Molecular editing of 3-hydroxyphenyl oxindole derivatives via formal O-insertion and N-insertion: synthesis of dioxolane spirooxindoles and quinoxalin-2(1H)-ones

Abstract

Molecular editing represents a powerful tool for rapid access to privileged skeletons. Described herein for the first time was the single-atom molecular editing of 3-hydroxyphenyl oxindole derivatives through light/acid-promoted formal O-insertion and FeBr₃-catalyzed formal N-insertion. Two kinds of biologically significant scaffolds-dioxolane spirooxindoles and quinoxalin-2(1H)-ones-were synthesized in moderate to good yields. The developed methods expanded the reactivity profiles of 3-aryl oxindoles, featuring broad functional group tolerance, operational simplicity, and the ability to synthesize analogs of anticonvulsant and Eis inhibitory compounds.

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Introduction

Dioxolane spirooxindole and quinoxaline-2-(1H)-one are privileged structures present in a wide array of biologically active compounds that display attractive bioactivities (Scheme 1A).^1,2 The development of synthetic methods for these scaffolds has thus attracted considerable interest. Typically, dioxolane spirooxindoles are synthesized via the ketalization of isatins with ethylene glycol (Scheme 1B, a), while quinoxaline-2-(1H)-ones are prepared through the Hinsberg-type cascade condensation/amidation between 1,2-diaminobenzene and α-keto acid derivatives (Scheme 1B, b).³ Beyond the sporadic reports on direct construction of these two skeletons,⁴ current research focuses primarily on structural modification of dioxolane spirooxindoles⁵ and C–H functionalization of quinoxaline-2-(1H)-ones⁶ to generate various derivatives. It is noteworthy that the photocatalytic C–H functionalization of quinoxaline-2-(1H)-ones has emerged as a sustainable strategy, leveraging renewable energy sources and operating under mild reaction conditions. Notably, most existing methods rely on de novo synthesis, which is often time-consuming and lacks step-economy. Therefore, developing straightforward, step-economical approaches for efficient assembly of dioxolane spirooxindole and quinoxaline-2-(1H)-one scaffolds remains highly desirable.

Scheme 1 Research backgrounds and this work.

Molecular editing through single-atom insertion has emerged as a powerful technique for directly converting core skeletons into diverse privileged architectures at a late stage, circumventing multistep de novo synthesis.⁷ Exploring such single-atom skeletal editing reactions using readily available starting materials significantly expands the intermediate chemical space available for drug discovery. For instance, 3-aryl/alkyl oxindoles, commonly employed as accessible building blocks for preparing 3,3-disubstituted oxindoles (Scheme 1C, a),⁸ were recently applied by Morandi in 2024 to an innovative regiodivergent molecular editing transformation (Scheme 1C, b).⁹ This elegant approach demonstrated the conversion of oxindoles into quinolines via a C-insertion-enabled ring expansion process. Despite impressive progress, to the best of our knowledge, single-atom molecular editing strategies that transform 3-aryl/alkyl oxindoles into some other valuable scaffolds such as dioxolane spirooxindoles or quinoxaline-2-(1H)-ones are still underdeveloped. The primary challenge resides in the direct and selective cleavage of inert C–C bonds, coupled with the precise control of new bond formation.

3-Hydroxyphenyl oxindole derivatives, a newly designed subclass of 3-aryl oxindoles, have exhibited notable reactivities in oxidative conjugate addition and [4 + n] cyclization reactions for synthesizing 3,3-disubstituted and spirocyclic oxindoles (Scheme 1D).¹⁰ Nevertheless, novel reactivities and applications of such scaffolds are to be developed, particularly in single-atom molecular editing for constructing privileged structures. In line with our ongoing investigation into novel reactivities of 3-hydroxyphenyl oxindole derivatives^10d–f and our continued efforts in heterocycle synthesis,¹¹ we unexpectedly discovered a light/acid-promoted formal O-insertion reaction that enabled the synthesis of dioxolane spirooxindoles (Scheme 1E, a). Furthermore, we disclosed an FeBr₃-catalyzed formal N-insertion transformation to construct quinoxalin-2(1H)-ones (Scheme 1E, b). These methodologies were characterized by moderate to good yields, excellent functional group tolerance, and operational simplicity. Herein, we reported these findings.

Results and discussion

Given the environmentally benign nature of photocatalysis and the importance of spirocycles in medicinal chemistry,¹² we initiated our investigation using 3-hydroxyphenyl oxindole 1a as the model substrate for the light/acid-promoted formal O-insertion reaction. Systematic evaluation of the reaction parameters revealed that the optimal yield of 75% for dioxolane spirooxindole 2a was achieved using 10 mol% of Rhodamine B as photocatalyst, 30 mol% of diphenyl hydrogen phosphate (DPP) as additive, and 3 mL of EA as solvent under air at room temperature with blue LED irradiation for 6 h (Table 1, entry 1; see Table S1 in SI for details). The structure of compound 2a was unequivocally determined by X-ray single crystallographic analysis. Other photocatalysts including 4CzIPN, anthraquinone, and Eosin Y proved ineffective (entries 2–4). Additives such as 1,1′-binaphthyl-2,2′-diyl hydrogenphosphate (PA), p-toluenesulfonic acid monohydrate (p-TSA·H₂O), and N,N-diisopropylethylamine (DIPEA) were also ineffective (entries 5–7). Changing solvent to dichloromethane (DCM) or reducing the amounts of Rhodamine B, DPP, and EA resulted in diminished yields (entries 8–11). Control experiments conducted in the absence of Rhodamine B, DPP, an air atmosphere, or blue LED irradiation confirmed the essential roles of these four parameters in promoting the transformation (entries 12–15). At a 0.2 mmol scale, the reaction provided 2a in 75% yield (entry 16).

Table 1 Selected reaction condition optimization^a

Entry	Variation from the standard conditions	Yield (%)
a Reaction conditions: 1a (0.1 mmol), Rhodamine B (10 mol%), DPP (30 mol%), and EA (3.0 mL) under air atmosphere at room temperature with blue LED irradiation (5.5 W, 435–475 nm) for 6 h; n.d. = no detection of 2a; n.r. = no reaction. Isolated yields after column chromatography.
1	None	75
2	4CzIPN instead of Rhodamine B	28
3	Anthraquinone instead of Rhodamine B	Trace
4	Eosin Y instead of Rhodamine B	46
5	PA instead of DPP	51
6	p-TSA·H2O instead of DPP	10
7	DIPEA instead of DPP	n.d.
8	DCM as solvent	58
9	Rhodamine B (5 mol%) used	73
10	DPP (20 mol%) used	72
11	EA (2 mL) used	64
12	Without Rhodamine B	n.d.
13	Without DPP	23
14	Under N2 atmosphere	n.r.
15	In the dark	20
16	On a 0.2 mmol scale for 12 h	75

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Under optimized conditions, we investigated the scope for synthesizing dioxolane spirooxindoles via light/acid-promoted formal O-insertion (Table 2). First, a series of 3-hydroxyphenyl oxindoles 1b–1j that bear various substituents on the oxindole phenyl ring were examined. Excellent compatibility with functional groups, including trifluoromethoxy (CF₃O), methoxy (MeO), methyl (Me), fluoro (F), chloro (Cl), bromo (Br), and iodo (I) groups was observed, and the corresponding edited products 2b–2j were obtained in yields ranging from 50% to 76%. The electrical nature (electron-donating or -withdrawing) and the position of substituents showed no significant influence. Moreover, a disubstituted substrate afforded dioxolane spirooxindole 2k in 67% yield. Substrates bearing strong electron-withdrawing NO₂ and CN groups were found to exhibit poor reactivity and yield unsatisfactory results. Next, 3-hydroxyphenyl oxindoles 1l–1u that feature diverse substituents on the N-atom of oxindole were investigated. Specifically, the N–H substrate 1l successfully engaged in the reaction and afforded 2l in 65% yield. Diverse alkyl groups-methyl (Me), ethyl (Et), iso-propyl (i-Pr), and n-butyl (n-Bu)-were well-tolerated, and the targeted products 2m–2p were furnished in 60–80% yields. Notably, the N-phenyl oxindole could deliver product 2q in 70% yield. Substrates 1r–1u that bear reactive alkenyl, alkynyl, cyclopropyl, and cyclobutyl groups also proved compatible, providing 2r–2u in 70–81% yields.

Table 2 Substrate scope for the synthesis of dioxolane spirooxindoles via light/acid-promoted formal O-insertion^a

a Reaction conditions (unless otherwise noted): 1 (0.2 mmol), Rhodamine B (10 mol%), DPP (30 mol%), and EA (6.0 mL) under air atmosphere at room temperature with blue LED irradiation (5.5 W, 435–475 nm); isolated yield after column chromatography.

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Inspired by the success of O-insertion reaction, we hypothesized that N-insertion-based skeletal editing of oxindole to quinoxalin-2(1H)-one could proceed under appropriate reaction conditions. To test this, we systematically explored reactions between 3-hydroxyphenyl oxindole derivatives and azidotrimethylsilane (TMSN₃) (Table 3). While no expected product 4a was detected using 1a, the O-methyl protected substrate 3a successfully afforded 4b in 74% yield using FeBr₃ catalysis (see Table S2 in SI for details). The molecular structure of 4b was confirmed by X-ray single crystal analysis. Subsequently, the substrate scope was explored. The benzyl and propargyl ethers reacted and yielded products 4c and 4d in 72% and 45% yields, respectively. A variety of 3-hydroxyphenyl oxindole derivatives 3d–3k that incorporate MeO, Me, F, Cl, and Br groups underwent smooth conversion to the desired quinoxalin-2(1H)-ones 4e–4l in 60–75% yields. Additionally, N-substituted oxindoles 3l–3p containing ethyl, allyl, propargyl, cyclobutylmethyl, and 3,5-dimethoxybenzyl groups participated effectively in the N-insertion reactions, affording 4m–4q in good yields.

Table 3 Scope for the synthesis of quinoxalin-2(1H)-ones via FeBr₃-catalyzed formal N-insertion^a

a Reaction conditions (unless otherwise noted): 1a or 3 (0.2 mmol), TMSN₃ (0.4 mmol), FeBr₃ (20 mol%), and MeCN (4.0 mL) under air atmosphere at 120 °C; isolated yield after column chromatography.

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To demonstrate the synthetic utility of the developed methods, several product transformations were conducted (Scheme 2). Reduction and Grignard reactions of 2a led to alcohols 5 and 6 in good yields (Scheme 2A, a and b). The transformation of 2a into 6 may proceed through nucleophilic addition of PhMgBr to the amide motif, followed by hydrolysis of the ketal moiety. The N-unsubstituted 2l, an analog of anticonvulsant 7,^1d underwent alkylation with 2-bromoacetophenones to yield products 8a and 8b-analogs of Eis inhibitor 9 (Scheme 2A, c).^1b Treatment of 4b with Lawesson's reagent provided quinoxaline-2(1H)-thione 10 in 80% yield (Scheme 2B, d), while Suzuki coupling of 4i afforded compound 11 in 80% yield (Scheme 2B, e).

Scheme 2 Transformation of products.

Control experiments were carried out to probe the mechanism (Scheme 3A and B). Radical scavenging experiment using 2,2,6,6-tetramethylpiperidinooxy (TEMPO) suppressed 2a formation, manifesting the possible involvement of a radical process (Scheme 3A, a). When the oxindole-embedded ortho-quinone methide (o-QM) 12, a known reactive intermediate from 3-hydroxyphenyl oxindole derivatives,¹⁰ was subjected to standard conditions, no reaction occurred, excluding its participation (Scheme 3A, b). Light/dark control experiments demonstrated that light enhanced reaction efficiency (Scheme 3B). Based on experimental results and previous reports, plausible mechanisms were proposed (Scheme 3C). For the formal O-insertion pathway (Scheme 3C, a), under blue light irradiation, Rhodamine B (RhB) is initially excited and forms RhB*, which abstracts a hydrogen atom from benzylic position of 1a to generate RhB–H and the benzylic radical Int. A. Then molecular oxygen (O₂) in air traps Int. A to form a peroxy radical Int. B which undergoes a retro-hydrogen atom transfer (RHAT) with RhB–H and produces hydroperoxide Int. C.¹³ Afterwards, DPP-facilitated dearomative spirocyclization affords the spiroepoxide Int. E,¹⁴ followed by an aromatization-driven ring-expansion to furnish product 2a. The proposed pathway is consistent with those experimental results in Table 1 and Scheme 3, which demonstrates the vital roles of RhB, air, and DPP. For the formal N-insertion pathway (Scheme 3C, b), FeBr₃-catalyzed oxidation of 3a under aerobic conditions produces Int. F, which reacted with TMSN₃ to give azide Int. G. Then a Schmidt-type ring-expansion proceeds and generates zwitterion Int. H through the aryl (not acyl) migration with the release of N₂. Final aromatization delivers quinoxalin-2(1H)-one 4b.

Scheme 3 Control experiments and proposed mechanisms for the formal O-insertion and N-insertion.

Conclusions

In conclusion, we developed the single-atom molecular editing reactions of 3-hydroxyphenyl oxindole derivatives through light/acid-promoted formal O-insertion and FeBr₃-catalyzed formal N-insertion. The O-insertion reaction offered efficient access to dioxolane spirooxindoles, potentially proceeding through a photocatalytic radical-mediated peroxidation/acid-facilitated dearomative spirocyclization/aromatization-driven ring-expansion cascade. The N-insertion reaction enabled the synthesis of quinoxalin-2(1H)-ones possibly through a cascade FeBr₃-catalyzed aerobic oxidation/nucleophilic addition/Schmidt-type ring-expansion process. These methodologies exhibited moderate to good yields, excellent functional group tolerance, operational simplicity, and the capability to synthesize anticonvulsant and Eis inhibitor analogs. We anticipate such single-atom molecular editing reactions will advance oxindole diversification and offer novel synthetic approaches for drug discovery.

Author contributions

Y. S. and J. L. contributed equally. Y. S. performed conceptualization, methodology, supervision, and writing – original draft, review & editing. J. L. conducted the experiments for data collection. H. W. and T. S. revised the manuscript. F. H. and S. L. provided resources and performed supervision, funding acquisition, and writing – review & editing.

Conflicts of interest

There are no conflicts to declare.

Data availability

The data supporting this article have been included as part of the supplementary information (SI). Supplementary information is available. See DOI: https://doi.org/10.1039/d5qo01334h.

CCDC 2466249 and 2466250 contain the supplementary crystallographic data for this paper.^15a,b

Acknowledgements

This work was supported by the National Natural Science Foundation of China (22478218, 22208184, 21978144), and the Natural Science Foundation of Shandong Province (No. ZR2023QB218).

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Footnote

† These authors contributed equally to this work.

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