Alkylation of acyl and sulfonyl derivatives of 3,5-diamino-1-phenyl-1,2,4- triazole

Article abstract of DOI:10.1007/s10593-009-0290-y

Alkylation of 3-acylamino-, 5-amino-1-phenyl-3-tosylamino-1,2,4-triazoles and 3,5-diacetylamino-1-phenyl-1,2,4-triazole in the presence of an equimolar amount of sodium methylate in DMSO occurs regioselectively at the amide (sulfamide) group nitrogen atom

Full text of DOI:10.1007/s10593-009-0290-y

Chemistry of Heterocyclic Compounds, Vol. 45, No. 4, 2009
ALKYLATION OF ACYL AND SULFONYL
DERIVATIVES OF 3,5-DIAMINO-1-PHENYL-
1,2,4-TRIAZOLE
V. M. Chernyshev1*, V. A. Rakitov1, V. V. Blinov1,
V. A. Taranushich1, and Z. A. Starikova2
Alkylation of 3-acylamino-, 5-amino-1-phenyl-3-tosylamino-1,2,4-triazoles and 3,5-diacetylamino-
1-phenyl-1,2,4-triazole in the presence of an equimolar amount of sodium methylate in DMSO occurs
regioselectively at the amide (sulfamide) group nitrogen atom. The benzylation of 3-acetylamino-
5-amino-1-phenyl-1,2,4-triazole with excess base and benzyl chloride also alkylates the amino group at
position 5. Alkylamino-1-R-1,2,4-triazoles can be conveniently prepared by alkylation of the
corresponding acetylamino-1,2,4-triazoles in the presence of base and subsequent acid hydrolysis of the
N-acetyl-N-alkyl derivatives.
Keywords: 5-amino-3-(N-acyl-N-alkyl)amino-1-phenyl-1,2,4-triazoles, 5-amino-3-(N-alkyl-N-tosyl)-
amino-1-phenyl-1,2,4-triazoles, acylamino-1,2,4-triazoles, 3,5-di(N-acetyl-N-methylamino)-1-phenyl-
1,2,4-triazole, sulfonylamino-1,2,4-triazoles, alkylation, regioselectivity, X-ray structural analysis,
structure.
Alkylation of C-amino-1,2,4-triazoles by alkyl halides and alkyl sulfates usually occurs at the nitrogen
atom of the heterocycle to give the aminotriazoles or iminotriazolines substituted in the ring [1-6]. Such an
alkylation route is typical of the majority of amino azoles and azines in which the amino group is conjugated
with the pyridine type nitrogen atom of the heterocycle [7]. Thus alkylamino-1,2,4-triazoles are usually prepared
by cyclization of alkyl substituted acyclic precursors [3, 8-10], hydrogenation of arylideneamino- or acylamino-
1,2,4-triazoles [11-13], or ammonolysis of halo-substituted 1,2,4-triazoles [4].
We have proposed that the alkylation reaction route for the amino-1,2,4-triazoles can be altered by
initial acylation or sulfonation of the amino group. In the presence of base an electron acceptor acyl (sulfonyl)
group can facilitate deprotonation and give a conjugated N-anion, alkylation of which can give the
N-acyl(sulfonyl)-N-alkylamino-1,2,4-triazoles.
_______
* To whom correspondence should be addressed, e-mail: tnw@novoch.ru, chern13@yandex.ru.
1South-Russian State Technical University, Novocherkassk 346428, Russia.
2A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, Moscow 117813,
Russia; e-mail: star@xray.ineos.ac.ru.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 557-567, April, 2009. Original
article submitted September 26, 2007.
436
0009-3122/09/4504-0436©2009 Springer Science+Business Media, Inc.

A similar route is used, for example, in the alkylation of 2-acetylamino-5-(benzimidazol-2-yl)thiazole
where the reaction course depends strongly on the solvent used [14].
With respect to establishing the reaction route and developing a novel method for preparing alkylamino-
1,2,4-triazoles we have studied the alkylation of acyl and sulfonyl derivatives of 3,5-diamino-1-phenyl-1,2,4-triazole
in the presence of the strong base sodium methylate. Selection of 3,5-diamino-1,2,4-triazoles for this study was
dictated by their use in medicine (see [10, 13] and references cited there).
We have shown that the reaction of the 3-acylamino-5-amino-1-phenyl-1,2,4-triazoles 1a,b and
5-amino-1-phenyl-3-tosylamino-1,2,4-triazole (1c) with alkyl halides in the presence of an equimolar amount or
slight excess of MeONa occurs regioselectively to give the 5-amino-3-(N-acyl-N-alkyl)amino-1-phenyl-
1,2,4-triazoles 2a-f and 5-amino-3-(N-alkyl-N-tosyl)amino-1-phenyl-1,2,4-triazoles 2g,h. Products of alkylation
at an endocyclic nitrogen atom are not found.
Ph
Ph
N
N
N N
R
MeONa
DMSO
R
R1X
+
N
NH2
N
NH2
N
N
H
R1
1a–c
2a–h
1a, 2a–d R = Ac; 1b, 2 e, f R = PhCO; 1c, 2 g, h R = Ts; 2 a, e, g R1 = Me, b R1 = Et, c R1 = All,
d, f, h R1 = Bn, R1X = MeI, EtI, AllBr, BnCl
Compound 1a reacts similarly with dimethylsulfate in aqueous KOH solution.
1
As in the starting compounds 1a-c, the H NMR spectra of compounds 2a-h retain the two-proton
singlet for the 5-NH2 at 6.5-6.7 ppm but the singlet for the amide NH proton has disappeared. The values of the
13
chemical shifts of the triazole ring carbon atoms in the C NMR spectra of compounds 2b,c,f-h (C-3 155-158
and C-5 154 ppm) are close to those of other 1-R-3,5-diamino-1,2,4-triazoles [8, 15]. In the proton-coupled 13C
NMR spectra the signal for the C-3 atom is split due to spin-spin coupling interaction through three bonds with
the alkyl group protons to a triplet in compounds 2b,c,f,h (J = 3.5-4.1) and to a quartet in the methyl derivative
2g (J = 2.9 Hz) while the signal for the C-5 atom is a singlet (spin-spin interaction of the carbon nucleus with
amino group protons not being observed due to rapid exchange of these protons with the solvent [15, 16]).
Hence one can exclude a 4-alkyl-substituted alternative structure since a splitting of the C-5 signal due to
Fig. 1. Structure of compound 2e (two independent molecules shown).
437

interaction with alkyl group protons would be observed [8, 16]. In addition, compounds 2d,h are identical to
those synthesized in the study [12]. Unambiguous proof of the structure of the alkyl derivatives was obtained by
an X-ray structural investigation of compound 2e (Fig. 1).
TABLE 1. Some Bond Lengths (d) in Compound 2e
Bond
N(1)–C(1)
d, Å
Bond
d, Å
Bond
d, Å
1.337(4)
1.359(4)
1.318(4)
1.408(4)
1.365(4)
1.408(4)
1.337(4)
1.397(5)
N(5)–C(3)
1.396(4)
1.459(4)
1.460(5)
1.244(4)
1.328(4)
1.362(4)
1.303(4)
1.395(4)
N(3A)–C(1A)
N(3A)–C(11A)
N(4A)–C(1A)
N(5A)–C(2A)
N(5A)–C(3A)
N(5A)–C(4A)
C(3A)–C(5A)
O(1A)–C(3A)
1.366(4)
1.404(4)
1.334(4)
1.412(4)
1.393(4)
1.426(4)
1.489(5)
1.244(4)
N(1)–C(2)
N(2)–C(2)
N(2)–N(3)
N(3)–C(1)
N(3)–C(11)
N(4)–C(1)
N(5)–C(2)
N(5)–C(4)
C(3)–C(5)
O(1)–C(3)
N(1A)–C(1A)
N(1A)–C(2A)
N(2A)–C(2A)
N(2A)–N(3A)
TABLE 2. Some Valence Angles (ω) in Compound 2e
Angle
C(1)–N(1)–C(2)
ω, deg
Angle
ω, deg
101.8(3)
110.9(3)
101.0(3)
108.4(3)
117.6(4)
132.5(3)
118.6(3)
124.5(4)
124.6(4)
121.4(4)
120.8(4)
118.0(5)
123.9(4)
117.9(4)
120.3(4)
120.5(4)
118.0(4)
C(1A)–N(1A)–C(2A)
N(1A)–C(1A)–N(3A)
C(2A)–N(2A)–N(3A)
C(1A)–N(3A)–N(2A)
N(2A)–C(2A)–N(1A)
C(1A)–N(3A)–C(11A)
N(2A)–N(3A)–C(11A)
N(1A)–C(1A)–N(4A)
N(4A)–C(1A)–N(3A)
N(2A)–C(2A)–N(5A)
N(1A)–C(2A)–N(5A)
O(1A)–C(3A)–N(5A)
O(1A)–C(3A)–C(5A)
N(5A)–C(3A)–C(5A)
C(3A)–N(5A)–C(2A)
C(3A)–N(5A)–C(4A)
C(2A)–N(5A)–C(4A)
102.7(3)
109.9(3)
101.8(3)
108.7(3)
116.7(4)
131.0(3)
119.6(3)
124.6(4)
125.4(4)
122.2(4)
120.9(4)
119.4(4)
122.0(4)
118.2(4)
119.2(4)
120.4(4)
118.9(3)
N(1)–C(1)–N(3)
C(2)–N(2)–N(3)
C(1)–N(3)–N(2)
N(2)–C(2)–N(1)
C(1)–N(3)–C(11)
N(2)–N(3)–C(11)
N(1)–C(1)–N(4)
N(4)–C(1)–N(3)
N(2)–C(2)–N(5)
N(1)–C(2)–N(5)
O(1)–C(3)–N(5)
O(1)–C(3)–C(5)
N(5)–C(3)–C(5)
C(3)–N(5)–C(2)
C(3)–N(5)–C(4)
C(2)–N(5)–C(4)
In the crystal, compound 2e consists of two independent molecules (Fig. 1, Tables 1 and 2). The bond
lengths and valence angles in the triazole ring agree with the corresponding values in previously reported 1-R-3,5-
diamino-1,2,4-triazoles [15, 17-18]. In both molecules the amino group has a planar configuration and is conjugated
with the triazole ring (the bond lengths N(4)–C(1) and N(4A)–C(1A) being 1.337(4) and 1.334(4) Å respectively and the
deviation of atoms N(4) and N(4A) from the triazole ring plane being -0.125 and 0.076 Å). Atoms N(5) and N(5A) have
almost planar coordination (sum of valence angles 358.7 and 358.6º). The N(5)–C(2) and N(5A)–C(2A) are lengthened to
1.397(5) and 1.412(4) Å when compared with the corresponding length in the 3-alkylamino-1,2,4-triazoles [17, 19]
without the acyl group (1.37 Å) but are close to the corresponding bond length in 3-acylamino-1,2,4-triazoles [15,
20]. The torsional angles C(3)–N(5)–C(2)–N(2) and C(3A)–N(5A)–C(2A)–N(2A) are -49.8(6) and 48.7(5)º respectively.
Ph
Ph
N
N
N N
2MeONa
DMSO
Ac
Ac
Ac
Ac
2MeI
+
N
N
N
N
N
N
H
H
Me
Me
3
4
438

Methylation of 3,5-diacetylamino-1-phenyl-1,2,4-triazole (3) alkylates both amide groups to give the
corresponding compound 4 whose structure was proved by spectroscopic data and X-ray analysis (Fig. 2, Tables
3 and 4).
Atoms N(4) and N(5) in the compound 4 molecule (Fig. 2) have a planar coordination, their deviation from
the triazole ring plane being 0.039 and 0.078 Å respectively. The C(2)–N(5) bond is lengthened to 1.401(3) Å when
compared with the similar bond (1.33-1.37 Å) in compound 2e and other 3,5-diamino-1,2,4-triazoles [15, 17-18].
The C(3)N(4)C(4)O(1)C(5) fragment is planar to within ± 0.01 Å and the torsional angle C(4)–N(4)–C(1)–N(2) is 7.9(4)º.
Fig. 2. Structure of the compound 4 molecule.
TABLE 3. Some Bond Lengths (d) in Compound 4
Bond
N(1)–C(1)
d, Å
Bond
d, Å
Bond
d, Å
1.346(4)
1.324(3)
1.319(4)
1.376(3)
1.341(3)
1.435(3)
N(4)–C(1)
N(4)–C(3)
N(4)–C(4)
O(1)–C(4)
C(4)–C(5)
N(5)–C(2)
1.406(3)
1.481(4)
1.365(4)
1.230(3)
1.501(4)
1.401(3)
N(5)–C(6)
N(5)–C(7)
O(2)–C(7)
C(7)–C(8)
1.464(4)
1.358(4)
1.223(3)
1.506(4)
N(1)–C(2)
N(2)–C(1)
N(2)–N(3)
N(3)–C(2)
N(3)–C(9)
TABLE 4. Some Valence Angles (ω) in Compound 4
Angle
C(1)–N(1)–C(2)
ω, deg
Angle
C(3)–N(4)–C(4)
ω, deg
101.9(2)
115.9(2)
102.4(2)
108.0(2)
111.8(2)
118.5(3)
125.5(3)
123.7(3)
124.4(2)
120.6(2)
131.3(2)
117.7(2)
115.9(2)
126.3(3)
119.4(3)
117.8(3)
122.8(3)
117.9(2)
122.7(3)
119.4(2)
119.5(3)
122.7(3)
117.7(2)
N(1)–C(1)–N(2)
C(1)–N(2)–N(3)
N(2)–N(3)–C(2)
N(1)–C(2)–N(3)
N(1)–C(1)–N(4)
N(2)–C(1)–N(4)
N(1)–C(2)–N(5)
N(3)–C(2)–N(5)
N(2)–N(3)–C(9)
C(2)–N(3)–C(9)
C(1)–N(4)–C(3)
C(1)–N(4)–C(4)
N(4)–C(4)–C(5)
O(1)–C(4)–N(4)
O(1)–C(4)–C(5)
C(2)–N(5)–C(6)
C(2)–N(5)–C(7)
C(6)–N(5)–C(7)
O(2)–C(7)–N(5)
O(2)–C(7)–C(8)
N(5)–C(7)–C(8)
439

The C(6)N(5)C(7)O(2)C(8) fragment is also planar to within ± 0.05 Å but it is twisted relative to the triazole ring plane
as a result of a repulsive interaction between the acetyl group and the benzene ring (torsional angle C(7)–N(5)–
C(2)–N(3) -68.2(4) Å). A shortened intramolecular contact for H(C(8))···C(9) of 2.60 Å is observed in the molecule.
Hence the acyl and sulfonyl fragments in the molecules 1a-c and 3 take the role of activating groups and
this results in a regioselective alkylation of the N-anions formed in basic medium from the amide (sulfamide)
group.
Use, however, of an excess of benzyl chloride and sodium methylate relative to the substrate 1a gave the
alkyl derivatives 2d, 5 and 6 in the molar ratio 1.3:1.4:1 from the reaction mixture, the composition and
structure of which were confirmed by elemental analysis and spectroscopic data.
Ph
Ph
N
N
N
N
2.2 MeONa
DMSO
Ac
Ac
Bn
2d
1a
2.2 BnCl
+
+
+
N
NH
Bn
N
N
N
N
Bn
Bn
Bn
5
6
The ratio of reaction products indicates that the amide group having greatest acidity is initially alkylated.
As a result of deprotonation of the amino group, compound 2d forms an N-anion which is alkylated to give
compound 5. The latter gives compound 6 similarly. Evidently compounds 2d and 5 have comparable reactivity
towards alkylation in the presence of strong bases.
The acid hydrolysis of compounds 2a-d and 4 gave the alkylaminotriazoles 7a-d and 8 in good yields.
Ph
Ph
N
N
N
N
R1
HCl
Me
Me
2a–d, 4
N
NH2
N
N
EtOH
N
N
H
H
H
7a–d
8
7a R1 = Me, b R1 = Et, c R1 = All, d R1 = Bn
Hence the alkylation of acylamino-1,2,4-triazoles and subsequent hydrolysis of the N-acyl-N-alkyl
derivatives is a convenient method for the synthesis of 3- and 5-alkylamino-1,2,4-triazoles.
EXPERIMENTAL
1H and 13C NMR spectra were recorded on a Varian Unity-300 (300 and 75 MHz) instrument using
DMSO-d6 and with TMS as internal standard. Mass spectra were obtained on a Finnigan MAT Incos 50
spectrometer with direct introduction of the sample into the ion source and ionization energy 70 eV and on a
Finnigan LCQ Deca XP MAX instrument in electrospray mode with positive ionization and direct introduction
of the samples in acetonitrile at a concentration of 0.5 mg/ml.
The starting compounds 1a,c and 3 were synthesized by a known method [12].
5-Amino-3-benzoylamino-1-phenyl-1,2,4-triazole (1b) was prepared similarly. Yield 82%; mp
205-207ºC (a mixture of DMF and EtOH). 1H NMR spectrum, δ, ppm: 6.56 (2H, s, NH2); 7.35 (1H, m, arom.);
7.49-7.59 (7H, m, arom.); 7.97 (2H, m, arom.); 10.55 (1H, s, NH). 13C NMR spectrum, δ, ppm: 122.41, 126.67,
127.70, 128.21, 129.29, 134.58, 133.98, 137.15, 153.82 (C-5), 153.94 (C-3), 165.10 (CO). Found, %: C 64.80;
H 4.53; N 25.22. C15H13N5O. Calculated, %: C 64.51; H 4.69; N 25.07.
440

5-Amino-3-(N-acyl-N-alkyl)amino-1-phenyl-1,2,4-triazoles 2a-f and 5-Amino-3-(N-alkyl-N-tosyl)-
amino-1-phenyl-1,2,4-triazoles 2g,h (General Method). A. A solution of Na (0.12 g, 5.1 mmol) in MeOH
(1.5 ml) was added to a solution of compound 1a-c (4.6 mmol) in DMSO (10 ml). The product was stirred for
5 min at room temperature, cooled to 0-10ºC, and a solution of the corresponding alkyl halide (5.1 mmol) was
added dropwise with vigorous stirring and with cooling. The reaction mixture was stirred for 4 h, the DMSO
was distilled off in vacuo, and water (10 ml) was added to the residue. The precipitate obtained was filtered off,
dissolved in chloroform (30 ml), passed through an alumina column (4×3 cm), the chloroform distilled off, and
the residue was crystallized.
B. Compound 1a (1 g, 4.6 mmol) was dissolved with heating in a solution of KOH (0.52 g, 9.2 mmol) in
water (20 ml) and the solution obtained was cooled to 0-5ºC. Me2SO4 (0.61 g, 5.52 mmol) was added dropwise
with vigorous stirring and cooling. Stirring was continued for 4 h and the precipitate was filtered off, washed
with water, and crystallized to give compound 2a whose physicochemical properties were identical to those
obtained using method A.
5-Amino-3-(N-acetyl-N-methyl)amino-1-phenyl-1,2,4-triazole (2a). Yield 82% (method A), 40%
1
(method B); mp 200-202ºC (ethanol). H NMR spectrum, δ, ppm: 2.22 (3H, s, CH3); 3.18 (3H, s, CH3); 6.51
(2H, s, NH2); 7.36-7.58 (5H, m, C6H5). Mass spectrum (EI), m/z (Irel, %): 231 [M]+ (27), 189 (100), 160 (10),
133 (10), 119 (25), 104 (12), 91 (34), 44 (64). Found, %: C 56.90; H 5.81; N 30.18. C11H13N5O. Calculated, %:
C 57.13; H 5.67; N 30.28.
TABLE 5. Some Crystal Parameters for Compounds 2e and 4 and
Conditions for Carrying Out the X-ray Structural Investigation
Compound
Parameter
2e
4
Cell type
triclinic
orthorhombic
Cell parameters
a, Å
6.608(2)
13.121(4)
19.034(5)
71.406(5)
90.000(5)
75.415(4)
P-1
7.367(2)
14.712(3)
26.912(5)
b, Å
c, Å
α, deg.
β, deg.
γ, deg.
Space group
Cell volume, Å3
Z
Pbca
1508.1(7)
4
2917(1)
8
Dcalc, g/cm3
Absorption coefficient, mm-1
Crystal size, mm
Radiation
2θmax, deg.
1.292
1.309
0.086
0.092
0.45×0.30×0.25
0.50×0.35×0.25
λМоКα
58.00
λМоКα
56.00
Number of independent reflections 7865 (Rint = 0.0979)
with I>2σ(I)
2750 (Rint = 0.0091)
Number of refinement parameters
397
190
Final difference factors,
R1
0.0754
0.0652
(calculated using Fhkl
for 1749 reflections
with I>2σ(I))
(calculated using Fhkl
for 1844 reflections
with I>2σ(I))
0.1039 (calculated using Fhkl
for all 7865 reflections)
wR2
0.1243 (calculated using Fhkl
for all 2750 reflections)
G00F
0.921
0.972
441

5-Amino-3-(N-acetyl-N-ethyl)amino-1-phenyl-1,2,4-triazole (2b). Yield 60% (method A); mp
172-173ºC (ethanol). 1H NMR spectrum, δ, ppm (J, Hz): 1.08 (3H, t, J = 7.0, CH3); 2.13 (3H, s, CH3); 3.68 (2H,
13
q, J = 7.0, CH2); 6.66 (2H, s, NH2); 7.34-7.56 (5H, m, C6H5). C NMR spectrum, δ, ppm: 13.17 (NCH2CH3);
23.01 (COCH3); 40.78 (NCH2CH3); 122.64, 126.95, 129.28, 136.77, 154.25 (C-5); 157.06 (C-3); 169.12 (CO).
Mass spectrum (EI), m/z (Irel, %): 245 [M]+ (25), 203 (77), 188 (100), 175 (22), 160 (10), 119 (18), 91 (21), 77
(69). Found, %: C 58.72; H 5.22; N 28.82. C12H15N5O. Calculated, %: C 58.76; H 6.16; N 28.55.
5-Amino-3-(N-acetyl-N-allyl)amino-1-phenyl-1,2,4-triazole (2c). Yield 32% (method A); mp
1
164-165ºC (benzene). H NMR spectrum, δ, ppm, (J, Hz): 2.19 (3H, s, CH3); 4.30 (2H, d, J = 5.2, CH2); 5.08
(2H, m, 2CH); 5.77 (1H, m, CH); 6.67 (2H, s, NH2); 7.34-7.54 (5H, m, C6H5). 13C NMR spectrum, δ, ppm:
23.03 (COCH3); 47.94 (NCH2); 116.17 (CH=CH2); 122.61 (CH=CH2); 126.98, 129.33, 133.61, 136.77, 154.20
(C-5); 157.07 (C-3); 169.31 (CO). Mass spectrum (EI), m/z (Irel, %): 257 [M]+ (47), 215 (69), 188 (30), 160 (35),
123 (10), 119 (51), 91 (27), 77 (100). Found, %: C 60.79; H 5.92; N 27.42. C13H15N5O. Calculated, %: C 60.69;
H 5.88; N 27.22.
5-Amino-3-(N-acetyl-N-benzyl)amino-1-phenyl-1,2,4-triazole (2d) Yield 62% (method A); mp
1
194-196ºC (ethanol, mp 194-196ºC [12]). The H NMR spectrum was identical to that obtained in [12]. Mass
spectrum (EI), m/z (Irel, %): 307 [M]+ (18), 264 (57), 188 (10), 160 (30), 119 (36), 106 (23), 91 (100), 77 (56).
5-Amino-3-(N-benzoyl-N-methyl)amino-1-phenyl-1,2,4-triazole (2e). Yield 62% (method A); mp
1
209-211ºC (ethanol). H NMR spectrum, δ, ppm: 3.31 (3H, s, CH3); 6.58 (2H, s, NH2); 7.19-7.43 (10H, m,
2C6H5). Mass spectrum (EI), m/z (Irel, %): 293 [M]+ (17), 265 (46), 105 (100), 77 (98). Found, %: C 65.70;
H 5.10; N 24.03. C16H15N5O. Calculated, %: C 65.52; H 5.15; N 23.88.
5-Amino-3-(N-benzoyl-N-benzyl)amino-1-phenyl-1,2,4-triazole (2f). Yield 85% (method A); mp 230-
1
231ºC (ethanol). H NMR spectrum, δ, ppm: 5.05 (2H, s, CH2); 6.63 (2H, s, NH2); 7.16-7.45 (15H, m, 3C6H5).
13C NMR spectrum, δ, ppm: 50.70 (NCH2), 122.50, 126.89, 126.97, 127.42, 127.51, 127.71, 128.12, 129.18,
130.07, 136.15, 136.53, 137.58, 154.46 (C-5), 157.56 (C-3), 169.30 (CO). Mass spectrum (EI), m/z (Irel, %): 369
[M]+ (17), 264 (95), 105 (86), 91 (62), 77 (100). Found, %: C 71.62; H 5.23; N 19.22. C22H19N5O. Calculated,
%: C 71.53; H 5.18; N 18.96.
5-Amino-3-(N-methyl-N-tosyl)amino-1-phenyl-1,2,4-triazole (2g). Yield 79% (method A);
1
mp 132.5-134.5ºC (ethanol). H NMR spectrum, δ, ppm (J, Hz): 2.38 (3H, s, CH3); 3.17 (3H, s, NCH3); 6.60
(2H, s, NH2); 7.32-7.52 (7H, m, Ar); 7.79 (2H, d, J = 8.2, Ar). 13C NMR spectrum, δ, ppm: 20.88 (CH3); 35.83
(NCH3); 122.37, 126.81, 127.63, 129.27, 129.31, 135.13, 136.79, 143.59, 154.02 (C-5); 155.83 (C-3). Mass
spectrum (EI), m/z (Irel, %): 343 [M]+ (12), 278 (30), 187 (20), 146 (27), 105 (44), 91 (38), 82 (10), 77 (100).
Found, %: C 56.20; H 5.02; N 20.10. C16H17N5O2S. Calculated, %: C 55.96; H 4.99; N 20.39.
5-Amino-3-(N-benzyl-N-tosyl)amino-1-phenyl-1,2,4-triazole (2h). Yield 81% (method A); mp
1
170-172ºC (ethanol, mp 170-172ºC [12]). The H NMR spectrum was identical to that reported in [12]. 13C
NMR spectrum, δ, ppm: 20.88 (CH3), 51.79 (NCH2); 122.19, 126.75, 127.11, 127.47, 127.75, 128.05, 129.22,
129.26, 136.23, 136.76, 137.04, 143.56, 153.98 (C-5); 154.93 (C-3). Mass spectrum (EI), m/z (Irel, %): 419 [M]+
(2), 264 (28), 160 (10), 105 (12), 91 (100), 77 (54). Found, %: C 63.20; H 5.00; N 16.91. C22H21N5O2S.
Calculated, %: C 62.99; H 5.05; N 16.69.
3,5-Di(N-acetyl-N-methylamino)-1-phenyl-1,2,4-triazole (4). A solution of Na (0.22 g, 9.4 mmol) in
MeOH (1 ml) was added with stirring to a solution of the diacetyl derivative 3 (1 g, 3.9 mmol) in DMSO (5 ml).
The product was stirred at room temperature for 5 min, cooled to 0-10ºC, and MeI (1.33 g, 9.4 mmol) was added
over 10 min with vigorous stirring. The reaction mixture was stirred for 4 h, solvent removed by distillation in
vacuo, and the residue was dissolved in chloroform (50 ml), washed with a 5% NaOH solution (20 ml) and
water (20 ml), passed through an alumina column (4×3 cm), and the chloroform was distilled off to give
1
compound 4 (0.77 g, 70%) with mp 104-106ºC. H NMR spectrum, δ, ppm: 1.85 (3H, s, CH3); 2.27 (3H, s,
CH3); 3.02 (3H, s, NCH3); 3.26 (3H, s, NCH3); 7.45-7.60 (5H, m, C6H5). Mass spectrum (EI), m/z (Irel, %): 287
442

[M]+ (16), 245 (50), 203 (100), 189 (15), 118 (10), 91 (20), 77 (35). Found, %: C 58.71; H 6.00; N 24.50.
C14H17N5O2. Calculated, %: C 58.52; H 5.96; N 24.37.
5-Amino-3-(N-acetyl-N-benzyl)amino-1-phenyl-1,2,4-triazole (2d), 3-(N-Acetyl-N-benzyl)amino-
5-benzylamino-1-phenyl-1,2,4-triazole (5), and 3-(N-Acetyl-N-benzyl)amino-5-dibenzylamino-1-phenyl-
1,2,4-triazole (6). A solution of Na (0.24 g, 10.2 mmol) in MeOH (1.5 ml) was added to a solution of compound
1a (1 g, 4.6 mmol) in DMSO (10 ml). The reaction product was stirred at room temperature for 5 min, cooled to
0-10ºC, and a solution of benzyl chloride (1.29 g, 10.2 mmol) in DMSO was added dropwise with vigorous
stirring and cooling. The reaction mixture was then stirred for 4 h, DMSO was distilled off in vacuo, and water
(10 ml) was added to the residue. The oil produced was extracted with chloroform (30 ml), the extract washed
with water and dried over sodium sulphate, and solvent was distilled off. The residue was chromatographed on
an alumina column (30×3 cm) using chloroform as eluent.
Compound 2d. Rf 0.19, yield 0.49 g (35%).
Compound 5. Rf 0.46, yield 0.69 g (38%), mp 118-119ºC. 1H NMR spectrum, δ, ppm (J, Hz): 2.23 (3H,
s, CH3); 4.43 (2H, d, J = 5.4, CH2); 4.91 (2H, s, CH2); 7.24-7.51 (16H, m, 3 C6H5 + NH). 13C NMR spectrum, δ,
ppm: 23.29 (CH3); 46.72 (CH2); 48.92 (CH2); 122.05, 126.62, 126.65, 127.19, 127.35, 127.43, 127.94, 127.98,
129.38, 136.43, 137.88, 139.58, 154.20 (C-5); 157.14 (C-3); 169.66 (CO). Found, %: C 72.28; H 5.72; N 17.77.
C24H23N5O. Calculated, %: C 72.52; H 5.83; N 17.62.
1
Compound 6. Rf 0.57, yield 0.6 g (27%), mp 94-95ºC. H NMR spectrum, δ, ppm: 2.08 (3H, s, CH3);
4.19 (4H, s, 2CH2); 4.85 (2H, s, CH2); 7.08-7.55 (20H, m, 4C6H5). Mass spectrum (ES), m/z: 488 [M+H]+.
Found, %: C 76.29; H 6.02; N 14.51. C31H29N5O. Calculated, %: C 76.36; H 5.99; N 14.36.
3-Alkylamino-5-amino-1-phenyl-1,2,4-triazoles (7a-d) (General Method). A mixture of the
corresponding 5-amino-3-(N-acyl-N-alkyl)amino-1-phenyl-1,2,4-triazole 2a-d (2 mmol), EtOH (5 ml), and
conc. HCl (1 ml) was refluxed for 1 h, the solvent was removed by evaporation, and the residue was neutralized
with a 20% aqueous NH3 solution. The precipitate formed was filtered off and crystallized.
5-Amino-3-methylamino-1-phenyl-1,2,4-triazole (7a). Yield 71%; mp 141-142ºC. 1H NMR spectrum,
δ, ppm (J, Hz): 2.64 (3H, d, J =5.1, CH3); 5.51 (1H, q, J = 5.1, NH); 6.20 (2H, s, NH2); 7.16-7.52 (5H, m, C6H5).
13C NMR spectrum, δ, ppm: 29.11 (CH3); 121.62, 125.60, 129.08, 137.49, 152.66 (C-5); 160.57 (C-3). Mass
spectrum (EI), m/z (Irel, %): 189 [M]+ (79), 161 (8), 146 (10), 133 (8), 119 (32), 104 (20), 91 (100), 77 (93).
Found, %: C 57.29; H 5.93; N 36.81. C9H11N5. Calculated, %: C 57.13; H 5.86; N 37.01.
5-Amino-3-ethylamino-1-phenyl-1,2,4-triazole (7b). Yield 91%; mp 110-110.5ºC. 1H NMR spectrum,
δ, ppm (J, Hz): 1.08 (3H, t, J = 7.1, CH3); 3.06 (2H, m, CH2); 5.55 (1H, t, J = 5.4, NH); 6.21 (2H, s, NH2);
7.18-7.23 (2H, m, Ar); 7.38-7.50 (3H, m, Ar). Mass spectrum (EI), m/z (Irel, %): 203 [M]+ (56), 188 (100), 175
(13), 119 (12), 91 (10), 77 (16). Found, %: C 59.14; H 6.30; N 34.56. C10H13N5. Calculated, %: C 59.10; H 6.45;
N 34.46.
1
3-Allylamino-5-amino-1-phenyl-1,2,4-triazole (7c). Yield 72%; mp 87.5-88.5ºC. H NMR spectrum,
δ, ppm (J, Hz): 3.68 (2H, m, CH2); 5.02 (1H, dd, J = 10.3, J = 1.7, CH); 5.17 (1H, dd, J = 17.2, J = 1.7, CH);
5.79 (1H, t, J = 6.2, NH); 5.88 (1H, m, CH); 6.20 (2H, s, NH2); 7.18-7.50 (5H, m, C6H5). 13C NMR spectrum, δ,
ppm: 44.87 (CH2); 114.44, 121.11, 125.02, 128.97, 136.71, 137.93, 153.50 (C-5); 161.33 (C-3). Found, %:
C 61.49; H 6.11; N 32.81. C11H13N5. Calculated, %: C 61.38; H 6.09; N 32.53.
5-Amino-3-benzylamino-1-phenyl-1,2,4-triazole (7d). Yield 78%; mp 164-166ºC (mp 165-166ºC
1
[12]). The H NMR spectrum was identical to that reported before [12]. Mass spectrum (EI), m/z (Irel, %): 265
[M]+ (38), 160 (37), 119 (56), 106 (38), 91 (100), 77 (79).
3,5-Di(N-methylamino)-1-phenyl-1,2,4-triazole (8). A mixture of compound 4 (0.4 g, 1.4 mmol) and
conc. HCl (1 ml) was refluxed for 30 min, neutralized with a 20% aqueous solution of NH3, and the precipitate
1
formed was crystallized from water. Yield 0.2 g (71%); mp 123-123.5ºC. H NMR spectrum, δ, ppm (J, Hz):
2.65 (3H, d, J = 5.0, CH3); 2.76 (3H, d, J = 4.7, CH3); 5.68 (1H, q, J = 5.0, NH); 6.29 (1H, q, J = 4.7, NH);
443

7.19-7.24 (1H, m Ar); 7.39-7.48 (4H, m, Ar). Mass spectrum (EI), m/z (Irel, %): 203 [M]+ (71), 175 (10), 146
(24), 133 (19), 118 (39), 104 (50), 96 (35), 91 (100). Found, %: C 59.30; H 6.31; N 34.39. C10H13N5. Calculated,
%: C 59.10; H 6.45; N 34.46.
X-Ray structural analysis of compound 2e was carried out on a Bruker SMART CCD area detector
diffractometer at 200K, and of compound 4 on a Syntex P21 diffractometer at 193K. Single crystals of
compounds 2e were grown from a mixture of DMF and ethanol (1:5) and of compound 4 from a mixture of
DMF, ethanol, and water (1:5:0.5). Both structures were solved by a direct method. All non-hydrogen atoms
were localized in electron density difference syntheses and refined using Fhkl2 in the anisotropic approximation.
All hydrogen atoms were set up in the geometrically calculated positions and refined using the "riding" model
with U(H) = 1.2 U(C) where U(C) is the equivalent temperature factor for the carbon atom with which the
corresponding atom is bonded. The crystal parameters for compounds 2e and 4 and the conditions for the X-ray
structural experiments are given in Table 5. All calculations were made using the SHELXTL PLUS 5 program
package [21].
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