N-Arylamides are a ubiquitous component of a broad range of natural products and biologically active compounds. The significance of these motifs can be recognized from their presence in natural products (e.g., penicillin, paclitaxel), pharmaceuticals (e.g., atorvastatin, imatinib), agrochemicals, and in a large number of industrial materials including polymers, detergents and lubricants. More importantly, it constitutes the backbone of the biological crucial proteins and peptides. Among the several synthetic methods developed so far, the direct formation of the C–N bond through cross-coupling reaction of arylhalides (I, Br, Cl) or pseudohalides (OTf, OTs, OMs etc) with primary or secondary amides is one of the best method in terms of versatility. These amidation methods are mainly catalyzed by the transition metal such as palladium and copper catalysts; and it is necessary to install the leaving group beforehand on the aromatic coupling partner which finally ends up with undesirable waste. It is, therefore, highly desirable to develop an efficient and more environmental friendly method for the synthesis of N-arylamides.
N-Acetyl-para-aminophenol (APAP), commonly known as paracetamol or acetaminophen, is a representative of the N-arylamide class drug. This drug is one of the most consumed worldwide with a global production of more than 100,000 tons per year. Over the last century, many routes have been explored for the preparation of paracetamol but all those which have emerged industrially are based on the acetylation of para-aminophenol (PAP) in the final step. In this paper, we have demonstrated a new synthetic protocol for the preparation of acetanilides including paracetamol via hypervalent iodine mediated aza-Hofmann type rearrangement of amidines. The reaction proceeds smoothly at 100 °C in the presence of PhI(OAc)2 or PhINTs in toluene solvent. The requisite amidine substrates were prepared from amines and nitriles by applying Pinner reaction approach. Considering the easy access of amidines from nitriles, the overall process is the conversion of nitriles to acetanilides. As an application of the protocol, we have synthesized paracetamol from 4-cyanophenol.
