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.

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

References and Notes

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.

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 

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]⁺.

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 

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.