Enantioselective Intramolecular α-Arylation of Benzylamine Derivatives: Synthesis of a Precursor to Levocetirizine

Rakesh K. Saunthwal; Maria Schwarz; Rajendra K. Mallick; William Terry-Wright; Jonathan Clayden

doi:10.1002/anie.202216758

Enantioselective Intramolecular α-Arylation of Benzylamine Derivatives: Synthesis of a Precursor to Levocetirizine

Rakesh K. Saunthwal^*
, Maria Schwarz
, Rajendra K. Mallick
, William Terry-Wright
, Jonathan Clayden^*

^*Corresponding author for this work

School of Chemistry

Research output: Contribution to journal › Article (Academic Journal) › peer-review

18 Citations (Scopus)

168 Downloads (Pure)

Abstract

A practical, transition metal-free method allows the enantioselective synthesis of α,α-diarylmethylamines by asymmetric α-arylation of benzylamines. Enantioselective lithiation of N′-aryl-N-benzyl-N-isopropyl ureas using a chiral lithium amide base generates a benzyllithium that undergoes an unactivated stereospecific intramolecular nucleophilic aromatic substitution to generate an α,α-diarylmethylamine in the form of its urea derivative, in up to >99 % ee. Treatment with acid induces an “azatropic shift” with retention of configuration, the product of which may be hydrolysed to the target amine.

Original language	English
Article number	e202216758
Journal	Angewandte Chemie - International Edition
Volume	62
Issue number	14
Early online date	25 Jan 2023
DOIs	https://doi.org/10.1002/anie.202216758
Publication status	Published - 27 Mar 2023

Bibliographical note

Funding Information:
Financial support was provided by the EU through Marie Sklodowska Curie fellowships 839739 (COOPCAT) and 101023251 (PHOTOLITH), the ERC through Advanced Grant 883786 (DOGMATRON), and the Royal Society of Chemistry for an Undergraduate Research Bursary (to WTW).

Publisher Copyright:
© 2023 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.

Research Groups and Themes

Organic & Biological

Keywords

Arylation
Benzylamine
Chiral Lithium Amide
Enantioselective
Levocetirizine

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This is the accepted author manuscript (AAM). The final published version (version of record) is available online via Wiley at https://doi.org/10.1002/anie.202216758 . Please refer to any applicable terms of use of the publisher.
Accepted author manuscript, 1.21 MBLicence: Unspecified
Full-text PDF (final published version)
This is the final published version of the article (version of record). It first appeared online via Wiley at https://doi.org/10.1002/anie.202216758 . Please refer to any applicable terms of use of the publisher.
Final published version, 7.14 MBLicence: CC BY

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title = "Enantioselective Intramolecular α-Arylation of Benzylamine Derivatives: Synthesis of a Precursor to Levocetirizine",

abstract = "A practical, transition metal-free method allows the enantioselective synthesis of α,α-diarylmethylamines by asymmetric α-arylation of benzylamines. Enantioselective lithiation of N′-aryl-N-benzyl-N-isopropyl ureas using a chiral lithium amide base generates a benzyllithium that undergoes an unactivated stereospecific intramolecular nucleophilic aromatic substitution to generate an α,α-diarylmethylamine in the form of its urea derivative, in up to >99 \% ee. Treatment with acid induces an “azatropic shift” with retention of configuration, the product of which may be hydrolysed to the target amine.",

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note = "Funding Information: Financial support was provided by the EU through Marie Sklodowska Curie fellowships 839739 (COOPCAT) and 101023251 (PHOTOLITH), the ERC through Advanced Grant 883786 (DOGMATRON), and the Royal Society of Chemistry for an Undergraduate Research Bursary (to WTW). Publisher Copyright: {\textcopyright} 2023 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.",

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AU - Mallick, Rajendra K.

AU - Terry-Wright, William

AU - Clayden, Jonathan

N1 - Funding Information: Financial support was provided by the EU through Marie Sklodowska Curie fellowships 839739 (COOPCAT) and 101023251 (PHOTOLITH), the ERC through Advanced Grant 883786 (DOGMATRON), and the Royal Society of Chemistry for an Undergraduate Research Bursary (to WTW). Publisher Copyright: © 2023 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.

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AB - A practical, transition metal-free method allows the enantioselective synthesis of α,α-diarylmethylamines by asymmetric α-arylation of benzylamines. Enantioselective lithiation of N′-aryl-N-benzyl-N-isopropyl ureas using a chiral lithium amide base generates a benzyllithium that undergoes an unactivated stereospecific intramolecular nucleophilic aromatic substitution to generate an α,α-diarylmethylamine in the form of its urea derivative, in up to >99 % ee. Treatment with acid induces an “azatropic shift” with retention of configuration, the product of which may be hydrolysed to the target amine.

KW - Arylation

KW - Benzylamine

KW - Chiral Lithium Amide

KW - Enantioselective

KW - Levocetirizine

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M3 - Article (Academic Journal)

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JF - Angewandte Chemie - International Edition

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ER -

Enantioselective Intramolecular α-Arylation of Benzylamine Derivatives: Synthesis of a Precursor to Levocetirizine

Abstract

Bibliographical note

Research Groups and Themes

Keywords

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