Unexpected formation of benzothiazoles in the synthesis of new heterocycles: Benzo-1,2,4-dithiazines

Article abstract of DOI:10.1055/s-2008-1067008

The synthesis of benzo-1,2,4-dithiazines was investigated presuming a reversible sulfur-sulfur bond formation. 2-Aminothiophenol, when allowed to react with isothiocyanates, provided benzothiazoles. 2,2′-Diaminodiphenyl disulfide underwent cyclizations very readily without any reducing agent to give, according to the reaction conditions, benzothiazoles or benzo-1,2,4-dithiazines. The developed procedure offers a simple and convenient way to prepare the title compounds in very good to excellent yields. Until now, benzo-1,2,4-dithiazines as well as 2,2′-diaminodiphenyl disulfides bearing aminocarbonothioyl groups were unknown. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1067008

PAPER
1297
Unexpected Formation of Benzothiazoles in the Synthesis of New Heterocycles:
Benzo-1,2,4-dithiazines
S
ynthesis of Benzo
a
-1,2,4-dith
g
iazines mar Fajkusova,* Pavel Pazdera
Faculty of Science, Masaryk University, Kotlarska 2, 611 37 Brno, Czech Republic
Fax +420(54)9492688; E-mail: dagmar@chemi.muni.cz
Received 28 November 2007; revised 10 December 2007
NH
N
S
NH
NH
SO3Na
Abstract: The synthesis of benzo-1,2,4-dithiazines was investigat-
ed presuming a reversible sulfur–sulfur bond formation. 2-Ami-
5 N HCl
S
S
S
nothiophenol, when allowed to react with isothiocyanates, provided
benzothiazoles. 2,2¢-Diaminodiphenyl disulfide underwent cycliza-
tions very readily without any reducing agent to give, according to
the reaction conditions, benzothiazoles or benzo-1,2,4-dithiazines.
The developed procedure offers a simple and convenient way to
prepare the title compounds in very good to excellent yields. Until
now, benzo-1,2,4-dithiazines as well as 2,2¢-diaminodiphenyl disul-
fides bearing aminocarbonothioyl groups were unknown.
1
2
Scheme 1 Cyclization of sodium S-{2-[(anilinocarbonothioyl)ami-
no]ethyl} thiosulfate to 1,2,4-dithiazine
NH2
NH NH
C
S
R'
N
R'
S
S
pyridine, aq Na2CO3
R
S
SO3H
R
Key words: benzo-1,2,4-dithiazines, benzothiazoles, cyclizations,
heterocycles, sulfur
–
SO3
R' = Ph, Me
3a R = H
3b R = NHMe2
4
HCl
1,2,4-Dithiazines, six-membered heterocycles containing
two sulfur atoms in positions 1 and 2 and a nitrogen atom
in the position 4 of the ring, represent a class of com-
pounds that has not been studied much so far. The first re-
port of this kind was based on a reaction between thiourea
and Bunte salts, i.e. S-alkyl or S-aryl thiosulfates, in acidic
media and appeared in 1963.1 Since the corresponding
disulfides were previously obtained,2 a Bunte salt bearing
an (aminocarbonothioyl)amino group such as 1 was ex-
pected to undergo intramolecular cyclization on treatment
with an acid according to Scheme 1.
N
S
NH
N
R'
NH R'
S
S
R
R
–
+ S2O3
5
6
Scheme 2 Reactions of S-aryl hydrogen thiosulfates with isothio-
cyanates
N
S
NH
N
NH
NH NH
R
R
R
S
SH
S
SH
SH
6
7'
7
NH2
SH
Indeed, a crude product was formed, from which 3-anili-
no-5,6-dihydro-1,2,4-dithiazine (2) was isolated as a pi-
crate and identified by CHNO elemental analysis.
Attempts to release the free base were unsuccessful. A
similar transformation of S-aryl hydrogen thiosulfates
was supposed to lead to benzo-1,2,4-dithiazines 6. How-
ever, neither the presumed benzo-1,2,4-dithiazines nor 2-
[(aminocarbonothioyl)amino]phenyl thiosulfates 4 result-
ed from reactions of S-2-aminophenyl hydrogen thiosul-
fate (3a) and its 5-dimethylamino derivative 3b with
phenyl and methyl isothiocyanates (Scheme 2).
+
R
N
C
S
9a–e
8
Scheme 3 Retrosynthetic analysis of benzo-1,2,4-dithiazines
the literature; in this, Heller showed that 3b provides the
corresponding benzothiazole-2-thione with carbon disul-
fide in aqueous ammonia.3
The aim of this work was to find a suitable and reliable ap-
proach to this new class of compounds. Once benzo-1,2,4-
dithiazines are prepared, we assume that the formation of
the sulfur–sulfur bond could be reversible and, on this ba-
sis, their application, e.g. as free-radical scavengers, in
various fields of industry may follow.
Instead of the desired products, benzothiazole derivatives
5 were obtained in almost quantitative yields accompa-
nied by large amounts of the thiosulfate anion, which were
determined by iodometric analysis.1
Current knowledge on benzo-1,2,4-dithiazine synthesis is
quite limited because, except for the brief notes men-
tioned above, there is only one more report available in
We considered the formation of benzo-1,2,4-dithiazines 6
by an oxidative cyclization of intermediates 7 generated in
a reaction of 2-aminothiophenol (8) with isothiocyanates
9 (Scheme 3).
The reaction of 8 with benzoyl and acetyl isothiocyanate
(9a and 9c) has already been described; Uher4 obtained N-
benzoyl- and N-acetyl-N¢-(2-sulfanylphenyl) thioureas
SYNTHESIS 2008, No. 8, pp 1297–1305
Advanced online publication: 10.04.2008
DOI: 10.1055/s-2008-1067008; Art ID: Z27707SS
© Georg Thieme Verlag Stuttgart · New York
x
x
.
x
x
.2
0
0
8

1298
D. Fajkusova, P. Pazdera
PAPER
NH2
S
NH
C
S
NH
R
(7a and 7c) as solids precipitated from benzene solutions
within several days in 42% and 54% yield, respectively.
S
S
reduction
Taking into account that benzene has serious adverse ef-
fects on human health, our initial experiments were car-
ried out in acetone at temperatures near 0 °C. First, the
reaction of 8 with 9a afforded 2-benzoylaminobenzothi-
azole (5a). A possible explanation may consist in the more
polar solvent used. The lower temperature and shorter re-
action time in our case were expected to support the isola-
tion of 7a.
+
2 R
N
C S
S
9a R = COPh
b R = Ph
c R = COMe
d R = COOMe
e R = Me
S
C
NH2
NH
NH R
10
11
NH NH
N
S
NH
oxidation
R
R
S
S
SH
When 8 and 9a were used in a 1:2 ratio, the substitution
should occur on both the nitrogen and the sulfur since
there is a lone electron pair on both these atoms available
for nucleophilic reactions. Despite a sufficient amount of
benzoyl isothiocyanate (9a), only a complex mixture
arose. Subsequent basic hydrolysis was intended to re-
lease the thiourea 7a, however, 5a and 2-aminobenzothi-
azole (5) were formed instead. The unsubstituted
derivative 5 was identical to that given by basic hydrolysis
of 5a. When the same procedure was undertaken with
methoxycarbonyl isothiocyanate (9d), only 2-aminoben-
zothiazole (5) was obtained.
7
6
N
S
NH
R
5
R = H
5a R = COPh
b R = Ph
c R = COMe
d R = COOMe
e R = Me
Scheme 4 Transformation of 2,2¢-diaminodiphenyl disulfide (10)
into benzo-1,2,4-dithiazines 6
Table 1 Reaction Conditions and Yields of Pure Benzothiazole
Derivatives Obtained from 2,2¢-Diaminodiphenyl Disulfide (10) and
Isothiocyanates 9a–e
In all experiments, acyl isothiocyanates were prepared in
situ from ammonium thiocyanate and the corresponding
acyl chlorides. Quantities of acyl chlorides were calculat-
ed on the assumption of their 60% conversion into acyl
isothiocyanates; ammonium thiocyanate was used in 10%
additional excess. 2-Aminothiophenol required purifica-
tion by vacuum distillation since it is readily oxidized to
2,2¢-diaminodiphenyl disulfide (10) even by air oxygen.
The solid residue from the distillation was recrystallized
to provide 10 as a yellow crystalline compound.
Entry Product
R
Solvent
acetone
CHCl3
Temp Yield
(°C)
Other
conditions
(%)
1
2
5a
5b
COPh
0
93
solid
disulfide
r.t.
40
cf.
Method C
3
4
Ph
acetone
acetone
MeOH
EtOH
r.t.
r.t.
65
78
r.t.
r.t.
r.t.
r.t.
r.t.
0
34
44
49
55
22
66
82
22
59
10b
48c
83
35
–
The above mentioned mixture, produced in the reaction of
8 with 9a in a 1:2 ratio, might also contain derivatives of
disulfide 10 besides N-substituted and N,S-disubstituted
2-aminothiophenol. Use of freshly distilled 8, sufficiently
protected from air during all operations, would certainly
reduce or prevent its formation. The same disadvantage,
however, applies to all reactions with thiols and thiophe-
nols.
1:4a
5
Et3N
6
–
7
CHCl3
CHCl3
toluene
Et3N
8
–
–
–
–
–
–
–
–
In the next part, we chose 2,2¢-diaminodiphenyl disulfide
(10) as the starting compound. Although its transforma-
tion into benzo-1,2,4-dithiazines 6 requires an additional
step, i.e. a reduction of the sulfur–sulfur bond (Scheme 4),
this approach could represent a simple procedure involv-
ing relatively well-defined reaction mixtures. Moreover,
10 is much easier and more convenient to handle and is
less harmful than 2-aminothiophenol (8; skin, eye and
lung irritant).
9
10
11
12
13
14
15
5c
5d
5e
COMe acetone
CHCl3
COOMe acetone
CHCl3
r.t.
r.t.
r.t.
Me
EtOH
CHCl3
Surprisingly, reactions of 2,2¢-diaminodiphenyl disulfide
(10) with isothiocyanates 9a–e afforded the correspond-
ing benzothiazole derivatives 5a–e. These products were
formed without any reducing agent present in the reaction
mixture. The various conditions examined (solvent, tem-
perature, base) are summarized in Table 1.
a The ratio of starting compounds 10 to 9b.
b In addition to benzothiazole, substituted 2,2¢-diaminodiphenyl disul-
fide (17%) was isolated.
c Yield of benzothiazole containing unreacted isothiocyanate.
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Synthesis of Benzo-1,2,4-dithiazines
1299
Figure 1 1H NMR (a) and 13C NMR (b) spectra of 2,2¢-di[(methoxycarbonylamino)carbonothioyl]aminodiphenyl disulfide (11d) in CDCl3
In the case of phenyl isothiocyanate (9b), the use of re-
agents in a 1:4 ratio (10 to 9b) did not considerably in-
crease the yield in comparison with the same experiment
in a 1:2 ratio. When triethylamine was applied as a base in
chloroform, the isolated quantity of 2-phenylaminoben-
zothiazole (5b) was even two-thirds lower than in its ab-
sence. In this context, the reaction in boiling methanol
should provide a yield significantly higher than the ob-
served 49%; however, 55% was achieved in boiling etha-
nol. Apparently, higher temperatures still have a positive
effect upon the transformation in polar solvents; neverthe-
less, a very good yield (82%) was obtained at room tem-
perature in toluene. The reaction of 2,2¢-diaminodiphenyl
disulfide (10) with acetyl isothiocyanate (9c) at room tem-
perature also led to better results in chloroform than in
acetone.
During the experiment with methoxycarbonyl isothiocy-
anate (9d) in acetone, the intermediate 11d was trapped
and separated as a colorless crystalline compound. Al-
though the reaction was carried out at a temperature near
0 °C, the initially yellow solution turned gradually dark as
a consequence of significant decomposition (TLC). 11d
was isolated together with the corresponding benzothi-
azole derivative 5d; yields of both were, unfortunately,
low, being 17% and 10%, respectively.
Figure 2 1H NMR spectrum of 11d in DMSO-d6 recorded immedi-
ately
In DMSO-d6, however, 11d underwent an immediate con-
version (Figure 2). After a few days, all the solid dis-
solved and the NMR spectra (Figure 3) were almost
identical to those of 2-methoxycarbonylaminobenzothi-
azole (5d; Figure 4).
The purification of 2,2¢-di[(methoxycarbonylamino)car-
bonothioyl]aminodiphenyl disulfide (11d) was quite
smooth since it was either only slightly soluble or even in-
soluble in common organic solvents (acetone, acetoni-
trile, methanol, dichloromethane, carbon tetrachloride,
benzene, acetic acid) and water except pyridine and tri-
fluoroacetic acid. In spite of the low solubility, 1H and 13C
NMR spectra could be recorded in CDCl3 solution
(Figure 1a,b).
Similarly, melting of 11d was accompanied by a rapid
solidification and the resulting crystals took the shape of
needles characteristic of 5d; the subsequent sublimation at
205 °C confirmed the conversion of 11d into 5d.
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1300
D. Fajkusova, P. Pazdera
PAPER
Figure 3 1H NMR (a) and 13C NMR (b) spectra of 11d in DMSO-d6 recorded after a few days
Figure 4 1H NMR (a) and 13C NMR (b) spectra of 5d in CDCl3
Attempts at mass spectra measurements obviously failed; of our work, it represents important evidence that the re-
the expected molecular peak at m/z 482 was not even de- action follows the desired pathway as shown in Scheme 4.
tected. On the contrary, the most intensive peak (100%)
According to Table 1, the experiments with methyl
appeared at m/z 208, i.e. as expected for 5d. Nevertheless,
isothiocyanate (9e) and benzoyl isothiocyanate (9a) pro-
2,2¢-di[(methoxycarbonylamino)carbonothioyl]aminodi-
ceeded very well in polar solvents at room temperature
and in an ice bath, respectively. The yields achieved (83%
5e, 93% 5a) were the highest in the whole series. In con-
trast, the above-mentioned reaction of 9a with 2-amino-
phenyl disulfide (11d) was stable enough to be stored at
room temperature for several months without any signifi-
cant changes in its infrared spectrum. It is the only substi-
tuted 2,2¢-diaminodiphenyl disulfide bearing amino-
carbonothioyl groups that is known so far. In the context
conditions.
thiophenol (8) provided only 54% of 5a under the same
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Synthesis of Benzo-1,2,4-dithiazines
1301
Figure 5 Thermal analysis of 2-benzoylaminobenzo-1,2,4-dithiazine (6a)
All benzothiazole derivatives prepared were identified by tained from the remaining portion kept at room tempera-
IR, 1H and 13C NMR spectroscopy. In the course of their ture, showed very similar but not identical spectroscopic
mass spectra measurements, a fragment of m/z 96 was al- properties. It was identified by IR, 1H and 13C NMR spec-
ways revealed. Although its intensity varied between 40% troscopy; since the sole distinction between benzothi-
(5) and 18% (5b) decreasing even below 10% (5a, 5c), it azoles and benzo-1,2,4-dithiazines is the number of sulfur
is a common feature for all benzothiazole derivatives of atoms, only slight variances have to be expected. All data
this series, and may be assigned the formula C5H4S.
were recorded under the same conditions as those of 2-
benzoylaminobenzothiazole 5a.
Methyl derivative 5e gave an intense peak at m/z 135, cor-
responding to benzothiazole unsubstituted in position 2. Comparison of 13C NMR spectra of 5a and the new com-
An ion at m/z 108 probably belongs to C6H4S; fragmenta- pound 6a revealed that the number of carbons was equal
tion to 2-aminobenzothiazole (5) including its descen- but the chemical shifts were up to 1 ppm higher or lower.
dents (m/z 123; C6H5NS) was not observed. 2- The most significant difference (3.15 ppm) was found be-
Phenylaminobenzothiazole (5b) did not follow any of the tween 13C NMR signals of C=N; peaks at 167.36 ppm (5a)
mentioned pathways; the respective peaks were almost and 165.91 ppm represented the carbonyl groups and also
undetectable.
carbons with the highest chemical shift in both cases. This
indicated that (di)benzoylthiourea 11b was not present
since its thiocarbonyl group would appear at a higher ppm
value. Moreover, assignment of the particular signals
proved a displacement of one of the aromatic carbons,
which was detected among the quaternary carbons. The
structure of benzothiazole 5a was, in consequence, rather
unlikely. Based on these data, the above-mentioned sub-
stance 6a was most properly identified as the desired 2-
benzoylaminobenzo-1,2,4-dithiazine. Very good compli-
ance with a predicted 13C NMR spectrum was found as
well.
A characteristic behavior of acyl derivatives, i.e. splitting
off the acyl groups, was noticed in the mass spectra of 5a,
5c and 5d. Moreover, benzoyl derivative 5a evolved car-
bon monoxide under the formation of 2-phenylamino-
benzothiazole (5b; m/z 226); methoxycarbonyl derivative
5d eliminated methanol affording 2-isothiocyanatoben-
zothiazole (m/z 176).
As stated above, the reaction of 2,2¢-diaminodiphenyl di-
sulfide (10) with isothiocyanates 9 was believed to pro-
vide benzo-1,2,4-dithiazines 6. However, the competitive
cyclization to benzothiazoles occurred to a large extent.
To explain its possible mechanism, additional experi-
ments with selenium analogues have been performed and
these results will be reported in a forthcoming paper.
The structure of 6a was further confirmed by means of
thermal analysis. Melting of 2-benzoylaminobenzo-1,2,4-
dithiazine (6a) was observed at 147–150 °C (cf. 188–
190 °C for 5a). In agreement with this, thermal analysis
showed that an endothermic process took place at this
temperature (Figure 5).
Two different products were isolated from the reaction of
10 with 9a in chloroform. Immediately after the reagents
were combined, about half of the suspension was taken
and briefly boiled, giving 5a again. Another solid 6a, ob-
Melting was accompanied by 8% mass loss, i.e. by a sol-
vent evaporation. As most of the acetone would certainly
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1302
D. Fajkusova, P. Pazdera
PAPER
Figure 6 IR spectrum (detail) of (a) pure 2-benzoylaminobenzo-1,2,4-dithiazine (6a); (b) 6a showing the first traces of decomposition; (c)
pure 2-benzoylaminobenzothiazole (5a)
have been removed at much lower temperatures, the ace- measurements failed regardless of sample freshness. The
tone molecules left must have been trapped in the crystals. molecular peak was detected (0.4%) but the signal of 5a
Subsequent rearrangement of bonds and/or resolidifica- at m/z 254 was much more intense (25%).
tion occurred without any mass change and, finally, com-
plete decomposition took place.
None of the transformations described was carried out in
the presence of a reducing agent. In spite of this, the cy-
Besides the reaction in chloroform, 6a was also prepared clization of the substituted disulfides 11 occurred very
in acetone at –20 to –30 °C. A well-chilled 2,2¢-diamino- readily. Disulfide 11d was the only intermediate trapped
diphenyl disulfide solution was treated with 9a without and identified. According to the reaction conditions, ben-
exceeding –20 °C and kept at this temperature overnight. zothiazoles 5a–e or benzo-1,2,4-dithiazine (6a) were iso-
Compound 6a precipitated as an insoluble pale solid in lated. The five-membered rings were, however, preferred
yields of 80–93%. In comparison with the above-men- over their six-membered counterparts since they were ob-
tioned reaction, which, unfortunately, led only to ben- tained to a much larger extent and, in addition, the conver-
zothiazole derivatives, this procedure was much more sion of 6a into 5a was observed. Nevertheless, benzo-
reliable. Moreover, very good to excellent yields could be 1,2,4-dithiazine (6a) was a relatively stable solid and its
achieved.
formation was proved in a number of experiments. It
might be presumed, therefore, that the other derivatives
are also available in the same way.
2-Benzoylaminobenzo-1,2,4-dithiazine (6a) is a relative-
ly stable crystalline substance. However, when stored at
room temperature, the following changes in its infrared The aim of this work, i.e. the synthesis of the new hetero-
spectrum took place within two weeks (Figure 6).
cycles benzo-1,2,4-dithiazines, was achieved. The proce-
dure is simple and convenient, and gives very good to
excellent yields. Moreover, the substituted disulfide 11d,
which has not been previously described, was isolated and
Figure 6 shows that 6a underwent slow decomposition to
5a. It thus became clear why attempts at mass spectra
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PAPER
Synthesis of Benzo-1,2,4-dithiazines
1303
IR (KBr): 3398 (n, NH2), 3060 (n, ArH), 1643 (n, CN), 1531, 1448,
1106, 1018, 743 (g, Ar) cm–1.
identified. The properties of other benzo-1,2,4-dithiazine
derivatives, with special attention to the reversibility of
the sulfur–sulfur bond formation, are the subject of further 1H NMR (300 MHz, DMSO-d6): d = 7.00 (t, J = 7.6 Hz, 1 H, ArH),
7.20 (t, J = 7.6 Hz, 1 H, ArH), 7.33 (d, J = 7.9 Hz, 1 H, ArH), 7.63
(d, J = 7.9 Hz, 1 H, ArH).
research.
13C NMR (75 MHz, DMSO-d6): d = 117.62 (Ar), 120.65 (2 × Ar),
All chemicals and solvents used are commercially available. Reac-
tion conversions were monitored by TLC on Silufol UV 254 in
Et2O. IR spectra were recorded on an ATI Mattson Genesis spec-
125.24 (Ar), 130.86 (5-C), 152.71 (4-C), 166.30 (C=NH).
MS (EI, 30 eV): m/z (%) = 96 (40), 123 (29), 150 (100) [M]+.
trometer, NMR spectra on a Bruker Avance 300 spectrometer and
Reaction of 8 with Methoxycarbonyl Isothiocyanate 9d in 1:2
Ratio Followed by Basic Hydrolysis
mass spectra on a Trio 1000 spectrometer equipped with a direct in-
let probe. 13C NMR spectra were also predicted using ACD/CNMR
Spectrum Generator. The thermal analysis was carried out on a
Netzsch STA 449 C instrument in an Al2O3 crucible at a heating rate
of 10 °C/min and at a flow rate of anhydrous synthetic air of 70 mL/
min. Melting points were determined on a Kofler hot stage and are
uncorrected.
Freshly distilled 8 (15.4 g, 0.12 mol) was added dropwise to a solu-
tion of 9d in anhydrous acetone (200 mL) prepared from NH4SCN
(36.0 g, 0.47 mol) and methyl chloroformate (40.6 g, 0.43 mol). The
reaction mixture was stirred in an ice bath until a pale solid precip-
itated. After filtration, the solid was washed with toluene and dried
in air to give the crude product (15.1 g).
Reaction of 2-Aminothiophenol (8) with Benzoyl Isothiocyanate
(9a) in 1:1 Ratio
The crude material obtained above (0.4 g) was added to 5% K2CO3
solution in 65% MeOH (25 mL) and, under ultrasound activation,
slowly disappeared (monitored by TLC). The solution was then
evaporated to dryness, H2O was added and the solid was extracted
with CH2Cl2. The organic layer was dried with anhydrous Na2SO4
and evaporated to dryness to give pure 5 (0.14 g).
Compound 8 (36.3 g, 0.29 mol) was added dropwise to a solution of
9a in anhydrous acetone (400 mL) prepared from NH4SCN (40.1 g,
0.53 mol) and benzoyl chloride (67.5 g, 0.48 mol). The reaction
mixture was stirred in an ice bath until a yellow solid precipitated.
After filtration, the solid was dissolved in MeOH, insoluble residues
were removed and the solution was evaporated to dryness to give
pure 2-benzoylaminobenzothiazole (5a).
2,2¢-Diaminodiphenyl Disulfide (10)
As 2-aminothiophenol 8 is quite sensitive to air oxygen, it was pu-
rified by a vacuum distillation (60–70 °C/1–2 mmHg) to give pure
10 as a yellow crystalline compound.
Yield: 39.6 g (54%); mp 188–190 °C (Lit.4 188 °C, Lit.5 189–
190 °C).
Mp 91–93 °C (Lit.7a 91–92 °C, Lit.7b 93 °C).
IR (KBr): 3170 (n, NH), 3057 (n, ArH), 1673 (n, C=O), 1599 (n,
CN), 1553 (d, NH), 1445, 1296, 1277, 753 (g, Ar), 702 (g, Ar) cm–1.
1H NMR (300 MHz, DMSO-d6): d = 7.23 (t, J = 7.4 Hz, 1 H, ArH),
7.38 (t, J = 7.4 Hz, 1 H, ArH), 7.49–7.61 (m, 3 H, ArH), 7.69 (d,
J = 7.9 Hz, 1 H, ArH), 7.90 (d, J = 7.6 Hz, 1 H, ArH), 8.15–8.17 (m,
2 H, ArH).
13C NMR (75 MHz, DMSO-d6): d = 119.55 (Ar), 121.24 (Ar),
122.47 (Ar), 125.43 (Ar), 128.15 (2 × Ar), 128.18 (2 × Ar), 131.71
(Ar), 131.86 (5-C), 134.28 (13-C), 148.84 (4-C), 161.88 (C=N),
167.36 (C=O).
IR (KBr): 3381 (n, NH2), 3064 (n, ArH), 1624 (n, CN), 1473, 1306,
1246, 1155, 752 (g, Ar), 700, 669 cm–1.
1H NMR (300 MHz, CDCl3): d = 4.35 (s, 2 H, NH2), 6.61 (t, J = 7.5
Hz, 1 H, ArH), 6.72 (d, J = 7.8 Hz, 1 H, ArH), 7.15–7.21 (m, 2 H,
ArH).
13C NMR (75 MHz, CDCl3): d = 115.37 (Ar), 118.34 (Ar), 118.87
(CS), 131.72 (Ar), 136.92 (Ar), 148.77 (CN).
MS (EI, 30 eV): m/z (%) = 80 (54), 124 (100), 248 (46) [M]+.
MS (EI, 30 eV): m/z (%) = 77 (74), 105 (100), 226 (64), 254 (72)
Reactions of 2,2¢-Diaminodiphenyl Disulfide (10) with 9a
Method A (Table 1, entry 1): Compound 10 (2.0 g, 8.1 mmol) was
added to a solution of 9a in anhydrous acetone (15 mL) prepared
from NH4SCN (2.4 g, 31.5 mmol) and benzoyl chloride (4.0 g, 28.2
mmol). The reaction mixture was stirred in an ice bath until yellow
crystals precipitated. After filtration, the crystals were dried in air to
give pure 5a (3.8 g, 93%).
[M]+.
Reaction of 8 with 9a in 1:2 Ratio Followed by Basic Hydrolysis
Freshly distilled 8 (5.0 g, 0.04 mol) was added dropwise to a solu-
tion of 9a in anhydrous acetone (66 mL) prepared from NH4SCN
(11.7 g, 0.15 mol) and benzoyl chloride (19.7 g, 0.14 mol). The re-
action mixture was stirred in an ice bath until a yellow solid precip-
itated. After filtration, the solid was dried in air to give the crude
product (10.5 g).
Method B: The same quantities of reagents as described above were
used. A solution of 9a was added dropwise to 10 dissolved in anhy-
drous acetone (15 mL) under continuous stirring at –20 to –30 °C.
The reaction mixture was then kept at –20 °C overnight. The precip-
itated pale solid was filtered off, thoroughly washed with acetone
and dried in air to give pure 2-benzoylaminobenzo-1,2,4-dithiazine
(6a).
The crude material obtained above (0.4 g) was added to 5% K2CO3
solution in 65% MeOH (10 mL). Under ultrasound activation, the
yellow suspension turned pale. The solid was filtered off and iden-
tified as 5a; the solution was treated with charcoal. After filtration,
H2O was added, MeOH was evaporated and other crystals were pre-
cipitated by AcOH. These were identical to 2-aminobenzothiazole
(5) obtained by a basic hydrolysis of 5a as follows:
Yield: 3.7–4.3 g (80–93%); mp 147–150 °C.
IR (KBr): 3411, 1674 (n, C=O), 1574 (n, CN), 1533 (d, NH), 1333,
1252, 1147, 756 (g, Ar), 704 (g, Ar) cm–1.
1H NMR (300 MHz, DMSO-d6): d = 7.31–7.36 (m, 1 H, ArH),
7.44–7.49 (m, 1 H, ArH), 7.54–7.59 (m, 2 H, ArH), 7.63–7.68 (m,
1 H, ArH), 7.79 (d, J = 7.9 Hz, 1 H, ArH), 8.00 (d, J = 7.6 Hz, 1 H,
ArH), 8.12–8.15 (m, 2 H, ArH).
5a (0.3 g, 1.2 mmol) was boiled with KOH (0.1 g, 1.3 mmol) in
EtOH (15 mL) until only one compound was detected in the reac-
tion mixture (TLC). H2O was then added and EtOH was evaporated
to give pure 5, which was filtered off and dried at 40 °C under re-
duced pressure.
Yield: 0.1 g (56%); mp 126–129 °C (Lit.6a 126–128 °C, Lit.6b
129 °C).
13C NMR (75 MHz, DMSO-d6): d = 120.09 (Ar), 121.50 (Ar),
123.51 (Ar), 125.98 (Ar), 128.09 (2 × Ar), 128.43 (2 × Ar), 131.24
Synthesis 2008, No. 8, 1297–1305 © Thieme Stuttgart · New York

1304
D. Fajkusova, P. Pazdera
PAPER
(6-C), 131.74 (14-C), 132.66 (Ar), 147.97 (5-C), 158.73 (C=N),
165.91 (C=O).
d at r.t., a solid precipitated; only starting compounds were detected
(TLC) in the reaction mixture. After filtration, the solid was washed
with toluene to give pure 5b (1.5 g, 82%).
Method C: A solution of 9a in anhydrous acetone (10 mL), prepared
from NH4SCN (1.2 g, 15.8 mmol) and benzoyl chloride (2.0 g, 14.1
mmol), was evaporated to dryness, partially dissolved in CHCl3 (30
mL) and added dropwise to a solution of 10 (1.0 g, 4.0 mmol) in
CHCl3 (15 mL). The reaction mixture was immediately divided into
two parts. One was allowed to react at r.t.; no heat evolution was ob-
served. The second was briefly boiled. 6a and 5a, respectively, were
obtained.
Reactions of 2,2¢-Diaminodiphenyl Disulfide (10) with Acetyl
Isothiocyanate (9c)
Method A (Table 1, entry 10): A solution of 10 (0.3 g, 1.2 mmol) in
anhydrous acetone (5 mL) was added to a solution of 9c in anhy-
drous acetone (5 mL) prepared from NH4SCN (0.35 g, 4.6 mmol)
and acetyl chloride (0.3 g, 4.2 mmol). The reaction mixture was
stirred at r.t. and a pale solid precipitated from the brown solution
within 24 h. The solid was filtered off and dried in air to give pure
2-acetylaminobenzothiazole (5c).
Method D (Table 1, entry 2): In contrast to the procedure described
in Method C above, the solution of 10 was added dropwise to a sus-
pension of 9a in CHCl3 (15 mL). The reaction mixture was stirred
at r.t. until a yellow solid precipitated. After filtration, the solid was
dried in air to give pure 5a (0.82 g, 40%).
Yield: 0.1 g (22%); mp 185–189 °C (Lit.9a 186 °C, Lit.9b 187–
189 °C).
IR (KBr): 3062 (n, ArH), 2960 (n, CH3), 2855, 1695 (n, C=O), 1603
(n, CN), 1548 (d, NH), 1446, 1369, 1274, 758 (g, Ar) cm–1.
1H NMR (300 MHz, CDCl3): d = 2.31 (s, 3 H, CH3), 7.35 (t, J = 7.4
Hz, 1 H, ArH), 7.46 (t, J = 7.4 Hz, 1 H, ArH), 7.77 (d, J = 7.9 Hz,
1 H, ArH), 7.85 (d, J = 7.9 Hz, 1 H, ArH).
13C NMR (75 MHz, CDCl3): d = 23.69 (CH3), 120.38 (Ar), 121.90
(Ar), 124.33 (Ar), 126.68 (Ar), 131.92 (5-C), 147.48 (4-C), 160.32
(C=N), 169.11 (C=O).
Reactions of 2,2¢-Diaminodiphenyl Disulfide (10) with Phenyl
Isothiocyanate (9b)
Method A (Table 1, entry 3): Compound 9b (5.4 g, 40.3 mmol) was
added dropwise to a solution of 10 (5.0 g, 20.2 mmol) in acetone (30
mL). The reaction mixture was stirred at r.t. until a colorless solid
precipitated. After filtration, the solid was washed with acetone and
dried in air to give pure 2-phenylaminobenzothiazole (5b).
Yield: 3.1 g (34%); mp 161–164 °C (Lit.8a 161 °C, Lit.8b 163 °C).
MS (EI, 30 eV): m/z (%) = 43 (68), 150 (100), 192 (56) [M]+.
IR (KBr): 3190 (n, NH), 3057 (n, ArH), 1626 (n, CN), 1569 (d, NH),
1450, 1273, 1250, 1225, 746 (g, Ar), 717 (g, Ar) cm–1.
1H NMR (300 MHz, DMSO-d6): d = 7.02 (t, J = 7.4 Hz, 1 H, ArH),
7.15 (t, J = 7.6 Hz, 1 H, ArH), 7.30–7.39 (m, 3 H, ArH), 7.60 (d,
J = 8.0 Hz, 1 H, ArH), 7.79 (d, J = 7.7 Hz, 3 H, ArH), 10.44 (s, 1 H,
NH).
13C NMR (75 MHz, DMSO-d6): d = 117.76 (2 × Ar), 119.14 (Ar),
120.96 (Ar), 122.01 (Ar), 122.21 (Ar), 125.80 (Ar), 128.93 (2 × Ar),
129.93 (5-C), 140.59 (11-C), 152.05 (4-C), 161.55 (C=N).
Method B (Table 1, entry 11): A solution of 9c in anhydrous ace-
tone (10 mL), prepared from NH4SCN (1.2 g, 15.8 mmol) and
acetyl chloride (1.1 g, 14.1 mmol), was evaporated to dryness. The
residue was partially dissolved in CHCl3 (10 mL) and added drop-
wise to a solution of 10 (1.0 g, 4.0 mmol) in CHCl3 (15 mL). The
resulting suspension gradually dissolved under stirring at r.t. Within
48 h a solid crystallized (H2S evolution was observed). The solid
was removed and the solution was partially evaporated. The precip-
itated crystals were filtered off and dried in air to give pure 5c (0.9
g, 59%).
MS (EI, 30 eV): m/z (%) = 96 (18), 225 (100) [M – H]+, 226 (71)
[M]+, 227 (20) [M + H]+.
Reactions of 2,2¢-Diaminodiphenyl Disulfide (10) with
Methoxycarbonyl Isothiocyanate (9d)
Method B (Table 1, entry 4): Compound 10 (1.5 g, 6.1 mmol) in
acetone (15 mL) and 9b (3.3 g, 24.2 mmol) were used in the same
procedure as described in Method A above to give pure 5b (1.2 g,
44%).
Method A (Table 1, entry 12): A solution of 10 (1.8 g, 7.3 mmol) in
anhydrous acetone (10 mL) was added dropwise to a solution of 9d
in anhydrous acetone (15 mL), prepared from NH4SCN (2.0 g, 26.6
mmol) and methyl chloroformate (2.3 g, 24.2 mmol), under stirring
in an ice bath. The initially yellow solution turned gradually dark
and a solid slowly precipitated. The solid was filtered off and dis-
solved in acetone. An insoluble colorless portion was removed and
identified as 2,2¢-di[(methoxycarbonylamino)carbonothioyl]amino-
diphenyl disulfide (11d; 0.6 g, 17%). The acetone solution was par-
tially evaporated; another colorless solid was filtered off and dried
in air to give pure 2-methoxycarbonylaminobenzothiazole (5d;
0.3 g, 10%).
Method C (Table 1, entry 5): Using the same quantities of 10 and 9b
as in Method A, a suspension in MeOH (60 mL) was prepared. Un-
der stirring at r.t., Et3N (0.7 g, 7.2 mmol) was added and, since no
heat evolved, the reaction mixture was boiled for 2 h. When allowed
to cool down, a solid precipitated within several hours. Pure 5b (4.5
g, 49%) was obtained by filtration.
Method D (Table 1, entry 6): Similarly to Method C, 10 (1.5 g, 6.1
mmol) was boiled with 9b (1.6 g, 12.1 mmol) in EtOH (10 mL) for
1 h. The solid precipitated by cooling was filtered off, washed with
EtOH and dried in air to give pure 5b (1.5 g, 55%).
2,2¢-Di[(methoxycarbonylamino)carbonothioyl]aminodiphenyl
Disulfide (11d)
Mp 172–173 °C.
Method E (Table 1, entry 7): Compounds 10 (1.0 g, 4.0 mmol) and
9b (1.1 g, 8.1 mmol) were dissolved in CHCl3 (15 mL). Since only
starting materials were detected (TLC) in the reaction mixture after
2 d at r.t., Et3N (0.8 g, 8.1 mmol) was added. The precipitated solid
was filtered off and washed with CHCl3 to give pure 5b (0.4 g,
22%).
IR (KBr): 3044 (n, ArH), 1728 (n, C=O), 1577 (n, CN), 1530 (d,
NH), 1405, 1342, 1238, 1175, 1038, 768 (g, Ar) cm–1.
1H NMR (300 MHz, DMSO-d6): d = 3.88 (s, 3 H, CH3), 7.21 (t,
J = 7.4 Hz, 1 H, ArH), 7.38 (t, J = 7.4 Hz, 1 H, ArH), 7.53 (d,
J = 7.9 Hz, 1 H, ArH), 8.04 (d, J = 8.3 Hz, 1 H, ArH), 8.11 (s, 1 H,
NH), 11.55 (s, 1 H, NH).
13C NMR (75 MHz, DMSO-d6): d = 53.85 (CH3), 126.59 (Ar),
127.84 (Ar), 129.77 (Ar), 131.37 (CS), 133.83 (Ar), 138.53 (CN),
153.02 (C=O), 178.49 (C=S).
Method F (Table 1, entry 8): The procedure described in Method E
was repeated without the addition of Et3N. After 4 d, a solid precip-
itated (H2S evolution was observed). After filtration, the solution
was partially evaporated and the second crop crystallized. Both
were washed with CHCl3 to give pure 5b (1.2 g, 66%).
Method G (Table 1, entry 9): The same quantities of 10 and 9b as
used in Method E were allowed to react in toluene (30 mL). After 5
Synthesis 2008, No. 8, 1297–1305 © Thieme Stuttgart · New York

PAPER
Synthesis of Benzo-1,2,4-dithiazines
1305
2-Methoxycarbonylaminobenzothiazole (5d)
MS (EI, 30 eV): m/z (%) = 69 (31), 82 (24), 96 (28), 108 (35), 135
Mp 206–208 °C (sublimation) (Lit.10 210 °C).
(66), 163 (51) [M – H]+, 164 (100) [M]+, 165 (31) [M + H]+.
IR (KBr): 2852 (n, CH3), 1730 (n, C=O), 1610 (n, CN), 1572 (d,
NH), 1452, 1302, 1279, 1250, 760 (g, Ar) cm–1.
1H NMR (300 MHz, CDCl3): d = 3.97 (s, 3 H, CH3), 7.33 (t, J = 7.1
Hz, 1 H, ArH), 7.47 (t, J = 7.3 Hz, 1 H, ArH), 7.82 (d, J = 7.9 Hz,
1 H, ArH), 7.89 (d, J = 7.9 Hz, 1 H, ArH).
13C NMR (75 MHz, CDCl3): d = 53.66 (CH3), 120.48 (Ar), 121.55
(Ar), 124.13 (Ar), 126.55 (Ar), 131.44 (5-C), 147.89 (4-C), 154.27
(C=N), 161.72 (C=O).
Method B (Table 1, entry 15): The same quantities of 10 and 9e as
used in Method A were allowed to react in CHCl3 (30 mL). After
several days at r.t., the solution was partially evaporated; precipitat-
ed crystals were filtered off and the solution was further evaporated
to crystallize another solid. Both were washed with CHCl3 and dried
in air to give pure 5e (1.4 g, 35%) and sulfur (0.2 g).
Acknowledgment
MS (EI, 30 eV): m/z (%) = 59 (93), 64 (38), 77 (26), 96 (24), 105
(100), 108 (42), 122 (36), 136 (74), 149 (54), 176 (58), 208 (86)
[M]+.
This work was supported by the Grant Agency of the Czech
Republic (Grant No. 203/01/1333).
Method B (Table 1, entry 13): A solution of 9d in anhydrous ace-
tone (10 mL), prepared from NH4SCN (1.2 g, 15.8 mmol) and meth-
yl chloroformate (1.3 g, 14.1 mmol), was evaporated to dryness.
The residue was partially dissolved in CHCl3 (10 mL) and added
dropwise to a solution of 10 (1.0 g, 4.0 mmol) in CHCl3 (15 mL).
The resulting suspension gradually dissolved under stirring at r.t. A
solid precipitated within 4 d (H2S evolution was observed) was fil-
tered off, washed with CHCl3 and dried in air to give 5d (0.8 g,
48%) containing unreacted isothiocyanate.
References
(1) Caldwell, J. B.; Milligan, B.; Swan, J. M. J. Chem. Soc.
1963, 2097.
(2) Milligan, B.; Swan, J. M. J. Chem. Soc. 1962, 2172.
(3) Heller, G.; Quast, J.; Blanc, K. J. Prakt. Chem. 1924, 108,
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(4) Uher, M.; Berkeš, D.; Leško, J.; Floch, Ĺ. Collect. Czech.
Chem. Commun. 1983, 48, 1651.
(5) Donche, A.; Pfister, A.; Arretz, E. DE 2133649, 1972;
Reactions of 2,2¢-Diaminodiphenyl Disulfide (10) with Methyl
Isothiocyanate (9e)
Chem. Abstr. 1972, 76, 99647.
(6) (a) Gorokhovskaya, V. I. J. Gen. Chem. USSR 1962, 32,
3781. (b) Ried, W.; Schmidt, E. Justus Liebigs Ann. Chem.
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1974, 316, 154. (b) Kost, A. N.; Lebedenko, N. Y.;
Sviridova, L. A.; Torocheschnikov, V. N. Chem. Heterocycl.
Compd. 1978, 14, 380.
Method A (Table 1, entry 14): A suspension of 10 (3.0 g, 12.1
mmol) in EtOH (30 mL) was treated with solid 9e (1.8 g, 24.2
mmol). The reaction mixture was stirred at r.t.; a clear solution was
formed within 48 h. Afterwards, sulfur (0.3 g) precipitated and was
removed. The solution was partially evaporated; another solid crys-
tallized and was filtered off, washed with EtOH and dried in air to
give pure 2-methylaminobenzothiazole (5e).
Yield: 3.3 g (83%); mp 141–142 °C (Lit.11a 140–141 °C, Lit.11b
142–143 °C).
(9) (a) Hunter, R. F. J. Chem. Soc. 1926, 1385. (b) Sycheva, T.
P.; Kiseleva, I. D.; Shchukina, M. N. Chem. Heterocycl.
Compd. 1970, 6, 849.
(10) Janiak, S. DE 1953149, 1970; Chem. Abstr. 1970, 73, 25446.
(11) (a) Jordan, A. D.; Luo, C.; Reitz, A. J. Org. Chem. 2003, 68,
8693. (b) D’Amico, J. J.; Tung, C. C.; Dahl, W. E.
Phosphorus, Sulfur Silicon Relat. Elem. 1979, 7, 191.
IR (KBr): 3061 (n, ArH), 2867 (n, CH3), 1606 (n, CN), 1572 (d,
NH), 1450, 1280, 1254, 1224, 752 (g, Ar) cm–1.
1H NMR (300 MHz, CDCl3): d = 3.10 (s, 3 H, CH3), 7.09 (t, J = 7.6
Hz, 1 H, ArH), 7.31 (t, J = 7.6 Hz, 1 H, ArH), 7.53 (d, J = 7.9 Hz,
1 H, ArH), 7.61 (d, J = 7.9 Hz, 1 H, ArH).
13C NMR (75 MHz, CDCl3): d = 31.84 (CH3), 118.61 (Ar), 121.04
(Ar), 121.42 (Ar), 126.14 (Ar), 130.40 (5-C), 152.55 (4-C), 169.33
(C=N).
Synthesis 2008, No. 8, 1297–1305 © Thieme Stuttgart · New York