Studies On The C-N/C-S Cascade Forming Of Ortho-halobenzyl Halide With2-mercaptobenzimidazoles And2-mercapto-azoles’ Nucleophilic Substitution With Tert-butanesulfinamide

Heterocycles contain N and S atoms are a sort of important compounds withsignificant applications in many fields. In the discipline of medicine, imidazolemarine natural product Isonaamine and Isonaamidine E are found: to be cytotoxicagainst stomach (HM02) and liver (HepG2and Huh7) cancer cell lines to curestomach and lung cancers. Pifithrin–α with aminothiazole core-structure is leadingp53inactivator with applications in neurodegenerative disorders (Alzheimer’s disease,Parkinson’s disease and stroke) and cancers. In the adsorption and floating process ofminerals areas,2-mercaptobenzimidazole-modified silica gel can adsorb Cu(II),Zn(II), Cd(II) and Pb(II) from aqueous solutions with recoveries of100%for allmetals.2-mercaptobenzimidazole derivatives are well proved to function as chelatingcollectors in flotation separation of galena and pyrite. In the field of metirial science2-mercaptobenzimidazole and its directives are tested with good inhibition abilityagainst the corrosion of mild steel, zinc, and copper in acid conditions. Sm(Ⅲ)complex with2-mercaptobenzimidazole is with superb abilities of retard aging andanti-oxidation. Therefore, the study of N and S contained heterocycles has been beinga hot-pot within the area of material science, mineral separation and medicine. Incurrent dissertation, we focused our studies on the C-N/C-S cascade ofortho-halobenzyl halide with2-mercaptobenzimidazoles and2-mercapto-azoles’nucleophilic substitutions with tert-butanesulfinamide.Chapter one is the first part, in this part, we summarize significant applicationsof N and S contained heterocycles, and recent remarkable progress in the field of C-Xcoupling and the synthesis of2-amino-heterocycles.The second part (chapter two), we briefly investigated the C-N/C-S cascadecyclization of ortho-halo benzyl halide with2-mercaptobenzimidazoles to synthesis ofimidazobenzothiazines. We developed two different systems for the cyclization,namely trace transition metal contaminant in inorganic base promoted C-N/C-Scascade cyclization and transition metal free C-N/C-S cascade cyclization. We set thereaction of2-iodobenzyl bromide with2-mercaptobenzimidazole as model to test theinfluence of base, solvent and reaction temperature to the reaction and to obtain theoptimal reaction conditions. (1) The optimal of trace transition metal contaminant in inorganic base promotedsystem is react ortho-halobenzyl halide (1.0mmol) with2-mercaptobenzimidazoles inpresence of Cs2CO3(2.0mmol) in DMF (5.0mL) under argon at120oC for24h.(2) The optimal of transition metal free system is react ortho-halobenzyl halide(1.0mmol) with2-mercaptobenzimidazoles in presence of Cs2CO3(2.0mmol) inDMF (5.0mL) under argon at120oC for24h.And under the optimal conditions we expand the scope of the substrates in bothsystems, all the tested substrates were observed to undergo the reaction smoothly togive good yield of product, no matter with electron-withdrawing or electron-releasingsubstituent. The impact of substituent on the reaction can interpreted into:(3)2-mercaptobenzimidazoles were found: to affect the reaction in ways of①electron-releasing groups will surely promote the reaction, for example, in tracetransition metal contaminant promotion system2-iodobenzyl bromide react with2-mercaptobenzimidazole to give product in a78%yield while react with5-methyl-2-mercaptobenzimidazole give a84%yield. In transition metal free system,2-iodobenzyl bromide react with2-mercaptobenzimidazole to give product in83%yield while react with5-methyl-2-mercaptobenzimidazole give a90%yield.②electron-withdrawing groups were tested to lower the reaction rate, for example, intrace transition metal contaminant promotion system2-iodobenzyl bromide react with2-mercaptobenzimidazole to give product in a78%yield while react with5-nitro-2-mercaptobenzimidazole give a58%yield. In transition metal free system,2-iodobenzyl bromide react with2-mercaptobenzimidazole to give product in83%yield while react with5-nitro-2-mercaptobenzimidazole give a61%yield. Moreover,2-mercaptobenzimidazoles with substituent themselves exist in tautomer so as to givea pair of positional isomers mixed in ratio of1:1.(4) ortho-halobenzyl halides were observed to affect the reaction in ways of①electron-releasing groups deactivate the reactions, while②electron-withdrawinggroups promote the reactions significantly to prove the yields.We also surmised the mechanism for the transition metal free C-N/C-S cascade,while the yields peak when cesium-base used tell that Cs+plays important role in thecascade.2-mercaptobenzimidazoles easily form intermolecular H bond， and at thesame time calixcrowns were proved to show strong selectively molecular recognitionto Cs+, in accordance to these information we proposed a mechanism that2-mercaptobenzimidazole form a calixcrown-like cyclic compound throughintermolecular H bond, and introduce Cs+into the catalytic cycle through molecularrecognition to accelerate the reaction. Part three (chapter three and four), in this part we concentrated to learn the C-Nconstruction of2-mercapto-azoles with tert-butanesulfinamide to produce2-(N-tert-butylsulfinyl) amino-azole by way of C-S activation.Chapter three was introduced mainly to present the CuI/MgSO4catalyzedsynthesis of2-(N-tert-butylsulfinyl) amino-thiazoles by the reaction of2-mercapto-thiazoles with tert-butanesulfinamide. By screen copper catalyst, basicadditive and solvent, we obtained the optimal reaction conditions and learnt thecompact of the substrate on the reaction.(1) Under air, CuI (5mol%)/MgSO4(2.0mmol) catalyzes2-mercapto-thiazoles(1.0mmol) react with tert-butanesulfinamide (1.0mmol) under air for24h at100oCwas selected standard conditions for the reactions.(2) The more aromaticity of2-mercapto-thiazoles, the more reactive it is. Andelectron-releasing substituent on2-mercapto-thiazole was observed to put the reactionforward significantly.Unlike traditional C-X construction by C-X (X=halo, pseudo-halo) activation,this reaction role2-mercapto-thiazole as nucleophiles to react withtert-butanesulfinamide, which expand the methods of C-N construction and provide anew method for the synthesis of2-aminothiazole. Furthermore, in traditional C-Ncoupling inorganic base like K2CO3, or organic base like Et3N was used as basicadditive to absorb in-suit produced acid to advance the reaction. But in the reactionMgSO4was used as basic additive to function in two roles——Coordinate with Satom to weaken and activate the C-S bond to assure the oxidative addition of2-aminothiazole with catalyst; at the same time role as acid scavenger to neutralizethe in-suit produced acidic H2S to impel the reaction equilibrium forwards.Chapter four, based on the studies of chapter three, we developed a catalyst-freeand base-free C-N construction of2-mercaptoimidazole with tert-butanesulfinamide,the optimal reaction conditions tested to be2-mercaptoimidazole (1.0mmol) reactwith tert-butanesulfinamide (1.0mmol) under argon atmosphere at100oC for24h.Electronic effect played an important role in affecting the reaction in way that morearomaticity insures better reaction yield, and electron-releasing substituent acceleratesthe rate of reaction.The surmised mechanism suggests that2-mercaptoimidazoles play double rolesin reaction as substrate to react with tert-butanesulfinamide and as H bond donor tocatalyze the reaction.All the developed methods are simple and easy-performance, which will findapplication in near future.The fourth part is chapter five, we applied the polyols derivated from2-mercaptazoles in the minaral source chemistry and studied the extraction of boronfrom Sichuan Brine. The result showed that both2-trihydroxymethylamino benzimidazole and2-(benzo[d]thiazol-2-yl)propane-1,3-diol can extract boronic acidfrom brine, and the latter can perform in a much more effective manner (with a up to87%extraction efficiency), but still not as effective as reported1,3-diol extractants.