Synthesis, structure, and antimicrobial activity of heterocyclic phenylsulfonyl- and 4-aminophenylsulfonyl-carboximidamides

Article abstract of DOI:10.1007/s00706-012-0769-6

A series of novel phenylsulfonyl- and 4-amino-phenylsulfonyl- carboximidamides were synthesized by condensation of sulfonamides with heterocyclic methyl carbimi-dates obtained from heterocyclic carbonitriles and used 'at its inception.' The molecular structure of the obtained compounds is discussed. Compounds possessing heterocyclic systems with a nitrogen atom in the α position to the functional group showed a different single-crystal structure than expected. The synthesized derivatives were evaluated for antimicrobial activities: tuberculostatic, antibacterial, and antifungal.

Full text of DOI:10.1007/s00706-012-0769-6

Monatsh Chem (2012) 143:1161–1169
DOI 10.1007/s00706-012-0769-6
ORIGINAL PAPER
Synthesis, structure, and antimicrobial activity of heterocyclic
phenylsulfonyl- and 4-aminophenylsulfonyl-carboximidamides
•
Katarzyna Gobis Henryk Foks Katarzyna Wisniewska
•
•
´
Maria Da˛browska-Szponar Ewa Augustynowicz-Kopec
•
•
´
•
Agnieszka Napiorkowska Artur Sikorski
´
Received: 21 January 2012 / Accepted: 11 April 2012 / Published online: 15 May 2012
Ó The Author(s) 2012. This article is published with open access at Springerlink.com
Abstract A series of novel phenylsulfonyl- and 4-amino-
phenylsulfonyl-carboximidamides were synthesized by con-
densation of sulfonamides with heterocyclic methyl carbimi-
dates obtained from heterocyclic carbonitriles and used ‘at its
inception.’ The molecular structure of the obtained compounds
is discussed. Compounds possessing heterocyclic systems with
a nitrogen atom in the aposition to the functional group showed
a different single-crystal structure than expected. The synthe-
sized derivatives were evaluated for antimicrobial activities:
tuberculostatic, antibacterial, and antifungal.
included S. pneumonia, L. pneumophila, M. avium, E. coli,
H. pylori, S. aureus, C. albicans, and M. tuberculosis [2–4].
These microorganisms quickly develop a multidrug resis-
tance (MDR) to used chemotherapeutics and antibiotics. A
special case is M. tuberculosis, whose strains also develop
extensive drug-resistance (XDR). Resistant strains of
microorganisms are a major threat to immunocompromised
individuals, and infections caused by them are the most
common complication in HIV-positive patients [5]. At the
same time, a lack of development of new antimicrobial
drugs is observed, which can pose a serious threat to public
health [6]. Thus, the interest of many research groups is
focused on the search for new drugs active against resistant
strains.
Keywords Sulfonamidine ꢀ Heterocycles ꢀ Synthesis ꢀ
Crystal structure ꢀ Antimicrobial activity ꢀ
Structure–activity relationship
One of the research directions is to modify the structure
of already used drugs. So the interest in chemical groups
such as, for example, sulfonamides has not diminished.
This group is characterized by multidirectional pharma-
cological activity. Sulfonamides act as anhydrase inhibitors
[7], antifungal [8], antiviral [9], anticancer [10], anti-
inflammatory [11], and of course antibacterial agents.
Multidirectional biological activity also characterizes
compounds possessing an amidine functional group. Ami-
dine derivatives have anti-degenerative [12], antitumor
[13], and anti-platelet effects [14]. Compounds with anti-
HIV, antibacterial, and antifungal activities have also been
found among them [15, 16].
Introduction
At the end of the twentieth century, a number of new and
‘‘reemerging’’ pathogens were recognized [1]. These
K. Gobis (&) ꢀ H. Foks
Department of Organic Chemistry, Medical University
´
of Gdansk, Gdansk, Poland
e-mail: kgobis@gumed.edu.pl
´
´
K. Wisniewska ꢀ M. Da˛browska-Szponar
Department of Medicinal Microbiology, Chair of Microbiology,
´ ´
Medical University of Gdansk, Gdansk, Poland
There are few reports on the pharmacological activity of
sulfonamidines. So far, only their in vitro ability to com-
pete with triiodothyronine for binding to the thyroid
hormone-a1 receptor (hTHR-a1) has been described [17].
These compounds can be obtained in several ways. They
are formed as a result of the reaction of carbonitriles with
primary sulfonamides [18] or in a reaction of amidines
with sulfonyl chlorides [19]. The reports of reactions of
´
´
E. Augustynowicz-Kopec ꢀ A. Napiorkowska
Department of Microbiology, Institute of Tuberculosis
and Pulmonary Diseases, Warsaw, Poland
A. Sikorski
Department of Physical Chemistry, University of Gdansk,
´
Gdansk, Poland
´
123

1162
K. Gobis et al.
sulfonamides with alkyl- or phenylcarbimidates could also
be found in the chemical literature [20]. In the structure
assigned to the products, two protons are connected to
different nitrogen atoms of the amidine moiety [21]. That
The presented method of synthesis uses an intermediate
such as carbimidate ‘‘at its inception,’’ and this is its main
advantage. Carbimidates were obtained from the corre-
sponding carbonitriles in methanol in the presence of 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU) and without isola-
tion underwent further reaction with benzene sulfonamide
or 4-aminobenzenesulfonamide. The isolated carbimidates
were used for the synthesis of pyrazine (10, 11) and
6-methoxypyrazine (12, 13) derivatives. They were
obtained easily from 2-cyanopyrazine and 6-chloro-2-cy-
anopyrazine, respectively [22, 23]. Carbimidates were
refluxed with benzene sulfonamide or 4-aminobenzene-
sulfonamide in diglyme (2-methoxyethyl ether) solution.
All reactions proceeded with yields from moderate (38 %)
to very good (83 %).
1
structure was adopted on the basis of H NMR spectra in
which two different signals for those protons were
observed. The reaction of sulfonamides with heterocyclic
carbimidates has not been described so far.
The above facts prompt us to synthesize sulfonyl-car-
boximidamides possessing in their structure phenylsulfonyl
or 4-aminophenylsulfonyl moieties linked to heterocyclic
rings of pyridine, pyrimidine, or pyrazine by the sulfo-
namidine group. Synthesized compounds have been
evaluated for their antimicrobial activity in vitro: tuber-
culostatic, antibacterial, and antifungal.
The structures of all these new compounds were con-
firmed by IR and NMR spectra as well as elemental
analyses. Two signals for the NH groups shifted from each
Results and discussion
1
other have been observed in the H NMR spectra. These
The subject of this work was the synthesis of heterocyclic
phenylsulfonyl- and 4-aminophenylsulfonyl-carboximidamides
1–13. The performed reactions are shown in Scheme 1.
separated signals can be due to the taken amino-imine
structure of compounds obtained (Fig. 1, structure a) as we
suggest for 3- and 4-pyridine derivatives 3–6. They can
N
SO2
Ph
HAr
C
NH2
1, 7, 10, 12
H
HAr CN
N
SO2 Ph
3 5
H
C
H2NSO2Ph
N
SO2
SO2
NH2
HAr
NH2
C
MeOH/ orMeOH/
MeONa DBU
,
HAr
NH
NH
H
H2N
SO2
OMe
N
NH2
4, 6
HAr
C
HAr
N
C
NH
NH
SO2
NH2
H2N SO2
NH Ac
HAr
C
NH2
2, 8, 11, 13
for 8
Ac2O
N
SO2
NH Ac
HAr
C
NH2
9
7
12
13
8
9
10
11
4
5
6
No
3
1
2
N
N
N
N
MeO
N
N
MeO
N
N
N
N
N
N
HAr
N
N
N
N
N
N
N
N
Scheme 1
123

Phenylsulfonyl- and 4-aminophenylsulfonyl-carboximidamides
1163
H
O
O
N
N
H
N
S
N
S
Ph
Ph
N
O
N
O
H
H
A
B
Fig. 1 Possible systems of intramolecular hydrogen bonds in target
molecules
also be a result of the magnetic inequivalence of NH pro-
tons in the amine moiety upon formation of a hydrogen
bond in the case of the heterocyclic compounds in which
the amidine group is in the a position to the nitrogen atom
of heterocyclic ring (structure b). X-ray diffraction analysis
was performed for N0-(4-aminophenylsulfonyl)-4-chloro-
picolinimidamide to address that question. We have
described the synthesis of this compound previously [24].
It was chosen because we were able to obtain its crystals of
sufficient size. The results of the single-crystal diffraction
study confirmed a tautomeric structure b (Fig. 1). If both
hydrogen atoms are bonded to the same nitrogen atom in
the solid state, their magnetic inequivalence in the solution
is probably caused by formation of hydrogen bonds and
reduction of symmetry.
Fig. 2 Structure of N0-(4-aminophenylsulfonyl)-4-chloropicolinimid-
amide showing 25 % probability displacements for ellipsoids. H atoms
are shown as small spheres of arbitrary radius (intramolecular N–HꢀꢀꢀO
and N–HꢀꢀꢀN interactions are represented by dashed lines)
The study also resolved the molecular structure of the
products of the reaction between carbimidates and 4-amino-
benzenesulfonamide, as the active group in that reaction
couldbeboththeaminegroupofthe sulfonamidemoiety, asit
was in the case of the reaction of benzene sulfonamide, or the
aromatic amine group in the para position to the sulfonamide
moiety, since the reactions of aromatic and aliphatic amines
with carbimidates have been described [25, 26]. For that
purpose, the reaction of methyl pyrazine-2-carbimidate with
N-(4-sulfamoylphenyl)acetamide was carried out. The
resulting product 9 was identical with the compound that was
obtained by the acetic anhydride acylation of derivative
8, which was formed in the reaction of methyl pyrazine-2-
carbimidate with 4-aminobenzenesulfonamide. This
showed that the sulfonamide group was the active group in
the reactions carried out, and the resulting compounds had
structure c (Fig. 2).
˚
a = 14.6885(7) A, b = 5.7930(3) A, c = 16.0421(9) A,
˚
˚
3
˚
and b = 97.530(5)°, Z = 4, and V = 1353.25(12) A .
In the molecule of the title compound (Fig. 2), the bond
lengths and angles characterizing the geometry of the
4-aminophenylsulfonyl and pyridine fragments are typical
for compounds containing them (Table 2).
In the crystal structure of N0-(4-aminophenylsulfonyl)-4-
chloropicolinimidamide, the H atoms from the amino
group bonded with the C7 atom participate in the intra-
molecular
N16–H16AꢀꢀꢀO18
and
N16–H16BꢀꢀꢀN1
hydrogen bond (Table 3; Fig. 2). In the packing, the mol-
ecules are linked into chains of rings along the c axis
(Fig. 3b). In these rings, four molecules of N0-(4-amino-
phenylsulfonyl)-4-chloropicolinimidamide are linked via
N19–H19AꢀꢀꢀO17 and N19–H19BꢀꢀꢀN19 and form the R44
(20) hydrogen bond ring motif (Fig. 3a). The parallel lying
chains of rings are connected through the N16–
H16AꢀꢀꢀO17 hydrogen bond and form columns along the b
axis (Table 3; Fig. 3a). In the crystal lattice, these columns
form a zipper-type supramolecular motif.
Crystal structure of N0-(4-aminophenylsulfonyl)-4-
chloropicolinimidamide
The crystallographic data, data collection, and structure
refinement of N0-(4-aminophenylsulfonyl)-4-chloropicolin-
imidamide are summarized in Table 1. The bond lengths
and angles characterizing the geometry of the molecules
are presented in Table 2.
Tuberculostatic activity
The synthesized phenylsulfonyl- and 4-aminophenylsulfo-
nyl-carboximidamides 1–13 were examined in vitro for
their tuberculostatic activity against M. tuberculosis H37Rv
N0-(4-Aminophenylsulfonyl)-4-chloropicolinimidamide
crystallized in the P21/c monoclinic space group, with
123

1164
K. Gobis et al.
Table 1 Crystal data and structure refinement for N0-(4-amino-
phenylsulfonyl)-4-chloropicolinimidamide
Table 2 Selected bond
lengths, valence angles, and
torsion angles for N0-(4-amino-
phenylsulfonyl)-4-
˚
Bond lengths/A
N1–C2
1.331(3)
1.338(5)
1.496(3)
1.724(4)
1.355(5)
1.308(3)
1.311(3)
1.626(2)
1.742(2)
1.369(3)
Empirical formula
Formula weight
Temperature/K
C12H11ClN4O2S
310.76
N1–C6
chloropicolinimidamide
C2–C7
295 (2)
C4–Cl20
˚
Wavelength/A
Crystal system
0.71073
C5–C6
Space group
C7–N16
Monoclinic
P21/c
C7–N8
N8–S9
Unit cell dimensions
S9–C10
˚
a/A
14.6885 (7)
5.7930 (3)
16.0421 (9)
97.530 (5)
1353.25 (12)
4
C13–N19
˚
b/A
Valence angles/°
C2–N1–C6
N8–C7–C2
C7–N8–S9
N8–S9–C10
Torsion angles/°
N1–C2–C7–N8
C3–C2–C7–N8
C2–C7–N8–S9
C7–N8–S9–C10
˚
c/A
116.1(3)
115.9(2)
120.8(2)
104.6(1)
b/°
3
˚
V/A
Z
D
calc/Mg m-3
1.525
Absorption coefficient/mm-1
0.443
164.6(2)
-16.0(4)
178.1(2)
-87.8(2)
F(000)
640
Crystal size/mm
0.35 9 0.15 9 0.10
3.08–25.00
H Range for data collection/°
Limiting indices
-14 B h B 17, -6 B k B 6,
-19 B l B 13
N8–S9–C10–C11
108.4(2)
Reflections collected/unique
Completeness 2H = 50.0/%
Refinement method
8,544/2,373 (Rint = 0.0375)
Table 3 Hydrogen bonds for N0-(4-aminophenylsulfonyl)-4-chloro-
99.8
Full-matrix least-squares on F2
2,373/0/181
˚
picolinimidamide with distances (d/A): d(DꢀꢀꢀA) \ R(D) ?
˚
˚
R(A) ? 0.50 A; d(HꢀꢀꢀA) \ R(H) ? R(A) - 0.12 A and angle/°
Data/restraints/parameters
Goodness-of-fit on F2
(\) \ D–HꢀꢀꢀA [ 100.0°
1.006
D–H
A
d(D–H)
d(HꢀꢀA) \D–HꢀꢀꢀA
d(DꢀꢀA)
Final R indices [I [ 2r(I)]
R1 = 0.0406
wR2 = 0.1013
R1 = 0.0626
N16–H16A
N16–H16B
N16–H16A
N19–H19A
N19–H19B
a
O18a
N1a
O17b
O17c
N19d
0.86
0.86
0.86
0.86
0.86
2.15
2.26
2.37
2.31
2.58
2.758(3)
2.630(3)
2.988(3)
3.035(3)
3.424(3)
128
105
129
142
167
R indices (all data)
wR2 = 0.1060
0.369 and -0.345
-3
˚
Largest diff. peak and hole/e A
strain and two ‘‘wild’’ strains isolated from tuberculosis
patients: one (Spec. 210) resistant to p-aminosalicylic acid
(PAS), isonicotinic acid hydrazide (INH), etambutol
(ETB), and rifampicine (RFP), and the other (Spec. 192)
fully sensitive to the administered tuberculostatics
(Table 4).
Intramolecular H bond
b
c
d
Symmetry codes: x, y - 1, z; x, ‘ -y, z- ‘; -x, y-‘, ‘ -z
reference drug were used for comparison. Incubation was
performed at a temperature of 37 °C. The MIC values were
determined as minimum concentration inhibiting the
growth of tested tuberculous strains in relation to the probe
with no tested compound. The influence of the compound
on the growth of bacteria at a certain concentration, 3.1,
6.2, 12.5, 25, 50, and 100 lg/cm3, was evaluated.
The study showed that the newly synthesized sulfonyl-
carboximidamides 1–13 exhibited very low tuberculostatic
activity. Minimumal inhibitory concentration (MIC) values
for all the tested compounds ranged from 25 to 100 lg/
cm3. No significant differences in compounds’ activity
against the sensitive strain 192 and the resistant strain 210
Investigations were performed by a classical test-tube
method of successive dilution in Youmans’ modification of
Proskauer and Beck’s liquid medium containing 10 % of
bovine serum [33, 34]. Bacterial suspensions were prepared
from 14-day-old cultures of slowly growing strains and
from 48-h-old cultures of saprophytic strains [35, 36].
Solutions of the compounds in ethylene glycol were tested.
Stock solutions contained 10 mg of compounds in 1 cm3.
Dilutions (in geometric progression) were prepared in
Youmans’ medium. The medium containing no investi-
gated substances and containing isoniazid (INH) as a
123

Phenylsulfonyl- and 4-aminophenylsulfonyl-carboximidamides
1165
C. parapsilosis ATCC 22019 [38]. The susceptibility of the
microorganisms to the agents was determined by the broth
microdilution assay according to the procedures outlined by
the National Committee for Clinical Laboratory Standards
[37, 38]. The stock solutions of the agents were prepared by
dissolving the chemicals in DMSO. The final concentration of
the agents in 200 mm3 of Mueller-Hinton broth (for bacterial
strains) or in RPMI 1,640 (for fungi) ranged over 0.125–
256 lg/cm3.
In order to prepare the bacterial suspension, overnight
culture of bacteria in 3 % Triptic soy broth was diluted in
sterile saline to the final concentration of approximately
107 CFU/cm3. Aliquots (10 mm3) of bacterial suspension
were added to each agent solution. The MIC was defined as
the lowest concentration of the agent that completely
inhibited growth of the bacteria after 18 h incubation at
35 °C.
Inocula of candida strains were prepared by suspension
of five colonies picked from 24 h old cultures on Saburaud
agar in sterile saline to the concentration of 106 cells per
cm3. The final concentration of the working suspension
was approximately 104 cells per cm3. Aliquots (10 mm3)
of the suspension were added to each agar solution. The
MIC was defined as the lowest concentration of the agent
that completely inhibited growth of the fungi after 48 h
incubation at 35 °C. The final results were average values
from two independent experiments.
The study showed no antibacterial and antifungal
activity of the tested compounds. All of the synthesized
sulfonylcarboximidamides 1–13 exhibited activity with
MIC [ 256 lg/cm3, which meant that those values did not
fit standard test concentrations.
Conclusion
Fig. 3 The R44 (20) hydrogen bond motif (a) and the arrangement of
the molecules in the crystal structure of N0-(4-aminophenylsulfonyl)-
4-chloropicolinimidamide viewed along b axis (b). Dashed lines:
In conclusion, a series of novel sulfonyl-carboximidamides
with different six-membered nitrogen heterocyclic systems
were synthesized successfully in a reaction of heterocy-
clic methyl carbimidates with benzene sulfonamide and
4-aminobenzenesulfonamide. All these new compounds were
confirmed by IR and NMR spectra as well as elemental
analysis. The molecular structure of the obtained com-
pounds was discussed. Compounds possessing heterocyclic
systems with a nitrogen atom in the a position to the
N–HꢀꢀꢀO and N–HꢀꢀꢀN interactions.
H atoms not involved in
interactions omitted
have been observed. Isoniazid, the reference tuberculo-
static, exhibited much higher activity with the MIC value
0.5–1.1 lg/cm3. These results classify the compounds
tested as practically inactive against M. tuberculosis.
Antibacterial and antifungal activities
functional group showed
a
single-crystal structure
different from expected and described for that chemical
group in the literature. Antimicrobial activity of the
synthesized compounds was evaluated against M. tuber-
culosis, S. aureus, E. coli, P. aeruginosae, C. albicans, and
C. parapsilosis. Unfortunately, all of the studied com-
pounds were practically inactive towards microbial strains
tested.
Antibacterial and antifungal activities of newly synthesized
compounds were also examined. In the study of antibacterial
activitythree recommendedreference strainsS. aureus ATCC
25923, E. coli ATCC 25922, and P. aeruginosae ATCC
27853 were used [37]. Antifungal activity was determined
with use of two strains: C. albicans ATCC 90028 and
123

1166
K. Gobis et al.
Table 4 Antimicrobial activity
of newly synthesized sulfonyl-
carboximidamides 1–13
No.
MIC/lg/cm3
M. tuberculosis
Bacterial strains
Fungal strains
H37Rv
192
210
S. aureus
E. coli
P. aeruginosae
C. albicans
C. parapsilosis
1
100
100
50
50
50
50
50
50
50
100
100
50
50
50
50
50
0.5
50
50
50
50
50
50
50
50
50
50
50
50
25
1.1
[256
[256
[256
[256
[256
[256
[256
[256
[256
[256
[256
[256
[256
–
[256
[256
[256
[256
[256
[256
[256
[256
[256
[256
[256
[256
[256
–
[256
[256
[256
[256
[256
[256
[256
[256
[256
[256
[256
[256
[256
–
[256
[256
[256
[256
[256
[256
[256
[256
[256
[256
[256
[256
[256
–
[256
[256
[256
[256
[256
[256
[256
[256
[256
[256
[256
[256
[256
–
2
3
4
50
5
50
6
50
7
50
8
100
50
Minimum inhibitory
concentrations for bacterial
strains were determined by the
two-fold serial dilution method
for microdilution plates and for
mycobacterial strains by two-
fold classical test-tube method
of successive dilution
9
10
11
12
13
INH
100
50
50
50
0.5
INH isoniazid
N0-(Phenylsulfonyl)picolinimidamide (1, C12H11N3O2S)
Recrystallization from ethanol afforded 138 mg (66 %) 1.
Experimental
ꢀ
M.p.: 165–166 °C; IR (KBr): m = 3,432, 3,320 (m N–H),
All materials and solvents were of analytical reagent grade.
Thin-layer chromatography was performed on Merck silica
gel 60F254 plates and visualized with UV. The results of
elemental analyses (C, H, N) for all obtained compounds
were in agreement with calculated values within the range
1,613, 1,538 (m C = C), 1,280, 1,147 (m SO2), 757 (c C–H),
688 (c N–H), 589, 557 cm-1
;
1H NMR (200 MHz,
CDCl3): d = 7.43–7.59 (m, 4H, 3H Ph and 1H NH ? D2O
exchangeable), 7.82 (m, 1H, pyridine), 8.02 (m, 2H, Ph),
8.28 (m, 2H, pyridine), 8.33 (brs, 1H, NH ? D2O
exchangeable), 8.58 (m, 1H, pyridine) ppm; 13C NMR
(50 MHz, CDCl3): d = 123.10 (C-3), 126.38 (C-20, C-60),
127.82 (C-5), 129.32 (C-30, C-50), 132.71 (C-40), 138.40
(C-4), 142.39 (C-10), 148.71 (C-6), 149.20 (C-2), 159.20
(C = N) ppm.
1
of 0.3 %. H NMR spectra in CDCl3 or DMSO-d6 were
recorded on Varian Unity Plus (500 MHz) and Varian
Gemini (200 MHz) instruments (Varian, Palo Alto, CA).
Infrared spectra were determined as KBr pellets of the
solids on a Satellite FT-IR spectrophotometer (Mattson
Instruments, Madison, WI). Melting points were deter-
mined with a Boethius apparatus (Franz Ku¨stner Nachf.
KG, Dresden, Germany). Methyl pyrazine-2-carbimidate
and methyl 6-methoxypyrazine-2-carbimidate required for
further syntheses were obtained according to the method
described earlier by Foks and co-workers [22, 23].
N0-(4-Aminophenylsulfonyl)picolinimidamide
(2, C12H12N4O2S)
Recrystallization from dioxane afforded 124 mg (56 %)
ꢀ
2. M.p.: 202–205 °C; IR (KBr): m = 3,435, 3,400, 3,323,
3,253 (m N–H), 1,610, 1,588 (m C = C), 1,271, 1,144 (m
SO2), 1,091 (d C–H), 821 (c C–H), 566 (c N–H) cm-1
;
General method for the synthesis of sulfonyl-
carboximidamides 1–8
1H NMR (200 MHz, CDCl3): d = 5.94 (s, 2H,
NH2 ? D2O exchangeable), 6.52 (d, 2H, Ph,
J = 8.6 Hz), 7.57 (d, 2H, Ph, J = 8.8 Hz), 7.63–7.67
(m, 1H, pyridine), 7.93–8.11 (m, 3H, 2H pyridine and 1H
NH ? D2O exchangeable), 8.67 (d, 1H, pyridine,
J = 4.8 Hz), 8.84 (brs, 1H, NH ? D2O exchange-
able) ppm; 13C NMR (50 MHz, DMSO-d6): d = 112.79
(C-30, C-50), 122.83 (C-3), 127.57 (C-5), 128.38 (C-20, C-
60), 138.26 (C-4, C-10), 149.08 (C-6, C-40), 152.93 (C-2),
158.04 (C = N) ppm.
The respective carbonitrile (1 mmol) and 0.4 cm3
(2 mmol) of DBU were refluxed in 10 cm3 of methanol for
0.5 h. Then 0.8 mmol of benzene sulfonamide or 4-ami-
nobenzenesulfonamide was added. The mixture was
refluxed for another 3 h. Then methanol was evaporated in
vacuo, and 30 cm3 of water was added to the residue. The
precipitate of the product was filtered off, dried, and
purified by recrystallization from a suitable solvent.
123

Phenylsulfonyl- and 4-aminophenylsulfonyl-carboximidamides
1167
N0-(Phenylsulfonyl)nicotinimidamide (3, C12H11N3O2S)
Recrystallization from dioxane–methanol mixture (1:1)
afforded 98 mg (47 %) 3. M.p.: 176–178 °C; IR (KBr):
ꢀm = 3,439, 3,322 (m N–H), 3,054 (m C–H), 1,618, 1,518 (m
C = C), 1,274, 1,164, 1,149 (m SO2), 825, 789 (c C–H),
(d C–H), 828 (c C–H), 556 (c N–H) cm-1
;
1H NMR
(500 MHz, DMSO-d6): d = 5.96 (s, 2H, NH2 ? D2O
exchangeable), 6.59 (d, 2H, J = 8.8 Hz), 7.74 (d, 2H,
pyridine, J = 5.9 Hz), 8.25 (brs, 1H, NH ? D2O
exchangeable), 8.71 (d, 2H, pyridine, J = 5.9 Hz), 9.10
(brs, 1H, NH ? D2O exchangeable) ppm; 13C NMR
(50 MHz, DMSO-d6): d = 112.78 (C-30, C-50), 121.95
(C-3, C-5), 126.43 (C-20, C-60), 129.87 (C-10), 141.36
(C-4), 150.48 (C-2, C-6), 152.85 (C-40), 161.28
(C = N) ppm.
1
583 (c N–H), 561 cm-1; H NMR (200 MHz, DMSO-d6):
d = 7.47–7.66 (m, 4H, Ph), 7.94–7.98 (m, 2H, Ph), 8.16–
8.20 (m, 1H, pyridine), 8.30–8.60 (brs, 1H, NH ? D2O
exchangeable), 8.73–8.75 (m, 1H, pyridine), 8.98 (d, 1H,
pyridine, J = 1.47 Hz), 9.10–9.40 (brs, 1H, NH ? D2O
exchangeable) ppm; 13C NMR (50 MHz, DMSO-d6):
d = 123.71 (C-4), 125.83 (C-20, C-60), 126.40 (C-30,
C-50), 129.67 (C-3), 132.06 (C-40), 132.56 (C-4), 135.99
(C-10), 148.96 (C-2), 153.05 (C-6), 161.39 (C = N) ppm.
N0-(Phenylsulfonyl)pyrimidine-2-carboximidamide
(7, C11H10N4O2S)
Recrystallization from dioxane afforded 107 mg (51 %) 7.
ꢀ
M.p.: 206–208 °C; IR (KBr): m = 3,396, 3,330 (m N–H),
N0-(4-Aminophenylsulfonyl)nicotinimidamide
(4, C12H12N4O2S)
Recrystallization from dioxane–ethanol mixture (1:1)
1,621,1,554 (m C = C), 1,280, 1,151 (m SO2), 833, 790, 689
1
(c C–H), 590 (c N–H), 501 cm-1; H NMR (200 MHz,
DMSO-d6): d = 7.54–7.73 (4H, 3H Ph and 1H pyrimi-
dine), 7.91 (d, 2H, Ph, J = 8.2 Hz), 8.21 (brs, 1H,
NH ? D2O exchangeable), 8.53 (brs, 1H, NH ? D2O
exchangeable), 8.96 (d, 2H, pyrimidine, J = 4.6 Hz) ppm;
13C NMR (50 MHz, DMSO-d6): d = 123.58 (C-5), 126.50
(C-20, C-60), 129.27 (C-30, C-50), 132.68 (C-40), 142.39 (C-
10), 158.11 (C-4, C-6), 158.53 (C-2), 159.24 (C = N) ppm.
afforded 132 mg (60 %) 4. M.p.: 215–217 °C; IR (KBr):
ꢀ
m = 3,448, 3,394, 3,337, 3,313, 3,248 (m N–H), 2,923,
2,851 (m C–H), 1,643, 1,612, 1,591, 1,528 (m C = C),
1,269, 1,141 (m SO2), 1,089 (d C–H), 786, 698 (c C–H), 562
(c N–H) cm-1; 1H NMR (200 MHz, DMSO-d6): d = 5.92
(s, 2H, NH2 ? D2O exchangeable), 6.58 (d, 2H, Ph,
J = 8.7 Hz), 7.46–7.52 (m, 1H, pyridine), 7.58 (d, 2H,
Ph, J = 8.7 Hz), 8.12–8.18 (m, 2H, 1H pyridine and 1H
NH ? D2O exchangeable), 8.70–8.73 (m, 1H, pyridine),
8.95 (d, 1H, pyridine, J = 1.9 Hz), 9.02 (s, 1H, NH ? D2O
exchangeable) ppm; 13C NMR (50 MHz, DMSO-d6):
d = 112.76 (C-30, C-50), 123.68 (C-5), 127.81 (C-3),
128.39 (C-20, C-60), 129.86 (C-10), 135.84 (C-2, C-4),
148.85 (C-6), 152.82 (C-40), 160.13 (C = N) ppm.
N0-(4-Aminophenylsulfonyl)pyrimidine-2-carboximidamide
(8, C11H11N5O2S)
Recrystallization from ethylene glycol–methanol mixture
(1:1) afforded 175 mg (79 %) 8. M.p.: 259–261 °C; IR
ꢀ
(KBr): m = 3,380, 3,330, 3,237 (m N–H), 1,621, 1,592,
1,562, 1,503, 1,391 (m C = C), 1,268, 1,142 (m SO2), 830,
787 (c C–H), 678, 578 (c N–H), 546 cm-1 1H NMR
;
(500 MHz, DMSO-d6): d = 5.95 (s, 2H, NH2 ? D2O
exchangeable), 6.52 (d, 2H, Ph, J = 8.8 Hz), 7.54 (d, 2H,
Ph, J = 8.8 Hz), 7.57 (t, 1H, pyrimidine, J = 4.8 Hz),
8.20 (brs, 1H, NH ? D2O exchangeable), 8.87 (brs, 1H,
NH ? D2O exchangeable), 8.94 (d, 2H, pyrimidine,
J = 4.8 Hz) ppm; 13C NMR (50 MHz, DMSO-d6):
d = 112.76 (C-30, C-50), 123.50 (C-5), 127.51 (C-10),
128.54 (C-20, C-60), 152.96 (C-40), 157.71 (C-2), 158.09
(C-4, C-6), 158.50 (C = N) ppm.
N0-(Phenylsulfonyl)isonicotinimidamide
(5, C12H11N3O2S)
Recrystallization from methanol–water mixture (1:1) affor-
ded 111 mg (53%) 5. M.p.: 155–156 °C; IR (KBr):
ꢀ
m = 3,379 (m N–H), 3,058, 2,925 (m C–H), 1,644, 1,530
(m C = C), 1,281, 1,142 (m SO2), 1,086 (d C–H), 843 (c C–
1
H), 589 (c N–H), 556 cm-1; H NMR (200 MHz, DMSO-
d6): d = 7.54–7.76 (m, 5H, Ph), 7.96 (d, 2H, pyridine,
J = 6.6 Hz), 8.49 (s, 1H, NH ? D2O exchangeable), 8.71
(d, 2H, pyridine, J = 5 Hz), 9.30 (brs, 1H, NH ? D2O
exchangeable) ppm; 13C NMR (50 MHz, DMSO-d6):
d = 121.90 (C-3, C-5), 126.42 (C-20, C-60), 129.27 (C-30,
C-50), 132.65 (C-40), 141.26 (C-4), 142.41 (C-10), 150.52
(C-2, C-6), 161.23 (C = N) ppm.
N0-[4-[N-[Amino(pyrimidin-2-yl)methylene]sulfamoyl]-
phenyl]acetamide (9, C13H13N5O3S)
Method A: the title compound was obtained according to
the method described above for compounds 1–8 from
0.11 cm3 (1 mmol) of 2-cyanopyrimidine and 0.43 g
(2 mmol) of N-(4-sulfamoylphenyl)acetamide affording
112 mg (35 %) 9.
N0-(4-Aminophenylsulfonyl)isonicotinimidamide
(6, C12H12N4O2S)
Recrystallization from dioxane–ethanol mixture (1:1)
Method B: sulfonylcarboximidamide 8 (0.28 g, 1 mmol)
was refluxed for 0.5 h in a solution of 0.5 cm3 (5 mmol) of
acetic anhydride in 5 cm3 of pyridine. Then pyridine
was evaporated in vacuo, and 20 g of ice was added to
the residue. The precipitate was filtered off, dried, and
afforded 152 mg (69 %) 6. M.p.: 226–229 °C; IR (KBr):
ꢀ
m = 3,441, 3,357, 3,242 (m N–H), 2,957, 2,849 (m C–H),
1,644, 1,596, 1,527 (m C = C), 1,276, 1,136 (m SO2), 1,084
123

1168
K. Gobis et al.
recrystallized from ethylene glycol to afford 268 mg
d6): d = 112.82 (C-30, C-50), 128.53 (C-20, C-60), 143.83
(C-2), 144.02 (C-3, C-5), 144.78 (C-10), 148.23 (C-6),
153.05 (C-40), 157.05 (C = N) ppm.
(84 %) 9.
ꢀ
M.p.: 253–254 °C; IR (KBr): m = 3,385, 3,301 (m N–H),
2,924, 2,854 (m C–H), 1,684 (m C = O), 1,624, 1,590,
N0-(Phenylsulfonyl)-6-methoxypyrazine-2-carboximid-
amide (12, C12H12N4O3S)
Recrystallization from ethanol afforded 584 mg (80 %) 12.
1,562, 1,525, 1,401 (m C = C), 1,280, 1,148 (m SO2), 736 (c
1
C–H), 565 (c N–H) cm-1; H NMR (500 MHz, DMSO-
d6): d = 2.09 (s, 3H, CH3), 7.72 (t, 1H, pyrimidine,
J = 4.8 Hz), 7.75 (d, 2H, Ph, J = 8.8 Hz), 7.86 (d, 2H, Ph,
J = 8.8 Hz), 8.42 (brs, 1H, NH ? D2O exchangeable),
8.96 (d, 2H, pyrimidine, J = 4.1 Hz), 9.08 (brs, 1H,
NH ? D2O exchangeable), 10.33 (s, 1H, NH ? D2O
exchangeable) ppm; 13C NMR (50 MHz, DMSO-d6):
d = 24.39 (CH3), 118.73 (C-30, C-50), 123.58 (C-5),
127.73 (C-20), 136.03 (C-10), 143.08 (C-40), 158.11 (C-4,
C-6), 158.46 (C-2), 158.80 (C = N) ppm.
ꢀ
M.p.: 156–157 °C; IR (KBr): m = 3,395, 3,300 (m N–H),
1,640, 1,580, 1,543 (m C = C), 1,383 (d C–H), 1,306, 1,144
(m SO2), 1,008 (d C–H), 803 (c C–H), 591 (c N–H) cm-1
;
1H NMR (200 MHz, DMSO-d6): d = 4.03 (s, 3H, OCH3),
7.53–7.65 (m, 3H, Ph), 8.00 (d, 2H, Ph, J = 7.6 Hz), 8.50
(brs, 1H, NH ? D2O exchangeable), 8.53 (s, 1H, pyra-
zine), 8.77 (s, 1H, pyrazine), 9.02 (brs, 1H, NH ? D2O
exchangeable) ppm; 13C NMR (50 MHz, DMSO-d6):
d = 54.54 (OCH3), 126.44 (C-20, C-60), 129.33 (C-30,
C-50), 132.77 (C-3), 135.61 (C-40), 139.67 (C-2), 140.88
(C-10), 142.24 (C-5), 158.27 (C-6), 159.01 (C = N) ppm.
General procedure for the synthesis
of sulfonylcarboximidamides 10–13
N0-(4-Aminophenylsulfonyl)-6-methoxypyrazine-2-carbox-
imidamide (13, C12H13N5O3S)
Recrystallization from methanol afforded 637 mg (83 %)
Methyl pyrazine-2-carbimidate or methyl 6-methoxypyr-
azine-2-carbimidate (3 mmol) and the respective
sulfonamide (2.5 mmol) were refluxed in 5 cm3 of diglyme
for 15 min. After cooling down 20 g of ice was added to
the mixture, and the precipitate of the product was filtered
off, dried, and purified by recrystallization from a suitable
solvent with activated carbon.
ꢀ
13. M.p.: 188–189 °C; IR (KBr): m = 3,468, 3,417, 3,370,
3,309, 3,244 (m N–H), 1,634, 1,584, 1,545 (m C = C), 1,379
(d C–H), 1,318, 1,261, 1,133 (m SO2), 1,079 (d C–H), 788
(c C–H), 544 (c N–H) cm-1; 1H NMR (200 MHz, DMSO-
d6): d = 4.02 (s, 3H, OCH3), 5.95 (s, 2H, NH2 ? D2O
exchangeable), 6.59 (d, 2H, Ph, J = 8.8 Hz), 7.59 (d, 2H,
Ph, J = 8.5 Hz), 8.21 (s, 1H, NH ? D2O exchangeable),
8.51 (s, 1H, pyrazine), 8.73 (s, 1H, pyrazine), 8.77 (s, 1H,
NH ? D2O exchangeable) ppm; 13C NMR (50 MHz,
DMSO-d6): d = 54.52 (OCH3), 112.76 (C-30, C-50),
128.56 (C-20, C-60), 132.74 (C-3), 139.84 (C-2), 141.76
(C-10), 142.27 (C-5), 158.29 (C-6), 157.88 (C = N) ppm.
N0-(Phenylsulfonyl)pyrazine-2-carboximidamide
(10, C11H10N4O2S)
Recrystallization from dioxane afforded 249 mg (38 %)
ꢀ
10. M.p.: 218–219 °C; IR (KBr): m = 3,434, 3,321
(m N–H), 1,612, 1,545 (m C = C), 1,278, 1,151 (m SO2),
801, 686 (c C–H), 590 (c N–H) cm-1; 1H NMR (200 MHz,
DMSO-d6): d = 7.54–7.69 (m, 3H, Ph), 7.98 (d, 2H, Ph,
J = 7.3 Hz), 8.44 (brs, 1H, NH ? D2O exchangeable),
8.77 (s, 1H, pyrazine), 8.90 (s, 1H, pyrazine), 9.15 (brs, 1H,
NH ? D2O exchangeable), 9.23 (s, 1H, pyrazine) ppm;
13C NMR (50 MHz, DMSO-d6): d = 126.49 (C-20, C-60),
129.35 (C-30, C-50), 132.84 (C-40), 143.92 (C-2), 144.21
(C-3, C-5), 144.54 (C-10), 148.49 (C-6), 158.28 (C = N)
ppm.
Crystal structure of N0-(4-aminophenylsulfonyl)-4-
chloropicolinimidamide
Single crystals of N0-(4-aminophenylsulfonyl)-4-chloro-
picolinimidamide suitable for X-ray diffraction were
obtained from ethanol by slow evaporation of the solvent at
room temperature. Good quality single-crystal specimens
were selected for experiments at T = 295(2) K. They were
mounted with epoxy glue at the tip of glass capillaries.
Diffraction data were collected on an Oxford Diffraction
Gemini R ULTRA Ruby CCD diffractometer with MoKa
N0-(4-Aminophenylsulfonyl)pyrazine-2-carboximidamide
(11, C11H11N5O2S)
Recrystallization from dioxane afforded 381 mg (55 %) 11.
ꢀ
M.p.: 247–249 °C; IR (KBr): m = 3,431, 3,394, 3,320,
˚
3,252 (m N–H), 1,612, 1,593 (m C = C), 1,268, 1,145 (m
SO2), 1,092 (d C–H), 798 (c C–H), 567 (c N–H) cm-1; 1H
NMR (200 MHz, DMSO-d6): d = 5.97 (s, 2H, NH2 ? D2O
exchangeable), 6.57 (d, 2H, Ph, J = 8.7 Hz), 7.59 (d, 2H,
Ph, J = 8.7 Hz), 8.14 (brs, 1H, NH ? D2O exchangeable),
8.75 (d, 1H, pyrazine, J = 2.4 Hz), 8.89 (d, 1H, pyrazine,
J = 2.4 Hz), 8.92 (brs, 1H, NH ? D2O exchangeable),
9.20 (s, 1H, pyrazine) ppm; 13C NMR (50 MHz, DMSO-
radiation (k = 0.71073 A). The lattice parameters were
obtained by least-squares fit to the optimized setting angles
of the collected reflections by means of CrysAlis CCD
[27]. Data were reduced by using CrysAlis RED [27]
software with applying multi-scan absorption corrections
(empirical absorption correction using spherical harmonics,
implemented in SCALE3 ABSPACK scaling algorithm).
The structural resolution procedure was made using the
123

Phenylsulfonyl- and 4-aminophenylsulfonyl-carboximidamides
1169
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SHELXS-97 package solving the structures by direct
methods and carrying out refinements by full-matrix least-
squares on F2 using the SHELXL-97 program [28]. All H
atoms bound with aromatic C atoms were placed
geometrically and refined using a riding model with
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C–H = 0.93 A and Uiso(H) = 1.2 Ueq(C). All H atoms
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˚
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a
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iso(H) = 1.5 Ueq(N). The –NH2 group containing the N19
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?44-1223-336408; Fax: ?44-1223-336033; e-mail:depo-
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author(s) and the source are credited.
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