Radical-mediated ring expansion

Radical-mediated ring expansion of 2-halomethyl cycloalkanones. 

Scheme VII /19. A free radical mediated ring expansion of ds and trans a-alkylated /i-stanny-lated cyclohexanones [49] [50].

Free radical mediated ring expansions of haloalkyl p-ketoesters ... 

Dowd, P. and Zhang, W. (1993) Free-Radical-Mediated Ring Expansion and Related Annulations, Chem. Rev. 93, 2091-2115. 

Baldwin et al. used a radical-mediated ring expansion of 3-stannylcyclohexanones to provide efficient routes to cis-and trans-cyclononenones. Thus, bromo ketone 109 underwent a radical reaction to generate cyclopentyl aUcoxy radical 110. Fragmentation and elimination of a stannyl radical led to cyclononenone 111, which was further elaborated to rac-phoracantholide I (Scheme 25.52), originally isolated from the metastemal secretion of the eucalypt lon-gicom Phoracantha synonyma. 

In many instances, however, solvolysis of a halocyclopropane is deliberately accomplished in order to install an essential vinyl halide or hindered olefin. In 2000, Murphy and coworkers performed a silver ion-mediated ring expansion of gem-dibromocyclopropane 18 in wet acetone to afford the allylic alcohol 19 in 82% yield (Scheme 4.5).16 Under these conditions the desired cyclononene product was obtained as an inseparable mixture of E- and Z-isomers (7 93). Interestingly, two sets of peaks observed in the1H NMR spectrum indicated that the Z-isomer existed as two separate conformers at room temperature. This intermediate was subsequently used in Murphy s approach to the radical-based preparation of tricyclic indoles. 

The trimethylsilyl ethers 212 of four-membered 1-alkenyl-1-cyclobutanols rearrange to the ring-expanded 0-mercuriocyclopentanones 213. These can be converted into the a-methylenecyclopentanones 214 through elimination or further expanded by one-carbon atom into cyclohexanones 215 via the Bu3SnH-mediated free radical chain reactions [116]. A similar radical intermediate is suggested to be involved in the ring expansion of a-bromomethyl-fi-keto esters [117]. (Scheme 84)... 

More recently, the related indium-mediated radical reactions have been widely studied (Scheme 7.13).19 Indium iodide-mediated radical cyclisation was first reported by Cook et al.20 The indium-mediated 1,4-addition of alkyl radicals to (F)-but-2-enenitrile was investigated by using 1-ethylpiperidinum hypophosphite (EPHP) as a hydrogen donor in aqueous media (Scheme 7.13).21 Atom transfer radical cyclisation and reductive radical cyclisation were studied using indium and iodine.22 Indium mediated alkyl radical addition to dehydroamino acid derivatives was also reported.23 The indium-mediated radical ring expansion of a-halomethyl cyclic (3-keto esters, shown in Scheme 7.13, was achieved in aqueous alcohols.24... 

Ring expansion of cyclic ketones mediated by free radicals. 

The free-radical cyclization of enynes as a synthetic strategy was introduced by Stork and coworkers using BusSnH/AIBN-mediated ethynyl cyclization (equation 34) ". From a mechanistic point of view, the first step is the selective addition of the stannyl radical to the triple bond of the enyne generating a vinyl radical, which can cyclize onto the double bond. In the absence of the methyl substituents on the olefinic moiety, the groups of Beckwith and Stork have both postulated, and demonstrated with the aid of kinetic studies, that the 6-endo radical 30 arises from a ring expansion of the kinetically favored... 

The methodology of EtsB-mediated addition of RsSnH to an acetylenic bond has also been successfully applied in the cyclization of enynes . An example is given in equation 35. The use of triphenylgermanium hydride, thiophenol, diphenyl diselenide (equation 36), tris(phenylseleno)borane, Se-phenyl areneselenosulfonates (equation 37) and diphenylphoshine under free-radical conditions induces cyclization of enynes like tributyltin hydride. That is, if the chain-transfer step in Scheme 11 is much faster than the ring expansion, the methylenecyclopentane adduct should be the sole product. 

Scheme 5.9 Radical/cation-mediated domino ring expansion/cyclization.

On the other hand, ring strain reUef is triggered by reactive intermediates, and as a matter of fact, this is the alternative option. The reactive intermediates are carbocation, carbon radical and carbene, and their hetero-analogs. Once generated at the position adjacent to C-4, they mediate sequential ring expansion to a five-membered ring [23]. The similar story may be depicted by metal catalyses [73,74]. 

Pattenden, G. and Schulz, D.J. (1993) Cascade Radical Reactions in Synthesis. A New Radical Mediated Double Ring Expansion-Cyclization Process with Oxime Ethers, Tetrahedron Lett. 34, 6787-6790. 

Chatgilialoglu, C., Ferreri, C., Lucarini, M. and Zavitsas A. (submitted) Mechanistic Insights into the Free Radical Mediated One-Carbon Ring Expansion in Cyclopentanones, J. Am. Chem. Soc. 

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