Significant progress has been made in the field of Pd-catalyzed oxidative cyclization reactions using hypervalent iodine reagents, giving access to several oxygen-containing heterocycles. In 2010, Wang et al. developed a novel method for the construction of dihydrobenzofurans via Pd(OAc)₂-catalyzed hydroxyl group-directed C–H activation/C–O cyclization reaction in the presence of (diacetoxyiodo)benzene 1 as a terminal oxidant and promoted by base Li₂CO₃. Moreover, the scope of the reaction was extended to the preparation of important scaffolds such as spirocyclic dihydrobenzofurans (Wang X. et al., 2010).

Later, Gevorgyan's group demonstrated intramolecular silanol group-directed C–H oxygenation of phenoxy silanols 17 employing Pd(OPiv)₂ as catalyst and PhI(OAc)₂ 1 as an oxidant (Huang et al., 2011). This reaction involves the initial formation of cyclic silicon-protected catechols 18 which upon desilylation with TBAF/THF provides substituted catechols 19 (Scheme 1A). The plausible catalytic cycle involves initial coordination of Pd with silanols 17 to form palladacycle 20 accompanied by PIDA-mediated oxidation to forge Pd(IV)-intermediate 21. Next, intermediate 21 is transformed into acetoxylated intermediate 23 via reductive acetoxylation and regenerates back palladium catalyst. Finally, acid-catalyzed transesterification of 24 gives 25 which subsequently loose acetic acid to form cyclic silyl protected catechols 18 followed by subsequent desilylation with TBAF furnishes catechols 19. Further formation of products 22 through direct C–O reductive cyclization was eliminated based on ¹⁸O-labeling studies. Further reactions featured excellent site selectivity and broad substrates scope, particularly, electron-rich substrates reacted much faster and provided high yields. Another interesting work published by Gevorgyan's research group employing C–H oxygenation strategy is the convenient synthesis of oxasilacycles from substituted benzyl-silanols using combination of Pd(OAc)₂ and PhI(OAc)₂ 1 in PhCF₃ at 100°C (Huang et al., 2012).

Furthermore, Thompson et al. reported the preparation of cyclic ethers 27 via Pd-catalyzed oxime masked-alcohol directed dehydrogenative annulation of sp³ C–H bonds of substrates 26 using PhI(OAc)₂ 1 as an oxidant (Thompson et al., 2015). The reaction occurs selectively at the β-position and substrates 26 having primary, secondary, and tertiary hydroxyl group worked smoothly under the standard conditions (Scheme 1B). The reaction could proceed via C–H palladation, followed by oxidation of Pd to higher oxidation state species 28 and a subsequent intramolecular S_N2 reaction to form oxonium intermediate 29. Finally, cyclic ethers 27 were obtained through deprotonation or debenzylation and regenerate Pd-catalyst.

Yang et al. reported Pd-catalyzed intramolecular lactonization of α, α-disubstituted arylacetic acids 30 in the presence of PhI(OAc)₂ 1 to furnish a series of α, α-disubstituted benzofuran-2-ones 31 in variable yields (Yang et al., 2013). The catalytic system composed of Pd(OAc)₂ and the combination of NaOAc and CsOAc along with AgOAc as most effective bases (Scheme 2A). The authors proposed that C–H cleavage occurs via concerted metalation deprotonation to form six-membered palladacycle 32 which further undergoes oxidation and subsequent reductive elimination to afford 31. Similar catalytic C–H activation/C–O formation methods to construct functionalized benzofuranones (Cheng et al., 2013) and biaryl lactones (Li et al., 2013) were also developed employing acetyl-protected glycine (Ac-Gly-OH) as requisite ligand along with base KOAc in t-BuOH.

In 2016, Shi's group described a concise route to access γ-lactones 34 featuring Pd(II)-catalyzed PIP auxiliary-directed lactonization of unactivated methylene C(sp³)–H bonds using oxidant PIDA 1 (Liu and Shi, 2016). The lactonization of aliphatic acids 33 bearing various substituents on the alkyl chain proceeded remarkably well to furnish anticipated γ-lactones 34 in 32–77% yields (Scheme 2B). The probable mechanism for the lactonization of aliphatic acids 32 involves formation of five-membered palladacycle 35 through Pd-catalyzed C–H activation assisted by bidentate auxiliary. In the presence of PhI(OAc)₂ 1, palladacycle 35 underwent oxidation to give Pd(IV) intermediate 36 followed by ligand exchange to form 37 which finally undergoes reductive elimination to release target product 34 along with Pd(II) catalyst to complete the catalytic cycle (Scheme 11). Another path to generate lactone 34 is via direct S_N2-type attack by carboxylate group onto the Pd(IV)–C bond of 36 (Scheme 2B).

Over the years, C–H acyloxylation has made tremendous progress in transforming various unactivated sp² and sp³ hybridized C–H bonds into valuable C–O bonds using palladium catalysts and iodine(III) reagents as oxidants. This method provides a concise route for the introduction of valuable ester functionality on to the aromatic or aliphatic substrates under mild conditions. Several C(sp²)–H acyloxylation protocols have been developed employing Pd(OAc)₂/PhI(OAc)₂ 1 catalytic systems using a variety of directing groups such as pyrimidine (Gu et al., 2009), 8-aminoquinoline (Gou et al., 2009), oxime (Neufeldt and Sanford, 2010; Ren et al., 2015), pyridyldiisopropylsilyl (Chernyak et al., 2010; Gulevich et al., 2012), and 1,2,3-triazoles-pyridine (Ye et al., 2013).

Furthermore, a regioselective protocol featuring Pd(II)-catalyzed C–H benzoxylation of 2-arylpyridines 38 was performed by Zhang et al. affording mono-benzoxylation products 40 in moderate to excellent yields (Zhang et al., 2015). They employed easily accessible iodobenzene dibenzoate derivatives 39 as oxidants and sources of the benzoxyl group (Scheme 3). Furthermore, the present method was successfully applied for the benzoxylation of 2-thienyl pyridines to yield 3-benzoxylated thiophenes in high yields. The plausible mechanism proceeds via pyridyl-assisted C–H activation of substrates 38 with a palladium catalyst to form complex 41 which undergoes further oxidative addition with 39 to form high oxidation state complex 42. Finally, the reductive elimination of 42 gives desired product 40 and regenerates the palladium catalyst to complete the catalytic cycle.

Although substantial development has been accomplished in the Pd-catalyzed ligand-directed C–H oxygenation reactions, the non-chelate assisted transformations are rarely explored. For instance, Pd-catalyzed C–H acetoxylation of arenes devoid of directing groups remains a challenge as it leads to the formation of mixtures of isomers. In this context, Emmert et al. developed non-chelate assisted palladium-catalyzed C–H acetoxylation of simple arenes using pyridine (Emmert et al., 2011) and acridine (Cook et al., 2013) as ancillary ligands in combination with hypervalent iodine reagents as oxidants.

Furthermore, the Pd-catalyzed allylic C–H acyloxylation represents one of the efficient methods in C–H functionalization reactions. Pilarski et al. have presented an excellent protocol for the preparation of allylic acetates or allylic benzoates via Pd-catalyzed allylic C–H acetoxylation/benzoyloxylation using PhI(OAc)₂ 1 or PhI(OBz)₂ as oxidant and source of acyloxy group (Pilarski et al., 2009). Later, the same group described conversion of alkenes into allylic trifluoroacetates via Pd-catalyzed C–H trifluoroacetoxylation employing PhI(OCOCF₃)₂ 2 as an oxidant and trifluoroacetoxy source (Alam et al., 2012).

Regioselective C–H functionalization of indoles has been found to be a straight forward route to access biologically important 3-acetoxyindoles. In this regard, Suna's and Kwong's groups independently reported the synthesis of 3-acetoxyindoles via direct C3-oxidation of indole derivatives catalyzed by Pd(OAc)₂ (2–5 mol%) in the presence of terminal oxidant PhI(OAc)₂ 1 (Mutule et al., 2009; Choy et al., 2011). In continuation, Liu et al. developed a similar Pd-catalyzed approach for the selective C3-acetoxylation of substituted indoles 43 with reduced catalyst loading (1.5 mol%) using PhI(OAc)₂ 1 and KOH as a base (Scheme 4; Liu et al., 2011). Mechanistic insights revealed that the electrophilic palladation occurs at the C3 position of indole to generate Pd(II) species 45 which is oxidized to Pd(IV) intermediate 46 and subsequent reductive elimination affords corresponding C3-acetoxylated indoles 44.

Acyloxylation of aliphatic sp³ C–H bond is another important method for regioselective C–O bond formation. Elegant protocols have been developed employing various nitrogen-based directing groups for the selective oxygenation of unactivated C(sp³)–H bond. In 2010, a novel chelation-assisted Pd-catalyzed C(sp³)–H acyloxylation of 8-methylquinolines in the presence of a stoichiometric amount of oxidant PhI(OAc)₂ 1 was developed employing inexpensive arene carboxylic acids as acyloxy source (Zhang et al., 2010). A similar method for the catalytic acetoxylation of unactivated primary β-C(sp³)–H bond of S-methyl-S-2-pyridylsulfoximine-N-amides at room temperature was described by Sahoo's group (Rit et al., 2012). This method employs S-methyl-S-2-pyridylsulfoximine (MPyS) as a bidentate directing group and β-C–H acetoxylated products were synthesized using different carboxylic acids as solvent and acetate sources.

Furthermore, a Pd-catalyzed oxime-directed β-C(sp³)–H acetoxylation of substrates 47 was performed employing PhI(OAc)₂ 1 as a terminal oxidant (Ren et al., 2012). The catalytic reaction was expected to generate five-membered exo-palladacycle 49 which on oxidation gives masked 1,2-diols 48 (Scheme 5A). Also, the selective acetoxylation of β-methylene (CH₂) and β-methine (CH) groups in cyclopentanol and norbornyl-derived alcohols were also carried out under the same reaction conditions. Furthermore, the deprotection of DG and acetyl group was carried out by using Zn/AcOH & K₂CO₃/MeOH, respectively, to yield diols in excellent yield. Later, Zhang's group described an elegant work on Pd(II)-catalyzed benzylic C(sp³)–H acetoxylation of picolinoyl- or quinoline-2-carbonyl-protected toluidine derivatives using PhI(OAc)₂ 1 as an oxidant and acetate source (Ju et al., 2013).

In 2014, Li et al. performed a Pd(OAc)₂-catalyzed acetoxylation of γ-C(sp³)–H bond of simple alkylamines 50 directed by picolinamide (PA) using oxidant PhI(OAc)₂ 1 under an argon atmosphere (Li et al., 2014). The process provides an easy access to γ-acetoxylated product 51 in good yields (Scheme 5B). Additionally, C–H acetoxylation of γ-methyl group of arylamines proceeded smoothly under this condition. Authors speculated that reaction likely to procced via C, N, N-pincer type Pd(IV) intermediate 52, in which Li₂CO₃ plays a crucial role as it interacts with O-imidate thereby suppressing the formation of cyclic azetidine through intramolecular C–H amination.

Another interesting Pd-catalyzed transformation enabling C–O bond formation is the C–H alkoxylation of sp² and sp³ bonds using hypervalent iodine reagents as oxidant. Chen and Shi's group independently reported two methods for the palladium-catalyzed PhI(OAc)₂-mediated alkoxylation of methylene and methyl C(sp³)–H bonds with a range of aliphatic alcohols as alkoxylation reagents, using picolinamide (Zhang et al., 2012) and pyridine (Chen et al., 2013) as easily removable directing groups. Later, azo group-directed selective C(sp²)–H alkoxylation of azobenzene compounds with alcohols as the alkoxylation reagents was reported by Yin et al. using palladium catalysis in the presence of oxidant PhI(OAc)₂ 1 (Yin et al., 2013). Additionally, Zhang and Sun demonstrated the regioselective alkoxylation of ortho-C(sp²)–H bond of 2-aryloxypyridines to provide ortho-alkoxylation products in the presence of catalytic amounts of Pd(OAc)₂ and oxidant PhI(OAc)₂ 1 (Zhang and Sun, 2014).

Shan et al. for the first time employed cyclic hypervalent iodine(III) reagent 12 as an efficient oxidant in the Pd-catalyzed C(sp³)–H alkoxylation of unactivated methylene and methyl groups of 8-aminoquinoline-derived carboxylic acids 53 (Shan et al., 2013) (Scheme 6). The reaction worked perfectly well with DMP 8 (1.1 equivalents) at 110°C. Gratifyingly, C(sp³)-H alkoxylation of cyclic substrates such as cyclopentyl, cyclohexyl, and cycloheptyl were also perfomed under identical conditions. Furthermore, the synthetic applicability of present method was demonstrated for the alkoxylation of various analogs of Ibuprofen such as, Naproxen, Ketoprofen, and Flurbiprofen to afford alkoxylated products in variable yields. Based on preliminary mechanistic studies, authors proposed that either DMP 8 or 1-acetoxy-1,2-benziodoxole-3(1H)-one 12a serve as key precursors for the in situ generation of cyclic iodine(III) oxidant 56 which oxidizes cyclopalladium(II) intermediate 57 to Pd(IV) intermediate 58. Next, ArCO₂ ligand of intermediate 58 could be easily displaced by alcohol 54 to give Pd(IV) intermediate 59 which finally undergoes C–O bond-forming reductive elimination to yield alkoxylated products 55 and regenerates palladium catalyst. Later, the same research group developed a similar method to prepare symmetrical and unsymmetric acetals via Pd-catalyzed regioselective double C(sp³)–H bond alkoxylation of 8-aminoquinoline-derived substrates using cyclic iodine(III) reagent 12 as an oxidant (Zong and Rao, 2014).

Chaudhari and Fernandes developed a Wacker–type oxidation protocol to convert various aliphatic and aromatic terminal alkenes 61 into functionally diversified methyl ketones 62 employing Dess-Martin Periodinane (DMP) 8 as an oxidant under nitrogen atmosphere (Chaudhari and Fernandes, 2016). Furthermore, the oxidation of a number of allylic or homoallylic compounds were also investigated under identical conditions to deliver methyl ketones in high yields. Excellent functional group compatibility, wide substrates scope and high isolated yields with complete Markovnikov selectivity are the key features associated with this methodology (Scheme 7A). A similar method for the conversion of terminal olefins into α,β-unsaturated ketones was developed by Bigi and White via a Wacker oxidation-dehydrogenation process employing Pd(CH₃CN)₄(BF₄)₂ (10 mol%) and PhI(OAc)₂ 1 (25 mol%) co-catalytic system in the presence of 1,4-benzoquinone as oxidant (Bigi and White, 2013). Interestingly, PhI(OAc)₂ 1 acts as a dehydrogenation catalyst and not as a terminal oxidant in this reaction.

Very recently, He et al. reported Pd(II)-catalyzed phosphorylation and sulfonation of unactivated benzyl C(sp³)–H bond of 8-methylquinolines 63 employing organophosphorus or sulfonate hypervalent iodine(III) reagents 64 as an oxidant and as a functional group source (He et al., 2019). Using this protocol, desired products 65 or 66 were obtained in moderate to high yields with broad substrates scope (Scheme 7B). Additionally, the scope of reaction was extended for the C(sp²)–H hydroxylation and arylation of 2-phenylpyridines.

Furthermore, limited protocols are available for the direct C–O bond formation without involving C–H bond functionalization. For instance, Kitamura and his research group disclosed efficient conversion of (trimethylsilyl)arenes into acetoxyarenes via Pd(OAc)₂-catalyzed desilylative acyloxylation strategy using PhI(OCOCF₃)₂ 2 as an oxidant in AcOH (Gondo et al., 2015). Meanwhile, Cheng et al. reported Pd-catalyzed acetoxylative, hydroxylative and alkoxylative cycloisomerization of polysubstituted homoallenyl amides enabling preparation of functionalized 2-aminofurans using hypervalent iodine(III)reagents as oxidant (Cheng C. et al., 2015). Another striking example to prepare α-acetoxylated enones from propargylic substituted alkynes through Pd-catalyzed oxidative acetoxylation in the presence of terminal oxidant PhI(OAc)₂ 1 and additive benzoquinone (10 mol%) in DMSO was developed (Jiang et al., 2016).

An interesting domino process highlighting Pd-catalyzed C–H functionalization of N-arylpropiolamides 67 using iodine(III) reagent 68 as an aryl source was demonstrated by Tang et al. (2008a). This elegant protocol leads to the synthesis of 3-(1-arylmethylene)oxindoles 69 in useful yields (Scheme 8A). The effect of various electron-rich and electron-deficient substituents on the aryl ring as well as on the triple bond was investigated. The catalytic cycle for this reaction starts with the coordination of Pd(II)-catalyst with alkyne and nitrogen to form intermediate 70 followed by cis-addition with Pd and ArI(OAc)₂ 68 to give Pd(II) intermediate 71. Oxidation of intermediate 71 by ArI(OAc)₂ 68 forms Pd(IV) intermediate 72 which further gives intermediate 73 by activation of ortho C–H bond of 72. Finally, intermediate 73 underwent reductive elimination to provide anticipated products 69 and releases active Pd(II) species. The same group also reported the synthesis of (E)-(2-oxindolin-3-ylidene)phthalimides and (E)-(2-oxoindolin-3-ylidene)methyl acetates via Pd-catalyzed C–H functionalization of N-arylpropiolamides using phthalimide and carboxylic acids as nucleophiles, respectively (Tang et al., 2008b,c). Later, synthesis of CF₃-substituted oxindoles was accomplished through palladium-catalyzed PhI(OAc)₂-mediated intramolecular trifluoromethylation of N-alkyl-N-arylacrylamide derivatives using TMSCF₃ as an efficient trifluoromethyl source in the presence of Lewis acid Yb(OTf)₃ (Mu et al., 2012).

Tong et al. coined the first Pd-catalyzed oxidative cyclization of 1,6-enynes into the corresponding bicyclo[3.1.0]hexane derivatives using oxidant PIDA 1 (Tong et al., 2007). Later, Sanford and Tong's research groups independently developed similar pathways toward the synthesis of multi-substituted bicyclo[3.1.0] ring systems using bipyridine as ligand (Welbes et al., 2007; Liu et al., 2008; Lyons and Sanford, 2009). Furthermore, Tsujihara et al. developed the first example featuring asymmetric Pd(II)/Pd(IV) catalysis for the enantioselective synthesis of bicyclic lactones 76 from 1,6-enynes 74 in variable yields with up to 95% enantiomeric excess (Scheme 8B) (Tsujihara et al., 2009). Reaction utilizes the spiro bis(isoxazoline) 75 (abbreviated as SPRIXs) as chiral ligand, Pd-SPRIX 75 complex as catalyst and PhI(OAc)₂ 1 as terminal oxidant.

Very recently, Xu et al. published an excellent example on the Pd(II/IV)-catalyzed intramolecular cycloaddition of the propargylic alcohol/amine and alkene of substrates 77 via acetoxylative (3 + 2) annulation strategy enabling the synthesis of bicyclic heterocycles 78 in significant yields (Xu et al., 2019) (Scheme 9). The possible catalytic cycle for this oxidative cycloaddition reaction initiates through the acetoxypalladation process generating alkenyl-Pd(II) intermediate 79 which is subsequently transform into alkyl-Pd(II) intermediate 81 via chair-like transition state (TS) 80. Next, PhI(OAc)₂-mediated oxidation gives bicyclic Pd(IV) intermediate 82 which further gives 83 through loss of a molecule of AcOH. Finally, intermediate 83 undergoes direct C–O reductive elimination to deliver product 78 and regenerate palladium catalyst to continue the catalytic cycle (Scheme 9).

In 2011, Qu et al. demonstrated a Heck-type coupling reaction between olefins 61 and iodobenzene generated in situ from hypervalent iodine reagents 84 (Qu et al., 2011). The coupling reaction was performed using Pd(OAc)₂ (4 mol%), base K₂CO₃, and PEG-400 as solvent media under an open atmosphere at 40–60°C to afford coupling products 85 in 91–99% yields (Scheme 10). The catalytic system was free from any ligand or additive and possesses an excellent recyclability of catalyst (Scheme 10). A similar Pd-catalyzed Heck-type arylation of terminal alkenes with aryliodine(III) diacetates was developed by Evdokimov et al. (2011).

Later, Cheng's research group performed Pd(II)-catalyzed C–H functionalization of benzoxazoles 86 to furnish arylation products 88 using iodobenzene diacetates 84 as arylating reagent in the presence of ligand 1,10-phenanthroline 87 and base Cs₂CO₃ (Yu et al., 2012) (Scheme 10). Similarly, Fu et al. employed aryliodine(III) diacetates 84 as a coupling partner in the Pd-catalyzed C–H arylation of polyfluoroarenes 89 (Fu et al., 2015). Detailed mechanistic studies revealed in situ generation of aryliodides by the reduction of ArI(OAc)₂ 84 under basic conditions to furnish desired polyfluorobiaryls products 90 in moderate to good yields (Scheme 10).

Another interesting strategy to establish C–C bond formation is Pd-catalyzed oxidative coupling reactions of aromatic halides with different arylation reagents. Considering this, Xiong et al. illustrated the synthesis of useful symmetrical biaryls employing aryliodine(III) diacetates 68 as aryl precursor via Pd-catalyzed homocoupling reaction (Xiong et al., 2015). The reaction was carried out in DMF at 110°C in the presence of Pd(OAc)₂ (10 mol %), K₂CO₃ (4 equiv.) under an air atmosphere. In 2016, Wang et al. reported ligand-free arylation of pyridines and quinolines via direct coupling of bromo-substituted pyridines or quinolines with hypervalent iodine(III) compounds as efficient arylating reagents in the presence of catalyst PdCl₂ and base Cs₂CO₃ in DMF at 110°C (Wang et al., 2016).

Mu et al. reported Pd-catalyzed C–H trifluoromethylation to prepare C2-trifluoromethylated indoles employing Ruppert–Prakash reagent, TMSCF₃ as CF₃ source in presence of oxidant PhI(OAc)₂ 1 and base CsF at room temperature (Mu et al., 2011). In 2013, Tolnai et al. employed 2 mol% of Pd(MeCN)₄(BF₄)₂ catalyst in the regioselective C2-alkynylation of N-alkylated indoles using 1-[(Triisopropyllsilyl)ethynyl]-1,2-benziodoxol-3(1H)-one (TIPS-EBX) as an alkynylating reagent (Tolnai et al., 2013). This reaction gave direct access to substituted 1-alkylated-2-[(triisopropylsilyl)ethynyl]-1H-indole at ambient temperature under air atmosphere in significant yields. A number of substituents including Cl, Br, F, & I remained intact in the final products which could be used for further synthetic modifications.

Pd-catalyzed hypervalent iodine mediated 1,1-difunctionalization of alkenes are rare and only few examples are available in the literature. Moran and co-author published an article highlighting 1,1-difuntionalization of acrylate derivatives 119 using palladium catalysis (Rodriguez and Moran, 2009). This reaction involves three component coupling of activated alkenes 119, substituted arenes 120 and hypervalent iodine(III) reagent 121 in acetic acid. Reaction possibly involves formation of Heck intermediate 123 via Heck-type addition of aryl-Pd complex to the alkene 119, followed by β-hydride elimination and subsequent readdition of Pd-H species 126 at benzylic site to form intermediate 128. Finally, oxidation of 128 to Pd(IV) intermediate using iodine(III) reagent 121 and subsequent functionalization with acetate ion lead to the formation of desired 1,1-aryloxygenated compounds 122 (Scheme 15A).

Later, Satterfield et al. disclosed 1,1-aryloxygenation protocol wherein arylstannanes 129 were successfully coupled with terminal olefins 61 in the presence of hypervalent iodine reagents (PhI(O₂CR¹)₂) 130 as an oxidant and palladium catalyst, PdCl₂(PhCN)₂ (Satterfield et al., 2011). This catalytic approach enabled simultaneous generation of C–C and C–O bond in a single step furnishing 1,1-arylacetoxylated products 131 in significant yields (Scheme 15B).

Over the years, great progress has been achieved in the field of Pd-catalyzed 1,2-difunctionalization of olefins using various hypervalent iodine reagents. Based on this strategy, a number intra- and intermolecular synthetic transformations such as diamination, dioxygenation, aminoacetoxylation, fluoroamination, and oxidative amination have been developed.