Microwave-assisted molybdenum-catalyzed reductive cyclization of o -nitrobenzylidene amines to 2-Aryl-2 H -indazoles

Article abstract of DOI:10.1055/s-0033-1339195

The reductive cyclization of o-nitrobenzylidene amines under microwave conditions employing MoO₂Cl₂(dmf)₂ as catalyst and Ph₃P as reducing agent delivers 2-aryl-2H-indazoles with yields ranging from 61-92%. Georg Thieme Verlag Stuttgart. New York.

Full text of DOI:10.1055/s-0033-1339195

LETTER
▌1573
lMetteircrowave-Assisted Molybdenum-Catalyzed Reductive Cyclization of
o-Nitrobenzylidene Amines to 2-Aryl-2H-indazoles
Reductive Cyclization of o-Nitrobenzylidene Amines to 2-Aryl-2H-indazoles
Ahmed H. Moustafa,a,b Chandi C. Malakar,b Nayyef Aljaar,b Elena Merisor,b Jürgen Conrad,b Uwe Beifuss*b
a
Department of Chemistry, Faculty of Science, Zagazig University, Zagazig, Egypt
b
Bioorganische Chemie, Institut für Chemie, Universität Hohenheim, Garbenstr. 30, 70599 Stuttgart, Germany
Fax +49(711)45922951; E-mail: ubeifuss@uni-hohenheim.de
Received:29.03.2013; Accepted after revision: 20.05.2013
Here, we report the first molybdenum-catalyzed synthesis
of the 2H-indazole skeleton. The highly selective and
high-yielding approach towards the synthesis of 2-aryl-
2H-indazoles is based on the reductive heterocyclization
of easily available o-nitrobenzylidene amines using a
Abstract: The reductive cyclization of o-nitrobenzylidene amines
under microwave conditions employing MoO2Cl2(dmf)2 as catalyst
and Ph3P as reducing agent delivers 2-aryl-2H-indazoles with yields
ranging from 61–92%.
Key words: catalysis, cyclization, indazoles, molybdenum, Schiff
bases
13
combination of MoO2Cl2(dmf)2 as a catalyst and Ph3P
as a reducing agent under several conditions.
The synthesis of the substrates, the o-nitrobenzylidene
amines 3a–m could easily be achieved by heating equi-
molar amounts of o-nitrobenzaldehyde (1a) and aromatic
amines 2a–m in i-PrOH (Table 1). The Schiff bases were
obtained in crystalline form and purified by flash chroma-
tography to deliver the compounds in analytically pure
form with yields in the range between 84–97%.14
Indazoles are an important class of heterocyclic com-
pounds that possess diverse biological and pharmacologi-
cal activities, including anti-inflammatory, antitumor,
antiviral, antidepressant, and contraceptive activities.1 It
is thus not surprising that a number of methods for the
preparation of indazoles exist.2 However, the majority has
been developed for the preparation of 1H-indazoles. The
number of approaches to 2H-indazoles is still scarce.
Among the classical methods for the preparation of 2H-
indazoles are the unselective N-arylation and N-alkyla-
tion of indazoles,3 the reductive cyclization of secondary
2-nitrobenzylamines with Sn, SnCl2, Zn, TiCl4/Zn, and
Fe4 or under electrochemical conditions,5 as well as the re-
ductive cyclization of o-nitrobenzylidene amines with an
excess of (EtO)3P.6
Table 1 Synthesis of 2-Nitrobenzylidene Amines 3a–m
i-PrOH
reflux, 10 min
Ar
CHO
NO2
N
ArNH2
+
NO2
1a
2
3
Entry
Aromatic amine 2
Product 3
Yield
(%)a
Recently, a few methods for the transition-metal-cata-
lyzed synthesis of 2H-indazoles have been reported.
Among them are the palladium-catalyzed reaction be-
tween 2-halophenyl acetylenes and hydrazines,7 the palla-
dium-catalyzed intramolecular amination of N-aryl-N-(o-
bromobenzyl)hydrazines,8 the iron-catalyzed N,N-bond
formation of 2-azidophenyl ketoximes,9 the copper-cata-
lyzed reaction of 2-bromobenzaldehydes with primary
amines and NaN3,10 the copper-catalyzed reaction of 2-az-
idobenzaldehydes and anilines,11 and the palladium-cata-
lyzed reaction of 2-nitrobenzylidene amines with CO in
the presence of SnCl2 under high pressure.12 However,
most of them suffer from some drawbacks, such as limited
substrate scope, requirement for expensive catalysts and
ligands, long reaction times, and unsatisfactory yields.
This is why the development of new methods for the prep-
aration of 2H-indazoles based on catalytic transforma-
tions is subject to current research.
N
NO2
1
90
H2N
2a
3a
3b
3c
3d
N
NO2
2
3
4
97
95
90
NH2
2b
N
H2N
NO2
2c
N
H2N
SYNLETT 2013, 24, 1573–1577
Advanced online publication: 27.06.2013
NO2
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
2d
DOI: 10.1055/s-0033-1339195; Art ID: ST-2013-D0283-L
© Georg Thieme Verlag Stuttgart · New York

1574
A. H. Moustafa et al.
LETTER
Table 1 Synthesis of 2-Nitrobenzylidene Amines 3a–m (continued)
Table 1 Synthesis of 2-Nitrobenzylidene Amines 3a–m (continued)
i-PrOH
reflux, 10 min
i-PrOH
reflux, 10 min
Ar
Ar
CHO
NO2
CHO
NO2
N
N
ArNH2
ArNH2
+
+
NO2
NO2
1a
2
3
1a
2
3
Entry
Aromatic amine 2
Product 3
Yield
(%)a
Entry
Aromatic amine 2
Product 3
Yield
(%)a
OMe
Br
OCF3
Br
OCF3
OMe
N
NO2
N
5
97
13
84
H2N
H2N
NO2
2m
2e
3e
3m
OMe
a Isolated yield after crystallization.
OMe
It was found that the formation of the o-nitrobenzylidene
amines could also be performed in a number of different
alcohols, such as EtOH, PrOH, n-BuOH, s-BuOH, t-BuOH,
and ethylene glycol with comparable yields.
6
7
N
NO2
OMe 94
H2N
OMe
2f
3f
I
Based on our experience with the reductive cyclization of
ω-nitro alkenes to saturated N-heterocycles15 the o-nitro-
benzylidene amines 3 were reacted with Ph3P as reagent
and MoO2Cl2(dmf)2 as catalyst16 in toluene under micro-
wave conditions (Table 2).
I
N
88
H2N
NO2
2g
3g
3h
3i
Using the transformation of 3a to 4a as a model reaction
it was established that the treatment of 3a with 10 mol%
MoO2Cl2(dmf)2 and 2.4 equivalents Ph3P in toluene yield-
ed 2-phenyl-2H-indazole (4a) selectively in 84% yield
(Table 2, entry 1).17 A similar result was observed when
the amount of MoO2Cl2(dmf)2 was reduced to 5 mol%
(Table 2, entry 2). With 3 mol% of the catalyst, the yield
of 4a dropped slightly to 76% (Table 2, entry 3). The
indazole was obtained in 71% when the amount of Ph3P
F
F
N
8
80
93
H2N
NO2
2h
Br
Br
N
9
H2N
NO2
Table 2 Optimization of the MoO2Cl2(dmf)2-Catalyzed Cyclization
of o-Nitrobenzylidene Amine 3a to 2-Phenyl-2H-indazole (4a)a
2i
cat. MoO2Cl2(dmf)2
Ph3P
Br
Cl
Br
Cl
toluene
MW, 150 °C, 10 min
N
N
N
10
11
85
H2N
71–85%
N
NO2
NO2
3a
2j
4a
3j
Br
F
Entry
MoO2Cl2(dmf)2 (mol%)
10
Ph3P (equiv)
Yield (%)b
Br
F
N
1
2
3
4
5
6
2.4
2.4
2.4
2.0
–
84
85
76
71
–
97
H2N
NO2
5
3
5
5
–
2k
3k
Br
Br
N
CF3
12
88
H2N
CF3
2.4
–
NO2
2l
a Microwave irradiations were performed at 300 W and 20 bar.
b Isolated yield after column chromatography.
3l
Synlett 2013, 24, 1573–1577
© Georg Thieme Verlag Stuttgart · New York

LETTER
Reductive Cyclization of o-Nitrobenzylidene Amines to 2-Aryl-2H-indazoles
1575
Table 3 MoO2Cl2(dmf)2-Catalyzed Cyclization of o-Nitrobenzy-
lidene Amines 3a–m to 2-Aryl-2H-indazoles 4a–ma (continued)
was reduced from 2.4 equivalents to 2.0 equivalents (Ta-
ble 2, entry 4). In the absence of any Ph3P no cyclization
product was formed (Table 2, entry 5). The same result
was observed when the reaction was performed without
any MoO2Cl2(dmf)2 (Table 2, entry 6). The two control
experiments clearly demonstrate that the reaction needs to
be run in the presence of both the catalyst and the reducing
agent.
MoO2Cl2(dmf)2 (5 mol%)
Ph3P (2.4 equiv)
toluene
Ar
MW, 150 °C, 20 bar, 10 min
68–92%
N
N
Ar
N
NO2
3
4
Entry
Substrate 2H-Indazole 4
Yield
Apart from toluene the reductive cyclization of 3a can be
run in a broad range of other solvents, including several
aromatic (benzene, chlorobenzene, and mesitylene) and
ethereal solvents (THF and dioxane). Even in a dipolar
solvent like MeCN the product 4a was formed in 74%.
(%)b
2
3
3b
4b
89
N
It was established that the molybdenum-catalyzed cycli-
zation can also be performed selectively under thermal
conditions. Heating of 3a in a sealed tube at 150 °C for
five hours delivered 4a in 69% and heating the substrate
in refluxing toluene for five hours afforded the cyclization
product in 63%. These results indicate that the transfor-
mation can also be performed in the absence of micro-
wave irradiation. However, the microwave-assisted
reaction is 30 times faster and the yield is better.
N
3c
4c
90
N
N
N
4
5
3d
4d
4e
80
92
N
With the optimized reaction conditions in hand the o-ni-
trobenzylidene amines 3b–m were cyclized to the corre-
sponding indazoles 4b–m (Table 3). In addition to the
unsubstituted N-phenyl and N-naphthyl derivatives 3a–c
numerous substituted N-aryl derivatives 3d–m could be
used as substrates for the reductive cyclization (Table 3,
entries 4–13). The yields of the resulting 2-aryl-2H-inda-
zoles 4d–m were in the range between 68–92%; only in
two cases the yields were lower than 80% (Table 3, entries
6 and 8).18 All cyclizations proceed highly selective; that
is, the 2-aryl-2H-indazoles 4 were formed exclusively. In
many cases the products could be isolated as crystals upon
cooling of the reaction mixture. If necessary, further puri-
fication could be achieved by recrystallization or column
chromatography. It is noteworthy that the yields of the re-
ductive cyclizations are largely insensitive of the type and
degree of substitution of the N-aryl moiety of the
substrate. Not only alkyl-, alkoxy-, but also halogen- and
CF3-substituted o-nitrobenzylidene amines could be
cyclized without any difficulties.
N
OMe
3e
N
OMe
N
6
3f
4f
68
N
OMe
N
I
7
8
3g
4g
4h
84
78
N
F
3h
N
N
Br
9
10
11
3i
4i
86
88
82
N
N
N
N
N
N
N
N
Br
3j
3k
4j
4k
Cl
F
Table 3 MoO2Cl2(dmf)2-Catalyzed Cyclization of o-Nitrobenzy-
lidene Amines 3a–m to 2-Aryl-2H-indazoles 4a–ma
Br
Br
MoO2Cl2(dmf)2 (5 mol%)
Ph3P (2.4 equiv)
toluene
Ar
MW, 150 °C, 20 bar, 10 min
68–92%
N
N
Ar
N
NO2
12
3l
4l
82
88
3
4
CF3
Entry
1
Substrate 2H-Indazole 4
Yield
(%)b
Br
13
3m
4m
N
OCF3
N
3a
4a
85
N
N
a Microwave irradiations were performed at 300 W and 20 bar.
b Isolated yield after column chromatography.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 1573–1577

1576
A. H. Moustafa et al.
LETTER
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It was also desirable to show that the reaction allows for
substitution of the o-nitrobenzylidene moiety. For this
purpose the chloro-substituted o-nitrobenzylidene amine
3n was prepared and cyclized under standard conditions
to yield the 2H-indazole 4n in 61% yield (Scheme 1).
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M.; Lindenschmidt, A. Angew. Chem. Int. Ed. 2009, 48,
6879.
i-PrOH
reflux
10 min
Cl
CHO
NO2
Cl
N
+
90%
H2N
NO2
3n
1b
2a
MoO2Cl2(dmf)2 (5 mol%)
Ph3P (2.4 equiv)
toluene
(8) Song, J. J.; Yee, N. K. Org. Lett. 2000, 2, 519.
(9) Stokes, B. J.; Vogel, C. V.; Urnezis, L. K.; Pan, M.; Driver,
T. G. Org. Lett. 2010, 12, 2884.
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13, 3542.
Cl
MW, 150 °C, 20 bar, 10 min
N
61%
N
4n
Scheme 1 Synthesis of 4n
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47, 10133.
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The structures of all compounds were unambiguously elu-
cidated by NMR spectroscopy and mass spectrometry.
Structure elucidation of all compounds and full assign-
ment of the 1H and 13C chemical shifts were achieved by
evaluating their gCOSY, gHSQC, gHMBC, and NOESY
spectra.
(14) General Procedure for the Synthesis of o-
Nitrobenzylidene Amines 3
o-Nitrobenzaldehyde 1 (10 mmol) and aniline 2 (10 mmol)
in i-PrOH (3 mL) were placed in a round-bottomed flask and
heated under reflux with magnetic stirring for 10 min. The
reaction mixture was cooled to r.t., and the crystalline o-
nitrobenzylidene amine 3 was isolated by filtration. The
crude product was purified by crystallization from i-PrOH–
EtOH = 1:1.
In summary, it has been demonstrated that the reductive
cyclization of easily available o-nitrobenzylidene amines
using a catalytic system based on cheap Ph3P as a reduc-
ing agent and MoO2Cl2(dmf)2 as a catalyst under micro-
wave conditions is an efficient strategy for the facile and
selective synthesis of 2-aryl-2H-indazoles with high
yields.
(15) (a) Merişor, E.; Conrad, J.; Klaiber, I.; Mika, S.; Beifuss, U.
Angew. Chem. Int. Ed. 2007, 46, 3353. (b) Merişor, E.;
Conrad, J.; Mika, S.; Beifuss, U. Synlett 2007, 2033.
(c) Merişor, E.; Beifuss, U. Tetrahedron Lett. 2007, 48,
8383.
Acknowledgment
(16) Malakar, C. C.; Merişor, E.; Conrad, J.; Beifuss, U. Synlett
2010, 1766.
(17) General Procedure for the MoO2Cl2(dmf)2-Catalyzed
Reductive Cyclization of o-Nitrobenzylidene Amines 3 to
2-Aryl-2H-indazoles 4
Prof. Dr. Ahmed H. Moustafa is grateful to the Deutsche For-
schungsgemeinschaft for a short term grant. We thank Dipl.-Chem.
F. Mert-Balci, Dr. H. Leutbecher and Ms. S. Mika for recording of
mass and NMR spectra.
A mixture of 3 (1 mmol), Ph3P (2.4 mmol), MoO2Cl2(dmf)2
(0.05 mmol), and toluene (3 mL) was sealed in a 10 mL
septum reaction vial and irradiated with microwaves
(DiscoverTM by CEM, 2450 MHz, 300 W, 150 °C, 20 bar)
for 10 min. After filtration and removal of the solvent the
reaction mixture was poured into H2O (50 mL) and extracted
with EtOAc (3 × 30 mL). The combined organic extracts
were washed with brine (30 mL). After drying over anhyd
MgSO4 and concentration in vacuo the resulting residue was
purified by flash chromatography on silica gel
(cyclohexane–EtOAc = 20:1). Alternatively, the reaction
mixture can also be purified by flash column
chromatography without any workup procedure.
(18) SelectedDatafor2-(2,4,6-Trimethylphenyl)-2H-indazole
(4d)
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnoIufproig
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2747. (b) Lam, P. Y. S.; Clark, C. G.; Saubern, S.; Adams,
J.; Winters, M. P.; Chan, D. M. T.; Combs, A. Tetrahedron
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Fuente, J.; Pardo, C.; Ramos, M. Synth. Commun. 1993, 23,
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Rf = 0.36 (cyclohexane–EtOAc = 3:1). IR (ATR): 1627,
1518, 1490, 1377, 1349, 1267, 1195, 1144, 1044, 964, 939,
851, 782, 755, 733, 671 cm–1. UV (MeCN): λmax (log ε) =
276 nm (4.08). 1H NMR (300 MHz, CDCl3): δ = 7.96 (d, 5Ј
= 1.1 Hz, 1 H, 3-H), 7.81 [dq, 4Ј and 5Ј ~ 1.0 Hz, 3Ј (6-H, 7-
H) = 8.7 Hz, 1 H, 7-H], 7.75 [dt, 4Ј and 5Ј ~ 1.0 Hz, 3Ј (4-H,
(4) (a) Sun, F.; Feng, X.; Zhao, X.; Huang, Z.-B.; Shi, D.-Q.
Tetrahedron 2012, 68, 3851. (b) Shi, D.-Q.; Dou, G.-L.; Ni,
S.-N.; Shi, J.-W.; Li, X.-Y.; Wang, X.-S.; Wu, H.; Ji, S.-J.
Synlett 2013, 24, 1573–1577
© Georg Thieme Verlag Stuttgart · New York

LETTER
Reductive Cyclization of o-Nitrobenzylidene Amines to 2-Aryl-2H-indazoles
1577
5-H) = 8.4 Hz, 1 H, 4-H], 7.34 [ddd, 4Ј (4-H, 6-H) = 1.2 Hz,
137.3 (C-1′), 135.1 (C-2′ and C-6′), 128.7 (C-3′ and C-5′),
126.0 (C-6), 124.6 (C-3), 121.9 (C-5), 121.8 (C-3a), 120.3
(C-4), 118.0 (C-7), 21.1 (C-4′′), 17.1 (C-2′′ and C-6′′). MS
(EI, 70 eV): m/z (%) = 336 (100) [M+], 221 (21), 220 (14),
28 (23). HRMS (EI): m/z calcd for C16H16N2 [M+]: 236.1314;
found: 236.1334.
3Ј (5-H, 6-H) = 6.7 Hz, 3Ј (6-H, 7-H) = 8.8 Hz, 1 H, 6-H],
7.15 [ddd, 4Ј (5-H, 7-H) = 0.9 Hz, 3Ј (5-H, 6-H) = 6.6 Hz, 3Ј
(4-H, 5-H) = 8.5 Hz, 1 H, 5-H], 6.99 (br s, 2 H, 3′-H and 5′-
H), 2.37 (br s, 3 H, 4′′-H), 1.95 (br s, 6 H, 2′′-H and 6′′-H).
13C NMR (75 MHz, CDCl3): δ = 149.1 (C-7a), 139.2 (C-4′),
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 1573–1577