Development of a Method for the N‑Arylation of Amino Acid Esters with Aryl Triflates

A general method for the N-arylation of amino acid esters with aryl triflates is described. Both α- and β-amino acid esters, including methyl, tert-butyl, and benzyl esters, are viable substrates. Reaction optimization was carried out by design of experiment (DOE) analysis using JMP software. The mi...

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Bibliographic Details
Published inOrganic letters Vol. 18; no. 16; pp. 4128 - 4131
Main Authors King, Sandra M, Buchwald, Stephen L
Format Journal Article
LanguageEnglish
Published WASHINGTON American Chemical Society 19.08.2016
Amer Chemical Soc
Subjects
Amino Acids - chemistry
Chemistry
Chemistry, Organic
Esters - chemistry
Letter
Mesylates - chemistry
Molecular Conformation
Physical Sciences
Science & Technology
HALIDES
PRECATALYSTS
CROSS-COUPLINGS
PEPTIDES
C-N
ANALOGS
CATALYZED COUPLING REACTION
ANTAGONISTS
FACILE
DERIVATIVES
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Summary:A general method for the N-arylation of amino acid esters with aryl triflates is described. Both α- and β-amino acid esters, including methyl, tert-butyl, and benzyl esters, are viable substrates. Reaction optimization was carried out by design of experiment (DOE) analysis using JMP software. The mild reaction conditions, which use t-BuBrettPhos Pd G3 or G4 precatalyst, result in minimal racemization of the amino acid ester. This method is the first synthetic application of the t-BuBrettPhos Pd G4 precatalyst. Mechanistic studies show that the observed erosion in enantiomeric excess is due to racemization of the amino acid ester starting material and not of the product.
Bibliography:NIH RePORTER
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ISSN:1523-7060
1523-7052
DOI:10.1021/acs.orglett.6b02082