Development of novel methodology for the synthesis of an important class of functionalized indoles and related heterocyclic scaffolds

Abstract

This thesis presents research into the development of the metal-free based catalytic systems for the direct FC alkylation of indoles with a variety of biologically promising molecules such as 3-hydroxy-3-ethoxycarbonylisoindolin- 1-one, isoquinoline-1,3,4-trione, N-protected-γ-aminocrotonates/ γ-aminocrotonophenones in an efficient manner. To begin with a general introduction to the syntheses and applications of indoles and their derivatives with historical perspectives, synthetic methodologies developed for the functionalization of indoles through various organic transformations have been discussed in the first chapter. The next chapter describes an efficient one-pot method for the synthesis of biologically attractive 3-ethoxycarbonyl-3-(indol-3-yl)isoindol-1-one derivatives through a FC alkylation of both N-protected and unprotected indoles with 3-ethoxycarbonyl-3-hydroxyisoindol-1-one at room temperature catalyzed by (±)-camphor-10-sulfonic acid (CSA) as an efficient Brønsted acid catalyst. In the third chapter, a simple, convenient and one-pot method for the synthesis of a series of biologically promising 6,7-dihydrospiro[indole-3,1ʹ-isoindole]- 2,3′,4(1H,5H)-trione derivatives through a novel domino dehydration/ condensation/cyclization reaction of 3-ethoxycarbonyl-3-hydroxyisoindolin- 1-one derivatives with several cyclic enaminones using (±)-CSA as an inexpensive Brønsted acid catalyst has been reported. Biopolymeric alginic acid is shown to be a recyclable green catalyst for the Friedel-Crafts reaction of indoles with isoquinoline-1,3,4-triones in water as illustrated in the fourth chapter. The fifth chapter demonstrates a simple, convenient and practical one-pot two-step sequential method for the synthesis of N-protected γ-hetero aryl/aryl-substituted γ-aminoester/γ-aminoketone derivatives via π-bond isomerization of N-protected γ-aminocrotonates/γ-aminocrotonophenones using Et3N, followed by tandem π-bond isomerization/FC reaction of the resultant enamines with a variety of heteroarenes/arenes in the presence of B(C6F5)3 as a powerful Lewis acid catalyst. The synthesis of 3-ethoxycarbonyl-1,1-dimethoxycarbonyl-5-(2- nitrophenyl)-2-arylpentan-4-one derivatives as Michael adducts and salicylate scaffolds via organocatalyzed Michael addition of arylmethylidenemalonates with 4-(2-nitrophenyl)acetoacetate has been described in the sixth chapter. Also pharmacologically interesting 8,9- dihydropyrido[1,2-a]indol-6(7H)-ones have been achieved through a one-pot reductive cycloaromatization–lactamization sequence reaction of Michael adducts using Zn/NH4Cl as a reducing agent. The final chapter of this thesis focusses on the conclusions and future outcomes of the current synthetic methodologies accomplished during the entire series of works.