Cascade radical reactions radicals addition

Bennasar M-L, Roca T, Griera R, Bosch J (2001) New cascade 2-indolylacyl radical addition-cyclization reactions. J Org Chem 66 7547-7551... 

Extensive data exists on the physiochemical, biological and pharmacokinetic release properties of chitosan [30,32], making it an ideal system for the assessment and performance of the three fundamental free radical transformations radical addition reactions, atom transfer reactions and radical cascade reactions (Figure 11.5) [34,33]. These reactions are our main focus of investigation since they represent the three major transformations commonly associated with cell death and damage in a disease as a result of free radical generation in-vivo [18]. Our studies illustrate that the chitosan model is a successful experimental setup as a molecular prototype carrier system, suitable for evaluation of the fundamental aspects of a delivery system under laboratory conditions [35,33]. 

The radical chemistry of organotins is overwhelmed by the tin hydride chemistry. In the past decades, the knowledge of kinetic parameters authorized the expeditious construction of complex molecules by using cascade radical reaction based on BujSn" methodology. Moreover, these strategies also offered an excellent dia-stereocontrol, especially for the construction of polycyclic skeletons. These synthetic applications of BujSnH, which will not be covered in this chapter, were reviewed in recent years [279]. In addition to the tin hydride chemistry, there are several applications of organotins in radical syntheses involving mainly allylstan-... 

Radical-based carbonylation procedures can be advantageously mediated by (TMSlsSiH. Examples of three-component coupling reactions are given in Reactions (74) and (75). The cascade proceeds by the addition of an alkyl or vinyl radical onto carbon monoxide with formation of an acyl radical intermediate, which can further react with electron-deficient olefins to lead to the polyfunctionalized compounds. ... 

Chiral l,3-dioxin-4-ones photochemically react intermolecular with (cyclic) ethers, acetals, and secondary alcohols to give the addition products in reasonable yields. The radical addition was completely stereoselective at C-6 of the heterocycle <1999EJO1057>. The exocyclic diastereoselectivity, where relevant, was about 2 1 (Equation 30). In analogy, an intramolecular cascade reaction of a 1,3-dioxin -one derived from menthone was used to get a terpenoid or a steroid framework in optically active form <1997JA1129, 1999JA4894>. 

Radical reaction cascades can be initiated by (TMS)3Si radical addition to unsaturated bonds. Two recent examples are illustrated in equations 54 and 55. The reaction of (TMS)3SiH with the 1,6-enyne derivative 98 afforded the 6-membered cyclic compound having exclusively the exocyclic double bond in E configuration via a 6-exo mode106. On the other hand, hydrosilylation of 99 afforded the 6-membered ring via a 6-endo cyclization of the vinyl radical onto the C=N bond107. 

Cyclopenta-fused pyridines 48 have been synthesized through a cascade initiated by intermolecular addition of C radicals to the C = N triple bond in vinylisonitriles. The reaction in Scheme 2.8 shows addition of the nucleophilic alkynyl radical 49 to the carbon end of the isonitrile group in 46 to give vinyl radical 50, which undergoes a... 

However, oxidations based on addition of O-centered radicals to unsaturated compounds appear to be a highly desirable synthetic goal, especially when the new C—O bond could be formed under the mild conditions that are typical for radical reactions. If this radical addition would involve C = C triple bonds, the resulting reactive vinyl radical would be highly suitable for the promotion of intramolecular cascade reactions. 

Since the computational studies support the general perception of good or poor leaving groups in self-terminating radical reactions, but clearly contradict the experimental findings, radical cyclization cascades initiated by N-centered radical addition to alkynes are not terminated by homolytic p-fragmentation. 

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. 

However, their intermolecular addition reactions with alkynes are mostly aimed at synthesizing substituted aLkenes, ° and only very few cascade reactions that are initiated by P radical addition to C = C triple bonds have been reported. Renaud and coworkers developed a simple one-pot procedure for the cyclization of terminal alkynes mediated by dialkyl phosphites (Scheme 2.35). In this radical chain procedure, dialkyl phosphite radicals, (R0)2P =0, undergo addition to the C = C triple bond in 190, which triggers a radical translocation (l,5-HAT)/5-eAO cyclization cascade. The sequence is terminated by hydrogen transfer from dialkyl phosphite to the intermediate 194 and regeneration of P-centered radicals. 

Following the pioneer work of Kharasch [60], methods involving radical transfer of halides have been developed. The atom transfer method has emerged in the 1980s as one of the best method for conducting intra- and intermolecular radical additions to olefins [61]. This approach is particularly appealing from an atom economy point of view since all atoms remains in the final product. The non-reductive nature of these reactions is also particularly important for the preparation of functionalized molecules. Halides transfers and more particularly iodine atom transfers have found nice applications for cyclizations, annula-tions and cascade reactions [62]. These reactions are based on exothermic radical steps, such as the addition of an alkyl radical to an olefin, followed by an... 

Naito described the use of indium metal to initiate a radical addition/cyclization cascade in aqueous media. Stirring a mixture of isopropyl iodide, 453, and indium powder in water at 20 °C for 2h produced lactam 454 in 63% yield as a 3 l-mixture of trans- and (Tv-isomers (02OL3835). The reaction of sulfonamide 455 under similar conditions led to the isolation of sultam 456 as a 1 1.5-mixture of isomers in 81% yield. 

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