Hypervalent iodine reagents in organic synthesis: a review of methodology developments and synthetic applications

Abstract

Hypervalent iodine(iii/v) molecules, as environmentally benign catalysts and reagents, have been pervasively used in modern organic chemistry. Hypervalent iodine reagents are utilized in various organic transformations, such as cyclization and C–H functionalization reactions, thus emerging as a significant source for the synthesis of diverse organic molecules. This review entails the most recent advances in the versatility of hypervalent iodine reagents as important mediators in many oxidative-functionalization reactions reported since 2021. The proposed mechanistic details of hypervalent iodine reagents in catalyzing these reactions, along with the underlying rules that govern the reactivity and selectivity of these reactions, are also elaborated. Moreover, the synthetic and practical utilities of iodine-mediated reactions in synthesizing complex biologically active molecules are discussed.

The present manuscript covers the recent innovative methodologies using novel hypervalent iodine reagents furnishing a large variety of bioactive organic molecules (reported since 2021).

1. Introduction

In organic synthesis, catalysts are a requisite for expediting and improving the reaction processes. Due to the increase in the cost of synthesis and environmental pollution, the use of simple, cost-effective, green, eco-friendly and sustainable catalysts has become indispensable from the synthetic and economic viewpoints.^1–3 Hypervalent iodine(iii/v) reagents are excellent catalysts and reagents due to their sustainability, cost-effectiveness and benign nature.^4,5 Relative to transition metals and organometallic compounds, the non-toxicity and commercial availability of iodine reagents make them pivotal compounds in organic synthesis.⁶ Thus, hypervalent iodine and molecular iodine have been utilized as catalysts for years now, thereby promoting metal-catalyst-free organic synthesis.⁷

Iodine with an oxidation state of +1 forms mono-valent compounds, thereby yielding stable polyvalent compounds due to its large size and high polarizability. The compounds formed from iodine with more than one valency are known as hypervalent iodine compounds. Because hypervalent compounds consist of elements that belong to groups 15–18, their valence shell electrons do not obey the Lewis octet rule. Hypervalent iodine reagents are synthesized from iodine carrying the +3 or +5 oxidation states (the +7 state is also found in few purely inorganic compounds).^8,9 In the IUPAC nomenclature, iodine(iii) reagents are referred to as λ³-iodanes and iodine(v) reagents are referred to as λ⁵-iodanes (where λ represents non-standard bonding). Aryl iodides (aryl λ³-iodanes/aryl-λ⁵-iodanes) have a polarized three-center-four electron (3c–4e) bond that is called the hypervalent iodine bond.^10,11

Many review articles and a large number of synthetic methodologies have been published from year to year.^11–13 Due to the wide-ranging applications of hypervalent iodine reagents, they have become a hot topic of research.¹⁴ Formerly, HIRs were mainly acknowledged due to their oxidative nature, however, their importance is not only due to oxidation reactions but also because of their excellent electrophilic nature and ability to form bonds such as C–C, N–X (X = N, O, and S), C–X and S–N.^15–19 They have been remarkably used to accomplish various organic transformations as well as epoxidation reactions, especially for the epoxidation reaction of cyanostyrenes with cyanoepoxides in organic synthesis.^20–23 The incorporation of oxygen or nitrogen functional groups in organic molecules is also achieved via iodine-based reagents.²⁴ By using hypervalent iodine reagents, intermolecular oxidative-coupling reactions of aromatic compounds were performed, which involve heteroaromatic couplings, aromatic couplings and cross-couplings of heteroaromatic and aromatic rings, as illustrated in various research articles.^25–29 In addition, intramolecular oxidative-coupling reactions are catalyzed by hypervalent iodine reagents, in which the formation of fused rings, spiro structures and C(sp²)–N bonds is also of great interest.³⁰ Many synthetic and remarkable transformations, such as asymmetric transformations,³¹ annulation reactions,³² radical cyclization reactions, enantioselective C–H functionalization reactions, atom transfer, α-functionalization of carbonyl compounds, ligand transfer reactions, regioselective cycloaddition reactions, rearrangement reactions, halogenation reactions and photocatalytic reactions, are accomplished successfully via hypervalent iodine reagents.^33–37

Several classes of hypervalent iodine reagents (λ³ and λ⁵) with their synthetic applications have been studied. There is a library of λ³-hypervalent iodine reagents that are efficiently used in the synthesis of organic products, in which iodoxybenzene, iodosobenzene and aryliodine(iii) carboxylates such as bis(trifluoroacetoxy)iodobenzene (PIFA), (diacetoxyiodo)benzene (PIDA), bis(metachlorobenzoxy)iodobenzene, iodosylbenzene (PhIO), dimethylamino-iodine, N-chlorofluoroiodane(iii) reagent, and acetoxybenziodoxolone are involved. Due to oxidizing characteristics, they are used for the accomplishment of oxidative-functionalization reactions. Moreover, µ-(oxido)bis[phenyl(trifluoroacetoxy)iodine and aryliodine(iii) organosulfonates act as strong electrophiles. For the halide sources, (dichloroiodo)benzene, (difluoroiodo)benzene and 4,4′-bis-(dichloroiodo)biphenyl, and for triflouromethylation reactions, Togni's reagents are acknowledged.^38,39 [Hydroxy(tosyloxy)iodo]benzene (Koser's reagent) is another important λ³-hypervalent iodine reagent that is extensively utilized in organic synthesis as a moderately selective oxidizing agent, mainly for the α-oxidation of carbonyl molecules, dearomatization of phenols, contraction and expansion of cyclic compounds, dioxytosylation of many alkenes, formation of aryliodonium salts and many other transformations.⁴⁰ In addition, there is an array of λ⁵-hypervalnt iodine reagents in which 2-iodoxybenzoic acid (IBX) (used for the synthesis of heterocycles including ketones, oximes, imines and many other aromatic heterocycles), Dess–Martin periodinane (DMP) (used for the oxidation reactions), iodylbenzene (PhIO₂), etc., are present, which highlights the reagent-dependent reactivity and selectivity of these reagents, illustrating their utility for specific organic transformations.

Hypervalent iodine reagents have gained significant importance in the synthesis of natural products and bio-organic compounds such as ganoderma meroterpenoid ganoapplanin, (+)-voglibose, lycoposerramine congeners, cryptophycins, dactyloquinone A, spiroetherone A, (+)-mannolide C, eribulin, macrolactam, five lycopodium alkaloids, brassicicenes C, F, H, J, and K, and makaluvamine J.^41–47 Recently, these reagents have been utilized for the synthesis of many organic molecules such as sulfones, unsymmetrical 1,2-diaryl diketones and 2-amino-5-acyl-thiazoles/selenazoles.^48–50 Hypervalent organic polyiodides are efficiently used in dye-sensitized solar cells, polarizing films, disinfectants, and low-density graphitic films. The applications of hypervalent iodine reagents in industries are under progress.⁵¹

In previous years, the literature has been broadly reviewed to emphasize the novel protocols utilized for the synthesis of organic compounds via hypervalent iodine reagents. In 2018, Ghosh et al. described the asymmetric transformations using chiral hypervalent iodine reagents.⁵² Moreover, in 2019, Budhwan and coworkers reviewed the late-stage functionalization of an array of heterocycles through hypervalent iodine reagents.⁵³ Recently, in 2024, Yoshimura and coworkers have entailed the synthetic applications of hypervalent iodine reagents for the synthesis of organic products.¹² To date, using many novel hypervalent iodine reagents, a lot of protocols have been studied for the synthesis of organic and natural molecules. This review article systematically summarized the applications of hypervalent iodine reagents towards the construction of various bioactive synthetic scaffolds by classifying the reported methodologies based on the type of bond formed. The manuscript discusses the approaches for the formation of C–C, C–O, C–N, C–S, N–S, and C–halogen bonds followed by multiple bond-forming reactions, such as C–heteroatom, C–O/N–O, C–C/C–heteroatom, and N–I/C–O bond formations. This review covers all the innovative methodologies using novel hypervalent iodine reagents with mechanistic details to furnish a large number of organic molecules, reported during 2021–2026.

2. Literature review

2.1. Formation of C–C bonds

C–C bond forming reactions represent a key approach for the construction and diversification of significant molecular entities. Various hypervalent iodine reagents have been significantly exploited in these conversions owing to their potential to facilitate the carbon transfer, functionalization and oxidative coupling reactions.^54,55 Trifluoromethyl (CF₃) group is a valuable moiety in agrochemical and medicinal chemistry, and among hypervalent iodine reagents, Togni's reagents are efficiently used as CF₃ reagents for their introduction in organic molecules.^56,57 In this regard, in 2023, Zhao and coworkers pioneered a trifluoromethylative reaction of indole-tethered alkenes 1a mediated by iron II and Togni's reagents (A/B) to furnish CF₃-comprising spiro[indole-3,3′-pyrrolidine] derivatives 1b and diversely substituted tetrahydrocarbazoles 1c. In their synthetic approach, indole-tethered alkenes 1a were reacted with Fe(acac)₃, bipy (2,2′-bipyridine) (as ligand), Cs₂CO₃ and Togni's reagents (A/B) in the presence of 1,2-dichloroethane (DCE) at 80 °C for 24 hours to yield CF₃-comprising spiroindolenines 1b (46–99% yields) and tetrahydrocarbazoles 1c (46–89% yields). The proposed mechanism entailed that Fe(acac)₃ was made to react with Bipy and Cs₂CO₃ to synthesize LFeⁿI that was subjected to oxidation with Togni's reagents (A/B) to yield LFeⁿ⁺¹II followed by the formation of CF₃ radical III. In the next step, substrate 1a was oxidized by intermediate II with the subsequent regioselective attack of CF₃ radical III to synthesize the intermediate IV that further proceeded via two pathways. In the first path, intermediate IV underwent 5-exo cyclization for the formation of spiro intermediate V that synthesized spiroindolenines 1b by deprotonation. In the second path, intermediate IV underwent 6-endo cyclization for the synthesis of intermediate VI that yielded the tetrahydrocarbazoles 1c by deprotonation and aromatization. There was another three-center two-electron way to synthesize tetrahydrocarbazoles 1c by the migration of intermediate V with iron (as Lewis acid) via intermediate VI. However, entailed mechanisms were vague that required work on them for the exact mechanism [Scheme 1].⁵⁸

Scheme 1. Synthesis of the CF₃-comprising spiro[indole-3,3′-pyrrolidine] derivatives 1b and diversely substituted tetrahydrocarbazoles 1c.

In spite of ongoing developments in the homo-coupling of carbonyl compounds, their deoxygenative homo-coupling was challenging. Regarding this, in 2025, Han et al. pioneered a single-step trifluoromethylative homo-coupling reaction of carbonyl compounds 2avia hydrazones I with PIDA C to obtain three C–C bonds in trifluoromethylative coupling products 2b. In their novel methodology, diversely substituted aldehydes 2a were made to react with hydrazine monohydrate (N₂H₄ H₂O) to form hydrazones I, which reacted with PIDA C and CuCF₃ (in situ prepared by CuI, TMSCF₃ and CsF in 1.0 mL DMF) in the presence of air at room temperature for 10 min to form coupling products 2b in low to good yields (12–64%). Moreover, to validate the practical utility of the abovementioned methodology, the synthesized derivative 2ba (formed from 4-methoxybenzaldehyde) was transformed to 2c (used as the anticancer agent) and 2d (used as the waterproof material). The reaction mechanism involved the reaction of hydrazones (intermediate I) with PIDA C to afford intermediate II, which was made to react with CF₃Cu^I followed by the removal of nitrogen gas that gave rise to intermediate III. In the next step, intermediate III underwent homolysis to form intermediate IV followed by subsequent homo-coupling to furnish products 2b [Scheme 2].⁵⁹

Scheme 2. Synthesis of the trifluoromethylative coupling product 2b.

Due to the biological activities of triazolopyridazines, they are used in agrochemical and pharmaceutical chemistry. However, there was a challenge in C–H functionalization due to their poor chemo- and regio-selectivity that arose due to the presence of nitrogen atoms.^60,61 In this context, hypervalent iodine reagents have proven to be efficient reagents for group transfer or C–H bond activation.⁶² Regarding this, in 2025, Wang et al. reported the robust regioselective C(3)-H functionalization of triazolopyridazines 3a mediated by Ag/Au catalysis and hypervalent iodine(iii) reagents D to synthesize 3-alkynylated triazolopyridazines 3b. In their synthetic approach, triazolopyridazines 3a were reacted with hypervalent iodine(iii) reagents D, Ph₃PAuNTf₂, AgOTf, and 1,10-phenanthroline (Phen) in the presence of dichloromethane (CH₂Cl₂) to yield 3-alkynylated triazolopyridazines 3b with low to excellent yields (44–95%). The possible reaction mechanism deduced that Au⁺ species I was synthesized in situ from the reaction of Ph₃PAuNTf₂ and Phen, which underwent oxidative addition with D to form intermediate II. Following this, intermediate II was reacted with AgOTf to synthesize IV followed by the removal of III. In the next step, triazolopyridazines 3a underwent C–H functionalization with IV to form V by the elimination of VI, followed by transmetalation with III to yield VII. In the last step, VII underwent reductive elimination to furnish 3-alkynylated triazolopyridazines 3b followed by the removal of I. Gram-scale synthesis of the derivative 3bc and its derivatization was also done to validate the synthetic utility of the abovementioned approach [Scheme 3].⁶³

Scheme 3. Synthesis of the 3-alkynylated triazolopyridazines 3b.

In 2025, Solomin et al. reported an iron-catalyzed, piezoelectric material and ball-milling-mediated radical difluoromethylation of acrylamides 4a with (bis(difluoroacetoxy)iodo)benzene (PhI(OCOCF₂H)₂) E to furnish CF₂-containing oxindoles 4b. In their synthetic approach, diversely substituted acrylamides 4a were reacted with PhI(OCOCF₂H)₂E, Fe(OAc)₂ and PIDA-^tBu in the presence of THF using a ball-milling process to synthesize CF₂-containing oxindoles 4b (9–86% yield) via the unique solid-state generation of CF₂H radicals, which added to the double bond of 4a to generate intermediate 4d. This methodology illustrated a wide substrate scope with diverse functional-group tolerance (such as substitution on the aromatic ring or on the C C bond of acrylamides 4a). Control experiments indicated that ball-milling activation and iron played an important role in reactivity, and radical-quenching experiments highlighted that radical intermediates were involved in the reaction mechanism [Scheme 4].⁶⁴

Scheme 4. Synthesis of the oxindoles 4b.

In 2025, Pang et al. reported an efficient, inexpensive, base, metal and photo-catalyst-free difluoro-/aryldifluoro-methylation of benzimidazoles having unactivated alkenes 5b mediated by PIDA C to furnish CF₂H/PhCF₂-containing polycyclic imidazoles 5b. In their radical cyclization approach, benzimidazoles having unactivated alkenes 5a were reacted with CF₂R²COOH and PIDA C in the presence of 72 W white LED, THF and N₂ for 12 hours to synthesize CF₂H/PhCF₂-containing polycyclic imidazoles 5b (32–85% yield). The plausible mechanism entailed that through the ligand exchange process, PIDA C and CF₂R²COOH synthesized I (by the elimination of HOAc) that underwent homolysis in the presence of visible light to form iodanyl radicals II and III. Following this, III generated CF₂R² radical IV (by the removal of CO₂), which further underwent addition reaction with benzimidazoles 5a to yield V through intramolecular radical ring formation reaction. In the next step, V was reacted with II that underwent a single-electron-transfer process to form cationic intermediate VI (by the removal of PhI and CF₂HCOO⁻), which finally synthesized products 5bvia deprotonation [Scheme 5].⁶⁵

Scheme 5. Synthesis of the polycyclic imidazoles 5b.

Due to the wide-ranging applications of CF₃-containing compounds in different fields of agrochemicals, pharmaceutical and materials sciences, they are used as multi-functional chemicals. Regarding this, in 2025, Tang and coworkers demonstrated an efficient, photo-catalyzed, stereo- and regio-selective alkenyltrifluoromethylation reaction, mediated by Togni-II reagent A and blue light with 2-arylamino 1,4-naphthoquinones 6b (acting as both substrates and photosensitizers) to yield a library of CF₃-bearing alkenes 6c from alkynes 6a. In their synthetic approach, highly substituted alkynes 6a were reacted with 2-arylamino 1,4-naphthoquinones 6b and Togni's reagent A under 40 W blue LEDs, ethanol and nitrogen gas at room temperature for 20 hours to synthesize CF₃-bearing alkenes 6c (24–85% yield). The reaction mechanism entailed that visible light excited 2-arylamino 1,4-naphthoquinone 6ba to form I that oxidized with Togni reagent A to II by the removal of PhICOO⁻ and CF₃ radical III. Following this, CF₃ radical III underwent addition reaction with phenylacetylene 6aa to generate carbon-centered radical IV that yielded V by successive radical addition of 6ba and oxidation with IIvia the single-electron process (by the removal of 6ba). In the last step, V tautomerized to VI that synthesized CF₃-bearing alkene 6cavia deprotonation in the presence of PhICOO⁻. In addition, products 6d (95%) and 6e (30%) were synthesized to demonstrate the synthetic utility of this approach [Scheme 6].⁶⁶

Scheme 6. Synthesis of the CF₃-bearing alkenes 6c.

In 2025, Zhang et al. reported an efficient trifluoromethylative-(bi)cyclization reaction of 1,7-enynes 7a and alkenes 7b and 7c with Togni-II reagent A mediated by vanadium (V-1) C1 to obtain CF₃-substituted indeno[1,2-c]quinolones 7d, oxindoles 7e and isoquinoline-1,3-diones 7f, respectively. In their radical cascade methodology, Togni-II reagent A was reacted with V-1 C1 and 1,7-enynes 7a in the presence of DCM at 40 °C for 8 hours to synthesize CF₃-substituted indeno[1,2-c] quinolones 7d (70–85% yield), while Togni-II reagent A was reacted with alkenes 7b and 7c in the presence of V-1 C1 to synthesize CF₃-substituted oxindoles 7e (71–88% yield) in DCM at 40 °C in 8 hours and CF₃-substituted isoquinoline-1,3-diones 7f (21–80% yield) in MeCN at 120 °C in 12 hours, respectively. Moreover, an unpredicted compound, i.e., trifluoromethylated azaspiro[4.5]-decadientrione 7ea (22%), was synthesized in 22% yield along with the synthesis of indeno[1,2-c]quinolone 7da (78%), oxindole 7eb (85%) and isoquinoline-1,3-dione 7fa (68%) on a gram scale that reflected the practical utility of this methodology [Scheme 7]. The proposed mechanism entailed that Togni-II reagent A was made to react with catalyst V-1 C1 to give V^IV and CF₃ radical I that reacted with alkenes 7b and 7c to generate intermediates II and V, respectively. Intermediates II and V underwent radical 5-exo and 6-exo cyclization to yield intermediates III and VI, which synthesized CF₃-substituted oxindoles 7e and isoquinoline-1,3-diones 7fvia oxidation with V^IV and deprotonation, respectively. In addition, intermediate I was made to react with 1,7-enynes 7a to form IV that underwent subsequent 5-exo/6-exo bicyclization, oxidation with V^IV and deprotonation to yield CF₃-substituted indeno[1,2-c]quinolones 7d [Fig. 1].⁶⁷

Scheme 7. Synthesis of the indeno[1,2-c]quinolones 7d, oxindoles 7e and isoquinoline-1,3-diones 7f.

Fig. 1. Mechanism for the synthesis of the CF₃-substituted indeno[1,2-c]quinolones 7d, oxindoles 7e and isoquinoline-1,3-diones 7f.

Oxygen-containing heterocyclic compounds exhibit biological activities, and hence, they are efficiently used in pharmaceutical industries.⁶⁸ In 2025, Lv et al. illustrated a regioselective and one-step photo-catalytic cyclization reaction of diversely substituted benzaldehydes 8a with Togni-II reagent A catalyzed by photo-catalyst Ir[dF(CF₃)ppy₂](dtbbpy)PF₆C-2 to yield trifluoroethyl benzopyranones 8b and benzopyrans 8c. In their radical cascade protocol, benzaldehydes 8a were reacted with Togni-II reagent A and photo-catalyst C-2 in the presence of TFA, DMSO, 8 W CFL bulb and N₂ atmosphere for 11 hours to yield trifluoroethyl benzopyranones 8b (22–87% yield) and benzopyrans 8c (17–93% yield). In addition, gram-scale synthesis of trifluoroethyl benzopyranones 8ba and benzopyran 8ca and production of quinolinone 8bb and indanones 8bc and 8bd represented the practical and synthetic utilities of this protocol [Scheme 8].⁶⁹

Scheme 8. Synthesis of the trifluoroethyl benzopyranones 8b and benzopyrans 8c.

In 2025, Rupanawar et al. presented a one-pot base-free oxidative olefination reaction of substituted benzylic amines based on PIDA C to furnish α,β-unsaturated ketones 9c. Their synthetic protocol involved the reaction of substituted benzylic amines 9a with PIDA C and phenacyl(triphenyl)phosphonium bromide salts (Witting salts) 9b in the presence of ethanol at 70 °C to form α,β-unsaturated ketones 9c with 61–86% yields in 4 hours. The reaction mechanism proposed that PIDA C oxidized benzylic amines 9a to imine intermediate I followed by the removal of acetate ions, benzoiodine and acetic acid (in situ-generated acetate ion was converted into acetic acid by protonation), sequentially. In the next step, I was made to react with salts 9b to form azaphosphetane II by the removal of HBr and then II yielded α,β-unsaturated ketones 9c followed by the removal of NHPPh₃ (hygroscopic in nature, and hence, immediately hydrolyzed into OPPh₃). Moreover, α,β-unsaturated ketones 9c were used for the formation of diversely substituted ketones such as epoxy ketones 9d (96%), 1,2-diaryl ketones 9e (43%) and 4-nitro-1,3-diphenylbutan-1-one 9f (62%), as well as 1,3-diphenylpropane 9g (62%). The preparation of these organic compounds indicated the synthetic utility of this methodology [Scheme 9].⁷⁰

Scheme 9. Synthesis of the α,β-unsaturated ketones 9c.

In 2025, Lee et al. reported the synthesis of 1,3-difunctionalized bicyclo[1.1.1]pentanes (BCPs) employing Z-vinylbenziodoxolone (VBX) hypervalent reagents. In their novel methodology, BCP-VBXs were synthesized in the first step from BCP-ethynylbenziodoxolone, and then, synthetically exploited for vinylation, trifluoromethylation and arylation for the construction of BCP-incorporated enol ethers, enamides and vinyl sulfides. The structures of these newly synthesized BCP-VBXs are depicted in Fig. 2.⁷¹

Fig. 2. Structures of representative BCP-VBX reagents.

Indole is an important heterocyclic compound, which constitutes the core structure of various bioactive natural and synthetic scaffolds and the synthesis of these compounds attract significant consideration in synthetic chemistry. For this purpose, in 2026, Das et al. employed indole-derived benziodoxole (Indole-BX) reagents I–II [Fig. 3], for the facile synthesis of a tris-indolylmethane alkaloid.⁷²

Fig. 3. Structure of the indole-derived benziodoxoles I and II.

2.2. Formation of the C–O bond

The formation of the C–O bond is an indispensable transformation enabling access to biologically important aryl ethers and other oxygen containing moieties, which are also part of significant pharmaceutics and natural products.⁷³ Various asymmetric dihydroxylation reactions were employed for the enantioselective incorporation of oxygen into complex structures,⁷⁴ among which hypervalent iodine reagents such as uracil-benziodoxolone provide a straightforward and efficient route towards the construction and incorporation of oxygen in these scaffolds.⁷⁵ Similarly, IBX E is an important widely accessible hypervalent iodine reagent, characterized by excellent oxidizing property. It is broadly employed in the oxidation reactions especially for the oxidation of alcohols. However, the oxidation of 1° and 2° alcohols 10a substituted with heterocyclic rings has been less studied with IBX E. Regarding this, in 2021, Kumar et al. demonstrated the cheap and highly efficient IBX-(±)-CSA F-based oxidation reactions of 1° and 2° alcohols 10a, which included aliphatic, aromatic and heterocyclic molecules substituted with different functional groups. In their synthetic methodology, IBX-(±)-CSA F oxidized 1° and 2° alcohols 10a to corresponding aldehydes and ketones 10c (69–98% yields) in the presence of DCM and 1,4-dioxane (1 : 1). The mechanism of reaction involved that IBX E was made to react with camphor sulfonic acid (CSA) 10b to form IBX-(±)-CSA F. In the next step, F (synthesized in situ) underwent a ligand-exchange reaction with 1° and 2° alcohols 10a to form intermediate I that yielded aldehydes and ketones 10c, respectively (by the removal of IBA II) [Scheme 10].⁷⁶

Scheme 10. Synthesis of the aldehydes and ketones 10c.

Despite the broad-spectrum uses of IBX E as an oxidant, its regeneration from the oxidation reactions posed a great challenge. Regarding this, in 2022, Li and coworkers demonstrated a highly efficient and metal-free oxidative aromatization reaction of spiro[2.5]octa-4,7-dien-6 ones 11a based on IBX E-dimethyl sulfoxide (DMSO) 11b to achieve oxidative aromatized ketones 11c. In their synthetic approach, diversely substituted spiro[2.5]octa-4,7-dien-6-ones 11a were reacted with IBX E in the presence of DMSO 11b at 100 °C for 12 hours to synthesize oxidative aromatization ketones 11c (62–98% yields). The possible mechanism involved DMSO 11b reacting with spiro[2.5]octa-4,7-dien-6 ones 11a, which gave rise to aromatized intermediate I that reacted with IBX E to form II by the removal of proton. In the next step, II underwent deprotonation and O–S bond cleavage to form oxidative aromatized ketones 11c followed by the removal of 2-iodoxybenzoic acid anion III (that immediately protonated to form IBX E) and dimethyl sulfide [Scheme 11].⁷⁷

Scheme 11. Synthesis of the ketones 11c.

In 2025, He and coworkers demonstrated a selective oxidation reaction of C–H bonds of aryls 12a and N-heteroaryls 12c mediated by cyclic hypervalent iodine(iii) reagents (n-butoxy benziodoxole BI-OⁿBu G and acetoxy benziodoxole BI-OAc H) to furnish respective carbonyl compounds 12d and 12e. In their oxidative bifunctional photocatalytic radical-polar crossover methodology, alkyl aryls 12a underwent selective C–H oxidation with BI-OⁿBu G and eosin Y 12b in the presence of MeCN and H₂O (act as a quenching agent or as a nucleophile) in an inert atmosphere of argon (Ar) at 30 °C for 12 hours to yield respective carbonyl compounds 12d (42–91% yields). Moreover, heteroaryls 12c underwent selective C–H oxidation with BI-OAc H and Ru(bpy)₃(PF₆)₂ in the presence of MeCN in air at 30 °C for 12 hours to yield the respective carbonyl compounds 12e (57–88% yields). Cyclic hypervalent iodine reagents G and H performed dual functions in this methodology; BI-OⁿBu G used for the C–H functionalization of alkyl aryls 12a by hydrogen atom transfer and BI-OAc H functionalized the C–H bond of isomerized N-heteroaryls 12c by the radical-addition pathway. In addition, a carbonyl compound was used for the formation of different functionalized compounds such as heterocyclic compounds 12f (73%) and 12g (76%), esters 12h (83%), cyanides 12i (81%), reduced compound 12j (91%) and difluoromethylative compound 12k (87%) [Scheme 12].⁷⁸ This methodology was applicable in late-stage functionalization as well as utilized in pharmaceutical chemistry that represented its synthetic utility. Late-stage functionalization is an approach that enables direct diversification at advanced stages without disturbing the reaction sequence, and various hypervalent iodine reagents such as PIDA,⁷⁹n-butoxy benziodoxole BI-OⁿBu and acetoxy benziodoxole BI-OAc facilitate these transformations.

Scheme 12. Synthesis of the carbonyl compounds 12d and 12e.

Due to efficient physicochemical stabilities of porous organic polymers (POPs), they are highly used for the heterogeneous organo-catalysis. In 2025, Tamuly et al. synthesized an array of POP per-catalysts, i.e., m-OMeIA-POP Ia, p-OMeIA-POP Ib and DiMeIA-POP Ic from in-built o-iodobenzoic acid (IA) with twisted biaryl building-blocks via Friedel–Crafts alkylation. These pre-catalysts underwent in situ oxidation reactions with oxone to yield λ⁵-iodane species, especially modified forms of o-iodoxybenzoic acid that were efficiently used for oxidative transformation reactions. In their synthetic approach, m-OMeIA-POP Ic was efficiently used for the oxidation of 1°/2° alcohols 13a, acyloins 13b, olefins 13c and diols (13d and 13e) in the presence of oxone and CH₃CN : H₂O (1 : 3) at 60 °C to synthesize corresponding carbonyl compounds 13f (38–98% yields), carboxylic acids such as 13g (84–93% yields), 13h (85–96% yields), and 13i (64–95% yields) and lactones 13j (82–94% yields), respectively. Moreover, during these reactions, IA-precatalyst was recycled (up to eight times) with its catalytic activity and applications of this methodology in asymmetric organic-oxidations are under progress [Scheme 13].⁸⁰

Scheme 13. Synthesis of the carbonyl compounds 13f, carboxylic acids 13g, 13h and 13i and lactones 13j.

The functionalization of C–H to C–O had been significantly used in organic synthesis however, it was a challenging reaction. Regarding this, in 2025, Kittikool and coworkers demonstrated the efficient selective acetoxylation of diversely substituted pyrazolones 14a catalyzed by PIDA C to obtain acetoxylated pyrazolones 14b and 14c. In their synthetic approach, pyrazolones 14a were reacted with PIDA C in the presence of Pd(OAc)₂ and CH₃CN at room temperature to yield 4-acetoxylated pyrazolones 14b (68–91% yield). Moreover, pyrazolones 14a also underwent a metal-free reaction with PIDA C in the presence of 1,2-dichloro ethane (DCE) at 70 °C to furnish acetoxylated pyrazolones 14c (31–80% yield). On a gram scale, acetoxylated pyrazolones 14ba and 14ca were synthesized, and 14ca was further used to form acetoxylated product 14d using a conventional method that represented the practical and synthetic utilities of this reaction. The proposed mechanism deduced that metal-catalyzed acetoxylation was performed via the C–H metalation of pyrazolones 14a with Pd(OAc)₂ (Pd²⁺ oxidized to Pd⁴⁺) that formed intermediate I. In the next step, I was made to react with PIDA C that underwent oxidative addition reaction followed by the removal of PhI and the reductive elimination of Pd(OAc)₂ to yield 4-acetoxylated pyrazolones 14b. Moreover, metal-free direct acetoxylation of pyrazolones 14a was accomplished by the reaction of pyrazolones 14a with PIDA C that yielded iminium intermediate II. Following this, II formed acetoxylated pyrazolones 14cvia the removal of acetic acid and rearrangement reaction [Scheme 14].⁸¹

Scheme 14. Synthesis of the acetoxylated pyrazolones 14b and 14c.

2.3. Formation of the C–N bond

C–N coupling reactions from C–H/N–H bond functionalization is a versatile approach to obtain aminated compounds of medicinal interest such as synthesis of ciprofloxacin–aniline hybrids with potential anticancer properties.^82,83 In this regard, hypervalent iodine reagents have demonstrated their efficacy for C–N bond formation, enabling access to significant amination products under benign conditions.⁸⁴ Therefore, in 2022, Morimoto et al. performed metal-free oxidative cross-dehydrogenative C–N coupling reactions of phenols and anilines 15a with phenothiazines/phenoxazines 15b using cyclic 1-acetoxy-5-fluoro-1,2-benziodoxol-3(1H)ones J to achieve N-arylphenothiazines/N-arylphenoxazines 15c and 15d, respectively. In their synthetic approach, hypervalent iodine reagent J caused the selective oxidation of phenols 15a and formed the radical species of anilines 15a, which resulted in C–N coupling reactions with 15b at 20 °C for 9 hours to form 15c (57–95% yields) in the presence of CH₂Cl₂ and 15d (63–99% yields) in the presence of (CF₃)₂CH₂OH (HFIP) [Scheme 15]. However, this methodology is useful for many organoiodine reagent-based coupling reactions.⁸⁵

Scheme 15. Synthesis of the N-arylphenothiazines/N-arylphenoxazines 15c and 15d.

The oxidative functionalization of the C–H bond leads to an efficient atom-economic bond formation reaction to yield desired products. In 2023, Corrieri et al. envisioned a metal-free, efficient and chemoselective oxidative C–H amination reaction of nucleophilic α-arylhydrazones 16a mediated by PIFA K, to obtain 1-amino pyrroles 16b. In their synthetic approach, by using PIFA K, α-arylhydrazones 16a underwent oxidative cyclization in the presence of dichloromethane and tetrafluoroethylene (TFE) in 1 : 1 proportion to furnish 1-amino pyrroles 16b (38–83% yields). Moreover, 1-amino pyrrole 16be was utilized for the formation of 16c and 16d by using previously developed methods that indicated the synthetic utility of this approach. The plausible reaction mechanism inferred that α-arylhydrazones 16a underwent tautomerization (1,3 H-shift) to form ene-hydrazine 16a′, which was oxidized to intermediate I in the presence of PIFA K by the subsequent removal of CF₃COOH, PhI and CF₃COOH. In the next step, I underwent intramolecular nucleophilic attack of arenes on the azo group to form III that was subjected to a re-aromatization reaction to synthesize 1-amino pyrroles 16b. However, I formed cationic spiro dieniminium salt II by ipso attack, which yielded 1-amino pyrroles 16b as products via nitrogen-to-carbon bond migration [Scheme 16].⁸⁶

Scheme 16. Synthesis of the 1-amino pyrroles 16b.

Benzimidazol-2-ones are proved as efficient medicinal drugs due to their biological activities, however, their synthesis was rare. Regarding this, in 2025, Popescu and coworkers devised a metal-free oxidative cyclization reaction of amido-urea precursors 17b mediated by PIDA C to synthesize novel diversely substituted benzimidazol-2-ones 17cvia the Hofmann rearrangement. In their inventive methodology, amido-urea precursors 17b (that were synthesized from monoamides 17a) were reacted with PIDA C in the presence of DMF at room temperature to yield benzimidazol-2-ones 17c (9–95% yields). The possible reaction mechanism deduced that nucleophilic nitrogen of the amide of amido-urea precursors 17b attacked on the electrophilic center of PIDA C to form intermediate I (by the removal of AcOH) that underwent Hofmann rearrangement and yielded isocyanate II by the elimination of PhI and AcO⁻. Following this, II underwent an oxidative cyclization reaction to form five-membered intermediate III that yielded benzimidazol-2-ones 17c after deprotonation [Scheme 17].⁸⁷

Scheme 17. Synthesis of the benzimidazol-2-ones 17c.

The wide-ranging characteristics of nitro-aromatic compounds make them crucial components in pharmaceutical chemistry. However, during nitration reactions, attaining regioselectivity was a challenge. Regarding this, in 2025, Zhang and coworkers pioneered a regioselective C–H nitration of diversely substituted arenes 18a catalyzed by hypervalent iodine reagents L to furnish nitrated compounds 18b. In their novel approach, arenes 18a were reacted with hypervalent iodine reagents L and sodium triflate/tosylate to form intermediate diaryliodonium salts I that reacted with sodium nitrite (NaNO₂) in the presence of EtOAc at 70 °C to yield regio-selective nitrated products 18b (52–97% yield) in 3 to 12 hours. In addition, this methodology was accomplished for the late-stage synthesis of pharmaceutical compounds, i.e., methoxsalen 18ba (65–77% yield), fragments of canagliflozin 18bb (65–85% yield), intermediates of milnacipran 18bc (75–88% yield), drug intermediate 18bd (60–80% yield) and metaxalone 18be (75–78% yield), and material compounds such as coumarin derivative 18bf (74−94% yield) and fluorene derivatives 18bg (75–92% yield). Metaxalone 18be was also synthesized on a gram scale that represented the practical utility of this protocol [Scheme 18].⁸⁸

Scheme 18. Synthesis of the nitrated compounds 18b.

In 2025, Gelato et al. presented an efficient and atom-economical way for the synthesis of NH-aziridines 19c from highly substituted alkenes 19a and aqueous ammonia catalyzed by PIDA C. In their novel approach, alkenes 19a were reacted with aqueous ammonia and PIDA C in the presence of TFE at 0 °C for 30 minutes to 16 hours to obtain diversely substituted NH-aziridines 19b (8–90% yields). In addition, the functionalization of the synthesized NH-aziridines was also carried out to attain N-protected aziridines 19c (89–95% yield), and this methodology tackled the complexity in chemo-selectivity and performed controlled oxidation reactions. The proposed mechanism illustrated that the ligand exchange reaction of aqueous ammonia and PIDA C yielded the iminoiodinane I that reacted with PIDA C to form II. Subsequently, II yielded short-lived III (the removal of PhI and AcO⁻), which underwent a reaction with alkenes 19a to generate N-iodoniumaziridine IV. In the last step, IV reacted with the nucleophile and proton donor to synthesize NH-aziridines 19b with I(iii)species V [Scheme 19].⁸⁹

Scheme 19. Synthesis of the NH-aziridines 19b and N-protected aziridines 19c.

In 2025, Wang et al. reported the metal-free photo-catalytic C–H functionalization of (hetero)arenes 20a catalyzed by the hypervalent iodine reagent (amidation reagent) M to furnish C–H amidation molecules 20b. In their photo-catalytic protocol, (hetero)arenes 20a were reacted with the hypervalent iodine reagent M and Ru(bpy)₃Cl₂·6H₂O in the presence of 10 W Blue LEDs, N₂ and DCE for 24 hours to synthesize C–H amidation molecules 20b (46–95% yield). In addition, 20ba was synthesized on a gram scale and utilized to form reductive product 20c, and product 20d was also synthesized using this protocol to represent the practical and synthetic utilities of this methodology. The proposed mechanism illustrated that [Ru(bpy)₃]²⁺ was irradiated with visible light that formed a reductant I, which underwent a single-electron transfer process with M to generate anionic intermediate II and radical intermediate III by the removal of [Ru(bpy)₃]³⁺ (intermediate I′). Following this, III underwent a fragmentation reaction to yield IV and N-centered saccharin intermediate V, which reacted with (hetero)arenes 20a to form radical intermediate VI. In the last step, VI underwent a single-electron oxidation reaction, and subsequently, rearomatization with I′ in the presence of II to synthesize C–H amidation molecules 20b by the removal of HNSacc [Scheme 20].⁹⁰

Scheme 20. Synthesis of the C–H amidation molecules 20b.

In 2025, Kabadwal and coworkers carried out a metal-free fluoro-alkylation reaction of primary amines 21a catalyzed by diacetoxyiodo benzene (DIB) N with robust perfluoroalkanoic acids 21b to access fluoro-alkylated amides 21c. In their one-pot transformation methodology, primary amines 21a were reacted with perfluoroalkanoic acids 21b and DIB N in the presence of toluene at 50–80 °C for 24 hours to yield fluoro-alkylated amides 21c (20–90% yields). This methodology illustrated wide functional group tolerance, i.e. –CF₃, –CN, –CO₂Et, –acetyl, alkylamides, acetamides and alkyl ethers, as well as late-stage functionalization of many fatty acids, drug molecules and vitamins. The proposed mechanism entailed that trifluoroacetic acid 21ba was made to react with DIB N that generated PIFA K (formed in situ), which reacted with 21aa to deliver intermediate II by the elimination of CF₃OOH. Following this, II yielded phenyl isocyanate III (with the removal of PhI, CF₃OO⁻) via Hofmann-type rearrangement. In the last step, CF₃OOH underwent a reaction with III to form IV that gave fluoro-alkylated amide 21cavia decarboxylation [Scheme 21].⁹¹

Scheme 21. Synthesis of the fluoro-alkylated amides 21c.

In 2026, Xiao and coworkers devised a metal-free dimethylamination reaction of diversely substituted glyoxylic acids 22a catalyzed by a dimethylamino-iodine(iii) (DMI) O-PPh₃ system to yield α-ketoamides 22b. In their novel methodology, glyoxylic acids 22a were reacted with a DMI O-PPh₃ system in the presence of DMF at 70 °C for 2 hours to synthesize α-ketoamides 22b (51–91% yields). In addition, using this protocol, amino-based hypervalent iodine(iii) reagents were generated in situ and utilized for the synthesis of N-substituted α-ketoamides 22da (85%), 22db (61%) and 22dc (72%). The plausible mechanism illustrated that DMI O was made to react with PPh₃ to form intermediates dimethylaminophosphonium I and ortho-iodobenzoate II followed by the deprotonation of glyoxylic acids 22avia intermediate II to yield intermediate 2-oxo-2 phenylacetate IV by the removal of 2-iodobenzoic acid III. Following this, IV attacked on the electrophilic center (phosphonium center) of II to form VI by the elimination of dimethyl anion V, which attacked on VI to synthesize desired α-ketoamides 22b and byproduct triphenylphosphine oxide 22c [Scheme 22].⁹²

Scheme 22. Synthesis of the α-ketoamides 22b.

Uracil-benziodoxolone (uracil-BX) emerged as a useful hypervalent iodine reagent for the efficient construction of C–O, C–S and C–N bonds. In this context, Nandi et al. in 2026 synthesized a number of oxazolidinone-uracil derivatives employing a Pd-catalyze approach in the presence of newly synthesized hypervalent iodine reagent, i.e., uracil-BX and NaHCO₃ (acting as CO₂ surrogates).⁵⁴ By utilizing this methodology, a number of structurally diverse, tetra-substituted alkenes were obtained in good yield with excellent stereoselectivity. Similarly, in the same year, Das et al. reported the synthesis of a variety of novel uracil-BX reagents and employed them for amination and sulfenylation to incorporate uracil in various medicinally significant organic scaffolds via Umpolung functionalization [Fig. 4].⁸⁴

Fig. 4. Structures of representative uracil-BX reagents (I–VI).

2.4. Formation of the C–X (X = halogen) bond

1,3-Difluorinated compounds exhibit interesting conformational properties ascribed to 1,3-dipolar effects of minimization. In 2026, Liu et al. envisioned the efficient diastereoselective migratory 1,3-difluorination of highly substituted allylic azides 23a catalyzed by PhIO P for the synthesis of 1,3-difluoro-2-azides 23b having three adjacent stereo-centers. In the novel approach, allylic azides 23a were reacted with PhIO P and Olah's reagent (Py·HF) (for the fluorine source) in the presence dichloromethane (DCM) at −15 °C to synthesize major syn-1,3-difluoro-2-azides 23b (16–93% yield) along with minor anti-1,3-difluoro-2-azides 23c in 2 to 18 hours. According to DFT studies, high diastereoselectivity was accomplished due to the coordination among the azido group of allylic azides 23a and iodine(iii) reagent P, and crystal structure's analysis of products ensured that molecular conformation was determined via 1,3-diflurides. In addition, in order to represent the practical and synthetic utilities of this approach, 1,3-difluoro-2-azide 23ba was synthesized on a gram scale and further transformed to synthetic molecules, i.e., corresponding amine hydrochloride 23d (77%), phosphoramidate 23e (62%), and triazoles 23f (82%) and 23g (58%) [Scheme 23].⁹³

Scheme 23. Synthesis of the 1,3-difluoro-2-azides 23b.

In 2026, Chen and coworkers illustrated a chemoselective geminal chlorofluorination reaction of diazonium compounds 24a using a modular and bench-stable N-chlorofluoroiodane(III) reagent (CFBI) Q to synthesize α,α-chlorofluoro ketones/esters/amides 24b (efficiently used in medicinal chemistry). In their novel one-step protocol, diazonium compounds 24a were reacted with N-chlorofluoroiodane(iii) reagent (CFBI) Q in the presence of BF₃ C₂H₅O and DCM at 0 °C to room temperature to yield α,α-chlorofluoro ketones/esters/amides 24b (50–88% yields). During the reaction, moderately reduced iodane(iii) reagents were formed through the attack of diazonium compounds 24a on chlorine atom instead of the iodine center, which led to the synthesis of desired products 24b. Moreover, the synthetic utility of these synthesized α,α-chlorofluoro ketones 24b was elucidated via their employment in the synthesis of biologically active alcohol 24c (92%), geminal azidofluoride 24d (90%), fluoro epoxide 24e (68%), fluorinated 1,2,3-triazole 24f (98%), product 24g (70%), α-fluoro-β-ketosulfide 24h (88%), and thrombopoietin receptor agonist 24i [Scheme 24].⁹⁴

Scheme 24. Synthesis of the α,α-chlorofluoro ketones/esters/amides 24b.

2.5. Formation of the C–S bond

Hypervalent iodine reagents have exhibited considerable employment in the construction of C–S bonds, offering straightforward approaches towards bioactive organo-sulfur moieties. In this context, hypervalent iodine reagents such as uracil–benziodoxolone and di(4-tolyl)iodonium triflate have been previously employed for the effective construction of C–S and C–N bonds.^84,95 In 2025, Malashchenko et al. reported metal-free regio- and chemo-selective C–H functionalization catalyzed by Koser's hypervalent iodine reagent 3,5-dimethylisoxazol-4-yl)-I(OH)OTs [DMIX-I(OH)OTs] R, to synthesize O-alkyl-S-(indol-3-yl)xanthates 25b from indoles 25a. In their synthetic approach, indoles 25a were reacted with (3,5-dimethylisoxazol-4-yl)-I(OH)OTs R in the presence of CH₃CO₂C₂H₅ to form electrophilic (3,5-dimethylisoxazol-4-yl)(indol-3-yl)iodonium salts I (formed in situ) that reacted with potassium ethyl xanthate (KSC(S)OC₂H₅) in the presence of benzene at 80 °C for 8 hours to furnish O-alkyl-S-(indol-3-yl)xanthates 25b (71–91% yield). To demonstrate the practical utility of this protocol, xanthate 25ba (84% yield) was synthesized on a gram scale, and then, 25ba and 25bb were transformed into relevant indol-3-yl thiols 25c (90%) and 25d (82%) in the presence of NaBH₄. C–H functionalization of CCG-203926 25aa (replication inhibitor use against neurotropic alphavirus) was accomplished to achieve xanthate 25bc (57% yield), which reflected the synthetic utility of this methodology. Late-stage functionalization of OMe-estradiol 25e was also possible by using this methodology to afford the complex molecule 25f (54%) [Scheme 25].⁹⁶

Scheme 25. Synthesis of the O-alkyl-S-(indol-3-yl)xanthates 25b.

2.6. Formation of the N–S bond

Due to non-toxicity, electrophilicity, good oxidizing character, stability and selectivity, hypervalent iodine reagents (PIFA K and PIDA C) are efficiently used for the synthesis of many heterocyclic compounds.^13,97 In 2021, Panigrahi and coworkers reported robust N-trifluoromethyl sulfonylation mediated by phenyliodine(iii)bis(trifluoroacetate) PIFA K to synthesize trifluoromethyl sulfonylated molecules 26c from corresponding pyrazolones 26a and Langlois reagent 26b. In their novel methodology, diversely substituted pyrazolones 26a were reacted with the Langlois reagent 26b and PIFA K in the presence of TFE/H₂O in 3 : 1 ratio at room temperature for 5 minutes to yield trifluoromethyl sulfonylated molecules 26c (16–83% yield). The proposed mechanism illustrated that Langlois reagent 26b was made to react with PIFA K to synthesize reactive sulfonium ion I (with the subsequent removal of CF₃COO⁻, PhI and CF₃COO⁻) that reacted with pyrazolones 26avia two pathways to yield products 26c. In the first pathway, pyrazolones 26a tautomerized to its keto–enol form II, which underwent a reaction with I to furnish trifluoromethyl sulfonylated molecules 26c and CF₃COOH as byproducts. In the second pathway (which is more feasible than the first), pyrazolones 26a tautomerized to its –NH form III that reacted with I to synthesize trifluoromethyl sulfonylated molecules 26c and CF₃COOH as byproducts [Scheme 26].⁹⁸

Scheme 26. Synthesis of the trifluoromethyl sulfonylated molecules 26c.

2.7. Formation of the S–O bond

Due to the biological activities, sulfinamides have been significantly used in agrochemicals and pharmaceuticals. In 2026, Chen et al. successfully reported an efficient, green and metal-free oxidation reaction of sulfenamides 27a using PIDA/H₂O C to obtain sulfinamides 27b. In their novel methodology, diversely substituted sulfonamides 27a were reacted with PIDA/H₂O C in the presence of EtOH at room temperature to synthesize sulfinamides 27b (70–99% yield). In addition, sulfinamide 27ba was synthesized on a gram-scale and further leveraged to synthesize sulfonamide 27c (94%), sulfonimidoyl chloride 27d (91%), sulfonimidoyl fluoride 27e (70%), N-methyl sulfonamide 27f (42%), sulfuroimide 27g (92%), sulfinimidate ester 27h (78%) and sulfilimine 27i (90%) that illustrated the practical and synthetic potentials of this methodology [Scheme 27].⁹⁹

Scheme 27. Synthesis of the sulfinamides 27b.

2.8. Formation of miscellaneous bonds

2.8.1. Formation of the C–X (X = heteroatom) bond

Thioaminated 1,4-naphthoquinones had been demonstrated as privileged molecules in medicinal chemistry due to their wide pharmacological and biological activities.^100,101 Regarding this, in 2021, Pal and coworkers presented a metal-free one-step oxidative coupling reaction of diones (1,4-naphthoquinone 28c and maleimides 28d), thiols 28a and amines 28b, catalyzed by PIDA C to furnish thioaminated products 28e and 28f. In their synthetic approach, oxidative C–H difunctionalization process was accomplished to synthesize thioaminated products 28e (62–88% yield) by the reaction of 1,4-naphthoquinone 28c with aliphatic/aromatic thiols 28a, amines 28b and PIDA C and DCE at 80 °C for 12 hours. In addition, maleimides 28d also underwent a thioamination reaction with thiols 28a, amines 28b and PIDA C in the presence of CH₃CN to obtain the respective thioaminated products 28f (72–82% yield). The plausible reaction mechanism inferred that amines 28b were made to react with 1,4-naphthoquinone 28cvia the Michael addition reaction to form intermediate I that was oxidized to II in the presence of 28c followed by the removal of hydroquinone 28c′ (that immediately oxidized by air to 1,4-naphthoquinone 28c). In the next step, II was made to react with sulfenium ions (generated in situ by the reaction of thiols 28a with PIDA C) via a nucleophilic addition reaction to synthesize thioaminated products 28e by the subsequent removal of CH₃COOH, CH₃COO⁻ and PhI [Scheme 28].¹⁰²

Scheme 28. Synthesis of the thioaminated products 28e and 28f.

Oxazol-2(3H)-ones have been significantly used in medicinal chemistry, and hence, they are synthesized by many efficient methods. In 2025, Li et al. illustrated the metal-free chemo-selective oxidative cyclization and Hofmann-type rearrangement of diversely substituted α-acyl-β-aminoacrylamides 29a catalyzed by PIFA K in trifluoroacetic acid (TFA), to furnish poly-substituted oxazol-2(3H)-ones 29b and 29c. In their pot protocol, α-acyl-β-aminoacrylamides 29a were reacted with PIFA K in the presence of TFA and dichloromethane (DCM) to synthesize an imine group of oxazol-2(3H)-ones 29b (89–91% yield) and oxazol-2(3H)-ones 29c (61–86% yield). The proposed mechanism inferred that acrylamides 29a were made to react with PIFA K in the presence of TFA to synthesize iodonium intermediate I that yielded isocyanate II by a redox reaction and Hofmann-type rearrangement. Following this, II underwent intra-molecular cyclization to furnish an imine group of oxazol-2(3H)-ones 29b that yielded oxazol-2(3H)-ones 29c by the removal of NH₂Me in an acidic medium. Gram-scale synthesis of oxazol-2(3H)-one 29ba (69%) reflected the practical utility of this protocol. In addition, the advancement of this protocol and biological activities of oxazol 2(3H)-ones 29b and 29c are under progress [Scheme 29].¹⁰³

Scheme 29. Synthesis of the oxazol 2(3H)-ones 29b and 29c.

Benzo[d]imidazo[5,1-b]thiazoles exhibited a wide array of physiological functions, however, their derivatization reactions were hardly imparted. Concerning this, in 2022, Liu et al. reported a robust C–H chalcogenylation reaction of benzo[d]imidazo[5,1-b]thiazoles 30a based on PIFA K to furnish diverse derivatives of organochalcogen 30d and 30e. In their synthetic approach, using PIFA K, benzo[d]imidazo[5,1,b]thiazoles 30a were reacted with diselenides 30b in the presence of DCM at room temperature for 12 hours to form organochalcogen compounds 30d (88–97% yield). Benzo[d]imidazo[5,1,b]thiazoles 30a were also reacted with disulfides 30c in the presence of MeCN at 60 °C for 12 hours to furnish organochalcogen compounds 30e (83–93% yield). Moreover, organochalcogen compounds 30da and 30ea were synthesized on a gram scale and further utilized for the formation of oxidized product 30f (70%) and reduced products 30g (85%) and 30h (80%) [Scheme 30]. These applications represented the synthetic utility of this methodology. The proposed mechanism was deduced by both radical and ionic pathways, in which PIFA K was made to react with diselenides 30b to form intermediate I. In the radical pathway, intermediate I yielded selenide radicals III (with the removal of II) that reacted with 30a to give intermediate IV. In the next step, IV was oxidized by intermediate II to form VI followed by the removal of PhI and CF₃COO⁻. In the ionic pathway, intermediate I synthesized selenide ions V (via the removal of PhI and CF₃COO⁻) that reacted with 30a to form intermediate VI. At the end, intermediate VI protonated to furnish organochalcogen compounds 30d [Fig. 5].¹⁰⁴

Scheme 30. Synthesis of the organochalcogens 30d and 30e.

Fig. 5. Mechanism of the synthesis of the organochalcogen compounds 30d.

Organic compounds having an amide group have been significantly used in natural and medicinal products, whereas their selective reactions due to nitrogen and oxygen were a challenge. Regarding this, in 2023, He et al. envisioned PhIO P-catalyzed chemodivergent cycloisomerization of o-alkenylbenzamide derivatives 31a to achieve iminoisocoumarin skeletons 31b and isoquinolinones 31c by an elimination cascade/1,2-aryl migration. In their novel approach, o-alkenylbenzamide derivatives 31a were reacted with PhIO P, 2,4,6-tris isopropyl benzene sulfonic acid and Lewis acid LiClO₄ in dichloroethane (DCE) at 80 °C for 0.1 to 0.5 hours to yield iminoisocoumarin skeletons 31b (73–92% yield), and o-alkenylbenzamide derivatives 31a were reacted with PhIO P and TMSOTf in methanol to yield isoquinolinones 31c (62–86% yield) under reflux for 0.5 to 2 hours. In this protocol, DFT studies illustrated that iminoisocoumarin skeletons 31b were formed due to the selective nucleophilicity of nitrogen that was caused by PhI(OMe)₂ (formed in situ from PhIO and TMSOTf in methanol), while isoquinolinones 31c were formed due to the selective nucleophilicity of oxygen, which was caused by Koser's reagent (formed in situ by the reaction of PhIO, 2,4,6-tris isopropyl benzene sulfonic acid and Lewis acid LiClO₄ in dichloroethane). In addition, the economic utility of this protocol was demonstrated by generating hypervalent iodine species in situ from PhIO P and exogenous oxidants that were further used to synthesize 31ba (92%) and 31ca (56%) [Scheme 31].¹⁰⁵

Scheme 31. Synthesis of the iminoisocoumarin skeletons 31b and isoquinolinones 31c.

In 2023, Sodoor et al. presented a robust and metal-free brominative annulation reaction catalyzed by [hydroxy(tosyloxy)iodo]-4-clorobenzene (HTIB) S to synthesize 4-bromoisocoumarins 32b from 2-alkynylaryloate esters 32a. In their synthetic approach, 2-alkynylaryloate esters 32a were reacted with 4-chloro-HTIB S (from which bromoiodane I was generated in situ) and potassium bromide (KBr) in the presence of 1,2-dichloroethane at room temperature for 6 hours to yield highly substituted 4-bromoisocoumarins 32b (18–91% yield). In addition, 4-bromoisocoumarin 32ba was synthesized on a large scale and further transformed to 4-phenyl isocoumarin 32c (53%), π-extended isocoumarin derivative 32d (29%) and 4-unsubstituted isocoumarin 32e (81%) by using previously developed methods that indicated the practical and synthetic utilities of this approach. 4-Bromoisocoumarin 32f (70%), 4-chloroisocoumarin 32g (73%) and 4-iodoisocoumarin 32h (68%) were also synthesized catalytically. The plausible reaction mechanism entailed that transient bromoiodane I was formed in situ from 4-chloro-HTIB S and KBr by ligand exchange, and I reacted with 2-alkynylaryloate esters 32a by two pathways. In the first pathway, alkyne triple bond of 32a coordinated with bromine of I with the subsequent intramolecular attack of carbonyl oxygen on the triple bond of 32a to form oxonium ion IVvia intermediate II by the removal of OTs and ArI. In the second pathway, IV was synthesized by the intramolecular attack of carbonyl oxygen on the triple bond of 32a with subsequent attack of the triple bond on iodine of Ivia intermediate III with reductive elimination and eventual removal of OTs and ArI. Following this, water attacked on the electrophilic carbon atom of IV to yield 4-bromoisocoumarins 32b by the removal of MeOH [Scheme 32].¹⁰⁶

Scheme 32. Synthesis of the 4-bromoisocoumarins 32b.

Due to the broad spectrum of isoquinolinones in medicinal chemistry, they were synthesized by organic electrochemistry, visible light and metal-catalyzed strategies.^107,108 However, these methods required high temperatures and produced heavy metal residues. Regarding this, in 2023, Yang et al. envisioned a one-step metal-free DMP T-based oxidative C–N coupling reaction to synthesize isoquinoline-1,3-diones 33c and isoquinoline-1,3,4-triones 33d. Their one-step synthetic protocol involved the DMP T-catalyzed reaction of functionalized isoquinolines 33a with alkyl bromide 33b in the presence of N-methyl-2-pyrrolidone (NMP) and air at room temperature for 36 hours to furnish isoquinoline-1,3-diones 33c (61–98% yields) and isoquinoline-1,3,4-triones 33d (61–96% yield). However, the synthesis of isoquinoline-1,3,4-triones 33d highlighted the synthetic utility of this methodology [Scheme 33].¹⁰⁹

Scheme 33. Synthesis of the isoquinoline-1,3-diones 33c and isoquinoline-1,3,4-triones 33d.

In 2024, Zhang and coworkers illustrated the metal-free tellurolation and oxidative intramolecular cyclization of 2-alkynylanilines 34a catalyzed by PIFA K to obtain 3-aryltelluroindoles 34c. In their synthetic methodology, 2-alkynylanilines 34a were reacted with diaryl ditellurides 34b and PIFA K in the presence of HFIP at room temperature for 3 hours to furnish 3-aryltelluroindoles 34c (36–89% yield). In addition, 3-aryltelluroindole 34ca was utilized to synthesize indole 34da (50%) and indolone 34db (55%) derivatives. The plausible reaction mechanism entailed that diaryl ditellurides 34b nucleophilically attacked on PIFA K to synthesize intermediate I (with the removal of PhI) in situ, which underwent tellurolation and oxidative intramolecular cyclization with 2-alkynylanilines 34a to yield intermediate III through transition state II. In the next step, III deprotonated to yield 3-aryltelluroindoles 34c by the removal of HOCOCF₃ [Scheme 34].¹¹⁰

Scheme 34. Synthesis of the 3-aryltelluroindoles 34c.

Due to biological activities, spiroaminals and spiroiminals are markedly used in natural products. Regarding this, in 2024, Kumar and coworkers reported tandem aminyl-radical ring formation and the oxidation of amines (35c, 35d and 35e) catalyzed by PIDA C for the synthesis of C–H activation-mediated 5/5-spiroiminals (35f, 35i and 35l). In their radical ring formation approach, steroidal amines (35c, 35d and 35e) were synthesized from acetates 35a and 35b [Fig. 6]. In their synthetic methodology, amines 35c, 35d and 35e were reacted with PIDA C and I₂ in the presence of CH₃CN at 0 °C to yield spiroiminals [35f (63%), 35i (72%) and 35l (65%)], spiroaminals [35g (9%), 35j (7%) and 35m (9%)] and oxyimines [35h (8%), 35k (6%) and 35n (11%)], respectively. Varying product formation of spiroiminals (36f, 36i and 36l), spiroaminals (35g, 35j and 35m) and oxyimines (35h, 35k and 35n) were due to the substitution at alpha carbon of amines, which significantly affected the PIDA C-mediated ring formation of steroidal amines [Scheme 35]. Moreover, synthetic utilities of this methodology are under progress.¹¹¹

Fig. 6. Synthesis of the steroidal amines 35c, 35d and 35e.

Scheme 35. Synthesis of the spiroiminals (35f, 35i and 35l), spiroaminals (35g, 35j and 35m) and oxyimines (35h, 35k and 35n).

Cyclic-oxime ethers are abundantly present in natural products and used in pharmaceutical products due to their biological activities. In 2024, Gharpure et al. pioneered robust and metal-free intramolecular keto oximation catalyzed by PIDA C to synthesize cyclic-oxime ethers 1,2-oxazines 36b and 3-acyl Δ²-isoxazolines 36c from o-alkynyl hydroxylamines 36a. In their synthetic methodology, o-alkynyl hydroxylamines 36a were reacted with PIDA C to yield 1,2-oxazines 36b (16–84% yield) in the presence of TFE at −20 °C and yielded 3-acyl Δ²-isoxazolines 36c (22–92% yield) in the presence of DCE at room temperature in 2–5 minutes. In addition, to represent the synthetic application of this methodology, o-alkynyl hydroxylamine 36ca was transformed to 3-vinyl Δ²-isoxazoline 36d (81%), homoallyl alcohol 36e (92%), isoxazoline 36f (87%), isoxazolidine 36g (58%), oxime 36h (91%), phenyl ester 36i (66%) and 2,5-diphenylpyrazine derivative 36j (54%) by using previously developed methods. Due to the synthesis of isoxazolidine compound 36j, this methodology has great importance in the discovery of new drugs [Scheme 36]. The plausible reaction mechanism proceeded via nucleophilic substitution on PIDA C by nitrogen of o-alkynyl hydroxylamines 36a, which formed intermediate I that was converted into nitrenium ion IIvia the removal of PhI and AcO⁻. Following this, AcO⁻ attacked on alkyne of II to synthesize V. During this pathway, the activation of alkyne of o-alkynyl hydroxylamines was not done. Hence, alternatively, in the second pathway, the activation of alkyne of 36a was accomplished by PIDA C that catalyzed the intramolecular attack of nitrogen on alkyne to synthesize intermediate IVvia intermediate III. In the next step, IV underwent a reduction-elimination process to form intermediate V (by the removal of PhI) that yielded 3-acyl Δ²-isoxazolines 36cvia deacylative 1,4-elimination [Fig. 7].¹¹²

Scheme 36. Synthesis of the cyclic-oxime ethers 1,2-oxazines 36b and 3-acyl Δ²-isoxazolines 36c.

Fig. 7. Mechanism of the synthesis of the 3-acyl Δ²-isoxazolines 36c.

In 2025, Wasaki et al. envisioned a metal-free 1,3-iodoesterification reaction of 2-substituted indoles 37a mediated by a hypervalent iodine(iii) reagent U to synthesize 3-iodo-2-trihaloacetoxymethyl indoles 37b and 3-iodo-2-pivaloyl/acyl/benzoylmethyl indoles 37c. In their novel approach, 2-substituted indoles 37a were reacted with trihaloacetic acids, MesI(OAc)₂U and iodination reagents (DIH/NIS) in the presence of CH₂Cl₂ to yield 3-iodo-2-trihaloacetoxymethyl indoles 37b (63–95% yield) via acid-promoted C_sp²-H/C_sp³-H functionalization. Moreover, in their one-pot protocol, 3-iodo-2-pivaloyl/acyl/benzoylmethyl indoles 37c (28–86% yield) were formed via 1,3-iodoesterification/hydrolysis of trihaloesters 37b with K₂CO₃ aq./Et₃N and silica gel in the presence of THF/MeOH/AcOEt through the rearrangement of pivaloyl/acyl/benzoyl groups (R4) for 12 hours. In addition, in order to represent the synthetic application of this methodology, 3-iodo-2-pivaloylmethyl indole 37ca was used for the synthesis of many products such as 37d (78%), 37e (80%), 37f (92%), 37g (80%) and 37h (93%). The plausible mechanism involved the reaction of MesI(OAc)₂U with trihaloacetic acids to form (acetoxy)(trihaloacetoxy)iodomesitylene I, which reacted with 2-substituted indoles 37a to form intermediate II. Following this, II reacted with 37a and DIH to generate iodonium-ion III that converted to IVvia an acid-mediated ligand exchange process. In the next step, IV formed intermediate V that yielded exo-enamines VI, which underwent an S_N2 reaction with trihaloacetic acid to give 1,3-iodoesterification products 37b [Scheme 37].¹¹³

Scheme 37. Synthesis of the 3-iodo-2-trihaloacetoxymethyl indoles 37b and 3-iodo-2-pivaloyl/acyl/benzoylmethyl indoles 37c.

9-Membered ketolactams are mainly used as antimalarial agents, but their synthesis was very challenging due to complex pathways. In 2025, Yang et al. envisioned the robust oxidative cyclization of naphthol-anilines 38a mediated by PIDA C to synthesize unique 9-membered ketolactams 38c by double dehydrogenation. In their novel methodology, naphthol-anilines 38a were reacted with PIDA C and mildly basic sodium methanolate (DABCO) 38b in the presence of CHCl₃ at room temperature for 12 hours to furnish 9-membered ketolactams 38c (45–95% yield). Moreover, 9-membered ketolactams 38c underwent ring contraction in the presence of nucleophiles and formed 7-membered lactones by the expulsion of an aniline moiety, such as ketolactam 38ca, which transformed to lactones 38d (99%) and 38e (71%) in the presence of NaBH₄ and MeMgBr, respectively. In order to represent the synthetic utility of this methodology, 9-membered ketolactams 38c were further transformed to synthetic products such as N-acetylated 9-membered ketolactam 38f (82%), N-methylated substitution product 38g (76% yield) and product 38h (77%) [Scheme 38]. The plausible reaction mechanism proceeded via base (DABCO) 38b-assisted oxidation of naphthol-anilines 38a with PIDA C that formed ketoimine Ivia the removal of PhI. Following this, intermediate I underwent oxidative cyclization to yield zwitterionic intermediate II, which was subjected to 1,2-oxygen atom migration to form III. In the next step, H₂O attacked on III and formed 1,2-diol IVvia S_N1 mechanism, which synthesized 9-membered ketolactams 38c in the presence of PIDA C with the subsequent removal of AcOH, PhI and AcO⁻ [Fig. 8].¹¹⁴

Scheme 38. Synthesis of the 9-membered ketolactams 38c.

Fig. 8. Mechanism of the synthesis of the 9-membered ketolactams 38c.

In 2025, Chauhan et al. envisioned metal-free C–H selenylation and thiolation at the pseudoanomeric position of glycals (C-2 branched) 39a, catalyzed by PIFA K to synthesize thio-/seleno-glycosides/1-thiotrehaloses 39c. In their synthetic approach, glycals 439a were reacted with PIFA K, aliphatic, sugar and aromatic diselenides/disulfides 39b in the presence of dichloromethane (CH₂Cl₂) at room temperature for 12 hours to yield a series of thio-/seleno-glycosides/1-thiotrehaloses 39c (62–89% yield). In addition, the synthesis of Se-glycosides 39ca and S-glycosides 39cb on a gram scale and the de-acylation of 39cc and 39cd for the synthesis of products 39d (89%) and 39e (83%) represented the practical and synthetic utilities of this approach. The possible mechanism of this reaction proceeded via the oxidation of diselenides/disulfides 39b with PIFA K that formed I, which underwent homolytic cleavage to synthesize II. In the next step, the electrophilic attack of glycals 39a on II yielded the radical intermediate III, which underwent oxidation to give IV that yielded corresponding products 39c by deprotonation [Scheme 39].¹¹⁵

Scheme 39. Synthesis of the thio-/seleno-glycosides/1-thiotrehaloses 39c.

2.8.2. Formation of C–C and C–X (X = heteroatom) bonds

In 2021, Wang et al. developed an efficient, cost-effective and highly stereoselective four-component reaction mediated by copper and Togni's reagent A to synthesize stereodefined (Z)-enol carbamates 40c. In their novel approach, highly substituted alkenes 40a were reacted with amines 40b (acting as a base as well as a coupling reagent), CO₂, Togni's reagent A and Cu(OAc)₂ in the presence of DMSO at 60 °C for 8 hours to yield an array of stereodefined (Z)-enol carbamates 40c (42–74% yield). This methodology illustrated a wide substrate scope and good tolerance of functional groups [Scheme 40].¹¹⁶

Scheme 40. Synthesis of the stereodefined (Z)-enol carbamates 40c.

Seven-membered oxygen, sulphur, and nitrogen-heterocyclic compounds have been markedly used as medicinal and biological active compounds. They were synthesized in the presence of metals under harsh conditions however, the hypervalent iodine reagent (Koser's reagent) V made their synthesis under metal-free conditions easy. In 2021, Khan and coworkers presented the robust and metal-free PhI(OH)OTs (HTIB) (Koser's reagent) V-mediated ring expansion of methylenic heterocycles 41a to furnish seven-membered compounds 41b. In their novel approach, methylenic heterocycles 41a were reacted with HTIB V in the presence of CH₃CN and H₂O in 9 : 1 proportion at room temperature to yield seven-membered compounds 41b (36–88% yield). The reaction mechanism involved that methylenic heterocycles 41a were made to react with HTIB V (by electrophilic addition across the double bond) in the presence of CH₃CN and H₂O in 9 : 1 proportion via the removal of TsO⁻ to synthesize intermediate I, which underwent aryl migration to yield seven-membered compounds 41b with the elimination of H₂O and PhI [Scheme 41].¹¹⁷

Scheme 41. Synthesis of the seven-membered compounds 41b.

In 2022, Yang et al. reported the stereo-selective difluorinative ring expansion of alkynylcyclopropanes 42a with Olah's reagent (HF Py) catalyzed by 2,3,4,5,6-pentafluoro(diacetoxyiodo)benzene (HVI-3) W to synthesize difluorinated alkylidenecyclobutanes 42b. In their synthetic approach, alkynylcyclopropanes 42a were reacted with HVI-3 W and Olah's reagent (for fluorine source) in the presence of chloroform at −15 °C for 2 hours to yield difluorinated alkylidenecyclobutanes 42b (39–79% yield). However, some alkynylcyclopropanes such as 42aa, 42ab, 42ac and 42ad failed to yield the corresponding difluorinated alkylidenecyclobutanes via this methodology. The plausible mechanism entailed that the reaction of HVI-3 W with Olah's reagent (HF·Py) synthesized iodoarene difluoride I that reacted with the triple bond of alkynylcyclopropanes 42a to form II. Following this, stereo- and regio-selective fluoride ions attacked on II to form III, which underwent Wagner–Meerwein-type rearrangement to yield cyclobutyl cation IV trapped by other fluoride ions to synthesize E-isomer difluorinated alkylidenecyclobutanes 42b. However, Z-isomer difluorinated alkylidenecyclobutanes 42c (as minor products) were also formed via isomerization [Scheme 42].¹¹⁸

Scheme 42. Synthesis of the difluorinated alkylidenecyclobutanes 42b.

γ-Lactones have great importance due to their efficient use in the synthesis of natural and biologically active products. In 2023, Matsumoto and coworkers illustrated the metal-free, stereo-selective and PIDA C-catalyzed synthesis of 5-alkoxy-4-phenyltetrahydrofuran-2-ones (γ-lactones) 43b from diversely substituted trans-4-phenyl-3 butenoic acids 43a. In their synthetic approach, trans-4-phenyl-3 butenoic acids 43a were reacted with PIDA C (activated by TMSOTf) and alcohols in the presence of DCM at −40 °C for 5 minutes to furnish 5-alkoxy-4-phenyltetrahydrofuran-2-ones (γ-lactones) 43b (20–84% yield). The proposed mechanism entailed that PIDA C (activated by TMSOTf) was reacted with trans-4-phenyl-3 butenoic acids 43a to form iodolactone I by the removal of TfO⁻ that yielded intermediate II by the elimination of PhI and AcO⁻. Following this, nucleophiles (R²OH) attacked on intermediate II to synthesize trans-5-alkoxy-4-phenyltetrahydrofuran-2-ones 43bvia the S_N2 mechanism [Scheme 43].¹¹⁹

Scheme 43. Synthesis of the 5-alkoxy-4-phenyltetrahydrofuran-2-ones (γ-lactones) 43b.

Due to the diverse applications of isoxazolines in pharmaceutical chemistry, several successful synthetic methods catalyzed by metals were used for their synthesis. In 2023, Budhwan et al. reported a cost-effective, efficient, base- and metal-free oxidative reaction based on Koser's reagent V, to synthesize isoxazoline derivatives 44e, 44f and 44g. In their synthetic approach, using Koser's reagent V, nitrile oxides II (that were formed in situ from their respective aldoximes) underwent a 1,3-dipolar cycloaddition reaction individually with maleimides 44b, acrylonitrile 44c and styrene 44d in the presence of diethyl ether (Et₂O) at room temperature for one hour to furnish isoxazoline derivatives 44e (41–95% yield), 44f (51–94% yield), and 44g (54–94% yield), respectively. The plausible reaction mechanism deduced that aldoximes 44a were made to react with Koser's reagent Ta that formed intermediate I, which underwent a tautomerization reaction to form highly reactive nitrile oxide II followed by the subsequent removal of PhI, H₂O and TsOH. In the next step, II (formed in situ) underwent intermolecular cycloaddition with dipolarophile (maleimides 44b, acrylonitrile 44c and styrene 44d) to form respective isoxazolines 44e, 44f and 44g. In addition, Koser's reagent V was utilized for the synthesis of many medicinal heterocyclic compounds and for late-stage functionalization [Scheme 44].¹²⁰

Scheme 44. Synthesis of the isoxazoline derivatives 44e, 44f and 44g.

Carboline derivatives have been efficiently used as natural products, medicinal and functional compounds. In 2024, Wang and coworkers carried out the metal-free, efficient and chemoselective [3 + 3] annulation of indole-3-carboxaldehydes 45a and 3-aminocyclohex-2 enones 45b mediated by PIDA C and benzoic acid to furnish α-carboline derivatives 45c. In their novel [3 + 3] annulation, indole-3-carboxaldehydes 45a and 3-aminocyclohex-2 enones 45b were reacted with PIDA C and benzoic acid in the presence of 1,2-dichlorobenzene (o-DCB) at 130 °C for 12 hours to synthesize α-carboline derivatives 45c (43–78% yield). Moreover, in order to represent the practical and synthetic utilities of this methodology, 45ca was synthesized on a gram scale and synthetically transformed to the alkynylated product 46d (61%), diarylamine 45e (87%), alcohol 45f (72%) and arylated product 45g (81%). The proposed mechanism involved that indole-3-carboxaldehydes 45a were made to react with 3-aminocyclohex-2 enones 45b in the presence of benzoic acid to form imine intermediate I (by the removal of H₂O), which reacted with PIDA C to synthesize II by the elimination of AcO⁻. Following this, II yielded α-carboline derivatives 45cvia the removal of PhI and AcOH. Alternatively, in the other pathway (that is efficient presently), α-carboline derivatives 45c were also formed from imine intermediate I by 6π electrocyclization [Scheme 45].¹²¹

Scheme 45. Synthesis of the α-carboline derivatives 45c.

Due to their great pharmaceutical importance, isochroman-1-onederivatives and 3-substituted phthalides have been remarkably synthesized. In 2025, Meng et al. illustrated a hypervalent iodine(iii) (PIDA C\PIFA K)-catalyzed halogenated addition and ring-contraction rearrangement reaction to synthesize isochroman-1-one derivatives 46b and 3-substituted phthalides 46c from highly substituted naphthalen-1(2H)-ones 46a. In their synthetic protocol, naphthalen-1(2H)-ones 46a were reacted with n-Bu₄NR³ (TBAR³) in the presence of DCM to furnish isochroman-1-onederivatives 46b (39–95% yield) catalyzed by PIDA C with R⁴OH and 3-substituted phthalides 46c (40–91% yield) mediated by PIFA K with H₂O [Scheme 46]. Target products 46b and 46c were mainly formed through proton transfer succeeded by ring opening and cyclization. According to biological evaluations, isochroman-1-onederivatives 46b and 3-substituted phthalides 46c were used as PANC-1 inhibitors that represented the synthetic application of this protocol [Scheme 46].¹²²

Scheme 46. Synthesis of the isochroman-1-one derivatives 46b and 3-substituted phthalides 46c.

In 2025, An et al. carried out metal- and base-free intramolecular oxidative dearomatization of diversely substituted naphthols/phenols 47a catalyzed by PIFA K to synthesize diastereomeric hydronaphthofurans 47b and 47c and hydrobenzofurans 47d. In their one-pot synthesis, naphthols 47a were reacted with PIFA K in the presence of MeCN at room temperature for 1 hour and then reacted with Triton B in the presence of ^tBuOOH and THF for 20 minutes to yield hydronaphthofurans 47b (39–82% yield) and 47c (38–47% yield), respectively. Phenols 47a were reacted with PIFA K in the presence of MeCN at 0 °C for 15 minutes to furnish hydrobenzofurans 47d (59–93% yield). Moreover, hydronaphthofurans 47b and hydrobenzofurans 47d were used to form a library of natural products such as 47e (quantitative yield) by the Luche reduction, 47f (96%), 47g (97%) and 47h (99%) by an epoxidation reaction, 47i (88%) and 47j (95%) via the Diels–Alder reaction, and 47k (95%) and 47l (91%) via 1,4-addition, respectively [Scheme 47].¹²³

Scheme 47. Synthesis of the diastereomeric hydronaphthofurans 47b and 47c and hydrobenzofurans 47d.

Hypervalent iodine(iii) reagents have significantly served as single-electron oxidants that make them efficient for various transformations, among which the azidoarylation of alkenes to azide-substituted oxindoles is important. In 2025, Fang and coworkers reported a metal free cyclization of various imidazoles tethered to alkene 48a with TMSN₃ mediated by PIFA K to synthesize azide-substituted tricyclic imidazoles 48b and alkenyl-substituted tricyclic imidazoles 48c. In their novel approach, utilizing PIFA K, imidazoles tethered to alkene 48a were reacted with TMSN₃ to synthesize azide-substituted tricyclic imidazoles 48b (16–99% yield) in the presence of DCM at room temperature for one hour and alkenyl-substituted tricyclic imidazoles 48c (50–61% yield) in the presence of H₂O at 80 °C for 12 hours. In order to represent the practical and synthetic utilities of this approach, 48ba was synthesized on a gram scale and further transformed to N-Boc-protected product 48d (68%), phosphoramidate 48e (65%) and triazole 48f (82%) by using previously developed methods. The plausible reaction mechanism involved that TMSN₃ was made to react with PIFA K to synthesize intermediate I (by the removal of CF₃CO₂TMS) that yielded azidoiodanyl radical II and azide radical III. Following this, azide radical III was added at the terminal alkene of imidazole 48aa to synthesize intermediate IV that underwent intramolecular cyclization to yield radical intermediate V. In the next step, V underwent proton abstraction from azidoiodanyl radical II to synthesize azide-substituted tricyclic imidazole 48ba (with the removal of PhI and HN₃) that yielded alkenyl-substituted tricyclic imidazole 48cavia the removal of HN₃ [Scheme 48].¹²⁴

Scheme 48. Synthesis of the azide-substituted tricyclic imidazoles 48b and alkenyl-substituted tricyclic imidazoles 48c.

C–H functionalization is a cost-effective and atom-economical method to achieve C–C and C–X bonds, and it occurs mostly via a metal-catalyzed reaction. In 2025, Shakeena and coworkers illustrated a metal-free one-pot cascade C–H functionalization reaction of aryl isothiocyanates 49a mediated by 4,5-difluoro-2-iodobenzoic acid X to furnish 2-arylbenzothiazoles 49d and 2-heteroarylbenzothiazoles 49e. In their one-pot strategy, using 4,5-difluoro-2-iodobenzoic acid X, aryl isothiocyanates 49a were reacted with unsubstituted arenes 49b/heteroarenes 49c in the presence of triflic acid (TfOH) (acting as both the ligand source and Brønsted acid) in hexafluoroisopropanol (HFIP) and oxone at room temperature to synthesize 2-aryl benzothiazoles 49d (11–83% yield) and 2-heteroaryl benzothiazoles 49e (14–91% yield), respectively. In addition, 2-(thiophen-2-yl)benzo[d]thiazole 49da (81%) was synthesized on a gram scale, and an antitumor drug 2-(3,4 dimethoxyphenyl)-5-fluorobenzo[d][thiazole] (GW610) 49ea (44%) was also prepared by using this methodology. The proposed reaction mechanism entailed that aryl isothiocyanates 49a were made to react with heteroarenes 49b in the presence of TfOH (acting as Brønsted acid) that yielded thioamides I. In the next step, iodine(iii) reagent X′ (that formed in situ from X, ligand TfOH and HSO₅⁻K⁺ by subsequent removal of H₂O and HSO₄⁻K⁺) catalyzed the I by oxidative cyclization to synthesize II followed by the removal of X′ (which re-oxidized with oxone to iodine(iii) reagent X). Following this, II yielded the corresponding products 49d by an aromatization reaction [Scheme 49].¹²⁵

Scheme 49. Synthesis of the 2-arylbenzothiazoles 49d and 2-heteroarylbenzothiazoles 49e.

In 2025, Yan and coworkers demonstrated a vigorous oxidative ring opening reaction of catechols 50a with ammonium/methyl carbamates and PIFA K to furnish cis,cis-muconic acid mononitriles 50b. In their novel approach, cis,cis-muconic acid mononitriles 50b (3–98% yields) were formed by the reaction of catechols 50a with PIFA K and ammonium/methyl carbamates in the presence of alcohols or tetrahydrofuran (THF) at −15 °C for 0.5 hours and then at room temperature for 4.5 hours. The proposed reaction involved the oxidation of catechols 50a followed by the amine-quinone condensation and nucleophilic addition reaction that resulted in cis,cis-muconic acid mononitriles 50b by aromatic ring opening. Due to the slight difference in electronic and steric effects, asymmetrical substituted catechols generated a major isomer or a single isomer. Moreover, by using this methodology, 7,8-dihydroxy-4-methylcoumarin and 2-naphthol were converted into nitrile carboxylic acids 50c (76%) and 50d (49%), respectively [Scheme 50]. The scaling of this reaction to gram quantities represented the practical utility of this methodology.¹²⁶

Scheme 50. Synthesis of the cis,cis-muconic acid mononitriles 50b.

2.8.3. Formation of N–O and C–O bonds

In 2025, Chonradeenitchakul et al. pioneered the robust, one-pot, two-step oxidative annulation of 2-alkynylanilines 51a catalyzed by meta-chloroperbenzoic acid (m-CPBA), lithium iodide (LiI) and PIFA K to furnish a wide range of 3-acylanthranils 51b. In their one-pot annulation strategy, 2-alkynylanilines 51a were reacted with m-CPBA in the presence of dry MeCN at 0 °C to form intermediate I that reacted with LiI and PIFA K in the presence of MeCN at room temperature for 0.5–1 hour to synthesize 3-acylanthranils 51b (18–69% yields) [Scheme 51]. Moreover, this strategy has been significantly used in the construction of building blocks and synthetic products in the organic field.¹²⁷

Scheme 51. Synthesis of the 3-acylanthranils 51b.

2.8.4. Formation of N–I and C–N bonds

In 2025, Negrão and coworkers demonstrated a Cu-mediated electrophilic amination reaction of highly substituted organozinc compounds 52b using aminated hypervalent iodine reagents Z (prepared from hydroxybenziodoxolone Y and silylated amines 52a) to obtain alkyl/aryl/heteroaryl amines 52c. In their novel approach, amino-λ³-iodanes Z (25–100% yields) were synthesized by the reaction of hydroxybenziodoxolone Y with silylated amines 52a in the presence of MeCN at room temperature for 16 hours. Amino-λ³-iodanes Z were reacted with organozinc compounds 52b and Cu(OAc)₂ in the presence of N₂ in a closed Schlenk tube at room temperature to synthesize alkyl/aryl/heteroaryl amines 52c (24–91% yields). Moreover, alkyl amine 52ca was utilized for the synthesis of corresponding carboxylic acid 52d and biologically active benzonatate 52e that reflected the synthetic utility of this protocol [Scheme 52].¹²⁸

Scheme 52. Synthesis of the alkyl/aryl/heteroaryl amines 52c.

3. Conclusion and future perspectives

This review article summarizes the recent synthetic utilities of hypervalent iodine(iii/v) reagents. Due to ongoing advancement, during the period of 2021–2026, several new hypervalent iodine-based methodologies have been overviewed, which have been employed for the synthesis of C–C, C–N, C–O, C–S, C–halogen and many miscellaneous bonds. Due to their environmentally benign nature, commercial availability, and wide scope in agrochemical, material and pharmaceutical industries, the hypervalent iodine reagents are efficiently used in organic chemistry. Multiple studies have highlighted the wide use of hypervalent iodine reagents as alternatives of metal-catalyzed reagents. Recently, classic and many novel reagents such as PIFA, PIDA, bis(metachlorobenzoxy)iodobenzene, PhIO, dimethylamino-iodine, N-chlorofluoroiodane(iii) reagent, acetoxybenziodoxolone, IBX, DMP and Koser's reagent have been utilized for the synthesis of organic molecules. Among the important achievements in using hypervalent iodine reagents, the formation of a C–C bond has triggered the radical-based oxidative coupling, alkylation and arylation reactions in organic synthesis. The wide use of these reagents in the construction of C–N bonds has enabled azidation, heterocycle formation and oxidative amination. Moreover, intermolecular and intramolecular C–N coupling reactions facilitate the yielding of nitrogen-bearing bioactive products such as anti-cancer drugs and antibiotics. Similarly, the formation of the C–O bond has facilitated the accomplishment of complex oxygenated products. In addition, several novel synthetic approaches catalyzed by hypervalent iodine reagents and the exploration of enantioselective reactions mediated by chiral hypervalent iodine catalysts/reagents have introduced new efficient pathways in modern organic-chemistry. Hypervalent iodine reagents have also found wide-ranging applications in the late-stage functionalization of biomolecules. However, for most of the transformations based on hypervalent iodine reagents, external oxidizing agents are required, which decrease their atom economy. Due to the strong oxidizing and electrophilic nature of these reagents, the possibility of over-oxidation and side reactions still exits. Future advancement in the chemistry of hypervalent iodine reagents should mitigate the limitations related to the sustainability, scalability, selectivity and reagent stability. Further evolution of recyclable and catalytic iodine reagents in conjugation with their incorporation in electrochemistry, photochemistry and continuous-flow techniques offers promising research directions. Moreover, advancement towards late-stage functionalization, asymmetric synthesis and drug development could further strengthen the practical utility of hypervalent iodine reagents.

Conflicts of interest

There are no conflicts to declare.

Data availability

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