D. Song et al. / Bioorg. Med. Chem. 22 (2014) 4855–4866
4865
10.08 (br s, 1H), 9.19 (s, 1H), 8.40 (d, J = 2.4 Hz, 1H), 8.26ꢀ8.24
(m, 2H), 7.99 (dd, J = 8.8, 2.4 Hz, 1H), 7.97 (d, J = 8.0 Hz, 1H),
7.64 (t, J = 8.0 Hz, 1H), 7.59ꢀ7.55 (m, 2H), 7.50 (d, J = 8.0 Hz,
1H), 7.40 (t, J = 8.0 Hz, 1H), 7.21 (d, J = 8.8 Hz, 1H), 2.07 (s, 3H).
13C NMR (100 MHz, DMSO-d6): d 168.5, 165.5, 157.7, 147.2,
139.9, 139.1, 130.8, 130.1, 129.5 (q, JC–F = 31.3 Hz), 129.4,
128.7, 125.5, 124.4 (q, JC–F = 270.0 Hz), 124.3, 121.4, 120.5 (q,
JC–F = 3.7 Hz), 120.4, 119.7, 119.6, 118.9, 118.4, 116.7 (q,
JC–F = 3.7 Hz), 115.9, 24.1. LRMS m/z (rel int): 482 ([M+H]+, 100).
HRMS m/z calcd for C24H18F3N5O3 481.1362; found 481.1359.
(400 MHz, DMSO-d6): d 11.84 (br s, 1H), 10.99 (br s, 1H), 9.04
(s, 1H), 8.37 (d, J = 2.8 Hz, 1H), 8.24 (s, 1H), 7.99–7.96 (m, 2H),
7.78 (s, 1H), 7.63 (t, J = 8.0 Hz, 1H), 7.50 (d, J = 8.0 Hz, 1H), 7.32
(s, 1H), 7.21 (d, J = 8.8 Hz, 1H), 3.88 (s, 3H). 13C NMR (100 MHz,
DMSO-d6): d 165.4, 157.9, 139.2, 138.3, 131.7, 130.1, 129.5 (q,
JC–F = 31.4 Hz), 128.7, 128.4, 125.5, 124.2, 124.1 (q, JC–F = 270.0 Hz),
122.8, 121.6, 120.5, 120.1, 119.9, 118.5, 116.7 (q, JC–F = 3.7 Hz),
33.1. LRMS m/z (rel int): 429 ([M+H]+, 100). HRMS m/z calcd for
C20H15F3N6O2 428.1209; found 428.1215.
4.1.5. General procedure for the synthesis of 8h, 9q, and 9r
[hydrolysis reaction]
4.1.4.21. Methyl 3-(1-(4-hydroxy-3-((3-(trifluoromethyl)phenyl)car-
The suspension of methyl ester (100 lmol) in 1 N NaOH
bamoyl)phenyl)-1H-1,2,3-triazol-4-yl)benzoate (9n).
the general procedure for 9, using 13h (112 mg, 350
Following
mol), 3-ethy-
(1 mL), MeOH (1 mL) was stirred for 1 h at 80 °C. After the com-
pletion of the reaction, MeOH was evaporated. The residue was
acidified with 1 N HCl (pH 5) and extracted with EtOAc
(3 ꢁ 10 mL). The combined organic extracts were dried over
anhyd MgSO4, filtered, and concentrated by rotary evaporation
to afford carboxylic acid.
l
nylbenzoic acid methyl ester (62.0 mg, 380
lmol), CuSO4 (22.3 mg,
140 mol) and sodium ascorbate (69.0 mg, 350
l
l
mol) were dis-
solved in 1:1 t-BuOH/H2O (4 mL). The mixture was stirred for 2 h
at rt and 44 h at 80 °C. Column chromatography (4:1 hexane/
EtOAc ? 30:1 CH2Cl2/MeOH) afforded 9n (145 mg, 86%) as a
brown solid. TLC: Rf 0.10 (5:1 hexane/EtOAc). Mp: 214ꢀ216 °C.
1H NMR (400 MHz, DMSO-d6): d 11.77 (br s, 1H), 10.85 (br s, 1H),
9.41 (s, 1H), 8.54 (t, J = 1.2 Hz, 1H), 8.40 (d, J = 2.8 Hz, 1H), 8.25
(s, 1H), 8.23 (dt, J = 8.0, 1.2 Hz, 1H), 8.00 (dd, J = 8.8, 2.8 Hz, 1H),
7.98ꢀ7.96 (m, 2H), 7.67 (t, J = 7.6 Hz, 1H), 7.64 (t, J = 8.0 Hz, 1H),
7.51 (d, J = 7.6 Hz, 1H), 7.22 (d, J = 8.8 Hz, 1H), 3.91 (s, 3H). 13C
NMR (100 MHz, DMSO-d6): d 166.1, 165.3, 157.5, 146.3, 139.1,
130.9, 130.5, 130.1, 129.9, 129.7, 129.4 (q, JC–F = 31.5 Hz), 128.8,
128.7, 125.8, 125.4, 124.3, 124.2 (q, JC–F = 270.0 Hz), 121.4, 120.6
(m), 120.3, 119.9, 118.4, 116.8 (m), 52.4. LRMS m/z (rel int):
483 ([M+H]+, 100), 413 ([MꢀCF3]+, 3). HRMS m/z calcd for
4.1.5.1. 3-(5-(4-(3,5-Dimethoxyphenyl)-1H-1,2,3-triazol-1-yl)-2-
hydroxybenzamido)benzoic acid (8h).
eral procedure above, methyl ester 8g (33.6 mg, 70.0
Following the gen-
mol) in
l
1 N NaOH (0.7 mL) and MeOH (0.7 mL) afforded 8h (22.4 mg,
70%) as a light brown solid. TLC: Rf 0.16 (30:1 CH2Cl2/MeOH).
Mp: 235ꢀ237 °C. 1H NMR (400 MHz, DMSO-d6): d 13.02 (br s,
1H), 11.90 (br s, 1H), 10.91 (br s, 1H), 9.27 (s, 1H), 8.40–8.38 (m,
2H), 7.99–7.96 (m, 1H), 7.95 (dd, J = 8.8, 2.8 Hz, 1H), 7.72 (dt,
J = 8.0, 1.2 Hz, 1H), 7.52 (t, J = 8.0 Hz, 1H), 7.21 (m, 1H), 7.14 (d,
J = 2.4 Hz, 2H), 6.51 (t, J = 2.4 Hz, 1H), 3.82 (s, 6H). 13C NMR
(100 MHz, DMSO-d6): d 167.1, 165.2, 161.0, 157.9, 147.1, 138.5,
132.1, 131.4, 129.1, 128.6, 125.3, 125.0, 124.8, 121.4, 121.2,
120.1, 119.5, 118.4, 103.2, 100.2, 55.3. LRMS m/z (rel int): 461
([M+H]+, 100), 413 ([MꢀCH3O2]+, 10), 338 ([MꢀC7H6O2]+, 9). HRMS
m/z calcd for C24H20N4O6 460.1383; found 460.1386.
C24H17F3N4O4 482.1202; found 482.1200.
4.1.4.22. 2-Hydroxy-5-(4-(pyridin-2-yl)-1H-1,2,3-triazol-1-yl)-N-
(3-(trifluoromethyl)phenyl)benzamide (9o).
Following the
general procedure for 9, using 13h (35.4 mg, 110
l
mol), 2-ethynyl-
pyridine (28.0
sodium ascorbate (21.8 mg, 110
l
L, 280
l
mol), CuSO4 (7.0 mg, 44.0
lmol) and
4.1.5.2. 4-(1-(4-Hydroxy-3-((3-(trifluoromethyl)phenyl)carbam-
l
mol) were dissolved in 1:1 t-
oyl)phenyl)-1H-1,2,3-triazol-4-yl)benzoic acid (9q).
ing the general procedure above, methyl ester 9g (48.2 mg,
100 mol) in 1 N NaOH (1 mL) and MeOH (1 mL) afforded 9q
Follow-
BuOH/H2O (1 mL). The mixture was stirred for 1 h at rt and for
42 h at 60 °C. After the completion of the reaction, pyridine
(0.1 mL) was added to the crude mixture to improve poor solubil-
ity. Column chromatography (30:1 CH2Cl2/MeOH) afforded 9o
(12.5 mg, 27%) as a brown solid. TLC: Rf 0.43 (30:1 CH2Cl2/MeOH).
Mp: 274.5ꢀ276.5 °C. 1H NMR (400 MHz, acetone-d6): d 8.93 (s, 1H),
8.65 (d, J = 4.0 Hz, 1H), 8.59 (d, J = 2.8 Hz, 1H), 8.26 (s, 1H), 8.20 (d,
J = 7.6 Hz, 1H), 8.14 (dd, J = 8.8, 2.8 Hz, 1H), 8.07 (d, J = 8.0 Hz, 1H),
7.93 (td, J = 7.6, 1.6 Hz, 1H), 7.67 (t, J = 8.0 Hz, 1H), 7.55 (d,
J = 8.0 Hz, 1H), 7.37 (ddd, J = 7.6, 4.0, 1.2 Hz, 1H), 7.26 (d,
J = 8.8 Hz, 1H). 13C NMR (100 MHz, DMSO-d6): d 165.8, 158.3,
149.8, 149.6, 148.3, 139.1, 137.6, 130.3, 129.7 (q, JC–F = 31.5 Hz),
128.6, 128.3, 125.8, 124.6, 124.2 (q, JC–F = 270.0 Hz), 123.6, 121.4,
120.8, 120.0, 119.2, 118.6, 117.7 (q, JC–F = 3.7 Hz). LRMS m/z (rel
int): 426 ([M+H]+, 100). HRMS m/z calcd for C21H14F3N5O2
425.1100; found 425.1106.
l
(44.6 mg, 96%) as a light brown solid. TLC: Rf 0.10 (1:1 hexane/
EtOAc). Mp: 309.5ꢀ311.5 °C. 1H NMR (400 MHz, DMSO-d6): d
13.02 (br s, 1H), 11.77 (br s, 1H), 10.77 (br s, 1H), 9.41 (s, 1H),
8.40 (d, J = 2.8 Hz, 1H), 8.25 (s, 1H), 8.07ꢀ8.04 (m, 4H), 8.00 (dd,
J = 8.8, 2.8 Hz, 1H), 7.97 (d, J = 8.0 Hz, 1H), 7.64 (t, J = 8.0 Hz, 1H),
7.51 (d, J = 8.0 Hz, 1H), 7.24 (d, J = 8.8 Hz, 1H). 13C NMR
(100 MHz, DMSO-d6): d 167.0, 165.2, 157.4, 146.3, 139.1, 134.4,
130.2, 130.1, 130.0, 129.5 (d, JC–F = 31.3 Hz), 128.7, 125.4, 125.3,
124.2, 124.1 (d, JC–F = 270.0 Hz), 121.4, 120.8, 120.5, 119.9, 118.3,
116.7. LRMS m/z (rel int): 469 ([M+H]+, 100). HRMS m/z calcd for
C23H15F3N4O4 468.1045; found 468.1042.
4.1.5.3. 3-(1-(4-Hydroxy-3-((3-(trifluoromethyl)phenyl)carbam-
oyl)phenyl)-1H-1,2,3-triazol-4-yl)benzoic acid (9r). Follow-
ing the general procedure above, methyl ester 9n (48.2 mg,
100 mol) in 1 N NaOH (1 mL) and MeOH (1 mL) afforded 9r
4.1.4.23. 2-Hydroxy-5-(4-(1-methyl-1H-imidazol-5-yl)-1H-
1,2,3-triazol-1-yl)-N-(3-(trifluoromethyl)phenyl)benzamide
l
(44.9 mg, 98%) as a brown solid. TLC: Rf 0.37 (20:1 CH2Cl2/MeOH).
Mp: 299ꢀ301 °C. 1H NMR (400 MHz, DMSO-d6): d 11.76 (br s, 1H),
10.78 (br s, 1H), 9.42 (s, 1H), 8.53 (t, J = 1.2 Hz, 1H), 8.42 (d,
J = 2.8 Hz, 1H), 8.25 (s, 1H), 8.20 (dt, J = 8.0, 1.2 Hz, 1H), 8.02 (dd,
J = 8.8, 2.8 Hz, 1H), 7.98 (d, J = 8.8 Hz, 1H), 7.95 (dt, J = 8.0, 1.2 Hz,
1H), 7.66–7.62 (m, 2H), 7.51 (d, J = 7.6 Hz, 1H), 7.23 (d, J = 8.8 Hz,
1H). 13C NMR (100 MHz, DMSO-d6): d 167.1, 165.3, 157.5, 146.5,
139.1, 131.6, 130.7, 130.1, 129.7, 129.4, 129.3 (q, JC–F = 31.5 Hz),
128.9, 128.8, 126.0, 125.3, 124.2, 124.1 (q, JC–F = 268.5 Hz), 121.3,
120.5, 120.2, 119.9, 118.3, 116.7. LRMS m/z (rel int): 469
(9p).
(48.3 mg, 150
380 mol), CuSO4 (9.6 mg, 60.0
(29.7 mg, 150 mol) in 1:1 t-BuOH/H2O (1.5 mL). The mixture
Following the general procedure for 9, using 13h
mol), 5-ethynyl-1-methyl-1H-imidazole (40.0 L,
mol) and sodium ascorbate
l
l
l
l
l
was stirred for 2.5 h at rt and for 23 h at 60 °C. After the completion
of the reaction, pyridine (0.1 mL) was added to the crude mixture
to
improve
poor
solubility.
Column
chromatography
(40:1 ? 10:1 CH2Cl2/MeOH) afforded 9p (34.8 mg, 54%) as a white
solid. TLC: Rf 0.11 (20:1 CH2Cl2/MeOH). Mp: 259ꢀ261 °C. 1H NMR