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

3 years ago

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

Tetsuta Oshitari, Satoshi Inagaki, Hideyo Takahashi, Tomohiko Ohwada, Yuka Takahashi, Hideaki Natsugari, Kosho Makino, Hidetsugu Tabata, Hirotaka Ikeda, Yuki Kanase, Yuko Otani

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 CDCl₃. 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 (n_N) and the carbonyl oxygen atoms (n_O) 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 σ–σ repulsion along the amide linkage between the σ_N1N2 and σ_C1C2 orbitals in the anti-periplanar arrangement and between the σ_N1C5 and σ_C1C2 orbitals in the syn-periplanar arrangement, which lead to the overwhelming E-preference in N-acyl pyrazoles/triazoles. In the case of N-acyl imidazoles, similar vicinal σ–σ 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.

Publisher URL: http://dx.doi.org/10.1021/acs.joc.7b01759

DOI: 10.1021/acs.joc.7b01759