Conformational Properties of Aromatic Amides Bearing Imidazole Ring and Acid-Induced Trans–Cis Amide Switching

• Published in: Journal of organic chemistry 2023-12, Vol.88 (24), p.16707-16718
• Main Authors: Takubo, Chiharu, Kimura, Sakiko, Ichinomiya, Mami, Hayakawa, Arisa, Murata, Mako, Urushibara, Ko, Masu, Hyuma, Katagiri, Kosuke, Kawahata, Masatoshi, Kudo, Mayumi, Azumaya, Isao, Kagechika, Hiroyuki, Tanatani, Aya
• Format: Article
• Language: English
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/acs.joc.2c01295

Aromatic amides bearing secondary amide bond exist in trans conformation both in the crystal and in solution, whereas the conformation of the N-methylated derivatives is cis in the crystal and predominantly cis in various solvents. The cis conformational preference of N-alkylated benzanilide provides access to aromatic foldamers such as oligo­(N-alkyl-p-benzamide)­s, which adopt dynamic helical structures. Here, the conformational properties of imidazole-substituted amide in the crystal and in solution were examined. Imidazole-substituted amides 2a and 4a existed mainly in the cis conformation in solution. The ratio of the cis conformer of N-methyl-N-(1-methyl-1H-imidazol-4-yl)­benzamide (4a) was smaller than that of N,1-dimethyl-N-phenyl-1H-imidazole-2-carboxamide (2a) or N-methylbenzanilide, but the introduction of a substituent strongly affected the conformer ratio. Compounds 6a and 7a bearing an electron-withdrawing group on the imidazole ring existed predominantly in trans form. On the other hand, the introduction of an electron-withdrawing group on the phenyl ring or a bulky substituent on the amide nitrogen of 4a increased the ratio of cis conformer. Further, the major conformer of N-alkylated N-imidazolylamides was switched from cis to trans by the addition of acid. These results suggest that imidazole-substituted amides might be applicable as conformational switches in aromatic foldamers to enable environment-dependent structural change.