苯胺和β-酮酯的酯基反應(yīng)生成β-酮基酰苯胺中間體，接著在酸催化下較高溫度下關(guān)環(huán)生成2-羥基喹啉的反應(yīng)。此反應(yīng)最早由Ludwig Knorr (1859–1921)在1886年首次報(bào)道此反應(yīng)【 Justus Liebig's Annalen der Chemie Volume 236, Issue 1–2, Date: 1886, Pages: 69–115】。此反應(yīng)和Conrad–Limpach反應(yīng)類似，Conrad和Limpach在Knorr報(bào)道了此反應(yīng)后發(fā)現(xiàn)了苯胺和β-酮酯在較低溫度下關(guān)環(huán)得到4-羥基喹啉的反應(yīng)。
反應(yīng)機(jī)理
分子內(nèi)的親電取代反應(yīng)
2007年 Klumpp 等利用理論計(jì)算和核磁共振譜結(jié)果，提出超親電性的 O,O-二正離子中間體在反應(yīng)條件下比 N,O-二正離子更容易生成。而且他們還發(fā)現(xiàn)質(zhì)子酸性的三氟甲磺酸是此反應(yīng)最有效的酸催化劑。
【 J. Org. Chem. 2007, 72, 9761–9764】
反應(yīng)實(shí)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】
參考資料
一、維基百科：Knorr喹啉合成
二、Comprehensive Organic Name Reactions and Reagents, by Zerong Wang， 1638-1639.
