A simple and convenient method for the synthesis of 1,3,5-triazine-nitrolic acids. the first X-ray investigation of Z-isomeric nitrolic acid

Article abstract of DOI:10.1515/hc-2015-0218

A simple and convenient method for the preparation of 2,4-disubstituted 1,3,5-triazine-nitrolic acids has been developed. The first example of nitrolic acid with Z-configuration was revealed by X-ray crystallographic analysis.

Full text of DOI:10.1515/hc-2015-0218

Heterocycl. Commun. 2016; aop
Vladimir V. Bakharev, Victor E. Parfenov*, Alexander A. Gidaspov, Eugenia V. Selezneva,
Marat R. Baymuratov, Boris B. Averkiev and Aleksei B. Sheremetev
A simple and convenient method for the synthesis
of 1,3,5-triazine-nitrolic acids. The first X-ray
investigation of Z-isomeric nitrolic acid
DOI 10.1515/hc-2015-0218
differ NO-releasing moieties [6]. Some time ago we
described the synthesis and NO-releasing properties of
1,3,5-triazine-nitrolic acids [7]. The synthesis, however,
was inefficient and we sought to develop an improved
protocol in order to obtain more material for biological
studies. In the previously reported approach [7], construc-
tion of the nitrolic acid moiety gave mixture of products
that required laborious silica gel chromatography to
Received September 30, 2015; accepted December 20, 2015
Abstract: A simple and convenient method for the prepa-
ration of 2,4-disubstituted 1,3,5-triazine-nitrolic acids has
been developed. The first example of nitrolic acid with
Z-configuration was revealed by X-ray crystallographic
analysis.
Keywords: 2,4-disubstituted 1,3,5-triazin-nitrolic acids; obtain the desired product. Large scale synthesis using
nitrosation; NO-donors; potassium 1,3,5-triazine dini- this technique was therefore problematic. The crystalline
tromethanide; Z-configuration of nitrolic acid.
structures of the 1,3,5-triazinenitrolic acids have not so far
been determined. However, in order to understand the
chemical biology of 1,3,5-triazinenitrolic acids, a better
knowledge of their structural features is needed.
This report describes the optimization of 1,3,5-tria-
zine-nitrolic acids synthesis and the results of single-crys-
tal X-ray diffraction studies.
Introduction
Due to its integral role in human physiology, deficiencies
in nitric oxide (NO) biosynthesis have been linked to a
number of disease states [1–3]. A wide range of NO-releas-
ing compounds, such as organic nitrates, nitrites, oximes,
nitrosamines, N-diazeniumdiolates, S-nitrosothiols, and Results and discussion
furoxans, has emerged as potential therapeutic agents [1].
Although the nitrolic acids, R-C(ꢀ=ꢀNOH)NO2, has been In our previous work [7], 1,3,5-triazine-nitrolic acids 2
known since a 1873 report from Meyer [4], NO-releasing were obtained in ca. 65% yields using column chromatog-
molecules of this type are rare [1]. The first example of raphy. The synthesis was based on a nitrosation reaction
these is a 2005 report from Oresmaa and co-workers [5], of potassium 1,3,5-triazine-dinitromethanide 1 and prod-
who demonstrated that 1-R-imidazole nitrolic acids are ucts 2 were accompanied by zwitter-ionic dinitromethyl
potential NO donors. Efforts of our research group have derivatives 3 and furoxans 4 as byproducts (Scheme 1).
focused on the development of 1,3,5-triazines bearing
In this work, our initial investigations focused on the
reaction of potassium 2-dimethylamino-4-methoxy-1,3,5-
triazin-6-yl-dinitromethanide with N2O4 in an organic
solvent to generate 2-dimethylamino-4-methoxy-1,3,5-
triazin-6-yl-nitrolic acid. Optimization of the reaction
stoichiometry (1:N2O4 from 1:0.8 to 1:5), solvent (CH2Cl2,
CHCl3, CCl4, DCE, hexane, benzene, toluene, chloroben-
zene, xylene, and their mixtures), temperature (from -5°C
to +30°C) and reagent concentration (from 0.01 mmol/mL
to 1 mmol/mL) highlighted that this process could be
significantly improved, providing a convenient means
for the preparation of 1,3,5-triazin-nitrolic acids in high
yield. After extensive screening, it was determined that
*Corresponding author: Victor E. Parfenov, Samara State
Thechnical University, Samara 443100, Russian Federation,
e-mail: parfenovve@gmail.com.
http://orcid.org/0000-0002-0079-5670
Vladimir V. Bakharev, Alexander A. Gidaspov, Eugenia V. Selezneva
and Marat R. Baymuratov: Samara State Thechnical University,
Samara 443100, Russian Federation
Boris B. Averkiev: A.N. Nesmeyanov Institute of Organoelement
Compounds, Russian Academy of Sciences, Moscow 119991,
Russian Federation
Aleksei B. Sheremetev: N.D. Zelinsky Institute of Organic Chemistry,
Russian Academy of Sciences, Moscow 119991, Russian Federation
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8ꢀ
ꢀV.V. Bakharev et al.: Synthesis of 1,3,5-triazine-nitrolic acids
R1
R1
R1
R1
N
R1
N2O4 + H2O
N
N
N
N
N
N
N
N
N
N
H
R2
NOH
NO2
toluene
or DCE
R2
N
C(NO2)2
K
R2
N
R2
N
C(NO2)2
N
R2
N
N
O
O
1
2
3
4
Scheme 1ꢀ
potassium salts 1 (concentration of 0.5 mmol/mL) undergo
a reaction with 1.2 equiv of N2O4 in hexane/toluene (1/10)
in the presence of 1.8 equiv of H2O at 8–10°C for 30 min
to afford the desired nitrolic acids 2 in 78–93% isolated
yields. The yields reflect the amount of products that
precipitated directly from the reaction mixture as a fine
powder. This modification resulted in a decrease in the
yields of furoxanes and zwitter-ionic salts, and the desired
products 2 were obtained in high purity. Moreover, the
method allowed us to increase significantly the range of
substituents R1 and R2 at the 1,3,5-triazine ring and synthe-
size some new nitrolic acids, which could not earlier be
separated in pure form (Table 1).
Three nitrolic acids and four their salts [5, 8–12] have
been previously studied by X-ray crystallographic analysis
and showed to have E-configuration of the hydroxyimino
group in all cases.
X-ray crystallographic analysis of compound 2d
(Figure 1) surprisingly showed a Z-configuration of the
hydroxyimino group rather than an E-form as would be
expected from the literature data. An asymmetric unit cell
contains one molecule of compound 2d. Triazine ring is
planar and the methoxy group is located in the plane of
Figure 1ꢀGeneral view of the structure of compound 2d, as derived
from the X-ray diffraction analysis, with the atom numbering scheme.
Displacement ellipsoids are drawn at the 50% probability level.
the ring. The morpholine fragment adopts a chair confor-
mation. The hydroxyimino group of the nitrolic moiety
is coplanar with the triazine ring while the nitro group
appears to be nearly perpendicular to it: the C3-C4-N4-
O2 torsion angle is 81.6(2)°. No intramolecular hydrogen
bonds are observed. On the other hand, highly directed
intermolecular O1-H1…N3 hydrogen bond (O-N 2.751(3) Å,
H…N 1.90 Å, ꢀ<ꢀNHO 177°) is formed between molecules
related by the screw axis. Also, the O1…O4 close contact
(2.744(3) Å) is observed that results in formation of layers
parallel to the bc crystallographic plane.
Table 1ꢀYields of 1,3,5-triazin-nitrolic acids 2a–n.
Producta,b
ꢁ
R1
ꢁ
R2
ꢁ
ꢁ
Yield (%)c
Reported [7]ꢁ Modified
2a
2b
2c
2d
2e
2f
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
OMe
OMe
OMe
OMe
NMe2
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
NMe2
N(CH2)4
N(CH2)5
N(CH2CH2)2Oꢂ
NMe2
ꢂ
ꢂ
ꢂ
72ꢂ
55ꢂ
68ꢂ
75ꢂ
60ꢂ
57ꢂ
80ꢂ
68ꢂ
–ꢂ
92
84
85
91
78
81
93
82
84
79
80
92
84
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
OC6H4NO2-p ꢂ NMe2
2g
2i
OMe
OPr
ꢂ
ꢂ
OMe
OPr
2j
2k
2l
2m
2n
OC6H4NO2-p ꢂ N(CH2)5
Conclusion
OC6H4Br-p
OCy
OMe
ꢂ
ꢂ
ꢂ
N(CH2)5
OCy
N(CH2)6
–ꢂ
–ꢂ
A simple and short protocol for a rapid assembly of
1,3,5-triazine-nitrolic acids is described. The products
were isolated in good yields and with satisfactory purity
after a simple filtration and washing after short reaction
times. This approach is an improvement of the previously
–ꢂ
OC6H4NO2-mꢂ NEt2
–ꢂ
aThe identity of products 2a–i was confirmed by spectral comparison
with authentic samples [7]. bProducts 3 and 4 are minor impurities,
see [7] for isolation and characterization. cIsolated yields.
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V.V. Bakharev et al.: Synthesis of 1,3,5-triazine-nitrolic acidsꢃ ꢃ9
1118, 1049, 1006, 983, 929, 862, 852, 806, 786 cm-1; 1H NMR: δ 12.72 (s,
1H), 8.39–8.31 (m, 2H), 7.65–7.53 (m, 2H), 3.86–3.72 (m, 2H), 3.72–3.58
(m, 2H), 1.68 (ddd, 2H, J ꢀ=ꢀ 11.0, 5.8, 3.5 Hz), 1.57 (dtd, 4H, J ꢀ=ꢀ 16.9, 5.6,
2.8 Hz); 13C NMR: δ 171.2, 165.6, 163.8, 157.8, 151.6, 146.1, 125.9, 123.6,
45.7, 45.3, 26.2, 26.1, 24.8. Anal. Calcd for C15H15N7O6: C, 46.28; H, 3.88;
N, 25.18. Found: C, 46.19; H, 3.78; N, 25.08.
described method as it does not require column chro-
matography, can be performed on a large scale, and
allows facile isolation of the product as a stable and
easily handled solid. The procedure may prove useful for
the synthesis of a wide variety of new analogs. The first
example of a nitrolic acid moiety of Z-configuration is also
reported.
2-(Piperidin-1-yl)-4-(4-bromophenoxy)-1,3,5-triazin-6-yl-nitrolic
acid (2k)ꢁMp 107–108°C (dec); IR: 2945, 2927, 2860, 1737, 1595, 1550,
1498, 1481, 1450, 1390, 1373, 1296, 1255, 1238, 1203, 1164, 1120, 1053,
1012, 975, 925, 852, 808 cm-1; 1H NMR: δ 7.65–7.56 (m, 2H), 7.28–7.19 (m,
2H), 3.81–3.73 (m, 2H), 3.68–3.59 (m, 2H), 1.67 (qt, 2H, J ꢀ=ꢀ 7.8, 3,1 Hz),
1.56 (dtd, 4H, J ꢀ=ꢀ 16.9, 5.6, 2.8 Hz); 13C NMR: δ 171.5, 165.6, 163.8, 152.2,
151.6, 133.1, 124.7, 118.8, 45.5, 45.1, 26.2, 26.1, 24.9. Anal. Calcd for
C15H17N6O4Br: C, 42.43; H, 4.11; N, 19.85. Found: C, 42.37; H, 4.13; N,
1 9.9 7.
Experimental
All solvents and chemicals were reagent grade and used without fur-
ther purification. Melting points were determined on a Gallenkamp
melting point apparatus and are uncorrected. FT-IR spectra were
1
recorded on an Avatar 360 ESP spectrometer using KBr pellets. H
2,4-Bis(cyclohexyloxy)-1,3,5-triazin-6-yl-nitrolic acid (2l)ꢁMp
158–161°C (dec); IR: 2937, 2860, 1569, 1558, 1539, 1488, 1421, 1363, 1342,
1311, 1263, 1228, 1157, 1120, 1064, 1035, 1010, 995, 966, 891, 850, 821,
731 cm-1; 1H NMR: δ 12.99 (s, 1H), 5.08 (tt, 2H J ꢀ=ꢀ 9.1, 3.9 Hz), 2.01 (d, 2H
J ꢀ=ꢀ 4.1 Hz), 1,79 (dt, 4H, J ꢀ=ꢀ 12.9, 4.1 Hz), 1.58 (dtd, 7H, J ꢀ=ꢀ 12.6, 9.6, 9.1,
3.5), 1.49–1.26 (m, 7H); 13C NMR: δ 172.7, 165.2, 151.3, 77.9, 31.9, 25.96,
24.27. Anal. Calcd for C16H25N5O5: C, 51.38; H, 6.93; N, 19.13. Found: C,
51.38; H, 6.93; N, 19.06.
NMR (400 MHz) and 13C NMR (100 MHz) spectra were recorded on a
JEOL JNM ECX-400 spectrometer in acetone-d6 as a solvent. Elemental
analyses were performed on a Eurovector EA 3000 microanalyzer.
X-ray diffraction analysis
Single crystals of compound 2d, suitable for X-ray analysis, were
grown by slow cooling of an acetonitrile solution. Reflections for
compound 2d were collected on a SMART APEX2 difractometer
[λ(Mo-Kα)] ꢀ=ꢀ 0.71073 Å, graphite monochromator, ω-scans) at 100 K.
Collected data were analyzed by the SAINT and SADABS programs
incorporated into the APEX2 program package [13]. The structure
was solved by the direct methods and refined by the full-matrix
least-squares procedure against F2 in anisotropic approximation. All
hydrogen atoms were placed in geometrically calculated positions
and refined within a riding model. The refinement was carried out
with the SHELXTL program [14].
Compound 2d (C9H12N6O5): monoclinic, space group P21/c:
a ꢀ=ꢀ 17.353(3)Å, b ꢀ=ꢀ 5.9450(10)Å, c ꢀ=ꢀ 12.761(2)Å, β ꢀ=ꢀ 110.882(3)°, V ꢀ=ꢀ
1230.0(4)Å3, Z ꢀ=ꢀ 4, M ꢀ=ꢀ 284.25, dcalcꢀ=ꢀ 1.535 g·cm-3, μ ꢀ=ꢀ 0.127 mm-1,
F(000) ꢀ=ꢀ 592, wR2 ꢀ=ꢀ 0.1229, GOF ꢀ=ꢀ 1.008 for 2636 independent reflec-
tions with 2θꢀ<ꢀ54°, R1ꢀ=ꢀ 0.0513 for 1749 reflections with Iꢀ>ꢀ2σ(I).
CCDC 1062721 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge via
www.ccdc.cam.ac.uk/data_request/cif.
2-(Azepan-1-yl)-4-methoxy-1,3,5-triazin-6-yl-nitrolic acid (2m)ꢁ
Mp 86°C (dec); IR: 2919, 2848, 1581, 1546, 1519, 1475, 1438, 1373, 1288,
1255, 1151, 1058, 1018, 995, 842, 813 cm-1; 1H NMR: δ 12.66 (s, 1H), 3.94
(s, 3H), 3.84–3.76 (m, 2H), 3.76–3.68 (m, 2H), 1.80 (dt, 2H, J ꢀ=ꢀ 11.8,
6.5 Hz), 1.73 (dt, 2H, J ꢀ=ꢀ 9.8, 5.8 Hz), 1.55 (tt, 4H, J ꢀ=ꢀ 5.4, 3.1 Hz); 13C
NMR: δ 171.8, 166.2, 163.1, 151.9, 55.0, 47.9, 47.8, 27.9, 27.7. Anal. Calcd
for C11H16N6O4: C, 44.59; H, 5.44; N, 28,36. Found: C, 44.49; H, 5.56; N,
28.28.
2-Diethylamino-4-(2-nitrophenoxy)-1,3,5-triazin-6-yl-nitrolic
acid (2n)ꢁMp 104°C (dec); IR: 3145, 3066, 2977, 2935, 2898, 2873,
2835, 2813, 1587, 1558, 1548, 1506, 1446, 1388, 1365, 1323, 1265, 1222,
1
1134, 1087, 1051, 975, 918, 860, 831 cm-1; H NMR: δ 12.76 (s, 1H), 8.20
(d, 1H, J ꢀ=ꢀ 7.3 Hz), 7.88 (t, 1H, J ꢀ=ꢀ 7.2 Hz), 7.69–7.48 (m, 2H), 3.57 (q, 2H,
J ꢀ=ꢀ 7.0 Hz), 3.40 (q, 2H, J ꢀ=ꢀ 7.0 Hz), 1.12 (t, 3H, J ꢀ=ꢀ 7.0 Hz), 0.99 (t, 3H,
J ꢀ=ꢀ 7.0 Hz); 13C NMR: δ 171.1, 165.6, 163.6, 151.6, 145.8, 143.1, 136.1, 127.9,
126.3, 126.1, 43.3, 42.9, 12.9, 12.5. Anal. Calcd for C14H15N7O6: C, 44.57;
H, 4.01; N, 25.99. Found: C, 44.44, H; 4.05; N, 25.97.
Acknowledgments: This research was supported by the
Ministry of Education and Science of Russia within the
scope of the Project Section of the State task for Samara
State Technical University (project No. 4.813.2014/K).
General procedure for 2
A solution of N2O4 (12 mmol, 1.1 g) in hexane (2 mL) was added drop-
wise to a suspension of potassium salt 1 (10 mmol) in a mixture of
toluene (20 mL) and water (18 mmol, 0.32 mL) at room temperature.
The resulting mixture was stirred for 30 min at 8–10°C, and the white
solid formed (a mixture of the product 2 with KNO3) was filtered off
and washed with water (10 mL) and finally toluene (20 mL) to give
desired product 2. The yields are presented in Table 1.
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