Addition to C-N Double Bonds

Technically, the addition of carbon-centered radicals to C-N double bonds is as yet of little if any importance. In the free-radical chemistry of DNA it plays, however, a considerable role in the formation of the C(5 )-C(8) linkage between the sugar moiety and the purines (Chap. 10.5). Because of its importance, even an immune assay has been developed for the sensitive detection of this kind of damage in DNA (Chap. 13.2). The addition of the C(5 ) radical to the C(8) position of a purine is obviously facilitated for steric reasons (formation of a six-membered ring), but the same kind of reaction also occurs as an intermolecular reaction. Since alkyl radicals are nucleophilic, the rate of this reaction is noticeably increased upon protonation of the purine (Aravindakumar et al. 1994 for rate constants see Chap. 10.5). 

This addition reaction is not restricted to a-hydroxyalkyl radicals, although this type of radical has been most widely investigated. Thus, allylic radical derived from 5MeCyt (Zhang and Wang 2003) and radicals derived from amino acids (Elad and Rosenthal 1969) are also reported to undergo this reaction. In DNA, they play a role in the formation of tandem lesions (Chap. 12.5), and it is likely that this kind of reaction contributes to free-radical-induced DNA/DNA and DNA/protein cross-linking. 

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Entries 20 to 23 involve additions to C=N double bonds in oxime ethers and hydrazones. These reactions result in installation of a nitrogen substituent on the newly formed rings. Entry 20 involves the addition of the triphenylstannyl radical to the terminal alkyne followed by cyclization of the resulting vinyl radical. The product can be proto-destannylated in good yield. The ring closure generates an anti relationship for the amino substituent, which is consistent with the TS shown below. 

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. 

Although it has been proposed that this reaction is initiated by an alkoxide addition to C=N double bond followed by the loss of tosyloxy group to form a nitrene intermediate, which inserts to the of-carbon to form an alkoxy ethylenimine, more experimental evidence indicates that the Neber rearrangement involves an initial base-induced elimination of the more acidic a-proton accompanied by the loss of the tosyloxy group to give azirine... 

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