Synlett 2010(15): 2299-2303  
DOI: 10.1055/s-0030-1258538
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

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

Dmytro Ostrovskyia, Viktor O. Iaroshenko*a,b, Andranik Petrosyana, Sergii Dudkina, Iftikhar Alia, Alexander Villingera, Andrei Tolmachevb,c, Peter Langer*a,d
a Institut für Chemie, Universität Rostock, Albert-Einstein-Str. 3a, 18059 Rostock, Germany
Fax: +49(381)4986412; e-Mail: viktor.iaroshenko@uni-rostock.de; e-Mail: iva108@googlemail.com; e-Mail: peter.langer@uni-rostock.de;
b National Taras Shevchenko University, 62 Volodymyrska st., 01033 Kyiv-33, Ukraine
c ‘Enamine Ltd.’, 23 A. Matrosova st., 01103 Kyiv, Ukraine
d Leibniz-Institut für Katalyse an der Universität Rostock e.V., Albert Einstein Str. 29a, 18059 Rostock, Germany
Further Information

Publication History

Received 11 May 2010
Publication Date:
30 July 2010 (online)

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.

    References and Notes

  • 1a Dubey PK. Kumar RV. Naidu A. Kulkarni SMA. Asian J. Chem.  2002,  14:  1129 
  • 1b Lee SCh. Choi JS. Oh JH. Park B. Kim YE. Lee JH. Shin D. Kim ChM. Hyun Y.-L. Lee ChS. Cho J.-M. Ro S. WO 2007083978, 2007,  Chem. Abstr.  2007,  147:  817587 
  • 1c Kelly MG, Kincaid J, Duncton M, Sahasrabudhe K, Janagani S, Upasani RB, Wu G, Fang Y, and Wei Zh.-L. inventors; US  2006194801.  2006; Chem. Abstr. 2006, 145, 889269
  • 1d Randolph JT, Chen H, Degoey DA, Flentge ChA, Flosi WJ, Grampovnik DJ, Huang PP, Hutchinson DK, Kempf DJ, Klein LL, and Yeung MC. inventors; US  2005159469.  2005; Chem. Abstr. 2005, 143, 641882
  • 1e Kivlighn SD. Zingaro GJ. Gabel RA. Broten TP. Schorn TW. Schaffer LW. Naylor EM. Chakravarty PK. Patchett AA. Greenlee WJ. Siegl PKS. Am. J. Hypertens.  1995,  8:  58 
  • 2a Pagani ED. Dundore RL. Bode DC. Bacon ER. Singh B. Lesher GY. Buchholz RA. Silver PJ.
    J. Cardiovasc. Pharmacol.  1994,  24:  403 
  • 2b Joseph EC. Rees JA. Dayan A. Toxicol. Pathol.  1996,  24:  436 
  • 2c Garvey DS, Saenz de Tejada I, Earl RA, and Khanapure SP. inventors; US  6331543.  2001; Chem. Abstr. 2001, 136, 916407
  • 3a Ida K, Otsubo N, Kuboyama T, Arai H, Watanabe A, Saki M, Hiura N, Manabe H, Takada H, and Saito J. inventors; WO  2005082905.  2005; Chem. Abstr. 2005, 143, 979654
  • 3b Magnuson S, Dixon J, Phillips B, Khire U, Wang L, Zhang Zh, Patel M, Kumarasinghe ES, Wickens P, and Olague A. inventors; WO  2007064932.  2007; Chem. Abstr. 2007, 147, 618350
  • 3c Bavetsias V. Sun C. Bouloc N. Reynisson J. Workman P. Linardopoulos S. McDonald E. Bioorg. Med. Chem. Lett.  2007,  17:  6567 
  • 4 Zielke CI. Suelter CH. Purine, Purine Nucleoside, and Purine Nucleotide Aminohydrolases, In The Enzymes   Vol. 4:  Boyer PD. Academic Press; New York: 1971.  p.47 
  • 5a Cristalli G. Costanzi S. Lambertucci C. Lupidi G. Vittori S. Volpini R. Camaioni E. Med. Res. Rev.  2001,  21:  105 
  • 5b Maydanovych O. Beal PA. Chem. Rev.  2006,  106:  3397 
  • 5c Nair V. IMPDH Inhibitors: Discovery of Antiviral Agents Against Emerging Diseases, In Antiviral Drug Discovery for Emerging Diseases and Bioterrorism Threats   Torrence PF. John Wiley and Sons; Hoboken: 2005.  Chap. 8. p.179-202  
  • 5d Shu Q. Nair V. Med. Res. Rev.  2008,  219 
  • 6a Agarwal RP. Pharmac. Ther.  1982,  17:  399 
  • 6b Weber G. Cancer Res.  1983,  43:  3466 
  • 7 Pankiewicz KW. Goldstein BM. Inosine Mono Phosphate Dehydrogenase, ACS Symposium Series 839   American Chemical Society; Washington DC: 2003. 
  • 8a Burns CM. Chu H. Rueter SM. Hutchinson LK. Canton H. Sanders-Bush E. Emeson RB. Nature (London)  1997,  387:  303 
  • 8b Higuchi M. Single FN. Kohler M. Sommer B. Sprengel R. Seeburg PH. Cell  1993,  75:  1361 
  • 9a Giblett ER. Anderson JE. Cohen F. Pollara B. Meuwissen HJ. Lancet  1972,  2:  1067 
  • 9b Hirshhorn R. Clin. Immunol. Immunophathol.  1995,  76:  219 
  • 10a Niedzwicki JG. Kouttab NM. Mayer KH. Carpenter CC. Parks RE. Abushanab E. Abernethy DR. J. Acquir. Immune Defic. Syndr.  1991,  4:  178 
  • 10b Salvatore D. Claudio MM. Anna PM. Clin. Chem.  1987,  33:  1675 
  • 10c Valenzuela A. Blanco J. Callebaut C. Jacotot E. Lluis C. Hovanessian AG. Franco R.
    J. Immunol.  1997,  158:  3721 
  • 11a Ungerer JPJ. Oosthuizen HM. Retief JH. Bissbort SH. Chest  1994,  106:  33 
  • 11b Banales JL. Rivera Martinez E. Perez Gonzalez L. Selman M. Raymond Y. Nava A. Arch. Med. Res.  1999,  30:  358 
  • 12a Chiba S. Matsumoto H. Saitoh M. Kasahara M. Matsuya M. Kashiwagi MA. J. Neurol. Sci.  1995,  132:  170 
  • 12b Gakis C. Eur. Respir. J.  1996,  9:  632 
  • 13a Demeocq F. Viallard JL. Boumsell L. Richard Y. Chassgne J. Plagne R. Lemerle J. Bernard A. Leuk. Res.  1982,  6:  211 
  • 13b Carlucci F. Rosi F. Di Pietro C. Marinello E. Biochim. Biophys. Acta  1997,  1360:  203 
  • 14 Silverman RB. The Organic Chemistry of Drug Design and Drug Action   2nd ed.:  Elsevier Academic Press; New York: 2004.  p.617 ; ISBN 0-12-643732-7
  • 15 Agarwal RP. Spector T. Parks RE. Biochem. Pharmacol.  1977,  26:  359 
  • 16a Frick L. Yang C. Marquez VE. Wolfenden R. Biochemistry  1989,  28:  9423 
  • 16b Ashley GW. Bartlett PA. J. Biol. Chem.  1984,  259:  13621 
  • 17a Shewach DS. Krawczyk SH. Acevedo OL. Townsend LB. Biochem. Pharmacol.  1992,  44:  1697 
  • 17b Frieden C. Kurz LC. Gilbert HR. Biochemistry  1980,  19:  5303 
  • 18a Wang Z. Quiocho FA. Biochemistry  1998,  37:  8314 
  • 18b Wilson DK. Rudolph FN. Quiocho FA. Science  1991,  252:  1278 
  • 18c Kinoshita T. Nishio N. Nakanishi I. Sato A. Fujii T. Acta Crystallogr., Sect. D: Biol. Crystallogr.  2003,  59:  299 
  • 19a Illuminati G. Stegel F. Tetrahedron Lett.  1968,  39:  4169 
  • 19b Terrier F. Chatrousse A.-P. Schaal R. J. Org. Chem.  1972,  37:  3010 
  • 19c Biffin MEC. Miller J. Moritz AG. Paul D. Aust. J. Chem.  1970,  23:  957 
  • 19d Terrier F. Sebban M. Goumont R. Halle JC. Moutiers G. Cangelosi I. Buncel E. J. Org. Chem.  2000,  65:  7391 
  • 20 Seeliger F. Blazej S. Bernhardt S. Makosza M. Mayr H. Chem. Eur. J.  2008,  14:  6108 
  • 21a Iaroshenko VO. Sevenard DV. Kotljarov AV. Volochnyuk DM. Tolmachev AO. Sosnovskikh VYa. Synthesis  2009,  731 
  • 21b Iaroshenko VO. Wang Y. Sevenard DV. Volochnyuk DM. Synthesis  2009,  1851 
  • 21c Iaroshenko VO. Sevenard DV. Volochnyuk DM. Wang Y. Martiloga A. Tolmachev AO. Synthesis  2009,  1865 
  • 21d Iaroshenko VO. Wang Y. Zhang B. Volochnyuk DM. Sosnovskikh VYa. Synthesis  2009,  2393 
  • 21e Kotljarov A. Irgashev RA. Iaroshenko VO. Sevenard DV. Sosnovskikh VYa. Synthesis  2009,  3233 
  • 21f Kotljarov A. Iaroshenko VO. Volochnyuk DM. Irgashev RA. Sosnovskikh VYa. Synthesis  2009,  3869 
  • 21g Iaroshenko VO. Synthesis  2009,  3967 
  • 22a Perrella FW. Chen S.-F. Behrens DL. Kaltenbach RF. Seitz SP. J. Med. Chem.  1994,  37:  2232 
  • 22b Becket GJP. Ellis GP. Tetrahedron Lett.  1976,  9:  719 
  • 23a Takagi K. Tanaka M. Murakami Y. Ogura K. Ishii K. Morita H. Aotsuka T. J. Heterocycl. Chem.  1987,  24:  1003 
  • 23b Connor DT. Young PA. von Strandtmann M. J. Heterocycl. Chem.  1981,  18:  697 
  • 23c Haas G. Stanton JL. Winkler T. J. Heterocycl. Chem.  1981,  18:  619 
  • 24 Wesch T. Iaroshenko VO. Groth U. Synlett  2008,  1459 
  • 28a Dubois L, Evanno Y, Gille C, and Malanda A. inventors; WO  2009112677.  2009
  • 28b Boyd E, Brookfield F, Gridley J, Honold K, Lau R, and Scheiblich S. inventors; WO  2007014707.  2007
  • 28c Engh R, Hertenberger H, Honold K, Masjost B, Rueger P, Schaefer W, Scheiblich S, and Schwaiger M. inventors; WO  2007017143.  2007
  • 28d Honold K, Kaluza K, Masjost B, Schaefer W, and Scheiblich S. inventors; WO  2006066914.  2006
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:
+44 (1223)336033; e-mail: deposit@ccdc.cam.ac.uk or via www.ccdc.cam.ac.uk/data_request/cif.

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).