JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
347
1-Mesityl-3–(4-(trifluoromethyl)phenyl)thiourea (TKR14)
This compound was obtained as grey solid in 45% yield; Melting
point: 204–205 ꢀC. 1H NMR (300 MHz, CDCl3) d 7.70 (s, 1H), 7.58
(q, J ¼ 8.4 Hz, 4H), 7.10 (s, 1H), 6.99 (d, J ¼ 13.4 Hz, 2H), 2.31
(d, J ¼ 6.5 Hz, 9H).13C NMR (75 MHz, DMSO) d 180.96, 143.99,
136.38, 128.81, 126.12, 122.47. HRMS (ESI): calculated for
C17H17F3N2S [M þ H]þ: 339.1098; found: 339.1141.
Scheme 3. (h) G, CH3CN, TEA, rt; (i) E, CH3CN, TEA, rt. R1 ¼ 4-(trifluoromethyl)-
(1,10-biphenyl)/(3s,5s,7s)-adamantan-1-yl)/(4-phenoxyphenyl).
1,3-bis(4-(Trifluoromethyl)phenyl)thiourea (TKR15)
phenyl)/(3-chloro-4-methylphenyl); R2
¼
mesitylene/4-(trifluoromethyl)phenyl)/
This compound was obtained as grey solid in 49% yield; Melting
1
point: 179–181 ꢀC. H NMR (300 MHz, CDCl3) d 8.15 (s, 1H), 7.70 (d,
J ¼ 8.5 Hz, 3H), 7.56 (d, J ¼ 8.4 Hz, 3H).13C NMR (75 MHz, DMSO) d
180.17 (s), 143.54 (s), 126.29 – 125.92 (m), 123.49 (s). HRMS (ESI):
calculated for C15H10F6N2S [M þ H]þ: 365.0502; found: 365.0553.
123.13, 121.23, 118.74, 113.45. HRMS (ESI): calculated for
C15H9F6N5O5 [M þ H]þ: 454.0541; found:454.0586.
Synthetic routes of target compounds TKR10–TKR18 were outlined
in Scheme 3
1-([1,10-Biphenyl]-4-yl)-3–(4-(trifluoromethyl)phenyl)th-
iourea (TKR16)
To a solution of amine I (1.1 equiv.) in anhydrous acetonitrile was
added triethylamine (3.0 equiv.), and then the resulted solution
was added isocyanate G or isothiocyanate E (1.0 equiv.). The reac-
tion mixture was then stirred until complete conversion of the
starting material monitored by TLC. The solvent was removed
under reduced pressure and the residue was recrystallised from
EtOH or hexane to get the desired ureas J or thioureas K.
This compound was obtained as grey solid in 45% yield; Melting
point: 201–203 ꢀC. 1H NMR (300 MHz, DMSO) d 10.25 (s, 1H), 7.79
(d, J ¼ 8.6 Hz, 1H), 7.66 (ddd, J ¼ 19.9, 12.2, 6.8 Hz, 4H), 7.47 (dd,
J ¼ 10.3, 4.8 Hz, 1H), 7.39 – 7.32 (m, 1H).13C NMR (75 MHz, DMSO)
d 179.79, 144.01, 140.13, 139.20, 136.81, 129.40, 127.20, 126.87,
124.25, 123.14. HRMS (ESI): calculated for C20H15F3N2S [M þ H]þ:
373.0942; found: 373.0958.
1–(3-Chloro-4-methylphenyl)-3-mesitylurea (TKR10)
1-((3s,5s,7s)-Adamantan-1-yl)-3–(4-(trifluoromethyl)phenyl)th-
iourea (TKR17)
This compound was obtained as white solid in 46% yield; Melting
This compound was obtained as light yellow solid in 45% yield;
Melting point: 261–262 ꢀC. 1H NMR (300 MHz, DMSO) d 8.78 (s,
1H), 7.69 (d, J ¼ 1.8 Hz, 1H), 7.66 (s, 1H), 7.27 – 7.12 (m, 2H), 6.88
(s, 2H), 2.24 (d, J ¼ 4.4 Hz, 6H), 2.15 (s, 6H).13C NMR (75 MHz, point: 176–177 ꢀC. 1H NMR (300 MHz, DMSO) d 9.63 (s, 1H), 7.75
DMSO) d 153.72, 140.05, 135.83, 135.49, 133.53, 132.95, 131.48,
(d, J ¼ 8.5 Hz, 2H), 7.62 (d, J ¼ 8.7 Hz, 2H), 7.57 (s, 1H), 2.25 (d,
J ¼ 2.5 Hz, 6H), 2.07 (s, 3H), 1.65 (s, 6H).13C NMR (75 MHz, DMSO) d
128.79, 128.08, 118.37, 117.14. HRMS (ESI): calculated for
C17H19ClN2O [M þ H]þ: 303.1219; found: 303.1262.
178.93, 144.08, 125.77, 122.22, 54.06, 36.44, 29.51. HRMS (ESI): cal-
culated for C18H21F3N2S [M þ H]þ: 355.1411; found: 355.1421.
1–(3-Chloro-4-methylphenyl)-3–(4-(trifluoromethyl)pheny-
l)urea (TKR11)
1–(4-Phenoxyphenyl)-3–(4-(trifluoromethyl)phenyl)urea (TKR18)
This compound was obtained as light yellow solid in 46% yield;
Melting point: 235–236 ꢀC. 1H NMR (300 MHz, DMSO) d 9.15 (s,
1H), 8.91 (s, 1H), 7.69 (t, J ¼ 2.2 Hz, 1H), 7.64 (s, 4H), 7.22 (dt,
J ¼ 8.3, 5.2 Hz, 2H), 2.26 (s, 4H). 13 C NMR (75 MHz, DMSO) d
152.66, 143.77, 139.08, 133.64, 131.55, 129.10, 126.89, 125.99,
123.19, 122.64, 122.21, 118.89, 118.40, 117.56. HRMS (ESI): calcu-
lated for C15H12ClF3N2O [M þ H]þ: 329.0624; found: 329.0676.
This compound was obtained as white solid in 45% yield; Melting
1
point: 203–204 ꢀC. H NMR (300 MHz, DMSO) d 9.09 (s, 1H), 8.82 (s,
1H), 7.65 (q, J ¼ 9.1 Hz, 5H), 7.49 (t, J ¼ 6.2 Hz, 2H), 7.38 (dd,
J ¼ 11.2, 4.7 Hz, 2H), 7.10 (t, J ¼ 7.4 Hz, 1H), 6.99 (dd, J ¼ 11.6,
6.5 Hz, 5H).13C NMR (75 MHz, DMSO) d 158.07, 152.86, 151.53,
144.00, 135.74, 130.32, 126.47, 123.24, 120.73, 120.18, 118.23.
HRMS (ESI): calculated for C20H15F3N2O2 [M þ H]þ: 373.1119; found:
373.1182.
1-Mesityl-3–(4-(trifluoromethyl)phenyl)urea (TKR12)
This compound was obtained as light yellow solid in 44% yield;
Melting point: 207–209 ꢀC. 1H NMR (300 MHz, DMSO) d 9.15 (s,
1H), 7.78 (s, 1H), 7.63 (q, J ¼ 8.9 Hz, 5H), 6.90 (s, 2H), 2.24 (s, 4H),
2.16 (s, 7H).13C NMR (75 MHz, DMSO) d 153.51, 144.58, 135.73,
132.78, 128.80, 126.38, 118.01. HRMS (ESI): calculated for
C17H17F3N2O [M þ H]þ: 323.1327; found: 323.1367.
Synthetic routes of target compounds TKR19–TKR21 were outlined
in Scheme 4
The substituted urea or thiourea (1.0 equiv.) was dissolved in gla-
cial acetic acid with gentle heating, and then appropriate of conc.
HCl and distilled water were added. The mixture was cooled to
0–5 ꢀC, stirring constantly. A separate solution of NaNO2 (1.0
equiv.) in distilled water was then prepared and cooled to 0–5 ꢀC.
With efficient stirring, this solution was then added in small ali-
quots to the solution of urea or thiourea, maintaining the tem-
perature at less than 10 ꢀC throughout. After 5 min of further
stirring at or less than 5 ꢀC, the product was vacuum filtered,
washed with cold distilled water, and dried to constant weight in
an oven at 50–60 ꢀC to obtain product L.
1,3-bis(4-(Trifluoromethyl)phenyl)urea (TKR13)
This compound was obtained as light grey solid in 49% yield;
Melting point: 237–238 ꢀC. 1H NMR (300 MHz, DMSO) d 9.26 (s,
2H), 7.72 – 7.63 (m, 8H).13C NMR (75 MHz, DMSO) d 152.55, 143.54,
126.73 – 125.87, 123.13, 122.92, 122.50, 118.51. HRMS (ESI): calcu-
lated for C15H10F6N2O [M þ H]þ: 349.0731; found: 349.0779.