Synthesis and tautomerism of 5,7-diaryl-3-cyano-and 5,7-diaryl-3- ethoxycarbonyl-4,7(6,7)-dihydropyrazolo[1,5-a]pyrimidines

Article abstract of DOI:10.1007/s10593-007-0239-y

The cyclocondensation of 3-amino-4-cyanopyrazole and 3-amino-4- ethoxycarbonylpyrazole with 1,3-diaryl-2,3-propen-1-ones gives the corresponding 3-substituted 5,7-diaryl-4,7(6,7)-dihydropyrazolo[1,5-a]pyrimidines. Their tautomeric composition in solution has been investigated by ¹H NMR.

Full text of DOI:10.1007/s10593-007-0239-y

Chemistry of Heterocyclic Compounds, Vol. 43, No. 12, 2007
SYNTHESIS AND TAUTOMERISM
OF 5,7-DIARYL-3-CYANO- AND 5,7-DIARYL-
3-ETHOXYCARBONYL-4,7(6,7)-DIHYDRO-
PYRAZOLO[1,5-a]PYRIMIDINES
V. V. Lipson1, S. M. Desenko2, V. V. Borodina1, and M. G. Shirobokova1
The cyclocondensation of 3-amino-4-cyanopyrazole and 3-amino-4-ethoxycarbonylpyrazole with
1,3-diaryl-2,3-propen-1-ones gives the corresponding 3-substituted 5,7-diaryl-4,7(6,7)-dihydro-
pyrazolo[1,5-a]pyrimidines. Their tautomeric composition in solution has been investigated by 1H NMR.
Keywords: dihydropyrazolo[1,5-a]pyrimidine system, synthesis, imino–enamine tautomerism.
We previously obtained aryl derivatives of 2-methyl- and 2-phenyldihydropyrazolo[1,5-a]pyrimidines
by the cyclocondensation of 5-substituted 3-aminopyrazoles with α,β-unsaturated ketones and showed that these
compounds exist both in the solid phase and in solution mainly in the imine 6,7-dihydro form [1-3]. In a
continuation of these investigations, with the aim of clarifying the influence of substituents in the pyrazole
fragment on the the state of the imine–enamine tautomeric equilibrium of dihydropyrazolopyrimidines,
5,7-diaryl-3-cyano- and 5,7-diaryl-3-ethoxycarbonyldihydropyrazolo[1,5-a]pyrimidines have been synthesized
and the tautomeric state of their solutions have been studied.
C6H4–R2
C6H4–R2
C6H4–R2
N
NH
NH2
N
N
N
N
[Ar]
+
DMF
C6H4–R1
N
N
C6H4–R1
C6H4–R1
O
H
R
R
R
B
A
3a–j
1, 2
4a–j, 5a,b,e,g
C6H4–R2
N
N
[O2]
DMF
4a,c,g
5a,b,g
1, 2
3a–c,g
+
+
N
C6H4–R1
R
6a,c,g, 7a,b,g
1, 4, 6 R = CN; 2, 5, 7 R = COOEt; a, f–i R1 = H, b R1 = 4-Cl, c R1 = 4-Me, d, j R1 = 4-OMe,
e R1 = 4-NMe2; a–e R2 = H, f R2 = 4-Br, g R2 = 4-Cl, h R2 = 2,4-(Cl)2, i R2 = 4-F, j R2 = 4-OMe
__________________________________________________________________________________________
1V. Danilevsky Institute of Endocrine Pathology Problems, Academy of Medical Sciences of Ukraine,
2
Kharkiv 61002; e-mail: lipson@ukr.net. STC Institute of Single Crystals, Kharkiv 61001, Ukraine. Translated
from Khimiya Geterotsiklicheskikh Soedinenii, No. 12, pp. 1824-1832, December, 2007. Original article
submitted August 27, 2004; revision submitted November 26, 2007.
1544
0009-3122/07/4312-1544©2007 Springer Science+Business Media, Inc.

The desired compounds 4a-j and 5a,b,e,g were obtained by boiling equimolar quantities of 3-amino-
4-cyanopyrazole 1 or 3-amino-4-ethoxycarbonylpyrazole 2 with α,β-unsaturated ketones 3a-j in DMF for
15-20 min in an atmosphere of argon. In the case of free access to the oxygen of the air the formation was
observed of dihydro derivatives 4a,c,g or 5a,b,e,g mixed with their heteroaromatic analogs 6a,c,g or 7a,b,g
respectively.
The structures of the synthesized compounds were demonstrated by spectral methods (Tables 1-3) and
the nitrogen contents were confirmed by elemental analysis (Table 1). In the IR spectra of 3-cyano-
pyrazolo[1,5-a]pyrimidines 4a-j and 6a,c,g the most characteristic was the absorption band for the CN group at
2256-2268 cm-1. The significant differences informative for differentiating structures 4 and 6 were observed in
them only when dihydro products 4 in the solid phase were in the enamine 4,7-dihydro form A. Bands were
TABLE 1. Characteristics of Compounds 4a-j, 5a,b,e,g, 6a,c,g, and 7a,b,g
IR, spectrum
Com-
pound
Empirical
formula
Found N, %
Calculated N, %
——————
mp, ° С
Yield, %
ν, cm-1
4а
С19H14N4
18.82
18.79
170-172
2268, 1592
75*
34*2
4b
4c
С19H13СlN4
С20H19N4
16.78
16.84
17.73
17.78
202-203
142-144
2258, 1586
2262, 1592
66
72*
57*2
47
4d
С20H16N4O
17.15
17.07
187-190
3320, 2264,
1668
4e
4f
С21H19N5
20.68
20.53
14.94
14.85
198-200
235-237
2260, 1610
50
64
С19H13BrN4
3248, 2258,
1670
4g
4h
4і
С19H13СlN4
С19H12Сl2N4
С19H13FN4
16.88
16.84
220-221
240-243
200-201
3272, 2256,
1672, 1592
3248, 2264,
1676, 1596
3256, 2260,
1672, 1592
2263, 1628
64*
27*2
68
15.17
15.26
17.80
17.83
64
43
4j
С21H18N4O2
С21Н19N3О2
15.71
15.64
12.06
12.17
150-152
84-86
5а
3421, 1680
3423, 1678
67*
23*2
85*
63*2
45
5b
С21Н18ClN3О2
11.12
11.07
98
5e
5g
С23Н24 N4О2
14.37
14.43
11.02
11.07
131-134
122-124
3425, 1698
3423, 1682
С21Н18ClN3О2
82*
66*2
45
6а
6c
6g
7а
7b
7g
С19H12N4
18.87
18.91
18.09
18.12
16.89
16.94
12.28
12.24
11.17
11.13
11.09
11.13
195-196
197-199
256-258
96-98
2258, 1646
2261, 1608
2256, 1616
1688
С20H13N4
29
51
53
17
13
С19H11ClN4
С21Н17N3О2
С21Н16ClN3О2
С21Н16ClN3О2
102
1690
182-184
1694
_______
* In an argon atmosphere.
*2 With free access to oxygen of the atmosphere.
1545

present in the spectrum for the vibrations of NH and C=C fragments of the dihydropyrimidine ring with ν 3248-
3320 and 1668-1676 cm-1 respectively. Therefore, according to the IR spectra, pyrazolopyrimidines 4d,f-i exist
in the dihydro form A in the solid phase. In the spectra of the imine tautomers B (compounds 4a-c,e,j) and
heteroaromatic derivatives 6a,c,g a set of absorption bands was noted characteristic of condensed azoloazine
systems containing several C=N bonds [1, 3].
In the IR spectra of ethoxycarbonylpyrazolopyrimidines 5a,b,e,g there were characteristic absorption
bands for NH and –C=O at 3421-3425 and 1678-1698 cm-1 respectively. In the spectra of their heteroaromatic
analogs 7a,b,g the vibrations of the NH group were absent.
The most complete information on the structure of the compounds under consideration was given by
their H NMR spectra (Tables 2 and 3). The spectra of the hetaryl derivatives 6a,c,g (Table 2) contain three
1
groups of signals, multiplet for the protons of the aryl substituents, and singlets for the 2-CH and 6-CH
fragments of the pyrazole and pyrimidine rings. In the spectra of products 7a,b,g signals of the ethoxy groups
were also present in addition to those indicated above. For compounds 6a,c,g and 7a,b,g, as might have been
expected, the resonance of the methine protons is observed at lower field in comparison with the corresponding
signals in the spectra of dihydrocompounds 4a-j and 5a,b,e,g (Tables 2, 3).
The 1H NMR spectra made it possible to estimate the equilibrium tautomeric composition of solutions of
dihydro derivatives 4a-j and 5a,b,e,g (Table 3). The spectra of the dihydro forms A and B of compounds 4a-j,
5a,b,e,g differ essentially in the region of resonance of the azomethine and aliphatic protons. For the tautomeric
forms A of carbonitriles 4a-j the presence of a singlet for NH and two doublets for =CH–CH– fragment of the
pyrimidine ring are characteristic. In the case of the enamine form of the ethoxycarbonyl derivatives 5a,b,e,g the
singlet of the NH proton was absent, probably due to exchange. Indirect proof of the presence of the NH group is
4
the additional splitting of the 6-CH signal with J ~ 1.3-2.0 Hz. This splitting disappears on adding
deuteromethanol to solutions of ethoxycarbonyl derivatives 5a,b,e,g.
In the spectra of imine tautomers B of compounds of the 4 and 5 series the signal for the azomethine
group was absent, but the resonance of the –CH2–CH– protons was displayed as an ABX or an A2X system. In
the presence of a mixture of tautomers A and B the spectrum is a superposition of the signals of both forms.
Comparison of the integral intensities of the corresponding groups of signals enabled estimation of the
tautomeric composition of the compounds being investigated in solution (Table 3). From the data obtained it
TABLE 2. 1H NMR Spectra of Compounds 6a,c,g and 7a,b,g
Com-
pound
Chemical shifts, δ, ppm (J, Hz)*
Signals of substituents*2
2-СН (1Н, s)
Harom
H-6 (1H, s)
6а
6с
8.37
8.80
7.40-8.25 (10Н, m)
7.42 (2Н, d);
7.51
8.08
—
2.43 (3Н, s)
8.32 (2Н, d), J = 8.4;
7.64-8.18 (5Н, m)
7.70 (2Н, d);
6g
8.80
8.10
—
8.20 (2Н, d), J = 8.4;
7.58-8.38 (5Н, m)
7.41-8.32 (10Н, m)
7.53-7.62 (5Н); 8.08 (2Н, d);
8.27 (2Н, d), J = 7.8
7.33-7.62 (9Н, m)
7а
8.62
8.60
7.25
7.26
4.44 (2Н, q); 1.47 (3Н, t)
4.48 (2Н, q); 1.47 (3Н, t)
7b
7g
8.59
7.26
4.52 (2Н, q); 1.51 (3Н, t)
_______
* The spectra of compounds 6a and 7a,b,g were recorded in CDCl3, and of
compounds 6c,g in DMSO-d6.
*2 For compounds 7a,b,g J = 7.0 Hz in the ethyl fragment.
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follows that in CDCl3 solutions the cyano derivatives 4a-e are in the imine 6,7-dihydro form B, but the
ethoxycarbonyl derivatives 5a,b,g are in the enamine 4,7-dihydro form A within the limits of sensitivity of NMR
spectroscopy. A mixture of A and B forms was noted in CDCl3 for compounds 4i and 5e.
In DMSO-d6 cyano derivatives 4a-j and their ethoxycarbonyl analogs 5a,b,e form a mixture of 4,7- and
6,7- dihydro forms, but compound 5g is present exclusively in tautomeric form A.
It was shown previously that a decisive influence on the tautomeric composition of dihydroazolopyrimidines
is exerted by the nature of the annelated azole ring [4, 5]. The equilibrium concentration of the imine form B
increases in the series of dihydro derivatives tetrazolo[1,5-a]- ≤ 1,2,4-triazolo-[1,5-a]- < 1,2,3-triazolo[1,5-
a]pyrimidine < pyrimido[1,2-a]benzimidazole < imidazo[1,2-a]pyrimidine ≤ pyrazolo[1,5-a]pyrimidine in
accordance with the fall in electron-withdrawing properties of the azole fragment [4-6]. Consequently, the
introduction of the electron-withdrawing cyano or ethoxycarbonyl groups into the pyrazole ring must lead to
growth of the equilibrium concentration of tautomer A. In reality the presence of the enamine tautomeric form in
solution was noted for all compounds of the 4 and 5 series, while for the close structural analogs reported in the
literature [3], 2-methyl-6,7(4,7)-dihydropyrazolo[1,5-a]pyrimidines, the tautomeric form A is encountered in
only 40% of cases.
In the series of ethoxycarbonyl derivatives 5 an additional factor stabilizing dihydroform A is an
intramolecular hydrogen bond involving the NH proton of the dihydropyrimidine ring and the carbonyl oxygen
atom of the ethoxycarbonyl group. This leads to a markedly higher concentration of the enamine form A in the
case of compounds 5a,b,e,g in comparison with compounds 4a,b,e,g.
In the series of carbonitriles 4 the influence of the solvent on the position of the tautomeric equilibrium
is displayed in its displacement in the direction of the NH forms in the proton-withdrawing DMSO in
comparison with CDCl3, which is explained by the formation of NH···DMSO hydrogen bonds. In the case of the
ethoxycarbonyl derivatives of 5 on the other hand, on going from CDCl3 to DMSO-d6 a displacement of the
equilibrium takes place in the direction of form B, which is caused by competition between DMSO molecules
and ethoxycarbonyl groups binding with the NH proton of the enamine form.
In addition to the factors enumerated above the substituents R1 and R2 proved to have a significant
influence on the position of the imine–enamine equilibrium. For example, in the case of compound 4a
(R1 = R2 = H) the content of form A in DMSO did not exceed 10%, while in solutions of the methoxy-substituted
compounds 4d,j (d R1 = 4-OMe, R2 = H; j R1 = R2 = 4–OMe) the ratio between the concentrations of forms A
and B levels off. Growth of the concentration of dihydro form A in comparison with 4a is also observed in the
case of the halo-substituted 4b,f,g,i (see Table 3).
EXPERIMENTAL
1
The IR spectra were recorded on a Specord M-82 spectrometer in KBr disks. The H NMR spectra of
compounds 4a-j and 6a,c,g were taken on a Varian 200 (200 MHz) spectrometer, of compounds 5a,b,e,g, and
7a,b,g on a Varian VX-300 (300 MHz) spectrometer, internal standard was TMS. A check on the composition of
reaction mixtures and the purity of the substances obtained was carried out by TLC on Silufol UV 254 plates,
eluent was chloroform–methanol, 5:1.
3-Cyano-5,7-diphenyl-6,7-dihydropyrazolo[1,5-a]pyrimidine (4a). A mixture of amine 1 (0.22 g,
2 mmol) and 1,3-diphenyl-2-propen-1-one 3a (0.42 g, 2 mmol) in DMF (1 ml) was boiled for 20 min in an
atmosphere of argon, cooled, and water (7-10 ml) added. The mixture was extracted with chloroform, the extract
was dried over anhydrous Na2SO4, the excess solvent was removed under reduced pressure, the residue, a
light-yellow oil, was crystallized from methanol, and compound 4a (0.45 g) was filtered off.
Compounds 4b-j were obtained analogously.
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1548

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3-Ethoxycarbonyl-5,7-diphenyl-4,7-dihydropyrazolo[1,5-a]pyrimidine (5a). A mixture of amine 2
(0.16 g, 1 mmol) and compound 3a (0.21 g, 1 mmol) in DMF (0.5 ml) was boiled for 20 min in an atmosphere of
argon, cooled, and water (7-10 ml) was added. The mixture was extracted with chloroform, the extract dried, and
the excess solvent was removed under reduced pressure. The oily residue was dissolved with heating in
2-propanol (5 ml), and the solution left for 3 days at –5 to 0oC. Compound 5a (0.23 g) was filtered off.
Compounds 5b,e,g were obtained analogously.
3-Cyano-5,7-diphenylpyrazolo[1,5-a]pyrimidine (6a). A mixture of amine 1 (0.11 g, 1 mmol) and
compound 3a (0.21 g, 1 mmol) in DMF (0.5 ml) was boiled for 15 min under conditions of free access to the
oxygen of the air, cooled, methanol (5-7 ml) was added, the mixture was kept at a temperature below 0oC for 1
day, and compound 6a (0.13 g) was filtered off. In addition the dihydro derivative 4a (0.1 g) was isolated from
the filtrate.
Compounds 6c,g were obtained analogously.
3-Ethoxycarbonyl-5,7-diphenylpyrazolo[1,5-a]pyrimidine (7a). A mixture of amine 2 (0.32 g,
2 mmol) and compound 3a (0.42 g, 2 mmol) in DMF (1 ml) was boiled for 15 min under conditions of free
access to the oxygen of the air, cooled, 2-propanol (10 ml) was added, the mixture was kept at a temperature
below 0oC for 1 day, and compound 7a (0.35 g) was filtered off. In addition the dihydro derivative 5a (0.1 g)
was recovered from the filtrate.
Compounds 7b,g were obtained analogously.
The work was carried out with the support of the Fund for Fundamental Investigations (FFI) of Ukraine
(project No. 0307/00154).
REFERENCES
1.
2.
3.
S. M. Desenko, V. D. Orlov, V. V. Lipson, O. V. Shishkin, K. A. Potekhin, and Yu. T. Struchkov, Khim.
Geterotsikl. Soedin., 109 (1993). [Chem. Heterocycl. Comp., 29, 95 (1993)].
S. V. Lindeman, Yu. T. Struchkov, O. V. Shishkin, S. M. Desenko, V. V. Lipson, and V. D. Orlov, Acta
Crystallogr., C49, 896 (1993).
V. V. Lipson, S. M. Desenko, M. G. Shirobokova, V. V. Borodina, T. M. Karnozhitskaya, and
D. A. Krupchitskii, Vestn. Kharkov Natl. Univ., 28, No. 477, Issue 5, 97 (2000).
S. M. Desenko, Khim. Geterotsikl. Soedin., 147 (1995). [Chem. Heterocycl. Comp., 31, 125 (1995)].
S. M. Desenko and V. D. Orlov, Azaheterocycles from Aromatic Unsaturated Ketones [in Russian],
Folio, Kharkiv (1998).
4.
5.
6.
E. S. Gladkov, Author’s Abstract of Dissertation for Candidate of Chemical Sciences, Kharkiv (2001).
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