Rigioselective Synthesis Of 2,5-Disubstituted Pyrroles Via Stepwise Iododesilylation And Coupling Reactions

2,5-Disubstituted pyrroles is an important class of poly-substituted pyrrole derivatives,which is commonly found in natural products with（non）biological activity.Many of the 2,5-disubstituted pyrroles are the main structural element of many drugs,porphyrin analogues,macromolecules,alkaloids and amino acids.Therefore,2,5-disubstituted pyrrole derivatives have a good research prospects and the synthesis of 2,5-disubstituted pyrroles has aroused more and more attention of researchers.There are many methods for synthesizing 2,5-disubstituted pyrrole derivatives,which included conventional Paal-Knorr synthesis method,metal-catalyzed synthesis method,expansion method and so on.However,the exploration of the new method for synthesizing 2,5-disubstituted pyrrole is still a hot topic in the field of heterocyclic synthesis.In our research,we used the pyrrole as the starting material and N,N-dimethylaminosulfonyl group is introduced into the pyrrole nitrogen as a protecting group according to the literature method.Then,two symmetric silane groups are introduced by the reactions of α-hydrogen lithium exchange and nucleophilic substitution reaction and we obtain N,N-dimethyl-2,5-bis（trimethylsilyl）-¹H-pyrrole-1-sulfonamide.We use it as a starting material and synthesize ten diffrent final 2,5-disubstituted pyrroles by stepwise iododesilylation and coupling reaction.In this paper,the preliminary investigation of ipso-halogenation for TMS was carried out.In this reaction,the ipso-iodination and the ipso-bromination can take place,and the yields for the iodination are higher than that for bromination.However,the ipso-chlorination can not happened.We used the NIS and NBS as the halogenated reagents in the reaction and we obtained the target products.In the iodine reaction,we used CH₂Cl₂ and THF as the reaction solvent respectively,and we found that the yield of target products when CH₂Cl₂ was used as solvent was higher than that of THF as solvent.However,the yield of brominated products when THF was used as solvent was higher than that of CH₂Cl₂ as solvent in the bromination reaction,which show a significant solvent effect.In the Suzuki coupling reaction,we explored the conditions with regards to catalyst,base,solvent and temperature.The optimal condition is: at 100 °C,Pd（PPh₃）₄ is used as catalyst,and 2M Na₂CO₃ as a base,with toluene:methanol（1:1）as solvent.In the reaction,we selected a series of benzene group with different groups and obtained a series of 2,5-disubstituted pyrrole with different substituents.The experimental results show that different substituents can be introduced at the 2 and 5 positions of the pyrrole ring through the designed synthetic route,which increases the flexibility of introducing the group.Finally,we use TBAF to carry out the deprotection reaction of N,N-dimethylaminosulfonyl.However,we find that N,N-dimethylaminosulfonyl are rearranged during the removal process,and several new pyrrole compounds are obtained.We believe that this reaction is of a high research value in the future.During the entire course of this study,we obtain 29 compounds,and all of them are not reported in the literature.Their structures are well characterized by ¹H NMR,¹³C NMR and HRMS.