March 2012 An Efficient One-Pot Synthesis of Pyrimido[2,1-b][1,3]Oxazine Derivatives via the
Reaction of Isocyanides with Dialkyl Acetylenedicarboxylates in the Presence of 5-Substituted Uracils
313
spectrometer at 300.1, 75.5, and 282.4 MHz, respectively.
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Dimethyl-7-bromo-2-(tert-butylamino)-8-oxo-2H,8H-pyrimido
[2,1-b][1,3]oxazine-3,4-dicarboxylate (5c, C15H18BrN3O6). White
HMQC and HMBC spectra were measured at 500 MHz for H-
NMR and at 125 MHz for 13C-NMR. 1H-, 13C-, 19F-NMR,
HMQC, HMBC, and DEPT spectra were obtained in CDCl3 using
TMS or CFCl3 as internal standard. IR spectra were recorded as
KBr pellets on a Shimadzu IR-460 spectrometer. Chromatogra-
phy columns were prepared from Merck silica gel 60 mesh.
General procedure. To a magnetically stirred solution of
5-substituted uracils (2 mmol) and dialkyl acetylenedicarboxy-
lates (2 mmol) in anhydrous 1,4-dioxane (5 mL), a solution of
isocyanide (2 mmol) in 1,4-dioxane (2 mL) over a period of
10 minutes was added dropwise. The reaction mixture was
stirred 24 h at room temperature. After completion of the reac-
tion as indicated by TLC, the solvent was removed and the
residue was purified by silica gel column chromatography
(hexane–ethyl acetate, 3:1) to afford products 4a and 5a–5i.
When necessary, the isolated products were further purified by
recrystallization in diethyl ether–dichloromethane.
powder, mp 373–376ꢀC, 0.66 g, yield 85%; IR (KBr) (tmax
/
cmꢁ1): NH 3216, C¼¼O 1760, 1744, and 1608. 1H-NMR
(300.1 MHz, CDCl3): d 1.25 [9H, s, C(CH3)3], 3.76 and 3.89
(6H, 2s, 2OCH3), 6.89 (1H, s, NHCHO), 8.44 (1H, s, NCH),
8.75 (1H, br. s, NH). 13C-NMR (75.5 MHz, CDCl3): d 30.2
[C(CH3)3], 52.6 and 53.2 (2OCH3), 57.3 [C(CH3)3], 127.3
(CABr), 97.9 (NHCHO), 139.2 (NCH), 141.3 and 141.4 (2C),
149.2 (N¼¼CAO), 159.0, 163.4, and 164.5 (3C¼¼O). MS, m/z
(%): 416 (Mþ, 4), 418 [Mþþ2, 3.8)], 268 (4), 268 (50), 170
(25), 138 (56), 57 (100), 41 (44). Anal. Calcd for
C15H18BrN3O6 (416.22): C, 43.28; H, 4.36; N, 10.10. Found:
C, 44.15; H, 4.23; N, 10.05%.
Dimethyl-2-(tert-butylamino)-7-fluoro-8-oxo-2H,8H-pyrimido
[2,1-b][1,3]oxazine-3,4-dicarboxylate (5d, C15H18FN3O6). Yellow
oil, 0.62 g, yield 80%; IR (tmax/cmꢁ1): NH 3216, C¼¼O 1760,
1
1649, and 1608. H-NMR (300.1 MHz, CDCl3): d 1.46 [9H, s,
Dimethyl-2-(tert-butylamino)-7-methyl-8-oxo-4H,8H-pyrimido
[2,1-b][1,3]oxazine-3,4-dicarboxylate (4a, C16H21N3O6). White
powder, mp 380–382ꢀC; 0.1 g, yield 14%; IR (tmax/cmꢁ1):
NH 3402, C¼¼O 1744 and 1665. 1H-NMR (300.1 MHz,
CDCl3): d 1.49 (9H, s, C(CH3)3), 1.95 (3H, s, CH3), 3.76 and
3.81 (6H, 2s, 2OCH3), 5.69 (1H, s, NCHACO2Me), 7.35 (1H,
s NCH), 8.95 (1H, br. s, NH). 13C-NMR (75.5 MHz, CDCl3):
d 12.9 (CH3), 30.6 [C(CH3)3], 52.4 and 53.6 (2OCH3), 58.6
[C(CH3)3], 60.2 (NCHACO2Me), 63.2 (NHAC¼¼C), 110.7
(CCH3), 140.2 (NCH), 151.0 (N¼¼CAO), 161.4 (NHAC¼¼C),
164.5, 168.2, and 170.3 (3C¼¼O). MS, m/z (%): 351 (Mþ, 18),
294 (58), 279 (50), 213 (8), 190 (65), 160 (9), 57 (100), 41
(55). Anal. Calcd for C16H21N3O6 (351.35): C, 54.69; H, 6.02;
N, 11.96. Found: C, 55.35; H, 6.04; N, 11.85%.
C(CH3)3], 3.73 and 3.78 (6H, 2s, 2OCH3), 6.73 (1H,
3
s, NHCHO), 7.67 (1H, d, JHF ¼ 5.7 Hz, NCH), 9.55 (1H, br.
s, NH). 13C-NMR (75.5 MHz, CDCl3): d 30.2 [C(CH3)3], 52.1
and 53.4 (2OCH3), 57.9 [C(CH3)3], 96.9 (NHCHO), 128.0
2
1
(d, JCF ¼ 20.5 Hz, NCH), 140.0 (d, JCF ¼ 236.7 Hz, CF),
2
149.4 (C), 157.2 (d, JCF ¼ 26.2 Hz, C¼¼O), 159.9 (C), 163.7
(NAC¼¼O), 167.5 and 169.6 (2C¼¼O). 19F-NMR (282.4 MHz,
CDCl3): dF ꢁ165.48 (3JHF ¼ 5.7 Hz). MS, m/z (%): 416 (Mþ),
295 (28), 170 (28), 41 (28), 57 (100). Anal. Calcd for
C15H18FN3O6 (355.32): C, 50.70; H, 5.11; N, 11.83. Found:
C, 50.59; H, 5.09; N, 11.09%.
Diethyl-2-(tert-butylamino)-7-methyl-8-oxo-2H,8H-pyrimido
[2,1-b][1,3]oxazine-3,4-dicarboxylate (5e, C18H25N3O6). Yellow
oil, 0.62 g, yield 80%; IR (tmax/cmꢁ1): NH 3425, C¼¼O 1755,
1685, and 1675. 1H-NMR (300.1 MHz, CDCl3): d 1.26 and
Dimethyl-2-(tert-butylamino)-7-methyl-8-oxo-2H,8H-pyrimido
[2,1-b][1,3]oxazine-3,4-dicarboxylate (5a, C16H21N3O6). White
3
1.32 (6H, 2t, JHH ¼ 7.1 Hz, 2OCH2CH3), 1.25 [9H, s,
3
C(CH3)3], 1.97 (3H, s, CH3), 4.16 and 4.34 (4H, 2qd, JHH
powder, mp 380–383ꢀC, 0.61 g, yield 78%. IR (KBr; tmax
/
¼
cmꢁ1): NH 3332, C¼¼O 1744, 1704, and 1664. 1H-NMR
(300.1 MHz, CDCl3): d 1.30 (9H, s, C(CH3)3), 2.03 (3H, s,
CH3), 3.78 and 3.92 (6H, 2s, 2OCH3), 6.90 (1H, s, NHCHO),
8.01 (1H, s, NCH), 8.47 (1H, br. s, NH). 13C-NMR (75.5
MHz, CDCl3): d 12.9 (CH3), 30.7 [C(CH3)3], 52.8 and 53.4
(2OCH3), 57.4 [C(CH3)3], 126.9 (CCH3), 111.0 (NHCHO),
138.2 (NCH), 140.6 and 142.4 (2C), 150.3 (N¼¼CAO), 164.0,
164.4, and 165.1 (3C¼¼O). MS, m/z (%): 351 (Mþ, 10),
294 (65), 279 (54), 213 (4), 190 (55), 160 (7), 138 (30),
72 (8), 57 (100), 41 (45). Anal. Calcd for C16H21N3O6
(351.35): C, 54.69; H, 6.02; N, 11.96. Found: C, 54.35;
H, 6.12; N, 11.95%.
2
7.1 Hz, JHH ¼ 1.1 Hz, 2OCH2CH3), 6.84 (1H, s, NHCHO),
7.97 (1H, s, NCH), 9.23 (1H, br. s, NH). 13C-NMR (75.5
MHz, CDCl3): d 12.6 and 14.0 (2OCH2CH3), 30.3 [C(CH3)3],
56.9 [C(CH3)3], 61.5 and 62.3 (2OCH2CH3), 126.9 (CCH3),
110.4 (NHCHO), 137.9 (NCH), 140.4 and 142.0 (2C), 149.9
(N¼¼CAO), 163.1, 164.3, and 164.4 (3C¼¼O). MS, m/z (%):
379 (Mþ, 12), 338 (44), 332 (38), 293 (7), 233 (35), 231 (50),
146 (15), 57 (100), 41 (58). Anal. Calcd for C18H25N3O6
(379.41): C, 56.98; H, 6.64; N, 11.08. Found: C, 57.04; H,
6.53; N, 11.12%.
Diethyl-2-(tert-butylamino)-8-oxo-2H,8H-pyrimido[2,1-b][1,3]
oxazine-3,4-dicarboxylate (5f, C17H23N3O6). Yellow oil, 0.60
g, yield 78%; IR (tmax/cmꢁ1): NH 3308, C¼¼O 1704, 1673
and 1642. 1H-NMR (300.1 MHz, CDCl3): d 1.15 and 1.17
Dimethyl-2-(tert-butylamino)-8-oxo-2H,8H-pyrimido[2,1-b]
[1,3]oxazine-3,4-dicarboxylate (5b, C15H19N3O6). White
3
powder, mp 358–362ꢀC, 0.59 g, yield 76%; IR (KBr; tmax
/
(6H, 2t, JHH ¼ 7.1 Hz, 2OCH2CH3), 1.38 [9H, s, C(CH3)3],
cmꢁ1): NH 3328, C¼¼O 1724, 1694, and 1653. 1H-NMR
3
4.10 and 4.15 (4H, 2q, JHH ¼ 7.1 Hz, 2OCH2CH3), 5.62 and
3
(300.1 MHz, CDCl3): d 1.25 [9H, s, C(CH3)3], 3.74 and 3.89
7.49 (2H, 2d, JHH ¼ 8.1 Hz, 2CH), 7.23 (1H, s, NHCHO),
3
10.04 (1H, br. s, NH). 13C-NMR (75.5 MHz, CDCl3): 13C-
NMR (75.5 MHz, CDCl3): d 13.9 and 14.19 (2OCH2CH3),
30.1 [C(CH3)3], 62.8 [C(CH3)3], 65.8 and 70.1 (2OCH2CH3),
101.6 (CH), 91.1 (NHCHO), 144.1 (NCH), 150.8 and 155.7
(2C), 161.5 (N¼¼CAO), 164.1, 167.1, and 169.3 (3C¼¼O). MS,
m/z (%): 365 (Mþ, 10), 324 (2), 308 (30), 281 (6), 214 (8),
151 (65), 57 (100), 41 (50). Anal. Calcd for C15H19N3O6
(365.38): C, 55.88; H, 6.34; N, 11.50. Found: C, 55.69; H,
6.25; N, 12.04%.
(6H, 2s, 2OCH3), 5.78 and 8.11 (2H, d, JHH ¼ 8.3 Hz, 2CH),
6.88 (1H, s, NHCHO), 8.96 (1H, br. s, NH). 13C-NMR
(75.5 MHz, CDCl3):
d 30.2 [C(CH3)3], 52.5 and 53.1
(2OCH3), 57.1 [C(CH3)3], 126.9 (CH), 102.2 (NHCHO), 139.9
(NCH), 141.8 and 142.5 (2C), 149.9 (N¼¼CAO), 163.5, 163.6,
and 164.6 (3C¼¼O). MS, m/z (%): 337 (Mþ, 5), 281 (58), 266
(52), 190 (53), 138 (33), 119 (10), 57 (100), 41 (43). Anal.
Calcd for C15H19N3O6 (337.33): C, 53.41; H, 5.68; N, 12.46.
Found: C, 53.58; H, 5.78; N, 11.95%.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet