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Synlett 2004(10): 1844-1846  
DOI: 10.1055/s-2004-830852
LETTER
© Georg Thieme Verlag Stuttgart · New York

Palladium-Catalyzed Hydroamidation Reaction of Enones

Kiyosei Takasu*, Naoko Nishida, Masataka Ihara*
Department of Organic Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Aobayama, Sendai 980-8578, Japan
Fax: +81(22)217689; e-Mail: mihara@mail.pharm.tohoku.ac.jp;
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Publication History

Received 12 April 2004
Publication Date:
28 July 2004 (online)

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Abstract

A catalytic amount of Pd(PhCN)2Cl2 promotes conjugate addition reaction of amides with enones to afford β-amidoketones (aza-Michael reaction, hydroamidation reaction) under solvent-free conditions. The produced β-amidoketones could be transformed into multi-substituted piperidinones.

Key words

Michael additions - catalysis - amides - piperidines - green chemistry

    References

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10

General Procedure for Hydroamidation: A mixture of amide 1 (1.0 mmol), enone 2 (1.0 mmol), and Pd(PhCN)2Cl2 (1-5 mol%) was stirred for 24 h at 60 °C. The reaction mixture was diluted with CHCl3 and filtered off to remove Pd catalyst. The filtrate was concentrated and purified by silica gel chromatography.

11

General Procedure for Cyclization: A mixture of 3 and t-BuOK (1 equiv) in t-BuOH was stirred for 5 h at ambient temperature. The reaction mixture was quenched with HCl aq and extracted with EtOAc. The extracts were washed with brine, dried over MgSO4 and evaporated. The residue was purified by silica gel chromatography. Compound 4: IR (neat): ν = 2961, 1666 cm-1. 1H NMR (400 MHz, CDCl3): δ = 7.96 (d, 2 H, J = 7.5 Hz), 7.62 (t, 1 H, J = 7.5 Hz), 7.51 (t, 2 H, J = 7.5 Hz), 6.08 (br s, 1 H), 4.26 (dq, 1 H, J = 9.1, 6.3 Hz), 3.39 (ddd, 1 H, J = 12.4, 9.4, 3.2 Hz), 2.56-2.43 (m, 2 H), 2.12-2.07 (m, 1 H), 2.00-1.89 (m, 1 H), 1.18 (d, 1 H, J = 6.3 Hz). 13C NMR (100 MHz, CDCl3): δ = 200.0, 171.4, 136.0, 133.7, 128.9, 128.2, 50.5, 47.9, 30.4, 25.4, 21.5. HRMS: m/z calcd for C13H15NO2 (M+): 217.1103. Found: 217.1082. Compound 5a: mp 213-215 °C. 1H NMR (600 MHz, CDCl3): δ = 7.89-7.88 (m, 2 H), 7.58-7.55 (m, 1 H), 7.47-7.44 (m, 2 H), 7.18-7.15 (m, 1 H), 5.98 (br s, 1 H), 4.26 (dd, 1 H, J = 4.8, 9.6 Hz), 3.94-3.97 (m, 1 H), 3.71 (ddd, 1 H, J = 9.6, 9.6, 6.0 Hz), 2.80 (dd, 1 H, J = 18.0, 6.0 Hz), 2.55 (dd, 1 H, J = 18.0, 9.6 Hz), 1.14 (d, 1 H, J = 6.6 Hz). 13C NMR (150 MHz, CDCl3): δ = 198.2, 170.9, 142.6, 136.6, 133.6, 129.0, 128.9, 128.1, 127.0, 126.9, 49.7, 48.1, 38.0, 36.8, 19.4. HRMS: m/z calcd for C19H19NO2 (M+): 293.1416. Found: 293.1443. Compound 5b: mp 131-135 °C. 1H NMR (400 MHz, CDCl3): δ = 7.92-7.96 (m, 2 H), 7.63 (t, 1 H, J = 7.4 Hz), 7.54-7.50 (m, 2 H), 7.22-7.20 (m, 3 H), 6.89-6.81 (m, 2 H), 5.81 (br s, 1 H), 3.91-3.87 (m, 1 H), 3.73 (dd, 1 H, J = 3.7, 9.1 Hz), 3.67 (ddd, 1 H, J = 3.0, 3.7, 6.6 Hz), 2.97 (dd, 1 H, J = 17.8, 6.6 Hz), 2.83 (dd, 1 H, J = 17.8, 3.0 Hz), 1.23 (d, 1 H, J = 6.1 Hz). 13C NMR (100 MHz, CDCl3): δ = 197.9, 170.7, 138.7, 136.4, 133.5, 129.0, 128.4, 128.1, 127.7, 127.5, 52.1, 46.5, 40.3, 36.3, 21.6. HRMS: m/z calcd for C19H19NO2 (M+): 293.1416. Found: 293.1413. Compound 6: mp 179-181 °C. IR (KBr): ν = 3429, 2924, 1670, 1499, 762, 705 cm-1. 1H NMR (400 MHz, CDCl3): δ = 7.76 (d, 2 H, J = 7.8 Hz), 7.52 (t, 1 H, J = 7.3 Hz), 7.39 (dd, 2 H, J = 7.8, 7.3 Hz), 7.26-7.18 (m, 4 H), 7.14-7.10 (m, 1 H), 6.11 (br s, 1 H), 4.10 (ddd, 1 H, J = 9.8, 9.8, 5.4 Hz), 3.65-3.55 (m, 3 H), 2.81 (dd, 1 H, J = 6.3, 17.8 Hz), 2.68 (dd, 1 H, J = 10.7,17.8 Hz). 13C NMR (100 MHz, CDCl3): δ = 199.3, 170.8, 140.9, 136.0, 133.2, 128.5, 128.4, 127.8, 126.8, 46.8, 44.2, 41.6, 37.8. HRMS: m/z calcd for C18H17NO2 (M+): 279.1259. Found: 279.1242.