A Hofmann Rearrangement–ring Expansion Cascade For Thesynthesis Of 1-pyrrolines: Application To The Synthesis Of 2,3-dihydro-1H-pyrrolo[2,1-α]isoquinolinium Salts

Heterocyclic compounds enrich the world of organic chemistry significantly. The key role of heterocycles in nature has always been an anchor point for chemists in the pursuit of new molecules endowed with pronounced and diverse biological activities. Nowadays, heterocycles are eligible and versatile building blocks for the production of valuable compounds such as agrochemicals, pharmaceuticals, and even materials. Synthesis and elaboration of specific(classes of) heterocycles can be a very laborious and tedious approach, often associated with a rather limited scope in terms of structural diversity. An elegant way to overcome this hurdle comprises the ring expansion of small rings into larger heterocyclic systems.Pyrroline derivatives, which exist widely in nature, constitute an important family of heterocycle compounds. Pyrrolines have a great value in the field of pharmaceutical and pesticide discovery because of its potential physiological activity such as antibacterial, anti-inflammatory, antitumor and herbicidal effect. Therefore, it has practical significance to explore a new, simple and efficient synthetic methodology.Treatment of cyclobutanecarboxamide with bis(trifluoroacetoxy)iodobenzene, Ph I(OCOCF3)2, resulted in the formation of 1-pyrroline via Hofmann rearrangement of the former followed by in situ ring expansion reaction of the cyclobutylamine intermediate. Further elaboration of this methodology to the synthesis of 2,3-dihydro-1H-pyrrolo[2,1-a]isoquinolinium salts has also been described.