Synthesis of New γ-Lactams with gem-Difluorinated Side Chains

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.

Key words

fluorine - gamma lactams - gem-difluoropropargyl - heterocycles - synthesis

• References and Notes

• 1 For a recent comprehensive review, see: Caruano J, Muccioli GG, Robiette R. Org. Biomol. Chem. 2016; 14: 10134
• 2a Xuan J, Studer A. Chem. Soc. Rev. 2017; 46: 4329
• 2b Ordonez M, Cativiela C, Romero-Estudillo I. Tetrahedron: Asymmetry 2016; 27: 999
• 2c Nay B, Riache N, Evanno L. Nat. Prod. Rep. 2009; 26: 1044
• 2d Ramesh P, Suman D, Reddy KS. N. Synthesis 2018; 50: 211

For selected reviews on this topic, see:
• 3a Müller K, Faeh C, Diederich F. Science 2007; 317: 1881
• 3b O’Hagan D. Chem. Soc. Rev. 2008; 37: 308
• 3c Hunter L, Kirsch P, Slawin AM. Z, O’Hagan D. Angew. Chem. Int. Ed. 2009; 48: 5457
• 3d Welch JT. Tetrahedron 1987; 43: 3123
• 3e Selective Fluorination in Organic and Bioorganic Chemistry . Welch JT. ACS Symposium Series 456; Washington DC: 1991
• 3f Biomedical Frontiers of Fluorine Chemistry . Ojima I, McCarthy JR, Welch JT. ACS Symposium Series 639; Washington DC: 1996
• 3g Purser S, Moore PR, Swallow S, Gouverneur V. Chem. Soc. Rev. 2008; 37: 320
• 3h Hagmann WK. J. Med. Chem. 2008; 51: 4359
• 3i Fustero S, Sanz-Cervera JF, Acena JL, Sanchez-Rosello M. Synlett 2009; 525
• 3j Hunter L. Beilstein J. Org. Chem. 2010; 6: 38
• 3k Qing F.-L, Zheng F. Synlett 2011; 1052
• 3l Gillis EP, Eastman KJ, Hill MD, Donnelly DJ, Meanwell NA. J. Med. Chem. 2015; 58: 8315
• 3m Zhou Y, Wang J, Gu Z, Wang S, Zhu W, Aceňa JL, Soloshonok VA, Izawa K, Liu H. Chem. Rev. 2016; 116: 422
• 3n Yerien DE, Bonesi S, Postigo A. Org. Biomol. Chem. 2016; 14: 8398
• 3o Meanwell NA. J. Med. Chem. 2018; 61: 2022 ; and references cited therein
• 4a Okano T, Takakura N, Nakano Y, Okajima A, Eguchi S. Tetrahedron 1995; 51: 1903
• 4b Fustero S, Fernandez B, Bello P, del Pozo C, Arimitsu S, Hammond GB. A. Org. Lett. 2007; 9: 4251
• 4c Mai W.-P, Wang F, Zhang X.-F, Wang S.-M, Duan Q.-P, Lu K. Org. Biomol. Chem. 2018; 16: 6491
• 4d Phae-Nok S, Pomakotr M, Kuhakarn C, Reutrakul V, Soorukram D. Eur. J. Org. Chem. 2019; 4710
• 4e Sim JH, Park JH, Maity P, Song CE. Org. Lett. 2019; 21: 6715
• 5 Hachem A, Grée D, Chandrasekhar S, Grée R. Synthesis 2017; 49: 2101 ; and references cited therein
• 6a Camps P, Muñoz-Torrero D, Sánchez L. Tetrahedron: Asymmetry 2004; 15: 2039
• 6b Hassanloie N, Zeynizadeh B, Ashuri S, Hassanloie F. Org. Chem.: Indian J. 2014; 10: 59
• 7 CCDC 1941252 (for compound 7a), CCDC 1941251 (for compound 7e) and CCDC 1941250 (for compound 9b) contain the supplementary crystallographic data for this paper. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/getstructures.
• 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; R_f = 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. R_f = 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; R_f =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%); R_f = 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).