Subscribe to RSS
Please copy the URL and add it into your RSS Feed Reader.
https://www.thieme-connect.de/rss/thieme/en/10.1055-s-00000083.xml
Synlett 2021; 32(11): 1123-1130
DOI: 10.1055/a-1507-5878
DOI: 10.1055/a-1507-5878
letter
Highly Selective Difluoromethylations of β-Keto Amides with TMSCF2Br under Mild Conditions
We would like to thank the the University Key Research Projects of Henan Province (19A350009) and the Natural Science Foundation of Henan Province (202300410321) for their support.
Abstract
Without employing any transition metal and other additives, efficient methods for selective difluoromethylations of β-keto amides with TMSCF2Br reagent have been developed under mild conditions. This protocol allows a convenient access to various α-difluoromethyl β-keto amides with excellent yields (up to 93%) and high carbon/oxygen (C/O) regioselectivities (up to 99:1). The C/O selectivity of β-keto amides could be easily reversed and controlled by simply changing the base. This protocol can be easily scaled-up and the C-difluoromethylation product could be reduced into CF2H-containing amino alcohol derivatives. Moreover, the first enantioselective electrophilic difluoromethylation of β-keto amides has been achieved by phase-transfer catalysis.
Key words
difluoromethylation - β-keto amides - C/O selectivity - asymmetric synthesis - difluorocarbene - phase-transfer catalysisSupporting Information
- Supporting information for this article is available online at https://doi.org/10.1055/a-1507-5878.
- Supporting Information
Publication History
Received: 21 April 2021
Accepted after revision: 12 May 2021
Accepted Manuscript online:
12 May 2021
Article published online:
08 June 2021
© 2021. Thieme. All rights reserved
Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany
-
References and Notes
- 1a O’Hagan D. Nat. Prod. Rep. 1994; 11: 123
- 1b Hiyama T. Organofluorine Compounds: Chemistry and Applications . Springer; Berlin/Heidelberg: 2013
- 1c Hagmann WK. J. Med. Chem. 2008; 51: 4359
- 1d Wang J, Sánchez-Roselló M, Aceña JL, del Pozo C, Sorochinsky AE, Fustero S, Soloshonok VA, Liu H. Chem. Rev. 2013; 114: 2432
- 1e Gillis EP, Eastman KJ, Hill MD, Donnelly DJ, Meanwell NA. J. Med. Chem. 2015; 58: 8315
- 2a Sessler CD, Rahm M, Becker S, Goldberg JM, Wang F, Lippard SJ. J. Am. Chem. Soc. 2017; 139: 9325
- 2b Erickson JA, McLoughlin JI. J. Org. Chem. 1995; 60: 1626
- 2c Meanwell NA. J. Med. Chem. 2011; 54: 2529
- 3 Zafrani Y, Sod-Moriah G, Yeffet D, Berliner A, Amir D, Marciano D, Elias S, Katalan S, Ashkenazi N, Madmon M, Gershonov E, Saphier S. J. Med. Chem. 2019; 62: 5628
- 4 Boland S, Alen J, Bourin A, Castermans K, Boumans N, Panitti L, Vanormelingen J, Leysen D, Defert O. Bioorg. Med. Chem. Lett. 2014; 24: 4594
- 5 Li X.-Q, Andersson TB, Ahlström M, Weidolf L. Drug Metab. Dispos. 2004; 32: 821
- 6a Zhang W, Wang Y. Tetrahedron Lett. 2018; 59: 1301
- 6b Liu Q, Ni C, Hu J. Natl. Sci. Rev. 2017; 4: 303
- 6c Ni C, Hu J. Chem. Soc. Rev. 2016; 45: 5441
- 6d Hu J, Zhang W, Wang F. Chem. Commun. 2009; 7465
- 6e Feng Z, Xiao Y.-L, Zhang X. Acc. Chem. Res. 2018; 51: 2264
- 7a Rong J, Ni C, Hu J. Asian J. Org. Chem. 2017; 6: 139
- 7b Yerien DE, Barata-Vallejo S, Postigo A. Chem. Eur. J. 2017; 23: 14676
- 7c Belhomme MC, Besset T, Poisson T, Pannecoucke X. Chem. Eur. J. 2015; 21: 12836
- 7d Deng X.-Y, Lin J.-H, Xiao J.-C. Org. Lett. 2016; 18: 4384
- 7e Feng Z, Min Q.-Q, Fu X.-P, An L, Zhang X. Nat. Chem. 2017; 9: 918
- 8a Ni C, Hu J. Synthesis 2014; 46: 842
- 8b Ni C, Hu M, Hu J. Chem. Rev. 2015; 115: 765
- 8c Dilman AD, Levin VV. Acc. Chem. Res. 2018; 51: 1272
- 8d Wang F, Zhang W, Zhu J, Li H, Huang K.-W, Hu J. Chem. Commun. 2011; 47: 2411
- 9a Deng X.-Y, Lin J.-H, Zheng J, Xiao J.-C. Chem. Commun. 2015; 51: 8805
- 9b Zheng J, Li Y, Zhang L, Hu J, Meuzelaar GJ, Federsel H.-J. Chem. Commun. 2007; 5149
- 9c Song H.-X, Han Q.-Y, Zhao C.-L, Zhang C.-P. Green Chem. 2018; 20: 1662
- 9d Glenadel Q, Ismalaj E, Billard T. J. Org. Chem. 2016; 81: 8268
- 10a Hu M, Ni C, Li L, Han Y, Hu J. J. Am. Chem. Soc. 2015; 137: 14496
- 10b Xie Q, Zhu Z, Li L, Ni C, Hu J. Angew. Chem. Int. Ed. 2019; 131: 6405
- 11a Yang YD, Lu X, Liu G, Tokunaga E, Tsuzuki S, Shibata N. ChemistryOpen 2012; 1: 221
- 11b Wang J, Tokunaga E, Shibata N. Chem. Commun. 2018; 54: 8881
- 12 Zhu J, Zheng H, Xue XS, Xiao Y, Liu Y, Shen Q. Chin. J. Chem. 2018; 36: 1069
- 13 Lu S.-L, Li X, Qin W.-B, Liu J.-J, Huang Y.-Y, Wong HN, Liu G.-K. Org. Lett. 2018; 20: 6925
- 14a Qin W, Chen J, Xiong W, Liu G.-K. Chin. J. Org. Chem. 2020; 40: 3177
- 14b Barata-Vallejo S, Postigo A. Molecules 2019; 24: 4483
- 15 Yue C.-B, Lin J.-H, Cai J, Zhang C.-P, Zhao G, Xiao J.-C, Li H. RSC Adv. 2016; 6: 35705
- 16 Fier PS, Hartwig JF. Angew. Chem. Int. Ed. 2013; 52: 2092
- 17 Zheng J, Cai J, Lin J.-H, Guo Y, Xiao J.-C. Chem. Commun. 2013; 49: 7513
- 18 Zafrani Y, Sod-Moriah G, Segall Y. Tetrahedron 2009; 65: 5278
- 19 Xie Q, Ni C, Zhang R, Li L, Rong J, Hu J. Angew. Chem. Int. Ed. 2017; 56: 3206
- 20a Tsang AS. K, Kapat A, Schoenebeck F. J. Am. Chem. Soc. 2016; 138: 518
- 20b Chaudhari MB, Sutar Y, Malpathak S, Hazra A, Gnanaprakasam B. Org. Lett. 2017; 19: 3628
- 21a Wang Y, Zheng Z, Lian M, Yin H, Zhao J, Meng Q, Gao Z. Green Chem. 2016; 18: 5493
- 21b Zhao J, Yang F, Yu Z, Tang X, Wu Y, Ma C, Meng Q. Chem. Commun. 2019; 55: 13008
- 22 Li L, Wang F, Ni C, Hu J. Angew. Chem. Int. Ed. 2013; 125: 12616
- 23 Ho T.-L. Chem. Rev. 1975; 75: 1
- 24 Zhang R, Ni C, Xie Q, Hu J. Tetrahedron 2020; 76: 131676
- 25 Gómez S, Guerra D, López JG, Toro-Labbé A, Restrepo A. J. Phys. Chem. A 2013; 117: 1991
- 26a Maruoka K, Ooi T. Chem. Rev. 2003; 103: 3013
- 26b O’Donnell MJ. Acc. Chem. Res. 2004; 37: 506
- 26c Shirakawa S, Maruoka K. Angew. Chem. Int. Ed. 2013; 52: 4312
- 26d Tan J, Yasuda N. Org. Process Res. Dev. 2015; 19: 1731
- 27a Wang Y, Yin H, Tang X, Wu Y, Meng Q, Gao Z. J. Org. Chem. 2016; 81: 7042
- 27b Wang Y, Gao Q, Liu Z, Bai S, Tang X, Yin H, Meng Q. J. Org. Chem. 2018; 83: 2263
- 27c Wang Y, Gao Q, Li N, Chen Y, Cui J, Gao F, Meng Q. Tetrahedron 2018; 74: 4126
- 27d Wang Y, Li Y, Lian M, Zhang J, Liu Z, Tang X, Yin H, Meng Q. Org. Biomol. Chem. 2019; 17: 573
- 28a Banik SM, Medley JW, Jacobsen EN. Science 2016; 353: 51
- 28b Liu Y, Shi T, Zhou F, Zhao X, Wang X, Zhou J. Org. Lett. 2011; 13: 3826
- 29 General Procedure for the C-Difluoromethylation of β-Keto Amides The reaction was performed with β-keto amide 1a (0.1 mmol) and LiOH (7.2 mg, 0.3 mmol) in dry toluene (2.5 mL). The reaction mixture was stirred at 15 °C for 5 min. Then TMSCF2Br (0.15 mmol) was added slowly, and the reaction was stirred at this temperature for 24 h. After the reaction was completed, the mixture was diluted with EtOAc (20 mL), washed with water (3 × 10 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was subject to crude 19F NMR analysis to give the C/O isomer ratio (trifluoromethyl benzene 8 μL as internal standard). Subsequently, the residue was purified by flash chromatography (silica gel; petroleum ether/ethyl acetate = 25:1 to 2:1) to afford the α-difluoromethylation products 2a (white wax, 27.1 mg, 90% yield, C/O = 98:2). 1H NMR (400 MHz, CDCl3): δ = 9.18 (s, 1 H), 7.88–7.67 (m, 2 H), 7.63–7.52 (m, 3 H), 7.49–7.29 (m, 3 H), 7.21–7.05 (m, 1 H), 6.22 (t, J = 55.5 Hz, 1 H), 4.10 (d, J = 18.3 Hz, 1 H), 3.55 (d, J = 18.3 Hz, 1 H). 13C NMR (101 MHz, CDCl3): δ = 200.84 (d, J = 4.8 Hz), 160.94 (d, J = 9.1 Hz), 153.93, 137.09, 136.96, 129.07, 128.15, 126.62, 125.02, 120.15, 115.42 (m), 64.98 (d, J = 39.9 Hz). 19F NMR (376 MHz, CDCl3): δ = –121.15 (dd, J = 280.0, 55.3 Hz, 1 F), –123.85 (dd, J = 280.0, 55.3 Hz, 1 F). HRMS: m/z calcd for [C17H13F2NO2 + Na]+: 324.0812; found: 324.0815.