CN116135825A - Method for preparing chiral 2-substituted tetrahydroquinoline by nickel catalytic asymmetric hydrogenation - Google Patents
Method for preparing chiral 2-substituted tetrahydroquinoline by nickel catalytic asymmetric hydrogenationDownload PDFInfo
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Abstract
Description
Translated fromChinese技术领域Technical Field
本发明属于有机合成领域，具体涉及一种镍催化不对称氢化制备手性2-取代四氢喹啉的方法。The invention belongs to the field of organic synthesis, and specifically relates to a method for preparing chiral 2-substituted tetrahydroquinoline by nickel-catalyzed asymmetric hydrogenation.
背景技术Background Art
手性四氢喹啉及衍生物是化学品、制药、生物合成中重要的中间体，在生物碱研究中起着至关重要的作用。最简洁、方便的合成手性四氢喹啉的方法是直接喹啉衍生物的不对称氢化。它是在手性催化剂及其他助剂的帮助下，使喹啉衍生物直接氢化生成手性四氢喹啉衍生物类化合物。近些年，关于有机小分子催化喹啉衍生物的不对称转移氢化已有很大的进展，而关于金属催化不对称氢化喹啉衍生物的报道很少。2009年，周永贵团队(D.–W.Wang,X.-B.Wang,D.–S.Wang,S.–M.Lu,Y.–G.Zhou,Y.–X.Li.J.Org.Chem.2009,74,2780)利用(S)-MeO-BiPhep配体与环辛二烯氯化铱二聚体成功催化不对称氢化喹啉衍生物合成手性四氢喹啉衍生物，取得了最高96％的对映选择性。2011年，范青华团队(T.L.Wang,L.–G.Zhou,Z.W.Li,F.Chen,Z.Y.Ding,Y.M..He,Q.–H.Fan,J.F.Xiang,Z.–X.Yu,AlbertS.C.Chan.J.Am.Chem.Soc.2011,133,9878)利用手性阳离子钌催化不对称氢化喹啉衍生物合成手性四氢喹啉衍生物，取得了最高99％的对映选择性。与贵金属催化喹啉化合物不对称氢化相比，非贵金属催化亚胺的不对氢化由于催化活性总体上偏低，因而其发展相对缓慢。2019年，张万斌等在链状酮和苯并酮的叔丁基磺酰酮亚胺的不对称氢化中取得了突破性的进展，以中等到优秀的对映选择性得到一系列手性叔丁基磺酰胺产物(B.Li,J.Chen,Z.Zhang,I.D.Gridnev,W.Zhang,Angew.Chem.Int.Ed.,2019,58,7329)。随后，张绪穆课题组相继报道了镍催化亚胺类化合物的不对称氢化[a)Y.Liu,Z.Yi,X.Tan,X.-Q.Dong,X.Zhang.iScience 2019,19,63；b)X.Zhao,F.Zhang,K.Liu,X.Zhang,H.Lv.Org.Lett.2019,21,8966.]。近来，我们发展的膦-亚磷酰胺酯配体在铱催化2,3-二取代喹啉不对称氢化中有着优异的表现(X.-H.Hu,X.-P.Hu,Org.Lett.,2019,21,10003-10006)。Chiral tetrahydroquinoline and its derivatives are important intermediates in chemicals, pharmaceuticals, and biosynthesis, and play a vital role in alkaloid research. The simplest and most convenient method for synthesizing chiral tetrahydroquinoline is the asymmetric hydrogenation of direct quinoline derivatives. It is to directly hydrogenate quinoline derivatives with the help of chiral catalysts and other additives to generate chiral tetrahydroquinoline derivatives. In recent years, there has been great progress in the asymmetric transfer hydrogenation of quinoline derivatives catalyzed by small organic molecules, but there are few reports on metal-catalyzed asymmetric hydrogenation of quinoline derivatives. In 2009, Zhou Yonggui’s team (D.–W. Wang, X.-B. Wang, D.–S. Wang, S.–M. Lu, Y.–G. Zhou, Y.–X. Li. J. Org. Chem. 2009, 74, 2780) successfully catalyzed the asymmetric hydrogenation of quinoline derivatives to synthesize chiral tetrahydroquinoline derivatives using (S)-MeO-BiPhep ligand and cyclooctadiene iridium chloride dimer, achieving an enantioselectivity of up to 96%. In 2011, Qinghua Fan's team (T.L.Wang, L.–G.Zhou, Z.W.Li, F.Chen, Z.Y.Ding, Y.M..He, Q.–H.Fan, J.F.Xiang, Z.–X.Yu, Albert S.C.Chan. J.Am.Chem.Soc.2011,133,9878) used chiral cation ruthenium to catalyze the asymmetric hydrogenation of quinoline derivatives to synthesize chiral tetrahydroquinoline derivatives, achieving up to 99% enantioselectivity. Compared with the noble metal-catalyzed asymmetric hydrogenation of quinoline compounds, the non-noble metal-catalyzed asymmetric hydrogenation of imines has developed relatively slowly due to its generally low catalytic activity. In 2019, Zhang Wanbin and others made a breakthrough in the asymmetric hydrogenation of tert-butylsulfonylketone imines of chain ketones and benzophenones, obtaining a series of chiral tert-butylsulfonamide products with moderate to excellent enantioselectivity (B. Li, J. Chen, Z. Zhang, I. D. Gridnev, W. Zhang, Angew. Chem. Int. Ed., 2019, 58, 7329). Subsequently, Zhang Xumu's research group reported the nickel-catalyzed asymmetric hydrogenation of imine compounds [a) Y. Liu, Z. Yi, X. Tan, X.-Q. Dong, X. Zhang. iScience 2019, 19, 63; b) X. Zhao, F. Zhang, K. Liu, X. Zhang, H. Lv. Org. Lett. 2019, 21, 8966.]. Recently, the phosphine-phosphoramidite ligands we developed have shown excellent performance in the iridium-catalyzed asymmetric hydrogenation of 2,3-disubstituted quinolines (X.-H.Hu, X.-P.Hu, Org.Lett., 2019, 21, 10003-10006).
发明内容Summary of the invention
本发明的目的是提供一种镍/膦-亚磷酰胺酯配体催化2-取代喹啉的不对称氢化反应制备手性2-取代四氢喹啉的方法。The purpose of the present invention is to provide a method for preparing chiral 2-substituted tetrahydroquinoline by asymmetric hydrogenation reaction of 2-substituted quinoline catalyzed by nickel/phosphine-phosphoramidite ligand.
一种镍催化不对称氢化制备手性2-取代四氢喹啉的方法；该方法以2-取代喹啉化合物为原料，Ni(OAc)2/手性苯基骨架膦-亚磷酰胺酯配体(L)为催化剂，制备手性2-取代四氢喹啉化合物，A method for preparing chiral 2-substituted tetrahydroquinoline by nickel-catalyzed asymmetric hydrogenation; the method uses a 2-substituted quinoline compound as a raw material and Ni(OAc)2 /chiral phenyl skeleton phosphine-phosphoramidate ligand (L) as a catalyst to prepare a chiral 2-substituted tetrahydroquinoline compound.
所述的反应方程式如下：The reaction equation is as follows:
所述的酮化合物I，醇化合物II，结构如下式：The ketone compound I and the alcohol compound II have the following structure:
其中，R1为C1-C10的链状烷基，环上碳数为C3-C12的环烷基或带有取代基的环上碳数为C3-C12环烷基，苯基及取代苯基，苄基及取代苄基，含一个或二个以上氧、硫、氮原子中的一种或二种以上的五元或六元杂环芳香基团中的一种；所述环上碳数为C3-C12环烷基上的取代基、苯基上的取代基、苄基上的取代基分别为C1-C10的链状烷基、C1-C10的链状烷氧基、卤素(氟、氯、溴、碘)、硝基、酯基或氰基中的一种或二种以上；Wherein,R1 is a C1-C10 chain alkyl, a C3-C12 cycloalkyl or a C3-C12 cycloalkyl with a substituent, a phenyl and substituted phenyl, a benzyl and substituted benzyl, or a five-membered or six-membered heterocyclic aromatic group containing one or more oxygen, sulfur, or nitrogen atoms; the substituent on the C3-C12 cycloalkyl, the substituent on the phenyl, and the substituent on the benzyl are respectively one or more of a C1-C10 chain alkyl, a C1-C10 chain alkoxy, a halogen (fluorine, chlorine, bromine, iodine), a nitro, an ester group, or a cyano group;
R2为C1-C10的链状烷基、环上碳数为C3-C12的环烷基或带有取代基的环上碳数为C3-C12的环烷基、苯基及取代苯基、苄基及取代苄基、卤素(氟、氯、溴、碘)中的一种或二种以上；所述环上碳数为C3-C12环烷基上的取代基、苯基上的取代基、苄基上的取代基分别为C1-C10的链状烷基、C1-C10的链状烷氧基、卤素(氟、氯、溴、碘)、硝基、酯基或氰基中的一种或二种以上，R2个数为1。R2 is one or more of a C1-C10 chain alkyl group, a C3-C12 cycloalkyl group or a C3-C12 cycloalkyl group with a substituent, a phenyl group and a substituted phenyl group, a benzyl group and a substituted benzyl group, and a halogen (fluorine, chlorine, bromine, or iodine); the substituent on the C3-C12 cycloalkyl group, the substituent on the phenyl group, and the substituent on the benzyl group are one or more of a C1-C10 chain alkyl group, a C1-C10 chain alkoxy group, a halogen (fluorine, chlorine, bromine, or iodine), a nitro group, an ester group, or a cyano group, and the number ofR2 is 1.
所述的手性膦-亚磷酰胺酯配体(L)，其结构如下式：The chiral phosphine-phosphoramidite ligand (L) has the following structure:
式中：Where:
式中:R1、R2分别为H、C1-C10的链状烷基、环上碳数为C3-C12的环烷基、苯基及取代苯基、苄基及取代苄基中的一种；所述环上碳数为C3-C12环烷基上的取代基、苯基上的取代基、苄基上的取代基分别为C1-C10的链状烷基、C1-C10的链状烷氧基、卤素(氟、氯、溴、碘)、硝基、酯基或氰基中的一种或二种以上；In the formula:R1 andR2 are respectively one of H, a C1-C10 chain alkyl group, a C3-C12 cycloalkyl group, a phenyl group and a substituted phenyl group, a benzyl group and a substituted benzyl group; the substituent on the C3-C12 cycloalkyl group, the substituent on the phenyl group, and the substituent on the benzyl group are respectively one or more of a C1-C10 chain alkyl group, a C1-C10 chain alkoxy group, a halogen (fluorine, chlorine, bromine, iodine), a nitro group, an ester group, or a cyano group;
Ar为苯基或取代苯基；所述苯基上的取代基为C1-C10链状烷基、C1-C10的链状烷氧基、卤素(氟、氯、溴、碘)、硝基、酯基或氰基中的一种或二种以上；Ar is phenyl or substituted phenyl; the substituent on the phenyl is one or more of C1-C10 chain alkyl, C1-C10 chain alkoxy, halogen (fluorine, chlorine, bromine, iodine), nitro, ester or cyano;
X基团为：手性含或不含N、S、O、P等中的一种或二种以上官能团的联苯、联萘或四氢联萘类芳香基团中的一种。The X group is one of the chiral biphenyl, binaphthyl or tetrahydrobinaphthyl aromatic groups containing or not containing one or more functional groups of N, S, O, P, etc.
该方法的具体步骤为：在充满氮气的手套箱中，将Ni(OAc)2和手性膦-亚磷酰胺酯配体(L)溶于无水溶剂，室温下搅拌0.5-2小时；加入底物2-取代喹啉化合物，将其置于反应釜中，氢气置换3次，然后通入氢气，加热到指定温度反应；慢慢释放氢气，除去溶剂后用硅胶柱分离得到产物，以上反应物按摩尔比Ni(OAc)2:L:2-取代喹啉＝1:1～2:100～1000。The specific steps of the method are: in a glove box filled with nitrogen, dissolving Ni(OAc)2 and a chiral phosphine-phosphoramidate ligand (L) in an anhydrous solvent, and stirring at room temperature for 0.5-2 hours; adding a substrate 2-substituted quinoline compound, placing it in a reaction kettle, replacing it with hydrogen for 3 times, then introducing hydrogen, and heating to a specified temperature for reaction; slowly releasing hydrogen, removing the solvent, and separating the product with a silica gel column, wherein the molar ratio of the above reactants is Ni(OAc)2 :L:2-substituted quinoline=1:1-2:100-1000.
所述的溶剂为甲醇、乙醇、异丙醇、三氟乙醇、六氟异丙醇中的一种或两种以上，优选为三氟乙醇。The solvent is one or more of methanol, ethanol, isopropanol, trifluoroethanol and hexafluoroisopropanol, preferably trifluoroethanol.
所述氢化反应压力为20-80大气压，优选50大气压。The hydrogenation reaction pressure is 20-80 atmospheres, preferably 50 atmospheres.
所述氢化反应温度为20-100℃，优选50℃。The hydrogenation reaction temperature is 20-100°C, preferably 50°C.
所述氢化反应时间为12-36小时，优选24小时。The hydrogenation reaction time is 12-36 hours, preferably 24 hours.
所述柱层析洗脱剂参数为体积比石油醚：乙酸乙酯＝10:1-50:1，优选为10:1。The column chromatography eluent parameter is a volume ratio of petroleum ether:ethyl acetate = 10:1-50:1, preferably 10:1.
本发明的有益效果和优势：Beneficial effects and advantages of the present invention:
本发明所述的镍催化2-取代喹啉的不对称氢化反应制备手性2-取代四氢喹啉的反应具有条件温和、催化剂廉价、易于操作，且产物的对映选择性高等优点。The nickel-catalyzed asymmetric hydrogenation reaction of 2-substituted quinoline to prepare chiral 2-substituted tetrahydroquinoline has the advantages of mild conditions, cheap catalyst, easy operation, high enantioselectivity of the product, etc.
附图说明BRIEF DESCRIPTION OF THE DRAWINGS
图1是实施例1中产物II-a的核磁氢谱；Fig. 1 is the H NMR spectrum of product II-a in Example 1;
图2是实施例1中产物II-a的核磁碳谱。FIG. 2 is the NMR carbon spectrum of product II-a in Example 1.
具体实施方式DETAILED DESCRIPTION
下面的实施例将对本发明予以进一步的说明，但并不因此而限制本发明。核磁共振是通过Bruker核磁共振仪测定，高效液相色谱(HPLC)是通过Agilent 1100系列高效液相色谱测定。The following examples will further illustrate the present invention, but are not intended to limit the present invention. Nuclear magnetic resonance was measured by a Bruker nuclear magnetic resonance instrument, and high performance liquid chromatography (HPLC) was measured by an Agilent 1100 series high performance liquid chromatograph.
实施例1Example 1
在充满氮气的手套箱中，将Ni(OAc)2(0.18mg,0.001mmol)和手性膦-亚磷酰胺酯配体L1(0.74mg,0.0011mmol)溶于无水三氟乙醇(1.0mL)，室温下搅拌1小时。加入底物2-苯基喹啉I-a(20.5mg,0.1mmol)和无水三氟乙醇(1.0mL)，将其置于高压反应釜中，氢气置换3次，然后通入氢气至50个大气压，50℃下反应24小时。慢慢释放氢气，除去溶剂后用硅胶柱(洗脱剂参数为体积比石油醚：乙酸乙酯＝10:1)分离得到产物2-苯基四氢喹啉II-a。98％收率，93％ee。1H NMR(400MHz,CDCl3)δ7.25(dt,J＝14.9,7.3Hz,4H),7.17(t,J＝6.9Hz,1H),6.90(t,J＝7.7Hz,2H),6.54(t,J＝7.4Hz,1H),6.40(d,J＝7.9Hz,1H),4.30(dd,J＝9.2,3.0Hz,1H),3.88(bs,1H),2.80(ddd,J＝16.1,10.6,5.4Hz,1H),2.61(dt,J＝16.3,4.7Hz,1H),2.00(ddd,J＝12.9,8.5,4.5Hz,1H),1.94–1.80(m,1H).13C NMR(101MHz,CDCl3)δ144.89(d,J＝10.6Hz),129.40(s),128.68(s),127.54(s),127.01(s),126.66(s),120.96(s),117.26(s),114.09(s),56.34(s),31.09(s),26.48(s).HPLC(Chiralcel OD-H,n-hexane/i-PrOH＝80/20,1.0mL/min,254nm,40℃):tR(major)＝7.1min,tR(minor)＝8.7min.In a glove box filled with nitrogen, Ni(OAc)2 (0.18 mg, 0.001 mmol) and chiral phosphine-phosphoramidate ligand L1 (0.74 mg, 0.0011 mmol) were dissolved in anhydrous trifluoroethanol (1.0 mL) and stirred at room temperature for 1 hour. Substrate 2-phenylquinoline Ia (20.5 mg, 0.1 mmol) and anhydrous trifluoroethanol (1.0 mL) were added and placed in a high pressure reactor. Hydrogen was replaced 3 times, and then hydrogen was introduced to 50 atmospheres, and the reaction was carried out at 50°C for 24 hours. Hydrogen was slowly released, and the solvent was removed and separated using a silica gel column (eluent parameters were volume ratio of petroleum ether: ethyl acetate = 10:1) to obtain the product 2-phenyltetrahydroquinoline II-a. 98% yield, 93% ee.1 H NMR (400MHz, CDCl3 ) δ7.25 (dt, J = 14.9, 7.3Hz, 4H), 7.17 (t, J = 6.9Hz, 1H), 6.90 (t, J = 7.7Hz, 2H), 6.54 (t, J = 7.4Hz, 1H), 6.40 (d, J = 7.9Hz, 1H), 4.30 (dd, J = 9 .2,3.0Hz,1H),3.88(bs,1H),2.80(ddd,J＝16.1,10.6,5.4Hz,1H),2.61(dt,J＝16.3,4.7Hz,1H),2.00(ddd,J＝12.9,8.5,4.5Hz,1H),1.94–1.80(m,1H).13C NMR (101MHz, CDCl3 ) δ 144.89 (d, J = 10.6Hz), 129.40 (s), 128.68 (s), 127.54 (s), 127.01 (s), 126.66 (s), 120.96 (s), 117.26 (s), 114.09 (s), 56.34 (s), 31.09 (s), 26.48 (s). HPLC (Chiralcel OD-H, n-hexane/i-PrOH=80/20, 1.0mL/min, 254nm, 40°C): tR (major) = 7.1 min, tR (minor) = 8.7 min.
该类化合物是合成生物碱如angustureine、cuspareine的重要的中间体，参考文献(I.Jacquemond-Collet,J.M.Bessiere,S.Hannedouche,C.Bertrand,I.Fouraste,C.Moulis,Phytochem.Anal.2001,12,312-319)This type of compound is an important intermediate for the synthesis of alkaloids such as angustureine and cuspareine. References (I. Jacquemond-Collet, J. M. Bessiere, S. Hannedouche, C. Bertrand, I. Fouraste, C. Moulis, Phytochem. Anal. 2001, 12, 312-319)
化合物II-a的核磁氢谱如图1所示。The H NMR spectrum of compound II-a is shown in Figure 1.
化合物L1、I-a和II-a的结构分别如下：The structures of compounds L1, I-a and II-a are as follows:
实施例2Example 2
将配体L1替换为L2，其余同实施例1，得产物2-苯基四氢喹啉II-a，98％收率，62％ee。The ligand L1 was replaced by L2, and the rest was the same as in Example 1 to obtain the product 2-phenyltetrahydroquinoline II-a with a yield of 98% and 62% ee.
配体L2的结构如下：The structure of ligand L2 is as follows:
实施例3Example 3
将配体L1替换为L3，其余同实施例1，得产物2-苯基四氢喹啉II-a，96％收率，74％ee。The ligand L1 was replaced by L3, and the rest was the same as in Example 1 to obtain the product 2-phenyltetrahydroquinoline II-a with a yield of 96% and 74% ee.
配体L3的结构如下：The structure of ligand L3 is as follows:
实施例4Example 4
将配体L1替换为L4，其余同实施例1，得产物2-苯基四氢喹啉II-a，96％收率，49％ee。The ligand L1 was replaced by L4, and the rest was the same as in Example 1 to obtain the product 2-phenyltetrahydroquinoline II-a with a yield of 96% and 49% ee.
配体L4的结构如下：The structure of ligand L4 is as follows:
实施例5Example 5
将配体L1替换为L5，其余同实施例1，得产物2-苯基四氢喹啉II-a，96％收率，80％ee。The ligand L1 was replaced by L5, and the rest was the same as in Example 1 to obtain the product 2-phenyltetrahydroquinoline II-a with a yield of 96% and 80% ee.
配体L5的结构如下：The structure of ligand L5 is as follows:
实施例6Example 6
将配体L1替换为L6，其余同实施例1，得产物2-苯基四氢喹啉II-a，96％收率，75％ee。The ligand L1 was replaced by L6, and the rest was the same as in Example 1 to obtain the product 2-phenyltetrahydroquinoline II-a with a yield of 96% and 75% ee.
配体L6的结构如下：The structure of ligand L6 is as follows:
实施例7Example 7
将配体L1替换为L7，其余同实施例1，得产物2-苯基四氢喹啉II-a，93％收率，78％ee。The ligand L1 was replaced by L7, and the rest was the same as in Example 1 to obtain the product 2-phenyltetrahydroquinoline II-a with a yield of 93% and 78% ee.
配体L7的结构如下：The structure of ligand L7 is as follows:
实施例8Example 8
将配体L1替换为L8，其余同实施例1，得产物2-苯基四氢喹啉II-a，58％收率，52％ee。The ligand L1 was replaced by L8, and the rest was the same as in Example 1 to obtain the product 2-phenyltetrahydroquinoline II-a with a yield of 58% and 52% ee.
配体L8的结构如下：The structure of ligand L8 is as follows:
实施例9Example 9
将配体L1替换为L9，其余同实施例1，得产物2-苯基四氢喹啉II-a，96％收率，70％ee。The ligand L1 was replaced by L9, and the rest was the same as in Example 1 to obtain the product 2-phenyltetrahydroquinoline II-a with a yield of 96% and 70% ee.
配体L9的结构如下：The structure of ligand L9 is as follows:
实施例10Example 10
将配体L1替换为L10，其余同实施例1，得产物2-苯基四氢喹啉II-a，98％收率，80％ee。The ligand L1 was replaced by L10, and the rest was the same as in Example 1 to obtain the product 2-phenyltetrahydroquinoline II-a with a yield of 98% and 80% ee.
配体L10的结构如下：The structure of ligand L10 is as follows:
实施例11
将配体L1替换为L11，其余同实施例1，得产物2-苯基四氢喹啉II-a，85％收率，56％ee。The ligand L1 was replaced by L11, and the rest was the same as in Example 1 to obtain the product 2-phenyltetrahydroquinoline II-a with a yield of 85% and 56% ee.
配体L11的结构如下：The structure of ligand L11 is as follows:
实施例12Example 12
将配体L1替换为L12，其余同实施例1，得产物2-苯基四氢喹啉II-a，85％收率，73％ee。The ligand L1 was replaced by L12, and the rest was the same as in Example 1 to obtain the product 2-phenyltetrahydroquinoline II-a with 85% yield and 73% ee.
配体L12的结构如下：The structure of ligand L12 is as follows:
实施例13Example 13
将氢气压力改为20大气压，其余同实施例1，得产物2-苯基四氢喹啉II-a，58％收率，82％ee。The hydrogen pressure was changed to 20 atmospheres, and the rest was the same as in Example 1 to obtain the product 2-phenyltetrahydroquinoline II-a with a yield of 58% and 82% ee.
实施例14
将氢气压力改为80大气压，其余同实施例1，得产物2-苯基四氢喹啉II-a，98％收率，92％ee。The hydrogen pressure was changed to 80 atmospheres, and the rest was the same as in Example 1 to obtain the product 2-phenyltetrahydroquinoline II-a with a yield of 98% and 92% ee.
实施例15
将温度由50℃改为室温，其余同实施例1，得产物2-苯基四氢喹啉II-a，36％收率，92％ee。The temperature was changed from 50°C to room temperature, and the rest was the same as in Example 1 to obtain the product 2-phenyltetrahydroquinoline II-a with a yield of 36% and 92% ee.
实施例16Example 16
将温度由50℃改为100℃，其余同实施例1，得产物2-苯基四氢喹啉II-a，96％收率，83％ee。The temperature was changed from 50°C to 100°C, and the rest was the same as in Example 1 to obtain the product 2-phenyltetrahydroquinoline II-a with a yield of 96% and 83% ee.
实施例17Embodiment 17
将催化剂的量由1mol％改为10mol％，其余同实施例1，得产物2-苯基四氢喹啉II-a，96％收率，93％ee。The amount of catalyst was changed from 1 mol % to 10 mol %, and the rest was the same as in Example 1 to obtain the product 2-phenyltetrahydroquinoline II-a with a yield of 96% and 93% ee.
实施例18Embodiment 18
将催化剂的量由1mol％改为0.1mol％，其余同实施例1，得产物2-苯基四氢喹啉II-a，66％收率，92％ee。The amount of catalyst was changed from 1 mol% to 0.1 mol%, and the rest was the same as in Example 1 to obtain the product 2-phenyltetrahydroquinoline II-a with a yield of 66% and 92% ee.
实施例19Embodiment 19
将反应溶剂由CF3CH2OH改为CH3OH，其余同实施例1，得产物2-苯基四氢喹啉II-a，55％收率，49％ee。The reaction solvent was changed from CF3 CH2 OH to CH3 OH, and the rest was the same as in Example 1 to obtain the product 2-phenyltetrahydroquinoline II-a with a yield of 55% and 49% ee.
实施例20Embodiment 20
将反应溶剂由CF3CH2OH改为EtOH，其余同实施例1，得产物2-苯基四氢喹啉II-a，45％收率，55％ee。The reaction solvent was changed from CF3 CH2 OH to EtOH, and the rest was the same as Example 1 to obtain the product 2-phenyltetrahydroquinoline II-a with a yield of 45% and 55% ee.
实施例21Embodiment 21
将反应溶剂由CF3CH2OH改为iPrOH，其余同实施例1，得产物2-苯基四氢喹啉II-a，35％收率，32％ee。The reaction solvent was changed from CF3 CH2 OHto i PrOH, and the rest was the same as in Example 1 to obtain the product 2-phenyltetrahydroquinoline II-a with a yield of 35% and 32% ee.
实施例22Example 22
将反应溶剂由CF3CH2OH改为(CF3)2CHOH，其余同实施例1，得产物2-苯基四氢喹啉II-a，90％收率，82％ee。The reaction solvent was changed from CF3 CH2 OH to (CF3 )2 CHOH, and the rest was the same as Example 1 to obtain the product 2-phenyltetrahydroquinoline II-a with a yield of 90% and 82% ee.
实施例23-49Embodiment 23-49
反应底物适用性Reaction substrate suitability
在充满氮气的手套箱中，将Ni(OAc)2(0.18mg,0.001mmol)和手性膦-亚磷酰胺酯配体L1(0.74mg,0.0011mmol)溶于无水三氟乙醇(1.0mL)，室温下搅拌1小时。依次加入底物I(0.1mmol)和无水三氟乙醇(1.0mL)，将其置于高压反应釜中，氢气置换3次，然后通入氢气至50个大气压，50℃下反应24小时，得氢化产物II。In a glove box filled with nitrogen, Ni(OAc)2 (0.18 mg, 0.001 mmol) and chiral phosphine-phosphoramidate ligand L1 (0.74 mg, 0.0011 mmol) were dissolved in anhydrous trifluoroethanol (1.0 mL) and stirred at room temperature for 1 hour. Substrate I (0.1 mmol) and anhydrous trifluoroethanol (1.0 mL) were added in sequence, and the mixture was placed in a high-pressure reactor, replaced with
本发明具有广泛的底物适用性，按照上述反应条件，许多底物都能参与该反应，高收率和高对映选择性的获得手性2-取代四氢喹啉产物II，其反应式为：The present invention has a wide range of substrate applicability. According to the above reaction conditions, many substrates can participate in the reaction, and a chiral 2-substituted tetrahydroquinoline product II is obtained with high yield and high enantioselectivity. The reaction formula is:
Claims (6)
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