Generation of Enamides and Enol esters: Application to Oxazole and α-Naphthol Synthesis

Abstract

Enamides are key structural motifs in many natural products as well as pharmaceutically important metabolites. Furthermore, these are also synthons in numerous organic transformations. For instance, enamides undergo pericyclic reactions, photochemical reactions, nucleophilic reactions to produce chiral amines, electrophilic reaction to produce chiral amides, transition metal catalyzed reactions etc. Enamides are also used extensively for the synthesis of various heterocyclic compounds. Considering the numerous applications of enamides, several methods have been developed for their synthesis. Moreover, controls of stereochemistry across the double bond of enamide persuade a potential problem, particularly in the synthesis of thermodynamically disfavoured Z-enamides. Thus, it is highly desirable to develop general and practical methods for the stereoselective preparation of thermodynamically disfavourable Z-enamides under mild reaction conditions.

The oxygen analogue of enamide called “enol ester” is also an important building block in organic synthesis. Like enamides, enol ester motif is also abundant in numerous natural products as well as pharmaceuticals. Therefore, synthesis as well as the use of enol esters in organic transformation is an attractive area of research in recent years.
Our effort on the synthesis of enamides (particularly Z-enamide) and enol esters and their application is presented in this thesis.

The present thesis entitled “Generation of Enamides and Enol Esters: Their Application in Oxazole and α-Naphthol Synthesis” has been divided into two parts: Part-I and Part -II. Part-I divided into four Chapters whereas Part-II divided into two chapters. Brief summary of the chapters are as follows:
Part-I
Chapter 1. Synthesis and Reactions of Enamides: A Brief Overview
In this chapter up to date developments in the use of enamides in various transformations and their synthesis is described. Scope and limitations of the earlier works along with the objective of the present work have been presented briefly.
Chapter 2. Stereoselective Synthesis of Enamides by Palladium-catalyzed Oxidative
Amidation of Alkenes
This chapter describes the development of a novel catalytic protocol for the synthesis of Zenamides by the oxidative amidation of olefins in the presence of ambient air.This protocol is also found to be suitable for the cross coupling of sterically hindered secondary amides with electron deficient olefins leading to tertiary enamides in good yield.
Chapter 3. Stereoselective Synthesis of Enamides by Pd-Catalyzed Hydroamidation of
Electron Deficient Terminal Alkynes
This chapter reveals the first Pd-catalyzed hydroamidation of activated terminal alkynes to form Z-enamides selectively.The optimized cross-coupling reaction condition is found to be tolerant for the coupling of wide varieties of amides with electron deficient alkynes. A plausible catalytic cycle for the hydroamidation reaction also described.
Chapter 4. Synthesis of substituted oxazoles from enamides
In this chapter, NBS/Me2S-mediated annulation of enamides into 2,5- and 2,4,5-substituted oxazoles in the presence of mild base has been described. The developed reaction conditions are simple and tolerant to a wide variety of substituents including both electron-donating and withdrawing groups to produce oxazoles in one-pot without further purification of the intermediate.
Part - II
Chapter 5.Enol Esters in Organic Synthesis: A Brief Overview
A brief review on the generation and reactions of enol esters was presented in this chapter. Moreover, objective of the present work in line with the enol-ester chemistry is also mentioned.
Chapter 6. Synthesis of α-naphthols from Enol Esters
In this chapter, development of a de novo method for the synthesis of polysubstituted α- naphthols from simple monocyclic enol esters has been demonstrated. The developed reaction conditions are mild and do not require any anhydrous medium or expensive catalytic protocol to access α-naphthols in good yield.