Metal-catalyzed Approaches to the Synthesis of Indolizine Derivatives from 2-Pyridinyl-substituted para-Quinone Methides and/or 2-(2-Enynyl)pyridines

Abstract

Abstract The research work presented in this thesis primarily focuses on Metal-catalyzed Approaches to the Synthesis of Indolizine Derivatives from 2-Pyridinyl-substituted para-Quinone Methides (p-QMs) and/or 2-(2-Enynyl)pyridines. This thesis is divided into two parts, namely Part A and Part B. Part A describes the synthesis of indolizine-based heterocycles from 2-pyridinyl substituted para-quinone methides using suitable coupling partners such as terminal alkynes and N,N-dimethyl enaminones; Part B involves the synthesis of indolizine-based unsymmetrical triarylmethane derivatives through copper-catalyzed reactions between 2-(2- enynyl)pyridines and boronic acids or 2-hydroxyphenyl-substituted N,N-dimethyl enaminones. Part A: Synthesis of Indolizine-based heterocycles from 2-pyridinyl-substituted para- quinone methides (p-QMs) Part A is subdivided into three chapters. Chapter 1: General introduction to the synthesis of heterocycles from functionalized para- quinone methides In this Chapter, the synthetic applications of functionalized para-quinone methides for the syntheses of oxygen and nitrogen-containing heterocycles have been briefly discussed. Chapter 2: Pd(II)-Catalyzed annulation of terminal alkynes with 2-pyridinyl-substituted para-quinone methides: Direct access to indolizines This chapter describes the synthesis of 1,3-disubstituted indolizine derivatives from 2-pyridinyl substituted p-QMs through a Pd(II)-catalyzed regiospecific [3+2]-annulation with terminal alkynes. The indolizine scaffold is widely found in many natural products and biologically active molecules, and several of them display a variety of pharmacological activities such as anti-cancer, anti-bacterial, anti-oxidant, and cytotoxic properties. Besides these, they have also found application in material science as fluorescent probes, dye for dye-sensitized solar cells (DSSC), and as a material in organic light-emitting diodes (OLEDs) and in the agricultural sector as herbicide and fungicide (Figure 1). Although numerous synthetic approaches to efficiently access the indolizine moiety have been reported in the literature, most of them require pre-functionalized starting material and multistep synthesis of starting materials. As a result, both economically and in terms of reaction conditions, an easy and atom-economical approach to the synthesis of indolizine derivatives is highly desirable. While working in the field of p-QMs as a 1,6-conjugate acceptor and its utilization for the synthesis of various vFigure 1. Representative examples of natural products and bioactive indolizine derivatives carbocycles and heterocycles, we hypothesized that the 2-pyridinyl substituted p-QMs could be used as a three-atom synthon for the synthesis of substituted indolizine derivatives through a [3+2]-annulation with terminal alkynes (Scheme 1). This protocol worked well with most of the terminal alkynes, and the corresponding indolizine derivatives were obtained in moderate to good yields. Control experiments revealed that the reaction takes place through a regiospecific [3+2]-annulation of terminal alkynes with 2-pyridinyl substituted para-quinone methides. Scheme 1. Synthesis of 1, 3-disubstituted indolizines from p-QMs and terminal alkynes viChapter 3: Cu(II)-Catalyzed [3+2]-annulation of 2-pyridinyl-substituted p-quinone methides with enaminones: Access to functionalized indolizine derivatives This chapter describes the synthesis of 3-amino-1,2-disubstituted indolizine derivatives from p-QMs. While exploring the synthesis of indolizine heterocycles from p-QMs, we have further Scheme 2. Synthesis of 3-amino-1,2-disubstituted indolizine derivatives from p-QMs hypothesized that N,N-dimethyl enaminones could be utilized as a two-carbon synthon for the synthesis of functionalized indolizines through the initial 1,6-conjugate addition of enaminone to p-QMs followed by a 5-exo-trig-cyclization and subsequent aromatization to afford the functionalized indolizine derivatives (Scheme 2). In line with this concept, we have developed a Cu[II]-catalyzed one-pot approach for the synthesis of 3-amino-2,3-disubstituted indolizine derivatives from 2-pyridinyl substituted p-QMs and N,N-dimethyl enaminones as the reaction partners. Part B: Synthesis of indolizine-based unsymmetrical triarylmethanes from 2-(2- enynyl)pyridines Part B is further subdivided into two chapters. Chapter 1: Copper-catalyzed synthesis of indolizine containing unsymmetrical triarylmethane derivatives from 2-(2-enynyl)pyridines This chapter deals with the synthesis of indolizine-based unsymmetrical triarylmethane derivatives. In recent years, triarylmethanes (TAMs) have emerged as important and integral scaffolds in many pharmaceuticals and biologically active molecules (Figure 2). Several of them, especially the unsymmetrical ones, exhibit important therapeutic activities and are being explored as anti-breast cancer, anti-viral and anti-TB, and anti-fungal agents. Besides the viiFigure 2. Some biologically active triarylmethane derivatives medicinal applications, triarylmethanes have also found remarkable applications in the dye industry and materials science. These significant applications of triarylmethanes have attracted the scientific community toward the development of different easily accessible routes for the synthesis of functionalized triarylmethanes derivatives. Therefore we became interested in synthesizing indolizine-based unsymmetrical triarylmethane derivatives using 2-(2- enynyl)pyridine and boronic acids as the reaction partners (Scheme 3). The reaction proceeds through the Cu-catalysed 5-endo-dig-cyclization of 2-(2-enynyl)pyridine, followed by the addition of boronic acid. Scheme 3. Synthesis of indolizine-based unsymmetrical triarylmethanes from 2-(2- enynyl)pyridines and boronic acids viiiChapter 2: Copper-catalyzed synthesis of chromone and indolizine-based unsymmetrical triarylmethanes from 2-(2-enynyl)pyridines This chapter deals with the synthesis of chromone and indolizine-based unsymmetrical triarylmethane derivatives. Chromones are naturally occurring compounds mainly found in plants. This class of oxygen-containing heterocycles are found as an integral part of many natural products and bioactive molecules, and they are known to show various pharmacological Figure 3. Chromone-based natural products and bioactive compounds activities, such as anti-cancer, anti-oxidant, anti-fungal, etc. (Figure 3). Due to the importance of both indolizine and chromone derivatives, we developed a metal catalyzed protocol to access unsymmetrical triarylmethanes containing chromone and the indolizine scaffold in the same molecule using 2-hydroxyphenyl-substituted N,N-dimethylenaminones and 2-(2- enynyl)pyridines (Scheme 4). Scheme 4. Synthesis of indolizine and chromone containing unsymmetrical triarylmethanes