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Review Article
ARTICLE IN PRESS
doi:
10.25259/AJC_258_2025

Catalytic carbonylation for flavone synthesis: Advances and prospects. A mini-review

,
aSchool of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, 10 Poyanghu Road, West Area, Tuanbo New Town, Jinghai District, Tianjin, China
bSchool of Chemistry and Chemical Engineering, Guangxi University, No.100, East Daxue Road, Xixiangtang District, Nanning, China

* Corresponding author: E-mail address: zcwang@tjutcm.edu.cn (Z. Wang)

Received: , Accepted: ,
© 2026 Arabian Journal of Chemistry - Published by Scientific Scholar
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This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-Share Alike 4.0 License, which allows others to remix, transform, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.

Abstract

Flavones, with a C6-C3-C6 skeleton, are widely present in nature and many commonly used pharmaceuticals, exhibiting diverse biological activities and therapeutic potential. The significance and widespread application of flavones have sparked chemists’ interest in developing efficient synthesis methods. Traditional methods for the synthesis of flavones face challenges of inefficiency and impact. In recent years, various synthetic strategies have been established for the efficient construction of flavones. This review focuses on the catalytic carbonylative synthesis of flavones using carbon monoxide (CO) gas, CO surrogates, and CO2 as carbonyl sources, an atom-economical approach aligning with green chemistry. It scrutinizes recent advancements, exploring reaction types, mechanisms, catalysts, and substrate scope, providing a foundation for future synthetic endeavors in organic and medicinal chemistry.

Keywords

Flavone
Carbonylation Carbon monoxide gas
Carbon monoxide surrogate
CO2

1. Introduction

Flavones refer to compounds with a phenyl chromone basic structure, composed of two aromatic rings (Ring A and Ring B) linked by a central three-carbon bridge (Ring C) to form a C6-C3-C6 skeletal structure (Figure 1) [1]. Generally, flavones give colors. The chromogenicity of flavones stems from the fact that the two cross-conjugated systems of the parent ring in their structure are not conjugated, leading to cross-conjugation and elongation of electron transfer rearrangements on the conjugated chain, making them a member of the natural pigment family [2]. The solubility of flavones is associated with the length of the sugar chain in the structure. They are easily dissolved in highly polar solvents, including methanol and ethyl acetate, and sparingly dissolved in organic solvents, including benzene and chloroform [3]. The acidity and alkalinity of flavones are related to the quantity and substitution sites of phenolic hydroxyl substituents on their molecular structures [4]. Flavones are widely distributed in plants. Over 2000 natural flavones have been identified, predominantly concentrated in angiosperms, particularly in the Fabaceae, Rosaceae, and Rutaceae families [5]. Common flavone-rich foods encompass berries, citrus fruits, berries, broccoli, cherries, grapes, papayas, cantaloupes, plums, tea leaves, red wine, and tomatoes [6]. Additionally, some commonly used traditional Chinese medicines contain flavones as secondary metabolites [7]. Flavones not only impart vivid colors to plants but also play a crucial role in warding off pests, diseases, and ultraviolet radiation [8]. In the medical field, they have attracted considerable interest because of their wide range of biological activities [9]. Studies have shown that flavones possess remarkable pharmacological effects, containing antioxidant [10], anti-inflammatory [11], anticancer [12], antibacterial [13], antiviral [14], and cardiovascular protective properties [15-21].

Flavone and representative bioactive flavones.
Figure 1.
Flavone and representative bioactive flavones.

The synthesis of flavones not only contributes to a profound comprehension of the relationship between their structure and function but also makes a significant contribution to the development of novel drugs, the improvement of production processes, and the promotion of green chemistry and sustainable development [22]. Classical chemical synthesis methods of flavones primarily include the following (Figure 2): (a) Claisen condensation (Figure 2a). Through the condensation reaction of o-hydroxyacetophenone with benzaldehyde under alkaline conditions, a 2-hydroxychalcone intermediate is formed, which subsequently undergoes acid-catalyzed cyclization to yield flavones. This approach is suitable for synthesizing simple flavones but entails multiple steps and relatively harsh conditions [23]; (b) Baker-Venkataraman rearrangement (Figure 2b). o-Acetoxyacetophenone undergoes rearrangement to obtain β-diketone, and flavones can be synthesized through cyclization. This approach also involves multiple steps and employs strong acids and alkalis, imposing high demands on equipment [24]; (c) Auwer’s method (Figure 2c). It involves the condensation of benzofuran and benzaldehyde to produce 2-bromo-2-(α-bromobenzyl)-benzofuranone, which undergoes rearrangement upon alkali treatment to generate the desired flavones [25]; (d) Allan–Robinson reaction (Figure 2d). It takes aromatic carboxylic anhydrides as substrates, and the reaction yields flavones and isoflavones [26]. These flavone synthesis methods are fraught with multiple drawbacks, such as complex multistep operations and rigorous reaction conditions, including elevated temperatures, pressures, and strong acidic or basic media, leading to low atom utilization, abundant by-products, and poor tolerance of functional groups. These shortcomings have spurred researchers to explore more efficient synthesis strategies.

Traditional pathways to flavones.
Figure 2.
Traditional pathways to flavones.

Among the research on flavone synthesis, chemists have discovered that both carbon monoxide (CO) and CO2 can serve as an efficient synthon for realizing carbonylation reactions. CO, as a plentiful, atom-economical, and chemically reactive C1 synthon, plays an indispensable and pivotal role in constructing complex organic molecular architectures [27]. It participates in a diverse array of reaction types, encompassing oxidative carbonylation, reductive carbonylation, and radical carbonylation, enabling the precise introduction of carbonyl functional groups and providing essential support for constructing complex molecular structures [28]. Particularly in the synthesis of flavones, CO-mediated reactions exhibit unique advantages and substantial potential. In the pursuit of more efficient, convenient, and sustainable synthesis strategies, CO surrogates have emerged as novel carbonyl sources, gradually attracting extensive attention [29]. These CO surrogates, including metal carbonyl complexes and organic carbonyl compounds, possess distinct physicochemical properties and reactivity characteristics, presenting new ideas and challenges for flavone synthesis. Metal carbonyl complexes, with their relatively stable structures and controllable carbonyl release properties, exhibit unique reaction selectivity and activity patterns in specific reaction systems, enabling carbonylation transformations under mild conditions and providing mild and precise synthetic means for constructing sensitive or complex flavone structures [30]. Organic carbonyl compounds, with their rich variety, can be tailored and optimized based on their structural features and reactivity differences, realizing diversified carbonylation reaction pathways [31]. CO₂ is a highly abundant, inexpensive, and renewable carbon resource, making it an atom-economical and attractive alternative to fossil fuel-derived C1 sources like carbon monoxide, which aligns perfectly with the principles of green and sustainable chemistry.

Based on our current understanding, no focused work has addressed catalytic flavone synthesis via carbonylation. This review summarizes cutting-edge progress in flavone synthesis using CO gas, CO surrogates, and CO2 as carbonyl sources, covering core elements (reaction types, mechanisms, catalysts, substrates, conditions) and their interactions. It analyses strengths, limitations, and scopes of reaction systems, and via cases, explores applications/extensions in pharmaceutical chemistry, materials science, and natural product synthesis. Its goal is to guide organic chemists, advance the field, and support efficient flavone synthesis and application.

2. Catalytic synthesis of flavones

In recent years, chemists have paid increasing attention to the catalytic carbonylation synthesis of flavones (Figure 3). Through our analysis of the reaction mechanism, it was found that most flavones are catalytically synthesized through carbonylative Sonogashira reactions [32]. Other reaction types include the Heck reaction and the Suzuki reaction, etc. [33]. Most substrates are phenol derivatives. This section is primarily divided into three main parts: (2.1) synthesis of flavones with CO gas serving as a C1 building block, (2.2) synthesis of flavones using a CO surrogate as a C1 building block, and (2.3) synthesis of flavones with CO2 serving as a C1 building block, accompanied by further sub-classifications depending on the type of catalysts. Moreover, a detailed discussion is presented on various significant substrates and crucial mechanisms.

Recent new pathways to flavones.
Figure 3.
Recent new pathways to flavones.

2.1. Synthesis of flavones with CO gas serving as a C1 building block

2.1.1. Palladium-catalyzed cyclocarbonylative Sonogashira reactions

In recent years, a principal strategy for the construction of flavones by C1 chemistry is the carbonylative Sonogashira reaction. This part mainly summarizes the approaches employing palladium (Pd) catalysts, which include homogeneous reactions and heterogeneous reactions, both with ligand assistance and ligand-free ones. Different reports each have their own focus. In 2010, Yang and Alper unveiled a remarkable advancement in the field of flavone synthesis under ambient CO pressure in the presence of PdCl2 and triethylamine (Et3N), involving the synthesis step of 2-iodophenol coupling with terminal acetylenes in the phosphonium salt ionic liquid environment, specifically C14H29(C6H13)3P+Br- (Scheme 1a) [34]. The researchers devised an exceptionally efficient and selective Pd-catalyzed carbonylative Sonogashira reaction, which operated without the need for a ligand. The authors observed that the ionic liquid was essential in raising both the reaction yield and selectivity, which also hinted at the potential for recycling the reaction components. This recyclability was substantiated in subsequent trials, where a commendable 78% yield of the target flavone was achieved in the second iteration. The reaction system delivered impressive yields ranging from 64% to 96% across a diverse array of substrates, encompassing a range of aromatic and aliphatic types of terminal acetylenes (Scheme 1b). A notable example was the construction of 2-phenyl-4H-chromen-4-one from the reaction of 2-iodophenol with phenyl acetylene, which resulted in a 95% yield. Acetylenes bearing methyl groups or electron-withdrawing groups on the aromatic ring were also found to react efficiently, affording the target flavones in satisfactory yields. Furthermore, the reaction with heteroaromatic-substituted acetylenes led to the formation of 2-thiophene-substituted chromones with a 92% yield. Aliphatic acetylenes were also accommodated, resulting in the formation of 2-alkyl-substituted chromones. This capability to synthesize a broad spectrum of flavones with high efficiency and selectivity could herald significant developments in the synthesis of bioactive compounds. This ligand-free system, using atmospheric CO pressure and phosphonium salt ionic liquid as a green solvent, showed potential for industrial use.

Synthesis of flavones via Pd-catalyzed ligand-free cyclocarbonylation.
Scheme 1.
Synthesis of flavones via Pd-catalyzed ligand-free cyclocarbonylation.

In 2011, Xue and Li disclosed a groundbreaking method in the construction of flavones, employing a novel Pd-NHC complex as a potent catalyst (Scheme 2a) [35]. The authors crafted a series of carbene complexes and rigorously assessed catalytic prowess in the carbonylative Sonogashira coupling of 2-iodophenol with phenylacetylene. After an exhaustive screening, the Pd-NHC species, which included N-phenylimidazole as a co-ligand, was selected as the optimal catalyst. This complex showcased exceptional catalytic activity and selectivity, yielding flavones in excellent yields under comparatively moderate conditions (Scheme 2b). Researchers further expanded the substrate scope, demonstrating that an array of acetylenes was compatible with the reaction. Both electron-rich and electron-deficient phenylacetylenes, along with heteroaromatic and aliphatic counterparts, were successfully incorporated, leading to a rich diversity of flavone derivatives. Notably, the coupling of 2-iodophenol with electron-rich 4-alkyl phenylacetylenes proceeded smoothly, delivering the corresponding flavones with nearly quantitative yields. Moreover, the reaction tolerated a free amino group on the aryl acetylene, underscoring the remarkable chemoselectivity of the process. Future endeavors in this field could focus on tailoring NHC the ligands and seeking out alternative reaction adjuncts to further enhance the efficiency and versatility of this synthetic strategy. With low catalyst loading (0.5–1 mol%), mild CO pressure (1–4 bar), and broad substrate scope, this system was suitable for pharmaceutical synthesis.

Synthesis of flavones via Pd-NHC complex-catalyzed carbonylative Sonogashira coupling.
Scheme 2.
Synthesis of flavones via Pd-NHC complex-catalyzed carbonylative Sonogashira coupling.

In 2016, Zhu and Wu developed a superior efficiency and selectivity palladium on carbon (Pd/C)-catalyzed ligand-free cyclocarbonylation process for the preparation of flavones in 61-98% yields (Scheme 3a) [36]. This heterogeneous catalytic method utilized terminal acetylenes and 2-iodophenol serving as substrates with a temperature of 110°C and a CO pressure of 20 bar (Scheme 3b). The use of a heterogeneous Pd/C catalyst not only simplified the reaction setup but also enabled the catalyst to be easily recovered and reused (Scheme 3c), which was a crucial aspect for large-scale synthesis. The durability of the Pd/C catalyst was measured by its performance in five cycles, affording 9a with a 55% yield, demonstrating the durability of this catalytic system. The absence of a phosphine ligand in this system was a significant advantage, simplifying the reaction protocol and reducing costs associated with ligand synthesis and purification. This method demonstrated versatility with a wide variety of terminal acetylenes, accommodating both electron-rich and electron-deficient species, along with heteroaromatic and aliphatic acetylenes. Phenylacetylenes bearing methyl, ethyl, and halogen substituents engaged in the reaction seamlessly, delivering flavones with high efficiency. Similarly, heteroaromatic acetylenes incorporating pyridyl or thienyl moieties produced the desired flavone products with notable yields. Remarkably, propargylic substrates, which posed challenges in many catalytic systems, were successfully transformed into flavones with satisfactory yields. Whereas 2-iodoaniline served as a substrate, the target flavone could not be obtained. Using readily available aryl bromides instead of expensive aryl iodides, this method offered cost advantages for industrial flavone synthesis. However, homogeneous catalysis may limit large-scale use due to metal separation issues.

Palladium on carbon (Pd/C) catalyzed cyclocarbonylative synthesis of flavones.
Scheme 3.
Palladium on carbon (Pd/C) catalyzed cyclocarbonylative synthesis of flavones.

Similar to the above reports, Chandrasekhar and Sankararaman demonstrated an efficient strategy for the construction of flavones, through a carbonylative Sonogashira coupling-intramolecular aldol cascade reaction using 2-iodoaryl 2-arylacetates as substrates (Scheme 4a) [37]. The preparation of 2-iodoaryl 2-arylacetates was executed starting with 2-iodophenols and 2-arylacetyl chlorides. These esters were then subjected to carbonylative annulation reactions with arylacetylenes using Pd(PPh3)2Cl2 as the catalyst in toluene at 80°C under 1 atmosphere of CO. The reactions were carried out successfully and selectively, generating the target flavones in good yields (Scheme 4b). The modular nature of the method was demonstrated by the independent alterations in the groups of the three aryl rings, allowing for the construction of a diverse array of flavones. For example, the reaction conditions readily accommodated a variety of substituents, including Cl, Br, NO2, and OMe. The modular, one-pot synthesis with high yields and tolerance for diverse substituents made it applicable for industrial production. The hypothesized mechanism (Scheme 4c) involved the oxidative addition step across the C–I bond of the 2-iodoaryl 2-arylacetate, followed by carbonylation and Sonogashira coupling with the arylacetylene. This intermediate then underwent a series of steps, including oxidative addition, carbon monoxide insertion, and reductive elimination to form the carbonylative Sonogashira intermediate intermediate (Int) 4. The intermediate allenolate Int 5 was formed following a 1,4-addition of the Lewis base X to the Sonogashira intermediate Int 4. Subsequently, the aroyl group’s engagement with the phenol, paralleling the Baker-Venkataraman rearrangement, led to the acylated enone intermediate Int 6. Acting as a Michael acceptor, this acylated enone intermediate, Int 6, underwent an intramolecular cyclization with the phenoxide attacking the β-carbon. The final step involved the elimination of the Lewis base, culminating in the formation of the desired flavones 12.

Carbonylative Sonogashira coupling-aldol cascade synthesis of flavones from 2-iodoaryl 2-arylacetate.
Scheme 4.
Carbonylative Sonogashira coupling-aldol cascade synthesis of flavones from 2-iodoaryl 2-arylacetate.

In 2016, Chavan and Bhanage also reported an innovative heterogeneous palladium-catalyzed carbonylative annulation for the synthesis of flavones (Scheme 5a) [38]. The researchers designed and synthesized a Pd-based catalyst supported on amine-functionalized montmorillonite, denoted as Pd0APTES@K10 (APTES = 3-aminopropyl-triethoxysilane) Montmorillonite K10. This catalyst could be reused for up to four consecutive cycles without significant activity loss. Extensive characterization of the catalyst was conducted using a series of analytical instruments, including scanning electron microscopy (SEM), Fourier-transform infrared spectroscopy (FTIR), N2 adsorption-desorption, X-ray photoelectron spectroscopy (XPS), X-ray diffraction (XRD), and transmission electron microscopy (TEM). These analyses confirmed the successful anchoring of Pd nanoparticles on the amine-modified montmorillonite, characterized by a uniform particle size distribution and optimal dispersion. The catalytic prowess of Pd0APTES@K10 was rigorously evaluated in the carbonylative annulation of 2-iodophenol with terminal alkynes. A systematic optimization of the reaction conditions revealed that the solvent was crucial in determining the regioselectivity. In 1,2-dimethoxyethane (DME), the 5-exo cyclization pathway was favored, leading to the formation of aurones, whereas in dimethylformamide (DMF), the 6-endo cyclization pathway was predominant, yielding flavones. This solvent-dependent regioselectivity offered a unique avenue for the selective synthesis of either aurones or flavones based on the desired outcome. A broad spectrum of terminal alkynes, encompassing both aromatic and aliphatic species, was subjected to the reaction, generating the corresponding flavones in moderate to high yields (Scheme 5b). Phenylacetylenes with a variety of substituents, including electron-donating and electron-withdrawing groups, participated in the reaction smoothly, affording the flavone products with high regioselectivity. Furthermore, the reaction was also amenable to substituted 2-iodophenols, thereby broadening the substrate scope. Solvent-switchable regioselectivity (aurones/flavones) and mild conditions made it ideal for industrial batch processes needing flexible product profiles, such as fine chemical manufacturing. The proposed mechanism (Scheme 5c) initiated with the carbonylative Sonogashira coupling of 2-iodophenol with the terminal alkyne, resulting in an intermediate o-alkynoylphenol Int 10. Subsequently, it underwent in situ cyclization, with the direct 6-endo-dig cyclization pathway leading to the synthesis of flavones. The Pd catalyst was hypothesized to expedite both the carbonylation and cyclization steps.

Pd-catalyzed carbonylative annulation for the construction of flavones and aurones.
Scheme 5.
Pd-catalyzed carbonylative annulation for the construction of flavones and aurones.

In 2018, Xu and Gao unveiled a regioselective strategy for the synthesis of flavones through the Pd-catalyzed carbonylative annulation of 2-iodophenol and terminal alkynes under a CO atmosphere (Scheme 6a) [39]. Notably, they identified that the choice of amine base critically influenced the cyclization pathway. It was observed that piperazine specifically facilitated the 6-endo cyclization, directing the reaction towards flavone formation, whereas triethylamine induced the Pd-catalyzed 5-exo cyclization, resulting in aurones. This base-controlled regioselectivity offered a valuable synthetic tool for the targeted synthesis of flavones and aurones. The substrate scope was extensively explored, including both aliphatic and aromatic terminal alkynes (Scheme 6b). Aromatic alkynes with electron-donating substituents (e.g., Et, nBu, OMe) at the para position reacted smoothly with 2-iodophenol to afford the corresponding flavones in moderate to high yields with excellent regioselectivity. Although electron-withdrawing substituents also engaged in the reaction, their reactivity varied. With mild reaction conditions (50°C, 50 psi CO), high regioselectivity for flavones/aurones, and broad substrate tolerance, this method was suitable for industrial fine chemical synthesis. The proposed mechanism (Scheme 6c) initiated with the Pd-catalyzed carbonylative Sonogashira coupling of 2-iodophenol and phenylacetylene, leading to the formation of an o-hydroxyketone intermediate, Int 16. Then it was subjected to either 6-endo or 5-exo cyclization. For the 6-endo cyclization pathway that afforded flavones, piperazine was hypothesized to engage in a Michael addition to form an adduct, which subsequently underwent further transformations to deliver the desired flavone.

Pd-catalyzed divergent synthesis of flavones and aurones.
Scheme 6.
Pd-catalyzed divergent synthesis of flavones and aurones.

In 2020, Mansour and Ali also disclosed a one-pot regioselective synthesis of flavones via phosphine-free cyclocarbonylative Sonogashira coupling of 2-iodophenols with various alkynes, using new bridged-bis(N-heterocyclic carbene) palladium(II) complexes as catalysts under a CO atmosphere (Scheme 7a) [40]. The researchers designed and synthesized new bridged N,N’-substituted benzimidazolium salts and the corresponding palladium complexes. These complexes were thoroughly characterized using multiple techniques, including X-ray analysis, which revealed an altered square planar configuration around the Pd(II) ion. This method offered high regioselectivity for the synthesis of flavones, eliminating the need for additional phosphine ligands, which simplified the reaction system. The versatility of the reaction was subsequently investigated using diverse substrates (Scheme 7b). In the reactions of 2-iodophenols with aryl alkynes, excellent yields (86-98%) of flavones were obtained, regardless of the electronic nature of the groups on the aryl ring. For example, aryl alkynes with either electron-donating or electron-withdrawing substituents resulted in reactions that were successful and yielded high outputs. When reacting 2-iodophenol with alkyl alkynes, good to high yields (53-90%) of flavones were achieved. It was discovered that the reactivity correlated with the alkyl alkynes’ chain lengths. Additionally, the coupling of 2-iodophenol with dialkynes through cyclocarbonylation yielded symmetrical diflavones with high yields (74-92%). However, substrates with steric hindrance, such as 2-ethynylanisole, showed a decline in the yield of the target flavone. The suggested mechanism (Scheme 7c) involved the initial formation of a palladium(II) complex through the precatalyst’s encounter with the acetylide under the influence of the base. This intermediate then underwent a series of steps, including oxidative addition, carbon monoxide insertion, and reductive elimination to form the carbonylative Sonogashira intermediate Int 24. The choice of base determined the subsequent cyclization pathway, with diethylamine favoring the formation of flavones via a Michael addition and elimination process.

Bridged-bis(NHC)PdBr2-catalysed cyclocarbonylative Sonogashira coupling reaction.
Scheme 7.
Bridged-bis(NHC)PdBr2-catalysed cyclocarbonylative Sonogashira coupling reaction.

2.1.2. Palladium-catalyzed cyclocarbonylative reactions of aryl halides

Differing from the carbonylative Sonogashira methods described above, Wu and Beller developed an alternative and efficient palladium acetate (Pd(OAc)2)-catalysed carbonylative reaction of aryl bromides with 2-hydroxyacetophenones for the synthesis of flavones (Scheme 8a) [41]. The versatility of the reaction was explored across various substrates (Scheme 8b). Different substituted aryl bromides, including para-, ortho-, and meta-substituted bromobenzenes, as well as 1-naphthyl and 2-naphthyl bromides, reacted smoothly with 2-hydroxyacetophenone to afford the desired flavones in moderate yields (69-81% and 72-79%, respectively). Various substituents, including methoxy, methylthiol, and dimethylamine (electron-donating), and nitro, cyano, and trifluoromethyl (electron-withdrawing), were successfully accommodated to the aryl bromide substrates, affording the flavone derivatives in 42-85% and 70-78% yields, respectively. Additionally, heterocyclic substrates like pyridyl- and thiophenyl-substituted aryl bromides were successfully employed, producing the desired flavones in 50-71% yields. For 2-hydroxyacetophenone derivatives, substituents such as Me, OMe, and naphthyl substituents were compatible with the reaction, affording flavone products with high efficiency. 2-Hydroxyacetophenones with chloride and fluoride substitutions also generated the target flavones 27j and 27k in 77% and 70% yields, respectively. Moreover, 1-(2-hydroxyphenyl)propan-1-one was a viable substrate, generating 3-methyl-2-phenyl-4H-chromen-4-one 27l in 61% yield. This method provided a new pathway for the construction of flavones, starting from easily accessible 2-hydroxyacetophenones and (hetero)aryl bromides, which were more accessible compared to the previously required costly 2-iodophenols and terminal alkynes. The ability to produce 13C-labeled chromones and tolerate various substituents met industrial needs in pharmaceutical research (e.g., drug metabolism studies) and specialty chemical synthesis.

Pd-catalyzed carbonylative synthesis of flavones from aryl bromides and 2-hydroxyacetophenones.
Scheme 8.
Pd-catalyzed carbonylative synthesis of flavones from aryl bromides and 2-hydroxyacetophenones.

Similarly, Cai and Huang established a novel heterogeneous palladium-catalyzed carbonylative cyclization reaction for the synthesis of flavones from easily accessible aryl iodides and 2-hydroxyacetophenones (Scheme 9a) [42]. Researchers incorporated a bidentate phosphine palladium complex attached to mobil composition of matter no. 41 (MCM-41) as the catalytic agent, alongside 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) as the base. The reaction proceeded efficiently in dimethyl sulfoxide at 120°C under 3 bar of CO, affording diverse flavones in moderate to high yields (Scheme 9b). It was worth noticing that the heterogeneous Pd catalyst was easily prepared and recoverable via simple centrifugation, maintaining its catalytic activity even after nine cycles of reuse. A variety of aryl iodides, irrespective of electron-donating or electron-withdrawing substituents, smoothly reacted with 2-hydroxyacetophenone to produce the corresponding flavones in 77-89% yields. The reaction was compatible with substituents including alkyl, methoxy, chloro, bromo, and trifluoromethyl. Sterically hindered ortho-substituted aryl iodides and bulky 1-iodonaphthalene also participated effectively, providing flavones in satisfactory yields. Additionally, heteroaryl iodides, including 2-, 3-, and 4-iodopyridines and 2- and 3-iodothiophenes, were suitable substrates, leading to the formation of 2-heteroaryl-substituted chromen-4-ones. For 2-hydroxyacetophenones, various substituted derivatives, with both electron-donating substituents (MeO) and electron-withdrawing substituents (F, Cl, Br), underwent carbonylative cyclization smoothly, generating flavones in 71-83% yields. Bromo-substituted 2-hydroxyacetophenones selectively produced bromo-substituted flavones (30g), which were candidates for further functionalization. Its heterogeneous nature, low CO pressure (3 bar), broad substrate scope, and high functional group tolerance made it ideal for industrial-scale flavone production, especially in drug synthesis where metal-free products and catalyst reusability are critical. The proposed mechanism (Scheme 9c) involved the reduction of the Pd(II) to Pd(0) in the presence of CO. The MCM-41-bound arylpalladium(II) complex Int 29 was generated via the oxidative addition of an aryl iodide to Pd(0). Intermediate Int 29 then engaged in migratory insertion with CO to create the MCM-41-bound acylpalladium(II) complex Int 30. Subsequently, it reacted with 2-hydroxyacetophenone in the presence of DBU, leading to the formation of intermediate Int 31. Through reductive elimination, it transformed into 2-acetylphenyl benzoate intermediate Int 32, while simultaneously restoring the MCM-41-2P-Pd(0) species and thus finalizing the catalytic process. Hemiacetal complex Int 33 was established through the intramolecular aldol condensation of intermediate Int 32. Finally, dehydration of intermediate Int 33 released the final flavone 30.

Recyclable Pd-catalyzed carbonylative synthesis of flavones from aryl iodides and 2-hydroxyacetophenones.
Scheme 9.
Recyclable Pd-catalyzed carbonylative synthesis of flavones from aryl iodides and 2-hydroxyacetophenones.

Based on their previous reports [37,41], Shen and Wu developed a novel palladium-catalyzed carbonylative synthesis of flavones from 2-bromofluorobenzenes and ketones under 10 bar of CO pressure (Scheme 10a) [43]. The versatility of the reaction with different substrates was investigated (Scheme 10b), revealing that for 2-bromofluorobenzenes, a variety of substituents, including methyl, difluoromethyl, fluoro, and chloro groups at diverse positions, were well accommodated. This led to the synthesis of the target flavones with yields ranging from moderate to good. Regarding ketones, substrates such as differently substituted deoxybenzoins and 1,3-diphenylacetone were found to be compatible, with reactions proceeding smoothly and achieving moderate to good yields. However, when using acetophenone or dihydrochalcone, the outcomes were less favorable, with lower yields or no product observed. This discrepancy was similar due to differences in keto-enol tautomerism between these compounds. Additionally, they conducted a sequence of control experiments to elucidate the mechanism. It was found that the reaction mechanism (Scheme 10c) encompassed a series of steps: carbonylation, followed by Claisen-Hasse rearrangement, and culminating in intramolecular nucleophilic aromatic substitution (SNAr). Starting with the oxidative addition of Pd(0) to 31a, an aryl-Pd(II) complex, Int 34, was formed. Then it underwent CO insertion and transmetallation with the cesium enolate of deoxybenzoin, generating intermediate Int 35. Following reductive elimination, intermediate Int 36 emerged with the assistance of caesium carbonate, intermediate Int 36 transitioned into the 1,3-diketone intermediate Int 37 via a base-induced Claisen–Hasse rearrangement. Lastly, the final flavone 33a was generated via enolization and an intramolecular SNAr reaction.

Palladium-catalyzed carbonylative synthesis of flavones from 2-bromofluorobenzenes and ketones.
Scheme 10.
Palladium-catalyzed carbonylative synthesis of flavones from 2-bromofluorobenzenes and ketones.

2.1.3. Nickel-catalyzed cyclocarbonylative Sonogashira reaction

Besides Pd catalysts, other transition metal catalysts, such as Ni, Mn, and Ir, can also be used as catalysts in the synthesis of flavonoids. Charugandla and Chidara developed a nickel-catalyzed carbonylative Sonogashira coupling for the synthesis of flavones (Scheme 11a) [44]. This method showed a mild and robust synthetic route with a relatively inexpensive and non-toxic nickel catalyst instead of the commonly used palladium catalysts. The authors utilized terminal alkynes and 2-iodophenol as substrates. Through a series of optimization experiments, it was found that using 1,4-dioxane as the solvent, triethylamine as the base, and CO gas at a pressure of 2 bar, the desired flavones 36 could be achieved in moderate to high yields. The range of substrates for the reaction was investigated (Scheme 11b). Terminal alkynes, whether with electron-donating or electron-withdrawing groups, were found to be compatible, generating the target flavones in 42-85% yields. The reaction was amenable to the presence of substituents, including nitro, halides, esters, and nitriles. Heteroaromatic alkyne (3-ethynylpyridine) participated successfully and led to the product in 36 h in 75% yield. As a non-noble metal catalytic and ligand-free system with good functional group tolerance and mild conditions, it was suitable for large-scale production of flavones in fine chemicals and agrochemicals. According to the proposed mechanism (Scheme 11c), Ni(II) was transformed into Ni(0) with CO acting as a reducing agent. Following this, a 2-iodophenol engaged in oxidative addition, forming an intermediate Int 39 that subsequently underwent CO insertion. Anion exchange with the acetylene nucleophile occurred, thereafter reductive elimination to generate the intermediate Int 42, which underwent an intramolecular cyclization to produce the desired flavones.

Ni-catalyzed carbonylative Sonogashira synthesis of flavones.
Scheme 11.
Ni-catalyzed carbonylative Sonogashira synthesis of flavones.

2.1.4. Manganese-catalyzed cyclocarbonylative Sonogashira reaction

In 2019, Lakshmi and Sridhar developed a manganese chloride-mediated carbonylative Sonogashira coupling reaction for the synthesis of flavones from 2-iodophenols and aromatic terminal alkynes under 2 atmospheres of carbon monoxide (Scheme 12a) [45]. Through a series of optimization experiments, they found that in 1,4-dioxane solvent, with Et3N as the base, and at a reaction temperature of 110°C for 10 h, the desired flavones could be obtained in 55-85% yields. Various terminal alkynes were investigated (Scheme 12b), including both electron-withdrawing groups (nitro, chloro) and electron-donating groups (amino, methoxy). Heteroaryl iodides also participate in the reaction successfully, achieving the desired flavone 39b in 65% yield. With low catalyst loading, low CO pressure, and compatibility with aryl/heteroaryl iodides, this method provided an economical and eco-friendly option for industrial synthesis of 2-substituted flavones, reducing reliance on expensive noble metals. The proposed mechanism entailed the in-situ generation of Mn2(CO)5 from manganese chloride (MnCl2) and carbon monoxide. This was succeeded by the homolytic cleavage of the Mn-Mn bond, leading to the formation of the Mn(CO)5 radical. This radical species was pivotal in initiating the catalytic cycle. The reaction proceeded via a sequence of steps (Scheme 12c), including oxidative addition, carbonylation, and reductive elimination to form the alkynone intermediate Int 47. For the synthesis of flavones, the alkynone intermediate Int 47 underwent an intramolecular cyclization reaction, which was similar with the mechanism shown in Scheme 11.

Mn-catalyzed carbonylative Sonogashira synthesis of flavones.
Scheme 12.
Mn-catalyzed carbonylative Sonogashira synthesis of flavones.

2.1.5. Iridium-catalyzed cyclocarbonylative Sonogashira reaction

Zhu and Wu introduced an innovative approach to the synthesis of flavones through an iridium-catalysed and ligand-controlled carbonylative process (Scheme 13a) [46]. This method utilized readily available phenols and internal alkynes, conducting the reaction under 20 bar of carbon monoxide pressure at 140°C to achieve the desired flavone products. The desired flavones could be obtained in good yields with excellent regioselectivity (Scheme 13b). The compatibility of different substrates with the reaction was investigated. For alkynes, both aromatic and aliphatic internal alkynes proved to be compatible substrates, and the target flavones were produced in 59-78% yields. Even unsymmetrical alkynes reacted smoothly with phenol under the standard conditions. In the case of phenols, those with electron-donating or electron-withdrawing substituents were proceeded smoothly in up to 84% yields. However, hydroquinone did not proceed under the given conditions. The suggested mechanistic pathway started with the interaction of phenol with copper acetate, resulting in the formation of an ortho-activated copper-phenol intermediate Int 50 (Scheme 13c). It served as a precursor that subsequently underwent transmetalation with an iridium species, leading to the generation of an iridium intermediate Int 51. Following coordination and the insertion of carbon monoxide (CO), it underwent ligand exchange and subsequent alkyne insertion, culminating in the formation of a seven-membered iridium cycle Int 54 or Int 55. A reductive elimination step from this seven-membered iridium cycle released the final flavone product 42a, while the iridium complex was reoxidized, thereby completing the catalytic cycle. This method represented the initial instance of a direct carbonylation involving simple phenols and alkynes to deliver flavones, which simplified the starting materials and reduced the synthetic steps compared to previous methods.

Ir-catalyzed carbonylative synthesis of flavones from phenols and internal alkynes.
Scheme 13.
Ir-catalyzed carbonylative synthesis of flavones from phenols and internal alkynes.

Based on the palladium and other metal catalysts for flavone synthesis via carbonylation reveals that palladium-catalyzed systems, primarily employing carbonylative Sonogashira coupling, demonstrate good efficiency, broad substrate scope, and high functional group tolerance. Their versatility allows for precise control over regioselectivity (flavone vs. aurone) through ligand, solvent, or base modification, and they are effective in both homogeneous and recyclable heterogeneous forms. This high-performance stems from Pd’s favorable redox properties and its ability to mediate complex multi-step mechanisms. However, these advantages are offset by high cost, potential metal contamination, and frequent reliance on expensive ligands. In contrast, non-noble metals (Ni and Mn) offer economic and environmental benefits due to their lower cost and toxicity. Nickel acts as a direct, more cost-effective alternative for carbonylative couplings, yet it typically delivers only moderate product yields and has a more limited scope of application. Manganese catalysis employs a unique radical pathway, representing an even more economical option, but it currently lacks general efficiency. Iridium catalysis is notable for enabling direct synthesis from simple phenols and internal alkynes, streamlining the synthetic route. Although palladium catalysis continues to be the benchmark for efficiency and versatility, the drive toward sustainable chemistry is speeding up the advancement of more competitive non-noble metal alternatives.

2.2. Synthesis of flavones using a CO surrogate as a C1 building block

2.2.1. Palladium-catalysed cyclocarbonylative Sonogashira reaction using CO surrogates

Lately, many groups have reported Pd-catalyzed carbonylative annulation reactions using various CO surrogates as C1 building blocks in the synthesis of flavones. Ghosh and Das demonstrated a carbonylative Sonogashira annulation sequence for the synthesis of flavones (Scheme 14a) [47]. They employed a Pd-NHC catalyst and strategically utilized Molybdenum hexacarbonyl Mo(CO)6 as a solid CO surrogate. After a series of meticulous optimization experiments, they established that the reaction achieved optimal efficiency using 2 mol% of the Pd-NHC catalyst and 4 equivalents of dimethylamine as the base in dimethylformamide (DMF) at 95°C. This protocol was found to be robust across a variety of substrates, including electron-rich aromatic acetylenes and halo-substituted phenylacetylenes, which smoothly performed to afford the target flavones 45a-45h with excellent efficiency (Scheme 14b). A case in point was the reaction between 2-iodophenol and phenylacetylene under the optimized conditions, which generated the targeted flavone 45a in 82% yield. Furthermore, aliphatic alkynes, such as 3-methyl-but-1-yne and ethynylcyclopropane, also demonstrated good reactivity under these conditions, affording products 45g and 45h in 61% and 67% yields, respectively.

Molybdenum hexacarbonyl Mo(CO)6 as a carbon monoxide surrogate for carbonylative Sonogashira coupling synthesis of flavone.
Scheme 14.
Molybdenum hexacarbonyl Mo(CO)6 as a carbon monoxide surrogate for carbonylative Sonogashira coupling synthesis of flavone.

In 2023, Lokolkar and Bhanage reported a novel palladium catalyzed carbonylative Sonogashira coupling of 2-iodophenol phenylacetylene to synthesize flavones using dicobalt octacarbonyl CO2(CO)8 as a CO surrogate (Scheme 15a) [48]. The researchers synthesized a unique mononuclear cationic palladium complex. This complex featured 4-pyridylthiolate and Xantphos with a k3 phosphine-phosphinite ligand (POP)-coordinate mode. It was highly stable and exhibited insensitivity to air and moisture, which simplified handling and storage. This Pd complex was employed as a catalyst in the cyclocarbonylative construction of flavones. In the optimization process, a series of reaction parameters were screened. It was found that using 0.1 mol% of the Pd complex, triethylamine as the base, and CO2(CO)8 as the CO source at 100°C for 12 h provided the most favorable reaction conditions. In their investigation, the researchers observed that the reaction between 2-iodophenol and phenylacetylene afforded 48a in 82% yield. This finding set the stage for further exploration of the substrate scope, which included various terminal alkynes (Scheme 15b). Phenylacetylenes bearing electron-donating groups on the phenyl ring, including 4-methyl (4-Me), 4-methoxy (4-OMe), and 3-methyl (3-Me), smoothly performed to afford the target flavones with good to high yields. The incorporation of heteroaryl 3-ethynyl thiophene into the reaction proceeded the product 48e in 78% yield, while the reaction with ethynyl cyclohexane resulted 48f in 48% yield. Additionally, 4-chloro-2-iodophenol was employed as a coupling partner, and the resulting flavone (48 g) was isolated in 65% yield. These findings highlighted the adaptability of the catalytic system and its capacity for synthesizing a broad variety of flavones.

CO2(CO)8 as a carbon monoxide surrogate for carbonylative sonogashira coupling synthesis of flavone.
Scheme 15.
CO2(CO)8 as a carbon monoxide surrogate for carbonylative sonogashira coupling synthesis of flavone.

In 2024, Wang and Li disclosed a novel cellulose-based CO surrogate (cellulose-CO) for carbonylative synthesis of flavones (Scheme 16) [49]. The authors prepared cellulose-CO from cheap and abundant cellulose through a simple and green process. Cellulose was heated in formic acid, followed by filtration, concentration, and drying to obtain cellulose-CO with a degree of substitution of 1.27, good solubility in formic acid, and high CO density (5.06 mmol∙g-1). It exhibited excellent chemical stability, remaining stable up to 250°C and maintaining its structure when stored in air for 12 months. They achieved different types of reactions, including alkoxycarbonylation, aminocarbonylation, carbonylative Sonogashira coupling, and carbonylative Suzuki coupling. Notably, cellulose-CO demonstrated exceptional compatibility across a range of transformation types, showcasing its versatility in various synthetic applications. The authors conducted the synthesis of flavone reaction by using the in situ protocol. 2-2-iodophenol and phenylacetylene were employed as substrates under a Pd catalytic system, affording the desired flavone 51 in 51% yield.

Cellulose-based carbon monoxide surrogate for carbonylative Sonogashira coupling synthesis of flavone.
Scheme 16.
Cellulose-based carbon monoxide surrogate for carbonylative Sonogashira coupling synthesis of flavone.

Recently, Guo and Zhang introduced an effective route for the synthesis of flavones (Scheme 17a), leveraging a controlled carbon monoxide emission protocol with Fe(CO)5 and piperazine to modulate the kinetics of Pd-catalysed carbonylative Sonogashira coupling and the ensuing endo-cyclization [50]. The researchers proposed that piperazine fulfilled a dual function: activating the emission of CO from Fe(CO)5 and coordinating the endo-cyclization step. During the optimization, they determined that employing PdCl2 and 1,1’-Bis(diphenylphosphino) ferrocene (DPPF) as the catalyst and ligand, respectively, along with piperazine as the base in acetonitrile at 50°C, facilitated a smooth reaction. The substrate scope was thoroughly investigated, revealing that non-functionalized phenylacetylene generated the target flavones in excellent yields (Scheme 17b). Phenylacetylenes with various substituents displayed varying reactivities, with electron-donating and weak electron-withdrawing substituents generally enhancing the efficiency. In contrast, strong electron-withdrawing groups and nitro substituents impacted the yields to some extent. Aromatic alkynes with diverse structures and aliphatic alkynes also engaged in the reaction, exhibiting trends in flavone yields. Furthermore, 2-iodophenols with different substituents reacted effectively with terminal alkynes to afford the target flavones. This methodology was also suitable to synthesize the anti-inflammatory drug candidate dimethoxyflavone 54i on a gram scale in 81% yield (Scheme 17c). This demonstrated the practical potential of the methodology in the synthesis of therapeutic flavones. The proposed mechanism (Scheme 17d) involved the activation process by piperazine to release CO, which then inserted into the intermediate Int 57 formed by the oxidative addition of 2-iodophenol to the palladium catalyst. The resulting acylpalladium complex Int 58 reacted with phenylacetylene, followed by reductive elimination to form intermediate Int 60. Piperazine then promoted the intramolecular Michael addition and subsequent reactions to generate the flavone product 54a.

Iron pentacarbonyl Fe(CO)5 as a carbon monoxide surrogate for carbonylative Sonogashira coupling synthesis of flavone.
Scheme 17.
Iron pentacarbonyl Fe(CO)5 as a carbon monoxide surrogate for carbonylative Sonogashira coupling synthesis of flavone.

2.2.2. Palladium-catalysed cyclocarbonylative heck reaction using Mo(CO)6

Different from the types of reactions reported above, shortly before now, Guo and Hu developed a novel Pd-catalysed carbonylative Heck reaction using Mo(CO)6 as a carbonyl source to synthesize benzofuran-3(2H)-one 56 and flavone 57 (Scheme 18a) [51]. This method involved the reaction of 2-iodophenyl alkenyl ether with arylboronic acid in the presence of Pd(OAc)2, Mo(CO)6, and DPPF ligand, achieving benzofuran-3(2H)-one product. When the arylboronic acid was absent, the flavone product was obtained. The suggested mechanism (Scheme 18b) included the generation of an active Pd(0) species, after which the substrate underwent oxidative addition to Pd(0). Then the Pd(II) intermediate Int 63 was generated. The CO released from Mo(CO)6 coordinated with intermediate Int 63, leading to the generation of acylpalladium complex Int 64. Then, a migratory insertion occurred, generating intermediate Int 65. Finally, the desired flavone 57 was released by β-H elimination.

Mo(CO)6 as a CO surrogate for carbonylative coupling synthesis of flavone.
Scheme 18.
Mo(CO)6 as a CO surrogate for carbonylative coupling synthesis of flavone.

Mechanistically, Mo(CO)₆ released CO via thermal decomposition, typically requiring 80°C, and acted directly as a CO source in Pd-catalysed carbonylative Heck reactions. It donated CO to Pd intermediates without external activators, enabling stepwise CO insertion for benzofuran-3(2H)-one synthesis. In contrast, Fe(CO)₅ needed a base (piperazine) for controlled CO release at milder 50°C. Piperazine not only activated Fe(CO)₅ to liberate CO but also coordinated Pd intermediates, favoring homogeneous CO transfer for flavone synthesis via cyclocarbonylative Sonogashira coupling. Practically, Mo(CO)₆ suited high-temperature reactions with good functional group tolerance (halides, esters) and easy scale-up, ideal for complex heterocycles. Fe(CO)₅ excelled in mild conditions, and its base-aided release prevented explosion, making it safer for pharmaceutical synthesis. However, Mo(CO)₆ needed a higher temperature, limiting heat-sensitive substrates, while Fe(CO)₅ relied on specific bases, restricting its ligand compatibility.

The catalytic synthesis of flavones employs either CO gas or CO surrogates. CO gas, typically used in Pd-catalyzed carbonylative Sonogashira reactions, is highly efficient, delivering high yields and excellent functional group tolerance across a broad substrate scope. Its main disadvantages are significant safety risks due to high toxicity and the requirement for specialized high-pressure equipment, limiting its practicality in the laboratory. In contrast, CO surrogates such as Mo(CO)₆, Fe(CO)₅, or dicobalt octacarbonyl CO₂(CO)₈ offer a safer and more operationally simple alternative by releasing CO in situ, avoiding high-pressure gas handling. However, these surrogates often result in more moderate product yields, can introduce additional metal contaminants, and may require careful optimization of the CO release kinetics. While CO gas remains the benchmark for maximum efficiency, CO surrogates present a more accessible and user-friendly pathway.

2.3. Synthesis of flavones with CO2 serving as a C1 building block

Lately, Huang and Li introduced a more economical and sustainable approach using a copper catalyst for the carbonylative cyclization of CO₂ to synthesize flavones (Scheme 19a) [52]. The optimized conditions utilized CuCl, Xantphos as the ligand, 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU), and polymethylhydrosiloxane (PMHS) in dimethyl sulfoxide (DMSO) at 120°C. This system performed good functional group tolerance towards both coupling partners. A broad scope of aryl iodides with diverse substituents (OMe, Me, F, Cl, CF₃) and heteroaryl iodides (thiophene) were compatible (Scheme 19b), as were various substituted 2-hydroxyacetophenones and their derivatives, affording flavones in moderate to good yields (55-88%). The industrial potential of this method was enhanced using an abundant, non-noble metal and was demonstrated to be viable on a gram-scale experiment, which was successfully presented to afford 60a in 61% yield (Scheme 19c). The authors conducted a range of mechanistic experiments to describe the mechanism better. It’s proposed that the phenolic -OH group of the 2-hydroxyacetophenone 59a played a crucial role by accelerating CO₂ mass transfer via nucleophilic attack on a DBU-CO₂ intermediate Int 67, forming an O-aryl carbamate intermediate Int 68 (Scheme 19d). Then it reacted with an aryl-copper species Int 66 (from oxidative addition), eventually undergoing an intramolecular aldol condensation and dehydration to form the flavone 60a, bypassing the need for pre-functionalized alkynes or toxic CO gas.

Cu-catalyzed carbonylative synthesis of flavone using CO2.
Scheme 19.
Cu-catalyzed carbonylative synthesis of flavone using CO2.

Subsequently, Huang and Li presented a palladium-catalyzed reductive carbonylation system for synthesizing 13C-labeled flavones using 13CO2 as the C1 source (Scheme 20a) [53]. The optimized method employed Pd₂(dba)₃ with a specific bidentate phosphine ligand, DBU as the base, and PMHS as the reductant in DMSO at 80°C. The reaction demonstrated excellent functional group tolerance (Scheme 20b), successfully accommodating a wide range of aromatic and aliphatic terminal alkynes bearing electron-donating (methyl, methoxy, tBu) and electron-withdrawing groups (F, Cl, Br, CF₃, COOMe), as well as heteroaromatic alkynes (thiophene, pyridine). Various substituted 2-iodophenols also reacted smoothly, generating the corresponding 13C-flavones in good to excellent yields (74-92%). The potential for industrialization was hinted at by a successful gram-scale synthesis using reduced catalyst loading (0.5 mol% Pd), achieving a 71% yield (Scheme 20c). The proposed mechanism (Scheme 20d), supported by control experiments and in situ 13C-NMR, involved the formation of a DBU-CO₂ intermediate Int 71, oxidative addition to Pd(0), CO migration to form a key acylpalladium intermediate Int 72, carbonylative Sonogashira coupling with the alkyne, and final 6-endo in situ cyclization to form the flavone 63.

Pd-catalysed carbonylative synthesis of 13C-labeled flavone using 13CO2.
Scheme 20.
Pd-catalysed carbonylative synthesis of 13C-labeled flavone using 13CO2.

CO₂ is non-toxic, non-flammable, and abundant, eliminating the severe safety hazards and specialized high-pressure equipment required for handling toxic CO gas. This makes CO₂-based processes inherently safer and more operationally straightforward. From a green chemistry perspective, CO₂ is a renewable and inexpensive C1 feedstock, contributing to waste valorization and reducing reliance on fossil fuel-derived CO. The most distinctive advantage of using CO₂, as highlighted in both papers, is its direct applicability in the efficient synthesis of 13C-flavones. This provides a straightforward route for creating tracers for drug metabolism and pharmacokinetic studies, a task that is more challenging and costly with CO.

3. Conclusions

The catalytic synthesis of flavones via carbonylation reactions has witnessed remarkable progress in recent years. The exploration of various carbonylation strategies has unveiled a plethora of efficient strategies for the synthesis of flavones, underscoring the importance of green chemistry and sustainable development in modern synthetic approaches. The use of CO gas and CO surrogates as carbonyl sources has emerged as an atom-economical and environmentally benign method for flavone synthesis. Palladium-catalyzed carbonylative reactions, particularly the Sonogashira coupling, have been predominant in this field, demonstrating high efficiency and selectivity. These methods have been further enhanced by the employment of ligands, such as NHCs, and the utilization of heterogeneous catalysts, which facilitate catalyst recovery and reuse, aligning with sustainable chemistry principles. The versatility of the substrate scope, including both aryl halides and ketones, has been a significant advantage, allowing for the synthesis of a broad array of flavones with diverse substituents. The ability to synthesize a wide range of flavones with diverse substituents and structures renders these methods highly attractive for the synthesis of biologically active molecules and potential drug candidates.

However, some challenges remain to be addressed. The reliance on precious metals, such as palladium, can be a limitation due to their cost and availability. The exploration of other transition metals as catalysts presents an opportunity to diversify the synthetic toolbox and potentially reduce the reliance on palladium. Although substantial development has been made in the improvement of CO surrogates, there is still room for the discovery of more sustainable and efficient carbonyl sources. In addition, the scope of substrates and synthetic routes still needs to be further broadened to obtain the desired flavone products more diversly.

There are several promising directions for future research. The development of more efficient and selective non-noble metal catalysts is crucial. This includes the modification and synthesis of novel ligand systems and the exploration of heterogeneous catalysts with enhanced stability and recyclability. The search for alternative and more sustainable carbonyl sources is also an area of great interest. Additionally, further investigations into the reaction mechanisms will help to improve reaction conditions and expand substrate scopes. The application of these synthetic strategies in the synthesis of biologically active flavones and their derivatives for pharmaceutical and nutraceutical purposes holds great potential. Moreover, the combination of carbonylation reactions with other synthetic methods and technologies may lead to the discovery of new and more efficient synthetic routes.

In conclusion, the catalytic synthesis of flavones via carbonylation reactions represents a significant advancement in organic and medicinal chemistry. The methods discussed in this review not only provide a foundation for future synthetic endeavors but also inspire the development of more sustainable and efficient chemical processes. As the field continues to evolve, it is poised to contribute significantly to the discovery and production of flavones with therapeutic potential.

Acknowledgment

We acknowledge the financial support from The Science & Technology Development Fund of Tianjin Education Commission for Higher Education (Grant No. 2024KJ003).

CRediT authorship contribution statement

Zechao Wang: Investigation, Writing – original draft. Zhuan Zhang: Supervision, Writing – review & editing.

Declaration of competing interest

There are no conflicts of interest.

Data availability

This article does not contain any new data.

Declaration of generative AI and AI-assisted technologies in the writing process

The authors confirm that there was no use of artificial intelligence (AI)-assisted technology for assisting in the writing or editing of the manuscript and no images were manipulated using AI.

References

  1. , , . Selective palladium-catalyzed carbonylative synthesis of aurones with formic acid as the CO source. RSC Advances. 2016;6:62810-62813. https://doi.org/10.1039/C6RA13615J.
    [Google Scholar]
  2. , , . Flavonoids: A colorful model for the regulation and evolution of biochemical pathways. Trends in Plant Science. 2005;10:236-242. https://doi.org/10.1016/j.tplants.2005.03.002.
    [Google Scholar]
  3. , , , , , . Flavonoids: Chemical properties and analytical methodologies of identification and quantitation in foods and plants. Natural Product Research. 2011;25:469-495. https://doi.org/10.1080/14786419.2010.482054
    [Google Scholar]
  4. , , , , . Acidity constants of hydroxyl groups placed in several flavonoids: Two flavanones, two flavones and five flavonols. Talanta. 2023;253:124096. https://doi.org/10.1016/j.talanta.2022.124096
    [Google Scholar]
  5. , , , , , , , . A specialized flavone biosynthetic pathway has evolved in the medicinal plant, Scutellaria baicalensis. Science Advances. 2016;2:e1501780. https://doi.org/10.1126/sciadv.1501780.
    [Google Scholar]
  6. , , , , , . Plant flavonoids: Classification, distribution, biosynthesis, and antioxidant activity. Food Chemistry. 2022;383:132531. https://doi.org/10.1016/j.foodchem.2022.132531
    [Google Scholar]
  7. , , , , , , . Chemical diversity, biological activities and Traditional uses of and important Chinese herb Sophora. Phytomedicine. 2022;100:154054. https://doi.org/10.1016/j.phymed.2022.154054.
    [Google Scholar]
  8. , , . The role of flavonols in insect resistance and stress response. Current Opinion in Plant Biology. 2023;73:102353. https://doi.org/10.1016/j.pbi.2023.102353.
    [Google Scholar]
  9. , , , , , , . Plant flavonoids with antimicrobial activity against methicillin-Resistant Staphylococcus aureus (MRSA) ACS Infectious Diseases. 2024;10:3086-3097. https://doi.org/10.1021/acsinfecdis.4c00292.
    [Google Scholar]
  10. , , , , , , , . New flavone-cyanoacetamide hybrids with a combination of cholinergic, antioxidant, modulation of β-amyloid aggregation, and neuroprotection properties as innovative multifunctional therapeutic candidates for Alzheimer’s disease and unraveling their mechanism of action with acetylcholinesterase. Molecular Pharmaceutics. 2018;15:2206-2223. https://doi.org/10.1021/acs.molpharmaceut.8b00041
    [Google Scholar]
  11. , , , , , , , , , . Atypical nitrogen-containing flavonoid in the fruits of cumin (Cuminum cyminum L.) with anti-inflammatory activity. Journal of Agricultural and Food Chemistry. 2019;67:8339-8347. https://doi.org/10.1021/acs.jafc.9b02879
    [Google Scholar]
  12. , , . Flavone-based arylamides as potential anticancers: Design, synthesis, and in vitro cell-based/cell-free evaluations. European Journal of Medicinal Chemistry. 2020;187:111965. https://doi.org/10.1016/j.ejmech.2019.111965
    [Google Scholar]
  13. , , , , . Comparative transcriptomics reveals the mechanism of antibacterial activity of fruit-derived dihydrochalcone flavonoids against Porphyromonas gingivalis. Food & Function. 2024;15:9734-9749. https://doi.org/10.1039/d4fo02854f
    [Google Scholar]
  14. , , , , , . Antiviral activities of flavonoids. Biomedicine & Pharmacotherapy = Biomedecine & Pharmacotherapie. 2021;140:111596. https://doi.org/10.1016/j.biopha.2021.111596
    [Google Scholar]
  15. , , , , , , . Flavonoids: Potential therapeutic agents for cardiovascular disease. Heliyon. 2024;10:e32563. https://doi.org/10.1016/j.heliyon.2024.e32563
    [Google Scholar]
  16. , , , , , . Flavonols and flavones as potential anti-inflammatory, antioxidant, and antibacterial compounds. Oxidative Medicine and Cellular Longevity. 2022;2022:9966750. https://doi.org/10.1155/2022/9966750
    [Google Scholar]
  17. , , , , . Validating the nutraceutical and neuroprotective pharmacodynamics of flavones. Neurochemistry International. 2024;180:105829. https://doi.org/10.1016/j.neuint.2024.105829
    [Google Scholar]
  18. , , , , , , , , , , , . Two CYP82D enzymes function as flavone hydroxylases in the biosynthesis of root-specific 4′-deoxyflavones in Scutellaria baicalensis. Molecular Plant. 2018;11:135-148. https://doi.org/10.1016/j.molp.2017.08.009
    [Google Scholar]
  19. , , , , , , , . Food flavonols: Nutraceuticals with complex health benefits and functionalities. Trends in Food Science & Technology. 2021;117:194-204. https://doi.org/10.1016/j.tifs.2021.03.030
    [Google Scholar]
  20. , , , , , , , , . Luteolin, a flavone ingredient: Anticancer mechanisms, combined medication strategy, pharmacokinetics, clinical trials, and pharmaceutical researches. Phytotherapy Research : PTR. 2024;38:880-911. https://doi.org/10.1002/ptr.8066
    [Google Scholar]
  21. , , , , . Garcinia flavonoids for healthy aging: Anti-senescence mechanisms and cosmeceutical applications in skin care. Fitoterapia. 2025;180:106282. https://doi.org/10.1016/j.fitote.2024.106282
    [Google Scholar]
  22. , , , , , , , , , , , . Discovery of a unique flavonoid biosynthesis mechanism in fungi by genome mining. Angewandte Chemie (International ed. in English). 2023;62:e202215529. https://doi.org/10.1002/anie.202215529
    [Google Scholar]
  23. , , , , . Methyl 2-methoxytetrafluoropropionate as a synthetic equivalent of methyl trifluoropyruvate in the Claisen condensation. The first synthesis of 2-(trifluoroacetyl)chromones and 5-aryl-2-hydroxy-2-(trifluoromethyl)furan-3(2H)-ones. Tetrahedron Letters. 2009;50:4903-4905. https://doi.org/10.1016/j.tetlet.2009.06.067
    [Google Scholar]
  24. , , , . Synthesis of functionalized chromones via organocatalysis. Tetrahedron. 2014;70:9314-9320. https://doi.org/10.1016/j.tet.2014.10.045
    [Google Scholar]
  25. , . Umwandlung von Benzal‐cumaranonen in Flavonole. European Journal of Inorganic Chemistry. 1908;41:4233-4241. https://doi.org/10.1002/cber.190804103137
    [Google Scholar]
  26. , . CCXC.—An accessible derivative of chromonol. Journal of the Chemical Society. 1924;125:2192-2195. https://doi.org/10.1039/ct9242502192
    [Google Scholar]
  27. , , . The chemistry of CO: Carbonylation. Chemistry. 2023;5:526-552. https://doi.org/10.1016/j.chempr.2018.11.006.
    [Google Scholar]
  28. , , , , , . Transition metal-catalysed carbene- and nitrene transfer to carbon monoxide and isocyanides. Chemical Society Reviews. 2022;51:5842-5877. https://doi.org/10.1039/D1CS00305D.
    [Google Scholar]
  29. , , . Palladium-catalysed carboformylation of alkynes using acid chlorides as a dual carbon monoxide and carbon source. Nature Chemistry. 2021;13:123-130. https://doi.org/10.1038/s41557-020-00621-x.
    [Google Scholar]
  30. , , , . Nickel-catalyzed carbonylative domino cyclization of arylboronic acid pinacol esters with 2-alkynyl nitroarenes toward N-aroyl indoles. Organic Chemistry Frontiers. 2022;9:2685-2689. https://doi.org/10.1039/D2QO00112H.
    [Google Scholar]
  31. , , , , , . Carboxyboronate as a versatile in situ CO surrogate in palladium-catalyzed carbonylative transformations. Angewandte Chemie International Edition. 2020;60:4342-4349. https://doi.org/10.1002/anie.202010211.
    [Google Scholar]
  32. , , . Nanocrystalline copper(II) oxide catalyzed aza-Michael reaction and insertion of α-diazo compounds into N-H bonds of amines. Tetrahedron Letters. 1975;50:4467-4470. https://doi.org/10.1016/j.tetlet.2009.05.059.
    [Google Scholar]
  33. , . Acylation, methylation, and carboxyalkylation of olefins by Group VIII metal derivatives. Journal of the American Chemical Society. 1968;90:5518-5526. https://doi.org/10.1021/ja01022a034.
    [Google Scholar]
  34. , . Synthesis of chromones via palladium-catalyzed ligand-free cyclocarbonylation of o-iodophenols with terminal acetylenes in phosphonium salt ionic liquids. The Journal of Organic Chemistry. 2010;75:948-950. https://doi.org/10.1021/jo902210p
    [Google Scholar]
  35. , , , , , . Pd-carbene catalyzed carbonylation reactions of aryl iodides. Dalton Transactions (Cambridge, England : 2003). 2011;40:7632-7638. https://doi.org/10.1039/c1dt10433k
    [Google Scholar]
  36. , , , . Highly efficient synthesis of flavones via Pd/C-catalyzed cyclocarbonylation of 2-iodophenol with terminal acetylenes. Catalysis Science & Technology. 2016;6:2905-2909. https://doi.org/10.1039/c6cy00613b
    [Google Scholar]
  37. , , . Highly selective and modular synthesis of 3‐Aryl‐4‐(arylethynyl)‐2H‐chromen‐2‐ones from 2‐Iodoaryl 2‐arylacetates through a carbonylative Sonogashira coupling–intramolecular aldol cascade reaction. European Journal of Organic Chemistry. 2016;2016:4041-4049. https://doi.org/10.1002/ejoc.201600569
    [Google Scholar]
  38. , , , . Solvent‐switchable regioselective synthesis of aurones and flavones using palladium‐supported amine‐functionalized montmorillonite as a heterogeneous catalyst. ChemCatChem. 2016;8:2649-2658. https://doi.org/10.1002/cctc.201600549
    [Google Scholar]
  39. , , , , , , . Divergent synthesis of flavones and aurones via base-controlled regioselective palladium catalyzed carbonylative cyclization. Molecular Catalysis. 2018;452:264-270. https://doi.org/10.1016/j.mcat.2018.03.021
    [Google Scholar]
  40. , , . Regioselective synthesis of chromones via cyclocarbonylative Sonogashira coupling catalyzed by highly active bridged-Bis(N-Heterocyclic Carbene)palladium(II) complexes. ACS Omega. 2020;5:32515-32529. https://doi.org/10.1021/acsomega.0c04706
    [Google Scholar]
  41. , , . Palladium-catalyzed carbonylation reaction of aryl bromides with 2-hydroxyacetophenones to form flavones. Chemistry (Weinheim an der Bergstrasse, Germany). 2012;18:12595-12598. https://doi.org/10.1002/chem.201202141
    [Google Scholar]
  42. , , , . Recyclable palladium-catalyzed carbonylative cyclization of aryl iodides and 2-hydroxyacetophenones towards flavones. Synthesis. 2023;55:647-656. https://doi.org/10.1055/s-0042-1753042
    [Google Scholar]
  43. , , , , , . Palladium‐catalyzed carbonylative synthesis of 2,3‐disubstituted chromones. Advanced Synthesis & Catalysis. 2016;358:466-479. https://doi.org/10.1002/adsc.201500858
    [Google Scholar]
  44. , , , . Nickel catalysed carbonylative Sonogashira reaction for the synthesis of diarylalkynones and 2-substituted flavones. Tetrahedron Letters. 2018;59:3283-3287. https://doi.org/10.1016/j.tetlet.2018.07.042
    [Google Scholar]
  45. , , , , . MnCl2‐mediated carbonylative Sonogashira coupling of aryl iodides and aromatic terminal alkynes by using CO. ChemistrySelect. 2019;4:11553-11556. https://doi.org/10.1002/slct.201903132
    [Google Scholar]
  46. , , , . Iridium-catalyzed and ligand-controlled carbonylative synthesis of flavones from simple phenols and internal alkynes. Chemistry (Weinheim an der Bergstrasse, Germany). 2017;23:3276-3279. https://doi.org/10.1002/chem.201700233
    [Google Scholar]
  47. , , . Carbonylative Sonogashira annulation sequence: One-pot synthesis of 4-quinolone and 4H-chromen-4-one derivatives. Tetrahedron Letters. 2018;59:2025-2029. https://doi.org/10.1016/j.tetlet.2018.04.029
    [Google Scholar]
  48. , , , . POP-pincer xantphos Pd complex of 4-pyridylthiolate: cyclocarbonylative reaction for the synthesis of flavones using cobalt carbonyl as a C1 source. Catalysis Letters. 2023;153:2359-2367. https://doi.org/10.1007/s10562-022-04161-6
    [Google Scholar]
  49. , , , , , , . A sustainable and versatile cellulose-based CO surrogate for carbonylative reactions. ChemSusChem. 2024;17:e202301324. https://doi.org/10.1002/cssc.202301324
    [Google Scholar]
  50. , , , , , , , . Nongaseous Pd-catalyzed carbonylative annulation: Safe and atomic efficient flavone synthesis. Molecular Catalysis. 2024;555:113867. https://doi.org/10.1016/j.mcat.2024.113867
    [Google Scholar]
  51. , , , , , , , , . Construction of benzofuran‐3(2H)‐one scaffolds bearing a C2 quaternary center via palladium‐catalyzed carbonylative Heck reaction using Mo(CO)6 as carbonyl source. European Journal of Organic Chemistry. 2024;27 https://doi.org/10.1002/ejoc.202400589
    [Google Scholar]
  52. , , , , , , , . Copper-catalyzed carbonylative cyclization of CO2: A promising approach for synthesis of flavone. Advanced Science (Weinheim, Baden-Wurttemberg, Germany). 2025;12:e2415795. https://doi.org/10.1002/advs.202415795
    [Google Scholar]
  53. , , , , , , , . Palladium-catalyzed carbonylative synthesis of 13C-labeled flavones. Journal of Catalysis. 2025;443:115993. https://doi.org/10.1016/j.jcat.2025.115993
    [Google Scholar]

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