Reaction of thiosemicarbazide with N-cyanoguanidine: Synthesis of 3,5-diamino-1-thiocarbamoyl- and 3,5-diamino-1-thiazol-2-yl-1,2,4-triazoles

Article abstract of DOI:10.1007/s11172-006-0257-4

The reaction of thiosemicarbazide with N-cyanoguanidine in an acidic medium afforded 3,5-diamino-1-thiocarbamoyl-1,2,4-triazole, whose condensation with α-halo ketones gave 3,5-diamino-1-thiazol-2-yl-1,2,4-triazoles 7a-d. The latter were also prepared by

Full text of DOI:10.1007/s11172-006-0257-4

Russian Chemical Bulletin, International Edition, Vol. 55, No. 2, pp. 338—344, February, 2006
338
Reaction of thiosemicarbazide with Nꢀcyanoguanidine:
synthesis of 3,5ꢀdiaminoꢀ1ꢀthiocarbamoylꢀ and
3,5ꢀdiaminoꢀ1ꢀthiazolꢀ2ꢀylꢀ1,2,4ꢀtriazoles
V. M. Chernyshev,aꢀ A. E. Kosov,a E. S. Gladkov,b S. V. Shishkina,b
V. A. Taranushich,a S. M. Desenko,b and O. V. Shishkinb
aSouthꢀRussian State Technical University,
132 ul. Prosveshcheniya, 346428 Novocherkassk, Russian Federation.
Fax: +7 (863 52) 27 619. Eꢀmail: tnw@novoch.ru
bState Scientific Institution "Institute for Single Crystals," National Academy of Sciences of Ukraine,
60 prosp. Lenina, 61001 Kharkov, Ukraine.
Eꢀmail: gladkov@isc.kharkov.com
The reaction of thiosemicarbazide with Nꢀcyanoguanidine in an acidic medium afforded
3,5ꢀdiaminoꢀ1ꢀthiocarbamoylꢀ1,2,4ꢀtriazole, whose condensation with αꢀhalo ketones gave
3,5ꢀdiaminoꢀ1ꢀthiazolꢀ2ꢀylꢀ1,2,4ꢀtriazoles 7a—d. The latter were also prepared by the indeꢀ
pendent synthesis from 2ꢀhydrazinothiazoles and Nꢀcyanoguanidine. Acylation of compounds
7a,d under mild conditions and their condensation with aldehydes occur at the C(3´)NH2
group. The structure of aroyl derivative 11c was established by Xꢀray diffraction. Acylation of
diaminothiazolyltriazole 7a in boiling Ac2O afforded 3,5ꢀdiacetylaminoꢀ1ꢀ(4ꢀphenylthiazolꢀ
2ꢀyl)ꢀ1,2,4ꢀtriazole. Hydrogenation of arylidene derivatives 14b,c and aroyl derivative 11c gave
the corresponding benzylaminotriazoles 15a,b.
Key words: thiosemicarbazide, Nꢀcyanoguanidine, 3,5ꢀdiaminoꢀ1ꢀthiocarbamoylꢀ1,2,4ꢀ
triazole, 3,5ꢀdiaminoꢀ1ꢀthiazolꢀ2ꢀylꢀ1,2,4ꢀtriazoles, αꢀhalo ketones, acylation, hydrogenaꢀ
tion, Xꢀray diffraction study.
Thiosemicarbazide derivatives are typical polyfuncꢀ
proton singlets at δ 5.41 and 8.13 are indicative of
the presence of two amino groups in the molecule. Two
oneꢀproton singlets (δ 8.07 and 9.02) may be assigned to
both the imino groups of the tautomer of triazine strucꢀ
ture 3a and the thiocarbamoyl group in structure 5a. The
13C NMR spectrum of the reaction product shows signals
for carbon atoms whose chemical shifts are close to the
corresponding values in alkylꢀsubstituted 3,5ꢀdiaminoꢀ1ꢀ
thiocarbamoylꢀ1,2,4ꢀtriazoles.5 Refluxing of the reaction
product with phenacyl bromide (6a) in methanol gave a
compound whose melting point and elemental composiꢀ
tion are identical to those of the product, which has been
characterized earlier3 as structure 4a. However, the
1H NMR spectrum of this compound shows two twoꢀ
proton singlets of amino groups (which disappear after
deuteration) and it better corresponds to the structure of
3,5ꢀdiaminoꢀ1ꢀ(4ꢀphenylthiazolꢀ2ꢀyl)ꢀ1,2,4ꢀtriazole (7a)
(see Scheme 1). The protonꢀcoupled 13C NMR spectrum
has two singlets (δ 153.8 and 162.5). Based on the pubꢀ
lished data,6 these signals were assigned respectively to
the C(3´) and C(5´) atoms of the triazole ring (spinꢀspin
coupling between the C atoms and the protons of the
amino groups is not observed due to fast exchange of
these protons with solvent molecules7). The multiplicities
tional reagents, which can react with 1,3ꢀbielectrophiles
to form various heterocyclic compounds.1,2 Earlier,3 it
has been reported that the reaction of thiosemicarbazide
(1) with Nꢀcyanoguanidines 2a—d afforded 1ꢀaminoꢀ4,6ꢀ
diiminohexahydroꢀ1,3,5ꢀtriazineꢀ2ꢀthiones 3a—d, whose
condensation with phenacyl bromide gave [1,3,5]triꢀ
azino[2,1ꢀb][1,3,4]thiadiazines 4a—d (Scheme 1). Howꢀ
ever, it is known4 that the oxo analog of compound 1,
viz., semicarbazide, reacts with compound 2a at the hydrꢀ
azine fragment of the molecule to form 3,5ꢀdiaminoꢀ1ꢀ
carbamoylꢀ1,2,4ꢀtriazole. Hence, in our opinion, it
cannot be ruled out that the reaction of compound 1
with 2 proceeds analogously.
In the present study, we refined the structure of the
reaction product of thiosemicarbazide (1) with Nꢀcyanoꢀ
guanidine (2a) and the structures of the products of its
successive reactions with αꢀhalo ketones.
Heating of compounds 1 and 2a in concentrated hyꢀ
drochloric acid afforded a compound (in 40% yield),
whose melting point, elemental analysis data, and mass
spectrum are identical to those described earlier3 for strucꢀ
1
ture 3a. However, the H NMR spectrum of this comꢀ
pound is inconsistent with diimino structure 3a. Two twoꢀ
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 2, pp. 329—334, February, 2006.
1066ꢀ5285/06/5502ꢀ0338 © 2006 Springer Science+Business Media, Inc.

3,5ꢀDiaminoꢀ1ꢀthiocarbamoylꢀ1,2,4ꢀthriazole
Russ.Chem.Bull., Int.Ed., Vol. 55, No. 2, February, 2006
339
Scheme 1
2—5, 9: R = H (a), Ph (b), 4ꢀMeC6H4 (c), 4ꢀClC6H4 (d); 6: Hal = Br (a—c), Cl (d)
6, 7: R1 = Ph, R2 = H (a); R1 = 4ꢀClC6H4, R2 = H (b); R1 = Me, R2 = H (c); R1 = Me, R2 = CO2Et (d)
8: R1 = Ph, R2 = H (a); R1 = Me, R2 = CO2Et (b)
of the other signals correspond to structure 7a. The strucꢀ
ture of compound 7a was unambiguously proved by its
independent synthesis from 2ꢀhydrazinoꢀ4ꢀphenylꢀ1,3ꢀ
thiazole hydrochloride (8a) and nitrile 2a according to
the procedure developed for the synthesis of 1ꢀarylꢀ3,5ꢀ
diaminoꢀ1,2,4ꢀtriazoles.8 Compounds 7b—d were syntheꢀ
sized analogously (see Scheme 1).
Therefore, the reaction of thiosemicarbazide (1)
with compound 2a, like those of hydrazine and its deꢀ
rivatives,9,10 involves the nucleophilic addition of the
hydrazine fragment at the nitrile group followed by cyꢀ
clization to give 3,5ꢀdiaminoꢀ1ꢀthiocarbamoylꢀ1,2,4ꢀ
triazole (5a).
Analysis of the experimental data3 demonstrated
that the reactions of compound 1 with substituted
cyanoguanidines 2b—d also more likely give 3,5ꢀdiaminoꢀ
1ꢀthiocarbamoylꢀ1,2,4ꢀtriazoles 5b—d rather than triꢀ
azines 3b—d. This conclusion is consistent with the reꢀ
sults of analysis of fragment ions in the mass spectrum of
compound 5b and the fact that acid hydrolysis of comꢀ
pounds 5b—d affords triazoles 9b—d (see Ref. 3 and
Scheme 1).
of thiazolyltriazoles 7a,d with compounds 10a—e in acetoꢀ
nitrile in the presence of pyridine produced derivatives
11a—f (Scheme 2).
The positions of the acyl and sulfonyl groups in strucꢀ
tures 11a—f were established by analyzing their 1H NMR
spectra. It is known6,10—12 that the signals for the protons
of the amino groups in 3,5ꢀdiaminoꢀ1ꢀRꢀ1,2,4ꢀtriazoles
appear as two wellꢀresolved singlets, the signal of the
amino group at position 5 of the ring being shifted
downfield by 1—2 ppm in the spectra of all compounds.
The spectra of the starting diamines 7a—d show signals of
the C(3´)NH2 and C(5´)NH2 groups at δ 5.5—5.7 and
7.3—7.4, respectively. In the spectra of compounds 11a—f,
the singlet for the protons of the C(3´)NH2 group disapꢀ
pears, and a broadened singlet for the amide proton apꢀ
pears at δ 10.4—11.1, the signal of the C(5´)NH2 group
being retained and shifted downfield by 0.2—0.4 ppm.
Consequently, acylation occurs at the C(3´)NH2 group.
The position of the acyl group in compounds 11 was
unambiguously established by Xꢀray diffraction study of
compound 11c (Fig. 1, Tables 1 and 2).
In the crystals, compound 11c exists as a crystal solꢀ
vate with DMF of composition 2 : 3. One DMF molecule
occupies a special position on a center of symmetry, which
coincides with the position of the nitrogen atom.
Compounds 7a—d contain several nucleophilic cenꢀ
ters in the molecule and are of interest for studying the
reactions with electrophiles. Acylation and sulfonylation

340
Russ.Chem.Bull., Int.Ed., Vol. 55, No. 2, February, 2006
Chernyshev et al.
Scheme 2
R1 = Ph (11a—d, 14a,b, 15a), Me (11e,f, 14c, 15b); R2 = H (11a—d, 14a,b, 15a), CO2Et (11e,f, 14c, 15b)
3 = Ac (10a, 11a), 4ꢀMeC6H4CO (10b, 11b), 2ꢀClC6H4CO (10c, 11c), Ts (10d, 11d,f), PhCO (10e, 11e)
X = OAc (10a), Cl (10b—e); Ar = 4ꢀMeOC6H4 (13a, 14a), 2ꢀClC6H4 (13b, 14b, 15a), 4ꢀClC6H4 (13c, 14c, 15b)
R
Table 1. Selected bond lengths (d) in the structure of 11c
C(15)
N(5)
N(3)
Bond
d/Å
Bond
d/Å
C(14)
C(13)
C(16)
C(17)
Cl(1)—C(6)
S(1)—C(10)
N(1)—C(7)
N(2)—C(8)
N(3)—C(9)
N(4)—C(9)
N(5)—C(9)
N(6)—C(11)
C(1)—C(2)
C(2)—C(3)
C(4)—C(5)
1.744(2)
1.730(1)
1.360(2)
1.320(2)
1.335(2)
1.368(2)
1.337(2)
1.393(2)
1.402(2)
1.387(2)
1.385(2)
S(1)—C(12)
O(1)—C(7)
N(1)—C(8)
N(2)—N(4)
N(3)—C(8)
N(4)—C(10)
N(6)—C(10)
C(1)—C(6)
C(1)—C(7)
C(3)—C(4)
C(5)—C(6)
1.729(1)
1.219(2)
1.395(2)
1.397(2)
1.366(2)
1.390(2)
1.299(2)
1.396(2)
1.509(2)
1.385(2)
1.386(2)
O(1)
C(9)
N(6)
Cl(1)
C(6)
N(4)
C(8)
C(18)
C(7)
C(11)
C(12)
C(10)
N(2)
N(1)
C(1)
C(2)
C(5)
S(1)
C(4)
C(3)
C(11)—C(12) 1.360(2)
C(13)—C(14) 1.399(2)
C(14)—C(15) 1.389(2)
C(16)—C(17) 1.386(2)
C(11)—C(13) 1.480(2)
C(13)—C(18) 1.399(2)
C(15)—C(16) 1.392(2)
C(17)—C(18) 1.392(2)
Fig. 1. Structure of compound 11c (DMF solvate molecules are
omitted).
The trigonalꢀpyramidal amino group (the sum of the
bond angles at the nitrogen atom is 355.3°) and the thiꢀ
azole ring are linked to each other by the intramolecular
N(5)—H(5Na)...N(6) hydrogen bond (2.26 Å), and the
N—H...N angle is 128°, which is, apparently, responsible
for noncoplanarity of the triazole and thiazole rings (the
C(9)—N(4)—C(10)—N(6) torsion angle is 11.1(2)°). The
hydrogen bonding also influences the degree of pyraꢀ
midalization of the amino group. The bond lengths in the
triazole ring are consistent with the corresponding values
in substituted triazoles studied earlier.13—15 The carbonyl
group of the substituent at the C(8) atom is in the
ap position with respect to the C(8)—N(2) bond of
the triazole ring (the C(7)—N(1)—C(8)—N(2) torsion
angle is 167.1(1)°) and is almost coplanar with the
N(1)—C(8) bond (the C(8)—N(1)—C(7)—O(1) torsion
angle is 5.1(2)°). The oꢀchlorophenyl ring is in the
ap conformation relative to the N(1)—C(8) bond (the
C(8)—N(1)—C(7)—C(1) torsion angle is –172.0(1)°).
Repulsion between the chlorine atom and the carbonyl
group leads to rotation of the substituent about the
C(7)—N(1) bond (the C(2)—C(1)—C(7)—N(1) torsion
angle is 57.1(2)°), resulting in the formation of the
shortened intramolecular H(1N)...C(2) contact (2.78 Å;
the sum of the van der Waals radii is 2.87 Å).16 The
phenyl substituent at the C(11) atom is virtually coꢀ
planar with the plane of the thiazole ring (the
C(12)—C(11)—C(13)—C(18) torsion angle is –5.1(2)°)
in spite of the shortened intramolecular H(14)...N(6) and
H(18)...C(12) contacts (2.54 and 2.74 Å, respectively;

3,5ꢀDiaminoꢀ1ꢀthiocarbamoylꢀ1,2,4ꢀthriazole
Russ.Chem.Bull., Int.Ed., Vol. 55, No. 2, February, 2006
341
Table 2. Selected bond angles (ω) in the structure of 11c
tives according to this procedure. The structures of comꢀ
pounds 14a—c were confirmed by spectroscopic data, elꢀ
emental analysis, and the synthesis of benzyl derivatives
15a,b based on these compounds. In the 1H NMR spectra
of compounds 14a—c, the signal for the protons of the
C(3´)NH2 group is absent, whereas the singlet of the
C(5´)NH2 group persists (δ 7.6—7.8). The spectra of benꢀ
zyl derivatives 15a,b show signals of the A2X system of the
protons of the C(3´)NHCH2 fragment. In the protonꢀ
coupled 13C NMR spectra of compounds 14b and 15a,b,
the signal for the C(5´) atom is observed as a singlet
at δ 154.0—154.5. The signal for the C(3´) atom
(δ 161.5—163.7) is split due to spinꢀspin coupling with
the methine and methylene protons of the benzylidene
and benzyl groups, respectively, to form a doublet (J =
11.1 Hz (14b)) and a triplet (J = 3.1 Hz (15a), J =
2.8 Hz (15b)). The pathway of condensation of diamines
7 with aldehydes was additionally confirmed by the inꢀ
dependent synthesis of compound 15a by reduction of
aroyl derivative 11c with lithium aluminum hydride (see
Scheme 2).
Angle
ω/deg
Angle
ω/deg
C(12)—S(1)—C(10) 87.77(7) C(7)—N(1)—C(8)
C(8)—N(2)—N(4) 100.7(1) C(9)—N(3)—C(8)
126.2(1)
102.7(1)
C(9)—N(4)—C(10) 129.1(1) C(9)—N(4)—N(2) 110.0(1)
C(10)—N(4)—N(2) 120.9(1) C(10)—N(6)—C(11) 109.7(1)
C(6)—C(1)—C(2)
C(2)—C(1)—C(7)
C(4)—C(3)—C(2)
C(4)—C(5)—C(6)
C(5)—C(6)—Cl(1)
O(1)—C(7)—N(1)
N(1)—C(7)—C(1)
N(2)—C(8)—N(1)
N(3)—C(9)—N(5)
N(5)—C(9)—N(4)
117.9(1) C(6)—C(1)—C(7)
119.6(1) C(3)—C(2)—C(1)
119.8(2) C(3)—C(4)—C(5)
119.1(1) C(5)—C(6)—C(1)
118.2(1) C(1)—C(6)—Cl(1) 120.1(1)
125.0(1) O(1)—C(7)—C(1) 121.4(1)
113.6(1) N(2)—C(8)—N(3) 117.1(1)
118.4(1) N(3)—C(8)—N(1) 124.6(1)
126.4(1) N(3)—C(9)—N(4) 109.5(1)
124.1(1) N(6)—C(10)—N(4) 122.2(1)
122.4(1)
120.8(1)
120.7(1)
121.7(1)
N(6)—C(10)—S(1) 116.7(1) N(4)—C(10)—S(1) 121.0(1)
C(12)—C(11)—N(6) 114.6(1) C(12)—C(11)—C(13) 127.0(1)
N(6)—C(11)—C(13) 118.4(1) C(11)—C(12)—S(1) 111.2(1)
C(14)—C(13)—C(18) 118.8(1) C(14)—C(13)—C(11) 120.5(1)
C(18)—C(13)—C(11) 120.7(1) C(15)—C(14)—C(13) 120.4(1)
C(14)—C(15)—C(16) 120.5(1) C(17)—C(16)—C(15) 119.4(1)
C(16)—C(17)—C(18) 120.6(1) C(17)—C(18)—C(13) 120.3(1)
The aboveꢀdescribed transformations show that comꢀ
pounds 7, as a whole, behave in the reactions with
electrophiles analogously to 3,5ꢀdiaminoꢀ1ꢀarylꢀ1,2,4ꢀ
triazoles, in which the amino group at position 5 of the
triazole ring has a low nucleophilicity.12,17
the corresponding sums of the van der Waals radii are 2.67
and 2.87 Å).
The amino group at position 5´ is less nucleophilic
and is not subjected to acylation under conditions of the
synthesis of compounds 11 due, apparently, to the elecꢀ
tronꢀwithdrawing effect of two "pyridine" nitrogen atoms
of the triazole ring, which are linearly conjugated with
this amino group (Scheme 3). The C(3´)NH2 group is
conjugated with only one "pyridine" nitrogen atom and is,
consequently, more nucleophilic.
Experimental
The 1H and 13C NMR spectra were measured on Varian
Unityꢀ300 (300 MHz for 1H and 75 MHz for 13C) and Varian
Mercury VXꢀ200 (200 MHz for 1H) spectrometers in DMSOꢀd6
with Me4Si as the internal standard. The IR spectra were reꢀ
corded on a Specord IRꢀ75 instrument in Nujol mulls. The mass
spectra were obtained on a Varian 1200L spectrometer (direct
inlet, EI, 70 eV). The melting points are uncorrected. Comꢀ
pounds 8a 18 and 8b 19 were synthesized according to procedures
described earlier.
Scheme 3
3,5ꢀDiaminoꢀ1ꢀthiocarbamoylꢀ1,2,4ꢀtriazole (5a) was preꢀ
pared by the reaction of compounds 1 and 2a in concentrated
hydrochloric acid according to a known procedure.3 The yield
was 40%, m.p. 163—165 °C (cf. lit. data3: m.p. 170 °C).
Found (%): C, 22.81; H, 3.81; N, 53.16; S, 20.20. C3H6N6S.
Calculated (%): C, 22.78; H, 3.82; N, 53.13; S, 20.27. IR,
ν/cm–1: 3400 (NH), 3260 (NH), 1290 (C=S). 1H NMR, δ: 5.41
(br.s, 2 H, C(3)NH2); 8.07 (br.s, 1 H, CSNH2); 8.13 (br.s, 2 H,
C(5)NH2); 9.02 (br.s, 1 H, CSNH2). 13C NMR, δ: 157.1 (C(5)),
159.7 (C(3)), 174.0 (C=S). MS, m/z (Irel (%)): 158 [M]+ (100),
124 (14).
Synthesis of 3,5ꢀdiaminoꢀ1ꢀthiazolꢀ2ꢀylꢀ1,2,4ꢀtriazoles 7a—d
(general procedure). A. A mixture of compound 5a (0.91 g,
5.75 mmol) and halo ketone 6a—d (5.75 mmol) in methanol
(20 mL) was refluxed for 2 h. Then the reaction mixture was
cooled and neutralized with a saturated NaOAc solution. The
precipitate that formed was filtered off, washed with water, and
crystallized.
In spite of low nucleophilicity of the C(5´)NH2 group,
we succeeded in synthesizing diacetyl derivative 12 by
refluxing diamine 7a in acetic anhydride.
Heating of compounds 7a,d with substituted benzꢀ
aldehydes 13a—c in DMF led to condensation at the
C(3´)NH2 group giving rise to arylidene derivatives 14a—c
(see Scheme 2). We failed to prepare diarylidene derivaꢀ
B. A mixture of compound 2a (2.4 g, 2.85 mmol) and
2ꢀhydrazinothiazole hydrochloride 8a,b (2.85 mmol) in H2O

342
Russ.Chem.Bull., Int.Ed., Vol. 55, No. 2, February, 2006
Chernyshev et al.
(100 mL) was refluxed for 1 h. The product was isolated as
described in the method A.
H, 4.28; N, 22.32; S, 8.52. IR, ν/cm–1: 3410 (NH), 3310 (NH),
1670 (C=O). 1H NMR, δ: 2.41 (s, 3 H, Me); 7.20—7.42 (m,
5 H, H arom.); 7.62 (s, 1 H, H(5)); 7.85 (br.s, 2 H, NH2);
7.87—7.93 (m, 4 H, H arom.); 10.59 (br.s, 1 H, NH). MS,
m/z (Irel (%)): 376 [M]+ (22), 348 (17), 119 (100).
5ꢀAminoꢀ3ꢀ(oꢀchlorobenzoylamino)ꢀ1ꢀ(4ꢀphenylthiazolꢀ2ꢀyl)ꢀ
1,2,4ꢀtriazole (11c). The yield was 65%, m.p. 271—272 °C (from
a DMF—EtOH mixture). Found (%): C, 54.33; H, 3.36;
N, 22.11; S, 8.01. C18H13ClN6OS. Calculated (%): C, 54.48;
H, 3.30; N, 21.18; S, 8.08. 1H NMR, δ: 7.35—7.50 (m, 7 H,
H arom.); 7.70 (br.s, 2 H, NH2); 7.85 (s, 1 H, H(5)); 8.00—8.07
(m, 2 H, H arom.); 11.07 (br.s, 1 H, NH). 13C NMR, δ: 109.6
(C(5)), 126.0, 127.0, 128.3, 128.7, 128.9, 129.5, 129.9, 131.1,
133.3, 136.1, 151.2 (C(4)), 153.6 (C(5´)), 155.0 (C(3´)), 158.9
(C(2)), 164.2 (C=O). MS, m/z (Irel (%)): 398 (16), 396 (50),
368 (37), 361 (100), 216 (39), 187 (69).
3,5ꢀDiaminoꢀ1ꢀ(4ꢀphenylthiazolꢀ2ꢀyl)ꢀ1,2,4ꢀtriazole (7a).
The yield was 80% (method A) and 41% (method B), m.p.
224—225 °C (from EtOH) (cf. lit. data3: m.p. 225 °C).
Found (%): C, 51.21; H, 3.86; N, 32.39; S, 12.38. C11H10N6S.
Calculated (%): C, 51.15; H, 3.90; N, 32.54; S, 12.41. IR,
ν/cm–1: 3420 (NH). 1H NMR, δ: 5.73 (br.s, 2 H, C(3´)NH2);
7.31—7.47 (m, 3 H, H arom.); 7.41 (br.s, 2 H, C(5´)NH2); 7.70
(s, 1 H, H(5)); 7.93—7.97 (m, 2 H, H arom.). 13C NMR, δ:
107.9 (C(5)), 125.9 (mꢀC arom.), 128.1 (pꢀC arom.), 128.7
(oꢀC arom.), 133.5 (iꢀC arom.), 151.0 (C(4)), 153.8 (C(5´)),
159.1 (C(2)), 162.5 (C(3´)). MS, m/z (Irel (%)): 258 [M]+ (61),
174 (45), 102 (88).
3,5ꢀDiaminoꢀ1ꢀ(4ꢀpꢀchlorophenylthiazolꢀ2ꢀyl)ꢀ1,2,4ꢀtriazole
(7b). The yield was 78% (method A), m.p. 265—266 °C (from an
AcOH—EtOH mixture). Found (%): C, 45.17; H, 3.21; N, 28.89;
S, 11.00. C11H9ClN6S. Calculated (%): C, 45.13; H, 3.10;
N, 28.71; S, 10.95. IR, ν/cm–1: 3470 (NH). 1H NMR, δ: 5.72
(br.s, 2 H, C(3´)NH2); 7.39 (br.s, 2 H, C(5´)NH2); 7.47 (m,
2 H, H arom.); 7.76 (s, 1 H, H(5)); 8.01 (m, 2 H, H arom.). MS,
m/z (Irel (%)): 292 [M]+ (100), 258 (19), 208 (22), 173 (37),
136 (43).
5ꢀAminoꢀ1ꢀ(4ꢀphenylthiazolꢀ2ꢀyl)ꢀ3ꢀ(pꢀtoluenesulfonyl)amiꢀ
noꢀ1,2,4ꢀtriazole (11d). The yield was 80%, m.p. 300 °C
(decomp.) (from a DMF—MeCN mixture). Found (%):
C, 52.69; H, 4.00; N, 20.50; S, 15.72. C18H16N6O2S2. Calcuꢀ
lated (%): C, 52.41; H, 3.91; N, 20.37; S, 15.55. IR, ν/cm–1
:
1
3450 (NH), 3340 (NH), 1160 (SO2). H NMR, δ: 2.41 (s, 3 H,
Me); 7.26—7.40 (m, 5 H, H arom.); 7.59 (s, 1 H, H(5)); 7.62
(br.s, 2 H, NH2); 7.85—7.89 (m, 4 H, H arom.); 11.03 (br.s,
1 H, NH). MS, m/z (Irel (%)): 412 [M]+ (14), 216 (66), 215
(87), 162 (39), 160 (90).
3,5ꢀDiaminoꢀ1ꢀ(4ꢀmethylthiazolꢀ2ꢀyl)ꢀ1,2,4ꢀtriazole (7c).
The yield was 50% (method A), m.p. 251—252 °C (from EtOH).
Found (%): C, 36.88; H, 4.20; N, 42.51; S, 16.31. C6H8N6S.
Calculated (%): C, 36.72; H, 4.11; N, 42.83; S, 16.34.
IR, ν/cm–1: 3460 (NH). 1H NMR, δ: 2.27 (s, 3 H, Me); 5.62
(br.s, 2 H, C(3´)NH2); 6.82 (s, 1 H, H(5)); 7.30 (br.s, 2 H,
C(5´)NH2). MS, m/z (Irel (%)): 196 [M]+ (100), 154 (20),
112 (59).
5ꢀAminoꢀ3ꢀbenzoylaminoꢀ1ꢀ(5ꢀethoxycarbonylꢀ4ꢀmethylꢀ
thiazolꢀ2ꢀyl)ꢀ1,2,4ꢀtriazole (11e). The yield was 60%, m.p.
258—260 °C (from an AcOH—MeCN mixture). Found (%):
C, 51.68; H, 4.25; N, 22.49; S, 8.47. C16H16N6O3S. Calcuꢀ
lated (%): C, 51.60; H, 4.33; N, 22.57; S, 8.61. IR, ν/cm–1
:
3,5ꢀDiaminoꢀ1ꢀ(5ꢀethoxycarbonylꢀ4ꢀmethylthiazolꢀ2ꢀyl)ꢀ
1,2,4ꢀtriazole (7d). The yield was 8% (method A) and 60%
(method B), m.p. 222—224 °C (from an AcOH—MeCN mixꢀ
ture). Found (%): C, 40.07; H, 4.62; N, 31.50; S, 12.10.
C9H12N6O2S. Calculated (%): C, 40.29; H, 4.51; N, 31.32;
S, 11.95. IR, ν/cm–1: 3390 (NH), 1710 (C=O). 1H NMR, δ:
1.25 (t, 3 H, OCH2CH3, J = 7.2 Hz); 2.55 (s, 3 H, Me); 4.21 (q,
2 H, OCH2CH3); 5.88 (br.s, 2 H, C(3´)NH2); 7.50 (br.s, 2 H,
C(5´)NH2). MS, m/z (Irel (%)): 268 [M]+ (30), 112 (35).
3ꢀAcylaminoꢀ5ꢀaminoꢀ1ꢀthiazolꢀ2ꢀylꢀ1,2,4ꢀtriazoles
11a—c,e and 5ꢀaminoꢀ3ꢀtosylaminoꢀ1ꢀthiazolꢀ2ꢀylꢀ1,2,4ꢀtriꢀ
azoles 11d,f (general procedure). A solution of acylating agent
10a—e (2.6 mmol) in MeCN (1 mL) was added to a mixture of
compound 7a or 7d (2 mmol), MeCN (1 mL), and pyridine
(1 mL). The reaction mixture was refluxed for 10 min. The
precipitate that formed after cooling was filtered off and crysꢀ
tallized.
3ꢀAcetylaminoꢀ5ꢀaminoꢀ1ꢀ(4ꢀphenylthiazolꢀ2ꢀyl)ꢀ1,2,4ꢀtriꢀ
azole (11a). The yield was 65%, m.p. 294 °C (from a
DMF—EtOH mixture). Found (%): C, 60.10; H, 4.11; N, 28.12;
S, 10.57. C13H12N6OS. Calculated (%): C, 51.99; H, 4.03;
N, 27.98; S, 10.68. IR, ν/cm–1: 3440 (NH), 3300 (NH), 1670
(C=O). 1H NMR, δ: 2.06 (s, 3 H, Me); 7.34—7.48 (m, 3 H,
H arom.); 7.67 (br.s, 2 H, NH2); 7.84 (s, 1 H, H(5)); 8.01 (m,
2 H, H arom.); 10.42 (br.s, 1 H, NH). MS, m/z (Irel (%)): 300
[M]+ (32), 258 (100), 216 (22), 174 (25), 134 (36).
3410 (NH), 3370 (NH), 1710 (C=O), 1670 (C=O). 1H NMR, δ:
1.34 (t, 3 H, OCH2CH3, J = 7.2 Hz); 2.65 (s, 3 H, Me); 4.30 (q,
2 H, OCH2CH3); 7.40—7.58 (m, 3 H, H arom.); 7.72 (br.s, 2 H,
NH2); 7.87—8.01 (m, 2 H, H arom.); 10.78 (br.s, 1 H, NH).
MS, m/z (Irel (%)): 372 [M]+ (82), 344 (73), 292 (24), 226 (28).
5ꢀAminoꢀ1ꢀ(5ꢀethoxycarbonylꢀ4ꢀmethylthiazolꢀ2ꢀyl)ꢀ3ꢀ
(pꢀtoluenesulfonyl)aminoꢀ1,2,4ꢀtriazole (11f). The yield was 60%,
m.p. 288—290 °C (from a DMF—EtOH mixture). Found (%):
C, 45.60; H, 4.34; N, 20.02; S, 15.31. C16H18N6O4S2. Calcuꢀ
lated (%): C, 45.49; H, 4.29; N, 19.89; S, 15.18. IR, ν/cm–1
:
1
3380 (NH), 3250 (NH), 1690 (C=O), 1160 (SO2). H NMR, δ:
1.36 (t, 3 H, OCH2CH3, J = 7.2 Hz); 2.40 (s, 3 H, Me); 2.60 (s,
3 H, C(4)Me); 4.30 (q, 2 H, OCH2CH3); 7.31 (m, 2 H, H arom.);
7.65 (br.s, 2 H, NH2); 7.84 (m, 2 H, H arom.); 11.15 (br.s, 1 H,
NH). MS, m/z (Irel (%)): 422 [M]+ (22), 284 (22), 226 (59), 225
(83), 200 (87).
3,5ꢀDiacetylaminoꢀ1ꢀ(4ꢀphenylthiazolꢀ2ꢀyl)ꢀ1,2,4ꢀtriazole
(12). A mixture of compound 7a (1 g, 3.9 mmol) and Ac2O
(3 mL) was refluxed for 4 h. Then EtOH (3 mL) was added, the
solvent was distilled off, and the residue was treated with water
and recrystallized. The yield was 1.2 g (90%), m.p. 240—242 °C
(from a AcOH—MeCN mixture). Found (%): C, 52.49; H, 4.16;
N, 24.63; S, 9.40. C15H14N6O2S. Calculated (%): C, 52.62;
H, 4.12; N, 24.55; S, 9.36. 1H NMR, δ: 2.08 and 2.27 (both s,
3 H each, Me); 7.38—7.50 (m, 3 H, H arom.); 7.92 (m, 2 H,
H arom.); 8.00 (s, 1 H, H(5)); 10.84 and 10.91 (both br.s,
1 H each, NH). MS, m/z (Irel (%)): 342 [M]+ (7), 300 (20), 258
(83), 216 (68), 174 (34).
5ꢀAminoꢀ3ꢀ(pꢀmethylbenzoylamino)ꢀ1ꢀ(4ꢀphenylthiazolꢀ2ꢀ
yl)ꢀ1,2,4ꢀtriazole (11b). The yield was 70%, m.p. 299—300 °C
(from a DMF—EtOH mixture). Found (%): C, 60.49; H, 4.26;
N, 22.22; S, 8.61. C19H16N6OS. Calculated (%): C, 60.62;
5ꢀAminoꢀ3ꢀ(pꢀmethoxybenzylideneamino)ꢀ1ꢀ(4ꢀphenylthiꢀ
azolꢀ2ꢀyl)ꢀ1,2,4ꢀtriazole (14a). A mixture of compound 7a (0.5 g,

3,5ꢀDiaminoꢀ1ꢀthiocarbamoylꢀ1,2,4ꢀthriazole
Russ.Chem.Bull., Int.Ed., Vol. 55, No. 2, February, 2006
343
1.9 mmol), DMF (2 mL), and pꢀmethoxybenzaldehyde (0.31 g,
2.3 mmol) was refluxed for 5 min and then cooled. Ethanol
(5 mL) was added and the precipitate that formed was filtered
off. The yield was 0.5 g (70%), m.p. 261—262 °C (from a
DMF—EtOH mixture). Found (%): C, 60.68; H, 4.14; N, 22.53;
S, 8.64. C19H16N6OS. Calculated (%): C, 60.62; H, 4.28;
N, 22.32; S, 8.52. 1H NMR, δ: 3.88 (s, 3 H, OMe); 7.01 (m, 2 H,
H arom.); 7.28—7.43 (m, 4 H, H arom.); 7.61 (br.s, 2 H, NH2);
7.90—7.93 (m, 4 H, H arom., H(5)); 9.03 (s, 1 H, CH=N). MS,
m/z (Irel (%)): 376 [M]+ (48), 242 (19), 176 (19), 159 (34),
146 (39).
The yield was 0.1 g (10%). The properties of the reaction prodꢀ
uct were identical to those of the product prepared according to
the method A.
5ꢀAminoꢀ3ꢀ(pꢀchlorobenzylamino)ꢀ1ꢀ(5ꢀethoxycarbonylꢀ4ꢀ
methylthiazolꢀ2ꢀyl)ꢀ1,2,4ꢀtriazole (15b) was prepared by reducꢀ
tion of compound 14c (0.5 g, 1.3 mmol) as described above for
the synthesis of compound 15a according to method A. The
yield was 0.3 g (59%), m.p. 168—170 °C (from a DMF—EtOH
mixture). Found (%): C, 49.08; H, 4.29; N, 21.42; S, 8.20.
C
16H17ClN6O2S. Calculated (%): C, 48.92; H, 4.36; N, 21.39;
S, 8.16. 1H NMR, δ: 1.30 (t, 3 H, OCH2CH3, J = 7.2 Hz); 2.60
(s, 3 H, C(4)Me); 4.26 (q, 2 H, OCH2CH3); 4.28 (d, 2 H,
NHCH2, J = 5.8 Hz); 6.80 (t, 1 H, NH, J = 5.8 Hz); 7.22—7.36
(m, 4 H, H arom.); 7.48 (br.s, 2 H, C(5´)NH2). 13C NMR, δ:
14.1 (OCH2CH3), 17.2 (C(4)CH3), 44.9 (CH2NH), 60.8
(OCH2CH3), 114.5 (C(5)), 128.0, 129.0, 131.1, 139.27, 154.5
(C(5´)), 158.1 (C(4)), 159.8 (C(2)), 161.5 (C=O), 162.9 (C(3´)).
MS, m/z (Irel (%)): 392 [M]+ (17), 200 (23), 181 (74).
Compounds 14b,c were prepared analogously.
5ꢀAminoꢀ3ꢀ(oꢀchlorobenzylideneamino)ꢀ1ꢀ(4ꢀphenylthiazolꢀ
2ꢀyl)ꢀ1,2,4ꢀtriazole (14b). The yield was 69%, m.p. 272—273 °C
(from a DMF—EtOH mixture). Found (%): C, 56.51; H, 3.52;
N, 22.21; S, 8.40. C18H13ClN6S. Calculated (%): C, 56.77;
H, 3.44; N, 22.07; S, 8.42. 1H NMR, δ: 7.34—7.64 (m, 6 H,
H arom.); 7.85 (br.s, 2 H, NH2); 7.93 (s, 1 H, H(5)); 8.05 (m,
2 H, H arom.); 8.24 (m, 1 H, H arom.); 9.53 (s, 1 H, CH=N).
13C NMR, δ: 110.1 (C(5)), 126.0, 127.9, 128.4, 128.8, 130.3,
131.8, 133.2, 134.0, 135.9, 151.4 (C(4)), 154.4 (C(5´)), 158.9
(C(2)), 161.0 (CH=N), 163.8 (C(3´)). MS, m/z (Irel (%)):
380 [M]+ (95), 345 (100), 337 (17), 303 (15), 242 (35), 176
(38), 134 (63).
Xꢀray diffraction study. Single crystals of compound 11c
were grown by crystallization from a DMF—ethanol mixture.
Crystals of 11c are triclinic, C18H13ClN6OS•1.5C3H7NO, at
–173 °C a = 10.104(1) Å, b = 11.033(1) Å, c = 11.641(1) Å,
α = 72.04(1)°, β = 74.16(1)°, γ = 79.85(1)°, V = 1181.6(1) Å3,
–
Mr = 506.50, Z = 2, space group P1, dcalc = 1.424 g cm–3
,
5ꢀAminoꢀ3ꢀ(pꢀchlorobenzylideneamino)ꢀ1ꢀ(5ꢀethoxycarboꢀ
nylꢀ4ꢀmethylthiazolꢀ2ꢀyl)ꢀ1,2,4ꢀtriazole (14c). The yield was
60%, m.p. 253—254 °C (from a AcOH—EtOH mixture). Found
(%): C, 48.98; H, 3.96; N, 21.82; S, 8.32. C16H15ClN6O2S.
Calculated (%): C, 49.17; H, 3.87; N, 21.50; S, 8.20. 1H NMR,
δ: 1.28 (t, 3 H, OCH2CH3, J = 7.2 Hz); 2.63 (s, 3 H, Me); 4.28
(q, 2 H, OCH2CH3); 7.60 (m, 2 H, H arom.); 7.83 (br.s, 2 H,
NH2); 8.01 (m, 2 H, H arom.); 9.09 (s, 1 H, CH=N). MS,
m/z (Irel (%)): 392 [M]+ (53), 390 (81), 347 (18), 186 (13),
181 (24).
5ꢀAminoꢀ3ꢀ(oꢀchlorobenzylamino)ꢀ1ꢀ(4ꢀphenylthiazolꢀ2ꢀyl)ꢀ
1,2,4ꢀtriazole (15a). A. Sodium borohydride (0.1 g, 2.6 mmol)
was added portionwise with stirring to a suspension of comꢀ
pound 14b (0.5 g, 1.3 mmol) in EtOH (5 mL) at 50—70 °C. The
reaction mixture was refluxed for 10 min and then H2O (30 mL)
was added. The precipitate that formed was washed with water
and recrystallized. The yield was 0.3 g (42%), m.p. 221—223 °C
(from a DMF—EtOH mixture). Found (%): C, 56.52; H, 4.01;
N, 21.64; S, 8.41. C18H15ClN6S. Calculated (%): C, 56.47;
H, 3.95; N, 21.95; S, 8.37. 1H NMR, δ: 4.39 (d, 2 H, CH2, J =
6.2 Hz); 6.94 (t, 1 H, NH, J = 6.2 Hz); 7.23—7.46 (m, 7 H,
H arom.); 7.50 (br.s, 2 H, C(5´)NH2); 7.71 (s, 1 H, H(5)); 7.97
(m, 2 H, H arom.). 13C NMR, δ: 43.4 (CH2), 108.0 (C(5)),
125.8, 126.9, 128.1, 128.2, 128.6, 128.7, 128.9, 131.8, 133.5,
137.4, 151.0 (C(4)), 154.0 (C(5)), 159.1 (C(2)), 162.5 (C(3´)).
MS, m/z (Irel (%)): 382 [M]+ (31), 347 (29), 242 (55), 173 (50),
160 (29), 134 (40), 125 (100).
µ(MoꢀKα) = 0.290 mm–1, F(000) = 528. The unit cell paramꢀ
eters and intensities of 14994 reflections (4019 independent
reflection, Rint = 0.019) were measured on a Xcaliburꢀ3
diffractometer (MoꢀKα radiation, CCD detector, graphite
monochromator, ω scanning technique, 2θmax = 50°). The strucꢀ
ture was solved by direct methods using the SHELXTL program
package.20 The positions of the hydrogen atoms were located
from difference electron density maps and refined isotropically.
The structure was refined by the fullꢀmatrix leastꢀsquares method
against F 2 with anisotropic displacement parameters for all
nonhydrogen atoms to wR2 = 0.077 using 3971 reflections
(R1 = 0.030 for 3792 reflections with F > 4σ(F ), S = 1.051). The
atomic coordinates in the structure of 11c and complete tables
of the bond lengths and bond angles were deposited with the
Cambridge Structural Database. Selected bond lengths and bond
angles are given in Tables 1 and 2, respectively.
References
1. T. Klimova, E. I. Klimova, M. Martínez García, J. M.
Méndez Stivalet, and L. Luíz Ramírez, J. Organomet. Chem.,
2001, 633, 137.
2. V. Ya. Kauss, E. E. Liepin´sh, I. Ya. Kalvin´sh, and
E. Lukevits, Khim. Geterotsikl. Soedin., 1990, 120 [Chem.
Heterocycl. Compd., 1990 (Engl. Transl.)].
3. C. P. Joshua and V. P. Rajan, Aust. J. Chem., 1976, 29, 1051.
4. US Pat. 2456090; Chem. Abstr., 1949, 43, 3843.
5. J. Barkóczy and J. Reiter, J. Heterocycl. Chem., 1991,
28, 1597.
6. J. Reiter, L. Pongo, T. Somorai, and P. Dvortsák,
J. Heterocycl. Chem., 1986, 23, 401.
B. A mixture of compound 11c (1.0 g, 2.6 mmol) and LiAlH4
(0.3 g, 7.9 mmol) in THF (10 mL) was refluxed for 12 h. Then
LiAlH4 (0.3 g, 7.9 mmol) was added, the reaction mixture was
refluxed for 12 h, H2O (3 mL) was added, and the solvent was
distilled off. The residue was dissolved with heating in 10% HCl
(5 mL). The precipitate that formed upon cooling was filtered
off, washed with a small amount of water, and treated with a 5%
NaOH solution (10 mL) at high temperature. The precipitate
was filtered off and recrystallized from a DMF—EtOH mixture.
7. P. Dvortsák, J. Reiter, T. Somorai, and P. Sohár, Magn.
Reson. Chem., 1985, 23, 194.
8. E. A. Steck, R. P. Brundage, and L. T. Fletcher, J. Am.
Chem. Soc., 1958, 80, 3929.

344
Russ.Chem.Bull., Int.Ed., Vol. 55, No. 2, February, 2006
Chernyshev et al.
9. V. M. Chernyshev, N. D. Zemlyakov, and V. A. Taranushich,
Zh. Prikl. Khim, 1999, 72, 1685 [Russ. J. Appl. Chem., 1999,
72 (Engl. Transl.)].
10. M. T. Wu, J. Heterocycl. Chem., 1977, 14, 443.
11. A. R. Dunstan, H.ꢀP. Weber, G. Rihs, H. Widmer, and
E. K. Dziadulewicz, Tetrahedron Lett., 1998, 39, 7983.
12. J. J. Fuentes and J. A. Lenoir, Can. J. Chem., 1976,
54, 3620.W
13. G. Reck, M. Czugler, L. Parkanyi, and E. Sauer, Cryst.
Struct. Commun., 1981, 10, 565.
14. A. Kalman, L. Parkanyi, and J. Reiter, J. Mol. Struct., 1984,
118, 293.
16. Yu. V. Zefirov, Kristallografiya, 1997, 42, 936 [Crystallogr.
Repts, 1997, 42, 865 (Engl. Transl.)].
17. N. K. Beresneva, V. A. Lopyrev, and K. L. Krupin, Khim.
Geterotsikl. Soedin., 1969, 732 [Chem. Heterocycl. Compd.,
1969, 5 (Engl. Transl.)].
18. H. Beyer, H. Höhn, and W. Lässig, Chem. Ber., 1952,
85, 1122.
19. H. Beyer and J. Wolter, Chem. Ber., 1956, 89, 1652.
20. G. M. Sheldrick, SHELXTL PLUS. PC Version. A System of
Computer Programs for the Determination of Crystal Structure
from Xꢀray Diffraction Data. Rev. 5.1, 1998.
15. B. Ribar, S. Stankovic, G. Argay, A. Kalman, and F. Koczo,
Acta Crystallogr., Sect. C, 1987, 43, 1712.
Received September 1, 2005;
in revised form December 15, 2005