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Synlett 2004(14): 2525-2528  
DOI: 10.1055/s-2004-834819
LETTER
© Georg Thieme Verlag Stuttgart · New York

Direct Carbodiimide-Mediated Conjugation of Carboxylates Using ­Pyridinium p-Toluenesulfonate and Tertiary Amines as Additives

Simon Ficht, Lars Röglin, Matthias Ziehe, David Breyer, Oliver Seitz*
Institut für Chemie der Humboldt-Universität zu Berlin, Institut für Chemie, Brook-Taylor-Str. 2, 12489 Berlin, Germany
Fax: +49(30)20937266; e-Mail: oliver.seitz@chemie.hu-berlin.de;
Further Information

Publication History

Received 4 August 2004
Publication Date:
20 October 2004 (online)

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Abstract

The use of carboxylates in the carbodiimide-mediated coupling to amines was investigated. The addition of pyridinium p-toluenesulfonate (PPTS) and a tertiary amine was found to significantly improve acylation yields by up to 70%.

Key words

amides - coupling - carbodiimides - carboxylates - solid-phase synthesis

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    General Procedure for the Carbodiimide-Mediated Amidation: The carboxylic acid or carboxylate was diluted/suspended in DMF to yield a 0.1 M concentration. Under stirring HOBt (1 equiv), PPTS (specified amount), carbodiimide (1 equiv) and DIPEA (2 equiv when mentioned) was added. After 10 min 1 equiv of amine was added. The resulting mixture was stirred for 4 h and analyzed by RP-HPLC.

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14

HPLC was performed on a Gilson 1105 HPLC-system (Nebula series) using a reverse-phase Nucleodur C-18 Gravity 3 µm column (Macherey-Nagel, Düren) and detection wavelengths of 260 nm and 450 nm. Eluents: A: 98.9% H2O, 1% MeCN (HPLC-grade, Biosolve BV, Valkenswaard, NL) 0.1% TFA (Peptide Synthesis Grade, Biosolve BV); B: 98.9% MeCN, 1% H2O, 0.1% TFA. Gradient: 3-30% B in 30 min.