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

Abstract

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

quinazolines - benzannulation - alkynes - cyclization

References and Notes

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7

Crystal structure analysis for 3a: C₂₁H₂₁N₃O₂S, M_r = 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) Å^³, ρ = 1.320 g/cm^³, F(000) = 800. X-ray diffraction data were collected on a Nonius Kappa CCD diffractometer at 293 K using graphite-monochromated Mo-K_α radiation (λ = 0.71073 Å). Structure 3a was solved by direct methods with SIR97 program^¹¹ 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 ORTEP^¹³ 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).

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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.

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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.