2116 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 7
Lilienkampf et al.
the solvent was evaporated and the crude product was purified by
flash chromatography using gradient elution from hexane to 8%
EtOAc-hexane. Yield 37% (white powder). H NMR (CDCl3) δ
ethyl)-2-furancarboxylate as the alkyhalide. Yield 75% (white
powder). 1H NMR (CD3OD) δ 1.36 (3H, t, J ) 7.1 Hz), 4.35 (2H,
q, J ) 7.1 Hz), 5.55 (2H, s), 6.86 (1H, d, J ) 3.4 Hz), 7.27 (1H,
d, J ) 3.4 Hz), 7.60 (1H, s), 7.76 (1H, apparent t, J ) 7.7 Hz),
8.22 (1H, d, J ) 7.3 Hz), 8.51 (1H, d, J ) 8.5 Hz). 13C NMR
(CDCl3) δ 14.3, 61.4, 62.9, 97.8 (q, J ) 2 Hz), 113.1, 118.4, 121.1
(q, J ) 276 Hz), 122.2, 123.6 (q, J ) 273 Hz), 126.3, 126.5, 128.4
(q, J ) 30 Hz), 129.5 (q, J ) 5 Hz), 144.7, 145.9, 149.6 (q, J )
35 Hz), 151.5, 158.4, 162.1. HRMS (ESI) calculated for
C19H13F6NO4 [M + H]+ 434.0822, found 434.0829.
4-[(5-Nitro)-2-furanylmethoxy]-2,8-bis(trifluoromethyl)quino-
line (32). Was synthesized by the typical procedure described above
using 2-(bromomethyl)-5-nitrofuran as the alkyhalide. Yield 71%
(pale-yellow solid). 1 H NMR (CDCl3) δ 5.40 (2H, s), 6.84 (1H, d,
J ) 3.7 Hz), 7.23 (1H, s), 7.37 (1H, d, J ) 3.7 Hz), 7.68 (1H,
apparent t, J ) 7.9 Hz), 8.16 (1H, d, J ) 7.3 Hz), 8.43 (1H, d, J
) 8.4 Hz). 13C NMR (CDCl3) δ 62.6, 97.7 (q, J ) 2 Hz), 111.9,
114.0, 121.0 (q, J ) 276 Hz), 121.9, 123.5 (q, J ) 273 Hz), 126.2,
126.7, 128.5 (q, J ) 30 Hz), 129.7 (q, J ) 5 Hz), 144.7, 149.5 (q,
J ) 35 Hz), 150.6, 152.5 (broad s), 161.7. HRMS (ESI) calculated
for C16H8F6N2O4 [M + H]+ 407.0467, found 407.0469.
1
3.17 (1H, s), 6.84 (1H, s), 7.22 (1H, m), 7.35 (1H, m), 7.48 (2H,
m), 7.71 (1H, m), 7.87 (1H, m), 8.22 (1H, d, J ) 8.4 Hz), 8.40
(1H, d, J ) 8.5 Hz). 13C NMR (CDCl3) δ 78.9, 82.2, 100.2 (q, J
) 2 Hz), 121.3 (q, J ) 276 Hz), 121.70, 121.75, 121.8, 124.6,
124.8, 128.2, 129.9, 129.9, 130.1, 130.6, 131.5, 148.8, 148.9 (q, J
) 35 Hz), 153.6, 163.0.
Typical Procedure for the Synthesis of Compounds 19, 22,
26, 28, 30-33. 2,8-Bis(trifluoromethyl)-4-quinolinol 4s (0.2 g, 0.7
mmol) and anhydrous K2CO3 (0.6 g, 4 mmol) were refluxed in
anhydrous acetone (20 mL) for 15 min. Subsequently, KI (60 mg,
0.36 mmol) and methyl 2-(chloromethyl)-1,3-oxazole-4-carboxylate
(0.15 g, 0.85 mmol) were added. The reaction mixture was refluxed
for 2 h until disappearance of the starting material on TLC (EtOAc-
hexane 1:4 as an eluent). The reaction mixture was cooled, filtered,
and the filtrate was evaporated in vacuo. The residue was purified
by flash chromatography using gradient elution from 5% EtOAc-
hexane to 60% EtOAc-hexane to give 33 as a white powder in
97% yield.
3-[[[2,8-Bis(trifluoromethyl)-4-quinolinyl]oxy]methyl]-5-isox-
azolecarboxylic Acid Ethyl Ester (19). Compound 19 was
synthesized by the typical procedure described above using 4s and
4-[[[2,8-Bis(trifluoromethyl)-4-quinolinyl]oxy]methyl]benzo-
ic Acid Ethyl Ester (30). Compound 30 was synthesized by the
typical procedure described above using ethyl 4-(bromomethyl)-
1
1
18 as starting materials. According to H NMR, the product 19 is
benzoate as the alkyhalide. Yield 86% (white powder). H NMR
an inseparable 15:1 mixture of 3,5 and 3,4 regioisomers. Yield 64%
(white solid). For the major isomer 19: H NMR (DMSO-d6) δ
(CDCl3) δ 1.42 (3H, t, J ) 7.1 Hz), 4.41 (2H, q, J ) 7.1 Hz), 5.43
(2H, s), 7.21 (1H, s), 7.59 (2H, d, J ) 8.0 Hz), 7.68 (1H, apparent
t, J ) 7.8 Hz), 8.15 (3H, m), 8.51 (1H, d, J ) 8.4 Hz). 13C NMR
(CDCl3) δ 14.3, 61.2, 70.5, 98.1 (q, J ) 2 Hz), 121.1 (q, J ) 276
Hz), 122.3, 123.6 (q, J ) 274 Hz), 126.33, 126.35, 127.3, 128.4
(q, J ) 30 Hz), 129.5 (q, J ) 5 Hz), 130.2, 131.0, 139.4, 144.7,
149.7 (q, J ) 35 Hz), 162.6, 166.1. HRMS (ESI) calculated for
C21H15F6NO3 [M + H]+ 444.1029, found 444.1036.
1
1.33 (3H, t, J ) 7.1 Hz), 4.39 (2H, q, J ) 7.1 Hz), 5.79 (2H, s),
7.58 (1H, s), 7.80 (1H, s), 7.88 (1H, apparent t, J ) 7.9 Hz), 8.35
(1H, d, J ) 7.2 Hz), 8.58 (1H, d, J ) 8.4 Hz). 13C NMR (DMSO-
d6) δ 13.9, 62.2, 62.7, 99.6 (q, J ) 2 Hz), 109.4, 121.0 (q, J ) 275
Hz), 121.7, 123.7 (q, J ) 273 Hz), 126.3 (q, J ) 30 Hz), 127.1,
127.4, 130.2 (q, J ) 5 Hz), 143.5, 148.5 (q, J ) 35 Hz), 156.0,
160.5 (two overlapping resonances), 162.4. HRMS (ESI) calculated
for C18H12F6N2O4 [M + H]+ 435.0774, found 435.0781.
5-[[[2,8-Bis(trifluoromethyl)-4-quinolinyl]oxy]methyl]-2-thia-
zolecarboxylic Acid Ethyl Ester (22). Compound 22 was synthe-
sized by the typical procedure described above using 21 as the
alkyhalide. Yield 58% (pale-yellow powder). 1H NMR (CDCl3) δ
1.47 (3H, t, J ) 7.1 Hz), 4.53 (2H, q, J ) 7.1 Hz), 5.60 (2H, s),
7.26 (1H, s), 7.66 (1H, apparent t, J ) 8.0 Hz), 7.75 (1H, s), 8.15
(1H, d, J ) 7.2 Hz), 8.49 (1H, d, J ) 8.4 Hz). 13C NMR (CDCl3)
δ 14.3, 63.0, 66.7, 98.1 (q, J ) 2 Hz), 121.1 (q, J ) 276 Hz),
122.2, 123.6 (q, J ) 274 Hz), 123.7, 126.29, 126.33, 128.5 (q, J )
30 Hz), 129.5 (q, J ) 5 Hz), 144.8, 145.3, 149.7 (q, J ) 35 Hz),
152.3, 159.4, 159.6, 162.3. HRMS (ESI) calculated for
C18H12F6N2O3S [M + H]+ 451.0546, found 451.0568.
2-[[[2,8-Bis(trifluoromethyl)-4-quinolinyl]oxy]methyl]-4-ox-
azolecarboxylic Acid Methyl Ester (33). Compound 33 was
synthesized by the typical procedure described above using 2-(chlo-
romethyl)-4-oxazolecarboxylic acid methyl ester as the alkyhalide.
1
Yield 97% (white solid). H NMR (CDCl3) δ 3.96 (3H, s), 5.52
(2H, s), 7.30 (1H, s), 7.13 (1H, s), 7.68 (1H, apparent t, J ) 7.9
Hz), 8.16 (1H, d, J ) 7.3 Hz), 8.34 (1H, s), 8.47 (1H, d, J ) 8.4
Hz). 13C NMR (CDCl3) δ 52.5, 62.4, 97.9 (q, J ) 2 Hz), 121.0 (q,
J ) 276 Hz), 122.0, 123.5 (q, J ) 274 Hz), 124.9, 125.1, 128.5 (q,
J ) 30 Hz), 129.7 (q, J ) 5 Hz), 134.1, 144.7, 145.3, 149.6 (q, J
) 35 Hz), 158.3, 161.0, 161.7. HRMS (ESI) calculated for
C17H10F6N2O4 [M + H]+ 421.0618, found 421.0618.
2-[[[2,8-Bis(trifluoromethyl)-4-quinolinyl]oxy]methyl]-4-ox-
azolecarboxylic Acid Ethyl Ester (34). Compound 33 (80 mg,
0.19 mmol) and KOH (8 mg, 0.14 mmol) were refluxed overnight
in abs EtOH (20 mL). The solvent was evaporated in vacuo and
the residue was dissolved into EtOAc (30 mL), washed with 1 M
HCl (15 mL) and brine (15 mL), and dried with Na2SO4. After
filtration the solvent was evaporated and the crude product was
purified by flash chromatography using gradient eluation from 5%
EtOAc-hexane to 90% EtOAc-hexane. Yield 81% (white solid).
1H NMR (CDCl3) δ 1.41 (3H, t, J ) 7.1 Hz), 4.43 (2H, q, J ) 7.1
Hz), 5.51 (2H, s), 7.31 (1H, s), 7.68 (1H, apparent t, J ) 7.9 Hz),
8.16 (1H, d, J ) 7.3 Hz), 8.34 (1H, s), 8.47 (1H, d, J ) 8.4 Hz).
13C NMR (CDCl3) δ 14.3, 61.7, 62.4, 97.9 (q, J ) 2 Hz), 121.0 (q,
J ) 276 Hz), 122.0, 123.5 (q, J ) 274 Hz), 126.3, 126.6, 128.5 (q,
J ) 30 Hz), 129.7 (q, J ) 5 Hz), 134.4, 144.8, 145.2, 149.6 (q, J
) 35 Hz), 158.2, 160.6, 161.8. HRMS (ESI) calculated for
C18H12F6N2O4 [M + H]+ 435.0774, found 435.0783.
6-[[[2,8-Bis(trifluoromethyl)-4-quinolinyl]oxy]methyl]-2-py-
ridinecarboxylic Acid Ethyl Ester (25). A solution of 6-(hy-
droxymethyl)-2-pyridinecarboxylic acid ethyl ester (24)14 (0.3 g,
1 mmol), 2,8-bis(trifluoromethyl)quinolin-4-ol (4s) (0.2 g, 0.7
mmol), and PPh3 (0.4 g, 1 mmol) in anhydrous THF (15 mL) was
cooled to 0 °C. DEAD (0.25 g, 1.4 mmol, 0.22 mL) was added
dropwise, and the reaction mixture was stirred for 45 min at room
temperature. The solvent was evaporated in vacuo, and the residue
was purified by column chromatography using CH2Cl2 as an eluent
2-[[2,8-Bis(trifluoromethyl)-4-quinolinyl]oxy]acetic Acid Eth-
yl Ester (26). Compound 26 was synthesized by the typical
procedure described above using ethyl bromoacetate as the alky-
1
halide. Yield 90% (white powder). H NMR (CDCl3) δ 1.33 (3H,
t, J ) 7.1 Hz), 4.34 (2H, q, J ) 7.1 Hz), 4.94 (2H, s), 7.00 (1H,
s), 7.69 (1H, apparent t, J ) 7.8 Hz), 8.16 (1H, d, J ) 7.1 Hz),
8.55 (1H, d, J ) 8.4 Hz). 13C NMR (DMSO-d6) δ 14.0, 61.1, 65.9,
99.6 (q, J ) 2 Hz), 121.1 (q, J ) 276 Hz), 121.7, 123.7 (q, J )
273 Hz), 126.4 (q, J ) 30 Hz), 126.8, 127.4, 130.3 (q, J ) 5 Hz),
143.6, 148.5 (q, J ) 34 Hz), 162.5, 167.5. HRMS (ESI) calculated
for C15H11F6NO3 [M + H]+ 368.0716, found 368.0712.
2-[[2,8-Bis(trifluoromethyl)-4-quinolinyl]oxy]acetonitrile (28).
Was synthesized by the typical procedure described above using
bromoacetonitrile as the alkyhalide. Yield 90% (pale-yellow
powder). 1H NMR (CDCl3) δ 5.13 (2H, s), 7.31 (1H, s), 7.20 (1H,
s), 7.75 (1H, apparent t, J ) 7.6 Hz), 8.21 (1H, d, J ) 7.2 Hz),
8.45 (1H, d, J ) 8.4 Hz). 13C NMR (CDCl3) δ 53.9, 97.9 (q, J )
2 Hz), 113.2, 121.0 (q, J ) 276 Hz), 121.8, 123.6 (q, J ) 273 Hz),
126.0, 127.7, 128.9 (q, J ) 31 Hz), 130.2 (q, J ) 5 Hz), 145.0,
149.6 (q, J ) 34 Hz), 160.7. HRMS (ESI) calculated for
C13H6F6N2O [M + H]+ 321.0457, found 321.0442.
5-[[[2,6-Bis(trifluoromethyl)-4-quinolinyl]oxy]methyl]-2-furan-
carboxylic Acid Ethyl Ester (31). Compound 31 was synthesized
by the typical procedure described above using ethyl 5-(chlorom-