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Study on 1,3,5-Triazine Chemistry in Dehydrocondensation: Gauche Effect on the Generation of Active Triazinylammonium Species

Authors

  • Prof. Dr. Munetaka Kunishima,

    Corresponding author
    1. Faculty of Pharmaceutical Sciences, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920-1192 (Japan), Fax: (+81) 76-264-6201
    2. Cooperative Research Center of Life Sciences, Kobe Gakuin University, 1-1-3 Minatojima Chuo-ku, Kobe 655-8586 (Japan)
    • Faculty of Pharmaceutical Sciences, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920-1192 (Japan), Fax: (+81) 76-264-6201
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  • Takae Ujigawa,

    1. Faculty of Pharmaceutical Sciences, Kobe Gakuin University, 1-1-3 Minatojima Chuo-ku, Kobe 655-8586 (Japan)
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  • Yoshie Nagaoka,

    1. Faculty of Pharmaceutical Sciences, Kobe Gakuin University, 1-1-3 Minatojima Chuo-ku, Kobe 655-8586 (Japan)
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  • Chiho Kawachi,

    1. Faculty of Pharmaceutical Sciences, Kobe Gakuin University, 1-1-3 Minatojima Chuo-ku, Kobe 655-8586 (Japan)
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  • Dr. Kazuhito Hioki,

    1. Faculty of Pharmaceutical Sciences, Kobe Gakuin University, 1-1-3 Minatojima Chuo-ku, Kobe 655-8586 (Japan)
    2. Cooperative Research Center of Life Sciences, Kobe Gakuin University, 1-1-3 Minatojima Chuo-ku, Kobe 655-8586 (Japan)
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  • Dr. Motoo Shiro

    1. Rigaku Corporation, 3-9-12 Matsubara, Akishima, Tokyo 196-8666 (Japan)
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Abstract

The reaction of 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) with various nitrogen-containing compounds, particularly tertiary amines (tert-amines), has been studied for the preparation of 2-(4,6-dimethoxy-1,3,5-triazinyl)trialkylammonium salts [DMT-Am(s)]. DMT-Ams derived from aliphatic tert-amines exhibited activity for the dehydrocondensation between a carboxylic acid and an amine to form an amide in a model reaction. Based on a conformational analysis of DMT-Ams and tert-amines by NMR and X-ray diffraction methods, we concluded that a β-alkyl group maintained in a gauche relationship with the nitrogen lone pair of tert-amines significantly hinders the approach of CDMT to the nitrogen. Thus, trimethylamine and quinuclidine without such alkyl groups readily react with CDMT whereas triethylamine, possessing two or three such gauche β-alkyl groups in the stable conformations, does not react at all. The theory of “gauche β-alkyl group effect” proposed here provides useful guidelines for the preparation of DMT-Ams possessing various tertiary amine moieties. An investigation of the dehydrocondensation activity of tert-amines in a CDMT/tert-amine system that involves in situ generation of DMT-Am, showed that the gauche effect of the β-alkyl group becomes quite pronounced; the yield of the amide decreases significantly with tert-amines possessing an unavoidable gauche β-alkyl group. Thus, the tert-amine/CDMT systems are useful for judging whether tert-amines can readily react with CDMT without isolation of DMT-Ams.

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