An efficient synthesis of 1-H indazoles

Article abstract of DOI:10.1016/j.tetlet.2007.07.162

The reaction of substituted salicyaldehydes with hydrazine hydrochloride under different conditions gave the corresponding 1-H indazoles. However, the reaction of benzaldehydes with hydrazine hydrate under the same conditions yielded only hydrazones.

Full text of DOI:10.1016/j.tetlet.2007.07.162

Tetrahedron Letters 48 (2007) 6890–6892
An efficient synthesis of 1-H indazoles
*
P. D. Lokhande, Abdul Raheem, S. T. Sabale, A. R. Chabukswar and S. C. Jagdale
The Center for Advanced Studies, Department of Chemistry, University of Pune, Pune 411 007, India
Received 24 July 2006; revised 1 July 2007; accepted 25 July 2007
Available online 28 July 2007
Abstract—The reaction of substituted salicyaldehydes with hydrazine hydrochloride under different conditions gave the correspond-
ing 1-H indazoles. However, the reaction of benzaldehydes with hydrazine hydrate under the same conditions yielded only
hydrazones.
Ó 2007 Elsevier Ltd. All rights reserved.
During the course of our work on the synthesis of pyr-
Syntheses of indazoles involving the cyclization of aryl
0
10
11
12
azoles from the reaction of 2 -hydroxychalcones with
hydrazones substituted with bromo, chloro, nitro,
1
13
14
hydrazine hydrochloride (Scheme 1) we noticed the for-
fluoro or mesylates have been reported. There are
several other methods reported on the synthesis of
mation of 3-methylindazole in low yields. Thus, we envi-
sioned, that on reacting salicyaldehydes with excess
hydrazine hydrochloride under reflux in ethanol the
corresponding indazoles would be obtained. Indazole
derivatives have been shown to possess a wide range
of pharmacological activity including nitric oxide (NO)
1
5
indazoles, which include reduction of protected azides
1
6
and cyclization of arylazosulphides. In addition, di-
azotization and cyclization of substituted o-methyl-
1
2
anilines has been reported. However, the elevated
temperatures required for indazole formation makes
this approach impractical. These methods also have
limitations from the point of view of yields, reaction
conditions, availability of starting materials and
generality.
2
3
4
synthase inhibition, analgesic, antiinflammatory and
5
antiviral. Indazoles also possess HIV protease inhibi-
tory activity, antifertility, anticancer and antisperma-
6
7
8
9
togenic activity.
.
OH
N
OH
O
H N
-
NH HCl
2
2
1
(
2 equiv.)
R
R1
R
R
DMSO
N
- .
H N NH HCl
2
2
H
(
excess)
ArCHO,
NaOH/EtOH
DMSO
H
N
OH
O
N
.
2
H N
-
NH HCl
R
2
R
EtOH
CH3
0
Scheme 1. Formation of indazole from 2 -hydroxychalcones.
Keywords: Indazoles; Hydrazones; Salicyaldehyde; Hydrazine hydrochloride.
*
Corresponding author. Tel./fax: +91 20 25691728; e-mail: pdlokhande56@rediffmail.com
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.07.162

P. D. Lokhande et al. / Tetrahedron Letters 48 (2007) 6890–6892
6891
2
Table 2. Synthesis of substituted indazoles (R = H)
.
OH
H N
-
NH H O
OH
2
2
2
5
R
R
(2 equiv.)
R
ethanol
NNH2
CHO
4
R
1
N
2
.
N
H N
(excess)
-
NH HCl
2
2
.
H N
-
NH H O
+
2
2
2
H / ethanol
ethanol
(1 equiv.)
3
R
1
H
2
R
R
OH
HO
N
N
N
1
3
4
5
Entry
R
R
R
R
R
Mp (°C)
Yield (%)
R
N
1
5
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
H
Ph
H
Ph
H
Ph
Ph
H
H
Ph
H
Ph
H
H
H
H
H
H
H
H
H
H
H
H
H
H
CH
CH
H
H
H
NO
NO2
H
H
H
H
CH
CH
Cl
Cl
H
CH
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
NO
NO
Cl
Cl
H
Lit. 144 70
1
7
Lit. 78
90
R
R
15
3
2
Lit. 144 85
1
7
4
Lit. 180 92
1
2
2
Lit. 187 78
Scheme 2. Formation of indazole and other derivatives. Reagents and
conditions: H N–NH ÆHCl, reflux,70%.
2
205
221
75
70
2
2
1
5
Lit. 134 80
1
5
Our initial approach towards the synthesis of indazole
from salicyaldehyde is shown in Scheme 2. On reaction
of salicyaldehyde with hydrazine hydrochloride in acidic
ethanol, indazole 3 was obtained in 92% yield. The use
of acetic acid or hydrochloric acid was preferred. The
use of aprotic solvents such as dimethylformamide and
dimethylsulphoxide gave higher yields (Table 1). Other
solvents did not have any significant effect on the yields
of the product. In benzene, the corresponding hydrazine
was usually formed in higher yield compared to the
indazole. If the more nucleophilic hydrazine hydrate
was used in excess, hydrazone 2 was formed exclusively.
The hydrazones were fully characterized from spectral
data. Reaction of two moles of salicyaldehyde with
one mole of hydrazine hydrate gave dimer 4.
3
Lit. 111 85
190 76
Lit. 200 79
226 72
Lit. 113 79
1
1
1
1
1
1
1
3
H
1
8
Cl
Cl
H
H
H
1
2
3
19
3
3
Lit.
102
152
76
70
74
H
Ph
–NEt
–NEt
2
H
2
H
undergo cyclization in practical yields when using base.
The hydrazone of 1 gave only 20% of indazole when
heated at 150 °C in t-butoxide/t-butanol.
It is evident from Table 2 that the reaction can be car-
ried out with a variety of electron rich or electron defi-
cient salicylaldehydes and acetophenones with different
substitution patterns. In all cases, we observed rapid
conversion to the hydrazones, which underwent cycliza-
tion under acidic condition. The use of bases gave
negligible yields for salicyaldehyde 1. Cyclization was
Various salicylaldehydes on refluxing with acidic etha-
nol gave the corresponding indazoles (Table 2). The for-
mation of indazole using hydrazine has been reported in
1
the literature. The structures of all compounds were
0
0
1
13
observed when 2,2 ,4,4 -tetrahydroxybenzophenone
was refluxed with hydrazine, phenyl hydrazine or methyl
confirmed by IR, H NMR, C NMR and mass spec-
tral analysis. The reaction was then extended to the
preparation of 3-methylindazoles under similar condi-
tions. 2-Hydroxyacetophenones were refluxed with
hydrazine hydrochloride in acidic ethanol to give 3-
methylindazoles in quantitative yields (Scheme 1). Aryl
hydrazines could also be used. The attempted acidic
cyclization of 2-halosubstituted arylaldehydes in ethanol
failed to provide the desired indazole.
1
1
hydrazine at 200 °C. As acidic conditions are an essen-
tial requirement, cyclization probably follows the
Fischer-indole synthesis mechanism. Under acidic con-
ditions the phenolic –OH group tautomerizes to a keto
hydrazine, which undergoes cyclodehydration to afford
the indazole as depicted in Scheme 3. Benzaldehydes
without an ortho-hydroxy group gave only hydrazones
in ethanol as was observed with acetophenones having
no ortho-hydroxy group. Similarly O-methoxy, O-allyl-
oxy and O-benzyloxy benzaldehydes yielded only
hydrazones under similar conditions showing that the
presence of –OH was necessary for indazole formation.
Although the conversion of o-substituted benzaldehy-
des to the desired 1-H-indazole could be achieved by
6
–11
base,
2-hydroxybenzaldehyde hydrazones did not
Table 1. Effect of solvent on the yield of indazole
The significance of the present work lies in the availabil-
ity of starting materials, fewer reaction steps, simplicity
and good yields of products. This method allowed the
synthesis of 7-methoxy- and 7-nitro-1-H indazoles,
Entry
Solvent
Yield (%)
1
2
3
4
5
6
7
Dichloromethane
DMF
Toluene
IPA
Ethanol
Methanol
DMSO
70
85
66
71
78
75
92
2
which are known NO synthase inhibitors.
General procedure for the formation of indazoles: To a
solution of salicylaldehyde 1 in ethanol (5 ml) was added
hydrazine hydrochloride (in excess). The solution was

6892
P. D. Lokhande et al. / Tetrahedron Letters 48 (2007) 6890–6892
NH HCl
2. Lokhande, P. D.; Kuchekar, B. S.; Chabukswar, A. R.;
Jagdale, S. C. Asian J. Biochem. 2006, 1, 1–17.
OH
2
OH
HCl
R
R
NH+
3. Kuroda, T.; Goto, H.; Ishikawa, T. Indazole derivatives,
Jpn. Kokai Tokkyo Koho, Japanese Patent, 50130759,
R
1
975; Chem. Abstr. 85, 46631.
4
. Banno, K.; Kawahata, T.; Ikeda, T.; Nakagawa, K.; Dohi,
T., Japanese Patent , 48048407, 1973; Chem. Abstr. 1973,
R
NNH2
7
9, 92214.
5
. Rodgers, J. D.; Johnson, B. L.; Wang, H.; Gienberg,
R. A.; Erickson, V. S.; Klabe, R. M.; Cordova, B. C.;
Rayner, N. M.; Lam, G. N.; Chang, C. H. Bioorg. Med.
Chem. Lett. 1996, 6, 2916.
NH HCl
O
R
2
6
. Behr, L. C.; Fusco, R.; Jarbose, C. H. Chem. Heterocycl.
Comp. 1967, 22, 1.
R
NH
7
. Baiocchi, G.; Corsi, G.; Palazzo, G. Synthesis 1978,
6
33.
8. Szmant, H. H.; Harmayth, C. J. Am. Chem. Soc. 1959, 81,
62.
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0. Carn, S.; Vazancz, F. Synthesis 1999, 5852.
1. Krishnan, R.; Lang, S. A.; Lin, Y. I.; Wilkinson, R. G.
J. Heterocycl. Chem. 1988, 25, 447.
9
9
(
OH
+
H
1
1
N-H
NH
N-H
R
N
H
+
1
2. Rakib, E. M.; Benchidmi, M.; Essass, E. M.; Bouadil, A.
E.; Mansour, A. I.; Bellan, J.; Lopaz, L.; Lamande, L. Ind.
J. Chem. B 2000, 39, 339.
R
R
1
3. Cheng, C. Y.; Mo, M.; Grima, J.; Saso, L.; Tita, B.;
Mruk, D.; Silvestrini, B. Contraception 2002, 65, 265.
4. (a) Silvestrini, R.; Caputo, A. Oncology 1984, 412; (b)
Gasperi, C.; Roncuzzi, L.; Zoli, Lo.; Amadoni, D.
Anticancer Drug Des. 1997, 12, 91.
1
N-H
N
R
1
5. Dell’erba, C. l.; Novi, M.; Petrillo, G.; Tsavani, C.
Tetrahedron 1994, 50, 3529.
1
6. (a) Bartsch, R. A.; Yang, I. W. J. Heterocycl. Chem. 1984,
21, 1063; (b) Sun, J. H.; Teleha, C. A.; Yan, J. S.; Rodgers,
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7. Lebedev, A. Y.; Khartulyari, A. S.; Voskoboynikov, A. Z.
J. Org. Chem. 2005, 70, 596.
R
Scheme 3. Proposed mechanism for the synthesis of indazoles from
substituted salicylaldehydes.
1
1
1
2
8. Auwers, K. V.; Ernecke, A.; Wolter, E. Ann 1930, 478,
refluxed for 2–3 h and the solvent was distilled under
reduced pressure. Purification of the residue by filtration
through a pad of silica afforded indazole 3 as a yellow
solid. The products were characterized from spectral
1
54.
9. Fujimura, Y.; Shiraki, Y.; Nawata, Y.; Matsunaga, I.
Yakugaku Zasshi 1986, 106, 1002.
1
0. H NMR data of new compounds: (i) 5-(Diethylamino)-1-
2
0
1
data and melting points.
H-indazole (Table 2, entry 15), mp 102 °C H NMR
(
3
CDCl ) d 8.01 (s,1H), 7.75 (s,1H), 7.58 (d, J = 8.6 Hz,
1
H), 7.43 (dd, J = 8.6, 1.5 Hz, 1H), 5.2 (s, 1H), 3.2 (q,
References and notes
J = 4H), 1.03 (t, J = 6H); (ii) 5-(diethylamino)-1-pheny-
lindazole (Table 2, entry 16), mp 152 °C H NMR
3
(CDCl ) d 8.00 (s, 1H), 7.63 (s, 1H), 7.58 (d, 1H,
J = 8.6 Hz, 1H) 7.52 (dd, J = 8.6, 1.5H), 7.42 (m, 5H),
3.2 (q, J = 4H), 1.03 (t, J = 6H).
1
1
. (a) Gaikwad, D. D. M.Phil Thesis, University of Pune,
003; (b) Lokhande, P. D.; Waghmare, B. Y.; Sakate, S. S.
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2