DMDO oxidation

By H NMR monitoring of the oxidation of benzene oxide-oxepine with dimethyldioxirane (DMDO), a significant by-product, oxepine 4,5-dioxide, was identified <1997CRT1314>. This fact supports the hypothesis that the route from oxepine to muconaldehyde proceeds via oxepine 2,3-oxide with a minor pathway leading to symmetrical oxepine 4,5-oxide. The DMDO oxidations provide model systems for the cytochrome P450-dependent metabolism of benzene and atmospheric photooxidation of benzenoid hydrocarbons. 

An alternative route by the Danishefsky group was developed [142e-g] (Scheme 84). The aldol reaction of ethyl ketone 580, prepared from P-keto ester 579, with aldehyde 581 stereoselectively afforded 582 (dr = 5.4 1). After Troc protection followed by hydrolysis of the enol ether, Suzuki coupling with 583 followed by TBS deprotection gave the desired (12Z)-olefin 584. The Noyori reduction of the P-keto ester 584 gave 3a-alcohol with high stereoselectivity, which was converted into hydroxy carboxylic acid 585. Macrolactonization of 585 was accomplished by the Yamaguchi method, and subsequent deprotection and DMDO oxidation efficiently afforded epothilone B (5b). 

It has been suggested that the TS for DMDO oxidation of electron-poor alkenes, such as acrylonitrile, has a dominant nucleophilic component. DMDO oxidations have a fairly high sensitivity to steric effect. The Z-isomers of alkenes are usually more reactive than the f-isomers because in the former case the reagent can avoid the alkyl groups. We say more about this in Section 5.8. 

The DMDO oxidation of iodocyclohexane affords lran5-2-iodocyclohexanol as the final product via intermediate formation of iodosylcyclohexane followed by elimination of hypoiodous acid, which then adds to the alkene generated in the elimination step [103]. The oxidative deiodination of iodoalkanes via conversion into iodosylalkanes followed by nucleophilic substitution of the iodosyl group has found some synthetic application, particularly in the synthesis of steroidal products (Section 3.1.19) [107]. 

Ab initio studies using the B3LYP hybrid density functional theoretical method for the DMDO oxidation of nitrosamine (H2N—N=0), nitrosodimethylamine (MeaN—N=0), and nitrosoethylmethylamine (EtMeN—N=0) have concluded that the nitroso nitrogen atom is the most readily attacked, followed by the a-CH bond of the anft -alkyl group, the amine nitrogen being the least reactive. The A-oxidation of picolinaldehydes with DMDO proceeds with remarkable selectivity, giving A -oxides preferentially over carboxylic acids. ... 

Murray s finding that dimethyldioxirane (DMDO) can be readily prepared with acetone and oxone [54] allowed the development of epoxidation reactions under essentially neutral conditions [55]. Such DMDO oxidations were utilized by Danishefsky in an efficient direct epoxidation of glycals, as illustrated by the formation of epoxide 10 (dr >99 1, Equation 5) [56]. 

A retroaldol fragmentation subsequent to the addition of p-TsOI I and a small amount of water to epoxide 206, obtained by oxidation of enol ether 205 with DMDO, resulted in the direct formation of dialdehyde hydrate 208, possessing the spirostructure necessary for the construction of the fused-rings core of ( )-ginkoli-de B. Apparently, hydrolysis of the epoxide produces the hemiacetal 207, which undergoes retroaldol fragmentation of the cydobutane to afford the dialdehyde, which forms the stable hydrate 208 (Scheme 8.52) [94]. 

The yields and rates of oxidation by DMDO under these in situ conditions depend on pH and other reaction parameters.90... 

Other ketones besides acetone can be used for in situ generation of dioxi-ranes by reaction with peroxysulfate or another suitable peroxide. More electrophilic ketones give more reactive dioxiranes. 3-Methyl-3-trifluoromethyldioxirane is a more reactive analog of DMDO.99 This reagent, which is generated in situ from 1,1,1-trifluoroacetone, can oxidize less reactive compounds such as methyl cinnamate. 

Reaction of dihydropyrrolizine 87 with DMDO in aqueous acetone gives the oxidative rearrangement compound 88 in 59% yield <20030L785>. A plausible mechanism was proposed as shown in Scheme 11. 

The Diels-Alder reaction outlined above is a typical example of the utilization of axially chiral allenes, accessible through 1,6-addition or other methods, to generate selectively new stereogenic centers. This transfer of chirality is also possible via in-termolecular Diels-Alder reactions of vinylallenes [57], aldol reactions of allenyl eno-lates [19f] and Ireland-Claisen rearrangements of silyl allenylketene acetals [58]. Furthermore, it has been utilized recently in the diastereoselective oxidation of titanium allenyl enolates (formed by deprotonation of /3-allenecarboxylates of type 65 and transmetalation with titanocene dichloride) with dimethyl dioxirane (DMDO) [25, 59] and in subsequent acid- or gold-catalyzed cycloisomerization reactions of a-hydroxyallenes into 2,5-dihydrofurans (cf. Chapter 15) [25, 59, 60],... 

Only a few isolated allene oxides have been synthesized from allenes and characterized. Most often peracids are used but the oxidative and acidic conditions usually result in a complex mixture of products. To overcome this problem, dimethyldioxirane (DMDO) can be used, which rapidly oxidizes allenes to spirodiepoxides. Several synthetically useful methods have been developed via in situ reaction of the intermediate allene oxide or spirodioxide with different nucleophiles. 

In situ epoxidation of allenyl alcohols [20], aldehydes [21], acids [22] and sulfonamides [23] followed by intramolecular ring opening of the intermediates was thoroughly investigated by Crandall and co-workers. They showed that products formed either from the allene oxide or the spirodioxide intermediate can be prepared selectively. Allenyl acids 56, for example, react first with DMDO on their more substituted double bond. When the concentration of the oxidant is low (DMDO is formed... 

When allenyl aldehydes are allowed to react with DMDO, the aldehyde moiety is not oxidized to the acid except for monosubstituted allenes [21]. In all other cases, the carbonyl oxygen participates as a nucleophile in the opening of the intermediate epoxide. From 2,2,5-trimethy]-3,4-hexadienal 67, for example, five different products can be synthesized selectively under different reaction conditions (Scheme 17.22). When p-toluenesulfonic acid (TsOH) is present or DMDO is formed in situ, then the initially formed allene (mono)oxide reacts with the aldehyde moiety to give 68 or 69. In the presence of excess DMDO and the absence of acid, three other products (70-72) can be formed via the spirodioxide intermediate. These reactions, however, seem to be less general compared with similar reactions of allenyl acids and allenyl alcohols. y-Allenylaldehydes 73 can be cyclized to five-membered hemiacetals 74 via the spirodioxide intermediate. 

The oxidation of allenylsulfonamides 75 is also possible by using DMDO [23], Unlike the corresponding reaction of allenyl acids, oxidation of allenyl sulfonamides usually cannot be stopped after the formation of the allene oxide 76 but proceeds further to the spirodiepoxide intermediate 77, finally giving hydroxypyrrolidinone 78 and hydroxypiperidone 79, respectively (Scheme 17.23). Similarly to y-allenyl alcohols, aldehydes and acids, five-membered heterocycles, e.g. 80, are also formed from y-allenylsulfonamides. In the latter case the reaction can be terminated after the first epoxidation by addition of p-toluenesulfonic acid. 

In a different study, a d-allenyl alcohol 81 containing a chiral substituent was oxidized by DMDO and then cyclized to afford the substituted tetrahydropyran 82 with good diastereoselectivity [19] (Scheme 17.24). Interestingly, when oxone was used instead of DMDO, the eight-membered cyclic ether 83 was formed via the allene oxide intermediate. 

Kinetics of the dimethyidioxirane oxidation of adamantane in an oxygen atmosphere support a radicai mechanism. The kinetics of the oxidation of 2-methyibutane by DMDO in acetone soiution have been studied and the mechanisms of the reaction and of inhibition of the reaction by O2 were discussed. 

Oxidation of tetrathioianes (8) with DMDO gave mixtures of dithiirane 1-oxides (10) and thioketones (11) (Scheme 5). The existence of the intermediate tetrathioiane 1-oxides (9) was verified by NMR of the cooled and evaporated reaction mixture. ... 

Hexamethylbenzene reacts with DMDO via three pathways (i) to an arene oxide, which rapidly rearranges to an oxepin tautomer that then is oxidized to a cw-diepoxide and then to a cis, cis,trans-triepoxide (ii) a methyl group migrates in the first epoxide to give a cyclohexadienone, which then reacts to give a frani -diepoxide (iii) C—H insertion to give the benzyl alcohol and then the corresponding benzoic acid. ... 

Peroxyacids are the most widely used class of oxidant for aromatic amino to nitro group conversion and include peroxydisulfuric, peroxymonosulfuric, peroxyacetic, peroxytrifluo-roacetic and peroxymaleic acids. The oxidizing potential of the peroxyacid is, as a rule, proportional to the strength of the parent deoxy-acid. Dimethyldioxirane (DMDO) and ozone have also found use for amino to nitro group conversion. 

The yields and rates of oxidation by DMDO under these in situ conditions depend on pH and other reaction conditions.75 Various computational models of the transition state agree that the reaction occurs by a concerted mechanism.76 Kinetics and isotope effects are consistent with this mechanism.77... 

TABLE 2. Comparison of the calculated barriers (kcal mol ) for the oxidation of alkenes, dimethyl sulfide, trimethylamine and trimethylphosphine with peroxynitrous add, peroxyformic acid and dimethyldioxirane (DMDO)... 

The barrier for ethylene epoxidation with DMDO was calculated at the QClSD(T)//QClSD(ftill)/6-31G level. The barrier for ethylene oxidation with the parent dioxirane is lower (16.6 kcalmoL at the same level). 

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