Recent Advances in Synthesis of 4-Arylcoumarins

4-Arylcoumarins (4-aryl-2H-1-benzopyran-2-one), also known as neoflavones, comprise a minor subclass of naturally occurring flavonoids. Because of their broad-spectrum biological activities, arylcoumarins have been attracting the attention of the organic and medicinal chemistry communities, and are considered as an important privileged scaffold. Since the development of Pechmann condensation, a classical acid-catalyzed condensation between phenol and β-keto-carboxylic acid, several versatile and efficient synthetic approaches for 4-arylcoumarins have been reported. This review summarizes recent advances in the synthesis of the 4-arylcoumarin scaffold by classifying them based on the final bond-formation type. In particular, synthetic methods executed under mild and highly efficient conditions, such as solvent-free reactions and transition metal catalysis, are highlighted.


Introduction
The Flavonoid families, a broad collection of natural products with a C 6 -C 3 -C 6 carbon framework, exhibit diverse and potent biological activities, and hence, are valuable research tools in pharmacological and related sciences. The 15-carbon tricyclic skeleton of this family, aryl benzopyrone, is considered an important natural privileged scaffold in the fields of synthetic and medicinal chemistry [1]. Hence, various synthetic methodologies have been developed and continually improved to provide natural, as well as synthetic flavonoids in a highly efficient and atom-economical fashion.
4-Arylcoumarins (4-aryl-2H-1-benzopyran-2-ones), also called as neoflavones, are a relatively minor class of naturally-occurring flavonoids, as compared to isomeric flavones (2-aryl chromen-4-one) and isoflavones (3-aryl chromen-4-one). However, these compounds have also attracted a great deal of attention, and are considered important privileged structures because of their diverse biological activities and high synthetic versatility [2][3][4][5][6]. As described in a very recent review [7], their biological activities are mainly attributed to electrophilic lactone core. The electrophilic lactone moiety that gives the coumarins the ability to form strong interactions with target proteins, such as covalent bonds or hydrogen bonds, has been considered as an essential pharmacophore to express biological activities. Liphophilic parts including 4-aryl moiety can also contribute to improving their biological activities, target selectivity, or physico-chemical properties. In this connection, derivatizations of 4-arylcoumarins to identify bioactive compounds have been focused on the modification of two aryl moieties (A and B rings), rather than the 2-pyrone moiety.
Molecules 2018, 23 While classifying synthetic routes in this review, we have focused on the final bond formation of the 4-arylcoumarin skeleton, rather than extensively covering the literature for the modification of 4-arylcoumarins and their biological activities. Generally, to synthesize the 4-arylcoumarin skeleton, a bond between the 2-pyrone nucleus (C ring) and the 4-aryl group (B ring) or bonds in the C ring have been connected at the final step. In this regard, we classified the synthetic routes on the basis of the final bond-formation type, as shown in Figure 1, and reviewed recent advancements in each case.
Molecules 2018, 23 While classifying synthetic routes in this review, we have focused on the final bond formation of the 4-arylcoumarin skeleton, rather than extensively covering the literature for the modification of 4-arylcoumarins and their biological activities. Generally, to synthesize the 4-arylcoumarin skeleton, a bond between the 2-pyrone nucleus (C ring) and the 4-aryl group (B ring) or bonds in the C ring have been connected at the final step. In this regard, we classified the synthetic routes on the basis of the final bond-formation type, as shown in Figure 1, and reviewed recent advancements in each case. First, this review introduces the synthetic methods for the formation of two bonds: the O(1)−C (2) and A ring−C(4) bonds, in the C ring. Acid-catalyzed condensation between phenols and β-ketocarboxylic acid derivatives, also known as Pechmann condensation, is one of the popular approaches to furnish the 2-pyrone moiety of the 4-arylcoumarin in one pot (Section 2.1). Alternatively, Lewis acid-promoted inter-and intramolecular hydroarylation can form the two bonds of the 2-pyrone moiety when an aryl propiolate is used as synthetic equivalent for the electrophilic synthon instead of the β-keto carboxylic acid (Section 2.2). Transition-metal-catalyzed C-H functionalization and subsequent intramolecular esterification between the phenolic compound and the arylpropionate or its equivalent has also been utilized to construct the O(1)−C(2) and A ring−C(4) bonds (Section 2.3).
In addition to a summary of recent synthetic methods for the 2-pyrone moiety via the formation of O(1)−C(2) and A ring−C(4) bonds, this review provides an update of other synthetic routes toward the central 2-pyrone. Cyclocarbonylation as well as cyclocaboxylation can provide the 2-pyrone structure of 4-arylcoumarins by connecting a carbonyl synthon with the 2-vinylphenol intermediate (Section 3). A 2-hydroxybenzophenone intermediate with a two-carbon (C2 and C3) synthon can also be used to synthesize 4-arylcoumarins via esterification along with olefin formation reactions, such as Wittig-type reactions (Section 4.1) and aldol-type reactions (Section 4.2). Nucleophilic addition of an acetylide to the 2-hydroxybenzophenone intermediate, and subsequent cycloisomerization, also affords 4-arylcoumarin by forming the two aforesaid bonds (Section 4.3).
Most synthetic routes to the central 2-pyrone moiety of 4-arylcoumarins involve O(1)−C(2) ester bond formation, as mentioned above. However, bond formation between the A ring and O(1), such as intramolecular cyclization of phenylacrylic acids, can be an exceptional method for the construction of the 2-pyrone moiety (Section 5).
The formation of a bond between the C ring and the 4-aryl group (B ring) can be considered a useful synthetic strategy, especially for the late-stage diversification of bioactive 4-arylcoumarins. Moreover, transition-metal-catalyzed coupling reactions, such as Suzuki and Stille reactions, have First, this review introduces the synthetic methods for the formation of two bonds: the O(1)−C (2) and A ring−C(4) bonds, in the C ring. Acid-catalyzed condensation between phenols and β-keto-carboxylic acid derivatives, also known as Pechmann condensation, is one of the popular approaches to furnish the 2-pyrone moiety of the 4-arylcoumarin in one pot (Section 2.1). Alternatively, Lewis acid-promoted inter-and intramolecular hydroarylation can form the two bonds of the 2-pyrone moiety when an aryl propiolate is used as synthetic equivalent for the electrophilic synthon instead of the β-keto carboxylic acid (Section 2.2). Transition-metal-catalyzed C-H functionalization and subsequent intramolecular esterification between the phenolic compound and the arylpropionate or its equivalent has also been utilized to construct the O(1)−C(2) and A ring−C(4) bonds (Section 2.3).
In addition to a summary of recent synthetic methods for the 2-pyrone moiety via the formation of O(1)−C(2) and A ring−C(4) bonds, this review provides an update of other synthetic routes toward the central 2-pyrone. Cyclocarbonylation as well as cyclocaboxylation can provide the 2-pyrone structure of 4-arylcoumarins by connecting a carbonyl synthon with the 2-vinylphenol intermediate (Section 3). A 2-hydroxybenzophenone intermediate with a two-carbon (C2 and C3) synthon can also be used to synthesize 4-arylcoumarins via esterification along with olefin formation reactions, such as Wittig-type reactions (Section 4.1) and aldol-type reactions (Section 4.2). Nucleophilic addition of an acetylide to the 2-hydroxybenzophenone intermediate, and subsequent cycloisomerization, also affords 4-arylcoumarin by forming the two aforesaid bonds (Section 4.3).
Most synthetic routes to the central 2-pyrone moiety of 4-arylcoumarins involve O(1)−C(2) ester bond formation, as mentioned above. However, bond formation between the A ring and O(1), such as intramolecular cyclization of phenylacrylic acids, can be an exceptional method for the construction of the 2-pyrone moiety (Section 5). The formation of a bond between the C ring and the 4-aryl group (B ring) can be considered a useful synthetic strategy, especially for the late-stage diversification of bioactive 4-arylcoumarins. Moreover, transition-metal-catalyzed coupling reactions, such as Suzuki and Stille reactions, have been widely used to introduce diverse aryl groups at the 4-position of 4-halocoumarins or activated coumarin intermediates. In addition to activated coumarin intermediates, several 4H-coumarins and their equivalents (such as cinnamate derivatives) have been used for the synthesis of 4-arylcoumarins by transition-metal-catalyzed coupling reactions such as Heck-type reactions (Section 6.1). Several examples of 4-arylcoumarin preparation from 2-hydroxycinnamic acid derivatives via transition-metal-catalyzed coupling reactions and concurrent lactonization are also discussed (Section 6.2).

Pechmann Condensation
Pechmann condensation, named after the German chemist Hans von Pechmann [8], is one of the most popular reactions for the synthesis of coumarins, including 4-arylcoumarins. This reaction starts with the condensation between a phenol and a β-keto-carboxylic acid, or its equivalent, under acidic conditions. The immense interest in the biological and medicinal importance of coumarin derivatives has triggered the development of various catalysts and reactions conditions in this regard. In addition, the mechanism undelaying the Pechmann condensation, which is still controversial, has been discussed in depth by both theoretical and experimental methods [9][10][11]. Recently, advances in the synthesis of coumarins via the Pechmann condensation have been extensively reviewed [12]. Thus, the selected syntheses of 4-arylcoumarins via the Pechmann condensation reported over the period 2000-2017 are summarized here.
Typically, the Pechmann condensation is catalyzed by a classical acid such as sulfuric acid, hydrochloric acid, hydrofluoric acid, phosphoric acid, or trifluoroacetic acid. In contrast, recently reported methods claim milder conditions which generate less toxic waste. From this point of view, the development of a solvent-free variant of the Pechmann reaction is an apparent trend toward the synthesis of 4-arylcoumarins. Establishing solvent-free reactions simplified not only the experimental procedure, but also the work-up procedure, thus saving labor and reducing pollution. In particular, the non-chromatographic purification of products, such as simple recrystallization, is in good accordance with the principle of green chemistry.
The conditions developed for the synthesis of 4-arylcoumarins through solvent-free Pechmann condensation are summarized in Table 1. Sugino and Tanaka reported a simple operation and easy work-up procedure using p-TsOH, so that wastes were minimized (Entry 1) [13]. Sharma et al. also reported the use of p-TsOH, with grinding at room temperature (Entry 2) [14]. The moisture absorbed during the grinding made the reaction mixture homogeneous, and the product could be isolated by dilution with ice-cold water. A microwave-accelerated variant of the reaction in the presence of p-TsOH has been investigated (Entry 3) [15]. Sulfamic acid [16] and meglumine sulfate [17] were found to be efficient and mild acids for the synthesis of 4-arylcoumarins (Entries 4-6). Microwave-accelerated reaction in the presence of meglumine sulfate was also compared with the corresponding thermal reaction. Efforts aimed at identifying a readily available and inexpensive organic acid revealed that trichloroacetic acid would be as an efficient catalyst (Entry 7) [18]. Selectfluor TM , a well-known fluorinating agent, is reported to be an efficient catalyst for the synthesis of 4-arylcoumarins as it is acidic (Entry 8) [19]. Metal halides such as ZrCl 4 [20], VCl 3 [21], SnCl 4 [22], CuCl 2 , CuBr 2 [23], BaCl 2 [24], and LiBr [25] were investigated for use in a mild and solvent-free Pechmann condensation to provide 4-arylcoumarins (Entries 9-14). Ultrasound was found to synergistically accelerate the condensation in the presence of BiCl 3 [26] (Entry 15). Thermal and microwave-accelerated reactions were compared in the presence of a highly efficient and recyclable catalyst, CoPy 2 Cl 2 [27] (Entries 16,17). Sc(OTf) 3 [28] and Mg(NTf 2 ) 2 [29] served as efficient catalysts for the synthesis of 4-arylcoumarins under solvent-free conditions (Entry [18][19]. Unlike most Lewis acids, which are deactivated in the presence of aqueous or protic solvents, Sc(OTf) 3 and Mg(NTf 2 ) 2 are known to be stable and work well even in water. In fact, Mg(NTf 2 ) 2 recovered by a simple extraction with water catalyzed the same Pechmann condensation without significant loss of catalytic activity after several runs [29]. Pechmann condensations could also be catalyzed by Bi(NO 3 ) 3 ·5H 2 O [30], CAN [31], and Y(NO 3 ) 3 [32] (Entries 20-23). Among them, CAN-catalyzed reactions under thermal and microwave conditions were also compared [31]. Cu(CH 3 CN) 4 PF 6 [33], and MnSO 4 [34] were also found to be efficient Lewis acids for the synthesis of coumarins (Entries 24,25). Moradi and Belali reported the use of molybdate sulfuric acid in the synthesis of 4-substituted coumarins via the Pechmann condensation (Entry 26) [35]. Molybdate sulfuric acid has the advantage of being insoluble in organic solvents, making the work-up procedure easy (filtration). Goswami reported organo-and nano-cocatalytic conditions, i.e., the use of pyridine dicarboxylic acid and nanocrystalline zinc oxide, for the synthesis of coumarins via the Pechmann condensation (Entry 27) [36]. Nanosized WO 3 -ZrO 2 particles were prepared by solution combustion synthesis using urea as the fuel and applied to the Pechmann condensation [37] (Entry 28). (Entries 20-23). Among them, CAN-catalyzed reactions under thermal and microwave conditions were also compared [31]. Cu(CH3CN)4PF6 [33], and MnSO4 [34] were also found to be efficient Lewis acids for the synthesis of coumarins (Entries 24,25). Moradi and Belali reported the use of molybdate sulfuric acid in the synthesis of 4-substituted coumarins via the Pechmann condensation (Entry 26) [35]. Molybdate sulfuric acid has the advantage of being insoluble in organic solvents, making the work-up procedure easy (filtration). Goswami reported organo-and nano-cocatalytic conditions, i.e., the use of pyridine dicarboxylic acid and nanocrystalline zinc oxide, for the synthesis of coumarins via the Pechmann condensation (Entry 27) [36]. Nanosized WO3-ZrO2 particles were prepared by solution combustion synthesis using urea as the fuel and applied to the Pechmann condensation [37] (Entry 28). As an alternative approach, Pechmann condensation using solid supports has been devised ( Table 2). Silica-supported solid catalysts such as silica chloride [38], silica-supported sulfuric acid [39,40], silica gel-supported zirconyl chloride ocatahydrate [41], silica-supported boric trisulfuric anhydride [42], and SnCl 4 grafted on silica gel [43] have been applied successfully for the synthesis of 4-arylcoumarins via the Pechmann condensation (Entry 1-6). Silica supports have the advantages of good accessibility, excellent chemical and thermal stability, and large surface area for easy functionalization. In addition, ASA [44] has been reported as the catalyst for Pechmann condensation reactions, similar to silica-supported sulfuric acid (Entry 7). reactions, similar to silica-supported sulfuric acid (Entry 7).
Both synthetic polymers and biopolymers have been investigated for use in the synthesis of 4arylcoumarins. PVSA [45], an aliphatic polymeric sulfonic acid, could be easily recovered from a water filtrate after completion of the reaction, as it is highly soluble in water and lower alcohols (Entry 8). XSA [46] is based on the biodegradable polymer xanthan, which is readily available from a renewable agro resource (Entry 9). Thermal and microwave-accelerated reactions were compared in the presence of CSA (Entries 10, 11) [47].
Magnetic solid-supported catalysts were prepared and explored for the synthesis of 4arylcoumarins. An apparent advantage of these catalysts is the ease of recovery using an external magnet. MNESA was recovered and reused in seven cycles without significant loss of activity (Entry 12) [48]. The recovered γ-Fe2O3@Hap-Ag NPs were reused in ten consecutive cycles (Entry 13) [49]. KAl(SO4)2·12H2O (alum) is a solid Lewis acid with mild acidity, and it is insoluble in organic solvents. Dabiri   Both synthetic polymers and biopolymers have been investigated for use in the synthesis of 4-arylcoumarins. PVSA [45], an aliphatic polymeric sulfonic acid, could be easily recovered from a water filtrate after completion of the reaction, as it is highly soluble in water and lower alcohols (Entry 8). XSA [46] is based on the biodegradable polymer xanthan, which is readily available from a renewable agro resource (Entry 9). Thermal and microwave-accelerated reactions were compared in the presence of CSA (Entries 10, 11) [47].
Magnetic solid-supported catalysts were prepared and explored for the synthesis of 4-arylcoumarins. An apparent advantage of these catalysts is the ease of recovery using an external magnet. MNESA was recovered and reused in seven cycles without significant loss of activity (Entry 12) [48]. The recovered γ-Fe 2 O 3 @Hap-Ag NPs were reused in ten consecutive cycles (Entry 13) [49]. KAl(SO 4 ) 2 ·12H 2 O (alum) is a solid Lewis acid with mild acidity, and it is insoluble in organic solvents. Dabiri et al. and Azizian et al. independently reported the synthesis of coumarins via the Pechmann condensation in the presence of alum as a solid acid catalyst (Entry 14) [50,51].
It is noteworthy that substituents strongly affect the Pechmann condensation. Although recent advances in the development of methods for the Pechmann condensation provided milder conditions with less toxic wastes, substituents are still limited to hydroxy, alkoxy, or alkyl substituents in many cases. Thus, the issue of applying Pechmann condensation for the preparation of 4-arylcoumarins possessing various substituents by using a green condition should be resolved in the future.

Hydroarylation of Phenylpropiolate
Lewis acid-promoted hydroarylation of arylpropiolates is an alternative method of Pechmann condensation for the synthesis of 4-arylcoumarins. Recently, several improved versions of the reaction have been reported, as summarized in Table 3.  Solvent-free condensation reactions in the presence of a catalytic amount of indium chloride or zinc chloride have been explored (Entries 1, 2) [52,53]. H14P5NaW30O110, a heteropolyacid with a Preyssler structure, has also been investigated as an efficient catalyst (Entry 3) [54]. This catalyst is recyclable, and both air-and moisture stable.
Li et al. developed an intramolecular alkenylation of arenes to be applied for the synthesis of 4arylcoumarins during the course of their study on the addition of electron-rich arenes to arylsubstituted alkynes in the presence of FeCl3 (Entry 4) [55]. The proposed mechanism is quite different from that of some other hydroarylations that proceed via aromatic C-H activation. This is suggested to be a Friedel-Crafts-type process, which involves the formation of aryl-substituted alkenyl cation intermediate 3, followed by electrophilic aromatic substitution, to produce intermediate 4 (Scheme 1). Kutubi  Solvent-free condensation reactions in the presence of a catalytic amount of indium chloride or zinc chloride have been explored (Entries 1, 2) [52,53]. H 14 P 5 NaW 30 O 110 , a heteropolyacid with a Preyssler structure, has also been investigated as an efficient catalyst (Entry 3) [54]. This catalyst is recyclable, and both air-and moisture stable.
Li et al. developed an intramolecular alkenylation of arenes to be applied for the synthesis of 4-arylcoumarins during the course of their study on the addition of electron-rich arenes to aryl-substituted alkynes in the presence of FeCl 3 (Entry 4) [55]. The proposed mechanism is quite different from that of some other hydroarylations that proceed via aromatic C-H activation. This is suggested to be a Friedel-Crafts-type process, which involves the formation of aryl-substituted alkenyl cation intermediate 3, followed by electrophilic aromatic substitution, to produce intermediate 4 (Scheme 1). Kutubi [59]. Mechanistic studies confirmed that the reaction proceeds via a vinyl cationic intermediate [60].

Transition-Metal-Catalyzed C-H Bond Functionalization
Trost and Toste reported a seminal report on the atom-economic synthesis of coumarins, including 4-arylcoumarins, in the presence of palladium catalysts in formic acid (Scheme 2) [61,62]. The proposed mechanism involves the formation of palladium phenoxide 12 from hydridopalladium carboxylate 8 and phenol 5, or alternatively, the formation of vinylpalladium intermediate 9 from 8 and alkynoate 6, wherein Pd(0) is the precatalyst, rather than Pd(II) species.  4 , were successfully extended to the synthesis of 4-phenylcoumarins [59]. Mechanistic studies confirmed that the reaction proceeds via a vinyl cationic intermediate [60].

Transition-Metal-Catalyzed C-H Bond Functionalization
Trost and Toste reported a seminal report on the atom-economic synthesis of coumarins, including 4-arylcoumarins, in the presence of palladium catalysts in formic acid (Scheme 2) [61,62]. The proposed mechanism involves the formation of palladium phenoxide 12 from hydridopalladium carboxylate 8 and phenol 5, or alternatively, the formation of vinylpalladium intermediate 9 from 8 and alkynoate 6, wherein Pd(0) is the precatalyst, rather than Pd(II) species.  [59]. Mechanistic studies confirmed that the reaction proceeds via a vinyl cationic intermediate [60].

Transition-Metal-Catalyzed C-H Bond Functionalization
Trost and Toste reported a seminal report on the atom-economic synthesis of coumarins, including 4-arylcoumarins, in the presence of palladium catalysts in formic acid (Scheme 2) [61,62]. The proposed mechanism involves the formation of palladium phenoxide 12 from hydridopalladium carboxylate 8 and phenol 5, or alternatively, the formation of vinylpalladium intermediate 9 from 8 and alkynoate 6, wherein Pd(0) is the precatalyst, rather than Pd(II) species.

Scheme 2. Pd-catalyzed formation of 4-arylcoumarins via C-H insertion.
Jia et al. also reported a method for hydroarylation with the activation of the C-H bond for addition to multiple C-C bonds (Scheme 3A) [63,64]. Direct functionalization of the C-H bond for the synthesis of 4-arylcoumarins 16 proceeds through electrophilic metalation of the aromatic C-H bond (15), leading to C-C bond formation, followed by regio-and stereoselective addition to alkynes. In this case, the requirement of a large excess of TFA as the solvent to keep the cationic Pd(II) species is noteworthy. Following this, intermolecular versions of the one-step methods were also reported (Scheme 3B,C) [65,66]. Intriguingly, Tunge and Foresee argued that the hydroarylation proceeds not via C-H bond activation, but via aromatic electrophilic substitution [67]. Jia et al. also reported a method for hydroarylation with the activation of the C-H bond for addition to multiple C-C bonds (Scheme 3A) [63,64]. Direct functionalization of the C-H bond for the synthesis of 4-arylcoumarins 16 proceeds through electrophilic metalation of the aromatic C-H bond (15), leading to C-C bond formation, followed by regio-and stereoselective addition to alkynes. In this case, the requirement of a large excess of TFA as the solvent to keep the cationic Pd(II) species is noteworthy. Following this, intermolecular versions of the one-step methods were also reported (Scheme 3B,C) [65,66]. Intriguingly, Tunge and Foresee argued that the hydroarylation proceeds not via C-H bond activation, but via aromatic electrophilic substitution [67]. Gold [68] and platinum [67] were also found to be efficient catalysts for the preparation of 4arylcoumarins through C-H bond functionalization. Shi and He reported an intramolecular addition reaction for the synthesis of 4-arylcoumarin 23 in the presence of AuCl3 pretreated with 3 equiv. of AgOTf (Scheme 4A) [68]. The use of silver salts was suggested to help generate a more electrophilic Au(III) species. Oyamada and Kitamura also reported PtCl2 and K2PtCl4 as efficient catalysts in the presence of AgOTf as an additive for the synthesis of coumarin 25 (Scheme 4B) [67]. The mechanism is supposed to be similar to that for the Pd(II)-catalyzed reaction of propiolates with phenols to afford coumarins [65]. Utilizing carbon dioxide (CO2) as a C1 synthon for organic synthesis has received much attention from the synthetic community, because it is a user-friendly and abundant source [74][75][76]. Hence, the direct carboxylation of alkenyl C-H bonds with CO2 is a highly attractive method for straightforward coumarin synthesis. In 2013, Iwasawa et al. reported 4-arylcoumarin synthesis via an unprecedented palladium-catalyzed direct carboxylation of the alkenyl C-H bond of α-phenyl-2-hydroxystyrene 42 with CO2 [77]. Scheme 8 shows the mechanism of the Pd-catalyzed alkenyl C-H carboxylation. Utilizing carbon dioxide (CO 2 ) as a C1 synthon for organic synthesis has received much attention from the synthetic community, because it is a user-friendly and abundant source [74][75][76]. Hence, the direct carboxylation of alkenyl C-H bonds with CO 2 is a highly attractive method for straightforward coumarin synthesis. In 2013, Iwasawa et al. reported 4-arylcoumarin synthesis via an unprecedented palladium-catalyzed direct carboxylation of the alkenyl C-H bond of α-phenyl-2-hydroxystyrene 42 with CO 2 [77]. Scheme 8 shows the mechanism of the Pd-catalyzed alkenyl C-H carboxylation. In 2017, Zhi et al. reported a transition-metal-free and redox neutral lactonization by cyclocarboxylation of 2-alkenylphenol 46 to afford 4-arylcoumarin 47 [71] (Scheme 9). They stated that the yield varies depending on the para substituent on the phenol ring. When R 1 and R 2 were H, the product was generated in 38% yield, with the ortho-and para carboxylated byproducts of the phenol ring. However, improved yields could be obtained when R 1 was a methoxy or methyl group. In 2017, Zhi et al. reported a transition-metal-free and redox neutral lactonization by cyclocarboxylation of 2-alkenylphenol 46 to afford 4-arylcoumarin 47 [71] (Scheme 9). They stated that the yield varies depending on the para substituent on the phenol ring. When R 1 and R 2 were H, the product was generated in 38% yield, with the ortho-and para carboxylated byproducts of the phenol ring. However, improved yields could be obtained when R 1 was a methoxy or methyl group. In 2017, Zhi et al. reported a transition-metal-free and redox neutral lactonization by cyclocarboxylation of 2-alkenylphenol 46 to afford 4-arylcoumarin 47 [71] (Scheme 9). They stated that the yield varies depending on the para substituent on the phenol ring. When R 1 and R 2 were H, the product was generated in 38% yield, with the ortho-and para carboxylated byproducts of the phenol ring. However, improved yields could be obtained when R 1 was a methoxy or methyl group.

Oxidative Cyclization toward Central 2-Pyrone of the 4-Arylcoumarin by A Ring−O(1) Bond Formation
Most of the reported syntheses of 4-arylcoumarins require phenol derivatives as the starting materials, indicating that methodologies featured with intermolecular linking of aryl groups (A ring) and carboxylic acids are scarcely reported.

Oxidative Cyclization toward Central 2-Pyrone of the 4-Arylcoumarin by A Ring−O(1) Bond Formation
Most of the reported syntheses of 4-arylcoumarins require phenol derivatives as the starting materials, indicating that methodologies featured with intermolecular linking of aryl groups (A ring) and carboxylic acids are scarcely reported. In 2013, Li et al. reported the synthesis of 4-arylcoumarins 69 via phenyliodine diacetate (PIDA)/I 2 -mediated oxidative cyclization of substituted phenylacrylic acids 68; in other words, this reaction facilitates intermolecular assembly between aryl groups and carboxylic acids [90] (Scheme 13).

Transition-Metal-Catalyzed Introduction of 4-Aryl Group
Recently, numerous synthetic approaches for 4-arylcoumarins via the direct functionalization of coumarin intermediates have been reported. These methodologies mainly involve transition-metalcatalyzed reactions, and are widely applicable to the synthesis of natural or synthetic 4arylcoumarins, partly because they are suitable for the introduction of various substituents on the 4aryl moieties. Initially, Pd(0) species were used as the transition-metal catalysts in these reactions. In 1988, Wattanasin first demonstrated the feasibility of Pd(0)-catalyzed Stille coupling for the synthesis Scheme 13. Synthesis of 4-arylcoumarins by oxidative cyclization.

Transition-Metal-Catalyzed Introduction of 4-Aryl Group
Recently, numerous synthetic approaches for 4-arylcoumarins via the direct functionalization of coumarin intermediates have been reported. These methodologies mainly involve transition-metal-catalyzed reactions, and are widely applicable to the synthesis of natural or synthetic 4-arylcoumarins, partly because they are suitable for the introduction of various substituents on the 4-aryl moieties. Initially, Pd(0) species were used as the transition-metal catalysts in these reactions. In 1988, Wattanasin first demonstrated the feasibility of Pd(0)-catalyzed Stille coupling for the synthesis of 4-arylcoumarins 71 from 4-triflated coumarin 70 and aryl stannane species [91] (Scheme 14A). Following this report, another version of Stille coupling for the synthesis of 4-arylcoumarins 73 using 4-tosylated coumarins 72 instead of 4-triflated coumarins was reported; this reaction allowed easy access to highly functionalized 4-arylcoumarins [92] (Scheme 14B). Ciattini et al. reported a similar route to various 4-arylcoumarins 75 using 4-stannylcoumarins 74, which is the reverse version of the aforementioned reactions [93] (Scheme 14C). More recently, it was reported that 4-chlorocoumarin 76 underwent Stille coupling with arylstannyl species, in the presence of a highly active palladium catalyst 78, to afford 4-arylcoumarin 77 [94] (Scheme 14D). In 1996, a Pd(0)-catalyzed Suzuki reaction for the synthesis of 4-arylcoumarins 80 using 4halocoumarin 79 and aryl boronic acids was reported [95] (Scheme 15A). This methodology yielded diverse 4-arylcoumarins in moderate to good yields, and it has been used in the synthesis of various 4-arylcoumarins and their fluorescent derivatives [96]. Wu et al. showed that 4-tosylated coumarins 81 could be used as manageable synthetic equivalents of 4-triflated coumarins for the coupling reaction with aryl boronic acids (Scheme 15B), similar to the Stille reaction for 4-arylcoumarins [3]. In the case of using aryl trifluoroborates, instead of aryl boronic acids, the Suzuki coupling reaction was also found to be working in another report [97] (Scheme 15C). Zhang and his colleagues reported the synthesis of diverse 4-arylcoumarins 87 via site-specific arylation to the 4-carbon linked with triflate group despite the presence of a 3-bromo group in coumarins 86 [98] (Scheme 15D). Such chemoselectivity, i.e., preference for the trifloxy group over the bromo group on the coumarin skeletons, was also observed by Langer and his colleagues, who reported regioselective arylation to the 4-carbon linked with triflate group, rather than the 7-triflate group on the coumarin skeleton [99,100] (Scheme 15E,F). Recently, the Suzuki reaction was used in the synthesis of 3-hydroxymethyl- In 1996, a Pd(0)-catalyzed Suzuki reaction for the synthesis of 4-arylcoumarins 80 using 4-halocoumarin 79 and aryl boronic acids was reported [95] (Scheme 15A). This methodology yielded diverse 4-arylcoumarins in moderate to good yields, and it has been used in the synthesis of various 4-arylcoumarins and their fluorescent derivatives [96]. Wu et al. showed that 4-tosylated coumarins 81 could be used as manageable synthetic equivalents of 4-triflated coumarins for the coupling reaction with aryl boronic acids (Scheme 15B), similar to the Stille reaction for 4-arylcoumarins [3]. In the case of using aryl trifluoroborates, instead of aryl boronic acids, the Suzuki coupling reaction was also found to be working in another report [97] (Scheme 15C). Zhang and his colleagues reported the synthesis of diverse 4-arylcoumarins 87 via site-specific arylation to the 4-carbon linked with triflate group despite the presence of a 3-bromo group in coumarins 86 [98] (Scheme 15D). Such chemoselectivity, i.e., preference for the trifloxy group over the bromo group on the coumarin skeletons, was also observed by Langer and his colleagues, who reported regioselective arylation to the 4-carbon linked with triflate group, rather than the 7-triflate group on the coumarin skeleton [99,100] (Scheme 15E,F). Recently, the Suzuki reaction was used in the synthesis of 3-hydroxymethyl-4-arylcoumarins 93, in an effort to identify 4-arylcoumarins with biological activities [101] (Scheme 15G). In 2001, another Pd(0)-catalysis involving the use of organozinc reagents as synthetic equivalents for the 4-aryl synthons, known as the Negishi-type coupling reaction, was reported by Wu et al.
In 2006, Wu et al. reported several strategies for the Rh(I)-catalyzed Suzuki cross-coupling reaction toward the synthesis of 4-arylcoumarins. They successfully synthesized the desired coumarins by using aryl boronic acids [112] and potassium aryltrifluoroborates [113] (Scheme 18). All of the above-mentioned reactions require 4-halocoumarins or other activated coumarins, and involve transition metal-catalyzed coupling with synthetic equivalents of the 4-aryl synthon for the preparation of the corresponding 4-arylcoumarins. Recently, simple coumarins that do not have halo or metal species at the 4-position were reported to be successfully transformed into 4-arylcoumarins via a Pd(II)-catalyzed oxidative Heck coupling reaction. In 2012, Khoobi et al. reported that the coupling reaction of 4H-coumarins 119 with aryl boronic acids furnished the corresponding 4arylcoumarins 120 in good yields [114] (Scheme 19A). Li et al. concurrently reported a similar but independent work using nitrophenanthroline as a ligand [115] (Scheme 19B). More recently, Min et al. reported a novel and regioselective Pd(II)-catalyzed coupling reaction of 4H-coumarins 123 with simple arenes, involving C-H activation subject to an oxidative Heck coupling reaction [116,117] (Scheme 19C). Regioselective arylation at the 4-position of coumarin was also reported by Khoobi et al., who used coumarin-3-carboxylic acids and coumarins as the starting materials [118]. They also proposed the plausible mechanism of the reaction, which mainly involved protodecarboxylation and Pd(II)catalyzed oxidative Heck coupling (Scheme 20). Scheme 20. Synthesis of 4-arylcoumarins via protodecarboxylation-induced Heck reaction.

Domino Reactions Assisted by Transition Metal Catalysis
Recently, domino reactions initiated and assisted by transition-metal catalysis were reported for 4-arylcoumarin synthesis. These methodologies are based on cascade reactions involving the Pd(II)- Regioselective arylation at the 4-position of coumarin was also reported by Khoobi et al., who used coumarin-3-carboxylic acids and coumarins as the starting materials [118]. They also proposed the plausible mechanism of the reaction, which mainly involved protodecarboxylation and Pd(II)-catalyzed oxidative Heck coupling (Scheme 20). All of the above-mentioned reactions require 4-halocoumarins or other activated coumarins, and involve transition metal-catalyzed coupling with synthetic equivalents of the 4-aryl synthon for the preparation of the corresponding 4-arylcoumarins. Recently, simple coumarins that do not have halo or metal species at the 4-position were reported to be successfully transformed into 4-arylcoumarins via a Pd(II)-catalyzed oxidative Heck coupling reaction. In 2012, Khoobi et al. reported that the coupling reaction of 4H-coumarins 119 with aryl boronic acids furnished the corresponding 4arylcoumarins 120 in good yields [114] (Scheme 19A). Li et al. concurrently reported a similar but independent work using nitrophenanthroline as a ligand [115] (Scheme 19B). More recently, Min et al. reported a novel and regioselective Pd(II)-catalyzed coupling reaction of 4H-coumarins 123 with simple arenes, involving C-H activation subject to an oxidative Heck coupling reaction [116,117] (Scheme 19C). Regioselective arylation at the 4-position of coumarin was also reported by Khoobi et al., who used coumarin-3-carboxylic acids and coumarins as the starting materials [118]. They also proposed the plausible mechanism of the reaction, which mainly involved protodecarboxylation and Pd(II)catalyzed oxidative Heck coupling (Scheme 20). Scheme 20. Synthesis of 4-arylcoumarins via protodecarboxylation-induced Heck reaction.

Domino Reactions Assisted by Transition Metal Catalysis
Recently, domino reactions initiated and assisted by transition-metal catalysis were reported for 4-arylcoumarin synthesis. These methodologies are based on cascade reactions involving the Pd(II)-Scheme 20. Synthesis of 4-arylcoumarins via protodecarboxylation-induced Heck reaction.

Domino Reactions Assisted by Transition Metal Catalysis
Recently, domino reactions initiated and assisted by transition-metal catalysis were reported for 4-arylcoumarin synthesis. These methodologies are based on cascade reactions involving the Pd(II)-catalyzed oxidative Heck-type arylation of 2-hydroxycinnamate derivatives, followed by concurrent cyclization. Thus, these approaches could be efficient tools for 4-arylcoumarin synthesis from 2-hydroxycinnamic acid derivatives by the introduction of a 4-aryl groups. In 2005, Cacchi et al. reported the first domino reaction for the synthesis of 4-arylcoumarin 128 using aryl halides as the 4-aryl sources in a molten n-Bu 4 NOAc/n-Bu 4 NBr mixture via a Heck reaction/cyclization sequence of 2-hydroxycinnamate 127 [119] (Scheme 21A). A similar approach toward 4-arylcoumarin 130 using aryldiazo compounds as the 4-aryl sources was also reported and applied for the total synthesis of (R)-toleterodine [120] (Scheme 21B). Wang et al. reported that diaryliodonium(III) salts 133 could be used as synthetic equivalents for the 4-aryl synthon in domino reactions for the synthesis of 4-arylcoumarin 132 [121]. In 2016, a method using Pd(II) oxide impregnated on magnetite as the catalyst (heterogenous palladium catalyst) was reported by an independent group for the synthesis of 132 via a Heck-arylation/cyclization process [122] (Scheme 21C). Another domino reaction involving the Cu(I)-catalyzed 1,4-addition of an arylboronic acid to alkyne 134 and sequential cyclization was also reported by Yamamoto and his colleague [123] (Scheme 21D). catalyzed oxidative Heck-type arylation of 2-hydroxycinnamate derivatives, followed by concurrent cyclization. Thus, these approaches could be efficient tools for 4-arylcoumarin synthesis from 2hydroxycinnamic acid derivatives by the introduction of a 4-aryl groups. In 2005, Cacchi et al. reported the first domino reaction for the synthesis of 4-arylcoumarin 128 using aryl halides as the 4aryl sources in a molten n-Bu4NOAc/n-Bu4NBr mixture via a Heck reaction/cyclization sequence of 2-hydroxycinnamate 127 [119] (Scheme 21A). A similar approach toward 4-arylcoumarin 130 using aryldiazo compounds as the 4-aryl sources was also reported and applied for the total synthesis of (R)-toleterodine [120] (Scheme 21B). Wang et al. reported that diaryliodonium(III) salts 133 could be used as synthetic equivalents for the 4-aryl synthon in domino reactions for the synthesis of 4arylcoumarin 132 [121]. In 2016, a method using Pd(II) oxide impregnated on magnetite as the catalyst (heterogenous palladium catalyst) was reported by an independent group for the synthesis of 132 via a Heck-arylation/cyclization process [122] (Scheme 21C). Another domino reaction involving the Cu(I)-catalyzed 1,4-addition of an arylboronic acid to alkyne 134 and sequential cyclization was also reported by Yamamoto and his colleague [123] (Scheme 21D) Scheme 21. Introduction of 4-aryl group via sequential domino reactions involving Pd(II)-catalyzed oxidative Heck-type arylation (A-C) and Cu(I)-catalyzed 1,4-addition (D).

Conclusions
4-Arylcoumarins are considered biologically-important scaffolds for the development of bioactive probes and in drug discovery. Since the Pechmann condensation was first utilized for the synthesis of 4-arylcoumarins, various synthetic routes have been developed to improve the yields, efficiency, and scope of the reaction. This review discusses recent advances in the synthetic methods

Conclusions
4-Arylcoumarins are considered biologically-important scaffolds for the development of bioactive probes and in drug discovery. Since the Pechmann condensation was first utilized for the synthesis of 4-arylcoumarins, various synthetic routes have been developed to improve the yields, efficiency, and scope of the reaction. This review discusses recent advances in the synthetic methods for 4-arylcoumarins by classifying them based on the final bond-formation type. We hope that this review will be helpful for readers who are interested in developing novel bioactive 4-arylcoumarins and new related synthetic methods.
Author Contributions: All authors contributed to and approved the final manuscript. Acknowledgments: We are truly grateful to Young-Ger Suh, our advisor and lifetime mentor, for the valuable opportunities to have great experiences in organic and medicinal chemistry.

Conflicts of Interest:
The authors declare no conflict of interest.

Abbreviations
The following abbreviations are used in this manuscript: