Synlett 2019; 30(20): 2258-2262
DOI: 10.1055/s-0039-1690715
letter
© Georg Thieme Verlag Stuttgart · New York

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

Ali Soulieman
a  Lebanese University, Faculty of Sciences (I) Laboratory for Medicinal Chemistry and Natural Products, and PRASE-EDST, Hadath, Lebanon   Email: ahachem@ul.edu.lb
b  Univ Rennes, CNRS (Institut for Chemical Sciences in Rennes), UMR 6226, 35000 Rennes, France   Email: rene.gree@univ-rennes1.fr
,
Nicolas Gouault
b  Univ Rennes, CNRS (Institut for Chemical Sciences in Rennes), UMR 6226, 35000 Rennes, France   Email: rene.gree@univ-rennes1.fr
,
Thierry Roisnel
b  Univ Rennes, CNRS (Institut for Chemical Sciences in Rennes), UMR 6226, 35000 Rennes, France   Email: rene.gree@univ-rennes1.fr
,
Frédéric Justaud
b  Univ Rennes, CNRS (Institut for Chemical Sciences in Rennes), UMR 6226, 35000 Rennes, France   Email: rene.gree@univ-rennes1.fr
,
Joël Boustie
b  Univ Rennes, CNRS (Institut for Chemical Sciences in Rennes), UMR 6226, 35000 Rennes, France   Email: rene.gree@univ-rennes1.fr
,
René Grée
b  Univ Rennes, CNRS (Institut for Chemical Sciences in Rennes), UMR 6226, 35000 Rennes, France   Email: rene.gree@univ-rennes1.fr
,
Ali Hachem
a  Lebanese University, Faculty of Sciences (I) Laboratory for Medicinal Chemistry and Natural Products, and PRASE-EDST, Hadath, Lebanon   Email: ahachem@ul.edu.lb
› Author Affiliations
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)

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

 
  • 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; 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).