One-Pot Synthesis of Isomeric Cycloalkatriazolopyrimidines

Article abstract of DOI:10.1134/S107042801503015X

Three-component condensation of 4H-1,2,4-triazol-3-amine with furfural (benzaldehyde) and cycloalkanone gave [1,2,4]triazolo[1,5-a]pyrimidine derivatives with a C₆-C₈ cycloalkene ring fused at the C⁵-C⁶ bond as mixtures of two isomers differing by the position of the double bond in the cycloalkene ring. The double bond in the major isomers is common to the cycloalkene and tetrahydropyrimidine rings, while the minor isomers have the C^4a=C⁵ double bond. The isomers were isolated in the pure state, and their structure was determined on the basis of spectral data.

Full text of DOI:10.1134/S107042801503015X

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2015, Vol. 51, No. 3, pp. 378–381. © Pleiades Publishing, Ltd., 2015.
Original Russian Text © A.A. Matveeva, A.A. Matikenova, A.A. Anis’kov, A.P. Kriven’ko, 2015, published in Zhurnal Organicheskoi Khimii, 2015, Vol. 51,
No. 3, pp. 394–396.
One-Pot Synthesis of Isomeric Cycloalkatriazolopyrimidines
A. A. Matveeva, A. A. Matikenova, A. A. Anis’kov, and A. P. Kriven’ko
Chernyshevskii Saratov State University, ul. Astrakhanskaya 83-1, Saratov, 410012 Russia
e-mail: annamatveeva2008@yandex.ru
Received July 8, 2014
Abstract—Three-component condensation of 4H-1,2,4-triazol-3-amine with furfural (benzaldehyde) and
6 8
cycloalkanone gave [1,2,4]triazolo[1,5-a]pyrimidine derivatives with a C –C cycloalkene ring fused at
5
6
the C –C bond as mixtures of two isomers differing by the position of the double bond in the cycloalkene ring.
The double bond in the major isomers is common to the cycloalkene and tetrahydropyrimidine rings, while
4
a
5
the minor isomers have the C =C double bond. The isomers were isolated in the pure state, and their structure
was determined on the basis of spectral data.
DOI: 10.1134/S107042801503015X
In recent years, multicomponent condensations
have been extensively used to synthesize partially
hydrogenated azolopyrimidines and azoloquinazolines,
and the potential of such reactions is far from being
exhausted [1]. Three-component cyclocondensations
could give rise to hitherto unknown azolocycloalka-
pyrimidines, including those possessing practically im-
portant properties [2].
ever, unlike the condensation with tetrazol-5-amine,
minor isomers 2a–2d were also formed (Scheme 1).
Compounds 1e and 2a were isolated in the pure
1
state, and their structure was determined by H and
1
3
1
13
1
13
C NMR spectra, including H– C HMQC, H– C
1
1
HSQC, H– H COSY, and 1D NOESY techniques. The
1
H NMR spectra of isomer mixtures 1/2 contained
singlets from NH protons (δ 5.37–9.97 ppm) and RCH
proton in the pyrimidine ring (1, δ 4.97–6.30 ppm);
these signals are also characteristic of structurally
similar tetrazole derivatives [3]. Isomers 2 were iden-
tified by the presence of a triplet at δ 6.01–6.65 ppm
due to 5-H and a doublet at δ 4.13–4.89 ppm due to
We previously found that three-component con-
densation of tetrazol-5-amine with an aromatic (hetero-
aromatic) aldehyde and cycloalkanone provides com-
pletely selective synthesis of 4,7-dihydrotetrazolo-
pyrimidines with a linearly fused C –C -carbocycle
6
8
9
(10,11)-H. Replacement of the tetrazole ring by tri-
[3, 4]. In the present article we report on analogous
azole leads to upfield shift of the RCH signal of
compounds 1 (δ 5.96–6.43 ppm in the spectra of
tetrazole analogs) and appearance of a signal at δ 7.52–
reaction with 4H-1,2,4-triazol-5-amine which is more
nucleophilic than tetrazol-5-amine. The reactions of
4
H-1,2,4-triazol-5-amine with equimolar amounts of
7
.65 ppm due to 2-H.
benzaldehyde (furfural) and C –C -cycloalkanone on
6
8
heating at the boiling point led to the formation of
phenyl(furyl)-substituted linearly fused cycloalkatri-
azolopyrimidines 1a–1e as the major products. How-
The position of the C=C double bond in isomers 2
was determined using H– H COSY and 1D NOESY
data for a mixture of 10-phenyl-5,6,7,8,9,10-hexahy-
1
1
Scheme 1.
R
R
N
N
O
N
N
N
Δ
N
N
+
RCHO
+
+
NH2
( )n
( )n
( )n
N
N
H
N
H
N
H
1
a–1e
2a–2d
n = 1, R = Ph (a); n = 2, R = Ph (b), 2-furyl (c); n = 3, R = Ph (d), 2-furyl (e).
3
78

ONE-POT SYNTHESIS OF ISOMERIC CYCLOALKATRIAZOLOPYRIMIDINES
379
dro-4H- and 10-phenyl-6,7,8,9,9a,10-4H-cyclohepta-
d][1,2,4]triazolo[1,5-a]pyrimidines 1b and 2b. The
COSY spectrum revealed spin–spin coupling between
0-H (δ 4.15 ppm) and 9a-H (δ 2.81 ppm). In the
NOESY spectrum of 2b, nuclear Overhauser effects
were observed on the ortho-protons of the benzene9
ring (δ 7.37 ppm) and methylene protons on C
(δ 37.3 ppm) for compound 2c; while isomer 1c
C
[
showed coupling between 11-H (δ 5.79 ppm) and
3
11
sp -C (δ 63.1 ppm).
C
1
9
-Phenyl-4,6,7,8,8a,9-hexahydro[1,2,4]triazolo-
5,1-b]quinazoline (2a) was isolated by slow crystal-
lization of isomer mixture 1a/2a from a saturated
[
1
13
solution in DMF–i-PrOH (1:1). The H– C HMQC
spectrum of 2a showed correlations between 5-H
(δ 1.60 ppm) upon selective saturation of the 10-H
signal (see below).
2
5
(
9
δ 6.12ppm) and sp -C (δ 109.0 ppm) and between
C
9
3
-H (δ 4.15 ppm) and sp -C (62.0 ppm). No couplings
were observed for the NH proton, and methylene
protons in the cyclohexene ring displayed correlations
3
with the corresponding sp -carbon signals located in
the upfield region.
H
N
H
H
H
11-(2-Furyl)-4,5,6,7,8,9,10,11-octahydrocycloocta-
[d][1,2,4]triazolo[1,5-a]pyrimidine (1e) was isolated as
well-shaped crystals from a solution in DMF–i-PrOH,
and its structure was unambiguously determined by
X-ray analysis. The complete set of crystallographic
data for compound 1e was deposited to the Cambridge
Crystallographic Data Centre (entry no. 843484).
N
H
N
N
H
2
b
1
13
The H– C HSQC spectrum of isomer mixture
1
c/2c displayed correlations between 5-H (δ 6.01 ppm)
Presumably, compounds 1 and 2 are formed accord-
ing to the general scheme proposed previously for
tetrazole derivatives via initial formation of Schiff base
and subsequent addition of cycloalkanone [5]. Isomers
2
5
and sp -hybridized C carbon atom (δ 109.2 ppm),
between 11-H (δ 4.75 ppm) and sp -C (δ 56.8 ppm),
and between 10a-H (δ 3.19 ppm) and sp -C
C
3
11
C
3
10a
Scheme 2.
O
–O
N
HO
N
(
)n
O
·
·
( )n
( )n
N
N
N
N
( )n
N
N
N
N
N
RCHO
Z
Z
Z
Z
Z
NH2 –H O
N
N
H
R
2
N
H
N
N
H
N
H
N
R
N
R
H
H
H
R
A
R
H
H
(
)n
( )n
( )n
N
Z
··
N
N
N
N
N
N
N
N
N
Z
Z
(
)n
·
·
N
N
Z
N
R
N
R
N
R
N
H
H
1
–
H O
2
R
H
H
(
)n
( )n
( )n
N
Z
··
N
N
N
N
N
N
N
N
Z
Z
(
)n
·
·
N
N
Z
N
N
R
N
R
N
R
N
H
H
2
Z = CH, N.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 51 No. 3 2015

3
80
MATVEEVA et al.
2
with different position of the double C=C bond
Yield 40%, mp 225–227°C (from DMF–i-PrOH).
H NMR spectrum, δ, ppm: 1.19–2.68 m (6H, 6-H,
4
a
5
1
(
C =C ) are likely to result from dehydration of inter-
9
mediate A with proton elimination from C (rather than
C ), which is favored by higher basicity of aminotri-
azole compared to aminotetrazole (Scheme 2).
7-H, 8-H), 4.15 d (1H, 9-H, J = 10.8 Hz), 5.32 s (1H,
NH), 6.12 t (1H, 5-H, J = 2.2 Hz), 7.26–7.39 m (5H,
5
a
1
13
Ph), 7.51 s (1H, 2-H). H– C HMQC spectrum, δ/δ ,
C
5
9
ppm: 4.15/62.0 (9-H/C ), 6.12/109.0 (5-H/C ),
.51/131.5 (2-H/C ). Found, %: C 71.25; H 6.22;
Thus, unlike tetrazol-5-amine, the three-component
condensation of 4H-1,2,4-triazol-5-amine with aromat-
ic aldehyde is not selective, and it leads to the forma-
tion of isomeric cycloalkatriazolopyrimidine deriva-
tives differing by the position of the double bond in the
cycloalkapyrimidine fragment.
2
7
N 21.10. C H N . Calculated, %: C 71.40; H 6.39;
1
5
16
4
N 22.21.
10-Phenyl-5,6,7,8,9,10-hexahydro-4H-cyclohepta-
[d][1,2,4]triazolo[1,5-a]pyrimidine (1b) and 10-phe-
nyl-6,7,8,9,9a,10-4H-cyclohepta[d][1,2,4]triazolo-
EXPERIMENTAL
[1,5-a]pyrimidine (2b) (mixture of isomers). Yield
1
4
1
9
0%, mp 205–207°C. H NMR spectrum, δ, ppm:
1
13
1
13
.18–2.67 m (10H, CH ), 4.13 d (1H, 10-H in 2b, J =
The H and C NMR spectra (including H– C
2
1
13
1
1
.2 Hz), 4.97 s (1H, 10-H in 1b), 6.14 t (1H, 5-H in 2b,
HMQC, H– C HSQC, H– H COSY, and 1D NOESY
experiments) were recorded on a Varian 400 spectrom-
eter at 400 and 100 MHz, respectively, from solutions
in CDCl or DMSO-d (1d, 2d) using tetramethylsilane
J = 5.2 Hz), 7.47–7.24 m (5H, C H ), 7.65 s (1H, 2-H),
6
5
1
3
8
3
.59 s (1H, NH). C NMR spectrum, δ , ppm: 24.8–
1.8 (C in 1b, C , C , C , C ), 42.4 (C in 2b), 59.7
C
5
6
7
8
9
9a
3
6
1
0
a
10
5
(
C
in 1b), 60.0 (C in 2b), 111.8 (C in 2b), 118.0
as internal reference. The mixing time in NOESY
experiments was set at 0.5 s. The progress of reactions
and the purity of products were monitored by TLC on
Silufol UV-254 plates using hexane–ethyl acetate–
chloroform (2:2:1) as eluent; development with iodine
vapor. The melting points were measured in open
capillaries. The elemental analyses were obtained on
a Vario MICROcube CHNS analyzer.
9
4a
(
C
in 1b), 127.3–135.7 (C H ), 141.5 (C in 1b),
6 5
3
a
2
4a
1
1
1
49.0 (C ), 150.3 (C ), 153.2 (C in 2b). H– H
COSY spectrum, δ/δ, ppm: 10-H/9a-H 4.15/2.81,
5
1
-H/6-H 6.14/2.25. NOESY spectrum, δ/δ, ppm:
0-H/o-H 4.15/7.37, 10-H/9-H 4.15/1.60. Found, %:
C 72.45; H 6.93; N 21.31. C H N . Calculated, %:
1
6
18
4
C 72.15; H 6.81; N 21.04.
1-Phenyl-4,5,6,7,8,9,10,11-octahydrocycloocta-
d][1,2,4]triazolo[1,5-a]pyrimidine (1c) and 11-phe-
1
Compounds 1 and 2 (general procedure). A mix-
ture of equimolar amounts (5.88 mmol) of 4H-1,2,4-
triazol-5-amine, benzaldehyde or furfural, and cycloal-
kanone was heated for 40–50 min under reflux (TLC).
After cooling, the colorless crystals were washed with
propan-2-ol and dried in air.
[
nyl-4,6,7,8,9,10,10a,11-octahydrocycloocta[d][1,2,4]-
triazolo[1,5-a]pyrimidine (2c) (mixture of isomers).
1
Yield 49%, mp 250–252°C. H NMR spectrum, δ,
ppm: 0.18–3.29 m (12H, CH ), 4.75 d (1H, 11-H in 2c,
2
J = 9.4 Hz), 5.79 s (1H, 11-H in 1c), 6.01 t (1H, 5-H in
9
-Phenyl-4,5,6,7,8,9-hexahydro[1,2,4]triazolo-
5,1-b]-quinazoline (1a) and 9-phenyl-4,6,7,8,8a,9-
hexahydro[1,2,4]triazolo[5,1-b]quinazoline (2a)
mixture of isomers). Yield 40%, mp 195–200°C
decomp.). H NMR spectrum, δ, ppm: 1.22–2.67 m
8H, 5-H, 6-H, 7-H, 8-H), 4.15 d (1H, 9-H in 2a, J =
0.8 Hz), 5.50 s (1H, NH in 2a), 5.67 s (1H, 9-H in
a), 6.11 t (1H, 5-H in 2a, J = 2.2 Hz), 7.26–7.39 m
2
2
2
2
1
c, J = 8.4 Hz), 7.13–7.48 m (5H, C H ), 7.54 s (1H,
6 5
1
3
[
-H), 9.36 s (1H, NH). C NMR spectrum, δ , ppm:
C
5
6
7
8
9
10
10a
4.9–30.4 (C in 1c, C , C , C , C , C ), 37.3 (C in
c), 56.8 (C in 2c), 63.1 (C in 1c), 104.1 (C in
c), 109.2 (C in 2c), 127.4–139.2 (C H ), 142.2 (C
11
11
10a
(
(
(
1
1
1
5
4a
6
5
2
3a
4a
in 1c), 149.6 (C ), 150.4 (C ), 153.1 (C in 2c).
1
13
10a
H– C HSQC spectrum, δ/δ , ppm: 10a-H/C
C
1
1
11
3
.19/37.3, 11-H/C 4.75/56.8, 11-H/C 5.79/63.1,
5
(
%
5H, C H ), 7.51 s (1H, 2-H). 9.04 s (1H, 1a). Found,
6 5
5-H/C 6.01/109.2. Found, %: C 72.95; H 7.49;
N 20.40. C H N . Calculated, %: C 72.83; H 7.19;
: C 70.95; H 6.63; N 21.95. C H N . Calculated, %:
15 16 4
1
7
20
4
C 71.40; H 6.39; N 22.21.
N 19.98.
Compound 2a. A saturated solution of 0.50 g
5.00 mmol) of mixture 1a/2a in 2 mL of DMF–pro-
pan-2-ol (1:1) was heated for 2 min under reflux. The
solution was slowly cooled, and the crystals were
filtered off, washed with propan-2-ol, and dried in air.
10-(2-Furyl)-5,6,7,8,9,10-hexahydro-4H-cyclo-
hepta[d][1,2,4]triazolo[1,5-a]pyrimidine (1d) and
10-(2-furyl)-6,7,8,9,9a,10-4H-cyclohepta[d][1,2,4]tri-
azolo[1,5-a]pyrimidine (2d) (mixture of isomers).
(
1
H NMR spectrum, δ, ppm: 1.29–2.48 m (10H, CH2),
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 51 No. 3 2015

ONE-POT SYNTHESIS OF ISOMERIC CYCLOALKATRIAZOLOPYRIMIDINES
.90 d (1H, 10-H in 2d, J = 10.8 Hz), 6.30 s (1H, 10-H
REFERENCES
381
4
in 1d), 6.42 t (1H, 5-H in 2d, J = 1.6 Hz), 6.64 d.d
1
2
. Chebanov, V.A. and Desenko, S.M., Chem. Heterocycl.
Compd., 2012, vol. 48, no. 4, p. 566.
(
1H, 3′-H, J = 3.6, 2.0 Hz), 7.21 d (1H, 4′-H, J =
3
2
.2 Hz), 7.59 d (1H, 5′-H, J = 3.6 Hz), 7.62 s (1H,
-H), 9.97 s (1H, NH). Found, %: C 65.34; H 6.15;
. Lipson, V.V., Svetlichnaya, N.V., Borodina, V.V.,
Shirobokova, M.G., Shishkina, S.V., Shishkin, O.V., and
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p. 1388.
N 21.52. C H N O. Calculated, %: C 65.61; H 6.29;
14
16
4
N 21.86.
1-(2-Furyl)-4,5,6,7,8,9,10,11-octahydrocyclo-
octa[d][1,2,4]triazolo[1,5-a]pyrimidine (1e). Yield
1
3
. Matveeva, A.A., Poplevina, N.V., Borisova, N.O., and
Kriven’ko, A.P., Chem. Heterocycl. Compd., 2013,
vol. 48, no. 12, p. 1877.
1
7
1
0%, mp 221–223°C. H NMR spectrum, δ, ppm:
.09–2.47 m (12H, CH ), 5.90 s (1H, 11-H), 6.32 d.d
2
4. Matveeva, A.A., Reshetov, P.V., and Kriven’ko, A.P.,
(
1H, 3′-H, J = 2.0, 3.2 Hz), 6.39 d (1H, 4′-H, J =
J. Struct. Chem., 2013, vol. 54, no. 3, p. 642.
3
9
.2 Hz), 7.34–7.36 m (1H, 5′-H), 7.52 s (1H, 2-H),
.16 s (1H, NH). Found, %: C 66.35; H 6.12; N 20.14.
5
. Matveeva, A.A., Borisova, M.Yu., Boiko, V.S., and
Kriven’ko, A.P., Izv. Sarat. Univ. Nov. Ser. Ser. Khim.
Biol. Ekol., 2013, vol. 13, no. 4, p. 24.
C H N O. Calculated, %: C 66.64; H 6.71; N 20.73.
1
5
18
4
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 51 No. 3 2015