8-[(3,4,4-三氟丁-3-烯-1-基)硫基]取代的新型甲基黄嘌呤及其衍生物的合成和生物活性

doi:10.6023/cjoc202012006

摘要/Abstract

以8-氯茶碱和4-溴-1,1,2-三氟丁-1-烯为原料, 经由亲核取代、保护、脱保护、氧化等多步反应合成了一系列结构新颖的8-[(3,4,4-三氟丁-3-烯-1-基)硫基]取代的甲基黄嘌呤及其衍生物, 并通过熔点、¹H NMR、¹³C NMR、¹⁹F NMR和HRMS对新化合物进行了结构确认. 初步生物活性测试结果表明, 这些化合物大多具有较好的杀虫活性, 其中1,3,7-三甲基-8-[(3,4,4-三氟丁-3-烯-1-基)硫基]-3,7-二氢-1H-嘌呤-2,6-二酮(5a)、7-异丁基-1,3-二甲基-8-[(3,4,4-三氟丁-3-烯-1-基)硫基]-3,7-二氢-1H-嘌呤-2,6-二酮(5c)和7-异丁基-1,3-二甲基-8-[(3,4,4-三氟丁-3-烯-1-基)磺酰基]-3,7-二氢-1H-嘌呤- 2,6-二酮(5h)在200 mg?L^–1浓度下对东方粘虫(Mythimna separata Walker)具有70%的致死率; 5a、5c和1,3,7-三甲基- 8-[(3,4,4-三氟丁-3-烯-1-基)磺酰基]-3,7-二氢-1H-嘌呤-2,6-二酮(5f)在10 mg?L^–1浓度下对小菜蛾(Plutella xylostellaL.)分别具有72%、80%和65%的致死率. 部分化合物在50 mg?L^–1浓度下也表现出一定的抑菌活性, 其中7-环丙基甲基-1,3-二甲基-8-[(3,4,4-三氟丁-3-烯-1-基)硫基]-3,7-二氢-1H-嘌呤-2,6-二酮(5b)对辣椒疫霉病菌(Phytophthora capsici)和黄瓜灰霉病菌(Botrytis cinerea)分别具有66.7%和61.1%的抑制率, 5c对黄瓜灰霉病菌具有55.6%的抑制率. 该类化合物为新型杀虫剂的研究和开发提供了新的先导结构.

关键词: 8-取代甲基黄嘌呤衍生物, 合成, 杀虫活性, 抑菌活性, 构效关系

Using 8-chlorotheophylline and 4-bromo-1,1,2-trifluorobut-1-ene as materials, a series of novel 8-((3,4,4-tri- fluorobut-3-en-1-yl)thio)-substituted methylxanthines and their derivatives were successfully synthesized through nucleophilic substitution, protection, deprotection, and oxidation. The structures of the title compounds were confirmed and characterized by melting point, ¹H NMR, ¹³C NMR, ¹⁹F NMR and HRMS. Their preliminary bioassay results showed that most of the compounds in this series have good insecticidal activity. Among them, 1,3,7-trimethyl-8-((3,4,4-trifluorobut-3-en-1-yl)thio)- 3,7-dihydro-1H-purine-2,6-dione (5a), 7-isobutyl-1,3-dimethyl-8-((3,4,4-trifluorobut-3-en-1-yl)thio)-3,7-dihydro-1H-purine- 2,6-dione (5c) and 7-isobutyl-1,3-dimethyl-8-((3,4,4-trifluorobut-3-en-1-yl)sulfonyl)-3,7-dihydro-1H-purine-2,6-dione (5h) had 70% lethality rate against Mythimna separata Walker at a concentration of 200 mg?L^–1. 5a, 5c and 1,3,7-trimethyl- 8-((3,4,4-trifluorobut-3-en-1-yl)sulfonyl)-3,7-dihydro-1H-purine-2,6-dione (5f) exhibited lethality rates of 72%, 80% and 65% against Plutella xylostellaL. at a concentration of 10 mg?L^–1, respectively. Some of the compounds also showed certain fungicidal activity at 50 mg?L^–1, among which 7-(cyclopropylmethyl)-1,3-dimethyl-8-((3,4,4-trifluorobut-3-en-1-yl)thio)-3,7- dihydro-1H-purine-2,6-dione (5b) possessed inhibition rates of 66.7% and 61.1% against Phytophthora capsici and Botrytis cinerea, respectively. 5c held a 55.6% inhibition rate towards Botrytis cinerea. This type of compounds provides new lead structures for the further research and development of novel insecticides.

Key words: 8-substituted methylxanthine derivative, synthesis, insecticidal activity, fungicidal activity, structure-activity relationship

引用此文

刘航, 张舒昀, 李欢, 张燕, 李正名, 王宝雷. 8-[(3,4,4-三氟丁-3-烯-1-基)硫基]取代的新型甲基黄嘌呤及其衍生物的合成和生物活性[J]. 有机化学, 2021, 41(5): 2091-2098.

Hang Liu, Shuyun Zhang, Huan Li, Yan Zhang, Zhengming Li, Baolei Wang. Synthesis and Biological Activities of Novel 8-((3,4,4-Trifluorobut-3-en-1-yl)thio)-substituted Methylxanthines and Their Derivatives[J]. Chinese Journal of Organic Chemistry, 2021, 41(5): 2091-2098.

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Compd.	杀虫活性/%
	东方粘虫	小菜蛾				番茄早疫病菌	辣椒疫霉病菌	油菜菌核病菌	黄瓜灰霉病菌	苹果轮纹病菌	小麦纹枯病菌
		200 mg/L	200 mg/L	100 mg/L		番茄早疫病菌	辣椒疫霉病菌	油菜菌核病菌	黄瓜灰霉病菌	苹果轮纹病菌	小麦纹枯病菌	10 mg/L
5a	70		100	90	72	28.6	23.8	39.1	38.9	54.7	43.0
5b	50		80	40	NT ^a	28.6	66.7	60.9	61.1	47.2	54.4
5c	70		100	90	80	42.9	61.9	60.9	55.6	45.3	60.8
5d	55		45	NT	NT	14.3	9.5	13.0	38.9	32.1	22.8
5e	15		67	NT	NT	7.1	19.0	8.7	16.7	37.7	29.1
5f	60		100	85	65	7.1	23.8	21.7	16.7	34.0	29.1
5g	50		100	75	NT	7.1	9.5	30.4	27.8	32.1	31.6
5h	70		100	67	NT	14.3	14.3	21.7	38.9	20.8	27.8
5i	50		65	NT	NT	7.1	14.3	8.7	33.3	49.1	35.4
5j	30		90	60	NT	7.1	9.5	17.4	33.3	54.7	29.1
C-1^b	65		88	55	NT	28.6	28.6	30.4	33.3	69.8	60.8
C-2^c	NT		NT	NT	NT	100.0	66.7	100.0	50.0	94.3	84.8
C-3^d	NT		NT	NT	NT	57.1	100.0	100.0	100.0	88.7	73.4

Compd.	杀虫活性/%
	东方粘虫	小菜蛾				番茄早疫病菌	辣椒疫霉病菌	油菜菌核病菌	黄瓜灰霉病菌	苹果轮纹病菌	小麦纹枯病菌
		200 mg/L	200 mg/L	100 mg/L		番茄早疫病菌	辣椒疫霉病菌	油菜菌核病菌	黄瓜灰霉病菌	苹果轮纹病菌	小麦纹枯病菌	10 mg/L
5a	70		100	90	72	28.6	23.8	39.1	38.9	54.7	43.0
5b	50		80	40	NT ^a	28.6	66.7	60.9	61.1	47.2	54.4
5c	70		100	90	80	42.9	61.9	60.9	55.6	45.3	60.8
5d	55		45	NT	NT	14.3	9.5	13.0	38.9	32.1	22.8
5e	15		67	NT	NT	7.1	19.0	8.7	16.7	37.7	29.1
5f	60		100	85	65	7.1	23.8	21.7	16.7	34.0	29.1
5g	50		100	75	NT	7.1	9.5	30.4	27.8	32.1	31.6
5h	70		100	67	NT	14.3	14.3	21.7	38.9	20.8	27.8
5i	50		65	NT	NT	7.1	14.3	8.7	33.3	49.1	35.4
5j	30		90	60	NT	7.1	9.5	17.4	33.3	54.7	29.1
C-1^b	65		88	55	NT	28.6	28.6	30.4	33.3	69.8	60.8
C-2^c	NT		NT	NT	NT	100.0	66.7	100.0	50.0	94.3	84.8
C-3^d	NT		NT	NT	NT	57.1	100.0	100.0	100.0	88.7	73.4