CN111848623A - 一种手性磷酸催化合成含氟的手性缩酮胺的方法 - Google Patents

一种手性磷酸催化合成含氟的手性缩酮胺的方法 Download PDF

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CN111848623A
CN111848623A CN201910340722.4A CN201910340722A CN111848623A CN 111848623 A CN111848623 A CN 111848623A CN 201910340722 A CN201910340722 A CN 201910340722A CN 111848623 A CN111848623 A CN 111848623A
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chiral
phosphoric acid
fluorine
indole
nmr
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CN111848623B (zh
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周永贵
王新维
陈木旺
吴波
孙蕾
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Dalian Institute of Chemical Physics of CAS
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Abstract

一种手性磷酸催化含氟的酮和2‑(2‑吲哚)苯胺合成六元环状含氟的手性缩酮胺的方法。反应能在下列条件内进行，温度：30‑90℃；溶剂：1,2‑二氯乙烷或芳烃类溶剂如甲苯、二甲苯、苯、氯苯等；底物和催化剂的比例是20/l；用到的催化剂为手性磷酸。对含三氟甲基的芳香酮、脂肪酮和三氟丙酮酸酯与2‑(2‑吲哚)苯胺反应均能得到相应的手性含三氟甲基的缩酮胺，其对映体过量可达到97％。本发明操作简便实用，对映选择性和产率好，具有潜在的应用价值。

Description

一种手性磷酸催化合成含氟的手性缩酮胺的方法
技术领域
本发明属于不对称催化领域，具体涉及一种手性磷酸催化含氟的酮和2-(2-吲哚)苯胺合成六元环状含氟的手性缩酮胺的方法。
技术背景
手性缩醛胺和缩酮胺是天然产物和药物分子的常见结构单元[1]。含有吲哚结构的手性缩醛胺具有重要的生物活性，可以在天然产物、药物分子中找到，也可以作为有机合成的中间体[2]。如式所示，天然产物和活性分子含有缩醛胺的结构单元：
Figure BDA0002040614250000011
由于手性的缩醛胺、缩酮胺具有重要的生物活性，因此吸引了有机化学家的兴趣。在 2003年，Ramsden课题组报道了首例合成缩醛胺的反应[3]，使用双膦双氮配体和铑的配合物对二氢吡咯苯并氧化噻二嗪进行不对称氢化合成手性的AMPA受体调节器。2005年Antilla课题组报道了手性磷酸催化的亚胺的氨基化反应合成手性的缩醛胺[4]。随后，合成手性缩醛胺的报道便如雨后春笋般出现，不同的课题组使用不同的方法相继报道了手性缩醛胺的合成，合成了一个到多个手性中心的缩醛胺分子[5]。然而到目前为止，合成手性缩酮胺的报道相对较少[6]。通常引入氟原子或含氟砌块可以改善分子的物理、化学和生物活性[7]。因此合成手性含氟的缩酮胺具有重要的意义。在2015年，Smith课题组阳离子催化的吡咯的N的烷基化反应合成手性缩酮胺。这是目前仅有的合成含氟的具有季碳手性中心的缩酮胺的报道，在这篇文献中只有两个例子，使用含有三氟甲基的脂肪族的酮作为底物，这种方法要求预先将苯胺和酮缩合，制备亚胺。由于芳香族的酮具有相对较低的反应活性，目前还没有人使用直链的芳香酮合成手性的缩酮胺。
发明内容
本发明的目的是提供一种手性磷酸催化含氟的酮和2-(2-吲哚)苯胺反应合成手性含氟缩酮胺的方法。本发明以简单的2-(2-吲哚)苯胺和含氟的酮为原料，以手性磷酸为催化剂，通过一锅法合成含氟的具有季碳手性中心的缩酮胺分子。
本发明原料易得，操作简便实用，对映选择性高，产率好，且反应环境友好等优点。
为实现上述目的，本发明的技术方案如下：
本发明提供一种合成手性含氟缩酮胺的方法，其特征在于，所述反应以含氟的酮和2-(2- 吲哚)苯胺为反应底物，以手性磷酸为催化剂，不对称合成手性含氟缩酮胺，反应式和条件如下：
反应式和条件如下：
Figure BDA0002040614250000021
式中：
Ar1、Ar2为独立选自苯基或含有取代基的苯环，R1为氢或甲基，R2为芳基、烷基、酯基，Rf为CF3或CHF2；所述取代基为甲基，甲氧基，溴，
反应条件：
温度：30-90℃；
时间：12-120小时；
CPA为手性磷酸。
基于以上技术方案，优选的，所述方法的反应步骤为：
在氮气保护下，在封管中加入2-(2-吲哚)苯胺、手性磷酸、甲苯和
Figure BDA0002040614250000022
分子筛，将含氟的酮加入其中，30-90℃；反应12-120h，直接旋干溶剂，柱层析得到相应的手性缩酮胺化合物；所述2-(2-吲哚)苯胺、含氟的酮、催化剂的摩尔比为1:(1～2):0.05。
基于以上技术方案，优选的，所述反应中还可以加入
Figure BDA0002040614250000024
分子筛，
Figure BDA0002040614250000023
分子筛的作用是除去反应中的水。
基于以上技术方案，优选的，所述有机溶剂为1,2-二氯乙烷或芳烃类溶剂。
进一步优选的，所述芳烃类溶剂为甲苯、二甲苯、苯、氯苯等。
所述的反应为含氟的酮和2-(2-吲哚)苯胺为反应底物合成手性缩酮胺化合物，Ar1苯环， Ar2为2-(2-吲哚)-4-甲基苯基，R1为甲基，R2为苯基，Rf为CF3，催化剂手性磷酸(R)-TRIP，溶剂为甲苯，温度为70℃，在
Figure BDA0002040614250000025
分子筛存在下，对映体过量为97％。基于以上技术方案，优选的，所述手性磷酸为(R)-TRIP.
本发明具有以下优点
1.原料简单易得，合成方便。
2.反应活性和对映选择性高，分离方便，能获得高纯度产物。
3.催化剂合成路线成熟，且商业可得。
具体实施方式
下面通过实施例详述本发明，但本发明并不限于下述的实施例，本发明的原料化合物2 和催化剂手性磷酸商业可得，化合物1按照文献方法合成。文献：(a)Copey,L.；Jean-Gérard,L.； Framery,E.；Pilet,G.；Andrioletti,B.Synthesis,Solid-State Analyses,and Anion-Binding Properties of meso-Aryldipyrrin-5,5-diylbis(phenol)and-bis(aniline)Ligands.Eur.J.Org.Chem. 2014,4759.(b)Rubio-Presa,R.；Pedrosa,M.R.；Fernández-Rodríguez,M.A.；Arnáiz,F.J.；Sanz, R.Molybdenum-Catalyzed Synthesisof Nitrogenated Polyheterocycles from Nitroarenes and Glycols with Reuse ofWaste Reduction Byproduct.Org.Lett.2017,19,5470.(c)Helliwell,M.； Corden,S.；Joule,J.A.Gauthier,D.；Dodd,R.H.；Dauban,P.Regioselective Access to SubstitutedOxindoles via Rhodiumcatalyzed Carbene C–H Insertion.Tetrahedron 2009,65,8542.(d)Billimoria,A.D.；Cava,M.P.Chemistry of Indolo[1,2-c]quinazoline:AnApproach to the Marine Alkaloid Hinckdentine A.J.Org.Chem.1994,59,6777.
实施例1-21
条件的优化
在氮气保护下，在25毫升封管中加入2-(2-吲哚)苯胺(0.1毫摩尔，22.2毫克)、手性磷酸(0.005毫摩尔)、溶剂(1毫升)，将含氟的酮加入其中，80℃反应48h，直接旋干溶剂，加入内标测核磁收率；改变反应中的溶剂和催化剂手性磷酸的种类，具体结构如表(表 1)：
Figure BDA0002040614250000031
产率为分离收率，产物的对映体过量用手性液相色谱测定，见表1。
表1.手性磷酸催化合成手性的缩酮胺条件优化
Figure BDA0002040614250000041
a反应条件:1a(0.10毫摩尔)，2a(0.10毫摩尔)溶剂为甲苯(1.0毫升)，手性磷酸(0.005毫摩尔)，反应48h；b利用核磁测定的产率.c高效液相色谱测定的产率.d50毫克
Figure BDA0002040614250000042
分子筛被.e1a(0.10毫摩尔), 手性磷酸(0.005毫摩尔)2a(0.15毫摩尔).f使用0.5毫升甲苯.g使用2.0毫升甲苯.j反应72小时.
实施例22-39
手性磷酸催化合成手性的缩酮胺底物拓展
在氮气保护下，在25毫升封管中加入2-(2-吲哚)苯胺(0.2毫摩尔)、手性磷酸(R)-4a (0.01毫摩尔，7.6毫克)、甲苯(2毫升)和
Figure BDA0002040614250000043
分子筛(100毫克)，将含氟的酮(0.3毫摩尔)加入其中，70℃反应72h，直接旋干溶剂，柱层析分离得到纯的产物。产率为分离收率，产物的对映体过量用手性液相色谱测定。改变反应中原料和底物的种类得到18个不同的实施例，改变底物种类得到不同的产物3，产物3由于底物种类的改变，得到的产物为 3aa到3al和3ba到3ga，改变的种类具体见表2。
表2.手性磷酸催化合成手性的缩酮胺底物拓展
Figure BDA0002040614250000051
实施例40-42
手性磷酸催化合成手性的缩酮胺底物拓展
在氮气保护下，在25毫升封管中加入2-(2-吲哚)苯胺(0.2毫摩尔)、手性磷酸(0.010 毫摩尔，7.6毫克)、甲苯(2毫升)，将三氟丙酮酸乙酯(0.3毫摩尔)加入其中，50℃反应72h，直接旋干溶剂柱层析分离得到纯的产物，改变含氟的酮的种类，得到三个不同的产物3，分比为3am、3em和3fm，反应式和具体结果见表3：
表3.手性磷酸催化合成手性的缩酮胺底物拓展
Figure BDA0002040614250000061
(R)-(+)-12-Methyl-6-phenyl-6-(trifluoromethyl)-5,6-dihydroindolo[1,2-c]quinazoline(3aa)71mg, 94％ yield,white solid,m.p.＝96-97℃,new compound,Rf＝0.65(hexanes/ethyl acetate 10:1),93％ee,[α]20 D＝+61.54(c 1.42,EtOAc)；1H NMR(400MHz,CDCl3)δ7.97(d,J＝7.8Hz,1H),7.77(d,J＝7.6Hz,2H), 7.62(d,J＝7.9Hz,1H),7.58–7.43(m,3H),7.20(t,J＝7.2Hz,1H),7.14–7.00(m,2H),6.86(t,J＝7.7Hz, 1H),6.77(d,J＝7.8Hz,1H),6.25(d,J＝8.4Hz,1H),4.67(brs,1H),2.74(s,3H)；13C NMR(100MHz,CDCl3) δ138.1,136.4,134.7,130.7,130.1,129.6,128.9,128.4,127.8,125.6(q,J＝296.0Hz),125.1,122.1,120.3, 120.0,118.4,117.1,113.7,112.8,108.5,75.4(q,J＝30Hz),11.1；19F NMR(376MHz,CDCl3)δ-72.0. Enantiomeric excess was determined byHPLC(IA column,elute:n-Hexane/i-PrOH＝98/2,detector:254nm, flow rate:1.0mL/min,30℃),retention time 7.2min(major)and 9.5min.HRMS(ESI)m/z Calculated forC23H18F3N2[M+H]+379.1417,found 379.1421.
(+)-6-(4-Fluorophenyl)-12-methyl-6-(trifluoromethyl)-5,6-dihydroindolo[1,2-c]quinazoline(3ab)68 mg,86％ yield,colorless oil,newcompound,Rf＝0.70(hexanes/ethyl acetate 10:1),91％ee,[α]20 D＝+48.23 (c 1.36,EtOAc)；1H NMR(400MHz,CD3OD)δ7.75(d,J＝7.8Hz,1H),7.66–7.52(m,2H),7.42(d,J＝7.9Hz,1H),7.14–6.97(m,3H),6.87(t,J＝7.5Hz,1H),6.80(t,J＝7.5Hz,1H),6.75(d,J＝7.9Hz,1H),6.66(t, J＝7.5Hz,1H),6.10(d,J＝8.4Hz,1H)2.52(s,3H)；13C NMR(100MHz,CD3OD)δ163.2(d,J＝247.0Hz), 139.4,134.5,133.0(d,J＝3.0Hz),130.7,130.6(dq,J＝8.0Hz,J＝1.0Hz),129.8,127.6,125.8(q,J＝296.0 Hz),124.4,121.4,119.6,118.9,117.8,116.2,115.1(d,J＝22.0Hz),113.3,112.3,107.2,75.0(q,J＝30.0Hz), 9.7；19FNMR(376MHz,CD3OD)δ-73.3(s,3F),-113.3(s,1F).Enantiomeric excess was determinedby HPLC(IA column,elute:n-Hexane/i-PrOH＝95/5,detector:254nm,flow rate:1.0mL/min,30℃),retention time 5.9min(major)and 6.9min.HRMS(ESI)m/z Calculated forC23H17F4N2[M+H]+397.1322,found 379.1350.
(+)-6-(4-Chlorophenyl)-12-methyl-6-(trifluoromethyl)-5,6-dihydroindolo[1,2-c]quinazoline(3ac)77 mg,93％ yield,colorless oil,newcompound,Rf＝0.80(hexanes/ethyl acetate 10:1),91％ee,[α]20 D＝+64.67 (c 1.54,EtOAc)；1H NMR(400MHz,CD3OD)δ7.71(dd,J＝7.9,0.9Hz,1H),7.48(d,J＝8.1Hz,2H),7.37(d,J＝7.9Hz,1H),7.27(d,J＝8.8Hz,2H),7.01–6.94(m,,1H),6.87–6.80(m,1H),6.80–6.69(m,2H), 6.67–6.59(m,1H),6.09(d,J＝8.4Hz,1H),2.47(s,3H)；13C NMR(100MHz,CD3OD)δ139.3,135.6, 135.4,134.4,130.7,129.9,129.7,128.4,127.6,125.7(q,J＝295.0Hz),124.4 121.4,119.7,118.9,117.9,116.2, 113.3,112.3,107.3,75.0(q,J＝30.0Hz),9.7；19F NMR(376MHz,CD3OD)δ-73.2.Enantiomeric excess was determined byHPLC(IA column,elute:n-Hexane/i-PrOH＝95/5,detector:254nm,flow rate:1.0mL/min,30 ℃),retention time 6.0min(major)and 7.4min.HRMS(ESI)m/z Calculated forC23H17ClF3N2[M+H]+ 413.1027,found 413.1041.
(+)-6-(4-Bromophenyl)-12-methyl-6-(trifluoromethyl)-5,6-dihydroindolo[1,2-c]quinazoline(3ad)84 mg,91％ yield,colorless oil,new compound,Rf＝0.70(hexanes/ethyl acetate 10:1),92％ee,[α]20 D＝+58.26 (c 1.67,EtOAc)；1H NMR(400MHz,CD3OD)δ7.75(d,J＝7.7Hz,1H),7.55–7.37(m,5H),7.06–6.96(m, 1H),6.88(t,J＝7.3Hz,1H),6.80(t,J＝7.6Hz,1H),6.74(d,J＝7.9Hz,1H),6.71–6.62(m,1H),6.12(d,J＝ 8.4Hz,1H),2.52(s,3H)；13C NMR(100MHz,CD3OD)δ139.2,136.1,134.4,131.5,130.7,130.1,129.7, 127.6,125.7(q,J＝295.0Hz),124.4,123.6,121.5,119.7,119.0,117.9,116.2,113.4,112.3,107.4,75.1(q,J＝ 30.0Hz),9.8；19F NMR(376MHz,CD3OD)δ-73.3(s,3F).Enantiomeric excess was determined by HPLC (IA column,elute:n-Hexane/i-PrOH＝95/5,detector:254nm,flow rate:1.0mL/min,30℃),retention time 6.5 min(major)and 7.9min.HRMS(ESI)m/z Calculated for C23H17BrF3N2[M+H]+457.0522,found457.0517.
(+)-6-(4-Methoxyphenyl)-12-methyl-6-(trifluoromethyl)-5,6-dihydroindolo[1,2-c]quinazoline(3ae)49 mg,60％ yield,colorless oil,newcompound,Rf＝0.25(hexanes/ethyl acetate 20:1),89％ee,[α]20 D＝+45.30 (c 0.98,EtOAc)；1H NMR(400MHz,CD3OD)δ7.74(d,J＝7.9Hz,1H),7.47(d,J＝8.5Hz,2H),7.40(d,J＝8.0Hz,1H),7.00(t,J＝7.7Hz,1H),6.89–6.81(m,3H),6.81–6.75(m,1H),6.72(d,J＝8.0Hz,1H), 6.66–6.59(m,1H),6.13(d,J＝8.5Hz,1H),3.68(s,3H),2.51(s,3H)；13C NMR(100MHz,CD3OD)δ160.6, 139.6,134.7,130.6,129.8,129.6,128.6,127.5,126.0(q,J＝295.0Hz),124.3,121.2,119.4,118.7,117.6,116.3, 113.5,113.3,112.6,107.0,75.1(q,J＝30.0Hz),54.4,9.7；19F NMR(376MHz,CD3OD)δ-73.4. Enantiomeric excess wasdetermined by HPLC(IA column,elute:n-Hexane/i-PrOH＝95/5,detector:254nm, flowrate:1.0mL/min,30℃),retention time 8.6min(major)and 10.7min.HRMS(ESI)m/zCalculated for C24H20F3N2O[M+H]+409.1522,found 409.1533.
(+)-12-Methyl-6-(p-tolyl)-6-(trifluoromethyl)-5,6-dihydroindolo[1,2-c]quinazoline(3af)69 mg,88％ yield,colorless oil,new compound,Rf＝0.30(hexanes/ethyl acetate 50:1),92％ee,[α]20 D＝+54.85(c 1.38, EtOAc)；1H NMR(400MHz,CD3OD)δ7.72(d,J＝7.8,1H),6.47–6.33(m,3H),7.10(d,J＝8.1Hz,2H), 6.97(t,J＝7.4Hz,1H),6.83(t,J＝7.5Hz,1H),6.76(t,J＝7.5Hz,1H),6.70(d,J＝7.9Hz,1H),6.57(t,J＝ 7.6Hz,1H)6.09(d,J＝8.4Hz,1H),2.49(s,3H),2.23(s,3H)；13C NMR(100MHz,CD3OD)δ139.7,139.5, 134.6,133.9,130.6,129.8,128.8,128.1,127.5,126.0(q,J＝295.0Hz),124.3,121.2,119.4,118.7,117.6,116.2, 113.3,112.6,107.0,75.2(q,J＝30.0Hz),19.8,9.8；19F NMR(376MHz,CD3OD)δ-73.2.Enantiomeric excess wasdetermined by HPLC(IA column,elute:n-Hexane/i-PrOH＝98/2,detector:254nm,flowrate:1.0 mL/min,30℃),retention time 7.2min(major)and 11.0min.HRMS(ESI)m/zCalculated for C24H20F3N2 [M+H]+393.1573,found 393.1608.
(+)-12-Methyl-6-(m-tolyl)-6-(trifluoromethyl)-5,6-dihydroindolo[1,2-c]quinazoline(3ag)67mg,85％ yield,white solid,m.p.＝150-151℃,new compound,Rf＝0.30(hexanes/ethyl acetate 50:1),93％ee,[α]20 D＝ +60.67(c 1.34,EtOAc)；1H NMR(400MHz,CD3OD)δ7.73(d,J＝7.8,1H),7.44–7.31(m,3H),7.23–7.11 (m,2H),6.97(t,J＝7.5Hz,1H),6.82(t,J＝7.5Hz,1H),6.75(t,J＝7.6Hz,1H),6.70(d,J＝7.9Hz,1H),6.58(t,J＝7.7Hz,1H),6.09(d,J＝8.4Hz,1H),2.49(s,3H),2.15(s,3H)；13C NMR(100MHz,CH3OD)δ139.5, 138.3,136.8,134.6,130.6,130.1,129.8,128.9,128.0,127.5,126.0(q,J＝295.0Hz),125.0,124.4,121.2,119.5, 118.7,117.7,116.2,113.3,112.6,107.0,75.3(q,J＝29.0Hz),20.2,9.8；19F NMR(376MHz,CH3OD)δ-73.1. Enantiomeric excess wasdetermined by HPLC(IA column,elute:n-Hexane/i-PrOH＝95/5,detector:254nm, flowrate:1.0mL/min,30℃),retention time 4.8min(major)and 6.2min.HRMS(ESI)m/zCalculated for C24H20F3N2[M+H]+393.1573,found 393.1608.
(+)-12-Methyl-6-(naphthalen-2-yl)-6-(trifluoromethyl)-5,6-dihydroindolo[1,2-c]quinazoline(3ah)68 mg,79％ yield,white solid,m.p.＝214-215℃,new compound,Rf＝0.30(hexanes/ethyl acetate 100:1),95％ ee,[α]20 D＝+20.85(c 1.18,EtOAc)；1H NMR(400MHz,CD2Cl2)δ8.28(s,1H),7.94–7.85(m,2H), 7.84–7.73(m,2H),7.59–7.41(m,4H),7.13–7.05(m,1H),6.70–6.88(m,2H),6.72–6.57(m,2H),6.18(d, J＝8.5Hz,1H),4.71(brs,1H),2.63(s,3H)；13C NMR(100MHz,CD2Cl2)δ138.1,134.7,133.6,133.4,132.4, 130.7,129.5,129.1,129.0,127.9,127.8,127.6,127.0,126.9(q,J＝3.0Hz),125.77,125.76(q,J＝295.0Hz), 125.0,122.1,120.2,120.1,118.4,116.8,113.8,112.6,108.6,75.6(q,J＝30.0Hz),10.8；19F NMR(376MHz, CD2Cl2)δ-72.1.Enantiomeric excess was determined by HPLC(IA column,elute:n-Hexane/i-PrOH＝95/5, detector:254nm,flow rate:1.0mL/min,30℃),retention time 7.3min(major)and 10.5min.HRMS(ESI)m/z Calculated for C27H20F3N2[M+H]+429.1573,found429.1571.
(+)-6-Phenyl-6-(trifluoromethyl)-5,6-dihydroindolo[1,2-c]quinazoline(3ba)54mg,74％ yield, colorless oil,new compound,Rf＝0.60(hexanes/ethylacetate 20:1),88％ee,[α]20 D＝+97.40(c 1.08,EtOAc)；1H NMR(400MHz,CD3OD)δ7.61(d,J＝7.7Hz,3H),7.44–7.28(m,4H),7.05–6.96(m,1H),6.90–6.79 (m,2H),6.78–6.66(m,2H),6.63–6.54(m,1H),6.10(d,J＝8.5Hz,1H)；13C NMR(100MHz,CD3OD)δ 138.7,136.6,135.7,135.1,129.9,129.5,128.43,128.38,128.1(q,J＝2.0Hz),125.9(q,J＝295.0Hz),123.2,120.9,120.1,119.8,118.8,114.4,113.3,112.7,96.3,75.7(q,J＝30.0Hz)；19F NMR(376MHz,CD3OD)δ -73.5.Enantiomeric excess was determined by HPLC(IA column,elute:n-Hexane/i-PrOH＝90/10,detector: 254nm,flow rate:1.0mL/min,30℃),retention time 6.7min(major)and 10.2min.HRMS(ESI)m/z Calculated for C22H16F3N2[M+H]+365.1260,found 365.1258.
(+)-12-Ethyl-6-phenyl-6-(trifluoromethyl)-5,6-dihydroindolo[1,2-c]quinazoline(3ca)71mg,90％ yield, colorless oil,new compound,Rf＝0.50(hexanes/ethyl acetate 20:1),92％ee,[α]20 D＝+38.73(c 1.42,EtOAc)；1H NMR(400MHz,CD3OD)δ7.71(dd,J＝7.9,0.8Hz,1H),7.56(d,J＝7.6Hz,2H),7.41(d,J＝7.9Hz, 1H),7.37–7.26(m,3H),6.99(d,J＝6.8Hz,1H),6.89–6.69(m,3H),6.64–6.53(m,1H),6.07(d,J＝8.5Hz,1H),3.12–2.95(m,2H),1.27(t,J＝7.5Hz,3H)；13C NMR(100MHz,CD3OD)δ139.5,136.9,134.7,129.8, 129.4,129.2,128.3,128.2,127.6,125.9(q,J＝295.0Hz),124.1,121.3,119.5,118.9,117.6,115.9,114.1,113.5, 112.6,75.3(q,J＝30.0Hz),17.8,13.5；19F NMR(376MHz,CD3OD)δ-73.0.Enantiomeric excess was determined by HPLC(IA column,elute:n-Hexane/i-PrOH＝95/5,detector:254nm,flow rate:1.0mL/min,30 ℃),retention time 5.1min(major)and 6.5min.HRMS(ESI)m/z Calculated for C24H20F3N2[M+H]+393.1573, found 393.1592.
(+)-3-Bromo-12-methyl-6-phenyl-6-(trifluoromethyl)-5,6-dihydroindolo[1,2-c]quinazoline(3da)26 mg,28％ yield,colorless oil,new compound,Rf＝0.70(hexanes/ethyl acetate 10:1),96％ee,[α]20 D＝+8.65(c 0.52,EtOAc)；1H NMR(400MHz,CD3OD)δ7.68–7.53(m,3H),7.46–7.31(m,4H),6.96–6.90(m,2H), 6.96–6.84(m,1H),6.67–6.58(m,1H),6.07(d,J＝8.5Hz,1H),2.50(s,3H)；13C NMR(100MHz,CD3OD) δ140.7,136.4,134.6,130.5,129.6,128.9,128.4,128.1,125.8(q,J＝295.0Hz),125.7,121.6,121.5,120.7, 119.7,117.9,115.8,115.3,112.5,107.8,75.2(q,J＝30.0Hz),9.7；19F NMR(376MHz,CD3OD)δ-73.4. Enantiomeric excess was determined by HPLC(IA column,elute:n-Hexane/i-PrOH＝95/5,detector:254nm, flow rate:1.0mL/min,30℃),retention time 6.1min(major)and 7.2min.HRMS(ESI)m/z Calculated for C23H17BrF3N2[M+H]+457.0522,found 457.0532.
(+)-3,12-Dimethyl-6-phenyl-6-(trifluoromethyl)-5,6-dihydroindolo[1,2-c]quinazoline(3ea)57mg, 73％ yield,pink solid,m.p.＝190-191℃,new compound,Rf＝0.55(hexanes/ethyl acetate 20:1),97％ee, [α]20 D＝+39.38(c 1.14,EtOAc)；1H NMR(400MHz,CD2Cl2)δ7.70(d,J＝8.0Hz,1H),7.59(d,J＝8.0Hz, 2H),7.48–7.30(m,4H),6.95–6.86(m,1H),6.72(d,J＝8.0Hz,1H),6.69–6.61(m,1H),6.46(s,1H),6.07 (d,J＝8.5Hz,1H),4.59(brs,1H),2.55(s,3H),2.21(s,3H)；13C NMR(100MHz,CD2Cl2)δ138.3,138.1,136.5,134.6,130.8,130.1,129.8,128.8,128.2(q,J＝2.0Hz),125.7(q,J＝295.0Hz),124.9,121.7,121.2, 120.0,118.2,114.2,112.5,107.6,75.4(q,J＝30.0Hz),21.1,10.7；19F NMR(376MHz,CD2Cl2)δ-72.3. Enantiomeric excess was determined by HPLC(IAcolumn,elute:n-Hexane/i-PrOH＝95/5,detector:254nm, flow rate:1.0mL/min,30℃),retention time 5.6min(major)and 8.1min.HRMS(ESI)m/z Calculated for C24H20F3N2[M+H]+393.1573,found 393.1581.
(+)-10-Bromo-12-methyl-6-phenyl-6-(trifluoromethyl)-5,6-dihydroindolo[1,2-c]quinazoline(3fa)70 mg,77％ yield,colorless oil,new compound,Rf＝0.55(hexanes/ethyl acetate 10:1),95％ee,[α]20 D＝+66.28 (c 1.40,EtOAc)；1H NMR(400MHz,CD3OD)δ7.73(dd,J＝7.9,0.9Hz,1H),7.59–7.51(m,3H), 7.39–7.26(m,3H),7.06–6.99(m,1H),6.82–6.72(m,2H),6.67(dd,J＝8.9,2.0Hz,1H),5.95(d,J＝8.9Hz,1H),2.45(s,3H)；13C NMR(100MHz,CD3OD)δ139.6,136.4,133.2,132.5,131.3,129.6,128.4,128.12, 128.08,125.9(q,J＝295.0Hz),124.6,123.8,120.3,118.9,115.7,114.0,113.5,112.9,106.5,75.4(q,J＝30.0 Hz),9.7；19F NMR(376MHz,CD3OD)δ-73.2.Enantiomeric excess was determined by HPLC(IA column, elute:n-Hexane/i-PrOH＝95/5,detector:254nm,flow rate:1.0mL/min,30℃),retention time 6.1min(major) and 7.7min.HRMS(ESI)m/z Calculated for C23H17BrF3N2[M+H]+457.0522,found457.0546.
(+)-10-Methoxy-12-methyl-6-phenyl-6-(trifluoromethyl)-5,6-dihydroindolo[1,2-c]quinazoline(3ga)69 mg,84％ yield,pink oil,new compound,Rf＝0.65(hexanes/ethyl acetate 10:1),90％ee,[α]20 D＝+48.37(c 0.86,EtOAc)；1H NMR(400MHz,CD3OD)δ7.74(dd,J＝7.9,1.0Hz,1H),7.62–7.54(m,2H),7.41–7.29 (m,3H),7.02–6.97(m,1H)6.89(d,J＝2.5Hz,1H),6.82–6.76(m,1H),6.73(dd,J＝8.0,0.8Hz,1H),6.26 (dd,J＝9.1,2.5Hz,1H),5.94(d,J＝9.1Hz,1H),3.66(s,3H),2.50(s,3H)；13C NMR(100MHz,CD3OD)δ 154.2,139.4,136.9,131.2,130.5,129.7,129.4,128.3,128.2,127.4,125.9(q,J＝296.0Hz),124.2,118.7,116.2, 113.3,113.2,111.0,106.8,99.6,75.3(q,J＝30.0Hz),54.7,9.8；19F NMR(376MHz,CD3OD)δ-73.2. Enantiomeric excess wasdetermined by HPLC(IA column,elute:n-Hexane/i-PrOH＝95/5,detector:254nm, flowrate:1.0mL/min,30℃),retention time 7.0min(major)and 8.2min.HRMS(ESI)m/zCalculated for C24H20F3N2O[M+H]+409.1522,found 409.1530.
(+)-6-(Difluoromethyl)-12-methyl-6-phenyl-5,6-dihydroindolo[1,2-c]quinazoline(3aj)72 mg,99％ yield,colorless oil,new compound,Rf＝0.55(hexanes/ethyl acetate 10:1),25％ee,[α]20 D＝+15.94(c 1.38, EtOAc)；1H NMR(400MHz,CD2Cl2)δ7.79(d,J＝7.8Hz,1H),7.65(d,J＝7.5Hz,2H),7.45(d,J＝7.9Hz, 1H),7.43–7.32(m,3H),7.08–7.00(m,1H),6.94–6.84(m,2H),6.70–6.62(m,2H),6.24(t,J＝54.5Hz, 1H),6.04(d,J＝8.5Hz,1H),4.63(brs,1H),2.56(s,3H)；13C NMR(100MHz,CD2Cl2)δ138.6,137.0,134.9,130.7,129.9,129.3,128.8,128.6(t,J＝2.0Hz),128.0,125.1,121.9,120.1,119.8,118.4,117.0,115.1(t,J＝ 254.0Hz),114.3,112.2,108.3,74.1(t,J＝23.0Hz),10.8；19FNMR(376MHz,CD2Cl2)δ-123.6(d,J＝ 276.8Hz,1F),-128.4(d,J＝276.8Hz,1F).Enantiomeric excess was determined by HPLC(IA column,elute: n-Hexane/i-PrOH＝95/5,detector:254nm,flow rate:1.0mL/min,30℃),retention time 6.7min(major)and 8.1min.HRMS(ESI)m/z Calculated for C23H19F2N2[M+H]+361.1511,found 361.1543.
(+)-6-Benzyl-12-methyl-6-(trifluoromethyl)-5,6-dihydroindolo[1,2-c]quinazoline(3ak)70mg,89％ yield,white solid,m.p.＝145-146℃,new compound,Rf＝0.75(hexanes/ethyl acetate 10:1),84％ee,[α]20 D＝ +94.28(c 1.40,EtOAc)；1H NMR(400MHz,CD2Cl2)δ7.68(d,J＝7.9Hz,1H),7.59(d,J＝8.3Hz,1H), 7.51(d,J＝7.8Hz,1H),7.15–6.95(m,8H),6.81(t,J＝7.6Hz,1H),6.60(d,J＝7.9Hz,1H),4.32–4.19(m, 2H),3.60(d,J＝15.4Hz,1H),2.48(s,3H)；13C NMR(100MHz,CD2Cl2)δ137.6,134.7,132.6,131.1,130.4, 129.2,128.4,128.0,125.7(q,J＝295.0Hz),127.6,125.0,122.6,120.27,120.26,118.9,116.6,114.1,113.2(q, J＝2.0Hz),108.9,73.8(q,J＝29.0Hz),38.5,10.9；19F NMR(376MHz,CD2Cl2)δ-78.2.Enantiomeric excess was determined by HPLC(IA column,elute:n-Hexane/i-PrOH＝95/5,detector:254nm,flow rate:1.0 mL/min,30℃),retention time 6.3min(major)and 7.1min.HRMS(ESI)m/z Calculated for C24H20F3N2[M+H]+393.1573,found 393.1573.
6,12-Dimethyl-6-phenyl-5,6-dihydroindolo[1,2-c]quinazoline(3al)61mg,94％ yield,white solid, known compound,[4]Rf＝0.50(hexanes/ethyl acetate 10:1),<1％ee；1H NMR(400MHz,CDCl3)δ7.88(dd, J＝7.9,1.0Hz,1H),7.66–7.59(m,2H),7.56(d,J＝7.9Hz,1H),7.42–7.34(m,3H),7.14–7.06(m,1H), 7.05–6.98(m,1H),6.94(t,J＝7.4Hz,1H),6.85–6.76(m,1H),6.68(dd,J＝7.9,0.7Hz,1H),6.22(d,J＝8.4 Hz,1H),4.24(brs,1H),2.66(s,3H),2.02(s,3H)；13C NMR(100MHz,CDCl3)δ143.4,140.0,134.1,130.5,129.9,129.0,128.7,127.6,127.5,125.2,121.5,119.8,119.1,118.4,117.9,115.2,111.7,107.3,73.5,24.9,11.1. Enantiomeric excess was determined by HPLC(IBcolumn,elute:n-Hexane/i-PrOH＝70/30,detector:254nm, flow rate:0.7mL/min,30℃),retention time 7.1min and 7.6min(major).
(+)-Ethyl 12-methyl-6-(trifluoromethyl)-5,6-dihydroindolo[1,2-c]quinazoline-6-carboxy-late(3am)56 mg,75％ yield,pale yellow solid,m.p.＝156-158℃,new compound,Rf＝0.40(hexanes/ethyl acetate 10:1), 89％ee,[α]20 D＝+69.10(c 1.12,EtOAc)；1H NMR(400MHz,CD3OD)δ7.70(d,J＝7.9Hz,1H),7.53–7.43 (m,1H),7.10–6.98(m,4H),6.86–6.73(m,2H),4.31–4.14(m,2H),2.49(s,3H),1.07(t,J＝7.1Hz,3H)；13CNMR(100MHz,CD3OD)δ164.9,137.8,134.0,130.5,127.8,124.4,124.2(q,J＝294.0Hz),122.0,120.2, 119.2,118.2,115.5,113.6,110.1(q,J＝3.0Hz),107.4,73.7(q,J＝30.0Hz),63.1,12.7,9.5；19F NMR(376 MHz,CD3OD)δ-77.3.Enantiomeric excess wasdetermined by HPLC(IA column,elute:n-Hexane/i-PrOH＝ 80/20,detector:254nm,flow rate:0.8mL/min,30℃),retention time 5.4min and5.9min(major).HRMS(ESI) m/z Calculated for C20H18F3N2O2[M+H]+375.1315,found 375.1319.
(+)-Ethyl 3,12-dimethyl-6-(trifluoromethyl)-5,6-dihydroindolo[1,2-c]quinazoline-6-carbo-xylate(3em) 46mg,59％ yield,pink solid,m.p.＝137-138℃,new compound,Rf＝0.40(hexanes/ethyl acetate 10:1),91％ ee,[α]20 D＝+58.80(c0.92,EtOAc)；1H NMR(400MHz,CD3OD)δ7.58(d,J＝8.5Hz,1H),7.50–7.44(m, 1H),7.05–6.98(m,3H),6.67–6.59(m,2H),4.30–4.16(m,2H),2.46(s,3H),2.20(s,3H),1.07(t,J＝7.1Hz, 3H)；13C NMR(100MHz,CD3OD)δ165.0,138.1,137.8,133.9,130.6,128.1,124.4,124.3(q,J＝294.0Hz), 121.7,120.2,120.1,118.0,114.0,112.9,110.1(q,J＝2.0Hz),106.6,73.7(q,J＝30.0Hz),63.0,20.1,12.7,9.4；19F NMR(376MHz,CD3OD)δ-77.2.Enantiomeric excess was determined by HPLC(OD-H column,elute: n-Hexane/i-PrOH＝70/30,detector:254nm,flow rate:0.7mL/min,30℃),retention time 5.5minand 5.9min (major).HRMS(ESI)m/z Calculated for C21H20F3N2O2[M+H]+389.1471,found375.1475.
(+)-Ethyl(R)-10-bromo-12-methyl-6-(trifluoromethyl)-5,6-dihydroindolo[1,2-c]quinazolin e-6-carboxylate(3fm)47mg,52％ yield,pale yellow solid,m.p.＝203-204℃,new compound,Rf＝0.45 (hexanes/ethyl acetate 10:1),89％ee,[α]20 D＝+50.95(c 0.94,EtOAc)；1H NMR(400MHz,CD2Cl2)δ7.75(d, J＝7.8Hz,1H),7.67(d,J＝1.9Hz,1H),7.18(dd,J＝8.8,1.9Hz,1H),7.15–7.08(m,1H),6.99–6.88(m,2H), 6.77(d,J＝8.0Hz,1H),4.94(brs,1H),4.38–4.19(m,2H),2.50(s,3H),1.14(t,J＝7.1Hz,3H)；13CNMR (100MHz,CD2Cl2)δ164.3,136.3,132.8,132.5,128.8,128.7,125.4,125.2,123.7(q,J＝293Hz),121.5,121.3, 116.0,114.8,114.0,112.3(q,J＝2.0Hz),108.5,73.9(q,J＝30.0Hz),64.2,13.6,10.6；19F NMR(376MHz, CD2Cl2)δ-75.8.Enantiomeric excess wasdetermined by HPLC(IA column,elute:n-Hexane/i-PrOH＝70/30, detector:254nm,flow rate:0.7mL/min,30 ℃),retention time 5.5min(major)and 6.7min.HRMS(ESI)m/z Calculated for C20H17BrF3N2O2[M+H]+453.0420,found 453.0420.

Claims (6)

1.一种合成手性含氟缩酮胺的方法，其特征在于，所述方法以含氟的酮和2-(2-吲哚)苯胺为反应底物，以手性磷酸为催化剂，不对称合成手性含氟缩酮胺，反应式和条件如下：
Figure FDA0002040614240000011
式中：
Ar1、Ar2为独立选自苯基或含有取代基的苯环，R1为氢或甲基，R2为芳基、烷基、酯基，Rf为CF3或CHF2；所述的取代基为甲基、甲氧基或溴；
反应条件：
温度：30-90℃；
时间：12-120小时；
CPA为手性磷酸。
2.根据权利要求1所述的方法，其特征在于，所述方法的反应步骤为：
在氮气保护下，在Schlenk管中加入2-(2-吲哚)苯胺、手性磷酸、有机溶剂和
Figure FDA0002040614240000012
分子筛，将含氟的酮加入其中，30-90℃反应12-120h，旋干溶剂，柱层析得到所述的手性缩酮胺化合物；所述2-(2-吲哚)苯胺、含氟的酮、催化剂的摩尔比为1:1～2:0.05。
3.根据权利要求1所述的方法，其特征在于：所述的反应为含氟的酮和2-(2-吲哚)苯胺为反应底物合成手性缩酮胺化合物，Ar1苯环，Ar2为2-(2-吲哚)-4-甲基苯基，R1为甲基，R2为苯基，Rf为CF3，催化剂手性磷酸(R)-TRIP，溶剂为甲苯，温度为70℃，在
Figure FDA0002040614240000013
分子筛存在下，对映体过量为97％。
4.根据权利要求2所述的方法，其特征在于，所述有机溶剂为1,2-二氯乙烷或芳烃类溶剂。
5.根据权利要求1或2所述的方法，其特征在于，所述手性磷酸为联萘骨架的手性磷酸。
6.根据权利要求4所述的方法，其特征在于，所述芳烃类溶剂为甲苯、二甲苯、苯、氯苯。
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