Study On The Synthesis Of Aryl Thioether / Thioester Catalyzed By Nickel

Aryl sulfides are an important class of organic compounds,which are widely used in medicine,pesticides,and materials.For example,axitinib is an anti-tumor drug,5-lipoxygenase inhibitor AZD4407 is a class of organic compounds,that are broadly applied in pharmaceuticals,farm chemicals and materials,flame retardant materials,photochromic compound,fuel and other field.Therefore,it is very important to find economical and green synthetic methods to synthesize aryl sulfides.In the process of aryl sulfide synthesis,it is important to study the formation of C-S bonds.At present,there are some mature methods for the formation of C-S bonds.For example,palladium or nickel catalyzed the couplings of aryl halides or aryl boronic with aromatic thiols.In recent years,some novel synthetic methods have also been developed,such as:no transition metal catalysts,electrochemical processes,desulfurization and free radical pathways to build C-S bonds.Among all these methods,the most compelling method currently is the nickel catalyzed process.Nickel has the advantages of good catalytic performance,easy electronic gains and losses,low price,simple preparation,easy storage,etc.Therefore,the use of nickel to catalyze the synthesis of aryl sulfides is currently a hot spot in the research of preparing such compounds.This thesis mainly studies the new synthetic methods of diaryl sulfide derivatives,monoaryl sulfide derivatives and aryl thioester derivatives.（1）Synthesis of diaryl sulfide derivatives catalyzed by nickelUsing phenyl acetyl thioester and iodobenzene as the model reaction,the types of nickel catalysts,different ligands,solvents,reaction temperatures,reaction time and other conditions were investigated,and the products were selected from all experimental records.The final reaction conditions are:（1.0 equiv）aromatic acetyl thioester,（1.0 equiv）4-iodoanisole,（0.1 equiv）Ni Br₂ as the catalyst,（0.2 equiv）Bpy as the ligand,（2.0 equiv）Zn powder,DMF was used as the solvent,the reaction temperature was 110℃,and the reaction was carried out for 15 h under the protection of nitrogen.After obtaining the optimal reaction conditions,we continued to test the applicability of the aryl acetyl thioester derivatives and different kinds of aromatic iodides to investigate the applicability of the reaction in a further step.Finally,20 products were obtained with accepted yield.It can reach up to 90%.All products were characterized by nuclear magnetic resonance,mass spectrometry and other methods,and they were identified as target compounds.（2）Synthesis of monoaryl sulfide derivatives catalyzed by nickelUsing methyl acetyl thioester and 4-iodoanisole as a model reaction,the types and amounts of nickel catalysts,different solvents,reaction temperatures,reaction times and other conditions were investigated and selected from all experimental records The reaction conditions feature high efficiency,good yields and low cost.Thus the optimal reaction conditions were obtained as following:（1.0 equiv）methyl acetyl thioester,（1.0 equiv）4-iodoanisole,（0.1 equiv）Ni Br₂ as the catalyst,（0.2 equiv）Bpy as the ligand,（2.0 equiv）Zn powder,DMF as solvent,nitrogen protection,reaction temperature 110℃,for 15 h.After obtaining the optimal reaction conditions,continue to screen different alkyl substituted acetyl thioesters and different substituted iodobenzenes to obtain 11 desired products with a maximum yield of 60%.All products have been characterized by nuclear magnetic resonance,mass spectrometry and other methods to confirm that the target structure is correct.After analyzing the reaction mechanism,it is speculated that this reaction is nickel-insertion transfer reaction.（3）Synthesis of aryl thioester derivatives catalyzed by nickelUsing ethyl ethyl ethsulfate and iodobenzene as model reactions,the types and amounts of nickel catalysts,different solvents,reaction temperatures,reaction times,gas environments and other conditions were investigated,and all experimental records were recorded.The reaction conditions feacture moderate yield and low costs.The optimal reaction conditions were thus obtained as following:（1.0 equiv）iodobenzene,（3.0 equiv）methyl acetyl thioester,（0.1 equiv）Ni Br₂ as the catalyst,（0.2 equiv）BPy as the ligand,（2.0equiv）Zn powder,DMF/H₂O（10:1）as solvent,one atmosphere carbon monoxide gas protection,reaction temperature at 110℃for 15 hours.After obtaining the optimal reaction conditions,we continued to test the applicability of different acetyl thioesters and different aromatic iodides,so that the applicability of the reaction was further investigated,and finally 17 desired products were obtained with the moderate yields.All products were characterized by nuclear magnetic resonance,mass spectrometry and other methods to confirm that the target structure is correct.After experimental comparison,the reaction mechanism was preliminarily provided.