Cyclization of alkyl radicals

In addition to the radical ipso-substitution of indolyl sulfones producing stannanes described earlier <96T11329>, Caddick has also reported an approach to fused [l,2-a]indoles based on the intramolecular cyclization of alkyl radicals. Thus, treatment of 112 with BuaSnH leads to the fused ring derivatives 113 (n = 1-4) <96JCS(P1)675>. 

From a synthetic point of view, the regioselectivity and stereoselectivity of the cyclization are of paramount importance. As discussed in Section 11.2.3.3 of Part A, the order of preference for cyclization of alkyl radicals is 5-exo > 6-endo 6-exo > 7-endo S-endo > 1-exo because of stereoelectronic preferences. For relatively rigid cyclic structures, proximity and alignment factors determined by the specific geometry of the ring system are of major importance. Theoretical analysis of radical addition indicates that the major interaction of the attacking radical is with the alkene LUMO.321 The preferred direction of attack is not perpendicular to the it system, but rather at an angle of about 110°. 

Even though radical intermediates are involved in many reductive metallations, cyclizations of alkyl radicals by reductive trapping methods are relatively uncommon. When protonated products are formed, the overall transformations are similar to a tin hydride reductions however, reductive methods may facilitate purification of the cyclic product because tin by-products are absent Two examples of simple reductive cyclizations are shown in Scheme 35. The first example illustrates that Sheffold s procedure, which uses catalytic quantities of vitamin B12 with a chemical or electrochemical coreductant, is attrac-... 

The rate constants for die 5-exo and 6-exo cyclization of alkyl radicals on to imines37 and oxime ethers38 have been reported, as have the cyclizations of alkyl radicals on to azides29 and hydrazones.36... 

Cyclization of alkyl radicals derived from acryl enamides gives piperidin-2-ones (Equation (10)).51 Radical carbonyla-tions have become a promising tool for the introduction of carbon monoxide into organic molecules. Macrocyclic compounds are prepared by intramolecular cyclization via radical carbonylation (Equation (1l)).53... 

Cyclizations of alkyl radicals onto electrophilic alkenes give tetrahydrofurans in high yields as well. This strategy has been employed in the synthesis of r-wZ-nocardione A 51 (Scheme 68) <2004JOC3282>. 

Figure I. Radical cyclizations of alkyl radicals to alkenes.

Kinetic studies provide valuable information for the understanding and the application of radical reactions. The kinetics for the cyclization of alkyl radicals onto C=C and C=0 bonds has been investigated extensively. Kinetic measurements involving C=N bonds have, however, received much less attention. We carried out kinetic studies on the intramolecular addition of alkyl radicals onto yV-azirid-inylimines. In order to determine the rate constant for 6-exo cyclization of alkyl radicals to yV-aziridinylimines (Scheme 7), we prepared compound 53 by standard procedures. The product ratio (54/55) is related to the concentration of BUjSnH as shown in Eq. 13. 

Kinetic data for the 5-exo cyclization of alkyl radical additions to the yV-aziridinylimino groups were obtained by competitive 5-exo cyclization to the A-aziridinylimino group versus an alkenyl group (Eq. 15). Reaction of compound 59 with BujSnH in benzene at 20 °C at 350 nm yielded only 61. Apparently, the primary alkyl radical... 

Reactions of 2,4-pentanedione or ethyl acetoacetate with ethene in the presence of manganese(III) acetate and copper(II) acetate in an autoclave under 50 atm at 60 °C give a mixture of 443 and 444 (equation 150). This reaction involves an oxidative 1,3-cyclization of alkyl radicals . 

Some examples of more elaborate radical cyclizations accompanied by I-transfer are illustrated in Scheme 3. The cyclization of alkyl radicals onto propargyl esters has been demonstrated in synthesis of a-methylene butyrolactones [17]. This procedure uses thermolysis in the presence of benzoyl peroxide in order to induce initiation, and appears to progress in the absence of a distannane reagent. Attempts to carry out the cyclization under tin hydride conditions led to uncyclized, reduced substrate. A series of more complex radical cyclizations involving both I-transfer and unimolecular H-transfer have recently been reported. In these reactions, the radical initially formed by I-abstraction underwent 5>-exo cyclization to generate a vinyl radical. This radical, in turn, abstracted H from silicon in an intramolecular... 

The electron-transfer formulation in equation (23) was further substantiated by Ashby et al.49 by using cyclizable probes for the detection of alkyl radicals from the mesolytic scission of RMgX+ (Scheme 10). 

Fhe electrochemical generation of alkyl radicals catalysed by square planar nickel complexes has been used to achieve radical-alkene addition reactions. Complex 64 was the catalyst of choice. Intramolecular cyclizations to give five raem-... 

Among the oxidants that have been used to generate radicals, manganese (HI) acetate has emerged as a powerful reagent to mediate radical cyclizations.147 The manganese(III) acetate-mediated oxidation of enolizable carbonyl compounds is one of the best methods available for the cyclization of electrophilic radicals. The substrates are vety easily prepared by standard alkylation and acylation reactions. Radicals are formed with high selectivity by oxidation of acidic C—H bonds, and, because the reaction is an oxi-... 

Table 5 Cobalt(I)-catalyzed radical 5-exo cyclizations of alkyl halides...

In mechanistic matters, it has been demonstrated that co-alkenyl iodides undergo cyclization onto the vinyl function upon treatment with Me2CuLi, in competition with direct substitution. This, as well as the generation of trityl radical in the reaction of Me2CuLi with trityl chloride, constitutes evidence for single electron transfer in reactions of cuprates with iodides (and, to a lesser extent, bromides)16. The intermediacy of alkyl radicals in the substitution process (equation 12) is likely the source of the aforementioned racemization in reactions of secondary iodides4. 

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