A new methodology for the synthesis of 3-amino-1H-indole-2-carboxylates

Jitendra Rameshlal Harjani, Andrew X Tang, Raymond Stanley Norton, Jonathan Bayldon Baell

Research output: Contribution to journalArticleResearchpeer-review

Abstract

A new methodology has been developed for the synthesis of 3-amino-1H-indole-2-carboxylates. 2-Aminobenzonitriles were protected as benzyl (2-cyanophenyl)carbamates and converted into corresponding glycinate esters using sodium hydride and bromoacetate esters. Sodium hydride efficiently promotes the addition of the glycinate a-carbon to the cyano group at low temperatures, resulting in the formation of the desired indole core with 3-amino and 2-carboxylate groups. This new methodology uses Pd-C mediated hydrogenolysis with molecular hydrogen, providing neutral conditions for removal of the N-carbamate protecting group. This methodology demonstrates good functional group tolerance towards a variety of substituents in the aromatic ring and ester groups. The overall yield of 3-amino-1H-indole-2-carboxylates obtained by this four-step methodology is at least 30 or higher with yields as high as 50 realised for three of the indoles investigated in this study.
Original languageEnglish
Pages (from-to)8047 - 8055
Number of pages9
JournalTetrahedron
Volume70
Issue number43
DOIs
Publication statusPublished - 2014

Cite this

Harjani, Jitendra Rameshlal ; Tang, Andrew X ; Norton, Raymond Stanley ; Baell, Jonathan Bayldon. / A new methodology for the synthesis of 3-amino-1H-indole-2-carboxylates. In: Tetrahedron. 2014 ; Vol. 70, No. 43. pp. 8047 - 8055.
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abstract = "A new methodology has been developed for the synthesis of 3-amino-1H-indole-2-carboxylates. 2-Aminobenzonitriles were protected as benzyl (2-cyanophenyl)carbamates and converted into corresponding glycinate esters using sodium hydride and bromoacetate esters. Sodium hydride efficiently promotes the addition of the glycinate a-carbon to the cyano group at low temperatures, resulting in the formation of the desired indole core with 3-amino and 2-carboxylate groups. This new methodology uses Pd-C mediated hydrogenolysis with molecular hydrogen, providing neutral conditions for removal of the N-carbamate protecting group. This methodology demonstrates good functional group tolerance towards a variety of substituents in the aromatic ring and ester groups. The overall yield of 3-amino-1H-indole-2-carboxylates obtained by this four-step methodology is at least 30 or higher with yields as high as 50 realised for three of the indoles investigated in this study.",
author = "Harjani, {Jitendra Rameshlal} and Tang, {Andrew X} and Norton, {Raymond Stanley} and Baell, {Jonathan Bayldon}",
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A new methodology for the synthesis of 3-amino-1H-indole-2-carboxylates. / Harjani, Jitendra Rameshlal; Tang, Andrew X; Norton, Raymond Stanley; Baell, Jonathan Bayldon.

In: Tetrahedron, Vol. 70, No. 43, 2014, p. 8047 - 8055.

Research output: Contribution to journalArticleResearchpeer-review

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AB - A new methodology has been developed for the synthesis of 3-amino-1H-indole-2-carboxylates. 2-Aminobenzonitriles were protected as benzyl (2-cyanophenyl)carbamates and converted into corresponding glycinate esters using sodium hydride and bromoacetate esters. Sodium hydride efficiently promotes the addition of the glycinate a-carbon to the cyano group at low temperatures, resulting in the formation of the desired indole core with 3-amino and 2-carboxylate groups. This new methodology uses Pd-C mediated hydrogenolysis with molecular hydrogen, providing neutral conditions for removal of the N-carbamate protecting group. This methodology demonstrates good functional group tolerance towards a variety of substituents in the aromatic ring and ester groups. The overall yield of 3-amino-1H-indole-2-carboxylates obtained by this four-step methodology is at least 30 or higher with yields as high as 50 realised for three of the indoles investigated in this study.

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