Alkylation homolytic

The synthetic success of the homolytic alkylation of heteroaromatic bases, as well as that of other free-radical substitutions, is mainly determined by the following factors  

The radical source S gives rise to an electrophilic radical X-, which adds to the olefin, but does not attack the protonated base. The newly-formed alkyl radical 

In the absence of protonated base, the radical 72 is oxidized to carbonium ion. The attack to the heteroaromatic base successfully competes with the electron-transfer oxidation. 

These examples emphasize the very high versatility of the homolytic alkylation as far as the free-radical sources are concerned, and the possibility of obtaining complex substitutions in a simple way. 

Thus the use of oxidative decarboxylation of carboxylic acids by peroxydisul-phate as source of alkyl radicals is often effective enough in determining good delds of rearomatization of the radical adduct (74) the presence of small amounts of Fe + or Cu +, however, determines in all cases a very clean substitution reaction. 

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It is estimated that thiophene reacts with phenyl radicals approximately three times as fast as benzene. Intramolecular radical attack on furan and thiophene rings occurs when oxime derivatives of type (112) are treated with persulfate (8UCS(Pt)984). It has been found that intramolecular homolytic alkylation occurs with equal facility at the 2- and 3-positions of the thiophene nucleus whereas intermolecular homolytic substitution occurs mainly at position 2. 

Note The C-alkylation of quinoxaline has been done by addition (with or without subsequent aromatization see also preceding subsection), by reductive alkylation, or by homolytic alkylation. 

Quinoxaline also underwent many other homolytic alkylations or arylations usually to give, for example, mixtures of 2-alkyl-, 6-alkyl-, and sometimes 2,3- or 2,6-dialkyl derivatives, according to the agent and conditions used. Percentage conversions, ratios of products, separability, and yields appear to... 

Homolytic alkylation of homocyclic aromatic substrates is of much less interest than homolytic arylation because, in addition to the low selectivity, which also characterizes arylation, yields are usually poor, due to side reactions which compete seriously with the simple substitution reaction. The behavior of nonprotonated heteroaromatic substrates is similar. The case is quite different with protonated heteroaromatic bases because side reactions are eliminated or minimized, yields are generally good, and, above all, the selectivity is very high. Moreover, very versatile and easily available sources of alkyl radicals can be used under simple experimental condition it follows that homolytic alkylation of protonated heteroaromatic bases can be considered one of the main reactions of this class of compounds. 

A wide variety of peroxides have been used to produce alkyl radicals, either directly as fragments of the decomposition of peroxides, or indirectly by hydrogen abstraction from suitable solvents. The production of alkyl radicals used in homolytic alkylation has been accomplished by thermal or photochemical homolysis and recently also by redox reactions due to the possibilities offered by alkylation in acidic aqueous solution. 

Photochemical and y-Ray-Induced Processes Recently numerous homolytic alkylations of heteroaromatics have been carried out by photochemical and y-ray-induced processes. The photochemical process involves hydrogen abstraction from various hydrogen donors (RH) by the excited state of the heteroaromatic (A) (Scheme 6). 

Homolytic Alkylation of Heterocyclic Compounds in Acidic Medium... 

The homolytic alkylation of protonated heteroaromatic bases is characterized by a very high selectivity (Table II). 

The fact that such selectivity was not found with homolytic alkylation of nonprotonated heteroaromatics (Table I) or with homocyclic aromatics indicates that polar factors play a major role in the reactivity of alkyl radicals with protonated bases. These effects were determined by the study of the relative reaction rates in the alkylation of 4-substituted pyridines in acidic medium. The results obtained with methyl, n-propyl, w-butyl, sec-butyl, i-butyl, and benzyl radicals are summarized in Table III. 

This high sensitivity to polar effects of the homolytic alkylation of protonated heteroaromatic bases has been interpreted in terms of the transition state.This would be similar to a w-complex in which an enhanced contribution of polar forms (5) would explain the high sensitivity to polar influence. 

Also, the results of the substituent effects in homolytic acylation of protonated heteroaromatic bases must be connected, as for homolytic alkylation, with the polar characteristics of the acyl radicals and the aromatic substrates, but not with the stabilization of the intermediate a-complexes. 

Minisci-type substitution is one of the most useful reactions for the synthesis of alkyl- and acyl-substituted heteroaromatics. The acyl radicals are formed by the redox decomposition from aldehyde and /-butyl hydroperoxide or by silver-catalyzed decarboxylation of a a-keto acid with persulfate. Synthesis of acylpyrazines 70 as ant pheromones are achieved by this methodology using trialkyl-substituted pyrazines 69 with the acyl radicals generated from aldehydes or a-keto acids (Equation 10) <1996J(P1)2345>. The latter radicals are highly effective for the acylation. Homolytic alkylation of 6-chloro-2-cyanopyrazine 71 is performed by silver-catalyzed decarboxylation of alkanoic acids to provide 5-alkyl-substituted pyrazines 72 (Scheme 18) <1996CCC1109>. 

Benzylquinoxaline (62) is the only product isolated from the homolytic benzylation of quinoxaline with dibenzyl mercury.73 Gardini and Minisci found that homolytic alkylation,74 acylation,75 cr-oxy-alkylation,76 carboxylation,77 and <5-aminoalkylation78 of quinoxaline always gave the 2-substituted product. When a mixture of quinoxaline and ferrous sulfate is treated with A-chlorodi-n-butylamine, exclusive 2-substitution occurs in 50% sulfuric acid, but in concentrated acid a... 

These and other homolytic alkylations of neutral heteroaromatics usually proceed in poor yields, but if protonated heteroaromatic bases are used, many of the side reactions are minimized and selectivity is high and yields are good. Selectivity is increased because the alkyl radicals are nucleophilic in character and thus selectively attack the a-position. 

Preparation of Homologues by Homolytic Alkylation of Acetic Acid and Related Compounds. J. chem. Soc. 1965, 1918. 

Part B Reactions with [bis(acyloxy)iodo]arenes. Oxidations. Homolytic Alkylation and Arylation. 

Enamines have so far been shown to undergo two types of radical reactions as shown by equations 1 and 2. The addition of a carbon-centered radical to the C=C bond of enamines (equation 1) leads to a nitrogen substituted radical which then either transfers an electron to a suitable electron acceptor to form an iminium ion or abstracts a hydrogen atom (reductive homolytic alkylation). 

Russell and Wang27 carried out detailed studies on the homolytic alkylation of various enamines by electrophilic radicals generated from / -nitrobenzyl chloride and 2,2-dinitropropane. A free radical chain mechanism similar to that shown in Scheme 1 was... 

Free Radical Processes. Homolytic alkylation and arylation of pyridines has been studied extensively and reviewed (U ). The products are almost invariably mixtures of several Isomers depending on the nature of the pyridine substrate, the free radical (audits method of generation) and the type of medium in which the reaction is carried out. Tho gh early reports suggested 2-, and -substitution exclusively, more sensitive analytical techniques have shown the earlier claims to be erroneous 6ind studies into the various factors affecting product formation have been reported (1 6-62). 

Although a number of such radical reactions are known, few promise much synthetic potential, Examples include the 2-phenylation of imidazole and benzimidazole by benzoyl peroxide, but both products are more readily obtained by other routes. Homolytic alkylations of imidazole and benzimidazole also occur at C-2, but usually give indifferent yields [10]. A potentially useful reaction is the synthesis of 2- and 4-trifluoromethylimidazoles from imidazoles and photochemically generated trifluoromethyl radicals. 1-Substituted imidazoles are largely substituted at C-5 in these reactions benzimidazole reacts initially at the 4-position [11-14]. 

Fontana, F., Minisci, F., Barbosa, M. C. N., Vismara, E. New general processes of homolytic alkylation of heteroaromatic bases by tert-butyl peroxide or di-tert-butyl peroxide and alkyl iodides. Acta Chem. Scand. 1989,43, 995-999. 

Bertini, F., Caronna, T., Galli, R., Minisci, F., Porta, O. New processes for the homolytic alkylation of protonated heteroaromatic bases. Chim. Ind. (Milan) 1972, 54,425-426. 

Minisci, F., Kintzinger, J. P., Porta, O., Barilli, P., Gardini, G. P. Nucleophilic character of alkyl radicals. VIII. Kinetics and mechanism of induced decomposition of decanoyl peroxide in the homolytic alkylation of protonated quinoline. Tetrahedron 1972, 28, 2415-2427. 

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