5736
Z. Ge et al. / Tetrahedron 70 (2014) 5730e5738
ꢀ
1
before evaporation. The residue was purified by column chroma-
FTIR (KBr, cm ): 3291, 2949, 1629, 1578, 1496, 1400, 1119, 631. MS
þ
tography on silica gel using 1:8 EA/hexane as eluent to give a white
(EI, m/z): calcd: 277.0; found: 277 (M ).
1
solid of 6. Yield: 0.220 g, 75%. H NMR (600 MHz, CDCl
3
): 7.18 (br, s,
2
9
6
H), 3.90e3.91 (m, 9H), 1.36e1.39 (t, J¼7.2 Hz, 3H), 0.27e0.28 (m,
4.2.10. Synthesis of methyl 3,5-dimethoxy-4-((5-(methylamino)pyr-
imidin-2-yl) ethynyl)benzoate (11a). A mixture of 10a (0.168 g,
0.7 mmol), 7 (0.172 g, 0.8 mmol), PdCl (PPh ) (0.050 g, 0.07 mmol),
2 3 2
13
H). C NMR (150 MHz, CDCl
3
): 163.3, 160.6, 159,0, 133.8, 123.7,
þ
2.2, 14.2. MS (EI, m/z): calcd: 292.1; found: 292 (M ).
and CuI (0.014 mg, 0.07 mmol) was degassed and replaced by argon,
to which dried THF (5.5 mL) and diisopropylamine (0.27 mL) were
injected subsequently. The mixture was stirred for 24 h at room
temperature before evaporation to remove THF. The residue was
purified by column chromatography on silica gel using ethyl ace-
4
.2.5. Synthesis of methyl 4-ethynyl-3,5-dimethoxybenzoate (7). A
2 3
mixture of 6 (0.220 g, 0.8 mmol), K CO (0.518 g, 3.8 mmol), dried
methanol (10 mL), and dichloromethane (10 mL) was stirred at
room temperature for 2 h, which was then quenched with water
and extracted with ether (20 mLꢁ3). The organic layer was washed
tate/hexane¼3:1 as the eluent to give a yellow solid of 11a (0.180 g,
1
with brine and dried over MgSO
4
before evaporation to give
78%). H NMR (600 MHz, CDCl
3
): 8.11 (s, 2H), 7.21 (s, 2H), 4.01 (br s,
1
13
a brown solid of 7. Yield: 0.165 g, 100%. H NMR (600 MHz, CDCl
3
):
.20 (s, 2H), 3.92 (s, 6H), 3.90 (s, 3H), 3.65 (s, 1H); C NMR
150 MHz, CDCl ): 166.4, 161.8, 131.5, 104.6, 104.5, 87.8, 75.7, 56.3,
1H), 3.93 (s, 6H), 3.90 (s, 3H), 2.82 (s, 3H). C NMR (150 MHz,
CDCl ): 168.5,161.7, 142.4,140.8,140.5, 131.3, 105.3,104.3, 98.7, 56.2,
13
7
(
3
ꢀ1
3
29.7. FTIR (KBr, cm ): 3276, 2947, 1725, 1579, 1420, 1326, 1239,
1125, 765. MS (EI, m/z): calcd: 327.1; found: 327 (M ).
ꢀ1
þ
5
6
2.5. FTIR (KBr, cm ): 3272, 2952,1714,1578,1458,1129,1000, 766,
þ
70. MS (EI, m/z): calcd: 220.0; found: 220 (M ).
4.2.11. Synthesis of methyl 4-((5-(butylamino)pyrimidin-2-yl)ethy-
4.2.6. Synthesis of 2-chloropyrimidin-5-amine (8). A mixture of 2-
nyl)-3,5-dimethoxybenzoate (11b). Compound 11b was synthesized
chloro-5-nitropyrimidine (0.160 g, 1 mmol), iron powder (0.200 g,
.6 mmol), dried ethanol (2.5 mL), and acetic acid (0.4 mL) was
refluxed for 6 h, which was then diluted with ethyl acetate, and
neutralized with aqueous NaHCO before it was filtered with Celite.
The filtrate was extracted with ethyl acetate (20 mLꢁ3), washed
with brine, and dried over MgSO . Evaporation of the solvents gives
a yellow solid of 8. Yield: 0.127 g, 98%. H NMR (600 MHz, DMSO-
in the similar Sonogashira cross-coupling reaction as 11a starting
1
3
3
from 10b and 7. Yield: 78%. H NMR (600 MHz, CDCl ): 8.07 (s, 2H),
7.19 (s, 2H), 3.96 (br s, 1H), 3.91(s, 6H), 3.89 (s, 3H), 3.12e3.15 (t,
J¼7.2 Hz, 2H), 1.58e1.61 (quint, J¼7.2 Hz, 2H), 1.38e1.40 (sext,
3
1
3
J¼7.2 Hz, 2H), 0.91e0.94 (t, J¼7.2 Hz, 3H). C NMR (150 MHz, CDCl
3
):
4
166.5, 161.6, 142.4, 140.6, 140.2, 131.3, 105.3, 104.3, 98.8, 56.2, 52.3,
42.7, 31.1, 20.0, 13.7. FTIR (KBr, cm ): 3267, 2934, 1731, 1580, 1431,
1329, 1238, 1132, 762. MS (EI, m/z): calcd: 369.2; found: 369 (M ).
1
ꢀ1
13
þ
d
6
): 8.03 (s, 2H), 5.76 (br s, 2H). C NMR (150 MHz, DMSO-d
6
):
ꢀ
1
146.0, 144.2, 142.3. FTIR (KBr, cm ): 3394, 3332, 3212, 1649, 1585,
þ
1545, 1412, 1163, 644. MS (EI, m/z): calcd: 129.0; found: 129 (M ).
4.2.12. Synthesis
of
4-iodo-3,5-dimethoxyaniline
(12). 3,5-
Dimethoxyaniline (1.532 g, 10 mmol) was dissolved in THF
ꢂ
4
.2.7. Synthesis of 2-iodopyrimidin-5-amine (9). A 20 mL flask was
(25 mL) and H
(2.665 g, 10.5 mmol) and NaHCO
in three portions, respectively, in 3 h. The mixture was diluted with
ether and stirred with K SO before the red colour disappeared and
then extracted with ether. The organic layer was washed with brine
and dried over anhydrous MgSO . After evaporation, the residue was
recrystallized from methanol and THF to afford 12 as a grey crystal.
2
O (25 mL) and cooled to 0 C, to which iodine
charged with 8 (0.648 g, 5.0 mmol) and cooled by salt ice bath to
3
(0.882 g, 10.5 mmol) were added
ꢂ
ꢀ
5
C, then HI (57%, 6.67 mL, 10 equiv) was added dropwise and
ꢂ
stirred for 5 h at ꢀ5 C. The mixture was quenched with water and
2
3
neutralized carefully by 5 g NaHCO
colorized with K SO . The solution was extracted by ethyl acetate
and the organic layer was washed with brine and dried over an-
hydrous MgSO . Evaporation of the solvents afforded a yellow
crystal of 9. Yield: 0.939 g, 85%. H NMR (600 MHz, CDCl
3
to pH¼7e8 followed by de-
2
3
4
1
4
6
Yield: 1.25 g, 45%. H NMR (600 MHz, DMSO-d ): 5.93 (s, 2H), 5.37
(br s, 2H), 3.69(s, 6H); C NMR (150 MHz, DMSO-d
91.0, 59.0, 55.7. MS (EI, m/z): calcd: 279.0; found: 279 (M ).
1
13
3
): 7.93 (s,
): 144.4,143.1, 110.8. FTIR
6
): 159.0, 151.0,
13
þ
2
H), 5.72 (s, 2H). C NMR (150 MHz, CDCl
3
ꢀ1
(
KBr, cm ): 3368, 3300, 3185, 1629, 1571, 1536, 1402, 1123, 890,
þ
735, 638. MS (EI, m/z): calcd: 220.9; found: 221 (M ).
4.2.13. Synthesis of 2,2,2-trifluoro-N-(4-iodo-3,5-dimethoxyphenyl)
acetamide (13). A 10 mL flask was charged with 12 (0.279 g,
4
.2.8. Synthesis of N-methyl-2-iodo pyrimidin-5-amine
2 2
1 mmol), then degassed and backfilled with argon. Dried CH Cl
(
10a). Compound 9 (2.300 g, 10.4 mmol) was dissolved in 25 mL
(5 mL) and pyridine (0.12 mL) were added by injection. The mixture
was cooled by ice bath, and then trifluoric acid anhydride (TFAA,
0.2 mL) was added dropwise. The mixture was stirred for 1.5 h at
0 C, warmed to room temperature, and stirred for 1.5 h. The mixture
was quenched with brine and extracted with ethyl acetate, washed
ꢂ
dried THF and cooled to 0 C, to which NaH (60% in paraffin liquid,
0
.200 g, 5 mmol) was added in potions under nitrogen. The mixture
was stirred at for 1 h, then warmed to room temperature for an-
other 1 h before Bu NBr (0.161 g, 5 mmol) and MeBr (1.56 mL,
5 mmol) were added under nitrogen. The mixture was stirred
ꢂ
4
2
with 5% HCl, brine, NaHCO
tion, the yellow residue was purified by columnwith SiO
acetate/hexane¼1:4 as eluent to give a white crystal of 13. Yield:
3
, and brine, respectively. After evapora-
overnight and then quenched with methanol and extracted with
ethyl acetate. After removing the solvents, the residue was purified
by column chromatography (silica gel using EA/hexane¼1:3 then
2
using ethyl
1
3
0.3000 g, 80%. H NMR (600 MHz, CDCl ): 7.94 (br s, 2H), 6.81 (s, 2H),
1
3
increased 2:1 as eluent) to give a yellow solid of 10a (0.470 g, 40%).
3.76 (s, 6H). C NMR (150 MHz, CDCl
3
): 59.8, 154.6, 137.2, 114.6, 96.6,
1
þ
H NMR (600 MHz, DMSO-d
6
): 7.84 (s, 2H), 6.25 (br s, 1H), 2.67 (s,
73.8, 56.7. MS (EI, m/z): calcd: 375.0; found: 375 (M ).
13
3
(
H). C NMR (150 MHz, DMSO-d ): 143.4, 142.5, 111.6, 28.7. FTIR
6
ꢀ1
KBr, cm ): 3326, 2992, 1580, 1486, 1391, 1128, 627. MS (EI, m/z):
4.2.14. Synthesis of N-butyl-2,2,2-trifluoro-N-(4-iodo-3,5-
dimethoxyphenyl)acetamide (14). A 50 mL flask was charged with
þ
calcd: 235.0; found: 235 (M ).
2 3
13 (1.522 g, 4 mmol), K CO (1.658 g,12 mmol), acetone (15 mL) and
4
. 2. 9. Synthesis of N-butyl-2-iodopyrimidin-5-amine
BuBr (2.58 mL, 24 mmol). The mixture was heated at reflux for 16 h
(
1
10b). Compound 10b was prepared in the similar procedure as
0a using n-butylbromide instead of methylbromide. Yield: 39%. H
before acetone was removed in vacuum. The residue was extracted
with ethyl acetate and the organic phase was dried over MgSO .
4
1
NMR (600 MHz, CDCl ): 7.84 (s, 2H), 3.80 (br s, 1H), 3.06e3.09 (t,
3
After removing the solvents, the residue was purified by column
13
2
H), 1.57e1.60 (m, 2H), 1.36e1.42 (m, 2H), 0.91e0.94 (q, 3H).
C
chromatography (on silica gel using EA/hexane¼1:6) to give a col-
1
NMR (150 MHz, CDCl
3
): 144.4, 143.1, 111.4, 42.78, 31.0, 20.0, 13.7.
ourless liquid of 14 (1.500 g, 87%). H NMR (600 MHz, CDCl
3
): 6.30