2-Amino-4,5,6,7-tetrahydro-1,2,4-triazolo[1,5-a]pyrimidines: Synthesis and reactions with electrophilic reagents

Article abstract of DOI:10.1134/S107042800805014X

The hydrogenation of 2-amino-5-R-7-R′-4,7-dihydro-1,2,4-triazolo[1,5- a]pyrimidines with NaBH₄ led to the formation of 2-amino-5-R-7- R′-4,5,6,7-tetrahydro-1,2,4-triazolo[1,5-a]pyrimidines. Acylation, sulfonylation, and alkylation of these compounds depending on conditions and the reagent character occur at the amino group, atoms N³ or N ⁴. The treatment with alkali of 2-amino-3-benzyl-5-R-7-R′-4,5, 6,7-tetrahydro-1,2,4-triazolo-[1,5-a]pyrimidinium bromide resulted in 2-amino-3-benzyl-5-R-7-R′-3,5,6,7-tetrahydro-1,2,4-triazolo[1,5-a] -pyrimidine, similar reaction of 2-acetamido-3-benzyl-5-R-7-R′-4,5,6,7- tetrahydro-1,2,4-triazolo[1,5-a]-pyrimidinium bromide gave a mesoionic product of a hydrogen elimination from the amide nitrogen atom.

Full text of DOI:10.1134/S107042800805014X

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2008, Vol. 44, No. 5, pp. 715−722. © Pleiades Publishing, Ltd., 2008.
Original Russian Text © V.M. Chernyshev, A.N. Sokolov, D.A. Khoroshkin, V.A. Taranushich, 2008, published in Zhurnal Organicheskoi Khimii,
2008, Vol. 44, No. 5, pp. 724−731.
2-Amino-4,5,6,7-tetrahydro-1,2,4-triazolo[1,5-a]pyrimidines:
Synthesis and Reactions with Electrophilic Reagents
V. M. Chernyshev, A. N. Sokolov, D. A. Khoroshkin, and V. A. Taranushich
South-Russian State Technical University, Novocherkassk, 346428 Russia
e-mail: tnw@novoch.ru
Received September 9, 2007
Abstract—The hydrogenation of 2-amino-5-R-7-R'-4,7-dihydro-1,2,4-triazolo[1,5-a]pyrimidines with NaBH4
led to the formation of 2-amino-5-R-7-R'-4,5,6,7-tetrahydro-1,2,4-triazolo[1,5-a]pyrimidines.Acylation, sulfonyla-
tion, and alkylation of these compounds depending on conditions and the reagent character occur at the amino
group, atoms N3 or N4. The treatment with alkali of 2-amino-3-benzyl-5-R-7-R'-4,5,6,7-tetrahydro-1,2,4-triazolo-
[1,5-a]pyrimidinium bromide resulted in 2-amino-3-benzyl-5-R-7-R'-3,5,6,7-tetrahydro-1,2,4-triazolo[1,5-a]-
pyrimidine, similar reaction of 2-acetamido-3-benzyl-5-R-7-R'-4,5,6,7-tetrahydro-1,2,4-triazolo[1,5-a]-
pyrimidinium bromide gave a mesoionic product of a hydrogen elimination from the amide nitrogen atom.
DOI: 10.1134/S107042800805014X
A considerable interest was recently turned to
triazolopyrimidines with partially hydrogenated pyrimi-
dine fragment [1−3]. These compounds exhibit versatile
biological activity [4, 5] and are used in the studies of
structure and reactivity of partially hydrogenated
heterocycles [2, 3]. Certain opportunities for modification
of physiological properties of triazolopyrimidines provide
the functional groups in the position 2 of the bicycle [2,
5, 6]. For instance, 2-amino-4,7-dihydro-1,2,4-triazolo-
[1,5-a]pyrimidines I are easily acylated at the amino
group forming amides possessing a pronounced analgesic
and hypoglycemic action [5, 6]. More hydrogenated
analogs of these compounds, 2-amino-4,5,6,7-tetrahydro-
1,2,4-triazolo[1,5-a]pyrimidines II, and their derivatives
were not documented up till now.
yielding the corresponding tetrahydro derivatives. The
reason of the different effect of ethoxycarbonyl and
arylcarboxamide groups on the stability of the dihydro-
pyrimidine ring against hydrogenation is unclear.
The composition and structure of compounds IIa−
IIe were confirmed by elemental analysis and spectral
data. 1H NMR spectra indicate the formation of a single
diastereomer (also for crude substances) and are unlike
the spectra of other 4,5,6,7-tetrahydro-1,2,4-triazolo-
[1,5-a]pyrimidines [7, 8] because of the presence of
a two-proton singlet of the amino group in the region
Scheme 1.
R1
R1
7
1N
6
N
N
NaBH4
EtOH
N
2
N
The target of the present study was the synthesis of
amines II and investigation of their acylation,
sulfonylation, and alkylation.
H2N
H2N
4
3a
5
R2
N
N
R2
N
3
H
H
Ia_Ie
IIa_IIe
2-Amino-4,5,6,7-tetrahydro-1,2,4-triazolo[1,5-a]-pyr-
imidines IIa−IIe we obtained in 71–91% yield by hydro-
genation of compounds Ia–Ie with sodium borohydride
in ethanol (Scheme 1). Compound If turned out to be
stable against hydrogenation even at the use of a large
excess of NaBH4, prolonging the reaction to 4 h and
performing it in boiling 2-propanol or 1-butanol. Dihydro-
Ph
N
O
N
NaBH4
EtOH
OEt
H2N
N
N
H
Me
If
I, II: R1 = Ph (a–d), 4-MeOC6H4 (e); R2 = Me (a), Ph
(b, e), 4-MeC6H4 (c), 4-ClC6H4 (d).
t
riazolopyrimidines with a 6-arylcarboxamide group accord
-
ing to [2] were hydrogenated with NaBH4 in 2-propanol
715

CHERNYSHEV et al.
716
4.8 ppm. Inasmuch as the coupling of protons H5 and H7
with one of the methylene group protons is characterized
by the coupling constant 10.6−11.4 Hz typical for Jaa [9],
to compounds II should be assigned a cis-structure with
the equatorial orientation of substituents in the positions
5 and 7 of the bicycle [8].
pound IV the NH signals are absent, the multiplet of H5
is shifted downfield by ~1 ppm compared with the
spectrum of initial amine IIe and those of acyl derivatives
IIa and IIc; besides, in the 13C NMR spectrum of
compound IV signals of both carbons of the triazole ring
are shifted upfield due to the effect of the magnetic
anisotropy of the carbonyl groups. The complete
equivalence of two C=O groups in the 13C NMR spectrum
unambiguously confirms the structure of compound IV
and excludes the possible isomers with a benzoyl group
at N1 or N3.
Compounds IIa−IIe contain in their molecules several
nucleophilic centers (NH2, N1, N3, and N4H) prone to
the probable attack of electrophilic reagents. The
reactivity of compounds II was studied by an example
of amine IIe.
The results obtained in acylation and sulfonylation
of compound IIe show that 2-amino-4,5,6,7-tetrahydro-
1,2,4-triazolo[1,5-a]-pyrimidine II behaves in these
reactions analogously to 1-substituted 3,5-diamino-1,2,4-
triazoles [10].
The reaction of compound IIe with a small excess of
acetic anhydride or p-toluenesulfonyl chloride in pyridine
at boiling led to the formation of acetyl derivative IIIa
and tosyl derivative IIIb (Scheme 2). We succeeded to
synthesize benzoyl derivative IIIc by acylating amine
IIe with an equimolar amount of benzoyl chloride in
pyridine at 0−5°C for at higher themperature an
intractable mixture of compounds was obtained. The
reaction of amine IIe with excess benzoyl chloride in
boiling pyridine gave tribenzoyl derivative IV in 71%
yield (Scheme 2).
In the 1H NMR spectra of compounds IIIa−IIIc the
amino group signal is lacking, and appears a broadened
singlet of amide proton in the region 10.0−10.6 ppm,
and the singlet of N4H remains. Also in the 13C NMR
spectra of compounds IIIb and IIIc an upfield shift was
observed of C2 atom by nearly 8 ppm as compared with
the spectrum of initial amine IIe apparently due to the
magnetic anisotropy of sulfonyl and carbonyl groups,
whereas the position of the peak of C3a atom virtually
remained unchanged. In the 1H NMR spectrum of com-
This originates from the fact that the pyrimidine ring
in compounds II is unsaturated and does not sifnificanly
affect the distribution of the electron density in the
diaminotriazole fragment.
The alkylation of compound IIe with benzyl bromide
in DMSO in the presence of powdered KOH led to the
formation of 4-benzyl derivative V in 81% yield
(Scheme 3). The reaction is likely to proceed through
the intermediate formation of salt A, as by alkylation of
5,7-diphenyl-4,5,6,7-tetrahydro-1,2,4-triazolo[1,5-a]pyr-
imidine [8] or 1-phenyl-3,5-diamino-1,2,4-triazole [11]
in the presence of strong bases. The alkylation in a neutral
medium resulted in a mixture of quaternary salt VI (70%)
with alkylamino derivative VII (12%) that were success-
fully separated by column chromatography.
The position of the benzyl group in compounds V−
VII was established with the use of heteronuclear
correlation NMR spectra HMBC and HSQC. In the
HMBC spectrum of compound V appeared a correlation
peak of vicinal spin-spin coupling of the methylene
protons of the benzyl group (3.86 and 4.82 ppm) with the
nuclei C3a (155.4 ppm) and C5 (48 ppm), and the ana-
logous peak of carbon atom in the position 2 (160.5 ppm)
was absent. In the HMBC spectrum of compound VI the
benzyl protons (5.18 ppm) correlate with atoms C2
(149.8 ppm) and C3a (146.7 ppm), but have no correlation
with atom C5 (54.1 ppm). In the HMBC spectrum of
compound VII in its turn appears a correlation peak of
benzyl protons (4.2 ppm) only with atom C2 (160.8 ppm).
Besides the structure of the alkyl derivative VII was
unambiguously proved by an independent synthesis: by
hydrogenation of azomethine IX obtained by condensa-
tion of amine IIe with benzaldehyde (Scheme 3).
Scheme 2.
IIe
iiii
i-iii
4-MeO-C6H4
4-MeO-C6H4
N
Bz
N
N
N
R
N
N
H
Bz
N
N
N
Ph
N
Ph
H
Bz
IV
IIIc_IIIc
Reagents and conditions: i, Ac2O/Py, boiling (IIIa); ii,
TsCl/Py, boiling (IIIb); iii, BzCl/MeCN-Py, 0–5°C
(IIIc); iiii, BzCl/Py, boiling (IV); R = Ac (a), Ts (b), Bz
(c).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 5 2008

2-AMINO-4,5,6,7-TETRAHYDRO-1,2,4-TRIAZOLO[1,5-a]PYRIMIDINES
717
Scheme 3.
R
R
K
N
N
N
N
N
BnBr
N
KOH
H2N
H2N
DMSO
N
_
Ph
N
Ph
Bn
A
V
R
R
Br_
Ph
N
N
N
N
N
N
Bn
BnBr
DMF
IIe
N
H
H2N
+
N
Ph
N
H
H
Bn
VI
VII
R
N
N
NaBH4
EtOH
PhCHO
DMF
Ph
N
VII
N
N
Ph
H
IX
R = 4-MeOC6H4.
N4H is absent. Thus in the basic medium the deprotona-
tion of salt VI, same as that of triazolopyrimidines II,
occurs with the elimination of proton N4H.
The formation of compound VII in the alkylation of
amine IIe is somewhat unexpected for according to
published data [12] the alkylation of aminotriazoles in
neutral media occurrs at the nitrogen atoms of the
heterocycle and does not involve the exocyclic amino
group. In similar way behaves the majority of amino
derivatives of azoles and azines where the amino group
is conjugated with the “pyridine” nitrogen atom of the
heterocycle [13]. It is presumable that compound VII
forms from salt VI by a rearrangement proceeding by
the type of Dimroth rearrangement. However the heating
of solutions of pure salt VI in ethanol or DMF in the
presence of acids or bases did not yield even traces of
compound VII. Consequently, the alkyl derivative VII
results from a direct attack of the alkylation agent on the
amino group of compound IIe.
The treatment of compound VIII with alcoholic
solution of KOH at cooling results in the formation of
mesoionic compound XI (Scheme 5). The proton elimin-
ation in initial bromide VIII may occur both from the
amide group and N4H. Since the 1H NMR spectrum did
not unambiguously prove the structure of compound XI,
we compared its acid-base characteristics with those of
compound X. The basicity of compound XI (pKa 7.90 ±
0.02) proved to be significantly lower than that of amine
X (pKa 9.79±0.05). We believe that if the dehydro-
bromination product obtained from compound VIII
possesses the structure similar to compound X, the acetyl
group should not so strongly affect the basicity. The
structure XI is also consistent with the high solubility of
this substance in polar and nonpolar solvents and with
its yellow color, whereas compound X is colorless. For
instance, it is known that the mesoionic compounds
obtained by treating with bases 2-amino-3-alkyl-1,2,4-
triazolo-[1,5-a]pyrimidinium salts also are colored sub-
stances [14].
The more convenient preparative synthesis of com-
pound VI consists in benzylation of acetyl derivative IIIa
followed by hydrolysis of compound VIII with an aqueous-
alcoholic solution of hydrobromic acid (Scheme 4).
The treatment of salt VI with an alcoholic solution of
KOH yields 3-benzyl-3,5,6,7-tetrahydro-1,2,4-triazolo-
[1,5-a]pyrimidine (X) that can also be obtained by alka-
line hydrolysis of acetyl VIII (Scheme 5). The 1H NMR
spectrum of compound X contains a two-proton singlet
of the amino group at 5.8 ppm, but the signal of the group
The experimental findings obtained in this study
suggest a conclusion on a high reactivity of 2-amino-
4,5,6,7-tetrahydro-1,2,4-triazolo[1,5-a]pyrimidines
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 5 2008

CHERNYSHEV et al.
718
Scheme 4.
Initial compounds Ia–Ie were obtained by procedures
[8, 16], If, by procedure [17].
4-MeOC6H4
2-Amino-4,5,6,7-tetrahydro-1,2,4-triazolo-[1,5-
a]pyrimidines IIa–IIe. To a dispersion of 1.5 mmol of
an appropriate dihydrotriazolopyrimidine Ia–Ie in 5 ml
of ethanol was added by portions within 30 min 0.11 g
(3 mmol) of NaBH4 powder at 50–60°C. After the end
of gas evolution the reaction mixture was cooled and
diluted with 20 ml of water, the separated precipitate
was filtered off and crystallized from a mixture DMF–
ethanol, 1:5.
N
Br
Ph
N
Ac
BnBr
DMF
IIIa
N
H
N
Bn
N
H
VIII
HBr
EtOH
VI
Scheme 5.
4-MeOC6H4
2-Amino-5-methyl-7-phenyl-4,5,6,7-tetrahydro-
1,2,4-triazolo[1,5-a]pyrimidine (IIa). Yield 0.31 g
1
(91%), mp >320°C. H NMR spectrum, δ, ppm: 1.11 d
(3H, CH3, J 6.2 Hz), 1.65 m (1H, C6H2), 2.20 m (1H,
C6H2), 3.49 m (1H, H5), 4.77 s (2H, NH2), 4.96 d.d (1H,
H7, J6A,7 4.8, J6B,7 11.0 Hz), 6.63 C (1H, NH), 7.12–
7.34 m (5H, C6H5). 13C, δ, ppm: 20.90 (CH3), 41.43
(C6), 45.64 (C5), 57.95 (C7), 127.02, 127.30, 128.21,
141.36, 154.55 (C3a), 160.72 (C2). Mass spectrum, m/z
(Irel, %): 229 (85.1) [M]+, 131 (77.6), 125 (100), 115
(12.1), 99 (11.5), 91 (16.9), 43 (22.3). Found, %: C 62.73;
H 6.69; N 30.58. C12H15N5. Calculated, %: C 62.86;
H 6.59; N 30.54. M 229.28.
N
KOH
N
KOH
EtOH,
20oC
VI
H2N
EtOH,
boiling
N
Bn
N
Ph
X
VIII
4-MeOC6H4
O
N
N
Me
KOH
EtOH, 20oC
N
N
N
Ph
H
2-Amino-5,7-diphenyl-4,5,6,7-tetrahydro-1,2,4-
Bn
XI
triazolo[1,5-a]pyrimidine (IIb). Yield 0.36 g (82%), mp
279–280°C. H NMR spectrum, δ, ppm: 1.99 m (1H,
1
toward electrophilic reagents and on the opportunity of
purposeful modification of their structure by acylation,
sulfonylation, and alkylation.
C6H2), 2.33 m (1H, C6H2), 4.60 d.d (1H, H5, J5,6A 1.9,
J5,6B 11.4 Hz), 4.85 s (2H, NH2), 5.12 d.d (1H, H7,
J6A,7 4.8, J6B,7 10.8 Hz), 7.03 s (1H, NH), 7.18–7.37 m
(8Harom), 7.42 m (2Harom). Mass spectrum, m/z (Irel, %):
291 (50.0) [M]+, 193 (16.9), 186 (100), 115 (50.1),
104 (10.4), 90 (27.1), 43 (29.9). Found, %: C 70.13;
H 5.92; N 23.95. C17H17N5. Calculated, %: C 70.08; H 5.88;
N 24.04. M 291.36.
EXPERIMENTAL
1H and 13C NMR spectra were registered on
spectrometers Varian Unity-300 (300 and 75 MHz
respectively) and Bruker DRX-500 (500 and 125 MHz
respectively), solvent DMSO-d6, internal reference TMS.
The assignment of 13C NMR signals was performed
based on heteronuclear correlation spectra HSQC and
HMBC. Mass spectra were measured on an instrument
Finnigan MAT INCOS-50 with a direct admission of the
sample into the ion source, ionizing ions energy 70eV.
The elemental analysis was carried out on an analyzer
Perkin-Elmer 2400. Ionization constants of compounds
X and XI were estimated by potentiometric titration of
0.01 M solutions in 80% ethanol at 23°C along procedure
[15] applying a pH-meter pH-150M, glass electrode
ESL-63-07, and reference electrode EVL-1M3. The
melting points were measured on PTP device by the
capillary method.
2-Amino-5-(4-methylphenyl)-7-phenyl-4,5,6,7-
tetrahydro-1,2,4-triazolo[1,5-a]pyrimidine (IIc). Yield
1
0.35 g (77%), mp 223–224°C. H NMR spectrum, δ,
ppm: 1.97 m (1H, C6H2), 2.26 s (3H, CH3), 2.30 m (1H,
C6H2), 4.55 d (1H, H5, J 11.1 Hz), 4.83 s (2H, NH2),
5.11 d.d (1H, H7, J6A,7 4.8, J6B,7 10.9 Hz), 6.97 s (1H,
NH), 7.13 d (2H, C6H4, J 7.8 Hz), 7.08–7.34 m (7Harom).
Mass spectrum, m/z (Irel, %): 305 (98.2) [M]+, 207 (66.1),
200 (47.9), 192 (19.1), 186 (100), 129 (31.0), 115 (44.7),
91 (42.8), 43 (27.3). Found, %: C 71.00; H 6.33; N 22.66.
C18H19N5. Calculated, %: C 70.80; H 6.27; N 22.93.
M 305.38.
2-Amino-7-phenyl-5-(4-chlorophenyl)-4,5,6,7-
tetrahydro-1,2,4-triazolo[1,5-a]pyrimidine (IId).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 5 2008

2-AMINO-4,5,6,7-TETRAHYDRO-1,2,4-TRIAZOLO[1,5-a]PYRIMIDINES
719
Yield 0.35 g (71%), mp 239–240°C. 1H NMR spectrum,
δ, ppm: 1.99 m (1H, C6H2), 2.33 m (1H, C6H2), 4.61 d.d
(1H, H5, J5,6A 1.9, J5,6B 11.4 Hz), 4.86 s (2H, NH2),
5.11 d.d (1H, H7, J6A,7 4.3, J6B,7 10.6 Hz), 7.06 s (1H,
NH), 7.19–7.31 m (5H, C6H5), 7.37 d (2H, C6H4,
J 8.5 Hz), 7.44 d (2H, C6H4, J 8.5 Hz). Mass spectrum,
m/z (Irel, %): 325 (44.7) [M]+, 220 (17.7), 192 (12.9),
186 (100), 115 (20.5), 101 (16.7), 59 (73.2), 43 (33.2).
Found, %: C 62.74; H 4.99; N 21.78. C17H16ClN5.
Calculated, %: C 62.67; H 4.95; N 21.50. M 325.80.
it was diluted with 10 ml of water. The precipitate formed
on cooling was filtered off and recrystallized from a mix-
ture DMF–ethanol, 1:5. Yield 0.69 g (91%), mp 286–
1
287°C. H NMR spectrum, δ, ppm: 1.99 m (1H, C6H2),
2.29 m (1H, C6H2), 2.36 s (3H, CH3), 3.74 s (3H, CH3O),
4.61 d.d (1H, H5, J5,6A 1.7, J5,6B 11.6 Hz), 5.19 d.d (1H,
H7, J6A,7 4.7, J6B,7 10.9 Hz), 6.85 d (2H, C6H4, J 8.6 Hz),
7.06 d (2H, C6H4, J 8.6 Hz), 7.22–7.45 m (7Harom; 1H,
NH), 7.66 d (2H, C6H4, J 8.3 Hz), 10.59 s (1H, NH).
13C NMR spectrum, δ, ppm: 21.06 (CH3), 41.98 (C6),
53.75 (C5), 55.17 (CH3O), 57.95 (C7), 113.67, 126.58,
127.18, 127.62, 128.44, 129.18, 131.65, 137.83, 141.65,
142.82, 152.62 (C2), 154.69 (C3a), 158.80. Mass
spectrum, m/z (Irel, %): 475 (48.6) [M]+, 321 (20.9), 277
(78.8), 223 (100), 200 (80.1), 187 (66.2), 134 (57.0),
131 (62.5), 117 (57.4), 115 (30.7), 91 (65.6), 43 (13.2).
Found, %: C 63.37; H 5.21; N 14.81. C25H25N5O3S.
Calculated, %: C 63.14; H 5.30; N 14.73. M 475.57.
2-Amino-7-(4-methoxyphenyl)-5-phenyl-4,5,6,7-
tetrahydro-1,2,4-triazolo[1,5-a]pyrimidine (IIe). Yield
0.36 g (74%), mp 282–283°C. 1H NMR spectrum, δ, ppm:
1.99 m (1H, C6H2), 2.27 m (1H, C6H2), 3.70 s (3H, CH3O),
4.58 d.d (1H NMR spectrum, H5, J5,6A 1.8, J5,6B 11.4 Hz),
4.84 s (2H, NH2), 5.06 d.d (1H, H7, J6A,7 5.0,
J6B,7 10.8 Hz), 6.84 d (2H, C6H4, J 8.6 Hz), 6.99 s (1H,
NH), 7.14 d (2H, C6H4, J 8.6 Hz), 7.23–7.43 m (5H,
C6H5). 13C NMR spectrum, δ, ppm: 42.52 (C6), 54.00
(C5), 55.02 (CH3O), 57.56 (C7), 113.51, 126.47, 127.39,
128.20, 128.29, 132.56, 142.07, 154.57 (C3a), 158.50,
160.61 (C2). Mass spectrum, m/z (Irel, %): 321 (39.8)
[M]+, 223 (15.3), 186 (100), 117 (22.1), 115 (12.6),
43 (26.1). Found, %: C 67.44; H 5.97; N 21.93.
C18H19N5O. Calculated, %: C 67.27; H 5.96; N 21.79.
M 321.38.
2-Benzamido-7-(4-methoxyphenyl)-5-phenyl-
4,5,6,7-tetrahydro-1,2,4-triazolo[1,5-a]pyrimidine
(IIIc). To a dispersion of 0.5 g (1.6 mmol) of amine IIe
in 2 ml of acetonitrile and 0.5 ml of pyridine was added
while stirring at cooling to 0–5°C a solution of 0.25 g
(1.8 mmol) of benzoyl chloride in 1 ml of acetonitrile.
The reaction mixture was stirred for 30 min and then
diluted with 10 ml of water, the separated precipitate
was filtered off and recrystallized from ethanol. Yield
0.52 g (77%), mp 210–212°C. 1H NMR spectrum δ, ppm:
2.14 m (1H, C6H2), 2.37 m (1H, C6H2), 3.71 s (3H,
CH3O), 4.71 d.d (1H, H5, J5,6A 1.9, J5,6B 11.4 Hz),
5.31 d.d (1H, H7, J6A,7 4.6, J6B,7 10.9 Hz), 6.88 d (2H,
C6H4, J 8.6 Hz), 7.20 d (2H, C6H4, J 8.6 Hz), 7.26–
7.55 m (8Harom; 1H, NH), 7.87 m (2H, C6H5), 10.37 s
(1H, NH). 13C NMR spectrum, δ, ppm: 42.03 (C6), 53.86
(C5), 55.05 (CH3O), 58.12 (C7), 113.72, 126.49, 127.50,
127.63, 128.16, 128.33, 128.45, 131.48, 131.69, 133.98,
141.69, 153.03 (C2), 154.88 (C3a), 158.80, 165.10 (CO).
Mass spectrum, m/z (Irel, %): 425 (22.3) [M]+, 397 (24.2),
290 (16.8), 263 (25.4), 223 (45.8), 186 (26.4), 134 (21.0),
115 (15.1), 105 (94.3), 91 (25.6), 77 (100), 43 (33.4).
Found, %: C 70.87; H 5.39; N 16.28. C25H23N5O2.
Calculated, %: C 70.57; H 5.45; N 16.46. M 425.49.
2-Acetamido-7-(4-methoxyphenyl)-5-phenyl-
4,5,6,7-tetrahydro-1,2,4-triazolo[1,5-a]pyrimidine
(IIIa). Amixture of 0.5 g (1.6 mmol) of amine IIe, 0.21 g
(2.1 mmol) of acetic anhydride, and 3 ml of pyridine
was boiled for 5 min, then it was diluted with 10 ml of
water. The precipitate formed on cooling was filtered
off and recrystallized from a mixture DMF–ethanol, 1:5.
Yield 0.48 g (83%), mp 233–235°C. 1H NMR spectrum,
δ, ppm: 1.89 br.s (3H, CH3), 2.07 m (1H, C6H2), 2.33 m
(1H, C6H2), 3.71 s (3H, CH3O), 4.66 d.d (1H, H5,
J5,6A 1.8, J5,6B 11.4 Hz), 5.25 d.d (1H, H7, J6A,7 4.6,
J6B,7 10.9 Hz), 6.87 d (2H, C6H4, J 8.6 Hz), 7.16 d (2H,
C6H4, J 8.6 Hz), 7.23–7.46 m (5H, C6H5, 1H, NH),
9.96 br.s (1H, NH). Mass spectrum, m/z (Irel, %): 363
(38.2) [M]+, 321 (25.2), 229 (22.1), 223 (90.7), 186 (100),
115 (40.5), 43 (36.7). Found, %: C 66.29; H 5.91; N 19.02.
C20H21N5O2. Calculated, %: C 66.10; H 5.82; N 19.27.
M 363.42.
4-Benzoyl-2-dibenzoylamino-7-(4-methoxy-
phenyl)-5-phenyl-4,5,6,7-tetrahydro-1,2,4-triazolo-
[1,5-a]pyrimidine (IV). A mixture of 0.5 g (1.6 mmol)
of amine IIe, 0.9 g (6.4 mmol) of benzoyl chloride, and
3 ml of pyridine was boiled for 30 min, then it was diluted
with 10 ml of water. The precipitate formed on cooling
was filtered off and recrystallized from a mixture DMF–
7-(4-Methoxyphenyl)-2-(p-toluenesulfonylamino)-
5-phenyl-4,5,6,7-tetrahydro-1,2,4-triazolo[1,5-a]-
pyrimidine (IIIb). A mixture of 0.5 g (1.6 mmol) of
amine IIe, 0.36 g (1.9 mmol) of p-toluenesulfonyl
chloride, and 3 ml of pyridine was boiled for 5 min, then
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 5 2008

CHERNYSHEV et al.
720
ethanol, 1:5. Yield 0.72 g (71%), mp 210–211°C. 1H NMR
spectrum, δ, ppm: 2.76 m (1H, C6H2), 3.10 m (1H, C6H2),
3.58 s (3H, CH3O), 5.53 d.d (1H, H5, J5,6A 3.1, J5,6B 6.7 Hz),
5.66 t (1H, H7, J 4.2 Hz), 6.00 d (2H, C6H4, J 8.5 Hz),
6.25 d.d (2H, C6H4, J 8.5 Hz), 6.88–7.11 m (5H, C6H5),
7.31–7.69 m (15H, 3C6H5). 13C NMR spectrum, δ, ppm:
36.51 (C6), 54.65 (C5), 54.86 (CH3O), 56.63 (C7), 112.83,
125.26, 126.57, 126.63, 127.77, 127.97, 128.59, 128.65,
128.73, 130.68, 131.51, 132.82, 133.04, 134.30, 138.13,
150.41 (C3a), 153.73 (C2), 157.47, 168.51 (CO), 170.81
(2CO). Found, %: C 73.67; H 5.05; N 11.19. C39H31N5O4.
Calculated, %: C 73.92; H 4.93; N 11.05.
spectrum, δ, ppm: 39.8 (C6), 44.31 (CH2C6H5), 54.14
(C5), 55.26 (CH3O), 58.49 (C7), 113.89, 126.99, 127.10,
128.02, 128.41, 128.72, 128.80, 128.99, 129.32, 134.26,
139.54, 146.73 (C3a), 149.81 (C2), 159.37. Found, %:
C 70.17; H 5.20; N 14.27. C25H26BrN5O. Calculated, %:
C 60.98; H 5.32; N 14.22.
2-Benzylamino-7-(4-methoxyphenyl)-5-phenyl-
4,5,6,7-tetrahydro-1,2,4-triazolo[1,5-a]pyrimidine
(VII). To a dispersion of 0.5 g (1.2 mmol) of azomethine
IX in 5 ml of boiling ethanol was added by portions
within 30 min 0.11 g (3 mmol) of NaBH4 powder. After
the end of hydrogen evolution 15 ml of water was poured
into the reaction mixture, the separated precipitate was
filtered off and recrystallized from ethanol. Yield 0.37 g
2-Amino-4-benzyl-7-(4-methoxyphenyl)-5-phenyl-
4,5,6,7-tetrahydro-1,2,4-triazolo[1,5-a]-pyrimidine
(V). A mixture of 0.5 g (1.6 mmol) of amine IIe, 0.1 g
(1.8 mmol) of KOH powder, and 2 ml of DMSO was
stirred for 15 min and then 0.3 g (1.7 mmol) of benzyl
bromide was added. The reaction mixture was stirred
for 30 min at room temperature, then 6 ml of water was
added, the precipitated substance was filtered off, washed
on the filter with 5 ml of water, and recrystallized from
a mixture DMF–ethanol, 1:5. Yield 0.52 g (81%), mp
1
(74%), mp 184–186°C. H NMR spectrum, δ, ppm:
1.96 m (1H, C6H2), 2.30 m (1H, C6H2), 3.72 s (3H,
CH3O), 4.15 m (2H, CH2C6H5), 4.60 d.d (1H, H5,
J5,6A 2.1, J5,6B 11.2 Hz), 5.12 d.d (1H, H7, J6A,7 4.7,
J6B,7 10.7 Hz), 6.04 t (1H, NH, J 5.9 Hz), 6.85 d (2H,
C6H4, J 8.8 Hz), 7.13 d (2H, C6H4, J 8.8 Hz), 7.16–
7.43 m (10H, 2C6H5; 1H, NH). 13C NMR spectrum, δ,
ppm: 42.66 (C6), 46.06 (CH2C6H4), 53.78 (C5), 54.98
(CH3O), 57.57 (C7), 113.48, 126.19, 126.38, 127.09,
127.35, 127.82, 128.05, 128.24, 132.46, 141.01, 141.81,
154.37 (C3a), 158.47, 160.79 (C2). Mass spectrum, m/z
(Irel, %): 411 (100) [M]+, 277 (91.2), 223 (78.7), 115
(35.0), 91 (35.5), 43 (40.1). Found, %: C 73.16; H 6.24;
N 17.07. C25H25N5O. Calculated, %: C 72.97; H 6.12;
N 17.02. M 411.51.
1
224–225°C. H NMR spectrum, δ, ppm: 2.32 m (2H,
C6H2), 3.71 s (3H, CH3O), 3.86 d (1H, CH2C6H5,
J 15.5 Hz), 4.42 d.d (1H, C5H, J5,6A 3.6, J5,6B 10.1 Hz),
4.82 d (1H, CH2C6H5, J 15.5 Hz), 5.03 s (2H, NH2),
5.11 m (1H, H7), 6.83 d (2H, C6H4, J 8.7 Hz), 7.03 m
(2H, C6H5), 7.17 d (2H, C6H4, J 8.7 Hz), 7.29–7.35 m
(8Harom). 13C NMR spectrum, δ, ppm: 41.79 (C6), 49.98
(CH2C6H5), 55.01 (CH3O), 56.82 (C5), 57.97 (C7),
113.42, 126.86, 127.39, 127.69, 128.04, 128.30, 128.34,
128.47, 132.08, 137.29, 139.62, 155.41 (C3a), 158.53,
160.53 (C2). Mass spectrum, m/z (Irel, %): 411 (78.3)
[M]+, 276 (38.0), 223 (100), 186 (19.8), 115 (93.7),
91 (74.5), 43 (24.3). Found, %: C 73.11; H 6.18; N 17.23.
C25H25N5O. Calculated, %: C 72.97; H 6.12; N 17.02.
M 411.51.
2-Acetamido-3-benzyl-7-(4-methoxyphenyl)-5-
phenyl-4,5,6,7-tetrahydro-1,2,4-triazolo[1,5-a]-pyr-
imidinium bromide (VIII).Amixture of 1.0 g (2.8 mmol)
of finely dispersed acetyl derivative IIIa, 2 ml of DMF,
and 0.52 g (3.0 mmol) of benzyl bromide was stirred for
3 h at 80°C, then it was diluted with 50 ml of water and
cooled. After 3 days the settled precipitate was filtered
off and recrystallized from acetonitrile. Yield 1.3 g (89%),
1
2-Amino-3-benzyl-7-(4-methoxyphenyl)-5-phenyl-
4,5,6,7-tetrahydro-1,2,4-triazolo[1,5-a]-pyrimidinium
bromide (VI). A mixture of 0.5 g (1.0 mmol) of acetyl
derivative VIII, 2 ml of ethanol, and 0.5 ml of 40% hydro-
bromic acid was boiled for 2 h and then cooled. The
settled precipitate was recrystallized from acetonitrile.
Yield 0.45 g (85%), mp 209–210°C. 1H NMR spectrum,
δ, ppm: 2.35 m (1H, C6H2), 2.46 m (1H, C6H2), 3.74 s
(3H, CH3O), 4.91 d.d (1H, H5, J5,6A 3.1, J5,6B 10.9 Hz),
5.18 s (2H, CH2C6H5), 5.28 d.d (1H, H7, J6A,7 4.2,
J6B,7 10.5 Hz), 6.72 s (2H, NH2), 6.90 d (2H, C6H4,
J8.6 Hz), 7.31–7.47 m (12Harom), 9.24 s (1H, NH). 13C NMR
mp 233−235°C. H NMR spectrum, δ, ppm: 1.92 s (3H,
CH3), 2.45 m (2H, C6H2), 3.75 s (3H, CH3O), 5.01 t (1H,
H5, J 6.8 Hz), 5.16 s (2H, CH2C6H5), 5.45 t (1H, H7,
J 7.7 Hz), 6.93 d (2H, C6H4, J 8.6 Hz), 7.30−7.53 m
(12Harom), 9.69 s (1H, NH), 10.73 s (1H, NH). 13C NMR
spectrum, δ, ppm: 22.45 (CH3), 38.67 (C6), 46.22
(CH2C6H5), 54.39 (C5), 55.27 (CH3O), 59.45 (C7),
114.03, 127.25, 127.34, 128.12, 128.27, 128.56, 128.77,
128.82, 129.63, 133.61, 139.28, 141.87 (C2), 148.43
(C3a), 159.60, 170.50 (CO). Found, %: C 60.51; H 5.41;
N 13.29. C27H28BrN5O2. Calculated, %: C 60.68; H 5.28;
N 13.10.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 5 2008

2-AMINO-4,5,6,7-TETRAHYDRO-1,2,4-TRIAZOLO[1,5-a]PYRIMIDINES
721
Alkylation of compound (IIe). A mixture of 1.5 g
(4.7 mmol) of amine IIe, 4 ml of DMF, and 0.86 g
(5.0 mmol) of benzyl bromide was stirred for 3 h at 80°C.
Then the solvent was distilled off in a vacuum, the residue
was dissolved in 10 ml of chloroform and subjected to
column chromatography on aluminum oxide (column
2.5×15 cm, eluent chloroform). We isolated 0.12 g (8%)
of initial amine IIe, Rf 0.3, and 0.23 g (12%) of compound
VII, Rf 0.5.
126.56, 127.20, 127.46, 127.83, 128.35, 128.41, 133.14,
137.53, 146.80, 148.15, 150.40, 158.50. Mass spectrum,
m/z (Irel, %): 411 (1.8) [M]+, 276 (55.9), 119 (10.9), 116
(56.5), 91 (100), 65 (32.0), 39 (13.0). Found, %: C 73.19;
H 5.96; N 17.20. C25H25N5O. Calculated, %: C 72.97;
H 6.12; N 17.02. M 411.51.
b. A mixture of 0.5 g (0.9 mmol) of acetyl derivative
VIII, 0.16 g (2.7 mmol) of KOH, and 3 ml of ethanol
was boiled for 2 h and then cooled. The reaction product
was isolated as described above. Yield 0.29 g (75%).
The sorbent after isolation of compounds VII and IIe
was boiled in 200 ml of ethanol, filtered off, the filtrate
was evaporated to a volume of 2−3 ml and diluted with
5 ml of water. The separated precipitate was filtered off
and dried. We obtained 1.67 g (70%) of compound VI.
N-{3-Benzyl-7-(4-methoxyphenyl)-5-phenyl-
4,5,6,7-tetrahydro-1,2,4-triazolo[1,5-a]-pyrimidin-2-
yl}acetamidate (XI). To a solution of 0.5 g (0.9 mmol)
of compound VIII in 2 ml of ethanol was added a solution
of 0.05 g (0.95 mmol) of KOH in 1 ml of ethanol, then
10 ml of water. The reaction product was extracted into
chloroform (10 ml), the extract was washed with water,
dried over sodium sulfate, and chloroform was distilled
off. To the residue 3 ml of hexane was poured, the formed
crystalline precipitate was filtered off. Yield 0.13 g
The properties of compounds obtained were identical
to those synthesized by the above procedures.
2-Benzylydeneamino-7-(4-methoxyphenyl)-5-
phenyl-4,5,6,7-tetrahydro-1,2,4-triazolo[1,5-a]pyr-
imidine (IX). A mixture of 1 g (3.2 mmol) of amine IIe,
0.36 g (3.4 mmol) of benzaldehyde, and 2 ml of DMF
was boiled for 15 min. Then 5 ml of ethanol was added
to the reaction mixture, and it was cooled. The settled
precipitate was filtered off and washed on the filter with
5 ml of ethanol. Yield 1.1 g (82%), mp 198−199°C.
1H NMR spectrum, δ, ppm: 2.16 m (1H, C6H2), 2.38 m
(1H, C6H2), 3.74 s (3H, CH3O), 4.74 d.d (1H, H5,
J5,6A 2.2, J5,6B 11.4 Hz), 5.06 d.d (1H, H7, J6A,7 4.6,
J6B,7 11.1 Hz), 6.91 d (2H, C6H4, J 8.5 Hz), 7.23 d (2H,
C6H4, J 8.5 Hz), 7.26−7.60 m (8Harom; 1H, NH), 7.89 m
(2Harom), 9.01 s (1H, CH=N). Mass spectrum, m/z (Irel,
%): 409 (76.6) [M]+, 274 (92.8), 223 (100), 186 (28.9),
131 (34.7), 115 (44.1), 91 (25.1), 43 (11.4). Found, %:
C 73.61; H 5.29; N 17.17. C25H23N5O. Calculated, %:
C 73.33; H 5.66; N 17.10. M 409.49.
1
(31%), mp 146–148°C. H NMR spectrum, δ, ppm:
1.90 s (1H, CH3), 2.41 m (2H, C6H2), 3.72 s (3H, CH3O),
4.73 m (1H, H5), 4.85 s (2H, CH2C6H5), 5.22 m (1H,
H7), 6.87 d (2H, C6H4, J 8.5 Hz), 7.20 d (2H, C6H4,
J 8.5 Hz), 7.28−7.44 m (10Harom), 10.22 br.s (1H, NH).
Found, %: C 71.19; H 5.94; N 15.62. C27H27N5O2. Cal-
culated, %: C 71.50; H 6.00; N 15.44.
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