Preparation of 4,6-diarylindazole derivatives in ionic liquid under solvent-free conditions

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Preparation of 4,6-Diarylindazole
Derivatives in Ionic Liquid under Solvent-
free Conditions
a
a
Javad Safaei-Ghomi , Mahdi Taheri & Mohammad Ali
a
Ghasemzadeh
a
Department of Organic Chemistry, Faculty of Chemistry, University
of Kashan, Kashan, I. R. Iran
Published online: 01 Oct 2010.
To cite this article: Javad Safaei-Ghomi , Mahdi Taheri & Mohammad Ali Ghasemzadeh (2010)
Preparation of 4,6-Diarylindazole Derivatives in Ionic Liquid under Solvent-free Conditions, Organic
Preparations and Procedures International: The New Journal for Organic Synthesis, 42:5, 485-489,
DOI: 10.1080/00304948.2010.514795
To link to this article: http://dx.doi.org/10.1080/00304948.2010.514795
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Organic Preparations and Procedures International, 42:485–489, 2010
Copyright © Taylor & Francis Group, LLC
ISSN: 0030-4948 print
DOI: 10.1080/00304948.2010.514795
OPPI BRIEFS
Preparation of 4,6-Diarylindazole Derivatives
in Ionic Liquid under Solvent-free Conditions
Javad Safaei-Ghomi, Mahdi Taheri,
and Mohammad Ali Ghasemzadeh
Department of Organic Chemistry, Faculty of Chemistry, University of Kashan,
Kashan, I. R. Iran
Ionic liquids have been the subject of considerable current interest as environmentally be-
nign reaction media in organic synthesis because of their unique properties of non-volatility,
non-flammability, recyclability, and ability to dissolve a wide range of organic and inorganic
1
–3
compounds. Ionic liquids are also thermally stable, have negligible vapor pressure and
increased reaction rates, show selectivity and a tendency to immobilize starting materials
and catalysts. Ionic liquids can play a significant role in controlling reactions as solvents or
4
5,6
7
catalysts and have been applied in various organic reactions, such as the Friedel-Crafts,
the Diels-Alder and Biginelli reactions, the Beckmann rearrangement,11,12 Michael
8
,9
10
addition and other reactions.14–16
13
Among the new transformations, cyclocondensation reactions are attractive method-
17
ologies for the synthesis of heterocyclic compounds. Indazole derivatives exhibit anti-
inflammatory, anti-depressant, anti-arthritic, anti-tumor21 and analgesic activities.
Most of the methods to prepare indazoles proceed from benzene derivatives on which the
pyrazole moiety is attached by ring closure.21 We report a convenient synthesis of indazole
derivatives from cyclohexenone derivatives in ionic liquid media.
1
8
19
20
22
A mixture of chalcone with ethyl acetoacetate and 1-butyl-3-methylimidazo
liumbromide ([bmim]Br) was stirred at room temperature for the period of times shown in
Table 1. The reaction mixture was then extracted with ether and the product was recrys-
tallyzed from ethanol. The best results were obtained with a ratio of [1:1:0.7] mmols of
chalcone, ethyl acetoacetate, [bmim]Br. Electron-withdrawing groups on phenyl rings led
to shorter reaction times than electron-donating groups.
The present procedure catalyzed by a simple ionic liquid, [bmim]Br, provides an effi-
cient and general methodology for Robinson Annulations. This method has the advantages
Submitted February 12, 2009.
Address correspondence to Javad Safaei-Ghomi, Department of Organic Chemistry, Faculty of
Chemistry, University of Kashan, 51167 Kashan, I. R. Iran. E-mail: safaei@kashanu.ac.ir
485

486
Safaei-Ghomi et al.
R2
R1
O
[
bmim]Br
+
CH COCH COOC H
3 2 2 5
R.T.
R1
R2
EtOOC
O
1
2
3
a) R = R = H; b) R = Cl, R = H; c) R = H, R = Me; d) R = Cl, R = Me; e) R = H, R = Br;
1
2
1
2
1
2
1
2
1
2
f) R = Cl, R = Br; g) R = H, R = NO ; h) R = Cl, R = NO
1
2
1
2
2
1
2
2
of shorter reaction times and higher yields compared to another representative method,
catalyzed by K2CO3 (Table 1).23
Treatment of cyclohexenones (3a-h) with hydrazine hydrate or phenylhydrazine in
◦
[
bmim]Br as solvent and catalyst at 90 C for 3.5 h produced indazole derivatives. The
results are given in Table 2. The conditions led to shorter reaction times and higher yields
compared with another representative method in which acetic acid was used as catalyst
25
(
Table 2).
Ar
Ar1
Ar
Ar1
+
[
bmim]Br
0
RNHNH2
HO
EtOOC
90 C, 3.5 h
N
N
O
R
3
4
5
a) R = H, Ar = Ar1 = C H ; b) R = H, Ar = C H , Ar = 4-Cl-C H ; c) R = H, Ar = 4-Me-C H , Ar = C H ;
1
1
6
5
6
5
6
4
6
4
6 5
1
1
d)R = H, Ar = 4-Me-C H , Ar = 4-Cl-C H ; e)R = H, Ar = 4-Br-C H , Ar = C H ; f)R = H, Ar = 4-Br-C H ,
Ar = 4-Cl-C H ; g) R = H, Ar = 4-NO -C H , Ar = C H ; h) R = H, Ar = 4-NO -C H , Ar = 4-Cl-C H ;
i)R = Ar = Ar = C H ; j)R = C H , Ar = C H , Ar = 4-Cl-C H ; k)R = C H , Ar = 4-Me-C H , Ar = C H ;
l) R = C H , Ar = 4-Me-C H , Ar = 4-Cl-C H ; m) R = C H ,Ar = 4-Br-C H , Ar = C H ; n)R = C H ,
6
4
6
4
6
4
6
5
6 4
1
1
1
6
4
2
6
4
6
5
2
6
4
6 4
1
1
1
6
5
6
5
1
6
5
6
4
6
5
6
4
6 5
1
6
5
6
4
6
4
6
5
6
4
6
5
6 5
1
1
Ar = 4-Br-C H , Ar = 4-Cl-C H ; o)R = C H , Ar = 4-NO -C H , Ar = C H ; p)R = C H ,Ar = 4-NO -C H ,
6
4
6
4
6
5
2
6
4
6
5
6
5
2
6 4
1
Ar = 4-Cl-C H
6
4
Table 1
Comparison of Two Methods in Robinson Annulation
Stirred in K2CO323
Stirred in [bmim]Br
◦
lit. mp.23
Cmpd
mp( C)
Time (min) Yield (%) Time (min) Yield (%)
2
4
3
3
3
3
3
3
3
3
a
b
c
d
e
f
109–111 111–112
60
40
50
60
30
30
20
20
85
80
85
80
80
82
60
60
35
30
35
30
20
15
15
10
95
90
95
90
90
90
85
90
2
3
90–91
90–91
141–143 139–1422
4
3
3
3
4
115–117 115–1172
2
153–155 153–155
111–113 110–1122
2
g
h
107–109 105–107
134–136 134–13623

4,6-Diarylindazole Derivatives in Ionic Liquid
487
Table 2
Comparison of two Procedures in the Preparation of Indazoles
◦
lit. mp.25
Acetic Acida,25
Yield (%)
[bmim]Brb
Yield (%)
Cmpd
mp( C)
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
p
215–216
123–125
159–160
120–122
146–148
141–143
157–158
167–168
170–173
166–167
182–184
186–188
213–215
167–168
150–151
160–161
215–217
123–125
158–160
120–121
146–148
141–143
157–158
167–168
170–173
167–168
182–184
186–188
213–215
167–168
150–151
161–162
77
72
75
72
70
71
65
66
82
70
80
75
71
72
77
75
85
80
85
83
80
78
78
80
85
78
85
83
75
78
85
83
a) 6 hours in Ref. 25; b) 3.5 hours.
One of the advantages of ionic liquids is their ability to function as a recyclable reaction
medium. The catalyst [bmim]Br could be recovered and reused from the reaction medium
26
easily by washing with ether and evaporating the solvent under vacuum.
Experimental Section
Yields refer to isolated pure products. The products were characterized by comparison
1
13
of their spectral (IR, H NMR, C NMR) and melting points with authentic samples.
All of the reactions were carried out in a hood with strong ventilation. IR spectra were
recorded on a Magna-550 IR spectrophotometer. Spectra of solids were carried out using
1
13
KBr pellets. H NMR and C NMR spectra were determined on a Bruker DPX-400 M Hz
using [D6]DMSO as solvent and TMS as internal standard.
Typical Procedure for the Robinson Annulation Reaction in [bmim]Br (3a–h)
A mixture of the chalcone (1mmol), ethyl acetoacetate (130 mg, 1 mmol) and [bmim]Br
(153 mg, 0.7 mmol) was stirred at room temperature for the period of time required to
complete the reaction (TLC). The reaction mixture was extracted with ether (3 × 10 mL)
and separated from the ionic liquid phase. The residual ionic liquid may be reused in the
next run if necessary after a 2 h heat treatment under vacuum. The ethereal layer was

488
Safaei-Ghomi et al.
evaporated under reduced pressure and the product was recrystallyzed from ethanol. The
23
spectral data of all products were identical to those reported in a previous paper.
Typical Procedure for the Preparation of Indazole Derivatives (5a–p) in [bmim]Br
A mixture of 3a-h (1 mmol) and [bmim]Br (153 mg, 0.7 mmol) was added to hydrazine
◦
hydrate or phenylhydrazine (1.5 mmol). The mixture was refluxed for 3.5 h at 90 C. The
reaction mixture was extracted with ether (3×10 mL) and the ionic liquid phase was
separated. The residual ionic liquid may be reused in the next run if necessary after a 2 h
heat treatment under vacuum. The ethereal layer was evaporated under reduced pressure
and the product was recrystallyzed from ethanol. The spectral data of all products were
25
identical to those reported in a previous paper.
Acknowledgements
Financial support from the Research Affairs Office of the University of Kashan, Kashan, I.
R. Iran is gratefully acknowledged.
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