Contra-thermodynamic hydrogen atom abstraction in the selective C−H functionalization of trialkylamine N‑CH3 groups

John Murphy, Joshua Barham, Matthew John

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

We report a simple one-pot protocol that affords functionalization of N-CH3 groups in N-methyl-N,N-dialkylamines with high selectivity over N-CH2R or N-CHR2 groups. The radical cation DABCO+•, prepared in situ by oxidation of DABCO with a triarylaminium salt, effects highly selective and contra-thermodynamic C−H abstraction from N-CH3 groups. The intermediates that result react in situ with organometallic nucleophiles in a single pot, affording novel and highly selective homologation of N-CH3 groups. Chemoselectivity, scalability, and recyclability of reagents are demonstrated, and a mechanistic proposal is corroborated by computational and experimental results. The utility of the transformation is demonstrated in the late-stage site-selective functionalization of natural products and pharmaceuticals, allowing rapid derivatization for investigation of structure−activity relationships.
LanguageEnglish
Pages15482−15487
Number of pages6
JournalJournal of the American Chemical Society
Volume138
Issue number47
Early online date3 Nov 2016
DOIs
Publication statusPublished - 30 Nov 2016

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Nucleophiles
Organometallics
Thermodynamics
Drug products
Scalability
Hydrogen
Positive ions
Salts
Atoms
Oxidation
Structure-Activity Relationship
Biological Products
Cations
Pharmaceutical Preparations
triethylenediamine

Keywords

  • hydrogen aton abstraction
  • medicinal chemistry
  • opioid chemistry

Cite this

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Contra-thermodynamic hydrogen atom abstraction in the selective C−H functionalization of trialkylamine N‑CH3 groups. / Murphy, John; Barham, Joshua; John, Matthew.

In: Journal of the American Chemical Society, Vol. 138, No. 47, 30.11.2016, p. 15482−15487.

Research output: Contribution to journalArticle

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AU - Barham, Joshua

AU - John, Matthew

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N2 - We report a simple one-pot protocol that affords functionalization of N-CH3 groups in N-methyl-N,N-dialkylamines with high selectivity over N-CH2R or N-CHR2 groups. The radical cation DABCO+•, prepared in situ by oxidation of DABCO with a triarylaminium salt, effects highly selective and contra-thermodynamic C−H abstraction from N-CH3 groups. The intermediates that result react in situ with organometallic nucleophiles in a single pot, affording novel and highly selective homologation of N-CH3 groups. Chemoselectivity, scalability, and recyclability of reagents are demonstrated, and a mechanistic proposal is corroborated by computational and experimental results. The utility of the transformation is demonstrated in the late-stage site-selective functionalization of natural products and pharmaceuticals, allowing rapid derivatization for investigation of structure−activity relationships.

AB - We report a simple one-pot protocol that affords functionalization of N-CH3 groups in N-methyl-N,N-dialkylamines with high selectivity over N-CH2R or N-CHR2 groups. The radical cation DABCO+•, prepared in situ by oxidation of DABCO with a triarylaminium salt, effects highly selective and contra-thermodynamic C−H abstraction from N-CH3 groups. The intermediates that result react in situ with organometallic nucleophiles in a single pot, affording novel and highly selective homologation of N-CH3 groups. Chemoselectivity, scalability, and recyclability of reagents are demonstrated, and a mechanistic proposal is corroborated by computational and experimental results. The utility of the transformation is demonstrated in the late-stage site-selective functionalization of natural products and pharmaceuticals, allowing rapid derivatization for investigation of structure−activity relationships.

KW - hydrogen aton abstraction

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KW - opioid chemistry

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