Protein, renowned as the “first substance of life”, invariably comprises an essential synthetic scaffold, amide. The widespread presence of different amide functionalities in a variety of natural products, pharmaceuticals, pesticides, etc. renders them profound significance as resourceful intermediates in synthetic chemistry. The American Chemical Society Green Chemistry Institute Pharmaceutical Roundtable’s (ACS GCIPR) remark in 2007, on the “synthesis of amides averting the use of poor atom economy reagents” being the top challenging aspect of organic chemistry, further raised the interest towards the development of new synthetic strategies. Formamides, among these, are critical intermediates that are broadly used in the construction of important medicinal compounds including fluoroquinolones, quinazolinones, substituted aryl imidazoles, benzimidazoles, 1,2-dihydroquinolines, therapeutic cancericidal agents and so on. Over the years, a diversity of formylating reagents have been reported, but each suffers from its own limitations. Overcoming the drawbacks of the conventional methods and providing a greener, environmentally and economically benign alternative; a transition-metal, ligand, and additive-free method for synthesizing highly reactive and eminently prevalent formamides have been developed. The new synthetic protocol employs formohydrazide as the formyl radical source, under the influence of K₂S₂O₈ as the sole oxidant at ambient temperature with water as a green solvent. The key feature of the developed methodology involves the use of readily available, inexpensive, eco-friendly formylating reagent that can easily avoid the conventional toxic formylation protocols, viz. chloral, cyanide, acetic/formic anhydride, formyl fluoride, and formic acid for the chemoselective N-formylation of primary, secondary, (hetero)aromatic and aliphatic amines. This strategy is compatible with a diversity of functional groups and provides easy access to a wide variety of N-formamides in good to excellent yields. It is extremely appealing as it requires no catalyst, promoters, or additives, and has straightforward separation and purification with excellent scalability. To mark the translational potential of the laboratory method, gram scale synthesis of highly prescribed, antidiuretic drug, chlorothiazide has been demonstrated in significant yield, along with the synthesis of a key intermediate of a biologically active natural product, Luotonin F.

Joydev Laha

Appearances