Heterocyclic synthesis with nitriles: Synthesis of pyrazolopyrimidine and pyrazolopyridine derivatives

Article abstract of DOI:10.1080/00397910802517814

The reaction of N1-substituted-5-amino-4-cyanopyrazoles with malononitrile and diethylmalonate occurs with formation of 6-substituted pyrazolo[3,4-d] pyrimidines, and pyrazolo[3,4-b]pyridines respectively. The structures of the products and conceivable mechanisms are discussed. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910802517814

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Heterocyclic Synthesis
with Nitriles: Synthesis of
Pyrazolopyrimidine and
Pyrazolopyridine Derivatives
Abdellatif M. Salaheldin a , Ana M. F. Oliveira-
Campos a & Lígia M. Rodrigues a
a Chemistry Center, IBQF, University of Minho,
Campus de Gualtar , Braga, Portugal
Published online: 04 Mar 2009.
To cite this article: Abdellatif M. Salaheldin , Ana M. F. Oliveira-Campos & Lígia M.
Rodrigues (2009) Heterocyclic Synthesis with Nitriles: Synthesis of Pyrazolopyrimidine
and Pyrazolopyridine Derivatives, Synthetic Communications: An International Journal
for Rapid Communication of Synthetic Organic Chemistry, 39:7, 1186-1195
To link to this article: http://dx.doi.org/10.1080/00397910802517814
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Synthetic Communications1, 39: 1186–1195, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802517814
Heterocyclic Synthesis with Nitriles:
Synthesis of Pyrazolopyrimidine and
Pyrazolopyridine Derivatives
Abdellatif M. Salaheldin, Ana M. F. Oliveira-Campos,
´
and Lıgia M. Rodrigues
Chemistry Center, IBQF, University of Minho, Campus de Gualtar, Braga,
Portugal
Abstract: The reaction of N1-substituted-5-amino-4-cyanopyrazoles with
malononitrile and diethylmalonate occurs with formation of 6-substituted
pyrazolo[3,4-d]pyrimidines, and pyrazolo[3,4-b]pyridines respectively. The struc-
tures of the products and conceivable mechanisms are discussed.
Keywords: Aminopyrazole, diethylmalonate, malononitrile, pyrazolo[3,4-b]pyri-
dines, pyrazolo[3,4-d]pyrimidines
INTRODUCTION
Pyrazolopyridines, pyrazolopyrimidines, and related fused heterocycles
are of interest as potential bioactive molecules. Pyrazolo[3,4-d]pyrimi-
dines were identified as a general class of adenosine receptors[1–3] because
of the similarity between their structures and purines. Pyrazolo[3,4-b]
pyridines are also important compounds as a result of their biological
activity and structural relationship to azaindoles. A number of pyrazolo-
[3,4-b]pyridines are potentially biologically active compounds as new
inhibitors of xantine oxidase.[4,5]
Received April 4, 2008.
Address correspondence to Abdellatif M. Salaheldin, Centro de Quımica,
´
IBQF, Universidade do Minho, Campus de Gualtar, 4710-057 Braga, Portugal.
E-mail: salaheldin@quimica.uminho.pt
1186

Heterocyclic Synthesis with Nitriles
1187
Scheme 1. Reaction of compound 1 with active methylene reagents.
Because of this wide range of activities, we have been interested on
ortho-aminocyanopyrazoles[5,6] or their derivatives as inhibitors of
xanthine oxidase.[7] For this purpose, we started from the key intermedi-
ates 1a–d (N1-substituted-5-amino-4-cyanopyrazoles) 1 (Scheme 1) and
reacted them with malononitrile and diethylmalonate to obtain pyra-
zolo[3,4-d]pyrimidines and pyrazolo[3,4-b]pyridines respectively.
RESULTS AND DISCUSSION
With the aim of obtaining condensed pyrazolo[3,4-d]pyrimidine and
pyrazolo[3,4-b]pyridine systems, the condensation was carried out with
a substituted aminopyrazole, which contains a cyano group in the ortho
position, with malononitrile and diethylmalonate.
The N1-substituted-5-amino-4-cyanopyrazoles 1, were used as start-
ing materials as they contain an amino and a cyano group in adjacent
positions, which are required for the synthesis of the condensed systems
including pyridine and pyrimidine.
Reaction of compound 1a with malononitrile in refluxing ethanol
in the presence of triethylamine afforded a yellow crystalline solid of

1188
A. M. Salaheldin, A. M. F. Oliveira-Campos, and L. M. Rodrigues
mp 254–256 ꢀC. It was expected that this reaction would give the
pyrazolopyrimidine 4a or pyrazolopyridine 5a via the intermediate 3a.
However, the micro-analytical data showed that this product has the
molecular formula C20H16N8. Furthermore, the mass spectrum (EI) of
this product showed a molecular ion at m=z ¼ 368, and the IR spectrum
displayed an absorption at 3463 cmꢁ1, corresponding to NH2 stretching,
and no CN absorption. The 1H NMR spectrum revealed two singlets for
the amino groups at 5.44 and 5.88 ppm and two singlets for the pyrazole
H-3 protons. Structure 2a was thus suggested for this product. The
formation of compound 2a may be envisaged via initial condensation
of the amino group of one molecule of the o-aminonitrile with the cyano
group of a second molecule to give an intermediate amidine, which then
undergoes a second, but intramolecular, amine–nitrile condensation to
give the isolated product. To confirm this hypothesis, reflux of
compound 1a in ethanol and triethylamine afforded a product completely
identical to 2a. A similar result had been established by Taylor and
Borror in the formation of 2a (Scheme 1).[8]
Compounds 1b–d were refluxed under the same reaction conditions
to afford 2b–d.
In ethanolic sodium ethoxide solution, compounds 1a and 1b reacted
with malononitrile to afford white powders of mp 242–244 ꢀC for 4a and
296–298 ꢀC for 4b, respectively. The 1H NMR spectrum of compound 4a
revealed a methylene singlet at d 4.17 ppm and pyrazole H-3 as a singlet
at 8.34 ppm besides other signals attributable to an aromatic compound
and only one NH2 group at 8.0 ppm as expected. Based on these data, it
seemed that a –CH2CN side chain was present and that the cyclization
took place by addition of the NH2 in the pyrazole 1 to the CN of the mal-
ononitrile to form the amidine intermediate 3, followed by an attack of
the newly formed amino group to the CN of 1 to afford the pyrazolopyr-
imidine 4 and not the pyrazolopyridine 5, as shown in Scheme 1. Similar
cyclizations with other nitriles have been reported.[9]
In contrast, reaction of compounds 1a,b with diethylmalonate in etha-
nolic sodium ethoxide solution gave pyrazolopyrimidines 6a,b. The struc-
ture of compounds 6 was confirmed by mass and NMR spectroscopic
1
data. The H NMR spectrum of compound 6a revealed the ester group
as a triplet for the CH3 protons at 1.33 ppm and a quartet for the CH2 pro-
tons at 4.40 ppm, besides other signals assigned to aromatics, pyrazole
H-3, one NH2 group, and an OH signal at 12.31 ppm (Scheme 1).[10]
In an attempt to introduce a formyl group at position 3 in pyrazole 1,
aminopyrazole 1 was reacted with Vilsmeier reagent (DMF–POCl3) at
70 ꢀC for 3 h. For the product which was obtained, structure 8 was pro-
posed based on the NMR data, which indicated the presence of an OH
group and the pyrazole H-3. The reaction proceeded via the intermediacy

Heterocyclic Synthesis with Nitriles
1189
Scheme 2. Preparation of 4-hydropyrazolopyrimidine 8.
of 7 (Scheme 2). The structure of compound 8b could be confirmed by an
alternative synthesis, as described previously, converting 1b to the amide
9, by treatment with cold concentrated sulfuric acid, followed by boiling
compound 9 [mp 202–204 ꢀC (lit. mp 204–205 ꢀC)[11]], in formamide. The
product isolated was the 4-hydroxypyrazolo[3,4-d]pyrimidine 8b, whose
spectral characteristics were completely coincident with the sample
obtained before (Scheme 2).
Compound 8b, 4-hydroxypyrazolopyrimidine, was easily converted
to the corresponding 4-chloropyrazolopyrimidine, the precursor to the
4-substituted aminopyrazolopyrimidine, as we described recently.[6]
EXPERIMENTAL
General Procedures
Melting points were determined on a Gallenkamp melting-point appara-
tus and are uncorrected. IR spectra were registered on a Perkin-Elmer
1
FTIR-1600. H NMR (300 MHz) and 13C NMR (75.4 MHz) spectra
were recorded on a Varian Unity Plus spectrometer. Double resonance,
heteronuclear multiple quantum correlation (HMQC) and heteronuclear
multiple bond correlation (HMBC) experiments were carried out for

1190
A. M. Salaheldin, A. M. F. Oliveira-Campos, and L. M. Rodrigues
complete assignment of proton and carbon signals in the NMR spectra
whenever possible. High-resolution mass spectra (HRMS) were deter-
mined on a AutoSpec E spectrometer. Elemental analyses were obtained
on a Leco CHNS-932 instrument. Compound 9 was prepared by a
known method.[11]
General Procedure for Preparation of 2a–d
A solution of N1-substituted-5-amino-4-cyanopyrazoles 1a–d (0.2 mol) in
ethanol (20 mL) and triethylamine (2 mL) was heated under reflux for 7 h
and then concentrated under reduced pressure. The solid product so
formed was collected by filtration, washed with ethanol, and crystallized
from EtOH–H2O.
Data
6-(5-Amino-1-phenyl-1H-pyrazol-4-yl)-1-phenyl-1H-pyrazolo[3,4-d]-
pyrimidin-4-amine (2a)
Pale yellow solid (84%), mp 254–256 ꢀC (EtOH) (lit.[8] mp 255–257 ꢀC);
tmax (Nujol mull): 3462 and 3302 (NH2) cmꢁ1; dH (CDCl3): 5.57 (s,
2H, C-500-NH2), 5.89 (s, 2H, C-4-NH2), 7.30–7.42 (m, 2H, Ar-H), 7.52
(d, 2H, 8.1 Hz, Ar-H), 7.60–7.67 (m, 2H, Ar-H), 8.02 (s, 1H, H-300),
8.11 (d, 2H, J ¼ 8.1 Hz, Ar-H), 8.23 (s, 1H, H-3); dC (CDCl3): 99.04
(C-400), 103.34 (C-3a), 121.72 (C-20, C-60 or C-2000, C-6000), 123.78 (C-20,
C-60 or C-2000, C-6000), 126.45 (C-40 or C-4000), 127.68 (C-4000 or C-40),
129.06 (C-30, C-50 or C-3000, C-5000), 129.64 (C-30, C-50 or C-3000, C-5000),
132.30 (C-300), 138.23 (C-10 or C-1000), 139.12 (C-1000 or C-10), 141.03
(C-3), 146.89 (C-7a), 154.19 (C-500), 157.14 (C-4), 160.42 (C-6). m=z (%)
368 [Mþ] (100). Anal. calcd. for C20H16N8 (368.39): C, 65.21; H, 4.38;
N, 30.42. Found: C, 65.10; H, 4.46; N, 29.99.
6-(5-Amino-1-(4-chlorophenyl)-1H-pyrazol-4-yl)-1-(4-chlorophenyl)-
1H-pyrazolo[3,4-d]pyrimidin-4-amine (2b)
Pale yellow solid (72%), mp 277–278 ꢀC (EtOH–DMF); tmax (Nujol
mull): 3463 and 3304 (NH2) cmꢁ1; dH (DMSO-d6): 6.89 (s, 2H, NH2),
7.56–7.70 (m, 6H, Ar-H), 7.92 (br s, 2H, NH2), 8.08 (s, 1H, H-3 or
H-300), 8.28 (s, 1H, H-3 or H-300), 8.30 (d, 2H, J ¼ 9.0, Ar-H). Anal. calcd.
for C20H14Cl2N8 (437.28): C, 54.93; H, 3.23; N, 25.62. Found: C, 55.00;
H, 3.23; N, 25.47.

Heterocyclic Synthesis with Nitriles
1191
6-(5-Amino-1-p-tolyl-1H-pyrazol-4-yl)-1-p-tolyl-1H-pyrazolo[3,4-d]-
pyrimidin-4-amine (2c)
Pale yellow solid (78%), mp 262–264 ꢀC (EtOH); tmax (Nujol mull):
3395, 3336, and 3318 (NH2) cmꢁ1; dH (DMSO-d6): 2.35 (3H, s,
CH3), 2.36 (3H, s, CH3), 6.74 (2H, s, C-4-NH2), 7.33 (2H, d,
J ¼ 8.1 Hz, H-30, H-50 or H-3000, H-5000), 7.34 (2H, d, J ¼ 8.1 Hz, H-30,
H-50 or H-3000, H-5000), 7.50 (2H, d, J ¼ 8.4 Hz, H-20, H-60 or H-2000,
H-6000), 7.81 (2H, br s, C-500-NH2), 7.98 (1H, s, H-3), 8.04 (2H, d,
J ¼ 8.4 Hz, H-20, H-60 or H-2000, H-6000), 8.24 (1H, s, H-300); dC
(DMSO-d6): 20.66 (CH3), 20.61 (CH3), 98.58 (C-400), 102.40 (C-3a),
120.58 (C-200, C-60 or C-2000, C-6000), 123.24 (C-20, C-60 or C-2000, C-6000),
129.65 (C-3 , C-50 or C-3000, C-5000), 129.81 (C-30, C-50 or C-3000, C-5000),
134.05 (C-300), 135.12 (C-40 or C-4000), 136.21 (C-4000 or C-40), 136.41
(C-10 or C-1000), 136.90 (C-1000 or C-10), 140.05 (C-3), 147.71 (C-7a),
153.82 (C-500), 157.98 (C-4), 160.14 (C-6). Anal. calcd. for C22H20N8
212 H2O (441.45): C, 59.80; H, 4.53; N, 25.37. Found: C, 59.82; H,
4.83; H, 25.06.
6-(5-Amino-1-(4-bromophenyl)-1H-pyrazol-4-yl)-1-(4-bromophenyl)-
1H-pyrazolo[3,4-d]pyrimidin-4-amine (2d)
Pale yellow solid (74%), mp 284–285 ꢀC (EtOH–DMF); tmax (Nujol
mull): 3449, 3391, and 3301 (NH2) cmꢁ1; dH (DMSO-d6): 6.90
(2H, s, NH2), 7.33 (2H, d, J ¼ 9.0 Hz, Ar-H), 7.69–7.78 (4H, m,
Ar-H), 7.92 (2H, br s, NH2), 8.09 (1H, s, H-3 or H-300), 8.26
(2H, d, J ¼ 9.0 Hz, Ar-H), 8.28 (1H, s, H-300 or H-30). m=z (%)
(FABþ) 525 [Mþ þ 1, 79Br, 79Br] (18), 527 [Mþ þ 1, 79Br, 81Br]
(32), 529 [Mþ þ 1, 81Br, 81Br] (19). Anal. calcd. for C20H14Br2N8
(526.19): C, 45.65; H, 2.68; N, 21.30. Found: C, 45.70; H, 2.75;
N, 21.05.
General Procedure for Preparation of 4a,b and 6a,b
A mixture of 1 (20 mmol) and malononitrile or diethylmalonate (20
mmol) was added to 20 mL freshly prepared sodium ethoxide solu-
tion [prepared by adding 1.0 g sodium metal into absolute ethanol
(20 mL)], and the mixture was refluxed for 7 h and left to cool over-
night. The solid product so formed was collected by filtration,
washed with ethanol, and crystallized from ethanol, unless other-
wise stated.

1192
A. M. Salaheldin, A. M. F. Oliveira-Campos, and L. M. Rodrigues
Data
2-(4-Amino-1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-
acetonitrile (4a)
Pale yellow crystals (77%), mp 242–244 ꢀC (EtOH); tmax (Nujol mull):
3463 and 3296 (NH2), 2213 (CN) cmꢁ1; dH (DMSO-d6): 4.17 (s, 2H,
CH2), 7.33 (t, 1H, J ¼ 7.5 Hz, H-40), 7.54 (t, 2H, J ¼ 7.2 Hz, H-30,
H-50), 8.00 (br s, 1H, NH2), 8.07 (br s, 2H, NH2), 8.10–8.25 (br s,
1H, NH2), 8.20 (d, 2H, J ¼ 7.5 Hz, H-20, H-60), 8.34 (s, 1H, H-3); dC
(DMSO-d6): 27.77 (CH2), 100.13 (C-3a), 117.61 (CN), 120.45 (C-20,
C-60), 124.12 (C-40), 129.12 (C-30, C-50), 134.13 (C-3), 138.86 (C-10),
153.75 (C-7a), 158.34 (C-4), 159.67 (C-6). Anal. calcd. for C13H10N6
(250.26): C, 62.39; H, 4.03; N, 33.58. Found: C, 62.27; H, 4.22; N,
33.63.
2-[4-Amino-1-(4-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-
acetonitrile (4b)
Yellow powder (81%), mp 296–298 ꢀC (EtOH–DMF); tmax (Nujol mull):
3469 and 3306, (NH2), 2218 (CN) cmꢁ1; dH (DMSO-d6): 4.17 (s, 2H,
CH2), 7.61 (d, 2H, J ¼ 9.3 Hz, H-30, H-50), 8.04 (br s, 2H, NH2), 8.25
(d, 2H, J ¼ 9.0 Hz, H-20, H-60), 8.37 (s, 1H, H-3); dC (DMSO-d6): 27.81
(CH2), 100.23 (C-3a), 117.63 (CN), 121.82 (C-20, C-60), 129.18 (C-30,
C-50), 130.22 (C-40), 134.63 (C-3), 137.75 (C-10), 153.89 (C-7a), 158.37
(C-4), 159.90 (C-6). m=z (%) (TOF) 284 [Mþ, 35Cl] (100), 286 [Mþ,
37Cl] (18). C13H9ClN6 (284.70): C, 54.84; H, 3.19; N, 29.52. Found: C,
54.78; H, 3.08; N, 29.42.
Ethyl 4-Amino-1-(phenyl)-6-hydroxy-1H-pyrazolo[3,4-b]pyridine-
5-carboxylate (6a)
White powder (89%), mp 197–199 ꢀC (EtOH); tmax (Nujol mull): 3505
and 3395 (NH2), 3245 (br, OH), 1660 (C¼O) cmꢁ1; dH (DMSO-d6):
1.34 (t, 3H, J ¼ 7.5 Hz, CH3), 4.38 (q, 2H, J ¼ 7.5 Hz, CH2), 7.31 (t,
1H, J ¼ 7.5 Hz, H-40), 7.51 (t, 2H, J ¼ 7.5 Hz, H-30), 8.06 (d, 4H,
J ¼ 7.8 Hz, H-20, H-60, NH2), 8.44 (s, 1H, H-3), 12.32 (br s, 1H, OH);
dC (DMSO-d6): 14.30 (CH3), 61.24 (CH2), 86.57 (C-5), 102.09 (C-3a),
121.01 (C-20, C-60), 126.05 (C-40), 129.05 (C-30, C-50), 135.12 (C-3),
138.87 (C-10), 148.95 (C-7a), 152.76 (C-4), 165.99 (C-6), 170.33 (C¼O).
Anal. calcd. for C15H14N4O3 (298.30): C, 60.40; H, 4.73; N, 18.78.
Found: C, 59.99; H, 4.93; N, 18.58.

Heterocyclic Synthesis with Nitriles
1193
Ethyl 4-Amino-1-(4-chlorophenyl)-6-hydroxy-1H-pyrazolo[3,4-b]-
pyridine-5-carboxylate (6b)
White powder (82%), mp 314–315 ꢀC (EtOH–DMF); tmax (Nujol mull):
3486 and 3363 (NH2), 3179 (br, OH), 1687 (C¼O) cmꢁ1; dH (DMSO-
d6): 1.32 (t, 3H, J ¼ 7.5 Hz, CH3), 4.36 (q, 2H, J ¼ 7.5 Hz, CH2), 7.55
(d, 2H, J ¼ 7.0 Hz, Ar-H), 7.95 (s, 2H, NH2), 8.20 (d, 2H, J ¼ 7.0 Hz,
Ar-H), 8.40 (s, 1H, H-3), 11.80–12.90 (br s, 1H, OH). m=z(%) (TOF)
332 [Mþ, 35Cl] (16), 334 [Mþ, 37Cl] (5). Anal. calcd. for C15H13ClN4O3
(332.74): C, 54.14; H, 3.94; N, 16.84. Found: C, 54.25; H, 4.09; N, 16.66.
General Procedure for Preparation of 8a,b
A mixture of 1 (20 mmol) and phosphoryl chloride (3.83 g, 25 mmol) in
anhydrous DMF (5 mL) was heated under stirring at 70 ꢀC for 3 h. Then,
the reaction mixture was poured onto ice and treated with aqueous
ammonia (pH 8). A white solid separated, and it was filtered off, washed
with water, dried, and recrystallized from an appropriate solvent to
afford the products in 60–82% yields.
Data
1-Phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-ol (8a)
White powder (70%), mp 294–296 ꢀC (EtOH–DMF) (lit. mp 299 ꢀC[11]);
dH (DMSO-d6): 7.38 (t, 1H, J ¼ 7.8 Hz, H-40), 7.54 (t, 2H, J ¼ 7.8 Hz,
H-30 and H-50), 8.03 (d, 2H, J ¼ 7.5 Hz, H-20, H-60), 8.19 (s, 1H, H-6),
8.32 (s, 1H, H-3), 12.46 (br s, 1H, OH); dC (DMSO-d6): 107.62 (C-3a),
121.75 (C-20, C-60), 127.13 (C-40), 129.22 (C-30, C-50), 136.00 (C-3),
132.22 (C-10), 148.81 (C-6), 151.85 (C-7a), 157.23 (C-4). Anal. calcd.
for C11H8N4O (212.21): C, 62.26; H, 3.80; N, 26.40. Found: C, 61.89;
H, 3.87; N, 26.75.
1-(4-Chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ol (8b)
White powder (74%), mp 314–316 ꢀC (EtOH–DMF) (lit. mp > 300 ꢀC[11]);
dH (DMSO-d6): 7.63 (d, 2H, J ¼ 9.3 Hz, Ar-H), 8.10 (d, 2H, J ¼ 9.0 Hz,
Ar-H), 8.22 (s, 1H, H-6), 8.35 (s, 1H, H-3), 12.30–12.70 (br s, 1H,
OH). Anal. calcd. for C11H7ClN4O (246.65): C, 53.56; H, 2.86; N,
22.71. Found: C, 53.16; H, 3.04; N, 22.55.

1194
A. M. Salaheldin, A. M. F. Oliveira-Campos, and L. M. Rodrigues
5-Amino-1-(4-chlorophenyl)-1H-pyrazole-4-carboxamide (9)
White powder (81%), mp 202–204 ꢀC (EtOH) (lit. mp 204–205 ꢀC[11]);
tmax (Nujol mull): 3471, 3337, (NH2), 1662 (C ¼ O) cmꢁ1; dH
(CDCl3): 6.42 (s, 2H, NH2), 6.86 (br s, 1H, NH), 7.41 (br s, 1H,
NH), 7.54–7.57 (m, 4H, Ar-H), 7.90 (s, 1H, H-3); dC (CDCl3):
97.65 (C-4), 124.75 (C-20, C-60), 129.30 (C-30, C-50), 131.21 (C-40),
137.13 (C-10), 139.30 (C-3), 149.48 (C-5), 166.03 (C¼O). m=z (%)
(TOF) 236 [Mþ, 35Cl] (30), 238 [Mþ, 37Cl] (6). Anal. calcd. for
C10H9ClN4O (236.66): C, 50.75; H, 3.83; N, 23.67. Found: C, 51.21;
H, 3.91; N, 23.71.
ACKNOWLEDGMENTS
ˆ
We thank Fundac¸a˜o para a Ciencia e Tecnologia and FEDER (POCTI-
SFA-3-686) and are grateful for a postdoctoral grant for A. Salaheldin
(SFRH=BPD=31490=2006). We thank Elisa Pinto for obtaining the
NMR and elemental analysis data.
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