SOLVENT-FREE MICROWAVE MICHAEL ADDITION OF ISATIN AND ANILINE SCHIFF BASE OF ISATIN TO Α,β-Unsaturated ESTERS

Abstract

The rapid, simple, microwave-assisted Michael addition of isatin and aniline Schiff base of isatin to a wide variety of alkyl and aryl acrylates in the presence of, tetrabutylammonium bromide (TBAB) and 1,4-diazabicyclo[2.2.2]octane (DABCO), under solvent-free conditions, is presented. Under these conditions the addition of isatin to some of alkyl and aryl acrylates afford both related Baylis-Hillman adducts as minor products and the corresponding Michael adducts as major products. Addition of isatin to ethyl acrylate leads to produce Baylis-Hillman/Michael adduct in good yield. This system dose not work on Michael acceptors of methyl acrylate and methyl methacrylate.

Weak Nucleophiles in the Aza‐Michael Reaction

“…[85] Microwave-promoted solvent-free aza-Michael addition of isatin and its imine to alkyl or aryl acrylates in the presence of DABCO and TBAB is described. [86,87] The concept of the remove activation of reactivity has been first applied for asymmetric organocatalytic version of an aza-Michael reaction of isatin. [88][89][90] The isatin is much less effective in terms of yield, enantioselectivity, and chemical reactivity than its imine derivative.…”

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.…”

“…Any organic or inorganic base in an optimized method could not show consistent products in diverse isatin derivatives and electrophiles. For example, 1,4-diazabicyclo[2.2.2]­octane (DABCO)/tetrabutylammonium bromide of catalytic amount could only be applicable to Schiff imine protection of isatins for aza-Michael product (N 1 -functionalization) . 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.…”

“…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).…”

“…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). , 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).…”