Organocatalysed C-2 and C-3 functionalisation of chromones

Abstract

This review highlights the recent advancements in organocatalysed Michael addition reactions involving chromones, an important class of heterocyclic compounds with significant biological and pharmacological properties. Chromones, with their versatile conjugated structure, act as both electrophilic and nucleophilic partners, providing an ideal platform to synthesise diverse stereochemically enriched molecular frameworks. The work highlights various organocatalysed examples using chiral carbenes, phosphoric acids, thioureas and squaramides, that have demonstrated high efficiency and stereocontrol in a range of reactions. Mechanistic insights into how these catalytic systems activate the chromone scaffold and promote enantioselective transformations are also discussed in detail. Finally, we underline emerging trends and future directions in this research area, addressing current limitations, such as the need for more efficient catalytic systems and broader substrate compatibility.

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Juan Carlos Morales-Solís

Juan Carlos Morales-Solís was born in Mexico in 1996. He graduated with honors in Medicinal Chemistry (QFB) from Universidad Veracruzana in 2019. He obtained his Master's degree with honors from Universidad Autónoma del Estado de Morelos (UAEM) supervised by Prof. Mario Ordoñez, working on diastereoselective synthesis of heterocyclic aminophosphonic acids analogs of the hydroxypipecolic acid. He is currently completing his PhD through a cotutelle program between UAEM and the University of Zaragoza (Spain) at the HOCA group (ISQCH-CSIC), under the joint supervision of Prof. Mario Ordoñez and Dr. Eugenia Marqués-López, respectively. His research focuses on the enantioselective synthesis of hydroxyphosphonates derived from chromones, using organocatalysed strategies.

Mario Ordoñez

Mario Ordoñez born in Tlaxcala, Mexico. Received his Ph.D. in Chemistry from the University of Sevilla (Spain) in 1995. Since 1998 is Full Professor of Organic Chemistry at the University of Morelos State (Mexico). His research interests include the racemic and stereoselective synthesis of heterocyclic α-aminophosphonates and α-aminophosphinates through phosphonylation of N-acyliminium ions and Kabachnik–Fields reaction using new catalysts and their applications in medicinal and organic chemistry. Current research interests also involves the synthesis of a wide variety of α,β-unsatutared amides bearing α-aminophosphonates via Horner–Wadsworth–Emmons reaction, as well as the synthesis of isoindolin-2-ones and 2-phospho-4-oxochromanes.

Eugenia Marqués-López

Dr. Marqués-López obtained her degree in Chemical Sciences from the University of Seville (2002), where she also earned her PhD in the Department of Organic Chemistry (2007). Her research has focused on the development of asymmetric synthetic methodologies using chiral auxiliaries and catalysis. She conducted research stays at the University of Oxford (2005) and TU Dortmund (2008–2010), the latter supported by a Humboldt Fellowship. Since 2011, she has been based at the University of Zaragoza, where she has held the position of Associate Professor since 2020. Her scientific output includes numerous publications, book chapters, a patent, and active international collaborations.

Raquel P. Herrera

Raquel P. Herrera completed her Ph.D. (1999–2003) under the supervision of Prof. Guijarro and Prof. Yus, at the University of Alicante. She then took up a European postdoctoral contract with Prof. Ricci (Bologna, Italy) until March 2006. Then, joined Prof. Lassaletta's and Fernández's group at the IIQ-CSIC (Seville, Spain). She was appointed to her present position at the ISQCH-University of Zaragoza in January 2008, first as ARAID Researcher, since 2012 as Tenured Scientist and currently, as Scientific Researcher (2021). In 2012 she was awarded with the Lilly Prize for the best young scientist less than 40 years, in Spain. She is the head of the Asymmetric Organocatalysis research group.

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Introduction

The field of organocatalysis has gained significant attention since the early 2000s.¹ Organocatalytic methods represent an exciting and sustainable approach to chemical synthesis of complex and chiral molecules, which are particularly important in medicine and the pharmaceutical industry,² where the stereochemistry of a molecule can drastically affect its biological activity.³ Additionally, this field is recognised for its advantages in terms of environmental impact, reaction versatility, and access to enantiomerically enriched products, making it a valuable tool for chemists in academic, industrial, and pharmaceutical research.

Among the plethora of organic reaction developed in this field, the Michael addition reaction is a cornerstone transformation in organic chemistry, particularly valued for its ability to create carbon–carbon and carbon-heteroatom bonds.⁴ This kind of reaction provides a powerful alternative for building complex molecular frameworks, especially in the synthesis of natural products, pharmaceuticals, and advanced materials. One interesting application of the Michael addition involves the use of chromones as electrophilic (nucleophilic) partners.⁵

Chromones (1-benzopyran-4-ones) are heterocyclic compounds containing a benzopyran core with a ketone group. The chromone skeleton is found in a wide variety of naturally occurring compounds, including flavonoids, coumarins, and certain alkaloids, many of which exhibit valuable pharmacological properties.⁶ These properties make chromones an attractive target for chemical modification through reactions like the Michael addition, enabling the construction of new molecules with potential biological activity. In the context of the Michael reaction, chromones can act as both nucleophiles and electrophiles, although they are more commonly employed as electrophilic partners. The most reactive site in chromones for nucleophilic additions is the C-2 position, which is activated due to electron withdrawal from the carbonyl group at C-4 (Scheme 1). Therefore, in this review, we aim to highlight the chameleonic behaviour exhibited by these fascinating structures.

Scheme 1 Activated electrophilic/nucleophilic C-2 and C-3 positions for conjugated addition reactions in chromones.

One key feature of chromones is the conjugation between the carbonyl group at C-4 and the adjacent double bond. This conjugation not only stabilises the molecule but also broadens the reactivity potential of the chromone nucleus.

The resulting chromanone adducts also constitute an important structural motif found in many bioactive and natural compounds, making this reaction valuable for the synthesis of pharmacologically active molecules (Fig. 1). This reaction opens new pathways for constructing complex molecules, including those with potential anticancer, antiviral, or anti-inflammatory properties,⁷ further highlighting the importance of the Michael addition reaction in the context of chromone chemistry.⁸

Fig. 1 Structure of bioactive chromanone natural products.

Recent advances in asymmetric Michael additions using chromones have focused on the development of enantioselective variants, allowing for the creation of chiral centres in a controlled manner. In this context, asymmetric transition-metal complexes have also been employed to achieve high enantioselectivity, leading to significant advancements in this area of research.⁹ The racemic approach using silyl compounds to activate the carbonyl group of this structure also deserves special mention, as it represents a pioneering approach for activating this conjugated skeleton and has served as a source of inspiration for further research in this area.¹⁰

In addition, organocatalysts have been successfully developed to enhance the efficiency and selectivity of Michael additions with chromones. These catalytic strategies allow for mild reaction conditions, improved yields, and stereocontrol over the product, making them highly attractive for large-scale and industrial applications.

Although other valuable reviews have been published covering various aspects of chromone chemistry,⁵ such as annulation reactions and C–H activation processes, there remains a lack of a comprehensive overview specifically focused on organocatalytic approaches. This gap has motivated us to undertake the present review, with a particular emphasis on the use of chiral organocatalysts. Our aim is to highlight recent advances and provide a detailed analysis of the progress made in organocatalysed C-2 and C-3 functionalisation of chromones.

Michael addition reactions using chromones as electrophilic C-2 synthons

In the context of chromones acting as electrophilic C-2 synthons, the Michael addition reaction is an interesting synthetic approach that usually requires organometallic reagents, as in the Zimmerman's strategy, which uses Zn(OTf)₂ as a catalyst,¹¹ or in Feringa's method,^9c which employs a copper catalyst to produce 2-alkylchromanones. However, recent advances in the C–H functionalisation of chromones under metal-free conditions, which deserve special mention, have been developed by Han's group in 2014.¹² They demonstrated that the reaction of chromone 1a and cyclohexane (2a) in the presence of 4 eq. of di-tert-butyl peroxide (DTBP) at 120 °C for 24 h, yielded 2-cyclohexylchroman-4-one (3aa) in 72% yield (Scheme 2).

Scheme 2 Synthesis of 2-cyclohexylchroman-4-one (3aa) via sp³ C–H functionalisation.

Attempts to increase the yield by using additional DTBP or alternative oxidants such as 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), NaClO, K₂S₂O₈, 1,4-benzoquinone (BQ), or O₂ were unsuccessful. The method exhibited broad applicability, tolerating a variety of chromones 1a–h and alkanes 2a–d. Chromones bearing a methyl or bromine substituent at the C-6 position, as well as methoxy groups at the C-5 and C-7 positions, afforded the corresponding chromanones 3 with yields ranging from 58% to 83% (see the original article for a complete scope of the process).¹² Notably, the electron-withdrawing nature of the bromine at C-6 enhanced the yield, whereas steric hindrance and electron-donating groups, such as a methoxy substituent at C-5, seemed to have a moderate impact on the yield (Fig. 2).

Fig. 2 Selected examples from the general scope for the synthesis of 2-alkylchroman-4-ones 3.

The proposed mechanism proceeds through a radical pathway (Scheme 3). Initial homolysis of DTBP 4 would generate a tert-butoxy radical 5˙, which would abstract a hydrogen atom from cyclohexane 2a to form a cyclohexane radical 2˙. This radical would add to chromone 1a, yielding an intermediate 6aa that would react further with the tert-butanol to form an enol intermediate 7aa. Subsequent keto–enol tautomerisation would produce the final 2-alkylchromanone product 3aa.

Scheme 3 Mechanism via radical course.

In other hand, the gem-difluoroalkyl moiety have shown great importance in drug design to enhance the metabolic stability and biological properties of molecules.¹³ Therefore, Hao and co-workers have selectively introduced a gem-difluoroalkyl moiety by developing an efficient metal-free Michael addition of difluoroenoxysilanes 8a to chromone 1a, using trifluoromethanesulfonic acid (HOTf) as a catalyst (Scheme 4).¹⁴ Initially, the reaction of chromone 1a with the difluoroenoxysilane 8a in dichloromethane was tested with 10 mol% of different Lewis acids as Fe(OTf)₃, Al(OTf)₃, Bi(OTf)₃, Cu(OTf)₃, and trimethylsilyl trifluoromethansulfonate (TMSOTf) over 72 h, obtaining the 2-difluoroalkylated chroman-4-one 9aa in moderate yields. Notably, among all of them, the best yield was obtained with TMSOTf (72%), prompting further exploration to enhance the yields by exploring the Brønsted acid catalyst HOTf in dichloromethane (78%) and hexane (85%) over 27 h. However, the optimal reaction conditions were established using 5 mol% of HOTf in THF as solvent, after 9 h of reaction, resulting in the synthesis of 2-difluoroalkylated chroman-4-one 9aa with 76% yield (Scheme 4).

Scheme 4 Highly efficient Michael addition of difluoroenoxysilane 8a to chromone 1a.

After establishing the optimal reaction conditions, the scope of the reaction was evaluated (Fig. 3). It was found that chromones substituted at the C-7 position (1h,i) with electron-donating groups (Me, OMe) led the desired products 9ha and 9ia at higher yields compared to those bearing electron-withdrawing groups (F, Cl, Br) (9ja, 9ka, 9la). Furthermore, electron-withdrawing groups (F, Cl, Br, NO₂) at the C-6 position (9da, 9ea, 9fa, 9ga) resulted a higher yield than those with electron-donating groups (Me, OMe) (9ba, 9ca). Subsequently, the scope of phenyl-substituted difluoroenoxysilanes 8b–e was evaluated, revealing that substituents in para position improved the yield, achieving values between 89 and 93% (9ab, 9ac and 9ad) (Fig. 3).

Fig. 3 Highly efficient Michael addition of difluoroenoxysilane 8a–e to chromones 1a–l.

However, the need to prepare enantiomerically pure compounds requires new stereoselective strategies that consider both environmental impact and reaction versatility. Consequently, as illustrated in the following methods, asymmetric organocatalysis has played a crucial role in addressing this challenge.

Enantioselective Michael addition reactions using chromones as electrophilic C-2 synthons

This approach enables the synthesis of highly functionalised, stereochemically enriched compounds that are crucial intermediates in pharmaceuticals, natural products, and advanced materials.^2,3

Interestingly, based on the anion-binding ability of silanediols as catalysts,¹⁵ Mattson and co-workers pioneered the first enantioselective C-2 functionalisation of chromones.¹⁶ Their approach uses enolsilyl acetals as nucleophiles within a catalytic silanediol ion-pair strategy. In this methodology, the reaction of chromone 1a with a trialkylsilyl triflate 10 in toluene, at 60 °C, afforded its 4-siloxybenzopyrylium triflate 11a, which was captured with the silanediol catalyst 12 to form a chiral ion pair 13.¹⁶ Subsequently, the addition of the silyl acetal 14 at −78 °C provided the corresponding 2-alkylchroman-4-one 15a (Scheme 5). Notable, the nature of silyl group present on both the silyl acetal 14 and the silyl triflate 10 significantly influenced the enantioselectivity of the reaction, where the tri-iso-propyl group was better than tert-butyldimethylsilyl group.

Scheme 5 Enantioselective C-2 functionalisation of chromones 1avia chiral ion-pair 13.

Further studies exploring the scope of this reaction, using 20 mol% of catalyst 12, provided evidence about the effect of the substituents on the chromone backbone (Fig. 4). In fact, electron-withdrawing substituents such as Br, F, and Cl at the C-6 position (15c, 15e, 15f) led to higher yields compared to electron-donating groups like H and Me (15a, 15b). Notably, the highest yield was achieved when a CF₃ group was introduced at the C-7 position (15h). Additionally, the enantioselectivity improved in the presence of electron-withdrawing groups (Br, F, Cl, NO₂) at the C-6 position (15c, 15e, 15f, 15g). The best enantiomeric excess (ee) was observed for the 3,5-(F₃C)Ph-substituted derivative (15d) (Fig. 4).

Fig. 4 Highly efficient enantioselective Michael addition of difluoroenoxysilane 14 to chromones 1a–i.

The absolute configuration of the newly formed stereogenic centre at the C-2 position of chromanones 15 was determined by X-ray crystallography of its iminochromanone derivative 16a (Scheme 6). This derivative was obtained by reacting a racemic (rac) mixture of 2-substituted chromanone 15c with (R)-2-methylpropane-2-sulfinamide using Ti(OMe)₄ as catalyst in THF at reflux, affording the iminochromanone 16a in 80% yield and a diastereomeric ratio (dr) of 55 : 45. The diastereoisomers were then separated by crystallisation from dichloromethane and hexanes. Finally, the X-ray analysis and the deprotection of the iminochromanone 16a revealed the absolute configuration (S) of its chromanone 15c (Scheme 6).

Scheme 6 Chiral resolution of chroman-4-one 15c by formation of the iminochromanone 16a.

In the context of chromone as C-2 electrophilic synthon, the presence of a carboxylic acid at the C-3 position has demonstrated significant potential in enhancing the activation of the Michael acceptor, facilitating the synthesis of novel 2-substituted chroman-4-ones. Albrecht's group has been a pioneer in developing a decarboxylative Michael addition using malonic acid half-thioesters in their first enantioselective approach.¹⁷ Subsequently, Albrecht and co-workers explored the Michael addition of azlactones 18 to chromone-3-carboxylic acids 17 to synthesise novel α-amino acid moieties.¹⁸ Initially, the reaction between chromone 1a with azlactone 18a was carried out in the presence of 20 mol% of quinine in THF at room temperature. However, no reaction was observed under these conditions. Introducing a carboxylic acid moiety at the C-3 position of chromone 17a successfully facilitated the formation of the desired product 20aa in over 95% yield via a decarboxylative Michael addition, albeit initially with low diastereoselectivity. In this context, to improve the enantioselectivity of the process, they conducted a screening of different organocatalysts. Notably, cinchonidine-derived squaramide 19 significantly improved the stereoselectivity, yielding the 2-substituted chromone 20aa with >95% yield, a diastereomeric ratio of >20 : 1, and 82% enantiomeric excess (Scheme 7).¹⁸

Scheme 7 Decarboxylative Michael addition of azlactone 18a to chromone-3-carboxylic acid 17a.

The method showed a broad scope in the preparation of 2-substituted chromanones 20 (Fig. 5 and 6). In all cases, the final products were obtained with moderate-to-high yields. Notably, good diastereoselectivities were achieved with the model azlactone 18a, although lower enantioselectivity was observed in all cases compared to product 20aa (Fig. 5). Additionally, electron-withdrawing groups (Br, F, Cl) in the chromone-3-carboxylic acid (17c–17e) gave the products 20 in higher yield than those with an electron-donating group (Me) in 17b (Fig. 6). Despite these variations, the best outcome in this series was still achieved with the reaction model, leading to the formation of product 20aa (see the original article for a complete scope of the process).

Fig. 5 Selected examples from the general scope of the decarboxylative Michael addition of azlactones 18a–f to chromone-3-carboxylic acid 17a.

Fig. 6 Selected examples from the general scope of the decarboxylative Michael addition of azlactone 18a to chromone-3-carboxylic acids 17a–e.

Furthermore, the absolute configuration of the newly formed stereogenic centre was confirmed by X-ray crystallographic analysis of one of the chromanones 20. Finally, the hydrolysis of the azlactone 20aa using TsOH in a MeOH : CHCl₃ (2 : 1) at 40 °C produced the α,α-disubstituted amino acid 21aa (Scheme 8).

Scheme 8 Azlactone-ring opening to afford protected α,α-disubstituted amino acid 21aa.

Additionally, a transition state model 22 was proposed by the authors to explain the observed stereoselectivity (Fig. 7). It is suggested that the chromone-3-carboxylic acid 17 would interact with the cinchona catalyst 19via hydrogen bonding with the NHs of the squaramide. At the same time, the tertiary amine moiety, on the quinuclidine ring of 19, would promote the deprotonation of the azlactone 18. The simultaneous interaction between the protonated catalyst and the resulting enolate, forming an ion pair, would facilitate the enantioselective Michael addition.

Fig. 7 Proposed transition state 22 to explain the observed stereochemistry in 20.

Contemporaneously, García Mancheño and co-workers reported a highly enantioselective nucleophilic dearomatisation reaction of pyrylium salts using a chiral multicoordination triazole anion-binding catalyst 23 to afford 2-alkyl chromanones 26.¹⁹ Initially, the reaction was performed as previously described by Akiba,^10a wherein the active benzopyrylium ion was generated through the reaction of chromone 1a with a silyl derivative [tert-butyldimethylsilyl trifluoromethanesulfonate (TBSOTf)] in the presence of catalytic amounts of chiral H-donor catalyst 23 and 2,4,6-collidine at 60 °C in toluene. The optimal conditions involved the use of TBSOTf with a remarkably low catalyst loadings (1 mol%) of the multicoordination triazole 23, followed by the reaction with a silyl ketene acetal 25a at −78 °C, affording the 2-alkyl chromanone 26aa in 90% yield and 94% ee (Scheme 9).

Scheme 9 General reaction by chiral ion-pair 24 to obtain chromanone 26aa.

The scope of the reaction was investigated by testing various silyl ketene acetals 25a–e. The substitution pattern on the nucleophile was found to significantly influence on the enantioselectivity of the process, with more sterically hindered nucleophiles proceeding smoothly and exhibiting lower enantioselectivity (25c–e) than smaller nucleophiles (25a–b). Chromones substituted at C-6 position with either electron-donating and electron-withdrawing groups delivered final products 26 in high yields and with moderate to excellent enantioselectivities (Fig. 8). Interestingly, the method also proved effective for challenging thiochromones and 4-pyrones, producing final products with moderate yields but good to excellent enantioselectivity (see the original article for a complete scope of the process).¹⁹

Fig. 8 Selected examples from the general scope using chiral ion-pair to obtain chromanones 26.

Enantioselective conjugated addition reactions using chromones as nucleophilic C-2 synthons

Additionally, enantioselective Michael addition reactions using chromones as nucleophilic synthons are also of significant importance in synthetic organic chemistry, as they provide a powerful and efficient approach for constructing structurally complex and biologically relevant molecules with high stereocontrol.²⁰

Recently, in the field of C–H functionalisation to obtain new 2-functionalised chromones,²¹ Zlotin and co-workers,²² reported a metal-free C-2 functionalisation of 3-hydroxychromones 27via electrophilic olefination with electron-deficient olefins, such as nitroolefins 28 (Scheme 10) or β,γ-unsaturated-α-keto esters 32 (Scheme 11), using a recyclable C₂-symmetric squaramide 29 as organocatalyst. The reaction was optimised between the 3-hydroxychromone 27a and nitroolefin 28a in the presence of 2 mol% of the chiral C₂-symmetric squaramide 29 at room temperature in EtOH (95%). This process afforded 2-alkyl-3-hydroxychromone 30aa in 97% yield and 94% ee (Scheme 10). Transition state 31 was proposed by the authors to explain the absolute configuration observed in the final products 30. In this mechanism, the bifunctional squaramide 29 would deprotonate the chromone 27a through its tertiary amino group. Then, the catalyst would interact with the enolate to influence the geometry of the active complex. Simultaneously, strong hydrogen bonds formed between the electron-deficient olefins 28a and the NH groups of the squaramide, would drive the nucleophilic attack determining the absolute configuration of final products 30.

Scheme 10 Model reaction for the formation of chromenone 30aa through C₂-symmetric squaramide catalyst 29.

Scheme 11 General scope using β,γ-unsaturated-α-keto esters 32a,b to obtain chromenone derivatives 33 and 34.

With the best reaction conditions established, the scope of this methodology was evaluated with various 3-hydroxychromones 27a–c and several nitroolefins 28a–f, leading to the corresponding 2-alkyl-chromones 30 with yields of up to 99% and excellent enantioselectivity (90–99% ee, see the original article for a complete scope of the process). In general, this method demonstrated an excellent tolerance to electronic effects of the substituents in the 3-hydroxychromones 27a–c and nitroolefins 28a–f (Fig. 9).²²

Fig. 9 Selected examples from the general scope using chiral squaramide 29 to obtain chromenone derivatives 30.

Additionally, β,γ-unsaturated-α-keto esters 32a,b showed almost quantitative yield and high enantioselectivity, leading to the formation of the corresponding Michael adducts 33 and 34 in a lactonisation/ring opening equilibrium (Scheme 11).

Following the same approach of chromones as nucleophilic C-2 synthon, Rafiński and co-workers reported a very interesting asymmetric organocatalysed conjugated addition of 3-hydroxychromones 27via chiral α,β-unsaturated acyl azoliums.²³ In this methodology, initially, 3-hydroxychromone 27a reacted with ynal 35a in the presence of a carbene, generated from chiral aminoindanol-derived triazolium salt 36, using a proton sponge (PS) as sterically hindered and non-nucleophilic base, in dichloromethane. Subsequent treatment with MeOH, afforded the C2-alkylated 3-hydroxychromone 37aa in 99% yield (as determined by ¹H NMR analysis), and 95% ee (Scheme 12).

Scheme 12 General reaction by chiral carbene to obtain chromenone 37aa.

Under the best reaction conditions, this strategy showed a great scope as shown in Fig. 10 (see the original article for a complete scope of the process). Notably, various 3-hydroxychromones 27 were tested with different substituents at C-6 and C-7 position (27a–i), affording the desired products 37 in 66–99% yield and excellent enantioselectivities (56–99% ee). Notably, a methoxy group at C-5 position (27h) gave its respective chromone 37ha in 97% yield and 99% ee. Additionally, a series of ynals with electron-withdrawing (35b–d) and electron-donating groups (35e–g) on the para position of the phenyl ring worked well. However, the CF₃ moiety (35h) exhibited only moderate selectivity. A similar trend was observed for the phenyl ortho-substituted ynals (35i–l) giving high stereoselectivities. However, phenyl meta-substituted ynals (35m and 35n) showed slightly lower enantioselectivity without affecting the yield (37am and 37an). The reaction also showed good tolerance for challenging ynals bearing alkyl substituents, yielding the desired C2-alkylated chromenones in moderate to high yields with consistent enantioselectivities. To further extend this approach, the ring opening was performed using different oxygen or nitrogen nucleophiles, successfully generating the corresponding chromenones without compromising the enantioselectivity (see the original article for a complete scope of the process).²³ Notably, trimethylsilylpropynal, used as precursor for α,β-unsaturated acyl azolium, efficiently produced the C2-alkylated product 37, despite undergoing complete desilylation under the reaction conditions. In this regard, the silyl derivative serves as a safer alternative to propynal, which is known for its explosive nature.

Fig. 10 Selected examples from the general scope using chiral carbene 36 to obtain chromenone derivatives 37.

The absolute stereochemistry of the chiral centre was determined through single-crystal X-ray analysis.

The authors propose a reaction mechanism that begins with the formation of the α,β-unsaturated acyl azolium 38via redox isomerisation of ynal 35a. This intermediate undergoes a 1,2-addition with 3-hydroxychromone 27a, yielding intermediate 39. A subsequent Coates–Claisen rearrangement generates the 2-alkyl-chroman-3,4-dione 40, which, through tautomerisation and lactonisation of amide 41, forms the tricyclic chromone 42. Finally, reaction with a nucleophile (MeOH) produces the C2-functionalised 3-hydroxychromone 37aa with high enantioselectivity (Scheme 13). The authors proposed this mechanism based on common experimental observations, particularly the formation of esterification by-products, which is typically associated with 1,2-addition pathways. This behaviour is consistent with the involvement of an NHC catalyst. In their study, esterification side reactions were also observed, supporting the idea that the reaction does not proceed via a nucleophilic 1,4-addition of the enol to the catalytically generated α,β-unsaturated acyl azolium. Instead, it likely follows a 1,2-addition route, leading to O-acylation products. Additionally, based on the [3,3]-sigmatropic rearrangement mechanism previously described by Bode for kojic acid derivatives,²⁴ the authors suggest that a similar rearrangement could be occurring in the reaction between 3-hydroxychromenones 27 and α,β-unsaturated acyl azoliums 38.

Scheme 13 Proposed mechanism for obtaining C2-functionalised chromenone derivative 37aa.

Simultaneously, Jiang and co-workers design an enantioselective reductive cross coupling of chromones 1 and electron deficient olefins 43, applying a visible-light-driven cooperative photoredox system in combination with a chiral Brønsted acid catalyst.²⁵ The reaction was performed using chromone 1a and 2-vinylpyridine 43a as model substrates. A dicyanopyrazine-derived chromophore (DPZ) 44 (2 mol%) was employed as photoredox catalyst in the presence of 20 mol% of the chiral phosphoric acid (CPA) 45 and the Hantzsch ester 46 in dichloromethane at −25 °C. The reaction was conducted under 3 W blue LED light in an oxygen-free environment for 60 hours, affording the 2-alkylchromanone 47aa with a 63% yield and 97% of enantiomeric excess (Scheme 14).

Scheme 14 Model enantioselective reductive cross coupling of chromone 1a with 2-vinylpyridine 43a.

The scope of this asymmetric cross coupling protocol was evaluated using several chromones 1a–i containing electron-withdrawing and electron-donating substituents, affording the 2-alkylchromanones 47 in moderate to high yields with excellent enantioselectivities. Furthermore, to improve the yield of the reaction, 2-vinylpyridines substituted with a methyl group at the C-3 and C-4 position were tested (43b and 43c). The best result (93% yield, 96% ee) was obtained with the pyridine substituted at C-3 (47ab). On the other hand, when the reaction was performed with a thiochromone, the best result was using the 2-vinylpyridine 43c bearing a methyl group at C-4 position affording thiochromanone 48ic. Moreover, different substituted thiochromones exhibited excellent enantioselectivities, albeit with lower yield (48aa–ga, 48hb and 48ic) (Fig. 11).

Fig. 11 Scope of the enantioselective reductive cross coupling of chromones 1 to obtain 2-alkylchromanone derivatives 47 and 2-alkylthiochromanones 48.

Based on the success of this process, the authors proposed a reaction mechanism involving radical intermediates generated under photoredox conditions (Scheme 15). Simultaneously, the chiral phosphoric acid 45 would form hydrogen-bonding interactions with the substrates, stabilising the intermediate and organising the reactive components in a well-defined transition state (TS 51). This precise arrangement ensures enantioselective C-2 functionalisation of the chromone 1a. This dual catalytic system, combining photoredox and CPA catalysis, enables effective control over both reactivity and selectivity, facilitating the formation of C2-functionalised chromones 47 with excellent stereochemical outcomes.

Scheme 15 Proposed mechanism through radical intermediates.

Chromones as nucleophilic C-3 synthons and ulterior Michael addition reactions

Addition reactions using chromones as nucleophilic C-3 synthons are highly valuable in organic synthesis, offering a versatile strategy to access diverse, stereochemically enriched scaffolds that are crucial for the development of bioactive compounds and natural product derivatives.

In this context, homoisoflavonoids²⁶ are an important subclass of flavonoids with significant potential in drug design due to their demonstrated biological activities, including antioxidant,²⁷ cytotoxic²⁸ or antimicrobial effects (Fig. 12).²⁹

Fig. 12 Potential homoisoflavonoids with biological properties.

In this framework, Seo and co-workers³⁰ have established a diastereodivergent synthesis of anti- and syn-9-hydroxyflavanones 54 and 58, respectively, starting from chromones 1 and carbaldehydes 52via a reductive aldol reaction or the Morita–Baylis–Hillman (MBH) reaction, followed by a syn-selective Michael reduction. Initially, they demonstrated the feasibility of the 3,9-anti selective synthetic route. Under reductive conditions, the enolate of chromone 1 was generated using Na, K or Li tri-sec-butylborohydride (Selectride) in THF at −78 °C, which provided the (E)-enolate. This enolate subsequently reacted with arylaldehydes 52, affording the anti-3,9-hydroxyflavanones 54 through a Zimmerman–Traxler transition state 53, giving the products from 68 to 97% yield and up to 1 : 14 diastereomeric ratio (Scheme 16 and Scheme 18).

Scheme 16 Transition state 53 in the reductive aldol reaction conducting to the anti-product 54.

On the other hand, it is very important to consider that α-substituent-β-hydroxy ketones, such as the aldol chromone derivatives 55, are highly prone to H-3 deprotonation (pK_a 14.8), which lead to β-elimination or retro-oxa-Michael reaction. To optimise the reaction conditions to obtain the desired syn-products 58, the MBH reaction was carried out using 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in MeOH at room temperature to produce the enone intermediates 55. A subsequent Michael reduction with 3 eq. of L-selectride facilitated the formation of a highly organised chelated transition state 56, positioning H-3 on the opposite face of the phenyl group. Various proton sources were then tested, with phenol giving rise to the highest product formation. Additionally, 2-methylbenzimidazole (57a) provided a comparable yield and with an improved dr compared to MeOH, NH₄Cl or AcOH, which instead led to retro-aldol by-products or degradation (Scheme 17).

Scheme 17 Synthesis of the syn-product 58 by MBH/Michael reduction strategy.

Finally, higher anti- and syn-selectivity was observed in both methods using electron-rich aromatic rings than electron-deficient aromatic rings. However, the MeO group located on the C-5 position of chromones and/or C-2′ position of the carbaldehyde got worse diastereoselectivity due to possible involvement in the cation chelation during the stereochemistry-determining step (Scheme 18, see the original article for a complete scope of the process).³⁰

Scheme 18 Selected examples from the general scope of the highly efficient MBH reaction for obtaining 3-alkylchromanones 54 and 58; ^a For details in the SI of ref. 30. ^b Yield of the MBH; ^cCombined yield of both diastereoisomers of syn-selective 1,4-reduction; ^dResult obtained by using 52b as a PS.

Furthermore, Chen and co-workers³¹ initially reported the synthesis of chiral 3-aminomethylene-flavanones by In(III)-catalysed reactions of chromone-derived MBH adducts with amines via a tandem allylic amination/ring opening/oxa-Michael addition reactions in a one pot process.³² In the next step of synthesis of this type of compounds, an organocatalytic oxa-Michael addition was employed.³³ This reaction began with the treatment of chromone-derived MBH carbonate 59a with naphthylmethylenamine (60a) in the presence of 20 mol% of cinchonidine-derived thiourea catalyst in toluene at 40 °C for 60 h, affording the product 62a in 74% yield and 36% ee. To improve the enantioselectivity, as reported by Zhu and Lu,³⁴ trifunctional catalysts containing primary amino acid units were found to be more effective for asymmetric conjugate addition than bifunctional thioureas. Following this method, different trifunctional catalysts were tested, resulting in a significant improvement in enantioselectivity when trifunctional cinchonidine-derived catalyst 61 was used, producing the 3-aminomethylene-flavone 62a in 75% yield and 82% ee (Scheme 19).

Scheme 19 Enantioselective organocatalytic synthesis of 3-aminomethylene-flavanones 62a.

With the optimal reaction conditions, several carbonates 59 and amines 60 were examined (Fig. 13), yielding moderate to high yields and enantioselectivities for all products 62 (see the original article for a complete scope of the process). The absolute configuration of the new stereogenic centre at C-2 position was then confirmed as R by X-ray crystallographic analysis of product 62c. Drawing on these findings, the authors suggested a plausible transition state 63 for the tandem reaction (Scheme 19). Firstly, amines (ArCH₂NH₂) would react with the MBH carbonate, which is activated by the thiourea-based catalyst 61, through hydrogen bond formation, leading to the generation of intermediate 63 (Scheme 19). This step is followed by an intramolecular oxa-Michael addition, stablishing multiple hydrogen bonds between the trifunctional catalyst and the intermediate 63. These interactions enhance the reaction rate and ensure precise stereochemical control, facilitating the oxa-Michael addition to the α,β-unsaturated imine produced in situ, attacking from the Si face of the double bond.

Fig. 13 Selected examples from the general scope for the enantioselective organocatalytic synthesis of 3-aminomethylene-flavanones 62.

Conclusions

The Michael addition reactions involving chromones represent a cornerstone in modern organic synthesis, offering an interesting alternative for the construction of complex, stereochemically enriched molecules. The remarkable versatility of chromones, acting as electrophilic or nucleophilic partners, has enabled the development of methodologies applicable in pharmaceuticals, natural products, and materials science.

Recent advancements have been driven by innovative organocatalytic systems that leverage non-metal-based strategies for asymmetric transformations, providing a sustainable and highly efficient approach to chemical synthesis. Despite these successes, several challenges remain, including improving the scalability of reactions, expanding the substrate scope to obtain more functionalised chromones, and achieving higher enantioselectivity even under milder or greener conditions. Future research in enantioselective Michael addition reactions involving chromones should focus on several key areas to address current challenges and unlock new opportunities. One priority is the development of novel organocatalysts with enhanced activity, selectivity, and environmental compatibility. These catalysts should not only improve reaction efficiency but also align with principles of green chemistry by reducing waste and utilising sustainable resources, such as greener solvents.

Additionally, a deeper understanding of the reaction mechanisms is essential. Employing advanced computational techniques could shed light on the underlying processes, helping to refine transition state models and guide the rational design of more effective catalytic systems.

Moreover, exploring tandem or cascade reactions to achieve multi-functionalised products in a single synthetic step could pave the way for even more complex and diverse molecular architectures.

By addressing these priorities, future research can further establish enantioselective Michael addition reactions as a cornerstone methodology in modern synthetic organic chemistry, with broad applications in both academia and industry.

Author contributions

All authors wrote and approved the paper.

Conflicts of interest

There are no conflicts to declare.

Data availability

No primary research results, software or code have been included and no new data were generated or analysed as part of this review.

Acknowledgements

The authors thank Ministerio de Ciencia, Innovación y Universidades and Agencia Estatal de Investigación for the project PID2023-147471NB-I00 funded by MICIU/AEI10.13039/501100011033, Gobierno de Aragón-Fondo Social Europeo (Research Group E07_23R) and Secretaría de Ciencia, Humanidades Tecnología e Innovación (SECIHTI) for financial support through projects 286614 and 140607. J. C. M. S. also thanks SECIHTI for predoctoral scholarship 1004402. We gratefully acknowledge funkderulz for the free use of their image shared on Pixabay, which was used to illustrate this work.

References

1. For recent reviews in this area of research, see: (a) S.-H. Xiang and B. Tan, Advances in asymmetric organocatalysis over the last 10 years, Nat. Commun., 2020, 11, 3786; (b) A. Antenucci, S. Dughera and P. Renzi, Green chemistry meets asymmetric organocatalysis: A critical overview on catalysts Synthesis, ChemSusChem, 2021, 14, 2785–2853; (c) Z. Chen, Q.-Q. Yang, W. Du and Y.-C. Chen, Asymmetric organocatalysis involving double activation, Tetrahedron Chem, 2022, 2, 100017; (d) S. Ardevines, E. Marqués-López and R. P. Herrera, Horizons in asymmetric organocatalysis: En route to the sustainability and new applications, Catalysts, 2022, 12, 101; (e) O. García Mancheño and M. Waser, Recent developments and trends in asymmetric organocatalysis, Eur. J. Org. Chem., 2023, e202200950.
2. (a) A. Acarlone and L. Bernardi, Enantioselective organocatalytic approaches to active pharmaceutical ingredients – selected industrial examples, Phys. Sci. Rev., 2019, 4, 20180097; (b) B. Han, X.-H. He, Y.-Q. Liu, G. He, C. Peng and J.-L. Li, Asymmetric organocatalysis: an enabling technology for medicinal chemistry, Chem. Soc. Rev., 2021, 50, 1522–1586; (c) A. J. Burke, Asymmetric organocatalysis in drug discovery and development for active pharmaceutical ingredients, Expert Opin. Drug Discovery, 2022, 18, 37–46; (d) E. Reyes, L. Prieto and A. Milelli, Asymmetric organocatalysis: A survival guide to medicinal chemists, Molecules, 2023, 28, 271.
3. K. A. Scott, N. Ropek, B. Melillo, S. L. Schreiber, B. F. Cravatt and E. V. Vinogradova, Stereochemical diversity as a source of discovery in chemical biology, Curr. Res. Chem. Biol., 2022, 2, 100028.
4. For selected reviews, see: (a) D. R. López, D. Sadaba, I. Delso, R. P. Herrera, T. Tejero and P. Merino, Asymmetric organocatalytic synthesis of γ-nitrocarbonyl compounds through Michael and Domino reactions, Tetrahedron: Asymmetry, 2010, 21, 2561–2610; (b) Y. Zhang and W. Wang, Recent advances in organocatalytic asymmetric Michael reactions, Catal. Sci. Technol., 2012, 2, 42–53; (c) Y. Wang and D.-M. Du, Recent advances in organocatalytic asymmetric oxa-Michael addition triggered cascade reactions, Org. Chem. Front., 2020, 7, 3266–3283; (d) T. Das, S. Mohapatra, N. P. Mishra, S. Nayak and B. P. Raiguru, Recent advances in organocatalytic asymmetric Michael addition reactions to α,β-unsaturated nitroolefins, ChemistrySelect, 2021, 6, 3745–3781; (e) P. Sharma, R. Gupta and R. K. Bansal, Recent advances in organocatalytic asymmetric aza-Michael reactions of amines and amides, Beilstein J. Org. Chem., 2021, 17, 2585–2610; (f) S. D. Pasuparthy and B. Maiti, Enantioselective organocatalytic Michael addition reactions catalyzed by proline/prolinol/supported proline based organocatalysts: An overview, ChemistrySelect, 2022, 7, e202104261; (g) R. Ballini, A. Palmieri and M. Petrini, Catalysts’ evolution in the asymmetric conjugate addition of nitroalkanes to electron-poor alkenes, Org. Chem. Front., 2022, 9, 6077–6113.
5. For very elegant and interesting reviews about annulation reactions using chromones, see: (a) M. Zhang, Y. Gong, W. Zhou, Y. Zhou and X.-L. Liu, Recent advances of chromone-based reactants in the catalytic asymmetric domino annulation reaction, Org. Chem. Front., 2021, 8, 3968–3989; (b) P. Langer, Domino reactions of chromones with activated carbonyl compounds, Beilstein J. Org. Chem., 2024, 20, 1256–1269. For a very interesting review about C-H activation using metal catalysts, see: (c) A. T. Benny and E. K. Radhakrishnan, Advances in the site-selective C-5, C-3 and C-2 functionalization of chromones via sp² C–H activation, RSC Adv., 2022, 12, 3343–3358.
6. (a) M. Costa, T. A. Dias, A. Brito and F. Proença, Biological importance of structurally diversified chromenes, Eur. J. Med. Chem., 2016, 123, 487–507; (b) J. Yang, J. Lai, W. Kong and S. Li, Asymmetric synthesis of Sakuranetin-relevant flavanones for the identification of new chiral antifungal leads, J. Agric. Food Chem., 2022, 70, 3409–3419.
7. (a) S. Emami and Z. Ghanbarimasir, Recent advances of chroman-4-one derivatives: Synthetic approaches and bioactivities, Eur. J. Med. Chem., 2015, 93, 539–563; (b) S. Kamboj and R. Singh, Chromanone-A prerogative therapeutic scaffold: An overview, Arabian J. Sci. Eng., 2022, 47, 75–111.
8. For the synthesis of 4-chromanone-derived compounds following other strategies, see: E. J. Diana, U. S. Kanchana and T. V. Mathew, Current developments in the synthesis of 4-chromanone-derived compounds, Org. Biomol. Chem., 2021, 19, 7995–8008.
9. For selected metal-catalysed examples, see: (a) J. Chen, J. Chen, F. Lang, X. Zhang, L. Cun, J. Zhu, J. Deng and J. Liao, A C₂-symmetric chiral bis-sulfoxide ligand in a rhodium-catalyzed reaction: Asymmetric 1,4-addition of sodium tetraarylborates to chromenones, J. Am. Chem. Soc., 2010, 132, 4552–4553; (b) T. Korenaga, K. Hayashi, Y. Akaki, R. Maenishi and T. Sakai, Highly enantioselective and efficient synthesis of flavanones including Pinostrobin through the rhodium-catalyzed asymmetric 1,4-addition, Org. Lett., 2011, 13, 2022–2025; (c) C. Vila, V. Hornillos, M. Fañanás-Mastral and B. L. Feringa, Catalytic asymmetric conjugate addition of Grignard reagents to chromones, Chem. Commun., 2013, 49, 5933–5935; (d) J. C. Holder, A. N. Marziale, M. Gatti, B. Mao and B. M. Stoltz, Palladium-catalyzed asymmetric conjugate addition of arylboronic acids to heterocyclic acceptors, Chem. – Eur. J., 2013, 19, 74–77; (e) Q. He, C. M. So, Z. Bian, T. Hayashi and J. Wang, Rhodium/chiral diene-catalyzed asymmetric 1,4-addition of arylboronic acids to chromones: A highly enantioselective pathway for accessing chiral flavanones, Chem. – Asian J., 2015, 10, 540–543; (f) L. G. DeRatt, M. Pappoppula and A. Aponick, A facile enantioselective alkynylation of chromones, Angew. Chem., Int. Ed., 2019, 58, 8416–8420; (g) B. M. Trost, E. Gnanamani, C. A. Kalnmals, C.-I. J. Hung and J. S. Tracy, Direct enantio- and diastereoselective vinylogous addition of butenolides to chromones catalyzed by Zn-prophenol, J. Am. Chem. Soc., 2019, 141, 1489–1493; (h) Y. Guan, J. W. Attard and A. E. Mattson, Copper bis(oxazoline)-catalyzed enantioselective alkynylation of benzopyrylium ions, Chem. – Eur. J., 2020, 26, 1742–1747; (i) Y. Guan, T. A. Buivydas, R. F. Lalisse, J. W. Attard, R. Ali, C. Stern, C. M. Hadad and A. Mattson, Robust, enantioselective construction of challenging, biologically relevant tertiary ether stereocenters, ACS Catal., 2021, 11, 6325–6333; (j) J. Cui, N. Kumagai, T. Watanabe and M. Shibasaki, Direct catalytic asymmetric and anti-selective vinylogous addition of butenolides to chromones, Chem. Sci., 2020, 11, 7170–7176; (k) Y. Mo, Q. Chen, J. Li, D. Ye, Y. Zhou, S. Dong, X. Liu and X. Feng, Asymmetric catalytic conjugate addition of cyanide to chromones and β-substituted cyclohexenones, ACS Catal., 2023, 13, 877–886; (l) S. Samanta, J. Cui, H. Noda, T. Watanabe and M. Shibasaki, Asymmetric syn-selective vinylogous addition of butenolides to chromones via Al-Li-BINOL catalysis, J. Org. Chem., 2023, 88, 1177–1184.
10. (a) H. Iwasaki, T. Kume, Y. Yamamoto and K.-y. Akiba, Reaction of 4-t-butyldimethylsiloxy-1-benzopyrylium salt with enol silyl ethers and active methylenes, Tetrahedron Lett., 1987, 28, 6355–6358; (b) Y.-G. Lee, K. Ishimaru, H. Iwasaki, K. Ohkata and K.-y. Akiba, Tandem reactions in 4-siloxy-1-benzopyrylium salts: Introduction of substituents and cyclohexene and cyclopentane annulation in chromones, J. Org. Chem., 1991, 56, 2058–2066; (c) I. Mori, Y. Zimura, T. Nakano, S.-i. Matsunaga, G. Iwasalfi, A. Ogawa and K. Hayakawa, Trimethylsilyl triflate promoted 1,4-addition of silyl phosphites to cyclic enones, Tetrahedron Lett., 1997, 38, 3543–3546; (d) T. Qin, R. P. Johnson and J. A. Porco Jr., Vinylogous addition of siloxyfurans to benzopyryliums: A concise approach to the tetrahydroxanthone natural products, J. Am. Chem. Soc., 2011, 133, 1714–1717; (e) J. Liu, Z. Li, P. Tong, Z. Xie, Y. Zhang and Y. Li, TMSI-promoted vinylogous Michael addition of siloxyfuran to 2-substituted chromones: A general approach for the total synthesis of chromanone lactone natural products, J. Org. Chem., 2015, 80, 1632–1643; (f) E. Kerste, M. P. Beller and U. Koert, Second generation total synthesis of (–)-Preussochromone D, Eur. J. Org. Chem., 2020, 3699–3711; (g) R. O. Argüello-Velasco, J. C. Morales-Solís, M. Muñoz-Vidales, J. L. Viveros-Ceballos, I. Romero-Estudillo and M. Ordoñez, An efficient synthesis of cis-4-hydroxyphosphonic and cis-4-hydroxyphosphinic analogs of pipecolic acid from cyclic enaminones, Amino Acids, 2022, 54, 299–310; (h) M. Ordoñez, R. O. Argüello-Velasco, T. Miranda-Blancas, I. Romero-Estudillo and V. Labastida-Galván, First stereoselective synthesis of diethyl cis- and trans-(4-hydroxy-1,2,3,4-tetrahydroquinolin-2-yl)phosphonates and ethyl phenylphosphinates from quinolin-4(1H)-one, Synthesis, 2023, 55, 4181–4190.
11. J. R. Zimmerman, M. Manpadi and R. Spatney, Tin-free radical reactions under minimal solvent conditions for the synthesis of substituted chromones and coumarins, Green Chem., 2011, 13, 3103–3106.
12. J. Zhao, H. Fang, P. Qian, J. Han and Y. Pan, Metal-free oxidative C(sp³)–H bond functionalization of alkanes and conjugate addition to chromones, Org. Lett., 2014, 16, 5342–5345.
13. (a) K. Ando, F. Koike, F. Kondo and H. Takayama, An improved synthesis of 24,24-difluoro-1α,25-dihydroxyvitamin D₃ from readily available vitamin D₂, Chem. Pharm. Bull., 1995, 43, 189–192; (b) Y. Zhou, J. Wang, Z. Gu, S. Wang, W. Zhu, J. L. Aceña, V. A. Soloshonok, K. Izawa and H. Liu, Next generation of fluorine-containing pharmaceuticals, compounds currently in phase II–III clinical trials of major pharmaceutical companies: New structural trends and therapeutic areas, Chem. Rev., 2016, 116, 422–518; (c) Y. Zafrani, D. Yeffet, G. Sod-Moriah, A. Berliner, D. Amir, D. Marciano, E. Gershonov and S. Saphier, Difluoromethyl bioisostere: Examining the “lipophilic hydrogen bond donor” concept, J. Med. Chem., 2017, 60, 797–804.
14. X.-Y. Wang, M. Yang, Y. Zhou, J. Zhou and Y.-J. Hao, A highly efficient metal-free selective 1,4-addition of difluoroenoxysilanes to chromones, Org. Biomol. Chem., 2023, 21, 1033–1037.
15. (a) S.-i. Kondo, T. Harada, R. Tanaka and M. Unno, Anion recognition by a silanediol-based receptor, Org. Lett., 2006, 8, 4621–4624; (b) A. G. Schafer, J. M. Wieting and A. E. Mattson, Silanediols: A new class of hydrogen bond donor catalysts, Org. Lett., 2011, 13, 5228–5231; (c) K. Brak and E. N. Jacobsen, Asymmetric ion-pairing catalysis, Angew. Chem., Int. Ed., 2013, 52, 534–561; (d) A. G. Schafer, J. M. Wieting, T. J. Fisher and A. E. Mattson, Chiral silanediols in anion-binding catalysis, Angew. Chem., Int. Ed., 2013, 52, 11321–11324; (e) N. Busschaert, C. Caltagirone, W. Van Rossom and P. A. Gale, Applications of supramolecular anion recognition, Chem. Rev., 2015, 115, 8038–8155.
16. A. M. Hardman-Baldwin, M. D. Visco, J. M. Wieting, C. Stern, S.-i. Kondo and A. E. Mattson, Silanediol-catalyzed chromenone functionalization, Org. Lett., 2016, 18, 3766–3769.
17. A. Albrecht, Utilization of chromone-3-carboxylic acids as acceptors in the Michael-type decarboxylative addition, Eur. J. Org. Chem., 2018, 6482–6485.
18. J. Bojanowski, L. Siero and A. Albrecht, Enantioselective synthesis of chromanones bearing an α,α-disubstituted α-amino acid moiety via decarboxylative Michael reaction, Molecules, 2019, 24, 2565.
19. T. Fischer, J. Bamberger, M. Gómez-Martínez, D. G. Piekarski and O. García Mancheño, Helical multi-coordination anion-binding catalysts for the highly enantioselective dearomatization of pyrylium derivatives, Angew. Chem., Int. Ed., 2019, 58, 3217–3221.
20. For some non-asymmetric protocols of this approach, see: S. Paul and A. K. Bhattacharya, Hydroxyl directed C-arylation: synthesis of 3-hydroxyflavones and 2-phenyl-3-hydroxy pyran-4-ones under transition-metal free conditions, Org. Biomol. Chem., 2018, 16, 444–451.
21. (a) X.-F. Xu, L. Guo, Y.-X. Liu, X.-Z. He, Y. Guo and Y.-F. Zeng, Silver-catalyzed regioselective alkylation of chromones with carboxylic acids, ChemistrySelect, 2022, 7, e202202650; (b) Y. Peng, H. Gong, J. Wang, H. Chen, H. Deng, J. Hao and W. Wan, Regiospecific C₂-difluoroalkylation on chromone via transition-metal-free oxidative decarboxylation of aryldifluoroacetic acids, Asian J. Org. Chem., 2022, 11, e202200031.
22. R. A. Kovalevsky, A. S. Kucherenko, A. A. Korlyukov and S. G. Zlotin, Asymmetric conjugate addition of 3-hydroxychromen-4-ones to electron-deficient olefins catalyzed by recyclable C₂-symmetric squaramide, Adv. Synth. Catal., 2022, 364, 426–439.
23. K. Dzieszkowski, M. Słotwiński, K. Rafińska, T. M. Muzioł and Z. Rafiński, NHC-catalyzed enantioselective C2-functionalization of 3-hydroxychromenones via α,β-unsaturated acyl azoliums, Chem. Commun., 2021, 57, 9999–10002.
24. J. Mahatthananchai, P. Zheng and J. W. Bode, α,β-Unsaturated acyl azoliums from N-heterocyclic carbene catalyzed reactions: Observation and mechanistic investigation, Angew. Chem., Int. Ed., 2011, 50, 1673–1677.
25. K. Cao, C. Li, D. Tian, X. Zhao, Y. Yin and Z. Jiang, Catalytic enantioselective reductive cross coupling of electron-deficient olefins, Org. Lett., 2022, 24, 4788–4792.
26. (a) B. M. Abegaz, J. Mutanyatta-Comar and M. Nindi, Naturally occurring homoisoflavonoids: Phytochemistry, biological activities and synthesis, Nat. Prod. Commun., 2007, 2, 475–498; (b) K. du Toit, S. E. Drewes and J. Bodenstein, The chemical structures, plant origins, ethnobotany and biological activities of homoisoflavanones, Nat. Prod. Res., 2010, 24, 457–490; (c) B. M. Abegaz and H. H. Kinfe, Naturally occurring homoisoflavonoids: Phytochemistry, biological activities, and synthesis (Part II), Nat. Prod. Commun., 2019, 14, 1–20; (d) F. C. Demidoff, P. R. R. Costa and G. S. Caleffi, Advances in the synthesis of rearranged homoisoflavonoids, Org. Biomol. Chem., 2024, 22, 4839–4863.
27. M. Machala, R. Kubínová, P. Hořavová and V. Suchý, Chemoprotective potentials of homoisoflavonoids and chalcones of Dracaena cinnabari: modulations of drug-metabolizing enzymes and antioxidant activity, Phytother. Res., 2001, 15, 114–118.
28. J. Mutanyatta, B. G. Matapa, D. D. Shushu and B. M. Abegaz, Homoisoflavonoids and xanthones from the tubers of wild and in vitro regenerated Ledebouria graminifolia and cytotoxic activities of some of the homoisoflavonoids, Phytochemistry, 2003, 62, 797–804.
29. (a) G. O'Donnell, F. Bucar and S. Gibbons, Phytochemistry and antimycobacterial activity of Chlorophytum inornatum, Phytochemistry, 2006, 67, 178–182; (b) V. L. N. Reddy, V. Ravikanth, V. V. N. S. J. Lakshmi, U. S. Murty and Y. Venkateswarlu, Inhibitory activity of homoisoflavonoids from Caesalpinia sappan against Beauveria bassiana, Fitoterapia, 2003, 74, 600–602.
30. S. Lee, S. Kwon, J. Hur and S.-Y. Seo, Diastereodivergent synthesis of syn- and anti-9-hydroxyhomoisoflavanone and its application to the total syntheses of (±)-Homoferrugenone and (±)-Portulacanone F, Adv. Synth. Catal., 2022, 364, 3489–3495.
31. (a) C. Wu, Y. Liu, H. Zeng, L. Liu, D. Wang and Y. Chen, In(III)-Catalyzed tandem reaction of chromone-derived Morita–Baylis–Hillman alcohols with amines, Org. Biomol. Chem., 2011, 9, 253–256; (b) C. Wu, H. Zeng, L. Liu, D. Wang and Y. Chen, Tandem allylic amination/ring-opening/oxa-Michael addition reactions of chromone-derived Morita–Baylis–Hillman acetates with amines, Tetrahedron, 2011, 67, 1231–1237.
32. For a non-racemic version of a similar process, see also: J. Lei, Y. Li, L.-J. He, Y.-F. Luo, D.-Y. Tang, W. Yan, H.-K. Lin, H.-y. Li, Z.-Z. Chen and Z.-G. Xu, Expeditious access of chromone analogues via a Michael addition-driven multicomponent reaction, Org. Chem. Front., 2020, 7, 987–992.
33. N.-j. Zhong, L. Liu, D. Wang and Y.-J. Chen, Enantioselective tandem reaction of chromone-derived Morita–Baylis–Hillman carbonates with benzylamines catalyzed by a trifunctional organocatalyst: the synthesis of chiral 3-aminomethylene-flavanones, Chem. Commun., 2013, 49, 3697–3699.
34. Q. Zhu and Y. X. Lu, Stereocontrolled creation of all-carbon quaternary stereocenters by organocatalytic conjugate addition of oxindoles to vinyl sulfone, Angew. Chem., Int. Ed., 2010, 49, 7753–7756.

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