Synthesis of new pyrazolo[1,5-a]pyrimidines and pyrazolo[3,4-b]pyridines

Article abstract of DOI:10.1002/jhet.5570380430

While 3(5)-aminopyrazole reacts with enaminonitrile to yield pyrazolo[1,5-a]pyrimidines, 3-amino-5-pyrazolone reacts with the same reagents to yields pyrazolo[3,4-b]pyridines.

Full text of DOI:10.1002/jhet.5570380430

Jul-Aug 2001
Synthesis of New Pyrazolo[1,5-a]pyrimidines
And Pyrazolo[3,4-b]pyridines
989
Saleh M. Al-Mousawi [a], Mohammad A. Mohammad [a]
and Mohamad H. Elnagdi* [b]
[a] Department of Chemistry, Faculty of Science, University of Kuwait, P.O. Box 5969, Safat 13060, KUWAIT
[b] Department of Chemistry, Faculty of Science, Cairo University, Giza, A. R. EGYPT
Received May 11, 2000
While 3(5)-aminopyrazole reacts with enaminonitrile to yield pyrazolo[1,5-a]pyrimidines, 3-amino-5-
pyrazolone reacts with the same reagents to yields pyrazolo[3,4-b]pyridines.
J. Heterocyclic Chem., 38, 989 (2001).
Azoloazines are biologically interesting molecules and
(DMFDMA) and subsequent treatment of the amidine 3
with benzoylacetonitrile and malononitrile to give 2a,b
respectively (Figure 1).
their chemistry is now receiving considerable attention
[1-3]. One of the major routes to azoloazines is the
reaction of α,β-unsaturated ketones, and/or nitriles with
azolylamine derivatives [4,5]. However, in many cases
the exact structure of the reaction products is difficult to
identify as a result of the close similarities between
possible reaction products. Previous publications, from
our laboratories recently described the synthesis of a
variety of new azoloazines whose structure was
established by NOE experiments [6,7] In conjunction with
this work, we report here the synthesis of a variety of new
pyrazolo[1,5-a]pyrimidines and pyrazolo[3,4-b]pyridines
via reaction of 3-aminopyrazole 1 and 3-amino-1-phenyl-
1H-pyrazole-5-one 8 with enaminones and with enamino-
nitriles.
The product of the reaction of 1 with 7c depended on the
reaction conditions. Thus refluxing 1 and 7c in pyridine for
3 hours afforded the pyrazolylaminoacrylate derivative 4,
in analogy with the reported formation of pyrazolyl-
aminoacrylate on reaction of 3-amino-5-phenylpyrazole
with the same reagent in refluxing ethanol [8]. However,
when a mixture of 1 and 7c was heated at reflux in xylene
in the presence of sodium hydride, a mixture of 5 and 6 in
a 2:3 ratio was formed. Compound 5 could also be formed
by cyclization of 4 in refluxing acetic acid, while long
reflux of 4 in xylene afforded again 5 and 6 in the same
ratio (2:3).
Compound 8 also reacted with 7a,d to yield products
of condensation by elimination of water and dimethyl-
Thus, we found that 1 reacts with the enamines 7a,b to
yield products of condensation by elimination of dimethyl-
1
amine. The H NMR of the product indicated disappear-
1
amine and water. The H NMR spectra clearly indicated
ance of both amino and methylene signals. Structure 9
was established by authentic synthesis. The condensa-
tion of 8 with DMFDMA gave the dimethylamino-
methylene derivative 10 which was then treated with
that the pyrazole 4-H were not involved in the reactions.
Structure 2 was established through authentic synthesis by
condensation of 1 with dimethylformamide-dimethylacetal

990
Vol. 38
S. M. Al-Mousawi, M. A. Mohammad and M. H. Elnagdi
N,N-Dimethyl-N-(1H-pyrazol-3-yl)-formamidine (3).
benzoylacetonitrile to give 11. Reaction of 11 with
ethanolic sodium ethoxide at reflux yielded 9a identical
in all respects with the product obtained from treatment
of 8 with 7a (Figure 2).
A mixture of 1 (0.01 mol) and DMFDMA (0.01mol) was
refluxed in xylene (25 ml) for 3 hours. The reaction mixture was
then allowed to cool to room temperature and the product was
collected and crystallized. Compound 3 formed colorless crystals
-1
from toluene, mp 115-117°, yield 95 %; ir: ν (cm ) : 3149 (NH),
1
2919 and 2830 (CH aliph.); H-nmr (DMSO-d ): δ 3.00 (s; 6H,
6
2CH ), 3.15 (s; NH + DMSO), 5.83 (d; 1H, H-4), 7.33 (d; 1H,
3
H-5), 7.89 (s; 1H,aminomethylene CH).
Anal. Calcd. for C H N : C, 52.17; H, 7.25; N, 40.58. Found:
6
10 4
C, 51.98; H, 7.09; N, 40.39.
Ethyl 2-Cyano-3-(pyrazol-3-yl)aminoacrylate (4).
A mixture of 1 (0.01 mol) and 7c (0.01 mol) was refluxed in
pyridine (25 ml) for 3 hours. The reaction mixture was then
poured on water. The product was collected and crystallized.
Compound 4 formed colorless crystals from methanol, mp
-1
185-186°, yield 32 %; ir: ν (cm ) 3290 and 3115 (2NH's), 2945
1
(CH aliph.), 2195 (CN), 1706 (CO); H-nmr (DMSO-d ): δ
6
1.18-1.38 (t; 3H, CH ), 4.07-4.30 (q; 2H, CH ), 6.11(d; 1H, H-4),
3
2
7.67 (d; 1H, H-3'), 8.19-8.51 (m; 1H, H-5), 10.82 (bd; 1H,
3-NH), 12.53 (bd; 1H, 1-NH).
Anal. Calcd. for C H N O : C, 52.42; H, 4.85; N, 27.18.
9
10 4 2
Found: C, 52.58; H, 4.78; N, 26.97.
Ethyl 7-Aminopyrazolo[1,5-a]pyrimidine-6-carboxylate (5).
A mixture of 1 (0.01 mol) and 7c (0.01 mol) was refluxed in
xylene (25 ml) in the presence of sodium hydride (0.01 mol) for
3hours. The solid product which precipitated during reflux was
collected while hot. The product separated was crystallized and
identified as 6. The filtrate was then allowed to cool to room
temperature and the product (compound 5) was then collected
and crystallized. Compound 5 formed colorless crystals from
EXPERIMENTAL
All melting points are uncorrected. IR spectra were recorded
on a Perkin Elmer FT-IR 2000 spectrometer. H NMR spectra
were obtained on a Bruker AC-80 spectrometer with DMSO-d
as solvent and TMS as internal standard. Elemental analysis were
performed on a LECO CHNS-932 analyzer.
1
6
-1
methanol, mp 136-138°, yield 25 %; ir: ν (cm ) 3345 (NH ),
2
1
2950 (CH aliph.), 1683 (CO); H-nmr (DMSO-d ): δ
1.26-1.44(t; 3H, CH ), 4.22-4.48(q; 2H, CH ), 6.53 (d; 1H, H-3),
6
3
2
7-Phenylpyrazolo[1,5-a]pyrimidine-6-carbonitrile (2a,b).
8.18 (d; 1H, H-2), 8.42 (bs; 2H, NH ), 8.62 (s; 1H, H-5).
2
Anal. Calcd. for C H N O : C, 52.43; H, 4.85; N, 27.10.
Found: C, 52.29; H, 4.95; N, 26.87.
Method A.
9
10 4 2
A mixture of 1 (0.01 mol) and 7a,b (0.01 mol) was refluxed in
ethanol (30 ml) in the presence of piperidine for 3hrs. The
reaction mixture was then allowed to cool to room temperature
and the product, was collected and recrystallized.
7-Oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-6-carbonitrile (6).
Compound 6 formed red crystals from ethanol/DMF, mp
-1
>300°, yield 36 %; ir: ν (cm ): 3390 (NH), 2205 (CN), 1663
1
(CO), H-nmr (DMSO-d ): δ 3.22 (s; NH + DMSO), 6.37 (d; 1H,
Method B.
6
H-3), 7.99 (d; 1H, H-2), 8.64 (s; 1H, H-5).
A mixture of 6 (0.01 mol) and benzoylacetonitrile (or malono-
nitrile) (0.01 mol) was refluxed in ethanol (30 ml) in the presence
of piperidine for 3 hours. The reaction mixture was then allowed to
cool to room temperature and the solid product formed, was
collected and crystallized. Compound 2a formed yellow crystals
Anal. Calcd. for C H N O: C, 52.50; H, 2.50; N, 35.00.
7
4 4
Found: C, 52.34; H, 2.60; N, 34.88.
3-Oxo-2,6-diphenyl-2H-pyrazolo[3,4-b]pyridine-5-carbonitrile
(9a).
-1
from ethanol, mp 220-221°, yield 25%; ir: ν (cm ) 3045
Method A.
1
(CH arom.), 2230 (CN); H-nmr (DMSO-d ): δ 6.89 (d; 1H, H-3),
6
A mixture of 8 (0.01 mol) and 7a (0.01 mol) was refluxed in
pyridine (20 ml) for 3 hours. The reaction mixture was then
poured on water. The product was collected and crystallized.
7.60-7.96 (m ; 5H, aromatic.), 8.28 (d; 1H, H-2),8.64 (s; 1H, H-5).
Anal. Calcd. for C H N : C, 70.90; H, 3.64; N, 25.45. Found:
C, 70.67; H, 3.58; N, 25.23.
13
8 4
Compound 2b formed yellow crystals from ethanol/DMF, mp
Method B.
-1
309-311°, yield 36%; ir: ν (cm ) 3350-3306 (NH ),2216 (CN);
2
1
A mixture of 11 (0.01 mol) and a solution of sodium ethoxide
(prepared from 0.01 mol sodium in 25 ml of ethanol) was
refluxed for 3 hours. The reaction mixture was then allowed to
cool to room temperature and neutralized with hydrochloric acid
H-nmr (DMSO-d ): δ 6.55 (d; 1H, H-3), 8.18 (d; 1H, H-2), 8.28
6
(s; 1H, H-5), 8.69 (bs; 2H, NH ).
2
Anal. Calcd. for C H N : C, 52.83; H, 3.14; N, 44.00. Found:
7
5 5
C, 752.75; H, 3.14; N, 43.70.

991
Jul-Aug 2001
Synthesis of New Pyrazolo[1,5-a]pyrimidines And Pyrazolo[3,4-b]pridines
(HCl). The product, was collected and crystallized. Compound
temperature and the solid product was collected and crystallized.
9a formed pale yellow crystals from ethanol, mp 259-261°, yield
Compound 11 formed orange crystals from ethanol, mp
-1
-1
32 %; ir: ν (cm ): 3428 (NH), 3071 (CH arom.) 2223 (CN), 1663
239-241°, yield 35 %; ir: ν (cm ) 3434 (NH), 3029 (CH arom.),
1
1
(CO), H-nmr (DMSO-d ): δ 7.22-7.94 (m; 11H, NH + arom.),
2210 (CN), 1607 (CO); H-nmr (DMSO-d ): δ 2.55 (s; 7H, NH +
6
6
8.80 (s; 1H, H-4).
2CH ), 6.98-8.34 (m; 12H, 2CH + arom.).
3
Anal. Calcd. for C H N O: C, 73.07; H, 3.85; N, 17.95.
Anal. Calcd. for C H N O: C, 70.58; H, 5.32; N, 19.60.
19 12
4
21 19
5
Found: C, 73.11; H, 3.90; N, 18.0.
Found: C,70.72; H, 5.49; N, 19.42.
3-Oxo-2,6-diphenyl-2H-pyrazolo[3,4-b]pyridine (9b).
Acknowledgment.
A mixture of 8 (0.01 mol) and 7d (0.01 mol) was refluxed in
pyridine (20 ml) for 3 hours. The reaction mixture was then
poured on water. The product, was collected and crystallized.
Compound 9b formed buff crystals from ethanol, mp 261-263°,
This work is financed through Kuwait University Research
Project Sc 099. We are grateful to the ANALAB facility at
Chemistry Department for the analytical and spectral
measurements.
-1
yield 58 %; ir: ν (cm ) 3445 (NH), 3030 (CH arom.), 1640 (CO),
1
H-nmr (DMSO-d ): δ 7.16-8.34 (m; 13H, all H's).
6
REFERENCES AND NOTES
Anal. Calcd. for C H N O: C, 75.26; H, 4.52; N, 14.63.
18 13
3
Found: C, 75.15; H, 4.59; N, 14.51.
[1] M. H. Elnagdi, N. Al-Awadi and A. W. Erian, in
"Comprehensive Heterocyclic Chem. II" A. R. Katritzky, C. W. Rees, and
E. F. V. Scriven, (ed's), Pergamon Press, Oxford, 4, p 431 (1996).
[2] S. M. Desenko, S. A. Komykhov, V. D. Orlov and H. Meier,
J. Heterocyclic Chem., 35, 989 (1998).
[3] J. Quiroga, B. Insuasty, S. Craz, P. Hernandez, A. Bolafios,
R. Moreno, A. Hormoza and R. H. de Almeidas, J. Heterocyclic
Chem.,35, 1333 (1998).
5-Amino-4-dimethylaminomethylene-2-phenyl-2,4-dihydro-
pyrazol-3-one (10).
A mixture of 8 (0.01 mol) and DMFDMA (0.01 mol) was fused
at room temperature for 3 minutes and the reddish orange paste, so
formed, was washed with acetone and then filtered. The residual
yellow solid, which is compound 10, was then crystallized.
Compound 10 formed bright yellow crystals from ethanol, mp
-1
167-169°, yield 45 %; ir: ν (cm ) 3352 and 3208 (NH ), 3027
[4] J. V. Greenhill, in "Comprehensive Heterocyclic Chemistry"
A. R. Katritzky and C. W. Rees, (ed's). Pergamon Press, Oxford, 5, p 305
(1984).
2
1
(CH arom.), 1663 (CO), H-nmr (DMSO-d ): δ 3.74 (s; 6H, 2CH ),
5.35 (bs; 2H, NH ), 6.94-7.98 (m; 6H,CH olefinic + arom.).
6
3
2
Anal. Calcd. for C H N O: C, 62.61; H, 6.09; N, 24.35.
Found: C, 62.48; H, 6.17; N, 24.16.
[5] M. H. Elnagdi, M. R. H. Elmoghayar and G. E. H. Elgemeie,
Adv. Heterocycl. Chem., 41, 319 (1987).
12 14
4
[6] A. Al-Enezi, B. Al-Saleh and M. H. Elnagdi, J. Chem. Res.
(S),4 (1997).
[7] S. M. Al-Mousawi, K. Kaul, M. A. Mohammad and
M. H. Elnagdi, J. Chem Res. (S), 318 (1997).
[8] M. H. Elnagdi, E. M. Kandeel and M. R. H. Elmoghayer,
Z. Naturforsch, 32b, 307 (1997).
3-(4-Dimethylaminomethylene-5-oxo-1-phenyl-4,5-dihydro-1H-
pyrazol-3-ylimino)-3-phenylpropionitrile (11).
A mixture of 10 (0.01 mol) and benzoylacetonitrile (0.01 mol)
was refluxed in ethanol (25 ml) in the presence of piperidine for
4 hours. The reaction mixture was then allowed to cool to room