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

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.

Key words

HAT - piperidinone - Michael addition - piperidines - iron - radicals

• References and Notes

• 1 Vitaku IE, Smith DT, Njardarson JT. J. Med. Chem. 2014; 57: 10257
• 2a Adkins H, Kuick LF, Farlow M, Wojcik B. J. Am. Chem. Soc. 1934; 56: 2425
• 2b Freifelder M. Adv. Catal. 1963; 14: 203
• 2c Glorius F, Spielkamp N, Holle S, Goddard R, Lehmann CW. Angew. Chem. Int. Ed. 2004; 43: 2850
• 2d Legault CY, Charette AB. J. Am. Chem. Soc. 2005; 127: 8966
• 2e Lemire A, Charette AB. Org. Lett. 2005; 7: 2747
• 3a Spangler JE, Kobayashi Y, Verma P, Wang D.-H, Yu J.-Q. J. Am. Chem. Soc. 2015; 137: 11876
• 3b Pastine SJ, Gribkov DV, Sames D. J. Am. Chem. Soc. 2006; 128: 14220
• 3c Shi L, Xia W. Chem. Soc. Rev. 2012; 41: 7687
• 3d Mitchell EA, Peschiulli A, Lefevre N, Meerpoel L, Maes BU. W. Chem. Eur. J. 2012; 18: 10092
• 3e Topczewski J, Cabrera PJ, Saper NI, Sanford MS. Nature 2016; 531: 220
• 3f Affron DP, Davis OA, Bull JA. Org. Lett. 2014; 16: 4956
• 3g Griffiths RJ, Kong WC, Richards SA, Burley GA, Willis MC, Talbot EP. A. Chem. Sci. 2018; 9: 2295

For selected reviews on piperidine synthesis, see:
• 4a Bailey PD, Millwood PA, Smith PD. Chem. Commun. 1998; 633
• 4b Borcherding DR, Kane JM, Sabol JS, Weintraub PM. Tetrahedron 2003; 59: 2953
• 4c Buffat MG. P. Tetrahedron 2004; 60: 1701
• 4d Escolano C, Amat M, Bosch J. Chem. Eur. J. 2006; 12: 8198
• 4e Kallstrom S, Leino R. Bioorg. Med. Chem. 2008; 16: 601
• 4f Liu G.-Q, Opatz T. Adv. Heterocycl. Chem. 2018; 125: 107
• 5 Mukayama S, Isayama S, Inoki K, Kato T, Yamada T, Takai T. Chem. Lett. 1989; 449

For a recent review, see:
• 6a Crossley SW. M, Obradors C, Martinez RM, Shenvi RA. Chem. Rev. 2016; 116: 8912
• 6b Hoffmann RW. Chem. Soc. Rev. 2016; 45: 577
• 7a Lo JC, Yabe Y, Baran PS. J. Am. Chem. Soc. 2017; 139: 2484 (proposed mechanism)
• 7b Lo JC, Gui J, Yabe Y, Pan C.-M, Baran PS. Nature 2014; 516: 343
• 7c Lo JC, Yabe Y, Baran PS. J. Am. Chem. Soc. 2014; 136: 1304
• 8 All chiral amines 1a, 1b, 1e and 1f were purified by column chromatography and isolated as a single diastereoisomer and no racemisation of the stereocentre was observed after HAT reaction.
• 9 Slower conversion of the desired product as well as increased production of the hydrogenated allylic amine was observed with use of less catalyst or lower temperatures. Low conversion was also observed with Fe(dibm)₃ as well as Mn(dpm)₃.
• 10 Turner OJ, Murphy JA, Hirst DJ, Talbot EP. A. Chem. Eur. J. 2018; 24: 18658
• 11a Zheng Y, Tice CM, Singh SB. Bioorg. Med. Chem. 2014; 24: 3673
• 11b Carreira EM, Fessard TC. Chem. Rev. 2014; 114: 8257
• 11c Griggs SD, Tape DT, Clarke PA. Org. Biomol. Chem. 2018; 16: 6620
• 12 The piperidine version of 2j was also synthesised but gave no desired product even with 100 mol% of Fe(acac)₃.
• 13 Analogy of this chemistry could be observed with the rhodium-catalysed 1,4-additions of boronic acid on a small-sized ring; Collier PN. Tetrahedron Lett. 2009; 50: 3909
• 14 Hydrolysis of the amide was also observed during the reaction and carefully monitoring the reaction was key to good conversion: Cronyn R. J. Am. Chem. Soc. 1953; 75: 1664
• 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.