First example of reaction of asymmetric dienone derivatives of cyclohexane with 3-amino- 1,2,4-triazole. Formation of isomeric ctahydrotriazoloquinazolines

Full text of DOI:10.1007/s10593-009-0376-6

Chemistry of Heterocyclic Compounds, Vol. 45, No. 8, 2009
FIRST EXAMPLE OF REACTION OF
ASYMMETRIC DIENONE DERIVATIVES
OF CYCLOHEXANE WITH 3-AMINO-
1,2,4-TRIAZOLE. FORMATION OF ISOMERIC
OCTAHYDROTRIAZOLOQUINAZOLINES
I. E. Varshalomidze1*, A. G. Golikov1, and A. P. Krivenko1
Keywords: 3-amino-1,2,4-triazole, isomeric octahydrotriazoloquinazolines, cross-conjugated dienone
derivatives of cyclohexane.
The cyclocondensation of cross-conjugated dienone derivatives of cycloalkanes is commonly used for
constructing condensed nitrogen heterocyclic systems [1]. One example is the preparation of dihydro-1,2,4-
triazolo-[1,5-a]pyrimidines fused with carbocycles by the cyclocondensation of dibenzylidenecycloalkanones
(dienones) with 3-amino-1,2,4-triazole [2]. Such dienones with asymmetric structure have not yet been studied
in this reaction and their use requires knowledge of the regioselectivity of the azacyclization. We were the first
to study the reaction of dienic derivative of cyclohexanone 1 containing benzene and thiophene rings in its
peripheral substituents with 3-amino-1,2,4-triazole. The reaction was carried out by heating equimolar amounts
1
of the reagents in DMF. H and 13C NMR spectroscopy, HSQC, and NOESY were used to establish the
formation of previously unreported octahydrotriazoloquinazolines with linear (2a, 2a') and angular (2b, 2b')
1
ring fusion and different positioning of the substituents. The H NMR spectrum of the isomer mixture shows
four NH proton singlets, two strong H-4 proton singlets (2a, 2a'), and two less intense H-8 proton singlets (2b,
2b').
The reaction of symmetrical dienones with 3-amino-1,2,4-triazole was carried out to assign the signals in
this spectrum: 2,6-dibenzylidenecyclohexanone (3) described by Desenko et al. [2] and previously unreported
1
2,6-dithienylidenecyclohexanone (4). The H NMR spectrum of the products with cyclohexanone 3 showed a
relatively weak signal for the H-8 proton at 5.64 ppm of the angular b form for the first time in addition to the
strong signal for the H-4 proton at 5.79 ppm for the reported linear system, 8-benzylidene-4-phenyl-
3a,4,5,6,7,8,9,9a-octahydro[1,2,4]triazolo[3,4-b]quinazoline (5a).
Similar behavior was noted for thienyldienone 4 (H-4, 6.13 ppm; H-8, 5.60 ppm). The absence of an
interaction of the H-4 proton in 5a and the vinyl proton in 5b with a triazole ring proton in the NOESY spectra
indicated the position of the nitrogen atoms in the triazole ring in products 5.
_______
* To whom correspondence should be addressed, e-mail: vie21@mail.ru.
1N. G. Chernyshevskii Saratov State University, Saratov 410012, Russia.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 8, pp. 1269-1271, August, 2009.
Original article submitted June 9, 2009.
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0009-3122/09/4508-1014©2009 Springer Science+Business Media, Inc.

The formation of isomers may be attributed to initial nucleophilic attack of the NH2 group of the reagent
at the carbonyl carbon atom (regioisomers a, a') or the β-carbon and β'-carbon atoms of the substrates
(regioisomers b, b') with subsequent azacyclization.
Ar
Ar1
H
N
N
H
N
NH2
4
N
N
N
N
+
+
Ar1
Ar
Ar1
H
8
DMF
N
N
H
N
N
β1
β
H
O
Ar
1, 3, 4
2a, 5a, 6a
2b, 5b, 6b
Ar1
Ar
H
4
N
N
+
N
N
+
H
8
N
N
H
N
N
Ar
H
Ar1
2b'
2a'
1, 2a,b,a',b' Ar = 2-thienyl, Ar1 = Ph; 3, 5a,b Ar = Ar1 = Ph; 4, 6a,b Ar = Ar1 = 2-thienyl
Thus, we are the first to obtain spectral evidence for the formation of the angular b form in addition to
the major linear a form and establish the capacity of asymmetric dienone derivatives of cyclohexane to undergo
azacyclization through alternative pathways in their reaction with 3-amino-1,2,4-triazole.
1
13
The H and C NMR, HSQC, and NOESY spectra were obtained on a Varian-400 spectrometer at 400
1
13
and 100 MHz for the H and C NMR spectra, respectively, in CDCl3 with TMS as the internal standard. The
reaction course and purity of the products were followed by thin-layer chromatography on Silufol
UV-254 plates using 2:2:1 hexane–ethyl acetate–chloroform as the eluent.
8-Thienylidene-4-phenyl-3a,4,5,6,7,8,9,9a-octahydro[1,2,4]triazolo[3,4-b]quinazoline (2a), 8-Benzyl-
idene-4-thienyl-3a,4,5,6,7,8,9,9a-octahydro[1,2,4]triazolo[3,4-b]quinazoline
(2a'),
4-Thienylidene-
8-phenyl-3a,4,5,6,7,8,9,9a-octahydro[1,2,4]triazolo[3,4-b]quinazoline (2b), and 4-Benzylidene-4-thienyl-
3a,4,5,6,7,8,9,9a-octahydro[1,2,4]triazolo[3,4-b]quinazoline (2b'). A solution of 3-amino-1,2,4-triazole
(0.15 g, 2 mmol), 2-thienylidene-6-benzylidenecyclohexanone (1) (0.55 g, 2 mmol) in DMF (0.5 ml) was
heated at reflux for 2 h, cooled, distilled water added, filtered, and dried for 1 h at 125°C to give 0.48 g (69%)
product as light-yellow crystals; mp 232-234°C (DMF). 1H NMR spectrum, δ, ppm: 9.44, 9.54, 9.95, 10.02 (1H,
s, NH); 5.81, 6.13 (1H, s, H-4); 5.66, 5.86 (1H, s, H-8); 2.08-2.33 (2H, m, H-5); 1.64-2.04 (2H, m, H-6);
2.36-3.03 (2H, m, H-7); 7.51 (1H, s, H-2); 6.90-8.52 (8H, m, H Ar). Found, %: C 69.34; H 5.63; N 15.97.
C20H18N4S. Calculated, %: C 69.36; H 5.20; N 16.18.
8-Benzylidene-4-phenyl-3a,4,5,6,7,8,9,9a-octahydro[1,2,4]triazolo[3,4-b]quinazoline
(5a)
and
4-Benzylidene-8-phenyl-3a,4,5,6,7,8,9,9a-octahydro[1,2,4]triazolo[3,4-b]quinazoline (5b) were synthesized
1
analogously in 82% yield; mp 228-230°C (DMF) [2]. H NMR spectrum, δ, ppm: 9.39, 9.00 (1H, s, NH); 5.79
(1H, s, H-4); 5.64 (1H, s, H-8); 1.91-2.08 (2H, m, H-5); 1.59-1.74 (2H, m, H-6); 2.08-2.78 (2H, m, H-7); 7.41
(1H, s, H-2); 6.98-7.57 (10H, m, H Ar). Found, %: C 77.43; H 5.60; N 16.77. C22H20N4. Calculated, %: C 77.65;
H 5.88; N 16.47.
8-Thienylidene-4-thienyl-3a,4,5,6,7,8,9,9a-octahydro[1,2,4]triazolo[3,4-b]quinazoline (6a) and
4-Thienylidene-8-thienyl-3a,4,5,6,7,8,9,9a-octahydro[1,2,4]triazolo[3,4-b]quinazoline (6b) were synthesized
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analogously in 68% yield; mp 189-191°C. 1H NMR spectrum, δ, ppm: 9.51, 9.39 (1H, s, NH); 6.13 (1H, s, H-4);
5.60 (1H, s, H-8); 2.09-2.13 (2H, m, H-5); 1.78-1.98 (2H, m, H-6); 2.72-3.01 (2H, m, H-7); 7.50 (1H, s, H-2);
6.88-7.61 (6H, m, H Ar). 13C NMR spectrum, δ, ppm: 59.1 (C-4); 64.8 (C-8); 26.5 (C-5); 22.2 (C-6); 27.5 (C-7);
149.5 (C-2); 155.7 (C-9a); 135.8, 127.1, 128.9, 130.8, (C-2, C-3, C-4, C-5 thienylmethylene substituent); 139.8,
126.8, 127.0, 119.3 (C-2, C-3, C-4, C-5 thienyl substituent); 109.3 (C-4a); 148.9 (C-7a). HSQC spectrum,
ppm/ppm: 6.13/59.1 (H-4/C-4); 5.60/64.8 (H-8/C-8); 2.11/26.5 (H-5/C-5); 1.81/22.1, 1.94/22.1 (H-6/C-6);
2.75/27.5 (H-7/C-7); 7.50/149.5 (H/C-5 triazole ring). Found, %: C 64.22; H 5.44; N 15.52. C18H16N4S2.
Calculated, %: C 61.36; H 4.55; N 15.91.
REFERENCES
1.
2.
S. Z. Vatsadze, A. G. Golikov, A. P. Krivenko, and N. V. Zyk, Usp. Khim., 77, 707 (2008).
S. M. Desenko, J. Estrada, V. D. Orlov, and O. A. Ponamarev, Khim. Geterotsikl. Soedin., 105 (1991).
[Chem. Heterocycl. Comp., 27, 88 (1991)].
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