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

Chandrashekar Mudithanapelli; Chandra Sekhar Vasam; Ravinder Vadde; Mi-Hyun Kim

doi:10.1021/acsomega.8b02361

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

ACS Omega. 2018 Dec 18;3(12):17646-17655. doi: 10.1021/acsomega.8b02361. eCollection 2018 Dec 31.

Authors

Chandrashekar Mudithanapelli^{1

2}, Chandra Sekhar Vasam³, Ravinder Vadde², Mi-Hyun Kim¹

Affiliations

¹ Gachon Institute of Pharmaceutical Science & Department of Pharmacy, College of Pharmacy, Gachon University, 191 Hambakmoeiro, Yeonsu-gu, Incheon 21936, Republic of Korea.
² Department of Chemistry, Kakatiya University, Warangal 506009, India.
³ Department of Pharmaceutical Chemistry, Telangana University, Nizamabad 503322, India.

Abstract

Ecofriendly N-heterocyclic carbene (NHC) organocatalysis can control the N₁-functionalization (aza-Michael addition) and C₃-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 N₁-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 (N₁/C₃-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 C₃/N₁-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.