An unexpected formation of pyrazolopyrimidines during the attempted to obtain 5-substituted tetrazoles from carbonitriles

Article abstract of DOI:10.1016/j.tetlet.2013.08.033

In this Letter, we described the synthesis of new 5-(5-amino-1-aryl-1H- pyrazole-4-yl)-1H-tetrazoles 2a-c from 5-amino-1-aryl-1H-pyrazole-4- carbonitriles 1a-c as well as the unexpected 1H-pyrazolo[3,4-d]pyrimidine derivatives 6a-c from 5-amino-1-aryl-3-m

Full text of DOI:10.1016/j.tetlet.2013.08.033

Accepted Manuscript
An unexpected formation of pyrazolopyrimidines during the attempted to obtain
5-substituted tetrazoles from carbonitriles
Jéssica Venância Faria, Maurício Silva dos Santos, Percilene Fazolin Vegi, Julio
Cesar Borges, Alice M.R. Bernardino
PII:
S0040-4039(13)01386-5
DOI:
http://dx.doi.org/10.1016/j.tetlet.2013.08.033
TETL 43395
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
17 April 2013
9 August 2013
10 August 2013
Please cite this article as: Faria, J.V., Santos, c.S.d., Vegi, P.F., Borges, J.C., Bernardino, A.M.R., An unexpected
formation of pyrazolopyrimidines during the attempted to obtain 5-substituted tetrazoles from carbonitriles,
Tetrahedron Letters (2013), doi: http://dx.doi.org/10.1016/j.tetlet.2013.08.033
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Graphical Abstract
2
NaN3, NH4Cl, DMF
120-130oC, 48h
2
2
2
i: NaH, Boc, rt, 4h
ii:NaN3, NH4Cl, DMF
130-140oC, 48h

An unexpected formation of pyrazolopyrimidines during the attempted to obtain 5-substituted
tetrazoles from carbonitriles
Jéssica Venância Fariaa, Maurício Silva dos Santosb,*, Percilene Fazolin Vegi,a Julio Cesar Borgesa, Alice M.
R. Bernardinoa
aDepartamento de Química Orgânica, Instituto de Química, Universidade Federal Fluminense, 24020-150,
Niterói, RJ, Brazil
bInstituto de Física e Química, Universidade Federal de Itajubá, 37500-903, Itajubá, MG, Brazil
Corresponding author: Tel.+55 35 3629-1628
E-mail address: mauriciounifei@yahoo.com.br
Abstract
In this letter, we described the synthesis of new 5-(5-amino-1-aryl-1H-pyrazole-4-yl)-1H-tetrazoles 2a-c from
5-amino-1-aryl-1H-pyrazole-4-carbonitriles 1a-c as well as the unexpected 1H-pyrazolo[3,4-d]pyrimidines
derivatives 6a-c from 5-amino-1-aryl-3-methyl-1H-pyrazole-4-carbonitriles 4a-c, instead of 5-(5-amino-1-aryl-
3-methyl-1H-pyrazole-4-yl)-1H-tetrazoles 5a-c as desired. In attempt to obtain these tetrazole derivatives
containing the methyl group at C3-position in pyrazole ring, the amino group in the 5-amino-1-(4-
methoxyphenyl)-3-methyl-1H-pyrazole-4-carbonitrile 4c was protected by the reaction with sodium hydride
and di-tert-butyl-dicarbonate (Boc). The tetrazole derivative 5c was synthesized from the protected
compound 7c using analogue methodology to obtain 2a-c and 6a-c.
Keywords: unexpected reaction, pyrazolo[3,4-d]pyrimidine, tetrazole, cycloaddition.

In recent years, tetrazoles have received considerable attention because they represent an important class
of heterocycles, which exhibit a wide range of biological activity, including antiprozoal, antihypertensive and
antibiotic effects.1 Tetrazoles show greater lipophilicity and hence may serve as non-classical isosteres for
the carboxylic acid group.2 The classical method for the preparation of 5-substituted tetrazoles occurs
through the reaction of nitriles with sodium azide and ammonium chloride in DMF, at 120–130°C, by an [3 +
2] cycloaddition.3 Recently, our research group reported the synthesis of new 5-(1-aryl-1H-pyrazole-4-yl)-1H-
tetrazoles from 1-aryl-1H-pyrazole-4-carbonitriles, sodium azide, ammonium chloride in DMF as solvent,
during 14 hours at 120-130°C.4 In the course of our search for new tetrazole derivatives, we prepared three
new 5-(5-amino-1-aryl-1H-pyrazole-4-yl)-1H-tetrazoles 2a-c using analog methodology (Scheme 1). 5-
amino-1-aryl-1H-pyrazole-4-carbonitriles 1a-c were reacted with sodium azide (2 equiv.), ammonium chloride
(2 equiv.) in DMF at 130-140oC. After 16-18 hours the tetrazoles 2a-c were isolated in good yields: 62-74%.
Lower temperatures resulted in long time reaction.
Scheme 1
We have also investigated the influence of the methyl group at C3-position in pyrazole ring. In attempt to
synthesize new tetrazoles from 5-amino-1-aryl-3-methyl-1H-pyrazole-4-carbonitriles 4a-c, employing the
same methodology, the desired compounds 5-(5-amino-1-aryl-3-methyl-1H-pyrazole-4-yl)-1H-tetrazoles 5a-c
weren´t obtained. Thus, we have investigated alternative methodologies. When we worked with sodium
azide, ammonium chloride in DMF at 120-130oC for 48 hours, unexpected products were isolated (Scheme
2). After purification by recrystallization, FT-IR spectra data showed C=N band as well as NH2 bands.
1
However, in H NMR spectroscopy it was found in each compound two singlet signals related to methyl
group: 2.66-2.67 ppm and 2.71-2.72ppm. Besides, two aryl groups were identified in aromatic region. The
13C NMR analysis showed signals which corresponding to 1H-pyrazolo[3,4-d]pyrimidine system. In mass
spectra (ESI-MS) the mass/charge ratio values of molecular ion peaks obtained were higher than expected
for the derivatives 5a-c. According to all analytical results, the 6-(5-amino-1-aryl-3-methyl-1H-pyrazol-4-yl)-1-
aryl-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine derivatives 6a-c were isolated. Since the analogs 5-(5-
amino-1-aryl-1H-pyrazole-4-yl)-1H-tetrazoles 2a-c were obtained, as mentioned above, the presence of
methyl group at C3-position in pyrazole ring affects the reaction. We have also examined the influence of
ammonium chloride and sodium azide in this reaction. When we worked with 5-amino-1-aryl-3-methyl-1H-
pyrazole-4-carbonitriles 4a-c, ammonium chloride (2 equiv.) in DMF the reaction did not proceed. We tried
using different temperatures, from 120oC to under reflux, as well as different reaction times, from 24 hours to
48 hours. Treatment of 5-amino-1-aryl-3-methyl-1H-pyrazole-4-carbonitriles 4a-c with sodium azide (2
equiv.) in DMF did not generated the products desired using the same conditions.
Scheme 2
With regard to mechanism, the reaction starts by a nucleophilic attack of the amine group of one molecule to
nitrile of another one. Afterwards, an intramolecular cyclization produces the pyrazolo[3,4-d]pyrimidine
system. The compounds 6a-c are new, but 1H-pyrazolo[3,4-d]pyrimidine obtained from 5-amino-1-aryl-1H-
pyrazole-4-carbonitriles have been published in the literature. Salaheldin et. al.5 synthesized 6-(5-amino-1-
aryl-1H-pyrazol-4-yl)-1-aryl-1H-pyrazolo[3,4-d]pyrimidin-4-amine reacting 5-amino-1-aryl-1H-pyrazole-4-

carbonitriles with triethanolamine, ethanol under reflux by 6 hours. Taylor & Borror6 described the synthesis
of similar products after several hours, using sodium ethoxide and ethanol in reflux. Smith & co-workers7
employed potassium t-butoxide, in toluene, microwave at 160oC.
Since 1H-pyrazolo[3,4-d]pyrimidines present wide applicability in medicinal chemistry such as
anticancer,8 antibacterial,9 antileishmanial,10 antitrypanosomal,10 and antiviral,11 the biological activity of
compounds 6a-c will be evaluated.
In another experiment the raw material 5-amino-1-(4-methoxyphenyl)-3-methyl-1H-pyrazole-4-
carbonitrile 4c was reacted with sodium hydride and di-tert-butyl-dicarbonate (Boc) to protect the amino
group. The protected product obtained 7c was treated with sodium azide and ammonium chloride in DMF, at
130–140°C, during 48 hours. Analytical results showed that the tetrazole ring was obtained and the Boc
protecting group was removed and the compound 5c was completely characterized (Scheme 3).
Scheme 3
In conclusion, the synthesis of new 5-(5-amino-1-aryl-1H-pyrazole-4-yl)-1H-tetrazoles 2a-c from 5-
amino-1-aryl-1H-pyrazole-4-carbonitriles 1a-c occurred as expected in good yields. The presence of the
methyl group at C3-position in 5-amino-1-aryl-3-methyl-1H-pyrazole-4-carbonitriles 4a-c impeded the
formation of analogue tetrazoles 5a-c and the unexpected 1H-pyrazolo[3,4-d]pyrimidines derivatives 6a-c
was isolated. The tetrazole 5c was synthesized employing an alternative synthetic route. In the first step, the
compound 4c was protected by the reaction with sodium hydride and di-tert-butyl-dicarbonate (Boc). After
that, the tetrazole was obtained using analogue methodology to obtain 2a-c and 6a-c. Therefore, this
synthetic route can be employed to access the 5-(5-amino-1-aryl-3-methyl-1H-pyrazole-4-yl)-1H-tetrazoles
5a-c initially planned (Scheme 1) and other derivatives from this system.
.
Acknowledgements
We thank the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Coordenação de
Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Fundação de Amparo à Pesquisa do Estado do
Rio de Janeiro (FAPERJ), Rede Mineira de Química (RMQ), Universidade Federal Fluminense
(PROPP/UFF) and Centro de Estudos e Inovação em Materiais Biofuncionais Avançados/UNIFEI for
fellowships and financial support.
Supplementary data
Supplementary data associated with this article can be found in the online version.
References and Notes
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2. Nguyen-Trung, A. T.; Tritsch, D.; Grosdemange-Billiard, C.; Rohmer, M. Bioorg. Med. Chem. Lett. 2013,
23, 1643.
3. Sharon, A.; Pratap, R.; Tiwari, P.; Srivastava, A.; Maulik, P. R.; Ram, V. J. Bioorg. Med. Chem. Lett. 2005,
15, 2115.

4. Santos, M. S.; Bernardino, A. M. R.; Pinheiro, L. C. S.; Canto-Cavalheiro, M. M.; Leon, L. L. J.
Heterocyclic Chem. 2012, 49, 1425.
5. Salaheldin, A. M.; Oliveira-Campos, A. M. F.; Rodrigues, L. M. Synth. Commun. 2009, 39, 1186.
6. Taylor, E. C.; Borror, A. L. J. Org. Chem. 1961, 26, 4967.
7. Smith, C. J.; Iglesias-Sigüenza, F. J.; Baxendale, I. R.; Ley, S. V. Org. Biomol. Chem. 2007, 5, 2758.
8. Abd El Hamid, M. K.; Mihovilovic, M. D.; El-Nassan, H. B. Eur. J. Med. Chem. 2012, 57, 323.
9. Bakalovi, M.; Bagherzadeh, G.; Vaseghifar, M.; Shiri, A.; Pordel, M.; Mashreghi, M.; Pordeli, P.; Araghi, M.
Eur. J. Med. Chem. 2010, 45, 647.
10. Gatta, F.; Perotti, F.; Gradoni, L.; Gramiccia, M.; Orsini, S.; Palazzo, G.; Rossi, V. Eur. J. Med. Chem.
1990, 25, 419.
11. Rashad, A. E.; Hegab, M. I.; Abdel-Megeid, R. E.; Micky, J. A.; Abdel-Megeid, F. M. E. Bioorg. Med.
Chem. 2008, 16, 7102.

2
2
2a-c
Products desired and obtained
2
1a-c
R= 4-F, 3-F, 3-Br
2
3a-c
Products not obtained
o
3
4

2
2
5a-c
Products desired
2
4a-c
R= 4-F, 4-Br, 4-OCH3
2
6a-c
Products obtained
H
d
o
3
4

N
N
N
CN
CN
NH
O
N
N
N
N
H
O
NH2
NH2
N
N
N
OCH3
OCH3
OCH3
5c
7c
4c
Scheme 3.
Synthesis of tetrazoles. Reagents and conditions: i: NaH, Boc, room temperature, 4h; ii: NaN3,
NH4Cl, DMF, 130-140oC, 48h.