Recent Advances in Regioselective C–H Bond Functionalization of Free Phenols

Phenols are important readily available synthetic building blocks and starting materials for organic synthetic transformations, which are widely found in agrochemicals, pharmaceuticals, and functional materials. The C–H functionalization of free phenols has proven to be an extremely useful tool in organic synthesis, which provides efficient increases in phenol molecular complexity. Therefore, approaches to functionalizing existing C–H bonds of free phenols have continuously attracted the attention of organic chemists. In this review, we summarize the current knowledge and recent advances in ortho-, meta-, and para-selective C–H functionalization of free phenols in the last five years.


Introduction
Phenols are readily available and have emerged as ubiquitous building blocks in natural products, pharmaceuticals, and functional materials [1][2][3][4][5][6]. For example, many natural products such as hormones, antibiotics, vitamins, and neurotransmitters are derived from or contain phenols; Approximately, more than 10% of the top 200 selling pharmaceuticals bear at least one phenol or employ phenols as synthetic intermediates; phenols are also key components of functional materials such as polymer resins (Scheme 1). Consequently, straightforward and highly efficient site-selective C-H bond functionalization of free phenols has continuously attracted the attention of organic chemists [7][8][9][10].
With developments made in organic synthesis, the direct C-H functionalization of phenols has been explored extensively as an efficient and powerful tool to synthesize complex phenol molecules. In the previous selective conversion of phenol, most of the directing groups installed on the phenolic hydroxyl group were used to realize the indirect strategy of activation of ortho C-H bond functionalization. However, as the most straightforward and atom-economical strategy, directly using free phenolic hydroxyl groups as directing groups to synthesize highly substituted phenolic derivatives, there are many challenges for chemo-and regioselective C-H functionalization of unprotected free phenols. The major barrier stems from several aspects: (1) the phenolic hydroxyl group has strong acidity and nucleophilicity, so that the reaction site mostly occurs on the phenolic hydroxyl group instead of the benzene ring; (2) the ortho and para positions of the phenolic hydroxyl group in the benzene ring are highly active, which reduces the regioselectivity of the C-H bond functionalization reaction; (3) it is often necessary to add a stoichiometric oxidant in the C-H functionalization reaction, and the phenols are typical electron-rich aromatic hydrocarbons, which are easily oxidatively decomposed during the reaction. Thus, more economical and green synthetic approaches for the direct regioselective C-H bond functionalization of free phenols are a significant challenge of great interest. Some reviews on the transition-metal-catalyzed functionalization of C-H bonds in phenols have been reported so far. Lumb and co-workers [11] wrote a review on phenoldirected C-H functionalization in 2018. Luo [12] summarized the progress of the transition metal-catalyzed directing-group-assisted C-H activation of phenols until 2019. Immediately afterward, Mamari [13] outlined a comprehensive advance in regard to metalcatalyzed C-H bond functionalization of phenol derivatives in 2020. Later, Youn and coworkers [14] reported a comprehensive overview of transition-metal-catalyzed ortho-selective C-H functionalization reactions of free phenols until 2021. Recently, Zhai [15] published an excellent review on recent advances in catalytic oxidative reactions of phenols and naphthalenols. We want to focus on the recent development on the C-H functionalization of different positions on the free phenol aromatic ring. Thus, we will summarize recent advances since 2018 in regioselective C-H bond functionalization of free phenols in this review. This review is classified into three sections according to the position of functionalization, treating ortho-, meta-, and para-positions of free phenol successively, and only some selected examples are described schematically (Figure 1). Scheme 1. Phenol-containing molecules. Some reviews on the transition-metal-catalyzed functionalization of C-H bonds in phenols have been reported so far. Lumb and co-workers [11] wrote a review on phenoldirected C-H functionalization in 2018. Luo [12] summarized the progress of the transition metal-catalyzed directing-group-assisted C-H activation of phenols until 2019. Immediately afterward, Mamari [13] outlined a comprehensive advance in regard to metal-catalyzed C-H bond functionalization of phenol derivatives in 2020. Later, Youn and co-workers [14] reported a comprehensive overview of transition-metal-catalyzed ortho-selective C-H functionalization reactions of free phenols until 2021. Recently, Zhai [15] published an excellent review on recent advances in catalytic oxidative reactions of phenols and naphthalenols. We want to focus on the recent development on the C-H functionalization of different positions on the free phenol aromatic ring. Thus, we will summarize recent advances since 2018 in regioselective C-H bond functionalization of free phenols in this review. This review is classified into three sections according to the position of functionalization, treating ortho-, meta-, and para-positions of free phenol successively, and only some selected examples are described schematically (Figure 1).

Metal-Catalyzed C-H Bond Functionalization of Free Phenol
Over the past decades, there have been tremendous advances in the field of catalytic C-H bond functionalization [16][17][18], among which metal-catalyzed C-H bond functionalization of free phenol has proven to be an extremely useful tool in the synthesis of complex phenol molecules.

Cu-Catalyzed C-H Bond Functionalization
In 2018, Jain's group [19] synthesized a GO-Cu7S4NPs from Cu2S to achieve an highly efficient ortho-selective C-H aminomethylation of free phenol derivatives 1 with N,N-dimethylbenzylamines 2 using tert-Butyl hydroperoxide (TBHP) as an oxidant under solvent-free conditions. The nano-copper catalyst could be reused for Csp2-Csp3 cross-dehydrogenative coupling, with no requirement for pre-functionalization of substrates. A variety of C-C coupled products 3 are obtained with 68-89% yields. Furthermore, more challenging substrates like β-naphthols and substituted halohydroxypyridine derivatives were successfully used in the aminomethylation reaction to afford the corresponding aminomethylated products in 70-80% yields. Control experiments suggested that this reaction may undergo the nucleophilic attack by ortho-phenol carbon 4 on iminium ion 5, which was formed by the loss of hydrogen atom via a single electron transfer under the action of the nano-copper catalyst and TBHP, to generate the Cu-coordinated ketone 7 (Scheme 2).

Metal-Catalyzed C-H Bond Functionalization of Free Phenol
Over the past decades, there have been tremendous advances in the field of catalytic C-H bond functionalization [16][17][18], among which metal-catalyzed C-H bond functionalization of free phenol has proven to be an extremely useful tool in the synthesis of complex phenol molecules.

Cu-Catalyzed C-H Bond Functionalization
In 2018, Jain's group [19] synthesized a GO-Cu 7 S 4 NPs from Cu 2 S to achieve an highly efficient ortho-selective C-H aminomethylation of free phenol derivatives 1 with N,Ndimethylbenzylamines 2 using tert-Butyl hydroperoxide (TBHP) as an oxidant under solvent-free conditions. The nano-copper catalyst could be reused for C sp2 -C sp3 crossdehydrogenative coupling, with no requirement for pre-functionalization of substrates. A variety of C-C coupled products 3 are obtained with 68-89% yields. Furthermore, more challenging substrates like β-naphthols and substituted halohydroxypyridine derivatives were successfully used in the aminomethylation reaction to afford the corresponding aminomethylated products in 70-80% yields. Control experiments suggested that this reaction may undergo the nucleophilic attack by ortho-phenol carbon 4 on iminium ion 5, which was formed by the loss of hydrogen atom via a single electron transfer under the action of the nano-copper catalyst and TBHP, to generate the Cu-coordinated ketone 7 (Scheme 2).
Simultaneously, Patureau's group [20] reported a highly selective Cu(II)-catalyzed cross-dehydrogenative ortho-aminomethylation of free phenols 8 with aniline derivatives 9 using Di-tert-butyl peroxide (DTBP) as an oxidant. As illustrated in Scheme 3, a series of aminomethylated products 10 were obtained with 32-82% yields and based on controlled experiments; the authors proposed that this reaction involved the aminomethyl radical 13 by a Cu-centered six membered transition state 15. However, this method required an excess of amines (6.3-9.5 equiv.) and only tertiary N-methyl aromatic amines were compatible with the reaction system, which limited its synthetic utility. Simultaneously, Patureau's group [20] reported a highly selective Cu(II)-catalyzed cross-dehydrogenative ortho-aminomethylation of free phenols 8 with aniline derivatives 9 using Di-tert-butyl peroxide (DTBP) as an oxidant. As illustrated in Scheme 3, a series of aminomethylated products 10 were obtained with 32-82% yields and based on controlled experiments; the authors proposed that this reaction involved the aminomethyl radical 13 by a Cu-centered six membered transition state 15. However, this method required an excess of amines (6.3-9.5 equiv.) and only tertiary N-methyl aromatic amines were compatible with the reaction system, which limited its synthetic utility. In 2021, a copper(II)-modified nitrogen-rich covalent organic polymer (Cu/N-COP-1) was prepared and employed to achieve the cross-dehydrogenative ortho-aminomethylation of free phenols 16 with N,N-dimethylanilines 17 under mild conditions by Xie et al. [21]. Various aminomethylated products 18 were obtained in 42-59% yields (Scheme 4). In addition, the catalyst could be easily reused for at least five consecutive runs without significant loss of catalytic activity, which is attributed to the interaction between the nitrogen-containing group of the covalent organic polymer and copper chloride. Having the Simultaneously, Patureau's group [20] reported a highly selective Cu(II)-catalyzed cross-dehydrogenative ortho-aminomethylation of free phenols 8 with aniline derivatives 9 using Di-tert-butyl peroxide (DTBP) as an oxidant. As illustrated in Scheme 3, a series of aminomethylated products 10 were obtained with 32-82% yields and based on controlled experiments; the authors proposed that this reaction involved the aminomethyl radical 13 by a Cu-centered six membered transition state 15. However, this method required an excess of amines (6.3-9.5 equiv.) and only tertiary N-methyl aromatic amines were compatible with the reaction system, which limited its synthetic utility. In 2021, a copper(II)-modified nitrogen-rich covalent organic polymer (Cu/N-COP-1) was prepared and employed to achieve the cross-dehydrogenative ortho-aminomethylation of free phenols 16 with N,N-dimethylanilines 17 under mild conditions by Xie et al. [21]. Various aminomethylated products 18 were obtained in 42-59% yields (Scheme 4). In addition, the catalyst could be easily reused for at least five consecutive runs without significant loss of catalytic activity, which is attributed to the interaction between the nitrogen-containing group of the covalent organic polymer and copper chloride. Having the Scheme 3. Cu-catalyzed ortho-aminomethylation of phenols with aniline derivatives.
In 2021, a copper(II)-modified nitrogen-rich covalent organic polymer (Cu/N-COP-1) was prepared and employed to achieve the cross-dehydrogenative ortho-aminomethylation of free phenols 16 with N,N-dimethylanilines 17 under mild conditions by Xie et al. [21]. Various aminomethylated products 18 were obtained in 42-59% yields (Scheme 4). In addition, the catalyst could be easily reused for at least five consecutive runs without significant loss of catalytic activity, which is attributed to the interaction between the nitrogen-containing group of the covalent organic polymer and copper chloride. Having the di-substituted products 19 and moderate yields (mostly 42-59%) of the desired products were the drawbacks of this method.
In 2020, Ma et al. [22] reported the first copper-catalyzed highly efficient ortho-C-H bond functionalization rather than O-H insertion of free phenols 20 with a-aryl-a-diazoesters 21 (Scheme 5). A range of alkylation products 22 were obtained in 76-98% yields under mild reaction conditions. A preliminary mechanistic study indicated that the hydroxyl group was important not only for site-selectivity but also for the reactivity of the C-H bond functionalization reaction, and the ortho-selectivity could be improved via the interaction between the hydroxyl group and the copper catalyst. Herein, the authors proposed two possible reaction mechanisms for this transformation, which involved the Cu-carbene 27 di-substituted products 19 and moderate yields (mostly 42-59%) of the desired products were the drawbacks of this method. In 2020, Ma et al. [22] reported the first copper-catalyzed highly efficient ortho-C-H bond functionalization rather than O-H insertion of free phenols 20 with a-aryl-a-diazoesters 21 (Scheme 5). A range of alkylation products 22 were obtained in 76-98% yields under mild reaction conditions. A preliminary mechanistic study indicated that the hydroxyl group was important not only for site-selectivity but also for the reactivity of the C-H bond functionalization reaction, and the ortho-selectivity could be improved via the interaction between the hydroxyl group and the copper catalyst. Herein, the authors proposed two possible reaction mechanisms for this transformation, which involved the Cucarbene 27 and the carbocation intermediate 28 formed by coordination between the CuCl2 and the nitrogen of a-aryl-a-diazoesters, respectively. Scheme 5. Cu-catalyzed ortho-aminomethylation of phenols with a-aryl-a-diazoesters.
One year later, Xie's group [23] developed a copper-catalyzed tandem cross-coupling/annulation of free phenols 30 with ketoximes 29 via dual C-H functionalization. A  In 2020, Ma et al. [22] reported the first copper-catalyzed highly efficient ortho-C-H bond functionalization rather than O-H insertion of free phenols 20 with a-aryl-a-diazoesters 21 (Scheme 5). A range of alkylation products 22 were obtained in 76-98% yields under mild reaction conditions. A preliminary mechanistic study indicated that the hydroxyl group was important not only for site-selectivity but also for the reactivity of the C-H bond functionalization reaction, and the ortho-selectivity could be improved via the interaction between the hydroxyl group and the copper catalyst. Herein, the authors proposed two possible reaction mechanisms for this transformation, which involved the Cucarbene 27 and the carbocation intermediate 28 formed by coordination between the CuCl2 and the nitrogen of a-aryl-a-diazoesters, respectively. Scheme 5. Cu-catalyzed ortho-aminomethylation of phenols with a-aryl-a-diazoesters.
One year later, Xie's group [23] developed a copper-catalyzed tandem cross-coupling/annulation of free phenols 30 with ketoximes 29 via dual C-H functionalization. A variety of oximes, including 1-naphthyl-bearing oxime and heteroaryl-bearing oximes, were compatible for this reaction system and afforded the corresponding products 31 in good yields. Control experiments disclosed that the benzoquinone 33 might be the vital intermediate of the dual C-H functionalization reaction, as the para-dihydroxyl was crucial in the process of reaction (Scheme 6).
In 2022, Zhao et al. [24] reported a copper-catalyzed C2-site selective amination of free p-aminophenol derivatives 35 with arylamines 36 under mild conditions, using air as a terminal oxidant, and a variety of C2-site functional aminophenol derivatives 37 were obtained with 39-78% yields (Scheme 7). Interestingly, the para-benzomorpholine substituted phenol was also compatible with the reaction system for transformation into the desired C2-site selective aminated product 37a in 58% yield with oxidation of the benzomorpholine group to 4H-benzo[b] [1,4]oxazine. Based on controlled experiments, the authors proposed that the amination reaction may undergo a process of radical-radical cross-coupling between the phenoxyl radical 39 and the N-radical 40.
Molecules 2023, 28, x FOR PEER REVIEW 6 of 27 variety of oximes, including 1-naphthyl-bearing oxime and heteroaryl-bearing oximes, were compatible for this reaction system and afforded the corresponding products 31 in good yields. Control experiments disclosed that the benzoquinone 33 might be the vital intermediate of the dual C-H functionalization reaction, as the para-dihydroxyl was crucial in the process of reaction (Scheme 6).
In 2022, Zhao et al. [24] reported a copper-catalyzed C2-site selective amination of free p-aminophenol derivatives 35 with arylamines 36 under mild conditions, using air as a terminal oxidant, and a variety of C2-site functional aminophenol derivatives 37 were obtained with 39-78% yields (Scheme 7). Interestingly, the para-benzomorpholine substituted phenol was also compatible with the reaction system for transformation into the desired C2-site selective aminated product 37a in 58% yield with oxidation of the benzomorpholine group to 4H-benzo[b] [1,4]oxazine. Based on controlled experiments, the authors proposed that the amination reaction may undergo a process of radical-radical crosscoupling between the phenoxyl radical 39 and the N-radical 40.

Scheme 7.
Copper-catalyzed C2-site functionalization of p-aminophenols with arylamines. In 2022, Zhao et al. [24] reported a copper-catalyzed C2-site selective amination of free p-aminophenol derivatives 35 with arylamines 36 under mild conditions, using air as a terminal oxidant, and a variety of C2-site functional aminophenol derivatives 37 were obtained with 39-78% yields (Scheme 7). Interestingly, the para-benzomorpholine substituted phenol was also compatible with the reaction system for transformation into the desired C2-site selective aminated product 37a in 58% yield with oxidation of the benzomorpholine group to 4H-benzo[b] [1,4]oxazine. Based on controlled experiments, the authors proposed that the amination reaction may undergo a process of radical-radical crosscoupling between the phenoxyl radical 39 and the N-radical 40. Scheme 7. Copper-catalyzed C2-site functionalization of p-aminophenols with arylamines. Scheme 7. Copper-catalyzed C2-site functionalization of p-aminophenols with arylamines.

Co-Catalyzed C-H Bond Functionalization
In 2018, Khakyzadeh, Zolfigol, and co-workers [25] disclosed a Co(II)-catalyzed regioselective synthesis of 2-(aryl/alkylthio)phenols 44 via formal C-H bond functionalization of free phenols 42 with aryl/alkyl thiols 43 using acetic anhydride as the directing group under mild conditions. A variety of 2-(aryl/alkylthio)phenols 44 were obtained with moderate to excellent yields (Scheme 8). In addition, 2-naphthol and 1-naphthol were also compatible with this reaction system. Later, this reaction was further developed through Fe 3 O 4 @SiO 2 -UT@Co(II), using pivalic anhydride as the directing group, by Khaef et al. [26]. In fact, the two reactions were stepwise processes. By introducing directing groups to protect the hydroxyl group, the ortho-C-H functionalization of phenol was achieved. Finally, 2-(aryl/alkylthio)phenols were obtained by an acidic hydrolysis strategy. Depending on the control experiment, both thiolation reactions may undergo a process of free radicals 45.
Fe3O4@SiO2-UT@Co(II), using pivalic anhydride as the directing group, by Khaef et al. [26]. In fact, the two reactions were stepwise processes. By introducing directing groups to protect the hydroxyl group, the ortho-C-H functionalization of phenol was achieved. Finally, 2-(aryl/alkylthio)phenols were obtained by an acidic hydrolysis strategy. Depending on the control experiment, both thiolation reactions may undergo a process of free radicals 45. In 2019, a Cobalt(II)[salen]-catalyzed selective aerobic oxidative cross-coupling of electron-rich free phenols 46 with 2-naphthols 47 was developed by the Pappo group [27] in a recyclable 1,1,1,3,3,3-hexafluoropropan-2-ol (HFIP) solvent. A variety of nonsymmetric biphenols 48 were obtained with 40-92% yields under mild waste-free conditions by a selectivity-driven catalyst design approach. However, the nonsymmetric biphenols 50, 51 and 52 were obtained by the para-C-H bond functionalization rather than ortho-positions of free phenols with 2-naphthols (Scheme 9). Besides, a strong electron-withdrawing group such as ester was not compatible with the current system, failing to afford the corresponding biaryl coupling product. Detailed control experiments and kinetic studies suggested that a liberated phenoxyl radical 53 and a ligated 2-naphthoxyl radical 54 were involved in the reaction pathway. In 2019, a Cobalt(II)[salen]-catalyzed selective aerobic oxidative cross-coupling of electron-rich free phenols 46 with 2-naphthols 47 was developed by the Pappo group [27] in a recyclable 1,1,1,3,3,3-hexafluoropropan-2-ol (HFIP) solvent. A variety of nonsymmetric biphenols 48 were obtained with 40-92% yields under mild waste-free conditions by a selectivity-driven catalyst design approach. However, the nonsymmetric biphenols 50, 51 and 52 were obtained by the para-C-H bond functionalization rather than ortho-positions of free phenols with 2-naphthols (Scheme 9). Besides, a strong electron-withdrawing group such as ester was not compatible with the current system, failing to afford the corresponding biaryl coupling product. Detailed control experiments and kinetic studies suggested that a liberated phenoxyl radical 53 and a ligated 2-naphthoxyl radical 54 were involved in the reaction pathway.

Electrochemical/Photochemical C-H Bond Functionalization
Electrochemistry/photochemistry has been a powerful synthetic tool for organic chemistry [28][29][30][31][32][33]. Compared with the chemical methods of the C-H functionalization of free phenols, the electrochemistry/photochemistry method uses electrons/light as a renewable and environmentally friendly reagent to replace the metal catalysts and the stoichiometric amounts of oxidant in the C-H functionalization reactions. Undoubtedly, the electrochemical/photochemical C-H bond functionalization of free phenols has attracted increasing attention from organic chemists.
The highly efficient arylation of benzothiophenes 55 with free phenols 56 was realized by the Waldvogel group [34] under exogenous oxidant-free and metal catalyst-free electrochemical oxidation conditions in 2018. The 2-or 3-(hydroxyphenyl)benzo[b]thiophenes 57 were regioselective, obtained with 38-88% yields in an undivided cell equipped with a BDD anode and a BDD cathode at a constant current of 5.2 mA/cm 2 , using

Electrochemical/Photochemical C-H Bond Functionalization
Electrochemistry/photochemistry has been a powerful synthetic tool for organic chemistry [28][29][30][31][32][33]. Compared with the chemical methods of the C-H functionalization of free phenols, the electrochemistry/photochemistry method uses electrons/light as a renewable and environmentally friendly reagent to replace the metal catalysts and the stoichiometric amounts of oxidant in the C-H functionalization reactions. Undoubtedly, the electrochemical/photochemical C-H bond functionalization of free phenols has attracted increasing attention from organic chemists. The highly efficient arylation of benzothiophenes 55 with free phenols 56 was realized by the Waldvogel group [34] under exogenous oxidant-free and metal catalyst-free electrochemical oxidation conditions in 2018. The 2-or 3-(hydroxyphenyl)benzo[b]thiophenes 57 were regioselective, obtained with 38-88% yields in an undivided cell equipped with a BDD anode and a BDD cathode at a constant current of 5.2 mA/cm 2 , using Bu 3 NMeO 3 SOMe as the electrolyte at RT or 40 • C (Scheme 10). Later, Yue et al. [35] developed an electrochemical oxidative C-H/C-H coupling of free phenols 58 with 3-phenylbenzothiophenes 59, which delivered highly tunable benzothiophene derivatives 60 with 33-89% yields in an undivided cell equipped with a RVC anode and a Pt plate cathode at a constant current of 10 mA, using n-Bu 4 NPF 6 as the electrolyte at 25 • C under the protection of nitrogen (Scheme 10). Both monofunctional and bifunctional groups could be achieved in this electrochemical oxidation reaction under external oxidant-and catalyst-free conditions. However, the thiophene and benzothiophene were not compatible with the reaction system. Control experiments suggested that a cross-coupling process between the p-methoxylphenol radical 62 and the 3-phenylbenzothiophene radical cation 63 might be involved in this electrochemical transformation. In 2018, the Lei group [36] reported an electrochemical oxidative C-H amination of free phenols 65 with phenothiazine derivatives 66 under metal catalyst-and chemical oxidant-free conditions. A host of N-aryl phenothiazines 67 were obtained with 17-93% yields in an undivided cell equipped with a graphite rod anode and a nickel plate cathode  In 2018, the Lei group [36] reported an electrochemical oxidative C-H amination of free phenols 65 with phenothiazine derivatives 66 under metal catalyst-and chemical oxidantfree conditions. A host of N-aryl phenothiazines 67 were obtained with 17-93% yields in an undivided cell equipped with a graphite rod anode and a nickel plate cathode at a constant current of 7 mA, using n-Bu 4 NBF 4 as the electrolyte at room temperature under nitrogen protection (Scheme 11). Notably, 2-naphthol and 1-naphthol were also compatible with this reaction system, the products of the ortho-C-H bond functionalization of 2-naphthol and the para-C-H bond functionalization of 1-naphthol were obtained in 89% yield and 88% yield, respectively. Besides, the electro-oxidative double C-H amination of ortho-substituted phenols was also observed in this reaction. Based on cyclic voltammetry (CV) experiments, the authors proposed that the electrocatalytic amination reaction involved the oxidation of amine substrate to generate the radical cation 70. Subsequently, Feng et al. [37] reported an electro-oxidative and regioselective C-H azolation of free phenols 72 under external oxidant-free conditions with H2 evolution. The electrosynthesis proceeds in a simple undivided cell equipped with two platinum electrodes at a constant potential of 2.5 V, using n-Bu4NPF6 as an electrolyte at room temperature under the protection of nitrogen. Moreover, the para-methoxyl aniline derivatives were successfully employed as the reaction substrate under standard conditions. Detailed experiments and cyclic voltammetry studies suggested that a radical coupling process between the carbon radical 76 and the nitrogen-centered radical 77 might be involved in this electrochemical transformation (Scheme 12).
Subsequently, Feng et al. [37] reported an electro-oxidative and regioselective C-H azolation of free phenols 72 under external oxidant-free conditions with H 2 evolution. The electrosynthesis proceeds in a simple undivided cell equipped with two platinum electrodes at a constant potential of 2.5 V, using n-Bu 4 NPF 6 as an electrolyte at room temperature under the protection of nitrogen. Moreover, the para-methoxyl aniline derivatives were successfully employed as the reaction substrate under standard conditions. Detailed experiments and cyclic voltammetry studies suggested that a radical coupling process between the carbon radical 76 and the nitrogen-centered radical 77 might be involved in this electrochemical transformation (Scheme 12). In 2019, Sun, Zeng, and co-workers [38] reported a selective electro-oxidative crosscoupling of different free phenols 79 and naphthols 80 using tri(p-bromophenyl)amine(TBPA) 82 as a redox mediator. A variety of non-symmetric biphenols 81 were obtained with 27-83% yields in an H-type divided cell equipped with a Pt plate anode and a graphite plate cathode at 0.8 V vs. Ag/AgNO3, using LiClO4 as the electrolyte (Scheme 13). When 2,6-dimethoxyphenol 84 was used as a substrate, the para-C-H bond functionalization of 2,6-dimethoxyphenol was observed. Based on the CV analyses, the authors proposed that this cross-coupling reaction started from an electrochemical oxidation of TBPA 82 at the surface of anode to generate its cation radical TBPA +• 83. Then, homogeneous electron transfer of TBPA +• with 2,6-dimethoxyphenol 84 formed the cation radical 85, which underwent nucleophilic addition with 2-naphthol. In 2019, Sun, Zeng, and co-workers [38] reported a selective electro-oxidative crosscoupling of different free phenols 79 and naphthols 80 using tri(p-bromophenyl)amine(TBPA) 82 as a redox mediator. A variety of non-symmetric biphenols 81 were obtained with 27-83% yields in an H-type divided cell equipped with a Pt plate anode and a graphite plate cathode at 0.8 V vs. Ag/AgNO 3 , using LiClO 4 as the electrolyte (Scheme 13). When 2,6-dimethoxyphenol 84 was used as a substrate, the para-C-H bond functionalization of 2,6-dimethoxyphenol was observed. Based on the CV analyses, the authors proposed that this cross-coupling reaction started from an electrochemical oxidation of TBPA 82 at the surface of anode to generate its cation radical TBPA +• 83. Then, homogeneous electron transfer of TBPA +• with 2,6-dimethoxyphenol 84 formed the cation radical 85, which underwent nucleophilic addition with 2-naphthol.
Afterwards, the Waldvogel group [39] further developed an electrochemical dehydrogenative coupling reaction of free phenols 86 carrying electron-withdrawing groups using DIPEA as an additive. The homo-coupling reaction was conducted in an undivided cell equipped with BDD electrodes at a constant current of 5 mA/cm 2 , lacking a supporting electrolyte at room temperature. Besides, this method could be extended to cross-coupling reactions with naphthalenes to form biaryls and precursors for dibenzofurans. Nevertheless, the moderate yield of the products was the drawback of this method. Control experiments suggested that the C-C coupling reaction may involve the coupling of free radicals (Scheme 14).
In 2021, Wen, Yang, and co-workers [40] reported an electrochemical in situ oxidative sulfonylation of free phenols 88 with sulfinic acids 89 to give sulfonylated hydroquinones 90 with 32-95% yields in an undivided cell equipped with a graphite rod anode and a platinum plate cathode at a constant current of 10 mA, using LiClO 4 as the electrolyte (Scheme 15). When the applicable scope of phenols with different substituents was explored under standard conditions, the regional selectivity of the sulfonylated reaction is slightly poor, due to the steric and electronic effect of the phenols. Besides, the aliphatic sulfinic acids were not compatible with this reaction system. Based on controlled experiments, two postulated reaction pathways were involved in sulfonylated reactions, which were radical-radical cross-coupling between the sulfone radical 98 and the carbon radical 95 or the anodic oxidation of hydroquinone to form benzoquinone 92 followed by Michael addition with sulfinic acids. Afterwards, the Waldvogel group [39] further developed an electrochemical dehydrogenative coupling reaction of free phenols 86 carrying electron-withdrawing groups using DIPEA as an additive. The homo-coupling reaction was conducted in an undivided cell equipped with BDD electrodes at a constant current of 5 mA/cm 2 , lacking a supporting electrolyte at room temperature. Besides, this method could be extended to cross-coupling reactions with naphthalenes to form biaryls and precursors for dibenzofurans. Nevertheless, the moderate yield of the products was the drawback of this method. Control experiments suggested that the C-C coupling reaction may involve the coupling of free radicals (Scheme 14).

Scheme 14.
Electrochemical C-H functionalization of phenols with electron-withdrawing groups.
In 2021, Wen, Yang, and co-workers [40] reported an electrochemical in situ oxidative sulfonylation of free phenols 88 with sulfinic acids 89 to give sulfonylated hydroquinones 90 with 32-95% yields in an undivided cell equipped with a graphite rod anode and a platinum plate cathode at a constant current of 10 mA, using LiClO4 as the electrolyte (Scheme 15). When the applicable scope of phenols with different substituents was explored under standard conditions, the regional selectivity of the sulfonylated reaction is Afterwards, the Waldvogel group [39] further developed an electrochemical dehydrogenative coupling reaction of free phenols 86 carrying electron-withdrawing groups using DIPEA as an additive. The homo-coupling reaction was conducted in an undivided cell equipped with BDD electrodes at a constant current of 5 mA/cm 2 , lacking a supporting electrolyte at room temperature. Besides, this method could be extended to cross-coupling reactions with naphthalenes to form biaryls and precursors for dibenzofurans. Nevertheless, the moderate yield of the products was the drawback of this method. Control experiments suggested that the C-C coupling reaction may involve the coupling of free radicals (Scheme 14). In 2021, Wen, Yang, and co-workers [40] reported an electrochemical in situ oxidative sulfonylation of free phenols 88 with sulfinic acids 89 to give sulfonylated hydroquinones 90 with 32-95% yields in an undivided cell equipped with a graphite rod anode and a platinum plate cathode at a constant current of 10 mA, using LiClO4 as the electrolyte (Scheme 15). When the applicable scope of phenols with different substituents was explored under standard conditions, the regional selectivity of the sulfonylated reaction is slightly poor, due to the steric and electronic effect of the phenols. Besides, the aliphatic Scheme 14. Electrochemical C-H functionalization of phenols with electron-withdrawing groups.
In 2021, Li and co-workers [41] reported a catalyst-free visible-light-driven ortho-C(sp 2 )-H arylation of free phenols 100 with arylbromides 99 under irradiation of a blue LED or natural sunlight. A series of 2-arylated phenols 101, including the electron-donating and electron-withdrawing groups, were obtained with 38-73% yields at room temperature (Scheme 16). However, anisole was not successfully used in the arylation reaction to afford the corresponding product, and heteroaryl halides were also incompatible with this reaction system. Based on controlled experiments, the authors proposed that the reaction proceeded via visible light photoexcitation of an EDA complex 102 between an aryl bromide and a phenolate ion.
Subsequently, a photocatalytic oxidative coupling of free phenols 103 with alkenylphenols was reported, using a recyclable heterogeneous titanium dioxide photocatalyst in air and visible light, by Kozlowski group [42]. When 2,6-dimethylphenol and 2-isopropyl-5-methylphenol were used as substrates in homo-coupling reaction, the para-C-H bond functionalization was observed. The incomplete conversion with moderate yields of the desired products limited the application of the reaction. The bare leak of the phenol hydroxyl group played a key role in the reaction, since anisole was incompatible with this reaction system. Depending on the control experiment, the authors proposed that this reaction may involve the TiO 2 -phenol complex 105, which was activated through a ligand to metal charge transfer effect (LMCT) (Scheme 17).
Molecules 2023, 28, x FOR PEER REVIEW 13 of 27 sulfinic acids were not compatible with this reaction system. Based on controlled experiments, two postulated reaction pathways were involved in sulfonylated reactions, which were radical-radical cross-coupling between the sulfone radical 98 and the carbon radical 95 or the anodic oxidation of hydroquinone to form benzoquinone 92 followed by Michael addition with sulfinic acids. In 2021, Li and co-workers [41] reported a catalyst-free visible-light-driven ortho-C(sp 2 )-H arylation of free phenols 100 with arylbromides 99 under irradiation of a blue LED or natural sunlight. A series of 2-arylated phenols 101, including the electron-donating and electron-withdrawing groups, were obtained with 38-73% yields at room temperature (Scheme 16). However, anisole was not successfully used in the arylation reaction to afford the corresponding product, and heteroaryl halides were also incompatible with this reaction system. Based on controlled experiments, the authors proposed that the reaction proceeded via visible light photoexcitation of an EDA complex 102 between an aryl bromide and a phenolate ion. were radical-radical cross-coupling between the sulfone radical 98 and the carbon radical 95 or the anodic oxidation of hydroquinone to form benzoquinone 92 followed by Michael addition with sulfinic acids.

Scheme 15. Electrochemical C-H functionalization of phenols with sulfinic acids.
In 2021, Li and co-workers [41] reported a catalyst-free visible-light-driven ortho-C(sp 2 )-H arylation of free phenols 100 with arylbromides 99 under irradiation of a blue LED or natural sunlight. A series of 2-arylated phenols 101, including the electron-donating and electron-withdrawing groups, were obtained with 38-73% yields at room temperature (Scheme 16). However, anisole was not successfully used in the arylation reaction to afford the corresponding product, and heteroaryl halides were also incompatible with this reaction system. Based on controlled experiments, the authors proposed that the reaction proceeded via visible light photoexcitation of an EDA complex 102 between an aryl bromide and a phenolate ion. Subsequently, a photocatalytic oxidative coupling of free phenols 103 with alkenylphenols was reported, using a recyclable heterogeneous titanium dioxide photocatalyst in air and visible light, by Kozlowski group [42]. When 2,6-dimethylphenol and 2-isopropyl-5-methylphenol were used as substrates in homo-coupling reaction, the para-C-H bond functionalization was observed. The incomplete conversion with moderate yields of the desired products limited the application of the reaction. The bare leak of the phenol hydroxyl group played a key role in the reaction, since anisole was incompatible with this reaction system. Depending on the control experiment, the authors proposed that this reaction may involve the TiO2-phenol complex 105, which was activated through a ligand to metal charge transfer effect (LMCT) (Scheme 17).

Scheme 17.
Photochemical C-H functionalization of free phenols with alkenylphenols.

Others
In 2018, Li and co-workers [43] reported a B(C 6 F 5 ) 3 -catalyzed hydroarylation of free phenols 106 with 1,3-dienes 107 under mild reaction conditions. A series of structurally diverse ortho-allyl phenols 108 were obtained with 32-91% yields. When the phenol was applied as the substrate, a small quantity of para-allylation products was obtained. Moreover, 1,4-dimethoxybenzene was not successfully used in the hydroarylation reaction to afford the corresponding product. A preliminary mechanistic study suggested that the hydroarylation reaction took place via a borane-promoted protonation/Friedel-Crafts pathway, which involved a π-complex of carbocation-anion contact ionpairs 109 (Scheme 18). Subsequently, this method was developed by Zhou et al. to realize a B(C 6 F 5 ) 3 catalyzed hydroarylation of free phenols 110 with terminal alkynes 111 at room temperature (Scheme 18) [44]. As compared with hydroarylation of 1,3-dienes, the difference was that when 2,6-disubstituted free phenol was employed as the substrate, no para-hydroarylation product was observed in the hydroarylation of terminal alkynes with free phenols. Scheme 17. Photochemical C-H functionalization of free phenols with alkenylphenols.

Others
In 2018, Li and co-workers [43] reported a B(C6F5)3-catalyzed hydroarylation of free phenols 106 with 1,3-dienes 107 under mild reaction conditions. A series of structurally diverse ortho-allyl phenols 108 were obtained with 32-91% yields. When the phenol was applied as the substrate, a small quantity of para-allylation products was obtained. Moreover, 1,4-dimethoxybenzene was not successfully used in the hydroarylation reaction to afford the corresponding product. A preliminary mechanistic study suggested that the hydroarylation reaction took place via a borane-promoted protonation/Friedel-Crafts pathway, which involved a π-complex of carbocation-anion contact ionpairs 109 (Scheme 18). Subsequently, this method was developed by Zhou et al. to realize a B(C6F5)3 catalyzed hydroarylation of free phenols 110 with terminal alkynes 111 at room temperature (Scheme 18) [44]. As compared with hydroarylation of 1,3-dienes, the difference was that when 2,6-disubstituted free phenol was employed as the substrate, no para-hydroarylation product was observed in the hydroarylation of terminal alkynes with free phenols. Scheme 18. B(C 6 F 5 ) 3 -catalyzed hydroarylation of free phenols with 1,3-dienes or terminal alkynes.
In 2020, Lei's group [45] reported a K 2 S 2 O 8 -induced azolation of electron-rich free phenol derivatives 114 with pyrazoles 115 under catalyst-free conditions. A variety of N-arylazoles 116 bearing the electrondonating groups were obtained with 20-76% yields via oxidant-induced strategy. Detailed experiment studies suggested that a radical coupling process between the N-centered radical 117 and the C-centered radical 118 might be involved in this azolation transformation, which was generated by the oxidation of K 2 S 2 O 8 (Scheme 19).
In 2021, Liu and co-workers [46] reported a Brønsted acid catalyzed chemo-and orthoselective aminomethylation of free phenols 120 with N,O-acetals 121 under mild conditions. Various aminomethylated phenol products 122 were obtained with 42-97% yields. The high ortho-selectivity was attributed to the formation of an intermediate 123 via the interaction of CF 3 COOH with the free phenol (Scheme 20). Later, Zhou et al. [47] developed an aqueous C-H ortho-aminomethylation of free phenols 124 with trifluoroborates 125 by iodine catalysis, affording various functionalized phenol derivatives 126 in 20-98% yields. Based on controlled experiments, the authors proposed that the aminomethyl radical intermediate 127 was involved in the reaction pathway by oxidation of the hypoiodous acid (Scheme 20).
In 2020, Lei's group [45] reported a K2S2O8 -induced azolation of electron-rich free phenol derivatives 114 with pyrazoles 115 under catalyst-free conditions. A variety of Narylazoles 116 bearing the electrondonating groups were obtained with 20-76% yields via oxidant-induced strategy. Detailed experiment studies suggested that a radical coupling process between the N-centered radical 117 and the C-centered radical 118 might be involved in this azolation transformation, which was generated by the oxidation of K2S2O8 (Scheme 19).

C3-Functionalization
The meta functionalization of free phenols is challenging because the phenolic hydroxyl group can not only activate the aromatic ring for aromatic electrophilic substitution, but also guide its ortho or para-substitution [48][49][50]. Besides, the meta-sites of phenol are not easily activated by metal chelation [51,52]. As a result, the meta-C-H functionalization of free phenols could not be achieved via existing methods based on conventional C-H functionalization, electrophilic aromatic substitution, or oxidative coupling. Recently, Senior et al. [53] reported a meta-selective C-H arylation of polysubstituted free phenols 130 via regiodiversion of electrophilic aromatic substitution. This method achieved the meta-selective C-H arylation of sterically congested phenols through a Bi(V)mediated electrophilic arylation and a subsequent aryl migration/rearomatization. A variety of the products of the meta-selective C-H arylation of phenols 135, including the electron-donating and electron-withdrawing groups, were obtained in excellent yields. A preliminary mechanistic study suggested that this reaction involved a phenonium ion intermediate 133 (Scheme 21).

C3-Functionalization
The meta functionalization of free phenols is challenging because the phenolic hydroxyl group can not only activate the aromatic ring for aromatic electrophilic substitution, but also guide its ortho or para-substitution [48][49][50]. Besides, the meta-sites of phenol are not easily activated by metal chelation [51,52]. As a result, the meta-C-H functionalization of free phenols could not be achieved via existing methods based on conventional C-H functionalization, electrophilic aromatic substitution, or oxidative coupling. Recently, Senior et al. [53] reported a meta-selective C-H arylation of polysubstituted free phenols 130 via regiodiversion of electrophilic aromatic substitution. This method achieved the meta-selective C-H arylation of sterically congested phenols through a Bi(V)-mediated electrophilic arylation and a subsequent aryl migration/rearomatization. A variety of the products of the meta-selective C-H arylation of phenols 135, including the electron-donating and electron-withdrawing groups, were obtained in excellent yields. A preliminary mechanistic study suggested that this reaction involved a phenonium ion intermediate 133 (Scheme 21). achieved the meta-selective C-H arylation of sterically congested phenols through a Bi(V)mediated electrophilic arylation and a subsequent aryl migration/rearomatization. A variety of the products of the meta-selective C-H arylation of phenols 135, including the electron-donating and electron-withdrawing groups, were obtained in excellent yields. A preliminary mechanistic study suggested that this reaction involved a phenonium ion intermediate 133 (Scheme 21).

C4-Functionalization
The electron-donating hydroxyl group and the reduced steric of C4 relative to either the C2 or the C6 of free phenols are capable of promoting the para-selective C-H functionalization of free phenols. Here, we introduced the para-selective C-H functionalization of free phenols according to metal catalysis, electrocatalysis, and other methods.

Metal-Catalyzed C-H Bond Functionalization of Free Phenol
In 2018, Bhanage and co-workers [54] reported a palladium-catalyzed aerobic oxidative carbonylation of a C-H bond of free phenols 136 for the synthesis of p-hydroxybenzoates 137 in 50-76% yields using molecular oxygen as a terminal oxidant. The substrates bearing the electron-withdrawing meta-nitro, meta-trifluoromethyl groups on phenol were not compatible with this reaction system and no corresponding products were observed. Besides, p-cresol with methanol also failed to react under the optimized reaction conditions. Based on controlled experiments, the authors proposed that the carbonylation reaction involved the in-situ production of an intermediate 4-iodophenol 138 that subsequently underwent the nucleophilic attack of alcohol to offered p-hydroxybenzoate 137 via reductive elimination of palladium metal (Scheme 22).
Later, a gold-catalyzed highly chemo-and regioselective C-H bond functionalization of free phenols 142 with haloalkynes 143 was developed at room temperature by Hashmi's group [55]. A series of the products of para-C-H functionalization instead of OH-additions 144 were obtained in good to excellent regio-selectivity and diastereoselectivity, which was attributed to the catalyst and the base-free condition in this reaction. When the preferred position was blocked, the ortho-C-H functionalization of free phenols was feasible. A preliminary mechanistic study suggested that the gold catalyst directly coordinated the chloroalkyne carbon, which formed the more stable π-activated alkyne 145/vinylcation 146. Then, the C-4 position of free phenols attacked the highly electrophilic alkyne instead of O-H insertion to generate β-haloalkenes 144 (Scheme 23).
In 2021, the Liu group [56] reported a regiospecific and site-selective C-H allylation of free phenols 148 with vinyldiazo compounds 149 catalyzed by In(OTf) 3 . A series of phenol-allylation products instead of OH-additions 151 were obtained with 50-99% yields (Scheme 24). The reactions of aryl substituted vinyldiazoacetates with phenols provided the para-C-H allylation products, but alkyl-substituted vinyldiazoacetates transformed the ortho-selective-C-H allylation products under the standard catalytic conditions. Based on controlled experiments, the authors proposed that this allylation reaction involved a carbene intermediate 150, which was generated during the reaction process by In(OTf) 3 releasing of N 2 .
In 2018, Bhanage and co-workers [54] reported a palladium-catalyzed aerobic oxidative carbonylation of a C-H bond of free phenols 136 for the synthesis of p-hydroxybenzoates 137 in 50-76% yields using molecular oxygen as a terminal oxidant. The substrates bearing the electron-withdrawing meta-nitro, meta-trifluoromethyl groups on phenol were not compatible with this reaction system and no corresponding products were observed. Besides, p-cresol with methanol also failed to react under the optimized reaction conditions. Based on controlled experiments, the authors proposed that the carbonylation reaction involved the in-situ production of an intermediate 4-iodophenol 138 that subsequently underwent the nucleophilic attack of alcohol to offered p-hydroxybenzoate 137 via reductive elimination of palladium metal (Scheme 22).

Electrochemical C-H Bond Functionalization
Waldvogel's group [57] reported an efficient electrochemical synthesis by dehydrogenative coupling of free 2,6-or 2,5-substituted phenols under metal catalyst-and oxidant-free conditions in 2019. A variety of the desired 4,4 -biphenols 154 were obtained with 10-77% yields by anodic dehydrogenative cross-and homo-coupling in an undivided beaker-type cell equipped with two boron-doped diamond (BDD) electrodes at a constant current of 5.7 mA/cm 2 , using Bu 3 NMeO 3 SOMe as the electrolyte in 1,1,1,3,3,3-hexafluoropropan-2-ol with 0-6 vol.% water (Scheme 25). A preliminary mechanistic study suggested that this reaction involved a radical intermediate produced by the anodizing of the phenol at the anode, which was subsequently trapped by the phenolic component.
In 2022, Banerjee and co-workers [58] developed an efficient electrochemical approach to the Ritter-type reaction at the C(sp 2 )-H of free phenols 155 in the presence of acetonitrile 156 for the direct synthesis of paracetamol 157 under exogenous oxidant-and catalyst-free conditions. The amination reaction was conducted in an undivided cell equipped with a graphite anode and a nickel cathode at a constant current of 6.0 mA, using n-Bu 4 NPF 6 as the electrolyte at room temperature (Scheme 26). The substrate range of this reaction was mainly free phenol derivatives, and the naphthols (α and β) and benzyl cyanide were not compatible with these reaction conditions. Based on the results of this reaction, the electrochemical C-H amination reaction was proposed to initiate via anodic oxidation of the phenol to generate carbocation 158, which underwent classical Ritter steps in the presence of acetonitrile 156 to deliver the desired product 157.
Later, a gold-catalyzed highly chemo-and regioselective C-H bond functionalization of free phenols 142 with haloalkynes 143 was developed at room temperature by Hashmi's group [55]. A series of the products of para-C-H functionalization instead of OH-additions 144 were obtained in good to excellent regio-selectivity and diastereoselectivity, which was attributed to the catalyst and the base-free condition in this reaction. When the preferred position was blocked, the ortho-C-H functionalization of free phenols was feasible. A preliminary mechanistic study suggested that the gold catalyst directly coordinated the chloroalkyne carbon, which formed the more stable π-activated alkyne 145/vinylcation 146. Then, the C-4 position of free phenols attacked the highly electrophilic alkyne instead of O-H insertion to generate β-haloalkenes 144 (Scheme 23). In 2021, the Liu group [56] reported a regiospecific and site-selective C-H allylation of free phenols 148 with vinyldiazo compounds 149 catalyzed by In(OTf)3. A series of phenol-allylation products instead of OH-additions 151 were obtained with 50-99% yields (Scheme 24). The reactions of aryl substituted vinyldiazoacetates with phenols provided the para-C-H allylation products, but alkyl-substituted vinyldiazoacetates transformed the ortho-selective-C-H allylation products under the standard catalytic conditions. Based on controlled experiments, the authors proposed that this allylation reaction involved a carbene intermediate 150, which was generated during the reaction process by In(OTf)3 releasing of N2.

Electrochemical C-H Bond Functionalization
Waldvogel's group [57] reported an efficient electrochemical synthesis by dehydrogenative coupling of free 2,6-or 2,5-substituted phenols under metal catalyst-and oxidant-free conditions in 2019. A variety of the desired 4,4′-biphenols 154 were obtained with 10-77% yields by anodic dehydrogenative cross-and homo-coupling in an undivided beaker-type cell equipped with two boron-doped diamond (BDD) electrodes at a constant current of 5.7 mA/cm 2 , using Bu3NMeO3SOMe as the electrolyte in 1,1,1,3,3,3hexafluoropropan-2-ol with 0-6 vol.% water (Scheme 25). A preliminary mechanistic study suggested that this reaction involved a radical intermediate produced by the anodizing of the phenol at the anode, which was subsequently trapped by the phenolic component.

Electrochemical C-H Bond Functionalization
Waldvogel's group [57] reported an efficient electrochemical synthesis by dehydrogenative coupling of free 2,6-or 2,5-substituted phenols under metal catalyst-and oxidant-free conditions in 2019. A variety of the desired 4,4′-biphenols 154 were obtained with 10-77% yields by anodic dehydrogenative cross-and homo-coupling in an undivided beaker-type cell equipped with two boron-doped diamond (BDD) electrodes at a constant current of 5.7 mA/cm 2 , using Bu3NMeO3SOMe as the electrolyte in 1,1,1,3,3,3hexafluoropropan-2-ol with 0-6 vol.% water (Scheme 25). A preliminary mechanistic study suggested that this reaction involved a radical intermediate produced by the anodizing of the phenol at the anode, which was subsequently trapped by the phenolic component. Recently, the Banerjee group [59] further developed an electrochemical sulfinylation of free phenols 162 with sulfides 163 under catalyst-and oxidant-free conditions. The aromatic sulfoxides 164 were obtained with 38-65% yields in an undivided cell equipped with a graphite anode and a nickel cathode at a constant current of 15 mA, using n-Bu4NPF6 as the electrolyte at room temperature (Scheme 27). The phenols bearing the electron-withdrawing groups such as nitro, ester, and aldehyde, were unsuccessfully employed as the reaction substrates under standard conditions. Control experiments suggested that the electrochemical sulfonated reaction was proposed to initiate via the anodic oxidation of phenol to generate carbocation, which was then attacked by the nucleophilic sulfide to generate the desired product.

Others
In 2020, Procter and co-workers [60] revealed an efficient transition-metal free C-H/C-H-type cross-coupling of free phenols 166 with benzothiophenes 165 to form C2/C3 arylated benzothiophenes 167 with 34-95% yields in trifluoroacetic acid using TFAA as an activator. A variety of substrates, including C2-substituted benzothiophene S-oxides and C3-substituted benzothiophene S-oxides, were successfully used in the arylated reaction to realize the C-H bond functionalization of free phenols. However, when using 4- Recently, the Banerjee group [59] further developed an electrochemical sulfinylation of free phenols 162 with sulfides 163 under catalyst-and oxidant-free conditions. The aromatic sulfoxides 164 were obtained with 38-65% yields in an undivided cell equipped with a graphite anode and a nickel cathode at a constant current of 15 mA, using n-Bu 4 NPF 6 as the electrolyte at room temperature (Scheme 27). The phenols bearing the electronwithdrawing groups such as nitro, ester, and aldehyde, were unsuccessfully employed as the reaction substrates under standard conditions. Control experiments suggested that the electrochemical sulfonated reaction was proposed to initiate via the anodic oxidation of phenol to generate carbocation, which was then attacked by the nucleophilic sulfide to generate the desired product. Recently, the Banerjee group [59] further developed an electrochemical sulfinylation of free phenols 162 with sulfides 163 under catalyst-and oxidant-free conditions. The aromatic sulfoxides 164 were obtained with 38-65% yields in an undivided cell equipped with a graphite anode and a nickel cathode at a constant current of 15 mA, using n-Bu4NPF6 as the electrolyte at room temperature (Scheme 27). The phenols bearing the electron-withdrawing groups such as nitro, ester, and aldehyde, were unsuccessfully employed as the reaction substrates under standard conditions. Control experiments suggested that the electrochemical sulfonated reaction was proposed to initiate via the anodic oxidation of phenol to generate carbocation, which was then attacked by the nucleophilic sulfide to generate the desired product.

Others
In 2020, Procter and co-workers [60] revealed an efficient transition-metal free C-H/C-H-type cross-coupling of free phenols 166 with benzothiophenes 165 to form C2/C3 arylated benzothiophenes 167 with 34-95% yields in trifluoroacetic acid using TFAA as an activator. A variety of substrates, including C2-substituted benzothiophene S-oxides and C3-substituted benzothiophene S-oxides, were successfully used in the arylated reaction to realize the C-H bond functionalization of free phenols. However, when using 4-Scheme 27. Electrochemical sulfinylation of phenols with sulfides.

Others
In 2020, Procter and co-workers [60] revealed an efficient transition-metal free C-H/C-H-type cross-coupling of free phenols 166 with benzothiophenes 165 to form C2/C3 arylated benzothiophenes 167 with 34-95% yields in trifluoroacetic acid using TFAA as an activator. A variety of substrates, including C2-substituted benzothiophene S-oxides and C3-substituted benzothiophene S-oxides, were successfully used in the arylated reaction to realize the C-H bond functionalization of free phenols. However, when using 4-methoxyphenol as the substrate, the ortho-difunctionalization of 4-methoxyphenol was observed to give the corresponding product in 85% yield. Based on controlled experiments, the authors proposed that this reaction was initiated by reaction of the benzothiophene S-oxides with TFAA to give the activated sulfoxides 168, which could engage directly at the para-position of phenol to generate the corresponding products by a vinylogous Pummerer-type mechanism (Scheme 28).
Molecules 2023, 28, x FOR PEER REVIEW 21 of 27 methoxyphenol as the substrate, the ortho-difunctionalization of 4-methoxyphenol was observed to give the corresponding product in 85% yield. Based on controlled experiments, the authors proposed that this reaction was initiated by reaction of the benzothiophene S-oxides with TFAA to give the activated sulfoxides 168, which could engage directly at the para-position of phenol to generate the corresponding products by a vinylogous Pummerer-type mechanism (Scheme 28).
Later, a triflic acid-catalyzed chemo-and site-selective C-H bond functionalization of free phenols 170 with 1,3-dienes 169 was realized by Liu et al. [61] in 2020. A series of para-selective allyl phenols 171 were obtained with 40-88% yields under mild conditions in a site-selective manner. However, the ortho-selective allylic alkylation of phenols with 1,3-dienes were observed under standard conditions in this transformation, and the ortho-C-H bond allylic alkylation product was obtained with 40% yield when the p-cresol was employed as the substrate to react with diene. The authors proposed that this HOTf-catalyzed allylic alkylation involved an ion-pair 172 including allylic cation and triflate anion, which was pushed away by the phenolic hydroxyl, owing to its steric hindrance to giving the para-selective product (Scheme 29). Later, a triflic acid-catalyzed chemo-and site-selective C-H bond functionalization of free phenols 170 with 1,3-dienes 169 was realized by Liu et al. [61] in 2020. A series of para-selective allyl phenols 171 were obtained with 40-88% yields under mild conditions in a site-selective manner. However, the ortho-selective allylic alkylation of phenols with 1,3-dienes were observed under standard conditions in this transformation, and the ortho-C-H bond allylic alkylation product was obtained with 40% yield when the p-cresol was employed as the substrate to react with diene. The authors proposed that this HOTfcatalyzed allylic alkylation involved an ion-pair 172 including allylic cation and triflate anion, which was pushed away by the phenolic hydroxyl, owing to its steric hindrance to giving the para-selective product (Scheme 29).
Molecules 2023, 28, x FOR PEER REVIEW 21 of 27 methoxyphenol as the substrate, the ortho-difunctionalization of 4-methoxyphenol was observed to give the corresponding product in 85% yield. Based on controlled experiments, the authors proposed that this reaction was initiated by reaction of the benzothiophene S-oxides with TFAA to give the activated sulfoxides 168, which could engage directly at the para-position of phenol to generate the corresponding products by a vinylogous Pummerer-type mechanism (Scheme 28).
Later, a triflic acid-catalyzed chemo-and site-selective C-H bond functionalization of free phenols 170 with 1,3-dienes 169 was realized by Liu et al. [61] in 2020. A series of para-selective allyl phenols 171 were obtained with 40-88% yields under mild conditions in a site-selective manner. However, the ortho-selective allylic alkylation of phenols with 1,3-dienes were observed under standard conditions in this transformation, and the ortho-C-H bond allylic alkylation product was obtained with 40% yield when the p-cresol was employed as the substrate to react with diene. The authors proposed that this HOTf-catalyzed allylic alkylation involved an ion-pair 172 including allylic cation and triflate anion, which was pushed away by the phenolic hydroxyl, owing to its steric hindrance to giving the para-selective product (Scheme 29).

Ortho-Functionalization-Cyclization Process
There were also some examples in which the -OH group took part in further transformations. Due to the 1C,3O-bisnucleophilic reactivity, free phenols have been applied to a variety of [3 + n] cycloaddition reactions with biselectrophilic compounds for the synthesis of various heterocyclic compounds [62][63][64].
In 2019, Tang et al. [65] developed a recyclable nickel-catalyzed C-H/O-H dual functionalization of mandelic acids 173 with free phenols 174. Various of 3-aryl benzofuran-2((3H)-ones 175 were obtained with 31-97% yields under solvent-free conditions. The authors proposed a possible pathway for dual activation of phenols (Scheme 30). Intermediate 176 was generated from mandelic acid in the presence of Ni(OTf) 2 . Then, an inter-molecular Friedel-Crafts alkylation of 176 with phenol took place to give intermediate 177, which underwent intramolecular esterification to give the corresponding product 175. This method can be enlarged and applied to synthesize antioxidant Irganox HP-136 in an excellent yield.

Ortho-Functionalization-Cyclization Process
There were also some examples in which the -OH group took part in further transformations. Due to the 1C,3O-bisnucleophilic reactivity, free phenols have been applied to a variety of [3 + n] cycloaddition reactions with biselectrophilic compounds for the synthesis of various heterocyclic compounds [62][63][64].
In 2019, Tang et al. [65] developed a recyclable nickel-catalyzed C-H/O-H dual functionalization of mandelic acids 173 with free phenols 174. Various of 3-aryl benzofuran-2((3H)-ones 175 were obtained with 31-97% yields under solvent-free conditions. The authors proposed a possible pathway for dual activation of phenols (Scheme 30). Intermediate 176 was generated from mandelic acid in the presence of Ni(OTf)2. Then, an intermolecular Friedel-Crafts alkylation of 176 with phenol took place to give intermediate 177, which underwent intramolecular esterification to give the corresponding product 175. This method can be enlarged and applied to synthesize antioxidant Irganox HP-136 in an excellent yield.

Ortho-Functionalization-Cyclization Process
There were also some examples in which the -OH group took part in further transformations. Due to the 1C,3O-bisnucleophilic reactivity, free phenols have been applied to a variety of [3 + n] cycloaddition reactions with biselectrophilic compounds for the synthesis of various heterocyclic compounds [62][63][64].
In 2019, Tang et al. [65] developed a recyclable nickel-catalyzed C-H/O-H dual functionalization of mandelic acids 173 with free phenols 174. Various of 3-aryl benzofuran-2((3H)-ones 175 were obtained with 31-97% yields under solvent-free conditions. The authors proposed a possible pathway for dual activation of phenols (Scheme 30). Intermediate 176 was generated from mandelic acid in the presence of Ni(OTf)2. Then, an intermolecular Friedel-Crafts alkylation of 176 with phenol took place to give intermediate 177, which underwent intramolecular esterification to give the corresponding product 175. This method can be enlarged and applied to synthesize antioxidant Irganox HP-136 in an excellent yield. In 2020, Li et al. [66] developed a base promoted diastereoselective [3 + 3] cycloaddition reaction of 2-arylideneindan-1,3-diones 178 with free β-naphthols 179. Various functionalized pentacyclic indeno[1,2-b]chromen-(4bH)-ones 180 were synthesized with 47-99% yields under mild conditions (Scheme 31). Splenocyte cells were treated with the synthesized compounds, and cell viability was determined by CCK-8 assay. These tested compounds showed selective inhibitive activity against ConA-induced T-cell proliferation. Subsequently, the Ren group [67] reported a silver(I)-mediated cascade reaction of 2-(1-alkynyl)-2-alken-1-ones 181 with free 2-naphthols 182. A series of ortho-functionalization-cyclization 1,2-dihydronaphtho[2,1-b]furans 183 were obtained with 53-84% yields (Scheme 32). The controlled experiments indicated that the silver trifluoroacetate first coordinated with the triple bond of 2-(phenylethynyl)cyclohex-2-en-1-one to give the incomplex 184, which then formed furan intermediate 185. The naphthalen-2-ol attacked the intermediate 185 to afford furan compound 186 and regenerated silver trifluoroacetate. In the presence of AgTFA and oxygen, the furan ring in compound 186 was further oxidized to 2-buten-1,4-dione intermediate 187. Finally, the 1,2-dihydronaphtho[2,1-b]furan 183 was obtained through a highly regio-and diastereoselective oxa-Michael addition. In addition, there were some reactions in which C-H functionalization outside the original phenol ring. For example, in 2019, Yao group [68] reported a palladium-catalyzed remote 1,n-arylamination of unactivated terminal alkenes with aryl iodides and arylamines. In 2020, Wu's group [69] developed a quadruple C-H activation coupled to hydro functionalization and C-H silylation/borylation based on weakly coordinated palladium catalyst. The mechanisms of both reactions involved the coordination of phenol with palladium and activation of C-H bond outside the original phenol ring. In addition, there were some reactions in which C-H functionalization outside the original phenol ring. For example, in 2019, Yao group [68] reported a palladium-catalyzed remote 1,n-arylamination of unactivated terminal alkenes with aryl iodides and arylamines. In 2020, Wu's group [69] developed a quadruple C-H activation coupled to hydro functionalization and C-H silylation/borylation based on weakly coordinated palladium catalyst. The mechanisms of both reactions involved the coordination of phenol with palladium and activation of C-H bond outside the original phenol ring.

Conclusions
This review has described recent progress in regioselective C-H bond functionalization of free phenols, which are readily available chemical feedstocks in organic synthesis. We have identified a number of methodologies which have been made to overcome longstanding challenges of selectivity in the field of the C-H activation of free phenols without directing groups. These include the ortho-, meta-, and paraselective C-H functionalization of free phenols, which have been successfully achieved by transition-metal catalysis such as Cu, Co, Bi, Pd, Ag, Au and In, electrocatalysis, photocatalysis, and so on, leading to the productions of many useful functionalized phenols.
Although significant progress has been made, there are still some challenges to the regioselective C-H bond functionalization of free phenols, including as below: (1) there are few reaction types, especially the metaselective C-H functionalization of free phenols, which remains an important area for future development; (2) how to make proper use of electrocatalysis or photocatalysis to avoid the use of a lot of oxidants and chemical reagents, which will be more efficient and environmentally friendly in organic synthesis; (3) the asymmetric C-H bond functionalization of free phenols is rarely developed, which is a very interesting area of research. With regard to these challenges, we hope that the explanation of the regioselective C-H bond functionalization of free phenols in this review will provide useful guidance for further development methods for C-H activation of free phenols to proceed in efficient, simple, mild and environmentally friendly conditions.