Cyclization radical homolytic additions

Under appropriate circumstances, free-radical methods can also be used to prepare macrocyclic systems. For example, Maillard and coworkers prepared the 12-membered macrocyclic ether (102) by Bu3SnH-mediated intramolecular homolytic addition to a remote, but activated (a, / unsaturated) olefin as depicted in equation 77460. Tozer and coworkers employed 7-, 8- and 9-endo cyclization in their preparations of conformationally constrained amino acids (103), an example of which is provided in equation 78448. 

Homolytic additions. Xanthates in which the 5-bearing carbon site can support a free radical readily undergo homolysis by heating with t-Bu202. The two radical fragments can be taken up by an unsaturated compound. Group transfer to a remote double bond concurrent with cyclization of certain unsaturated xanthates is an intramolecular version. An oxocane precursor of lauthisan can be acquired (35%) in this manner. ... 

Redox and homolytic substitution reactions almost never directly form C—C, C—N and C—O bonds. Such bonds are generated in radical addition reactions (Scheme 14). Intermolecular addition reactions are presented in this chapter. Cyclization reactions have important similarities with, and differences from, bimolecular additions, and they are presented in Chapter 4.2 of this volume. Falling under the umbrella of addition reactions are radical eliminations (the reverse of addition) and radical migrations (which are usually, but not always, comprised of an addition and an elimination). 

Co-cyclization of 1,6-diene (113) with a thiyl radical can be carried out involving the addition of thiyl radical to an olefinic group, cyclization via 5-exo-trig manner with a chair-like transition state, and termination by homolytic substitution at the sulfur (SHi). Preparation of cis-fused thiabicyclo[3.3.0]octane (114) is shown in eq. 4.39. 

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. 

This presents an interesting analytical quandary. Epoxides are major products of lipid oxidation and derive from LO cyclization as well as LOO additions (see Section 3.2.2). Consequently, it may be difficult to determine the mechanism that is operative in a given reaction system, and indeed, both may contribute. For example, Hendry (283) reacted a series of ROO with their parent compounds at 60°C and found 40% of the products were epoxides. Rate constants of k = 20 to 1130 M sec were calculated assuming the reactions were aU additions, but at the elevated temperature of the study, hydrogen abstraction to form the hydroperoxides, followed by homolytic scission to alkoxyl radicals, could also have contributed to the yields. 

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