Novel Approach toward 3,3-Difluoropiperidines from Easily Available Starting Materials and Synthesis of a New Phosphodiesterase Inhibitor

Abstract

A novel methodology for the synthesis of 3,3-difluoropiperidines has been developed. The target compounds are prepared in three steps using a robust protocol and simple starting materials. The incorporation of the fluorine is achieved by using the cheap and easily available ethyl 2-bromo-2,2-difluoroacetate as building block. Using this methodology, a new potent in vitro phosphodiesterase 2A (PDE2A) inhibitor containing the functionalized fluorinated piperidine scaffold has been prepared.

Key words

fluorine - piperidine - ethyl 2-bromo-2,2-difluoroacetate - reductive amination - phosphodiesterase

• References and Notes

• 1 O’Hagan D, Harper B. J. Fluorine Chem. 1999; 100: 127
• 2 Muller K, Faeh C, Diederich F. Science 2007; 317: 1881
• 3 Wang J, Sanchez-Rosell M, Acena JL, del Pozo C, Sorochinsky AE, Fustero S, Soloshonok VA, Liu H. Chem. Rev. 2014; 114: 2432
• 4a Bégué JP, Bonnet-Delpon D. J. Fluorine Chem. 2006; 127: 992
• 4b O’Hagan D. J. Fluorine Chem. 2010; 131: 1071
• 5 Zhou Y, Wang J, Gu Z, Wang S, Zhu W, Acena JL, Soloshonok VA, Izawa K, Liu H. Chem. Rev. 2016; 116: 422
• 6 Fujiwara T, O’Hagan D. J. Fluorine Chem. 2014; 167: 16
• 7 Jeschke P. Pest. Manage. Sci. 2010; 66: 10
• 8 Barnes NA, Brisdon AK, Ellis MJ, Pritchard RG. J. Fluorine Chem. 2001; 112: 35
• 9 Brisdon AK, Ali Ghaba H, Beutel B, Egjandi A, Addaraidi A, Pritchard RG. Dalton Trans. 2015; 44: 19717
• 10 Couturier O, Luxen A, Chatal JF, Vuillez JP, Rigo P, Hustinx R. Eur. J. Nucl. Med. Mol. Imaging 2004; 31: 1182
• 11 Brooks AF, Topczewski JJ, Ichiishi N, Sanford MS, Scott PJ. H. Chem. Sci. 2014; 5: 4545
• 12 Verniest G, Surmont R, Hende EV, Deweweire A, Deroose F, Thuring JW, De Kimpe N. J. Org. Chem. 2008; 73: 5458
• 13a Kim BC, Park A, An JE, Lee WK, Lee HB, Shin H. Synthesis 2012; 44: 3165

For earlier reports on the addition of 1 to Michael acceptors, see:
• 13b Sato K, Tamura M, Tamoto K, Omote M, Ando A, Kumadaki I. Chem. Pharm. Bull. 2000; 48: 1023
• 13c Sato K, Nakazato S, Enko H, Tsujita H, Fujita K, Yamamoto T, Omote M, Ando A, Kumadaki I. J. Fluorine Chem. 2003; 121: 105
• 13d Sato K, Omote M, Ando A, Kumadaki I. J. Fluorine Chem. 2004; 125: 509

For examples of synthesis of fluorinated piperidines starting from 2-bromo-2,2-difluoroacetate, see:
• 14a Surmont R, Verniest G, Thuring JW, Macdonald G, Deroose F, De Kimpe N. J. Org. Chem. 2010; 75: 929
• 14b Moens M, Verniest G, De Schrijver M, ten Holte P, Thuring JW, Deroose F, De Kimpe N. Tetrahedron 2012; 68: 9284
• 15 Formation of side products with mass corresponding to 8 and 9 was detected by LC–MS.
• 16 Incompatibility of the catalyst cartridge with acetic acid as solvent is reported in the user manuals for H-Cube.
• 17 For a detailed description of the preparation of the organolithium reagents, see Supporting Information.
• 18 The hydrogenation of 5c could also be conducted in batch mode using an autoclave. The benzyl protecting group was stable under these reaction conditions (see Supporting Information) and the fluorinated piperidine 7h (R² = Bn) was isolated in 42% yield.
• 19 General Experimental Procedures for the Addition of the Organolithium Reagents to 4-Cyano-2,2-difluorobutanoate (3) To a solution of ethyl 4-cyano-2,2-difluorobutanoate (3, 1 equiv, 0.3 M) in Et₂O was added dropwise a solution of commercially available organolithium (1.1 equiv) at –78 °C. After 2 h the reaction was quenched with an aq sat. solution of NH₄Cl, EtOAc was added, and the phases were separated. The aqueous phase was further extracted twice with EtOAc. The combined organic phases were dried over MgSO₄, filtered, concentrated in vacuo, and purified using silica gel chromatography to provide the desired product. 4,4-Difluoro-5-oxo-5-phenylpentanenitrile (5a) The title compound 5a (1.51 g, 5.02 mmol, 89% yield) was obtained according to the general procedure starting from a solution of ethyl 4-cyano-2,2-difluorobutanoate (3) in Et₂O (5.56 mmol, 0.3 M) and a commercially available 1.8 M solution of 4a in n-dibutyl ether (3.45 mL, 6.21 mmol) at –78 °C. ¹H NMR (600 MHz, CDCl₃): δ = 8.17–8.12 (2 H, m), 7.69–7.66 (1 H, m), 7.54–7.51 (2 H, m), 2.71–2.68 (2 H, m), 2.66–2.58 (2 H, m). ¹⁹F NMR (471 MHz, CDCl₃): δ = –101.1 (t, J = 16.0 Hz). ¹³C NMR (151 MHz, CDCl₃): δ = 187.8 (C, t, J = 31.6 Hz), 135.0 (CH, s), 131.4 (C, t, J = 3.32 Hz), 130.4 (CH, t, J= 3.4 Hz), 128.9 (CH, s), 118.1 (C, s), 120.0–116.0 (CF₂, t, J = 255.8 Hz), 30.0–29.6 (CH₂, t, J = 23.5 Hz), 10.7–10.5 (CH₂, t, J = 6.71 Hz).
• 20 General Experimental Procedures for the Reduction–Reductive Amination Reaction A solution of 5 in acetic acid (0.01 M) was reduced using H-Cube Pro^® (ThalesNano) continuous-flow hydrogenation system; CartCart Raney nickel THS01112; Temperature T = 50 °C and the flow rate of 1 mL/min. After full conversion of the starting material (reaction followed by LC–MS), the solvent was removed in vacuo, and the product was purified by flash column chromatography. 3,3-Difluoro-2-phenylpiperidine (7a) The title compound 7a (81 mg, 0.411 mmol, 86% yield) was obtained according to the general procedure starting from a solution of 5a in AcOH (100.0 mg, 0.478 mmol, 0.01 M). ¹H NMR (600 MHz, CDCl₃): δ = 7.46–7.43 (2 H, m), 7.38–7.32 (3 H, m), 3.89–3.84 (1 H, d, J = 23.2 Hz), 3.25–3.19 (1 H, m), 2.83–2.75 (1 H, m), 2.59 (1 H, br s), 2.35–2.25 (1 H, m), 1.95–1.80 (3 H, m). ¹⁹F NMR (471 MHz, CDCl₃): δ = –99.5 (d, J = 240.7 Hz), –117.5 (m). ¹³C NMR (151 MHz, CDCl₃): δ = 135.9 (C, s), 128.8 (CH, s), 128.3 (CH, s), 128.1 (CH, s), 121.1–117.8 (CF₂, dd, J = 244.9, 248.0 Hz), 66.0–65.4 (CH, dd, J = 26.5, 22.0 Hz), 45.9 (CH₂, s), 33.8–33.4 (CH₂, dd, J = 25.9, 21.7 Hz), 24.0–23.9 (CH₂, d, J = 9.9 Hz). ESI-HRMS: m/z calcd for C₁₁H₁₃F₂N [MH⁺]: 198.1089; found: 198.1090.
• 21 Formation of a product with mass corresponding to 2-butyl-3,3-difluoropiperidine was observed by LC–MS.
• 22 For the determination of the PDE2A activity, see: Redrobe JP, Jørgensen M, Christoffersen CT, Montezinho LP, Bastlund JF, Carnerup M, Bundgaard C, Lerdrup L, Plath N. Psychopharmacology 2014; 231: 3151

For selected references on PDE2A as a potential therapeutic target, see:
• 23a Gomez L, Breitenbucher JG. Bioorg. Med. Chem. Lett. 2013; 23: 6522
• 23b Buijnsters P, De Angelis M, Langlois X, Rombouts FJ. R, Sanderson W, Tresadern G, Ritchie A, Trabanco AA, VanHoof G, Roosbroeck YV, Andrés JI. ACS Med. Chem. Lett. 2014; 5: 1049
• 23c Lueptow LM, Zhan C, O’Donnel JM. Psycopharmacology 2016; 233: 447