M. Bakavoli et al. / Tetrahedron xxx (2013) 1e7
5
1617 cmꢀ1; m/z 154 (Mþ). Found: C, 54.49; H, 6.44; N, 18.12.
C7H10N2O2 requires C, 54.54; H, 6.54; N, 18.17%.
4.1.2. 6-Methyl-4-propoxypyrimidin-2(1H)-one(4b). Mp 107e108 ꢁC;
dH (400 MHz, CDCl3) 1.00 (3H, t, J 7.6 Hz, CH3), 1.71e1.81 (2H, m, CH2),
2.33 (3H, s, CH3), 4.35 (2H, t, J 6.8 Hz, CH2O), 5.76 (1H, s, CH), 12.85
(1H, br s, NH); dC (100 MHz, CDCl3) 10.4, 18.7, 21.0, 68.6, 94.9, 156.3,
160.7,173.3; nmax (KBr disk): 3145, 2970, 2937, 2872,1672,1632 cmꢀ1
;
m/z 168 (Mþ). Found: C, 57.02; H, 7.03; N, 16.60. C8H12N2O2 requires
C, 57.13; H, 7.19; N, 16.66%.
4.1.3. 4-Butoxy-6-methylpyrimidin-2(1H)-one (4c). Mp 125e127 ꢁC;
dH (400 MHz, CDCl3) 1.00 (3H, t, J 7.5 Hz, CH3), 1.7e1.8 (4H, m,
CH2CH2), 2.18 (3H, s, CH3), 4.41 (2H, t, J 8.5 Hz, CH2O), 5.61 (1H, s, CH),
9.85 (1H, br s, NH); dC (100 MHz, CDCl3) 10.3, 19.0, 19.6, 21.8, 68.6,
89.9,155.0,158.9,168.5; nmax (KBr disk) 3120, 2955, 2933, 2871, 2765,
1669, 1632, 1324 cmꢀ1; m/z 182 (Mþ). Found: C, 59.12; H, 7.63; N,
15.20. C9H14N2O2 requires C, 59.32; H, 7.74; N, 15.37%.
4.1.4. 4-(Benzyloxy)-6-methylpyrimidin-2(1H)-one
(4d). Mp
Fig. 4. Graph showing the linear correlation between the experimentally measured
and calculated [GIAO mPW1PW91/6-31þG(d,p)-PCM//B3LYP/6-31þG(d,p)] 13C NMR
chemical shifts.
179e180 ꢁC; dH (400 MHz, CDCl3) 2.29 (3H, s, CH3), 4.45 (2H, s,
CH2O), 6.08 (1H, s, CH), 7.28e7.40 (5H, m, phenyl), 12.87 (1H, br s,
NH); dC (100 MHz, CDCl3) 18.6, 67.5, 99.2, 128.5, 128.6, 128.9, 136.8,
157.4, 164.5, 172.1; nmax (KBr disk) 3199, 3076, 3031, 3011, 2917,
2824, 1654, 1572, 1546, 1494, 1454, 1393 cmꢀ1; m/z 216 (Mþ).
Found: C, 66.54; H, 5.50; N, 12.91. C12H12N2O2 requires C, 66.65; H,
5.59; N, 12.96%.
fitted by dexp¼1.0323dcalcdꢀ2.9313. As shown in Table 6, if the linear
regression approach for empirical scaling of the calculated 13C
chemical shifts is used, the single reference approach with TMS has
lower MAD values, while without scaling of results, the multi-
standard (MSTD) approach has better values as has been ob-
served by other workers.21
4.1.5. Ethyl 2-((6-methyl-2-oxo-1,2-dihydropyrimidin-4-yl)oxy)ace-
tate (4e). Mp 197 ꢁC; dH (400 MHz, CDCl3) 1.29 (3H, t, J 10.0 Hz,
CH3), 2.34 (3H, s, CH3), 4.25 (2H, q, J 7.5 Hz, OCH2CH3), 4.99 (2H, s,
OCH2CO), 5.91 (1H, s, CH), 12.80 (1H, br s, NH); dC (100 MHz, CDCl3)
3. Conclusion
14.1, 18.8, 61.5, 62.4, 94.7, 157.4, 160.2, 167.8, 172.2 cmꢀ1
; nmax (KBr
disk): 3145, 2998, 2965, 2883, 1751, 1676, 1635, 1453, 1334; m/z 212
(Mþ). Found: C, 50.82; H, 5.66; N, 13.03. C9H12N2O4 requires C,
50.94; H, 5.70; N, 13.20%.
HMDS promoted O-alkylation of uracil is a high yielding che-
moselective and regioselective mono-alkylation strategy. The use of
various alkyl halides in the presence of aprotic solvents such as
DMF results in chemoselective mono-O4-alkylation except with
methyl iodide, which gave the N1þN3-dimethylated uracil de-
rivatives. GIAO/13C NMR calculations with mPW1PW91 hybrid
functional and 6-31þG(d,p) standard basis set is preferred for
elucidation of chemo- and regioselectivity in these reactions.
4.1.6. 6-Methyl-4-(2-oxo-2-phenylethoxy)pyrimidin-2(1H)-one
(4f). Mp 210e211 ꢁC; dH (400 MHz, CDCl3) 2.23 (3H, s, CH3), 4.95 (2H,
s, CH2O), 7.21e7.44 (5H, m, phenyl),11.75 (1H, br s, NH); dC (100 MHz,
CDCl3) 14.5, 68.5, 83.2, 128.6, 133.0, 134.5, 138.7, 155.2, 159.0, 160.4,
168.5; nmax (KBr disk) 3113, 3061, 3012, 2929, 2846, 2735, 1701, 1661,
1616, 1446, 1386, 1357 cmꢀ1; m/z 244 (Mþ). Found: C, 63.90; H, 4.92;
N, 11.45. C13H12N2O3 requires C, 63.93; H, 4.95; N, 11.47%.
4. Experimental
4.1. General procedure for the preparation of O-alkylated
uracils 4(aer)
4.1.7. 5-Bromo-4-ethoxy-6-methylpyrimidin-2(1H)-one
(4g). Mp
247e248 ꢁC; dH (400 MHz, CDCl3) 1.42 (3H, t, J 7.5 Hz, CH3), 2.48
(3H, s, CH3), 4.52 (2H, q, J 7.5 Hz, CH2O), 13.12 (1H, br s, NH); dC
(100 MHz, CDCl3) 14.2, 19.7, 64.8, 90.2, 155.1, 158.9, 168.4; nmax (KBr
disk) 3113, 2970, 2929, 2892, 2819,1651, 1608, 1421, 1382 cmꢀ1; m/z
232 (Mþ), 234 (Mþþ2). Found: C, 35.01; H, 3.86; N, 12.04.
C7H9BrN2O2 requires C, 36.07; H, 3.89; N, 12.02%.
To a mixture of 5-substituted uracils 1(aec) (1 mmol) and am-
monium sulfate (0.06 mmol, 0.008 g), HMDS (4 mL) was added and
refluxed until the precipitate was dissolved. Then, the solvent was
removed under reduced pressure and the resulting oily liquid was
dissolved in dry DMF (4 mL) and NaH (2 mmol, 0.048 g) was added at
ꢀ10 ꢁC. After stirring of the reaction mixture for 1 h, various alkyl
halides (1 mmol) were added. The progress of the reaction was
monitored by TLC using chloroform/methanol as eluent (20:1). After
the completion of the reaction, the mixture was neutralized by 2 N
HCl and extracted by CH2Cl2 (2ꢂ30 mL). The combined organic phase
was dried over Na2SO4 and removed under reduced pressure. The
resulting solid was recrystallized in EtOAc and n-hexane.
4.1.8. 5-Bromo-6-methyl-4-propoxypyrimidin-2(1H)-one (4h). Mp
214e216 ꢁC; dH (400 MHz, CDCl3) 1.02 (3H, t, J 7.5 Hz, CH3),
1.82e1.91 (2H, m, CH2), 2.47 (3H, s, CH3), 4.41 (2H, t, J 7.5 Hz, CH2O),
13.12 (1H, br s, NH); dC (100 MHz, CDCl3) 10.3, 19.6, 21.9, 70.3, 90.3,
154.9, 158.9, 168.5; nmax (KBr disk) 3113, 2970, 2921, 2872, 2831,
1658, 1611, 1358 cmꢀ1; m/z 246 (Mþ), 248 (Mþþ2). Found: C, 38.82;
H, 4.41; N, 11.30. C8H11BrN2O2 requires C, 38.89; H, 4.49; N, 11.34%.
4.1.1. 4-Ethoxy-6-methylpyrimidin-2(1H)-one (4a). Mp 187e189 ꢁC;
dH (400 MHz, CDCl3) 1.37 (3H, t, J 9.0 Hz, CH3), 2.33 (3H, s, CH3), 4.50
(2H, q, J 9.0 Hz, CH2O), 5.75 (1H, s, CH), 12.89 (1H, br s, NH); dC
(100 MHz, CDCl3) 14.3, 18.6, 62.0, 94.9, 156.3, 160.8, 173.1; nmax (KBr
disk): 3141, 3031, 2987, 2945, 2882, 2819, 2766, 1664, 1634,
4.1.9. 5-Bromo-4-butoxy-6-methylpyrimidin-2(1H)-one
(4i). Mp
159e161 ꢁC; dH (400 MHz, CDCl3) 1.02 (3H, t, J 7.5 Hz, CH3), 1.72e1.87
(4H, m, CH2CH2), 2.48 (3H, s, CH3), 4.42 (2H, t, J 7.5 Hz, CH2O), 13.12
(1H, br s, NH); dC (100 MHz, CDCl3) 10.3, 19.1, 19.6, 21.9, 68.7, 90.3,
155.1,159.0,168.5; nmax (KBr disk) 3121, 2961, 2932, 2873, 2828, 1658,