Hypervalent iodine-mediated synthesis and late-stage functionalization of heterocycles

Hypervalent iodine chemistry has witnessed exponential growth in organic synthesis in recent times. Because of the electrophilic and good-leaving nature of hypervalent iodine reagents, they react with different nucleophiles in various synthetic transformations such as rearrangements, α-functionalization of carbonyl compounds, alkene difunctionalization and oxidation reactions. Importantly, the application of hypervalent iodine reagents in the construction of heterocycles is of great interest and has been well studied over the years. This review article highlights the recent developments accomplished by hypervalent iodine reagents in the synthesis and functionalization of heterocyclic compounds.


Introduction
Hypervalent iodine chemistry has become a focus of valuable research for designing robust methodologies in synthetic 1 and natural product chemistry. 2 Hypervalent iodine reagents are promising alternatives to the heavymetal oxidants due to their ready availability, easy handling, low toxicity and environmentally-benign nature. 3 Synthetic applications of these reagents have seen exponential growth as realised by several books, 4,5 chapters in books 6,7 and comprehensive reviews [8][9][10][11] published in this area. Both iodine(III) and iodine(V) compounds (also known as λ 3 -iodane and λ 5 -iodane) have been commonly used as reagents in the oxidative transformations of various simple and complex organic molecules. [12][13][14] Most importantly, the unique reactivity and oxidizing ability of λ 3 -and λ 5 -iodanes has prompted their use as efficient oxidants in variety of synthetic transformations including α-functionalization of carbonyl compounds, 15,16 oxidative rearrangements, 17,18 alkene defunctionalization 19,20 and cyclization reactions. 21,22 However, most of this transformation requires stoichiometric Scheme 1. Synthesis of syn-β-fluoroaziridines 3 using chiral iodide 2 as precatalyst.
Later, Reboul's team developed an unprecedented approach towards the synthesis of terminal diazirines 7 from amino acids 5 using ammonia as the nitrogen source (Scheme 2). 35 This one-pot reaction involves PIDAmediated decarboxylation of amino acid 5 giving an imine intermediate, followed by insertion of the iodonitrene (formed in situ from the reaction of PIDA 6 and NH3) to form a diaziridine 8 and final oxidation to provide the desired diazirines 7. Several functional groups such as arene, heteroarene, ester, carboxylic acid, amide, sulfide, sulfoxide, etc. present in the amino acid side chain were well tolerated. Additionally, synthesis of terminal 15 N2diazirines was achieved from unlabelled amino acids using 15 NH3 as a nitrogen source. Finally, hyperpolarization of 15 N2-diazirine derivative was investigated using the SABRE-SHEATH method, demonstrating its potential application as hyperpolarized molecular tag.
Subsequently, Mukthar and co-workers described synthesis of flavone-and coumarin-based isoxazoles 65 and 67 through one-pot reaction of aryl aldehydes 54, hydroxylamine 62 and 3-O-propargylflavones 64/3-Opropargylcoumarin 66 via PIDA-mediated sequential oxidative cyclization and [3+2] cycloaddition reaction (Scheme 16). 53 Further synthesis of tri-substituted isoxazoles 68 was accomplished by using dimethyl acetylenedicarboxylate (DMAD) 59 as an alkyne source. High product yields, excellent functional group tolerance, shorter reaction time, easy-workup and purification are key advantages of developed protocol. Further, synthesized compounds have been tested for the antibacterial activity. Acetonitrile plays dual role of solvent and the amine source (Scheme 17). 54 Notably, activation of PhI(OAc)2 6 by BF3·OEt2 generates active iodine(III) species in situ, that reacts with 69 to form electrophilic iodonium intermediate 71 which could give desired product 70 through sequential 5-exo-type cyclization and Ritter-typesubstitution using excess acetonitrile as the nucleophile. A variety of ketone oximes with aryl, heteroaryl and alkyl substituents were well tolerated. Specifically, electron-deficient aryl ketone oximes displayed robust reactivity thereby giving corresponding products in moderate yields while electron-rich ones gave inferior results. Further a similar method for the construction of heteroatom-containing isoxazolines 73 was demonstrated by Cai and co-workers. 55 This cascade reaction featured PIDA-mediated sulfeno-/seleno-/functionalization of several β,γ-unsaturated oximes 69 using substituted disulfides/diselenides 72 as S/Sesources.
The mechanism for the catalytic reaction is depicted in Scheme 19. Cationic species 75 is formed in situ through oxidation of 2-iodobenzoic acid 76 by m-CPBA in the presence of TfOH. This active iodine(III) species 75 reacts with aldoximes 57 via ligand exchange and generates nitrile oxides 79, which further react with nitriles 74 to deliver desired product 77. The regenerated precatalyst 76 is reoxidized by m-CPBA to continue the catalytic cycle. Scheme 19. The proposed catalytic cycle for the oxidative cyclization of aldoximes 57 using 76 as precatalyst.
In 2019, Sen and coworkers prepared 1,3,4-oxadiazoles 84 from variety of N′-arylidene acetohydrazides 82 in the presence of isobutyraldehyde 83 and p-anisolyl iodide 18. In this reaction, autoxidation of isobutyraldehyde 83 forms acyloxy radical that oxidizes p-anisolyl iodide 18 into active hypervalent iodine species in situ which promotes the cyclization reaction (Scheme 20). 58 The precursors 82 were synthesized through condensation of variety of aromatic or heteroaromatic aldehydes 80 with acetyl, p-chlorobenzoyl, or tolyl hydrazides 81 in ethanol at room temperature. This method exhibits broad substrates scope and amenable for scale up reaction. Scheme 20. Synthesis of 1,3,4-oxadiazole 84 using p-anisolyl iodide 18 as precatalyst.
The postulated mechanism for this transformation follows two main stages as shown in Scheme 21. In the preliminary stage, autoxidation of isobutyraldehyde 83 forms per acid 87 through acyl radical 85 and acyl peroxy radical 86 respectively. Further acyloxy radical 88 generated from acyl peroxy radical 86, enacts as oxidant for the oxidation of p-anisolyl iodide 18 leading to the in situ formation of hypervalent iodines(III) species 89. Finally, 89 react with substrate 82 to afford 90, which cyclizes to give 91 and aromatizes to afford 84. The regenerated p-anisolyl iodide 18 later continues the catalytic cycle.
Wang and co-workers demonstrated I2/PIDA-promoted one-pot synthesis of polysubstituted trans-2,3dihydropyrroles 130 through multi-component reaction of aryl/alkyl amines 128 with alkyne esters 59 and chalcone derivatives 129 under ball-milling conditions (Scheme 31). 69 Further using DDQ as an oxidant, one potthree step synthesis of multi-substituted pyrroles 131 were achieved under similar conditions. The present reaction featured broad substrates scope, shorter reaction time, and provides feasibility for larger-scale preparation.   54 This reagent system in combination with acetonitrile as the solvent and the amine source has led to the synthesis of pyrazoline scaffolds 137 at ambient temperature. Proposed mechanism involved activation of PIDA 6 by the Lewis acid generating active hypervalent iodine(III) species in situ that forms cyclic iodonium intermediate 138 with the alkene, which subsequently undergoes 5-exo-type cyclization and Rittertype-substitution to deliver product 137. Scheme 33. Preparation of pyrazolines 137 using PIDA 6 as an oxidant.
Later, a similar methodology was developed for the construction of heteroatom-containing pyrazolines 139 from β,γ-unsaturated tosyl hydrazones 136 using PIDA 6 as the sole oxidant (Scheme 34). 55 This cascade reaction proceeds through the generation of N-centered radical 140 from corresponding N-H bond, that undergoes sequential radical cyclization and sulfenylation/selenylation using disulfides/diselenides 72 as the S/Se-nucleophiles to form desired product 139. Aliphatic, aromatic and heteroaromatic disulfides/diselenides were well tolerated. Scheme 34. PIDA-mediated synthesis of pyrazolines 139 using PIDA 6 as the sole oxidant.

Synthesis of lactam and imidazolidinones.
Shen and Wang reported the first example of the introduction of a CF3-group onto the lactam ring 149 via Cu-catalyzed intramolecular aminotrifluoromethylation of unsaturated amides 147 (Scheme 37). 72 A series of N-methoxyamides 147 smoothly underwent 5-exo cyclization followed by C−N bond formation by using Togni's reagent 148 to provide desired CF3-containing γlactam 149 in 48-82% yields. Later, the same team demonstrated aminoazidation of several unactivated alkenes 147 by employing azidoiodinane 108 as an azide precursor. 73 This diamination reaction enabled the installation of two distinct amino groups onto the alkenes with excellent regio-and stereoselectivity. An elegant method featuring PIDA-mediated halocyclization of S-alkenylsulfoximines 166 was developed by Bolm's research group (Scheme 43). 77 Among the various iodine sources screened, potassium iodide provided the best result. The present intramolecular iodoamination process enabled synthesis of tetrahydro-1,2-thiazine-1-oxides 167 in variable yields with remarkable regioselectivities and diastereoselectivities. However, substrates with tri-substituted double bonds were unsuitable for this cyclization reaction. Additionally, preparation of dihydro isothiazoles was achieved in 69-90% yields with high dr (71:29−80:20) under identical conditions. Scheme 43. Synthesis of tetrahydro-1,2-thiazine-1-oxides 167 using oxidant PIDA 6.
In 2016, an intramolecular cyclization of N-(E)-alkenylamides 168 to the corresponding 6-aryl-5-acetoxy-2oxazines 169 induced by PIDA 6 was described by Ranjith et al. (Scheme 44). 44 In the proposed mechanism, aryliodinium ion 38 formed from PIDA 6 and HF·py interacts with the alkene 168 and generates cyclic iodonium ion 170 which is attacked by the amide moiety to give alkyl iodane 171. Notably, the presence of aryl group at the end of the alkene stabilizes the incipient carbocation thereby facilitating endo-cyclization of intermediate 171. Wengryniuk's research group prepared six or seven membered cyclic ethers 175 by employing (poly)cationic  3 -iodane (N-HVI) 174 as electrophilic reagent for the activation of secondary alcohols 173 (Scheme 46). 78 Presence of N-HVI 174 was crucial for the excellent selectivity achieved for C-O bond migration over direct oxidation via -elimination pathways. Additionally, ring expansion strategy was successfully applied in the latestage derivatization of several natural products. Further synthesized HFIP-acetals could be easily derivatized with different nucleophiles, providing scope for subsequent manipulations.
The synthesis of benzo-fused heterocycles has been well studied using different hypervalent iodine reagents. Further in this section, we will be discussing the synthesis of variety of heterocyclic compounds in which benzene ring is fused with five-, six-and seven-membered heterocycles in briefly. In 2017, Bedford et al. performed intramolecular benzylic C−H sulfamidation of 2-benzyl-N-sulfonylbenzamide substrates 201 catalysed by Cu(OTf)2 in the presence of PIDA 6 as the terminal oxidant (Scheme 53). 85 The present method leads to the synthesis of N-arylsulfonyl-1-arylisoindolinones 202 in useful yields. Interestingly, sulfonamide moiety behaves as directing group as well as functionalizing reagent in this reaction. Further samarium iodidemediated deprotection of 202 provides valuable free 1-arylisoindolinone. Scheme 53. Synthesis of N-arylsulfonyl-1-arylisoindolinones 202 using PIDA 6 as the terminal oxidant.
In the same year, an elegant catalytic strategy to prepare biologically important scaffolds indolizines 208 (X = C) and imidazopyridines 208 (X = N) was developed by Wang and co-workers (Scheme 54). 86  Further for the synthesis of 1,2-disubstituted benzimidazoles 221, an intramolecular benzylic C(sp 3 )-H imination strategy involving 4-H elimination was designed by Mal's research group. 89 This method enabled selective functionalization of two aliphatic-C(sp 3 )H and two aryl-N(sp 3 )H at 1,5 position facilitated by in situ generated hypervalent iodine(III) species from PhI-mCPBA catalytic system (Scheme 58). Later, the same group developed another catalytic route employing precatalyst tetrabutylammonium iodide 222 in combination with t-BuOOH in DMSO as relatively inexpensive replacement for the previously designed PhI-mCPBA-HFIP system. 90 Symmetrical dibenzylamines 220 gave single isomer of benzimidazoles while unsymmetrical ones yielded mixture of isomers of imination product under both catalytic conditions. In 2019, Cui's research group developed an expedient strategy to prepare quinoxalines 228 from N-(2acetaminophenyl)enaminones 227 via hypervalent iodine(III)-induced intramolecular oxidative C-N bond forming tandem process (Scheme 61). 93 Inspection of various substrates revealed that electron-rich substrates gave desirable product yields while electron-deficient ones provided relatively lower yields. The proposed mechanism initiates with the reaction of 227 with PIDA 6 that generates -iodo iminoketone 229, which undergoes intramolecular condensation cyclization to afford 230 with the release of PhI 13 and AcOH. Finally, oxidation of 230 in the presence of oxygen forms 231, which gives final product 228 with the elimination of CH3COOH. Previously, Zheng and co-workers had constructed quinoxaline scaffolds through PhI(OAc)2-mediated cascade cycloamination of N-aryl ketimines by employing sodium azide as the nitrogen source under copper catalysis. 94 Scheme 61. Synthesis of quinoxalines 228 using PIDA 6 as the oxidant.
Meanwhile, Cai's research group described asymmetric intramolecular C−N bond forming reaction of substituted amides 232 via catalytic desymmetrization process (Scheme 62). 95 This reaction was promoted by in situ generated chiral hypervalent iodine(III) species from diiodospirobiindane derivative 233 in the presence of mCPBA. Addition of TFA as acid promoter and HFIP as solvent media provided the best result. The desired lactams 234 were obtained in decent yields with enantiomeric excess up to 89%. Notably, cyclopentoxy substituent on the nitrogen of amide gave products with better enantioselectivity than with other alkoxy substituents.
Wang and co-workers employed hypervalent iodine(III) reagent 236 as an efficient oxidant for the intramolecular decarboxylative Heck-type reaction of readily accessible 2-vinyl-phenyl oxamic acids 235 (Scheme 63). 96 This operationally simple lactamization method enabled preparation of various 2-quinolinones 237 in variable yields with excellent chemoselectivity. Later, Möckel et al. developed a novel electrochemical method for the lactonization of vinyl benzoates 243 using as precatalyst iodobenzene 13. The reaction was performed in the presence of lithium perchlorate and trifluoroacetic acid as electrolyte and supporting acid respectively. Trifluoroethoxy-substituted isochromanones 247 were isolated in appreciable yields (Scheme 66). 98 Reaction scope was administered by changing the steric and electronic components of the substrates. Further functional group tolerance was determined using compatibility test and it indicated that functional groups labile to oxidative conditions show low yields. In case of vinyl substituted substrates, satisfying diastereomeric ratio were observed. Scheme 66. Synthesis of isochromanones 247 using iododobenzene 13 as precatalyst.
In 2016, Wengryniuk's research group reported synthesis of benzo-fused oxygen heterocycles 257 via oxidative rearrangement of benzylic tertiary alcohols 255. This reaction was facilitated by (poly)cationic hypervalent iodine reagent 256 promoting C-to-O alkyl migration and represents the first example showing the unique reactivity of this class of reagents (Scheme 68). 100 Although detailed mechanism is not provided, authors envisioned attack of the alcohol on the iodine center that would generate an activated intermediate 258 followed by carbon to oxygen alkyl migration to generate oxonium ion 259 which could be trapped by a nucleophile to give cyclic ethers 257. Reaction was highly scalable, demonstrated by gram scale reaction and also HFIP-derived acetals 257 were subjected to subsequent derivatization under different reaction conditions. Scheme 68. Synthesis of Benzo-fused oxygen heterocycles 257 using polycationic hypervalent iodine reagent 256.
In 2019, PIDA-induced oxidative rearrangement of primary amines 260 via 1,2-C to N migration was developed by Murai's research group. This method enabled facile synthesis of cyclic amines such as benzoazepine 261 (n = 1) and benzosuberan 261 (n = 2) in significant yields (Scheme 69). 101 Substituents such as chloro, methoxy, ester and trifluoromethyl groups were well tolerated. Scheme 69. Synthesis of cyclic amines 261 using PIDA 6 as an oxidant. In continuation, Mal's group employed iodine(III) reagent as sole oxidant to prepare multi-substituted carbazoles from anilides 262 and simple arenes 263 either by using stoichiometric PIDA 6 (Method A) or catalytic PhI−mCPBA system (Method B) (Scheme 72). 103 Reactions were performed at ambient temperature and tolerates range of functional groups. Notably, stoichiometric pathway provided better yields as compared to catalytic ones. Further synthetic utility of this method was well documented in the synthesis of bio-active natural products. Murai and co-workers performed the first oxidative rearrangement of cyclic secondary amines 274 using hypervalent iodine reagent 6 (Scheme 74). 105 This method comprises PhI(OAc)2-promoted 1,2-C-to-N alkyl migration of secondary amines 274 followed by subsequent reduction using NaCNBH3 to provide tetracyclic compounds 275. Further scope of the reaction was extended towards the synthesis of macrocyclic indole-fused compounds. Meanwhile, Sugimura's team presented an enantioselective intramolecular oxyarylation of (E)-6-aryl-1silyloxylhex-3-ene 276 promoted by lactate-based chiral iodine(III) reagent 277, 278 and 279 in the presence of BF3·OEt2 (Scheme 75). 106 Tricyclic products 280 were obtained in variable yields under metal-free conditions. Further experimental evidences revealed that silyl group as a protecting group accelerates this oxidative cyclization reaction and also contribute for high enantioselectivity. Additionally, aminoarylation of methanesulfonylamide provided hexahydrobenz[e]indole in 85% yield (ee 80%) using tris(pentafluorophenyl)borane as promoter.

Synthesis of spirocyclic heterocycles
Oxidative dearomatizative spirocyclization constitutes an important platform for the preparation of functionalized spirocyclic skeletons. Chiral hypervalent iodine reagents are frequently employed as reagents or catalyst to achieve asymmetric dearomatization of phenols and other related electron-rich organic compounds. The current section of the review highlights the recent progress made in the enantioselective dearomatizative spirocyclization reactions. In 2015, Zhang et al. constructed spirooxindole derivatives 301 from 1-hydroxy-Naryl-2-naphthamides 300 via chiral organoiodine-catalyzed enantioselective oxidative dearomatization process (Scheme 80). 111 This reaction enabled stereoselective creation of all-carbon stereogenic center containing spiro products 301 in good yields with excellent enantioselectivities (up to 92% ee). Notably, the active hypervalent species, phenyl- 3 -iodanes generated in situ through mCPBA-mediated oxidation of chiral iodoarene 102 catalyze this asymmetric spirocyclization reaction. Later, Murphy's research team presented an unprecedented metal-free approach to access 3,3′spirooxindolo dihydrofurans 303 by reacting cyclic iodonium ylides 183 with 3-alkylidene-2-oxindoles 302 using Bu4NI catalysis (Scheme 81). 112 The reaction was tolerant to a variety of electron-poor and electron-neutral substituents on the alkylidene substrates and the products were isolated in high to excellent yields. Other iodonium ylides derived from 1,3-diketones, pyrimidines and 1,3-ketoesters smoothly gave spirocyclic products in significant yields.
In 2017, Ishiara's group adapted oxidative dearomatization strategy to prepare enantioselective masked ortho-benzoquinones 306 and 308 from ortho-hydroquinone derivatives using chiral organoiodine(III) catalysis (Scheme 82). 113 Reactions works well with both phenols O-tethered to an acetic acid 304 or to an ethanol unit 307 by employing chiral iodoarene 305 as precatalyst. Further the use of synthesized spiroketal in the asymmetric synthesis of natural product, bis(monoterpene) (-)-biscarvacrol highlights the potential scope of this method. Additionally, synthesis of dioxolanone-type masked para-benzoquinones from para-hydroquinone derivatives were achieved under similar conditions with ee up to 89%. Scheme 82. Synthesis of masked ortho-benzoquinones 306 and 308 using chiral organoiodine(III) catalyst 305.
In continuation, the same team employed organoiodine catalyst 305 for the enantioselective intramolecular oxidative dearomatization of naphthol derivatives 309 using mCPBA as an oxidant (Scheme 83). 114 This conformationally flexible catalyst 305 was found very effective for inducing excellent enantioselectivities to the corresponding spirolactones 310 (ee up to 98%). Notably, presence of HFIP and ethanol as an additive for the oxidation of 2-naphthols and 1-naphthols respectively was necessary for achieving high enantioselectivity. Scheme 83. Synthesis of spirolactones 310 using organoiodine catalyst 305.
In the same year, Nachtsheim and co-workers designed a new C1 symmetric triazole-based chiral iodoarene catalyst 311 and successfully utilized this compound for the intramolecular asymmetric Kita-type spirolactonization of 4-substituted 1-naphthols 309. 115 This method provided spirolactones 312 in variable yields and high enantioselectivity, facilitated by in situ generated hypervalent iodine(III) species using terminal oxidant mCPBA (Scheme 84). Reaction scope was investigated under distinct conditions that is by maintaining reaction temperature to 0 o C (Method A) and -20 o C (Method B), and by using catalytic amount of 311 (Method C). Though this "first-generation" triazole-based catalyst provided highest enantioselectivities for this reaction compared to other C1-symmetric iodoarenes, their reactivities were comparatively low. Therefore, the same group synthesized "second-generation" triazole-based catalyst 313 by introducing ortho-substituent at the aryl iodide. 116 This catalyst showed remarkable reactivity and excellent selectivity in the oxidative spirocyclization of 309. The spirolactone 310 was obtained in 85% yield with 99% ee, the highest enantioselectivities observed for this reaction. Several groups designed novel chiral iodoarene reagents for the asymmetric Kita-spirolactonization. For instance, Ogasawara et al. synthesized conformationally rigid C2-symmetric atropisomeric chiral diiododiene 314 and successfully applied as chiral organocatalyst in the dearomatizing spirolactonization of 1-naphthols 309 to yield (S)-spirolactone 310 with ee up to 73% (Scheme 85). 117 Further, Imrich and Ziegler prepared the first carbohydrate-based chiral aryl iodide catalyst 315 by condensing partially protected glucosides with iodoresorcinol via Mitsunobu reaction. 118 This catalyst was further employed for the oxidative spriolactonisation of 309 to provide spirolactone 312 in 77% yield with er up to 80:20. Later, Quideau's research group succeeded in constructing helicine-based chiral iodoarene catalyst 316 from inexpensive precursors (L)-(+)-tartaric acid and 4-methylstyrene. 119  Meanwhile, Ciufolini and co-workers disclosed catalytic, enantioselective intramolecular oxidative cyclization of naphtholic alcohols 327 promoted by newly designed chiral aryl iodide 328 and mCPBA (Scheme 89). 122 Using the present cycloetherification process, an efficient synthesis of spirocyclic products 329 bearing different substituents were achieved in high yields (ee upto 98%). Interestingly, presence of chiral center nearer to the H-bonding amido group in 328 was found useful for effective optical induction. Also, asymmetric oxidative cyclization of naphtholic sulphonamide was accomplished using catalyst 328 under identical conditions. Scheme 89. Enantioselective synthesis of spirocyclic products 329 using chiral aryl iodide 328 as precatalyst.
Very recently, Deng et al. have reported a synthesis of spiro-ethers 332 via ring-opening/dearomatization of 9H-fluoren-9-ol derivatives 330 promoted by iodosobenzene 331. 123 A variety of substituents on the 9-aryl ring were well tolerated. Reaction occurs under mild condition with excellent substrates scope, regio-and diastereochemistry (Scheme 90). Very recently, Tariq and Moran synthesized spirooxazolines 342 via oxidative dearomatization of amidetethered phenols 340 facilitated by active  3 -iodane generated in-situ from 4-MeC6H4I 51/m-CPBA catalytic system (Scheme 92). 124 Authors predicted that the  3 -iodane would activate the phenolic oxygen to form intermediate 341 and subsequent cyclization of pendent amide on to the aromatic ring results in the formation of desired product 342. Scope of the reaction was investigated with a range of aryl, alkyl and heteroaryl amidebased phenols under optimized conditions. Additionally, oxidative dearomatization of naphthol derivatives 343 yielded spirocycles 344 in moderate yields using 40 mol % of 4-iodotoluene 51. Moreover, synthetic utility of this approach in the preparation of dihydrooxazines was successfully demonstrated. Scheme 92. Synthesis of spirooxazolines 342 using 4-iodotoluene 51.
Cai and co-workers demonstrated synthesis of N-fused spirolactams 345 from corresponding 3-arylpropanamides 232 via an asymmetric desymmetrization strategy (Scheme 93). 95 The protocol was catalyzed by hypervalent iodine(III) species generated in situ from chiral precatalyst diiodospirobiindane 233 in the presence of mCPBA as the terminal oxidant. para-substituted substrates 232 with halide or −OR groups smoothly underwent cyclization reaction to deliver products in high yields and moderate to good enantioselectivities. Scheme 93. Synthesis of spirolactams 345 using 233 as precatalyst.

Hypervalent Iodine-Mediated Late-Stage Functionalization of Heterocycles
Direct functionalization of heterocycles using hypervalent iodine reagents is fast-growing field in organic chemistry. These reagents find profound applications in the functionalization of variety heterocyles via synthetic transformations such as oxidative amination, alkylation, acetoxylation, halogenation, etc. In this section, all recent developments acheived in this area will be covered.
A regioselective C2-alkylation of N-heteroaromatic N-oxides 375 using tert-/sec-alkyl alcohol 376 as an alkylating reagent has been reported by Sen and Ghosh (Scheme 102). 132 This PIDA-promoted reaction involves formation of intermediate 378, which upon homolytic C−C bond cleavage of alcohols (via SET pathway), followed by alkylation and final aromatization to deliver 2-alkylated products 377 in useful yields. Scheme 102. PIDA-promoted C2-alkylation of N-heteroaromatic N-oxides 375 using secondary/tertiary alcohols 376 as an alkylating reagent.
Frenette's team developed a photoredox protocol featuring visible light-induced C−H alkylation of heteroaromatics 379 by using carboxylic acids 380 as coupling partner (Scheme 103). 133 The present decarboxylative coupling method employs organic photocatalyst, 9-mesityl-10-methyl acridinium and oxidant PIFA 120. This catalytic system converts carboxylic acids 380 (primary, secondary and tertiary) into alkyl radicals that undergo radical substitution process to deliver corresponding alkylated products 381 in variable yields. Several heteroaromatic compounds 379 such as quinaldine, benzimidazole, benzothiazole, 2,6-dichloropurine, pyridines, pyrimidine, pyrazine and phthalazines were successfully tested under the optimized reaction conditions. Additionally, late-stage C−H functionalization of drugs such as Voriconazole, quinine and Varenicline were also achieved in variable yields.

Alkoxylation and acetoxylation of heterocycles
Kotagiri's group reported C-3 alkoxylation of simple oxindoles 388 via PIFA-mediated oxidative cross-coupling with different linear or branched alcohols 297 (Scheme 106). 137 This reaction provides 3-alkoxyoxindoles 389 in 43-93% yields under mild conditions in shorter reaction time. Further using PIFA/I2 system, in situ iodo-alkoxylation of oxindoles 388 resulted in the one-pot synthesis of 5-iodo-3-monoalkoxyoxindoles 390 or 5-iodo-3,3-dialkoxyoxindoles 391 in appreciable yields. Later, Majee's research group performed visible-light-promoted C(sp 3 )-H acetoxylation of aryl-2H-azirines 392 using PIDA 6 as the reagent. 138 Rose Bengal was used as the organophotoredox catalyst (Scheme 107). Reaction proceeds through radical pathway involving single electron transfer mechanism that requires presence of light irradiation. A library of acyloxylated azirines 393 was isolated in variable yields with excellent regioselectivity and functional group compatibility. Moreover, reaction occurs at room temperature under aerobic condition and applicable for gram scale synthesis.

Halogenation/cyanation of heterocycles
In 2018, a mild method for the selective C-H halogenation of indoles 397 with PhI(OAc)2 6/NaX system was developed by Rao and co-workers (Scheme 109). 140 This method is applicable for the chlorination, bromination and iodination of functionally diverse indoles providing privileged scaffold, 3-haloindoles 398 in moderate to excellent yields. Reaction mechanism involves PIDA-mediated oxidation of NaX generating positive halogen species (X + ) which is attacked by indole regioselectively at the C-3 position to form intermediate 399 and subsequent proton loss yields halo product 398. Scheme 109. PIDA-mediated C-H halogenation of indoles 397 using NaX as the halide source.
Further, Indukuri et al. devised a regioselective protocol for the C-3 halogenation/thiocyanation of imidazo[1,2-a]pyridines/pyrimidine 400 by grinding with alkali metal/ammonium salts (M-X) mediated by PIDA 6 (Scheme 110). 141 This method enabled greener synthesis of halogenated/thiocyanated imidazoheterocycles 401 under solvent-free conditions. Reaction mechanism possibly involves in situ formation of [acetoxy(halo/thiocyanato)iodo]benzene from PIDA 6 and M-X, which serve as source of X + species facilitating electrophilic substitution on electron-rich substrates 400. Additionally, in situ bromination protocol was developed by utilizing HBr generated as by-product during the synthesis of fused N-heterocycles 402 and 404 from the condensation reaction of heterocyclic amine with bromoketone. The desired brominated products 403 and 405 are obtained in good yields. In 2019, Sun and co-workers developed a regioselective C-2 cyanation of quinoline N-oxides 375 by using trimethylsilyl cyanide 406 as an cyanating reagent with PIDA 6 as the oxidant (Scheme 111). 142 Notably, PIDA activates the substrates and accelerates cleavage of N-O bond. The present system showed remarkable compatibility for a wide range of substituents; particularly electron-rich substrates 375 produce 2cyanoquinolines 407 in better yields as compared to electron-deficient ones. Moreover, the scope of the reaction was extended towards pyridine N-oxide and isoquinoline N-oxide and desired products were obtained in useful yields.

Conclusions
Hypervalent iodine compounds are valuable reagents in organic synthesis due to their ready availability, easy handling, environment benign nature and low toxicity. Excellent electrophilic nature and versatile oxidizing ability of these reagents makes them promising alternate candidates for the heavy metal oxidants/catalysts. This review article summarizes the recent developments in the construction of heterocyclic scaffolds using hypervalent iodine reagents. Various stoichiometric or catalytic protocols have been developed to achieve synthesis of monocyclic, bicyclic, polycyclic and spirocyclic heterocycles under mild reaction conditions. More importantly, substantial work in the stereoselective synthesis of different heterocycles using chiral hypervalent reagents has been done with excellent enantioselectivities. Moreover, the application of hypervalent iodine reagents in the late-stage functionalization of heterocycles has been discussed briefly. Furthermore, development of new catalytic transformations that generates iodine(III) species in situ would be area of main focus in future. Apart from this, designing chiral hypervalent iodine-mediated enantioselective reactions still remains a great challenge because of the limited availability of chiral reagents, unsatisfactory enantioselectivity and limited substrate scope. Thus, development of novel asymmetric transformations promoted by chiral iodine(III) species provides an interesting field of research. area organotrifluoroborate chemistry. In 2010, he joined as Marie Curie postdoctoral fellow with Prof. Thomas Wirth at Cardiff University, UK and worked two years in the area of organoselenium and hypervalent iodine chemistry. He received Dr D S Kothari fellowship in 2013 and worked with Prof. G Mugesh at IISc Bangalore, India for a short stay. In 2014, he started his independent career and joined VIT University, Chennai as an Assistant Professor. Mainly, his research group is interested in the findings of new organoselenium and hypervalent catalysts for organic synthesis. Moreover, his research group is also involved in the development of new organic fluorescent molecules for OLEDs and chemical sensors. Currently, he is having different research grants from Government of India. He has already published more than 50 research papers, several book chapters and review articles.