Direct formation of ring-fused 1,3-thiazine-2,4-dithiones from aromatic o-amino carboxylic acids: Observation of a carbon disulfide mediated thionation

Article abstract of DOI:10.1021/ol101471g

A facile synthesis of 2H-3,1-benzothiazine-2,4(1H)-dithiones (trithioisatoic anhydrides) or 2H-naphtho[2,3-d][1,3]thiazine-2,4(1H)-dithione solely from anthranilic acids or 3-amino-2-naphthoic acid and carbon disulfide, performed at room temperature in 1,4-dioxane in the presence of Et₃N, is reported. Corresponding 2-alkylsulfanyl derivatives were obtained in one-pot reactions under the same conditions after addition of alkyl halides. The mechanism of the thiazine cyclization was investigated using ¹³C-labeled carbon disulfide to reveal that carbon disulfide was incorporated into the heterocycle and additionally acted as a thionation reagent.

Full text of DOI:10.1021/ol101471g

ORGANIC
LETTERS
2010
Vol. 12, No. 16
3662-3665
Direct Formation of Ring-Fused
1,3-Thiazine-2,4-dithiones from Aromatic
o-Amino Carboxylic Acids: Observation
of a Carbon Disulfide Mediated
Thionation
Philipp A. Ottersbach, Paul W. Elsinghorst,† Hans-Georg Ha¨cker, and
Michael Gu¨tschow*
Pharmaceutical Institute, Pharmaceutical Chemistry I, UniVersity of Bonn, An der
Immenburg 4, D-53121 Bonn, Germany
guetschow@uni-bonn.de
Received June 25, 2010
ABSTRACT
A facile synthesis of 2H-3,1-benzothiazine-2,4(1H)-dithiones (trithioisatoic anhydrides) or 2H-naphtho[2,3-d][1,3]thiazine-2,4(1H)-dithione solely
from anthranilic acids or 3-amino-2-naphthoic acid and carbon disulfide, performed at room temperature in 1,4-dioxane in the presence of
Et3N, is reported. Corresponding 2-alkylsulfanyl derivatives were obtained in one-pot reactions under the same conditions after addition of
alkyl halides. The mechanism of the thiazine cyclization was investigated using 13C-labeled carbon disulfide to reveal that carbon disulfide
was incorporated into the heterocycle and additionally acted as a thionation reagent.
Thionation, the conversion of a carbonyl to a thiocarbonyl
group, is a commonly used procedure for the preparation of
organosulfur compounds that are valued for their rich and
varied chemistry, as well as many important biological
activities.1,2 Usually, thionation reactions are performed with
phosphorus pentasulfide1,3 or Lawesson’s reagent.4 Elemental
sulfur has also been employed for this purpose,1,5 and novel
thionation protocols have been discovered to overcome
(3) Curphey, T. J. J. Org. Chem. 2002, 67, 6461
.
(4) For reviews on the use of Lawesson’s reagent, see: (a) Jesberger,
M.; Davis, T. P.; Barner, L. Synthesis 2003, 1929. (b) Ozturk, T.; Ertas,
E.; Mert, O. Chem. ReV. 2007, 107, 5210.
† Present address: Central Institute of the Bundeswehr Medical Service
Munich, Ingolsta¨dter Landstrasse 102, D-85748 Garching, Germany.
(1) For reviews on thionation reactions, see: (a) Polshettiwar, V.;
Kaushik, M. P. J. Sulfur Chem. 2006, 27, 353. (b) Brillon, D. Sulfur Rep.
(5) For recent examples, see: (a) O-Yang, C.; Rotstein, D. M.; Labadie,
S. S.; Walker, K. A. M. Synlett 1995, 655. (b) Janosik, T.; Bergman, J.;
Stansland, B.; Stålhandske, C. J. Chem. Soc., Perkin Trans. 1 2002, 330.
1992, 12, 297
.
(2) Zang, Y.; Munday, R. Mol. Cancer Ther. 2008, 7, 3470
.
(c) Shibahara, F.; Sugiura, R.; Murai, T. Org. Lett. 2009, 11, 3064.
10.1021/ol101471g  2010 American Chemical Society
Published on Web 07/28/2010

disadvantages of the common thionation reagents.3,6 Herein,
we report that carbon disulfide unexpectedly facilitates a
carbonyl oxygen-sulfur exchange at room temperature. A
convenient one-pot procedure to directly form trithioisatoic
anhydride derivatives from commercially available aromatic
o-amino carboxylic acids and carbon disulfide in moderate
to excellent yields is presented. The mechanism of the 1,3-
thiazine-2,4-dithione formation has been elucidated using
13C-labeled carbon disulfide.
Anthranilic acid (3) can be transformed into alkylated
dithiocarbamates 1 by the reaction with carbon disulfide and
alkyl halides (Scheme 1). In a second, separate step,
compounds 1 can undergo cyclocondensation in refluxing
acetic anhydride to yield 2-alkylsulfanyl-4H-3,1-benzothi-
azin-4-ones 2 as colorless or yellow compounds.7
(R ) Me) bearing a sulfur in place of an oxygen at C-4 was
formed, and the structure was assigned as 2-methylsulfanyl-
4H-3,1-benzothiazine-4-thione (11, Table 1). The organo-
sulfur compound 11 is a derivative of trithioisatoic anhydride.
The parent compound 7, exhibiting a benzo-condensed cyclic
NH-C(dS)-S-C(dS) moiety, is shown in Table 1.9,10
Table 1. Synthesis of Ring-Fused Thiazine-4-thiones 7-18
Scheme 1
.
Preparation of 2-Alkysulfanyl-4H-3,1-
benzothiazin-4-ones7b
Surprisingly, when 3 is reacted with 5 equiv of carbon
disulfide in the presence of triethylamine in dioxane at room
temperature and iodomethane is added after an extended
reaction time of 120 h, the corresponding yellow S-methyl
dithiocarbamate 1 (R ) Me) was not obtained. Instead, a
bright red product was isolated with a 13C NMR resonance
at 210 ppm, whereas in 1 (R ) Me) the most downfield
signal appears at 198 ppm.7b As a result of the prolonged
reaction time, a spontaneous cyclocondensation of the
corresponding dithiocarbamate followed by alkylation at the
exocyclic sulfur was considered to form the 2-methylsulfa-
nyl-4H-3,1-benzothiazin-4-one (2, R ) Me). However, the
most downfield signal of 2 (R ) Me) would appear at 182
ppm,7b not at 210 ppm. This indicated an unexpected course
of the reaction. The comparison of our product’s melting
point with literature values,8a,b its striking red color, and the
NMR and MS data revealed that the 4-thioxo analogue of 2
compound
R1
R2
yield (%)
7
H
Me
Cl
84
82
98
24
88
45
46
58
63
35
71
72
8
9
10
11
12
13
14
15
16
17
18
H
H
Me
Bn
Me
Bn
Me
Bn
Me
Bn
Me
Me
Cl
Cl
Trithioisatoic anhydrides are usually obtained from isatoic
anhydrides and phosphorus pentasulfide in high-boiling
solvents (e.g., xylene, 1,2,4-trimethylbenzene) in moderate
yields.9-11 These attractive heterocycles possess a wide range
(6) For examples, see: (a) Srinivas Rao, S.; Chowdary, K. S.; Prashant,
A.; Krishnan, V. S. H. Synth. Commun. 2001, 31, 3469. (b) Polshettiwar,
V.; Nivsarkar, M.; Paradashani, D.; Kaushik, M. P. J. Chem. Res. 2004,
474. (c) Krstic´, N. M.; Bjelakovic´, M. S.; Dabovic´, M. M.; Pavlovic´., V. D.
Molecules 2010, 15, 3462. (d) Pathak, U.; Pandey, L. K.; Tank, R. J. Org.
Chem. 2008, 73, 2890. (e) Varma, R. S.; Kumar, D. Org. Lett. 1999, 1,
697. (f) Kaleta, Z.; Makowski, B. T.; Soo´s, T.; Dembinski, R. Org. Lett.
(8) (a) Leistner, S.; Wagner, G.; Iffland, E. Z. Chem. 1972, 12, 289. (b)
Takahashi, M.; Gunji, T.; Ichikawa, A. J. Heterocycl. Chem. 2002, 39, 1029.
(c) Abdel-Megeed, M. F.; Saleh, M. A.; Aly, Y. L.; Abdo, I. M. Nucleosides,
Nucleotides 1995, 14, 1985. (d) Wagner, G.; Rothe, L. Pharmazie 1971,
26, 271. (e) Leistner, S.; Wagner, G. Z. Chem. 1973, 13, 135. (f) Leistner,
S.; Wagner, G. Pharmazie 1980, 35, 582. (g) Walter, W.; Fleck, T.; Voꢀ,
J.; Gerwin, M. Liebigs Ann. Chem. 1975, 275. (h) Leistner, S.; Hentschel,
2006, 8, 1625
.
(7) (a) Mazuoka, M.; Segawa, J.; Makita, Y.; Ohmachi, S.; Kishima,
T.; Nakamura, K.-L.; Hattori, M.; Kitano, M.; Kise, M. J. Heterocycl. Chem.
1997, 34, 1773. (b) Ha¨cker, H.-G.; Grundmann, F.; Lohr, F.; Ottersbach,
P. A.; Zhou, J.; Schnakenburg, G.; Gu¨tschow, M. Molecules 2009, 14, 378.
K.; Wagner, G. Monatsh. Chem. 1983, 114, 915
(9) Wagner, G.; Rothe, L. Z. Chem. 1967, 7, 339
(10) (a) Copolla, G. M. Synthesis 1980, 505. (b) Kappe, T.; Stadlbauer,
W. AdV. Heterocycl. Chem. 1981, 28, 127
.
.
.
Org. Lett., Vol. 12, No. 16, 2010
3663

of preparative applications, e.g., to form S-glycosides,8c
o-aminothiobenzamides,8b,d,11 o-(thioureido)thiobenzoic
acids,8b 2-amino-4-thioxo-4H-3,1-benzothiazines,8e and in the
course of ring transformation reactions, imidazo[1,2-
c]quinazolines,8a quinazoline-2,4-dithiones,8d-g and guani-
dino- and triazolo[1,5-c]quinazolines8f or thiadiazoles.8h
We decided to evaluate the applicability of the conditions
leading to 11 for the synthesis of trithioisatoic anhydride (7)
and further analogues by reacting aromatic o-amino carboxylic
acids with carbon disulfide (Table 1). Indeed, the trithioisatoic
anhydrides 7-9 and the naphtho[2,3-d][1,3]thiazine derivative
10 were readily obtained by this facile synthetic procedure.
Additionally, one-pot, two-step reactions with alkyl halides
conveniently afforded a series of S-alkylated derivatives 11-18
(Table 1). Noteworthy, the easy access to 7-18 does not require
the preparation of intermediate isatoic anhydrides10,12 and
proceeds under mild conditions.13
The unexpected formation of trithioisatoic anhydrides
solely from o-amino carboxylic acids and carbon disulfide
raised the question whether carbon disulfide, besides its
obvious role as a donor for the C(2)S-S unit, acts as a
thionation agent to form the C(4)-S group. Only very few
cases of a thionation promoted by carbon disulfide have been
reported until today.1 The reaction of N-methyl-2-pyrroli-
dinone and carbon disulfide at elevated temperatures (>200 °C)
to N-methylpyrrolidine-2-thione14a was shown to proceed Via
a cycloaddition-elimination mechanism.14b
For a mechanistic investigation of the observed 1,3-
thiazine-2,4-dithione formation, anthranilic acid (3) was
used as a representative educt. A ring closure of the
anthranilic acid derived dithiocarbamate to 1,2-dihydro-
2-thioxo-4H-3,1-benzothiazin-4-one 19 (for structure, see
Scheme 2) was assumed. As a possible intermediate, 19 could
then react at the C-4 carbonyl function with carbon disulfide
in a cycloaddition-elimination mechanism Via a 1,3-oxathi-
etane15 to produce 7.16 Corresponding Wittig-type 1,3,2-
oxathiaphosphetane intermediates have been considered for
the thionation of esters, thioesters, and carboxamides with
Lawesson’s reagent.4 Moreover, a carbon disulfide addition
to the phosphorus-nitrogen double bond of 1,2-azaphosp-
holes has been reported.17 Hence, 19 was prepared18 and
subjected to the reaction with carbon disulfide (Scheme 2)
Scheme 2. Reaction of
1,2-Dihydro-2-thioxo-4H-3,1-benzothiazin-4-one (19) with
Carbon Disulfide
to test it as a possible intermediate in the conversion of 3 to
7. However, as only unthionated educt was isolated, this route
to introduce the thiocarbonyl sulfur at C-4 was excluded.
2-(Trifluoromethyl)aniline, when reacted with sodium
sulfide, gave the corresponding dithiocarboxylic acid,
which in turn produced trithioisatoic anhydride (7) upon
reaction with carbon disulfide.19 Thus, we next supposed
a dithiocarboxylic acid intermediate in the course of the
transformation of anthranilic acid (3) to 7. A thionation
of the carboxylic acid to the dithiocarboxylic acid function
was hereby assumed prior to cyclization to 7 and the
simultaneous release of hydrogen sulfide. Benzoic acid
was reacted under the same conditions as before anthra-
nilic acid (CS2 (5 equiv), Et3N (2 equiv), 1,4-dioxane,
120 h, rt). Instead of dithiobenzoic acid (or thiobenzoic
acid), again only unreacted educt was recovered, indicating
that this mechanism did not occur.
It is known that a dithiocarboxylic acid moiety may
originate from carbon disulfide, for example, in reactions
with cyclic enamines,20a ketones,20b or m-phenyl-
endiamine.20c Thus, the reaction of carbon disulfide with
the amino group of 3, accompanied by decarboxylation
and immediate electrophilic substitution with carbon
disulfide,21 followed by thiazine cyclization to trithioisa-
toic anhydride (7) was considered. This hypothesis
prompted us to react anthranilic acid (3) with 13C-labeled
carbon disulfide (Scheme 3). If the decarboxylation
mechanism was correct, both thiocarbonyl carbons of 7
Scheme 3
.
Reaction of Anthranilic Acid (3) with 13C-Labeled
(11) Navas, F., III; Tang, F. L. M.; Schaller, L. T.; Norman, M. H.
Bioorg. Med. Chem. 1998, 6, 811.
Carbon Disulfide
(12) Gu¨tschow, M. J. Org. Chem. 1999, 64, 5109
.
(13) A similar conversion of 3 (CS2, KOH, MeOH, 65 °C, 4 h) to
trithioisatoic anhydride (7) has been reported; see: Abdel-Megeed, M. F.;
Aly, Y. L.; Saleh, M. A.; Abdo, I. M.; El-Hiti, G. A.; Smith, K. Sulfur
Lett. 1995, 19, 129. However, the compound characterization by NMR
clearly indicates that not the postulated, three-sulfur-containing compound
but the 4-oxo analogue 19 was obtained; see ref 18.
(14) (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. (b)
Fu, X.; Zhang, C.; Zhang, D.; Yuan, S. Chem. Phys. Lett. 2006, 420, 162.
(15) For the formation of 1,3-oxathiethanes by intramolecular cycload-
dition, see: (a) Ishii, A.; Ding, M.-X.; Nakayama, J.; Hoshino, M. J. Chem.
Soc., Chem. Commun. 1992, 7. (b) Ishii, A.; Akazawa, T.; Maruta, T.;
Nakayama, J.; Hoshino, M.; Shiro, M. Angew. Chem. 1994, 106, 829. (c)
Ishii, A.; Akazawa, T.; Ding, M.-X.; Honjo, T.; Maruta, T.; Nakamura, S.;
Nagaya, H.; Ogura, M.; Teramoto, K.; Shiro, M.; Hoshino, M.; Nakayama,
J. Bull. Chem. Soc. Jpn. 1997, 70, 509.
(17) von Criegern, T.; Polborn, K.; Schmidpeter, A. Heteroat. Chem.
1999, 10, 167.
(18) Ottersbach, P. A.; Ha¨cker, H.-G.; Elsinghorst, P. W.; Schnakenburg,
G.; Gu¨tschow, M. Tetrahedron Lett. 2010, 51, 2727.
(19) Jourdan, G. P.; Dreikorn, B. A. J. Org. Chem. 1982, 47, 5255.
(20) For examples to generate a dithiocarboxylic acid moiety with carbon
disulfide, see: (a) Gompper, R.; Wetzel, B.; Elser, W. Tetrahedron Lett.
1968, 9, 5519. (b) Borda´s, B.; Soha´r, P.; Matolcsy, G.; Berenesci, P. J.
Org. Chem. 1972, 37, 1727. (c) Yu, Y.; Zhong, H.-P.; Yang, K.-B.; Huang,
R.-B.; Zheng, L.-S. Acta Crystallogr. 2005, E61, o387.
(16) For an ab initio study of the [2 + 2] cycloaddition of XdCdY
molecules, see: Rode, J. E.; Dobrowolski, J. C. J. Phys. Chem. A 2006,
110, 207.
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Org. Lett., Vol. 12, No. 16, 2010

at position 2 and 4 would be donated by carbon disulfide
and would be 13C-labeled. However, the 13C NMR
spectrum of the 13C-labeled trithioisatoic anhydride (20)
showed one strong signal at 187 ppm (Figure 1, NMR
assignment of the carbons is supported by HMQC and
HMBC spectra; see Supporting Information). This clearly
proves that only the C-2 thiocarbonyl carbon originated
from carbon disulfide, while C-4 derived from the carbon
of the carboxylic acid function of 3.
Scheme 4. Proposed Mechanism for the Formation of
Trithioisatoic Anhydride (7) from Anthranilic Acid (3)
Figure 1.
13C NMR Spectra of trithioisatoic anhydride (7) (bottom)
and the 13C-labeled analogue 20 (top).
was performed with only 1 equiv of CS2 (with Et3N (2 equiv)
in 1,4-dioxane, 120 h, rt), the amount of 19 was not enhanced
and a mixture was formed containing 7 and further products
besides unreacted educt 3.
In conclusion, we present a one-pot procedure to produce
trithioisatoic anhydride derivatives with easy workup in
moderate to excellent yields. The method is superior to the
common one using isatoic anhydrides and phosphorus
pentasulfide. The mechanism underlying the formation of
ring-fused 1,3-thiazine-2,4-dithiones was investigated using
13C-labeled carbon disulfide to reveal that carbon disulfide
indeed acted as a thionation reagent, which has been rarely
observed before.
These results led us to the conclusion that yet another
mechanism for the formation of trithioisatoic anhydride (7) from
anthranilic acid (3) should be proposed as follows (Scheme 4).
After formation of the dithiocarbamate and subsequent cycliza-
tion, a geminal diol is trapped by the electrophilic attack of
carbon disulfide. The intermediate dithiocarbonate sulfur attacks
C-4, and finally, the three-sulfur-containing compound 7 is
formed along with the release of water and carbonyl sulfide.
The formation of the latter product was, however, not verified.
The fact that the oxo compound 19 could be identified in traces
by NMR and LC/MS analysis of the crude product corroborates
the mechanism, in that the formation of 19 and 7 represents
competing branches in the reaction course. Compound 19 might
either result from the dehydratization of the diol intermediate
(Scheme 4) or from the loss of unstable22 hydrogen dithiocar-
bonate after attack of carbon disulfide. When the reaction of 3
Acknowledgment. This work was supported by the
German Research Foundation (Graduate College 804).
Supporting Information Available: Experimental pro-
(21) For decarboxylation and trapping with carbon disulfide to generate
a dithiocarboxylate from pyridinium-2-carboxylates or 1,2-dimethylimida-
zolium-2-carboxylate Via an N-heterocyclic carbene, respectively, see: (a)
Katritzky, A. R.; Cozens, A. J.; Ossana, A.; Rubio, O.; Dabbas, N. J. Chem.
Soc., Perkin Trans. 1 1985, 2167. (b) Schmidt, A.; Beutler, A.; Albrecht,
M.; Snovydovych, B.; Ram´ırez, F. J. Org. Biomol. Chem. 2008, 6, 287.
(22) Stueber, D.; Patterson, D.; Mayne, C. L.; Orendt, A. M.; Grant,
D. M.; Parry, R. W. Inorg. Chem. 2001, 40, 1902.
1
cedures, analytical data, H NMR and 13C NMR spectra of
compounds 7-18 and 20, HMQC spectra of 7 and 11, and
HMBC spectrum of 7. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL101471G
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