Alkylation of heteroaromatic bases

Photochemical decomposition of (diacyloxyiodo)arenes provides a method for decarboxylative alkylation of heteroaromatic bases such as lepidine [Eq. (80)] [141,142]. 

Further modification of this procedure allows the use of alcohols as the source of alkyl radicals. In this case, alcohols are first converted into the oxalic acid monoalkyl esters 6, which are used as reagents in the radical alkylation of heteroaromatic bases (Scheme 3) [12,14]. 

Alkyl iodides have been widely used for selective alkylation of heteroaromatic bases. The method is based on rapid iodine abstraction by aryl radicals (obtained from benzoyl peroxide or diazonium salts) or by a methyl radical (obtained from MeCOOH, t-BuOH, t-BuOOH, (t-BuO)2, (MeCOO)2, MeS0Me/H202, or MeC0Me/H202) [2]. An example is depicted in Eq. (14) of Table 3. 

Radical decarboxylative alkylation of heteroaromatic bases mediated by [bis(acyloxy)iodo]arenes... 

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. 

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 ... 

Radical alkylation of heteroaromatic bases. Carboxylic acids undergo decarboxylation to generate free radicals, which can be captured by heterocycles. Thus 2-(l-adamantyl)-4-cyanopyridine is obtained in 88% yield from 1-adamantylcar-boxylic acid and 4-cyanopyridine. 

F. Minisci, R. Bernard , F. Bertini, R. GalH, M. Perchinummo, Nucleophilic character of alkyl radicals. VI. New convenient selective alkylation of heteroaromatic bases. Tetrahedron 27 (1971) 3575-3580. 

Togo, H., Aoki, M., and Yokoyama, M., Facile radical decarboxylative alkylation of heteroaromatic bases using carboxylic acids and trivalent iodine compounds, Tetrahedron Lett., 32, 6559, 1991. Togo, H., Aoki, M., and Yokoyama, M., Alkylation of aromatic heterocycles with oxalic acid monoalkyl esters in the presence of trivalent iodine compounds, Chem. Lett., 1691,1991. Vismara, E., Torri, G., Pastori, N., and Marchiandi, M., A new approach to the stereoselective synthesis of C-nucleosides via homolytic heteroaromatic substitution. Tetrahedron Lett., 33, 7575, 1992. 

O3yhydroperoxides. Peroxides of the oxyhydro type are obtained by the addition of hydrogen peroxide to ketones. High yields of alkyl radicals are then often obtained by reaction with ferrous salts. 1-Meth-oxycyclohexyl hydroperoxide is easily obtained from cyclohexanone and hydrogen peroxide in methanol. It gives rise to the 5-(methoxy-carbonyl)-pentyl radical, which has been used to alkylate protonated heteroaromatic bases in high yield [Eq. (6)]. 

Oxidation of tertiary alcohols by lead tetraacetate gives alkyl radicals by /3-scission of the initially formed alkoxy radicals. The reaction has been used to alkylate protonated heteroaromatic bases using 1-methyl-cyclohexanol. (Scheme 4). 

Buratti, W., Gardini, G. P., Minisci, F., Bertini, F., Galli, R., Perchinunno, M. Nucleophilic character of alkyl radicals. V. Selective homolytic a-oxyalkylation of heteroaromatic bases. Tetrahedron 1971, 27, 3655-3668. 

Alkylation and Acylation by Free-radical Reactions. Heteroaromatic bases, being electron-deficient compounds, readily react with nucleophilic reagents, particularly when protonation enhances their electron-deficient nature. Because of the nucleophilic character of the wide range of available alkyl radicals, homolytic alkylation of heteroaromatics is of interest comparable to that of electrophilic alkylation in the homocyclic series. Homolytic acylation is of no less importance because of the wide applicability of this general reaction in the heterocyclic field. 

Alkylation and arylation. The homolytic a-oxyalkylation of heteroaromatic bases using alcohols and ethers as radical sources has been studied. Although detailed experiments were chiefly concerned with quinoline and quinoxaline, benzothiazole was shown to yield 2-dioxanylbenzothiazole (40%) under the standard conditions. ... 

Tlie interest in the preparation and use of dithiolium salts in connection with the synthesis of TTF derivatives led to the development of a new uses of heteroaromatic cations in organic synthesis. Based on that, a new carbonyl olefination for the synthesis of numerous heterofulvalenes was developed (77S861). For example, 2-dimethoxyphosphinyl-l,3-benzodithiole was deprotonated with butyllithium in THF at -78°C and the resulting phosphonate carbanion reacted with 9-alkyl-acridones to give the dithia-azafulvalenes of type 45 (78BCJ2674) (Scheme 15). 

Alkylation of potentially tautomeric heteroaromatic systems under basic phase-transfer catalytic conditions normally occurs on the softer heteroatom [cf 57]. Thus, although 2- and 4-pyridones are alkylated on the annular nitrogen atom and the exocyclic oxygen atom, -alkylation of the 2-pyridones predominates to the extent of ca. 5 1 (or greater under soliddiquid reaction conditions [58]), whereas the relative predominance of A -alkylation of the 4-isomer is only ca. 3 1 [59] (Table 5.37 and 5.38). These ratios are comparable with those obtained for the base-catalysed alkylation of the pyridones by traditional methods and, not unexpectedly, S-alkyla-tion of the corresponding pyridthiones occurs to the total exclusion of A-alkylation [60]. Catalysed soliddiquid acylation has also been reported [58]. 

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. 

The oxidative decarboxylation of carboxylic acids is the most convenient source for the alkylation of protonated heteroaromatic bases owing to their easy availability and the high versatility of the reaction, which permits methyl, primary, secondary, and tertiary alkyl radicals to be obtained under very simple experimental conditions. The following methods have been utilized. 

A quite different reaction course was observed with benzoyl peroxide. The increase in the decomposition rate on going from nonprotonated to protonated quinoline is relatively small. The high decomposition rate of decanoyl peroxide in the presence of protonated heteroaromatic bases was mainly ascribed to the nucleophilic character of the alkyl radicals, which allows the complete capture of the nonyl radicals escaping from the solvent cage and the consequently rapid induced decomposition. The... 

The alkylation with alcohols and amines can lead to alkyl derivatives or a-hydroxy and a-aminoalkyl derivatives according to the nature of the heteroaromatic base and the reaction conditions. The intermediate products in both cases are, however, the a-hydroxy and a-aminoalkyl dihydro derivatives, which can be aromatized by disproportionation or oxidation, while the loss of water or ammonia leads to the alkyl derivatives (Scheme 7). 

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. 

The homolytic acylation of protonated heteroaromatic bases is, as with alkylation, characterized by high selectivity. Only the positions a and y to the heterocyclic nitrogen are attacked. Attack in the position or in the benzene ring of polynuclear heteroaromatics has never been observed, even after careful GLC analysis of the reaction products. Quinoline is attacked only in positions 2 and 4 the ratio 4-acyl- to 2-acylquinoline was 1.3 with the acetyl radical from acetaldehyde, 1.7 with the acetyl radical from pyruvic acid, and 2.8 with the benzoyl radical from benzaldehyde. 

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. 

The a-oxyalkyl radicals used for alkylating heteroaromatic bases are formed by the oxidation of alcohols and ethers with a variety of electrophilic radicals or photochemically. 

If the mechanism in acid and without acid are the same, one might have expected 4-alkylation under both conditions, and the failure to observe any 4-alkylation when acid is not present is as yet unexplained. Possibly with nonprotonated bases the hydroxyalkylation occurs according to Scheme 11, in which dimerization of two radicals within the solvent cage would lead to attack only at position 2, while in acid the attack could take place, at least in part, according to Scheme 12 but with protonated base, leading to both the isomers (2 and 4), as in the hydroxyalkylation by oxidation of alcohols. The much higher affinity of alkyl radicals toward protonated heteroaromatic bases in comparison with nonprotonated bases would support this interpretation. 

The ethyl radical directly attacks the heteroaromatic base, while the acetaldehyde acts as a source of acetyl radical. Photochemical oxy-alkylation has also been tried with ethers. The reaction has been successfully carried out with pyridines, quinolines, isoquinolines,cinno-lines, and quinoxalines. Particularly good yields were obtained with caffeine (16) (Scheme 14). ... 

The usual sources used for the homolytic aromatic arylation have been utilized also in the heterocyclic series. They are essentially azo- and diazocompounds, aroyl peroxides, and sometimes pyrolysis and photolysis of a variety of aryl derivatives. Most of these radical sources have been described in the previous review concerning this subject, and in other reviews concerning the general aspects of homolytic aromatic arylation. A new source of aryl radicals is the silver-catalyzed decarboxylation of carboxylic acids by peroxydisulfate, which allows to work in aqueous solution of protonated heteroaromatic bases, as for the alkyl radicals. 

The first class of amine-based nucleophilic catalysts to give acceptable levels of selectivity in the KR of aryl alkyl. yec-alcohols was a series of planar chiral pyrrole derivatives 13 and 14, initially disclosed by Fu in 1996 [25, 26]. Fu and co-workers had set out to develop a class of robust and tuneable catalysts that could be used for the acylative KR of various classes of. yec-alcohols. Planar-chiral azaferrocenes 13 and 14 seemed to meet their criteria. These catalysts feature of a reasonably nucleophilic nitrogen and constitute 18-electron metal complexes which are highly stable [54-58]. Moreover, by modifying the substitution pattern on the heteroaromatic ring, the steric demand and hence potentially the selectivity of these catalysts could be modulated. 

In a series of important papers, MacMillan described the alkylation of electron rich aromatic and heteroaromatic nucleophiles with a,P-unsaturated aldehydes, using catalysts based upon the imidazoUdinone scaffold, further establishing the concept and utility of iminium ion activation. In line with the cycloaddition processes described above, the sense of asymmetric induction of these reactions can be rationalised through selective (F)-iminium ion formation between the catalyst and the a,P-unsaturated aldehyde substrate, with the benzyl arm of the catalyst blocking one diastereoface of the reactive Jt-system towards nucleophilic attack (Fig. 3). 

---