SYNTHETIC PROTOCOLS FOR THE GENERATION OF ARYL/ARYLSULFONYL SUCCINIMIDES AND DIARYLMETHYL SULFONES

Abstract

The thesis entitled “Synthetic protocols for the generation of aryl/arylsulfonyl succinimides and diarylmethyl sulfones” is divided into three chapters, viz. (i) Introduction, (ii) Objectives, Results and Discussion, and (iii) Experimental. Novel protocols for the synthesis of Brønsted acid mediated functionalized C-3 arylated succinimide derivatives, functionalized 3-sulfonyl succinimide, diarylmethyl sulfone and diarylsulfone derivatives mediated by metal-free, electron-transfer reagent have been developed. Further, novel metal-free and photocatalyst-free synthetic methodology for the functionalization of arylsulfonyl chlorides with p-quinone methide derivatives mediated by hypervalent iodine reagent has been developed. Chapter 1: Introduction The chapter details with a brief review on the reactivity and synthesis of maleimide, succinimde and p-quinone methide scaffolds with their versatile application. Succinimide, and diarylmethyl sulfone derivatives are of great biological importance due to their ubiquitous occurrence in nature as well as in various pharmaceuticals. Succinimide scaffolds such as drugs-like phensuximide and ethosuximide are particularly used as anticonvulsant agents. Various sulfone derivatives are prominent drugs for the treatment of infectious disease such as leprosy and are also effective against inflammatory diseases. Maleimides and p-quinone methides both being electrophilic olefins, serve as excellent Michael-acceptor and thus have been utilized to achieve various useful molecules of therapeutic importance via C–C and C–heteroatom bond formation. Chapter 2: Objectives, Results and Discussion This chapter deals with objectives, results and discussion and is divided into three sections. 2.1. Synthesis of 3-aryl succinimide derivatives via Friedel-Crafts reaction of maleimide derivatives We have carried out a highly facile, metal-free and novel methanesulfonic acid catalyzed Friedel–Crafts protocol to access 3-arylsuccinimide derivatives with C(sp2)–H nucleophiles i.e., electron-rich arenes and N-arylmaleimide electrophiles, in high yield under mild reaction conditions. A variety of electron-rich arenes such as 1,3-dimethoxybenzene, 1,3,5-trimethoxy-benzene, -naphthol and resorcinol readily underwent the reaction to afford 3-aryl succinimides. We also demonstrated the C-3 arylation of an N-arylmaleimide with heteroarene i.e., N-methylindole under metal-free conditions and generated corresponding succinimide hybrids in high yield (Scheme 1).Scheme 1: Synthesis of C-3 arylated succinimides 2.2. Synthesis of diarylmethyl sulfones, diarylsulfones and 3-sulfonyl succinimides via freeradical oxidative coupling In subsequent attempts, we developed an I2/TBHP mediated oxidative sulfonylation protocol using odorless, bench stable and easily available arylsulfonyl hydrazides as sulfonyl radical source for the synthesis of various 3-sulfonyl succinimides, and diarylmethyl sulfones.Scheme 2: Synthesis of 3-sulfonyl succinimides, diarylmethyl sulfones and diarylsulfones. The reaction proceeded smoothly with a variety of N-arylmaleimides and para-quinone methides under mild conditions in aqueous media under air atmosphere at room temperature. The approach is free from the metal-catalysis which is generally used for the electron-transfer reactions. Herecatalytic amount of the iodine acted as an efficient promoter for this transformation. This protocol could also be successfully employed further to achieve diaryl sulfones in good yield. It is widely compatible with different substituted p-QMs, as well as with quinones such as p-benzoquinone and quinone imine ketal delivering products with high regioselectivity (Scheme 2). 2.3. Synthesis of diarylmethyl sulfones using arylsulfonyl chlorides as sulfonyl source under hypervalent-iodine catalysis Further we employed metal-free and photocatalyst-free, hypervalent-iodine mediated sulfonyl radical-addition to the p-QMs in acetonitrile solvent. Novel, rapid and efficient methodology for the construction of diarylmethyl sulfones has been developed using inexpensive and commercially available arylsulfonyl chlorides. Diacetoxyiodobenzene (DIB) (1.5 equiv) as hypervalent iodine catalyst was used for the formation of the diarylmethyl sulfone derivatives in moderate to good yield (Scheme 3).Scheme 3: Hypervalent-iodine mediated synthesis of diarylmethyl sulfones using arylsulfonyl chlorides. Chapter 3: Experimental All the compounds were purified either by crystallization or by silica gel column chromatography and are fully characterized by modern analytical tools such as NMR and HRMS. Some of the products were further characterized by single crystal X-ray analysis. The experimental data is presented in this chapter.