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Synthesis 2006(17): 2799-2814  
DOI: 10.1055/s-2006-942549
REVIEW
© Georg Thieme Verlag Stuttgart · New York

3,5-Dihalo-2(1H)-pyrazinones: Versatile Scaffolds in Organic Synthesis

Vijaykumar G. Pawar, Wim M. De Borggraeve*
Chemistry Department, Molecular Design and Synthesis, Katholieke Universiteit Leuven, Celestijnenlaan 200F, 3001 Leuven, Belgium
Fax: +32(16)327990; e-Mail: Wim.DeBorggraeve@chem.kuleuven.be;
Further Information

Publication History

Received 7 February 2006
Publication Date:
15 August 2006 (online)

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Abstract

3,5-Dihalo-2(1H)-pyrazinones have proven to be versatile scaffolds in organic synthesis. This review describes the methods to synthesise and functionalise these compounds. Applications of the 2(1H)-pyrazinone scaffold in peptide mimicry and drug design are discussed.

  • 1 Introduction

  • 2 Synthesis of 3,5-Dihalo-2(1H)-pyrazinones

  • 3 Functionalisation of the Scaffold

  • 3.1 Functionalisation at C3

  • 3.2 Functionalisation at C5

  • 3.3 Deblocking of N1

  • 3.4 Alkylation of N1

  • 4 Diels-Alder Reactions

  • 4.1 Cycloaddition Reactions with Alkynes

  • 4.2 Cycloaddition Reactions with Alkenes

  • 5 Application of 2(1H)-Pyrazinones in Drug and Peptido­mimetic Design

  • 6 Solid-Phase Chemistry

  • 7 Conclusion

Key words

pyrazinone - Diels-Alder reaction - nucleophilic aromatic substitution - cross-coupling reactions - peptidomimetic chemistry

    References

  • 1 Norcross RD. Peterson I. Chem. Rev.  1995,  95:  2041 
    CrossrefGoogle Scholar
  • 2 Faulkner DJ. Nat. Prod. Rep.  2002,  19:  1 
    PubMedGoogle Scholar
  • 3 Im HK. Im WB. Judge TM. Gammill RB. Hamilton BJ. Carter DB. Pregenzer JF. Mol. Pharmacol.  1993,  44:  468 
    Google Scholar
  • 4 Heeres J. de Jonge MR. Koymans LMH. Daeyaert FFD. Vinkers M. Van Aken KJA. Arnold E. Das K. Kilonda A. Hoornaert GJ. Compernolle F. Cegla M. Azzam RA. Andries K. de Bethune MP. Azijn H. Pauwels R. Lewi PJ. Janssen PAJ. J. Med. Chem.  2005,  48:  1910 
    CrossrefGoogle Scholar
  • 5 Hirano K. Kubota T. Tsuda M. Watanabe K. Fromont J. Kobayashi Ji. Tetrahedron  2000,  56:  8107 
    CrossrefGoogle Scholar
  • 6 Dunn G. Newbold GT. Spring FS. J. Chem Soc.  1949,  2586 
    Google Scholar
  • 7 Dutcher JD. J. Biol. Chem.  1947,  171:  321 
    Google Scholar
  • 8 Okada Y. Taguchi H. Yokoi T. Tetrahedron Lett.  1996,  37:  2249 
    CrossrefGoogle Scholar
  • 9 Japp FR. Knox J. J. Chem. Soc.  1905,  87:  701 
    CrossrefGoogle Scholar
  • 10 Tota YA. Elderfield RC. J. Org. Chem.  1942,  7:  313 
    CrossrefGoogle Scholar
  • 11 Karmas G. Spoerri PE. J. Am. Chem. Soc.  1952,  74:  1580 
    CrossrefGoogle Scholar
  • 12 Vekemans J. Pollers-Wieërs C. Hoornaert G. J. Heterocycl. Chem.  1983,  20:  919 
    CrossrefGoogle Scholar
  • 13 De Borggraeve WM. Verbist BMP. Rombouts FJR. Pawar VG. Smets WJ. Kamoune L. Alen J. Van der Eycken EV. Compernolle F. Hoornaert GJ. Tetrahedron  2004,  60:  11597 
    CrossrefGoogle Scholar
  • 14 Zhang X. Schmitt AC. Jiang W. Wasserman Z. Decicco CP. Bioorg. Med. Chem. Lett.  2003,  13:  1157 
    CrossrefGoogle Scholar
  • 15 Janssen PAJ, Van Aken KJA, Lewi PJ, Koymans LMH, De Jonge MR, Heeres J, Daeyaert FFD, Hoornaert GJC, Compernolle FJC, and Kilonda A. inventors; WO  02078708.  ; Chem. Abstr. 2002, 137, 294978
  • 16 Loosen PK. Tutonda MG. Khorasani MF. Compernolle F. Hoornaert GJ. Tetrahedron  1991,  47:  9259 
    CrossrefGoogle Scholar
  • 17 Hoornaert G. Bull. Soc. Chim. Belg.  1994,  103:  583 
    Google Scholar
  • 18 Azzam R. Ph.D. Thesis   Katholieke Universiteit Leuven; Belgium: 2003. 
    Google Scholar
  • 19 Azzam R. De Borggraeve W. Compernolle F. Hoornaert GJ. Tetrahedron Lett.  2004,  45:  1885 
    CrossrefGoogle Scholar
  • 20 Azzam R. De Borggraeve WM. Compernolle F. Hoornaert GJ. Tetrahedron  2005,  61:  3953 
    CrossrefGoogle Scholar
  • 21 Kaval N. Bisztray K. Dehaen W. Kappe CO. Van der Eycken E. Mol. Divers.  2003,  7:  125 
    CrossrefGoogle Scholar
  • 22 De Borggraeve WM. Appukkuttan P. Azzam R. Dehaen W. Compernolle F. Van der Eycken E. Hoornaert G. Synlett  2005,  777 
    Article in Thieme ConnectGoogle Scholar
  • 23 Buysens K. Ph.D. Thesis   Katholieke Universiteit Leuven; Belgium: 1996. 
    Google Scholar
  • 24 Buysens KJ. Vandenberghe DM. Hoornaert GJ. Tetrahedron  1996,  52:  9161 
    CrossrefGoogle Scholar
  • 25 Vanchuyen N. Kurata T. Fujimaki M. Agric. Biol. Chem.  1973,  37:  327 
    CrossrefGoogle Scholar
  • 26 Matsushita H. Lee S.-H. Yoshida K. Clapham B. Koch G. Zimmermann J. Janda KD. Org. Lett.  2004,  6:  4627 
    CrossrefGoogle Scholar
  • 27 Rombouts F. Ph.D. Thesis   Katholieke Universiteit Leuven; Belgium: 2002. 
    Google Scholar
  • 28 Rombouts FJR. De Borggraeve W. Toppet SM. Compernolle F. Hoornaert GJ. Tetrahedron Lett.  2001,  42:  7397 
    CrossrefGoogle Scholar
  • 29 Rogiers J. De Borggraeve WM. Toppet SM. Compernolle F. Hoornaert GJ. Tetrahedron  2003,  59:  5047 
    CrossrefGoogle Scholar
  • 30 Tutonda M. Vanderzande D. Hendrickx M. Hoornaert G. Tetrahedron  1990,  46:  5715 
    CrossrefGoogle Scholar
  • 31 Tutonda M. Vanderzande D. Vekemans J. Toppet S. Hoornaert G. Tetrahedron Lett.  1986,  27:  2509 
    CrossrefGoogle Scholar
  • 32 Tutonda MG. Vandenberghe SM. Van Aken KJ. Hoornaert GJ. J. Org. Chem.  1992,  57:  2935 
    CrossrefGoogle Scholar
  • 33 Vandenberghe DM. Hoornaert GJ. Bull. Soc. Chim. Belg.  1994,  103:  185 
    Google Scholar
  • 34 Buysens KJ. Vandenberghe DM. Toppet SM. Hoornaert GJ. Tetrahedron  1995,  51:  12463 
    CrossrefGoogle Scholar
  • 35 Buysens KJ. Vandenberghe DM. Toppet SM. Hoornaert GJ. J. Chem. Soc., Perkin Trans. 1  1996,  231 
    CrossrefGoogle Scholar
  • 36 Loosen PK. Khorasani MF. Toppet SM. Hoornaert GJ. Tetrahedron  1991,  47:  9269 
    CrossrefGoogle Scholar
  • 37 Vandenberghe SM. Buysens KJ. Meerpoel L. Loosen PK. Toppet SM. Hoornaert GJ. J. Org. Chem.  1996,  61:  304 
    CrossrefGoogle Scholar
  • 38 Tahri A. Buysens KJ. Van der Eycken EV. Vandenberghe DM. Hoornaert GJ. Tetrahedron  1998,  54:  13211 
    CrossrefGoogle Scholar
  • 39 Tahri A. De Borggraeve W. Buysens K. Van Meervelt L. Compernolle F. Hoornaert GJ. Tetrahedron  1999,  55:  14675 
    CrossrefGoogle Scholar
  • 40 Rombouts FJR. Vanraes DAJ. Wynendaele J. Loosen PK. Luyten I. Toppet S. Compernolle F. Hoornaert GJ. Tetrahedron  2001,  57:  3209 
    CrossrefGoogle Scholar
  • 41 De Borggraeve WM. Rombouts FJR. Verbist BMP. Van der Eycken EV. Hoornaert GJ. Tetrahedron Lett.  2002,  43:  447 
    CrossrefGoogle Scholar
  • 42 Govaerts TC. Vogels IA. Compernolle F. Hoornaert GJ. Tetrahedron  2003,  59:  5481 
    CrossrefGoogle Scholar
  • 43 Rombouts FJR. Van den Bossche J. Toppet SM. Compernolle F. Hoornaert GJ. Tetrahedron  2003,  59:  4721 
    CrossrefGoogle Scholar
  • 44 Govaerts TC. Vogels IA. Compernolle F. Hoornaert GJ. Tetrahedron  2004,  60:  429 
    CrossrefGoogle Scholar
  • 45 Rombouts FJR. De Borggraeve WM. Delaere D. Froeyen M. Toppet SM. Compernolle F. Hoornaert GJ. Eur. J. Org. Chem.  2003,  1868 
    CrossrefGoogle Scholar
  • 46 Vandenberghe S. Ph.D. Thesis   Katholieke Universiteit Leuven; Belgium: 1990. 
    Google Scholar
  • 47 Cappelle SL. Vogels IA. Govaerts TC. Toppet SM. Compernolle F. Hoornaert GJ. Tetrahedron  2002,  58:  3655 
    CrossrefGoogle Scholar
  • 48 Govaerts TC. Vogels I. Compernolle F. Hoornaert G. Tetrahedron Lett.  2002,  43:  799 
    CrossrefGoogle Scholar
  • 49 Kaval N. Ermolat"ev D. Appukkuttan P. Dehaen W. Kappe CO. Van der Eycken E. J. Comb. Chem.  2005,  7:  490 
    CrossrefGoogle Scholar
  • 50 Hopkins C. Neuenschwander K. Scotese A. Jackson S. Nieduzak T. Pauls H. Liang G. Sides K. Cramer D. Cairns J. Maignan S. Mathieu M. Bioorg. Med. Chem. Lett.  2004,  14:  4819 
    CrossrefGoogle Scholar
  • 51 Reiner JE. Siev DV. Araldi G.-L. Cui JJ. Ho JZ. Reddy KM. Mamedova L. Vu PH. Lee K.-SS. Minami NK. Gibson TS. Anderson SM. Bradbury AE. Nolan TG. Semple JE. Bioorg. Med. Chem. Lett.  2002,  12:  1203 
    CrossrefGoogle Scholar
  • 52 Young MB. Barrow JC. Glass KL. Lundell GF. Newton CL. Pellicore JM. Rittle KE. Selnick HG. Stauffer KJ. Vacca JP. Williams PD. Bohn D. Clayton FC. Cook JJ. Krueger JA. Kuo LC. Lewis SD. Lucas BJ. McMasters DR. Miller-Stein C. Pietrak BL. Wallace AA. White RB. Wong B. Yan Y. Nantermet PG. J. Med. Chem.  2004,  47:  2995 
    CrossrefPubMedGoogle Scholar
  • 53 South MS. Case BL. Wood RS. Jones DE. Hayes MJ. Girard TJ. Lachance RM. Nicholson NS. Clare M. Stevens AM. Stegeman RA. Stallings WC. Kurumbail RG. Parlow JJ. Bioorg. Med. Chem. Lett.  2003,  13:  2319 
    CrossrefGoogle Scholar
  • 54 Han Y. Giroux A. Colucci J. Bayly CI. McKay DJ. Roy S. Xanthoudakis S. Vaillancourt J. Rasper DM. Tam J. Tawa P. Nicholson DW. Zamboni RJ. Bioorg. Med. Chem. Lett.  2005,  15:  1173 
    CrossrefGoogle Scholar
  • 55 Miyazaki A. Tsuda Y. Tachibana Y. Yokoi T. Bryant SD. Lazarus LH. Keri G. Okada Y. Biopolymers  2003,  71:  367 
    Google Scholar
  • 56 Breslin MJ. Duggan ME. Halczenko W. Fernandez-Metzler C. Hunt CA. Leu CT. Merkle KM. Naylor-Olsen AM. Prueksaritanont T. Stump G. Wallace A. Rodan SB. Hutchinson JH. Bioorg. Med. Chem. Lett.  2003,  13:  1809 
    CrossrefGoogle Scholar
  • 57 Breslin MJ. Halczenko W. Duggan ME. Gorham L. Fernandez-Metzler C. Hoffman WF. Hunt CA. Leu CT. Merkle K. Nagy R. Naylor-Olsen AM. Prueksaritanont T. Rodan S. Stump G. Wallace A. Hutchinson JH. Abstracts of Papers, 221st National Meeting of the American Chemical Society, San Diego, CA, April 1-5, 2001; American Chemical Society: Washington, DC,  2001,  U46-U47  
    Google Scholar
  • 58 Boehner B, and Meyer W. inventors; US  4940482A.  ; Chem. Abstr. 1991, 114, 42813
  • 59 Parlow JJ. Case BL. Dice TA. Fenton RL. Hayes MJ. Jones DE. Neumann WL. Wood RS. Lachance RM. Girard TJ. Nicholson NS. Clare M. Stegeman RA. Stevens AM. Stallings WC. Kurumbail RG. South MS. J. Med. Chem.  2003,  46:  4050 
    CrossrefGoogle Scholar
  • 60 Sanderson PE, Lyle TA, Dorsey BD, and Varsolona RJ. inventors; WO  9740024A1.  ; Chem. Abstr. 1998, 128, 22922
  • 61 Yaso M, Suzuki Y, Shibata K, and Hayashi E. inventors; JP  62198671A2.  ; Chem. Abstr. 1988, 108, 167501
  • 62 Arvanitis AG, Gilligan PJ, and Hartz RA. inventors; WO  2002092090A1.  ; Chem. Abstr. 2002, 137, 370110
  • 63 Arvanitis AG, Olson RE, Arnold CR, and Frietze WE. inventors; WO  9811075A1.  ; Chem. Abstr. 1998, 128, 244063
  • 64 Boys ML, Clare M, and Mitton-Fry MJ. inventors; WO  2005035527A1.  ; Chem. Abstr. 2005, 142, 411378
  • 65 Liang J, Chakravarty PK, Pan DE, Parsons WH, Shao PP, Ye F, and Zhou B. inventors; WO  2005097136A1.  ; Chem. Abstr. 2005, 143, 387064
  • 66 De Borggraeve WM. Rombouts FJR. Van der Eycken EV. Toppet SM. Hoornaert GJ. Tetrahedron Lett.  2001,  42:  5693 
    CrossrefGoogle Scholar
  • 67 Pawar VG. De Borggraeve WM. Maes V. Tourwé DA. Compernolle F. Hoornaert GJ. Tetrahedron Lett.  2005,  46:  1707 
    CrossrefGoogle Scholar
  • 68 Kamoune L. De Borggraeve WM. Verbist BMP. Vanden Broeck J. Coast GM. Compernolle F. Hoornaert G. Tetrahedron  2005,  61:  9555 
    CrossrefGoogle Scholar
  • 69 Verbist BMP. De Borggraeve WM. Toppet S. Compernolle F. Hoornaert GJ. Eur. J. Org. Chem.  2005,  2941 
    CrossrefGoogle Scholar
  • 70 Kaval N. Van der Eycken J. Caroen J. Dehaen W. Strohmeier GA. Kappe CO. Van der Eycken E. J. Comb. Chem.  2003,  5:  560 
    CrossrefGoogle Scholar
  • 71 Kaval N. Dehaen W. Van der Eycken E. J. Comb. Chem.  2005,  7:  90 
    CrossrefGoogle Scholar