Novel (E)- and (Z)-3(5)-(2-hydroxyphenyl)-4-styrylpyrazoles from (E)- and (Z)-3-styrylchromones: the unexpected case of (E)-3(5)-(2-hydroxyphenyl)-4-(4-nitrostyryl)pyrazoles

Article abstract of DOI:10.1016/j.tetlet.2007.03.147

An efficient synthetic method for the preparation of (E)- and (Z)-3(5)-(2-hydroxyphenyl)-4-styrylpyrazoles has been developed. The reaction of (E)- and (Z)-3-styrylchromones with hydrazine hydrate afforded the corresponding (E)- and (Z)-4-styrylpyrazoles,

Full text of DOI:10.1016/j.tetlet.2007.03.147

Tetrahedron Letters 48 (2007) 3859–3862
Novel (E)- and (Z)-3(5)-(2-hydroxyphenyl)-4-styrylpyrazoles
from (E)- and (Z)-3-styrylchromones: the unexpected case of
(E)-3(5)-(2-hydroxyphenyl)-4-(4-nitrostyryl)pyrazoles
Vera L. M. Silva,a Artur M. S. Silva,a,* Diana C. G. A. Pinto,a
a
b
´
´
Jose A. S. Cavaleiro and Jose Elguero
aDepartment of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal
bInstituto de Quı´mica Me´dica, Juan de la Cierva, 3, E-28006 Madrid, Spain
Received 30 October 2006; revised 24 March 2007; accepted 27 March 2007
Available online 31 March 2007
Abstract—An efficient synthetic method for the preparation of (E)- and (Z)-3(5)-(2-hydroxyphenyl)-4-styrylpyrazoles has been
developed. The reaction of (E)- and (Z)-3-styrylchromones with hydrazine hydrate afforded the corresponding (E)- and (Z)-4-styr-
ylpyrazoles, respectively, saved 40-nitro-derivatives where both (E)- and (Z)-40-nitro-3-styrylchromones afforded (E)-3(5)-(2-
hydroxyphenyl)-4-(4-nitrostyryl)pyrazoles. The reaction mechanism for these transformations was discussed and the stereochemis-
try of all products was assigned by NMR experiments.
ꢀ 2007 Elsevier Ltd. All rights reserved.
Pyrazoles are widely studied five-membered heterocyclic
compounds which possess promising pharmacological,
agrochemical and analytical applications.1 In the last
decade, these compounds received considerable atten-
tion since some well-known drugs such as sildenafil (Via-
gra) and celecoxib (Celebrex) are pyrazole derivatives.2
Furthermore, derivatives containing pyrazole ring
systems have demonstrated potent activities, such as
anti-inflammatory activity,3,4 cytotoxicity against
several human cancer cell lines,5 and inhibitory activity
against monoamine oxidase which is crucial in
compounds used in the treatment of Parkinson’s and
Alzheimer’s diseases.6 Certain 3(5)-(2-hydroxyphenyl)-
pyrazoles can be used as ultraviolet stabilisers,7 as
analytical reagents in the complexation of transition
metal ions,8 as analgesic agents and platelet aggregation
inhibitors,9 and also as potent inhibitors of Hsp90 ATP-
ase activity.10–14
with hydrazine derivatives15–18 prompted us to devote
our attention to the reaction of 3-styrylchromones with
hydrazine hydrate. It is already known that the reaction
of hydrazine hydrate with chromone derivatives affords
3(5)-(2-hydroxyphenyl)pyrazoles,9–21 and using 2-styryl-
chromones we have prepared a series of new 3-(2-
hydroxyphenyl)-5-styrylpyrazoles.15,16 In the present
Letter, we used 3-styrylchromones22,23 in the synthesis
of new 3-(2-hydroxyphenyl)-4-styrylpyrazoles (Scheme
1).
The reactions of (E)-3-styrylchromones 1a–d with an
excess of hydrazine hydrate, at room temperature and
under nitrogen, led to the formation of novel (E)-3(5)-
(2-hydroxyphenyl)-4-styrylpyrazoles 3a–d in good yields
(68–87%).24 These good results prompted us to study the
reaction of (Z)-3-styrylchromones 2a–c with hydrazine
hydrate, which afforded the expected (Z)-3(5)-(2-
hydroxyphenyl)-4-styrylpyrazoles 4a–c in 88–94%
yield.25 The same procedure was applied in the reaction
of (Z)-40-nitro-3-styrylchromone 2d with hydrazine
hydrate, however, the results were not as expected, the
(E)-3(5)-(2-hydroxyphenyl)-4-(4-nitrostyryl)pyrazole 3d
was obtained in excellent yield (98%).26 Due to this
unexpected result we decided to further explore this
reaction and other (Z)-40-nitro-3-styrylchromones 2e–g
were prepared22 and left to react with hydrazine hydrate.
The biological importance of pyrazole ring systems and
our interest to study the reactivity of some chromones
Keywords: 3-Styrylchromones; 3(5)-(2-Hydroxyphenyl)-4-styrylpyr-
azoles; NMR; Nitrogen heterocycles; Reaction mechanism.
*
Corresponding author. Tel.: +351 234 370 714; fax: +351 234 370
084; e-mail: arturs@dq.ua.pt
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.03.147

3860
V. L. M. Silva et al. / Tetrahedron Letters 48 (2007) 3859–3862
Scheme 1.
These reactions gave in all cases novel (E)-3(5)-(2-
hydroxyphenyl)-4-(4-nitrostyryl)pyrazoles 3e–g, in very
good yields (>70%). These results indicate that the
40-nitro group has an important role in the (Z)!(E)
isomerisation during the transformation of (Z)-40-
nitro-3-styrylchromones 2d–g into the corresponding
(E)-4-(4-nitrostyryl)pyrazoles 3d–g.
nitro-3-styryl moiety instead of the 4-carbonyl group
(B, Scheme 2). This conjugate addition allowed the
(Z)!(E) isomerisation of the vinylic double bond of
the styryl group,27 the most stable configuration, and
consequent ring opening. The last step of this reaction
mechanism is the pyrazole ring closure by an intra-
molecular reaction of the hydrazine and carbonyl gro-
ups. In order to confirm the proposed mechanism, we
studied the reaction of (Z)-30-nitro-3-styrylchromones
2h–j, where there is no electronic conjugation between
the 30-nitro group and the 3-styrylchromone moiety,
with hydrazine hydrate (Scheme 3). As expected (Z)-
3(5)-(2-hydroxyphenyl)-4-(3-nitrostyryl)pyrazoles 4h–j28
have been obtained in very good yields (>80%), which
confirms the proposed mechanism depicted in Scheme 2.
The reaction mechanism of the unsubstituted or
2-substituted-chromones with hydrazine has been
reported to involve a nucleophilic attack at C-2 of the
chromone and consequent ring opening, followed by
the intramolecular reaction between the hydrazine and
carbonyl groups.15 This seems to be the mechanism of
the reaction of 3-styrylchromones 1a–d and 2a–c with
hydrazine hydrate, which does not involve the 3-styryl
group and consequently we have found that the config-
uration of the vinyl system is unchanged in their
transformation into the corresponding (E)- and (Z)-4-
styrylpyrazoles 3a–d and 4a–c (A, Scheme 2). From
the results obtained with the (Z)-40-nitro-3-styrylchro-
mones 2d–g, it emerged that the mechanism should be
different in these cases. On the basis that nitro and
carbonyl groups are considered strong electron-with-
drawing groups and the nitro group could be envisaged
as the more powerful one, we could envisage that after
the nucleophilic attack at C-2 of the chromone nucleus
the electronic conjugation should move towards the 40-
Scheme 3.
Scheme 2.

V. L. M. Silva et al. / Tetrahedron Letters 48 (2007) 3859–3862
3861
The NMR spectra of 3(5)-(2-hydroxyphenyl)-4-styrylpyr-
azoles 3a–c and 4a–c have been run in CDCl3, while
those of 3d–g and 4h–j have been acquired in DMSO-
d6 due to their insolubility in the former solvent. The
1
main features of the H NMR spectra of (E)- and (Z)-
3(5)-(2-hydroxyphenyl)-4-styrylpyrazoles (3a–c and 4a–
c) are the resonances of: (i) H-5 appearing as a singlet
at dH 7.79–7.85 ppm for 3a–c and dH 7.32–7.37 ppm
for 4a–c. A simple minimization of the geometries of
compounds 3a and 4a using molecular mechanics shows
that the shielding in the 4 series is due to the proximity
and geometrical disposition of the phenyl ring (Pauling–
Pople currents); (ii) the vinylic protons H-a (dH 6.84–
6.85 ppm for 3a–c and dH 6.45–6.58 ppm for 4a–c) and
H-b (dH 7.01–7.14 ppm for 3a–c and dH 6.63–6.70 ppm
for 4a–c). The values of the olefinic coupling constants
(3JHa–Hb 11.8–11.9 Hz) in the case of compounds 4a–c
indicate the cis configuration for this vinylic moiety,
whereas those of compounds 3a–c (3JHa–Hb 16.2–
17.4 Hz) indicate the trans configuration. This is the
main criterion to distinguish between compounds 3a–c
Figure 1. Main connectivities found in the HMBC spectra of 3a–g,
4a–c and 4h–j.
styrylpyrazoles in excellent yields and with a simple
purification process. The influence of the 40-substituent
of 3-styrylchromones in this transformation was studied
and it was also demonstrated that the methodology can
be used to prepare (E)- and (Z)-3-(2-hydroxyphenyl)-4-
styrylpyrazoles from the corresponding (E)- and (Z)-3-
styrylchromones which do not have the 40-nitro group.
In this case, the reaction of both (E)- and (Z)-40-nitro-
3-styrylchromones gave only (E)-3-(2-hydroxyphenyl)-
4-(4-nitrostyryl)pyrazoles. Further application of this
methodology for the synthesis of other 3(5)-(2-hydroxy-
phenyl)-4-styrylpyrazoles will be described in due
course.
1
and 4a–c. The H NMR spectra of these 4-styrylpyr-
azoles 3a–c present one deshielded broad singlet
(dH 10.02–10.14 ppm) and those of 4a–c show two
deshielded broad singlets (dH 9.99–10.21 and 10.55–
10.79 ppm) corresponding to the NH and 20-OH proton
resonances.
Acknowledgments
1
The H NMR spectra of 3(5)-(2-hydroxyphenyl)-4-styr-
We are pleased to acknowledge the financial support
ylpyrazoles 3d–g and 4h–j in DMSO-d6 present some
characteristic resonances, namely those of H-5 appear-
ing as a broad singlet (dH 8.05–8.49 ppm for 3d–g and
dH 7.71–7.74 ppm for 4h–j), H-a (dH 6.93–7.20 ppm
for 3d–g and dH 6.26–6.45 ppm for 4h–j) and H-b (dH
7.08–7.13 ppm for 3d–g and dH 6.57–6.62 ppm for 4h–
j). The coupling constant values of the olefinic protons
(3JHa–Hb 16.4–17.4 Hz) of 3d–g indicate a trans configu-
ration for this vinylic moiety, while those of 4h–j
(3JHa–Hb 11.9–12.0 Hz) support a cis configuration.
These NMR spectra also present two broad singlets at
high frequency values due to the NH (dH 9.76–
10.27 ppm) and 20-OH (dH 12.71–13.01 ppm) proton
resonances.29 In DMSO-d6 solution, both 1H- and 2H-
tautomers of pyrazoles 3d–g and 4h–j are probably pres-
ent since the 20-OH–N-2 hydrogen bond is broken and
another is formed 20-OH–DMSO, which are responsible
for the 20-OH deshielding. The broadening of the several
from the University of Aveiro, ‘Fundac¸ao para a Cieˆn-
˜
cia e Tecnologia’ and FEDER. One of us (V.L.M.S.)
is also grateful to FCT and FSE for a PhD grant
(SFRH/BD/6647/2001).
References and notes
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1
signals in the H and 13C NMR spectra of these 4-styr-
ylpyrazoles 3d–g and 4h–j confirms the existence of
prototropy. The prototropy is relatively fast and average
signals are observed. In order to fully characterise
these compounds, we have performed these spectra in
DMSO-d6 with some drops of TFA, which increase
the prototropy.
´
´
7. Catalan, J.; Fabero, F.; Claramunt, R. M.; Santa Marıa,
The connectivities found in the HMBC spectra of pyr-
azoles 3a–g and 4a–c (Fig. 1) allowed the unequivocal
assignments of their C-3 and C-5 carbon resonances,
and also the resonances of all the other quaternary
carbons.
´
M. D.; Foces-Foces, M. C.; Cano, F. H.; Martınez-Ripoll,
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Aotsuka, T. Eur. J. Med. Chem.—Chim. Ther. 1986, 21,
65–69.
In conclusion, we have successfully applied the use of 3-
styrylchromones to prepare 3(5)-(2-hydroxyphenyl)-4-

3862
V. L. M. Silva et al. / Tetrahedron Letters 48 (2007) 3859–3862
10. 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.
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M. G.; Boxall, K. J.; Sharp, S. Y.; Maloney, A.; Roe, S.
M.; Prodromou, C.; Pearl, L. H.; Aherne, G. W.;
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Drysdale, M. J.; Wright, L.; Grant, K.; Massey, A.;
Surgenor, A.; Workman, P. Bioorg. Med. Chem. Lett.
2005, 15, 5197–5201.
13. 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.
14. 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.
NMR (CDCl3): d 116.9 (C-30), 117.2 (C-10), 118.5 (C-4),
118.9 (C-a), 119.5 (C-50), 126.3 (C-200,600), 127.6 (C-5 and C-
40), 128.5 (C-60), 128.7 (C-300,500), 129.5 (C-400), 130.0 (C-b),
137.2 (C-100), 147.8 (C-3), 155.6 (C-20). EI-MS: 262 (M+Å,
87), 261 (27), 245 (4), 233 (5), 216 (3), 206 (3), 189 (4), 185
(26), 171 (100), 165 (2), 155 (2), 140 (4), 131 (5), 115 (25), 102
(8), 89 (7), 77 (11), 63 (8). Anal. Calcd for C17H14N2O: C,
77.84; H, 5.38; N, 10.68. Found: C, 77.71; H, 5.60; N, 10.89.
25. The procedure for the preparation of (Z)-3-(2-hydroxy-
phenyl)pyrazole 4a is similar to that described in Ref. 24
for pyrazole 3a: The product 4a was obtained, as a white
1
solid (mp 119–121 ꢁC), in 88% yield; H NMR: d 6.56 (d,
1H, H-a, J = 11.9 Hz), 6.70 (d, 1H, H-b, J = 11.9 Hz),
6.94 (ddd, 1H, H-50, J = 7.5, 7.6 and 1.2 Hz), 7.06 (dd, H-
30, J = 8.2 and 1.2 Hz), 7.19–7.33 (m, 7H, H-
200,300,400,500,600, H-40 and H-5), 7.84 (dd, 1H, H-60,
J = 7.6 and 1.6 Hz), 9.99 (br s, 1H, NH), 10.56 (br s,
1H, 20-OH).13C NMR: d 115.5 (C-4), 116.9 (C-30), 117.2
(C-10), 119.3 (C-50), 120.8 (C-a), 127.1 (C-400), 127.3 (C-5),
128.2 (C-60), 128.3 (C-200,600), 128.7 (C-300,500), 129.4 (C-40),
131.3 (C-b), 137.0 (C-100), 148.9 (C-3), 155.9 (C-20). EI-
MS: 262 (M+Å, 99), 261 [(MꢀH)+, 35], 245 (5), 233 (6), 216
(3), 206 (3), 190 (2), 185 (27), 171 (100), 165 (2), 152 (2),
140 (4), 131 (7), 115 (20), 102 (7), 89 (6), 77 (8), 63 (6).
Anal. Calcd for C17H14N2O: C, 77.84; H, 5.38; N, 10.68.
Found: C, 77.94; H, 5.63; N, 10.31.
15. Pinto, D. C. G. A.; Silva, A. M. S.; Cavaleiro, J. A. S.;
Foces-Foces, C.; Llamas-Saiz, A. L.; Jagerovic, N.;
Elguero, J. Tetrahedron 1999, 55, 10187–10200.
16. Pinto, D. C. G. A.; Silva, A. M. S.; Cavaleiro, J. A. S. J.
Heterocycl. Chem. 2000, 37, 1629–1634.
17. 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.
26. Compound 3d was obtained, as a yellow solid (mp 212–
1
214 ꢁC) in 87% yield; H NMR (DMSO-d6 + some drops
of TFA): d 6.93 (dt, 1H, H-50, J = 7.5 and 1.0 Hz), 7.01 (d,
1H, H-30, J = 7.5 Hz), 7.08 (AB, 1H, H-b, J = 16.4 Hz),
7.20 (AB, 1H, H-a, J = 16.4 Hz), 7.26–7.33 (m, 2H, H-40
and H-60), 7.64 (d, 2H, J = 8.9 Hz, H-200,600); 8.15 (d, 2H,
J = 8.9 Hz, H-300,500), 8.19 (s, 1H, H-5). 13C NMR
(DMSO-d6 + some drops of TFA): d 116.7 (C-10), 117.1
(C-30), 118.2 (C-4), 120.3 (C-50), 124.5 (C-a), 124.8 (C-
300,500), 125.9 (C-b), 127.3 (C-200,600), 131.5 and 131.6 (C-40
and C-60), 134.1 (C-5), 142.5 (C-3), 145.1 (C-100), 146.6 (C-
400), 155.9 (C-200). EI-MS: 307 (M+Å, 88); 306 [(MꢀH)+,
15]; 290 (8), 277 (7), 260 (26), 244 (2), 231 (4), 215 (3), 201
(7), 191 (2), 185 (20), 171 (100), 165 (3), 152 (3), 130 (5),
115 (13), 102 (7), 89 (5), 77 (6), 63 (6), 57 (2). EI-HRMS:
Calcd. for (C17H14N3O3) 308.1035; Found 308.1027.
27. Dugave, C.; Demange, L. Chem. Rev. 2003, 103, 2475–
2532.
´
18. Levai, A.; Silva, A. M. S.; Pinto, D. C. G. A.; Cavaleiro, J.
A. S.; Alkorta, I.; Elguero, J.; Jeko¨, J. Eur. J. Org. Chem.
2004, 4672–4679.
19. Koenigs, E.; Freund, J. Ber. 1947, 80, 143–149.
20. Baker, W.; Harborne, J. B.; Ollis, W. D. J. Chem. Soc.
1952, 1303–1309.
21. Scho¨nberg, A.; Sidky, M. M. J. Am. Chem. Soc. 1953, 75,
5128–5130.
22. Sandulache, A.; Silva, A. M. S.; Pinto, D. C. G. A.;
Almeida, L. M. P. M.; Cavaleiro, J. A. S. New J. Chem.
2003, 27, 1592–1598.
23. Silva, V. L. M.; Silva, A. M. S.; Pinto, D. C. G. A.;
Cavaleiro, J. A. S.; Patonay, T. Synlett 2004, 2717–2720.
24. The procedure for the preparation of (E)-3(5)-(2-hydroxy-
phenyl)-4-styrylpyrazole 3a is described as example: Hydra-
zine hydrate (0.08 ml, 1.61 mmol) was added to a solution
of (E)-3-styrylchromone 1a (200 mg, 8.06 · 10ꢀ1 mmol) in
methanol (50 mL). The reaction mixture was stirred at
room temperature, under nitrogen atmosphere, until the
disappearance of the starting material. After that period,
the mixture was poured into chloroform (100 mL) and
washed with acidified water (2 · 100 mL; pH = 5). The
organic layer was dried over anhydrous sodium sulphate,
the solvent was evaporated to dryness and the solid residue
was purified by column chromatography using chloroform
as eluent. The residue obtained after solvent evaporation
28. The structural characterisation of (Z)-3(5)-(2-hydroxyphen-
yl)-4-(3-nitrophenyl)pyrazole 4h is described as example: It
was obtained as a beige solid (mp 108–110 ꢁC) in
1
quantitative yield. H NMR (DMSO-d6 + some drops of
TFA): d 6.45 (d, 1H, H-a, J = 11.9 Hz), 6.62 (d, 1H, H-b,
J = 11.9 Hz), 6.76 (ddd, 1H, H-50, J = 7.8, 7.3 and
0.7 Hz), 6.85 (dd, 1H, H-30, J = 8.1 and 0.7 Hz), 7.14
(ddd, 1H, H-40, J = 8.1, 7.3 and 1.6 Hz), 7.27 (dd, 1H, H-
60, J = 7.8 and 1.6 Hz), 7.33 (t, 1H, H-500, J = 8.0 Hz),
7.40–7.46 (m, 1H, H-600), 7.71 (s, 1H, H-5), 7.86 (t, 1H, H-
200, J = 2.0 Hz), 7.90 (ddd, 1H, H-400, J = 8.0, 2.0 and
0.9 Hz). 13C NMR (DMSO-d6 + some drops of TFA):
115.2 (C-10), 117.3 (C-4), 117.7 (C-30), 120.8 (C-50), 122.2
(C-a), 123.4 (C-400), 124.0 (C-200), 131.0 (C-500), 131.3 (C-b),
131.8 (C-60), 132.9 (C-40), 134.1 (C-5), 135.9 (C-600), 139.8
(C-100), 143.9 (C-3), 149.5 (C-300), 156.7 (C-20). ES+-MS:
308 [(M+H)+, 91], 330 [(M+Na)+, 100]. Anal. Calcd for
C17H13N3O3: C, 66.44; H, 4.26; N, 13.67. Found: C, 66.21;
H, 4.22; N, 12.92.
was recrystallised from
a mixture of dichlorometh-
ane:cyclohexane. The product 3a was obtained, as a white
1
solid (mp 138–140 ꢁC), in 75% yield (158.6 mg); H NMR
(CDCl3): d 6.85 (d, 1H, H-a, J = 16.2 Hz), 6.96 (t, 1H, H-50,
J = 7.6 and 7.4 Hz), 7.08 (d, 1H, H-30, J = 8.1 Hz), 7.14 (d,
1H, H-b, J = 16.2 Hz), 7.24–7.29 (m, 2H, H–40 and H-400),
7.35 (t, 2H, H-300,500, J = 7.7 and 7.2 Hz), 7.45 (d, 2H, H-
200,600, J = 7.2 Hz), 7.61 (dd, 1H, H-60, J = 7.6 and 1.4 Hz),
7.79 (s, 1H, H–5), 10.02 (br s, 2H, NH and 20-OH). 13C
29. Levai, A.; Silva, A. M. S.; Cavaleiro, J. A. S.; Alkorta, I.;
Elguero, J.; Jeko¨, J. Eur. J. Org. Chem. 2006, 2825–
2832.