CN112538033B - 一种环芳烷类面手性化合物的拆分方法 - Google Patents

一种环芳烷类面手性化合物的拆分方法 Download PDF

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CN112538033B
CN112538033B CN201910895177.5A CN201910895177A CN112538033B CN 112538033 B CN112538033 B CN 112538033B CN 201910895177 A CN201910895177 A CN 201910895177A CN 112538033 B CN112538033 B CN 112538033B
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周永贵
赵洋
孙蕾
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Dalian Institute of Chemical Physics of CAS
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Abstract

本发明提供一种环芳烷类面手性化合物的拆分方法，其用到的催化剂是钯的手性膦氮配合物。通过该方法可以得到环芳烷亚胺类面手性化合物(对映体过量可达99.9％)，以及环芳烷胺类面手性化合物(对映体过量可达99.4％，非对映体比例可达>20:1)，拆分系数可达到s＝368。本发明可以实现催化拆分，操作简单易行，催化剂商业可得，条件温和，能耗低，环境友好且拆分系数高，产率好。

Description

一种环芳烷类面手性化合物的拆分方法
技术领域
本发明属于不对称催化合成领域，就提涉及一种通过钯均相体系催化的加成反应实现环芳烷类面手性化合物拆分的方法。
技术背景
面手性[2.2]环芳烷化合物广泛应用于各种手性材料中，同时也可以作为配体或辅基在不对称合成中起着不可或缺的作用。(参考文献一：(a)Morisaki,Y.；Inoshita,K.；Chujo,Y.Chem.Eur.J.2014,20,8386.(b)Gibson,S.E.；Knight,J.D.Org.Biomol.Chem.2003,1,1256.(c)Fringuelli,F.；Piermatti,O.；Pizzo,F.；Ruzziconi,R.Chem.Lett.2000, 38.)。目前，获得面手性[2.2]环芳烷化合物的方法主要有传统的化学拆分，手性色谱分离等方法。(参考文献二：(a)Braddock,D.C.；MacGilp,I.D.；Perry,B.G.J.Org.Chem. 2002,67,8679.(b)Wang,Y.；Yuan,H.；Lu,H.；Zheng,W.-H.Org.Lett.2018,20,2555.)。近年来，通过催化动力学拆分制备面手性环芳烷引起了人们的注意，相比其他方法，它的优势在于可以显著降低手性试剂的用量。但目前发展的方法底物范围受限。(参考文献三：(a)Dorizon,P.；Martin,C.；Daran,J.-C.；Fiauda,J.-C.；Kagana,H.B.Tetrahedron: Asymmetry 2001,12,2625.(b)Akagawa,K.；Nishi,N.；Yoshikawa,I.；Kudo,K.Eur.J.Org. Chem.2015,5055.)。
金属催化芳基硼试剂对亚胺的加成反应是一种构建手性化合物的有效手段。近年来钯催化硼酸对亚胺的加成反应上取得了重要进展(参考文献四：(a)Yan,Z.；Wu,B.； Gao,X.；Zhou.Y.-G.Chem.Commun.2016,52,10882.(b)Quan,M.；Wu,L.；Yang,G.； Zhang,W.Chem.Commun.2018,54,10394.(c)Zhao,Z.-B.；Shi,L.；Meng,F.-J.；Li,Y.； Zhou,Y.-G.Org.Chem.Front.2019,6,1572.)，我们设想能否通过钯催化环芳烷亚胺的不对称加成反应实现该面手性化合物的动力学拆分，并且一次性获得含有中心手性和面手性的环芳烷衍生物。
发明内容
本发明的目的是提供一种通过对亚胺的硼酸加成反应实现环芳烷类外消旋面手性化合物拆分的方法。
本发明操作简便实用，原料易得，拆分系数高，产率好，能耗低且反应具有环境友好等优点。
为实现上述目的，本发明以钯的手性膦氮配合物为催化剂，以环芳烷亚胺和硼酸类化合物为底物，通过对亚胺的硼酸加成反应实现环芳烷类外消旋面手性化合物拆分。
本发明的技术方案如下：
本发明一方面提供一种拆分环芳烷亚胺的方法，所述方法以钯的手性膦氮配合物为催化剂，以环芳烷亚胺和硼酸类化合物为底物，通过对亚胺的硼酸反应实现环芳烷类外消旋面手性化合物拆分，拆分得到面手性环芳烷亚胺1和手性胺3；手性胺3与烯丙基溴反应得到烯丙基保护的手性胺2。所述方法的反应式如下：
Figure BDA0002209966200000021
式中：
R为苯基、萘基或含有取代基的苯环，所述的取代基为卤素，烷氧基或C1-C20的烷基取代基中的至少一种；
Ar为含有取代基的芳环，所述的取代基为C1-C20的烷基取代基中的至少一种；
Ts为对甲苯磺酰基。
基于以上技术方案，优选的，所述方法使用的有机溶剂为三氟乙醇、六氟异丙醇中的一种或两种混合。
基于以上技术方案，优选的，所述方法的反应温度为40-80℃，反应时间为15h。
催化剂的制备方法为：把钯的金属前体和手性膦氮配体在丙酮中室温搅拌1小时，然后真空浓缩除去丙酮。
基于以上技术方案，优选的，所述钯的金属前体为三氟醋酸钯；所述手性膦氮配体为一系列膦噁唑啉配体。
基于以上技术方案，优选的，所述方法的具体反应步骤为：
在氮气保护下，在反应瓶中投入三氟醋酸钯(环芳烷亚胺用量的5mol％)和手性膦氮配体(环芳烷亚胺用量的5mol％)，氮气置换后加入1毫升丙酮，室温搅拌1h。然后真空浓缩，氮气下加入有机溶剂，环芳烷亚胺和芳基硼酸，60℃反应15h。除去溶剂后直接柱层析分离得到纯的面手性环芳烷亚胺和产物前体。在反应瓶中将产物前体用N,N-二甲基甲酰胺溶解，0℃下加入氢化钠，随后加入烯丙基溴，于室温搅拌2h 后柱层析分离得到产物。；所述催化剂(mmol)、环芳烷亚胺(mmol)、硼酸类化合物(mmol) 和有机溶剂(ml)的用量比为0.05:1:1～1.5:20；所述产物前体(mmol)、氢化钠(mmol)、烯丙基溴(mmol)和N,N-二甲基甲酰胺(ml)的用量比为1:3:6:10。
基于以上技术方案，优选的，所述的反应为环芳烷亚胺与硼酸类化合物发生钯催化的加成反应实现环芳烷亚胺的拆分，R为苯基，Ar为C6H3，所述的催化剂为钯的手性二茂铁骨架膦噁唑啉配体L2的配合物，有机溶剂为三氟乙醇，温度为60℃，反应时间为15h，拆分后得到的面手性环芳烷亚胺1a对映体过量94.0％，烯丙基保护的手性胺2a对映体过量97.8％，s值为115。
有益效果
本发明具有以下优点
1.反应活性和对映选择性高，且拆分系数高。
2.能得到环芳烷亚胺面手性化合物以及环芳烷胺类面手性化合物。
3.催化剂商业可得，反应操作简便。
4.反应条件温和，能耗低。
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。
本发明手性二茂铁骨架膦噁唑啉配体的合成参考文献(a)Richards,C.J.；Mulvaney,A.W.Tetrahedron:Asymmetry,1996,7,1419.
本发明的底物环芳烷亚胺分两个步骤合成：步骤(1)氮气保护下，向反应瓶中加入环芳烷、二氯甲烷，0℃下向该体系中加入1,1-二氯甲醚、四氯化钛，搅拌3小时，可以得到环芳烷醛；步骤(2)氮气保护下，将步骤(1)得到的环芳烷醛投入反应瓶中，随后加入对甲苯磺酰胺、原硅酸四乙酯，升温至160℃，搅拌10小时，可以得到环芳烷亚胺。
本发明实施例18-19进行底物拓展使用的环芳烷亚胺为rac-1b是由4-甲基环芳烷为原料合成的，环芳烷亚胺rac-1b具体合成步骤参照上文。4-甲基环芳烷的合成参考文献(a)Gready,J.E.；Hambley,T.W.；Kakiuchi,K.；Kobiro,K.；Sternhell,S.；Tansey,C. W.；Tobe,Y.J.Am.Chem.Soc.1990,112,7537.其余原料均商业可得。
Figure BDA0002209966200000031
本发明得到的产物面手性环芳烷亚胺可以作为手性碳氮配体应用于不对称合成中。产物烯丙基保护的手性胺可以进行一系列的转化合成带有面手性的胺基化合物，可以作为手性辅基应用于手性合成中。
实施例1-7
条件的优化
改变手性膦氮配体、有机溶剂的种类以及硼酸类化合物的量。
在反应瓶中投入三氟醋酸钯(1a用量的5mol％)和手性膦氮配体(1a用量的5mol％)，氮气置换后加入1毫升丙酮，室温搅拌1h。然后真空浓缩，氮气下加入2 毫升有机溶剂，环芳烷亚胺1a(0.1毫摩尔)和苯硼酸(实施例1-6中为1a用量的150 mol％，实施例7中为1a用量的100mol％)。60℃反应15h。除去溶剂后直接柱层析分离得到纯的面手性环芳烷亚胺1a和产物前体3a。在反应瓶中将产物前体3a用1ml N,N-二甲基甲酰胺溶解，0℃下加入6mg氢化钠(质量分数为60％)，随后加入26μl 烯丙基溴，于室温搅拌2h后柱层析分离得到产物2a。回收环芳烷亚胺1a的转化率用核磁测定，回收环芳烷亚胺1a和产物2a的对映体过量用手性液相色谱测定，产物2a 的非对映体比例用核磁测定，拆分系数s值用这一算式算得s＝ln[(1-C)(1-ee of 1a)]/ln[(1-C)(1+ee of 1a)]，改变配体、有机溶剂的种类以及硼酸的量，具体结果如表1； dr为非对映体比例。
Figure BDA0002209966200000041
表1.环芳烷亚胺类面手性化合物动力学拆分条件的优化
Figure BDA0002209966200000042
实施例8-19
用一系列硼酸拆分环芳烷亚胺化合物。
在反应瓶中投入三氟醋酸钯(1用量的5mol％)和手性膦氮配体L2(1用量的5mol％)，氮气置换后加入1毫升丙酮，室温搅拌1h。然后真空浓缩，氮气下加入4 毫升三氟乙醇，环芳烷亚胺1(0.2毫摩尔，实施例8-17中所用环芳烷亚胺为rac-1a，实施例18-19中所用环芳烷亚胺为rac-1b)和芳基硼酸(1用量的100mol％)，60℃反应15h。除去溶剂后直接柱层析分离得到纯的面手性环芳烷亚胺1和产物前体3。在反应瓶中将产物前体3用2ml N,N-二甲基甲酰胺溶解，0℃下加入12mg氢化钠(质量分数为60％)，随后加入52μl烯丙基溴，于室温搅拌2h后柱层析分离得到产物2。回收环芳烷亚胺1的转化率用核磁测定，回收环芳烷亚胺1和产物2的对映体过量用手性液相色谱测定，产物2的非对映体比例用核磁测定，s值用这一算式算得s＝ ln[(1-C)(1-ee of 1)]/ln[(1-C)(1+ee of 1)]，改变反应中环芳烷亚胺和硼酸的种类得到12 个不同的实施例，改变的种类具体见表2。
Figure BDA0002209966200000051
表2.用一系列硼酸拆分环芳烷亚胺
Figure BDA0002209966200000052
Figure BDA0002209966200000061
(+)-N-Allyl-N-{[2.2]paracyclophan-4-yl(phenyl)methyl}-4-methylbenzenesulfonamide(2a):48.9 mg,48％yield,12:1 dr,white solid,mp＝144-146℃,new compound,Rf＝0.50(hexanes/ethyl acetate
Figure BDA0002209966200000062
3H).13CNMR(100 MHz,CDCl3)δ143.5,140.9,140.0,139.5,139.2,138.9,138.6,136.9,136.0,134.0, 133.7,132.6,132.3,132.2,131.4,130.5,129.7,129.4,128.4,128.2,128.0,117.2,64.6,48.5,35.5,35.4, 34.6,34.5,21.7.HPLC:Chiracel AD-H column,254nm,30℃,n-Hexane/i-PrOH＝90/10,flow＝1.0 mL/min,retention time 6.9min(major)and7.5min.HRMS:Calculated for C33H33KNO2S[M+K]+ 546.1864,found:546.1861.
(-)-N-Tosyl[2.2]paracyclophane-4-methanimine(1a):Kinetic resolutionfrom the addition of [2.2]paracyclophane aldimine 1a with phenylboronic acid,30.7mg,39％yield,93.7％ee,[α]20 D＝ -356.96(c 0.63,CHCl3).HPLC:Chiralcel AD-3column,254nm,30℃,n-Hexane/i-PrOH＝80/20,flow ＝0.8mL/min,retention time16.6min and 18.9min(major).
(+)-N-Allyl-N-{[2.2]paracyclophan-4-yl(o-tolyl)methyl}-4-methylbenzenesulfonamide(2b):51.9 mg,50％yield,7:1 dr,white solid,mp＝58-60℃,new compound,Rf＝0.60(hexanes/ethyl acetate
Figure BDA0002209966200000063
143.6,140.0,139.7,139.4,139.3,138.5,138.2,137.7,137.1,136.0,133.6,133.4,132.6,132.1,132.0, 131.1,130.9,130.4,130.3,129.4,128.6,127.9,125.6,115.7,61.1,47.4,35.5,35.4,34.8,34.1,21.6,20.0. HPLC:Chiracel AD-H column,254nm,30℃,n-Hexane/i-PrOH＝90/10,flow＝1.0mL/min,retention time 5.3min(major)and 7.0min.HRMS:Calculated for C34H35NaNO2S[M+Na]+544.2281,found: 544.2282.
(-)-N-Tosyl[2.2]paracyclophane-4-methanimine(1a):Kinetic resolutionfrom the addition of [2.2]paracyclophane aldimine 1a with 2-methylphenylboronic acid,29.6mg,38％yield,80.1％ee.HPLC: Chiralcel AD-3column,254nm,30℃,n-Hexane/i-PrOH＝80/20,flow＝0.8mL/min,retention time16.7min and 18.9min(major).
(+)-N-Allyl-N-{[2.2]paracyclophan-4-yl(m-tolyl)methyl}-4-methylbenzenesulfonamide(2c):50.7 mg,49％yield,12:1 dr,white solid,mp＝63-65℃,new compound,Rf＝0.60(hexanes/ethyl acetate
Figure BDA0002209966200000071
2H),2.12(s,3H).13C NMR(100MHz,CDCl3)δ143.4,140.7,140.0,139.6,139.2,139.0,138.7,137.9, 137.0,136.0,134.3,133.8,132.7,132.3,132.2,131.5,130.5,130.2,129.7,128.7,128.3,128.2,126.3, 117.3,64.6,48.6,35.5,35.4,34.6,34.6,21.7,21.4.HPLC:Chiracel IC column,254nm,30℃, n-Hexane/i-PrOH＝90/10,flow＝1.0mL/min,retention time 15.8min and 21.7min(major).HRMS: Calculated for C34H35NaNO2S[M+Na]+544.2281,found:544.2282.
(-)-N-Tosyl[2.2]paracyclophane-4-methanimine(1a):Kinetic resolutionfrom the addition of [2.2]paracyclophane aldimine 1a with 3-methylphenylboronic acid,21.7mg,28％yield,91.2％ee.HPLC: Chiralcel AD-3column,254nm,30℃,n-Hexane/i-PrOH＝80/20,flow＝0.8mL/min,retention time16.6min and 18.9min(major).
(+)-N-Allyl-N-{[2.2]paracyclophan-4-yl(p-tolyl)methyl}-4-methylbenzenesulfonamide(2d):55.2 mg,53％yield,13:1 dr,white solid,mp＝56-58℃,new compound,Rf＝0.55(hexanes/ethyl acetate
Figure BDA0002209966200000072
3H)2.28(s,3H).13C NMR(100MHz,CDCl3)δ143.4,140.0,139.5,139.3,139.0,138.7,137.9,137.7,137.2,136.0,134.2,133.7,132.6,132.3,132.2,131.5,130.5,129.7,129.3,129.0,128.2,117.2,64.4,48.5, 35.5,35.4,34.6,34.6,21.7,21.2.HPLC:Chiracel AD-Hcolumn,254nm,30℃,n-Hexane/i-PrOH＝ 90/10,flow＝1.0mL/min,retention time7.1min and 8.5min(major).HRMS:Calculated for C34H35NaNO2S[M+Na]+544.2281,found:544.2284.
(-)-N-Tosyl[2.2]paracyclophane-4-methanimine(1a):Kinetic resolutionfrom the addition of [2.2]paracyclophane aldimine 1a with 4-methylphenylboronic acid,27.8mg,36％yield,88.0％ee.HPLC: Chiralcel AD-3column,254nm,30℃,n-Hexane/i-PrOH＝80/20,flow＝0.8mL/min,retention time16.5min and 18.8min(major).
(+)-N-Allyl-N-{[2.2]paracyclophan-4-yl(4-fluorophenyl)methyl}-4-methylbenzenesulfonamide (2e):51.9mg,49％yield,16:1 dr,white solid,mp＝164-166℃,new compound,Rf＝0.45
Figure BDA0002209966200000073
(100MHz,CDCl3)δ162.4(d,JC-F＝247.7Hz),143.7,140.2,139.6,139.2,138.9,138.5,137.0(d,JC-F＝ 3.3Hz),136.8,136.1,133.9,133.7,132.7,132.5,132.3,131.4,131.1(d,JC-F＝8.1Hz),130.4,129.8, 128.1,117.4,115.3(d,JC-F＝21.3Hz),63.8,48.5,35.5,35.4,34.6,34.5,21.7.19F NMR(376MHz, CDCl3)δ-113.8.HPLC:Chiracel IB column,254nm,30℃,n-Hexane/i-PrOH＝80/20,flow＝1.0 mL/min,retention time 5.1min(major)and 5.5min.HRMS:Calculated for C33H32FNaNO2S[M+Na]+ 548.2030,found:548.2026.
(-)-N-Tosyl[2.2]paracyclophane-4-methanimine(1a):Kinetic resolutionfrom the addition of [2.2]paracyclophane aldimine 1a with 4-fluorophenylboronic acid,33.8mg,43％yield,99.2％ee.HPLC: Chiralcel AD-3column,254nm,30℃,n-Hexane/i-PrOH＝80/20,flow＝0.8mL/min,retention time16.4min and 18.6min(major).
(+)-N-Allyl-N-{[2.2]paracyclophan-4-yl(4-(trifluoromethyl)phenyl)methyl}-4-methylbenzenesulfo namide(2f):58.2mg,51％yield,>20:1 dr,whitesolid,mp＝108-110℃,new compound,Rf＝0.43
Figure BDA0002209966200000081
(100MHz,CDCl3)δ145.1,143.8,140.3,139.6,139.1,138.7,138.3,136.2,135.9,133.6,133.5,132.7, 132.7,132.4,131.4,130.4,130.2(q,JC-F＝32.4Hz),129.8,129.8,128.1,125.3(q,JC-F＝3.7Hz),124.0 (q,JC-F＝272.2Hz),117.5,64.0,48.6,35.4,35.4,34.6,34.5,21.7.19F NMR(376MHz,CDCl3)δ-62.5. HPLC:Chiracel IB column,254nm,30℃,n-Hexane/i-PrOH＝90/10,flow＝1.0mL/min,retention time 5.9min(major)and6.6min.HRMS:Calculated for C34H36F3N2O2S[M+NH4]+593.2444,found: 593.2462.
(-)-N-Tosyl[2.2]paracyclophane-4-methanimine(1a):Kinetic resolutionfrom the addition of [2.2]paracyclophane aldimine 1a with 4-trifluoromethylphenylboronic acid,28.8mg,37％yield,98.5％ ee.HPLC:ChiralcelAD-3 column,254nm,30℃,n-Hexane/i-PrOH＝80/20,flow＝0.8mL/min, retention time16.1min and 18.3min(major).
(+)-N-Allyl-N-{[2.2]paracyclophan-4-yl(4-chlorophenyl)methyl}-4-methylbenzenesulfonamide (2g):54.1mg,50％yield,>20:1 dr,white solid,mp＝139-141℃,new compound,Rf＝0.43
Figure BDA0002209966200000082
2.50(s,3H),2.44-2.33(m,1H).13C NMR(100MHz,CDCl3)δ143.7,140.2,139.6,139.5,139.1,138.8,138.4,136.4,136.1,133.9,133.8,133.6,132.7,132.6,132.3,131.4,130.7,130.4,129.8,128.6,128.1, 117.5,63.8,48.5,35.4,35.4,34.6,34.5,21.7.HPLC:Chiracel IBcolumn,254nm,30℃, n-Hexane/i-PrOH＝80/20,flow＝0.8mL/min,retention time6.4min(major)and 7.0min.HRMS: Calculated for C33H36ClN2O2S[M+NH4]+559.2181,found:559.2175(35Cl),561.2160(37Cl).
(-)-N-Tosyl[2.2]paracyclophane-4-methanimine(1a):Kinetic resolutionfrom the addition of [2.2]paracyclophane aldimine 1a with 4-chlorophenylboronic acid,31.2mg,40％yield,99.6％ee.HPLC: Chiralcel AD-3column,254nm,30℃,n-Hexane/i-PrOH＝80/20,flow＝0.8mL/min,retention time16.4min and 18.6min(major).
(+)-N-Allyl-N-{[2.2]paracyclophan-4-yl(3-fluorophenyl)methyl}-4-methylbenzenesulfonamide (2h):52.2mg,50％yield,>20:1 dr,white solid,mp＝134-136℃,new compound,Rf＝0.43
Figure BDA0002209966200000083
(m,2H),3.06-2.89(m,4H),2.57-2.46(m,1H),2.51(s,3H),2.46-2.37(m,1H).13C NMR(100MHz,CDCl3)δ162.7(d,JC-F＝246.7Hz),143.8,143.5(d,JC-F＝6.6Hz),140.2,139.6,139.2,138.7,138.5, 136.2,136.1,133.8,133.7,132.7,132.6,132.3,131.4,130.4,129.8(d,JC-F＝8.0Hz),129.8,128.1,125.1 (d,JC-F＝2.8Hz),117.4,116.4(d,JC-F＝22.1Hz),115.0(d,JC-F＝21.1Hz),64.0(d,JC-F＝1.6Hz),48.5, 35.4,35.4,34.6,34.5,21.7.19F NMR(376MHz,CDCl3)δ-112.6.HPLC:Chiracel IA column,254 nm, 30℃,n-Hexane/i-PrOH＝90/10,flow＝1.0mL/min,retention time 6.4min(major)and 7.2min.HRMS: Calculatedfor C33H32FNaNO2S[M+Na]+548.2030,found:548.2061.
(-)-N-Tosyl[2.2]paracyclophane-4-methanimine(1a):Kinetic resolutionfrom the addition of [2.2]paracyclophane aldimine 1a with 3-fluorophenylboronic acid,31.9mg,41％yield,97.4％ee.HPLC: Chiralcel AD-3column,254nm,30℃,n-Hexane/i-PrOH＝80/20,flow＝0.8mL/min,retention time16.2min and 18.3min(major).
(+)-N-Allyl-N-{[2.2]paracyclophan-4-yl(3-chlorophenyl)methyl}-4-methylbenzenesulfonamide (2i):54.4mg,50％yield,>20:1 dr,white solid,mp＝56-58℃,new compound,Rf＝0.41(hexanes/ethyl
Figure BDA0002209966200000091
MHz,CDCl3)δ143.9,142.9,140.2,139.6,139.1,138.6,138.4,136.2,136.1,134.3,133.8,133.7,132.7, 132.6,132.3,131.4,130.4,129.9,129.6,129.5,128.2,128.1,127.4,117.6,64.0,48.6,35.4,35.4,34.6, 34.5,21.7.HPLC:Chiracel IC column,254nm,30℃,n-Hexane/i-PrOH＝80/20,flow＝0.8mL/min, retention time 11.2min and 13.2(major)min.HRMS:Calculated for C33H36ClN2O2S[M+NH4]+ 559.2181,found:559.2175(35Cl),561.2155(37Cl).
(-)-N-Tosyl[2.2]paracyclophane-4-methanimine(1a):Kinetic resolutionfrom the addition of [2.2]paracyclophane aldimine 1a with 3-chlorophenylboronic acid,32.7mg,42％yield,98.4％ee.HPLC: Chiralcel AD-3column,254nm,30℃,n-Hexane/i-PrOH＝80/20,flow＝0.8mL/min,retention time16.3min and 18.5min(major).
(+)-N-Allyl-N-{[2.2]paracyclophan-4-yl(4-methoxyphenyl)methyl}-4-methylbenzenesulfonamide (2j):51.6mg,48％yield,13:1 dr,white solid,mp＝65-67℃,new compound,Rf＝0.25(hexanes/ethyl
Figure BDA0002209966200000092
2.49(s,3H).13C NMR(100MHz,CDCl3)δ159.2,143.4,140.0,139.5,139.3,139.0,138.7,137.4,136.0, 134.3,133.7,133.1,132.7,132.3,132.2,131.5,130.6,130.5,129.7,128.2,117.2,113.6,64.1,55.3,48.5, 35.5,35.4,34.6,34.6,21.7.HPLC:Chiracel AD-Hcolumn,254 nm,30℃,n-Hexane/i-PrOH＝80/20, flow＝1.0mL/min,retention time6.5min and 7.2min(major).HRMS:Calculated for C34H35KNO3S [M+K]+576.1969,found:576.1959.
(-)-N-Tosyl[2.2]paracyclophane-4-methanimine(1a):Kinetic resolutionfrom the addition of [2.2]paracyclophane aldimine 1a with 4-methoxyphenylboronic acid,35.1mg,45％yield,83.9％ee. HPLC:Chiralcel AD-3column,254nm,30℃,n-Hexane/i-PrOH＝80/20,flow＝0.8mL/min,retention time16.3min and 18.5min(major).
(+)-N-Allyl-N-{[2.2]paracyclophan-4-yl(2-naphthyl)methyl}-4-methylbenzenesulfonamide(2k): 54.0mg,48％yield,12:1 dr,white solid,mp＝66-68℃,new compound,Rf＝0.38(hexanes/ethyl
Figure BDA0002209966200000101
3.31-3.20(m,2H),3.12-2.96(m,3H),2.95-2.85(m,1H),2.54(s,3H),2.48-2.39(m,2H).13C NMR(100 MHz,CDCl3)δ143.5,140.1,139.6,139.2,138.9,138.7,138.2,136.9,136.1,134.1,133.8,133.0,132.9, 132.7,132.5,132.3,131.6,130.5,129.8,128.5,128.3,128.1,128.1,127.7,127.3,126.4,126.3,117.4, 64.7,48.7,35.5,35.4,34.6,21.7.HPLC:Chiracel AD-3 column,254nm,30℃,n-Hexane/i-PrOH＝ 90/10,flow＝1.0mL/min,retention time 9.0min and 13.8min(major).HRMS:Calculated for C37H35NaNO2S[M+Na]+580.2281,found:580.2279.
(-)-N-Tosyl[2.2]paracyclophane-4-methanimine(1a):Kinetic resolutionfrom the addition of [2.2]paracyclophane aldimine 1a with 2-naphthaleneboronic acid,31.9mg,41％yield,82.3％ee.HPLC: Chiralcel AD-3column,254nm,30℃,n-Hexane/i-PrOH＝80/20,flow＝0.8mL/min,retention time16.3min and 18.5min(major).
(+)-N-Allyl-N-{7-methyl[2.2]paracyclophan-4-yl(phenyl)methyl}-4-methylbenzenesulfonamide (2l):52.1mg,50％yield,8:1 dr,white solid,mp＝183-185℃,new compound,Rf＝0.50(hexanes/ethyl
Figure BDA0002209966200000102
1H),3.40-3.29(m,1H),3.19(t,J＝11.8Hz,1H),3.04-2.74(m,4H),2.50(s,3H),2.41-2.29(m,2H), 2.13(s,3H).13C NMR(100MHz,CDCl3)δ143.4,141.1,139.2,139.0,138.9,138.5,138.2,138.1,136.6, 134.7,134.2,133.9,132.6,131.3,130.8,129.7,129.4,128.4,128.2,128.0,127.8,117.2,64.5,48.4,34.3, 34.0,33.6,33.4,21.7,19.8.HPLC:Chiracel IB column,254nm,30℃,n-Hexane/i-PrOH＝80/20,flow ＝0.8mL/min,retention time 6.2min(major)and 7.1min.HRMS:Calculated for C34H35NaNO2S [M+Na]+544.2281,found:544.2262.
(-)-N-Tosyl-7-methyl[2.2]paracyclophane-4-methanimine(1b):Kineticresolution from the addition of[2.2]paracyclophane aldimine 1b withphenylboronic acid,32.2mg,40％yield,99.4％ee,[α]20 D＝ -400.28(c 0.65,CHCl3).HPLC:Chiralcel AD-H column,254nm,30℃,n-Hexane/i-PrOH＝80/20, flow＝0.8mL/min,retention time 16.8min and 20.5min(major).
(+)-N-Allyl-N-{7-methyl[2.2]paracyclophan-4-yl(4-chlorophenyl)methyl}-4-methylbenzenesulfon amide(2m):52.3mg,47％yield,17:1 dr,white solid,mp＝55-57℃,new compound,Rf＝0.50
Figure BDA0002209966200000103
(s,3H),2.41-2.27(m,2H),2.12(s,3H).13C NMR(100MHz,CDCl3)δ143.7,139.7,139.2,138.9,138.8, 138.6,138.2,138.0,136.9,134.1,133.9,133.8,133.8,132.6,131.4,130.7,130.7,129.8,128.6,128.1, 127.9,117.5,63.7,48.5,34.3,34.1,33.6,33.4,21.7,19.8.HPLC:Chiracel IB column,254nm,30℃, n-Hexane/i-PrOH＝80/20,flow＝0.8mL/min,retention time 6.4min(major)and 7.5min.HRMS: Calculated for C34H38ClN2O2S[M+NH4]+573.2337,found:573.2376(35Cl),575.2360(37Cl).
(-)-N-Tosyl-7-methyl[2.2]paracyclophane-4-methanimine(1b):Kineticresolution from the addition of[2.2]paracyclophane aldimine 1b with 4-chlorophenylboronic acid,33.8mg,42％yield,99.9％ee. HPLC:Chiralcel AD-Hcolumn,254nm,30℃,n-Hexane/i-PrOH＝80/20,flow＝0.8mL/min,retention time16.7min and 20.5min(major)。

Claims (6)

1.一种环芳烷类面手性化合物的拆分方法，其特征在于，所述拆分方法的催化剂是钯的手性膦氮配合物，具体反应式如下：
Figure FDA0003430443130000011
式中：
R为苯基、萘基或含有取代基的苯环，所述的取代基为卤素，烷氧基或C1-C20的烷基中的至少一种；
Ar为含有取代基的亚苯基或C6H3，所述的取代基为C1-C20的烷基中的至少一种；
Ts为对甲苯磺酰基；
所述催化剂的制备方法为：在氮气气氛保护下，将钯的金属前体、手性膦氮配体和丙酮混合，室温搅拌1h，除去丙酮，得到所述催化剂；
所述钯的金属前体为三氟醋酸钯；
所述手性膦氮配体为下述中的一种：
Figure FDA0003430443130000012
2.根据权利要求1所述的拆分方法，其特征在于，所述拆分方法的具体反应步骤为：
(1)在氮气保护下将催化剂、环芳烷亚胺、硼酸类化合物和有机溶剂混合，于40-80℃搅拌反应15h后，旋干溶剂，柱层析分离得到面手性环芳烷亚胺和产物前体；
(2)将产物前体用N,N-二甲基甲酰胺溶解，0℃下加入氢化钠，随后加入烯丙基溴，于室温搅拌2h后柱层析分离得到烯丙基保护的手性胺；
所述催化剂、环芳烷亚胺、硼酸类化合物和有机溶剂的用量比为0.05mmol:1mmol:1～1.5mmol:20ml；所述产物前体、氢化钠、烯丙基溴和N,N-二甲基甲酰胺的用量比为1mmol:3mmol:6mmol:10ml。
3.根据权利要求1所述的拆分方法，其特征在于，所述钯的金属前体和手性膦氮配体的比例为1:1。
4.根据权利要求2所述的拆分方法，其特征在于，所述有机溶剂为三氟乙醇、六氟异丙醇中的一种或两种混合。
5.根据权利要求2所述的拆分方法，其特征在于，所述方法的反应温度为60℃，反应时间为15h。
6.根据权利要求2所述的拆分方法，其特征在于：R为苯基，Ar为C6H3，所述的催化剂为钯的手性二茂铁骨架膦噁唑啉配体的配合物，有机溶剂为三氟乙醇，温度为60℃，反应时间15h，拆分后得到的面手性环芳烷亚胺对映体过量94.0％，烯丙基保护的手性胺对映体过量97.8％，拆分系数s值为115。
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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1299820A (zh) * 2000-12-19 2001-06-20 中国科学院上海有机化学研究所 一种具有多种手性中心的二茂铁噁唑啉膦配体合成方法及用途
CN1398865A (zh) * 2002-08-30 2003-02-26 中国科学院上海有机化学研究所 一种平面手性[2.2]对环芳烷噁唑啉膦配体、合成方法及用途
CN1884290A (zh) * 2006-07-11 2006-12-27 南开大学 新型螺环膦－噁唑啉配体及其在不对称催化氢化中的应用
CN101012241A (zh) * 2007-02-02 2007-08-08 中国科学院上海有机化学研究所 具有手性中心的苄位取代的噁唑啉膦配体、合成方法和应用
CN103772445A (zh) * 2014-02-25 2014-05-07 中国科学院上海有机化学研究所 一种1,1’-二茂铁全氟烷基膦氮配体、其制备方法及应用
CN105541925A (zh) * 2016-01-22 2016-05-04 中国人民解放军第四军医大学 二茂铁骨架n,n配体及其制备方法和应用

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE10004044A1 (de) * 2000-01-31 2001-08-02 Degussa Epoxidierungskatalysatoren auf Paracyclophanbasis
CN101003549B (zh) * 2007-01-19 2011-12-07 中国科学院上海有机化学研究所 一种具有平面手性环芳烷的膦化合物、合成方法及用途

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1299820A (zh) * 2000-12-19 2001-06-20 中国科学院上海有机化学研究所 一种具有多种手性中心的二茂铁噁唑啉膦配体合成方法及用途
CN1398865A (zh) * 2002-08-30 2003-02-26 中国科学院上海有机化学研究所 一种平面手性[2.2]对环芳烷噁唑啉膦配体、合成方法及用途
CN1884290A (zh) * 2006-07-11 2006-12-27 南开大学 新型螺环膦－噁唑啉配体及其在不对称催化氢化中的应用
CN101012241A (zh) * 2007-02-02 2007-08-08 中国科学院上海有机化学研究所 具有手性中心的苄位取代的噁唑啉膦配体、合成方法和应用
CN103772445A (zh) * 2014-02-25 2014-05-07 中国科学院上海有机化学研究所 一种1,1’-二茂铁全氟烷基膦氮配体、其制备方法及应用
CN105541925A (zh) * 2016-01-22 2016-05-04 中国人民解放军第四军医大学 二茂铁骨架n,n配体及其制备方法和应用

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
One-step Preparation of N-tosylimines Using Zeolite Catalysts;Kaiming Wang等;《Catalysis Letters》;20081231;第123卷(第1-2期);129-134页 *

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