Chiral Phosphoric Acid Catalyzed Kinetic Resolution of 2‐Amido Benzyl Alcohols: Asymmetric Synthesis of 4H‐3,1‐Benzoxazines

An efficient method for the asymmetric synthesis of 4H‐3,1‐benzoxazines was developed by kinetic resolution of 2‐amido benzyl alcohols using chiral phosphoric acid catalyzed intramolecular cyclizations. A broad range of benzyl alcohols (both secondary and tertiary alcohols) were kinetically resolved...

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Published inAngewandte Chemie International Edition Vol. 59; no. 6; pp. 2333 - 2337
Main Authors Rajkumar, Subramani, Tang, Mengyao, Yang, Xiaoyu
Format Journal Article
LanguageEnglish
Published WEINHEIM Wiley 03.02.2020
Wiley Subscription Services, Inc
EditionInternational ed. in English
Subjects
Alcohol
Alcohols
Asymmetric synthesis
Asymmetry
Benzoxazines
Benzyl alcohol
Biological activity
Chemical industry
Chemistry
Chemistry, Multidisciplinary
heterocycles
kinetic resolution
Modularity
organocatalysis
Phosphoric acid
Physical Sciences
reaction mechanisms
Science & Technology
Sigma factor
BRONSTED ACID
ENANTIOSELECTIVE SYNTHESIS
ALKYLATION
reaction mechanisms
alcohols
organocatalysis
CYCLOADDITION
POTENT
TERTIARY ALCOHOLS
heterocycles
CHLOROCYCLIZATION
CONSTRUCTION
kinetic resolution
HYDROXY ESTERS
INHIBITORS
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Summary:An efficient method for the asymmetric synthesis of 4H‐3,1‐benzoxazines was developed by kinetic resolution of 2‐amido benzyl alcohols using chiral phosphoric acid catalyzed intramolecular cyclizations. A broad range of benzyl alcohols (both secondary and tertiary alcohols) were kinetically resolved with high selectivities, with an s factor of up to 94. Mechanistic studies were performed to elucidate the mechanism of these reactions, wherein the amide moieties reacted as the electrophiles. Gram‐scale reaction and facile transformations of the chiral products demonstrate the potential of this method in asymmetric synthesis of biologically active chiral heterocycles. A practical approach for the asymmetric synthesis of 4H‐3,1‐benzoxazines was achieved by the kinetic resolution of 2‐amido benzyl alcohols in the presence of a chiral phosphoric acid (CPA). The method demonstrates broad substrate scope and excellent kinetic resolution (with an s factor of up to 94).
Bibliography:These authors contributed equally to this work.
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ISSN:1433-7851
1521-3773
1521-3773
DOI:10.1002/anie.201913896