A-Alkoxy hydroperoxides

An alternative method for dialkyl peroxide synthesis is the nucleophilic addition of an alkyl hydroperoxide to an alkene under acid catalysis reported by Davies and coworkers (Scheme 31, path B) ". A similar reaction is the nucleophilic addition of alkylhy-droperoxides to vinyl ethers under acid catalysis, producing perketals. Perketals can be deprotected under mild conditions (THF/water/acetic acid) and this hydroperoxide protection-deprotection sequence has been used by Dussault and Porter as a means for the resolution of racemic hydroperoxides (see also Section II.A.2) . In this respect more detailed studies were carried out with the perketals 75, which were prepared via reaction of alkyl hydroperoxides with vinyl ethers (Scheme 33). Weissermel and Lederer reported that in the presence of teri-butyl hypochlorite, a-chlorodialkyl peroxides can be formed in yields between 12% and 45% (Scheme 31, path C)". a-Alkoxydialkyl peroxides and diperoxyacetals were prepared by Rieche and coworkers via acid catalyzed reaction of one or two equivalents of alkyl hydroperoxides with acetals, ketals or aldehydes (Scheme 31, path D)" or by methylation of the corresponding a-alkoxy hydroperoxides with diazomethane (yields 11%, 27%)" . The diperoxyacetals 76 were isolated in yields ranging from 39 to 77%. 

Fragmentation of a-alkoxy hydroperoxides. Schrciber1 has reported a short synthesis ol I be mucrolide ( + )-recileiolide (2) in which the key step involves Irngmeutnliim of llie /(-alkoxy hydroperoxide 1. available in two steps from... 

The paper also reports fragmentation by this reaction of the a-alkoxy hydroperoxide 3, derived from ( —)-carvone, as a novel route to the optically active 4. 

Ozonolysis of cycloalkenes.b Cycloalkenes are converted by ozonation in the presence of an alcohol (usually methanol) into an acyclic product with an aldehyde group and an a-alkoxy hydroperoxide group at the terminal positions. The products are usually difficult to purify, but they can be converted into useful products that retain differentiated terminal functionality. 

The method is particularly useful for preparation of 6-nitrogalactopyranosides, which cannot be prepared by the usual Komblum route (Sn2 displacement of I by AgN02). Criegee rearrangement of a-alkoxy hydroperoxidesf The a-alkoxy hydroperoxides formed by ozonolysis in CH,OH rearrange on treatment with Ac,0 to esters or lactones. 

Criegee rearrangement of a-alkoxy hydroperoxides.4 The a-alkoxy hydroperoxides formed by ozonolysis in CH3OH rearrange on treatment with Ac20 to esters or lactones. 

The acylations of a-alkoxy hydroperoxides such as (79) furnish peroxy esters that are related to the intermediate produced in the Baeyer-Villiger reaction. " The peroxy ester undergoes the Criegee rearrangement to a dioxonium ion which in turn is converted into an ester. Thus, ozonolysis of (+)-( )-dihydrocarvone (78) affords a 1 1 mixture of diastereomers (79). Acetylation and rearrangement... 

Schreiber et al. have reported the iron(II)/copper(II)-mediated fragmentation of a-alkoxy hydroperoxides as a route to unsaturated macrolides. The ferrous ion promoted the alkoxyl radical formation, and the C-radical in the presence of the... 

Heterocycloadditions. a-Alkoxy hydroperoxides undergo ionization on treatment with a Lewis acid (e.g., SnCy. Trapping such species with nucleophilic aDcenes delivers l,2-dioxolanes. The use of TiCl in this reaction leads to lower yields of the heterocyclic products or even only to the homoallylic ethers resulting from displacement of the peroxy group by an allyl group. 

Experimental set up as in section a). Alkoxy radicals were produced by photolysis of di-tert.-butyl peroxide (2 Mol/1). The build up of hydroperoxide concentration was measured by a modified version of the iodometric method used by Carlsson and Wiles—. 

SCHEME 13. Synthesis of a-alkoxy hydroxy hydroperoxides by ozonolysis, OMe OOH... 

By analogy with Reaction 2 oxygen should be evolved from alkoxy hydroperoxide oxidation and a nonacidic diperoxide produced (Reaction... 

The C8 aldehyde ester may be produced by cleavage of the 9-hydroperoxide of ethyl llnoleate followed by terminal hydroperoxidation. Further oxidation would produce the corresponding dicarboxylic acid which upon decarboxylation would give rise to ethyl heptanoate. The 8-alkoxy radical may also decompose to give the C7 alkyl radical, which would yield ethyl heptanoate or form a terminal hydroperoxide, and so on. Polymerization, both intra- and intermolecular, is also a major reaction in high temperature oxidation. Combination of alkyl, alkoxy, and peroxy radicals yields a variety of dimeric and polymeric compounds with C-O-C or C-O-O-C crosslinks. 

Caprolactam is a thermally unstable compound that on distillation may form methyl-, ethyl-, propyl- and n-amylamines. Also, at high temperatures, caprolactam reacts with oxygen to form hydroperoxides that in the presence of iron or cobalt ions are converted into adipimide. A-alkoxy compounds are also formed by the reaction of caprolactam with aldehydes during storage. 

Mn (IT) is readily oxidized to Mn (ITT) by just bubbling air through a solution in, eg, nonanoic acid at 95°C, even in the absence of added peroxide (186). Apparently traces of peroxide in the solvent produce some initial Mn (ITT) and alkoxy radicals. Alkoxy radicals can abstract hydrogen to produce R radicals and Mn (ITT) can react with acid to produce radicals. The R radicals can produce additional alkylperoxy radicals and hydroperoxides (reactions 2 and 3) which can produce more Mn (ITT). If the oxygen feed is replaced by nitrogen, the Mn (ITT) is rapidly reduced to Mn (IT). 

The reactions of alkyl hydroperoxides with ferrous ion (eq. 11) generate alkoxy radicals. These free-radical initiator systems are used industrially for the emulsion polymerization and copolymerization of vinyl monomers, eg, butadiene—styrene. The use of hydroperoxides in the presence of transition-metal ions to synthesize a large variety of products has been reviewed (48,51). 

Alkoxy radicals from hydroperoxides can undergo a -scission reaction (eq. 2) to yield an alkyl radical and a ketone. The higher stabiUty of the generated alkyl radical compared to that of the parent alkoxy radical provides the driving force for this reaction, and the R group involved is the one that forms the most stable alkyl radical. 

Alkyl hydroperoxides give alkoxy radicals and the hydroxyl radical. r-Butyl hydroperoxide is often used as a radical source. Detailed studies on the mechanism of the decomposition indicate that it is a more complicated process than simple unimolecular decomposition. The alkyl hydroperoxides are also sometimes used in conjunction with a transition-metal salt. Under these conditions, an alkoxy radical is produced, but the hydroxyl portion appears as hydroxide ion as the result of one-electron reduction by the metal ion. ... 

Process 5, the conversion of hydroperoxides to alkoxy and hydroxyl radicals, can be interrupted by incorporation of a secondary antioxidant such as phosphites (e.g. Irgafos 168) or thioesters (e.g. Evanstab 12). These materials act as reducing agents, converting hydroperoxides to alcohols and themselves being converted to phosphates or sulfoxides, respectively (see Fig. 16). 

Hydroperoxides react with transition metals in lower oxidation states (TiJ, Fe", Cu+, etc.) and a variety of other oxidants to give an alkoxy radical and hydroxide anion (Scheme 3.38)46 224,22"... 

Variable valence transition metal ions, such as Co VCo and Mn /Mn are able to catalyze hydrocarbon autoxidations by increasing the rate of chain initiation. Thus, redox reactions of the metal ions with alkyl hydroperoxides produce chain initiating alkoxy and alkylperoxy radicals (Fig. 6). Interestingly, aromatic percarboxylic acids, which are key intermediates in the oxidation of methylaromatics, were shown by Jones (ref. 10) to oxidize Mn and Co, to the corresponding p-oxodimer of Mn or Co , via a heterolytic mechanism (Fig. 6). 

Figure 17.2 Lipid peroxidation scheme. LH, a polyunsaturated fatty acid LOOM, lipid hydroperoxide LOH, lipid alcohol L, lipid radical LOO, lipid hydroperoxyl radical LO, lipid alkoxyl radical. Initiation the LH hydrogen is abstracted by reactive oxygen (e.g. lipid alkyl radical, lipid alkoxy radical, lipid hydroperoxyl radical, hydroxy radical, etc.) to produce a new lipid alkyl radical, L. Propagation the lipid alkyl, alkoxyl or hydroperoxyl radical abstracts hydrogen from the neighbouring LH to generate a new L radical.

Basically, three reactions were evoked to support the occurrence of 5a-C-centered radicals 10 in tocopherol chemistry. The first one is the formation of 5a-substituted derivatives (8) in the reaction of a-tocopherol (1) with radicals and radical initiators. The most prominent example here is the reaction of 1 with dibenzoyl peroxide leading to 5a-a-tocopheryl benzoate (11) in fair yields,12 so that a typical radical recombination mechanism was postulated (Fig. 6.6). Similarly, low yields of 5a-alkoxy-a-tocopherols were obtained by oxidation of a-tocopherol with tert-butyl hydroperoxide or other peroxides in inert solvents containing various alcohols,23 24 although the involvement of 5 a-C-centered radicals in the formation mechanism was not evoked for explanation in these cases. 

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