1,2-Dihydro-2-thioxo-4H-3,1-benzothiazin-4-one: formation from carbon disulfide and isatoic anhydride

Article abstract of DOI:10.1016/j.tetlet.2010.03.042

The reaction of isatoic anhydride (1) with carbon disulfide at room temperature unexpectedly afforded 1,2-dihydro-2-thioxo-4H-3,1-benzothiazin-4-one (2). The use of ¹³C-labeled carbon disulfide elucidated that CS₂ was entirely incorp

Full text of DOI:10.1016/j.tetlet.2010.03.042

Tetrahedron Letters 51 (2010) 2727–2729
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Tetrahedron Letters
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1,2-Dihydro-2-thioxo-4H-3,1-benzothiazin-4-one: formation from carbon
disulfide and isatoic anhydride
Philipp A. Ottersbach a, Hans-Georg Häcker a, Paul W. Elsinghorst a, Gregor Schnakenburg b,
Michael Gütschow a,
*
a Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, 53121 Bonn, Germany
b Institute of Inorganic Chemistry, University of Bonn, Gerhard-Domagk-Strasse 1, 53121 Bonn, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
The reaction of isatoic anhydride (1) with carbon disulfide at room temperature unexpectedly afforded
1,2-dihydro-2-thioxo-4H-3,1-benzothiazin-4-one (2). The use of 13C-labeled carbon disulfide elucidated
that CS2 was entirely incorporated into the product.
Received 3 December 2009
Revised 9 March 2010
Accepted 12 March 2010
Available online 17 March 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Carbon disulfide
Isatoic anhydride
3,1-Benzothiazin-4-ones
Representatives of 4H-3,1-benzoxazin-4-ones have attracted
much attention as bioactive heterocycles. For example, 2-amino-,
2-alkoxy-, and 2-alkylthio-substituted 4H-3,1-benzoxazin-4-ones
are potent inhibitors of serine hydrolases acting through the for-
mation of covalent acyl-enzyme intermediates.1 Corresponding
4H-3,1-benzothiazin-4-ones, bearing sulfur in place of the ring
oxygen, are hitherto less investigated.2 Recently, we reported on
the inhibitory activity of a series of 4H-3,1-benzothiazin-4-ones
against a panel of proteases and esterases and identified 2-methyl-
thio-4H-3,1-benzothiazin-4-one (3) as a selective inhibitor of hu-
man leukocyte elastase.3
As reported, the formation of 2-methylthio-4H-3,1-benzothia-
zin-4-one (3) was achieved by reacting anthranilic acid with car-
bon disulfide and methyl iodide to yield the dithiocarbamate 4,
which was subsequently cyclized by the use of acetic anhydride
(Scheme 1).3,4 The parent compound of this class, 1,2-dihydro-2-
thioxo-4H-3,1-benzothiazin-4-one (2), was recently described
using a similar procedure, but was isolated only in poor yield.5
Here we report on an improved one-step synthesis of 1,2-dihy-
dro-2-thioxo-4H-3,1-benzothiazin-4-one (2) from isatoic anhy-
dride (1) and carbon disulfide. We investigated the intriguing
reaction with 13C-labeled carbon disulfide. Further structural evi-
dence was obtained by a derivatization reaction and X-ray crystal-
lographic analysis of 2. To the best of our knowledge, the reaction
Scheme 1. Reagents and conditions: (a) CS2 (15 equiv), Et3N, 1,4-dioxane, rt, 120 h,
45%;8 (b) Et3N, MeI, 1,4-dioxane, 10 °C to rt, 24 h, 83%;9 (c) Ac2O, reflux, 30 min,
91%.3
of carbon disulfide with isatoic anhydride (1) has not been de-
scribed before.6,7
The reaction was performed at room temperature in 1,4-diox-
ane in the presence of 2 equiv of triethylamine and excess of car-
bon disulfide. The procedure afforded a product with a molecular
weight of 195 g molÀ1 as detected by mass spectrometry.8 In com-
parison with isatoic anhydride (1), the molecular mass differed by
32 g molÀ1 indicating an unexpected twofold oxygen–sulfur ex-
change. Only very few cases of thionation reactions with carbon
disulfide have been reported until today.10
* Corresponding author. Tel.: +49 228 732317; fax: +49 228 732567.
E-mail address: guetschow@uni-bonn.de (M. Gütschow).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.03.042

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P. A. Ottersbach et al. / Tetrahedron Letters 51 (2010) 2727–2729
Thus, in first instance we assumed a twofold, carbon disulfide-
promoted cycloaddition–elimination at the carbonyl functions in
positions 2 and 4 of isatoic anhydride (1) to give the 2,4-dithio ana-
log 5 (Scheme 2).
For structure verification, the product of this reaction was alkyl-
ated with methyl iodide, to give, however, the unexpected, though
known3 compound 2-methylthio-4H-3,1-benzothiazin-4-one (3).
This led us to the hypothesis that not the benzoxazine 5 was iso-
lated after the reaction of isatoic anhydride (1) with carbon disul-
fide, but the isomeric benzothiazine 2 (Scheme 1). The structure of
2 was confirmed by X-ray crystallographic analysis (see Supple-
mentary data, S17, S18). A preliminary assumption to explain the
formation of the benzothiazine 2 was a Dimroth rearrangement
of 5 as a consequence of thermal exposure through solvent evapo-
ration during workup (Scheme 2). To further elucidate the mecha-
nism of the oxygen–sulfur exchange, we repeated the conversion
with 13C-labeled carbon disulfide and subjected the product to
13C NMR analysis.
If thionation proceeded according to Scheme 2, the product
would not be 13C-labeled, because only sulfur would be donated
by carbon disulfide. Unexpectedly, the 13C NMR spectrum showed
a strong signal at 188 ppm demonstrating that the 13CS2 carbon
was incorporated into isatoic anhydride (1) (Fig. 1; assignment to
the thiocarbonyl carbon at position 2 is supported by HMQC and
HMBC spectra; see Supplementary data, S15, S16). Thus, carbon
disulfide did not act as a thionation reagent and the reaction affor-
ded the labeled [2-13C]-1,2-dihydro-2-thioxo-4H-3,1-benzothia-
zin-4-one (6) (Fig. 2).
Figure 2. Products isolated after reaction with carbon disulfide.
Furthermore, it is known that isatoic anhydrides can form imi-
noketene intermediates by thermal loss of carbon dioxide.11,12
These heterodienes can react with dienophiles such as
iso(thio)cyanates in a Diels–Alder type reaction to yield the corre-
sponding quinazolines (see Supplementary data, S8).13 One might
assume that 1 similarly reacts with carbon disulfide in a [4+2]
cycloaddition to give 2.
To prove this hypothesis, the denoted iminoketene was gener-
ated according to a literature procedure14 and reacted with carbon
disulfide. As compound 2 was not obtained, the iminoketene
mechanism cannot be applied to the reaction of isatoic anhydride
(1) with carbon disulfide. This conclusion is corroborated by the
finding that N-methylisatoic anhydride (7) did not react with car-
bon disulfide (see below), though iminoketene formation from 7
can be anticipated.12
With respect to the aforementioned results, another mechanism
can be postulated (Scheme 3). In a first step, the nitrogen of isatoic
anhydride (1) is deprotonated by triethylamine and attacks the
electrophilic carbon of CS2. Then, the resulting dithiocarbamate
undergoes a subsequent intermolecular nucleophilic attack on
the carbonyl carbon at position 4 of another isatoic anhydride mol-
ecule. Finally, 1,2-dihydro-2-thioxo-4H-3,1-benzothiazin-4-one
(2) is formed by release of isatoic anhydride (1) and CO2.
There are several literature reports on the activation of carbon
disulfide by basic catalysts15 or salts of NH-acidic compounds7
and subsequent reactions of the sulfur-based nucleophiles with
electrophiles, for example, oxiranes.15
Obviously, the acidic NH moiety of 1 is necessary for the reac-
tion to proceed. To provide further evidence for this prerequisite,
N-methylisatoic anhydride (7) was treated in place of 1 under
the same reaction conditions and, indeed, no conversion was ob-
served. Furthermore, the less NH-acidic phthalimide (8) and isatine
(9) were reacted in the same way and, again, only educts were
recovered from the reaction mixtures. Thus, we conclude that the
Scheme 2. Initially assumed thionation mechanism for the reaction of isatoic
anhydride (1) with carbon disulfide.
200
160
120
80
40
0
Figure 1. 13C NMR spectra of 1,2-dihydro-2-thioxo-4H-3,1-benzothiazin-4-one (2)
(bottom) and the 13C-labeled analog 6 (top).
Scheme 3. Putative mechanism for the formation of 1,2-dihydro-2-thioxo-4H-3,1-
benzothiazin-4-one (2).

P. A. Ottersbach et al. / Tetrahedron Letters 51 (2010) 2727–2729
2729
4. Matsuoka, M.; Segawa, J.; Makita, Y.; Ohmachi, S.; Kashima, T.; Nakamura,
K. I.; Hattori, M.; Kitano, M.; Kise, M. J. Heterocycl. Chem. 1997, 34, 1773–
1779.
5. Lin, L.-R.; Fang, W.; Huang, R.-B.; Zheng, L.-S. Chin. J. Struct. Chem. 2008, 27,
1059–1064.
6. (a) Copolla, G. M. Synthesis 1980, 505–535; (b) Kappe, T.; Stadlbauer, W. Adv.
Heterocycl. Chem. 1981, 28, 127–182; (c) Brouillette, Y.; Martinez, J.; Lisowski,
V. Eur. J. Org. Chem. 2009, 3487–3503.
NH acidity of the educt is a precondition for the conversion and as-
sume that carbon dioxide elimination is its driving force.
Alternative reaction conditions for the conversion of 1 to 2, that
is, microwave irradiation or elevated temperature, did not improve
the yield (see Supplementary data, S1, S2). However, as indicated
by TLC, more by-products were produced in these cases. Addition-
ally, 5-methyl- and 5-chloroisatoic anhydride were reacted with
carbon disulfide applying the abovementioned reaction conditions
(1,4-dioxane, rt). Indeed, the expected 1,2-dihydro-2-thioxo-4H-
3,1-benzothiazin-4-ones were formed and recovered in traces
(see Supplementary data, S4, S5).
In summary, we have introduced a new and unexpected syn-
thetic entry to 1,2-dihydro-2-thioxo-4H-3,1-benzothiazin-4-one
(2) from isatoic anhydride (1) and carbon disulfide. It was demon-
strated that carbon disulfide is entirely incorporated into the het-
erocyclic product and does not act as a thionation reagent. The
scope and limitations of this reaction are still under investigation
in our laboratories.
7. Rudorf, W.-D. J. Sulfur Chem. 2007, 28, 295–339.
8. Preparation of 1,2-dihydro-2-thioxo-4H-3,1-benzothiazin-4-one (2): To
a
suspension of isatoic anhydride (1; 1.63 g, 10 mmol) and Et3N (2.02 g,
20 mmol) in 1,4-dioxane (70 mL), CS2 (11.42 g, 150 mmol) was added. The
mixture was stirred for 120 h at room temperature. The meanwhile formed
orange-brown solution was evaporated to dryness and the residue was taken
up in EtOAc (400 mL) and washed with HCl (0.2 M, 3 Â 150 mL), H2O
(1 Â 150 mL), and brine (1 Â 150 mL). The organic layer was dried over
Na2SO4, and the solvent was removed under reduced pressure to obtain a
brownish crude product that was subjected to column chromatography
(petroleum ether/EtOAc/AcOH 80:20:1) to obtain a yellow solid, yield 0.88 g
(45%), mp 217–218 °C (lit.5 270–271 °C); 1H NMR (500 MHz, DMSO-d6): d 7.39
(ddd, J = 1.3, 7.3, 7.6 Hz, 1H, H-6), 7.56 (dd, J = 1.0, 8.2 Hz, 1H, H-8), 7.82 (ddd,
J = 1.6, 7.3, 8.2 Hz, 1H, H-7), 7.90 (dd, J = 1.6, 7.9 Hz, 1H, H-5), 13.71 (br s, 1H,
NH); 13C NMR (125 MHz, DMSO-d6): d 118.97 (C-4a), 119.74 (C-8), 125.52,
125.79 (C-5, C-6), 137.07 (C-7), 142.21 (C-8a), 183.86 (C-4), 188.20 (C-2); MS
ESI+ (m/z, ion, rel. intensity %): 196.0 ([C8H6NOS2]+, 43), 162.0 ([C8H4NOS]+,
100); Anal. Calcd for C8H5NOS2: C, 49.21; H, 2.58; N, 7.17. Found: C, 49.61; H,
2.91; N, 7.25.
Acknowledgments
9. Preparation of 2-methylthio-4H-3,1-benzothiazin-4-one (3): 1,2-Dihydro-2-
thioxo-4H-3,1-benzothiazin-4-one (2; 0.74 g, 3.8 mmol) and Et3N (0.38 g,
3.8 mmol) were dissolved in dry 1,4-dioxane (20 mL). The orange solution
was cooled to 10 °C with a water bath, followed by the dropwise addition of
methyl iodide (0.54 g, 3.8 mmol) in dry 1,4-dioxane (10 mL). The reaction
mixture was allowed to warm to room temperature and after 30 min a white
precipitate was formed. After additional 23.5 h, the solvent was evaporated and
the residue was taken up in EtOAc (100 mL) and washed with HCl (0.2 M,
3 Â 100 mL), H2O (1 Â 100 mL), and brine (1 Â 100 mL). The organic layer was
dried over Na2SO4 and the solvent was removed under reduced pressure to
yield a brown oil. Purification by column chromatography (petroleum ether/
EtOAc/AcOH 80:20:1) provided a yellow solid, yield 0.66 g (83%), mp 53–55 °C
(lit.3 54–56 °C); 1H NMR (500 MHz, DMSO-d6): d 2.72 (s, 3H, SCH3), 7.57 (ddd,
J = 1.3, 7.3, 7.9 Hz, 1H, H-6), 7.71 (dd, J = 1.3, 8.2 Hz, 1H, H-8), 7.91 (ddd, J = 1.6,
7.3, 8.1 Hz, 1H, H-7), 8.05 (dd, J = 1.6, 8.2 Hz, 1H, H-5); 13C NMR (125 MHz,
DMSO-d6): d 13.91 (SCH3), 118.62 (C-4a), 124.66 (C-5), 128.31 (C-6), 129.84 (C-
8), 136.81 (C-7), 147.47 (C-8a), 163.44 (C-2), 182.30 (C-4); MS ESI+ (m/z, ion,
rel. intensity %): 264.0 ([C9H7NOS2 + Na+CH3OH], 15), 232.0 ([C9H7NOS2 + Na+],
15), 210.0 ([C9H8NOS2]+, 7), 162.0 ([C8H4NOS]+, 100); Anal. Calcd for C9H7NOS2:
C, 51.65; H, 3.37; N, 6.69. Found: C, 51.78; H, 3.57; N, 6.71.
This work was supported by the German Research Society
(Graduate College 804). G.S. thanks Professor A.C. Filippou for
support.
Supplementary data
Supplementary data (crystallographic data, HMQC and HMBC
spectra of 2, 1H NMR and 13C NMR data of 2, 3 and of the 13C-la-
beled analog 6, alternative synthetic procedures for 2, preparation
of 5-methylisatoic anhydride, as well as reaction of 5-methyl- and
5-chloroisatoic anhydride with carbon disulfide, and experiments
regarding the iminoketene mechanism) associated with this article
can be found, in the online version, at doi:10.1016/j.tetlet.
2010.03.042.
10. (a) Zong, Z.-M.; Peng, Y.-L.; Liu, Z.-G.; Zhou, S.-L.; Wu, L.; Wang, X.-H.; Wei, X.-
Y.; Lee, C. W. Korean J. Chem. Eng. 2003, 20, 235–238; (b) Fu, X.; Zhang, C.;
Zhang, D.; Yuan, S. Chem. Phys. Lett. 2006, 420, 162–165; (c) Polshettiwar, V.;
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Smalley, R. K.; Suschitzky, H.; Tanner, E. M. Tetrahedron Lett. 1966, 7, 3465–
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