Palladium-catalyzed dearomative Heck/[4 + 3] decarboxylative cyclization of indoles with α-oxocarboxylic acids via C–H activation

Abstract

Herein, we report a novel palladium-catalyzed dearomative Heck/[4 + 3] decarboxylative cyclization of C2-tethered indoles with α-oxocarboxylic acids via C–H activation. In this reaction, dearomatization of C2-tethered indoles occurs via a Heck reaction pathway, leading to the formation of the alkyl-Pd(II) species. Subsequently, this species undergoes C–H activation, rather than the typical nucleophilic trapping or β-H elimination, to generate C,C-palladacycles, which are then captured by α-oxocarboxylic acids to afford hexacyclic and octocyclic fused indolines containing a seven-membered ring.

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Introduction

Polycyclic indoline frameworks are ubiquitous in a multitude of alkaloids exhibiting diverse biological activities.^1,2 In this regard, significant efforts have been devoted to the dearomatization of indoles, which provides a straightforward and efficient strategy for constructing such important molecules.^2–4 Among them, palladium-catalyzed dearomative Heck reactions of indoles have attracted considerable attention.⁴ Mechanistically, this type of reaction starts with oxidative addition of aryl halides to Pd(0), followed by dearomative migratory insertion of indoles to generate the alkyl-Pd(II) species, which can be intercepted to forge diverse indoline derivatives. Over the past decade, numerous elegant dearomative transformations of aryl halide-tethered indoles have been established by Jia and others, including Heck reactions,⁵ reductive Heck reactions,⁶ and Heck/difunctionalization reactions (Scheme 1A).^7–10 However, the reported terminations have primarily focused on β-H elimination and nucleophilic trapping of the alkyl-Pd(II) species. Consequently, developing new dearomative Heck reactions for the synthesis of polycyclic indoline derivatives by exploring alternative transformation pathways of the alkyl-Pd(II) species is in great demand.

Scheme 1 Palladium-catalyzed dearomative Heck reactions of N- or C-tethered indoles.

Given the aforementioned circumstances and driven by our ongoing interest in palladium-catalyzed cascade C–H annulation involving C,C-palladacycles,^11,12 we recently reported two examples of dearomative Heck/[4 + 1] decarboxylative cyclization of C2-tethered indoles via C(sp³)–H or C(sp²)–H activation (Scheme 1B).¹² In this endeavor, the alkyl-Pd(II) species generated by dearomative Heck reaction underwent intramolecular C–H activation, instead of direct β-H elimination or nucleophilic trapping, to form five-membered C,C-palladacycles,¹³ which were subsequently captured by α-bromoacrylic acids to furnish pentacyclic fused pyridinediones. However, such examples are extremely rare and limited to the construction of five-membered rings. Thus, we aim to further explore the construction of more challenging seven-membered rings via C–H bond activation in the dearomative Heck reaction. Herein, we report a dearomative Heck/[4 + 3] decarboxylative cyclization of C2-tethered indoles with α-oxocarboxylic acids, which enables the synthesis of hexacyclic and octocyclic fused indolines containing a seven-membered ring (Scheme 1C).

Results and discussion

We initiated our studies by examining dearomative Heck/[4 + 3] decarboxylative cyclization of N-(2-iodobenzoyl)-1H-indole-2-carboxamide 1a with α-oxocarboxylic acid 2a. After screening a range of reaction conditions, the expected hexacyclic fused indoline 3aa could be isolated in 84% yield using Pd(OAc)₂, dippf, NaOPiv, and TBAB in DMA at 130 °C for 12 h (see Table S1†). Subsequently, we explored the substrate scope of this cascade dearomative C–H annulation (Scheme 2). This protocol was applicable to various indole-tethered aryl iodides 1, affording hexacyclic indolines 3 in moderate to good yields. ortho- or meta-substituents (Me, OMe, F, Cl and CF₃) relative to the amide group on the iodobenzene ring were well-tolerated, furnishing products 3ba–ga. However, the para-substituted substrate 3ha was ineffective due to the presence of steric hinder. Substituents (Me and Ph) on the nitrogen atom of the imide moiety could survive to provide products 3ia and 3ja. Regarding the indole unit, N-Bn, 5-Me and 5-Cl substituted substrates could be smoothly converted into products 3ka–ma in 60–85% yields. Furthermore, when substrates 1n–p containing only one carbonyl group were subjected to the standard conditions, only 1n was capable of yielding the target product 3na, while 1o and 1p underwent intramolecular C–H cyclization at the 3-position of indole to deliver tetracyclic fused indoles.^12b Then, we examined the scope of α-oxocarboxylic acids. A range of substituents on the benzene ring, including both electron-donating (Me, OMe, OPh, morpholinyl and dioxolyl) and electron-withdrawing groups (F, Cl and CF₃), were compatible (3ab–al). Their electronic property had no obvious impact on the reaction efficiency, but increasing the steric hindrance retarded this transformation, resulting in a yield of only 36% for 3aj. Happily, thiophenyl-substituted α-oxocarboxylic acid was also a viable substrate, albeit with a lower yield (3am). Note that the activity of C–X bond in α-oxocarboxylic acids 2 has a significant impact on the reaction. In addition, we conducted a scale-up experiment using 1 mmol of 1a, and product 3aa could be obtained in 72% yield.

Scheme 2 The synthesis of hexacyclic fused indolines. Reaction conditions: 1 (0.1 mmol), 2 (3 equiv.), Pd(OAc)₂ (10 mol%), dippf (10 mol%), NaOPiv (5 equiv.), TBAB (1 equiv.) and DMA (2 mL) at 130 °C under N₂ for 12 h. dippf = 1,1′-bis(diisopropylphosphino)ferrocene. dr > 20 : 1. The diastereomeric ratio (dr) was determined by ¹H NMR spectra of products. ^a 2-(2-Iodophenyl)-2-oxoacetic acid was used. ^b 2-(2-Chlorophenyl)-2-oxoacetic acid was used. ^c 1 mmol of 1a was used.

To emphasize the applicability of this strategy, we next attempted to assess the feasibility of the cascade dearomative annulation between diindole-tethered aryl iodide 4a and α-oxocarboxylic acid 2a (Scheme 3). Happily, the anticipated octocyclic fused indoline 5aa was afforded in 79% yield. Following this, we evaluated the substrate scope of this transformation. Various diindole-tethered aryl iodides 4 with different functional groups (Me, F and Cl) undergo this cascade reaction with 2a to deliver octocyclic fused indolines 5ba–ha in moderate to good yields. Regarding α-oxocarboxylic acids, this reaction showed good compatibility. A variety of α-oxocarboxylic acids bearing different functional groups on the benzene ring, such as Me, OMe, OPh, F, Cl, morpholinyl and dioxolyl, were subjected to the standard conditions to provide the target products 5ab–af and 5ah–al in 40–84% yields. Additionally, 2-(3-bromothio-phen-2-yl)-2-oxoacetic acid was also a competent substrate, delivering product 5am in 38% yield.

Scheme 3 The synthesis of octocyclic fused indolines. Reaction conditions: 4 (0.1 mmol), 2 (3 equiv.), Pd(OAc)₂ (10 mol%), dippf (10 mol%), NaOPiv (5 equiv.), TBAB (1 equiv.) and DMA (2 mL) at 130 °C under N₂ for 12 h. dippf = 1,1′-bis(diisopropylphosphino)ferrocene. dr > 20 : 1. The diastereomeric ratio (dr) was determined by ¹H NMR spectra of the corresponding product.

In the presence of KOH and a mixed solvent of EtOH and H₂O, 3aa could be successfully converted into dibenzocyclohepta[1,2-b]indole 6 by sequential hydrolysis and decarboxylative aromatization (Scheme 4a). Subsequently, the kinetic isotope effect in the reaction was investigated. When substrate 1a or its deuterated variant 1a-D₄ was reacted with 2a under the standard conditions for 1 h, and products 3aa and 3aa-D₃ were afforded in 38 and 33% yields, respectively (Scheme 4b). Competition reaction of 1a and 1a-D₄ with α-oxocarboxylic acid 2a provided 3aa and 3aa-D₃ with a ratio of 1.27 : 1 in 37% overall yield (Scheme 4c). These results suggested that the C–H bond activation is not the rate-determining step for this reaction. Furthermore, we performed the reaction of 1a with 2-oxo-2-phenylacetic acid 7, no target product 8 was detected (Scheme 4d). This result indicated that the pathway involving decarboxylative coupling of alkyl-Pd(II) species A with 2a followed by intramolecular C–H cyclization is ruled out.

Scheme 4 Synthetic transformation and mechanistic studies.

On the basis of the above results and previous reports,¹² a plausible mechanism for this dearomative transformation was illustrated in Scheme 5. Initially, alkyl-Pd(II) species A is formed by a sequence that involves oxidative addition of aryl halides 1 or 4 to Pd(0), followed by migratory insertion of the C2–C3 double bond of indoles. Subsequently, C–H activation of intermediate A generates indoline-fused palladacycle B, which is then captured by α-oxocarboxylic acid 2a to produce Pd(IV) species Cvia an oxidative addition process with the aid of the carboxyl group. Afterward, Intermediate C undergoes a selective transformation into intermediate D by reductive elimination followed by decarboxylation. Ultimately, reductive elimination of D yields products 3 or 5 and regenerates active Pd(0) species.

Scheme 5 Possible reaction mechanism.

Conclusions

In conclusion, we have disclosed a palladium-catalyzed dearomative Heck/[4 + 3] decarboxylative cyclization of C2-tethered indoles. In this reaction, the forming alkyl-Pd(II) species undergoes intramolecular C–H activation to form C,C-palladacycle, which then reacts with α-oxocarboxylic acids to produce hexacyclic and octocyclic fused indolines containing a seven-membered ring. The method further expands the scope of the conversion pathway involving C–H activation for alkyl-Pd(II) species in palladium-catalyzed dearomative Heck reactions.

Author contributions

L. Zhou performed the experiments and analysed the data. P. Jing, W. Deng and S. Guo contributed to data analysis and scientific discussion. Y. Yang and Y. Liang conceived and designed the experiments. Y. Yang and L. Zhou analysed the results and wrote the manuscript.

Data availability

The data supporting this article have been included as part of the ESI.†

Conflicts of interest

The authors declare no competing interests.

Acknowledgements

The authors thank the National Natural Science Foundation of China (22271088 and 22371070), the Natural Science Foundation of Hunan Province (2023JJ20028), the Science and Technology Innovation Program of Hunan Province (2021RC4059 and 2024RC3155), the Training Program for Excellent Young Innovators of Changsha (kq2209014), the Scientific Research Fund of Hunan Provincial Education Department (22A0029 and 24A0688), and the Natural Science Foundation of Changsha (kq2402045) for financial support.

References

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Footnote

† Electronic supplementary information (ESI) available. CCDC 2340392 and 2359843. For ESI and crystallographic data in CIF or other electronic format see DOI: https://doi.org/10.1039/d4qo02024c

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