Unexpected course of rearrangement of substituted S-(1(3H)- isobenzofuranone-3-yl)isothiuronium bromides

Article abstract of DOI:10.1016/j.tet.2012.09.005

Three series of S-(1(3H)-isobenzofuranone-3-yl)isothiuronium bromides differing in substitution at the isothiuronium moiety (none, one or two methyl groups) and at the benzene ring were prepared and characterized. These salts were then treated with variou

Full text of DOI:10.1016/j.tet.2012.09.005

Tetrahedron 68 (2012) 9808e9817
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Unexpected course of rearrangement of substituted S-(1(3H)-isobenzofuranone-
3-yl)isothiuronium bromides
a
a
a,
*
ꢀ
ꢁꢀ
ꢀ
ꢁ
ꢀ
ꢀ
ꢁ b
ꢀ
Jirí Vana , Milos Sedlak , Zdenka Padelkova , Jirí Hanusek
a
ꢁ
Faculty of Chemical Technology, Institute of Organic Chemistry and Technology, University of Pardubice, Studentska 573, CZ-532 10 Pardubice, Czech Republic
Faculty of Chemical Technology, Department of General and Inorganic Chemistry, University of Pardubice, Studentska 573, CZ-532 10 Pardubice, Czech Republic
b
ꢁ
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 7 June 2012
Received in revised form 14 August 2012
Accepted 3 September 2012
Available online 11 September 2012
Three series of S-(1(3H)-isobenzofuranone-3-yl)isothiuronium bromides differing in substitution at the
isothiuronium moiety (none, one or two methyl groups) and at the benzene ring were prepared and
characterized. These salts were then treated with various bases (acetate, triethylamine, Na2CO3) to give
either 1-hydroxy-3-oxo-1,3-dihydro-2H-isoindol-2-carbothioamides or the product of S to
N iso-
benzofuranone-3-yl migration, i.e., 1,3-dimethyl-1-(3-oxo-1,3-dihydro-2-benzofuran-1-yl)thioureas. If
ammonia was used in reaction with N,N0-dimethyl isothiuronium salts then 3-hydroxy-2,3-dihydro-1H-
isoindol-1-ones were formed together with 1,3-dimethyl-1-(3-oxo-1,3-dihydro-2-benzofuran-1-yl)thio-
ureas in parallel reaction with the yields increasing with ammonia concentration. The formation of
isoindolones takes place in two steps with an aldehyde intermediate, which can be trapped with N,N-
dimethylhydrazine.
ꢀ
ꢀ
Dedicated to Professor Vojeslav Sterba on
the occasion of his 90th birthday
Keywords:
S to N migration
Rearrangement
Mechanism
Ó 2012 Elsevier Ltd. All rights reserved.
Intermediate trapping
Ring transformation
Isothiuronium salt
1. Introduction
1,3-thiazolidin-4-ones, but also for their potential application as
pro-drugs,4 because this heterocyclic skeleton represents an im-
Heterocyclic compounds containing sulfur and nitrogen atoms
are some of the most discussed molecules in organic chemistry.
Many different approaches for their synthesis are known. One of
the most interesting groups of methods are the transformation
reactions where one heterocyclic system rearranges to another.1
These transformations sometimes offer a simple approach to
compounds that could be prepared by the classical methods with
appreciable difficulties. Unfortunately, the course of these reactions
is usually unpredictable and can bring various surprises. This
problem can be reduced by the study of the reaction mechanisms
that enables deeper understanding of such processes.
portant pharmacophore.5
The aim of the work reported here was to examine ring trans-
formations of theisothiuronium salts 1aed, 2a and 3aed derived from
6-substituted
thalides) and alkyl-substituted thioureas (Scheme 1).
The 3-bromo-1(3H)-isobenzofuranone skeleton was chosen for
the study as it is representative of (acyloxy)alkyl -halides whose
3-bromo-1(3H)-isobenzofuranones
(3-bromoph-
a
reactions with various types of nucleophiles give important
In our previous works we extensively studied the ability of
butyrolactam2 and butyrolactone3 rings containing a substituted or
an unsubstituted isothiuronium side chain in the
a-position to
undergo ring transformation reactions. In all cases the corre-
sponding substituted 1,3-thiazolidin-4-ones were formed exclu-
sively under mild conditions in aqueous buffer solutions. Such
a transformation has great importance, not only for the synthesis of
* Corresponding author. Tel.: þ420 466037015; fax: þ420 466 037 068; e-mail
Scheme 1.
address: jiri.hanusek@upce.cz (J. Hanusek).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.09.005

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J. Vana et al. / Tetrahedron 68 (2012) 9808e9817
9809
heterocycles.6 For example, S-(1(3H)-isobenzofuranone-3-yl)iso-
thiuronium bromides (1aed) appear to be the synthetic equiva-
lents of S-[2-(methoxycarbonyl)-benzyl]isothiuronium chloride
whose transformation under basic conditions gives7 3H-benzo[c]
thiophen-1-one (thiophthalide) (Scheme 2), whose heterocyclic
skeleton is also found in materials, such as pharmaceutical drugs
and fluorescent probes for optical imaging.8
Scheme 3.
Scheme 2.
2. Results and discussion
2.1. Preparation of isothiuronium salts
S-(1(3H)-Isobenzofuranone-3-yl)isothiuronium
bromides
(1aed, 2a, 3aed) were obtained from reaction of freshly prepared9
6-substituted 3-bromo-1(3H)-isobenzofuranones with the corre-
sponding thioureas in acetone. After a short period at reflux and
a few hours standing at room temperature the isothiuronium salt
precipitated in very good yield (80e90%). All the salts were char-
acterized by 1H and 13C NMR spectroscopy, elemental analysis and
HRMS.
It is well known that 3-halo-1(3H)-isobenzofuranones behaves
as ambident electrophiles. Various nucleophiles, such as amines,6,10
phenoxides,11 and xanthates12 can attack them at the carbonyl
carbon (acylation) or at the halo carbon atom (alkylation) to give
different products, depending on nucleophilicity of the nucleophile
(in terms of nucleophilicity scale by Pearson,13a Ritchie13b and
Mayr13c,d), the nucleofugality of the leaving group and the nature of
the solvent.6b Stronger nucleophiles (aliphatic amines and certain
phenoxides) combined with a poorer leaving group (chloride) tend
to give more of the acylation product while poorer nucleophiles
and better leaving groups (bromide, iodide) favor the formation of
alkylated products. In our case we observed only the formation of
the S-alkylated product, i.e., corresponding isothiuronium salt
1aed, 2a, 3aed, although the nucleophilicity of thiourea is com-
parable13 with aliphatic amines. On the other hand, our result is in
accordance with the reaction of 3-bromo-1(3H)-isobenzofuranone
with another strong S-nucleophile (potassium O-ethyl xanthate),12
which gave rise to a 88% yield of corresponding S-alkylated product
via simple nucleophilic substitution. S-Alkylation was also proven
by X-ray analysis of a single crystal of S-(3-oxo-1,3-dihydro-2-
benzofuran-1-yl)-N-methyl-N-phenyl isothiouronium bromide
(see Supplementary data).
Fig. 1. ORTEP view of compound 4a (thermal ellipsoids at 50% probability level).
ꢁ
ꢂ
Selected interatomic distances [A] and angles [ ]: S1 C10 1.6918(19), N1 C10 1.383(3),
N2 C10 1.314(3), O1 C9 1.391(2), O2 C2 1.218(2); S1 C10 N1 120.31(14), N1 C10 N2
117.10(16).
methods (see Experimental part) confirmed corresponding 1-
hydroxy-3-oxo-1,3-dihydro-2H-isoindol-2-carbothioamides (4aed)
or their N-methyl analogue 5a to be formed (Scheme 3). The yields of
all transformations were almost quantitative and only a small
amount of undetermined impurity was detected in the crude
product.
This type of product is not totally unexpected because the for-
mation of a similar 1-oxo-1,3-dihydro-isoindole-2-carbothioamide,
which closely resembles 4aed and 5a, was observed7 in the re-
action of 2-(chloromethyl)benzoyl chloride with thiourea. How-
ever, in this case the reaction must involve quick S-acylation of
thiourea with a strongly electrophilic acyl chloride,14 consecutive S
to N benzoyl migration15 and finally very fast ring closure giving the
five-membered isoindole ring. Such a mechanism is impossible in
our case and another explanation for the formation of 4aed and 5a
must be sought.
In order to explain the preferential formation of five-membered
isoindoles over the corresponding seven-membered 2,4-
benzothiazepin-5(1H)-ones (Scheme 3), their energies were cal-
culated in the gas phase using B3LYP/AUG-cc-pVTZ/B3LYP/6-
31þG(d,p) level of theory with the zero point energy correction.
The results show that the isoindolone ring is favored by ca.
100 kJ molꢀ1 over the 2,4-benzothiazepin-5(1H)-one ring. How-
ever, we did observed the formation of 3-imino-3,4-dihydro-2,4-
benzothiazepin-5(1H)-one (7) in almost quantitative yield when
S-[2-(phenoxycarbonyl)benzyl] isothiuronium bromide (6) was
treated with a base (Scheme 4).
Therefore it is clear that the stability of the seven-membered
ring is not the only decisive factor but the quality of a leaving
group (phenoxide) also affects the product of the reaction (cf.
Schemes 2 and 4) This conclusion is supported by the fact that the
isothiuronium salts derived from 2-(chloromethyl)benzoyl chloride
and N,N0-disubstituted thioureas7 or heterocycles containing
2.2. Transformation of the isothiuronium salts 1aed and 2a
The formation of various types of products comes into consid-
eration during the transformation of isothiuronium salts 1e3. In
analogy with S-[2-(methoxycarbonyl)benzyl]isothiuronium chlo-
ride7 the formation of 3H-benzo[c]thiophen-1-one (thiophthalide;
cf. Scheme 2) or ring expansion giving substituted 1-hydroxy-3-
imino-3,4-dihydro-2,4-benzothiazepin-5(1H)-ones could occur
under basic conditions (Scheme 3). Also the formation of stable free
isothioureas or their base-catalyzed decomposition to 3-sulfanyl-
1(3H)-isobenzofuranones should be taken into account.
Different reaction conditions were adopted (aqueous ammonia,
Na2CO3 in acetone, aqueous sodium acetate, and triethylamine
buffers), but only one product was isolated in the case of the salts
1aed and 2a. The X-ray analysis (Fig. 1) together with other spectral

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J. Vana et al. / Tetrahedron 68 (2012) 9808e9817
9810
dimethylhydrazine occurs significantly slowly (ca. one day) giving
the same 1H and 13C NMR spectra. The stability of the aldehyde
intermediate (Int) is highly influenced by the properties of the
solvent. In aqueous and methanolic solutions of individual buffers
(up to pH 10) all UVevis spectra recorded during the rearrange-
ment reaction 1a/4a showed sharp isosbestic points (see
Supplementary data) and the absorbance-time dependence (ki-
netic curve) was a single exponential decay/formation. In these
solvents Int behaves as a short-lived intermediate, which is present
only in negligible concentration due to its very fast consecutive ring
closure reaction. This fact was also confirmed by 1H NMR spec-
troscopic measurements in CD3OD where no sign of an aldehyde
absorption was observed even at low temperature (ꢀ50e0 ꢁC). On
the other hand, in aprotic solvents (DCM, DMSO) the consecutive
ring closure Int/4a is much slower and double exponential ki-
netics, without any sharp isosbestic point, are observable from
UVevis spectra recorded in triethylamine solution. The same con-
secutive reaction is observable in aqueous solutions with pH >10,
where the rate of cyclization of 1a0ed0 to Int probably approaches
the rate of consecutive cyclization Int/4aed.
Scheme 4.
thiourea motif16 produces 2,4-benzothiazepin-5(1H)-ones or 3-
thioxo-2,4-benzodiazepin-1-ones. Therefore, during trans-
formation of 1aed and 2a an unstable intermediate or even tran-
sition state containing a seven-membered ring can exist on the
reaction coordinate.
According to our previous works2,3 the following mechanism
can be proposed for the transformation reaction (Scheme 5):
treatment of the isothiuronium salt with base produces a reactive
isothiourea in a fast pre-equilibrium (for pKa-s and kc of the in-
dividual salts see Table 1). The resulting isothiourea then undergoes
cyclization (kc) to give the zwitterionic intermediate (Tꢂ). If
a strained intermediate Tꢂ exists (see discussion above) then it
undergoes very quick acidebase-catalyzed stepwise or concerted
breakdown to the corresponding aldehyde (Int), which is trapped
by the internal acylureido nitrogen to form the final product. A
second, less probable mechanism involving the possibility of al-
dehyde intermediate (Int) formation may involve17 a concerted
process, which avoids strained intermediate Tꢂ. In such a case the
lactone oxygen as well as sulfur atoms leave simultaneously with
the attack of the imino nitrogen on the carbonyl group.
The acidebase-catalyzed rearrangement of isothiuronium salts
1a0d giving isoindoles 4aed as the only products was studied
spectrophotometrically under pseudo-first-order conditions in
aqueous acetate (AC; 1:1), hydroxylamine (HA; 1:1, 1:2b), 4-
picoline (PIC; 1:1), imidazole (IM; 1:1) tris(hydroxymethyl)ami-
nomethane (TRIS; 3:1a), morpholine (MOR; 1:1) and ethanolamine
(EAH) buffers (the numbers mean the molar ratio of acid vs base
form, e.g., AcOH/AcONa or the other way round and which
formdacid(a) or base(b)dprevails) at constant ionic strength
(I¼1 mol Lꢀ1) and at 25 ꢁC. The observed rate constants, kobs, were
calculated in each buffer solution from the absorbance versus time
dependence of the absorptions at 286 nm and were plotted against
the total buffer concentration (cBuff¼cBþcBH). It was found that in all
buffers except HA the observed rate constant (kobs) increases only
with the basicity (pH) of the medium but are independent on the
total buffer concentration (see Supplementary data). From this
observation it is clear that the transformation involves only
specific-base catalysis. For individual buffers where kobs was in-
avr
obs
dependent on cBuff, the average values (k ; see Supplementary
data) were used to generate the corresponding pH rate profiles
(Fig. 2) in the pH region 4.5e10; whose shapes are typical for re-
actions with fast acidebase pre-equilibrium. The dependences are
linear up to pH z8 with unit slope giving a unit reaction order with
respect to hydroxide anion for all isothiuronium salts. From ca. pH
z8 these dependences gradually break downward to zero slope.
Unfortunately it was impossible to measure kinetics in buffers with
pH >10 because the consecutive cyclization of Int to 4aed gradu-
ally appears (cf. behavior in DCM and DMSO) and the calculation of
both rate constants from a double exponential kinetic curve is
much less precise.
The breaks at pH z8e9 give the values of the ionization con-
stant pKa for the individual isothiuronium salts 1aed. On the other
hand, the values of the cyclization rate constant (kc) can be ob-
tained from the plateau at pH z10 (Table 1). Their precise values
quoted in Table 1 were calculated from the pH rate profiles using
Eq. 1 derived from Scheme 5.
Scheme 5.
Table 1
The values of the cyclization rate constants (kc) and ionization constant pKa obtained
for 1aed from pH rate profile in Fig. 2
Compound
kc (sꢀ1
)
pKa
1a
1b
1c
1d
1.20
1.70
4.80
25.0
8.26
8.52
8.19
7.82
The presence of the aldehyde intermediate (Int) formed from 1a
was confirmed by trapping it with an external nucleophile, N,N-
dimethylhydrazine, in the NMR tube (Scheme 5). The iso-
thiuronium salt 1a was dissolved in DMSO-d6 and N,N-di-
methylhydrazine was added. The solution turned green and in the
1H NMR spectrum recorded immediately a new singlet at 8.32 ppm
corresponding to CH]N group appeared (see Experimental part
and Supplementary data). Unfortunately it was impossible to iso-
late and characterize the pure hydrazone. The formation of the
aldehyde intermediate (Int) from the transformation product 4a
should also be considered but the reverse reaction of 4a with N,N-
kcKa
avr
obs
Â
Ã
k
¼
(1)
Hþ þ Ka
First, the products kcKa were determined from the linear parts of
the pH profile where [Hþ]>>Ka. At higher pH where [Hþ]<<Ka the
avr
obs
Eq. 1 is simplified to log k ¼log kc and the plateau therefore di-
rectly gives cyclization rate constant (kc).
The kc values obtained for individual salts 1aed were used to
generate the Hammett plot (Fig. 3). The sm values were adopted for

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J. Vana et al. / Tetrahedron 68 (2012) 9808e9817
9811
2.3. Transformation of the isothiuronium salts 3aed
Transformations of the isothiuronium salts 3aed were also
studied under basic conditions. In this case the formation of 1-
hydroxy-3-oxo-1,3-dihydro-2H-isoindol-2-carbothioamides cannot
be expected due to the presence of the methyl group, which blocks
ring closure within the aldehyde intermediate to generate the iso-
indolone ring. Therefore, we expected either aldehyde intermediates
containing a methyl group on nitrogen (see Scheme 5) or 1-hydroxy-
4-methyl-3-methylimino-3,4-dihydro-2,4-benzothiazepin-5(1H)-
ones (cf. Ref. 7,16) to be the stable reaction products. In reality we
obtained one single product or a mixture of two products depending
on the reaction conditions (Scheme 6).
O
O
O
Y
Y
Y
+
Br
base
O
O
NH
OH
H
N
S
CH3
S
N
H3C
HN
NH
CH3
3a-d
8a-d
9a-d
H3C
a: Y = H; b: Y = OCH ; c: Y = Cl; d: Y = NO
3
2
Fig. 2. pH Profile for the rearrangement of the isothiuronium salts 1a (B and solid
line), 1b (C and dashed line), 1c (,) and 1d (-). Lines represent fit of the data points
using Eq. 1 with parameters quoted in Table 1.
Scheme 6.
The first set of experiments with 3a was carried out in aqueous
ammonia solutions (Method A). After work up of the reaction
mixture two different products were isolated. The structure of the
major product formed in diluted ammonia was determined by X-
ray analysis (Fig. 4) to be 1,3-dimethyl-1-(3-oxo-1,3-dihydro-2-
benzofuran-1-yl)thiourea (8a).
Fig. 4. ORTEP view of compound 8a (thermal ellipsoids at 50% probability level). Se-
ꢁ
ꢂ
lected interatomic distances [A] and angles [ ]: S1 C1 1.690(2), N1 C1 1.329(3), N2 C1
1.372(3), O2 C3 1.205(3); S1 C1 N1 122.54(18), N1 C1 N2 115.7(2).
Fig. 3. Hammett correlation for transformation of isothiuronium salts 1aed.
The structure of the minor product was confirmed by 1H, 13C
NMR spectroscopy and by elemental analysis to be the known19 3-
hydroxy-2,3-dihydro-1H-isoindol-1-one (9a). It was found that the
yields of both products strongly depend on the ammonia concen-
tration and also on the manner of the mixing of the isothiuronium
salt 3a with the ammonia solution. If the crystalline salt 3aed and
ammonia solution are mixed together then increasing ammonia
concentration linearly decreases the yield of 8aed, respectively
(Table 2). When a saturated aqueous solution of the same amount
of salt 3a is added to an ammonia solution a much lower yield of 8a
log kc plot because the nucleophilic attack of an internal nucleo-
phile (isothiourea nitrogen) occurs at the lactone carbonyl group in
the meta-position. The substituents in position-5 of the iso-
benzofuranone ring can also affect the acidity of the starting salts
1aed but their influence on the pKa values of the individual salts is
much less (see Table 1 from which
r
¼ꢀ0.6 using sp values can be
obtained) due to the long distance between substituent and the
isothiuronium nitrogen. Therefore the Hammett plot in Fig. 3
clearly shows the transmission of the polar effects from sub-
stituent to lactone carbonyl in the transition state of the rate lim-
(40% at cNH ¼3.5 mol Lꢀ1) is obtained (cf. Table 2). Electron with-
3
iting step. The
r
-value obtained from Hammett plot (
r
¼1.85) is
drawing substituent in position 6 also facilitates nucleophilic attack
at the lactone group by the external nucleophile (ammonia) thus
increasing the yield of 9 (cf. Table 2).
consistent18 with rate limiting formation of the Tꢂ and confirms
conclusions resulting from solvent changes mentioned above.

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J. Vana et al. / Tetrahedron 68 (2012) 9808e9817
9812
Table 2
formation of the four-membered ring containing only carbon atoms
is unfavorable but the presence of a sulfur atom enables easier
torsion deformation so that the four-membered rings containing
a sulfur atom with a bonding angle smaller than 90ꢁ have been
observed.20
Influence of ammonia concentration on the ratio 8/9 during transformation 3/8þ9
cNH (mol Lꢀ1
) 8a (%) 9a (%) 8b (%) 9b (%) 8c (%) 9c (%) 8d (%) 9d (%)
3
3.5
5.7
8.7
84
57
22
16
43
78
76
d
d
24
d
d
61
21
3
39
79
97
44
0
56
100
d
d
The application of the classical Winstein scheme for nucleo-
philic substitution reactions leads to the proposal of the three
limiting reaction mechanisms (Scheme 2). In our case S to N S-
(1(3H)-isobenzofuranone-3-yl) migration could involve either
intramolecular front-side SN2 reaction through a four-membered
transition state (path a) or an intramolecular SN1 reaction in-
volving rearrangement of the ion pair formed after dissociation of
the thiourea moiety (path b). The third possibility (path c) involves
a double displacement mechanism, i.e., two consecutive back-side
SN2 reactions where carboxylate anion acts as both leaving group
as well as internal nucleophile (Scheme 8). The last possibility
evokes neighboring group participation.21
Values obtained from 1H NMR integrals of the crude reaction mixture.
Under different basic conditions (Na2CO3/acetone, Na2CO3/H2O,
TEA/DCMdMethods BeD) the 1,3-dimethyl-1-(3-oxo-1,3-dihydro-
2-benzofuran-1-yl)thioureas (8aed) are the only products of the
reaction.
There exist two possible explanations for the formation of the
products 9aed formed in ammonia solutions from 3aed. The most
probable reaction pathway (Scheme 7) involves external nucleo-
philic attack of the ammonia nitrogen at the lactone carbonyl
group of 3aed and subsequent decomposition of the tetrahedral
intermediate formed into 2-formylbenzamide and 1,3-
dimethylthiourea. 2-Formylbenzamide then quickly undergoes
ring closure to give the final product 9aed. To prove the presence of
the reactive 2-formylbenzamide during the course of the trans-
formation reaction 3a/9a we added a stronger external nucleo-
phile, N,N-dimethylhydrazine, to the reaction mixture to act as
a trap. In the 1H NMR spectrum measured immediately, a charac-
teristic signal at 8.32 ppm corresponding to the hydrazone group
was observed (see Supplementary data). Our proposal is also in
accordance with the literature6a,10 stating that ammonia, as
a strong nucleophile, should prefer attack on the carbonyl group.
The mechanism suggested in Scheme 7 is similar to that depicted in
Scheme 5 for 1aed and 2a. The only difference is that an external
nucleophile (ammonia) reacts more quickly than the internal
methylamino group of the isothiuronium salt 3aed due to steric
hindrance.
Scheme 8.
The front-side SN2 reaction pathway belongs to relatively rarely
suggested mechanisms: it was proposed for intramolecular de-
composition of alkyl chlorosulfites,22 for reaction of cumylar-
enesulphonates and anilinothioethers with anilines23 and
especially for some glycosyltranferase-catalyzed reactions24 in
which retention of configuration was observed. On the other hand,
SN1 reaction proceeding through an intimate ion pair can also ex-
plain the retention of configuration.25 Moreover, most quantum
chemical calculations26 give energy barriers of 170e200 kJ molꢀ1
higher for front-side attack as compared to classical back-side SN2
reaction pathway although the difference steeply decreases for
protonated alcohols and amines containing bulky alkyl group.27 In
summary, there is no definitive evidence for front-side SN2 occur-
ring on the aliphatic carbon atom.
Scheme 7.
The second possible explanation for the formation of 9aed
would involve external nucleophilic attack of ammonia at the
benzylic carbon atom with simultaneous cleavage of the iso-
thiouronium moiety. The 3-aminophthalide formed would be too
unstable and would undergo spontaneous rearrangement to the
corresponding isoindolone 9aed. However such nucleophilic sub-
stitution requires6,10 an aprotic solvent and a very good leaving
group, which is not the case for 1,3-dimethylthiourea; therefore
this mechanism is improbable.
More interesting is the formation of 8aed, which can be clas-
sified as alkyl migration from sulfur to nitrogen. In contrast to the
well-known S to N acyl migration15 in S-acylthioureas, which takes
place under mild reaction conditions a similar S to N alkyl migration
was not observed at all. Rearrangements of S-acylthioureas15 were
proposed to occur via a four-membered ring. Generally, the
The mechanism of the S to N migration is now under in-
vestigation and the results will be published soon in the separated
paper.
3. Conclusions
Treatment of the isothiuronium salts derived from 6-substituted
3-bromo-1(3H)-isobenzofuranones with bases give various un-
expected heterocyclic products whose structure depends on sub-
stitution of the isothiuronium moiety and the base used. In the case
of the salts derived from unsubstituted thiourea (1aed) and N-
methylthiourea (2a) corresponding 1-hydroxy-3-oxo-1,3-dihydro-
2H-isoindol-2-carbothioamides (4aed) or their N-methyl analogue

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9813
5a are formed in two consecutive steps through a detectable al-
dehyde intermediate. In the first step the unsubstituted iso-
thiuronium nitrogen attacks the lactone carbonyl to give the
strained zwitterionic intermediate (Tꢂ), which quickly decomposes
to a relatively stable aldehyde intermediate (Int). This aldehyde can
be trapped either with an external nucleophile (N,N-di-
methylhydrazine) to give a hydrazone or with the internal acylur-
eido nitrogen to form the final product 4aed and 5a. Initial
intramolecular attack of the lactone carbonyl does not take place
when N,N0-dimethyl isothiuronium salts 3aed are treated under
basic conditions. In this case the relatively bulky methyl group on
the nitrogen atom sterically hinders the attacking internal nucle-
ophile. If a stronger external nucleophile (ammonia) is present in
large excess then it attacks the lactone carbonyl to give unstable 2-
formylbenzaldehyde, which undergoes subsequent cyclization to
give 3-hydroxy-2,3-dihydro-1H-isoindol-1-ones (9aed) and N,N0-
dimethylthiourea. If there is no external nucleophile in the reaction
mixture then unexpected S to N S-(1(3H)-isobenzofuranone-3-yl)
migration occurs producing 1,3-dimethyl-1-(3-oxo-1,3-dihydro-2-
benzofuran-1-yl)thioureas (8aed). Three limiting reaction mecha-
nisms: classical SN1, front-side SN2 or double displacement mech-
anism can explain this migration.
NMR (100 MHz, DMSO)
d
167.8, 165.8, 161.9, 135.4, 126.8, 125.1,
123.7, 108.6, 81.5, 56.3; HRMS: Mþ, found 239.0486. C10H11N2O3S
requires 239.0485.
4.2.3. S-(5-Chloro-3-oxo-1,3-dihydro-2-benzofuran-1-yl)iso-
thiuronium bromide (1c). Yield 0.65 g (81%) of white solid; mp
213e215 ꢁC; [found: C, 33.54; H, 2.57; N, 8.93; S, 9.73.
C9H8BrClN2O2S requires C, 33.40; H, 2.49; Br, 24.69; Cl, 10.96; N,
8.66; S, 9.91%]; nmax(neat) 3194, 3072, 1778, 1710, 1656, 1427, 1287,
970 cmꢀ1; 1H NMR (400 MHz, DMSO)
d 9.83 (br s, 2H, NH2), 9.57 (br
s, 2H, NH2), 8.07 (d, 1H, J¼2.0 Hz, AreH), 8.02 (dd, 1H, J¼8.4, 2.0 Hz,
AreH), 7.89e7.92 (m, 2H, AreHþCH); 13C NMR (100 MHz, DMSO)
d
166.7, 165.4, 142.2, 136.3, 135.7, 127.3, 126.0, 125.6, 81.7; HRMS:
MHþ, found 242.9993. C9H8ClN2O2S requires 242.9990 (with 35Cl).
4.2.4. S-(5-Nitro-3-oxo-1,3-dihydro-2-benzofuran-1-yl)iso-
thiuronium bromide (1d). Yield: 0.65 g (78%) of white solid; mp
207e210 ꢁC; [found: C, 32.65; H, 2.66; Br, 23.71; N, 12.73; S, 9.74.
C9H8BrN3O4S requires C, 32.35; H, 2.41; Br, 23.91, N,12.58, S, 9.60%];
nmax(neat) 3144, 3073, 1778, 1710, 1662, 1535, 978 cmꢀ1
;
1H NMR
(400 MHz, DMSO)
d 9.84 (br s, 2H, NH2), 9.55 (br s, 2H, NH2), 8.70
(dd, 1H, J¼8.4, 2.0 Hz, AreH), 8.59 (d, 1H, 2.0 Hz, AreH), 8.12 (d, 1H,
J¼8.4 Hz, AreH), 8.00 (s, 1H, CH), 13C NMR (100 MHz, DMSO)
4. Experimental section
4.1. Compounds
d 166.1, 165.1, 149.7, 148.9, 130.2, 126.9, 126.0, 120.8, 81.8; HRMS:
Mþ, found 254.0231. C9H8N3O4S requires 254.0230.
4.2.5. S-(3-Oxo-1,3-dihydro-2-benzofuran-1-yl)-N-methyl isothiuro-
niumbromide(2a). Yield 0.62 g (82%); mp 203e205 ꢁC of white solid;
[found: C, 39.89; H, 3.98; Br, 26.16; N, 9.52; S, 10.33 C10H11BrN2O2S
requires C, 39.62; H, 3.66; Br, 26.36; N, 9.24; S, 10.58%]; nmax(neat)
3006, 2807, 1763, 1710, 1664, 1357, 960, 679 cmꢀ1; 1H NMR (400 MHz,
Starting 6-substituted 3-bromo-1(3H)-isobenzofuranones were
synthesized9 by radical bromination of 6-substituted-1(3H)-iso-
benzofuranones28 and were immediately used for the preparation
of S-(1(3H)-isobenzofuranone-3-yl)isothiuronium bromides (1aed,
2a, 3aed)dsee below.
DMSO) d 10.35 (br s, 1H, NH), 10.02 (br s, 1H, NH), 9.59 (br s, 1H, NH),
Methyl 2-(bromomethyl)benzoate29 and phenyl 2-(bromo-
methyl)benzoate30 were also synthesized by radical bromination of
the corresponding commercially available 2-methyl benzoates.
7.41 (d, 1H, J¼7.6 Hz, AreH), 7.89e7.91 (m, 2H, AreHþCH), 7.81 (d,1H,
J¼7.6 Hz, AreH), 7.74 (t, 1H, J¼7.6 Hz, AreH), 2.95 (s, 3H, NCH3); 13
C
NMR (100 MHz, DMSO) d 167.8, 161.4, 143.5, 135.5, 131.4, 125.7, 124.8,
123.8, 82.4, 31.1; HRMS: Mþ, found 223.0543. C10H11N2O2S requires
223.0536.
4.2. General procedure for the preparation of isothiuronium
salts
4.2.6. S-(3-Oxo-1,3-dihydro-2-benzofuran-1-yl)-N,N0-dimethyl iso-
thiuronium bromide (3a). Yield 0.73 g (92%) of white solid; mp
191e193 ꢁC; [found: C, 41.85; H, 4.37; Br, 25.40; N, 9.12; S, 10.42
C11H13BrN2O2S requires C, 41.65; H, 4.13; Br, 25.19; N, 8.83; S,
10.11%]; nmax(neat) 2991, 2894, 2822,1783,1710,1639, 957 cmꢀ1; 1H
To a hot solution containing 6-substituted 3-bromo-1(3H)-iso-
benzofuranone (2.5 mmol), methyl 2-(bromomethyl)benzoate or
phenyl 2-(bromomethyl)benzoate in acetone (10 mL) a saturated
solution of corresponding thiourea (2.5 mmol) in acetone (ca.
15 mL) was added. The mixture was heated at reflux for 5 min and
left to stand overnight. Precipitated crystals were collected by
filtration.
NMR (400 MHz, DMSO)
d 10.20 (br s, 1H, NH), 9.71 (br s, 1H, NH),
7.87e7.95 (m, 3H, AreH), 7.81 (s, 1H, CH), 7.75 (t, 1H, J¼7.2 Hz,
AreH), 3.07 (s, 3H, NCH3), 2.98 (s, 3H, NCH3); 13C NMR (100 MHz,
DMSO)
d 167.7, 161.7, 143.8, 135.4, 131.3, 125.5, 124.6, 123.9, 83.0,
4.2.1. S-(3-Oxo-1,3-dihydro-2-benzofuran-1-yl)isothiuronium bro-
mide (1a). Yield: 0.61 g (84%) of white solid; mp 206e210 ꢁC;
[found: C, 37.54; H, 3.25; Br, 27.41; N, 9.85; S, 10.89. C9H9BrN2O2S
requires C, 37.38; H, 3.14; Br, 27.63; N, 9.69; S, 11.09%]; nmax(neat)
32.2, 31.4; HRMS: Mþ, found 237.0687. C11H13N2O2S requires
237.0692.
4.2.7. S-(5-Methoxy-3-oxo-1,3-dihydro-2-benzofuran-1-yl)-N,N0-di-
methyl isothiuronium bromide (3b). Yield 0.72 g (83%) of white
solid; mp 112e115 ꢁC; [found: C, 41.81; H, 4.54; Br, 22.74; N, 7.81; S,
9.52. C12H15BrN2O3S requires C, 41.51; H, 4.35; Br, 23.01; N, 8.02; S,
9.23%]; nmax(neat) 2990, 1775, 1710, 1641, 1286, 954 cmꢀ1; 1H NMR
3210, 3142, 3083, 1767, 1662, 1653, 969, 677 cmꢀ1 1H NMR
;
(400 MHz, DMSO)
d 9.74 (br s, 2H, NH2), 9.51 (br s, 2H, NH2),
7.91e7.99 (m, 2H, AreH), 7.84e7.75 (m, 3H, AreHþCH); 13C NMR
(100 MHz, DMSO)
d 167.8, 165.4, 143.3, 135.6, 131.5, 125.8, 124.9,
123.9, 81.3; HRMS: Mþ, found 209.0379. C9H9N2O2S requires
209.0379.
(400 MHz, DMSO) d 10.12 (br s, 1H, NH), 9.66 (br s, 1H, NH), 7.78 (d,
1H, J¼8.8 Hz, AreH), 7.64 (s, 1H, CH), 7.47 (dd, 1H, J¼8.8, 2.4 Hz,
AreH), 7.42 (d, 1H, J¼2.4 Hz, AreH), 3.88 (s, 3H, OCH3), 3.07 (s, 3H,
4.2.2. S-(5-Methoxy-3-oxo-1,3-dihydro-2-benzofuran-1-yl)iso-
thiuronium bromide (1b). Yield 0.55 g (69%) of white solid; mp
213e215 ꢁC; [found: C, 37.75; H, 3.66; Br, 24.75; N, 8.98; S, 10.32.
C10H11BrN2O3S requires C, 37.63; H, 3.47; Br, 25.03; N, 8.78; S,
10.05%]; nmax(neat) 3193, 3068,1768,1711, 1656,1306, 963 cmꢀ1; 1H
NCH3), 2.97 (s, 3H, NCH3); 13C NMR (100 MHz, DMSO)
d 167.8, 162.3,
162.1, 136.3, 126.9, 125.5, 123.9, 108.6, 83.3, 56.6, 32.5, 31.7; HRMS:
Mþ, found 267.0797. C12H15N2O3S requires 267.0798.
4.2.8. S-(5-Chloro-3-oxo-1,3-dihydro-2-benzofuran-1-yl)-N,N0-di-
methyl isothiuronium bromide (3c). Yield 0.57 g (65%) of white
solid; mp 183e185 ꢁC; [found: C, 37.86; H, 3.34; N, 7.88; S, 9.31.
C11H12BrClN2O2S requires C, 37.57; H, 3.44; Br, 22.72; Cl, 10.08; N,
NMR (400 MHz, DMSO)
d 9.76 (br s, 2H, NH2), 9.49 (br s, 2H, NH2),
7.81 (s, 1H, CH), 7.71 (d, 1H, J¼8.4 Hz, AreH), 7.46 (dd, 1H, J¼8.4,
2.4 Hz, AreH), 7.40 (d, 1H, J¼2.4 Hz, AreH), 3.86 (s, 3H, OCH3); 13
C

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J. Vana et al. / Tetrahedron 68 (2012) 9808e9817
9814
7.97; S, 9.12%]; nmax(neat) 3271, 3002, 2812, 1776, 1735, 1710, 1639,
1631, 918 cmꢀ1 1H NMR (400 MHz, DMSO)
10.19 (br s, 1H, NH),
77, 66, 51, 44. CCDC 876131 contains the supplementary crystallo-
graphic data for this compound.
;
d
9.71 (br s, 1H, NH), 8.09 (s, 1H, AreH), 8.03 (d, 1H, J¼8.0 Hz, AreH),
7.96 (d, 1H, J¼8.4 Hz, AreH), 7.69 (s, 1H, CH), 3.13 (s, 3H, NCH3), 2.99
4.3.2. 1-Hydroxy-5-methoxy-3-oxo-1,3-dihydro-2H-isoindole-2-
carbothioamide (4b). Yield 0.37 g (99%) of white solid; mp
231e233 ꢁC; [found: C, 50.67; H, 4.30; N,11.93; S,13.21 C10H10N2O3S
requires C, 50.41; H, 4.23; N,11.76; S, 13.46%]; nmax(neat) 3003,1710,
(s, 3H, NCH3); 13C NMR (100 MHz, DMSO)
d 166.7, 161.8, 143.0,
136.2, 135.5, 127.1, 126.0, 125.3, 83.2, 32.5, 31.4; HRMS: Mþ, found
271.0301. C11H12ClN2O2S requires 271.0303.
1358, 1221, 1090, 902, 787, 670 cmꢀ1 1H NMR (400 MHz, DMSO)
;
4.2.9. S-(5-Nitro-3-oxo-1,3-dihydro-2-benzofuran-1-yl)-N,N0-di-
methyl isothiuronium bromide (3d). Yield 0.71 g (78%) of white
solid; mp 220e225 ꢁC; [found: C, 36.75; H, 3.61; Br, 22.15; N, 11.75;
S, 9.08. C11H12BrN3O4S requires C, 36.48; H, 3.34; Br, 22.06; N,11.60;
S, 8.85%]; nmax(neat) 2983, 2949, 2900, 2835, 1770, 1710, 1649, 1611,
d
9.57 (vbs, 2H, NH2), 7.54 (d,1H, J¼8.4 Hz, AreH), 7.32 (dd,1H, J¼8.4,
2.4 Hz, AreH), 7.25 (d, 1H, J¼2.4 Hz, AreH), 7.0e7.5 (vbs, 1H, OH),
6.68 (s, 1H, CH), 3.87 (s, 3H, OCH3); 13C NMR (100 MHz, DMSO)
d
180.4, 166.9, 161.0, 136.6, 130.6, 125.4, 122.6, 107.0, 83.0, 55.9.
937, 707 cmꢀ1
;
1H NMR (400 MHz, DMSO)
d
10.29 (br s, 1H, NH),
4.3.3. 5-Chloro-1-hydroxy-3-oxo-1,3-dihydro-2H-isoindole-2-
carbothioamide (4c). Yield 0.35 g (92%) of white plates; mp
245e250 ꢁC; [found: C, 44.72; H, 2.87; Cl, 14.35; N, 11.78; S, 12.99.
C9H7ClN2O2S requires C, 44.54; H, 2.91; Cl, 14.61; N, 11.54; S,
9.76 (br s, 1H, NH), 7.75 (dd, 1H, J¼7.6, 2.0 Hz, AreH), 8.61 (d, 1H,
J¼2 Hz, AreH), 8.23 (d, 1H, J¼3.6 Hz, AreH), 7.77 (s, 1H, CH), 3.14 (d,
3H, J¼3.6 Hz, NCH3), 3.00 (d, 3H, J¼3.6 Hz, NCH3); 13C NMR
(100 MHz, DMSO)
d
166.2, 161.6, 149.8, 149.7, 130.2, 126.9, 126.2,
13.21%]; nmax(neat) 3347, 3233, 3148, 1712, 1590, 1195, 1031 cmꢀ1
;
120.7, 83.7, 32.6, 31.5; HRMS: Mþ, found 282.0541. C11H12N3O4S
requires 282.0543.
1H NMR (400 MHz, DMSO)
d
9.71 and 9.49 (2ꢃ br s, 2H, NH2),
7.80e7.82 (m, 2H, AreH), 7.67 (m, 1H, AreH), 6.81 (d, 1H, J¼7.2 Hz,
OH), 6.75 (d, 1H, J¼6.8 Hz, CH); 13C NMR (100 MHz, DMSO)
d 180.2,
4.2.10. S-[2-(Phenoxycarbonyl)benzyl]isothiuronium
bromide
165.5, 142.9, 135.0, 134.7, 131.0, 126.3, 123.9, 83.1.
(6). Yield: 0.70 g (76%) of white plates; mp 180e182 ꢁC; [found: C,
49.27; H, 4.22; Br, 21.83; N, 7.93; S, 8.57. C15H15BrN2O2S requires C,
49.06; H, 4.12; Br, 21.76; N, 7.63; S, 8.73%]; nmax(neat) 3286, 3095,
1722, 1711, 1620, 1244, 1198, 705 cmꢀ1; 1H NMR (400 MHz, DMSO)
4.3.4. 1-Hydroxy-5-nitro-3-oxo-1,3-dihydro-2H-isoindole-2-
carbothioamide (4d). Yield 0.34 g (90%) of yellowish solid; mp
223e226 ꢁC; [found: C, 42.73; H, 2.85; N, 16.73; S, 12.51 C9H7N3O4S
requires C, 42.69; H, 2.79; N,16.59; S,12.66%]; nmax(neat) 3356, 3225,
d
9.33 (br s, 2H, NH2), 9.10 (br s, 2H, NH2), 8.20 (d, 1H, J¼7.2 Hz,
AreH), 7.70e7.75 (m, 2H, AreH), 7.57e7.62 (m, 1H, AreH),
7.47e7.52 (m, 2H, AreH), 7.31e7.35 (m, 3H, AreH), 4.84 (s, 2H,
3140, 3071, 1709, 1598, 1535, 1338, 1222 cmꢀ1
DMSO)
;
1H NMR (400 MHz,
d
9.81 and 9.51 (2ꢃ br s, 2H, NH2), 8.59 (dd, 1H, J¼8.3, 2.2 Hz,
CH2); 13C NMR (100 MHz, DMSO)
d
169.3, 164.9, 150.5, 137.3, 133.8,
AreH), 8.46 (d,1H, J¼2.2 Hz, AreH), 7.93 (d,1H, J¼8.3 Hz, AreH), 7.10
131.9, 131.6, 129.8, 129.1, 128.1, 126.4, 122.1, 33.4; HRMS: MHþ,
found 287.0841. C15H15N2O2S requires 287.0849.
(d, 1H, J¼7.5 Hz, OH), 6.90 (d, 1H, J¼7.5 Hz, CH); 13C NMR (100 MHz,
DMSO)
d 180.0, 164.8, 149.9, 149.3, 130.6, 129.6, 126.2, 119.4, 83.2.
4.3. General procedure for the base-catalyzed transformation
of isothiuronium salts
4.3.5. 1-Hydroxy-N-methyl-3-oxo-1,3-dihydro-2H-isoindole-2-
carbothioamide (5a). Yield 0.20 g (55%) of white needles; mp
133e135 ꢁC; [found: C, 53.94; H, 4.61; N, 12.68; S, 14.13.
C10H10N2O2S requires C, 54.04; H, 4.53; N, 12.60; S, 14.43%]; nmax(-
neat) 3422, 3225, 3004, 2927, 1701, 1679, 1535, 1223, 717 cmꢀ1; 1H
Method AdDiluted (1:1) ammonia solution was added to the
salt. After 1 h of stirring, the precipitate was filtered off followed by
recrystallization from a water-methanol solution.
NMR (400 MHz, DMSO)
d 10.35 (s, 1H, NH), 7.75e7.80 (m, 2H,
Method BdTo a 100 mL Erlenmeyer flask a salt (0.5 g), sodium
carbonate (1 g) and acetone (50 mL) were added. After heating at
reflux for 5 h the reaction mixture was filtered and the filtrate
evaporated. The crude product was recrystallized from water-
emethanol solution.
AreH), 7.60e7.65 (m, 2H, AreH), 6.78e6.80 (m, 2H, CHþOH), 3.11
(d, 3H, J¼2.4 Hz, NCH3); 13C NMR (100 MHz, DMSO)
d 179.1, 166.6,
144.1, 134.5, 130.1, 128.9, 124.1, 124.0, 83.3, 32.0. EI-MS: m/z (%) 222,
189, 175, 161, 149 (100), 137, 130, 105, 77, 51, 42.
Method CdAn aqueous solution of sodium carbonate (15 mL;
c¼1 mol Lꢀ1) was added to the salt (0.5 g) and left to stand for 1 h.
After this time, the mixture was extracted with dichloromethane
(2ꢃ20 mL). Combined extracts were washed with water and brine,
dried over Na2SO4, filtered and evaporated.
Method DdTo a solution of TEA (3 mL; 20 mmol) in water
(20 mL) was added to the salt (0.5 g) and stirred for 0.5 h. After this
time, the mixture was extracted with dichloromethane (2ꢃ20 mL).
Combined extracts were washed with water and brine, dried over
Na2SO4, filtered and evaporated.
4.3.6. 3-Imino-3,4-dihydro-2,4-benzothiazepin-5(1H)-one (7). Yield
0.17 g (67%) of white solid; mp 216e218 ꢁC; [found: C, 56.45; H, 4.14;
N, 14.31; S, 16.49. C9H8N2OS requires C, 56.23; H, 4.19; N, 14.57; S,
16.68%]; nmax(neat) 3003, 1710, 1358, 1221, 718, 687 cmꢀ1; 1H NMR
(400 MHz, DMSO)
7.28e7.31 (m, 2H, AreH), 4.04 (s, 2H, CH2); 13C NMR (100 MHz,
DMSO) 172.2, 165.5, 140.1, 135.3, 129.8, 128.0, 127.0, 126.1, 31.1.
d
8.15 (br s, 2H, 2ꢃ NH), 7.32e7.38 (m, 2H, AreH),
d
4.3.7. 1,3-Dimethyl-1-(3-oxo-1,3-dihydro-2-benzofuran-1-yl)thio-
urea (8a). Yield 0.35 g (95%) of white solid; mp 155e156 ꢁC;
[found: C, 55.84; H, 4.90; N, 11.86; S, 13.65. C11H12N2O2S requires C,
55.91; H, 5.12; N, 11.86; S, 13.57%]; nmax(neat) 3327, 3003, 1754,
The following compounds were prepared according to
Method B.
1710, 1358, 725 cmꢀ1; 1H NMR (400 MHz, DMSO)
d 8.6 (s, 1H, CH),
4.3.1. 1-Hydroxy-3-oxo-1,3-dihydro-2H-isoindole-2-carbothioamide
(4a). Yield: 0.25 g (70%) of white solid; mp 145e150 ꢁC; [found: C,
51.99; H, 4.05; N, 13.72; S, 15.22. C9H8N2O2S requires C, 51.91; H,
3.87; N, 13.45; S, 15.40%]; nmax(neat) 3335, 3221, 3156, 1714, 1596,
8.33 (br s, 1H, NH), 7.92 (d, 1H, J¼7.6 Hz, AreH), 7.83 (dt, 1H, J¼7.6,
1.2 Hz, AreH), 7.69 (dt, 1H, J¼7.6, 1.2 Hz, AreH), 7.55 (dd, 1H, J¼7.6,
0.8 Hz, AreH), 3.03 (d, 3H, J¼2 Hz, NCH3), 2.53 (s, 3H, NCH3); 13C
NMR (100 MHz, DMSO)
d 184.0, 168.2, 144.8, 135.0, 130.6, 127.0,
1336, 1220, 667 cmꢀ1
;
1H NMR (400 MHz, DMSO)
d
9.81 and 9.51
125.2, 123.0, 89.4, 33.1, 30.4. CCDC 876132 contains the supple-
mentary crystallographic data for this compound.
(2ꢃ br s, 2H, NH2), 7.76e7.81 (m, 2H, AreH), 7.60e7.67 (m, 2H,
AreH), 6.76 (d, 1H, J¼6.8 Hz, OH), 6.72 (d, 1H, J¼6.8 Hz, CH); 13C
NMR (100 MHz, DMSO)
d
180.3, 166.8, 144.0, 134.7, 130.2, 128.9,
4.3.8. 1-(5-Methoxy-3-oxo-1,3-dihydro-2-benzofuran-1-yl)-1,3-
124.2, 124.1, 83.2. EI-MS (%): m/z 208, 191, 174, 149, 130, 105 (100),
dimethylthiourea (8b). Yield 0.27 g (70%) of white solid; mp

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J. Vana et al. / Tetrahedron 68 (2012) 9808e9817
9815
112e115 ꢁC; [found: C, 54.36; H, 5.22; N, 10.63; S, 12.23.
nmax(neat) 3228, 1701, 1548, 1346, 1050, 743 cmꢀ1
(400 MHz, DMSO)
;
1H NMR
C12H14N2O3S requires C, 54.12; H, 5.30; N, 10.52; S, 12.04%]; nmax(-
d
9.32 (s, 1H, NH), 8.47 (dd, 1H, J¼8.4, 2.0 Hz,
neat) 3359, 2954, 2918, 2848, 1745, 1710, 1315, 1061 cmꢀ1; 1H NMR
AreH5), 8.29 (d, 1H, J¼1.7 Hz, AreH7), 7.85 (d, 1H, J¼8.0 Hz, AreH4),
(400 MHz, DMSO)
d
8.60 (s, 1H, CH), 8.33 (q, 1H, J¼4.4 Hz, NH),
6.69 (d, 1H, J¼7.2 Hz, OH), 6.03 (d, 1H, J¼6.0 Hz, CH); 13C NMR
7.46e7.48 (m, 1H, AreH), 7.37e7.39 (m, 2H, AreH), 3.89 (s, 3H,
OCH3), 3.05 (d, 3H, J¼4.4 Hz, NCH3), 2.56 (s, 3H, NCH3); 13C NMR
(100 MHz, DMSO)
78.0.
d 166.4, 152.8, 148.8, 133.6, 127.4, 125.5, 117.5,
(100 MHz, DMSO)
d
184.0, 168.2, 161.3, 137.0, 128.9, 124.2, 123.0,
Reaction of 1a, 3a and 4a with N,N-dimethylhydrazine (1H NMR
study). The isothiouronium salt 1a, 3a or transformation product 4a
(ca. 20 mg) were dissolved in DMSO-d6 (0.5 mL) and pure N,N-di-
methylhydrazine (1 mL) (SigmaeAldrich) was added. After thor-
ough stirring the solutions of 1a and 3a turned green immediately
whereas no color change was observed for 4a. 1H NMR spectra were
recorded and new singlet at 8.32 ppm corresponding to CH]N
group appeared in the case of salts 1a and 3a (for 1H NMR spectrum
see Supplementary data). The same experiment was repeated with
4a but the same spectrum was obtained after 24 h.
107.0, 89.4, 56.0, 32.2, 30.5.
4.3.9. 1-(5-Chloro-3-oxo-1,3-dihydro-2-benzofuran-1-yl)-1,3-
dimethylthiourea (8c). Yield 0.33 g (87%) of white solid; mp
183e185 ꢁC; [found: C, 49.07, H, 4.37; N, 10.55; S, 12.11.
C11H11ClN2O2S requires C, 48.80; H, 4.10; N, 10.35; S, 11.84%];
nmax(neat) 3291, 2931, 1769, 1710, 1547, 1535, 1361, 1051 cmꢀ1 1H
;
NMR (400 MHz, DMSO)
d
8.68 (s,1H, CH), 8.36 (q,1H, J¼4.4 Hz, NH),
7.98 (d, 1H, J¼1.6 Hz, AreH), 7.87 (dd, 1H, J¼8.4, 2 Hz, AreH), 7.60
(d, 1H, J¼8.4 Hz, AreH), 3.04 (d, 3H, J¼4.0 Hz, NCH3), 2.57 (s, 1H,
Trapping of azetidine intermediate during transformation of 3a
to 8a. The isothiouronium salt 3a (0.2 g; 0.6 mmol), sodium car-
bonate (0.5 g) was suspended in acetone (30 mL). Then 1 mL of
methyliodide was added and reaction mixture was heated at reflux
for 5 h. Reaction mixture was filtered, evaporated and crude ma-
terial was analyzed by NMR spectroscopy.
NCH3); 13C NMR (100 MHz, DMSO)
d 184.1, 167.0, 143.6, 135.4, 135.0,
129.4, 125.0*, 89.6, 33.2, 30.7. *Probably two signals with the same
chemical shift.
4.3.10. 1,3-Dimethyl-1-(5-nitro-3-oxo-1,3-dihydro-2-benzofuran-1-
yl)thiourea (8d). Yield 0.34 g (87%) of white solid; mp 212e213 ꢁC;
[found: C, 46.74; H, 4.21; N, 14.79; S, 11.26. C11H11N3O4S requires C,
46.97; H, 3.94; N, 14.94; S, 11.40]; nmax(neat) 3393, 3072, 2929, 1774,
4.5. Kinetic measurements
1710, 1530, 1348, 1087, 915 cmꢀ1; 1H NMR (400 MHz, DMSO)
d
8.82
All the kinetic measurements were carried out in 1 cm closable
cell using diode array spectrophotometer or using stopped-flow
spectrophotometer at 25ꢂ0.1 ꢁC. The observed pseudo-first order
rate constants kobs were calculated from absorbance-time de-
pendences at the wavelength of 300 nm and at the substrate con-
centrations of ca. 5ꢃ10ꢀ5 mol Lꢀ1. Ionic strength I¼1 mol Lꢀ1 was
adjusted by KCl. In all kinetic runs the standard deviation in the fit
was always less than 1% of the quoted value, and was more usually
between 0.2 and 0.4% of the quoted value. The pH of individual
buffers was measured using a pH-meter equipped with glass
electrode. Redistilled water, commercially available substituted
acetic acids, amines and potassium chloride (p.a.) for adjustment of
ionic strength of buffer solutions were used.
(s, 1H, CH), 8.62 (dd, 1H, J¼8.4, 2.0 Hz, AreH), 8.57 (d, 1H, J¼1.6 Hz,
AreH), 8.43 (d,1H, J¼4 Hz, NH), 7.86 (d,1H, J¼8.4 Hz, AreH), 3.05 (d,
3H, J¼4 Hz, NCH3), 2.61 (s, 3H, NCH3); 13C NMR (100 MHz, DMSO)
d
183.9,166.3,150.4,149.4,129.6,129.0,124.8,120.3, 89.8, 33.2, 30.9.
4.4. General procedure for the preparation of 9aed
Concentrated aqueous ammonia solution (15 mL) was added to
an appropriate 3-bromo phthalide (0.5 g). The reaction mixture
was stirred for 30 min and then filtered to obtain the crude product,
which was recrystallized from aqueous ethanol (1:1). Thus pre-
pared 9aed were used as standards in the study of product dis-
tribution in the reaction of 3aed with aqueous ammonia solutions
(see Table 2 and Method A).
4.6. NMR experiments
3-Hydroxy-2,3-dihydro-1H-isoindol-1-one (9a) has the same
mp and NMR spectra as reported in Ref. 18
1H and 13C NMR spectra were recorded on a 400 MHz or
500 MHz instrument. Chemical shifts
d
are referenced to TMS (
d
¼0)
4.4.1. 3-Hydroxy-6-methoxy-2,3-dihydro-1H-isoindol-1-one
(9b). Yield 0.32 g (87%) of white solid; mp 167e169 ꢁC; [found: C,
60.21; H, 5.07; N, 7.79. C9H9NO3 requires C, 60.33; H, 5.06; N,
7.82%]; nmax(neat) 3357, 3161, 3060, 1701, 1358, 1289, 1235 cmꢀ1; 1H
or solvent residual peaks
d
(DMSO-d6)¼2.50 (1H) and 39.6 ppm
(
13C), and
d
(CDCl3)¼7.27 (1H) and 77.0 (13C). The CH, CH3, and CH2,
Cquart groups in the 13C NMR spectra were distinguished by the APT
method. 1He13CeHMBC NMR experiment was carried out using
manufacturer’s settings at 400 MHz with coupling constant 10 Hz.
NMR (400 MHz, DMSO)
AreH4), 7.16 (dd, 1H, J¼8.2 and 2.5 Hz, AreH5), 7.13 (d, 1H, J¼2.3 Hz,
AreH7), 6.30 (br s, 1H, OH), 5.83 (s, 1H, CH), 3.83 (s, 3H, OCH3); 13
d
8.88 (br s, 1H, NH), 7.47 (d, 1H, J¼8.1 Hz,
C
4.7. IR experiments
NMR (100 MHz, DMSO)
106.3, 77.9, 55.7.
d 168.5, 160.5, 139.2, 133.7, 124.8, 119.0,
IR spectra of neat samples were recorded on a Perkin Elmer FT-
IR System Spectrum BX equipped with a ZnSe ATR crystal for solid
samples.
4.4.2. 6-Chloro-3-hydroxy-2,3-dihydro-1H-isoindol-1-one
(9c). Yield 0.34 (92%) of white solid; mp 220e222 ꢁC; [found: C,
52.58; H, 3.32; N, 7.52; Cl, 19.32. C8H6ClNO2 requires C, 52.34; H,
3.29; N, 7.63; Cl, 19.31%]; nmax(neat) 3203, 1709, 1687, 1679, 1354,
4.8. Mass spectrometric experiments
1069,723 cmꢀ1
;
1H NMR (400 MHz, DMSO)
d
9.08 (br s, 1H, NH),
The positive ions for HRMS spectra were generated by electro-
spray ionization (ESI) from methanolic solutions and detected in
microTOF-Q detector.
7.67 (dd, 1H, J¼8.1, 2.0 Hz, AreH5), 7.62 (d, 1H, J¼1.8 Hz, AreH7),
7.60 (d, 1H, J¼8.1 Hz, AreH4), 6.44 (d, 1H, J¼9.0 Hz, OH), 5.89 (d, 1H,
J¼9.0 Hz, CH); 13C NMR (100 MHz, DMSO)
d 167.1, 145.6, 134.2,
134.1, 132.0, 125.8, 122.3, 77.9.
4.9. Computational details
4.4.3. 3-Hydroxy-6-nitro-2,3-dihydro-1H-isoindol-1-one (9d). Yield
0.30 g (81%) of white solid; mp 193e195 ꢁC; [found: C, 49.11; H,
3.05; N, 14.46. C8H6N2O4 requires C, 49.49; H, 3.12; N, 14.43%];
The calculations were performed using the density functional
method B3LYP31 in conjunction with AUG-cc-pVTZ//B3LYP/6-
31þG(d,p) basis set as implemented in the Gaussian 09 suite.32

ꢁꢀ
J. Vana et al. / Tetrahedron 68 (2012) 9808e9817
9816
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The X-ray data for colorless crystals of S-(3-oxo-1,3-dihydro-2-
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(Supplementary data), Compound 4a (Fig. 1) and 8a (Fig. 4) were
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a
radiation (
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¼0.71073 A), a graphite mono-
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€
Chemie (HoubeneWeyl), 4th ed.; Muller, E., Bayer, O., Meerwein, H., Ziegler, K.,
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½
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Crystallographic data for structural analysis have been deposited
with the Cambridge Crystallographic Data Centre, CCDC no. 876130,
876131 and 876132 for S-(3-oxo-1,3-dihydro-2-benzofuran-1-yl)-
N-methyl-N-phenyl isothiouronium bromide, 4a and 8a, re-
spectively. Copies of this information may be obtained free of charge
from The Director, CCDC, 12 Union Road, Cambridge CB2 1EY, UK
(fax: þ44-1223-336033; e-mail: deposit@ccdc.cam.ac.uk or www:
http://www.ccdc.cam.ac.uk).
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Financial support by Ministry of Education, Youth and Sports of
the Czech Republic and European Social Fund (project No. CZ.1.07./
2.3.00/30.0021 - ‘Enhancement of R&D Pools of Excellence at the
University of Pardubice’), the Grant agency of the Czech Republic
(207/11/0338) The access to computing and storage facilities
owned by parties and projects contributing to the National Grid
Infrastructure MetaCentrum, provided under the programme
‘Projects of Large Infrastructure for Research, Development, and
Innovations’ (LM2010005) is highly appreciated.
Supplementary data
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All kinetic data (the observed rate constants measured in
buffers), selected spectral records, HRMS, NMR spectra and X-ray.
Supplementary data associated with this article can be found in the
online version, at http://dx.doi.org/10.1016/j.tet.2012.09.005. These
data include MOL files and InChiKeys of the most important com-
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