1,3,5-Triazinenitrolic acids. Synthesis and NO-releasing properties

Article abstract of DOI:10.1007/s11172-009-0268-z

Reactions of salts of 1,3,5-triazine dinitromethyl derivatives with nitrogen dioxide that result mainly in 1,3,5-triazinenitrolic acids are investigated. The behavior of nitrolic acid in electroreduction at a mercury drop electrode at various pH was studied; oxygen was shown to accelerate the process. The promoting effect of nitrolic acids on the activity of soluble guanylate cyclase of human platelets was shown. The studied nitrolic acids are active donors of nitric oxide, a universal and important regulator of cell metabolism functions. NO-releasing properties of furoxans are investigated.

Full text of DOI:10.1007/s11172-009-0268-z

Russian Chemical Bulletin, International Edition, Vol. 58, No. 9, pp. 1962—1972, September, 2009
1962
1,3,5ꢀTriazinenitrolic acids.
Synthesis and NOꢀreleasing properties
V. V. Bakharev,a A. A. Gidaspov,a E. V. Peresedova,а V. G. Granik,b N. B. Grigor’ev,b
V. I. Levina,b I. S. Severina,c A. Yu. Shchegolev,c D. E. Dmitriev,d and A. B. Sheremetev d
aSamara State University,
244 Molodogvardeiskaya ul., 443100 Samara, Russian Federation.
Eꢀmail: knil@sstu.smr.ru
bCenter for Drug Chemistry,
bld.1, 7 Zubovskaya ul., 119021 Moscow, Russian Federation.
Eꢀmail: vggranik@mail.ru
cV. N. Orekhovich Institute of Biomedical Chemistry,
Russian Academy of Medical Sciences,
10 Pogodinskaya ul., 119121 Moscow, Russian Federation.
Eꢀmail: irina.severina@ibmc.msk.ru
dN. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
47 Leninsky prosp., 119991 Moscow, Russian Federation.
Fax: (499) 135 5328. Еꢀmail: sab@ioc.ac.ru
Reactions of salts of 1,3,5ꢀtriazine dinitromethyl derivatives with nitrogen dioxide that
result mainly in 1,3,5ꢀtriazinenitrolic acids are investigated. The behavior of nitrolic acid in
electroreduction at a mercury drop electrode at various pH was studied; oxygen was shown to
accelerate the process. The promoting effect of nitrolic acids on the activity of soluble guanylate
cyclase of human platelets was shown. The studied nitrolic acids are active donors of nitric
oxide, a universal and important regulator of cell metabolism functions. NOꢀreleasing properꢀ
ties of furoxans are investigated.
Key words: nitrolic acids, 1,3,5ꢀtriazine, furoxan, nitration, NOꢀdonors.
At present it is reliably established that nitric oxide
found NOꢀdonors, high efficiency of some oximes4,6 is
noted.
(NO) is an intraꢀ and intercellular second messenger
(neurotransmitter). It plays a key role in regulation of the
major biological processes of cardiovascular, gastroenꢀ
teric, urinogenital, respiratory, central and peripheral nerꢀ
vous systems. Chemical, biochemical, and pharmaceutiꢀ
cal aspects of action of nitric oxide donors are considered
in detail in recent reviews.1—8
It is known that the formation of NO in an organism
in insufficient quantities leads to a number of serious
consequences. In this connection, one of the most
actively developing now directions1—6 is the search for
various compounds that can serve as NO generators, i.e.,
xenobiotics, that are transformed with its formation. At
present a number of drugs the activity of which is reasonꢀ
ably connected with their ability to liberate NO in vivo is
employed in medical practice.
Nitrolic acids, RC(=NOH)NO2, containing the oxime
and nitro groups at the same carbon atom, are interesting
class of potential prodrugs. Antithrombotic and hypotenꢀ
sive activity9 was shown for some nitrolic acids. Ophthalꢀ
mologic effects of imidazolenitrolic acids were recently
described.10,11 On the basis of a structure of the nitrolic
acids it is logical to suppose that they are capable to genꢀ
erate nitric oxide. It is established, for example, that some
nitrolic acids decompose with formation of HNO even at
room temperature. 5
The basic analytical methods that allow identifiꢀ
cation of NO are described in detail in a review.7 The
colorimetric method that quantifies the nitrite ion, a
marker of NO formation, is one of the most common
methods (see Ref. 8). It is this method that is employed
in the present work.
A review12 on development of the synthesis methods
and the reactivity of monoꢀ, diꢀ, and trinitromethyl
derivatives of 1,3,5ꢀtriazines has recently been published.
The substances containing Sꢀ, Oꢀ, Nꢀ, and Cꢀnitrosoꢀ
and nitro groups, viz., diazeniumdiolates, furoxans, NOꢀ
metal complexes, etc.,6 are related to the compounds
showing properties of nitric oxide donors. Among the
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 9, pp. 1900—1910, September, 2009.
1066ꢀ5285/09/5809ꢀ1962 © 2009 Springer Science+Business Media, Inc.

1,3,5ꢀTriazinenitrolic acids
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 9, September, 2009 1963
In continuation of our investigations13—17 in this field of
chemistry, we published a preliminary report on possible
preparation of model nitrolic acid of the 1,3,5ꢀtriazine
series.18
Scheme 1
In the present work, a synthetic scheme that allows
designing 1,3,5ꢀtriazinenitrolic acids is described in
detail, and data on NO release (detected as the nitrite
anion) upon transformations of these compounds at difꢀ
ferent рН are also presented. Furthermore, a question of
the NOꢀdonor activity of furoxan derivatives obtained
in the present work is considered
Results and Discussion
Nitrolic acids are important building blocks for synꢀ
thesis as well as intermediates in nitration—nitrosation
processes.19 Compounds containing nitromethyl groups
serve most often as the starting substances for the syntheꢀ
sis of nitrolic acids. 1,3,5ꢀTriazines with these groups are
very scarce.12 1,3,5ꢀTriazineꢀ2,4,6ꢀtris(nitrolic) acid was
synthesized by destructive nitration of the corresponding
tris(hydroxyiminoacetic) acid,20 which is accessible with
difficulty. Therefore, in the present work the readily availꢀ
able diꢀ and trinitromethyl derivatives of alkoxy(dialkylꢀ
amino)ꢀ1,3,5ꢀtriazine were chosen as the starting comꢀ
pounds.
R = Me (2, 5, 8a—d), Prn (3, 6), рꢀOC6H4NO2 (4, 7, 8f)
R´ = R″ = Me (8a,f), R´—R″ = (CH2)4 (b), (CH2)5 (c),
(CH2CH2)2O (d)
For the first time, the reaction of aryldinitromethane
salts with N2O4 in CCl4 at –12 °C, resulting in aryltrinitroꢀ
methanes, was carried out in the 1950s.21 Later, Russian
scientists have studied the reactions of salts of various
dinitromethyl compounds with N2O4 in inert organic solꢀ
vents, which resulted in the corresponding trinitromethyl
derivatives and/or nitrolic acids, nitrile oxides, furoxans,
nitriles.17,22—27 The first step of this process is nitrosation
of the dinitromethane anion resulting in α,αꢀdinitroꢀ
αꢀnitrosomethyl intermediate,25,26 which can be converted
in different products depending on the reaction condiꢀ
tions. Probably, salts of α,αꢀdinitromethyl compounds
containing the hydroxyimino group in the βꢀposition that
are also involved in this reaction28—30 react with N2O4
according to a similar mechanism. Simple and effective
reaction of salts of dinitromethyl compounds with N2O4
seemed rather attractive for our purposes.
The treatment of aqueous suspension of the dimethoxy
derivative salt 5 with a small excess of secondary amines
at room temperature results in nucleophilic substitution
of one methoxy group. The yields of the reaction products
8a—d were 82—93%. The pꢀnitrophenoxy group in comꢀ
pound 7 is substituted analogously. The substitution of
the propoxy group in compound 6 is less straightforward,
a mixture of products is formed, and the starting comꢀ
pound remains unconsumed. Bis(dimethylamino) derivaꢀ
tive 8e is formed under the action of Me2NH (2.5 equiv.).
Earlier, we have shown17 that potassium salts of
2,4ꢀdialkoxyꢀ6ꢀdinitromethylꢀ1,3,5ꢀtriazine are converted
into furoxans with yields of 60—85% when treated with
N2O4 in an inert solvent (for example, toluene or dichloroꢀ
ethane) at room temperature. The reaction of 1,3,5ꢀtriꢀ
azines with a dialkylamino group instead of an alkoxy
group as a substituent, follows another pathway.18
The reactions of potassium salts 8a—f with N2O4 at
room temperature in anhydrous nonpolar solvents (chloroꢀ
organic solvents, toluene, etc.) leads mainly to triazineꢀ
nitrolic acids 10a—f (~60%), furoxans 11a—f (20—30%)
being found only as byproducts (Scheme 2). A mixture of
a solution of N2O4 in an organic solvent (initially brown)
and colorless salts 8a—f acquired a bright blueꢀgreen color
for short time, which suggests the formation of nitrosoꢀ
intermediate 9 (see Refs 25, 26). The blueꢀgreen color
In the reaction of trinitromethane potassium salt
with the commercially available 2,4,6ꢀtrichloroꢀ1,3,5ꢀtriꢀ
azine (cyanuric chloride) (1) in the presence of methaꢀ
31
nol, nꢀpropanol, or pꢀnitrophenol as described earlier,
one trinitromethyl group and two alkoxyl or aryloxide
groups were introduced into the molecule of 1,3,5ꢀtriazꢀ
ine with formation of products 2—4 in yields 60—75%
(Scheme 1).
The trinitromethyl group of compounds 2—4 underꢀ
goes denitration on treatment with potassium iodide in
methanol,32 which results in potassium salts 5—7.

1964
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 9, September, 2009
Bakharev et al.
Scheme 2
8—11: R´ = R″ = Me (a), R´—R″ = (CH2)4 (b), (CH2)5 (c), (CH2CH2)2O (d)
Scheme 4
soon disappeared, and the reaction mixture became pale
yellow.
We observed an interesting and unusual fact of the
effect of water on the studied reaction. It was found that if
nitrosation of salts 5—7, 8a—f was carried out in the
presence of water (1—2 mol), the formation of furoxans
11 is completely suppressed. The reactions appear to proꢀ
ceed in a similar manner (the dissolution of the initial
salts, formation of a new precipitate, and change in the
color of the reaction mixture), but the yields of nitrolic
acids 10 increase by 15—25%. The zwitterionic33 dinitroꢀ
methyl derivetives 12a—f are formed as byꢀproducts in
the case of dialkylamino derivatives 8a—f (Scheme 3).
Dinitromethyl derivitives 13g—i are formed as byꢀprodꢀ
ucts from compounds 5 and 6 (Scheme 4).
Scheme 3
R = OMe (g), Pr (h)
with nitrogen dioxide. Actually, the yields of nitrolic
acids decrease with increasing amount of water.
The nitrolic acids 10 exist in the form of one stereoꢀ
isomer (one set of signals in the NMR spectra), which,
probably, has Eꢀconfiguration. In the 1Н NMR spectra of
acids 10, the protons of the hydroxyimino groups appear
in the range of δ 14. The presence of signals at δ 151
and –12.8 (nitrogen atom of the NO2 group) in the 13C
and 14N NMR spectra is characteristic of αꢀnitroꢀ
αꢀhydroxyiminomethyl group, which agrees with the
literature data. 26
The resulting nitrolic acids 10 are stable at room temꢀ
perature; insignificant signs of decomposition are recorded
after 2—3 months. They can be kept for a long time at
0—5 °С. Fast decomposition with nitrous acid release
is observed on heating of acids 10a—h in toluene at
90—110 °C (Scheme 5), and the nitrile oxides 14 formed
undergo dimerization resulting in the corresponding
furoxans 11a—e,g,h (up to 95%).
The presence in 13C NMR spectra of signals in
the region δ 111—112, for the С(3) atom adjacent to the
Nꢀoxide function, and signals in the region δ 153—154
corresponding to the carbon atom С(4) remote from the
R = OMe, R´ = R″ = Me (a), R´—R″ = (CH2)4 (b), (CH2)5 (c),
(CH2CH2)2O (d),
R = NMe2, R´ = R″ = Me (e), R = OC6H4NO2ꢀp, R´ = R″ = Me (f)
Probably, the formation of dinitromethyl derivatives
12 and 13 is the result of concurrent reactions of salts
5—8 with nitric acid emerging in the reaction mixture
upon the reaction of nitrogen dioxide with water. On the
one hand, water is required for the formation of nitrolic
acids from intermediate 9, but, on the other hand, it
competes with the dinitromethyl anion in the reaction

1,3,5ꢀTriazinenitrolic acids
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 9, September, 2009 1965
Scheme 5
10a—d in ethanol in the presence of oxygen, 10—15% of
the nitrite anion is detected in 15—20 min, and 20%, in
24 h. In ethanol in the absence of oxygen, the amount
of the nitrite ion detected after 20 h decreases to 10 %.
In deaerated 10 % ethanol in the presence of AcOH
upon contact with air for 2.5 h the nitrite anion (2—6 %)
is formed. In 0.1 M HCl in 10 % ethanol, no formation
of the nitrite anion is observed. In a buffer with pH 10,
which is not oxygenꢀfree, 80—90 % of the nitrite anion is
released from nitrolic acids 10a—d even in 1 h.
Thus, the presence of oxygen in an alkaline solution is
important for increasing the rate of the nitrite ion generaꢀ
tion from nitrolic acids. In general, alkaline hydrolysis
in the presence of oxygen causes efficient NO formation
from the nitrolic acids 10a—d.
The activation of soluble guanylate cyclase is a charꢀ
acteristic effect of nitric oxide. All investigated compounds
activate this enzyme (Table 1).
The ability of nitrolic acids to activate the soluble
guanylate cyclase is caused, apparently, by generation
of exogenous NO. For the nitrolic acids studied earlier, a
correlation between the amount of NO formed and the
6,38
Nꢀoxide function is characteristic of the furoxan ring (see
Ref. 19). The difference in chemical shifts of the carbon
atoms of the furoxan ring in the investigated series is
41.9 0.4 ppm and almost invariable.
Nitrolic acids containing nitroꢀ and hydroxyimino
groups, can potentially be NO donors.6,34 The transforꢀ
mations of the nitrolic acids under hydrolytic conditions
result in the nitrite ion, polarography being the most suitꢀ
able for monitoring these transformations.35,36
The polarographic study showed that the height of the
first wave of reduction of the nitro group of compounds
10a—d in alkaline solutions decreases to its full disapꢀ
pearance. The process is dependent, its rate increases with
increasing pH. This suggests hydrolysis of the compounds
under study with abstraction of the nitro groups in the
form of the nitrite anion. The formation of this anion in
both the phosphate buffer (рН 8), and 0.01 M NaOH is
confirmed by the Griess reaction.37
The electronꢀwithdrawing character of the 1,3,5ꢀtriꢀ
azine ring is possibly responsible for the behavior of
nitrolic acids 10a—d in media with different рН. Thus
they rapidly decompose in alkaline and neutral solutions
and are stable only in strong acids (1 M HClO4). It should
be noted that alkanenitrolic acids are also relatively stable
in weakly alkaline solutions. Earlier,35 it has been shown
that the polarographic waves for alkanenitrolic acids in
acidic and alkaline solutions relate to reduction of the
nitro groups.
degree of activation of guanylate cyclase
established.
has been
Several alternative pathways of NO generation (more
exactly, the molecules that are NO precursors) from
nitrolic acids are feasible. Thus, it is known that therꢀ
molysis of or action of bases on the nitrolic acids brings
about elimination of nitrous acid and conversion to nitrile
oxides, which undergo either dimerization into furoxans,
as is presented in Scheme 5 (see Refs 19, 39), or hydrolyꢀ
sis with formation of the corresponding carboxylic acids,
RCOOH (see Refs 40—45).
Table 1. Influence of nitrolic acids 10a—d on activity of soluble
guanylate cyclase of human platelets
b
Compound
C/mol L–1
aa
K∝
SNPc
10a
10–4
10–7
10–6
10–5
10–7
10–6
10–5
10–7
10–6
10–5
10–7
10–6
10–5
533
76
104
198
86
93
109
42
108
187
65
106
181
12.4
1.8
2.4
4.6
2.0
2.2
2.5
1.0
2.5
4.3
1.5
2.5
4.2
10b
10c
10d
The elimination of the nitro group from compounds
10 in the presence of oxygen (when using the Griess reacꢀ
tion for the detection of the nitrite anion) proceeds faster
than in the absence of oxygen (the similar effect was
observed in another case38). In solutions of nitrolic acids
a Activity of soluble guanylate cyclase/pmol cGMP•mg–1•min–1
.
Base activity is 43 5 pmol cGMP•mg–1•min–1 b Enzyme
.
activation coefficient . c SNP — sodium nitroprusside (strongest
NO donor).

1966
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 9, September, 2009
Bakharev et al.
Scheme 6
At the same time, it should be noted once again that in
acidic media no nitrite anion is determined in the system
under consideration and, hence, no formation of nitric
oxide occurs, whereas in solution with pH ≥ 8 its formaꢀ
tion is dramatically activated. Thus, the preliminary forꢀ
mation of an anion from nitrolic acids is necessary for the
process to proceed. It is logical to assume (Scheme 6) that
anion A is further oxidized by atmospheric oxygen to
carbonyl nitro compounds В and nitroxyl (HNO) in
several steps. It is well known1,6 that nitroxyl can be
oxidized to NO or undergo dimerization in an organism.
However, in a chemical experiment the nitroxyl is not
oxidised to NO, i.e., only transformation products of the
nitro group are detected. Triazinecarboxylic acid C is a
final product of the given process (see Scheme 6) (it was
also obtained by an independent method, see Experimenꢀ
tal), which has been found in the reaction mixture.
The main pathway by which the nitrite anions
obtained is the transformation of the nitro group of the
starting nitrolic acid (see Scheme 6). In spite of the fact
that the oxime group can also serve as an NO precursor in
biological systems, this pathway seems to be secondary
one according to the results of chemical studies, because
in this case the amount of the detected nitrite anion
corresponds to the transformation of one nitrogenꢀconꢀ
taining group.
important for quantitation of furoxans in a solution under
their degradation.
We have found yet another pathway of NO generation
from furoxans that is based not on reductive but on oxiꢀ
dative cleavage of this heterocycle. The oxidation of
furoxans in weakly alkaline media leads to the nitrite anꢀ
ions. The data for the yield of NO2– formed from furoxans
11c,d upon oxidation are listed in Table 2. Note that no
nitrite anion is formed from furoxans under acidic condiꢀ
tions (pH <4).
In alkaline media, the furoxan ring is unstable and
undergoes ring opening with conversion into αꢀnitrooxime
15 (see Ref. 49). Depending on the type of substitutents,
nitrooximes 15 can undergo either cyclization to the
initial furoxans or (if R is an electronꢀwithdrawing group)
the Nef reaction50 (Scheme 7), i.e., hydrolytic abstraction
of the nitro group (with formation of N2O) resulting in
diketone monoxime 16. At the same time, the deoximaꢀ
tion51 proceeds easily under the oxidation conditions, and
compounds 15 and 16 can be involved in this process.
Thus, both the nitro group and the oxime group of the
intermediate 15 can be a source of NO in vivo (see Ref. 6).
Thus, several pathways of NO generation are feasible,
which, most likely, will depend on both the decomposiꢀ
tion conditions and the nature of the fragment R linked
with the nitrolic group, R—C(=NOH)NO2.
As follows from Scheme 5, furoxans 11 can arise upon
dimerization of intermediate nitrile oxides formed from
nitrolic acids 10. Therefore, triazinylfuroxans 11 became
yet another subject of the research of NOꢀdonor activity.
It should be pointed out that the fact of NO generaꢀ
tion from furoxans is well known.1,6,46,47 It is established
that the ability to generate NO by the reductive mechaꢀ
nism in the presence of thiols1 is characteristic of furoxans.
Furthermore, it is known that furoxan derivatives can be
photochemically decomposed with liberation of NO.48
A study of the polarographic behavior of furoxans 11
was carried out in 0.1 M solutions of sodium perchlorate
in DMSO. Thus, for example, E1/2 values for compounds
11с and 11d, were –0.11 and –0.14 V, respectively, relaꢀ
tive to the saturated calomel electrode. These data are
Table 2. Formation of the nitrite anion upon oxidation of furoxans 11c,d
–
Conditions
NO2 (%)
Oxidant
Solvent
Media
τ/h
T/°C
11c
11d
a
O2a
DMSO—2% H2O
DMSO—25% H2O
DMSO—22% H2O
0.1 M ammonia buffer (pH 9.5)
0.08 M Bu4NOH
72
24
2
18
18
80
3.1
4.7
28
0.6
2.6
12
O2
b
H2O2
0.1 M NaOH
a Atmospheric oxigen. b 0.01 M H2O2 (10ꢀfold excess).

1,3,5ꢀTriazinenitrolic acids
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 9, September, 2009 1967
Scheme 7
drugs. Design and studies of new compounds incorporating
a fragment of nitrolic acid can lead to disclosure of origiꢀ
nal derivatives possessing specific physiological activity.
Experimental
Attention! Polynitrocompounds are potential explosives and are
sensitive to shock, friction, and heating. Operations with such comꢀ
pounds require great care.
Melting points were determined in a Gallenkamp melting
1
block and are uncorrected. Н, 13С and 14N NMR spectra with
the natural content of isotopes were recorded on a Bruker AMꢀ300
spectrometer with the working frequencies 300.13, 75.7, and
21.5 МHz, respectively. Chemical shifts in the 14N NMR specꢀ
tra were measured in the δ scale with nitromethane as the interꢀ
1
nal standard. Spinꢀspin coupling constants J15
were
1
N, H
measured using the INEPT technique. Mass spectra were reꢀ
corded on Varian MAT CHꢀ6 and Varian MAT CHꢀ111 (70 eV)
instruments. IR spectra were recorded on a PerkinꢀElmer
Model 577 spectrometer (in pellets with KBr for solids, and in
thin layer for liquids). The course of the reactions and the purity
of the products were monitored by TLC on Silufol UVꢀ254
plates; silica gel SiO2 40/100 was used for preparative chromaꢀ
tography. Compounds 2—4 (see Ref. 31) and 5—7 (see Ref. 32)
were obtained according to the published procedures. Solvents
were purified by conventional methods.
This research has designated new aspects of the beꢀ
havior of furoxans that should be taken into account in
further studying their biological action.
Certain furoxans obtained in the present work were
investigated in relation to ability to activate the soluble
guanylate cyclase52 (Table 3).
Polarography. A universal polarograph PUꢀ1 (Byelorussia)
and a twoꢀcoordinate recorder LKD4ꢀ0.03 (Russia) were used
for research. Polarograms were recorded by means of a threeꢀ
electrode scheme. The working electrode was a mercury dropꢀ
ping electrode with parameters m = 1 mg•s–1, τ = 2.0 s, the
auxiliary electrode was a platinum wire, the reference electrode
was a saturated calomel or silver electrode. The measurements
were performed in a cell at 25 °С. Solutions in cell were purged
with argon for removal of dissolved oxygen. Solutions of unꢀ
stable compounds were prepared directly in the polarographic
cell for recording polarograms. For this purpose, the exactly
weighted sample of a compound under study was dissolved
in the cell, with the background electrolyte previously purged
with argon.
Determination of the nitrite anion according to the Griess
reaction. Sulfanilic acid was used as the diazo component and
Nꢀ(αꢀnaphthyl)ethylenediamine as the azo component. The
reaction was carried out at pH 1 (0.1 M HCl). The content of
the nitrite anion was determined by the addition technique.37
Activity of guanylate cyclase. Human platelets were used as
the source of soluble guanylate cyclase. Platelets were isolated
from blood of healthy donors as described earlier.52 A suspenꢀ
sion of washed platelets in a 50 mМ TrisꢀНСl buffer (рН 7.6)
containing 0.2 mМ dithiothreitol was disintegrated in an ultraꢀ
sonic disintegrator MSE 5ꢀ78 (Great Britain) for 20 s and
centrifuged for 1 h at 105 000 g. The supernatant obtained from
40 mL of blood of one donor was used as a source of soluble
guanylate cyclase in one experiment.
A comparison of the results presented in Tables 1 and
3 suggests that furoxan derivatives are less active than
nitrolic acids with the same substituents in the triazine
ring. Nevertheless, it should be taken into account that
furoxans can be formed in the process of NO generation
from nitrolic acids. The net result of their action can be
rather efficient.
In conclusion, we note that both nitrolic acids and
furoxans of the 1,3,5ꢀtriazine series are generators of niꢀ
tric oxide, a universal and necessary regulator of funcꢀ
tions of a cellular metabolism. Altogether, this shows
that compounds of this type are doubtless of interest for
further biological studies and search for new efficient
Table 3. Influence of furoxans 11с,d on activity of soluble
guanylate cyclase of human platelets
b
Compound
C/mol L–1
aa
K∝
SNPc
11с
10–4
10–8
10–7
10–6
10–8
10–7
10–6
10–5
561 39
11.0
0.8
6.0
2.2
1.5
2.1
0.9
2.2
41
3
306 21
112
77
8
7
11d
107
46
6
3
The activity of guanylate cyclase was quantified as
described.53 The samples (total volume 150 μL) contained a
50 mМ TrisꢀНСl buffer (рН 7.6), 1 mМ guanosine 5ꢀtriphosꢀ
phate, 4 mМ МgCl2, 4 mМ creatine phosphate, 20 μg creatine
phosphokinase, 10 mМ theophyilline, 105 000 g supernatant
(20 μg of protein), and optionally other additives. The influence
122
8
a Activity of soluble guanylate cyclase/pmol cGMP•mg–1•min–1
.
Base activity is 51 3 pmol cGMP•mg–1•min–1 b Enzyme
.
activation coefficient . c SNP (100 μmol) — sodium nitroprusꢀ
side (strongest NO donor).

1968
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 9, September, 2009
Bakharev et al.
of the used compounds on the basal activity of soluble guanylate
cyclase and activation of the enzyme by sodium nitroprusside
were investigated at concentrations of 10 μmol•L–1. First, all
the components mentioned were incubated with the enzyme
(10 min at 2 °C), then the NOꢀdonor under study was added.
Due to low solubility of the compounds in the buffer, they were
previously dissolved in DMSO with subsequent dilution of soluꢀ
tion with the 50 mМ TrisꢀНСl buffer (рН 7.6) to desired conꢀ
centration. Control samples contained the same amount of
DMSO. The amount of cGMP formed in 15 min at 37 °C was
determined by ELISA. The protein was determined by the
Bradford method.54 Guanosine 5´ꢀtriphosphate sodium salt
was from Fluka (Switzerland), other chemicals were from
Sigma (USA).
Preparation of 2ꢀdimethylaminoꢀ4ꢀdinitromethylꢀ6ꢀmethoxyꢀ
1,3,5ꢀtriazine potassium salt (8а). A 33% aqueous solution of
dimethylamine (1.8 mL, 0.012 mol) was added with stirring at
20—25 °С to a suspension of salt 5 (2.83 g, 0.01 mol) (see Ref. 32)
in water (25 mL). The reaction mixture was stirred for 24 h at
20—25 °С (TLC). The precipitated product was filtered off
and washed with cold water (5 mL) and crystallized from 50%
aqueous methanol. The yield was 85%. m.p. 240—241 °С
(decomp.). IR, ν/cm–1: 3020, 2932, 2870, 1602, 1570, 1500,
1479, 1460, 1400, 1387, 1360, 1230, 1125, 1075, 1015, 785.
1Н NMR (DMSOꢀd6, δ): 3.08 (s, 6 H, NCH3), 3.82 (s, 3 H,
OCH3). Found (%): С, 28.30; H, 3.12; N, 28.49. C7H9N6О5K.
Calculated (%): С, 28.38; H, 3.06; N, 28.37.
Found (%): С, 35.60; H, 2.62; N, 24.25. C12H10N7О7K. Calcuꢀ
lated (%): С, 35.74; H, 2.76; N, 24.12.
2,4ꢀBis(dimethylamino)ꢀ6ꢀdinitromethylꢀ1,3,5ꢀtriazine
potassium salt (8e). A 33% aqueous solution of dimethylamine
(7.6 mL, 0.05 mol) was added with stirring at 20—25 °С to a
suspension of salt 5 (2.83 g, 0.01 mol) (see Ref. 32) in water
(20 mL). The reaction mixture was stirred for 5 h at 45—50 °С,
and cooled to 0—5 °С. The precipitate of the product was filꢀ
tered off, washed with cold water (5 mL), and crystallized from
50% aqueous methanol. The yield was 78%, m.p. 196—198 °С
(decomp.). IR, ν/cm–1: 3002, 2946, 2850, 1600, 1587, 1560,
1520, 1503, 1470, 1410, 1370, 1355, 1320, 1235, 1200, 1115,
1015, 980, 775. 1Н NMR (DMSOꢀd6, δ): 3.05 (s, 12 H, NCH3).
Found (%): С, 30.95; H, 3.83; N, 31.74. C8H12N7О4K. Calcuꢀ
lated (%): С, 31.06; H, 3.91; N, 31.70.
The reaction of 2ꢀR´ꢀ4ꢀR″ꢀ6ꢀdinitromethylꢀ1,3,5ꢀtriazine
Кꢀsalts with nitrogen dioxide in the presence of water (general
procedure). To a stirred suspension of 2ꢀR´ꢀ4ꢀR″ꢀ6ꢀdinitroꢀ
methylꢀ1,3,5ꢀtriazine potassium salt 5, 7, 8a—f (0.003 mol) in a
mixture of toluene (or dichloroethane) (7 mL) and water
(0.11 mL, 0.006 mol), a solution of N2O4 (0.24 ml, 0.0039 mol) in
the same solvent (3 mL) was poured in one portion at 15—20 °С.
The precipitate of the starting salt gradually disappeared and
the precipitate of potassium nitrate sedimented; the solution
colored blueꢀgreen. The color of the reaction mixture changed
gradually from blueꢀgreen to yellowꢀgreen and then to yellow.
Nitrolic acids 10a—i precipitated in 30—60 min. The reaction
mixture was cooled to 0 °С, kept for 60 min. The mixture of
nitrolic acid and potassium nitrate was filtered off and washed
with cold toluene or dichloroethane (2×3 mL). The product
was dried in air and then washed with water (10—15 mL) for
removing potassium nitrate.
Alkylamine derivatives 8b—d and 8f were prepared accordꢀ
ing to this procedure.
2ꢀDinitromethylꢀ4ꢀmethoxyꢀ6ꢀpyrrolidinoꢀ1,3,5ꢀtriazine
potassium salt (8b). The yield was 90%, m.p. 234—235 °С
(decomp.). IR, ν/cm–1: 3013, 2972, 2899, 1606, 1581, 1512,
1486, 1471, 1438, 1412, 1398, 1367, 1344, 1263, 1240, 1205,
1142, 1044, 1028, 816, 772, 752. 1Н NMR (DMSOꢀd6, δ):
1.96 (m, 4 H, CH2CH2); 3.38 and 3.50 (both t, 4 H, CH2NCH2,
J = 6.4 Hz), 3.84 (s, 3 H, OCH3). Found (%): С, 33.63; H, 3.50;
N, 26.10. C9H11N6О5K. Calculated (%): С, 33.54; H, 3.44;
N, 26.07.
The organic solution was concentrated and an additional
amount of nitrolic acids 10a—i and zwitterionic salts 12a—f
were isolated from the residue by column chromatography
(Merck Silica gel 60 (0.063—0.200), dichloroethane—methanol,
4 : 1, as the eluent). Nitrolic acid is eluted first followed by
zwitterionic salt.
2ꢀDinitromethylꢀ4ꢀmethoxyꢀ6ꢀpiperidinoꢀ1,3,5ꢀtriazine
potassium salt (8с). The yield was 84%, m.p. 202—203 °С
(decomp.). IR, ν/cm–1: 3359, 3232, 3006, 2935, 2858, 1591,
1506, 1488, 1411, 1369, 1295, 1249, 1226, 1130, 1091, 1024,
998, 896, 856, 819, 769, 755. 1Н NMR (DMSOꢀd6, δ): 1.52 and
1.63 (both m, 6 H, CH2), 3.72 (m, 4 H, CH2NCH2), 3.85 (s, 3 H,
OCH3). Found (%): С, 35.80; H, 3.92; N, 24.90. C10H13N6О5K.
Calculated (%): С, 35.61; H, 3.82; N, 24.99.
2ꢀDinitromethylꢀ4ꢀmethoxyꢀ6ꢀmorpholinoꢀ1,3,5ꢀtriazine
potassium salt (8d). The yield was 93%, m.p. 245—246 °С
(decomp.). IR, ν/cm–1: 2962, 2928, 2880, 1608, 1587, 1520,
1492, 1466, 1420, 1386, 1316, 1252, 1204, 1173, 1132, 1073,
1043, 1012, 924, 898, 852, 828, 816, 768. 1Н NMR (DMSOꢀd6,
δ): 3.65 (br.s, 4 H, CH2NCH2), 3.74 (br.s, 4 H, CH2OCH2),
3.87 (s, 3 H, OCH3). Found (%): С, 31.89; H, 3.38; N, 24.76.
C9H11N6О6K. Calculated (%): С, 31.95; H, 3.47; N, 24.62.
2ꢀ(Dimethylamino)ꢀ4ꢀdinitromethylꢀ6ꢀ(pꢀnitrophenoxy)ꢀ
1,3,5ꢀtriazine potassium salt (8f). The yield was 82%, m.p. 190—
192 °С (decomp.). IR, ν/cm–1: 3080, 1602, 1580, 1576, 1524,
1514, 1492, 1464, 1432, 1380, 1348, 1272, 1222, 1144, 1114,
1068, 1020, 996, 948, 870, 856, 776, 752, 706. 1Н NMR
(DMSOꢀd6, δ): 3.02 and 3.08 (6 H, NCH3, Δν = 12.0 Hz);
7.44—7.53 and 8.24—8.33 (4 H, pꢀC6H4, J = 1.2 Hz).
2ꢀDimethylaminoꢀ4ꢀmethoxyꢀ1,3,5ꢀtriazineꢀ6ꢀnitrolic acid
(10a). The yield was 52 + 20% (hereinafter; the first value
denotes the amount of precipitated product, the second one
refers to the additional portion isolated by chromatography),
m.p. 109—111 °С (decomp.), Rf 0.71 (dichloroethane—
methanol, 4 : 1). IR, ν/cm–1: 3145, 3049, 3004, 2933, 2879,
2811, 1608, 1587, 1552, 1511, 1417, 1382, 1268, 1224, 1149,
1074, 1051, 1002, 902, 864, 806, 727, 646. 1Н NMR (DMSOꢀd6,
δ): 3.12 and 3.20 (both s, 6 H, NCH3, Δν = 16 Hz), 3.96 (s, 3 H,
OCH3), 13.63 (br.s, 1 H, NOH). 13С NMR (DMSOꢀd6, δ):
36.4, 36.6 (NCH3), 55.0 (OCH3), 151.3 (C(NO2)=NOH), 163.0
(N=C—C); 166.5 (N=C—N), 171.5 (N=C—OCH3). 14N NMR
(DMSOꢀd6, δ): –13.6 (NO2). Found (%): С, 34.77; H, 4.20;
N, 34.64. C7H10N6O4. Calculated (%): С, 34.71; H, 4.16;
N, 34.70.
2ꢀMethoxyꢀ4ꢀpyrrolidinoꢀ1,3,5ꢀtriazineꢀ6ꢀnitrolic acid (10b).
The yield was 43 + 12%, m.p. 119—121 °С (decomp.), Rf 0.72
(dichloroethane—methanol, 4 : 1). IR, ν/cm–1: 3104, 2973,
2887, 2802, 2780, 1596, 1562, 1508, 1477, 1457, 1380, 1340,
1245, 1054, 1008, 970, 806, 727. 1Н NMR (DMSOꢀd6, δ): 2.46
(m, 4 H, CH2CH2), 4.00 (m, 4 H, CH2NCH2), 4.39 (m, 3 H,
OCH3); 14.10 (s, 1 H, NOH). 13С NMR (DMSOꢀd6, δ): 25.5,
25. 6 (CH2CH2), 47.2, 47.4 (CH2NCH2), 55.0 (OCH3), 151.3

1,3,5ꢀTriazinenitrolic acids
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 9, September, 2009 1969
(C(NO2)=NOH), 162.9 (N=C—C), 164.4 (N=C—N), 171.4
(N=C—OCH3). 14N NMR (DMSOꢀd6, δ): –12.8 (NO2).
Found (%): С, 40.25; H, 4.59; N, 31.40. C9H12N6O4. Calcuꢀ
lated (%): С, 40.30; H, 4.51; N, 31.33.
(t, 4 H, CH2); 4.49 (t, 4 H, OCH2); 13.07 (br.s, 1 H, NOH).
Found (%): С, 41.88; H, 6.02; N, 24.45. C10H17N5O5. Calcuꢀ
lated (%): С, 41.81; H, 5.96; N, 24.38.
2ꢀDimethylaminoꢀ4ꢀdinitromethylꢀ6ꢀmethoxyꢀ1,3,5ꢀtriazine
zwitterionic salt (12а). The yield was 18%, m.p. 110—112 °С
(decomp.), Rf 0.34 (dichloroethane—methanol, 4 : 1). IR,
ν/cm–1: 3176, 2942, 2888, 1620, 1564, 1536, 1500, 1476, 1380,
1316, 1244, 1200, 1136, 1048, 1004, 968, 904, 856, 780, 728,
712. 1Н NMR (acetoneꢀd6, δ): 3.12 and 3.19 (both s, 6 H,
NCH3, Δν = 4.2), 3.92 (s, 3 H, OCH3), 7.98 (s, 1 H, NH).
Found (%): С, 32.51; H, 3.94; N, 32.62. C7H10N6O5. Calcuꢀ
lated (%): С, 32.56; H, 3.90; N, 32.55.
2ꢀDinitromethylꢀ4ꢀmethoxyꢀ6ꢀpyrrolidinoꢀ1,3,5ꢀtriazine
zwitterionic salt (12b). The yield was 15%, m.p. 111—112 °С
(decomp.), Rf 0.32 (dichloroethane—methanol, 4 : 1). IR,
ν/cm–1: 3103, 2987, 2958, 2883, 1635, 1608, 1567, 1540, 1483,
1432, 1392, 1340, 1301, 1257, 1232, 1211, 1182, 1141, 1033, 1002,
966, 894, 856, 833, 777, 752, 729. 1Н NMR (acetoneꢀd6, δ):
1.96—2.04 (m, 4 H, CH2CH2), 3.54 and 3.66 (both t, 4 H,
NCH2, J = 4.6 Hz), 3.94 (s, 3 H, OCH3), 7.95 (s, 1 H, NH).
Found (%): С, 38.00; H, 4.35; N, 29.54. C9H12N6O5. Calcuꢀ
lated (%): С, 38.05; H, 4.26; N, 29.57.
2ꢀDinitromethylꢀ4ꢀmethoxyꢀ6ꢀpiperidinoꢀ1,3,5ꢀtriazine
zwitterionic salt (12c). The yield was 16%, m.p. 115—116 °С
(decomp.), Rf 0.36 (dichloroethane—methanol, 4 : 1). IR,
ν/cm–1: 3174, 3014, 2946, 2927, 2858, 1629, 1592, 1564, 1535,
1488, 1421, 1382, 1311, 1272, 1251, 1201, 1162, 1132, 1047,
1024, 993, 854, 821, 777, 736. 1Н NMR (acetoneꢀd6, δ):
1.62—1.80 (m, 6 H, CH2CH2CH2), 3.79 and 3.88 (both t, 4 H,
NCH2, J = 4.4 Hz), 3.98 (s, 3 H, OCH3), 7.96 (s, 1 H, NH).
Found (%): С, 40.36; H, 4.78; N, 28.44. C10H14N6O5. Calcuꢀ
lated (%): С, 40.27; H, 4.73; N, 28.28.
2ꢀMethoxyꢀ4ꢀpiperidinoꢀ1,3,5ꢀtriazineꢀ6ꢀnitrolic acid (10c).
The yield was 58 + 10%, m.p. 113—114 °С (decomp.), Rf 0.77
(dichloroethane—methanol, 4 : 1). IR, ν/cm–1: 3131, 3043,
3010, 2937, 2861, 2806, 1589, 1560, 1508, 1473, 1450, 1382,
1295, 1234, 1099, 1052, 1016, 993, 889, 856, 831, 808, 786, 721.
1Н NMR (DMSOꢀd6, δ): 2.04 (m, 6 H, CH2CH2CH2), 4.25 (t,
4 H, CH2NCH2), 4.37 (s, 3 H, OCH3), 14.06 (s, 1 H, NOH).
13С NMR (DMSOꢀd6, δ): 25.0 (CH2), 26.2, 26.3 (CH2), 45.1,
45.5 (CH2NCH2), 55.1 (OCH3), 151.4 (C(NO2)=NOH), 163.5
(N=C—C), 165.7 (N=C—N), 172.0 (N=C—OCH3). 14N NMR
(DMSOꢀd6, δ): –12.3 (NO2). Found (%): С, 42.66; H, 4.97;
N, 29.82. C10H14N6O4. Calculated (%): С, 42.55; H, 5.00;
N, 29.77.
2ꢀMethoxyꢀ4ꢀmorpholinoꢀ1,3,5ꢀtriazineꢀ6ꢀnitrolic acid
(10d). The yield was 64 + 11%, m.p. 110—111 °С (decomp.),
Rf 0.68 (dichloroethane—methanol, 4 : 1). IR, ν/cm–1: 3216,
3012, 2968, 2912, 2860, 2782, 2686, 1600, 1550, 1517, 1473,
1442, 1380, 1305, 1286, 1243, 1157, 1112, 1068, 1029, 998, 896,
840, 813, 800, 725. 1Н NMR (DMSOꢀd6, δ): 4.12—4.35 (m,
8 H, NCH2CH2O), 4.38 (s, 3 H, OCH3), 14.15 (s, 1 H, NOH).
13С NMR (DMSOꢀd6, δ): 44.0, 44.4 (NCH2), 54.7 (OCH3),
66.2 (OCH2), 150.7 (C(NO2)=NOH), 162.9 (N=C—C), 165.6
(N=C—N), 171.3 (N=C—OCH3). NMR 14N (DMSOꢀd6,
δ): –12.2 (NO2). Found (%): С, 38.10; H, 4.20; N, 29.51.
C9H12N6O5. Calculated (%): С, 38.03; H, 4.26; N, 29.57.
2,4ꢀBis(dimethylamino)ꢀ1,3,5ꢀtriazineꢀ6ꢀnitrolic acid (10e).
The yield was 45 + 15%, m.p. 88—89 °С (decomp.), Rf 0.66
(dichloroethane—methanol, 4 : 1). IR, ν/cm–1: 3589, 3143,
3043, 3012, 2935, 2879, 2811, 1606, 1585, 1554, 1511, 1479,
1417, 1376, 1272, 1226, 1149, 1070, 1047, 1002, 902, 863, 808,
2ꢀDinitromethylꢀ4ꢀmethoxyꢀ6ꢀmorpholinoꢀ1,3,5ꢀtriazine
zwitterionic salt (12d). The yield was 20%, m.p. 135—136 °С
(decomp.), Rf 0.32 (dichloroethane—methanol, 4 : 1). IR,
ν/cm–1: 3212, 2956, 2928, 2890, 1634, 1602, 1566, 1546, 1536,
1500, 1448, 1438, 1392, 1312, 1280, 1268, 1246, 1184, 1156,
1
727, 644. Н NMR (DMSOꢀd6, δ): 3.10 and 3.24 (both s, 6 H,
NCH3, Δν = 24 Hz), 13.10 (s, 1 H, NOH). Found (%):
С, 37.54; H, 5.22; N, 38.55. C8H13N7O3. Calculated (%):
С, 37.65; H, 5.13; N, 38.41.
1
1116, 1076, 1038, 1004, 958, 888, 856, 828, 772, 746. Н NMR
2ꢀDimethylaminoꢀ4ꢀ(pꢀnitrophenoxy)ꢀ1,3,5ꢀtriazineꢀ
6ꢀnitrolic acid (10f). The yield was 47% + 10%, m.p. 114—115 °С
(acetoneꢀd6, δ): 3.69—3.80 (m, 8 H, NCH2CH2O), 3.92 (s,
3 H, OCH3), 7.95 (s, 1 H, NH). Found (%): С, 36.07; H, 4.10;
N, 27.90. C9H12N6O6. Calculated (%): С, 36.00; H, 4.03;
N, 27.99.
2,4ꢀBis(dimethylamino)ꢀ6ꢀdinitromethylꢀ1,3,5ꢀtriazine zwitꢀ
terionic salt (12e). The yield was 25%, m.p. 124—125 °С
(decomp.), Rf 0.46 (dichloroethane—methanol, 4 : 1). IR,
ν/cm–1: 3050—2850, 1630, 1600—1555, 1520, 1480, 1455, 1380,
1330, 1295, 1200, 1135—1100, 1080, 1025, 990, 965, 930, 845.
1Н NMR (acetoneꢀd6, δ): 3.02 (s, 3 H, NCH3), 3.07 (s, 3 H,
NCH3), 3.10 (s, 3 H, NCH3), 3.15 (s, 3 H, NCH3), 8.26 (s, 1 H,
NH). Found (%): С, 35.35; H, 4.62; N, 36.23. C8H13N7O4.
Calculated (%): С, 35.42; H, 4.80; N, 36.16.
2ꢀDimethylaminoꢀ4ꢀdinitromethylꢀ6ꢀ(4ꢀnitrophenoxy)ꢀ
1,3,5ꢀtriazine zwitterionic salt (12f). The yield was 12%,
m.p. 117—118 °С (decomp.), Rf 0.38 (dichloroethane—
methanol, 4 : 1). IR, ν/cm–1: 3116, 3077, 3023, 2962, 2935,
2879, 2852, 1616, 1592, 1571, 1519, 1488, 1380, 1342, 1263,
1243, 1216, 1197, 1133, 1062, 1039, 1010, 977, 946, 914, 856,
809, 779, 755, 700. 1Н NMR (acetoneꢀd6, δ): 3.05 and 3.12
(both s, 6 H, NCH3, Δν = 14.0 Hz); 7.61 and 8.28 (both d, 4 H,
pꢀC6H4); 8.71 (br.s, 1 H, NH). Found (%): С, 39.46; H, 3.04;
N, 26.84. C12H11N7O7. Calculated (%): С, 39.34; H, 3.18;
N, 26.91.
(decomp.), Rf 0.7 (dichloroethane—methanol, 4 : 1). IR, ν/cm–1
:
3116, 3087, 2935, 2852, 1618, 1554, 1521, 1486, 1419, 1386,
1369, 1344, 1255, 1224, 1166, 1132, 1045, 983, 939, 862, 809.
1Н NMR (DMSOꢀd6, δ): 3.09 and 3.18 (both s, 6 H, NCH3,
Δν = 18 Hz); 7.62 and 8.34 (both d, 4 H, OC6H4NO2ꢀp,
J = 6 Hz); 12.70 (s, 1 H, NOH). Found (%): С, 41.34; H, 3.30;
N, 28.00. C9H12N6O5. Calculated (%): С, 41.27; H, 3.17;
N, 28.07.
2,4ꢀDimethoxyꢀ1,3,5ꢀtriazineꢀ6ꢀnitrolic acid (10g). The yield
was 60% + 20%, m.p. 130—131 °С (decomp.), Rf 0.78 (dichloroꢀ
ethane—methanol, 4 : 1). IR, ν/cm–1: 3168, 3141, 3066, 3012,
2964, 2921, 2848, 2690, 2640, 2482, 1587, 1552, 1529, 1490,
1458, 1394, 1373, 1240, 1217, 1166, 1101, 1060, 1012, 871, 823,
727, 661. 1Н NMR (DMSOꢀd6, δ): 4.10 (s, 6 Н, ОMe), 13.45
(br.s, 1 H, NOH). Found (%): С, 31.24; H, 3.97; N, 30.26.
C6H9N5O5. Calculated (%): С, 31.17; H, 3.92; N, 30.30.
2,4ꢀDi(nꢀpropoxy)ꢀ1,3,5ꢀtriazineꢀ6ꢀnitrolic acid (10i). The
yield was 52% + 16%, m.p. 73—75 °С (decomp.), Rf 0.81
(dichloroethane—methanol, 4 : 1). IR, ν/cm–1: 3485, 3203,
3081, 2987, 2966, 2943, 2883, 1579, 1556, 1542, 1496, 1434,
1384, 1355, 1303, 1230, 1149, 1109, 1053, 997, 912, 873, 823,
765, 728. 1Н NMR (DMSOꢀd6, δ): 1.05 (t, 6 H, CH3); 1.86

1970
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 9, September, 2009
Bakharev et al.
The reaction of 2ꢀR´ꢀ4ꢀR″ꢀ6ꢀdinitromethylꢀ1,3,5ꢀtriazine
Кꢀsalts with nitrogen dioxide under anhydrous conditions
(general procedure). To a suspension of potassium salts 8a—e
(0.003 mol) in toluene (or dichloroethane) (7 mL) at 15—20 °С,
a solution of N2O4 (0.24 mL, 0.0039 mol) in the same solvent
(3 mL) was poured in one portion. The precipitate of the starting
salt gradually disappeared and the precipitate of potassium
nitrate sedimented; the solution turned blueꢀgreen. The color of
the reaction mixture changed gradually from blueꢀgreen to green.
Nitrolic acid 10a—e precipitated in 30—60 min. The reaction
mixture was cooled to 0 °С, kept for 60 min, a mixture of nitrolic
acid and potassium nitrate was filtered off, and washed with a
cold solvent (2×3 mL). The product was dried in air, then washed
with water (10—15 mL) to remove potassium nitrate. The yields
of 10a, 10b, 10c, 10d, 10e were 56%, 53%, 59%, 67% and 49%
respectivelly.
Filtrates were kept for 24 h at 20—25 °С and the solvent
was distilled under reduced pressure. Furoxans 11a—e were
isolated from the residue by silica gel chromatography in
dichloroethane—methanol (4 : 1).
3,4ꢀBis(4ꢀdimethylaminoꢀ6ꢀmethoxyꢀ1,3,5ꢀtriazinꢀ2ꢀyl)ꢀ
furoxan (11a). The yield was 32%, m.p. 140—142 °С (decomp.),
Rf 0.84 (dichloroethane—methanol, 4 : 1). IR, ν/cm–1: 3031,
2964, 2921, 2856, 1627, 1569, 1548, 1481, 1367, 1311, 1230,
1116, 1018, 1004, 931, 819, 779. 1Н NMR (acetoneꢀd6, δ): 3.08
and 3.16 (both s, 6 H, NCH3, Δν = 24 Hz), 3.92 (s, 3 H, OCH3).
Found (%): С, 43.12; H, 4.59; N, 35.86. C14H18N10O4. Calcuꢀ
lated (%): С, 43.08; H, 4.65; N, 35.72.
3,4ꢀBis[4,6ꢀbis(dimethylamino)ꢀ1,3,5ꢀtriazinꢀ2ꢀyl)furoxan
(11e). The yield was 38%, m.p. 210—212 °С, Rf 0.77 (dichloroꢀ
ethane—methanol, 4 : 1). IR, ν/cm–1: 2935, 2871, 1618, 1569,
1523, 1502, 1398, 1330, 1299, 1201, 1049, 979, 970, 846, 813,
746. 1Н NMR (DMSOꢀd6, δ): 3.06 (s, 12 H, NCH3), 3.15 (s, 12 H,
NCH3). Found (%): С, 46.02; H, 5.97; N, 40.44. C16H24N12O2.
Calculated (%): С, 46.15; H, 5.81; N, 40.36.
Synthesis of furoxans 11a—e,g,h from nitrolic acids
10a—d,e—i (general procedure). Nitrolic acid 10a—d,e—i
(0.03 mol) was heated in toluene (20 ml) at 90—110 °С. The
evolution of brown nitrogen oxides was observed beginning from
90 °С. The end of the reaction was monitored by disappearance
of the starting compounds (TLC, dichloroethane—methanol,
4 : 1). The resulting solution was cooled to room temperature
and passed through a small silica gel layer (1—2 cm). The solꢀ
vent was removed under residue pressure. The residue was treated
with water, the insoluble crystalline product was filtered off and
dried in air. The yields of 11a, 11b, 11c, 11d, 11e were 89%,
92%, 82%, 86% and 84% respectivelly.
3,4ꢀBis(4,6ꢀdimethoxyꢀ1,3,5ꢀtriazinꢀ2ꢀyl)furoxan (11g). The
yield was 86%, m.p. 148—150 °С. IR, ν/cm–1: 3022, 2960, 2919,
2885, 2852, 1629, 1591, 1548, 1481, 1367, 1311, 1230, 1201,
1105, 1018, 1004, 931, 819, 779, 759. 1Н NMR (DMSOꢀd6, δ):
3.84 (s, 6 H, OCH3), 3.92 (s, 6 H, OCH3). 13С NMR (DMSOꢀd6,
δ): 55.97, 56.15 (OCH3), 111.81 (C=N+—O–), 153.35 (C=N—O),
164.42, 166.09 (N—C—C=NO), 172.43, 172.63 (C—OCH3).
Found (%): С, 39.67; H, 3.41; N, 30.88. C12H12N8O6. Calcuꢀ
lated (%): С, 39.57; H, 3.32; N, 30.76.
3,4ꢀBis(4ꢀmethoxyꢀ6ꢀpyrrolidinoꢀ1,3,5ꢀtriazinꢀ2ꢀyl)furoxan
(11b). The yield was 30%, m.p. 132—134 °С (decomp.), Rf 0.82
(dichloroethane—methanol, 4 : 1). IR, ν/cm–1: 2971, 2956,
2877, 1623, 1587, 1569, 1533, 1504, 1457, 1371, 1342, 1315,
1238, 1222, 1012, 998, 968, 912, 858, 817, 767. 1Н NMR
(acetoneꢀd6, δ): 1.94 (m, 8 H, CH2CH2), 3.38 and 3.52 (t, d,
8 H, CH2NCH2), 3.88 (s, 3 H, OCH3), 3.92 (s, 3 H, OCH3).
Found (%): С, 48.95; H, 5.10; N, 31.73. C18H22N10O4. Calcuꢀ
lated (%): С, 48.80; H, 5.01; N, 31.66.
3,4ꢀBis(4ꢀmethoxyꢀ6ꢀpiperidinoꢀ1,3,5ꢀtriazinꢀ2ꢀyl)furoxan
(11c). The yield was 20%, m.p. 139—141 °С (decomp.), Rf 0.83
(dichloroethane—methanol, 4 : 1). IR, ν/cm–1: 3010, 2939,
2858, 1623, 1577, 1535, 1508, 1467, 1448, 1375, 1324, 1294,
1222,1091, 1062, 1020, 985, 898, 854, 819, 748. 1Н NMR
(DMSOꢀd6, δ): 1.36—1.69 (m, 12 H, CH2), 3.54 and 3.73
(both m, 8 H, NCH2), 3.92 (s, 6 H, OCH3). 13С NMR (DMSOꢀd6,
δ): 23.83, 25.29 (СН2—СН2—СН2), 44.19 (СH2—N), 54.54,
54.59 (OCH3), 112.00 (C=N+—O–), 154.07 (C=N—O), 162.55,
163.91 (N—C—C=NO), 164.15 (C—NCH2), 170.65 (C—OCH3).
Found (%): С, 51.19; H, 5.61; N, 29.65. C20H26N10O4. Calcuꢀ
lated (%): С, 51.06; H, 5.57; N, 29.77.
3,4ꢀBis(4ꢀmethoxyꢀ6ꢀmorpholinoꢀ1,3,5ꢀtriazinꢀ2ꢀyl)furoxan
(11d). The yield was 24%, m.p. 180—182 °С (decomp.), Rf 0.86
(dichloroethane—methanol, 4 : 1). IR, ν/cm–1: 2968, 2925,
2869, 1631, 1577, 1565, 1529, 1486, 1467, 1444, 1371, 1301,
1284, 1230, 1114, 1068, 1025, 999, 989, 852, 813, 756, 636, 540.
1Н NMR (DMSOꢀd6, δ): 3.6—3.8 (m, 16 H, NCH2CH2O),
3.96 (s, 6 H, OCH3). NMR 13С (DMSOꢀd6, δ): 43.85 (СH2—N),
54.59 (OCH3), 65.72 (СH2—O), 111.73 (C=N+—O–), 153.85
(C=N—O), 162.72, 164.16 (N—C—C=NO), 165.05, 165.15
(C—NCH2), 170.79, 170.91 (C—OCH3). Found (%): С, 45.50;
H, 4.72; N, 29.37. C18H22N10O6. Calculated (%): С, 45.57;
H, 4.67; N, 29.52.
3,4ꢀBis(4,6ꢀdiꢀnꢀpropoxyꢀ1,3,5ꢀtriazinꢀ2ꢀyl)furoxan (11i).
The yield was 85%, pale yellow viscous liquid. IR, ν/cm–1
:
2969, 2939, 2879, 1629, 1554, 1484, 1454, 1419, 1355, 1330,
1301, 1218, 1122, 1056, 987, 931, 827, 790, 755. 1Н NMR
(DMSOꢀd6, δ): 1.00 (m, 16 H, CH3); 1.78 (m, 8 H, CH2); 4.25
(t, 4 H, OCH2, J = 6.7 Hz), 4.34 (t, 4 H, OCH2, J = 6.7 Hz).
Found (%): С, 50.35; H, 6.03; N, 23.46. C20H28N8O6. Calcuꢀ
lated (%): С, 50.41; H, 5.92; N, 23.52.
2ꢀMethoxyꢀ4ꢀpyrrolidinylꢀ1,3,5ꢀtriazineꢀ6ꢀcarboxylic acid.
Sodium nitrite (0.21 g, 0.003 mol) was added with stirring
at 20—25 °С to a solution of nitrolic acid 7b (0.536 g, 0.002 mol)
in DMF (5 mL). The reaction mixture was kept at 20—25 °С
until the starting compound disappeared (TLC, 1—1.5 h),
DMF was evaporated with a flow of air, and the residue was
suspended in water (20 mL). Sodium hydroxide (0.12 g)
was added and stirred for 1 h. The filtered solution was acidified
with 10% HCl to рН 1—2. Water was evaporated with a flow
of air, the residue was extracted with methanol (3×5 mL). The
combined methanolic extracts were concentrated under reduced
pressure, the residue was washed with cold acetone (3 mL) dried
in air. The colorless amorphous compound (0.2 g, 45%) was
obtained, m.p. 125—126 °С (decomp.). IR, ν/cm–1: 2973, 2933,
2890, 1726, 1600, 1556, 1511, 1459, 1375, 1342, 1241, 1058, 1014,
972, 914, 867, 811, 792. 1Н NMR (DMSOꢀd6, δ): 2.06 (m, 4 H,
CH2); 3.65 (m, 4 H, NCH2), 3.96 (s, 3 H, OCH3), 4.30 (br.s,
H3O+). Found (%): С, 48.14; H, 5.31; N, 25.10. C9H12N4O3.
Calculated (%): С, 48.21; H, 5.39; N, 24.99.
The work was partially financially supported by
the Russian Foundation for Basic Research (Project Nos
05ꢀ04ꢀ48577 and 07ꢀ03ꢀ00403) and the Russian
Academy of Sciences (Program of the Presidium of RAS
“Basic Research”).

1,3,5ꢀTriazinenitrolic acids
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Received October 20, 2008;
in revised form Februare 24, 2009