Isothiazolephenylacetamide Proinsecticides
J. Agric. Food Chem., Vol. 45, No. 5, 1997 1921
5-Am in o-4-ch lor o-3-m eth ylisoth ia zole (3). 5-Amino-3-
methylisothiazole (18.9 g, 0.166 mol), obtained by neutraliza-
tion of the hydrochloride (Aldrich Chemical Company, Mil-
waukee, WI), was slurried in carbon tetrachloride (600 mL)
under nitrogen. N-Chlorosuccinimide (22.1 g, 0.166 mol) was
then added over a 5 min period at 30-44 °C, and the mixture
was stirred overnight at room temperature. The mixture was
then diluted with ether and was filtered. The filtrate was
concentrated to a red oil which was taken up in ethyl acetate
and was washed with two portions of water, once with brine,
and dried (MgSO4). Concentration gave 22.0 g (79%) of 3 as
a brown solid: 1H NMR δ 2.3 (s, 3H), 4.7 (bs, 2H).
[p-[(r,r,r-Tr iflu or o-p-tolyl)oxy]p h en yl]a cetic Acid (6).
To a mixture of 21.4 g (0.535 mol) of 60% sodium hydride/
mineral oil dispersion in 80 mL of dry dimethyl sulfoxide
(DMSO) was added slowly with cooling a solution of 40.2 g
(0.264 mol) of (p-hydroxyphenyl)acetic acid in 80 mL of dry
DMSO. This was followed by the addition of 95.4 g (0.528 mol)
of p-chloro-R,R,R-trifluorotoluene in 50 mL of dry DMSO. The
contents were then heated for 16 h at 160-175 °C. Upon
cooling, the contents were poured onto 700 mL of ice water
and washed with three portions of tetrachloroethylene. The
aqueous volume was then adjusted to pH 1-2 with concen-
trated hydrochloric acid, and the precipitate was collected and
dried in vacuo at 40-50 °C to afford 62 g (79%) of 6 as a light
brown solid: 1H NMR δ 3.65 (s, 2H), 7.0 (m, 2H), 7.05 (m, 2H),
7.3 (m, 2H), 7.6 (m, 2H).
tetrahydrofuran. CAUTION! Halomethyl alkyl ethers, such
as bromomethyl methyl ether, are highly toxic and should
always be handled in a hood with gloves. The mixture was
held at -50 °C for 2 h and was then allowed to gradually warm
to room temperature and was stirred overnight. The contents
were then poured onto ice water and extracted twice with ethyl
ether. The combined extracts were then washed once with
brine and dried (MgSO4). Concentration gave an oil which was
purified by silica gel chromatography. Amide-nitrogen alkyl-
ated derivatives 7 were eluted first followed by the ring-
nitrogen alkylated isomers 8 as described in the general
procedure for Method A.
Gen er a l P r oced u r e for th e P r ep a r a tion of Am id e-
Nitr ogen (7o,p ) a n d Rin g-Nitr ogen (8o,p ) Alk yla ted
Isoth ia zolylp h en yla ceta m id es (Meth od C). A 0.5 M mix-
ture of the amide 1 in dry acetone, potassium carbonate (1.0
equiv), and the alkyl bromide (ca. 4-5 equiv) was heated at
reflux overnight. The mixture was then concentrated in vacuo
to a residue which was then partitioned between ethyl ether
and water. The organic layer was washed once with brine and
then dried (MgSO4). Concentration gave an oil which was
purified by silica gel chromatography. Amide-nitrogen alkyl-
ated derivatives 7 were eluted first followed by the ring
nitrogen-alkylated isomers 8 as described in the general
procedure for Method A.
Data for N-alkylated amides 7 and 8 are assembled in
Tables 1-3.
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]a ceta m id e (1). A solution of
26.8 g (0.0904 mol) of the phenylacetic acid 6 in 240 mL of
thionyl chloride was heated at reflux for 2 h, cooled, and
concentrated in vacuo to an oil which was dissolved in 200
mL of xylenes and added dropwise to a mixture of 13.4 g
(0.0904 mol) of the amine 3 in 50 mL of xylenes. The contents
were heated at reflux for 2 h, cooled, and diluted with toluene.
The volume was then washed twice with saturated sodium
bicarbonate, once with brine, and dried (MgSO4). Concentra-
tion gave a solid which was triturated under heptane to afford
37 g (86%) of 1 as a light brown solid, mp 125-129°C; 1H NMR
δ 2.4 (s, 3H), 3.9 (s, 2H), 7.1 (m, 2H), 7.2 (m, 2H), 7.4 (m, 2H),
7.6 (m, 2H), 8.1 (bs, 1H); MS (EI) m/ z 428 ([M + 2]+, 4), 426
(M+, 11), 251 (100). Anal. Calcd for C19H14ClF3N2O2S: C,
53.46; H, 3.30; N, 6.56. Found: C, 53.73; H, 3.40; N, 6.49.
Gen er a l P r oced u r e for th e P r ep a r a tion of Am id e-
Nitr ogen (7a -l) a n d Rin g-Nitr ogen (8a -l) Alk yla ted
Isoth ia zolylp h en yla ceta m id es (Meth od A). A 0.16 M
solution of the amide 1 in 1 part water and 2 parts dichlo-
romethane, potassium carbonate (3.54 equiv), triethylben-
zylammonium bromide (TEBAB, 1.07 equiv), 10% aqueous
sodium hydroxide (ca. 3.2 equiv), and the alkyl halide (ca. 1.1-
20 equiv) was stirred at room temperature. Reaction progress
was monitored by thin-layer analysis on silica gel which was
developed using dichloromethane/ethyl acetate and heptane/
ethyl acetate mixtures and was complete within 48 h. The
organic phase was passed through phase-separating paper and
was concentrated to a residue which was partitioned between
water and ethyl acetate. The organic phase was then washed
once with brine and dried over magnesium sulfate. Concen-
tration usually gave an oil which was chromatographed on
silica gel. Amide-nitrogen alkylated derivatives 7 were eluted
first using relatively nonpolar eluants such as 4:1 heptane:
ethyl acetate (see Table 1) and, in general, existed as oils at
room temperature. Ring-nitrogen alkylated amides 8 were
eluted with increasing polarity of the eluant (such as ethyl
acetate, see Table 2) and, without exception, existed as solids
at room temperature. Compounds 8d and 8l crystallized from
their crude reaction mixtures after workup and were recrys-
tallized from heptane/ethyl acetate.
N-[4-Ch lor o-2-(2-h yd r oxyeth yl)-3-m eth yl-3-isoth ia zo-
lin -5-ylid en e]-2-[p -[(r,r,r-t r iflu or o-p-t olyl)oxy]p h en yl]-
a ceta m id e (8q). To a mixture cooled in ice of 2.00 g (3.90
mmol) of the ester 8l in 20 mL of absolute ethanol was added
in one portion 0.147 g (3.90 mmol) of sodium borohydride. The
mixture was allowed to warm to room temperature and was
stirred overnight. Sodium borohydride (68 mg) was added to
the reaction mixture and after 4 h was cooled in ice and was
treated portionwise with 10 mL of 0.1 N hydrochloric acid
followed by dilution with 100 mL of water and 200 mL of ethyl
acetate. The acidified mixture was then treated with satu-
rated sodium bicarbonate to facilitate separation. The organic
phase was then washed once with brine and was dried
(MgSO4). Concentration afforded 1.78 g (97%) of 8q as a white
solid, mp 164-166 °C: 1H NMR δ 1.28 (bs, 1H), 2.48 (s, 3H),
3.92 (t, 2H, J ) 4.8 Hz), 4.00 (s, 2H), 4.06 (t, 2H, J ) 4.8 Hz),
6.95 (m, 2H), 7.00 (m, 2H), 7.36 (m, 2H), 7.51 (m, 2H); IR (KBr)
v 3398 (m); MS (EI) m/ z 471 ([M + H]+, 2), 351 (100). Anal.
Calcd for C21H18ClF3N2O3S: C, 53.56; H, 3.85; N, 5.95; S, 6.81.
Found: C, 53.78; H, 4.14; N, 5.75; S, 6.99.
4-Ch lor o-3-m eth yl-5-[[[p-[(r,r,r-tr iflu or o-p-tolyl)oxy]-
p h en yl]a cetyl]im in o]-3-isoth ia zolin e-2-a cetic Acid (8r ).
A solution of 0.40 g (0.78 mmol) of the ester 8l and 0.78 mL of
1.0 N sodium hydroxide in 15 mL of ethanol was stirred at
room temperature for 20 h. Hydrochloric acid (0.78 mL of a
1.0 N solution) was then added, and the solution was concen-
trated to a residue which was partitioned between ethyl
acetate and brine. The organic phase was then dried over
magnesium sulfate. Concentration gave 340 mg of 8r as a pale
yellow solid which was shown by 1H NMR and HPLC to be
95% pure. This material was recrystallized from ethyl acetate/
tetrahydrofuran to afford 165 mg (44%) which was shown by
HPLC to be 99.6% pure, mp 164-167 °C (dec): 1H NMR δ
2.49 (s, 3H), 4.02 (s, 2H), 4.59 (s, 2H), 7.00 (m, 2H), 7.04 (m,
2H), 7.41 (m, 2H), 7.55 (m, 2H); MS (CI) m/ z 296 ([M + H -
C5H6ClNO2]+, 69), 193 ([M + 2H - C15H12F3NO2]+, 68), 51
(100). Anal. Calcd for C21H16ClF3N2O4S: C, 52.02; H, 3.33;
N, 5.79. Found: C, 51.16; H, 3.27; N, 5.82.
4-Ch lor o-3-m eth yl-5-[[[p-[(r,r,r-tr iflu or o-p-tolyl)oxy]-
p h en yl]a cetyl]im in o]-3-isoth ia zolin e-2-a cetic Acid , So-
d iu m Sa lt (8s). A solution of 0.70 g (1.36 mmol) of the ester
8l and 0.68 mL of 2.0 N aqueous sodium hydroxide in 15 mL
of ethanol was stirred at room temperature for 20 h. The
mixture was cooled in ice and then filtered and dried in vacuo
at 80 °C to afford 270 mg (39%) of 8s as a white solid: 1H
NMR (D2O) δ 2.22 (s, 3H), 3.75 (bs, 2H), 4.37 (bs, 2H), 6.45
(m, 2H), 6.55 (m, 2H), 7.02 (m, 2H), 7.13 (m, 2H). Anal. Calcd
for C21H15ClF3N2NaO4S: C, 49.76; H, 2.98; N, 5.53; S, 6.33.
Found: C, 49.90; H, 2.65; N, 5.57; S, 6.13.
Gen er a l P r oced u r e for th e P r ep a r a tion of Am id e-
Nit r ogen (7m ,n ) a n d R in g-Nit r ogen (8m ,n ) Alk oxy-
m eth yla ted Isoth ia zolylp h en yla ceta m id es (Meth od B).
To a suspension (ca. 0.8 M) at 0 °C of 60% sodium hydride
(1.05 equiv) in tetrahydrofuran was added dropwise a 0.8 M
solution of the amide 1 in tetrahydrofuran. The solution was
stirred for 1 h, cooled to -50 °C, and treated dropwise with a
4 M solution of the halomethyl alkyl ether (ca. 3-4 equiv) in