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

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

• 3 Magnus P. Ladlow M. Elliott J. J. Am. Chem. Soc.  1987,  109:  7929 
• 4a Houlihan WJ, and Manning RE. inventors; US  3,478,051. 
• 4b Herbst DR, and Smith H. inventors; US  3,943,148. 
• 4c Herbst D. Rees R. Hughes GA. Smith H. J. Med. Chem.  1966,  9:  864 
• 5a Calverley MJ. J. Chem. Soc., Chem. Commun.  1981,  1209 
• 5b Calverley MJ. Harley-Mason J. Quarrie SA. Edwards PD. Tetrahedron  1981,  22:  1635 
• 5c Schill G. Priester CU. Windhövell UF. Fritz H. Helv. Chim. Acta  1986,  69:  438 
• 6a Magnus P. Ladlow M. Elliott J. Kim CS. J. Chem. Soc., Chem. Commun.  1989,  518 
• 6b Takahashi T, Inoue H, Horigome M, Momose K, Sugita M, Katsuyama K, Suzuki C, Nagai S, Nagase M, and Nakamaru K. inventors; EP  535529. 
• 7 Olofson RA. Martz JT. Senet J.-P. Piteau M. Malfroot T. J. Org. Chem.  1984,  49:  2081 
• 8 Corsano S. Algieri S. Ann. Chim.  1960,  50:  75 
• 9 Fokas D. Wang Z. Synth. Commun.  2008,  38:  3816 
• For the reaction of 3a with carboxylic acid anhydrides, see:
• 13a Schill G. Loewer H. Priester CU. Windhöevel UF. Fritz H. Tetrahedron  1987,  43:  3729 
• 13b Harley-Mason J. . Tetrahedron  1980,  36:  1057 
• 13c Foster GH. Harley-Mason J. Waterfield WR.
  J. Chem. Soc., Chem. Commun.  1967,  21 

1

Current address: Department of Materials Science and Engineering, University of Ioannina, 45110 Ioannina, Greece; [phone]; [e-mail].

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.