4.7 Article

Elucidation of the E-Amide Preference of N-Acyl Azoles

期刊

JOURNAL OF ORGANIC CHEMISTRY
卷 82, 期 21, 页码 11370-11382

出版社

AMER CHEMICAL SOC
DOI: 10.1021/acs.joc.7b01759

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资金

  1. Japan Society for the Promotion of Science [15108030]
  2. MEXT-Supported Program for the Strategic Research Foundation at Private Universities
  3. Hoansha Foundation
  4. Grants-in-Aid for Scientific Research [16K08326, 16K08157, 15K08030, 16H00822] Funding Source: KAKEN

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The conformational properties of N-acyl azoles (imidazole, pyrazole, and triazole) were examined. The N-2',4',6'-trichlorobenzoyl azoles were stable in methanol at room temperature, and no hydrolyzed products were observed over 7 days in the presence of 5% trifluoroacetic acid or 5% triethylamine in CDCI3. The high stability may be explained by the double-bond amide character caused by the steric hindrance due to the ortho-substituents in the benzoyl group. While specific E-amide preferences were observed in N-acyl pyrazoles/triazoles, the amides of the imidazoles gave a mixture of E and Z. One of the conceivable ideas to rationalize this conformational preference may be repulsive interaction between two sets of lone-pair electrons on the pyrazole 2 nitrogen (nu) and the carbonyl oxygen atoms (no) in the Z-conformation of N-acyl pyrazoles/triazoles. However, analysis of orbital interactions suggested that in the case of the E-conformation of N-acyl pyrazoles, such electron repulsion is small because of distance. The interbond energy calculations suggested that the Z-conformer is involved in strong vicinal sigma-sigma repulsion along the amide linkage between the sigma(N1N2), and sigma(C1C2) orbitals in the anti-periplanar arrangement and between the C-NICS and sigma(C1C2) orbitals in the syn-periplanar arrangement, which lead to the overwhelming E -preference in Nacyl pyrazoles/triazoles. In the case of N-acyl imidazoles, similar vicinal sigma-sigma repulsions were counterbalanced, leading to a weak preference for the E-conformer over the Z-conformer. The chemically stable and E -preferring N-acyl azoles may be utilized as scaffolds in future drug design.

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