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

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.

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

References

<A NAME="RD10904ST-1">1</A> Brugnara C, Halperin J, and Bellot E. inventors; WO  9926628.  ; Chem. Abstr. 1999, 131, 18936

<A NAME="RD10904ST-2">2</A> Nallet JP, Megard A, and Dreux J. inventors; FR  2745812.  ; Chem. Abstr. 1998, 128, 22823

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<A NAME="RD10904ST-5B">5b</A> Nadelson J, and Houlihan WJ. inventors; US  3976634.  ; Chem. Abstr. 1997, 86, 5500

<A NAME="RD10904ST-6">6</A> García A. Paz S. Domínguez D. Tetrahedron Lett.  2001,  42:  665 

For a related cyclization of carbamates to simple 2-benzazepines, see:

<A NAME="RD10904ST-7A">7a</A> Sánchez IH. López FJ. Soria JJ. Larraza MI. Flores HJ. J. Am. Chem. Soc.  1983,  105:  7640 

<A NAME="RD10904ST-7B">7b</A> Sánchez IH. Larraza MI. Flores HJ. Martell EA. Linzaga I. Carter AA. Heterocycles  1985,  23:  251 

<A NAME="RD10904ST-8">8</A>

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

<A NAME="RD10904ST-9">9</A> Filippatos E. Papadaki-Valiraki A. Roussakis C. Verbist JF. Arch. Pharm. (Weinheim, Ger.)  1993,  326:  451 

<A NAME="RD10904ST-10">10</A> Fodor G. Nagubandi S. Tetrahedron  1980,  36:  1279 

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:

<A NAME="RD10904ST-11A">11a</A> Alonso R. Takahashi K. Schönenberger B. Brossi A. Heterocycles  1987,  26:  1595 

<A NAME="RD10904ST-11B">11b</A> Bird CW. Brown AL. Chan CC. Lewis A. Tetrahedron Lett.  1989,  30:  6223 

<A NAME="RD10904ST-11C">11c</A> Clark RD. Weinhardt KK. Berger J. Fisher LE. Brown CM. MacKinnon AC. Kilpatrick AT. Spedding M. J. Med. Chem.  1990,  33:  633 

<A NAME="RD10904ST-12">12</A> Banwell MG. Bissett BD. Busato S. Cowden CJ. Hockless DCR. Holman JW. Read RW. Wu AW. J. Chem. Soc., Chem. Commun.  1995,  2551 

Some recent examples of electrophilic cyclization of carbamates leading to isoquinolones:

<A NAME="RD10904ST-13A">13a</A> Wang YC. Georghiou PE. Org. Lett.  2002,  4:  2675 

<A NAME="RD10904ST-13B">13b</A> Kakefuda A. Watanabe T. Takahashi T. Sakamoto S. Tsukamota SI. Synth. Commun.  2001,  31:  401 

<A NAME="RD10904ST-13C">13c</A> Pampin MC. Estévez JC. Castedo L. Estévez RJ. Tetrahedron Lett.  2001,  42:  2307 

<A NAME="RD10904ST-13D">13d</A> Banwell MG. Harvey JE. Hockless DCR. Wu AW. J. Org. Chem.  2000,  65:  4241 

<A NAME="RD10904ST-13E">13e</A> Treus M. Estévez JC. Castedo L. Estévez RJ. Tetrahedron Lett.  2000,  41:  6351 

<A NAME="RD10904ST-14">14</A> 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

<A NAME="RD10904ST-15">15</A>

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.

<A NAME="RD10904ST-16">16</A> 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 

Cyclization by intramolecular amidoalkylation of aromatics with reactive N-acyliminium ions allows the synthesis of a variety of benzofused heterocyclic systems:

<A NAME="RD10904ST-17A">17a</A> Speckamp WN. Hiemstra H. Tetrahedron  1985,  41:  4367 

<A NAME="RD10904ST-17B">17b</A> Speckamp WN. Moolenaar MJ. Tetrahedron  2000,  56:  3817 

<A NAME="RD10904ST-18">18</A>

(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.

<A NAME="RD10904ST-19A">19a</A> 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

<A NAME="RD10904ST-19B">19b</A> 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