Bicyclic radical formation

After bicyclic radical formation, 02 rapidly adds to the radical, forming a bicyclic peroxy radical, for example... 

Radical cyclization reactions have proven to be a very efficient approach for polycyclic natural product synthesis. In many cases, the last step involves a reduction of a cyclic radical with formation of a new stereogenic center. Very good stereochemical control has been achieved with such polycyclic radicals. For example, Beckwith has reported a highly stereoselective formation of a quinolizidine ring (Scheme 19, Eq. 19.1) [41b]. This process is the key reaction in a four-step synthesis of epilupinine and the stereochemical outcome results from a stereoselective axial reduction by tin hydride of a bicyclic radical. In a related process, Tsai has prepared silylated hydroxyquinolizidine by radical cyclization to an acylsilane followed by a radical-Brook rearrangement (Scheme 19, Eq. 19.2) [42]. 

The unexpected products 18 and 19 were formed by further oxidation of the major product 14, which occurred at 60 °C, but not at room temperature. Tandem oxidative cyclization of P-Keto ester 13 with 4 equivalents of Mn(OAc)3 and 1 equivalent of Cu(OAc>2 in acetic acid at room temperature provided only 14-16. However 18 was the major product from oxidation of 13 with 4 equivalents of Mn(OAc)3 and 1 equivalent of Cu(OAc)2 at 60 °C. The intermediacy of 14 was established by oxidation of 14 with 2 equivalents of Mn(OAc)3 and 1 equivalent of Cu(OAc)2 in AcOH at 60 °C to provide 70% of a 10 1 mixture of 18 and 19. Oxidation of 14 will afford a-keto radical 17, which will be oxidized to give 19 or cyclize to give a bicyclic radical that will be oxidized by Cu(II) to give 18. The formation of 18 and 19 in the Mn(III)-mediated electrochemical oxidation of 13 thus results solely from the necessity of using a higher reaction temperature to obtain a reasonable rate of reaction at the lower Mn(III) concentration of Mn(III)-mediated electrochemical oxidative cyclization. 

Another interesting example of bicyclic system formation has been observed (Scheme 114) in the attempted acyloin condensation of the diester 284. The major product (50% yield) was 287 (cis/trans= 1.0 2.3), whose formation was believed to involve transannular interaction in the radical anion 286 formed from the dione 285. 

Since peroxyl radicals add so easily to double bonds (see Sections VIII.2.D and XI.4.B.a) 3-cyclopentenyl peroxyl radicals appeared to be attractive models for prostaglandin bicyclic endoperoxide formation, by analogy with the cycliza-tion discussed in Scheme 116. Under the conditions used, however, disproportionation was preferred to intramolecular cyclization. ... 

The first cyclization gives a mixture of cis- and from -isomers and only the cis-isomer goes on to give bicyclic products. The relatively slow rate of the second cyclization step, and the formation of rrou.s-product which does not cyclize, provides an explanation for the observation that radical polymerizations of triallyl monomers often give a crosslinked product. 

Radical cyclization is compatible with the presence of other functional groups. Treatment of XCH2CON(R)-C(R )=CH2 derivatives (X = Cl, Br, 1) with Ph3SnH and AIBN led to formation of a lactam via radical cyclization. " Cyclization of N-iodoethyl-5-vinyl-2-pyrrolidinone led to the corresponding bicyclic lactam, " and there are other examples of radical cyclization with molecules containing a lactam unit " or an amide unit. Radical cyclization occurs with enamines as well. Photochemical irradiation of A,A-dialIyl acrylamide leads to formation of a lactam ring, and in this case thiophenol was added to generate the phenylthio derivative. Phenylseleno N-allylamines lead to cyclic amines. co-Iodo acrylate esters cyclize to form lactones. " ... 

Clive and coworkers have developed a new domino radical cyclization, by making use of a silicon radical as an intermediate to prepare silicon-containing bicyclic or polycyclic compounds such as 3-271 and 3-272 (Scheme 3.69) [109], After formation of the first radical 3-267 from 3-266, a 5-exo-dig cyclization takes place followed by an intramolecular 1,5-transfer of hydrogen from silicon to carbon, providing a silicon-centered radical 3-269 via 3-268. Once formed, this has the option to undergo another cyclization to afford the radical 3-270, which can yield a stable product either by a reductive interception with the present organotin hydride species to obtain compounds of type 3-271. On the other hand, when the terminal alkyne carries a trimethylstannyl group, expulsion of a trimethylstannyl radical takes place to afford vinyl silanes such as 3-272. 

As in the case of linear peroxidation products, the initiation step of the formation of isoprostanes is the abstraction of a hydrogen atom from unsaturated acids by a radical of initiator. Initiation is followed by the addition of oxygen to allylic radicals and the cyclization of peroxyl radicals into bicyclic endoperoxide radicals, which form hydroperoxides reacting with hydrogen donors. 

The formation of the bridged product 191 was investigated using the cyclopentadiene system as a model. Thus, the salt of the tosylhydrazone 198 was prepared and thermolyzed in order to examine three possible variants of rearrangements (equation 62)75. Analysis of the reaction products 200-202 and their transformations [e.g. the pyrolysis of bicyclic triene 202 to cA-8,9-dihydroindene 203 (equation 63) rather than to product 200 or 201] allows one to conclude that the mechanism involves a transformation of carbene 188 into diradical 204 which can be the precursor of all the products observed (equation 64)75. An analogous conversion takes place via radical 205 in the case of carbene 199 (equation 65). 

Transient digermene 86 was postulated as possible intermediate in the reaction of 1,2-dichlorodigermacyclobutane 87 with Mg/MgBr2 in the presence of an alkene, leading to the bicyclic compound 8878 [Eq. (17)]. However, an electron transfer reaction with the intermediate formation of a germyl radical is also a possibility.78 Similarly, transient 1,2-digermacyclobu-... 

A series of bicyclo[3.3.0]octanols are accessible by electroreductive tandem cyclization of linear allyl pentenyl ketones 189, as shown by Kariv-Miller et al. [189]. The electrolyses are carried out with an Hg-pool cathode and a Pt-flag anode. As electrolyte, tetrabutylammonium tetrafluororborate is used. The reaction is stereoselective, yielding only two isomers 192 and 193. In a competing reaction, a small amount of the monocyclic alcohol is formed. Since all the monocycles have the 1-allyl and the 2-methyl group in trans geometry it is assumed that this terminates the reaction. The formation of a bicyclic product requires that the first cyclization provides the cis radical anion which leads to cis-ring juncture [190] (Scheme 37). 

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