Cyclization reactions of 5-aminopyrazoles with β-ketoesters, enamines and β-keto anilides: New synthetic routes to pyrazolo[1,5-a]pyrimidine derivatives

Article abstract of DOI:10.1002/jccs.200200151

The pyrazolo[1,5-a]pyrimidines 4, 10, 11 and 14 were synthesized from reaction of 4-aryazo-2,5-diaminopyrazoles 1 with cyclic β-ketoesters 2a,b or cyclic β-ketoesters 7, 8 or acetoacetanilide 12, respectively. The reaction of 1 with the enamines 15, 16 and 17 yielded also the pyrazolo[1,5-a]pyrimidines 18, 20 and 21, respectively.

Full text of DOI:10.1002/jccs.200200151

Journal of the Chinese Chemical Society, 2002, 49, 1051-1055
1051
Cyclization Reactions of 5-Aminopyrazoles with -Ketoesters, Enamines
and -Keto Anilides: New Synthetic Routes to Pyrazolo[1,5-a]pyrimidine
Derivatives
F. M. A. El-Taweela and T. M. Abu Elmaatib*
aChemistry Department, Faculty of Science, New Damietta, Mansoura University, Egypt
bFaculty of Specific Education, New Damietta, Mansoura University, P.O. Box 34517, Egypt
The pyrazolo[1,5-a]pyrimidines 4, 10, 11 and 14 were synthesized from reaction of 4-aryazo-2,5-
diaminopyrazoles 1 with cyclic -ketoesters 2a,b or cyclic -ketoesters 7, 8 or acetoacetanilide 12, respec-
tively. The reaction of 1 with the enamines 15, 16 and 17 yielded also the pyrazolo[1,5-a]pyrimidines 18, 20
and 21, respectively.
INTRODUCTION
5-Aminopyrazoles are versatile reagents and have been
4a was also preferred following a procedure recently re-
ported.6
Similarly, 5-aminopyrazole 1 reacted with -methyl-
acetoacetate 2b in refluxing acetic acid to yield also a product
via ethanol and water elimination. Structure 4b was estab-
lished for the reaction product on the bas i s of 1H-NMR spec-
trum that clearly indicated the absence of ester group and the
presence of signals corresponding to two methyl groups (cf.
Scheme I).
extensively utilized as synthetic starting components for
preparation of several polysubstituted fused pyrazoles.1-3
These fused pyrazoles are interesting as pharmaceuticals1-3
and biodegradable agrochemicals.4,5 In conjunction with our
interest in this class of compounds, we report here on the syn-
thesis of several new aminopyrazol[1,5-a]pyrimidines and
their azo analogues as potential antischistosomal agents. The
synthesized compounds possess latent functional substitu-
ents and appear promising for utility in further chemical
transformations and also for biological studies.
Scheme I
N
NH2
NH
ArN
H2N
N
R2
1
R1CH2COCHCO2Et
RESULTS AND DISCUSSION
2a, R1 = CO2Et, R2 = H
b, R1 = CH3, R2 = CH3
It has been found that compound 1 reacts with diethyl
acetonedicarboxylate (2a) to yield cyclocondensation prod-
uct that may be formulated as 4a and isomeric 6a. Although
structure 6a seemed more likely based on similarity to the
well established behavior of 5-aminopyrazoles 1 towards
-keto esters, an independent structure proof seemed mand a -
tory, as marked increment in reactivity of exocyclic amino ni-
trogen in 1 compared with other monoaminopyrazoles is to
be expected. Such increment results from the opposition of
the mesomeric effects of the two amino groups that increase
the electron density at each nitrogen atom. Structure 4a ap-
CH2R1
O
N
N
ArN
N
HN
NH
ArN
R2
R2
NH
CO2Et
H2N
N
CH2R1
H2N
N
O
5
3
-H2O
N
CH2R1
R2
H
O
N
N
N
ArN
H2N
ArN
R2
N
N
H2N
N
N
CH2R1
O
6
4
a, R1 = CH2CO2Et, R2 = H, Ar = C6H4Cl(p)
b, R1 = CH3, R2 = CH3, Ar = C6H4Cl(p)
c, R1 = CH3, R2 = CH3, Ar = C6H4OCH3(p)
1
Similarly, treatment of 1 with cyclic -ketoesters 7 and
pears more likely based on H-NMR spectrum which re-
8 in acetic acid afforded the pyrazolo[1,5-a]pyrimidine deriv-
atives 10 and 11, respectively (cf. Scheme II). The IR and
vealed one proton signal at = 5.96 ppm and = 10.5 ppm for
pyrimidine ring H-6 and NH groups, respectively. Structure
* Corresponding author. E-mail: email.tasaid@hotmail.com

1052 J. Chin. Chem. Soc., Vol. 49, No. 6, 2002
El-Taweel and Abu Elmaati
Scheme II
EtO2C
N
O
CH3
O
N
NH
NH
ArN
7 O
N
CH3
H2N
N
-C2H5OH
O
-H2O
O
9
H
O
N
N
ArN
N
H2N
N
N
Ph
CH3
O
EtO2C
10
H
O
a, Ar = C6H5
b, Ar = C6H4Cl(p)
O
Ph
N
N
ArN
N
NH2
NH
ArN
8
Ph
N
H2N
N
H2N
N
1
Ph
a, Ar = C6H5
b, Ar = C6H4Cl(p)
11
CH3
CH3COCH2CONHR
N
N
ArN
H2N
13
12
NH
-RNH2
NHR
N
-H2O
O
a, R = C6H4Cl(p)
b, R = C6H4OCH3(p)
CH3
N
N
ArN
N
H2N
N
OH
14
a, Ar = C6H5
b, Ar = C6H4OCH3(p)
mass spectra were consistent with the proposed structures.
pyrimidine 18 and 4-aminopyrazolo[1,5-a]pyrimidine 19
seemed possible products for such reaction; however, the
7-aminopyrazolo[1,5-a]pyrimidine 18 was established as a
reaction product based on 1H NMR spectra which revealed a
signal corresponding to the amino group at > 7.00 ppm. If
4-aminopyrazolo[1,5-a]pyrimidine 19 is the reaction prod-
uct, one would expect a signal at = 4-6 ppm for the amino
group. Deshielding of 7-aminopyrazolopyrimidine protons
by ring nitrogen anisotropy has been previously observed.12
Compound 18 proposed to form via initial addition of the
exocyclic amino group in 1 to the activated double bond in 15
by elimination of dimethylamine and cyclization through ad-
dition of the pyrazole NH to the cyano group.
Also, the reaction of 1 with acetoacetanilides 12 in ben-
zene containing a few drops of HCl afforded products via wa-
ter and primary aromatic amine elimination. The pyrazolo-
pyrimidines 14 were established as reaction products based
on their correct elemental analysis and spectral data (cf.
Scheme II). Compounds 14 are assumed to be formed via ini-
tial condensation of the exocyclic amino function in 1 with
the carbonyl group in 12 to give the intermediate 13 which
readily cyclized to the final isolable product 14.
Enamines are versatile reagents and their utilization in
synthesis of heterocycles has received considerable inter-
est.6-11 In continuation of our interest in synthesis of fused az-
oles, we report here on the reactivity of 5-aminopyrazoles 1
towards enaminonitrile 15 and the enaminones 16 and 17.
Thus, reaction of 1 with the enaminonitrile 15 in ethanol con-
taining a few drops of acetic acid afforded a product with
dimethylamine elimination. The 7-aminopyrazolo[1,5-a]-
In a similar way, compound 1 reacted with 1-(3-
coumarinyl)-3-(N,N-dimethylamino)-2-propen-1-one (16)
and 2-(N,N-dimethylaminomethylene)indane-1,3-dion (17)
to afford the pyrazolo[1,5-a]pyrimidines 20 and 21, respec-
tively (cf. Scheme III).

New Synthetic Routes to Pyrazolo[1,5-a]pyrimidines
J. Chin. Chem. Soc., Vol. 49, No. 6, 2002 1053
Scheme III
N
N
ArN
R`
N
R`
CN
H2N
N
NH2
N
NMe2
18a, Ar = C6H4Cl(m), R` =
15
N
H
N
-NHMe2
b, Ar = C6H4CH3(O), R` =
N
H
NH2
N
N
ArN
R`
N
H2N
N
19
O
R
NMe2
N
N
ArN
N
NH2
NH
ArN
16
N
H2N
N
H2N
N
-HNMe2
-H2O
R
1
20
a, Ar = C6H4Cl(m), R =
b, Ar = C6H4CH3(m), R =
O
O
O
O
O
NMe2
N
N
ArN
O
17
O
N
-HNMe2
-H2O
H2N
N
21, Ar = C6H4Cl(m)
EXPERIMENTAL
ppm): 1.21-1.28 (t, J = 7 Hz, 3H, CH3), 3.86 (s, 2H, CH2),
4.16-4.23 (q, J = 7 Hz, 2H, CH2), 5.96 (s, 1H, pyrimidine
H-6), 6.74 (s, 2H, NH2), 7.56-7.60 (d, J = 8.8 Hz, 2H, aro -
matic protons), 7.85-7.90 (d, J = 8.8 Hz, 2H, aromatic pro-
tons), 10.5 (s, 1H, NH). C16H15ClN6O3 (374.74). MS m/z 374
(M+). Calcd. C, 51.28, H, 4.03, N, 22.42. Found C, 51.23, H,
4.11, N, 22.12%.
All melti n g points are uncorrected. IR spectra were re-
corded in KBr disks using a Shimadzu IR-740 spectropho-
tometer. 1H NMR spectra were recorded on a Bruker Ac-80
spectrometer with [2H6] DMSO as solvent and TMS as inter-
nal standard; chemical shifts are reported in units (ppm).
Mass spectra were measured on Gs/MS INCOS XL Finnigan
MAT. Microanalysis was performed on LECOCHNS-932.
2-Amino-3-(4-chlorophenylazo)-6,7-dimethyl-4,5-dihydro-
5-oxo-pyrazolo[1,5-a]pyrimidine (4b)
Preparation of pyrazolo[1,5-a]pyrimidines (4)
Red crystals from DMF, m.p. 294-296 C, yield 70%.
IR ( max/cm-1): 3443, 3254 (NH2, NH), 1660 (CO), 1640
A solution of 1 (0.01 mol) and (0.01 mol) of 2a or 2b in
acetic acid (20 mL) was heated under reflux for 4 hours. The
reaction mixture was cooled and the solid products so formed
were collected by filtration and recrystallized from the proper
solvent and then identified as 4a,b.
1
(C=N). H-NMR [2H6] DMSO ( , ppm): 1.9 (s, 3H, CH3),
2.30 (s, 3H, CH3), 6.65 (s, 2H, NH2), 7.40-7.60 (d, J = 8.8 Hz,
2H, aromatic protons), 7.75-7.92 (d, J = 8.8 Hz, 2H, aromatic
protons), 8.10 (s, 1H, NH). C14H13ClN6O (316.75). Calcd. C,
53.09, H, 4.16, N, 26.53. MS m/z 316 (M+). Found C, 53.23,
H, 4.11, N, 26.12%.
Ethyl 2-amino-3-(4-chlorophenylazo)-4,5-dihydro5-oxo-
pyrazolo[1,5-a]pyrimidine-7-yl]ethanoate (4a)
Red crystals from ethanol/dioxane, m.p. 162-164 C,
yield 65%. IR ( max/cm-1): 3473, 3294 (NH2, NH), 1726
2-Amino-6,7-dimethyl-4,5-dihydro-5-oxo-3-(4-methoxy-
phenylazo)pyrazolo[1,5-a]pyrimidine (4c)
1
(CO), 1660 (CO), 1600 (N=N). H-NMR [2H6] DMSO ( ,
Orange crystals from ethanol/dioxane, m.p. 286-288

1054 J. Chin. Chem. Soc., Vol. 49, No. 6, 2002
El-Taweel and Abu Elmaati
C, yield 65%. IR ( max/cm-1): 3500, 3340 (NH, NH2), 1680
C, yield 73%. IR ( max/cm-1): 3490, 3433, 3278 (OH, NH2),
1
1
(CO), 1630 (C=N), 1610 (N=N). H-NMR [2H6] DMSO ( ,
1640 (C=N), 1610 (N=N). H-NMR [2H6] DMSO ( , ppm):
ppm): 1.93 (s, 3H, CH3), 2.21 (s, 3H, CH3), 3.70 (s, 3H,
OCH3), 6.80 (s, 2H, NH2), 7.10-7.30 (d, J = 8.8 Hz, 2H, aro -
matic protons), 7.66-7.80 (d, J = 8.8 Hz, 2H, aromatic pro-
tons), 8.10 (s, 1H, NH). C15H16N6O2 (312.33). Calcd. C,
57.67, H, 5.16, N, 26.91. MS m/z 312 (M+). Found C, 57.11,
H, 5.34, N, 26.84%.
2.3 (s, 3H, CH3), 5.83 (s, 1H, CH), 6.65 (s, 2H, NH2), 7.36-
7.80 (m, 5H, aromatic H), 10.2 (s, 1H, OH). C13H12N6O
(268.27). MS m/z 268 (M+). Calcd. C, 58.20, H, 4.51, N,
31.33. Found C, 58.00, H, 4.70, N, 31.22%.
2-Amino-3-(4-methoxyphenylazo)-5-methyl-7-hydroxy-
pyrazolo[1,5-a]pyrimidine (14b)
Reaction of 1 with -ketoesters 7, 8, acetoacetanilide
derivatives 12: Formation of compounds 10, 11 & 14
A mixture of 1 (0.01 mol) and (0.01 mol) of each of cy-
clic -ketoesters 7, 8 or acetoacetanilide derivatives 12 in
acetic acid (30 mL) was heated under reflux for 3 hours. The
solvent was then evaporated und e r vacuo and the resulting
solid products were filtered off and recrystallized from the
suitable solvent.
Red crystals from DMF, m.p. 260-263 C, yield 75%.
IR ( max/cm-1): 3480, 3433, 3278 (OH, NH2), 1635 (C=N),
1
1615 (N=N). H-NMR [2H6] DMSO ( , ppm): 2.2 (s, 3H,
CH3), 3.8 (s, 3H, OCH3), 5.65 (s, 1H, CH), 6.60 (s, 2H, NH2),
6.95-7.15 (d, J = 8 Hz, 2H, aromatic H), 7.80-7.95 (d, J = 8
Hz, 2H, aromatic H), 10.10 (s, 1H, OH). C14H14N6O2
(298.30). MS m/z 298 (M+). Calcd. C, 56.37, H, 4.73, N,
28.17. Found C, 56.30, H, 4.74, N, 28.12%.
2-Amino-3-phenylazo-7,12-dihydro-6-methylpyrazolo[3,4-
d]pyrimidine-5,8-dione (10a)
Preparation of pyrazolopyrimidines 18, 20 and 21
A solution of 1 (0.01 mol) in acetic acid (30 mL) which
treated with (0.01 mol) of 15, 16 or 17 was heated under re-
flux for 2 hours. The solvent was then evaporated und e r
vacuo and triturated with ethanol. The solid deposited was
collected by filtration and recrystallized from the suitable
solvent to give 18, 20 and 21 respectively.
Brown crystals from DMF, m.p. > 300 C, yield 65%.
IR ( max/cm-1): 3350, 3300 (NH2, NH), 1715, 1700 (CO),
1600 (N=N). C15H13N7O2 (323.3). MS m/z 323 (M+) Calcd. C,
55.72, H, 4.05, N, 30.32. Found C, 55.63, H, 4.32, N, 30.11%.
2-Amino-3-(4-chlorophenylazo)-7,12-dihydro-6-methyl-
pyrazolo[3,4-d]pyrimidine-5,8-dione (10b)
6-(1H-Benzimidazol-2-yl)-3-(3-chlorophenylazo)-pyrazolo-
[1,5-a]pyrimidine-2,7-diamine (18a)
Brown crystals from DMF, m.p. > 300 C, yield 70%. IR
(
max/cm-1): 3350, 3300 (NH2, NH), 1715, 1700 (CO), 1600
Red crystals from acetic acid, m.p. > 300 C, yield
75%. IR ( max/cm-1): 3490, 3395 (NH2, NH), 1605 (N=N).
1H-NMR [2H6] DMSO ( , ppm): 7.40 (s, 2H, NH2), 7.45-7.70
(m, 8H, aromatic H), 8.32 (s, 1H, pyrimidine H-5), 8.99 (s,
2H, NH2), 9.60 (s, 1H, NH). C19H14ClN4 (403.83). MS m/z
403 (M+). Calcd. C, 56.51, H, 3.49, N, 31.22. Found C, 56.50,
H, 3.80, N, 31.34%.
(N=N). C15H12ClN7O2 (357.75). MS m/z 357 (M+). Calcd. C,
50.36, H, 3.38, N, 27.41. Found C, 50.23, H, 3.11, N, 27.12%.
2-Amino-3-phenylazo-6,8-diphenyl-6,7-dihydro-4H-
pyrazolo[1,5-a]quinazoline-5-one (11a)
Brown crystals from DMF, m.p. 292 C, yield 63%. IR
(
max/cm-1): 3340, 3300 (NH2), 1700 (CO), 1605 (N=N).
C28H20N6O (456.49). MS m/z 456 (M+). Calcd. C, 73.66, H,
6-(1H-Benzimidazol-2-yl)-3-(2-methylphenylazo)pyrazolo-
[1,5-a]pyrimidine-2,7-diamine (18b)
4.41, N, 18.41. Found C, 73.34, H, 4.20, N, 18.23%.
Brown powd e r from ethanol/DMF, m.p. 280-282 C,
yield 70%. IR ( max/cm-1): 3460, 3356 (NH2, NH), 1620
2-Amino-3-(4-chlorophenylazo)-6,8-diphenyl-6,7-dihydro-
4H-pyrazolo[1,5-a]quinazoline-5-one (11b)
1
(N=N). H-NMR [2H6] DMSO ( , ppm): 2.00 (s, 3H, CH3),
Brown crystals from DMF, m.p. 290 C, yield 63%. IR
7.43 (s, 2H, NH2), 7.50-7.80 (m, 8H, aromatic H), 8.40 (s, 1H,
pyrimidine H-5), 8.90 (s, 2H, NH2), 9.70 (s, 1H, NH).
C20H17N9 (383.42). MS m/z 383 (M+). Calcd. C, 62.65, H,
4.47, N, 32.88. Found C, 62.32, H,4.11, N, 32.64%.
(
max/cm-1): 3340, 3300 (NH2, NH), 1700 (CO), 1605 (N=N).
C28H21ClN6O (492.96). MS m/z 492 (M+). Calcd. C, 68.22, H,
4.29, N, 17.05. Found C, 68.23, H, 4.11, N, 17.12%.
2-Amino-3-phenylazo-5-methyl-7-hydroxypyrazolo[1,5-a]-
pyrimidine (14a)
2-Amino-2-(3-chlorophenylazo)-4-(coumarin-3-yl)pyrazolo-
[1,5-a]pyrimidine (20a)
Scarlet red crystals from ethanol/DMF, m.p. 250-252
Red crystals from methanol/DMF, m.p. 276-278 C,

New Synthetic Routes to Pyrazolo[1,5-a]pyrimidines
J. Chin. Chem. Soc., Vol. 49, No. 6, 2002 1055
yield 70%. IR ( max/cm-1): 3433, 3278 (NH2), 1725 (CO),
1620 (N=N). 1H-NMR [2H6] DMSO ( , ppm): 7.36-7.92 (m,
10H, aromatic H), 8.70 (s, 2H, NH2), 9.10 (s, 1H, coumarin
H-4). MS m/z 416 (M+) C21H13ClN6O2 (416.82). Calcd. C,
60.51, H, 3.14, N, 20.16. Found C, 60.00, H, 3.70, N, 20.22%.
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Red crystals from dioxan, m.p. 198-200 C, yield 75%.
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(m, 10H, aromatic H), 8.80 (s, 2H, NH2), 9.10 (s, 1H,
coumarin H-4). C22H16N6O2 (396.41). MS m/z 396 (M+)
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(
max/cm-1): 3410, 3294 (NH2), 1708 (CO), 1620 (N=N). MS
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Received December 3, 2001.
Key Words
2,5-Diaminopyrazoles; Pyrazolo[1,5-a]pyrimidines.