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Synlett 2009(4): 581-584  
DOI: 10.1055/s-0028-1087565
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

One-Pot Synthesis of 7-Aryl-Octahydroazonino[5,4-b]indoles Based on the Fragmentation of Indolizino[8,7-b]indoles and the Insertion of Indoles and 3,4,5-Trimethoxyphenol

Demosthenes Fokas*, James A. Hamzik
Department of Chemistry, ArQule, Inc., 19 Presidential Way, Woburn, MA 01801, USA
e-Mail: dfokas@cc.uoi.gr;
Further Information

Publication History

Received 23 October 2008
Publication Date:
16 February 2009 (online)

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Abstract

A series of 7-aryl-octahydroazonino[5,4-b]indoles were prepared in one pot via a three component reaction from indolizino[8,7-b]indoles, α-chloroethyl chloroformate (ACE-Cl) and activated arenes such as indoles and 3,4,5-trimethoxyphenol.

Key words

indolizino[8,7-b]indole - fragmentation - arene - insertion - 7-aryl-octahydroazonino[5,4-b]indole

    References and Notes

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1

Current address: Department of Materials Science and Engineering, University of Ioannina, 45110 Ioannina, Greece; +30 (26510)97034; dfokas@cc.uoi.gr.

2

Current address: Millipore Corporation, 80 Ashby Road, Bedford, MA 01730, USA.

10

Reaction was found to work equally well in other chlorinated solvents such as CH2Cl2 and CHCl3.

11

Attempts to achieve the same insertion reaction with 1,2 dimethoxybenzene as well as other less oxygenated phenols such as phenol, 4-methoxyphenol, 4-methylphenol, and
4-bromophenol, failed to generate the desired products.

12

Compound 11 was isolated in 47% yield after purification by preparative TLC with EtOAc-hexanes (1:4) as the eluent: ¹H NMR (400 MHz, CDCl3): δ = 7.48 (d, 2 H, J = 7.0 Hz), 7.24-7.02 (m, 5 H), 6.94 (d, 1 H, J = 7.0 Hz), 6.75 (d, 1 H, J = 7.4 Hz), 6.53 (s, 1 H), 4.10 (m, 1 H), 3.87 (s, 3 H), 3.79 (s, 3 H), 3.74 (s, 3 H), 3.64 (m, 2 H), 3.38 (m, 3 H), 2.80 (br s, 1 H), 2.20 (br s, 2 H), 2.10 (s, 1 H). MS (ES+): m/z calcd for C31H29ClN2O7: 576.17; found: 577.10 [M + H]+.

14

Typical Experimental Procedure for the Synthesis of 7-Aryl-octahydroazonino[5,4- b ]indoles 5, 6, 9, and 10
To a solution of indolizinoindole 3 (0.1 mmol) and aromatic nucleophile (1.1 equiv) in DCE at r.t., α-chloroethyl chloroformate (1.2 equiv) was added. The reaction mixture was stirred at r.t. overnight and then treated with MeOH
(1 mL) at 50 ˚C for 1 h. The reaction mixture was then concentrated and the crude product was purified by silica gel column chromatography with CH2Cl2-MeOH (from 100:0 to 90:10) as the eluent.
Spectroscopic Data for Selected Compounds Compound 5g: ¹H NMR (400 MHz, CD3OD): δ = 7.52 (m, 1 H), 7.26 (s, 1 H), 7.22-7.17 (m, 2 H), 7.07-7.02 (m, 3 H), 6.80 (t, 1 H, J = 7.8 Hz), 4.75 (t, 1 H, J = 9.0, 7.0 Hz), 3.55-3.38 (m, 3 H), 3.30-3.20 (m, 2 H), 3.10 (m, 1 H), 2.45 (m,
2 H), 1.93 (m, 1 H), 1.65 (m, 1 H). ¹³C NMR (100.6 MHz, CD3OD): δ = 138.1, 136.5, 134.1, 128.7, 127.6, 122.9, 121.3, 120.9, 119.5, 119.0, 117.9, 117.5, 117.2, 116.5, 111.0, 106.5, 46.9, 44.9, 33.9, 30.8, 23.7, 20.8. MS (ES+): m/z calcd for C22H22ClN3: 363.15; found: 364.08 [M + H]+.

Compound 6a: ¹H NMR (400 MHz, CDCl3): δ = 9.70-8.80 (br s, 1 H), 7.42 (d, 1 H, J = 8.4 Hz), 7.35-7.17 (m, 5 H), 7.11 (t, 1 H, J = 7.7, 7.0 Hz), 7.07 (s, 1 H), 6.98 (t, 1 H, J = 7.7, 7.3 Hz), 3.76 (s, 3 H), 3.73 (s, 3 H), 3.50-3.25 (m, 6 H), 3.15 (m, 1 H), 3.00 (br s, 1 H), 2.85 (s, 1 H), 2.00 (br s, 1 H), 1.90 (s, 1 H). ¹³C NMR (75.4 MHz, CDCl3): δ = 174.5, 137.6, 134.8, 133.9, 127.8, 125.8, 122.7, 122.2, 120.1, 119.9, 117.9, 115.7, 111.6, 110.0, 109.8, 109.4, 53.2, 51.7, 46.8, 44.6, 33.2, 32.4, 23.6, 22.4. MS (ES+): m/z calcd for C25H27N3O2: 401.21; found: 402.19 [M + H]+.
Compound 9: ¹H NMR (400 MHz, CDCl3): δ = 9.17 (br s,
1 H), 7.35 (d, 1 H, J = 7.4 Hz), 7.25 (d, 1 H, J = 6.7 Hz), 7.07 (m, 2 H), 6.56 (s, 1 H), 4.97 (d, 1 H, J = 9.0 Hz), 3.98 (s, 3 H), 3.80 (s, 3 H), 3.76 (s, 3 H), 3.50-3.30 (m, 3 H), 3.25-2.95 (m, 3 H), 2.78 (br s, 1 H), 2.10 (br s, 1 H), 1.98 (s, 1 H), 1.78 (br s, 1 H). ¹³C NMR (100.6 MHz, CDCl3): δ = 152.9, 151.7, 150.6, 139.9, 136.4, 135.9, 129.6, 127.1, 122.1, 119.6, 117.5, 115.5, 111.3, 98.6, 62.0, 61.2, 56.1, 47.6, 46.2, 33.5, 31.7, 25.4, 21.5. MS (ES+): m/z calcd for C23H28N2O4: 396.20; found: 397.04 [M + H]+.
Compound 10: ¹H NMR (400 MHz, CDCl3): δ = 9.80 (br s, 1 H), 7.66 (br s, 1 H), 7.46 (d, 1 H, J = 7.4 Hz), 7.23-7.11 (m, 3 H), 6.60 (s, 1 H), 3.91 (s, 3 H), 3.82 (s, 3 H), 3.79 (s, 3 H), 3.70 (m, 1 H), 3.58 (br s, 2 H), 3.38 (s, 3 H), 3.17-2.82 (br s, 1 H), 2.80-2.50 (br s, 1 H), 2.35 (s, 1 H), 2.20 (s, 1 H). ¹³C NMR (75.4 MHz, CDCl3): δ = 176.1, 156.0, 150.2, 148.9, 138.8, 135.1, 129.2, 128.5, 123.4, 120.6, 118.1, 113.5, 112.1, 111.1, 92.2, 61.4, 61.1, 56.7, 47.1, 43.9, 36.6, 33.0, 23.9, 22.0. MS (ES+): m/z calcd for C24H26N2O5: 422.18; found: 423.04 [M + H]+.

15

Indolylazonines 5 were found to be acid sensitive. They gradually decomposed when samples were dissolved in CDCl3, presumably by traces of HCl present in the solvent. In contrast, no decomposition was observed when samples were dissolved in CD3OD and stored at r.t. for over two weeks. Indolylazonines 6 were found to be stable when dissolved in CDCl3.

16

A series of 7-alkyl and 7-aryl-octahydroazonino[5,4-b]indoles have exhibited a wide range of biological properties as CNS stimulants, antidepressants, anti-inflammatories, diuretics, and anti-ulcer agents. For more information, see ref. 4 and 6b.