Construction of Thiocarbonyl in Situ and Bioactivity of Related Compounds

Author:Tan Wei

Supervisor:jiang xue feng

Database:Doctor

Degree Year:2019

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Pages:187

Size:12143K

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Thiocarbonyl(C=S)compounds are a kind of organic sulfides with unique motif,which can be applied in many research fields.The development of related compounds has been widely concerned and explored by researchers.At present,the synthetic methods of these compounds are mainly based on the conventional sulfide reagents like Lawesson reagent,thiophosgene and carbon disulfide.Although these reagents have their own advantages,they also have some unavoidable problems such as bad smell,poor atomic economy,high toxicity,high corrosiveness and high flammability,etc.Here,we have developed a new and practical in-situ reaction model for the direct construction of thiocarbonyl structure,avoiding the use of traditional thiocarbonyl reagents,realizing the synthesis of various structural types of thiocarbonyl compounds,and successfully applied these methods to the exploration of functional thiocarbonyl compounds.It mainly includes the following contents:(1)Study on thiocarbamide compounds.The thiocarbamide compounds are synthesized based on the combination of sulfur powder and chloroform via the in situ constructed thiocarbonyl structure interacting with amine sources in the reaction.The reaction has a wide range of substrate universality.Various highly reactive groups such as hydroxyl and alkenyl groups can be effectively compatible in the system and the chiral center of the substrates can be maintained in the reaction as well.Meanwhile,it also has the advantages of high atom economy and environment-friendly,avoiding the use of traditional thiocarbonyl reagents with high pollution and toxicity.In addition,we smoothly applied this method to the synthesis of various chiral thiocarbamide catalysts and pesticide molecules,and completed the gram-scale preparation of related compounds.(2)Study on benzothiazine-thione and benzothiazole-thione compounds.The benzothiazine-thione and benzothiazole-thione compounds are synthesized in one-pot reaction with o-iodobenzylamine or o-iodoaniline derivatives as raw materials in the presence of potassium sulfide and chloroform,along with the formation of five new chemical bonds and in situ the construction of thiocarbonyl group,realizing the introduction of carbon disulfide in form.The method has been smoothly applied to the gram-scale preparation of functional molecule 2-Mercaptobenzothiazole(MBT).In terms of mechanism,we found that potassium sulfide and N-methyl pyrrolidone(NMP)can interact at room temperature to form trisulfide anion radical(S3.-)through the detection of ultraviolet absorption spectrum and electron paramagnetic resonance(EPR),and proposed the mechanism involving the participation of S3.-species and dichlorocarbene(:CCl2)in the reaction.In addition,we investigated the biological activities of benzothiazine-thione and benzothiazole-thione compounds obtained from the reaction,and found for the first time that these compounds has obvious inhibitory activities against histone deacetylase 8(HDAC8)and the catalytic domain of histone deacetylase 4(cHDAC4).(3)Study on dithiocarbamate.The dithiocarbamate compounds are synthesized in one-pot reaction by using organic thiosulfates and amines as substrates with the participation of potassium sulfide and chloroform,along with the formation of four new chemical bonds and in situ the construction of thiocarbonyl group,avoiding the use of traditional thiocarbonyl reagents.In terms of mechanism,combined the experimental results with the previous chapter on the research of S3.-,we further proposed the mechanism involving the participation of S3.-species and dichlorocarbene(:CCl2)in the reaction.On the other hand,we also investigated the biological activities of the open-chain dithiocarbamate compounds synthesized in the reaction.It was found that these compounds also exhibit bioactivities against HDAC8and cHDAC4,and some compounds shows good selectivity between HDAC8 and cHDAC4.(4)Study on thiolactam.The thiolactam compounds are synthesized through visible-light-mediated thiocarbonylation ofα-amine C(sp3)-H bond with the participation of cyclic organic amines and potassium sulfide as substrates,realizing the construction of thiocarbonyl group in situ.This method exhibits novel reaction model and has the characteristics of mild conditions and high atom economy etc.,and it has been smoothly applied to the structural modification of natural product Tetrahydroberberine.In the mechanism part,it is proved that iminium ion is the crucial intermediate in the reaction through the control experiment.According to the results of UV-visible spectra and fluorescence quenching experiments,we proposed that the inorganic sulfur anions such as S2.-and S3.-are reactive species generating from potassium sulfide of solution in the reaction and participate in the quenching of excited state photosensitizer and the recycling of catalysts.