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Synlett 2019; 30(20): 2258-2262
DOI: 10.1055/s-0039-1690715
DOI: 10.1055/s-0039-1690715
letter
Synthesis of New γ-Lactams with gem-Difluorinated Side Chains
This research has been supported in Lebanon by the Research Grant program at the Lebanese University. In France it was supported by the CNRS and the University of Rennes 1 (CNRS UMR 6226). We thank the European FEDER funds for acquisition of the D8Venture X-ray diffractometer used for crystal structure determination. The authors would like to acknowledge the National Council for Scientific Research of Lebanon (CNRS-L)/Agence Universitaire de la Francophonie (AUF)/and the Lebanese University (UL) for granting a doctoral fellowship to Ali Soulieman.Further Information
Publication History
Received: 10 September 2019
Accepted after revision: 29 September 2019
Publication Date:
14 October 2019 (online)
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Abstract
A short and efficient approach has been designed for the synthesis of new γ-lactams that feature gem-difluorinated side-chains in position 4. The key steps involve 1,4-addition of nitroalkane anions on electrophilic gem-difluoroalkenes, followed by a cascade nitro reduction–heterocyclization. This flexible strategy also allows easy introduction of substituents in positions 3 or 5.
Supporting Information
- Supporting information for this article is available online at https://doi.org/10.1055/s-0039-1690715.
- Supporting Information
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References and Notes
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- 8 Typical Procedures: Synthesis of Methyl 4,4-Difluoro-4-phenylbut-2-ynoate (4a) To propargylic ketone 3a (1 g, 5.31 mmol), one drop of 95% ethanol and DAST (4.2 mL, 31.8 mmol, 6 equiv) were added. The reaction mixture was stirred at 60 °C for 6 h. After returning to room temperature and aqueous work-up, the reaction mixture was extracted with DCM (3 × 40 mL). The organic layers were separated, washed with H2O (3 × 20 mL), dried over Na2SO4, and filtrated through silica. After purification by chromatography on silica gel, the fluorinated compound 4a (0.73 g, 65%) was obtained as a yellow oil; Rf = 0.4 (cyclohexane/EtOAc, 9:1). 1H NMR (500 MHz, CDCl3): δ = 7.71–7.59 (m, 2 H), 7.56–7.41 (m, 3 H), 3.84 (s, 3 H). 13C NMR (126 MHz, CDCl3): δ = 152.4, 134.4 (t, 2 J C–F = 26.8 Hz), 131.4 (t, 5 J C–F = 1.7 Hz), 128.8 (2C), 125.3 (t, 3 J C–F = 4.9 Hz, 2C), 111.5 (t, 1 J C–F = 235.1 Hz), 78.0 (t, 3 J C–F = 5.9 Hz), 77.4 (t, 2 J C–F = 44.3 Hz), 53.4. 19F {H} NMR (471 MHz, CDCl3): δ = –79.61 (s). HRMS (ESI): m/z [M + Na]+ calcd for C11H8O2F2Na: 233.03846; found: 233.0383 (1 ppm). Synthesis of Methyl (Z)-4,4-Difluoro-4-phenylbut-2-enoate (5a) Methyl 4,4-difluoro-4-phenylbut-2-ynoate (4a; 0.5 g, 2.38 mmol) was stirred with Lindlar catalyst (10%) in MeOH (15 mL) under hydrogen. The reaction was monitored by TLC and, on completion, the reaction mixture was filtrated through Celite® and the product was purified by chromatography to obtain the methyl (Z)-4,4-difluoro-4-phenylbut-2-enoate (5a; 434 mg, 86%) as a colorless oil. Rf = 0.4 (cyclohexane/EtOAc, 8:2). 1H NMR (500 MHz, CDCl3): δ = 7.63–7.59 (m, 2 H), 7.46–7.41 (m, 3 H), 6.22 (dd, 3 J H–F = 25.0, 3 J H–H = 12.5 Hz, 1 H), 6.13 (dt, 3 J H–H = 12.6, 4 J H–F = 1.3 Hz, 1 H), 3.69 (s, 3 H). 13C NMR (126 MHz, CDCl3): δ = 165.5, 135.9 (t, 2 J C–F = 27.1 Hz), 134.7 (t, 2 J C–F = 32.3 Hz), 130.4 (t, 5 J C–F = 1.7 Hz), 128.6 (s, 2C), 125.5 (t, 3 J C–F = 5.6 Hz, 2C), 124.9 (t, 3 J C–F = 7.1 Hz), 118.6 (t, 1 J C–F = 240.5 Hz), 52.1. 19F {H} NMR (471 MHz, CDCl3): δ = –88.90 (s). HRMS (ESI): m/z [M + Na]+ calcd for C11H10O2F2Na: 235.05411; found: 235.0540 (0 ppm). Synthesis of Methyl 4,4-Difluoro-3-(nitromethyl)-4-phenylbutanoate (6a) To methyl (Z)-4,4-difluoro-4-phenylbut-2-enoate (5a; 150 mg, 0.7 mmol) were added nitromethane (75 μL, 1.4 mmol) and potassium carbonate (289 mg, 2.1 mmol) in DMSO (3 mL). The reaction mixture was stirred at room temperature and analyzed by TLC. On completion, saturated NH4Cl (10 mL) was added and the reaction mixture was extracted with EtOAc (3 × 20 mL). The combined organic layers were separated, washed with H2O (3 × 10 mL), dried over Na2SO4, filtered, and concentrated under vacuum. After purification by chromatography on silica gel, methyl 4,4-difluoro-3-(nitromethyl)-4-phenylbutanoate (6a; 174 mg, 90%) was obtained as a yellow oil; Rf =0.4 (cyclohexane/EtOAc, 7:3). 1H NMR (300 MHz, CDCl3): δ = 7.55–7.45 (m, 5 H), 4.73 (dd, 2 J H–H = 13.8 Hz, 3 J H–H = 5.8 Hz, 1 H), 4.53 (dd, 2 J H–H = 13.8 Hz, 3 J H–H = 6.2 Hz, 1 H), 3.77–3.57 (m, 1 H), 3.62 (s, 3 H), 2.66 (dd, 2 J H–H = 16.9 Hz, 3 J H–H = 5.2 Hz, 1 H), 2.50 (dd, 2 J H–H = 16.9 Hz, 3 J H–H = 8.2 Hz, 1 H). 13C NMR (75 MHz, CDCl3): δ = 170.8, 133.9 (t, 2 J C–F = 25.8 Hz), 131.0, 129.0 (2C), 125.5 (t, 3 J C–F = 6.4 Hz, 2C), 123.7 (dd, 1 J C–F = 247.4 Hz), 73.4 (t, 3 J C–F = 3.4 Hz), 52.3, 42.6 (t, 2 J C–F = 27.1 Hz), 31.4 (dd, 3 J C–F = 4.2, 3.0 Hz). 19F {H} NMR (282 MHz, CDCl3): δ = –98.05 (AB system, J = 250.8 Hz), –104.55 (AB system, J = 250.8 Hz). HRMS (ESI): m/z [M + Na]+ calcd. for C12H13NO4F2Na: 296.07048; found: 296.0706 (0 ppm). Synthesis of 4-(Difluoro(phenyl)methyl)pyrrolidin-2-one (7a) To a stirred solution of methyl 4,4-difluoro-3-(nitromethyl)-4-phenylbutanoate (6a; 50 mg, 0.18 mmol) in MeOH (2 mL), NiCl2·6H2O (85 mg, 0.36 mmol) was added at room temperature. After stirring for 5 min, NaBH4 (75 mg, 1.98 mmol) was added in four portions. The reaction mixture was stirred for 30 min at room temperature, then a saturated solution of NH4Cl was added and the reaction mixture was extracted with EtOAc (3 × 5 mL). The combined organic layers were separated, washed with H2O (3 × 5 mL), dried over Na2SO4, filtered and concentrated under vacuum. 4-(Difluoro(phenyl)methyl)pyrrolidin-2-one 7a was precipitated and washed with Et2O to give a white solid. Yield: 31 mg (80%); Rf = 0.2 (DCM/MeOH, 95:5); mp 95 °C. 1H NMR (300 MHz, CDCl3): δ = 7.45 (s, 5 H), 6.55 (s, 1 H, NH), 3.2 (dd, 2 J H–H = 9.9 Hz, 3 J H–H = 7.0 Hz, 1 H), 3.40 (dd, 2 J H–H = 9.9 Hz, 3 J H–H = 8.8 Hz, 1 H), 3.35–3.13 (m, 1 H), 2.51 (dd, 2 J H–H = 17.3 Hz, 3 J H–H = 8.1 Hz, 1 H), 2.35 (dd, 2 J H–H = 17.3 Hz, 3 J H–H = 9.6 Hz, 1 H). 13C NMR (75 MHz, CDCl3): δ = 176.4, 135.4 (t, 2 J C–F = 26.4 Hz), 130.5 (t, 5 J C–F = 1.7 Hz), 128.9 (2C), 125.2 (t, 3 J C–F = 6.3 Hz, 2C), 121.9 (t, 1 J C–F = 244.7 Hz), 42.5 (t, 2 J C–F = 28.4 Hz), 42.0 (t, 3 J C–F = 4.8 Hz), 30.8 (t, 3 J C–F = 3.7 Hz). 19F NMR {H} (282 MHz, CDCl3): δ = –103.04 (AB system, F A , 2 J F–F = 248.2 Hz), –104.48 (AB system, F B , 2 J F–F = 248.2 Hz). HRMS (ESI): m/z [M + Na]+ calcd for C11H11NOF2Na: 234.07009; found: 234.0699 (1 ppm).
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