reported for the assembly of 2H-indazole: (1) a Pd-cata-
lyzed domino reaction of 2-halophenyl acetylenes with
hydrazines,11 (2) an Fe-catalyzed NꢀN bond formation
of 2-azidophenyl ketoximes,12 (3) a reaction of 2-chloro-
methylarylzinc reagents and aryldiazonium salts,13 and (4)
a [3 þ 2] cycloaddition of arynes and sydnones.14 However,
all four have drawbacks, such as the generation of regioi-
somers, the requirement for expensive phosphine ligands,
and a low tolerance toward functional groups such as
alcohols. In addition, all of these methods require several
steps to prepare the starting materials. A variety of one-pot
multicomponent reactions have been developed because of
their powerful ability to assemble complex structures with
high efficiency using simple processes and their atom
efficiency.15 This type of reaction has especially been
employed in the synthesis of heterocyclic compounds.16
However, there have not previously been any reports on
multicomponent reactions for the synthesis of 2H-indazoles.
Here, we report the first one-pot three-component reac-
tion of 2-bromobenzaldehydes, primary amines, and so-
dium azide toproduce2H-indazolesthroughcondensation
and CꢀN and NꢀN bond formation. To achieve our goal,
we initiated our studies by screening a variety of metal
catalysts (Table 1).
Table 1. Optimized Conditions for the Synthesis of 2H-Indazolea
entry
cat.
FeBr2
ligand
solvent
yield (%)d
1
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
0
0
2
FeCl3
Pd(OAc)2
Pd(PPh3)2Cl2
Ni(OAc)2
CoBr2
CuBr2
CuI
3
0
4
0
5
0
6
0
7
41
61
65
52
98
72
2
8
9
CuI
2-Bipyridyl
L-Proline
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
10
11
12
13
14
15
16
CuI
CuI
CuI
CuI
p-Xylene
Diglyme
DMSO
DMSO
CuI
31
92
64
CuIb
CuIc
Accordingly, we tested FeBr2, known to be an efficient
catalyst for the synthesis of 2H-indazoles from 2-azido-
phenyl ketoximes.12 However, this yielded no 2H-inda-
zoles, the desired product (Table 1, entry 1). When the
catalyst was changed to other metals such as Pd, Ni, and
Co, only N-(2-bromobenzylidene)aniline (7) was found in
the reaction mixture (Table 1, entries 3ꢀ6). Gratifyingly,
using CuBr2 and CuI yielded 41% and 61% of 2-phenyl-
2H-indazole, respectively (Table 1, entries 7 and 8). After
investigating the effect of ligands on the Cu-catalyzed
reaction, we found N,N,N0,N0-tetramethylethylenedia-
mine (TMEDA) was the best ligand for this reaction
(Table 1, entry 11). Among the solvents screened, polar
solvents showed better results than nonpolar solvents
(Table 1, entries 11ꢀ14). When the catalyst loading was
decreased from 10 mol % to 5 mol %, the product yield
decreased to 92% with trace amounts of imine intermedi-
ate, while 3 mol % of catalyst afforded a yield of 64%
(entry 16). Considering a complete coupling of imine
intermediate 7, we continued with 10 mol % of catalyst
for the subsequent investigation. We next examined the
a Reaction conditions: 1a (0.30 mmol), 2a (0.36 mmol), 3 (0.60 mmol),
and catalyst (0.03 mmol) in solvent (1.0 mL). b 0.015 mmol. c 0.009 mmol.
d Determined by gas chromatography with internal standard.
scope of the reaction using various amines. We tested
aromatic, heteroaromatic, and aliphatic amines in the
above reaction which yielded a series of 2H-indazoles
(Table 2). In the case of aromatic amines bearing electron-
neutral and -donating groups, such as aniline, p-toluidine,
and 4-methylthioaniline, good yields were seen (Table 2,
entries 1ꢀ3). Heteroaromatic amines such as 2-aminopyr-
idine produced the corresponding 2H-indazole 4ad in 82%
yield (Table 2, entry 4). However, sterically demanding
anilines such as 2,4,6-trimethylaniline yielded only 46% of
product 4ae (Table 2, entry 5). Anilines with electron-with-
drawing groups produced 2H-indazoles in moderate to
good yields. Benzocaine, which bears a base sensitive ester
group, also showed a 64% yield (Table 2, entry 6).
However, 4-trifluoromethyl- and 4-nitroaniline yielded
46% and 20% of their corresponding products, and the
reaction mixture showed a variety of spots in thin layer
chromatography (TLC). To increase the yield, the reac-
tions of 2-bromoaldehyde and aniline derivatives were
carried out first, and then NaN3 with CuI/TMEDA was
added to the reaction mixture. By using stepwise addition,
their yields were increased to 72% and 48%, respectively
(Table 2, entries 8 and 9). Aliphatic amines all showed
good yields of 2H-indazoles. Even sterically demanding
amines such as 1-adamantylamine yielded 84% of 2H-
indazole 4aj (Table 2, entry 10). In addition, an aliphatic
amine with an alcohol group yielded 80% of the desired
product (Table 2, entry 11). 2,2-Diethoxyethylamine and
cyclopropylamine yielded 76% and 63% of 2H-indazole
4al and 4am, respectively (Table 2, entries 12 and 13).
ꢀ
(11) Halland, N.; Nazare, M.; R’kyek, O.; Alonso, J.; Urmann, M.;
Lindenschmidt, A. Angew. Chem., Int. Ed. 2009, 48, 6879.
(12) Stokes, B. J.; Vogel, C. V.; Urnezis, L. K.; Pan, M.; Driver, T. G.
Org. Lett. 2010, 12, 2884.
(13) Haag, B.; Peng, Z.; Knochel, P. Org. Lett. 2009, 11, 4270.
(14) Wu, C.; Fang, Y.; Larock, R. C.; Shi, F. Org. Lett. 2010, 12,
2234.
(15) Wasilke, J.-C.; Obrey, S. J.; Baker, R. T.; Bazan, G. C. Chem.
Rev. 2005, 105, 1001.
(16) For selective recent examples, see: (a) Wen, L. -R.; Ji, C.; Li, M.;
Xie, H.-Y. Tetrahedron 2009, 65, 1287. (b) Attanasi, O. A.; Crescentini,
L. D.; Favi, G.; Filippone, P.; Giorgi, G.; Mantellini, F.; Moscatelli, G.;
Behalo, M. S. Org. Lett. 2009, 11, 2265. (c) Wu, X.; Dai, X.; Nie, L.;
Fang, H.; Chen, J.; Ren, Z.; Cao, W.; Zhao, G. Chem. Commun. 2010,
46, 2733. (d) Shen, Z.-L.; Xu, X.-P.; Ji, S.-J. J. Org. Chem. 2010, 75, 1162.
(e) Ma, D.; Lu, X.; Shi, L.; Zhang, H.; Jiang, Y.; Liu, X. Angew. Chem.,
Int. Ed. 2011, 50, 1118.
Org. Lett., Vol. 13, No. 13, 2011
3543