Synthesis of β-Fluoro Amides Using Partially Hydrated Nickel Difluoride as Fluorine Source

Abstract

β-Fluoro amides were obtained from the reactions of ­activated aziridines with partially hydrated nickel difluoride (NiF₂·nH₂O, n <4) in good yields (47–82%) in the presence of tetra-n-butylammonium fluoride (20 mol%), while the non-activated aziridines did not react under the same conditions.

Key words

nickel - fluorine - halogenation - ring opening - sulfonamide

• References

• 1 Liu F, Martin-Mingot A, Jouannetaud M.-P, Zunino F, Thibaudeau S. Org. Lett. 2010; 13: 868
• 2a Purser S, Moore PM, Swallow S, Gouverneur V. Chem. Soc. Rev. 2008; 37: 320
• 2b Zimmer LE, Sparr C, Gilmour R. Angew. Chem. Int. Ed. 2011; 50: 11860
• 2c Hagmann WH. J. Med. Chem. 2008; 51: 4359
• 2d Kirk KL. Org. Process Res. Dev. 2008; 12: 305
• 3a Hakman S, Beguin CG. J. Fluorine Chem. 1987; 37: 343
• 3b Toulgui C, Chaabouni MM, Baklouti A. J. Fluorine Chem. 1990; 46: 385
• 3c D’hooghe M, De Kimpe N. Synlett 2006; 2089
• 3d Thibaudeau S, Martin-Mingot A, Jouannetaud M.-P, Karam O, Zunino F. Chem. Commun. 2007; 3198
• 3e Jing ZT, Huang YG, Qing FL. Chin. Chem. Lett. 2011; 22: 919
• 3f Schulte ML, Lindsley CW. Org. Lett. 2011; 13: 5684
• 4a Hu XE. Tetrahedron 2004; 60: 2701
• 4b Ding C.-H, Dai L.-X, Hou X.-L. Synlett 2004; 2218
• 5 Fang RH, Zhou YG, Zhang WX, Hou XL, Dai LX. J. Org. Chem. 2004; 69: 335
• 6a Lee SJ, Oh SJ, Chi DY, Lee BS, Ryu JS, Moon DH. J. Label Compd. Radiopharm. 2008; 51: 80
• 6b Kim DW, Ahn DS, Oh YH, Lee S, Kil HS. J. Am. Chem. Soc. 2006; 128: 16394
• 7 Fang RH, Hou XL. Org. Biomol. Chem. 2003; 1: 1565
• 8 Complete dehydration of NiF₂·4H₂O needs vigorous condition: heating it to 500 °C under an atmosphere of HF.
• 9 Typical Procedure for the Ring Opening of Aziridine with Partially Hydrated Nickel Difluoride: To a stirred solution of aziridine 1a (0.5 mmol) and partially hydrated nickel difluoride (NiF₂·nH₂O, n <4, 1.68 g, approx. 1 mmol) in i-PrOH (3.0 mL) was added Bu₄NF (0.1 mmol), and the mixture was stirred at 90 °C until 1a was consumed (monitored by TLC). The mixture was filtered by short silica gel column and washed with CH₂Cl₂, then the solvent was removed in vacuum and the residue was purified by flash column chromatography on silica gel to yield 2a as a white amorphous solid. N-(2-Fluorocyclohexyl)-4-methylbenzenesulfonamide (2a): 82% yield; mp 95–96 °C (lit.⁵ 95–97 °C). ¹H NMR (600 MHz, CDCl₃, 25 °C, TMS): δ = 1.22–1.26 (m, 4 H), 1.57–1.70 (m, 2 H), 2.01–2.13 (m, 2 H), 2.43 (s, 3 H), 3.17 (m, 1 H), 4.15, 4.25 (double multiplet, ² J _HF = 50.1 Hz, 1 H), 4.81 (d, J = 5.4 Hz, 1 H), 7.30 (d, J = 7.8 Hz, 2 H), 7.76 (d, J = 8.4 Hz, 2 H). ¹⁹F NMR (600 MHz, CDCl₃, 25 °C, CF₃COOH): δ = –179.3. IR (KBr): 3302, 2951, 1598, 1327, 1163, 1091, 1045, 893, 816, 667, 572, 551 cm^–1.