Citation: Song Xiaoning, Yang Shan, Wang Xin, Wang Mang. Difluorohomologization-Halogenation of Methyl Ketones: One-Pot Synthesis of β-Halo-α, α-Difluoroketones[J]. Acta Chimica Sinica, ;2018, 76(12): 983-987. doi: 10.6023/A18080337 shu

Difluorohomologization-Halogenation of Methyl Ketones: One-Pot Synthesis of β-Halo-α, α-Difluoroketones

Song Xiaoning ^a ,
Yang Shan ^a ,
Wang Xin ^b,, ,
Wang Mang ^a,,

a.
Faculty of Chemistry, Northeast Normal University, Changchun 130024
b.
First Hospital of Bethune, Jilin University, Changchun 130021

Corresponding author: Wang Xin, wangm452@nenu.edu.cn Wang Mang, docxinwang@126.com
Received Date: 15 August 2018
Available Online: 5 December 2018
Fund Project: Project supported by the National Natural Science Foundation of China (No. 21672032)the National Natural Science Foundation of China 21672032

Figures(2)

α, α-Difluoroketones represent an important subclass of organofluorine compounds, and have been widely applied in medicinal chemistry, particularly as enzyme inhibitors. Efficient use of organofluorine reagents plays a key role for the synthesis of fluorine-containing organic compounds. As an environmental and efficient difluorocarbene reagent, TMSCF₂Br has been well utilized in synthetic applications. In 2013, Hu first utilized TMSCF₂Br as a general difluorocarbene source for the difluoromethylenation of alkenes/alkynes as well as the difluoromethylation of O-, S-, N-, and P-nucleophiles. Moreover, Dilman realized the rapid assembly of various CF₂-containing products by using TMSCF₂Br as a difluorocarbene source, which depended on the concept of three independent components: difluorocarbene, nucleophile, and electrophile. Compared with the previous works, we recently reported a catalytic difluorocyclopropanation of enolizable ketones by using TMSCF₂Br reagent, which acts as not only the difluorocarbene source but also the TMS transfer agent. The in situ generated siloxydifluorocyclopropanes were used for the synthesis of α-fluoroenones, o-fluoronaphthols, α, α-difluorocyclopentenones and α, α-difluorocyclopentanones compounds. Here, we report a simple and effective method for the conversion of enolizable ketones to α, α-difluoro-β-halo-substituted ketones. The whole process involves the in situ formation and regioselective ring opening halogenation of siloxydifluorocyclopropanes. The reaction features easily available raw materials, simple operation and practical method. A representative procedure for this reaction is as following: To a dried polytetrafluoroethene (PTFE) sealed pressure tube were added ketone 1 (0.5 mmol), n-Bu₄NBr (0.05 mmol, 10 mol%), TMSCF₂Br (0.75 mmol) and toluene (2.5 mL) in sequence. The reaction mixture was stirred at 110 ℃ for 2 h, followed by adding an additional amount of TMSCF₂Br (0.5 mmol) for another 4 h. Removal of toluene under reduced pressure delivered a mixture mainly containing 2. The reaction system was allowed to cool to room temperature followed by adding NBS/NIS (0.75 mmol) and CH₃CN (2 mL). The resulting mixture was stirred at room temperature for 2 h to consume 2 and then poured into saturated NaCl solution (30 mL), extracted with CH₂Cl₂ (10 mL×3). The combined organic extracts were dried over anhydrous MgSO₄, filtered and concentrated under reduced pressure to yield the crude product, which was purified by silica gel chromatography (petroleum ether/ethyl acetate: 100/1, V/V) to afford the pure product 4/5.
- ketone,
- α, α-difluoroketone,
- siloxydifluorocyclopropane,
- domino reaction
1. [1]
  (a) Pattison, G. Eur. J. Org. Chem. 2018, 2018, 3520; (b) O'Hagan, D. Chem. Soc. Rev. 2008, 37, 308; (c) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Chem. Soc. Rev. 2008, 37, 320; (d) Gillis, E. P.; Eastman, K. J.; Hill, M. D.; Donnelly, D. J.; Meanwell, N. A. J. Med. Chem. 2015, 58, 8315.
2. [2]
  (a) Béguè, J.-P.; Bonnet-Delpon, D. Inhibition of Enzymes by Fluorinated Compounds. Bioorganic and Medicinal Chemistry of Fluorine, Wiley, Hoboken, NJ, 2008; Chapter 7, p. 246; (b) Ojima, I. Fluorine in Medicinal Chemistry and Chemical Biology, Wiley & Sons, Chichester, 2009; (c) Imperiali, B.; Abeles, R. H. Biochemistry 1986, 25, 3760; (d) Sham, H. L.; Wideburg, N. E.; Spanton, S. G.; Kohlbrenner, W. E.; Betebenner, D. A.; Kempf, D. J.; Norbeck, D. W.; Plattner, J. J.; Erickson, J. W. J. Chem. Soc., Chem. Commun. 1991, 110; (e) Giovani, S.; Penzo, M.; Brogi, S.; Brindisi, M.; Gemma, S.; Novellino, E.; Savini, L.; Blackman, M. J.; Campiani, G.; Butini, S. Bioorg. Med. Chem. Lett. 2014, 24, 3582.
3. [3]
  (a) Han, C.; Salyer, A. E.; Kim, E. H.; Jiang, X.; Jarrard, R. E.; Powers, M. S.; Kirchhoff, A. M.; Salvador, T. K.; Chester, J. A.; Hockerman, G. H.; Colby, D. A. J. Med. Chem. 2013, 56, 2456; (b) Fah, C.; Hardegger, L. A.; Baitsch, L.; Schweizer, W. B.; Meyer, S.; Bur, D.; Diederich, F. Org. Biomol. Chem. 2009, 7, 3947; (c) Fah, C.; Hardegger, L. A.; Ebert, M.-O.; Schweizer, W. B.; Diederich, F. Chem. Commun. 2010, 46, 67.
4. [4]
  The direct fluorination methods: (a) Verniest, G.; Van Hende, E.; Surmont, R.; De Kimpe, N. Org. Lett. 2006, 8, 4767; (b) Iacono, C. E.; Stephens, T. C.; Rajan, T. S.; Pattison, G. J. Am. Chem. Soc. 2018, 140, 2036; (c) Zupan, M.; Iskra, J.; Stavber, S. J. Org. Chem. 1995, 60, 259; (d) Ramírez, J.; Fernández, E. Tetrahedron Lett. 2007, 48, 3841.
5. [5]
  Strategies based on already difluorinated building blocks: (a) Honraedt, A.; Van Der Lee, A.; Campagne, J. M.; Leclerc, E. Adv. Synth. Catal. 2017, 359, 2815; (b) Arimitsu, S.; Fernandez, B.; del Pozo, C.; Fustero, S.; Hammond, G. B. J. Org. Chem. 2008, 73, 2656; (c) Guo, C.; Wang, R.-W.; Qing, F.-L. J. Fluorine Chem. 2012, 143, 135; (d) Ge, S.; Chaładaj, W.; Hartwig, J. F. J. Am. Chem. Soc. 2014, 136, 4149; (e) Cao, C. R.; Jiang, M.; Liu, J. T. Eur. J. Org. Chem. 2015, 2015, 1144; (f) Xiao, Y. L.; Guo, W. H.; He, G. Z.; Pan, Q.; Zhang, X. Angew. Chem., Int. Ed. 2014, 53, 9909; (g) Zhao, H. Y.; Feng, Z.; Luo, Z.; Zhang, X. Angew. Chem., Int. Ed. 2016, 55, 10401; (h) Qu, C.; Xu, P.; Ma, W.; Cheng, Y.; Zhu, C. Chem. Commun. 2015, 51, 13508; (i) Adouama, C.; Keyrouz, R.; Pilet, G.; Monnereau, C.; Gueyrard, D.; Noel, T.; Medebielle, M. Chem. Commun. 2017, 53, 5653; (j) Yu, J. S.; Liu, Y. L.; Tang, J.; Wang, X.; Zhou, J. Angew. Chem., Int. Ed. 2014, 53, 9512; (k) Han, C.; Kim, E. H.; Colby, D. A. J. Am. Chem. Soc. 2011, 133, 5802; (l) Yang, M. H.; Orsi, D. L.; Altman, R. A. Angew. Chem., Int. Ed. 2015, 54, 2361.
6. [6]
  (a) Ni, C.; Hu, J. Synthesis 2014, 46, 842; (b) Hu, J.; Zhang, W.; Wang, F. Chem. Commun. 2009, 7465; (c) Pan, X.-Y.; Zhao, Y.; Qu, H.-A.; Lin, J-H.; Hang, X.-C.; Xiao, J.-C. Org. Chem. Front. 2018, 5, 1452; (d) Zhang, Z.; Yu, W.; Zhou, Q.; Li, T.; Zhang, Y.; Wang, J. Chin. J. Chem. 2016, 34, 473.
7. [7]
  (a) Kosobokov, M. D.; Dilman, A. D.; Levin, V. V.; Struchkova, M. I. J. Org. Chem. 2012, 77, 5850; (b) Dilman, A. D.; Levin, V. V. Acc. Chem. Res. 2018, 51, 1272.
8. [8]
  (a) Wang, F.; Zhang, W.; Zhu, J.; Li, H.; Huang, K.; Hu, J. Chem. Commun. 2011, 47, 2411; (b) Li, L.; Wang, F.; Ni, C.; Hu, J. Angew. Chem., Int. Ed. 2013, 52, 12390; (c) Wang, W.; Yu, Q.; Zhang, Q.; Li, J.; Hui, F.; Yang, J.; Lv, J. Chin. J. Org. Chem. 2018, 38, 1569. (王为强, 余秦伟, 张前, 李江伟, 惠丰, 杨建明, 吕剑, 有机化学, 2018, 38, 1569.); (d) Deng, X., Lin, J.; Zheng, J.; Xiao, J. Chin. J. Chem. 2014, 32, 689.
9. [9]
  (a) Xie, Q.; Ni, C.; Zhang, R.; Li, L.; Rong, J.; Hu, J. Angew. Chem., Int. Ed. 2017, 56, 1; (b) Hu, M.; Ni, C.; Li, L.; Han, Y.; Hu, J. J. Am. Chem. Soc. 2015, 137, 14496.
10. [10]
  Zhang, Z.; Yu, W.; Wu, C.; Wang, C.; Zhang, Y.; Wang, J. Angew. Chem., Int. Ed. 2015, 54, 1. doi: 10.1002/anie.201410930
11. [11]
  (a) Levin, V. V.; Smirnov, V. O.; Struchkova, M. I.; Dilman, A. D. J. Org. Chem. 2015, 80, 9349; (b) Tsymbal, A. V.; Kosobokov, M. D.; Levin, V. V.; Struchkova, M. I.; Dilman, A. D. J. Org. Chem. 2014, 79, 7831; (c) Zemtsov, A. A.; Kondratyev, N, S.; Levin, V. V.; Struchkova, M. I.; Dilman, A. D. J. Org. Chem. 2014, 79, 818; (d) Smirnov, V. O.; Struchkova, M. I.; Arkhipov, D. E.; Korlyukov, A. A.; Dilman, A. D. J. Org. Chem. 2014, 79, 11819; (e) Levin, V. V.; Zemtsov, A. A.; Struchkova, M. I.; Dilman, A. D. Org. Lett. 2013, 15, 917; (f) Kosobokov, M. D.; Levin, V. V.; Struchkova, M. I.; Dilman, A. D. Org. Lett. 2014, 16, 3784; (g) Kosobokov, M. D.; Levin, V. V.; Struchkova, M. I.; Dilman, A. D. Org. Lett. 2015, 17, 760; (h) Fedorov, O. V.; Kosobokov, M. D.; Levin, V. V.; Struchkova, M. I.; Dilman, A. D. J. Org. Chem. 2015, 80, 5870; (i) Trifonov, A. L.; Zemtsov, A. A.; Levin, V. V.; Struchkova, M. I.; Dilman, A. D. Org. Lett. 2016, 18, 3458; (j) Trifonov, A. L.; Levin, V. V.; Struchkova, M. I.; Dilman, A. D. Org. Lett. 2017, 19, 5304; (k) Supranovich, V. I.; Levin, V. V.; Struchkova, M. I.; Korlyukov, A. A.; Dilman, A. D. Org. Lett. 2017, 19, 3215.
12. [12]
  (a) Song, X.; Chang, J.; Zhu, D.; Li, J.; Xu, C.; Liu, Q.; Wang, M. Org. Lett. 2015, 17, 1712; (b) Chang, J.; Song, X.; Huang, W.; Zhu, D.; Wang, M. Chem. Commun. 2015, 51, 15362; (c) Chang, J.; Xu, C.; Gao, J.; Gao, F.; Zhu, D.; Wang, M. Org. Lett. 2017, 19, 1850; (d) Song, X.; Tian, S.; Zhao, Z.; Zhu, D.; Wang, M. Org. Lett. 2016, 18, 3414.
1. [1]
  Guojie Xu , Fang Yu , Yunxia Wang , Meng Sun . Introduction to Metal-Catalyzed β-Carbon Elimination Reaction of Cyclopropenones. University Chemistry, 2024, 39(8): 169-173. doi: 10.3866/PKU.DXHX202401060
2. [2]
  Liangzhen Hu , Li Ni , Ziyi Liu , Xiaohui Zhang , Bo Qin , Yan Xiong . A Green Chemistry Experiment on Electrochemical Synthesis of Benzophenone. University Chemistry, 2024, 39(6): 350-356. doi: 10.3866/PKU.DXHX202312001
3. [3]
  Zhuoming Liang , Ming Chen , Zhiwen Zheng , Kai Chen . Multidimensional Studies on Ketone-Enol Tautomerism of 1,3-Diketones By ¹H NMR. University Chemistry, 2024, 39(7): 361-367. doi: 10.3866/PKU.DXHX202311029
4. [4]
  Yue Zhao , Yanfei Li , Tao Xiong . Copper Hydride-Catalyzed Nucleophilic Additions of Unsaturated Hydrocarbons to Aldehydes and Ketones. University Chemistry, 2024, 39(4): 280-285. doi: 10.3866/PKU.DXHX202309001
5. [5]
  Lihui Jiang , Wanrong Dong , Hua Yang , Yongqing Xia , Hongjian Peng , Jun Yuan , Xiaoqian Hu , Zihan Zeng , Yingping Zou , Yiming Luo . Study on Extraction of p-Hydroxyacetophenone. University Chemistry, 2024, 39(11): 259-268. doi: 10.12461/PKU.DXHX202402056
6. [6]
  Xiaoning TANG , Shu XIA , Jie LEI , Xingfu YANG , Qiuyang LUO , Junnan LIU , An XUE . Fluorine-doped MnO₂ with oxygen vacancy for stabilizing Zn-ion batteries. Chinese Journal of Inorganic Chemistry, 2024, 40(9): 1671-1678. doi: 10.11862/CJIC.20240149
7. [7]
  Tingting Yu , Si Chen , Lianglong Sun , Tongtong Shi , Kai Sun , Xin Wang . Comprehensive Experimental Design for the Photochemical Synthesis, Analysis, and Characterization of Difluoropyrroles. University Chemistry, 2024, 39(11): 196-203. doi: 10.3866/PKU.DXHX202401022
8. [8]
  Yongqing Kuang , Jie Liu , Jianjun Feng , Wen Yang , Shuanglian Cai , Ling Shi . Experimental Design for the Two-Step Synthesis of Paracetamol from 4-Hydroxyacetophenone. University Chemistry, 2024, 39(8): 331-337. doi: 10.12461/PKU.DXHX202403012
9. [9]
  Yurong Tang , Yunren Shi , Yi Xu , Bo Qin , Yanqin Xu , Yunfei Cai . Innovative Experiment and Course Transformation Practice of Visible-Light-Mediated Photocatalytic Synthesis of Isoquinolinone. University Chemistry, 2024, 39(5): 296-306. doi: 10.3866/PKU.DXHX202311087
10. [10]
  Yang Chen , Peng Chen , Yuyang Song , Yuxue Jin , Song Wu . Application of Chemical Transformation Driven Impurity Separation in Experiments Teaching: A Novel Method for Purification of α-Fluorinated Mandelic Acid. University Chemistry, 2024, 39(6): 253-263. doi: 10.3866/PKU.DXHX202310077
11. [11]
  Chengqian Mao , Yanghan Chen , Haotong Bai , Junru Huang , Junpeng Zhuang . Photodimerization of Styrylpyridinium Salt and Its Application in Silk Screen Printing. University Chemistry, 2024, 39(5): 354-362. doi: 10.3866/PKU.DXHX202312014
12. [12]
  Tianlong Zhang , Rongling Zhang , Hongsheng Tang , Yan Li , Hua Li . Online Monitoring and Mechanistic Analysis of 3,5-diamino-1,2,4-triazole (DAT) Synthesis via Raman Spectroscopy: A Recommendation for a Comprehensive Instrumental Analysis Experiment. University Chemistry, 2024, 39(6): 303-311. doi: 10.3866/PKU.DXHX202312006
13. [13]
  Shahua Huang , Xiaoming Guo , Lin Lin , Guangping Chang , Sheng Han , Zuxin Zhou . Application of “Integration of Industry and Education” in Engineering Chemistry: Improvement of the Pesticide Fipronil Production. University Chemistry, 2024, 39(3): 199-204. doi: 10.3866/PKU.DXHX202309064
14. [14]
  Xiaofeng Xia , Jielian Zhu . Innovative Comprehensive Experimental Design: Synthesis of 6-Fluoro-N-benzoyl Tetrahydroquinoline. University Chemistry, 2024, 39(10): 344-352. doi: 10.12461/PKU.DXHX202405063
15. [15]
  Yinuo Wang , Siran Wang , Yilong Zhao , Dazhen Xu . Selective Synthesis of Diarylmethyl Anilines and Triarylmethanes via Multicomponent Reactions: Introduce a Comprehensive Experiment of Organic Chemistry. University Chemistry, 2024, 39(8): 324-330. doi: 10.3866/PKU.DXHX202401063
16. [16]
  Daojuan Cheng , Fang Fang . Exploration and Implementation of Science-Education Integration in Organic Chemistry Teaching for Pharmacy Majors: A Case Study on Nucleophilic Substitution Reactions of Alkyl Halides. University Chemistry, 2024, 39(11): 72-78. doi: 10.12461/PKU.DXHX202403105
17. [17]
  Xingyang LI , Tianju LIU , Yang GAO , Dandan ZHANG , Yong ZHOU , Meng PAN . A superior methanol-to-propylene catalyst: Construction via synergistic regulation of pore structure and acidic property of high-silica ZSM-5 zeolite. Chinese Journal of Inorganic Chemistry, 2024, 40(7): 1279-1289. doi: 10.11862/CJIC.20240026
18. [18]
  Jiaqi AN , Yunle LIU , Jianxuan SHANG , Yan GUO , Ce LIU , Fanlong ZENG , Anyang LI , Wenyuan WANG . Reactivity of extremely bulky silylaminogermylene chloride and bonding analysis of a cubic tetragermylene. Chinese Journal of Inorganic Chemistry, 2024, 40(8): 1511-1518. doi: 10.11862/CJIC.20240072
19. [19]
  Tingbo Wang , Yao Luo , Bingyan Hu , Ruiyuan Liu , Jing Miao , Huizhe Lu . Quantitative Computational Study on the Claisen Rearrangement Reaction of Allyl Phenyl Ethers: An Introduction to a Computational Chemistry Experiment. University Chemistry, 2024, 39(11): 278-285. doi: 10.12461/PKU.DXHX202403082
20. [20]
  Xiaoling LUO , Pintian ZOU , Xiaoyan WANG , Zheng LIU , Xiangfei KONG , Qun TANG , Sheng WANG . Synthesis, crystal structures, and properties of lanthanide metal-organic frameworks based on 2, 5-dibromoterephthalic acid ligand. Chinese Journal of Inorganic Chemistry, 2024, 40(6): 1143-1150. doi: 10.11862/CJIC.20230271

Get Citation

PDF

XML

Metrics

PDF Downloads(10)
Abstract views(946)
HTML views(125)

通讯作者: 陈斌, bchen63@163.com

1.
沈阳化工大学材料科学与工程学院沈阳 110142