Asymmetric Synthesis of 2-Arylindolines and 2,2-Disubstituted Indolines by Kinetic Resolution |
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Authors: | Dr Anthony Choi Dr Ashraf El-Tunsi Yuhang Wang Prof Anthony J H M Meijer Jia Li Dr Xiabing Li Dr Ilaria Proietti Silvestri Prof Iain Coldham |
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Institution: | 1. Department of Chemistry, University of Sheffield Brook Hill, Sheffield, S3 7HF UK;2. School of Chemistry and Chemical Engineering, Shaanxi Normal University, Xi'an, 710062 PR China;3. Liverpool ChiroChem Department of Chemistry, University of Liverpool, Liverpool, L69 7ZD UK |
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Abstract: | Kinetic resolution of 2-arylindolines (2,3-dihydroindoles) was achieved by treatment of their N-tert-butoxycarbonyl (Boc) derivatives with n-butyllithium and sparteine in toluene at −78 °C followed by electrophilic quench. The unreacted starting materials together with the 2,2-disubstituted products could be isolated with high enantiomer ratios. Variable temperature NMR spectroscopy showed that the rate of Boc rotation was fast (ΔG≠≈57 kJ/mol at 195 K). This was corroborated by DFT studies and by in situ ReactIR spectroscopy. The enantioenriched N-Boc-2-arylindolines were converted to 2,2-disubstituted products without significant loss in enantiopurity. Hence, either enantiomer of the 2,2-disubstituted products could be obtained with high selectivity from the same enantiomer of the chiral ligand sparteine (one from the kinetic resolution and the other from subsequent lithiation-trapping of the recovered starting material). Secondary amine products were prepared by removing the Boc group with acid to provide a way to access highly enantioenriched 2-aryl and 2,2-disubstituted indolines. |
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Keywords: | asymmetric synthesis enantioselectivity heterocycles kinetic resolution lithiation |
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