Efficient multicomponent synthesis of highly substituted [1,2,3]triazolo[1,5-a]pyrimidines

Article abstract of DOI:10.1007/s00706-010-0326-0

An efficient and facile multicomponent procedure for the synthesis of highly substituted [1,2,3]triazolo-[1,5-a]pyrimidines by reaction of equimolar amounts of aromatic aldehyde, CH-acid, and 5-amino-1,2,3-triazole in refluxing dimethylformamide is described. Springer-Verlag 2010.

Full text of DOI:10.1007/s00706-010-0326-0

Monatsh Chem (2010) 141:773–779
DOI 10.1007/s00706-010-0326-0
ORIGINAL PAPER
Efficient multicomponent synthesis of highly substituted
[1,2,3]triazolo[1,5-a]pyrimidines
•
Eugene S. Gladkov Svetlana N. Sirko Svetlana V. Shishkina
•
•
•
Oleg V. Shishkin Irina V. Knyazeva Sergey M. Desenko Valentin A. Chebanov
•
•
Received: 25 November 2008 / Accepted: 11 May 2010 / Published online: 3 June 2010
Ó Springer-Verlag 2010
Abstract An efficient and facile multicomponent proce-
dure for the synthesis of highly substituted [1,2,3]triazolo-
[1,5-a]pyrimidines by reaction of equimolar amounts of
aromatic aldehyde, CH-acid, and 5-amino-1,2,3-triazole in
refluxing dimethylformamide is described.
on reactions of synthetic precursors of unsaturated
ketones—aromatic aldehydes and active methylene com-
pounds—are considered more efficient and have attracted
the attention of scientists. Diverse partially hydrogenated
azolopyrimidines were synthesized by the reactions of am-
inoazoles with aldehydes and numerous CH-acids like
acetoacetic acid derivatives, b-diketones, b-ketosulfones,
pyruvic acids, etc. [9, 11–17].
Keywords Combinatorial chemistry ꢀ Cyclizations ꢀ
Heterocycles ꢀ Multicomponent reactions ꢀ
Triazolo[1,5-a]pyrimidines
However, in most cases reported 3-amino-1,2,4-triazoles,
5-aminotetrazole, 2-aminoimidazoles, and 2-aminobenz-
imidazole have been used, whereas application of
4-amino-1,2,3-triazoles has not been described for the
above-mentioned multicomponent cyclocondensations.
There are only a few examples of heterocyclizations involv-
ing 4-amino-1,2,3-triazoles: with b-diketones yielding
[1–3]triazolo[1,5-a]pyrimidines [18], with N-cyanomethane-
imidates giving rise to 4-amino[1,2,3]triazolo[1,5-a]-
[1,3,5]triazines [19], and with isocyanates leading to
[1,2,3]triazolo[5,1-d][1,2,3,5]tetrazin-4-ones [20]. In addi-
tion, one of our recent publications described the treatment
of chalcone derivatives with 4-amino-5-phenyl- and
4-amino-1,2,3-triazole-5-carboxamide as an efficient syn-
thetic pathway to 4,7-dihydro-5,7-diaryl[1,2,3]triazolo-
[1,5-a]pyrimidines [21] followed by the study of their tau-
tomerism. In particular, it was shown that reactions with
chalcone did not affect the carboxamide group though het-
erocyclizations despite the fact that the participation of
the carboxamide had been reported in other publications
[22, 23].
Introduction
In recent years, considerable attention has been devoted to
the development of new efficient methodology for the
synthesis of highly substituted partially hydrogenated
azolopyrimidines. These fused heterocycles belong to an
important class of organic compounds due to their physi-
ological activities, e.g., as cardiovascular vasodilators,
calcium channel blocking agents, and potassium channel
inhibitors and openers [1–8].
The most facile and widespread method for the synthesis
of substituted azoloazines is reaction of aminoazoles with
a,b-unsaturated ketones [9, 10]. In contrast to the analogous
reaction with b-diketones, cyclocondensations involving
a,b-unsaturated carbonyls are characterized by high regi-
oselectivity. However, multicomponent procedures based
E. S. Gladkov (&) ꢀ S. N. Sirko ꢀ S. V. Shishkina ꢀ
O. V. Shishkin ꢀ I. V. Knyazeva ꢀ S. M. Desenko ꢀ
V. A. Chebanov
State Scientific Institution ‘‘Institute for Single Crystals’’
of National Academy of Sciences of Ukraine, Lenin Ave,
60, Kharkiv 61001, Ukraine
Results and discussion
The synthesis of highly substituted 4,7-dihydro-
[1,2,3]triazolo[1,5-a]pyrimidines was based on the
e-mail: gladkov@isc.kharkov.com
123

774
E. S. Gladkov et al.
multicomponent reaction of 4-amino-1,2,3-triazoles 1a–1c
with aromatic aldehydes 2a–2d and several types of
CH-acids 3a, 3b, 4a, and 4b. It was established that
the treatment of 4-phenyl-1H-1,2,3-triazol-5-amine (1a),
5-amino-N-(4-methylphenyl)-1H-1,2,3-triazole-4-car-
boxamide (1b), or 5-amino-N-(2-methylphenyl)-1H-1,2,3-
triazole-4-carboxamide (1c) with N-(4-methoxyphenyl)
acetoacetamide (3a) or ethyl acetoacetate (3b) and aro-
matic aldehydes 2a–2d in boiling DMF for 5–15 min
afforded 3,5,6,7-tetrasubstituted 4,7-dihydro[1,2,3]triazol-
o[1,5-a]pyrimidines 5a–5l in satisfactory or good yields
(Scheme 1; Table 1). Longer durations of the multicom-
ponent reaction led to resinification of the reaction mixture
which resulted in drastically reduced yields. The most
drastic case was the reaction of 4-phenyl-1H-1,2,3-triazol-
5-amine (1a). Correspondingly, the reaction times for the
treatment involving 1a were the shortest (about 5 min),
while the yields were the lowest (35–42%). For 5-amino-
1,2,3-triazoles 1b and 1c the influence of the reaction time
was not so dramatic.
room temperature and, when needed, crystallized from
DMF/methanol mixture (1:2).
Because of the multicomponent character of the reaction
and the high number of commercially available aldehydes,
b-diketones, and acetoacetic acid derivatives, substituents
in position 5 of the aminotriazoles can easily be varied. The
reported method represents an attractive combinatorial
synthesis of moderately complicated heterocycles, which
can be realized in short reaction times.
The compositions and structures of the heterocycles
synthesized were established with help of elemental anal-
1
ysis, mass spectrometry, H and 13C NMR spectroscopy,
and X-ray data. The 1H NMR spectra of compounds 5a–5l
and 6a–6c show the expected signals for the aromatic rings
and terminal functional groups. Characteristic signals were:
a singlet for the 7-methyne proton of the dihydropyrimi-
dine moiety at ca. 6.55–6.86 ppm, the broad singlet of the
pyrimidine NH (9.70–10.34 ppm), the signal of the car-
boxamide NH at 9.67–10.50 ppm (for compounds 5d–5l,
6b, and 6c), and the signals of CH2 groups of the cyclo-
hexanone ring at 2.09–2.85 ppm.
The procedure works also for three-component reactions
involving cyclic 1,3-diketones as CH-acid component.
Refluxing of aminotriazoles 1a and 1b with benzaldehyde
(2a) and dimedone (4a) or 1,3-cyclohexanedione (4b) in
DMF for 10 min gave rise to 3,6,6,9-tetrasubstituted
6,7-dihydro[1,2,3]triazolo[5,1-b]quinazolin-8-ones 6a–6c
in good yields (Scheme 1; Table 1).
This 1H NMR spectra are compatible with several
alternative structures 5–8 with different orientation of the
substituents in the dihydropyrimidine ring (Fig. 1).
Importantly, our earlier experience with similar compounds
demonstrated a distinct dependence of the chemical shift of
the amino group in the 1H NMR spectrum on its position in
the dihydroazine fragment [12, 24–26]. Linear structures
like 5 and 6 exhibit a signal for the NH proton at
9.5–10.5 ppm, whereas in the case of structures similar to 7
and 8 this signal usually was shifted to high field by
2–3 ppm. As a further confirmation, no NOE and COSY
correlations in the structures of type 5 and 6 were found
The multicomponent reactions were monitored with the
help of HPLC. The target heterocycles 5 and 6 and the
corresponding azomethines of aminotriazoles 1a–1c with
the aldehydes 2a–2d could be detected by HPLC. For
work-up methanol was added to the cooled reaction mix-
ture. The precipitate formed was filtered, dried in air at
Scheme 1
O
R3
R2
O
N
3a, 3b
CH3
O
N
R3
N
Δ
DMF, , 5-15 min
N
H
CH3
O
R1
H
N
N
O
5a-5l
NH2 + R2CHO
N
R2
R3
R1
O
N
R3
4a 4b
,
N
2a 2d
1a 1c
-
-
N
R3
Δ
DMF, , 5-15 min
N
H
R3
R1
6a-6c
123

Synthesis of highly substituted pyrimidines
775
Table 1 Synthesis of 4,7-dihydro[1,2,3]triazolo[1,5-a]pyrimidines 5a–5l and 6a–6c
Building blocks
Reaction
time (min)
Product
Yield (%)
Amine
Aldehyde
CH-acid
R1
R2
R3
1a
1a
1a
1a
1b
1b
1b
1b
1b
1b
1b
1c
1c
1c
1c
C6H5
2a
2b
2c
2a
2a
2b
2d
2a
2d
2a
2a
2a
2b
2a
2b
C6H5
3a
3a
3a
4a
3a
3a
3a
3b
3b
4b
4a
3a
3a
3b
3b
4-CH3OC6H4NH
4-CH3OC6H4NH
4-CH3OC6H4NH
CH3
10
10
10
5
5a
5b
5c
6a
5d
5e
5f
37
35
42
45
47
65
71
55
41
45
65
40
50
65
57
C6H5
4-CH3OC6H4
4-ClC6H4
C6H5
C6H5
C6H5
4-CH3C6H4NHCO
4-CH3C6H4NHCO
4-CH3C6H4NHCO
4-CH3C6H4NHCO
4-CH3C6H4NHCO
4-CH3C6H4NHCO
4-CH3C6H4NHCO
2-CH3C6H4NHCO
2-CH3C6H4NHCO
2-CH3C6H4NHCO
2-CH3C6H4NHCO
C6H5
4-CH3OC6H4NH
4-CH3OC6H4NH
4-CH3OC6H4NH
OC2H5
10
10
10
15
15
5
4-CH3OC6H4
4-BrC6H4
C6H5
5g
5h
6b
6c
5i
4-BrC6H4
C6H5
OC2H5
H
C6H5
CH3
5
C6H5
4-CH3OC6H4NH
4-CH3OC6H4NH
OC2H5
10
10
15
15
4-CH3OC6H4
C6H5
5j
5k
5l
4-CH3OC6H4
OC2H5
Fig. 1 Possible alternative
structures of the
multicomponent reaction
products
R3
R3
R2
O
R2
O
CH3
N
O
N
N
N
N
R3
N
N
N
O
N
R3
CH3
R3
N
N
N
R2
N
H
R2
N
H
N
H
N
R3
R1
R1
R1
R1
H
5
7
6
8
˚
between the CH and the NH group in the pyrimidine
moiety.
is 3.3(6)°), stabilized by the H3ꢀꢀꢀO2 (2.32 A) and
˚
H9cꢀꢀꢀO1 (2.28 A) attractive interactions, which can be
The structure of the heterocycles synthesized was con-
firmed by an X-ray structural analysis. Suitable crystals of
compound 5h were selected for an X-ray diffraction study.
The X-ray structure confirmed that 5h is ethyl 7-(4-
bromophenyl)-4,7-dihydro-5-methyl-3-[(4-methylphenyl)-
aminocarbonyl][1,2,3]triazolo[1,5-a]pyrimidine-6-carboxylate
(Fig. 2).
considered as very weak intramolecular hydrogen bonds, as
the values of the angles C3–H3ꢀꢀꢀO2 and C9–H9cꢀꢀꢀO1 are
rather small (95° and 117°). The ethyl group of the ester
substituent has the ap-conformation relative the C4–C6
bond (the C7–O2–C6–C4 torsion angle is 177.6(3)°) and it
is disordered over two positions (A and B) with equal
populations owing to the rotation around the O2–C7 bond
(the C6–O2–C7–C8 torsion angle is 158.3(6)° in A and
-174.6(6)° in B). The carbamide fragment of the sub-
stituent at the C2 atom is almost coplanar to the plane of
the triazole ring (the C1–C2–C16–O3 torsion angle is
The dihydropyrimidine ring of the compound 5h adopts
a sofa conformation (the puckering parameters [27] are
S = 0.29, H = 59.8°, W = 9.2°). Deviation of the C3
atom from the mean plane of the remaining atoms of the
˚
ring is -0.29 A. The p-bromophenyl substituent has
˚
7.8(5)°), stabilized additionally by the H5NꢀꢀꢀN2 2.51 A
pseudo-axial orientation and it is turned relative to the
plane of the partially hydrogenated ring (the C1–N4–C3–
C10 and N4–C3–C10–C15 torsion angles are 99.1(3) and
119.3(3)°). The ester substituent is coplanar to the C4–C5
endocyclic double bond (the C5–C4–C6–O1 torsion angle
attractive interaction and the N1–H1NꢀꢀꢀO3 weak intra-
˚
molecular hydrogen bond (HꢀꢀꢀO 2.45 A N–HꢀꢀꢀO 117°).
The p-methylphenyl group is practically coplanar to the
carbamide fragment (the C16–N5–C17–C18 torsion angle
is 9.0(5)°). The conformation of this group is stabilized by
123

776
E. S. Gladkov et al.
Fig. 2 Molecular structure
(X-ray diffraction data) of
compound 5h
5-Amino-N-(4-methylphenyl)-1H-1,2,3-triazole-4-
carboxamide (1b, C10H11N5O)
the C18–H18ꢀꢀꢀO3 intramolecular hydrogen bond (HꢀꢀꢀO
˚
2.28 A C–HꢀꢀꢀO 121°) on the one hand and is destabilized
A solution of 13.3 g benzyl azide (0.1 mol) and 17.4 g
2-cyano-N-(4-methylphenyl)acetamide (0.1 mol) in 250 cm3
absolute alcohol containing 0.1 mol sodium ethoxide was
refluxed for 6 h. After cooling, the reaction mixture was
poured into 1 dm3 water and allowed to stand overnight.
The resulting precipitate was filtered, washed with water,
and dried in vacuo. Recrystallization from DMF/methanol
(1:2) gave 27.3 g (89% yield) of the N-benzyl derivative.
5-Amino-1-benzyl-N-(4-methylphenyl)-1H-1,2,3-tria-
zole-4-carboxamide (15.35 g, 0.05 mol) was suspended in
150 cm3 liquid ammonia and small pieces of sodium were
added with stirring until a permanent blue color was
produced. The color was discharged with a small amount of
ammonium chloride and the solvent was allowed to
evaporate. The solid was dissolved in minimal amount of
water and after filtration the solution was adjusted to pH 1
with concentrated hydrochloric acid. After cooling and
crystallization from DMF/methanol (1:2) amine 1b was
obtained in 74% yield (8.03 g). M.p.: 176–177 °C; 1H
NMR (200 MHz, DMSO-d6): d = 2.24 (s, 3H, CH3), 5.97
(bs, 2H, NH2), 7.07 (d, 2H), 7.65 (d, 2H), 9.86 (s, 1H, NH),
13.5 (bs, 1H, NH) ppm; 13C NMR (100 MHz, DMSO-d6):
d = 21.1, 120.8, 124.7, 129.5, 132.7, 137.0, 133.2,
161.5 ppm; MS (70 eV): m/z = 217 (M?), 107 (100).
by the repulsion between hydrogen atoms (H22ꢀꢀꢀH5N
˚
2.29 A as compared with van der Waals radii sum [28] of
˚
2.34 A) on the other hand.
In the crystal of 5h two intermolecular weak hydrogen
0
˚
bonds are observed: N5–H5NꢀꢀꢀN3 HꢀꢀꢀN 2.64 A N–HꢀꢀꢀN
0
˚
156° and C3–H3ꢀꢀꢀN2 HꢀꢀꢀN 2.65 A C–HꢀꢀꢀN 155°.
In conclusion, we developed a new facile procedure for
the synthesis of diverse highly substituted dihydro[1,2,3]
triazolo[1,5-a]pyrimidines by the multicomponent reaction
of 5-amino-1,2,3-triazoles with aromatic aldehydes and
CH-acids like acetoacetic acid derivatives and cyclic 1,3-
diketones. The method is simple and provides the target
compounds in good yields.
Experimental
Melting points of all compounds synthesized were deter-
mined with a Gallenkamp melting point apparatus. The
NMR spectra were recorded in DMSO-d6 at 400 MHz
(100 MHz for 13C) with Jeol Lambda 400 and at 200 MHz
with Varian Mercury VX-200 spectrometers. The mass
spectra were measured on a GC–MS Varian 1200L
instrument (ionizing voltage 70 eV) and on a Hewlett-
Packard LC/MSD 1100 series instrument in atmospheric
pressure chemical ionization (positive APCI) mode. Ele-
mental analysis was realized on EuroVector EA-3000, and
results agreed with calculated values. Starting 4-phenyl-
1H-1,2,3-triazol-5-amine (1a) was obtained by a known
method [29].
5-Amino-N-(2-methylphenyl)-1H-1,2,3-triazole-4-carbox-
amide (1c, C10H11N5O)
Compound 1c was synthesized by an analogous method to
1b. Yield 7.60 g (70%); m.p.: 158–159 °C; 1H NMR
(200 MHz, DMSO-d6): d = 2.23 (s, 3H, CH3), 6.17 (bs,
2H, NH2), 7.16 (m, 4H, Ar), 9.29 (s, 1H, NH), 14.3 (bs, 1H,
123

Synthesis of highly substituted pyrimidines
777
NH) ppm; 13C NMR (100 MHz, DMSO-d6): d = 18.2,
121.8, 124.8, 125.5, 126.7, 130.9, 131.1, 136.8, 142.0,
161.4 ppm; MS (70 eV): m/z = 217 (M?), 111 (100).
9.49 (bs, NH), 9.72 (s, NH), 10.24 (s, NH) ppm; 13C NMR
(100 MHz, DMSO-d6): d = 17.2, 20.5, 55.2, 59.3, 101.1,
113.9, 118.7, 120.2, 121.3, 122.8, 127.1, 128.5, 128.8,
129.1, 132.1, 132.5, 135.5, 136.3, 137.0, 140.6, 155.6,
160.3, 164.4 ppm; MS (70 eV): m/z = 494 (M?), 149
(100).
4,7-Dihydro-N-(4-methoxyphenyl)-5-methyl-3,7-
diphenyl[1,2,3]triazolo[1,5-a]pyrimidine-6-carboxamide
(5a, C26H23N5O2)
A mixture of 1.60 g 4-phenyl-1H-1,2,3-triazol-5-amine
(1a, 10 mmol), 2.07 g amide 3a (10 mmol), and 1.06 g
benzaldehyde (10 mmol) in 0.5 cm3 DMF was refluxed for
10 min. The reaction mixture was cooled to 20 °C, mixed
with 10 cm3 methanol, and the precipitate formed was
filtered and washed with methanol. Recrystallization from
DMF/methanol afforded 1.62 g (37%). M.p.: 154–155 °C;
1H NMR (200 MHz, DMSO-d6): d = 2.28 (s, 3H, CH3),
3.69 (s, 3H, OCH3), 6.83 (d, 2H), 6.86 (s, 1H, 7-H), 7.33
(m, 10H), 7.76 (d, 2H), 9.37 (s, 1H, NH), 9.68 (s, 1H, NH)
ppm; 13C NMR (100 MHz, DMSO-d6): d = 18.1, 56.0,
60.1, 104.0, 114.6, 122.2, 126.6, 127.3, 127.6, 128.8,
129.1, 129.3, 131.5, 132.4, 132.9, 137.3, 141.7, 156.3,
165.2 ppm; MS (70 eV): m/z = 437 (M?), 259 (100), 149,
123.
4,7-Dihydro-N6,7-bis(4-methoxyphenyl)-5-methyl-N3-(4-
methylphenyl)-[1,2,3]triazolo[1,5-a]pyrimidine-3,6-
dicarboxamide (5e, C29H28N6O4)
Yield 3.41 g (65%); m.p.: 238–240 °C; 1H NMR
(200 MHz, DMSO-d6): d = 2.25 (s, 3H, CH3), 2.27 (s,
3H, CH3), 3.67 (s, 3H, OCH3), 3.69 (s, 3H, OCH3), 6.78 (s,
1H, H-7), 6.80 (d, 2H), 6.86 (d, 2H), 7.11 (d, 2H), 7.21 (d,
2H), 7.41 (d, 2H), 7.70 (d, 2H), 9.38 (bs, NH), 9.70 (s, NH),
10.22 (s, NH) ppm; 13C NMR (100 MHz, DMSO-d6):
d = 17.2, 20.5, 55.1, 55.2, 58.9, 104.3, 113.9, 114.1, 120.3,
121.3, 122.8, 128.6, 129.1, 132.2, 132.5, 132.7, 135.5,
136.4, 136.9, 155.6, 159.4, 160.4, 164.5 ppm; MS (70 eV):
m/z = 524 (M?), 123 (100).
7-(4-Bromophenyl)-4,7-dihydro-N6-(4-methoxyphenyl)-5-
methyl-N3-(4-methylphenyl)-[1,2,3]triazolo[1,5-a]-
pyrimidine-3,6-dicarboxamide (5f, C28H25BrN6O3)
Yield 4.10 g (71%); m.p.: 254–256 °C; 1H NMR
(200 MHz, DMSO-d6): d = 2.24 (s, 3H, CH3), 2.26 (s,
3H, CH3), 3.68 (s, 3H, OCH3), 6.81 (d, 2H), 6.83 (s, 1H,
7-H), 7.11 (d, 2H), 7.22 (d, 2H), 7.40 (d, 2H), 7.53 (d, 2H),
7.69 (d, 2H), 9.56 (bs, 1H, NH), 9.76 (s, 1H, NH), 10.26 (s,
1H, NH) ppm; 13C NMR (100 MHz, DMSO-d6): d = 17.8,
55.7, 59.2, 94.5, 104.1, 114.3, 120.6, 121.8, 122.2, 123.2,
129.5, 129.8, 132.1, 132.4, 132.9, 136.2, 137.3, 140.3,
153.2, 156.0, 159.6, 164.5 ppm; MS (70 eV): m/z = 574
(M?), 123 (100).
4,7-Dihydro-N,7-bis(4-methoxyphenyl)-5-methyl-3-
phenyl[1,2,3]triazolo[1,5-a]pyrimidine-6-carboxamide
(5b, C27H25N5O3)
Yield 1.63 g (35%); m.p.: 247–249 °C; 1H NMR
(200 MHz, DMSO-d6): d = 2.55 (s, 3H, CH3), 3.70 (s,
3H, OCH3), 3.71 (s, 3H, OCH3), 6.76 (s, 1H, 7-H), 6.85 (d,
2H), 6.89 (d, 2H), 7.10 (d, 2H), 7.45 (m, 5H), 7.70 (d, 2H),
9.77 (s, 1H, NH), 12.06 (s, 1H, NH) ppm; 13C NMR
(100 MHz, DMSO-d6): d = 34.7, 55.2, 94.1, 114.0, 114.3,
121.0, 124.4, 127.1, 127.6, 129.4, 130.9, 132.1, 132.2,
146.6, 155.4, 159.2, 167.4 ppm; MS (70 eV): m/z = 467
(M?), 289 (100), 123, 108.
Ethyl 4,7-dihydro-5-methyl-3-[(4-methylphenyl)-
aminocarbonyl]-7-phenyl[1,2,3]triazolo-[1,5-a]-
pyrimidine-6-carboxylate (5g, C23H23N5O3)
7-(4-Chlorophenyl)-4,7-dihydro-N-(4-methoxyphenyl)-5-
methyl-3-phenyl[1,2,3]triazolo[1,5-a]pyrimidine-6-
carboxamide (5c, C26H22ClN5O2)
Yield 2.29 g (55%); m.p.: 221–222 °C; 1H NMR
(200 MHz, DMSO-d6): d = 1.06 (t, 3H, CH3), 2.24 (s,
3H, CH3), 2.53 (s, 3H, CH3), 3.97 (q, 2H, CH2), 6.67 (s,
1H, 7-H), 7.10 (d, 2H), 7.29 (m, 5H, Ar), 7.69 (d, 2H), 9.99
(bs, 1H, NH), 10.28 (s, 1H, NH) ppm; 13C NMR
(100 MHz, DMSO-d6): d = 13.9, 18.2, 20.5, 58.5, 59.7,
97.7, 120.3, 123.7, 127.1, 128.4, 128.8, 129.1, 132.6,
135.7, 136.2, 142.0, 146.6, 159.1, 165.0 ppm; MS (70 eV):
m/z = 417(M?), 340 (89).
Yield 1.98 g (42%); m.p.: 201–202 °C; 1H NMR
(200 MHz, DMSO-d6): d = 2.33 (s, 3H, CH3), 3.68 (s,
3H, OCH3), 6.85 (s, 1H, 7-H), 6.82 (d, 2H), 7.42 (m, 9H),
8.04 (d, 2H), 9.04 (s, 1H, NH), 10.50 (s, 1H, NH) ppm; 13
C
NMR (100 MHz, DMSO-d6): d = 17.5, 55.2, 64.5, 113.9,
114.1, 121.3, 127.1, 128.9, 129.0, 129.4, 130.9, 131.2,
131.5, 134.5, 135.5, 137.2, 139.8, 150.9, 156.1, 161.7,
162.0, 196.5 ppm; MS (70 eV): m/z = 471 (M?), 122.
4,7-Dihydro-N6-(4-methoxyphenyl)-5-methyl-N3-(4-
methylphenyl)-7-phenyl[1,2,3]triazolo[1,5-a]pyrimidine-
3,6-dicarboxamide (5d, C28H26N6O3)
Yield 2.32 g (47%); m.p.: 261–262 °C; 1H NMR
(200 MHz, DMSO-d6): d = 2.23 (s, 3H, CH3), 2.27 (s,
3H, CH3), 3.67 (s, 3H, OCH3), 6.82 (d, 2H), 6.84 (s, 1H, H-
7), 7.10 (d, 2H), 7.28 (m, 5H), 7.39 (d, 2H), 7.70 (d, 2H),
Ethyl 7-(4-bromophenyl)-4,7-dihydro-5-methyl-3-
[(4-methylphenyl)aminocarbonyl]-[1,2,3]-triazolo-
[1,5-a]pyrimidine-6-carboxylate (5h, C23H22BrN5O3)
Yield 2.03 g (41%); m.p.: 211–212 °C; 1H NMR
(200 MHz, DMSO-d6): d = 1.07 (t, 3H, CH3), 2.24 (s,
3H, CH3), 2.52 (s, 3H, CH3), 3.97 (q, 2H, CH2), 6.66 (s,
1H, 7-H), 7.10 (d, 2H), 7.25 (d, 2H), 7.53 (d, 2H), 7.68 (d,
123

778
E. S. Gladkov et al.
2H), 10.0 (bs, 1H, NH), 10.32 (s, 1H, NH) ppm; 13C NMR
(100 MHz, DMSO-d6): d = 14.6, 18.9, 21.1, 58.7, 60.4,
98.0, 121.0, 122.1, 124.3, 129.6, 129.7, 132.2, 133.3,
136.3, 136.7, 141.7, 147.2, 159.5, 165.4 ppm; MS (70 eV):
m/z = 495 (M?), 440 (41), 340 (59).
1H, 7-H), 6.82 (d, 2H), 6.87 (d, 2H), 7.14 (m, 5H), 7.41 (d,
2H), 7.53 (dd, 1H), 9.44 (bs, 1H, NH), 9.67 (s, 1H, NH),
9.70 (s, 1H, NH) ppm; 13C NMR (100 MHz, DMSO-d6):
d = 17.7, 18.2, 55.6, 55.7, 59.3, 104.6, 114.3, 114.5, 121.7,
122.9, 125.3, 125.7, 126.5, 129.0, 130.8, 132.4, 132.5,
133.0, 136.0, 136.3, 137.0, 155.9, 159.6, 159.7, 164.7 ppm;
MS (70 eV): m/z = 524 (M?), 375 (25), 149 (100).
X-ray diffraction study of 5h
The colourless crystals of 5h (C23H22BrN5O3) are
orthorhombic. At 293 K a = 8.7078(4), b = 22.7737(6),
Ethyl 4,7-dihydro-5-methyl-3-[(2-methylphenyl)aminocar-
bonyl]-7-phenyl[1,2,3]triazolo[1,5-a]pyrimidine-6-carbox-
ylate (5k, C23H23N5O3)
3
˚
˚
c = 22.7737(6) A, V = 4,516.2(3) A , Mr = 496.37, Z =
8, space group Pbca, dcalc = 1.460 g/cm3, l(MoKa) =
1.855 mm-1, F(000) = 2,032. Intensities of 46,884 reflec-
tions (6,579 independent, Rint = 0.100) were measured on
the ‘‘Xcalibur-3’’ diffractometer (graphite monochromated
1
Yield 2.71 g (65%); m.p.: 90–92 °C; H NMR (200 MHz,
DMSO-d6): d = 1.04 (t, 3H, CH3), 2.24 (s, 3H, CH3), 2.53
(s, 3H, CH3), 3.99 (q, 2H, CH2), 6.65 (s, 1H, 7-H), 7.48 (m,
7H, Ar), 7.52 (d, 2H), 9.76 (s, 1H, NH), 10.0 (bs, 1H, NH)
ppm; 13C NMR (100 MHz, DMSO-d6): d = 14.4, 18.2,
18.6, 19.0, 56.5, 59.0, 60.1, 98.0, 123.9, 125.5, 125.8,
126.4, 127.5, 128.7, 129.1, 130.7, 132.5, 135.9, 136.2,
142.2, 146.9, 159.3, 165.3 ppm; MS (70 eV): m/z = 417
(M?), 340 (79), 284 (42).
MoKa radiation, CCD detector, x-scanning, 2Hmax
=
60°). The structure was solved by direct methods by using
the SHELXTL package [30]. The absorption correction
was performed by multi-scan method (Tmin = 0.402,
Tmax = 0.964). The restraints for the bond lengths (Csp3–
Csp3 1.54 A) in the disordered fragment were applied
˚
during the refinement of the structure. Positions of the
hydrogen atoms were located from electron density differ-
ence maps and refined by using the ‘‘riding’’ model with
Uiso = nUeq of the carrier atom (n = 1.5 for methyl group
and n = 1.2 for other hydrogen atoms). Full-matrix least-
squares refinement against F2 in anisotropic approximation
for non-hydrogen atoms using 6,505 reflections was
converged to wR2 = 0.142 (R1 = 0.044 for 1,755 reflec-
tions with F [ 4(F), S = 0.789). The final atomic
coordinates, and crystallographic data for 5h have been
deposited at the Cambridge Crystallographic Data Centre,
12 Union Road, CB2 1EZ, UK (fax: ?44-1223-336033;
e-mail: deposit@ccdc.cam.ac.uk) and are available on
request quoting the deposition number CCDC 768488.
Ethyl 4,7-dihydro-7-(4-methoxyphenyl)-5-methyl-3-
[(2-methylphenyl)aminocarbonyl]-[1,2,3]triazolo-
[1,5-a]pyrimidine-6-carboxylate (5l, C24H25N5O4)
Yield 2.55 g (57%); m.p.: 100–102 °C; 1H NMR
(200 MHz, DMSO-d6): d = 1.07 (t, 3H, CH3), 2.23 (s,
3H, CH3), 2.51 (s, 3H, CH3), 3.69 (s, 3H, OCH3), 3.97 (q,
2H, CH2), 6.60 (s, 1H, 7-H), 6.87 (d, 2H), 7.18 (m, 5H),
7.49 (d, 1H), 9.74 (s, 1H, NH), 9.95 (s, 1H, NH) ppm; 13C
NMR (100 MHz, DMSO-d6): d = 14.4, 18.2, 18.6, 55.6,
58.4, 60.1, 98.3, 114.4, 114.9, 123.8, 125.5, 125.9, 126.4,
128.7, 130.7, 132.6, 134.5, 135.8, 136.2, 146.6, 159.3,
159.6, 165.4 ppm; MS (70 eV): m/z = 447 (M?), 390
(100).
4a,5,6,7,8a,9-Hexahydro-6,6-dimethyl-3,9-
diphenyl[1,2,3]triazolo[5,1-b]quinazolin-8(4H)-one
(6a, C23H22N4O)
4,7-Dihydro-N6-(4-methoxyphenyl)-5-methyl-N3-(2-
methylphenyl)-7-phenyl[1,2,3]triazolo[1,5-a]pyrimidine-
3,6-dicarboxamide (5i, C28H26N6O3)
Yield 1.67 g (45%); m.p.: 282–284 °C; 1H NMR
(200 MHz, DMSO-d6): d = 0.96 (s, 3H, CH3), 1.05 (s,
3H, CH3), 2.17 (q, 2H, CH2), 2.67 (s, 2H, CH2), 6.55 (s,
1H, 7-H), 7.25 (m, 5H, Ar), 7.45 (t, 2H), 7.75 (d, 2H), 10.3
(bs, 1H, NH) ppm; 13C NMR (100 MHz, DMSO-d6):
d = 27.6, 29.3, 40.7, 50.7, 57.7, 105.8, 127.1, 127.5, 128.0,
128.4, 129.0, 129.3, 131.0, 131.1, 142.5, 151.0, 193.4 ppm;
MS (70 eV): m/z = 370 (M?), 341 (100).
Yield 1.98 g (40%); m.p.: 227–228 °C; 1H NMR
(200 MHz, DMSO-d6): d = 2.26 (s, 3H, CH3), 2.28 (s,
3H, CH3), 3.68 (s, 3H, OCH3), 6.87 (d, 2H), 6.85 (s, 1H, 7-
H), 7.32 (m, 10H, Ar), 7.50 (d, 1H), 9.49 (s, 1H, NH), 9.69
(s, 1H, NH), 9.72 (s, 1H, NH) ppm; 13C NMR (100 MHz,
DMSO-d6): d = 17.9, 18.2, 56.0, 60.1, 104.9, 114.6, 122.2,
122.4, 126.6, 126.8, 127.7, 129.2, 129.4, 130.9, 132.7,
136.2, 136.6, 136.9, 141.0, 159.8, 164.9, 192.4 ppm; MS
(70 eV): m/z = 494 (M?), 345 (27), 123 (100).
4,4a,5,6,7,8,8a,9-Octahydro-N-(4-methylphenyl)-8-oxo-9-
phenyl[1,2,3]triazolo[5,1-b]quinazoline-3-carboxamide
(6b, C23H21N5O2)
Yield 1.80 g (45%); m.p.: 189–190 °C; 1H NMR
(200 MHz, DMSO-d6): d = 2.09 (m, 2H), 2.25 (s, 3H,
CH3), 2.31 (m, 2H), 2.82 (m, 2H), 6.60 (s, 1H, 7-H), 7.11
(d, 2H), 7.27 (m, 5H, Ar), 7.70 (d, 2H), 10.32 (s, 1H, NH),
10.50 (bs, 1H, NH) ppm; 13C NMR (100 MHz, DMSO-d6):
4,7-Dihydro-N6,7-bis(4-methoxyphenyl)-5-methyl-N3-
(2-methylphenyl)-[1,2,3]triazolo[1,5-a]pyrimidine-3,
6-dicarboxamide (5j, C29H28N6O4)
Yield 2.62 g (50%); m.p.: 220–221 °C; 1H NMR
(200 MHz, DMSO-d6): d = 2.24 (s, 3H, CH3), 2.26 (s,
3H, CH3), 3.67 (s, 3H, OCH3), 3.69 (s, 3H, OCH3), 6.79 (s,
123

Synthesis of highly substituted pyrimidines
779
12. Chebanov VA, Saraev VE, Desenko SM, Chernenko VN,
Knyazeva IV, Groth U, Glasnov T, Kappe CO (2008) J Org Chem
73:5110
13. Chebanov VA, Muravyova EA, Desenko SM, Musatov VI,
Knyazeva IV, Shishkina SV, Shishkin OV, Kappe CO (2006) J
Comb Chem 8:427
d = 20.5, 20.6, 26.3, 36.4, 56.8, 106.7, 120.4, 124.1, 127.1,
128.2, 128.7, 129.1, 132.7, 135.6, 136.2, 141.5, 152.3,
159.1, 193.7 ppm; MS (70 eV): m/z = 399(M?), 322 (38),
266 (56).
4,4a,5,6,7,8,8a,9-Octahydro-6,6-dimethyl-N-(4-
methylphenyl)-8-oxo-9-phenyl[1,2,3]triazolo[5,1-b]-
quinazoline-3-carboxamide (6c, C25H25N5O2)
14. Chebanov VA, Sakhno YI, Desenko SM, Shishkina SV, Musatov
VI, Shishkin OV, Knyazeva IV (2005) Synthesis 15:2597
15. Lipson VV, Desenko SM, Shishkina SV, Shirobokova MG,
Shishkin OV, Orlov VD (2003) Chem Heterocycl Compd
39:1041
16. Lipson VV, Desenko SM, Borodina VV, Shirobokova MG,
Musatov VI (2005) Russ J Org Chem 41:114
17. Lipson VV, Desenko SM, Shirobokova MG, Borodina VV (2003)
Chem Heterocycl Compd 39:1213
Yield 2.78 g (65%); m.p.: 179–180 °C; 1H NMR
(200 MHz, DMSO-d6): d = 0.93 (s, 3H, CH3), 1.03 (s,
3H, CH3), 2.04 (s, 3H, CH3), 2.25 (q, 2H, CH2), 2.72 (q,
2H, CH2), 6.59 (s, 1H, 7-H), 7.11 (d, 2H), 7.26 (m, 5H, Ar),
7.70 (d, 2H), 10.34 (s, 1H, NH), 10.42 (s, 1H, NH) ppm;
13C NMR (100 MHz, DMSO-d6): d = 20.5, 20.6, 26.3,
36.4, 56.8, 106.7, 120.4, 124.1, 127.1, 128.2, 128.7, 129.1,
132.7, 135.6, 136.2, 141.5, 152.3, 159.1, 193.7 ppm; MS
(70 eV): m/z = 427 (M?), 322 (41), 294 (50).
18. Okabe FT, Bhooshan B, Novinson T, Hillyard IW, Garner GE,
Robins RK (1983) J Heterocycl Chem 20:735
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21. Desenko SM, Gladkov ES, Shishkina SV, Shishkin OV,
Komykhov SA, Orlov VD, Meier H (2006) J Heterocycl Chem
43:1563
22. Biagi G, Giorgi I, Livi O, Scartoni V, Lucacchini A (1989)
Farmaco 44:843
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