三组分串联反应一锅合成多环稠合的1,5-苯并二氮杂䓬化合物

doi:10.6023/cjoc202006040

摘要/Abstract

以取代的邻苯二胺、1,3-环戊二酮或1,3-环己二酮(5,5-二甲基-1,3-环己二酮)、2,3-二羰基化合物为原料, 无水乙醇为溶剂, 对甲苯磺酸为催化剂, 经2~5 h串联反应一锅合成43种新颖的1,5-苯并二氮杂?化合物, 产率最高可达95%. 该反应序列首先通过两次的亲核加成-脱水反应过程, 形成分子内亚胺和烯胺结构的活性中间体, 然后再经分子内的碳碳偶联环合-质子转移等过程, 生成多环稠合的1,5-苯并二氮杂?目标化合物, 实现了在一个反应体系中形成一个二氮杂七元环和四个新化学键(两个C—N, 一个C=C, 一个C—C). 该方法操作简单, 反应便捷, 对环境友好, 产率高, 为1,5-苯并二氮杂?化合物的合成提供绿色环保, 高效简便的合成思路.

关键词: 1,5-苯并二氮杂?类化合物, 串联反应, 绿色合成, 机理

43 novel 1,5-benzodiazepine compounds were obtained via one-pot multicomponent and tadem reactions for 2~5 h and the yield of the target compounds is up to 95%. These reactions were achieved by reacting substituted 1,2-phenylene- diamines, 1,3-cyclopentanedione or 1,3-cyclohexanedione (5,5-dimethyl-1,3-cyclohexanedione), 2,3-dicarbonyl compounds with p-toluenesulfonic acid as catalyst in EtOH. The active intermediates with the imine and enamine structures in the molecule were formed by two nucleophilic addition-dehydration processes and then 1,5-benzodiazepine compounds were obtained via carbon-carbon coupling cyclization and proton transfer processes, which realized the construction of one new seven- membered ring and four new chemical bonds (two C—N, one C=C, one C—C) in one-pot. It provides a green, environmentally friendly, efficient and simple synthetic thought for the synthesis of 1,5-benzodiazepine compounds.

Key words: 1,5-benzodiazepine compound, tadem reaction, green synthesis, mechanism

引用此文

李静, 郝振芳, 张凯悦, 王兰芝. 三组分串联反应一锅合成多环稠合的1,5-苯并二氮杂䓬化合物[J]. 有机化学, 2021, 41(2): 806-818.

Jing Li, Zhenfang Hao, Kaiyue Zhang, Lanzhi Wang. One-Pot Synthesis of 1,5-Benzodiazepine Compounds by Three-Component Tadem Reaction[J]. Chinese Journal of Organic Chemistry, 2021, 41(2): 806-818.

导出引用 EndNote|Reference Manager|ProCite|BibTeX|RefWorks

分享此文

图/表 7

参考文献 21

[1]	Wang K.X.; Wang L.Z. Chin. J. Org. Chem. 2019, 39, 1147. (in Chinese) doi: 10.6023/cjoc201809038 pmid: 5C3905C4-3AAA-4459-A30B-B8D2D6DC7D08
	王凯旋, 王兰芝, 有机化学, 2019, 39, 1147.). doi: 10.6023/cjoc201809038 pmid: 5C3905C4-3AAA-4459-A30B-B8D2D6DC7D08
[2]	Reen G.K.; Ahuja M.; Kumar A.; Patidar R.; Sharma P. Org. Prep. Proced. Int. 2017, 49, 273. doi: 10.1080/00304948.2017.1320927
[3]	Praveen C.; Nandakumar A.; Dheenkumar P.; Muralidharan D.; Perumal P.T. J. Chem. Sci. 2012, 124, 609. doi: 10.1007/s12039-012-0251-3
[4]	Wang N.; Arulkumar M.; Chen X.Y.; Wang B.W.; Chen S.H.; Yao C.; Wang Z.Y. Chin. J. Org. Chem. 2019, 39, 2771. (in Chinese) doi: 10.6023/cjoc201904061 pmid: BC8398ED-3A73-4294-9632-8B4D858A4B4D
	王能, Arulkumar, M., 陈孝云, 王柏文, 陈思鸿, 姚辰, 汪朝阳, 有机化学, 2019, 39, 2771.). doi: 10.6023/cjoc201904061 pmid: BC8398ED-3A73-4294-9632-8B4D858A4B4D
[5]	Tseng C.H.; Lin C.K.; Chen Y.L.; Hsu C.Y.; Wu H.N.; Tseng C.K.; Lee J.C. Eur. J. Med. Chem. 2014, 79, 66. doi: 10.1016/j.ejmech.2014.03.074
[6]	Giroux S.; Xu J.; Reddy T.J.; Morris M.; Cottrell K.M.; Cadilhac C.; Henderson J.A.; Nicolas O.; Bilimoria D.; Denis F.; Mani N.; Ewing N.; Shawgo R.; L'Heureux L.; Selliah S.; Chan L.; Chauret N.; Berlioz-Seux F.; Namchuk M.N.; Grillot A.-L.; Bennani Y.L.; Das S.K.; Maxwell J.P. ACS Med. Chem. Lett. 2014, 5, 240. doi: 10.1021/ml300461f pmid: 24900811
[7]	Yin L.Y.; Wang L.Z. Tetrahedron Lett. 2016, 57, 5935. doi: 10.1016/j.tetlet.2016.11.089
[8]	Fontaine R.; Mercier P.; Beaudry P.; Annable L.; Chouinard G. Acta Psychiatr. Scand. 1986, 74, 2.
[9]	Nguema Ongone, T.; Achour, R.; El Ghoul, M.; El Ouasif, L.; Taghzouti, K.; El Jemli, M.; Cherrah, Y.; Alaoui, K.; Zellou, A. Adv. Pharmacol. Sci. 2018, 2018, 6042602.
[10]	Indalkar K.S.; Patil M.S.; Chaturbhuj G.U. Tetrahedron Lett. 2017, 58, 4496. doi: 10.1016/j.tetlet.2017.10.030
[11]	Shearer C.; Desaunay O.; Zorc S.; Richaud A.D.; Samanta S.S.; Jeedimalla N.; Roche S.P. Tetrahedron 2019, 75, 43.
[12]	Zhou L.Y.; Wang M.L.; Wang K.X.; Wen T.T.; Wang L.Z. Appl. Organomet. Chem. 2020, 34, e5757.
[13]	Wu H.T.; Wang L.Z. New J. Chem. 2020, 44, 10428. doi: 10.1039/C9NJ06332C
[14]	Yin L.Y. M.S. Thesis, Hebei Normal University, Shijiazhuang, 2017. (in Chinese)
	尹刘燕, 硕士论文, 河北师范大学, 石家庄, 2017.).
[15]	He L. M.S. Thesis, Hebei Normal University, Shijiazhuang, 2019. (in Chinese)
	何林, 硕士论文, 河北师范大学, 石家庄, 2019.).
[16]	Sun Y.W.; Zhou L.Y.; Wang L.Z. Chin. J. Org. Chem. 2019, 39, 3516. (in Chinese) doi: 10.6023/cjoc201904026 pmid: 58004467-964E-4682-B3F1-C24DA6F65D6A
	孙悦玮, 周来运, 王兰芝, 有机化学, 2019, 39, 3516.). doi: 10.6023/cjoc201904026 pmid: 58004467-964E-4682-B3F1-C24DA6F65D6A
[17]	Sun Y.W.; Wang L.Z. New J. Chem. 2018, 42, 20032. doi: 10.1039/C8NJ04893B
[18]	Leyva-Perez A.; Cabrero-Antonino J.R.; Corma A. Tetrahedron 2010, 66, 8203. doi: 10.1016/j.tet.2010.08.022
[19]	Fader L.D.; Bethell R.; Bonneau P.; Bos M.; Bousquet Y.; Cordingley M.G.; Coulombe R.; Deroy P.; Faucher A.M.; Gagnon A.; Goudreau N.; Grand-Maitre C.; Guse I.; Hucke O.; Kawai S.H.; Lacoste J.E.; Landry S.; Lemke C.T.; Malenfant E.; Mason S.; Morin S.; O'Meara J.; Simoneau B.; Titolo S.; Yoakim C. Bioorg. Med. Chem. Lett. 2011, 21, 398. doi: 10.1016/j.bmcl.2010.10.131
[20]	Schimer J.; Cigler P.; Vesely J.; Saskova K.G.; Lepsik M.; Brynda J.; Rezacova P.; Kozisek M.; Cisarova I.; Oberwinkler H.; Kraeusslich H.G.; Konvalinka J. J. Med. Chem. 2012, 55, 10130. doi: 10.1021/jm301249q
[21]	McGowan D.; Nyanguile O.; Cummings M.D.; Vendeville S.; Vandyck K.; Van den Broeck W.; Boutton C.W.; De Bondt H.; Quirynen L.; Amssoms K.; Bonfanti J.-F.; Last S.; Rombauts K.; Tahri A.; Hu L.; Delouvroy F.; Vermeiren K.; Vandercruyssen G.; Van der Helm L.; Cleiren E.; Mostmans W.; Lory P.; Pille G.; Van Emelen K.; Fanning G.; Pauwels F.; Lin T.I.; Simmen K.; Raboisson P. Bioorg. Med. Chem. Lett. 2009, 19, 2492. doi: 10.1016/j.bmcl.2009.03.035

Entry	Solvent	Temp./℃	Catalyst^b	Time/h	Yield^c/%
1	EtOH	r.t.	Free	9	30
2	EtOH	r.t.	Et₃N^d	—	—
3	EtOH	r.t.	CeCl₃	6	65
4	EtOH	r.t.	PMA	5	60
5	EtOH	r.t.	Mandelic acid	4	75
6	EtOH	r.t.	PTSA	3	90
7	EtOH	–10	PTSA	24	53
8	EtOH	0	PTSA	17	57
9	EtOH	Reflux	PTSA	2	64
10	MeOH	r.t.	PTSA	3	90
11	PhMe	r.t.	PTSA	4.5	73
12	MeCN	r.t.	PTSA	4	70

Entry	Solvent	Temp./℃	Catalyst^b	Time/h	Yield^c/%
1	EtOH	r.t.	Free	9	30
2	EtOH	r.t.	Et₃N^d	—	—
3	EtOH	r.t.	CeCl₃	6	65
4	EtOH	r.t.	PMA	5	60
5	EtOH	r.t.	Mandelic acid	4	75
6	EtOH	r.t.	PTSA	3	90
7	EtOH	–10	PTSA	24	53
8	EtOH	0	PTSA	17	57
9	EtOH	Reflux	PTSA	2	64
10	MeOH	r.t.	PTSA	3	90
11	PhMe	r.t.	PTSA	4.5	73
12	MeCN	r.t.	PTSA	4	70


5aaa, 2 h, 90%	5baa, 2 h, 92%	5caa, 1.5 h, 90%	5daa, 2 h, 86%	5eaa, 3 h, 74%

5faa,3 h, 80%	5gaa, 4 h, 70%	5haa, 4 h, 80%	5aab, 3 h, 90%	5bab, 3 h, 90%

5cab, 2 h, 90%	5dab, 4 h, 88%	5eab, 3 h, 80%	5fab, 3.5 h, 77%	5gab, 4 h, 72%

5aba, 2 h, 90%	5bba, 1.5 h, 92%	5cba, 1.5 h, 95%	5dba, 3 h, 88%	5eba, 2 h, 83%

5fba, 2 h, 86%	5gba, 4 h, 77%	5abb, 1.5 h, 88%	5bbb, 2.5 h, 90%	5cbb, 3 h, 90%

5dbb, 3 h, 82%	5ebb, 2.5 h, 78%	5fbb, 3 h, 80%	5gbb, 5 h, 75%	5aca, 3 h, 90%


5aaa, 2 h, 90%	5baa, 2 h, 92%	5caa, 1.5 h, 90%	5daa, 2 h, 86%	5eaa, 3 h, 74%

5faa,3 h, 80%	5gaa, 4 h, 70%	5haa, 4 h, 80%	5aab, 3 h, 90%	5bab, 3 h, 90%

5cab, 2 h, 90%	5dab, 4 h, 88%	5eab, 3 h, 80%	5fab, 3.5 h, 77%	5gab, 4 h, 72%

5aba, 2 h, 90%	5bba, 1.5 h, 92%	5cba, 1.5 h, 95%	5dba, 3 h, 88%	5eba, 2 h, 83%

5fba, 2 h, 86%	5gba, 4 h, 77%	5abb, 1.5 h, 88%	5bbb, 2.5 h, 90%	5cbb, 3 h, 90%

5dbb, 3 h, 82%	5ebb, 2.5 h, 78%	5fbb, 3 h, 80%	5gbb, 5 h, 75%	5aca, 3 h, 90%


5bca, 2 h, 92%	5cca, 2 h, 90%	5dca, 3 h, 88%	5eca, 3.5 h, 81%	5fca, 3 h, 86%

5gca, 4.5 h, 80%	5acb, 3 h, 88%	5bcb, 3 h, 88%	5ccb, 2 h, 90%	5dcb, 3.5 h, 83%

5ecb, 3.5 h, 83%	5fcb, 3 h, 83%	5gcb, 5 h, 80%