Download PDF
Synlett 2009(2): 284-286  
DOI: 10.1055/s-0028-1087514
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

The First and Efficient Synthesis of 7-Aryl-6-methoxycarbonylquinazolines via Unexpected Reaction of 6-Arylethynylpyrimidine-5-carbaldehydes and Methyl Mercaptoacetate

Inga Cikotiene*, Marius Morkunas
Department of Organic Chemistry, Faculty of Chemistry, Vilnius University, Naugarduko 24, 03225 Vilnius, Lithuania
Fax: +370(5)2330987; e-Mail: inga.cikotiene@chf.vu.lt;
Further Information

Publication History

Received 30 September 2008
Publication Date:
15 January 2009 (online)

   Permissions and Reprints All articles of this category
Preview

Abstract

A highly concise synthesis of 7-aryl-6-methoxycarbonylquinazolines via reaction of 6-arylethynylpyrimidine-5-carbaldehydes and methyl mercaptoacetate is described.

Key words

quinazolines - benzannulation - alkynes - cyclization

    References and Notes

  • 1a Smaill JB. Rewcastle GW. Bridges AJ. Zhou H. Showalter HDH. Fry DW. Nelson JM. Sherwood V. Elliott WL. Vincent PW. DeJohn DE. Loo JA. Greis KD. Chan OH. Reyner EL. Lipka E. Denny WA. J. Med. Chem.  2000,  43:  3199 
    Search in Google Scholar
  • 1b Eckhardt M. Langkopf E. Mark M. Tadayyon M. Thomas L. Nar H. Pfrengle W. Guth B. Lotz R. Sieger P. Fuchs H. Himmelsbach F. J. Med. Chem.  2007,  50:  6450 
    Search in Google Scholar
  • 1c Bavetsias V. Skelton LA. Yafai F. Mitchell F. Wilson SC. Allan B. Jackman AL. J. Med. Chem.  2002,  45:  3692 
    Search in Google Scholar
  • 1d Tsou H.-R. Mamuya N. Johnson BD. Reich MF. Gruber BC. Ye F. Nilakantan R. Shen R. Discafani C. DeBlanc R. Davis R. Koehn FE. Greenberger LM. Wang Y.-F. Wissner A. J. Med. Chem.  2001,  44:  2719 
    Search in Google Scholar
  • 1e Gackenheimer SL. Schaus JM. Gehlert DR. J. Pharmacol. Exp. Ther.  1995,  274:  1558 
    Search in Google Scholar
  • 1f Dempcy RO. Skibo EB. Biochemistry  1991,  30:  8480 
    Search in Google Scholar
  • 2a Connolly DJ. Cusack D. O’Sullivan TP. Guiry PJ. Tetrahedron  2005,  61:  10153 
    Search in Google Scholar
  • 2b Hill MD. Movassaghi M. Chem. Eur. J.  2008,  14:  6836 
    Search in Google Scholar
  • 2c Nikpour F. Paibast T. Chem. Lett.  2005,  34:  1438 
    Search in Google Scholar
  • 3a Wada A. Yamamoto H. Ohki K. Nagai S. Kanatomo S. J. Heterocycl. Chem.  1992,  29:  911 
    Search in Google Scholar
  • 3b Kim SK. Russel KC. J. Org. Chem.  1998,  63:  8229 
    Search in Google Scholar
  • 4a Cikotiene I. Buksnaitiene R. Brukstus A. Chem. Heterocycl. Comp.  2007,  43:  515 
    Search in Google Scholar
  • 4b Cikotiene I. Morkunas M. Rudys S. Buksnaitiene R. Brukstus A. Synlett  2008, 2799
  • 5 Cikotiene I. Morkunas M. Motiejaitis D. Rudys S. Brukstus A. Synlett  2008,  1693 
    Thieme Connect
  • 6 Cikotiene I. Pudziuvelyte E. Brukstus A. Tumkevicius S. Tetrahedron  2007,  63:  8145 
    CrossrefSearch in Google Scholar
  • 8a Scott GP. J. Am. Chem. Soc.  1953,  75:  6332 
    Search in Google Scholar
  • 8b Dimroth K. Lenke G. Chem. Ber.  1956,  89:  2608 
    Search in Google Scholar
  • 11 Altomare A. Burla MC. Camalli M. Cascarano GL. Giacovazzo C. Guagliardi A. Moliterni AGG. Polidori G. Spagna R. J. Appl. Crystallogr.  1999,  32:  115 
    CrossrefSearch in Google Scholar
  • 12 Sheldrick GM. SHELXL97, Program for the Refinement of Crystal Structures   University of Göttingen; Germany: 1997. 
  • 13 Johnson CK. ORTEP-II, Report ORNL-5138   Oak Ridge National Laboratory; Oak Ridge TN (USA): 1976. 
7

Crystal structure analysis for 3a: C21H21N3O2S, Mr = 379.47 g mol-¹, monoclinic, space group P21/a, a = 7.5916 (2), b = 19.0791 (4), c = 13.2219 (4) Å, α = 90.00˚, β = 94.3120 (9)˚, γ = 90.00˚, V = 1909.65 (9) ų, ρ = 1.320 g/cm³, F(000) = 800. X-ray diffraction data were collected on a Nonius Kappa CCD diffractometer at 293 K using graphite-monochromated Mo-Kα radiation (λ = 0.71073 Å). Structure 3a was solved by direct methods with SIR97 program¹¹ and refined by full-matrix least squares techniques with anisotropic non-hydrogen atoms. Hydrogen atoms were refined in the riding model. The refinement calculations were carried out with the help of SHELX97 program.¹² ORTEP¹³ view of the molecule is shown in Figure  [¹] . Crystallographic data for structure 3a have been deposited at the Cambridge Crystallographic Data Centre (CCDC number 703429).

9

Typical Procedure for the Preparation of 2,4-Disub-stituted 7-Aryl-6-methoxycarbonylquinazolines 3a-o: To a solution of the corresponding 6-arylethynylpyrimidine-5-carbaldehyde 1a-o (0.3 mmol) in methanol (5 mL) a solution of potassium salt of methyl mercaptoacetate, prepared from potassium (11.7 mg, 0.3 mmol), methyl mercaptoacetate (31.8 mg, 0.3 mmol) and methanol (3 mL) was added. The resulting reaction mixture was stirred for 2 h at r.t. The solvent was evaporated under reduced pressure, the residue was washed with H2O, filtered and recrystallized to give compounds 3a-o.
6-Methoxycarbonyl-2-methylthio-7-phenyl-4-pyrroli-dinoquinazoline (3a): yield: 86%; mp 185-187 ˚C (from MeOH). IR (KBr): 1708 (C=O) cm-¹. ¹H NMR (300 MHz, DMSO-d 6): δ = 2.01 [br s, 4 H, (CH2)2], 2.54 (s, 3 H, SMe), 3.62 (s, 3 H, OMe), 3.92 [br s, 4 H, N(CH2)2], 7.37-7.47 (m, 5 H, ArH), 7.45 (s, 1 H, CH), 8.64 (s, 1 H, CH). ¹³C NMR (75 MHz, DMSO-d 6): δ = 13.4, 25.0, 50.6, 51.9, 11.9, 125.0, 127.2, 127.6, 127.9, 128.1, 129.2, 139.7, 144.8, 152.9, 157.5, 167.4, 168.7. Anal. Calcd for C21H21N3O2S: C, 66.47; H, 5.58; N, 11.07. Found: C, 66.37; H, 5.53; N, 11.11.

10

Compounds 2a,b and 3b-o were also fully characterized by IR, ¹H NMR, ¹³C NMR spectroscopic and microanalytical data.