Kharasch oxidation

In 1959, Kharasch et al.43 reported an allylic oxyacylation of olefins. In the presence of f-butyl perbenzoate and a catalytic amount of copper salt in refluxing benzene, olefin was oxidized to allyl benzoate, which could then be converted to an allyl alcohol upon hydrolysis. It is desirable to introduce asymmetric induction into this allylic oxyacylation because allylic oxyacylation holds great potential for nonracemic allyl alcohol synthesis. Furthermore, this reaction can be regarded as a good supplement to other asymmetric olefinic reactions such as epoxidation and dihydroxylation. 

This chapter will begin with a discussion of the role of chiral copper(I) and (II) complexes in group-transfer processes with an emphasis on alkene cyclo-propanation and aziridination. This discussion will be followed by a survey of enantioselective variants of the Kharasch-Sosnovsky reaction, an allylic oxidation process. Section II will review the extensive efforts that have been directed toward the development of enantioselective, Cu(I) catalyzed conjugate addition reactions and related processes. The discussion will finish with a survey of the recent advances that have been achieved by the use of cationic, chiral Cu(II) complexes as chiral Lewis acids for the catalysis of cycloaddition, aldol, Michael, and ene reactions. 

The allylic acyloxylation of alkenes, the Kharasch-Sosnovsky reaction, Eq. 81, would be an effective route to nonracemic allylic alcohol derivatives, if efficient, enantioselective catalysts were available. The reaction is mediated by a variety of copper salts, and as such, has been the target of considerable research in an attempt to render the process enantioselective. The original reaction conditions described by Kharasch require high temperatures when CuBr is used as the catalyst (93). However, the use of CuOTf (PhH)0 5 allows the reaction to proceed at temperatures as low as -20°C. Unfortunately, long reaction times are endemic in these processes and the use of excess alkene (2-100 equiv) is conventional. Most yields reported in this field are based on the oxidant. 

Scheme 8. General mechanism of the copper-catalyzed allylic oxidation of alkenes (Kharasch-Sosnovsky reaction).

The application of dinuclear metal catalysts to the Kharasch-Sosnovsky reaction is mechanistically intriguing due to their illustrated role in mediating biological oxidations (119). Fahmi (120) examined a variety of dinucleating ligands with Cu(MeCN)4PF6 as catalysts in the allylic oxidation of cyclohexene, Eq. 102. In these studies, early results have been inferior to those obtained from bis(oxa-zoline)-copper catalysts. 

The synthesis of (XVIII), (XIX), (XX) and (XXI) from methyl fluorocrotonate was accomplished according to the annexed scheme. Methyl y-fluorocrotonate had previously been prepared, and was reported by Kharasch and his co-workers to be a highly toxic compound. It possesses the carbon structure of methyl y-fluorobutyrate, and the double bond in the opposition would undoubtedly facilitate oxidation. The American workers prepared methyl y-fluorocrotonate by an ingenious five-stage process from epifluorohydrin. For the above syntheses we... 

Asymmetric allylic oxidation and benzylic oxidation (Kharasch-PSosnovsky reaction) are important synthetic strategies for constructing chiral C—O bonds via C—H bond activation.In the mid-1990s, the asymmetric Kharasch-Sosnovsky reaction was first studied by using chiral C2-symmetric bis(oxazoline)s. " Later various chiral ligands, based mainly on oxazoline derivatives and proline derivatives, were used in such asymmetric oxidation. Although many efforts have been made to improve the enantioselective Kharasch-Sosnovsky oxidation reaction, most cases suffered from low to moderate enantioselectivities or low reactivities. 

For a review of the oxidation of disulfides, see Savige Maclaren. in Kharasch Meyers Organic Sulfur Compounds, vol. 2 pp. 367-402. Pergamon, New York. 1966. 

Co-oxidation of indene and thiophenol takes place readily if the reactants in benzene solution are shaken with oxygen at temperatures in the range 20° to 40°C. (7). The major primary product has been shown to be frans-2-phenylmercapto-1 -indanyl hydroperoxide, I, which rearranges spontaneously to the two racemes of frans-2-phenylsulfinyl-l-indanol, II (8), and a tentative reaction scheme involving a three-step radical chain based on the suggestion of Kharasch, Nudenberg, and Mantell (11) was proposed for the formation of I. These three products accounted for 86% of the oxygen absorbed. 

According to Kharasch, primary and secondary nitrates which have been hydrolysed in accordance with the scheme (57) produce a certain quantity of oxidation... 

Another example is the palladium-catalyzed oxidation of ethylene to acetaldehyde in the presence of oxygen and cupric salts, the so-called Wacker reaction. This catalytic cycle combines two stoichiometric processes, which involve first the reduction of Pd11 to Pd°, followed by reoxidation with Cu11. The understanding of the first step of this process came from the earlier work of Kharasch et al., who showed that the stoichiometric dinuclear complex shown in Figure 2.14 decomposed in the presence of water to acetaldehyde (ethanal), Pd° and HC1 [38]. 

Although the first example of an asymmetric Kharasch-Sosnovski reaction with a chiral perester was reported as early as 1965 [17], major advances have only been made in the last ten years. In the early 1990s, Muzart carefully reinvestigated earlier results obtained by Araki and Nagase [18]. After intensive optimization of the reaction conditions, the acyloxylation of cydopentene and cyclohexene gave products with up to 59 and 45 % ee, respectively. The best conditions for the oxidation of cyclohexene were found to involve the use of 5 mol% copper oxide, 10 mol% proline (1), and tert-butyl perbenzoate/benzoic acid in benzene under reflux (Scheme 2) [19]. 

Kharasch ED, Hankins D, Mautz D, et al. Identification of the enzyme responsible for oxidative halothane metabolism implications for prevention of halothane hepatitis. Lancet 1996 347 1367-1371. 

The homolysis of a metal alkyl may be regarded as a reductive elimination however, it is convenient to consider such reactions separately (Section V,B). Electron-transfer mechanisms for organometallic intermediates in catalytic reactions have been reviewed (129) examples are in the formation of transient RCu(I) or RCr(III) in oxidation (by Cu(II)) or reduction (by Cr (II)) of R, and in the role of Fe in the Kharasch-Grignard... 

Nedelec and coworkers reported a manganese(III)-initiated cyanoacetate-catalyzed atom-transfer radical addition of polyhalomethanes or dibromomalonate 172 to alkenes 126 (Fig. 48) [272]. Since neither Mn(II) nor Mn(III) is useful to initiate Kharasch-type additions, an organocatalyst served this purpose. Thus, a short electrolysis of a mixture of 126,172,10 mol% of Mn(OAc)2, and 10 mol% of methyl cyanoacetate 171 led to initial oxidation of Mn(II) to Mn(III), which served to form the cyanoacetate radical 171A oxidatively. The latter is able to abstract a halogen atom from 172. The generated radical 172A adds to 126. The secondary... 

Recently, iron catalysis gained general importance. Its catalytic chemistry has been summarized ([2] recent reviews [3, 4]). Iron(II) and iron(III) salts have a long history in radical chemistry. The former are moderately active in atom-transfer reactions as well as initiators for the Fenton reaction with hydrogen peroxide or hydroperoxides (reviews [5-12]). Important applications of this principle are the Kharasch-Sosnovsky reaction (the allylic oxidation of olefins) [13], which often... 

The most prominent reactions catalyzed by low-valent iron species involving radical intermediates are cross-coupling reactions of alkyl halides (recent reviews [32-35]) and atom transfer radical reactions. In cross-coupling reactions the oxidation state of the catalytically active species can vary significantly depending on the reaction conditions very often it is not known exactly. To facilitate a summary, all iron-catalyzed cross-coupling reactions are treated together and involved oxidation states, where known, are mentioned at the example. In contrast, iron-catalyzed Kharasch reactions will be treated at the oxidation state of the iron precursors. 

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