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Synlett 2012(3): 423-427  
DOI: 10.1055/s-0031-1290138
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Combining Two-Directional Synthesis and Tandem Reactions, Part 17: Expedient Formation of Functionalised Azabicycles

Pooja Aggarwala, George Procopioua, Diane Robbinsa, Gareth Harbottleb, William Lewis, Robert A. Stockman*a
a School of Chemistry, University of Nottingham, Nottingham, NG7 2RD, UK
Fax: +44(115)9513564; e-Mail: Robert.Stockman@Nottingham.ac.uk;
b Pfizer Global Research and Development, Ramsgate Road, Sandwich, Kent, CT13 9NJ, UK
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Publication History

Received 5 October 2011
Publication Date:
27 January 2012 (online)

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Abstract

Synthesis of a range of functionalised azabicycles from simple linear keto dienoates has been achieved using a tandem enamine formation/Michael addition/aza-Michael addition reaction.

Key words

aziridine - imine - ylide - sulfonium - vinyl

    References and Notes

  • For examples see:
  • 1a Gignoux C. Newton AF. Barthelme A. Lewis W. Alcaraz M.-L. Stockman RA. Org. Biomol. Chem.  2012,  10:  67 
    Google Scholar
  • 1b Roe SJ. Aggarwal P. Stockman RA. Synthesis  2009,  3375 
    Google Scholar
  • 1c Legeay J.-C. Lewis W. Stockman RA. Chem. Commun.  2009,  2207 
    Google Scholar
  • 1d Roe SJ. Stockman RA. Chem. Commun.  2008,  3432 
    Google Scholar
  • 1e Newton AF. Rejzek M. Alcaraz M.-L. Stockman RA. Beilstein J. Org. Chem.  2008,  4:  No. 4 
    Google Scholar
  • 1f Karatholuvhu MS. Sinclair A. Newton AF. Alcaraz M.-L. Stockman RA. Fuchs PL. J. Am. Chem. Soc.  2006,  128:  12656 
    Google Scholar
  • 2 Spande TF. Jain P. Garraffo HM. Pannell LK. Yeh HJC. Daly JW. Fukumoto S. Inamura K. Tokuyama T. Torres JA. Snelling RR. Jones TH. J. Nat. Prod.  1999,  62:  5 
    Google Scholar
  • 3 Daly JW. Witkop B. Tokuyama T. Nishikawa T. Karle IL. Helv. Chim. Acta  1977,  60:  1128 
    Google Scholar
  • 4a For isolation of lepadins (+)-F, (+)-G, and (+)-H, see: Davis RA. Carroll AR. Quinn RJ. J. Nat. Prod.  2002,  65:  454 
    Google Scholar
  • 4b For isolation of lepadins (+)-D, (-)-E, and (-)-F, see: Wright AD. Goclik E. Koening GM. Kaminsky R. J. Med. Chem.  2002,  45:  3067 
    Google Scholar
  • 4c For isolation of (-)-lepadin A, see: Steffan B. Tetrahedron  1991,  47:  8729 
    Google Scholar
  • 4d For isolation of lepadins (-)-B and (-)-C, see: Kubanek J. Williams DE. de Silva ED. Allen T. Andersen RJ. Tetrahedron Lett.  1995,  36:  6189 
    Google Scholar
  • 5 Robbins D. Newton AF. Gignoux C. Legeay J.-C. Sinclair A. Rejzek M. Laxton CA. Yalamanchili SK. Lewis W. O’Connell M. Stockman RA. Chem. Sci.  2011,  2:  2232 
    Google Scholar
6

Representative Procedure; Synthesis of 2a: To a solution of (2E,11E)-diethyl 7-oxotrideca-2,11-dienedioate (100 mg, 0.32 mmol) in CH2Cl2 (10 mL) at -10 ˚C was added TiCl4 (1 M soln in CH2Cl2, 0.64 mL, 0.64 mmol). The mixture was stirred at -10 ˚C for 30 min, then aniline (40.0 µL, 0.48 mmol) was added. The mixture was allowed to warm to r.t., then heated to reflux overnight. The reaction was quenched with sat. aq NaHCO3 (10 mL) and filtered through a pad of Celite. The filtrate was extracted with EtOAc (3 × 10 mL), the combined organics washed with brine (20 mL), dried over anhyd Na2SO4 and concentrated in vacuo. The resulting product was purified using column chromatography on silica gel (PE-EtOAc, 6:1) to give the title compound as a yellow oil (80.0 mg, 65%), as a 3:1 mixture of diastereomers (data for major diastereomer detailed). IR (thin film): 3664, 3008, 1724 cm-¹. ¹H NMR (400 MHz, CDCl3): δ = 7.24-7.30 (m, 2 H), 6.96-7.06 (m, 3 H), 4.16-4.23 (m, 4 H), 4.04-4.15 (m, 1 H), 2.77 (ddd, J = 14.6, 9.6, 4.1 Hz, 1 H), 2.73-2.81 (m, 1 H), 2.59-2.72 (m, 2 H), 2.27-2.44 (m, 2 H), 1.78-1.93 (m, 3 H), 1.62-1.74 (m, 3 H), 1.45-1.61 (m, 3 H), 1.31 (t, J = 7.1 Hz, 3 H), 1.32 (t, J = 7.0 Hz, 3 H). ¹³C NMR (100 MHz, CDCl3): δ = 173.5, 172.8, 149.2, 133.9, 128.7, 124.5, 122.5, 116.4, 60.4, 60.3, 58.0, 39.7, 38.7, 36.5, 29.7, 29.3, 28.1, 22.7, 21.0, 14.4, 14.3. MS (ES): m/z (%) = 386 (100) [M + 1], 408 (16). HRMS: m/z [M + H+] calcd for C23H32NO4: 386.2326; found: 386.2335.

7

Data for major diastereomer of products: 2b: IR (thin film): 1730 cm-¹. ¹H NMR (300 MHz, CDCl3): δ = 7.22-7.35 (m, 5 H), 3.98-4.22 (m, 6 H), 3.42-3.53 (m, 1 H), 2.43-2.58 (m, 3 H), 2.19-2.34 (m, 3 H), 1.91-2.10 (m, 3 H), 1.58-1.70 (m, 4 H), 1.14-1.33 (m, 8 H). ¹³C NMR (100 MHz, CDCl3): δ = 173.7, 172.5, 140.6, 135.6, 128.3, 127.5, 126.7, 109.6, 60.26, 53.98, 52.82, 39.12, 37.18, 35.37, 27.84, 27.64, 23.91, 21.90, 19.42, 17.49, 14.64, 14.30. MS (ES): m/z (%) = 400 (100) [M + 1]. HRMS: m/z [M + H+] calcd for C24H34NO4: 400.2482; found: 400.2429. 2g: IR (thin film): 1732, 1641, 1541 cm-¹. ¹H NMR (300 MHz, CDCl3): δ = 5.70-5.90 (m, 1 H), 5.17 (d, J = 17.1 Hz, 1 H), 5.08 (d, J = 10.2 Hz, 1 H), 4.10-4.35 (m, 4 H), 3.50 (m, 3 H), 2.50 (m, 3 H), 2.25 (m, 3 H), 2.00 (m, 2 H), 1.80 (m, 2 H), 1.60 (m, 5 H), 1.35 (t, J = 7.2 Hz, 6 H). ¹³C NMR (100 MHz, CDCl3): δ = 173.7, 172.6, 136.5, 134.9, 115.6, 106.5, 60.1, 60.0, 53.7, 53.1, 38.9, 36.8, 36.7, 28.3, 27.0, 24.6, 22.3, 20.2, 14.3, 14.2. MS (ES): m/z (%) = 350 (100) [M + 1]. HRMS: m/z [M + H+] calcd for C20H32NO4: 350.2326; found: 350.2320. 2h: IR (thin film): 1730 cm-¹. ¹H NMR (400 MHz, CDCl3): δ = 4.12 (q, J = 7.2 Hz, 4 H), 4.80 (dd, J = 18.4, 2.4 Hz, 1 H), 3.67 (m, 1 H), 3.62 (dd, J = 18.4, 2.4 Hz, 1 H), 2.50-2.60 (m, 3 H), 2.25-2.35 (m, 4 H), 2.10 (m, 1 H), 1.90 (m, 1 H), 1.70 (m, 1 H), 1.55-1.65 (m, 5 H), 1.47 (m, 1 H), 1.17 (t, J = 7.1 Hz, 3 H), 1.15 (t, J = 7.1 Hz, 3 H). ¹³C NMR (100 MHz, CDCl3): δ = 173.6, 172.3, 133.7, 109.6, 81.2, 71.5, 60.2, 60.1, 54.4, 40.3, 38.8, 37.5, 36.7, 28.0, 26.9, 24.8, 22.5, 19.9, 14.3, 14.25. MS (ES): m/z (%) = 348 (100) [M + 1]. HRMS: m/z [M + H+] calcd for C20H30NO4: 348.2175; found: 348.2135. 9: IR (thin film): 1598, 1490, 1446, 1302, 1144 cm-¹. ¹H NMR (400 MHz, CDCl3): δ = 7.96 (t, J = 7.2 Hz, 2 H), 7.88 (t, J = 6.8 Hz, 1 H), 7.67 (m, 1 H), 7.50 (m, 6 H), 7.25 (m, 2 H), 6.95 (m, 3 H), 4.12 (t, J = 3.6 Hz, 1 H), 3.75 (dd, J = 14.2, 8.4 Hz, 1 H), 3.27 (dd, J = 14.2, 2.4 Hz, 1 H), 3.15 (m, 2 H), 2.68 (d, J = 5.6 Hz, 1 H), 2.20-2.40 (m, 2 H), 1.70-2.10 (m, 2 H), 1.48-1.65 (m, 6 H). ¹³C NMR (100 MHz, CDCl3): δ = 148.0, 140.8, 139.8, 135.4, 133.8, 133.4, 129.4, 129.1, 128.9, 127.8, 127.6, 124.5, 123.4, 122.8, 117.6, 114.6, 58.6, 56.7, 56.5, 35.3, 28.4, 27.3, 26.7, 22.3, 21.9. MS (ES): m/z (%) = 522 (38.2) [M + 1]. HRMS: m/z [M + H+] calcd for C29H32NO4S2: 522.1767; found: 522.1755. 10: IR (thin film): 1725, 1601, 1498 cm-¹. ¹H NMR (400 MHz, CDCl3): δ = 7.26 (t, J = 8.0 Hz, 2 H), 6.89 (m, 1 H), 6.70 (t, J = 7.2 Hz, 1 H), 6.60 (d, J = 8.0 Hz. 1 H), 4.17 (q, J = 7.2 Hz, 2 H), 4.11 (q, J = 7.2 Hz, 2 H), 3.79-3.85 (m, 2 H), 2.58 (m, 3 H), 2.50 (m, 2 H), 2.44 (m, 2 H), 1.90 (m, 2 H), 1.29 (t, J = 7.2 Hz, 3 H), 1.23 (t, J = 7.2 Hz, 3 H). ¹³C NMR (100 MHz, CDCl3): δ = 171.7, 171.0, 147.1, 129.4, 129.2, 128.8, 124.3, 122.1, 117.81, 113.4, 60.8, 60.2, 40.8, 39.6, 28.8, 25.6, 24.4, 14.25, 14.23. MS (ES): m/z (%) = 358 (100) [M + 1]. HRMS: m/z [M + H+] calcd for C21H28NO4: 358.2013; found: 358.2015.