Minisci radical alkylation

Minisci Radical Alkylation and Acylation 212 Ombretta Porta and Francesco Minisci... 

Cowden, C. J. Use of W-Protected Amino Acids in the Minisci Radical Alkylation. Org. Lett. 2003, 5,4497-4499. 

O. Porta, F. Minisci, Minisci, Radical alkylation and acylation, in G. Dyker (Ed.), Artificial Photosynthesis, Wiley-VCH Verlag GmbH Co. 

Even more pronounced steric effects have been observed for the free radical alkylation of protonated N-heterocyclic bases by the procedure of Minisci ... 

Vismara, E., Fontana, F., Minisci, F. Alkyl iodides as source of alkyl radicals, useful for selective syntheses. NATOASI Ser., Sen C1989, 260, 53-69. 

The radical alkylation of protonated heteroaromatic compounds-the so-called Minisci reaction-has been intensively investigated [2e, g, 111]. Protonated hetero-arenes are electron-deficient substrates, which react with nucleophilic radicals with high regioselectivity to yield the corresponding homolytic aromahc substitution products. For para-substituted pyridine derivatives the reaction occurs with complete regioselectivity at the 2-position, whereas for nonprotonated pyridines, arylations occur with low regioselectivity and in low yields. 

A completely different method of synthesis of azo compounds from diazonium salts involving radical intermediates was found by Citterio et al. (1980, 1982 c), Cit-terio and Minisci (1982), and Fontana et al. (1988). It is a new general synthesis of arylazoalkanes based on the addition of an alkyl radical to an arenediazonium ion followed by reduction of the intermediate azo radical cation adduct by a metal salt (Scheme 12-80). The preferred source for the alkyl radical R in this reaction is an alkyl iodide, which gives rise to alkyl radicals cleanly in the presence of an arenediazonium salt and a Ti3+ or Fe2+ salt as in Scheme 12-81. The overall stoichiometric equation is therefore as given in Scheme 12-82. The yields vary between 36% and 79% (with respect to alkyl iodide). 

The dependence of relative rates in radical addition reactions on the nucleophilicity of the attacking radical has also been demonstrated by Minisci and coworkers (Table 7)17. The evaluation of relative rate constants was in this case based on the product analysis in reactions, in which substituted alkyl radicals were first generated by oxidative decomposition of diacyl peroxides, then added to a mixture of two alkenes, one of them the diene. The final products were obtained by oxidation of the intermediate allyl radicals to cations which were trapped with methanol. The data for the acrylonitrile-butadiene... 

This reaction resembles decarboxylation of carboxylates during electrode one-electron oxidation (Kolbe reaction). Kolbe reaction also consists of one-electron oxidation, decarboxylation, and culminates in dimerization of alkyl radicals just after their formation at the electrode surface. When the sulfate radical acts as a one-electron oxidant, the caboradical dimerization is hampered. The radicals can be used in preparative procedures. One typical example is alkylation of heterocyclic nitrogen bases (Minisci et al. 1983). This difference between Kolbe reaction and the reaction with the help of a dissolved electrode (the sulfate radical) deserves some explanation. The concentration of the one-electron oxidation products in the electrode vicinity is significantly higher than that in the bulk of the solution. Therefore, in the case of anode-impelled reactions, the dimerization of radicals produced from carboxylates proceeds easily. Noticeably, 864 secures the single electron nature of oxidation more strictly than an anode. In electrode reactions, radical intermediates can... 

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>. 

In Reaction 1-100, the sulfate anion radical, and not the anode, acts as a one-electron oxidant. In this case, the caboradical dimerization is hampered. The radicals can be used in preparative procedures. One typical example is alkylation of heterocyclic nitrogen bases (Minisci et al. 1983). 

In particular, the alkylation and acylation of protonated heteroarenes under oxidative conditions, commonly known as Minisci reaction, has attracted increasing interest in recent decades because of its synthetic involvement in biochemistry and pharmacology [3]. Beyond the fact that this reaction can be applied to all heteroaromatic bases and almost all carbonyl and alkyl radicals (without electron-withdrawing groups directly bonded to the radical center), the main characteristics of this process are high chemoselectivity and regioselectivity, the substitution usually occurring only in a and y positions. 

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. These reactions are generally referred to as Minisci reactions. Selectivity is increased because the alkyl radicals are nucleophilic in character and thus selectively attack the - and -positions reaction with adamantyl radical illustrates this (Scheme 52) <1995ZOR670>. 

Radical nucleophile oxidation based on one-electron oxidation, known as the Minisci reaction, is employed for the functionalization of /V-heterocycles with acidic hydrogen peroxide in the presence of iron(II) salts (Figure 3.112).472 A range of A-heterocycles (pyridines, pyrazines, quinolines, etc.) which are activated towards attack by nucleophilic radicals when protonated are suited to this chemistry. The Minisci reaction is suitable for the preparation of carboxylic amides (from formamide), carboxylic esters (from pyruvic esters via a hydroxyhydroperoxide), aldehydes (from 1,3,5-trioxane) and alkylated pyridines (either from carboxylic acids or from alkyl iodides in dimethyl sulfoxide).473 The latter reaction uses dimethyl sulfoxide as the source of methyl radical (Figure 3.112). 

In hydrogen atom abstractions, alkyl radicals change, as the degree of substitution increases, from being mildly electrophilic (the methyl radical) to being mildly nucleophilic (the ferf-butyl radical). In addition reactions to pyridinium cations, the Minisci reaction, they are all relatively nucleophilic, as shown by their... 

By contrast, substitution in position 7 is much easier thanks to the well-known Minisci reaction, which involves a nucleophilic radical attack on a protonated quinoline [31]. Moreover, due to the unavailability of position 2 of the quinoline nucleus, the reaction shows complete regioselectivity. Minisci alkylation with an ethyl radical produced in situ by decarbonylation of propionaldehyde is a crucial step in the process of preparation of irinotecan (4) (Scheme 16.6) [32], whereas the same kind of reaction led to the semisynthesis (Scheme 16.7) of gimatecan (9)[33], silatecan (10)[34], and belotecan (ll)[35j. This last compound entered clinical practice in Korea in 2005. 

F. Minisci and co-workers generated alkyl radicals from alkyl iodides under simple conditions (thermal decomposition of dibenzoyl peroxide) and used it for selective C-C bond formation on protonated heterocycles. The method was successfully applied to complex substrates, such as 6-iodo-1,2,3,4-diisopropylidene-a-galactose, which was reacted with protonated 2-methylquinoline to give the corresponding C-nucleoside in excellent yield. 

Minisci, F., Gain, R., Cecere, M., Malatesta, V., Caronna, T. Nucleophilic character of alkyl radicals new syntheses by alkyl radicals generated in redox processes. Tetrahedron Lett. 1968, 5609-5612. 

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. 

Malatesta, V., Minisci, F. Steric effects in homolytic substitution of benzene by dialkylamine radicals. Effect of the alkyl group nature. Chim. Ind. (Milan) 1971,53,1154-1155. 

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