Knorr喹啉合成反应
苯胺和β-酮酯的酯基反应生成β-酮基酰苯胺中间体，接着在酸催化下较高温度下关环生成2-羟基喹啉的反应。此反应最早由Ludwig Knorr (1859–1921)在1886年首次报道此反应【 Justus Liebig's Annalen der Chemie Volume 236, Issue 1–2, Date: 1886, Pages: 69–115】。此反应和Conrad–Limpach反应类似，Conrad和Limpach在Knorr报道了此反应后发现了苯胺和β-酮酯在较低温度下关环得到4-羟基喹啉的反应。
反应机理
分子内的亲电取代反应
2007年 Klumpp 等利用理论计算和核磁共振谱结果，提出超亲电性的 O,O-二正离子中间体在反应条件下比 N,O-二正离子更容易生成。而且他们还发现质子酸性的三氟甲磺酸是此反应最有效的酸催化剂。
【 J. Org. Chem. 2007, 72, 9761–9764】
反应实例
【Chem. Rev., 1944, 35, 157】
To 20 mL ethyl acetoacetate heated to 160–165◦C was added 5.5 g 4-amino-6-bromoveratrole over 3 min. After continuing the heating for an additional 30 min, the excess ethyl acetoacetate was distilled off under reduced pressure, and the residue was washed with light petroleum ether, leaving a thick oil in an apparently quantitative yield.
This thick oil was mixed with 8 mL concentrated H2SO4, and the mixture was heated for 2 min at 60–70◦C. The mixture immediately solidified, which was thrown into water. The solid was filtered out and crystallized from a mixture of chloroform and alcohol to give 60% 2-hydroxy-5-bromo-6,7-dimethoxylepidine as long white needles, m.p. 274–276◦C (dec.).
【J. Org. Chem., 1945, 10, 347】
To a flame-dried, 100-mL, round-bottomed flask containing 210 mg aminotetrahydroquinoline (1.19 mmol) and 20 mL ethanol at room temperature was added 190 μL ethyl-4,4,4-trifluoroacetoacetate (1.31 mmol, 1.10 eq.) and 244 mg ZnCl2 (1.79 mmol, 1.50 eq.). The reaction mixture was heated to reflux for 6 h, at which time TLC analysis indicated complete consumption of the starting material. The reaction mixturewas cooled to room temperature, and the solvent was removed under reduced pressure. Dichloromethane (20 mL)was added, and the organic phasewaswashed with saturated NaHCO3 (2 × 10mL) and brine (10 mL), then dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography (CH2Cl2/MeOH, 15:1) to give 24.4 mg 4-ethyl-1,2,3,4-tetrahydro-6-(trifluoromethyl)-8-pyridono[5,6-g]quinoline as a yellow solid, in a yield of 82%, Rf = 0.37 (CH2Cl2/MeOH, 9:1). Recrystallization from EtOAc provided an analytically pure sample as yellow needles, m.p. 264–265◦C
【J. Med. Chem., 1999, 42, 210】
【 J. Org. Chem., 2007, 72, 9761–9764】
【Bioorganic and Medicinal Chemistry, 2012, 20, 1624-1638】
【Tetrahedron, 2012, 68, 7892-7900】
参考资料
一、维基百科：Knorr喹啉合成
二、Comprehensive Organic Name Reactions and Reagents, by Zerong Wang， 1638-1639.
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