Arylsulfonyl-N-2-carbamoylguanidines in synthesis of hetarylsulfonamides and characterization of the compounds obtained

Article abstract of DOI:10.1134/S0965544114030074

It has been found that despite the presence of three active amino moieties of carbamoylguanidine, it adds to sulfonyl chloride by the amino group, not the carbamoyl groups, to give monosulfonamides. Being 1,3-dipolar compounds, the arylsulfonylcarbamoylguanidines obtained readily add to polarophiles, such as chloroacetonitrile and benzoin, to form imidazolylsulfonamides or make pyrimidinylsulfonamides by react-ing with arylidene malonodinitrile. A study of the reactivity of sulfonyl-2-carbamoylguanidine in the N-alky-lation reaction has revealed that the reaction proceeds exceptionally via the replacement of the hydrogen atom at the sulfonamide nitrogen. Examination of some sulfonyl-N-carbamoylguanidine derivatives has shown their high rust-preventing and tribological properties in lubricating oils and greases, as well as antimi-crobic activity. Pleiades Publishing, Ltd., 2014.

Full text of DOI:10.1134/S0965544114030074

ISSN 0965ꢀ5441, Petroleum Chemistry, 2014, Vol. 54, No. 3, pp. 229–233. © Pleiades Publishing, Ltd., 2014.
Original Russian Text © S.A. Mamedov, S.I. Mamedova, N.P. Ladokhina, I.Sh. Guseinov, F.A. Fatalizade, Sh.K. Kyazimzade, 2014, published in Neftekhimiya, 2014, Vol. 54, No. 3,
pp. 230–234.
ArylsulfonylꢀNꢀ2ꢀcarbamoylguanidines
in Synthesis of Hetarylsulfonamides and Characterization
of the Compounds Obtained
S. A. Mamedov, S. I. Mamedova, N. P. Ladokhina, I. Sh. Guseinov,
F. A. Fatalizade, and Sh. K. Kyazimzade
Institute of Chemistry of Additives, National Academy of Sciences of Azerbaijan, Baku, Azerbaijan
eꢀmail: nina_fuad@rambler.ru
Received October 24, 2013
Abstract—It has been found that despite the presence of three active amino moieties of carbamoylguanidine,
it adds to sulfonyl chloride by the amino group, not the carbamoyl groups, to give monosulfonamides. Being
1,3ꢀdipolar compounds, the arylsulfonylcarbamoylguanidines obtained readily add to polarophiles, such as
chloroacetonitrile and benzoin, to form imidazolylsulfonamides or make pyrimidinylsulfonamides by reactꢀ
ing with arylidene malonodinitrile. A study of the reactivity of sulfonylꢀ2ꢀcarbamoylguanidine in the
lation reaction has revealed that the reaction proceeds exceptionally via the replacement of the hydrogen
atom at the sulfonamide nitrogen. Examination of some sulfonylꢀ ꢀcarbamoylguanidine derivatives has
Nꢀalkyꢀ
N
shown their high rustꢀpreventing and tribological properties in lubricating oils and greases, as well as antimiꢀ
crobic activity.
Keywords: arylsulfonylcarbamoylguanidines, Nꢀalkylation reaction, tribological properties, antimicrobial
activity, antirust properties
DOI: 10.1134/S0965544114030074
According to published data, compounds containꢀ mula C9H12N4O3S; 4ꢀbromphenylsulfonylꢀNꢀ2ꢀcarꢀ
ing various functional groups and heterocyclic moiꢀ bamoylguanidine (2), yield, 72.8%; mp <350°C; eleꢀ
eties together with the sulfonamide group, have high mental analysis, %: found: N 16.88, calculated:
antimicrobial, antirust, antioxidant, and tribological N 17.5; empirical formula C8H9N4O3S
.
properties in compositions with lubricating oils and
greases [1–4].
N
ꢀAlkylꢀNꢀ(4ꢀmethylphenylsulfonyl)ꢀNꢀ2ꢀcarꢀ
bamoylguanidine (3, 4). Sodium metal (0.07 mol)
was dissolved in freshly distilled isopropanol. 4ꢀPheꢀ
nylsulfonylꢀNꢀ2ꢀcarbamoylguanidine (0.05 mol) was
EXPERIMENTAL
added to the solution. The mixture was heated for 1 h,
and butyl bromide or octyl bromide (0.05 mol) was
slowly added dropwise after dissolving the sulfonaꢀ
mide. The reaction mixture was boiled under reflux for
6 h, after which water (50 mL) and benzene (70 mL)
were added. Then, the benzene solution was sepaꢀ
rated. Another 50 mL of benzene was added to the
aqueous solution and stirred, and the benzene layer
was separated again. The both benzene solutions were
combined, washed with water to the neutral medium,
and dried; benzene was evaporated to halve its volume;
and hexane was added until total crystals were precipꢀ
itated. Compounds 3 and 4 were obtained.
Preparation Procedures
Procedures for synthesis of various arylsulfonylꢀNꢀ
2ꢀcarbamoylguanidine derivatives are given below, and
their formulas are presented in the Results and Disꢀ
cussion section.
ArylsulfonylꢀNꢀ2ꢀcarbamoylguanidines (1, 2). To a
mixture of carbamoylguanidine (0.6 mol), 4ꢀmethylꢀ
or 4ꢀbromophenylsulfonyl chloride (0.5 mol), benꢀ
zene (100 mL), and water (50 mL), a 30% NaOH
aqueous solution (1.3 mol) was added dropwise with
stirring at 40–50°C. The reaction mixture was boiled
under reflux for 2 h, cooled to room temperature, and
diluted with hexane (50 mL). The crystals obtained
N
ꢀButylꢀNꢀ(4ꢀmethylphenylsulfonyl)ꢀNꢀ2ꢀcarꢀ
were filtered out, washed with water, dried, and recrysꢀ bamoylguanidine (3) prepared in this way had a yield
tallized from ethanol. The results of synthesis: 4ꢀ of 68.7% and mp 137–139°C. Found, %: N 18.42.
methylphenylsulfonylꢀ
yield, 79.9%; mp 318–321°C; elemental analysis, %: NMR (ppm): 1.0 triplet (CH3 of butyl group), 2.9
found: N 23.55, calculated: N 22.93; empirical forꢀ CH2–CH2 group), 3.4 singlet (CH3Ph), 3.8 (NCH2),
N
ꢀ2ꢀcarbamoylguanidine (1), Calculated for C13H20N4O3S, %: N 17.99. 1H
(
229

230
MAMEDOV et al.
7.3 (NHCO), 7.7 (C=NH), 8.1 (aromatic fragment). mp 155−157°C. Found, %: N 13.68. Calculated for
Integral intensity of the spectra corresponds to the C23H20N4O3S, %: N 13.00. 1ꢀ(4ꢀbromophenylsulfonylꢀ
proton amount of molecule.
ꢀOctylꢀNꢀ(4ꢀmethylphenylsulfonyl)ꢀNꢀ2ꢀcarbamꢀ
oylguanidine (4) was obtained in a yield of 65.8%. Mp =
55–57°C. Found, %: N 15.79. Calculated for
C17H28N4O3S, %: N 15.26.
2ꢀcarbamidoꢀ4,5ꢀdiphenylimidazole (8) yield of 69.8%,
mp 243–244°C. Found, %: N 11.68. Calculated for
C22H17N4O3SBr, %: N 10.97.
N
Analysis
1ꢀArylsulfonylꢀ2ꢀcarbamidoꢀ3ꢀaminoimidazoles (5, 6).
4ꢀMethylꢀ or 4ꢀbromophenylsulfonylꢀNꢀ2ꢀcarbaꢀ
1H NMR spectra of the compounds were recorded
on a Varian Tꢀ60 and Teslaꢀ467 spectrometers using
operating frequencies of 60 and 92 MHz, respectively.
Elemental analysis was made on a TruSpec analyzer.
moylguanidine (0.03 mol) and chloroacetonitrile
(0.035 mol) were dissolved in ethanol (30 mL). A 20%
~
NaOH alcohol solution (0.038 mol) was dropwise added
to the solution with stirring. The reaction mixture was
boiled under reflux until the complete precipitation of
yellow crystals (~1.5 h) and cooled; the crystals were
washed with water, dried, and recrystallized from ethaꢀ
nol. Synthesis results: yield of 1ꢀ(4ꢀmethylphenylsulfoꢀ
nyl)ꢀ2ꢀcarbamidoꢀ3ꢀaminoimidazole (5) 71.3%, mpꢀ
275°C. Found, %: C 46.21, H 4.69, N 23.68. Calculated
for C11H13N5O3S, %: C 45.81, H 4.33, N 23.32. The
yield of 1ꢀ(4ꢀbromophenylsulfonylꢀ2ꢀcarbamidoꢀ3ꢀ
aminoimidazole (6) is 69.6%, mp 295–297°C.
Found, %: N 19.62. Calculated for C10H10N5O3SBr, %:
N 19.08.
1
The H NMR spectrum of compound 3 (ppm):
1.0 triplet (CH3 of butyl group), 2.9 (CH2CH2 group),
3.4 singlet (CH3Ph), 3.8 (NCH2), 7.3 (NHCO),
7.7 (C=NH), 8.1 (aromatic fragment). The integral
intensity of the spectrum corresponds to the amount
of protons in the molecule.
RESULTS AND DISCUSSION
The reactions of some sulfonyl chlorides with subꢀ
stituted guanidines were studied in detail previously
[5–8]; however, the reactions of arylsulfonyl chlorides
with carbamoylguanidine have been little studied if
at all.
Arylsulfonylꢀ2ꢀcarbamidoꢀ4,5ꢀdiphenylimidazoles
(7, 8). The synthesis procedures are similar to those
for compounds 5 and 6. The difference is that a catalytic
It has been found that despite the presence of three
amount of morpholine (10–15 drops) was used instead of active amino groups in the carbamoylguanidine moleꢀ
the alkali. Synthesis results: 1ꢀ(4ꢀmethylphenylsulfonyl)ꢀ cule, monosulfonamides alone are produced in the
2ꢀcarbamidoꢀ4,5ꢀdiphenylimidazole (7) yield of 67.9%, reaction:
NH
NH
4ꢀRꢀ
4ꢀRꢀC H SO Cl +
6
C6H4SO2NH
HN2
4
2
NHCONH2
NHCONH2
where R = CH3 (1); Br (2)
It is known that the hydrogen atom at the sulꢀ mides [9, 10]. We carried out the Nꢀalkylation reacꢀ
fonamide nitrogen is ready to replace and ꢀalkylꢀ tion of carbamoylguanidinesulfonamide (1) with
sulfamides are formed by reacting with alkyl broꢀ butyl bromide and octyl bromide.
N
NH
NH
R–Br
CH3
SO2N
H
CH3
SO2N
R
R = C4H9 (3); C8H17 (4).
NHCONH2
NHCONH2
Compounds 1 and 2 obtained owing to the presꢀ effect of carbamoyl group on heterocyclization reacꢀ
ence of 1,3ꢀdipolar groups can be the synthons in
hetarylsulfonamide synthesis. These evidence are
absent in the literature. Only the heterocyclization
reaction of guanidinesulfonamides with 1,2ꢀ and 1,3ꢀ
tion has not been studied.
We have found that imidazolylsulfonamides form in
reaction of sulfonylcarbamoylguanidines with chloroacꢀ
dipolarophiles has been studied [3, 11]. However, the etonitrile and benzoin:
PETROLEUM CHEMISTRY Vol. 54
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ARYLSULFONYLꢀ
N
ꢀ2ꢀCARBAMOYLGUANIDINES IN SYNTHESIS
231
Table 1. Results of Nꢀcarbamoylguanidinesulfonamide testing as additives for lubricating oils and greases
Antiwear and antigalling properties
Compounds,
lube oils, greases
Concentration, % Corrosion, g/m2
critical load,
Pc (N)
welding load,
Pw (N)
load wear index,
N
Mꢀ8 oil
AKꢀ15 oil
with comp. 3
with comp. 4
DFꢀ11
–
–
3
150–180
–
–
441
–
–
1500
3100
3350
2870
–
20.1
61
65
64
–
11.2
6.8
1050
1100
820
3
3
4.0
0.6
58.5
18.5
0.6
VNIINPꢀ300
ICAꢀ141/l grease
with comp. 1
2.4
–
3
–
760
2850
–
34
–
–
with comp. 4
3
850
3500
3550
3550
2900
3820
3750
3650
3810
3700
3180
66
67
65
55
68
66
65
67
–
with comp. 5
3
6.1
860
with comp. 7
3
6.5
820
IKhP141/okhm grease
with comp. 4
–
3
42.9
5.4
870
1050
950
with comp. 5
3
9.6
with comp. 7
3
3.9
890
with comp. 8
3
2.5
970
Armatolꢀ238 grease
Rꢀ416 grease
–
–
–
780–1000
750–900
–
–
NH
NHCONH2
NHCONH2
1
4ꢀR
C6H4SO2NH
ClCH2CN
R2
4ꢀR1ꢀ
C6H4SO2N
R2
R3
N
O
OH
R3
R1 = CH3, R2 = H, R3 = NH2 (5); R1 = Br, R2 = H,
R3 = NH2 (6); R1 = CH3, R2 = R3 = C6H5 (7);
R1 = Br, R2 = R3 = C6H5 (8).
It has been noted [1–4] that sulfonamide comꢀ length of the alkyl radical on the sulfonamide nitrogen
pounds containing various functional groups and hetꢀ increases, their performance is enhanced. The antiꢀ
erocyclic moieties impart high performance characꢀ wear and extremeꢀpressure properties of compounds 3
teristics to lubricants. These compounds are used for and 4 are better than those of the industrial additive
improving the properties of greases [12]. In this conꢀ DFꢀ1.
text, the investigation of the effect of the carbamꢀ
oylguanidine group in combination with the sulfonaꢀ
mide group was of great interest. Therefore, the comꢀ
pounds synthesized were examined in compositions
with greases, and those soluble in lubricating oils were
studied as an additive in the Mꢀ8 oil.
The data in Table 1 show that Nꢀalkylated derivaꢀ
tives of 4ꢀmethylphenylsulfonylcarbamoylguanidines
(compounds 3, 4) exhibit very good antioxidant, antiꢀ
Examination of these sulfonamides as an additive
for jointing paste and thread lubricant also showed
high rustꢀprotecting, antiwear, and antigalling properꢀ
ties. Their effectiveness is at the level of that of the
Armatolꢀ238 industrial grease. The imidazole moiety
imparts greater plasticity and mechanical and colloiꢀ
dal stability to greases, and elevates the dropping point
by 6–10°C.
The antimicrobial properties of
Nꢀ2ꢀcarbamꢀ
rust, and tribologic properties due to the presence of oylguanidinesulfonamides were tested in two direcꢀ
the carbamide, Nꢀalkyl, and imino groups. As the tions, the oilꢀsoluble derivatives (compounds 3, 4)
PETROLEUM CHEMISTRY Vol. 54
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232
MAMEDOV et al.
Table 2. Results of testing synthesized sulfonamides 3
ants (LC)
⎯
5 and 7 as antimicrobial additives for lubricating oils and lubricoolꢀ
Diameter of inhibition zone for microorganisms, cm
Mꢀ8 oil or LC
Compound no.
Concentration, %
mixture of Pseudomnas aerogiꢀ mixture of Aspergillus niger
nosa and Mycobacterium bacteria and Penicillium ch. fungi
1
3.0
2.8
2.4
3.1
2.8
2.4
3.4
3.2
3.0
3.7
3.5
3.0
3.9
3.7
3.2
1.9
1.4
1.2
3.6
3.4
3.2
3.7
3.5
3.1
3.9
3.7
3.6
3.8
3.6
3.2
3.6
3.4
3.2
3.4
2.4
2.0
Mꢀ8 oil
1
3
4
5
7
0.5
0.25
1
0.5
0.25
1
0.5
0.25
1
0.5
0.25
1
0.5
0.25
1
0.5
0.25
Mꢀ8 oil
Mꢀ8 oil
Azerol LC
Azerol LC
Sulfaktsid
were examined in the Mꢀ8 oil and the waterꢀsoluble
derivatives, in the Azerol lubricoolant (LC) (Table 2).
In this method, an octanol–water mixture is used
as the liquid phase to dissolve the compounds under
investigation. The phase can serve as a reference
model for evaluating the interaction of active moleꢀ
cules with bacteria and fungi lipid biophases. As a criꢀ
terion for the biologic effect of antimicrobial preparaꢀ
tions on anaerobic cultures, the difference of the iniꢀ
tial rates of uptake of oxygen consumed by the cultures
in a control experiment in the presence and absence
As is n from the data inable 2,
Nꢀalkylated derivaꢀ
tives of ꢀ2ꢀcarbamoylguanidinesulfonamides have a
N
high bactericidal and fungicidal activity, and their
effectiveness exceeds that of the Sulfaktsid industrial
biocide. The greater length of the alkyl radical, the
higher the activity, with the fungicidal activity of these
compounds being always higher than the bactericidal
activity.
of a biocide in the culture medium: WO without bioꢀ
2
cide – WO with biocide =
а
. The rate of biological
action (Kr h–1) was determined by the equation
AC = Kr h–1, where
is the probability that a bioacꢀ
tive compound reaches the bioreceptor within a given
time, and is the extracellular molar concentration of
the compound. The product AC was named the effecꢀ
value is related to the hydroꢀ
Of the sulfonamides obtained, compounds 5 and 7
exhibit the best bactericidal and fungicidal properties,
which are due to the presence of the imidazole moiety
in the molecule.
2
a/
А
С
Evaluation of the bactericidal and fungicidal propꢀ
erties of compounds according to the existing State
Standards does not ensure an exact quantitative estiꢀ tive concentration. The
A
mate of the activity of the biocides. In many cases, the
antimicrobial effect is masked because of a low rate of
transport of molecules to blocked receptors, and this
complicates the determination of their ability to peneꢀ
trate into the location zone of inhibited receptors of
the microorganism. Taking this into account, in order
to more completely characterize the biocidal properꢀ
ties of the compounds synthesized, we used the upꢀtoꢀ
date Hansch method [13]. The method is based on the
assumption that there is correlation between the facꢀ
tors that determine the biochemical activity and the
physicochemical parameters of substances.
phobicity parameter of the test compounds.
The dependence of the rate of biological action on
the effective concentration in the presence of bacteria
mixture (Fig. 1) showed that sulfonamides containing
the imidazole moiety have a high antibacterial effecꢀ
tiveness. The rate of biological action of these comꢀ
pounds even at a concentration of 2.0–2.3 mol/L is
below that of compounds 1–4, and this proves their
fast penetration into the intracellular space and blockꢀ
ing the vital centers of microorganisms. The effectiveꢀ
ness of compounds 1–4 is below that of compounds
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ARYLSULFONYLꢀ
N
ꢀ2ꢀCARBAMOYLGUANIDINES IN SYNTHESIS
233
than that of other sulfonamides, but their fungicidal
activity turned out to be very strong. The rate of bioꢀ
logical action ranges within 0.237–0.387, and the
slopes of the curves are almost equal to one another.
0.70
0.60
0.50
0.40
0.30
0.20
0.10
3
4
It can be concluded from the results obtained that
the derivatives of Nꢀ2ꢀcarbamoylguanidinesulfamides
1
have a high antimicrobial activity and their effectiveꢀ
ness is higher than that of the biocides used in the
industry. The mechanism of bactericidal action of sulꢀ
fonamides consist in the inhibition of the formation of
the cell wall of microorganisms, protein denaturation,
and disturbance of permeability of the cytoplasmic
membrane involving the inhibition of enzymes vital
for bacterial metabolism.
5
7
6
REFERENCES
1.0
2.0
3.0
4.0
5.0
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Fig. 1. The rate of biological action versus the effective
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0.20
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2.0
3.0
4.0
5.0
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6, 449
5–7, but it is higher than the antibacterial activity of 12. O. E. Polyakov and P. G. Cherednichenko, UA Patent
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Sulfaktsid.
The fungicidal activity of the test sulfonamides is
also higher than that of Sulfaktsid (Fig. 2).
In contrast, the sulfonamides that have weak antiꢀ
bacterial effectiveness showed very fungicidal properꢀ
13. Practical Studies for Medicinal Chemistry Ed. by
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analysis.
ties. The antibacterial activity of
Nꢀalkyl derivatives of
Nꢀ2ꢀcarbamoylguanidinesulfamide is slightly weaker
Translated by S. Lebedev
PETROLEUM CHEMISTRY Vol. 54
No. 3 2014