Construction Of 2-arylbenzo[4,5]thieno[2,3-d]thiazole Skeleton Via CuCl/S-mediated Three-Component Reaction

Both thiophene and thiazole frameworks are ubiquitous in nature and constitute the core of a wide range of biologically active natural products and pharmaceutical agents.Accordingly,many synthetic methods have been reported for the construction of thiophene and thiazol skeletons,respectively.However,to the best of our knowledge,there has been less study on the construction of the fused heterocyclic ring systems containing both thiophene and thiazole moieties.Specifically,benzo[4,5]thieno[2,3-d]thiazole,being an exclusive S-containing fused heterocyclic ring system,has received attention from both synthetic and medicinal chemists.Accordingly,a number of useful synthetic methods have been developed in pursuit of the construction of this exclusive scaffold.These methods have their own merits in the synthesis of each particular type of benzo[4,5]thieno[2,3-d]thiazole,however,one obvious drawback of these methods is that all of the substituted benzo[4,5]thieno[2,3-d]thiazole products had to be derived from the preformed benzothiophenes skeleton in the starting material.And all the reported methods were restricted to the synthesis of methyl or amino substituted benzo[4,5]thieno[2,3-d]thiazole.Herein,a novel reaction of aryl substituted benzo[4,5]thieno[2,3-d]thiazole mediated by copper reagent is developed.The investigation was started by choosing2-（2-bromo-4,5-dimethoxyphenyl）acetonitrile and benzaldehyde as model substrates,elemental sulfur as sulfur source,and 1,10-phenanthroline as ligand.The optimal condition was discovered after a series of conditions screening.So the product6,7-dimethoxy-2-phenylbenzo[4,5]thieno[2,3-d]thiazole could be achieved in a high yield by using Cu Cl as oxidant in DMSO under base condition.The synthesis of2-arylbenzo[4,5]thieno[2,3-d]thiazole was performed by means of simple substrates via one-pot three-componnets reactions.To study the adaptability of the new method to synthesize the target heterocyclic compounds,a series of substituted substrates were prepared to test the generality.Experimental results show that twenty benzo[4,5]thieno[2,3-d]thiazole derivatives have been synthesized under optimal conditions.The structures of synthesised substrates and products have been well characterized by melting point,¹H NMR,¹³C NMR and high resolution mass spectrometry.All the 2-arylbenzo[4,5]thieno[2,3-d]thiazole compounds were found to possess striking fluorescent features due to their existing polycyclicπ-conjugated systems.According to the X-ray crystal structure of 2-phenylbenzo[4,5]thieno[2,3-d]thiazole seems to be basically planar and can serve as a novel fluorophore,since the rigidity andπ-conjugation are commonly recognized as positive structural factors in enhancing the fluorophore brightness because of the reduction of the energy consumption from rotation and vibration.All those compounds exhibited very strong blue fluorescence when excited at around 365 nm.In general,the alkoxy substitution on theα-phenyl ring led to red shifts of the maximum absorbance and improvements in the Stokes shift.Substitution with the electron-donating group and halide in theβ-phenyl ring at 4-position did not lead to the substantial change of the quantum yield.The mechanism was studied through several control experiments.First,a new unreported dibenzo[b,f]thieno10,11-dicarbonitrile was produced under standard reaction conditions without the involvement of aldehyde.Second,when benzo[b]thiophen-2-amine prepared by article as starting material reacted with benzaldehyde and S₈ under standard conditions,the title2-arylbenzo[4,5]thieno[2,3-d]thiazole could be achieved in 35%yield.These results might indicate that benzo[b]thiophen-2-amine serves as the crucial intermediate for this three-component reaction,but was impractical to be detected and isolated due to its high reactivity under the conditions.Third,when introducing 3 equiv of BHT or TEMPO to the reaction under standard conditions,the yield of desired product was not significantly decreased.On the basis of results from the literature and control experiments,a plausible mechanism is proposed for this newly discovered three-component one-pot reaction.In the presence of the copper catalyst,2-（2-bromophenyl）acetonitrile was converted to benzo[b]thiophen-2（3H）-imine.Further is the nucleophilic attack to the electrophilic S₈.Finally,the condensation of intermediate with aromatic aldehyde and oxidation by sulfur delivered the target compound.In this work,we have successfully designed and developed a novel method for the synthesis of a class of 2-arylbenzo[4,5]thieno[2,3-d]thiazoles.After screening a series of conditions the final one selected was heating to 120°C and alkaline conditions,cuprous chloride as the oxidant and 1,10-phenanthroline as the ligand converted the substrates to the products.The experimental results show that under the optimal reaction conditions 20 2-arylbenzo[4,5]thieno[2,3-d]thiazoles derivatives were successfully synthesized from cheap and readily available substrates.Note that all products have fluorescence characteristics,the UV and fluorescence analysis on90%of the compounds,and a mechanism about this three-component Cu Cl-mediated one-pot synthesis of 2-arylbenzo[4,5]thieno[2,3-d]thiazoles reaction proposed followed by the accuracy checking of the reaction mechanism through verification experiments.This work may represent the first three-component synthesis of 2-arylbenzo[4,5]thieno[2,3-d]thiazoles skeleton via the successive formation of the thiophene and thiazole rings.