A novel synthesis of 2-aryl-2H-indazoles via a palladium-catalyzed intramolecular amination reaction.

Article abstract of DOI:10.1021/ol990409x

[reaction: see text] A variety of 2-aryl-2H-indazoles were synthesized by the palladium-catalyzed intramolecular amination of the corresponding N-aryl-N(o-bromobenzyl)hydrazines. Of several sets of reaction conditions surveyed, the combination of Pd(OAc)2

Full text of DOI:10.1021/ol990409x

ORGANIC
LETTERS
2000
Vol. 2, No. 4
519-521
A Novel Synthesis of
2-Aryl-2H-indazoles via a
Palladium-Catalyzed Intramolecular
Amination Reaction†
Jinhua J. Song* and Nathan K. Yee
Department of Chemical DeVelopment, Boehringer Ingelheim Pharmaceuticals, Inc.,
900 Old Ridgebury Road, P.O. Box 368, Ridgefield, Connecticut 06877-0368
jsong@rdg.boehringer-ingelheim.com
Received December 21, 1999
ABSTRACT
A variety of 2-aryl-2H-indazoles were synthesized by the palladium-catalyzed intramolecular amination of the corresponding N-aryl-N-(o-
bromobenzyl)hydrazines. Of several sets of reaction conditions surveyed, the combination of Pd(OAc)2/dppf/tBuONa gave the best results.
This method applies to a wide scope of substrates containing electron-donating and electron-withdrawing substituents.
The indazole nucleus is a pharmaceutically important
structure1 and constitutes the key subunit in many drug
substances with a broad range of pharmacological activities
including antiinflammatory,2 antitumor,3 anti-HIV,4 antide-
pressant,5 and contraceptive activities.6 However, there is still
a lack of general and efficient methodologies for the synthesis
of N-substituted indazoles (Figure 1).1
of N(1) and N(2) regioisomers with poor selectivities. The
most widely employed method for the construction of
N-substituted indazoles involves the creation of N(1)-N(2)
bond by treating o-nitrobenzylamines with Sn, Zn, or Fe in
acidic medium9 or by treating (o-nitrobenzylidene)amines
10
with P(OEt)3 or PdCl2(PPh3)2/SnCl2/CO(g).11 In a recent
(1) Elguero, J. In ComprehensiVe Heterocyclic Chemistry; Katritzky, A.
R., Rees, C. W., Eds.; Pergamon Press: New York, 1984; Vol. 5, p 167.
(2) (a) Bistochi, G. A.; De Meo, G.; Pedini, M.; Ricci, A.; Brouilhet,
H.; Bucherie, S.; Rabaud, M.; Jacquignon, P. Farmaco Ed. Sci. 1981, 36,
315. (b) Picciola, G.; Ravenna, F.; Carenini, G.; Gentili, P.; Riva, M.
Farmaco Ed. Sci. 1981, 36, 1037.
(3) Keppler, B. K.; Hartmann, M. Met.-Based Drugs 1994, 1 (2-3), 145.
(4) (a) Sun, J.-H.; Teleha, C. A.; Yan, J.-S.; Rodgers, J. D.; Nugiel, D.
A. J. Org. Chem. 1997, 62, 5627. (b) 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. BioMed. Chem. Lett. 1996,
6, 2919.
(5) Ykeda, Y.; Takano, N.; Matsushita, H.; Shiraki, Y.; Koide, T.;
Nagashima, R.; Fujimura, Y.; Shindo, M.; Suzuki, S.; Iwasaki, T. Arzneim.-
Forsch. 1979, 29, 511.
Figure 1.
(6) Corsi, G.; Palazzo, G.; Germani, C.; Barcellona, P. S.; Silvestrini,
B. J. Med. Chem. 1976, 19, 778.
(7) (a) Lopez-Alvarado, P.; Avendano, C.; Menendez, J. C. J. Org. Chem.
1995, 60, 5678. (b) Lam, P. Y. S.; Clark, C. G.; Saubern, S.; Adams, J.;
Winters, M. P.; Chan, D. M. T.; Combs, A. Tetrahedron Lett. 1998, 39,
2941. (c) Yu. Fedorov, A.; Finet, J. Tetradedron Lett. 1999, 2747.
(8) Claramunt, R. M.; Elguero, J.; Garceran, R. Heterocycles 1985, 2895.
Attempts to synthesize N-substituted indazoles by direct
N-arylation7 or N-alkylation8 inevitably yielded a mixture
† Dedicated to Professor Dietmar Seyferth on the occasion of his 71st
birthday for his more than four-decade excellence in chemical research.
10.1021/ol990409x CCC: $19.00 © 2000 American Chemical Society
Published on Web 01/28/2000

report,12 reduction of o-nitrobenzylamines and subsequent
cyclization to 2-substituted indazoles were achieved by an
electrochemical method. Certain N-substituted indazoles have
been prepared via intramolecular N(2)-C(3) bond forma-
tion13 and also by thermal or photolytic decomposition of
an appropriate precursor.14 All of these existing methods
require the use of either forcing reaction conditions or special
equipment, which has severely limited their applications. In
this Letter, we wish to describe a novel synthesis of 2-aryl-
2H-indazoles through the creation of the N(1)-C(7a) bond
via a palladium-catalyzed intramolecular amination reaction.
Palladium-catalyzed sp2-carbon-nitrogen bond-forming
reactions have proven to be a valuable synthetic method and
found wide applications in organic synthesis.15 Intramolecular
variant of this reaction has been utilized to construct
indoline16 and oxindole derivatives.17 During the course of
our research on the synthesis of N-substituted indazoles, we
proposed that the cyclization of N-aryl-N-(o-bromobenzyl)-
hydrazines such as A (Scheme 1) should give the intermedi-
Table 1. Optimization of Solvent, Ligand, and Base in
Palladium-Catalyzed Intramolecular Amination
Scheme 1
modified literature procedure,18 was used to define the
reaction conditions for the amination/oxidation sequence.
When compound 1a was subjected to the conditions of
Pd(OAc)2/(R)-BINAP/t-BuONa at 90 °C for 15 h in toluene,
the desired 2-(p-tolyl)-2H-indazole 2a was directly obtained
in ∼22% yield. Interestingly, the anticipated intermediate
(B) was not observed under these reaction conditions.
Apparently, the intermediate B was dehydrogenated either
in situ or during the isolation. As a matter of fact, it has
been recorded in the literature that dihydroindazoles, which
were produced by electrochemical methods, are prone to air
oxidation to generate indazoles.12 However, the nature of
the oxidation in the present case is still not clearly understood
and is a subject of further investigation.19
ate dihydroindazoles (B) which, upon oxidation, would
furnish the desired 2-aryl-2H-indazole derivatives (C).
In a preliminary study, N-(o-bromobenzyl)-N-(p-tolyl)-
hydrazine (1a, Table 1), which was readily prepared by a
(9) (a) Paal, C.; Krecke, Fr. Chem. Ber. 1890, 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, Cartrin,
A. M.; McCubbin, Q. J. Aust. J. Chem. 1995, 48, 2023.
(10) (a) Cadogan, J. I. G.; Cameron-Wood, M.; Mackie, R. K.; Searle,
R. J. G. J. Chem. Soc. 1965, 4831. (b) Armour, M. A.; Cadogan, J. I. G.;
Grace, D. S. B. J. Chem. Soc., Perkin Trans. 2 1975, 1185. (c) Cadogan,
J. I. G.; Mackie, R. K. Org. Synth. 1968, 48, 113.
Further optimization of the reaction conditions revealed
20
(11) Akazome, M.; Kondo, T.; Watanabe, Y. J. Org. Chem. 1994, 59,
3375.
that the use of dppf as the ligand gave superior results
than those with BINAP. Both toluene and dioxane were
suitable for this reaction, but the former seemed to give
slightly better yields. It was found that sodium tert-butoxide
was a more effective base than cesium carbonate for the
amination. Attempts to use the less expensive dppp20 as the
ligand led to a decrease in the yield. It was also noted that
the use of PdCl2/PPh3 for the cyclization afforded the product
(12) Frontana-Uribe, B. A.; Moinet, C. Tetrahedron 1998, 54, 3197.
(13) (a) Alberti, A.; Bedogni, N.; Benaglia, M.; Leardini, R.; Nanni, D.;
Pedulli, G. F.; Tundo, A.; Zanardi, G. J. Org. Chem. 1992, 57, 607. (b)
Davies, R. R. J. Chem. Soc. 1955, 2412.
(14) (a) Ardakani, M. A.; Smalley, R. K.; Smith, R. H. J. Chem. Soc.,
Perkin Trans. 1 1983, 2501. (b) Shibata, K.; Mimura, T.; Matsui, M.;
Sugiura, T.; Minoura, H. J. Chem. Soc., Chem. Commun. 1988, 1318. (c)
Dyall, L. K.; Holmes, A. Aust. J. Chem. 1988, 41, 1677. (d) Buscemi, S.;
Vivona, N. J. Org. Chem. 1996, 61, 8397. (e) Soos, T.; Hajos, Gy.; Messmer,
A. J. Org. Chem. 1997, 62, 1136.
(15) (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.
(16) (a) Wolfe, J. P.; Rennels, R. A.; Buchwald, S. L. Tetrahedron 1996,
52, 7525. (b) Yang, B. H.; Buchwald, S. L. Org. Lett. 1999, 1, 35.
(17) Shaughnessy, K. H.; Hamann, B. C.; Hartwig, J. F. J. Org. Chem.
1998, 63, 6546.
(18) (a) Lerch, U.; Konig, J. Synthesis 1983, 157. (b) See Supporting
Information for the modified experimental procedures.
(19) More experiments need to be conducted to determine whether the
oxidation occurred with the exposure to the air or through disproportionation.
(20) Ligand abbreviations: dppf ) 1,1′-bis(diphenylphosphino)ferrocene;
dppp ) 1,3-bis(diphenylphosphino)propane; dba ) dibenzylideneacetone.
520
Org. Lett., Vol. 2, No. 4, 2000

in ∼20% yield. Finally, the control experiments clearly
indicated that the cyclization did not proceed without Pd(0)
catalysis.
Table 2. Indazole Synthesis via a Palladium-Catalyzed
Intramolecular Amination Reaction
To explore the scope of this transformation, a series of
cyclization precursors (1a-1j, Table 2) were prepared by
the selective benzylation of various arylhydrazines.18 The
cyclizations were carried out using the reaction conditions
of [Pd(OAc)2/dppf/t-BuONa/toluene/90 °C].21 In all cases
examined, starting materials were completely consumed and
the desired 2-aryl-2H-indazoles (2a-2j) were readily ob-
tained in moderate to good yields. The major byproduct in
this reaction was identified to be the debromonated starting
material (10-20%). As can be seen from the table, the
catalytic system is equally effective for electron-rich and
electron-deficient substrates. The cyclized products are
diversely functionalized and amenable to further structural
modifications. While a great deal of mechanistic work awaits
to be conducted on this reaction sequence, we believe that
the reaction proceeds through the initial Pd(0) catalyzed sp2-
C-N bond formation followed by the spontaneous dehy-
drogenation to yield the 2-aryl-2H-indazoles.
In summary, we have demonstrated that the selective
alkylation of aryl hydrazines followed by the palladium-
catalyzed intramolecular amination and spontaneous aroma-
tization is an efficient strategy for the facile synthesis of a
variety of 2-aryl-2H-indazoles. It represents the first general
method by which the 2-aryl-2H-indazoles are constructed
through the creation of the N(1)-C(7a) bond. This method
applies to a wide scope of substrates and is tolerant of a
range of functional groups. Extensions of this methodology
to the synthesis of other related compounds are under
investigation and will be reported in due course.
Supporting Information Available: Representative ex-
1
perimental procedures for the synthesis of 1a-1j, H and
13C NMR data for 1a-1j, 2e, and 2i, and characterization
1
data including the reproduction of the H NMR spectra for
compounds 2d, 2g, 2h, and 2j. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL990409X
(21) Representative procedure for the synthesis of 2-aryl-2H-inda-
zoles: 5-fluoro-2-(4-methoxyphenyl)-2H-indazole (2g): To a solution of
the N-(2-bromo-5-fluorobenzyl)-N-(4-methoxyphenyl)hydrazine (325.2 mg,
1.0 mmol) in anhydrous toluene (3.5 mL) in a pressure tube were added
Pd(OAc)2 (11.2 mg, 0.05 mmol), dppf (41.6 mg, 0.075 mmol), and t-BuONa
(144.2 mg, 1.5 mmol). Then the pressure tube was filled with Ar and closed.
The reaction was heated at 90 °C for 15 h and filtered through a pad of
silica gel (50% ether/hexanes). After the removal of the volatiles, the residue
was purified by flash chromatography on silica (5-10% ether/hexanes) to
provide the desired product 2g as white crystals (137.0 mg, 52%): 1H NMR
(400 MHz, CDCl3) δ 8.28 (s, 1H), 7.79-7.73 (m, 3H), 7.27 (dd, J ) 2.36,
11.5 Hz, 1H), 7.11 (ddd, J ) 2.52, 9.40, 9.40 Hz, 1H), 7.03 (m, 2H), 3.88
(s, 3H); 13C NMR (100 MHz, CDCl3) δ 158.6 (d, JC-F ) 238.6 Hz), 159.4,
147.0, 134.0, 122.3, 121.9 (d, JC-F ) 11.7 Hz), 120.3 (d, JC-F ) 8.4 Hz),
119.8 (d, JC-F ) 9.7 Hz), 118.0 (d, JC-F ) 28.8 Hz), 114.7, 102.6 (d, JC-F
) 24.2 Hz), 55.6; mp 137.6-138.5 °C. Anal. Calcd for C14H11FN2O: C,
69.41; H, 4.58; N, 11.56. Found: C, 69.21; H, 4.46; N, 11.59.
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