一锅法合成两种含有季碳中心的氰基化合物

doi:10.6023/cjoc202107017

摘要/Abstract

α-溴代酰胺和亲电氰化试剂在锌粉存在条件下转化为相应的含有季碳中心的α-氰基酰胺和烯酮亚胺锌中间体; 向反应体系中引入亲电试剂捕获该中间体, 顺利得到另一种含有季碳中心的氰基产物, 实现了一锅法合成两种含有季碳中心的氰基化合物. 该反应体系可以构建含有碳-碳、碳-硫或碳-氟键的季碳中心. 该方法可用于关键药物中间体如洛哌丁胺、普罗地芬、维拉帕米、戈洛帕米、α-氟代布洛芬以及α-氟代氟比洛芬的形式合成, 体现了其潜在应用价值.

关键词: 亲电氰化试剂, 腈, 季碳中心, 药物中间体

α-Bromocarboxamides and electrophilic cyanide reagent were transformed into the corresponding α-cyanocarboxamides and ketene imine zinc intermediate in the presence of Zn reductant. Trapping of such Zn species with additional electrophiles resulted another type of nitriles, which realized the synthesis of two types of nitriles both bearing quaternary carbon centers in one-pot manner. This approach could be used to construct C—C, C—S, or C—F bond. Formal synthesis of several key pharmaceutical intermediates including loperamide, proadifen, verapamil, and gallopamil as well as α-fluoroibuprofen and α-fluoroflurbiprofen demonstrated the potential application of this methodology.

Key words: electrophilic cyanide reagent, nitrile, quaternary carbon center, pharmaceutical intermediate

引用此文

任新意, 王广柱, 纪晓雷, 董开武. 一锅法合成两种含有季碳中心的氰基化合物[J]. 有机化学, 2022, 42(2): 526-533.

Xinyi Ren, Guangzhu Wang, Xiaolei Ji, Kaiwu Dong. Synthesis of Two Types of Nitriles Both Bearing Quaternary Carbon Centers in One-Pot Manner[J]. Chinese Journal of Organic Chemistry, 2022, 42(2): 526-533.

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图/表 5

Scheme 1. Selected pharmaceuticals with a nitrile-bearing quaternary center and cyanation of organometallic reagents with electrophilic CN source

. Shceme 2 Synthesis of two types of nitriles both bearing quaternary carbon centers in one-pot manner

Electrophile (E-Y)	Nitrile	Electrophile (E-Y)	Nitrile

Table 1. Scope of various electrophilesa

Table 2. Scope of electrophilic cyanide reagents

Table 3. Cyanation with allyl bromidesa

参考文献 27

[1]	(a) Pollak, P.; Romeder, G.; Hagedorn, F.; Gelbke, H.In Ullman’s Encyclopedia of Industrial Chemistry, 5th ed., Vol. A17, Wiley-VCH, Weinheim, Germany, 1985, p. 363. pmid: 20804202
	(b) Fleming, F. F.; Yao, L.; Ravikumar, P. C.; Funk, L.; Shook, B. C. J. Med. Chem. 2010, 53, 7902. doi: 10.1021/jm100762r pmid: 20804202
	(c) Wang, J.; Liu, H. Chin. J. Org. Chem. 2012, 32, 1643. (in Chinese) doi: 10.6023/cjoc1202132 pmid: 20804202
	( 王江, 柳红, 有机化学, 2012, 32, 1643.) doi: 10.6023/cjoc1202132 pmid: 20804202
	(d) Qin, T.; Zhang, S.; Liao, W. Chin. J. Org. Chem. 2014, 34, 2187. (in Chinese) doi: 10.6023/cjoc201406038 pmid: 20804202
	( 秦天游, 张晓安, 寮渭巍, 有机化学, 2014, 34, 2187.) doi: 10.6023/cjoc201406038 pmid: 20804202
[2]	Wang, Y.; Du, Y.; Huang, N. Future Med. Chem. 2018, 10, 2713. doi: 10.4155/fmc-2018-0252
[3]	(a) Rappoport, Z. Chemistry of the Cyano Group, Wiley, London, 1970. pmid: 27701109
	(b) Larock, R. C. Comprehensive Organic Transformations: A Guide to Functional Group Preparations, Wiley, New York, 1989. pmid: 27701109
	(c) Zhang, W.; Wang, F.; McCann, S. D.; Wang, D.; Chen, P.; Stahl, S. S.; Liu, G. Science 2016, 353, 1014. pmid: 27701109
[4]	(a) Hideji, T.; Kazuo, H. Toxicol. Lett. 1984, 22, 267. doi: 10.1016/0378-4274(84)90077-8
	(b) Ahmed, A. E.; Trieff, N. M. Prog. Drug Metab. 1983, 7, 229.
[5]	Yurino, T.; Tani, R.; Ohkuma, T. ACS Catal. 2019, 9, 4434. doi: 10.1021/acscatal.9b00858
[6]	Reetz, M. T.; Chatziiosifidis, I. Angew. Chem., Int. Ed. Engl. 1981, 20, 1017.
[7]	(a) Wu, W. B.; Yu, J.-S.; Zhou, J. ACS Catal. 2020, 10, 7668. doi: 10.1021/acscatal.0c01918 pmid: 26491957
	(b) Ratani, T. S.; Bachman, S.; Fu, G. C.; Peters, J. C. J. Am. Chem. Soc. 2015, 137, 13902. doi: 10.1021/jacs.5b08452 pmid: 26491957
	(c) Miwa, N.; Tanaka, C.; Ishida, S.; Hirata, G.; Song, J.; Torigoe, T.; Kuninobu, Y.; Nishikata, T. J. Am. Chem. Soc. 2020, 142, 1692. doi: 10.1021/jacs.9b11349 pmid: 26491957
	(d) Fang, X.; Yu, P.; Morandi, B. Science 2016, 351, 832. doi: 10.1126/science.aae0427 pmid: 26491957
	(e) Guo, F.; You, J.; Wu, W.; Yu, Y.; Jing, B.; Liu, B. Chin. J. Org. Chem. 2021, 41, 1968. (in Chinese) pmid: 26491957
	郭芳, 由君, 武文菊, 喻艳超, 井彬, 刘波, 有机化学, 2021, 41, 1968. doi: 10.6023/cjoc20210203 pmid: 26491957
	(f) Xu, W.; Huang, D.; Wang, K.; Zhao, F.; Zhao, Z.; Hu, Y.; Su, Y.; Hu, Y. Chin. J. Org. Chem. 2020, 40, 922. (in Chinese) pmid: 26491957
	( 徐炜刚, 黄丹凤, 王克虎, 赵芳霞, 赵转霞, 虎永琴, 苏瀛鹏, 胡雨来, 有机化学, 2020, 40, 922.) doi: 10.6023/cjoc201910011 pmid: 26491957
[8]	(a) Schörgenhumer, J.; Waser, M. Org. Chem. Front. 2016, 3, 1535. doi: 10.1039/C6QO00390G pmid: 30209455
	(b) Nauth, A. M.; Opatz, T. Org. Biomol. Chem. 2019, 17, 11. doi: 10.1039/C8OB02140F pmid: 30209455
	(c) Chaitanya, M.; Anbarasan, P. Org. Biomol. Chem. 2018, 16, 7084. doi: 10.1039/c8ob01770k pmid: 30209455
	(d) Anbarasan, P.; Neumann, H.; Beller, M. Angew. Chem., Int. Ed. 2011, 50, 519. doi: 10.1002/anie.201006044 pmid: 30209455
	(e) Chen, H.; Sun, S.; Liu, Y. A.; Liao, X. ACS Catal. 2020, 10, 1397. doi: 10.1021/acscatal.9b04586 pmid: 30209455
	(f) Li, X.; Golz, C.; Alcarazo, M. Angew. Chem., Int. Ed. 2019, 58, 9496. doi: 10.1002/anie.v58.28 pmid: 30209455
	(g) Kiyokawa, K.; Nagata, T.; Minakata, S. Angew. Chem., Int. Ed. 2016, 55, 10458. doi: 10.1002/anie.201605445 pmid: 30209455
	(h) Lu, Z.; Hu, X.-D.; Zhang, H.; Zhang, X.-W.; Cai, J.; Usman, M.; Cong, H.; Liu, W.-B. J. Am. Chem. Soc. 2020, 142, 7328. doi: 10.1021/jacs.0c02075 pmid: 30209455
	(i) Hu, X.-D.; Chen, Z.-H.; Zhao, J.; Sun, R.-Z.; Zhang, H.; Qi, X.-T.; Liu, W.-B. J. Am. Chem. Soc. 2021, 143, 3734. doi: 10.1021/jacs.1c00840 pmid: 30209455
	(j) Cai, J.; Bai, L.-G.; Zhang, Y.; Wang, Z.-K.; Yao, F.; Peng, J.-H.; Yan, W.; Wang, Y.; Zheng, C.; Liu, W.-B. Chem 2021, 7, 799. doi: 10.1016/j.chempr.2021.02.013 pmid: 30209455
	(k) Malapit, C. A.; Caldwell, D. R.; Luvaga, I. K.; Reeves, J. T.; Volchkov, I.; Gonnella, N. C.; Han, Z. S.; Busacca, C. A.; Howell, A. R.; Senanayake, C. H. Angew. Chem., Int. Ed. 2017, 56, 6999. doi: 10.1002/anie.201703471 pmid: 30209455
	(l) Zhou, F.; Zhou, J. Chin. J. Org. Chem. 2020, 40, 2180. (in Chinese) doi: 10.6023/cjoc202000044 pmid: 30209455
	( 周锋, 周剑, 有机化学, 2020, 40, 2180.) doi: 10.6023/cjoc202000044 pmid: 30209455
[9]	(a) Reeves, J. T.; Malapit, C. A.; Buono, F. G.; Sidhu, K. P.; Marsini, M. A.; Sader, C. A.; Fandrick, K. R.; Busacca, C. A.; Senanayake, C. H. J. Am. Chem. Soc. 2015, 137, 9481. doi: 10.1021/jacs.5b06136
	(b) Malapit, A.; Luvaga, I. K.; Reeves, J. T.; Volchkov, I.; Busacca, C. A.; Howell, A. R.; Senanayake, C. H. J. Org. Chem. 2017, 82, 4993. doi: 10.1021/acs.joc.7b00567
	(c) Alazet, S.; West, M. S.; Patel, P.; Rousseaux, S. A. L. Angew. Chem., Int. Ed. 2019, 58, 10300. doi: 10.1002/anie.v58.30
[10]	Ren, X.; Shen, C.; Wang, G.; Shi, Z.; Tian, X.; Dong, K. Org. Lett. 2021, 23, 2527. doi: 10.1021/acs.orglett.1c00465
[11]	Knochel, P.; Singer, R. D. Chem. Rev. 1993, 93, 2117. doi: 10.1021/cr00022a008
[12]	Mills, L. R.; Graham, J. M.; Patel, P.; Rousseaux, S. A. L. J. Am. Chem. Soc. 2019, 141, 19257. doi: 10.1021/jacs.9b11208
[13]	(a) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Chem. Soc. Rev. 2008, 37, 320. doi: 10.1039/B610213C pmid: 17901324
	(b) Müller, K.; Faeh, C.; Diederich, F. Science 2007, 317, 1881. pmid: 17901324
[14]	Harrington, P. J.; Lodewijk, E. Org. Process Res. Dev. 1997, 1, 72. doi: 10.1021/op960009e
[15]	Schlosser, M.; Michel, D.; Guo, Z.-W.; Sih, C. J. Tetrahedron 1996, 52, 8257. doi: 10.1016/0040-4020(96)00411-5
[16]	Wang, M.; Gao, M.; Zheng, Q.-H. Bioorg. Med. Chem. Lett. 2013, 23, 5259. doi: 10.1016/j.bmcl.2013.08.024 pmid: 23981899
[17]	Lu, M. C.; Wung, W. E.; Shih, L. B.; Callejas, S.; Gearien, J. E.; Thompson, E. B. J. Med. Chem. 1987, 30, 273. pmid: 3806612
[18]	(a) Wu, L.; Hartwig, J. F. J. Am. Chem. Soc. 2005, 127, 15824. doi: 10.1021/ja053027x
	(b) Mermerian, A. H.; Fu, G. C. Angew. Chem., Int. Ed. 2005, 44, 949. doi: 10.1002/(ISSN)1521-3773
	(c) Grenning, A. J.; Tunge, J. A. J. Am. Chem. Soc. 2011, 133, 14785. doi: 10.1021/ja205717f
	(d) Toma, M.-J.; Turnbulla, B. W. H.; Evans, P. A. Synthesis 2020, 52, 2185. doi: 10.1055/s-0040-1707390
[19]	Brogden, R. N.; Benfield, P. Drugs 1994, 47, 93. pmid: 7510624
[20]	Theodore, L. J.; Nelson, W. L. J. Org. Chem. 1987, 52, 1309. doi: 10.1021/jo00383a026
[21]	Mills, L. R.; Graham, J. M.; Patel, P.; Rousseaux, S. A. L. J. Am. Chem. Soc. 2019, 141, 19257. doi: 10.1021/jacs.9b11208
[22]	Sherwood, A. M.; Williamson, S. E.; Johnson, S. N.; Yilmaz, A.; Day, V. W.; Prisinzano, T. E. J. Org. Chem. 2018, 83, 980. doi: 10.1021/acs.joc.7b02324
[23]	Katritzky, A. R.; Abdel-Fattah, A. A. A.; Wang, M. J. Org. Chem. 2003, 68, 4932. pmid: 12790602
[24]	Yoneda, R.; Osaki, T.; Harusawa, S.; Kurihara, T. J. Chem. Soc., Perkin Trans. 1 1990, 607.
[25]	Orecchia, P.; Yuan, W.; Oestreich, M. Angew. Chem., Int. Ed. 2019, 58, 3579. doi: 10.1002/anie.201813853
[26]	Huang, Y.; Li, X.; Wang, X.; Yu, Y.; Zheng, J.; Wu, W.; Jiang, H. Chem. Sci. 2017, 8, 7047. doi: 10.1039/C7SC02867A
[27]	Shen, H.; Liu, Z.; Zhang, P.; Tan, X.; Zhang, Z.; Li, C. J. Am. Chem. Soc. 2017, 139, 9843. doi: 10.1021/jacs.7b06044