Syntheses of potassium 1,1-dioxopyrido[4,3-e]-1,4,2-dithiazine-3-thiolate and its application to the synthesis of novel sulfonamides with potential biological activity

Article abstract of DOI:10.1002/jhet.5570450525

(Chemical Equation Presented) Potassium 1,1-dioxopyrido[4,3-e]-1,4,2- dithiazine-3-thiolate 2 has been synthesized and applied to the syntheses of 7H-1,1-dioxopyrido[4,3-e]-1,4,2-dithiazolium-3-thiolate 3 and 3-methylthiopyrido[4,3-e]-1,4,2-dithiazine 1,1-dioxide 4 which provided easy access to a variety of its 3-amino derivatives 5-10. Hydrazinolysis of 7, 8 and 10 afforded the corresponding 3-amino-2-(1,4-dihydro-4-thioxopyrid-3-ylsulfonyl) guanidines 11-13. Subsequent reaction of 12 with 4-chlorobenzaldehyde gave condensation product 14. 1,4-Dihydro-2-thioxopyridine-3-sulfonamide 15 was also prepared from the potassium salt 2 upon alkaline hydrolysis, whereas alkylation of 15 gave the appropriate S-substituted derivatives 16-19 or S,N-disubstituted compounds 20-21.

Full text of DOI:10.1002/jhet.5570450525

Sep-Oct 2008
1407
Syntheses of Potassium 1,1-Dioxopyrido[4,3-e]-1,4,2-dithiazine-3-
thiolate and Its Application to the Synthesis of Novel Sulfonamides
with Potential Biological Activity
Zdzisꢀaw Brzozowskia, Franciszek Sꢁczewskia,* and Jarosꢀaw Sꢀawiꢂskib
a Department of Chemical Technology of Drugs, Medical University of Gdaꢂsk, Al. Gen. J. Hallera 107, 80-416 Gdaꢂsk, Poland, e-mail:
saczew@amg.gda.pl
b Department of Organic Chemistry, Medical University of Gdaꢂsk, Al. Gen. J. Hallera 107,
80-416 Gdaꢂsk, Poland
Received March 2, 2008
R1
Cl
S
S
S
S
R2
N
HN
N
NH
N
N
SO2NH2
R3
O
O
HN
O
2-10
O
N
R4
1
11-14
S
SR
SR
I
HN
N
N
SO2NH2
SO2NH2
Me
SO2NH2
15
16-19
20-21
Potassium 1,1-dioxopyrido[4,3-e]-1,4,2-dithiazine-3-thiolate 2 has been synthesized and applied to the
syntheses of 7H-1,1-dioxopyrido[4,3-e]-1,4,2-dithiazolium-3-thiolate 3 and 3-methylthiopyrido[4,3-e]-
1,4,2-dithiazine 1,1-dioxide 4 which provided easy access to a variety of its 3-amino derivatives 5-10.
Hydrazinolysis of 7, 8 and 10 afforded the corresponding 3-amino-2-(1,4-dihydro-4-thioxopyrid-3-
ylsulfonyl)guanidines 11-13. Subsequent reaction of 12 with 4-chlorobenzaldehyde gave condensation
product 14. 1,4-Dihydro-2-thioxopyridine-3-sulfonamide 15 was also prepared from the potassium salt 2
upon alkaline hydrolysis, whereas alkylation of 15 gave the appropriate S-substituted derivatives 16-19 or
S,N-disubstituted compounds 20-21.
J. Heterocyclic Chem., 45, 1407 (2008).
of novel sulfonamides with remarkable antitumor activity
(A [6-17], B [18-21], C [22-24] and D [25], Figure 1) or
anti-HIV activity (A [6-9,17,26-30], B [31], C [24] E and
F [32], Figure 1). All the sulfonamides of types A-F have
been obtained starting from 1,4,2-benzodithiazine 1,1-
dioxides (B, R3 = SK, SH, SMe or NHR4, Figure 1).
The above results prompted us to investigate the
chemistry of the related 1,1-dioxopyrido[4,3-e]-1,4,2-
dithiazine heterocyclic ring system (G, Figure 1). In this
study we describe the facile syntheses of potassium 1,1-
INTRODUCTION
Arylsulfonamides constitute an important class of
compounds with several types of biological activities and
well-established safety profile [1]. Currently, there is
significant interest in the discovery and development of
novel arylsulfonamides for the treatment of cancer and
HIV infections [2-5]. Previously, as part of a broad
investigation of structures containing 2-thiobenzene-
sulfonamide scaffold, we have synthesized several series
Cl
R1
S
S
R3
Cl
R1
S
Cl
R1
SR2
N
H
N
N
N
S
R3
S
R3
O
O
R2
R2
O O
O
O
A
B
C
Cl
R
S
S
Cl
R1
S
S
Cl
R
S
S
N
N
N
N
NHAr
R4
N
N
N
R3
R2
O
O
O
O
O O
D
E
F
S
R
S
S
SR
S
R1
N
N
N
HN
N
NH2
S
R2
O
O
O
O
O
O
G
HH
I
Figure 1

1408
Z. Brzozowski, F. Sꢀczewski and J. Sꢁawiꢂski
Vol 45
addition-elimination (SNAr) process which gave rise to the
formation of 2 via the potassium salt K (Scheme 1). Then,
upon acidification of the salt 2 with hydrochloric acid the
corresponding internal salt 3 was produced in 91% yield.
The later compound upon treatment with methyl iodide
under mild reaction conditions was converted to the S-
methyl derivative 4 which subsequently reacted with
primary and secondary aliphatic amines in boiling
methanol to afford the expected 3-aminopyrido[4,3-e]-
1,4,2-dithiazine derivatives 5-10 (Scheme 2).
The desired 3-amino-2-(1,4-dihydro-4-thioxopyrid-3-
ylsulfonyl)guanidine derivatives 11-13 were obtained by
reacting the pyrido[4,3-e]-1,4,2-dithiazines 7, 8 or 10 with
hydrazine hydrate in methanol at room temperature
(Scheme 3). The intermediary formed nucleophilic ring
opening products of type L were not isolated and were
converted to the corresponding thiols M by acidification
of the reaction mixtures to pH = 6 with hydrochloric acid.
dioxopyrido[4,3-e]-1,4,2-dithiazine-3-thiolate which pro-
vides access to 3-substituted pyrido[4,3-e]-1,4,2-
dithiazines, 1,4-dihydro-4-thioxopyridine-3-sulfonamide
as well as S-substituted 4-mercaptopyridine-3-sulfon-
amides (G, H and I, Figure 1).
RESULTS AND DISCUSSION
As shown in Schemes 1 and 2, the syntheses of the
target pyrido[4,3-e]-1,4,2-dithiazine 1,1-dioxides 2-10
were achieved by convenient procedures starting from
commercially available 4-chloropyridine-3-sulfonamide
1. First, the reaction of 1 with carbon disulfide and KOH
carried out in ethanol at temperatures gradually increasing
(from –1 ºC to reflux) led to the formation of potassium
1,1-dioxopyrido[4,3-e]-1,4,2-dithiazine-3-thiolate
2
in
90% yield. The reaction sequence involved the initial
formation of dipotassium salt of dithiocarbamic acid J,
followed by intermolecular ring closure via two-step
Scheme 1
Cl
Cl
a
SK
N
N
N
SO2NH2
S
SK
O
N
O
J
1
Cl
S
SK
S
S
SK
N
N
N
S
- KCl
O
O
O
O
K
K
2
Synthesis of potassium 1,1-dioxopyrido[4,3-e]-1,4,2-dithiazine-3-thiolate 2. Reagents, conditions and yield: (a) KOH (2.5 molar equiv.),
carbon disulfide (1.5 molar equiv.), ethanol, -1 to 2 ºC 1 h, room temperature 2 h, reflux 32 h, 90%.
Scheme 2
S
S
SK
S
S
S
S
S
SMe
a
b
N
N
N
N
N
N
H
O
O
O
O
O
O
2
3
4
R1
c
Compd
d
6
7
8
9
PhCH2-
H
CH2=CHCH2-
HC C-CH2-
(MeO)2CHCH2-
MeNH-
S
S
N
S
S
N
R1
N
N
N
N
10
O
O
O
O
5
6-10
Application of thiolate 2 to the synthesis of 3-substituted pyrido[4,3-e]-1,4,2-benzodithiazine 1,1-dioxides 3-10. Reagents, conditions and
yields: (a) 36% hydrochloric acid (1.1 – 1.2 molar equiv.), water, room temperature, 3 h, 91%; (b) Et3N (1.05 molar equiv.), MeI (1.05 molar
equiv.), CH2Cl2, 0 ºC, 1-2 h, room temperature, 16 h, 88%; (c) pyrrolidine (1.1 molar equiv.), methanol, reflux, 28 h, 90%; (d) RNH2 (1.03
molar equiv.), methanol, room temperature, 48 h, reflux, 26-40 h, 84-98%.

Sep-Oct 2008
Syntheses of Potassium 1,1-Dioxopyrido[4,3-e]-1,4,2-dithiazine-3-thiolate
1409
Scheme 3
H2NNH2
H
S
S
N
S
S
SH
R1
a
R1
b
R1
N
N
N
N
NH
N
N
NH
S
R2
O O
HN
O
O
O
O
HN
R2
N
N
H
H
M
7, 8, 10
L
S
S
c
S
R1
NH
HN
N
NH
N
HN
N
R1
2 = H
=
S
HC C-CH2-
R2
O
O
O
O
HN
HN
R
N
H
14
11-13
Cl
Compd
R1
R2
7, 11
8, 12
10, 13
H2C=CH-CH2-
HC C-CH2-
MeNH-
H
H
Me
Usage of 3-aminopyrido[4,3-e]-1,4,2-dithiazines 7, 8 and 10 to the synthesis of 2-(1,4-dihydro-4-thioxopyrid-3-ylsulfonyl)guanidine derivatives
11-14. Reagents, conditions and yields: (a) hydrazine hydrate or methylhydrazine (2.0 molar equiv.), methanol, room temperature, 28-30 h; (b) 1%
hydrochloric acid to pH 6, 82-91%; (c) 4-chlorobenzaldehyde (1.08 molar equiv.), ethanol, reflux, 10 h, 85%).
Scheme 4
S
S
SK
SNa
NHNa
SR
a
N
N
N
N
S
SO2NH2
O
O
O
O
2
18
e
g
b
N
S
SR
SO2NH2
S
I
c
N
Me
SO2NH2
HN
SO2NH2
N
SO2NH2
20-21
15
16
17
d
h
Compd
R
O
N
18, 20
19, 21
Me
CH2CONH2
S
S
f
NH2
N
N
SO2NH2
SO2NH2
19
Practical application of thiolate 2 to the synthesis of 2-mercaptopyridine-3-sulfonamide derivatives 15-22. Reagents, conditions and yields: (a)
NaOH (3.0 molar equiv.), water, reflux, 6 h; (b) 1.5% hydrochloric acid to pH 3, room temperature, 8 h, 78%; (c) 4-chloropyridine-3-sulfonamide
(1.0 molar equiv.), acetonitrile, reflux, 60 h, room temperature, water, NaOH to pH 7.8, 65%; (d) Et3N (1.06 molar equiv.), bromoacetonitrile (1.06
molar equiv.), acetonitrile, 10-18 ºC, 1 h, room temperature, 2 h, reflux, 2 h, 94%; (e) Et3N (1.13 molar equiv.), methyl iodide (1.0 molar equiv.),
0-20 ºC, 1.5 h, reflux, 1.5 h, 96%; (f) aqueous solution of H2O2 (3.0 molar equiv.), NaOH (3.0 molar equiv.), DMSO, EtOH, 0 ºC, 0.5 h, 74%; (g)
methyl iodide (1.1 molar equiv.), acetonitrile, 0-8 ºC, 1 h, room temperature, 8 h, reflux 15 h, 95%; (h) methyl iodide (2.5 molar equiv.),
acetonitrile, reflux, 20 h, 96%.

1410
Z. Brzozowski, F. Sꢀczewski and J. Sꢁawi ski
Vol 45
1
cm-1 Perkin Elmer 1600 FTIR spectrometer; H and 13C nmr:
Varian Gemini 200 apparatus at 200 and 50 MHz, respectively;
chemical shifts are expressed at ꢀ values relative to Me4Si as
standard.
As evidenced by the IR and NMR spectroscopic data (see
Experimental), the products M, both in solid state and in
DMSO solution, exist in pyridine-4-thione tautomeric
form 11-13. Finally, the aminoguanidine 12 was subjected
to the reaction with 4-chlorobenzaldehyde in boiling
ethanol to give the condensation product 14 in 85% yield.
We have also applied potassium pyrido[4,3-e]-1,4,2-
dithiazine-3-thiolate (2) to the synthesis of various N- and
S-substituted 4-mercaptopyridine-3-sulfonamide deriv-
atives 15-21, as shown in Scheme 4. Thus, the selective
alkaline hydrolysis of the thiolate 2 led to the formation of
the readily water soluble 4-mercapto-pyridine-3-sulfon-
amide salt N, which upon acidification afforded 1,4-
dihydro-4-thioxopyridine-3-sulfonamide 15 in 78% yield.
Then, the reactions of 15 with alkyl or aryl halides in
acetonitrile followed by neutralization of the reaction
mixtures with aqueous NaOH led to the formation of S-
substituted products 16-18 in high yields (Scheme 4).
The alkaline hydrolysis of cyanomethyl sulfide 17
furnished carbamoylmethyl sulfide 19 in 74% yield.
Subsequent N-alkylation of S-substituted 4-mercapto-
pyridine-3-sulfonamides 18 and 19 with methyl iodide in
acetonitrile led to the formation of the desired
3-sulfamoyl-1-methylpyridinium iodide derivatives 20
and 21 in excellent yields.
The structures of the compounds 2-21 were confirmed
by elemental analyses (C, H, N) and spectroscopic data
presented in the experimental section. For example, the 1H
nmr spectra of compounds 2-19 revealed characteristic
two doublet signals of H-5 and H-6 of the 3,4-
disubstituted pyridine protons in the region ꢀ 7.23 – 7.83
ppm and ꢀ 7.52 – 8.77 ppm (J = 4.4 – 6.8 Hz),
respectively, while the singlet of H-2 proton appeared in
the downfield region ꢀ 8.29 – 9.26 ppm. The presence of
the sulfonamide moiety in compounds 15, 16 and 17-21
was indicated by singlet (2H) of NH2 protons at ꢀ 7.21 –
8.21 ppm. Furthermore, the inspection of 13C nmr spectra
of 11, 12, 14 and 15 revealed the signal in the downfield
region ꢀ 186.1 – 188.1 ppm attributable to the carbon
atom of thione group C=S
Potassium 1,1-dioxopyrido[4,3-e]-1,4,2-dithiazine-3-thiol-
ate (2). To an ice-cold solution of KOH (42.07 g, 0.75 mol) in
96% ethanol (370 mL), 4-chloro-3-pyridinesulfonamide (57.8 g,
0.3 mol) and carbon disulfide (34.2 g, 0.45 mol) were added
with stirring (CAUTION: due to a high toxicity of CS2 reaction
should be performed under the hood). The reaction mixture was
stirred at –1 to 2 ºC for 1 h, followed at room temperature for 2
h, and then at reflux for 32 h. After cooling to room temperature
the suspension was left overnight. The precipitate was collected
by filtration, washed with ethanol (20 mL) and water (6 x 15
mL), and dried at temperatures gradually increasing to 105 ºC.
Yield 73.1 g (90%), mp 232-234 ºC; ir (KBr): 1570, 1535 (C=N,
C=C), 1380, 1155 (SO2) cm-1; 1H nmr (dimethyl sulfoxide-d6): ꢀ
7.35 (d, J = 5.5 Hz, 1H, H-5), 8.56 (d, J = 5.5 Hz, 1H, H-6), 8.90
(s, 1H, H-8) ppm; 13C nmr (dimethyl sulfoxide-d6): ꢀ 118.99,
126.22, 144.77, 147.03, 150.82, 188.72 ppm. Anal. Calcd. for
C6H3KN2O2S3 (270.39): C, 26.65; H, 1.12; N, 10.36. Found: C,
26.60, H, 1.25, N, 10.46.
7H-1,1-Dioxopyrido[4,3-e]-1,4,2-dithiazolium-3-thiolate (3).
To a suspension of potassium thiolate 2 (76.6 g, 0.25 mol) in
water (360 mL), 36% hydrochloric acid (28 mL) was added with
stirring. The reaction mixture was stirred at room temperature
for 3 h, and the resulting yellow precipitate was collected by
filtration, washed with water (4 x 3 mL) and dried under reduced
pressure to give pure thiolate 3. Yield 52.6 g (91%), mp 169-170
ºC dec.; ir (KBr): 2720, 2700, 2650, 2550, 2060 (NH+), 1620,
1590 (C=N and C=C), 1375, 1350, 1165, 1155 (SO2) cm-1; H
1
nmr (dimethyl sulfoxide-d6): ꢀ 7.71 (d, J = 5.8 Hz, 1H, H-5),
8.38 (br.s, 1H, NH+), 8.67 (d, J = 5.8 Hz, 1H, H-6), 9.11 (s, 1H,
H-8) ppm. Anal. Calcd. for C6H4N2O2S3 (230.30): C, 30.42; H,
1.74; N, 12.16. Found: C, 30.11, H, 1.88, N, 12.27.
3-Methylthiopyrido[4,3-e]-1,4,2-dithiazine 1,1-dioxide (4).
To an ice-cold suspension of dithiazolium thiolate 3 (46.06 g,
0.2 mol) in CH2Cl2 (250 mL) was added drop by drop with
stirring triethylamine (21.2 g, 0.21 mol) and solution of methyl
iodide (29.8 g, 0,21 mol) in CH2Cl2 (100 mL). After 1 h ice-bath
was removed and the resulting solution was stirred at room
temperature for 16 h. A small amount of insoluble by-products
was filtered out, and the solvent was evaporated in vacuo.
Resulting residue was triturated with water (200 mL), and
precipitate was filtered off, washed successively with water (5 x
30 mL), 50% methanol (3 x 15 mL) and finally with dry
methanol (3 x 10 mL), then dried at temperatures gradually
increasing to 80 ºC. Yield 43.5 g (88%), mp 153-154 ºC; ir
CONCLUSION
We have developed a method for the preparation of
potassium 1,1-dioxopyrido[4,3-e]-1,4,2-dithiazine-3-thi-
olate (3) representing a new heterocyclic ring system,
which in turn, provides access to a variety of substituted
pyrido[4,3-e]-1,4,2-dithiazine 1,1-dioxides 3-10, and
novel series of pyridine-3-sulfonamide derivatives 11-21.
Further structural modifications and biological
evaluation of these compounds are in progress and will be
described elsewhere.
(KBr): 1565, 1540 (C=N and C=C), 1330, 1170 (SO2) cm-1; H
1
nmr (deuteriochloroform): ꢀ 2.70 (s, 3H, CH3S), 7.33 (d, J = 5.1
Hz, 1H, H-5), 7.75 (d, J = 5.1 Hz, 1H, H-6), 9.26 (s, 1H, H-8)
ppm; 13C nmr (deuterio-chloroform): ꢀ 16.83, 120.91, 126.80,
141.43, 147.40, 152.39, 179.34 ppm. Anal. Calcd. for
C7H6N2O2S3 (246.63): C, 34.13; H, 2.45; N, 11.37. Found: C,
34.17, H, 2.54, N, 11.53.
3-(Pyrrolidino)pyrido[4,3-e]-1,4,2-dithiazine 1,1-dioxide (5).
A mixture of 4 (1.73 g, 7 mmol) and pyrrolidine (0.57 g, 8
mmol) in anhydrous methanol (15 mL) was refluxed for 28 h,
then allowed to cool to room temperature. The precipitate that
obtained was filtered off, washed with methanol ( 3 x 1 mL) and
dried to give 5. Yield 1.7 (90%), mp 206-207 ºC; ir (KBr): 1565,
1530 (C=N and C=C), 1310, 1165 (SO2) cm-1; 1H nmr (dimethyl
EXPERIMENTAL
The following instruments and parameters were used: melting
points Bꢂchi 535 apparatus; ir spectra: KBr pellets, 400-4000

Sep-Oct 2008
Syntheses of Potassium 1,1-Dioxopyrido[4,3-e]-1,4,2-dithiazine-3-thiolate
1411
sulfoxide-d6): ꢀ 1.89-2.07 (m, 4H, pyrrolidine), 3.58-3.65 (m,
4H, pyrrolidine), 7.83 (d, J = 5.3 Hz, 1H, H-5), 8.75 (d, J = 5.3
Hz, 1H, H-6), 9.05 (s, 1H, H-8) ppm; Anal. Calcd. for
C10H11N3O2S2 (269.35): C, 44.59; H, 4.12; N, 15.60. Found: C,
44.66, H, 4.17, N, 15.64.
General Procedure for the Preparation of 3-(R-
Amino)pyrido[4,3-e]-1,4,2-dithiazine 1,1-dioxides (6-10). A
mixture of 4 (1.73 g, 7 mmol) and the appropriate amine RNH2
(7.2 mmol) in anhydrous methanol (10 mL) was stirred at room
temperature for 48 h, followed at reflux until the evolution of
MeSH had ceased (26-40 h) (Caution: because of high toxicity,
MeSH should be trapped in aqueous NaOH solution). After
cooling to room temperature the precipitate was collected by
filtration, washed with methanol (3 x 2 mL) and dried. In this
manner the following products were obtained.
5), 8.73 (d, J = 5.3 Hz, 1H, H-6), 9.03 (s, 1H, H-8) ppm. Anal.
Calcd. for C7H8N4O2S2 (244.30): C, 34.41; H, 3.29; N, 22.93.
Found: C, 34.40, H, 3.36, N, 23.11.
Procedures for the Preparation of 2-(1,4-Dihydro-4-
thioxopyrid-3-ylsulfonyl) guanidine derivatives (11-13). A
mixture of the corresponding pyridodithiazine 7, 8 or 10 (4
mmol) and 99-100% hydrazine hydrate (0.4 g, 8 mmol) or
methylhydrazine (0.37 g, 8 mmol) in anhydrous methanol (4
mL) was stirred at room temperature for 28-30 h. The
suspension obtained (pH ~8.5) was acidified with 1%
hydrochloric acid to pH 6. The resulting precipitate was
collected by filtration, washed successively with methanol (4 x 1
mL) water (6 x 1 mL) and methanol (3 x 1 mL), and dried at
temperatures gradually increasing to 90 ºC. In this manner the
following guanidines were obtained.
3-Benzylaminopyrido[4,3-e]-1,4,2-dithiazine 1,1-dioxide (6).
Starting from benzylamine (0.77 g), the title compound 6 was
obtained (1.9 g, 89%): mp 194-195 ºC; ir (KBr): 3180 (NH),
1-Allyl-3-amino-2-(1,4-dihydro-4-thioxopyrid-3-ylsulfon-yl)-
guanidine (11). Starting from pyridodithiazine 7 (1.02 g) and
hydrazine hydrate, the title compound 11 was obtained (0.95 g,
82%): mp 185-186 ºC dec.; ir (KBr): 3445, 3265, 3170, 3130
(NH2, NH), 1650, 1615, 1560 (C=N and C=C), 1340, 1190
(SO2) cm-1; 1H nmr (dimethyl sulfoxide-d6): ꢀ 3.65 (t, J = 5.0 Hz,
2H, CH2), 4.50 (br s, 2H, NH2), 4.93-5.09 (m, 3H, NH-
CH2CH=CH2), 5.66-5.85 (m, 1H, CH2-CH=CH2), 7.23 (d, J =
6.7 Hz, 1H, H-5, pyrid), 7.30 (t, J = 6.0 Hz, 1H, NH-NH2), 7.52
(d, J = 6.7 Hz, 1H, H-6, pyrid.), 8.23 (s, 1H, H-2, pyrid.), 8.29
(s, 1H, H-1, pyrid.) ppm; 13C nmr (dimethyl sulfoxide-d6): ꢀ
42.41, 115.05, 131.50, 134.03, 135.48, 135.85, 141.68, 158.61,
187.15 ppm. Anal. Calcd. for C9H13N5O2S2 (287.36): C, 37.61;
H, 4.56; N, 24.37. Found: C, 37.60, H, 4.71, N, 24.50.
3-Amino-1-(2-propynyl)-2-(1,4-dihydro-4-thioxopyrid-3-yl-
sulfonyl)guanidine (12). Starting from pyridodithiazine 8 (1.01
g) and hydrazine hydrate, the title compound 12 was obtained
(1.04 g, 91%): mp 199-201 ºC dec.; ir (KBr): 3440, 3280, 3170,
3150 (NH2, NH), 1620, 1575, 1550 (C=N and C=C), 1350, 1190
(SO2) cm-1; 1H nmr (dimethyl sulfoxide-d6): ꢀ 3.04 (s, 1H,
CꢀCH), 3.81 (s, 2H, CH2), 3.94 (s, 1H, NHCH2), 4.54 (s, 2H,
NH2), 7.24 (d, J = 5.8 Hz, 1H, H-5, pyrid.), 7.48 (s, 1H, HN-N),
7.55 (d, J = 5.8 Hz, 1H, H-6, pyrid.), 8.31 (s, 1H, H-2, pyrid.),
8.33 (s, 1H, H-1, pyrid.) ppm; 13C nmr (dimethyl sulfoxide-d6): ꢀ
30.48, 73.67, 82.06, 132.74, 134.72, 137.11, 142.06, 158.79,
187.33 ppm. Anal. Calcd. for C9H11N5O2S2 (285.35): C, 37.88;
H, 3.88; N, 24.54. Found: C, 37.86, H, 3.95, N, 24.45.
1
1590, 1575 (C=N and C=C), 1325, 1160 (SO2) cm-1; H nmr
(dimethyl sulfoxide-d6): ꢀ 4.61 (s, 2H, CH2), 7.30-7.38 (m, 5H,
Ph), 7.81 (d, J = 5.5 Hz, 1H, H-5), 8.75 (d, J = 5.5 Hz, 1H, H-6),
9.04 (s, 1H, H-8), 10.33 (s, 1H, NH) ppm. Anal. Calcd. for
C13H11N3O2S2 (305.38): C, 51.13; H, 3.63; N, 13.76. Found: C,
51.11, H, 3.74, N, 13.82.
3-Allylaminopyrido[4,3-e]-1,4,2-dithiazine 1,1-dioxide (7).
Starting from allylamine (0.41 g), the title compound 7 was
obtained (1.5 g, 84%): mp 136-137 ºC; ir (KBr): 3160 (NH),
1
1645, 1575 (C=N and C=C), 1320, 1170 (SO2) cm-1; H nmr
(dimethyl sulfoxide-d6): ꢀ 4.02 (d, J = 5.4 Hz, 2H, CH2), 5.20
(dd, Jcis = 10.2 Hz, Jgem = 1.0 Hz, 1H, NCH2CHC=CHA), 5.25
(dd, Jtrans = 16.1 Hz, Jgem = 1.0 Hz, 1H, NCH2CHC=CHB), 5.83-
5.90 (m, 1H, NCH2CHC=CH2), 7.81 (d, J = 5.3 Hz, 1H, H-5),
8.75 (d, J = 5.3 Hz, 1H, H-6), 9.03 (s, 1H, H-8), 10.05 (s, 1H,
NH) ppm. Anal. Calcd. for C9H9N3O2S2 (255,32): C, 42.33; H,
3.55; N, 16.46. Found: C, 42.30, H, 3.63, N, 16.41.
3-(2-Propynylamino)pyrido[4,3-e]-1,4,2-dithiazine 1,1-
dioxide (8). Starting from 2-propynylamine (0.4 g), the title
compound 8 was obtained (1.6 g, 90%): mp 192-194 ºC; ir
(KBr): 3280 (NH), 2110 (CꢀCH), 1620, 1575 (C=N and C=C),
1
1325, 1170 (SO2) cm-1; H nmr (dimethyl sulfoxide-d6): ꢀ 3.33
(s, 1H, CꢀCH), 4.21 (s, 2H, CH2), 7.81 (d, J = 5.3 Hz, 1H, H-5),
8.74 (d, J = 5.3 Hz, 1H, H-6), 9.04 (s, 1H, H-8), 10.37 (br s, 1H,
NH) ppm; 13C nmr (dimethyl sulfoxide-d6): ꢀ 32.28, 75.19,
78.38, 122.58, 127.89, 139.67, 144.39, 151.68, 160.90 ppm.
Anal. Calcd. for C9H7N3O2S2 (253.31): C, 42.67; H, 2.78; N,
16.59. Found: C, 42.60, H, 2.87, N, 16.67.
1,3-Di(methylamino)-2-(1,4-dihydro-4-thioxopyrid-3-ylsul-
fonyl)guanidine (13). Starting from pyridodithiazine 10 (0.98 g)
and methylhydrazine, the title compound 13 was obtained (1.04
g, 89%): mp 188-189 ºC dec.; ir (KBr): 3310, 3280, 3210 (NH),
1
1630, 1610 (C=N and C=C), 1380, 1165 (SO2) cm-1; H nmr
N-(1,1-Dioxopyrido[4,3-e]-1,4,2-dithiazin-3-yl)aminoacetal-
dehyde dimethyl acetal (9). Starting from aminoacetaldehyde
dimethyl acetal (0.79 g), the title compound 9 was obtained (1.9
g, 89%): mp 172-173 ºC; ir (KBr): 3200 (NH), 1570, 1550 (C=N
(dimethyl sulfoxide-d6): ꢀ 2.42 (s, 4H, 2 x HN-NH), 3.36 (s, 6H,
2 x NCH3), 7.27 (d, J = 6.8 Hz, 1H, H-5, pyrid.), 7.58 (d, J = 6.8
Hz, 1H, H-6, pyrid.), 8.30 (br s, 1H, H-1, pyrid.), 8.38 (s, 1H, H-
2, pryid.) ppm. Anal. Calcd. for C8H14N6O2S2 (290.37): C, 33.09;
H, 4.86; N, 28.94. Found: C, 33.16, H, 4.19, N, 28.89.
1
and C=C), 1330, 1170 (SO2) cm-1; H nmr (dimethyl sulfoxide-
d6): ꢀ 3.37 (s, 6H, 2 x CH3O), 3.53 (d, J = 5.1 Hz, 2H, CH2),
4.55 (t, J = 5.1 Hz, CHCH2), 7.84 (d, J = 5.4 Hz, 1H, H-5), 8.78
(d, J = 5.4 Hz, 1H, H-6), 9.07 (s, 1H, H-8), 10.03 (s, 1H, NH)
ppm. Anal. Calcd. for C10H13N3O4S2 (303.36): C, 39.59; H, 4.32;
N, 13.85. Found: C, 39.65, H, 4.41, N, 13.97.
3-(4-Chlorobenzylideneamnio)-2-(1,4-dihydro-4-thioxopyrid-
3-ylsulfonyl)-1-(2-propynyl)guanidine (14).
A mixture of
aminoguanidine 12 (1.14 g, 4 mmol) and 4-chlorobenzalehyde
(0.6 g, 4.3 mmol) in ethanol (40 mL) was stirred at reflux for 10
h. After cooling to room temperature the resulting suspension
was left overnight. The precipitate was collected by filtration,
washed successively with ethanol (2 x 2 mL) and methanol (3 x
1 mL), and dried initially at room temperature and then at 90 ºC
to give 14 (1.4 g, 85%): mp 190-191 ºC dec.; ir (KBr): 3290,
3255, 3220 (NH), 2110 (CꢀCH), 1620, 1600, 1560 (C=N and
3-(2-Methylhydrazino)pyrido[4,3-e]-1,4,2-dithiazine 1,1-
dioxide (10). Starting from methylhydrazine (0.33 g), the title
compound 10 was obtained (1.5 g, 87%): mp 231-232 ºC dec.; ir
(KBr): 3325, 3235 (NH-NH), 1645, 1575, 1550 (C=N and C=C),
1
1315, 1160 (SO2) cm-1; H nmr (dimethyl sulfoxide-d6): ꢀ 3.37
(s, 3H, CH3), 5.82 (s, 2H, NH-NH), 7.80 (d, J = 5.3 Hz, 1H, H-

1412
Z. Brzozowski, F. Sꢀczewski and J. Sꢁawiꢂski
Vol 45
C=C), 1365, 1345, 1185 (SO2), 1260 (C=S) cm-1; 1H nmr
(dimethyl sulfoxide-d6): ꢀ 3.11 (s, 1H, CꢀCH), 3.93 (d, J = 3.4
Hz, 2H, CH2), 7.27 (d, J = 6.6 Hz, 1H, H-5, pyrid.), 7.52 (d, J =
8.1 Hz, 2H, 4-ClPh), 7.59 (d, J = 6.6 Hz, 1H, H-6, pyrid.), 7.92
(d, J = 8.1 Hz, 2H, 4-ClPh), 8.27 (s, 2H, 2 x NH, guanidine),
8.40 (s, 1H, H-2, pyrid.), 10.17 (s, 1H, N=CHPh), 12.80 (s, 1H,
H-1, pyrid.) ppm; 13C nmr (dimethyl sulfoxide-d6): ꢀ 30.77,
73.93, 81.61, 129.44, 129.87, 132.43, 133.54, 134.85, 135.33,
136.94, 141.58, 144.97, 154.11, 188.01 ppm. Anal. Calcd. for
C16H14ClN5O2S2 (407.90): C, 47.11; H, 3.46; N, 17.16. Found:
C, 47.21, H, 3.50, N, 17.15.
Calcd. for C7H7N3O2S2 (229.29): C, 36.67; H, 3.08; N, 18.32.
Found: C, 36.63, H, 3.17, N, 18.34.
4-Methylthiopyridine-3-sulfonamide (18). Ta an ice-cold
solution of 15 (2.85 g, 15 mmol) and triethylamine (1.72 g, 17
mmol) in acetonitrile (20 mL) a solution of methyl iodide (2.13
g, 15 mmol) in acetonitrile (12 mL) was added drop by drop
with stirring. After 1 h, the ice bath was removed and the
reaction mixture was refluxed for 1.5 h. The solvent was
partially evaporated under normal pressure and the resulting
suspension was stirred at room temperature for 4 h. The
precipitate was collected by filtration, washed with acetonitrile
(2 x 1 mL) and water (5 x 3 mL), and dried. Yield 2.95 g (96%),
mp 222-223 ºC.; ir (KBr): 3295, 3160 (SO2NH2), 1570vs (C=N
1,4-Dihydro-4-thioxopyridine-3-sulfonamide (15). To
a
solution of NaOH (6 g, 0.15 mol) in water (60 mL) the thiolate 2
(11.52 g, 0.05 mol) was added. The reaction mixture was
refluxed with stirring for 6 h. The resulting solution was
acidified with 15% hydrochloric acid to pH 3. After stirring at
room temperature for 8 h, the crude product was collected by
filtration, washed with water (2 x 5 mL) and purified by
crystallization from water. Yield 7.5 g (78%), mp 225-226 ºC
dec.; ir (KBr): 3220, 3180, 3105 (NH2), 1620, 1575 (C=N and
1
and C=C), 1345, 1165 (SO2) cm-1; H nmr (dimethyl sulfoxide-
d6): ꢀ 2.55 (s, 3H, CH3S), 7.44 (d, J = 5.5 Hz, 1H, H-5), 7.60 (s,
2H, SO2NH2), 8.53 (d, J = 5.5 Hz, 1H, H-6), 8.79 (s, 1H, H-2)
ppm; 13C nmr (dimethyl sulfoxide-d6): ꢀ 14.37, 119.92, 135.80,
147.31, 149.69, 151.71 ppm. Anal. Calcd. for C6H8N2O2S2
(204.27): C, 35.28; H, 3.94; N, 13.71. Found: C, 35.30, H, 4.11,
N, 13.83.
1
C=C), 1365, 1340, 1170, 1160 (SO2), 1230 (C=S) cm-1; H nmr
4-(Carbamoylmethythio)pyridine-3-sulfonamide (19). To
an ice-cold solution of thioacetonitrile 17 (1.38 g, 6 mmol) in
DMSO (5 mL) and ethanol (10 mL) aqueous solutions of H2O2
(0.6 g, 17.6 mmol) in 2 mL of water and aqueous solution of
NaOH (0.7 g) in 3 mL of water were added successively with
stirring. After 0.5 h the ice bath was removed and the reaction
mixture obtained was poured into water (40 mL). The precipitate
thus obtained was immediately collected by filtration and
washed thoroughly with water, and dried. Yield 1.1 g (74%), mp
199-200 ºC dec.; ir (KBr): 3405, 3315, 3170 (NH2), 1690, 1665
(dimethyl sulfoxide-d6): ꢀ 7.21 (s, 2H, NH2), 7.38 (d, J = 6.7 Hz,
1H, H-5), 7.70 (d, J = 6.7 Hz, 1H, H-6), 8.37 (s, 1H, H-2), 13.04
(s, 1H, H-1) ppm; 13C nmr (dimethyl sulfoxide-d6): ꢀ 133.25,
133.92, 135.65, 140,44, 186.10 ppm. Anal. Calcd. for
C5H6N2O2S2 (190.24): C, 31.56; H, 3.18; N, 14.12. Found: C,
31.58, H, 3.21, N, 14.22.
4,4'-Thiodipyridine-3-sulfonamide (16). A mixture of 15
(0.95 g, 5 mmol) and 4-chloropyridine-3-sulfonamide (0.96 g, 5
mmol) in acetonitrile (50 mL) was stirred at reflux for 60 h.
After cooling to room temperature the suspension was left
overnight. The mixture of crude product and its hydrochloride
was collected by filtration, washed with acetonitrile (3 x 1.5 mL)
and then treated with water (15 mL). The resulting suspension
(pH ~1.5) was adjusted to pH 7.8 with 1% aqueous solution of
NaOH. After 1 h of stirring the title product was collected by
filtration, washed successively with water (5 x 3 mL) and hot
acetonitrile (5 x 3 mL), and dried. Yield 1.13 g (65%), mp 216-
218 ºC dec.; ir (KBr): 3300, 3205 (SO2NH2), 1635, 1560 (C=N
1
(C=O) 1635 (C=N), 1330, 1160 (SO2) cm-1; H nmr (dimethyl
sulfoxide-d6): ꢀ 3.85 (s, 2H, CH2), 7.33 (s, 1H, CONHA), 7.50
(d, J = 4.4 Hz, 1H, H-5), 7.64 (s, 2H, SO2NH2), 7.70 (s, 1H,
CONHB), 8.56 (d, J = 4.4 Hz, 1H, H-6), 8.82 (2, 1H, H-2) ppm.
Anal. Calcd. for C7H9N3O3S2 (247.30): C, 33.99; H, 3.67; N,
16.99. Found: C, 34.06, H, 3.73, N, 17.10.
4-Methylthio-3-sulfamoyl-1-methylpyridinium iodide (20).
To an ice-cold suspension of 18 (2.04 g, 10 mmol) in acetonitrile
(20 mL) a solution of methyl iodide (1.56 g, 11 mmol) in
acetonitrile (15 mL) was added dropwise with stirring while the
temperature was maintained below 8 ºC. Stirring was continued
at room temperature for 8 h, and at reflux for 15 h. After cooling
to room temperature, the precipitate was collected by filtration,
washed with acetonitrile (3 x 2 mL), and dried. Yield 3.3 g
(95%), mp 218-219 ºC.; ir (KBr): 3210, 3125 (NH2), 1630vs
(C=N and C=C), 1350, 1165 (SO2) cm-1; 1H nmr (dimethyl
sulfoxide-d6): ꢀ 2.81 (s, 3H CH3S), 4.26 (s, 3H, CH3N+), 8.05 (d,
J = 6.9 Hz, 1H, H-5), 8.17 (s, 2H, SO2NH2), 8.82 (dd, Jortho = 6.9
Hz, Jmeta = 1.3 Hz, 1H, H-6), 9.07 (d, J = 1.3 Hz, 1H, H-2) ppm.
Anal. Calcd. for C7H11IN2O2S2 (346.21): C, 24.28; H, 3.20; N,
8.08. Found: C, 24.33, H, 3.24, N, 8.12.
4-(Carbamoylmethylthio)-3-sulfamoyl-1-methylpyridinium
iodide (21). A mixture of 19 (0.99 g, 4 mmol) and methyl
iodide (1.42 g, 10 mmol) in acetonitrile (20 mL) was refluxed
with stirring for 20 h, then allowed to cool to room
temperature. The precipitate was collected by filtration,
washed with acetonitrile (4 x 2 mL), and dried. Yield 1.5 g
(96%), mp 220-221 ºC dec.; ir (KBr): 3385, 3285, 3240, 3180,
3120 (SO2NH2, CONH2), 1680 (C=O), 1630, 1605 (C=N and
C=C), 1340, 1155 (SO2) cm-1; 1H nmr (dimethyl sulfoxide-d6):
ꢀ 4.19 (s, 2H, SCH2), 4.25 (s, 3H, CH3N+), 7.49 (s, 1H,
CONHA), 7.82 (s, 1H, CONHB), 8.04 (d, J = 5.6 Hz, 1H, H-5),
1
and C=C), 1335, 1160 (SO2) cm-1; H nmr (dimethyl sulfoxide-
d6): ꢀ 7.25 (d, J = 5.5 Hz, 2H, H-5 and H-5'), 7.88 (s, 4H, 2 x
SO2NH2), 8.65 (d, J = 5.5 Hz, 2H, H-6 and H-6'), 9.16 (s, 2H, H-
2 and H-2') ppm; 13C nmr (dimethyl sulfoxide-d6): ꢀ 128.27,
139.74, 143.76, 148.79, 153.58 ppm. Anal. Calcd. for
C10H10N4O4S3 (346.41): C, 34.67; H, 2.91; N, 16.17. Found: C,
34.61, H, 3.06, N, 16.13.
4-(Cyanomethylthio)pyridine-3-sulfonamide (17). To
a
solution of the sulfonamide 15 (1.52 g, 8 mmol) and triethyl-
amine (0.85 g, 8,5 mmol) in acetonitrile (15 mL) a solution of
bromoacetonitrile (1.02 g, 8.5 mmol) in acetonitrile (10 mL) was
added with stirring while the temperature was maintained below
18 ºC with external cooling. Stirring was continued at room
temperature for 2 h, and at reflux for additional 2 h. After
cooling to room temperature, the precipitate was collected by
filtration, washed with water (5 x 4 mL) and dried at
temperatures gradually increasing to 100 ºC. Yield 1.73 g (94%),
mp 205-206 ºC dec.; ir (KBr): 3340, 3170 (SO2NH2), 2250
1
(CꢀN), 1570vs (C=N and C=C), 1340, 1170 (SO2) cm-1; H nmr
(dimethyl sulfoxide-d6): ꢀ 4.54 (s, 2H, CH2), 7.62 (d, J = 5.4 Hz,
1H, H-5), 7.85 (s, 2H, NH2), 8.72 (d, J = 5.4 Hz, 1H, H-6), 8.92
(s, 1H, H-2) ppm; 13C nmr (dimethyl sulfoxide-d6): ꢀ 16.23,
117.26, 120.39, 136.33, 144.99, 148.02, 152.18 ppm. Anal.

Sep-Oct 2008
Syntheses of Potassium 1,1-Dioxopyrido[4,3-e]-1,4,2-dithiazine-3-thiolate
1413
Med. Chem. Lett. 2006, 16, 4846.
[15] Brzozowski, Z.; Sꢀczewski, F.; Sꢁawiꢂski, J. Eur. J. Med.
Chem. 2007, 42, 1218.
[16] Brzozowski, Z.; Sꢁawiꢂski, J. Pol. J. Chem. 2007, 81, 1419.
[17] Brzozowski, Z.; Sꢁawiꢂski, J.; Sꢀczewski, F.; Sanchez T.;
Neamati, N. Eur. J. Med. Chem. 2007, 42, (in press).
[18] Brzozowski, Z.; Sꢀczewski, F.; Gdaniec, M. Bioorg. Med.
Chem. 2003, 11, 3673.
8.21 (s, 2H, SO2NH2), 8.84 (d, J = 5.6 Hz, 1H, H-6), 9.09 (s,
1H, H-2) ppm; 13C nmr (dimethyl sulfoxide-d6): ꢀ 35.73,
47.22, 123.75, 137.21, 142.80, 145.08, 160.02, 167.80 ppm.
Anal. Calcd. for C8H12IN3O3S2 (389.24): C, 24.68; H, 3.10; N,
10.79. Found: C, 24.70, H, 3.15, N, 10.84.
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