Regioselective synthesis of 1-alkyl- Or 1-aryl-1H-indazoles via copper-catalyzed cyclizations of 2-haloarylcarbonylic compounds

Article abstract of DOI:10.1021/ol062890e

A general method for the one-step regioselective synthesis of 1-alkyl- or 1-aryl-1H-indazoles from ortho-halogenated alkanoylphenones, benzophenones, and arylcarboxylic acids, via copper-catalyzed amination, was developed by using 0.2% mol of CuO in the p

Full text of DOI:10.1021/ol062890e

ORGANIC
LETTERS
2007
Vol. 9, No. 3
525-528
Regioselective Synthesis of 1-Alkyl- or
1-Aryl-1H-indazoles via
Copper-Catalyzed Cyclizations of
2-Haloarylcarbonylic Compounds
Dolores Vin˜a, Esther del Olmo,* Jose´ L. Lo´pez-Pe´rez, and Arturo San Feliciano
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, CIETUS,
Campus Unamuno, 37007 Salamanca, Spain
olmo@usal.es
Received November 29, 2006
ABSTRACT
A general method for the one-step regioselective synthesis of 1-alkyl- or 1-aryl-1H-indazoles from ortho-halogenated alkanoylphenones,
benzophenones, and arylcarboxylic acids, via copper-catalyzed amination, was developed by using 0.2% mol of CuO in the presence of
K2CO3. The reaction involves amination followed by intramolecular dehydration. Different functionalized alkyl aryl ketones, diaryl ketones, and
benzoic acid derivatives were efficiently coupled with several hydrazines. Ligands commonly employed as catalysts for intermolecular amination
were shown to be ineffective for this cyclization.
Indazoles constitute an important class of organic compounds
which have found various biomedical applications in the anti-
inflamatory, antitumor, anti-HIV, antidepressant, and con-
traceptive therapeutic areas.1 The most widely employed
method for the construction N-substituted indazoles involves
the creation of the N1-N2 bond by intramolecular reduction
of o-nitrobenzylamines with Sn, Zn, or Fe in acidic medium2
and, most recently, by Pd-catalyzed cyclization of aryl-
hydrazones or arylhydrazines of 2-halobenzaldehyde.3 How-
ever, the formation of hydrazones from alkyl aryl ketones is
difficult. This requires a very long reaction time, and often
a low conversion rate is attained.4 Despite significant
improvements in the Pd-catalyzed N-arylation of amines,5
some limitations still remain. These include the reactivity
of some functional groups in presence of the amine and base
required in C-N coupling protocols.6 Moreover, the high
cost of palladium invites the search toward less expensive
alternatives.
Both the Ullmann reaction (copper-catalyzed N-arylation
of amines)7 and the Goldberg reaction (copper-catalyzed
N-arylation of amides)8 predate the Pd-catalyzed amination
methodology by several decades. However, the use of high
temperatures, poor substrate scope, and the need for stoi-
(1) (a) Picciola, G.; Ravenna, F.; Carenini, G.; Gentili, P.; Riva, M.
Farmaco 1981, 36, 1037. (b) Keppler, B. K.; Hartmann, M. Met. Based
Drugs 1994, 1, 145. (c) Rodgers, J. D.; Johnson, B. L.; Wang, H.; Greenberg,
R. A.; Erickson-Viitanen, S.; Klabe, R. M.; Cordova, B. C.; Rayner, M.
M.; Lam, G. N.; Chang, C.-H. Bioorg. Med. Chem. Lett. 1996, 6, 2919. (d)
Ykeda, Y.; Takano, N.; Matsushita, H.; Shiraki, Y.; Koide, T.; Nagashima,
R.; Fujimura, Y.; Shindo, M.; Suzuki, S.; Iwasaki, T. Arzneimittel.-Forsch.
1979, 29, 511. (e) Corsi, G.; Palazzo, G.; Germani, C.; Barcellona, P. S.;
Silvestrini, B. J. Med. Chem. 1976, 19, 778.
(2) (a) Paal, C.; Krecke, F. Chem. Ber. 1980, 23, 2640. (b) Paal, C. Chem.
Ber. 1891, 24, 959. (c) Busch, V.; Hartman, P. J. Prakt Chem. 1895, 2,
404. (d) Campi, E. M.; Habsuda, J.; Jackson, W. R.; Jonasson, C. A. M.;
McCubbin, Q. J. Aust. J. Chem. 1995, 48, 2023.
(4) Lebedev, A. Y.; Khartulyari, A. S.; Voskoboynikov, A. Z. J. Org.
Chem. 2005, 70, 596.
(5) (a) Wolfe, J. P.; Wagaw, S.; Marcoux, J.-F.; Buchwald, S. L. Acc.
Chem. Res. 1998, 31, 805. (b) Hartwig, J. F. Angew. Chem., Int. Ed. 1998,
37, 2046. (c) Yang, B. H.; Buchwald, S. L. J. Organomet. Chem. 1999,
576, 125. (d) Muci, A. R.; Buchwald, S. L. Top. Curr. Chem. 2002, 219,
133.
(6) (a) Batch, A.; Dodd, R. H. J. Org. Chem. 1998, 63, 872. (b) Deng,
B.-L.; Lepoivre, J. A.; Lemie`re, G. Eur. J. Org. Chem. 1999, 2638.
(7) Ullmann, F. Ber. Dtsch. Chem. Ges. 1903, 36, 2382.
(8) Goldberg, I. Ber. Dtsch. Chem. Ges. 1906, 39, 1691.
(3) (a) Song, J. J.; Yee, N. K. Org. Lett. 2000, 2, 519. (b) Song, J. J.;
Yee, N. K. Tetrahedron Lett. 2001, 42, 2937.
10.1021/ol062890e CCC: $37.00
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Published on Web 01/10/2007

chiometric amounts of the copper reagent have limited the
usefulness of these reactions. In recent years, a milder
Ullmann-type methodology (CuI, 1,10-phenanthroline, and
Cs2CO3) for the N-arylation of hydrazides has been reported.
Although C-N coupling of N-Boc hydrazine with para- and
meta-substituted aryl iodides usually yields regioselectively
the desired N-arylated products, a reversal in regioselectivity
has been observed for the arylation of benzoic acid hydrazide
with ortho-substituted aryl iodides, providing the N′-arylated
products.9
In view of these antecedents, aiming to develop an easier
and less expensive route to a library of potential antimicrobial
indazoles, we became interested into searching whether a
strategy based on arylation of alkyl (aryl) hydrazines with
ortho-carbonylated aryl halides, followed by intramolecular
cyclization, would be effective in obtaining the desired
indazoles.
Changing CuO to the more expensive Cu2O or Cu/CuO11
as catalysts gave similar results. Then, the above-mentioned
conditions [substrate/hydrazine derivative/CuO/K2CO3],12
with control of the reaction temperature (110-200 °C), were
subsequently applied in all of the reactions.
To explore the scope of this methodology, first, the
reaction of a number of haloaryl ketones with methylhydra-
zine was assayed (Table 1).
In all of the examined cases, the desired 1-methyl-1H-
indazoles (2a-g) were readily obtained in moderate to good
yields. Reaction yields were not too different for chloro- and
fluoroacetophenones (1a/1b). Acetophenones and benzo-
phenones bearing electron-donating (methoxy, amino) sub-
stituents at the para position relative to the halogen gave
Table 1. CuO-Catalyzed Coupling of 2-Haloarylketones with
In this study, we describe our preliminary results in
developing a new regioselective procedure leading, through
a convenient one-step route, to a range of 1-alkyl- or 1-aryl-
1H-indazoles displaying varied functionalizations. This
methodology is based on the CuO-catalyzed reaction between
N-alkyl- or N-arylhydrazine with 2-haloaryl ketones and
2-halobenzoic acids, followed by intramolecular dehydration
(Scheme 1).
Methylhydrazine
Scheme 1
The effect of the base on the coupling reaction was also
examined. In general, the use of K2CO3 gave yields superior
to those achieved with Cs2CO3. Further optimization of the
reaction conditions revealed that the use of ligands as 1,10-
phenantroline and N,N′-dimethylethylenediamine, commonly
employed for intermolecular amination,10 were shown to be
ineffective for cyclization.
In preliminary experiments, we observed that the reaction
of 2-chloroacetophenone with methylhydrazine could be
performed in the presence of CuO and anhydrous K2CO3,
affording 1,3-dimethyl-1H-indazole (2a) in 54% yield, after
20 h at 110 °C in a sealed tube. Attempts to carry out the
reaction in a conventional flask were unsuccessful, leading
only to the corresponding unstable hydrazone.
1
a All new compounds were characterized by H/13C NMR and HRMS
(9) Wolter, M.; Klapars, A.; Buchwald, S. L. Org. Lett. 2001, 3, 3803.
(10) Klapars, A.; Huang, X.; Buchwald, S. L. J. Am. Chem. Soc. 2002,
124, 7421.
data. b After chromatography. c Modified reactions conditions: DMA/THF.
526
Org. Lett., Vol. 9, No. 3, 2007

Table 2. CuO-Catalyzed Coupling of 2-Haloarylcarboxylic
Table 3. CuO-Catalyzed Coupling of 2-Fluoroarylketones with
Acids with Methylhydrazine
Alkyl- and Arylhydrazines
a All new compounds were characterized by 1H/13C NMR andHRMS
data. b After chromatography.
enough in methylhydrazine; therefore, we used other solvents
(benzene, THF, n-butyl alcohol) for improving the reaction
rate. The best results were achieved in benzene. The presence
of 1,10-phenanthroline, often used as ligand in this type of
reactions, failed to yield the desired product. The best result
for the series of 2-haloarylcarboxylic acids was obtained with
nicotinic acid, easily soluble in methylhydrazine. In the
presence of enough K2CO3, salt formation occurred and the
yield of the desired compound decreased, whereas lowering
the amount of the base led to improved yields. Additionally,
dehalogenation of the starting material ocurred in several
cases (5a,c).
To explore further the generality of this practical approach,
condensations of o-halobenzoic acids 5a-e and that of
2-chloronicotinic acid (7) with methylhydrazine were per-
formed, using the best conditions found (Table 2). The
starting halobenzoic acids included in Table 2 were selected
for evaluating the influence of the electrostatic nature of
additional substituents on the reaction.
Similar to those results found for acetophenones, in
comparison with 2-chlorobenzoic acid itself, the additional
presence of the electron-withdrawing 5-chloro group (5d)
led to a reduced indazole yield, whereas the electron-donating
5-methoxy substituent (5c) and the 5-nitro group (5e), being
reduced to the corresponding amine (6e), increased the
indazole formation. It is worthy to note that the presence of
the nitrogen atom at the R position of the chlorine atom to
be substituted, practically doubled the conversion rate and
yield.
1
a All new compounds were characterized by H/13C NMR and HRMS
data. b After chromatography. c Benzene was used as solvent.
higher indazole yields than that provided by the p-chloro-
substituted compound 1f. The high yield observed in the
conversion of the nitro derivative 1g into the corresponding
the amine 2g would be explained by the reduction of the
nitro group, prior to the condensation, due to hydrazine
excess. In the cases of 1a, 1d, and 1f, the starting substrate
was recovered unchanged and further refluxing resulted in
a decrease of the yield due to the formation of byproducts.
In the case of compound 3, under the above-mentioned
conditions, a complex crude mixture was obtained. However,
in the absence of catalyst and using DMA/THF as solvent,13
a fairly high yield of compound 4 was achieved (Table 1).
We then attempted to extend the method to 2-haloaryl
acids (Table 2). Under the above-mentioned conditions,
2-chlorobenzoic acid or 2-bromobenzoic acid was not soluble
(11) Wolf, C.; Liu, S.; Mei, X.; August, A. T.; Cusinur, K. D. J. Org.
Chem. 2006, 71, 3270.
(12) Representative Procedure for the Synthesis of 1-Alkyl-1H-
indazoles: 1,3-Dimethyl-1H-indazole (2a). An oven-dried reseable Schlenk
tube was charged with CuO (4 mg, 2 mol %) and K2CO3 (150 mg, 1.5
mmol), evacuated, and back-filled with argon. 2-Chloroacetophenone (154
mg, 0.13 mL, 1 mmol) and methylhydrazine (0.35 mL, 6.4 mmol) were
added under argon. The Schlenk tube was sealed, and the reaction was
stirred magnetically at 110 °C for 20 h. The resulting suspension was cooled
to room temperature, filtered, diluted with ethyl acetate, and washed with
water. The organic phase was concentrated. Purification of the residue by
flash cromatography on silica gel (hexane/EtOAc, 95:5) gave the desired
product.
Finally, we turned our attention to the influence of the
hydrazine used in the reaction. We carried out the condensa-
tion with representative alkyl and arylhydrazines. The results
(Table 3), showed that this method can be extended to other
(13) Zhang, L.; Meier, W. E.; Watson, E. J.; Gibson, E. P. Tetrahedron
Lett. 1994, 35, 3675.
Org. Lett., Vol. 9, No. 3, 2007
527

hydrazines, with similar yields, by changing only the reaction
temperature.
the scope of the method to other aryl halides (esters, amides)
are in progress in our laboratory.
In summary, we have developed a general methodology
for synthesis of indazoles, based on the N-arylation of alkyl-
and arylhydrazines, followed by intramolecular dehydration
in the presence of a common and cheap catalyst. It results
as an efficient strategy for the easy synthesis of a variety
1-alkyl- or 1-aryl-1H-indazoles, that can be extended as well
to the preparation of pyrazolo[3,4-b]pyridines and presum-
ably to that of other pyrazolo-fused polyheterocyclic systems.
This method applies to a variety scope of substrates and is
tolerant with a range of functional groups. Efforts to expand
Acknowledgment. Financial support came from the
Ministerio de Educacio´n y Ciencia (Spain), Project AGL2005-
02-168/GAN, and Junta de Castilla y Leo´n (Spain), Project
SAO30A06.
Supporting Information Available: Detailed experi-
mental procedures and characterization data for the reaction
products included in this paper. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL062890E
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