The Journal of Organic Chemistry
Note
bis(trifluoromethyl)phenyl isothiocyanate (0.50 mL; 2.70 mmol), and
the resulting mixture was heated at 50 °C for 80 h. The reaction
mixture was concentrated in vacuo to obtain a yellow oil. Purification
by flash chromatography over silica gel (230−400 mesh) using
CH2Cl2/petroleum ether (30:70 followed by 50:50) afforded a white
solid (1.30 g, 2.59 mmol, 99%). FT-IR (KBr): 3207 (m), 3050 (m),
in 25 mL round-bottom flask was added NaH (60% suspension in oil;
132 mg, 5.50 mmol), and the reaction mixture was stirred at rt for 16
h. The reaction was diluted with EtOAc (10 mL), and H2O (5 mL)
was added dropwise to the reaction mixture, the organic layer was
collected, and the aqueous layer was extracted with EtOAc (10 mL ×
2). Combined organic layers were dried over anhyd Na2SO4 and
concentrated in vacuo to obtain light yellow oil. Purification by
column chromatography over silica gel (230−400 mesh) using
petroleum ether and then 2:98 EtOAc/petroleum ether afforded a
white solid (523 mg, 1.47 mmol, 65%). Mp: 107−110 °C. FT-IR
(KBr): 3308 (s), 3120 (m), 2946 (s), 1703 (s), 1567 (s), 1272 (s),
1
1557 (s), 1376 (s), 1290 (s). H NMR (400 MHz, DMSO-d6): δ
10.65 (s, 2H), 8.20 (s, 4H), 7.86 (s, 2H). 13C NMR (100 MHz,
DMSO-d6): δ 180.6, 141.2, 130.3 (q, J = 33 Hz), 124.1, 123.1 (q, J =
271 Hz), 117.8. HRMS (ESI+): calcd for C17H9F12N2S ([M + H]+)
501.0295, found 501.0296.
1
1240 (s). H NMR (400 MHz, CDCl3): δ 7.89 (s, 2H), 7.54 (s, 1H),
1,3-Bis(3,5-bis(trifluoromethyl)phenyl)-1,3-dimethylthiour-
ea (3b). To the suspension of NaH (60% suspension in oil, 86.0 mg,
2.15 mmol) in THF (0.6 mL) was added a solution of 1,3-bis(3,5-
bis(trifluoromethyl)phenyl)urea (416 mg, 0.86 mmol) dropwise at rt.
After 10 min, MeI (0.14 mL, 2.15 mmol) was added, and the resulting
yellow solution was heated at 50 °C for 18 h. Water (5 mL) was added
dropwise to the reaction mixture and extracted with DCM (15 mL ×
4). The combined organic layers were dried over anhyd Na2SO4 and
concentrated in vacuo to obtain a yellowish white solid. Recrystalliza-
tion from a MeOH−DCM mixture afforded 1,3-bis(3,5-bis-
(trifluoromethyl)phenyl)-1,3-dimethylurea as a white crystalline solid
(243 mg, 0.47 mmol, 55%). Mp: 149−151 °C. FT-IR (KBr): 3546
6.94 (s, 1H), 4.83−4.73 (m, 1H), 1.98−1.90 (m, 2H), 1.80−1.69 (m,
2H), 1.61−1.22 (m, 6H). 13C NMR (100 MHz, CDCl3): δ 152.7,
139.7, 132.40 (q, J = 33 Hz), 121.60 (q, J = 271 Hz), 118.1, 116.5,
74.8, 31.7, 25.2, 23.6. HRMS (ESI+): calcd for C15H17F6NO2Na ([M
+ Na]+) 378.0905, found 378.0901.
1,3-Bis-(4-methoxyphenyl)thiourea (7). A solution of 4-
methoxyaniline (2.0 g; 16.24 mmol) in CH2Cl2 (100 mL) in a 250
mL round-bottom flask was cooled to 0 °C, and satd aqueous
NaHCO3 solution (100 mL) was added. Stirring was stopped, and
thiophosgene (1.4 mL, 17.87 mmol) was added to the CH2Cl2 layer.
The resulting mixture was stirred vigorously at rt for 30 min. The
organic phase was separated, dried over anhyd Na2SO4, and
concentrated in vacuo to obtain a yellow oil. To this oil in CH2Cl2
(35 mL) in a 100 mL round-bottom flask was added a solution of 4-
methoxyaniline (1.82 g; 14.77 mmol) in CH2Cl2 (5 mL), and the
resulting mixture was stirred at rt for 48 h. The reaction mixture was
concentrated in vacuo to obtain a pale yellow solid. This solid was
filtered and washed with cold CH2Cl2 (25 mL × 2) to obtain white
solid (3.40 g, 11.79 mmol, 72%). FT-IR (KBr): 3221 (s), 1546 (s),
1512 (s), 1337 (s), 1246 (s). 1H NMR (400 MHz, DMSO-d6): δ 9.52
(s, 2H), 7.32 (d, J = 8.8 Hz, 4H), 6.88 (d, J = 8.8 Hz, 4H), 3.74 (s,
6H). 13C NMR (100 MHz, DMSO-d6): δ 180.2, 156.5, 132.3, 126.0,
113.6, 55.2. HRMS (ESI+): calcd for C15H16N2O2SNa ([M + Na]+)
311.0830, found 311.0840.
1,3-Diphenylthiourea (9a). To the solution of phenyl iso-
thiocyanate (742 mg, 5.49 mmol) in 10 mL of abs THF in a 25 mL
round-bottom flask was added aniline (0.45 mL, 4.99 mmol), and the
resulting mixture was stirred at rt for 40 h. The reaction mixture was
concentrated in vacuo to obtain a yellow solid. Washing the crude with
petroleum ether (25 mL × 4) afforded a white crystalline solid (1.1 g,
4.82 mmol, 88%). FT-IR (KBr): 3208 (s), 1551 (s), 1345 (s), 697 (s).
1H NMR (400 MHz, DMSO-d6): δ 9.94 (s, 2H), 7.52 (m, 4H), 7.34
(m, 2H), 7.13 (m, 2H). 13C NMR (100 MHz, DMSO-d6): δ 179.6,
139.5, 128.4, 124.4, 123.6. HRMS (ESI+): calcd for C13H12N2SNa
([M + Na]+) 251.0619, found 251.0611.
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(m), 3098 (m), 1676 (s), 1386 (s), 1285 (s). H NMR (400 MHz,
CD3OD): δ 7.52 (s, 2H), 7.43 (s, 4H), 3.35 (s, 6H). 13C NMR (100
MHz, CD3OD): δ 160.8, 148.2, 134.0 (q, J = 34 Hz), 127.5, 124.7 (q, J
= 270 Hz), 120.1, 39.7. HRMS (ESI+): calcd for C19H13F12N2O ([M +
H]+) 513.0836, found 513.0842. To the mixture of 1,3-bis(3,5-
bis(trifluoromethyl)phenyl)-1,3-dimethylurea (50 mg, 0.10 mmol) and
Lawesson’s reagent (79.3 mg, 0.19 mmol) in a 10 mL round-bottom
flask was added o-xylene (0.4 mL), and the resulting mixture was
refluxed at 170 °C for 5 h. The reaction mixture was concentrated in
vacuo to obtain a yellow solid. Purification by column chromatography
over silica gel (100−200 mesh) using 5:95 EtOAc/petroleum ether
afforded 3b as a white solid (44 mg, 0.084 mmol, 84% yield). Mp:
172−174 °C. FT-IR (KBr): 3434 (m), 1472 (m), 1381 (s), 1278 (s),
1147 (s). 1H NMR (400 MHz, CD3OD): δ 7.57 (s, 2H), 7.30 (s, 4H),
3.61 (s, 6H). 13C NMR (100 MHz, CD3OD): δ 191.3, 149.7, 133.9 (q,
J = 34 Hz), 126.8, 124.1 (q, J = 270 Hz), 120.0, 45.0. HRMS (ESI+):
calcd for C19H12F12N2S ([M]+) 528.0530, found 528.1403.
N-Cyclohexyl-N′-(3,5-bis(trifluoromethyl)phenyl)thiourea
(4). To a solution of 3,5-bis(trifluoromethyl)phenyl isothiocyanate
(0.34 mL, 1.85 mmol) in 2 mL of abs THF in a 10 mL round-bottom
flask was added cyclohexylamine (0.21 mL, 1.85 mmol), and the
resulting mixture was stirred at 30 °C for 2 h. The reaction mixture
was concentrated in vacuo to obtain an off-white solid. The solid was
triturated with petroleum ether (10 mL × 2) to obtain a white solid
(600 mg, 1.62 mmol, 88%). FT-IR (thin film): 3272 (w), 2932 (w),
1527 (m), 1383 (m), 1274 (m). 1H NMR (400 MHz, CDCl3): δ 8.11
(br, 1H), 7.75 (s, 2H), 7.71 (s, 1H), 6.04 (br, 1H), 4.20 (br, 1H),
2.12−2.02 (m, 2H), 1.76−1.59 (m, 3H), 1.48−1.35(m, 2H), 1.28−
1.12 (m, 3H). 13C NMR (100 MHz, CDCl3): δ 179.1, 138.9, 133.1 (q,
J = 33 Hz), 123.8, 122.7 (q, J = 271 Hz), 119.3, 54.0, 32.3, 25.2, 24.5.
HRMS (ESI+): calcd for C15H16F6N2SNa ([M + Na]+) 393.0836,
found 393.0836.
N,N′-Dimethyl-N,N′-diphenylthiourea (9b). To a solution of N-
methylaniline (0.41 mL; 3.73 mmol) in toluene (8 mL) in a 25 mL
round-bottom flask were added thiophosgene (0.15 mL, 1.87 mmol)
and Et3N (0.53 mL, 3.73 mmol), and the resulting mixture was heated
at 50 °C for 24 h. The resulting yellow solution was diluted with
CH2Cl2 (20 mL) and then washed with 1 N HCl (10 mL × 2) and
brine (5 mL × 1). The organic layer was dried over anhtd Na2SO4 and
concentrated in vacuo. Purification by column chromatography on
silica gel (230−400 mesh) using 1.5:98.5 and then 3:97 EtOAc/
petroleum ether afforded a white solid (42 mg, 0.19 mmol, 5%). FT-IR
N-Cyclohexyl-N′-(3,5-bis(trifluoromethyl)phenyl)urea (5). To
a solution of cyclohexyl isocyanate (0.51 mL, 3.99 mmol) in 4 mL of
THF in a 10 mL round-bottom flask was added 3,5-bis-
(trifluoromethyl)aniline (0.56 mL, 3.63 mmol), and the reaction
mixture was stirred at 50 °C for 72 h. The reaction mixture was
concentrated in vacuo to obtain an off-white solid. The solid was
washed with cold CH2Cl2 (10 mL × 2) to obtain a white solid (600
1
(KBr): 3422 (br), 2924 (m), 1595 (m), 1492 (m). H NMR (400
MHz, CDCl3): δ 7.05−6.99 (m, 4H), 6.98−6.92 (m, 2H), 6.66 (d, J =
7.8 Hz, 4H), 3.51 (s, 6H). 13C NMR (100 MHz, CDCl3): δ 190.8,
147.5, 128.7, 125.4, 125.3, 45.2. HRMS (ESI+): calcd for
C15H16N2SNa ([M + Na]+) 279.0932, found 279.0934.
O-Phenyl-N-methyl-N-phenylthiocarbamate (10). To a sol-
ution of thiophosgene (0.30 mL, 3.99 mmol) in CH2Cl2 (22 mL) in a
100 mL two-neck round-bottom flask was added a solution of phenol
(250 mg, 2.66 mmol) in 0.3 M NaOH (8.87 mL, 2.66 mmol), and the
resulting mixture was stirred at rt for 1 h. The reaction was diluted by
CH2Cl2 (10 mL). The organic phase was separated, washed with brine
(8 mL × 1), and concentrated in vacuo to obtain a yellow oil. CH2Cl2
(22 mL) was added to this oil followed by addition of N-methylaniline
1
mg, 1.69 mmol, 43%). H NMR (400 MHz, CD3OD): δ 8.01(s, 2H),
7.49(s, 1H), 3.62−3.52 (m, 1H), 1.99−1.89 (m, 2H), 1.80−1.55 (m,
4H), 1.46−1.16 (m, 6H). 13C NMR (100 MHz, CD3OD): δ 156.4,
143.3, 132.9 (q, J = 33 Hz), 125.0 (q, J = 270 Hz), 118.7, 115.1, 34.6,
34.1, 26.5, 26.5, 25.9, 25.8.
Cyclohexyl (3,5-Bis(trifluoromethyl)phenyl)carbamate (6).
To a solution of bis(trifluoromethyl)phenyl isocyanate (0.42 mL;
2.27 mmol) and cyclohexanol (250 mg; 2.50 mmol) in THF (10 mL)
1595
dx.doi.org/10.1021/jo202269p | J. Org. Chem. 2012, 77, 1592−1598