Reactivity of C-amino-1,2,4-triazoles toward electrophiles: A combined computational and experimental study of alkylation by halogen alkanes

Article abstract of DOI:10.1021/jo502405q

A combination of computational and experimental methods was used to examine the structure-reactivity relationships in the reactions of C-amino-1H-1,2,4-triazoles with electrophiles. The global nucleophilicity of 3-amino- and 3,5-diamino-1H-1,2,4-triazoles was predicted to be higher than that of 5-amino-1H-1,2,4-triazoles. Fukui functions and molecular electrostatic potential indicate that reactions involving an amino group should occur more easily for the 3-amino- than for the 5-amino-1H-1,2,4-triazoles. Increasing electrophile hardness should increase the probability of attack at the N-4 atom of the triazole ring, whereas increasing softness should enhance the probability of attack at the N-2 atom and 3-NH₂ group. Calculated transition state energies of model S_N2 reactions and experimental studies showed that quaternization of 1-substituted 3-amino- and 3,5-diamino-1H-1,2,4-triazoles by many alkyl halides proceeds with low selectivity and can involve the N-2 and N-4 atoms as well as the 3-NH₂ group as reaction centers. A new method for the selective synthesis of 1,4-disubstituted 3-amino- and 3,5-diamino-1,2,4-triazoles based on quaternization of readily available 1-substituted 3-acetylamino-1,2,4-triazoles with subsequent removal of the acetyl protecting group by acid hydrolysis was developed.

Full text of DOI:10.1021/jo502405q

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Article
Reactivity of C-amino-1,2,4-triazoles towards electrophiles: a combined
computational and experimental study of alkylation by halogen alkanes
Victor M. Chernyshev, Anna G. Vlasova, Alexander V. Astakhov, Svitlana V Shishkina, and Oleg V Shishkin
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo502405q • Publication Date (Web): 02 Dec 2014
Downloaded from http://pubs.acs.org on December 7, 2014
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Reactivity of Cꢀaminoꢀ1,2,4ꢀtriazoles towards electrophiles: a combined
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computational and experimental study of alkylation by halogen alkanes
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Victor M. Chernyshev,†,* Anna G. Vlasova,† Alexander V. Astakhov,† Svitlana V. Shishkina,‡ and
Oleg V. Shishkin‡,§1
†Platov SouthꢀRussian State Polytechnic University (NPI), Prosveschenya 132, 346428
Novocherkassk, Russian Federation
‡State Scientific Institution ‘Institute for Single Crystals’ of National Academy of Sciences of
Ukraine, Lenin Ave. 60, 61001 Kharkiv, Ukraine
§V. N. Karazin Kharkiv National University, 4 Svobody sq., Kharkiv 61202, Ukraine
chern13@yandex.ru
TOC graphic:
ABSTRACT: A combination of computational and experimental methods was used to examine the
structureꢀreactivity relationships in the reactions of Cꢀaminoꢀ1Hꢀ1,2,4ꢀtriazoles with electrophiles.
The global nucleophilicity of 3ꢀaminoꢀ and 3,5ꢀdiaminoꢀ1Hꢀ1,2,4ꢀtriazoles was predicted to be
higher than that of 5ꢀaminoꢀ1Hꢀ1,2,4ꢀtriazoles. Fukui functions and molecular electrostatic potential
indicate that reactions involving an amino group should occur more easily for the 3ꢀaminoꢀ than for
the 5ꢀaminoꢀ1Hꢀ1,2,4ꢀtriazoles. Increasing electrophile hardness should increase the probability of
1 Prof. Oleg V. Shishkin passed away unexpectedly on July 17, 2014. He had been fully in charge of this project.
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attack at the Nꢀ4 atom of the triazole ring, while increasing softness should enhance the probability
of attack at the Nꢀ2 atom and 3ꢀNH2 group. Calculated transition state energies of model SN2
reactions and experimental studies showed that quaternization of 1ꢀsubstituted 3ꢀaminoꢀ and 3,5ꢀ
diaminoꢀ1Hꢀ1,2,4ꢀtriazoles by many alkyl halides proceeds with low selectivity and can involve the
Nꢀ2 and Nꢀ4 atoms as well as the 3ꢀNH2 group as reaction centers. A new method for the selective
synthesis of 1,4ꢀdisubstituted 3ꢀaminoꢀ and 3,5ꢀdiaminoꢀ1,2,4ꢀtriazoles based on quaternization of
readily available 1ꢀsubstituted 3ꢀacetylaminoꢀ1,2,4ꢀtriazoles with subsequent removal of the acetyl
protecting group by acid hydrolysis was developed.
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Introduction
Cꢀaminoꢀ1,2,4ꢀtriazoles are used as reagents for the synthesis of pesticides,1 pharmaceuticals,2
dyes,3 photographic materials,4 antiꢀcorrosion additives,5 polymers,6 magnetic,7 optical8 and
energetic materials,9 adsorbents and catalysts.10 The wide application of these compounds as
reagents is largely based on their high reactivity towards electrophiles.11 Molecules of Cꢀaminoꢀ
1,2,4ꢀtriazoles contain several nucleophilic centers, namely the NH2 group and any of the ring
nitrogen atoms and, therefore, can be considered as multifunctional nucleophilic reagents. Such
multifunctionality, on the one hand, opens up exciting possibilities for the synthesis of various
substituted triazoles and condensed heterocycles; however, on the other hand, it causes the problem
of low selectivity in the reactions of Cꢀaminoꢀ1,2,4ꢀtriazoles with many electrophilic reagents.11,12
Alkylation of Cꢀaminoꢀ1,2,4ꢀtriazoles by alkyl halides is used as a general method for
preparing Nꢀalkylated aminotriazoles, including quaternary salts.11,13ꢀ15 It is largely reported that in a
neutral medium the reaction affords products alkylated at the nitrogen atoms of the triazole cycle
while the less nucleophilic NH2 group is not alkylated, even in the case of triazoles 1,2, and 3a,
which are substituted at the Nꢀ1 or Nꢀ2 atoms (Scheme 1). Thus, products 4 and 5, which are
quaternized at the Nꢀ4 of the triazole ring, were obtained by the alkylation of 1ꢀsubstituted 5ꢀaminoꢀ
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(1) and 3ꢀaminoꢀ1,2,4ꢀtriazoles (2).14,15 However, quaternization of 3,5ꢀdiaminoꢀ1ꢀphenylꢀ1,2,4ꢀ
triazole (3a) in methanol, as reported,16 afforded Nꢀ2 alkylated products 6 (Scheme 1).
Scheme 1
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As far as we know, examples of alkylation of the NH2ꢀgroup of 3ꢀaminoꢀ and 5ꢀaminoꢀ1,2,4ꢀ
triazoles by alkyl halides in neutral medium have not been described in the literature. However,
benzylation of 7 (reactivity of compounds 7, in many aspects, is analogous to the 1ꢀsubstituted 3ꢀ
aminoꢀ1,2,4ꢀtriazoles 2 and 3)17 afforded alkylamino derivative 9 as a byꢀproduct, in addition to the
expected quaternary salt 8 (Scheme 2).18
Scheme 2
Notably, the calculated (MP2/6ꢀ31+G*, gas phase) transition state (TS) energies of SN2
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attacks of methyl chloride on Nꢀ2 or NH2 of 3ꢀaminoꢀ1,2,4ꢀtriazoles (2, R = H, Me; Rʹ = H) are no
more than 3 kcal/mol higher than the TS energies of the SN2 attack on Nꢀ4.15 The published
results15,18 suggest that the formation of alkylamino derivatives is possible in the reactions of
aminotriazoles of types 2 or 3 with halogen alkanes, and, apparently, the position of the endocyclic
R substituent sufficiently affects the selectivity of alkylation of Cꢀaminoꢀ1,2,4ꢀtriazoles. A careful
investigation of reactions between aminotriazoles of types 2 and 3 is required for examination of
these hypotheses.
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In this work, we investigated the influence of Cꢀaminoꢀ1,2,4ꢀtriazole structure, namely the
position and type of substituent at the hydrazine fragment of triazole molecules, on their reactivity
towards electrophiles, particularly halogen alkanes. For these purposes, we applied quantumꢀ
chemical methods in combination with experimental investigations of alkylation of 1ꢀsubstituted Cꢀ
aminoꢀ1,2,4ꢀtriazoles and their acetyl derivatives by halogen alkanes.
Results and discussion
1. Computational investigation of reactivity of Cꢀaminoꢀ1,2,4ꢀtriazoles towards
electrophiles
To assess the influence of the substituent position in the triazole ring on the reactivity of isomeric
Cꢀaminoꢀ1,2,4ꢀtriazoles and predict the direction of electrophilic attack, we calculated the soꢀcalled
static reactivity indices19ꢀ25 as well as the transition state energies of SN2 alkylation at various
potential reaction centers for model molecules of aminotriazoles. It should be noted that the results
obtained can be correctly applied to the kinetically controlled reactions in which the initial reaction
products cannot isomerize to thermodynamically more stable compounds. Reactions of
aminotriazoles with alkyl halides satisfy this limitation in most cases.
1.1 Computational Details
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Quantum chemical calculations were performed using the Gaussian’09 suite of computational
programs.26 For all investigated species, a charge density analysis was performed by a natural
population analysis (NPA)27 at the DFT B3LYP/6ꢀ311++G(2d,2p)28 or MP2/augꢀccꢀpVDZ levels of
theory.29 We note that the cationic systems required in the calculations of local reactivity indices
were kept at the same geometry of the neutral system. The structures and transition state energies
were computed at the B3LYP/6ꢀ311++G(2d,2p) level of theory. The character of the stationary
points on the potential energy surface (minimum or transition state) was confirmed by calculation of
the Hessian matrix at the same level of theory within the harmonic approximation. The optimized
ground states had only real frequencies while transition states had one imaginary frequency. The
imaginary frequencies of the transition states were subsequently visualized and in all cases clearly
indicated connection of reactants to products. Solvent effects were modeled by the integral equation
formalism version of the polarizable continuum method (IEFꢀPCM) of Tomasi.30 The computed
energetic parameters and atomic coordinates of all species are given in the Supporting Information.
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1.2 Static Reactivity Indices
For static reactivity indices, global and local reactivity descriptors were considered (for
detailed description, see the Supporting Information). The global reactivity descriptors, such as the
electronic chemical potential (ꢁ),19a chemical hardness (η),19b global softness (S),19c and
nucleophilicity index (Nu),20a,b are believed to provide intermolecular reactivity trends.
The global nucleophilicity indices Nu were calculated by three different methods.20b
According to the first method, Nu(1) was computed as the inverse of the electrophilicity index,20a in
20b
the second method, Nu(2) was calculated as the inverse of the electrodonating power,
and in the
third approach, nucleophilicity Nu(3) is considered as the negative value of the (intrinsic) ionization
potential.22a
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For local reactivity descriptors that reflect the intramolecular reactivity sequence, i.e., site
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ꢀ 20,21
selectivity in an individual molecule, the condensed Fukui functions (fk )
and molecular
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ꢀ
electrostatic potential (MESP)24 were considered. The Fukui functions (fk ) reflect reactivity in the
frontierꢀcontrolled softꢀsoft reactions at the specific site in a molecule.23 MESP can be applied as a
reasonably good criterion to estimate the probability of hardꢀhard interactions, i.e., reactivity in
chargeꢀcontrolled reactions.24 Corresponding descriptors of local reactivity in chargeꢀcontrolled
reactions are the most negative valued points (Vmin) in electron rich regions obtained from the MESP
topography calculation.25
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1ꢀMethyl substituted Cꢀaminoꢀ1,2,4ꢀtriazoles 1a and 2a and 3,5ꢀdiaminoꢀ1ꢀmethylꢀ1,2,4ꢀ
triazole (3b) were applied as model molecules for the calculations of the static reactivity indices
(Figure 1). The use of diaminotriazole 3b as an object of theoretical investigation was stipulated by
an effective combination of reactive fragments of both isomers 1a and 2a in one molecule. Analysis
of the electron density of the molecules according to the “atomsꢀinꢀmolecules” (AIM)31 theory
reveal that topological parameters of 1a and 2a are similar to the parameters of analogous
fragments, especially CꢀNH2 bonds, in 3b (see Supporting Information, Tables Sꢀ02, Sꢀ03, and Sꢀ
04). This topological similarity, in our opinion, allows the application of 1ꢀsubstituted 3,5ꢀdiaminoꢀ
1,2,4ꢀtriazoles as suitable models for comparative analysis of reactivity of isomeric 1ꢀsubstituted 3ꢀ
aminoꢀ and 5ꢀaminoꢀ1,2,4ꢀtriazoles.
Figure 1. Structures of model compounds 2a, 3b and 1a.
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Table 1. HOMO and LUMO (εHOMO, εLUMO) energies and global reactivity indices (electronic chemical potential (ꢀ), chemical hardness (η),
global softness (S) and nucleophilicity indexa (Nu(i))) for Cꢀaminoꢀ1,2,4ꢀtriazoles 1a, 2a, and 3b calculated at the DFT B3LYP/6ꢀ311++G(2d,2p)
and MP2/augꢀccꢀpVDZ levels of theory in gas and aqueous phases
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Gas phase
Aqueous phase
Reactivity
Index
DFT
MP2
DFT
MP2
2a
3b
1a
2a
3b
1a
2a
3b
1a
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3b
1a
εHOMO, eV
εLUMO, eV
ꢁ, au
ꢀ6.101 ꢀ5.683 ꢀ6.477 ꢀ8.842 ꢀ8.558 ꢀ9.220 ꢀ6.355 ꢀ5.927 ꢀ6.525 ꢀ9.093 ꢀ8.783 ꢀ9.292
ꢀ0.343 ꢀ0.559 ꢀ0.642 0.802 0.766 0.723 ꢀ0.240 ꢀ0.273 ꢀ0.244 1.002 1.002 1.009
ꢀ0.118 ꢀ0.115 ꢀ0.131 ꢀ0.148 ꢀ0.143 ꢀ0.156 ꢀ0.121 ꢀ0.114 ꢀ0.124 ꢀ0.149 ꢀ0.143 ꢀ0.152
0.106 0.094 0.107 0.177 0.171 0.183 0.112 0.104 0.115 0.185 0.180 0.189
4.726 5.310 4.664 2.822 2.918 2.737 4.450 4.813 4.332 2.696 2.781 2.642
15.09 14.31 12.53 16.24 16.71 14.99 15.30 16.01 14.92 16.79 17.59 16.34
η, au
S, auꢀ1
Nu(1), auꢀ1
Nu(2), auꢀ1
Nu(3), eV
8.42
3.39
8.63
3.81
7.57
3.02
6.71
2.98
6.93
3.26
6.37
2.60
8.24
3.14
8.76
3.57
8.03
2.97
6.65
2.73
6.90
3.04
6.49
2.53
aThe HOMO energy of the reference system (TCE) has been calculated at the MP2/augꢀccꢀpVDZ (ꢀ11.821 eV) and B3LYP/6ꢀ311++G(2d,2p) (ꢀ9.496
eV).
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Figure 2. Molecular electrostatic potential isosurface at ꢀ 33 kcal·molꢀ1 of molecules 2a, 3b and 1a computed at the MP2/augꢀccꢀpVDZ level in
vacuum. The black dots represent the location of the Vmin points (in kcal·molꢀ1).
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As seen from the global reactivity indices presented in the Table 1, 3ꢀaminoꢀ1Hꢀ1,2,4ꢀ
triazoles, modeled by 2a, should be stronger nucleophiles than 5ꢀaminoꢀ1Hꢀ1,2,4ꢀtriazoles,
modeled by 1a (indices N, εHOMO, S and ꢁ are higher for the molecule 2a). Changing the method
of calculation or the medium polarity did not fundamentally affect the ratio of reactivity indices.
Apparently, these findings are also valid for the analogous tautomers of aminotriazoles
(hydrogen as a substituent at the N atoms of the triazole cycle). It should be noted that the higher
nucleophilicity of the 3ꢀamino tautomer compared to the 5ꢀamino tautomer follows from the
values of global reactivity indices obtained by the B3LYP/6ꢀ31G** calculations.32
Nucleophilicity of diaminotriazole 3b should be higher compared to the aminotriazoles 1a and
2a, presumably owing to the presence of two electronꢀdonating amino groups in the molecule.
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ꢀ
Table 2. Nucleophilic Fukui functions (fk ) for the molecule 3b calculated at the DFT
B3LYP/6ꢀ311++G(2d,2p) and MP2/augꢀccꢀpVDZ in gas and aqueous phases
Gas phase
Aqueous phase
Atom
DFT
0.225
0.061
0.196
0.109
MP2
0.175
0.042
0.223
0.076
DFT
0.246
0.066
0.184
0.124
MP2
0.193
0.050
0.193
0.105
Nꢀ2
Nꢀ4
3ꢀNH2
5ꢀNH2
Local Fukui functions presented in Table 2 show that Nꢀ2 and the 3ꢀNH2 group are the
most probable sites for the attack of soft electrophiles in 3b. Values of Vmin and MESP contours
(Figure 2) predict that Nꢀ4 of the triazole ring is the most probable center for attack of hard
electrophiles in all types of aminotriazoles. Chances of attack of hard electrophiles on the Nꢀ2
atom or the nitrogen of 3ꢀNH2 are also sufficiently high. Values of Fukui functions and Vmin also
show that in reactions with either soft or hard electrophiles, nucleophilicity of the 3ꢀNH2 group
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should be substantially higher than that of the 5ꢀNH2 group because electron density on the latter
is substantially decreased. This finding is in agreement with the experimental data for the
reactions of 1ꢀsubstituted 3,5ꢀdiaminoꢀ1,2,4ꢀtriazoles with various carbonyl compounds and
derivatives of carboxylic acids and sulfonyl chlorides.17
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In summary, local reactivity indices indicate that reactions involving amino groups will
proceed more readily for 3ꢀaminoꢀ1Hꢀ1,2,4ꢀtriazoles than for 5ꢀaminoꢀ1Hꢀ1,2,4ꢀtriazoles.
Increasing electrophile hardness should enhance the likelihood of attack on Nꢀ4 in all of the
above types of aminotriazoles. With increasing electrophile softness, the probability of attack on
Nꢀ2 and 3ꢀNH2 in 3ꢀaminoꢀ1Hꢀ1,2,4ꢀtriazoles and diaminotriazoles should rise.
1.3. Transition State Free Energies
Tautomers 1b and 2b of 3(5)ꢀaminoꢀ1Hꢀ1,2,4ꢀtriazole and 1ꢀsubstituted 3,5ꢀdiaminoꢀ1,2,4ꢀ
triazoles 3aꢀc with different R substituents (see Figure 3) were selected as model molecules for
the calculation of free energies of activation (ꢁG≠). The ꢁG≠ (Table 3) of hypothetical transition
states (TS) that form during SN2 alkylation by chloromethane in aqueous solution were
calculated as the difference between the Gibbs free energy of the transition state G298(TS) and the
Gibbs free energies of starting compounds.30b,33 Figure 3 also shows the relative free energies of
activation (ꢁꢁG≠) representing the difference between ꢁG≠ for a given reaction center and that
calculated for the lowest energy. Rate constants (k) were estimated using Transition State Theory
(TST) according to eq 1:33
where kB is the Boltzmann constant and h is the Planck constant, ꢁG≠, ꢁH≠ and ꢁS≠ are the
Gibbs free energy, enthalpy and entropy of activation, correspondingly, and R is the gas
constant.
As seen in Figure 3 and Table 3, Nꢀ4 (TS B≠) and Nꢀ2 (TS A≠) are preferable sites for SN2
attack of chloromethane in the aminotriazoles 1ꢀ3. Furthermore, formation of the products of
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alkylation of the 3ꢀNH2 group can be expected for 2b and 3aꢀc because relative Gibbs free
energies of TS C≠ were 0.7 ꢀ 2.2 kcal/mol higher than the energies of the most stable transition
states B≠ or A≠. Thus, for 3b, the estimated rate constant for alkylation at 3ꢀNH2 is three times
less than those at Nꢀ4. On the examples of substrates 1b and 3aꢀc it is clear that alkylation of the
5ꢀNH2 group is scarcely probable because TS D≠ is sufficiently higher in energy (~4ꢀ5 kcal/mol)
than other possible TSs.
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Cl
H
N
Cl
N
H
CH3
H
CH3
H2N
N
N
N
H2N
H
N
N
N
CH3
Cl
H
N
H
H2N
(1b)A
(1b)B
(1b)D
0.94
0
5.03
G :
Cl
CH3
H
N
N
N
Cl
NH2
CH3
NH2
H
H
H
H
H
N
N
N
N
N
CH3
NH2
N
Cl
(2b)A
(2b)B
(2b)C
2.15
1.73
0
G :
Cl
CH3
R
N
N
N
Cl
CH3
NH2
NH2
Cl
R
R
H2N
R
CH3
H2N
N
N
N
N
N
N
N
CH3
Cl
NH2
N
H2N
N
H2N
NH2
A
B
C
D
3a: R = Ph,
3b: R = Me,
3c: R = H,
G :
G :
G :
0
0.74
0
1.55
0.66
1.50
5.36
4.24
4.97
0.46
0
0.85
Figure 3. Transition states A≠ ꢀ D≠ and their relative Gibbs free energies (ꢁꢁG≠, kcal/mol).
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Table 3. The calculated TransitionꢀState Gibbs free energies (ꢁG≠)* and rate constants (k) for SN2 alkylation of compounds 1b, 2b, 3aꢀc at various
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reaction centers at 298 K in water (DFT B3LYP/6ꢀ311++G(2d,2p), IEFꢀPCM)
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ꢁG≠, kcal/mol
k, Mꢀ1·sꢀ1
3a
TS
1b
2b
3a
3b
3c
1b
2b
3b
3c
A≠
B≠
C≠
D≠
30.0
29.1
—
30.3
28.6
30.7
—
28.5
29.3
30.1
33.9
29.2
28.7
29.4
33.0
28.5
29.4
30.0
33.5
6.3·10ꢀ10
3.1·10ꢀ9
—
3.9·10ꢀ10
7.2·10ꢀ9
1.9·10ꢀ10
—
7.7·10ꢀ9
2.2·10ꢀ9
5.6·10ꢀ10
9.0·10ꢀ13
2.5·10ꢀ9
5.5·10ꢀ9
1.8·10ꢀ9
4.3·10ꢀ12
7.5·10ꢀ9
1.8·10ꢀ9
6.0·10ꢀ10
1.7·10ꢀ12
34.1
6.3·10ꢀ13
*ꢁG≠ = G298(TS) – [G298(CH3Cl) + G298(aminotriazole)], corresponding values of G298(TS), G298(CH3Cl) and G298(aminotriazole) are presented in the Supporting
Information.
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It is interesting to consider the effect of the R substituent on the relative energy of the
transition states A≠ and B≠ in 3aꢀc. TS A≠ is more favorable if R = H (TS (3c)A≠) or Ph (TS
(3a)A≠), whereas TS B≠ is slightly more stable if R = CH3 (TS (3b)B≠). Owing to these
differences, the ratios k(A≠)/k(B≠) are 4.2 and 3.5 for 3a and 3c, respectively, while the same
ratio is only 0.46 for 3b (R = Me). It is likely that the transition state (3b)A≠ is destabilized by
steric repulsions between R = Me (which is more bulky than a small hydrogen or a phenyl group
that can be twisted almost perpendicularly relative to the plane of the triazole ring to decrease
steric repulsions) and attacking methyl chloride. Nevertheless, in the optimized transition states
A≠, the distances between the R substituent and the attacking molecule of methyl chloride are
greater than or equal to the sum of the van der Waals radii (Figure 4). Furthermore, AIM31
analyses do not show any bond paths between the atoms of R and methyl chloride (Figure 4).
More detailed examination of the activation parameters (Table 4) shows that the change in the
positional selectivity in the case of R = Me is caused by two factors. First, the entropy
component of the rate constant for TS (3b)A≠ is slightly decreased in relation to TS (3a)A≠ and
(3c)A≠, presumably owing to the decreased probability of the bulky methyl group adopting an
appropriate conformation in the (3b)A≠. Second, the enthalpy component of the rate constant for
TS (3b)B≠ is slightly increased relative to TS (3a)B≠ and (3c)B≠ likely due to the higher electron
donating character of the methyl substituent.
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Figure 4. Structures and molecular graphs (AIMALL34 representation) of the transition states
(3a)A≠, (3b)A≠, and (3c)A≠. Numbers at the dotted lines show the distances (Å) between specific
atoms.
Table 4. Entropy [exp(ꢁS≠/R)] and enthalpy [exp(ꢁH≠/RT)] components of the rate constant for
the transition states A≠ and B≠
exp(ꢁS≠/R) for the transition state
exp(ꢁH≠/R) for the transition state
Substrate
A≠
B≠
A≠
B≠
7.61·10ꢀ8
2.54·10ꢀ8
4.10·10ꢀ8
6.80·10ꢀ8
8.30·10ꢀ8
4.48·10ꢀ8
1.62·10ꢀ14
1.60·10ꢀ14
2.96·10ꢀ14
5.21·10ꢀ15
1.06·10ꢀ14
6.51·10ꢀ15
3a
3b
3c
Calculated TS energies indicate that aminotriazoles quaternized at the Nꢀ4 or Nꢀ2 atoms
are the expected major products in SN2 reactions of Cꢀaminoꢀ1Hꢀ1,2,4ꢀtriazoles with halogen
alkanes in the absence of strong bases. Formation of 3ꢀalkylaminotriazoles as byproducts is
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expected in the alkylation of 3ꢀaminoꢀ and 3,5ꢀdiaminoꢀ1Hꢀ1,2,4ꢀtriazoles; however,
quaternization of 5ꢀaminoꢀ or 3,5ꢀdiaminoꢀ1Hꢀ1,2,4ꢀtriazoles at the 5ꢀNH2 group is unlikely
because of its poor nucleophilicity. These findings are consistent with the conclusions based on
the static reactivity indices (Section 1.1).
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2. Experimental investigation of alkylation of 1ꢀsubstituted Cꢀaminoꢀ1,2,4ꢀtriazoles by
halogen alkanes
Alkylation of 1ꢀsubstituted Cꢀaminoꢀ1,2,4ꢀtriazoles was investigated experimentally with
2c, 3a and 3d (Scheme 3). Three nucleophilic centers, Nꢀ2, Nꢀ4, and the 3ꢀNH2 group, were
determined to take part in the reaction. Quaternization products of N2 and N4 are dominant, and
the selectivity for such products is determined by the nature of the alkyl halide and
aminotriazole. Interaction of 3a (R = Ph) with a majority of alkyl halides resulted in the
formation of the N2ꢀalkylated compounds 6bꢀe as major products. In the reaction with
iodomethane a mixture of Nꢀ2ꢀ and Nꢀ4ꢀalkylated products, 6a and 10a, was obtained, while
with iodoacetamide the only product isolated was compound 10b. It is likely that in the case of
iodomethane and particularly iodoacetamide the role of charge control of the reaction selectivity
increases, thus leading to an enhanced yield of Nꢀ4ꢀalkylated products, as predicted by the static
reactivity indices (section 1.1). In agreement with the TS energy calculation predictions (section
1.2), the benzylation of 1ꢀalkylsubstituted triazoles 2c and 3d affected the Nꢀ4 atom of the
triazole ring resulting in formation of 10c and 5a, while Nꢀ2ꢀalkylated products were not
obtained.
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In most cases, 3ꢀalkylamino derivatives were detected chromatographically as byproducts
in the reaction mixtures (see the Supporting Information for GCꢀMS data); moreover, the 3ꢀ
benzylamino triazoles 11aꢀc and N,Nꢀdibenzylaminotriazoles 12a and 12b were isolated from
the reaction mixtures (Scheme 3). Formation of 12a and 12b indicates that alkylamino
derivatives are formed by the direct alkylation of the 3ꢀNH2 group rather than by the possible
Dimroth rearrangement35 of Nꢀ4ꢀ or Nꢀ2ꢀalkylated products. Notably, the proposed Dimroth
rearrangements of 6 and 10 were not obtained under the reaction conditions. Thus, 6e and 10d
did not undergo transformation upon heating in acetonitrile or ethanol at 80ꢀ90 °C for 48 hours,
despite the addition of an equimolar amount of 40% aqueous HBr as a catalyst. In aqueous
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NaOH solution, 6e decomposes to form a complex mixture of products, while 10d gives the free
base 13 (Scheme 4).
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9
Therefore, the experimentally obtained results are in accordance with the theoretical
predictions discussed in section 1: alkylation of 1ꢀsubstituted 3ꢀaminoꢀ and 3,5ꢀdiaminoꢀ1,2,4ꢀ
triazoles generally proceeded with low selectivity and involved Nꢀ4, Nꢀ2, and the 3ꢀNH2 group,
while the 5ꢀNH2 group was unaffected by alkyl halides.
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As previously mentioned, quaternization of 1ꢀsubstituted 5ꢀaminoꢀ1,2,4ꢀtriazoles, in many
cases, proceeds selectively at Nꢀ4 of the triazole cycle and serves as an important method for the
preparation of 1,5ꢀdisubstituted 5ꢀaminoꢀ1,2,4ꢀtriazoles.14,15 However, our theoretical and
experimental results indicate that the analogous approach is inefficient for the preparation of 1,4ꢀ
disubstituted 3ꢀaminoꢀ and 3,5ꢀdiaminoꢀ1,2,4ꢀtriazoles due to low reaction selectivity of these
substrates with the majority of alkyl halides. We proposed that the selectivity of alkylation can
be enhanced if the 3ꢀNH2 group is protected and its electronꢀdonating influence on Nꢀ2 of the
triazole cycle is decreased by acylation. An analogous approach (acetylation of 3ꢀNH2 before Nꢀ
alkylation of the triazole ring) was applied in the synthesis of alkylated 2ꢀaminoꢀ4,5,6,7ꢀ
tetrahydro[1,2,4]triazolo[1,5ꢀa]pyrimidines to prevent the formation of alkylamino byproducts.18
While the quaternization of 3ꢀacylaminoꢀ1Hꢀ1,2,4ꢀtriazoles was not studied previously, we
expected that acylation of the 3ꢀNH2 group would enhance the selectivity of the subsequent Nꢀ4
alkylation of the triazole ring. This proposition was partly based on the observation of
regioselective cyclization of 3ꢀchloropropanoyl derivatives of partially hydrogenated 2ꢀ
amino[1,2,4]triazolo[1,5ꢀa]pyrimidines, the key step of the cyclization is the selective
intramolecular alkylation at Nꢀ4 of the 1,2,4ꢀtriazole ring.36 Therefore, we investigated the
alkylation of 3ꢀacetylaminoꢀ1,2,4ꢀtriazoles 14a,17a 14b17a and 14c, which are readily available
from the acetylation of corresponding aminotriazoles 2c, 3a, and 3d.
It was established that the quaternization of 3ꢀacetylaminoꢀ1,2,4ꢀtriazoles 14aꢀc by alkyl
halides in DMF resulted in selective formation of Nꢀ4ꢀalkylated compounds 15a and 15cꢀf
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(Scheme 4). The methylation product of 14a was isolated also in the form of the picrate 15b.
Some alkyl derivatives were separated as the free bases 16aꢀc (Scheme 4). Target compounds
5a, 10a, and 10cꢀe were obtained by acid hydrolysis of the acetyl derivatives 15 and 16 (Scheme
4). Therefore, alkylation of 1ꢀsubstituted 3ꢀacetylaminoꢀ1,2,4ꢀtriazoles by alkyl halides with
subsequent elimination of the acetyl group by hydrolysis is a new method for the selective
synthesis of 1,4ꢀdisubstituted 3ꢀaminoꢀ and 3,5ꢀdiaminoꢀ1,2,4ꢀtriazoles.
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Scheme 4
The structures of the synthesized compounds were established by elemental analysis, massꢀ
1
spectrometry and NMR spectroscopic data, including Hꢀ13C heteronuclear correlation HSQC
and HMBC spectra for the majority of compounds, NOESY spectra for 6e and 10b, and XꢀRay
diffraction studies of 6e, 10a (for details, see Supporting information), and 16a.37
Some NMR spectral peculiarities and schemes of key correlations in the HMBC and
NOESY spectra used for the assignment of structures of 6 and 10 are presented in Figure 5. It is
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notable that in the C NMR spectra of compounds 6, the signals of both carbon atoms of the
triazole cycle are observed in the region of 160ꢀ162 ppm, whereas in the spectra of isomers 10
these signals are shifted upfield to 146ꢀ151 ppm, which is analogous to other salts of 1,4ꢀ
disubstituted Cꢀaminoꢀ1,2,4ꢀtriazoles.38
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Figure 5. NMR spectral characteristics (chemical shifts, δ, ppm) of compounds 6 and 10 in
DMSOꢀd6 and key correlations in the NOESY and HMBC spectra.
1
The H NMR spectra of the mesoionic compounds 16a and 16b displayed significantly
broadened NH2 proton signals that merged into the background, apparently due to rapid
exchange with the solvent. Similar broadening was observed for the NH signals of the
structurally analogous mesoionic compounds.18,36b Moreover, the mesoionic structure of 16a was
supported by pKa measurements36b and Xꢀray analysis.37
Conclusion
The position of the endocyclic R substituent has a significant influence on the reactivity of
Cꢀaminoꢀ1ꢀRꢀ1,2,4ꢀtriazoles. The global nucleophilicity of the 1ꢀsubstituted 3ꢀaminoꢀ and 3,5ꢀ
diaminoꢀ1,2,4ꢀtriazoles is higher than that of the 1ꢀsubstituted 5ꢀaminoꢀ1,2,4ꢀtriazoles.
Therewith, the amino group in the 3ꢀposition of the triazole ring is substantially more
nucleophilic than in the 5ꢀposition. Nꢀ2 and Nꢀ4 of the triazole ring as well as the 3ꢀNH2 group
in the 1ꢀsubstituted Cꢀaminoꢀ1,2,4ꢀtriazoles are the most favorable sites for the attack of
electrophiles, including the majority of alkyl halides. The selectivity of alkylation of 1ꢀ
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substituted 3,5ꢀdiaminoꢀ1,2,4ꢀtriazoles by alkyl halides can be sufficiently enhanced if the 3ꢀNH2
group is initially acetylated. The acetyl group not only protects the highly nucleophilic 3ꢀamino
group but also affects the selectivity of endocyclic alkylation in favor of the quaternization at Nꢀ
4 in the substrates where alkylation at Nꢀ2 is sterically possible. An increase in the selectivity of
the endocyclic alkylation is likely achieved by the reduction of the electronꢀdonating resonance
effect of the acylated 3ꢀamino group on Nꢀ2 in the transition state.
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Experimental section
General Information
Melting points were determined in open capillary tubes in a Thiele apparatus and are
uncorrected. IR spectra were recorded using a single reflection diamond ATR system as a
sampling accessory. 1H NMR spectra were acquired at 300, 500 or 600 MHz and 13C {1H} NMR
spectra were acquired at 125 or 150 MHz in DMSOꢀd6 using TMS as an internal standard. Mass
spectra were recorded in the form of m/z (intensity relative to base 100) using electron impact
ionization (70 eV). GCꢀMS measurements were acquired with a GC system equipped with a
massꢀselective detector (electron impact, 70 eV) and an HPꢀ5ꢀMS column (30 m × 0.25 mm ×
0.25 ꢂm film) using He as carrier gas at a flow of 1.0 mL/min. The following temperature
program was used in all GCꢀMS measurements: initial temperature 65 °C, hold for 7 min, then
25 °C/min to 190 °C for 1 min, then 10 °C/min to 260 °C for 20 min, then 10 °C/min to 280 °C
for 18 min. High resolution mass spectra (HRMS) were obtained on a TOF MS instrument using
electrospray ionization (ESI) in positive ion mode (interface capillary voltage – 4500 V).
Starting compounds 3a,16 3d,39 2c,12a and 14a,b17a were prepared by known methods. All
other chemicals are commercially available.
General procedure for the synthesis of compounds 6bꢀd and 10b
A magnetically stirred mixture of 3a (0.5 g, 2.86 mmol), the corresponding alkyl halide (3.43
mmol) and acetonitrile (1.5 mL) was heated in a sealed ampoule at 80ꢀ90 °C for 12 h then cooled
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to room temperature. The solid obtained was isolated by filtration and recrystallized from an
appropriate solvent.
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3,5ꢀDiaminoꢀ1ꢀethylꢀ2ꢀphenylꢀ1Hꢀ1,2,4ꢀtriazolꢀ2ꢀium iodide (6b)
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Yield 0.274 g (29%) of yellowish crystals, mp 260ꢀ261 °C (from iꢀPrOH). IR (cmꢀ1): 3319,
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1
3279, 3104, 2950, 1680, 1630, 1585, 1549, 1518, 1488, 1458, 1107, 773. H NMR (600 MHz,
DMSOꢀd6): δ 0.96 (t, J = 7.0 Hz, 3H, Me), 3.59 (q, J = 7.0 Hz, 2H, CH2), 7.51ꢀ7.63 (m, 5H, Ph),
8.14 (br s, 4Н, 2NН2). 13C NMR (150 MHz, DMSOꢀd6): δ 10.9 (CH3), 41.2 (CH2), 127.4, 130.4,
130.6, 132.7 (carbons of Ph), 161.3 (Cꢀ3), 161.8 (Cꢀ5). MS (EI, 70 eV), m/z (%): 203 (15) [M ꢀ
HI]+, 188 (18) [M – HI – CH3]+, 175 (100), 128 (94) [HI]+. Anal. Calcd for C10H14N5I: C, 36.27;
H, 4.26; N, 21.15. Found: С, 35.98; H, 4.39; N, 21.29.
3,5ꢀDiaminoꢀ2ꢀphenylꢀ1ꢀpropylꢀ1Hꢀ1,2,4ꢀtriazolꢀ2ꢀium iodide (6c)
Yield 0.297 g (30%) of yellowish crystals, mp 223ꢀ224 °С (from water). IR (cmꢀ1): 3319, 3238,
3121, 2968, 1689, 1629, 1588, 1546, 1514, 1490, 1458, 1102, 774. 1H NMR (600 MHz, DMSOꢀ
d6): δ 0.73 (t, J = 7.4 Hz, 3H, CH3), 1.40 (m, 2H, CH2), 3.56 (t, J = 7.2 Hz, 2H, CH2), 7.50ꢀ7.63
(m, 5H, Ph), 7.91 (br s, 2H, NH2), 8.23 (br s, 2Н, NH2). 13C NMR (150 MHz, DMSOꢀd6): δ 10.2
(CH3), 19.6 (CH2), 46.9 (CH2), 127.6, 130.3, 130.6, 132.7 (carbons of Ph), 161.1 (Cꢀ3), 161.3
(Cꢀ5). MS (EI, 70 eV), m/z (%): 217 (9) [M ꢀ HI]+, 175 (100), 128 (12) [HI]+. Anal. Calcd for
C11H16N5I: C, 38.28; H, 4.67; N, 20.29. Found: С, 37.95; H, 4.84; N, 20.01.
3,5ꢀDiaminoꢀ2ꢀphenylꢀ1ꢀ(propꢀ2ꢀenꢀ1ꢀyl)ꢀ1Hꢀ1,2,4ꢀtriazolꢀ2ꢀium bromide (6d)
Yield 0.618 g (63%) of white crystals, mp 212ꢀ213 °C (from iꢀPrOH). IR (cmꢀ1): 3492, 3370,
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3283, 3094, 2936, 1688, 1629, 1589, 1542, 1515, 1488, 1456, 1419, 1108, 928, 775. H NMR
(600 MHz, DMSOꢀd6): δ 4.27 (d, J = 5.6 Hz, 2H, CH2), 5.07 (m, 1Н, CH), 5.20 (m, 1H, CH),
5.67 (m, 1H, CH), 7.46ꢀ7.47 (m, 2H, Ph), 7.59ꢀ7.60 (m, 3H, Ph), 8.03 (br s, 2H, NH2), 8.45 (br s,
2Н, NН2). 13C NMR (150 MHz, DMSOꢀd6): δ 48.0 (CH2), 119.8 (Cꢀ1ʹ), 127.9 (Сꢀ2ʹ), 129.6,
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130.3, 130.7, 132.6 (carbons of Ph), 161.1 (Cꢀ3), 161.3 (Сꢀ5). MS (EI, 70 eV), m/z (%): 215 (54)
[M ꢀ HBr]+, 175 (56), 77 (100). Anal. Calcd for C11H14N5Br: C, 44.61; H, 4.76; N, 23.65. Found:
С, 44.86; H, 4.52; N, 23.39.
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3,5ꢀDiaminoꢀ4ꢀ(2ꢀaminoꢀ2ꢀoxoethyl)ꢀ1ꢀphenylꢀ4Hꢀ1,2,4ꢀtriazolꢀ1ꢀium iodide (10b)
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Yield 0.834 g (81%) of creamꢀcolored crystals, mp 217ꢀ219 °C (from EtOH). IR (cmꢀ1): 3391,
3340, 3261, 3174, 3111, 2974, 1677, 1648, 1607, 1523, 1497, 1457, 1396, 1303, 1089, 809, 764.
1H NMR (600 MHz, DMSOꢀd6): δ 4.58 (s, 2H, CH2), 6.75 (br s, 2H, 3ꢀNH2), 7.45 (br s, 1H,
CONH2), 7.47ꢀ7.51 (m, 3H, Ph), 7.58ꢀ7.59 (m, 2H, Ph), 7.72 (br s, 1H, CONH2), 8.32 (br s, 2H,
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5ꢀNH2). C NMR (150 MHz, DMSOꢀd6): δ 44.4 (CH2), 124.1, 128.8, 129.8, 134.8 (carbons of
Ph), 147.1 (Cꢀ5), 150.6 (Cꢀ3), 165.9 (CO). MS (EI, 70 eV), m/z (%): 232 (100) [M ꢀ HI]+, 175
(22). Anal. Calcd for C10H13N6IO: C, 33.35; H, 3.64; N, 23.33. Found: C, 33.59; H, 3.51; N,
23.18.
3,5ꢀDiaminoꢀ1ꢀmethylꢀ2ꢀphenylꢀ1Hꢀ1,2,4ꢀtriazolꢀ2ꢀium iodide (6a) and 3,5ꢀdiaminoꢀ4ꢀ
methylꢀ1ꢀphenylꢀ4Hꢀ1,2,4ꢀtriazolꢀ1ꢀium iodide (10a)
A magnetically stirred mixture of 3a (0.5 g, 2.86 mmol), iodomethane (0.49 g, 3.43 mmol),
and acetonitrile (2 mL) was heated in a sealed ampoule at 80ꢀ90 °C for 12 h then cooled to room
temperature. The solid obtained was isolated by filtration and dried at room temperature to give a
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mixture that contained ~56% 6a (yield 36%) and ~44% 10a (yield 28%) according to H NMR.
The mixture was crystallized four times from iꢀPrOH and twice from water to give pure 6a.
Yield 0.078 g (9%) of yellowish crystals, mp 246ꢀ247 °С. IR (cmꢀ1): 3342, 3282, 3117, 2940,
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1680, 1633, 1587, 1547, 1516, 1486, 1457, 772. H NMR (600 MHz, DMSOꢀd6): δ 3.14 (s, 3H,
CH3), 7.48ꢀ7.51 (m, 2H, Ph), 7.61ꢀ7.63 (m, 3H, Ph), 7.92 (br s, 2H, NH2), 8.16 (br s, 2Н, NН2).
13C NMR (150 MHz, DMSOꢀd6): δ 33.4 (CH3), 127.9, 130.3, 130.7, 132.3 (carbons of Ph), 160.1
(Cꢀ3), 161.6 (Cꢀ5). MS (EI, 70 eV), m/z (%): 189 (5) [M ꢀ HI]+, 175 (75), 127 (100). Anal. Calcd
for C9H12N5I: C, 34.09; H, 3.81; N, 22.08. Found: C, 33.75; H, 4.01; N, 21.81.
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Mother liquors, after removal of 6a, were combined and evaporated to dryness. A residue
obtained was crystallized three times from water (last crystallization was performed by slow
evaporation of the solution to a small volume at room temperature for three days) to give pure
10a. Yield 0.045 g (5%) of yellowish crystals, mp 238ꢀ239 °C. IR (cmꢀ1): 3260, 3200, 3125,
2928, 1679, 1643, 1592, 1541, 1497, 1457, 1158, 1118, 1013, 758. 1H NMR (600 MHz, DMSOꢀ
d6): δ 3.37 (s, 3H, CH3), 6.78 (br s, 2H, 3ꢀNH2), 7.44ꢀ7.61 (m, 5H, Ph), 8.24 (br s, 2Н, 5ꢀNН2).
13C NMR (150 MHz, DMSOꢀd6): δ 29.5 (CH3), 124.2, 128.8, 129.7, 134.9 (carbons of Ph), 146.8
(Cꢀ5), 150.5 (Сꢀ3). MS (EI, 70 eV), m/z (%): 189 (100) [M ꢀ HI]+, 91 (98). Anal. Calcd for
C9H12N5I: C, 34.09; H, 3.81; N, 22.08. Found: C, 34.18; H, 3.69; N, 21.87.
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3,5ꢀDiaminoꢀ1ꢀbenzylꢀ2ꢀphenylꢀ1Hꢀ1,2,4ꢀtriazolꢀ2ꢀium bromide (6e), N3ꢀbenzylꢀ1ꢀphenylꢀ
1Hꢀ1,2,4ꢀtriazoleꢀ3,5ꢀdiamine (11a), and N3,N3ꢀdibenzylꢀ1ꢀphenylꢀ1Hꢀ1,2,4ꢀtriazoleꢀ3,5ꢀ
diamine (12a)
A magnetically stirred mixture of 3a (0.5 g, 2.86 mmol), benzyl bromide (0.58 g, 3.43
mmol), and acetonitrile (2 mL) was heated in a sealed ampoule at 80ꢀ90 °C for 12 h and
acetonitrile was evaporated off at reduced pressure. The residue obtained was dissolved in a hot
(80ꢀ90 °C) water solution (6 mL) of sodium acetate trihydrate (10%). The precipitate formed
after cooling to 20 °C was filtered off and recrystallized from EtOH to give 12a. Yield 0.091 g
(9%) of colorless crystals, mp 142ꢀ143 °C (from EtOH). IR (cmꢀ1): 3448, 3298, 3087, 2922,
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1685, 1644, 1590, 1546, 1485, 1454, 1388, 1369, 1296, 1123, 940, 751. H NMR (600 MHz,
DMSOꢀd6): δ 4.48 (s, 4H, 2CH2), 6.36 (br s, 2H, NH2), 7.22ꢀ7.32 (m, 11H, Ar), 7.42ꢀ7.44 (m,
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2H, Ar), 7.52ꢀ7.53 (m, 2H, Ar). C NMR (150 MHz, DMSOꢀd6): δ 49.9 (2CH2), 121.2, 125.2,
126.7, 127.6, 128.2, 129.1, 137.9, 138.8 (carbons of benzene rings), 154.0 (Cꢀ5), 162.3 (Cꢀ3).
MS (EI, 70 eV), m/z (%): 355 (18) [M]+, 91 (100). Anal. Calcd for C22H21N5: C, 74.34; H, 5.96;
N, 19.70. Found: C, 74.05; H, 6.12; N, 19.83.
The mother liquor after separation of 12a was extracted by chloroform (3×3 mL). The
extract was dried by anhydrous Na2SO4 and evaporated to dryness. The residue obtained was
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recrystallized from acetonitrile to give 11a: yield 0.113 g (15%), colorless crystals with mp 165ꢀ
166 °С (lit. mp 165ꢀ166 °C).17a The product obtained was identical in both its physical and
spectral characteristics with an authentic sample of 11a.17a
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The water solution, after extraction of 11a, was evaporated to a volume of ~2 mL and
cooled to 5ꢀ10 °C. The solid obtained was isolated by filtration and recrystallized from water,
then from iꢀPrOH to give 6e. Yield 0.532 g (54%) of colorless crystals, mp 225ꢀ226 °C (from iꢀ
PrOH). IR (cmꢀ1): 3348, 3246, 3060, 2750, 1685, 1629, 1591, 1547, 1517, 1494, 1456, 1115,
768. 1H NMR (600 MHz, DMSOꢀd6): δ 4.91 (s, 2H, CH2), 7.03ꢀ7.04 (m, 2Н, Ar), 7.31ꢀ7.35 (m,
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5H, Ar), 7.55 (m, 3H, Ar), 8.03 (br s, 2H, NH2), 8.65 (br s, 2H, 2NH2). C NMR (150 MHz,
DMSOꢀd6): δ 49.0 (CH2), 127.48, 127.53, 128.3, 128.7, 130.2, 130.4, 132.7, 133.5 (carbons of
benzene rings), 161.4 (Cꢀ3), 162.0 (Cꢀ5). MS (EI, 70 eV), m/z (%): 265 (5) [M ꢀ HBr]+, 91 (100).
Anal. Calcd for C15H16N5Br: C, 52.04; H, 4.66; N, 20.23. Found: C, 51.78; H, 4.68; N, 19.92.
3,5ꢀDiaminoꢀ1,4ꢀdibenzylꢀ4Hꢀ1,2,4ꢀtriazolꢀ1ꢀium bromide (10c) and N3,1ꢀdibenzylꢀ1Hꢁ
1,2,4ꢀtriazoleꢀ3,5ꢀdiamine (11b)
A magnetically stirred mixture of 3d (0.541 g, 2.86 mmol), benzyl bromide (0.58 g, 3.43
mmol), and acetonitrile (2 mL) was heated in a sealed ampoule at 80ꢀ90 °C for 12 h. After
cooling to room temperature, the precipitate formed was collected by filtration and recrystallized
from acetonitrile to give 0.258 g (25%) of 10c as colorless crystals (mp 215ꢀ217 °C). IR (cmꢀ1):
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3433, 3329, 3267, 3094, 1681, 1648, 1588, 1529, 1456, 1362, 1143, 737. H NMR (600 MHz,
DMSOꢀd6): δ 5.08 (s, 2H, 1ꢀCH2Ph), 5.14 (s, 2H, 4ꢀCH2Ph), 6.77 (s, 2H, 3ꢀNH2), 7.23ꢀ7.42 (m,
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10Н, 2Ph), 8.44 (s, 2H, 5ꢀNH2). C NMR (150 MHz, DMSOꢀd6): δ 44.5 (1ꢀCH2Ph), 49.9 (4ꢀ
CH2Ph), 126.8, 127.8, 127.98, 128.00, 128.6, 128.7, 134.0, 134.8 (carbons of benzene rings),
147.1 (Cꢀ5), 150.1 (Cꢀ3). MS (EI, 70 eV), m/z (%): 280 (2) [MꢀBr]+, 279 (10) [MꢀHBr]+, 91
(100). Anal. Calcd for C16H18N5Br: C, 53.34; H, 5.04; N, 19.44. Found: C, 53.01; H, 5.19; N,
19.27.
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The reaction mixture, after separation of 10c, was evaporated to a small volume in vacuum
and the residue obtained was dissolved in a hot (80ꢀ90 °C) 5% water solution of sodium acetate
trihydrate (50 mL). The resulting solution was extracted by CHCl3 (4×5 mL). The extract was
dried by Na2SO4, evaporated to a small volume (~5 mL) and chromatographed on a neutral
Al2O3 (activity III) column (2.5 cm × 30 cm) with elution by CHCl3 to give 11b, Rf = 0.22. Yield
0.04 g (5%), mp 173ꢀ175 °C (from EtOH), (lit. mp 173ꢀ175 °C).17c The product obtained was
identical in both its physical and spectral characteristics with an authentic sample of compound
11b.17c
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3ꢀAminoꢀ4ꢀbenzylꢀ1ꢀtertꢀbutylꢀ4Hꢀ1,2,4ꢀtriazolꢀ1ꢀium bromide (5a), Nꢀbenzylꢀ1ꢀtertꢀbutylꢀ
1Hꢀ1,2,4ꢀtriazolꢀ3ꢀamine (11c), and N,Nꢀdibenzylꢀ1ꢀtertꢀbutylꢀ1Hꢀ1,2,4ꢀtriazolꢀ3ꢀamine
(12b)
A magnetically stirred mixture of 2c (0.8 g, 5.72 mmol), benzyl bromide (1.16 g, 6.86
mmol), and acetonitrile (4 mL) was heated in a sealed ampoule at 80ꢀ90 °C for 12 h then cooled
to room temperature. The precipitate formed was collected by filtration and recrystallized from
EtOH to give 5a. Yield 0.267 g (15%) of colorless crystals, mp 223ꢀ224 °C (from EtOH). IR
(cmꢀ1): 3281, 3242, 3137, 3023, 2973, 1645, 1598, 1552, 1465, 1371, 1197, 1092, 988, 871, 739.
1H NMR (300 MHz, DMSOꢀd6): δ 1.53 (s, 9H, 3CH3), 5.27 (s, 2H, CH2), 7.36ꢀ7.42 (m, 7H, Ph +
NH2), 9.83 (s, 1H, Hꢀ5). 13C NMR (150 MHz, DMSOꢀd6): δ 27.7 (3CH3), 47.2 (CH2), 61.4
(C(CH3)3), 128.0, 128.4, 128.7, 133.7 (carbons of benzene ring), 137.2 (Cꢀ5), 154.0 (Cꢀ3).
HRMS (ESIꢀTOF), m/z [C13H19N4]+ calcd for C13H19N4Br 231.1604, found 231.1606.
The reaction mixture, after removal of 5a, was evaporated to a small volume in vacuum
and the residue obtained was dissolved in a hot (80ꢀ90 °C) water solution (50 mL) of sodium
acetate trihydrate (5%). The solution obtained was extracted by CHCl3 (4×5 mL). The extract
was dried by Na2SO4, evaporated to a small volume (~5 mL) and chromatographed on a neutral
Al2O3 (activity III) column (2.5 cm × 30 cm). The column was initially eluted with hexane and
the first fraction (predominantly BnBr) was rejected. Then, the column was eluted by
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hexane/CHCl3 (9:1) to afford 12b, yield 0.056 g (3%), viscous oil, IR (cmꢀ1): 3028, 2975, 2858,
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1562, 1494, 1453, 1228, 1029, 749. H NMR (600 MHz, DMSOꢀd6): δ 1.47 (s, 9H, tꢀBu), 4.49
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(s, 4H, 2CH2), 7.21ꢀ7.29 (m, 10H, 2Ph), 8.10 (s, 1H, Hꢀ5). C NMR (150 MHz, DMSOꢀd6): δ
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28.7 (3CH3), 50.5 (2CH2), 56.8 (C(CH3)3), 126.7, 127.8, 128.1, 138.7 (carbons of benzene rings),
139.7 (Cꢀ5), 156.0 (Cꢀ3). MS (EI, 70 eV), m/z (%): 320 (30) [M]+, 173 (100). Anal. Calcd for
C20H24N4: C, 74.97; H, 7.55; N, 17.48. Found: C, 75.24; H, 7.49; N, 17.27.
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Further the column was eluted by hexane/CHCl3 (1:1) to afford the compound 11c (0.053
g, yield 4%) as colorless crystals, mp 95ꢀ97 °C (from CCl4). IR (cmꢀ1): 3236, 3071, 2975, 2858,
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1567, 1452, 1368, 1228, 1115, 992, 850, 746. H NMR (600 MHz, DMSOꢀd6): δ 1.44 (s, 9H,
3CH3), 4.30 (d, J = 6.5 Hz, 2H, CH2), 6.28 (t, J = 6.5 Hz, 1H, NH), 7.18ꢀ7.33 (m, 5H), 7.98 (s,
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1H, Hꢀ5). C NMR (150 MHz, DMSOꢀd6): δ 28.8 (3CH3), 46.6 (CH2), 56.6 (C(CH3)3), 126.3,
127.4, 127.9, (carbons of Ph), 139.3 (Cꢀ5), 141.1 (Cꢀipso of phenyl), 164.3 (Cꢀ3). MS (EI, 70
eV), m/z (%): 230 (58) [M]+, 173 (100). Anal. Calcd for C13H18N4: C, 67.80; H, 7.88; N, 24.33.
Found: C, 68.05; H, 7.76; N, 24.19.
General procedure for the synthesis of compounds 15aꢀc and 16aꢀc
A magnetically stirred mixture of 14aꢀc (2.30 mmol), the corresponding alkyl halide (2.99
mmol) and dry DMF (1 mL) was heated in a sealed ampoule at 80ꢀ90 °C for 8 h. To isolate 15a
and 15c, the reaction mixture was evaporated to almost dryness at reduced pressure and the
residue obtained was dissolved in hot acetonitrile (3 mL). The crystals that separated after
cooling to 0ꢀ5 °C were collected by filtration, recrystallized from an appropriate solvent and
dried at 100 °C to give 15a and 15c. To isolate picrate 15b, the reaction mixture was evaporated
to almost dryness at reduced pressure and the residue obtained was dissolved in water (1 mL).
Then, the solution was mixed with a solution of picric acid (0.69 g, 2.3 mmol) and LiOH·2H2O
(0.18 g, 3.0 mmol) in water (3 mL). The precipitate formed was collected by filtration and
recrystallized to give 15b. To isolate 16a and 16b, the reaction mixture was cooled to room
temperature and diluted with 10% NH3 solution in water (6 mL). The solid obtained was
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collected by filtration, recrystallized from an appropriate solvent and dried at 100 °C to give 16a
and 16b. To isolate 16c, the reaction mixture was evaporated to dryness at reduced pressure and
the residue obtained was dissolved in hot water (30 mL). The solution obtained was evaporated
to ~3 mL at atmospheric pressure to remove traces of DMF and BnBr. The resulting solution was
diluted with water (5 mL), alkalized to pH 8ꢀ9 by addition of Na2CO3 and extracted by CHCl3
(4×4 mL). The extract was dried by Na2SO4 and evaporated to dryness. The residue obtained was
recrystallized from acetonitrile to give pure 16c.
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3ꢀ(Acetylamino)ꢀ5ꢀaminoꢀ4ꢀmethylꢀ1ꢀphenylꢀ4Hꢀ1,2,4ꢀtriazolꢀ1ꢀium iodide (15a)
Yield 0.603 g (73%) of yellowish crystals, mp 194ꢀ195 °C (from iꢀPrOH). IR (cmꢀ1): 3220,
3043, 2904, 2725, 1694, 1662, 1608, 1529, 1484, 1455, 1398, 1369, 1325, 1247, 1006, 867, 760.
1H NMR (600 MHz, DMSOꢀd6): δ 2.15 (s, 3H, CH3CO), 3.37 (s, 3Н, CH3), 7.57ꢀ7.66 (m, 5H,
Ph), 8.65 (br s, 2H, NH2), 11.02 (br s, 1Н, NН). 13C NMR (150 MHz, DMSOꢀd6): δ 22.7
(CH3CO), 30.7 (CH3), 125.0, 129.8, 129.9, 134.2 (carbons of Ph), 143.5 (Сꢀ3), 148.8 (Сꢀ5),
170.4 (CO). MS (EI, 70 eV), m/z (%): 232 (2) [M ꢀ Iꢀ]+, 231 (16) [M ꢀ HI]+, 43 (100). Anal.
Calcd for C11H14N5IO: C, 36.78; H, 3.93; N, 19.50. Found: С, 37.05; H, 4.05; N 19.21.
3ꢀ(Acetylamino)ꢀ5ꢀaminoꢀ4ꢀmethylꢀ1ꢀphenylꢀ4Hꢀ1,2,4ꢀtriazolꢀ1ꢀium picrate (15b)
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Yield 0.825 g (78%) of yellow crystals, mp 193ꢀ194 °C (from EtOH). H NMR (600 MHz,
DMSOꢀd6): δ 2.15 (s, 3H, CH3CO), 3.38 (s, 3Н, CH3), 7.59ꢀ7.63 (m, 5H, Ph), 8.59 (s, 2H, PkOꢀ),
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8.66 (br s, 2H, NH2), 11.03 (br s, 1Н, NН). C NMR (150 MHz, DMSOꢀd6): δ 22.6 (CH3CO),
30.6 (CH3), 124.2 (Сꢀ4ʹ, PkOꢀ), 125.0 (Ph), 125.1 (Сꢀ3ʹ, PkOꢀ), 129.86, 129.91, 134.2 (carbons of
Ph), 141.8 (Сꢀ2ʹ, PkOꢀ), 143.6 (Сꢀ3), 148.9 (Сꢀ5), 160.8 (Сꢀ1ʹ, PkOꢀ), 170.4 (CO). Anal. Calcd
for C17H16N8O8: C, 44.35; H, 3.50; N, 24.34. Found: С, 44.01; H, 3.68; N 24.61.
3ꢀ(Acetylamino)ꢀ5ꢀaminoꢀ4ꢀethylꢀ1ꢀphenylꢀ4Hꢀ1,2,4ꢀtriazolꢀ1ꢀium iodide (15c)
Yield 0.626 g (73%) of yellowish crystals, mp 235ꢀ236 °C (from EtOH). IR (cmꢀ1): 3232,
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3044, 2924, 2730, 1693, 1660, 1595, 1521, 1485, 1455, 1417, 1248, 1019, 771. H NMR (600
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MHz, DMSOꢀd6): δ 1.27 (t, 3Н, J = 6.9 Hz, CH3CH2), 2.16 (s, 3H, CH3CO), 3.92 (q, 2Н, J = 6.9
Hz, CH2), 7.58ꢀ7.63 (m, 5H, Ph), 8.66 (br s, 2H, NH2), 10.84 (br s, 1Н, NН). 13C NMR (150
MHz, DMSOꢀd6) δ: 12.7 (CH3CH2), 22.7 (CH3CO), 38.8 (CH3CH2), 125.1, 129.86, 129.87,
134.1 (carbons of Ph), 142.6 (Cꢀ3), 148.2 (Cꢀ5), 170.7 (CO). MS (EI, 70 eV), m/z (%): 246 (3)
[M ꢀ Iꢀ]+, 245 (25) [M ꢀ HI]+, 175 (100). Anal. Calcd for C12H16N5IO: C, 38.62; H, 4.32; N,
18.77. Found: С, 38.29; H, 4.39; N, 18.48.
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Acetyl(5ꢀaminoꢀ4ꢀbenzylꢀ1ꢀphenylꢀ4Hꢀ1,2,4ꢀtriazolꢀ1ꢀiumꢀ3ꢀyl)azanide (16a)
Yield 0.580 g (82%) of colorless crystals, mp 199ꢀ200 °C (from EtOH). IR (cmꢀ1): 3319, 3213,
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3061, 1659, 1618, 1572, 1547, 1474, 1454, 1387, 1345, 1067, 1009, 993, 723. H NMR (600
MHz, DMSOꢀd6): δ 2.03 (s, 3Н, CH3), 4.85 (s, 2H, CH2), 7.14ꢀ7.42 (m, 8Н, Ar), 7.96ꢀ7.97 (m,
2H, Ar). 13C NMR (150 MHz, DMSOꢀd6): δ 22.6 (CH3), 44.0 (CH2), 118.5, 123.9, 127.1, 127.5,
128.5, 128.8, 135.9, 138.8 (carbons of benzene rings), 141.2 (Cꢀ3), 150.4 (Cꢀ5), 170.6 (CO). MS
(EI, 70 eV), m/z (%): 307 (6) [M]+, 91 (100). Anal. Calcd for C17H17N5O: C, 66.43; H, 5.58; N,
22.79. Found: C, 66.27; H, 5.49; N, 22.98.
Acetyl(5ꢀaminoꢀ1,4ꢀdibenzylꢀ4Hꢀ1,2,4ꢀtriazolꢀ1ꢀiumꢀ3ꢀyl)azanide (16b)
Yield 0.480 g (65%) of colorless crystals, mp 182ꢀ183 °C (from EtOH). IR (cmꢀ1): 3331, 3236,
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3060, 1659, 1617, 1572, 1546, 1475, 1386, 1345, 1067, 1009, 933, 744. H NMR (600 MHz,
DMSOꢀd6): δ 1.87 (s, 3Н, CH3CO), 4.81 (s, 2H, CH2), 4.94 (s, 2H, CH2), 7.25ꢀ7.32 (m, 10Н,
2Ph). 13C NMR (150 MHz, DMSOꢀd6): δ 23.7 (CH3CO), 43.9 (4ꢀCH2), 48.8 (1ꢀCH2), 127.0,
127.3, 127.4, 128.3, 136.2, 136.7 (carbons of benzene rings), 144.4 (Cꢀ3), 150.5 (Cꢀ5), 171.6
(CO). MS (EI, 70 eV), m/z (%): 321 (3) [M]+, 91 (100). Anal. Calcd for C18H19N5O: C, 67.27; H,
5.96; N, 21.79. Found: C, 66.95; H, 5.78; N, 22.08.
Acetyl(4ꢀbenzylꢀ1ꢀtertꢀbutylꢀ4Hꢀ1,2,4ꢀtriazolꢀ1ꢀiumꢀ3ꢀyl)azanide (16c)
Yield 0.626 g (72%) of colorless crystals, mp 253 °C with dec. IR (cmꢀ1): 3321, 2977, 1590,
1503, 1376, 1213, 1119, 936, 709. 1H NMR (500 MHz, DMSOꢀd6): δ 1.52 (s, 9Н, tertꢀBu), 1.83
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The Journal of Organic Chemistry
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(s, 3Н, CH3CO), 5.09 (s, 2H, CH2), 7.29ꢀ7.36 (m, 5Н, Ph), 9.51 s (1H, Hꢀ5). 13C NMR (125
MHz, DMSOꢀd6): δ 26.6 (CH3CO), 27.8 (3C, C(CH3)3), 46.8 (CH2), 60.3 (C(CH3)3), 127.8 ,
128.0, 128.5 (carbons of Ph), 134.8 (Cꢀ5), 135.6 (Ph), 157.3 (Cꢀ3), 174.2 (CO). HRMS (ESIꢀ
TOF), m/z [M + H]+ calcd for C15H20N4O 273.1710, found 273.1710.
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General procedure for the synthesis of compounds 10a,cꢀe, 5a
A mixture of the acetyl derivative 15a, 15c and 16aꢀc (1 mmol), ethanol (3 mL), and
concentrated hydrochloric or hydrobromic acid (1 mL) was refluxed for 1 h then evaporated to
dryness at reduced pressure. To isolate 10c, 10d and 5a, acetonitrile (3 mL) was added to the
residue and the precipitate formed was collected by filtration and recrystallized. To isolate 10a
and 10e, a hot 50% water solution of KI (2 mL) was added to the residue. The solid that
separated after cooling was collected by filtration and recrystallized.
3,5ꢀDiaminoꢀ4ꢀmethylꢀ1ꢀphenylꢀ4Hꢀ1,2,4ꢀtriazolꢀ1ꢀium iodide (10a)
Yield 0.25 g (79%). The product obtained was identical in both its physical and spectral
characteristics with the described above sample of compound 10a obtained by direct alkylation
of compound 22.
3,5ꢀDiaminoꢀ4ꢀbenzylꢀ1ꢀphenylꢀ4Hꢀ1,2,4ꢀtriazolꢀ1ꢀium bromide (10d)
Yield 0.325 g (94%) of yellowish crystals, mp 136ꢀ137 °C (from acetonitrile). IR (cmꢀ1): 3473,
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3253, 3107, 1670, 1635, 1595, 1522, 1496, 1454, 1359, 1211, 1073, 735. H NMR (600 MHz,
DMSOꢀd6) δ: 5.34 (s, 2H, CH2), 6.95 (s, 2H, 3ꢀNH2), 7.36ꢀ7.58 (m, 10Н, 2Ph), 8.46 (s, 2H, 5ꢀ
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NH2). C NMR (150 MHz, DMSOꢀd6) δ: 44.6 (CH2), 124.5, 126.9, 128.0, 128.7, 129.0, 129.7,
133.9, 134.8 (carbons of benzene rings), 146.6 (Cꢀ5), 150.4 (Сꢀ3). MS (EI, 70 eV), m/z (%): 266
(11) [M – Br]+, 91 (100). Anal. Calcd for C15H16N5Br: C, 52.04; H, 4.66; N, 20.23. Found: C,
51.81; H, 4.79; N, 19.84.
3,5ꢀDiaminoꢀ4ꢀethylꢀ1ꢀphenylꢀ4Hꢀ1,2,4ꢀtriazolꢀ1ꢀium iodide (10e)
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