Hypervalent iodine(V) reagents in organic synthesis

This review summarizes the synthetic applications of hypervalent iodine(V) reagents: iodylbenzene, IBX (2-iodoxybenzoic acid), DMP (Dess-Martin periodinane) and pseudocyclic IBX analogs. Application of these reagents allows mild and highly selective oxidative transformations in a facile and environmentally friendly manner.


Introduction
In the past decade, the organic chemistry of hypervalent iodine compounds has experienced an immense development.This growing interest in iodine compounds is due to the mild and highly chemoselective oxidizing properties of polyvalent organic iodine reagents, combined with their benign environmental character and commercial availability.A variety of new chemical transformations effected by hypervalent iodine reagents have recently been developed by many synthetic chemists.These protocols include catalytic imidations with iodonium imides, hypervalent iodine mediated oxidative coupling of phenols and related compounds, applications of iodine(III) compounds as useful carbene and nitrene precursors and the broad synthetic applications of hypervalent iodine heterocycles derived from benziodoxoles and benziodazoles.Many reviews, some comprehensive, but most dealing with specific aspects of hypervalent organoiodine chemistry, have been published just in the last 5-6 years.  Mosnotable are the monograph by Varvoglis on the application of hypervalent iodine compounds in organic synthesis 1 and the volume of Topics in Current Chemistry on hypervalent iodine chemistry. 2espite being less developed in comparison with trivalent iodine reagents, the chemistry of iodine(V) compounds (λ 5 -iodanes) has also attracted substantial attention in recent years.This widespread practical interest to λ 5 -iodanes is mainly due to Dess-Martin periodinane (DMP) and, especially, to 2-iodoxybenzoic acid (IBX), both of which are mild and useful oxidizers for alcohols and amines, for conversions of carbonyl compounds to the respective α,β-unsaturated derivatives and for effecting a number of other unique and useful synthetic transformations.Various IBX analogs, having better solubility profile and/or being recyclable, have emerged recently.3][34] However, the chemistry of iodine(V) reagents have never been systematically reviewed.The purpose of the present review is to summarize the recent literature data on synthetically useful hypervalent iodine(V) reagents; literature coverage is through the first half of 2005.

Iodylbenzene and other noncyclic reagents
The noncyclic iodyl (also known as iodoxy) compounds, RIO 2 , in general have found only very limited practical application due to their low stability.While the aryl derivatives, ArIO 2 , can form relatively stable compounds, iodylalkanes are extremely unstable and can exist only at very low temperatures.Thus, Clark and coworkers reported the matrix isolation and FTIR spectra of the unstable iodyl derivatives, RIO 2 , generated by the co-deposition and photolysis of ozone with iodoethane, 2-iodopropane, pentafluoroiodoethane, 1,1,1-trifluoroiodoethane, 1,1,2,2tetrafluoroiodoethane, 1,1,1,2-tetrafluoroiodoethane, or iodine cyanide in an argon matrix at 14-16 K. [35][36][37] Several noncyclic ArIO 2 have been reported in the literature.These compounds possess a polymeric structure, which makes them insoluble in the majority of organic solvents, with the exception of DMSO.9] Also noncyclic iodylarenes are explosive under excessive heating (> 200 o C) or mechanical impact.Despite their low solubility and explosive character, iodylarenes have found some practical application as oxidizing reagents.Among various ArIO 2 , iodylbenzene PhIO 2 is the most popular reagent. 40he first preparation of iodylbenzene, PhIO 2 (1), dates back to more then 100 years ago.Specifically, Willgerodt observed that the disproportionation of iodosylbenzene 2 under steam distillation afforded iodylbenzene 1 and iodobenzene 3 (Scheme 1). 41IO 0.5 PhIO 2 0.5 PhI H 2 O, 100 °C +

Scheme 1
Several methods for the selective preparation of iodylarenes from iodoarenes have been reported.These methods include the oxidation of iodoarenes with inorganic oxidants such as Caro's acid, potassium bromate and sodium hypochlorite. 42Recently Skulski and coworkers developed a new procedure for the preparation of various iodylarenes from the corresponding iodoarenes 4 using sodium periodate as the oxidant (Scheme 2). 40

Scheme 3
This protocol was utilized in the synthesis of cadalenquinone 10, a naturally occurring sesquiterpene, starting from naphthol 9 (Scheme 4). 44

Scheme 4
Several catalytic oxidative systems which employ iodylbenzene as a stoichiometric cooxidant have been developed.Barton and coauthors reported an efficient allylic oxidation protocol with 2-pyridineseleninic anhydride 12 (Ar = 2-Py) as the principal oxidant, generated in situ by oxidation of the corresponding diselenide 13 with iodylbenzene 1 or 3-iodylbenzoic acid 11 (Scheme 5). 45

Scheme 5
This reaction proceeds in chlorobenzene at 100 ºC within 2.5-3 hours.Most likely the initial oxidation leads to the formation of allylic alcohols, which undergo further oxidation into α,β-unsaturated ketones 15.In contrast with the classic allylic oxidation technique employing selenium dioxide, only a catalytic amount of the corresponding diselenide is required.In order to simplify the reaction workup, iodylbenzene 1 can be replaced with 3-iodylbenzoic acid 11.In the latter case an excess of pyridine has to be added into the reaction mixture to neutralize acid 11.
This convenient oxidation protocol was recently used in a number of syntheses of complex organic molecules.In the stereoselective synthesis of (-)-tetrodotoxin by Du Bois and coworkers, ARKAT the protected pentaol 16 was oxidized with PhIO 2 /Py 2 Se 2 to afford the unsaturated carbonyl compound 17 in a good yield (Scheme 6).

Five-membered iodine(V) heterocycles: benzoiodoxole oxides
The most important representative of pentavalent iodine heterocycles, 2-iodoxybenzoic acid (IBX, 35), was first prepared in 1893 by Hartman and Mayer. 56IBX has the structure of the cyclic benziodoxole oxide (1-hydroxy-1-oxo-1H-1λ 5 -benzo[d] [1,2]iodoxol-3-one according to the IUPAC nomenclature), as determined by X-ray structural analysis. 57,58 ost commonly IBX is prepared by the oxidation of 2-iodobenzoic acid with potassium bromate in aqueous solution of sulfuric acid. 59IBX was reported to be explosive under excessive heating or impact, and Dess and Martin attributed the explosive properties of some samples to the presence of bromate impurities. 60An alternative preparation of IBX involves oxidation of 2-iodobenzoic acid 36 with excess peracetic acid or aqueous sodium hypochlorite. 61A convenient procedure for the preparation of IBX

Scheme 16
Until the 1990s IBX was rarely used in organic synthesis, apparently because of its insolubility in most organic solvents.In 1983 Dess and Martin transformed IBX to the soluble triacetoxybenziodoxole 37 by heating IBX with acetic anhydride to 100 o C. 63 In the following years, the triacetate 37 has emerged as the reagent of choice for the oxidation of alcohols to the respective carbonyl compounds, 64 and now it is commonly referred to as Dess-Martin periodinane (DMP).An improved procedure for the preparation of DMP 37 consists in the reaction of IBX with acetic anhydride in the presence of p-toluenesulfonic acid (TsOH) (Scheme 17). 65

Scheme 17
Recently, Kawashima et al. reported on the preparation and oxidative properties of aliphatic iodoxole oxide 39, which is the first example of this class of iodine(V) compounds. 66he tetracoordinate 1,2-iodoxetane 39 was prepared by the fluorination of a tricoordinate 1,2iodoxetane 38 with xenon difluoride followed by hydrolysis (Scheme 18).Compound 39 oxidized alcohols and a sulfide to the corresponding aldehydes and ketones and a sulfoxide, respectively, in good yields under mild conditions.

ARKAT
Since the seminal works of Dess and Martin, 63,64 a variety of benziodoxole oxide derivatives including solid-supported reagents have been disclosed as mild and selective oxidizing reagents.

Scheme 20
The IBX oxidation of diol 44 was applied in the synthesis of the functionalized hexahydroanthracene dione 46 (Scheme 21), a model for the D ring of taxoids. 69

Scheme 22
The IBX oxidation of carbohydrate 49 was utilized in the synthetic studies of moenomycin A disaccharide analogs (Scheme 23). 71 one pot oxidation of benzylic, allylic, and propargylic alcohols, as well as diols, with IBX in the presence of the stabilized Wittig ylide 53 affords α,β-unsaturated esters 54 in generally good yields (Scheme 25). 73This is a useful one-pot procedure because the intermediate aldehydes are often unstable and difficult to isolate.

Scheme 25
The oxidation of alcohols with IBX in DMSO was also used in the development of a new silyl ether linker for solid-phase organic synthesis, 74 in the kinetic study of organic reactions on polystyrene grafted microtubes 75 and in the total synthesis of a cyclic depsipeptide somamide A. 76 IBX is especially useful for the oxidation of 1,2-diols.In contrast to DMP, which generally cleaves the glycol C-C bond, IBX in DMSO oxidizes 1,2-diols to α-ketols 77,78 or αdiketones. 66,79In the key step of the total synthesis of Streptomyces maritimus metabolitewailupemycin B 56, the IBX oxidation led to the desired hydroxyketone moiety without any cleavage of the glycol C-C bond (Scheme 26).The synthetic usefulness of IBX in general is significantly restricted by its low solubility in most organic solvents with the exception of DMSO.However, in several recent reports [81][82][83] it has been shown that IBX can be used as effective oxidant in other than DMSO solvents.More and Finney have found that primary and secondary alcohols can be oxidized into the corresponding aldehydes or ketones in excellent yields (90-100%) by heating a mixture of alcohol and IBX in common organic solvents. 81All reaction by-products can be completely removed by filtration.This method was recently used for the efficient preparation of the ribosyl aldehyde 58 (Scheme 27), the key intermediate in the stereoselective synthesis of the core structure of the polyoxin and nikkomycin antibiotics. 82

Scheme 27
Chen and co-workers reported a mild, efficient, and environmentally benign protocol for the oxidation of alcohols with IBX in the ionic liquid 1-butyl-3-methylimidazolium chloride and water. 83Upon stirring a solution of the alcohol and IBX in 1-butyl-3-methyl-imidazolium chloride followed by removal of water at room temperature and subsequent extraction with ether or ethyl acetate and removal of the solvent gives excellent yields (88-99%) of the corresponding carbonyl compounds.No overoxidation to acids was observed in the case of aldehyde products, and various functionalities such as methoxy and nitro groups, double bonds, and a furan ring can be tolerated.The oxidation of glycols under these conditions, depending of the amount of IBX used, affords α-ketols or α-diketones.

ARKAT
An interesting IBX-mediated oxidation of primary alcohols (or aldehydes) to Nhydroxysuccinimide esters 59 was developed by Giannis and coworkers. 84The generality of this procedure was demonstrated on a variety of aliphatic, allylic, and benzylic alcohols (Scheme 28).

Scheme 28
IBX in DMF has been shown to be an excellent reagent for the oxidation of various phenols to o-quinones. 85This procedure was recently used for the oxidation of phenol 60 to quinone 61 (Scheme 29), the key intermediate in total synthesis of a novel cyclooxygenase inhibitor (±)-aiphanol.86a The same protocol was recently utilized in the synthesis of (±)-brazilin, a tinctorial compound found in the alcoholic extracts of trees collectively referred to as Brazil wood, by Pettus et al.

Scheme 29
8][89][90][91][92][93][94] In a series of papers, Nicolaou and coworkers have demonstrated the utility of IBX for the one-step synthesis of α, β-unsaturated carbonyl systems from saturated alcohols and carbonyl compounds, 87,88 for the selective oxidation of the benzylic carbon, 89 for the oxidative cyclization of anilides and related compounds, 90,91 and for the synthesis of amino sugars and libraries thereof. 92Specifically, alcohols, ketones, and aldehydes are oxidized to the corresponding α,β -unsaturated species in one pot using IBX under mild conditions. 87For example, cycloalkanols 62 react with two equivalents of IBX in a 2:1 mixture of either fluorobenzene or toluene and DMSO at gentle heating to afford the corresponding α, β -unsaturated ketones 63 in good yields (Scheme 30).IBX is an efficient and a selective reagent for the oxidation of benzylic positions (Scheme 31).89a This reaction is quite general and can tolerate a variety of substituents within the aromatic ring.Overoxidation to the corresponding carboxylic acids is not observed even in the presence of electron-rich substituents.

Scheme 31
Similar to the oxidation of alcohols, secondary amines can be oxidized with IBX in DMSO to yield the corresponding imines 66 in good to excellent yields (Scheme 32).89b

Scheme 32
A variety of new heterocycles 67 can be synthesized by the treatment of unsaturated aryl amides, carbamates, thiocarbamates, and ureas with IBX (Scheme 33). 90The mechanism of this reaction has been investigated in detail.91a On the basis of solvent effects and D-labeling studies, it was proposed that the IBX-mediated cyclization of anilides in THF involves an initial single ARKAT electron transfer (SET) to a THF-IBX complex followed by deprotonation, radical cyclization, and concluding termination by hydrogen abstraction from THF.

Scheme 33
A similar IBX-mediated cyclization was applied in the synthetic protocol for the stereoselective preparation of amino sugars.91b Recently, Studer and coworkers reported a method for the generation of alkoxyamidyl radicals starting from the corresponding acylated alkoxyamines using IBX as a single electron transfer (SET) oxidant.Stereoselective 5-exo and 6-exo reactions with these N-heteroatomcentered radicals lead to isoxazolidines and [1,2]oxazinanes (Scheme 34).92a

Scheme 39
Benziodazole oxides 79 can be regarded as selective, chiral oxidizing reagents for organic synthesis.Preliminary results indicate that reagents 79 can selectively oxidize primary alcohols to aldehydes in chloroform at 50 o C.Under similar conditions, reagents 79 oxidize organic sulfides to sulfoxides in almost quantitative yield.Oxidation of non-symmetric sulfides affords chiral sulfoxides with moderate enantioselectivity (11-16% ee). 97][100][101] These supported IBX reagents are non-explosive and can be used in common organic solvents like THF or dichloromethane.Three research groups have used 4hydroxy-2-iodobenzoic acid as derivative, suitable for attaching onto a variety of resins.Rademann and coworkers employed Merrifield resin as a solid support to give a derivative 80 with a loading of 0.8 mmol g -1 (Scheme 40). 98Janda et al. used a similar ether linkage to attach 4-hydroxy-2-iodobenzoic to a set of soluble and insoluble polymer supports. 99In the other synthesis by Giannis and coworkers aminopropyl-silica gel was employed as a solid matrix affording a supported reagent 81 (Scheme 40). 100 In the latter case, Oxone in aqueous medium was used for resin activation.A conceptually different approach was used by Sutherland et al. 101 Thus, during the preparation of the oxidizing polymer 82, iodobenzoic acid moiety was introduced directly to the resin backbone by iodination/oxidation sequence (Scheme 40).Reagents 80-82 oxidize various primary, secondary, benzylic, allylic, terpene alcohols, and the carbamate-protected aminoalcohols to afford the respective aldehydes or ketones in excellent yields and purities.Polymers 80-82 can be recycled by repeated oxidation after extensive washings.

Dess-Martin Periodinane
In recent years, the acetate derivative of IBX, 37, which is commonly known as Dess-Martin periodinane [DMP; 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one] has emerged as a reagent of choice for the oxidation of primary and secondary alcohols to aldehydes and ketones, respectively.In addition, DMP is currently commercially available from Sigma-Aldrich 102 and other chemical companies.The synthetic applications of DMP were highlighted in two overviews. 103,104he mild reaction conditions (room temperature, absence of acidic or basic additives), high chemoselectivity, and preparative convenience have made this reagent especially suitable for the oxidation of substrates containing sensitive functional groups (e.g.unsaturated moieties, amino groups, silyl ethers, phosphine oxides, sulfides, selenides).In case of epimerization sensitive substrates, DMP allows clean oxidation with virtually no loss of enantiomeric excess.Thus, oxidation of N-protected β-amino alcohols with DMP afforded the respective aldehydes with 99% ee and excellent chemical yields, while Swern oxidation gave unsatisfactory results (50-68% ee). 105DMP oxidation is accelerated by the addition of water to the reaction mixture immediately before or during the reaction. 106arlow and coworkers developed an efficient and convenient method for entrapping excess DMP and acetoxybenziodoxole byproduct 83 from the solution phase using a thiosulfate resin 84.All the hypervalent iodine species are reduced to 2-iodobenzoic acid, which is then sequestered by the basic resin leaving the pure carbonyl product in solution (Scheme 41). 107

Scheme 41
It is worth mentioning that during oxidation of 1,2-diols DMP generally cleaves the glycol C-C bond.When IBX is employed, exclusive formation of 1,2-diketones or 2-hydroxyketones is observed, and no C-C bond cleavage occurs.Different product distribution from 1,2-diols in case of DMP and IBX was rationalized in terms of the different intermediate periodinane adducts DMP and IBX can form. 108This characteristic difference in DMP reactivity was utilized during the synthesis of tricyclic enol ether 86 by tandem 1,2-diol cleavage-intramolecular cycloaddition (Scheme 42). 109HO HO DMP, toluene 85 86

Pseudocyclic Iodine(V) Reagents
Noncovalent, attractive interactions between iodine and oxygen atoms are extremely important forces that can influence molecular, solution, and solid state properties.Being often termed secondary bonds 127 , such interactions can be successfully utilized in the design of new hypervalent iodine(V) reagents.Aryliodyl derivatives bearing an appropriate substituent in the ortho-position to the iodine, are characterized by the presence of a pseudocyclic structural moiety due to a strong intramolecular secondary bonding between the hypervalent iodine center and the oxygen atom in the ortho-substituent.When iodine(V) atom and the ortho-sustituent's oxygen atom are located in 1,5-position, the planar, five-membered pseudo-benziodoxole structural moiety 90 arises.On the other hand, 1,6-arrangement of iodine and oxygen atoms ARKAT results in a non-planar six-membered ring of pseudo-benziodoxazines 91.Generally, the distance between the iodine and oxygen atoms amounts to 2.6 -2.7 Å in pseudo-benziodoxoles 90 and pseudo-benziodoxazines 91, [128][129][130][131][132][133][134] which is comparable with the I-O bond length in benziodoxoles 92 from 2.2 Å to 2.5 Å (Scheme 44).

Scheme 45
The X-ray structure of product 95 shows a pseudo octahedral geometry with the I-O bond lengths in the iodyl group of 1.796 and 1.822 Å and an intramolecular distance of 2.693 Å between one of the sulfone oxygen atoms and the hypervalent iodine center. 128Authors stated that if strong internal dipoles (such as sulfonyl or carbonyl groups) are introduced into the ortho ARKAT position to the IO 2 group, they are capable of introducing intramolecular I•••O secondary bonds, replacing the intermolecular ones.This secondary bond redirection leads to structures which are less polymeric and more soluble in the conventional organic solvents, such as dichloromethane and benzene.
Esters of 2-iodoxybenzoic acid (IBX-esters) 97, a new class of pentavalent iodine compounds with a pseudo-benziodoxole structure, can be conveniently prepared by hypochlorite oxidation of iodobenzoate esters 96 in the form of stable, white, microcrystalline solids (Scheme 46). 131,134This facile procedure allows for the preparation of reagents 97 derived from a wide variety of precursors, including primary, secondary, and tertiary alcohols, adamantanols, as well as optically active menthols and borneol.All products 97 have moderate to good solubility in common organic solvents, such as chloroform, dichloromethane, and acetonitrile.Structures of compounds 97a, c, d were established by single crystal X-ray analysis.In particular, the structure of 97c shows a unit cell consisting of two crystallographically independent molecules.Strong secondary I•••O bonding interactions between neighboring molecules affords dimeric pairs, which are then linked together by a combination of strong and weak interactions, forming a polymeric motif.Within each molecule, an intramolecular close contact of 2.697 Å between the iodine(V) center and the oxygen atom of the ester group affords the pseudo-benziodoxole ring. 131,134 range of alcohols can be oxidized by reagents 97 to the respective carbonyl compounds under mild conditions.For example, oxidation of benzyl alcohol in the presence of KBr in chloroform at 50 o C cleanly gives benzaldehyde as the only product detected by 1 H NMR spectroscopy.A variety of secondary alcohols, such as cyclohexanol and cycloheptanol, are converted to the corresponding ketones in 95-98% yields. 131,134he novel 2-iodoxybenzamides (IBX-amides) 99, prepared by our group, are stable and soluble compounds with unique and synthetically valuable oxidizing properties. 132These compounds are synthesized by the dioxirane oxidation of the readily available 2-iodobenzamides 98 (Scheme 47).This procedure allows for the preparation of products 99 derived from numerous types of amino compounds, such as esters of natural α-amino acids 99a, c-d 2-Iodoxybenzamides 99 are useful oxidizing reagents towards alcohols with a reactivity pattern similar to IBX.A wide range of alcohols can be oxidized by these reagents to the respective carbonyl compounds under mild conditions in chloroform. 134,135For example, benzyl alcohol cleanly gives benzaldehyde as the only product detected by 1 H NMR spectroscopy.A variety of secondary alcohols are effectively converted to the corresponding ketones in good yields using any of the reagents 99a-c.Oxidative kinetic resolution of racemic sec-phenethyl alcohol using reagents 99 has also been investigated.In particular, the reaction of 99c showed a very modest 9% ee.In contrast to DMP, reaction of reagent 99b with cis-hexanediol effects oxidative cleavage to give hexanedial in 30% yield.It should be emphasized that iodylbenzene, PhIO 2 , as well as other non-cyclic iodylarenes, do not react with alcohols in the absence of acidic catalysis.In agreement with their structural features, the oxidizing reactivity of 2iodoxybenzamides 99 is closer to the benziodoxole-based pentavalent iodine reagents, in contrast to the non-cyclic iodylarenes.
Lee and coworkers have synthesized an IBX-amide resin 100 based on BTCore EM OH resin (Scheme 48). 136,137A loading of 0.98 mmol g -1 was achieved and 2 equiv of resin were necessary for the total conversion of an alcohol to the corresponding carbonyl compound.Linclau et al. reported an improved synthesis of a solid-supported IBX amide resins 101a, b using inexpensive and commercially available 2-iodobenzoic acid chloride and Merrifield resin (Scheme 48). 138Oxidation of a range of alcohols to the corresponding carbonyl compounds can be accomplished using 1.2 equiv of the resins 101a, b.Recycling of the resin was also possible with minimal loss of activity after two reoxidations.

Scheme 48
Amides of 2-iodoxybenzenesulfonic acid 103a-e were recently prepared by the dioxirane oxidation of the corresponding 2-iodobenzenesulfamides and isolated as stable, microcrystalline products (Scheme 49). 139These newest representatives of the pseudocyclic hypervalent iodine compounds can selectively oxidize benzyl alcohols to aldehydes.

Pseudo-benziodoxazines
Very recently, we have described the design, preparation, structure and oxidative properties of novel N-(2-iodyl-phenyl)-acylamides 91 (Scheme 51). 133X-ray data on compounds 91 revealed a unique pseudo benziodoxazine structure with intramolecular secondary I•••O (2.647 Å) bonding, which is the first reported example of six-membered pseudo-cyclic scaffold for iodine(V).Preliminary experiments indicate the reagents 91 can oxidize alcohols and sulfides, the reactivity very largely depending on the substitution pattern on amide group adjacent to iodyl moiety.A mechanistic rationale accounting for the 91 reactivity pattern was recently proposed. 133 The synthesis employs commercially available aminomethylated polystyrene, includes three simple steps, and affords the resin with good loading of 0.70 -0.80 mmol g -1 .The prepared resin 107 effects fast and efficient oxidation of a wide range of alcohols, including heteroatomic and unsaturated structures.

Scheme 8 General Papers ARKIVOC 2006 (ix) 26-58 ISSN 1424-6376 Page 31 © ARKAT A
49w method for the preparation of allochenodeoxycholic and allocholic acids from the corresponding cholic acids was reported by Iida et al.The key step in the synthesis is the oxidation-dehydrogenation of 3α-hydroxy-5β-bile acid formyl esters 22 to give oxodienes 23 (Scheme 9).49

4 34 Scheme 15
62ported by Santagostino and coworkers.62Thisprotocol substantially reduced the amount of explosive impurities in the prepared IBX samples.

ARKAT
97ody and coworkers used reagent 72 under similar conditions in the synthesis of benzofuranone derivative 77, a potential precursor for the synthesis of the cytotoxic marine alkaloid diazonamide A (Scheme 38).96New benziodazole oxides 79 were prepared by oxidation of the readily available 2iodobenzamides 78 with potassium bromate (Scheme 39).97