Unexpected ring-opening of 3-aroylbenzo[b]furans at room temperature: A new route for the construction of phenol-substituted pyrazoles

Article abstract of DOI:10.1016/j.tetlet.2013.04.085

A new and convenient route for the synthesis of phenol-substituted pyrazoles 11-18 is starting from 3-aroylbenzo[b]furans 1-8 and hydrazine hydrate at room temperature.

Full text of DOI:10.1016/j.tetlet.2013.04.085

Tetrahedron Letters 54 (2013) 3424–3426
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Tetrahedron Letters
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Unexpected ring-opening of 3-aroylbenzo[b]furans at room temperature:
a new route for the construction of phenol-substituted pyrazoles
Hatem A. Abdel-Aziz a,b, , Pervez Ahmad a, Adnan Kadi a, Khalid A. Al-Rashood a, Hazem A. Ghabbour a,
⇑
Hoong-Kun Fun a
a Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, PO Box 2457, Riyadh 11451, Saudi Arabia
b Department of Applied Organic Chemistry, National Research Centre, Dokki, Cairo 12622, Egypt
a r t i c l e i n f o
a b s t r a c t
Article history:
A new and convenient route for the synthesis of phenol-substituted pyrazoles 11–18 is starting from 3-
aroylbenzo[b]furans 1–8 and hydrazine hydrate at room temperature.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 23 December 2012
Revised 10 April 2013
Accepted 19 April 2013
Available online 28 April 2013
Keywords:
Ring-opening
3-Aroylbenzo[b]furans
Phenol-substituted pyrazoles
The construction of pyrazoles has gained significant interest
among the azole family1–3 due to their diverse therapeutic poten-
tial as versatile anticancer,4 antifungal,5 antimicrobial,6, and anti-
inflammatory agents7 and osteogenesis activity.8 The pyrazole
moiety is the main pharmacophore in the established anti-inflam-
matory drugs, Celecoxib9 and SC-558.10 On the other hand, pheno-
lic compounds have received considerable attention owing to their
widespread occurrence in a large number of natural products, and
for their useful biological and pharmacological properties, for
example, as antioxidant,11 antibacterial,12 and cardiovascular
agents,13 in addition to their estrogen receptor activity.14 As part
of an ongoing research program devoted to study benzofurans
and pyrazoles with potential chemical activities,15–17 in the pres-
ent communication, we have investigated the reactions of 3-aro-
ylbenzo[b]furans with hydrazine hydrate (Scheme 1).
to be formed through intermediate 9 followed by the nucleophilic
attack on the electron-deficient C-2 of furan to produce com-
pounds 11–18. The formation of compounds 11–18 via intermedi-
ate 10 is more possible under basic conditions of hydrazine.
However, all attempts to isolate intermediates 9 and 10 failed.
The 1H NMR (CDCl3) spectra of the isolated reaction products
revealed the existence of the pyrazole NH around d 7.59 and the
phenolic OH in the region d 8.4–8.9. The appearance of the pyra-
zole C-5 proton in a pattern in DMSO-d6 that was different from
21
that in CDCl3 is probably due to the tautomerism of 1H-3(5)-R
pyrazoles.22 Owing to the latter tautomerism, 1H-3(5)-R pyrazoles
can exist in two tautomeric forms, 1H-3-R and 1H-5-R in solution
in a ratio that depends on the temperature.23 Moreover, these pyr-
azoles showed 1H chemical shifts for the N–H proton in DMSO-d6
that differed from the corresponding shifts in CDCl3, which can
be explained by the presence of intra- or intermolecular hydrogen
bonding.24
The structures of benzofurans 4–818 were confirmed from their
spectroscopic data and elemental analyses19 in addition to X-ray
single crystal analysis of compound 6 (Fig. 1).20 Benzofurans 1–8
reacted rapidly with hydrazine hydrate at room temperature to
produce phenol-substituted pyrazoles 11–18 (Scheme 1).
In the solid state, the most common situation is the presence of
only one tautomer of 1H-3(5)-R pyrazoles.22 The single crystal X-
ray structure of pyrazole 16 not only provided unambiguous con-
firmation of the structure of pyrazoles 11–18, but also confirmed
the presence of only one tautomeric form, that is, that of the 1H-
3-R pyrazole (Fig. 2).
In conclusion, the electron-deficient C-2 of 3-aro-
ylbenzo[b]furans is extremely reactive toward the nitrogen nucle-
ophilic ring-opening, and this reactivity is employed for the
development of an effective new route for the construction of
3,4-disubstituted-pyrazoles.
The structures of pyrazoles 11–18 were established on the basis
of their elemental analyses, spectral data21 and single crystal X-ray
analysis of compound 16 (Fig. 2).20 Scheme 1 illustrates the mech-
anism of the formation of compounds 11–18 which are suggested
⇑
Corresponding author. Tel.: +966 1 4677343; fax: +966 1 4676220
E-mail address: hatem_741@yahoo.com (H.A. Abdel-Aziz).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.04.085

H. A. Abdel-Aziz et al. / Tetrahedron Letters 54 (2013) 3424–3426
3425
O
Ar
RO
O
1-8
H2N NH2
NH2
N
O
Ar
NH2
NH
Ar
RO
or
RO
OR
OH
O
10
9
Product Ar
Yield (%)
R
H
H
H
Ph
67
64
70
65
11
12
13
14
15
16
17
18
OR
4-MeC6H4
4-ClC6H4Ph
Ph
Ph
Ph
Ar
Me
Ar
HO
CH2COOMe 70
CH2COOEt 78
HO
N
NH
N
N
H
4-MeC6H4
4-ClC6H4
Me
Me
69
73
11-18 (A)
11-18 (B)
Scheme 1. The reaction of benzofurans 1–8 with hydrazine hydrate at room temperature.
Acknowledgments
The authors extend their appreciation to the Deanship of Scien-
tific Research and Research Centre, College of Pharmacy at the King
Saud University for funding this work.
References and notes
1. Makino, K.; Kim, H. S.; Kurasawa, Y. J. Heterocycl. Chem. 1999, 36, 321–332.
2. Tinarelli, A.; Righi, P.; Rosini, G.; Andreotti, D.; Profeta, R.; Spada, S. Tetrahedron
2011, 67, 612–617.
3. Longhi, K.; Moreira, D. N.; Marzari, M. R. B.; Floss, V. M.; Bonacorso, H. G.;
Zanatta, N.; Martins, M. A. P. Tetrahedron Lett. 2010, 51, 3193–3196.
ˇ
´
´
4. Vujasinovic´, I.; Paravic´-Radicevic, A.; Mlinaric-Majerski, K.; Brajša, K.; Bertoša,
B. Bioorg. Med. Chem. 2012, 20, 2101–2110.
5. Zhang, C.-Y.; Liu, X.-H.; Wang, B.-L.; Wang, S.-H.; Li, Z.-M. Chem. Biol. Drug Des.
2010, 75, 489–493.
6. Gadakh, A. V.; Pandit, C.; Rindhe, S. S.; Karale, B. K. Bioorg. Med. Chem. Lett. 2010,
20, 5572–5576.
Figure 1. ORTEP diagram of 6.
7. El-Sayed, M. A.-A.; Abdel-Aziz, N. I.; Abdel-Aziz, A. A.-M.; El-Azab, A. S.; Asiri, Y.
A.; ElTahir, K. E. H. Bioorg. Med. Chem. 2011, 19, 3416–3424.
8. Lv, H.-S.; Han, Q.-Q.; Ding, X.-L.; Zhou, J.-L.; Yang, P.-S.; Miao, J.-Y.; Zhao, B.-X.
Arch. Pharm. 2012, 345, 870–877.
9. Bing, R. J.; Lomnicka, M. J. Am. Coll. Cardiol. 2002, 39, 521–522.
10. Kurumbail, R. G.; Stevens, A. M.; Gierse, J. K.; McDonald, J. J.; Stegeman, R. A.;
Pak, J. Y.; Gildehaus, D.; Miyashiro, J.; Penning, T. D.; Seibert, K.; Isakson, P. C.;
Stallings, W. C. Nature 1996, 384, 644–648.
11. Maestri, D. M.; Nepote, V.; Lamarque, A. L.; Zygadlo, J. A. Phytochem. Adv. Res.
2006, 105–135.
12. Mourer, M.; Dibama, H. M.; Fontanay, S.; Grare, M.; Duval, R. E.; Finance, C.;
Regnouf-de-Vains, J.-B. Bioorg. Med. Chem. 2009, 17, 5496–5509.
13. Fragopoulou, E.; Apostoakis, C.; Nomikos, T.; Panayotou, G.; Pliakis, E.;
Karantonis, H. C.; Samiotaki, M.; Antonopoulou, S. J. Agric. Food Chem. 2007,
55, 80–89.
14. Nishiguchi, G. A.; Rodriguez, A. L.; Katzenellenbogen, J. A. Bioorg. Med. Chem.
Lett. 2002, 12, 947–950.
15. Abdel-Aziz, H. A.; Mekawey, A. A. I. Eur. J. Med. Chem. 2009, 44, 3985–4997.
16. Abdel-Aziz, H. A.; Mekawey, A. A. I.; Dawood, K. M. Eur. J. Med. Chem. 2009, 44,
3637–3644.
17. Abdel-Aziz, H. A.; El-Zahabi, H. S. A.; Dawood, K. M. Eur. J. Med. Chem. 2010, 45,
2427–2432.
18. (a) Benzofurans 1–3 were synthesized by the reaction of enaminones with
benzoquinone in acetic acid.; (b) Antczak, C.; Shum, D.; Bassit, B.; Li, Y.; De
Stanchina, E.; Scheinberg, D. A.; Djaballah, H.; Frattini, M. G. Bioorg. Med. Chem.
Lett. 2011, 21, 4528–4532.
Figure 2. ORTEP diagram of 16.

3426
H. A. Abdel-Aziz et al. / Tetrahedron Letters 54 (2013) 3424–3426
19. Synthesis of benzofurans 4–8.
A
mixture of benzofuran derivative 1–3
0.51H, NH), 13.10 (br s, D2O-exch., 0.49H, NH); 13C NMR (125 MHz, CDCl3) d
114.50, 115.25, 116.07, 117.42, 126.72, 127.98, 128.43, 129.69, 147.45, 149.45;
MS (ESI) m/z 253.2 [M+1]+. Anal. Calcd for C15H12N2O2 (252.27): C, 71.42; H,
4.79; N, 11.10. Found: C, 71.26; H, 4.82; N, 10.88.
(10 mmol), the appropriate haloalkane (10 mol), and anhydrous K2CO3
(2.76 g, 20 mmol) in dry DMF (30 mL) was stirred for 6 h. Next, H2O
(100 mL) was added to the mixture and the precipitated solid was filtered
off and recrystallized from an appropriate solvent to afford the corresponding
alkoxy derivatives 4–8.
Methyl
Colorless crystals, 70% yield; mp 187–189 °C; IR (KBr)
(OH+NH), 1748 (C@O) cmÀ1 1H NMR (500 MHz, CDCl3)
d 3.77 (s, 3H, –
2-[4-hydroxy-3-(3-phenyl-1H-pyrazol-4-yl)phenoxy]acetate
(15).
m
3500–2700
Methyl 2-(3-benzoylbenzofuran-5-yloxy)acetate (5). White powder, 68% yield;
;
mp 105–107 °C; IR (KBr)
m
1751, 1637 (2C@O) cmÀ1
;
1H NMR (500 MHz, CDCl3)
OCH3), 4.66 (s, 2H, –OCH2CO), 6.58 (s, 1H, ArH), 6.71 (d, J = 8.5 Hz, 1H, ArH),
6.82 (d, J = 8.5 Hz, 1H, ArH), 7.17–7.20 (m, 3H, ArH), 7.23–7.37 (m, 2H, ArH),
7.59 (s, 1H, pyrazole), 8.75 (br s, D2O-exch., 2H, OH+NH); 1H NMR (500 MHz,
DSMO-d6) d 3.75 (s, 3H, –OCH3), 4.51 (s, 2H, –OCH2CO), 6.55 (s, 1H, ArH), 6.69
(dd, J = 2.8, 8.5 Hz, 1H, ArH), 6.77 (d, J = 8.5 Hz, 1H, ArH), 7.29–7.43 (m, 5H,
ArH), 7.58 (s, 0.42H, pyrazole), 7.79 (s, 0.58H, pyrazole), 8.90 (s, D2O-exch., 1H,
d 3.80 (s, 3H, –OCH3), 4.72 (s, 2H, CH2), 7.08 (d, J = 8.5 Hz, 1H, ArH), 7.44–7.51
(m, 3H, ArH), 7.58–7.59 (m, 1H, ArH), 7.68 (s, 1H, ArH), 7.83–7.85 (m, 2H, ArH),
8.04 (s, 1H, furan); 13C NMR (125 MHz, CDCl3) d 52.29 (–OCH3), 65.96 (–CH2),
105.63, 112.40, 116.00, 121.24, 125.90, 128.71, 132.50, 139.21, 151.01, 153.14,
155.44, 169.35 (C@O ester), 190.28 (C@O ketone); MS (ESI) m/z 311.1 [M+1]+,
333.1 [M+23]+. Anal. Calcd for C18H14O5 (310.30): C, 69.67; H, 4.55. Found: C,
69.51; H, 4.73.
OH), 12.91 (br s, D2O-exch., 0.58H, NH), 13.15 (br s, D2O-exch., 0.42H, NH); 13
C
NMR (125 MHz, CDCl3) d 52.03 (–OCH3), 65.88 (–CH2), 106.07, 112.40, 116.74,
120.67, 126.89, 129.19, 132.78, 139.97, 151.11, 153.89, 155.29, 168.28 (C@O
ester); MS (ESI) m/z 325.1 [M+1]+, 347.2 [M+23]+. Anal. Calcd for C18H16N2O4
(324.33): C, 66.66; H, 4.97; N, 8.64. Found: C, 66.42; H, 5.15; N, 8.83.
Ethyl 2-[4-hydroxy-3-(3-phenyl-1H-pyrazol-4-yl)phenoxy]acetate (16). Colorless
Ethyl 2-(3-benzoylbenzofuran-5-yloxy)acetate (6). Colorless crystals, 75% yield;
mp 85–87 °C; IR (KBr)
m ;
1744, 1643 (2C@O) cmÀ1 1H NMR (500 MHz, CDCl3) d
1.25 (t, J = 7.0 Hz, 3H, –CH3), 4.22 (q, J = 7.0 Hz, 2H, –OCH2CH3), 4.66 (s, 2H, –
OCH2CO), 7.04 (dd, J = 2.0, 8.5 Hz, 1H, ArH), 7.39–7.47 (m, 3H, ArH), 7.53–7.56
(m, 1H, ArH), 7.64 (d, J = 8.5 Hz, 1H, ArH), 7.79–8.05 (m, 2H, ArH), 7.99 (s, 1H,
furan); 13C NMR (125 MHz, CDCl3) d 13.16 (CH2CH3), 60.37 (CH2CH3), 65.00 (–
CH2), 104.62, 111.32, 115.00, 120.21, 124.83, 127.68, 131.44, 138.20, 149.95,
152.08, 154.46, 167.86 (C@O ester), 189.23 (C@O ketone); MS (ESI) m/z 325.0
[M+1]+. Anal. Calcd for C19H16O5 (324.33): C, 70.36; H, 4.97. Found: C, 70.09; H,
5.21.
crystals, 78% yield; mp 166–168 °C; IR (KBr)
m 3500–2750 (OH+NH), 1745
(C@O) cmÀ1 1H NMR (500 MHz, CDCl3) d 1.17 (t, J = 7.0 Hz, 3H, –CH3), 4.13 (q,
;
J = 7.0 Hz, 2H, –OCH2CH3), 4.35 (s, 2H, –OCH2CO), 6.55 (s, 1H, ArH), 6.72 (d,
J = 8.5 Hz, 1H, ArH), 6.84 (d, J = 8.5 Hz, 1H, ArH), 7.19–7.21 (m, 3H, ArH), 7.26–
7.38 (m, 2H, ArH), 7.59 (s, 1H, pyrazole), 8.77 (br s, D2O-exch., 2H, OH+NH); 1
H
NMR (500 MHz, DSMO-d6) d 1.17 (t, J = 7.0 Hz, 3H, –CH3), 4.10 (q, J = 7.0 Hz, 2H,
–OCH2CH3), 4.53 (s, 2H, –OCH2CO), 6.57 (s, 1H, ArH), 6.70 (dd, J = 2.8, 8.5 Hz,
1H, ArH), 6.78 (d, J = 8.5 Hz, 1H, ArH), 7.29–7.45 (m, 5H, ArH), 7.58 (s, 0.44H,
pyrazole), 7.81 (s, 0.56H, pyrazole), 8.93 (s, D2O-exch., 1H, OH), 12.96 (br s,
D2O-exch., 0.56H, NH), 13.15 (br s, D2O-exch., 0.44H, NH); 13C NMR (125 MHz,
CDCl3) d 13.11 (CH2CH3), 60.33 (CH2CH3), 65.17 (–CH2), 115.30, 116.00, 116.19,
117.60, 126.50, 127.58, 127.94, 128.43, 134.29, 143.23, 147.60, 150.50, 168.17
(C@O ester); MS (ESI) m/z 339.2 [M+1]+, 361.1 [M+23]+. Anal. Calcd for
20. Crystallographic data for the structures 6 (914845) and 16 (914846) have been
deposited with the Cambridge Crystallographic Data Centre (CCDC). Copies of
the data can be obtained, free of charge, on application to CCDC 12 Union Road,
Cambridge
CB2
1EZ,
UK
[Fax:
+44
1223
336033;
e-mail:
deposit@ccdc.cam.ac.uk or http://www.ccdc.cam.ac.uk].
21. Synthesis of pyrazoles 11–18. A solution of benzofuran 1–8 (1 mmol) in MeOH
(50 ml) and hydrazine hydrate (1 mmol) was stirred for 6 h. The separated
solid was recrystallized from the appropriate solvent to afford the
corresponding pyrazoles 11–18, respectively.
C19H18N2O4 (338.36): C, 67.44; H, 5.36; N, 8.28. Found: C, 67.70; H, 5.23; N,
8.43.
2-(3-Phenyl-1H-pyrazol-4-yl)benzene-1,4-diol (11). Colorless crystals, 67% yield;
mp 230–232 °C; IR (KBr)
22. De Paz, J. L. G.; Llamas-Saiz, A. L.; Elguero, J.; Foces-Foces, C.; Aguilar-Parrilla,
F.; Klein, O.; Limbach, H.-H. J. Chem. Soc., Perkin Trans. 2 1997, 101–109.
23. Claramunt, R. M.; García, M. A.; López, C.; Trofimenko, S.; Yap, G. P.; Alkorta, I.;
Elguero, J. Magn. Reson. Chem. 2005, 43, 89–91.
24. Aguilar-Parrilla, F.; Cativiela, C.; De Villegas, M. D. D.; Elguero, J.; Foces-Foces,
C.; Laureiro, J. I. G.; Cano, F. H.; Limbach, H.-H.; Smithe, J. A. S.; Toiron, C. J.
Chem. Soc., Perkin Trans. 2 1992, 1737–1742.
m ;
3450–2700 (OH+NH) cmÀ1 1H NMR (500 MHz,
CDCl3) d 6.40 (s, 1H, ArH), 6.51 (d, J = 8.5 Hz, 1H, ArH), 6.75 (d, J = 8.5 Hz, 1H,
ArH), 7.24–7.31 (m, 3H, ArH), 7.41–7.46 (m, 2H, ArH), 7.59 (s, 1H, pyrazole),
8.48, 8.60, 8.73 (3s, D2O-exch., 3H, 2OH+NH); 1H NMR (500 MHz, DSMO-d6) d
6.44 (s, 1H, ArH), 6.52 (dd, J = 2.8, 8.5 Hz, 1H, ArH), 6.68 (d, J = 8.5 Hz, 1H, ArH),
7.10–7.50 (m, 5H, ArH), 7.58 (s, 0.49H, pyrazole), 7.75 (s, 0.51H, pyrazole), 8.53
(s, D2O-exch., 1H, OH), 8.61 (s, D2O-exch., 1H, OH), 12.89 (br s, D2O-exch.,