含二苯醚结构的联苯胺类衍生物的合成及活性研究

doi:10.6023/cjoc201904049

摘要/Abstract

采用活性亚结构拼接的方法将二苯醚活性结构单元引入到联苯胺的结构中, 设计并合成了一系列未见文献报道的新型含二苯醚结构的联苯胺类衍生物. 此外, 所得目标化合物的结构经 ¹H NMR、 ¹³C NMR、高分辨质谱(HRMS)及熔点(m.p.)确认. 测试了该类化合物对猪心来源琥珀酸-细胞色素c氧化还原酶(SCR)的抑制活性, 活性结果表明: N-{4-[2-氯-4-(三氟甲基)苯氧基]-3-氟苯基}-[1,1'-联苯]-4-胺(3o)的抑制活性较好, 抑制率达到了46.44%.

关键词: 联苯胺, 二苯醚, 合成, 生物活性

According to the principle of "splicing-up" bioactive substructures, a new series of target compounds were designed and synthesized by incorporating a diphenyl ether moiety into 4-phenylanilines. Moreover, the structures of the synthesized compounds were confirmed by ¹H NMR, ¹³C NMR, HRMS and melting points measurements. The inhibitory activities of these compounds were evaluated against succinate-cytochrome reductase (SCR). Based on the bioassay results, target compound N-(4-(2-chloro-4-(trifluoromethyl)phenoxy)-3-fluorophenyl)-[1,1'-biphenyl]-4-amine (3o) exhibited an inhibition rate of 46.44% at a concentration of 10 μmol?L ^–1, which demonstrated potential values for further investigations.

Key words: 4-phenylanilines, diphenyl ether, synthesis, biological activities

引用此文

汪万强, 程兰, 彭宏英, 姚维忠, 张锐, 陈宬, 程华. 含二苯醚结构的联苯胺类衍生物的合成及活性研究[J]. 有机化学, 2019, 39(10): 2851-2859.

Wang Wanqiang, Cheng Lan, Peng Hongying, Yao Weizhong, Zhang Rui, Chen Cheng, Cheng Hua. Synthesis and Biological Activities of New 4-PhenylanilinesContaining the Diphenyl Ether Moiety[J]. Chinese Journal of Organic Chemistry, 2019, 39(10): 2851-2859.

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Entry	[Cu] (equiv.)	Base (equiv.)	Solvent	Time/ h	Yield^a/ %
1	Cu(OAc)₂ (1.00)	K₂CO₃ (2.00)	DMF	60	65
2	Cu(OAc)₂?H₂O (1.00)	K₂CO₃ (2.00)	DMF	60	58
3	CuCl₂ (1.00)	K₂CO₃ (2.00)	DMF	60	Trace
4	CuCl₂?2H₂O (1.00)	K₂CO₃ (2.00)	DMF	60	Trace
5	CuBr₂ (1.00)	K₂CO₃ (2.00)	DMF	60	Trace
6	CuCl (1.00)	K₂CO₃ (2.00)	DMF	60	Trace
7	CuBr (1.00)	K₂CO₃ (2.00)	DMF	60	Trace
8	CuI (1.00)	K₂CO₃ (2.00)	DMF	60	Trace
9	Cu(OAc)₂ (1.00)	Cs₂CO₃ (2.00)	DMF	60	Trace
10	Cu(OAc)₂ (1.00)	Pyridine (2.00)	DMF	60	Trace
11	Cu(OAc)₂ (1.00)	Et₃N (2.00)	DMF	48	75
12	Cu(OAc)₂ (1.00)	Et₃N (2.00)	DCM	48	84
13	Cu(OAc)₂ (1.00)	Et₃N (2.00)	MeCN	48	90
14	Cu(OAc)₂ (0.50)	Et₃N (2.00)	MeCN	72	70
15	Cu(OAc)₂ (0.25)	Et₃N (2.00)	MeCN	72	65
16	Cu(OAc)₂ (1.00)	Et₃N (2.00)	MeCN	72	30

Entry	[Cu] (equiv.)	Base (equiv.)	Solvent	Time/ h	Yield^a/ %
1	Cu(OAc)₂ (1.00)	K₂CO₃ (2.00)	DMF	60	65
2	Cu(OAc)₂?H₂O (1.00)	K₂CO₃ (2.00)	DMF	60	58
3	CuCl₂ (1.00)	K₂CO₃ (2.00)	DMF	60	Trace
4	CuCl₂?2H₂O (1.00)	K₂CO₃ (2.00)	DMF	60	Trace
5	CuBr₂ (1.00)	K₂CO₃ (2.00)	DMF	60	Trace
6	CuCl (1.00)	K₂CO₃ (2.00)	DMF	60	Trace
7	CuBr (1.00)	K₂CO₃ (2.00)	DMF	60	Trace
8	CuI (1.00)	K₂CO₃ (2.00)	DMF	60	Trace
9	Cu(OAc)₂ (1.00)	Cs₂CO₃ (2.00)	DMF	60	Trace
10	Cu(OAc)₂ (1.00)	Pyridine (2.00)	DMF	60	Trace
11	Cu(OAc)₂ (1.00)	Et₃N (2.00)	DMF	48	75
12	Cu(OAc)₂ (1.00)	Et₃N (2.00)	DCM	48	84
13	Cu(OAc)₂ (1.00)	Et₃N (2.00)	MeCN	48	90
14	Cu(OAc)₂ (0.50)	Et₃N (2.00)	MeCN	72	70
15	Cu(OAc)₂ (0.25)	Et₃N (2.00)	MeCN	72	65
16	Cu(OAc)₂ (1.00)	Et₃N (2.00)	MeCN	72	30

Entry	Compd.	R¹	R²	Yield^a/%	I^b/%
1	3a	H	H	90	30.42
2	3b	4-Br	H	76	36.95
3	3c	2,4-Cl₂	H	71	36.09
4	3d	2-Cl-4-CF₃	H	86	39.01
5	3e	2-Br-4-Cl	H	74	32.16
6	3f	2,4,6-Cl₃	2-Cl	94	13.72
7	3g	2,4-Cl₂	2-Cl	69	6.30
8	3h	2-Me-4-Cl	2-Cl	67	12.71
9	3i	2-Cl-4-CF₃	2-Cl	74	24.47
10	3j	2-Br-4-Cl	2-Cl	68	6.81
11	3k	2-Naphthyl^c	2-Cl	76	5.73
12	3l	1-Br-2-naphthyl^c	2-Cl	70	1.91
13	3m	2,4-Cl₂	2-F	75	37.70
14	3n	2-Me-4-Cl	2-F	95	37.39
15	3o	2-Cl-4-CF₃	2-F	73	46.44
16	3p	2,4,6-Cl₃	2-F	70	16.02
17	3q	2-Naphthyl^c	2-F	65	20.59
18	3r	1-Br-2-naphthyl^c	2-F	76	7.62
19	3s	2,4-Cl₂	2,6-Cl₂	50	4.07
20	3t	2-Br-4-Cl	2,6-Cl₂	54	10.07
21	3u	2-Naphthyl^c	2,6-Cl₂	78	26.09
22	3v	1-Br-2-naphthyl^c	2,6-Cl₂	71	3.74
23	3w	2,4-Cl₂	2,6-F₂	81	38.96
24	3x	4-Cl-2-Me	2,6-F₂	68	37.78
25	3y	2-Br-4-Cl	2,6-F₂	62	43.25
26	3z	2-Naphthyl^c	2,6-F₂	61	43.20
27	3a'	1-Br-2-naphthyl^c	2,6-F₂	68	10.23
28	嘧菌酯^d				95.95

Entry	Compd.	R¹	R²	Yield^a/%	I^b/%
1	3a	H	H	90	30.42
2	3b	4-Br	H	76	36.95
3	3c	2,4-Cl₂	H	71	36.09
4	3d	2-Cl-4-CF₃	H	86	39.01
5	3e	2-Br-4-Cl	H	74	32.16
6	3f	2,4,6-Cl₃	2-Cl	94	13.72
7	3g	2,4-Cl₂	2-Cl	69	6.30
8	3h	2-Me-4-Cl	2-Cl	67	12.71
9	3i	2-Cl-4-CF₃	2-Cl	74	24.47
10	3j	2-Br-4-Cl	2-Cl	68	6.81
11	3k	2-Naphthyl^c	2-Cl	76	5.73
12	3l	1-Br-2-naphthyl^c	2-Cl	70	1.91
13	3m	2,4-Cl₂	2-F	75	37.70
14	3n	2-Me-4-Cl	2-F	95	37.39
15	3o	2-Cl-4-CF₃	2-F	73	46.44
16	3p	2,4,6-Cl₃	2-F	70	16.02
17	3q	2-Naphthyl^c	2-F	65	20.59
18	3r	1-Br-2-naphthyl^c	2-F	76	7.62
19	3s	2,4-Cl₂	2,6-Cl₂	50	4.07
20	3t	2-Br-4-Cl	2,6-Cl₂	54	10.07
21	3u	2-Naphthyl^c	2,6-Cl₂	78	26.09
22	3v	1-Br-2-naphthyl^c	2,6-Cl₂	71	3.74
23	3w	2,4-Cl₂	2,6-F₂	81	38.96
24	3x	4-Cl-2-Me	2,6-F₂	68	37.78
25	3y	2-Br-4-Cl	2,6-F₂	62	43.25
26	3z	2-Naphthyl^c	2,6-F₂	61	43.20
27	3a'	1-Br-2-naphthyl^c	2,6-F₂	68	10.23
28	嘧菌酯^d				95.95