Advances in the site-selective C-5, C-3 and C-2 functionalization of chromones via sp2 C–H activation

In this work, site-selective C–H activation at C-5, C-3 and C-2 positions of chromones for the introduction of structural diversity to the chromone scaffold was studied. The keto group of the chromone moiety acts as the directing group for the selective functionalization of chromones at the C-5 position. Furthermore, the C–H functionalization at the electron-rich C-3 position of the chromone can be achieved using electrophilic coupling partners. The C–H functionalization at the C-2 position can be possible using nucleophilic coupling partners. The direct functionalization methods provide a better pathway for the generation of C-5, C-3 and C-2-substituted chromones with good atom economy than that of classical pre-functionalized reaction protocols.

Anjitha Theres Benny is currently a doctoral research scholar at Department of Chemistry, School of Advanced Sciences, VIT, Vellore. She has received her Master's degree in Chemistry from St. Berchmans College, Changanassery, Mahatma Gandhi University, Kerala. Her research interests include synthesis of heterocyclic compounds of pharmaceutical interests and medicinal Chemistry.
Direct C-H bond activation/functionalization has practical and fundamental challenges but it is a highly attractive strategy in the formation of a new functionality or a new C-C bond. The substrate scope by C-H activation is unlimited, including hydrocarbons, complex organic compounds of small molecular weight, and synthetic and biological polymers. [45][46][47][48][49][50][51][52][53] C-H functionalization of chromones is a useful method for the construction of carbon-carbon and carbon-heteroatom bonds. The cross dehydrogenative coupling (CDC) for the formation of Csp 2 -Csp, Csp-Csp 2 and Csp 2 -Csp 2 bonds enables the synthesis of signicant building blocks from a simple chromone moiety. 54 The C-5 functionalization of chromones by transition metal-catalyzed reactions is reported through chelation-assisted metal-catalyzed reaction transformation. The method proceeds by the effect of the weakly coordinating ability of the keto group on the chromone to the metal catalyst forming a metallacycle. 55,56 Similarly, the C-3 position of the chromone is functionalized by a transition metal-catalyzed reaction through a nucleophilic attack of chromones to metals forming a metal-chromone complex. The C-3 functionalization of the chromones occurs predominantly if its C-2 position is already substituted. The C-2 functionalization of chromones occurs when the coupling partners are arylpalladium species or alkyl radicals. The selective functionalization at C-5, C-3 or C-2 positions of chromones by a direct functionalization method acts as a substitution for the classical cross-coupling reactions including Ullmann, Suzuki, Heck, Negishi, Goldberg, Buckwald-Hartwig, Sonogashira, Hiyama, Cadiot-Chodkiewicz, Stille and Kumada coupling, and the carbonylation coupling, which includes pre-functionalization or generation of halogen wastes. [57][58][59][60][61] The coupling reaction without prefunctionalization catalyzed by a transition metal or other metal-free methodologies with a directing group containing a substrate are more efficient and atom-economic pathways. 62,63 Dahye et al. earlier in 2018 discussed the siteselective C-H functionalization of chromones and coumarins. 64 This review covers the selective functionalization of substituted chromones at C-2, C-3 and C-5 positions with recent advancements in the eld.  (III)-catalyzed C-C bond  formation without a pre-functionalized reaction protocol for the  synthesis of hybrid molecules of synthetic and medicinal importance. The direct oxidative cross-coupling reaction at the C-5 site of chromones with various olens (Scheme 1) was carried out in an atom-economic, highly efficient, and concerted reaction pathway.
Mechanistically, the transition metal-catalyzed directing group (keto group)-assisted dehydrogenative coupling starts with the C-H bond activation (Scheme 2). Initially, the chloride ligand of the complex [(Rh(III)Cp*Cl 2 ) 2 ] will be removed as AgCl by the action of AgSbF 6 to generate an active rhodium complex. The active rhodium species thus generated may contain ligands such as acetate or solvent in addition to pentamethylcyclopentadienyl (Cp*) ligands. Then, the active Rh species coordinates with the keto group of chromone and a concerted metalation/deprotonation (CMD) process activates the ortho C-H. The CMD process yields a ve-membered rhodacycle 14 intermediate.  55 S. Kathiravan et al. in 2014 developed a mild Rh(III)-catalyzed reaction protocol for the activation of ortho C-H of aromatic and aliphatic ketones (Scheme 3). The reaction protocol was applicable for the selective peruoroalkenylation of chromones at its C-5 position. The reaction proceeds under a mild condition with low catalyst loading and very good functional group tolerance and good to excellent yield. The synthetic scope of the method was enhanced by the excellent reactivity of the coupling partners and the regioselectivity of the reaction.
Rhodium(II)-catalyzed C-H functionalization of bi-or tricyclic scaffolds such as chromones and xanthones was carried out by Sang Hoon Han et al. in 2016 (Scheme 9). This biologically active compound upon site-selective functionalization with maleimide yields a succinimide substitute at their respective C-5 position with good functional group compatibility and excellent site selectivity. The succinimide generated in the C-5 position of the chromones was obtained by olen insertion into the metallacycle reaction intermediate followed by a protonation step. 68 The C-C bond formation with metal-catalyzed C-H activation of aryl ketones was studied by R. Shang et al. 2016 (Scheme 10). The main attraction of the reaction is the usage of inexpensive methylaluminum as the methylating agent and the economic and environmental merits of iron catalysts. The reaction proceeds by the combined activity of 4-(bis(2-(diphenylphosphanyl)phenyl)phosphanyl)-N,N-dimethylaniline (Me 2 N-TP) and methylaluminium for the transformation of ortho C-H to C-CH 3 under an iron-catalyzed reaction condition. The reaction proceeds well for various functional groups. 69 1,2-Diacylbenzene as a valuable precursor for the synthesis of medicinally important compounds such as isobenzofurans, phthalazines, and isoindoles can be generated by decarboxylative acylation of aromatic ketones via a palladium-catalyzed reaction (Scheme 11). The decarboxylative acylation reaction yields 1,2-diacylbenzene in excellent yields with ortho selectivity. This reaction protocol put forward by Wing-Yiu Yu et al. 2017 demonstrates a successful attempt for the direct C-H acylation reaction of aromatic ketones with a-oxocarboxylic acids, which proceeds without pre-derivatization to imines. Scheme 6 A plausible mechanism for ruthenium-catalyzed stereodivergent hydroarylation of chromones with alkynes.
Scheme 8 A plausible mechanism for the ruthenium-catalyzed hydroxylation of chromones for the synthesis of 5hydroxychromones.
The plausible reaction mechanism for the acylation of chromones under a palladium-catalyzed reaction condition is depicted in (Scheme 12). First, Pd(OAc) 2 gets transformed to Pd(TFA) 2 in situ by the action of triuoroacetic acid (TFA). The acylation gets initiated by the directing group (keto) via orthoselective electrophilic palladation on the olen by Pd(TFA) 2 . Palladacycle 43 obtained will then undergo oxidative coupling with acyl radical 44a generated in situ by decarboxylation of aoxocarboxylic acid. Reductive elimination from Pd(III) or Pd(IV) intermediate would then furnish the nal product 1,2-diacylbenzene 46 and an active Pd(II) catalyst. 70 Ir(III)-catalyzed selective C-H bond alkynylation is a useful synthetic transformation of ketones and esters for the construction of molecular complexity and developing drug molecules. The alkynyl functionality introduced with the facilitation of the carbonyl group on ketones and esters was catalyzed by Ir(III) and Ag(I) (Scheme 13). The feasibility of the reaction with both electron-donating and electron-withdrawing substituents was investigated. The yield of the reaction implies the feasibility of electron-rich species over electron-decient substituents. The substrate scope was also extended with halogen-substituted aromatic rings, which may increase the scope of reaction transformation further. The terminal alkynes were afforded using the desilylation reaction under mild reaction conditions.
Li, X et al. 2017 explained the mechanism for the alkynylation reaction of chromones, as depicted in Scheme 14. The reactive Ir(III) is initially generated from [Cp*IrCl 2 ] 2 and AgNTf 2 via ligand exchange. Later, the carbonyl-anchored Ir(III) facilitates the bond cleavage of C-5-H with the aid of acetate ligands. The reaction yields cyclometalated Ir(III) complex 49 the key intermediate of the reaction. The Ir(III) complex obtained undergoes oxidation with Ag(I) and alkynyl bromide in a concerted step or a multistep pathway yielding the product along with the regenerated Ir(III) catalyst. 71 Direct C-5 arylation of chromones catalyzed by [IrCP*Cl 2 ] 2 for the synthesis of C-5-functionalized chromones was introduced by K. Shin et al. 2018 (Scheme 15). The reaction afforded C-5 aryl chromones in good yields with functional group tolerance at ambient temperature. The reaction proceeds via C-H cleavage at the C-5 position and subsequent transmetallation.

Scheme 12
Proposed mechanism for palladium-catalyzed C-5 acylation of aromatic ketones.

Scheme 14
Proposed mechanism for regioselective C-5 bond alkynylation of chromones via iridium catalysis.
The transmetallated complex forms a high-valent aryl species by one-electron oxidation. The formation of this high-valent species reduces the barrier of reductive elimination by approximately 19 kcal mol À1 . Finally, the oxidatively induced reductive elimination yields the C-5 arylated chromones. 72 Tan, G et al. 2018 discovered a [IrCp*Cl 2 ]-catalyzed C-H arylation of diverse arenes with heteroarenes in a modest yield (Scheme 16). The C-H heteroarylation of aromatic ketones and enamides was carried out by the Cp*Ir catalyst via oxidatively induced reductive elimination. The reaction protocol works well for the synthesis of aryl-heteroaryl and vinyl-heteroaryl scaffolds. 73 S. Debbarma further studied the wide applicability of chromones. S. Debbarma et al. in 2019 synthesised a set of C-5 substituted chromones by metal-catalyzed C-5 activation of chromones (Scheme 17). The ketone-directed C-H functionalization of C-5 carbon leads to the diversication of chromones by transition metal-catalyzed allylation, amidation, alkenylation, and 1,4-addition reactions. 74 A C-5 functionalization method for the synthesis of b-aryland b-heteroarylethenesulfonyl uoride was carried out by G. Ncube et al. 2019. The reaction utilizes a catalytic system of tris(acetonitrile)-(pentamethyl cyclopentadienyl)rhodium(III) hexauoroantimonate, [Cp*Rh(MeCN) 3 ], and (SbF 6 ) 2 by oxidative C-H alkenylation of arenes with ethenesulfonyl uoride (Scheme 18). The directing group strategy allows the synthesis of b-aryland b-heteroarylethenesulfonyl uoride without the pre-installation of halogens, boronic acids, or diazonium functional groups on arenes with modest to good yields for a broad variety of directing groups. The reaction strategy provides an excellent and harmonizing approach for the attainment of novel building blocks in sulfur(IV) exchange click chemistry. 75 Vinylarenes are structurally important scaffolds due to their applicability as a starting material for various ne chemicals, polymers, and drugs. The synthesis of vinylarenes with ketonedirected C-H vinylation using vinyl acetate was reported by M. R. Sk et al. 2020 (Scheme 19). The vinylation on a set of compounds including diaryls, acetophenones, chalcones, and chromones was carried out by rst-row transition metals via ketone-directed C-H bond activation. This is the recently reported reaction for the cobalt-catalyzed carbonyl group-directed C-H vinylation with vinyl acetate.
The active catalyst for the vinylation reaction was obtained from [Cp*CoI 2 ] 2 complexes in the presence of silver hexa-uoroantimonate and acetate by removal of AgI (Scheme 20).  . Switching the additives with benzoic acid and silver acetate yields 1,4 addition products and oxidative Heck-type products respectively. The products were obtained in good to excellent yields with good functional group tolerance under a solvent-free reaction condition.
The mechanism of the reaction was studied by deuteration techniques. Initially, the ruthenium complex [Ru(p-cymene) Cl 2 ] 2 reacts with AgNTf 2 and benzoic acid or AgOAc accordingly for the generation of an active monomeric form or A 0 respectively (Scheme 22). The oxygen of the keto group coordinates with the active ruthenium species, which provides a vemembered metallacycle 76. Subsequent insertion of maleimide to the carbon-ruthenium bond of 76 gives a bicyclic  The zirconated chromones upon copper-catalyzed allylation yields a S N 2 substituted C-3 allylated product. 80 A direct C-3 alkenylation of chromones through a palladium(II) catalyzed methodology was achieved by D. Kim et al. in 2011 (Scheme 26). In this reaction, the reactivity of the coupling reaction between chromones and alkenes was attained by the combined activity of pivalic acid and Cu(OAc) 2 /Ag 2 CO 3 systems. The cross-coupling method leads to the formation of 3-vinylchromones, which are good structural scaffolds for the generation of biologically and synthetically active compounds. The method represents a C-3 derivatization of chromones with considerable advances over the current two-step methods with a good functional group tolerance and remarkable yield.
The possible mechanism for the transformation of the chromones to 3-vinylchromones initiates with a nucleophilic attack of chromones on palladium and the subsequent generation of palladium(II) intermediate 88 by the deprotonation by a pivalate ligand (Scheme 27). Next, the C-3 palladated species was inserted into the alkene substrate followed by reductive elimination, which generates the desired C-3 functionalized chromones. The catalyst Pd(II) was then regenerated from Pd(0) using Cu(OAc) 2 /Ag 2 CO 3 to continue the catalytic cycle further. 81 Oxidative arylation of chromones catalyzed by a Pd(II) catalyst was conducted by K. H. Kim et al. in 2012 (Scheme 28). The chromone selected for the arylation reaction was C-2, and C-3 was unsubstituted, and hence, the reaction yields a trace amount of C-3 functionalized product. 82 F. Chen et al. 2012 investigated the regioselective intermolecular arylation of chromones with polyuoroarenes using a palladium-catalyzed reaction protocol (Scheme 29). The reaction afforded uoroarylated enones by a two-fold C-H bond functionalization method. The scope of the reaction extends to C-3 uoroarylation of quinolones, chromones and pyrimidones in reasonable yields. The proposed reaction mechanism for the cross-coupling reaction proceeds by the formation of a palladated intermediate of both enone and uoroarene. The intermediates thus formed couple with uoroarene and enone and the succeeding reductive elimination yields desired products along with the Pd(II) catalyst. 83 The C-3 functionalization of avones with tert-butylperoxybenzoate (TBPB)/potassium persulphate (K 2   solvent was altered from cycloalkane to N,N-dimethylformamide. In both reactions, the solvent itself acts as a coupling partner for the progress of the reaction. The radical forming capability of cycloalkane and N,N-dimethylformamide ensures the formation of a product with the active participation of solvents in reactions. Again, when the solvent was changed to chlorobenzene, the C-3 methylated product was obtained by utilizing tert-butylperoxybenzoate (TBPB) as the source of the methyl group.
The C-3 functionalization reaction is set off by thermal homolytic bond cleavage of peroxide oxidant tert-butyl peroxybenzoate (TBPB) forming peroxybenzoate and tert-butoxy radicals. Both of these radicals generated are capable of scavenging hydrogen from cyclohexane 96 and N,N-dimethylformamide 98. A stable benzyl radical will generate upon the addition of any of these radicals on avone 1. The radical species 110 generates a cationic intermediate 111 through the reduction of catalyst Fe 3+ to Fe 2+ . Finally, the C-3 proton of the avone gets abstracted by the base affording the C-3functionalized product. In the absence of radical-generating solvents, TBPB acts as the source of the CH 3 group. The method allows the synthesis of a C-3-functionalized product through cycloalkylation, amidation and methylation by varying the solvents 84 (Scheme 31).
Youngtaek Moon et al. 2012 put forward an efficient and straightforward methodology for the direct cross-coupling of Scheme 27 Proposed mechanism for palladium(II)-catalyzed intermolecular C-3 alkenylation of chromones.

Scheme 28 Palladium-catalyzed C-3 arylation of chromones.
Scheme 29 Palladium-catalyzed dehydrogenative coupling of chromones with polyfluoroarenes. the C-3 position of chromones with quinones using palladium acetate as the catalyst. The reaction afforded good to excellent yields of quinones with tolerance for a wide range of functional groups on both the chromone and quinone moieties. Later, H. Choi et al. 2016 developed Pd(II)-catalyzed direct arylation of chromones (Scheme 32) by site-selective C-3 functionalization. The C-H activation progresses through a single-step metalation deprotonation method, which selectively activates the C-3 position of chromones. 85 The synthesis of a C-3 acylated chromone via acylation of 2,3unsubstituted chromones through decarboxylative C-C crosscoupling with a-keto acid was described by Satenik Mkrtchyan et al. 2018 (Scheme 33). The title transformation was effectively catalyzed by using a set of silver and palladium salts.
The mechanism for the C-3 acylation of chromones involves an initial O-acylated radical-chromone adduct 115 formation (Scheme 34). Subsequently, the adduct formed get oxidised into an O-acyl pyrylium moiety, which further undergoes Fries-type rearrangement followed by deprotonation yielding the preferred product 73 in moderate quantity. 86  . The reaction proceeds with sodium benzenesulnates as the sulphur source and odourless ammonium iodide as the reaction inducer. Sodium benzenesulnate was selected as the sulfur source due to its stability and efficiency in synthesising regioselective products in good yields. The regioselectiveness of the reaction on avones was studied by substitution with methyl groups at the C-3 and C-2 positions. Once the C-3 position was blocked by the methyl group, no thioether was Scheme 32 Palladium-catalyzed site-selective C-3 functionalization of chromones.

Scheme 33 Silver nitrate-catalyzed C-3 acylation of chromones.
Scheme 34 Proposed mechanism for AgNO 3 -catalyzed C-3 acylation of chromones. formed, verifying the regioselectivity of the sulfenylation reaction. 90 W. Zhao et al. 2015 introduced arylthiols as a new sulfur source and the same colourless odourless ammonium iodide as the reaction inducer (Scheme 38). The sulfenylation method introduced here was an efficient and regioselective methodology for obtaining organosulfur compounds of avones in good to excellent yields in a metal-free synthetic protocol.
At 135 C, the reaction inducer ammonium iodide was split into NH 3 and HI (Scheme 39). The obtained HI gets oxidized into iodine in the air atmosphere. The generated iodine will then react with thiophenol to form an electrophilic species ArS-I. ArS-I upon reaction with avone 1c at the electron-rich C-3 position gives the corresponding intermediate 128. The intermediate 128 on deprotonation yields the desired thioether 130. 91 Later in 2015, W. Zhao et al. introduced another sulfenylation method with dimethylsulfoxide or benzenesulfonyl hydrazide as the sulfenylating reagents and ammonium iodide as the reaction inducer (Scheme 40). The reaction proceeds at elevated temperatures, leading to the splitting of ammonium iodide into HI and NH 3 . HI reduces the reaction inducers, DMSO and benzenesulfonyl hydrazide. The electrophilic intermediate obtained from DMSO easily reacts with nucleophilic avone and subsequently attacks I and NH 3 to give the nal thioether product from DMSO. Similarly, the benzenesulfonyl hydrazide counterpart undergoes dehydration followed by reductive dehydration supported by HI to give thiodiazonium. The thiodiazonium regioselectively attacks the nucleophilic avone, yielding the corresponding thioether. The regioselectivity of the reaction was studied by blocking the C-3 position of avone, yielding no desired product, which implicates the regioselectivity of the reaction. 92 T. Guo et al. 2020 synthesised a C-3-functionalized chromone by the C-3 vulcanisation of imidazoheterocycle (Scheme 41). The dual C-H sulfenylation was achieved by odourless elemental sulphur under an additive and catalyst-free reaction condition. The C-3-functionalized asymmetric sulphides were obtained in good yields with C-H activation of both chromones and imidazoheterocycles using DMSO as both solvent and internal oxidant. The method acts as an efficient methodology for the synthesis of different organosulfur compounds using commercially available S8. benzene (Scheme 42). The reaction proceeds with regioselective C-2 arylation of chromones via a double C-H activation process. The reaction yields C-2 arylated chromones in moderate yields through regioselective palladation on the C-2 position of chromones via a CMD process and a subsequent C-H bond activation. 52 Similarly, M. Min et al. 2012 put forward the regiocontrolled C-H activation at the C-2 position of chromones. The method enables the palladium-catalyzed oxidative cross coupling reaction of nonactivated arenes with the C-2 position of chromones. The reaction offers a direct route to the C-2 arylation under mild conditions with a wide substrate scope. 94 The mechanism proceeds via regioselective palladation at the C-2 position of chromones via a CMD process with 138 for the generation of intermediate 139. . They suggested that iodine(III) supplied in the reaction generates alkyl radicals in situ, which will attack the most electrophilic C-2 position of chromones. The presence of the catalytic amount of PhI(O 2 CCF 3 ) 2 and NaN 3 under room temperature conditions yields C-2 alkylated chromones. 98 The reaction mechanism was proposed as a radical pathway and supported by the suppression of the reaction in the presence of radical scavengers (Scheme 50). Initially, tri-uoroacetate of PhI(O 2 CCF 3 ) 2 was exchanged by azides of sodium azide by a ligand exchange method to form 156, and thermolysis of 156 generates 160 and an azide radical. The azide radical abstracts H from the alkane to afford alkyl radical 157, which upon reaction with the electrophilic C-2 position of chromones and further oxidation gives C-2 alkylated chromones.
R. Samanta et al. in 2015 introduced transition metal-free oxidative, regioselective cross-coupling of chromones with non-functionalized azoles for the generation of C-2functionalized chromones with a new C-N bond (Scheme 51). The reaction is having prior importance due to the formation of the C-N bond, which is ubiquitous in natural products and bioactive molecules. 99 Initially, 162 reacts with molecular iodine forming an electrophilic iodine source 163 (Scheme 52). The reaction of 164 with 1c gives an oxonium ion. The oxonium ion 164 thus formed exists in equilibrium with the corresponding iodonium ion 165. Subsequently, 164 or 165 gets trapped by iodide to form product 166. The compound 166, which is not stable under basic conditions, thus undergoes a base-mediated dehydroiodination to generate 3-iodochromone 167.

Conclusion
To summarize, the review covered the site-selective functionalisation of non-prefunctionalized chromones at the C-5, C-3 and C-2 positions. All the functionalization reactions either catalyzed by a transition metal or occurring under metal-free conditions were mentioned in the review. A detailed review of all the reaction transformations by hydrogen at the active positions of chromone into different functional groups was presented. The review classies the reactions into two categories to enhance the understanding. They are transition metalcatalysed reactions in which the reaction proceeds by the formation of a metallacycle intermediate and the other one as a metal-free reaction transformation. The second topic is a wider one where the reaction can be nitration, a base-catalysed allylation, a nucleophilic or an electrophilic reaction, and a catalyst-and ligand-free reaction. The C-2 position of chromones is more electron decient and it may go for reactions with nucleophilic coupling partners or alkyl radicals. Similarly, the C-3 position is electron rich and it undergoes reactions with electrophilic coupling partners. There are also reports for catalyst and additive-free sulfenylation at the C-3 position. Therefore, to include all the functionalization reactions in the review, we summarise all these reactions under metal-free functionalization.
The non-pre-functionalized reactions are having greater importance compared to conventional prefunctionalized reactions. The reaction occurs in fewer steps without the liberation of halogen wastes when compared to conventional reaction methods. Despite these immense advancements in the siteselective sp 2 C-H activation of chromones, the methodologies suffer from serious drawbacks. It is difficult to attain siteselective substitution on the C-3 site of the chromone. Most of the reactions depend on the pre-functionalization of the C-2 sites before the functionalization at the C-3 position. On studying the yield of the functionalization reactions, we can see that the yield of these reactions is comparatively low. The lower yield of these site-selective products needed to be addressed in future. Similarly, all the C-H functionalization reactions on the arene ring of chromone take place at the C-5 position alone. This is because of the inherent direction of the carbonyl group on the chromone moiety. Methodologies focusing on these Scheme 51 Oxidative regioselective amination of chromones.
Scheme 52 Proposed mechanism for oxidative regioselective amination of chromones.

Conflicts of interest
There are no conicts to declare.