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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Published inJournal of organic chemistry Vol. 84; no. 8; pp. 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 Journal Article
LanguageEnglish
Published United States American Chemical Society 19.04.2019
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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.
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content type line 23
ISSN:0022-3263
1520-6904
DOI:10.1021/acs.joc.8b02909