Synthesis of α-oxo-sulfines in the indole series

Article abstract of DOI:10.1002/jhet.453

(Chemical Equation Presented) Oxindole was found to react readily with thionyl chloride to give (in an excellent yield) the isolable sulfine (13a), which on heating (refluxing acetonitrile) gave isoindigo (15a). The dark violet 3-sulfinatooxindole (13a) readily reacted with 2,3-dimethylbutadiene to give a colorless cyclo-adduct (14a). The sulfine also reacted readily with various nucleophilic reagents, thus, thioloacetic acid gave 3-carboxymethylthiolo- oxindole (23a).

Full text of DOI:10.1002/jhet.453

September 2010
Synthesis of a-Oxo-Sulfines in the Indole Series
Jan Bergman* and Ivan Romero
1215
Department of Biosciences and Nutrition, Karolinska Institute, SE 141 57 Huddinge, Sweden
*E-mail: jan.bergman@ki.se
Received October 13, 2009
DOI 10.1002/jhet.453
Published online 18 August 2010 in Wiley Online Library (wileyonlinelibrary.com).
Oxindole was found to react readily with thionyl chloride to give (in an excellent yield) the isolable
sulfine (13a), which on heating (refluxing acetonitrile) gave isoindigo (15a). The dark violet 3-sulfinato-
oxindole (13a) readily reacted with 2,3-dimethylbutadiene to give a colorless cyclo-adduct (14a). The
sulfine also reacted readily with various nucleophilic reagents, thus, thioloacetic acid gave 3-carboxyme-
thylthiolo-oxindole (23a).
J. Heterocyclic Chem., 47, 1215 (2010).
INTRODUCTION
13C NMR spectroscopy. In Scheme 1, the sulfine 3 is
drawn as the more stable E-isomer although the Z-iso-
mer is more likely to be formed initially due to attack
of SOCl2 on the enol tautomer of 2, which would yield
an intermediate sulfinyl chloride stabilized by hydrogen
bonding. This sulfinyl chloride is then biased to give
primarily the Z-sulfine. However the E-isomer is ther-
modynamically more stable and will eventually be
formed. The structure (determined by X-ray technique)
of 4 showed that its sulfine precursor 3 leading to 4 had
indeed exclusively been the E-isomer [6].
Sulfines, which can be considered as oxides of thio-
nes, are nonlinear and have the general structure 1, and
as indicated in Figure 1, E and Z isomers are possible
[1–6].
Several synthetic methods [1–6] for the production of
sulfines are available and perhaps the simplest and most
general route is given by Zwanenburg, which involves
treatment of silylated molecules, such as silylated
ketones with thionyl chloride [5–7]. In a few cases, keto
derivatives have been reported to yield a-oxo-sulfines
directly (i.e., without activation). For example, Hull and
Faull reacted the anion of ethyl 4-chloroacetoacetate
with phenyl isothiocyanate in dimethoxyethane and
obtained 52% of the thiophene derivative 2. By chang-
ing the solvent to dioxane, the yield of 2 could be
improved to 87%. The thiophene 2 reacted readily with
thionyl chloride to yield the isolable a-oxosulfine 3 [8].
In terms of yields, acetonitrile was found to be a more
suitable solvent than dimethoxyethane. The a-oxosulfine
3 could readily be intercepted by 2,3-dimethylbutadiene
Interestingly, the related (to 2) molecule 5, when
treated with SOCl2, failed to yield an isolable sulfine.
Instead, the coupled molecule 6 was isolated [8] indicat-
ing that the intermediate sulfine is unstable in this case.
Interception with 2,3-dimethylbutadiene is however pos-
sible [6], which gave a separable mixture of diasterom-
ers; thus, indicating that the kinetic product (the Z-iso-
mer) only had been partially converted to the E-isomer.
This type of cycloaddition with 2,3-dimethylbutadiene is
a standard operation to trap and to characterize sulfines,
as have been done with intermediate sulfines generated
1
to give 4, which could be fully characterized by H and
C
V
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1216
J. Bergman and I. Romero
Vol 47
Scheme 2
Figure 1. E and Z isomers of sulfines.
from doubly activated methylene compounds, such as
dibenzoylmethane [2,7,9,10].
Another stable a-oxosulfine is given by Black, who
reported formation of the a-oxosulfine 9 from the nitro-
ketone 7. The nitro group is considered to play an im-
portant role as indicated in Scheme 2. The intermediate
8 could not be isolated but its presence was supported
by an ABX pattern observed during an NMR study of
the reaction [11]. The product, the stable a-oxo-sulfine
9, featured diagnostic resonances at 188.9 and 189.3
ppm in the 13C NMR spectrum.
never been isolated before. The sulfine 13a was isolated
in 95% yield accompanied with a small amount of
3-chloro-oxindole (2%, isolated) and can be recrystal-
lized from acetonitrile but prolonged heating in this
medium will convert 13a to isoindigo (Scheme 3).
In analogy with the known sulfine 3, the indolic sul-
fine 13a and 2,3-dimethylbutadiene readily (within
2 min at 30–35ꢀC in acetonitrile) gave the colorless
adduct 14a as a single diastereomer. The same is true
for the N-methyl derivative 13b, which gave 14b. It is
assumed that the sulfine 13a is formed via an initial
electrophilic attack in 3-position of oxindole leading to
the nonisolable intermediate sulfinyl chloride 12, which
quickly will eliminate HCl leading to the a-oxosulfine
13a (E-isomer). However, it is assumed that initially the
kinetic product, the Z-isomer, is formed but that it will
quickly be converted to the more stable E-isomer. This
E-stereochemistry was deduced from the fact that only
one isomer of the S-oxide 14a was obtained. Interest-
ingly, other sulfines generated in other ways, for exam-
ple, via diazo compounds, usually will give diastereo-
meric mixtures with 2,3-dimethylbutadiene [13–16].
A solution of 13a in DMSO-d6 features a 13C NMR
spectrum similar to but distinctively different from that
of isatin [17,18]. In isatin (10), the signals from carbon
The structure of 9 was confirmed by X-ray crystallo-
graphy [11]. Simple aromatic ketones (like propiophenone)
gave a-chlorosulfenyl chlorides and not a-oxosulfines
(Scheme 2) [11].
RESULTS AND DISCUSSION
It has now, somewhat surprisingly, been found that
several sulfines in the indole series can readily and
quickly (2–3 min) be prepared in excellent yields by the
reaction of oxindole itself (11a) with thionyl chloride in
acetonitrile at 30–35ꢀC that gave the a-oxosulfine 13a
as a dark violet solid. N-Methyloxindole similarly gave
13b. Many years ago, oxindole had been treated with
thionyl chloride as reagent and solvent at reflux temper-
ature. Under these conditions isoindigo (15a) was the
sole product [12] and it seems that the sulfine 13a has
Scheme 1
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DOI 10.1002/jhet

September 2010
Synthesis of a-Oxo-Sulfines in the Indole Series
1217
Scheme 3
is, the oxindoles 11a and 11b, will be formed slowly.
This type of decomposition has been observed previ-
ously for other sulfine derivatives on several occasions
[11,19]. When 13a and 13b are dissolved in chloroform
and saturated with water, the cleavage process is quite
quick (e.g., total decomposition within 15 min at 40ꢀC).
A number of substituted oxindoles, for example, [20–25]
6-chloro-oxindole, 6-bromo-oxindole, and 5-nitro-oxindole
likewise could be converted to sulfines as well as adducts
with 2,3-dimethyl-butadiene. All these derivatives of 13a
substituted in the benzene ring could readily be converted
to ring-substituted derivatives of isoindigo.
As expected, the sulfine 13a reacted readily with a
number of nucleophilic reagents. Thus, morpholine gave
the known [26] adduct 19 (previously prepared form isa-
tin and morpholine) as shown in Scheme 4. Thus, addi-
tion of morpholine to a solution of the sulfine 13a in
acetonitrile at 35ꢀC quickly faded the dark violet color
and a solid precipitated within 2 min, which consists of
16 and morpholinium sulfite, which could be easily
removed by extraction of the mixture with water. The
nature of the side-product, morpholinium sulfite, was
established in an independent experiment, wherein mor-
pholine dissolved in water was reacted with sulfur diox-
ide. As indicated in Scheme 4, the sulfine 13a could be
converted to isatin 10. However, simple treatment with
water could not effect this transformation.
atoms 2 and 3 appeared at 159.4 and 184.3 ppm [17],
respectively, whereas the corresponding signals from the
sulfine 13a appeared at 160.0 and 168.9 ppm, respec-
tively. In the proton NMR spectrum, the signal from the
4-H proton was shifted significantly more downfield in
the spectrum of 13a (8.08 ppm) as compared with 7.47
for isatin 10 and actually even more so in isoindigo 15a
(9.10 ppm). These data clearly indicate that the proton
in position 4 is strongly influenced by the anisotropic
deshielding of the cone of interaction from the SO group
(for 13a) and the C¼¼O group in the neighboring ring
(for 15a).The general similarity of the spectra of 10 and
13a, however, was taken as evidence that the species
present in the solution is (13a) actually not an adduct,
as a result of nucleophilic addition of DMSO to 13a. A
solution of 13a in DMSO is, however, not permanently
stable and after 7 days 90% of the sulfine will be con-
verted to isoindigo 15a. This type of conversion was
faster for derivatives substituted with halogen atoms in
the benzene ring.
Thiols also reacted readily with the sulfine 13a, thus,
methanethiol gave the known [17] compound 17 and
thiolacetic acid and methyl thiolacetate, respectively, the
new molecules 18a and 18b, both in excellent yields.
The NMR data of 18a are in disagreement with those
reported in the literature, wherein a mixture composed
of isatin, pentafluoroaniline, and thiolacetic acid has
been claimed to give 18a. This unusual experiment
should be repeated [27].
The sulfines 13a and 13b can, under dry conditions,
be stored for several months at room temperature with-
out decomposition. In the presence of moisture, the sul-
fines will eliminate SO2 and the starting materials, that
Although isatin and thiolacetic acid readily could be
converted to the adduct 19a, this molecule could not be
converted to 18a because the adduct 19a is quite labile
Scheme 4
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1218
J. Bergman and I. Romero
Vol 47
Scheme 5
Ethyl 2-phenylamino-4-oxo-5-sulfinato-4,5-dihydrothiophene-
3-carboxylate (3). The ester 2 (2.63 g, 10 mmol) in acetonitrile
(35 mL) was treated with thionyl chloride (1.25 mL, 15 mmol)
at 35ꢀC. A precipitate of yellow needles was collected after
1 h, (2.90 g, 96%), mp. >260ꢀC dec.; IR 3161, 2968, 1641,
under basic as well as acidic conditions. The product
formed was a coupled reduction product of isatin,
namely isatid 20, a well-known molecule [28,29]. Treat-
ment of the adduct 19a with acetic anhydride at ambient
temperature quickly cleaved the adduct yielding isatin
10. The bis-adduct 19b, however, is quite stable under
these conditions (Scheme 5).
1538, 1408, 1377, 1172, 1018, 941, 788 cmꢂ1 1H NMR d:
;
1.44 (t, 3H, CH3), 4.24 (q, 2H, OCH2), 7.38–7.57 (m, 5H,
arom CH), 11.4 (br. s, 1H, NH); 13C NMR d: 14.3 (q), 59.6
(t), 97.5 (s), 125.9 (d), 129.1 (d), 129.4 (d), 137.0 (s), 163.5
(s), 172.1 (s), 178.8 (s), 191.0 (s).
The adduct (4). The yellow sulfine 3 (3.09 g, 10 mmol)
was suspended in acetonitrile (85 mL) and 2,3-dimethylbuta-
diene in excess was introduced to the stirred mixture at
50–55ꢀC. The solution obtained was concentrated and the col-
orless product was collected (3.25 g, 86%); mp. 200–202ꢀC
(lit. [6] 200–202ꢀC); IR 3162, 3058, 2974, 1660, 1548, 1415,
EXPERIMENTAL
Melting points were uncorrected and determined using a
Bu¨chi B-545 apparatus. NMR spectra were obtained in DMSO-
d6 on a Bruker 300-MHz spectrometer. IR (neat) was recorded
with an Avatar 330 FTIR apparatus (Thermo Nicolet).
1
1400, 1210, 1063, 1032, 800, 769, 696 cmꢂ1; H NMR d: 1.27
Ethyl 2-phenylamino-4-oxo-4,5-dihydrothiophene-3-car-
boxylate (2). Ethyl 4-chloro-acetoacetate (16.5 g, 0.1 mol) in
dioxane (80 mL) was treated with sodium hydride (4.5 g, 60%
in oil) at 30ꢀC. When the evolution of hydrogen had ceased
(ꢁ20 min), phenyl isothiocyanate (13.5 g, 0.1 mol) in dioxane
(20 mL) was added at 25–30ꢀC to the stirred mixture. The
temperature was allowed to reach 40ꢀC, and at this point, a
thick slurry was formed. After 1 h at 35–40ꢀC, the mixture
was poured into water and the solid formed was collected,
washed with water, and recrystallized from ethanol, 22.9 g
(87%), mp. 146–148ꢀC (lit. [8] 146–148ꢀC). IR 3198, 2983,
2926, 1643, 1555, 1548, 1406, 1382, 1344, 1283, 1223, 1152,
(t, 3H, CH3), 1.59 (s, 6H, 2 CH3), 2.75 (2H, CH2), 3.45 (2H,
CH2), 4.26 (q, 2H, OCH2), 7.40–7.55 (m, 5H, arom CH), 11.4
(s, 1H, NH); 13C NMR d: 14.3 (q), 19.0 (q), 19.2 (q), 39.7 (t),
52.3 (t), 59.7 (t), 79.0 (s), 97.2 (s), 119.1 (s), 125.4 (d), 126.7
(s), 128.3 (d), 129.7 (d), 137.2 (s), 164.2 (s), 180.4 (s), 188.1 (s).
2-Oxindole-3-thione S-oxide 13a. Thionyl chloride (15.0
mL) was added during 3 min to a stirred solution of oxindole
(13.3 g, 0.1 mol) in acetonitrile (120 mL) at 25–30ꢀC. The
dark violet product started to separate within 1 min and the
reaction is completed in 10 min. The sulfine 13a was collected
and dried in a desiccator (17.08 g, 95%); mp. ꢁ120ꢀC dec;
IR: NH 3240 (br), 1702, 1666, 1607, 1456, 1326, 1201, 1126,
1
1037, 997, 800, 784, 754 cmꢂ1; H NMR d: 1.25 (t, 3H, CH3),
1089, 1070, 764 cmꢂ1 1H NMR d: 6.83 (d), 7.00 (d), 7.40
;
3.67 (s, 2H, CH2), 4.22 (q, 2H, OCH2), 7.36–7.51 (m, 5H,
arom CH), 11.2 (br s, 1H, NH); 13C NMR d: 14.4 (q), 38.0 (t),
59.3 (t), 97.0 (s), 125.1 (d), 127.8 (d), 129.5 (d), 137.3 (s),
156.1 (s), 182.7 (s), 190.5 (s).
(d), 8.07 (d, 4-H), 10.9 (s, NH); 13C NMR d: 110.5 (d), 122.1
(s), 122.6 (d), 126.1 (d), 134.3 (d), 140.7 (s), 166.0 (s), 169.0
(s); Anal. calcd. for C8H5NO2S: C, 53.2; H, 2.88; N, 7.78
Found: C, 53.5; H, 3.15; N, 7.65.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

September 2010
Synthesis of a-Oxo-Sulfines in the Indole Series
1219
7.53 (dd, 1H, 6-H), 11.0 (s, 1H, NH). 13C NMR d 19.2 (q),
19.6 (q), 34.7 (t), 50.0 (t), 65.9 (s), 111.7 (s), 113.6 (d),
117.8 (s), 125.7 (d), 127.7 (s), 127.9 (s), 132.4 (d), 142.3 (s),
174.1 (s).
N-Methyl-2-oxindole-3-thione S-oxide 13b. The procedure
given for the parent compound 13a was used, except that
methyl acetate was used as medium starting with N-methyl-ox-
indole. Before isolation of the product, part of the solvent was
partially evaporated; (Yield 78%); mp 130–140ꢀC (violent
dec);1H NMR d: 3.12 (s, 3H, NCH3), 7.05–7.11 (ddþd, 2H
arom CH), 7.49 (dd, 1H, arom CH), 8.10 (d, 1H, 4-H); 13C
NMR d: 125.8 (q), 109.5 (d), 120.9 (s), 121.7 (d), 125.8 (d),
134.2 (d), 141.8 (s), 164.5 (s), 168.2 (s); Anal. calcd. for
C9H7NO2S: C, 56.1; H, 3.70; N, 7.28. Found: C, 55.7, H,
3.80; N, 7.35.
Adduct between 6-chloro-2-oxindole-3-thione S-oxide and
2,3-dimethylbutadiene. Yield: 92%, mp. 190ꢀC dec. IR 3193,
1
1720, 1614, 1481, 1449, 1322, 1238, 1040, 926, 806 cmꢂ1; H
NMR d 1.68 (s, 3H, CH3), 1.77 (s, 3H, CH3), 2.56 (2H, CH2),
3.62 (2H, CH2), 6.93 (d, 1H, 7-H), 7.09 (dd, 1H, 5-H), 7.17
(d, 1H, 4-H), 11.0 (br s, 1H, NH). 13C NMR d; 19.2 (q), 19.6
(q), 35.1 (t), 50.2 (t), 66.0 (s), 109.9 (d), 113.6 (s), 121.7 (d),
124.0 (s), 125.8 (s), 126.7 (d), 134.1 (s), 144.6 (s), 174.6 (s).
Anal. calcd. for C14H14ClNO2S. C, 56.90; H, 4.75; N, 4.69.
Found: C, 56.71; H, 4.90; N, 4.58.
6,60-Dichloroisoindigo. The 6-chloro-S-oxide (2.0 g) obtained
above was heated at reflux in acetonitrile (50 mL) for 1 h and
the dark blue precipitate of 6,60-dichloroisoindigo was col-
lected and washed with ethanol. Yield: 96% mp. > 300ꢀC.
The spectroscopic data were in agreement with those in the
literature [30,31].
The adduct 14a. The sulfine 13a (179 mg, 1 mmol) was
suspended in acetonitrile (5.0 mL), and 2,3-dimethyl-butadiene
(123 mg, 1.5 mmol) was introduced at 30–35ꢀC. The dark vio-
let starting material went into solution and was soon replaced
by the colorless adduct 14a, which has a low solubility in ace-
tonitrile, 247 mg, (95%); mp. 195–196ꢀC; IR 3255, 2919,
2888, 1716 (s), 1617, 1469, 1324, 1186, 1030, 738, 678 cmꢂ1
;
1H NMR d: 1,63 (s, 3H, CH3), 1.79 (s, 3H, CH3), 2.61 (2H,
CH2), 3.60 (2H, CH2), 6.91 (d, 1H), 7.03 (dd, 1H), 7.20 (d,
1H), 7.33 (dd, 1H), 10.8 (s, 1H, NH) 13C NMR d: 19.2 (q),
19.6 (q), 35.4 (t), 50.1 (t), 66.1 (s), 109.8 (d), 118.2 (s), 122.1
(s), 125.3 (s), 125.3 (d), 125.8 (s), 129.7 (d), 143.1 (s), 174.5
(s). Anal. calcd. for C14H15NO2S: C, 64.33; H, 5.78; N, 7.25;
Found, C, 64.12; H, 5.90; N, 7.15.
5-Nitro-2-oxindole-3-thione S-oxide. The procedure above
was used. Yield: 75%, mp. (violent dec.) 140ꢀC. 1H NMR d;
7.03 (d, 7-H, J1 ¼ 8.75), 8.27 (dd, 6-H, J1 ¼ 8.75, J2 ¼ 2.31),
8.72 (d, 4-H, J2 ¼ 2.31), 11.6 (s, NH). 13C NMR d; 110.7 (d),
120.4 (d), 121.4 (s), 129.6 (d), 142, 2 (s), 145.7 (s), 166.0 (s),
167.0 (s). No acceptable elemental analysis data could be
obtained for this molecule, but its adduct could be analyzed.
Adduct between 5-nitro-2-oxindole-3-thione S-oxide and
2,3-dimethylbutadiene. The procedure above was used. Yield:
The adduct 14b. The same procedure as for 14a was used.
Yield (94%), mp. 191–192ꢀC; IR; 3060 (w), 1704 (s), 1609,
1
1468, 1372, 1344, 1052 (s), 755 (s) cmꢂ1; H NMR d: 1.69 (s,
3H, CH3), 1.80 (s, 3H, CH3), 2.62 (2H, CH2), 3.17 (s, 3H,
NCH3), 3.62 (2H, CH2), 7.10–7.46 (m, 4H, arom CH); 13C
NMR d: 19.2 (q), 19.6 (q), 26.6 (q), 35.3 (t), 50.2 (t), 65.5 (s),
108.9 (d), 118.2 (s), 122.7 (d), 124.6 (s), 125.0 (d), 125.7 (s),
129.8 (d), 144.5 (s), 172.9 (s). Anal. calcd. for C15H17NO2S:
C, 65.80; H, 6.23; N, 5.11 Found: C, 65.91; H, 6.32; N, 5.15.
6-Bromo-2-oxindole-3-thione S-oxide. The procedure given
for 13a was used, starting with 6-bromo-oxindole [24]. Yield
1
84%, mp. 150ꢀC dec. H NMR d: 1.67 (s, 3H, CH3), 1.73 (s,
3H, CH3), 2.50 (2H, CH2), 3.65 (2H, CH2), 7.09 (d, 1H, 7-H),
7.93 (d, 1H, 4-H), 8.30 (dd, 1H, 6-H, J1 ¼ 8.75, J2 ¼ 2.31),
11.5 (s, 1H, NH). 13C NMR d; 19.2 (q), 19.5 (q), 34.4 (t), 50.3
(t), 65.9 (s), 109.9 (d), 118.1 (s), 120.5 (d), 125.9 (s), 126.1
(s), 126.8 (d), 142.4 (s), 149.3(s), 175.0 (s). Anal. calcd. for
C14H14N2O4S: C, 31.30; H, 4.59; N, 4.56. Found: C, 31.19; H,
4.63; N, 4.45.
Isoindigo 15a. The sulfine 13a (1.79 g, 10 mmol) in aceto-
nitrile (35 mL) was refluxed until no more precipitate of the
product 15a was formed (ꢁ15 min). Yield: (100%); mp.
>300ꢀC; 1H NMR d; 6.83 (d), 6.91 (dd), 7.40 (dd), 9.06 (d),
10.9 (s, NH); 13C NMR d; 109.5 (d), 121.1 (d), 121.7 (s),
129.4 (d), 132.4 (d), 133.4 (s), 144.2 (s), 169.1 (s). UV in
agreement with data in ref. 30. The 1H NMR data were in
agreement with those in the literature [32,33]. However, the
signal just above 9.0 ppm was incorrectly reported as a
singlet.
1
98%, mp. 140ꢀC dec. H NMR d 7.10 (dd, 1H, 5-H), 7.18 (d,
1H, 7-H), 7.94 (d, 1H, 4-H). 13C NMR d: 113.3 (d), 123.5 (s),
125.3 (d), 127.1 (d), 127.2 (s), 141.8 (s), 165.7 (s), 167.8 (s).
Anal. calcd. for C8H4BrNO2S: C, 37.61; H, 1.57; N, 5.46
Found: C, 37.40; H, 1.66; N, 5.30.
Adduct between 6-bromo-2-oxindole-3-thione S-oxide and
2,3-dimethylbutadiene. The procedure described for 14a was
used. Yield 98%, mp. 220ꢀC dec. IR 3110, 3080, 1720, 1609,
1
1447, 1038, 821 cmꢂ1; H NMR d 1.68 (s, 3H, CH3), 1.77 (s,
3H, CH3), 2.62 (2H, CH2), 3.61 (2H, CH2), 7.06 (d, 1H, 7-H,
J ¼ 1.83 ppm), 7.11 (d, 1H, 4-H, J ¼ 8.25), 7.22 (dd, 1H,
5-H), 11.0 (s, 1H, NH). 13C NMR d; 19.7 (q), 20.1 (q), 35.7
(t), 50.8 (t), 66.7 (s), 113.2 (d), 118.8 (s), 123.1 (s), 125.0 (s),
125.2 (d), 126.4 (s), 127.6 (d), 145.3 (s), 175.1 (s). Anal.
calcd. for C11H14BrNO2S: C, 49.39; H, 4.13; N, 4.09 Found:
C, 49.19; H, 4.29; N, 3.97.
6-Chloro-2-oxindole-3-thione S-oxide. The procedure above
was used. Yield 92%, IR 3102, 1712, 1606, 1330, 1104, 1067,
808, 719 cmꢂ1 13C NMR d 109.1 (d), 120.8 (d), 124.7 (s),
;
125.7 (s), 131.7 (d), 145.1 (s), 165.9 (s), 167.8 (s).
N,N0-Dimethylisoindigo 15b. The same procedure as for
15a was used, Yield 100%, mp. 270–271ꢀC (lit. [33] 270ꢀC;
267–269ꢀC [34]); IR 3130 (w), 2980 (w), 1681 (s), 1605,
1469, 1374, 1338, 1089, 1076, 944, 866, 773, 740 cmꢂ1 1H
;
NMR d: 3.20 (s, 6H, 2NCH3), 7.0–7.5 (m, 6H, arom CH),
9.12 (2d, 2H, 4-H); 13C NMR d: 26.1 (q), 108.5 (d), 120.6 (s),
121.8 (d), 129.1 (d), 132.7 (d), 132.8 (s), 145.1 (s), 168.0 (s).
3,30-Bis(morpholino)oxindole 16. Morpholine (261 mg, 3
mmol) was added to the sulfine 13a (358 mg, 2 mmol) in
acetonitrile (6 mL). A white solid appeared within 2 min,
which was collected and washed with water after 30 min at
25ꢀC, 395 mg (64%), mp. 177–179ꢀC (lit. [26] 177–179ꢀC).
The spectral data were in agreement with those in the litera-
ture [26].
Adduct between 5-bromo-2-oxindole-3-thione S-oxide and
2,3-dimethylbutadiene. Yield: 87%, mp. 220ꢀC dec. IR 3176,
3145, 2902, 1715, 1618, 1468, 1300, 1227, 1039, 823 cmꢂ1
;
1H NMR d 1.70 (s, 3H, CH3), 1.78 (s, 3H, CH3), 2.57 (2H,
CH2), 3.62 (2H, CH2), 6.88 (d, 1H, 7-H), 7.26 (d, 1H, 4-H),
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1220
J. Bergman and I. Romero
Vol 47
REFERENCES AND NOTES
S-Methyl-3-thiolo-oxindole 17. A stream of methanthiol
was introduced into a stirred suspension of the sulfine 13a,
1.79 g, 10 mmol) in acetonitrile (80 mL) at 35ꢀC. When the
dark violet starting material had been consumed (ꢁ1 h) the so-
lution was evaporated and the crude product recrystallized
form ethanol, 1.41 g (72%) mp. 125–127ꢀC (lit. [18] 125.5–
127ꢀC). The NMR data were in agreement with those reported
in the literature [21]. The signal from the 3-C carbon atom res-
onated at 45.5 ppm.
[1] Zwanenburg, B. Houben-Weyl 2002, E 11/2, 911.
[2] Zwanenburg, B. Sci Synth 2004, 27, 135.
[3] Zwanenburg, B.; Damen, T. J. G.; Philipse, H. J. F.; De Laet,
R. C.; Lucassen, A. C. B. Phosphorus Sulfur Silicon 1999, 153/154, 119.
[4] Zwanenburg, B. Rec Trav Chim 1982, 101, 1.
[5] Lenz, B. G.; Regeling, H.; van Rozendaal, H. L. M.;
Zwanenburg, B. J Org Chem 1985, 50, 2930.
[6] Lenz, B. G.; Haltiwanger, R. C.; Zwanenburg, B. JCS
Chem Commun 1984, 502.
S-Carboxymethyl-3-thiolo-oxindole 18a. The sulfine 13a
(358 mg, 2 mmol) was added to a solution of thioloacetic acid
(202 mg, 2.3 mmol) in acetonitrile (8 mL). As there seemed to
be no reaction at ambient temperature the reaction mixture
was heated at reflux for 20 min. During this period, the solu-
tion became colorless. After concentration and treatment with
ether, the product was obtained as colorless crystals, 360 mg,
(81%) mp. 160–162ꢀC. IR 3280, 1700, 1621, 1469, 1177,
[7] Lenz, B. G.; Regeling, H.; Zwanenburg, B. Tetrahedron
Lett 1984, 25, 5947.
[8] Faull, A. W.; Hull, R. J Chem Soc Perkin Trans 1, 1981,
1078.
[9] Morita, H.; Takeda, M.; Yoshimura, T.; Fujii, T.; Ono, S.;
Shimasaki, C. J Org Chem 1999, 64, 6730.
[10] Pfeifer, K.-P.; Himbert, G. Tetrahedron Lett 1990, 31,
5725.
1
1120, 872, 740 cmꢂ1; H NMR d: 3.48 (q, 2H, CH2, J ¼ 15.2
[11] Black D. St. C.; Fallon, G. D.; Gatehouse, B. M.; Wishart,
J. D. Aust J Chem 1984, 37, 777.
ppm), 4.81 (s, 1H, 3-CH), 6.85–7.34 (m, 4H, arom CH), 10.6
(s, 1H, NH), 12.8 (br. s, 1H, OH). 13C NMR d: 40.7 (t), 50.6
(d), 109.6 (d), 121.8 (d), 124.9 (d), 126.4 (s), 129.5 (d), 143.0
(s), 170.0 (s), 175.2 (s). Anal. calcd. for C10H9NO3S: C,
53.80; H, 4.07; N, 6.27; Found: C, 53.63; H, 4.20; N, 6.05.
Methyl S-carboxymethyl-3-thiolo-oxindole 18b. Methyl
thioloacetate (233 mg, 2.3 mmol) was added to the sulfine 13a
(351 mg, 2.0 mmol) in acetonitrile (6.0 mL) at 45ꢀC. The
color faded quickly. After 10 min the solution was evaporated
and the oil obtained was treated with methyl acetate/diiso-
propyl ether (1:4), which gave crystals of the product, 371 mg
(79%), mp. 109–110ꢀC; IR: 3146, 1730, 1704, 1673, 1617,
[12] De Martiis, F. Ann Chim (Rome) 1957, 47, 1238.
[13] O’Sullivan, O. C. M.; Collins, S. G.; Maguire, A. R. Syn
Lett 2008, 659.
[14] Sander, W.; Strehl, A.; Maguire, A. R.; Collins, S.;
Kelleher, P. G. Eur J Org Chem 2000, 3329.
[15] Maguire, A. R.; Kelleher, P. G.; Lawrence, S. E. Tetrahedron
Lett 1998, 39, 3849.
[16] Boccardo, G.; Capozzi, G.; Giuntini, M.; Menichetti, S.;
Nativi, C.; Tetrahedron 1997, 53, 17383.
[17] Gassman, P. G.; Cue, B. W., Jr., Luh, T.-Y. J Org Chem
1977, 42, 1344.
1
1470, 1281, 1266, 1005, 743, 676 cmꢂ1; H NMR 3.53 (q, 2H,
[18] Gassman, P. G.; van Bergen, T. J. J Am Chem Soc 1974,
96, 5508.
CH2), 3.63 (s, 3H, OCH3), 4.84 (s, 1H, 3-CH), 6.83–7.33 (m,
4H, arom CH), 10.6 (s, 1H, NH); 13C NMR 40.1 (t), 50.6 (q),
52.2 (d), 109.7 (d), 121.8 (d), 125.2 (d), 126.3 (s), 129.4 (d),
143.0 (s), 169.1 (s), 175.1 (s). Anal. calcd. for C11H11NO3S:
C, 55.68; H, 4.67; N, 5.90 Found: C, 55.73; H, 4.78, N, 5.90.
The monocarboxylic acid 19a. Isatin (14.7 g, 0.1 mmol)
and thioloacetic acid (9.2 g, 0.1 mol) was heated in dioxan (30
mL) for 0.5 h. After concentration, the residue was treated
with methanol/water 1:2, which gave the title compound, 20.1
g (84%), mp. 191–193ꢀC. IR 3288, 3100–2550, 1728, 1693,
[19] Strating, J.; Thijs, L.; Zwanenburg, B. Rec Trav Chem
1967, 86, 641.
[20] Giovannini, E.; Portmann, P. Helv Chim Acta 1948, 31, 1375.
[21] Gassman, P. G.; Gilbert, D. P.; Luh, T.-Y. J Org Chem
1977, 42, 1340.
[22] Coutts, R. T.; Hindmarsch, K. W.; Mah, E. Can J Chem
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[23] Sumpter, W. C.; Miller, M.; Hendrick, L. N. J Am Chem
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1
1613, 1469, 1422, 1267, 1131, 916, 822, 749 cmꢂ1; H NMR
[24] Kosuge, T.; Ishida, H.; Inaba, A.; Nukaya, H. Chem Pharm
Bull 1985, 33, 1414.
d: 3.75 (2H, q), 6.88 (d, 1H), 7.02 (dd, 1H), 7.13 (dd, 1H),
7.39 (d, 1H), 10.4 (s, 1H); 13C NMR d: 29.7 (t), 77.9 (s),
109.9 (d), 121.9 (d), 124.0 (d), 129.1 (s), 130.1 (d), 139.8 (s),
171.1 (s), 174.6 (s). Anal. calcd. for C10H8NO4S: C, 50.20; H,
3.79; N, 5.84; Found: C, 49.81; H, 3.85; N, 5.72.
[25] Bergman, J.; Bergman, S.; Brimert, T. Tetrahedron 1999,
55, 10447.
˚
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[27] Joshi, K. C.; Dandia, A.; Bhagat, S. J Fluorine Chem 1990,
48, 169.
The dicarboxylic acid 19b. Isatin (14.7 g, 0.1 mmol) and
thioloacetic acid (20.2 g, 0.22 mmol) in dioxane (50 mL) was
heated to reflux for 3 h. After concentration, the residue was
treated with methanol/water 1:1, which quickly yielded crys-
tals of the product 26.8 (86%); mp. 202–204 ꢀC. IR 3288,
3170–2300, 1731, 1697, 1615, 1469, 1175, 1057, 904, 750
[28] Bergmann, E. D. J Am Chem Soc 1955, 77, 1549.
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1963, 94, 453.
` ´
[30] Perpete, E. A.; Preat, J.; Andre, J.-M.; Jacquemin, D.
J Phys Chem 2006, 110, 5629.
cmꢂ1 1H NMR d: 3.96 (s, 4H), 6.90 (d, 1H), 7.03 (dd, 1H),
;
[31] Shermolovich, Y. G.; Emets, S. V.; Tolmachev, A. A.
Chem Het Comp 2003, 39, 1076.
7.29 (dd, 1H), 7.33 (d, 1H), 10.9 (s, 1H, NH), 12.7 (s, 2H,
OH); 13C NMR d: 32.4 (t), 55.1 (s), 110.3 (d), 122.4 (d),
124.3 (d), 127.8 (s), 130.1 (d), 140.3 (s), 170.0 (s), 173.6 (s).
Anal. calcd. for C12H11NO5S2: C, 45.99; H, 3.54; N, 4.47
Found: C, 45.85; H, 3.66; N,4.32.
[32] Lathourakis, G. E.; Litinas, K. E. J Chem Soc Perkin Trans
1, 1996, 491.
[33] Banerji, A.; Maiti, S. Ind J Chem B 1994, 33, 532.
[34] Harley-Mason, J.; Ingleby, R. T. J. J Chem Soc 1958, 4782.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet