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Review

Recent Developments in Direct C–H Functionalization of Quinoxalin-2(1H)-Ones via Multi-Component Tandem Reactions

by
Qiming Yang
1,2,*,
Biao Wang
1,
Mian Wu
2 and
Yi-Zhu Lei
1,*
1
Guizhou Provincial Key Laboratory of Coal Clean Utilization, School of Chemistry and Materials Engineering, Liupanshui Normal University, Liupanshui 553004, China
2
Henan Key Laboratory of New Optoelectronic Functional Materials, College of Chemistry and Chemical Engineering, Anyang Normal University, Anyang 455000, China
*
Authors to whom correspondence should be addressed.
Molecules 2023, 28(6), 2513; https://doi.org/10.3390/molecules28062513
Submission received: 6 February 2023 / Revised: 25 February 2023 / Accepted: 6 March 2023 / Published: 9 March 2023
(This article belongs to the Special Issue Multicomponent Reactions in Organic Synthesis)
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Abstract

:
The direct C–H multifunctionalization of quinoxalin-2(1H)-ones via multicomponent reactions has attracted considerable interest due to their diverse biological activities and chemical profile. This review will focus on recent achievements. It mainly covers reaction methods for the simultaneous introduction of C–C bonds and C–RF/C/O/N/Cl/S/D bonds into quinoxalin-2(1H)-ones and their reaction mechanisms. Meanwhile, future developments of multi-component reactions of quinoxalin-2(1H)-ones are envisaged, such as the simultaneous construction of C–C and C–B/SI/P/F/I/SE bonds through multi-component reactions; the construction of fused ring and macrocyclic compounds; asymmetric synthesis; green chemistry; bionic structures and other fields. The aim is to enrich the methods for the reaction of quinoxalin-2(1H)-ones at the C3 position, which have rich applications in materials chemistry and pharmaceutical pharmacology.

1. Introduction

In multi-component reactions (MCRs), three or more substrate molecules are transformed in a single pot to produce the desired product. In some cases, they are also referred to as multi-component assembly processes (MCAPs). Through MCRs, a large number of organic compounds can be synthesized in an efficient and atom-economic manner, with little waste and no hazardous substances, and with high yields of final products [1,2,3]. MCRs were first proposed by Strecker in 1850 for the synthesis of α-amino nitriles from ammonia, carbonyl compounds and hydrogen cyanide [4,5,6,7]. Subsequently, more and more researchers have become interested in this approach, as this multiple bonding route involving C–C and C–heteroatom bond formation can be used to prepare a variety of heterocyclic compounds with combinatorial, medicinal and agricultural chemistry applications [8,9]. In recent years, multicomponent reactions using quinoxalin-2(1H)-ones as a substrate have gained increasing interest (Scheme 1). A range of ingenious and innovative methods have been developed to offer prosperous prospects for this highly applicable compound.
Quinoxalin-2(1H)-ones have been considered as a specific class of heterocyclic structural groups existing in a diverse range of biologically active natural products and pharmaceutical compounds [10,11,12]. Furthermore, the quinoxalin-2(1H)-one fragment is a promising electron-withdrawing substituent for the development of push-pull systems with promising photophysical properties for various applications in material science [13,14]. In particular, the C3-substituted quinoxalin-2(1H)-one derivatives show a broad range of biological activities (Scheme 2) [15,16,17,18,19,20,21,22,23,24]. The direct C–H functionalization of quinoxalin-2(1H)-ones at the C3 position is the most cost-effective way to synthesize a wide range of quinoxalin-2(1H)-one derivatives containing valuable functional groups. In recent years, quinoxalin-2(1H)-one has been prominently studied [15,16,17,18,19,20,21,22,23,24]. Furthermore, the direct acid-catalyzed C–H bond functionalization of quinoxalin-2(1H)-one based on a nucleophilic aromatic substituted hydrogen approach (SNH-reaction) is of equal interest [25,26,27,28,29]. Several reviews summarize the C-3 functionalization of quinoxalin-2(1H)-one and were published between 2019 and 2021 [15,16,17,18,19,20,21,22,23,24]. However, there are no reviews discussing the topical issue of the C–H functionalization of quinoxalin-2(1H)-one via multicomponent reactions. Our group has also conducted some studies on the functionalization of quinoxalin-2(1H)-one at the C3 position [30,31,32]. Therefore, a review is necessary in order to better develop the functionalization of quinoxalin-2(1H)-one at the C3 position via a multi-component tandem approach. This review focuses on the C–H functionalization of quinoxalin-2(1H)-one by multi-component tandem reaction methods in recent years and demonstrates the corresponding reaction mechanisms. We classify them according to the different chemical bonds formed and the simultaneous construction of both C–C and C–RF/C/O/N/Cl/S/D bonds via multi-component tandem reactions.

2. Direct C–H Functionalization of Quinoxalin-2(1H)-Ones via Multi-Component Tandem Reactions

2.1. Simultaneous Construction of Both C–C and C–RF Bonds via Multi-Component Tandem Reactions

Organic fluorides are widely found in pharmaceuticals, agrochemistry, and materials science. The introduction of fluorine atoms into the organic framework not only produces profound changes in the physical and chemical properties of the target molecules, but also has special biological properties [33]. During the direct C–H bifunctionalization of quinoxalin-2(1H)-ones through multi-component tandem reactions, it is possible to construct bonds C–C bonds and C–RF bonds in a single step. Recently reported reactions include trifluoroalkylation, difluoroalkylation and perfluoroalkylation.

2.1.1. Trifluoroalkylation

In 2020, Wei et al. [34] reported a simple and efficient three-component protocol for the construction of various 3-trifluoroalkylquinoxalin-2(1H)-ones via K2S2O8-mediated difunctionalization of unactivated alkenes with quinoxalin-2(1H)-ones and CF3SO2Na under metal-free conditions (Scheme 3). As soon as water was added to this reaction system, the reaction efficiency was evidently improved. The optimal reaction conditions were determined after screening a variety of oxidants and solvents. K2S2O8 proved to be the preferred oxidant, and a 4:1 ratio of CH3CN/H2O produced the highest quality product with 77% yield. Differently substituted quinoxalin-2(1H)-ones and unactivated alkenes were used to investigate substrate scope after the reaction conditions were established. Following a series of control experiments, the mechanism of the reaction was established. The addition of TEMPO resulted in the complete quenching of the reaction progress, confirming the presence of a radical mechanism. Furthermore, the radical addition product was detected by LC-MS when the radical capture reaction of ethene-1,1-diyldibenzene was conducted under standard conditions. As shown in Scheme 3, a possible reaction mechanism has been proposed. At the beginning, K2S2O8 was used to produce CF3 radical 1e. In subsequent steps, alkene 1b was selectively added to the CF3 radical to generate alkyl radical 1f. In turn, alkyl radical 1f added to quinoxalin-2(1H)-one 1a produced nitrogen radical 1g. Then, intermediate 1g was further oxidized by K2S2O8 to give a nitrogen cation intermediate 1h. Finally, the desired product 1d was obtained by the deprotonation of intermediate 1h.
In 2020, Li et al. [35] also used CF3SO2Na, unactivated alkenes and quinoxalin-2(1H)-ones to complete a three-component reaction (Scheme 4). The difference was the use of PhI(OAc)2 as the oxidant and ethyl acetate as the solvent. A variety of different unactivated alkenes and quinoxalin-2(1H)-ones are suitable for this reaction method. Maximum yields of 80% were achieved. The reaction mechanism was also found to be a free radical mechanism after controlled experiments, which is basically consistent with the reaction mechanism reported by Wei’s group (Scheme 4).
In the same year, Huang et al. [36] reported an unexpected three-component reaction of quinoxalin-2(1H)-one, tert-butyl peroxybenzoate (TBPB) and hexafluoroisopropanol (HFIP) (Scheme 5). A variety of hydroxyhexafluoroisobutylated quinoxalin-2(1H)-ones were formed under CuBr-catalyzed and TBPB-oxidized conditions. In screening the reaction conditions, the addition of K2CO3 resulted in a significant increase in yield. The range of substrates was extended with a maximum isolated yield of 72%. The methylene in the product was deduced from TBPB, and the reaction mechanism was proposed after controlled experiments and literature reports. TBPB was reduced by Cu(I) to produce the tert-butoxy radical. β-Scission of the tert-butoxy radical yielded acetone and a methyl radical, which was then added to quinoxalin-2(1H)-one 3a to form the radical intermediate 3e. On the other hand, a two-step hydrogen atom transfer (HAT) from HFIP to methyl generated hexafluoroacetone. Finally, the nucleophilic addition of 3f and hexafluoroacetone produced product 3d (Scheme 5).
In the year 2021, Wei’s group [37] reported different photocatalytic methods for the same reaction (Scheme 6). They have developed a facile and efficient visible-light-induced three-component reaction of quinoxalin-2(1H)-ones, alkenes and CF3SO2Na, leading to various 3-trifluoroalkylated quinoxalin-2(1H)-ones at room temperature. The present photocatalytic tandem reaction, which utilizes 4CzIPN (1,2,3,5-tetrakis(carbazol-9-yl)-4,6-dicyanobenzene) as the photocatalyst and air as the green oxidant, offers a mild and environmentally friendly protocol to access a number of 3-trifluoroalkylated quinoxalin-2(1H)-ones in moderate to favorable yields. Through this methodology, various 3-trifluoroalkylated quinoxalin-2(1H)-ones could be obtained in moderate to high yields from simple and readily available materials in the absence of any strong external oxidant. Following a series of control experiments, the mechanism of the reaction was established. Moreover, Stern–Volmer quenching experiments were conducted to prove an energy transfer process between 4CzIPN and substrates under visible-light irradiation. As shown in Scheme 6, a possible reaction pathway was proposed. In the first step, 4CzIPN* was excited from 4CzIPN by visible-light irradiation. Afterwards, 4CzIPN•− and radical cation 4e were produced by a single electron transfer (SET) from 4a to the excited state of 4CzIPN*. 4CzIPN•− was oxidized by dioxygen to give the ground state 4CzIPN and O2•−. At the same time, CF3SO2Na 4c was oxidized by O2 (air) to produce the O-centered radical 4f. Radical 4f underwent self-induced loss reduction in SO2 to give CF3 radical 4g. Subsequently, 4g was added to the olefin 4b to form the alkyl radical 4h, which attacked the radical cation 4e and formed a nitrogen cation 4i. Lastly, the deprotonation of 4i produced the desired product 4d.
In the same year, the Huang team [38] reported a three-component tandem reaction for the photocatalytic bifunctionalization of olefins using quinoxalin-2(1H)-ones and ICH2CF3/ICH2CF2H as feedstocks and Ir(ppy)2(dtbbpy)PF6 (ppy = 2-phenylpyridine, dtbbpy = 4,4′-di-tert-butyl-2,2′-bipyridine) as catalyst. (Scheme 7). Various trifluoroacetylated and difluoroacetylated quinoxalin-2(1H)-ones were synthesized. In the substrate extension, the highest yield of the three-component reaction of trifluoroethylated quinoxalin-2(1H)-ones reached 77%, and the highest yield of the three-component reaction of difluoroethyl quinoxalin-2(1H)-ones reached 74%. After controlled experiments and literature analysis, they suggested that the mechanism of this three-component reaction might be a free radical cascade reaction, but no reaction details were given.
Graphene oxide (GO) has an abundance of defects and a wide range of oxygen functional groups that can be used in organocatalytic reactions. In 2021, Liu et al. [39] proposed a three-component tandem reaction using GO as a catalyst and CF3SO2Na as a powerful CF3 radical source to form olefinic C–CF3 with quinoxalin-2(1H)-ones and alkynes, resulting in a series of E/Z isomeric mixed 3-trifluoroalkyl quinoxalin-2(1H)-ones. Based on mechanistic studies, GO is capable of auto-tandem radical addition to trifluoromethyl and superoxide radicals (Scheme 8).
In 2022, Shen et al. [40] developed a three-component reaction consisting of indole, quinoxalin-2(1H)-one and CF3SO2Na, using CuF2 as a catalyst and K2S2O8 as an oxidant, to easily obtain various 3-[2-(trifluoromethyl)1H-indol-3-yl]quinoxalin-2(1H)-ones (Scheme 9). The strategy exhibited high site selectivity, step economy and a wide range of substrates. A possible reaction mechanism was suggested in Scheme 9. A weak coordination between Cu(II)Ln species and the nitrogen atom of quinoxalin-2(1H)-one led to the generation of 7e. By oxidative dehydrogenation, 7e reacted with 7b to form 7f, which was then converted to 7h. In addition, Cu(I)Ln was oxidized by K2S2O8 to Cu(II)Ln. By weak coordination of Cu(II)Ln species with the carbonyl group of the quinoxalin-2(1H)-one motif, 7h combined with Cu(II)Ln to produce complex 7i. As a result of the oxidation of CF3SO2Na and K2S2O8, a trifluoromethyl radical was generated. Then, the indole ring of complex 7i was attacked by a CF3· to produce 7j, which was transformed into intermediate 7k through the single electron transfer (SET) process. Thereafter, the oxidation of 7k occurred, leading to compound 7l by oxidation. Eventually, the target product 7d was obtained by the deprotonation of 7l with the regeneration of Cu(II)Ln.

2.1.2. Perfluoroalkyl

In 2019, Studer et al. [41] described the reaction of α-perfluoroalkyl-β-heteroaryl groups with perfluoroalkyl iodides and quinoxalin-2(1H)-ones on various alkenes initiated under visible light (Scheme 10). This three-component free radical cascade reaction allowed the efficient synthesis of a series of quinoxalin-2(1H)-one derivatives containing perfluoroalkyl groups in moderate to excellent yields under mild conditions. The reactions proceed through acidic amino radicals that are readily deprotonated to give the corresponding radical anions capable of maintaining the radical chains. The radical chains act as reducing reagents for single electron transfer (Scheme 10).

2.1.3. Difluoroalkylation

In 2022, Lu et al. [42] published a photocatalytic three-component reaction consisting of quinoxalin-2(1H)-ones, alkenes and hypervalent iodine(III) reagents (Scheme 11). They used an original difluoroiodine(III) reagent of their own design, showing high reactivity with [bis(trifluoroacetoxy)iodo]benzene (PIFA) as the oxidizing agent. Under mild conditions, a wide range of difluoroalkyl-substituted quinoxalin-2(1H)-ones can be obtained in up to 95% yield. The experimental mechanism suggests the involvement of a difluoroalkyl radical intermediate in this reaction (Scheme 11).
In the same year, Li et al. [43] reported visible-light photoredox-catalyzed, unactivated olefin, quinoxalin-2(1H)-one and bromodifluorinated reagents involved in a three-component reaction via fac-Ir(ppy)3 catalysis (Scheme 12). The difluoroalkyl-containing quinoxalin-2(1H)-ones were synthesized by the single-step formation of two novel C–C bonds under mild reaction conditions. Three-component reactions showed high functional group compatibility and a wide range of substrates. Free radical processes may be responsible for this three-component transformation, according to preliminary mechanistic studies (Scheme 12).

2.2. Simultaneous Construction of Double C–C Bonds via Multi-Component Tandem Reactions

The establishment of C–C bonds by direct C–H functional grouping is more atomically economical than the establishment of C–C bonds based on transition metal-catalyzed cross-coupling reactions of halogenated hydrocarbons [44].

2.2.1. Alkylation

In 2021, Yao et al. [45] described a metal-free catalytic, H2O2-mediated three-component reaction of quinoxalin-2(1H)-ones, DMSO and styrene. A series of 3-substituted quinoxalin-2(1H)-ones were synthesized using DMSO as the methylation reagent (Scheme 13). The reaction substrates were well tolerated and the products were obtained in moderate to acceptable yields, with the highest yields up to 86%. The reaction was shown to be a free radical reaction mechanism by controlled experiments. Initially, hydroxyl radicals were generated through the homolytic cleavage of H2O2 and subsequently reacted with DMSO to produce methyl radicals 11e. The methyl radical then selectively attacked styrene 11b, generating alkyl radical 11f. As a result of the addition of alkyl radical 11f to quinoxalin-2(1H)-one 11a, a nitrogen radical 11g was formed, which was then oxidized by H2O2, resulting in a nitrogen cation intermediate 11h. In the end, intermediate 11h was deprotonated to produce the desired product (Scheme 13).
In 2022, Baishya et al. [46] reported a three-component reaction of quinoxalin-2(1H)-ones with 4-hydroxycoumarin/4-hydroxy-6-methyl-2-pyrone and aryl ethylene (Scheme 14). The 3-alkylquinoxalin-2(1H)-one was synthesized using K2S2O8 as the oxidant and DMSO as the solvent. During the optimization of the reaction conditions, the highest yield of the three-component product was only 44%. They performed substrate extensions with yields below 48%. The involvement of free radicals in the reaction process was demonstrated by controlled experiments. The reaction mechanism was essentially similar to the above reaction, with K2S2O8 initiating free radicals (Scheme 14).

2.2.2. Cyanoalkylation

In the same year, Baishya and his group [47] published a K2S2O8-mediated three-component reaction (Scheme 15). The reaction of quinoxalin-2(1H)-ones with azobis(alkylcarbonitrile)s and aryl ethylenes was used to synthesize 3-cyanoalkyl quinoxalin-2(1H)-ones. This scheme introduced cyano into quinoxalin-2(1H)-ones and is widely used in reasonable yields and acceptable functional group tolerances. The replacement of aryl ethylene with phenylacetylene is also applicable to this method. Controlling experimental and literature knowledge, they proposed a radical reaction mechanism similar to the above alkylation (Scheme 15). The reaction started by heating AIBN to form the 1,1-dimethyl-1-cyanomethyl radical 13e, which added to the terminal position of the olefin to give the secondary alkyl radical 13f. Then, 13f attacked the C3 position of the quinoxalin-2(1H)-one 13a to give the N-radical 13g which, after H-atom abstraction by the excess SO4•− present in the reaction medium, gave the three-component desired product 13d (pathway a). Again, 13g was deprotonated to form the radical anion 13h. Then, 13h reacted with persulphate via SET to give the desired product 13d (pathway b).

2.3. Simultaneous Construction of Both C–C and C–O Bonds via Multi-Component Tandem Reactions

Ether functional groups constructed through C–C and C–O bonds are an essential structural characteristic of many natural products, pharmaceutical functional materials and agrochemicals [48].
In 2022, Yao et al. [49] implemented a simple strategy for the synthesis of 3-substituted quinoxalin-2(1H)-ones containing ether units via a three-component synthesis of quinoxalin-2(1H)-one, styrene, and tert-butyl peroxybenzoate (TBPB) using CuCl as a catalyst (Scheme 16). This method introduced both C–C and C–O bonds in the product with acceptable functional group tolerance. After controlled experiments, a reaction mechanism was proposed in Scheme 16. First, TBPB 14c was homolytically cleaved under heating conditions to produce benzoyloxy radicals (BzO·) and tert-butoxy radicals 14e. Simultaneously, Cu(I) was converted to Cu(II) and BzO− was converted to benzoyloxy anion (BzO−) due to electron transfer. At the same time, 14e selectively attacked styrene 14b, leading to the generation of alkyl radical 14f. Next, 14f was added to 14a to produce nitrogen radical 14g. Then, 14g provided the nitrogen cation 14h via Cu(II) single-electron oxidation. Finally, the expected coupling product 14d was provided by the deprotonation of 14h.
In the same year, Wang et al. [50] reported the visible light-induced bifunctionalized three-component reaction of 2,3-dihydrofuran with quinoxalin-2(1H)-one and tert-butyl hydroperoxide (Scheme 17). They synthesized a series of 2,3-disubstituted tetrahydrofurans in high yields by simultaneously forming C–C and C–O bonds using 2,4,6-triphenylpyrylium tetrafluorborate (TPPT) as a photocatalyst. The multicomponent reactions exhibited excellent site-selectivity of carbon–carbon double bonds, superior functional group tolerance and high diastereoselectivity (d.r. > 99%). The mechanism was determined by controlled experiments and hydroxyl radical assay as a visible light-induced radical reaction (Scheme 17). First, the photocatalyst (PC+) was excited under visible light irradiation to generate the excited species (PC+*), which then underwent a single electron transfer (SET) process with substrate 15a to afford a radical cation intermediate 15e and a PC•. tert-Butyl hydroperoxide (TBHP) abstracted an electron from the obtained PC· to give a HO· radical, which could be detected by EPR, and a tBuO− together with the oxidation of PC• to PC+ for the catalytic cycle. On the other hand, A reacted with 2,3-dihydrofuran (15b) to give intermediate 15f, which was attacked by TBHP as a nucleophilic reagent to give intermediate 15g. In the presence of tBuO−, the deprotonation of 15g gave the intermediate 15h. Finally, 15h underwent SET oxidation and deprotonation to give the desired product 15d.

2.4. Simultaneous Construction of Both C–C and C–N Bonds via Multi-Component Tandem Reactions

2.4.1. Azidoalkylation

It is highly attractive to synthesize organic azides by difunctionalizing alkenes, owing to the efficient and consecutive introduction of N3 and other functional groups [51]. Specifically, organic azides resulting from this process could undergo a variety of transformations and have a wide range of synthetic applications.
In 2019, Zhang et al. [51] reported for the first time a three-component tandem reaction of quinoxalin-2(1H)-ones with unactivated olefins and TMSN3 (Scheme 18). The reaction used a hypervalent iodine(III) reagent as an oxidant to synthesize a series of quinoxalin-2(1H)-ones containing azide groups. Remarkably, this was an efficient transformation accomplished within 1 min. Through controlled experiments, a single electron transfer (SET) mechanism was revealed in Scheme 18. Initially, TMSN3 was oxidized by PhI(TFA)2 to produce the azide radical 16e. The resulting 16e was then chemically selectively added to 16b to yield an alkyl radical 16f. Next, the addition of 16f to substrate 16a yielded the nitrogen radical intermediate 16g. Thereafter, 16g was converted to a carbon radical 16h via a 1,2-hydrogen transfer process. Then, 16h was further oxidized by PhI(TFA)2 to form a carbon cation intermediate 16i via another single electron transfer (SET) process. Lastly, the desired product 16d was provided by the deprotonation of 16i.
In 2020, Qin et al. [52] published a cascade azidoalkylation reaction with a free radical mechanism (Scheme 19). This three-component reaction used PhI(OAc)2 as an oxidant to provide a valuable series of β-azidoalkylated quinoxalinones by coupling olefins, quinoxalin-2(1H)-ones, and TMSN3. Notably, the reaction was completely blocked when the base was removed from the reaction system. Why the presence of bases was indispensable was not answered by the authors. There was a puzzling result in contrast to Zhang’s study [51] where the same oxidant (PhI(OAc)2), solvent (MeCN) and temperature (r.t.) gave 0% yield while Zhang’s result was 52% yield. The only difference was that Zhang was an open bottle reaction and Qin was N2 protected. A free radical reaction mechanism similar to that described above was proposed by controlled experiments and previous reports (Scheme 19).
In 2022, the same Zhang group [53] demonstrated a visible light-mediated three-component tandem reaction method using 9-mesityl-10-methylacridinium perchlorate (Acr+MesClO4−) as a photocatalyst for the reaction of N-heterocyclic aromatic hydrocarbons with unactivated olefins and TMSN3 (Scheme 20). This strategy achieved a room temperature conversion that was not achieved by previous authors and does not use a polyvalent iodine reagent. It is noteworthy that the reaction cannot be carried out under an N2 atmosphere. The method is very tolerant of functional groups and enables the synthesis of various heterocyclic olefins with medicinal value. The mechanism of the visible light-driven free machine reaction was proposed by controlled experiments. The overall process is consistent with the thermocatalytic reaction mechanism except that it starts with the photocatalytic initiation of the azide free machine and ends with O2·− deprotonation to obtain the product (Scheme 20).

2.4.2. Oxime

In 2021, Zhang et al. [54] developed a multicomponent reaction for the synthesis of (E)-quinoxalin-2(1H)-ones oximes (Scheme 21). The reaction consisted of quinoxalin-2(1H)-ones, ketone and tert-butyl nitrite (TBN) as three components. It should be noted that the reaction cannot be completed in the absence of CH3SO3 or under a N2 atmosphere. A variety of gram-level oxime-containing quinoxalin-2(1H)-ones were obtained by recrystallization. The reaction mechanism is proposed by controlled experiments in Scheme 21. Initially, the imino ion 18e was produced by the protonation of 18a. Simultaneously, acetone 18b was converted to the enol form 18f under acidic conditions. Next, A reacted with 18f to give 18h. Then, 18h was turned into 18i by an oxidative dehydrogenation process. Simultaneously, the homogeneous decomposition of TBN produced tert-butoxy (tBuO·) and nitroso (·NO) radicals. Subsequently, the nitroso (·NO) radical assaulted the C=C bond of 18i to give intermediate 18j, which then oxidized to intermediate 18k through tert-butoxy (tBuO·). Lastly, the goal product was produced by the isomerization of 18k.

2.5. Simultaneous Construction of Both C–C and C–Cl Bonds via Multi-Component Tandem Reactions

In 2021, Zhang’s group [55] published the second three-component reaction on quinoxalin-2(1H)-ones (Scheme 22). A novel clean green multicomponent transformation of methyl ketones with α-bifunctionalization was achieved by a homogeneous ion-exchange resin Amberlyst 15 catalyst and sunlight catalysis. The reaction was carried out in water and air. Quinoxalinones containing both chloro- and keto-functional groups were obtained in moderate to acceptable yields. A similar reaction mechanism to that previously reported in Scheme 21 was proposed through a series of controlled experiments.

2.6. Simultaneous Construction of Both C–C and C–S Bonds via Multi-Component Tandem Reactions

Chemicals and physiologists are very interested in sulfur-containing compounds since they play an instrumental role in drug discovery and structural modification. Sulfones can not only act as wonderful pharmaceuticals, such as anticancers, antioxidants, and antifungals, but also serve as significant precursors for the synthesis of Sulphonic acids, sulfoxides, sulfanilamides and thioethers [56].

2.6.1. Sulfonyl Hydroxylation

In 2019, Koley et al. [57] proposed a three-component radical cascade reaction using TBHP as oxidant for the synthesis of α-sulfonyl-β-heteroaryl scaffolds using olefins, aryl sulfites and quinoxalin-2(1H)-ones (Scheme 23). When screening the reaction conditions, oxygen was found to be unfavorable for the reaction. A series of quinoxalin-2(1H)-ones containing sulfonyl groups were synthesized with high yields and functional group tolerance. A free radical reaction mechanism was postulated by controlled experiments (Scheme 23).
In 2020, Lee et al. [58] reported a stereoselective synthesis of various functionalized vinyl sulfones via a three-component vinyl sulfonation reaction of quinoxalin-2(1H)-ones, terminal alkynes and sulfonyl hydrazides under copper catalysis and TBHP oxidation. (Scheme 24). The reaction had a vast range of substrates. In the absence of a catalyst, this reaction could not proceed. Preliminary studies suggest that the reaction was a single electron transfer (SET) reaction mechanism. Sulfonyl hydrazide can be used as a source of sulfonyl radicals, which form through the interaction between Cu(II) and TBHP (Scheme 24).
In 2021, He’s group [59] proposed a visible-light photocatalytic four-component sulfur dioxide insertion reaction using Rhodamine 6G as a catalyst to synthesize a series of vinyl sulfone-containing quinoxalin-2(1H)-ones from alkynes, sodium metabisulfite, aryldiazonium and quinoxalin-2(1H)-ones (Scheme 25). Both C–C bonds and C–S bonds could be constructed in a single operation. By comparing NMR spectra, the vinyl sulfone product was determined to be in the Z-configuration, with only trace amounts of isomers in the E-configuration (Z/E > 30/1). A possible mechanism for visible light-induced reactions is proposed in Scheme 25. In the same year, their group [60] proposed a similar visible-light photocatalytic four-component sulfur dioxide insertion reaction. The difference is that alkynes are replaced with alkenes.
In 2021, Jiang et al. [56] published a direct bifunctionalized three-component cascade reaction of olefins with quinoxalin-2(1H)-one and sodium sulfonate using potassium persulfate (K2S2O8) as an oxidant to obtain a series of sulfone derivatives (Scheme 26). This method used only environmentally friendly water as the reaction solvent. A free radical reaction mechanism similar to such reactions was proposed by controlled experiments (Scheme 26). Initially, sodium sulfonates were converted to the corresponding radicals (22e) by the oxidation of K2S2O8. Subsequently, a radical addition of a sulfone radical via the C=C bond of alkenes was a critical step and led to the formation of the alkyl radical intermediate 22f. The active alkyl radical species 22f then reacted with quinoxalinones (22a) by addition at the most electrophilic C3 position to give the nitrogen radical species (22g), which rapidly underwent further dehydrogenation/oxidation by potassium persulfate to give the bifunctional sulfone derivatives (22d).
In 2022, Wei’s group [61] reported the photocatalytic three-component tandem reaction of quinoxalin-2(1H)-ones, alkenes, and sulfites (Scheme 27). Using 4CzIPN as the catalyst and oxygen (air) as the oxidant, the tandem reaction prepared a series of sulfonated quinoxalin-2(1H)-ones. Free radical trapping experiments and fluorescence quenching experiments elucidated the visible light-mediated free radical reaction process (Scheme 27).

2.6.2. Thioalkylation

In the same year, Roy et al. [62] first developed an efficient and environmentally friendly three-component cascade reaction for the thioalkylation of quinoxalin-2(1H)-ones with olefins and aryl disulfides under visible light in the presence of no catalyst (Scheme 28). It is worth noting that oxygen is very detrimental to product generation. A series of sulfur-containing quinoxalin-2(1H)-ones were synthesized with excellent functional group tolerance and broad substrate suitability. This approach is also applicable to phenylacetylene instead of olefins. Mechanistic studies suggest that a major pathway is the involvement of quinoxalin-2(1H)-ones in the reaction as photosensitizers.

2.7. Simultaneous Construction of Both C–C and C–D Bonds via Multi-Component Tandem Reactions

In 2020, Li et al. [63] first reported a fast three-component deuterated quinoxalin-2(1H)-ones reaction promoted by Fe(III) with alkenes and NaBD4 (Scheme 29). A series of deuterated quinoxalin-2(1H)-ones were synthesized with moderate to high yields. Through controlled experiments, they proposed a free radical reaction mechanism similar to that of other three-component reactions (Scheme 29).

3. Summary and Outlook

The direct C–H functionalization of quinoxalin-2(1H)-ones via multicomponent reactions allows the one-pot introduction of diverse functional groups, a facile and efficient method that has attracted increasing interest from synthetic chemists and which holds broad promise for medicinal chemistry and functional materials. In this review, we provide an overview of the C–H functionalization of quinoxalin-2(1H)-ones at the C3 position via multi-component reactions that have been reported in recent years in terms of the different categories of bond formation, and show the mechanisms of reactions that are mostly radical-based in order to provide a more in-depth and rapid understanding of the reactions. In addition, a number of meaningful functional groups commonly found in drugs such as trifluoromethyl, difluoromethyl, perfluoromethyl, alkyl, cyano, oxime, azide, alkoxy, sulfonyl, sulfur, deuterium and chloride are introduced into these quinoxalin-2(1H)-ones are summarized.
Despite these outstanding achievements, relatively few multicomponent reactions of quinoxalin-2(1H)-ones have been reported, and further work on the development of multicomponent reactions of quinoxalin-2(1H)-ones is essential. Firstly, the multicomponent reactions of quinoxalin-2(1H)-ones have not yet involved the simultaneous construction of C–C bonds and C–B/SI/P/F/I/SE bonds. In particular, the C–B/F/I/SE bond at the C3 position of quinoxalin-2(1H)-ones, which has not yet been completed, is expected to be completed by the multicomponent reactions of quinoxalin-2(1H)-ones. Secondly, the construction of fused ring and macrocyclic compounds by multicomponent reactions of quinoxalin-2(1H)-ones is also unexplored. Thirdly, asymmetric synthesis is a constant topic of research in organic methodology and the direct completion of asymmetric catalytic reactions at the C3 position of quinoxalin-2(1H)-ones is challenging, whereas the introduction of chiral centers via multicomponent reactions of quinoxalin-2(1H)-ones is a concise route. Fourthly, from the perspective of green chemistry, both photocatalysis and non-homogeneous catalysts that can be recycled are indispensable for the development of multi-component reactions of quinoxalin-2(1H)-ones. Fifthly, the parent nucleus structure of quinoxalin-2(1H)-ones is present in the metabolites of Streptomyces [64] (Scheme 2), and it is necessary to investigate the mimetic structure through the multicomponent reactions of quinoxalin-2(1H)-ones. In conclusion, we hope that this review will be useful for research in this field. The multicomponent reactions of quinoxalin-2(1H)-ones offer an atomically economical, environmentally friendly and sustainable approach for the preparation of a wide range of functionalized quinoxalin-2(1H)-ones with promising applications in materials science and medicinal chemistry.

Author Contributions

Conceptualization, writing—review and editing, Q.Y. and Y.-Z.L.; validation, B.W. and M.W.; supervision, Y.-Z.L. All authors have read and agreed to the published version of the manuscript.

Funding

This work was supported by the National Natural Science Foundation of China (Grant No. 22162017), the Key Research Projects of Henan Higher Education Institutions (CN) (Grant No. 21A350001), the Top Science and Technology Talents Project of Guizhou Education Department ([2020]038), the State Key Laboratory of Materials-Oriented Chemical Engineering (No. KL-MCE-22B01), Guizhou Provincial Key Laboratory of Coal Clean Utilization ([2020]2001) and Guizhou Provincial Science and Technology Planning Project of China (No. QKHPTRC[2019]5907).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

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Molecules 28 02513 sch001 550
Scheme 1. Direct C–H functionalization of quinoxalin-2(1H)-ones via multi-component tandem reactions.
Scheme 1. Direct C–H functionalization of quinoxalin-2(1H)-ones via multi-component tandem reactions.
Molecules 28 02513 sch001
Molecules 28 02513 sch002 550
Scheme 2. C-3 substituted bio-active quinoxalin-2(1H)-ones derivatives.
Scheme 2. C-3 substituted bio-active quinoxalin-2(1H)-ones derivatives.
Molecules 28 02513 sch002
Molecules 28 02513 sch003 550
Scheme 3. Trifluoroalkylation of quinoxalin-2(1H)-ones with unactivated alkenes.
Scheme 3. Trifluoroalkylation of quinoxalin-2(1H)-ones with unactivated alkenes.
Molecules 28 02513 sch003
Molecules 28 02513 sch004 550
Scheme 4. Trifluoroalkylation of quinoxalin-2(1H)-ones with unactivated alkenes.
Scheme 4. Trifluoroalkylation of quinoxalin-2(1H)-ones with unactivated alkenes.
Molecules 28 02513 sch004
Molecules 28 02513 sch005 550
Scheme 5. C–H functionalization of quinoxalin-2(1H)-ones with hexafluoroisopropanol.
Scheme 5. C–H functionalization of quinoxalin-2(1H)-ones with hexafluoroisopropanol.
Molecules 28 02513 sch005
Molecules 28 02513 sch006 550
Scheme 6. Visible-light-induced trifluoroalkylated quinoxalin-2(1H)-ones.
Scheme 6. Visible-light-induced trifluoroalkylated quinoxalin-2(1H)-ones.
Molecules 28 02513 sch006
Molecules 28 02513 sch007 550
Scheme 7. Photoredox-catalyzed trifluoroethylation and difluoroethylation.
Scheme 7. Photoredox-catalyzed trifluoroethylation and difluoroethylation.
Molecules 28 02513 sch007
Molecules 28 02513 sch008 550
Scheme 8. Graphene oxide-catalyzed trifluoromethylation.
Scheme 8. Graphene oxide-catalyzed trifluoromethylation.
Molecules 28 02513 sch008
Molecules 28 02513 sch009 550
Scheme 9. Copper-catalyzed multicomponent reaction to construct fluorinated indole-quinoxalin-2(1H)-ones.
Scheme 9. Copper-catalyzed multicomponent reaction to construct fluorinated indole-quinoxalin-2(1H)-ones.
Molecules 28 02513 sch009
Molecules 28 02513 sch010 550
Scheme 10. Photoinitiated three-component α-perfluoroalkyl-β-heteroarylation of unactivated alkenes.
Scheme 10. Photoinitiated three-component α-perfluoroalkyl-β-heteroarylation of unactivated alkenes.
Molecules 28 02513 sch010
Molecules 28 02513 sch011 550
Scheme 11. Photoinduced three-component difluoroalkylation of quinoxalin-2(1H)-ones.
Scheme 11. Photoinduced three-component difluoroalkylation of quinoxalin-2(1H)-ones.
Molecules 28 02513 sch011
Molecules 28 02513 sch012 550
Scheme 12. Visible-light photoredox-catalyzed three-component difluoromethylative quinoxalin-2(1H)-ones.
Scheme 12. Visible-light photoredox-catalyzed three-component difluoromethylative quinoxalin-2(1H)-ones.
Molecules 28 02513 sch012
Molecules 28 02513 sch013 550
Scheme 13. H2O2-promoted alkylation of quinoxalin-2(1H)-ones.
Scheme 13. H2O2-promoted alkylation of quinoxalin-2(1H)-ones.
Molecules 28 02513 sch013
Molecules 28 02513 sch014 550
Scheme 14. K2S2O8-mediated three-component radical cascade C3 alkylation of quinoxalin-2(1H)-ones.
Scheme 14. K2S2O8-mediated three-component radical cascade C3 alkylation of quinoxalin-2(1H)-ones.
Molecules 28 02513 sch014
Molecules 28 02513 sch015 550
Scheme 15. Cyanoalkylation of quinoxalin-2(1H)-ones with vinylarenes and azobis(alkylcarbonitrile)s.
Scheme 15. Cyanoalkylation of quinoxalin-2(1H)-ones with vinylarenes and azobis(alkylcarbonitrile)s.
Molecules 28 02513 sch015
Molecules 28 02513 sch016 550
Scheme 16. Alkylation of quinoxalin-2(1H)-ones with styrenes and tert-butyl peroxybenzoate.
Scheme 16. Alkylation of quinoxalin-2(1H)-ones with styrenes and tert-butyl peroxybenzoate.
Molecules 28 02513 sch016
Molecules 28 02513 sch017 550
Scheme 17. Visible-light-induced difunctionalization of 2,3-dihydrofuran.
Scheme 17. Visible-light-induced difunctionalization of 2,3-dihydrofuran.
Molecules 28 02513 sch017
Molecules 28 02513 sch018 550
Scheme 18. Three-component reaction of quinoxalin-2(1H)-ones with olefins and TMSN3.
Scheme 18. Three-component reaction of quinoxalin-2(1H)-ones with olefins and TMSN3.
Molecules 28 02513 sch018
Molecules 28 02513 sch019 550
Scheme 19. Three-component reaction of quinoxalin-2(1H)-ones with olefins and TMSN3.
Scheme 19. Three-component reaction of quinoxalin-2(1H)-ones with olefins and TMSN3.
Molecules 28 02513 sch019
Molecules 28 02513 sch020 550
Scheme 20. Photoinitiated multicomponent cascade reaction of N-heteroarenes.
Scheme 20. Photoinitiated multicomponent cascade reaction of N-heteroarenes.
Molecules 28 02513 sch020
Molecules 28 02513 sch021 550
Scheme 21. A multicomponent reaction for the synthesis of (E)-quinoxalin-2(1H)-ones oximes.
Scheme 21. A multicomponent reaction for the synthesis of (E)-quinoxalin-2(1H)-ones oximes.
Molecules 28 02513 sch021
Molecules 28 02513 sch022 550
Scheme 22. Multicomponent transformation of methyl ketones with α-bifunctionalization.
Scheme 22. Multicomponent transformation of methyl ketones with α-bifunctionalization.
Molecules 28 02513 sch022
Molecules 28 02513 sch023 550
Scheme 23. The synthesis of α-sulfonyl-β-heteroaryl scaffolds.
Scheme 23. The synthesis of α-sulfonyl-β-heteroaryl scaffolds.
Molecules 28 02513 sch023
Molecules 28 02513 sch024 550
Scheme 24. A three-component vinyl sulfonation reaction of quinoxalin-2(1H)-ones.
Scheme 24. A three-component vinyl sulfonation reaction of quinoxalin-2(1H)-ones.
Molecules 28 02513 sch024
Molecules 28 02513 sch025 550
Scheme 25. Visible-light photocatalytic four-component sulfur dioxide insertion reaction.
Scheme 25. Visible-light photocatalytic four-component sulfur dioxide insertion reaction.
Molecules 28 02513 sch025
Molecules 28 02513 sch026 550
Scheme 26. Three-component reaction of olefins with quinoxalin-2(1H)-one and sodium sulfonate.
Scheme 26. Three-component reaction of olefins with quinoxalin-2(1H)-one and sodium sulfonate.
Molecules 28 02513 sch026
Molecules 28 02513 sch027 550
Scheme 27. Photocatalytic three-component tandem reaction of quinoxalin-2(1H)-ones.
Scheme 27. Photocatalytic three-component tandem reaction of quinoxalin-2(1H)-ones.
Molecules 28 02513 sch027
Molecules 28 02513 sch028 550
Scheme 28. Three-component reaction for the thioalkylation of quinoxalin-2(1H)-ones.
Scheme 28. Three-component reaction for the thioalkylation of quinoxalin-2(1H)-ones.
Molecules 28 02513 sch028
Molecules 28 02513 sch029 550
Scheme 29. Three-component deuterated quinoxalin-2(1H)-ones reaction promoted by Fe(III) with alkenes and NaBD4.
Scheme 29. Three-component deuterated quinoxalin-2(1H)-ones reaction promoted by Fe(III) with alkenes and NaBD4.
Molecules 28 02513 sch029
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MDPI and ACS Style

Yang, Q.; Wang, B.; Wu, M.; Lei, Y.-Z. Recent Developments in Direct C–H Functionalization of Quinoxalin-2(1H)-Ones via Multi-Component Tandem Reactions. Molecules 2023, 28, 2513. https://doi.org/10.3390/molecules28062513

AMA Style

Yang Q, Wang B, Wu M, Lei Y-Z. Recent Developments in Direct C–H Functionalization of Quinoxalin-2(1H)-Ones via Multi-Component Tandem Reactions. Molecules. 2023; 28(6):2513. https://doi.org/10.3390/molecules28062513

Chicago/Turabian Style

Yang, Qiming, Biao Wang, Mian Wu, and Yi-Zhu Lei. 2023. "Recent Developments in Direct C–H Functionalization of Quinoxalin-2(1H)-Ones via Multi-Component Tandem Reactions" Molecules 28, no. 6: 2513. https://doi.org/10.3390/molecules28062513

APA Style

Yang, Q., Wang, B., Wu, M., & Lei, Y. -Z. (2023). Recent Developments in Direct C–H Functionalization of Quinoxalin-2(1H)-Ones via Multi-Component Tandem Reactions. Molecules, 28(6), 2513. https://doi.org/10.3390/molecules28062513

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