CHEMMEDCHEM
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and the resulting mixture was left to stand at 0–48C for 3 days. In
most cases, the precipitate formed was collected by filtration.
When the solid did not meet the purity standard of >98% (LC–
MS), it was subjected to further chromatography (SiO2). In a few
cases no precipitate formed. Solvents and volatiles were then
evaporated under reduced pressure, and the resulting residue was
purified by silica gel chromatography to afford the title compound.
Preparation of 4-methoxybenzyl 4-(furan-2-yl)-6-methyl-2-oxo-
1,2,3,4-tetrahydropyrimidine-5-carboxylate (93). Compound 93
was prepared using Method A from 4-methoxybenzyl acetoacetate
2 (111 mg), furan-2-carboxaldehyde (50 mL), and urea (45 mg). Isola-
tion by chromatography on silica gel (cHex/EtOAc 100:0!60:40)
afforded 93 as an ochre powder (68 mg, 40%): Rf =0.26 (cHex/
1
EtOAc 1:1); mp: 158–1598C; H NMR (400 MHz, [D6]DMSO): d=2.23
(s, 3H), 3.74 (s, 3H), 4.99 (s, 2H), 5.20 (d, J=3.2 Hz, 1H), 6.04 (d, J=
2.8 Hz, 1H), 6.35 (dd, J=2.0, 3.2 Hz, 1H), 6.89 (d, J=8.4 Hz, 2H),
7.20 (d, J=8.4 Hz, 2H), 7.55 (s, 1H), 7.76 (s, 1H), 9.29 ppm (s, 1H);
13C NMR (100 MHz, [D6]DMSO): d=18.2, 48.1, 55.5, 65.2, 96.9, 105.8,
110.8, 114.2, 128.9, 129.9, 142.6, 150.4, 152.8, 156.3, 159.4,
165.5 ppm; HPLC: tR =13.1 min (>98%); MS-ESI: m/z 343 [M+H]+;
HRMS-ESI-TOF (neg.): m/z calcd for C18H17N2O5: 341.1137 [MꢀH]ꢀ,
found: 341.1141.
Method B: b-Ketoester (0.50 mmol), aldehyde (0.60 mmol), urea
(0.75 mmol), and Zn(OTf)2 (10 mol%) were dissolved in MeCN and
held at reflux for 2–16 h. The reaction mixture was allowed to cool
to room temperature. The solvent was evaporated under reduced
pressure, and the residue was subjected to chromatography on
silica gel or purified by preparative HPLC to afford the title com-
pound.
Method C: b-Ketoester (1.0 equiv), aldehyde (1.0 equiv), and urea
(2.0 equiv) were dissolved in MeOH/HClconc 1:1 at a final concentra-
tion of 1m (versus aldehyde). The mixture was stirred at 408C for
1–3 days. The reaction mixture was allowed to cool to room tem-
perature. The solid formed was collected by filtration and washed
with H2O and/or EtOH to afford the title compound.
Preparation of 4-methoxyphenyl 6-methyl-2-oxo-4-phenyl-
1,2,3,4-tetrahydropyrimidine-5-carboxylate (122). In a 10-mL mi-
crowave vial, carboxylic acid 42 (0.42 mmol), 4-methoxyphenol
(0.84 mmol), EDCI (0.63 mmol), and DMAP (0.42 mmol) were dis-
solved in dimethylacetamide (2.0 mL). This reaction mixture was
microwaved for 1 h at 1208C. Excess solvent was removed under
reduced pressure. The residue was dissolved in EtOAc (10 mL),
washed twice with HCl (1m, 5 mL) and once with H2O (5 mL). The
dried (Na2SO4) organic layer was concentrated in vacuo. The result-
ing residue was triturated in EtOH, filtered, and dried to afford 122
as a white powder (53 mg, 37%): Rf =0.31 (cHex/EtOAc 1:1); mp:
Preparation of 4-methoxybenzyl 6-methyl-2-oxo-4-phenyl-
1,2,3,4-tetrahydropyrimidine-5-carboxylate (1). Compound 1 was
prepared using Method A from 4-methoxybenzyl acetoacetate 2
(111 mg), benzaldehyde (51 mL), and urea (45 mg). Isolation by fil-
tration afforded 1 as a white solid (97 mg, 55%): Rf =0.24 (cHex/
1
265–2688C; H NMR (400 MHz, [D6]DMSO): d=2.31 (s, 3H), 3.71 (s,
1
EtOAc 1:1); mp: 162–1648C; H NMR (400 MHz, [D6]DMSO): d=2.25
3H), 5.31 (d, J=2.8 Hz, 1H), 6.79 (d, J=9.2 Hz, 2H), 6.89 (d, J=
9.2 Hz, 2H), 7.29–7.39 (m, 5H), 7.89 (s, 1H), 9.45 ppm (s, 1H);
13C NMR (100 MHz, [D6]DMSO): d=18.5, 54.6, 55.8, 98.4, 114.7,
123.0, 126.8, 127.9, 129.0, 144.2, 145.2, 151.3, 152.0, 157.0,
164.6 ppm; HPLC: tR =13.7 min (>98%); MS-ESI: m/z 339 [M+H]+.
(s, 3H), 3.74 (s, 3H), 4.95 (s, 2H), 5.13 (s, 1H), 6.86 (d, J=8.8 Hz,
2H), 7.13 (d, J=8.4 Hz, 2H), 7.15–7.20 (m, 2H), 7.24–7.30 (m, 3H),
7.74 (s, 1H), 9.24 ppm (s, 1H); 13C NMR (100 MHz, [D6]DMSO): d=
18.3, 54.3, 55.5, 65.1, 99.4, 114.1, 126.7, 127.8, 128.8, 128.9, 130.0,
145.1, 149.4, 152.5, 159.4, 165.6 ppm; HPLC: tR =14.9 min (>98%);
MS-ESI: m/z 353 [M+H]+; HRMS-ESI/TOF (neg.): m/z calcd for
C20H19N2O4: 351.1345 [MꢀH]ꢀ, found: 351.1361.
Preparation of N-4-methoxybenzyl 6-methyl-2-oxo-4-phenyl-
1,2,3,4-tetrahydropyrimidine-5-carboxamide (135). In a 10-mL
microwave vial, carboxylic acid 42 (0.86 mmol), 4-methoxybenzyla-
mine (0.86 mmol), EDCI (1.29 mmol), and (iPr)2NH (1.29 mmol) were
dissolved in dimethylacetamide (5.0 mL). The reaction mixture was
microwaved for 15 min at 1108C. HCl (1m, 10 mL) was added, and
this solution was extracted with EtOAc (3ꢁ20 mL). The organic
layers were pooled, dried (Na2SO4) and concentrated in vacuo. The
resulting residue was purified by chromatography on silica gel
(CH2Cl2/MeOH 100:0!90:10) to yield 135 as a pale-yellow powder
(178 mg, 59%): Rf =0.25 (CH2Cl2/MeOH, 95:5); mp: 153–1558C;
1H NMR (400 MHz, [D6]DMSO): d=2.00 (s, 3H), 3.71 (s, 3H), 4.15 (d,
J=6.0 Hz, 2H), 5.28 (d, J=2.0 Hz, 1H), 6.76 (d, J=8.8 Hz, 2H), 6.93
(d, J=8.4 Hz, 2H), 7.22–7.33 (m, 5H), 7.49 (s, 1H), 8.06 (t, J=5.8 Hz,
1H), 8.55 ppm (s, 1H); 13C NMR (100 MHz, [D6]DMSO): d=17.4,
42.0, 55.4, 55.5, 105.4, 113.9, 126.9, 127.7, 128.7, 128.8, 132.1, 137.8,
144.7, 153.1, 158.4, 166.7 ppm; HPLC: tR =7.7 min (>98%); MS-ESI:
m/z 352 [M+H]+.
6-Methyl-2-oxo-4-phenyl-1,2,3,4-tetrahydropyrimidine-5-carbox-
ylic acid (42). To a solution of 108 (21.4 mmol) in MeOH (60 mL),
under H2 atmosphere was added Pd/C 10% (0.1 equiv, 2.14 mmol).
The mixture was stirred at room temperature for 3.5 h. Excess sol-
vent was removed in vacuo, and the residue was suspended in
0.5m KOH (100 mL). After vigorous stirring for 3 h at room temper-
ature, the suspension was filtered on Celite. The filtrate was acidi-
fied to pH 1–2 with HCl (37%, ~15 mL), and the resulting precipi-
tate was collected by filtration and air dried to afford 42 as a white
solid (3.92 g, 79%): Rf =0.35 (cHex/EtOAc 1:1); mp: 232–2338C;
1H NMR (400 MHz, [D6]DMSO): d=2.24 (s, 3H), 5.11 (d, J=3.2 Hz,
1H), 7.24–7.34 (m, 5H), 7.68 (s, 1H), 9.09 (s, 1H), 11.89 ppm (bs,
1H); 13C NMR (100 MHz, [D6]DMSO): d=18.2, 54.4, 100.3, 126.7,
127.6, 128.8, 145.3, 148.2, 152.8, 167.6 ppm; HPLC: tR =3.9 min (>
98%); MS-ESI: m/z 233 [M+H]+.
Preparation of 6-methyl-4-phenyl-2-thioxo-1,2,3,4-tetrahydro-
pyrimidine-5-carboxylic acid (43). Et2NH (24.3 mmol) and
Pd(PPh3)4 (0.24 mmol) were added to a solution of 136 (2.4 mmol)
in anhydrous THF (5.5 mL) under Ar. The reaction mixture was
stirred at room temperature for 4 h. Excess solvent was removed in
vacuo. KOH (0.5m, 20 mL) was added to the residue, and the re-
sulting suspension was filtered on Celite. The filtrate was acidified
to pH 1–2 with HCl (37%), and the resulting precipitate was col-
lected by filtration and air dried to afford 43 as a yellow powder
Preparation of 4-methoxybenzyl 6-methyl-4-phenyl-2-thioxo-
1,2,3,4-tetrahydropyrimidine-5-carboxylate (155). A solution of
43 (0.83 mmol), 4-methoxybenzyl alcohol (1.67 mmol), EDCI
(1.25 mmol), and DMAP (0.83 mmol) in anhydrous dimethylaceta-
mide (6.0 mL) was heated under Ar at 808C for 5 h. In vacuo con-
centration of the reaction mixture followed by preparative HPLC
purification (19ꢁ150 mm, 5 mm, XBridge C18 in H2O/MeCN) afford-
ed 155 as a white solid (55 mg,18%): Rf =0.77 (cHex/EtOAc 4:6);
mp: 174–1758C; 1H NMR (400 MHz, [D6]DMSO): d=2.29 (s, 3H),
3.74 (s, 3H), 4.95 (d, J=12.4 Hz, 1H), 5.00 (d, J=12.0 Hz, 1H), 5.16
(d, J=3.6 Hz, 1H), 6.86 (d, J=8.4 Hz, 2H), 7.13 (d, J=8.8 Hz, 2H),
7.15–7.17 (m, 2H), 7.28–7.32 (m, 3H), 9.66 (s, 1H), 10.37 ppm (s,
1
(208 mg, 35%): H NMR (400 MHz, [D6]DMSO): d=2.28 (s, 3H), 5.15
(d, J=3.6 Hz, 1H), 7.22–7.37 (m, 5H), 9.60 (s, 1H), 10.26 (s, 1H),
12.25 ppm (bs, 1H); MS-ESI: m/z 249 [M+H]+.
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ChemMedChem 2013, 8, 104 – 111 110