Synthesis Of Polysubstituted Pyrroles Via Stepwise Halogenation And Suzuki Coupling Reactions

Polysubstituted pyrroles is an important structural unit in some natural productswith biological activity.In addition,it is also an essential part of many polymer materials,proteins,drugs,pesticides and so on.Due to the wide range of applications,polysubstituted pyrroles have attracted widespread attention.There are many methods to synthesize polysubstituted pyrroles,including Paal-Knorr reaction,multicomponent Hantzsch reaction,and cycloaddition reaction and so on.However,some limitations are involved,such as equivalent reagents,harsh reaction conditions with high pressure and limited substrate scope.Therefore,the synthesis of polypyrroles is still an essential research issue in the field of organic chemistry.In this study,N,N-dimethyl-2,4-bis(trimethylsilyl)-1H-pyrrole-sulfonamide was initially prepared from N,N-dimethylaminosulfonyl-1H-pyrroles with a dimethylaminosulfonyl as protecting group,and then rearrangement under acidic condition leading to its 2,4-isomer according to literature method.We used them as starting materials to synthesize three kinds of polysubstituted pyrroles,including nine 2,4-disubstituted pyrrole and two 2,3,5-trisubstituted pyrroles by stepwise halogenation and Suzuki coupling reaction.The bromination afforded monobromo-substituted pyrrole product through the ipso-halogenation of trimethylsilyl group.The first bromination was performed using a NBS/THF system and 2-bromo-4-(trimethylsilyl)pyrrole was obtained.Coupling reaction with arylboronic acids generated a series of 2-aryl-4-(trimethylsilyl)pyrrole products under Suzuki coupling conditions.The fact that the first bromination occurred at the ?-position of pyrroles was confirmed by the X-ray crystal structure of coupling products.According to the optimization of reaction conditions,we used Pd(PPh3)4 as a catalyst,2M K2CO3 as a base,and DMF as a solvent.Under anaerobic conditions,the reaction was performed at 110?.By changing the type of phenylboronic acid,it was found that the coupling reaction has obvious electronic and positional effects.The second bromination was also highly regioselective.When the 5-position of the phenyl ring was connected with an electron-donating group,ipso-substitution occured at the 3-position of the pyrrole ring with the TMS [1,2] C-C rearrangement(confirmed by HMBC);while with an electron-withdrawing group,ipso-bromination occured.Through the subsequent Suzuki coupling reaction,the TMS on this processwas cleaved to produce 2,4-disubstituted pyrroles;and the ipso-bromination substrate coupled to give 2,4-disubstituted products.Finally,the 2-(trimethylsilyl)-3-bromo-5-aryl-pyrroles which obtained with ipsobromination and TMS migration work well with iodine to give ipso-iodination product.This pyrrolyl iodide is more active towards aryl boronic acids than bromide and the Suzuki coupling reaction selectively accorded with the iodide to give two different 2,3,5-trisubstituted pyrroles.Through the designed synthetic route,various polysubstituted pyrrole could be synthesized,and different groups were introduced at different positions of the pyrrole ring,which increases the flexibility of this mothodology.In this study,a total of 34 compounds were obtained,and all of them were not previously reported in the literature.Their structures were confirmed by 1H NMR,13 C NMR and HRMS.