Synthesis of novel series of 6-chloro-1,1-dioxo-1,4,2-benzodithiazine derivatives with potential biological activity

Article abstract of DOI:10.1002/jhet.1562

A series of 6′-chloro-1′,1′-dioxo-2′H- spiro[benzo[d][1,3,7]oxadiazocine-4,3′-(1,4,2-benzodithiazine)]-2,6(1H,5H) -dione derivatives 2a, 2b and 3a, 3b have been synthesized starting from 3-aminobenzodithiazines 1a, 1b and isatoic anhydride. Subsequent reactions of 2a with 3-chlorophenyl isocyanate gave condensation products 4 and 5. Compound 2a was also converted into 3-(2-aminobenzamido)-6-chloro-7-methyl-1,1-dioxo-1,4,2- benzodithiazine derivatives 6, 7, 8, 9, 10. The mechanisms of the reactions are discussed.

Full text of DOI:10.1002/jhet.1562

Month 2013
Synthesis of Novel Series of 6-Chloro-1,1-dioxo-1,4,2-benzodithiazine
Derivatives with Potential Biological Activity
*
Zdzisław Brzozowski and Jarosław Sławiński
Department of Organic Chemistry, Medical University of Gdańsk, 80-416 Gdańsk, Poland
*
E-mail: jaroslaw@gumed.edu.pl
Received July 13, 2011
DOI 10.1002/jhet.1562
Published online 00 Month 2013 in Wiley Online Library (wileyonlinelibrary.com).
A series of 60-chloro-10,10-dioxo-20H-spiro[benzo[d][1,3,7]oxadiazocine-4,30-(1,4,2-benzodithiazine)]-2,6
(1H,5H)-dione derivatives 2a–b and 3a–b have been synthesized starting from 3-aminobenzodithiazines 1a–b
and isatoic anhydride. Subsequent reactions of 2a with 3-chlorophenyl isocyanate gave condensation products
4 and 5. Compound 2a was also converted into 3-(2-aminobenzamido)-6-chloro-7-methyl-1,1-dioxo-1,4,2-
benzodithiazine derivatives 6–10. The mechanisms of the reactions are discussed.
J. Heterocyclic Chem., 00, 00 (2013).
INTRODUCTION
Alternatively, access to the 2-R-1,1-dioxo-2,3-dihydro-1,4,2-
benzodithiazine-3-one (R = Me or Ph) is provided by the
reaction of N-methyl or N-phenylbenzenesulfonamides with
butyllithium and sulfur at ꢀ78º [18]. It has been demonstrated
that many of 1,4,2-benzodithiazine derivatives possessed low
acute toxicity in mice and rats and, depending on their struc-
ture, acted as potential radioprotective [1,2], hypertensive
[1], diuretic [1,2,4,6,9], or cholagogue [9] agents.
Recently, it has also been shown that some 1,4,2-
benzodithiazines exhibited remarkable antitumor (Fig. 1,
types I [17,19–21] and II [15,22]) or anti-HIV activity
(Fig. 1, types I [23,24], II [15], III and IV [25]).
Compounds containing 1,4,2-benzodithiazine ring sys-
tem were synthesized in our laboratories in 1984 and
received considerable attention over the past several years
because of their wide range of biological activities. Hence,
3-mercapto-1,4,2-benzodithiazine 1,1-dioxides were obtained
by reacting 2-chlorobenzene\sulfonamides with carbon
disulfide in the presence of potassium hydroxide [1,2].
Various 3-substituted benzodithiazine derivatives of type I
(Fig. 1) have been prepared by the nucleophilic displace-
ment of the preformed 3-methylthio-1,4,2-benzodithiazine
1,1-dioxides [1–3] with the respective amines [4–15], hydra-
zines [5,10,12,13], guanidines [5,16], or sulfonamides [17].
Furthermore, 3-methylthio-1,4,2-benzodithiazine 1,1-
dioxides have received our investigative attention with
© 2013 HeteroCorporation

Z. Brzozowski and J. Sławiński
Vol 000
Figure 1. General structures of known benzodithiazine derivatives I–V with antitumor and/or anti-HIV activity, and new 1,1-dioxo-1,4,2-benzodithiazines of
type VI and VII with expected biological activity.
regard to their susceptibility for chemical transformation
into otherwise not readily obtainable 2-mercaptobenzene-
sulfonamides. This concerns the synthesis of 4-chloro-2-
mercaptobenzenesulfonamides of type V (Fig. 1) with the
nitrogen atom of the sulfonamide moiety attached to a vari-
ety of heterocyclic ring systems. These compounds exhibited
structure-dependent remarkable antitumor activity [14,26–34],
remarkable anti-HIV activity [13,16,26,27,35,36], or strong
inhibitory activity of human carbonic anhydrase isozymes
I, II, IX, and XII [37–39]. Some of the compounds were
described as novel class of HIV-1 integrase inhibitors
(MBSAs) [40–43]. In the present work, the possibility of
using reactions of 3-amino-6-chloro-1,4,2-benzodithiazine
1,1-dioxides with isatoic anhydride to the synthesis of novel
benzodithiazines of types VI and VII (Fig. 1) with expected
biological activity or as useful starting materials for further
chemical transformations has been surveyed.
in 75% yield. However, the analogous transformation of 2a
carried out in tetrahydrofuran in the presence of equiva-
lent amount of triethylamine led to the formation of
3-(2-aminobanzamido)-1,4,2-benzodithiazine 7 via initial
formation of triethylaminium salts B and C. The later com-
pound 7 upon treatment with 2a in boiling toluene readily
converted to 2-[N-(6-chloro-7-methyl-1,1-dioxo-1,4,2-ben-
zodithiazin-3-yl)benzamido-2-aminocarbonyl] phenylcarbamic
acid 8. Apparently, the first step of the reaction sequence is
the nucleophilic attack of amine 7 at the C-6 carbon atom of
2a to give intermediate D, which, upon elimination of ben-
zodithiazine 1a, led to the formation of carbamic acid 8.
In contrast, as shown in Scheme 3, the reaction of 2a
with catalytic amount of NaOH (0.075 molar equiv.) car-
ried out in toluene under similar conditions furnished ben-
zodithiazine 9, which separated in 44.9% yield. The initial
step is believed to be the formation of intermediate sodium
salts E and F, which after decarboxylation gave benzo-
dithiazine intermediate G. The latter compound reacts with
a second molecule of 2a, which is present in the reaction
mixture, to give intermediate H, which upon subsequent
elimination of benzodithiazine 1a affords sodium salt of
carbamic acid I, and then upon decarboxylation gave the
final benzodithiazine 9. However, the alkaline hydrolysis of
9 with a small amount of NaOH gave intermediate G and
sodium anthranilate J, which upon acidification afforded
anthranilic acid in 3.6% yield.
Further reaction of 9 with carbon disulfide and KOH
carried out in ethanol led to the formation of the desired
benzodithiazine 10, as outlined in Scheme 4. The initial
step is believed to be the formation of dithiocarbamic acid
potassium salt K followed by intramolecular ring closure via
two-step addition–elimination process, which gave rise to the
insoluble potassium salt L. Then, upon acidification of the
salt L with hydrochloric acid, the free benzodithiazine 10
was produced in 81% yield via its tautomeric thiol form M.
Spiro compounds 2a–b, 3a–b, and 4–5 are stable when
stored at room temperature for several months. However,
these compounds are relatively unstable either in DMSO
or alkaline water solution. Proposed mechanisms of the
RESULTS AND DISCUSSION
The synthesis of the target compounds 2a–b, 3a–b, 4, and
5 was achieved by convenient one-step or two-step proce-
dure starting from 3-amino-6-chloro-1,4,2-benzodithiazine
1,1-dioxides 1a–b, as shown in Scheme 1. First, the reaction
of the appropriate benzodithiazines 1a or 1b with isatoic anhy-
dride carried out in boiling toluene led to the formation of spiro
[benzo[d][1,3,7]oxadiazocine-4,30-(1,4,2-benzodithiazine)]-
2,6(1H,5H)-dione derivatives 2a–b, which were obtained in
98% yield. Then, upon treatment of 2a–b with isatoic anhy-
dride in boiling toluene, the desired 2-(2,6-dioxo-1,2,5,6-
tetrahydro-20H-spiro[benzo[d] [1,3,7]oxadiazocine-4,30-
(1,4,2-benzodithiazine)-1-ylcarbonyl] phenylcarbamic acid
derivatives 3a and 3b were obtained in 85 and 87% yield,
respectively. An analogous reaction of spiro compound
2a with aryl isocyanates furnished N-phenyl-2,6-dioxo-5,6-
dihydro-20H-spiro[benzo[d] [1,3,7]oxadiazocine-4,30-(1,4,2-
benzodithiazine)]-1-(2H)-carboxamide derivatives 4 and 5.
As shown in Scheme 2, compound 2a heated in boiling
p-dioxane (0.5 h) gave 2-(1,4,2-benzodithiazine-3-ylami-
nocarbamoyl)phenylcarbamic acid 6, which was separated
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2013
Synthesis of Novel Series of 6-Chloro-1,1-dioxo-1,4,2-benzodithiazine
Derivatives with Potential Biological Activity
Scheme 1. Synthesis of 60-chloro-10,10-dioxo-20H-spiro[benzo[d][1,3,7]oxadiazocine-4,30-(1,4,2-benzodithiazine)]-2,6(1H,5H)-dione derivatives 2a–b,
3a–b, 4, and 5. Reagents and conditions: (a) isatoic anhydride (1.08 molar equiv.) dry toluene, reflux, 55 h; (b) isatoic anhydride (1.14 molar equiv.), dry
toluene, reflux, 48 h; (c) aryl isocyanate (1.25 molar equiv.), toluene, reflux, 32 h.
regioselective two-step alkaline hydrolysis of compound
3a is outlined in Scheme 5. The reaction of 3a with equiv-
alent amount of NaOH water solution carried out at room
temperature for 8 h led to the formation of 2a and anthrani-
lic acid, which were isolated in 94 and 73% yields, respec-
tively. On the other hand, upon treatment of 2a with an
excess of NaOH in water solution at room temperature
for 30 h, 3-aminobenzodithiazine 1a and isatoic anhydride
could be isolated in 76 and 46% yields, respectively.
The structures of the final products were confirmed by
elemental analyses as well as IR and NMR spectroscopy
as evidenced in the Experimental section. Inspection of the
13C NMR spectra of spirocyclic compounds 2a–b, 3a, 4,
and 5 revealed the characteristic signals of spiro carbon
atom (C-4,30) in the upfield region d 110.50–111.42 ppm,
whereas the presence of two carbonyl C═O groups in posi-
tions 2 and 6 of benzo[d][1,3,7]oxadiazocine ring was indi-
cated by characteristic signals in the regions 160.13–164.13
and 162.27–166.27 ppm, respectively. The IR spectra of
compounds 2a–b, 3a, 4, and 5 showed strong absorption
bands of these two carbonyl C═O groups in the regions
CONCLUSION
We have developed methods for the preparation of 60-
chloro-10,10-dioxo-20H-spiro[benzo[d][1,3,7]oxadiazocine-
4,30-(1,4,2-benzodithiazine)]-2,6(1H,5H)-dione derivatives
2a–b, 3a–b, 4, and 5, representing a new type of constitu-
tionally nonsymmetrical spirans, which in turn provide
access to a variety of new 3-substituted 1,4,2-benzodithiazine
1,1-dioxide derivatives (6–10).
Further structural modifications and biological evalua-
tions of these compounds are in progress and will be
described elsewhere.
EXPERIMENTAL
The following instruments and parameters were used: melting
points: Büchi 535 apparatus; IR spectra: KBr pellets, 400–4000 cmꢀ1
Perkin Elmer 1600 FTIR spectrophotometer; H and 13C NMR:
1
Varian Gemini 200 apparatus at 200 and 50MHz, respectively.
Chemical shifts are expressed as d value to Me4Si as standard.
The results of elemental analyses for C, H, and N were in agreement
with the calculated values within ꢁ0.4% range. The starting
3-amino-6-chloro-1,4,2-benzodithiazine dioxides 1a and 1b were
prepared according to the method described previously [44].
1720–1780 and 1770–1790 cmꢀ1
.
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Z. Brzozowski and J. Sławiński
Vol 000
Scheme 2. Synthesis and proposed mechanism of the formation of benzodithiazines 6–8 from compound 2a. Reagents and conditions: (a) 1,4-dioxane,
reflux 10 min; (b) TEA (1.05 molar equiv.), THF, RT, 6 h; (c) distillation of THF under reduced pressure, heating, slowly increasing temperature to 200ꢃC,
6 h; (d) glacial acetic acid (large excess), reflux, 3 min; (e) compound 2a (1.0 molar equiv.), dry toluene, reflux, 32 h.
Procedures for the preparation of spiro[benzo[d] [1,3,7]
oxadiazocine-4,30-(1,4,2-benzodithiazine)] derivatives (2a, 2b).
A mixture of isatoic anhydride (2.82 g, 17.3 mmol) and the
corresponding 3-amino-1,4,2-benzodithiaznes (16 mmol) in dry
toluene (40 mL) was refluxed with stirring for 55 h. After
cooling to room temperature, the precipitate was collected by
filtration, washed successively with toluene (2 ꢂ 2 mL), methanol
(5 ꢂ 1mL), and petroleum ether (3 ꢂ 2 mL), and dried. In this
manner, the following spiro compounds were obtained.
7.10 (br.s, 2H, 2 ꢂ O═C–NH), 7.17 (d, J = 8.3Hz, 1H, H-10),
7.28 (t, J = 7.6 Hz, 1H, H-9), 7.60 (s, 1H, H-50), 7.73 (t,
J = 7.6 Hz, 1H, H-8), 7.97 (s, 1H, H-80), 8.00 (d, J =7.8 Hz, 1H,
H-7), 9.23 (s, 1H, H-20) ppm; 13C NMR (CD3CN) d 19.98,
111.42, 115.94, 124.92, 127.61, 128.36, 128.83, 130.25, 131.70,
138.04, 138.74, 139.02, 141.97, 147.94, 160.71, 166.27 ppm.
Anal. Calcd for C16H12ClN3O5S2 (425.88): C, 45.12; H, 2.84; N,
9.86. Found: C, 45.11; H, 2.91; N, 9.91.
60-Chloro-80-methyl-10,10-dioxo-20H-spiro[benzo[d][1,3,7]
oxadiazocine-4,30-(1,4,2-benzodithiazine)]-2,6(1H,5H)-dione (2b).
Starting from 3-amino-6-chloro-8-methyl-1,4,2-benzodithiazine
1,1-dioxide 1b (4.2 g), the title compound 2b was obtained
(6.7 g, 98%): mp 191–193ꢃC dec.; IR (KBr): 3340, 3300, 3210
(NH), 1765, 1725, 1650, 1620 (C═O), 1360, 1165 (SO2),
1270, 1110, 1010, 885, 765, 615, 540, 480, and 460 (other
60-Chloro-70-methyl-10,10-dioxo-20H-spiro[benzo[d][1,3,7]
oxadiazocine-4,30-(1,4,2-benzodithiazine)]-2,6(1H,5H)-dione (2a).
Starting from 3-amino-6-chloro-7-methyl-1,4,2-benzodithiazine
1,1-dioxide 1a (4.2 g), the title compound 2a was obtained
(6.7 g, 98%): mp 231–233ꢃC dec.; IR (KBr) 3290, 3205, 3145
(NH), 1785, 1730, 1655, 1620 (C═O), 1360, 1170, (SO2),
1290, 1085, 1015, 935, 755, 680, 575, 480, and 460 (other
strong) cmꢀ1
;
1H NMR (acetonitrile-d3): d 2.68 (s, 3H, CH3),
1
strong ) cmꢀ1; H NMR (acetonitrile-d3): d 2.46 (s, 3H, CH3),
7.07 (br.s, 2H, 2 ꢂ O═C–NH), 7.16 (d, J = 8.3 Hz, 1H, H-10),
Journal of Heterocyclic Chemistry
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Month 2013
Synthesis of Novel Series of 6-Chloro-1,1-dioxo-1,4,2-benzodithiazine
Derivatives with Potential Biological Activity
Scheme 3. One-pot synthesis and proposed mechanism of the formation of benzodithiazine 9 from compound 2a. Reagents and conditions: (a) NaOH
(0.075 molar equiv.), water (0.2 mL), toluene, RT, 8 h, reflux, 34 h.
7.27 (t, J = 7.6 Hz, 1H, H-9), 7.40 (d, Jmetha = 2.9 Hz, 1H, H-50)
7.72 (t, J = 7.6 Hz, 1H, H-8), 7.75 (d, Jmetha = 7.6 Hz, 1H,
H-70), 7.79 (d, J = 7.8 Hz, 1H, H-7), 9.35 (s, 1H, H-20) ppm;
13C NMR (dimethyl sulfoxide-d6) d 21.10, 110.50, 115.59,
123.76, 125.41, 129.19, 130.44, 131.56, 131.94, 135.69,
137.18, 139.19, 141.66, 147.36, 160.13, 162.68 ppm. Anal.
Calcd for C16H12ClN3O5S2 (425.88): C, 45.12; H, 2.84; N,
9.86. Found: C, 45.20; H, 2.88; N, 9.90.
methanol (30 mL). After 1 h of stirring at room temperature, the
precipitate was filtered off, washed with methanol (2ꢂ 4 mL) and
petroleum ether (2ꢂ 5 mL), and dried. In this manner, the
following spiro compounds were obtained.
2-(60-Chloro-70-methyl-10,10-dioxo-2,6-dioxo-1,2,5,6-tetrahydro-
20H-spiro[benzo[d] [1,3,7]oxadiazocine-4,30-(1,4,2-benzodithiazine)-
1-ylcarbonyl]phenylcarbamic acid (3a). Starting from 2a, the
title compound 3a was obtained (3.5g, 85%): mp 270–271ꢃC
dec; IR (KBr) 3330, 3290, 3200, 3140 (NH and COOH), 2800,
2715, 2540 (COOH), 1790, 1780, 1655, 1620 (C═O), 1360,
Procedures for the preparation of spiro[benzo[d] [1,3,7]
oxadiazocine-4,30-(1,4,2-benzodithiazine)] derivatives (3a, 3b).
A mixture of isatoic anhydride (1.3g, 8 mmol) and spiro
compound 2a or 2b (3.0g, 7 mmol) in dry toluene (70mL) was
refluxed with stirring for 48 h. The precipitate was filtered off
when hot and washed with toluene (2 ꢂ 5 mL) and ethanol
(3ꢂ 4 mL), and then the crude product obtained was added to
1170 (SO2) cmꢀ1 1H NMR (dimethyl sulfoxide-d6): d 2.42 (s,
;
3H, CH3), 7.15 (d, J = 8.3Hz, 2H, arom.), 7.25 (t, J =7.8 Hz, 2H,
arom.), 7.74 (t, J = 7.8Hz, 2H, arom.), 7.78 (s, 1H, H-50), 7.91 (d,
J = 7.8 Hz, 2H, arom.), 7.97 (s, 1H, H-80), 9.10 (s, 1H, H-20),
9.18 (br.s, 1H, HN–C═O), 11.73 (s, 2H, HN–COOH) ppm; 13C
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Z. Brzozowski and J. Sławiński
Vol 000
Scheme 4. Synthesis of benzodithiazine 10. Reagents and conditions: (a) KOH (1.33 molar equiv.), CS2 (1.33 molar equiv.), 95% ethanol, RT, 4 h, reflux
34 h; (b) water, RT, 1% hydrochloric acid to pH 1.
Scheme 5. Proposed mechanism of the regioselective two-step alkaline hydrolysis of spiro compound 3a into spiro compound 2a and benzodithiazine 1a.
Reagents and conditions: (a) NaOH (1.0 molar equiv.) water, RT, 8 h; (b) NaOH (1.1 molar equiv.), RT, 30 h.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2013
Synthesis of Novel Series of 6-Chloro-1,1-dioxo-1,4,2-benzodithiazine
Derivatives with Potential Biological Activity
Procedure for the preparation of 2-(6-chloro-7-methyl-1,1-
dioxo-1,4,2-benzodithiazin-3-ylaminocarbonyl)phenylcarbamic
acid (6) from spiro compound (2a). A suspension of 2a (2.13 g,
5 mmol) in dry 1,4-dioxane (25 mL) was refluxed with stirring for
10 min. The small amount of insoluble side products was filtered
out when hot, and the filtrate left to stand at room temperature
overnight. The precipitate was filtered off, washed with 1,4-dioxane
(2 ꢂ 1.5 mL), dried (1.8 g), and purified by heating in boiling
acetonitrile (10 mL) for 5 min. After cooling to room temperature,
the precipitate of title compound 6 was collected by filtration,
washed with acetonitrile (2ꢂ 1 mL), and dried. Yield 1.6 g (75%);
mp 229–230ꢃC dec.; IR (KBr): 3345, 3285, 3195, 3145 (HN–
COOH, HNC═O) 1785, 1730, 1655, (NHC═O, and COOH),
NMR (dimethyl sulfoxide-d6) d 19.54, 110.51, 115.59, 123.76,
126.54, 127.92, 128.17, 129.19, 131.09, 131.19, 137.37, 141.65,
147.36, 160.13, 164.87ppm. Anal. Calcd for C24H17ClN4O8S2
(589.01): C, 48.94; H, 2.21; N, 9.51. Found: C, 49.03; H, 2.94;
N, 9.53.
2-(60-Chloro-80-methyl-10,10-dioxo-2,6-dioxo-1,2,5,6-tetrahydro-
20H-spiro[benzo[d] [1,3,7]oxadiazocine-4,30-(1,4,2-benzodithiazine)-
1-ylcarbonyl]phenylcarbamic acid (3b). Starting from 2b, the
title compound 3b was obtained (3.6 g, 87%): mp 190–191ꢃC
dec.; IR (KBr): 3345, 3330, 3210, 3110 (NH and COOH), 2935,
2880, 2780, 2530 (COOH), 1770, 1730, 1650, 1620 (C═O),
1
1360, 1165, (SO2) cmꢀ1; H NMR (dimethyl sulfoxide-d6) d 2.64
(s, 3H, CH3), 7.16 (d, J = 8.3 Hz, 2H, arom.), 7.26 (t, J = 7.6Hz,
2H, arom.), 7.54 (s, 1H, H-70), 7.71–7.77 (m, 4H, arom.), 7.92 (s,
1H, H-50), 7.94 (s, 1H, H-20), 9.04 (br.s, 1H, HN–C═O), 11.73 (s,
2H, HN–COOH) ppm. Anal. Calcd for C24H17ClN4O8S2 (589.01):
C, 48.94; H, 2.21; N, 9.51. Found: C, 48.99; H, 2.27; N, 9.60.
1
1360, 1170 (SO2) cmꢀ1; H NMR (dimethyl sulfoxide-d6) d 2.41
(s, 3H, CH3), 7.14 (d, J= 8.3 Hz, 1H, H-5, Ph), 7.23 (t, J=7.6Hz,
1H, H-4, Ph), 7.26 (t, J= 7.6 Hz, 1H, H-3, Ph), 7.88 (s, 1H, H-5,
benzodithiazine), 7.90 (d, J = 8.3 Hz, 1H, H-2, Ph), 7.96 (s, 1H,
H-8, benzodithiazine), 9.08 (s, 1H, NH), 9.16 (s, 1H, NH), 11.71
(s, 1H, COOH) ppm. Anal. Calcd for C16H12Cl N3O5S2 (425.88):
C, 45.12; H, 2.84; N, 9.88 Found: C, 45.18; H, 2.94; N, 10.02.
Procedures for the preparation of spiro[benzo[d] [1,3,7]
oxadiazocine-4,30-(1,4,2-benzodithiazine)] derivatives (4 and 5).
A suspension of spiro compound 2a and the corresponding phenyl
isocyanate (10 mmol) in dry toluene (80 mL) was refluxed
with stirring for 32 h. After cooling to room temperature, the
precipitate was collected by filtration, washed successively with
toluene (5 ꢂ 5 mL) and acetonitrile (4ꢂ 4 mL) and dried.
Procedure for the transformation of spiro compound (2a) into
3-(2-aminobenzamido)-6-chloro-7-methyl-1,4,2-benzodithiazine
1,1-dioxide (7).
A solution of spiro compound 2a (4.26 g,
10mmol) and triethylamine (1.06 g, 10.5 mmol) in tetrahydrofuran
(70 mL) was stirred at room temperature for 6 h. The small
amount of insoluble side products was filtered out together with
charcoal added. The solvent was evaporated under reduced
procedure at room temperature. The oily residue was heated at
temperatures gradually increasing to 200ꢃC for 6 h. The resulting
solid residue was treated with glacial acetic acid (25mL) and then
stirred at reflux for 3 min. After cooling to room temperature, the
precipitate was collected by filtration, washed successively
with acetic acid (2 ꢂ 1.5 mL), water (5 ꢂ 3 mL), and methanol
(3 ꢂ 2 mL), and dried. Yield 3.2 g (83%); mp 299–300ꢃC dec.;
IR (KBr): 3325, 3285, 3240 (NH, NH2) 1725, 1700, ( C═O),
60-Chloro-N-(3,4-dichlorophenyl)-70-methyl-10,10-dioxo-2,6-
dioxo-5,6-dihydro-20H-spiro[benzo[d] [1,3,7]oxadiazocine-4,30-
(1,4,2-benzodithiazine)]-1-(2H)-carboxamide (4). Starting from
3,4-dichlorophenyl isocyanate (1.88 g), the title compound 3a
was obtained (3.7 g, 75%): mp 201–202ꢃC dec.; IR (KBr):
3300, 3260, 3185, (NH), 1785, 1730, 1655, 1620 (C═O),
1
1360, 1165 (SO2) cmꢀ ; 1H NMR (dimethyl sulfoxide-d6): d
2.44 (s, 3H, CH3), 7.15 (d, J = 7.8 Hz, 1H, H-10), 7.24 (t,
J = 7.8 Hz, 1H, H-9), 7.41 (d, J = 8.7 Hz, 1H, H-6, 3,4-diClPh),
7.60 (d, J = 8.7 Hz, 1H, H-5, 3,4-diClPh), 7.73 (t, J = 7.8 Hz,
1H, H-8), 7.84 (s, 1H, H-50), 7.89 (s, 1H, H-2, 3,4-diClPh),
8.00 (s, 1H, H-80), 8.05 (s, 1H, O═C–NH-5), 9,13 (d,
J = 12 Hz, 1H, H-7), 9.68 (s, 1H, H-20), 11.72 (s, 1H, NH, 3,4-
diClPh) ppm; 13C NMR (dimethyl sulfoxide-d6) d 19.60, 110.50,
115.59, 119.95, 121.03, 123.76, 125.81, 126.55, 128.16, 128.38,
128.98, 129.19, 129.84, 131.09, 131.51, 137.18, 137.36, 137.94,
138.61, 141.55, 150.88, 164.13, 164.85 ppm. Anal. Calcd for
C23H15Cl3N4O6S2 (613.90): C, 45.00; H, 2.46; N, 9.13. Found: C,
45.10; H, 2.51; N, 9.20.
1655, (C═N) 1340, 1305,1150, 1135 (SO2) cmꢀ1
;
1H NMR
(dimethyl sulfoxide-d6): 2.33 (s, 3H, CH3), 7.38 (t,
d
J = 7.3 Hz, 1H, H-4, Ph), 7.61 (d, J = 8.3 Hz, 1H, H-3, Ph), 7.75
(s, 1H, NH, benzodithiazine), 7.77–7.82 (m, 2H, H-5, Ph and
H-5, benzodithiazine), 7.97 (d, J = 7.3 Hz, 1H, H-6, Ph), 8.06
(s, 1H, H-8, benzodithiazine), 11.48 (s, 1H, PhNHB), 11.87 (s,
1H, PhNHA) ppm; 13C NMR (dimethyl sulfoxide-d6) d 19.64,
116.44, 118.21, 125.62, 127,51, 131.51, 133.59, 135.96,
136.41, 138.84, 139.77, 149.29, 160.64 ppm. Anal. Calcd for
60-Chloro-N-(3-chlorophenyl)-70-methyl-10,10-dioxo-2,6-dioxo-
5,6-dihydro-20H-spiro[benzo[d] [1,3,7]oxadiazocine-4,30-(1,4,2-
C
15H12Cl N3O3S2 (381.87): C, 47.18; H, 3.17; N, 11.00,
benzodithiazine)]-1-(2H)-carboxamide (5).
Starting from 3-
Found: C, 47.19; H, 3.20; N, 11.01.
chlorophenyl isocyanate (1.53 g), the title compound 4 was
obtained (3.9g, 84%): mp 186–187ꢃC dec.; IR (KBr): 3305,
3260, 3195, (NH) 1770, 1725, 1655, 1620 (C═O), 1365, 1170,
Synthesis of 2-[N-(6-chloro-7-methyl-1,1-dioxo-1,4,2-benzo-
dithiazin-3-yl)benzamido-2-aminocarbonyl)]phenylcarbamic
acid (8) and 3-amino-6-chloro-7-methyl-1,1-dioxo-1,4,2-benzo-
(SO2) cmꢀ1 1H NMR (dimethyl sulfoxide-d6) d 2.44 (s, 3H,
;
dithiazine (1a) as by-product.
A mixture of compound 2a
CH3), 7.14 (d, J = 8.4 Hz, 1H, H-10), 7.23 (t, J = 8.4 Hz, 1H, H-9),
7.33–7.43 (m, 2H, H-5 and H-6, 3ClPh), 7.66 (s, 1H, H-50),
7.73 (t, J = 8.4Hz, 1H, H-8), 7.88 (s, 1H, H-2, 3-ClPh), 7.94 (d,
J = 7.3Hz, 1H, H-4, 3-ClPh), 8.01 (s, 1H, H-80), 8.05 (s, 1H,
O═C–NH-5), 9.13 (d, J = 14 Hz, 1H, H-7, benzoxadiazocine),
9.66 (s, 1H, H-20), 11.73 (s, 1H, NH, 3-ClPh) ppm; 13C NMR
(dimethyl sulfoxide-d6) d 19.60, 110.51, 115.59, 118.26, 119.18,
123.77, 123.94, 126.55, 128.39, 129.01, 129.17, 129.88, 130.94,
133.58, 137.18, 137.93, 138.59, 139.24, 141.66, 147.35, 150.80,
164.12, 164.86 ppm. Anal. Calcd for C23H16Cl2N4O6S2
(579.46): C, 47.67; H, 2.78; N, 9.67. Found: C, 47.64; H,
2.82; N, 9.74.
(1.28 g, 3 mmol) and 3-(aminobenzamido)-6-chloro-7-methyl-
1,4,2-benzodithiazine 1,1-dioxide 7 (1.16 g, 3 mmol) in dry
toluene (40 mL) was refluxed with stirring for 32h. After cooling
to room temperature, the precipitate was collected by filtration,
washed with toluene (3 ꢂ 2.5mL), and dried. The mixture of
products was thus obtained (2.2g), and methanol (100mL) was
refluxed with stirring for 0.5 h. The precipitate of title compound
8 was filtered out when hot, washed with methanol (3 ꢂ 5 mL)
and acetonitrile (3ꢂ 3 mL), and dried. Yield 1.43 g (87%); mp
295–296ꢃC dec.; IR (KBr): 3490, 3285, 3260 (NH and COOH)
1725, 1700, 1655, 1630 (HOC═O, HNC═O, and C═N), 1360,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Z. Brzozowski and J. Sławiński
Vol 000
1305, 1150, 1135 (SO2) cmꢀ1; 1H NMR (dimethyl sulfoxide-d6): d
2.31 (s, 3H, CH3), 6.07 (t, J = 7.1 Hz, 1H, arom.), 6.36 (d,
J = 7.8Hz, 1H, arom.), 6.75 (s, 1H, H-5, benzodithiazine), 6.91 (t,
J = 7.1Hz, 1H, arom.), 7.24 (t, J = 7.3 Hz, 1H, arom.), 7.35–7.73
(m, 3H, arom.), 7.94 (d, J = 7.3 Hz, 1H, arom.), 8.04 (s, 1H, H-8,
benzodithiazine), 11.15 (s, 1H, NH), 11.45 (s, 1H, NH), 11.78 (s,
1H, NH), 11.85 (s, 1H, COOH) ppm. Anal. Calcd for C23H17Cl
N4O6S2 (545.0): C, 50.69; H, 3.14; N, 10.28, Found: C, 50.63;
H, 3.19; N, 10.37.
The methanol–acetonitrile filtrate mixture was evaporated to
one-fourth volume at reduced pressure. After cooling to room
temperature, the suspension was left overnight. The precipitate
of benzodithiazine 1a thus obtained as a side product was filtered
off, washed with acetonitrile (3 ꢂ 1 mL), and dried. Yield 0.5 g
(63%); mp 161–162ꢃC; IR data were in accordance with those
reported previously to the authentic sample of 1a [44].
4 mmol), benzodithiazine 9 (1.5 g, 3 mmol) was added with
stirring. The reaction mixture was stirred at room temperature
for 4 h followed at reflux until the evolution of H2S had ceased
(34–36 h)(Caution: because of high toxicity, H2S should be
trapped in aqueous NaOH solution). After cooling to room
temperature, the suspension was left overnight. The precipitate
was collected by filtration, washed with ethanol (3 ꢂ 1.5 mL),
and dried. The crude potassium salt of 10 (1.7 g); mp 300–
302ꢃC dec.; IR (KBr) 3420, 3300, 3205 (NH), 1660, 1620
(C═O) 1360, 1135, (SO2) cmꢀ1 was suspended in water
(15 mL) (pH ~9.5) then acidified with 1% hydrochloric acid to
pH 1. After 3 h of stirring, the title compound 10 was
collected by filtration, washed successively with water
(5 ꢂ 3 mL), methanol (2 ꢂ 1 mL), and acetonitrile (3 ꢂ 1.5 mL),
and dried. Yield 1.33 g (81%); mp 269–270ꢃC; IR (KBr):
3285, 3240 (NH), 1725, 1700 (C═O), 1635, (C═N), 1360,
1
1130 (SO2), 1100 (C═S) cmꢀ1; H NMR (dimethyl sulfoxide):
One-pot synthesis of 3-[2-anthranilamido)benzamido]-6-
chloro-7-methyl-1,1-dioxo-1,4,2-benzodithiazine (9) and 3-amino-
6-chloro-1,1-dioxo-1,4,2-benzodithiazine (1a) and anthranilic
acid as side products. A mixture of NaOH (0.06 g, 0.0015 mol)
in water (0.2mL), toluene (160 mL), and compound 2a (8.52 g,
0.02mol) was stirred at room temperature for 8 h followed at
reflux for 34h. After cooling to room temperature, the precipitate
was collected by filtration, washed with toluene (3ꢂ 5 mL), dried,
and mixed with water (20 mL) for 1h. Resulting precipitate of 1a
and 9 was filtered off, washed with water (3ꢂ 10mL), dried, and
left for further work-up (7.4g). The water filtrate (pH ~7) was
acidified with 1% hydrochloric acid to pH 1. The resulting
precipitate of anthranilic acid was collected by filtration,
washed with water (3 ꢂ 1 mL), and dried. Yield 0.1 g (3.6%);
mp 144–146ꢃC, and IR were identical with authentic sample of
commercially available anthranilic acid.
d 2.30 (s, 3H, CH3), 7.02–7.20 (m, 2H, arom.), 7.22–7.38 (m,
2H, arom.), 7.52 (s, 1H, H-5, benzodithiazine), 7.58–7.65 (m,
2H, arom.), 7.80–7.90 (m, 2H, arom.), 8.03 (s, 1H, H-8,
benzodithiazine), 11.40 (br.s, 2H, 2 ꢂ NH) ppm. Anal. Calcd
for C23H15Cl N4O4S3 (543.05): C, 50.87; H, 2.78; N, 10.32.
Found: C, 50.91; H, 2.87; N, 10.30.
Regioselective hydrolysis of spiro compound 3a into spiro
compound 2a and anthranilic acid as side product.
To a
solution of NaOH (0.12 g, 3 mmol) in water (15 mL), compound
3a (1. 76 g, 3 mmol) was added, and the reaction mixture was
stirred at room temperature for 8 h. The precipitate of 2a was
filtered off, washed with water (5 ꢂ 2 mL), and dried initially at
room temperature and then at temperatures gradually increasing
to 100ꢃC. Yield 1.2 g (94%): mp 231–232ꢃC dec.; IR and 1H
NMR data were in accordance with those reported previously to
the authentic sample of 2a. The water filtrate (pH ~7.5) was
acidified with 1% hydrochloric acid to pH 3. Anthranilic acid
thus obtained as a side product was filtered out, washed with
water (2 ꢂ 1 mL), and dried. Yield 0.3 g (73%); mp 145–147ꢃC.
A mixture of 1a and 9 obtained (7.4 g) in methanol (160 mL)
was stirred at reflux for 1 h. The precipitate of 9 was filtered out
when hot, washed with methanol (4 ꢂ 5 mL) (methanol filtrate
was left for further work-up), and dried. Yield 4.5 g (44.9%);
mp 270–271ꢃC dec.; IR (KBr): 3490, 3380, (NH2), 3260, 3230
Regioselective hydrolysis of spiro compound 2a into3-
amino-6-chloro-7-methyl-1,4,2-benzodithiazine 1,1-dioxide (1a)
(NH), 1710, 1655 (C═O), 1630 (C═N), 1360, 1150 (SO2) cmꢀ1
;
1H NMR (dimethyl sulfoxide-d6): d 2.50 (s, 3H, CH3), 6.10 (t,
J= 7.1Hz, 1H, Ph), 6.39 (d, J = 8.3 Hz, 1H, Ph), 6.78 (s, 2H,
NH2), 6.94 (t, J= 7.1 Hz, 1H, Ph), 7.26 (t, J = 7.3 Hz, 1H, Ph), 7.32
(d, J= 7.8 Hz, 1H, Ph), 7.41 (d, J= 7.8 Hz, 1H, Ph), 7.63 (t,
J= 7.3 Hz, 1H, Ph), 7.72–7.80 (m, 2H, Ph and H-5, benzodithiazine),
8.18 (s, 1H, H-8, benzodithiazine), 11.17 (s, 1H, NH), 11.81 (s, 1H,
NH) ppm; 13C NMR (dimethyl sulfoxide-d6): d 20.24, 114.71,
115.33, 115.86, 117.56, 117.80, 125.04, 125.59, 127.26, 129.28,
131.37, 135.12, 136.06, 137.43, 139.09, 139.53, 140.35, 145.21,
149.27, 150,25, 160.02, 186.68 ppm. Anal. Calcd for C22H17Cl
N4O4S2 (500.99): C, 52.74; H, 3.42; N, 11.18. Found: 52.76; H,
3.51; N, 11.20.
The methanol–filtrate mixture was evaporated to one-fifth
volume at reduced pressure. After cooling to room temperature,
the suspension was left overnight. The precipitate of benzodithia-
zine 1a was filtered off, washed with methanol (4 ꢂ 2 mL), and
dried. Yield 1.94 g (36.1%); mp 160–162ꢃC; 1H NMR data were
in accordance with those reported previously for authentic sample
of 1a [44].
and isatoic anhydride as side product.
To a solution of
NaOH (0.18 g, 4.4 mmol) in water (70 mL), compound 2a
(1.7 g, 4 mmol) was added, and the reaction mixture was
stirred at room temperature for 30 h. The precipitate of isatoic
anhydride thus obtained was filtered off, washed successively
with water (5 ꢂ 5 mL) and petroleum ether (4 ꢂ 1 mL), and
dried. Yield 0.3 g (46%); mp 235–237ꢃC. The water filtrate
(pH ~7.5) was acidified with 1% hydrochloric acid to pH 6.
The precipitate of benzodithiazine 1a was collected by filtration,
washed successively with water (4 ꢂ 4 mL) and methanol
(5ꢂ 2 mL), and dried. Yield 0.8 g (76%); mp 261–262ꢃC; IR and
1H NMR data were in accordance with those reported previously
to the authentic sample of 1a [44].
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2013
Synthesis of Novel Series of 6-Chloro-1,1-dioxo-1,4,2-benzodithiazine
Derivatives with Potential Biological Activity
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet