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graphy (eluent: petroleum ether (60–908C)/CH2Cl2 =10:1) to afford
3a as a white crystalline solid (209.8 mg, 92%).
column chromatography (eluent: petroleum ether (60–908C)/
CH2Cl2 =10:1) to afford 10 as a yellow oil (216.3 mg, 68%).
Typical procedure for the direct trifluoromethylation of 1’
with TMSCF3 (2)
Typical procedure for the reactions of 4 with guanidine (11)
Synthesis of 4-(methylthio)-6-phenyl-5-(trifluoromethyl)pyrimi-
din-2-amine (12a): A mixture of 4b (292.0 mg, 1.0 mmol), guani-
dine nitrate (122 mg, 1.0 mmol), and K2CO3 (275.8 mg, 2 mmol)
was stirred in CH3CN (10 mL) at 1008C for 20 h. The resultant mix-
ture was cooled to ambient temperature and poured into ice-cold
water (20 mL), and extracted with ethyl acetate (3ꢁ25 mL), dried
over anhydrous Na2SO4, and filtered. The combined orgainc filtrate
was evaporated under reduced pressure. The resulting residue was
purified by silica-gel column chromatography (eluent: petroleum
ether (60–908C)/ethyl acetate=4:1) to afford 12a as a white solid
(213.8 mg, 75%).
Synthesis of 4,4-bis(methylthio)-3-(trifluoromethyl)but-3-en-2-
one (4a): Under an argon atmosphere, a mixture of a-oxoketene
dithioacetal 1a’ (162 mg, 1.0 mmol), TMSCF3 2 (426 mg, 3.0 mmol),
Cu(OH)2 (19.4 mg, 0.2 mmol), phen (36.0 mg, 0.2 mmol), KF
(174.0 mg, 3.0 mmol), and Ag2CO3 (547.6 mg, 2.0 mmol) in DCE
(8 mL) was stirred at 1008C for 24 h. After cooling to ambient tem-
perature, the resulting mixture was filtered through a short pad of
Celite and rinsed with CH2Cl2 (20 mL). The combined organic fil-
trate was evaporated under reduced pressure. The resultant resi-
due was purified by silica-gel column chromatography (eluent: pe-
troleum ether (60–908C)/CH2Cl2 =10:1) to afford 4a as a yellow oil
(184.0 mg, 80%).
Typical procedure for the reactions of 4 with hydrazine (13)
Typical procedure for the direct trifluoromethylation of 5
with TMSCF3 (2)
Synthesis of 5-(methylthio)-3-p-tolyl-4-(trifluoromethyl)-1H-pyra-
zole (14a): To a stirred solution of 4d (306.0 mg, 1.0 mmol) in eth-
anol (10 mL), hydrazine hydrate (85%, 88.3 mg, 1.5 mmol) was
added, and the resultant mixture was refluxed for 8 h. After the re-
action was complete (monitored by TLC), the volatiles were re-
moved under reduced pressure. The resulting residue was dis-
solved in chloroform (20 mL), and washed with water (2ꢁ20 mL)
and brine (20 mL), and dried over anhydrous Na2SO4. The organic
filtrate was evaporated under reduced pressure. The resultant resi-
due was purified by silica-gel column chromatography (eluent: pe-
troleum ether (60–908C)/ethyl acetate=10:1) to afford 14a as
a colorless crystalline solid (201.3 mg, 74%). m.p. 128–1308C.
1H NMR (CDCl3, 400 MHz): d=11.94 (br, 1H, NH), 7.30 (d, J=8.0 Hz,
2H, aromatic CH) and 7.21 (d, J=8.0 Hz, 2H, aromatic CH), 2.43 (s,
3H, SCH3), 2.39 ppm (s, 3H, CH3C6H4); 13C{1H} NMR (CDCl3,
100 MHz): d=146.5 (br), 140.2 and 125.3 (Cq), 129.5 and 128.5 (aro-
matic CH), 123.1 (q, J=266 Hz, CF3), 108.6 (q, J=36 Hz, CÀCF3),
21.4 (CH3C6H4), 15.6 ppm (SCH3); 19F NMR (CDCl3, 376.5 MHz): d=
À53.99 ppm (s, 3 F); HRMS (ESI): m/z calcd for C12H12F3N2S:
273.0673 [M+H]+; found: 273.0680.
Synthesis of 4-(methylthio)-4-phenyl-3-(trifluoromethyl)but-3-
en-2-one (6a): Under an argon atmosphere, a mixture of 5a
(192.0 mg, 1.0 mmol), TMSCF3 (2) (426 mg, 3.0 mmol), Cu(OH)2
(19.4 mg, 0.2 mmol), phen (36.0 mg, 0.2 mmol), KF (174.0 mg,
3.0 mmol), and Ag2CO3 (547.6 mg, 2.0 mmol) in DCE (8 mL) was
stirred at 1008C for 24 h. After cooling to ambient temperature,
the resulting mixture was filtered through a short pad of Celite
and rinsed with CH2Cl2 (20 mL). The combined organic filtrate was
evaporated under reduced pressure. The resultant residue was pu-
rified by silica-gel column chromatography (eluent: petroleum
ether (60–908C)/CH2Cl2 =10:1) to afford 6a as
a yellow oil
(182.0 mg, 70%).
Typical procedure for the arylation of 6 with phenylboronic
acid (7)
Synthesis of 4,4-diphenyl-3-(trifluoromethyl)but-3-en-2-one (8a):
Under a nitrogen atmosphere, a mixture of 6a (260 mg, 1.0 mmol),
phenylboronic acid (7) (183 mg, 1.5 mmol), Pd(PPh3)4 (86 mg,
0.075 mmol), 1,2-bis(diphenylphosphino)ethane (dppe, 30 mg,
0.075 mmol), copper(I) thiophene-2-carboxylate (CuTC, 382 mg,
2.0 mmol), and K2CO3 (276 mg, 2.0 mmol) in THF (10 mL) was
stirred at 508C for 13 h. After cooling to ambient temperature, the
resulting mixture was filtered through a short pad of Celite and
rinsed with CH2Cl2 (20 mL). The combined organic filtrate was
evaporated under reduced pressure. The resultant residue was pu-
rified by silica-gel column chromatography (eluent: petroleum
ether (60–908C)/CH2Cl2 =10:1) to afford 8a as a yellow solid
(235 mg, 81%).
Kinetic isotope effect (KIE) experiments
The trifluoromethylation reactions of 1b and its deuterated form,
1b[D], were carried out in a parallel manner under the optimized
conditions. The GC yields from the reactions were carefully
checked by the signal integration of the target product 3b with n-
dodecane as the internal standard. The kH/kD (0.41/0.42=1.0) value
was calculated according to the yields of 3b from the reactions at
2 h.
Trifluoromethylation of 9 with TMSCF3 (2)
TEMPO- or BHT-trapping radical experiment
Synthesis of 4,4-dip-tolyl-3-(trifluoromethyl)but-3-en-2-one (10):
Under an argon atmosphere, a mixture of 9 (250.0 mg, 1.0 mmol),
TMSCF3 (2) (426 mg, 3.0 mmol), Cu(OH)2 (19.4 mg, 0.2 mmol), phen
(36.0 mg, 0.2 mmol), KF (174.0 mg, 3.0 mmol), and Ag2CO3
(547.6 mg, 2.0 mmol) in DCE (8 mL) was stirred at 1008C for 24 h.
After cooling to ambient temperature, the resulting mixture was
filtered through a short pad of Celite and rinsed with CH2Cl2
(20 mL). The combined organic filtrate was evaporated under re-
duced pressure. The resultant residue was purified by silica-gel
Under an argon atmosphere, a mixture of a-oxoketene dithioacetal
1a (160 mg, 1.0 mmol), TMSCF3 (2) (426 mg, 3.0 mmol), Cu(OH)2
(9.7 mg, 0.1 mmol), phen (18.0 mg, 0.1 mmol), KF (174.0 mg,
3.0 mmol), TEMPO or BHT (2.0 mmol), and Ag2CO3 (547.6 mg,
2.0 mmol) in DCE (8 mL) was stirred at 1008C for 24 h. The resul-
tant mixture was cooled to room temperature and subject to GC
analysis by using PhCF3 as the internal standard. No target product
3a was found in the reaction mixture.
Chem. Eur. J. 2014, 20, 3439 – 3445
3444
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