3382 J. Agric. Food Chem., Vol. 47, No. 8, 1999
Samaritoni et al.
mass spectroscopic, and analytical information. Table 2 con-
tains specific procedural and experimental details and NMR
data (given for the predominant isomer).
Anal. Calcd for C21H16ClF3N2O3S: C, 53.79; H, 3.44; N, 5.98;
S, 6.84. Found: C, 54.04; H, 3.77; N, 5.91; S, 6.63.
N-(4-Ch lor o-3-m et h yl-5-isot h ia zolyl)-â-isop r op oxy-p -
[(r,r,r-tr iflu or o-p-tolyl)oxy]a tr op a m id e (4c). To a suspen-
sion of 0.045 g (1.1 mmol) of 60% sodium hydride-mineral oil
dispersion in 2 mL of dry tetrahydrofuran was added dropwise
a solution of 0.51 g (1.1 mmol) of 4a in 10 mL of THF. After
0.5 h, 0.6 mL (6 mmol) of isopropyl iodide was then added.
The contents were heated at 35 °C for 20 h and then at 45 °C
for 9 h. Upon cooling the mixture was added to ice water that
had been treated with 1.1 mL of 1.0 N hydrochloric acid. It
was then extracted with ethyl acetate, and the extract was
washed once with brine and dried (MgSO4). Concentration
gave 0.59 g of a brown oil, which was chromatographed eluting
with 9:1 heptane/ethyl acetate and progressing to 4:1 to afford
220 mg (40%) of 4c as a solid, mp 111.5-114 °C: 1H NMR δ
1.28 (d, 6H, J ) 6.4 Hz), 2.33 (s, 3H), 4.44 (m, 1H, J ) 6.4
Hz), 7.02-7.10 (m, 5H), 7.39 (d, 2H, J ) 9.3 Hz), 7.58 (d, 2H,
J ) 7.8 Hz), 10.52 (br s, 1H); IR (KBr) 1580, 1656, 2979, 3316
cm-1; MS (EI) m/z 498 ([M + 2]+, 6), 496 (M+, 13), 279 (100).
N-[(E,Z)-â-[(4-Ch lor o-3-m eth yl-5-isoth ia zolyl)ca r ba m -
oyl]-p-[(r,r,r-tr iflu or o-p-tolyl)oxy]styr yl]glycin e (3m ). To
a solution of 1.30 g (2.16 mmol) of the benzyl ester 3l in 15
mL of methanol was added 0.300 g (2.17 mmol) of potassium
carbonate followed by 3 mL of water. After 6 h, the mixture
was poured onto ice water, which was then adjusted to pH 3
with dilute hydrochloric acid. The contents were extracted two
times with ethyl acetate, and the combined extracts were
washed with brine and dried (MgSO4). Concentration gave 1.0
g of a solid, which was triturated under heptane/ethyl acetate
to afford 0.68 g, mp 177-83 °C. This material was recrystal-
lized from heptane and ethyl acetate (2:1) giving 0.27 g of 3m
(see Tables 1 and 2).
N-[(E,Z)-â-[(4-Ch lor o-3-m eth yl-5-isoth ia zolyl)ca r ba m -
oyl]-p-[(r,r,r-tr iflu or o-p-tolyl)oxy]styr yl]glycin e, Sodiu m
Sa lt (3o). To a mixture of 0.185 g (0.361 mmol) of the acid
3m in 5 mL of methanol was added 0.18 mL (0.36 mmol) of
2.0 N sodium hydroxide. After 3 h, the precipitate was collected
and dried in vacuo at 120 °C for 3 h to afford 0.10 g (50%) of
the sodium salt of 3m as its monohydrate and as a 1:1 mixture
of Z and E isomers in DMSO-d6 (the methylene group is not
observed but is believed to be under the broad water signal of
the proton NMR spectrum, see Tables 1 and 2).
N-[(E,Z)-â-[(4-Ch lor o-3-m eth yl-5-isoth ia zolyl)ca r ba m -
oyl]-p-[(r,r,r-tr iflu or o-p-tolyl)oxy]styr yl]-â-a la n in e (3p ).
A mixture of 0.770 g (1.39 mmol) of the ester 3n and 0.390 g
(2.82 mmol) of potassium carbonate in 15 mL of methanol, 5
mL of tetrahydrofuran, and 5 mL of water was stirred at room
temperature for 24 h. The solution was concentrated, and the
resulting mixture was partitioned between ethyl acetate and
water. The pH of the aqueous phase was adjusted to 4 with
0.5 N hydrochloric acid, and the organic layer was then washed
with brine and was dried (MgSO4). Concentration gave a solid,
which was triturated under heptane/ethyl acetate to afford 410
mg of crude acid, which was recrystallized from ethyl acetate
to give 250 mg (34%) of 3p (see Tables 1 and 2).
N-(4-Ch lor o-3-m eth yl-5-isoth iazolyl)-â-h ydr oxy-p-[(r,r,r-
tr iflu or o-p-tolyl)oxy]a tr op a m id e (4a ). A solution of 0.40
g (0.83 mmol) of 2 and 0.080 g (0.83 mmol) of methanesulfonic
acid in 25 mL of absolute methanol was heated at reflux for
3.5 h and allowed to cool. The methanol was removed in vacuo,
and the resulting oil was partitioned between ethyl ether and
aqueous sodium bicarbonate. The organic layer was washed
with brine and was dried (MgSO4). Concentration gave a
residue that was chromatographed eluting with dichlo-
romethane initially and progressing to 1:1 dichloromethane/
ethyl acetate to afford 123 mg (33%) of 4a as a white solid,
mp 182-83.5 °C: 1H NMR δ 2.38 (s, 3H), 7.12 (d, 2H, J ) 8.3
Hz), 7.17 (d, 2H, J ) 8.8 Hz), 7.32 (d, 1H, J ) 12.5 Hz), 7.37
(d, 2H, J ) 8.8 Hz), 7.63 (d, 2H, J ) 8.6 Hz), 8.05 (s, 1H),
12.52 (d, 1H, J ) 12.5 Hz); MS (CI) m/z 457 ([M + H + 2]+,
14), 455 ([M + H]+, 37), 306 (22), 149 (100).
Anal. Calcd for C23H20ClF3N2O3S: C, 55.59; H, 4.06; N, 5.64;
S, 6.45. Found: C, 57.44; H, 3.94; N, 5.67; S, 6.02.
â-(Bu t ylt h io)-N-(4-ch lor o-3-m et h yl-5-isot h ia zolyl)-p -
[(r,r,r-tr iflu or o-p-tolyl)oxy]a tr op a m id e (4d ). A mixture
of 0.454 g (1.00 mmol) of 4a , 90.2 mg (1.00 mmol) of n-
butanethiol, and 0.190 g (1.00 mmol) of p-toluenesulfonic acid
monohydrate in 10 mL of benzene was heated at 50 °C for 3 h
and then at 60 °C for 8 h. Upon cooling the contents were
diluted with ethyl acetate, washed three times with saturated
sodium bicarbonate and once with brine, and dried (MgSO4)
and decolorized with carbon black. Concentration gave 500 mg,
which was chromatographed eluting with dichloromethane and
progressing to 97:3 dichloromethane/ethyl acetate to afford 180
mg (34%) of 4d as a solid, mp 119.5-122.5 °C: 1H NMR δ
0.90 (t, 3H, J ) 7.4 Hz), 1.40 (m, 2H, J ) 7.5 Hz), 1.66 (m,
2H, J ) 7.5 Hz), 2.34 (s, 3H), 2.85 (t, 2H, J ) 7.4 Hz), 7.10 (d,
2H, J ) 8.5 Hz), 7.18 (d, 2H, J ) 8.7 Hz), 7.37 (d, 2H, J ) 8.6
Hz), 7.61 (d, 2H, J ) 8.4 Hz), 7.94 (br s, 1H), 8.10 (s, 1H); IR
(KBr) 1557, 1662, 3384 cm-1; MS (CI) m/z 529 ([M + H + 2]+,
29), 527 ([M + H]+ 60), 379 (43), 57 (100).
Anal. Calcd for C24H22ClF3N2O2S2: C, 54.69; H, 4.21; N, 5.32;
S, 12.16. Found: C, 54.45; H, 4.35; N, 5.22; S, 11.98.
N-(4-Ch lor o-3-m et h yl-5-isot h ia zolyl)-2-[p -[(r,r,r-t r i-
flu or o-p-tolyl)oxy]p h en yl]glyoxyla m id e (5). To a mixture
of 6.00 g (12.4 mmol) of 2 and 5.30 g (24.8 mmol) of sodium
periodate in 45 mL of tetrahydrofuran cooled in ice water was
added dropwise 23 mL of water. The mixture was allowed to
warm to room temperature and stirred for 24 h. It was then
filtered, and the filtrate was concentrated to remove most of
the THF and then diluted with ethyl acetate and brine. The
organic layer was washed with brine, dried (MgSO4), and
decolorized (carbon black). Concentration gave 6.1 g of a golden
solid, which was flashed chromatographed eluting with dichlo-
romethane to afford 4.36 g (80%) of 5 as a yellow solid, mp
130-2 °C: 1H NMR δ 2.44 (s, 3H), 7.07 (d, 2H, J ) 9.1 Hz),
7.16 (d, 2H, J ) 8.3 Hz), 7.66 (d, 2H, J ) 8.9 Hz), 8.53 (d, 2H,
J ) 9.1 Hz), 9.83 (br s, 1H); IR (KBr) 1675, 3357 cm-1; MS
(EI) m/z 442 ([M + 2]+, 3), 440 (M+, 7), 265 (100).
Anal. Calcd for C20H14ClF3N2O3S: C, 52.81; H, 3.10; N, 6.16.
Found: C, 52.91; H, 3.16; N, 6.09.
N-(4-Ch lor o-3-m eth yl-5-isoth ia zolyl)-â-m eth oxy-p-[(r,-
r,r-tr iflu or o-p-tolyl)oxy]a tr op a m id e (4b). To a suspension
of 40.7 mg (1.02 mmol) of 60% sodium hydride-mineral oil
dispersion in 0.5 mL of dry tetrahydrofuran cooled in ice water
was added dropwise a solution of 0.460 g (1.02 mmol) of 4a in
5 mL of THF. After 20 min, 0.60 mL (9.6 mmol) of methyl
iodide was added. The contents were stirred for 40 h and were
added to 60 mL of ice water that had been treated with 1.02
mL of 1.0 N hydrochloric acid. The mixture was extracted once
with ethyl ether, and the extract was washed once with brine
and dried (MgSO4). Concentration gave 0.4 g, which was
chromatographed using 4:1 heptane/ethyl acetate as the eluant
to afford 0.24 g (50%) of 4b as a solid, mp 153.5-6.5 °C: 1H
NMR δ 2.34 (s, 3H), 4.15 (s, 3H), 6.94 (s, 1H), 7.03-7.09 (m,
4H), 7.37 (d, 2H, J ) 8.6 Hz), 7.58 (d, 2H, J ) 8.6 Hz), 10.3
(br s, 1H); MS (CI) m/z 471 ([M + 2 + H]+, 39), 469 ([M + H]+,
100), 321 (54).
Anal. Calcd for C19H12ClF3N2O3S: C, 51.76; H, 2.74; N, 6.36.
Found: C, 51.58; H, 2.72; N, 6.19.
Gen er a l P r oced u r e for th e P r ep a r a tion of 6a -d . A
solution of 5 in ethanol (0.10 M) and the amine hydrochloride
was heated at 60 °C and then concentrated in vacuo to give 6.
Table 1 contains infrared, mass spectroscopic, and analytical
information. Table 2 contains specific procedural and experi-
mental details and NMR data.
N-(4-Ch lor o-3-m et h yl-5-isot h ia zolyl)-2-[p -[(r,r,r-t r i-
flu or o-p-tolyl)oxy]ph en yl]glyoxylam ide 2-Hydr azon e (6e)
a n d N-(4-Ch lor o-3-m eth yl-5-isoth ia zolyl)-2-[p-[(r,r,r-tr i-
flu or o-p-tolyl)oxy]p h en yl]glyoxyla m id e 2,2′-Azin e (8). A
solution of 0.250 g (0.567 mmol) of 5, 0.100 g (1.35 mmol) of
acetic hydrazide, and 3.28 mL (1.35 mmol) of a 0.41 M
ethanolic solution of dry hydrogen chloride gas in 10 mL of