Synlett 2021; 32(11): 1123-1130
DOI: 10.1055/a-1507-5878
letter

Highly Selective Difluoromethylations of β-Keto Amides with ­TMSCF2Br under Mild Conditions

Yakun Wang
,
Shuaifei Wang
,
Conghui Zhang
,
Ting Zhao
,
Yanqin Hu
,
Mingwei Zhang
,
Pengli Chen
,
Yang Fu
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.

Supporting Information



Publication History

Received: 21 April 2021

Accepted after revision: 12 May 2021

Publication Date:
12 May 2021 (online)

© 2021. Thieme. All rights reserved

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 
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  • 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.