Reactions of 3-nitro-1,2,4-triazole derivatives with alkylating agents. 2.* Alkylation of a neutral heterocycle by dimethyl sulfate

Article abstract of DOI:10.1007/s10593-005-0266-5

The reaction of 3-nitro-1,2,4-triazole and 5-methyl-3-nitro-1,2,4-triazole with dimethyl sulfate leads to mixtures of N-mono- and N,N- dimethylnitrotriazolium compounds and products of the subsequent conversion of the latter, namely, N,N-dimethyl-1,2,4-triazol-5-ones.

Full text of DOI:10.1007/s10593-005-0266-5

Chemistry of Heterocyclic Compounds, Vol. 41, No. 8, 2005
REACTIONS OF 3-NITRO-1,2,4-TRIAZOLE
DERIVATIVES WITH ALKYLATING AGENTS.
2.* ALKYLATION OF A NEUTRAL
HETEROCYCLE BY DIMETHYL SULFATE
G. T. Sukhanov1, G. V. Sakovich1, A. G. Sukhanova2, and A. Yu. Lukin2
The reaction of 3-nitro-1,2,4-triazole and 5-methyl-3-nitro-1,2,4-triazole with dimethyl sulfate leads to
mixtures of N-mono- and N,N-dimethylnitrotriazolium compounds and products of the subsequent
conversion of the latter, namely, N,N-dimethyl-1,2,4-triazol-5-ones.
Keywords: N-alkyl-3-nitro-1,2,4-triazole, N,N-dimethyl-1,2,4-triazol-5-one, alkylation, regioselectivity.
The presence of nitrogen atom of pyrrole and pyridine type in 3-nitro-1,2,4-triazoles permits two
methods for the alkylation of these compounds in neutral and alkaline media. The strong nucleophilicity of the
nitrogen atoms in the triazolate anion in the alkylation of the azoles in alkaline media permits us to carry out the
reaction under extremely mild conditions, minimizing the formation of by-products of the hydrolysis of the alkyl
halides and dialkyl sulfates, olefinization of alkyl halides, the formation of quaternary salts etc. [1-3]. The
alkylation of the neutral heterocycle gives rise to the possibility of several side reactions. This method is rarely
used and has not been studied extensively. On the other hand, an examination of this method of alkylation of
3-nitro-1,2,4-triazoles holds interest relative to the preparation of isomeric N-monoalkyl derivatives and the
products of their quaternization, namely, N,N-dialkyl-3-nitro-1,2,4-triazolium salts.
The alkylation of 3-nitro-1,2,4-triazole by dialkyl sulfates and alkyl halides in the presence of alkali has
been described in our previous work [1]. This reaction proceeds with low selectivity. The yield of the mixture of
N(1)- and N(2)-isomers is 75-89%. The mass fraction of the N(2)-isomer in the mixture is 14.6-33.8%.
In a continuation of a study of the alkylation of nitrotriazoles, we have found that 3-nitro-1,2,4-triazoles
react vigorously with dimethyl sulfate (DMS) upon heating to give mixtures of N-monoalkyl- and
N,N-dialkylnitrotriazole derivatives as well as the products of the subsequent transformations.
In this study, we examined 3-nitro-1,2,4-triazole (1) and 5-methyl-3-nitro-1,2,4-triazole (2). The reaction
was carried out in the medium of the alkylating agent at temperatures not exceeding 80°C.
A special feature of the alkylation of 3-nitro-1,2,4-triazoles through the neutral molecule lies in the
failure of the substituent to add at the site of the N–H proton but rather at the free azo group, i.e., formation of
the N-derivative of less stable tautomer (the ratio of the 1-H and 4-H tautomers of 3-nitro-1,2,4-triazole is about
_______
* For Communication 1, see [1].
__________________________________________________________________________________________
1 Institute of Problems of Chemical Energetic Technologies, Siberian Branch of the Russian Academy of
2
Sciences, 659322 Biisk, Russia; e-mail: admin@ipcet.ru. Federal Research and Production Center "Altai",
659322 Biisk, Russia; e-mail: post@frpc.secna.ru, lukin@mail.biysk.ru. Translated from Khimiya
Geterotsiklicheskikh Soedinenii, No. 8, pp. 1168-1173, August, 2005. Original article submitted August 1, 2003.
994
0009-3122/05/4108-0994©2005 Springer Science+Business Media, Inc.

180:1) [4]. The reaction of triazole 1 with DMS gave 1-methyl-3-nitro-1,2,4 triazole (3a), 1-methyl-5-nitro-
1,2,4-triazole (4a), 4-methyl-3-nitro-1,2,4-triazole (5a), and the 1,4-dimethyl-3-nitro-1,2,4-triazolium
methylsulfate (6a), which was isolated from the reaction mixture as 1,4-dimethyl-3-nitro-1,2,4-triazolium
perchlorate (7a) and 1,4-dimethyl-1,2,4-triazol-5-one (8a). We should note that 1,4-dimethyl-5-nitro-1,2,4-
triazolium salt (9a), which is the precursor of triazolone 8a, was not found in the reaction mixture.
O2N
O2N
Me
O2N
Me
R
O
N
N
N
N
N
N
N
N
Me
R
R
Me
R
N
N
N
N
Me
5a,b
4a,b
8a,b
3a,b
Me
O2N
O2N
Me
Me
O2N
N
N
+
N
N
+
–
–
–
+
MeSO4
R
ClO4
MeSO4
R
N
N
R
Me
N
N
N
Me
6a,b
Me
9a,b
7a,b
3–9 a R = H, b R = Me
The reaction of triazole 2 with DMS gave 1,5-dimethyl-3-nitro-1,2,4-triazole (3b), 1,3-dimethyl-5-nitro-
1,2,4-triazole (4b), 4,5-dimethyl-3-nitro-1,2,4-triazole (5b), and 1,4,5-trimethyl-3-nitro-1,2,4-triazolium
methylsulfate (6b), which, as in the case of salt 6a, was isolated as 1,4,5-trimethyl-3-nitro-1,2,4-triazolium
perchlorate (7b). In this case, we did not detect 1,3,4-trimethyl-5-nitro-1,2,4-triazolium methylsulfate (9b),
which is the precursor of triazolone 8b.
On the basis of the signals of the protons at C(5) in the 1H NMR spectra, triazole 5a was identified as the
4H-isomer. Thus, the chemical shift of the proton at C(5) in 4-methyltriazole 5a at 8.82 ppm is downfield relative
to the ring protons in 1-methyltriazole 3a at 8.75 ppm and in 2-methyltriazole 4a at 8.15 ppm [1], while the
singlet for the N–CH3 group protons in triazole 5a at 3.93 ppm is upfield relative to the signal of the analogous
protons in 1-methyltriazole 3a at 4.03 ppm and in 2-methyltriazole 4a at 4.18 ppm [1]. A similar regularity in the
1H NMR spectra of triazoles 3b-5b permit us to identify triazole 5b as the 4-isomer. The agreement of the
physical constants, in particular, the melting points, of triazoles 5a,b with the values given in earlier work [2, 5,
1
6] and comparative analysis of the H NMR, IR, and UV spectra of these compounds and their analogs, 3a,b,
4a,b [1, 4, 8] also support these assignments.
Triazoles 7a,b were identified as 1,4-dimethyl- and 1,4,5-trimethyl-3-nitro-1,2,4-triazolium salts using
1
13
their H NMR, C NMR, and IR spectra. The IR spectra of triazolium salts 7a and 7b retain the nitro group
bands characteristic for nitrotriazoles [7], namely, symmetrical antiphased vibrations at 1565 and 1587 cm-1 and
synphased vibrations at 1340 and 1335 cm-1. Intense bands are found for the perchlorate anion at 1085 and
1100 cm-1. The 1H NMR spectra of quaternary salt 7a show a pair of singlets of equal intensity for the protons of
13
the two methyl groups at 4.16 and 4.21 ppm and a signal for the ring C–H proton at 10.31 ppm. The C NMR
spectra of this compound feature methyl group carbon singlets at 37.09 and 40.22 ppm as well as signals for the
1
C–H ring carbon at 147.17 ppm and the carbon attached to the nitro group at 150.99 ppm. The H NMR
spectrum of triazolium salt 7b has three singlets of equal intensity (two singlets at 4.05 ppm and 4.15 ppm for
the methyl group protons at N(4) and N(1)) and singlet for the methyl group protons at C(5) at 2.89 ppm.
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In examining the isomeric composition of the N-monoalkylation products, we should first note the
virtual absence of the N(1)-isomer (0.2-0.3%), low content of the N(2)-isomer (6-8%),and rather high content of
the N(4)-isomer (46-65%). As a rule, the N(1)- and N(2)-isomers predominate in the alkylation of 3-nitro-1,2,4-
triazoles [1-4], while the N(4)-alkylated compounds are formed in only slight amounts (3%) when the
dimethylacetal of DMF is used [6] and are not formed at all when nonselective alkylating agents such as
diazomethane are used [2]. Hence, in our case, the 3-nitro-5-R-1,2,4-triazolate anion does not undergo alkylation
but rather the N–H form of triazole 1 and 2.
A special feature of the alkylation of the neutral heterocycle is that the reaction likely proceeds through
formation of intermediate salts 10a,b and the formation of the N(4)-isomers may be represented in the following
scheme. The electrophilic agent attacks triazoles 1 and 2 at the unshared electron pair of N(4), which is available
for coordination, or at the π-bond of this atom with subsequent localization of the substituent at N(4) and
formation of compounds protonated at N(1), namely, 1-H-4-methyl- or 1-H-4,5-dimethyl-3-nitro-1,2,4-triazolium
salts 10a,b. This proposal is in good accord with the result of the reaction of nitrotriazoles with the simplest
electrophile, the proton [4]. The nitrotriazolium salts formed 10a,b are unstable, lose a proton upon dilution of
the reaction mixture by water, and are converted to the corresponding N(4)-substituted triazoles 5a,b.
.
.
O2N
O2N
H
K1
K2
N
N
Me2SO4
N
N
.
.
R
.
.
R
N
N
H
.
.
1, 2
Me
R
Me
R
O2N
O2N
N
N
–
– MeHSO4
+
MeSO4
N
N
N
N
H
5a,b
10a,b
a R = H, b R = Me, when R = H K1: K2 = 180 : 1 [4]
The formation of the N(2)-isomer is unexpected in this reaction. Since the predominant tautomer for
3-nitro-1,2,4-triazole derivatives is the 1-H isomer [4], we would have predicted a low probability for alkylation
of triazoles 1 and 2 at N(2) due to the reduced nucleophilicity of this atom relative to N(4) related to the presence
of a "pyrrolic" nitrogen atom adjacent to N(2). Nevertheless, rather significant amounts of the N(2)-isomer (up to
8%) are detected in the products of the reaction of DMS with triazoles 1 and 2.
In the absence of moisture, 1,4-dimethyl salts 9a and 9b are rather stable. Dissociation–recombination is
a possible pathway for formation of the N(2)-isomer.
Me
Me
O2N
O2N
O2N
–
– Me2SO4
N
N
N
MeSO4
+
+
N
N
N
Me
R
Me
R
N
N
R
N
R = H, Me
Another possible pathway for formation of the N(2)-isomer is analogous to the scheme for formation of
the N(4)-isomer and involves attack of N(2) in triazoles 1 and 2 by the electrophilic agent.
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N,N-Dimethyl-1,2,4-triazoles 8a,b are formed from the corresponding azolium salts 9a,b as a
consequence of the great sensitivity of these compounds to the action of nucleophilic reagents due to
delocalization of positive charge on the carbon atom at the nitro group.
A study of the effect of the reaction conditions on the product yields showed that the reagent ratio and
reaction time are significant factors.
A significant amount of unreacted starting components (up to 60%) remains after a relatively short
reaction time (15-20 min) and the use of a 10-25% molar excess of triazoles 1 and 2. The predominant reaction
products are N-monomethyltriazoles 3a,b–5a,b (15-30%), while the yields of N,N-dimethyl derivatives 7a,b and
triazolones 8a,b are only 2-3%. The triazolones, as a rule, are obtained in only trace amounts.
Increasing the reaction time to 2.0-2.5 h leads to virtually quantitative conversion of DMS. The ratio of
the N-monomethyl and N,N-dimethyl derivatives and the triazolones is markedly altered. The total yield of
monomethyl derivatives 3a,b–5a,b rises to 53-73% and the yield of triazolones 7a,b rises to 3-6%. The
relatively ready formation of N,N-dimethyl-3-nitro-1,2,4-triazolium salts 6a,b isolated as salts 7a,b in 12 and
8% yield, respectively, is unusual in this reaction despite the less than equivalent amount of alkylating agent and
the presence of the electron-withdrawing nitro group in heterocycles 1 and 2.
When the excess of DMS is increased to two- or three-fold and the reaction time is extended to 2-3 h,
starting triazoles 1 and 2 are no longer found in the reaction mixture. The mass yield of the N-monoalkylation
products 3a,b–5a,b is significantly reduced to 15-24% and N(1)-methyl isomers 3a,b are lacking and N(4)-methyl
isomers 5a and 7a may also completely disappear. The yield of the N,N-dimethylnitrotriazoles is increased to
45-60% and 1,4-dimethylation products 7a,b predominate in these products. The fraction of triazolones 8a,b is
5-7%. The synthesis of 1,4-dialkyl- and 1,4,5-trialkyl-3-nitro-1,2,4-triazolium salts will be described in a
subsequent communication.
EXPERIMENTAL
1
The H and 13C NMR spectra were taken on a Bruker AM-400 spectrometer at 400 and 100 MHz,
respectively, in DMSO-d6 with DMSO as the internal standard. The IR spectra were taken on a Perkin Elmer
spectrometer for KBr pellets. The UV spectra were taken on a Specord spectrometer. The gas chromatographic
analysis of the reaction products was carried out using an internal standard method on a Chrom-5 chromatograph
with a flame ionization detector using a glass column (l = 200 mm, d = 3 mm) packed with SE-30 siloxane
elastomer. The flow rate of the nitrogen gas carrier was 40 ml/min. The thermostat temperature was 180°C. The
temperature of the injector and detector was 220°C. Melting points were found on a Boetius block with an
RNMK-05 observation device.
Preparation of Components and Reagents. N-Methyl-1,2,4-triazoles and triazolones (3a-5a, 8a,
1
3b-5b, 8b) prepared by reported procedures [2, 6, 9] were used as standards for studying the H NMR spectra
and in gas–liquid chromatography. In order to remove impurities, a sample of dimethyl sulfate was washed with
3% aq. sodium carbonate and then distilled water, dried, and distilled in vacuum (purity ≥99.9%, the amount of
acid calculated relative to sulfuric acid was ≤0.1%). Triazoles 1 and 2 were recrystallized twice from water and
then from methanol; mp 214°C for 1 (210°C [5]) and mp 197°C for 2 (194°C [5]).
Reaction of 3-Nitro-1,2,4-triazole (1) with DMS. A suspension of 1 (22.8 g, 0.2 mol) and DMS
(22.4 g, 0.178 mol) was stirred at 78-80°C for 2.5 h, cooled to 30°C, and extracted with CH2Cl2. The following
1
compounds were detected in the extract by H NMR spectroscopy and gas–liquid chromatography using
authentic samples as references: DMS in 7.2%, 3a in 1.9% yield, 4a in 38.6% yield, 5a in 52.5% yield, and 8a in
trace yield. The total yield of the mixture after distilling off CH2Cl2 in vacuum was 2.8 g. The residue of the
1
reaction mixture was stirred with water (100 ml) and extracted with CH2Cl2. H NMR spectroscopy and
gas-liquid chromatography indicated that the extract contained 4a in 2.85% yield, 5a in 90.75% yield, and 8a in
6.40% yield. The total yield of the reaction mixture after distilling off CH2Cl2 was 9.9 g.
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Methylnitrotriazole 5a was isolated from this mixture by recrystallization from 2-propanol and water;
mp 122-124°C (118-120°C [6]). IR spectrum, νNO2, cm-1: 1565, 1330. UV spectrum, λmax, nm: 261, 218.
1H NMR spectrum, δ, ppm: 3.93 (3H, s, N–CH3); 8.82 (1H, s, C–H). 13C NMR spectrum, δ, ppm: 34.40
(N–CH3), 148.37 (C–H), 154.49 (C–NO2). IR spectrum, νNO2, cm-1: 1550, 1335 [7]. UV spectrum, λmax, nm: 260,
225 [4]. 1H NMR spectrum (DMSO-d6), δ, ppm: 3.9 (3H, s, N–CH3), 8.8 (1H, s, C–H) [6].
The reaction mixture was extracted twice with CH2Cl2 and then heated to 75-80°C. Ammonium
perchlorate (3.2 g) was added to the residue, the mixture was cooled to 20°C, and the precipitate was filtered off
to give 5.2 g (12.2%) of compound 7a, mp 175-177°C (water). IR spectrum, ν, cm-1: 1565 (NO2), 1340 (NO2),
1
1085 (ClO4). UV spectrum, λmax, nm: 230. H NMR spectrum, δ, ppm: 4.16 (3H, s, N–CH3); 4.21 (3H, s,
N–CH3); 10.31 (1H, s, C–H). 13C NMR spectrum, δ, ppm: 37.09 (N–CH3), 40.22 (N–CH3), 147.17 (C–H),
150.99 (C–NO2).
Reaction of 5-Methyl-3-nitro-1,2,4-triazole (2) with DMS. A suspension of 3-nitro-1,2,4-triazole
(25.6 g, 0.2 mol) and DMS (23.2 g, 0.184 mol) was stirred at 75-80°C for 2 h and then cooled to 30°C. The
1
mixture was extracted with methylene chloride. H NMR spectroscopy and gas-liquid chromatography with
reference standards indicated the presence of DMS in 22% yield, 4b in 55% yield, 5b in 24% yield, and 8b in
trace yield. The total yield of the mixture after distilling off CH2Cl2 in vacuum was 3.3 g. The residue was stirred
1
with water (60 ml) and extracted with CH2Cl2. H NMR spectroscopy and gas-liquid chromatography with
reference standards indicated the presence of DMS in 1.6% yield, 3b in 0.4% yield, 4b in 2.4% yield, 5b in
91.7% yield, and 8b in 8.1% yield. The total yield of the mixture after distilling off CH2Cl2 in vacuum was
17.5 g.
Dimethylnitrotriazole 5b was obtained from this mixture by recrystallization from 2-propanol and then
1
from water; mp 75-76°C. IR spectrum, νNO2, cm-1: 1520, 1328. UV spectrum, λmax, nm: 275, 210. H NMR
spectrum, δ, ppm: 2.50 (3H, s, C–CH3); 3.83 (3H, s, N–CH3). 13C NMR spectrum, δ, ppm: 10.84 (C–CH3), 33.15
(N–CH3), 154.61 (C–NO2), 155.78 (C–H). The residue of the reaction mixture was extracted twice with CH2Cl2
and then heated to 75-80°C. Then, ammonium perchlorate (3.6 g) was added. The mixture was cooled to 20°C
and filtered to give 3.6 g (7.6%) 7b; mp 194-195°C (water). IR spectrum, ν, cm-1: 1587 (NO2), 1100 (ClO4).
UV spectrum, λmax, nm: 238. 1H NMR spectrum, δ, ppm: 2.89 (3H, s, C–CH3); 4.05 (3H, s, N–CH3); 4.15 (3H, s,
N–CH3). 13C NMR spectrum, δ, ppm: 10.38 (C–CH3), 35.67 (N–CH3), 38.93 (N–CH3), 150.38 (C–NO2), 156.18
(C–CH3).
REFERENCES
1.
2.
G. T. Sukhanov and A. Yu. Lukin, Khim. Geterotsikl. Soedin., 1020 (2005).
L. I. Bagal, M. S. Pevzner, N. I. Sheludyakova, and V. M. Kerusov, Khim. Geterotsikl. Soedin., 265
(1970).
3.
A. F. Pozharskii, Theoretical Basis for Heterocyclic Chemistry [in Russian], Khimiya, Moscow (1985),
280 p.
4.
5.
L. I. Bagal and M. S. Pevzner, Khim. Geterotsikl. Soedin., 558 (1970).
L. I. Bagal, M. S. Pevzner, A. N. Frolov, and N. I. Sheludyakova, Khim. Geterotsikl. Soedin., 259
(1970).
6.
7.
R. W. Middleton, H. Monney, and J. Parrick, Synthesis, 740 (1984).
V. V. Mel'nikov, V. V. Stolpakova, M. S. Pevzner, and B. V. Gidaspov, Khim. Geterotsikl. Soedin., 707
(1973).
8.
9.
L. I. Bagal and M. S. Pevzner, Khim. Geterotsikl. Soedin., 272 (1971).
A. Bernardini, P. Viallefont, J. Daunis, and M. L. Roumestant, Bull. Soc. Chem., 1191 (1975).
998