Cu(im)₂-derived Cu@N–C catalyst for one-pot synthesis of 2-substituted indoles via domino Sonogashira coupling-cyclization reactions

ABSTRACT

Cu(im)₂-derived Cu@N–C(600) catalyst has been efficiently utilized for the preparation of N-tosyl(H)−2-substituted indoles through one-pot domino Sonogashira coupling-cyclization reactions between N-tosyl(acetyl)−2-iodo anilines and aryl acetylenes. The catalytic system was heterogeneous and showed excellent functional group compatibility and could be performed well, affording the corresponding coupling products in good to excellent yields.

GRAPHICAL ABSTRACT

KEYWORDS:

• MOF-derived catalyst
• Cu@N–C
• Sonogashira coupling-cyclization
• 2-substituted indole
• heterogeneous catalyst

Introduction

Indole and its derivatives are a significant type of heterocycles as they are not only privileged scaffolds in natural products, but also as important subunits in a number of synthetic biologically active molecules due to their exceptional therapeutic efficacy in the pharmaceutical or medicinal areas (1–4). Since its initial discovery in 1866 by Baeyer and Kop while investigating the plant of indigo (5), the continued development of synthetic routes toward indoles has been a central theme in organic synthesis for over 150 years and still widely concerned nowadays. Especially over the last 40 years, the synthetic protocols for transition-metal catalyzed reactions have been extensively reported and are widely considered as the most powerful and practical alternative strategies for the construction of indole skeletons and its derivatives (1, 6–15). Among the numerous methods established for indoles synthesis, Pd- or Cu-catalyzed domino Sonogashira coupling-cyclization reactions of ortho-haloanilines with terminal/internal alkynes or 1,3-dicarbonyl compounds (β-keto esters or β-diketones) stand out as one of the most convenient approaches for the synthesis of 2-substituted or 2,3-disubsituted indoles. This is attributed to the diversity of commercially available starting materials and ease of preparation or modification (Scheme 1). Although significant improvements have been achieved by using Pd-/Cu-complexes or ‘Pd-/Cu – ligand in situ’ catalytic systems under homogenous conditions, they inherently suffer from non-recovery and non-regeneration of the catalysts, as well as the metal impurities in the final products. Therefore, from the perspective of green and sustainable chemistry, various heterogeneous catalysts have been employed to overcome the aforementioned drawbacks (16–26). Nevertheless, most of these methodologies required to use of noble metals or external ligand, or harsh conditions to complete the cyclization reactions.

Scheme 1. Pd- or Cu-catalyzed indole synthesis from 2-haloanilines and terminal/internal alkynes or 1,3-dicarbonyl compounds.

In recent years, the approaches involving the use of metal–organic frameworks (MOFs) as sacrificial templates to prepare MOF-derived carbon supported nanoparticles (NPs) and applying them as heterogeneous catalysts have received much extensive attentions (27–35). These solid materials can be easily synthesized by direct pyrolysis of pre-designed MOFs, wherein the metal cations and ligands in MOFs are converted to metal NPs (or metal oxides) and carbon matrix, respectively. Moreover, the derived composites often inherit the unique properties of their precursor MOF, including high surface area, ordered structures and high metal content. Additionally, they demonstrate enhanced tolerance to harsh reaction conditions (especially in aqueous environment and/or acidic/basic environment) and improved recyclability compared to their MOFs precursors, when utilized as the heterogeneous catalysts. Recently, we reported an efficient protocol for the synthesis of 1,4-disubstituted 1,2,3-triazoles in the mixture solvent of t-BuOH/H₂O via Cu(im)₂-derived Cu@N–C-catalyzed one-pot 1,3-dipolar cycloaddition of terminal alkynes, aryl halides, and sodium azide (36). The derived catalyst exhibited a higher efficiency with excellent yields, mild reaction conditions, and a broad range of substrate scopes than other reported methods. In addition, it can be recovered and reused at least 5 times without the significant loss of activity or alterations in its structure and morphology, and the results of metal leaching test further confirmed the heterogeneity nature of the catalyst. Based on these interesting results and in order to further expand the applicability of Cu(im)₂-derived Cu@N–C to other type of organic transformations, we describe herein the synthesis of 2-substituted indoles through heterogeneous Cu@N–C-catalyzed domino Sonogashira coupling-cyclization reactions of 2-iodoanilines with aryl terminal alkynes.

To begin our study, the heterogeneous Cu(im)₂-derived Cu@N–C were prepared and characterized following our previously reported procedure (Scheme 2) (36). Subsequently, N-tosyl-2-iodoaniline and phenyl acetylene were chosen as model substrates to optimize the reaction conditions for this domino coupling/cyclization reaction, and the results are summarized in Table 1. As expected, Cu@N–C(600) (600 represents pyrolysis temperature) exhibited the highest efficiency, affording the desired annulated product in 99% isolated yield. Other Cu@N–C, Cu(0) or copper salts resulted in lower yields, and no reaction occurred in the absence of copper catalyst (entries 1-7). An investigation of commonly used polar or nonpolar solvents showed that dimethyl sulfoxide (DMSO) was the most suitable than others (entries 8-10). Subsequently, bases were also screened, and NaHCO₃ was proved to be the best one (entries 2 and 11-16). Lowering the reaction temperature, shortening the reaction time or decreasing the catalyst loading all led to low yield of the product (entries 17-19). Finally, the optimal reaction conditions as shown in entry 2 in Table 1.

Scheme 2. Schematic illustration of the synthesis process of Cu@N-C(x).

Table 1. Optimization of the reaction conditions^a.

Entry	Catalyst	Solvent	Base	Yield (%)^b
1	Cu@N-C(400)	DMSO	NaHCO3	55
2	Cu@N-C(600)	DMSO	NaHCO3	99
3	Cu@N-C(800)	DMSO	NaHCO3	80
4	Cu	DMSO	NaHCO3	39
5	CuCl	DMSO	NaHCO3	19
6	CuSO4	DMSO	NaHCO3	74
7	–	DMSO	NaHCO3	trace
8	Cu@N-C(600)	DMF	NaHCO3	70
9	Cu@N-C(600)	NMP	NaHCO3	10
10	Cu@N-C(600)	Toluene	NaHCO3	60
11	Cu@N-C(600)	DMSO	Na2CO3	50
12	Cu@N-C(600)	DMSO	K2CO3	35
13	Cu@N-C(600)	DMSO	K3PO4	65
14	Cu@N-C(600)	DMSO	Cs2CO3	trace
15	Cu@N-C(600)	DMSO	KOH	70
16	Cu@N-C(600)	DMSO	Et3N	75
17	Cu@N-C(600)	DMSO	NaHCO3	71^c
18	Cu@N-C(600)	DMSO	NaHCO3	50^d
19	Cu@N-C(600)	DMSO	NaHCO3	65^e

^a Reaction conditions: 1a (0.2 mmol), 2a (0.3 mmol), catalyst (10 mg), base (0.4 mmol), solvent (2 mL), 130 °C, 24 h.

^b Isolated yield.

^c 120 °C.

^d 12 h.

^e Catalyst (5 mg).

Having established the optimized conditions, we then evaluated the substrates scope of N-tosyl-2-iodo anilines and aryl terminal alkynes, and the results were listed in Table 2. In the case of alkynes, most of aryl terminal alkynes reacted with N-tosyl-2-iodo aniline to provide the corresponding 2-substituted indoles in good to excellent yields (3a-3k). The results indicated that the substrates of aryl terminal alkynes bearing electron-rich groups seem to be more reactive than the cases containing electron-deficient groups. Ortho-substituted alkyne such as 2-ethynyltoluene did not hamper the reaction and gave the corresponding cyclized product in 82% yield (3f). For ortho-iodoanilines, both electron-donating and electron-withdrawing groups on the aromatic motifs could undergo cyclization smoothly and give the desired products with good yields (3l-3y). Additionally, the reaction of 3-iodopyridin-2-amine provided the heteroindole in 60% and 58% yield, respectively (3z and 3za). Additionally, gram-scale reaction was carried out by taking 4 mmol of 1a and 6 mmol of 2a under the standard conditions, and the expected product was generated in 89% yield (3a, 1.24 g), indicating the practical application of the present method (Scheme 3). However, examination of the reaction of aliphatic alkynes under the standard conditions showed that only a trace amount of the desired product can be generated maybe due to the low conversion and side reactions.

Scheme 3. Gram-scale preparation.

Table 2. Investigation of substrate scopes and limitations^a.

^a Reaction conditions: 1 (0.2 mmol), 2 (0.3 mmol), Cu@N-C(600) (10 mg), NaHCO₃ (0.4 mmol), DMSO (2 mL), 130 °C, 24 h; isolated yield.

As we know, among the N-protecting groups, the N-acetyl groups can be easily removed in acidic or basic aqueous environment. Therefore, the reaction of N-acetyl 2-iodoaniline with phenyl acetylene was carried out under the same reaction condition to test whether 2-phenylindole could be obtained. To our delight, the domino coupling/cyclization/deprotection reaction occurred well to give 2-phenylindole (4a) as the major product instead of N-acetyl 2-phenylindole in 70% yield (entry 1 in Table 3). Encouraged by this result, we then optimized the reaction conditions, including bases, copper species, solvents and reaction temperature, and the results were illustrated in Table 3. It was observed that the optimal conditions are very similar with the reaction for N-tosyl-2-iodoaniline, only replacing the base of NaHCO₃ with Na₂CO₃ (88% yield, entry 2 in Table 3).

Table 3. Optimization of the reaction conditions^a.

Entry	Catalyst	Solvent	Base	Yield (%)^b
1	Cu@N-C(600)	DMSO	NaHCO3	70
2	Cu@N-C(600)	DMSO	Na2CO3	88
3	Cu@N-C(400)	DMSO	Na2CO3	50
4	Cu@N-C(800)	DMSO	Na2CO3	65
5	Cu	DMSO	Na2CO3	35
6	CuCl	DMSO	Na2CO3	22
7	CuSO4	DMSO	Na2CO3	60
8	–	DMSO	Na2CO3	trace
9	Cu@N-C(600)	DMF	Na2CO3	68
10	Cu@N-C(600)	Toluene	Na2CO3	50
11	Cu@N-C(600)	DMSO	Na2CO3	64^c
12	Cu@N-C(600)	DMSO	Na2CO3	45^d

^a Reaction conditions: 1a (0.2 mmol), 2a (0.3 mmol), catalyst (10 mg), base (2.0 equiv.), solvent (2 mL), 130 °C, 24 h.

^b Isolated yield.

^c 120 °C.

^d Catalyst (5 mg).

The reactivity of other substituted N-acetyl-2-iodo anilines and aryl terminal alkynes were then examined. As shown in Table 4, all of the domino coupling/cyclization/deprotection reactions proceeded smoothly and provide the 2-substituted indoles in 69-88% yields (4a-4k). The electronic influence of the substituted groups, such as Me, Et, F and Cl, were found to have negligible impact on the reactivity. Furthermore, control experiments indicated that the deprotection of the acetyl group in 2-substituted indole likely occurred following the step of cyclization, attribute to the trace water in the solvent of DMSO (Scheme S1). However, complicated results were also observed for aliphatic alkynes, which were similar with the reactions between N-tosyl-2-iodo anilines and aliphatic alkynes.

Table 4. Investigation of substrate scopes and limitations.^a

^a Reaction conditions: 1 (0.2 mmol), 2 (0.3 mmol), Cu@N-C(600) (10 mg), Na₂CO₃ (0.4 mmol), DMSO (2 mL), 130 °C, 24 h; isolated yield.

As a heterogeneous catalyst, the recoverability and reusability of Cu@N–C(600) was then investigated in the domino coupling-cyclization reactions between 1a and 2a. The used Cu@N–C(600) can be recovered by a simple centrifugation, washed with ethyl acetate, and dried in an oven. As illustrated in Scheme 4 and Table 5, it was found that the catalytic performance of the solid catalyst maintained well and could be reused at least 3 cycles, albeit with a slight drop of product yields after the initial reaction, which was attributed to the loss of some surface copper species via mechanical abrasion-induced exfoliation during the reaction procedure (36). These results were also confirmed by the field emission scanning electron microscope (FE-SEM), elemental mapping and energy dispersive spectrometer (EDS) results (Figure S1-S5). X-ray diffraction (XRD) pattern of Cu@N–C(600) after 3 runs of the reaction was examined, which clearly indicates that the crystallinity and structure of Cu@N–C(600) can be retained during the course of the reaction (Scheme 5). Furthermore, the hot filtration experiments were carried out with the reactions between 1a and 2a under the optimized reaction conditions. After four hours, the reaction mixture was filtered to remove the catalyst and the filtrate was stirred for additional 20 h. We can see that the yield of corresponding product was not increased after the removal of the catalyst (Scheme 6), suggesting that the Cu@N–C(600) catalyst was a good heterogeneous catalyst for this present domino reaction.

Scheme 4. Reuse of Cu@C-N(600).

Scheme 5. XRD analysis of Fresh Cu@N-C(600) and Used Cu@N-C(600).

Scheme 6. Time-concentration profile of the model reaction (between 1a and 2a) and the yield was determined by ¹H NMR with 1,3,5-trimethoxybenzene as the standard. (a) Reaction under the optimized conditions; (b) reaction after removal of Cu@N-C(600) catalyst by hot filtration at 4 h.

Table 5. The Cu leaching test of model reaction.

Sample	Cu leaching (%)^a
The initial run	2.2%
The first cycle	0.8%
The second cycle	0.7%
The third cycle	0.8%

^a Measured by ICP-OES analysis.

On the basis of the experiment results and the related previous mechanistic studies, (18, 37–41) a proposed reaction mechanism is outlined in Scheme 7. First, the solid catalyst Cu@N–C reacted with teminal aryl alkyne to form the Cu-phenylaceylide complex A in the presence of NaHCO₃ or Na₂CO₃. Oxidation addition of A with N-tosyl(acetyl)−2-iodo anilines to provide complex B, followed by reductive elimination led to Sonogashira coupling intermediate. The cyclization step probably involves the intramolecular nucleophilic attack of the nitrogen atom to copper coordinated alkyne C, which could provide the corresponding 2-substituted indole derivatives and regenerate the solid catalyst. The deprotection products (4a-4k) were obtained directly via hydrolysis of the acetamide bond with the trace water from the solvent of DMSO during the reaction process.

Scheme 7. Proposed mechanism for Cu@N-C-catalyzed domino Sonogashira coupling-cyclization reaction.

Conclusions

In conclusion, a new Cu(im)₂-derived Cu@N–C catalyst was established for domino Sonogashira coupling-cyclization reactions between N-tosyl(acetyl)−2-iodo anilines and aryl acetylenes. The solid catalyst exhibits good catalytic activities to generate a variety of N-tosyl(H)−2-substituted indoles in good to excellent yields with the merits of broad substrate scope, good functional compatibility, low metal leaching and operational simplicity. Moreover, the catalyst could be reused for several times without decreasing the activity, and the structure maintained well during the reaction process, confirming the heterogeneous nature of the present solid catalyst.

Experimental

General information

Unless otherwise stated, all reagents were purchased from commercial suppliers (such as Adamas-beta and Energy Chemical) and used without further purification. Column chromatography and thin-layer chromatography were performed with silica gel (200-300 mesh) and GF₂₅₄ plates purchased from Qingdao Haiyang Chemical Co. Ltd. ¹H NMR, ¹³C NMR and ¹⁹F NMR were recorded on a Bruker Avance III HD 400 instrument using DMSO-d₆ or CDCl₃ as the solvent. XRD was measured on Bruke D8 Advance spectrometer. ICP-OES was tested on Agilent 5110 spectrometer. FE-SEM images, elemental mapping and EDS spectrum were recorded using on TESCAN MIRA LMS Scanning Electron Microscope. Catalysts were calcined in a tube furnace of SLG 1200-50.

Cu(im)₂ and Cu@N–C(x) used in this work

Cu(im)₂ and Cu(im)₂-derived Cu@N–C were prepared and characterized according our previously reported procedure (36).

General procedure for the domino coupling/cyclization reaction between N-tosyl-2-iodo anilines and aryl terminal alkynes

To a 25 mL Schlenk tube was added Cu@N–C(600) (10 mg), N-tosyl-2-iodo anilines (0.20 mmol), NaHCO₃ (0.40 mmol), aryl alkynes (0.3 mmol) and DMSO (2.0 mL). The mixture was stirred at 130°C for 24 h under Ar. After cooling to room temperature, saturated brine was added and the mixture was extracted with ethyl acetate (3 × 10 mL). The organic phase was collected, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatograph on silica gel to afford the target products 3a-3za in Table 2.

General procedure for the domino coupling/cyclization reaction between N-acetyl-2-iodo anilines and aryl terminal alkynes

To a 25 mL Schlenk tube was added Cu@N–C(600) (10 mg), N-acetyl-2-iodo anilines (0.20 mmol), Na₂CO₃ (0.40 mmol), aryl alkynes (0.3 mmol) and DMSO (2.0 mL). The mixture was stirred at 130°C for 24 h under Ar. After cooling to room temperature, saturated brine was added and the mixture was extracted with ethyl acetate (3 × 10 mL). The organic phase was collected, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatograph on silica gel to afford the target products 4a-4k in Table 4.

Recycling of Cu@N–C(600) catalyst

After completion of the reaction of 1a and 2a, the catalyst was separated by centrifugation, washed with ethyl acetate, and dried in an oven at 100 °C for 12 h. The dried solid catalyst was reused in the next run under the standard conditions.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This work was financial supported by the Natural Science Foundation of Hunan Province (2021JJ30290), National Natural Science Foundation of China (NSFC, No. 21868032) and the construct program of applied characteristic discipline in Hunan University of Science and Engineering.