1,1,1-Triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one1

[87413-09-0]  · C13H13IO8  · 1,1,1-Triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one  · (MW 424.16)

(selective oxidation of primary,1 secondary,1 allylic,2 allenic,3 propargylic,4 benzylic,5 and a-fluorinated alcohols;6 monoprotected 1,2- and 1,3-diols and amino alcohols;7-10 a- and b-hydroxy ketones,11,12 a- and b-hydroxy esters,13,14 b-hydroxy amides,15 b-hydroxy sulfones;16 nucleosides;17 carbohydrates;18 compatible with a variety of protecting groups,19,20 unsaturation,21,22 basic nitrogen,23 divalent sulfur24 and selenium,25 and halogen26)

Alternate Names: Dess-Martin periodinane; TAPI.

Physical Data: mp 124-126 °C (dec).

Solubility: appreciably sol CH2Cl2, CHCl3, MeCN, THF; effectively insol aromatic and aliphatic hydrocarbons, ether.

Form Supplied in: white free-flowing moisture- and light-sensitive solid; not currently commerically available due to the potential explosion hazard (see below).

Analysis of Reagent Purity: recommended methods include 1H NMR,1 and standardization by oxidation of benzyl alcohol;27 however, a typical iodimetric titration used for the standardization of peracids and other oxidants can likely also be employed. NMR data for the reagent: 1H NMR (300 MHz in CDCl3): d 8.29 (d, J = 8.1 Hz, 2H), 8.09 (t, J = 8.1 Hz, 1H), 7.91 (t, J = 7.4 Hz, 1H), 2.32 (s, 3H), 1.99 (s, 6H); minor impurity peaks are observed at d 8.39 (d), 8.21 (d), 8.00 (d), 7.27 (s), and 2.08 (s); 13C NMR (75 MHz in CDCl3): d 175.7, 174.0, 166.1, 142.2, 135.8, 133.8, 131.7, 126.5, 125.9, 20.4, 20.2.

Preparative Method: prepared from commercially available 2-iodobenzoic acid (recrystallized) by oxidation with Potassium Bromate in aqueous sulfuric acid at 65 °C for 3.6 h to afford the highly insoluble and sensitive (explosion hazard) hydroxyiodinane oxide (2) which is washed free of residual KBrO3 by sequential washing with water, ethanol, and then water again; vacuum filtration then affords the oxide as a moist solid (thorough drying is not recommended due to explosion hazard). This moist oxide is directly transformed to the reagent by treatment with excess Acetic Anhydride and Acetic Acid at 62 -> 96 °C for ~35 min (or until conversion is complete by analysis of an aliquot of the reaction mixture by NMR) followed by cooling for 12 h at room temperature. The solid reagent is collected by vacuum filtration under an inert atmosphere (glove bag/box or Schlenk techniques should be employed), and dried on the filter bed for 0.5 h; this affords the reagent (1) in 68-75% yield over the two steps (eqs 1 and 2).1,27 A recent modification by Ireland recommends the use of p-Toluenesulfonic Acid as a catalyst in the conversion of the oxide (2) to (1).28

Difficulties have sometimes attended the preparation of (1) for a variety of reasons, including but not limited to: (1) incomplete removal of KBrO3 and possibly Br2 during preparation of the hydroxyiodinane oxide (2); (2) incomplete or lack of removal of traces of ethanol used in washing the oxide intermediate (an obligatory process to avoid a potential explosion hazard); (3) incomplete acetylation of the oxide (2), as the presence of the monoacetoxy periodinane oxide has been implicated in the impact sensitivity shown by some but apparently not all samples of the reagent; and (4) partial or complete hydrolysis of the reagent during isolation by excessive exposure to atmospheric moisture (partial hydrolysis affords the aforementioned monoacetoxyiodinane oxide, and complete hydrolysis produces iodoxybenzoic acid, known to be explosive, which may contribute to the impact sensitivity observed).1

Purification: the reagent, when prepared properly, is sufficiently pure for use after standardization if desired. No purification method has been described.

Handling, Storage, and Precautions: the reagent is a moisture- and light-sensitive material.1 While it can be handled briefly in the air, extensive exposure to moisture should be avoided. Transfers of solutions should be conducted using syringe techniques, and transfers of the solid are best done in a glove bag or box to avoid deterioration of the reagent. The pure solid reagent is stable indefinitely at room temperature when precautions are taken to avoid exposure to moisture and light.1 Storage should be in an amber bottle under an inert atmosphere or other means of protection from atmospheric moisture. Safety evaluations show that the precursor oxide is impact sensitive, and explosively decomposes when heated (>150 °C), with the onset varying with the sample. Handling the material as a moist solid appears to significantly reduce, but not completely remove, this explosion hazard. The pure periodinane has been stated to not exhibit impact sensitivity and to thermally decompose without explosion.1 An independent evaluation of typical samples prepared as above shows that, although the reagent is less sensitive than the precursor oxide, it has the potential to decompose violently when heated (>200 °C) and shows impact sensitivity, although less than the oxide precursor. Thus, prudence requires that the preparation, handling, and use of this reagent and its precursor be conducted with due care and precaution against potential explosion (use of appropriate explosion shields, etc.), particularly on a substantial scale. Nevertheless, as the following discussion will attest, the reagent has been prepared and utilized widely with only one report of an explosion,29 so that there is good cause to believe that, with appropriate precautions, the reagent can be prepared and handled safely on a normal laboratory scale.

Introduction.

In the short time since its original description in the literature in 1983, the Dess-Martin periodinane (1) has enjoyed remarkably widespread use as a reagent for the oxidation of complex, sensitive, multifunctional alcohols of a startling array of structural types. The periodinane (1) is a member of the 12-I-5 group of hypervalent iodine species. A number of related structures, which also function as oxidizing agents for alcohols, have been described.1 Among the advantages of the periodinane (1) over the myriad of other oxidizing agents which are available are: (1) functional groups lacking a hydroxylic function are exchanged into the ligand sphere of (1) slowly. Alcohols, particularly primary alcohols, undergo rapid and near-quantitative ligand exchange which is largely insensitive to the steric environment of the OH group. This ligand exchange is the obligatory first step in oxidation, which provides an inherent functional group selectivity in the oxidation reactions of (1). (2) The reagent is exceptionally versatile, having probably the broadest scope of any of the oxidizing agents commonly employed to convert alcohols to carbonyl derivatives, and generally provides exceptionally clean reactions and excellent yields. (3) When pyridine or di-t-butylpyridine is employed to buffer the reaction mixture and sodium thiosulfate/sodium bicarbonate is employed for workup, the entire oxidation/workup procedure can be conducted under near-neutral conditions compatible with even the most sensitive functionality. (4) The workup procedure is very simple, and the byproducts from the oxidation are readily removed by precipitation or chromatography, even without use of an aqueous workup. (5) The reagent is a shelf-stable solid, possessing adequate stability to moisture to permit ready metering and handling, even on very small scale, as is typically required in synthetic sequences leading to complex multifunctional molecules. The rates of oxidation of allylic and benzylic alcohols are highest, but oxidation of electron deficient carbinols such as a-fluorinated alcohols still occurs in good yields.

Typical Oxidation and Workup Procedures.

The oxidation of alcohols is conducted at temperatures ranging from -20 to 35 °C (with ambient temperature being most common), typically in CH2Cl2 and occasionally in CHCl3, acetonitrile, or THF, by admixing the reagent (typically 1-3 equiv per OH group), either as the solid or as a solution in the reaction solvent, with a solution of the alcohol. For very acid-sensitive substrates or products, the reaction mixture is buffered by the prior addition of 3-10 equiv of pyridine or 2,6-di-t-butylpyridine. The reaction mixture is then held at the appropriate temperature for as little as 5 min to as long as 120 h (most commonly 0.5-1.5 h) before dilution with ether (precipitation of periodinane byproducts occurs), addition of either aqueous NaOH solution or, for base-sensitive products, a mixture of aqueous Na2S2O3 and NaHCO3, stirring until the phases are homogeneous (~15 min), and isolation of the products by extraction. It is possible to avoid the use of aqueous workup conditions altogether by introduction of the reaction mixture, after dilution with ether, directly onto a chromatographic column for separation of the organic oxidation product(s).

Oxidation of Primary Alcohols to Aldehydes.

Since many oxidants will satisfactorily accomplish this transformation, this discussion will focus on cases where (1) has been of particular value. The strength of the periodinane (1) is its ability to effect oxidation under neutral conditions, thus avoiding side reactions in sensitive substrates possessing multiple functional groups such as the enediyne (3) (eq 3),30 or a variety of protecting groups, as in the azadirachtin intermediate (4) (eq 4).31 Side reactions, such as b-elimination of oxygen and nitrogen functions, are seen with other oxidants for (5) (eq 5),32,33 as are epimerization of a-stereogenic centers or exchange of label in labeled substrates,34,35 and conjugation of b,g-unsaturation.36

Disubstituted malondialdehydes (6) (eq 6) and malonaldehyde esters have been prepared without the intervention of oxidative cleavage.37,38 Relative reactivity data based on steric environment is sparse; however, a notable case of selectivity for a primary over a hindered secondary alcohol in the preparation of the spiroacetal aldehyde (7) (eq 7) has been recorded.39 Very few failures have been documented, and often no other oxidation reagent proved satisfactory in these cases.40

Oxidation of Secondary Alcohols to Ketones.

In the case of secondary alcohols, (1) has also proven valuable in avoiding epimerization of a-stereogenic centers,41,42 loss of b-acyloxy, b-alkoxy, and protected nitrogen functions during oxidations such as of b-acyloxy ketone (8) (eq 8), and undesired conjugation of b,g-unsaturation as in the case of the alkaloid intermediate (9) (eq 9).43-45 Overoxidation at activated methylene groups, such as benzylic centers or susceptible aromatic systems, is not normally a problem.46,47

Appropriately protected a-heteroatom-substituted systems are smoothly oxidized without epimerization or isomerization of the b,g-double bond, as in the ketone (10) (eq 10).48 Oxidation of secondary alcohols in suitably protected nucleosides and carbohydrates has also been documented, even in cases where the substrates are exceedingly acid-sensitive such as the trisaccharide (11) (eq 11).49,50 Even sterically-congested secondary alcohols undergo smooth oxidation, most often in excellent yield as in the case of ketone (12) (eq 12).51-53

Secondary a- and b-hydroxy ketones and esters, and b-hydroxy amides and sulfones, are also smoothly oxidized to the corresponding a- and b-diketones, a- and b-keto esters, b-keto amides, and b-keto sulfones, such as the b-keto ester (13) (eq 13).54 Remarkably, even substrates containing divalent sulfur and selenium, as well as bromine, have been smoothly oxidized to the corresponding ketones, such as the b-lactam (14) (eq 14).55,56 Furthermore, substrates containing secondary basic nitrogen centers have been smoothly oxidized without concomitant oxidation at nitrogen, for example ketone (15) (eq 15).57 Even electron-deficient, weakly nucleophilic substrates such as a-trifluoromethyl and a,a-difluoroalkyl alcohols also undergo smooth transformation to the corresponding ketones.58,59

In some cases, unprotected 1,2-diols undergo fragmentation to carbonyl compounds in a manner similar to their reactions with related periodates and periodic acid.1,60 However, an example of the selective oxidation of a complex 2,3-dihydroxypyran to the related a-hydroxy d-lactone (16) in excellent yield has been described (eq 16).61 Of course, oxidation of remote primary-primary and secondary-secondary diols to the dicarbonyl compounds proceeds uneventually when sufficient periodinane (1) is employed, but statistical mixtures usually result from attempts at selective oxidation, except in cases where the hydroxyl groups differ markedly in steric environment.39,69

Oxidation of Primary and Secondary Allylic, Benzylic, Propargylic, and Allenyl Alcohols.

The oxidation of allylic and benzylic alcohols by the periodinane (1) has been demonstrated to be significantly faster (&egt;~5×) than that of the corresponding saturated alcohols in competition experiments.1 This selectivity is exemplified by the oxidation of the precursor secondary allylic-secondary diol to the ketol (17) (eq 17).62

However, in some instances, oxidative cleavage occurs in preference to simple oxidation (see below). It is in the oxidation of this general class of allylic, benzylic, and related unsaturated and acetylenic alcohols that the periodinane (1) has proven consistently superior to other oxidants for complex acid and base-sensitive substrates. As shown below, the range of complex substrates is truly impressive. For example, acid- and oxidation-sensitive benzyl and pyridyl alcohols are smoothly oxidized to the corresponding carbonyl compounds (18) and (19) (eqs 18 and 19).63,64 In the latter case, the aldehyde (19) is obtainable in acceptable yields only by use of the periodinane (1). In the case of 6a-epipretazzetine (20) (eq 20), no overoxidation and isomerization to tazzetine is observed.65 Furthermore, no concomitant oxidation of susceptible aromatic systems or nitrogen is detected.

In the case of allylic alcohols, including a-methylenecycloalkanols and cyclopentenols, the periodinane (1) has afforded exceedingly acid-, base-, thermal-, and/or oxidation-sensitive enones, e.g. (21) and (22), in excellent yields (eqs 21 and 22).66,67 Most impressively, (Z)-allylic alcohols afford the corresponding aldehydes and ketones with minimal or no loss of the geometric integrity of the alkene, as seen in the oxidations affording (23) and (24) (eqs 23 and 24).68,69

Allylic and propargylic alcohols possessing a- or d-stereogenic centers can be oxidized without compromising the integrity of the stereogenic centers, even in demanding situations such as the cases of the ketone (25) (eq 25) and the diynone (26) (eq 26).70,71 Primary and secondary allenic alcohols also afford the corresponding carbonyl derivatives smoothly upon oxidation with (1).72,73 Even allylic benzylic systems afford the corresponding aryl vinyl ketones largely or completely without oxygen transposition, even in the remarkably hindered ketone (27) (eq 27).74,75 Note that the ketone (27) has an internal barrier to rotation about the aryl-carbonyl single bond of in excess of 20 kcal mol-1.

Examples have also been reported of oxidation of allylic or benzylic alcohols by (1) in the presence of divalent sulfur and basic nitrogen without concomitant oxidation at these heteroatoms.76,77

Oxidation at Methine and Methylene Groups.

Relatively recently, as a result of the interest in the synthesis of derivatives of the immunosuppressive agent FK-506, which possesses the relatively rare 2,3-dioxo amide unit, it has been recognized that the periodinane (1), when employed in excess, is capable of oxidizing a-thioaryl b-keto amides to the related 2,3-dioxo amides, accompanied by the derived enol(s) and the hydrate of the 2-oxo function. This oxidation, whose mechanism has not been established as yet, may proceed via the enol or via the corresponding sulfoxide by way of a Pummerer-type rearrangement.78 Subsequently, the direct oxidation of b-keto esters and amides by the periodinane (1) to 2,3-dioxo esters and amides has been reported.79


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Robert J. Boeckman, Jr.

University of Rochester, NY, USA



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