Concise synthesis and displacement reactions of model 3-(alkylthio)- 6-chloro- and 2,6-dichlorothieno[2,3-e][1,4,2]dithiazine 1,1-dioxides

Article abstract of DOI:10.1515/znb-2011-0712

A series of 3-(alkylthio)-6-chlorothieno[2,3-e][1,4,2]dithiazine 1,1-dioxides (7a - e) were prepared via interaction of deprotonated 2,5-dichlorothiophene-3-sulfonamide with carbon disulfide under reflux, followed by alkylation with alkyl halides. Employment of dimethyl sulfate afforded the isomeric 2-methyl-3-thione derivative 8 together with the expected 3-(methylthio) derivative 7ain a molar ratio of 1 : 4. Treatment of 7a or 10 with ethylamine, aniline or p-chloroaniline produced the corresponding N-ethyl- (or N-phenyl)-6-chlorothieno[2,3-e][1,4,2]dithiazine-3-amine 1,1-dioxides 3a - c. Likewise, interaction of 7a with methylhydrazine (or phenylhydrazine) gave the respective 3-(1-methylhydrazinyl or 2-phenylhydrazinyl) 1,1-dioxides9a, b. Desulfonation of 6-chloro-3-(methylthio)thieno[ 2,3-e][1,4,2]dithiazine 1,1-dioxide (7a) with sulfuryl chloride produced 3,6-dichlorothieno[2,3- e][1,4,2]dithiazine 1,1-dioxide (10). The latter compound was used as a substrate for the preparation of N-alkyl- (or aryl)-6-chlorothieno[2,3-e][1,4,2] dithiazin-3-amine 1,1-dioxides 3a - c representing a new approach for the synthesis of similar derivatives. Compounds 7a -e showed modest to low antibacterial activity against E. coli and S. aureus.

Full text of DOI:10.1515/znb-2011-0712

Concise Synthesis and Displacement Reactions of Model 3-(Alkylthio)-
6-chloro- and 2,6-Dichlorothieno[2,3-e][1,4,2]dithiazine 1,1-Dioxides
Rajab Abu-El-Halawaa, Mohanad Masada, Yaser Bathicha, Mahmoud Al-Refaia,
Mohammad M. Ibrahima, Mustafa M. El-Abadelahb, and Wolfgang Voelterc
a Chemistry Department, Faculty of Science, Al al-Bayt University, Mafraq, Jordan
b Chemistry Department, Faculty of Science, The University of Jordan, Amman, Jordan
c Interfakulta¨res Institut fu¨r Biochemie, Universita¨t Tu¨bingen, Hoppe-Seyler-Straße 4,
72076 Tu¨bingen, Germany
Reprint requests to Prof. Dr. R. Abu-El-Halawa. E-mail: halawarajab@yahoo.com
Z. Naturforsch. 2011, 66b, 715 – 720; received April 27, 2011
Dedicated to Professor Johannes C. Jochims
A series of 3-(alkylthio)-6-chlorothieno[2,3-e][1,4,2]dithiazine 1,1-dioxides (7a – e) were prepared
via interaction of deprotonated 2,5-dichlorothiophene-3-sulfonamide with carbon disulfide under re-
flux, followed by alkylation with alkyl halides. Employment of dimethyl sulfate afforded the isomeric
2-methyl-3-thione derivative 8 together with the expected 3-(methylthio) derivative 7a in a molar
ratio of 1 : 4. Treatment of 7a or 10 with ethylamine, aniline or p-chloroaniline produced the corre-
sponding N-ethyl- (or N-phenyl)-6-chlorothieno[2,3-e][1,4,2]dithiazine-3-amine 1,1-dioxides 3a – c.
Likewise, interaction of 7a with methylhydrazine (or phenylhydrazine) gave the respective 3-(1-meth-
ylhydrazinyl or 2-phenylhydrazinyl) 1,1-dioxides 9a, b. Desulfonation of 6-chloro-3-(methylthio)thi-
eno[2,3-e][1,4,2]dithiazine 1,1-dioxide (7a) with sulfuryl chloride produced 3,6-dichlorothieno[2,3-
e][1,4,2]dithiazine 1,1-dioxide (10). The latter compound was used as a substrate for the preparation
of N-alkyl- (or aryl)-6-chlorothieno[2,3-e][1,4,2]dithiazin-3-amine 1,1-dioxides 3a – c representing
a new approach for the synthesis of similar derivatives. Compounds 7a – e showed modest to low
antibacterial activity against E. coli and S. aureus.
Key words: 2,5-Dichlorothiophene-3-sulfonamide, Cyclization with Carbon Disulfide,
Thieno[2,3-e][1,4,2]dithiazine 1,1-Dioxides, SN-Ar Reactions
Introduction
Quite recently, we have reported [7] on the syn-
thesis of N-(alkyl/aryl)thieno[2,3-e][1,4,2]dithiazin-3-
amine 1,1-dioxides (3; vide infra), bioisosteres of
1,4,2-benzodithiazine 1,1-dioxides (such as 1a).
We thought it would be worthwhile to explore a
synthetic route towards a new set of 3-alkylthio-6-
chlorothieno[2,3-e][1,4,2]dithiazine1,1-dioxides (7a –
7e) as depicted in Scheme 1. The latter compounds
would also be useful substrates for the synthesis of
N-(substituted) 6-chlorothieno[2,3-e][1,4,2]dithiazin-
3-hydrazine 1,1-dioxides (9a, b; Scheme 2) as well as
Several 1,4,2-benzodithiazine 1,1-dioxides 1 have
been prepared and have shown interesting phar-
macological activities [1]. Examples include com-
pounds 1a [2] and 1b [3] that exhibit antihyperten-
sive and diuretic activities, while 1c [4] exhibits mod-
erate anticancer activity (Fig. 1). The 1,4,2-benzodi-
thiazine ring system is currently utilized in the prepa-
ration of new S,N-disubstituted 2-mercaptobenzene-
sulfonamides (2) that are used for the treatment of can-
cer [5, 6a] and HIV [6] infections.
O
O
O
N
O
O
O
R1
R2
R1
R2
S
S
S
S
S
NHR
R3
N
Cl
S
R3
S
NHR
1
3
2
1a ( R1 = CO2H; R2 = H, Cl; R3 = NHAr)
1b ( R1 = CO2H; R2 = Cl; R3 = SMe)
1c ( R1 = Cl; R2 =Me; R3 = NHNHR)
Fig 1.
c
0932–0776 / 11 / 0700–0715 $ 06.00 ꢀ 2011 Verlag der Zeitschrift fu¨r Naturforschung, Tu¨bingen · http://znaturforsch.com
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716 R. Abu-El-Halawa et al. · Model 3-(Alkylthio)-6-chloro- and 2,6-dichlorothieno[2,3-e][1,4,2]dithiazine 1,1-Dioxides
Scheme 1.
N-(substituted) 6-chlorothieno[2,3-e][1,4,2]dithiazin-
3-amine 1,1-dioxides (3a, b) as illustrated in Scheme 3.
Results and Discussion
In the present work, a new selected set of 3-alk-
ylthio-6-chlorothieno[2,3-e][1,4,2]dithiazine1,1-diox-
ides (7a – e) were synthesized utilizing 2,5-dichloro-
thiophene-3-sulfonamide (4). The latter substrate was
prepared according to a reported procedure [8] that
Scheme 2.
involves the reaction of 2,5-dichlorothiophene with
chlorosulfonic acid, followed by treatment of the re-
sulting 2,5-dichlorothiophene-3-sulfonyl chloride with
excess concentrated aqueous ammonium hydroxide.
Deprotonation of 4 with sodium hydride in dry DMF
(or potassium hydroxide in absolute ethanol) gave the
sulfonamide anion which reacts with carbon disulfide
in the presence of excess NaH (or KOH) to deliver the
intermediate 5. Upon heating, the latter underwent in-
tramolecular cyclization to produce the cyclic sodium
(or potassium) salt 6 (Scheme 1), desired for further
derivatization.
The intermediate salt (6, M = NH4+) was character-
ized as its ammonium salt, (obtained upon treatment
of 6 with ammonium chloride), the structure of which
has been confirmed by single-crystal X-ray diffraction
analysis [9].
yl) (8) derivatives in a 4 : 1 molar ratio (Scheme 1).
The reaction of methylhydrazine or phenylhy-
drazine with 7a gave the corresponding 6-chloro-3-
(1-methyl or 2-phenylhydrazinyl)thieno[2,3-e][1,4,2]-
dithiazine 1,1-dioxides (9a, b) (Scheme 2).
Desulfonation of 7a with sulfuryl chloride produced
3,6-dichlorothieno[2,3-e][1,4,2]dithiazine 1,1-dioxide
(10) (Scheme 2).
Compounds 7 and 10, incorporating a good leaving
groups at C-3, were used for the preparation of 3-alk-
yl- (or aryl)amino-6-chlorothieno[2,3-e][1,4,2]dithiaz-
ine 1,1-dioxides 3a – c. This represents a new approach
for the synthesis of this class of derivatives (Scheme 3).
The latter compounds were identical with authentic
samples previously prepared by another route involv-
ing direct interaction of deprotenated 4 with the appro-
priate ethyl or phenyl isothiocyanate [7] (Scheme 3).
Elemental analyses and spectral (MS and NMR)
Treatment of 6 with excess alkyl halides yielded the
corresponding 3-(S-alkyl) derivatives 7a – e. However,
treatment of 6 with excess dimethyl sulfate afforded a data of the new compounds 7 – 10, given in the Ex-
separable mixture of 3-(S-methyl) (7a) and 2-(N-meth- perimental Part, are in accordance with the assigned
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R. Abu-El-Halawa et al. · Model 3-(Alkylthio)-6-chloro- and 2,6-dichlorothieno[2,3-e][1,4,2]dithiazine 1,1-Dioxides 717
Scheme 3.
structures. Thus, the MS spectra display the correct compounds 3a – c did not show any significant antibac-
molecular ions as suggested by their molecular formu- terial activity.
las. The isotopic cluster in the molecular ion region of
Experimental Section
the prepared compounds 7 – 9 (M and M+2, with rela-
tive intensities 3 : 1) is in accordance with the presence
of only one chlorine atom, while the isotopic cluster
in the molecular ion region of 10 (M, M+2 and M+4
with relative intensities 9 : 6 : 1) is in agreement with
the presence of two chlorine atoms. The EI fragmen-
tation of 7a – e proceeds via elimination of an alkyl
thiocyanate fragment (R-SCN) from the molecular ion
leading to the formation of the respective ion with
m/z = 212. The latter ion suffers consecutive extrusion
of SO2, chlorine atom and CS with ultimate produc-
tion of ions with m/z = 148, m/z = 113, and m/z = 69,
respectively.
2,5-dichlorothiophene was purchased from Acros. The
alkyl halides and hydrazines used in this study were pur-
chased from Fluka. Melting points were determined on an
Electrothermal-9002 apparatus. IR spectra were obtained
from KBr discs on a Nicolet Impact-400 FT-IR spectropho-
tometer. 1H and 13C NMR spectra were recorded on a Bruker
AV-300 ultrashield instrument. Chemical shifts are expressed
in ppm with reference to TMS as internal standard. Elec-
tron impact mass spectra (EIMS) were taken with a Shi-
madzo QP instrument at 70 eV and at an ion source tem-
◦
perature of 250 C. High-resolution mass spectra (HRMS)
were measured using the electrospray ion trap (ESI) tech-
nique by collision-induced dissociation on a Bruker APEX-4
(7 Tesla) instrument. The samples were dissolved in acetoni-
trile, diluted in spray solution (methanol-water 1 : 1 v/v +
0.1 % formic acid) and infused using a syringe pump with a
1
The H and 13C NMR spectral data of the dithi-
azines 7 – 10 are in agreement with the proposed struc-
tures. Thus, the thieno proton 7-H resonates as a
singlet around δ = 7.3 – 7.7 ppm. The exchangeable flow rate of 2 µL min−1. External calibration was conducted
using arginine cluster in a mass range of m/z = 175 – 871.
For analyses, all new compounds were further purified on
preparative TLC silica-gel plates using chloroform as eluent.
Elemental analyses were carried out at Al al-Bayt University
(Jordan), and the results were found to be in good agreement
( 0.4 %) with the calculated values.
hydrazino-NH protons’ signals of 9a, b appear in the
region 7.6– 9.6 ppm. Signal assignments to the dif-
ferent alkyl and aryl protons in compounds 7a – e are
straightforward. Compounds 7a and 8 are differenti-
1
ated by their N-CH3 and S-CH3 resonances in the H
and 13C NMR spectra, with singlet signals appearing
at 2.74 (16.7) and 3.60 (35.3) ppm, respectively. DEPT
experiments were used to differentiate between the dif-
ferent primary, secondary and tertiary carbon atoms.
Antibacterial tests
The MICs were determined by the conventional agar dilu-
tion procedures according to the method of Mueller-Hinton.
Stock solutions (1000 µg mL−1) of the test compounds were
prepared with DMSO. Serial dilutions were then made to ob-
tain test concentrations in the range 128 – 0.5 µg mL−1. The
agar plates were inoculated with approximately 105 CFU per
spot. The agar plates were then incubated at 37 ◦C for 18 h.
The MICs were taken as the lowest concentration of the test
compounds that inhibits visible growth.
Antibacterial activity
Compounds 3a – c and 7a – e were tested in vitro in
aqueous DMSO solutions against Gram-negative Es-
cherichia. coli. ATCC 8739 and Gram-positive Staphy-
lococcus aureus ATCC 6538 bacterial species using
ciprofloxacin as reference. The antibacterial activity
was evaluated by the minimal inhibitory concentra-
tion (MIC) technique. Compounds 7a – e exhibit mod-
erate to low level of antibacterial activity (MIC 32 –
2,5-Dichlorothiophene-3-sulfonamide (4)
This compound was prepared via interaction of 2,5-di-
128 µg mL−1) against E. coli. and S. aureus. However, chlorothiophene-3-sulfonyl chloride with excess NH4OH
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718 R. Abu-El-Halawa et al. · Model 3-(Alkylthio)-6-chloro- and 2,6-dichlorothieno[2,3-e][1,4,2]dithiazine 1,1-Dioxides
◦
(28 %) at 100 C for 30 min according to a reported pro- (82), 113 (25), 69 (100). – Anal. for C6H4ClNO2S4 (285.81):
cedure [8]. The required 2,5-dichlorothiophene-3-sulfonyl calcd. C 25.21, H 1.41, N 4.90, S 44.87; found C 24.98,
chloride was, in turn, obtained by the reaction of 2,5-di- H 1.21, N 4.77, S 44.62.
chlorothiophene with excess chlorosulfonic acid at 100 –
110 ◦C for 2 h, by following a literature method [8].
3-(Ethylthio)-6-chlorothieno[2,3-e][1,4,2]dithiazine
1,1-dioxide (7b)
Sodium/potassium 6-chlorothieno[2,3-e][1,4,2]dithiazine-3-
thiolate 1,1-dioxide (6)
Colorless solid, m. p. 145 – 146 ◦C, 57 % yield. – 1H NMR
(300 MHz, [D6]DMSO): δ = 7.77 (s, 1H, 7-H), 1.35 (t,
Method a): A suspension of sodium hydride (60 % disper-
sion in mineral oil, 0.17 g, 5 mmol) in dry DMF (20 mL) was
added to a stirred solution of 2,5-dichlorothiophene-3-sulf-
onamide (4) (1.0 g, 4.4 mmol) dissolved in DMF (10 mL).
The resulting mixture was stirred for 15 min at r. t., followed
by dropwise addition of CS2 (0.35 g, 4.6 mmol). The whole
reaction mixture was stirred over night at r. t., and then used
immediately for the next alkylation step.
J = 7.4 Hz, 3H, CH3), 3.28 (q, J = 7.4 Hz, 2H, CH2). –
13C NMR (75 MHz, [D6]DMSO): δ = 177.1, 133.2, 132.1,
128.8 (Cq-3, 4a, 6, 7a), 122.8 (CH-7), 29.0 (SCH2), 16.8
(CH3). – MS (EI, 70 eV): m/z (%) = 297 (10) [M]+, 298 (5)
[M+1]+, 299 (6) [M+2]+, 212 (20), 148 (25), 113 (31), 69
(100). – Anal. for C7H6ClNO2S4 (299.84): calcd. C 28.04,
H 2.02, N 4.67, S 42.77; found C 28.43, H 2.22, N 4.96,
S 42.57.
Method b): Sulfonamide 4 (3.0 g, 13 mmol) was added
to a stirred solution of KOH (2.8 g, 52 mmol) in abso-
lute ethanol (40 mL), and the resulting mixture was warmed
(40 ◦C) for 30 min. Carbon disulfide (5 mL) was then added
dropwise, and the mixture was further refluxed for 12 h. The
yellow precipitate of potassium-salt 6, formed in the cooled
reaction mixture, was collected under suction, washed with
diethyl ether (2×20 mL), dried and then used for the follow-
ing alkylation step as shown below.
3-(i-Propylthio)-6-chlorothieno[2,3-e][1,4,2]dithiazine
1,1-dioxide (7c)
Yellow oily residue, 40 % yield. – 1H NMR (300 MHz,
[D6]DMSO): δ = 7.76 (s, 1H, 7-H), 3.95 – 4.19 (m, 1H, CH),
1.45 (d, J = 6.6 Hz, 6H, CH3-C-CH3). – 13C NMR (75 MHz,
[D6]DMSO): δ = 176.4, 133.3, 132.1, 128.7 (Cq-3, 4a, 6,
7a), 122.8 (CH-7), 41.6 (SCH), 22.3 (CH3). – HRMS ((+)-
ESI): m/z = 313.9205 (calcd. 313.9218 for C8H9ClNO2S4,
[M+H]+). – Anal. for C8H8ClNO2S4 (313.87): calcd.
C 30.61, H 2.57, N 4.46, S 40.86; found C 30.42, H 2.70,
N 4.29, S 41.13.
3-(Alkylthio)-6-chlorothieno[2,3-e][1,4,2]dithiazine
1,1-dioxides (7a – e)
General procedure
An excess of the appropriate alkyl halide (MeI, EtI, t-
BuBr, i-PrBr or BnBr) (30 mmol) was added to the sodium/
potassium salt 6 (10 mmol) in DMF (20 mL), and the reaction
mixture was refluxed for 2 h, then diluted with H2O (20 mL)
and extracted with diethyl ether (3 ×10 mL). The combined
ether extracts were washed with water (2×10 mL) and dried
over sodium sulfate; evaporation of ether and excess alkyl
halide gave the respective title compounds as solid or oily
residues. Upon washing with hexane, the desired compounds
formed. Further purification was done using silica gel TLC
plates (UV active, 245 nm) and chloroform as the eluent. Ac-
cordingly, the following compounds were prepared:
3-(t-Butylthio)-6-chlorothieno[2,3-e][1,4,2]dithiazine
1,1-dioxide (7d)
Yellow oily residue, 37 % yield. – 1H NMR (300 MHz,
[D6]DMSO): δ = 7.76 (s, 1H, 7-H), 1.24 (s, 9H, C-
(CH3)3). – 13C NMR (75 MHz, [D6]DMSO): δ = 162.7,
140.6, 127.3, 126.2 (Cq-3, 4a, 6, 7a), 122.8 (CH-7), 41.6
(SCH), 22.3 (CH3). – HRMS ((+)-ESI): m/z= 327.9348
(calcd. 327.9361 for C9H11ClNO2S4, [M+H]+). – Anal. for
C9H10ClNO2S4 (327.89): calcd. C 32.97, H 3.07, N 4.27,
S 39.12; found C 33.03, H 3.19, N 4.57, S 39.36.
3-(Benzylthio)-6-chlorothieno[2,3-e][1,4,2]dithiazine
1,1-dioxide (7e)
3-(Methylthio)-6-chlorothieno[2,3-e][1,4,2]dithiazine
1,1-dioxide (7a)
Colorless solid, m. p. 195 – 196 ◦C, 48 % yield. – 1H NMR
Pale-yellow solid, m. p. 180 – 181 ◦C, 55 % yield. – (300 MHz, [D6]DMSO): δ = 7.77 (s, 1H, 7-H), 7.43 (d, J =
IR (KBr) ν = 3100, 2910 (C-H), 1580 (C=N), 1180 6.9 Hz, 2H, arom.), 7.35 (t, J = 5.7 Hz, 2H, arom.), 7.30
1
(SO2) cm−1. – H NMR (300 MHz, [D6]DMSO): δ = 7.77 (t, J = 5.7 Hz, 1H, arom.), 4.69 (s, 2H, CH2). – 13C NMR
(s, 1H, 7-H), 2.71 (s, 3H, CH3). – 13C NMR (75 MHz, [D6]- (75 MHz, [D6]DMSO): δ = 176.3, 135.6, 129.1, 129.0, 128.8
DMSO): δ = 178.0, 133.1, 132.0, 128.8 (Cq-3, 4a, 6, 7a), (Cq-3, 4a, 6, 7a, arom.), 129.7, 129.1, 128.4 (CH-arom.),
122.5 (CH-7), 16.8 (CH3). – MS (EI, 70 eV): m/z (%) = 285 122.8 (CH-7), 37.9 (SCH2). – HRMS ((+)-ESI): m/z =
(20) [M]+, 286 (3) [M+1]+, 287 (10) [M+2]+, 212 (75), 148 316.9201 (calcd. 361.9205 for C12H9ClNO2S4, [M+H]+). –
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R. Abu-El-Halawa et al. · Model 3-(Alkylthio)-6-chloro- and 2,6-dichlorothieno[2,3-e][1,4,2]dithiazine 1,1-Dioxides 719
Anal. for C12H8ClNO2S4 (361.91): calcd. C 39.83, H 2.23,
N 3.87, S 35.44; found C 39.90, H 2.09, N 4.11, S 35.08.
C11H8ClN3O2S3 (345.85): calcd. C 38.20, H 2.33, N 12.15,
S 27.81; found C 38.06, H 2.25, N 12.12, S 27.68.
3-Methylthio-6-chlorothieno[2,3-e][1,4,2]dithiazine 1,1-di-
oxide (7a), and 2-methyl-6-chlorothieno[2,3-e][1,4,2]di-
thiazine-3(2H)-thione 1,1-dioxide (8)
3,6-Dichlorothieno[2,3-e][1,4,2]dithiazine 1,1-dioxide (10)
Sulfuryl chloride (0.40 g, 3 mmol) was added portion-
wise to 3-methylthio-6-chlorothieno[2,3-e][1,4,2]dithiazine-
1,1-dioxide (7a) (1.8 mmol, 0.51 g). The mixture was then
refluxed for 3 h at 50 ◦C. The excess amount of sulfuryl chlo-
ride was removed by vacuum filtration, and the residue was
washed with diisopropyl ether. Pale-yellow solid, m. p. 179 –
181 ◦C, 77 % yield. – 1H NMR (300 MHz, [D6]DMSO): δ =
7.31 (s, 1H, 7-H). – 13C NMR (75 MHz, [D6]DMSO): δ =
142.8, 137.3, 129.7, 128.7 (Cq-3, 4a, 6, 7a), 122.7 (CH-7). –
MS (EI, 70 eV): m/z (%) = 273 (28) [M]+, 274 (3) [M+1]+,
275 (21) [M+2]+, 212 (96), 148 (100), 113 (21), 69 (85). –
Anal. for C5HCl2NO2S3 (274.17): calcd. C 21.90, H 0.37,
N 5.11, S 35.09; found C 21.98, H 0.35, N 4.98, S 35.22.
Potassium salt 6 (3.1 g, 10 mmol) was refluxed with
dimethyl sulfate (15 mL) for 30 min. Chloroform (150 mL)
was added, the organic layer was washed with water (2 ×
50 mL) and dried. Thin-layer chromatography showed that
the product is a mixture of 7a and 8 which were separated by
thick-layer chromatography using TLC silica gel glass plates
and eluting with chloroform. Herein 7a has Rf value of 0.67,
while that of 8 is 0.84. Both compounds were recrystallized
from chloroform/petroleum ether (b. p. 40 – 60 ◦C).
Compound 8: pale-yellow, m. p. 118 – 120 ◦C, 28 %
yield. – IR (KBr): ν = 3100, 2935 (C-H), 1335 (C=S), 1185
(SO2) cm−1. – 1H NMR (300 MHz, CDCl3): δ = 3.60 (s,
CH3N), 7.31 (s, 7-H). – 13C NMR (75 MHz, CDCl3): δ =
35.3 (CH3N), 126.9 (C-7), 127.7 (C-4a), 132.9, 134.4 (C-7a,
C-6a), 190.7 (C3=S). – MS (EI, 70 eV): m/z (%) = 285 (7)
[M]+, 242 (3), 212 (53), 151 (12), 148 (58), 116 (100), 81
(25), 69 (95). – Anal. for C6H4ClNO2S4 (285.81): calcd.
C 25.21, H 1.41, N 4.90, S 44.87; found C 25.29, H 1.32,
N 4.73, S 44.69.
N-Substituted-6-chlorothieno[2,3-e][1,4,2]dithiazin-3-
amine 1,1-dioxides 3a – c
General procedure utilizing 7a
A mixture of compound 7a (1.50 g, 5 mmol) and the par-
ticular amine (25 mmol) was refluxed for 18 h. Upon cooling,
the precipitated product was filtered, washed with 50 % aque-
ous methanol (2×30 mL) and dried.
6-Chloro-3-(N-substituted hydrazinyl)thieno[2,3-e][1,4,2]-
dithiazin 1,1-dioxides 9a, b
General procedure utilizing 10
A mixture of compound 7a (3.0 g, 10 mmol) and methyl-
hydrazine (or phenylhydrazine) (50 mmol) was refluxed
for 18 h. Upon cooling, the precipitated product was filtered,
washed with 50 % aqueous methanol (2×30 mL) and dried.
To a solution of 3,6-dichlorothieno[2,3-e][1,4,2]dithiaz-
ine 1,1-dioxide (10) (0.11 g, 0.4 mmol) in dioxane (20 mL)
was added dropwise the particular amine (0.4 mmol). The
reaction mixture was stirred at r. t. for 2 h, followed by re-
flux for 4 h. Thereafter, potassium hydrogencarbonate (5 mL,
1 M) was added and the mixture stirred for 1 h at r. t. The re-
sulting solid product was filtered and recrystallized from a
mixture of chloroform-petroleum ether (6 : 1, v/v).
6-Chloro-3-(1-methylhydrazinyl)thieno[2,3-e][1,4,2]dithi-
azine 1,1-dioxide (9a)
◦
Pale-yellow solid, m. p. 163 – 165 C, 57 % yield. – IR
(KBr): ν = 3310, 3230 (br, NH2), 3085, 2940 (C-H), 1575
1
(C=N), 1160 (SO2) cm−1. – H NMR (300 MHz, CDCl3):
6-Chloro-N-ethylthieno[2,3-e][1,4,2]dithiazin-3-amine 1,1-
dioxide (3a)
δ = 3.42 (s, CH3N), 7.21 (s, 7-H), 7.82 (br s, NH2-N). – MS
(EI, 70 eV): m/z (%) = 283 (7) [M]+, 268 (16), 234 (35),
232 (100), 212 (28), 148 (35), 116 (21), 81 (30), 69 (42). –
Anal. for C6H6ClN3O2S3 (283.78): calcd. C 25.40, H 2.13,
N 14.18, S 33.90; found C 25.24, H 2.02, N 14.37, S 33.74.
Colorless solid, m. p. 180 – 182 ◦C (lit. [7]: 180 – 182 ◦C),
63 % yield.
6-Chloro-N-phenylthieno[2,3-e][1,4,2]dithiazin-3-amine
1,1-dioxide (3b)
6-Chloro-3-(2-phenylhydrazinyl)thieno[2,3-e][1,4,2]dithi-
Colorless solid, m. p. 242 – 244 ◦C (lit. [7]: 243 – 245 ◦C),
78 % yield.
azine 1,1-dioxide (9b)
◦
Pale-yellow solid, m. p. 245 – 247 C, 63 % yield. – IR
(KBr): ν = 3480 (br, N-H), 3110, 3080 (C-H), 1595 (C=N),
1175 (SO2) cm−1. – 1H NMR (300 MHz, [D6]DMSO): δ =
7.15 (s, 1H, 7-H), 7.28 – 7.72 (m, 7-H, Ph-H+NH-NH). – MS
(EI, 70 eV): m/z (%) = 345 (3) [M]+, 268 (16), 234 (76),
6-Chloro-N-(p-chlorophenyl)thieno[2,3-e][1,4,2]dithiazin-
3-amine 1,1-dioxide (3c)
Colorless solid, m. p. 162 – 164 ◦C, 83 % yield. – 1H NMR
232 (100), 212 (45), 186 (27), 148 (33), 116 (28). – Anal. for (300 MHz, [D6]DMSO): δ = 11.50 (s, 1H, NH), 7.63 (s, 1H,
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720 R. Abu-El-Halawa et al. · Model 3-(Alkylthio)-6-chloro- and 2,6-dichlorothieno[2,3-e][1,4,2]dithiazine 1,1-Dioxides
7-H), 7.68 (d, J = 8.9 Hz, 2H, arom.), 7.54 (d, J = 8.9 Hz, Acknowledgements
2H, arom.). – 13C NMR (75 MHz, [D6]DMSO): δ = 158.8,
We are grateful to the Deanship of Graduation Studies of
Al al-Bayt University (Mafraq, Jordan) and the DFG (Ger-
many) for financial support and to Professor Dr. Gerhard
Maas (University of Ulm, Germany) for his valuable sup-
port. We thank Dr. Y. M. Al-Hiari (Faculty of Pharmacy, The
University of Jordan) for performing the antibacterial tests.
137.0, 131.5, 130.9, 130.8, 130.1 (Cq-3, 4a, 6, 7a, arom.),
122.8 (CH-7), 129.6, 123.9 (CH-arom.). – HRMS ((+)-ESI):
m/z = 364.9035 (calcd. 364.9047 for C11H7Cl2N2O2S3,
[M+H]+). – Anal. for C11H6Cl2N2O2S3 (365.28): calcd.
C 36.17, H 1.66, N 7.67, S 26.33; found C 36.34, H 1.93,
N 7.82, S 26.76.
[1] a) E. Pomarnacka, Z. Brzozowski, M. Filczewski,
K. Szymanska, K. Malgorzata, K. Oledzka, Acta Pol.
Pharm. 1985, 42, 501 – 510; Chem. Abstr. 1987, 106,
38415; b) Z. Brzozowski, J. Slawinski, F. Gajewski,
E. Pomarnacka, W. Janiec, T. Piekarska, PL 14183,
1987; Chem. Abstr. 1990, 112, 235345; c) Z. Brzo-
zowski, F. Saczewski, J. Slawinski, P. Bednarski,
R. Gruenert, M. Gdaniec, Bioorg. Med. Chem. 2007,
15, 2560 – 2572; d) Z. Brzozowski, F. Saczewski,
M. Gdaniec, Eur. J. Med. Chem. 2003, 38, 991 – 999;
e) Z. Brzozowski, F. Saczewski, M. Gdaniec, Bioorg.
Med. Chem. 2003, 11, 3673 – 3681.
[2] a) Z. Brzozowski, J. Slawinski, F. Gajewski, S. Angiel-
ski, A. Hoppe, Acta Pol. Pharm. 1985, 42, 413 – 420;
Chem. Abstr. 1987, 106, 138414; b) Z. Brzozowski,
J. Slawinski, F. Gajewski, S. Angielski, A. Hoppe,
W. Janiec, T. Piekarska, PL 140677, 1987; Chem. Ab-
str. 1990, 112, 98564r.
enczak, W. Werel, R. Halasa, Eur. J. Med. Chem. 2006,
41, 633 – 639.
[5] a) J. Slawinski, Z. Brzozowski, Pol. J. Chem. 2007,
81, 1433 – 1440; Chem. Abstr. 2007, 149, 53685);
b) J. Slawinski, Z. Brzozowski, Eur. J. Med. Chem.
2006, 41, 1180 – 1189; c) J. Slawinski, M. Gdaniec,
Eur. J. Med. Chem. 2005, 40, 377 – 389; d) J. P. Slaw-
inski, P. Bednarski, P. Reszka, Pol. J. Chem. 2004, 78,
369 – 379; Chem. Abstr. 2004, 141, 260332; e) J. Slaw-
inski , P. Bednarski, R. Grunert, P. Reszka, Pol. J.
Chem. 2003, 77, 53 – 64; Chem. Abstr. 2003, 138,
353721.
[6] a) Z. Brzozowski, J. Slawinski, Pol. J. Chem. 2007, 81,
1419 – 1426; Chem. Abstr. 2007, 148, 585866; b) Z. Br-
zozowski, J. Slawinski, Pol. J. Chem. 2006, 80, 1807 –
1815; Chem. Abstr. 2006, 147,142767.
[7] R. Abu-El-Halawa, M. Al-Refai, M. M. El-Abadelah,
H. D. Tabba, Heterocycles 2008, 75, 1749 – 1755.
[8] A. Buzas, T. Teste, Bull. Soc. Chem. Fr. 1960, 793 –
803; Chem. Abstr. 1961, 55, 27817.
[3] Z. Brzozowski, J. Slawinski, Acta Pol. Pharm. 1984,
41, 5 – 13; Chem. Abstr. 1985, 102, 78840.
[4] a) E. Pomarnacka, P. J. Bednarski, R. Grunert, Z. Br-
zozowski, J. Lach, Pol. J. Chem. 2006, 80, 429 – 438;
Chem. Abstr. 2007, 146, 2779; b) E. Pomarnacka, P. J.
Bednarski, P. Reszka, E. Dziemidowicz-Borys, A. Bi-
[9] M. Al-Refai, M. H. Masad, R. Abu-El-Halawa, J. N.
Dawoud, M. M. Ibrahim, Z. Judeh, B. F. Ali, J. Chem.
Crystallogr. 2011 (in press).
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