Download PDF
Synlett 2009(4): 628-632  
DOI: 10.1055/s-0028-1087915
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

An Efficient, Regioselective, Versatile Synthesis of N-Fused 2- and 3-Aminoimidazoles via Ugi-Type Multicomponent Reaction Mediated by Zirconium(IV) Chloride in Polyethylene Glycol-400

Sankar K. Guchhait*, Chetna Madaan
Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), S. A. S. Nagar (Mohali)-160062, Punjab, India
Fax: +91(172)2214692; e-Mail: skguchhait@niper.ac.in;
Further Information

Publication History

Received 3 November 2008
Publication Date:
16 February 2009 (online)

    Permissions and Reprints All articles of this category

Abstract

An Ugi-type multicomponent reaction of heterocyclic amidines with aldehydes and isocyanides catalyzed by zirconium(IV) chloride in PEG-400 was developed. The protocol offers the rapid, environment friendly, regioselective and versatile synthesis of medicinally important N-fused 2- and 3-aminoimidazoles in good to high yields. The combination of catalyst and solvent, that was judiciously explored, was crucial for regioselectivity and versatility of the method.

Key words

multicomponent reaction - regioselective synthesis - N-heterocycles - zirconium(IV) chloride - polyethylene glycol

    References and Notes

  • 1a Budriesi R. Ioan P. Locatelli A. Cosconati S. Leoni A. Ugenti MP. Andreani A. Di Toro R. Bedini A. Spampinato S. Marinelli L. Novellino E. Chiarini A.
    J. Med. Chem.  2008,  51:  1592 
    Google Scholar
  • 1b Fookes CJR. Pham TQ. Mattner F. Greguric I. Loc’h C. Liu X. Berghofer P. Shepherd R. Gregoire M.-C. Katsifis A.
    J. Med. Chem.  2008,  51:  3700 
    Google Scholar
  • 1c Jin Z. Nat. Prod. Rep.  2005,  22:  196 
    Google Scholar
  • 2 Rival Y. Grassy G. Michel G. Chem. Pharm. Bull.  1992,  40:  1170 
    CrossrefPubMedGoogle Scholar
  • 3a Hamdouchi C. de Blas J. del Prado M. Gruber J. Heinz BA. Vance L. J. Med. Chem.  1999,  42:  50 
    Google Scholar
  • 3b Lhassani M. Chavignon O. Chezal J.-M. Teulade J.-C. Chapat J.-P. Snoeck R. Andrei G. Balzarini J. De Clercq E. Gueiffier A. J. Med. Chem.  1999,  34:  271 
    Google Scholar
  • 4a Fisher MH. Lusi A. J. Med. Chem.  1972,  15:  982 
    Google Scholar
  • 4b Rival Y. Grassy G. Taudou A. Ecalle R. Eur. J. Med. Chem.  1991,  26:  13 
    Google Scholar
  • 5 Rupert KC. Henry JR. Dodd JH. Wadsworth SA. Cavender DE. Olini GC. Fahmy B. Siekierka JJ. Bioorg. Med. Chem. Lett.  2003,  13:  347 
    CrossrefGoogle Scholar
  • 6 Hamdouchi C. Zhong B. Mendoza J. Collins E. Jaramillo C. De Diego JE. Robertson D. Spencer CD. Anderson BD. Watkins SA. Zhang F. Brooks HB. Bioorg. Med. Chem. Lett.  2005,  15:  1943 
    CrossrefGoogle Scholar
  • 7 Goodacre SC. Street LJ. Hallett DJ. Crawforth JM. Kelly S. Owens AP. Blackaby WP. Lewis RT. Stanley J. Smith AJ. Ferris P. Sohal B. Cook SM. Pike A. Brown N. Wafford KA. Marshall G. Castro JL. Atack JR. J. Med. Chem.  2006,  49:  35 
    CrossrefGoogle Scholar
  • 8 Abe Y. Kayakiri H. Satoh S. Inoue T. Sawada Y. Imai K. Inamura N. Asano M. Hatori C. Katayama A. Oku T. Tanaka H. J. Med. Chem.  1998,  41:  564 
    CrossrefGoogle Scholar
  • 9 Sanfilippo PJ. Urbanski M. Press JB. Dubinsky B. Moore JB. J. Med. Chem.  1988,  31:  2221 
    CrossrefGoogle Scholar
  • 10a Koubachi J. El Kazzouli S. Berteina-Raboin S. Mouaddib A. Guillaumet G. J. Org. Chem.  2007,  72:  7650 
    Google Scholar
  • 10b Imaeda Y. Kawamoto T. Tobisu M. Konishi N. Hiroe K. Kawamura M. Tanaka T. Kubo K. Bioorg. Med. Chem.  2008,  16:  3125 
    Google Scholar
  • 11 Katritzky AR. Xu Y.-J. Tu H. J. Org. Chem.  2003,  68:  4935 
    CrossrefPubMedGoogle Scholar
  • 12a Bienayme H. Bouzid K. Angew. Chem. Int. Ed.  1998,  37:  2234 
    Google Scholar
  • 12b Blackburn C. Guan B. Fleming P. Shiosaki K. Tsai S. Tetrahedron Lett.  1998,  39:  3635 
    Google Scholar
  • 12c Groebke K. Weber L. Mehlin F. Synlett  1998,  661 
    Google Scholar
  • 12d DiMauro EF. Kennedy JM. J. Org. Chem.  2007,  72:  1013 
    Google Scholar
  • 12e Parchinsky VZ. Shuvalova O. Ushakova O. Kravchenko DV. Krasavin M. Tetrahedron Lett.  2006,  47:  947 
    Google Scholar
  • 12f Mandair GS. Light M. Russell A. Hursthouse M. Bradley M. Tetrahedron Lett.  2002,  43:  4267 
    Google Scholar
  • 12g Rousseau AL. Matlaba P. Parkinson CJ. Tetrahedron Lett.  2007,  48:  4079 
    Google Scholar
  • 12h Ireland SM. Tye H. Whittaker M. Tetrahedron Lett.  2003,  44:  4369 
    Google Scholar
  • 12i Varma RS. Kumar D. Tetrahedron Lett.  1999,  40:  7665 
    Google Scholar
  • 12j Chen JJ. Golebiowski A. McClenaghan J. Klopfenstein SR. West L. Tetrahedron Lett.  2001,  42:  2269 
    Google Scholar
  • 12k Blackburn C. Tetrahedron Lett.  1998,  39:  5469 
    Google Scholar
  • 13 Parenty ADC. Song Y.-F. Richmond CJ. Cronin L. Org. Lett.  2007,  9:  2253 
    CrossrefGoogle Scholar
  • 14 Bakherad M. Nasr-Isfahani H. Keivanloo A. Doostmohammadi N. Tetrahedron Lett.  2008,  49:  3819 
    CrossrefGoogle Scholar
  • 15 Dömling A. Chem. Rev.  2006,  106:  17 
    CrossrefPubMedGoogle Scholar
  • For greener use of PEG-400 as solvent, see:
  • 16a Han W. Liu C. Jin Z.-L. Org. Lett.  2007,  9:  4005 
    Google Scholar
  • 16b Kouznetsov VV. Merchan Arenas DR. Romero Bohórquez AR. Tetrahedron Lett.  2008,  49:  3097 ; and references cited therein
    Google Scholar
  • 17a For significant use of ZrCl4, see: Review paper: Smitha G. Chandrasekhar S. Reddy CS. Synthesis  2008,  829 
    Google Scholar
  • 17b Bhagat S. Chakraborti AK. J. Org. Chem.  2008,  73:  6029 
    Google Scholar
  • 17c Chakraborti AK. Kondaskar A. Tetrahedron Lett.  2003,  44:  8315 
    Google Scholar
  • 19 Lyon MA. Kercher TS. Org. Lett.  2004,  6:  4989 
    CrossrefPubMedGoogle Scholar
  • 20 Blackburn C. Guan B. Tetrahedron Lett.  2000,  41:  1495 
    CrossrefGoogle Scholar
18

Representative Experimental Procedure for the Synthesis of N - tert -Butyl-2-(4-chlorophenyl)imidazo[1,2- a ]pyridin-3-amine (Table 2, entry 1): To a mixture of 2-aminopyridine (0.19 g, 2 mmol) and 4-chlorobenzaldehyde (0.28 g, 2 mmol) in PEG-400 (2 mL), tert-butyl isocyanide (0.17 g, 2 mmol) and ZrCl4 (47 mg, 10 mol%) were added. The mixture was allowed to stir at 50 ˚C under open air. After completion of the reaction (4.5 h, monitored by TLC), the resulting mixture was extracted with EtOAc and washed with H2O. The organic layer was dried over anhyd Na2SO4, filtered and concentrated under reduced pressure. The column chromatographic purification of crude product over silica gel (mesh size: 60-120) eluting with EtOAc-hexane (1:1.5) afforded N-tert-butyl-2-(4-chlorophenyl)imidazo-[1,2-a]pyridin-3-amine (0.48 g, 85%); white solid; mp 146-149 ˚C. MS (ESI): m/z = 300 [M + 1]. ¹H NMR (400 MHz, CDCl3): δ = 1.06 (s, 9 H), 3.00 (br, NH), 6.78 (t, J = 6.8 Hz, 1 H), 7.15 (t, J = 8.0 Hz, 1 H), 7.40 (d, J = 8.8 Hz, 2 H), 7.54 (d, J = 7.2 Hz, 1 H), 7.92 (d, J = 8.8 Hz, 1 H), 8.20 (d, J = 6.8 Hz, 1 H). ¹³C NMR (100 MHz, CDCl3): δ = 30.3 (3 × Me), 56.4 (C), 111.5 (CH), 117.3 (CH), 123.3 (CH), 123.4 (C), 124.3 (CH), 128.4 (2 × CH), 129.3 (2 × CH), 133.1 (C), 133.7 (C), 138.3 (C), 142.0 (C). IR (KBr): 3457, 2972, 1635, 1194, 770 cm-¹. Anal. Calcd for C17H18ClN3: C, 68.11; H, 6.05; N, 14.02. Found: C, 67.89; H, 6.07; N, 13.99.
All reactions (Tables  [¹] -  [³] ) were carried out following this procedure.