Heterocycles radical cyclization

Ihara, M., Setsu, F., Shohda, M., Taniguchi, N. and Fumumoto, K. (1994) A Total Synthesis of ( )-Tacamonine (Pseudovincamone I) Through Radical Cyclization, Heterocycles 37, 289-292. 

Free-radical cyclization in the synthesis of N-heterocycles 97T17543. 

Radical cyclization to triple bonds is used as the key step for the synthesis of oxygen heterocycles. This methodology can benefit from a Lewis acid, such as aluminum fns(2,6-diphenyl phenoxide) (ATPH), which forms a complex with the... 

The N,0- and N,S-heterocyclic fused ring products 47 were also synthesized under radical chain conditions (Reaction 53). Ketene acetals 46 readily underwent stereocontrolled aryl radical cyclizations on treatment with (TMSlsSiH under standard conditions to afford the central six-membered rings.The tertiary N,0- and N,S-radicals formed on aryl radical reaction at the ketene-N,X(X = O, S)-acetal double bond appear to have reasonable stability. The stereoselectivity in hydrogen abstractions by these intermediate radicals from (TMSlsSiH was investigated and found to provide higher selectivities than BusSnH. 

Bowman and coworkers described another nice approach in this field combining one anionic and two radical cyclization steps (Scheme 2.160) [368], Thus, they were able to construct differenttypes of nitrogen-containing heterocycles such as annulated pyrrolidines 2-724 and spiropyrrolidines 2-726 as well as indolizidines as 2-729. 

The silicon containing (5 5 5) heterocycle 32 has been efficiently synthesized starting from. Y-prolinc 375 via silanes 376, 378, and 379. The final step has been achieved via radical cyclization. The amine 377 was treated with COCl2 and the resulting carbamoyl chloride 378 reacted with PhSeNa to give the radical precursor 379 (84% overall yield from 376). Compound 379 when refluxed with Ph3SnH or Bu3SnH in the presence of AIBN afforded the desired heterocycle 32 in 75% yield (Scheme 81). 

The construction of the central ring can also be accomplished by a radical cyclization of a non-fused heterobiaryl system composed of two six-membered heterocycles and linked by a two-atom bridge. An example is the synthesis of 106 from the bromo derivative 105 in the presence of AIBN and Bu3SnH (Equation 8) <1999TL4073>. 

The synthesis of oxygen heterocycles in which cyclization onto a pendant alkyne is a key step has also been achieved. Reaction (7.36) shows an example of iodoacetal 29 cyclization at low temperature that afforded the expected furanic derivative in moderate Z selectivity [47]. A nice example of Lewis acid complexation which assists the radical cyclization is given by aluminium tris(2,6-diphenyl phenoxide) (ATPH) [48]. The (3-iodoether 30 can be com-plexed by 2 equiv of ATPH, which has a very important template effect, facilitating the subsequent radical intramolecular addition and orienting the (TMS)3SiH approach from one face. The result is the formation of cyclization products with Z selectivity and in quantitative yield (Reaction 7.37). 

The photolysis of donor-acceptor systems provides unique synthetic opportunities. Direct irradiation of the donor-acceptor systems, such as systems containing arene and amine components, leads to intramolecular electron transfer, that is, to amine cation-radical and arene anion-radical moieties. After generation, these moieties undergo cyclization reactions providing efficient synthetic routes to fV-heterocycles with a variety of ring sizes. Thus, direct irradiation of secondary amino-ethyl and aminopropyl stilbenes leads to benzazepines in improved yields (Hintz et al. 1996). As known, benzazepines are used in medicine as antidepressants. Scheme 7.44 illustrates ion-radical cyclization with the formation of benzazepine derivative (65% yield). 

Radical cyclization of polyfunctional 5-hexenyl halides mediated by Et2Zn and catalyzed by nickel or palladium salts has been demonstrated to produce stereoselectively polyfunctional 5-membered carbo- and heterocycles [56, 57]. Based on this strategy a formal synthesis of methylenolactocin (11) was achieved (Scheme 20). The acetal 130, readily being built up by asymmetric alkylation of aldehyde 127 followed by reaction with butyl vinyl ether and NBS, served as the key intermediate for the construction of the lactone ring. Nickel(II)-catalyzed carbometallation was initiated with diethylzinc to yield exclusively the frans-disubstituted lactol 132, which could be oxidized directly by air to 134. Final oxidation under more forcing conditions then yielded the lactone (-)-75 as a known intermediate in the synthesis of (-)-methylenolactocin (11) [47aj. 

Free-radical cyclizations using ethyl radicals generated by EtsB/air system or stannyl radicals systems provide a range of carbocyclic and heterocyclic hydroxylamines (equation 77). Stereoselectivity in these reactions is variable but can be semiquaUtatively predicted by Beckwith-Houk models . Depending on the substitution pattern of the emerging cyclic system, stereoselectivity can be very high, especially in fused polycyclic systems (equation... 

It was reported that Pd(0)-catalyzed coupling reactions of allenic alcohols, amines and acids with hypervalent iodonium salts afforded cyclized heterocyclic tetrahydrofurans, tetrahydropyrans, pyrrolidines, piperidines, or lactones under mild conditions <99SL324>. Intramolecular 1,5-hydrogen atom transfer radical cyclization reaction of pyrrolidine derivatives was examined. Reaction of 3,4-dialiyloxy-JV-(0-bromobenzyl)pyrtolidine gave hexahydro-... 

As with the other procedures for the preparation of six-membered heterocyclic systems which proceed via formation of only one ring bond there are relatively few methods which involve formation of a ring bond y to the heteroatom and which can best be classified as [6 + 0] processes rather than [4 + 2], [3 + 3], etc, processes. Of those which can be so represented, however, a number are important processes which are widely used for the synthesis of saturated, partially saturated and aromatic six-membered heterocyclic systems and their benzo derivatives. Mechanistically, the nucleophile —> electrophile approach is by far the most common, but in contrast to the reactions discussed in the previous three sections, radical cyclizations are of considerable utility here. 

These palladium- or nickel-catalyzed reactions are radical reactions leading to an organometallic product. By using a precursor such as 37 as a 1 1 mixture of diastereoisomers, the palladium-catalyzed cyclization provides in a stereoconvergent way the cyclopentylmethylzinc derivative 38 which, after allylation, produces the unsaturated ester 39 in 71% yield". The intermediate radical cyclizes via a transition state A where all the substituents are in an equatorial position. Interestingly, the analogous reaction using Ni(acac)2 as a catalyst allows the preparation of heterocyclic compounds such as 40. The... 

Scheme 22 presents some selected aryl radical cyclizations. The first example shows that isomerization of the intermediate radicals is again a concern. This isomerization, which is usually called the neo-phyl rearrangement,101 is promoted by the activating aldehyde group in the case at hand.102-103 The other examples illustrate that aryl radical cyclizations provide practical routes to benzo-fused heterocycles.104-105... 

Volume 58 consists of six chapters. John L. Esker and Martin Newcomb of Wayne State University describe radical cyclization routes to pyrrolidines, illustrating some of the significant recent advances which have arisen from the application of radical chemistry to heterocycles. 

Intramolecular addition of vinyl radicals to olefins as a method for heterocycle synthesis has been examined. The vinyl radicals can be conveniently generated from vinyl bromides and samarium(II) diiodide [95JOC7424], The intermediate radical after cyclization undergoes a further electron transfer from samarium to furnish a carbanion which is quenched at the end of the reaction. A samarium(II) diiodide mediated aryl radical cyclization onto a dihydrofuran has been reported [95T8555],... 

Beckwith and Storey have developed a tandem translocation and homolytic aromatic substitution sequence en route to spiro-oxindoles [95CC977]. Treatment of the bromoaniline derivative 122 with tin hydride at 160 °C generated the aryl radical 123 which underwent a 1,5-hydrogen atom transfer to give intermediate 124. Intramolecular homolytic aromatic substitution and aromatization gave the spiro-oxindole 125. Intramolecular aryl radical cyclization on to a pyrrole nucleus has been used to prepare spirocyclic heterocycles [95TL6743]. 

Imines have been employed as radical acceptors in the preparation of nitrogen heterocycles [95AJC291]. A highly selective 6-endo-trig radical cyclization onto a chiral aldehyde imine has been developed by Werstiuk et al. Reductive cyclization of 218 provides a 3.8 1 diastereomeric mixture of the tetrahydroisoquinoline 219. A minor amount of 220, a product arising from a 5-exo cyclization is also produced. 

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