Synthesis of N-substituted 7-aryl-5-methyl-4,7-dihydrotetrazolo[1,5-a] pyrimidine-6-carboxamides

Article abstract of DOI:10.1134/S107042801203013X

Three-component reaction of N-methyl- or N,N-diethyl-3-oxobutanamide with aromatic aldehydes and tetrazol-5-amine monohydrate gave the corresponding N-substituted 7-aryl-5-methyl-4,7-dihydrotetrazolo- [1,5-a]pyrimidine-6- carboxamides. Pleiades Publishing, Ltd., 2012.

Full text of DOI:10.1134/S107042801203013X

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2012, Vol. 48, No. 3, pp. 419–422. © Pleiades Publishing, Ltd., 2012.
Original Russian Text © V.L. Gein, T.M. Zamaraeva, N.V. Nosova, M.I. Vakhrin, P.A. Slepukhin, 2012, published in Zhurnal Organicheskoi Khimii, 2012,
Vol. 48, No. 3, pp. 422–425.
Synthesis of N-Substituted 7-Aryl-5-methyl-4,7-dihydro-
tetrazolo[1,5-a]pyrimidine-6-carboxamides
V. L. Geina, T. M. Zamaraevaa, N. V. Nosovaa, M. I. Vakhrina, and P. A. Slepukhinb
a Perm State Pharmaceutical Academy, ul. Polevaya 2, Perm, 614990 Russia
e-mail: geinvl48@mail.ru
b Postovskii Institute of Organic Synthesis, Ural Division, Russian Academy of Sciences,
ul. S. Kovalevskoi 20, Yekaterinburg, 620219 Russia
Received April 2, 2011
Abstract—Three-component reaction of N-methyl- or N,N-diethyl-3-oxobutanamide with aromatic aldehydes
and tetrazol-5-amine monohydrate gave the corresponding N-substituted 7-aryl-5-methyl-4,7-dihydrotetrazolo-
[1,5-a]pyrimidine-6-carboxamides.
DOI: 10.1134/S107042801203013X
Extension of synthetic potential of known reactions
via the use of new functional reagents is one of the
most important lines in the development of organic
chemistry. An example of such reactions leading to the
formation of pyrimidine derivatives is the three-com-
ponent Biginelli reaction. It was originally proposed
for the synthesis of pyrimidinones from aromatic alde-
hydes, urea, and ethyl acetoacetate [1, 2]; at present,
this reaction is successfully used for the preparation of
various fused pyrimidines, in particular azolopyrimi-
dines [3–5].
amides and tetrazol-5-amine. Following the procedure
proposed in [6] we synthesized previously unknown
compounds Ia–Il (Scheme 1). Their yield depended on
the substituent nature in the initial aldehyde. Aromatic
aldehydes having an electron-withdrawing group in the
para-position reacted more readily. The reactions of
N-methyl-3-oxobuanamide with aromatic aldehydes
and tetrazole-5-amine (120–150°C, 5–10 min) gave
7-aryl-N,5-dimethyl-4,7-dihydrotetrazolo[1,5-a]pyrim-
idine-6-carboxamides Im–Io. The three-component
condensation with N-methyl-3-oxobutanamide ensured
higher yield of tetrazolopyrimidines as compared to
N,N-dimethyl(or diethyl)-3-oxobutanamide. Presum-
ably, the presence of two donor alkyl groups on the
nitrogen atom in the initial β-carbonyl compound
reduces its reactivity as CH acid.
We previously reported on the three-component
Biginelli reaction of N,N-dimethyl(diethyl)-3-oxo-
butanamide with formation of a fused heterocyclic
system, namely tetrazolopyrimidines containing a di-
alkylcarbamoyl group [6]. While continuing studies in
this field we made an attempt to synthesize new fused
heterocyclic systems by extending the series of aro-
matic aldehydes reacting with N,N-dialkyl-3-oxobutan-
Compounds Ia–Io were isolated as colorless crys-
talline substances which were soluble in chloroform,
DMF, and DMSO and insoluble in water. Their IR
Scheme 1.
O
Me
O
O
H2N
R1R2N
NH
R1
N
+
ArCHO
+
Me
N
HN
N
Ar
N
N
N
R2
N
N
Ia–Io
I, R1 = R2 = Et (a–l); R1 = Me, R2 = H (m–o); Ar = 4-EtC6H4 (a), 4-MeOC(O)C6H4 (b), 4-MeC6H4 (c), 4-FC6H4 (d), 3-MeOC6H4 (e),
pyridin-3-yl (f), 4-MeOC6H4 (g), 4-O2NC6H4 (h), 4-BrC6H4 (i), 3-O2NC6H4 (j), 2-MeOC6H4 (k, o), 2-O2NC6H4 (l), Ph (m),
4-HOC6H4 (n).
419

GEIN et al.
420
spectra contained absorption bands belonging to
stretching vibrations of the amide carbonyl group
(1660–1680 cm–1), NH groups (3150–3200 and 3420–
3440 cm–1), and C=C bonds (1600–1620 cm–1). Com-
pounds Ia–Io displayed in the 1H NMR spectra signals
from protons in the aromatic ring and substituent
attached thereto, as well as singlets from methyl group
(δ 1.75–1.92 ppm), 7-H (δ 6.26–6.66 ppm), and N4H
(10.30–10.68 ppm). In the spectra of N,N-diethyl
derivatives, signals from ethyl groups on the nitrogen
atom were observed at δ 0.75–0.91 (CH3) and 3.03–
3.15 ppm (CH2), and N-methyl amides Im–Io were
characterized by singlets from the NH and NCH3 pro-
tons at δ 9.40–9.50 and 3.40–3.50 ppm, respectively.
Molecule Ib is planar, and the bond lengths and bond
angles therein do not differ from the corresponding
standard values. The NH proton in the pyrimidine ring
is involved in intermolecular hydrogen bond with the
carbonyl oxygen atom in the neighboring molecule
[N5–H5 0.89(2), H5···O3 1.93(2), N5···O3 2.806(3) Å,
∠N5H5O3 171(2)°], symmetry transformation [x – 1/2,
y, –z + 3/2].
The X-ray diffraction data for compound Ib were
obtained from a 0.25×0.12×0.07-mm colorless needle-
shaped crystal on an Xcalibur-3 diffractometer with
a CCD detector [λ(MoKα) 0.71073 Å, graphite mono-
chromator, ω-scanning, scan step 1°, temperature
295(2) K]. The structure was solved by the direct
method and was refined using SHELXTL-97 software
package [7]. No correction for absorption was intro-
duced. The positions and temperature parameters of
non-hydrogen atoms were refined first in isotropic and
then in anisotropic approximation by the full-matrix
least-squares procedure (by F2). The positions of C–H
hydrogen atoms were determined from the electron
density maxima and were refined according to the
riding model; the N–H protons were localized by the
direct method and were refined independently. Prin-
cipal crystallographic parameters: rhombic crystals,
space group Pbca; unit cell parameters: a = 7.9755(5),
b = 16.128(2), c = 30.846(2) Å; V = 3967.8(6) Å3; Z =
8; μ = 0.088 mm–1. Total of 16052 reflection inten-
sities were measured in the range 2.85 < θ < 26.38°;
4039 reflections were independent (Rint 0.0556), and
1611 of them were characterized by I > 2σ(I); com-
pleteness 99.7% for θ = 26.38°. The final divergence
factors were R1 = 0.0465, wR2 = 0.0984 [reflections
with I > 2σ(I)] and R1 = 0.1284, wR2 = 0.1059 (all
reflections); goodness of fit S = 1.006. The maximal
and minimal residual spatial electron densities were
0.299 and –0.220 ē/Å3. The set of crystallographic data
for compound Ib was deposited to the Cambridge
Crystallographic Data Centre (entry no. CCDC
865252) and is available at http://www.ccdc.cam.ac.uk/
data_request/cif upon request.
In the mass spectrum of compound Ij we detected
[M – CO]+ ion peak with m/z 329) and the following
fragment ion peaks: m/z 257 [M – Et2NCO]+, 77 [Ph]+,
and 72 [Et2N]+. The mass spectrum of Io contained the
molecular ion peak [M]+ with m/z 300 and fragment
ion peaks with m/z 242 [M – CH3NHCO]+, 107
[CH3OC6H4]+, and 58 [CH3NHCO]+. These data were
consistent with the assumed structures.
The structure of compound Ib was unambiguously
determined by X-ray analysis (see figure). Single crys-
tals of Ib were obtained by slow crystallization from
ethanol. Despite the presence of an asymmetric center
(C7), compound Ib crystallized in centrosymmetric
space group belonging to rhombic crystal system.
C18
C5
N6
C12
C14
C6
C13
C2
C11
C9
N5
C15
C8
C10
C4
N4
N1
N2
C17
EXPERIMENTAL
C1
O1
C16
C7
The IR spectra were measured on a Specord M-80
spectrometer from samples dispersed in mineral oil.
C3
N3
O2
1
The H NMR spectra were recorded on a Bruker 500
instrument at 500.13 MHz using DMSO-d6 as solvent
and tetramethylsilane as internal reference. The mass
spectra (electron impact, 70 eV) were obtained on
a Finnigan MAT INCOS-50 spectrometer.
Structure of the molecule of methyl 4-(6-diethylcarbamoyl-
5-methyl-4,7-dihydrotetrazolo[1,5-a]pyrimidin-7-yl)benzo-
ate (Ib) according to the X-ray diffraction data.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 48 No. 3 2012

SYNTHESIS OF N-SUBSTITUTED 7-ARYL-5-METHYL-4,7-DIHYDROTETRAZOLO...
421
N,N-Diethyl-7-(4-ethylphenyl)-5-methyl-4,7-di-
hydrotetrazolo[1,5-a]pyrimidine-6-carboxamide
(Ia). A mixture of 0.01 mol of N,N-diethyl-3-oxobu-
tanamide, 0.01 mol of 4-ethylbenzaldehyde, and
0.01 mol of tetrazol-5-amine monohydrate was heated
for 20–60 min at 120–150°C until gaseous products no
longer evolved and the mixture solidified. The mixture
was cooled and treated with ethanol, and the precip-
itate was filtered off and recrystallized from ethanol.
Yield 2.1 g (62%), mp 236–238°C. IR spectrum, ν,
(Ie). Yield 2.01 g (59%), mp 179–181°C. IR spectrum,
ν, cm–1: 3190 (NH), 1680 (C=O), 1620 (C=C).
1H NMR spectrum, δ, ppm: 0.80 m (6H, CH3CH2),
1.79 s (3H, 5-CH3), 3.12 m (4H, CH3CH2), 3.61 s (3H,
CH3O), 6.27 s (1H, 7-H), 7.13 m (4H, C6H4), 10.30 s
(1H, NH). Found, %: C 59.57, 59.76; H 6.37, 6.57;
N 24.49, 24.56. C17H22N6O2. Calculated, %: C 59.63;
H 6.48; N 24.54.
N,N-Diethyl-5-methyl-7-(pyridin-3-yl)-4,7-dihy-
drotetrazolo[1,5-a]pyrimidine-6-carboxamide (If).
Yield 1.97 g (63%), mp 215–217°C. IR spectrum, ν,
1
cm–1: 3200 (NH), 1680 (C=O), 1612 (C=C). H NMR
1
cm–1: 3190 (NH), 1680 (C=O), 1620 (C=C). H NMR
spectrum, δ, ppm: 1.84 s (3H, 5-CH3), 0.80 m (6H,
CH3CH2N), 1.11 t (3H, C6H4CH2CH3), 3.04 m (4H,
CH3CH2N), 4.02 q (2H, CH3CH2C6H4), 6.31 s (1H,
7-H), 7.13 m (4H, C6H4), 10.31 s (1H, NH). Found, %:
C 63.43, 63.64; H 7.06, 7.22; N 24.57, 24.77.
C18H24N6O. Calculated, %: C 63.51; H 7.11; N 24.69.
spectrum, δ, ppm: 0.81 m (6H, CH3CH2), 1.80 s (3H,
5-CH3), 3.14 m (4H, CH3CH2), 6.39 s (1H, 7-H),
7.15 m (4H, pyridine), 10.62 s (1H, NH). Found, %:
C 57.42, 57.60; H 6.07, 6.19; N 31.21, 31.41.
C15H19N7O. Calculated, %: C 57.49; H 6.11; N 31.29.
Compounds Ib–Io were synthesized in a similar
way.
N,N-Diethyl-7-(4-methoxyphenyl)-5-methyl-4,7-
dihydrotetrazolo[1,5-a]pyrimidine-6-carboxamide
(Ig). Yield 2.39 g (70%), mp 246–248°C. IR spectrum,
ν, cm–1: 3190 (NH), 1680 (C=O), 1620 (C=C).
1H NMR spectrum, δ, ppm: 0.80 m (6H, CH3CH2),
1.75 s (3H, 5-CH3), 3.12 m (4H, CH3CH2), 3.58 s (3H,
CH3O), 6.55 s (1H, 7-H), 7.27 m (4H, C6H4), 10.56 s
(1H, NH). Found, %: C 59.57, 59.76; H 6.37, 6.57;
N 24.49, 24.56. C17H22N6O2. Calculated, %: C 59.63;
H 6.48; N 24.54.
Methyl 4-(6-diethylcarbamoyl-5-methyl-4,7-di-
hydrotetrazolo[1,5-a]pyrimidin-7-yl)benzoate (Ib).
Yield 2.66 g (72%), mp 234–236°C. IR spectrum, ν,
cm–1: 3180 (NH), 1680 (C=O, amide), 1620 (C=C).
1H NMR spectrum, δ, ppm: 0.83 m (6H, CH3CH2),
1.85 s (3H, 5-CH3), 3.09 m (4H, CH3CH2), 3.79 s (3H,
OCH3), 6.46 s (1H, 7-H), 7.79 m (4H, C6H4), 10.43 s
(1H, NH). Found, %: C 58.27, 58.41; H 5.88, 6.08;
N 22.61, 22.74. C18H22N6O3. Calculated, %: C 58.37;
H 5.99; N 22.69.
N,N-Diethyl-5-methyl-7-(4-nitrophenyl)-4,7-di-
hydrotetrazolo[1,5-a]pyrimidine-6-carboxamide
(Ih). Yield 2.43 g (68%), mp 244–246°C. IR spectrum,
ν, cm–1: 3190 (NH), 1680 (C=O), 1620 (C=C).
1H NMR spectrum, δ, ppm: 0.90 m (6H, CH3CH2),
1.89 s (3H, 5-CH3), 3.09 m (4H, CH3CH2), 6.66 s (1H,
7-H), 8.21 m (4H, C6H4), 10.67 s (1H, NH). Found, %:
C 53.69, 53.91; H 5.29, 5.39; N 27.36, 27.46.
C16H19N7O3. Calculated, %: C 53.78; N 5.36; N 27.44.
N,N-Diethyl-5-methyl-7-(4-methylphenyl)-4,7-di-
hydrotetrazolo[1,5-a]pyrimidine-6-carboxamide
(Ic). Yield 1.89 g (58%), mp 218–220°C. IR spectrum,
ν, cm–1: 3190 (NH), 1680 (C=O), 1620 (C=C).
1H NMR spectrum, δ, ppm: 0.91 m (6H, CH3CH2),
1.86 s (3H, 5-CH3), 2.19 s (3H, CH3C6H4), 3.07 m
(4H, CH3CH2), 6.26 s (1H, 7-H), 7.23 m (4H, C6H4),
10.34 s (1H, NH). Found, %: C 62.50, 62.69; H 6.74,
6.90; N 25.63, 25.83. C17H22N6O. Calculated, %:
C 62.56; H 6.79; N 25.75.
7-(4-Bromophenyl)-N,N-diethyl-5-methyl-4,7-
dihydrotetrazolo[1,5-a]pyrimidine-6-carboxamide
(Ii). Yield 2.78 g (71%), mp 246–247°C. IR spectrum,
ν, cm–1: 3190 (NH), 1680 (C=O), 1620 (C=C).
1H NMR spectrum, δ, ppm: 0.90 m (6H, CH3CH2),
1.87 s (3H, 5-CH3), 3.08 m (4H, CH3CH2), 6.46 s
(1H, 7-H), 7.55 m (4H, C6H4), 10.56 s (1H, NH).
Found, %: C 49.06, 49.24; H 4.81, 4.98; N 21.37,
21.50. C16H19BrN6O. Calculated, %: C 49.12; H 4.89;
N 21.48.
N,N-Diethyl-7-(4-fluorophenyl)-5-methyl-4,7-di-
hydrotetrazolo[1,5-a]pyrimidine-6-carboxamide
(Id). Yield 2.38 g (72%), mp 207–209°C. IR spectrum,
ν, cm–1: 3190 (NH), 1680 (C=O), 1620 (C=C).
1H NMR spectrum, δ, ppm: 0.81 m (6H, CH3CH2),
1.86 s (3H, 5-CH3), 3.14 m (4H, CH3CH2), 6.39 s (1H,
7-H), 7.15 m (4H, C6H4), 10.37 s (1H, NH). Found, %:
C 58.07, 58.21; H 5.73, 5.83; N 25.33, 25.56.
C16H19FN6O. Calculated, %: C 58.17; H 5.80; N 25.44.
N,N-Diethyl-5-methyl-7-(3-nitrophenyl)-4,7-di-
hydrotetrazolo[1,5-a]pyrimidine-6-carboxamide
(Ij). Yield 2.28 g (64%), mp 236–238°C. IR spectrum,
ν, cm–1: 3190 (NH), 1680 (C=O), 1620 (C=C).
N,N-Diethyl-7-(3-methoxyphenyl)-5-methyl-4,7-
dihydrotetrazolo[1,5-a]pyrimidine-6-carboxamide
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 48 No. 3 2012

GEIN et al.
422
1H NMR spectrum, δ, ppm: 0.88 m (6H, CH3CH2),
1.92 s (3H, 5-CH3), 3.12 m (4H, CH3CH2), 6.62 s (1H,
7-H), 7.55 m (4H, C6H4), 10.62 s (1H, NH). Found, %:
C 53.69, 53.65; H 5.29, 5.40; N 27.32, 27.50.
C16H19N7O3. Calculated, %: C 53.78; H 5.36; N 27.44.
Yield 2.34 g (72%), mp 272–274°C. IR spectrum, ν,
cm–1: 3440 (NH, amide), 3200 (NH), 1675 (C=O),
1
1600 (C=C). H NMR spectrum, δ, ppm: 1.90 s (3H,
5-CH3), 3.50 s (3H, NCH3), 7.90 s (1H, OH), 6.64 s
(1H, 7-H), 6.85 m (4H, C6H4), 9.40 s (1H, NH), 10.40
s (1H, 4-H). Found, %: C 54.46, 54.66; H 4.87, 5.02;
N 29.23, 29.44. C13H14N6O2. Calculated, %: C 54.54;
H 4.93; N 29.35.
N,N-Diethyl-7-(2-methoxyphenyl)-5-methyl-4,7-
dihydrotetrazolo[1,5-a]pyrimidine-6-carboxamide
(Ik). Yield 1.64 g (44%), mp 198–199°C. IR spectrum,
ν, cm–1: 3190 (NH), 1680 (C=O), 1620 (C=C).
1H NMR spectrum, δ, ppm: 0.80 m (6H, CH3CH2),
1.82 s (3H, 5-CH3), 3.12 m (4H, CH3CH2), 3.65 s (3H,
CH3O), 6.57 s (1H, 7-H), 7.67 m (4H, C6H4), 10.34 s
(1H, NH). Found, %: C 59.57, 59.76; H 6.37, 6.57;
N 24.49, 24.56. C17H22N6O2. Calculated, %: C 59.63;
H 6.48; N 24.54.
7-(2-Methoxyphenyl)-N,5-dimethyl-4,7-dihydro-
tetrazolo[1,5-a]pyrimidine-6-carboxamide (Io).
Yield 2.22 g (69%), mp 235–237°C. IR spectrum, ν,
cm–1: 3420 (NH, amide), 3150 (NH), 1680 (C=O),
1
1620 (C=C). H NMR spectrum, δ, ppm: 1.91 s (3H,
5-CH3), 3.40 s (3H, NCH3), 3.70 s (3H, CH3O), 6.65 s
(1H, 7-H), 7.10 m (4H, C6H4), 9.50 s (1H, 4-H),
10.50 s (1H, NH). Found, %: C 55.91, 56.11; H 5.32,
5.46; N 27.85, 28.06. C14H16N6O2. Calculated, %:
C 55.99; H 5.37; N 27.98.
N,N-Diethyl-5-methyl-7-(2-nitrophenyl)-4,7-di-
hydrotetrazolo[1,5-a]pyrimidine-6-carboxamide
(Il). Yield 1.93 g (54%), mp 225–227°C. IR spectrum,
ν, cm–1: 3190 (NH), 1680 (C=O), 1620 (C=C).
1H NMR spectrum, δ, ppm: 0.80 m (6H, CH3CH2),
1.86 s (3H, 5-CH3), 3.15 m (4H, CH3CH2), 6.58 s (1H,
7-H), 7.79 m (4H, C6H4), 10.68 s (1H, NH). Found, %:
C 53.69, 53.65; H 5.29, 5.40; N 27.32, 27.50.
C16H19N7O3. Calculated, %: C 53.78; H 5.36; N 27.44.
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