A-Carbonyl radicals

Surprisingly little preparative work has been done on the anodic oxidation of enols and enolates, although the resulting a-carbonyl radicals are important intermediates in synthetic organic chemistry and biological systems [94]. Due to... 

Two possible mechanisms are proposed. Primarily the enol radical cation is formed. It either undergoes deprotonation because of its intrinsic acidity, producing an a-carbonyl radical, which is oxidized in a further one-electron oxidation step to an a-carbonyl cation. Cyclization leads to an intermediate cyclo-hexadienyl cation. On the other hand, cyclization of the enol radical cation can be faster than deprotonation, producing a distonic radical cation, which, after proton loss and second one-electron oxidation, leads to the same cyclo-hexadienyl cation intermediate as in the first reaction pathway. After a 1,2-methyl shift and further deprotonation, the benzofuran is obtained. Since the oxidation potentials of the enols are about 0.3-0.5 V higher than those of the corresponding a-carbonyl radicals, the author prefers the first reaction pathway via a-carbonyl cations [112]. Under the same reaction conditions, the oxidation of 2-mesityl-2-phenylethenol 74 does not lead to benzofuran but to oxazole 75 in yields of up to 85 %. The oxazole 75 is generated by nucleophilic attack of acetonitrile on the a-carbonyl cation or the proceeding enol radical cation. 

Calculations indicate that the unpaired electron density in the cation-radical of tetrathiafulvalene resides principally on sulfur, hut with the internal carbon being the site of second highest density. The product of coupling of an a-carbonyl radical to sulfur, an a-carbonyl-sulfonium salt would be destabilized by the adjacent dipoles. The transition state would be expected to mirror this, thus slowing down the C-S coupling and permitting the observed coupling to the carbon of tetrathiafulvalene. 

Although the mechanism of the reaction is unknown, Moore and Waters188 have shown that addition of a carbonyl radical to a carbonyl double bond occurs when benzaldehyde is irradiated in the presence of phenanthraquinone, yielding, ultimately, the hydroquinone monobenzoate. 

Takasu and coworkers reported the construction of the dodecahydrophenanthrene system (111) through the use of a B SnH-mediated 6-endo, 6-endo, 6-exo cascade process (equation 86)707, while Sha and coworkers described the total synthesis of (+)-paniculatine (112) by a tandem sequence involving a-carbonyl radicals (equation 87)710. 

The addition of a-carbonyl radicals derived from bromo esters 47 to olefins 48 proceeded smoothly using 7.5-15 mol% of Ni(OAc)2 [100]. The reaction furnished reduced esters and amides 49 in 15-91% yield. Reactions to 1,2-disubstituted... 

Decarboxylation Removal of a carbonyl radical, especially from amino acids and proteins... 

For several tautomeric systems ketones/enols, imines/enamin and others) a distinct reversal of the stability order is observed when going from the neutral compounds to the radical cations, the first use of which in a new preparative a-Umpolung reaction has been documented for keto/enol systems. The present review provides a critical evaluation of the chemistry of enol radical cations in solution with a special emphasis on the Umpolung reaction and the intermediates thereof. Other enol type of radical cations are discussed with respect to their potential to provide a-carbonyl radical and a-carbonyl cation intermediates. Hence, this article does not constitute a comprehensive summary on all enol type of radical cation reactions. All potentials in this review are referenced versus SCE, unless noted otherwise. Potentials measured against the ferrocene/ferrocenium couple were converted to SCE by adding 0.334 V. 

From a mechanistic point of view two possible hypotheses were discussed (Scheme 2). Since radical cations are intrinsically very acidic [29-32] one would expect enol radical cation 27 to deprotonate efficiently and rapidly thus providing an a-carbonyl radical (mechanism 1). In a further one-electron oxidation step the a-carbonyl cation is formed, that cyclizes to an intermediate cyclohexadienyl cation 28. After a 1,2-methyl shift and deprotonation the benzofuran 29 is obtained. The mechanistic proposal is in line with benzofuran formation from a-carbonyl cations as demonstrated by Okamoto [120]. Interestingly, the above mechanism was first proposed by Bailey to explain the formation of 3% of benzofuran 24 in the ozonization of enol 8 [121], Years later, however, the mechanistic hypothesis was proven to be untenable [122] under ozonization conditions. A priori, it cannot be excluded that intramolecular cyclization of the enol radical cation 27 " is faster than deprotonation (mechanism 2). The distonic radical cation formed is expected to lose a proton readily and after a second one-electron oxidation the same cyclohexadienyl cation intermediate as in mechanism 1 is formed. 

Since Scheme 4 implies formation of a-carbonyl radicals after deprotonation of enol radical cations, the same oxidation chemistry should potentially be accessible from various enol derivatives as enolates, silyl enol ethers and enol esters (Scheme 5). On the other hand, enol ether radical cations do not fit in this systematization since they are attacked by nucleophiles at the double bond faster than providing a-carbonyl radical intermediates through O-C bond cleavage (Sect. 4.3). 

A rational approach to either a-carbonyl radical or cation chemistry from enol oxidation thus necessitates explicit knowledge of the oxidation potentials of... 

A novel pathway to enol radical cations in solution through protonation of ) -hydroxy vinyl radicals 39 has recently been postulated by Gilbert [126]. Using ESR techniques it was demonstrated that l -hydroxyl vinyl radicals rearrange to a-carbonyl radicals 41 when the pH was lowered, and enol radical cations were proposed as intermediates. 

Oxidation of Enolates to a-Carbonyl Radicals and a-Carbonyl Cations... 

Pandey has tentatively proposed the involvement of enolates in the photo-induced electron transfer oxidation of arylacetones by the system 1,4-dicyano-naphthalene (8 mol%)/acetonitrile/aqueous NaOH [1 ]. The corresponding benzofurans were obtained in 50-60% yield, but the mechanism is speculative since no oxidant in stoichiometric amounts was present. It was assumed that cyclization takes place on the stage of the a-carbonyl radical. 

Recent work has now provided a comprehensive view on enolate oxidation since the controlled generation of either a-carbonyl radicals or a-carbonyl cations was possible depending on the conditions [147]. In line with the prediction made in Scheme 5 enolates 60-63 could be oxidized by 2 eq. of FePHEN ( i/2 = 109 V) to the corresponding benzofurans 19-21,24. 

Thermodynamically relevant oxidation potentials of enolates were recently obtained from cyclic voltammetry studies on 60-63. Since the a-carbonyl radicals proved to be sufficiently stable, also their oxidation potentials were determined. They are much higher than the ones from the corresponding enolates and agree qualitatively with the reduction potentials of three related a-carbonyl cations as determined by Okamoto [157,158], Thus, depending on the oxidation power of the used oxidant either a-carbonyl radical or a-carbonyl cation chemistry can be triggered from enolates as demonstrated above. 

Table 8. Oxidation potentials of enolates, a-carbonyl radicals, enols and ketones in comparison [147]...

The above oxidation potential order for enolates and a-carbonyl radicals parallels that of related phenolates and phenoxyl radicals [124]. Recently, reversible oxidation potentials for phenolates have been determined in either organic or aqueous media [80-85], whereas oxidation potentials of phenoxyl radicals are as scarce as for a-carbonyl radicals [124],... 

Hence, the first clearcut evidence for the involvement of enol radical cations in ketone oxidation reactions was provided by Henry [109] and Littler [110,112]. From kinetic results and product studies it was concluded that in the oxidation of cyclohexanone using the outer-sphere one-electron oxidants, tris-substituted 2,2 -bipyridyl or 1,10-phenanthroline complexes of iron(III) and ruthenium(III) or sodium hexachloroiridate(IV) (IrCI), the cyclohexenol radical cation (65" ) is formed, which rapidly deprotonates to the a-carbonyl radical 66. An upper limit for the deuterium isotope effect in the oxidation step (k /kjy < 2) suggests that electron transfer from the enol to the metal complex occurs prior to the loss of the proton [109]. In the reaction with the ruthenium(III) salt, four main products were formed 2-hydroxycyclohexanone (67), cyclohexenone, cyclopen tanecarboxylic acid and 1,2-cyclohexanedione, whereas oxidation with IrCl afforded 2-chlorocyclohexanone in almost quantitative yield. Similarly, enol radical cations can be invoked in the oxidation reactions of aliphatic ketones with the substitution inert dodecatungstocobaltate(III), CoW,20 o complex [169]. Unfortunately, these results have never been linked to the general concept of inversion of stability order of enol/ketone systems (Sect. 2) and thus have never received wide attention. 

In line with the mechanistic results from above and from the oxidation of stable enols (Sect. 3.1), the following mechanism was postulated (Scheme 8). Considering the multistep nature of the mechanism it is obvious that several, sometimes conflicting requirements have to be accomodated in the reaction system to maximize yields. For example, the redox potential of the oxidant has to be low in order to avoid dir rt oxidation of the carbonyl compound, but should still allow oxidation of the enol tautomer. In this case the chosen oxidant may turn out to be too weak for fast oxidation of the a-carbonyl radical intermediate, and as a consequence only radical reactions will be triggered. 

If a-carbonyl radicals are intermediates, what are their oxidation potentials ... 

Although the estimated oxidation potentials of the a-carbonyl radicals 90 are lower than those of the corresponding enols 86, a strong oxidant is needed to prevent radical type of reactions. According to the rates calculated on the basis of the Marcus theory [188], one-electron oxidation of the radicals can only compete with other radical processes when the electron transfer step is strongly exergonic. Thus, for radicals 90a and 90b the one-electron oxidant TTA" is too weak an oxidant, as reflected by both the yields of the a-Umpolung (Table 14) and the slow electron transfer rates (Table 13). 

Table 13. Estimated oxidation potentials of a-carbonyl radicals 90a-d and calculated electron transfer oxidation rates with TTA + ( , 2 = 0.76 V), TBPA + ( ,2 = 1-06 V) and FcPHEN ( 2 = 1.09 V) [171]...

In the following section, the chemistry of other enol type of radical cations will be analyzed with respect to the a-Umpolung reaction. Thus, emphasis was given to reactions of masked enol radical cations that provide a-carbonyl radical and/or a-carbonyl cation intermediates. 

In summary, the literature survey provides clear evidence for a-carbonyl radical intermediates but no convincing proof for further oxidation to a-carbonyl cation in the vast majority of silyl enol ether radical cation reactions. This suggests that for most cases, silyl enol ethers are more readily oxidized than the corresponding a-carbonyl radicals. Only in oxidations of -aryl substituted silyl enol ethers, a-carbonyl cation intermediates have been invoked. For example, one-electron oxidation of 87d with TTA" " in acetonitrile/MeOH afforded 76 in analogy to the a-Umpolung of ketones via enol radical cations (Scheme 4), and oxidation of 124 with FePHEN provided benzofuran 19 [171]. 

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