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11 November 2025

Synthesis of Quinoxalin-2(1H)-One Derivatives via the Novel Ugi 4CR, Followed by Palladium-Catalyzed Cyclization Process †

,
and
1
Centro Conjunto de Investigación en Quimica Sustentable UAEM-UNAM, Toluca de Lerdo 50200, Mexico
2
Facultad de Quimica, Universidad Autonoma del Estado de Mexico, Toluca 50120, Mexico
3
Departamento de Química, Universidad de Guanajuato, Guanajuato 36050, Mexico
4
Laboratoire de Synthèse Organique (LSO), CNRS, Ecole Polytechnique, ENSTA, Institut Polytechnqiue de Paris, 828 Bd des Maréchaux, 91128 Palaiseau, France
Chem. Proc.2025, 18(1), 148;https://doi.org/10.3390/ecsoc-29-26672
This article belongs to the Proceedings of The 29th International Electronic Conference on Synthetic Organic Chemistry
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Abstract

A novel synthetic methodology has been developed for the efficient preparation of Quinoxalin-2(1H)-one derivatives through a strategically designed combination of Ugi four-component reaction (4CR) followed by metal-catalyzed cross-coupling reactions. This innovative approach demonstrates exceptional versatility in generating molecular diversity by systematically modulating the reactivity profiles of the initially formed Ugi adducts, thereby enabling access to a broad library of structurally diverse quinoxalinone compounds. The synthetic protocol consistently delivered the desired final products in good to moderate yields, demonstrating the reliability and practicality of this methodology for preparative applications. Comprehensive structural characterization of all synthesized derivatives was accomplished through a combination of advanced spectroscopic techniques, including proton nuclear magnetic resonance (1H NMR), carbon-13 nuclear magnetic resonance (13C NMR), and high-resolution mass spectrometry, ensuring unambiguous confirmation of product identities and purities. The methodological framework employs 2-iodoaniline and 2-chloroacetic acid as the fixed amine and carboxylic acid components, respectively, in the multicomponent Ugi reaction, providing a consistent synthetic foundation. Subsequently, the resulting Ugi adducts undergo palladium-catalyzed cross-coupling transformations under optimized reaction conditions, facilitating the crucial cyclization and functionalization steps necessary for the formation of the target Quinoxalin-2(1H)-one derivatives. This sequential approach represents a significant advancement in heterocyclic synthesis methodology.

1. Introduction

In recent years, the swift synthesis of intricate molecular architectures has been facilitated by the implementation of diversity-oriented synthetic methodologies alongside so-called complexity-generating reactions. Multicomponent reactions (MCRs) [1,2], which amalgamate a minimum of three fundamental building blocks within a single reaction vessel, constitute an exceptionally potent framework for achieving both diversity and complexity while minimizing the number of reaction steps required. In this discourse, we delineate innovative modular reaction sequences predicated upon our earlier reported MCR chemistry in conjunction with cycloaddition reactions and transition-metal catalyzed cross-coupling processes [1]. Transformations catalyzed by palladium rank among the most robust and adaptable techniques in organic synthesis for the construction of C–C and C-heteroatom bonds [3], frequently providing unparalleled access to molecular frameworks that are otherwise challenging to synthesize.
In the context of our ongoing research initiative aimed at the identification of novel post-modifications [4,5] for compounds synthesized via multicomponent reactions (MCRs) [5], we sought to explore the potential of utilizing this cyclization with adducts generated through an Ugi reaction. From this perspective, we proposed a synthetic approach based on the Ugi reaction, which is subsequently followed by a sequential palladium-catalyzed cross-coupling reaction (Scheme 1) to yield Quinoxalin-2(1H)-one [6,7,8,9] derivatives.
Scheme 1. Reagents and conditions: (a) MeOH, rt, 24 h (b) 6 mol%PdCl2(CH3CN)2, 12 mol% C20H27P, Cs2CO3, DMA, 120 °C.
Quinoxalinones represent a category of nitrogen-containing fused heterocyclic compounds that have garnered significant interest owing to their multifunctional scaffolds pertinent to pharmacological agents [10,11], (Figure 1). These compounds manifest a multitude of biological activities, including antimicrobial [12], antifungal [13], antidiabetic [14], antiviral [15], anticancer [16], and anti-inflammatory properties [17]. The exploration of quinoxalinone scaffolds constitutes an exceptionally compelling endeavor within the realm of drug discovery initiatives.
Figure 1. Structures of some pharmaceutically relevant quinoxalin-2(1H)-one derivatives.
To advance our research focus [18,19,20] on the establishment of resilient methodologies with substantial user adoption in the pharmaceutical industry, we herein elucidate our synthetic protocol to produce quinoxalin-2(1H)-ones through the Ugi four-component reaction coupled with metal-catalyzed cross-coupling processes.
In this synthesis, the classical Ugi 4-component reaction is employed, wherein the constituent elements are meticulously adjusted to achieve diverse structural points, specifically incorporating aldehyde (1), 2-halo aniline (2), 2-chloroacetic acid (4), and isocyanide (3). The compounds 2-chloroacetic acid and 2-halo aniline serve as critical agents for modulating the diversity points during the subsequent modification reaction. The Ugi multicomponent reaction was executed under conventional conditions, wherein equimolar amounts of aldehyde (1), 2-halo aniline (2), 2-chloroacetic acid (4), and isocyanide (3) were solubilized in 1 M methanol and agitated at ambient temperature for 24 h, yielding Ugi adduct 5a–b in satisfactory to moderate yields. (Figure 2: 5a–b). The products obtained are characterized by 1H-NMR, 13C-NMR. The synthesized derivatives are mentioned below with their respective yields (Figure 2).
Figure 2. Ugi adducts (5a–b).
Following the synthesis of Ugi adducts 5a–b, we advance to palladium-mediated cyclization as a subsequent modification of the Ugi adduct, specifically selecting Ugi adduct 5a for the purpose of optimizing reaction conditions. The objective is to generate a diversity of products and modulate the reactivity of the Ugi adduct through the simultaneous formation of C-C and C-N bonds in a one-step process. Prior to initiating experimental procedures, we employed classical palladium catalysts and conducted a systematic screening of various catalysts and ligands. The efficacy of palladium-catalyzed reactions is largely contingent upon the judicious selection of appropriate ligands and catalysts, as well as the base utilized, which plays a crucial role in the overall reaction dynamics. The evaluation of various catalysts delineated in Table 1 substantiates the structural integrity through the application of 2D spectroscopic methodologies such as HMBC and HSQC, further corroborated by High-Resolution Mass Spectrometry (HRMS). The fundamental moiety of the resultant compound is identified as quinoxalin-2(1H)-one [1], which represents a significant category of heterocycles, holding substantial relevance in both biological and pharmaceutical contexts.
Table 1. Screening of catalysts and conditions for the Pd-catalyzed cyclization.
The product formed is confirmed by NMR. The proposed mechanism is mentioned in (Scheme 2). By this reaction, we observed the whole process of the first formation of diketopiperazine, which leads to product. The following mechanism explains the product formation. The reaction mechanism followed by the formation of Buchwald hartwig product 6, which is not isolable, undergoes base catalyzed intramolecular substitution and the nucleophilic reaction results in the formation of beta-lactam intermediate 7, which is unstable where retro cycloaddition reaction occurs, and elimination of ketene 8 leads to the formation of substituted quinoxalin-2(1H)-ones.
Scheme 2. The proposed palladium-catalyzed cyclization mechanism.
The compounds obtained (Figure 3), including intermediates characterized by 1H-NMR, 13C-NMR, and final product 6a, 6b were confirmed and described by HRMS, in which we found the mass of 6a to be 373. The observations were based on 1H -NMR and 13C-NMR, where characteristic signals of Ugi adduct 5a of 3.75 ppm and 3.82 ppm represent methoxy groups substituted on phenyl rings, 3.82–3.92 ppm represents the multiplet methylene group of benzyl of isocyanide, and 4.39–4.52 ppm represents the methylene protons of the acid component in the adduct. Meanwhile, the 5.95 ppm singlet is the amide proton and the 6.05 singlet represents the quaternary proton. These are the characteristic signals that confirm the formation of Ugi Adduct 5a, as well as the product. For 13C-NMR, the particular signs of adduct are aliphatic carbons which correspond to methylene carbons at 43.33 ppm and 43.68 ppm and methoxymethyl carbons at 55.18 ppm and 55.32 ppm and quaternary carbon at 65.06 ppm and aromatic halogenated carbon at 103.76 ppm. Their presence in the final product mainly confirms the absence of methylene carbon at 45.5 ppm and the absence of the quaternary proton. This changes the chemical shift in the carbon in response to 169.9 ppm palladium-mediated cyclization, which is confirmed by the absence of aromatic carbon at 103.76 ppm. These observations, as well as the HRMS analysis, provides us with brief confirmation of the final product containing substituted quinoxalin-2(1H)-ones.
Figure 3. The obtained derivatives.
Chemproc 18 00148 i001a
Chemproc 18 00148 i001b
Chemproc 18 00148 i001c
Chemproc 18 00148 i001d

2. Conclusions

In summary, we have developed an alternative synthetic route for quinoxalin-2(1H)-one derivatives in two steps of the reaction using Ugi 4CR followed by palladium-mediated cyclization as a post-condensation process in moderate yields. We have studied the tuning of the points of diversity in Ugi adduct. The quinoxalin-2(1H)-one derivatives are well characterized by NMR.

Author Contributions

Conceptualization, L.E.K. and R.G.M.; methodology, M.V.B.U.; software, M.V.B.U.; validation, R.G.M., M.V.B.U. and L.E.K.; formal analysis, M.V.B.U.; investigation, M.V.B.U.; resources, L.E.K. and R.G.M.; data curation, M.V.B.U., L.E.K. and R.G.M.; writing—original draft preparation, M.V.B.U., L.E.K. and R.G.M.; writing—review and editing, M.V.B.U., L.E.K. and R.G.M.; visualization, L.E.K. and R.G.M.; supervision, L.E.K. and R.G.M.; project administration, L.E.K. and R.G.M.; funding acquisition, L.E.K. and R.G.M. All authors have read and agreed to the published version of the manuscript.

Funding

This investigation received financial support from SECIHTI, Mexico, under the funding number 378051 (M.V.B.U.).

Institutional Review Board Statement

Not applicable.

Data Availability Statement

The raw data supporting the conclusions of this article will be made available by the authors on request.

Acknowledgments

M.V.B.U. thanks SECIHTI, Mexico, for the financial support provided through Scholarship 378051.

Conflicts of Interest

The authors declare no conflicts of interest.

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