Alkyl radicals heterocyclic formation

This reaction resembles decarboxylation of carboxylates during electrode one-electron oxidation (Kolbe reaction). Kolbe reaction also consists of one-electron oxidation, decarboxylation, and culminates in dimerization of alkyl radicals just after their formation at the electrode surface. When the sulfate radical acts as a one-electron oxidant, the caboradical dimerization is hampered. The radicals can be used in preparative procedures. One typical example is alkylation of heterocyclic nitrogen bases (Minisci et al. 1983). This difference between Kolbe reaction and the reaction with the help of a dissolved electrode (the sulfate radical) deserves some explanation. The concentration of the one-electron oxidation products in the electrode vicinity is significantly higher than that in the bulk of the solution. Therefore, in the case of anode-impelled reactions, the dimerization of radicals produced from carboxylates proceeds easily. Noticeably, 864 secures the single electron nature of oxidation more strictly than an anode. In electrode reactions, radical intermediates can... 

Small radicals such as tert-butylperoxy and ethylperoxy can, however, react via 1,4 H-transfer only the strain energy involved in O-heterocycle formation is 28 kcal. per mole. In this case, k.4(x — 106 sec."1 whereas krta = 10r> 4 sec. 1 and when [02] = 200 mm. of Hg, ko[02] = 105,3 sec. 1, so that k.4ct < < (tkr,a + k [02]). The result is that in the oxidation of small alkyl radicals, the route via alkylperoxy radicals will be blocked because reverse Reaction —4 competes successfully with Reaction 5. Reaction 2 will thus be a more effective mode of reaction of alkyl radicals with oxygen and the conjugate alkene will be a major product. 

In contrast to classical Meerwein arylations, non-activated alkenes are well suited for this reaction type for two reasons. First, due to the relatively slow formation of azo compounds by addition of aryl radical 49 to 48, this undesired pathway cannot compete successfully with the attack of 49 on the alkene to give radical adduct 50. Second, a nucleophilic alkyl radical 50 arises from the addition step, which is effectively trapped by electrophilic salt 48 to give azo compound 51. As a result of several improvements, the methodology is now applicable for a wide range of polar to non-polar alkenes with almost no restrictions on the substitution pattern of the diazonium salt [101, 102]. Moderate diastereoselectivities have been obtained in first attempts with chiral auxiliaries [103]. The azo compounds accessible, such as 51, can be converted to carboamination products 52 by hydrogenation and to various other heterocycles. 

F. Minisci and co-workers generated alkyl radicals from alkyl iodides under simple conditions (thermal decomposition of dibenzoyl peroxide) and used it for selective C-C bond formation on protonated heterocycles. The method was successfully applied to complex substrates, such as 6-iodo-1,2,3,4-diisopropylidene-a-galactose, which was reacted with protonated 2-methylquinoline to give the corresponding C-nucleoside in excellent yield. 

The importance of alkylperoxy radicals as intermediates had long been realized (see Sect. 2) and their subsequent reaction to yield the alkyl-hydroperoxide or decomposition products such as aldehydes and alcohols had been reasonably successful in describing the mechanism of the autocatalytic oxidation of alkanes. However, even though 0-heterocycles (which cannot be derived from intermediate aldehydes) had been found in the products of the oxidation of n-pentane as early as 1935 [66], the true extent of alkylperoxy radical isomerization reactions has been recognized only recently. Bailey and Norrish [67] first formulated the production of O-heterocycles in terms of alkylperoxy radical isomerization and subsequent cyclization in order to explain the formation of 2,5-dimethyl-tetrahydrofuran during the cool-flame oxidation of n-hexane. Their mechanism was a one-step process which involved direct elimination of OH. However, it is now generally formulated as shown in reactions (147) and(I67)... 

Kim developed a new entry into A -heterocycles by radical cyclizations onto alkyl azides. Iodides, bromides and thionocarbonates (Scheme 28, Eq. 28.1) are suitable radical precursors. 5-Exo cyclizations afford 3,3-triazenyl radicals that lose N2 to furnish an aminyl radical [79]. Following this work, Kilburn has applied this strategy to the formation of spiro-heterocycles from methylenecyclopropanes [80]. Finally, this reaction was applied as a key step in a very elegant cascade synthesis of aspi-dospermidine developed by Murphy (Scheme 28, Eq. 28.2) [81]. 

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