Deprotection of N‑Boc Groups under Continuous-Flow High-Temperature Conditions

The scope of thermolytic, N-Boc deprotection was studied on 26 compounds from the Pfizer compound library, representing a diverse set of structural moieties. Among these compounds, 12 substrates resulted in clean (≥95% product) deprotection, and an additional three compounds gave ≥90% product. The t...

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Bibliographic Details
Published in:Journal of organic chemistry 2019-04, Vol.84 (8), p.4846-4855
Main Authors: Li, Bryan, Li, Ruizhi, Dorff, Peter, McWilliams, J. Christopher, Guinn, Robert M, Guinness, Steven M, Han, Lu, Wang, Ke, Yu, Shu
Format: Article
Language:English
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Summary:The scope of thermolytic, N-Boc deprotection was studied on 26 compounds from the Pfizer compound library, representing a diverse set of structural moieties. Among these compounds, 12 substrates resulted in clean (≥95% product) deprotection, and an additional three compounds gave ≥90% product. The thermal de-Boc conditions were found to be compatible with a large number of functional groups. A combination of computational modeling, statistical analysis, and kinetic model fitting was used to support an initial, slow, and concerted proton transfer with release of isobutylene, followed by a rapid decarboxylation. A strong correlation was found to exist between the electrophilicity of the N-Boc carbonyl group and the reaction rate.
ISSN:0022-3263
1520-6904
DOI:10.1021/acs.joc.8b02909