The synthesis of N-substituted isothiazol-3(2H)-ones from N-substituted 3-benzoylpropionamides

Article abstract of DOI:10.1002/jhet.5570390122

N-Substituted isothiazol-3(2H)-ones can be easily prepared from N-substituted 3-benzoylpropionamides in two experimentally simple steps, in satisfactory overall yields. Reaction of the amides with excess thionyl chloride results in the formation of N-subs

Full text of DOI:10.1002/jhet.5570390122

Jan-Feb 2002
The Synthesis of N-Substituted Isothiazol-3(2H)-ones from
N-Substituted 3-Benzoylpropionamides
149
Stylianos Hamilakis, Demetrios Kontonassios and Athanase Tsolomitis*
Laboratory of Organic Chemistry, National Technical University, Zografou Campus, Athens-15780, Greece
Received July 24, 2000
N-Substituted isothiazol-3(2H)-ones can be easily prepared from N-substituted 3-benzoylpropi-
onamides in two experimentally simple steps, in satisfactory overall yields. Reaction of the amides
with excess thionyl chloride results in the formation of N-substituted 5-benzoylisothiazol-3(2H)-
ones, which are readily debenzoylated with alkali to the corresponding N-substituted isothiazol-
3(2H)-ones. This method has now been successfully applied to the synthesis of isothiazolones
N-substituted with a bulky alkyl group, such as the tert-butyl group, and with a phenyl group bear-
ing either a strong electron-withdrawing substituent, such as the 3-nitrophenyl and 4-nitrophenyl
group, or an electron-releasing substituent, such as the 4-methylphenyl and 4-methoxyphenyl group.
J. Heterocyclic Chem., 39, 149 (2002).
Introduction.
chloride and reacted with a range of aliphatic and aro-
matic amines to yield the amides 5, which were then oxi-
dized to the corresponding sulfoxides 6 on reaction with
3-chloroperbenzoic acid in good overall yields.
Cyclization of the sulfoxides 6 was accomplished using
trichloroacetic anhydride in dichloromethane and the cor-
responding isothiazolones 3 were isolated in good yields,
after chromatographic separation from benzyl
trichloroacetate formed during the reaction. The method
was successfully used for a wide range of N-substitution,
The synthesis of a series of N-substituted isothiazol-
3(2H)-ones 3 was first reported in 1971 by Lewis et al. [1]
starting with 3,3'-dithiodipropionic acid (1) (Scheme 1).
This was achieved by the one-step chlorination-cyclization
of the readily available 3,3'-dithiodipropionamides 2.
including the bulky N-tert-butyl group (R=-CMe ).
3
However, the cyclization step, 6 → 3, failed in the case of
an aromatic amide 6 bearing a strong electron-withdraw-
1
2
3
ing substituent, R=-C H NO -4.
6
4
2
We have already described [3] the preparation of isothia-
zolones 3 (R=-CH , -CH Ph, -C H and -C H Cl-4) from
the appropriate 3-aroylpropionamides 7, by the sequence of
reactions shown in Scheme 3. A simple cyclization reaction
of amides 7 with excess thionyl chloride has been shown to
give the corresponding 5-aroylisothiazolones 8, which are
However, Beeley et al. [2] have recently experienced
difficulties in the cyclization of secondary amides 2 with
sulfuryl chloride; the corresponding isothiazolones 3 were
obtained only in low yields, contaminated by appreciable
quantities of 5-chloroisothiazol-3(2H)-ones.
A novel general route to the synthesis of N-substituted
isothiazolones 3 was then developed by Beeley et al. [2],
via a ring closure reaction of N-substituted (Z)-3-(ben-
zylsulfinyl) propenamides 6 (Scheme 2). The readily
available acid 4 was activated with diphenylphosphinic
3
2
6
5
6 4
readily dearoylated with alkali to the corresponding N-sub-
stituted isothiazolones 3. We now report an extension of this
approach to the synthesis of isothiazolones 3 N-substituted
with either a bulky alkyl group or a phenyl group bearing

150
S. Hamilakis, D. Kontonassios and A. Tsolomitis
Vol. 39
both electron-withdrawing and electron-releasing sub-
stituents.
An equally effective method for the preparation of N-
substituted amides of the general formula 7 from 3-aroyl-
propionic acids 10, using the mixed anhydride conditions
(Scheme 4), has also been described [9]. Actually, under
these conditions, we have prepared the N-tert-butyl amide
7a in excellent yield, and the N-4-methylphenyl and N-4-
methoxyphenyl amides (compounds 7d and 7e, respec-
tively) in satisfactory yields as well (see Experimental).
The N-3-nitrophenyl and N-4-nitrophenyl 3-benzoylpro-
pionamides (compounds 7b and 7c, respectively) were
obtained in satisfactory yields from the reaction of the lac-
Results and Discussion.
The synthesis of isothiazolones 3, as shown in Scheme
3, will finally depend on (a) the availability of the appro-
priate open chain amides 7, (b) their transformation to the
aroylisothiazolones 8, and (c) the dearoylation of the latter
to the isothiazolones 3. The preparation of amides 7 and
their transformations to isothiazolones 8 and 3 are dis-
cussed in the following sections, with respect to the syn-
thesis of the N-tert-butyl, N-3-nitrophenyl, N-4-nitro-
phenyl, N-4-methylphenyl and N-4-methoxyphenyl isoth-
iazolones 3 (compounds 3a-3e, in Scheme 3).
tone 11 (Ar=-C H ) with the corresponding nitroanilines
6
5
(see Experimental). These two amides were, however, iso-
lated as pale pink-colored solids, the color probably result-
ing from the formation of "Pechmann dyes" in alcoholic
solutions of the lactones 11 [6].
γ-Keto amides of the general formula 7 are known to
exhibit ring-chain tautomerism [10]. 3-Benzoylpropion-
amide and its N-substituted derivatives have been shown to
A. N-Substituted 3-Aroylpropionamides 7.
N-Substituted 3-aroylpropionamides 7, mostly 3-ben-
zoylpropionamides (7, Ar=-C H ), have been prepared
6
5
using the Grignard reaction of ArMgX with N-substituted
succinimides 9 [4] (Scheme 4). On the other hand, a large
number of N-substituted 3-aroylpropionamides 7 have
been prepared starting with the corresponding 3-aroylpro-
pionic acids 10, where Ar is a phenyl group bearing both
electron-withdrawing and electron-releasing substituents.
exist as the open chain amides 7 (Ar=-C H ; R=-H, -C H ,
6
5
6 5
-CH Ph and -C H ), while the N-methyl derivative was
2
6 11
assigned the cyclic hydroxy-pyrrolidinone structure 12
(Ar=-C H ) shown in Scheme 4 [7]. The tautomeric struc-
6
5
ture of a series of N-substituted 3-aroylpropionamides has
been studied by Chiron and Graff [4] and these compounds
were also assigned the open chain amide structure 7, with
the exception of the N-methyl derivatives. The cyclic
hydroxy-pyrrolidinone structure 12 was actually observed
for Ar=-C H NO -3, -C H Br-4, -C H and -C H CH -4.
6
4
2
6
4
6
5
6
4
3
However, the open chain amide structure was observed
when the aroyl group of the N-methyl derivative was sub-
stituted with an electron-releasing substituent (compound
7, Ar=-C H OCH -4, R=-CH ).
6
4
3
3
Pmr spectroscopy has been used in order to establish the
open chain or ring structure of 3-aroylpropionamides [4,11].
The open chain amides 7 are characterized by the -CH CH -
2
2
methylene proton signals, which appear as two distinct
triplets, J= 6 Hz, at approximately δ 2.65 and 3.35 ppm.
Moreover, the characteristic aromatic protons' signals of the
benzoyl group, at δ 7.20-8.00 ppm, appear in the spectra of
the open chain 3-benzoylpropionamides (7, Ar=-C H ).
6
5
Acids 10 are easily lactonized to the corresponding
5-arylfuran-2(3H)-ones 11 by heating with acetic anhy-
The tautomeric structure of the γ-keto amides is directly
related to the present study, since aroylisothiazolones 8 are
readily obtained from the corresponding open chain amides
7 (Scheme 3), as described in the following section.
dride or with acetyl chloride [5]. Primary amines RNH ,
2
where R is an alkyl, an aralkyl or a substituted aryl group,
readily react with lactones 11 to yield N-substituted
3-aroylpropionamides 7 [4,7]. The only exception to this
general method was noted for the reaction with tert-buty-
B. N-Substituted 5-Aroylisothiazol-3(2H)-ones 8.
A simple cyclization reaction of 3-benzoylpropi-
lamine; in this case, the lactones 11 (Ar= -C H and
onamides 7 (Ar=-C H ) has been shown to give the corre-
6
5
6 5
-C H OCH -4) were reported to isomerize to the corre-
sponding 5-arylfuran-2(5H)-ones [4]. However, the isola-
tion of the N-tert-butyl amide 7a (Scheme 3), from the
sponding 5-benzoylisothiazolones 8 (Scheme 3). Thus, a
mixture of the amide 7 (Ar=-C H , R=-CH Ph) and an
excess of thionyl chloride was stirred at room temperature
for 1 hour, when a dark solution was obtained, the excess
thionyl chloride was then removed under vacuum and the
6
4
3
6
5
2
reaction of the lactone 11 (Ar=-C H ) and tert-butylamine
6
5
in refluxing acetonitrile, has been described [8].

Jan-Feb 2002
The Synthesis of N-Substituted Isothiazol-3(2H)-ones
151
solid residue was crystallized from ethanol to give the cor-
responding isothiazolone 8 as a yellow product, in 70%
yield [12]. Following this simple procedure, N-aryl 5-ben-
8a (as the base) was readily isolated when a chloroform
solution of its hydrochloride was just washed with water
(see Experimental).
The basic character of the isothiazolone 8a could be
observed in its pmr spectra. The signal of the vinyl proton
of 8a (as the base) appears as a singlet at δ 6.60 ppm in
deuteriochloroform [16] and at δ 7.38 ppm in trifluo-
roacetic acid. The significant downfield shift of this signal
in acid solution is consistent with the formation of the con-
jugate acid of 8a (Scheme 6). Furthermore, the structure
zoylisothiazolones 8 (Ar=-C H and R=-C H X, where X
6
5
6 4
is either an electron-withdrawing or an electron-releasing
substituent) could also be easily isolated in better than
50% yields. On the other hand, Beer and Wright [13]
reported the synthesis of N-substituted 5-benzoylisothia-
zolones 8 (Ar=-C H ; R=-C H , -CH Ph, -C H Cl-4 and
6
5
6
5
2
6 4
-C H NO -4) using similar reaction conditions; the corre-
6
4
2
sponding amides 7 were refluxed with thionyl chloride and
compounds 8 were finally isolated, after chromatography,
in about 40% yield.
The cyclization reaction of amides 7 with thionyl chlo-
ride has been suggested [12,13] to proceed through inter-
mediate sulfenyl chlorides 13 (Scheme 5), resulting from
of the hydrochloride of 8a is confirmed from its spectrum
in deuteriochloroform; the vinyl proton appears again at a
significantly low field, δ 7.63 ppm, while a strongly
deshielded one-proton singlet at δ 15.13 ppm can be
assigned to the protonated enol form. In agreement with
the weak basic character of the isothiazolone 8a and the
ready hydrolysis of its hydrochloride, the spectrum of the
the oxidation of the methylene group adjacent to the aroyl
carbonyl. Formation of such an intermediate would only be
possible for the open chain amides 7 and the N-methyl
aroylisothiazolone 8 was actually obtained from the open
chain (4-methoxybenzoyl)propionamide 7 (Ar=
-C H OCH -4, R=-CH ) [12]. Other 3-aroylpropi-
latter in deuteriochloroform after addition of pyridine-d
5
or deuterium oxide is identical to the spectrum of the base
8a in deuteriochloroform.
The preparation of the N-substituted 5-benzoylisothia-
zolones 8b-8e has already been reported [12,13]. A reexam-
ination of the cyclization reaction of the amides 7b and 7c
revealed, however, that appropriate experimental conditions
should be used in this case (see Experimental). The 3-nitro-
phenyl isothiazolone 8b could be isolated in 67% yield from
the reaction of the amide 7b with an excess of thionyl chlo-
ride at room temperature. On the other hand, the cyclization
reaction of the 4-nitrophenyl amide 7c was only possible on
refluxing with thionyl chloride and the corresponding isoth-
iazolone 8c was then isolated in 55% yield.
5-Aroylisothiazolones 8 are thus readily accessible from
the corresponding 3-aroylpropionamides 7. The cycliza-
tion reaction (Scheme 5) is effectively accomplished with
a variety of open chain γ-keto amides 7, for a wide range of
β-aroyl groups and N-substituents. Compounds 8 are suit-
able intermediates in a general synthesis of the corre-
sponding N-substituted isothiazolones 3, as described in
the following section.
6
4
3
3
onamides 7 have been found to be equally reactive; thus,
the N-benzyl isothiazolones 8 (R=-CH Ph) with variously
2
substituted aroyl groups, such as the 4-chlorobenzoyl [14],
the mesitoyl [15] and the 3-nitrobenzoyl [3] derivatives,
have been prepared in good yields. Moreover, the cycliza-
tion reaction with thionyl chloride has been used in the
preparation of a series of compounds 8, with a wide range
of aroyl groups and N-substituents, which were investi-
gated as active fungicides [9].
We have experienced some difficulty in preparing the N-
tert-butyl 5-benzoylisothiazolone 8a (Scheme 3). This com-
pound could not be easily isolated from the reaction of the
corresponding 3-benzoylpropionamide 7a with an excess of
thionyl chloride either at room temperature or at reflux.
However, the hydrochloride of compound 8a was isolated in
very good yield when the amide 7a was treated with an
excess of thionyl chloride in ether at room temperature (see
Experimental). Lewis et al. [1] have already noted the weak
basic character of isothiazolones 3; these compounds could
be isolated from the reaction of amides 2 with chlorine or
sulfuryl chloride (Scheme 1) as the corresponding
hydrochlorides, which were completely dissociated in
water. In agreement with this observation, the isothiazolone
C. N-Substituted Isothiazol-3(2H)-ones 3.
N-Substituted isothiazolones 3 have been found [17] to
dimerize readily by bases to 2,4-bismethylene-1,3-dithi-
etanes 15 (Scheme 7). The dimerization was shown to

152
S. Hamilakis, D. Kontonassios and A. Tsolomitis
Vol. 39
proceed through attack of the initially formed 5-anion 14
on the S-N bond of a second isothiazolone molecule.
Dithietanes of the general formula 15 were also obtained
Isothiazolones 3a-3e were also readily obtained from the
corresponding benzoylisothiazolones, 8a-8e (Scheme 3).
Compounds 8a-8c are hardly soluble in benzene, but it was
found that the debenzoylation reaction could be success-
fully accomplished when a solution of the benzoylisothia-
zolone in dichloromethane was treated either with a 10%
aqueous sodium hydroxide solution or with solid sodium
hydroxide (see Experimental). Thus, the hydrochloride of
8a in dichloromethane was stirred at room temperature for
40 minutes with solid sodium hydroxide and the N-tert-
butyl isothiazolone 3a was isolated in 80% yield. The syn-
thesis of the isothiazolone 3a has thus been accomplished
by two experimentally simple reactions (Scheme 3), in
62% overall yield from the readily available benzoylpropi-
onamide 7a. Likewise, compounds 8b-8e in dichloro-
methane were stirred at room temperature for 5 days with a
10% aqueous sodium hydroxide solution and the corre-
sponding N-substituted isothiazolones 3b-3e were isolated
in excellent yields, about 80%.
Conclusion.
N-Substituted isothiazol-3(2H)-ones 3 can be prepared
from N-substituted 3-aroylpropionamides 7, via the corre-
sponding 5-aroylisothiazol-3(2H)-ones 8 (Scheme 3), in
satisfactory overall yields. In particular, N-substituted 3-
benzoylpropionamides, readily available from 3-benzoyl-
propionic acid, are suitable starting materials in a general
synthesis of isothiazolones 3 N-substituted with various
alkyl, aralkyl and aryl groups.
[12,15] from N-substituted 5-aroylisothiazolones 8; in this
case, the 5-anion 14 would result from a nucleophilic dis-
placement on the 5-aroyl group of compound 8. When,
however, a solution of an aroylisothiazolone 8 in benzene
was stirred at room temperature, usually for 24 to 48 hours,
with a 10% aqueous sodium hydroxide solution, the corre-
sponding isothiazolone 3 was actually isolated almost
quantitatively from the benzene layer [3]. In the two-phase
aqueous-organic system, the anion 14 resulting from the
displacement reaction is protonated and the isothiazolone
3 is finally transferred into the organic phase prior to its
transformation to the dithietane derivative 15. The overall
transformation of aroylisothiazolones 8 to the correspond-
ing isothiazolones 3 was also found to proceed easily and
almost quantitatively when a solution of compound 8 in
benzene was stirred for just five minutes at room tempera-
ture in the presence of solid sodium hydroxide.
EXPERIMENTAL
Melting points were determined in capillary tubes and are
uncorrected. The ir spectra were obtained with a Perkin Elmer
267 spectrometer (as nujol mulls) or with a Nicolet Magna 560
spectrometer (in potassium bromide pellets) and were calibrated
-1
against the polystyrene 1601 cm band; absorption bands, in rec-
iprocal centimeters, are characterized as of strong (s), medium
(m) or weak (w) intensity and as broad (br) or sharp (sh). The pmr
spectra were recorded on a Varian EM-360 60 MHz spectrome-
ter; chemical shifts are given in ppm (δ) downfield from TMS
(internal standard) and are accurate to ±0.02 ppm. Elemental
analyses were obtained from the microanalytical laboratory of
CNRS (France) and from the Liverpool University Chemistry
Department (England).
The dearoylation reaction, 8 → 3, would be expected to
depend only on the reactivity of the aroyl group. Actually,
the isothiazolones 3 (R=-CH Ph, -C H and -C H Cl-4)
2
6
5
6 4
were obtained [3] from the corresponding 5-benzoylisothia-
zolones (8, Ar=-C H ). The N-methyl isothiazolone (3, R=-
N-tert-Butyl-3-benzoylpropionamide (7a).
6
5
To a solution of 3-benzoylpropionic acid (5 g, 28 mmoles) and
triethylamine (4 ml) in dry chloroform (50 ml), cooled at 0°,
ethyl chloroformate (2.7 ml, 28.3 mmoles) was added dropwise.
After stirring for 20 minutes, a solution of tert-butylamine (2.5 g,
34.2 mmoles) in chloroform (25 ml) was added and the mixture
was stirred at room temperature for 20 hours. The mixture was
then washed successively with 10% hydrochloric acid and 5%
aqueous sodium hydrogen carbonate, and the organic layer was
separated, dried (magnesium sulfate) and concentrated under
CH ) was prepared from the corresponding (4-methoxyben-
3
zoyl)isothiazolone (8, Ar=-C H OCH -4), while the reac-
6
4
3
tion of a (3-nitrobenzoyl)isothiazolone (8, Ar=-C H NO -3,
6
4
2
R=-CH Ph) was found to proceed faster. On the other hand,
2
a mesitoylisothiazolone (8, Ar=-C H Me -2,4,6, R=-
6
2
3
CH Ph) was recovered unchanged from a similar treatment,
2
since the sterically hindered carbonyl of the mesitoyl group
is not accessible to nucleophilic attack.

Jan-Feb 2002
The Synthesis of N-Substituted Isothiazol-3(2H)-ones
153
vacuum. The white solid residue (5.5 g, 84%), mp 110-113°,
proved to be almost pure amide 7a (pmr spectrum).
Recrystallization from ethyl acetate-petroleum ether yielded a
crystalline solid (72% yield), mp 116-117°, lit [8] mp 115-116°
(after recrystallization from benzene-hexane); ir (nujol): 3425
(br, m), 1678 (sh, s), 1642 (sh, s) and 1555 (sh, s); pmr (deuteri-
the workup and concentration of the organic layer was recrystal-
lized from ethanol to give compound 7e as a crystalline solid (11
g, 69%), mp 121-123°, lit [19] mp 124°; ir (nujol): sharp bands at
3268 (s), 1681 (s), 1658 (s), 1597 (w) and 1534 (s); pmr (deuteri-
ochloroform): 2.82 and 3.44 (two t, J=6 Hz, 4H, -CH CH -), 3.81
2
2
(s, 3H, -OCH ), 7.66-8.25 (m, 9H, aromatic protons) and 8.40 (br
3
ochloroform): 1.33 (s, 9H, -CMe ), 2.50 and 3.28 (two t, J=6 Hz,
s, 1H, -NH-).
3
4H, -CH CH -), 5.61 (br s, 1H, -NH-) and 7.26-8.00 (m, 5H, aro-
matic protons). The ir and pmr data agree with those already
reported [8].
2
2
5-Benzoyl-2-tert-butylisothiazol-3(2H)-one (8a).
Thionyl chloride (10 ml) was added to a suspension of the keto
amide 7a (3 g) in ether (30 ml) and the mixture was stirred at room
temperature. The initially insoluble material gradually dissolved,
while a new precipitate appeared after some time. After 20 hours,
the reaction mixture was concentrated under vacuum and the solid
residue was triturated with ether, filtered and washed again with
ether to give the hydrochloride of isothiazolone 8a as an almost
colorless solid (3 g, 78%), mp 129-131°; pmr (deuteriochloro-
N-3-Nitrophenyl-3-benzoylpropionamide (7b).
A mixture of 8.99 g (56.2 mmoles) of 5-phenylfuran-2(3H)-
one, obtained from the reaction of 3-benzoylpropionic acid with
acetyl chloride [6], and 7.9 g (57.2 mmoles) of 3-nitroaniline in
50 ml of ethanol was refluxed for 15 hours. The insoluble mater-
ial was then filtered and washed successively with ethanol and
ether. Compound 7b was thus obtained as a slightly pink-colored
solid (12.1 g, 72%), mp 154-156° dec., lit [18] mp 157° (after
recrystalization from methanol). A recrystallization from
dimethyl sulfoxide gave an analytically pure sample, mp 156-
157°dec.; ir (nujol): sharp bands at 3345 (m), 1703 (m), 1666 (s),
1592 (m) and 1526 (s); pmr (trifluoroacetic acid): 3.15 and 3.75
(two t, J= 6 Hz, 4H, -CH CH -), 7.28-8.62 (m, 9H, aromatic pro-
form): 1.80 (s, 9H, -CMe ), 7.43-8.00 (m, 6H, aromatic protons
3
and vinylic proton −the vinylic proton appears as a singlet at δ
7.63 ppm) and 15.13 (s, 1H, acidic proton); after addition of pyri-
dine-d or deuterium oxide: 1.70 (s, 9H, -CMe ), 6.60 (s, 1H,
5
3
vinylic proton) and 7.40-8.00 (m, 5H, aromatic protons).
Anal. Calcd. for C ClNO S: C, 56.46; H, 5.41; N, 4.70.
H
14 16
2
Found: C, 56.74; H, 5.42; N, 4.66.
2
2
tons) and 9.30 (br s, 1H, -NH-).
The hydrochloride of 8a (0.1 g) was dissolved in chloroform (5
ml) and the solution was washed twice with 10 ml of water; the
organic layer was dried (magnesium sulfate) and concentrated
under vacuum to give the isothiazolone 8a (0.08 g, 91%) as a yel-
lowish solid, mp 83-85°; this compound has been reported to be
an oil [9]. A recrystallization from ether-petroleum ether gave an
analytical sample as a yellow crystalline solid, mp 85-86°; ir
(nujol): sharp bands at 1661 (s), 1634 (s), 1595 (w) and 1548 (w);
Anal. Calcd. For C N O : C, 64.42; H, 4.73; N, 9.39.
H
16 14
2 4
Found: C, 64.57; H, 4.51; N, 9.53.
N-4-Nitrophenyl-3-benzoylpropionamide (7c).
A mixture of 16.02 g (0.1 mole) of 5-phenylfuran-2(3H)-one,
obtained from the reaction of 3-benzoylpropionic acid with
acetyl chloride [6], and 13.81 g (0.1 mole) of 4-nitroaniline was
heated at a steam bath for 6 hours. The solid mixture was then
crystallized from dimethyl sulfoxide-ethanol to give compound
7c as a slightly pink-colored solid (15 g, 50%), mp 216-219°
dec., lit [18] mp 198° (after recrystalization from benzene-petro-
leum ether). A recrystallization from dimethyl sulfoxide gave an
analytically pure sample, mp 219-220° dec.; ir (nujol): sharp
bands at 3314 (m), 1709 (s), 1667 (s), 1611 (m), 1593 (m), 1559
pmr (deuteriochloroform): 1.71 (s, 9H, -CMe ), 6.60 (s, 1H,
3
vinylic proton) and 7.36-8.03 (m, 5H, aromatic protons); (trifluo-
roacetic acid): 1.92 (s, 9H, -CMe ), 7.38 (s, 1H, vinylic proton)
3
and 7.48-8.06 (m, 5H, aromatic protons).
Anal. Calcd. for C
H NO S: C, 64.34; H, 5.78; N, 5.36.
14 15 2
Found: C, 64.37; H, 5.78; N, 5.33.
5-Benzoyl-2-(3-nitrophenyl) isothiazol-3(2H)-one (8b).
(s) and 1505 (s); pmr (DMSO-d ): 2.80 and 3.38 (two t, J=6 Hz,
6
4H, -CH CH -), 7.33-8.30 (m, 9H, aromatic protons) and 10.6
(br s, 1H, -NH-).
A mixture of the keto amide 7b (2.7 g) and thionyl chloride (40
ml) was stirred at room temperature for 24 hours. The excess
thionyl chloride was then removed under vacuum and the residue
was triturated with ethanol, filtered and washed with ethanol and
ether to give compound 8b (2 g, 67%) as a yellow solid. A recrys-
tallization from dimethyl sulfoxide gave an analytical sample, mp
220-222° dec., lit [12] mp 220-222°; ir (nujol): sharp bands at
1670 (s), 1637 (m) and 1527 (s); pmr (deuteriochloroform/triflu-
oroacetic acid): 7.29 (s, 1H, vinylic proton) and 7.65-8.77 (m,
9H, aromatic protons).
2
2
Anal. Calcd. for C
H N O : C, 64.42; H, 4.73; N, 9.39.
16 14 2 4
Found: C, 64.32; H, 4.75; N, 9.42.
N-4-Methylphenyl-3-benzoylpropionamide (7d).
Following the procedure described for the preparation of com-
pound 7a, 3-benzoylpropionic acid (10 g, 56 mmoles) was
treated with 4-aminotoluene. The solid residue obtained after the
workup and concentration of the organic layer was recrystallized
from ethanol to give compound 7d as a crystalline solid (11.1 g,
74%), mp 134-136°, lit [18] mp 136° (after recrystallization from
methanol); ir (nujol): sharp bands at 3268 (s), 1678 (s), 1656 (s),
1603 (s) and 1538 (s); pmr (deuteriochloroform): 2.25 (s, 3H, -
Anal. Calcd. for C
H N O S: C, 58.89; H, 3.09; N, 8.58; S,
16 10 2 4
9.83. Found: C, 58.92; H, 3.13; N, 8.55; S, 9.78.
5-Benzoyl-2-(4-nitrophenyl) isothiazol-3(2H)-one (8c).
CH ), 3.06 and 3.33 (two t, J=6 Hz, 4H, -CH CH -), 6.73-8.00
(m, 9H, aromatic protons) and 8.13 (br s, 1H, -NH-).
A mixture of the keto amide 7c (1 g) and thionyl chloride (20
ml) was refluxed for 4 hours. The excess thionyl chloride was
then removed under vacuum and the yellow-greenish residue was
briefly heated with 20 ml of ethanol. The insoluble material was
filtered and washed with ether to give compound 8c (0.6 g, 55%)
as a yellow solid. A recrystallization from dimethyl sulfoxide
gave an analytical sample, mp 224° dec, lit [13] mp 240-242°; ir
3
2
2
N-4-Methoxylphenyl-3-benzoylpropionamide (7e).
Following the procedure described for the preparation of com-
pound 7a, 3-benzoylpropionic acid (10 g, 56 mmoles) was
treated with 4-methoxyaniline. The solid residue obtained after

154
S. Hamilakis, D. Kontonassios and A. Tsolomitis
Vol. 39
(nujol): sharp bands at 1667 (s), 1629 (m), 1595 (m) and 1510
(m); pmr (trifluoroacetic acid): 7.26 (s, 1H, vinylic proton) and
7.56-8.63 (m, 9H, aromatic protons).
dichloromethane was vigorously stirred at room temperature for
two days with aqueous sodium hydroxide solution and compound
3c was obtained as a yellow solid (0.72 g, 88%), mp 208-210°. A
recrystallization from ethanol gave an analytical sample, mp 208-
210°, lit [1] mp 188-190°; ir (nujol): 1624 (br, s), 1583 (sh, m)
Anal. Calcd. for C
H N O S: C, 58.89; H, 3.09; N, 8.58.
16 10 2 4
Found: C, 58.70; H, 3.08; N, 8.48.
and 1506 (sh, m); pmr (deuteriochloroform/DMSO-d ): 6.23 (d,
6
5-Benzoyl-2-(4-methylphenyl) isothiazol-3(2H)-one (8d).
J=6 Hz, 1H, vinylic proton), 7.88 and 8.25 (two d, J=9 Hz, 4H,
aromatic protons), and 8.43 (d, J=6 Hz, 1H, vinylic proton).
Anal. Calcd. for C H N O S: C, 48.64; H, 2.72; N, 12.60.
A solution of the keto amide 7d (7 g) in thionyl chloride (45
ml) was stirred at room temperature for 45 minutes. The excess
thionyl chloride was then removed under vacuum and the residue
was recrystallized from ethanol to give compound 8d (4.15 g,
53%) as a yellow crystalline solid, mp 153-156°, lit [12] mp 154-
156°; ir (nujol): sharp bands at 1650 (s) and 1631 (w); pmr (deu-
9
6 2 3
Found: C, 48.73; H, 2.68; N, 12.65.
2-(4-Methylphenyl)isothiazol-3(2H)-one (3d).
To a solution of the benzoylisothiazolone 8d (3 g, 10.17
mmoles) in dichloromethane (60 ml) a 10% aqueous sodium
hydroxide solution (30 ml) was added and the mixture was stirred
vigorously at room temperature for five days. The organic layer
was then separated, washed successively with 10% sulfuric acid
(15 ml) and water (10 ml), dried (magnesium sulfate) and concen-
trated under vacuum. The solid residue was recrystallized from
ethanol to give compound 3d as a yellowish crystalline solid (1.35
g, 69%), mp 89-91°, lit. [20] mp 91-93°. A second recrystalliza-
tion from ethanol gave an analytical sample, mp 92.5-93°; ir
(potassium bromide): sharp bands at 3115 (s), 3086 (s), 1609 (s)
teriochloroform): 2.47 (s, 3H, -CH ), 6.96 (s, 1H, vinylic proton)
3
and 7.25-8.25 (m, 9H, aromatic protons).
5-Benzoyl-2-(4-methoxylphenyl) isothiazol-3(2H)-one (8e).
Following the procedure described for the preparation of com-
pound 8d, compound 8e was obtained from the keto amide 7e
(6g) as a yellow crystalline solid (3.56 g, 54%, after recrystalliza-
tion from ethanol), mp 143-145°, lit [12] mp 145-146°; ir (nujol):
sharp bands at 1664 (s) and 1645 (m); pmr (deuteriochloroform):
3.92 (s, 3H, -OCH ), 6.95 (s, 1H, vinylic proton) and 6.98-8.28
3
and 1512 (s); pmr (deuteriochloroform): 2.35 (s, 3H, -CH ), 6.20
(m, 9H, aromatic protons).
3
(d, J=7 Hz, 1H, vinylic proton), 7.11 and 7.40 (two d, J=9 Hz, 4H,
aromatic protons), and 8.03 (d, J=7 Hz, 1H, vinylic proton).
2-tert-Butylisothiazol-3(2H)-one (3a).
To a solution of the hydrochloride of compound 8a (2 g, 6.7
mmoles) in dichloromethane (40 ml), powdered solid sodium
hydroxide (0.8 g) was added. The mixture was stirred vigorously
at room temperature for 40 minutes, when a fading of the initially
yellow color of the organic solution was observed. The
dichloromethane layer was then filtered and concentrated under
vacuum to give a colorless solid residue. This material, 0.84 g
(80%), proved to be pure compound 3a, as evidenced from its
pmr spectrum in deuteriochloroform [1,2]. Recrystallization from
ether-petroleum ether yielded 0.7 g (66%) of compound 3a, mp
84-85°, lit mp 85-86° [1] and 83.5° [2]; pmr (deuteriochloro-
Anal. Calcd. for C H NOS: C, 62.80; H, 4.74; N, 7.32; S,
16.77. Found: C, 62.83; H, 4.58; N, 7.34; S 17.03.
10 9
2-(4-Methoxyphenyl) isothiazol-3(2H)-one (3e).
Following the procedure described for the preparation of com-
pound 3d, compound 3e was obtained from the benzoylisothia-
zolone 8e (3 g, 9.64 mmoles) as a yellowish crystalline solid (1.6 g,
80%, after recrystallization from ethanol), mp 115-116.5°, lit [2]
mp 92-93° [21]. This material proved to be almost pure compound
3e, as evidenced from its pmr spectrum. A second recrystallization
from ethanol gave an analytical sample, mp 124.5-127°; ir (potas-
sium bromide): sharp bands at 3151 (s), 3104 (m), 1646 (s), 1604
form): 1.62 (s, 9H, -CMe ), 6.08 and 7.88 (two d, J=6.5 Hz, 2H,
3
vinylic protons); (trifluoroacetic acid): 1.87 (s, 9H, -CMe ), 6.93
(m) and 1508 (s); pmr (deuteriochloroform): 3.78 (s, 3H, -OCH ),
3
3
and 8.80 (two d, J=6.5 Hz, 2H, vinylic protons).
6.16 (d, J=7 Hz, 1H, vinylic proton), 6.86 and 7.30 (two d, J=9 Hz,
4H, aromatic protons), and 8.05 (d, J=7 Hz, 1H, vinylic proton).
2-(3-Nitrophenyl)isothiazol-3(2H)-one (3b).
Anal. Calcd. for C H NO S: C, 57.95; H, 4.38; N, 6.76; S,
10
9
2
To a solution of the benzoylisothiazolone 8b (0.5 g, 1.53
mmoles) in dichloromethane (170 ml) a 10% aqueous sodium
hydroxide solution (70 ml) was added and the mixture was stirred
vigorously at room temperature for five days. The organic layer
was then separated, washed successively with 10% sulfuric acid
and water, dried (magnesium sulfate) and concentrated under
vacuum to give compound 3b as a yellow solid (0.29 g, 85%), mp
156-157° dec. A recrystallization from toluene gave an analytical
sample, mp 156-157° dec; ir (nujol): sharp bands at 1653 (s),
1603 (m), 1570 (w) and 1508 (s); pmr (deuteriochloroform/
15.47. Found: C, 57.86; H, 4.28; N, 6.36; S, 15.09.
Acknowledgement.
We wish to thank the referee who recommended the synthesis
of isothiazolones N-substituted with a phenyl group bearing elec-
tron-releasing substituents.
REFERENCES AND NOTES
[1] S. N. Lewis, G. A. Miller, M. Hausman and E. C. Szamborski,
J. Heterocyclic Chem., 8, 571 (1971).
[2] N. R. A. Beeley, L. M. Harwood and P. C. Hedger, J. Chem.
Soc., Perkin Trans. 1, 2245 (1994).
[3] A. Tsolomitis and C. Sandris, Heterocycles, 25, 569 (1987).
[4] R. Chiron and Y. Graff, Bull. Soc. Chim. France, 575 (1970).
[5] For references and a discussion on the lactonization of 3-
aroylpropionic acids 10, see ref. [6].
DMSO-d ): 6.26 (d, J=6.5 Hz, 1H, vinylic proton), 7.75-8.65 (m,
6
5H, aromatic protons and vinylic proton −the vinylic proton
appears as a doublet, J=6.5 Hz, at δ 8.55ppm).
Anal. Calcd. for C H N O S: C, 48.64; H, 2.72; N, 12.60.
9
6 2 3
Found: C, 48.83; H, 2.72; N, 12.63.
2-(4-Nitrophenyl)isothiazol-3(2H)-one (3c).
Following the procedure described for the preparation of com-
pound 3b, the benzoylisothiazolone 8c (1.2 g, 3.68 mmoles) in
[6] A. Tsolomitis and C. Sandris, J. Heterocyclic Chem., 20, 1545
(1983).

Jan-Feb 2002
The Synthesis of N-Substituted Isothiazol-3(2H)-ones
155
[7] N. H. Cromwell and K. E. Cook, J. Am. Chem. Soc., 80, 4573
(1958).
[8] A. Padwa, F. Albrecht, P. Singh and E. Vega, J. Am. Chem.
[15] A. Tsolomitis and C. Sandris, J. Heterocyclic Chem., 22, 1635
(1985).
[16] For isothiazolones 8 in deuteriochloroform, the vinyl proton
singlet appears at δ 6.70-6.90 ppm [12, 13].
Soc., 93, 2928 (1971).
[9] C. R. A. Godfrey, Eur. Pat. Appl. EP 246, 735 (1987); Chem.
Abstr., 108, 150464s (1988).
[17] A. W. K. Chan, W. D. Crow and I. Gosney, Tetrahedron, 26,
1493 (1970).
[10] R. E. Valters and W. Flitsch, Ring-chain Tautomerism,
Plenum Press, New York, NY, 1985, p 57.
[11] W. Flitsch, Chem. Ber., 103, 3205 (1970).
[12] A. Tsolomitis and C. Sandris, J. Heterocyclic Chem., 17, 1645
(1980).
[18] R. Ramachandran, R. Chiron and Y. Graff, Bull. Soc. Chim.
France, 1031 (1972).
[19] R. Chiron and Y. Graff, Bull. Soc. Chim. France, 3715 (1967).
[20] H. O. Bayer, W. S. Hurt and H. E. Aller, U.S. Patent 3, 816,
622 (1974); Chem. Abstr., 81, 91072m (1974).
[13] R. J. S. Beer and D. Wright, Tetrahedron, 37, 3867 (1981).
[14] A. Tsolomitis and C. Sandris, J. Heterocyclic Chem., 21, 1679
(1984).
[21] This melting point is compared in ref. [2] to a literature value,
mp 91-92° in ref. [1]; however, compound 3e is not reported by Lewis et
al. [1].