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Synlett 2016; 27(20): 2803-2806
DOI: 10.1055/s-0036-1588313
DOI: 10.1055/s-0036-1588313
letter
Novel Approach toward 3,3-Difluoropiperidines from Easily Available Starting Materials and Synthesis of a New Phosphodiesterase Inhibitor
Further Information
Publication History
Received: 12 July 2016
Accepted after revision: 25 August 2016
Publication Date:
12 September 2016 (online)
![](https://www.thieme-connect.de/media/synlett/201620/lookinside/thumbnails/st-2016-b0451-l_10-1055_s-0036-1588313-1.jpg)
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 - phosphodiesteraseSupporting Information
- Supporting information for this article is available online at http://dx.doi.org/10.1055/s-0036-1588313.
- Supporting Information
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References and Notes
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- 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).
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For earlier reports on the addition of 1 to Michael acceptors, see:
For examples of synthesis of fluorinated piperidines starting from 2-bromo-2,2-difluoroacetate, see:
For selected references on PDE2A as a potential therapeutic target, see: