Phenyliodine(III)diacetate (PIDA): Applications in Organic Synthesis

Abstract

One of the hypervalent iodines most widely used as an oxidizing agent in organic chemistry is (diacetoxyiodo)benzene (PhI(OAc)₂), also known as (DAIB), phenyliodine(III) diacetate (PIDA). In this septennial mini-review, the authors have concisely and systematically presented representative applications of PIDA in organic synthesis involving C-H functionalization, hetero-hetero bond formations, heterocyclic ring construction, rearrangements or migrations and miscellaneous reactions along with their interesting mechanistic aspects starting from the summer of 2015 to the present.

1. Introduction

In comparison to conventional heavy-metal oxidants, hypervalent iodine (III) reagents, also known as “3-iodanes”, have attracted a lot of attention over the past three decades because they are plentiful, stable, non-toxic, environmentally friendly, and mild 2e⁻ oxidants with a variety of applications [1,2,3,4,5,6]. They consistently support distorted trigonal bipyramidal geometry with the electronegative ligands in the axial positions and the less electronegative aryl ring and two lone pairs of electrons in the equatorial positions. Hypervalent iodine (III) reagents are electrophilic in nature due to the node in a hypervalent nonbonding orbital, a 3-center-4-electron (3c-4e) bond (L-I-L), which is created by the overlap of the iodine atom’s 5p orbital with the orbitals of two ligands [7].

Many new heterocyclic compounds have been created as a result of the extensive usage of hypervalent iodine (III) reagents to generate carbon-carbon, carbon-hetero atom, and hetero-hetero atom bonds, such as phenyliodine(III) bis(trifluoroacetate), phenyliodine(III) diacetate, iodosobenzene (PhIO). The hypervalent iodine compound (diacetoxyiodo)benzene (PhI(OAc)₂), commonly abbreviated as (DAIB) or phenyliodine(III) diacetate (PIDA), is widely utilized as an oxidizing agent in organic chemistry (Figure 1) [8,9,10]. In addition, (diacetoxyiodo)benzene is utilized in a wide range of pharmaceutical intermediates, liquid crystal display (LCD) polarizing films, industrial, human, and animal nutrition products [https://seemafinechem.com/iodobenzene-diacetate/, accessed on 10 December 2022].

The original PIDA was synthesized by Willgerodt in 1886 by reacting iodobenzene with a solution of acetic and peracetic acid [11]. Current methodologies use a variant of this process that entails the oxidative diacetoxylation of iodoarenes in acetic or trifluoroacetic acid with suitable oxidants such as periodates, m-chloroperoxybenzoic acid, potassium peroxodisulfate, H₂O₂-urea, selectfluor, and sodium perborate [12,13,14]. The applications of PIDA in relation to a few illustrative organic syntheses are the main subject of this brief review, which spans the summer of 2015 to the present.

2. Recent Applications of PIDA (from 2015)

2.1. C-H Functionalization and Hetero-Hetero Bond Formations

2.1.1. C-C Bond Formation

(a)

C-Alkylation reaction

Due to the importance of alkyl groups in the life and material sciences, alkylation reactions to create alkylated heterocycles have garnered the attention of chemists as a key area of research. On the other hand, quinoxalin-2(1H)-ones are widely present in a variety of pharmacologically active molecules and naturally occurring chemicals, making them a valuable class of heterocycles. The decarboxylative alkylation of quinoxalin-2(1H)-ones (2) with phenyliodine(III) dicarboxylates under visible light was established by He and co-workers, as an effective and sustainable method for producing 3-alkylquinoxalin-2(1H)-ones (3 and 4) in the presence of PIDA (1) and PEG-200 as solvent (Scheme 1) [15].

The current ruthenium(II) catalytic system, which could be successfully recycled five times without major decrease in its effectiveness, made it simple to create various 3-alkylquinoxalin-2(1H)-ones. The optimized reaction parameters are: PIDA (1 equiv.), Ru(bpy)₃Cl₂·6H₂O (1 mol%) in PEG-200 and 3W Blue LED. Additionally, PhI(OTfa)₂ was employed in place of PhI(OAc)₂ without causing any reaction. In general, the synthesis of quinoxalin-2(1H)-ones with phenyl rings carrying electron-withdrawing and electron-donating substituents went without a hitch, yielding the intended products in good to exceptional amounts. Notably, this methylation process also demonstrated high compatibility with functionalities, and some functional groups, such as halogen, acyl, nitro, and ester groups, were tolerated to produce compounds that can be used for additional synthesis.

As shown in Figure 2, a potential reaction pathway was suggested. Initial visible light exposure produces the excited-state *Ru(ppy)₃²⁺. After this, a single electron transfer (SET) process occurs. Radical 5 and Ru(ppy)₃³⁺ are produced between the reaction of PhI(OAc)₂ (1) and *Ru(ppy)₃²⁺. The radical 5’s I-O link is then broken, resulting in an acyloxy radical, which is then converted to a different compound by decarboxylation to produce the methyl radical 6. Next, the resulting methyl radical 6 is added to 2a, which results in the formation of the nitrogen radical 7. This nitrogen radical 7 is then oxidized by Ru(ppy)₃³⁺, which results in the formation of the nitrogen cation 8. In conclusion, the creation of product 3a will take place as a consequence of the abstraction of β-H from 8 by carboxylic anion.

(b)

C-C bond formation reaction on alkenes

Fluorinated substances have a significant role in the creation of pharmaceuticals. The difluoro-methyl group (CF2H) stands out among them as a physiologically stable lipophilic bioisostere of weak hydrogen bond donors such as alcohols, anilines, amines, or thiophenols and has been used in a variety of medicinal compounds as a result. Terminal alkenes (9) were hydrodifluoromethylated (11) regioselectively in the presence of PIDA, in accordance with a protocol devised by Gouverneur and his group (Scheme 2) [16]. By adopting this metal-free method, it was possible to obtain bio-relevant building blocks that would have otherwise required many deoxyfluorination-based processes in synthetic chemistry. It is photocatalyst-free, exhibits broad functional group tolerance, and employs inexpensive reagents.

The optimized reaction parameters are: PIDA (3 equiv.), CF2HCO2H (10, 6 equiv.) in THF under visible light (λ = 450 nm). Esters, amides, alcohols, aldehydes, halides, and nitriles were all tolerated, and yields ranging from moderate to good were obtained when separating the necessary products. The intended compounds were effectively produced from alkenes containing carboxylic acids or aldehydes in modest yields; however, such functional groups would need to be protected using deoxyfluorination chemistry. Heteroarenes survived the reaction conditions well and did not compete with other heteroarenes for heteroaryl C-H difluoromethylation. The reaction mechanism was claimed to proceed via radical pathway. Difluoroacetic acid 10 is exchanged for the acetate group on 1 to produce 12. When exposed to blue light, photolysis produces 14 that can be decarboxylated to produce •CF₂H (Figure 3). The alkene substrate would benefit from the regioselective addition of this radical. The net hydrodifluoromethylation product would then be produced by the further reaction of the resulting carbon radical 15 with THF. Tetrahydrofuran’s hydrogen atom can be extracted to release the THF α-radical 16, which can then undergo a single electron transfer to the third dimension while simultaneously releasing the oxonium ion 17, iodobenzene, difluoroacetate, and radical 14 for additional alkene functionalization. Given the greater stability of CF₂H than CH₃, hydromethylation was not seen as predicted.

2.1.2. C-O and C-X Bond Formation

Quinoline is a flexible N-based heterocyclic system that is well-known for being present in a wide range of natural products, agrochemicals, medicines, functional materials, and ligands for transition-metal catalysis. Therefore, it is important to create effective synthetic processes for substituted quinolines. The more difficult site-selective C(sp³)-H activation/functionalization of 8-methylquinoline is particularly noteworthy in this domain. A report was developed by Jia et al. on an effective Pd-catalyzed C(sp³)-H selective iodination of 8-methylquinolines (18) [17]. The method provided simple access to a variety of C8-substituted quinolines due to the adaptability of organic iodides (Scheme 3). The effective C(sp³)-H acetoxylation of 8-methylquinolines was also made possible by slightly altering the reaction conditions.

Both strategies had a wide range of substrates, gentle reaction conditions, and strong functional group tolerance. The optimized reaction parameters are: PhI(OAc)₂ (2.0 equiv.), I₂ (1 equiv.), Pd(dba)₂ (10 mol%) in DCE at RT (for C(sp³)-H iodination, 20) and PhI(OAc)₂ (2.0 equiv.), K₂S₂O₈ (2 equiv.), Pd(dba)₂ (10 mol%) in DCE at RT (for C(sp³)-H acetoxylation, 19). It is important to note that the halides F, Cl, Br, and I were all well tolerated at the reaction conditions utilized at the time. These halides were also useful synthetic handles that could be used in additional transformations with ease. The reactivity was essentially unaffected by the position of the substituent on the aromatic rings. The acetoxylation procedure demonstrated excellent functional group compatibility, much like the iodination process mentioned above. Sequential transformations were made possible because a variety of electron-withdrawing and electron-donating groups, at various positions of the quinoline ring, were all well tolerated under the reaction circumstances. It should be noted that substrates having substituents at the C7 position produced lower yields, which was likely due to the steric hindrance of substituent groups at the ortho-position.

According to Figure 4, a possible mechanism for the Pd-catalyzed C(sp³)-H iodization and acetoxylation of 8-methylquinoline (18) was proposed. PhI(OAc)₂ oxidizes Pd₂(dba)₃ to produce a Pd(II) species, which is then palladium-directed by quinoline to produce cyclopalladated complex 21. It should be noted that Pd(II) compounds, such as Pd(OAc)₂ and Pd(PPh₃)₂Cl₂, produced worse results, which can likely be attributed to newly formed Pd(II) species that were produced in situ and had higher catalytic activity. I₂ is added oxidatively to produce Pd(IV) intermediate 22, which is subsequently eliminated reductively to produce iodide 20 and regenerate Pd(II) catalyst. As opposed to this, the oxidative addition of cyclometalated Pd(II) complex 21 with IOAc, which can be produced in situ by the reaction of I₂ with PhI(OAc)₂, results in Pd(IV) species 23, which then produces the acetoxylation product 19 and the Pd(II) catalyst through a subsequent reductive elimination.

2.1.3. C-N Bond Formation

Organoazide compounds are important synthetic building blocks and intermediates in organic chemistry. In addition, the azido moiety is added to lead compounds in drug discovery to boost biological activity. The reasons β-keto acids are often employed as raw materials in organic synthesis include stability, operability, accessibility, and low cost. Selective synthesis of acyl azides (25) or α-azido ketones (26) from keto acids (24) using PIDA(1) was developed by the research group of Xu and Wei [18].

The quantity of reagents used affects selectivity. When 1.2 or 2.2 equiv. of (diacetoxyiodo)benzene were added to derivatives of β-keto acids, the resulting products were α-azido ketone or acyl azide, respectively (Scheme 4). The optimized reaction parameters for obtaining α-azido ketone are: PIDA (1.2 equiv.), NaN₃ (3 equiv.) and NaBr (1.1 equiv.) in acetone: H₂O (5/1, v/v) at RT-Condition A. The optimized reaction parameters for obtaining acyl azide are: PIDA (2.2 equiv.), NaN₃ (6 equiv.) and NaBr (2.5 equiv.) in acetone: H₂O at RT-Condition B. Other hypervalent iodine(III) reagents were found to be less successful in this transformation, including [bis(trifluoroacetoxy)iodo]benzene (PIFA) and (dichloroiodo)benzene. In order to produce the appropriate α-azido ketones in moderate to good yields, authors subjected a variety of different β-keto acids to the optimal reaction conditions. At room temperature, these reactions moved quickly, and utilizing Condition A, quantitative conversion was attained in less than two hours. The reaction conditions were consistent with a variety of substitution patterns, including ortho-, para-, and meta-substituted aromatic rings, naphthyl, and heterocycles (thiophene and furan). As anticipated, benzyl, as well as primary, secondary, tertiary, and cyclic alkyl groups, were all well tolerated.

The authors also examined how various β-keto acids reacted when exposed to Conditions B. It was possible to easily convert both electron-rich and electron-deficient aryl-substituted β-keto acids into the necessary compounds. The fact that halo-substituted aryl ketones survived the reaction well and produced halo-substituted compounds, which may be useful for subsequent transformations, was also remarkable. Additionally, this transformation was tolerable to the substituted naphthyl and heteroaryl (thiophene) keto acids, which produced the respective products in good yields.

Following the findings of the control experiments, it can be said that the decarboxylation step precedes the ligand exchange between the β-keto acid and the hypervalent iodine reagent and that the carboxyl group is crucial to these processes. Keto acid 24 would react with PIDA and sodium bromide under Condition A to produce intermediate 27, which would then undergo decarboxylation to produce compound 28 (Figure 5). The introduction of azide would then cause compound 28 to produce the observed product 26. There are two alternative paths under Condition B. To create enolate intermediate 29, which would then combine with PIDA and sodium bromide to produce dibromo compound 31, intermediate 27 may undergo decarboxylation in Path A. Dibromide intermediate 30 would be decarboxylated in process B to produce 31. Following nucleophilic substitution, an unstable diazido molecule 32 would be created, which would then go through rearrangement to produce product 25 (Figure 4).

2.1.4. C-Se Bond Formation

Organoselenium compounds serve as crucial building blocks in the synthesis of organic molecules. The derivatives of organoselenium compounds are also used as fluorescence probes in the study of materials. More recently, organic and medicinal chemists have paid close attention to organoselenium compounds and subsequent studies of their biological activities. Numerous aryl-Se-heteroaryl compounds that are unsymmetrical exhibit a variety of pharmacological traits, including anticancer, antioxidant, anti-proliferative, antibacterial, and anticholinesterase actions. Diphenyl diselenide was used by Karade et al. to enable metal-free (diacetoxy)iodobenzene-mediated C(sp²)-H phenylselenation of imidazo[1,2-a]pyridines and imidazo[2,1-b]thiazoles (33) in the presence of PIDA [19]. The imidazoheterocycle phenyl selenation product (34) of this procedure demonstrated broad substrate scope, good to outstanding yields, and rapid reaction times (Scheme 5).

The optimized reaction parameters are: PIDA (2 equiv.) in DCM at RT. Numerous imidazo[1,2-a]pyridines with electron-donating and electron-withdrawing groups at aryl or pyridine moieties can be synthesized using this approach. The electronic effect of the substituents does not proportionally affect the yield of the reactions. The steric barrier had no impact either.

In Figure 6, a possible process for phenylselenating imidazo[1,2-a]pyridines using 1,2-diphenyldiselane is depicted. PhI(OAc)SePh 35 is a potential intermediate that can be produced by the ligand exchange reaction between 1 and PhSeSePh. Electrophilic benzeneselenyl acetate 37 may be produced as a result of intermediate 35’s tendency for the reductive elimination of iodobenzene. Through its C3 position, the electrophilic benzeneselenenyl acetate 37 is attacked by the imidazo[1,2-a]pyridines 33 to create the complex 38, which then undergoes aromatization to produce the 3-phenylseleno imidazo[1,2-a]pyridines 34. The use of DIB and PhSeSePh for phenylselenation of imidazo[1,2-a]pyridines cannot, however, completely rule out the possibility of a free radical process.

2.1.5. Hetero-Hetero Bond Formation

With its widespread use in anticancer, anti-inflammatory, and antiviral drugs, the sulfonamide group has long been a very significant pharmacophore in drug discovery. Sulfonimidamides, the mono-aza analogues of sulfonamides, on the other hand, have received relatively little attention in the life sciences up to this point despite having some very intriguing properties such as high stability, advantageous physicochemical characteristics, numerous hydrogen-bond acceptor/donor functionalities, and structural diversity. Through NH transfer, unprotected tertiary sulfonimidamides (40) have been produced in one-pot in good to outstanding yields from tertiary sulfonamides (39). Commercially accessible PIDA and ammonium carbamate in methanol were used by Stockman et al. to conveniently facilitate the reaction (Scheme 6) [20].

Numerous functional groups were tolerated, and preliminary findings showed that the N-H transfer was stereospecific. A recent, expanding area of interest in the life sciences, sulfonimidamides, can now be approached safely, quickly, and effectively thanks to this novel reaction. The optimized reaction parameters are: H₂NCO₂NH₄ (4 equiv.), PIDA (3 equiv.) in MeOH at room temperature. However, the authors discovered that the reaction was only possible when tertiary sulfinamides were used. The equivalent sulfonimidamide was not formed when the commercial, primary sulfinamide was subjected to the normal conditions; instead, sulfonimidate was separated in a moderate yield along with sulfonamide in low yield. The secondary ethyl sulfinamide reacted to produce a variety of compounds, the main one being sulfonimidate.

2.2. Heterocyclic Ring Formations

2.2.1. Synthesis of Oxazoline and Thiazoline Derivatives

The creation of the oxazoline moiety via a novel methodology was described by Li et al. [21]. Intramolecular halooxygenation and halothionation of N-allylcarboxamides/N-allylcarbothioamides (41) proceeded easily, producing the corresponding 5-halomethyloxazolines/5-halomethylthiazolines (42) in good to excellent isolated yields, using PIDA as the reaction promoter and halotrimethylsilane as the halogen source (Scheme 7).

The 5-halomethyl compounds could be modified using conventional nucleophilic substitution patterns to create various derivatives. The reactions did not require harsh reaction conditions and were carried out utilizing readily available starting ingredients. The optimized reaction conditions for the synthetic protocol are: TMSI (1.1 equiv.), PIDA (1.1 equiv.) in DCM at RT. Substrates with either electron-donating or electron-withdrawing groups on aromatic rings could all be cyclized in good isolated yields despite the electronic effects of the substituents on the aryl groups, which had less of an impact on the reactions. Scale up was also performed satisfactorily using the present optimized reaction parameters.

A tentative chemical route was suggested as illustrated in Figure 7. When the substrate (41a) and TMSI interacted, intermediate 43 was silylated and could then be further tautomerized to become intermediate 44. In the interim, PhI(OAc)₂ activated the C=C double bond in the substrate, and the intramolecular oxygen nucleophilic attack on the iodinium three-membered ring (45) formed the intermediate 46, which ultimately gave rise to the halooxygenation product (42a) after workup.

2.2.2. Synthesis of Quinoxaline Derivatives

Quinoxaline is a major heterocyclic skeleton that is present in a variety of compounds with biological and pharmacological importance. Quinoxaline (48) synthesis was developed using a novel methodology by Yu and co-workers in which N-arylenamines (47) and TMSN₃ as the nitrogen source were used as the starting materials, and (diacetoxyiodo)benzene was used as the common oxidant to implement two oxidative C-N bond-forming processes in a tandem pattern (Scheme 8) [22].

When (ditrifluoroacetoxyiodo)benzene was employed in place of DIB, comparable yields were achieved. The optimized reaction conditions for the present synthetic methodology are: TMSN₃ (2 equiv.), PIDA (2 equiv.), CuCl₂ (10 mol%) in DMF at RT. Finding that compounds with an ortho-substituent at the N-phenyl ring also interacted to produce quinoxalines is fascinating. When meta-substituted substrates were utilized, the mixture of two regioisomers was produced, with the sterically hindered ones making up the majority of the mixture.

It is possible that the nonradical process depicted in Figure 8 is used to change 47a into final product 48. The oxidation of component 47a must be a fast process because it could never be isolated from the reaction mixture, even though we are unable to determine which mechanism is more likely at this time.

2.2.3. Synthesis of Imidazolidinones

1,4-imidazolidinones and their derivatives have been employed as organocatalysts. Additionally, this heterocycle is a key component of antipsychotic, antibacterial, anti-inflammatory, and antineuropathic drugs due to its potent therapeutic qualities. Hulme and co-workers synthesized imidazolidinones (53) by using 5-endo trig oxidative radical cyclization strategy via benzylamine-derived Ugi three-component reaction (52) with three diversity elements (Scheme 9) [23].

Low yields and a range of side products that frequently co-eluted with the product were produced when IBX was used. Other oxidants with lower yields and a smaller range of substrates included PIFA, DMP, iodobenzene, and TBHP. The optimized conditions for this methodology are: PIDA (1.2 equiv.), KBr (1 equiv.) and 18-crown-6 (1.2 equiv.) in acetonitrile at RT. The authors used 18-crown-6 to coordinate potassium in order to increase the solubility after observing that KBr was poorly soluble in acetonitrile. To prevent the development of mixtures of diastereomers during 5-endo-trig oxidative cyclization, symmetrical ketones were utilized throughout. Because the resultant C-H is vulnerable to oxidation and can produce cleavage products, aldehydes from the Ugi-3CR were not tolerated in the oxidation. Additionally, under these oxidative circumstances, Cbz- and Boc-protected Ugi-3CR products remained stable, showing that a variety of components suitable to further functionalization were present. Additionally, the synthesis was carried out on a gram scale with no yield loss. The aliphatic amine-containing Ugi-3CR product produced nothing.

Figure 9 shows a possible mechanism for this oxidative cyclization. The Br anion activates PIDA to produce 54, which, along with 55a, produces N-I complex 56b. The generation of the numerous radical species throughout this hypothesized pathway may be attributed to the weak I-Br bond, which is susceptible to homolytic cleavage in 56. The α-amino radical 56, is then oxidized to imine (57). Since the aryl amide is a bioisostere of carboxylic acids, the authors hypothesized that 57 undergoes N-H abstraction to generate radical 58a, albeit a non-radical process cannot be completely ruled out. Following a 5-endo-trig radical cyclization, this amidic radical produces 59, which can be easily quenched to produce product 53a.

2.3. Rearrangement/Migration Reactions

2.3.1. Hetero Diels-Alder Addition

1,2-Oxazines are widely acknowledged as helpful synthons in the synthesis of biologically active natural compounds. 1,2-Oxazines can be easily and highly stereoselectively synthesized using the hetero-Diels–Alder (HDA) reaction between N-acylnitroso species and dienes. In the presence of different dienes (61), either PIDA or [bis(trifluoroacetoxy)iodo]benzene (BTI) effectively stimulated the production of acylnitroso species (62) from hydroxamic acids (60), yielding the required hetero-Diels–Alder (HDA) adducts in moderate to high yields, as reported by Saito and co-workers [24]. The current approach could be used in HDA reactions involving masked o-benzoquinones (MOBs), which are produced after the oxidative dearomatization of guaiacols, as well as simple dienes (Scheme 10).

2.3.2. Beckmann-Type Rearrangement

Despite significant progress in this area, the synthesis of benzoxazoles and benzimidazoles via hypervalent iodine-mediated Beckmann rearrangement is still uncharted ground. Many commercially available drugs and therapeutic prospects have these heterocycles as common structural components. Additionally, polymers, natural products, and diverse functional materials all contain benzoxazoles and benzimidazoles. Benzoxazoles and N-Ts benzimidazoles (64) were synthesized by Xiong et al. using Beckmann-type rearrangements of the o-hydroxy and o-aminoaryl N-H ketimines (63), respectively (Scheme 11) [25].

The necessary heterocycles were formed by condensation of ammonia with the appropriate ketones to produce the ketimine derivatives, and it was discovered that PIDA functions as an effective oxidant to initiate [1,2]-aryl migration. The benzoxazole was produced in good yields by the reaction of test imine with PhI(OAc)₂ or PhIO, but no reaction occurred when imine was combined with PhI(OH)(OTs) or PhI(OTf)₂. The optimized conditions for this methodology are: PIDA (1.5 equiv.) in MeOH at RT. It is important to note that the synthesis of corresponding product was not possible when m-chloroperbenzoic acid was used as a stoichiometric terminal oxidant together with a catalytic quantity of iodobenzene. Only degradation byproducts from imine were seen in these circumstances. The same reaction conditions were successfully applied for the synthesis of benzimidazole derivatives, as well. The outcomes showed another mechanistic route through which benzisoxazoles or 1H-indazoles could be produced, depending on the substitution pattern. The synthesis of benzimidazole-containing bio-relevant targets such as chlormidazole and clemizole used the Beckmann-type rearrangement strategy.

Based on the control experiments performed and information from the literature, a likely mechanism is shown below to explain how the various products are formed (Figure 10). The corresponding hypervalent iodine species 56 would be produced by the imine’s reaction with PhI(OAc)₂. Following the path a, an aryl moiety would undergo a Beckmann-type [1,2]-migration to produce the intermediate 67. This intermediate would then go through an intramolecular cyclization to produce either benzoxazole or benzimidazole (64a). The intramolecular cyclization of the phenol or amine onto the imine nitrogen following path b would result in the formation of the benzisoxazole and indazole (64b) through the intermediate 68.

2.3.3. Hofmann Rearrangement

Urea-containing compounds are increasingly utilized in many different research domains, including medicinal chemistry, agrochemistry, and petrochemistry, due to their intriguing physicochemical and biological features. The widespread use of such molecules as bioisosteres of peptide bonds in drug development is specifically due to their structural, biological, and electronic similarities. Reboul et al. reported that primary amides (69) when treated with PIDA in the presence of an ammonia source (NH₃ or ammonium carbamate) in MeOH produced N-substituted ureas (71) in a straightforward and practical manner (Scheme 12) [26]. The electrophilicity of the hypervalent iodine species is increased when 2,2,2-trifluoroethanol (TFE) is used as the solvent, which enables the synthesis of electron-poor carboxamides. The isocyanate intermediate (70) produced in situ by a Hofmann rearrangement of the initial amide which was nucleophilically added to by ammonia source throughout this transformation.

The optimized conditions for this methodology are: Condition A: PIDA (2 equiv.) and NH₃ (17.5 equiv.) in MeOH (7 M) at 0 °C to RT and Condition B: PIDA (3 equiv.) and ammonium carbamate (AC) (2.5 equiv.) in TFE at 0 °C to RT. In addition to pyridyl-, phenyl-, and benzylureas, reactions involving aromatic amides bearing electron-donating or deactivating groups also produced the corresponding ureas in good to outstanding yields. Aliphatic amides were entirely converted into the desired ureas; however, because of their volatility, some of the products were lost during purification, which had an impact on the isolated yields. However, it appeared that the reaction yield of this transition was decreased by the presence of an electron-withdrawing group on the aromatic amide. While a substrate with a 2-OH group produced the isolated cyclic carbamate in a quantifiable yield, one with a 4-OH group failed to produce the required urea. However, under neither set of circumstances did 2-furamide react.

The authors believed that ammonia, which was more nucleophilic, trapped the isocyanate intermediate, which was generated in situ via a Hofmann-like rearrangement (69→71, Figure 11).

2.3.4. Morin Rearrangement

In the weak chemical space being investigated at the moment, N,S-containing heterocyclic systems (such as 1,4-thiazines and benzo[1,4]thiazines) play a significant role as heterocyclic scaffolds. Various pigments and dyestuffs serve as examples of how these rings can be found in a variety of uncommon and fascinating natural and artificial items. They have several uses in pharmaceutical sciences and chemical manufacture. Particularly intriguing are the rare pyrrolo[1,4]thiazines, which can be represented with various degrees of biological relevance. Starting with N,S-acetals (74/76), an effective domino transformation using the PIDA/I₂ combination was developed by Daïch et al. [27]. for Morin 1,4-thiazine compounds (75). They achieved ‘one-step’ regioselective methylene insertion in good yields without the use of conventional sulfoxide intermediates (Scheme 13).

The Morin product formed as the only reaction product in this instance when PIDA/I₂ was used. The optimized conditions for this methodology are: PIDA (1 equiv.) and I₂ (0.5 equiv.) in dioxane at RT. A vast assemblage of 1,4-thiazines that have been fused or not to pyrrolidones/isoindolones could be accessed quickly and effectively, with good yields and complete regioselectivity, where applicable. The predicted Morin products were formed in moderate to good yields along with the excessively oxidizing compounds when another proton is present at the endocyclic position of the sulphur atom, which is commonly in the pyrrolidone or piperidone family.

In terms of mechanism (Figure 12), the oxidation of sulphur would start the domino process, with PIDA producing the release of acetate and the sulfonium ion 77. Both molecules underwent an acid-base reaction that produced the enamide 78 that was never isolated before the S-I bond broke down under the influence of acid to produce 79. The medium then allowed 79 with PIDA to regenerate while providing the dimer 80 and iodobenzene. The latter, when combined with diiodide, can form the hypoiodothioite intermediate 81, which can then provide the anticipated Morin product 75a via the N-acyliminium ion 82. Only 0.5 equivalents of I₂ are required in this case to produce the Morin product 75a, suggesting that the dimer 80 is crucial for the domino process.

2.3.5. Grob-Type Fragmentation

The 4H-3,1-benzoxazin-4-one core is a crucial structural skeleton present in a variety of pharmaceuticals and bioactive substances. The 2-substituted 4H-3,1-benzoxazin-4-ones are also useful building blocks for the synthesis of molecules with medicinal activity, which is significant. A successful oxidative reaction conducted by PIDA and aided by water was used by Li and co-workers to produce a number of synthetically intriguing 2-arylbenzoxazinones (84) from 2-arylindoles (83). Water was a critical ingredient and the only oxidant used was PIDA (Scheme 14) [28].

A number of iodine(III) oxidants with various oxy ligands, such as PhI(OCOCF₃)₂, PhI(OPiv)₂, PhI(OCOPh)₂, PhIO, PhI(OH)OTs, and iodosodilactone, were utilized in place of PhI(OAc)_2, although a negative impact on the reaction yield was noted in these instances. While IBX and DMP, two iodine (V) reagents, were also investigated as oxidants, the anticipated 2-arylbenzoxazinone was not identified. The optimized conditions for this methodology are: LiI (1 equiv.), PIDA (4 equiv.) in DMF (10 mL) and H₂O (10 equiv.) at 60 °C. The intended 2-phenylbenzoxazinones might be produced in fair to moderate yields by first using a succession of 2-phenylindoles with electronically distinct substituents (R=H, Me, F, Cl, Br, NO₂). Similar reactivity to that of the aforementioned 6-substituted indoles was displayed by the 7- and 8-substituted indoles as well.

Figure 13 suggested a possible mechanism for this reaction, and the conversion of 83a to 84a serves as an illustration. Initially, 3-acetoxy-substituted indole 86 was produced by electrophilic attack of PhI(OAc)₂ at the C-3 position of indole 83a via intermediate 85.

2.3.6. 1,2-Diaza-Cope Rearrangement

Hydrazones are a significant group of nitrogen-containing chemicals with exceptional biological properties that are found in both medicines and natural products. In organic chemistry, they are also useful synthetic intermediates for the Bamford–Stevens reaction, Shapiro reaction, Eschenmoser–Tanabe fragmentation, and Wolff–Kishner reduction. As a result, the synthesis of hydrazone compounds and the subsequent modification of hydrazones have drawn a lot of interest and prompted the creation of novel synthetic methodologies. Recently, radical tandem cyclization has made β,γ-unsaturated hydrazones into desirable substrates for the synthesis of pyrazoline derivatives, which are known to have strong biological activity. Based on the 1,2-diaza-cope rearrangement reaction of β,γ-unsaturated hydrazones (81) with acetate/H₂O, a novel metal-free methodology for the synthesis of diacyl/acyl N-allylhydrazines (94/97) was described by Qi, Wang and co-workers [29]. Under favorable conditions, this cascade reaction operated effectively (Scheme 15).

The optimized conditions for this methodology are: PIDA (2 equiv.) and HOAc (1 equiv.) in toluene at 80 °C under argon atmosphere. The reaction showed broad functional group compatibility, as hydrazone substrates bearing either electron-withdrawing (Cl, Br, F) or electron-donating (methyl, methoxyl, isopropyl) aryl substituents interacted well to produce the desired rearrangement products in moderate to good yields (58–82%).

However, in this transformation, aryl groups with an electron-rich group performed better than those with an electron-deficient group. Later, the authors carried on exploring the potential structural range of the N-phenyl moiety. Under the reaction conditions, a wide range of functional groups with different electronic characteristics were well tolerated, and the corresponding rearrangement products were produced in moderate to good yields (52–89%). However, N-aliphatic substrates could not function under the ideal circumstances; thus, a stable N radical I-I was essential to figuring out the regioselectivity (Figure 14).

It is crucial to consider the following pathway of a potential mechanism in the reaction for producing the desired product: it was possible that PhI(OAc)₂ first reacted with N-phenyl β,γ unsaturated hydrazone 91 to produce an N-I(III) intermediate 101. Intermolecular nucleophilic attack of the carbon-nitrogen double bond on intermediate 101 by AcOH resulted in intermediate 100, which was then produced by a 1,2-diaza-Cope rearrangement process to yield intermediate 102. The final product 94a was then obtained by transferring 102 through a [1,3] O→N acyl transfer (Path II).

2.4. Miscellaneous Reactions

2.4.1. Synthesis of Aryl(trifloxyalkenyl)iodonium Triflate Salts

Numerous useful chemical compounds have been synthesized where the alkenyl activity appears as a significant molecular motif. Therefore, there is enormous synthetic potential in the development of direct alkenylation processes and multifunctional alkenyl building blocks. To meet this synthetic need, (trifloxyalkenyl)iodonium triflate salts were created and put to use in ligand exchange processes that produced different diaryliodonium species, cross-coupling events catalyzed by palladium, as well as metal-free substituted oxazole ring formation reactions.

Using widely available (diacetoxyiodo)benzene, trimethylsilyl trifluoromethanesulfonate, and acetylenes (93), a straightforward procedure was established by Toth and Novak research groups, to quickly produce aryl(trifloxyalkenyl)iodonium triflate salts (104, Scheme 16) [30]. They created nucleophilic and electrophilic multifunctional hypervalent vinyliodonium salts which could be employed as novel C2 synthons in organic transformations. The optimized conditions for this methodology are: PIDA (1 equiv.) and TMSOTf (2 equiv.) in dichloromethane at 0 °C to RT. The authors investigated the synthesis of phenyl-(alkenyltrifloxy)iodonium triflate salts using alkyl acetylene reactants because, fortunately, the reaction was not restricted to the aromatic acetylenes. They investigated how various terminal alkylacetylenes functionalized with OAc, OH, Br, Cl, and CN groups at the alkyl terminal could be applied synthetically. With the aid of nucleophilic or electrophilic reagents, these functionalities allow for further side chain modifications. However, the ester functionality was not tolerated at the reaction conditions. They even discovered that an alkyl or aryl group was preferred in the E position of the (vinyltrifloxy)-iodonium molecule.

2.4.2. Dearomative Spirocyclization

Peng, Wang and co-workers reported PIDA-promoted/HFIP-controlled dearomative spirocyclization of phenolic ketones (105) through a spirocyclohexadienone-oxocarbenium cation species [31]. It was found that 1,1,1,3,3,3-hexafluoroisopropanol (HFIP) inhibits and PIDA promotes dearomative spirocyclization of phenolic ketones (Scheme 17). Under favorable conditions, this protocol generated two libraries of structurally intriguing scaffolds, including spirocyclohexadienonic ketals (106) and their acetoxylated counterparts (107), with moderate to good yields.

2.4.3. Generation of α-Aminoalkyl Radicals

Since radical reactions allow for transformations of organic compounds that are not seen in ionic reactions, significant research efforts have been put into developing new protocols for creating organic radicals in synthetic organic chemistry. Particularly, the creation of functional group-containing organic radicals is a very promising method for adding functional groups to other molecules. Among these radicals, α-aminoalkyl radicals (109) have garnered a lot of interest due to the significance of scaffolds containing nitrogen for synthetic purposes.

It was reported by Maruoka et al. that sodium α-aminoalkanesulfinates (108) can be made synthetically and used as α-aminoalkyl radical precursors (Scheme 18) [32]. The reaction between the anions of N-Boc-protected alkylamines and 1,4-diazabicyclo[2.2.2]octanebis(sulfur dioxide) produced a range of α-aminoalkanesulfinates (99) easily. The corresponding α-aminoalkyl radicals were easily produced by treating sodium α-aminoalkanesulfinates with (diacetoxyiodo)benzene under benign conditions. These radicals were then used in radical 1,2-addition to imines, radical 1,4-addition to electron-deficient olefins, and radical addition/cyclization to 2-isocyanobiphenyls. The optimized conditions for this methodology are: PIDA (1 equiv.) in DMSO or DMF at RT. The range of the addition reaction between aminoalkyl radicals and imines is shown in Scheme 18. The application of primary sulfinates in the addition reaction between α-aminoalkyl radicals and imines resulted in good yields for the corresponding α,β-diamino ester derivatives. A diastereomeric product combination of secondary sulfinate was produced. Cyclic sulfinates made from piperidine and piperazine provided the appropriate products; however, those made from pyrrolidine did not. Alkyl, alkenyl, and aryl-containing α-keto imines were also well-tolerated and produced moderately to favorably yields of α,β-diamino ketone derivatives.

The authors proposed that the present reaction should proceed via a radical chain process; in order to produce RSO₂. (109), DIB should specifically act as an activator for the oxidation of 108a (Figure 15). The removal of sulphur dioxide from 109 should then result in the production of an aminoalkyl radical (110). Then, adding 110 to an imine should provide a 111-type aminyl radical that might oxidize sulphate to create a simultaneous formation of 113 via 112.

2.4.4. Ring Opening Reaction

Due to their bifunctionality, α-iminonitriles are adaptable intermediates in the synthesis of organic compounds. They can be thought of as a veiled form of α-amino acids because of their near structural similarity to Strecker α-aminonitriles. A latent possibility to produce optically active α-amino acid derivatives would be served by the presence of a sp²-prochiral centre (a C=N bond) in α-iminonitriles. Amidines, N-alkylketene-imines, amides, and cyanoenamides are just a few of the additional valuable building blocks that may be made using α-imimonitriles as a precursor. Imidazo[1,2-a]pyridines, on the other hand, are a significant class of fused heterocyclic motifs that exhibit a wide range of biological activities, including antitumor, antiprotozoal, antiviral, antimicrobial, antiherpes, anticancer, anticonvulsant, and others. Due to their unique pharmacological profile, imidazo[1,2-a]pyridines are being synthesized and structurally decorated to create novel scaffolds with altered biological functions.

Imidazo[1,2-a]pyridine and NaN₃ interacted under friendly conditions via ring opening reaction (RoR) strategy to produce extremely high quantities of α-iminonitriles in the presence of PIDA. Through this method, Karade et al. synthesized α-iminonitriles (115) in cyanide- and metal-free reaction conditions (Scheme 19) [33]. The optimized conditions for this methodology are: PIDA (2 equiv.), NaN₃ (3 equiv.) in CH₃CN: H₂O (9:1) at RT. This approach worked well with a wide range of imidazo[1,2,a]pyridines that had aryl or pyridine type rings with electron-donating and -withdrawing groups. It was discovered that the electronic impact of the substituents was not a factor in the yields of the reactions. The impact of steric hindrance was also not seen because imidazo[1,2,a]pyridines bearing methyl groups in various positions were able to generate the corresponding α-iminonitriles with DIB/NaN₃ in efficient reactions with good yields. α-Iminonitriles were produced in good yields when imidazo[1,2,a]pyridines with -OMe, -Cl, -Br, and -CF₃ substituents were used. This approach can also be used to successfully synthesize α-iminonitriles with pyrimidine and naphthalene moiety.

Figure 16 illustrates a possible process for the synthesis of α-iminonitriles from imidazo[1,2-a]pyridines. PhI(OAc)N₃ is created when PhI(OAc)₂ and NaN₃ swap ligands. The intermediate 117 is created when the imidazo[1,2-a]pyridines attack the electrophilic PhI(OAc)N₃ through the C3 position.

Thus, two reactive ligands have been gathered around the coordination sphere of the hypervalent iodine(III). Due to intermediate 117’s propensity for reductive elimination of iodobenzene, an azide group is introduced to imidazo[1,2-a]pyridines at position C3, forming a complex called σ-complex 118, which then undergoes aromatization to produce 3-azido imidazo[1,2-a]pyridines 116a. It is well known that the heat breakdown of aryl azides produces nitrene as an intermediate. Thus, 116a is capable of thermally decomposing to produce nitrene 119, which is then trapped intramolecularly to produce strained azirine 120. In order to create α-iminonitrile 115a, 120 finally suffers ring opening of the azirine unit while simultaneously cleaving the five member ring.

2.4.5. Oxidative Cleavage of C2–C3 Bond

Isatin is a classic indole derivative that contains both keto and lactam carbonyl groups. Isatin can be attacked by nucleophiles at the C2 and/or C3 locations, and the chemoselectivity of these reactions depends on a number of variables, including the type of nucleophile. Karade and group reported that when isatin and N-acetyl isatin (112/114) interact with PIDA, oxidative C2–C3 bond cleavage occurs, resulting in carbamates of alkyl anthranilates (113) and alkyl 2-acetamidobenzoate (115), respectively (Scheme 20) [34].

Even after refluxing for 24 hours in methanol, molecular iodine was found to be insufficient to cause oxidative C2–C3 cleavage of isatin. The C2–C3 oxidative cleavage of isatin was tried by the authors using in situ produced hypervalent iodine(III) reagents from catalytic iodoarene reactions with terminal oxidants such as mCPBA or oxone. However, they were never able to find the corresponding carbamate, which was consistent with the literature’s claim that the Baeyer–Villiger oxidation product is created when isatin is oxidized with m-CPBA. The optimized conditions for this methodology are: PIDA (1.7 equiv.) in alcohol at RT. For the oxidative C2–C3 cleavage of isatin, a variety of primary alcohols including methanol, ethanol, propanol, CF₃CH₂OH, and ethoxyethanol have been utilized successfully. The use of methanol as a solvent was shown to maximize the output of carbamates. The kind of the substituents affected the yields of isatin’s oxidative C2–C3 cleavage. Isatins with electron-withdrawing groups (F, Cl, Br, and NO₂) produced corresponding compounds in higher yields than isatins with electron-releasing groups (Me and OMe). It was significant to note that just one carbamate derivative produced by the modified isatins resulted in the oxidative cleavage of the C2–C3 bond.

Figure 17 depicts the possible mechanism for the C2–C3 oxidative cleavage of isatin utilizing PIDA and alcohol. Isatin (121a) can create hemiketal 125 and then produce 126, because of a ligand-exchange reaction with PIDA. The affinity of 126 for iodobenzene reductive elimination facilitates the concurrent oxidative breakage of the C2–C3 bond, which results in the creation of the isocyanate derivative 129, which is then trapped by alcohol to produce the carbamate derivative 122a.

2.4.6. Oxidation

Alcohol oxidation is a process that has garnered interest for a very long time. The recent need for environmentally friendly oxidation methods has prompted the creation of cleaner and more secure oxidation processes. By utilizing supported metal catalysts, the usage of soluble metal-based oxidants or catalysts can be eliminated. On the other hand, it is highly desirable to use metal-free catalysts for the selective oxidation of organic substrates.

Using PIDA and a catalytic quantity of bromide ions from tetrabutylammonium bromide or KBr in ethyl acetate, primary and secondary benzylic alcohols (130) and secondary aliphatic alcohols (131) were oxidized to the corresponding aldehydes and ketones (132), as reported by Gruttadauria and co-workers (Scheme 21) [35]. In the oxidation of primary aliphatic alcohols and secondary allylic alcohols carried out in the presence of 1 mol% TEMPO, the catalytic significance of the bromide ions was also underlined.

The creation of bis(acyloxy)bromate(I) anions, which in turn release acetyl hypobromite (AcOBr) and potassium acetate (Figure 18, pathways a and b), explains how bromide ions promote reactions in the presence of PIDA. The carbonyl molecule is produced via oxidation mediated by AcOBr (route c), while the initial bromide salt is produced by proton exchange between acetate and HBr (path d). The extra pathways e-i can be used to explain how primary aliphatic alcohols are oxidized with PIDA, TEMPO, and bromide.

2.4.7. Synthesis of Furylpyrazolino[60]fullerene Derivatives

Due to their distinctive structure, fullerenes have drawn attention from all around the world from the first discovery of the well-known class of spherical molecules and have pioneered the way in numerous scientific fields. Due to their intriguing physical and chemical characteristics, such as their ability to form endohedral and exohedral derivatives, electrical properties, electron-accepting nature (which facilitates their use in the preparation of photovoltaic cells), mechanical strength, and minimal biotoxicity, researchers are interested in studying these unusual molecules. By using PIDA as an oxidant in o-dichlorobenzene (ODCB), a [3+2] cycloaddition procedure was efficiently developed by Shalaby et al. to create a new series of furylpyrazolino[60]fullerene derivatives (135, Scheme 22) under microwave conditions [36].

In addition, researchers also looked into the photophysical and electrochemical properties of the new compounds. Three of these pyrazolino[60]fullerene compounds displayed higher ground-state electron affinities than the parent C60. First, the reaction between PhI(OAc)₂ and substituted furylhydrazone (134) produced the nitrile imine intermediate. The resultant intermediate (136) is then subjected to a 1,3-dipolar cycloaddition reaction with C60 to produce derivatives of furylpyrazolino[60]fullerene (135), as depicted in Figure 19.

2.4.8. Catalytic Oxidation of Styrene

As oxide-supported catalysts for the catalytic oxidation of styrene, atomically precise bimetallic M_xAu_25-x(SR)₁₈ (M=Cu and Ag, R = CH₂CH₂Ph) nanoclusters were explored by Jin and Li (Scheme 23) [37]. They were compared to the homogold Au₂₅(SR)₁₈ nanocluster in terms of their catalytic characteristics. Using PIDA (0.1 equiv.) as the oxidant, the oxide-supported M_xAu_25-x(SR)₁₈ catalysts resulted in a 42–82% conversion of styrene at 70 °C. The activity (i.e., conversion of styrene, 137) and selectivity to styrene epoxide (139) or benzaldehyde (138) were discovered to be modulated by the Ag and Cu dopants (major products).

2.4.9. Synthesis of 1,4-Bridged Dihydroisoquinolin-3-Ones

The isoquinoline structural core can be found in a wide variety of naturally occurring products as well as bioactive compounds. There are a lot of bridging isoquinoline derivatives that exist naturally, and many of them have interesting bioactivities. The building of bridging cyclic skeletons having dense functionalities has been the focus of a significant amount of study over the past few decades. This has been done in an effort to discover methods for the synthesis of these molecules. Because isoquinolinium ions include two electrophilic sites, the tandem dearomatizative annulation of isoquinolinium salts with tethered bis-nucleophiles is a straightforward protocol.

Cai et al. presented a metal-free switchable synthesis of isoquinoline-1,3,4-triones (137) and 1,4-bridged dihydroisoquinoline-3-ones (138) from isoquinolinium salts. The first 1,4-bridged dihydroisoquinolin-3-ones (138) were made in excellent yields by sequentially oxidizing and annulating isoquinolinium salts with 4-hydroxycoumarins (Scheme 24) [38]. The combination of the bromide anion and PIDA was found to be a good carrier of very labile carboxyl radicals and moderately stable bromine radicals, as shown by these site-selective transformations that rely on an iodine(III)-mediated dual radical addition/radical coupling strategy.

The optimized conditions for this methodology are: PIDA (3 equiv.) and KBr (1 equiv.) in MeCN at 50 °C. At first, a variety of alkyl groups were attached to the N atom of the isoquinolinium salts. With a wide variety of bridging dihydroisoquinoline-3-ones, it was possible to successfully synthesize isoquinolinium salts that contained para-, meta-, or ortho-substituted phenylmethyls. Substituent electronic effects did not seem to have much of an influence on the yields for the vast majority of benzyl-substituted substrates, with the exception of those that were replaced with strong electron-withdrawing substituents.

Other N-primary alkyl-substituted isoquinolinium salts performed admirably as well. These isoquinolinium salts included fused and hetero arylmethyl-, long-chain alkyl-, allyl-, cycloalkylmethyl-, 2-methoxyethyl-, and 2-alkoxycarbonylethyl-substituted substrates. These substrates produced the corresponding products in satisfactory yields. Compared to their N-secondary alkyl equivalents, which are more sterically hindered and less stable, N-primary alkyl substrates performed significantly better. The benzene ring of the isoquinolinium salts was then modified by the addition of a variety of substituents. Because of steric hindrances, isoquinolinium salts with the substitution at the 6-position were found to be of higher quality than those with the substitution at the 5-position. Initiation of the PIDA-mediated oxidation of 133a occurred not via a nucleophilic addition pathway, but rather via a radical addition pathway (Figure 20).

Through the process of ligand exchange, PIDA was able to produce 142c after reacting with the bromide anion 141a. 142c was the catalyst that started the oxidative process, which then produced radical cation 142a and radical 142b. As a result of the transfer of the bromine atom from 142b to C-4 of 142a, iminium 143a and PhI were produced. Lactam 143c was produced as a result of a nucleophilic attack on lactam 143a by water, which was then followed by PIDA oxidation. The polysubstituted dihydroisoquinoline-3-one (144a) was produced when the benzyl hydrogen of compound 143c was brominated by compound 142c.

2.4.10. Regioselective Synthesis of 1-(Benzoxazol-2-yl)-1-Alkoxynaphthalen-2(1H)-Ones

Naphthalen-2(1H)-ones are pharmacologically active chemicals; for example, 1-hydroxy-1-methylnaphthalen-2(1H)-ones belong to the phytoalexines category. Both 1-alkoxy-naphthalen-2(1H)-one and 1-methyl-1-(2-oxazolyl)-naphthalen-2(1H)-one are inhibitors of HIV-1 reverse transcriptase and 1-alkoxy-naphthalen-2(1H)-one has been shown to have chemotactic action in vitro toward human polymorphonuclear leukocytes. 1-Hydroxyl-2-naphthalenones are also a key structural motif, scattered throughout a variety of lacinilene derivatives. In recent years, benzoxazole derivatives have grabbed a lot of attention as a result of their utilization as intermediates in the production of novel biological materials.

According to Kumar and co-workers, the dearomatized products 1-(benzoxazol-2-yl)-1-alkoxynaphthalen-2(1H)-ones (152) and 1-(benzoxazol-2-yl)naphthalene-2,3-diones were produced regioselectively by PIDA-induced oxidation of 2-(2-hydroxynaphthyl)benzoxazoles (151) in alcohols (Scheme 25) [39]. Additionally, by adjusting the concentration of PIDA in various alcohols, these products were also produced in one-pot, either from (E)-1-(((2-hydroxyphenyl) imino)methyl)naphthalen-2-ol (150) or 2-aminophenol (148) and 2-hydroxynaphthaldehyde (149).

Two different routes seem to be involved in the most likely mechanism for the synthesis of compounds 152 and 158 (Figure 21). Compound 152 is formed via the intermediary of 153 in the pathway a of the reaction. Path b involves the conversion of the intermediate 154 to 155, which exists in the form of keto-enol tautomers. 155 then reacts in situ with PhI(OAc)₂ to produce 157, which ultimately affords 158. There is also the potential that 155 might be formed through an intramolecular rearrangement of 150, which would most likely result in 159 being derived from 151 and PhI(OR)₂ (which would be created in situ from PhI(OAc)₂ and ROH).

2.4.11. Synthesis of Acylated Benzimidazo/Indolo[2,1-a]isoquinolines

In recent years, photocatalysis has established itself as a sustainable and environmentally friendly synthetic platform that is able to convert light energy into chemical energy in an effective manner. This allows for the formation of new chemical bonds. In particular, the benzimidazole-isoquinoline fused framework and the indole[2,1-a]isoquinoline containing tetracyclic core structure are not only widely present in some biologically active molecules, but they are also important components of synthetic intermediates and functional materials. This is because they contain tetracyclic cores. Several typical polyheterocycles that contain skeletons are known to have potentially useful applications in the treatment of hemoglobinopathies and cancer, as a peripheral benzodiazepine receptor ligand, in the modulation of the potassium ion flux, and in organic electronics.

Sun and others described the synthesis of acylated benzimidazo/indolo[2,1-a]isoquinolines, a metal-free visible-light-induced decarboxylative radical addition/cyclization process at room temperature. The process was developed in water using a one-step, moderate reaction involving functionalized 2-arylbenzoimidazoles or 2,3-diarylindoles (160) and oxocarboxylic acids (161) in the presence of PIDA (Scheme 26). Using this protocol, it was possible to get benzimidazo/indolo[2,1-a]isoquinoline-6(5H)-ones (162) containing 1,4-dicarbonyl in acceptable yields without using conventional heating or metal reagents [40].

The optimized conditions for this methodology are: PIDA (2 equiv.) in H₂O at RT in the presence of blue LED.

As a result, a feasible mechanism for the reaction was proposed, which can be seen displayed in Figure 22. To begin with, a ligand exchange interaction between PIDA and 152a resulted in the production of hypervalent iodine(III) reagent 163. This reagent 163 then underwent an I-O bond cleavage when it was exposed to visible light, which resulted in the delivery of radicals 164 and 165.

Subsequently, the benzoyl radical might be produced through the fragmentation of both 164 and 165. After this, the benzoyl radical was introduced into the C=C bond of 160a, which resulted in the production of the radical species 166. This radical species subsequently underwent an intramolecular cyclization, which led to the formation of the radical 167. After that, a procedure involving oxidation with a single electron was used to transform radical 167 into carbocation 168 using either PIDA or oxygen. Last but not least, the formation of product 162a is possible through the fast deprotonation of the carbon cation 168.

2.4.12. Oxidative Dearomatization

Diels–Alder cycloaddition of 2,4-cyclohexadienones or ortho-quinols with activated alkenes is the typical method for synthesizing the bicyclo[2.2.2]octenone skeleton that is present in many natural products. However, 2,4-cyclohexadienones can also undergo spontaneous [4+2] dimerization to homodimeric bicyclo[2.2.2]octenones. Kumar and co-workers described a variety of stereochemically defined oxidative dearomatization products by using PIDA to treat 2-(2-hydroxyaryl)benzoxazoles and 2-(2-hydroxyaryl)benzothiazoles [9]. These products exhibited remarkable regiochemical and stereochemical properties that were determined by the nature of the phenol substituents. Tetramethoxy-substituted cyclohexenones were synthesized using the regio- and stereoselective process of dearomatization of benzoxazole-substituted phenols. However, regio- and stereoselective [4+2] dimerization of benzothiazole-substituted phenols could easily yield bicyclo[2.2.2]octenone (171). Additionally, 2-(2-hydroxyaryl)benzoxazoles (170) created a variety of tetramethoxy-substituted cyclohexenones (172), whilst halogenated 2-(2-hydroxyaryl)benzothiazoles produced 4-methoxycyclohexa-2,5-dien-1-ones (173) (Scheme 27).

The optimized conditions for this methodology are: PIDA (2 equiv.) in MeOH at RT. Figure 22 depicts what appears to be a reasonable mechanism for the transformation of compound 1 into product 5. The regiochemistry of the initial oxidative attack determines whether the oxidation of phenols with PhI(OAc)₂ in methanol will yield 4,4-dimethoxy-cyclohexa-2,5-dienones, 4-substituted-4-methoxycyclohexa-2,5-dienones, or 6-substituted-6-dimethoxy-cyclohexa-2,4-dien-1-ones. Therefore, it seems plausible that the cyclohexadienone 176 was one of the initially generated intermediates in the conversion of 175 to 179 (Figure 23). Compound 177 can be produced by performing a regiospecific conjugate addition of methanol to dienone 176 under the direction of the benzoxazole substituent. Oxidation of 177 by PhI(OAc)₂ results in the formation of the 178, which is then intercepted by methanol to produce the product 179 that is seen. It is likely that the decreased ability of higher alcohols to intercept intermediates that are analogous to 176 and 180 is the cause of the observation that reactions carried out in higher alcohol solvents do not afford products that are analogous to 179, but rather lead only to complex product mixtures. This was observed when reactions were carried out in higher alcohol solvents.

3. Conclusions

In this mini-review, we have concisely and systematically presented the various applications of phenyliodine(III) diacetate (PIDA) in organic synthesis involving C-H functionalization, hetero-hetero bond formations, heterocyclic ring construction, rearrangements or migrations and miscellaneous reactions along with their interesting mechanistic aspects from the summer of 2015 to the present. We do hope that this primitive compilation would be a valuable addition for synthetic organic and allied researchers.