Reaction of 3-nitro-1,2,4-triazole derivatives with alkylating agents. 1. Alkylation in the presence of alkali

Article abstract of DOI:10.1007/s10593-005-0239-8

Alkylation of 3-nitro-1,2,4-triazole and 5-methyl-3-nitro-1,2,4-triazole with dialkyl sulfates or alkyl halides in the presence of alkali proceeds with a low selectivity for the alkylating agent with the formation of two regioisomers at the N₍₁₎ and N₍₂₎ atoms of the heterocycle. Depending on the reaction conditions the proportion of the N₍₂₎ isomer was 14.6-33.8%. 2005 Springer Science+Business Media, Inc.

Full text of DOI:10.1007/s10593-005-0239-8

Chemistry of Heterocyclic Compounds, Vol. 41, No. 7, 2005
REACTION OF 3-NITRO-1,2,4-TRIAZOLE
DERIVATIVES WITH ALKYLATING AGENTS.
1. ALKYLATION IN THE PRESENCE OF ALKALI
G. T. Sukhanov1 and A. Yu. Lukin2
Alkylation of 3-nitro-1,2,4-triazole and 5-methyl-3-nitro-1,2,4-triazole with dialkyl sulfates or alkyl
halides in the presence of alkali proceeds with a low selectivity for the alkylating agent with the
formation of two regioisomers at the N(1) and N(2) atoms of the heterocycle. Depending on the reaction
conditions the proportion of the N(2) isomer was 14.6-33.8%.
Keywords: 1-alkyl-3-nitro-1,2,4-triazoles, 1-alkyl-5-nitro-1,2,4-triazoles, 3-nitro-1,2,4-triazoles,
alkylation, regioselectivity.
The selectivity of reactions is a general problem of heterocyclic chemistry. At the present time the
selectivity of electrophilic substitution reactions in nitro derivatives of 1,2,4-triazoles has not been studied
adequately. 3-Nitro-5-R-1,2,4-triazoles have three potential reaction centers, the N(1), N(2), and N(4) atoms,
consequently on alkylation the formation of three isomers is theoretically possible. According to the data of
[1, 2] alkylation of salts of 3-nitro-5-R-1,2,4-triazole derivatives with alkyl halides and dimethyl sulfate (DMS)
proceeds regioselectively. The authors' opinion on the place of attack on the ring by an electrophilic reagent
varied. On interacting 3-nitro-1,2,4-triazole (1) and 5-methyl-3-nitro-1,2,4-triazole (2) with DMS in acetone,
alcohol, and mixtures of them with water in the presence of alkali only the N(1) isomer [1] was isolated, viz.
1-methyl-3-nitro-1,2,4-triazole (3) and 1,5-dimethyl-3-nitro-1,2,4-triazole (4), in 66 and 55% yield respectively.
According to [2] alkylation of the sodium salt of triazole 1 in propanol also leads to one isomer, which however
was erroneously assigned the structure of the corresponding 1-alkyl-2-nitro-1,3,4-triazole. However the selective
course of the reaction in this and other cases seems less probable and this point requires defining more
accurately.
O2N
O2N
O2N
R1Hal
N
N
N
1
+
[R1 SO4]
N
N
N
2
R
R
N
R
N
R
N
H
R1
1,2
3a–7a
3b–7b
1, 3a,b, 5a,b-7a,b R = Н; 2, 4 a,b R = Me; 3 a,b, 4а,b R1 = Me; 5а,b R1 = Et;
6a,b R1 = Pr; 7a,b R1 = i-Pr
__________________________________________________________________________________________
1
Institute of Problems of Chemical Energy Technology, Siberian Branch of the Russian Academy of
2
Sciences, Biisk 659322; e-mail: post@frpc.secna.ru. Federal State Unitary Enterprise, Altai Federal Industrial
Science Center, Biisk 659322, Russia; e-mail: lukin@mail.biysk.ru. Translated from Khimiya
Geterotsiklicheskikh Soedinenii, No. 7, pp. 1020-1025, July, 2005. Original article submitted January 13, 2003.
0009-3122/05/4107-0861©2005 Springer Science+Business Media, Inc.
861

On investigating the alkylation products of triazoles 1 and 2 more thoroughly by the method described in
[1, 2], we established that the selectivity of methylation was not confirmed. It was found that on interacting salts
of compounds 1 and 2 with dialkyl sulfates (DAS) and alkyl halides, in reality monoalkylation products were
formed in all cases.
The reaction products, isolated in high yield (50-89%) and identified, were mixtures of two regioisomers
(3a-7a and 3b-7b). This was confirmed by data of GLC and 1H NMR, IR, and UV spectroscopy (Tables 1-4).
The marked differences in dipole moment [3] and volatility of isomers a and b enabled us to use solvent
extraction and distillation in vacuum for their separation (Table 2).
From the mixture of high-melting triazoles 3 and 4 (by method A), isomers 3b and 4b were isolated by
extraction with hexane. From the residues triazole isomers 3a and 4a respectively were isolated by
crystallization from alcohols.
TABLE 1. Alkylation Products of Salts of Triazoles 1 and 2 with Alkyl
Sulfates and Alkyl Halides
% by weight
(GLC)
Isomer Isomer
Reaction
time,
h
Com-
pounds
(mixtures)
Exp Initial Alkylating
No. triazole Agent
Tempera-
ture, °C
Yield of
isomers
a + b, %
Alkali
a
b
1
2
1
1
1
1
1
1
1
1
1
1
2
2
DMS
NaOH
LiOH
LiOH
LiOH
LiOH
LiOH
LiOH
20-25
75-78
20-25
20-25
20-25
15-18
75-78
75-78
75-78
72-78
20-25
20-25
72
3
3a + 3b
3a + 3b
3a + 3b
5a + 5b
5a + 5b
5a + 5b
5a + 5b
5a + 5b
6a + 6b
7a + 7b
4a + 4b
4a + 4b
70.8
72.5
78.8
68.2
79.9
66.7
71.2
78.3
82.2
74.8
66.2
75.3
29.2
27.5
21.2
31.8
20.1
33.3
28.8
21.7
17.8
25.2
33.8
24.7
76.2
84.2
75.0
88.1
76.8
50.1
85.8
82.5
89.4
79.4
84.5
78.2
DMS
3
MeI
200
24
200
700
7
4
DES*
5
6
MeСН2I
MeСН2Br
MeСН2Br
7
8
9
MeСН2Br NaOH
Me(СН2)2Br NaOH
7
20
20
24
200
10
11
12
Me2СНBr
DMS
MeI
NaOH
LiOH
LiOH
_______
* Diethyl sulfate.
TABLE 2. Properties of the Isomeric Alkyl-substituted Triazoles 3a,b-7a,b
Separation
method
Bp., °С
(mm Hg)
Compound
mp, °С [lit.]
mp, °С
Yield, %
3a
3b
65-66
81-82
64-65 [4]
79-80 [4]
51.2
19.1
A
4a
4b
90-91
57-58
89-90 [1]
55-56 [1]
45.6
20.4
A
B
B
C
5a
5b
32-33
29-30
—
—
125-130 (1)
62-65 (0.5)
50.0
31.0
6a
6b
—
—
140-142 (1)
74-75 (1)
72.1
11.5
7a
7b
52-53
—
—
92-95
(12-15)
63.1
14.7
862

TABLE 3. Influence of the Nature of the Alkaline Agent on the Total Yield
and Ratio in the Mixture of Triazoles 5a and 5b*
K2CO3 Na2CO3
KOH
74.5
NaOH
71.3
LiOH
69.3
NH4OH TMA·OH*2
Total yield
of mixture 5a+5b, %
74.8
69.9
73.0
88.7
Content in mixture
(GLC), %
5a
5b
83.5
16.5
83.7
16.3
82.2
17.8
82.5
17.5
82.0
18.0
85.4
14.6
83.2
16.8
_______
* Solvent was water, alkylating agent ethyl bromide.
*2 TMA·OH is tetramethylammonium hydroxide.
TABLE 4. Spectral Characteristics of Triazoles 3-7
IR spectrum,
UV spectrum,
max, nm
1Н NMR spectrum (DMSO-d6),
δ, ppm. (J, Hz)
Com-
pound
ν, cm-1
λ
3a
3b
1546, 1310
1555, 1313 [6]
255 255 [5]
265 270 [5]
4.03 (3H, s, N−СН3); 8.75 (1H, s, =СН)
4.02 (3H, s, N−СН3); 8.22 (1H, s, =СН) [4]
4.18 (3H, s, N−СН3); 8.15 (1H, s, =СН)
4.08 (3H, s, N−СН3); 8.04 (1H, s, =СН) [4]
2.50 (3H, s, С−СН3 ); 3.91 (3H, s, N−СН3)
2.32 (3H, s, С−СН3); 4.10 (3H, s, N−СН3)
1556, 1338
1555, 1320 [7]
4a
4b
5a
1540, 1312
1562, 1346
1550, 1305
266 262.5 [5]
280 279 [5]
257
1.47 (3H, t, J = 7.0, CH2СН3); 4.39 (2H, q,
J =6.0, СН2CH3 ); 8.78 (1H, s, =СН)
5b
6a
6b
7a
7b
1558, 1336
1550, 1305
1560, 1335
1555, 1305
1558, 1330
266
255
267
257
266
1.47 (3H, t, J = 7.2, CH2СН3); 4.61 (2H, q,
J =6.2, СН2CH3 ); 8.12 (1H, s, =СН)
0.87 (3H, t, J = 7.4, CH2СН3); 1.85 (2H, m, =CH2);
4.29 (2H, t, N−CH2−); 8.78 (1H, s, =CH)
0.90 (3H, t, J = 7.7, CH2СН3); 1.90 (2H, m, =CH2);
4.52 (2H, t, N−CH2−); 8.13 (1H, s, =CH)
1.50 (6H, d, J = 6.7, CH(CH3)2); 4.76 (1H, m,
CH(CH3)2); 8.67 (1H, s, =CH)
1.48 (6H, d, J = 6.6, CH(CH3)2); 5.30 (1H, m,
CH(CH3)2); 8.20 (1H, s, =CH)
The mixture of liquid and low-melting 1-ethyl-3-nitro-1,2,4-triazole (5a) and 1-ethyl-5-nitro-1,2,4-
triazole (5b), and also 3-nitro-1-propyl-1,2,4-triazole (6a) and 5-nitro-1-propyl-1,2,4-triazole (6b) were
separated (method B) by vacuum distillation. Finally, from the mixture of 1-isopropyl-3-nitro-1,2,4-triazole (7a)
and 1-isopropyl-5-nitro-1,2,4-triazole (7b) the latter was isolated by vacuum distillation, and triazole 7a was
isolated by crystallization of the still residue from ethanol (method C).
The correctness of the assignments made were confirmed by the agreement of the melting points
(Table 2) of the isomeric triazoles 3a,b 4a,b isolated from the mixture with the melting points of these triazoles
given in [1,4].
When alkylating triazoles 1 and 2 with alkyl halides and dialkyl sulfates, the ratio of isomeric triazoles a
and b depends on the reaction conditions.
The solvent proved to have a significant influence on reaction selectivity. Carrying out the reaction in
water leads to the formation of a product with a larger proportion of the polar isomer a (Table 3). An increase in
the polarity of the reaction medium by increasing the reactant concentrations to double that given in the general
procedure increases the proportion of this isomer further by 3-3.5%. In all cases water in comparison with
863

ethanol levels the effect of the nature of the counter ion on the selectivity of alkylation (Table 3). The proportion
of isomer b depends significantly on the nature of the alkylating agent and the reaction temperature (Table 1).
The structures of the isomeric 1-alkyltriazoles obtained were confirmed by analysis of their spectral data.
1
In the H NMR spectra a singlet was recorded for the proton of the ring carbon atom at 8.12-8.78 ppm and the
protons of the alkyl groups were recorded (Table 4). In the spectra of all the 1-alkyl-3-nitro-1,2,4-triazoles (3a,
5a-7a) the signal for the proton at C(5) is found at lower field (δ 8.67-8.78 ppm), but the signals for the CH3
(CH2, CH) group protons at position 1 were found at higher field than the signals of the same protons in the
spectra of the isomeric 1-alkyl-5-nitro-1,3,4-triazoles 3b, 5b-7b.
Similarly in the spectrum of compound 4a the signal of the 5-CH3 protons was at 2.5 ppm, and in the
spectrum of the isomeric 5-methyltriazole 4b the protons of the 3-CH3 group resonate at higher field
(δ 2.32 ppm).
Two absorption maxima were observed in the UV spectra of triazoles 3-7. The short wave maximum in
the derivatives of 3-(5)-nitro-1,2,4-triazoles a(b) had low sensitivity towards the nature of the substituent, while
in the long wave region the absorption maximum of the nitrotriazole derivatives depends on the position of the
nitro group [5]. In the spectra of isomers 3a-7a a characteristic displacement is observed for the absorption
maximum by 9-14 nm into the short wave region [5] compared with isomers 3b-7b (Table 4).
The IR spectra were also fairly informative. In them were present the absorption bands of the nitro
group, most characteristic in frequency for derivatives of 3-nitro-1,2,4-triazoles [6, 7], localized in fairly narrow
spectral ranges, the symmetrical antiphase stretching vibration at 1540-1562 and the synphase at 1305-1346 cm-1
(Table 4). Both bands for isomers a were displaced compared with isomers b towards lower frequencies, and the
synphase vibrations were displaced to a greater extent (by 25-34 cm-1).
EXPERIMENTAL
1
The H NMR spectra were taken on a Bruker AM 400 (400 MHz) spectrometer in DMSO-d6, internal
standard was DMSO-d6. The IR spectra were taken on a Perkin-Elmer instrument in KBr disks, and the UV
spectra on a Specord instrument and an M-80 spectrophotometer. 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) packed with SE-30 siloxane elastomer, carrier gas was nitrogen
(40 ml/min), thermostat temperature 220°C, detector temperature 220°C. Melting points were determined on a
Boetius small scale hot stage with a RNMK-05 viewing device.
Preparation of Reactants. Dialkyl sulfates were washed with 3% sodium carbonate solution, then with
distilled water, dried, and distilled in vacuum (≥99.9%) main substance, acid calculated on sulfur ≤0.1%).
Triazoles 1 and 2 were recrystallized twice from water and had mp 214 and 197°C respectively (210 and 194°C
[7]). Alkyl halides were obtained by the procedures of [8]. The remaining reactants and solvents of chemically
pure grade were used without further purification.
Preparation of Triazoles 3-7 (General Procedure). A 0.25 M alcoholic (aqueous) solution of lithium
(sodium) hydroxide (36 ml) and dialkyl sulfate (0.1 mol) or alkyl halide* (0.08-0.15 mol) were added to a
suspension of triazole 1 or 2 (0.1 mol) in ethanol or water (30 ml). In water the reaction time was 8 h,
temperature 75-78°C (Table 1). The precipitated inorganic salt was filtered off, the solvent removed in vacuum
from the filtrate, and the residue was treated with methylene chloride. The solution obtained was washed
sequentially with 3% aqueous sodium carbonate solution, and with water, dried over anhydrous magnesium
sulfate, and the solvent distilled in vacuum. The ratio of isomers was determined before and after separation of
the mixture (Table 2). Isomers 3b and 4b were isolated from the mixture by extraction with hexane and were
_______
* At a reaction temperature of 75°C C2H5Br was added evenly during the synthesis.
864

recrystallized from aqueous isopropyl alcohol (method A). Triazoles 3a and 4a were isolated from the residue by
recrystallization from 2-propanol or ethanol. The mixture of compounds 5a,b and 6a,b was fractionated in
vacuum (method B). Isomer 7b was distilled in vacuum from the mixture of triazoles 7a,b. Triazoles 5a and 7a
were additionally recrystallized from ethanol and 5b from hexane. The characteristics of the products are given
in Tables 1-3.
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