Chemistry of an Unexplored Heterocyclic Ring System: Versatile Synthesis of 5-Aryl-2,3,4-benzothiadiazepine 2,2-dioxides

Article abstract of DOI:10.1002/jhet.2141

The article gives insight into the synthetic approach of a practically new heterocyclic ring system, 2,3,4-benzothiadiazepines. Starting from the easily available phthalides, an efficient synthesis of 5-aryl-2,3,4-benzothiadiazepine 2,2-dioxides is described here. Owing to their close structural similarity to 2,3-benzodiazepines and 2,3-benzodiazepine-4-ones, two well-known bioactive compound families, the new derivatives can be of importance in medicinal chemistry.

Full text of DOI:10.1002/jhet.2141

Month 2014
Chemistry of an Unexplored Heterocyclic Ring System: Versatile
Synthesis of 5-Aryl-2,3,4-benzothiadiazepine 2,2-dioxides
a
a
b
b
b
*
József Fetter, Ferenc Bertha, Balázs Molnár, Balázs Volk, and Gyula Simig
aBudapest University of Technology and Economics, Department of Organic Chemistry and Technology, P.O. Box 91,
H-1521 Budapest, Hungary
bEgis Pharmaceuticals Plc., Chemical Research Division, P.O. Box 100, Budapest H-1475 Hungary
*
E-mail: volk.balazs@egis.hu
Additional Supporting Information may be found in the online version of this article.
Received September 8, 2013
DOI 10.1002/jhet.2141
Published online 00 Month 2014 in Wiley Online Library (wileyonlinelibrary.com).
The article gives insight into the synthetic approach of a practically new heterocyclic ring system,
2,3,4-benzothiadiazepines. Starting from the easily available phthalides, an efficient synthesis of 5-
aryl-2,3,4-benzothiadiazepine 2,2-dioxides is described here. Owing to their close structural similarity
to 2,3-benzodiazepines and 2,3-benzodiazepine-4-ones, two well-known bioactive compound families,
the new derivatives can be of importance in medicinal chemistry.
J. Heterocyclic Chem., 00, 00 (2014).
INTRODUCTION
that is, compound 6a itself (Scheme 1) [18]. Moreover, it
is noteworthy that apart from 6a, there is no other
compound described in the literature that corresponds to
the general structure 6 (2,3,4-benzothiadiazepine and
related compounds).
Compound 6a was prepared more than 40 years ago with
the aim of studying the chlorination reactions of “heterocy-
clic sulfonhydrazones.” It was obtained by cyclization of
(2-formylphenyl)methanesulfonyl chloride (7) with hydra-
zine (Scheme 2) [18]. Sulfonyl chloride 7 was produced by
treatment of an aqueous suspension of 1,3-dihydro-benzo
[c]thiophene (8) with chlorine.
Biological efficacy of compounds bearing a phthalazine
(1, Scheme 1), phthalazinone (2), or the homologous 2,3-
benzodiazepine (3) and 2,3-benzodiazepine-4-one (4)
skeleton is discussed in several papers and patent applica-
tions. Various pharmacological and therapeutic effects are
described for these compounds ranging from poly(ADP-
ribose) polymerase inhibition [1] and antagonism of
chemoattractant receptor-homologous molecule expressed
on T helper type 2 cells [2] to phosphodiesterase inhibition
[3,4] and to the treatment of gastric disorders [5]. The
biological importance of 2,3-benzodiazepines (3) is even
better demonstrated by tofisopam [6], a well-known anxio-
lytic drug from this family, or the drug candidates
girisopam [7], nerisopam [8], and talampanel [9], which
reached the clinical development stage. Phthalazines 1 are
known to be advanced intermediates for the preparation
of tricyclic sydnonimine derivatives exhibiting an antihy-
pertensive effect [10]. Representatives of the 1,2,3-
benzothiadiazine 1,1-dioxide (5) family, structurally
related to compounds 2, also act as antagonists of the
chemoattractant receptor-homologous molecule expressed
on T helper type 2 cells [2] or as advanced intermediates
for the preparation of disinfectants and herbicides [11].
The syntheses of phthalazines (1) [12], phthalazinones
(2) [12], 2,3-benzodiazepines (3) [13–15], and 2,3-benzo-
diazepine-4-ones (4) [16] are well elaborated. However,
while numerous 1,2,3-benzothiadiazine 1,1-dioxides (5)
[17] have been synthesized, the only representative of the
homologous 2,3,4-benzothiadiazepine 2,2-dioxide family
described in the literature is the unsubstituted congener,
RESULTS AND DISCUSSION
We aimed at elaborating an efficient synthesis of new
2,3,4-benzothiadiazepine 2,2-dioxides (9) exhibiting an
aryl substituent at the 5-position and various substituents
on the benzene ring, by ring closure of sulfonyl chlorides
10 with hydrazine (Scheme 3). Because the reaction condi-
tions applied for the preparation of sulfonyl chloride 7
(Scheme 2) are not generally suitable for the synthesis of
the related type 10 compounds, we decided to elaborate a
new synthesis for these key intermediates.
In recent publications, we have described the synthesis of
phthalides 11, which now serve as the starting compounds
in our synthesis [19,20]. The reaction sequence starting
from phthalides monosubstituted at the aromatic ring
(11a,b) is depicted in Scheme 3, while that starting from
the thiadiazolophthalide congener (5H,7H-furo[3,4-f]
[2,1,3]benzothiadiazol-5-one, 11c) is shown in Scheme 4.
© 2014 HeteroCorporation

J. Fetter, F. Bertha, B. Molnar, B. Volk, and G. Simig
Vol 000
Scheme 1
Scheme 2
analysis data and proven by gravimetric determination of
the sodium content of 14a. 2,3,4-Benzothiadiazepine 2,2-di-
oxides 9 were then prepared from methanesulfonates 14 in
one-pot reaction with thionyl chloride furnished sulfonyl
chlorides 10, which were cyclized with hydrazine to give
the target compounds 9. The structure of 9d has also been
determined by single-crystal X-ray diffraction (see the
Supporting Information).
o-Chloromethyl benzoyl chlorides 12 were prepared as
described in the literature [21], by the reaction of phthalides
11 with thionyl chloride in xylene in the presence of boron
trifluoride diethyl etherate and benzyltriethylammonium
chloride. Ketones 13a–c were obtained by the reaction of
compounds 12a,b with an organomagnesium (13a,c) or
organolithium (13b) reagent. It is remarkable that com-
pound 13d could not be prepared in a similar manner. It
was obtained by treatment of benzoyl chloride 12c with
fluorobenzene under Friedel–Crafts conditions (Scheme 4).
o-Aroylbenzyl chlorides 13 were treated with sodium
sulfite [22]. To our surprise, the products obtained after
acidic workup were not the sulfonic acids but sodium
methanesulfonates 14, as indicated by the elementary
Attempts to N-methylate benzothiadiazepine 9a with
methyl iodide in the presence of sodium hydrogen carbonate
in refluxing acetonitrile resulted in only low yields (10–15%)
of the required product 15a, indicating the occurrence of a
side reaction. Indeed, when refluxing compound 9a with
sodium hydrogen carbonate in the absence of a methylating
agent, benzo[c]thiophene 2,2-dioxide 16 was obtained in
83% yield (Scheme 5). The structure of 16 has been proven
by X-ray diffraction (see the Supporting information). A
similar ring contraction was observed by King et al. when
compound 6a was heated at 175–180°C for 5 min [18].
Finally, benzothiadiazepines 9 were successfully meth-
ylated to compounds 15 in high yield, using methyl iodide
Scheme 3
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

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Versatile Synthesis of 5-Aryl-2,3,4-benzothiadiazepine 2,2-dioxides
Scheme 4
Inova 500 (Palo Alto, CA; 500 and 125 MHz for 1H and 13C
Scheme 5
NMR spectra, respectively) or a Varian Mercury Plus 200 (200
and 50 MHz for 1H and 13C NMR spectra, respectively), or a
Bruker Avance III 400 (400 and 100 MHz for 1H and 13C spectra,
respectively) spectrometer. DMSO-d6 or CDCl3 was used as the
solvent and TMS as the internal standard. Chemical shifts (δ)
and coupling constants (J) are given in parts per million and in
Hertz, respectively. Elemental analyses were performed on a
Vario EL III analyzer (Elementar Analysensysteme GmbH,
Hanau, Germany). The reactions were followed by analytical thin
layer chromatography on silica gel 60 F254 (Merck Millipore,
Darmstadt, Germany). All reagents were purchased from com-
mercial sources. Analytical samples of new compounds were
obtained by recrystallization from the solvents given as follows.
in the presence of DBU in acetonitrile at ambient tempera-
ture (Schemes 3 and 4). It is important to note that the
N-methylated derivative 15a proved to be completely
stable when refluxing for 15 h in acetonitrile in the pres-
ence of sodium hydrogen carbonate.
5-Chloro-2-(chloromethyl)-benzoyl chloride (12a).
To a
suspension of 11a (18.7g, 0.111mol) in xylene (100mL), thionyl
chloride (22 mL, 36.0g, 0.303 mol), boron trifluoride diethyl
etherate (1.6 mL, 1.84 g, 13 mmol), and benzyltriethylammonium
chloride (2.30g, 10 mmol) were added, and the mixture was
refluxed for 5 h. The solvent was evaporated, and diethyl ether
(100mL) was added to the residue. After treatment with charcoal
and evaporation of the solvent, the oily residue was distilled in
vacuo (bp 118–121°C, 4 × 10À2 Hgmm) to give 12a (22.9g, 89%)
as a colorless oil, which solidified in the refrigerator to give a
colorless solid (mp 30–32°C). 1H NMR (CDCl3, 400MHz): δ
8.20 (s, 1H), 7.60 (d, J= 8.4 Hz, 1H), 7.55 (d, J= 8.3 Hz, 1H), 4.85
(s, 2H) ppm. 13C NMR (CDCl3, 100 MHz): δ 166.5, 137.4, 134.8,
134.4, 133.5, 133.3, 132.3, 43.0 ppm. IR (KBr, cmÀ1): 1766, 1560,
1479. Elemental analysis for C8H5Cl3O (223.49): Calcd C 43.00,
H 2.26, Cl 47.59%; Found C 43.16, H 2.40, Cl 47.14%.
In conclusion, a high-yielding reaction sequence has
been elaborated for the preparation of a novel compound
family, 5-aryl-2,3,4-benzothiadiazepine 2,2-dioxides.
Besides the target compounds described earlier (9a–d and
15a–d), several other representatives of this family were
synthesized at our laboratory, and preliminary in vivo ani-
mal experiments demonstrated their central nervous system
pharmacological activity [23]. Nevertheless, thanks to the
novel, versatile intermediates (10 and 12–14), the signifi-
cance of the synthetic route described earlier goes beyond
the synthesis of these particular compounds. Further efforts
are in progress for the application of these intermediates for
the synthesis of other new heterocyclic ring systems.
2-(Chloromethyl)-4-fluorobenzoyl chloride (12b).
This
compound was prepared according to the procedure described
for the synthesis of 12a, starting from 11b (20.0 g, 0.132 mol)
[19] to give after distillation 12b (23.6 g, 86%) as a colorless oil
1
(bp 120–122°C, 10À1 Hgmm). H NMR (DMSO-d6, 400 MHz):
EXPERIMENTAL
δ 8.35 (dd, J = 8.9, 5.6 Hz, 1H), 7.42 (dd, J = 9.3, 2.4 Hz, 1H),
7.18 (td, J = 9.7, 2.6 Hz, 1H), 4.91 (s, 2H) ppm. 13C NMR
(DMSO-d6, 100 MHz): δ 166.4, 166.1 (d, J = 259.3 Hz), 143.2
(d, J = 9.3 Hz), 137.5 (d, J = 9.8 Hz), 127.8, 118.1
(d, J = 23.9 Hz), 115.7 (d, J = 21.6 Hz), 43.6 ppm. IR (KBr, cmÀ1):
1768, 1607, 1583, 1220. Elemental analysis for C8H5Cl2FO
All melting points were determined on a Büchi (Flawil,
Switzerland) B-540 capillary melting point apparatus and are
uncorrected. IR spectra were obtained on a Bruker Vector 22
FT spectrometer (Billerica, MA) in KBr pellets or in neat. 1H
and 13C NMR spectra were recorded at 303 K on a Varian Unity
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

J. Fetter, F. Bertha, B. Molnar, B. Volk, and G. Simig
Vol 000
(207.03): Calcd C 46.41, H 2.43, Cl 34.25%; Found C 46.48,
59.83, H 3.14, Cl 22.07, S 9.98%; Found C 59.60, H 3.15, Cl
H 2.48, Cl 34.10%.
6-(Chloromethyl)-2,1,3-benzothiadiazole-5-carbonyl chloride
22.14, S 9.87%.
[2-(Chloromethyl)-4-fluorophenyl](4-fluorophenyl)methanone
(12c). This compound was prepared according to the procedure
described for the synthesis of compound 12a, starting from 11c
(60.5 g, 0.315 mol) [20] to give after distillation 12c (73.8 g, 95%)
as a colorless oil (bp 110–115°C, 10À2 Hgmm), which solidified at
ambient temperature (mp 45–47°C). 1H NMR (DMSO-d6,
400 MHz): δ 8.59 (s, 1H), 8.31 (s, 1H), 5.30 (s, 2H) ppm. 13C
NMR (DMSO-d6, 100 MHz): δ 167.4, 154.8, 153.3, 138.2, 132.3,
124.5, 123.0, 44.9 ppm. IR (KBr, cmÀ1): 1749, 1145, 880.
Elemental analysis for C8H4Cl2N2OS (247.10): Calcd C 38.89, H
1.63, N 11.34, Cl 28.69, S 12.98%; Found C 39.22, H 1.61, N
(13c). This compound was prepared according to the procedure
described for the synthesis of compound 13a, starting from 12b
(8.0 g 38.6 mmol) to give crude 3c (10.2 g) as a pale green oil,
which was used in the next reaction step without further
purification. An analytical sample of compound 13c was
prepared by flash chromatography (eluent:hexane/EtOAc = 95:5),
to give colorless crystals, mp 62–63°C (after trituration with
pentane). 1H NMR (CDCl3, 400 MHz): δ 7.83 (dd, J = 9.0,
5.5 Hz, 2H), 7.38 (dd, J = 8.4, 5.5 Hz, 1H), 7.33 (dd, J = 9.3,
2.4 Hz, 1H), 7.14 (t, J = 9.0 Hz, 2H), 7.06 (td, J = 8.2, 2.6 Hz,
1H), 4.75 (s, 2H) ppm. 13C NMR (CDCl3, 100 MHz): δ 194.6,
165.9 (d, J = 255.9 Hz), 163.6 (d, J = 252.9 Hz), 140.5
(d, J = 8.3 Hz), 133.7 (d, J = 2.9 Hz), 133.7 (d, J = 2.9 Hz), 132.9
(d, J = 9.3 Hz), 131.7 (d, J = 9.3 Hz), 117.7 (d, J = 22.5 Hz),
115.7 (d, J = 22.0 Hz), 114.5 (d, J = 21.5 Hz), 42.6 (d, J = 1.5 Hz)
ppm. IR (KBr, cmÀ1): 1652, 1593, 1411, 1282. Elemental
analysis for C14H9ClF2O (266.68): Calcd C 63.06, H 3.40, Cl
11.38, Cl 28.41, S 12.77%.
[5-Chloro-2-(chloromethyl)phenyl](4-fluorophenyl)methanone
(13a). To a solution of 12a (56.7 g, 0.254 mol) in toluene (500 mL)
was added an ethereal solution of 4-fluorophenylmagnesium bromide
[prepared from 4-bromofluorobenzene (31 mL, 49.4 g, 0.282 mol)
and magnesium (7.0 g, 0.288 mol) in diethyl ether (250 mL)]
dropwise under vigorous stirring at À20°C. The cooling bath
was removed, and the mixture was stirred for 2 h, while the
temperature rose to 0°C. An aqueous HCl solution (1.0M,
110 mL, 0.11 mol) was added, the mixture was stirred for 5 min,
and then the layers were separated. The aqueous layer was
extracted with diethyl ether (2 × 200 mL), the combined organic
layer was washed with saturated aqueous NaHCO3 solution
(100 mL) and brine (100 mL), dried (MgSO4), and evaporated to
give crude 13a (72.0 g) as a yellow oil, which was used in the
next reaction step without further purification. An analytical
sample of compound 13a was prepared by flash chromatography
(eluent:hexane/EtOAc = 98:2), to give a colorless solid, mp 100–
101°C (hexane). 1H NMR (CDCl3, 400 MHz): δ 7.86 (dd,
J = 9.0, 5.5 Hz, 2H), 7.51 (d, J = 8.3 Hz, 1H), 7.47 (dd, J = 8.3,
2.1 Hz, 1H), 7.32 (d, J = 2.1 Hz, 1H), 7.16 (t, J = 8.7 Hz, 2H),
4.68 (s, 2H) ppm. 13C NMR (DMSO-d6, 100 MHz): δ 194.3,
166.2 (d, J = 256.4 Hz), 139.6, 135.4, 134.0, 133.1
(d, J = 3.0 Hz), 133.0 (d, J = 9.3 Hz), 132.0, 130.8, 128.8, 115.9
(d, J = 22.5 Hz), 42.4 ppm. IR (KBr, cmÀ1): 1668, 1597, 1504.
Elemental analysis for C14H9Cl2FO (283.13): Calcd C 59.39,
13.29%; Found C 63.04, H 3.36, Cl 13.16%.
[6-(Chloromethyl)-2,1,3-benzothiadiazol-5-yl](4-fluorophenyl)
methanone (13d). To a solution of 12c (12.3 g, 50 mmol) and
fluorobenzene (45 mL, 72.0 g, 411 mmol) in dichloromethane
(45 mL) was added AlCl3 (13.8 g, 104 mmol) at 0°C in small
portions, under stirring. The resulting mixture was stirred for further
2 h at ambient temperature. It was poured on ice, concentrated
aqueous HCl (10 mL) was added, and the layers were separated.
The aqueous layer was extracted with dichloromethane
(2 × 50 mL). The combined organic layer was dried (MgSO4)
and evaporated. The residue was triturated with cold (À20°C)
methanol (20 mL) to give 13d (13.4 g, 87%) as colorless
crystals, mp 106–107°C (hexane–EtOAc). 1H NMR (CDCl3,
200 MHz): δ 8.15 (q, J = 0.7 Hz, 1H), 8.01 (s, 1H), 7.97 (dd,
J = 9.2, 5.5 Hz, 2H), 7.19 (t, J = 8.6 Hz, 2H), 4.97 (s, 2H) ppm.
13C NMR (CDCl3, 50 MHz): δ 194.3, 166.2, (d, J = 256.8 Hz),
154.7, 153.2, 138.9, 138.4, 133.2 (d, J = 9.5 Hz), 123.0, 122.9,
115.9 (d, J = 22.1 Hz), 43.8 ppm. IR (KBr, cmÀ1): 1660, 1592,
1504. Elemental analysis for C14H8ClFN2OS (306.75): Calcd C
54.82, H 2.63, N 9.13, Cl 11.56, S 10.45%; Found C 54.99, H
H 3.20, Cl 25.04%; Found C 58.35, H 3.13, Cl 24.35%.
1-Benzothiophen-2-yl[5-chloro-2-(chloromethyl)phenyl]
2.66, N 9.19, Cl 11.48, S 10.35%.
Sodium {4-chloro-2-[(4-fluorophenyl)carbonyl]phenyl}
methanone (13b).
To a solution of 12a (16.0 g, 72 mmol) in
methanesulfonate (14a).
A mixture of crude 13a (32 g,
THF (300 mL) was added a solution of 2-benzo[b]thienyllithium
[prepared by lithiation of a solution of benzo[b]thiophene (8.1 g,
60mmol) in THF (200 mL) with butyllithium (31.2mL of a 2.5M
solution in hexane, 78mmol) at À78°C] dropwise at À78°C. The
mixture was allowed to warm to À20°C over a period of 3 h. A
saturated aqueous solution of NH4Cl (280 mL) and ethyl acetate
(240 mL) was added. After separation, the organic layer was
washed with saturated aqueous NaHCO3 solution (200 mL) and
brine (200mL), dried (MgSO4), and evaporated to give crude 13b
(20.2 g) as a pale yellow oil, which was used in the next reaction
step without further purification. An analytical sample of
compound 13b was prepared by flash chromatography (eluent:
hexane/EtOAc = 98:2) as pale yellow crystals, mp 94–96°C. 1H
NMR (DMSO-d6, 400 MHz): δ 8.12 (d, J = 8.2Hz, 1H), 8.08
(d, J = 8.0Hz, 1H), 7.96 (s, 1H), 7.82 (s, 1H), 7.72 (m, 2H), 7.59
(t, J = 7.6Hz, 1H), 7.49 (t, J = 7.6Hz, 1H), 4.83 (s, 2H) ppm. 13C
NMR (DMSO-d6, 100MHz): δ 188.9, 142.7, 142.5, 139.3, 139.1,
135.1, 134.9, 133.3, 133.0, 131.2, 128.8, 128.5, 127.2, 125.5,
123.3, 42.5ppm. IR (KBr, cmÀ1): 1637, 1511, 1294, 1184.
an aliquot portion of the 72g crude 13a described earlier), sodium
sulfite (30.0g, 238 mmol), dioxane (420 mL), and water (620mL)
was refluxed for 2 h and evaporated to dryness. tert-Butyl methyl
ether (30 mL) was added, the mixture was stirred for 5 min, and
the solvent was decanted. Concentrated aqueous HCl (50mL,
60g, 0.61 mol) was added at a temperature of 0–5°C. The
suspension obtained was filtered, and the crystalline product was
washed with cold (ca. 5°C) water (2 × 20mL) and dried to give
14a (23.8g, 60%, calculated for 12a) as a colorless solid, mp
1
254–256°C (water). H NMR (DMSO-d6, 500MHz): δ 7.80 (dd,
J = 8.8, 5.7 Hz, 2H), 7.55 (m, 2H), 7.35 (t, J = 8.8 Hz, 2H), 7.23
(m, 1H), 3.98 (s, 2H) ppm. 13C NMR (DMSO-d6, 125MHz): δ
194.9, 165.1 (d, J = 251.5Hz), 141.0, 134.6, 134.0 (d, J = 2.9Hz),
133.6, 133.4 (d, J =9.3 Hz), 130.8, 129.9, 127.9, 115.5
(d, J = 22.0 Hz), 53.0 ppm. IR (KBr, cmÀ1): 1667, 1598, 1412.
Elemental analysis for C14H9ClFO4SNa (350.73): Calcd C
47.94, H 2.59, Cl 10.11, S 9.14%; Found C 47.56, H 2.77, Cl
10.00, S 9.06%. Sodium content (gravimetric): Calcd 6.55%,
Found 6.22%.
Elemental analysis for C16H10Cl2OS (321.23): Calcd
C
Journal of Heterocyclic Chemistry
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Versatile Synthesis of 5-Aryl-2,3,4-benzothiadiazepine 2,2-dioxides
Sodium [2-(1-benzothiophen-2-ylcarbonyl)-4-chlorophenyl]
methanesulfonate (14b). This compound was prepared
(dd, J = 8.2, 2.1 Hz, 1H), 7.46 (d, J = 8.2 Hz, 1H), 7.25
(d, J = 2.2 Hz, 1H), 7.15 (t, J = 8.6 Hz, 2H), 7.08 (br s, 1H), 4.39
(s, 2H) ppm. 13C NMR (CDCl3, 125 MHz): δ 171.2, 165.1
(d, J = 254.4 Hz), 135.3, 135.0, 131.7 (d, J = 8.8 Hz), 131.7,
131.0 (d, J = 2.9 Hz), 130.7, 129.5, 129.2, 116.0 (d, J = 22.0 Hz),
55.7. IR (KBr, cmÀ1): 3222, 1602, 1508, 1329. Elemental
analysis for C14H10ClFN2O2S (324.76): Calcd C 51.78, H 3.10,
according to the procedure described for the synthesis of
compound 14a, starting from crude 13b (20.2g, 63 mmol) to give
the title compound 14b (13.4 g, 48%, calculated for 12a) as a
colorless solid, mp 313–315°C (water). 1H NMR (DMSO-d6,
200 MHz): δ 8.09 (m, 1H), 8.05 (m, 1H), 7.82 (d, J = 0.4 Hz, 1H),
7.58 (m, 3H), 7.55 (m, 1H), 7.46 (m, 1H), 3.94 (s, 2H) ppm. 13C
NMR (DMSO-d6, 50MHz): δ 189.7, 143.3, 142.1, 140.1, 139.2,
134.5, 134.1, 133.6, 130.8, 129.9, 128.0, 127.9, 126.9, 125.3,
123.2, 53.0 ppm. IR (KBr, cmÀ1): 1650, 1512, 1300, 1182, 1040.
Elemental analysis for C16H10ClO4S2Na (388.83): Calcd C 49.43,
H 2.59, S 16.49, Cl 9.12%; Found C 48.93, H 2.61, S 16.27, Cl
N 8.63%; Found C 51.87, H 3.13, N 8.51%.
5-(1-Benzothiophen-2-yl)-7-chloro-1,3-dihydro-2,3,4-
benzothiadiazepine 2,2-dioxide (9b).
This compound was
prepared analogously to 9a starting from 14b (13.2 g, 33.9 mmol)
to give 9b (7.38 g, 60%) as colorless crystals, mp 194–195°C
(ethanol). 1H NMR (DMSO-d6, 200 MHz): δ 10.52 (s, 1H),
8.02 (t, J = 7.0 Hz, 1H), 7.94 (d, J = 1.5 Hz, 1H), 7.78–7.64 (m,
3H), 7.62 (s, 1H), 7.55–7.36 (m, 2H), 4.76 (s, 2H) ppm. 13C
NMR (DMSO-d6, 125 MHz): δ 166.3, 140.5, 139.7, 139.2,
134.6, 133.2, 131.5, 131.4 130.8, 128.7, 127.1, 125.6, 125.0,
122.7, 122.6, 54.6 ppm. IR (KBr, cmÀ1): 3200, 1322, 1158.
Elemental analysis for C16H11ClN2O2S2 (362.86): Calcd C
52.96, H 3.06, N 7.72, Cl 9.77%; Found C 52.74, H 3.18, N
8.92%.
Sodium {5-fluoro-2-[(4-fluorophenyl)carbonyl]phenyl}
methanesulfonate (14c).
This compound was prepared
according to the procedure described for the synthesis of
compound 14a, starting from crude 13c (5.0 g, 18.7 mmol, an
aliquot portion of the 10.2 g crude 13a described earlier) to
give the title compound 14c (4.30 g, 68%, calculated for 12b)
as a colorless solid, mp 286–288°C (water). 1H NMR (DMSO-d6,
400 MHz): δ 7.75 (m, 2H), 7.33 (t, J = 8.2 Hz, 2H), 7.32 (m, 1H),
7.25 (dd, J = 7.2, 6.2 Hz, 1H), 7.14 (t, J = 7.6 Hz, 1H), 3.99
(s, 2H) ppm. 13C NMR (DMSO-d6, 100 MHz): δ 195.4, 164.9
(d, J = 249.6 Hz), 162.4 (d, J = 244.7 Hz), 138.3 (d, J = 9.0 Hz),
135.8 (d, J = 2.9Hz), 134.6 (d, J = 2.6 Hz), 133.2 (d, J = 9.5 Hz),
131.0 (d, J = 8.9 Hz), 119.1 (d, J = 21.8 Hz), 115.3 (d,
J = 22.0Hz), 112.6 (d, J = 21.4 Hz), 53.3 ppm. IR (KBr, cmÀ1):
1766, 1665, 1598, 1504, 1411, 1233, 1049. Elemental analysis for
C14H9F2O4SNa (334.28): Calcd C 50.30, H 2.71, S 9.59%; Found
7.66, Cl 9.88%.
8-Fluoro-5-(4-fluorophenyl)-1,3-dihydro-2,3,4-benzothiadiazepine
2,2-dioxide (9c). This compound was prepared analogously to
9a starting from 14c (4.3 g, 12.9 mmol) to give 9c (2.38 g, 60%) as
colorless crystals, mp 229–230°C (ethanol). 1H NMR (DMSO-d6,
400 MHz): δ 10.31 (s, 1H), 7.66 (dd, J = 8.9, 5.6 Hz, 2H), 7.55 (dd,
J = 9.3, 2.5 Hz, 1H), 7.33 (t, J = 8.8Hz, 2H), 7.33 (td, J = 8.5,
2.0 Hz, 1H), 7.26 (dd, J = 8.6, 5.7 Hz, 1H), 4.73 (s, 2H) ppm. 13C
NMR (DMSO-d6, 100 MHz): δ 170.7, 164.1 (d, J = 249.5 Hz),
163.1 (d, J = 249.0 Hz), 135.1 (d, J = 9.3Hz), 132.5 (d, J = 2.9 Hz),
131.9 (d, J = 8.8 Hz), 131.7 (d, J = 9.3Hz), 130.7 (d, J = 2.9Hz),
116.4 (d, J = 23.0Hz), 115.7 (d, J = 22.0 Hz), 115.3
(d, J = 22.0 Hz), 55.0 ppm. IR (KBr, cmÀ1): 3098, 1610, 1511,
1327. Elemental analysis for C14H10F2N2O2S (308.31): Calcd C
54.54, H 3.27, N 9.09, S 10.40%; Found C 54.62, H 3.28, N 9.07,
C 50.17, H 2.65, S 9.69%.
Sodium {6-[(4-fluorophenyl)carbonyl]-2,1,3-benzothiadiazol-
5-yl}methanesulfonate (14d).
This compound was prepared
according to the procedure described for the synthesis of
compound 14a, starting from compound 13d (20.0g, 65.2mmol)
to give the title compound 14d (22.0 g, 90%) as a pale yellow
powder, mp 320–323°C (water, dec.). 1H NMR (DMSO-d6,
500 MHz): δ 8.09 (d, J = 0.6 Hz, 1H), 7.91 (d, J= 0.6 Hz, 1H), 7.90
(dd, J= 8.8, 5.5 Hz, 2H), 7.36 (t, J= 8.9 Hz, 2H), 4.21 (s, 2H) ppm.
13C NMR (DMSO-d6, 125 MHz): δ 194.9, 165.1 (d, J= 251.5 Hz),
154.6, 152.4, 141.2, 136.5, 134.0 (d, J = 2.9 Hz), 133.8
(d, J= 9.3 Hz), 124.1, 121.5, 115.3 (d, J = 22.0 Hz), 53.7 ppm. IR
(KBr, cmÀ1): 1657, 1600, 1207. Elemental analysis for
C14H8FN2O4S2Na (374.35): Calcd C 44.92, H 2.15, N 7.48%;
S 10.33%.
9-(4-Fluorophenyl)-5H,7H-[1,2,5]thiadiazolo[3,4-h][2,3,4]
benzothiadiazepine 6,6-dioxide (9d).
This compound was
prepared analogously to 9a starting from 14d (23.1 g,
61.8 mmol) with a favorable change in the final workup. After
addition of concentrated aqueous HCl (200 mL) and water
(200 mL) to the reaction mixture, a suspension was formed.
The crystalline precipitation was filtered, washed with cold
(À20°C) ethanol (25 mL) to give 9d (15.9 g, 74%) as colorless
1
crystals, mp 222–225°C (ethanol–DMF). H NMR (DMSO-d6,
Found C 44.59, H 2.16, N 7.23%.
7-Chloro-5-(4-fluorophenyl)-1,3-dihydro-2,3,4-benzothiadiazepine
500 MHz): δ 10.34 (s, 1H), 8.38 (s, 1H), 8.02 (s, 1H), 7.80
(dd, J = 8.7, 5.5 Hz, 2H), 7.36 (t, J = 8.9 Hz, 2H), 4.96 (s, 2H)
ppm. 13C NMR (DMSO-d6, 125 MHz): δ 172.0, 164.3 (d,
J = 250.0 Hz), 154.4, 153.0, 136.3, 133.1, 132.4 (d, J = 2.9 Hz),
132.2 (d, J = 8.7 Hz), 122.6, 121.5, 115.8 (d, J = 22.0 Hz),
55.1 ppm. IR (KBr, cmÀ1): 1569, 1508, 1326. Elemental
analysis for C14H9FN4O2S2 (348.38): Calcd C 48.27, H 2.60,
2,2-dioxide (9a). A mixture of methanesulfonate 14a (9.50 g,
27 mmol) and thionyl chloride (30 mL, 49.2 g, 413 mmol) was
refluxed for 3 h. The excess of thionyl chloride was removed in
vacuo. Toluene (60 mL) was added, and the solution evaporated
to dryness. The oily residue (compound 10a) was dissolved in
dichloromethane (50 mL), and the solution was added dropwise
to a stirred mixture of hydrazine monohydrate (16.5 mL, 17.0 g,
340 mmol) and dichloromethane (140 mL) at 0°C. It was stirred
for 2 h at ambient temperature, and concentrated aqueous HCl
(80 mL) and water (60 mL) were added. After separation, the
aqueous layer was extracted with dichloromethane (2 × 20 mL),
and the combined organic layer was dried (MgSO4), treated with
charcoal, and evaporated to dryness. The residue was triturated
with cold (À20°C) ethanol (10 mL) to give compound 9a (6.0 g,
N 16.08, S 18.41%; Found C 48.30, H 2.55, N 16.17, S 18.43%.
7-Chloro-5-(4-fluorophenyl)-3-methyl-1,3-dihydro-2,3,4-
benzothiadiazepine 2,2-dioxide (15a).
DBU (0.5 mL, 0.51 g,
3.3 mmol) and methyl iodide (0.21 mL, 0.48 g, 3.3 mmol) was
added to a solution of 9a in acetonitrile (30mL) at ambient
temperature. After stirring for 30 min at ambient temperature, the
solvent was evaporated; then dichloromethane (40 mL) and water
(10 mL) were added to the residue. After separation, the organic
layer was washed with water (2× 10 mL), dried (MgSO4), and
evaporated. The residue was triturated with methanol (3 mL), and
1
68%) as colorless crystals, mp 195–198°C (methanol). H NMR
(CDCl3, 500 MHz): δ 7.70 (dd, J = 5.3, 2.2 Hz, 2H), 7.57
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

J. Fetter, F. Bertha, B. Molnar, B. Volk, and G. Simig
Vol 000
as colorless crystals, mp 112–114°C. 1H NMR (DMSO-d6,
500 MHz): δ 7.54 (m, 2H), 7.30 (m, 4H), 7.10 (s, 1H), 5.93
(s, 1H), 4.70 (d, J = 16 Hz, 1H), 4.63 (d, J = 16 Hz, 1H) ppm.
13C NMR (DMSO-d6, 125 MHz): δ 162.8, 138.5, 133.2, 132.7,
131.1, 129.0, 128.2, 126.7, 125.8, 116.0, 69.4, 54.1 ppm. IR
(KBr, cmÀ1): 1510, 1316, 1140. Elemental analysis for
C14H10ClFO2S (296.74): Calcd C 56.67, H 3.40, Cl 11.95, S
10.81%; found C 56.61, H 3.27, Cl 11.77, S 11.15%.
The ORTEP drawings of 9d and 16, CIF structure files (atomic
coordinates, bond lengths, bond angles, and torsion angles), and
conditions of the single-crystal X-ray measurements are available
free of charge via the Internet.
the crystalline product was filtered to give 15a (0.91 g, 90%) as
colorless crystals, mp 218–219°C (2-propanol). 1H NMR
(DMSO-d6, 500 MHz): δ 7.71 (dd, J = 8.9, 5.4 Hz, 2H), 7.55 (dd,
J = 8.2, 2.2 Hz, 1H), 7.45 (d, J = 8.3 Hz, 1H), 7.24 (d, J = 2.2Hz,
1H), 7.14 (t, J = 8.4 Hz, 2H), 4.35 (s, 2H), 3.14 (s, 3H) ppm. 13C
NMR (DMSO-d6, 125MHz): δ 169.8, 165.0 (d, J = 253.9 Hz),
135.7, 134.8, 131.7 (d, J = 8.8 Hz), 131.6, 130.9 (d, J = 3.4 Hz),
130.4, 128.9, 128.6, 115.9 (d, J = 22.0Hz), 55.2, 35.3 ppm. IR
(KBr, cmÀ1): 1323, 1135, 842. Elemental analysis for
C15H12ClFN2O2S (338.79): Calcd C 53.18, H 3.57, N 8.27, S
9.46, Cl 10.46%; Found C 52.96, H 3.56, N 8.23, S 9.55, Cl
10.53%.
5-(1-Benzothiophen-2-yl)-7-chloro-3-methyl-1,3-dihydro-
2,3,4-benzothiadiazepine 2,2-dioxide (15b).
This compound
was prepared analogously to 15a starting from 9b (1.09 g,
3.0 mmol) to give 15b (0.90 g, 80%) as colorless crystals, mp
249–251°C (acetonitrile). 1H NMR (DMSO-d6, 500 MHz): δ 8.03
(d, J = 7.9 Hz, 1H), 7.97 (d, J = 7.9 Hz, 1H), 7.78 (dd, J = 8.3,
2.3 Hz, 1H), 7.75 (d, J = 2.0Hz, 1H), 7.71 (d, J = 8.2 Hz, 1H),
7.65 (s, 1H), 7.50 (t, J = 6.9 Hz, 1H), 7.42 (t, J = 6.9 Hz, 1H), 4.89
(br s, 2H), 2.99 (s, 3H) ppm. 13C NMR (DMSO-d6, 125 MHz):
δ 165.8, 140.8, 139.2, 139.0, 134.8, 133.5, 132.2, 131.7, 131.4,
129.8, 128.5, 127.3, 125.7, 125.1, 122.8, 53.8, 35.0 ppm. IR
(KBr, cmÀ1): 1317, 1191, 1159, 1135. Elemental analysis for
C17H13ClN2O2S2 (376.89): Calcd C 54.18, H 3.48, N 7.43, Cl
9.41, S 17.02%; Found C 54.01, H 3.51, N 7.44, Cl 9.40,
Acknowledgments. The authors thank Dr. Tibor Bakó and Dr.
András Dancsó for the NMR assignments, Dr. László Párkányi
and Dr. András Dancsó for the single-crystal X-ray
measurements, and Ms. Tímea Törő for the help in the
preparation of the manuscript.
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benzothiadiazepine 2,2-dioxide (15c).
This compound was
prepared analogously to 15a starting from 9c (0.92 g, 3.0mmol) to
give 15c (0.85 g, 88%) as colorless crystals, mp 205–206°C
(methanol). 1H NMR (CDCl3, 500MHz): δ 7.70 (dd, J = 8.4,
5.4 Hz, 2H), 7.25 (m, 2H), 7.18 (dt, J = 8.3, 2.4 Hz, 1H), 7.12 (t,
J = 8.4Hz, 2H), 4.35 (s, 2H), 3.14 (d, J = 0.6 Hz, 3H) ppm. 13C
NMR (CDCl3, 125 MHz): δ 170.3, 165.0 (d, J = 253.4Hz), 163.9
(d, J =253.9Hz), 132.9 (d, J = 8.8 Hz), 131.7 (d, J =8.8 Hz), 131.3
(d, J = 3.4Hz), 131.1 (d, J = 9.3Hz), 130.4 (d, J = 3.4 Hz), 116.5
(d, J =22.9 Hz), 115.9 (d, J =22.0 Hz), 115.8 (d, J =22.0 Hz), 55.5
(d, J = 2.0Hz), 35.3 ppm. IR (KBr, cmÀ1): 1601, 1555, 1493,
1326, 1263, 1231. Elemental analysis for C15H12F2N2O2S
(322.34): Calcd C 55.89, H 3.75, S 9.95, N 8.69%; Found C
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55.98, H 3.57, S 9.98, N 8.79%.
9-(4-Fluorophenyl)-7-methyl-5H,7H-[1,2,5]thiadiazolo[3,4-h]
[2,3,4]benzothiadiazepine 6,6-dioxide (15d).
This compound
was prepared analogously to 15a starting from 9d (4.98 g,
14.3 mmol) to give 15d (4.80 g, 92%) as colorless crystals, mp
1
273–275°C (2-propanol–DMF). H NMR (DMSO-d6, 500 MHz):
δ 8.41 (s, 1H), 8.04 (s, 1H), 7.83 (dd, J= 8.9, 5.5Hz, 2H), 7.36 (t,
J =8.9Hz, 2H), 5.10 (s, 2H), 2.98 (s, 3H) ppm. 13C NMR
(DMSO-d6, 125 MHz): δ 171.1, 164.5 (d, J = 251.0 Hz), 154.5,
153.0, 136.0, 132.5 (d, J= 8.8 Hz), 132.1, 131.8 (d, J =2.9Hz),
122.3, 121.6, 115.8 (d, J= 22.0 Hz), 54.4, 34.6 ppm. IR (KBr,
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6-Chloro-1-(4-fluorophenyl)-1,3-dihydro-2-benzothiophene
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2014
Versatile Synthesis of 5-Aryl-2,3,4-benzothiadiazepine 2,2-dioxides
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet