Synlett 2019; 30(07): 821-826
DOI: 10.1055/s-0037-1610700
letter
© Georg Thieme Verlag Stuttgart · New York

Synthesis of Polyfunctionalised 2-Piperidinones Catalysed by Fe(acac)3

Eric P. A. Talbot*
Pharmaron Drug Discovery Services, Hoddesdon, Hertfordshire, EN11 9BU, UK   Email: eric.talbot@pharmaron-uk.com
› Author Affiliations
Further Information

Publication History

Received: 21 December 2018

Accepted after revision: 19 February 2018

Publication Date:
07 March 2019 (online)


Abstract

Herein is reported the synthesis of polyfunctionalised piperidines and 2-piperidinones, through hydrogen atom transfer (HAT) chemistry catalysed by Fe(acac)3. The nature and substitution around the Michael acceptor, as well as the allylic amine, allowed access to all positions of the piperidine ring. The chemistry tolerates a range of different functionalities, allowing the investigation of new and diverse scaffolds.

Supporting Information

 
  • References and Notes

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  • 15 General Procedure with Allylic Amine 2a Phenylsilane (2 equiv) was added to a solution of Michael acceptor (1 to 3 equiv), allylic amine (1 to 3 equiv), Fe(acac)3 (0.3 equiv) in EtOH (~0.2 M). The reaction was heated at 60 °C for 15 h. Then, a solution of HCl in 1,4-dioxane (4 M, 0.5 ml) was added and the reaction mixture was stirred at room temperature for 2 h then concentrated. The mixture was then dissolved in toluene (2 mL) and formic acid (0.5 ml) and heated at 110 °C for 15 h. The reaction mixture was then concentrated and purified by flash chromatography (0–100% EtOAc in hexanes) or preparative HPLC (0–95% acetonitrile in water) to give the desired compound. Analytical Data for (S)-5,5-Dimethyl-6-phenylpiperidin-2-one (3a) 1H NMR (400 MHz, CDCl3): δ 7.39–7.29 (m, 3 H), 7.25–7.19 (m, 2 H), 5.87 (s, 1 H), 4.27 (s, 1 H), 2.60–2.39 (m, 2 H), 1.81–1.64 (m, 2 H), 0.99 (s, 3 H), 0.78 (s, 3 H). 13C NMR (101 MHz, CDCl3): δ 172.25, 138.64, 128.29, 128.08, 128.02, 127.89, 127.68, 127.65, 66.67, 34.47, 32.92, 28.49, 27.27, 20.29.