ꢀ
D. Sterk et al. / Tetrahedron 68 (2012) 2155e2160
2159
HRMS (ESIþ) calcd for C15H19FNþ3 ([MþH]þ): 260.1558; found:
d
1.36 (6H, d, J¼6.6 Hz, CH3 of Pr), 3.47e3.52 (4H, m, CH3N, CH),
3.56 (3H, s, CH3SO2), 4.48 (2H, s, CH2), 7.18e7.24 (2H, m, ArH),
7.79e7.83 (2H, m, ArH). 13C NMR (CDCl3):
21.8, 27.7, 31.5, 33.1,
i
260.1566.
d
4.4. Preparation of N-[4-(4-fluorophenyl)-6-isopropyl-5-
methylpyrimidin-2-yl]-N-methylmethanesulfonamide (7)
42.5, 115.6 (d, JCF¼21.7 Hz), 119.3, 130.7 (d, JCF¼8.4 Hz), 133.7 (d,
JCF¼2.5 Hz), 158.0, 163.6 (d, JCF¼250.6 Hz), 165.6, 177.5. 19F NMR
(CDCl3):
d
ꢁ110.6 (m). IR (KBr)
n 3435, 2971, 1548, 1512, 1450, 1376,
A
solution of 4-(4-fluorophenyl)-6-isopropyl-N,5-dimethyl-
1339, 1238, 1164, 1154, 1132, 955, 847, 815, 773, 510 cmꢁ1. HRMS
(ESIþ) calcd for C16H20BrFN3O2Sþ ([MþH]þ): 416.0438; found:
416.0441.
pyrimidin-2-amine (6, 1.00 g, 3.86 mmol) in dichloromethane
(15 mL) was prepared under inert atmosphere (by nitrogen flush-
ing) and cooled to ꢁ5 ꢀC. Then Et3N (2.15 mL, 15.4 mmol, 4.0 equiv)
was added and the reaction mixture was stirred for 10 min. A so-
4.6. Preparation of N-[4-(4-fluorophenyl)-5-(hydroxymethyl)-
6-isopropylpyrimidin-2-yl]-N-methylmethanesulfonamide (2)
lution of MsCl (750
mL, 9.65 mmol, 2.5 equiv) in dry dichloro-
methane (1 mL) was prepared and slowly added (flow rate¼250
m
L/
h) into the reaction mixture. The stirring was continued for addi-
tional 8 h at ꢁ5 ꢀC. After dilution with dichloromethane (5 mL) and
gradual warming up to room temperature, the reaction mixture
was washed with water (6 mL). Aqueous layer was re-extracted
with dichloromethane (5 mL) and the combined organic layers
were washed with HCl (1 M, 3ꢂ6 mL), saturated aq NaHCO3 solu-
tion (3ꢂ6 mL) and brine (2ꢂ7 mL). The combined organic layers
were passed through a thin pad of silica gel-MgSO4, which was
subsequently washed with dichloromethane (5 mL). To the com-
bined filtrates n-hexane (10 mL) was added. Solvents were evapo-
rated to 1/5 of the initial volume. The addition of MeOH (7 mL)
resulted in precipitation of the first crop of the product, which was
collected by filtration. After the evaporation of the mother liquors
to 1/10, second crop of the product precipitated, which was also
collected by filtration and combined with the first crop to give 5-
methylpyrimidine 7 (1.18 g, 91%) as colorless crystals after drying.
Mp¼119.0 ꢀC (DSC onset) and 120.0 ꢀC (DSC peak) (lit.12 118 ꢀC). 1H
A solution of N-[4-(4-fluorophenyl)-5-(bromomethyl)-6-iso-
propylpyrimidin-2-yl]-N-methylmethanesulfonamide (3, 0.50 g,
1.20 mmol) in THF (10 mL) and water (10 mL) was stirred and
heated under reflux for 6 h. The reaction mixture was cooled to
room temperature and THF was evaporated under reduced pres-
sure. The product was extracted from the residue with MeTHF
(3ꢂ6 mL). The combined organic layers were washed with brine
(10 mL), dried over MgSO4, and the solvent was evaporated under
reduced pressure to give alcohol 2 in quantitative yield as colorless
oil, which crystallized upon standing. Mp¼131.5 ꢀC (DSC onset) and
133.6 ꢀC (DSC peak). 1H NMR (CDCl3):
d
1.32 (6H, d, J¼6.7 Hz, CH3 of
iPr), 2.27 (1H, br s, OH), 3.47e3.54 (4H, m, CH3N, CH), 3.55 (3H, s,
CH3SO2), 4.61 (2H, s, CH2), 7.12e7.17 (2H, m, ArH), 7.79e7.83 (2H, m,
ArH). 13C NMR (CDCl3):
d 22.2, 31.5, 33.0, 42.3, 57.4, 115.3 (d,
JCF¼21.6 Hz), 120.7, 131.4 (d, JCF¼8.4 Hz), 133.9 (d, JCF¼2.5 Hz), 157.8,
163.7 (d, JCF¼250.0 Hz), 166.1, 175.4. 19F NMR (CDCl3):
ꢁ111.3 (m).
d
IR (KBr) n 3308, 2979, 2934, 2909, 2875,1606,1557, 1513, 1457,1397,
NMR (CDCl3):
d
1.29 (6H, d, J¼6.7 Hz, CH3 of iPr), 2.27 (3H, s, ArCH3),
1379, 1340, 1318, 1234, 1168, 1158, 955, 859, 823, 775, 523 cmꢁ1
.
3.30 (1H, sep, J¼6.7 Hz, CH), 3.51 (3H, s, CH3N), 3.55 (3H, s, CH3SO2),
HRMS (ESIþ) calcd for C16H21FN3O3Sþ ([MþH]þ): 354.1282; found:
7.12e7.17 (2H, m, ArH), 7.79e7.83 (2H, m, ArH). 13C NMR (CDCl3):
354.1284.
d
14.3, 21.3, 31.9, 33.1, 42.4, 115.2 (d, JCF¼21.7 Hz), 118.6, 131.2 (d,
JCF¼8.7 Hz), 133.9 (d, JCF¼2.5 Hz), 157.8, 163.6 (d, JCF¼249.2 Hz),
164.7, 175.4. 19F NMR (CDCl3):
4.7. Preparation of N-[4-(4-fluorophenyl)-5-formyl-6-
isopropylpyrimidin-2-yl]-N-methylmethanesulfonamide (1)
d
ꢁ111.3 (m). This is a known com-
pound with spectroscopic and physical properties consistent with
those reported in the literature.12
4.7.1. From alcohol 2. A solution of N-[4-(4-fluorophenyl)-5-
(hydroxymethyl)-6-isopropylpyrimidin-2-yl]-N-methylmethanes-
ulfonamide (2, 2.00 g, 5.66 mmol) in DMSO (20 mL) was heated to
85 ꢀC Ac2O (2.15 mL, 22.79 mmol, 4.0 equiv) was slowly added (flow
4.5. Preparation of N-[4-(4-fluorophenyl)-5-(bromomethyl)-
6-isopropylpyrimidin-2-yl]-N-methylmethanesulfonamide (3)
rate 150 mL/h) and the reaction mixture was left to stir for 17 h at
4.5.1. Using low pressure Hg-lamp. A solution of N-[4-(4-fluoro-
phenyl)-6-isopropyl-5-methylpyrimidin-2-yl]-N-methylmethane-
sulfonamide (7, 3.94 g, 11.69 mmol) and NBS (4.37 g, 24.50 mmol,
2.1 equiv) in acetonitrile (70 mL) was poured into the photo-
chemical reactor. The solution was purged with nitrogen gas for
10 min and the reactor was sealed. The reaction mixture was agi-
tated and irradiated for 68 h at ambient temperature. The dark-red
colored reaction mixture was diluted with H2O (70 mL). The pre-
cipitate was collected by filtration, and washed with MeOH/H2O
(1:1, 2ꢂ15 mL) and then MeOH (20 mL) to afford bromide 3 (3.59 g,
74%) as off-white crystals after drying.
85 ꢀC. Water (15 mL) was added and the resulting precipitate was
collected by filtration. The precipitate was dissolved in hot EtOAc
(20 mL), cooled to 4 ꢀC and the precipitated solid was collected by
filtration and dried to give product 1 (0.62 g, 31%) as colorless
crystals.
4.7.2. From bromide 3. A mixture of NaHCO3 (0.40 g, 4.80 mmol,
2 equiv) and NaI (36.0 mg, 0.24 mmol 0.1 equiv) in DMSO
(10 mL) was flushed with nitrogen, sealed, and maintained at 20 ꢀC
while
a solution of N-[4-(4-fluorophenyl)-5-(bromomethyl)-6-
isopropylpyrimidin-2-yl]-N-methylmethanesulfonamide (3, 1.00 g,
2.40 mmol) in DMSO (9 mL) was slowly added over 3 h time. The
reaction mixture was stirred for 68 h at 20 ꢀC, then warmed to 70 ꢀC
and Ac2O (1.5 mL, 16.4 mmol, 6.6 equiv) was added dropwise in 3 h.
The stirring was continued for additional 4 h at 70 ꢀC. Then, the
reaction mixture cooled on an ice bath, and the product was pre-
cipitated by slow addition of water (20 mL). The precipitate was
collected by filtration, washed with water (10 mL) and MeOH
(10 mL), and dried under reduced pressure to afford aldehyde 1
(0.79 g, 94%) as colorless solid. Mp¼178.2 ꢀC (DSC onset) and
4.5.2. Using medium pressure Hg-lamp. A solution of N-[4-(4-
fluorophenyl)-6-isopropyl-5-methylpyrimidin-2-yl]-N-methylme-
thanesulfonamide (7, 3.94 g, 11.69 mmol) and NBS (4.37 g,
24.50 mmol, 2.1 equiv) in acetonitrile (75 mL) was poured into the
photochemical reactor. The solution was purged with nitrogen gas
for 10 min and the reactor was sealed. The reaction mixture was
agitated and irradiated for 16 h at ambient temperature. The dark-
red colored reaction mixture was diluted with H2O (100 mL). The
precipitate was collected by filtration, washed with water (50 mL),
and then with MeOH/H2O (1:9, 3ꢂ15 mL) and dried to afford bro-
mide 3 (3.91 g, 80%) as yellowish crystalline solid after drying.
Mp¼141.8 ꢀC (DSC onset) and 142.9 ꢀC (DSC peak). 1H NMR (CDCl3):
179.1 ꢀC (DSC peak) (lit.13 147e148 ꢀC). 1H NMR (CDCl3):
d
1.32 (6H,
i
d, J¼6.7 Hz, CH3 of Pr), 3.55 (3H, s, NCH3), 3.64 (3H, s, SCH3), 4.01
(1H, sep, J¼6.7 Hz, CH), 7.20e7.27 (2H, m, ArH), 7.61e7.66 (2H, m,
ArH), 9.97 (1H, s, CHO). 13C NMR (CDCl3):
d 21.6, 31.9, 33.0, 42.5,