Simple and efficient synthesis of substituted 1H-indazoles

Article abstract of DOI:10.1016/j.mencom.2012.05.020

3-Aryl-5-aroylindazoles were prepared by a simple two-stage protocol from 3,5-diaroyl-2,6-dimethylpyridines.

Full text of DOI:10.1016/j.mencom.2012.05.020

Mendeleev
Communications
Mendeleev Commun., 2012, 22, 167–168
Simple and efficient synthesis of substituted 1H-indazoles
Galina P. Sagitullina,* Anna K. Garkushenko, Nikolay V. Poendaev and Reva S. Sagitullin
Department of Organic Chemistry, F. M. Dostoevsky Omsk State University, 644077 Omsk, Russian Federation.
Fax: +7 3812 64 2410; e-mail: sagitullina@orgchem.univer.omsk.su
DOI: 10.1016/j.mencom.2012.05.020
3-Aryl-5-aroylindazoles were prepared by a simple two-stage protocol from 3,5-diaroyl-2,6-dimethylpyridines.
Indazoles are heterocyclic compounds structurally close to indoles
(‘azaindoles’) being their bioisosteres.1 However, unlike indoles,
derivatives of indazoles are of rare natural occurrence. For the
last three decades only three alkaloids with indazole ring system,
that is Nigellicine, Nigellidine and Nigeglanine, have been isolated
from the plants of Ranunculáceae: Nigella sativa and Nigella
glandulifera family.2–6 Furthermore, pharmaceutically important
indazoles (bendazac, benzydamine, lonidamine, bindarit, grani-
setron) show anti-inflammatory, anticancer, immunosuppressive,
serotonergic activity.7–16
The standard synthetic methods yielding 1H-indazoles are based
on, first, the pyrazole ring closure in ortho-methyl-, diazo- and
N-nitrosoaromatic compounds by intramolecular heterocyclization;
second, reaction of ortho-halogen- or ortho-hydroxyaromatic com-
pounds with hydrazine; third, reactions of 2-azidobenzoic esters.17–19
Intramolecular cyclization of o-halobenzaldehyde or o-halophenone
hydrazones leads to 3-unsubstituted indazoles in high yields.17
To date, only four general methods for the synthesis of 3-aryl-
indazoles are known. There are aryne annulation using dialkyl- and
N-tosylhydrazones, Diels–Alder cycloaddition between 1-acetyl-
4-styrylpyrazoles and N-methyl- or N-phenylmaleimide, Pd-
catalyzed intramolecular amination of hydrazones of o-bromo-
benzophenones and intramolecular cyclization of o-hydroxybenzo-
phenone hydrazones.20–25 Sodium hydride-promoted interaction
between arylidenehydrazines and nitroarenes in DMF affords
3-arylindazoles;26 however, this reaction due to poor yields is of
low synthetic importance.
The aim of this research was to develop a new approach to
functionalized indazoles from 3,5-diaroyl-2,6-dimethylpyridines
1 by a two-step pyrazole ring formation (Schemes 1 and 2).
Apparently, transformation of pyridinium salts 2a–c into
diaroylanilines 3a–c proceeds through the nucleophilic attack
by the hydroxide ion at the most electrodeficient carbon in the
pyridine ring at 2-position to form pseudo-base A (a neutral
analogue of a s-complex). The following base catalyzed ionic
ring opening with C–N bong cleavage leads to open form B,
which undergoes intramolecular aldol condensation involving
methyl and acetyl groups in open form C (Scheme 1).†,27
At the next stage, N-nitrozation of N-methylanilines 3a–c and
intramolecular reductive cyclization were performed. Pyrazole
ring closure took place as a result of intramolecular condensation
in intermediate N-methyl-N-arylhydrazine A formed in situ upon
reduction of N-nitroso compounds 4a–c. Both nitrosation of
compounds 3a–c and reductive heterocyclization of compounds
4a–c into indazoles 5a–c proceed at room temperature in pre-
parative yields (Scheme 2).‡
†
Structures of compounds 2–5 were confirmed by 1H NMR (Bruker
Advance AC-400, 400.13 MHz) and ATR-FTIR (Simex FT-801) spectro-
scopy, while their composition was determined by elemental analysis
(Perkin Elmer 2400).
3,5-Diaroyl-1,2,6-trimethylpyridinium fluoridosulfates 2a–c (general
procedure). A solution of methyl fluoridosulfate (3.42 g, 30 mmol) in
1,2-dichloroethane (12 ml) was added dropwise at 0°C to a stirred solu-
tion of the corresponding pyridine 1a–c28 (20 mmol) in 1,2-dichloroethane
(24 ml). The reaction mixture was stirred for 30 min at 0°C and then 2 days
at room temperature. The reaction mixture was diluted with diethyl ether
(30 ml). The precipitated product was filtered off and dried.
ArOC
Me
COAr
Me
ArOC
Me
COAr
i
ii
N
N
Me
Me
SO3F
1a–c
2a–c
3,5-Dibenzoyl-1,2,6-trimethylpyridinium fluoridosulfate 2a: colourless
crystals, yield 95%, mp 252–253°C (ethanol). H NMR (DMSO-d6) d:
2.70 (s, 6H, 2,6-Me), 4.18 (s, 3H, NMe), 7.59–7.64 (m, 4H, 3,5-COPh),
7.75–7.80 (m, 2H, 3,5-COPh), 7.87–7.92 (m, 4H, 3,5-COPh), 8.62 (s, 1H,
4-H). Found (%): C, 61.57; H, 4.65; N, 3.20. Calc. for C22H20FNO5S (%):
C, 61.53; H, 4.69; N, 3.26.
1
ArOC
COAr
Me
ArOC
HO
COAr
Me
H
O
Me
N
HN
Me
Me
Me
A
B
2,4-Diaroyl-N,5-dimethylanilines 3a–c (general procedure). A mixture
of the corresponding pyridinium salt 2a–c (5 mmol) in ethanol (10 ml)
and 10% solution of sodium hydroxide in ethanol (10 ml) was heated in
a water bath at 80°C for 1 h. Cooled to room temperature reaction mixture
was diluted with water (40 ml), the precipitated light-yellow crystals were
filtered off and dried. The crude product was purified by LC (silica gel,
CHCl3) and recrystallization.
(4-Methyl-6-methylamino-1,3-phenylene)bis(phenylmethanone) 3a:
pale yellow crystals, yield 73%, mp 120–121°C (ethanol).29 IR (n/cm–1):
3318 (NH), 1676, 1612 (C=O). 1H NMR (CDCl3) d: 1.92 (s, 3H, 4-Me),
3.02 (d, 3H, HN–Me, J 5.1 Hz), 6.63 (s, 1H, 5-H), 7.34–7.69 (m, 10H,
1,3-COPh), 8.02 (s, 1H, 2-H), 8.95 (br.s, 1H, HN–Me).
ArOC
Me
COAr
ArOC
COAr
O
Me
– H2O
NH
Me
Me
NH
Me
3a–c
C
a Ar = Ph
b Ar = 4-ClC6H4
c Ar = 1-Naphthyl
For characteristics of compounds 2b,c and 3b,c, see Online Supple-
mentary Materials.
Scheme 1 Reagents and conditions: i, FSO3Me/DCE, 0°C, 30 min, then
room temperature, 48 h; ii, 10% NaOH/EtOH, 80°C, 1 h.
© 2012 Mendeleev Communications. All rights reserved.
– 167 –

Mendeleev Commun., 2012, 22, 167–168
References
ArOC
Me
COAr
i
ii
1 C. G. Wermuth and P. Ciapetti, Compr. Med. Chem. II, 2006, 2, 649.
2 K. Inamoto, M. Katsuno, T. Yoshino, Y. Arai, K. Hiroya and T. Sakamoto,
Tetrahedron, 2007, 63, 2695.
3 A. Rahman and S. Malik, Tetrahedron Lett., 1985, 26, 2759.
4 A. Rahman, S. Malik, S. S. Hasan, M. I. Choudhary, C.-Z. Ni and J. Clardy,
Tetrahedron Lett., 1995, 36, 1993.
5 Y.-M. Liu, J.-S. Yang and Q.-H. Liu, Chem. Pharm. Bull., 2004, 52, 454.
6 A. Schmidt, Adv. Heterocycl. Chem., 2003, 85, 67.
7 J. A. Balfour and S. P. Clissold, Drugs, 1990, 39, 575.
8 A. Guglielmotti, A. Capezzone de Joannon, N. Cazzolla, M. Marchetti,
L. Soldo, G. Cavallo and M. Pinza, Pharmacol. Res., 1995, 32, 369.
9 K. MacD. Hunter, Aust. Dent. J., 1978, 23, 164.
10 M. M. Canelas, J. C. Cardoso, M. Gonçalo and A. Figueiredo, Contact
Dermatitis, 2010, 63, 85.
3a–c
N
N
O
Me
4a–c
Ar
Ar
ArOC
Me
ArOC
Me
O
N
NH2
– H2O
N
N
Me
Me
A
5a–c
a Ar = Ph
b Ar = 4-ClC6H4
c Ar = 1-Naphthyl
11 H. Pelicano, D. S. Martin, R.-H. Xu and P. Huang, Oncogene, 2006, 25,
4633.
12 G. Grassia, M. Maddaluno, A. Guglielmotti, G. Mangano, G. Biondi,
P. Maffia and A. Ialenti, Cardiovasc. Res., 2009, 84, 485.
13 M. Bhatia, R. D. Ramnath, L. Chevali andA. Guglielmotti, Am. J. Physiol.
Gastrointest. Liver Physiol., 2005, 288, 1259.
14 G. L. Plosker and K. L. Goa, Drugs, 1991, 42, 805.
15 G. J. Sanger and D. R. Nelson, Eur. J. Pharmacol., 1989, 159, 113.
16 http://www.genengnews.com
17 A. Schmidt, A. Beutler and B. Snovydovych, Eur. J. Org. Chem., 2008,
4073.
18 W. Stadlbauer, Science of Synthesis: Houben-Weyl Methods of Molecular
Transformations, Georg ThiemeVerlag, Stuttgart, NewYork, 2007, vol. 12,
p. 227.
19 B. Cottyn, D. Vichard, F. Terrier, P. Nioche and C. S. Raman, Synlett,
2007, 1203.
20 P. Li, J. Zhao, C. Wu, R. C. Larock and F. Shi, Org. Lett., 2011, 13,
3340.
21 N. A. Markina, A. V. Dubrovskiy and R. C. Larock, Org. Biomol. Chem.,
2012, 10, 2409.
Scheme 2 Reagents and conditions: i, NaNO2, AcOH, room temperature,
1 h; ii, Zn, AcOH, 5–10°C, then room temperature, 30 min.
Online Supplementary Materials
Supplementary data associated with this article can be found
in the online version at doi:10.1016/j.mencom.2012.05.020.
‡
2,4-Diaroyl-N,5-dimethyl-N-nitrosoanilines 4a–c (general procedure).
Sodium nitrite (0.97 g, 14 mmol) was added portionwise to a solution of the
corresponding aniline 3a–c (7 mmol) in glacial acetic acid (14 ml) at room
temperature on stirring. After more 1 h of stirring the reaction mixture was
poured into water (30 ml). The precipitated crystalline solid was filtered
off and dried.
[4-Methyl-6-(N-methyl-N-nitrosoamino)-1,3-phenylene]bis(phenyl-
methanone) 4a: colourless crystals, yield 94%, mp 173–174°C (ethanol).
1
IR (n/cm–1): 1680, 1670 (C=O), 1440 (N–N=O). H NMR (CDCl3) d:
22 V. L. M. Silva, A. M. S. Silva, D. C. G. A. Pinto, J. Elguero and J. A. S.
2.07 (s, 3H, 4-Me), 3.27 (s, 3H, NMe), 7.40–7.46 (m, 5H, COPh, 5-H),
7.48–7.52 (m, 3H, COPh), 7.54–7.59 (m, 1H, COPh), 7.74–7.78 (m, 2H,
COPh), 7.81 (s, 1H, 2-H). Found (%): C, 73.77; H, 5.04; N, 7.80. Calc.
for C22H18N2O3 (%): C, 73.73; H, 5.06; N, 7.82.
[4-Methyl-6-(N-methyl-N-nitrosoamino)-1,3-phenylene]bis[(4-chloro-
phenyl)methanone] 4b: colourless crystals, yield 95%, mp 202–203°C
(ethanol). IR (n/cm–1): 1693, 1672 (C=O), 1460 (N–N=O). 1H NMR (CDCl3)
d: 2.14 (s, 3H, 4-Me), 3.29 (s, 3H, NMe), 7.33–7.42 (m, 5H, COAr,
5-H), 7.46–7.50 (m, 2H, COAr), 7.67–7.71 (m, 2H, COAr), 7.78 (s, 1H,
2-H). Found (%): C, 61.88; H, 3.81; N, 6.60. Calc. for C22H16Cl2N2O3 (%):
C, 61.84; H, 3.77; N, 6.56.
Cavaleiro, Eur. J. Org. Chem., 2009, 4468.
23 K. Inamoto, M. Katsuno, T.Yoshino, I. Suzuki, K. Hiroya and T. Sakamoto,
Chem. Lett., 2004, 33, 1026.
24 Q. Guofu, S. Jiangtao, F. Xichum, W. Lamei, X. Wenjin and H. Xianming,
J. Heterocycl. Chem., 2004, 41, 601.
25 R. Krishnan, S. A. Lang, Jr., Y. Lin and R. G. Wilkinson, J. Heterocycl.
Chem., 1988, 25, 447.
26 K. Uehata, T. Kawakami and H. Suzuki, J. Chem. Soc., Perkin Trans. 1,
2002, 696.
27 A
. K. Garkushenko, N. V. Poendaev, M. A. Vorontsova and G. P. Sagitullina,
Khim. Geterotsikl. Soedin., 2011, 573 [Chem. Heterocycl. Compd. (Engl.
Transl.), 2011, 47, 470].
[4-Methyl-6-(N-methyl-N-nitrosoamino)-1,3-phenylene]bis(1-naphthyl-
methanone) 4c: colourless crystals, yield 85%, mp 172–173°C (propanol).
28 A. K. Garkushenko, M. A. Makarova, O. P. Sorokina, N. V. Poendaev,
M. A. Vorontsova and G. P. Sagitullina, Khim. Geterotsikl. Soedin., 2011,
586 [Chem. Heterocycl. Compd. (Engl. Transl.), 2011, 47, 482].
29 G. P. Sagitullina, V. Lusis, D. Muceniece and R. S. Sagitullin, Tetrahedron,
1995, 51, 8599.
1
IR (n/cm–1): 1698, 1650 (C=O), 1468 (N–N=O). H NMR (CDCl3) d:
2.60 (s, 3H, 4-Me), 3.16 (s, 3H, NMe), 7.28–7.34 (m, 1H, 1-Naphthoyl),
7.37 (s, 1H, 5-H), 7.43–7.48 (m, 1H, 1-Naphthoyl), 7.51–7.60 (m, 6H,
1-Naphthoyl), 7.73 (s, 1H, 2-H), 7.72–7.75 (m, 1H, 1-Naphthoyl), 7.81–7.86
(m, 1H, 1-Naphthoyl), 7.89–7.95 (m, 2H, 1-Naphthoyl), 8.00–8.05 (m,
1H, 1-Naphthoyl), 8.53–8.57 (m, 1H, 1-Naphthoyl), 8.65–8.70 (m, 1H,
1-Naphthoyl). Found (%): C, 78.62; H, 4.88; N, 6.19. Calc. for C30H22N2O3
(%): C, 78.59; H, 4.84; N, 6.11.
3-Aryl-5-aroyl-1,6-dimethyl-1H-indazoles 5a–c (general procedure).
Corresponding nitrosoaniline 4a–c (10 mmol) was dissolved in a mixture
of DMF (30 ml) and glacial acetic acid (30 ml). To this solution zinc dust
(3.2 g, 50 mmol) was added portionwise on stirring so that temperature
of the reaction mixture did not exceed 10°C. The mixture was stirred for
additional 30 min at room temperature. Then it was heated to 100°C, the
solid residue was filtered off hot and washed on the filter with hot acetic
acid (5 ml). The combined filtrate was cooled and diluted with water (30 ml).
The precipitated crystalline indazole 5a–c was filtered off and dried.
(1,6-Dimethyl-3-phenyl-1H-indazol-5-yl)(phenyl)methanone 5a: colour-
less crystals, yield 62%, mp 161–162°C (ethanol). IR (n/cm–1): 1688
(C=O). 1H NMR (CDCl3) d: 2.05 (s, 3H, 6-Me), 4.15 (s, 3H, N-Me), 7.36
(s, 1H, 7-H), 7.41–7.55 (m, 8H, COPh, 3-Ph), 7.95–8.01 (m, 2H, COPh),
8.32 (s, 1H, 4-H). Found (%): C, 81.02; H, 5.60; N, 8.53. Calc. for
C22H18N2O (%): C, 80.96; H, 5.56; N, 8.58.
Received: 14th December 2011; Com. 11/3847
(4-Chlorophenyl)[3-(4-chlorophenyl)-1,6-dimethyl-1H-indazol-5-yl]-
methanone 5b: colourless crystals, yield 73%, mp 169–170°C (ethanol).
IR (n/cm–1): 1673 (C=O). 1H NMR (CDCl3) d: 2.13 (s, 3H, 6-Me), 4.14
(s, 3H, NMe), 7.30–7.38 (m, 3H, 3-Ar, 7-H), 7.41–7.51 (m, 4H, COAr,
3-Ar), 7.87–7.94 (m, 2H, COAr), 8.26 (s, 1H, 4-H). Found (%): C, 66.84;
H, 4.10; N, 7.15. Calc. for C22H16Cl2N2O (%): C, 66.85; H, 4.08; N, 7.09.
[1,6-Dimethyl-3-(1-naphthyl)-1H-indazol-5-yl](1-naphthyl)methanone
5c: colourless crystals, yield 76%, mp 170–171°C (ethanol). IR (n/cm–1):
1659 (C=O). 1H NMR (CDCl3) d: 2.74 (s, 3H, 4-Me), 4.23 (s, 3H, NMe),
7.30–7.63 (m, 9H, 1-Naphthoyl, 1-Naphthyl, H-7), 7.73 (s, 1H, H-2),
7.81–7.86 (m, 4H, 1-Naphthoyl), 8.15–8.20 (m, 1H, 1-Naphthoyl), 8.42–8.46
(m, 1H, 1-Naphthoyl). Found (%): C, 84.47; H, 5.17; N, 6.59. Calc. for
C30H22N2O (%): C, 84.48; H, 5.20; N, 6.57.
– 168 –