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Paper
Synthesis
reported in Hz. The following abbreviations are used to indicate mul-
tiplicities: s = singlet, d = doublet, t = triplet, q = quartet, quin = quin-
tet, m = multiplet. HRMS (ESI) spectra were recorded on a Thermo-
Fisher MicroTOF II instrument by using CH3CN as solvent.
tered and concentrated under reduced pressure. The residue was pu-
rified by column chromatography on silica gel (CH2Cl2/CH3OH, 200:1)
to give 16 as a white solid; yield: 861.1 mg (91%).
Mp 42.1–42.7 °C.
1H NMR (600 MHz, CDCl3): = 7.69 (s, 1 H), 7.50 (s, 1 H), 7.06 (d, J =
8.5 Hz, 2 H), 6.82 (d, J = 8.5 Hz, 2 H), 4.38 (t, J = 7.2 Hz, 2 H), 3.78 (s, 3
H), 2.59 (t, J = 7.6 Hz, 2 H), 1.93 (quin, J = 7.3 Hz, 2 H), 1.61 (dq, J = 9.5,
7.5 Hz, 2 H).
13C NMR (151 MHz, CDCl3): = 157.90, 133.79, 133.45, 129.26,
123.14, 113.84, 55.28, 50.04, 34.23, 29.74, 28.38.
4-Chloro-1-(4-methoxyphenyl)-1-butanone (14)
Anisole (13; 1.93 g, 17.87 mmol, 2.0 equiv), aluminum chloride (1.55
g, 11.62 mmol, 1.3 equiv) and dry CH2Cl2 (3 mL) were taken into a
round-bottom flask. The solution was cooled to 0 °C and 4-chloro-
butyryl chloride (1.0 mL, 8.94 mmol, 1.0 equiv) was added dropwise
under ice-cooled conditions. The resulting suspension was stirred at
room temperature for 1 h. The reaction was quenched by pouring the
orange-colored solution into an ice–water mixture. CH2Cl2 was used
to extract the desired product, and the organic layer was washed with
water, dried with Na2SO4, filtered and concentrated under reduced
pressure. The residue was purified by column chromatography on sil-
ica gel (petroleum ether/EtOAc, 125:1) to give 14 as a white solid;
yield: 1.88 g (99%).
HRMS (ESI): m/z [M + H]+ calcd for C13H18N3O: 232.1444; found:
232.1447.
4-[4-(1H-1,2,3-Triazol-1-yl)butyl]phenol (9)
1-[4-(4-Methoxyphenyl)butyl]-1H-1,2,3-triazole (16; 500 mg, 2.16
mmol) and 40% aqueous HBr (5 mL) were heated to 80 °C for 24 h.
After completion of the reaction, the mixture was diluted with water
and adjusted to pH 6 by addition of saturated aqueous NaHCO3.
CH2Cl2 was used to extract the desired product, and the organic layer
was dried with Na2SO4, filtered and concentrated under reduced pres-
sure. The residue was purified by column chromatography on silica
gel (CH2Cl2/CH3OH, 100:1) to give 9 as a white solid; yield: 393.4 mg
(84%).
Mp 31.7–32.7 °C.
1H NMR (600 MHz, DMSO-d6): = 7.94 (d, J = 8.9 Hz, 2 H), 7.04 (d, J =
8.9 Hz, 2 H), 3.84 (s, 3 H), 3.70 (t, J = 6.7 Hz, 2 H), 3.11 (t, J = 7.1 Hz, 2
H), 2.05 (quin, J = 6.9 Hz, 2 H).
13C NMR (151 MHz, DMSO-d6): = 197.72, 163.59, 130.68, 129.87,
114.28, 56.18, 45.39, 35.19, 27.47.
Mp 117.7–118.9 °C.
HRMS (ESI): m/z [M + H]+ calcd for C11H14ClO2: 213.0677; found:
213.0679.
1H NMR (600 MHz, DMSO-d6): = 9.15 (s, 1 H), 8.10 (s, 1 H), 7.71 (s, 1
H), 6.94 (d, J = 8.4 Hz, 2 H), 6.65 (d, J = 8.4 Hz, 2 H), 4.37 (t, J = 7.1 Hz, 2
H), 2.46 (t, J = 7.6 Hz, 2 H), 1.79 (quin, J = 7.2 Hz, 2 H), 1.44 (tt, J = 9.4,
6.7 Hz, 2 H).
1-(4-Methoxyphenyl)-4-(1H-1,2,3-triazol-1-yl)-1-butanone (15)
4-Chloro-1-(4-methoxyphenyl)-1-butanone (14; 1.00 g, 4.70 mmol,
1.0 equiv) was dissolved in DMF (10 mL) in a sealed tube, solid NaN3
(366.8 mg, 5.64 mmol, 1.2 equiv) was added and the mixture was
stirred at 70 °C. After 3 h, propiolic acid (658.7 mg, 9.40 mmol, 2.0
equiv), CuI (179.1 mg, 0.94 mmol, 0.2 equiv), sodium ascorbate (372.6
mg, 1.88 mmol, 0.4 equiv) and Cs2CO3 (766.0 mg, 2.35 mmol, 0.5
equiv) were added to the above system. The mixture was stirred at
100 °C for 5 h until the azide had been completely consumed (moni-
tored by TLC). The mixture was diluted with water and then extracted
with EtOAc or CH2Cl2. The combined organic layers were washed with
saturated brine, dried with Na2SO4, filtered and concentrated under
reduced pressure. The residue was purified by column chromatogra-
phy on silica gel (CH2Cl2/CH3OH, 100:1) to give 15 as a white solid;
yield: 1.05 g (91%).
13C NMR (151 MHz, DMSO-d6): = 155.78, 133.70, 132.21, 129.60,
125.13, 115.48, 49.40, 34.00, 29.84, 28.59.
HRMS (ESI): m/z [M + H]+ calcd for C12H16N3O: 218.1288; found:
218.1295.
4-(Trifluoromethyl)cinnamamide (11)
4-(Trifluoromethyl)cinnamic acid (10; 1.00 g, 4.63 mmol) was dis-
solved in dry CH2Cl2 (12 mL) and DMF (0.16 mL) under N2, and SOCl2
(0.47 mL) was added dropwise. This system was stirred at room tem-
perature for 3 h. The obtained reaction mixture was added dropwise
to 25% aqueous ammonia (12 mL). The mixture was stirred at room
temperature for 3 h. The crystals were filtered, washed with water
and dried under reduced pressure to give 11 as a white solid; yield:
908.6 mg (91%).
Mp 89.0–89.3 °C.
1H NMR (600 MHz, DMSO-d6): = 8.17 (s, 1 H), 7.91 (d, J = 8.7 Hz, 2
H), 7.73 (s, 1 H), 7.03 (d, J = 8.7 Hz, 2 H), 4.45 (t, J = 7.1 Hz, 2 H), 3.83 (s,
3 H), 2.99 (t, J = 7.1 Hz, 2 H), 2.15 (quin, J = 7.1 Hz, 2 H).
13C NMR (151 MHz, DMSO-d6): = 197.64, 163.59, 133.70, 130.66,
129.85, 125.21, 114.28, 56.20, 49.06, 34.68, 25.08.
Mp 186.9–187.0 °C.
1H NMR (600 MHz, DMSO-d6): = 7.76 (d, J = 7.7 Hz, 4 H), 7.65 (s, 1
H), 7.49 (d, J = 15.8 Hz, 1 H), 7.26 (s, 1 H), 6.74 (d, J = 15.8 Hz, 1 H).
13C NMR (151 MHz, DMSO-d6): = 166.62, 139.43, 137.94, 129.65 (q,
J = 31.9 Hz), 128.62, 126.23 (q, J = 3.9 Hz), 125.62, 124.56 (q, J = 272.1
Hz).
HRMS (ESI): m/z [M + H]+ calcd for C13H16N3O2: 246.1237; found:
HRMS (ESI): m/z [M + H]+ calcd for C10H9F3NO: 216.0631; found:
246.1233.
216.0634.
1-[4-(4-Methoxyphenyl)butyl]-1H-1,2,3-triazole (16)
To a solution of 1-(4-methoxyphenyl)-4-(1H-1,2,3-triazol-1-yl)-1-bu-
tanone (15; 1.00 g, 4.08 mmol, 1.0 equiv) in TFA (10 mL) was added
triethylsilane (1.30 mL, 8.15 mmol, 2.0 equiv). The reaction mixture
was stirred at room temperature for 24 h. After completion of the re-
action, the mixture was diluted with EtOAc and washed with saturat-
ed aqueous NaHCO3, saturated brine and water, dried with Na2SO4, fil-
4-Chloromethyl-2-[(E)-2-(4-trifluoromethylphenyl)ethenyl]-1,3-
oxazole (12)
4-(Trifluoromethyl)cinnamamide (11; 500 mg, 2.32 mmol) and 1,3-
dichloroacetone (737.6 mg, 5.81 mmol) were added to toluene (3 mL)
and the mixture was refluxed under heating for 7 h. EtOAc (20 mL)
was added and the mixture was washed with water, dried with
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