Copper-Powder-Catalyzed Synthesis of Pyrimidines from β-Bromo α,β-Unsaturated Ketones and Amidine Hydrochlorides

Abstract

β-Bromo α,β-unsaturated ketones are coupled and cyclized with amidine hydrochlorides in the presence of a catalytic amount of copper powder along with a base to give the corresponding pyrimidines in good yields.

Key words

copper - coupling - cyclization - heterocycles - hetero­geneous catalysis

• References and Notes

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• 21 Pyrimidines 3 – General Procedure To a 5 mL screw-capped vial was added β-bromo α,β-unsaturated ketone 1 (0.5 mmol) and amidine hydrochloride 2 (0.75 mmol), together with copper powder (Shinyo Pure Chemicals Co., 0.05 mmol), K₃PO₄ (1.5 mmol), and DMF (3 mL). The reaction mixture was stirred at 110 °C for 24 h. The mixture was then cooled to r.t. and filtered through a short column of silica gel (EtOAc) to remove inorganic salts. Removal of the solvent left a crude mixture, which was separated by TLC [silica gel 60 GF254 (Merck), EtOAc–hexane] to give desired products. Except for known 3e ²³ and 3l,²⁴ all new products were characterized spectroscopically as shown below. 4-Pentyl-2-phenyl-5,6,7,8-tetrahydroquinazoline (3a) Oil; yield 107 mg (76%). ¹H NMR (400 MHz, CDCl₃): δ = 0.93 (t, J = 7.1 Hz, 3 H), 1.34–1.45 (m, 4 H), 1.76–1.91 (m, 6 H), 2.69–2.74 (m, 4 H), 2.90–2.93 (m, 2 H), 7.39–7.47 (m, 3 H), 8.38–8.41 (m, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 14.28, 22.51, 22.80, 22.86, 24.71, 27.51, 32.06, 32.91, 34.34, 128.08, 128.54, 129.89, 138.77, 161.19, 165.16, 168.71. HRMS (EI): m/z [M⁺] calcd for C₁₉H₂₄N₂: 280.1939; found: 280.1941. 2-Methyl-4-pentyl-5,6,7,8-tetrahydroquinazoline (3b) Oil; yield 75 mg (69%). ¹H NMR (400 MHz, CDCl₃): δ = 0.89–0.92 (m, 3 H), 1.33–1.41 (m, 4 H), 1.61–1.68 (m, 2 H), 1.80–1.88 (m, 4 H), 2.60–2.68 (m, 4 H), 2.62 (s, 3 H), 2.80–2.83 (m, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 14.14, 22.37, 22.67, 22.75, 24.41, 25.81, 28.21, 32.14, 32.53, 34.58, 124.23, 164.08, 164.96, 168.75. HRMS (EI): m/z [M⁺] calcd for C₁₄H₂₂N₂: 218.1783; found: 218.1782. 4-Isopropyl-2-phenyl-5,6,7,8-tetrahydroquinazoline (3c) Solid; yield 86 mg (68%); mp 82–83 °C. ¹H NMR (400 MHz, CDCl₃): δ = 1.30 (d, J = 6.5 Hz, 6 H), 1.83–1.89 (m, 4 H), 2.72–2.74 (m, 2 H), 2.90–2.92 (m, 2 H), 3.19 (sept, J = 6.5 Hz, 1 H), 7.38–7.46 (m, 3 H), 8.44–8.46 (m, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 21.32, 22.42, 22.90, 24.32, 30.71, 33.02, 124.47, 128.07, 128.44, 129.86, 138.88, 161.13, 165.27, 172.71. HRMS (EI): m/z [M⁺] calcd for C₁₇H₂₀N₂: 252.1626; found: 252.1624. 4-Isopropyl-2-methyl-5,6,7,8-tetrahydroquinazoline (3d) Oil; yield 53 mg (56%). ¹H NMR (400 MHz, CDCl₃): δ = 1.22 (d, J = 6.5 Hz, 6 H), 1.82–1.85 (m, 4 H), 2.62 (s, 3 H), 2.67–2.69 (m, 2 H), 2.80–2.82 (m, 2 H), 3.14 (quint, J = 6.5 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 21.21, 22.38, 22.92, 24.17, 26.02, 30.43, 32.75, 123.23, 164.39, 164.83, 172.89. HRMS (EI): m/z [M⁺] calcd for C₁₂H₁₈N₂: 190.1470; found: 190.1467. 2-Methyl-4-phenyl-5,6,7,8-tetrahydroquinazoline (3f) Oil; yield 53 mg (47%). ¹H NMR (400 MHz, CDCl₃): δ = 1.71–1.76 (m, 2 H), 1.89–1.94 (m, 2 H), 2.67–2.69 (m, 2 H), 2.71 (s, 3 H), 2.91–2.94 (m, 2 H), 7.40–7.46 (m, 3 H), 7.50–7.52 (m, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 22.51, 22.93, 25.91, 26.66, 32.58, 124.43, 128.43, 128.75, 129.00, 138.53, 164.57, 165.48, 166.46. HRMS (EI): m/z [M⁺] calcd for C₁₅H₁₆N₂: 224.1313; found: 224.1311. 2,6-Dimethyl-4-pentyl-5,6,7,8-tetrahydroquinazoline (3g) Oil; yield 66 mg (57%). ¹H NMR (400 MHz, CDCl₃): δ = 0.91 (t, J = 7.1 Hz, 3 H), 1.12 (d, J = 6.6 Hz, 3 H), 1.31–1.50 (m, 5 H), 1.61–1.69 (m, 2 H), 1.82–1.97 (m, 2 H), 2.17–2.25 (m, 1 H), 2.61–2.66 (m, 2 H), 2.62 (s, 3 H), 2.76–2.89 (m, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 14.11, 21.86, 22.64, 25.76, 28.18, 28.97, 30.42, 32.09, 32.22, 32.88, 34.55, 123.80, 164.07, 164.69, 168.64. HRMS (EI): m/z [M⁺] calcd for C₁₅H₂₄N₂: 232.1939; found: 232.1941. 2-Methyl-4-pentyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine (3h) Oil; yield 72 mg (70%). ¹H NMR (400 MHz, CDCl₃): δ = 0.90 (t, J = 7.0 Hz, 3 H), 1.33–1.37 (m, 4 H), 1.66–1.69 (m, 2 H), 2.08–2.14 (m, 2 H), 2.64 (t, J = 8.0 Hz, 2 H), 2.67 (s, 3 H), 2.89 (t, J = 7.5 Hz, 2 H), 2.96 (t, J = 8.0 Hz, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 14.14, 22.12, 22.67, 25.91, 28.17, 28.26, 31.96, 34.31, 35.86, 129.26, 165.52, 166.07, 174.25. Anal. Calcd for C₁₃H₂₀N₂: C, 76.42; H, 9.87; N, 13.71. Found: C, 76.28; H, 9.80; N, 13.75. 2-Methyl-4-pentyl-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidine (3i) Oil; yield 78 mg (67%). ¹H NMR (400 MHz, CDCl₃): δ = 0.90 (t, J = 7.0 Hz, 3 H), 1.31–1.42 (m, 4 H), 1.57–1.71 (m, 6 H), 1.84–1.90 (m, 2 H), 2.62 (s, 3 H), 2.72–2.79 (m, 4 H), 2.92–2.95 (m, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 14.12, 22.65, 25.79, 26.00, 27.43, 27.77, 29.42, 32.05, 32.34, 35.72, 38.78, 129.66, 164.08, 166.87, 171.16. HRMS (EI): m/z [M⁺] calcd for C₁₅H₂₄N₂: 232.1939; found: 232.1940. 2-Methyl-4-pentyl-5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidine (3j) Oil; yield 74 mg (60%). ¹H NMR (400 MHz, CDCl₃): δ = 0.91 (t, J = 7.1 Hz, 3 H), 1.33–1.47 (m, 8 H), 1.63–1.73 (m, 4 H), 1.76–1.82 (m, 2 H), 2.64 (s, 3 H), 2.68–2.72 (m, 2 H), 2.78–2.81 (m, 2 H), 2.86–2.89 (m, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 14.18, 22.73, 25.53, 25.91, 25.94, 26.47, 29.54, 30.39, 30.50, 32.23, 34.90, 35.10, 127.16, 164.74, 167.83, 169.37. HRMS (EI): m/z [M⁺] calcd for C₁₆H₂₆N₂: 246.2096; found: 246.2095. 2-Methyl-4-pentyl-5,6,7,8,9,10,11,12,13,14-decahydrocyclododeca[d]pyrimidine (3k) Oil; yield 91 mg (60%). ¹H NMR (400 MHz, CDCl₃): δ = 0.91 (m, J = 7.1 Hz, 3 H), 1.31–1.72 (m, 20 H), 1.81–1.88 (m, 2 H), 2.62 (s, 3 H), 2.66–2.76 (m, 6 H). ¹³C NMR (100 MHz, CDCl₃): δ = 14.18, 22.48, 22.75, 23.12, 25.21, 25.88, 26.04, 26.57, 26.90, 27.42, 27.83, 28.57, 29.62, 32.23, 32.26, 35.01, 127.49, 164.22, 168.80, 169.20. HRMS (EI): m/z [M⁺] calcd for C₂₀H₃₄N₂: 302.2722; found: 302.2719. 2-Methyl-4-pentyl-5,6-diphenylpyrimidine (3m) Solid; yield 55 mg (35%); mp 62–64 °C. ¹H NMR (400 MHz, CDCl₃): δ = 0.70–0.74 (m, 3 H), 1.09–1.14 (m, 4 H), 1.49–1.57 (m, 2 H), 2.51–2.55 (m, 2 H), 2.74 (s, 3 H), 7.00–7.02 (m, 2 H), 7.08–7.14 (m, 3 H), 7.19–7.24 (m, 5 H). ¹³C NMR (100 MHz, CDCl₃): δ = 14.07, 22.45, 26.36, 29.25, 31.93, 35.71, 127.62, 127.97, 128.53, 128.63, 129.37, 129.78, 130.48, 136.74, 138.76, 164.17, 166.47, 169.65. HRMS (EI): m/z [M⁺] calcd for C₂₂H₂₄N₂: 316.1939; found: 316.1938.
• 22 A reviewer suggested that the present reaction might be tolerant of several functional groups such as hydroxy, amino, and ester. However, it is difficult to examine such functional-group compatibility at present since the synthetic course of the starting 1 uses Grignard reagents as a step. Thus, further application of this method to the synthesis of such functional-group-containing pyrimidines needs more elaborate plans.
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