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The Conrad–Limpach synthesis is the condensation of anilines (1) with β-ketoesters (2) to form 4-hydroxyquinolines (4) via a Schiff base (3). The overall reaction type is a combination of both an addition reaction as well as a rearrangement reaction. This reaction was discovered by Max Conrad (1848–1920) and Leonhard Limpach (1852–1933) in 1887 while they were studying the synthesis of quinoline derivatives. == Reaction mechanism == The mechanism begins with an attack of aniline on the keto group of the β-ketoester to form a tetrahedral intermediate. The newly formed oxide is then twice protonated to form the Schiff base, which then undergoes keto-enol tautomerization before an electrocyclic ring closing. The mechanism concludes with the removal of an alcohol, a series of proton transfers, and a keto/enol tautomerization to form a 4-hydroxyquinoline, the final product of the Conrad-Limpach synthesis. New Conrad Perhaps the most important step (and the rate-determining step) in the reaction mechanism is the annulation of the molecule via an electrocyclic ring closing. For this step, the Schiff base must be heated to ~250 °C for the ring closure to occur. Furthermore, the type of solvent used is very important to ensuring high yields of the 4-hydroxyquinoline product. In the early work, the cyclization was accomplished by heating the Schiff base without a solvent and the yields were very moderate (below 30%). Limpach reported many years later that the yields in the cyclization were raised to 95% in many cases when an inert solvent, such as mineral oil, was used for the reaction. The Conrad-Limpach reaction mechanism also involves multiple keto-enol tautomerizations, all of which are catalyzed through the use of a strong acid, often HCl or H2SO4. With much of the literature on the synthesis of quinolines, there is some discrepancy on whether a substituted 4-hydroxyquinoline or a substituted 4-quinolone is the final product of the Conrad-Limpach synthesis. Although the reaction product is often shown as a hydroxyquinoline (the enol form), it is believed that the quinolone (keto form) predominates. For the purposes of this page and based on the reaction mechanism as it is shown in ''Name Reactions: A Collection of Detailed Mechanisms and Synthetic Applications'' by Ji Jack Li, the product is a hydroxyquinoline. 抄文引用元・出典: フリー百科事典『 ウィキペディア（Wikipedia）』 ■ウィキペディアで「Conrad–Limpach synthesis」の詳細全文を読む スポンサード リンク
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