甲基酮的二氟同系化-卤化反应:一锅法合成β-卤代-α,α-二氟代酮
收稿日期: 2018-08-15
网络出版日期: 2018-11-07
基金资助
项目受国家自然科学基金（No.21672032）资助.
Difluorohomologization-Halogenation of Methyl Ketones: One-Pot Synthesis of β-Halo-α,α-Difluoroketones
Received date: 2018-08-15
Online published: 2018-11-07
Supported by
Project supported by the National Natural Science Foundation of China (No. 21672032).
宋晓宁 , 杨杉 , 汪欣 , 王芒 . 甲基酮的二氟同系化-卤化反应:一锅法合成β-卤代-α,α-二氟代酮[J]. 化学学报, 2018 , 76(12) : 983 -987 . DOI: 10.6023/A18080337
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.
Key words： ketone; α,α-difluoroketone; siloxydifluorocyclopropane; domino reaction
[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] (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] (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] 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] 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.; Chaladaj, 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] (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] (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] (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] (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] Zhang, Z.; Yu, W.; Wu, C.; Wang, C.; Zhang, Y.; Wang, J. Angew. Chem., Int. Ed. 2015, 54, 1.
[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] (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.
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