Synthesis and structure determination of 2,3-diaryl-9,9-dioxo-1H-9-thia-1, 4,4a,7,10-pentaazaphenanthrene-2-ols

Article abstract of DOI:10.1016/j.tet.2013.08.006

3-Amino-1,1-dioxopyrido[4,3-e]-1,4,2-dithiazine has been synthesized and applied to the synthesis of 3-amino-2-(4-thioxo-1,4-dihydropyridin-3-ylsulfonyl) guanidine. The reaction of the aminoguanidine with the appropriate 1,2-diarylethane-1,2-diones afforded 2,3-diaryl-9,9-dioxo-1H-9-thia-1,4,4a,7,10- pentaazaphenanthrene-2-ol derivatives. The structure of these compounds, which represent a novel heterocyclic ring system, was confirmed on the basis of elemental analysis and spectroscopic data including COSY, NOESY, ROESY, HSQC, and HMBC.

Full text of DOI:10.1016/j.tet.2013.08.006

Tetrahedron 69 (2013) 8675e8679
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Tetrahedron
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Synthesis and structure determination of 2,3-diaryl-9,9-dioxo-1H-9-
thia-1,4,4a,7,10-pentaazaphenanthrene-2-ols
a
,
a
a
b
_
*
ꢀ
Jaros1aw S1awinski , Aneta Pogorzelska , Beata Zo1nowska , Tomasz Laskowski ,
b
ꢀ
Pawe1 Sowinski
a
ꢀ
ꢀ
Department of Organic Chemistry, Medical University of Gdansk, Al. Gen. J. Hallera 107, 80-416 Gdansk, Poland
Faculty of Chemistry, Gdansk University of Technology, Narutowicza 11/12, 80-213 Gdansk, Poland
b
ꢀ
ꢀ
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 10 June 2013
Received in revised form 24 July 2013
Accepted 5 August 2013
Available online 11 August 2013
3-Amino-1,1-dioxopyrido[4,3-e]-1,4,2-dithiazine has been synthesized and applied to the synthesis of 3-
amino-2-(4-thioxo-1,4-dihydropyridin-3-ylsulfonyl)guanidine. The reaction of the aminoguanidine with
the appropriate 1,2-diarylethane-1,2-diones afforded 2,3-diaryl-9,9-dioxo-1H-9-thia-1,4,4a,7,10-
pentaazaphenanthrene-2-ol derivatives. The structure of these compounds, which represent a novel
heterocyclic ring system, was confirmed on the basis of elemental analysis and spectroscopic data in-
cluding COSY, NOESY, ROESY, HSQC, and HMBC.
Keywords:
Ó 2013 Elsevier Ltd. All rights reserved.
4-Chloropyridine-3-sulfonamide
1,1-Dioxopyrido[4,3-e]-1,4,2-dithiazine
Synthesis
NMR studies
1. Introduction
Arylsulfonamides have been shown to exhibit a variety of bi-
ological activities.1 Among them, the derivatives modified by sub-
stitution of the arylsulfonamide core by pyridothiadiazine ring
system as well as 1,2,4-triazine scaffold constitute an important
class of compounds with pharmacological properties.2,3
Pyridothiadiazines act as AMPA potentiators4,5 (Fig. 1, I), KATP
channel openers6,7 (Fig. 1, II), CCK receptor ligands,8 antibacterial
and anticancer agents2,3 (Fig. 1, III, IV, V). The aforementioned bi-
ological activity of these compounds means it could find diverse
therapeutic applications including the treatment of cognitive dis-
orders,4e6,9,10 gastro-intestinal disturbances,8 anxiety,8 cancer,2,3
bacterial infections,2,3 pancreatitis,8 pain,8 schizophrenia,8,11 drug
abuse,8 arterial hypertension,6,7 depression, and Parkinson’s
disease.12
The 1,2,4-triazine scaffold has been found in numerous bi-
ologically active compounds.13 An array of biological activities re-
lated to 1,2,4-triazine containing compounds, including
antitumor3,13e15 (Fig. 1, VI) and antiviral16,17 properties, has been
reported. It is worth noting that various condensed 1,2,4-triazines
also display a broad spectrum of therapeutically interesting
activity.18e24
Fig. 1. Structures of known AMPA potentiators I5, potassium channel openers II6,
antibacterial and anticancer pyridothiadiazine derivatives IIIeV2, antitumor N-(1,2,4-
triazin-3-yl)benzenosulfonamides VI3, and novel 9,9-dioxo-1H-9-thia-1,4,4a,7,10-
pentaazaphenanthrene-2-ol derivatives VII.
* Corresponding author. Tel.: þ48 58 349 10 98; fax: þ48 58 349 12 77; e-mail
ꢀ
address: jaroslaw@gumed.edu.pl (J. S1awinski).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.08.006

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8676
Due to a number of biological properties of nitrogen-containing
heterocycles, the synthesis of these compounds is an important
point of the search for new therapeutic agents. One of the general
strategies in the preparations of these molecules is reaction between
dicarbonyl compounds and an amine group. Depending on the
chemical structure of the two substrates, the reaction product can
give mono- or polyazacycles. In the case of guanidine and 1,2-
dicarbonyl compounds, the documented product is an appropri-
ately substituted imidazole derivative,25,26 while use of amino-
guanidine leads to the corresponding triazine.3,27e29 Herein we
report the unexpected course of reaction between an amino-
guanidine component, i.e., 3-amino-2-(4-thioxo-1,4-dihydropyridin-
3-ylsulfonyl)guanidine, and benzil derivatives, which consequently
led to formation of the new ring system 9,9-dioxo-1H-9-thia-
1,4,4a,7,10-pentaazaphenanthrene-2-ol (Fig. 1, VII). It could be seen
that this structure may be consider as a condensed system of pyr-
idothiadiazine with a 1,2,4-triazine ring.
2. Results and discussion
2.1. Synthetic chemistry
As presented in Scheme 1 the synthesis of the starting 2-(4-
thioxo-1,4-dihydropyridin-3-ylsulfonyl)guanidine derivatives
4
and 5 was achieved in a multi-step reaction sequence starting from
commercially available 4-chloropyridine-3-sulfonamide 1. At first,
3-methylthio-1,1-dioxopyrido[4,3-e]-1,4,2-dithiazine 2 was readily
obtained according to the previously described procedure.30 Fur-
ther treatment of 2 with 1 M equiv of 25% ammonium hydroxide in
ethanolic solution resulted in the formation of 3-amino-1,1-
dioxopyrido[4,3-e]-1,4,2-dithiazine 3 in an excellent yield 95%. On
the other hand, when a 2 M excess of ammonium hydroxide was
used the ring opening reaction readily proceeded to furnish 2-(4-
thioxo-1,4-dihydropyridin-3-ylsulfonyl)guanidine 4. Similarly, re-
action of 3 with 2 M equiv of hydrazine hydrate afforded 3-amino-
2-(4-thioxo-1,4-dihydropyridin-3-ylsulfonyl)guanidine 5. Yields of
these reactions were high, 88% for both 4 and 5 (Schemes 1 and 2).
Inspection of the IR and NMR spectroscopic data (see Experimental
section) revealed that compounds 4 and 5, in the solid state as well
as DMSO solution, exist in a single 4-thioxopyridine tautomeric
form.
Scheme 2. Proposed mechanism for the formation of 2-(4-thioxo-1,4-dihydropyridin-
3-ylsulfonyl)guanidine derivatives 4, 5.
substitution of thiomethyl group via a non-isolable adduct of type
A. The subsequent transformation of 3 led to the formation of an
intermediate guanidine B, containing a 4-mercaptopyridine ring,
which tautomerized to the stable 4-thioxopyridine giving com-
pound 4. In turn, reaction of 3 with an excess of hydrazine hydrate
yielded an intermediate salt C, which upon acidification afforded 4-
mercaptopyridine D. Further D tautomerization resulted in the
stable 4-thioxopyridine derivative 5.
The reaction of aminoguanidine 5 with the appropriate 1,2-
diarylethane-1,2-diones carried out in anhydrous dimethylsulf-
oxide (DMSO) at 80e85 ꢀC for 42e58 h afforded the novel pen-
taazaphenanthrene ring system 6e11. The proposed mechanism
leading to the formation of products 6e11 is outlined in Scheme 3.
The initial step is believed to be the formation of intermediate
condensation/tautomerization product of type E, which undergoes
SNAr additioneelimination process on the activated 4-position of
pyridine ring to form pyridothiadiazine intermediate F with si-
multaneous H2S elimination, and further tautomerization to the
more stable 3-aminopyridothiadiazine2,31 intermediate G. The final
six-membered ring closure leading to the desired 2,3-diaryl-9,9-
dioxo-1H-9-thia-1,4,4a,7,10-pentaazaphenanthrene-2-ol
de-
rivatives 6e11 was ensued upon attack of the amino group on the
next carbonyl carbon atom (Scheme 3).
Scheme 1. Reagents and conditions: (i) 1 equiv 25% NH3 aq, EtOH, 120 h, rt, 95%; (ii)
2 equiv 25% NH3 aq, EtOH, 90 h, rt then 3 h, reflux, 88%; (iii) 2 equiv 99% N2H4 hydrate,
dry MeOH, 30e40 h, 88%; (iv) AcOH, 88%.
An attempt was also made to apply 2-(4-thioxo-1,4-dihydro-
pyridin-3-ylsulfonyl)guanidine 4 to the reaction with benzil that
would allow the preparation of the corresponding cyclocondensation
product of type H (Scheme 3). However, the reaction failed, even at
a prolonged reaction time of over 60 h, apparently due to the rela-
tivelylow nucleophilicityof the sulfonylguanidinenitrogen atoms. As
a result, an intractable mixture of products was formed.
The structures of 6e11 were confirmed by IR, NMR and MS data
and elemental analyses.
The proposed mechanism for the formation of 2-(4-thioxo-1,4-
dihydropyridin-3-ylsulfonyl)guanidine derivatives
shown in Scheme 2. The reaction sequence involved the initial
formation of 3-aminopyridodithiazine by nucleophilic
4 and 5 is
3

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8677
Fig.
2. The
structure
of
9,9-dioxo-2,3-di(thien-2-yl)-1H-9-thia-1,4,4a,7,10-
pentaazaphenanthrene-2-ol 11; the atom numbers are correlated with the NMR
results.
namely C5eC6, C14eC16, and C19eC21 to be traced. The C14eC16
and C19eC21 spin systems were distinguished by the presence of
H5/H19 ROE and upon the C2/H14 and C2/H16 heteronuclear cor-
relations. The chemical shift of carbon C2 in the 13C NMR spectrum
(77.5 ppm) indicated its sp3 hybridization. The H11/H14 and H11/
H19 ROEs with C2/H11 and C14/H11 HMBC correlations determined
the position of the hydroxyl group. The presence of H1/H11 and H1/
H14 ROEs with C2/H1, C3/H1, C4b/H1, C10a/H1, C13/H1, and C18/H1
HMBC correlations revealed the position of the protonated nitrogen.
The assignments of quaternary sp2 carbons C3, C4b, C8a, C10a, C13,
and C18 were made upon several heteronuclear correlations ob-
served in the HMBC spectrum, listed in Table 2.
3. Conclusion
We have demonstrated that the reactions of 3-methylthio-1,1-
dioxopyrido[4,3-e]-1,4,2-dithiazine 2 with 1 M equiv of 25% am-
monium hydroxide lead to the formation of 3-amino-1,1-
dioxopyrido[4,3-e]-1,4,2-dithiazine 3 while the 2 M excess of am-
monium hydroxide proceeded to furnish 2-(4-thioxo-1,4-
dihydropyridin-3-ylsulfonyl)guanidine 4. Reaction of
3 with
2 M equiv of hydrazine hydrate afforded 3-amino-2-(4-thioxo-1,4-
dihydropyridin-3-ylsulfonyl)guanidine 5, which reacting with the
appropriate 1,2-diarylethane-1,2-diones gave the new ring system
9,9-dioxo-1H-9-thia-1,4,4a,7,10-pentaazaphenanthrene-2-ol
(6e11) with potential biological activity.
Scheme 3. Proposed mechanism for the formation of 2,3-diaryl-9,9-dioxo-1H-9-thia-
1,4,4a,7,10-pentaazaphenanthrene-2-ol derivatives 6e11; (i) 1,2-diarylethane-1,2-
dione, dry DMSO, 80e85 ꢀC, 42e58 h, 17e60%.
4. Experimental section
4.1. General
In the IR spectra of compounds 6e11 the characteristic OH and
NH groups appeared as overlapping broad absorption bands in the
3378e3302 cmꢁ1. In the 1H NMR spectra (DMSO-d6) of the com-
pounds 6e11 the chemical shifts of the two singlets in the
8.24e8.57 ppm and 10.31e10.73 ppm regions were assigned to the
protons of OH and NH groups, respectively. The presence of these
groups was also confirmed by the rapid exchange observed in the
NMR spectra of compounds 10 made in DMSO with deuterium
oxide (D2O). Moreover, signals of protons H-8, H-5, and H-6 from
the pyridine ring of the tricyclic pentaazaphenanthrene system
shifted downfield in comparison with the analogous 4-thioxo-1,4-
dihydropyridine protons H-2, H-5, and H-6 of 2.
The following instruments and parameters were used: melting
points Stuart SMP30; IR spectra: KBr pellets, 400e4000 cmꢁ1
Thermo Mattson Satellite FTIR spectrometer; 1H NMR and 13C NMR:
VarianGemini200 apparatus; chemicalshifts (d) arereported inparts
per million downfield from TMS; coupling constants (J) are given in
hertz; multiplicity in 1H NMR is reported as singlet (s), broad singlet
Table 1
1H NMR data for 11
Proton no.
1H
d
(ppm)
3J (HH) contacts (Hz)
NOE/ROE contacts
2.2. NMR spectroscopy studies
H-1
H-5
H-6
H-8
H-11
H-14
H-15
H-16
H-19
H-20
H-21
10.72
7.87
8.86
8.98
8.56
7.22
7.00
7.59
7.47
7.05
7.73
d
H-11; H-14
H-6; H-19
H-5
5.94 (H-6)
5.94 (H-5)
d
The NMR spectroscopy studies, consisting of COSY, NOESY,
ROESY, HSQC, and HMBC experiments, resulted in structure confir-
mation of 9,9-dioxo-2,3-di(thien-2-yl)-1H-9-thia-1,4,4a,7,10-penta
azaphenanthrene-2-ol 11 (Fig. 2) by proton and carbon assign-
ments, which are given inTables 1 and 2, respectively. The resonance
signal of proton H8 was identified as the only one singlet showing
a correlation to a sp2 carbon in HSQC spectrum. The COSY spectrum
of 11 allowed the connectivities within three structural blocks,
d
d
H-1; H-14; H-19
H-1; H-11; H-15; H-19
H-14; H-16
H-15
H-5; H-11; H-14; H-20
H-19; H-21
H-20
3.41 (H-15)
3.41 (H-14); 4.78 (H-16)
4.78 (H-15)
3.34 (H-20)
3.34 (H-19); 4.84 (H-21)
4.84 (H-20)

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J. Sławinski et al. / Tetrahedron 69 (2013) 8675e8679
8678
Table 2
4.4. 2-(4-Thioxo-1,4-dihydropyridin-3-ylsulfonyl)guanidine
(4)
13C NMR data for 11 with long-range C/H couplings observed in HMBC spectrum
Carbon no.
13C
d
(ppm)
HMBC to proton [see: Table 1]
According to the procedure for 3. Starting from 2 (4.92 g,
20 mmol), ethanol (30 mL), 25% NH3 aq (3.28 mL, 43.80 mmol) after
90 h at rt and 3 h at reflux the 2-(4-thioxo-1,4-dihydropyridin-3-
ylsulfonyl)guanidine (4) was obtained. Yield (solid powder): 88%
(4.09 g); mp¼230e231 ꢀC (dec); IR (KBr) v¼3424, 3319, 3205 (NH,
NH2), 1620 (NH def.), 1537 (C]N), 1338 (SO2 asym.), 1226 (C]S), 1133
C-2
C-3
C-4b
C-5
C-6
77.5
148.5
142.7
110.3
153.6
145.5
121.5
148.5
145.5
127.8
127.9
127.9
135.9
132.0
128.4
131.2
H-11; H-14; H-16
H-1; H-11; H-19; H-20; H-21
H-1; H-5; H-6; H-8
H-6; H-8
H-5; H-8
H-6
H-5; H-6; H-8
H-1
H-1; H-11; H-14; H-15; H-16
H-11; H-15; H-16
H-14; H-16
H-14; H-15
H-1; H-19; H-20; H-21
H-20; H-21
C-8
C-8a
C-10a
C-13
C-14
C-15
C-16
C-18
C-19
C-20
C-21
(SO2 sym.) cmꢁ1
;
1H NMR (200 MHz, DMSO-d6)
d
¼6.55 (br s, 4H),
7.13 (d, J¼6.2 Hz, 1H), 7.54 (d, J¼6.2 Hz, 1H), 8.34 (s, 1H). Anal. Calcd
for C6H8N4O2S2 (232.29): C, 31.02; H, 3.47; N, 24.12. Found: C, 31.09;
H, 3.50; N, 24.18.
4.5. 3-Amino-2-(4-thioxo-1,4-dihydropyridin-3-ylsulfonyl)
guanidine (5)
H-19; H-21
H-19; H-20
To a suspension of 3-amino-1,1-dioxopyrido[4,3-e]-1,4,2-dithia-
zine (3) (2.15 g, 10 mmol) in dry methanol (10 mL) 99% hydrazine
hydrate (1.00 g, 20 mmol) was added and stirred at rt for 30e40 h.
The precipitate was collected by filtration, washed with methanol
(2ꢃ3 mL), water (2ꢃ3 mL), methanol (3 mL) then dried to afford
(br s), doublet (d), triplet (t), and multiplet (m). Mass spectra were
recorded on Applied Biosystem QStar XL MS/MS mass spectrometer
with an electrospray ionization (ESI) and hybrid quadrupole time-of-
flight analyzer (Q-TOF). The results of elemental analyses for C, H, and
N were in agreement with the calculated values within ꢂ0.4% range.
Thin-layer chromatography (TLC) was performed on Merck Kieselgel
60F254 plates and visualized with UV. The starting substrate 3-
methylthio-1,1-dioxopyrido[4,3-e]-1,4,2-dithiazine (2) was obtained
from commercially available 4-chloropyridine-3-sulfonamide 1 ap-
plying procedure described previously.30
2.47
g (88.4%) of 3-amino-2-(4-thioxo-1,4-dihydropyridin-3-
ylsulfonyl)guanidine (5) as a hydrazine salt; mp¼196e200 ꢀC
(dec). The hydrazine salt of 5 (1.0 g, 3.58 mmol) was suspended in
glacial acetic acid (5 mL) and stirred for 1 h. The yellow solid was
filtered off, washed with methanol (3ꢃ3 mL), and dried to give 5.
Yield (solid powder): 99.8% (0.884 g); mp¼208e210 ꢀC (dec); IR
(KBr) v¼3431, 3332, 3290, 3211, 3096 (NH, NH2), 1625 (NHdef.), 1576
(C]N), 1351 (SO2 asym.), 1231 (C]S), 1133 (SO2 sym.) cmꢁ1; 1H NMR
4.2. NMR studies
(200 MHz, DMSO-d6)
d
¼4.43 (br s, 2H); 6.95 (br s, 2H); 7.21 (d,
J¼6.7 Hz, 1H); 7.53 (d, J¼6.7 Hz, 1H); 8.25 (br s, 1H); 8.29 (s, 1H); 13C
NMR spectra for 11 were recorded with a Varian Unity 500 Plus
spectrometer in DMSO-d6 solvent at temperature of 302 K. The
spectra of 13C and one-dimensional 1H were collected with stan-
dard parameters.
NMR (50 MHz, DMSO-d6)
d 132.0, 134.2, 136.4, 142.2, 160.5, 187.4.
Anal. Calcd for C6H9N5O2S2 (247.30): C, 29.11; H, 3.66; N, 28.32.
Found: C, 29.14; H, 3.67; N, 28.30.
NOESYand ROESY spectra were acquired in phase-sensitive mode
with a spectral width of 3398 Hz. The NOESY spectrum was acquired
with mix time 350 ms in 1024ꢃ200 matrix with 32 accumulations
per increment and processed in 1 Kꢃ1 K matrix. The ROESY spectrum
was acquired with mix time 300 ms in 1024ꢃ200 matrix with 24
accumulations per increment and processed in 1 Kꢃ1 K matrix.
COSY, HSQC, and HMBC experiments were performed with pulse
fieldgradients. The COSY spectrumwas acquired in 1024ꢃ256 matrix
with four accumulations and processed in 1 Kꢃ1 K matrix. The HSQC
spectrum was acquired in phase-sensitive mode. The spectral win-
dows for 1H and 13C axes were 3398 Hz and 16,341 Hz, respectively.
Data were collected in 672ꢃ170 matrix and processed in 1 Kꢃ1 K
matrix. The HMBC spectrum was acquired in phase-sensitive mode.
The spectral windows for 1H and 13C axes were 3398 Hz and
16,341 Hz, respectively. Data were collected in 736ꢃ180 matrix and
processed in 1 Kꢃ1 K matrix.
4.6. General procedure for the synthesis of 2,3-diaryl-9,9-
dioxo-1H-9-thia-1,4,4a,7,10-pentaazaphenanthrene-2-ol de-
rivatives (6e11)
To a suspension of 5 (0.495 g, 2 mmol) in dry DMSO (3.5e10 mL)
appropriate 1,2-diarylethane-1,2-dione (2 mmol) was added and
stirred at 80e85 ꢀC for 42e58 h. After cooling the precipitate of side
products was filtered off, then to filtrate methanol (30 mL) was
added dropwise and the mixture was left overnight to crystalliza-
tion at ambient temperature. The crude products were collected by
filtration, washed with methanol, and dried. A final purification was
described below.
4. 6.1. 2, 3-Diphenyl-9, 9-dioxo-1H-9-thia-1, 4, 4a, 7,10-
pentaazaphenanthrene-2-ol (6). Starting from 5, DMSO (3.5 mL),
benzil (0.420 g) for 42 h the title compound 6 was obtained. The
product was purified by extraction of contaminations with boiling
mixture of ethanol/DMF (v/v 4:1) (32 mL). Yield (solid powder):
(60%) 0.486 g; mp¼215e216 ꢀC (dec); IR (KBr) v¼3331 (wide) (OH,
NH), 2923, 2852, 1619, 1591 (C]N, C]C), 1282, 1162 (SO2) cmꢁ1; 1H
4.3. 3-Amino-1,1-dioxopyrido[4,3-e]-1,4,2-dithiazine (3)
To a suspension of 3-methylthio-1,1-dioxopyrido[4,3-e]-1,4,2-
dithiazine (2) (9.0 g, 36.5 mmol) in ethanol (36 mL) 25% NH3
aq (2.87 mL, 38.33 mmol) was added and stirred at rt for 120 h. The
reaction mixture was refluxed with stirring until the evolution of
MeSH had ceased (25 h). After 12 h the precipitate was collected by
filtration, washed with ethanol (3ꢃ3 mL), dried, and applied without
further purification. Yield (solid powder): 95% (7.45 g);
mp¼256.5e257 ꢀC (dec); IR (KBr) v¼3379, 3294, 3206 (NH2), 1626
(NH2 def.), 1568, 1551 (C]N, C]C), 1298, 1159 (SO2) cmꢁ1; 1H NMR
NMR (200 MHz, DMSO-d6)
d
¼7.26e7.35 (m, 6H), 7.50e7.58 (m, 2H),
7.78e7.75 (m, 2H), 7.96 (d, J¼5.9 Hz, 1H), 8.38 (s, 1H), 8.83 (d,
J¼5.9 Hz, 1H), 8.99 (s, 1H), 10.44 (s, 1H); 13C NMR (50 MHz, DMSO-
d6)
d 78.2 (CeOH), 110.5, 121.2, 126.9, 128.4, 128.5, 128.9, 129.0,
130.5, 132.9, 141.0, 142.6, 142.8, 145.3, 152.2, 153.3. Anal. Calcd for
C20H15N5O3S (405.43): C, 59.25; H, 3.73; N,17.27. Found: C, 59.20; H,
3.69; N, 17.20.
(200 MHz, DMSO-d6)
9.03 (s, 1H); 9.33 (br s, 2H). Anal. Calcd for C6H5N3O2S2 (215.25): C,
33.48; H, 2.34; N, 19.52. Found: C, 33.55; H, 2.30; N, 19.26.
d
¼7.79 (d, J¼5.3 Hz, 1H), 8.74 (d, J¼5.3 Hz, 1H),
4.6.2. 2,3-Di(4-bromophenyl)-9,9-dioxo-1H-9-thia-1,4,4a,7,10-
pentaazaphenanthrene-2-ol (7). Starting from 5, DMSO (3.5 mL),

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8679
4,40-dibromobenzil (0.736 g) for 49 h the title compound 7 was
obtained. The product was purified by extraction of contaminations
with boiling chloroform (25 mL) and dried. Yield (solid powder):
34% (0.378 g); mp¼178e180 ꢀC; IR (KBr) v¼3378 (wide) (OH, NH),
1617, 1589 (C]N, C]C), 1291, 1163 (SO2) cmꢁ1; 1H NMR (200 MHz,
contaminations with boiling chloroform (6 mL) and dried. Yield
(solid powder): 29% (0.240 g); mp¼190e193 ꢀC; IR (KBr) v¼3312
(wide) (OH, NH),1644,1592 (C]N, C]C),1289,1160 (SO2) cmꢁ1; 1H
NMR (200 MHz, DMSO-d6)
d
¼6.99e7.09 (m, 2H), 7.22e7.25 (m, 1H),
7.48e7.58 (m, 1H), 7.59e7.62 (m, 1H), 7.73e7.76 (m, 1H), 7.89 (d,
J¼5.9 Hz, 1H), 8.57 (s, 1H), 8.88 (d, J¼5.9 Hz, 1H), 8.99 (s, 1H), 10.73
DMSO-d6)
J¼5.9 Hz, 1H), 8.52 (s, 1H), 8.83 (d, J¼5.9 Hz, 1H), 9.00 (s, 1H), 10.46
(s, 1H); 13C NMR (50 MHz, DMSO-d6)
77.7 (CeOH), 110.4, 121.1,
d¼7.43e7.56 (m, 6H), 7.67 (d, J¼8.7 Hz, 2H), 7.95 (d,
(s,1H); 13C NMR (50 MHz, DMSO-d6)
d 77.2, 110.2,121.2, 127.7, 128.3,
d
131.1, 131.9, 135.3, 142.3, 142.4, 145.3, 148.1, 153.5. Anal. Calcd for
C16H11N5O3S3 (417.5): C, 46.03; H, 2.66; N, 16.78. Found C, 45.73; H,
2.46; N, 16.38.
122.4, 124.4, 129.3, 130.9, 131.4, 131.6, 132.0, 140.3, 142.5, 142.6,
145.4, 150.5, 153.3. Anal. Calcd for C20H13Br2N5O3S (563.22): C,
42.65; H, 2.33; N, 12.43. Found: C, 42.59; H, 2.23; N, 12.22.
Supplementary data
4.6.3. 2,3-Di(4-fluorophenyl)-9,9-dioxo-1H-9-thia-1,4,4a,7,10-
pentaazaphenanthrene-2-ol (8). Starting from 5, DMSO (6 mL), 4,40-
difluorobenzil (0.492 g) for 48 h the title compound 8 was obtained.
Yield (solid powder): 17% (0.150 g); mp¼291e293 ꢀC; IR (KBr)
v¼3302 (wide) (OH, NH), 1608, 1512 (C]N, C]C), 1287, 1161
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2013.08.006.
(SO2) cmꢁ1
;
1H NMR (200 MHz, DMSO-d6)
d¼7.12e7.21 (m, 4H),
References and notes
7.59e7.66 (m, 2H), 7.74e7.82 (m, 2H), 7.97 (d, J¼5.9 Hz, 1H), 8.48 (s,
1H), 8.83 (d, J¼5.9 Hz, 1H), 9.01 (s, 1H), 10.45 (s, 1H). Anal. Calcd for
C20H13F2N5O3S (441.41): C, 54.42; H, 2.97; N, 15.87. Found: C, 54.32;
H, 2.75; N, 15.48.
1. Negwer, M. Organic-chemical Drugs and Their Synonyms; Akademie: Berlin,
2004.
ꢀ
2. Brzozowski, Z.; S1awinski, J.; Ke˛dzia, A.; Kwapisz, E.; Gdaniec, M. J. Heterocycl.
Chem. 2009, 46, 1396e1403.
ꢀ
3. S1awinski, J.; Gdaniec, M. Eur. J. Med. Chem. 2005, 40, 377e389.
4.6.4. 2,3-Di(4-methylphenyl)-9,9-dioxo-1H-9-thia-1,4,4a,7,10-
pentaazaphenanthrene-2-ol (9). Starting from 5, DMSO (10 mL),
4,40-dimethylbenzil (0.477 g) for 58 h the title compound 9 was
obtained. The product was purified by crystallization from DMSO
(1 mL) at 88 ꢀC. Yield (solid powder): 39% (0.166 g);
mp¼201e204 ꢀC; IR (KBr) v¼3372 (wide) (OH, NH), 2922, 2852
4. Pirotte, B.; Podona, T.; Diouf, O.; de Tullio, P.; Lebrun, P.; Dupont, L.; Somers, F.;
Delarge, J.; Morain, P.; Lestage, P.; Lepagnol, J.; Spedding, M. J. Med. Chem. 1998,
41, 2946e2959.
5. Francotte, P.; de Tullio, P.; Podona, T.; Diouf, O.; Fraikin, P.; Lestage, P.; Danober,
L.; Thomas, J. V.; Caignard, D. H.; Pirotte, B. Bioorg. Med. Chem. 2008, 16,
9948e9956.
6. Khelili, S.; de Tullio, P.; Lebrun, P.; Fillet, M.; Antoine, M. H.; Ouedraogo, R.;
Dupont, L.; Fontaine, J.; Felekidis, A.; Leclerc, G.; Delarge, J.; Pirotte, B. Bioorg.
Med. Chem. 1999, 76, 1513e1520.
7. Lebrun, P.; Becker, B.; Morel, N.; Ghisdal, P.; Antoine, M. H.; de Tullio, P.; Pirotte,
B. Biochem. Pharmacol. 2008, 75, 468e475.
8. Pirotte, B.; de Tullio, P.; Podona, T.; Diouf, O.; Dewalque, D.; Neven, P.;
Masereel, B.; Caignard, P. ,G. H.; Renard, P.; Delarge, J.; Morain, P. Eur. J.
Pharm. Sci. 1998, 7, 29e40.
9. Graindorge, E.; Francotte, P.; Boverie, S.; de Tullio, P.; Pirotte, B. Curr. Med.
Chem.: Cent. Nerv. Syst. Agents 2004, 4, 95e103.
10. Lynch, G. Curr. Opin. Pharmacol. 2005, 179, 154e163.
11. Hashimoto, K.; Okamura, N.; Shimizu, E.; Iyo, M. Curr. Med. Chem.: Cent. Nerv.
Syst. Agents 2004, 4, 147e154.
(CH3), 1614, 1591 (C]N, C]C), 1288, 1161 (SO2) cmꢁ1 1H NMR
;
(200 MHz, DMSO-d6)
d
¼2.24 (s, 6H), 7.09e7.14 (m, 4H), 7.42 (d,
J¼7.4 Hz, 2H), 7.66 (d, J¼7.4 Hz, 2H), 7.96 (d, J¼5.8 Hz, 1H), 8.27 (s,
1H), 8.83 (d, J¼5.8 Hz, 1H), 8.98 (s, 1H), 10.34 (s, 1H); 13C NMR
(50 MHz, DMSO-d6) d 20.9, 21.1, 78.2,110.4,121.2,126.7,128.9,129.0,
130.2, 138.1, 138.4, 140.3, 142.6, 142.8, 145.3, 152.2, 153.3. Anal. Calcd
for C22H19N5O3S (433.48): C, 60.96; H, 4.42; N, 16.16. Found: C,
60.81; H, 4.22; N, 15.83.
12. Black, M. D. Psychopharmacology 2005, 179, 154e163.
13. Sztanke, K.; Pasternak, K.; Rzymowska, J.; Sztanke, M.; Kandefer-Szerszen, M.
4.6.5. 2,3-Di(4-methoxyphenyl)-9,9-dioxo-1H-9-thia-1,4,4a,7,10-
pentaazaphenanthrene-2-ol (10). Starting from 5, DMSO (3.5 mL),
4,40-dimethoxybenzil (0.540 g) for 48 h the title compound 10 was
obtained. The product was purified by extraction of contaminations
with boiling mixture of ethanol/DMF (v/v 4:1) (16 mL). Yield (yel-
low powder): 53% (0.493 g); mp¼208e210 ꢀC; IR (KBr) v¼3319
(wide) (OH, NH), 2931, 2838 (CH3), 1609, 1515 (C]N, C]C), 1304,
ꢀ
Eur. J. Med. Chem. 2008, 43, 1085e1094.
€
14. Krauth, F.; Dahse, H. M.; Ruttinger, H. H.; Frohberg, P. Bioorg. Med. Chem. 2010,
18, 1816e1821.
15. Walters, T. R.; Aur, R. J. A.; Hernandez, K.; Vietti, T.; Pinkel, D. Cancer 1972, 29,
1057e1060.
16. Sidwell, R. W.; Dixon, G. J.; Sellers, S. M.; Schabel, F. M. Appl. Microbiol. 1968, 16,
370e392.
17. Falke, D.; Rada, B. Acta Virol. 1970, 14, 115e123.
1169 (SO2) cmꢁ1; 1H NMR (200 MHz, DMSO-d6)
d¼3.71 (s, 3H), 3.73
18. Diana, P.; Barraja, P.; Lauria, A.; Montalbano, A.; Almerico, A. M.; Dattolo, G.;
Cirrincione, G. Eur. J. Med. Chem. 2002, 37, 267e272.
19. Patil, S. A.; Otter, R. S.; Klein, R. S. Tetrahedron Lett. 1994, 35, 5339e5342.
20. Kurasawa, Y.; Kanoh, M.; Kamigaki, J.; Okiyama, M.; Takada, A.; Okamoto, Y. J.
Heterocycl. Chem. 1988, 25, 1015e1018.
(s, 3H), 6.84 (d, J¼3.3 Hz, 2H), 6.89 (d, J¼3.3 Hz, 2H), 7.45 (d,
J¼8.8 Hz, 2H), 7.73 (d, J¼8.8 Hz, 2H), 7.96 (d, J¼5.9 Hz, 1H), 8.24 (s,
1H), 8.82 (d, J¼5.9 Hz, 1H), 8.98 (s, 1H), 10.31 (s, 1H); NH and OH
protons
d 8.24 (s, 1H, NH), 10.31 (s, 1H, OH) ppm were exchanged
21. de Clercq, E. J. Med. Chem. 1986, 29, 1561e1569.
22. de Clercq, E. Anticancer Res. 1986, 6, 549e556.
with D2O; 13C NMR (50 MHz, DMSO-d6)
d 55.4 (OCH3), 55.5 (OCH3),
23. Heidelberg, C.; Arafield, F. G. Cancer Res. 1963, 23, 1226e1243.
24. Baba, M.; Pauwels, R.; Herwig, P.; de Clercq, E.; Desmyster, J.; Vandepulfe, M.
Biochem. Biophys. Commun. 1987, 142, 128e134.
25. Nishimura, T.; Kitajima, K. J. Org. Chem. 1979, 44, 818e824.
26. Dalkafouki, A.; Ardisson, J.; Kunesch, N.; Lacombe, L.; Poisson, J. E. Tetrahedron
Lett. 1991, 32, 5325e5328.
78.1 (CeOH), 110.4, 113.77, 113.82, 121.2, 125.2, 128.1, 130.7, 133.5,
142.7, 142.9, 145.2, 152.0, 153.3, 159.4, 160.9; MS ESI Q-TOF: m/
z¼466 (Mþþ1). Anal. Calcd for C22H19N5O5S (465.48): C, 56.77; H,
4.11; N, 15.05. Found: C, 56.57; H, 4.05; N, 14.72.
27. Erickson, J. G. J. Am. Chem. Soc. 1952, 74, 4706e4707.
28. Saikawa, I.; Maeda, T. Yakugaku Zasshi 1967, 87, 1501e1508.
29. Kurzer, F.; Godfrey, L. E. A. Angew. Chem. 1963, 75, 1157e1175.
4.6.6. 9,9-Dioxo-2,3-di(thien-2-yl)-1H-9-thia-1,4,4a,7,10-
pentaazaphenanthrene-2-ol (11). Starting from 5, DMSO (6 mL), 1,2-
di(thien-2-yl)ethane-1,2-dione (0.495 g) for 50 h the title com-
pound 11 was obtained. The product was purified by extraction of
ꢀ
30. Brzozowski, Z.; Sa˛czewski, F.; S1awinski, J. J. Heterocycl. Chem. 2008, 45,
1407e1413.
ꢀ
31. S1awinski, J. Pol. J. Chem. 2001, 75, 1309e1316.