Acyclic radical cyclization

Radical cyclization of acyclic sulfinamides 239 provides easy access to cyclic sulfinamides 241 <06AG(E)633>. Conceivably, the reaction pathway involves thiophilic attack by the aryl radical with a concomitant or successive expulsion of the p-tolyl or tert-butyl radical. 

Whitlock et al.14 discovered a reductive cyclization of enediynes promoted by lithium naphthalenide that provides substituted fulvenes and suggested a dianionic mechanism (Scheme 6). However, even now it is still unclear whether the enediyne dianion is indeed the cyclizing species or whether the initially formed acyclic radical-anion cyclizes first to give a fulvene radical-anion which is further reduced by lithium to give the cyclic dianion. 

J. Marco-Contelles, C. Pozuelo, M. L. Jimeno, L. Martinez, and A. M. Grau, 6-exo Free radical cyclization of acyclic carbohydrate intermediates A new synthetic route to enantiomerically pure polyhydroxylated cyclohexane derivatives, J. Org. Chem. 57 2625 (1992). 

In less reactive 6-fluorohex-1-ene (19), the nonactivated sp3 C-F bond reacts with sodium naphthalenide in tetrahydrofuran to give a complex mixture of acyclic and cyclic nonfluorinated products.28 The intermediate hex-5-enyl radical cyclizes to the methylcyclopentyl radical, and both are reduced further with the naphthalenide to the corresponding anions before forming the products.29 30... 

Marcus treatment does not exclude a radical pathway in lithium dialkyl-amide reduction of benzophenone. It does, however, seem to be excluded (Newcomb and Burchill 1984a,b) by observations on the reductions of benzophenone by N-lithio-N-butyl-5-methyl-l-hex-4-enamine in THF containing HMPA. Benzophenone is reduced to diphenylmethanol in good yield, and the amine yields a mixture of the acyclic imines no cyclic amines, expected from radical cyclization of a putative aminyl radical, were detected. An alternative scheme (17) shown for the lithium diethylamide reduction, accounts for rapid formation of diphenylmethoxide, and for formation of benzophenone ketyl under these conditions. Its key features are retention of the fast hydride transfer, presumably via the six-centre cyclic array, for the formation of diphenylmethoxide (Kowaski et al., 1978) and the slow deprotonation of lithium benzhydrolate to a dianion which disproportion-ates rapidly with benzophenone yielding the ketyl. The mechanism demands that rates for ketyl formation are twice that for deprotonation of the lithium diphenylmethoxide, and, within experimental uncertainty, this is the case. 

In the event, Mitsunobu-type displacement of the unprotected hydroxyl of 24 delivered the iodinated sugar 25, which was then elaborated into acyclic iodohexenitol 26 via ring opening using activated zinc in refluxing ethanol, followed by reduction, tosylation and iodination. The pivotal radical cyclization/oxygenation of 26 was finally carried out in the presence of a catalytic amount of cobalt(salen) complex in air. This... 

Carretero and co-workers reported that the a-sulfonyl radicals resulting from such radical additions to y-oxygenated-a,P-unsaturated sulfones are useful intermediates for the generation of a second carbon-carbon bond via intramolecular addition to a suitably located carbon-carbon double bond.46,47 The highly functionalized acyclic y-hydroxy vinyl sulfone 68 underwent a novel cascade process, based on two sequential radical cyclizations, affording the bicyclic compounds 69 and 70 in good yield (Scheme 18). 

Acyclic tu-yne sulfides 443 react with tributyltin hydride in the presence of AIBN to produce 4,5-dihydrothiophenes 444 through free-radical cyclization (Scheme 72) <1997JOC8630>. 

A diastereoselective formal addition of a 7ra i-2-(phenylthio)vmyl moiety to a-hydroxyhydrazones through a radical pathway is shown in Scheme 2.29. To overcome the lack of a viable intermolecular vinyl radical addition to C=N double bonds, not to mention a reaction proceeding with stereocontrol, this procedure employs a temporary silicon tether, which is used to hold the alkyne unit in place so that the vinyl radical addition could proceed intramolecularly. Thus, intermolecular addition of PhS" to the alkyne moiety in the chiral alkyne 161 leads to vinyl radical 163, which cyclizes in a 5-exo fashion, according to the Beckwith-Houk predictions, to give aminyl radical 164 with an a 7z-arrangement between the ether and the amino group. Radical reduction and removal of the silicon tether without prior isolation of the end product of the radical cyclization cascade, 165, yields the a-amino alcohol 162. This strategy, which could also be applied to the diastereoselective synthesis of polyhydroxylated amines (not shown), can be considered as synthetic equivalent of an acetaldehyde Mannich reaction with acyclic stereocontrol. 

A major focus of our research program has been the development of synthetically useful radical-mediated methodologies in recent years. Our interest in this area was partly initiated by asking how to generate five- and six-membered ring radicals from acyclic radical precursors. This problem has been unsolved in radical chemistry due to a disfavored 5-endo cyclization in pentenyl radical cyclizations. This simple but intriguing curiosity led us to study radical reactions of yV-aziridinylimines. The outcome of this research is the development of a novel consecutive carbon-carbon bond formation approach, which has tremendous synthetic potential. This review provides a full account of radical cyclizations of V-aziridinylimines and their applications to sesquiterpene natural products. 

SCHEME 7.84 Formation of C-glycosides via radical cyclizations of acyclic precursors. 

Haney, B.P., and Curran, D.P., Round trip radical reactions from acyclic precursors to tricy-clo[5.3.1.0 - ]undecanes. A new cascade radical cyclization approach to ( )-isogymnomitrene and ( )-gymnomitrene, J. Org. Chem., 65, 2007, 2000. 

Marco-Contelles, J. et al. 6-Exo Free Radical Cyclization of Acyclic Carbohydrate Intermediates A New Synthetic Route to Enantiomerically Pure Polyhydroxylated Cyclohexane Derivatives. 3.1 1992 [144]... 

Annulated ring systems have as /1,7-substituents, when compared to annulated cyclopentyl radical systems, a stronger effect on the stereoselectivity than the corresponding combination of acyclic substituents. In all cases, attack tram to the /J.y-m-annulated ring is preferred. The stereoselectivity depends, furthermore, on additional substituents at the radical and the alkene, but it appears that the reactions of cyclohexyl radicals proceed less selectively than their cyclopentyl analogs. One frequently used route to these systems is sequential cyclization/ addi-tion reactions, in which the primary radical cyclizes to form the bicyclic ring system, followed by intermolecular addition to an alkene45,47 74. 

The mechanism takes a different course with more acidic compounds such as )5-keto ester 7a (p/fa = 10). Mn(IlI) enolate 8a forms rapidly and reversibly. The rate-determining step is cyclization of the double bond to the Mn(lll) enolate of 8a with loss of Mn(ll) to give cyclohexanealkyl radical 11a, without the intermediacy of acyclic radical 9a, which is oxidized by Cu(OAc)2 to generate 71% of 12a. Similar mechanisms are operable with very acidic 1,3-diketones Mn(acac)j is stable and isolable. 

---