Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
J Am Chem Soc. 2010 Jan 20;132(2):807-15. doi: 10.1021/ja908749u.
The chemical features, such as substrate stability, product distribution, and substrate generality, and the reaction mechanism of Brønsted superacid-catalyzed cyclization reactions of aromatic ring-containing acetoacetates (beta-ketoesters) were examined in detail. While two types of carbonyl cyclization are possible, i.e., keto cyclization and ester cyclization, the former was found to take place exclusively. The reaction constitutes an efficient method to synthesize indene and 3,4-dihydronapthalene derivatives. Acid-base titration monitored with (13)C NMR spectroscopy showed that the acetoacetates are fully O(1),O(3)-diprotonated at H(0) = -11. While the five-membered ring cyclization of the arylacetoacetates proceeded slowly at H(0) = -11, a linear increase in the rate of the cyclization was found with increasing acidity in the high acidity region of H(0) = -11.8 to -13.3. Therefore, the O(1),O(3)-diprotonated acetoacetates exhibited some cyclizing reactivity, but they are not the reactive intermediates responsible for the acceleration of the cyclization in the high acidity region. The reactive cationic species might be formed by further protonation (or protosolvation) of the O(1),O(3)-diprotonated acetoacetates; i.e., they may be tricationic species. Thermochemical data on the acid-catalyzed cyclization of the arylacetoacetates showed that the activation energy is decreased significantly as compared with that of the related acid-catalyzed cyclization reaction of a compound bearing a single functional group, such as a ketone. These findings indicate that intervention of the trication contributes to the activation of the cyclization of arylacetoacetates in strong acid, and the electron-withdrawing nature of the O-protonated ester functionality significantly increases the electrophilicity of the ketone moiety.
详细考察了 Brønsted 超强酸催化的含芳环乙酰乙酸酯（β-酮酯）的环化反应的化学特征，如底物稳定性、产物分布和底物通用性，以及反应机理。虽然可能发生两种类型的羰基环化，即酮环化和酯环化，但前者被发现是唯一发生的。该反应构成了合成茚和 3,4-二氢萘衍生物的有效方法。用（13）C NMR 光谱监测的酸碱滴定表明，乙酰乙酸酯在 H（0）=-11 时完全 O（1）、O（3）-二质子化。虽然芳基乙酰乙酸酯的五元环环化在 H（0）=-11 时缓慢进行，但在高酸度区域 H（0）=-11.8 至-13.3 时，环化速率线性增加。因此，O（1）、O（3）-二质子化的乙酰乙酸酯表现出一定的环化反应性，但它们不是负责在高酸度区域加速环化的反应性中间体。反应性的阳离子物种可能是通过进一步质子化（或质子化）O（1）、O（3）-二质子化的乙酰乙酸酯形成的；即，它们可能是三阳离子物种。芳基乙酰乙酸酯的酸催化环化的热化学数据表明，与具有单个官能团（如酮）的相关酸催化环化反应相比，活化能显著降低。这些发现表明，三阳离子的介入有助于在强酸中环化芳基乙酰乙酸酯的活化，并且 O-质子化酯官能团的吸电子性质显著增加了酮部分的亲电性。
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