Visible-Light-Induced Defluorinative Acylation of α-Trifluoromethyl Alkenes with Aromatic Carboxylic Anhydrides

doi:10.6023/A25060238

Abstract

Fluorine-containing organic molecules offer beneficial biological activity, lipophilicity, and metabolic stability. Among these, gem-difluoroalkenes are known for their distinctive structures and wide-ranging uses in biology, medicine, and agriculture. As important synthetic building blocks, converting them into various functionalized compounds attracts significant scientific interest. Recent progress has focused on innovative methods for synthesizing gem-difluoroalkenes, especially through C—F bond activation of α-trifluoromethyl alkenes. This study introduces a new defluorinative difluoroalkenylation reaction that uses acyl radicals from readily available, cost-effective aromatic carboxylic anhydrides. Under visible-light irradiation, these anhydrides react with α-trifluoromethyl alkenes to produce γ,γ-difluoroallylic ketones. The optimized procedure employs 4CzIPN as the photocatalyst, Cs₂CO₃ as the base, PPh₃ as the reductant, and N,N-dimethylformamide (DMF) as the solvent, with blue light emitting diode (LED) light. This gentle, in situ formation of acyl radicals shows excellent tolerance for various functional groups and works with a broad range of substrates (32 examples, up to 82% yield). Additionally, mechanistic studies show that the electronic and steric properties of substituents on asymmetric anhydrides influence selectivity; electron-withdrawing groups promote C—O bond cleavage, while steric hindrance determines regioselectivity. Importantly, this method avoids the use of transition metals and ligands, reducing steps and costs. Scale-up experiments confirmed its potential for practical applications, including late-stage functionalization. Mechanistic insights suggest visible-light-induced single-electron transfer in radical chain activation and a radical/polar crossover process. This straightforward and eco-friendly approach efficiently synthesizes γ,γ-difluoroallylic ketones by breaking C—O and C—F bonds.

Key words: visible-light-induced, α-trifluoromethyl alkenes, anhydrides, β-fluorine eliminating, defluorinative acylation, γ,γ-difluoroallylic ketones

Cite this article

Su Qin, Lei Ping, Wang Dong, Shahid Ali Khan, Ablajan Keyume. Visible-Light-Induced Defluorinative Acylation of α-Trifluoromethyl Alkenes with Aromatic Carboxylic Anhydrides[J]. Acta Chimica Sinica, 2025, 83(11): 1372-1378.

Export EndNote|Reference Manager|ProCite|BibTeX|RefWorks

share this article

Fig. & Tab. 8

Figure 1. Bioactive pharmaceuticals with gem-difluoroalkene molecules

Figure 2. Methods for the synthesis of gem-difluoroalkenes

Entry	Variations from standard conditions	Yield^b/%
1	None	82
2	Ir[dF(CF₃)ppy]₂(dtbbpy)PF₆ or Eosin Y was used	43, 16
3	Ru(bpy)₃Cl₂ was used	N.R.
4	DBU or DIPEA was used	46, 50
5	NaHCO₃ or K₂CO₃ was used	36, 38
6	EA, MeOH, DCE or DMSO was used	34, Trace, 33, 30
7	Addition 4 Å molecular sieves	64
8	No PC, or no Cs₂CO₃	trace
9	No light, or no Ph₃P	N.R.
10	Under air	N.R.
11	λ=390~395 nm	69

Table 1. Conditions optimization

Figure 3. Substrate scope a Reaction conditions: 1a~1v (0.3 mmol), 2a~2j (0.6 mmol), 4CzIPN (0.009 mmol), PPh3 (0.45 mmol), and Cs2CO3 (0.15 mmol) in DMF (3 mL) under 10 W blue LED light, under nitrogen atmosphere at room temperature for 12 h; the ratio of product 3 or 4 to byproduct 5 is given in parentheses, determined by 19F NMR. b Isolated yield.

Figure 4. Study on the selectivity of photocatalytic decarbonylation of aryl anhydrides

Figure 5. Proportional enlargement of the synthesis of γ,γ-difluoroallyl ketones and their applications

Figure 6. Mechanistic studies

Figure 7. Plausible reaction mechanism

References 26

[3]	(a) Wang Q.; Yu X.; Jin J.; Wu Y.; Liang Y. Chin. J. Chem. 2018, 36, 223.
	(b) Olsavsky N. J.; Kearns V. M.; Beckman C. P.; Sheehan P. L.; Burpo F. J.; Bahaghighat H. D.; Nagelli E. A. Appl. Sci. 2020, 10, 6921.
	(c) Jin W.; Lu G.; Li Y.; Huang X. Acta Chim. Sinic. 2018, 76, 739 (in Chinese).
	(金维则, 陆国林, 李永军, 黄晓宇, 化学学报, 2018, 76, 739.)
	(d) Zhu W.-Q.; Tang G.-F.; Gou H. Acta Chim. Sinic. 2007, 65, 1875 (in Chinese).
	(朱万强, 唐国风, 勾华, 化学学报, 2007, 65, 1875.)
	(e) Wang S.; Hu M.; Chen H.; Zhao Y. Acta Chim. Sinic. 2024, 82, 925 (in Chinese).
	(王甦昊, 胡明霞, 陈卉, 赵彦英, 化学学报, 2024, 82, 925.)
	(f) Yi J.; Chen M. Acta Chim. Sinic. 2024, 82, 126 (in Chinese).
	(易敬霖, 陈茂, 化学学报, 2024, 82, 126.)
[4]	(a) Nie J.; Guo H.-C.; Cahard D.; Ma J.-A. Chem. Rev. 2011, 111, 455.
	(b) Alonso C.; de Marigorta E. M.; Rubiales G.; Palacios F. Chem. Rev. 2015, 115, 1847.
	(c) Neil E.; Marsh G. Acc. Chem. Res. 2014, 47, 2878.
	(d) Liu C.; Zhu C.; Cai Y.; Jiang H. Angew. Chem. Int. Ed. 2021, 60, 12038.
[1]	(a) Jeschke P. Pest Manag. Sci. 2024, 80, 3065.
	(b) Liu Y.; Wang F.; Li L.; Fan B.; Kong Z.; Tan J.; Li M. Ecotoxicol. Environ. Saf. 2025, 289, 117615.
	(c) Wang B.; Wang H.; Liu H.; Xiong L.; Yang N.; Zhang Y.; Li Z. Chin. Chem. Lett. 2020, 31, 739.
	(d) Tang C.; Zhu Y.; Liang Y.; Xia D.; Xu J.; Zheng R.; Liu L.; Ma S.; Lin H.; Luo X.-J.; Huang Q.; Mai B.-X. J. Agric. Food Chem. 2025, 73, 2322.
	(e) Huang W.; Qian Z. Acta Chim. Sinic. 1987, 45, 1175 (in Chinese).
	(黄维垣, 钱昭辉, 化学学报, 1987, 45, 1175.)
	(f) Hu J. Acta Chim. Sinic. 2024, 82, 103 (in Chinese).
	(胡金波, 化学学报, 2024, 82, 103.)
[2]	(a) Purser S.; Moore P. R.; Swallow S.; Gouverneur V. Chem. Soc. Rev. 2008, 37, 320.
	(b) Hagmann W. K. J. Med. Chem. 2008, 51, 4359.
	(c) Gillis E. P.; Eastman K. J.; Hill M. D.; Donnelly D. J.; Meanwell N. A. J. Med. Chem. 2015, 58, 8315.
	(d) Huchet Q. A.; Kuhn B.; Wagner B.; Kratochwil N. A.; Fischer H.; Kansy M.; Zimmerli D.; Carreira E. M.; Müll K. J. Med. Chem. 2015, 58, 9041.
	(e) Gu Y.; Dong X.; Chen H.; Chen M.; Zhang S.; Yuan S.; Zheng C. Acta Chim. Sinic. 2000, 58, 1540 (in Chinese).
	(谷妍, 董喜城, 陈海峰, 陈敏伯, 张世相, 袁身刚, 郑崇直, 化学学报, 2000, 58, 1540.)
[5]	(a) O’Hagan, D. Chem. Soc. Rev. 2008, 37, 308.
	(b) Sodeoka M. Scienc. 2011, 334, 1651.
	(c) Cahard D.; Bizet V. Chem. Soc. Rev. 2014, 43, 135.
	(d) Wu J.-Q.; Zhang S.-S.; Gao H.; Qi Z.; Zhou C.-J.; Ji W.-W.; Liu Y.; Chen Y.; Li Q.; Li X.; Wang H. J. Am. Chem. Soc. 2017, 139, 3537.
	(e) Qin P.; Ma H.; Zhang F.-G.; Ma J.-A. Acta Chim. Sinic. 2023, 81, 697 (in Chinese).
	(秦沛, 马海, 张发光, 马军安, 化学学报, 2023, 81, 697.)
	(f) Guo M.; Yu Z.; Chen Y.; Ge D.; Ma M.; Shen Z.; Chu X. Chin. J. Org. Chem. 2022, 42, 3562 (in Chinese).
	(郭檬檬, 于子伦, 陈玉兰, 葛丹华, 马猛涛, 沈志良, 褚雪强, 有机化学, 2022, 42, 3562.)
[6]	(a) Leriche C.; He X.; Chang C.-W. T.; Liu H.-W. J. Am. Chem. Soc. 2003, 125, 6348.
	(b) Pan Y.; Qiu J.; Silverman R. B. J. Med. Chem. 2003, 46, 5292.
	(c) Naret T.; Bignon J.; Bernadat G.; Benchekroun M.; Levaique H.; Lenoir C.; Dubois J.; Pruvost A.; Saller F.; Borgel D.; Manoury B.; Leblais V.; Darrigrand R.; Apcher S.; Brion J.-D.; Schmitt E.; Leroux F. R.; Alami M.; Hamze A. Eur. J. Med. Chem. 2018, 143, 473.
	(d) Magueur G.; Crousse B.; Ourévitch M.; Bonnet-Delpon D.; Bégué J.-P. J. Fluor. Chem. 2006, 127, 637.
	(e) Lim M. H.; Kim H. O.; Moon H. R.; Chun M. W.; Jeong L. S. Org. Lett. 2002, 4, 529.
	(f) Moore W. R.; Schatzman G. L.; Jarvi E. T.; Gross R. S.; McCarthy J. R. J. Am. Chem. Soc. 1992, 114, 360.
[7]	(a) Skibinska M.; Warowicka A.; Koroniak H.; Cytlak T.; Crousse B. Org. Lett. 2024, 26, 692.
	(b) Messaoudi S.; Tréguier B.; Hamze A.; Provot O.; Peyrat J. F.; De Losada J. R.; Liu J.-M.; Bignon J.; Wdzieczak-Bakala J.; Thoret S.; Dubois J.; Brion J.-D.; Alami M. J. Med. Chem. 2009, 52, 4538.
	(c) Bobek M.; Kavai I.; De Clercq E. J. Med. Chem. 1987, 30, 1494.
	(d) Yang C.; Chen J.; Li X.; Meng L.; Wang K.; Sun W.; Fan B. Acta Chim. Sinic. 2023, 81, 1 (in Chinese).
	(杨春晖, 陈景超, 李新汉, 孟丽, 王凯民, 孙蔚青, 樊保敏, 化学学报, 2023, 81, 1.)
	(e) Li Z.; Qiu X.; Lou J.; Wang Q. Chin. J. Org. Chem. 2021, 41, 4192 (in Chinese).
	(李志清, 邱潇杨, 娄江, 王强, 有机化学, 2021, 41, 4192.)
	(f) Ni C.; Hu J. Chin. J. Org. Chem. 2020, 40, 2997 (in Chinese).
	(倪传法, 胡金波, 有机化学, 2020, 40, 2997.)
[8]	(a) Meanwell N. A. J. Med. Chem. 2011, 54, 2529.
	(b) Liu C.; Zeng H.; Zhu C.; Jiang H. Chem. Commun. 2020, 56, 10442.
	(c) Anand D.; Sun Z.; Zhou L. Org. Lett. 2020, 22, 2371.
[9]	Wang X.; Cai J.; Song H.; Liu L.; Duan X.-H.; Hu M. Org. Lett. 2024, 26, 1635.
[10]	Mao Y.; Liu Y.; Wang X.; Ni S.; Pan Y.; Wang Y. Chin. Chem. Lett. 2024, 35, 109443.
[11]	(a) Lei P.; Chen B.; Zhang T.; Chen Q.; Xuan L.; Wang H.; Yan Q.; Wang W.; Zeng J.; Chen F. Org. Chem. Front. 2024, 11, 458.
	(b) Zhang D.; Zhao H.; Feng X.; Gu Y.; Zhang X. Acta Chim. Sinic. 2024, 82, 105 (in Chinese).
	(张大伟, 赵海洋, 冯笑甜, 顾玉诚, 张新刚, 化学学报, 2024, 82, 105.)
	(c) Li J.; Guo Z.; Zhang X.; Meng X.; Dai Z.; Gao M.; Guo S.; Tang P. Green Chem. 2023, 25, 9292.
	(d) Jiang Y.; Han C.; Guo Z.; Dai Z.; Liang G.; Guo S.; Szymczak N. K.; Tang P. Green Chem. 2024, 26, 4518.
[12]	(a) Faqua S. A.; Duncan W. G.; Silverstein R. M. Tetrahedron Lett. 1964, 5, 1461.
	(b) Wang F.; Li L.; Ni C.; Hu J. Beilstein J. Org. Chem. 2014, 10, 344.
	(c) Aikawa K.; Toya W.; Nakamura Y.; Mikami K. Org. Lett. 2015, 17, 4996.
	(d) Zheng J.; Cai J.; Lin J.-H.; Guo Y.; Xiao J.-C. Chem. Commun. 2013, 49, 7513.
[13]	(a) Gao B.; Zhao Y.; Hu M.; Ni C.; Hu J. Chem. Eur. J. 2014, 20, 7803.
	(b) Luo Q.; Wang X.; Hu J. Tetrahedron. 2022, 113, 132694.
[14]	(a) Edwards M. L.; Stemerick D. M.; Jarvi E. T.; Matthews D. P.; McCarthy J. R. Tetrahedron Lett. 1990, 31, 5571.
	(b) Obayashi M.; Ito E.; Matsui K.; Kondo K. Tetrahedron Lett. 1982, 23, 2323.
[15]	(a) Hu M.; He Z.; Gao B.; Li L.; Ni C.; Hu J. J. Am. Chem. Soc. 2013, 135, 17302.
	(b) Hu M.; Ni C.; Li L.; Han Y.; Hu J. J. Am. Chem. Soc. 2015, 137, 14496.
	(c) Zhang Z.; Yu W.; Wu C.; Wang C.; Zhang Y.; Wang J. Angew. Chem. Int. Ed. 2016, 55, 273.
[16]	Lang S. B.; Wiles R. J.; Kelly C. B.; Molander G. A. Angew. Chem. Int. Ed. 2017, 56, 15073.
[17]	(a) Xiao T.; Li L.; Zhou L. J. Org. Chem. 2016, 81, 7908.
	(b) Guo Y.-Q.; Wang R.; Song H.; Liu Y.; Wang Q. Org. Lett. 2020, 22, 709.
	(c) Zhang L.; Yu X.; Ouyang S.; Zhu C.; Li W.; Xie J. Eur. J. Org. Chem. 2024, 27, e202400392.
[18]	Liu Y.; Zhou X.; Li R.; Sun Z. Org. Lett. 2024, 26, 6424.
[19]	Ai C.; Wang T.; Bao Y.; Yan S.; Zhang Y.; Wang J.-Y. Org. Biomol. Chem. 2024, 22, 9197.
[20]	Shi H.; Dong H.; Wang C. Org. Chem. Front. 2023, 10, 5843.
[21]	Hao J.; Ren L.; Tan J.; Peng Y.; Jing L.; Han P. Adv. Synth. Catal. 2025, 367, e202401594.
[22]	(a) Zhou Y.; He Y.-Q.; Nie X.; Lu L.; Song X.-R.; Zhou Z.-Z.; Tian W.-F.; Xiao Q. Org. Chem. Front. 2024, 11, 4269.
	(b) Zhang L.; Wang W.; Shen C.; Dong K. ACS Catal. 2025, 15, 7578.
	(c) Li G.; Zhu B.; Hu T.; Fan R.; Sun W.; He Z.; Chen J.; Fan B. Acta Chim. Sinic. 2025, 83, 319 (in Chinese).
	(李国凯, 朱滨锋, 胡涛, 樊瑞峰, 孙蔚青, 和振秀, 陈景超, 樊保敏, 化学学报, 2025, 83, 319.)
[23]	Zhou Y.; Zhao L.; Hu M.; Duan X.-H.; Liu L. Org. Lett. 2023, 25, 5268.
[24]	Liu D.; Patureau F. W. Org. Lett. 2024, 26, 6841.
[25]	Luo J.; Zhang J. ACS Catal. 2016, 6, 873.
[26]	Pandey G.; Pooranch D.; Bhalerao U. T. Tetrahedro. 1991, 47, 1745.

可见光诱导的α-三氟甲基烯烃与芳香酸酐的脱氟酰化反应