Enol ethers, radical reactions

Novel bridged spirolactones have been synthesized via tandem radical cycli-zations of enol ether radical. In Reaction (7.85) the first 5-exo spirocyclization is followed by a 6-endo cyclization to give the bridged derivative as a single diastereoisomer [96]. 

Reactions of Silyl Enol Ether Radical Cations. 213... 

In a kinetic study, it was demonstrated that enol ether radical cations react very sluggishly with nucleophiles like acetonitrile (k = 7M s (37 ), k<0.1s (38 )) or methanol (k<700M s (37" ) k< 300M s (38) )). If we accept the plausible assumption that enol ether radical cations are good models for enol radical cations in their reaction with nucleophiles, the short lifetime of the enol radical cations can only be rationalized by assuming a fast deprotonation step. 

Oxidative coupling of silyl enol ethers as a useful synthetic method for carbon-carbon bond formation has been known for a long time. Several oxidants have been successfully applied to synthesize 1,4-diketones from silyl enol ethers, e.g. AgjO [201], Cu(OTf)2 [202], Pb(OAc)4 [203] and iodosobenzene/BFj EtjO [204]. Although some of these reagents above are known to react as one-electron oxidants, the potential involvement of silyl enol ether radical cations in the above reactions has not been studied. Some recent papers, however, have now established the presence of silyl enol ether radical cations in similar C-C bond formation reactions under well-defined one-electron oxidative conditions. For example, C-C bond formation was reported in the photoinduced electron transfer reaction of 2,3-dichIoro-1,4-naphthoquinone (98) with various silyl enol ethers 99 [205], From similar reactions with methoxy alkenes [206,207] it was assumed that, after photoexcitation, an ion radical pair is formed. 

Although several intermediates are possible in the cyclization reaction, strong evidence was presented for the mechanistic proposal, that cyclization takes place at the stage of the silyl enol ether radical cation. 

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]. 

Enol ether radical cations undergo a variety of reactions, e.g. carbon-carbon bond formation [206,230-235], isomerization [236,237], oxygenation [238-241], cycloaddition [242-245], and they play an important role in the damage to DNA by ionizing radiation [246,247]. According to ESR studies most of the spin density resides at the -carbon (89% for EtO" = CH-CH2 [248]) [234,249,250]. The focus of the present brief section, however, will be conremed with their role as potential intermediates in a formal a-Umpolung reaction of ketones. 

The reaction of enol ether radical cations with hydroxide is six orders of magnitude faster than with water [249], but products have not been identified. In contrast, reaction of 37 and 38 with acetonitrile or methanol is very slow. In a comparative study, it was demonstrated that enol ether reacted much slower than enol ester radical cations with fluoride [227] affording ot-fluoroke-tones only in poor yield. Hitherto, reports in the literature give no evidence for the loss of an alkyl group from enol ether radical cations which would allow to enter ot-carbonyl radical and ot-carbonyl cation chemistry. 

A further use of Barton esters has been described as a path to enol ether radicals. The reaction involves the photochemical decomposition at 355 nm of the derivative (85). As part of an approach to the synthesis of a series of Kopsia alkaloids, the reductive decarboxylation of the derivative (86) was carried out. This involved irradiation of the Barton ester (86a) in the presence of t-BuSH. This affords the product (86b). The photochemical decomposition of the Barton ester (87) provides a path to the silyl derivatives (88). The nature of the trapping agent X is dependent on the conditions under which the reaction is carried out. Thus a variety of derivatives can be obtained using alcohols to afford ethers, or using ethanesulfonyl azide to give azides. The Barton esters (89) undergo the usual photochemical decarboxylation to afford ethenoyloxy radicals. Cyclization within these, in the presence of tributylstannane yields the lactones (90). ... 

Moeller synthesized tetrahydrofuran natural products (+)-linalool oxide <01OL2685> and (+)-nemorensic acid <01TL7163> by employing intramolecular coupling reactions of enol ether radical cations as well as ketene dithioacetal radical cations with oxygen nucleophiles. 

Stannyl enol ethers have an adequate reactivity toward aldehydes to give aldol adducts without any additive or catalyst (Scheme 3-194). In order to enhance the reactivity and selectivity of stannyl enol ethers, a variety of catalysts like Lewis acids, Lewis bases, and radical initiators is applied to this reaction. In contrast to silyl enol ethers, the reaction proceeds through acyclic or cyclic transition states, depending on the reaction conditions. 

The two reaction channels described represent the most important steps following the generation of the initial radical cation and can be directly incorporated into synthetic applications involving silyl enol ether radical cations. Deprotonation of the radical cation is a way to conduct a ketone-enone transformation via the silyl enol ether. Other synthetic applications utilizing the radical cation or the a-carbonyl radical are coupling reactions of silyl enol ethers, intramolecular addition to double bonds, or introduction of substituents other than carbon at the a-carbonyl position, respectively. Examples for these synthetic transformations will be presented in the following sections. 

Kochi and co-workers presented a synthesis of a-nitroketones involving silyl enol ether radical cations as key intermediates. Remarkably, the reaction of silyl enol ethers with tetranitromethane yielded a-nitroketones under both thermal and photochemical conditions. 

The same authors also observed an interesting difference in the behavior of the a- and (3-tetralone silyl enol ethers 3 and 4, providing a further indication for the presence of radical ions as reactive intermediates in this reaction. The a-tetralone silyl enol ether radical cation 36 reacted with nitrogen dioxide to form cation 37, whereas the (3-tetralone based radical cation 38 reacted much more slowly and gave a mixture of products (Scheme 8). Due to the mesomeric stabilization of the radical cation 38, its lifetime increased dramatically as observed by time resolved spectroscopy. This favors a cage escape of the radical cation and opens the possibility for further reactions. 

Ramsden et al. have obtained similar results for tetralone silyl enol ether radical cations. They investigated the reaction of various silyl enol ethers with xenon difluoride in acetonitrile and found a new method for the selective preparation of a-fluoroketones (Scheme 9). 

Coupling reactions of silyl enol ether radical cations with double bonds other than silyl enol ethers have been investigated as well. Reactions with butadiene, ethyl vinyl ether, and allylic silanes have been reported. 

The hydrogenolyaia of cyclopropane rings (C—C bond cleavage) has been described on p, 105. In syntheses of complex molecules reductive cleavage of alcohols, epoxides, and enol ethers of 5-keto esters are the most important examples, and some selectivity rules will be given. Primary alcohols are converted into tosylates much faster than secondary alcohols. The tosylate group is substituted by hydrogen upon treatment with LiAlH (W. Zorbach, 1961). Epoxides are also easily opened by LiAlH. The hydride ion attacks the less hindered carbon atom of the epoxide (H.B. Henhest, 1956). The reduction of sterically hindered enol ethers of 9-keto esters with lithium in ammonia leads to the a,/S-unsaturated ester and subsequently to the saturated ester in reasonable yields (R.M. Coates, 1970). Tributyltin hydride reduces halides to hydrocarbons stereoselectively in a free-radical chain reaction (L.W. Menapace, 1964) and reacts only slowly with C 0 and C—C double bonds (W.T. Brady, 1970 H.G. Kuivila, 1968). 

An efficient two-step annelation of functionalized orthoesters with trimethyl-silyloxyfuran derivatives has been reported that produces bicyclo[3. .0]lactones. ° The reaction in Scheme 7 shows an example in which the initial condensation between silyl enol ether and orthoester is followed by the radical cyclization reaction under standard conditions. It is worth underlining the complete diastereocontrol in which three contiguous stereocenters are generated in one step with >95% stereoselectivity. 

The efficiency of this injection system depends upon the reaction conditions. 02) which traps the first formed radical 6, reduces the yield of enol ether 8. Therefore, we are using our assay under anaerobic conditions. Also, the pH of the solution influences the product ratio because it changes the nucleophilicity of the water. Figure 1 shows how the efficiency of the electron transfer is reduced as the pH value increases from 5.0 to 7.0 [5]. This is in accord with an increase of the nucleophilicity of water, which traps the radical cation (7—>9+10) in competition to the electron transfer step (7—>8). 

This reaction is extended to the intramolecular ring closure of the intermediate radical 224 with olefinic or trimethylsilylacetylenic side chains [121]. Cu(BF4)2 is also effective as an oxidant (Scheme 89) [122]. Conjugate addition of Grignard reagents to 2-eyclopenten-l-one followed by cyclopropanation of the resulting silyl enol ethers gives the substituted cyclopropyl silyl ethers, which are oxidized to 4-substituted-2-cyclohexen-l-ones according to the above-mentioned method [123]. (Scheme 88 and 89)... 

Only a few examples exist for the intermolecular trapping of allyl radicals with alkenes68,69. The reaction of a-carbonyl allyl radical 28 with silyl enol ether 29 occurs exclusively at the less substituted allylic terminus to form, after oxidation with ceric ammonium nitrate (CAN) and desilylation of the adduct radical, product 30 (equation 14). Formation of terminal addition products with /ram-con figuration has been observed for reaction of 28 with other enol ethers as well. 

Anodic oxidation reactions have been utilized to reverse the polarity of enol ethers and to initiate radical cation cyclizations. As shown below, the ketene acetal 97 is oxidized on a... 

In addition to the tert-butyl enol ethers mentioned above (15% yield), the action of KOtBu on l-iodo-4-methylcyclohexene in DM SO furnished the dimers 85 and tri-mers of 81 in 30 and -25% yield (Scheme 6.24). As in the case of 6 (see Scheme 6.10), the formation of oligomers of 81 was completely suppressed on performance of this reaction in the presence of (tBu)2NO, whereas theenol ethers (86 and its 5-methyl isomer, with the former originating in part and the latter totally from 4-methylcydohex-yne) were observed as in the reaction in the absence of the stable radical. Instead of the dimers 85 and the trimers of 81, a mixture of the hydroxylamine derivatives 87 was isolated in 38% yield. These findings indicate that 81 has no diradical character, in contrast to its immediate dimer 84, which is hence trapped quantitatively by (tBu)2NO [61]. 

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