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DOI: 10.1055/s-2006-941604
A Facile Synthesis of an Oxazolo[5,4]pyrimidin-2-one and a Pyrimido[5,4][1,3]oxazin-2-one
Publication History
Publication Date:
12 June 2006 (online)
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Abstract
A facile synthesis is reported for the construction of the five- and six-membered fused carbamate rings of an oxazolo[5,4]pyrimidin-2-one and a pyrimido[5,4][1,3]oxazin-2-one, respectively. The method utilises a controlled two-step procedure in which a reactive p-nitrophenylcarbamate intermediate ring closes upon treatment with base, affording the bicyclic pyrimidine-carbamate scaffolds in good yields.
Key words
pyrimidines - cyclic carbamates - ring-closing - heterocyclic chemistry
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Synthesis of 4-Nitrophenyl Benzyl(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)carbamate ( 4). N,N′-Diethyltrimethylsilylamine (5.5 mL, 30.32 mmol) was added to a suspension of 5-(benzylamino)uracil (1.75 g, 7.58 mmol) in THF (120 mL) and the resulting mixture was heated to reflux for 1 h, affording a clear solution. The reaction mixture was cooled to ambient temperature and subsequently all volatiles were removed in vacuo, affording the disilylated intermediate as a sticky white residue. The intermediate was dissolved in THF (120 mL) and cooled to 0 °C. Then, Et3N (1.02 mL, 7.58 mmol) was added, followed by the dropwise addition of p-nitrophenyl chloroformate in THF (10 mL). The temperature of the resulting mixture was allowed to rise to r.t. and stirring was continued for 3 h. The reaction mixture was filtered to remove Et3N salts and H2O (5 mL) was added to the filtrate to hydrolyse the trimethylsilyl-oxygen bonds. Next, the THF layer was concentrated to dryness, leaving a yellow solid. This solid was redissolved in THF (50 mL) and filtered to remove traces of insoluble material. The filtrate was concentrated to ca. 20 mL and upon addition of Et2O (ca. 20 mL), an off-white solid precipitated. This precipitate was collected by filtration, washed with Et2O (2 × 10 mL) and dried in vacuo, affording the product as an off-white solid; yield 2.23 g (77%). 1H NMR (250 MHz, DMSO-d 6): δ = 4.50-4.91 (m, 2 H, CH2, different rotamers exist), 7.32-7.50 (m, 8 H, ArH + PyrH6), 8.29 (d, 3 J H,H = 9.0 Hz, 2 H, ArH), 11.01 (br s, 1 H, NH), 11.42 (br s, 1 H, NH). 13C NMR (62.9 MHz, DMSO-d 6): δ = 52.93, 114.39, 115.71, 122.67, 125.11, 126.09, 127.46, 128.27, 128.32, 136.37, 144.52, 150.50, 156.06, 161.17. MS (ES+): m/z = 406.09 [M + Na+].
Synthesis of 1-Benzyl-5-hydroxyoxazolo[5,4- d ]pyrimi-din-2(1 H )-one ( 5). 4-Nitrophenyl benzyl(2,4-dioxo-1,2,3,4-tetrahydropyrimi-din-5-yl)carbamate (4, 1.58 g, 4.13 mmol) was dissolved in THF (140 mL) and t-BuOK (0.97 g, 8.26 mmol) was added in one portion and the resulting mixture was heated to reflux for 1.5 h. After cooling the reaction mixture to r.t., the reaction mixture was concentrated to dryness. Then, H2O (25 mL) was added to the brightly yellow-coloured solid and this mixture was stirred vigorously for 5 min. Next, this layer was acidified with 1 M HCl aq (ca. 15 mL), resulting in an off-white precipitate. The precipitate was collected by filtration, washed with H2O (2 × 15 mL) and Et2O (2 × 30 mL) and dried in vacuo, affording the product as an off-white solid; yield 0.77 g (77%). 1H NMR (250 MHz, DMSO-d 6): δ = 4.88 (s, 2 H, CH2), 7.33-7.42 (m, 5 H, ArH), 7.66 (s, 1 H, PyrH), 11.60 (br s, 1 H, OH). 13C NMR (62.9 MHz, DMSO-d 6): δ = 45.40, 111.98, 123.72, 127.68, 127.79, 127.91, 128.61, 134.56, 151.06, 154.93. HRMS: m/z calcd for C12H10N3O3 [M + H+]: 244.0722. Found: 244.0726. Anal. Calcd for C12H9N3O3: C, 59.26; H, 3.73; N, 17.28. Found: C, 59.16; H, 4.17; N, 17.64.
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Synthesis of 5-(Benzylaminometh-yl)uracil ( 6). Paraformaldehyde (2.91 g, 97.0 mmol) and benzylamine were mixed in EtOH (320 mL) and this mixture was stirred at r.t. for 10 min. Subsequently, uracil (10.0 g, 88.2 mmol) was added in one portion followed by the addition of H2O (80 mL) and the resulting mixture was heated at reflux for 20 h. Next, the filtrate was evaporated to dryness, leaving a white solid. After washing with acetone (3 × 25 mL) and drying in vacuo, the product was obtained as a white solid; yield 13.2 g (65%). 1H NMR (250 MHz, DMSO-d 6): δ = 3.29 (s, 2 H, CH2), 3.66 (s, 2 H, CH2), 7.17-7.31 (m, 5 H, ArH), 7.32 (s, 1 H, PyrH). 13C NMR (62.9 MHz, DMSO-d 6): δ = 44.26, 52.10, 110.61, 126.49, 127.82, 128.07, 138.46, 140.70, 151.26, 164.42. MS (ES+) m/z = 232 [M + H+].
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References and Notes
Synthesis of 4-Nitrophenyl Benzyl[(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)methyl]carbamate (
7).
5-(Benzylaminomethyl)uracil (2.0 g, 8.7 mmol) was dissolved in THF (40 mL) and cooled to 0 °C with an ice-bath. Then, Et3N (1.2 mL, 8.7 mmol) was added followed by the dropwise addition of a solution of p-nitrophenyl chloroformate in THF (10 mL). The temperature was allowed to rise to r.t. and stirring was continued for 20 h at that temperature. Next, all volatiles were evaporated, leaving a yellow solid. This solid was washed with H2O (2 × 20 mL), Et2O (2 × 20 mL), and CH2Cl2 (2 × 20 mL) and dried in vacuo. Afterwards, THF (15 mL) was added to this solid and the resulting suspension was stirred at r.t. for 10 min. Subsequently, Et2O (30 mL) was added and the precipitate was collected and dried in vacuo, leaving a slightly yellow solid; yield: 2.82 g (82%). 1H NMR (250 MHz, DMSO-d
6, 100 °C): δ = 4.24 (s, 2 H, CH2), 4.66 (s, 2 H, CH2), 7.30-7.44 (m, 8 H, ArH + PyrH), 8.24 (d, 3
J
H,H = 9.0 Hz, 2 H, ArH), 10.48 (br s, 2 H, NH). 13C NMR (62.9 MHz, DMSO-d
6, 100 °C): δ = 43.53, 50.24, 107.46, 122.77, 125.07, 127.01, 127.31, 128.53, 137.52, 141.24, 144.41, 151.14, 153.12, 156.17, 164.25. HRMS: m/z calcd for C19H17N4O6 [M + H+] 397.1148; found: 397.1145.
Synthesis of 3-Benzyl-7-hydroxy-3,4-dihydropyrimi-do[5,4-
e
][1,3]oxazin-2-one (
8).
4-Nitrophenyl benzyl[(2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-yl)methyl]carbamate (7, 1.0 g, 2.5 mmol) was dissolved in THF (100 mL) and t-BuOK (0.57 g, 5.1 mmol) was added in one portion. The resulting solution was heated to reflux for 2 h and subsequently cooled to r.t. and concentrated to dryness. Then, H2O (20 mL) was added to the yellow solid and this mixture was stirred vigorously for 5 min. This layer was acidified with 1 M HCl aq (ca. 20 mL), resulting in a white precipitate. The precipitate was collected, washed with H2O (2 × 10 mL) and Et2O (2 × 15 mL) and dried in vacuo, affording the product as a white solid; yield 0.50 g (84%). 1H NMR (250 MHz, DMSO-d
6): δ = 4.15 (s, 2 H, CH2), 4.60 (s, 2 H, CH2), 7.31-7.41 (m, 5 H, ArH), 7.94 (s, 1 H, PyrH), 11.95 (br s, 1 H, OH).
13C NMR (62.9 MHz, DMSO-d
6): δ = 42.54, 51.65, 95.35, 127.70, 127.77, 128.65, 135.47, 144.67, 148.65, 155.87, 166.03. HRMS: m/z calcd for C13H11N3O3Na [M + Na+]: 280.0698; found: 280.0696. Anal. Calcd for C13H11N3O3·0.2H2O: C, 59.86; H, 4.41; N, 16.11. Found: C, 60.02; H, 4.37; N, 15.73.