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Synthesis 2013; 45(24): 3404-3412
DOI: 10.1055/s-0033-1339977
paper
© Georg Thieme Verlag Stuttgart · New York

A Novel Synthesis of Tetrahydropyrazolo[1,5-c]pyrimidine-2,7(1H,3H)-diones

Jona Mirnik
a   Faculty of Chemistry and Chemical Technology, University of Ljubljana, Aškerčeva 5, 1000 Ljubljana, Slovenia   Fax: +386(1)2419360   Email: Jurij.svete@fkkt.uni-lj.si
,
Uroš Grošelj*
a   Faculty of Chemistry and Chemical Technology, University of Ljubljana, Aškerčeva 5, 1000 Ljubljana, Slovenia   Fax: +386(1)2419360   Email: Jurij.svete@fkkt.uni-lj.si
,
Ana Novak
a   Faculty of Chemistry and Chemical Technology, University of Ljubljana, Aškerčeva 5, 1000 Ljubljana, Slovenia   Fax: +386(1)2419360   Email: Jurij.svete@fkkt.uni-lj.si
,
Georg Dahmann
b   Boehringer Ingelheim Pharma GmbH & Co. KG, Medicinal Chemistry, 88397 Biberach, Germany
,
Amalija Golobič
a   Faculty of Chemistry and Chemical Technology, University of Ljubljana, Aškerčeva 5, 1000 Ljubljana, Slovenia   Fax: +386(1)2419360   Email: Jurij.svete@fkkt.uni-lj.si
,
Marta Kasunič
a   Faculty of Chemistry and Chemical Technology, University of Ljubljana, Aškerčeva 5, 1000 Ljubljana, Slovenia   Fax: +386(1)2419360   Email: Jurij.svete@fkkt.uni-lj.si
,
Branko Stanovnik
a   Faculty of Chemistry and Chemical Technology, University of Ljubljana, Aškerčeva 5, 1000 Ljubljana, Slovenia   Fax: +386(1)2419360   Email: Jurij.svete@fkkt.uni-lj.si
,
Jurij Svete*
a   Faculty of Chemistry and Chemical Technology, University of Ljubljana, Aškerčeva 5, 1000 Ljubljana, Slovenia   Fax: +386(1)2419360   Email: Jurij.svete@fkkt.uni-lj.si
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Further Information

Publication History

Received: 19 July 2013

Accepted after revision: 18 September 2013

Publication Date:
18 October 2013 (online)

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Abstract

A novel simple five-step synthesis of 1,6-disubstituted tetrahydropyrazolo[1,5-c]pyrimidine-2,7(1H,3H)-diones has been developed. The synthetic protocol starts with ‘ring switching’ transformation of commercially available 5,6-dihydro-2H-pyran-2-one into the 5-(2-hydroxyethyl)pyrazolidin-3-one, followed by addition of the latter to isocyanates, Appel bromination, cyclization, and N(1)-alkylation with alkyl halides to give the title compounds. In comparison to a 12-step synthesis reported recently, the present method is clearly superior with respect to the number of synthetic steps and versatility of substituents at position 6.

Key words

pyrazolo[1,5-c]pyrimidines - ring-switching - cyclization - saturated heterocycles - 3-pyrazolidinones

Supporting Information

    for this article is available online at http://www.thieme-connect.com/ejournals/toc/synthesis. Included are 1H and 13C NMR spectra of compounds 4, 6, and 8–10, as well as ORTEP views and diffraction data for compounds 8b, 10d, and 4f.
  • Supporting Information
 

  • References

    • 1a Joule JA, Mills K. Heterocyclic Chemistry . 5th ed. Wiley-Blackwell; New York: 2010
      Google Scholar
    • 1b Patrick GL. An Introduction to Medicinal Chemistry . 4th ed. Oxford University Press; Oxford: 2009
      Google Scholar
    • 1c Pernerstorfer J. Molecular Design and Combinatorial Compound Libraries. In Handbook of Combinatorial Chemistry. Drugs, Catalysts, Materials. Vol. 2. Nicolaou KC, Hanko R, Hartwig W. Wiley-VCH; Weinheim: 2002: 725
      Google Scholar
    • 1d Dolle RE. Solid-phase Synthesis of Heterocyclic Systems (Heterocycles Containing One Heteroatom). In Handbook of Combinatorial Chemistry. Drugs, Catalysts, Materials. Vol. 2. Nicolaou KC, Hanko R, Hartwig W. Wiley-VCH; Weinheim: 2002: 643
      Google Scholar
    • 2a Hajos G, Riedl Z. Aza Analogues of Pyrazolo[1,5-a]pyridines Containing Additional Nitrogen Atoms in the Six-Membered Ring. In Science of Synthesis. Vol. 12. Neier R. Thieme; Stuttgart: 2006: 667
      Google Scholar
    • 2b Regan AC. Pyrazolo[1,5-c]pyrimidine . In Comprehensive Heterocyclic Chemistry III . Vol. 11. Katritzky AR, Ramsden CA, Scriven EF. V, Taylor RJ. K. Cossy, J.; Elsevier Science Ltd; Oxford: 2008: 577
      Google Scholar
    • 2c Sliskovic DR. Pyrazolo[1,5-c]pyrimidine . In Comprehensive Heterocyclic Chemistry III . Vol. 8. Katritzky AR, Rees CV, Scriven EF. V. Elsevier Science Ltd; Oxford: 1996: 362 ; and references cited therein
      Google Scholar
    • 3a Maier T, Baer T, Lindenmaier A, Vennemann M, Braunger J, Boehm M, Gekeler V, Zimmermann A. PCT Int. Appl WO 2007144384, 2007 ; Chem. Abstr. 2007, 148, 79077.
    • 3b Mallams AK, Madison V, Paruch K. PCT Int. Appl WO 2007032936, 2007 ; Chem. Abstr. 2007, 146, 358880.
    • 3c Maier T, Zuelch A, Ciossek T, Baer T, Beckers T. PCT Int. Appl WO 2006027346, 2006 ; Chem. Abstr. 2006, 144, 350709.
    • 4a Gudmundsson K, Johns BA. PCT Int. Appl WO 2003076441, 2003 ; Chem. Abstr. 2003, 139, 261327.
    • 4b Gudmundsson KS, Johns BA, Waterhead J. Bioorg. Med. Chem. Lett. 2009; 19: 5689
      Crossref
  • 5 Casebier D. PCT Int. Appl WO 2010091303, 2010 ; Chem. Abstr. 2010, 153, 260549.
    • 6a Kahraman M, Smith ND, Bonnefous C, Noble SA, Payne JE. PCT Int. Appl WO 2010088518, 2010 ; Chem. Abstr. 2010, 153, 260364.
    • 6b Smith ND, Bonnefous C, Kahraman M, Noble SA, Payne JE, Govek SP. PCT Int. Appl WO 2010048149, 2010 ; Chem. Abstr. 2010, 152, 501397.
    • 7a Atta KF. M, Farahat OO. M, Ghobashy M, Marei MG. Molecules 2011; 16: 10387
      Crossref
    • 7b Atta KF. M, Marei MG, Abd El-MagiadS. M, El-Nashar FH. A. Heterocycles 2011; 83: 1873
      Crossref
  • 8 Lee W.-C, Carter MB, Sun L, Lyne P, Chuaqui C, Zheng Z, Singh J, Boriack-Sjodin P. PCT Int. Appl WO 2004022054, 2004 ; Chem. Abstr. 2004, 140, 270867.
    • 9a Kaneko Y, Kita H, Ikesu S. Jpn. Kokai Tokkyo Koho JP 04283272, 1992 ; Chem. Abstr. 1992, 119, 74607.
    • 9b Kaneko Y, Kita H, Ikesu S. Jpn. Kokai Tokkyo Koho JP 04204441, 1992 ; Chem. Abstr. 1992, 118, 90726.
    • 9c Yamakawa K, Ishii Y. Jpn. Kokai Tokkyo Koho JP 04191736, 1992 ; Chem. Abstr. 1992, 117, 261569.
    • 9d Kaneko Y. Jpn. Kokai Tokkyo Koho JP 02236545, 1990 ; Chem. Abstr. 1990, 115, 18490.
  • 10 Mahgoub FM, Abdel-Nabey BA, El-Samadisy YA. Mater Chem. Phys. 2010; 120: 104
    Crossref
  • 11 Grošelj U, Podlogar A, Novak A, Dahmann G, Golobič A, Stanovnik B, Svete J. Synthesis 2013; 45: 639
    Article in Thieme Connect
    • 12a Svete J. (4R*,5R*)-4-Benzoylamino-5-phenyl-3-pyrazolidinone – A Useful Building Block in the Synthesis of Functionalized Pyrazoles. Horvat MA, Golob JH. Nova Science Publishers; New York: 2008: 129 ; (open-access item, the pdf is available at https://www.novapublishers.com/catalog/product_info.php?products_id=16416); and references cited therein
      Google Scholar
    • 12b Novak A, Testen A, Bezenšek J, Grošelj U, Hrast M, Kasunič M, Gobec S, Stanovnik B, Svete J. Tetrahedron 2013; 69: 6648 ; and references cited therein
      Crossref
    • 13a Grošelj U, Kralj D, Wagger J, Dahmann G, Stanovnik B, Svete J. ARKIVOC 2012; (iii): 49 ; and references cited therein
    • 13b Perdih P, Baškovč J, Dahmann G, Grošelj U, Kočar D, Stanovnik B, Svete J. Synthesis 2011; 2822
      Article in Thieme Connect
    • 13c Žerovnik D, Grošelj U, Kralj D, Malavašič Č, Bezenšek J, Dahmann G, Stare K, Meden A, Stanovnik B, Svete J. Synthesis 2010; 3363
      Article in Thieme Connect
  • 14 Farrugia LJ. J. Appl. Crystallogr. 1997; 30: 565
  • 15 Structural and other crystallographic data have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication numbers CCDC 941194–941199 for compounds 4b, 4f, 8a, 8b, 10a, and 10d, respectively. A copy of the data can be obtained, free of charge, by applying to CCDC, 12 Union Road, Cambridge, CB2 1EZ, UK [fax: +44(1223)336033 or e-mail: deposit@ccdc.cam.ac.uk].