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. 2025 Jan 29;5(2):948–954. doi: 10.1021/jacsau.4c01166

N-Heterocyclic-Carbene-Catalyzed Imine Umpolung for the Cross-Coupling of Quinoxalin-2-ones with Isatins

Shilpa Barik 1, Anusree A Kunhiraman 1, Rohan Chandra Das 1, Akkattu T Biju 1,*
PMCID: PMC11862942  PMID: 40017773

Abstract

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The N-heterocyclic carbene (NHC)-catalyzed umpolung of aldimines using quinoxalin-2-ones for intermolecular reactions is demonstrated. Specifically, NHC-catalyzed cross-coupling of quinoxalin-2-ones with isatins proceeds via the generation of aza-Breslow intermediates by the addition of carbene to the C=N moiety of quinoxalinones followed by interception with isatins to afford diverse oxindoles in moderate to good yields and good functional group compatibility. Moreover, detailed mechanistic studies involving the isolation and characterization of the imidoyl azoliums (oxidized form of the aza-Breslow intermediates) are provided. Considering the significance of scaffolds bearing both quinoxalin-2-one and oxindole moieties in medicine and natural products, the synthesized molecules employing the NHC-catalyzed imine umpolung strategy are likely to find promising applications.

Keywords: NHC organocatalysis, imine umpolung, aza-Breslow intermediates, oxindoles, imidoyl azoliums, quinoxalin-2-ones

Introduction

Over the past three decades, organocatalysis employing N-heterocyclic carbenes (NHCs) has become a widely used synthetic strategy for the convenient synthesis of a variety of heterocycles and carbocycles.1−12 The success of many carbene-catalyzed reactions largely stems from the remarkable ability of these catalytically active species to reverse the polarity of aldehydes, a process known as umpolung.13−15 The resulting nucleophilic Breslow intermediates, which act as acyl anion equivalents, can be intercepted by aldehydes (benzoin reaction),16,17 Michael acceptors (Stetter reaction),18,19 and electron-neutral olefins (hydroacylation reactions).20 Moreover, the addition of carbenes to α,β-unsaturated aldehydes can generate homoenolate equivalents (conjugate umpolung), which can then be intercepted by aldehydes to form γ-lactones.21 Additionally, the umpolung concept using carbenes has been extended to Michael acceptors22 and alkyl halides.23−25 Further, NHCs are also useful for catalyzing reactions proceeding without the polarity reversal, and the generation of α,β-unsaturated acylazolium is an important mode of reactivity in this domain.26,27

While NHCs are well-known catalysts for the umpolung of aldehydes, this polarity reversal strategy has not been widely explored for aldimines, particularly in intermolecular reactions. The addition of carbenes to imines leading to the formation of the aza-Breslow intermediates was demonstrated by Douthwaite28 and Rovis groups,29 but this strategy was not applied to catalytic reactions.30,31 In 2017, our group32 and Suresh’s group33 independently reported the NHC-catalyzed umpolung of imines followed by the trapping of the aza-Breslow intermediates with activated alkenes for the synthesis of 2,3-disubstituted indoles (Scheme 1A). Subsequently, we have demonstrated the trapping of the nucleophilic aza-Breslow intermediates with imines34 and carbonyls35 in an intramolecular fashion for the synthesis of dihydroquinoxalines and indoxyls, respectively. Very recently, we have demonstrated the interception of the aza-Breslow intermediates with unactivated alkynes in a cascade process leading to the synthesis of dihydrochromeno indoles.36 In addition, the oxidation of the aza-Breslow intermediates using air or external oxidants could result in the generation of imidoyl azolium intermediates.37−42

Scheme 1. (A) Previous Reports on NHC-Catalyzed Aldimine Umpolung, (B) Biological Importance of Quinoxalin-2-ones, and (C) NHC-Catalyzed Imine Umpolung for the Cross-Coupling of Quinoxalin-2-ones with Isatins.

Scheme 1

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Intriguingly, the trapping of the aza-Breslow intermediates in intermolecular reactions has received only scant attention. The only report was by Lupton and co-workers demonstrating the capture of aza-Breslow intermediates with 3-methylene chroman-2-one in an enantioselective imine umpolung process (aza-Stetter reaction).43 The potential challenges in NHC-catalyzed imine umpolung for intermolecular reactions are the competing hydrolysis pathway that can convert the desired imine product into an undesired carbonyl side product thus diminishing yields and the irreversible binding of the NHCs with the imines,44,45 in addition to the higher entropic barrier and the probable chemoselectivity issues due to bringing separate reactants together. Realizing the fact that intermolecular imine umpolung demands judicious choice of substrates and careful optimization, we envisioned an imine moiety in such a way that the imine center is electrophilic enough for the facile generation of the aza-Breslow intermediate.

In this context, quinoxalin-2-one was chosen as a reaction partner, where the adjacent amide carbonyl group present helps the initial attack by NHC to the imine. Also, functionalized quinoxalin-2-ones are highly significant and valuable nitrogen-containing heterocyclic motifs commonly found in natural products and biologically active molecules. Compounds containing this privileged scaffold exhibit a wide range of pharmaceutical properties, including antitumor, antiviral, antiallergic, antithrombotic, antimicrobial, anti-inflammatory, and antioxidant activities (Scheme 1B).46−49 Herein, we report the NHC-catalyzed umpolung of imines for intermolecular reactions via the cross-coupling of quinoxalin-2-one with isatin derivatives, resulting in the synthesis of functionalized oxindoles (Scheme 1C). The nucleophilic attack of the carbene on the electrophilic imine moiety of quinoxalin-2-one could generate the tetrahedral intermediate A, which could undergo a proton transfer to form the key aza-Breslow intermediate B. Trapping of B with the electrophilic carbonyl of isatin resulted in the formation of the oxindoles.

Results and Discussion

With the envisioned idea in mind, the present studies were initiated by the treatment of 1-methylquinoxalin-2(1H)-one 1a and N-benzyl isatin 2a in the presence of the carbene generated from 4 by using DBU and DMF as the solvent. Using these conditions, the functionalized oxindole derivative 3a was formed in 59% yield (Table 1, entry 1, isolated yield). Notably, in contrast to the carbene generated from the triazolium salt 4, other common NHCs derived from precursors 5–8 are less effective (entries 2–5). This cross-coupling reaction did not proceed in the absence of triazolium salt 4 (entry 6). Reducing the temperature to 80 °C instead of 100 °C furnished 53% yield of the product (entry 7). The reaction conducted in other solvents such as DMSO, toluene, and 1,4-dioxane furnished the desired product in reduced yields (entries 8–10). A quick base screening revealed that Na2CO3 is the best choice for the reaction, and oxindole was formed in 90% yield (entries 11–15). Hence, entry 15 was chosen as the optimal condition for this NHC-catalyzed intermolecular imine umpolung.50

Table 1. Optimization of the Reaction Conditionsb.

graphic file with name au4c01166_0006.jpg

graphic file with name au4c01166_0007.jpg

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a

Standard conditions: 1a (0.25 mmol), 2a (0.375 mmol), 4 (20 mol %), DBU (1.0 equiv), DMF (2.0 mL), 36 h, 100 °C.

b

Given is the yield of chromatographically purified 3a.

With the identified reaction conditions in hand, we evaluated the scope and drawbacks of this carbene-catalyzed umpolung (Scheme 2). Initially, the influence of substitution on isatins has been examined. The parent N-benzyl isatin reacted well, while the –OMe group at the 4 position of the isatin ring resulted in a 30% yield of the product (3a and 3b). Moreover, isatins with various electron-releasing and neutral groups as well as halides at the 5-position underwent successful cross-coupling under the optimized conditions, yielding the desired oxindole products in moderate to good yields (3c–3h). Additionally, substituents at positions 6 and 7 of the isatin core did not affect the reaction outcome, and the corresponding products were obtained in reasonable yields (3i–3k). 5,6-Dimethyl-substituted isatin provided the oxindole derivative 3l in 73% yield. Further, the N substitution on isatin using methyl, allyl, propargyl, and phenyl groups was investigated, and in all cases, the target product was formed in good yields (3m–3p). The structure of 3p was further confirmed using X-ray analysis of the crystals.51 Unfortunately, the reaction performed using N-unprotected isatin did not provide the desired product under the present conditions.

Scheme 2. Substrate Scope of the Reaction.

Scheme 2

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Reaction conditions: 1 (0.25 mmol), 2 (0.375 mmol), 4 (20 mol %), Na2CO3 (0.25 mmol), DMF (2.0 mL), 100 °C, 36 h. Yields of chromatographically purified products are given.

Next, the tolerance of the reaction was evaluated by using variously substituted quinoxalin-2(1H)-ones. The reaction conducted using substitution at the 7 position of quinoxalin-2(1H)-one worked well, and the products were formed in moderate yields (3q and 3r). The 6-methoxy quinoxalin-2-one substrate afforded the product 3s in 32% yield. The 6,7-disubstituted quinoxalin-2-one derivatives also provided the desired oxindole derivatives in moderate yields (3t and 3u). In addition, reactions performed using quinoxalin-2-ones bearing ethyl, benzyl, allyl, phenyl, and 3-thienyl groups as the N substituent afforded the target products in good yields (3v–3z). Disappointingly, the reaction performed using the quinoxalinone substrates with an electron-withdrawing –NO2 group at the 6 position was not successful and the substrate decomposed under the present conditions. Further, the reaction of 1a and 2a could be performed under the optimized conditions in a 1.0 mmol scale producing 3a in 85% yield, indicating that the present carbene-catalyzed umpolung strategy is scalable and practical.

To gain insight into the mechanism of the present NHC-catalyzed umpolung, several mechanistic experiments were conducted. Given the knowledge that quinoxalin-2-one serves as a potential substrate for various radical reactions,52 experiments were carried out in the presence of radical scavengers. The reaction carried out in the presence of 1.0 equiv of BHT afforded the cross-coupled product 3a in 85% yield, without the formation of the BHT adduct (Scheme 3, eq 1). This suggests that the reaction does not proceed through radical intermediates. To exclude the radical pathway, another reaction was performed in the presence of 1.0 equiv of TEMPO. In this case, 3a was formed in a reduced yield of 40%, but no adduct formation with TEMPO was detected. The reduced yield could be attributed to the decomposition of free carbene in the presence of TEMPO.

Scheme 3. Mechanistic Experiments.

Scheme 3

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Moreover, performing a stoichiometric reaction of 1a with 4 in the presence of excess Na2CO3 resulted in the formation of aza-Breslow intermediate 9a. Although intermediate 9a was not isolable in our hands, this key intermediate was detected in HRMS (Scheme 3, eq 2). Interestingly, when the reaction was conducted using 1a and imidazolium salt 10, the key imidoyl azolium adduct 11a was isolated in 34% yield (Scheme 3, eq 3). The structure of 11a was confirmed using X-ray analysis of the crystals.51 It is likely that the initially generated aza-Breslow intermediate 12a in this case was oxidized in the presence of air to form the imidoyl azolium 11a.53−56 Moreover, when the reaction of 1a with 2a was carried out in the presence of carbene generated from 10, the desired product 3a was formed in 10% yield along with the formation of the imidoyl azolium 11a in 15% yield (Scheme 3, eq 4). Although 3a was formed in a low yield, this confirms the generation of the aza-Breslow intermediate under the reaction conditions.

Based on the mechanistic studies and literature precedence,30,31 a tentative catalytic cycle for this NHC-catalyzed imine umpolung is presented in Scheme 4. The free carbene generated from precursor 4 undergoes a nucleophilic attack on the C=N moiety of 1a generating the tetrahedral intermediate (I), which on proton transfer forms the key aza-Breslow intermediate (II). The nucleophilic intermediate (II) then undergoes an intermolecular 1,2-addition with electrophilic carbonyl of isatin 2a to form the alkoxide (III), which undergoes a proton transfer and the elimination of free carbene resulting in the formation of the cross-coupled product 3a.

Scheme 4. Proposed Mechanism of the Reaction.

Scheme 4

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The functionalization of synthesized oxindole 3a has been explored. When 3a was subjected to reaction with aryne generated from 2-(trimethylsilyl)-aryl triflate 13a at 60 °C in THF, a highly selective multicomponent coupling occurred with THF acting as a nucleophilic trigger.57 This process afforded the 1-methylquinoxalin-2(1H)-one derivative 14a in 40% yield (Scheme 5). Additionally, treatment of 3a with bromine resulted in the formation of 5-bromo oxindole product 3f in 99% yield.

Scheme 5. Synthetic Utility of the Synthesized Oxindoles.

Scheme 5

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In summary, we have demonstrated the synthesis of oxindole derivatives via the cross-coupling reaction between imines and isatins employing the NHC-catalyzed umpolung of imines. In this process, the catalytically generated aza-Breslow intermediate engages in cross-coupling with activated ketones, leading to the formation of the desired products. A noteworthy aspect of this reaction is its wide substrate scope, accommodating various starting materials, thus underscoring the versatility and potential of this methodology. Preliminary mechanistic studies were conducted to gain deeper insights into the reaction mechanism, and the oxidized form of the aza-Breslow intermediate (imidoyl azolium) is isolated and characterized. Overall, this work is poised to enrich our understanding of NHC-catalyzed umpolung of imines for intermolecular reactions, and further studies on developing an enantioselective version of this reaction are ongoing.

Acknowledgments

Financial support by the Science and Engineering Research Board (SERB), Government of India (file Number: SCP/2022/000837), is greatly acknowledged. S.B. thanks IISc (for SRF) and R.C.D. thanks the Ministry of Education (for the PMRF) for the research fellowship. We thank Kishorkumar Sindogi (SSCU, IISc) for collecting the X-ray data of 3p and 11a and Dr. S. Kamilya (SSCU, IISc) for solving the X-ray data. We thank Sayan Shee (OC, IISc) for the helpful discussion.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/jacsau.4c01166.

  • Details on experimental procedures, characterization, and NMR spectra of functionalized oxindole derivatives (PDF)

  • X-ray data of 3p (CIF)

  • X-ray data of 11a (CIF)

Author Contributions

† S.B. and A.A.K. contributed equally. The manuscript was written through contributions of all authors. All of the authors approved the final version of the manuscript.

The authors declare no competing financial interest.

Supplementary Material

au4c01166_si_001.pdf (7.1MB, pdf)
au4c01166_si_002.cif (644.7KB, cif)
au4c01166_si_003.cif (4.2MB, cif)

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

au4c01166_si_001.pdf (7.1MB, pdf)
au4c01166_si_002.cif (644.7KB, cif)
au4c01166_si_003.cif (4.2MB, cif)

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