CN109438261B - 一种催化不对称合成联萘酚胺的方法 - Google Patents

一种催化不对称合成联萘酚胺的方法 Download PDF

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CN109438261B
CN109438261B CN201811503178.2A CN201811503178A CN109438261B CN 109438261 B CN109438261 B CN 109438261B CN 201811503178 A CN201811503178 A CN 201811503178A CN 109438261 B CN109438261 B CN 109438261B
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谭斌
汪君
漆良文
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Southwest University of Science and Technology
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Abstract

本发明属于不对称合成领域，公开了一种催化不对称合成联萘酚胺的方法，包括以下步骤：以Ni(OTf)2和手性双噁唑啉配体为催化剂，式A化合物和式B化合物反应，得到式C化合物：
Figure DDA0001898733270000011
其中，R1选自烷基或苄基，R2选自烷基、烷氧基、苯基、氰基、卤素，R3选自烷基、烷氧基、乙酰氧基、苯基、羧酸酯基、卤素。本发明的方法催化效果好，底物适用范围广，催化效率高，操作简单，成本低廉，具有原子经济性高、环境友好等优点，具有非常良好的工业化应用前景。

Description

一种催化不对称合成联萘酚胺的方法
技术领域
本发明属于不对称合成领域，具体涉及一种催化不对称合成联萘酚胺的方法。
背景技术
阻转异构的联芳基骨架存在于各种天然产物、药物和生物活性分子。它们还是各种轴手性结构的对映体结构单元，可以作为对映选择性分离的固定相，液晶材料中的掺杂剂，手性分子开关，微孔可溶性聚合物和纳米管；它们最突出的作用是作为不对称合成中的手性配体或催化剂。
Figure BDA0001898733260000011
鉴于联芳基骨架的显著重要性，其高效制备方法得到了发展。其中，通过过渡金属催化的芳基-芳基偶联是最有效和最简单的方法，包括：(1)过渡金属催化的交叉偶联反应和芳基C-H活化；(2)由金属络合物通过自由基过程实现氧化性C-H/C-H交叉偶联。
虽然直接C-H官能化策略不需要对两个偶联底物进行预功能化处理，但由于旋转轴的温度耐受性与C-H活化所需的高温之间的矛盾，对映选择性构建联芳基化合物存在困难。另一方面，通过金属诱导的自由基过程进行的氧化芳基C-H/C-H交叉偶联受到化学选择性和底物范围的限制，因为两个偶联底物之间需要一定的氧化还原电位差。
除了通过金属诱导的自由基过程的氧化芳基C-H/C-H交叉偶联外，从BINOL合成联萘酚胺(NOBIN)对映体仍然需要冗长的合成路线。
因此，寻找光学纯联芳化合物的通用且稳定的催化方法具有重要的合成意义，将为对映选择性催化转化的出现奠定基础。
发明内容
本发明的目的是提供一种催化不对称合成联萘酚胺的方法。
本发明的另一目的是提供该方法涉及的中间体化合物。
为了解决现有技术存在的困难，将亲核芳基转为亲电性质然后进行手性芳基C-H/C-H交叉偶联可能是一种可行的途径。手性亲电催化剂与连接在芳烃上的共轭官能团的相互作用可以增强芳环的亲电性，同时施加空间位阻以抑制1,2-加成。
考虑到轴手性控制通常需要温和的催化条件，这使得氧化还原中性芳基-芳基交叉偶联的实现面临困难。之前有研究者通过芳烃极性翻转(API)策略实现了吲哚的有机催化不对称芳基化，表明偶氮基团是芳烃的理想活化和导向基团，而且，偶氮官能团可以为二芳基化合物NOBIN提供氮源。
为了获得新颖、简洁和实用的合成方法，发明人探索将偶氮-芳基底物用于氧化还原-中性交叉偶联，从而不对称构建NOBIN衍生物。
一种催化不对称合成联萘酚胺的方法，以Ni(OTf)2和手性双噁唑啉配体为催化剂，式A化合物和式B化合物反应，得到式C化合物：
Figure BDA0001898733260000021
其中，R1选自烷基或苄基，R2选自烷基、烷氧基、苯基、氰基、卤素，R3选自烷基、烷氧基、乙酰氧基、苯基、羧酸酯基、卤素。
需要强调的是，R2并非局限于偶氮萘环的C5、C6、C7、C8位取代，而是在C3、C4、C5、C6、C7、C8位取代均可；同理，R3并非局限于2-萘酚的C5、C6、C7、C8位取代，而是在C3、C4、C5、C6、C7、C8位取代均可。
在优选的方案中，R1选自甲基、乙基、丙基、丁基、苄基，R2选自甲基、乙基、丙基、丁基、甲氧基、乙氧基、丙氧基、苯基、氰基、卤素，R3选自甲基、乙基、丙基、丁基、甲氧基、乙氧基、丙氧基、乙酰氧基、苯基、羧酸甲酯基、羧酸乙酯基、卤素。
在更优选的方案中，所述R1选自甲基、乙基、异丙基、苄基，R2选自甲基、甲氧基、苯基、氰基、溴，R3选自甲基、甲氧基、乙酰氧基、苯基、羧酸甲酯基、溴。
在优选的方案中，所述手性双噁唑啉配体选自以下结构之一：
Figure BDA0001898733260000031
在优选的方案中，所述手性双噁唑啉配体的用量至少是2.5mol％。
在优选的方案中，所述反应中加入三乙胺、2，6-二甲基吡啶或NaHCO3作为添加剂。
在优选的方案中，所述添加剂的用量至少是20mol％。
在优选的方案中，所述反应的温度为0℃以上。
在优选的方案中，所述反应以二氯甲烷、氯仿或甲苯为溶剂，至少反应6h。
在优选的方案中，该方法还包括以下步骤：
化合物C经雷尼镍氢化得到联萘酚胺，
Figure BDA0001898733260000032
一种合成联萘酚胺的中间体，其结构为：
Figure BDA0001898733260000033
其中，R1选自烷基或苄基，R2选自烷基、烷氧基、苯基、氰基、卤素，R3选自烷基、烷氧基、乙酰氧基、苯基、羧酸酯基、卤素。
在优选的方案中，R1选自甲基、乙基、丙基、丁基、苄基，R2选自甲基、乙基、丙基、丁基、甲氧基、乙氧基、丙氧基、苯基、氰基、卤素，R3选自甲基、乙基、丙基、丁基、甲氧基、乙氧基、丙氧基、乙酰氧基、苯基、羧酸甲酯基、羧酸乙酯基、卤素。
在更优选的方案中，所述R1选自甲基、乙基、异丙基、苄基，R2选自甲基、甲氧基、苯基、氰基、溴，R3选自甲基、甲氧基、乙酰氧基、苯基、羧酸甲酯基、溴。
除非有相反陈述，在说明书和权利要求书中使用的术语具有下述含义。
术语“烷基”指饱和脂肪族烃基团，其为包含1至20个碳原子的直链或支链基团，优选含有1至12个碳原子的烷基，更优选含有1至6个碳原子的烷基。非限制性实例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基。
术语“烷氧基”指-O-(烷基)和-O-(非取代的环烷基)，其中烷基的定义如上所述。烷氧基的非限制性实例包括：甲氧基、乙氧基、丙氧基、丁氧基、环丙氧基、环丁氧基、环戊氧基、环己氧基。烷氧基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。
术语“苯基”指-Ph。
术语“氰基”指-CN。
术语“卤素”指氟、氯、溴或碘。
术语“乙酰氧基”指-AcO。
术语“羧酸酯基”指-C(O)O(烷基)，其中烷基如上所定义。
术语“Cy”指环己基。
本发明具有以下有益效果：
1、催化效果好，通过采用合理设计的两个芳基配体的氧化还原中性交叉偶联，以很高的产率和对映体纯度获得联萘酚胺中间体，成功地避免了传统氧化交叉偶联反应中普遍存在的同型偶合副产物问题，所得中间体经过镍催化加氢即可得到联萘酚胺及其衍生物，ee值没有下降。
2、底物适用范围广，为对映选择性合成联萘酚胺及其衍生物提供了一种新途径，为探索联萘酚胺类催化剂的应用奠定了基础。
3、催化效率高，催化剂用量小，可以在短时间内得到产物。
4、本发明操作简单，成本低廉，具有原子经济性高、环境友好等优点，具有非常良好的工业化应用前景。
具体实施方式
下面结合具体实施例对本发明做进一步的说明。
除非另有说明，化学品均购自商业化产品并且不用经进一步纯化。薄层色谱分析(TLC)使用60GF254硅胶板。硅胶柱层析使用青岛海洋硅胶(粒径0.040-0.063mm)。TLC显色采用UV光(254nm)。1H NMR和13C NMR使用Bruker 400MHz或者500MHz核磁共振仪表征，溶剂为氘代氯仿、氘代丙酮或氘代DMSO。化学位移的单位是ppm，耦合常数的单位是Hz。在1H NMR中，δ表示化学位移，s表示单峰，d表示双峰，t表示三重峰，q表示四重峰，p表示五重峰，m表示多重峰，br表示宽峰。在13C NMR中，δ表示化学位移。通过Agilent手性HPLC仪器和大赛璐CHIRALCEL、CHIRALPAK色谱柱测定对映体过量值。高分辨质谱(HRMS)使用Q-Exactive(Thermo Scientific)Inc质谱设备。
实施例1
底物的合成
偶氮萘衍生物1(化合物A)可以通过文献Qi,L.-W.；Mao,J.-H.；Zhang,J.；Tan,B.Nat.Chem.2018,10,58-64.披露的方法合成。
取代的2-萘酚2(化合物B)可以通过文献Chen,Y.-H.；Cheng,D.-J.；Zhang,J.；Wang,Y.；Liu,X.-Y.；Tan,B.J.Am.Chem.Soc.2015,137,15062-15065.披露的方法合成。
底物2a可以从商业化渠道购买。
实施例2
除L12外，本发明中使用的所有BOX(双恶唑啉)配体均为已知化合物(参考以下文献合成：Honma,M.；Sawada,T.；Fujisawa,Y.；Utsugi,M.；Watanabe,H.；Umino,A.；Matsumura,T.；Hagihara,T.；Takano,M.；Nakada,M.J.Am.Chem.Soc.2003,125,2860-2861.、Liu,F.-P.,L.；Zhong,J.-C.,Z.；Yun,Z.；Gao,Z.-D.；Bing,Q.-H.Chem.-Eur.J.2018,24,2059-2064.、Liu,Q.-J.；Wang,L.；Kang,Q.-K.；Zhang,X.P.；Tang,Y.Angew.Chem.Int.Ed.2016,55,9220-9223.、Zhang,Z.；Sheng,Z.；Yu,W.；Wu,G.；Zhang,R.；Chu,W.-D.；Zhang,Y.；Wang,J.Nat.Chem.2017,9,970-976.、Xiong,H.；Xu,H.；Liao,S.；Xie,Z.；Tang,Y.J.Am.Chem.Soc.2013,135,7851-7854.)。L1、L2、L3可以从商业化渠道购买。
L12的合成
Figure BDA0001898733260000051
在0℃、N2气氛下，向搅拌的L12-a(1.0g，3.03mmol)的无水THF(30mL)溶液中加入NaH(0.60g，5.0当量，60％在矿物油中的分散体)。然后将混合物在室温下搅拌2小时，并缓慢加入4-叔丁基苄基溴(1.72g，2.5当量)。然后将反应混合物加热至60℃。当TLC显示L12-a消失时，将混合物用冰浴冷却，用饱和NH4Cl水溶液淬灭，用DCM(3×40mL)萃取。将合并的有机相用盐水洗涤，用Na2SO4干燥并真空蒸发，得到残余物，将其通过硅胶快速色谱法纯化，用PE/EA洗脱，得到L12，为白色固体(1.66g，88％产率)。
1H NMR(400MHz,CDCl3)δ7.45(d,J＝7.4Hz,2H),7.37–7.24(m,6H),6.80(d,J＝8.2Hz,4H),6.69(d,J＝8.2Hz,4H),5.60(d,J＝7.9Hz,2H),5.31(t,J＝7.2Hz,2H),3.34(dd,J＝18.1,6.8Hz,2H),3.20(d,J＝14.2Hz,2H),3.10–2.97(m,4H),1.20(s,18H).13C NMR(100MHz,CDCl3)δ＝167.5(2C),148.8(2C),141.6(2C),139.9(2C),132.9(2C),129.9(4C),128.4(2C),127.5(2C),125.9(2C),125.1(2C),124.5(4C),83.4(2C),47.7,39.4(2C),37.8(2C),34.2(2C),31.3(6C),26.9(2C).HRMS(ESI)精确质量计算[M+H]C43H47N2O2,m/z:623.3632,实测值:623.3624。
实施例3
反应条件的优化
除非另有说明，在室温下，反应在2mL溶剂中以0.1mmol规模进行，1a：2a的比例为1：1.2。
Figure BDA0001898733260000061
Figure BDA0001898733260000062
Figure BDA0001898733260000071
a：使用4mL CHCl3；b：反应在15℃进行；c：反应在0℃进行。
化合物3a的表征数据：
Figure BDA0001898733260000073
1H NMR(400MHz,DMSO-d6)δ9.41(s,1H),9.16(s,1H),7.95–7.88(m,3H),7.84(d,J＝8.0Hz,1H),7.40(d,J＝8.9Hz,1H),7.32(d,J＝8.9Hz,1H),7.27(t,J＝7.3Hz,1H),7.21(q,J＝6.8Hz,2H),7.14(t,J＝7.4Hz,1H),6.99(d,J＝8.4Hz,1H),6.84(d,J＝8.4Hz,1H),6.10(s,1H),3.56(s,3H).13C NMR(100MHz,DMSO-d6)δ＝157.9,154.1,145.1,134.2,133.9,130.0,128.9,128.9,128.8,128.4,128.4,126.6,126.5,124.9,124.5,123.1,122.6,119.3,114.5,114.1,113.6,52.2.HRMS(ESI)精确质量计算[M+Na]C22H18N2O3Na,m/z:381.1210,实测值:381.1207.HPLC分析:HPLC DAICEL CHIRALCEL ID,正己烷/异丙醇＝80/20,1.0mL/min,λ＝240nm,tR(major)＝11.6min,tR(minor)＝10.1min。
通过实施例3的条件筛选，获得了通用合成方法：
将Ni(OTf)2(3.6mg，0.01mmol)，手性双噁唑啉配体L12(9.3mg，0.015mmol)和NaHCO3(4.2mg，0.05mmol)在CHCl3(4mL)中的混合物在室温、氮气气氛下搅拌过夜。然后将偶氮萘化合物1(0.1mmol，即化合物A)和2-萘酚衍生物2(0.12mmol，即化合物B)加入到反应管中。将混合物在室温下搅拌直至TLC显示偶氮化合物2消失。通过硅胶快速色谱法直接纯化反应混合物，得到产物3(即化合物C)，为白色固体。
Figure BDA0001898733260000072
用上述通用方法来拓展底物(实施例4～29)，具有不同取代基的底物均以良好的产率和ee值获得所需的联萘酚胺衍生物。
通过将HPLC图谱与市售(S)-NOBIN的图谱比较，确定3a的绝对构型为(S)。
实施例4
Figure BDA0001898733260000081
按照通用方法，99％产率，93％ee。
Figure BDA0001898733260000084
1H NMR(400MHz,DMSO-d6)δ9.42(s,1H),9.11(s,1H),7.98–7.85(m,3H),7.83(d,J＝8.0Hz,1H),7.38(d,J＝8.9Hz,1H),7.33–7.09(m,5H),6.98(d,J＝8.4Hz,1H),6.82(d,J＝8.4Hz,1H),6.07(s,1H),4.00(s,2H),1.16(s,3H).13C NMR(100MHz,DMSO-d6)δ＝157.4,154.0,145.1,134.2,133.9,130.0,128.9(2C),128.7,128.4,128.4,126.6,126.5,124.9,124.5,123.1,122.6,119.3,114.5,114.1,113.5,60.8,15.0.HRMS(ESI)精确质量计算[M+Na]C23H20N2O3Na,m/z:395.1366,实测值:395.1363.HPLC分析:HPLC DAICEL CHIRALCEL AD-3,正己烷/异丙醇＝80/20,1.0mL/min,λ＝240nm,tR(minor)＝9.1min,tR(major)＝11.8min。
实施例5
Figure BDA0001898733260000082
按照通用方法，99％产率，93％ee。
Figure BDA0001898733260000085
1H NMR(400MHz,DMSO-d6)δ9.40(s,1H),9.05(s,1H),7.97–7.86(m,3H),7.83(d,J＝8.0Hz,1H),7.39(d,J＝8.9Hz,1H),7.32–7.24(m,2H),7.24–7.10(m,3H),6.99(d,J＝8.4Hz,1H),6.83(d,J＝8.4Hz,1H),6.05(s,1H),4.83–4.62(m,1H),1.17(s,6H).13C NMR(100MHz,DMSO-d6)δ＝157.0,154.0,145.1,134.2,133.9,130.0,128.9,128.9,128.7,128.4,128.4,126.6,126.5,124.9,124.4,123.1,122.6,119.3,114.4,114.1,113.5,68.2,22.4(2C).HRMS(ESI)精确质量计算[M+Na]C24H22N2O3Na,m/z:409.1523,实测值:409.1519.HPLC分析:HPLC DAICEL CHIRALCEL AS-3,正己烷/异丙醇＝80/20,1.0mL/min,λ＝240nm,tR(major)＝11.0min,tR(minor)＝8.1min。
实施例6
Figure BDA0001898733260000083
按照通用方法，98％产率，93％ee。
Figure BDA0001898733260000086
1H NMR(400MHz,DMSO-d6)δ9.42(s,1H),9.29(s,1H),7.94–7.83(m,4H),7.40–7.13(m,11H),6.98(d,J＝7.1Hz,1H),6.83(d,J＝8.4Hz,1H),6.18(s,1H),5.06(s,2H).13C NMR(100MHz,DMSO-d6)δ＝157.3,154.0,145.0,137.3,134.2,133.9,130.0,128.9(2C),128.8(2C),128.7,128.4,128.4,128.1(3C),126.6,126.5,124.9,124.5,123.1,122.6,119.3,114.4,114.1,113.5,66.2.HRMS(ESI)精确质量计算[M+Na]C28H22N2O3Na,m/z:457.1523,实测值:457.1519.HPLC分析:HPLC DAICEL CHIRALCEL AD-3,正己烷/异丙醇＝80/20,0.5mL/min,λ＝240nm,tR(major)＝29.0min,tR(minor)＝27.0min。
实施例7
Figure BDA0001898733260000091
按照通用方法，98％产率，91％ee。
Figure BDA0001898733260000093
1H NMR(500MHz,DMSO-d6)δ9.38(s,1H),9.14(s,1H),7.92(d,J＝8.9Hz,1H),7.88(d,J＝7.9Hz,1H),7.82(d,J＝9.0Hz,1H),7.61(s,1H),7.38(d,J＝8.9Hz,1H),7.28–7.25(m,2H),7.20(t,J＝7.4Hz,1H),7.00(dd,J＝8.7,1.6Hz,1H),6.97(d,J＝8.4Hz,1H),6.75(d,J＝8.6Hz,1H),5.99(d,J＝1.5Hz,1H),3.56(s,3H),2.38(s,3H).13C NMR(125MHz,DMSO-d6)δ＝157.9,154.0,144.3,134.2,132.1,131.5,130.0,129.0,128.9,128.7,128.4,128.2,127.2,126.5,125.0,124.5,123.1,119.3,114.6,114.2,113.7,52.2,21.4.HRMS(ESI)精确质量计算[M+Na]C23H20N2O3Na,m/z:395.1366,实测值:395.1364.HPLC分析:HPLC DAICEL CHIRALCEL ID,正己烷/异丙醇＝80/20,1.0mL/min,λ＝240nm,tR(major)＝12.1min,tR(minor)＝9.7min。
实施例8
Figure BDA0001898733260000092
按照通用方法，98％产率，91％ee。
Figure BDA0001898733260000094
1H NMR(500MHz,DMSO-d6)δ9.38(s,1H),9.14(s,1H),7.93(d,J＝8.9Hz,1H),7.88(d,J＝8.0Hz,1H),7.83(d,J＝9.0Hz,1H),7.77(d,J＝8.9Hz,1H),7.39(d,J＝8.9Hz,1H),7.27(ddd,J＝8.1,6.8,1.2Hz,1H),7.22(t,J＝7.4Hz,1H),7.14(d,J＝8.9Hz,1H),7.03(d,J＝8.4Hz,1H),6.93(dd,J＝8.9,2.5Hz,1H),6.17(d,J＝2.5Hz,1H),6.04(s,1H),3.56(s,3H),3.41(s,3H).13C NMR(125MHz,DMSO-d6)δ＝157.9,157.8,154.0,145.5,135.2,134.0,130.0,130.0,128.9,128.7,128.4,126.6,124.9,124.3,123.1,119.3,114.2,113.9,112.6,112.1,104.2,55.0,52.2.HRMS(ESI)精确质量计算[M+Na]C23H20N2O4Na,m/z:411.1315,实测值:411.1316.HPLC分析:HPLC DAICELCHIRALCEL IC,正己烷/异丙醇＝80/20,0.5mL/min,λ＝240nm,tR(major)＝15.8min,tR(minor)＝14.2min。
实施例9
Figure BDA0001898733260000101
按照通用方法，96％产率，91％ee。
Figure BDA0001898733260000103
1H NMR(500MHz,DMSO-d6)δ9.45(s,1H),9.18(s,1H),8.16(d,J＝1.8Hz,1H),8.02(d,J＝9.0Hz,1H),7.95(d,J＝8.9Hz,1H),7.90(d,J＝8.1Hz,1H),7.73(dd,J＝8.2,1.0Hz,2H),7.52(dd,J＝8.9,2.0Hz,1H),7.46(dd,J＝10.7,4.9Hz,2H),7.41(d,J＝8.9Hz,1H),7.38–7.31(m,2H),7.28(ddd,J＝8.1,6.8,1.2Hz,1H),7.23(t,J＝7.4Hz,1H),7.05(d,J＝8.4Hz,1H),6.92(d,J＝8.8Hz,1H),6.19(s,1H),3.58(s,3H).13CNMR(125MHz,DMSO-d6)δ＝157.9,154.1,145.3,140.8,134.3,134.2,133.2,130.1,129.4,129.4(2C),129.0,128.9,128.4,127.4,127.0(2C),126.7,125.9,125.7,125.2,124.9,123.1,119.3,114.9,114.0,113.3,52.3.HRMS(ESI)精确质量计算[M+Na]C28H22N2O3Na,m/z:457.1523,实测值:459.1523.HPLC分析:HPLC DAICEL CHIRALCEL IA,正己烷/异丙醇＝80/20,1.0mL/min,λ＝254nm,tR(major)＝18.7min,tR(minor)＝9.7min。
实施例10
Figure BDA0001898733260000102
按照通用方法(反应温度为15℃)，99％产率，91％ee。
Figure BDA0001898733260000104
1H NMR(400MHz,DMSO-d6)δ9.50(s,1H),9.16(s,1H),8.10(d,J＝1.8Hz,1H),7.96–7.84(m,3H),7.39(d,J＝8.9Hz,1H),7.35(d,J＝9.0Hz,1H),7.28(dd,J＝11.6,4.5Hz,2H),7.22(t,J＝7.4Hz,1H),6.97(d,J＝8.3Hz,1H),6.77(d,J＝9.1Hz,1H),6.26(s,1H),3.56(s,3H).13C NMR(100MHz,DMSO-d6)δ＝157.8,154.1,145.7,134.1,132.5,130.2,130.1,129.8,129.4,128.9,128.5,128.2,126.8,126.7,124.7,123.1,119.3,115.6,115.3,113.5,113.4,52.3.HRMS(ESI)精确质量计算[M+Na]C22H17N2O3BrNa,m/z:459.0315,实测值:459.0316.HPLC分析:HPLC DAICEL CHIRALCEL IB,正己烷/异丙醇＝80/20,1.0mL/min,λ＝240nm,tR(minor)＝8.3min,tR(major)＝10.7min。
实施例11
Figure BDA0001898733260000111
按照通用方法(反应温度为15℃)，95％产率，89％ee。
Figure BDA0001898733260000114
1H NMR(400MHz,DMSO-d6)δ9.55(s,1H),9.21(s,1H),8.44(d,J＝0.7Hz,1H),8.05(d,J＝9.1Hz,1H),7.95(d,J＝8.9Hz,1H),7.89(d,J＝7.9Hz,1H),7.44–7.38(m,3H),7.28(t,J＝7.2Hz,1H),7.22(t,J＝7.4Hz,1H),6.96(d,J＝8.3Hz,1H),6.90(d,J＝8.8Hz,1H),6.72(s,1H),3.57(s,3H).13C NMR(100MHz,DMSO-d6)δ＝157.7,154.3,148.1,135.6,134.9,134.0,130.4,130.0,129.0,128.5,127.2,127.0,126.8,125.4,124.5,123.2,120.4,119.3,115.7,113.0,112.8,104.0,52.3.HRMS(ESI)精确质量计算[M+Na]C23H17N3O3Na,m/z:406.1162,实测值:406.1164.HPLC分析:HPLC DAICELCHIRALCEL AD-3,正己烷/异丙醇＝80/20,1.0mL/min,λ＝254nm,tR(minor)＝10.4min,tR(major)＝22.8min。
实施例12
Figure BDA0001898733260000112
按照通用方法，99％产率，92％ee。
Figure BDA0001898733260000115
1H NMR(400MHz,DMSO-d6)δ9.31(s,1H),9.16(s,1H),7.92–7.82(m,3H),7.78(d,J＝8.3Hz,1H),7.31(d,J＝8.8Hz,2H),7.22(t,J＝7.2Hz,1H),7.16(t,J＝7.4Hz,1H),7.11(d,J＝8.3Hz,1H),6.86(d,J＝8.4Hz,1H),6.81(s,1H),6.02(s,1H),3.57(s,3H),2.18(s,3H).13C NMR(100MHz,DMSO-d6)δ＝157.9,154.1,144.9,135.7,134.3,133.9,129.8,128.9,128.8,128.4,128.4,127.2,126.5,125.3,124.5,123.7,122.6,118.3,114.5,113.8,113.5,52.3,22.1.HRMS(ESI)精确质量计算[M+Na]C23H20N2O3Na,m/z:395.1366,实测值:395.1365.HPLC分析:HPLC DAICEL CHIRALCEL AS-3,正己烷/异丙醇＝80/20,1.0mL/min,λ＝240nm,tR(minor)＝10.7min,tR(major)＝13.3min。
实施例13
Figure BDA0001898733260000113
按照通用方法，99％产率，93％ee。
Figure BDA0001898733260000116
1H NMR(500MHz,DMSO-d6)δ9.38(s,1H),9.14(s,1H),7.92(d,J＝8.9Hz,1H),7.88(d,J＝7.9Hz,1H),7.82(d,J＝9.0Hz,1H),7.61(s,1H),7.38(d,J＝8.9Hz,1H),7.28–7.25(m,2H),7.20(t,J＝7.4Hz,1H),7.01–6.96(m,2H),6.75(d,J＝8.6Hz,1H),5.99(d,J＝1.5Hz,1H),3.56(s,3H),2.38(s,3H).13C NMR(125MHz,DMSO-d6)δ＝157.9,154.0,144.3,134.2,132.1,131.5,130.0,129.0,128.9,128.7,128.4,128.2,127.2,126.5,125.0,124.5,123.1,119.3,114.6,114.2,113.7,52.2,21.4.HRMS(ESI)精确质量计算[M+Na]C23H20N2O3Na,m/z:395.1366,实测值:395.1364.HPLC分析:HPLC DAICELCHIRALCEL ID,正己烷/异丙醇＝80/20,1.0mL/min,λ＝240nm,tR(minor)＝9.8min,tR(major)＝10.7min。
实施例14
Figure BDA0001898733260000121
按照通用方法，99％产率，92％ee。
Figure BDA0001898733260000123
1H NMR(500MHz,DMSO-d6)δ9.35(s,1H),9.17(s,1H),7.91(d,J＝9.0Hz,1H),7.85–7.79(m,3H),7.31(d,J＝8.9Hz,1H),7.23–7.20(m,2H),7.17(ddd,J＝8.2,6.8,1.4Hz,1H),6.95(d,J＝7.7Hz,1H),6.91(d,J＝8.4Hz,1H),6.45(s,1H),6.05(s,1H),3.58(s,3H),3.49(s,3H).13C NMR(125MHz,DMSO-d6)δ＝158.2,157.9,154.6,144.8,135.4,133.7,130.0,129.8,128.9,128.8,128.4,126.4,124.5,124.2,122.6,116.6,115.0,114.3,113.6,113.3,104.1,55.0,52.3.HRMS(ESI)精确质量计算[M+Na]C23H20N2O4Na,m/z:411.1315,实测值:411.1312.HPLC分析:HPLC DAICEL CHIRALCEL AD-3,正己烷/异丙醇＝80/20,1.0mL/min,λ＝240nm,tR(major)＝16.4min,tR(minor)＝18.9min。
实施例15
Figure BDA0001898733260000122
按照通用方法，99％产率，92％ee。
Figure BDA0001898733260000124
1H NMR(500MHz,DMSO-d6)δ9.17(s,1H),9.14(s,1H),7.91(d,J＝9.0Hz,1H),7.85–7.82(m,2H),7.36–7.29(m,3H),7.22(ddd,J＝8.0,6.8,1.2Hz,1H),7.16(ddd,J＝8.2,6.8,1.3Hz,1H),6.89(s,2H),6.84(d,J＝8.5Hz,1H),6.05(s,1H),3.84(s,3H),3.56(s,3H).13C NMR(125MHz,DMSO-d6)δ＝157.9,155.6,152.3,145.0,133.9,129.8,129.3,128.9,128.8,128.7,128.3,126.5,126.5,124.5,122.7,119.6,118.9,114.5,114.4,113.8,107.1,55.6,52.3.HRMS(ESI)精确质量计算[M+Na]C23H20N2O4Na,m/z:411.1315,实测值:411.1314.HPLC分析:HPLC DAICEL CHIRALCEL AD-3,正己烷/异丙醇＝80/20,1.0mL/min,λ＝240nm,tR(major)＝19.5min,tR(minor)＝16.8min。
实施例16
Figure BDA0001898733260000131
按照通用方法，99％产率，91％ee。
Figure BDA0001898733260000133
1H NMR(500MHz,DMSO-d6)δ9.50(s,1H),9.18(s,1H),8.21(d,J＝1.8Hz,1H),8.03(d,J＝8.9Hz,1H),7.94(d,J＝9.0Hz,1H),7.85(d,J＝7.7Hz,1H),7.75(dd,J＝8.3,1.1Hz,2H),7.57(d,J＝8.6Hz,1H),7.51–7.41(m,3H),7.39–7.30(m,2H),7.23(ddd,J＝8.0,6.8,1.2Hz,1H),7.17(ddd,J＝8.2,6.7,1.3Hz,1H),7.09(d,J＝8.8Hz,1H),6.89(d,J＝8.4Hz,1H),6.20(s,1H),3.57(s,3H).13C NMR(125MHz,DMSO-d6)δ＝157.9,154.3,145.1,140.8,134.8,133.9,133.5,130.5,129.4(2C),129.2,129.0,128.7,128.4,127.5,127.1(2C),126.6,126.0,125.7(2C),124.5,122.6,119.7,114.5,114.1,113.4,52.3.HRMS(ESI)精确质量计算[M+Na]C28H22N2O3Na,m/z:457.1523,实测值:457.1518.HPLC分析:HPLC DAICEL CHIRALCEL AD-3,正己烷/异丙醇＝80/20,1.0mL/min,λ＝240nm,tR(minor)＝11.1min,tR(major)＝12.2min。
实施例17
Figure BDA0001898733260000132
按照通用方法，98％产率，91％ee。
Figure BDA0001898733260000134
1H NMR(500MHz,DMSO-d6)δ9.48(s,1H),9.20(s,1H),7.98(t,J＝8.6Hz,2H),7.93(d,J＝9.0Hz,1H),7.83(d,J＝7.8Hz,1H),7.57(dd,J＝8.4,1.1Hz,1H),7.50(s,2H),7.41(d,J＝8.9Hz,1H),7.35–7.31(m,3H),7.26–7.23(m,2H),7.19(t,J＝7.0Hz,1H),7.15(t,J＝7.4Hz,1H),6.88(d,J＝8.0Hz,1H),6.23(s,1H),3.59(s,3H).13C NMR(125MHz,DMSO-d6)δ＝157.9,154.6,145.1,141.3,138.5,134.5,133.9,129.8,129.2(3C),129.2,129.0,128.6,128.4,128.2,127.6,127.4(2C),126.5,124.4,122.8,122.6,122.5,119.4,114.5,113.3,52.2.HRMS(ESI)精确质量计算[M+Na]C28H22N2O3Na,m/z:457.1523,实测值:457.1521.HPLC分析:HPLC DAICEL CHIRALCEL IC,正己烷/异丙醇＝80/20,0.5mL/min,λ＝240nm,tR(major)＝14.5min,tR(minor)＝13.1min。
实施例18
Figure BDA0001898733260000141
按照通用方法，94％产率，92％ee。
Figure BDA0001898733260000144
1H NMR(400MHz,DMSO-d6)δ9.67(s,1H),9.14(s,1H),7.94(t,J＝9.9Hz,2H),7.86(t,J＝7.6Hz,2H),7.42(d,J＝8.9Hz,1H),7.38(dd,J＝8.7,1.7Hz,1H),7.31(d,J＝9.0Hz,1H),7.23(t,J＝7.1Hz,1H),7.18(t,J＝7.5Hz,1H),7.10(d,J＝1.0Hz,1H),6.80(d,J＝8.3Hz,1H),6.30(s,1H),3.57(s,3H).13C NMR(100MHz,DMSO-d6)δ＝157.8,155.2,145.3,135.7,133.8,130.8,130.2,129.2,128.6,128.5,127.5,126.7,126.4,125.9,124.1,122.7,120.5,119.9,114.5,113.6,112.4,52.3.HRMS(ESI)精确质量计算[M+Na]C22H17N2O3BrNa,m/z:459.0315,实测值:459.0312.HPLC分析:HPLC DAICELCHIRALCEL AS-3,正己烷/异丙醇＝80/20,1.0mL/min,λ＝240nm,tR(major)＝14.6min,tR(minor)＝18.9min。
实施例19
Figure BDA0001898733260000142
按照通用方法(温度为15℃)，99％产率，91％ee。
Figure BDA0001898733260000145
1H NMR(500MHz,DMSO-d6)δ9.60(s,1H),9.14(s,1H),8.16(d,J＝2.1Hz,1H),7.92(t,J＝9.1Hz,2H),7.83(d,J＝7.6Hz,1H),7.42(d,J＝9.0Hz,1H),7.33–7.29(m,2H),7.23–7.20(m,1H),7.16(ddd,J＝8.1,6.8,1.3Hz,1H),6.92(d,J＝9.0Hz,1H),6.80(d,J＝8.4Hz,1H),6.23(s,1H),3.56(s,3H).13C NMR(125MHz,DMSO-d6)δ＝157.9,154.7,145.2,133.8,132.9,130.2,130.1,129.4,129.3,129.1,128.6,128.4,127.3,126.6,124.2,122.6,120.5,116.0,114.5(2C),112.6,52.2.HRMS(ESI)精确质量计算[M+Na]C22H17N2O3BrNa,m/z:459.0315,实测值:459.0314.HPLC分析:HPLC DAICELCHIRALCEL AD-3,正己烷/异丙醇＝80/20,1.0mL/min,λ＝240nm,tR(minor)＝8.9min,tR(major)＝10.6min,ee＝92％。
实施例20
Figure BDA0001898733260000143
按照通用方法，98％产率，91％ee。
Figure BDA0001898733260000153
1H NMR(500MHz,DMSO-d6)δ9.55(s,1H),9.13(s,1H),7.97–7.90(m,3H),7.83(d,J＝7.6Hz,1H),7.37(d,J＝8.9Hz,1H),7.29(d,J＝9.0Hz,1H),7.22(ddd,J＝8.0,6.8,1.2Hz,1H),7.17(ddd,J＝8.2,6.8,1.4Hz,1H),7.09(dd,J＝8.8,2.3Hz,1H),6.83(d,J＝8.4Hz,1H),6.59(d,J＝2.3Hz,1H),6.19(s,1H),3.56(s,3H),2.13(s,3H).13C NMR(125MHz,DMSO-d6)δ＝169.7,157.9,154.8,149.4,145.1,135.0,133.7,130.0,129.8,129.1,128.6,128.4,126.8,126.6,124.3,122.7,119.0,118.8,115.3,114.5,114.0,112.9,52.2,21.2.HRMS(ESI)精确质量计算[M+Na]C24H20N2O5Na,m/z:439.1264,实测值:439.1262.HPLC分析:HPLC DAICEL CHIRALCEL IC,正己烷/异丙醇＝80/20,0.5mL/min,λ＝240nm,tR(major)＝19.8min,tR(minor)＝17.3min。
实施例21
Figure BDA0001898733260000151
按照通用方法，98％产率，85％ee。
Figure BDA0001898733260000154
1H NMR(500MHz,DMSO-d6)δ9.63(s,1H),9.11(s,1H),8.73(d,J＝9.4Hz,1H),7.91(d,J＝9.0Hz,1H),7.86–7.82(m,2H),7.49(d,J＝9.4Hz,1H),7.30–7.26(m,2H),7.22–7.18(m,2H),7.15–7.12(m,1H),6.76(dd,J＝8.3,1.1Hz,1H),6.26(s,1H),3.95(s,3H),3.54(s,3H).13C NMR(125MHz,DMSO-d6)δ167.9,157.4,154.0,144.8,134.5,133.5,129.6,128.7,128.2,128.0,127.4,126.9,126.3,126.2,125.8,125.1,123.8,122.2,120.4,114.5,114.1,112.5,52.3,51.8.HRMS(ESI)精确质量计算[M+Na]C24H20N2O5Na,m/z:439.1264,实测值:439.1264.HPLC分析:HPLC DAICEL CHIRALCEL AD-3,正己烷/异丙醇＝80/20,1.0mL/min,λ＝220nm,tR(minor)＝20.9min,tR(major)＝24.7min。
实施例22
Figure BDA0001898733260000152
按照通用方法，99％产率，91％ee。
Figure BDA0001898733260000155
1H NMR(400MHz,DMSO-d6)δ9.24(s,1H),9.14(s,1H),7.81(dd,J＝8.9,4.2Hz,2H),7.65(s,1H),7.60(s,1H),7.34(d,J＝8.9Hz,1H),7.26(d,J＝8.9Hz,1H),7.05(d,J＝8.6Hz,1H),7.00(d,J＝8.7Hz,1H),6.88(d,J＝8.6Hz,1H),6.74(d,J＝8.6Hz,1H),5.93(s,1H),3.55(s,3H),2.39(s,3H),2.38(s,3H).13C NMR(100MHz,DMSO-d6)δ＝157.9,153.3,144.3,132.4,132.1,132.0,131.6,129.3,129.0,129.0,128.7,128.6,128.2,127.3,127.2,125.0,124.6,119.2,114.6,114.1,114.0,52.2,21.4(2C).HRMS(ESI)精确质量计算[M+Na]C24H22N2O3Na,m/z:409.1523,实测值:409.1520.HPLC分析:HPLC DAICEL CHIRALCEL IB,正己烷/异丙醇＝80/20,1.0mL/min,λ＝240nm,tR(minor)＝8.2min,tR(major)＝11.5min。
实施例23
Figure BDA0001898733260000161
按照通用方法，99％产率，87％ee。
Figure BDA0001898733260000163
1H NMR(400MHz,DMSO-d6)δ9.67(s,1H),9.13(s,1H),8.15(d,J＝2.0Hz,1H),8.09(d,J＝2.0Hz,1H),7.92(t,J＝9.2Hz,2H),7.42(d,J＝9.0Hz,1H),7.34(d,J＝9.0Hz,2H),7.29(dd,J＝9.1,2.1Hz,1H),6.91(d,J＝9.0Hz,1H),6.75(d,J＝9.1Hz,1H),6.39(s,1H),3.56(s,3H).13C NMR(100MHz,DMSO-d6)δ＝157.8,154.7,145.8,132.8,132.5,130.2,130.2,130.1,129.8,129.5(3C),128.4,127.1,126.5,120.5,116.0,115.6,115.3,113.9,112.6,52.3.HRMS(ESI)精确质量计算[M-H]C22H15N2O3Br2,m/z:514.9434,实测值:514.9422.HPLC分析:HPLC DAICEL CHIRALCEL AD-3,正己烷/异丙醇＝80/20,1.0mL/min,λ＝254nm,tR(minor)＝9.1min,tR(major)＝12.5min。
实施例24
Figure BDA0001898733260000162
按照通用方法，91％产率，90％ee。
Figure BDA0001898733260000164
1H NMR(400MHz,DMSO-d6)δ9.54(s,1H),9.20(s,1H),8.22(s,1H),8.17(s,1H),8.04(t,J＝8.2Hz,2H),7.75(t,J＝7.1Hz,4H),7.59(d,J＝8.7Hz,1H),7.54(dd,J＝8.9,1.5Hz,1H),7.49–7.44(m,5H),7.38–7.31(m,3H),7.13(d,J＝8.8Hz,1H),6.97(d,J＝8.8Hz,1H),6.28(s,1H),3.57(s,3H).13C NMR(100MHz,DMSO-d6)δ＝157.9,154.4,145.4,140.8,140.8,134.9,134.3,133.6,133.3,130.6,129.5,129.4(2C),129.4(2C),129.2,129.0,127.5,127.4,127.1(2C),127.0(2C),126.0,126.0,125.8(2C),125.7,125.2,119.8,115.0,114.0,113.1,52.3.HRMS(ESI)精确质量计算[M+Na]C34H26N2O3Na,m/z:533.1836,实测值:533.1833.HPLC分析:HPLC DAICEL CHIRALCEL AD-3,正己烷/异丙醇＝70/30,1.0mL/min,λ＝300nm,tR(major)＝23.6min,tR(minor)＝11.2min,ee＝90％。
实施例25
Figure BDA0001898733260000171
按照通用方法，98％产率，91％ee。
Figure BDA0001898733260000174
1H NMR(400MHz,DMSO-d6)δ9.32(s,1H),9.14(s,1H),7.89–7.71(m,4H),7.21(d,J＝8.8Hz,1H),7.13(d,J＝8.9Hz,1H),6.96–6.91(m,2H),6.47(s,1H),6.24(d,J＝2.5Hz,1H),5.99(s,1H),3.57(s,3H),3.51(s,3H),3.45(s,3H).13C NMR(100MHz,DMSO-d6)δ＝158.2,157.9,157.9,154.6,145.3,135.3,135.0,130.1,130.0,129.8,128.7,124.3,124.2,116.6,114.9,113.9,113.4,112.7,111.9,104.2,104.1,55.1,55.0,52.2.HRMS(ESI)精确质量计算[M+Na]C24H22N2O5Na,m/z:441.1421,实测值:441.1415.HPLC分析:HPLC DAICEL CHIRALCEL IB,正己烷/异丙醇＝80/20,1.0mL/min,λ＝254nm,tR(major)＝9.0min,tR(minor)＝10.7min。
实施例26
Figure BDA0001898733260000172
按照通用方法(反应温度为15℃)，94％产率，91％ee。
Figure BDA0001898733260000175
1H NMR(400MHz,DMSO-d6)δ9.28(s,1H),9.13(s,1H),7.87–7.76(m,3H),7.60(s,1H),7.28(dd,J＝12.3,8.9Hz,2H),7.10(d,J＝8.3Hz,1H),7.01(dd,J＝8.7,1.0Hz,1H),6.79–6.76(m,2H),5.91(s,1H),3.56(s,3H),2.38(s,3H),2.18(s,3H).13C NMR(100MHz,DMSO-d6)δ＝157.9,154.0,144.2,135.7,134.3,132.1,131.6,129.7,129.0,128.7,128.4,128.2,127.3,127.1,125.3,124.6,123.7,118.3,114.6,113.9,113.6,52.3,22.1,21.4.HRMS(ESI)精确质量计算[M+Na]C24H22N2O3Na,m/z:409.1523,实测值:409.1520.HPLC分析:HPLC DAICEL CHIRALCEL AD-3,正己烷/异丙醇＝80/20,0.5mL/min,λ＝240nm,tR(major)＝25.5min,tR(minor)＝13.6min。
实施例27
Figure BDA0001898733260000173
按照通用方法(反应温度为15℃)，96％产率，90％ee。
Figure BDA0001898733260000176
1H NMR(400MHz,DMSO-d6)δ9.73(s,1H),9.13(s,1H),8.10(d,J＝1.7Hz,1H),7.96(d,J＝9.0Hz,1H),7.92(d,J＝9.1Hz,1H),7.86(d,J＝8.7Hz,1H),7.41–7.37(m,2H),7.33(d,J＝9.0Hz,1H),7.30(dd,J＝9.1,1.9Hz,1H),7.07(s,1H),6.73(d,J＝9.0Hz,1H),6.46(s,1H),3.56(s,3H).13C NMR(100MHz,DMSO-d6)δ＝157.8,155.3,145.9,135.6,132.4,130.9,130.4,130.2,129.7,129.6,128.5,127.5,126.4,126.2,126.0,120.7,119.9,115.6,115.3,113.0,112.3,52.3.HRMS(ESI)精确质量计算[M+Na]C22H16N2O3Br2Na,m/z:536.9420,实测值:536.9419.HPLC分析:HPLC DAICEL CHIRALCELAD-3,正己烷/异丙醇＝80/20,0.5mL/min,λ＝254nm,tR(major)＝16.8min,tR(minor)＝15.1min。
实施例28
Figure BDA0001898733260000181
按照通用方法，98％产率，90％ee。
Figure BDA0001898733260000183
1H NMR(400MHz,DMSO-d6)δ9.66(s,1H),9.13(s,1H),7.95(d,J＝8.9Hz,1H),7.85(dd,J＝8.8,5.2Hz,2H),7.78(d,J＝8.9Hz,1H),7.43(d,J＝8.9Hz,1H),7.39(dd,J＝8.6,1.7Hz,1H),7.14(d,J＝7.1Hz,2H),6.94(dd,J＝8.9,2.4Hz,1H),6.24(s,1H),6.14(d,J＝2.1Hz,1H),3.56(s,3H),3.44(s,3H).13C NMR(100MHz,DMSO-d6)δ＝158.1,157.9,155.2,145.8,135.6,135.1,130.8,130.2,130.2,129.0,127.5,126.4,126.0,124.1,120.5,119.9,113.9,113.7,112.1,111.4,103.9,55.1,52.3.HRMS(ESI)精确质量计算[M+Na]C23H19N2O4BrNa,m/z:489.0420,实测值:489.0419.HPLC分析:HPLC DAICEL CHIRALCEL AD-3,正己烷/异丙醇＝80/20,0.3mL/min,λ＝254nm,tR(major)＝25.4min,tR(minor)＝27.2min。
实施例29
Figure BDA0001898733260000182
按照通用方法(反应温度为15℃)，99％产率，90％ee。
Figure BDA0001898733260000184
1H NMR(400MHz,DMSO-d6)δ9.35(s,1H),9.16(s,1H),8.09(d,J＝1.8Hz,1H),7.90(d,J＝9.0Hz,1H),7.83(d,J＝8.9Hz,1H),7.65(s,1H),7.34(d,J＝8.9Hz,2H),7.28(dd,J＝9.1,1.9Hz,1H),7.07(d,J＝8.6Hz,1H),6.87(d,J＝8.6Hz,1H),6.76(d,J＝9.1Hz,1H),6.18(s,1H),3.56(s,3H),2.39(s,3H).13C NMR(100MHz,DMSO-d6)δ＝157.8,153.4,145.6,132.5,132.2,132.1,130.0,129.9,129.5,129.3,129.1,128.9,128.2,127.4,126.8,124.7,119.2,115.6,115.3,113.7,113.3,52.3,21.3.HRMS(ESI)精确质量计算[M+Na]C23H19N2O3BrNa,m/z:473.0471,实测值:473.0474.HPLC分析:HPLC DAICEL CHIRALCEL AD-3,正己烷/异丙醇＝80/20,1.0mL/min,λ＝240nm,tR(minor)＝8.7min,tR(major)＝13.3min。
实施例30
后期转化
通过去除3的N-N键获得NOBIN及其衍生物
Figure BDA0001898733260000191
将用MeOH洗涤三次的Raney-Ni(～100mg)加入到3(0.1mmol)的MeOH(5.0mL)和KOH水溶液(1.0mL，2M)中。将反应小瓶换气并用H2回填。然后在氢气填充的气球、60℃下搅拌反应。在TLC证实不存在起始原料后，将反应混合物通过布氏漏斗过滤。真空中除去MeOH后，将混合物用10mL水和10mL DCM稀释。除去有机层，水层用10mL DCM洗涤两次。将合并的有机层用Na2SO4干燥、过滤、并浓缩，得到灰白色固体，将其通过硅胶柱色谱(PE/EA＝15/1)纯化，得到化合物6。
Figure BDA0001898733260000192
通过以上步骤，以92％产率、93％ee获得6a。经过重结晶之后，ee可以达到99％。
Figure BDA0001898733260000194
1H NMR(400MHz,DMSO-d6)δ9.33(s,1H),7.91(d,J＝8.9Hz,1H),7.88(d,J＝8.3Hz,1H),7.76–7.74(m,2H),7.40(d,J＝8.9Hz,1H),7.28–7.24(m,1H),7.22–7.17(m,2H),7.13–7.06(m,2H),6.98(d,J＝8.3Hz,1H),6.81–6.78(m,1H),4.57(s,2H).13C NMR(100MHz,DMSO-d6)δ＝153.8,144.4,134.5,134.2,129.6,129.0,128.6,128.5,128.3,127.5,126.6,126.2,124.6,124.0,123.0,121.3,119.3,119.0,115.5,111.8.HRMS(ESI)精确质量计算[M+H]C20H16NO,m/z:286.1226,实测值:286.1221.HPLC分析:HPLC DAICEL CHIRALCEL AD-3,正己烷/异丙醇＝70/30,1.0mL/min,λ＝254nm,tR(major)＝14.7min,tR(minor)＝7.7min。
Figure BDA0001898733260000193
通过以上步骤，以92％产率、91％ee获得6g。
Figure BDA0001898733260000203
1H NMR(400MHz,DMSO-d6)δ9.33(s,1H),7.89(t,J＝9.3Hz,2H),7.68–7.65(m,2H),7.39(d,J＝8.8Hz,1H),7.24(dt,J＝14.7,6.8Hz,2H),7.02(t,J＝7.9Hz,2H),6.81(d,J＝8.6Hz,1H),6.15(s,1H),4.54(s,2H),3.41(s,3H).13C NMR(100MHz,DMSO-d6)δ＝157.9,153.8,144.9,135.8,134.0,129.9,129.6,129.0,128.6,128.5,126.6,124.7,123.0,123.0,119.3,116.5,115.5,112.3,111.0,104.1,55.0.HRMS(ESI)精确质量计算[M+H]C21H18NO2,m/z:316.1332,实测值:316.1326.HPLC分析:HPLCDAICEL CHIRALCEL AD-3,正己烷/异丙醇＝70/30,1.0mL/min,λ＝240nm,tR(major)＝13.8min,tR(minor)＝8.4min。
Figure BDA0001898733260000201
通过以上步骤，以94％产率、92％ee获得6l。
Figure BDA0001898733260000204
1H NMR(400MHz,DMSO-d6)δ9.22(s,1H),7.83(d,J＝8.8Hz,1H),7.79–7.72(m,3H),7.29(d,J＝8.8Hz,1H),7.19(d,J＝8.8Hz,1H),7.11–7.05(m,3H),6.80–6.77(m,1H),6.76(s,1H),4.53(s,2H),2.16(s,3H).13C NMR(100MHz,DMSO-d6)δ＝153.9,144.3,135.7,134.5,134.4,129.4,128.6(2C),128.3,127.5,127.2,126.2,125.2,124.0,123.4,121.3,119.0,118.3,114.9,112.0,22.1.HRMS(ESI)精确质量计算[M+H]C21H18NO,m/z:300.1383,实测值:300.1375.HPLC分析:HPLC DAICEL CHIRALCEL IC,正己烷/异丙醇＝80/20,0.5mL/min,λ＝240nm,tR(major)＝9.7min,tR(minor)＝10.5min。
Figure BDA0001898733260000202
通过以上步骤，以88％产率、90％ee获得6ak。
Figure BDA0001898733260000205
1H NMR(400MHz,DMSO-d6)δ9.47(s,1H),8.20(d,J＝1.6Hz,1H),8.08(d,J＝1.7Hz,1H),8.02(d,J＝8.9Hz,1H),7.86(d,J＝8.8Hz,1H),7.73–7.68(m,4H),7.56–7.52(m,1H),7.47–7.41(m,6H),7.34–7.26(m,3H),7.11(dd,J＝8.8,2.2Hz,1H),6.92(dd,J＝8.8,2.6Hz,1H),4.72(s,2H).13C NMR(100MHz,DMSO-d6)δ＝154.2,144.9,141.1,140.8,134.9,133.9,133.5,133.0,130.2,129.4(2C),129.4(2C),129.3,129.3(2C),127.8,127.5,127.1(2C),126.9(2C),126.2,126.0,125.9,125.5,125.4,124.8,119.8,119.4,115.3,111.5.HRMS(ESI)精确质量计算[M+H]C32H24NO,m/z:438.1852,实测值:438.1846.HPLC分析:HPLC DAICEL CHIRALCEL ID,正己烷/异丙醇＝80/20,1.0mL/min,λ＝254nm,tR(major)＝13.2min,tR(minor)＝10.1min。
以上结果表明，3a等中间体在碱性条件下，用雷尼镍在1atm氢气氛下通过N-N键裂解，以高收率转化成相应的NOBIN衍生物，而且ee值没有改变。
基于相似的结构，3b等化合物也可以通过上述方法获得相应的NOBIN衍生物，NOBIN及其衍生物是商业化的化合物，具有作为配体等多种用途。
3a通过高压去除N-N键获得4H-NOBIN
当在中性条件下、较高压力下进行反应时，NOBIN可以进一步氢化成化合物7。
Figure BDA0001898733260000211
在不锈钢高压釜中，向反应小瓶中加入Raney-Ni(～100mg)和3a(35.8mg，0.1mmol，93％ee)的MeOH(10mL)溶液。将反应在室温、30bar的H2压力下搅拌8小时。将反应混合物通过布氏漏斗过滤，将滤液真空蒸发。通过硅胶柱色谱(PE/EA＝20/1)纯化残余物，得到化合物7(24.8mg，86％收率，93％ee)，为白色固体。
Figure BDA0001898733260000212
1H NMR(400MHz,DMSO-d6)δ8.62(s,1H),7.69(d,J＝7.6Hz,1H),7.64(d,J＝8.7Hz,1H),7.19–7.0(m,3H),6.98(t,J＝7.2Hz,2H),6.83(d,J＝8.2Hz,1H),4.54(s,2H),2.72(t,J＝6.2Hz,2H),2.24(dt,J＝16.9,6.1Hz,1H),1.97(dt,J＝16.9,6.4Hz,1H),1.73–1.44(m,4H).13C NMR(100MHz,DMSO-d6)δ＝153.6,143.2,137.6,133.8,129.6,128.2,128.0,127.9,127.5,126.2,123.5,122.1,121.3,118.8,114.0,113.8,29.3,26.9,23.3,23.3.HRMS(ESI)精确质量计算[M+H]C20H20NO,m/z:290.1539,实测值:290.1533.HPLC分析:HPLC DAICEL CHIRALCEL AD-3,正己烷/异丙醇＝80/20,1.0mL/min,λ＝240nm,tR(major)＝13.7min,tR(minor)＝8.5min。
实施例31
放大试验
为了验证该方法的实用性，在最佳反应条件下进行产物3a的制备规模合成；反应性、产率和立体选择性没有变化，当催化剂的用量降低至2.5mol％，ee值仅略有下降(91％)，表明该反应具有工业化应用价值。
Figure BDA0001898733260000221
以上所述，仅为本发明的具体实施方式，但本发明的保护范围并不局限于此，任何属于本技术领域的技术人员在本发明揭露的技术范围内，可轻易想到的变化或替换，都应涵盖在本发明的保护范围之内。因此，本发明的保护范围应该以权利要求的保护范围为准。

Claims (8)

1.一种催化不对称合成联萘酚胺的方法，其特征在于，包括以下步骤：以Ni(OTf)2和手性双噁唑啉配体为催化剂，式A化合物和式B化合物反应，得到式C化合物：
Figure FDA0003031969640000011
其中，R1选自烷基或苄基，R2选自烷基、烷氧基、苯基、氰基、卤素，R3选自烷基、烷氧基、乙酰氧基、苯基、羧酸酯基、卤素；
所述手性双噁唑啉配体选自以下结构之一：
Figure FDA0003031969640000012
2.根据权利要求1所述的方法，其特征在于，所述R1选自甲基、乙基、异丙基、苄基，R2选自甲基、甲氧基、苯基、氰基、溴，R3选自甲基、甲氧基、乙酰氧基、苯基、羧酸甲酯基、溴。
3.根据权利要求1所述的方法，其特征在于，所述手性双噁唑啉配体的用量至少是2.5mol％，所述Ni(OTf)2的用量至少是2.5mol％。
4.根据权利要求1或2所述的方法，其特征在于，所述反应中加入三乙胺、2，6-二甲基吡啶或NaHCO3作为添加剂。
5.根据权利要求4所述的方法，其特征在于，所述添加剂的用量至少是20mol％。
6.根据权利要求1或2所述的方法，其特征在于，所述反应的温度为0℃以上。
7.根据权利要求1或2所述的方法，其特征在于，所述反应以二氯甲烷、氯仿或甲苯为溶剂，至少反应6h。
8.根据权利要求1或2所述的方法，其特征在于，还包括以下步骤：
化合物C经雷尼镍氢化得到联萘酚胺，
Figure FDA0003031969640000021
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