we found that 1-alkyl-3-arylmaleimides (4) show aggregation-induced emistion (AIE) and can be used as fluorescence-turn-on probes for the critical micelle concentration (CMC) determination of anion surfactants, sodium dodecyl sulfate (SDS) and sodium dodecyl sulfonate (SDSN).Methods:Dimethyl acetylenedicarboxylate and aromatic primary amines were added in ethanol successively, kept at room temperature for 10-30 min. Then aliphatic primary was added into the mixture, stirred at room temperature for desired time (monitored by TLC). After the reaction was completed, the product mixtures were purified by preparative TLC with petroleum ether-ethyl acetate (6:1-1:1) as eluent to afford the desired products in 20-75% yields. And these compounds were used to determine the CMC determination of anionic surfactants SDS and SDSN.Results:(1) We have synthetized 10 1-alky-3-arylmaleimides (4) via reported three component reaction.(2) Structural characteristics of all synthesized 4 were determined by ESI-MS,1H和13C NMR, elemental analysis, IR.(3) The synthesized 4 were used to determine the CMC values of anionic surfactants, sodium dodecyl sulfate (SDS) and sodium dodecyl sulfonate (SDSN).Conclusions:(1) We found that 1-alky-3-aryl maleimides (4) exhibit important AIE properties.(2) All synthesized 4 can be used as fluorescence-turn-on probes for CMC asTHPs.(3) The aryl electron-withdrawing substitutents can increase the sensitity of 4 for CMC determination.We found that 1-alkyl-3-arylmaleimides compounds exhibit important AIE properties.