New practical synthesis of indazoles via condensation of o-fluorobenzaldehydes and their O-methyloximes with hydrazine

Article abstract of DOI:10.1021/jo0613784

The reaction of o-fluorobenzaldehydes and their O-methyloximes with hydrazine has been developed as a new practical synthesis of indazoles. Utilization of the methyloxime derivatives of benzaldehydes (in the form of the major E-isomers) in this condensation effectively eliminated a competitive Wolf-Kishner reduction to fluorotoluenes, which was observed in the direct preparations of indazoles from aldehydes. Reaction of Z-isomers of methyloximes with hydrazine resulted in the formation of 3-aminoindazoles via a benzonitrile intermediate.

Full text of DOI:10.1021/jo0613784

New Practical Synthesis of Indazoles via Condensation of
o-Fluorobenzaldehydes and Their O-Methyloximes with Hydrazine
Kirill Lukin,* Margaret C. Hsu, Dilinie Fernando, and M. Robert Leanna
GPRD Process Research and DeVelopment, Abbott Laboratories, North Chicago, Illinois 60064
kirill.lukin@abbott.com
ReceiVed July 3, 2006
The reaction of o-fluorobenzaldehydes and their O-methyloximes with hydrazine has been developed as
a new practical synthesis of indazoles. Utilization of the methyloxime derivatives of benzaldehydes (in
the form of the major E-isomers) in this condensation effectively eliminated a competitive Wolf-Kishner
reduction to fluorotoluenes, which was observed in the direct preparations of indazoles from aldehydes.
Reaction of Z-isomers of methyloximes with hydrazine resulted in the formation of 3-aminoindazoles
via a benzonitrile intermediate.
Introduction
the literature4 revealed that the indazoles substituted on the six-
membered ring (including 3 and 4) were generally prepared via
diazotation of the corresponding toluidines 5 (eq 1)5,6 or the
Investigation of biologically active compounds possessing the
indazole (1) heterocyclic core has resulted in the discovery of
potent HIV protease inhibitors, serotonin receptor antagonists,
aldol reductase inhibitors, and acetylcholinesterase inhibitors.1,2
Recently, another indazole derivative, ABT-102 (2), has been
identified as a potent vanilloid receptor (VR1) antagonist.
Compound 2 is currently undergoing advanced clinical develop-
ment for the treatment of chronic pain.3
nitrozation of their N-acetyl derivatives 7 (Jacobsen modifica-
tion, eq 2).7,8
Unfortunately, these methods could not be considered practi-
cal for multikilogram preparations.9,10
Other innovative approaches for indazoles synthesis have been
reported, but they either gave mixtures of isomeric products11
or were only limited to the synthesis of indazoles substituted at
the 1-N or 3-C positions.4,12 However, among the latter methods,
(4) For reviews see: (a) Elguero, J. In ComprehensiVe Heterocyclic
Chemistry; Katrizky, A. R., Rees, C. W., Eds.; Pergamon Press: New York,
1984; Vol. 5, p 167. (b) Behr, L. C.; Fusco, R.; Jarobe, C. H. In Pyrazoles,
Pyrazolines, Pyrazolidines, Indazoles and Condensed Rings; Wiley, R. H.,
Ed.; Wiley Int.: New York, 1969; p 28.
(5) Ruechardt, C.; Hassmann, V. Liebigs Ann. Chem. 1980, 6, 908-
927.
(6) For other examples of indazoles synthesis via diazonium salt see:
Schumann, P.; Collot, V.; Hommet, Y.; Gsell, W.; Dauphin, F.; Sopkova,
J.; MacKenzie, E. T.; Duval, D.; Boulouard, M.; Rault, S. Bioorg. Med.
Chem. Lett. 2001, 11, 1153-1156.
(7) (a) Tono-oka, S.; Tone, Y.; Marques, V. E.; Cooney, D.; Sekikawa,
I.; Azuma, I. Bull. Chem. Soc. Jpn. 1985, 58, 309-315. (b) Shoda, M.;
Kuriyama, H. U.S. Patent Application 2003070686, Aug 28, 2003.
(8) (a) Jacobsen, P.; Huber, L. Chem. Ber. 1908, 41, 660. (b) Ruchardt,
C.; Hassmann, V. Liebigs Ann. Chem. 1980, 908-927.
The current synthesis of 2 utilizes 4-haloindazoles 3 or 4 as
starting materials. Development of a reliable and efficient
preparation of these indazoles was required to provide access
to large quantities of bulk drug for the studies. Inspection of
(1) Rodgers, J. D.; Johnson, B. L.; Wang, H.; Greenberg, R. A.; Erickson-
Viitanen, S.; Klabe, R. M.; Cordova, B. C.; Reyner, M. M.; Lam, G. N.;
Chang, C.-H. Bioorg. Med. Chem. Lett. 1996, 6, 2919-2924.
(2) See, for example: Brase, S.; Gil, C.; Knepper, K. Bioorg. Med. Chem.
2002, 10, 2415-2437.
(3) Gomtsyan, A.; Bayburt, E. K.; Koenig, J. R.; Lee, C.-H. U.S. Patent
Application 2004254188, Dec 16, 2004.
10.1021/jo0613784 CCC: $33.50 © 2006 American Chemical Society
Published on Web 09/15/2006
8166
J. Org. Chem. 2006, 71, 8166-8172

Synthesis of Indazoles from o-Fluorobenzaldehydes
Surprisingly though, we could not find any references of
similar condensations involving o-fluorobenzaldehydessstarting
materials required for the preparation of indazoles unsubstituted
at the 3-position. The results of our investigation of the latter
reaction, which led to the development of a new practical
synthesis of indazoles, are provided below.
Results and Discussion
a condensation of ortho-substituted benzaldehydes with hydra-
zines (eq 3) looked particularly straightforward and attractive
1. Synthesis of 4-Haloindazoles. Our initial investigation into
the synthesis of 4-bromo and 4-chloroindazoles (3, 4) via a
condensation of the corresponding 6-halo-2-fluorobenzaldehydes
11 and 12 with hydrazine gave fairly promising results. For
example, when the reaction of aldehyde 11 with hydrazine
hydrate (3 equiv) in the presence of sodium bicarbonate was
monitored by HPLC, a fast and quantitative formation of
hydrazone intermediate 13 was initially observed (eq 5). Further
for the adaptation for the synthesis of indazoles 3 and 4.
The condensation outlined in eq 3, utilizing nitro as a leaving
group (Z ) NO2) was first reported more than a century ago.13
It was demonstrated that several substituted hydrazones (R *
H), which were initially formed in the reactions of o-nitroben-
zaldehydes with the corresponding hydrazines, could be further
converted into the indazoles in the presence of a base under
very forcing conditions. Later, this method was adapted by
employing the corresponding o-fluoro- and o-mesyloxy-
substituted14 benzocarbonyl compounds. Several groups reported
that various 3-substituted indazoles 9 (R * H, eq 4) could be
heating of this mixture to 90-100 °C for 5 h resulted in
conversion of 13 into an approximately 2:3 mixture of the
desired indazole 3 and an unknown side product. The side
product was subsequently identified as bromofluorotoluene 14,19
apparently resulting from the Wolf-Kishner type reduction of
the intermediate hydrazone 13 (eq 5). Similar results were
observed with 6-chloro analogue 12.
efficiently prepared via condensations of the corresponding
esters of 2-fluorobenzoic acid (10a, R ) OMe), fluoroaceto,
and fluorobenzophenones (10a, R ) Me, Ar), as well as
2-fluorobenzonitriles 10b, with hydrazine.15-18
As it was generally presumed that the formation of indazoles
from ortho-substituted hydrazones proceeded as an intramo-
lecular cyclization (eq 3), we decided to further optimize the
reaction conditions for this cyclization using the isolated pure
hydrazone 13. First, we found that a careful selection of a base
was critical for minimizing the Wolf-Kishner pathway. Thus,
in the presence of bases stronger than sodium bicarbonate (e.g.,
potassium carbonate, triethylamine) fast and quantitative reduc-
tion of hydrazone 13 to toluene 14 was observed. The formation
of indazole 3 was only observed in the presence of weak bases
(e.g., sodium bicarbonate, pyridine). However, the cyclization
of the isolated hydrazone 13 proceeded remarkably slower,
compared to the described above reaction of the same hydra-
zone, when it was formed in situ. Even after 72 h at 100 °C,
some of the starting hydrazone remained in the mixture.
Moreover, the yield of indazole 3 obtained in this experiment
was lower than 10%, due to the formation of toluene 14 and
other numerous side products. These data suggested that the
(9) The diazotation method generally requires the isolation of a potentially
explosive diazonium salt intermediate. The formation and cyclization of
the diazonium salt proceed simultaneously under the reaction conditions
only in the presence of additional highly electron-withdrawing groups (e.g.,
nitro): (a) Bartsch, R. A.; Tang, I.-W. J. Heterocycl. Chem. 1984, 21, 1063.
(b) Porter, H. D.; Peterson, W. D. Org. Synth. 1955, III (Collective Vol.),
660.
(10) Even the most advanced modification of the Jacobsen reaction
remains relatively impractical, as it requires the addition of 0.1 equiv of
expensive and toxic crown ether catalyst, employs toxic chloroform as a
preferred solvent, and adds a deprotection step to recover the indazole: (a)
Beadle, J. R.; Korzeniowski, S. H.; Rosenberg, D. E.; Garcia-Slanga, B. J.;
Gokel, G. W. J. Org. Chem. 1984, 49, 1594-1603. (b) Sun, J.-H.; Teleha,
C. A.; Yan, J.-S.; Rodgers, J. D.; Nugiel D. A. J. Org. Chem. 1997, 62,
5627-5629.
(11) Bromoindazole 3 was obtained as one of the products resulting from
the condensation of bromobenzyne with (trimethylsilyl)diazomethane: Shoji,
Y.; Hari, Y.; Aoyama, T. Tetrahedron Lett. 2004, 45, 1769-1771.
(12) Song, J. J.; Yee, N. K. Tetrahedron Lett. 2001, 42, 2937-2940.
(13) (a) Meyer, V. Chem. Ber. 1889, 22, 319. (b) Reich, S.; Gaigalian,
G. Chem. Ber. 1913, 46, 2380-2387.
(14) Caron, S.; Vazquez, E. Synthesis 1999, 4, 588-592.
(15) Cui, J. J.; Araldi, G.-L.; Reiner, J. E.; Reddy, K. M.; Kemp, S. J.;
Ho, J. Z.; Siev, D. V.; Mamedova, L.; Gibson, T. S.; Gaudette, J. A.;
Minami, N. K.; Anderson, S.; M.; Bradbury, A. E.; Nolan, T. G.; Semple,
J. E. Bioorg. Med. Chem. Lett. 2002, 12, 2925-2930.
(16) Henke, B. R.; Aquino, C. J.; Birkemo, L. S.; Croom, D. K.;
Dougherty, R. W.; Ervin, G. N.; Grizzle, M. K.; Hirst, G. C.; James, M.
K.; Johnson, M. F.; Queen, K. L.; Sherrill, R. G.; Sugg, E. E.; Suh, E. M.;
Szewczyk, J. W.; Unwalla, R. J.; Yingling, J.; Willson, T. M. J. Med. Chem.
1997, 40, 2706-2725.
(17) (a) Shutske, G. M.; Allen, R. C.; Forsch, M. F.; Setescak, L. L.;
Wilker, J. C. J. Med. Chem. 1983, 26, 1307-1311. (b) Dehmlow, H.; Aebi,
J. D.; Jolidon, S.; Ji, Y.-H.; Mark, E. M.; Himber, J.; Morand, O. H. J.
Med. Chem. 2003, 46, 3354-3370.
(18) Witherington, J.; Bordas, V.; Gaiba, A.; Naylor, A.; Rawlings, A.
D.; Slingsby, B. P.; Smith, D. G.; Takle, A. K.; Ward, R. W. Bioorg. Med.
Chem. Lett. 2003, 13, 3059-3062.
(19) Dewar, M. J. S.; Grisdale, P. J. J. Org. Chem. 1963, 28, 1759-
1762.
J. Org. Chem, Vol. 71, No. 21, 2006 8167

Lukin et al.
SCHEME 1
however, still negatively affected by the formation of toluenes
14 and 15, as side products. Upon further optimization of the
reaction parameters, we have found that the extent of the
reduction could be attenuated by conducting the reaction in
etheral solvents such as THF, DME, or dioxane and employing
anhydrous hydrazine as a cosolvent. Under these optimized
conditions (1:1 THF-98% hydrazine, 70 °C, 15 h) the isolated
yields of indazoles 3 and 4 were increased to 80-85%,
respectively.
2. Condensation of Other o-Fluorobenzaldehydes with
Hydrazine. In an attempt to determine the generality of this
practical approach, the condensations of several substituted
o-fluorobenzaldehydes (18-24) were evaluated using the condi-
tions found optimal for aldehydes 11 and 12. The selection of
the o-fluorobenzaldehydes was designed to evaluate both the
impact of the substitution pattern and the electronic effect of
substituents (eq 7). The results of this study are summarized in
formation of indazoles in reactions of o-fluorobenzaldehydes
with hydrazine under the investigated set of conditions did not
proceed via an intramolecular cyclization of hydrazone 13.20
In search of an explanation for the above results, we found
that the indazole formation from 11 could be facilitated in the
presence of excess hydrazine. Indeed, when the isolated hydra-
zone 13 was added to hydrazine hydrate, which was used as a
solvent, heating the solution to 100 °C for only 1 h resulted in
consumption of the starting material.
Based on these data we rationalized that the mechanism for
the conversion of the o-fluorophenylhydrazones into indazoles
in the presence of excess hydrazine proceeded by substitution
of the aryl fluoride with another molecule of hydrazine, followed
by the cyclization of 13b as outlined in Scheme 1.
According to this mechanism, the hydrazine molecule, which
was initially incorporated into the hydrazone fragment of 13,
would be later eliminated as a result of a subsequent cyclization
step via aminal 13c (Scheme 1). To support this proposed
mechanism we prepared benzyl-substituted hydrazone 16 and
subjected it to the cyclization conditions in hydrazine hydrate
(eq 6). As we expected, nonbenzylated indazole 3 was formed
Table 1.
We were pleased to find that the desired indazoles could be
obtained in good yields in most of the cases studied. At the
same time, the data in Table 1 show that the cyclizations of
unsubstituted fluorobenzaldehyde 18 and 5-bromo-2-fluoroben-
zaldehyde (20) gave reduced yields of the corresponding
indazoles, whereas 5-methoxy-substituted aldehyde 23 gave only
the corresponding toluene reduction product. The lower ef-
ficiency of the condensation reaction in the latter examples could
be rationalized by considering the effect of substituents on the
rates of the two competitive processessnucleophilic substitution
of the fluoride leading to indazole formation and the hydrazone
intermediate reduction leading to the toluene. For example,
introduction of the electron-donating methoxy substituent in para
or ortho positions relative to the carbonyl group (compounds
22, 24) would presumably decelerate the hydrazone reduction,
while having little effect on the fluoride substitution. At the
same, introduction of the methoxy substituent in the para
position relative to the fluoride (compound 23) would deactivate
the fluoride substitution, with little effect on the hydrazone
reduction rate. Accordingly, the condensation of aldehyde 24
resulted in a high yield of 4-methoxyindazole (31), whereas the
analogous reaction of aldehyde 23 gave the reduction product
only. Although in all studied cases the toluene side products
could be conveniently removed from the indazoles by a heptane
wash, or simply during the product drying under vacuum, we
still sought better control over the reduction pathway to achieve
higher yields of indazoles regardless of the substitution.
3. Condensation of 2-Fluorobenzaldehyde O-Methyloximes
with Hydrazine. The condensation of benzylhydrazone 16 with
hydrazine (eq 6) provided important clues for further method
development. As noted above, this reaction resulted in replace-
ment of benzylhydrazine and gave nearly exclusively indazole
unsubstituted at the 1-N position. These findings allowed us to
propose that not only various substituted hydrazones (e.g., 16)
but other appropriately protected aldehydes could be utilized
in the condensations with hydrazine for indazoles preparation.
Moreover, elimination of the hydrazone intermediate from this
new process would avoid the Wolf-Kishner pathway leading
to the toluene side products. We thought that easily accessible
oximes could be good surrogates to investigate this approach.
as a major product (the 10:1 ratio of indazole 3 and benzylin-
dazole 17 was determined by HPLC methodology). Importantly,
only traces of toluene side product were observed in the reaction
mixture (in comparison to the cyclization of 13 which gave 30-
40% of reduction product), suggesting that hydrazone 13 was
not a major intermediate in this reaction and that the indazole
formation proceeded in an intramolecular fashion, after the
fluoride substitution in 16 (Scheme 1).
As an outcome of the above mechanistic rationalization, we
were able to prepare 4-haloindazoles 3 and 4 simply by refluxing
the corresponding aldehydes in hydrazine hydrate. Upon the
completion of the reaction, the product typically precipitated
out during cooling of the crude reaction mixture and was
conveniently isolated through filtration. The yields of indazoles
3 and 4 obtained in this reaction were satisfactory (50-60%),
(20) It is possible that intramolecular cyclization of hydrazones with the
formation of indazoles still could be accomplished at higher temperatures.
In the related study of the intramolecular cyclizations of 2-mesyloxyac-
etophenones hydrazones (ref 18, eq 4), the indazole formation was observed
at temperatures above 130 °C. However, a DSC scan of hydrazone 13
indicated that it underwent highly exothermic decomposition at 140-150
°C, prompting us to set 110 °C as the upper limit for all our experiments.
8168 J. Org. Chem., Vol. 71, No. 21, 2006

Synthesis of Indazoles from o-Fluorobenzaldehydes
TABLE 1. Indazole Formation from Benzaldehydes 11, 12, 18-24
the standard conditions using the hydrazone intermediate (Table
1, entry 3). Adding to the convenience of this procedure, no
isolation of the methyloxime intermediate was required before
the indazole formation step. The reaction with hydrazine was
conducted simply after filtering off the inorganics from the crude
oxime solution (vide infra).
In a similar manner, the benzaldehydes referenced in Table
1, as well as 2,6-difluorobenzaldehyde (39), were converted into
the corresponding methyloximes and, subsequently, indazoles
in high yields, as summarized in Table 2. The only exception
to this generality was the methyloxime of highly deactivated
5-methoxy-substituted aldehyde 23, which upon extended reac-
tion time gave only 5% yield of 30.
Surprisingly, 6-bromo- and 6-chloro-substituted benzalde-
hydes 11 and 12, which gave the highest yields of indazoles in
the cyclizations via hydrazone intermediate (Table 1, entries 1
and 2), behaved unusually in the cyclization via their requisite
methyloxime. It was found that in addition to the corresponding
indazoles 3 and 4, other more polar products (12-14% by HPLC
peak area vs 3 or 4) were formed in these reactions (eq 10).
These side products were identified as 3-aminoindazoles 34a
and 34b,22 respectively. It was also observed that formation of
34 could be related to the increased amounts of the minor
Z-isomers of oximes 35 or 36 formed during the oximation of
aldehydes 11 and 12, respectively (see Table 2).23 To confirm
that 3-aminoindazoles were indeed formed from the correspond-
ing Z-oxime isomers, we attempted the isolation of individual
compounds 35a and 35b. Although the separation of these
isomers via chromatography was not achievable, it was possible
to isolate the major E-form 35b (<5% Z) by fractional
crystallization of the mixture from pentane at 0 °C. The
cyclization of this enriched material under the standard condi-
tions resulted in the expected decrease in the yield of 34a, which
dropped to 3% vs 3, confirming the aminoindazole origination
from Z-isomer 35a.
a Reaction yield, as determined by HPLC assay. b Additionally, toluene
15 was formed in 13% yield (HPLC assay). c Additionally, 2-fluorotoluene
was formed in 45% yield (HPLC assay).
However, it has been reported that unprotected oximes of
substituted 2-fluorobenzaldehydes could undergo a self-cycliza-
tion into isoxazoles, as outlined in eq 8.21
The isoxazole side product formation was obviated by using
O-methyloximes 32 instead of oximes. Compounds 32 could
be simply prepared in quantitative yields by reacting the
equivalent amounts of fluorobenzaldehydes and methyloxime
hydrochloride in the presence of potassium carbonate (eq 9).
We were pleased to find that the reaction of 2-fluorobenzalde-
hyde O-methyloxime prepared in this manner with hydrazine
cleanly gave indazole, which was isolated in 80% yield (eq 9,
X ) H) representing a nearly 3-fold yield improvement over
We do not have an explanation for the increased amounts of
Z-isomers formation in the oximations of aldehydes 11 and 12.
However, a comparison of the oxime ratios listed in Table 2
suggests that this phenomenon is related to the size of the
substituent at the 6-position of the aldehyde. Thus, a gradual
(22) Voss, G.; Eichner, S. J. Prakt. Chem. 2000, 342, 201-204.
(23) The Z/E ratios of 25:75 and 22:78 were determined for methyloximes
35 and 36 by HPLC methodology. Other investigated methyloximes had
less than 10% of Z-isomer. Isomers assignment in methyloximes is based
on 13C NMR data: Gordon, M. S.; Sojka, S. A.; Krause J. G. J. Org. Chem.
1984, 49, 97-100.
(21) Strupczewski, J. T.; Allen, R. C.; Gardner, B. A.; Schmid, B. L.;
Stache, U.; Glamkowski, E. J.; Jones, M. C.; Ellis, D. B.; Huger, F. P.;
Dunn, R. W. J. Med. Chem. 1985, 28, 761-769.
J. Org. Chem, Vol. 71, No. 21, 2006 8169

Lukin et al.
TABLE 2. Conversion of o-Fluorobenzaldehydes into the
Indazoles via the Methyloxime Method
isolated from the reaction of nitrile 37 with hydrazine at room
temperature (eq 12).27-29
isolated yield
(%)a
Z/E oximes
indazole
X (eq 9)
ratiob
25
26
27
28
29
30
33
31
3
H
80
70
94
84
5/95
6/94
6/94
6/94
8/92
4/96
9/91
15/85
25/75
22/78
6-Br
5-Br
7-Cl
6-MeO
5-MeO
4-F
4-MeO
4-Br
4-Cl
69
5b
As expected, compound 38 was further converted into
indazole 34b by heating the reaction mixture to 75 °C.
75
70
70 (86/14)c
72 (88/12)d
Conclusions
4
a The isolated yields of individual compounds were not optimized.
b Determined by HPLC methodology. c Compounds 3/34a ratio in the
reaction mixture determined by HPLC methodology. d Compounds 4/34b
ratio in the reaction mixture determined by HPLC methodology.
We have established a new practical synthesis of indazoles
via reaction of o-fluorobenzaldehydes and/or their O-methyl-
oximes with excess hydrazine. High yields of indazoles (70-
85%) were obtained in the condensations of aldehydes with
various substitution patterns with the exception of those
possessing electron-donating groups in the 5-position, as well
as unsubtituted o-fluorobenzaldehyde. The yields of indazoles
prepared from the nonoptimal aldehydes were lower due to
competitive Wolf-Kishner reduction. This side reaction was
effectively eliminated via utilization of O-methyloxime deriva-
tives of the aldehydes for the preparation of indazoles in the
condensation with hydrazine. All studied aldehydes (with the
exception of the poorly reactive 5-methoxy compound) were
efficiently converted into the corresponding indazoles using the
methyloxime method. A side reaction, resulting in the formation
of 3-aminoindazoles, was observed in the experiments with
oximes possessing relatively high levels of Z-isomers. The
aminoindazole side products were selectively formed from
Z-isomers of these oximes, via the corresponding nitrile
intermediates under the reaction conditions.
increase in the amounts of Z-isomers was observed when the
6-substituent in the benzaldehyde molecule was changed from
hydrogen to bromine (Br > Cl > MeO > F > H, see Table 2).
The same substituents did not significantly affect the ratio of
oxime isomers, if they were placed in other positions in the
molecule. Accordingly, we did not observe the formation of
any side products with an HLPC peak area higher than 5% in
the condensations of the latter oximes (see Table 2).24
A plausible mechanism for the observed formation of
3-aminoindazoles in the condensations of Z-methyloximes with
hydrazine is outlined in eq 11.
Finally, we would like to note that condensations of O-
methyloximes with nucleophiles other than hydrazine could
potentially provide a new practical methodology for the prepara-
tion of various heterocyclic systems. We will report on this
chemistry in a due time.
This mechanism is based on the reported literature prece-
dents.14,17 It was also demonstrated that O-methyloximes of
benzaldehydes, possessing electron-withdrawing groups, could
be converted into the corresponding nitriles in the presence of
bases as strong as aqueous sodium hydroxide.25 The selective
benzonitrile formation from the Z-isomer of oxime under the
reaction conditions probably represented a kinetic effect.
Relatively faster elimination of methanol from the Z-isomer
could be explained by the preferred orbital orientation in the
elimination transitions state of this isomer, in line with the
general stereochemical considerations for the reactions proceed-
ing via an E2 mechanism.26
Experimental Section
General. Commercially available o-fluorobenzaldehydes and
2-chloro-6-fluorobenzonitrile (37) were used in this study.
Reaction mixtures and isolated products were analyzed by HPLC
(Zorbax Rx C8 column, detection at 205 nm). All isolated indazole
compounds had an HPLC purity better than 95%. 1H NMR spectra
were recorded at 400 MHz; 13C NMR spectra were recorded at
100 MHz.
General Procedure for the Preparation of Indazoles from
Fluorobenzaldehydes. Method A. Hydrazine (98%, 10 mL) was
added over 5 min to a solution of an aldehyde (10 mmol) in DME
(10 mL). The reaction mixture was refluxed for 15 h and
concentrated in vacuo to approximately 10 mL. Water (10-20 mL)
was added to the mixture. The resulting product precipitate was
filtered off and dried in vacuo. Indazoles 3, 4, 25-29, and 31 were
obtained using this procedure. DME solvent could be replaced with
THF or dioxane.
Further support of the mechanism outlined in eq 11 was
obtained during monitoring the condensation of oximes 36 with
hydrazine by HPLC. While no intermediates were observed in
the cyclization of 36b into 4, the formation of aminoindazole
34b clearly proceeded via an intermediate (40% peak area vs
34b after 1 h; 10% after 2 h; <1%, after 4 h). Although we
could not detect the presence of nitrile 37 in this reaction mixture
directly, the intermediate was identified as its derivative,
hydrazide 38, by spiking the reference compound into the HPLC
sample of the reaction mixture. Hydrazide 38 was in turn
(27) The structure of intermediate 37 was supported by 13C NMR, which
showed the presence of a nitrile carbon at 155.1 ppm and the disappearance
of 13C-19F coupling.
(28) For examples of halogen displacement with hydrazine in substituted
benzonitrile see: (a) Parnell J. Chem. Soc. 1959, 2363. (b) Voss, G.; Eichner,
S. J. Prakt. Chem. 2000, 342, 201-204.
(29) Alternatively, nitrile formation could occur after fluoride substitution
with hydrazine. This, however, seems less likely, as a highly electron-
donating hydrazide will deactivate the methyloxime group for elimination.
(24) We did not attempt to identify the structures of minor side products
formed in these reactions in less than 5% peak area by HPLC methodology.
(25) Hagarty, A. F.; Tuobey, P. J. J. Chem. Soc., Perkin Trans. 2 1980,
1313.
(26) Marchese, G.; Naso, F.; Modena, G. J. J. Chem. Soc. B 1968, 958.
8170 J. Org. Chem., Vol. 71, No. 21, 2006

Synthesis of Indazoles from o-Fluorobenzaldehydes
General Procedure for the Preparation of Indazoles from
Fluorobenzaldehydes via O-Methyloxime Intermediates. Method
B. An aldehyde (5 mmol), methylhydroxylamine hydrochloride
(0.41 g, 5 mmol), and potassium carbonate (0.76 g, 5.5 mmol) were
mixed in DME (10 mL) for 4-5 h at 40 °C. The reaction mixture
was filtered, and the filtrate containing the oxime intermediate was
concentrated in vacuo to approximately 5 mL. Hydrazine (98%, 5
mL) was added to the concentrated oxime solution, and the mixture
was refluxed for 5-25 h, until the reaction was complete per HPLC
analysis. The reaction mixture was concentrated in vacuo to
approximately 5 mL. Water (10 mL) was added to the mixture.
The resulting product precipitate was filtered off and dried in vacuo.
Indazoles 3, 4, 25, 27-29, 31, and 33 were obtained using this
procedure.
4-Bromoindazole (3)7b,11 was obtained in 81% yield by method
A: 1H NMR (DMSO-d6, δ, ppm) 7.28 (t, 1H, J ) 7.6 Hz), 7.34
(d, 1H, J ) 7.4 Hz), 7.59 (d, 1H, J ) 7.5 Hz), 8.05 (s, 1H), 13.46
(s, 1H, -NH).
Attempted preparation of 4-bromoindazole by method B gave a
mixture of indazoles 3 and 34a in 86:14 ratio. The mixture was
separated by column chromatography on silica gel eluting with 9:1
heptane-ethyl acetate. Bromoindazole 3 was eluted first and
isolated in 70% yield.
3-Amino-4-bromoindazole (34a) was obtained in 10% yield:
1H NMR (DMSO-d6, δ, ppm) 5.18 (s, 2H, -NH), 7.05-7.19 (m,
2H), 7.29 (d, 1H, J ) 7.8 Hz), 11.88 (s, 1H, -NH). 13C NMR
(DMSO-d6, δ, ppm) 109.0 (CH), 111.5 (C), 113.1 (C), 120.7 (CH),
127.0 (CH), 141.8 (C), 147. 7 (C). Anal. Calcd for C7H6BrN3: C,
39.65; H, 2.85; N, 19.82. Found: C, 39.75; H, 2.80; N, 19.36.
4-Chloroindazole (4)5,7a was obtained in 82% yield by method
A: 1H NMR (CDCl3, δ, ppm) 7.15 (d, 1H, J ) 7.4 Hz), 7.30 (t,
1H, J ) 7.4 Hz), 7.40 (d, 1H, J ) 7.5 Hz), 8.16 (s, 1H), 10.61 (s,
1H, -NH).
Attempted preparation of 4-chloroindazole by method B gave a
mixture of indazoles 3 and 34b in 88:12 ratio. The mixture was
separated by column chromatography on silica gel eluting with 9:1
heptane-ethyl acetate. Chloroindazole 3 was eluted first and
isolated in 72% yield.
3-Amino-4-chloroindazole (34b)26 was obtained in 8% yield:
1H NMR (methanol-d4, δ, ppm) 5.18 (s, 2H, -NH), 7.05-7.19
(m, 2H), 7.29 (d, 1H, J ) 7.8 Hz), 11.88 (s, 1H, -NH). 13C NMR
(methanol-d4, δ, ppm) 109.0 (CH), 111.5 (C), 113.1 (C), 120.7
(CH), 127.0 (CH), 141.8 (C), 147.7 (C).
Indazole (25) was obtained in 29% yield by method A and 80%
yield by method B: 1H NMR (DMSO-d6, δ, ppm) 7.09 (t, 1H, J )
7.5 Hz), 7.33 (t, 1H, J ) 7.5 Hz), 7.52(d, 1H, J ) 8.4 Hz), 7.75 (d,
1H, J ) 8.1 Hz), 8.05 (s, 1H), 13.01 (s, 1H, -NH).
(s, 3H), 6.81-6.84 (m, 2H), 7.60 (d, 1H, J ) 8.7 Hz), 7.97 (s,
1H), 8.16 (s, 1H).
4-Methoxyindazole (31)7a was obtained in 47% yield by method
A and 70% yield by method B: 1H NMR (CDCl3, δ, ppm) 3.97 (s,
3H), 6.48 (d, 1H, J ) 7.7 Hz), 7.07 (d, 1H, J ) 7.6 Hz), 7.29 (t,
1H, J ) 7.7 Hz), 8.16 (s, 1H), 10.48 (s, 1H).
4-Fluoroindazole (33)30 was obtained in 75% yield by method
B: 1H NMR (CDCl3, δ, ppm) 6.80 (m, 1H), 7.28-7.32 (m, 2H),
8.16 (s, 1H), 10.5 (s, 1H, -NH).
Bromo-6-fluorobenzaldehyde Hydrazone (13). Bromofluo-
robenzaldehyde 11 (2.0 g, 10 mmol) was added to a magnetically
stirred mixture of hydrazine hydrate (∼55% in water, 2.0 g) and
toluene (10 mL) over 0.5 h at 50 °C. After additional 1 h at 50 °C
the mixture was cooled to room temperature and diluted with water
(5 mL). The organic layer was separated and concentrated to dryness
in vacuo. The residue was slurried in heptane (30 mL). Filtration
and drying (40 °C, vacuum) gave hydrazone 13 (1.83 g, 91%): 1H
NMR (DMSO-d6, δ, ppm) 7.13-7.27 (m, 2H), 7.31 (s, 2H, -NH2),
7.42-7.49 (m, 1H), 7.79 (s, 1H, -NH). 13C NMR (DMSO-d6, δ,
ppm) 115.3 (d, CH, J ) 22.2 Hz), 121.7 (d, C, J ) 4.2 Hz), 123.3
(d, C, J ) 13.1 Hz), 128.3 (d, CH, J ) 3.4 Hz), 128.6 (d, CH, J )
9.4 Hz), 131.1 (d, CH, J ) 4.3 Hz), 158.8 (d, C, J ) 254 Hz).
Anal. Calcd for C7H6BrFN2: C, 38.74; H, 2.79; N, 12.91. Found:
C, 38.82; H, 2.76; N, 12.70.
Reduction of Bromofluorobenzaldehyde Hydrazone 13. 2-Bro-
mo-6-fluorotoluene (14). A mixture of hydrazone 13 (0.22 g, 1
mmol), potassium carbonate (0.28 g, 2 mmol), hydrazine hydrate
(∼55%, 1 mL), and DMA (1 mL) was heated to 100 °C for 1 h
under nitrogen atmosphere. The mixture was cooled to room
temperature and diluted with hexane (2 mL) and water (3 mL).
The hexane layer was separated and washed with water (2 × 2
mL). Careful evaporation of the hexane solution in vacuo gave
bromofluorotoluene 1419 (0.15 g, 81%): 1H NMR (CDCl3, δ, ppm)
2.33 (s, 3H), 6.91-7.08 (m, 2H), 7.32 (d, 1H, J ) 7.8 Hz).
2-Bromo-6-fluorobenzaldehyde Benzylhydrazone (16). Ben-
zylhydrazine dihydrochloride (0.98 g, 5 mmol) and sodium
hydroxide (0.6 g, 15 mmol) were mixed in THF (5 mL) for 10 h.
The mixture was filtered, and the filtrate containing benzylhydrazine
was combined with bromofluorobenzaldehyde 11 (0.97 g, 4.8
mmol). After 2 h at room temperature the mixture was concentrated
to dryness in vacuo. The residue was slurried in heptane (30 mL).
Filtration and drying (40 °C, vacuum) gave benzylhydrazone 16
(1.35 g, 92%): 1H NMR (CDCl3, δ, ppm) 4.46 (s, 2H), 6.99-7.08
(m, 2H), 7.24-7.41 (m, 6H), 7.64 (s, 1H). 13C NMR (CDCl3, δ,
ppm) 52.8 (CH2), 115.3 (d, CH, J ) 22.6 Hz), 123.1 (C), 123.5 (d,
C, J ) 23 Hz), 127.3 (CH), 127.9 (2C, CH), 128.38 (2C, CH),
128.42 (CH), 128.5 (CH), 130.5 (d, CH, J ) 3.8 Hz), 137.0 (C),
159.8 (d, C, J ) 255 Hz).
5-Bromoindazole (27)31 was obtained in 45% yield by method
A and 94% yield by method B: 1H NMR (CDCl3, δ, ppm) 7.38
(d, 1H, J ) 8.8 Hz), 7.47 (dd, 1H, J ) 1.7, 8.7 Hz), 7.90 (dd, 1H,
J ) 0.9, 1.7 Hz), 8.01 (d, 1H, J ) 0.9 Hz), 10.08 (s, 1H, -NH).
6-Bromoindazole (26)32 was obtained in 78% yield by method
A and 70% yield by method B: 1H NMR (DMSO-d6, δ, ppm) 7.24
(d, 1H, J ) 8.5 Hz), 7.74 (d, 1H, J ) 8.5 Hz), 7.78 (s, 1H), 8.11
(s, 1H), 13.18 (s, 1H, -NH). 13C NMR (DMSO-d6, δ, ppm) 112.2
(CH), 118.9 (C), 121.3 (C), 121.9 (CH), 122.9 (CH), 133.3 (CH),
140.1 (C).
7-Chloroindazole (28)32 was obtained in 74% yield by method
A and 84% yield by method B: 1H NMR (CDCl3, δ, ppm) 7.12 (t,
1H, J ) 7.9 Hz), 7.38 (d, 1H, J ) 7.5 Hz), 7.66 (d, 1H, J ) 7.9
Hz), 8.12 (s, 1H).
6-Methoxyindazole (29)6 was obtained in 72% yield by method
A and in 69% yield by method B: 1H NMR (CDCl3, δ, ppm) 3.86
Reaction of Bromofluorobenzaldehyde Benzylhydrazone 16
with Hydrazine. Hydrazine (98%, 1 mL) was added to a solution
of benzylhydrazone 16 (0.31 g, 1 mmol) in THF (1 mL). The
reaction mixture was refluxed for 15 h and cooled to room
temperature.
A 10:1 ratio of bromoindazole 3 and 1-benzylbromoindazole 17
was determined by HPLC methodology.
1-Benzyl-4-bromoindazole (17). A solution of bromoindazole
3 (1.0 g, 5 mmol), benzylbromide (0.9 g, 5.5 mmol), and potassium
tert-butoxide (0.59 g, 5.3 mmol) in DMF (5 mL) was mixed at 25
°C for 1 h. The mixture was diluted with heptane (10 mL) and
water (20 mL). The organic layer was separated, washed with
potassium dihydrogen phosphate solution (10% in water, 10 mL),
and concentrated in vacuo. The resulting 55:45 mixture of 1- and
2-benzylated indazoles was separated by column chromatography
on silica gel eluting with 5:1 heptane-ethyl acetate; the 1-N isomer
eluted last. Concentration of the desired fractions gave benzylbro-
moindazole 17 (0.57 g, 40%): 1H NMR (CDCl3, δ, ppm) 5.56 (s,
2 H), 7.10-7.18 (m, 3H), 7.23-7.32 (m, 5H), 8.04 (s, 1H). 13C
NMR (CDCl3, δ, ppm) 53.51 (CH2), 108.3 (CH), 114.5 (C), 123.24
(CH), 125. 2 (C), 126.8 (2C, CH), 126.9 (CH),128.5 (2 C, CH),
(30) Suschitzky, H. J. Chem. Soc. 1955, 4026-4027.
(31) Boulton, B. E.; Coller, B. A. W. Aust. J. Chem. 1974, 27, 2343-
2347.
(32) Ruchardt, C.; Hassmann, V. Synthesis 1955, 375.
J. Org. Chem, Vol. 71, No. 21, 2006 8171

Lukin et al.
133.2 (CH), 136.0 (C), 139.7 (C). Anal. Calcd for C14H11BrN2: C,
58.56; H, 3.86; N, 9.76. Found: C, 58.63; H, 3.73; N, 9.41.
2-Bromo-6-fluorobenzaldehyde O-Methyloxime (35). The
oxime solution was prepared according to the above method B. It
was concentrated in vacuo, and the residue was chromatographed
on silica gel (eluent 10:1 heptane-ethyl acetate) to give pure oxime
For the E-isomer (36b): 1H NMR (CDCl3, δ, ppm) 4.02 (s, 3H),
6.93-7.09 (m, 1H), 7.17-7.31 (m, 2H), 8.32 (s, 1H). 13C NMR
(CDCl3, δ, ppm) 62.5 (CH3), 114.7 (d, CH, J ) 23 Hz), 118.7 (d,
C, J ) 14 Hz), 125.4 (CH), 130.2 (d, CH, J ) 9.0 Hz), 134.5 (C),
142.1 (CH), 160.3 (d, C, J ) 257 Hz). Anal. Calcd for C8H7-
ClFNO: C, 51.22; H, 3.76; N, 7.47. Found: C, 51.40; H, 3.86; N,
7.30.
1
35 as a 25:75 mixture of Z/E isomers as determined by H NMR.
Anal. Calcd for C8H7BrFNO: C, 41.41; H, 3.04; N, 6.04. Found:
C, 41.44; H, 2.69; N, 6.07. The E-isomer (35b, E/Z > 95 : 5) was
obtained by crystallization of the mixture from pentane at 0 °C:
1H NMR (CDCl3, δ, ppm) 4.02 (s, 3H), 7.08 (m, 1 Hz), 7.17 (dt,
1H, J ) 5.4, 8.2 Hz), 7.40 (d, 1H, J ) 7.9 Hz), 8.28 (s, 1H). 13C
NMR (CDCl3, δ, ppm) 62.5 (CH3), 115.4 (d, CH, J ) 22.2 Hz),
120.1 (d, C, J ) 14.5 Hz), 123.9 (C), 128.6 (CH), 130.6 (d, CH, J
) 9.4 Hz), 144.0 (CH), 160.1 (d, C, J ) 257 Hz). For Z-isomer
35a: 1H NMR (CDCl3, δ, ppm) 3.95 (s, 3H), 7.05 (m, 1H), 7.20
(dt, 1H, J ) 5.8, 7.9 Hz), 7.36 (d, 1H, J ) 7.9 Hz), 8.28 (s, 1H).
13C NMR (CDCl3, δ, ppm) 62.5 (CH3), 114.4 (d, CH, J ) 22 Hz),
121.8 (d, C, J ) 14.5 Hz), 122.1 (C), 127.8 (CH), 130.9 (d, CH, J
) 9.0 Hz), 140.0 (CH), 159.0 (d, C, J ) 254 Hz).
2-Chloro-6-hydrazidobenzonitrile (38). Hydrazine (98%, 5 mL)
was added over 15 min to a solution of 2-chloro-6-fluorobenzonitrile
(0.78 g, 5 mmol) in THF (5 mL) while maintaining the internal
temperature below 30 °C. After an additional 0.5 h at room
temperature the THF layer was separated and concentrated to
dryness in vacuo maintaining the internal temperature below 30
°C to give hydrazide 38 (0.75 g, 90%): 1H NMR (DMSO-d6, δ,
ppm) 4.37 (s, 2 H), 6.73 (d, 1H, J ) 7.7 Hz), 7.17 (d, 1H, J ) 8.6
Hz), 7.38 (t, 1H, J ) 8.3 Hz), 7.64 (s, 1H). 13C NMR (DMSO-d6,
δ, ppm) 91.9 (C), 110.2 (CH), 114.76 (C), 115.6 (CH), 134.0 (CH),
134.7 (C), 155. 1 (C). Anal. Calcd for C7H6ClN3: C, 50.17; H,
3.61; N, 25.07. Found: C, 49.78; H, 3.54; N, 24.97.
2-Chloro-6-fluorobenzaldehyde O-Methyloxime (36). The
oxime solution was prepared according to the method B. It was
concentrated in vacuo, and the residue was chromatographed on
silica gel (eluent 10:1 heptane-ethyl acetate) to give pure oxime
Heating of the above reaction mixture to 75 °C for 1 h resulted
in the quantitative conversion of intermediate 38 into aminoinda-
zole 34b, as determined by HPLC methodology.
1
36 as a 22:78 mixture of Z/E isomers as determined by H NMR.
JO0613784
8172 J. Org. Chem., Vol. 71, No. 21, 2006