Faculty of Pharma Sciences, Teikyo University , 2-11-1 Kaga, Itabashi-ku, Tokyo 173-8605, Japan.
Graduate School of Pharmaceutical Sciences, The University of Tokyo , 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
J Org Chem. 2017 Nov 3;82(21):11370-11382. doi: 10.1021/acs.joc.7b01759.
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 CDCl. 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) and the carbonyl oxygen atoms (n) 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 and σ orbitals in the anti-periplanar arrangement and between the σ and σ 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.
研究了 N-酰基唑（咪唑、吡唑和三唑）的构象性质。在室温下，N-2'，4'，6'-三氯苯甲酰唑在甲醇中稳定，在存在 5%三氟乙酸或 5%三乙胺的情况下，在 CDCl 中 7 天内未观察到水解产物。高稳定性可能是由于苯甲酰基中邻位取代基引起的空间位阻导致双键酰胺特性所致。虽然在 N-酰基吡唑/三唑中观察到特定的 E-酰胺偏好，但咪唑的酰胺则产生 E 和 Z 的混合物。一种可以合理说明这种构象偏好的想法可能是在 Z-构象的 N-酰基吡唑/三唑中，吡唑 2-氮（n）和羰基氧原子（n）上的两组孤对电子之间存在排斥相互作用。然而，轨道相互作用分析表明，在 N-酰基吡唑的 E-构象中，由于距离较远，这种电子排斥作用很小。键能计算表明，Z-构象涉及酰胺键之间的强邻位 σ-σ 排斥，这种排斥作用沿反式稠合排列的σ和σ轨道以及顺式稠合排列的σ和σ轨道发生，这导致 N-酰基吡唑/三唑中 E-构型的强烈偏好。在 N-酰基咪唑的情况下，类似的邻位 σ-σ 排斥相互作用相互平衡，导致 E-构象对 Z-构象的微弱偏好。化学稳定且 E-优先的 N-酰基唑类化合物可用作未来药物设计的支架。
