Metal-free Oxidants

It should be noted that the related imine-oxaziridine couple E-F finds application in asymmetric sulfoxidation, which is discussed in Section 10.3. Similarly, chiral oxoammonium ions G enable catalytic stereoselective oxidation of alcohols and thus, e.g., kinetic resolution of racemates. Processes of this type are discussed in Section 10.4. Whereas perhydrates, e.g. of fluorinated ketones, have several applications in oxidation catalysis [5], e.g. for the preparation of epoxides from olefins, it seems that no application of chiral perhydrates in asymmetric synthesis has yet been found. Metal-free oxidation catalysis - achiral or chiral - has, nevertheless, become a very potent method in organic synthesis, and the field is developing rapidly [6]. 

For a general review of metal-free oxidation, including achiral and chiral catalysts, see W. Adam, C. R. Saha-Moller, P. A. Ganeshpure, Chem. Rev. 2001, 101, 3499-3548. 

There are problems associated with the expensive disposal of toxic waste from metal-based oxidations of alcohols. Thus, the focus has been largely on catalytic reactions as typified by Ley and Griffith s tetrapropylammonium perruthenate oxidant (section 7.1.6). Completely metal-free oxidations have much potential for environment-friendly oxidations, particularly if the reagent can be recovered and recycled. The most common metal-free oxidation of alcohols are TEMPO/oxone or TEMPO/N-chlorosuccinimide oxidation, Dess-Martin periodane oxidation (section 7.1.5) and Swern oxidation (section 7.1.4) and its several variants. 

Equation (33)), which then oxidize substrate. A prominent example of Equations (29), (31), and (32) is formation of a POM-bound oxygen atom donor, which transforms to a POM oxometal intermediate, which then oxidizes the substrate. The last mode (generation of metal-free oxidizing intermediates) can involve oxygen donors, such as iodosylarenes, peroxides (formation of alkyl-peroxy, alkoxy radicals, etc.), or 02 (formation of all the radicals associated with radical chain oxidation or autoxidation ).335-338... 

A new polymer-bound reagent system for the efficient oxidation of primary alcohols to aldehydes and of secondary alcohols to ketones in the presence of a catalytic amount of 2,2,6,6-tetramethyl-l-piperidonoxyl (TEMPO) has been described [102]. Work-up of this heavy metal free oxidation is achieved by simple filtration followed by removal of the solvent. Benzyl alcohol was oxidized in 94% yield. The more demanding cyclohexyl alcohol was converted into cyclohexanone in 96 % yield. 

Soonafterward, Buchwald and coworkers reported an efficient Pd-catalyzed oxidative cross-coupling of A-acetanilides with simple arenes in a similar manner [70]. In the presence of 5-10 mol% Pd(OAc)2 and 10-20 mol% DMSO, the cross-coupling reaction took place smoothly between anilides and 4—11 equiv. of simple arenes in TFA under an oxygen atmosphere (Scheme 23). The reaction conditions could tolerate a wide range of substrates. The metal-free oxidant represents a great advantage of the current catalytic system. 

Bao and co-workers recently reported a metal-free oxidative coupling reaction of benzy lie/ally lie C-H bonds of 57 with activated methylene 46 using DDQ as the oxidant to generate the alkylated product 58 (Scheme 32) [55]. 

Alkanes can be oxidized in the presence of some transition metal complexes in aqueous and acidic media For example, in concentrated sulfuric acid the oxidative properties of the complexes are enhanced. Solutions of derivatives of palladium(II), platinum(III), manganese(III) and mercury(II) as well as some other compounds (hydrogen peroxide, ammonium persulfate, nitric acid and even concentrated sulfuric acid itself) can be used as oxidants. In the cases of metal-free oxidants the active species are apparently electrophiles such as NO2 or SO3I-C (for nitration of aromatics, see, for example, recent publication [40] and references therein). 

The oxidation of alcohols to carbonyl compounds is one of the most fundamental and important processes in the fine chemical industry. The classical methodology is based on the stoichiometric use of heavy metals, notably Cr and Mn (1,2). Alternatively metal-free oxidation, such as the Swern and Pfitzner-Moffat protocols, is based on e.g., dimethylsulfoxide as oxidant in the presence of an activating reagent such as N,N -dicyclohexylcarbodiimide, an acid anhydride or acid halide (3). Although the latter methods avoid the use of heavy metals, they usually involve moisture-sensitive oxidants and environmentally undesirable reaction media, such as chlorinated solvents. The desired oxidation of alcohols only requires the formal transfer of two hydrogen atoms, and therefore the atom economy of these methods is extremely disadvantageous. The current state of the art in alcohol oxidations... 

After precomplexation with ji-CD, a variety of alcohols, including aromatic alcohols, were oxidized to their corresponding carbonyl compounds in good yields with NaOCl-KBr in aqueous solution. A substrate-selective and transition metal-free oxidation of benzoic and allylic alcohols with NaOCl oxidant mediated by j8-CD in water was developed. In the presence of one molar equivalent of jS-CD, benzyl alcohol, 4-methoxybenzyl alcohol and some primary aromatic alcohols were oxidated to form benzaldehyde, 4-methoxybenzaldehyde and aromatic aldehydes, respectively, at 50 °C for 1-4 h. When 20% of acetone was added to the reaction system, the yield of aldehyde was dramatically decreased. 

As before, the exploration of the metal-free oxidative amination was a competitive process. Both Chang" and Antonchick" simultaneously discovered nearly identical I(III)-mediated aminations. They both proposed that the reactions operated by generating an electrophilic nitrogen source in situ. This new species then acted as an R2N equivalent and aminated the arene via an electrophilic aromatic substitution mechanism. This hypothesis seemed appealing, but their data could not be directly compared to ours, as neither Chang nor Antonchick performed reactions on arene substrates that could provide mixtures of regiomers (e.g., toluene). 

Lin and coworkers prepared 2-substituted quinazolines via a metal-free oxidative sp C—H/sp C—H cyclization of amidines (Scheme 23) (140L2822). Two methods were developed. Method A uses iodobenzene diacetate as a source of hypervalent iodine(lll) and a nonpolar solvent, toluene. In Method B potassium persulfate is used as the oxidant in the presence of a catalyst, TEMPO, and a polar solvent, acetonitrile. Both methods... 

Metal-free oxidative carbon—heteroatom bond formation through C—H bond functionalization 13EJ05769. 

Ammonium-directed metal-free oxidation of cyclic allylic and homoallylic amines has been reviewed. Such reactions yield all four diastereoisomers of the corresponding 3-amino-1,2-diols, and have featured in recent syntheses of ( )-l-deoxynojirimycin and ( )-l-deoxyaltronojirimycin. ... 

The hypervalent iodine reagent PhI(OTf)2 (generated in situ) promotes the metal-free oxidative production of C-O bonds, through an intramolecular oxidative cyclization of substituted N-styrylbenzamides 131 to give oxazoles 132 (13SL2119). 

Scheme 40 Metal-free oxidation/C(sp )-H functionalization of unactivated alkynes...

Metal-Free Oxidation of Aldehydes to Carboxylic Acids... 

Scheme 3 First report of metal-free oxidative cross-biaryl-coupling...

Scheme 21 A metal-free oxidation of iV-lithio hydrazones with (EtsNlsPNs Br"...

The reaction of Al-methyl-Al-phenylcinnamamides with phenyliodine bis (trifluoroacetate) in the presence of Lewis acids provides 3-arylquinolin-2-ones and involves a metal-free oxidative C(sp )-C sp ) bond formation and a 1,2-aryl migration (Scheme 89). " ... 

The Swern-MofFatt oxidation is a versatile metal-free oxidation method that finds application in the transformation of primary and secondary alcohols into aldehydes and ketones, respectively. However, its application in process chemistry is hampered by the low-temperature requirement, namely, 70 °C, and the highly exothermic behavior, which makes temperature control very diEBcult. The highly efficient heat transfer in the microreactor should solve the problem of limited cooling capacity in a batch reactor. 

Scheme 2.17 The metal-free, oxidant-mediated alkylarylation of alkenes with alcohols [94, 95]...

The mechanism of this reaction was discussed by the authors (Scheme 4.40). Initially, aldehydes are formed by the PIDA mediated oxidative C-C bond cleavage of 1,2-diols, which are generated from the dihydroxylation of alkenes [142]. Upon the decomposition of ammonium bicarbonate, the aldehydes could be trapped by ammonia to give imines, which would be further oxidized to give nitriles. This reaction shows the efiftciency of the combination of metal-free oxidant and inexpensive nitrogenation agent for the synthesis of nitriles, which should be of great value in further studies. 

Scheme 6.18 Transition-metal-free oxidative aliphatic C-H azidation...

Zhang X, Yang H, Tang P (2015) Transition-metal-free oxidative ahphatic C-H azidation. Org Lett 17(23) 5828-5831... 

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