492 JOURNAL OF CHEMICAL RESEARCH 2007
O
O
OEt
OH
N
i,ii
N
iii,iv
MeS
N
1
MeS
N
8
O
C
N
NH2
N
N
9
vi
R
N
H
R
N
R = SMe
11 R = MeS
12 R = MeO
v
10 R = OMe
Scheme 3 Reagent and conditions: (i) NaOH, EtOH; (ii) HCl; (iii) SOCl2; (iv) NH3.H2O; (v) MeONa; (vi) LiAlH4.
refluxed for 30 min. The mixture was cooled and filtered, then the
filtrate was condensed and purified by column chromatography to
give 1 (6.0 g, 61.5% from 6) as a white solid: m.p. 38–40ºC. (Ref: 12
chromatography (petroleum ether and ethyl acetate 2:1 to 1:1 as
eluent) to give compound 3 and (2-(methylthio)pyrimidin-5-yl)
methanol (MPOL).
1
36–37ºC) H NMR(CDCl3): δ1.34 (t, J = 7.2 Hz, 3H, CH3), 2.55 (s,
Method B: To a suspension of 1 (0.99 g, 5.0 mmol) in anhydrous
tetrahydrofuran or ether (15 ml), cooled to certain temperature as
listed in Table 1, was added LiAlH4 (0.27 g, 7.1 mmol) in batch. The
reaction mixture was then stirred at room temperature and worked up
as described in Method A.
3H, SCH3), 4.34 (q, J = 7.2 Hz, 2H, CH2), 8.96 (s, 2H, pyrimidine).
Ethyl 2-ethoxy-pyrimidine-5-carboxylate (2): To anhydrous ethanol
(50 ml) was added sodium (0.8 g, 0.035 mol). After the sodium had
disappeared, 1 (1.1 g, 5.5 mmol) was added, and the reaction mixture
was refluxed for 1 h. Then the reaction mixture was cooled and
hydrogen chloride (5 mol/l) was added dropwise to pH = 6. Sodium
chloride was filtered and the filtrate was condensed. The residue
was dissolved in ether and washed with water. Then ether layer was
evaporated to afford 2 (0.4 g, 40%) as a yellow solid: m.p. 55–57ºC.
1H NMR(CDCl3): δ 1.40 (t, 3H, J = 7.2 Hz, CH3), 1.46 (t, 3H,
J = 7.2 Hz, CH3), 4.40 (q, 4H, J = 7.2 Hz, OCH2), 4.51(q, 4H, J = 7.2
Hz, OCH2), 9.07(s, 2H, pyrimidine). Anal. Calcd. For C9H12N2O3: C,
55.09; H, 6.16; N, 14.28. Found: C, 55.17; H, 6.33; N, 14.18.
MPOL: White solid, m.p. 62–64ºC [ref:10 63–64ºC]. 1H NMR
(CDCl3): δ 2.57 (s, 3H, SCH3), 4.67 (s, 2H, OCH2), 8.52 (s, 2H,
pyrimidine).
3: Colourless solid. m.p. 137–138ºC (ethyl acetate); 1H NMR
(CDCl3): δ 1.27 (t, 3H, J = 7.2 Hz, CH3), 2.40–2.44 (ds, 3H, SCH3),
4.12–4.35 (m, 4H, CH2O, CH2), 5.25 (bs, 0.47H, NH), 6.23 (bs,
0.53H, NH), 7.10 (d, 0.53H, J = 4.2 Hz, CH=C), 7.42 (s, 0.47H,
CH=C); IR (KBr) cm-1: 3351, 3321(NH), 1661(C=O), 1592(C=N),
1542(C=C). HRMS m/z: 201.0695, Calcd. For C8H12N2O2S + H+:
201.0692.
2-(Methylthio)pyrimidine-5-carboxylic acid (8): To ethanol
(100 ml) was added 1 (10.2 g, 5.15 mmol) and 82% potassium
hydroxide (4.57 g, 67 mmol) in ethanol (110 ml) and stirred at r.t.
for 1.5 h, then sodium carboxylate was collected by filtration.
The salt was dissolved in 25 ml water and hydrogen chloride
(5 mol/l) added to pH = 4, then filtrated and collected carboxylic
acid 8 (8.1 g, 92.5%) as a white solid: m.p. 264–266ºC (ref:6 267ºC);
Ethyl 1,6-dihydro-2-(ethoxy)pyrimidine-5-carboxylate (4): To a
suspension of LiAlH4 (0.21 g, 5.5 mmol) in anhydrous tetrahydrofuran
(10 ml) was dropwise added 2 (0.67 g, 3.4 mmol) in anhydrous
tetrahydrofuran (10 ml) at 0ºC. The mixture was stirred for 10 min
then worked up as described in Method A.
4: Colourless solid, m.p. 121–128ºC (ethyl acetate); 1H NMR
(CDCl3): δ 1.20–1.38 (m, 6H, CH3), 4.08–4.22 (m, 4H, CH2O), 4.28
(s, 2H, CH2), 4.76 (bs, 0.7H, NH), 5.82 (bs, 0.3H, NH), 7.15 (bs,
0.3H, CH=C) 7.42 (bs, 0.7H, CH=C); IR (KBr) cm-1: 3230, 3198
(N-H),1704(C=O),1641(C=N),1537(C=C);GC-MSm/z:199(M+1).
Anal. Calcd. For C9H14N2O3: C, 54.53; H, 7.12; N, 14.13. Found: C,
54.27; H, 6.99; N, 14.18.
1H NMR (DMSO-d6):
δ
2.58 (s, 3H, SCH3), 9.01 (s, 2H,
pyrimidine).
2-(Methylthio)pyrimidine-5-carboxamide (9): To
8
(1.2 g,
7.1 mmol) was added thionyl chloride (12 ml) and refluxed for
1 h, then the excess thionyl chloride was distilled off to give
2-(methylthio)pyrimidine-5-carbonyl chloride. The chloride was
diluted with 30 ml toluene and then dropwise added to 28% ammonia
solution (10 ml) at 0ºC. The reaction mixture was stirred at r. t. for
3 h, and filtered and washed with water to afford 9 (1.13 g, 95%) as
a white solid: m.p. 220–222ºC (ref: 5 218–220ºC); 1H NMR (DMSO-
d6): δ 2.56 (s, 3H, SCH3), 7.70 (bs, 1H, NH), 8.19 (bs, 1H, NH), 9.00
(s, 2H, pyrimidine).
2-Methoxypyrimidine-5-carboxamide (10): To anhydrous methanol
(50 ml) was added sodium (0.5 g, 0.022 mol). After the sodium had
disappeared, 9 (1.48 g, 8.76 mmol) was added and refluxed for
1 h. The solvent was removed, and to the residue was added water
(10 ml) and diluted hydrogen chloride to pH = 7, then filtered and
washed with water to give 10 (1.13 g, 84.3%) as a white solid: m.p.
228–230ºC; 1H NMR (DMSO-d6): δ 4.01 (s, 3H, OCH3), 7.50, 8.12
(2H, NH2), 9.02 (s, 2H, pyrimidine). IR (KBr) cm-1: 3159(NH),
1672(C=O), 1615(C=N). Anal. Calcd. For C6H7N3O2: C, 47.06; H,
4.61; N, 27.44. Found: C, 47.23; H, 4.52; N, 27.65.
1,6-Dihydro-2-(methylthio)pyrimidine-5-carbonitrile (11): To a
suspension of LiAlH4 (0.18 g, 7.1 mmol) in anhydrous tetrahydrofuran
(10 ml) was added 9 (0.8 g, 4.7 mmol) in anhydrous tetrahydrofuran
(10 ml) under reflux. After the reaction was complete detected by
TLC, to the cooled mixture water (no more than 2 ml) was carefully
added and stirred for 1h, then the inorganic salt was filtrated and
the filtrate was concentrated in vacuum. The residue was purified
by column chromatography to give compound 11 as colourless
1
solid, m.p. 116–119ºC (ethyl acetate); H NMR (CDCl3): δ 3.32 (s,
3H, SCH3), 4.15 (s, 2H, CH2), 5.50 (bs, 0.2H, NH), 6.50 (bs, 0.8H,
NH), 6.80 (bs, 1H, CH=C); IR (KBr) cm-1: 3150(N–H), 2201(CN),
1662(C=C), 1615(C=N); GC-MS m/z: 154 (M + 1). Anal. Calcd.
For C6H7N3S: C, 47.04; H, 4.61; N, 27.43. Found: C, 47.47; H, 4.77;
N, 27.79.
1,6-Dihydro-2-(methoxy)pyrimidine-5-carbonitrile (12): 12 was
isolated from the reaction mixture of LiAlH4 with 10 as described
above. 1H NMR data showed 12 could maintain equilibrium with its
1,4-dihydro isomer in solution. Colourless solid, m.p. 184–187ºC
(ethyl acetate); 1H NMR (CDCl3): 3.70, 3.80 (s, s, about 1:2 estimated
Ethyl 1,6-dihydro-2-(methylthio)pyrimidine-5-carboxylate (3)
Method A: To a suspension of LiAlH4 (0.27 g, 7.1 mmol) in 10 ml
anhydrous tetrahydrofuran or ether, cooled to certain temperature
as listed in Table 1, was added 1 (0.99 g, 5.0 mmol) in 10 ml
solvent. The reaction mixture was then stirred at room temperature.
After the reaction was complete detected by TLC, to the mixture
water was carefully added (no more than 2 ml) and stirred for
1h, then the inorganic salt was filtrated and the filtrate was
concentrated in vacuum. The residue was purified by column
1
by H NMR, 3H, OCH3),4.24, 4.26 (s, s, 2H, CH2), 4.88, 6.15 (bs,
bs, 1H, NH), 6.77 (d, 1H, J = 5.4 Hz, CH=C), 7.04 (s, 1H, CH=C);
IR (KBr) cm-1: 3183, 3114(N-H), 2207(CN), 1639(C=C), 1526(C=N).
GC-MS m/z: 138 (M + 1). Anal. Calcd. For C6H7N3O: C, 52.55;
H, 5.14; N, 30.64. Found: C, 52.64; H, 5.13; N, 30.83.
PAPER: 07/7428