2-Iodoxybenzoic Acid: an Oxidant for Functional Group Transformations: (A-Review)

Home , Tropinone

ORIENTAL JOURNAL OF CHEMISTRY ISSN: 0970-020 X CODEN: OJCHEG An International Open Access, Peer Reviewed Research Journal 2020, Vol. 36, No.(5): Pg. 792-803 www.orientjchem.org

2-Iodoxybenzoic Acid: An Oxidant for Functional Group Transformations: (A-Review)

Vipin A. Nair

Department of chemistry, REVA University, Yelahanka, Bangalore 560064, India. *Corresponding author E-mail: [email protected]

http://dx.doi.org/10.13005/ojc/360501

(Received: August 28, 2020; Accepted: September 29, 2020)

Abstract

A major application of 2-Iodoxybenzoic acid (IBX) is the oxidation of alcohols to carbonyl compounds, at room temperature. IBX is insoluble in almost all solvents, except DMSO. IBX tolerates amine functionality and is therefore used for the oxidation of amino alcohols to amino carbonyl compounds. IBX oxidizes 1,2-glycols without the cleavage of the glycol carbon-carbon bond. Allylic and benzylic positions are also susceptible to oxidation by IBX. Synthesis of a,b-unsaturated carbonyl compounds from carbonyl compounds can be accomplished by using IBX as oxidant. Silyl enol ethers undergo oxidation upon exposure to IBX and 4-methoxypyridine N-oxide. Water-soluble derivatives of IBX, and polymer-based IBX, with additional advantages, have also been developed. IBX mediated transformations facilitate the construction of diverse heterocyclic systems.

Keywords: 2-Iodoxybenzoic acid, Oxidation, Alcohols, Carbonyl compounds, Single electron transfer. Introduction useful oxidants in organic synthesis.

O OH AcO OAc 2-Iodoxybenzoic acid (IBX), a hypervalent I I OAc iodine(V) reagent (Fig. 1) finds numerous applications O O as an oxidant. It is effective in carrying out oxidation O O of alcohols, benzylic and allylic sites, and carbon centres adjacent to carbonyl functionalities. 2-Iodoxybenzoic acid (IBX) Dess-Martin Periodinane (DMP) Inferences drawn from studies indicate that some Fig. 1. Hypervalent Iodine reagents of these reactions proceed by single electron 2-Iodoxybenzoic acid (IBX) is known transfer (SET) mechanism. Electron transfer from for several decades, but its utility was limited by the substrate to IBX forms a radical cation, which insolubility in most organic solvents, except DMSO. is converted to product. Detailed investigations on IBX is easily prepared from 2-iodobenzoic acid by an multifunctional substrates would allow to decipher oxidation reaction. Oxone (2KHSO5-KHSO4-K2SO4) the chemo- and regioselectivity of the reactions. is widely employed as an oxidant in the preparation The reagent has the potential to be one of the highly of IBX.1 The oxidation is performed at 70°C in water

This is an Open Access article licensed under a Creative Commons license: Attribution 4.0 International (CC- BY). Published by Oriental Scientific Publishing Company © 2018 Nair., Orient. J. Chem., Vol. 36(5), 792-803 (2020) 793

(Fig. 2). IBX is crystallized out of the reaction mixture OH O in high yields and good purity, by cooling. Use of NR NR excess of oxone reduces the reaction time. The 2 IBX 2 procedure is environment friendly, with the sulfate salts as the only by products. DMSO, TFA Scheme 2. Oxidation of amino alcohols O OH Carboxylic acids and esters remain intact in I I Oxone (1.3 equiv.) presence of IBX, while phenols are unstable (Table O H2O, 70°C, 3h 1, Entry 4). At room temperature, phenols undergo CO2H double oxidation (Scheme 3) to afford o-quinones.4 O IBX However, phenols with electron withdrawing groups are not oxidised. Fig. 2. Preparation of IBX using Oxone IBX has been used to convert alcohols and O O 1,2-diols to carbonyl compounds (Scheme 1). The OH IBX transformation occurs without over-oxidation (Table DMF X X 1, Entries 1,2) to carboxylic acids.2 IBX does not Y Y require an inert atmosphere for the reaction. X, Y - Electron donating groups Scheme 3. Oxidation of phenols OH IBX O 2 1,4-Diols are oxidised to g-lactols (Table 1, 1 R DMSO, RT 2 R R1 R Entry 5) in good yields.5 No over-oxidation to lactones was observed. For instance, the diol prepared OH OH IBX OH O O O by hydroboration of (1S)-isopulegol afforded a or R R diastereomeric mixture of lactols (Scheme 4). DMSO, RT R R R R Scheme 1. Oxidation of alcohols and 1,2-diols CH3 CH3 Alcohols can be selectively oxidised in the IBX presence of amines (Table 1, Entry 3). Thus IBX converts amino alcohols to amino carbonyl compounds OH DMSO O OH (Scheme 2). Amines are usually protonated in situ with H3C H3C OH an acid (TFA), during the reaction.3 Scheme 4. Oxidation of 1,4-diols Table 1: IBX mediated functional group transformations

Entry Substrate Product Conditions Yield

H 1 OH IBX (1.0 equiv.), 97% O DMSO, RT

OH O 2 IBX (2.5 equiv.), 81% DMSO, RT OH O OH O 3 IBX (1.1 equiv.), 89% NH2 NH2 TFA (1.1 equiv.), DMSO, RT O OH O 4 IBX (1.0 equiv.), 99% MeO MeO DMF, 25°C H H OH OH H 5 O IBX (1.2 equiv.), 88% OH DMSO, 23°C H H

OH CHO 6 aM-IBX (2.0 equiv.), 90%

H2O, RT Nair., Orient. J. Chem., Vol. 36(5), 792-803 (2020) 794

OH CHO 7 bP-IBX (1.2 equiv.), 97% MeO MeO THF, RT OTMS O 8 cIBX-MPO (1.5 equiv.), 90% DMSO, -10°C to 25°C

9 IBX (1.0 equiv.), 96% OH CHO db-CD (0.1 equiv.),

H2O, RT

CH3 CHO 10 IBX (3.0 equiv.), 85% PhF:DMSO (2:1), 85°C

aModified IBX (Water soluble derivative);b Polymer supported IBX; cIBX-Methoxy Pyridine N-oxide; db-Cyclodextrin A water-soluble derivative of IBX was A complex of IBX and 4-methoxypyridine developed for oxidizing alcohols. The synthesis was N-oxide (MPO) (Scheme 6) converts carbonyl achieved by the conversion of 3-nitrophthalic acid to compounds and trimethyl silyl enol ethers into 3-iodophthalic acid (Fig. 3) and subsequent oxidation corresponding a,b-unsaturated carbonyl compounds.8 using KBrO .6 This derivative of IBX oxidises allylic and 3 Reactive groups such as amines, sulfides and benzylic alcohols in water (Scheme 5). Over-oxidation products were not observed (Table 1, Entry 6). mesylates were unaffected. The enolate formed by

NO the conjugate addition of a cuprate reagent (RMgX, 2 NO2 H , Pd-C NH2 SOCl2, heat 2 NaNO2, HCl

CH OH, heat CH3OH KI CuBr.SMe ) to an enone was trapped as the silyl enol CO2H 3 CO2CH3 CO2CH3 2 CO2H CO2CH3 CO2CH3 ether. Subsequent oxidation of the silyl enol ether

O OH regenerated a b-substituted enone (Table 1, Entry 8). I I I NaOH, THF–H2O KBrO3 O aq. HCl H2SO4 O OTMS O CO2CH3 CO2H CO CH CO H CO H O 2 3 2 2 MgX CuBr.SMe2 IBX-MPO

Fig. 3. Preparation of water-soluble derivative of IBX TMEDA, TMSCl, THF DMSO

HO O -78°C to 25°C I O H Scheme 6. Conversion of silyl enol ethers to enones O OH CO2H O

H2O, RT The dehydrogenation reactions of carbonyl HO O I compounds proceed through enolization facilitated O H CO H O by IBX. This is followed by a single electron OH 2 O H2O, 60°C transfer to IBX. The resulting radical cation affords Scheme 5. Oxidation of allylic and benzylic alcohols a,b-unsaturated carbonyl compound (Fig. 5). It is 2-Amino-5-hydroxybenzoic acid was assumed that the silyl enol ethers also undergo a transformed to the tert-butyl ester of 2-iodo-5- hydroxy benzoic acid (Fig. 4). The phenolic hydroxy similar oxidation with IBX. MeO MeO MeO group was subsequently coupled to aminopropylsilica O O O MeO O gel with acetyl group as the linker. Cleavage of the N O N O N O O N tert-butyl ester and oxidation with oxone afforded O I O I O I I O O O O HO 7 O O O the polymer-supported IBX reagent. Primary and O R1 R1 R1 secondary alcohols were oxidized by this reagent, in H 1 2 R R2 R2 R THF medium (Table 1, Entry 7). This reagent offers R2 the advantages of polymer-support and the oxidant. Fig. 5. Formation of a,b-unsaturated carbonyl compounds The reduced reagent was separated by filtration, and b-Cyclodextrin catalyses the oxidation of regenerated by oxidation. alcohols and diols, with IBX. Water-acetone mixture OH OH OH N,N-dimethyl formamide 9 NaNO , H SO di-tert-butyl acetal 2 2 4 1.NaH, BrCH2COOEt was employed as the solvent. Cyclodextrin exerts

COOH KI COOH CO2tBu 2. NaOH NH2 I I catalytic effect through non-covalent interactions.

H H N SiO2 N SiO O COOH O O 2 Aryl carbinols (Table 1, Entry 9) gave better yields aminopropylsilica gel O 1. TFA O than the aliphatic alcohols. Selectivity was observed DIC, HOBt 2. Oxone CO2tBu CO2tBu O I I HO I O with vicinal diols, oxidizing only the secondary O Fig. 4. Preparation of polymer supported IBX hydroxy group a to the benzene ring (Scheme 7). Nair., Orient. J. Chem., Vol. 36(5), 792-803 (2020) 795

OH O OH IBX cat. 2-Iodoxy benzoic acid/Oxone OH OH or 1 O b-Cyclodextrin cat. 2-Iodoso benzoic acid/Oxone R Water-Acetone, RT R1 OH Scheme 7. b-cyclodextrin catalysed oxidation of benzyl alcohol MeCN-H2O Oxidation of benzylic positions (Table 1, R2 Entry 10) occurs efficiently with IBX in DMSO at 80- R2 90°C.10 Over-oxidation products were not observed R1 O 1 OH even in the case of electron-rich substrates. R Tetrahydronaphthalenes yielded the corresponding Scheme 11. Oxone as a co-oxidant in IBX or IBA mediated ketones (Scheme 8). The selective oxidation of oxidations tetrahydronaphthalenes to mono-carbonyl systems IBX oxidation of aldol substrates (Scheme is achieved by retardation of the reaction using 12) yielded diketones.14 Substitution at the α-position electron withdrawing substituents. of the hydroxyketone was tolerated. The reaction did not discriminate between the syn and anti aldol OAc OAc O OAc diastereomers. The mild nature of the reaction IBX (3.0 equiv.) + 85°C condition was demonstrated in the reactions of O α-iodosubstrates, which gave the relatively stable Scheme 8. Oxidation of tetrahydronaphthalene a-iodo-b-diketones (Table 2, Entry 4). Surprisingly, IBX behaves as a heterogeneous oxidant in the oxidation of b-hydroxyketones failed with DMP. insoluble solvents.11 However at elevated temperatures, O OH IBX (3.0 equiv.) O O IBX becomes sufficiently soluble in solvents such as 1 3 1 3 EtOAc or DCE to permit oxidation of alcohols (Table 2, R R EtOAc, Reflux R R 2 2 Entry 1) to the corresponding aldehydes and ketones R R (Scheme 9). It was observed that with excess oxidant, Scheme 12. Oxidation of aldol substrates the reaction rate increases. IBX was effective in converting carbonyl functionalities to a,b-unsaturated carbonyl compounds O O OH IBX (3.0 equiv.) O (Scheme 13). Benzylic centers were oxidized to O EtOAc or DCE, 80°C O form conjugated aromatic carbonyl compounds. On varying the stoichiometry and temperature, IBX Scheme 9. Oxidation using IBX in insoluble solvents dehydrogenates cyclooctanol to either cyclooctenone Oxidation of benzyl alcohol to benzaldehyde or cyclooctadienone (Table 2, Entry 5).15 The was achieved using IBX in DCM-H2O (1:1) medium cyclooctadienone formation paved the way for the 12 (Scheme 10) with 0.5 equiv. of n-Bu4NBr (TBAB). total synthesis of a tropinone analog. While the oxidation of alcohols was effective with 1.5 O equiv. of IBX, it was found that for diols 3.0 equiv. of IBX O O was required (Table 2, Entry 2). Very small amounts of IBX (2,0 equiv.) IBX (3.0 equiv.) dicarbonyls or lactones were observed in the oxidation 65°C 80°C of diols. The transformation was also chemoselective Scheme 13. Conversion of carbonyl compounds to with respect to the nature of the hydroxy groups. When a,b-unsaturated carbonyl compounds present in the same molecule, the secondary hydroxy Oxidation of electron rich sites, such as group was converted to ketone whereas the primary the benzylic position occurs through single electron hydroxy group remained intact. transfer (Fig. 6). Subsequent loss of a proton IBX (3.0 equiv.) generates the benzyl radical. This intermediate OH n-Bu4NBr (0.5 equiv.) O undergoes another oxidation to give the benzyl R OH DCM-H O, RT n 2 R n OH carbocation which is transformed to alcohol, and Scheme 10. TBAB assisted oxidation of alcohols and diols further oxidised to the carbonyl functionality. In the presence of oxone (Scheme 11), IBX IBX the oxidation of alcohols could be carried out with R R R R SET SET catalytic amount of IBX, in acetonitrile-water (2:1) -H+ 13 medium. 2-Iodosobenzoic acid (IBA) formed during OH O the reaction was re-oxidised in situ (Table 2, Entry H2O IBX H R R R 3). This observation prompted the use of IBA as a catalytic oxidant in place of IBX. Fig. 6. Oxidation of benzylic centres by SET mechanism Nair., Orient. J. Chem., Vol. 36(5), 792-803 (2020) 796

Table 2: IBX mediated oxidation reactions

Entry Substrate Product Conditions Yield

H 1 O IBX (3.0 equiv.), 90% OH O O EtOAc, 80°C O O 2 OH O IBX (3.0 equiv.), 81%

OH OH n-Bu4NBr (0.5 equiv.),

DCM:H2O (1:1), RT

O 3 OH IBA (0.4 equiv.), 93% OH Oxone (1.2 equiv.),

MeCN:H2O (2:1), 70°C O OH O O 4 IBX (3.0 equiv.), 99% I I EtOAc, 77°C O O 5 IBX (3.0 equiv.), 74% DMSO, 80°C

6 O O OH IBX (1.0 equiv.), 84%

I2 (2.2 equiv.), H3C H3C DMSO, RT I

CH2CONH2 CN 7 IBX (5.0 equiv.), 85% N N TEAB (15.0 equiv.), MeCN, 60°C

8 S IBX (1.0 equiv.), 90% N C N Et3N (2.0 equiv.), N N DCM, 0°C H H O 9 IBX (1.1 equiv.) 74% Br TEAB (1.1 equiv.), DCM, RT

O Ph O Ph 10 OH IBX (1.5 equiv.), DMSO, 23°C

In the presence of molecular iodine, IBX OH I CN CN generates hypoiodous acid (HOI). Hypoiodous IBX/I2 IBX/I2 1 R1 R DMSO I MeCN-TFA acid reacts with olefins and a,b-unsaturated R2 R2 ketones to afford iodohydrins (Scheme 14) O O with anti stereochemistry (Table 2, Entry 6).16 O 1.IBX/I2/DMSO/RT Epoxides can be obtained by a one-pot reaction 2 2 R1 R 2. 10% NaOH/RT R1 R through sequential iodohydroxylation and dehydroiodocyclization. An acidified solution of Scheme 14. IBX-Iodine mediated reactions of unsaturated HOI produces iodonium ions (Fig. 7), which can systems iodinate aromatic compounds. An equimolar ratio of IBX and tetraethyla-

HO O mmonium bromide (TEAB) in acetonitrile converts I I 4HOI N,N-disubstituted glycylamides (Table 2, Entry 7) O + 2I2 + 2H2O OH + to cyanamides,17 by one carbon dehomologation O O (Scheme 15). In the case of 2-(4-benzylpiperidin- 1-yl)acetamide, the benzylic position remains I HOI + H + H2O unaffected during the oxidation, illustrating the Fig. 7. Formation of hypoiodous acid and iodonium ions chemoselectivity. Nair., Orient. J. Chem., Vol. 36(5), 792-803 (2020) 797

OH IBX/TEAB N IBX O N CH2CONH2 N CN 2 b-Cyclodextrin/H O/RT 1 2 Ph MeCN, 60°C Ph R1 R 2 R R Scheme 15. Dehomologation of glycylamides and Scheme 19. Conversion of oximes to carbonyl compounds cyanamide formation Hydrolysis of thioacetals/thioketals (Table 3, Thioureas are rapidly transformed to Entry 2) to the corresponding carbonyl compounds carbodiimide18 using IBX and triethylamine in (Scheme 20) was attained with IBX in presence 22 DCM (Scheme 16). Sulfur is precipitated during of a-cyclodextrin at room temperature. Various the reaction. A molar ratio of 1:1:2 for substrate/ functional groups are compatible with this procedure. However reactions with thioacetals of aliphatic IBX/triethylamine was required for the reaction to aldehydes were not encouraging. complete (Table 2, Entry 8). O RS SR IBX S IBX, Et N 3 N C N 1 2 b-Cyclodextrin/H O/RT 1 2 N N DCM, 0°C R R 2 R R H H Scheme 20. Hydrolysis of thioacetals/thioketals Scheme 16. Formation of carbodiimide from thiourea The reaction of phenylglyoxal and Olefins were converted toa -bromoketones benzohydrazide in acetonitrile at room temperature (Scheme 17) by employing IBX in combination with generates hydrazide-hydrazone (Scheme 21), tetraethylammonium bromide (Table 2, Entry 9). An When this intermediate is reacted with IBX and equimolar ratio of IBX/TEAB in anhydrous DCM, tetraethylammonium bromide, α-keto-1,3,4- yielded a-bromocyclohexanone from cyclohexene.19 oxadiazoles (Table 3, Entry 3) are produced.23 The Regioselectivity was observed with terminal olefins reaction was successful with a variety of aryl and which gave only a-bromo ketones, but not the heteroaryl glyoxaldehydes, as well as alkyl, aryl and isomeric a-bromoaldehydes. heteroaryl hydrazides. The tetraethylammonium bromide facilitates the polarization of the I=O O IBX/TEAB bond of IBX to generate a reactive adduct I anhyd. DCM (Fig. 8). Nucleophilic displacement of bromine from Br RT the adduct I by the imine nitrogen of hydrazide- O hydrazone yields adduct II. Oxidative cyclization and IBX/TEAB Br loss of water generates α-keto-1,3,4-oxadiazoles. anhyd. DCM RT O O O N N R2CONHNH 1 O 2 N IBX, TEAB R R1 R1 N R2 R2 Scheme 17. TEAB mediated formation of a-bromoketones MeCN O H H H O IBX effects a-hydroxylation of a-alkynyl Scheme 21. Formation of α-keto-1,3,4-oxadiazoles carbonyl compounds (Scheme 18). Thus hydroxylation R2 of 2-(2-phenylethynyl) cyclohexanone to 2-hydroxy- O O O R2 N O NH O H O O HO HO HO N 2-(2-phenylethynyl) cyclohexanone (Table 2, Entry N I 2 2 R N I R N I O - N -IBA 1 10) was achieved using IBX in DMSO at room Br O O- N O- R 1 O O 20 R O H H O temperature. This mildly acidic method serves as O O I 1 II 1 III an alternative to other a-hydroxylation protocols. R R Fig. 8. Conversion of hydrazide-hydrazones to O R O R OH α-keto-1,3,4-oxadiazoles R1 IBX (1.5 equiv.) R1 DMSO, RT Reaction of o-aminobenzylamine with R2 R2 aldehydes in acetonitrile (Scheme 22) at room Scheme 18. a-Hydroxylation of a-alkynyl carbonyl compounds temperature using 1.0 or 2.0 equiv. of IBX (Table Conversion of oximes to carbonyl 3, Entry 4) afforded dihydroquinazolines and compounds (Scheme 19) was achieved by IBX quinazolines, respectively.24 The transformation in presence of a-cyclodextrin.21 The reaction was was accomplished with aliphatic, aromatic and performed in aqueous medium at room temperature heteroaromatic aldehydes. The plausible mechanism involves an attack by the nitrogen N1 of 1,2,3,4- (Table 3, Entry 1). Oximes having an aromatic tetrahydroquinazoline, formed In situ, on the moiety gave better yields. The reaction tolerates iodine centre of IBX to afford the intermediate I. halo, nitro, hydroxy and methoxy groups. The This is followed by an elimination reaction to give deoximation reaction does not occur in the absence dihydroquinazoline. A similar attack by N2 on IBX of a-cyclodextrin. converts dihydroquinazoline into quinazoline. Nair., Orient. J. Chem., Vol. 36(5), 792-803 (2020) 798

NH2 MeCN NH 2 + RCHO + IBX (1.0 equiv) NH RT NH2 N R 1 H N R H O I O H NH2 MeCN N O + RCHO + IBX (2.0 equiv) NH RT N R 2 O Intermediate I Scheme 22. Formation of quinazoline derivatives Table 3: Synthetic reactions mediated by IBX

Entry Substrate Product Conditions Yield

OH O 1 N IBX (1.0 equiv.) 92% ab-CD (0.1 equiv.), H H H2O, RT

O 2 S S IBX (1.0 equiv.) 90% H H b-CD (0.1 equiv.),

H2O, RT

O H 3 O N N IBX (1.0 equiv.) 90% + TEAB (1.2 equiv.), O O NH N 2 MeCN, RT H O

NH2 N

4 NH2 IBX (2.0 equiv.), 88% + N CHO MeCN, RT

O OMe 5 TPSO O OMe 1. IBX (4.0 equiv.), 76% TPSO O THF:DMSO (10:1), 90°C HN O O 2. bCAN (5.0 equiv.) HN MeCN:H2O (3:1), 25°C OMe O

OH O 6 cP-IBX (1.75 equiv.), 95% DCM, RT

O O 7 IBX (1.0 equiv.), 90% OH b-CD (0.1 equiv.),

H2O, 60°C to RT

O O 8 S IBX (2.0 equiv.), 76% + p-Tol O I2 (1.1 equiv.), p-TolSO 2Na MeCN:DMSO (2:1), RT

O O

O O 9 CH3 IBX (2.0 equiv.), 85% S I (0.25 equiv.), + p-Tol 2 O EtOAc, Reflux p-TolS O 2Na

HO OH O 10 Ph Ph IBX (2.0 equiv.), 90% Ph Ph Ph Ph DMSO, 80°C ab-Cyclodextrin; bCerium(IV) ammonium nitrate; cPolymer supported IBX Nair., Orient. J. Chem., Vol. 36(5), 792-803 (2020) 799

2-Cyclohexen-1-ol reacts with p-methoxy Combination of IBX-I2 facilitates the phenyl isocyanate in the presence of catalytic reactions of alkenes with arenesulfinates (Table 3, amount of DBU to form cyclohexenyl carbamate Entry 8). This method yields a-keto sulfones (Scheme (Scheme 23). The product on reaction with IBX 26) in a one-pot reaction.28 Acetonitrile–dimethyl (Table 3, Entry 5) furnishes bicyclic oxazol-2-one.25 sulfoxide (2:1) was used as the medium. The The amino group was restored by reaction with mechanism involves the formation of phenacyl iodide cerium(IV) ammonium nitrate. as the intermediate followed by the nucleophilic attack of sulfur atom of arenesulfinate. H H O O O O O O IBX CAN IBX, I2 O O O HN N NH MeCN-DMSO (2:1) S H H R R Ar ArSO2Na OMe OMe Scheme 26. Formation of a-keto sulfones from alkenes Scheme 23. Formation of bicyclic oxazol-2-one Sodium sulfinates in presence of IBX and 5-Hydroxy-2-iodobenzoic acid coupled catalytic amount of I2 was used for sulfonylation to chloromethyl polystyrene cross-linked with 1% of 1,3-dicarbonyl compounds (Scheme 27), divinylbenzene using Cs CO . It was oxidised to 2 3 subsequent to deacylation.29 The method affords obtain polystyrene supported periodinane reagent b-carbonyl sulfones (Table 3, Entry 9) in one step, (Fig. 9). The reagent converts alcohols to carbonyl and in good yields. compounds (Table 3, Entry 6), in good yields.26 a,b- O O O O O Desaturation of carbonyl compounds, and the radical I2 (cat.), IBX 4 S 1 3 + R SO2Na 1 4 cylization of unsaturated carbamates were also R R EtOAc, Reflux R R successfully carried out by employing this polymer R2 R2 supported reagent (Scheme 24). Scheme 27. Formation of a-keto sulfones from 1,3-dicarbonyl compounds 1. HO COOH HO COOMe Cl Cs CO 1. NaNO2, KI 2 3 IBX oxidizes sec,sec-1,2-diols to the 2. SOCl2, MeOH 2. KOSiMe NH2 I 3 corresponding a-ketols without cleaving the glycolic C-C bond. However it does not react with O O COOH O tert,tert-1,2-diols, but DMP accomplishes the NBu4SO5H O MeSO H same transformation. This difference is due to the I 3 I HO O formation of a 10-I-4 intermediate species with IBX Fig. 9. Preparation of polystyrene supported IBX and a 12-I-5 species with DMP. The latter species O decomposes rapidly into dicarbonyl compounds, O O while the former cannot undergo cleavage. The H I N O use of a protonating solvent such as TFA with IBX HO O N O O promotes the formation of the 12-I-5 intermediate O THF-DMSO (10:1), 90°C (Scheme 28). Consequently, with IBX and TFA, all Scheme 24. Heterocyclization mediated by polymer 1,2-diols provide ketones (Table 3, Entry 10) by supported IBX oxidative fragmentation.30 Epoxides and aziridines were reacted with IBX in presence of a-cyclodextrin (Scheme 25) at F3C O O O O room temperature to obtain b-hydroxyketones (Table OH O OH I I O 3, Entry 7) and b-aminoketones, respectively.27 The TFA I OH OH O O O reactions do not occur in the absence of cyclodextrin. -IBA The cyclodextrin-IBX complex transforms the O O O epoxide to 1,2-diol, and aziridine to amino alcohol, Scheme 28. Oxidative fragmentation of 1,2-diols which is thereafter oxidized. IBX in DMSO promotes the oxidative O 31 X rearrangement of tertiary allylic alcohols. Thus XH IBX 1-phenyl-2-cyclohexen-1-ol (Table 4, Entry 1) at H2O R R room temperature yielded 3-phenyl-2-cyclohexenone + X = O, N Ts (Scheme 29). A rate enhancement was observed with b-cyclodextrin increase in temperature. This indicates that heat is Scheme 25. Formation of b-hydroxyketones and b-aminoketones effective for allylic transposition. One of the suggested Nair., Orient. J. Chem., Vol. 36(5), 792-803 (2020) 800 mechanisms (Fig. 10) involves the solvolysis of the tertiary alcohol to an allylic cation (path a). Thereafter path b O I O R an iodic ester is formed at the less substituted terminus O O that undergoes oxidation. The second mechanism proposes the formation of a tertiary iodic ester HO R R R I O I OH O O (path b) followed by rearrangement and oxidation. O O O O H O R IBX OH path a + DMSO, 55°C OH R R I n n O O O Scheme 29. Oxidative rearrangement of tertiary allylic alcohols Fig. 10. Oxidative rearrangement of tertiary allylic alcohols Table 4: Substituent modifications promoted by IBX

Entry Substrate Product Conditions Yield

O 1 OH IBX (2.0 equiv.), 85% DMSO, 55°C Ph Ph

CHO Ph 2 N IBX (1.1 equiv.), 59%

MeO + TMSCN TBAB (1.1 equiv.), N MeCN, RT PhCH2CH2NH2 MeO OMe 3 O O IBX (2.2 equiv.), 77%

Ph N Ph NH2 aHFIP:H O (2:1), 25°C H 2

4 NH2 CN IBX (2.5 equiv.), 95% TEAB (2.5 equiv.), O MeCN, 60°C OBn OBn N N 5 H IBX (1.1 equiv.), 89% DMSO, 45°C O NH 2 O 6 IBX (2.0 equiv.), 96% TEAB (1.0 equiv.), MeCN, 60°C

O O 7 OH IBX (1.5 equiv.), 78% Me CO2Me Me CO2Me DMSO:H2O (3:1), 50°C

aHexafluoro-2-propanol The reaction of aldehydes, amines and amides (Scheme 31) IBX was used in a mixture TMSCN with IBX (Table 4, Entry 2) in the presence of hexafluoro-2-propanol (HFIP) and water.33 This of tetrabutylammonium bromide (TBAB) afforded method demonstrates that an aryl group can be used a-iminonitriles (Scheme 30) in good yields.32 The as a removable protecting group for amides. three-component one-pot reaction works well for a O wide range of aldehydes and amines. IBX O 1 2 2 N 1 R R R HFIP/H2O, 25°C R NH2 O HN N H 2 MeCN IBX/TBAB + R NH2 + TMSCN Scheme 31. Oxidative cleavage of secondary N-aryl amides 1 RT 1 RT R1 R H R N N Primary carboxamides (Table 4, Entry 4) were Scheme 30. Formation of a-iminonitriles transformed to one-carbon dehomologated nitriles For the oxidative cleavage of inert N-aryl (Scheme 32) using IBX and tetraethylammonium bonds (Table 4, Entry 3) in secondary aromatic bromide.34 The mechanism involves the transformation Nair., Orient. J. Chem., Vol. 36(5), 792-803 (2020) 801 of amides to isocyanates and then to imines (Fig. 11). a,a-Diphenylacetamide (Table 4, Entry Imines on further oxidation give nitriles. 6) when treated with IBX in presence of TEAB in acetonitrile yielded benzophenone (Scheme 35) in excellent yields.36 The reaction was optimized with IBX induces the generation of imines 2.0 equiv. of IBX and 1.0 equiv. of TEAB. Acetamides (Table 4, Entry 5) from secondary amines (Scheme with aryl and heteroaryl substituents at the a-position 35 33) under mild conditions. In DMSO-H2O medium, reacted better than the alkyl counterparts (Figure 12). IBX facilitates the cleavage of dithianes also CONH2 O (Scheme 34). IBX/TEAB

O MeCN, 60°C IBX/TEAB R R-CN Scheme 35. Conversion of a,a-disubstituted acetamides to NH2 MeCN, 60°C ketones R = alkyl or aryl or benzoyl b-Keto esters were converted to tertiary Scheme 32. Formation of dehomologated nitriles alcohols (Scheme 36) in the presence of IBX (Table 4, Entry 7) in a solvent mixture of DMSO and 1 IBX R 1 water.37 At a temperature of 50°C, reaction rate was N R2 R H DMSO N R2 accelerated. Apart from b-ketoesters, b-ketoamides Scheme 33. Formation of imines and b-diketones also undergo b-hydroxylation.

O O S S O OH CO2Et CO2Et H IBX H IBX (1.5 equiv.)

DMSO-H2O (9:1) DMSO-H2O Scheme 34. Cleavage of dithianes Scheme 36. Conversion of b-ketoesters to tertiary alcohols

- O OH -O OH O H I + - I Br H N I N O (CH3CH2)4N Br 2 R Br R O O O O O O O

H O O O H I N C O I HN O R O R HN N R - CO2 R O O I - OH

O Fig. 11. Conversion of carboxamides to dehomologated nitriles

Br + O + O - HO - O NEt4 O NEt 1 R1 I 4 R H I NH N 2 + O + O 2 2 R R Br O O

OH 1 1 R I I R O I O O + OH O + O C N R1 HN H 2 2 R2 R R O C N O O H H2O

R1 O R2 Fig. 12. Conversion of a,a-disubstituted acetamides to ketones Nair., Orient. J. Chem., Vol. 36(5), 792-803 (2020) 802

Conclusion the scope and potential of this hypervalent iodine reagent. Refinement of the existing methods and Over the last three decades, IBX has demonstration of novel applications would definitely become a popular oxidant in organic synthesis. make IBX as one among the widely used oxidants A vast amount of literature is available on the in organic synthesis. applications of this reagent, especially in the total synthesis of natural products.38 IBX enjoys its Acknowledgment unique position in chemical space because of its mild nature and simple conditions, transforming a This research did not receive any specific variety of functional groups to desired substituents, with chemoselectivity, and no over-oxidation. grant from funding agencies in the public, commercial, The single electron transfer process generates a or not-for-profit sectors. radical species, which substantiates the reaction mechanisms in many cases. However, detailed Conflicts of Interest investigations need to be carried out to evaluate The authors declare no conflict of interest.

References 1. Frigerio, M.; Santagostino, M.; Sputore, S. J. 14. Bartlett, S. L.; Beaudry C. M. J. Org. Chem., Org. Chem., 1999, 64, 4537-4538. 2011, 76, 9852-9855. 2. Frigerio, M.; Santagostino, M. Tetrahedron 15. a) Nicolaou, K. C., Montagnon, T.; Baran, P. S.; Lett., 1994, 35, 8019-8022. Zhong, Y.-L J. Am. Chem. Soc., 2002, 124, 2245- 3. Frigerio, M.; Santagostino, M.; Sputore, S.; 2258; b) Nicolaou, K. C.; Zhong, Y.-L.; Baran, P. Palmisanoj, G. J. Org. Chem., 1995, 60, 7272- S. J. Am. Chem. Soc., 2000, 122, 7596-7597; 7276. c) Nicolaou, K. C.; Montagnon, T.; Baran, P. S. 4. Magdziak, D.; Rodriguez, A. A.; Van De Water, R. Angew. Chem. Int. Ed., 2002, 41, 993-996. W., Pettus, T. R. R. Org. Lett., 2002, 4, 285-288. 16. Moorthy, J. N.; Senapati, K.; Kumar S. J. Org. 5. Corey, E. J.; Palani, A. Tetrahedron Lett., 1995, Chem., 2009, 74, 6287-6290. 36, 3485-3488. 17. Chaudhari, K. H.; Mahajan, U. S.; Bhalerao, D. S. 6. Thottumkara, A. P.; Vinod, T. K. Tetrahedron Akamanchi, K. G. Synlett., 2007, 2815-2818. Lett., 2002, 43, 569-572. 18. Chaudhari, P. S.; Dangate, P. S.; Akamanchi, 7. Mülbaier, M. M.; Giannis, A. Angew. Chem. K. G. Synlett., 2010, 3065-3067. Int. Ed., 2001, 40, 4393-4394. 19. Deshmukh, S. S.; Chaudhari, K. H.; Akamanchi, 8. Nicolaou, K. C.; Gray, D. L. F.; Montagnon, T.; K. G. Synlett., 2011, 81-83. Harrison, S. T. Angew. Chem. Int. Ed., 2002, 20. Kirsch S. F. J. Org. Chem., 2005, 70, 10210-10212. 41, 996-1000. 21. Krishnaveni, N. S.; Surendra, K.; Nageswar, Y. V. 9. Surendra, K.; Krishnaveni, N. S.; Reddy, M. A.; D.; Rao, K. R. Synthesis., 2003, 1968-1970. Nageswar, Y. V. D.; Rao, K. R. J. Org. Chem., 22. Krishnaveni, N. S.; Surendra, K.; Nageswar, Y. V. 2003, 68, 2058-2059. D.; Rao, K. R. Synthesis., 2003, 2295-2297. 10. Nicolaou, K. C.; Baran, P. S.; Zhong, Y-L. J. 23. Kumar, D.; Pilania, M.; Arun, V.; Mishra, B. Am. Chem. Soc., 2001, 123, 3183-3185. Synlett., 2014, 25, 1137-1141. 11. More, J. D., Finney, N. S. Org. Lett., 2002, 4, 24. Hati, S.; Sen, S. Synthesis., 2016, 48, 1389- 3001-3003. 12. Kuhakarn, C.; Kittigowittana, K.; Pohmakotr, 1398. M.; Reutrakul V. Tetrahedron., 2005, 61, 8995- 25. Nicolaou, K. C.; Baran, P. S.; Zhong Y-L.; Vega, J. 9000. A. Angew. Chem. Int. Ed., 2000, 39, 2525-2529. 13. Thottumkara, A. P.; Bowsher, M. S.; Vinod T. 26. Sorg, G.; Mengel, A.; Jung, G.; Rademann, J. K. Org. Lett., 2005, 7, 2933-2936. Angew. Chem. Int. Ed., 2001, 40, 4395-4397. Nair., Orient. J. Chem., Vol. 36(5), 792-803 (2020) 803

27. Surendra, K.; Krishnaveni, N. S.; Reddy, M. Zhu, J. Org. Lett., 2008, 10, 1509-1512. A.; Nageswar, Y. V. D.; Rao K. R. J. Org. Chem., 33. Zhang, Z.; Zheng, D.; Wan, Y.; Zhang, G.; Bi, 2003, 68, 9119-9121. J.; Liu, Q.; Liu, T.; Shi, L. J. Org. Chem., 2018, 28. Samakkanad, N.; Katrun, P.; Techajaroonjit, 83, 1369-1376. T.; Hlekhlai, S.; Pohmakotr, M.; Reutrakul, 34. Bhalerao, D. S.; Mahajan, U. S.; Chaudhari, V.; Jaipetch, T.; Soorukram, D.; Kuhakarn, C. K. H.; Akamanchi, K. G. J. Org. Chem., 2007, Synthesis., 2012, 44, 1693-1699. 72, 662-665. 29. Katrun, P.; Songsichan, T.; Soorukram, D.; 35. Nicolaou, K. C.; Mathison, C. J. N.; Montagnon T. Pohmakotr, M.; Reutrakul, V.; Kuhakarn, C. Angew. Chem. Int. Ed., 2003, 42, 4077-4082. Synthesis., 2017, 49, 1109-1121. 36. Bellale, E. V.; Bhalerao, D. S.: Akamanchi, K. 30. Moorthy, J. N.; Singhal, N.; Senapati, K. Org. G. J. Org. Chem., 2008, 73, 9473-9475. Biomol. Chem., 2007, 5, 767-771. 37. Duschek, A.; Kirsch S. F. Chem. Eur. J., 2009, 31. Shibuya, M.; Ito, S.; Takahashi, M.; Iwabuchi, 15, 10713-10717. Y. Org. Lett., 2004, 6, 4303-4306. 38. Duschek, A.; Kirsch, S. F. Angew. Chem. Int. 32. Fontaine, P.; Chiaroni, A.; Masson, G.; Ed., 2011, 50, 1524-1552.