可见光驱动下卤键诱导的α-碘甲基膦酸二乙酯与香豆素/喹啉酮的直接偶联反应

doi:10.6023/cjoc202506016

摘要/Abstract

α-芳基膦酸酯作为一类重要的有机膦化合物, 在药物化学中具有重要应用价值; 同时, 香豆素和喹啉酮也是该领域十分常见的骨架结构. 然而, 目前α-膦酸化的香豆素/喹啉酮及其衍生物的合成方法十分有限. 为此, 开发了一种可见光驱动下卤键诱导的直接偶联反应, 实现了α-碘甲基膦酸二乙酯与香豆素或喹啉酮的高效连接. 该反应条件温和、操作简便, 且具有优异的底物普适性和区域选择性.

关键词: 可见光, 卤键, α-碘甲基膦酸二乙酯, 香豆素/喹啉酮, 直接偶联反应

α-Aryl phosphonates represent an important class of organophosphorus compounds with significant application value in medicinal chemistry. Meanwhile, coumarin and quinolinone are ubiquitous scaffold structures in this field. However, synthetic methods for α-phosphonylated coumarin/quinolinone derivatives remain limited. To address this, a visible-light- driven, halogen-bond-induced direct coupling reaction was developed, enabling the efficient covalent linkage between diethyl α-iodomethylphosphonate and coumarin or quinolinone. This transformation features mild reaction conditions, simple operation, excellent substrate compatibility, and high regioselectivity.

Key words: visible light, halogen bond, diethyl α-iodomethylphosphonates, coumarin/quinolone, direct coupling reaction

引用此文

梁家瑞, 李金兰, 蒋云, 姚秋丽, 徐应淑, 王安俊. 可见光驱动下卤键诱导的α-碘甲基膦酸二乙酯与香豆素/喹啉酮的直接偶联反应[J]. 有机化学, 2026, 46(1): 135-145.

Liang Jiarui, Li Jinlan, Jiang Yun, Yao Qiuli, Xu Yingshu, Wang Anjun. Visible-Light-Driven Halogen-Bond-Induced Direct Coupling of Diethyl α-Iodomethylphosphonates with Coumarins/Quinolinones[J]. Chinese Journal of Organic Chemistry, 2026, 46(1): 135-145.

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图/表 7

图1. (a)一些具有较好生物活性的α-芳基膦酸酯; (b)以香豆素、喹啉酮和吲哚为母核的药物

Figure 1. (a) α-Phosphorylated arenes with excellent bioactive properties; (b) drugs with coumarin, quinolinone and indole core structures

图式1. C-3位α-膦酸化的香豆素/喹啉酮的合成策略

Scheme 1. Synthetic strategies for C-3 α-phosphonated coumarins/quinolinones

Entry	Electron donor	LED light/nm	1a∶2a	Solvent	Yield/%
1	DMAP	410~415	1∶4	MeCN	39
2	DMAP	410~415	1∶4	DMF	48
3	DMAP	410~415	1∶4	THF	—
4	DMAP	410~415	1∶4	DCM	Trace
5	DMAP	410~415	1∶4	MeOH	Trace
6	DMAP	410~415	1∶4	DMSO	71
7	Et₃N	410~415	1∶4	DMSO	17
8	DBU	410~415	1∶4	DMSO	16
9	PhOH	410~415	1∶4	DMSO	—
10	HE	410~415	1∶4	DMSO	—
11	PPh₃	410~415	1∶4	DMSO	Trace
12	DMAP	410~415	1∶2	DMSO	36
13	DMAP	410~415	1∶6	DMSO	72
14	DMAP	390~395	1∶4	DMSO	38
15	DMAP	440~445	1∶4	DMSO	47
16	—	410~415	1∶4	DMSO	—
17	DMAP	Dark	1∶4	DMSO	—

表1. 反应条件优化的代表性结果a,b

Table 1. Representative results for the optimization of reaction conditions

表2. 底物普适性考察a,b

Table 2. Study on the substrate scope

图式2. 对照试验、克级规模实验和反应机理研究

Scheme 2. Controlled experiment, gram-scale experiment and reaction mechanism research

图2. 化合物2a在DMAP梯度滴定过程中的1H NMR谱图变化

Figure 2. 1H NMR spectra of titration between 2a and increasing quantity of DMAP

图式3. 提出的反应机理

Scheme 3. Proposed mechanism

参考文献 17

[1]	(a) Sayed M. T.; Mady M. F. Eur. J. Med. Chem. 2025, 286.
	(b) Chen J.; Fan R.; Liu Z.; Tan J. Adv. Synth. Catal. 2021, 363, 657.
	(c) Brahmachari G.; Karmakar I. J. Org. Chem. 2022, 2022, 133.
	(d) Yuan K.-N.; Xie T.; Wang J.-B.; Wang D.; Shang M. Angew. Chem. Int. Ed. 2025, e202500744.
	(e) Cui H.-M. Ph.D. Dissertation, University of Jilin, Changchun, 2024 (in Chinese).
	(崔洪铭, 博士论文, 吉林大学, 长春, 2024.)
	(f) Dzięgielewski M.; Pięta J.; Kamińska E.; Albrecht L. Eur. J. Org. Chem. 2015, 2015, 677.
	(g) Liu X.; Zhou L.; Yang R.; Song X. R.; Xiao Q. Adv. Synth. Catal. 2023, 365, 2280.
	(h) Baughman R. G.; Hall G. B. Cryst. Struct. Commun. 2014, 70, 975.
	(i) Hua X.; Eremin S. A.; Liu F.; Wang M. Curr. Org. Chem. 2017, 21, 2640.
	(j) Lášek T.; Petrová M.; Košiová I.; Šimák O.; Buděšínský M.; Kozák J.; Snášel J.; Vavřina Z.; Birkuš G.; Rosenberg I. Bioorg. Med. Chem. 2022, 56, 116632.
	(k) Kiiashko A.; Chaouche M.; Frouin L. Cem. Concr. Compos. 2021, 119, 103986.
	(l) Zhao Y. Q.; Liang D.; Jia J. H.; Yu R. M.; Lu C. M. Acta Chim. Sinica 2024, 82, 486 (in Chinese).
	(赵雨晴, 梁栋, 贾吉慧, 余荣民, 卢灿忠, 化学学报, 2024, 82, 486.)
	(m) Gao Q.; Chen L. R.; Qian J. Y.; Fan R. F.; Sun W. Q.; Guo Y. F., Fan B. M. Acta Chim. Sinica 2024, 82, 742 (in Chinese).
	(高琦, 陈丽蓉, 钱金一, 樊瑞峰, 孙蔚青, 郭亚飞, 樊保敏, 化学学报, 2024, 82, 742.)
	(n) Dong W. F.; Wang N.; Yang H.; Xu G. Q.; Tang W. J. Acta Chim. Sinica 2024, 82, 940 (in Chinese).
	(董文锋, 王楠, 杨贺, 徐广庆, 汤文军, 化学学报, 2024, 82, 940.)
	(o) Zhang Y. D.; Zhu S. F. Acta Chim. Sinica 2023, 81, 777 (in Chinese).
	(张艳东, 朱守非, 化学学报, 2023, 81, 777.)
[2]	(a) Brodzka A.; Kowalczyk P.; Trzepizur D.; Koszelewski D.; Kramkowski K.; Szymczak M.; Wypych A.; Lizut R.; Ostaszewski R. Molecules 2022, 27, 6865.
	(b) Yoshino K.; Kohno T.; Uno T.; Morita T.; Tsukamoto G. J. Med. Chem. 1986, 29, 820.
[3]	Wadsworth, W S.; Emmons, W. D. J. Am. Chem. Soc. 1961, 83, 1733.
[4]	Boutagy J.; Thomas R. Chem. Rev. 1974, 74, 87.
[5]	(a) Frédérick R.; Robert S.; Charlier C.; de Ruyck J.; Wouters J.; Pirotte B.; Masereel B.; Pochet L. J. Med. Chem. 2005, 48, 7592.
	(b) Abdelhafez O. M.; Amin K. M.; Batran R. Z.; Maher T. J.; Nada S. A.; Sethumadhavan S. Bioorg. Med. Chem. 2010, 18, 3371.
[6]	(a) Yang X. C.; Zeng C. M.; Avula S. R.; Peng X. M.; Geng R. X.; Zhou C. H. Eur. J. Med. Chem. 2023, 245, 114891.
	(b) Liu J.; Zhao S. Y.; Hu J. Y.; Chen Q. X.; Jiao S. M.; Xiao H. C.; Sun P. H. J. Med. Chem. 2023, 66, 14735.
	(c) Cheke R. S.; Patel H. M.; Patil V. M.; Ansari I. A.; Ambhore J. P.; Shinde S. D.; Deshmukh P. K. Antibiotics 2022, 11, 566.
	(d) Prasoona G.; Kishore B.; Brahmeshwari G. Lett. Org. Chem. 2021, 18, 303.
[7]	(a) Yan N. L.; Santos-Martins D.; Nair R.; Chu A.; Wilson I. A.; Johnson K. A.; Forli S.; Morgan G. J.; Petrassi H. M.; Kelly J. W. J. Med. Chem. 2021, 64, 6273.
	(b) Preisner A.; Albrecht S.; Cui Q. L.; Hucke S.; Ghelman J.; Hartmann C.; Kuhlmann T. Acta Neuropathologica 2015, 130, 247.
[8]	(a) Zhang L.; Xu Z. Eur. J. Med. Chem. 2019, 181, 111587.
	(b) Singh A.; Singh K.; Kaur K.; Singh A.; Sharma A.; Kaur K.; Bedi P. M. S. Biomedicines 2024, 12, 1192.
	(c) Song X. F.; Fan J.; Liu L.; Liu X. F.; Gao F. Arch. Pharm. 2020, 353, 2000025.
	(d) Kubrak T. P.; Makuch-Kocka A.; Aebisher D. Pharmaceutics 2025, 17, 595.
	(e) Kaur M.; Kohli S.; Sandhu S.; Bansal Y.; Bansal G. Anti-Cancer Agents Med. Chem. 2015, 15, 1032.
[9]	Zhu M.; Ma L.; Wen J.; Dong B.; Wang Y.; Wang Z.; Zhou J.; Zhang G.; Wang J.; Guo Y.; Liang C. Eur. J. Med. Chem. 2020, 186, 111900.
[10]	Fang M. C.; Go A. S.; Prasad P. A.; Hsu J. W.; Fan D.; Portugal C.; Sung S. H.; Reynolds K. J. Thromb. Thrombolysis 2021, 52, 1101.
[11]	Hanna G. J.; Guenette J. P.; Chau N. G.; Sayehli C. M.; Wilhelm C.; Metcalf R.; Wong D. J.; Brose M.; Razaq M.; Pérez-Ruiz E.; Cohen E. E. Cancer 2020, 126, 3972.
[12]	Lin T. M.; Chi J. E.; Chang C. C.; Kang Y. N. J. Pain Res. 2018, 12, 83.
[13]	(a) Xu Z.; Chen Q; Zhang Y.; Liang C. Fitoterapia 2021, 150, 104863.
	(b) Pu G.-L.; Song S.-Y.; Yang J.; Guo P.; Jia J.; Liu P.-J.; Li X.-F.; Liu P.; He C.-Y. Org. Chem. Front. 2024, 11, 3320.
	(c) Guo P.; Pu G.-L.; Wang G.-R.; Zeng L.-Y.; Li W.-P.; Li X.-F.; Zhou P.-P.; He C.-Y. Org. Lett. 2024, 26, 3097.
	(d) Wang G.-R.; Guo P.; Pu G. L.; Wang P.; Wang A.-J.; Liu P.; Jia J.; Li X.; He C.-Y. Org. Chem. Front. 2024, 11, 4722.
	(e) Kasperkiewicz K.; Ponczek M. B.; Owczarek J.; Guga P.; Budzisz E. Molecules 2020, 25, 1465.
	(f) Wang G.; Sun S.; Wu B.; Liu J. Curr. Top. Med. Chem. 2021, 21, 1725.
	(g) He C.-Y.; Kong J.; Li X.-F.; Li X.; Yao Q.-L.; Yuan F.-M. J. Org. Chem. 2017, 82, 910.
	(h) Hussain M. K.; Khatoon S.; Khan M. F.; Akhtar M. S.; Ahamad S.; Saquib M. Phytomedicine 2024, 134, 155972.
	(i) Mao T.; Ma M.-J.; Zhao L.; Xue D.-P.; Yu Y.-B.; Gu J.-W.; He C.-Y. Chem. Commun. 2020, 56, 1815.
	(j) Bautista-Aguilera Ó. M.; Ismaili L.; Chioua M.; Andrys R.; Schmidt M.; Bzonek P.; Marco-Contelles J. Int. J. Mol. Sci. 2020, 21, 3913.
	(k) Tao M.-L.; Wang A.-J.; Guo P.; Li W.-P.; Zhao L.; Tong J.; Wang H.-Y.; Yu Y.-B.; He C.-Y. Adv. Synth. Catal. 2022, 364, 24.
	(l) Huang Y.; Wang A. J.; Kong J.; Lou Y. G.; Li X. F.; He C. Y. Synth. Commun. 2018, 48, 91.
	(j) He X. K.; Lu J.; Zhang A. J.; Zhang Q. Q.; Xu G. Y.; Xuan J. Org. Lett. 2020, 22, 5984.
[14]	Rashamuse T. J.; Musa M. A.; Klein R.; Kaye P. T. J. Chem. Res. Synop. 2009, 2009, 302.
[15]	Abdelli A.; Gaucher A.; Efrit M. L.; M’rabet H.; Prim D. Tetrahedron Lett. 2015, 56, 1679.
[16]	(a) Cavallo G.; Metrangolo P.; Milani R.; Pilati T.; Priimagi A.; Resnati G.; Terraneo G. Chem. Rev. 2016, 116, 2478.
	(b) Mamone M.; Gentile G.; Dosso J.; Prato M.; Filippini G. Beilstein J. Org. Chem. 2023, 19, 575.
[17]	(a) Chen Y. L.; Han W.; Ren Y. Y.; Ma M.; Ge D.; Shen Z. L.; Chu X. Q. Adv. Sci. 2025, 12, 2404738.
	(b) Zhao L.; Huang Y.; Wang Z.; Zhu E.; Mao T.; Jia J.; He C. Y. Org. Lett. 2019, 21, 6705.
	(c) Lu H.; Wang D. Y.; Zhang A. J. Org. Chem. 2019, 85, 942.
	(d) Cai B. G.; Xuan J.; Xiao W. J. Sci. Bull. 2019, 64, 337.
	(e) Takeuchi T.; Minato Y.; Takase M.; Shinmori H. Tetrahedron Lett. 2005, 46, 9025.