Visible Light Promoted Synthesis Of Sulfonyl Substituted Pyrido[1,2-a] Indole/Pyrrole

Objective:Pyrido[1,2-a]indole/pyrrole skeleton widely exists in natural products and drug molecules.The introduction of sulfonyl group into drug molecules can enhance drug activity and improve drug bioavailability.Therefore,it is of great significance to study the synthesis of sulfonyl substituted pyrido[1,2-a]indole/pyrrole.The visible light mediated reaction is more and more favored by researchers because of its high efficiency,good selectivity and environmental friendliness.The purpose of this study is to develop a green and efficient synthetic method of sulfonyl substituted pyrido[1,2-a]indole/pyrrole,which provides a basis for the research and development of related drugs.Methods:Sulfonyl substituted pyrido[1,2-a]indole/pyrrole derivatives were prepared by indole/pyrrole derivatives and aryl/alkyl sulfonyl chloride under visible light irradiation without the participation of metal and external photocatalyst.The optimum reaction conditions were determined by optimizing various variables,and the applicability of the reaction system was studied with various types of substrates.The possible reaction mechanism was proposed by carrying out radical capture experiments,Stern-Volmer fluorescence quenching experiment,detecting UV-Vis absorption spectrum combined with LC-HRMS.Furthermore,the application of the obtained product was expanded to explore its application value,and indole was used as a pre-catalyst to preliminarily explore its application scope and application effect.Results:Through the screening of the reaction system,the optimum reaction conditions were determined:under the protection of argon,indole/pyrrole derivatives（0.2 mmol）,aryl/alkyl sulfonyl chloride（0.4mmol）,Na H₂PO₄（0.4 mmol）and ultra dry Me CN（2 ml）reacted under the irradiation of 5 W Blue LED for 24 hours to efficiently produce Sulfonyl substituted pyrido[1,2-a]indole/pyrrole derivatives.The reaction system is suitable for various types of substrates.A total of 52 target products were synthesized with a maximum yield of 94%.Moderate yield can also be obtained by expanding the same type of reaction to gram scale.At the same time,the application of indole as a pre-catalyst to promote the production of sulfonyl radical and further cyclization was explored.Conclusion:Herein we report a method of sulfonation/cyclization of indole/pyrrole derivatives with aryl/alkyl sulfonyl chloride under visible light without external photocatalyst to produce sulfonyl substituted pyrido[1,2-a]indole/pyrrole derivatives.Sulfonyl substituted pyrido[1,2-a]indole/pyrrole derivatives are obtained in medium to good yields by mild,simple reaction conditions and good substrate applicability.In addition,the reaction can be scaled up in gram scale,and the resulting products can be simply transformed into important synthetic blocks and potentially bioactive molecules.The mechanism study shows that the in-situ indole oligomer derivatives may be used as photocatalysts to promote the formation of sulfonyl radicals.Finally,the preliminary exploration shows that indole derivatives can be used as pre-photocatalysts to promote the photocatalytic reaction of aryl/alkyl sulfonyl chloride,so as to construct a variety of sulfonyl substituted heterocycles.