Synthesis of N-arylindazoles and benzimidazoles from a common intermediate

Article abstract of DOI:10.1021/ol101899q

A variety of N-aryl-1H-indazoles and benzimidazoles were synthesized from common arylamino oximes in good to excellent yields. The product selectivity depends upon the base used in the reaction, as triethylamine promoted the formation of benzimidazoles, whereas 2-aminopyridine promoted the formation of N-arylindazoles. This method is valuable to the synthetic community because both indazoles and benzimidazoles are prevalent in pharmaceuticals.

Full text of DOI:10.1021/ol101899q

ORGANIC
LETTERS
2010
Vol. 12, No. 20
4576-4579
Synthesis of N-Arylindazoles and
Benzimidazoles from a Common
Intermediate
Brenda C. Wray and James P. Stambuli*
EVans Chemical Laboratories, Department of Chemistry, The Ohio State UniVersity,
100 West 18th AVenue, Columbus, Ohio 43210
stambuli@chemistry.ohio-state.edu
Received August 12, 2010
ABSTRACT
A variety of N-aryl-1H-indazoles and benzimidazoles were synthesized from common arylamino oximes in good to excellent yields. The product
selectivity depends upon the base used in the reaction, as triethylamine promoted the formation of benzimidazoles, whereas 2-aminopyridine
promoted the formation of N-arylindazoles. This method is valuable to the synthetic community because both indazoles and benzimidazoles
are prevalent in pharmaceuticals.
The 1H-indazole nucleus is rarely found in nature1 but is a
common moiety in the pharmaceutical industry.2 Indazoles
exhibit anticancer, antimicrobial, and other important thera-
peutic properties. N-arylindazoles also elicit interesting
(1) (a) Atta-ur-Rahman, M. S.; He, C. H.; Clardy, J. Tetrahedron Lett.
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Yang, J. S.; Liu, Q. H. Chem. Pharm. Bull. 2004, 52, 454. (d) Ali, Z.;
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Figure 1. Some biologically active N-arylindazoles.
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biological responses as anti-inflammatories and Hedgehog
pathway antagonists (Figure 1).3 The prevalence of indazoles
in many pharmaceuticals may also be caused by the fact that
the indazole moiety is a bioisostere of phenol.4
The lack of methods to prepare indazoles has recently
inspired several groups to develop routes to these com-
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P. A.; Glen, R. C.; Goggin, M. C.; Hobbs, A. J.; Kling, M. R.; Liu, Q.;
Madge, D. J.; Meillerais, S.; Powell, K. L.; Reynolds, K.; Spacey, G. D.;
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Vickerstaff, E.; Washington, M. Bioorg. Med. Chem. Lett. 2007, 17, 4363.
10.1021/ol101899q  2010 American Chemical Society
Published on Web 09/17/2010

pounds.5 Previously, our group reported a practical, metal-
free synthesis of a variety of 1H-indazoles.6 This method
provided several 1H-indazoles in good yields. The mecha-
nism of this process is thought to proceed via chemoselective
mesylation of the oxime, followed by nucleophilic attack of
the arylamino group to the sp2-nitrogen center.7 Although
the formation of an N-methylated indazole was reported in
good yield, the syntheses of N-arylindazoles proceeded in
1-aryl-1H-indazoles but uses harsher conditions.9 A draw-
back to both of these methods is the inability to synthesize
2-substituted 1-aryl-1H-indazoles directly. Voskoboynikov
overcame this by employing a palladium-catalyzed intramo-
lecular cyclization using arylhydrazones of 2-bromoalde-
hydes and 2-bromoacetophenones.10 However, the yields are
poor for ketones and require high temperatures (120 °C) and
long reaction times (160 h). In addition to palladium, copper
can also be employed as a catalyst. Buchwald utilized a
copper-diamine catalyzed N-arylation reaction of indazoles.11
When aryl bromides are employed, mixtures of the 1H- and
2H-indazoles are produced. A single example using copper(I)
oxide to promote the cyclization of o-fluoro hydrazone to
give N-phenylindazole in 40% yield has been reported.12
Because of the lack of mild methods to prepare N-
arylindazoles, a closer examination of our previously reported
N-arylindazole attempt was undertaken. The reaction of
N-phenyl o-aminoacetophenone oxime (1a) (prepared by a
Cu-catalzyed amination of the o-amino acetophenone with
the corresponding aryl iodide followed by standard oxime
forming conditions, see Supporting Information) was rein-
vestigated under the standard conditions developed in our
lab (Scheme 1).6 During chromatographic separation of this
reaction mixture, a compound with an increased polarity
relative to the corresponding indazole was isolated. This side
product was determined to be a structural isomer of 1H-
indazole after 1H NMR spectroscopic and mass spectrometric
analysis. The compound was thought to contain a benzimi-
dazole ring, which was confirmed by independent preparation
of this product. This was an exciting discovery because
benzimidazoles are extremely important components in
pharmaceuticals as two of the top 25 selling drugs in the
world (esomeprazole and lansoprazole) contain the benz-
imidazole core structure.13 Therefore, conditions that would
selectively provide indazole or benzimidazole from a com-
mon intermediate would be extremely useful to synthetic
chemists.
1
low yields and were not reported. For example, H NMR
spectroscopic analysis of the crude reaction mixture consist-
ing of N-phenyl o-aminoacetophenone oxime (2a), MsCl,
and NEt3 in DCM gave the desired indazole (3a) product in
∼20% yield along with several products that included the
parent ketone from hydrolysis of the oxime and the N-
mesylated oxime starting material (Scheme 1). Because of
Scheme 1
the difficulty in preparing N-arylindazoles by direct arylation
of 1H-indazole, further investigation into conditions that
provide N-arylindazoles were undertaken. Herein, we report
these investigations and the synthesis of a variety of
N-arylindazoles from the corresponding N-aryl oxime com-
pounds. Moreover, we have discovered that benzimidazoles
can be produced from the same o-aminobenzoximes that
form N-arylindazoles, and the selectivity of this process
largely depends upon the identity of the base employed in
these reactions.
Initial attempts to selectively produce N-arylindazoles over
benzimidazoles were unsuccessful. Varying the temperature,
concentration, or solvent did not lead to a substantial increase
in the ratio of indazole to benzimidazole.14 The identity of
the base was then investigated. Exposure of oxime (2b) to
2.0 equiv of base and 2.0 equiv of MsCl in DCM for 6 h
provided the corresponding N-arylindazole (3b) and benz-
imidazole products (4b) (Table 1). In many cases, the choice
of base had a large influence on the outcome of the reaction.
The highest ratio of indazole (3b) to benzimidazole (4b) was
observed using 2-aminopyridine (entry 1). Alternatively, the
highest ratio of benzimidazole to indazole was observed
using NEt3, NBu3, or N,N-diisopropylethylamine (entries
The synthesis of N-substituted 1H-indazoles remains an
ongoing challenge. With the development of metal-catalyzed
carbon-nitrogen bond forming reactions, new methodologies
for forming 1-aryl-1H-indazoles have been developed. For
example, palladium-catalyzed intramolecular cyclization of
N-aryl-N′(o-bromobenzyl) hydrazines as well as [N-aryl-N′-
(o-bromobenzyl)-hydrazinato-N′]-triphenylphosphonium bro-
mides are converted to 1-aryl-1H-indazoles.8 An intramo-
lecular amination reaction from commercially available
2-bromobenzaldehydes and arylhydrazines also provides
(5) (a) Bouillon, I.; Zajicek, J.; Pudelova, N.; Krchnak, V. J. Org. Chem.
2008, 73, 9027. (b) Campetella, S.; Palmieri, A.; Petrini, M. Eur. J. Org.
Chem. 2009, 19, 3184. (c) Kylmala, T.; Udd, S.; Tois, J.; Franzen, R.
Tetrahedron Lett. 2010, 51, 3613. (d) Spiteri, C.; Keeling, S.; Moses, J. E.
Org. Lett. 2010, 12, 3368. (e) Stokes, B. J.; Vogel, C. V.; Urnezis, L. K.;
Pan, M.; Driver, T. G. Org. Lett. 2010, 12, 2884.
(9) Cho, C. S.; Lim, D. K.; Heo, N. H.; Kim, T. J.; Shim, S. C. Chem.
Commun. 2004, 1, 104.
(10) Lebedev, A. Y.; Khartulyari, A. S.; Voskoboynikov, A. Z. J. Org.
Chem. 2005, 70, 596.
(6) Counceller, C. M.; Eichman, C. C.; Wray, B. C.; Stambuli, J. P.
Org. Lett. 2008, 10, 1021.
(11) Antilla, J. C.; Baskin, J. M.; Barder, T. E.; Buchwald, S. L. J. Org.
Chem. 2004, 69, 5578.
(7) (a) Mori, S.; Uchiyama, K.; Hayashi, Y.; Narasaka, K.; Nakamura,
E. Chem. Lett. 1998, 2, 111. (b) Yoshida, M.; Uchiyama, K.; Narasaka, K.
Heterocycles 2000, 52, 681. (c) Kitamura, M.; Yoshida, M.; Kikuchi, T.;
Narasaka, K. Synthesis 2003, 15, 2415.
(12) Vina, D.; Olmo, E. d.; Lopez-Perez, J. L.; Feliciano, A. S. Org.
Lett. 2007, 9, 525.
(13) Mack, D. J.; Brichacek, M.; Plichta, A.; Njardarson, J. T. http://
www.chem.cornell.edu/jn96/outreach.html. Accessed September 1, 2010.
(14) Please refer to the Supporting Information.
(8) Song, J. J.; Yee, N. K. Tetrahedron Lett. 2001, 42, 2937.
Org. Lett., Vol. 12, No. 20, 2010
4577

Table 1. Effect of Base on the Ratio of Indazole to
Scheme 3
.
Synthesis of Indazoles Using 2-Aminopyridine as
Basea
Benzimidazole Productsa b
,
entry
base (pKa (H2O))
indazole: benzimidazole
1
2
3
4
5
6
7
8
2-aminopyridine (6.8)
2,6-diaminopyridine (6)
1-methylimidazole (7.4)
pyridine (3.4)
DBU (12)
Net3 (10.8)
9.2
5.8
2.5
1.7
0.41
0.32
0.28
0.26
NBu3 (10.9)
DIPEA (11.4)
a Ratio of indazole to benzimidazole was determined using gas
chromatography with 1,3,5-trimethoxybenzene as an internal standard. b All
reactions proceeded to >70% conversion except for entry 4.
6-8). The ratio of indazole to benzimidazole did not
correlate to the pKa values of the bases (although the
complete pKa values of all bases were only available in water)
but in general, weaker bases favored the formation of
indazole, while stronger bases favored benzimidazole prod-
ucts. The formation of the benzimidazole product may arise
from the pathway in Scheme 2. Upon mesylation of the
Scheme 2
a Isolated yields are an average of two 1 mmol reactions. b This reaction
was conducted at -78 to 23 °C. c This reaction was conducted at -20 °C.
substituted aryl amines. When aldoximes were employed as
starting materials (entries 3n, 3o), the reactions were
conducted at lower temperatures to avoid elimination of the
oxime, a Beckmann rearrangement occurs with intramolecu-
lar trapping of the formed nitrilium ion by the arylamine. It
is currently unclear why stronger bases would promote the
Beckmann rearrangement pathway that forms benzimidazoles
over the nucleophilic subsitution pathway to form inda-
zoles.15
Several substituted arylamino oximes were prepared (see
Supporting Information) and examined under the optimized
reaction condtions (Scheme 3). High yields were obtained
for most substrates that contained arenes with electron-
donating or electron-withdrawing groups at the ortho, meta,
or para positions. However, lower yields of indazoles were
obtained with p-CF3 (3f, 44%) and p-NO2 (3g, 20%)
(15) We thank the reviewer who suggested that the formation of
benzimidazole may occur through a deprotonation, migration, ketenimine
formation, and cyclization sequence.
Figure 2. Percent yield of indazole vs σ values of arenes.
Org. Lett., Vol. 12, No. 20, 2010
4578

the oxime nitrogen. This rate increase lessens the delay time
needed to allow the Beckmann rearrangement to occur.
We next investigated the selective formation of benzimi-
dazoles using the conditions uncovered in the reaction
screening from Table 1. The conditions employed are the
same conditions that produced 1H-indazoles in our previous
work. Surprisingly, benzimidazole was not observed in any
appreciable yields in reactions of primary aromatic amines.
Nonetheless, exposure of the same substrates that formed
indazoles in the presence of 2-aminopyridine gave benzimi-
dazoles with triethylamine (Scheme 4). Lower yields were
obtained with a methoxy group present at the para or meta
positions (4c, 36%; 4h, 41%). However, moderate to high
yields were obtained for electron-withdrawing substituents
at the ortho, meta, or para positions. Currently, this method
is not amenable to strongly electron-rich arenes, as treatment
of dimethoxy (2p) with MsCl and NEt3 gave the correspond-
ing N-arylindazole.
Scheme 4. Synthesis of Benzimidazoles Using Triethylamine as
Basea
In summary, we report the synthesis of both N-aryl-1H-
indazoles and benzimidazoles through a common oxime
intermediate. Product selectivity of these reactions was
achieved through selection of the base. The reactions that
produce indazoles correlate well to the σ values of the groups
on the N-aromatic ring. This method affords a broad range
of indazoles and benzimidazoles from good to excellent
yields and should provide synthetic chemists an additional
avenue to prepare indazoles and benzimidazoles. More
significant is the fact that two diverse heterocycles can be
generated from a common intermediate by simply changing
the identity of the base in the reaction.
a Isolated yields are an average of two 1 mmol reactions.
aldoximes to the corresponding nitriles. The method was also
amenable to substitution on the aromatic ring containing the
oxime. The dimethoxy product 3p and the chloro product
3q were isolated in 94 and 59% respectively.
Acknowledgment. This work was generously supported
by The Ohio State University. We thank the Ohio BioProd-
ucts Innovation Center (OBIC) for the grant that provided
the Bruker Micro TOF instrument used to obtain mass
spectral data.
In addition to the influence of base, the electronics of the
group attached to the arene influenced the reaction outcome.
A linear relationship exists between the yield of indazole
and the σ values of the aryl substituents (Figure 2).16
A
general trend was that the stronger σ donors produce a larger
amount of indazole product. The relationship is likely caused
by the increased nucleophilicity of the arylamine that attacks
Supporting Information Available: Experimental pro-
cedures and characterization of all compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
(16) Ritchie, C. D.; Sager, W. F. Prog. Phys. Org. Chem. 1964, 2, 323.
OL101899Q
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