Construction of 1-acryloyl-2-cyanoindoles: unveiling their potential in radical cascade cyclization

Abstract

To develop a novel skeleton for the construction of nitrogen-containing heterocycle compounds by radical cascade cyclization reactions, we designed and synthesized 1,n-enyne-type platform compounds i.e., 1-acryloyl-2-cyanoindole compounds. The synthesized compounds showed good potential in radical cascade reactions, which was demonstrated in the photocatalytic sulfonation/cyclization reaction to give sulfonated pyrrolidoindoledione in good yield.

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Introduction

Nitrogen-containing heterocyclic compounds are widely present in biological genetic materials (DNA, RNA), synthetic drugs, natural products, and bioactive molecules.¹ Over 60% of the drugs approved by the U.S. FDA contain nitrogen-containing heterocyclic frameworks.² Among them, indole is one of the most versatile heterocyclic compounds, particularly polycyclic compounds that feature fused indoles, such as pyrroloindole, which have garnered significant attention from organic synthesis researchers due to their biological activity and medicinal value. As illustrated in Fig. 1, several representative drug molecules include antimalarial agents (flinderole B),³ drugs with neuroendocrine immunomodulatory activity (melatonin),⁴ protein kinase C-β subtype-selective inhibitors (JTT-010),⁵ and hallucinogens (yuremamine).⁶ Therefore, there is an urgent need to develop new green and efficient synthetic strategies for pyrroloindole derivatives to promote the discovery of new drug molecules and bioactive compounds.

Fig. 1 Representative examples of pyrrolo[1,2-a]indoles.

In recent decades, cascade cyclization reactions, also referred to as cascade cyclization reactions,⁷ have emerged as a convenient and mild cyclization strategy that facilitates the rapid and continuous construction of multiple chemical bonds while circumventing the time-consuming and labor-intensive separation of intermediates.⁸ For specific platform scaffolds, a series of functionalized heterocyclic compounds can be synthesized by utilizing various radical precursors to generate the corresponding radicals through specific methodologies, followed by radical addition and cascade cyclization steps.⁹ Continuing the design and synthesis of novel radical cascade cyclization platform compounds holds significant importance in the field of organic synthesis and medicinal chemistry. Enhanced platform compounds are not only capable of facilitating more complex cyclization processes, but also allow for the creation of diverse structural motifs that are often difficult to access through conventional synthetic routes.

In particular, 1,n-enyne-type platform compounds have garnered extensive attention in radical cascade reactions;¹⁰ based on the cascade cyclization reactions of 1,n-enyne with different radicals, a diverse array of heterocyclic compounds can be synthesized, thereby providing the material basis for research in the development of biologically active molecules and drug discovery.¹¹ For instance, in recent years, our research team has developed various 1,n-enyne-type platform compounds, such as 1-(2-(arylethynyl)phenyl)indoles (Scheme 1a),¹²N-methylacrylyl-2-arylbenzimidazoles (Scheme 1b),¹³ and 3-(2-(ethynyl)phenyl)quinazolinones (Scheme 1c),¹⁴ which serve as robust platform compounds for radical cascade cyclization reactions. In addressing the synthesis of pyrroloindole derivatives, based on our previous successful examples in the development of novel radical cascade cyclization platform compounds, including N-methylacrylyl-2-arylbenzimidazoles and 1-(2-(arylethynyl)phenyl)indoles, we plan to design a class of 1,6-enyne compounds based on substituted indole scaffolds. Furthermore, considering that nitriles could serve as efficient radical acceptors in radical cascade reactions,¹⁵ we propose to incorporate both an acryloyl group and cyano group into the indole framework to access the 1,n-enyne-type 1-acryloyl-2-cyanoindole compounds, which could be an efficient good skeleton for the construction of pyrrolo[1,2-a]indolediones via radical cascade cyclization reactions (Scheme 1d).

Scheme 1 Construction of 1,n-enynes for radical cascade reactions.

Results and discussion

Our approach initiated from 2-aminobenzophenones involves initial protection of the amine group through a tosylation reaction under basic conditions, yielding compound 1. Subsequently, a nucleophilic substitution reaction was conducted under basic conditions to introduce a cyanomethyl group on the amino group, resulting in compound 2. Under basic conditions, compound 2 underwent an intramolecular aldol reaction leading to cyclization, followed by an elimination reaction to yield the aromatic product 2-cyanoindole 3. Compound 3 subsequently reacted with methacryloyl chloride under basic conditions to facilitate the synthesis of 1-acryloyl-2-cyanoindole 4 (Scheme 2).

Scheme 2 Synthesis of 1-acryloyl-2-cyanoindoles.

In the course of synthesizing compound 2a from 1a and bromoacetonitrile, we undertook a strategic modification by substituting trimethylamine with triethylamine as the nucleophilic reagent. This substitution resulted in a marked decrease in the reaction yield (Scheme 3). The diminished yield suggests that the steric hindrance introduced by the triethylamine may have adversely affected the reaction kinetics, potentially leading to a less favorable transition state.

Scheme 3 Optimization of amines for the synthesis of 2a.

In the synthesis of compound 3, when the two aromatic rings in the starting material 2 were substituted with electron-withdrawing groups (e.g., fluorine, chlorine, bromine), a marked decrease in the yields of compound 3 was observed (Scheme 4). This observation indicates that the electronic effect considerably influences this indole synthesis reaction. Additionally, temperature conditions markedly impacted this reaction; it was observed that conducting the reaction at room temperature also led to a significant decrease in the yield of compound 3, suggesting that low-temperature conditions are crucial for the success of this reaction.

Scheme 4 Selective examples for the synthesis of 3.

In this context, with the indole intermediate 3 in hand, we then conducted the amidation reactions for indoles to synthesize the desired products 4a–4l in the presence of DMAP and Et₃N at room temperature. As shown in Scheme 5, the results indicate that the electronic effects of substituents on the aromatic ring at the 3-position of indole significantly influence the amide formation reaction; specifically, compounds bearing halogen substituents yield the target product at relatively lower yields (4g–4i). Similar outcomes were also observed in reactions involving differently substituted indole aromatic rings (4j–4k). These findings suggest that electron-withdrawing substituents are detrimental to the progression of this reaction, whereas electron-donating substituents appear to promote its occurrence. Overall, we obtained twelve 1-acryloyl-2-cyanoindole compounds 4 with moderate to good yields (51–91%).

Scheme 5 Synthesis of 4.

The products 4 obtained from the aforementioned experiments are anticipated to have significant applications in cascade cyclization reactions. Considering that photochemically promoted organic synthesis reactions have emerged as a powerful strategy in recent years,¹⁶ the synthesized compound 4 was further applied in a photochemical catalytic radical cascade cyclization reaction, efficiently constructing a variety of pyrrolo[1,2-a]indoledione frameworks.¹⁷ As shown in Scheme 6, under the irradiation of blue light, the sulfonation/cyclization reaction of compound 4a and p-toluenesulfonyl hydrazine can be efficiently promoted by ammonium persulfate (2 equiv.), CH₃CN/H₂O (v/v = 3 : 1, 1 mL) in N₂ under the irradiation of a 10 W blue LED (460 nm) at room temperature for 12 h, affording sulfonylated pyrrolo[1,2-a]indoledione 5a with an 81% yield.

Scheme 6 Photochemical transformation of 4a.

Conclusion

In summary, we reported the design and synthesis of 1,n-enyne-type compounds, i.e., 1-acryloyl-2-cyanoindoles by incorporating both an acryloyl group and cyano group into the indole framework. The synthesized compound was successfully applied in photocatalytic cascade cyclization reactions to produce sulfonylated pyrrolo[1,2-a]indoledione, indicating its potential as a powerful platform, paving new avenues for the construction of diverse functionalized polycyclic compounds.

Data availability

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

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

We acknowledge the financial support from the National Natural Science Foundation of China (22171249), Science & Technology Innovation Talents in Universities of Henan Province (23HASTIT003), and Science and Technology Research and Development Plan Joint Fund of Henan Province (242301420006).

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. See DOI: https://doi.org/10.1039/d4nj04731a

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