9-Aryl-5,6,7,9-tetrahydrotetrazolo[5,1-b]quinazolin-8(4H)-ones

Full text of DOI:10.1134/S1070363215080332

ISSN 1070-3632, Russian Journal of General Chemistry, 2015, Vol. 85, No. 8, pp. 1984–1986. © Pleiades Publishing, Ltd., 2015.
Original Russian Text © V.L. Gein, M.I. Kazantseva, T.M. Zamaraeva, L.F. Gein, P.A. Slepukhin, 2015, published in Zhurnal Obshchei Khimii, 2015,
Vol. 85, No. 8, pp. 1397–1399.
LETTERS
TO THE EDITOR
Synthesis of
9-Aryl-5,6,7,9-tetrahydrotetrazolo[5,1-b]quinazolin-8(4H)-ones
V. L. Geina, M. I. Kazantsevab, T. M. Zamaraevaa, L. F. Geinb, and P. A. Slepukhinc
a Perm State Pharmaceutical Academy of the Ministry of Health of the Russian Federation,
ul. Polevaya 2, Perm, 614990 Russia
e-mail: geinvl48@mail.ru
b Perm State Medical University, Perm, Russia
c Postovskii Institute of Organic Synthesis, Ural Branch, Russian Academy of Sciences, Yekaterinburg, Russia
Received April 2, 2015
Keywords: three-component reaction, 1,3-cyclohexanedione, dimedone, aromatic aldehyde, 5-aminotetrazole
monohydrate, 9-aryl-5,6,7,9-tetrahydrotetrazolo[5,1-b]quinazolin-8(4H)-one
DOI: 10.1134/S1070363215080332
It has been earlier found that the reaction of keto
acids esters with a mixture of an aromatic aldehyde
and 5-aminotetrazole leads to the formation of fused
heterocyclic systems [1]. Reaction of methyl esters of
acylpyruvic acids with 5-aminotetrazole in the
presence of an aromatic aldehyde has yielded 5-aryl-6-
acyl-7-methoxycarbonyl-5,8-dihydrotetrazolo[1,5-а]-
pyrimidines [2]. The reaction with 3-amino-1,2,4-
triazole proceeds similarly to give 4-aryl-3-benzoyl-2-
methoxycarbonyl-1,4-dihydropyrimidino[1,2-d]tetra-
zoles [3]. It has been found that the fusion of various
acetylacetates with a mixture of aromatic aldehyde and
5-aminotetrazole affords dihydrotetrazolo[1,5-a]
pyrimidine derivatives [4], being the only reaction
product when using N-substituted amides of acetyl-
acetic acid as the dicarbonyl compound [5]. 5-Amino-
tetrazole is known to be a part of certain drugs such as
korazol, cefazolin, and cefoperazonum [6].
Aiming to synthesize new heterocyclic compounds
with potential biological activity containing 5-
aminotetrazole fragment, we used 1,3-cyclohexane-
dione and dimedone as the dicarbonyl components
instead of esters of acetylacetic and acylpyruvic acids.
Reaction of equimolar amounts of 1,3-cyclohexane-
dione or dimedone, an aromatic aldehyde, and 5-amino-
tetrazole monohydrate in bulk at 160–170°C during
10–12 min gave 9-aryl-5,6,7,9-tetrahydrotetrazolo[5,1-b]-
quinazolin-8(4H)-ones I–IV and 9-aryl-6,6-dimethyl-
5,6,7,9-tetrahydrotetrazolo[5,1-b]quinazolin-8(4Н)-
ones V–VIII (Scheme 1).
The resulting compounds I–VIII were pale-yellow
crystalline solids, soluble in ethanol, and insoluble in
water.
IR spectra of compounds I–VIII contained absorp-
tion bands assigned to stretching of the C=C (1580–
Scheme 1.
R1
R1
H
O
R1
R1
NH2
N
O
NH
+
HN
+
N N
O
O
N
N
I_VIII
R2
N
N
R2
R1 = Н, R2 = Н (I), 4-Сl (II), 4-MеО (III), 4-NO2 (IV); R1= Ме, R2= H (V), 4-Сl (VI), 4-ОMе (VII), 4-NO2 (VIII).
1984

SYNTHESIS OF 9-ARYL-5,6,7,9-TETRAHYDROTETRAZOLO[5,1-b]QUINAZOLIN-8(4H)-ONES
1985
1588 cm–1), C=O (1641–1654 cm–1), and N–H bonds
(3251–3290 cm–1).
1H NMR spectra of compounds V–VIII contained
the signals of aromatic fragments and related groups
along with the following characteristic signals: two
singlets of two methyl groups in position 6 at 0.80–
0.83 and 1.02–1.04 ppm, four doublets of the protons
H5 and H7 at 1.87–1.90, 2.04–2.06, 2.20–2.23, and
2.35–2.37 ppm, the signal of the H9 proton at 6.39–
6.65 ppm, and the signal of NH group at 11.40–
11.89 ppm. The spectra of compounds I–IV contained
multiplets of the methylene protons in position 6
(1.70–1.78 ppm) and of protons at positions 5 (1.83–
1.92 ppm) and 7 (2.11–2.25 ppm).
To determine the spatial structure of the obtained
compounds, we performed X-ray diffraction analysis
General view of the molecule of compound I.
of crystal of compound I grown via slow crystal-
lization from dioxane (see figure). The results were
9-(4-Chlorophenyl)-5,6,7,9-tetrahydrotetrazolo-
[5,1-b]quinazolin-8(4Н)-one (II). Yield 2.9 g (68%),
mp 245–247°C (EtOH). IR spectrum, ν, cm–1: 1584
fully consistent with the proposed structure. According
to the XRD analysis, compound I crystallized as a
1 : 1 solvate with 1,4-dioxane. Most of the bond
lengths and bond angles were close to the normal
values. The deviations were as follows. The formal
single bond C3–C4 was shortened to 1.461 Å due to the
effect of conjugation in the vinyl ketone moiety and
the expected alignment of the bond lengths of the
tetrazole ring. Cyclohexene ring had a sofa confor-
mation, and C6 atom was out of the ring plane. The
molecules formed dimers in the crystal, due to the
paired intermolecular hydrogen bonding NH···N
between NH group of the pyrimidine moiety and the
N4 atom of the tetrazole ring.
1
(С=С), 1646 (С=О), 3288 (N–Н). Н NMR spectrum,
δ, ppm: 1.73–1.76 m (2Н, С6Н2), 1.85–1.92 m (2Н,
С5Н2), 2.11–2.25 m (2Н, С7Н2), 6.54 s (1Н, С9Н), 7.10
s (4H, C6H4Cl), 11.60 s (1Н, NH). Found, %: С 55.57;
H 4.32; N 23.43. С14Н12ClN5О. Calculated, %: С
55.73; H 4.01; N 23.21. М 301.74.
9-(4-Methoxyphenyl)-5,6,7,9-tetrahydrotetrazolo-
[5,1-b]quinazolin-8(4Н)-one (III). Yield 2.4 g (64%),
mp 215–218°C (EtOH). IR spectrum, ν, cm–1: 1586
1
(С=С), 1641 (С=О), 3290 (N–Н). Н NMR spectrum,
δ, ppm (J, Hz): 1.70–1.74 m (2Н, С6Н2), 1.83–1.92 m
(2Н, С5Н2), 2.15–2.25 m (2Н, С7Н2), 3.65 s (3Н,
C6H4ОСН3), 6.43 s (1Н, С9Н), 6.65 d and 7.00 d (4H,
C6H4ОСН3, J 8.4), 11.50 s (1Н, NH). Found, %: С
60.37; H 4.92; N 23.78. С15Н15N5О2. Calculated, %: С
60.60; H 5.09; N 23.55. М 297.32.
9-Phenyl-5,6,7,9-tetrahydrotetrazolo[5,1-b]quino-
zolin-8(4H)-one (I) (general procedure). A mixture of
1.12 g (0.01 mol) of 1,3-cyclohexanedione, 1.06 mL
(0.01 mol) of benzaldehyde, and 1.03 g (0.01 mol) of
5-aminotetrazole monohydrate was incubated during
10–12 min at 160–170°C until the evolution of water
vapor ceased, and the reaction mixture solidified. After
cooling, the residue was treated with ethanol; the
resulting crystals were filtered off and dried. Yield
2.2 g (62%), mp 234–236°C (EtOH). IR spectrum, ν,
cm–1: 1580 (С=С), 1648 (С=О), 3280 (N–Н). 1Н NMR
spectrum, δ, ppm: 1.70–1.76 m (2Н, С6Н2), 1.85–1.92
m (2Н, С5Н2), 2.15–2.25 m (2Н, С7Н2), 6.46 s (1Н,
С9Н), 7.03–7.30 m (5H, C6H5), 11.40 s (1Н, NH).
Found, %: С 62.77; H 4.62; N 26.49. С14Н13N5О.
Calculated, %: С 62.91; H 4.90; N 26.20. М 267.29.
9-(4-Nitrophenyl)-5,6,7,9-tetrahydrotetrazolo-
[5,1-b]quinazolin-8(4Н)-one (IV). Yield 3.2 g (73%),
mp 233–235°C (EtOH). IR spectrum, ν, см–1: 1580
1
(С=С), 1648 (С=О), 3280 (N–Н). Н NMR spectrum,
δ, ppm (J, Hz): 1.73–1.78 m (2Н, С6Н2), 1.83–1.92 m
(2Н, С5Н2), 2.15–2.25 m (2Н, С7Н2), 6.68 s (1Н, С9Н),
7.73 d and 8.08 d (4H, C6H4NО2, J 9.3), 11.34 s (1Н,
NH). Found, %: С 53.97; H 3.92; N 26.88.
С14Н12N6О3. Calculated, %: С 53.85; H 3.87; N 26.97.
М 312.30.
9-Phenyl-6,6-dimethyl-5,6,7,9-tetrahydrotetrazolo-
[5,1-b]quinazolin-8(4Н)-one (V). Yield 2.78 g (68%),
Compounds II–VIII were obtained similarly.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 85 No. 8 2015

1986
GEIN et al.
mp 196–198°C (EtOH). IR spectrum, ν, cm–1: 1588
(С=С), 1652 (С=О), 3256 (N–Н). Н NMR spectrum,
analysis was performed with a Perkin Elmer 2400
instrument. Melting points were determined using an
M-565 apparatus. X-Ray diffraction analysis was
performed with an automated four-circle diffracto-
meter Xcalibur S via the standard procedure [MoKα
radiation, 295(2) K, ω/2θ-scanning with step of 1°].
Solution and refinement of the structure was carried
out using SHELXTL software package [7]. Main crys-
tallographic parameters were as follows: triclinic
crystal system, space group P-1, a = 6.1005(8), b =
11.2632(17), c = 12.595(3) Å, α = 107.36(2)°, β =
103.928(17)°, γ = 101.369(12)°, μ = 0.093 mm–1. 5967
reflections were collected over the range of reflection
angles of 3.11° < θ < 28.28°, 3605 of them being
independent (Rint 0.0235), including 1531 with I > 2σ(I),
GooF 1.004, R1 0.1085, wR2 0.0576 (for all reflec-
tions), Δρē = 0.212/–0.188 e/Å–3.
1
δ, ppm (J, Hz): 0.80 s and 1.02 s (6Н, СН3), 1.90 d
5
5
(1Н, НА , J 16.1), 2.06 d (1Н, НВ , J 16.1), 2.23 d (1Н,
7
7
НА , J 16.0), 2.37 d (1Н, НВ , J 16.1), 6.64 s (1Н,
С9Н), 6.85–7.23 m (5H, C6H5), 11.46 s (1Н, NH).
Found, %: С 65.28; H 5.52; N 23.85. С16Н17N5O.
Calculated, %: С 65.07; H 5.80; N 23.71. М 295. 34.
9-(4-Chlorophenyl)-6,6-dimethyl-5,6,7,9-tetrahyd-
rotetrazolo[5,1-b]quinazolin-8(4Н)-one (VI). Yield
3.28 g (74%), mp 193–195°C (EtOH). IR spectrum, ν,
cm–1: 1581 (С=С), 1650 (С=О), 3258 (N–Н). 1Н NMR
spectrum, δ, ppm (J, Hz): 0.83 s and 1.02 s (6Н, СН3),
5
5
1.87 d (1Н, НА , J 16.1), 2.06 d (1Н, НВ , J 16.1), 2.20
7
7
d (1Н, НА , J 16.0), 2.37 d (1Н, НВ , J 16.1), 6.56 s
(1Н, С9Н), 6.90 d and 7.21 d (4H, C6H4Cl, J 7.5),
11.67 s (1Н, NH). Found, %: С 58.48; H 4.62; N
21.15. С16Н16ClN5O. Calculated, %: С 58.27; H 4.89;
N 21.23. М 329.79.
The XRD data were deposited in the Cambridge
Structural Database (CCDC 1,410,335).
9-(4-Methoxyphenyl)-6,6-dimethyl-5,6,7,9-tetra-
hydrotetrazolo[5,1-b]quinazolin-8(4Н)-one (VII).
Yield 3.32 g (76%), mp 183–185°C (EtOH). IR spec-
trum, ν, cm–1: 1585 (С=С), 1654 (С=О), 3251 (N–Н).
1Н NMR spectrum, δ, ppm (J, Hz): 0.82 s and 1.02 s
ACKNOWLEDGMENTS
This work was financially supported by the Russian
Science Foundation (project no. 15-13-10029).
5
5
REFERENCES
(6Н, СН3), 1.87 d (1Н, НА , J 16.1), 2.06 d (1Н, НВ , J
7
7
16.1), 2.20 d (1Н, НА , J 16.0), 2.35 d (1Н, НВ , J
16.1), 3.65 s (3Н, C6H4ОСН3), 6.39 s (1Н, С9Н), 6.77
d and 7.08 d (4H, C6H4ОСН3, J 8.5), 11.46 s (1Н, NH).
Found, %: С 62.57; H 5.62; N 21.75. С17Н19N5O2.
Calculated, %: С 62.76; H 5.89; N 21.52. М 325.37.
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9-(4-Nitrophenyl)-6,6-dimethyl-5,6,7,9-tetrahyd-
rotetrazolo[5,1-b]quinazolin-8(4Н)-one (VIII). Yield
3.6 g (79%), mp 180–182°C (EtOH). IR spectrum, ν,
cm–1: 1588 (С=С), 1654 (С=О), 3256 (N–Н). 1Н NMR
spectrum, δ, ppm (J, Hz): 0.80 s and 1.02 s (6Н, СН3),
5
5
1.87 d (1Н, НА , J 16.1), 2.06 d (1Н, НВ , J 16.1), 2.20
7
7
d (1Н, НА , J 16.0), 2.35 d (1Н, НВ , J 16.1), 6.65 s
(1Н, С9Н), 7.85 m and 8.23 m (4H, C6H4NО2), 11.89 s
(1Н, NH). Found, %: С 56.67; H 4.53; N 24.85.
С16Н16N6O3. Calculated, %: С 56.47; H 4.74; N 24.69.
М 340.35.
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dovskaya, E.B., Nosova, N.V., and Vakhrin, M.I., Russ.
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RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 85 No. 8 2015