Reactions of 3-nitro-1,2,4-triazoles with alkylating agents. 6*. Alkylation of a neutral heterocycle by alcohols in acid media

Article abstract of DOI:10.1007/s10593-009-0194-x

Reaction of 3-nitro-1,2,4-triazole and 5-methyl-3-nitro-1,2,4-triazole with secondary and tertiary alcohols in conc. H₂SO₄ takes place at the N(2) atom. Alkylation by 2-propanol occurs regioselectively to form the 1-isopropyl-3-nitro-and 1-isopropyl-3-methyl-5-nitro-1,2,4-triazoles. As a consequence of isomerization the alkylation using cyclohexyl or tert-butyl alcohols gives respectively a mixture of regioisomers substituted at atom N(1) (1-cyclohexyl-3-nitro-and 1-cyclohexyl-5-methyl-3-nitro-1,2,4-triazoles) and at atom N(2) (5-nitro-1-cyclohexyl-and 1-cyclohexyl-3-methyl-5-nitro-1,2,4- triazoles) and, in the second case, to 1-tert-butyl-3-nitro-1,2,4-triazole.

Full text of DOI:10.1007/s10593-009-0194-x

Chemistry of Heterocyclic Compounds, Vol. 44, No. 11, 2008
REACTIONS OF 3-NITRO-1,2,4-TRIAZOLES
WITH ALKYLATING AGENTS. 6*. ALKYLATION
OF A NEUTRAL HETEROCYCLE BY ALCOHOLS
IN ACID MEDIA*
A. G. Sukhanova1, G. V. Sakovich2, and G. T. Sukhanov1
Reaction of 3-nitro-1,2,4-triazole and 5-methyl-3-nitro-1,2,4-triazole with secondary and tertiary
alcohols in conc. H2SO4 takes place at the N(2) atom. Alkylation by 2-propanol occurs regioselectively
to form the 1-isopropyl-3-nitro- and 1-isopropyl-3-methyl-5-nitro-1,2,4-triazoles. As a consequence of
isomerization the alkylation using cyclohexyl or tert-butyl alcohols gives respectively a mixture of
regioisomers substituted at atom N(1) (1-cyclohexyl-3-nitro- and 1-cyclohexyl-5-methyl-3-nitro-1,2,4-
triazoles) and at atom N(2) (5-nitro-1-cyclohexyl- and 1-cyclohexyl-3-methyl-5-nitro-1,2,4-triazoles)
and, in the second case, to 1-tert-butyl-3-nitro-1,2,4-triazole.
Keywords: 3-nitro-1,2,4-triazoles, alkylation, regioselectivity.
The physicochemical properties of N-substituted 3-nitro-5-R-1,2,4-triazoles are markedly affected by
the positioning and type of substituent on the cyclic nitrogen atoms [2-5].
The development of directed methodology for the synthesis of N-substituted azoles and the search for
conditions activating all three nitrogen atoms in the reactions of monofunctionalization of nitrotriazoles are
important problems in basic and applied science. On the one hand it contributes to deciding one of the key
challenges in the chemistry of heterocycles, (that of reaction selectivity) and, on the other, it allows users to
achieve directivity i.e. the targeted regulation of the properties of nitrotriazoles by synthesis of a given isomer
with the needed package of properties.
The N-monoalkylation of 3-nitro-5-R-1,2,4-triazoles in basic conditions at the pyrrole nitrogen atom and
N–H form of the heterocycle at the pyridine nitrogen atom by alkyl halides and dialkyl sulfates occur with
irregular selectivity [4-6]. Dependent on the type of reaction medium and alkylating agent there are principally
formed the N(1)- or N(4)-isomers. In the presence of alkali a mixture of the N(1)- and N(2)-alkylnitrotriazole
isomers [4] is formed with a predominance of the N(1)-isomer (fraction of the N(2)-isomer 18-34%). In neutral
medium [5, 6] it is the N(4)-isomer (the corresponding N(1)-, N(2)-, and N(4)-methyl isomers being 1:12:230)-,
with the ratio of N(2)- and N(4)-ethyl isomers being 1:2.5.
_______
* For Communication 5 see [1].
__________________________________________________________________________________________
1Institute for Problems of Chemical and Energetic Technologies, Siberian Branch of the Russian
2
Academy of Sciences, Biisk 659322, e-mail: admin@ipcet.ru. Altai Federal State Unitary Enterprise, Federal
Research & Production Center, Biisk 659322, Russia; e-mail: post@frpc.secna.ru. Translated from Khimiya
Geterotsiklicheskikh Soedinenii, No. 11, pp. 1680-1687, November, 2008. Original article submitted July 28,
2006; revision submitted July 24, 2008.
1368
0009-3122/08/4411-1368©2008 Springer Science+Business Media, Inc.

In continuing our work on the selectivity of alkylation of nitrotriazoles we have studied another type of
reaction involving the pyridine nitrogen atoms of nitrotriazoles by alkylation in acidic media controlling
selectivity of alkylation at the N(2) atom. The choice of alkylating agent determines the isomeric composition of
the reaction products:
O2N
N
i-PrOH
N
i
-Pr
R
N
3, 5
O2N
O2N
O2N
N
N
N
c-C6H11OH
N
+
N
N
R
N
N
N
c-H11C6
H
C H -
c
1, 2
6
11
8
7
O2N
N
t-BuOH
N
N
Bu-
9
t
1, 3 R = H, 2, 5 R = Me
With the high stability towards the action of mineral acids and the weakly basic properties of
nitrotriazole rings in mind we have undertaken in this work the alkylation of 3-nitro-5-R-1,2,4-triazoles by
alcohols in a medium of high acidity ensuring almost total protonation of the nitrotriazole ring hence excluding
the possibility of alkylating of the triazoles both in the form of the nitrotriazolate anions [4] and as the free N–H
acid [5, 6]. Sulfuric acid was used as such a medium in this reaction as it also plays a role as a universal solvent
and an agent taking up water.
Alkylation of the nitrotriazoles was carried out using alcohols, the structure of which, to a certain extent,
enables stabilization of the carbocations formed from them (isopropyl, cyclohexyl, tert-butyl).
As a result of carrying out the work it was found that the reaction of 3-nitro-1,2,4-triazole (1) and 5-methyl-
3-nitro-1,2,4-triazole (2) with isopropyl alcohol successfully occurred over 1.5-3.0 h at room temperature in a conc.
H2SO4 medium. The reaction products showed quite a high yield (Table 1) of only one of the three possible
isomeric products, i.e. 1-isopropyl-5-nitro-1,2,4-triazole (3) and 1-isopropyl-3-methyl-5-nitro-1,2,4-triazole (5)
respectively as shown by GLC data and by NMR and IR spectroscopy.
The regioselective course of this reaction in a high acidity medium can be represented by the following scheme:
.
.
NO2
NO2
NO2
H
H
N
N
N
+
R1
+
H
+
N
N
N
+
R1
.
.
R
R
+
R
.
N
N
H
.
N
H
–H
H
+
II
I
R1
1, 2
NO2
NO2
NO2
H
N
N
N
+
N
N
N
+
R1
R1
R
R
R
–H
N
N
N
III
R1
4, 6, 8, 9
3, 5, 7, 10
1, 3, 4, 7–10 R = Н; 2, 5, 6 R = Me; 3–6 R1 = i-Pr; 7, 8 R1 = c-С6Н11; 9, 10 R1 = t-Bu
1369

The protonation of the nitrotriazoles 1, 2 in a high acidity medium forms the 1H,4H-5-R-3-nitro-1,2,4-
triazolium cation 1. Only one reactive center (the N(2) atom) is available for attack by an electrophile, the N(1)
and N(4) atoms being blocked by protons. The likelihood of attack at atoms N(1) and N(4) is also lowered due
to localization of a significant positive charge on the ring carbon atom positioned between them. As a result of
+
protonation and dehydration of the 2-propanol molecule in the conc. H2SO4 medium a carbocation (C3H7 ) is
formed. This cation attacks the nitrotriazolium cation I at the N(2) electron pair available for coordination. Two
schemes for obtaining the N(2)-substituted nitrotriazoles 3, 5 are possible. The first is of three stages via
formation of the intermediate II. In the second stage the unstable intermediate II is stabilized by loss of a proton,
apparently neighboring to the isopropyl substituent. In the last stage the N(2)-substituted nitrotriazolium salt III,
protonated at atom N(4), is deprotonated to form the N(2)-substituted nitrotriazoles 3, 5. The deprotonation is
basically achieved through decreasing the acidity of the medium by dilution with water. The most likely second
scheme is a simultaneous attack at position N(2) in the heterocycle by the C3H7+ carbocation and deprotonation
of the N(1) atom to the nitrotriazolium salt I. The nitrotriazolium salt III is then deprotonated as in the first
scheme to the N(2)-substituted 1-isopropyl-3-R-5-nitro-1,2,4-triazoles 3, 5.
+
The proposal that the carbocation C3H7 attacks carbocation I seems unusual at first glance. However,
such a scheme explains the regioselectivity of the alkylation. Possible the course of this reaction and the
regioselectivity are due to the properties of the reaction medium and the reagents chosen. The isopropyl
carbocation is a powerful electrophilic agent since its central carbon atom has a marked positive charge +0.432
[7].
The nitrotriazoles 1 and 2 are weak bases with several reaction centers of different basicity. In the
conditions of carrying out this reaction (96% H2SO4, Ho = -9.9) the nitrotriazoles are virtually totally protonated
at the most basic N(4) atom [1] to form a nitrotriazolium 1H,4H-5-R-cation. However, protonation at one
nitrogen atom does not fully suppress the nucleophilic properties of the whole compound due to the presence of
an unshared electron pair on atom N(2) and, evidently, at N(2) of the protonated nitrotriazole ring quite a
negative π charge is preserved for attack by a powerful electrophile at this position of the heterocycle. Hence the
alkylation products of the nitrotriazoles are formed in quite high yields (Table 1).
The possibility of alkylation of the nitrotriazoles by the scheme reported above is confirmed by the
results of work presented previously by P. N. Gaponik in [8-10] regarding a detailed study of the selective
alkylation by alcohols of close tetrazole analogs of the nitrotriazoles. In particular, in [10] a scheme of attack by
a tetrazolium alkylcarbocation fully substantiated by a kinetic study was presented by V. A. Ostrovskii from the
Saint Petersburg Technological Institute for the example of alkylation of 5-phenyltetrazole by tert-butyl alcohol.
With regard to the absence of isomerization of the 1-isopropyl-3-R-5-nitro-1,2,4-triazoles 3, 5 in sulfuric
acid medium over 3 h it was concluded from special experiments that the alkylation of the N-unsubstituted
nitrotriazoles by isopropyl alcohol occurs specifically at position N(2) in the heterocycle.
TABLE 1. Reaction Conditions and Yields of the Nitrotriazoles 3, 5, 7-9
Starting reagents
Reaction
time, h
Reaction
product
bp, °C*
Yield, %
Azole
Alcohol
1
1
2
1
1
2-PrОН
2-PrОН
2-PrОН
c-С6Н11ОН
t-BuОН
1.5
3
3
90–92
90–92
98–100
—
60.7
66.7
43.3
45.4
80.0
3
2
5
2
7 + 8*2
3
9
—*3
_______
* 12-15 mm Hg.
*2 Ratio of nitrotriazoles 7, 8 = 0.8:1.0.
*3 Mp 95-97ºC.
1370

In addition, the nature of the attacking carbocation and the reaction conditions to a marked extent fix the
reaction products which, in turn, depend on the possibility of isomerization. Upon prolonged holding of the
reaction mixtures or individual 1-isopropyl-3-R-5-nitro-1,2,4-triazoles 3, 5 in conc. H2SO4 a partial
isomerization occurs to give the isomeric 1-isopropyl-3-nitro-5-R-1,2,4-triazoles 4, 6.
Reaction of the nitrotriazole 1 with cyclohexyl alcohol occurs to give a mixture of the regioisomers at
atoms N(1) and N(2). The mixture of 1-cyclohexyl-5-nitro- (7) and 1-cyclohexyl-3-nitro- (8) 1,2,4-triazole
1
isomer products formed are difficult to separate and the isomer ratio was determined using H NMR
spectroscopy.
The most likely explanation for formation of a mixture of isomeric cyclohexyl nitrotriazoles 7 and 8 is
an increase in the tendency in the acid media towards isomerization of the 1-cyclohexyl-5-nitro-1,2,4-triazole to
the corresponding 1-cyclohexyl-3-nitro-1,2,4-triazole by comparison with the isomerization of the 1-isopropyl-
5-nitro-3-R-1,2,4-triazole analogs 3, 5 to the 1-isopropyl-3-nitro-5-R-1,2,4-triazoles 4, 6.
Bearing in mind the sensitivity of the reaction of N(2)-substituted nitrotriazoles to N(1)-substituted
nitrotriazoles upon exchange of one alkylating agent for another (especially isopropyl for cyclohexyl alcohols) a
significant dependence of the isomerization process for the carbocation on the nature of the attacking
nitrotriazole substrates can be proposed. However, the appearance of a sharp change in the nature and products
of the reaction on going to the tert-butyl alcohol was unexpected since, in the reaction of nitrotriazole 1 with
tert-butyl alcohol in conc. H2SO4 medium, the only product is 1-tert-butyl-3-nitro-1,2,4-triazole (9). The
isomeric 1-tert-butyl-5-nitro-1,2,4-triazole (10) was only found in the reaction mixture in trace amounts in the
initial period of the reaction.
TABLE 2. Spectroscopic Characteristics of the Nitrotriazoles 3-9
Com- IR spectrum, UV spectrum,
1Н NMR spectrum,
δ, ppm (J, Hz)
13S NMR spectrum,
pound νNO2, сm–1
λmax, nm
δ, ppm
3
4
5
1558, 1330
1555, 1305
1562, 1340
266, 218
1.48 (6H, d, J = 6.6, (CH3)2);
5.30 (1H, m, CH(CH3)2);
8.20 (1H, s, =CH)
21.77 (ССН3)2);
54.18 (СН(СН3)2);
148.07 (СН–);
151.77 (C–NO2)
257, 222
282, 227
1.50 (6H, d, J = 6.7, (CH3)2;
4.76 (1Н, m, CH(CH3)2);
8.67 (1H, s, =CH)
21.82 (ССН3)2);
53.69 (СН(СН3)2);
144.99 (СН–);
161.94 (C–NO2)
1.45 (6H, d, СН(CH3)2);
5.22 (1H, m, СН(CH3)2);
2.34 (3H, s, ССН3)
11.43 (СН(СН3)2);
21.46 (СН(СН3)2);
51.35 (СН(СН3)2);
154.08 (Ск–СН3);
160.88 (С–NО2)
6
1558, 1320
266, 218
1.47 (6H, d, CH(CH3)2);
4.31 (1H, m, СН(CH3)2);
2.58 (3H, s, С–СН3)
13.78 (СН(СН3)2);
21.77 (СН(СН3)2);
53.75 (СН(СН3)2);
151.29 (C–NO2);
157.64 (ССН3)
7
8
9
1552, 1325
1550, 1305
1555, 1307
—
—
1.76-2.33 (10Н, m, (СН2)5);
4.90 (1Н, m, СН);
8.20 (1H, s, =CH)
60.74 (СНcycle);
149.00 (СН)к;
161.65 (C–NO2)
1.65-1.75 (10Н, m, (СН2)5);
4.88 (1Н, m, СН);
8.99 (1H, s, =CH)
62.94 (СНcycle);
144.73 (СН)к;
151.80 (C–NO2)
257, 220
1.6 (9Н, s, С(СН3)3);
8.95 (1Н, s, СН)
28.58 (С(СН3)3);
61.01 (С(СН3)3);
144.13 (СН)cycle
;
161.82 (C–NO2)
1371

Assignment of the nitrotriazoles 3, 5, 7 (Table 2) as the N(2)-substituted compounds was made on the
basis of the high sensitivity of the chemical shifts of atoms C-3 in the NMR spectra towards the position of an
alkyl substituent on the cyclic nitrogen atoms in N(1)- or N(2)-substituted 3-nitro-1,2,4-triazoles.
Thus the signals for the C-3 atom bound with the nitro group in the 2-mono- and 2,5-disubstituted
nitrotriazoles 3, 5, 7 lie in the narrow range 151.29-151.80 ppm. The signals for the N(1)-substituted
nitrotriazoles 4, 6, 8 in the same conditions are shifted by 9.59-10.14 ppm to low field (160.88-161.94 ppm).
Comparison of the physicochemical and spectroscopic characteristics for the N(1)-substituted nitro-
triazoles 4, 6, 8 with compounds 3, 5, 7 indicate that the latter materials are, in fact, 5-nitrotriazoles.
Compound 9 is identified as the N(1)-isomer on the basis that the singlet for the ring proton at 8.95 ppm
is found at characteristically low field for N(1)-alkyl-substituted nitrotriazoles [4, 11] relative to the N(2)-alkyl-
substituted isomers (including isomer 10 at 8.08 ppm). In addition, comparison of the chemical shift of the
cyclic C-3 atom with the nitro group in the 13C NMR spectrum of nitrotriazole 9 (161.82 ppm) with the chemical
shifts of the corresponding atoms of the N(1)-substituted nitrotriazoles 4, 6, 8 (160.88-161.94 ppm) and
nitrotriazoles 3, 5, 7 (151.29-151.80 ppm) indicates that compounds 9 is an N(1)-substituted nitrotriazole.
The IR spectra of the 5-nitrotriazoles 3, 5, 7 showed absorption bands typical of a nitro group [12, 13],
the asymmetric stretching bands being at 1562-1552 and symmetric streching bands at 1340-1325 cm-1. A
characteristic low field shift of the absorption bands of the N(1)-isomers 4, 6, 8, 9 was seen compared with those
of the isomers 3, 5, 7 [4, 12, 13].
The UV spectra of the nitrotriazoles 3, 5, 7 and 4, 6, 8, 9 show two absorption maxima. The short wave
maximum showed little sensitivity to the nature and position of the substituent. In the long wavelength region
the absorption maximum value for the alkyl nitrotriazoles depends on the position of the nitro group [14] and for
the 5-nitro isomers 3, 5, 7 it is found at longer wavelength than for the N(1)-isomers 4, 6, 8, 9. In the
N(1)-isomers 4, 6, 8, 9 a characteristic shift of the absorption maximum of 9-16 nm to shorter wavelength is
seen when compared with the isomers 3, 5, 7 (Table 2).
EXPERIMENTAL
1H and 13C NMR spectra were taken on a Bruker AM-400 (400 and 100 MHz respectively) for a
solution in DMSO-d6 with DMSO as internal standard. IR spectra were recorded on a Perkin-Elmer instrument
for KBr tablets and UV spectra on a Specord instrument. Gas chromatographic analysis of the reaction products
was carried out by the internal standard method on a CHROM-5 chromatograph with a flame ionization
detector, glass column (l = 200 mm, d = 3 mm) with an SE-30 siloxane packing, gas carrier nitrogen (40
ml/min), thermostat temperature 180ºC, evaporator 220ºC, and detector 220ºC. Melting points were determined
on a mini Boetius heating block with a PHMK-05 viewing attachment.
Preparation of Components and Reagents. Triazoles 1, 2 were recrystallized twice from water and
then from methanol, mp 214 and 197ºC [5] (mp 210 and 194ºC [13]).
The N-alkyl-1,2,4-triazoles 3-6 reference samples were obtained by a known method [4] and were
identified by 1H NMR and GLC. The properties of 3, 4 agreed with the literature: 1-isopropyl-5-methyl-3-nitro-
1,2,4-triazole (6) mp 42-43ºC, 1-isopropyl-3-methyl-5-nitro-1,2,4-triazole (5), bp 98-100ºC (12 mm Hg). The 1H
and 13C NMR and IR spectroscopic characteristics are given in Table 2.
Preparation of Nitrotriazoles 3, 5, 7-9 (General Method). The alcohol (0.28 mol) was added
dropwise over 10 min with stirring to a solution of the nitrotriazole 1 or 2 (0.25 mol) in conc. H2SO4 (180 ml)
holding the temperature 20-25ºC. The reaction mixture was stirred for the time indicated in Table 1, poured into
iced water (1 kg), and extracted with methylene chloride (3×250 ml). The combined extract was washed with a
3-5% solution of sodium carbonate ( 100 ml) to neutral pH, and dried over anhydrous MgSO4 (Tables 1 and 2).
1372

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