A Facile Synthesis of an Oxazolo[5,4]pyrimidin-2-one and a ­Pyrimido[5,4][1,3]oxazin-2-one

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

References and Notes

• For purine kinase inhibitors, see for example:
• 1a Meijer L. Raymond E. Acc. Chem. Res.  2003,  36:  417 
• 1b Laufer SA. Domeyer DM. Scior TRF. Albrecht W. Hauser DRJ. J. Med. Chem.  2005,  48:  710 
• 2a Manning G. Whyte DB. Martinez R. Hunter T. Sudarsanam S. Science  2002,  298:  1912 
• 2b Manning G. Whyte DB. Martinez R. Hunter T. Sudarsanam S. Science  2002,  298:  1933 
• 3 Huse M. Kuriyan J. Cell  2002,  109:  275 
• 4 For a review on protein kinase inhibitors, see: Bridges AJ. Chem. Rev.  2001,  101:  2541 
• 5 Levitzki A. Acc. Chem. Res.  2003,  36:  462 ; this review includes references to gleevec, iressa and sorafenib
• 6 Brown DJ. Comprehensive Heterocyclic Chemistry   Vol. 3:  Boulton AJ. McKillop A. Pergamon Press; Oxford: 1985.  p.57 
• 7a Wetzel B. Woitun E. Reuter W. Maier R. Lechner U. Drug. Res.  1985,  35:  343 
• 7b Wetzel B, Woitun E, Reuter W, Maier R, Lechner U, and Goeth H. inventors; Eur. Pat. Appl., EP  4499265. 
• 7c Maier R. Wetzel B. Woitun E. Reuter W. Lechner U. Appel K.-R. Arzneim.-Forsch.  1986,  9:  1297 
• 8 For the synthesis of 3, see: Gaulon C. Dijkstra HP. Springer CJ. Synthesis  2005,  13:  2227 
• 9

  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.
  For the use of p-nitrophenol esters in the synthesis of carbamates, see also:

• 9b Nakata T. Fukui M. Oishi T. Tetrahedron Lett.  1988,  29:  2223 
• 9c Vigroux A. Bergon M. Zedde C. J. Med. Chem.  1995,  38:  3983 
• 10a A modification from a literature procedure was used: Delia TJ. Scovill JP. Munslow WD. J. Med. Chem.  1976,  19:  344 
• 10b

  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⁺].

• Some examples can be found in the following papers:
• 12a Sandosham J. Undheim K. Heterocycles  1994,  37:  501 
• 12b Sandosham J. Undheim K. Rise F. Heterocycles  1993,  35:  235 
• 12c Sugimoto O. Mori M. Tanji K. Tetrahedron Lett.  1999,  40:  7477 

11

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.