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Synlett 2004(13): 2331-2334  
DOI: 10.1055/s-2004-832825
LETTER
© Georg Thieme Verlag Stuttgart · New York

Synthesis of Xantheno[1,9-cd]azepines: Electrophilic Cyclization of Carbamates and N-Acyliminium Ions

Alberto García, Eduardo Gómez, Domingo Domínguez*
Departamento de Química Orgánica y Unidad Asociada al CSIC, Facultad de Química, Universidad de Santiago de Compostela, 15782 Santiago de Compostela, Spain
Fax: +34(981)595012; e-Mail: qomingos@usc.es;
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Publication History

Received 28 April 2004
Publication Date:
24 September 2004 (online)

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Abstract

Tetracyclic xantheno[1,9-cd]azepines and pentacyclic pyrrolo[1,2-a]xantheno[1,9-cd]azepines can be synthesized by ­assembling the azepine ring via cyclization of tertiary carbamates and N-acyliminium ions, respectively.

Key words

2-benzazepines - xantheno[1,9-cd]azepines - cyclization of carbamates - N-acyliminium ions - pyrrolo[1,2-a]xantheno[1,9-cd]azepines

    References

  • 1 Brugnara C, Halperin J, and Bellot E. inventors; WO  9926628.  ; Chem. Abstr. 1999, 131, 18936
  • 2 Nallet JP, Megard A, and Dreux J. inventors; FR  2745812.  ; Chem. Abstr. 1998, 128, 22823
  • 3 Johnson RE, and Busacca CA. inventors; US  5098901.  ; Chem. Abstr. 1992, 117, 7949
  • 4 Sawa Y. Kato T. Masuda T. Chem. Pharm. Bull.  1975,  23:  1917 
    Google Scholar
  • 5a Stein RP, and Delecki DJ. inventors; US  4129561.  ; Chem. Abstr. 1979, 90, 152035
  • 5b Nadelson J, and Houlihan WJ. inventors; US  3976634.  ; Chem. Abstr. 1997, 86, 5500
  • 6 García A. Paz S. Domínguez D. Tetrahedron Lett.  2001,  42:  665 
    CrossrefGoogle Scholar
  • For a related cyclization of carbamates to simple 2-benzazepines, see:
  • 7a Sánchez IH. López FJ. Soria JJ. Larraza MI. Flores HJ. J. Am. Chem. Soc.  1983,  105:  7640 
    Google Scholar
  • 7b Sánchez IH. Larraza MI. Flores HJ. Martell EA. Linzaga I. Carter AA. Heterocycles  1985,  23:  251 
    Google Scholar
  • 9 Filippatos E. Papadaki-Valiraki A. Roussakis C. Verbist JF. Arch. Pharm. (Weinheim, Ger.)  1993,  326:  451 
    Google Scholar
  • 10 Fodor G. Nagubandi S. Tetrahedron  1980,  36:  1279 
    CrossrefGoogle Scholar
  • Although the Bischler-Napieralski cyclization of secondary formamides is very effective for the formation of six-membered rings, it is generally less useful for the synthesis of 2-benzazepines, low yields having frequently been reported:
  • 11a Alonso R. Takahashi K. Schönenberger B. Brossi A. Heterocycles  1987,  26:  1595 
    CrossrefGoogle Scholar
  • 11b Bird CW. Brown AL. Chan CC. Lewis A. Tetrahedron Lett.  1989,  30:  6223 
    CrossrefGoogle Scholar
  • 11c Clark RD. Weinhardt KK. Berger J. Fisher LE. Brown CM. MacKinnon AC. Kilpatrick AT. Spedding M. J. Med. Chem.  1990,  33:  633 
    CrossrefGoogle Scholar
  • 12 Banwell MG. Bissett BD. Busato S. Cowden CJ. Hockless DCR. Holman JW. Read RW. Wu AW. J. Chem. Soc., Chem. Commun.  1995,  2551 
    CrossrefGoogle Scholar
  • Some recent examples of electrophilic cyclization of carbamates leading to isoquinolones:
  • 13a Wang YC. Georghiou PE. Org. Lett.  2002,  4:  2675 
    CrossrefGoogle Scholar
  • 13b Kakefuda A. Watanabe T. Takahashi T. Sakamoto S. Tsukamota SI. Synth. Commun.  2001,  31:  401 
    CrossrefGoogle Scholar
  • 13c Pampin MC. Estévez JC. Castedo L. Estévez RJ. Tetrahedron Lett.  2001,  42:  2307 
    CrossrefGoogle Scholar
  • 13d Banwell MG. Harvey JE. Hockless DCR. Wu AW. J. Org. Chem.  2000,  65:  4241 
    CrossrefGoogle Scholar
  • 13e Treus M. Estévez JC. Castedo L. Estévez RJ. Tetrahedron Lett.  2000,  41:  6351 
    CrossrefGoogle Scholar
  • 14 A 15% yield has been reported in the cyclization of a secondary carbamate: Potapov VM. Dem’yanovich VM. Solov’eva LD. Vendrova OE. Khim. Geterotsikl. Soedin.  1981,  5:  675 ; Chem. Abstr. 1981, 95, 132135
    Google Scholar
  • 16 Tertiary amides, which cannot form nitrilium ions under the Bischler-Napieralski reaction conditions, are known not to afford seven-membered rings under these conditions: Schlüter G. Meise W. Liebigs Ann. Chem.  1988,  833 
    Google Scholar
  • Cyclization by intramolecular amidoalkylation of aromatics with reactive N-acyliminium ions allows the synthesis of a variety of benzofused heterocyclic systems:
  • 17a Speckamp WN. Hiemstra H. Tetrahedron  1985,  41:  4367 
    CrossrefGoogle Scholar
  • 17b Speckamp WN. Moolenaar MJ. Tetrahedron  2000,  56:  3817 
    CrossrefGoogle Scholar
  • 19a There are only a few known examples of N-acyliminium cyclizations leading to seven-membered benzofused heterocycles: Bahajaj AA. Vernon JM. Wilson GD. J. Chem. Soc., Perkin Trans. 1  2001,  1446 ; and references therein
    CrossrefGoogle Scholar
  • 19b For a related cyclization leading to a 5-7-6 tricyclic aza-analogue, see: Marson CM. Pink JH. Hall D. Hursthouse MB. Malik A. Smith C. J. Org. Chem.  2003,  68:  792 
    CrossrefGoogle Scholar
8

All new compounds were fully characterized spectroscopically and had satisfactory elemental analyses or HRMS data.

15

3-Butyl-7-methoxy-2,3,4,12b-tetrahydro-1 H -xantheno[1,9- cd ]azepin-4-one (2b):
A solution of Tf2O (1 mL, 5.9 mmol) in 1 mL CH2Cl2 was slowly added over 15 min to a cooled (0 °C) solution of 8 (90 mg, 0.23 mmol) and DMAP (85 mg, 0.69 mmol) in 6 mL of dry CH2Cl2 under Ar. The resulting mixture was allowed to reach r.t. overnight and was then worked up by pouring onto a sat. Na2CO3 solution. The organic phase was washed with 20% (v/v) aq HOAc, sat. solution of Na2CO3 and brine. After evaporation of solvent, the crude residue was chromatographed on an SiO2 column, elution with 50:50 hexane-EtOAc affording 51 mg (65%) of 2b as an oil. IR (film): ν = 3005-2810, 1649 (CO), 1467 cm-1. 1H NMR (250.13 MHz, CDCl3): δ = 1.00 (t, J = 7.3 Hz, 3 H), 1.43 (sextet, J = 7.4 Hz, 2 H), 1.60-1.71 (m, 2 H), 1.82 (m, 1 H), 2.50-2.60 (m, 1 H), 3.14 (dd, J = 14.8 and 6.3 Hz, 1 H), 3.35 (td, J = 13.4 and 5.5 Hz, 1 H), 3.45-3.54 (m, 1 H), 3.64-3.70 (m, 1 H), 3.94 (s, 3 H), 4.24 (dd, J = 14.8 and 7.4 Hz, 1 H), 6.89 (d, J = 8.5 Hz, 1 H), 7.04 (t, J = 7.7 Hz, 1 H), 7.07-7.20 (m, 3 H), 7.37 (d, J = 8.5 Hz, 1 H). 13C NMR/DEPT (62.83 MHz, CDCl3): δ = 14.3 (CH3), 20.7 (CH2), 31.4 (CH2), 33.4 (CH), 40.9 (CH2), 46.1 (CH2), 47.6 (CH2), 56.5 (CH3), 110.6 (CH), 117.3 (CH), 120.3 (C), 122.6 (C), 123.6 (CH), 123.9 (CH), 128.4 (CH), 128.3 (CH), 128.9 (C), 139.5 (C), 149.8 (C), 150.3 (C), 170.3 (C). MS (EI): m/z (%) = 337 (1) [M+], 306 (7), 254 (26), 253 (100), 238 (73), 210 (96). HRMS (EI): m/z calcd for C20H20NO2 [M+ - OMe]: 306.1494; found: 306.1502.

18

(11b R *,3a R *)-6-Methoxy-2,3,3a,11b,12,13-hexahydro-1 H -pyrrolo[1,2- a ]xantheno[1,9- cd ]azepin-1-one (15a):
A solution of hydroxylactam 14 (2.14 g, 6.31 mmol) in TFA (30 mL) was stirred at r.t. for 4 h and then cooled to 0 °C, cautiously neutralized by dropwise addition of 5 N NaOH and extracted twice with CH2Cl2. The organic extract was washed with H2O, dried with Na2SO4 and concentrated. The residue was crystallized from CH2Cl2-hexane, affording 15a as brown crystals (1.10 g, 55%). Mp: 219-221 °C. IR (KBr): ν = 3444, 1693 (CO) cm-1. 1H NMR (250.13 MHz, CDCl3): δ = 1.77-1.80 (m, 1 H), 2.05-2.09 (m, 1 H), 2.40-2.57 (m, 4 H), 2.80-2.90 (m, 1 H), 3.94 (s, 3 H), 4.03 (dd, J = 14.1 and 8.5 Hz, 1 H), 4.30 (dd, J = 12.1 and 5.3 Hz, 1 H), 4.85 (dd, J = 10.5 and 6.4 Hz, 1 H), 6.84 (s, 2 H), 7.05 (td, J = 6.6 and 1.9 Hz, 1 H), 7.10-7.24 (m, 3 H). 13C NMR/DEPT (62.83 MHz, CDCl3): δ = 30.23 (CH2), 31.54 (CH), 31.64 (CH2), 36.75 (CH2), 36.95 (CH2), 56.17 (OCH3), 65.61 (CH), 110.25 (CH), 116.61 (CH), 120.65 (C), 121.96 (CH), 122.54 (C), 123.44 (CH), 127.82 (CH), 128.44 (CH), 129.59 (C), 140.52 (C), 147.76 (C), 150.11 (C), 174.24 (C). MS (EI): m/z (%) = 321 (100) [M+], 265 (16), 237 (60). Anal. Calcd for C20H19NO3: C, 74.75; H, 5.96; N, 4.36. Found: C, 74.57; H, 5.77; N, 4.41.