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Synlett 2008(12): 1852-1856  
DOI: 10.1055/s-2008-1078567
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Synthesis of New Pyrrolobenzazepines via Pictet-Spengler Cyclization

Stéphanie Gracia, Jürgen Schulz*, Stéphane Pellet-Rostaing*, Marc Lemaire
Laboratoire de Catalyse et de Synthèse Organique, ICBMS, Institut de Chimie et Biochimie Moléculaires et Supramoléculaires, Université Claude Bernard Lyon 1, 43 Boulevard du 11 Novembre 1918, 69622 Villeurbanne, France
Fax: +33(4)72431408; e-Mail: jurgen.schulz@univ-lyon1.fr;
Further Information

Publication History

Received 15 March 2008
Publication Date:
02 July 2008 (online)

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Abstract

A new six-step divergent strategy was developed allowing access to pyrrolobenzazepine structures from pyrrole. This strategy was based on a regioselective Friedel-Crafts acylation followed by a Pictet-Spengler cyclization.

Key words

azepine - pyrrole - fused-ring systems - Pictet-Spengler reaction

    References and Notes

  • 1 Eder C. Proksh P. Wray V. Steube K. Bringmann G. van Soest RWM. Sudarsono . Fernandus E. Pattisina LA. Wiryowidagdo S. Moka W. J. Nat. Prod.  1999,  62:  184 
    Google Scholar
  • 2a Cimino G. De Rosa S. De Stefano D. Mazzarella L. Puliti R. Sodano G. Tetrahedron Lett.  1982,  23:  767 
    Google Scholar
  • 2b Kitagawa I. Kobayashi M. Kitanaka K. Kido M. Kyogoku Y. Chem. Pharm. Bull.  1983,  31:  2321 
    Google Scholar
  • 3a Kobayashi J. Ohizumi Y. Nakamura H. Hirata Y. Wakamatsu K. Miyazawa T. Experientia  1986,  42:  1064 
    Google Scholar
  • 3b Kobayashi J. Nakamura H. Ohizumi Y. Experientia  1988,  47:  86 
    Google Scholar
  • 4a Tasdemir D. Mallon R. Greenstein M. Feldberg LR. Kim SC. Collins K. Wojciechowicz D. Mangalindan GC. Concepcion GP. Harper MK. Ireland CM. J. Med. Chem.  2002,  45:  529 
    Google Scholar
  • 4b Meijer L. Flajolet M. Greengard P. Trends Pharmacol. Sci.  2004,  25:  471 
    Google Scholar
  • 4c Knockaert M. Greengard P. Meijer L. Trends Pharmacol. Sci.  2002,  23:  417 
    Google Scholar
  • 4d Meijer L. Thunnissen AMWH. White AW. Garnier M. Nikolic M. Tsai LH. Walter J. Cleverley KE. Salinas PC. Wu YZ. Biernat J. Mandelkow EM. Kim SH. Pettit GR. Chem. Biol.  2000,  7:  51 
    Google Scholar
  • 4e Wan Y. Hur W. Cho CY. Liu Y. Adrian FJ. Lozach O. Bach S. Mayer T. Fabbro D. Meijer L. Gray NS. Chem. Biol.  2004,  11:  247 
    Google Scholar
  • 5 Annoura H. Tatsuoka T. Tetrahedron Lett.  1995,  36:  413 
    CrossrefGoogle Scholar
  • 6a Xu YZ. Yakushijin K. Horne DA. J. Org. Chem.  1997,  62:  456 
    Google Scholar
  • 6b Barrios Sosa AC. Yakushijin K. Horne DA. J. Org. Chem.  2000,  65:  610 
    Google Scholar
  • 6c Papeo G. Posteri H. Borghi D. Vasari M. Org. Lett.  2005,  7:  5641 
    Google Scholar
  • 7 Kimbaris A. Varvounis G. Tetrahedron  2000,  56:  9675 
    CrossrefGoogle Scholar
  • 8 Anderson HJ. Loader CE. Xu RX. Le N. Gognan NJ. McDonald R. Edwards LG. Can. J. Chem.  1985,  63:  896 
    CrossrefGoogle Scholar
  • 9 Huffman JW. Smith VJ. Padgett LW. Tetrahedron  2008,  64:  2104 
    Google Scholar
  • 10 Lau CK. Tardif S. Dufresne C. Scheigetz J. J. Org. Chem.  1989,  54:  491 
    CrossrefGoogle Scholar
  • 11 Pictet A. Spengler T. Ber. Dtsch. Chem. Ges.  1911,  44:  2030 
    CrossrefGoogle Scholar
  • 12 Aubry S. Pellet-Rostaing S. Faure R. Lemaire M. J. Heterocycl. Chem.  2006,  43:  139 
    CrossrefGoogle Scholar
  • 13 David E. Rangheard C. Pellet-Rostaing S. Lemaire M. Synlett  2006,  2016 
    Article in Thieme ConnectGoogle Scholar
  • 14a Kundu B. Sawant D. Chhabra R. J. Comb. Chem.  2005,  7:  317 
    Google Scholar
  • 14b Kundu B. Sawant D. Partani P. Kesarwani AP. J. Org. Chem.  2005,  70:  4889 
    Google Scholar
  • 14c Duggineri S. Sawant D. Saha B. Kundu B. Tetrahedron  2006,  62:  3228 
    Google Scholar
  • 15 Testa ML. Lamartina L. Mingoia F. Tetrahedron  2004,  60:  5873 
    CrossrefGoogle Scholar
  • 16 Rousseau JF. Dodd RH. J. Org. Chem.  1998,  63:  2731 
    CrossrefGoogle Scholar
  • 17 Yokoyama A. Ohwada T. Shudo K. J. Org. Chem.  1999,  64:  611 
    CrossrefGoogle Scholar
  • 20 Sundberg RJ. Laurino JP. J. Org. Chem.  1984,  49:  249 
    CrossrefGoogle Scholar
  • 21 Boyles DA. Nichols DE. J. Org. Chem.  1988,  53:  5128 
    CrossrefGoogle Scholar
  • 22 Yasuhara A. Sakamoto T. Tetrahedron Lett.  1998,  39:  595 
    CrossrefGoogle Scholar
  • 23a Ko EY. Lim CH. Chung K.-H. Bull. Korean Chem. Soc.  2006,  27:  432 
    Google Scholar
  • 23b Bianchi AA. Kaufman TS. ARKIVOC  2003,  (x):  178 
    Google Scholar
18

The X-ray crystal structure has been filed with the Cambridge Crystallographic Centre with deposition number CCDC 640594.

19

General Procedure for Preparation of Compounds 10-13 To a stirred 1 M solution of amine 6, 7, 8, or 9 in anhyd toluene was added the para-substituted benzaldehyde derivative (1.1 equiv), under argon atmosphere (in the case of amines 8 and 9, 4 equiv of MgSO4 were added). The mixture was heated at reflux until total conversion of the amine into the intermediary imine (followed by ¹H NMR). Then, the mixture was cooled to r.t. to add TFA (5 or 10 equiv). The resulting mixture was left at specified temperature (r.t. or 70 ˚C) until completion of the reaction. Residual TFA was neutralized at 0 ˚C with an aq sat. NaHCO3 solution. The reaction mixture was extracted with CH2Cl2. The combined organic layers were successively washed with H2O and brine, dried over MgSO4, filtered, and solvents removed under reduced pressure. The crude product was purified by flash chromatography.
Analytical Data of Compound 11a Pale yellow solid obtained in 98% yield after flash chromatography (cyclohexane-EtOAc, 9:1). ¹H NMR (300 MHz, CDCl3): δ = 2.33 (s, 3 H), 3.63 (d, J = 16.2 Hz, 1 H), 3.73 (br s, 1 H), 4.14 (d, 16.2 Hz, 1 H), 6.06 (m, 1 H), 6.08 (dd, J = 1.3, 7.3 Hz, 1 H), 6.28 (d, J = 3.4 Hz, 1 H), 6.73 (d, J = 8.3 Hz, 2 H), 6.85 (m, 2 H), 6.97 (d, J = 8.3 Hz, 2 H), 7.04 (d, J = 8.3 Hz, 2 H), 7.11 (dd, J = 1.3, 7.1 Hz, 1 H), 7.15 (d, J = 8.3 Hz, 2 H), 7.30 (d, J = 3.4 Hz, 1 H). HRMS: m/z = 439.5326.

24

General Procedure for Preparation of Compounds 14-17 A mixture of the azepine 10a-e, 11a-e, 12a-e, or 13a-e (1 equiv) and TBAF 1 M solution in THF (10 equiv) was heated at 70 ˚C for 10 h. The mixture was washed with H2O. The aqueous phase was extracted with CH2Cl2. The combined organic layers were dried over MgSO4, filtered, and solvents removed under reduced pressure. The crude product was purified by flash chromatography.
Analytical Data of Compound 15a Yellow solid obtained in 88% yield after flash chromatography (heptane-EtOAc, 8:2). ¹H NMR (300 MHz, CDCl3): δ = 3.75 (s, 2 H), 6.21 (t, J = 2.6 Hz, 1 H), 6.93 (t, J = 2.6 Hz, 1 H), 7.2 (dd, J = 1.7, 6.6 Hz, 1 H), 7.22 (td, J = 1.7, 6.6 Hz, 1 H), 7.29 (td, J = 1.7, 6.6 Hz, 1 H), 7.48 (dd, J = 1.7, 7.2 Hz, 1 H), 7.76 (d, J = 8.3 Hz, 2 H), 8.0 (d, J = 8.3 Hz, 2 H), 8.24 (br s, 1 H). ¹³C NMR (300 MHz, CDCl3): δ = 32.6, 108.7, 114.1, 118.9, 123.3, 123.5, 126.9, 127.8, 128.2, 128.7, 130.5, 132.0, 132.8, 133.4, 144.2, 147.0, 155.0. HRMS: m/z = 437.5148.