Computational study on the NHC-catalyzed synthesis of 2, 3-disubstituted indoles: mechanism, key intermediate and the role of the catalyst. Issue 8 (8th March 2018)

• Record Type: Journal Article
• Authors: Tu, Peng-Cheng; Zhou, Lin; Kirillov, Alexander M.; Fang, Ran; Yang, Lizi
• Is Part Of: Organic chemistry frontiers. Volume 5:Issue 8(2018)
• Page Start: 1356
• Page End: 1365
• Publication Date: 2018-03-08
• Subjects: Chemistry, Organic -- Periodicals; 547.005
• DOI: 10.1039/c8qo00139a
• Languages: English
• ISSNs: 2052-4110

Abstract

Abstract : Mechanism, key intermediate and role of NHC for NHC-catalyzed umpolung of imines are clarified through our calculations. Abstract : In this work, the possible reaction mechanisms and the role of N-heterocyclic carbene (NHC) catalysts in the umpolung reaction of imines to generate 2-substituted indole-3-acetic acid derivatives were investigated by density functional theory (DFT). Two different NHCs (namedA-NHC andB-NHC ) were studied as model catalysts. Calculations revealed that the whole reaction includes four steps: (1) the formation of a key aza-Breslow intermediate, (2) an intramolecular 1, 4-addition, (3) a second 1, 2-proton transfer, and (4) the desorption of the NHC to give 2-substituted indole-3-acetic acid derivatives. Furthermore, the nucleophilic attack of the NHC on the imine carbon or β-carbon of the α, β-unsaturated ester is the rate-limiting step that determines which intermediate is formed (the aza-Breslow or deoxy-Breslow intermediate). Analysis of the global reaction index indicates that NHCs play a vital role in the polarity reversal of an imine carbon atom or a β-carbon from the α, β-unsaturated ester. This strengthens the nucleophilicity of an imine carbon or a β-carbon from the α, β-unsaturated ester as a Lewis base. In addition, B-NHC has a slightly higher nucleophilicity value, which makes the reactivity ofB-NHC slightly better than that ofA-NHC . The theoretical results obtained not only rationalize the experimental observations well but also provide important insight into the mechanistic details of the reaction.