A Novel Synthesis of Disubstituted Quinazoline Diones with Differential N-Substitution via a Copper-Catalysed Cross-Coupling of Acyl Ureas

Abstract

An efficient method for the synthesis of disubstituted quinazoline diones with differential N-substitution is reported. A wide range of substitutions on the aromatic and dione rings are tolerated, and the reaction proceeds in high yields under mild conditions.

Key words

acyl ureas - quinazoline diones - copper-catalysed - Ullmann - intramolecular cyclisation

• References and Notes

• 1 New address: Emma Durham, Department of Chemistry, University of Cambridge, Cambridge, CB2 1EW, UK.
• 2 New address: Jimmy Wang, Department of Chemistry, University of Warwick, Coventry, CV4 7AL, UK.
• 3 New address: Sam Watson, School of Chemistry, University of St. Andrews, St. Andrews, KY16 9ST, UK.
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• 16 General Procedure (Table 2, Entry 1) Copper(I) iodide (0.019 g, 0.10 mmol) was added to N-(ethylcarbamoyl)-2-iodo-N-methylbenzamide (0.33 g, 0.99 mmol), (2S,4R)-4-hydroxypyrrolidine-2-carboxylic acid (0.026 g, 0.20 mmol), and K₂CO₃ (0.412 g, 2.98 mmol) in DMF (18 mL) at 20 °C under nitrogen. The resulting suspension was stirred at 50 °C for 5 h. The reaction mixture was filtered to remove the K₂CO₃ and evaporated under reduced pressure to remove the DMF. The residue was purified by flash silica chromatography, elution gradient 0–100% EtOAc in heptane. Pure fractions were evaporated to dryness to afford 1-ethyl-3-methylquinazoline-2,4(1H,3H)-dione (0.160 g, 79%) as a white crystalline solid. ¹H NMR (400 MHz, CDCl₃): δ = 1.36 (t, J = 7.1 Hz, 3 H), 3.49 (s, 3 H), 4.21 (q, J = 7.1 Hz, 2 H), 7.19–7.25 (m, 2 H), 7.67 (ddd, J = 1.7, 7.3, 8.5 Hz, 1 H), 8.25 (ddd, J = 0.4, 1.6, 7.9 Hz, 1 H). ¹³C NMR (101 MHz, CDCl₃): δ = 12.59, 28.35, 38.81, 113.33, 115.74, 122.71, 129.17, 134.97, 139.51, 150.79, 162.00. MS (ES⁺): m/z = 205.0973 [M + H]⁺. For complete data, see Supporting Information.