光催化无过渡金属参与的烯烃的缩醛-吡啶化三组分反应

doi:10.1016/S1872-2067(21)63917-7

催化学报 ›› 2022, Vol. 43 ›› Issue (3): 571-583.DOI: 10.1016/S1872-2067(21)63917-7

• 可见光催化有机合成专栏 • 上一篇下一篇

光催化无过渡金属参与的烯烃的缩醛-吡啶化三组分反应

马春华^a, 吉钰^a, 赵杰^a, 何兴^a, 张淑婷^a^,^*(), 姜玉钦^a^,^#(), 於兵^b^,^$()

^a河南师范大学化学化工学院, 精细化学品绿色制造河南省协同创新中心, 绿色化学介质与反应教育部重点实验室, 河南省手性醇类药物工程技术研究中心,化学制药及生物医用材料河南省工程实验室, 河南新乡453007
^b郑州大学化学学院, 绿色催化中心, 河南郑州450001

收稿日期:2021-06-14 修回日期:2021-06-14 接受日期:2021-07-30 出版日期:2022-03-18 发布日期:2022-02-18
通讯作者: 张淑婷,姜玉钦,於兵
基金资助:
国家自然科学基金(82003585);国家自然科学基金(21971224);国家自然科学基金(21807026);河南省高等教育教学改革研究与实践项目(2019SJGLX008Y);河南省高等教育教学改革研究与实践项目(2019SJGLX034Y);河南省高等教育教学改革研究与质量提升工程(YJS2021AL079)

Transition-metal-free three-component acetalation-pyridylation of alkenes via photoredox catalysis

Chun-Hua Ma^a, Yu Ji^a, Jie Zhao^a, Xing He^a, Shu-Ting Zhang^a^,^*(), Yu-Qin Jiang^a^,^#(), Bing Yu^b^,^$()

^aCollaborative Innovation Centre of Henan Province for Green Manufacturing of Fine Chemicals, Key Laboratory of Green Chemical Media and Reactions, Ministry of Education, Henan Engineering Research Centre of Chiral Hydroxyl Pharmaceutical, Henan Engineering Laboratory of Chemical Pharmaceutical and Biomedical Materials, School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang 453007, Henan, China
^bGreen Catalysis Centre, College of Chemistry, Zhengzhou University, Zhengzhou 450001, Henan, China

Received:2021-06-14 Revised:2021-06-14 Accepted:2021-07-30 Online:2022-03-18 Published:2022-02-18
Contact: Shu-Ting Zhang, Yu-Qin Jiang, Bing Yu
About author:First author contact:
^† Dedicated to the 100th anniversary of Chemistry at Nankai University.
Supported by:
National Natural Science Foundation of China(82003585);National Natural Science Foundation of China(21971224);National Natural Science Foundation of China(21807026);Postgraduate Education Reform Project of Henan Province(2019SJGLX008Y);Postgraduate Education Reform Project of Henan Province(2019SJGLX034Y);Postgraduate Education Reform and Quality Improvement Project of Henan Province(YJS2021AL079)

摘要/Abstract

摘要：

吡啶作为优势骨架存在于90种上市药物中. 由于吡啶基团在药物研发中的广泛应用, 亟需开发新方法构建具有该药效团的结构多样性的分子骨架. 在过去十年中, 烯烃的双官能团化反应逐渐成为构建含吡啶的多官能团化合物的强有力手段. 虽然目前该领域取得了一定进展, 但开发环境友好的、高效的合成方法仍然是该领域的研究热点. 醛基是一种可以转化为醇、羧酸、烯烃等官能团的重要结构单元, 它在有机合成和药物结构优化中发挥重要作用. 但目前在烯烃上直接引入吡啶基团和醛基的方法报道较少. 因此, 本文报道了一种可见光诱导的氰基吡啶、乙醛酸缩醛、烯烃的三组分反应在温和条件下实现烯烃的缩醛-吡啶化反应.
通过对溶剂、光催化剂、碱的筛选, 确定烯烃缩醛-吡啶化反应的最优条件为: 氰基吡啶(0.2 mmol), 烯烃(2.5 equiv.), 乙醛酸缩醛(2.5 equiv.), 2,4,5,6-四(9-咔唑基)-间苯二腈(4CzIPN, 3 mol%)作为光催化剂, 碳酸铯(2.0 equiv.)作为碱, 二甲基亚砜(2 mL)作为溶剂, 在室温、氮气条件下, 455 nm蓝光照射24 h. 底物拓展结果表明, 该方法适用于多种取代4-氰基吡啶, 2-氰基吡啶和二氰基苯. 另一方面, 烷基、卤素以及其他药效团取代的苯乙烯以及杂环烯烃都能适用于该反应, 并以较高的收率得到目标化合物. 该方法还可以应用到雌酮、奥沙普秦、布洛芬等药物的后期修饰中. 所得的缩醛-吡啶化产物可以通过水解反应高收率转化为醛基化合物. 此外, 该方法也可通过“一锅两步”的策略, 直接合成醛基(酮基)-吡啶化合物. 所得的醛类产物通过简便的反应就能转化为相应的羟甲基化产物、羧基化产物和端烯基化产物. 机理研究表明, 乙醛酸缩醛是4CzIPN的光氧化还原循环中的重要的淬灭剂. 自由基捕捉实验和自由基钟实验等也进一步表明缩醛自由基参与该反应. 此外, 所合成的产物表现出抗肿瘤活性, 部分化合物表现出优于上市药物5-FU的抗淋巴瘤活性.
综上, 本文以4CzIPN为光催化剂、碳酸铯作碱, 在蓝光照射下实现了一种无金属参与的烯烃缩醛化-吡啶化反应, 结构多样的烯烃和氰基吡啶均能在该反应中兼容, 以较高的收率得到目标产物. 该方法可应用于药物的后期修饰和多种官能团转换, 为药物的结构修饰提供了环境友好的新方法. 所合成的部分化合物具有较好抗肿瘤活性, 为新药研发提供苗头化合物.

关键词: 可见光促进, 醛基, 多样性转化, 后期修饰, 抗肿瘤

Abstract:

A general transition-metal-free photoinduced acetalation-pyridylation of alkenes using diethoxyacetic acid and cyanopyridine was developed under mild conditions. By employing 4CzIPN as the photocatalyst and Cs₂CO₃ as the base, a diverse range of styrene derivatives and cyanopyridines worked well to give the desired products. The versatility of this method is highlighted by its application in the construction of various functional groups and the late-stage modification of drugs. Importantly, some of the synthesized compounds showed good in vitro antitumor activity, indicating that this protocol is of significance and potential for antitumor drug development.

Key words: Visible-light promoted, Aldehyde, Diverse transformation, Late-stage modification, Antitumor

马春华, 吉钰, 赵杰, 何兴, 张淑婷, 姜玉钦, 於兵. 光催化无过渡金属参与的烯烃的缩醛-吡啶化三组分反应[J]. 催化学报, 2022, 43(3): 571-583.

Chun-Hua Ma, Yu Ji, Jie Zhao, Xing He, Shu-Ting Zhang, Yu-Qin Jiang, Bing Yu. Transition-metal-free three-component acetalation-pyridylation of alkenes via photoredox catalysis[J]. Chinese Journal of Catalysis, 2022, 43(3): 571-583.

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链接本文: https://www.cjcatal.com/CN/10.1016/S1872-2067(21)63917-7

https://www.cjcatal.com/CN/Y2022/V43/I3/571

图/表 13

Scheme 1. Transition metal-free photocatalytic cascade acetalation/pyridylation reaction of alkenes.

Table 1 Optimization of reaction conditions a.

Entry	Catalyst (3 mol%)	Base (2 equiv.)	Solvent	Yield ^b (%)
1	4CzIPN	Cs₂CO₃	DMF	50
2	4CzIPN	Cs₂CO₃	DMAC	56
3	4CzIPN	Cs₂CO₃	NMP	53
4	4CzIPN	Cs₂CO₃	DMSO	86
5	4CzIPN	Na₂CO₃	DMSO	50
6	4CzIPN	K₂CO₃	DMSO	40
7	4CzIPN	Et₃N	DMSO	20
8	4CzIPN	DIPEA	DMSO	27
9	4CzIPN	DMAP	DMSO	17
10	4CzIPN	—	DMSO	N.R.
11 ^c	4CzIPN	Cs₂CO₃	DMSO	N.R.
12	—	Cs₂CO₃	DMSO	N.R.

Scheme 2. Scope of cyanopyridine. Reaction conditions: 1 (0.2 mmol), 2a (2.5 equiv.), 3a (2.5 equiv.), 4CzIPN (3 mol%), Cs2CO3 (2 equiv.), DMSO (2 mL), r.t., blue LED, 24 h under N2 atmosphere. Isolated yields were given. a Irradiation at 390 nm.

Scheme 3. Scope of styrene and glyoxylic acid acetal. Reaction conditions: 1a (0.2 mmol), 2 (2.5 equiv.), 3 (2.5 equiv.), 4CzIPN (3 mol%), Cs2CO3 (2 equiv.), DMSO (2 mL), r.t., blue LED, 24 h under N2 atmosphere. Isolated yields were given.

Scheme 4. Late-stage modification of natural resources and drug molecules. Reaction conditions: 1a (0.2 mmol), 2 (2.5 equiv.), 3a (2.5 equiv.), 4CzIPN (3 mol%), Cs2CO3 (2 equiv.), DMSO (2 mL), r.t., blue LED, 24 h under N2 atmosphere. Isolated yields were given.

Scheme 5. Hydrolysis of acetal products 4 or 5. Reaction conditions: 4 or 5 (0.1 mmol), 2 mol/L HCl (2 mL), r.t., 3 h. Isolated yields were given.

Scheme 6. The formylation-pyridylation reaction in one pot. Reaction conditions: 1a (0.2 mmol), 2 (2.5 equiv.), 3 (2.5 equiv.), 4CzIPN (3 mol%), Cs2CO3 (2 equiv.), DMSO (2 mL), r.t., blue LED, 24 h under N2 atmosphere; then 2 mol/L HCl (2 mL), r.t., 3 h. Isolated yields were given.

Scheme 7. Further functional group transformation. (i) 6a (0.2 mmol), NaBH4 (1.5 equiv.), MeOH (2 mL), r.t., 3 h. (ii) 6a (0.2 mmol), NaClO2 (5 equiv.), NaH2PO4 (10 equiv.), tert-butanol (2 mL), H2O (1 mL), r.t., 6 h. (iii) PPh3CH3Br (3 equiv.), t-BuOK (2 equiv.), THF (5 mL), r.t., 0.5 h; then 6a (0.2 mmol), r.t., 12 h. (iv) 6a (0.2 mmol), CH3MgBr (1 equiv.), THF (1 mL), r.t., 1 h. Isolated yields were given.

Fig. 1. The color-coded radar diagrams based on sensitivity experiments.

Fig. 2. Fluorescence quenching experiments.

Scheme 8. Control experiment.

Scheme 9. The proposed mechanism.

Scheme 10. The in vitro antitumor activity of 4o, 4ac, 6c, and 6u against Ramos cells, Rec-1 cells, and HeLa cells.

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光催化无过渡金属参与的烯烃的缩醛-吡啶化三组分反应

Transition-metal-free three-component acetalation-pyridylation of alkenes via photoredox catalysis

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