Synthesis of new pyrazole-1,2,3-triazole dyads

Article abstract of DOI:10.1016/j.tetlet.2013.07.120

An efficient two step synthetic methodology of new 5(4)-aryl-4(5)-[3(5)-(2- hydroxyphenyl)-1H-pyrazol-5(3)-yl]-1H-1,2,3-triazole dyads was established. The reaction of (E)-2-styryl-4H-chromen-4-ones, used as building blocks, with sodium azide, gave 4(5)-a

Full text of DOI:10.1016/j.tetlet.2013.07.120

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Synthesis of new pyrazole-1,2,3-triazole dyads
Joana P.A. Ferreira, Vera L.M. Silva, José Elguero, Artur M.S. Silva
PII:
S0040-4039(13)01288-4
DOI:
http://dx.doi.org/10.1016/j.tetlet.2013.07.120
TETL 43318
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Tetrahedron Letters
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Revised Date:
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19 July 2013
23 July 2013
Please cite this article as: Ferreira, J.P.A., Silva, V.L.M., Elguero, J., Silva, A.M.S., Synthesis of new pyrazole-1,2,3-
triazole dyads, Tetrahedron Letters (2013), doi: http://dx.doi.org/10.1016/j.tetlet.2013.07.120
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Graphical Abstract
Synthesis of new pyrazole-1,2,3-triazole dyads
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Joana P. A. Ferreira,a Vera L. M. Silva,a,* José Elguerob
and Artur M. S. Silvaa,*
aDepartment of Chemistry & QOPNA, University of Aveiro, 3810-193 Aveiro, Portugal; Instituto de Química Médica, C/
b
Juan de la Cierva 3, 28006 Madrid, Spain

1
Tetrahedron Letters
journal homepage: www.elsevier.com
Synthesis of new pyrazole-1,2,3-triazole dyads
Joana P. A. Ferreira,a Vera L. M. Silva,a,* José Elguerob and Artur M. S. Silvaa,*
aDepartment of Chemistry & QOPNA, University of Aveiro, 3810-193 Aveiro, Portugal
bInstituto de Química Médica, C/ Juan de la Cierva 3, 28006 Madrid, Spain
*Corresponding author. Tel.: +351-234-370714; fax: +351-234-370084; e-mail: artur.silva@ua.pt and verasilva@ua.pt
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An efficient two steps synthetic methodology of new 5(4)-aryl-4(5)-3(5)-(2-hydroxyphenyl)-
1H-pyrazol-5(3)-yl-1H-1,2,3-triazole dyads was established. The reaction of (E)-2-styryl-4H-
chromen-4-ones, used as building blocks, with sodium azide, gave 4(5)-aryl-5(4)-(chromon-2-
yl)-1H-1,2,3-triazoles bearing either electron-donating or electron-withdrawing substituents in
their styryl moiety which upon reaction with hydrazine hydrate afforded the expected pyrazoles
in moderate to very good yields.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Pyrazoles
1,2,3-Triazoles
(E)-2-Styryl-4H-chromen-4-ones
Hydrazine hydrate
1. Introduction
heterocyclic compounds, including cannabinoid-type compounds,
based on the 3(5)-(2-hydroxyphenyl)-5(3)-styryl-1H-pyrazole
scaffold,26-28 now we are describing the synthesis of novel 3(5)-
(2-hydroxyphenyl)pyrazole-1,2,3-triazole dyads.
1,2,3-Triazoles are five-membered nitrogen heterocyclic
compounds, which display a wide spectrum of pharmacological
properties.1,4 They are also used as intermediates in the synthesis
of antibiotics (e.g. Tazobactum),4,5 and applied as agrochemicals,
mainly as fungicides,6 insecticides,7 and plant growth
regulators.8,9 They have practical use in industrial applications as
dyes, corrosion inhibitors (of copper and copper alloys),
photostabilizers and in photographic materials.10 Likewise,
pyrazole derivatives are highly recognized because of their
significant biological activities, mainly as antimicrobial,
analgesic, anti-inflammatory (Celecoxib and Pirazolac), and
anticancer agents.11,12 In particular, certain C- and/or N-(2-
hydroxyphenyl)pyrazoles are used as ultraviolet stabilizers,13,14
analytical reagents in the complexation of transition metal ions,15
analgesic agents, platelet aggregation inhibitors,16 and also potent
inhibitors of Hsp90 ATP-ase activity.17-19 Similarly to 1,2,3-
triazoles, pyrazoles have also widespread application in the fields
of agriculture and in industry.11,12,20-22
2. Results and discussion
Our first approach to obtain pyrazole-1,2,3-triazole dyads
involved the 1,3-dipolar cycloaddition reaction of 3(5)-(2-
hydroxyphenyl)-5(3)-styryl-1H-pyrazole 1a27 with sodium azide
(Scheme 1), accordingly to the procedure reported by Silva et al.
for the synthesis of 4(5)-aryl-5(4)-(chromon-2-yl)-1H-1,2,3-
triazoles.28 An excess of sodium azide (5 molar equiv) was added
to a solution of pyrazole 1a in DMF being the mixture refluxed
and after 6 hours the formation of a new product was observed by
TLC. The NMR spectra of the isolated compound revealed the
formation of 5(3)-(2-azido-2-phenylethyl)-3(5)-(2-hydroxy-
phenyl)-1H-pyrazole 2a (20% yield),29 which results from the
nucleophilic attack of the azide anion to the -position of the
1
styryl double bond (Scheme 1). The analysis of the H NMR
spectra of compound 2a confirms the absence of the signals
typical of the vinylic protons H- and H- of compound 1a, and
the presence of two signals in the aliphatic region of the spectra:
i) a doublet at H 3.13 ppm due to the resonance of H-1” and a
triplet at H 5.03 ppm due to the resonance of H-2”. The 13C
NMR spectra of 2a also presents two signals in the aliphatic
region due to C-1’’ at C 34.9 ppm and C-2” at C 73.7 ppm, the
latter more deshielded due to the presence of the azide group.
Aiming to promote the dehydrogenation and intramolecular
cyclization of the azide 2a, it was treated with chloranil (1 molar
equiv) in DMF and the mixture was refluxed for 24 hours, but
unfortunately, under these conditions only degradation of the
starting material was observed.
Fused pyrazole-1,2,3-triazoles, such as pyrazole3,4-d-1,2,3-
triazoles are known to exhibit antiproliferative properties and
ability to cleave DNA upon activation by light.23 Moreover 1,2,4-
triazole-containing diarylpyrazolylcarboxamides, are potent
receptor antagonists for the CB1 cannabinoid-type receptors with
effect in the treatment of obesity animal models.24 Some
diarylpyrazoles with cannabinomimetic activity present an amide
bond that seems to be very important for their activity. 1,2,3-
Triazoles are units that can act as mimics of the position of atoms
and chemical properties of the amide bond, with no significant
susceptibility to hydrolysis.25
Considering the referred important applications and in
continuation of our previous work to find new biologically active

2
Tetrahedron Letters
In order to evaluate the electronic effect of the substituent on
The tautomerism of 1,2,3-triazoles generally involves the three
tautomers, N(1)H, N(2)H and N(3)H38 and was not determined in
the present work.
the para-position of the styryl group on the reactivity of the
vinylic double bond, we tried the reaction of (E)-3(5)-(2-
hydroxyphenyl)-5(3)-(4-methoxystyryl)-1H-pyrazole 1b and (E)-
3(5)-(2-hydroxyphenyl)-5(3)-(4-nitrostyryl)-1H-pyrazole 1d with
sodium azide under the conditions previously described (a big
excess of sodium azide in refluxing DMF for more than 72
hours). In the case of 1b only the starting material was recovered
(90%) after 5 days of reaction time, while in the case of 1d
azidopyrazole 2d was obtained (37% yield) after 14 hours of
reaction. These results indicates that the -addition of the azide
anion is favoured by the presence of an electron withdrawing
substituent on the para-position of the styryl group.
3. Conclusions
(E)-2-styryl-4H-chromen-4-ones were used as building blocks
in the synthesis of 5(4)-aryl-4(5)-3(5)-(2-hydroxyphenyl)-1H-
pyrazol-5(3)-yl-1H-1,2,3-triazoles. This methodology of
preparing pyrazole-1,2,3-triazole dyads is very expeditious since
the synthesis involves only two steps and compounds were
obtained in very good yields especially for (E)-2-styryl-4H-
chromen-4-ones bearing electron-withdrawing substituents in
their styryl moiety.
Scheme 1. Reaction of (E)-3(5)-(2-hydroxyphenyl)-5(3)-styryl-1H-
pyrazoles 1a,b,d and 4a with sodium azide.
Scheme 2. Synthesis of 5(4)-aryl-4(5)-3(5)-(2-hydroxyphenyl)-1H-
pyrazol-5(3)-yl-1H-1,2,3-triazoles 3a-d/8a-d/9a-d starting from 4(5)-
aryl-5(4)-(chromon-2-yl)-1H-1,2,3-triazoles 6a-d.
Our second approach towards the synthesis of pyrazole-1,2,3-
triazole dyads involved the protection of the NH of the pyrazole
with acetyl chloride in pyridine at room temperature. Acetyl was
selected as an electron withdrawing, in order to make the vinylic
double bond more electron deficient, and easily removable
protecting group. The reaction of 1-acetyl-3(5)-(2-hydroxy-
phenyl)-5(3)-styryl-1H-pyrazole 4a with 5 molar equiv of sodium
azide in refluxing DMF afforded pyrazole 1a (87% yield), due to
the cleavage of the acetyl group after 24 hours at reflux.
Table 1. Reaction conditions and yields obtained in the synthesis of 5(4)-
aryl-4(5)-3(5)-(2-hydroxyphenyl)-1H-pyrazol-5(3)-yl-1H-1,2,3-triazoles 3a-
d/ 8a-d/ 9a-d.
Compound
NH2NH2.H2O
(molar equiv)
5
Reaction
time (h)
24
Temperature
(ºC)
r.t
Yield of
3 (%)
50
6a, R = H
6a, R = H
Since our strategies were not succeeded we had to develop
another synthetic method in order to prepare the pyrazole-1,2,3-
triazole dyads in good yields. Following our previous work on
the synthesis of 4(5)-aryl-5(4)-(chromon-2-yl)-1H-1,2,3-
triazoles,28 we prepared 4(5)-aryl-5(4)-(chromon-2-yl)-1H-1,2,3-
triazoles 6a,c,d (76-89%) from the reaction of (E)-2-styryl-4H-
chromen-4-ones 5a,c,d with sodium azide, whereas 6b was
obtained (34%) from the reaction of 2-1,2-dibromo-2-(4-
methoxyphenyl)ethyl-4H-chromen-4-one 7 with sodium azide,
both reactions in DMF at 120ºC. Then, we performed the
reaction of compounds 6a-d with an excess of hydrazine hydrate
(5 molar equiv) in methanol at 60ºC and we obtained the 5(4)-
aryl-4(5)-3(5)-(2-hydroxyphenyl)-1H-pyrazol-5(3)-yl-1H-1,2,3-
triazoles 3a-d/8a-d/9a-d in moderate to very good yields
depending on the substituent in the phenyl ring (Scheme 2, Table
1).30-32 For compound 3a,b/8a,b/9a,b better yields were obtained
with a second addition of hydrazine hydrate (Table 1). The
reaction mechanism involves a nucleophilic attack at C-2 of the
4H-chromen-4-one nucleus and consequent ring opening,
followed by the intramolecular reaction between hydrazine and
the carbonyl group with consequent formation of the pyrazole
ring.33-35 Compound 3a-d/8a-d/9a-d has six tautomers, two of the
pyrazole ring and three of the 1,2,3-triazole ring. That of the
pyrazole is suggested as represented due to the O–H···N
hydrogen bond between the OH and the N2' lone pair.27,33,34,36,37
5+5
5
48+27
24
r.t then 60
86
86
54
67
96
90
60
60
60
60
60
6b, R = OCH3
5
48
6b, R = OCH3 5+5
48+24
72
6c, R = Cl
5
5
6d, R = NO2
72
Acknowledgments
Thanks are due to the University of Aveiro, “Fundação para a
Ciência e a Tecnologia”, European Union, QREN, FEDER and
COMPETE for funding the Organic Chemistry Research Unit
(project PEst-C/QUI/UI0062/2011) and the Portuguese National
NMR network. One of us Joana P. A. Ferreira is also grateful to
“Fundação para a Ciência e a Tecnologia” and FSE for a PhD
grant (SFRH/BD/45107/2008).
References and notes
1. Meldal, M.; Tornøe, C. W. Chem. Rev. 2008, 108, 2952-3015.
2. Melo, J. O. F.; Donnici, C. L.; Augusti R.; Ferreira, V. F.; Souza,
C. B. V.; Ferreira, M. L. G.;Cunha, A. C. Quim. Nova 2006, 29,
569-579.

3
3. Shafran, E. A.; Bakulev, V. A.; Rozin, Y. A.; Shafran, Y. M.
Chem. Heterocycl. Compd. 2008, 44, 1040-1069.
4. Agalave, S. G.; Maujan, S. R.; Pore, V. S. Chem. Asian J. 2011, 6,
2696-2718.
5. Aufort, M.; Herscovici, J.; Bouhours, P.; Moreau, N.; Girard, C.
Bioorg. Med. Chem. Lett. 2008, 18, 1195-1198.
6. Buechel, K. H.; Gold, H.; Frohberger, P. E.; Kaspers, H., German
Patent 2407305, 1975; Chem. Abstr. 1975, 83, 206290.
7. Boddy, I. K.; Briggs, G. G.; Harrison, R. P.; Jones, T. H.;
O’Mahony, M. J.; Marlow, I. D.; Roberts, B. G.; Willis, R. J.;
Bardsley, R.; Reid, J. Pestic. Sci. 1996, 48 189-196.
300.13 MHz):  3.13 (d, 2H, J = 6.2 Hz, H-1”), 5.03 (t, 1H, J =
6.2 Hz, H-2”), 6.42 (s, 1H, H-4), 6.89 (dt, 1H, J = 7.8, 1.1 Hz, H-
5’), 7.01 (dd, 1H, J = 7.8, 1.1 Hz, H-3’), 7.20 (dt, 1H, J = 7.8, 1.6
Hz, H-4’), 7.35-7.39 (m, 5H, H-2”’,3”’,4”’,5”’,6”’), 7.51 (dd, 1H,
J = 7.8, 1.6 Hz, H-6’), 13.00 (s, 1H, 2’-OH) ppm; 13C NMR
(DMSO-d6+TFA, 125.77 MHz): C 34.9 (C-1”), 73.7 (C-2”),
101.5 (C-4), 116.9 (C-1’), 117.1 (C-3’), 119.3 (C-5’), 125.8 (C-
3”’,5”’), 126.5 (C-6’), 128.5 (C-4”’), 129.0 (C-2”’,6”’), 129.2 (C-
4’), 141.3 (C-5), 143.1 (C-1”’), 151.9 (C-3), 156.1 (C-2’) ppm.
ESI(+) MS m/z (int. rel.) 306 ([M+H)+, 76), 328 ([M+Na]+, 10);
HR-ESI(+) MS m/z calcd. for (C17H15N5O+H)+: 306.1277; found
306.1276.
8. Reisser, F. British Patent 8101239, 1981; Chem. Abstr. 1981, 96,
69006.
30. General procedure for the synthesis of 5(4)-aryl-4(5)-3(5)-(2-
hydroxyphenyl)-1H-pyrazol-5(3)-yl-1H-1,2,3-triazoles 3a-d. To a
solution of 4(5)-aryl-5(4)-(chromon-2-yl)-1H-1,2,3-triazoles 6a–d
(0.52 mmol) in methanol (10 mL) were added an excess of
hydrazine monohydrate (see Table 1) and the mixture was heated
at 60ºC (for reaction time see Table 1) under nitrogen atmosphere.
After this period the mixture was poured into acidified water (pH
= 5) and the aqueous layer was extracted with chloroform and
dried over anhydrous sodium sulfate. The solvent was evaporated
to dryness and the solid residue was purified by thin layer
chromatography using a 3:1 mixture of ethyl acetate: light
petroleum as eluent. After several elutions, the main fraction was
collected and after solvent evaporation the residue was
recrystallized from ethanol to give compounds 3a-d in moderate to
very good yields (3a, 86%, 135.64 mg; 3b, 67%, 116.14 mg; 3c,
96%, 168.61 mg; 3d, 90%, 163.01 mg).
31. 4(5)-3(5)-(2-Hydroxyphenyl)-1H-pyrazol-5(3)-yl-5(4)-phenyl-
1H-1,2,3-triazole 3a. White solid, M.p. 246-247 ºC.; 1H NMR
(DMSO-d6+TFA, 300.13 MHz)  6.86 (dt, 1H, J = 7.8, 0.9 Hz,
H-5’’), 6.95 (dd, 1H, J = 7.8, 0.9 Hz, H-3”), 6.97 (s, 1H, H-4’),
7.16 (dt, 1H, J = 7.8, 1.5 Hz, H-4”), 7.41-7.48 (m, 3H, H-
2”’,6”’,4”’), 7.66 (dd, 1H, J = 7.8, 1.5 Hz, H-6”), 7.80 (dd, 2H, J =
8.2, 1.4 Hz, H-3”’,5”’), 13.00 (s, 2’’-OH) ppm; 13C NMR (DMSO-
d6+TFA, 75.47 MHz): C 103.8 (C-4’), 116.1 (C-1”), 116.7 (C-
3”), 119.6 (C-5”), 127.5 (C-6”), 128.2 (C-3”’,5”’), 128.7 (C-
2”’,6”’), 129.6 (C-4”’), 130.0 (C-4”), 130.1 (C-4), 133.7 (C-5),
139.0 (C-5’), 141.4 (C-1”’), 144.6 (C-3’), 154.4 (C-2”) ppm.
ESI(+)MS m/z (int. rel.) 304 ([M+H)+, 100), 326 ([M+Na]+, 30);
HR-ESI(+) MS m/z calcd. for (C17H13N5O+H)+: 304.1120; found
304.1118.
32. 5(4)-(4-Chlorophenyl)-4(5)-3(5)-(2-hydroxyphenyl)-1H-pyrazol-
5(3)-yl-1H-1,2,3-triazole 3c. Yellow solid; Mp 295-297 ºC. 1H
NMR (DMSO-d6+TFA, 300.13 MHz):  6.89 (t, 1H, J = 8.0 Hz,
H-5”), 6.96 (dd, 1H, J = 8.0, 1.0 Hz, H-3”), 6.97 (s, 1H, H-4’),
7.20 (t, 1H, J = 8.0 Hz, H-4”), 7.40 (d, 2H, J = 8.0 Hz, H-2”’,6”’),
7.70 (d, 1H, J = 8.0 Hz, H-6”), 7.74 (d, 2H, J = 8.0 Hz, H-3”’,5”’),
12.90 (s, 2”-OH); 13C NMR (75.47, MHz): C 102.6 (C-4’), 116.1
(C-1”), 116.5 (C-3”), 119.5 (C-5”), 127.5 (C-6”), 128.8 (C-
3”’,5”’), 130.1 (C-4,4”), 131.9 (C-2”’,6”’), 133.8 (C-5), 139.2 (C-
5’), 144.7 (C-3’), 145.0 (C-4”’), 147.6 (C-1”’), 154.2 (C-2”) ppm.
ESI(+) MS m/z (int. rel.) 339 ([M+H)+, 35Cl, 100), 341 [(M+H)+,
37Cl, 21)], 360 ([M+Na]+, 35Cl, 24); 362 [(M+Na) +, 37Cl, 24]; HR-
ESI(+)MS m/z calcd. for (C17H1235ClN5O+H)+: 338.0730; found
338.0729; m/z calcd. for (C17H1237ClN5O+H)+: 340.0740; found
340.0739.
9. Krueger, H. R.; Schroeer, U.; Baumert, D.; Joppien, H. German
Patent 2936951, 1981; Chem. Abstr. 1981, 96, 52509.
10. Fan, W.-Q.; Katritzky, A. R. in: Katritzky, A. R.; Rees, C. W.;
Scriven, E. F. V. (Eds.), Comprehensive Heterocyclic Chemistry
II, Elsevier Science, Oxford, 1996; Vol.4, pp. 1-126.
11. Elguero, J.; Goya, P.; Jagerovic, N.; Silva, A. M. S. In Pyrazoles
as Drugs: Facts and Fantasies in Targets in Heterocyclic
Systems—Chemistry and Properties, Attanasi, O. A.; Spinelli, D.
Eds., Italian Society of Chemistry, Camerino, Italy, 2002, vol 6.,
pp 52-98.
12. Fustero S.; Roselló M.-S.; Barrio, P.; Simón-Fuentes A. Chem.
Rev. 2011, 111, 6984-7034.
13. Catalán, J.; Fabero, F.; Claramunt, R. M.; Santa María, M. D.;
Foces-Foces, M. C.; Cano, F. H.; Martínez-Ripoll, M.; Elguero, J.;
Sastre, R. J. Am. Chem. Soc. 1992, 114, 5039-5048.
14. Catalán, J.; Fabero, F.; Guijano, M. S.; Claramunt, R. M.; Santa
María, M. D.; Foces-Foces, M.C.; Cano, F. H.; Elguero, J.; Sastre,
R. J. Am. Chem. Soc. 1990, 112, 747-759.
15. Ahmad, R.; Ahmad, N.; Zia-Ul-Haq, M. J. Chem. Soc. Pak. 1996,
18, 38-41.
16. Dymock, B. W.; Barril, X.; Brough, P. A.; Cansfield, J. E.;
Massey, A.; McDonald, E.; Hubbard, R. E.; Surgenor, A.;
Roughley, S. D.; Webb, P.; Workman, P.; Wright, L.; Drysdale,
M. J. J. Med. Chem. 2005, 48, 4212-4215.
17. Barril, X.; Beswick, M.; Collier, A.; Drysdale, M. J.; Dymock, B.
W.; Fink, A.; Grant, K.; Howes, R.; Jordan, A. M.; Massey, A;
Surgenor, A.; Wayne, J.; Workman, P.; Wright, L. Bioorg. Med.
Chem. Lett. 2006, 16, 2543-2548.
18. Howes, R; Barril, X.; Dymock, B. W.; Grant, K.; Northfield, C. J.;
Robertson, A. G. S.; Surgenor, A. ; Wayne, J.; Wright, L.; James,
K.; Matthews, T.; Cheung, K.-M.; McDonald, E.; Workman, P.;
Drysdale, M. J. Anal. Biochem. 2006, 350, 202-213.
19. Cheung, K.-M. J.; Matthews, T. P.; James, K.; Rowlands, M. G.;
Boxall, K. J.; Sharp, S. Y.; Maloney, A.; Roe, S. M.; Prodromou,
C.; Pearl, L. H.; Aherne, G. W.; McDonald, E.; Workman, P.
Bioorg. Med. Chem. Lett. 2005, 15, 3338-3343.
20. Elguero, J. In Comprehensive Heterocyclic Chemistry II; Katritzky
A. R.; Rees, C. W.; Scriven, E. F. Eds Pergamon Press: Oxford,
1996, Vol.3, pp 1-75.
21. Elguero, J. In: Comprehensive Heterocyclic Chemistry; Katritzky,
A. R.; Rees, C. W. Eds Pergamon, Oxford, 1984, Vol. 5, pp 167.
22. Stanovnik, B.; Svete, J. Chapter 12.1: Pyrazoles. In: Neier, R. (ed)
Science of Synthesis, vol 12. Georg Thieme, Stuttgart, 2002, Vol.
12, pp 15.
23. Manfredini, S.; Vicentini, C. B.; Manfrini. M.; Bianchi, N.;
Rutigliano, C.; Mischiati, C.; Gambari, R. Bioorg. Med. Chem.
2000, 8, 2343-2346.
24. Seo, H. J.; Kim, M. J.; Lee, S. H.; Lee, S.-H.; Jung, M. E.; Kim,
M.-S.; Ahn, K.; Kim, J.; Lee, J. Bioorg. Med. Chem. 2010, 18,
1149-1162.
25. Pedersen, D. S.; Abell, A. Eur. J. Org. Chem. 2011, 2399-2411.
26. Silva, V. L. M.; Silva, A. M. S.; Pinto, D. C. G. A.; Rodriguez, P.;
Gómez, M.; Jagerovic, N.; Callado, L. F.; Cavaleiro, J. A. S.;
Elguero, J.; Fernando-Ruiz, J. Arkivoc 2010, (x), 226-247.
27. Silva, V. L. M.; Silva, A. M. S.; Pinto, D. C. G. A.: Cavaleiro, J.
A. S.; Elguero, J. Eur. J. Org. Chem., 2004, 4348-4356.
28. Silva, A. M. S.; Vieira, J. S.; Brito, C. M.; Cavaleiro, J A. S.;
Patonay, T.; Lévai, A.; Elguero, J. Monatsth. Chem. 2004, 135,
293-308.
33. Pinto, D. C. G. A.; Silva, A. M. S.; Cavaleiro, J. A. S.; Foces-
Foces, M. C.; Llamas-Saiz, A. L.; Jagerovic, N.; Elguero, J.
Tetrahedron 1999, 55, 10187-10200.
34. Silva,V. L. M.; Silva, A. M. S.; Pinto, D. C. G. A.; Cavaleiro, J. A.
S., Elguero, J. Monatsh. Chem. 2009, 140, 87-95.
35. Pinto, D. C. G. A.; Silva, A. M. S.; Cavaleiro, J. A. S. J.
Heterocycl. Chem. 2000, 37, 1629-1643.
36. Pinto, D. C. G. A.; Silva, A. M. S.; Almeida, L. M. P. M.,
Cavaleiro, J. A. S.; Elguero, J. Eur. J. Org. Chem. 2002, 3807-
3815.
37. Silva, V. L. M.; Silva, A. M. S.; Pinto, D. C. G. A.; Cavaleiro, J.
A. S.; Elguero, j. Tetrahedron Lett. 2007, 48, 3859-3862.
38. Minkin, V. I.; Garnovskii, A. D.; Elguero, J.; Katritzky, A. R.;
Denisko, O. V. Adv. Heterocycl. Chem. 2000, 76, 157–323.
29. 5(3)-(2-Azido-2-phenylethyl)-3(5)-(2-hydroxyphenyl)-1H-pyrazole
2a: Orange solid; Mp 251-252 ºC. 1H NMR (DMSO-d6+TFA,

Scheme graphical abstract

Scheme 1

Scheme 2