K₂S₂O₈-mediated acylarylation of unactivated alkenes via acyl radical addition/C–H annulation cascade of N-allyl-indoles with silver cocatalysis

Abstract

A silver-catalyzed, K₂S₂O₈-mediated protocol to access regioselective acylarylation of unactivated alkenes was developed. The reaction between N-allyl-indoles and α-oxocarboxylic acids proceeded smoothly and involved an acyl radical addition/C–H cyclization cascade. The protocol showed a broad substrate scope and good tolerance of functional groups. The reaction proceeded with both internal and terminal alkenes to furnish many functional pyrrolo[1,2-a]indoles bearing the ketone carbonyl group, and this feature also provides the potential to construct structurally complex N-containing heterocycles.

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Introduction

Transition-metal-catalyzed difunctionalization of alkenes affords one of the most powerful strategies for constructing complex C(sp³)-hybridized molecular frameworks.¹ The difunctionalization transformation of alkenes has been well exploited by varying the coupling partners.² As for the transition-metal-catalyzed alkene dicarbofunctionalization, a radical addition/C–H functionalization cascade triggered by direct carboradical-addition to olefins represents one of the most efficient and promising processes, and features high atom/step economy and stands in stark contrast to the processes that deploy prefunctionalized substrates.³ In particular, the intramolecular dicarbofunctionalization reaction of alkenes with widely explored radical precursors offers an attractive synthetic strategy to construct diverse functional scaffolds for rapid access to complex molecules.⁴ Of the various radical precursors, user-friendly and readily available α-oxocarboxylic acids have attracted substantial attention, and can be used to produce valuable acyl radical species for carbon–carbon bond formations involving direct C–H acylation.^5,6 Nevertheless, successfully employing α-oxocarboxylic acids in regioselective difunctionalization of unactivated alkenes involving C–H activation—and in which direct C–H acylation is completely avoided—remains very challenging. In this regard, the development of a general and practical strategy to address this issue is highly desirable.

On the other hand, polycyclic indoles such as pyrrolo[1,2-a]indole constitute one of the important heterocycle classes with biological activities, and are widely found in numerous natural products and pharmaceutical chemicals.^7–9 Thus, tremendous efforts have been devoted to establishing diverse methodologies to construct these skeletons.¹⁰ In the alkene difunctionalizations, an activated alkene has generally been used as a “linchpin” to facilitate the regioselectivity of the transformation,¹¹ but few successes have been achieved when the more challenging yet appealing unactivated alkenes were used (Fig. 1a).^4q To address these limitations and as part of our continuing interest in heterocycle chemistry involving C–H activation,^12,13 we sought to develop an acyl-radical-based cascade reaction enabled by oxidative C–H annulation of unactivated alkene-linked indoles. Herein, we describe a K₂S₂O₈-mediated, silver-catalyzed process¹⁴ for regioselective acylarylation of unactivated alkenes with N-allyl-indoles and α-oxocarboxylic acids, a reaction that was shown to have a broad substrate scope and display good tolerance of functional groups (Fig. 1b). The reaction proceeded with both internal and terminal alkenes to furnish many functional pyrrolo[1,2-a]indoles bearing the ketone carbonyl group, which might be subject to readily accessible derivatization, thus leading to structurally complex N-containing heterocycles.

Fig. 1 Construction of pyrrolo[1,2-a]indoles via the radical difunctionalization of unactivated alkenes.

Results and discussion

We commenced the study of the acylarylation of unactived alkenes using 1-(1-cinnamyl-1H-indol-3-yl)ethanone and 2-oxo-2-phenylacetic acid (2a) as the model substrates (Table 1; for more details, see the ESI†). To our delight, the desired transformation occurred successfully in the presence of AgOAc (0.1 equiv.) and K₂S₂O₈ (2 equiv.) in CH₃CN/H₂O under an Ar atmosphere, giving the difunctionalized compound 3aa in 74% yield (Table 1, entry 1). While no reaction took place in the absence of K₂S₂O₈, a moderate yield was obtained without addition of AgOAc (Table 1, entries 2 and 3). Then several potential oxidants including Na₂S₂O₈, (NH₄)₂S₂O₈, and oxone were examined, but they did not provide better results (Table 1, entries 4–6). When a single solvent, namely H₂O or CH₃CN, was employed as the reaction medium, the reaction did not work at all (Table 1, entries 7 and 8). The reactivity was further improved when the loading of AgOAc was decreased to 0.05 equiv., generating the desired product in 84% yield (Table 1, entry 9). Lastly, the screening of other silver salts, namely Ag₂CO₃, Ag₂O and AgOTf, did not lead to a better efficiency (Table 1, entries 10–12).

Table 1 Optimization of the reaction conditions^a

Entry	[Ag]	Oxidant	Solvent	3aa, Yield^b (%)
a Reaction conditions: 1a (0.2 mmol), 2a (0.4 mmol), [Ag] (10 mol%), oxidant (0.4 mmol), solvent (2.0 mL), Ar, 70 °C, 16 h. b Isolated yield based on 1a and using flash column chromatography. c CH3CN : H2O (v/v = 1 : 1). d [Ag] (5 mol%).
1^c	AgOAc	K2S2O8	CH3CN : H2O	74
2	AgOAc	—	CH3CN : H2O	nr
3	AgOAc	K2S2O8	CH3CN : H2O	49
4	AgOAc	Na2S2O8	CH3CN : H2O	71
5	AgOAc	(NH4)2S2O8	CH3CN : H2O	69
6	AgOAc	Oxone	CH3CN : H2O	21
7	AgOAc	K2S2O8	H2O	nr
8	AgOAc	K2S2O8	CH3CN	Trace
9^d	AgOAc	K2S2O8	CH3CN : H2O	84
10^d	Ag2CO3	K2S2O8	CH3CN : H2O	72
11^d	Ag2O	K2S2O8	CH3CN : H2O	71
12^d	AgOTf	K2S2O8	CH3CN : H2O	80

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With an optimized set of conditions in hand, the scope of each reaction component was evaluated. First, as shown in Table 2, we investigated the generality of N-allyl-indoles in this transformation. In general, the reaction showed a broad substrate scope, and various functional groups on the phenyl ring of the indole were tolerated when carrying out the bifunctionalization of unactivated alkenes to produce functionalized 2,3-dihydro-1H-pyrrolo[1,2-a]indoles; a variety of such indoles were produced (3aa–3fa, 3ha–3ja), in moderate to good yields. Notably, the strongly electron-withdrawing cyano group was found to be compatible with the catalytic system and its use afforded the corresponding product 3ga in moderate yield. In addition to the diverse array of indoles, a range of C3-functionalized indoles were evaluated and their reactions showed good efficiency levels, generating products that could serve as linchpins for subsequent diversification of the pyrrole region (3ka–3ma). However, the current acylarylation protocol was found to not be suitable for an N-allyl-indole bearing no substituent as well a one bearing a strongly electron-withdrawing group at the C3 position (3na and 3oa).

Table 2 Scope of N-allyl-indole substrates^a,b

a Reaction conditions: 1 (0.2 mmol), 2a (0.4 mmol), AgOAc (5 mol%), K₂S₂O₈ (0.4 mmol), CH₃CN/H₂O (2.0 mL, v/v = 1 : 1), Ar, 70 °C, 16 h. b Isolated yield based on 1 and using flash column chromatography.

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Subsequently, we turned our attention to the scope of α-oxocarboxylic acids (Table 3). The successful utilization of various 2-oxo-2-arylacetic acids as acyl radical precursors demonstrated the good generality of this radical addition/cyclization cascade, allowing the facile access to structurally diverse 2,3-dihydro-1H-pyrrolo[1,2-a]indoles (3ab–3al). The absolute chemical structure of one of these indoles was determined using X-ray crystallography (3ab, CCDC 1965912; for more details, see the ESI†).¹⁵ Notably, 2-oxo-2-(3,4,5-trimethoxyphenyl)acetic acid and 2-(naphthalen-2-yl)-2-oxoacetic acid also underwent this reaction smoothly to offer the corresponding products 3ak and 3al in 63% and 53% yields, respectively. Moreover, aliphatic α-oxocarboxylic acids, while generating less stable acyl species, were also suitable and delivered the desired adducts (3am–3an), albeit with diminished efficiency levels (35% and 40% yields). Unfortunately, the reaction did not take place when testing a couple of heteroaromatic α-oxocarboxylic acids (3ao and 3ap) and when using 2-(4-nitrophenyl)-2-oxoacetic acid (3aq).

Table 3 Substrate scope of α-oxocarboxylic acids^a,b

a Reaction conditions: 1a (0.2 mmol), 2 (0.4 mmol), AgOAc (5 mol%), K₂S₂O₈ (0.4 mmol), CH₃CN/H₂O (2.0 mL, v/v = 1 : 1), Ar, 70 °C, 16 h. b Isolated yield based on 1a and using flash column chromatography.

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Interestingly, a series of indole-based unactivated alkenes also participated in this difunctionalization reaction smoothly, under slightly modified reaction conditions, to produce functionalized aliphatic cyclic fused indoles (Scheme 1). The flexibility of this transformation was investigated by deploying certain kinds of α-oxocarboxylic acids and indole substrates, which generated the desired products successfully (5a–5i), although the uncompleted conversion of indole-based alkene 4 led to a depressed yield. Notably, tetrahydropyrido[1,2-a]indole and tetrahydro-6H-azepino[1,2-a]indole motifs were generated successfully from indole-based pent-1-ene and hex-1-ene, respectively (5j and 5k). And the more bulky disubstituted alkenes also showed reactivity for this reaction to afford the corresponding products, albeit with low to moderate yields (5l and 5m). However, the cyclic alkene tested was not compatible with the current reaction conditions (5n). The type of substituent used at the C3-position of the indole seemed to be crucial for the success of this transformation, as several functional groups such as Me and CO₂Et were not tolerated (5o and 5p).

Scheme 1 Reaction of N-allyl-1H-indoles with α-oxocarboxylic acids. Conditions: 4 (0.2 mmol), 2 (0.4 mmol), AgNO₃ (10 mol%), K₂S₂O₈ (0.4 mmol), CH₃CN/H₂O (2.0 mL, v/v = 1 : 1), Ar, 70 °C, 16 h.

To gain more insight into the reaction details, experiments with radicals were carried out. The reaction was dramatically inhibited when either the radical scavenger TEMPO or BHT was included in the reaction mixture, and the radical coupling compound 6 was isolated successfully, thus providing evidence for the generation of an acyl radical intermediate (Scheme 2).

Scheme 2 Mechanistic studies.

Based on experimental results and previous research,¹⁶ a plausible reaction mechanism was proposed (Scheme 3). According to this proposed mechanism, an initial decarboxylation process was promoted by K₂S₂O₈ and AgOAc catalysis to form acyl radical species A, which participated in a radical addition to the alkene C=C bond to preferentially generate a more stable benzyl radical intermediate, namely B. The subsequent intramolecular radical annulation of the pyrrole core of the indole furnished a new radical, namely C, which participated in an oxidation and then deprotonation to terminate the process and afford the desired products 3.

Scheme 3 Plausible mechanism.

Conclusions

In summary, we successfully developed an efficient silver-catalyzed, K₂S₂O₈-mediated reaction of N-allyl-indoles with α-oxocarboxylic acids, thus achieving acylarylations of unactivated alkenes with high regioselectivity and a broad substrate scope. Both internal and terminal alkenes participated in the reaction effectively to generate many pyrrolo[1,2-a]indole-based ketones. The mechanistic study carried out provided evidence for a radical process in this transformation by capturing the acyl radical species. Further investigation of the application potential of this method for the synthesis of other biologically active molecules is ongoing in our laboratory.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

We thank the National Natural Science Foundation of China (21702237, 21272004), the Natural Science Research Project for Anhui Universities, the Start-up Research Fund of Anhui Normal University and the Project for Students’ Innovative Experiment of Anhui Normal University for their financial support.

Notes and references

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15. CCDC 1965912 contains the supplementary crystallographic data for this paper.†.
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Footnotes

† Electronic supplementary information (ESI) available: Experimental procedures, characterization data, and ¹H and ¹³C NMR charts. CCDC 1965912. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/d1qo01069g

‡ These three authors contributed equally to this work.

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