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Synlett 2009(19): 3119-3122  
DOI: 10.1055/s-0029-1218340
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Synthesis and Ring Opening of Alkaloid-Type Compounds with a Novel Indolo[2,3-c][2]benzazepine Skeleton

Joana Solovjovaa, Vytas Martynaitisa, Sven Mangelinckxb, Wolfgang Holzerc, Norbert De Kimpeb, Algirdas Šačkus*a
a Institute of Synthetic Chemistry, Kaunas University of Technology, 50270 Kaunas, Lithuania
Fax: +370(37)451432; e-Mail: algirdas.sackus@ktu.lt;
b Department of Organic Chemistry, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, 9000 Ghent, Belgium
c Department of Drug and Natural Product Synthesis, University of Vienna, Pharmaziezentrum, 1090 Vienna, Austria
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Received 13 August 2009
Publikationsdatum:
03. November 2009 (online)

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Abstract

Alkylation of the magnesium salts of 2,3-disubstituted indoles with 2-bromomethylbenzonitrile gave 3-(2-cyanobenzyl)-3H-indole derivatives. Reduction of the cyano group of N-methyl 3-(2-cyanobenzyl)-3H-indolium salts afforded previously unreported indolo[2,3-c][2]benzazepines, while acid hydrolysis gave the corresponding indolo[2,3-c][2]benzazepinones. The action of strong protonic acids on indolo[2,3-c][2]benzazepines causes opening of the benzazepine ring annelated to the indole system to form 3H-­indolium salts.

Key words

alkaloids - indoles - indolo[2,3-c][2]benzazepines - ring closure - ring opening

    References and notes

  • 2a Brossi A. Pei XF. Greig NH. Austr. J. Chem.  1996,  49:  171 
    Suche in Google Scholar
  • 2b Greig NH. Pei XF. Soncrant TT. Ingram DK. Brossi A. Med. Res. Rev.  1995,  15:  3 
    Suche in Google Scholar
  • 2c Robinson B. Heterocycles  2002,  57:  1327 
    Suche in Google Scholar
  • 2d Huang A. Kodanko JJ. Overman LE. J. Am. Chem. Soc.  2004,  126:  14043 
    Suche in Google Scholar
  • 3a Crich D. Banerjee A. Acc. Chem. Res.  2007,  40:  151 
    Suche in Google Scholar
  • 3b Takano S. Ogasawara K. In The Alkaloids   Vol. 36:  Brossi A. Academic Press; San Diego: 1989.  p.225-251  
    Suche in Google Scholar
  • 4 Ramírez A. García-Rubio S. Curr. Med. Chem.  2003,  10:  1891 
    CrossrefPubMedSuche in Google Scholar
  • 5a Fritz H. Fischer O. Tetrahedron  1964,  20:  1737 
    Suche in Google Scholar
  • 5b Rees JMH. Cox B. Tanzil S. Newboult L. Kimber K. Robinson B. Adv. Biosci.  1989,  75:  93 
    Suche in Google Scholar
  • 5c Lévy J. Sapi J. Laronze JY. Royer D. Toupet L. Synlett  1992,  601 
  • 5d Dounay AB. Humphreys PG. Overman LE. Wrobleski AD. J. Am. Chem. Soc.  2008,  130:  5368 
    Suche in Google Scholar
  • 5e Shen L. Zhang M. Wu Y. Qin Y. Angew. Chem. Int. Ed.  2008,  47:  3618 
    Suche in Google Scholar
  • 6a Sunazuka T. Shirahata T. Tsuchiya S. Hirose T. Mori R. Harigaya Y. Kuwajima I. Omura S. Org. Lett.  2005,  7:  941 
    Suche in Google Scholar
  • 6b Snider BB. Wu X. Org. Lett.  2007,  9:  4913 
    Suche in Google Scholar
  • 7a Okamoto T, Akase T, Izumi T, Inaba S, and Yamamoto H. inventors; JP  47020196.  Chem. Abstr. 1972, 77, 152142
  • 7b Cañas-Rodriquez A. Leeming PR. J. Med. Chem.  1972,  15:  762 
    Suche in Google Scholar
  • 7c Matthews N. Franklin RJ. Kendrick DA. Biochem. Pharmacol.  1995,  50:  1053 
    Suche in Google Scholar
  • 8a May JA. Zeidan RK. Stoltz BM. Tetrahedron Lett.  2003,  44:  1203 
    Suche in Google Scholar
  • 8b May JA. Stoltz B. Tetrahedron  2006,  62:  5262 
    Suche in Google Scholar
  • 9a George JH. Adlington RM. Synlett  2008,  2093 
  • 9b Fuchs JR. Funk RL. J. Am. Chem. Soc.  2004,  126:  5068 
    Suche in Google Scholar
  • 9c Siengalewicz P. Gaich T. Mulzer J. Angew. Chem. Int. Ed.  2008,  47:  8170 
    Suche in Google Scholar
  • 10a Hester JB. J. Org. Chem.  1970,  35:  875 
    Suche in Google Scholar
  • 10b Hester JB. inventors; US  3595874.  ; Chem. Abstr. 1971, 75, 98552
  • 11 Kaneko Y. inventors; JP  63163347.  ; Chem. Abstr. 1989, 110, 144847
  • For some examples on the alkylation of indolylmagnesium halides, see:
  • 12a Jackson AH. Smith P. J. Chem. Soc.  1968,  1667 
  • 12b Rodriguez JG. San Andres A. J. Heterocycl. Chem.  1991,  28:  1293 
    Suche in Google Scholar
  • 12c Gruda I. Leblanc RM. Can. J. Chem.  1976,  54:  576 
    Suche in Google Scholar
  • 15 Hinman RL. Whipple EB. J. Am. Chem. Soc.  1962,  84:  2534 
    CrossrefSuche in Google Scholar
1

Postdoctoral fellow of the Research Foundation-Flanders (FWO).

13

Analytical and Spectroscopic Data for Compound 12a
Yellow solid, mp >250 ˚C (from DMSO, with decomp.). ¹H NMR (500 MHz, DMSO-d 6): δ = 0.78 (3 H, s, CH3), 3.04 (1 H, d, ² J = 14.2 Hz, 12-H), 3.09 (1 H, d, J = 14.2 Hz, 12-H), 3.40 (1 H, s, C=NH), 5.91 (1 H, s, 6-H), 6.34 (1 H, br s, NH), 6.96 (1 H, m, 2-H), 7.13 (2 H, m, 3-H, 4-H), 7.29 (1 H, d, J = 7.3 Hz, 1-H), 7.38-7.40 (3 H, m, 9-H, 10-H, 11-H), 7.75 (1 H, m, 8-H). ¹³C NMR (125 MHz, DMSO-d 6): δ = 22.3 (CH3), 39.7 (C-12), 51.2 (C-12a), 96.6 (C-6), 117.2 (C-4), 120.9 (C-1), 122.6 (C-2), 127.1 (C-9), 127.6 (C-3), 127.7 (C-8), 129.7 (C-10), 131.8 (C-11), 133.8 (C-7a), 136.4 (C-11a), 144.5 (C-12b), 151.8 (C-7), 155.3 (C-4a), 185.3 (C-5a). IR (KBr): 3430 (NH), 3310 (NH), 1655 (N=C) cm-¹. MS (ES+): m/z (%) = 262 (50) [M + 2H]+, 261 (100) [M + H]+. Anal. Calcd for C18H16N2: C, 83.04; H, 6.19; N, 10.76. Found: C, 82.74; H, 5.99; N, 10.44.

14

Typical Procedure for the Preparation of an Indolo[2,3- c ][2]benzazepine A solution of 3H-indolium salt 13a (0.5 g, 1.24 mmol) in EtOH (15 mL) was poured in a solution of 5% Na2CO3 (50 mL) and extracted with Et2O (3 × 10 mL). The combined organic layers were washed with H2O, dried over Na2SO4 and the solvent was evaporated under reduced pressure. The residue was dissolved in dry Et2O (10 mL), LiAlH4 (94 mg, 2.48 mmol) was added, and the mixture was refluxed under argon for 5 h. The reaction mixture was allowed to cool to r.t. and H2O (1 mL) was dropped carefully into reaction flask. A finely suspended solid was filtered off using a fritted glass filter, and the solid material washed with Et2O (20 mL). The filtrate was washed with H2O, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (hexane-EtOAc, 7:1) to yield 14a (0.19 g, 55%) as a viscous oil. ¹H NMR (500 MHz, CDCl3): δ = 0.96 (3 H, s, 5a-CH3), 1.15 (3 H, s, 12a-CH3), 1.68 (1 H, s, NH), 2.36 (1 H d, ² J = 14.3 Hz, 12-H), 2.72 (3 H, s, NCH3), 3.56 (1 H, d, ² J = 15.1 Hz, 7-H), 3.68 (1 H, d, ² J = 14.3 Hz, 12-H), 4.52 (1 H, d, ² J = 15.1 Hz, 7-H), 6.47 (1 H, d, J = 7.6 Hz, 4-H), 6.71 (1 H, t, J = 7.3 Hz, 2-H), 7.00 (1 H, d, J = 7.1 Hz, 1-H), 7.05 (1 H, m, 8-H), 7.11 (1 H, t, J = 7.6 Hz, 3-H), 7.14-7.19 (3 H, m, 9-H, 10-H, 11-H). ¹³C NMR (125 MHz, CDCl3): δ = 18.7 (12a-CH3), 18.9 (5a-CH3), 27.0 (NCH3), 44.7 (C-12), 45.3 (C-7), 46.2 (C-12a), 87.9 (C-5a), 106.5 (C-4), 117.5 (C-2), 121.1 (C-1), 126.3 (C-8, C-9), 126.6 (C-10), 127.4 (C-3), 130.3 (C-11), 137.5 (C-12b), 138.4 (C-11a), 143.0 (C-7a), 149.1 (C-4a). ¹5N NMR (50.7 MHz, CDCl3, ref.: MeNO2): δ = -333.3 (N-6), -305.4 (N-3). IR (KBr): 3365 (NH) cm-¹. MS (ES+): m/z (%) = 280 (50) [M + 2H]+, 279 (100) [M + H]+. Anal. Calcd for C19H22N2: C, 81.97; H, 7.97; N, 10.06. Found: C, 81.48; H, 7.60; N, 10.34.

16

Typical Procedure for the Preparation of an Indolo[2,3- c ][2]benzazepin-7(5 H )-one A solution of 3H-indolium salt 13a (0.5 g, 1.24 mmol) in concentrated H2SO4 (12 mL) was heated at 50 ˚C for 5 h. The mixture was poured onto crushed ice, neutralized with 10% KOH solution and extracted with Et2O (3 × 15 mL). The combined organic layers were washed with H2O, dried over Na2SO4, and the solvent was removed under reduced pressure. The residue was purified by column chromatog-raphy (hexane-EtOAc, 2:1) to yield 19a (0.195 g, 53%), mp 226-227 ˚C (from EtOH). ¹H NMR (500 MHz, CDCl3): δ = 1.28 (3 H, s, 5a-CH3), 1.45 (3 H, s, 12a-CH3), 2.30 (3 H, s, NCH3), 2.44 (1 H, br s, 12-H), 3.29 (1 H, d, ² J = 12.7 Hz, 12-H), 5.85 (1 H, br s, 4-H), 6.54 (1 H, br s, 11-H), 6.66 (1H, br t, J = 7.4 Hz, 2-H), 6.82 (1 H, br s, NH), 6.94 (1 H, br t, J = 7.6 Hz, 3-H), 7.03 (1 H, br s, 10-H), 7.07 (1 H, d, J = 7.2 Hz, 1-H), 7.16 (1 H, br t, J = 7.3 Hz, 9-H), 7.57 (1 H, br d, J = 7.5 Hz, 8-H). ¹³C NMR (125 MHz, CDCl3): δ = 19.5 (5a-CH3), 21.5 (12a-CH3), 26.1 (NCH3), 47.6 (C-12), 55.1
(C-12a), 84.3 (C-5a), 104.5 (C-4), 117.1 (C-2), 121.9 (C-1), 126.5 (C-8, C-9), 128.1 (C-3), 128.9 (C-11), 130.1 (C-10), 131.8 (C-12b), 134.9 (C-7a), 136.3 (C-11a), 147.5 (C-4a), 172.8 (C=O). IR (KBr): 3180 (NH), 1650 (C=O) cm-¹. MS (ES+): m/z (%) = 293 (100) [M + H]+. Anal. Calcd for C19H20N2O: C, 78.05; H, 6.89; N, 9.58. Found: C, 78.31; H, 6.91; N, 9.65.