A Convenient One-Pot Synthesis of 7-Trifluoromethyl-Substituted Imidazo[4,5-b]pyridines

Abstract

This communication describes a practical and facile one-pot approach for the synthesis of 7-trifluoromethyl-substituted imidazo[4,5-b]pyridines by the reaction of in situ generated 5-aminoimidazole and a 1,3-CCC-biselectrophile.

Key words

cyclizations - fluorine - heterocycles - imidazopyridines - aminoimidazoles

References and Notes

• 1a Temple C. Rose JD. Comber RN. Rener GA. J. Med. Chem.  1987,  30:  1746 
• 1b Cristalli G. Vittori S. Eleuteri A. Grifantini M. Volpini R. Lupidi G. Capolongo L. Pesenti E. J. Med. Chem.  1991,  34:  2226 
• 2a Cristalli G. Vittori S. Eleuteri A. Volpini R. Camaioni E. Lupidi G. Mohmoud N. Belvilaqua F. Palu G. J. Med. Chem.  1995,  38:  4019 
• 2b Cundy DJ. Holan G. Otaegui M. Simpson GW. Bioorg. Med. Chem. Lett.  1997,  7:  669 
• 3 Temple C. J. Med. Chem.  1990,  33:  656 
• 4 Bukoski L. Janowiec M. Pharmazie  1989,  44:  267 
• 5a Mantlo NB. Chakravarty PK. Ondeyka DL. Siegl PKS. Chang RS. Lotti VJ. Faust KA. Chen T.-B. Schorn TW. Sweet CS. Emmert SE. Patchett AA. Greenlee WJ. J. Med. Chem.  1991,  34:  2922 
• 5b Bavetsias V. Sun C. Bouloc N. Reynisson J. Workman P. Linardopoulos S. McDonald E. Bioorg. Med. Chem. Lett.  2007,  17:  6567 
• 5c Chang LCW. von Frijtag Drabbe Künzel JK. Mulder-Krieger T. Westerhout J. Spangenberg T. Brussee J. Ijzerman AP. J. Med. Chem.  2007,  50:  828 
• 5d Mladenova G. Lee-Ruff E. Tetrahedron Lett.  2007,  48:  2787 
• 6a Lawhorn BG. Mehl RA. Begley TP. Org. Biomol. Chem.  2004,  2:  2538 
• 6b Clayton R. Davis ML. Fraser W. Li W. Ramsden CA. Synlett  2002,  1483 
• 6c Humphries MJ. Ramsden CA. Synthesis  1999,  985 
• 7 Bhat B. Groziak MP. Leonard NJ. J. Am. Chem. Soc.  1990,  112:  4891 
• 8a Bégué J.-P. Bonnet-Delpon D. In Chimie Bioorganique et Médicinale du Fluor   CNRS Édition; Paris: 2005. 
• 8b Hiyama T. In Organofluorine Compounds, Chemistry and Applications   Springer; Berlin, Heidelberg: 2000. 
• 9a McClinton MA. McClinton DA. Tetrahedron  1992,  48:  6555 
• 9b Nowak I. Robins MJ. J. Org. Chem.  2007,  72:  2678 
• 10a Ohkura H. Berbarasov DO. Soloshonok VA. Tetrahedron Lett.  2003,  44:  2417 
• 11a Zanatta N. Amaral SS. Esteves-Souza A. Echevarria A. Brondani PB. Flores DC. Bonacorso HG. Flores AFC. Martins MAP. Synthesis  2006,  2305 
• 11b Marins MAP. Pereira CMP. Zimmermann NEK. Cunico W. Moura S. Beck P. Zanatta N. Bonacorso HG. J. Fluorine Chem.  2003,  123:  261 ; and references cited therein
• 11c Narsaiah B. Sivaprasad A. Venkataratnam RV. J. Fluorine Chem.  1994,  66:  47 
• 11d Schlosser M. Volle J.-N. Leroux F. Schenk K. Eur. J. Org. Chem.  2002,  2913 
• 11e Druzhinin SD. Balenkova ES. Nenajdenko VG. Tetrahedron  2007,  63:  7753 
• 12a Krasovsky AL. Hartulyari AS. Nenajdenko VG. Balenkova ES. Synthesis  2002,  133 
• 12b Krasovsky AL. Moiseev AM. Nenajdenko VG. Balenkova ES. Synthesis  2002,  901 
• 13a Tamura K. Mizukami H. Maeda K. Watanabe H. Uneyama K. J. Org. Chem.  1993,  58:  32 
• 13b Uneyama K. J. Fluorine Chem.  1999,  97:  11 
• 14 Gaudry R. Org. Synth.  1955,  3:  436 
• 15 Menge GA. J. Am. Chem. Soc.  1934,  56:  2197 
• 16 Hosmane RS. Brunett FN. Albert MS. J. Org. Chem.  1984,  49:  1212 
• 18 Volochnyuk DM. Pushechnikov AO. Krotko DG. Sibgatulin DA. Kovalyova SA. Tolmachev AA. Synthesis  2003,  1531 
• 20a Al-Shaar AHM. Gilmour DW. Lythgoe DJ. McClenaghan I. Ramsden CA. J. Chem. Soc., Perkin Trans. 1  1992,  2779 
• 20b Al-Shaar AHM. Chambers RK. Gilmour DW. Lythgoe DJ. McClenaghan I. Ramsden CA. J. Chem. Soc., Perkin Trans. 1  1992,  2789 
• 20c Humphries MJ. Ramsden CA. Synlett  1995,  203 
• 21 Linderman RJ. Jamois EA. J. Fluorine Chem.  1991,  53:  79 
• 22a Pearson RG. J. Am. Chem. Soc.  1963,  85:  3533 
• 22b Pearson RG. Parr RG. J. Am. Chem. Soc.  1983,  105:  7512 
• 22c Ayers PW. Faraday Discuss.  2007,  135:  161 

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General Procedure A solution of amine 2a-i (5 mmol) in dried CH₂Cl₂ (2,5 mL) was heated until reflux. After a period of 15 min ethyl N-(cyanomethyl)formimidate 1 (5 mmol, 560 mg) was added under N₂ counterflow. The mixture was allowed to stir under reflux for 2 h. To the hot reaction mixture the 1,3-biselectrophile of type 4a-e (5 mmol) was added. The mixture was stirred for 8 h. Then it was cooled down to ambient temperature. The crude product was worked up through flash column chromatography to obtain the product as white needles.
Selected Data for 5o
¹H NMR (400 MHz, CDCl₃): δ = 3.79 (s, 3 H, OCH₃), 5.47 (s, 2 H, CH₂), 6.89 (m, 2 H, Ph), 7.33 (m, 2 H, Ph), 7.87 (s, 1 H, H-6), 8.31 (s, 1 H, H-2). ¹³C NMR (100 MHz, CDCl₃): δ = 47.5 (OCH₃), 55.3 (CH₂), 111.5 (m, C-6), 122.3 (q, ¹ J _CF = 278 Hz, CF₃), 121.6 (q, ¹ J _CF = 278 Hz, CF₃), 114.4 (Ph), 126.6 (Ph), 130.1 (Ph), 160.4 (Ph), 129.7 (q, ² J _CF = 36 Hz, C-7), 133.6 (C-7a), 143.1 (q, ² J _CF = 35 Hz, C-5), 148.4 (C-3a), 148.6 (C-2). ¹⁹F NMR (376 MHz, CDCl₃): δ =

-62.59, -66.55.

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CCDC 683462 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.