Regioselectivity of N-substitution in bis-alkylation of 1,2,4-triazolo[1,5-a]benzimidazole-2-thione

Article abstract of DOI:10.1007/s11172-012-0158-7

Cyclization of the corresponding N-substituted 1,2-diaminobenzimidazoles with carbon disulfide in refluxing DMF leads to 3-methyl- and 3-benzyl-1,2,4-triazolo[1,5-a]benzimidazole-2-thiones. Based on the results of their S-alkylation, quantum chemical calc

Full text of DOI:10.1007/s11172-012-0158-7

Russian Chemical Bulletin, International Edition, Vol. 61, No. 6, pp. 1161—1168, June, 2012
1161
Regioselectivity of Nꢀsubstitution in bisꢀalkylation
of 1,2,4ꢀtriazolo[1,5ꢀa]benzimidazoleꢀ2ꢀthione
T. A. Kuz´menko, V. V. Kuz´menko,† L. N. Divaeva, A. S. Morkovnik, and G. S. Borodkin
Research Institute of Physical and Organic Chemistry, Southern Federal University,
194/2 prosp. Stachki, 344090 Rostov on Don, Russian Federation.
Eꢀmail: asmork2@ipoc.rsu.ru
Cyclization of the corresponding Nꢀsubstituted 1,2ꢀdiaminobenzimidazoles with carbon
disulfide in refluxing DMF leads to 3ꢀmethylꢀ and 3ꢀbenzylꢀ1,2,4ꢀtriazolo[1,5ꢀa]benzimidꢀ
azoleꢀ2ꢀthiones. Based on the results of their Sꢀalkylation, quantum chemical calculations by
the density functional theory method, and 1D and 2D NMR spectroscopic studies, it was
concluded that the bisꢀalkylation of Nꢀunsubstituted 1,2,4ꢀtriazolo[1,5ꢀa]benzimidazoleꢀ2ꢀ
thione in the presence of a base proceeds with the formation of N(4)ꢀderivatives of 2ꢀalkylthioꢀ
1,2,4ꢀtriazolo[1,5ꢀa]benzimidazole, rather than N(3)ꢀderivatives as was believed earlier.
Key words: 1,2ꢀdiaminobenzimidazole, 1ꢀaminoꢀ2ꢀalkylaminobenzimidazoles, 1,2,4ꢀtriꢀ
azolo[1,5ꢀa]benzimidazoleꢀ2ꢀthiones, alkylation, quantum chemical calculations, density funcꢀ
tional theory method, 1D and 2D NMR spectroscopy, NOESY.
Recently, it was reported1 that 1,2,4ꢀtriazolo[1,5ꢀa]ꢀ
benzimidazoleꢀ2ꢀthione (1), obtained from 1,2ꢀdiaminoꢀ
benzimidazole and carbon disulfide, upon treatment with
1 equiv. of alkyl halides in acetone in the presence of
potash was converted to Sꢀalkylthio derivatives 2, whose
subsequent alkylation or reaction of the initial thione 1
with 2 equiv. of alkyl halides under the same conditions
led to 2ꢀalkylthioꢀ3ꢀalkyltriazolobenzimidazoles (3). These
compounds displayed antibacterial, antituberculosis, and
fungicide activities comparable with those for the clinicalꢀ
ly used agents. However, the authors of the work1 did not
show evidence to the fact that the Nꢀalkylation in this case
occurred at position 3 of the tricyclic system.
regioselectivity of their Nꢀalkylation should depend on
both the position of the tautomeric equilibrium and the
nucleophilicity of each of the tautomers.
Scheme 1
Earlier, the studies of the tautomerism of unsubstitutꢀ
ed 1,2,4ꢀtriazolo[1,5ꢀa]benzimidazole and its 2ꢀmethylꢀ
and 2ꢀphenyl derivatives showed that in all these cases
predominate the 4Hꢀforms, whose contents in the equiꢀ
librium mixtures exceeded the content of 3Hꢀtautomer by
2—3 orders of magnitude. No signs of existence of the
1Hꢀform were detected. As a result, alkylation of the indiꢀ
cated azoles in alkaline medium, which favors formation
of the substrate Nꢀanions, basically leads to N(4)ꢀalkyl
derivatives, rather than to N(3) derivatives.2
Meanwhile, the 2ꢀalkylthio derivative 2 formed in the
first step of the reaction can theoretically exist in three
tautomeric forms (1H, 3H, and 4H (Scheme 1)) and the
Taking the given data into account, it seemed reasonꢀ
able to perform additional studies in order to more preꢀ
†
Deceased.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 6, pp. 1150—1157, June, 2012.
1066ꢀ5285/12/6106ꢀ1161 © 2012 Springer Science+Business Media, Inc.

1162
Russ.Chem.Bull., Int.Ed., Vol. 61, No. 6, June, 2012
Kuz´menko et al.
Scheme 2
cisely determine the structure of the products of bisꢀalkyꢀ
lation of thione 1. To accomplish this goal, it was necesꢀ
sary to synthesize Nꢀsubstituted 1,2,4ꢀtriazolo[1,5ꢀa]ꢀ
benzimidazoleꢀ2ꢀthiones with a certain position of the
Nꢀsubstituent. We showed that 1ꢀaminoꢀ2ꢀRꢀaminobenzꢀ
imidazoles (4a—e), which are very reluctant to cyclize
with acid anhydrides to form the corresponding 3ꢀRꢀtriꢀ
azolo[1,5ꢀa]benzimidazoles,3 upon reflux with carbon
disulfide in DMF smoothly were converted to the N(3)ꢀsubꢀ
stituted thiones 5a—e (Scheme 2, Table 1). In this case,
the electrophile most likely initially attacks the Nꢀamino
group as the most nucleophilic center of the molecule.
1
In the H NMR spectra of compounds 5, the signals
for the protons H(5) and H(8), under the influence of
anisotropic effect of the atoms N(4) and N(9), are shifted
downfield by ~0.3 ppm as compared to the protons H(6)
and H(7) and resonate either as two multiplets (5a—c), or
as a combined multiplet (5d), or as two well resolved douꢀ
blets (5e). The structure of thiones 5 was confirmed by the
mass spectrometric data obtained for compound 5a.
The methylation of thione 5a with iodomethane in
acetone in the presence of potash gives rise to the authenꢀ
tic 3ꢀmethylꢀ2ꢀ(methylthio)triazolobenzimidazole (3a),
which in its physicochemical characteristics differs from
3: R = R´ = Me (a), R = R´ = Bn (b),
R = CH2CH2NEt2, R´ = 3,4ꢀCl Bn (e)
2
4, 5: R = Me (a), Bn (b), CH2CH2OH (c),
CH2CH2NEt2 (e)
(d),
the product described in the work1 (let us designate it
as 6a) and formed by bismethylation of thione 1. Comꢀ
pound 3b, which we synthesized by reflux of thione 5b
with benzyl chloride in DMF with potash, was not identiꢀ
Table 1. Yields and physicochemical characteristics of N(3)ꢀsubstituted 1,2,4ꢀtriazolo[1,5ꢀa]benzimidazoleꢀ2ꢀthiones 5
Comꢀ Yield
pound (%) (from DMF)
M.p./C
Found
Calculated
Molecular
formula
1H NMR
(DMSOꢀd6, , J/Hz)
(%)
С
Н
N
S
5а*
93
84
247—248
248—249
52.75 4.03 27.20 15.82
52.92 3.95 27.20 15.70
C9H8N4S
3.56 (s, 3 Н, Me); 7.33—7.40 (m, 2 Н, Н(6), H(7));
7.63—7.68 (m, 1 Н, Н(5) or H(8)); 7.70—7.75
(m, 1 Н, Н(8) or H(5)); 13.20 (br.s, 1 Н, NH)
5b
64.47 4.12 19.85 11.67
64.26 4.31 19.98 11.44
С15Н12N4S
5.42 (s, 2 Н, СН2); 7.23—7.42 (m, 5 Н, Н(3´),
H(4´), H(5´), Ph, Н(6), H(7)); 7.46 (d, 2 Н,
Н(2´), H(6´), Ph, J = 7.3); 7.60—7.68 (m, 1 Н,
Н(5) or H(8)); 7.72—7.80 (m, 1 Н, Н(8) or H(5));
13.80 (br.s, 1 Н, NH)
5c
72
224—225
51.43 4.17 23.70 13.52
51.27 4.30 23.91 13.69
С10Н10N4ОS 3.76 (t, 2 Н, СН2ОН, J = 5.0); 4.21 (t, 2 Н,
NCH2, J = 5.0); 5.11 (s, 1 Н, ОН); 7.33—7.42
(m, 2 Н, Н(6), H(7)); 7.59—7.67 (m, 1 Н, Н(5)
or H(8)); 7.70—7.78 (m, 1 Н, Н(8) or H(5));
13.56 (br.s, 1 Н, NH)
5d
5e
85
83
229—230
210—212
55.27 5.80 23.25 10.37
55.43 5.65 23.08 10.57
С14H17N5ОS 3.35—4.30 (m, 10 Н, 8 Н (morpholino),
СН2 (morpholino)); 4.61 (t, 2 Н, NCH2, J = 5.0);
7.38—7.49 (m, 2 Н, Н(6), H(7)); 7.72—7.85
(m, 2 Н, Н(5), H(8)); 9.60 (br.s, 1 Н, NH)
58.32 6.38 24.45 11.23
58.10 6.62 24.20 11.08
С14H19N5S
1.23 (t, 6 Н, 2 Ме, J =7.1); 3.24 (q, 4 Н,
2 СН2Ме); 3.60 (degen.t, 2 Н, СН2NEt2);
4.44 (t, 2 Н, NCH2, J = 5.5); 6.96—7.10
(m, 2 Н, Н(6), H(7)); 7.42 (d, 1 Н, Н(5) or H(8),
J = 7.3); 7.49 (d, 1 Н, Н(8) or H(5), J = 7.4);
9.61 (br.s, 1 Н, NH)
* MS, m/z (Irel (%)): 204 [M]+ (83.3), 146 (45.8), 118 (98.3), 104 (60.8), 90 (75.0), 77 (100), 64 (53.3), 59 (40.0), 51 (48.3), 39 (45.8).

Regioselectivity of Nꢀsubstitution
Russ.Chem.Bull., Int.Ed., Vol. 61, No. 6, June, 2012
1163
cal to compound 6b, obtained by bisbenzylation of thione 1
under analogous conditions, either (the comparative charꢀ
acteristics of compounds 3a,b and 6a,b are given below).
To sum up, it turned out that thione 1 in the presence of
a base gave no alkylation at position 3 and, hence, either
N(1)ꢀ or N(4)ꢀsubstituted 2ꢀalkylthiotriazolobenzimidꢀ
azoles were the reaction products.
shared pairs of electrons almost parallel oriented inclined to
the strong repulsive interaction. This leads to a reduction
in the aromaticity of the triazole ring in the 1Hꢀform, conꢀ
siderable elongation of the N—N bond, which, in the end,
makes it thermodynamically unfavorable. For example,
quantum chemical calculations (B3LYP/6ꢀ31G**) show
that in the 1Hꢀform of 2ꢀmercaptoꢀ1,2,4ꢀtriazolo[1,5ꢀa]ꢀ
benzimidazole, the N—N bond (1.397 Å) is ~0.02—0.03 Å
longer than that in two other tautomeric forms of the
indicated compound. In this case, the energy of the
1Hꢀform is higher by 18.3 and 9.9 kcal mol–1 than that for
the most stable 4Hꢀform and the intermediate in stability
3Hꢀform, respectively.
Quantum chemical studies of the model methylation
reaction of the Nꢀanion of 2ꢀ(methylthio)triazolobenzꢀ
imidazole with methyl chloride showed that the N(4) atom
is the most nucleophilic site in the indicated anion. Among
three isomeric transition states (TS) of this reaction, the
transition state TS1 leading to the methylation of position
For the preparation of authentic 1ꢀmethyl(benzyl)ꢀ
triazolobenzimidazoleꢀ2ꢀthiones 7, the corresponding
N(1)ꢀsubstituted 1,2ꢀdiaminobenzimidazoles are required
as the starting compounds, from which only 2ꢀaminoꢀ1ꢀ
benzylaminobenzimidazole (8) is easily available. The latꢀ
ter can be obtained by the reduction of 2ꢀaminoꢀ1ꢀbenzꢀ
ylidenaminobenzimidazole2. The cyclization of diamine 8
with carbon disulfide to thione 7 (Scheme 3) proceeds
considerably slower as compared to 1,2ꢀdiaminobenzimidꢀ
azole and amines 4, upon prolonged (25 h) reflux of the
reagents in DMF, in the not higher than 55—60% yield.
Apparently, this reaction is hindered not only by steric
shielding of the Nꢀamino group, but also by the insuffiꢀ
ciently high nucleophilicity of the Cꢀamino group. Note
that no cyclization of amine 8 to the corresponding
1ꢀsubstituted triazolobenzimidazoles was observed upon
the action of acid anhydrides or formamide.2 The strucꢀ
ture of thione 7 was confirmed by 1H NMR spectroscopic
and mass spectrometric data.
4 possesses the minimal energy (Fig. 1).
The transition
states for the N(1)ꢀ and N(3)ꢀmethylation TS2 and TS3
have higher energies by 6.3 and 3.1 kcal mol–1, respectively,
with respect to the TS1.
Along with the given experimental data, this indicates
that thione 1, like other 1,2,4ꢀtriazolo[1,5ꢀa]benzimidꢀ
azoles studied earlier, undergoes Nꢀalkylation in the presꢀ
ence of bases at position 4 with the formation of comꢀ
pounds 6.
Scheme 3
In comparison with 3ꢀsubstituted 2ꢀmethylthioꢀ and
2ꢀbenzylthiotriazolobenzimidazoles 3a,b, their 4ꢀalkylꢀ
(benzyl)ꢀsubstituted isomers 6a,b possess higher chroꢀ
matographic mobility (Rf 0.6 and 0.7, respectively). The
3ꢀmethyl derivative 3a has a melting point 20 C lower
than that in the case of compound 6a. The dibenzylꢀsubꢀ
stituted isomers 3b and 6b have very close melting points,
but, likewise compounds 3a and 6a, different IR spectra.
It is characteristic that in the 1H NMR spectra of disubstiꢀ
tuted 3a,b, like in the spectra of the starting thiones 5a,b,
the signals for the two protons H(5) and H(8) are found
downfield shifted from the multiplet of other aromatic
protons, whereas in the 4ꢀisomers 6a,b because of the abꢀ
sence of the sp2ꢀhybridized nitrogen atom neighboring to
the atom H(5), only signal for the proton H(8) is downꢀ
field shifted.
The Sꢀbenzylation of thione 7 with benzyl chloride
under the conditions of smooth dibenzylation of thione 1
leads to a complicated, difficult to separate mixture of
products, which does not contain compound 6b (Scheme 4).
Most likely, this is attributable to the instability of the
1Hꢀtautomeric form of triazolobenzimidazole system
found earlier,2 which, in our opinion, results from the
3
3
presence of the fragment N(9)sp —N(1)sp with two unꢀ
Additional evidence for the N(4)ꢀsubstitution in the
thione 1 upon its bisꢀalkylation was obtained during studꢀ
ies of compound 6a by heteronuclear 2D 13C—H and
15N—H NMR spectroscopy, as well as by NOESY.
Scheme 4
The total energies of the indicated tautomeric 4Hꢀ, 3Hꢀ, and
1Hꢀform (without allowance for the vibration energy) were found
to be –925.652766, –925.639314, and –925.623539 au, respecꢀ
tively.
The total energies of transition states TS1, TS2, and TS3 are
equal to –1425.195930, –1425.201742, and –1425.207095 au,
respectively.
6: R = Me (a), Bn (b), 4ꢀFC6H4OCH2CH2 (c)

1164
Russ.Chem.Bull., Int.Ed., Vol. 61, No. 6, June, 2012
Kuz´menko et al.
Cl
1.348
S
1.779
1.338
2.384
1.378
1.380
1.358
1.377
1.437
1.984
1.344
1.349
S
1.346
1.357
1.382
1.381
1.378
1.777
2.055
1.333
1.385
1.440
1.368
1.330
2.315
1.382
TS1
TS2
Cl
N
C
H
1.347
S
1.329
1.777
1.360
2.011
1.382
1.379
1.379
1.363
1.329
1.440
2.356
1.385
Cl
TS3
Fig. 1. The structures of the transition states TS1—TS3 for the methylation of 2ꢀmethylthioꢀ1,2,4ꢀtriazolo[1,5ꢀa]benzimidazole
Nꢀanion with methyl chloride. Here and in Fig. 2, the bond distances are given in Å.
The 13C NMR spectra of dimethyl derivative 6a with
proton decoupling (CDCl3) exhibited all the expected sigꢀ
nals from ten carbon nuclei, which were assigned based on
the analysis of the heteronuclear 2D 13C—1H NMR
HSQCꢀ and HMBC spectra.
The 13C—1H HSQC spectrum of this compound conꢀ
tains the expected crossꢀpeaks in the region for aliphatic
signals attributable to the carbonꢀproton interaction in
two methyl groups and the fragments C(5)—H, C(6)—H,
C(7)—H, and C(8)—H.
was assigned to the interaction of the nitrogen atom of this
fragment with the protons H(5) and H(6). The crossꢀpeak
from the nitrogen atom of the Nꢀmethyl group and the
protons of the Sꢀmethyl group is absent. In addition, this
spectrum has weak crossꢀpeaks of the nitrogen N(3) interꢀ
acting with the protons of the Nꢀ and Sꢀmethyl groups
(at  143.60, 3.74 and 143.60, 2.66, respectively), as
well as a crossꢀpeak attributable to the interaction of the
15N(1) nucleus with the proton of the Sꢀmethyl group at
 254.40, 2.66.
Attachment of the Nꢀmethyl group in the dimethyl
derivative 6a to the N(4) nitrogen atom, rather than to an
alternative N(1) position, was confirmed by the 13C—1H
HMBC spectrum and 2D 15N—1H spectrum. The 13C—1H
HMBC spectrum, besides other crossꢀpeaks, has two charꢀ
acteristic crossꢀpeaks C(10)/N—Me and C(12)/N—Me,
but has no crossꢀpeak for the protons C(2)/N—Me. In the
2D 15N—1H spectrum, besides very strong crossꢀpeak for
the fragment N—Me at  94.90, 3.74, a much weaker
double crossꢀpeak at  94.86, 3.74 were also found, which
In accordance with the structure of 6a, the NOESY
spectrum of the dimethyl derivative exhibited a crossꢀpeak
for the pair of proton groups NMe and H(5), but had no
crossꢀpeak for the protons of two methyl groups, whose
presence should have been expected for the N(1)ꢀisomer.
Unfortunately, attempted synthesis of N(4)ꢀmethylꢀ
substituted triazolobenzimidazoleꢀ2ꢀthione (9), from
which an authentic compound 6a could have particularly
been obtained, was unsuccessful. 1ꢀAminoꢀ2ꢀiminoꢀ3ꢀ
methylbenzimidazoline (10)4 taken for this synthesis as

Regioselectivity of Nꢀsubstitution
Russ.Chem.Bull., Int.Ed., Vol. 61, No. 6, June, 2012
1165
a starting compound, which readily cyclized with acid
anhydrides and formamide to the corresponding 4ꢀmethꢀ
ylꢀ1,2,4ꢀtriazolo[1,5ꢀa]benzimidazoles,2 in the reaction
with carbon disulfide in DMF at 20—25 C formed poorly
soluble yellow product 11 which, according to the elemenꢀ
tal analysis data, was the product of addition of imine 10
to CS2. Upon subsequent reflux of the reaction mixture,
this compound, undergoing no cyclization at the Nꢀamiꢀ
no group, unexpectedly reacted with dimethylamine
present in the reaction mixture. The process was accomꢀ
panied by Nꢀdeamination and led to 1ꢀmethylꢀ2ꢀ(3,3ꢀdiꢀ
methylthioureido)benzimidazole (12), which was conꢀ
firmed by the H NMR spectroscopic and mass spectroꢀ
metric data.
Attempted thermal cyclization of compound 11 in the
absence of a solvent was not successful, either: at 140 C it
rapidly decomposed with the formation of hardly identifiꢀ
able resinꢀlike residue.
It is obvious that compounds of the type 11 are always
intermediately formed in the reactions of amines with carꢀ
bon disulfide, but, as a rule, they are unstable and, thereꢀ
fore, seldom isolable. In the series of benzimidazole, for
example, only one analogous compound was described,
which was formed from 2ꢀaminoꢀ1ꢀ(ꢀaminoethyl)benzꢀ
imidazole and carbon disulfide at the aliphatic amino
group.5 In our case, the stability of the adduct 11 is apparꢀ
ently due to the very high nucleophilicity of the imine
group of the guanidine fragment in the starting molecule,
which not only facilitated its formation, but also made
difficult a reverse decomposition to the starting comꢀ
pounds.
For compound 11, there are four prototropic tautomers
theoretically possible: dithiocarbamoic acid 11a, two zwitꢀ
terionic forms with localization of the labile proton on the
amino or the imine group (11b,c), and a spirocyclic form
with thiazetidine ring (11d) (Scheme 5). The zwitterionic
form 11b can be ruled out from consideration based on the
1H NMR spectrum of compound 11, which has no a threeꢀ
proton signal for the +NH3 group, but does have two broad
singlets: a twoꢀproton one at  5.34 and a oneꢀproton at
 6.06. The firsts from them, undoubtedly, belongs to the
Nꢀamino group, whereas the second belongs to either the
SH group of the form 11a or the 2ꢀimine group of any of
the forms 11c,d. The choice between the forms 11a,c,d
was made in favor of the form 11c based on the mass
spectrometric and IR spectroscopic data, as well as on the
results of quantum chemical calculations. In the mass
spectrum of compound 11, a peak of the molecular ion is
absent, but two very strong peaks with m/z 162 (100%)
and 76 (93%) are observed, which respectively correspond
to the ions [M – CS2]+ and [M – M10]+, where M10 is the
molecular weight of imine 10. This indicates that comꢀ
pound 11 is very easily cleaved at the C—N bond with the
extrusion of carbon disulfide, which should be characterꢀ
istic of the zwitterionic tautomer 11c. The IR spectrum of
compound 11 has an absorption band at 3208 cm–1 (NH+),
1
Scheme 5

1166
Russ.Chem.Bull., Int.Ed., Vol. 61, No. 6, June, 2012
Kuz´menko et al.
S
1.458
1.363
1.456
1.681
1.398
1.392
1.399
1.371
1.346
1.342
1.352
1.799
1.402
1.461
1.698
1.406
1.315
S
1.358
1.037
1.377
1.398
1.678
1.388
1.400
2.252
11a (–1364.360369)
11c (–1364.346533)
1.453
1.393
C
H
N
1.377
1.401
1.745
1.400
S
1.381
1.407
1.651
2.409
1.393
1.395
11d (–1364.336333)
Fig. 2. The prototropic forms of Nꢀ(1ꢀaminoꢀ3ꢀmethylꢀ1,3ꢀdihydrobenzimidazolꢀ2ꢀylidene)dithiocarbamoic acids 11a,c,d and their
energies (in parentheses, at. units) according to the data of the B3LYP/6ꢀ31G** quantum chemical calculations.
but has no absorption band for the S—H bond in the inꢀ
dicative region ~2400 cm–1
the acid form 11a almost did not differ in energies (the
energy difference was only ~0.5 kcal mol–1). However,
the PCM method essentially underestimates solvation enꢀ
ergy of ions and highly polar molecules, and in the reality,
the most polar form 11c had proved to be the most stable
in solutions. It turned out that the thiazetidine form 11d,
when nonpolar solvents were changed to polar ones was
no longer in the minimum on the PES and underwent the
thiazetidine ring opening at its least strong C—S bond,
leading to the formation of zwitterionic form 11c.
Considerable localization of the positive charge on the
benzimidazolium fragment in the form 11c, apparently,
decreases the nucleophilicity of the Nꢀamino group to
a such extent, that deactivates it to further cyclization.
In conclusion, the investigation performed in this work
showed that bisꢀalkylation of 1,2,4ꢀtriazolo[1,5ꢀa]benzꢀ
imidazoleꢀ2ꢀthione (1) in the presence of a base led not to
N(3)ꢀalkylꢀ2ꢀ(alkylthio)triazolobenzimidazoles 3, as it
was mistakenly believed earlier, but to their N(4)ꢀsubstiꢀ
tuted isomers 6.
.
The quantum chemical calculations performed
(B3LYP/6ꢀ31G**) show that under the gasꢀphase condiꢀ
tions, the moderately polar (calc = 4.9 D) form 11a is the
most stable (Fig. 2). The relative energies of other forms
(in kcal mol–1) and their calculated dipole moments (in D,
given in parentheses) are as follows: 7.9 (12.3) for the
conformer 11c (A) with the Hꢀbond HN—H...S=C<, 13.1
(14.0) for the less stable conformer 11c (B), which does
not have such a bond, and 14.4 (10.1) for the tautomer 11d
with a thiazetidine ring (see Scheme 5). However, the
tautomer 11c should predominate in solutions in the form
of its most stable conformer A (11c (A)). The zwitterionic
structure with the benzimidazolium cationic center and
a considerable spatial separation of charges is one of its
important resonance forms. This is the factor which exꢀ
plains a high dipole moment of the tautomer 11c and the
fact that it becomes predominant in polar media, being
stabilized by solvation stronger than a competing tautoꢀ
meric form 11a.
This suggestions were confirmed by the PCM calculaꢀ
tions with the optimization of geometry, according to
which in DMSO, which is close to DMF in the polarity,
the zwitterionic tautomerꢀconformer form 11c (A) and
Experimental
IR spectra were recorded on a Varian Excalibur 3100 FTꢀIR
spectrometer in the solid phase, 1H NMR spectra were recorded
on a Varian Unityꢀ300 spectrometer (300 MHz) in the mode of
internal stabilization of the 2H polarꢀresonance line of the deuꢀ
terated solvent, 13C NMR spectra and 2D NMR spectra were
recorded on a Bruker Avance 600 spectrometer (600 MHz).
The calculations were performed with allowance for the
electrostatic effect, repulsive and dispersion interactions with
the solvent, as well as the cavitation energy.

Regioselectivity of Nꢀsubstitution
Russ.Chem.Bull., Int.Ed., Vol. 61, No. 6, June, 2012
1167
Chemical shifts for the 15N nuclei are given relative to ammonia.
Mass spectra were recorded on a Finnigan MAT INCOS50 inꢀ
strument with direct injection of the samples into the source of
ions (70 eV). The reaction progress and individuality of comꢀ
pounds were monitored by TLC on Al2O3 plates of III degree of
activity, CHCl3 was an eluent, iodine vapors were used for visuꢀ
alization.
Quantum chemical calculations were performed using the
Firefly program6 partially based on the code of the Gamess proꢀ
gram.7 The energy values were obtained without allowance for
the energies of the groundꢀstate vibrational levels (ZPE). Idenꢀ
tification of the energy minima and the transition states of the
molecular systems under study was performed with the calculaꢀ
tion of their force constant matrices.
Preparation and properties of 1,2,4ꢀtriazolo[1,5ꢀa]benzꢀ
imidazoleꢀ2ꢀthione (1)1, 1ꢀaminoꢀ2ꢀRꢀaminobenzimidazoles
(4a—e),3 2ꢀaminoꢀ1ꢀ(benzylamino)benzimidazole (8),2 and
1ꢀaminoꢀ2ꢀimineꢀ3ꢀmethylbenzimidazoline (10)4 have been deꢀ
scribed earlier.
3ꢀSubstituted 1,2,4ꢀtriazolo[1,5ꢀa]benzimidazoleꢀ2ꢀthiones
(5). Carbon disulfide (1.5 mL) was added to a solution of the
corresponding 1ꢀaminoꢀ2ꢀ(Rꢀamino)benzimidazole 4 (5 mmol)
in DMF (5 mL) and the mixture was refluxed for 5—8 h.
A colorless precipitate was formed in the refluxing solution, which
after cooling was filtered off and washed with acetone. Physicoꢀ
chemical constants and yields of the obtained thiones 5 are given
in Table 1.
3ꢀMethylꢀ2ꢀmethylthioꢀ1,2,4ꢀtriazolo[1,5ꢀa]benzimidazole
(3a). A mixture of thione 5a (0.41 g, 2 mmol) and iodomethane
(1.3 mL, 2 mmol) in acetone (10 mL) was stirred at 25 C in the
presence of potash (0.28 g, 2 mmol) for 4 h. A precipitate was
filtered off and washed with acetone (5 mL). The mother liquor
was concentrated to dryness. The residue was subjected to chroꢀ
matography on a column with Al2O3 (15×50 mm), using chloroꢀ
form as an eluent and collecting the fraction with Rf 0.6. The yield
was 0.35 g (80%), m.p. 139—140 C (ethyl acetate). Found (%):
C, 55.27; H, 4.68; N, 25.84; S, 14.52. C10H10N4S. Calculatꢀ
ed (%): C, 55.03; H, 4.62; N, 25.67; S, 14.69. 1H NMR (CDCl3),
: 2.73 (s, 3 H, SMe); 3.67 (s, 3 H, NMe); 7.18—7.27 (m, 2 H,
H(6), H(7)); 7.67—7.71 (m, 2 H, H(5), H(8)).
4ꢀMethylꢀ2ꢀmethylthioꢀ1,2,4ꢀtriazolo[1,5ꢀa]benzimidazole
(6a) was synthesized according to the procedure described earliꢀ
er,1 stirring thione 1 (0.38 g, 2 mmol) with iodomethane (2.6 mL,
4 mmol) in acetone (10 mL) in the presence of potash (0.56 g,
4 mmol). The yield was 73%. M.p. 159—160 C (ethyl acetate)
(cf. Ref. 1: m.p. 150—152 C, Rf 0.7). Found (%): C, 55.16;
H, 4.53; N, 25.47; S, 14.73. C10H10N4S. Calculated (%):
C, 55.03; H, 4.62; N, 25.67; S, 14.69. IR, /cm–1: 1625 m, 1599
s, 1495 s, 1475 s. 1H NMR (CDCl3), : 2.67 (s, 3 H, SMe); 3.79
(s, 3 H, NMe); 7.21—7.35 (m, 3 H, H(5)—H(7)); 7.71—7.74
(m, 1 H, H(8)). 13C NMR (CDCl3), : 14.49 (SMe); 29.52
(NMe); 109.99 (C(5)); 110.36 (C(8)); 121.48 (C(7)); 123.25 (C(6));
124.01 (C(9)); 134.36 (C(10)); 154.41 (C(12)), 165.25 (C(2)).
2D 13C—1H HMBC (CDCl3), : 165.31, 2.66 (C(2)/SMe);
134.42, 3.74 (C(10)/NMe); 154.47, 3.74 (C(12)/NMe); 110.47,
7.22 (C(8)/H(7)); 124.06, 7.22 (C(9)—H(7)); 121.65, 7.26
(C(5)/H(6)); 123.35, 7.65 (C(6)/H(8)); 134.37, 6.65 (C(10)/H(8)).
NOESY (CDCl3), : 3.74, 7.25 (NMe—H(5)); 7.22, 7.65
(H(7)—H(8)).
benzyl chloride (0.12 mL, 1 mmol) in DMF (2 mL) was refluxed
for 1 h in the presence of potash (0.14 g, 1 mmol), then cooled,
diluted with water (5 mL), and the thus formed precipitate was
filtered off. The residue was subjected to chromatography on
a column with Al2O3 (15×50 mm), using chloroform as an eluent
and collecting the fraction with Rf 0.6. The yield was 0.28 g
(75%), m.p. 129—131 C (ethyl acetate). Found (%): C, 71.40;
H, 4.72; N, 15.28; S, 8.54. C22H18N4S. Calculated (%): C, 71.33;
H, 4.90; N, 15.12; S, 8.65. IR, /cm–1: 1638 s, 1587 m, 1557 s,
1485 m, 1441 s. 1H NMR (CDCl3), : 4.36 (s, 2 H, SCH2); 5.11
(s, 2 H, NCH2); 7.16—7.38 (m, 12 H, 2 Ph, H(6), H(7)); 7.72
(d, 1 H, H(5), J = 8.5 Hz); 7.75 (d, 1 H, H(8), J = 8.7 Hz).
4ꢀBenzylꢀ2ꢀbenzylthioꢀ1,2,4ꢀtriazolo[1,5ꢀa]benzimidazole
(6b). A solution of thione 1 (0.19 g, 1 mmol) and benzyl chloride
(0.25 mL, 2 mmol) in DMF (2 mL) was refluxed for 3 h with
potash (0.28 g, 2 mmol). After cooling, the mixture was diluted
with water (5 mL), a precipitate formed was filtered off, and the
residue was subjected to chromatography on a column with Al2O3
(15×50 mm), using chloroform as an eluent and collecting the
fraction with Rf 0.7. The yield was 0.3 g (80%), m.p. 132—133 C
(ethyl acetate). Found (%): C, 71.27; H, 4.93; N, 15.00; S, 8.71.
C22H18N4S. Calculated (%): C, 71.33; H, 4.90; N, 15.12; S, 8.65.
IR, /cm–1: 1619 m, 1582 v.s, 1491 s, 1450 s (C=N, C=C).
1H NMR (CDCl3), : 4.46 (s, 2 H, SCH2); 5.38 (s, 2 H, NCH2);
7.17—7.39 (m, 11 H, H(5), H(6), H(7), Ph, H(3´), H(4´), H(5´));
7.44 (d, 2 H, H(2´), H(6´), J = 8.2 Hz); 7.75—7.76 (m, 1 H, H(8)).
2ꢀ(3,4ꢀDichlorobenzyl)thioꢀ3ꢀ(2ꢀdiethylaminoethyl)ꢀ1,2,4ꢀ
triazolo[1,5ꢀa]benzimidazole hydrochloride (3e). A solution of
thione 5e (0.58 g, 2 mmol) and 3,4ꢀdichlorobenzyl bromide
(0.48 g, 2 mmol) in DMF (4 mL) was refluxed for 45 min in the
presence of potash (0.28 g, 2 mmol). After cooling, the mixture
was diluted with water (20 mL) and the thus formed dense oil
was extracted with chloroform (15 mL). The extract was conꢀ
centrated to the minimum volume and subjected to chromatoꢀ
graphy on a column with Al2O3 (20×60 mm), using chloroform
as an eluent and collecting the fraction with Rf 0.45. Chloroform
was evaporated to dryness, the residue was dissolved in acetone
(5 mL) and treated with the saturated solution of HCl in isoꢀ
propyl alcohol to pH 1. The crystals formed were filtered off
and washed with acetone. The yield was 0.65 g (67%), m.p.
199—200 C (PriOH). The compound is readily soluble in
water. Found (%): C, 52.18; H, 5.12; N, 14.62; S, 6.47.
C21H23Cl2N5S•HCl. Calculated (%): C, 52.02; H, 4.95; N, 14.45;
S, 6.60. 1H NMR (DMSOꢀd6), : 1.24 (t, 6 H, 2 CH2Me,
J = 7.2 Hz); 3.25 (q, 4 H, 2 CH2Me, J = 7.2 Hz); 3.64 (t, 2 H,
CH2NEt2); 4.54 (s, 2 H, SCH2); 4.61 (t, 2 H, CH2Ncycl
,
J = 6.7 Hz); 7.33—7.40 (m, 2 H, H(6), H(7)); 7.49 (dd, 1 H,
H (6´), Ar, J = 8.4 Hz, J = 2.1 Hz); 7.62 (d, 1 H, H(2´), Ar,
J = 8.4 Hz); 7.72 (d, 1 H, H(5), J = 7.6 Hz); 7.79 (d, 1 H, H (5´), Ar,
J = 1.8 Hz); 7.86 (d, 1 H, H(8), J = 7.3 Hz); 10.98 (s, 1 H, NH).
4ꢀ[2ꢀ(4ꢀFluorophenoxyethyl)]ꢀ2ꢀ[2ꢀ(4ꢀfluorophenoxyethyl)]ꢀ
thioꢀ1,2,4ꢀtriazolo[1,5ꢀa]benzimidazole (6c) was obtained simiꢀ
larly to compound 6b from thione 1 (0.38 g, 2 mmol) and 2ꢀ(4ꢀ
fluorophenoxy)ethyl bromide (0.88 g, 4 mmol) in DMF (4 mL).
The yield was 0.68 g (73%). M.p. 109—110 C (heptane). Found (%):
C, 61.62; H, 4.50; N, 12.27; S, 6.93. C24H20F2N4O2S. Calculatꢀ
ed (%): C, 61.79; H, 4.32; N, 12.01; S, 6.87. 1H NMR (CDCl3),
: 3.53 (t, 2 H, SCH2, J = 6.9 Hz); 4.30 (t, 2 H, SCH2CH2O,
J = 6.9 Hz); 4.35 (t, 2 H, NCH2CH2O, J = 5.3 Hz); 4.53 (t, 2 H,
NCH2, J = 5.3 Hz); 6.66—6.73 (m, 2 H, H(2´), H(6´), Ar);
6.84—6.97 (m, 6 H, other protons of the Ar groups); 7.26—7.38
3ꢀBenzylꢀ2ꢀbenzylthioꢀ1,2,4ꢀtriazolo[1,5ꢀa]benzimidazole
(3b). A solution of 3ꢀbenzylꢀsubstituted 5b (0.28 g, 1 mmol) and

1168
Russ.Chem.Bull., Int.Ed., Vol. 61, No. 6, June, 2012
Kuz´menko et al.
(m, 2 H, H(6), H(7)); 7.53 (d, 1 H, H(5) or H(8), J = 7.3 Hz);
7.72 (d, 1 H, H(8) or H(5), J = 7.3 Hz); 10.96 (s, 1 H, NH).
1ꢀBenzylꢀ1,2,4ꢀtriazolo[1,5ꢀa]benzimidazoleꢀ2ꢀthione (7).
A solution of 2ꢀaminoꢀ1ꢀ(benzylamino)benzimidazole (8) (0.48 g,
2 mmol) in DMF (5 mL) was refluxed for 25 h with carbon
disulfide (2 mL). A precipitate formed on cooling was filtered
off and washed with acetone. The yield was 0.4 g (72%), m.p.
238—239 C (BuOH). Found (%): C, 64.00; H, 4.02; N, 19.67;
S, 11.77. C15H12N4S. Calculated (%): C, 64.26; H, 4.31; N, 19.98;
S, 11.44. IR, /cm–1: 3200—2500 (NH); 1606 s, 1590 s, 1486 m
(C=N, C=C). 1H NMR (DMSOꢀd6), : 5.91 (s, 2 H, CH2); 7.19
(t, 1 H, H(4´), Ph, J = 7.7 Hz); 7.23—7.36 (m, 4 H, H(6), H(7),
H(3´), H(5´), Ph); 7.40 (d, 2 H, H(2´), H(6´), Ph, J = 7.9 Hz);
7.44—7.53 (m, 2 H, H(5), H(8)); 13.17 (br.s, 1 H, NH). MS,
m/z (Irel (%)): 280 [M]+ (55.8), 222 (20.0), 148 (10.0), 91 (100),
65 (10,0).
194—195 C (BuOH). Found (%): C, 56.57; H, 5.83; N, 24.11;
S, 13.52. C11H14N4S. Calculated (%): C, 56.38; H, 6.02;
N, 23.91; S, 13.68. IR, /cm–1: 1627 s, 1594 v.s, 1492 s (C=S,
C=N, C=C). 1H NMR (CDCl3), : 3.36 (s, 3 H, NMe); 3.44
(s, 3 H, NMe); 3.54 (s, 3 H, NMe—benzimidazole); 7.10—7.29
(m, 4 H, H of benzimidazole); 13.71 (s, 1 H, NH). MS, m/z
(Irel (%)): 234 [M]+ (71.7), 201 (26.7), 190 (100), 158 (60.0), 145
(20.0), 132 (69.2), 88 (69.2), 77 (31.7), 42 (45.8).
References
1. B. G. Mohamed, M. A. Hussein, A.ꢀA. M. AbdelꢀAlim,
M. Hashem, Arh. Pharm. Res., 2006, 29, 26.
2. V. V. Kuz´menko, T. A. Kuz´menko, A. F. Pozharskii, V. N.
Doron´kin, N. L. Chikina, S. S. Pozharskaya, Khim. Geteroꢀ
tsikl. Soedin., 1989, 209 [Chem. Heterocycl. Compd.
(Engl. Transl.), 1989, 25, 168].
3. T. A. Kuz´menko, V. V. Kuz´menko, A. F. Pozharskii, A. M.
Simonov, Khim. Geterotsikl. Soedin., 1988, 1070 [Chem.
Heterocycl. Compd. (Engl. Transl.), 1988, 24, 880].
4. T. A. Kuz´menko, V. V. Kuz´menko, A. F. Pozharskii, N. A.
Klyuev, Khim. Geterotsikl. Soedin., 1988, 1226 [Chem. Heteroꢀ
cycl. Compd. (Engl. Transl.), 1988, 24, 1012].
5. B. Agai, G. Doleschall, G. Hornyak, K. Lempert, G. Simig,
Tetrahedron, 1976, 32, 839.
6. A. A. Granovsky, www http://classic.chem.msu.su/gran/fireꢀ
fly/index.html.
7. M. W. Schmidt, K. K. Baldridge, J. A. Boatz, S. T. Elbert,
M. S. Gordon, J. H. Jensen, S. Koseki, N. Matsunaga, K. A.
Nguyen, S. Su, T. L. Windus, M. Dupuis, J. A. Montgoꢀ
mery, J. Comput. Chem., 1993, 14, 1347.
Nꢀ(1ꢀAminoꢀ3ꢀmethylꢀ1,3ꢀdihydrobenzimidazolꢀ
2ꢀylidene)dithiocarbamoic acid (11). A solution of 1ꢀaminoꢀ2ꢀ
iminoꢀ3ꢀmethylbenzimidazoline (10) (0.32 g, 2 mmol) in DMF
(3 mL) was mixed with carbon disulfide (1.5 mL). After 3—5 min,
a lemonꢀyellow precipitate began to form, which was filtered off
after 0.5 h, washed with DMF (2 mL) and diethyl ether, dried in
a vacuum desiccator. The yield was 0.45 g (94%), m.p. 140—142 C
(with decomp.). The compound was not recrystallized because
of thermal instability. Found (%): C, 45.51; H, 4.33; N, 23.37; S,
26.75. C9H10N4S2. Calculated (%): C, 45.38; H, 4.20; N, 23.52;
S, 26.90. IR, /cm–1: 3208, 3119, 2360, 1671, 1538. MS, m/z
(Irel (%)): 162 [M10]
+ (100), 147 (65.0), 119 (51.6), 92 (28.3), 76
(93.3) [M+ CS2+], 65 (23.3), 51 (25.8), 44 (54.2).
2ꢀ(3,3ꢀDimethylthioureido)ꢀ1ꢀmethylbenzimidazole (12).
A solution of 1ꢀaminoꢀ3ꢀmethylbenzimidazolinꢀ2ꢀimine (10)
(0.49 g, 3 mmol) and carbon disulfide (2 mL) in DMF (4 mL)
was refluxed for 20 min until the yellow precipitate of the salt 11
was completely dissolved, then the mixture was refluxed for anꢀ
other 3 h, the latter was accompanied by the formation of
a colorless precipitate, which after cooling was filtered off and
washed with diethyl ether. The yield was 0.34 g (48%), m.p.
Received September 7, 2011;
in revised form January 24, 2012