PDF herunterladen
Synthesis 2012(7): 1109-1118  
DOI: 10.1055/s-0031-1289744
PAPER
© Georg Thieme Verlag Stuttgart ˙ New York

SNAr Reactions of 2-Methylthio-4-pyrimidinones in Pivalic Acid: Access to Functionalized Pyrimidinones and Pyrimidines

Matthew L. Maddess*, Rhiannon Carter
Department of Discovery Process Chemistry, Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA
Fax: +1(617)9922403; e-Mail: matthew_maddess@merck.com;
Weitere Informationen

Publikationsverlauf

Received 19 December 2011
Publikationsdatum:
15. März 2012 (online)

    Lizenzen und Reprints Alle Artikel dieser Rubrik

Abstract

Pivalic acid is a useful medium to effect the direct SNAr displacement of 2-methylthio-4-pyrimidinones with a variety of anilines. Products are easily isolated in good to excellent yields, and following chlorination, provide an opportunity to rapidly query structure-activity relationships at the 4-position of functionalized pyrimidines.

Key words

heterocycles - nucleophilic aromatic - solvent effects - medicinal chemistry - regioselectivity

    References

  • 1 Ali OM. Monatsh. Chem.  2007,  138:  917 ; and references cited therein
    Google Scholar
  • 2 Hurst DT. In An Introduction to the Chemistry and Biochemistry of Pyrimidines, Purines and Pteridines   Wiley; Chichester: 1980. 
    Google Scholar
  • 3 Brown DJ. In Comprehensive Heterocyclic Chemistry   Vol. 3:  Katritzky AR. Rees CW. Pergamon Press; Oxford: 1984.  Chap. 2.13.
    Google Scholar
  • 4 Brown DJ. In The Pyrimidines   Wiley Interscience; New York: 1994. 
    Google Scholar
  • 5 Chen X. Zhan P. Li D. De Clercq E. Liu X. Curr. Med. Chem.  2011,  18:  359 
    Google Scholar
  • 6 Sorbera LA. Serradell N. Rosa E. Bolós J. Drugs Future  2007,  32:  1046 
    Google Scholar
  • 7 Wang S. Meades C. Wood G. Osnowski A. Anderson S. Yuill R. Thomas M. Mezna M. Jackson W. Midgley C. Griffiths G. Fleming I. Green S. McNae I. Wu S.-Y. McInnes C. Zheleva D. Walkinshaw MD. Fischer PM. J. Med. Chem.  2004,  47:  1662 
    Google Scholar
  • 8 Bukowski RM. Yasothan U. Kirkpatrick P. Nat. Rev. Drug Discovery  2010,  9:  17 
    Google Scholar
  • 9 Undheim K. Benneche T. Heterocycles  1990,  30:  1155 
    Google Scholar
  • 10 Littke AF. Fu GC. Angew. Chem. Int. Ed.  2002,  41:  4176 
    Google Scholar
  • 11 Schomaker JM. Delia TJ. J. Org. Chem.  2001,  66:  7125 
    Google Scholar
  • 12 Solberg J. Undheim K. Acta Chem. Scand.  1989,  43:  62 
    Google Scholar
  • 13 Edo K. Yamanaka H. Sakamoto T. Heterocycles  1978,  9:  271 
    Google Scholar
  • 14 Delia TJ. Stark D. Glenn SK. J. Heterocycl. Chem.  1995,  32:  1177 
    Google Scholar
  • 15 Schomaker JM. Delia TJ. J. Heterocyl. Chem.  2000,  37:  1457 
    Google Scholar
  • 16 Peng Z.-H. Journet M. Humphrey G. Org. Lett.  2006,  8:  395 
    Google Scholar
  • 17 Zeng Z.-S. Liang Y.-H. Feng X.-Q. Chen F.-E. Pannecouque C. Balzarini J. De Clercq E. ChemMedChem  2010,  5:  837 
    Google Scholar
  • 18 Bamborough P. Angell RM. Bhamra I. Brown D. Bull J. Christopher JA. Cooper AWJ. Fazal LH. Giordano I. Hind L. Patel VK. Ranshaw LE. Sims MJ. Skone PA. Smith KJ. Vickerstaff E. Washington M. Bioorg. Med. Chem. Lett.  2007,  17:  4363 
    Google Scholar
  • 19 Waelchi R. Bollbuck B. Bruns C. Buhl T. Eder J. Feifel R. Hersperger R. Janser P. Revesz L. Zerwes H.-G. Schlapbach A. Bioorg. Med. Chem. Lett.  2006,  16:  108 
    Google Scholar
  • 20 Manley PJ. Balitza AE. Bilodeau MT. Coll KE. Hartman GD. McFall RC. Rickert KW. Rodman LD. Thomas KA. Bioorg. Med. Chem. Lett.  2003,  13:  1673 
    Google Scholar
  • 21 2-Methylthio-4-pyrimidinone may also be readily prepared from 2-thiouracil: Barrett HW. Goodman I. Dittmer K. J. Am. Chem. Soc.  1948,  70:  1753 
    Google Scholar
  • 22a Spychala J. Synth. Commun.  1997,  27:  1943 
    Google Scholar
  • For a recent report using refluxing BuOH, see:
  • 22b Grigoryan LA. Kaldrikyan MA. Melik-Ogandzhanyan RG. Arsenyan FG. Pharm. Chem. J.  2011,  45:  137 
    Google Scholar
  • 23 Conversion of thioethers into the corresponding sulfone is a common strategy to increase reactivity of the electrophile, but used rarely in the context of 2-methylthio-4-pyrimidi-nones, for example, see: Gibson CL. Huggan JK. Kennedy A. Kiefer L. Lee JH. Suckling CJ. Clements C. Harvey AL. Hunter WN. Tulloch LB. Org. Biomol. Chem.  2009,  7:  1829 
    Google Scholar
  • 24 Djung JF.-J, Golebiowski A, Hunter JA, and Shrum GP. inventors; US Patent Appl. Publ. US 20070293525  A1. For example, see example 2, page 15, of: ; Chem. Abstr. 2008, 148, 79042
  • 25 Feng X.-Q. Liang Y.-H. Zeng Z.-S. Chen F.-E. Balzarini J. Pannecouque C. De Clercq E. ChemMedChem  2009,  4:  219 
    Google Scholar
  • 28 Pivalic acid (bp 164 ˚C/760 Torr) offers the additional advantage of a wider convenient temperature operating range relative to AcOH (bp 119 ˚C/760 Torr)
  • 31 Sakamoto T. Kondo Y. Watanabe R. Yamanaka H. Chem. Pharm. Bull.  1986,  34:  2719 
    Google Scholar
  • 32 Gacek M. Undheim K. Acta Chem. Scand.  1982,  B36:  15 
    Google Scholar
  • 33 Mitchell SA, Currie KS, Blomgren PA, Kropf JE, Lee SH, Xu J, Stafford DG, Harding JP, Barbosa AJ, and Zhao Z. inventors; Patent PCT Int. Appl. WO 2010068257  A1. For example, see example 2, page 15, of: ; Chem. Abstr. 2010, 153, 87827
  • 35 Casillas LN, Chakravorty SJ, Charnley AK, Eidam P, Haile PA, Hughes TV, Jeong JU, Kang J, Lakdawala SA, Leister LK, Marquis RW, Miller NA, Price DJ, Sehon CL, Wang GZ, and Zhang D. inventors; Patent PCT Int. Appl. WO 2011120025  A1.  ; Chem. Abstr. 2011, 155, 484157
  • 36 Curd FHS. Richardson DN. Rose FL. J. Chem. Soc.  1946,  378 
    Google Scholar
  • 37 Johnson TB. Storey WF. Am. Chem. J.  1909,  40:  131 
    Google Scholar
  • 38 Tsuruoka H, Kanno Y, and Tatsuta T. inventors; Patent PCT Int. Appl. WO 2003091223  A1.  ; Chem. Abstr. 2003, 139, 364950
26

Reactions performed on 1 mmol scale in sealed vials.

27

Three examples have been previously reported in which AcOH was used as a solvent for SNAr reactions of 2-methylthio-4-pyrimidinones (see ref. 1).

29

Methanethiol is generated during the course of the reaction; a nitrogen sweep is recommended especially on large scale with the outlet bubbled through a bleach scrubber.

30

Efficient stirring is recommended and should it become ineffective additional PivOH can be added.

34

Variable levels of pivalic acid (up to 1 molar equiv) were observed in the isolated 2-anilinopyrimidinones. This was not found to be problematic in subsequent halogenation at the 4- or 5-position.