基于手性氨硼烷的<i>β</i>-烯胺腈不对称转移氢化反应

引用本文: 周启文, 冯向青, 杨晶, 杜海峰. 基于手性氨硼烷的β-烯胺腈不对称转移氢化反应[J]. 有机化学, 2019, 39(8): 2188-2195. doi: 10.6023/cjoc201904079 shu

Citation: Zhou Qiwen, Feng Xiangqing, Yang Jing, Du Haifeng. Asymmetric Transfer Hydrogenations of β-Enamine Cyanide with Chiral Ammonia Borane[J]. Chinese Journal of Organic Chemistry, 2019, 39(8): 2188-2195. doi: 10.6023/cjoc201904079 shu

基于手性氨硼烷的β-烯胺腈不对称转移氢化反应

周启文 ^a, ,
冯向青 ^b, ,
杨晶 ^{a,
,} ,
杜海峰 ^{b,
,}

a.
北京化工大学生命科学与技术学院化工资源有效利用国家重点实验室北京 100029
b.
中国科学院化学研究所北京国家分子科学研究中心中国科学院分子识别与功能重点实验室北京 100190

通讯作者: 杨晶, yangji@mail.buct.edu.cn; 杜海峰, haifengdu@iccas.ac.cn

基金项目:

国家自然科学基金（Nos.21825108，91856103）资助项目

摘要: 不对称转移氢化是获得光学活性化合物的一类重要反应.利用手性磷酸和氨硼烷释放氢气原位生成手性氨硼烷，水作为添加剂促进手性氨硼烷的循环再生，顺利实现了β-烯胺腈的不对称转移氢化反应，以48%~98%的收率和61%~95% ee获得了一系列手性β-胺基腈类化合物.

关键词:

English

Asymmetric Transfer Hydrogenations of β-Enamine Cyanide with Chiral Ammonia Borane

Zhou Qiwen ^a, ,
Feng Xiangqing ^b, ,
Yang Jing ^{a,
,} ,
Du Haifeng ^{b,
,}

a.
Key Laboratory of Chemical Resource Engineering Beijing Key Laboratory of Bioprocess, College of Life Sciences and Technology, Beijing University of Chemical Technology, Beijing 100029
b.
Beijing National Laboratory for Molecular Sciences, CAS Key Laboratory of Molecular Recognition and Function, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190

Corresponding author: Yang, Jing, E-mail: yangji@mail.buct.edu.cn; Du, Haifeng, E-mail: haifengdu@iccas.ac.cn

Received Date: 30 April 2019
Revised Date: 06 June 2019
Available Online: 25 August 2019
Fund Project:

Project supported by the National Natural Science Foundation of China (Nos. 21825108, 91856103)

Abstract: The asymmetric transfer hydrogenation represents one important class of reactions for the synthesis of optically active compounds. A chiral ammonia borane was generated in situ from an H₂ release reaction between chiral phosphoric acid and ammonia borane, which could be regenerated by the assistance of water after the hydrogen transfer process and made this reaction catalytic. With this chiral ammonia borane, asymmetric transfer hydrogenations of β-enamine cyanides were realized to afford the desired products in 48%~98% yields with 61%~95% ee.

Key words:

不对称转移氢化反应是合成光学活性化合物的一类重要方法, 避免了使用高压氢气.转移氢化反应通常使用异丙醇、甲酸和甲酸衍生物等作为氢源, 实现了过渡金属催化的各种各样的不饱和化合物的还原, 得到了很高的收率和对映选择性^[1]. Hantzsch酯^[2]及其衍生化合物是一类应用广泛的氢供体, 在有机小分子和过渡金属催化的转移氢化中得到了广泛的应用^[3~5].但是现有这些氢供体的理论释氢量相对较低, 原子经济性较差, 开发新型高储氢量的氢源具有重要的研究价值.

氨硼烷(Ammonia Borane, AB)具有分子量小(30.87 g/mol), 储氢含量高(质量分数为19.6%), 对水和氧气稳定等优点, 是一种理想的固体储氢材料.化学研究工作者对于氨硼烷的氢气释放和氢源再生开展了一系列研究, 取得了重要进展^{[6, 7]}.相对而言, 氨硼烷作为氢供体参与转移氢化反应中报道比较少. 2010年, Berke小组^[8]实现了首例直接转移氢化反应, 以亚胺为底物, 不需要催化剂的参与就能在温和条件下通过协同的双氢同步转移机理实现亚胺的还原(Scheme 1).此外, 氨硼烷也可以高效还原C＝C和C＝O等极性不饱和键^[9~13].在金属催化剂、有机小分子催化剂以及纳米材料催化剂的催化下, 氨硼烷作为氢供体的转移氢化也取得了一定的进展^[14~16].但是, 氨硼烷作为氢供体的不对称转移氢化反应研究还很少. 1984年, Williams课题组^[17]将氨硼烷和手性冠醚络合, 首次实现了异丁酰苯的不对称还原. 2016年, 我们课题组使用(R)-叔丁基亚磺酰胺与强路易斯酸Piers’硼烷HB(C₆F₅)₂络合得到的简单的手性受阻路易斯酸碱对, 高效高选择性地实现了氨硼烷对亚胺^[18]、喹喔啉^[19]和β-烯胺酯^[20]化合物的不对称转移氢化反应. 2018年, 我们课题组^[21]使用手性磷酸(CPA), 设计合成了可再生的手性氨硼烷试剂, 实现了一系列亚胺和β-烯胺酯以及一个β-烯胺腈底物的高对映选择性不对称转移氢化反应. β-烯胺酯的不对称还原是合成手性β-氨基酸的一种常用方法, 相关报道比较多^[22~24].而对烯胺腈类化合物的还原反应则报道很少^[25], 手性腈类化合物通常具有重要的生物活性, 具有很好的研究价值.本工作中, 我们利用手性氨硼烷体系开展了β-烯胺腈类化合物的不对称转移氢化反应研究.

图式 1

图式 1. 氨硼烷参与的转移氢化反应

Scheme 1. Transfer hydrogenations with ammonia borane

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1. 结果与讨论

以手性磷酸1a为催化剂对β-烯胺腈(2a)的不对称转移氢化反应进行了初步尝试.使用5 mol%的手性磷酸1a和1.1 equiv.的氨硼烷, 以甲苯为溶剂, 水为添加剂, 在60 ℃下反应5 h, 以58%的转化率和59%的ee得到手性胺基腈3a(表 1, Entry 1).随后, 对溶剂进行了筛选.对于氨硼烷的可溶性溶剂四氢呋喃、1, 4-二氧六环和乙腈, 反应活性和对映选择性都有明显的降低(表 1, Entries 2~4);低极性溶剂正己烷, 由于无法溶解底物导致反应效果较差(表 1, Entry 5);在甲醇中只能得到17%转化的手性产物(表 1, Entry 6).

表 1

表 1 溶剂筛选^a

Table 1. Optimization of reaction solvent

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Entry	Solvent	Conv.^b/%	ee^c/%
1	Toluene	58	59
2	THF	12	37
3	1, 4-Dioxane	18	49
4	CH₃CN	25	43
5	Hexane	18	37
6	MeOH	17	33
^a All reactions were carried out with enamine 2a (0.1 mmol), CPA (1a) and NH₃•BH₃ (1.1 equiv.) in solvent (0.5 mL) for 5 h at 60 ℃. ^b The conversion was determined by crude ¹H NMR. ^c The ee was determined by chiral HPLC, the absolute configuration of the product 3a were tentatively assigned by analogy with ref. [25].

使用甲苯作为溶剂, 进一步筛选了手性磷酸(Eq. 1).带有硅基的手性磷酸1a在反应活性和对映选择性上都优于带有普通芳环的手性磷酸1b和1c.在手性磷酸1a的基础上进行改进, 得到手性磷酸1d和1e, 其反应活性增加但对映选择性降低到43%和45% ee; 使用3, 3ꞌ-叔丁基二苯基硅基取代的手性磷酸1f能够得到更高的活性和92% ee, 延长反应时间到24 h, 反应能够得到91%的转化.此外还尝试了以甲基氨硼烷为氢源(Eq. 2), 在手性磷酸1f的催化下, 反应活性大幅度降低, 但对映选择性仍能保持在90% ee.

(1)

(2)

在最优反应条件下, 首先考察了氮原子上保护基团对反应的影响(表 2).研究发现, 一系列芳基取代基(2a~2e)都可以给出高的收率和对映选择性.当保护基是3, 5-二甲基苯基(2e)时, 反应得到更好的对映选择性, 而对甲氧基苯基(2d)底物给出了更高的产率.以对甲氧基苯基作为保护基, 进一步考察了该体系的底物适用性, 能够以78%~94%的产率得到相应的手性产物3f~3m, 对映选择性保持在90%~92% ee.不论是芳环上带有吸电子底物(2h, 2i, 2k和2l), 还是给电子基团的(2f, 2g和2j)底物都有很好的适用性; 对于含有噻吩环的底物2m也有很高的反应活性, 能够以92%的对映选择性得到手性产物3m.还考察了β-烷基取代的底物2n和N-烷基取代底物2o, 也可以顺利地进行反应, 得到中等的产率和对映选择性.

表 2

表 2 β-烯胺腈底物的不对称转移氢化

Table 2. Asymmetric transfer hydrogenation of β-enamino cyanides

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为进一步考察这一方法学的适用性, 在完成一系列β-烯胺腈的不对称氢化反应之后, 将这一催化体系放大到克级反应(Eq. 3), 发现催化剂的反应活性和对映选择性都能很好地保持, 得到91%的产率和91% ee.

(3)

在之前工作基础上, 我们提出了反应可能的机理, 如Scheme 2所示:手性磷酸1与氨硼烷反应, 释放出H₂并生成手性氨硼烷5, 与底物β-烯胺腈作用, 通过六元环过渡态发生双氢转移, 得到产物3和物种4.随后物种4通过四元环水解再生得到1, 完成反应循环.

图式 2

图式 2. 可能的反应机理

Scheme 2. Plausible reaction mechanism

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2. 结论

通过手性磷酸和氨硼烷放出氢气原位生成的手性氨硼烷, 实现了烯胺腈类底物的不对称转移氢化反应.以48%~98%的产率和61%~95%的对映选择性得到了手性β-氨基腈类化合物, 为这类化合物提供了一种新的合成方法.

3. 实验部分

3.1 仪器与试剂

X-4数字显示显微熔点仪; Autopol VI旋光仪; Nicolet 6700红外光谱仪; Bruker核磁共振仪(400MHz和300 MHz); Thermo Exactive LC/MS高分辨质谱仪; Agilent Technologies Model 1260高压液相色谱仪(手性柱购自Daicel).

所有的药品原料从伊诺凯试剂公司购得.分离所需要的H200-300和H300-400目硅胶和硅胶预制板均购自烟台化学工业研究所.

3.2 实验方法

3.2.1 烯胺腈类底物的合成

所有烯胺腈底物的合成参考已发表文献[25, 26], 以2a的制备为例.苯胺(0.6050 g, 6.5 mmol)、苯甲酰基乙腈(0.7258 g, 5 mmol)和乙酸(2.9 mL)加入到15 mL的封管中, 封好塞子, 将反应体系在80 ℃油浴中搅拌5 h.之后冷却到室温, 倒入10 mL水稀释反应液, 乙酸乙酯萃取(10 mL×3), 合并有机相, 无水硫酸钠干燥, 反应混合物经柱分离(硅胶, 石油醚/乙酸乙酯/二氯甲烷, V:V:V＝8:2:5)后, 再经过重结晶(正己烷/乙酸乙酯, V:V＝3:1)得到白色晶体0.48 g, 产率为44%.

3-苯基-3-(苯基氨基)丙烯腈(2a):白色固体, m.p. 128~129 ℃ (lit.^[25] m.p. 125~126 ℃); ¹H NMR (400 MHz, CDCl₃) δ: 7.79~7.65 (m, 2H), 7.55~7.46 (m, 3H), 7.45~7.36 (m, 2H), 7.26~7.16 (m, 3H), 5.97 (brs, 1H), 4.70 (s, 1H); ¹³C NMR (100 MHz, CDCl₃) δ: 160.4, 139.2, 135.6, 131.1, 130.0, 129.2, 128.4, 125.9, 123.6, 121.0, 67.1.

3-苯基-3-[(4-溴苯基)氨基]丙烯腈(2b)^[26]:白色固体, m.p. 161~162 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.77~7.60 (m, 2H), 7.59~7.38 (m, 5H), 7.15~6.94 (m, 2H), 5.97 (brs, 1H), 4.67 (s, 1H); ¹³C NMR (100 MHz, CDCl₃) δ: 160.0, 138.3, 135.1, 133.0, 131.3, 129.3, 128.4, 125.0, 120.6, 118.7, 68.0.

3-苯基-3-(对甲苯氨基)丙烯腈(2c)^[26]:白色固体, m.p. 156~157 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.76~7.64 (m, 2H), 7.58~7.43 (m, 3H), 7.26~7.17 (m, 2H), 7.16~7.01 (m, 2H), 5.90 (brs, 1H), 4.59 (s, 1H), 2.36 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 160.8, 136.4, 135.9, 135.7, 131.0, 130.5, 129.2, 128.3, 123.9, 121.2, 66.3, 21.2.

3-苯基-3-[(4-甲氧基苯基)氨基]丙烯腈(2d)^{[21, 25]}:白色固体, m.p. 131~132 ℃ (lit.^[25] m.p. 130~131 ℃); ¹H NMR (300 MHz, CDCl₃) δ: 7.76~7.60 (m, 2H), 7.55~7.40 (m, 3H), 7.21~7.06 (m, 2H), 7.00~6.83 (m, 2H), 5.88 (s, 1H), 4.40 (s, 1H), 3.82 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ: 161.7, 158.0, 135.6, 131.6, 130.9, 129.1, 128.2, 126.3, 121.4, 115.1, 65.4, 55.7.

3-苯基-3-[(3, 5-二甲基苯基)氨基]丙烯腈(2e):白色固体, m.p. 143~145 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.77~7.63 (m, 2H), 7.57~7.38 (m, 3H), 6.94~6.76 (m, 3H), 5.87 (brs, 1H), 4.70 (s, 1H), 2.32 (s, 6H); ¹³C NMR (100 MHz, CDCl₃) δ: 160.4, 139.7, 138.9, 135.8, 131.0, 129.2, 128.3, 127.6, 121.2, 121.1, 66.7, 21.5; IR (film) ν: 3446, 2198, 1590 cm^－1; HRMS (ESI) calcd. for C₁₇H₁₇N₂ [M+H]⁺ 249.1386, found 249.1384.

3-(4-甲氧基苯基)-3-[(4-甲氧基苯基)氨基]丙烯腈(2f):黄色固体, m.p. 153~155 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.67~7.61 (m, 1.5H), 7.32~7.26 (m, 0.5H), 7.16~7.11 (m, 1.5H), 7.00~6.95 (m, 1.5H), 6.93~6.89 (m, 1.5H), 6.83~6.78 (m, 0.5H), 6.75~6.58 (m, 1.2H), 5.83 (brs, 0.8H), 4.36 (s, 0.7H), 4.27 (s, 0.2H), 3.85 (s, 2.3H), 3.82 (s, 2.3H), 3.79 (s, 0.7H), 3.73 (s, 0.7H); ¹³C NMR (100 MHz, CDCl₃) δ: 161.7, 161.5, 161.3, 160.2, 157.9, 156.5, 133.4, 131.8, 129.8, 129.7(8), 129.7(4), 127.7, 126.9, 126.2, 124.4, 121.8, 115.1, 114.4, 114.3, 114.2, 68.5, 64.9, 55.7, 55.6, 55.5(7), 55.5(1); IR (film) ν: 3447, 2836, 2187, 1511 cm^－1; HRMS (ESI) calcd. for C₁₇H₁₆O₂N₂ [M－H]^－ 279.1139, found 279.1138.

3-(对甲苯基)-3-[(4-甲氧基苯基)氨基]丙烯腈(2g):白色固体, m.p. 174~175 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.74~7.43 (m, 2H), 7.43~7.21 (m, 2H), 7.21~7.03 (m, 2H), 7.03~6.75 (m, 2H), 5.81 (brs, 1H), 4.38 (s, 1H), 3.82 (s, 3H), 2.40 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 161.7, 158.0, 141.3, 132.8, 131.7, 129.8, 128.1, 126.3, 121.6, 115.1, 65.1, 55.7, 21.6; IR (film) ν: 3280, 2196, 1511 cm^－1; HRMS (ESI) calcd for C₁₇H₁₅ON₂ [M－H]^－ 263.1190, found 263.1190.

3-(4-氯苯基)-3-[(4-甲氧基苯基)氨基]丙烯腈(2h):黄色固体, m.p. 179~182 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.68~7.59 (m, 1.7H), 7.49~7.40 (m, 1.7H), 7.30~7.23 (m, 0.6H), 7.18~7.07 (m, 1.8H), 6.96~6.87 (m, 1.8H), 6.77 (brs, 0.1H), 6.75~6.68 (m, 0.6H), 5.83 (brs, 0.9H), 4.42 (s, 0.9H), 4.30 (s, 0.1H), 3.83 (s, 2.7H), 3.73 (s, 0.4H); ¹³C NMR (100 MHz, CDCl₃) δ: 160.5, 158.2, 137.0, 133.9, 131.3, 129.7, 129.6, 129.5, 129.2, 126.3, 124.7, 121.1, 115.2, 114.5, 66.1, 55.7; IR (film) ν: 3273, 2184, 1510 cm^－1; HRMS (ESI) calcd for C₁₆H₁₄ON₂Cl [M+H]⁺ 285.0789, found 285.0783.

3-(3-甲氧基苯基)-3-[(4-甲氧基苯基)氨基]丙烯腈(2i):黄色固体, m.p. 134~136 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.42~7.34 (m, 0.8H), 7.27~7.18 (m, 1.4H), 7.17~7.10 (m, 1.6H), 7.05~6.99 (m, 0.8H), 6.96~6.86 (m, 2.3H), 6.79~6.67 (m, 1.1H), 6.75~6.58 (m, 1.2H), 5.92 (brs, 0.8H), 4.40 (s, 0.8H), 4.32 (s, 0.2H), 3.84 (s, 2.4H), 3.82 (s, 2.4H), 3.74~3.70 (m, 1.3H); ¹³C NMR (100 MHz, CDCl₃) δ: 161.4, 160.4, 159.9, 159.7, 158.0, 156.7, 136.8, 136.3, 133.0, 131.5, 130.2, 129.9, 126.3, 124.5, 121.3, 120.6, 120.4, 119.1, 116.9, 116.2, 115.1, 114.4, 113.7, 113.5, 65.2, 55.7, 55.6, 55.5, 55.4; IR (film) ν: 3290, 2196, 1511 cm^－1; HRMS (ESI) calcd for C₁₇H₁₆O₂N₂ [M－H]^－ 279.1139, found 279.1138.

3-间甲苯基-3-[(4-甲氧基苯基)氨基]丙烯腈(2j):白色固体, m.p. 120~121 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.51~7.44 (m, 2H), 7.39~7.27 (m, 2H), 7.18~7.10 (m, 2H), 6.96~6.87 (m, 2H), 5.86 (brs, 1H), 4.39 (s, 1H), 3.82 (s, 3H), 2.41 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 161.8, 158.0, 138.9, 135.6, 131.6, 131.5, 129.0, 128.7, 126.3, 125.3, 121.5, 115.1, 65.1, 55.7, 21.6; IR (film) ν: 3446, 2196, 1511 cm^－1; HRMS (ESI) calcd for C₁₇H₁₇ON₂ [M+H]⁺ 265.1335, found 265.1331.

3-(3-氯苯基)-3-[(4-甲氧基苯基)氨基]丙烯腈(2k):白色固体, m.p. 124~126 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.68~7.63 (m, 1H), 7.62~7.56 (m, 1H), 7.50~7.38 (m, 2H), 7.18~7.10 (m, 2H), 6.98~6.89 (m, 2H), 5.82 (brs, 1H), 4.43 (s, 1H), 3.83 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 160.2, 158.2, 137.3, 135.1, 131.2, 131.0, 130.5, 128.2, 126.8, 126.4, 120.8, 115.2, 66.2, 55.7; IR (film) ν: 3446, 2191, 1510 cm^－1; HRMS (ESI) calcd for C₁₆H₁₄ON₂Cl [M+H]⁺ 285.0789, found 285.0784.

3-(3-溴苯基)-3-[(4-甲氧基苯基)氨基]丙烯腈(2l):白色固体, m.p. 125~127 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.88~7.74 (m, 1H), 7.67~7.56 (m, 2H), 7.39~7.30 (m, 1H), 7.18~7.07 (m, 2H), 6.98~6.87 (m, 2H), 5.91 (brs, 1H), 4.41 (s, 1H), 3.82 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 160.1, 158.2, 137.5, 133.9, 131.2, 131.0, 130.7, 127.3, 126.3, 123.0, 120.8, 115.1, 66.1, 55.7; IR (film) ν: 3446, 2199, 1516 cm^－1; HRMS (ESI) calcd for C₁₆H₁₂ON₂Br [M－H]^－ 327.0139, found 327.0137.

3-(噻吩-2-基)-3-[(4-甲氧基苯基)氨基]丙烯腈(2m):黄色固体, m.p. 118~120 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.91~7.69 (m, 0.8H), 7.57~7.42 (m, 0.8H), 7.36~7.33 (m, 0.2H), 7.21~7.11 (m, 2.5H), 7.00~6.88 (m, 2.3H), 6.82~6.74 (m, 0.5H), 6.62 (brs, 0.2H), 5.88 (brs, 0.8H), 4.49 (s, 0.2H), 4.40 (s, 0.8H), 3.82 (s, 2.4H), 3.76 (s, 0.6H); ¹³C NMR (100 MHz, CDCl₃) δ: 158.0, 153.9, 136.2, 131.2, 129.8, 128.8, 128.7, 128.0, 127.9, 127.8, 126.3, 125.1, 120.9, 115.0, 114.3, 68.7, 65.6, 55.5, 55.4; IR (film) ν: 3446, 2191, 1511 cm^－1; HRMS (ESI) calcd for C₁₄H₁₁ON₂S [M－H]^－ 255.0598, found 255.0596.

4-甲基-3-(对甲苯基氨基)戊-2-烯腈(2n)^[26]:白色固体, m.p. 138~139 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.22~7.13 (m, 2H), 7.08~6.97 (m, 2H), 5.76 (brs, 1H), 4.17 (s, 1H), 3.26 (sept, J＝7.0 Hz, 1H), 2.34 (s, 3H), 1.29 (d, J＝7.0 Hz, 6H); ¹³C NMR (100 MHz, CDCl₃) δ: 167.7, 136.1, 135.9, 130.4, 124.7, 121.1, 63.0, 32.6, 21.1, 20.8.

3-苯基-3-(苄基氨基)丙烯腈(2o):黄色固体, m.p. 83~85 ℃ (lit.^[29] 83~85 ℃); ¹H NMR (400 MHz, CDCl₃) δ: 7.64~7.52 (m, 2H), 7.52~7.28 (m, 8H), 4.71 (brs, 1H), 4.27 (d, J＝5.0 Hz, 2H), 3.26 (sept, J＝7.0 Hz, 1H), 4.11 (s, 1H); ¹³C NMR (100 MHz, CDCl₃) δ: 162.1, 136.4, 135.8, 130.7, 129.2, 129.0, 128.3, 128.0, 127.9, 121.5, 62.7, 48.5.

3.2.2 烯胺腈的不对称转移氢化反应

以3a合成为例, 将手性磷酸1f (0.0124 g, 0.015 mmol)、氨硼烷(0.0102 g, 0.33 mmol)和甲苯(1.5 mL)加入15 mL的封管中, 随后加入β-烯胺氰(2a, 0.0661 g, 0.30 mmol)和水(8.1 μL, 0.45 mmol), 封好塞子, 将反应体系在60 ℃油浴中剧烈搅拌24 h后, 旋干溶剂, 反应混合物经硅胶预制板分离(石油醚/乙酸乙酯/丙酮, V:V: V＝10:1:1)后得到产物3a白色固体0.0572 g, 产率为86%, 92% ee.

3.2.3 3h的克级制备

手性磷酸1f (0.1648 g, 0.2 mmol)、氨硼烷(0.1355 g, 4.4 mmol)和甲苯(20 mL)加入到150 mL的封管中.加入β-烯胺氰2h (1.138 g, 4 mmol)和水(108 μL, 6 mmol), 之后封好塞子, 将反应体系在60 ℃油浴中剧烈搅拌24 h后, 旋干溶剂, 反应混合物经硅胶柱分离(石油醚/乙酸乙酯/二氯甲烷, V:V:V＝50:1:1~10:1:1)后得到产物3h黄色液体1.0420 g, 产率为91%, 91% ee.

(S)-3-苯基-3-(苯基氨基)丙腈(3a)^{[25, 31]}:白色固体, 0.0572 g, 产率86%, 92% ee. m.p. 84 ℃ (lit.^[31] 82~83 ℃); [α]_D²⁰－12.1 (c 1.00, CHCl₃) [lit: [α]_D－10.7 (c 1.0, CHCl₃), 87% ee]; ¹H NMR (400 MHz, CDCl₃) δ: 7.46~7.30 (m, 5H), 7.21~7.10 (m, 2H), 6.81~6.72 (m, 1H), 6.68~6.50 (m, 2H), 4.84~4.74 (m, 1H), 4.20 (brs, 1H), 2.97~2.83 (m, 2H); ¹³C NMR (100 MHz, CDCl₃) δ: 146.0, 140.1, 129.6, 129.4, 128.7, 126.4, 119.0, 117.3, 114.1, 54.6, 26.4.

(S)-3-苯基-3-[(4-溴苯基)氨基]丙腈(3b):白色固体, 0.0796 g, 产率88%, 91% ee. m.p. 81~82 ℃; [α]_D²⁰ 20.1 (c 1.05, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ: 7.47~7.29 (m, 5H), 7.25~7.18 (m, 2H), 6.52~6.42 (m, 2H), 4.80~4.62 (m, 1H), 4.25 (brs, 1H), 2.98~2.82 (m, 2H); ¹³C NMR (100 MHz, CDCl₃) δ: 145.0, 139.6, 132.3, 129.5, 128.9, 126.3, 117.1, 115.7, 110.9, 54.6, 26.6; IR (film) ν: 3378, 2921, 2250 cm^－1; HRMS (ESI) calcd for C₁₅H₁₄N₂Br [M+H]⁺ 301.0335, found 301.0332.

(S)-3-苯基-3-(对甲苯氨基)丙腈(3c)^[27]:白色固体, 0.0709 g, 产率87%, 92% ee. m.p. 95~96 ℃; [α]_D²⁰－18.6 (c 1.00, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ: 7.52~7.28 (m, 5H), 7.05~6.87 (m, 2H), 6.59~6.44 (m, 2H), 4.81~4.67 (m, 1H), 4.07 (brs, 1H), 2.99~2.79 (m, 2H), 2.21 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 143.6, 140.2, 130.1, 129.4, 128.6, 128.3, 126.4, 117.4, 114.3, 54.9, 26.4, 20.6.

(S)-3-苯基-3-[(4-甲氧基苯基)氨基]丙腈(3d)^{[21, 25]}:黄色油状物, 0.0742 g, 产率98%, 90% ee. [α]_D²⁰－15.9 (c 1.00, CHCl₃) (lit: [α]_D－12.4 (c 1.0, CHCl₃), 87% ee); ¹H NMR (300 MHz, CDCl₃) δ: 7.51~7.25 (m, 5H), 6.82~6.66 (m, 2H), 6.65~6.47 (m, 2H), 4.72~4.60 (m, 1H), 3.94 (brs, 1H), 3.70 (s, 3H), 3.00~2.67 (m, 2H); ¹³C NMR (100 MHz, CDCl₃) δ: 153.1, 140.1, 139.8, 129.2, 128.4, 126.3, 117.3, 115.7, 114.9, 55.7, 55.4, 26.3.

(S)-3-苯基-3-[(3, 5-二甲基苯基)氨基]丙腈(3e):白色固体, 0.0654 g, 产率87%, 95% ee. m.p. 91~92 ℃; [α]_D²⁰－21.8 (c 0.93, CHCl₃); IR (film) ν: 3386, 2921, 1602 cm^－1; ¹H NMR (400 MHz, CDCl₃) δ: 7.48~7.29 (m, 5H), 6.43 (s, 1H), 6.26 (s, 2H), 4.83~4.73 (m, 1H), 4.08 (brs, 1H), 2.96~2.83 (m, 2H), 2.22 (s, 6H); ¹³C NMR (100 MHz, CDCl₃) δ: 146.0, 140.2, 139.4, 129.4, 128.6, 126.4, 121.0, 117.4, 112.0, 54.5, 26.2, 21.7; HRMS (ESI) calcd for C₁₇H₁₉N₂ [M+H]⁺ 251.1543, found 251.1544.

(S)-3-(4-甲氧基苯基)-3-[(4-甲氧基苯基)氨基]丙腈(3f):黄色油状物, 0.0792 g, 产率94%, 90% ee. [α]_D²⁰－25.8 (c 1.00, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ: 7.39~7.29 (m, 2H), 6.97~6.86 (m, 2H), 6.82~6.69 (m, 2H), 6.66~6.48 (m, 2H), 4.71~4.56 (m, 1H), 3.90 (brs, 1H), 3.80 (s, 3H), 3.72 (s, 3H), 2.91-2.79 (m, 2H); ¹³C NMR (100 MHz, CDCl₃) δ: 159.6, 153.3, 140.0, 132.3, 127.6, 117.5, 115.9, 115.1, 114.7, 55.9, 55.5, 55.1, 26.6; IR (film) ν: 3362, 2920, 2248 cm^－1; HRMS (ESI) calcd for C₁₇H₁₉O₂N₂ [M+H]⁺ 283.1441, found 283.1439.

(S)-3-(对甲苯基)-3-[(4-甲氧基苯基)氨基]丙腈(3g)^[28]:黄色油状物, 0.0662 g, 产率83%, 91% ee. [α]_D²⁰－21.8 (c 1.04, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ: 7.34~7.27 (m, 2H), 7.22~7.13 (m, 2H), 6.78~6.71 (m, 2H), 6.61~6.54 (m, 2H), 4.71~4.59 (m, 1H), 3.93 (brs, 1H), 3.72 (s, 3H), 2.91~2.79 (m, 2H), 2.34 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 153.2, 140.0, 138.4, 137.3, 130.0, 126.3, 117.5, 115.9, 115.1, 55.9, 55.3, 26.5, 21.3.

(S)-3-(4-氯苯基)-3-[(4-甲氧基苯基)氨基]丙腈(3h)^[28]:黄色油状物, 0.0500 g, 产率87%, 91% ee. [α]_D²⁰－22.9 (c 0.41, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ: 7.53~7.32 (m, 4H), 6.83~6.68 (m, 2H), 6.63~6.46 (m, 2H), 4.75~4.57 (m, 1H), 3.92 (brs, 1H), 3.72 (s, 3H), 2.94~2.77 (m, 2H); ¹³C NMR (100 MHz, CDCl₃) δ: 153.4, 139.6, 138.8, 134.4, 129.5, 127.9, 117.1, 116.0, 115.1, 55.8, 55.0, 26.5.

(S)-3-(3-甲氧基苯基)-3-[(4-甲氧基苯基)氨基]丙腈(3i)^[28]:黄色油状物, 0.0841 g, 产率91%, 91% ee. [α]_D²⁰－15.7 (c 0.99, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ: 7.36~7.27 (m, 1H), 7.03~6.90 (m, 2H), 6.89~6.81 (m, 1H), 6.79~6.68 (m, 2H), 6.65~6.53 (m, 2H), 4.70~4.57 (m, 1H), 3.93 (brs, 1H), 3.80 (s, 3H), 3.72 (s, 3H), 2.94~2.77 (m, 2H); ¹³C NMR (100 MHz, CDCl₃) δ: 160.4, 153.3, 142.1, 140.0, 130.5, 118.6, 117.4, 115.9, 115.1, 113.8, 112.3, 55.9, 55.6, 55.5, 26.5.

(S)-3-间甲苯基-3-[(4-甲氧基苯基)氨基]丙腈(3j)^[28]:黄色油状物, 0.0502 g, 产率94%, 91% ee. [α]_D²⁰－19.8 (c 1.04, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ: 7.29~7.23 (m, 1H), 7.23~7.16 (m, 2H), 7.16~7.10 (m, 1H), 6.81~6.69 (m, 2H), 6.64~6.54 (m, 2H), 4.68~4.57 (m, 1H), 3.93 (brs, 1H), 3.72 (s, 3H), 2.92~2.78 (m, 2H), 2.36 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 153.2, 140.3, 140.0, 139.1, 129.4, 129.2, 127.1, 123.5, 117.5, 115.8, 115.1, 55.9, 55.7, 26.5, 21.7.

(S)-3-(3-氯苯基)-3-[(4-甲氧基苯基)氨基]丙腈(3k):黄色油状物, 0.0516 g, 产率91%, 92% ee. [α]_D²⁰－8.7 (c 1.01, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ: 7.47~7.38 (m, 1H), 7.36~7.27 (m, 3H), 6.84~6.70 (m, 2H), 6.61~6.48 (m, 2H), 4.74~4.57 (m, 1H), 3.92 (brs, 1H), 3.72 (s, 3H), 2.94~2.78 (m, 2H); ¹³C NMR (100 MHz, CDCl₃) δ: 153.5, 142.5, 139.5, 135.4, 130.7, 128.9, 126.7, 124.7, 116.9, 116.0, 115.2, 55.9, 55.2, 26.5; IR (film) ν: 3366, 2921, 2250 cm^－1; HRMS (ESI) calcd for C₁₆H₁₆ON₂Cl [M+H]⁺ 287.0946, found 287.0943.

(S)-3-(3-溴苯基)-3-[(4-甲氧基苯基)氨基]丙腈(3l):黄色油状物, 0.0847 g, 产率86%, 92% ee. [α]_D²⁰－10.3 (c 1.02, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ: 7.62~7.51 (m, 1H), 7.50~7.42 (m, 1H), 7.39~7.31 (m, 1H), 7.30~7.21 (m, 1H), 6.81~6.68 (m, 2H), 6.64~6.47 (m, 2H), 4.70~4.56 (m, 1H), 3.92 (brs, 1H), 3.72 (s, 3H), 3.02~2.68 (m, 2H); ¹³C NMR (100 MHz, CDCl₃) δ: 153.5, 142.8, 139.5, 131.9, 131.0, 129.6, 125.2, 123.5, 117.0, 116.0, 115.2, 55.9, 55.2, 26.6; IR (film) ν: 3368, 2920, 2252 cm^－1; HRMS (ESI) calcd for C₁₆H₁₆ON₂Br [M+H]⁺ 331.0441, found 331.0438.

(S)-3-(噻吩-2-基)-3-[(4-甲氧基苯基)氨基]丙腈(3m):黄色油状物, 0.0606 g, 产率78%, 91% ee. [α]_D²⁰+6.4 (c 0.77, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ: 7.30~7.25 (m, 1H), 7.13~7.06 (m, 1H), 7.03~6.95 (m, 1H), 6.84~6.74 (m, 2H), 6.72~6.61 (m, 2H), 5.03~4.92 (m, 1H), 3.88 (brs, 1H), 3.74 (s, 3H), 3.04~2.89 (m, 2H); ¹³C NMR (100 MHz, CDCl₃) δ: 153.8, 144.3, 139.3, 127.4, 125.4, 124.9, 117.1, 116.5, 115.2, 55.8, 52.1, 26.3; IR (film) ν: 3349, 2930, 1510 cm^－1; HRMS (ESI) calcd for C₁₄H₁₃ON₂S [M－H]^－ 257.0743, found 257.0742.

(S)-4-甲基-3-(对甲苯基氨基)戊腈(3n):黄色油状物, 0.0466 g, 产率77%, 77% ee. [α]_D²⁰+116.0 (c 1.01, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ: 7.07~6.97 (m, 2H), 6.59~6.50 (m, 2H), 3.53 (brs, 1H), 3.47~3.38 (m, 1H), 2.70~2.54 (m, 2H), 2.25 (s, 3H), 2.08~1.95 (m, 1H), 1.12~1.02 (m, 6H); ¹³C NMR (100 MHz, CDCl₃) δ: 144.2, 130.2, 127.8, 118.0, 113.8, 56.0, 31.8, 20.9, 20.5, 19.7, 18.9; IR (film) ν: 3385, 2961, 1520 cm^－1; HRMS (ESI) calcd for C₁₃H₁₉N₂ [M+H]⁺ 203.1543, found 203.1544.

(S)-3-苯基-3-(苄基氨基)丙腈(3o)^[30]:黄色油状物, 0.0341 g, 产率48%, 61% ee. [α]_D²⁰－10.3 (c 0.80, CHCl₃) (lit: [α]_D²⁵59.0 (c 0.16, CHCl₃)); ¹H NMR (400 MHz, CDCl₃) δ: 7.46~7.20 (m, 10H), 4.00 (t, J＝6.4 Hz, 1H), 3.81~3.53 (m, 2H), 2.68 (d, J＝6.4 Hz, 2H), 1.79 (brs, 1H); ¹³C NMR (100 MHz, CDCl₃) δ: 140.7, 139.6, 129.2, 128.7, 128.6, 128.3, 127.5, 127.0, 117.9, 58.5, 51.5, 27.0.

辅助材料(Supporting Information) 烯胺腈底物2和产物3的核磁谱图和液相图谱.这些材料可以免费从本刊网站(http://sioc-journal.cn/)上下载.

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图式 1 氨硼烷参与的转移氢化反应

Scheme 1 Transfer hydrogenations with ammonia borane

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图式 2 可能的反应机理

Scheme 2 Plausible reaction mechanism

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表 1 溶剂筛选^a

Table 1. Optimization of reaction solvent


Entry	Solvent	Conv.^b/%	ee^c/%
1	Toluene	58	59
2	THF	12	37
3	1, 4-Dioxane	18	49
4	CH₃CN	25	43
5	Hexane	18	37
6	MeOH	17	33
^a All reactions were carried out with enamine 2a (0.1 mmol), CPA (1a) and NH₃•BH₃ (1.1 equiv.) in solvent (0.5 mL) for 5 h at 60 ℃. ^b The conversion was determined by crude ¹H NMR. ^c The ee was determined by chiral HPLC, the absolute configuration of the product 3a were tentatively assigned by analogy with ref. [25].

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表 2 β-烯胺腈底物的不对称转移氢化

Table 2. Asymmetric transfer hydrogenation of β-enamino cyanides

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