A simple yet novel strategies for the synthesis of pharmacologically versatile benzoxazole and benzothiazole scaffolds via transamidation.

Abstract

Transamidation is a popular way for amide transformation from another amide despite conventional amide bond formation methods. Acid and acid chloride were utilised as starting ingredients in previous procedures. Transamidation has shifted the perspective of researchers on amide synthesis. Nowadays, many methodologies have recently come to light for amide transformation, using non-metal and metalmediated techniques. On the other hand, a few approaches involving amide bond activators have been reported. Moreover, N-Boc, Tosyl, and Mesyl groups are commonly utilised as amide bond activators. As a result, many amides transformations have been synthesised and published in the literature over the last few decades. Based on previous research, we have attempted to develop cost-effective and novel techniques of transamidation for unactivated amides, which could serve as a potential alternative to synthesising amide bond containing compounds from lab to plant scale. We also demonstrated a novel approach for synthesising 2-substituted benzoxazole/benzothiazole compounds using this transformation. The history and development of unactivated amides transformation are briefly described in Chapter 2. This chapter also discusses different transamidation methods for primary, secondary, and tertiary unactivated amides that are transformed into other amides without the need for an amide bond activator. The development of a novel green, efficient catalyst-free, one-pot synthetic methodology to synthesise amides is described in Chapter 3. Under the optimisation investigations, the effects of various acids, solvents, temperatures, and time intervals were also described. The reaction was catalysed by hydrochloride, which activated the carbonyl bond, and then attacked the carbonyl carbon with an additive amine as a nucleophile. Finally, the amine as a byproduct is removed, resulting in the desired converted amide. Furthermore, this new transamidation process allows for a wide range of amide types, including primary, secondary, and tertiary. This approach also works with a variety of primary and secondary amines, including aliphatic and bulky, hetero-aromatic substituted amines. To continue the work begun in Chapter 4, we develop a new solvent-free and metal-free method for synthesising 2-substituted benzoxazole and benzothiazole in Chapter 4. In this approach, we increase the temperature and employ substituted 2-aminophenols or 2-aminothiophenols instead of amines. To lead the annulation product, the oxygen or sulphur atom of phenol or thiophenol attacks the carbonyl carbon of the transformed amide group. Furthermore, this technique works well with a variety of substituted 2-aminophenols. Additionally, the amide scope for this reaction is quite broad. Chapter 5 describes the development of a new method for the transamidation of aliphatic amides using CuCl2 as a catalyst. The effects of various catalysts and Lewis acids and the effect of different solvents were explained. Moreover, the annulated substituted 2-benzoxazole and 2-benzothiazole derivatives obtain in the case of 2-aminophenol and 2-aminothiophenol. Besides, this new versatile methodology provides a wide substrate scope for the synthesis of different functionally substituted amides and 1,3- benzoxazole scaffolds. It can be further exploited as building blocks for the synthesis of pharmaceutical drugs.