Green synthesis of novel isatin thioketal derivatives under solvent-free conditions

Abstract

A new series of spiro [[1,3]

Highly Efficient and Practical N-Heterocyclic Carbene Organocatalyzed Chemoselective N1/C3-Functionalization of Isatins with Green Chemistry Principles

“… − Specifically, this potential has been realized in designing useful drug scaffolds for emerging targets (e.g., chymotrypsin-like protease, Nrf2) as well as well-known targets binding to neurotransmitters or their precursors (e.g., MAO, CB2). − However, when compared with the powerful utility of isatin, it seems that efficiently controlled introduction of functional groups into isatin has not been reported enough. Even though reactive isatins prefer nucleophilic additions at the C 3 -position, − the control of N 1 - and C 3 -functionalization has been tried by various synthetic strategies (N-alkylation, − N-acylation, , N-carbamoylation, N-Mannich reaction, , and aza-Michael addition reaction − ). Despite reports, efficient chemoselective N 1 -functionalization of isatin is still difficult because of the undesired reactions resulting from the multifunctionality of isatins.…”

“…In N-unprotected isatins, DABCO is a more efficient base for Morita–Baylis–Hillman (MBH) reaction (C 3 -functionalization) rather than aza-Michael reaction (N 1 -functionalization). , Hence, surely C 3 -protecting groups of isatins (e.g. ketal, , Schiff imine, − thioketal) have been developed. Notably, aza-Michael reaction of Kanger group’s isatin Schiff imine are only applicable for fumarate derivatives as Michael acceptors, − and ketal/thioketal shows a loss of isatins as well as a high E-factor (low atom economy) through protection/reaction/deprotection procedures (Supporting Information).…”

“…Notably, aza-Michael reaction of Kanger group’s isatin Schiff imine are only applicable for fumarate derivatives as Michael acceptors, − and ketal/thioketal shows a loss of isatins as well as a high E-factor (low atom economy) through protection/reaction/deprotection procedures (Supporting Information). , Recently, aza-Michael addition of isatins without any C 3 -protecting group ,, made us to expect efficient direct N 1 -functionalization to be more considerable in view of green chemistry (E-factor, atom economy, and step economy). Kinetics of the saponification depend on the pH of reactions so that a stoichiometric inorganic base can result in the saponification of the aza-Michael products as well as isatins (Supporting Information).…”