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Synlett 2012; 23(11): 1691-1695
DOI: 10.1055/s-0031-1291162
letter
© Georg Thieme Verlag Stuttgart · New York

Synthesis of 3-Aroyl-4-hydroxy-4-arylpiperidine Derivatives by DBU-Catalyzed Reactions of Amines with Vinyl Ketones

Xiaodong Liu
Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Science, Institute of Biochemistry and Molecular Biology School of Life Science, Lanzhou University, Lanzhou 730000, P. R. of China, Fax: +86(931)8912567   Email: wangrui@lzu.edu.cn
,
Qiao Chen
Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Science, Institute of Biochemistry and Molecular Biology School of Life Science, Lanzhou University, Lanzhou 730000, P. R. of China, Fax: +86(931)8912567   Email: wangrui@lzu.edu.cn
,
Wenyi Li
Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Science, Institute of Biochemistry and Molecular Biology School of Life Science, Lanzhou University, Lanzhou 730000, P. R. of China, Fax: +86(931)8912567   Email: wangrui@lzu.edu.cn
,
Yuan Liang
Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Science, Institute of Biochemistry and Molecular Biology School of Life Science, Lanzhou University, Lanzhou 730000, P. R. of China, Fax: +86(931)8912567   Email: wangrui@lzu.edu.cn
,
Rui Wang*
Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Science, Institute of Biochemistry and Molecular Biology School of Life Science, Lanzhou University, Lanzhou 730000, P. R. of China, Fax: +86(931)8912567   Email: wangrui@lzu.edu.cn
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Further Information

Publication History

Received: 14 March 2012

Accepted after revision: 16 April 2012

Publication Date:
11 June 2012 (online)

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Abstract

In one-pot cascade reaction, a series of functionalized 3-aroyl-4-hydroxy-4-arylpiperidine derivatives were prepared from sulfonamides and vinyl ketones with good to excellent yields and diastereoselectivities. The reaction was catalyzed by the commercially available Lewis base 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and could be easily manipulated under mild condition.

Key words

Michael addition - vinyl ketones - cascade reaction - cyclization - stereoselectivity

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    for this article is available online at http://www.thieme-connect.com/ejournals/toc/synlett.
  • Supporting Information

Primary Data

    for this article are available online at http­://www.thieme-connect.com/ejournals/toc/synlett and can be cited using the following DOI:
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  • References and Notes

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  • 7 CCDC 857042 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif
  • 8 General Procedure for the Cascade Reaction: To a mixture of amines 1 (0.2 mmol) and vinyl ketones 2 (0.45 mmol) in toluene (1.0 mL) was added DBU (0.04 mmol) at room temperature. After 6–8 h the reaction was complete (as determined by TLC). The reaction mixture was concentrated and the residue was purified by flash chromatography (petroleum ether/ethyl acetate, 5:1) to afford the product 6. The analytical data of some typical compounds: Compound 6b: White solid; m.p.179–180 °C. 1H NMR (300 MHz, CDCl3): δ = 7.69 (d, J = 8.1 Hz, 2 H), 7.57 (dd, J = 7.7, 1.1 Hz, 1 H), 7.36 (dd, J = 13.7, 5.1 Hz, 3 H), 7.09 (t, J = 7.1 Hz, 1 H), 6.98–6.81 (m, 2 H), 6.78–6.63 (m, 2 H), 6.50 (d, J = 8.1 Hz, 1 H), 5.08 (dd, J = 11.4, 3.7 Hz, 1 H), 4.47 (d, J = 2.4 Hz, 1 H), 4.14 (dd, J = 10.6, 2.3 Hz, 1 H), 4.02 (s, 3 H), 3.76–3.67 (m, 1 H), 3.42 (s, 3 H), 2.92 (ddd, J = 11.0, 7.4, 3.2 Hz, 2 H), 2.74–2.52 (m, 1 H), 2.44 (s, 3 H), 1.57 (d, J = 13.6 Hz, 1 H). 13C NMR (75 MHz, CDCl3): δ = 207.6, 158.6, 155.6, 143.5, 133.9, 133.5, 132.4, 129.8, 129.2, 129.0, 128.7, 127.6, 127.5, 120.7, 120.5, 111.0, 110.7, 72.5, 55.8, 54.5, 51.9, 44.0, 42.3, 34.7, 21.6. IR (CDCl3): 3459, 2926, 1648, 1592, 1456, 1319, 1160, 913, 729, 573 cm–1. HRMS (ESI): m/z calcd for C27H29NO6S+Na+: 518.1608; found: 518.1587. Compound 6d: White solid; m.p. 162–163 °C. 1H NMR (300 MHz, CDCl3): δ = 7.96 (t, J = 1.6 Hz, 1 H), 7.74 (d, J = 7.9 Hz, 2 H), 7.58 (dd, J = 7.8, 1.6 Hz, 1 H), 7.51–7.31 (m, 2 H), 7.15–7.04 (m, 1 H), 6.91 (t, J = 8.4 Hz, 2 H), 6.80–6.62 (m, 2 H), 6.51 (d, J = 8.1 Hz, 1 H), 5.08 (dd, J = 11.4, 3.8 Hz, 1 H), 4.50 (d, J = 2.7 Hz, 1 H), 4.15 (dd, J = 11.0, 2.4 Hz, 1 H), 4.04 (s, 3 H), 3.82–3.66 (m, 1 H), 3.42 (s, 3 H), 3.00 (td, J = 11.1, 4.8 Hz, 2 H), 2.70–2.51 (m, 1 H), 1.60 (d, J = 13.6 Hz, 1 H). 13C NMR (75 MHz, CDCl3): δ = 207.4, 158.6, 155.5, 138.7, 135.8, 133.9, 132.2, 130.7, 130.3, 129.2, 128.9, 128.7, 127.5, 126.0, 123.3, 120.7, 120.5, 111.0, 110.7, 72.5, 55.8, 54.6, 51.8, 43.9, 42.3, 34.6. IR (CDCl3): 3432, 2934, 1655, 1597, 1462, 1245, 1166, 1022, 757, 580 cm–1. HRMS (ESI): m/z calcd for C26H26BrNO6S+H+: 560.0737; found: 560.0738. Compound 6e: White solid; m.p. 177–178 °C. 1H NMR (300 MHz, CDCl3): δ = 7.80–7.69 (m, 2 H), 7.57 (dd, J = 7.8, 1.7 Hz, 1 H), 7.41–7.31 (m, 1 H), 7.09 (td, J = 8.1, 1.7 Hz, 1 H), 7.05–6.98 (m, 2 H), 6.94–6.83 (m, 2 H), 6.72 (qd, J = 7.6, 1.4 Hz, 2 H), 6.55–6.41 (m, 1 H), 5.08 (dd, J = 11.4, 3.8 Hz, 1 H), 4.47 (d, J = 2.7 Hz, 1 H), 4.17–4.11 (m, 1 H), 4.02 (s, 3 H), 3.88 (s, 3 H), 3.75–3.65 (m, 1 H), 3.42 (s, 3 H), 3.01–2.81 (m, 2 H), 2.63 (tdd, J = 13.1, 4.8, 2.8 Hz, 1 H), 1.57 (dd, J = 11.2, 2.3 Hz, 1 H). 13C NMR (75 MHz, CDCl3): δ = 207.6, 162.9, 158.6, 155.5, 133.9, 132.4, 129.6, 129.2, 129.0, 128.7, 128.0, 127.4, 120.6, 120.5, 114.3, 111.0, 110.7, 72.5, 55.8, 55.6, 54.5, 51.8, 44.0, 42.3, 34.7. IR (CDCl3): 3454, 2936, 1656, 1597, 1254, 1159, 1023, 756, 559 cm–1. HRMS (ESI): m/z calcd for C27H29NO7S+Na+: 534.1557; found: 534.1568. Compound 6i: White solid; m.p. 95–96 °C. 1H NMR (300 MHz, CDCl3): δ = 7.99–7.81 (m, 2 H), 7.59–7.46 (m, 3 H), 7.41 (dd, J = 10.5, 4.7 Hz, 2 H), 7.27–7.21 (m, 2 H), 7.13 (ddd, J = 7.3, 3.8, 1.2 Hz, 1 H), 5.16 (d, J = 2.7 Hz, 1 H), 4.40 (d, J = 8.0 Hz, 1 H), 3.04–2.83 (m, 2 H), 2.69 (t, J = 11.4 Hz, 2 H), 2.44 (dd, J = 8.6, 7.2 Hz, 2 H), 2.07 (t, J = 12.8 Hz, 1 H), 1.82 (dt, J = 13.9, 2.6 Hz, 1 H), 1.64–1.46 (m, 2 H), 0.92 (t, J = 7.4 Hz, 3 H). 13C NMR (75 MHz, CDCl3): δ = 204.46, 147.21, 137.03, 135.90, 133.93, 133.05, 128.81, 128.60, 128.34, 128.28, 128.08, 126.76, 124.57, 73.16, 60.46, 52.83, 50.51, 49.17, 39.86, 20.15, 12.03. IR (CDCl3): 3458, 2959, 2929, 2818, 1663, 1448, 1377, 1205, 1070, 701 cm–1. HRMS (ESI): m/z calcd for C21H25NO2+H: 324.1958; found: 324.1959
  • 9 The analytical data of some typical compounds: Compound 6k: White solid; m.p. 197–198 °C. 1H NMR (300 MHz, CDCl3): δ = 7.73–7.56 (m, 4 H), 7.43–7.29 (m, 4 H), 7.23 (s, 1 H), 7.18–7.02 (m, 2 H), 6.93 (d, J = 7.1 Hz, 1 H), 4.95 (d, J = 2.6 Hz, 1 H), 4.38 (dd, J = 11.5, 3.8 Hz, 1 H), 3.94 (dd, J = 11.6, 2.3 Hz, 1 H), 3.85–3.66 (m, 1 H), 3.04–2.79 (m, 2 H), 2.44 (s, 3 H), 2.38 (s, 3 H), 2.25 (s, 3 H), 2.18–2.06 (m, 1 H), 1.82 (d, J = 14.0 Hz, 1 H). 13C NMR (75 MHz, CDCl3): δ = 203.4, 145.8, 143.9, 138.9, 138.0, 135.6, 135.3, 133.4, 129.9, 128.9, 128.9, 128.3, 127.9, 127.6, 125.7, 125.3, 121.4, 72.7, 49.5, 45.3, 42.5, 39.1, 21.6, 21.4. IR (CDCl3): 3443, 2925, 1654, 1584, 1387, 1341, 1280, 1163, 924, 545 cm–1. HRMS (ESI): m/z calcd for C27H29NO4S+Na+: 486.1710; found: 486.1689. Compound 6n: White solid; m.p. 192–193 °C. 1H NMR (300 MHz, CDCl3): δ = 8.50 (s, 1 H), 7.96 (d, J = 6.6 Hz, 2 H), 7.83–7.63 (m, 8 H), 7.55 (p, J = 6.7 Hz, 3 H), 7.40–7.27 (m, 4 H), 5.27 (d, J = 2.3 Hz, 1 H), 4.74 (dd, J = 11.4, 3.6 Hz, 1 H), 4.18–4.03 (m, 1 H), 3.88 (d, J = 11.2 Hz, 1 H), 3.08 (ddd, J = 16.1, 8.0, 4.0 Hz, 2 H), 2.41 (s, 3 H), 2.35–2.21 (m, 1 H), 1.92 (d, J = 14.0 Hz, 1 H). 13C NMR (75 MHz, CDCl3): δ = 203.0, 143.9, 143.3, 136.1, 133.4, 133.1, 132.7, 132.4, 132.4, 131.0, 130.0, 129.9, 129.4, 129.0, 128.4, 128.2, 127.8, 127.7, 127.4, 127.2, 126.2, 126.0, 123.7, 123.4, 122.6, 73.1, 49.4, 45.6, 42.6, 39.2, 21.6. IR (CDCl3): 3443, 3058, 2924, 1655, 1345, 1163, 922, 730, 549 cm–1. HRMS (ESI): m/z calcd for C33H29NO4S+Na+: 558.1710; found: 558.1716. Compound 6o: White solid; m.p. 159–160 °C. 1H NMR (300 MHz, CDCl3): δ = 7.66 (dd, J = 12.1, 3.9 Hz, 3 H), 7.60–7.52 (m, 2 H), 7.46–7.36 (m, 3 H), 7.24 (m, 7 H), 6.69 (dd, J = 30.5, 16.0 Hz, 2 H), 6.15 (d, J = 15.9 Hz, 1 H), 4.54 (d, J = 2.4 Hz, 1 H), 3.86 (dd, J = 11.5, 2.6 Hz, 1 H), 3.73 (dd, J = 9.4, 2.0 Hz, 1 H), 3.48 (dd, J = 11.6, 3.9 Hz, 1 H), 2.88–2.71 (m, 2 H), 2.44 (s, 3 H), 2.00–1.84 (m, 1 H), 1.75 (d, J = 15.2 Hz, 1 H). 13C NMR (75 MHz, CDCl3): δ = 202.3, 146.1, 143.9, 136.3, 133.8, 133.6, 133.0, 131.6, 129.9, 129.5, 129.1, 128.9, 128.5, 127.7, 127.6, 126.6, 125.4, 71.0, 52.0, 44.4, 41.9, 36.6, 21.6. IR (CDCl3): 3451, 3029, 2926, 2253, 1598, 1339, 1160, 1091, 919, 733 cm–1. HRMS (ESI): m/z calcd for C29H29NO4S+Na+: 510.1735; found: 510.1713. Compound 6p: White solid; m.p. 83–85 °C. 1H NMR (300 MHz, CDCl3): δ = 7.62 (d, J = 8.2 Hz, 2 H), 7.32 (d, J = 8.1 Hz, 2 H), 3.75–3.50 (m, 3 H), 2.97 (dd, J = 11.6, 3.8 Hz, 1 H), 2.80–2.47 (m, 4 H), 2.43 (s, 3 H), 1.68 (dd, J = 11.2, 2.5 Hz, 1 H), 1.60–1.51 (m, 1 H), 1.41 (dtd, J = 28.6, 14.2, 7.2 Hz, 2 H), 1.05 (t, J = 7.2 Hz, 3 H), 0.86 (t, J = 7.5 Hz, 3 H). 13C NMR (75 MHz, CDCl3): δ = 215.9, 143.8, 132.9, 129.8, 127.6, 70.5, 53.6, 44.2, 41.9, 38.3, 33.7, 33.3, 21.5, 7.6, 7.1. IR (CDCl3): 3488, 2971, 2930, 1696, 1343, 1161, 921, 744, 548 cm–1. HRMS (ESI): m/z calcd for C17H25NO4S+H+: 340.1577; found: 340.1587
  • 10 CCDC 857043 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif