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以汉斯酯1 4-二氢吡啶为还原剂的还原胺化反应研究
以汉斯酯1 4-二氢吡啶为还原剂的还原胺化反应研究
6023/cjoc201302016 研究论文
Chinese Journal of Organic Chemistry ARTICLE
以汉斯酯 1,4-二氢吡啶为还原剂的还原胺化反应研究
Abstract Reductive amination is an important reaction in organic synthesis. Aldehyde and ketone can react with primary and
secondary amine in the presence of appropriate reducing reagent to afford secondary and tertiary amine. Hantzsch ester
1,4-dihydropyridine (HEH) is employed in the selective reduction and reductive amination of α,β-unsaturated carbonyl com-
pounds, electron-deficient conjugate alkene and imine as a biomimetic organic reductant. In this paper, the possibility of la-
beling aldehyde by reductive amination using HEH as reductant, 7-amino-4-methylcoumarin and aldehydes as models was
studied. Sixteen products were synthesized, among them, thirteen compounds were not reported in the literature.
Keywords Hantzsch ester 1,4-dihydropyridine; reductive amination; coumarin; aldehyde; label
* E-mail: jlliu@nwu.edu.cn
Received March 2, 2013; revised April 26, 2013; published online May 24, 2013.
Project supported by the National Natural Science Foundation of China (Nos. 20872118, 30070905), the Key Laboratory Fund of Shaanxi Province of China
(Nos. 2010JS097, 11JS090, 12JS110) and the Foundation of the Education Department of Shaanxi Province (No. 08jk477).
国家自然科学基金(Nos. 20872118, 30070905)、陕西省重点实验室基金(Nos. 2010JS097, 11JS090, 12JS110)和陕西省教育厅基金(No. 08jk477)资助项目.
1960 http://sioc-journal.cn/ © 2013 Chinese Chemical Society & SIOC, CAS Chin. J. Org. Chem. 2013, 33, 1960~1964
Chinese Journal of Organic Chemistry ARTICLE
CH3 CH3
CHO
EtOOC EtOOC COOEt
COOEt
+ + (1)
+
O O S O O N
NH2 N N
R H H R
1 H2N NH2 5
2 3
4a ~ 4p
4a R = 2-OH-3-OCH3 4i R = 4-Br
4b R = 2-OH 4j R = 3,4-(OCH3)2
4c R = 2-OH-5-Cl 4k R = 4-OCH3
4d R = 2,4-Cl 4l R = 3,4-Cl2
4e R = 4-Cl 4m R = 2,4,5-(OCH3)3
4f R = 2-Cl 4n R = 2,3-Cl
4g R = 2-OH-3,5-Cl2 4o R = 2-OCH3
4h R = 2-OH-3,5-Br2 4p R = 2,3,4-(OCH3)3
Chin. J. Org. Chem. 2013, 33, 1960~1964 © 2013 Chinese Chemical Society & SIOC, CAS http://sioc-journal.cn/ 1961
有机化学 研究论文
2.0 Hz, 1H), 7.15 (t, J=6.0 Hz, 1H, NH), 7.11 (dd, J=8.0, 喃-2-酮(4h): 2.91 g 淡黄色固体, 产率 66.3%. m.p. 230~
2.0 Hz, 1H), 6.86 (d, J=8.0 Hz, 1H), 6.64 (dd, J=8.0, 2.0 232 ℃; 1H NMR (DMSO-d6, 400 MHz) δ: 9.71 (s, 1H,
Hz, 1H), 6.39 (d, J=2.0 Hz, 1H), 5.92 (s, 1H, H-3), 4.27 OH), 7.64 (d, J=2.0 Hz, 1H), 7.46 (dd, J=8.0, 2.0 Hz,
(d, J=6.0 Hz, 2H, CH2), 2.30 (s, 3H, CH3). Anal. calcd for 1H), 7.30 (s, 1H), 7.17 (t, J=6.0 Hz, 1H, NH), 6.63 (d,
C17H14NO3Cl: C 64.66, H 4.44, N 4.44; found C 64.42, H J=8.0 Hz, 1H), 6.38 (s, 1H), 5.94 (s, 1H, H-3), 4.36 (d,
4.17, N 4.23. J=6.0 Hz, 2H, CH2), 2.30 (s, 3H, CH3); ESI-MS m/z (%):
7-(2',4'-二氯苄基氨基)-4-甲基-2H-苯并吡喃-2-酮 462 ([M+Na]+, 100). Anal. calcd for C17H13NO3Br2: C
(4d): 2.73 g 白色固体, 产率 81.7%. m.p. 191~193 ℃; 1H 46.47, H 2.96, N 3.19; found C 46.64, H 2.79, N 3.11.
NMR (DMSO-d6, 400 MHz) δ: 7.66 (d, J=2.0 Hz, 1H), 7-(4'-溴苄基氨基)-4-甲基-2H-苯并吡喃-2-酮(4i):
7.46 (d, J=8.0 Hz, 1H), 7.42 (dd, J=8.0, 2.0 Hz, 1H), 2.36 g 灰白色固体, 产率 68.7%. m.p. 198~200 ℃; 1H
7.37 (d, J=8.0 Hz, 1H), 7.31 (t, J=6.0 Hz, 1H, NH), 6.64 NMR (DMSO-d6, 400 MHz) δ: 7.53 (d, J=8.0 Hz, 2H),
(dd, J=8.0, 2.0 Hz, 1H), 6.37 (d, J=2.0 Hz, 1H), 5.95 (s, 7.43 (d, J=8.0 Hz, 1H), 7.30~7.33 (m, 3H), 6.63 (dd, J=
1H, H-3), 4.42 (d, J=6.0 Hz, 2H, CH2), 2.30 (s, 3H, CH3); 8.0, 2.0 Hz, 1H), 6.38 (d, J=2.0 Hz, 1H), 5.92 (s, 1H,
ESI-MS m/z (%): 357 ([M+Na]+, 100). Anal. calcd for H-3), 4.35 (d, J=6.0 Hz, 2H, CH2), 2.29 (s, 3H, CH3);
C17H13NO2Cl2: C 61.08, H 3.89, N 4.19; found C 61.27, H ESI-MS m/z (%): 367 ([M+Na]+, 100), 711 ([二聚物+
3.64, N 4.12. Na]+, 95). Anal. calcd for C17H14NO2Br: C 59.30, H 4.07,
7-(4'-氯苄基氨基)-4-甲基-2H-苯并吡喃-2-酮(4e): N 4.07; found C 59.19, H 3.89, N 4.01.
2.36 g 白色固体, 产率 78.8%. m.p. 197~199 ℃; 1H 7-(3',4'-二甲氧基苄基氨基)-4-甲基-2H-苯并吡喃-2-
NMR (DMSO-d6, 400 MHz) δ: 7.44 (d, J=8.0 Hz, 1H), 酮(4j): 2.00 g 土黄色固体, 产率 61.5%. m.p. 200~203
7.41 (d, J=8.0 Hz, 2H), 7.38 (d, J=8.0 Hz, 2H), 7.32 (t, ℃; 1H NMR (DMSO-d6, 400 MHz) δ: 7.42 (d, J=9.0 Hz,
J=6.0 Hz, 1H, NH), 6.64 (dd, J=8.0, 2.0 Hz, 1H), 6.38 (s, 1H), 7.18 (t, J=6.0 Hz, 1H, NH), 6.98 (s, 1H), 6.90 (d, J=
1H), 5.93 (s, 1H, H-3), 4.37 (d, J=6.0 Hz, 2H, CH2), 2.30 8.0 Hz, 1H), 6.87 (d, J=8.0 Hz, 1H), 6.65 (d, J=9.0 Hz,
(s, 3H, CH3); ESI-MS m/z (%): 323 ([M+Na]+, 100). 1H), 6.40 (s, 1H), 5.91 (s, 1H, H-3), 4.27 (d, J=6.0 Hz,
Anal. calcd for C17H14NO2Cl: C 68.11, H 4.67, N 4.67; 2H, CH2), 3.73 (s, 3H, OCH3), 3.71 (s, 3H, OCH3), 2.29 (s,
found C 68.35, H 4.51, N 4.42. 3H, CH3); ESI-MS m/z (%): 348 ([M+Na]+, 100), 673
7-(2'-氯苄基氨基)-4-甲基-2H-苯并吡喃-2-酮(4f): ([二聚物+Na]+, 10). Anal. calcd for C19H19NO4: C 70.15,
2.09 g 灰白色固体, 产率 69.7%. m.p. 175~177 ℃; 1H H 5.85, N 4.31; found C 69.93, H 5.64, N 4.12.
NMR (DMSO-d6, 400 MHz) δ: 7.48~7.51 (m, 1H), 7.46 7-(4'-甲氧基苄基氨基)-4-甲基-2H-苯并吡喃-2-酮
(d, J=8.0 Hz, 1H), 7.38~7.40 (m, 1H), 7.27~7.34 (m, (4k): 2.27 g 灰色固体, 产率 77.1%. m.p. 142~145 ℃; 1H
3H), 6.65 (d, J=9.0 Hz, 1H), 6.38 (s, 1H), 5.94 (s, 1H, NMR (DMSO-d6, 400 MHz) δ: 7.42 (d, J=9.0 Hz, 1H),
H-3), 4.44 (d, J=6.0 Hz, 2H, CH2), 2.31 (s, 3H, CH3); 7.28 (d, J=8.0 Hz, 2H), 7.21 (t, J=6.0 Hz, 1H, NH), 6.90
ESI-MS m/z (%): 323 ([M+Na]+, 100). Anal. calcd for (d, J=8.0 Hz, 2H), 6.64 (dd, J=9.0, 2.0 Hz, 1H), 6.39 (d,
C17H14NO2Cl: C 68.11, H 4.67, N 4.67; found C 68.23, H J=2.0 Hz, 1H), 5.91 (s, 1H, H-3), 4.28 (d, J=6.0 Hz, 2H,
4.45, N 4.52. CH2), 3.72 (s, 3H, OCH3), 2.29 (s, 3H, CH3); ESI-MS m/z
7-(2'-羟基-3',5'-二氯苄基氨基)-4-甲基-2H-苯并吡 (%): 318 ([M+Na] + , 100), 613 ([二聚物+Na] + , 30).
喃-2-酮(4g): 2.18 g 淡黄色固体, 产率 62.3%. m.p. 235~ Anal. calcd for C18H17NO3: C 73.24, H 5.76, N 4.75; found
237℃; 1H NMR (DMSO-d6, 400 MHz) δ: 9.87 (s, 1H, C 73.12, H 5.83, N 4.56.
OH), 7.47 (d, J=8.0 Hz, 1H), 7.43 (d, J=2.0 Hz, 1H), 7-(3',4'-二氯苄基氨基)-4-甲基-2H-苯并吡喃-2-酮
7.19 (t, J=6.0 Hz, 1H, NH), 7.16 (d, J=2.0 Hz, 1H), 6.64 (4l): 2.37 g 灰白色固体, 产率 70.8%. m.p. 221~223 ℃;
1
(dd, J=8.0, 2.0 Hz, 1H), 6.39 (d, J=2.0 Hz, 1H), 5.96 (s, H NMR (DMSO-d6, 400 MHz) δ: 7.61~7.64 (m, 2H),
1H, H-3), 4.36 (d, J=6.0 Hz, 2H, CH2), 2.32 (s, 3H, CH3); 7.45 (d, J=8.0 Hz, 1H), 7.36 (dd, J=8.0, 2.0 Hz, 1H),
ESI-MS m/z (%): 373 ([M+Na]+, 100). Anal. calcd for 7.32 (t, J=6.0 Hz, 1H, NH), 6.65 (dd, J=8.0, 2.0 Hz, 1H),
C17H13NO3Cl2: C 58.29, H 3.71, N 4.00; found C 58.45, H 6.41 (d, J=2.0 Hz, 1H), 5.94 (s, 1H, H-3), 4.40 (d, J=6.0
3.53, N 3.91. Hz, 2H, CH2), 2.30 (s, 3H, CH3); ESI-MS m/z (%): 357
7-(2'-羟基-3',5'-二溴苄基氨基)-4-甲基-2H-苯并吡 ([M+Na]+, 100), 691 ([二聚物+Na]+, 75). Anal. calcd
1962 http://sioc-journal.cn/ © 2013 Chinese Chemical Society & SIOC, CAS Chin. J. Org. Chem. 2013, 33, 1960~1964
Chinese Journal of Organic Chemistry ARTICLE
Chin. J. Org. Chem. 2013, 33, 1960~1964 © 2013 Chinese Chemical Society & SIOC, CAS http://sioc-journal.cn/ 1963
有机化学 研究论文
表 3 反应温度对产物收率的影响 References
Table 3 Effects of temperature on yield of product
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2.2 荧光光谱
8815.
首先测定 11 个目标产物在甲醇溶液中的紫外吸收 [10] Nguyen, Q. P. B.; Kim, J. N.; Kim, T. H. Tetrahedron 2012, 68,
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[11] Itoh, T.; Nagata, K.; Miyazaki, M.; Ishikawa, H.; Kurihara, A.;
外光谱中的最大吸收峰值作为激发波长, 然后测定它们 Ohsawa, A. Tetrahedron 2004, 60, 6649
的荧光光谱. 测定结果见图 2. 从图中可以看出, 目标产 [12] Itoh, T.; Nagata, K.; Kurihara, A.; Miyazaki, M.; Ohsawa, A.
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[15] Yang, J.-H.; Ji, C.-B.; Zhao, Y.-M. Chin. J. Org. Chem. 2008, 28,
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图 2 室温下目标产物在甲醇中的荧光光谱 (Lu, Y.)
Figure 2 Fluorescence spectra of target compounds in CH3OH
at room temperature
The excitation λ=360 nm
1964 http://sioc-journal.cn/ © 2013 Chinese Chemical Society & SIOC, CAS Chin. J. Org. Chem. 2013, 33, 1960~1964