注册 English

An update on the advances in chromone and the derivatives synthesis based on the key chromone annulation of o-hydroxyaryl enaminones

Liu-Liang Mao ,  Yunyun Liu ,  Jie-Ping Wan

downloadPDF
Citation:  Liu-Liang Mao, Yunyun Liu, Jie-Ping Wan. An update on the advances in chromone and the derivatives synthesis based on the key chromone annulation of o-hydroxyaryl enaminones[J]. Chinese Chemical Letters, 2025, 36(7): 110784. doi: 10.1016/j.cclet.2024.110784 shu

An update on the advances in chromone and the derivatives synthesis based on the key chromone annulation of o-hydroxyaryl enaminones

English

  • 1. Introduction

    Chromones, as a class of oxygen-containing privileged heterocyclic scaffolds, are prominently featured in natural products, pharmaceuticals, and bioactive molecules [1–7]. These compounds, which include 3-substituted, 2-substituted, and 2,3-disubstituted chromones, exhibit a diverse array of biological activities, including antitumor, anti-inflammatory, antioxidant, anticancer, and antiviral properties. Moreover, they are recognized as promising candidates for the targeted therapy of complex and currently intractable diseases such as Alzheimer's disease [8,9], Parkinson's disease [10,11], and various cancers [12,13]. Fig. 1 illustrates several bioactive molecules that incorporate chromone skeletons. Consequently, it is undeniably important and valuable to construct chromones and their derivatives to broaden the chemical space of drug discovery. Over the past few decades, substantial attention has been devoted to the development of efficient synthetic methodologies for constructing structurally diverse chromones and their derivatives, leading to significant advancements in this field [14–17].

    Figure 1

    Figure 1.  Selected bioactive molecules featuring a chromone skeleton.
    DownLoad: Full-Size Img PowerPoint

    Among these development approaches, two principal strategies have been established for the efficient synthesis of chromones and their derivatives (Scheme 1). The first strategy focuses on the derivatization and transformation of natural and halogenated chromones to synthesize functionalized chromones and related derivatives. Key transformations include coupling reactions involving the sp2 C–H bonds of natural chromones [18,19], direct coupling reactions involving the sp2 C–X bonds of halogenated chromones [20–22], and reactions of 3-halogenated chromones based on chromonyl-norbornyl-palladacycles [23–26]. Although this approach facilitates the rapid and efficient synthesis of functionalized chromones and their derivatives, broader application remains constrained by both the high cost of natural chromones and the limited diversity of compatible functional groups. Alternatively, a more advantageous approach centers on the tandem cyclization of various acyclic precursors [27–34], such as functionalized chalcones [35–37], salicylaldehydes [38–42], functionalized phenyl alkynones [43–48], o-iodophenols [49,50], and others, to synthesize chromones and their derivatives with diverse structural frameworks. Among these readily available acyclic precursors, o-hydroxyenaminones have been identified as particularly effective and versatile substrates, enabling the synthesis of diversely functionalized chromones and their derivatives through cascade vinyl C–H bond functionalization and chromone annulation [51–54].

    Scheme 1

    Scheme 1.  Tandem C–H activation and chromone annulation.
    DownLoad: Full-Size Img PowerPoint

    In light of the significant advancements in the synthesis of chromones and their derivatives via tandem cyclization of o-hydroxyaryl enaminones in recent years, coupled with our longstanding commitment to enaminone chemistry, we believe that a comprehensive and up-to-date overview of the current status is warranted. This review will specifically focus on the latest developments in the synthesis of various types of chromones, including 3-substituted chromones, 2-substituted chromones, and 2,3-disubstituted chromones, as well as their derivatives, achieved through the tandem cyclization of o-hydroxyaryl enaminones since mid-2019. This work serves as an update to our previous review on the same topic [51].

    2. Synthesis of 3-carbonizated chromones

    Owing to their unique conjugated structural features, the vinyl α-C-H bond of o-hydroxyaryl enaminones is particularly susceptible to electrophilic attack by various carbon electrophiles. This reactivity facilitates chromone annulation, resulting in the formation of 3-carbonizated chromones with significant structural diversity.

    2.1 Synthesis of 3-trifluoromethylated chromones

    In 2020, our group reported a simple and efficient K2S2O8-mediated tandem vinyl α-C-H bond trifluoromethylation/annulation reaction of o-hydroxyaryl enaminones 1 for the synthesis of 3-trifluoromethyl chromones 3 (Scheme 2A) [55]. This reaction proceeds without the involvement of transition metal catalysts or additives, and it exhibits good functional-group tolerance. Based on the control experiments, we proposed a plausible reaction mechanism (Scheme 2A). Firstly, the trifluoromethyl source CF3SO2Na 2 is oxidized by K2S2O8 to generate an electrophilic trifluoromethyl radical. Then, the electrophilic CF3 radical undergoes intermolecular addition with the C=C bond of enaminones 1 to afford radical intermediate 2A, which is further oxidized by K₂S₂O₈ to produce the iminium intermediate 2B. Finally, 2B undergoes rapid intramolecular cyclization followed by the elimination of dimethylamine to generate the target product 3.

    Scheme 2

    Scheme 2.  Synthesis of 3-trifluoromethylated chromones.
    DownLoad: Full-Size Img PowerPoint

    In 2022, Behera et al. successfully employed a Cu(OAc)2/TBHP catalytic system to achieve the same transformation for the synthesis of 3-trifluoromethyl chromones 3 (Scheme 2B) [56]. Notably, the reaction also proceeds through a radical and imide cation process. This transformation differs from what we reported, as it involves the generation of an electrophilic trifluoromethyl radical through the oxidation of CF3SO2Na by TBHP, with the radical intermediate 2A undergoing single-electron oxidation by copper(Ⅱ) to form the iminium intermediate 2B (Scheme 2B).

    More recently, the Li's group developed both photochemical (Scheme 2C) and electrochemical (Scheme 2D) strategies to promote the tandem trifluoromethylation-cyclization of o-hydroxyaryl enaminones 1, enabling the efficient synthesis of 3-trifluoromethylchromones 3 [57]. These approaches demonstrate high substrate compatibility with enaminones 1, and both sodium trifluoromethanesulfinate and sodium perfluoroalkanesulfinates are compatible as fluorine sources within the reaction system. Mechanistic investigations suggest a pathway involving both radical and iminium ion intermediates. In the photochemical approach, visible-light irradiation excites the photosensitizer to an active state Eosin Y*, which then participates in single-electron transfer with sodium trifluoromethanesulfinate to produce a trifluoromethyl radical and the reduced form of Eosin Y (Eosin Y·-). Eosin Y·- is subsequently reoxidized by oxygen, regenerating the photosensitizer Eosin Y and producing O2·- species to complete the photocatalytic cycle. In the electrochemical approach, the CF3SO2Na 2 undergoes direct anodic single-electron oxidation to form the trifluoromethyl radical. This radical initiates an electrophilic attack on enaminone 1, yielding intermediate 2A. Intermediate 2A is then oxidized to the iminium intermediate 2B, either by O2·- species in the photochemical method or by anodic oxidation in the electrochemical method. The iminium intermediate 2B undergoes intramolecular cyclization to generate intermediate 2C, which then following deprotonation and elimination of dimethylamine, yields the target product 3.

    2.2 Synthesis of 3-allylated chromones

    Recently, Cheng and co-workers developed a convenient DDQ-promoted cascade intermolecular oxidative coupling and annulation reaction of o-hydroxyaryl enaminones 1, utilizing cycloheptatriene 4 (Scheme 3A) [58] and 1,3-diarylpropenes 6 (Scheme 3B) [59] as allylation reagents, for the synthesis of corresponding 3-allyl chromones 5 and 7, respectively. These reactions proceed via the key intermolecular interaction between DDQ and the allylation reagent, generating an ion-pair intermediate, which could couple the vinyl α-C-H bond in enaminones 1. For example, in the reaction using cycloheptatriene 4 as the allylation reagent, it interacts with DDQ to form a charge-transfer complex 3A, followed by the formation of the key ion-pair intermediate 3B via hydride transfer. Subsequently, the vinyl α-C-H bond in enaminones 1 couples with the tropylium in the key ion-pair intermediate 3B to form 3C, which undergoes rapid intramolecular cyclization and then elimination of dimethylamine through intermediate 3D, to generate 3-allyl chromones 5.

    Scheme 3

    Scheme 3.  Synthesis of 3-allylated chromones.
    DownLoad: Full-Size Img PowerPoint

    2.3 Synthesis of 3-alkenylated chromones

    In 2020, our group developed a palladium-catalyzed NaI-mediated one-pot domino vinyl α-C-H alkenylation and chromone annulation of o-hydroxyaryl enaminones 1 with alkenes 8 toward 3-vinyl chromones 9 (Scheme 4) [60]. The reaction exhibits good compatibility with the functional groups in enaminones 1, and both terminal and internal alkenes are well accommodated by the reaction system, resulting in the formation of the desired 3-alkenylated chromones 9 with moderate to excellent yields. Notably, this reaction system is also applicable for the modification of natural products containing double bonds. Furthermore, the iodine source in the reaction system is crucial for the reaction to proceed smoothly. Control experiments indicate that the reaction likely proceeds through a transient iodination process. Initially, in the presence of TBHP, the iodine ion is oxidized to iodine radical via a single-electron transfer. Subsequently, the iodine radical adds to the C=C bond in enaminones 1 to form intermediate 4A, which couples with a hydroxyl radical to yield intermediate 4B. Intermediate 4B undergoes cyclization and dehydration to generate intermediate 4C, which subsequently eliminates the dimethylamine to produce 3-iodochromone 4D. Finally, intermediate 4D undergoes a Heck-type coupling reaction with the alkenes 8 in the presence of a palladium catalyst, yielding the desired product 9.

    Scheme 4

    Scheme 4.  Synthesis of 3-alkenylated chromones.
    DownLoad: Full-Size Img PowerPoint

    2.4 Synthesis of 3-arylated chromones

    In 2020, Mkrtchyan and Iaroshenko developed two distinct strategies for synthesizing 3-arylated chromones 12 utilizing aryldiazonium tetrafluoroborates 10 and diaryliodonium triflates 11 as arylation reagents (Scheme 5) [61]. These methods employed a visible light-mediated tandem arylation-cyclization reaction of o-hydroxyaryl enaminones 1. Initially, the photosensitizers Eosin Y and Ru(Ⅱ) were excited to their respective excited states under suitable light irradiation. Subsequently, arylation reagents 10 and 11 were reduced by the excited states EY* and Ru(Ⅱ)*, generating aryl radicals 5A. These aryl radicals then underwent electrophilic addition to the enaminones 1, forming the intermediate 5B, which was further oxidized to produce 5C. Finally, 5C underwent intramolecular nucleophilic cyclization to form 5D, followed by the elimination of a dimethylamine cation to produce the desired 3-arylated chromones 12.

    Scheme 5

    Scheme 5.  Photocatalytic synthesis of 3-arylated chromones.
    DownLoad: Full-Size Img PowerPoint

    In 2021, the same research group successfully achieved the tandem arylation-cyclization reaction of o-hydroxyaryl enaminones 1 using different aryl sources, namely triarylsulfonium salts 13 and aryl sulfonyl chlorides 14, via a photocatalytic pathway, efficiently constructing 3-arylated chromones 12 (Scheme 6) [62]. In this process, the aryl radicals 5A were generated through single-electron reduction of 13 and 14 by an excited photosensitizer Ru(Ⅱ)*. These radicals 5A then underwent radical electrophilic addition to enaminones 1, forming intermediate 5B. Subsequently, 5B underwent single-electron oxidation, intramolecular nucleophilic cyclization, and elimination of a dimethylamine cation, yielding the final product 12. Interestingly, when dimethyl aryl sulfonium salts 15 were used as the aryl source, the efficient synthesis of 3-arylated chromones 12 was achieved without light irradiation. This reaction proceeded through the intermolecular nucleophilic addition of enaminones 1 and dimethyl aryl sulfonium salts 15 to form intermediate 6A, which then eliminated a molecule of dimethyl sulfide to generate 5C. Finally, 5C underwent intramolecular nucleophilic cyclization and elimination of dimethylamine, yielding the final product 12.

    Scheme 6

    Scheme 6.  Synthesis of 3-arylated chromones.
    DownLoad: Full-Size Img PowerPoint

    Recently, the same group described the efficient synthesis of 3-arylated chromones by combining mechanochemical methods with nickel catalysis, utilizing aryl bromides 16 and aryl carboxylic acids 17 as arylation agents (Scheme 7) [63]. This reaction represents the first application of mechanical energy in the synthesis of 3-arylated chromones 12. Based on control experiments and theoretical calculations, a plausible reaction mechanism involving aryl bromide 16 as the arylation agent has been proposed. Initially, o-hydroxyaryl enaminones 1 coordinates with the nickel catalyst to form intermediate 7A. Subsequently, 7A undergoes intramolecular nucleophilic cyclization and loses a molecule of HBF4 to yield intermediate 7C. Next, oxidative addition of aryl bromide to 7C forms intermediate 7D. Finally, 7D undergoes intramolecular dimethylamino transfer and elimination, resulting in the final products 12.

    Scheme 7

    Scheme 7.  Mechanochemical synthesis of 3-aryl chromones.
    DownLoad: Full-Size Img PowerPoint

    2.5 Synthesis of 3-acylated chromones

    In 2023, Mkrtchyan and Iaroshenko et al. developed a mechanochemical synthesis strategy utilizing halogenated difluoromethyl compounds 18 as acylating agents to achieve a tandem acylation-cyclization reaction of o-hydroxyaryl enaminones 1, efficiently constructing a diverse array of 3-acylated chromone derivatives 19 [64]. Notably, this reaction involves the activation of the inert C-F bond in halogenated difluoromethyl compounds by Yb₂O₃, enabling defluorination and conversion into the corresponding carbonyl functional groups. The reaction also demonstrates good substrate compatibility, accommodating both aryl and alkyl halogenated difluoromethyl compounds. Based on control experiments and density functional theory (DFT) calculations, a plausible reaction mechanism was proposed. As shown in Scheme 8, under ball-milling conditions, Yb₂O₃ first activates the C-F bond in trifluoromethyl compounds 18 to form intermediate 8A, which is then reduced by DBU via single-electron transfer, generating radical intermediate 8B. Subsequently, 8B undergoes radical addition with enaminone 1, forming intermediate 8C, which is oxidized to iminium ion 8D through single-electron oxidation. Next, 8D undergoes intramolecular nucleophilic cyclization, with the elimination of a proton and dimethylamine, yielding the 3-difluoro-substituted chromone intermediate 8E. Intermediate 8E then undergoes single-electron reduction and defluorination to generate radical intermediate 8F. Radical intermediate 8F reacts with DBU, loses an electron to form intermediate 8G, which finally undergoes hydrolysis to produce the final product 19.

    Scheme 8

    Scheme 8.  Mechanochemical synthesis of 3-acylchromones.
    DownLoad: Full-Size Img PowerPoint

    In the same year, the same group established a mechanochemical strategy for the efficient preparation of 3-acylated chromones 19 via tandem acylation and cyclization of o-hydroxyaryl enaminones 1 (Scheme 9) [65]. This method utilizes inexpensive and readily available carboxylic acids 20 as acylation reagents and nanocellulose as the reaction medium, with FeCl3 acting as a promoter. A key advantage of this strategy is that it does not require oxidants or solvents, and accommodates a broad range of substrates, effectively supporting both aryl and alkyl carboxylic acids. Notably, nanocellulose serves dual functions in this system: as a reaction medium and as a dehydrating agent that promotes the self-dehydration condensation of carboxylic acids. Based on experimental results, a plausible reaction mechanism for the tandem dehydration-acylation-cyclization of enaminone 1 is proposed. Initially, carboxylic acids 20 undergo self-dehydration condensation to form anhydride 9A in the presence of nanocellulose. The carbonyl group in 9A coordinates with FeCl3, increasing the electrophilicity of the carbonyl and forming intermediate 9B. Subsequently, the enaminone 1 initiates a nucleophilic attack on the carbonyl of 9B, resulting in the formation of zwitterionic intermediate 9C, which then decarboxylates to yield iminium ion 9D. Finally, 9D undergoes intramolecular nucleophilic cyclization, followed by deprotonation and dimethylamine elimination through intermediate 9E, to afford the final product 19.

    Scheme 9

    Scheme 9.  Mechanochemical synthesis of 3-acylchromones with Fe(Ⅲ) catalysis.
    DownLoad: Full-Size Img PowerPoint

    2.6 Synthesis of 3-alkylated chromones

    Traditionally, the synthesis of 3-alkylated chromones has primarily involved the hydrogenation of 3-alkenylchromones [66,67], the condensation of 3-formylchromones [68,69], and the C3-H bond functionalization of chromones [14–17]. However, these methods often suffer from cumbersome substrate preparation and low regioselectivity, which limit their applicability. With the ongoing development of enaminone chemistry [51–53], numerous approaches for constructing structurally diverse alkylated chromones via tandem vinyl C–H bond alkylation and chromone cyclization reactions have emerged, proliferating rapidly.

    In 2022, by utilizing simple p-quinone methides 21 to react with o-hydroxyaryl enaminones 1 in acetonitrile at room temperature (Scheme 10) [70]. Anand's group observed that the 3-diarylmethylated chromones 22 were successfully and efficiently synthesized through TsOH-mediated 1,6-conjugate addition of enaminones 1 to p-quinone methides 21 followed by intramolecular cyclization. The reaction conditions are mild, and the procedure is straightforward, offering additional options for the industrial synthesis of 3-diarylmethylated chromone-based pharmaceutical molecules.

    Scheme 10

    Scheme 10.  TsOH-mediated synthesis of 3-alkylated chromones.
    DownLoad: Full-Size Img PowerPoint

    In 2023, Wang and Zuo et al. reported an efficient protocol for the synthesis of 3-trifluoromethyl hydroxymethylated chromones 24 through annulation reactions of o-hydroxyaryl enaminones 1 and trifluoroacetaldehyde/ketone derivatives 23 in acetonitrile at 130 ℃ (Scheme 11A) [71]. The mechanistic study indicates that the reaction likely involves a nucleophilic addition of enaminones 1 to trifluoroacetaldehyde/ketone derivatives 23, followed by intramolecular cyclization and subsequent elimination. Soon thereafter, Yang and Liu et al. established a gentler approach for synthesis diverse 3-difluoromethyl hydroxymethylated chromones 26 and 3-trifluoromethyl hydroxymethylated chromones 24 in HFIP at room temperature through annulation reactions of o-hydroxyaryl enaminones 1 by using difluoroacetaldehyde ethyl hemiacetal 25 and trifluoroacetaldehyde/ketone derivatives 23 as fluorinated coupling partners, respectively (Scheme 11B) [72]. Although this reaction follows a similar mechanism as the previously described one, it operates under milder and more practical conditions. This improvement is primarily due to the use of HFIP, which serves both as the reaction solvent and as a Brønsted acid that provides protons to activate the substrates, thereby lowering the activation energy.

    Scheme 11

    Scheme 11.  Synthesis of 3-difluoro/trifluoromethyl hydroxymethylated chromones.
    DownLoad: Full-Size Img PowerPoint

    In the same year, Baell and Huang et al. developed an efficient and straightforward strategy for synthesizing 3-alkylated chromones 28 from o-hydroxyaryl enaminones 1 and α-diazo esters 27 under visible light irradiation (Scheme 12) [73]. This eco-friendly approach is characterized by a broad substrate scope, the absence of catalysts and additives, and good functional group tolerance. Based on experimental results and DFT computations, a plausible reaction mechanism was proposed. Initially, under blue light irradiation, α-diazo esters 27 decompose to release a molecule of nitrogen, generating a singlet carbene intermediate 12A. This intermediate then reacts with enaminone 1 to form the cyclopropane intermediate 12B, which rapidly undergoes intramolecular proton transfer to yield intermediate 12C. Intermediate 12C subsequently cyclizes to form intermediate 12D. Finally, 12D undergoes intramolecular proton transfer and spontaneous elimination of dimethylamine to produce 3-alkylated chromone 28.

    Scheme 12

    Scheme 12.  Photocatalytic synthesis of 3-alkylated chromones.
    DownLoad: Full-Size Img PowerPoint

    In 2022, Yu's group reported a silver-catalyzed tandem annulation reaction of o-hydroxyaryl enaminones 1 for the regioselective synthesis of 3-(1H-isochromen)-chromones 30, employing o-alkynylbenzaldehydes 29 as the carbon coupling partners (Scheme 13) [74]. This protocol demonstrates excellent regioselectivity and high bond-forming efficiency, facilitating the self-assembly of 1H-isochromene and chromone into a unified structure. The proposed reaction mechanism initiates with the activation of o-alkynylbenzaldehydes 29 by Ag₂O to generate intermediate 13A. This intermediate then undergoes a 6-endo-dig cyclization to form the intermediate 13B. Subsequently, intermediate 13B reacts with an enaminone 1 through nucleophilic addition to produce intermediate 13C. Finally, intermediate 13C undergoes intramolecular cyclization to yield 13D, which then eliminates dimethylamine to produce the target product 30.

    Scheme 13

    Scheme 13.  Ag2O-catalyzed synthesis of 3-alkylated chromones.
    DownLoad: Full-Size Img PowerPoint

    More recently, the same research group developed a tandem C–H bond alkylation and chromone cyclization reaction catalyzed by AgBF4, involving o-hydroxyaryl enaminones 1 and enynones 31 for the synthesis of 3-furylmethyl chromones 32 (Scheme 14) [75]. In this reaction, AgBF4 first activates enynone 31, resulting in the loss of a proton and formation of the five-membered ring intermediate 14A. Intermediate 14A then reacts with a proton to generate the silver carbene intermediate 14B. Subsequently, enaminones 1 undergo nucleophilic addition to intermediate 14B, producing intermediate 14C, which then undergoes intramolecular cyclization to form intermediate 14D. Finally, intermediate 14D is protonated and the silver catalyst is lost, yielding intermediate 14E, which is further converted to the final product 32 through the elimination of dimethylamine.

    Scheme 14

    Scheme 14.  AgBF4-catalyzed synthesis of 3-alkylated chromones.
    DownLoad: Full-Size Img PowerPoint

    In 2024, He's group developed a novel electrochemical catalytic approach for the regioselective synthesis of 3-alkylated chromones 34 and 35 (Scheme 15) [76]. This method involves tandem C–H bond alkylation of o-hydroxyaryl enaminones 1 and p-alkyl-substituted N,N-dimethylanilines 33, followed by chromone cyclization. Notably, the regioselectivity of the reaction is predominantly influenced by the choice of solvent. Methanol and HFIP (hexafluoroisopropanol) selectively activate the C(sp3)-H bonds at the ortho position relative to the nitrogen and at the benzylic position in substrate 33, respectively. Based on mechanistic experiments, the authors proposed a plausible reaction mechanism. Firstly, in the presence of methanol as the solvent (Scheme 15A), N,N, 4-trimethylaniline 33 undergoes two single-electron oxidations at the anode and loses a proton to form iminium ion 15B via the alkyl radical intermediate 15A. In contrast, when HFIP is used as the solvent (Scheme 15B), intermolecular hydrogen bonding between the hydroxyl group of HFIP and the nitrogen atom of 33 leads to the double oxidation of the methyl group on the aryl ring, resulting in the formation of alkyl carbocation 15B'. Subsequently, intermediates 15B and 15B' undergo electrophilic addition to enaminones 1, yielding iminium ions 15C and 15C', respectively. Finally, iminium ions 15C and 15C' undergo intramolecular nucleophilic cyclization and elimination of dimethylammonium cation, producing the final products 34 and 35, respectively.

    Scheme 15

    Scheme 15.  Electrochemical synthesis of 3-alkylated chromones.
    DownLoad: Full-Size Img PowerPoint

    In 2024, Yang and colleagues reported an HFIP-promoted tandem cyclization of halohydrocarbons 36 with o-hydroxyaryl enaminones 1, providing a streamlined approach for synthesizing 3-alkylchromone derivatives 37 (Scheme 16) [77]. HFIP is indispensable in this reaction, playing dual a role as both solvent and hydrogen bond donor, which significantly enhances the reaction efficiency. Mechanistic investigations reveal that HFIP forms an intermolecular hydrogen bond with the chlorine atom in alkyl chloride 36, facilitating chloride departure and generation of the carbocation intermediate 16B. This intermediate subsequently undergoes electrophilic addition with enaminone 1 to yield intermediate 16C, which tautomerizes to form the imine intermediate 16D. Subsequent intramolecular cyclization and elimination of a dimethylamine cation yield the desired product 37.

    Scheme 16

    Scheme 16.  HFIP-promoted synthesis of 3-alkylated chromones.
    DownLoad: Full-Size Img PowerPoint

    In 2024, the Anand group pioneered a CuI-catalyzed tandem cyclization of 2-(2-alkynyl)pyridines 38 with o-hydroxyaryl enaminones 1, presenting a novel and efficient pathway for constructing bioactive heterocyclic-substituted 3-alkylchromones 39 (Scheme 17) [78]. This reaction mechanism begins with CuI-mediated activation of the carbon-carbon triple bond in 2-(2-alkynyl)pyridine 38, forming intermediate 17A, which undergoes a 5-endo-dig cyclization to produce intermediate 17B. From this point, intermediate 17B may proceed via two mechanistic pathways to form product 39: In Pathway A, nucleophilic addition between the enaminone 1 and the exocyclic double bond of intermediate 17B generates intermediate 17C, followed by an intramolecular nucleophilic cyclization, yielding intermediate 17D. Subsequent elimination of a dimethylamine cation and copper metal from 17D leads to the target product 39. In Pathway B, enaminone 1 undergoes intramolecular cyclization facilitated by CuI, forming intermediate 17F. This intermediate then undergoes nucleophilic addition with the exocyclic double bond of intermediate 17B to form 17 G, which upon dimethylamine elimination and demetalation, yields the final product 39.

    Scheme 17

    Scheme 17.  CuI-catalyzed synthesis of 3-alkylated chromones.
    DownLoad: Full-Size Img PowerPoint

    In recent years, several research groups have advanced numerous decarboxylation strategies for the tandem alkylation-cyclization of o-hydroxyaryl enaminones, enabling the efficient construction of structurally diverse 3-alkylated chromone derivatives. For example, Tang, Yang et al. [79] and Shrivastav, Sharma et al. [80] have employed transition metal-mediated and photocatalytic methods, respectively, to achieve the tandem decarboxylative alkylation-cyclization of o-hydroxyaryl enaminones 1 and 3-indoleacetic acids 40 (Scheme 18). Mechanistic studies suggest two distinct reaction pathways. In pathway A, 3-indoleacetic acid 40 reacts with copper acetate to form intermediate 18A, which subsequently undergoes CO2 elimination to produce intermediate 18B. In pathway B, 3-indoleacetic acid 40 interacts with an excited-state photocatalyst to form 18A', which then undergoes decarboxylation to yield intermediate 18A''. This intermediate is further oxidized by oxygen via single-electron transfer to generate intermediate 18B. In both pathways, 18B reacts with enaminone 1 to form intermediate 18C, which then undergoes deprotonation to yield intermediate 18D. Finally, 18D undergoes reductive elimination, intramolecular nucleophilic cyclization, and elimination of dimethylamine to produce the final product 41.

    Scheme 18

    Scheme 18.  Decarboxylative synthesis of 3-alkylated chromones.
    DownLoad: Full-Size Img PowerPoint

    In 2022, Zhu and collaborators introduced a novel visible light-mediated sequential decarboxylative alkylation and cyclization reaction involving o-hydroxyaryl enaminones 1 and N-arylglycines 42 for the synthesis of 3-aminoalkyl chromones 43 (Scheme 19) [81]. This reaction is notable for its lack of requirement for photocatalysts or additional additives and exhibits excellent functional group compatibility. Upon exposure to light irradiation, enaminone 1 is first excited to its excited state 19A. In this state, 19A acts as a photocatalyst by transferring energy to molecular oxygen, thereby generating singlet oxygen (1O2). The singlet oxygen then reacts with the isomerized intermediate 19B, resulting in decarboxylation and the formation of the radical intermediate 19C and a superoxide radical (O2-·). The radical intermediate 19C undergoes single-electron oxidation by the superoxide radical to form the iminium ion 19D. Subsequently, iminium ion 19D reacts with enaminone 1 to yield intermediate 19E. Finally, intermediate 19E undergoes intramolecular cyclization and elimination of the dimethylammonium cation, producing the final product 43.

    Scheme 19

    Scheme 19.  Photocatalytic synthesis of 3-aminoalkyl chromones.
    DownLoad: Full-Size Img PowerPoint

    In the same year, Zhu's group integrated photochemical and enzymatic catalytic strategies, utilizing methylene blue (MB) as the photocatalyst and Candida antarctica lipase B (CALB) as the enzyme catalyst, to develop a novel tandem enzymatic decarboxylative alkylation-cyclization reaction of o-hydroxyaryl enaminones 1 with N-arylglycine esters 44, resulting in the synthesis of 3-aminoalkylated chromones 43 (Scheme 20) [82]. Based on control experiments, a plausible reaction mechanism was proposed. As depicted in Scheme 20, in the presence of enzymatic catalysis, N-arylglycine esters 44 undergo hydrolysis to yield N-arylglycine 42. The resulting 42 is then subjected to single-electron oxidation by an excited-state photocatalyst derived from methylene blue (MB) under light irradiation, forming 20A. Intermediate 20A subsequently undergoes deprotonation and CO₂ elimination to generate 19C, which is further oxidized to the iminium ion 19D. The iminium ion 19D then reacts with enaminone 1 to form 19E, which undergoes intramolecular cyclization and elimination of the dimethylammonium cation, ultimately producing the final product 43.

    Scheme 20

    Scheme 20.  Photochemical/enzymatic synthesis of 3-aminoalkyl chromones.
    DownLoad: Full-Size Img PowerPoint

    In 2024, Cheng's group developed an innovative electrochemical catalytic decarboxylation strategy, enabling the tandem alkylation-cyclization of o-hydroxyaryl enaminones 1 with N-arylglycines 42, resulting in the synthesis of structurally diverse 3-aminochromones 43 (Scheme 21) [83]. This method operates without the need for catalysts or additional oxidants. Mechanistic studies reveal that N-arylglycines 42 initially undergo single-electron oxidation and deprotonation at the anode to form intermediate 21A, which subsequently undergoes decarboxylation to yield 19C. The intermediate 19C can then proceed via two distinct pathways to generate 19E: (1) addition to enaminone 1 followed by single-electron oxidation, or (2) single-electron oxidation to produce an iminium ion 19D, which then adds to enaminone 1. The resultant intermediate 19E undergoes intramolecular cyclization, proton transfer, and elimination of the dimethylammonium cation, ultimately affording the desired 3-aminochromone 43.

    Scheme 21

    Scheme 21.  Electrochemical decarboxylative synthesis of 3-aminoalkyl chromones.
    DownLoad: Full-Size Img PowerPoint

    3. Synthesis of 3-sulfurated/selenylated chromones

    Sulfur- and selenium-containing organic molecules are extensively utilized in medicine, agriculture, and organic materials due to their unique physicochemical properties [84–86]. Consequently, the incorporation of sulfur and selenium atoms into specific bioactive molecules, particularly chromones, has garnered significant interest from organic chemists. In recent years, notable advancements have been made in the synthesis of structurally diverse 3-sulfurated and 3-selenylated chromones. These achievements primarily involve the direct activation of vinyl α-C-H bonds in o-hydroxyaryl enaminones, leading to α-sulfenylation, α-thiocyanation and α-selenylation, followed by chromone cyclization reactions.

    3.1 Synthesis of 3-sulfenylated chromones

    In 2019, Maddani's group developed a convenient strategy for the selective cascade thiolation-cyclization of o-hydroxyaryl enaminones 1 and arylthiols 45 using a combination reagent of HBr and DMSO. This approach efficiently synthesized a series of 3-arylthiochromone derivatives (Scheme 22) [87]. Comprehensive mechanistic studies revealed that the acid not only facilitated the in situ formation of disulfides but also enhanced the electrophilicity of the sulfur atoms in the disulfide through protonation. Initially, bromide ions were oxidized to elemental bromine by DMSO in an acidic medium, which then reacted with arylthiols 45 to form intermediate 22A. Subsequently, intermediate 22A reacted further with arylthiols 45 in the acidic environment to yield the disulfide cationic intermediate 22B. Enaminones 1 then underwent nucleophilic addition to intermediate 22B, resulting in the formation of intermediate 22C. This intermediate subsequently underwent intramolecular nucleophilic cyclization and elimination of the dimethylamine to produce the target compound 46.

    Scheme 22

    Scheme 22.  Synthesis of 3-arylthiochromones.
    DownLoad: Full-Size Img PowerPoint

    In 2021, our group demonstrated a tandem dithiocarbamation-cyclization reaction of o-hydroxyaryl enaminones 1 with thiurams 47 catalyzed by KIO3 and TEMPO, leading to the synthesis of 3-dithiocarbamyl chromones 48 (Scheme 23) [88]. The reaction proceeds with the addition of enaminones 1 to the I=O bond in KIO3, forming intermediate 23A, which then undergoes elimination of KOH to form intermediate 23B. Subsequently, intermediate 23B reacts with thiurams 47 to generate intermediate 23D, while simultaneously releasing a molecule of 23C. Finally, 23D undergoes intramolecular nucleophilic cyclization to form 23E, and dimethylamine is eliminated to produce the target compound 48. It is noteworthy that TEMPO plays a critical role in enhancing the reaction efficiency. This enhancement is primarily attributed to TEMPO's ability to scavenge 23C, a byproduct that significantly impedes the formation of 23D. By effectively removing 23C from the reaction milieu, TEMPO facilitates the progression and overall yield of the reaction.

    Scheme 23

    Scheme 23.  Synthesis of 3-dithiocarbamyl chromones.
    DownLoad: Full-Size Img PowerPoint

    In 2022, Yu and collaborators successfully developed an iodine-promoted tandem vinyl α-C-H bond phosphorothiolation and chromone cyclization reaction involving o-hydroxyaryl enaminones 1 and P(O)SH compounds 49. This method facilitates the construction of a series of highly valuable S-3-chromone phosphorothioates 50 (Scheme 24) [89]. Notably, this strategy circumvents the need for transition metals, exhibits a broad substrate scope, and operates under mild conditions. Mechanistic studies suggest that the reaction initiates with the elimination of HI from two molecules of (R'O)2P(O)SH 49 under iodine promotion, forming the phosphorylated persulfide intermediate 24A. Intermediate 24A subsequently interacts with HI to generate the active intermediates 24B and (R'O)2P(O)SH 49. The enaminone 1 then undergoes an SN2-type nucleophilic reaction with 24B, producing the iminium ion intermediate 24C, which proceeds through traditional chromone cyclization to yield intermediate 24D. Finally, 24D undergoes deprotonation and the elimination of dimethylamine, facilitated by iodide ions, to afford the target product 50.

    Scheme 24

    Scheme 24.  Synthesis of S-3-chromone phosphorothioates.
    DownLoad: Full-Size Img PowerPoint

    In the same year, Zhou's group reported an efficient method for synthesizing 3-aryl/alkylthiochromone derivatives 53 by utilizing thiols 51 and disulfanes 52 as sulfur sources. This method employs a tandem sulfenylation-cyclization strategy that involves the electrooxidation of o-hydroxyaryl enaminones 1 (Scheme 25) [90]. Notably, both aryl and alkyl thiols exhibited excellent compatibility with the reaction system, whereas only diaryl disulfanes among the disulfanes were compatible. The proposed reaction mechanism initiates with the single-electron oxidation of iodide ions to iodine at the anode. Thiols 51 then react with iodine to form intermediate 25A, which undergoes electrophilic addition to the C=C bond of enaminones 1, producing intermediate 25B. Intermediate 25B subsequently undergoes an intramolecular SN2-type nucleophilic substitution to form sulfonium ion 25C. This intermediate progresses through intramolecular electrophilic ring-opening and nucleophilic addition via intermediate 25D to yield intermediate 25E. Finally, intermediate 25E undergoes dimethylamine elimination and deprotonation, leading to the formation of the target product 53.

    Scheme 25

    Scheme 25.  Electrochemical synthesis of 3-aryl/alkylthiochromones.
    DownLoad: Full-Size Img PowerPoint

    After our work, the Dong group similarly utilized an iodine-promoted strategy to achieve a three-component tandem cyclization reaction of o-hydroxyaryl enaminones 1, tetramethylthiuram disulfide 47, and 2-amino-/aminothiophenols 54, efficiently synthesizing S-benzoazolyl/benzothiazolyl chromone derivatives 55 (Scheme 26) [91]. First, 2-aminophenols 54 undergoes nucleophilic substitution with tetramethylthiuram disulfide 47, to generate intermediate 26A, which then undergoes intramolecular nucleophilic addition and dimethylamine elimination through intermediate 26B to form intermediate 26C. Two molecules of 26C undergo dehydroiodination in the presence of iodine to produce intermediate 26D, which then reacts with HI to form the more reactive intermediate 26E. Intermediate 26E undergoes SN2-type nucleophilic substitution with enaminones 1 to yield intermediate 26F, which then undergoes intramolecular nucleophilic cyclization, deprotonation, and dimethylamine elimination through intermediate 26G to obtain the target product 55.

    Scheme 26

    Scheme 26.  Three-component synthesis of 3-heteroarylthiochromones.
    DownLoad: Full-Size Img PowerPoint

    Meanwhile, Zhu and collaborators utilized elemental sulfur as the sulfur source to achieve consecutive tandem vinyl α-C-H bond sulfenylation and cyclization reactions of o-hydroxyaryl enaminones 1 with imidazopyridines 56, for the synthesis of potentially bioactive 3-(imidazo[1,2-a]pyridin-3-ylthio)-chromones 57 (Scheme 27) [92]. The reaction requires only base promotion, without the involvement of transition metals or other additives, and occurs under mild conditions. Imidazopyridines 56 initially undergo oxidative homocoupling under the combined action of the base, elemental sulfur, and DMSO, resulting in the disulfide intermediate 27B through intermediate 27A. Intermediate 27B can then proceed via two distinct pathways to generate 27D: (1) the addition to enaminones 1 with the elimination of 27A, or (2) through the thioether intermediate 27C, followed by addition to enaminones 1 with the elimination of 56. Finally, 27D undergoes chromone cyclization, deprotonation, and dimethylamine elimination via intermediate 27E to produce the target product 57.

    Scheme 27

    Scheme 27.  Synthesis of 3-heteroarylthiochromones.
    DownLoad: Full-Size Img PowerPoint

    In 2024, our group developed a divergent and controllable tandem vinyl α-C-H bond functionalization and chromone cyclization reaction of o-hydroxyaryl enaminones 1 with sodium organosulfinate as the sulfurizing reagent. Utilizing PBr3 and POCl3 as deoxygenating agents, this method enabled the construction of structurally diverse 3-di/trifluoromethyl-thiochromones 60 and 3-sulfoxylated chromones 61, respectively (Scheme 28) [93]. This strategy operates under mild reaction conditions without the need for transition metal catalysts and demonstrates excellent functional group compatibility with various substrates. Notably, CF2HSO2Na and CF3SO2Na are effective for the synthesis of 3-functionalized chromones 60 and 61. Furthermore, sodium arylsulfinates and sodium alkylsulfinates can also be utilized for the synthesis of 3-aryl/alkylsulfinyl chromones 61. Mechanistic studies demonstrate that in the reaction where PBr3 serves as the dehydrating agent (Scheme 28A), CF3SO2Na initially interacts with PBr3 to generate intermediate 28A. This intermediate subsequently undergoes electrophilic substitution with enaminone 1, yielding intermediate 28C and releasing 28B. Following this, 28C participates in an SN2-type reaction with 28B, forming intermediate 28D. The presence of a bromide ion facilitates electron transfer between the phosphorus and oxygen atoms in 28D, leading to the cleavage of the S-O bond and the formation of intermediate 28E. This intermediate then undergoes classical chromone cyclization, followed by the elimination of dimethylamine, to afford the desired product 60. In the alternative reaction pathway employing POCl3 as the dehydrating agent (Scheme 28B), CF3SO2Na reacts with POCl3 to form intermediate 28F, which then reacts with enaminone 1 to yield imine intermediate 28G. The intermediate 28G undergoes subsequent intramolecular nucleophilic cyclization and deamination, resulting in the formation of the target product 61.

    Scheme 28

    Scheme 28.  Synthesis of 3-(trifluoromethylthio)- and 3-trifluoromethyl-sulfinyl chromones.
    DownLoad: Full-Size Img PowerPoint

    3.2 Synthesis of 3-thiocyanated chromones

    The thiocyano group, a typical sulfur-containing functional group, has garnered extensive attention for its unique physicochemical properties and potential for further organic transformations [94–96]. Recent advances have been made in introducing the thiocyanate group into the chromone framework, resulting in the construction of 3-thiocyanated chromone derivatives through more efficient and greener methods, such as the vinyl α-C-H bond thiocyanation and cyclization reactions of enaminones. For instance, in 2019, Zhou and collaborators utilized KSCN 62 as a thiocyanation reagent to achieve the tandem thiocyanation-cyclization reaction of o-hydroxyaryl enaminones 1 via both electrochemical synthesis [97] and PIDA (iodobenzene diacetate)-promoted [98] strategies, thereby efficiently synthesizing 3-thiocyanated chromone derivatives 63 (Scheme 29). Mechanistic studies suggest that both strategies involve a common iminium ion intermediate 29B, although the pathways to this intermediate differ slightly. As shown in Scheme 29, in pathway A, the thiocyano anion undergoes single-electron oxidation at the anode to form a thiocyano radical, which then adds to enaminones 1 and undergoes further single-electron oxidation to yield the iminium ion 29B through the radical intermediate 29A. In pathway B, the thiocyano anion is oxidized by PIDA to form a thiocyano radical, which subsequently adds to enaminones 1 to generate the intermediate 29A, followed by additional oxidation by PIDA to produce the iminium ion 29B. Ultimately, 29B undergoes intramolecular cyclization, dimethylamine elimination, and deprotonation through intermediates 29C and 29D to form the target product 63.

    Scheme 29

    Scheme 29.  Synthesis of 3-thiocyanated chromones.
    DownLoad: Full-Size Img PowerPoint

    3.3 Synthesis of 3-selenylated chromones

    In 2021, Zhou and colleagues reported a practical visible-light-driven tandem selenylation-cyclization reaction of o-hydroxyaryl enaminones 1 and diselenides 64, resulting in the construction of 3-selenylated chromones 65 (Scheme 30) [99]. This reaction utilizes environmentally friendly molecular as an oxidant and does not require photocatalysts or additional additives, although only diaryl diselenides 64 are compatible with the system. The reaction mechanism begins with the homolytic cleavage of diselenides 64 under light irradiation to generate selenium radicals 30A, which are subsequently oxidized by atmospheric oxygen to form selenium cations 30B. These cations then react with enaminones 1 to produce selenonium ion 30C. This intermediate undergoes intramolecular electrophilic ring-opening and nucleophilic cyclization, proceeding through intermediate 30D to form intermediate 30E. Finally, 30E undergoes deprotonation and elimination of dimethylamine to produce the target product 65.

    Scheme 30

    Scheme 30.  Synthyesis of 3-arylselenochromones.
    DownLoad: Full-Size Img PowerPoint

    In 2022, Wu's group developed a practical and green method using TsSeCF3 66 as a trifluoromethylselenylation reagent to achieve the tandem vinyl α-C-H bond trifluoromethylselenylation and cyclization of o-hydroxyaryl enaminones 1 under visible light irradiation (Scheme 31) [100]. This reaction proceeds without the need for photocatalysts or additional oxidants and demonstrates good functional group compatibility with substrates. Initially, the TsSeCF3 66 generates a trifluoromethylselenyl radical 31A under light irradiation and with the assistance of Et3N. This radical undergoes electrophilic addition to enaminones 1, followed by single-electron oxidation by oxygen, resulting in the formation of the imine intermediate 31C via the radical intermediate 31B. Finally, 31C undergoes intramolecular nucleophilic cyclization, deprotonation, and demethylamination, resulting in the formation of the 3-trifluoromethylselenylated chromone 67.

    Scheme 31

    Scheme 31.  Visible-light-indued synthesis of 3-CF3Se chromones.
    DownLoad: Full-Size Img PowerPoint

    In 2023, Braga and colleagues developed a method for the rapid synthesis of 3-selenylated chromones 69 from o-hydroxyaryl enaminones 1 and diselenides 68 using trichloroisocyanuric acid (TCCA) in ethanol (Scheme 32) [101]. This reaction demonstrates excellent substrate functional group compatibility, effectively accommodating diaryl, dialkyl, and heterodiaryl diselenides. Initially, diselenides 68 react with TCCA, potentially generating two electrophilic selenium intermediates, 32A and 32B. These intermediates subsequently undergo electrophilic addition to enaminones 1, forming the selenonium ion intermediate 32C. Following this, intermediate 32C undergoes intramolecular nucleophilic cyclization, concurrent with the ring opening of the seleniranium intermediate, yielding intermediate 32D. Finally, intermediate 32D undergoes demethylamination and deprotonation via intermediate 32E to produce the 3-selenylated chromones 69.

    Scheme 32

    Scheme 32.  TCCA-mediated synthesis of 3-selenylated chromones.
    DownLoad: Full-Size Img PowerPoint

    Recently, Cai et al. confirmed the electrochemical tandem vinyl α-C-H bond selenylation/cyclization of o-hydroxyaryl enaminones 1, employing diselenides 68 as selenylation reagents to construct 3-selenylated chromones 69 (Scheme 33) [102]. Notably, various selenylation reagents such as diaryl diselenides, dialkyl diselenides, and diheteroaryl diselenides successfully yielded the desired products. Furthermore, diaryl disulfides 52 were also compatible with this reaction system, efficiently producing 3-arylthiochromone derivatives 53 with excellent yields. A plausible reaction mechanism is proposed, as illustrated in Scheme 33. Initially, iodide ions are oxidized to iodine at the anode, which then reacts with diselenides 68 to generate intermediate 33A. Intermediate 33A undergoes electrophilic addition to the enaminones 1, forming intermediate 33B, which subsequently undergoes intramolecular SN2-type nucleophilic substitution to produce selenonium ion 33C. Following this, 33C undergoes electrophilic ring-opening and intramolecular nucleophilic cyclization, passing through imine intermediate 33D to form intermediate 32D. Finally, 32D undergoes demethylamination and deprotonation, proceeding through intermediate 32E to yield the final product 69.

    Scheme 33

    Scheme 33.  Electrochemical synthesis of 3-selenylated chromones.
    DownLoad: Full-Size Img PowerPoint

    Interestingly, the Yuan's group developed an efficient method for the synthesis of 3-selenylated chromones 65 and 3-thiocyanated chromones 63 using a Selectfluor-mediated oxidation strategy, with diaryl diselenides 64 as selenylation agents and KSCN 62 as the thiocyanation agent (Scheme 34) [103]. This reaction demonstrates a broad substrate scope and proceeds under mild conditions. Mechanistic studies propose a plausible tandem selenylation and cyclization pathway for the formation of 3-selenylated chromones 65. As shown in Scheme 34, the reaction of diaryl diselenides 64 with Selectfluor generates two potential electrophilic selenium intermediates, 34A and 34B. Subsequent nucleophilic addition of enaminones 1 to either intermediate 34A or 34B produces imine intermediate 33D. This intermediate undergoes intramolecular nucleophilic cyclization, deprotonation, and demethylamination, proceeding through intermediate 32D, to afford the final product 65.

    Scheme 34

    Scheme 34.  Selectfluor-mediated synthesis of 3-selenylated chromones.
    DownLoad: Full-Size Img PowerPoint

    4. Synthesis of 3-halogenated chromones

    3-Halogenated chromones, as pivotal intermediates for the synthesis of structurally diverse and high-value 3-functionalized chromone derivatives, have consistently garnered significant attention from the organic chemists [104–106]. In the early stages, the construction of 3-halogenated chromones via the cyclization of enaminones with halogen elements was considered the most straightforward approach [107,108]. However, this method was limited to the introduction of chlorine, bromine, and iodine, and the use of environmentally hazardous halogen elements constrained its broader application. In recent years, the rapid advancement of enaminone chemistry has led to the development and application of a variety of green and environmentally friendly halogenating reagents, such as fluorinating, chlorinating, brominating, and iodinating agents, for the construction of 3-halogenated chromone derivatives.

    In recent years, the Behera group (Scheme 35A) [109] and the Yu group (Scheme 35B) [110] have successfully synthesized 3-fluorinated chromone derivatives 72 under mild conditions using Selectfluor 70 as the electrophilic fluorination reagent. Additionally, the Akkineni group (Scheme 35C) [111] utilized NFSI (N-fluorobenzenesulfonimide) 71 as the electrophilic fluorination reagent to achieve an efficient cascade fluorination-cyclization reaction of o-hydroxyaryl enaminones 1, resulting in the synthesis of 3-fluorochromones 72. These reactions proceed through a similar mechanistic pathway, as illustrated in Scheme 35. Initially, enaminone 1 is converted to the resonance-limited form 1′, which then reacts with the electrophilic fluorination reagent (Selectfluor 70 or NFSI 71) to form the zwitterionic intermediate 35A. This intermediate undergoes keto-enol tautomerism to produce intermediate 35B, which then undergoes conventional chromone cyclization, deprotonation, and dimethylamine elimination to yield the target molecule 72 via intermediate 35C.

    Scheme 35

    Scheme 35.  Synthesis of 3-fluorinated chromones.
    DownLoad: Full-Size Img PowerPoint

    In 2020, Yang and cowokers employed Selectfluor 66 as an electrophilic fluorination reagent to synthesize 3-fluorochromones 72 via BHT (butylated hydroxytoluene) coordination (Scheme 36) [112]. Based on mechanistic studies, the authors proposed a novel reaction mechanism, as depicted in Scheme 36, the process begins with the nucleophilic substitution of enaminone 1 by Selectfluor 71, yielding intermediate 36A. This intermediate undergoes a second nucleophilic substitution with Selectfluor to form the difluorinated intermediate 36C via intermediate 36B. Assisted by NaOAc, intermediate 36C then undergoes rapid intramolecular nucleophilic cyclization to produce intermediate 36D. Finally, intermediate 36D undergoes defluorination and deamination, facilitated by BHT, to form the desired product 72.

    Scheme 36

    Scheme 36.  BHT-mediated synthesis of 3-fluorinated chromones.
    DownLoad: Full-Size Img PowerPoint

    In recent years, our group has focused on the chemistry of enaminones and developed several methodologies for the synthesis of 3-halogenated chromone derivatives 75. Specifically, we utilized inexpensive and readily available inorganic potassium halide 73 (Scheme 37A) [113] and sodium halide 74 (Scheme 37B) [114] as halogenating agents. By employing PhI(OAc)2 oxidation and electrochemical oxidation strategies, we achieved the synthesis of highly chemoselective 3-halogenated chromone derivatives 75. These methods offer mild reaction conditions, a broad substrate scope, and avoid the use of environmentally harmful elemental halogens. Mechanistic investigations suggest that these strategies follow the pathways illustrated in Scheme 37. Initially, halide anions are oxidized by either iodobenzene diacetate or the anode of an electrochemical cell to form the corresponding halogen species. Subsequently, the resonance form 1′ of enaminone 1 undergoes nucleophilic substitution with the halogen species, yielding the halogenated iminium ion 37A. This intermediate then undergoes intramolecular nucleophilic attack to form the halonium ion 37B, which then undergoes intramolecular nucleophilic ring-opening and deprotonation to yield intermediate 37C. Finally, intermediate 37C loses dimethylamine to afford the desired product 75. It is noteworthy that the PhI(OAc)2 oxidation system is ineffective for the synthesis of 3-chlorochromones, likely due to the insufficient oxidative power of PhI(OAc)2 to convert chloride ions into chlorine.

    Scheme 37

    Scheme 37.  Synthesis of 3-halochromones.
    DownLoad: Full-Size Img PowerPoint

    In 2024, Coelho and colleagues developed a streamlined and efficient tandem α-halogenation/cyclization reaction of o-hydroxyaryl enaminones 1 for synthesizing 3-halochromones 75 (X = Cl, Br, I) by employing KX 73 in combination with Oxone as the reagent system (Scheme 38) [115]. This reaction pathway offers a straightforward, operationally simple approach for accessing 3-halochromones 75. Mechanistic investigations reveal that the halide anions from KX are initially oxidized to X2 in the presence of Oxone. The X2 subsequently interacts with enaminone 1 to form intermediate 38A, which resonates to produce 38B. Following an intramolecular proton transfer, 38B is converted to intermediate 38C. This intermediate then undergoes an intramolecular nucleophilic cyclization to yield intermediate 38D, which finally eliminates dimethylamine to generate the target 3-halogenated chromone 75.

    Scheme 38

    Scheme 38.  Oxone-mediated synthesis of 3-halochromones.
    DownLoad: Full-Size Img PowerPoint

    5. Synthesis of 3-aminated/phosphorylated chromones

    3-Aminated/phosphorylated chromones and their derivatives are extensively utilized in drug development due to their remarkable biological activities, including anti-Alzheimer's, anticancer, antileukemic, and anti-inflammatory effects [1–7]. However, the synthesis of these compounds typically involves tedious substrate preparation, stringent reaction conditions, and limited substrate diversity. This challenge was addressed with the application of the tandem amination and chromone cyclization of o-hydroxyaryl enaminones for synthesizing 3-aminated/phosphorylated chromones.

    5.1 Synthesis of 3-aminated chromones

    Recently, Yang and Zhang et al. reported innovative methods for synthesizing structurally diverse 3-aminated chromones 78 through photocatalytic tandem amidation-cyclization reactions of o-hydroxyaryl enaminones 1. Yang et al. utilized tert-butyl ((perfluoropyridin-4-yl)oxy)carbamate 76 (Scheme 39A) [116], while Zhang et al. employed N-aminopyridinium salts 77 (Scheme 39B) [117] as precursors for amidyl radicals. Mechanistic investigations confirmed that these reactions involve amidyl radical intermediates, as depicted in Scheme 39. Under visible light irradiation, photocatalysts Ir3+ and 4CzIPN are excited to their respective states *Ir3+ and 4CzIPN*. These excited states then reduce and quench enaminone 1 via a single-electron transfer (SET) process, forming intermediates Ir2+ and 4CzIPN radical anion, while simultaneously generating nitrogen-centered radical 39A. Subsequently, photocatalysts Ir2+ and 4CzIPN radical anion oxidize amidyl radical precursors 76 and 77 to yield the corresponding amidyl radicals. Concurrently, the carbon-centered radical 39A', originating from nitrogen-centered radical 39A through resonance stabilization, engages in radical coupling with the amidyl radicals to produce the iminium ion intermediate 39B. The final stage involves intramolecular nucleophilic cyclization of intermediate 39B, followed by the elimination of dimethylamine and deprotonation, ultimately yielding the desired products 78.

    Scheme 39

    Scheme 39.  Photoredox synthesis of 3-aminated chromones.
    DownLoad: Full-Size Img PowerPoint

    5.2 Synthesis of 3-phosphorylated chromones

    In 2024, our group established an efficient protocol for constructing 3-phosphorylated chromone derivatives 80 via a palladium-catalyzed tandem cyclization of o-hydroxyaryl enaminones 1 by employing trialkoxy or triaryloxyphosphines 79 as phosphorylating agents (Scheme 40) [118]. This transformation is distinguished by a sequence of α-C–H iodination, chromone cyclization, and Arbuzov-type C–P cross-coupling. Notably, elemental iodine serves as a critical additive, enabling the reaction's progression. Mechanistic investigations suggest a pathway involving a 3-iodochromone intermediate. Initially, enaminone 1 undergoes α-C-H iodination, forming the imine intermediate 40A, which undergoes intramolecular nucleophilic attack to yield iodonium intermediate 40B. In the presence of K2CO3, intermediate 40B undergoes nucleophilic attack and iodonium ring opening, producing intermediate 4C, which then eliminates dimethylamine to yield 3-iodochromone 4D. Concurrently, in situ generated Pd(0) facilitates oxidative addition with the C–I bond of 4D, resulting in intermediate 40C. Subsequent ligand exchange with trivalent phosphine 79 generates intermediate 40D, which, following iodoalkane elimination, produces intermediate 40E. Finally, reductive elimination affords the desired product 80, regenerating Pd(0) and completing the catalytic cycle.

    Scheme 40

    Scheme 40.  Pd-catalyzed synthesis of 3-phosphorylated chromones.
    DownLoad: Full-Size Img PowerPoint

    6. Synthesis of C2-functionalized chromones

    2-Functionalized chromones, which are primarily derived from natural products, have gained significant attention in the pharmaceutical industry due to their distinct biological activities. Despite notable progress in the chemical synthesis of 2-functionalized chromones over the past few decades [14–17], the process remains challenging, often requiring multi-step syntheses, harsh reaction conditions, and offering a limited variety of functional groups, thereby restricting their broader application. Our group, specializing in enaminone chemistry, has identified that although the β-C-H bond in o-hydroxyaryl enaminones is typically considered relatively inert, it can be activated under specific conditions. This activation enables a formal tandem β-C-H bond functionalization and cyclization reaction of o-hydroxyaryl enaminones, offering a highly practical and efficient strategy for the synthesis of 2-functionalized chromones.

    In 2020, our group developed a copper-catalyzed method for the synthesis of 2-aminated chromones 82 via a tandem β-C-H amination-cyclization of o-hydroxyaryl enaminones 1, facilitated by coordination with elemental iodine (Scheme 41) [119]. Mechanistic studies suggest that the reaction proceeds through a 2-iodochromone intermediate 4D. The process begins with the electrophilic addition of iodine to the enaminone 1, followed by classic chromone cyclization and demethylamine elimination, leading to the formation of the 2-iodochromone intermediate 4D. This step also releases HI, which is subsequently oxidized by PhI(OAc)2 to regenerate iodine. The intermediate 4D is then activated by CuI to form 41A, which undergoes nucleophilic addition with the aminating agent 81 to produce intermediate 41B. Finally, 41B undergoes dehydroiodination under basic conditions, yielding the 2-aminated chromone 82.

    Scheme 41

    Scheme 41.  CuI-catalyzed synthesis of C2-aminated chromones.
    DownLoad: Full-Size Img PowerPoint

    Additionally, in 2023, our group achieved a highly efficient and selective tandem β-C–H cyanation and cyclization of o-hydroxyaryl enaminones 1 to synthesize 2-cyanochromones 84, using I2/AlCl3 as a promoter (Scheme 42) [120]. The reaction utilizes a simple and readily available potassium ferrocyanide trihydrate 83 as the cyanating reagent. Mechanistic investigations suggest the reaction proceeds through a 2-iodochromone intermediate, followed by a 1,2-hydride shift. Initially, the enaminone 1 reacts with iodine, leading to dehydroiodination and dimethylamine elimination, forming intermediate 4D. The coordination of metal ions with the carbonyl oxygen and iodine atom in 4D enhances the electrophilicity of the carbon center, resulting in the formation of intermediate 42A. Subsequently, a Michael-type 1,4-addition of the cyanide ion to 42A generates intermediates 42B/42C which then undergo protonation and dehydroiodination to yield the final 2-cyanochromones 84.

    Scheme 42

    Scheme 42.  Synthesis of 2-cyanochromones.
    DownLoad: Full-Size Img PowerPoint

    7. Synthesis of 2,3-disubstituted chromones and chromone derivatives

    In recent decades, significant progress has been made in the construction of 2,3-disubstituted chromone frameworks [121–124]. Despite these advancements, existing methodologies often face inherent challenges, including harsh reaction conditions, the necessity for pre-functionalized substrates, reliance on expensive metal catalysts, and limited substrate scope. Recently, o-hydroxyaryl enaminones have gained attention as versatile synthetic intermediates, providing an effective approach for constructing 2,3-disubstituted chromone frameworks.

    For example, our group recently developed a novel strategy utilizing microwave irradiation and N-haloimides 85 as halogen sources to achieve a rapid tandem halocyclization reaction with o-hydroxyaryl enaminones 1, resulting in the efficient synthesis of 3,3-dihalo-2-amino-substituted chromone derivatives 86 (Scheme 43) [125]. Although N-iodosuccinimide proved unsuitable for this reaction, the method benefits from mild conditions and obviates the need for catalysts or additives. Based on mechanistic studies, a plausible reaction mechanism is proposed, as depicted in Scheme 43. Initially, under microwave irradiation, NXS 85 undergoes homolytic cleavage to form succinimide anions and halogen cations. The halogen cation then participates in an electrophilic addition to enaminone 1, generating iminium ion 43A. This intermediate subsequently undergoes intramolecular nucleophilic cyclization and deprotonation, yielding 43B. The keto-enol tautomerism of 39B produces intermediate 43C, which, upon nucleophilic attack by another halogen cation followed by deprotonation, results in the formation of the final 3,3-dihalo-2-amino chromone derivatives 86.

    Scheme 43

    Scheme 43.  Synthesis of 3,3-dihalo-2-amino chromones.
    DownLoad: Full-Size Img PowerPoint

    Using TBN (tert-butyl nitrite) 87 as the aminating reagent, Yang's group in 2021 developed a novel formic acid-mediated tandem amination-cyclization reaction of o-hydroxyaryl enaminones 1, efficiently constructing structurally diverse 3-oximino-2-hydroxy-chromanones 88 (Scheme 44) [126]. In an acidic medium, enaminone 1 undergoes nucleophilic substitution with TBN 87 to generate the iminium ion 44A, which then undergoes intramolecular nucleophilic cyclization to form intermediate 44B. Intermediate 44B eliminates dimethylamine to yield 3-nitrosochromone 44C. Finally, water acts as a nucleophile to attack 44C, leading to the formation of intermediate 44D, which is subsequently deprotonated to yield the target product 88.

    Scheme 44

    Scheme 44.  HCOOH-mediated synthesis of 3-oximino-2-hydroxy-chromanones.
    DownLoad: Full-Size Img PowerPoint

    In 2023, Wu and Gao et al. achieved a three-component tandem double C–H bond functionalization and chromone cyclization reaction using o-hydroxyaryl enaminones 1, phenylacetones 89 and aromatic amines 90 with the classic I2-DMSO mediated reaction system developed by their group (Scheme 45) [127]. This reaction synthesized a series of chromeno[2,3-b]pyrrol-4(1H)-ones 91, which hold potential applications in bioimaging. The reaction constructs four new chemical bonds and two rings in one step and demonstrates good substrate functional group compatibility. Control experiments suggest the reaction might proceed via the following pathway (Scheme 45). First, phenylacetone 89 undergoes α-C-H iodination in the presence of iodine to form intermediate 45A, which is then transformed into 45B through Kornblum oxidation. Next, enaminones 1 and 45B undergo nucleophilic addition to form iminium ion 45C. Intramolecular nucleophilic cyclization and deprotonation of 45C yield 45D, which then eliminates dimethylamine to produce the 3-alkylated chromone intermediate 45E. Subsequently, aromatic amine 90 and 45E undergo 1,4-addition to form 45F, which dehydrates to 45G. Finally, the tautomer 45H undergoes intramolecular cyclization to form intermediate 45I, which dehydrates to yield the final product 91.

    Scheme 45

    Scheme 45.  Synthesis of chromeno[2,3-b]pyrrol-4(1H)-ones.
    DownLoad: Full-Size Img PowerPoint

    In 2024, Yu et al. successfully developed a temperature-controlled, SA (succinic anhydride)-promoted divergent and controllable cyclization reaction between o-hydroxyaryl enaminones 1 and aryldiazonium tetrafluoroborates 10. This innovative approach enabled the synthesis of pyridazine-fused chromones 92 and 3-pyridazinyl chromones 93 (Scheme 46) [128]. Remarkably, this method represents the first realization of an intermolecular chromone cyclization pathway with multiple enaminone molecules, contrasting with the traditional approach where a single enaminone molecule forms an intermediate via vinyl α-C-H bond functionalization, followed by intramolecular hydroxyl participation in chromone nucleophilic cyclization. Based on mechanistic experiments, a plausible mechanism for the switchable cyclization reaction was proposed. Initially, enaminone 1 undergoes nucleophilic addition to aryldiazonium tetrafluoroborates 10, forming intermediate 46A. Intermediate 46A then undergoes traditional chromone cyclization and intramolecular proton transfer to yield intermediate 46B. Subsequent elimination of dimethylamine from intermediate 46B produces the 3-aminated chromone intermediate 46C, which reacts with enaminone 1 to form intermediate 46D. This is followed by intramolecular nucleophilic cyclization, generating intermediate 46E. Intermediate 46E undergoes an intramolecular proton transfer, followed by the elimination of dimethylamine, resulting in the formation of intermediate 46F. At this point, two reaction pathways are possible: First, intermediate 46F undergoes deprotonation to produce the target compound 92. Second, enaminone 1 participates in a nucleophilic addition to intermediate 46F, leading to the formation of intermediate 46G. Subsequent intramolecular deprotonation and elimination of dimethylamine from intermediate 46G yield the target compound 93.

    Scheme 46

    Scheme 46.  Cyclization reaction between enaminones with aryldiazonium salts.
    DownLoad: Full-Size Img PowerPoint

    In the same year, the same group introduced a novel solvent-controlled selective cyclization reaction utilizing o-hydroxyaryl enaminones 1 and aryl diazonium tetrafluoroborates 10 for the divergent synthesis of structurally diverse compounds, including 2-(3′-chromonyl)−3-hydrazonyl chromone 94 (Scheme 47A) and 2-alkoxy-3-hydrazonyl chromone 95 (Scheme 47B) [129]. The approach features mild reaction conditions, excellent functional group compatibility, high chemoselectivity, and straightforward product isolation via filtration, avoiding tedious column chromatography purification, thus presenting significant industrial potential. Based on experimental results, a plausible mechanism for the controlled cyclization of enaminone 1 and aryl diazonium tetrafluoroborate 10 is proposed (Scheme 47). Initially, enaminone 1 undergoes nucleophilic addition with aryl diazonium tetrafluoroborate 10 to generate intermediate 46A. This is followed by traditional chromone cyclization to form iminium ion 46B. Subsequent elimination of dimethylamine from intermediate 46B yields the 3-aminated chromone intermediate 46C. At this point, intermediate 46C can proceed via two distinct pathways: (a) Nucleophilic addition of the solvent alcohol to 46C produces intermediate 47A, which then deprotonates to yield the target product 95. (b) Nucleophilic addition of enaminone 1 to 46C forms intermediate 46D, followed by intramolecular nucleophilic cyclization to produce intermediate 47B. Subsequent deprotonation and elimination of dimethylamine afford the target product 94.

    Scheme 47

    Scheme 47.  Synthesis of 2,3-disubstituted chromone derivatives.
    DownLoad: Full-Size Img PowerPoint

    8. Conclusions and perspectives

    In conclusion, o-hydroxyaryl enaminones have emerged as significant molecules in enaminone chemistry due to their multiple nucleophilic and electrophilic sites, particularly in the synthesis of chromones and derivatives. This approach resolves the traditionally laborious and inefficient processes associated with synthesizing structurally diverse chromones and their derivatives. Given the intrinsic properties of o-hydroxyaryl enaminones and their utility in constructing diverse chromone structures, this review focuses on recent developments since mid-2019. The review systematically explores the synthesis of various chromone types and provides an in-depth discussion of the reaction mechanisms for forming 3-substituted chromones, 2-substituted chromones, 2,3-disubstituted chromones, and their derivatives from o-hydroxyaryl enaminones.

    Despite the significant progress in synthesizing structurally diverse chromones and their derivatives through direct vinyl C–H bond functionalization and chromone annulation of o-hydroxyaryl enaminones, notable challenges and opportunities remain. The functionalization of C-3 chromones is currently limited, particularly regarding the introduction of heteroatoms such as phosphorus and silicon, which have not been extensively explored. Furthermore, research on the regioselective synthesis of 2-substituted and 2,3-disubstituted chromones and their derivatives is still in its early stages, characterized by a limited number of reported works. To address these gaps, future research should focus on designing novel functionalization reagents and developing efficient, sustainable methods for synthesizing structurally diverse 2-substituted and 2,3-disubstituted chromones and their derivatives. These efforts are essential for broadening the applications of o-hydroxyaryl enaminones. It is hoped that this review will provide some guides to stimulate the ongoing research interest, and foster further advancements in the field of enaminone chemistry.

    Declaration of competing interest

    The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

    CRediT authorship contribution statement

    Liu-Liang Mao: Writing – original draft, Investigation. Yunyun Liu: Investigation, Conceptualization. Jie-Ping Wan: Writing – review & editing, Supervision, Funding acquisition, Conceptualization.

    Acknowledgment

    This work is financially supported by National Natural Science Foundation of China (No. 22161022).


    1. [1]

      A. Gaspar, M.J. Matos, J. Garrido, et al., Chem. Rev. 114 (2014) 4960–4992. doi: 10.1021/cr400265z

    2. [2]

      M. Singh, M. Kaur, O. Silakari, Eur. J. Med. Chem. 84 (2014) 206–239.

    3. [3]

      C.F.M. Silva, D.C.G.A. Pinto, A.M.S. Silva, ChemMedChem 11 (2016) 2252–2260. doi: 10.1002/cmdc.201600359

    4. [4]

      J. Reis, A. Gaspar, N. Milhazes, et al., J. Med. Chem. 60 (2017) 7941–7957. doi: 10.1021/acs.jmedchem.6b01720

    5. [5]

      C.F.M. Silva, V.F. Batista, D.C.G.A. Pinto, et al., Expert Opin. Drug Discovery 13 (2018) 795–798.

    6. [6]

      W. Zhao, B. Wang, Y. Liu, et al., Eur. J. Med. Chem. 189 (2020) 112075.

    7. [7]

      A.I. Green, G.M. Burslem, J. Med. Chem. 64 (2021) 7231–7240. doi: 10.1021/acs.jmedchem.1c00592

    8. [8]

      S. Park, M. Kim, Y. Lin, et al., Chem. Sci. 14 (2023) 9293–9305. doi: 10.1039/d3sc00752a

    9. [9]

      G. Nam, M. Hong, J. Lee, et al., Chem. Sci. 11 (2020) 10243–10254. doi: 10.1039/d0sc02046j

    10. [10]

      U.J. Jung, S.R. Kim, J. Med. Food 21(2018) 421–432. doi: 10.1089/jmf.2017.4078

    11. [11]

      K.B. Magalingam, Radhakrishnan A.K, N. Haleagrahara, Oxid. Med. Cell. Longev. 1 (2015) 314560.

    12. [12]

      D.F. Romagnolo, O.I. Selmin, J. Nutr. Gerontol. Geriatr. 31 (2012) 206–238. doi: 10.1080/21551197.2012.702534

    13. [13]

      A.U. Khan, H.S. Dagur, M. Khan, et al., Eur. J. Med. Chem. Rep. 3 (2021) 100010.

    14. [14]

      C.M. Santos, A.M. Silva, Adv. Heterocycl. Chem. 138 (2022) 159–241.

    15. [15]

      A.T. Benny, E.K. Radhakrishnan, RSC Adv. 12 (2022) 3343–3358. doi: 10.1039/d1ra08214k

    16. [16]

      S. Tian, T. Luo, Y. Zhu, et al., Chin. Chem. Lett. 31 (2020) 3073–3082. doi: 10.1016/j.cclet.2020.07.042

    17. [17]

      D. Kang, K. Ahn, S. Hong, Asian J. Org. Chem. 7 (2018) 1136–1150. doi: 10.1002/ajoc.201800128

    18. [18]

      Q. Tang, Z. Bian, W. Wu, et al., J. Org. Chem. 82 (2017) 10617. doi: 10.1021/acs.joc.7b01320

    19. [19]

      R. Samanta, R. Narayan, J.O. Bauer, et al., Chem. Commun. 51 (2015) 925–928.

    20. [20]

      X. Qi, H. Xiang, C. Yang, Org. Lett. 17 (2015) 5590–5593. doi: 10.1021/acs.orglett.5b02795

    21. [21]

      V.L.M. Silva, R.G. Soengas, A.M.S. Silva, Molecules 25 (2020) 1564. doi: 10.3390/molecules25071564

    22. [22]

      S. Mkrtchyan, V.O. Iaroshenko, J. Org. Chem. 85 (2020) 7152–7174. doi: 10.1021/acs.joc.0c00537

    23. [23]

      Q. Tong, R. Xiu, J. Chen, et al., ACS Catal. 13 (2023) 12692–12699. doi: 10.1021/acscatal.3c03282

    24. [24]

      Y.C. Fang, J.H. Chen, M.Z. Li, et al., Chin. Chem. Lett. (2024) 110474.

    25. [25]

      C. He, W.Y. Han, B.-D. Cui, et al., Adv. Synth. Catal. 362 (2020) 3655–3661. doi: 10.1002/adsc.202000488

    26. [26]

      W.Q. Zhu, Z.W. Zhang, W.Y. Han, et al., Org. Chem. Front. 8 (2021) 3413–3420. doi: 10.1039/d1qo00458a

    27. [27]

      A. Elagamy, R. Shaw, C. Shah, et al., J. Org. Chem. 86 (2021) 9478–9489. doi: 10.1021/acs.joc.1c00788

    28. [28]

      I.C.H. Castañeda, S.E. Ulic, C.O.D. Védova, et al., Tetrahedron Lett. 52 (2011) 1436–1440.

    29. [29]

      J.H. Looker, J.H. McMechan, J.W. Mader, J. Org. Chem. 43 (1978) 2344–2347. doi: 10.1021/jo00406a008

    30. [30]

      E.J. Diana, U.S. Kanchana, T.V. Mathew, Org. Biomol. Chem. 19 (2021) 7995–8008. doi: 10.1039/d1ob01352a

    31. [31]

      J. Yao, L. Kong, X. Li, Chem. Commun. 56 (2020) 13169–13172. doi: 10.1039/d0cc05664b

    32. [32]

      A. St-Gelais, J. Alsarraf, J. Legault, et al., Org. Lett. 20 (2018) 7424–7428. doi: 10.1021/acs.orglett.8b03148

    33. [33]

      X.-J. Zhang, Z. Wang, H. Zhang, et al., J. Org. Chem. 87 (2022) 835–845.

    34. [34]

      J. Duan, Z. Xiong, Y. Zhou, et al., Org. Lett. 23 (2021) 8007–8012. doi: 10.1021/acs.orglett.1c03010

    35. [35]

      H. Kausar, M.U. Khan, S.N. Begum, et al., Inter. J. Pharm. Sci. Res. 5 (2013) 76–79.

    36. [36]

      P.D. Lokhande, S.S. Sakate, K.N. Taksande, et al., Tetrahedron Lett. 46 (2005) 1573–1574.

    37. [37]

      D.C.G.A. Pinto, A.M.S. Silva, J.A.S. Cavaleiro, J. Heterocycl. Chem. 33 (1996) 1887–1893. doi: 10.1002/jhet.5570330655

    38. [38]

      L. Cai, X. Zhu, J. Chen, et al., Org. Chem. Front. 6 (2019) 3688–3692. doi: 10.1039/c9qo00830f

    39. [39]

      M. Stangier, A.M. Messinis, J.C. Oliveira, et al., Nat. Comm. 12 (2021) 4736.

    40. [40]

      D.M. Lade, Y.N. Aher, A.B. Pawar, J. Org. Chem. 84 (2019) 9188–9195. doi: 10.1021/acs.joc.9b01139

    41. [41]

      S. Debbarma, M.R. Sk, B. Modak, et al., J. Org. Chem. 84 (2019) 6207–6216. doi: 10.1021/acs.joc.9b00418

    42. [42]

      S. Zhao, X. Cai, Y. Lu, et al., Chem. Commun. 58 (2022) 8966–8969. doi: 10.1039/d2cc02194c

    43. [43]

      T.K. Macklin, J. Panteleev, V. Snieckus, Angew. Chem. Int. Ed. 47 (2008) 2097–2101. doi: 10.1002/anie.200704360

    44. [44]

      C. Zhou, A.V. Dubrovsky, R.C. Larock, J. Org. Chem. 71 (2006) 1626–1632. doi: 10.1021/jo0523722

    45. [45]

      X. Li, Y. Li, Y. Yang, et al., Org. Lett. 24 (2022) 7216–7221. doi: 10.1021/acs.orglett.2c03017

    46. [46]

      J. Shen, Y. Xiao, P. Zhao, et al., Adv. Synth. Catal. 364 (2022) 291–295. doi: 10.1002/adsc.202100946

    47. [47]

      C. Jung, S.Y. Li, K. Lee, et al., Green Chem. 24 (2022) 2376–2384. doi: 10.1039/d1gc04848a

    48. [48]

      J. Liu, D. Ba, Y. Chen, et al., Chem. Commun. 56 (2020) 4078–4081. doi: 10.1039/c9cc09460a

    49. [49]

      W. Mansour, M. Fettouhi, B.E. Ali, ACS Omega 5(2020) 32515–32529. doi: 10.1021/acsomega.0c04706

    50. [50]

      F. Zhu, Y. Li, Z. Wang, et al., Catal. Sci. Technol. 6 (2016) 2905–2909.

    51. [51]

      L. Fu, J.P. Wan, Asian J. Org. Chem. 8 (2019) 767–776. doi: 10.1002/ajoc.201900196

    52. [52]

      X.Y. Chen, X. Zhang, J.P. Wan, Org. Biomol. Chem. 20 (2022) 2356–2369. doi: 10.1039/d2ob00126h

    53. [53]

      Y. Han, L. Zhou, C. Wang, et al., Chin. Chem. Lett. 35 (2024) 108977. doi: 10.1016/j.cclet.2023.108977

    54. [54]

      J. Huang, F. Yu, Synthesis 53 (2021) 587–610.

    55. [55]

      Q. Yu, Y. Liu, J.P. Wan, Org. Chem. Front. 7 (2020) 2770–2775. doi: 10.1039/d0qo00855a

    56. [56]

      M. Behera, P. Thota, K. Sheelam, et al., Synlett 33 (2022) 1660–1664. doi: 10.1055/a-1906-3382

    57. [57]

      S. Song, W. Wang, J. Sun, et al., Green Synth. Catal. (2024), doi: 10.1016/j.gresc.2024.03.001.

    58. [58]

      D. Cheng, Y. Pu, M. Wang, et al., Synthesis 53 (2021) 1372–1378. doi: 10.1055/s-0040-1705973

    59. [59]

      D. Cheng, M. Wang, Z. Deng, et al., Eur. J. Org. Chem. 28 (2019) 4589–4592. doi: 10.1002/ejoc.201900793

    60. [60]

      L. Fu, Z. Xu, J.P. Wan, et al., Org. Lett. 22 (2020) 9518–9523. doi: 10.1021/acs.orglett.0c03548

    61. [61]

      S. Mkrtchyan, V.O. Iaroshenko, Chem. Commun. 56 (2020) 2606–2609. doi: 10.1039/c9cc09945j

    62. [62]

      S. Mkrtchyan, V.O. Iaroshenko, J. Org. Chem. 86 (2021) 4896–4916. doi: 10.1021/acs.joc.0c02294

    63. [63]

      S. Mkrtchyan, M. Jakubczyk, S. Lanka, et al., Adv. Synth. Catal. 364 (2022) 3512–3521. doi: 10.1002/adsc.202200645

    64. [64]

      S. Mkrtchyan, V.B. Purohit, S. Khutsishvili, et al., Adv. Synth. Catal. 365 (2023) 2026–2035. doi: 10.1002/adsc.202300260

    65. [65]

      S. Mkrtchyan, V.B. Purohit, V.O. Iaroshenko, ACS Sustain. Chem. Eng. 11 (2023) 13877–13884. doi: 10.1021/acssuschemeng.3c03467

    66. [66]

      A. Robinson, H.Y. Li, J. Feaster, Tetrahedron Lett. 37 (1996) 8321–8324. doi: 10.1002/chin.199710115

    67. [67]

      E. Venkateswararao, V.K. Sharma, M. Manickam, et al., Bioorg. Med. Chem. Lett. 24 (2014) 5256–5259. doi: 10.1016/j.bmcl.2014.09.057

    68. [68]

      G.C. Kaspentakis, C.A. Tsoleridis, J.J. Stephanidou, J. Heterocycl. Chem. 44 (2007) 425–430. doi: 10.1002/jhet.5570440223

    69. [69]

      H. Stankovicová, W.M. Fabian, M. Lácová, Molecules 1 (1996) 223–235. doi: 10.1007/s007830050041

    70. [70]

      G. Singh, S. Sharma, Rekha, et al., Eur. J. Org. Chem. 32 (2022) e202200792.

    71. [71]

      S. Pan, M. Song, L. Zuo, et al., J. Org. Chem. 88 (2023) 5586–5596. doi: 10.1021/acs.joc.3c00093

    72. [72]

      L.H. Wu, X. Liu, Z.W. Liu, et al., Org. Biomol. Chem. 21 (2023) 9236–9241. doi: 10.1039/d3ob01582c

    73. [73]

      W. Zhao, Z. He, X. Yang, et al., J. Org. Chem. 88 (2023) 13634–13644. doi: 10.1021/acs.joc.3c01339

    74. [74]

      M. Zhang, Z. Liu, L. Chen, et al., Adv. Synth. Catal. 364 (2022) 4440–4446. doi: 10.1002/adsc.202201154

    75. [75]

      M. Zhang, M. Liu, Y. Qiu, et al., Adv. Synth. Catal. 366 (2022) 2363–2369. doi: 10.1111/1755-0998.13612

    76. [76]

      Y. Gao, M. Wang, J. Sun, et al., Chem. Commun. 60 (2024) 5050–5053. doi: 10.1039/d4cc00919c

    77. [77]

      K. Yang, L. Wu, X. Fu, et al., Tetrahedron 156 (2024) 133948.

    78. [78]

      F. Ahmad, P.K. Ranga, S. Fatma, et al., J. Org. Chem. 89 (2024) 12104–12117. doi: 10.1021/acs.joc.4c01006

    79. [79]

      K. Wen, Y. Li, Q. Gao, et al., J. Org. Chem. 87 (2022) 9270–9281. doi: 10.1021/acs.joc.2c01005

    80. [80]

      N. Talpada, A.S. Sharma, V.S. Sharma, et al., ChemNanoMat 10 (2024) e202300641.

    81. [81]

      Z.Q. Zhu, J.Y. Hu, Z.B. Xie, et al., Adv. Synth. Catal. 364 (2022) 2169–2173. doi: 10.1002/adsc.202200304

    82. [82]

      J.Y. Hu, Z.B. Xie, J. Tang, et al., J. Org. Chem. 87 (2022) 14965–14969. doi: 10.1021/acs.joc.2c01977

    83. [83]

      S. Han, C. Fang, Y. Zhang, et al., Eur. J. Org. Chem. 27 (2024) e202400401.

    84. [84]

      A. Chand, D.K. Sahoo, A. Rana, et al., Acc. Chem. Res. 53 (2020) 1580–1592. doi: 10.1021/acs.accounts.0c00289

    85. [85]

      B. Fan, F. Lin, X. Wu, et al., Acc. Chem. Res. 54 (2021) 3906–3916. doi: 10.1021/acs.accounts.1c00443

    86. [86]

      Y. Han, Y. Zhang, C. Xu, et al., Fuel, 221 (2018) 144–158.

    87. [87]

      G.S. Sorabad, M.R. Maddani, Asian J. Org. Chem. 8 (2019) 1336–1343. doi: 10.1002/ajoc.201900402

    88. [88]

      T. Zhang, W. Yao, J.P. Wan, et al., Adv. Synth. Catal. 363 (2021) 4811–4816. doi: 10.1002/adsc.202100617

    89. [89]

      B. Zhang, Z. Fu, H. Yang, et al., Adv. Synth. Catal. 364 (2022) 1602–1606. doi: 10.1002/adsc.202200089

    90. [90]

      P. Xu, Z, Zhong, H. Huang, et al., Tetrahedron 124 (2022) 133018.

    91. [91]

      X.Y. Jiang, X. Wang, C.L. Yang, et al., Eur. J. Org. Chem. 46 (2022) e202201196.

    92. [92]

      T. Guo, L. Bi, M. Zhang, et al., J. Org. Chem. 87 (2022) 16907–16912. doi: 10.1021/acs.joc.2c02248

    93. [93]

      T. Zhou, J. Zhou, Y. Liu, et al., Chin. Chem. Lett. 35 (2024) 109683. doi: 10.1016/j.cclet.2024.109683

    94. [94]

      T. Castanheiro, J. Suffert, M. Donnard, et al., Chem. Soc. Rev. 45 (2016) 494–505. doi: 10.1039/c5cs00532a

    95. [95]

      H. Chen, X. Shi, X. Liu, et al., Org. Biomol. Chem. 20 (2022) 6508–6527. doi: 10.1039/d2ob01018f

    96. [96]

      S. Majedi, L. Sreerama, E. Vessally, et al., J. Chem. Lett. 1 (2022) 25–31. doi: 10.22034/JCHEMLETT.2020.107760

    97. [97]

      Z. Yang, Y. Wang, L. Hu, et al., Synthesis 52 (2020) 711–718.

    98. [98]

      Z. Yang, L. Hu, T. Cao, et al., New J. Chem. 43 (2019) 16441–16444. doi: 10.1039/c9nj04580e

    99. [99]

      H.Y. Liu, J.R. Zhang, G.B. Huang, et al., Adv. Synth. Catal. 363 (2021) 1656–1661. doi: 10.1002/adsc.202001474

    100. [100]

      L. Lu, X. Zhao, W. Dessie, et al., Org. Biomol. Chem. 20 (2022) 1754–1758. doi: 10.1039/d1ob02402g

    101. [101]

      C.V. Doerner, J.S.S. Neto, C.R. Cabreira, et al., New J. Chem. 47 (2023) 5598–5602. doi: 10.1039/d2nj06043d

    102. [102]

      K. Cen, Y. Liu, J. Yu, et al., J. Org. Chem. 89 (2024) 8632–8640. doi: 10.1021/acs.joc.4c00567

    103. [103]

      J.H. Xia, Q. Chen, J.W. Yuan, et al., RSC Adv. 13 (2023) 26948–26959. doi: 10.1039/d3ra05246j

    104. [104]

      S.M. Tomé, A.M.S. Silva, C.M.M. Santos, Curr. Org. Synth. 11 (2014) 317–341. doi: 10.2174/15701794113109990063

    105. [105]

      Y.P. Zhao, J.L. Liao, J. Huang, et al., Org. Chem. Front. 11 (2024) 2579–2584. doi: 10.1039/d4qo00018h

    106. [106]

      Z. Zhang, J. Qiao, D. Wang, et al., Mol. Divers. 18 (2014) 245–251. doi: 10.1007/s11030-013-9495-1

    107. [107]

      R.B. Gammill, Synthesis 11 (1979) 901–903.

    108. [108]

      I. Yokoe, K. Maruyama, Y. Sugita, et al., Chem. Pharm. Bull. 42 (1994) 1697–1699. doi: 10.1248/cpb.42.1697

    109. [109]

      V. Kandula, P.K. Thota, P. Mallesham, et al., Synlett 30 (2019) 2295–2299.

    110. [110]

      Y. Wang, B. Hu, Q. Zhang, et al., J. Chem. Res. 45 (2021) 95–101.

    111. [111]

      R. Akkineni, K. Sheelam, V.R. Battula, et al., Syn. Comm. 53 (2023) 1559–1567. doi: 10.1080/00397911.2023.2236735

    112. [112]

      Q.L. Zhao, P.J. Xia, L. Zheng, et al., Tetrahedron 76 (2020) 130833.

    113. [113]

      Y. Lin, J.P. Wan, Y. Liu, New J. Chem. 44 (2020) 8120–8124. doi: 10.1039/d0nj00825g

    114. [114]

      Y. Lin, J. Jin, C. Wang, et al., J. Org. Chem. 86 (2021) 12378–12385. doi: 10.1021/acs.joc.1c01347

    115. [115]

      J.S. Neto, F.T. Coelho, C.V. Doerner, et al., Chem. Asian J. 19 (2024) e202300852.

    116. [116]

      Z.W. Wang, Y. Zheng, Y.E. Qian, et al., J. Org. Chem. 87 (2022) 1477–1484. doi: 10.1021/acs.joc.1c02796

    117. [117]

      W. Hu, X. Diao, J. Yuan, et al., J. Org. Chem. 89 (2024) 644–655. doi: 10.1021/acs.joc.3c02399

    118. [118]

      D. Cao, J.P. Wan, Y. Liu, Adv. Synth. Catal. 366 (2024), 3670–3675. doi: 10.1002/adsc.202400587

    119. [119]

      T. Luo, J.P. Wan, Y. Liu, Org. Chem. Front. 7 (2020) 1107–1112. doi: 10.1039/d0qo00065e

    120. [120]

      Y. Lin, J.P. Wan, Y. Liu, J. Org. Chem. 88 (2023) 4017–4023. doi: 10.1021/acs.joc.3c00206

    121. [121]

      M.Z. Li, Q. Tong, W.Y. Han, et al., Org. Biomol. Chem. 18 (2020) 1112–1116. doi: 10.1039/c9ob02690h

    122. [122]

      C. Shen, W. Li, H. Yin, et al., Adv. Synth. Catal. 358 (2016) 466–479. doi: 10.1002/adsc.201500858

    123. [123]

      A.G. Neo, J. Díaz, S. Marcaccini, et al., Org. Biomol. Chem. 10 (2012) 3406–3416. doi: 10.1039/c2ob07011a

    124. [124]

      M. Mohadeszadeh, M. Iranshahi, Mini. Rev. Med. Chem. 17 (2017) 1377–1397.

    125. [125]

      T. Luo, H. Wu, L.H. Liao, et al., J. Org. Chem. 86 (2021) 15785–15791. doi: 10.1021/acs.joc.1c01851

    126. [126]

      Y.E. Qian, L. Zheng, Q.L. Zhao, et al., Chem. Commun. 57 (2021) 12285–12288. doi: 10.1039/d1cc05389b

    127. [127]

      S.G. Lei, Y. Zhou, L.S. Wang, et al., Org. Chem. Front. 10 (2023) 4843–4847. doi: 10.1039/d3qo01149f

    128. [128]

      S. Song, Z. Zhang, M. Peng, et al., Org. Chem. Front. 11 (2024) 3906–3912. doi: 10.1039/d4qo00677a

    129. [129]

      S. Song, M. Peng, Z. Zhang, et al., Org. Lett. 26 (2024) 4980–4985. doi: 10.1021/acs.orglett.4c01571

  • Figure 1  Selected bioactive molecules featuring a chromone skeleton.

    下载: 全尺寸图片 幻灯片

    Scheme 1  Tandem C–H activation and chromone annulation.

    下载: 全尺寸图片 幻灯片

    Scheme 2  Synthesis of 3-trifluoromethylated chromones.

    下载: 全尺寸图片 幻灯片

    Scheme 3  Synthesis of 3-allylated chromones.

    下载: 全尺寸图片 幻灯片

    Scheme 4  Synthesis of 3-alkenylated chromones.

    下载: 全尺寸图片 幻灯片

    Scheme 5  Photocatalytic synthesis of 3-arylated chromones.

    下载: 全尺寸图片 幻灯片

    Scheme 6  Synthesis of 3-arylated chromones.

    下载: 全尺寸图片 幻灯片

    Scheme 7  Mechanochemical synthesis of 3-aryl chromones.

    下载: 全尺寸图片 幻灯片

    Scheme 8  Mechanochemical synthesis of 3-acylchromones.

    下载: 全尺寸图片 幻灯片

    Scheme 9  Mechanochemical synthesis of 3-acylchromones with Fe(Ⅲ) catalysis.

    下载: 全尺寸图片 幻灯片

    Scheme 10  TsOH-mediated synthesis of 3-alkylated chromones.

    下载: 全尺寸图片 幻灯片

    Scheme 11  Synthesis of 3-difluoro/trifluoromethyl hydroxymethylated chromones.

    下载: 全尺寸图片 幻灯片

    Scheme 12  Photocatalytic synthesis of 3-alkylated chromones.

    下载: 全尺寸图片 幻灯片

    Scheme 13  Ag2O-catalyzed synthesis of 3-alkylated chromones.

    下载: 全尺寸图片 幻灯片

    Scheme 14  AgBF4-catalyzed synthesis of 3-alkylated chromones.

    下载: 全尺寸图片 幻灯片

    Scheme 15  Electrochemical synthesis of 3-alkylated chromones.

    下载: 全尺寸图片 幻灯片

    Scheme 16  HFIP-promoted synthesis of 3-alkylated chromones.

    下载: 全尺寸图片 幻灯片

    Scheme 17  CuI-catalyzed synthesis of 3-alkylated chromones.

    下载: 全尺寸图片 幻灯片

    Scheme 18  Decarboxylative synthesis of 3-alkylated chromones.

    下载: 全尺寸图片 幻灯片

    Scheme 19  Photocatalytic synthesis of 3-aminoalkyl chromones.

    下载: 全尺寸图片 幻灯片

    Scheme 20  Photochemical/enzymatic synthesis of 3-aminoalkyl chromones.

    下载: 全尺寸图片 幻灯片

    Scheme 21  Electrochemical decarboxylative synthesis of 3-aminoalkyl chromones.

    下载: 全尺寸图片 幻灯片

    Scheme 22  Synthesis of 3-arylthiochromones.

    下载: 全尺寸图片 幻灯片

    Scheme 23  Synthesis of 3-dithiocarbamyl chromones.

    下载: 全尺寸图片 幻灯片

    Scheme 24  Synthesis of S-3-chromone phosphorothioates.

    下载: 全尺寸图片 幻灯片

    Scheme 25  Electrochemical synthesis of 3-aryl/alkylthiochromones.

    下载: 全尺寸图片 幻灯片

    Scheme 26  Three-component synthesis of 3-heteroarylthiochromones.

    下载: 全尺寸图片 幻灯片

    Scheme 27  Synthesis of 3-heteroarylthiochromones.

    下载: 全尺寸图片 幻灯片

    Scheme 28  Synthesis of 3-(trifluoromethylthio)- and 3-trifluoromethyl-sulfinyl chromones.

    下载: 全尺寸图片 幻灯片

    Scheme 29  Synthesis of 3-thiocyanated chromones.

    下载: 全尺寸图片 幻灯片

    Scheme 30  Synthyesis of 3-arylselenochromones.

    下载: 全尺寸图片 幻灯片

    Scheme 31  Visible-light-indued synthesis of 3-CF3Se chromones.

    下载: 全尺寸图片 幻灯片

    Scheme 32  TCCA-mediated synthesis of 3-selenylated chromones.

    下载: 全尺寸图片 幻灯片

    Scheme 33  Electrochemical synthesis of 3-selenylated chromones.

    下载: 全尺寸图片 幻灯片

    Scheme 34  Selectfluor-mediated synthesis of 3-selenylated chromones.

    下载: 全尺寸图片 幻灯片

    Scheme 35  Synthesis of 3-fluorinated chromones.

    下载: 全尺寸图片 幻灯片

    Scheme 36  BHT-mediated synthesis of 3-fluorinated chromones.

    下载: 全尺寸图片 幻灯片

    Scheme 37  Synthesis of 3-halochromones.

    下载: 全尺寸图片 幻灯片

    Scheme 38  Oxone-mediated synthesis of 3-halochromones.

    下载: 全尺寸图片 幻灯片

    Scheme 39  Photoredox synthesis of 3-aminated chromones.

    下载: 全尺寸图片 幻灯片

    Scheme 40  Pd-catalyzed synthesis of 3-phosphorylated chromones.

    下载: 全尺寸图片 幻灯片

    Scheme 41  CuI-catalyzed synthesis of C2-aminated chromones.

    下载: 全尺寸图片 幻灯片

    Scheme 42  Synthesis of 2-cyanochromones.

    下载: 全尺寸图片 幻灯片

    Scheme 43  Synthesis of 3,3-dihalo-2-amino chromones.

    下载: 全尺寸图片 幻灯片

    Scheme 44  HCOOH-mediated synthesis of 3-oximino-2-hydroxy-chromanones.

    下载: 全尺寸图片 幻灯片

    Scheme 45  Synthesis of chromeno[2,3-b]pyrrol-4(1H)-ones.

    下载: 全尺寸图片 幻灯片

    Scheme 46  Cyclization reaction between enaminones with aryldiazonium salts.

    下载: 全尺寸图片 幻灯片

    Scheme 47  Synthesis of 2,3-disubstituted chromone derivatives.

    下载: 全尺寸图片 幻灯片
  • 加载中
WeChat 扫一扫看文章
计量
  • PDF下载量:  0
  • 文章访问数:  30
  • HTML全文浏览量:  1
文章相关
  • 发布日期:  2025-07-15
  • 收稿日期:  2024-09-27
  • 接受日期:  2024-12-19
  • 修回日期:  2024-12-09
  • 网络出版日期:  2024-12-19
通讯作者: 陈斌, bchen63@163.com
  • 1. 

    沈阳化工大学材料科学与工程学院 沈阳 110142

  1. 本站搜索
  2. 百度学术搜索
  3. 万方数据库搜索
  4. CNKI搜索

/

返回文章

All Rights Reserved by the Chinese Chemical Society   中国化学会 版权所有 京ICP备05002797号

本系统由北京仁和汇智信息技术有限公司开发    技术支持: info@rhhz.net