Highly Efficient and Practical N-Heterocyclic Carbene Organocatalyzed Chemoselective N-1/C-3-Functionalization of Isatins with Green Chemistry Principles

Abstract

Ecofriendly N-heterocyclic carbene (NHC) organocatalysis can control the N-1-functionalization (aza-Michael addition) and C-3-functionalization (Morita-Baylis-Hillman reaction, MBH) of isatins in the absence of (1) a protecting group, (2) a stoichiometric reagent, and (3) heat energy. The challengeable N-1-functionalization of N-unsubstituted isatins into N-substituted (NS) isatins was realized through 10 mol % NHC and 10 mol % 1,8-diazabicyclo[5.4.0] undec-7-ene catalysts within 10 min with up to 98% isolation yield. The subsequent MBH adducts of as-synthesized NS-isatins (N-1/C-3-functionalization) was perfectly acquired in 10 mol % NHC and 10 mol % 1,4-diazabicyclo[2.2.2] octane catalysis within 30 min with superiority to C-3/N-1-functionalization (MBH/aza-Michael). For guiding the application to a versatile druggable isatin library, the NHC catalysis was compared with reported functionalization of isatins in view of green chemistry principles including solvent scoring of ACS GCI pharmaceutical roundtable, E-factor, atom economy, and so on.