802 Journal of Medicinal Chemistry, 2011, Vol. 54, No. 3
Patch et al.
NMR (400 MHz, CDCl3) δ 9.93 (s, 1H), 8.31 (br s, 1H), 7.89 (br
d, J=8.61 Hz, 1H), 7.54 (s, 1H), 7.45 (br d, J=8.22 Hz, 1H), 7.04
(d, J=7.83 Hz, 1H), 6.79 (d, J=8.61 Hz, 1H), 3.90 (s, 3H), 3.89
(s, 3H).
J=2.15, 8.80 Hz, 1H), 7.58(d, J=1.96 Hz, 1H), 7.53 (dd, J =1.76,
8.02 Hz, 1H), 7.24 (d, J=7.83 Hz, 1H), 6.81 (d, J=8.61 Hz, 1H),
3.87 (s, 3H).
(B) 4-(2,4-Bis-trifluoromethylphenoxy)-3-methoxybenzalde-
hyde was condensed with 2,4-thiazolidinedione according to
general procedure D to afford the title compound as cream-
colored granules (from MeOH). Yield: 72%. 1H NMR (400
MHz, DMSO-d6) δ 12.69 (br s, 1H), 8.07 (d, J=1.96 Hz, 1H),
7.95 (dd, J=2.15, 8.80 Hz, 1H), 7.87 (s, 1H), 7.52 (d, J=1.96 Hz,
1H), 7.35-7.40 (m, 1H), 7.28 (dd, J = 1.96, 8.22 Hz, 1H), 6.97
(d, J = 8.61 Hz, 1H), 3.80 (s, 3H). MS (APCIþ) m/z 463.0
[(M)þ•]. tR=8.06 min (98.6%).
4-[4-(2,4-Dioxothiazolidin-5-ylidenemethyl)-2-methoxyphenoxy]-
3-trifluoromethylbenzonitrile (29). (A) 4-Fluoro-3-trifluoromethyl-
benzonitrile was reacted with vanillin according to general proce-
dure A to afford 4-(4-formyl-2-methoxyphenoxy)-3-trifluorometh-
ylbenzonitrile as a white solid. Yield: 71%. 1H NMR (400 MHz,
CDCl3) δ10.41 (s, 1H), 7.91 (d, J =8.61 Hz, 1H), 7.83 (d, J= 8.61
Hz, 1H), 7.43 (d, J=2.35 Hz, 1H), 7.25 (dd, J=2.35, 9.00 Hz, 1H),
6.70 (d, J=v 2.35 Hz, 1H), 6.67 (d, J=8.22 Hz, 1H), 3.92 (s, 3H).
(B) 4-(4-Formyl-2-methoxyphenoxy)-3-trifluoromethylben-
zonitrile was condensed with 2,4-thiazolidinedione according
to the procedure B to afford the title compound as a pale yellow
solid. Yield: 84%. Mp: 205.2 °C. 1H NMR (400 MHz, DMSO-
d6) δ 12.67 (br s, 1H), 8.31 (d, J=1.96 Hz, 1H), 8.00 (dd, J =2.15,
8.80 Hz, 1H), 7.84 (s, 1H), 7.49 (d, J=1.96 Hz, 1H), 7.36 (d, J =
8.22 Hz, 1H), 7.26 (dd, J = 1.96, 8.61 Hz, 1H), 6.90 (d, J =
(B) 4-(4-Formyl-2-methoxyphenoxy)-3-bromobenzoic acid
methyl ester was condensed with 2,4-thiazolidinedione accord-
ing to general procedure C to afford the title compound as an
off-white solid. Yield: 82%. 1H NMR (400 MHz, DMSO-d6) δ
8.17 (d, J=1.96 Hz, 1H), 7.85 (dd, J=1.96, 8.61 Hz, 1H), 7.71 (s,
1H), 7.44 (d, J=1.57 Hz, 1H), 7.25 (d, J=8.61 Hz, 1H), 7.22 (dd,
J=1.57, 8.61 Hz, 1H), 6.77 (d, J=8.61 Hz, 1H), 3.82 (s, 3H), 3.78
(s, 3H). MS (APCIþ) m/z 462.8 [(M)þ•]. tR = 7.41 min (99.4%).
5-[4-(2-Bromo-4-trifluoromethylphenoxy)-3-methoxybenzyli-
dene]thiazolidine-2,4-dione (25). (A) 3-Bromo-4-fluorobenzotri
+fluoride was reacted with vanillin according to general pro-
cedure A (reaction temperature was 150 °C, 5 h) to afford 4-(2-
bromo-4-trifluoromethylphenoxy)-3-methoxybenzaldehyde as
1
an opaque syrup. Yield: 65%. H NMR (400 MHz, CDCl3) δ
9.96 (s, 1H), 7.92 (d, J=1.96 Hz, 1H), 7.57 (d, J=1.57 Hz, 1H),
7.45-7.53 (m, 2H), 7.06 (d, J=8.22 Hz, 1H), 6.87 (d, J=8.61 Hz,
1H), 3.92 (s, 3H).
(B) 4-(2-Bromo-4-trifluoromethylphenoxy)-3-methoxyben-
zaldehyde was condensed with 2,4-thiazolidinedione according
to general procedure C to afford the title compound as a pale
yellow powder. Yield: 87%. 1H NMR (400 MHz, DMSO-d6) δ
12.64 (br s, 1H), 8.09 (d, J=1.96 Hz, 1H), 7.73 (s, 1H), 7.65 (dd,
J=1.96, 8.61 Hz, 1H), 7.46 (d, 1H), 7.25 (d, J=8.22 Hz, 1H),
7.23 (dd, J = 1.57, 8.22 Hz, 1H), 6.85 (d, J=8.61 Hz, 1H), 3.80
(s, 3H). MS (APCIþ) m/z 472.8 [(M)þ•]. tR=8.03 min (100%).
4-[4-(2,4-Dioxothiazolidin-5-ylidenemethyl)-2-methoxyphenoxy]-
3-bromobenzonitrile (26). (A) 3-Bromo-4-fluorobenzonitrile was
reacted with vanillin according to general procedure A to afford
4-(4-formyl-2-methoxyphenoxy)-3-bromobenzonitrile as an off-
9.00 Hz, 1H), 3.77 (s, 3H). MS (APCIþ) m/z 419.9 [(M)þ•]. tR
=
7.19 min (100%). Anal. Calcd for C19H11F3N2O4S: C, 54.29%;
H, 2.64%; N, 6.66%. Found: C, 54.49%; H, 2.29%; N, 6.67%.
5-[4-(2-Trifluoromethylphenoxy)-3-methoxybenzylidene]-
thiazolidine-2,4-dione (30). (A) A mixture of 2-fluorobenzotri-
fluoride (0.5 mL), vanillin (152 mg, 1 mmol), and dimethylace-
tamide (1.5 mL) was heated to 220 °C in a microwave reactor for
0.5 h. The mixture was then partitioned between water and
EtOAc, and the organic phase was concentrated. The residue
was purified by radial chromatography [hexane/EtOAc (8:1)] to
afford 4-(2-trifluoromethylphenoxy)-3-methoxybenzaldehyde
1
white powder. Yield: 73%. H NMR (400 MHz, CDCl3) δ 9.96
(s, 1H), 7.92 (d, J=1.56 Hz, 1H), 7.55 (s, 1H), 7.43-7.54 (m,
2H), 7.16 (d, J=8.22 Hz, 1H), 6.73 (d, J=8.61 Hz, 1H), 3.87
(s, 3H).
(B) 4-(4-Formyl-2-methoxyphenoxy)-3-bromobenzonitrile was
condensed with 2,4-thiazolidinedione according to general pro-
cedure C to afford the title compound as a yellow powder. Yield:
94%. 1H NMR (400 MHz, DMSO-d6) δ 12.63 (br s, 1H), 8.28 (d,
J=1.96 Hz, 1H), 7.83 (s, 1H), 7.74 (dd, J=1.96, 8.61 Hz, 1H),
7.47 (d, J=1.57 Hz, 1H), 7.29 (d, J=8.61 Hz, 1H), 7.24 (dd, J =
1.96, 8.22 Hz, 1H), 6.79 (d, J=8.61 Hz, 1H), 3.78 (s, 3H). MS
(APCIþ) m/z 429.9 [(M)þ•]. tR=7.11 min (100%).
1
as a colorless oil. Yield: 9%. H NMR (400 MHz, CDCl3) δ
9.94 (s, 1H), 7.71 (dd, J=7.83, 1.17 Hz, 1H), 7.55 (d, J=1.57 Hz,
1H), 7.48 (t, J=7.83 Hz, 1H), 7.44 (dd, J=1.96, 8.22 Hz, 1H),
7.23 (t, J=7.63 Hz, 1H), 7.01 (d, J=8.22 Hz, 1H), 6.88 (d, J =
8.61 Hz, 1H), 3.92 (s, 3H).
(B) 4-(2-Trifluoromethylphenoxy)-3-methoxybenzaldehyde
was condensed with 2,4-thiazolidinedione according to general
procedure D. The reaction mixture was concentrated under
reduced pressure, and the solid orange residue was purified by
flash chromatography (DCM) to afford the title compound as
pale yellow needles (from MeOH). Yield: 76%. 1H NMR (400
MHz, DMSO-d6) δ 12.66 (br s, 1H), 7.84 (s, 1H), 7.77 (d, J =
6.65 Hz, 1H), 7.59 (t, J=7.24 Hz, 1H), 7.47 (d, J=1.96 Hz, 1H),
7.27 (t, J=7.63 Hz, 1H), 7.23 (dd, J=1.96, 8.61 Hz, 1H), 7.17 (d,
J=8.22 Hz, 1H), 6.85 (d, J=8.22 Hz, 1H), 3.81 (s, 3H). MS
(APCIþ) m/z 394.9 [(M)þ•]. tR=7.35 min (95.7%).
4-[4-(2,4-Dioxothiazolidin-5-ylidenemethyl)-2-methoxyphenoxy]-
3-trifluoromethylbenzoic Acid Methyl Ester (27). (A) 4-Fluoro-
3-trifluoromethylbenzoic acid methyl ester was reacted with
vanillin according to general procedure A to afford 4-(4-for-
myl-2-methoxy-phenoxy)-3-trifluoromethylbenzoic acid meth-
yl ester as a pale yellow oil that solidified after several days.
Yield: 54%. 1H NMR (400 MHz, CDCl3) δ 9.98 (s, 1H), 8.38 (d,
J=1.96 Hz, 1H), 8.09 (dd, J=1.96, 8.61 Hz, 1H), 7.56 (d, J =
1.96 Hz, 1H), 7.52 (dd, J = 1.76, 8.02 Hz, 1H), 7.23 (d, J =
7.83 Hz, 1H), 6.76 (d, J=8.61 Hz, 1H), 3.94 (s, 3H), 3.85 (s, 3H).
(B) 4-(4-Formyl-2-methoxyphenoxy)-3-trifluoromethylben-
zoic acid methyl ester was condensed with 2,4-thiazolidinedione
according to general procedure D to afford the title compound
as an off-white solid. Yield: 78%. 1H NMR (400 MHz, CDCl3) δ
1H NMR (400 MHz, DMSO-d6) δ 12.69 (br s, 1H), 8.22 (d, J =
1.96 Hz, 1H), 8.13 (dd, J=2.15, 8.80 Hz, 1H), 7.86 (s, 1H), 7.52
(d, J=1.96 Hz, 1H), 7.38 (d, J=8.22 Hz, 1H), 7.28 (dd, J=1.96,
8.61 Hz, 1H), 6.90 (d, J=9.00 Hz, 1H), 3.87 (s, 3H), 3.79 (s, 3H).
MS (APCIþ) m/z 452.9 [(M)þ•]. tR=v 7.50 min (100%).
5-[4-(2,4-Bis-trifluoromethylphenoxy)-3-methoxybenzylidene]-
thiazolidine-2,4-dione (28). (A) 1-Fluoro-2,4-bis-trifluoromethyl-
benzene was reacted with vanillin according to general procedure
A to afford 4-(2,4-bis-trifluoromethylphenoxy)-3-methoxyben-
zaldehyde as a colorless syrup. Yield: 87%. 1H NMR (400 MHz,
CDCl3) δ 9.99 (s, 1H), 7.95 (d, J = 1.56 Hz, 1H), 7.67 (dd,
2-[4-(2,4-Dioxothiazolidin-5-ylidenemethyl)-2-methoxyphenoxy]-
5-trifluoromethylbenzoic Acid Methyl Ester (31). (A) 2-Fluoro-
5-trifluoromethylbenzoic acid methyl ester was reacted with
vanillin according to general procedure A to afford 2-(4-for-
myl-2-methoxyphenoxy)-5-trifluoromethylbenzoic acid methyl
ester as a pale yellow oil. Yield: 94%. 1H NMR (400 MHz,
CDCl3) δ 9.93 (s, 1H), 8.24 (d, J=1.96 Hz, 1H), 7.69 (dd, J =
2.35, 8.61 Hz, 1H), 7.55 (d, J=1.56 Hz, 1H), 7.44 (dd, J=1.76,
8.02 Hz, 1H), 7.00 (d, J=8.22 Hz, 1H), 6.97 (d, J=8.61 Hz, 1H),
3.89-3.94 (m, 3H), 3.83-3.88 (m, 3H).
(B) 2-(4-Formyl-2-methoxyphenoxy)-5-trifluoromethylben-
zoic acid methyl ester was condensed with 2,4-thiazolidinedione
according to general procedure B to afford the title compound
as a canary yellow solid. Yield: 78%. 1H NMR (400 MHz,
CDCl3) δ 8.24 (d, J=2.31 Hz, 1 H), 7.82 (s, 1 H), 7.68 (dd, J =
8.57, 2.31 Hz, 1 H), 7.06-7.18 (m, 2 H), 6.97-7.06 (m, 1 H), 6.93