Partially hydrogenated aromatic substituted tetrazolo[1,5-a]pyrimidines

Article abstract of DOI:10.1023/A:1011925631511

By treating 5-aminotetrazole with aromatic αβ-unsaturated ketones or with Mannich base hydrochlorides there have been synthesized aromatic substituted 4,7-dihydrotetrazolo[1,5-a]-pyrimidines. They can be reduced to the corresponding 4,5,6,7-tetrahydro derivatives by the action of NaBH4. The high thermodynamic stability of the 4,7-dihydrotetrazolo[1,5-a]pyrimidines when compared with the 4,5-dihydro isomers has been revealed. Reaction of 5-aminotetrazole both with cyclohexanone as well as with 2-cyclohexylidenecyclohexanone leads to formation of 9,9-pentamethylene-4,5,6,7,8,9-hexahydrotetrazolo[5,1-b]quinazoline, the structure of which was demonstrated using X-ray crystallography.

Full text of DOI:10.1023/A:1011925631511

Chemistry of Heterocyclic Compounds, Vol. 37, No. 6, 2001
PARTIALLY HYDROGENATED
AROMATIC SUBSTITUTED
a
TETRAZOLO[1,5- ]PYRIMIDINES
S. M. Desenko1, E. S. Gladkov1, S. A. Komykhov1, O. V. Shishkin2, and V. D. Orlov1
By treating 5-aminotetrazole with aromatic , -unsaturated ketones or with Mannich base
α β
hydrochlorides there have been synthesized aromatic substituted 4,7-dihydrotetrazolo[1,5-a]-
pyrimidines. They can be reduced to the corresponding 4,5,6,7-tetrahydro derivatives by the action of
NaBH4. The high thermodynamic stability of the 4,7-dihydrotetrazolo[1,5-a]pyrimidines when
compared with the 4,5-dihydro isomers has been revealed. Reaction of 5-aminotetrazole both with
cyclohexanone as well as with 2-cyclohexylidenecyclohexanone leads to formation of
9,9-pentamethylene-4,5,6,7,8,9-hexahydrotetrazolo[5,1-b]quinazoline, the structure of which was
demonstrated using X-ray crystallography.
Keywords:
5-aminotetrazole,
dihydrotetrazolo[1,5-a]pyrimidines,
, -unsaturated
α β
ketones,
tetrahydrotetrazolo[1,5-a]pyrimidines, molecular structure, rearrangement, cyclocondensation.
A convenient regioselective method for the synthesis of azolopyrimidines with a nodal nitrogen atom is
the cyclocondensation of aminoazoles with unsaturated ketones [1]. However, in the case of non-equivalently
substituted tetrazolo[1,5-a]pyrimidines, a solution to the question of the position of the substituent in the
pyrimidine ring demands consideration of not only the route of formation of the pyrimidine ring but also the
possibility of tetrazoloazide tautomeric conversions in the final compounds. The aim of our work is the
synthesis of partially hydrogenated aromatic substituted tetrazolo[1,5-a]pyrimidines and an investigation of their
possible mutual interactions via the open azide form.
The dihydro derivatives 3a-l were obtained by condensation of 5-aminotetrazole (1) with Mannich base
hydrochlorides 2a-c or with , -unsaturated ketones 2d-l. The reaction was performed by refluxing solutions of
α β
equimolar amounts of the starting materials in isoamyl alcohol (compounds 3a-e, 3 h) or in DMF (compounds
3f-l, 20-30 min). By the action of NaBH4 on a suspension of compounds 3d-g,i,j,l they could be reduced to the
tetrahydro derivatives 4 (Scheme 1). Compounds 3f,i,j,l have been reported by us previously [2]; the
characteristics of the compounds obtained for the first time 3a-e,g,h,k are given in Table 1.
It is known that the dihydro derivatives of azolopyrimidines can exist in the enamine (A) and the imine
(B) tautomeric forms [1]. The IR spectra of compounds 3a-e,g,h,k contain strong absorption bands for the
–NH–C=C– fragment in the region 1650-1690 cm-1 (Table 1), typical for 1,4-dihydropyrimidine derivatives, and
1
this points to an enamine structure (A) for these substances in the solid phase. The H NMR spectra of
compounds 3 contain signals for the protons of the NH group, the aromatic nuclei, the substituent, and the
__________________________________________________________________________________________
1
V. N. Karazin National University, Kharkov 61077, Ukraine; e-mail: desenko@univer.kharkov.ua,
2
e-mail: gladkov@isc.kharkov.com. NTK "Institute of Monocrystals", Kharkov 61001, Ukraine. Translated
from Khimiya Geterotsiklicheskikh Soedinenii, No. 6, pp. 811-818, June, 2001. Original article submitted
September 27, 1999.
0009-3122/01/3706-0747$25.00©2001 Plenum Publishing Corporation
747

dihydropyrimidine ring (Table 2). The spectra of the dihydro derivatives 3c-l also characterize them as
compounds purely in the dihydro form A. In the case of the dihydrotetrazolopyrimidines 3a,b there are found
the spectra of the tautomers A and B in the integrated ratio of signals of ~95:5 for 3a and 75:25 for 3b (Table 2).
The relative stabilization of the dihydro form B was observed before for the 2-desaza analogs of compounds
3a,b (the dihydro derivatives of 1,2,4-triazolo[1,5-a]pyrimidine which contain the same substituents R and R1
[4]).
Scheme 1
Me2N
HCl
+
.
O
R1
2a–c
R
.
R
– Me2NH HCl
H
N
– H2O
N
N
N
N
N
N
N
N
N
N
R
1
NH2
N
H
3a–l
R1
N
N
1
N
B
R
O
A
+
NaBH4
R
R1
2d–l
– H2O
N
N
N
N
H
R1
4d–g,i,j,l
2-4 a-c R = H; d R = Me; e,f,j-l R = Ph; g R = p-MeOC6H4; h R = p-ClC6H4; i R = p-BrC6H4;
a,d,f-i R 1 = Ph; b,j R1 = p-MeOC6H4; c,l R1 = p-BrC6H4; e R1 = Me; k R 1 = p-ClC6H4
Reduction of the dihydro derivatives 3d-g,i,j,l leads to the disappearance of the
bands in the IR
νC=C
spectra (Table 1). The presence of two chiral centers in the molecules of substances 4d-g,i,j,l suggests the
1
possible formation of a mixture of diastereomers in them. However, the H NMR spectra of these compounds
(including the unpurified samples) show them to be single substances, evidence for additional doubling of
signals being absent. This fact infers that the reduction of the dihydro derivatives 3 gives only one of the
possible steric isomers. The values for the spin-spin coupling J5HA-HA and J7H-HA (10.8-11.4 Hz) are typical for a
Jaa type constant and this points to a diequatorial orientation for the substituents R and R1 in the predominant
conformers of these substances which are, thus, assigned to the cis-isomer series. The cis structure for
compound 4l was confirmed using the nuclear Overhauser effect. Additional irradiation at the resonance
frequency for the 5-H proton leads to an increase in the strength of the signal for the proton at position 7 of the
bicycle. In addition, there were also observed increases in the intensity of the signals for the protons of the
imino group and the ortho- protons of the p-bromophenyl substituent and this confirms the assignments of
signals for the 5-H and 7-H protons made by us on the basis of data in the study [5].
We have previously shown [6] that the reaction of 3-amino-1,2,4-triazole with
2-cyclohexylidenecyclohexanone (5) and cyclohexanone (6) leads to the formation of the isomeric
triazoloquinoxaline system which are 2-desaza analogs of compounds 7 and 8. By carrying out the condensation
of 5-aminotetrazole with ketones 5 and 6 under the same conditions (refluxing in DMF for 1 h) we have
observed that the same compound 7 is formed and its structure was confirmed by X-ray analysis.
In our view, the difference in the structure of the dihydropyrimidine fragment in the final products of the
reaction of cyclohexanone with 5-aminotetrazole and 3-amino-1,2,4-triazole is connected with the marked
ability of tetrazole derivatives to rearrange via the open azide form. In the reaction investigated this
748

TABLE 1. Characteristics of Compounds 3a-e,g,h,j, 4d-f,g,i, 7*
Found N, %
Empirical
formula
νC=С, cm-1
Compound
mp, °С
Yield, %
——————
Calculated N, %
C10H9N5
35.1
35.2
236-238
235-243
246-248
183-185
164-166
258
1665
1665
1665
1668
1690
1650
1660
1660
—
75
55
65
45
65
46
30
45
65
30
70
10
65
65
75
49*2
3a
3b
3c
3d
3e
3g
3h
3k
4d
4e
4f
C11H11N5O
C10H8BrN5
C11H11N5
30.8
30.6
25.2
25.2
32.9
32.8
C11H11N5
33.0
32.8
C17H15N5O
C16H12ClN5
C16H12ClN5
C11H13N5
23.0
22.9
22.6
22.6
244
22.9
270
22.6
32.5
32.5
198-201
166-168
212-214
178-180
219-220
210-213
221-223
224-226
C11H13N5
32.7
—
32.5
C16H15N5
25.4
25.3
—
C17H17N5O
C16H13 BrN5
C17H17N5O
C16H13BrN5
C13H19N5
22.8
—
4g
4i
22.8
19.8
19.7
—
22.7
—
4j
22.8
19.9
19.7
—
4l
28.5
1665
7
28.5
_______
* Compounds 3f,i,j,l have been reported by us before [2].
*2 By method A.
rearrangement relates to the isomeric structures 7 and 8. The possible realization of such a rearrangement was
studied for the tetrahydro derivatives 4d,e,g,i,j,l in which a close energetic isomer profile might be expected,
only differing in the position in the substituents R and R1.
O
H
N
N
5
N
N
N
N
NH2
N
– H2O
N
1
N
H
7
+ 2
N
– 2 H2O
O
6
N
N
N
7
N
N
N3
N
H
H
8
749

TABLE 2. Proton Chemical Shifts, δ, (Spin-spin Coupling, Hz) for Compounds 3a-l, 4d-g,i,j,l, 7
6-H
Aromatic
Compound
1
5-H
2
7-H
3
NH (1H, br. s)
6
CH3 (3H, s)
8
protons (m)
HA
4
HB
5
7
3a*
А
В
—
—
5.2 (2H, br. s)
4.68 (2Н, t)
5.3 (1H, br. s)
3.53 (2Н, t, 8.0)
10.2
10.0
7.3-8.2
6.9-8.2
3b*
А
В
—
—
—
—
—
—
—
—
—
—
—
—
5.1 (3H, br. s, 6-H, 7-H)
4.86 (3H, br. s, 6-H, 7-H)
3.79
3.88
4.65 (2H, t)
3.49 (2H, t, 8.1)
10.0
10.2
10.0
10.6
10.4
10.6
10.7
10.5
10.6
10.8
7.2-7.9
7.4-7.7
7.2-7.5
7.2-7.9
6.9-7.8
7.3-8.0
7.2-8.1
6.9-7.7
7.3-7.8
7.3-8.4
3с
3d
3e
3f
3g
3h
3i
3j
3k
3l
5.51 (1H, m)
5.20 (1H, d, 3.1)
4.66 (1H, br. s)
5.32 (1H, d)
1.63 (d, 6.1)
1.94
6.36 (1H, br. s)
6.65 (1H, d)
6.54 (1H, d)
6.63 (1, d)
6.70 (1H, d)
6.58 (1H, d)
6.61 (1H, d)
6.60 (1H, d)
5.26 (1H, d)
5.29 (1, d, 2.9)
5.35 (1H, d)
3.75
5.21 (1H, d, 2.7)
5.36 (1H, d, 2.7)
5.39 (1H, d, 2.8)
3.35

TABLE 2 (continued)
1
2
3
4
5
6
7
8
4.63 (1H, m,
5H-HA = 11.4)
3.68 (1H, br. s)
4.55 (1H, m)
5.49 (1H, dd,
1.79 (1H, m)
1.81 (1H, m)
2.32 (1H, m)
2.34 (1H, m)
7.8
7.6
7.2-7.5
7.2-7.5
1.54 (d, 6.0)
1.23 (d, 6.0)
4d
4e
J
J
5H-HA = 10.8;
5H-HB = 3.8)
J
4.78 (1H, dd,
5.66 (1H, dd,
2.20 (1H, m,
2.43 (1H, m)
2.40 (1H, m)
2.44 (1H, m)
2.40 (1H, m)
2.45 (1H, m)
—
8.0
8.03
8.06
8.0
7.2-7.7
6.8-7.6
7.2-7.7
6.9-7.5
7.2-7.7
1.2-2.2*2
—
3.75
—
4f
4g
4i
4j
4l
7
J
J
5H-HA = 11.4;
5H-HB = 1.7)
J
5H-HA = 11.0;
5H-HB = 4.2)
J
HA-HB = -12.9)
J
4.77 (1H, dd,
5.60 (1H, dd,
2.21 (1H, m,
J
HA-HB = -13.3)
J
5H-HA = 11.0;
5H-HB = 1.7)
J
5H-HA = 11.2;
5H-HB = 4.5)
J
J
4.77 (1H, dd,
5.68 (1H, dd,
2.20 (1H, m,
J
HA-HB = -13.2)
J
5H-HA = 10.8;
5H-HB = 1.2)
J
5H-HA = 11.1;
5H-HB = 4.3)
J
J
4.72 (1H, dd
5.64 (1H, dd,
2.18 (1H, m,
J
HA-HB = -13.2)
3.75
—
J
5H-HA = 11.3;
5H-HB = 1.9)
J
5H-HA = 11.0;
5H-HB = 4.4)
J
J
4.78 (1H, dd,
5.63 (1H, dd,
2.20 (1H, m,
8.03
9.6
J
J
5H-HA = 11.3;
5H-HB = 2.3)
J
J
5H-HA = 11.1;
5H-HB = 4.5)
J
HA-HB = -13.6)
—
—
—
—
_______
* A mixture of tautomeric forms A and B with a B content of 5% in 3a and 25% in 3b.
*2 (CH2)n.

In fact, after solutions of compounds 4d,e,g,i,j,l had been allowed to stand for 1 h at 120°C in
DMSO-d6, the 1H NMR spectra of the obtained samples pointed to the formation in solution of a 7: 3 mixture of
isomers for 4d+4e and an approximately 1:1 ratio for 4g+4j and 4i+4l.
R1
R
R1
R
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
H
R1
4d,e,g,i,j,l
N
H
R
N
H
R1
N
H
R
3
Under these conditions, the 1H NMR spectra of the dihydro derivatives 3d,e,g,i,j,l remained unchanged
and this is connected with the high thermodynamic stability of the 4,7-dihydro structure 3 when compared with
their 4,5- dihydro isomers. In our view, the inverse process (rearrangement of 8 to 7) is realized in the
cyclocondensation of 5-aminotetrazole with cyclohexanone.
According to X-ray data (Figure 1, Table 3) the tetrazole ring in compound 7 is planar. Because of the
symmetry of the spiro substituent at atom C(8) relative to the mean plane of the tetrazolopyrimidine fragment, the
dihydropyrimidine ring might also be expected to have a planar structure. However, the repulsion between the
hydrogen atoms of the methylene groups C(6), C(9), and C(13) (shortened intramolecular contacts H(9A)···H(6A)
2.24 Å, H(9A)···H(6C) 2.06 Å, H(13B)···H(6D) 2.05 Å, and H(13B)···H(6B) 2.23 Å, sum of van der Waal radii 2.32 Å [7])
causes the dihydro ring to change to a strongly flattened sofa type conformation. Atom C(8) deviates from the
plane of the remaining atoms in the ring by -0.12 Å. The cyclohexane ring is found in a slightly asymmetric
chair conformation. The deviation of atom C(8) from the mean square plane passing through atoms C(9), C(10)
,
C(12), and C(13) is slightly less than that of atom C(11) (-0.58 and 0.76 Å respectively). The cyclohexene fragment
is randomized in two equally probable, slightly asymmetric, half chair type conformations. The deviations of
atoms C(4) and C(5) from the plane of the remaining ring atoms are 0.24 and -0.39 Å respectively in conformation
A and -0.57 and 0.25 Å in conformation B.
Fig. 1. Partially hydrogenated aromatic substituted tetrazolo[1,5-a]pyrimidines.
752

TABLE 3. Coordinates (× 104) and Equivalent Isotropic Thermal Parameters
(Å2 × 103) for the Non-hydrogen Atoms in the Molecule of 7
Atom
x
y
z
U(eq)
N(1)
N(2)
N(3)
N(4)
N(5)
C(1)
4120(4)
3466(4)
2077(4)
3151(3)
784(4)
1941(4)
874(4)
-467(4)
-199(11)
533(8)
-834(8)
893(7)
2086(5)
2056(4)
3361(4)
5141(4)
6451(4)
5997(4)
4319(4)
2985(4)
-42(2)
-713(2)
-345(2)
818(2)
1293(2)
604(2)
2268(2)
2962(2)
4063(5)
4226(7)
3830(5)
4283(5)
3589(3)
2523(2)
1771(2)
2169(3)
1556(3)
1430(3)
927(3)
8417(3)
9052(3)
9550(3)
8488(2)
9424(3)
9178(3)
8946(3)
9339(3)
8984(6)
7839(6)
8506(7)
8342(7)
7751(3)
8242(3)
7822(3)
7996(3)
7394(3)
6162(3)
5998(3)
6574(3)
60(1)
60(1)
50(1)
39(1)
51(1)
36(1)
34(1)
45(1)
72(3)
61(3)
46(2)
41(2)
60(1)
34(1)
32(1)
42(1)
51(1)
54(1)
52(1)
42(1)
C(2)
C(3)
C(4A)
C(5A)
C(4B)
C(5B)
C(6)
C(7)
C(8)
C(9)
C(10)
C(11)
C(12)
C(13)
1540(3)
In crystal the molecules form centrosymmetric dimers through the intermolecular hydrogen bonds
N(5)–H···N(3) (–x, –y, 2 – z): N···H 2.10 Å, N–H···N 157.5°
EXPERIMENTAL
IR spectra for the compounds of types 3, 4, and 7 were recorded for KBr tablets on a Specord 75 IR
machine and 1H NMR and 13C NMR spectra (DMSO-d6 solvent) on a Bruker AM 400 spectrometer using TMS
as internal standard. The purity of the compounds was monitored using TLC (Silufol UV-254, chloroform, ethyl
acetate).
5-Phenyl-4,7-dihydrotetrazolo[1,5-a]pyrimidine (3a). A mixture of 5-aminotetrazole 1 (0.85 g,
10 mmol) and -dimethylaminopropiophenone hydrochloride 2a (2.13 g, 10 mmol) in isoamyl alcohol (25 ml)
β
was refluxed for 3 h and cooled. Filtration gave compound 3a (1.5 g, 75%); mp 236-238°C (isoamyl alcohol).
Compounds 3a-e were prepared similarly.
5,7-Diphenyl-4,7-dihydrotetrazolo[1,5-a]pyrimidine (3f). A solution of 5-aminotetrazole (0.85 g,
10 mmol) and the , -unsaturated ketone 2f (2.07 g, 10 mmol) in DMF (1 ml) was refluxed for 30 min, cooled,
α β
mixed with benzene (30 ml), and filtered to give compound 3f (2.2 g, 80%); mp 232-233°C (benzene–DMF, 3:1).
Compounds 3g-j were prepared similarly.
5,7-Diphenyltetrahydrotetrazolo[1,5-a]pyrimidine (4f). A suspension of compound 3f (2.75 g,
10 mmol) in absolute methanol (5 ml) was treated portionwise with NaBH4 (1.0 g). At the end of the reaction,
water (200 ml) was added and compound 4f (1.94 g, 71%) was filtered off; mp 212-214°C (methanol).
Compounds 4d,e,g,i were prepared similarly.
9,9-Pentamethylene-4,5,6,7,8,9-hexahydrotetrazolo[5,1-b]quinazoline (7). A.
A
solution of
5-aminotetrazole 1 (0.85 g, 10 mmol) and 2-cyclohexylidenecyclohexanone (1.78 g, 10 mmol) in DMF (0.5 ml)
was refluxed for 30 min, mixed with benzene (30 ml), and filtered to give 7 (1.21 g, 49%); mp 224-226°C
753

(isopropanol). 13C NMR spectrum (DMSO-d6), , ppm: 149.8 (3a-C); 128.2 (4a-C), 106.4 (8a-C), 62.8 (9-C),
δ
33.8 (10-C), 26.0 (5-C), 24.1 (8-C), 23.0, 22.7 (6-C + 7-C), 21.6, 21.4 (11-C + 12-C). Mass spectrum,
m/z (Irel, %): 245 (M+, 15), 202 (100), 174 (15), 133 (10).
B. A solution of 5-aminotetrazole 1 (0.85 g, 10 mmol) and cyclohexanone (1.96 g, 20 mmol) in DMF
(0.5 ml) was refluxed for 45 min, mixed with benzene (30 ml), and filtered to give compound 7 (1.65 g, 67%).
X-ray structural investigation. Crystals of compound 7 are monoclinic, C13H19N5, at 20°C
a = 8.040 (2), b = 13.092 (3), c = 11.896 (2) Å; = 91.88 (3)°; V = 1251.5 (4) Å3; Mr = 245.33; Z = 4; space
β
group P21/c; dcalc = 1.302 g/cm3; MoK = 0.083 mm-1; F(000) = 528. The unit cell parameters and intensities of
λ
α
3419 reflections (3189 independent, Rint = 0.09) were measured on a Siemens P3/PC automatic, four circle
diffractometer (MoK , graphite monochromator, 2 / scanning, 2θ max = 60°).
θ θ
α
The structure was solved by a direct method using the SHELXTL PLUS [8] program package. The
positions of the hydrogen atoms were calculated geometrically and refined using the "riding" model with fixed
Uiso = 1.2 Ueq of the non hydrogen atom bound to the given hydrogen atom. The randomized fragment was
refined with an applied restriction of the C–C bond length of 1.54 (1) Å. F2 refinement by full matrix least
squares analysis in the anisotropic approximation for non hydrogen atoms was carried out to wR2 = 0.125
(R1 = 0.082 for 991 reflections with F 4 (F), S = 1.28). The coordinates of the non hydrogen atoms are given
> σ
in Table 3.
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1.
2.
3.
4.
S. M. Desenko, Khim. Geterotsikl. Soedin., 147 (1995).
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V. D. Orlov, S. M. Desenko, K. A. Potekhin, and Yu. T. Struchkov, Khim. Geterotsikl. Soedin., 229
(1988).
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S. M. Desenko, O. V. Shishkin, V. D. Orlov, V. V. Lipson, S. V. Lindeman, and Yu. T. Struchkov,
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7.
8.
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754