Regioselective one-pot, three-component synthesis of substituted 2H-indazoles from 2-nitroarylaldehyde, alkyne and amine catalyzed by the CuBr/Zn(OTf)₂ system

Abstract

3-(Arylethynyl)-2H-indazoles can be effectively synthesized in one-pot using 2-nitroarylaldehydes, primary amines and alkynes co-catalyzed by copper(I) bromide and zinc(II) triflate. This method has a broad substrate scope with high to medium tolerance for a variety of functional groups.

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Indazoles are important structural units found in many biologically active molecules.¹ The isomeric form of indazoles, 2H-indazoles, are gaining considerable interest due to their anticancer,² imidazole I₂ receptor,³ 5-HT_1A receptor,⁴ estrogen receptor β,⁵ and antiangiogenic activities.⁶ There are several methods for the synthesis of indazoles, but most of them are restricted to the thermodynamically favoured 1H-indazole or mixtures of 1H- and 2H-indazoles.⁷ Methods for the regioselective synthesis of 2H-indazoles are limited due to the difficulty in their preparation. Therefore, selective preparation of 2H-indazoles remains challenging task in organic chemistry. Recently, several synthetic routes to 2H-indazoles have been developed,⁸ but considering the bioactivities of 2N-substituted indazoles,^2b,5,6,9 the development of new strategies for the general and efficient synthesis of highly substituted 2H-indazoles is needed. Although there are several methods for the synthesis of 2N-substituted 2H-indazoles, methods for the direct synthesis of 2N,3C-substituted 2H-indazoles are rare.^8a,c,g,j,10 These methods suffer from drawbacks, such as multistep synthesis,^8c,j,10d low selectivity,^10a low yields and formation of side products.^10b Multicomponent reactions are gaining importance in heterocyclic chemistry due to their ability to form a series of bonds in a single step.¹¹ Herein, we report a one-pot direct synthesis of 2,3-disubstituted 2H-indazoles using 2-nitroarylaldehydes, amines and alkynes co-catalyzed by CuBr and Zn(OTf)₂ in moderate to good yields.

Initially, we treated the 2-nitrobenzaldehyde 1a, 2-(3,4-dimethoxyphenyl)ethanamine 2a, and ethynylbenzene 3a with CuBr (30 mol%) and In(OTf)₃ (10 mol%) in dry toluene at reflux and it led to the formation of 2-(3,4-dimethoxyphenethyl)-3-(phenylethynyl)-2H-indazole 4a in 40% yield (Table 1, entry 1).

Table 1 Optimization of the reaction^a

Sl. No	Cu source (mol%)	Catalyst (mol%)	Solvent	Time/h	Yield^b (%)
a Reaction conditions: aldehyde (0.5 mmol), amine (0.55 mmol), alkyne (1.0 mmol), solvent (8 mL).b Yield refers to isolated yield.c Corresponding imine was isolated.
1	CuBr (30)	In(OTf)3 (10)	Toluene	21	40
2	CuBr (30)	Sn(OTf)2 (10)	Toluene	24	50
3	CuBr (30)	Zn(OTf)2 (10)	Toluene	18	83
4	CuBr (100)	Zn(OTf)2 (10)	Toluene	18	80
5	CuBr (30)	Bi(OTf)2 (10)	Toluene	24	35
6	CuBr (30)	Ag(OTf) (10)	Toluene	24	37
7	CuBr (30)	Sc(OTf)2 (10)	Toluene	24	32
8	CuBr (30)	FeCl3 (100)	Toluene	24	33
9	CuBr (30)	ZnCl2 (100)	Toluene	24	42
10	CuBr (30)	SnCl2·2H2O (100)	Toluene	24	36
11	CuBr (30)	InCl3 (100)	Toluene	24	12
12	CuBr (30)	P(Ph)3 (100)	Toluene	24	—^c
13	CuBr (30)	P(OEt)3 (100)	Toluene	24	17
14	CuBr (30)	Zn(OTf)2 (10)	Dioxane	24	—^c
15	—	Zn(OTf)2 (10)	Toluene	24	—^c
16	CuBr (30)	—	Toluene	36	Trace
17	CuI (30)	Zn(OTf)2 (10)	Toluene	24	28
18	CuCl (30)	Zn(OTf)2 (10)	Toluene	24	63

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Similarly, under the same reaction conditions Sn(OTf)₂ gave 50% yield (entry 2). Zn(OTf)₂/CuBr system was found to be more reactive and yielded 83% (entry 3). When the amount of CuBr was increased to 1 equivalent, 80% of the product was isolated (entry 4). Other Lewis acids and copper salts were also screened and the results are shown in Table 1. It was observed that bismuth, scandium and silver triflates gave lower yields (entries 5–7). Other metal salts such as FeCl₃, ZnCl₂, SnCl₂·2H₂O and InCl₃ also found to be less effective (entries 8–11). In the case of phosphorous reagents, P(Ph)₃ produced only imine (entry 12), whereas P(OEt)₃ gave 17% of the desired product (entry 13). Reaction with CuBr/Zn(OTf)₂ in dioxane (entry 14) and Zn(OTf)₂ (entry 15) alone in toluene gave the corresponding imines, whereas CuBr alone gave trace amount of the desired product (entry 16). Other copper salts such as CuI and CuCl gave 28 and 63% yields, respectively (entries 17 and 18).

With the established optimal conditions in hand, the scope of this reaction was investigated, and the results are summarized in Table 2. 2-Nitroarylaldehydes having electron-withdrawing groups were transformed into 2H-indazoles in 60–79% yields (Table 2, entries 2–4 and 18). Acetylenes with aromatic substituents containing electron-withdrawing or electron-donating groups were transformed in 57–81% yields (Table 2, entries 7–11 and 18). On the other hand, acetylene having alkyl group (Table 2, entry 21) was unable to give desired product, but corresponding imine was recovered in 90% yield. Similarly, heterocyclic alkyne (entry 22) also gave imine in 85% yield. The scope of the reaction was also extended to primary amines. The reaction yielded moderate to good yields with variously substituted primary amines. The reaction with aromatic amines with 2-nitrobenzaldehydes and alkynes under the same reaction conditions gave quinolines.¹²

Table 2 Synthesis of 3-alkynyl-2H-indazoles^a

Entry	Product	Time/h	Yield^b (%)
a Reaction conditions: aldehyde (0.5 mmol), amine (0.55 mmol), alkyne (1.0 mmol), CuBr (30 mol%), Zn(OTf)2 (10 mol%), toluene (8 mL), reflux.b Isolated yield.c Imine was isolated in 90% yield.d Imine was isolated in 85% yield.
1		18	83
2		24	75
3		36	79
4		48	71
5		48	30
6		48	35
7		36	60
8		48	57
9		36	62
10		36	65
11		24	81
12		48	78
13		36	48
14		24	59
15		24	66
16		24	64
17		24	70
18		30	60
19		24	51
20		24	56
21		72	0^c
22		72	0^d

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The reaction is highly regioselective and only 2N-substituted product could be obtained in high purity without any regioisomeric products as determined from ¹H and ¹³C NMR analysis of crude product. The structure of the compounds was determined by X-ray analysis of compound 4a (see the ESI†).¹³

In summary, we have developed a practical and general one-pot procedure for the synthesis of 2H-indazoles from 2-nitroarylaldehydes, primary amines and alkynes catalyzed by CuBr and Zn(OTf)₂. The practical and highly versatile one-pot, three-component procedure is a novel approach for the synthesis of highly substituted 2H-indazoles. The mechanism of the reaction is not yet known. Efforts to determine the mechanism of this unusual reaction is under investigation.

Acknowledgements

RU gratefully acknowledges Council of Scientific and Industrial Research (CSIR), New Delhi for his fellowship. Authors are grateful to Council of Scientific and Industrial Research (CSIR), New Delhi, for financial support (Grant no. 02/0159/13/EMR-II). Authors are also thankful to Central Instrument Facility (CIF) of IIT Guwahati for NMR and XRD facilities.

Notes and references

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13. ESI.†.

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Footnote

† Electronic supplementary information (ESI) available: Experimental procedures, ¹H, ¹³C and HRMS spectra of all new compounds. CCDC 1008821. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c4ra10093j

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