Heterocyclic compounds, radical reactions

Formation of six-member N-heterocycles in radical reactions of Hoffmann-Foffler-Freytag type with participation of iodine(III) compounds 97YGK90. 

The reactions to be discussed may be represented by Eq. (1), where heterocyclic-H is an aromatic heterocyclic compound and R- is a free radical. The reaction is a substitution in that R replaces H, but... 

In many cases, however, the ortho isomer is the predominant product, and it is the meta para ratio which is close to the statistical value, in reactions both on benzenoid compounds and on pyri-dine. " There has been no satisfactory explanation of this feature of the reaction. One theory, which lacks verification, is that the radical first forms a complex with the aromatic compound at the position of greatest electron density that this is invariably cither the substituent or the position ortho to the substituent, depending on whether the substituent is electron-attracting or -releasing and that when the preliminary complex collapses to the tr-complex, the new bond is most likely to be formed at the ortho position.For heterocyclic compounds such as pyridine it is possible that the phenyl radical complexes with the nitrogen atom and that a simple electronic reorganization forms the tj-complex at the 2-position. 

The reaction of benzyl radicals wdth several heterocyclic compounds W as more extensively studied by Waters and Watson, " - who generated benzyl radicals by decomposing di-tert-butyl peroxide in boiling toluene. The products of the reaction with acridine, 5-phenyl-acridine, 1 2- and 3 4-benzacridine, and phenazine were studied. Acridine gives a mixture of 9-benzylacridine (17%) (28) and 5,10-dibenzylacridan (18%) (29) but ho biacridan, w hereas anthracene gives a mixture of 9,10-dibenzyl-9,10-dihydroanthracene and 9,9 -dibenzyl-9,9, 10,10 -tetrahydrobianthryl. This indicates that initial addition must occur at the meso-carbon and not at the nitrogen atom. (Similar conclusions were reached on the basis of methylations discussed in Section III,C.) That this is the position of attack is further supported by the fact that the reaction of benzyl radicals with 5-... 

On the basis of the reaction of alkyl radicals with a number of polycyclic aromatics, Szwarc and Binks calculated the relative selectivities of several radicals methyl, 1 (by definition) ethyl, 1.0 n-propyl, 1.0 trichloromethyl, 1.8. The relative reactivities of the three alkyl radicals toward aromatics therefore appears to be the same. On the other hand, quinoline (the only heterocyclic compound so far examined in reactions with alkyl radicals other than methyl) shows a steady increase in its reactivity toward methyl, ethyl, and n-propyl radicals. This would suggest that the nucleophilic character of the alkyl radicals increases in the order Me < Et < n-Pr, and that the selectivity of the radical as defined by Szwarc is not necessarily a measure of its polar character. 

Heterocyclic compounds have in most cases been hydroxylated by modified forms of Fenton s reagent. For instance, EDTA or pyrophosphate have been added to the system to complex the ferrous ions. It has been shown in the reactions of bcnzenoid compounds, however, that addition of complexing agents does not affect the distribution of isomers obtained by Fenton s reagent,and therefore the hydroxyl radical must still be the hydroxylating species. 

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... 

Of more synthetic interest, at least as regards phenylation, is the reaction of heteroaromatic radicals with benzene. In this case, if the radical source is easily available, it is possible to work with a very large excess of benzene and to obtain complete conversion of the heterocyclic compound into only one phenylated isomer. The method has successfully been used with thienyP and thiazolyl radicals. 

Electrophilic radicals, such as halogen atoms, hydroxy, alkoxy, and amino radicals, do not seem to have great value in reactions with heterocyclic compounds. 

This awareness in a short time led to new homolytic aromatic substitutions, characterized by high selectivity and versatility. Further developments along these lines can be expected, especially as regards reactions of nucleophilic radicals with protonated heteroaromatic bases, owing to the intrinsic interest of these reactions and to the fact that classical direct ionic substitution (electrophilic and nucleophilic) has several limitations in this class of compound and does not always offer alternative synthetic solutions. Homolytic substitution in heterocyclic compounds can no longer be considered the Cinderella of substitution reactions. 

These palladium- or nickel-catalyzed reactions are radical reactions leading to an organometallic product. By using a precursor such as 37 as a 1 1 mixture of diastereoisomers, the palladium-catalyzed cyclization provides in a stereoconvergent way the cyclopentylmethylzinc derivative 38 which, after allylation, produces the unsaturated ester 39 in 71% yield". The intermediate radical cyclizes via a transition state A where all the substituents are in an equatorial position. Interestingly, the analogous reaction using Ni(acac)2 as a catalyst allows the preparation of heterocyclic compounds such as 40. The... 

A classical type of dimerization of heterocyclic compounds is the formation of a twin molecule consisting of the same fragments. Such a reaction is known for 2-benzopyrylium salts. Thus, the reduction of the 2-benzopyry-lium salt 261 by zinc dust leads to the intermediate radical 262, which is dimerized in situ to the bisisochromene 263 (76KGS999) (cf. Section IV, B). 

Traditionally, this radical addition reaction has been used for the preparation of new poly halo organic compounds by reaction of simple polyhalo alkanes with alkenes689 698. The products from these reactions have often been used as key intermediates for the synthesis of heterocyclic compounds690. In some cases it has been found that metal complexes significantly speed up reactions and/or increase yields. 

The formation of five- and six-membered heterocycles by radical cyclization is discussed in a comprehensive review <2004H(63)1903>. Representative examples of ring syntheses involving carbenoid (Table 6) or nitrenoid (Table 7) intermediates are given. In many cases, the free carbene or nitrene is probably not involved, and the distinction between insertion and addition reactions given in the tables is not always clear cut. Such reactions are particularly useful for the preparation of tricyclic compounds. The application of carbenes and carbenoids in the synthesis of heterocyles is summarized in a review <1996AHC(65)93>. 

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