An Efficient Synthesis of 6-Nitro- and 6-Amino-3H-imidazo[4,5-b]pyridines by Cyclocondensation of 1-Substituted 1H-Imidazol-5-amines with 3-Nitro-4H-chromen-4-one

Abstract

The reaction of 3-nitro-4H-chromen-4-one with in situ generated 1-substituted 5-amino-1H-imidazoles affords a set of 1-substituted 6-nitro-3H-imidazo[4,5-b]pyridines which represent potential adenosine deaminase (ADA) inhibitors. Reduction of the nitro group results in the formation of the corresponding 6-amino-3H-imidazo[4,5-b]pyridines.

cyclization - chromones - N-heterocycles - imidazoles - purine isosteres

References and Notes

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25

General Procedure for the Synthesis of Compounds 6a-q
To a Schlenk flask, set with reflux, CH₂Cl₂ (2.5 mL), primary amine (0.00131 mol), and methyl N-(cyanomethyl)-formimidate (1, 0.128 g, 0.00131 mol) were added under an argon atmosphere at r.t. The reaction mixture was refluxed during 2 h and after that, the mixture was cooled down to r.t., and then to 0 ˚C on an ice bath. Afterwards 3-nitro-4H-chromen-4-one (0.25 g, 0.00131 mol) was added, and the mixture continued to stir at the same temperature for 15-20 min (the color of reaction mixture became intensively red) and then refluxed for 5 h. The formed precipitate was filtered, and the obtained solid was washed with CH₂Cl₂ and dried. In the case of homogenous solution, the solvent was evaporated to dryness, and the residue was purified by column chromatography (EtOAc-i-PrOH = 5:1), to give 6a-q as light yellow crystals.

26

2-(3- tert -Butyl-6-nitro-3 H -imidazo[4,5- b ]pyridin-5-yl)phenol (6a)
^¹H NMR (300 MHz, DMSO-d ₆): δ = 1.82 (s, 9 H, t-Bu), 6.87 (d, 1 H, H-6′, ^³ J = 9 Hz), 7.01 (t, 1 H, H-4′, ^³ J = 9 Hz), 7.30 (t, 1 H, H-5′, ^³ J = 9 Hz), 7.57 (d, 1 H, H-3′, ^³ J = 9 Hz), 8.71 (s, 1 H, H-5), 8.74 (s, 1 H, H-2), 9.95 (s, 1 H, OH). ^¹³C NMR (250 MHz, DMSO-d ₆): δ = 28.5 (CH₃), 57.7 [(CH₃)₃C], 115.1 (C-4′), 119.5 (C-6′), 123.6 (C-5′), 125.7 (C-3′), 130.2 (C-2′), 130.5 (C-1′), 133.9 (C-7), 142.8 (C-4), 144.7 (C-5), 147.1 (C-9), 148.2 (C-6), 154.5 (C-2). MS (EI): m/z (%) = 313 [M + 1]⁺(11), 312 [M]⁺(98), 210 [M - C₁₂H₉N₃O]⁺(77).

27

CCDC-782287 contain the crystallographic data (excluding structure factors) for the structures of 6g reported in this paper. This data have been deposited with the Cambridge Crystallographic Data Centre as supplementary material and can be obtained free of charge on application to CCDC,
12 Union Road, Cambridge CB2 1EZ, UK; fax:
[phone]; e-mail: [e-mail] or via www.ccdc.cam.ac.uk/data_request/cif.

28a Dubois L, Evanno Y, Gille C, and Malanda A. inventors; WO  2009112677. 

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28c Engh R, Hertenberger H, Honold K, Masjost B, Rueger P, Schaefer W, Scheiblich S, and Schwaiger M. inventors; WO  2007017143. 

28d Honold K, Kaluza K, Masjost B, Schaefer W, and Scheiblich S. inventors; WO  2006066914. 

29

General Procedure for the Synthesis of Compounds 7a-q To a 100 mL Schlenk flask, filled with 200 mg of corresponding imidazo[4,5-b]pyridine 6a-q in MeOH (30 mL), Pd/C (20 mg, 10 mol%) was added. The flask was fitted with a septum, and then held under vacuum for 3 min, after that it was filled with hydrogen. Holding under vacuum was repeated one more time, and after sequent filling with hydrogen, the reaction mixture has been stirred for 2 d under H₂ atmosphere. After the reaction was stopped, the mixture was filtered through Celite pad and filtrate was evaporated to dryness or (if necessary) was purified by column chroma-tography (EtOAc-i-PrOH = 5:1) to give 7a-q as light brown crystals.

30

2-(3- tert -Butyl-6-amino-3 H -imidazo[4,5- b ]pyridin-5-yl)phenol (7a) ^¹H NMR (300 MHz, DMSO-d ₆): δ = 1.75 (s, 9 H, t-Bu), 4.86 (s, 2 H, NH₂), 6.97 (t, 1 H, H-4′, ^³ J = 9 Hz), 6.98 (d, 1 H, H-6′, ^³ J = 9 Hz), 7.28 (t, 1 H, H-5′, ^³ J = 9 Hz), 7.47 (d, 1 H, H-3′, ^³ J = 9 Hz), 7.48 (s, 1 H, H-5), 8,25 (s, 1 H, H-2), 10.27 (s, 1 H, OH). ^¹³C NMR (250 MHz, DMSO-d ₆): δ = 28.6 (CH₃), 56.1 [(CH₃)₃C], 113.5 (C-4′), 116.7 (C-6′), 119.4 (C-5′), 127.2 (C-3′), 129.1 (C-2′), 131.7 (C-1′), 136.2 (C-9), 137.5 (C-5), 140.2 (C-6), 141.0 (C-7), 142.6 (C-4), 154.6 (C-2). MS (EI): m/z (%) = 282 [M]⁺(71), 225 [M - C₁₂H₉N₄O]⁺(100).