Intramolecular Radical Reactions

GAUDUEL - Femtosecond laser pulses allow to monitor molecular dynamics of polar liquids and to provide new developments in the field of chemical or biochemical reaction dynamics initial events occurring in photosynthesis, ultrafast free radical reactions, intramolecular and intraionic dynamic proces-... 

Dimethyl iodo(4-pentenyl)malonate (926) undergoes a Pd-catalyzed intramolecular radical-type reaction to form the alkyl iodides 927 and 928. rather than a Heck-type reaction product(775]. The same products are also obtained by a radical reaction promoted by tin hydride(776]. Although yield was low, a similar cyclization of the n-chloro ester 929 to form the seven-membered ring 930 was ob,served(777(. 

The use of free-radical reactions for this mode of ring formation has received rather more attention. The preparation of benzo[Z)]thiophenes by pyrolysis of styryl sulfoxides or styryl sulfides undoubtedly proceeds via formation of styrylthiyl radicals and their subsequent intramolecular substitution (Scheme 18a) (75CC704). An analogous example involving an amino radical is provided by the conversion of iV-chloro-iV-methylphenylethylamine to iV-methylindoline on treatment with iron(II) sulfate in concentrated sulfuric acid (Scheme 18b)(66TL2531). 

In the case of carbon tetrachloride, the radical intermediate undergoes two competing reactions intramolecular hydrogen abstraction is competitive with abstraction of a chlorine atom from carbon tetrachloride ... 

Interniolecular hydrogen abstraction, 239 Intramolecular free radical reactions, 238 Intramolecular hydrogen abstraction, 239 Iodine azide, 24... 

The majority of sequential radical reactions deal with cyclizations as the key steps. The constructions of carbocycles, oxygen, and nitrogen heterocycles using (TMSlsSiH as a mediator are many and represents the expansion and importance of these synthetic approaches. For example, Nicolaou and coworkers found that (TMSlsSiH serves as a superior reagent in the radical-based approach toward the synthesis of azadirachtin, an antifeedant agent currently used as an insecticide, and in other related systems. ° ° Here below we collected a number of reactions mostly from the recent work in the area of intramolecular reactions. 

By the radical pathway l, -diesters, -diketones, -dienes or -dihalides, chiral intermediates for synthesis, pheromones and unusual hydrocarbons or fatty acids are accessible in one to few steps. The addition of the intermediate radicals to double bonds affords additive dimers, whereby four units can be coupled in one step. By way of intramolecular addition unsaturated carboxyhc acids can be converted into five raembered hetero- or carbocyclic compounds. These radical reactions are attractive for synthesis because they can tolerate polar functional groups without protection. 

Scheme 3.1. General scheme for an intramolecular domino radical reaction.

Scheme 3.83. First domino radical cyclization/intramolecular Diels-Alder reaction process.

The same group recently disclosed a related free radical process, namely an efficient one-pot sequence comprising a homolytic aromatic substitution followed by an ionic Homer-Wadsworth-Emmons olefination, for the production of a small library of a,/3-unsaturated oxindoles (Scheme 6.164) [311]. Suitable TEMPO-derived alkoxy-amine precursors were exposed to microwave irradiation in N,N-dimethylformam-ide for 2 min to generate an oxindole intermediate via a radical reaction pathway (intramolecular homolytic aromatic substitution). After the addition of potassium tert-butoxide base (1.2 equivalents) and a suitable aromatic aldehyde (10-20 equivalents), the mixture was further exposed to microwave irradiation at 180 °C for 6 min to provide the a,jS-unsaturated oxindoles in moderate to high overall yields. A number of related oxindoles were also prepared via the same one-pot radical/ionic pathway (Scheme 6.164). 

Dihydroperoxides were found to be the primary products of branched alkanes oxidation. The intramolecular peroxyl radical reaction was proposed F. F. Rust [55]... 

The IPM parameters for hydrogen transfer atom in alkoxyl radicals are presented in Table 6.12. Isomerization proceeds via the formation of a six-membered activated complex, and the activation energy for the thermally neutral isomerization of alkoxyl radicals is equal to 53.4 kJ mol-1. These parameters were used for the calculation of the activation energies for isomerization of several alkoxyl radicals via Eqns. (6.7, 6.8, 6.12) (see Table 6.14). The activation energies for the bimolecular reaction of hydrogen atom (H-atom) abstraction by the alkoxyl radical and intramolecular isomerization are virtually the same. 

The reactivity of allyl radicals does, however, appear to be sufficient for intramolecular radical reactions. In a systematic study, Stork and Reynolds investigated the feasibility of allyl radical 5-exo cyclizations41. It was found that cyclization proceeds readily for a variety of systems, especially for those with geminal 3,3-diester substitution. Mixtures of c/s/fraws-cyclopentanes are formed as the major products, while 6-enclo cyclization is hardly observed42. Allyl radicals behave in this respect much like alkyl radicals43. Cyclization is not even hindered by the presence of substituents at the attacked carbon... 

Reviewing now the last four sections, it is obvious that the major problem in radical chain reactions involving dienes or polyenes is the low reactivity of the diene (or polyene) adduct radicals. This allows for the occurrence of allyl radicals in intramolecular reactions but poses a major problem in intermolecular radical chain reactions. The obvious solution to this problem is to use methods in which radicals are produced stoichiometrically and not... 

Addition of halocarbons to alkenes in the presence of transition metals is a well-known radical reaction. Weinreb etal. have now reported an intramolecular version leading to cyclic esters or bicyclic lactones. Typical substrates are the a,a-dichloro ester 1 or the a,a-dichloro acid 2, readily available by reaction of ethyl lithiodi-chloroacetate with 5-bromo-l-pentene. When 1 is heated in benzene at 160° with a metal catalyst, mixtures of epimeric ot,w-dichloro esters 3 and 4 are obtained. The ratio and yields of 3 and 4 are dependent on the catalyst and concentration of 1, but 3 and 4 are the major products formed in the presence of Ru(II) and Fe(II) catalysts. In contrast cyclization of 2 under the same conditions gives the bicyclic y-lactone 5 in high yield. 

Ion-radical reactions also open convenient routes to fused benzoheterocycles as a result of intramolecular cyclization. The fused heterocycles are useful as compounds of potential physiological activity. Many of them are used as medications. Certainly, only those syntheses that do not change the functional groups needed to provide or enforce the curative effect, are of interest. At the same time, it is desirable to exclude acidic agents that lead to the splitting of the final heterocycles, which... 

The intramolecular version of the described radical reaction provides an easy approach to the synthesis of six-membered carbocycles. ... 

The success of such reactions depends on the intramolecular hydrogen transfer being faster than hydrogen-atom abstraction from the stannane reagent. In the example show, this is favored by the thermodynamic driving force of radical stabilization, by the intramolecular nature of the hydrogen transfer, and by the steric effects of the central quaternary carbon. This substitution pattern often favors intramolecular reactions as a result of conformational effects. Scheme 10.12 gives some other examples of tandem radical reactions. 

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