Download PDF
Synlett 2011(10): 1407-1412  
DOI: 10.1055/s-0030-1260568
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

A Regioselective and High-Yielding Method for Formaldehyde Inclusion in the 3CC Groebke-Blackburn-Bienaymé Reaction: One-Step Access to 3-Aminoimidazoazines

Anuj Sharma, Hong-yu Li*
College of Pharmacy, Department of Pharmacoloy/Toxicology, The University of Arizona, Tucson, AZ 85721, USA
Fax: +1(520)6260794; e-Mail: hongyuli@pharmacy.arizona.edu;
Further Information

Publication History

Received 27 January 2011
Publication Date:
16 May 2011 (online)

   Permissions and Reprints All articles of this category
Preview

Abstract

A regioselective, mild, convenient, and effective condition is developed for the inclusion of glyoxylic acid as formaldehyde equivalent in the 3CC reaction towards synthesis of 3-aminoalkyl imidazo-azines. In general, formaldehydes do not perform well with Ugi-type multicomponent sequences, and the method reported here is a regioselective and high-yielding one for the HCHO variant of Groebke-Blackburn-Bienaymé reaction.

Key words

Groebke-Blackburn-Bienaymé - multicomponent ­reaction - aminoimidazoazines - formaldehyde - glyoxylic acid

    References and Notes

  • 1a Groebke K. Weber L. Mehlin F. Synlett  1998,  661 
  • 1b Bienaymé H. Bouzid K. Angew. Chem. Int. Ed.  1998,  37:  2234 
    Search in Google Scholar
  • 1c Blackburn C. Guan B. Fleming P. Shiosaki K. Tsai S. Tetrahedron Lett.  1998,  39:  3635 
    Search in Google Scholar
  • 2a Varma RS. Kumar D. Tetrahedron Lett.  1999,  40:  7665 
    Search in Google Scholar
  • 2b Chen JJ. Golebiowski A. McClenaghan J. Klopfenstein SR. West L. Tetrahedron Lett.  2001,  42:  2269 
    Search in Google Scholar
  • 2c Lu Y. Zhang W. QSAR Comb. Sci.  2004,  23:  827 
    Search in Google Scholar
  • 2d Gudmundsson KS. Masquelin T. Perun T. Hulme C. Tetrahedron Lett.  2005,  46:  8355 
    Search in Google Scholar
  • 2e Mironov MA. Tokareva MI. Ivantsova MN. Mokruskin VS. Russ. Chem. Bull. Int. Ed.  2006,  55:  1835 
    Search in Google Scholar
  • 2f Parchinsky VZ. Schuvalova O. Ushalova O. Krachenko DV. Krasavin M. Tetrahedron Lett.  2006,  47:  947 
    Search in Google Scholar
  • 2g Masquelin T. Baui H. Brickley B. Stephenson G. Schwerkoske J. Hulme C. Tetrahedron Lett.  2006,  47:  2989 
    Search in Google Scholar
  • 2h Che C. Xiang J. Wang G.-X. Fathi R. Quan J.-M. Yang Z. J. Comb. Chem.  2007,  9:  982 
    Search in Google Scholar
  • 2i Shaabani A. Soleeimani E. Maleki A. Monatsh. Chem.  2007,  138:  73 
    Search in Google Scholar
  • 2j DiMauro EF. Kennedy JM. J. Org. Chem.  2007,  72:  1013 
    Search in Google Scholar
  • 2k Nenadjenko VG. Reznichenko AL. Balenkova ES. Russ. Chem. Bull. Int. Ed.  2007,  56:  560 
    Search in Google Scholar
  • 2l Umkehrer M. Ross G. Jager N. Burdack C. Kolb J. Hu H. Alvim-Gaston M. Hulme C. Tetrahedron Lett.  2007,  48:  2213 
    Search in Google Scholar
  • 2m Rousseau AL. Matlaba P. Parkinson CJ. Tetrahedron Lett.  2007,  48:  4079 
    Search in Google Scholar
  • 2n Adib M. Madhavi M. Noghani MA. Mirzaei P. Tetrahedron Lett.  2007,  48:  7263 
    Search in Google Scholar
  • 2o Guchhait SK. Madaan C. Synlett  2009,  628 
  • 3a Sablayrolles C. Cros GH. Milhavet JC. Rechenq E. Chapat J.-P. Boucard M. Serrano JJ. McNeill JH. J. Med. Chem.  1984,  27:  206 
    Search in Google Scholar
  • 3b Kaminski JJ. Bristol JA. Puchalski C. Lovey RG. Elliott AJ. Guzik H. Solomon DM. Conn DJ. Domalski MS. Wong SC. Gold EH. Long JF. Chiu PJS. Steinberg M. Mc Phail AT. J. Med. Chem.  1985,  28:  876 
    Search in Google Scholar
  • 3c Clements-Jewery S. Danswan G. Gardner CR. Matharu SS. Murdoch R. Tully WR. Westwood R. J. Med. Chem.  1988,  31:  1220 
    Search in Google Scholar
  • 3d Kaminski JJ. Wallmark B. Briving C. Andersson B.-M. J. Med. Chem.  1991,  34:  533 
    Search in Google Scholar
  • 3e Rival Y. Grassy G. Michel G. Chem. Pharm. Bull.  1992,  40:  1170 
    Search in Google Scholar
  • 3f Meurer L. Tolman RL. Chapin EW. Saperstein R. Vicario PP. Zrada M. MacCoss MM. J. Med. Chem.  1992,  35:  3845 
    Search in Google Scholar
  • 3g Lober S. Hubner H. Gmeiner P. Bioorg. Med. Chem. Lett.  1999,  9:  97 
    Search in Google Scholar
  • 3h Lhassani M. Chavignon O. Chezal J.-M. Teulade J.-C. Chapat J.-P. Snoeck R. Andrei G. Balzarini J. De Clerque E. Gueiffier A. Eur. J. Med. Chem.  1999,  271 
  • 3i Hamdouchi C. de Blas J. del Prado M. Gruber J. Heinz BA. Vance L. J. Med. Chem.  1999,  42:  50 
    Search in Google Scholar
  • 3j Trapini G. Franco M. Latrofa A. Ricciardi L. Carotti A. Serra M. Sanna E. Biggio G. Liso G. J. Med. Chem.  1999,  42:  3934 
    Search in Google Scholar
  • 3k Warshakoon NC. Wu S. Boyer A. Kawamoto R. Sheville J. Renock S. Xu K. Pokross M. Evdokimov AG. Walter R. Mekel M. Bioorg. Med. Chem. Lett.  2006,  16:  5598 
    Search in Google Scholar
  • 4a Georges G. Vercauteren DP. Vanderveken DJ. Horion R. Evrard GH. Durant FV. George P. Wick AE. Eur. J. Med. Chem.  1993,  323 
  • 4b Jain AK. J. Med. Chem.  2004,  47:  947 
    Search in Google Scholar
  • 4c Swainston Harrison T. Keating GM. CNS Drugs  2005,  19:  65 
    Search in Google Scholar
  • 4d Wiegand MH. Drugs  2008,  68:  2411 
    Search in Google Scholar
  • 4e Hanson SM. Morlock EV. Satyshur KA. Czajkowski C. J. Med. Chem.  2008,  51:  7243 
    Search in Google Scholar
  • 4f Chernyak N. Gevorgyan V. Angew. Chem. Int. Ed.  2010,  49:  2743 
    Search in Google Scholar
  • 5 Li HY. McMillen T. Heap CR. McCann DJ. Yan L. Campbell RM. Mundla SR. King CR. Dierks EA. Anderson BD. Britt KS. Huss KL. Voss MD. Wang Y. Clawson DK. Yingling JM. Sawyer JS.
    J. Med. Chem.  2008,  51:  2302 
    CrossrefSearch in Google Scholar
  • 6a Wu Z. Fraley ME. Bilodeau MT. Kaufman ML. Tasber ES. Balitza AE. Hartman GD. Coll KE. Rickert K. Shipman J. Shi B. Sepp-Lerenzino L. Thomas KA. Bioorg. Med. Chem.  2004,  14:  909 
    Search in Google Scholar
  • 6b Breitenbucher GJ. Tichenor MS. Merit JE. Hawryluk NA. Chambers AL. Keith JM.   , 
  • 7a Hulme C. Gore V. Curr. Med. Chem.  2003,  10:  51 
    Search in Google Scholar
  • 7b Hulme C. Nixey T. Curr. Opin. Drug Discovery Dev.  2003,  6:  921 
    Search in Google Scholar
  • 7c Dömling A. Chem. Rev.  2006,  106:  17 
    Search in Google Scholar
  • 7d Rivera DG. Pando O. Coll F. Tetrahedron  2006,  62:  8327 
    Search in Google Scholar
  • 7e Rivera DG. Wessjohann LA. Molecules  2007,  12:  1890 
    Search in Google Scholar
  • 7f Banfi L. Basso A. Cerulli V. Guanti G. Riva R. J. Org. Chem.  2008,  73:  1608 
    Search in Google Scholar
  • 7g Hulme C. Lee Y.-S. Mol. Diversity  2008,  12:  1 
    Search in Google Scholar
  • 7h Banfi L. Riva R. Basso A. Synlett  2010,  23 
  • 7i Nichol GS. Sharma A. Li H.-Y. Acta Crystallogr.  2011,  E67:  o833 
    Search in Google Scholar
  • 8a Sisko J. Kassik AJ. Mellinger M. Filan JJ. Allen A. Olsen MA. J. Org. Chem.  2000,  65:  1516 
    Search in Google Scholar
  • 8b Lyon MA. Kercher TS. Org. Lett.  2004,  6:  4989 
    Search in Google Scholar
  • 9a Kaminski JJ. Hilbert JM. Pramanik BN. Solomon DM. Conn DJ. Rizvi RK. Elliott AJ. Guzik H. Lovey RG. Domalski MS. Wong S.-C. Puchalski C. Gold EH. Long JF. Chiu PJS. McPhailt AT. J. Med. Chem.  1987,  30:  2031 
    Search in Google Scholar
  • 9b Groziak MP. Wilson SR. Clauson GL. Leonard NJ. J. Am. Chem. Soc.  1986,  108:  8002 
    Search in Google Scholar
  • 9c Katritzky AR. Xu Y.-J. Tu H. J. Org. Chem.  2003,  68:  4935 
    Search in Google Scholar
  • 12 Mandair GS. Light M. Russell A. Hursthouse M. Bradley M. Tetrahedron Lett.  2002,  43:  4267 
    CrossrefSearch in Google Scholar
10

Representative Procedure for the Synthesis of N -(2,6-dimethylphenyl)imidazo[1,2- a ]pyridin-3-amine (3b, Table 2)
To a solution of 2-aminopyridine (1b, 1.05 mmol) in MeOH (1.5 mL), was added glyoxylic acid (1.78 mmol) followed by HClO4 (0.105 mmol), and the solution was stirred for 10 min. 2-Isocyano-1,3-dimethylbenzene (1.05 mmol) was added to this mixture, and the solution was stirred for 12 h. MeOH was evaporated from the reaction mixture, and the crude was purified through silica gel chromatography to provide 3b in 77% yield. ¹H NMR (400 MHz, DMSO-d 6):
δ = 8.72 (d, J = 8 Hz, 1 H), 7.81 (d, J = 4 Hz, 2 H), 7.60 (s, 1 H), 7.52-7.48 (m, 1 H), 7.11 (d, J = 8 Hz, 2 H), 7.05-7.02 (m, 3 H), 2.09 (s, 6 H). ¹³C NMR (400 MHz, DMSO-d 6):
δ = 138.5, 136.4, 135.8, 133.4, 132.0, 131.7, 129.3, 128.0, 125.8, 125.3, 116.6, 112.9, 106.3, 18.1. HRMS: m/z calcd for C15H16N3: 238.13387; found: 238.13377. LC-MS (ES): 98.6% (λ = 214 nm).

11

Formation of regioisomer was observed during optimization studies using paraformaldehyde as formaldehyde source (entry 8, Table  [¹] ).

13

Nichol, G. S.; Sharma, A.; Li, H. Y. unpublished results.