Facile palladium-catalysed synthesis of 1-aryl-1H-indazoles from 2-bromobenzaldehydes and arylhydrazines

Abstract

2-Bromobenzaldehydes react with arylhydrazines in toluene at 100 °C in the presence of a catalytic amount of a palladium catalyst and phosphorus chelating ligands such as 1,1′-bis(diphenylphosphino)ferrocene and 1,3-bis(diphenylphosphino)propane along with NaO-t-Bu to afford 1-aryl-1H-indazoles in good yields.

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Palladium-catalysed aromatic carbon–nitrogen bond forming reaction by the cross-coupling of aryl halides (or triflates) and amines has recently had an upsurge as a useful synthetic tool.¹ Various primary, secondary and tertiary amines can be prepared by this protocol and its intramolecular version has been introduced to the synthesis of nitrogen heterocycles as an elegant synthetic alternative.¹ In connection with this report, Song et al. have reported a palladium-catalysed intramolecular amination of N-aryl-N′-(o-bromobenzyl)hydrazines leading to 1-aryl-1H-indazoles.^2–4 However, the uneasy accessibility of the starting substrates in this method, which are prepared via several steps from commercial products,⁵ precludes a straightforward approach. This led us to develop an efficient palladium-catalysed synthetic method for 1-aryl-1H-indazoles. Herein we report a successful palladium-catalysed synthesis of 1-aryl-1H-indazoles from readily available commercial substrates, 2-bromobenzaldehydes and arylhydrazines, via an intrinsic intramolecular amination.⁶

The results of several attempted cyclisations of 2-bromobenzaldehyde (1a) with phenylhydrazine (2a) are listed in Table 1 (Scheme 1). Treatment of equimolar amounts of 1a and 2a in toluene in the presence of a catalytic amount of Pd(OAc)₂ (2 mol%) and 1,3-bis(diphenylphosphino)propane (dppp) (3 mol%) along with NaO-t-Bu at 100 °C for 15 h afforded 1-phenyl-1H-indazole (3a) in 84% yield with concomitant formation of hydrazone (< 5%) by condensation between the starting substrates (run 1). The catalytic systems using Pd(OAc)₂ combined with 1,1′-bis(diphenylphosphino)ferrocene (dppf) and PdCl₂ combined with dppp were revealed to be as effective as that using Pd(OAc)₂ combined with dppp (runs 2, 3). With other phosphorus chelating ligands such as 1,1′-bis(di-i-propylphosphino)ferrocene (dipf) and (S)-(−)-BINAP, the yield of 3a was lower than that when dppp and dppf were employed (runs 4, 5), all combined with Pd(OAc)₂. However, catalytic systems such as Pd(OAc)₂–PPh₃, PdCl₂(PPh₃)₂ and Pd(PPh₃)₄ were not effective at all for the present reaction; hydrazone was mainly produced as an identifiable product (runs 6–8). As a result, among the various palladium precursors examined the systems shown in runs 1, 2 and 3 are the choices of preference for the effective formation of 3a.

Scheme 1

Table 1 Palladium-catalysed reaction of 1a with 2a under several catalytic systems^a

Run	Palladium catalysts	Ligands (mol%)	Isolated yield (%)
a Reaction conditions: 1a (1 mmol), 2a (1 mmol), palladium catalyst (2 mol%), NaO-t-Bu (2 mmol), toluene (10 ml), 100 °C, for 15 h, under argon.
1	Pd(OAc)2	dppp (3)	84
2	Pd(OAc)2	dppf (3)	84
3	PdCl2	dppp (3)	83
4	Pd(OAc)2	dipf (3)	65
5	Pd(OAc)2	(S)-(−)-BINAP (3)	69
6	Pd(OAc)2	PPh3 (6)	trace
7	PdCl2(PPh3)2	—	trace
8	Pd(PPh3)4	—	trace

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Given these results, the reactions of various 2-bromobenzaldehydes 1 and arylhydrazines 2 were screened using three sets of reaction conditions, Pd(OAc)₂–dppp (condition A), Pd(OAc)₂–dppf (condition B) and PdCl₂–dppp (condition C), and several representative results are summarised in Table 2.† The reaction of 1b–1d with 2a under conditions A–C gave the corresponding 1-phenyl-1H-indazoles (3b–3d) in 47–79% yield with minimal formation of hydrazones as identifiable side products (runs 1–5). The product yield was not significantly affected by the electronic nature of the substituent on 1. In contrast to the reaction between 1a and 2a, the product yield varied according to the employed reaction conditions (runs 1,2 and 4,5). From the reactions between 1a and various arylhydrazines (2b–2h), the corresponding 1-aryl-1H-indazoles (3e–3k) were also produced in good yields irrespective of the examined functional groups on the aromatic ring of 2 (runs 6–13). Comparing the result of runs 11 and 12 with that of two sets of reactions shown in runs (1 and 2) and (4 and 5), condition B was generally superior to condition C for the formation of 1-aryl-1H-indazoles.

Table 2 Palladium-catalysed synthesis of 3 from 1 and 2^a

Run	1	2	Conditions^b	Products	Yield (%)
a Reaction conditions: 1 (1 mmol), 2 (1 mmol), palladium catalyst (2 mol%), chelating ligand (3 mol%), NaO-t-Bu (2 mmol), toluene (10 ml), 100 °C, for 15 h, under argon. b A: Pd(OAc)2–dppp; B: Pd(OAc)2–dppf; C: PdCl2–dppp.
1	1b	2a	B	3b	79
2	1b	2a	C	3b	47
3	1c	2a	A	3c	65
4	1d	2a	B	3d	77
5	1d	2a	C	3d	51
6	1a	2b	B	3e	79
7	1a	2c	B	3f	55
8	1a	2d	B	3g	61
9	1a	2e	A	3h	78
10	1a	2f	A	3i	73
11	1a	2g	B	3j	86
12	1a	2g	C	3j	60
13	1a	2h	A	3k	86

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A plausible reaction pathway is depicted in Scheme 2. Oxidative addition of the carbon–bromide bond of hydrazone 4, initially formed in situ between 1a and 2, to Pd(0) produces an arylpalladium(II) complex 5. This is followed by intramolecular closure to give a palladacycle 6 which can reductively eliminate to afford 1-aryl-1H-indazole 3.^7,8

Scheme 2

In summary, we have demonstrated that 2-bromobenzaldehydes are cyclised with various arylhydrazines in the presence of a catalytic amount of a palladium catalyst and a phosphorus chelating ligand along with NaO-t-Bu to give 1-aryl-1H-indazoles in good yields. The present reaction is a straightforward methodology for the synthesis of 1-aryl-1H-indazoles from readily available 2-bromobenzaldehydes and arylhydrazines. Similar reaction of alkyl 2-bromoaryl ketones with arylhydrazines leading to 1,3-disubstituted indazoles is currently under investigation.

This work was supported by the Brain Korea 21 Project in 2003 and a Korea Research Foundation Grant (KRF-2002-070-C00055). C.S.C. gratefully acknowledges an MOE-KRF Research Professor Program (2001-050-D00015).

Notes and references

1. J. P. Wolfe, S. Wagaw, J.-F. Marcoux and S. L. Buchwald, Acc. Chem. Res., 1998, 31, 805; J. F. Hartwig, Angew. Chem., Int. Ed., 1998, 37, 2046; B. H. Yang and S. L. Buchwald, J. Organomet. Chem., 1999, 576, 125.
2. J. J. Song and N. K. Yee, Tetrahedron Lett., 2001, 42, 2937.
3. The same authors have also reported on palladium-catalysed synthesis of 2-aryl-2H-indazoles from N-aryl-N-(o-bromobenzyl)hydrazines under similar reaction conditions: J. J. Song and N. K. Yee, Org. Lett., 2000, 2, 519.
4. Conventional synthetic methods for indazoles: J. Elguero, Comprehensive Heterocyclic Chemistry; ed. A. R. Katritzky and C. W. Rees, Pergamon, New York, 1984, vol. 5, pp. 167–303.
5. J. Barluenga, I. Merino, S. Vina and F. Palacios, Synthesis, 1990, 398.
6. Our recent report on palladium-catalysed synthesis of N-heterocycles such as isoindolinones and β-lactams, see: C. S. Cho, J. W. Lee, D. Y. Lee, S. C. Shim and T. J. Kim, Chem. Commun., 1996, 2115; C. S. Cho, D. Y. Chu, D. Y. Lee, S. C. Shim, T. J. Kim, W. T. Lim and N. H. Heo, Synth. Commun., 1997, 27, 4141; C. S. Cho, L. H. Jiang and S. C. Shim, Synth. Commun., 1998, 28, 849; C. S. Cho, L. H. Jiang, D. Y. Lee, S. C. Shim, H. S. Lee and S.-D. Cho, J. Heterocycl. Chem., 1997, 34, 1371; C. S. Cho, X. Wu, L. H. Jiang, S. C. Shim, H.-J. Choi and T. J. Kim, J. Heterocycl. Chem., 1998, 35, 265; C. S. Cho, X. Wu, L. H. Jiang, S. C. Shim and H. R. Kim, J. Heterocycl. Chem., 1999, 36, 297; C. S. Cho, H. S. Shim, H.-J. Choi, T.-J. Kim, S. C. Shim and M. C. Kim, Tetrahedron Lett., 2000, 41, 3891; C. S. Cho, L. H. Jiang and S. C. Shim, Synth. Commun., 1999, 29, 2695.
7. A. S. Guram, R. A. Rennels and S. L. Buchwald, Angew. Chem., Int. Ed., 1995, 34, 1348.
8. Palladium-catalysed arylation of diphenylhydrazone with aryl halides is known: J. F. Hartwig, Angew. Chem., Int. Ed., 1998, 37, 2090.

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Footnote

† Typical experimental procedure: a mixture of 1a (1 mmol), 2a (1 mmol), Pd(OAc)₂ (0.02 mmol), dppp (0.03 mmol) and NaO-t-Bu (2 mmol) in dry toluene (10 ml) was placed in a pressure vessel. The system was flushed with argon and allowed to react at 100 °C for 15 h. The reaction mixture was filtered through a short silica gel column (ethyl acetate) to eliminate inorganic salts. Removal of the solvent left a crude mixture, which was separated by column chromatography (silica gel, ethyl acetate–hexane = 1 : 5) to give 3a (84%).

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