MINISCI Radical Aromatic Substitution

The first examples of selective substitution of heteroaromatic bases by carbon-centered radicals were reported by Minisci and his group at the end of the 1960s (Scheme 1) [1,2]. Those manuscripts, which can be considered the first accounts of the so-called "Minisci reaction" [3], played a decisive role to the chemical community in reconsidering the potentiality of free-radical aromatic substitutions. In fact, until then the homolytic process had been considered of poor interest compared with the electrophilic and nucleophilic ionic substitutions, due to the discouraging results achieved witii homolytic arylation, the reaction most studied so far [4]. The low selectivity observed for that reaction was erroneously assumed as a general feature of homolytic aromatic substitution and this misinterpretation was overcome only when it was recognized that the polar effect could play a key role in free-radical reactions as well. 

Vismara, E., Donna, A., Minisci, F., Naggi, A., Pastori, N., Torri, G. Reactivity of carbohydrate radicals derived from iodo sugars and dibenzoyl peroxide. Homolytic heteroaromatic and aromatic substitution, reduction, and oxidation. J. Org. Chem. 1993, 58, 959-963. 

Acylpyrazines, constituents in foodstuffs and pheromones, have been prepared by the Minisci-type radical reactions of pyrazines even though these methods often suffer from poor regioselectivity of aromatic substitution. Alternatively, synthesis of acetylpyrazines and propionylpyrazines 33 was achieved via a Stille coupling of bromopyrazines 31 with tributyl-(l-ethoxyalkenyl)tin (32), followed by acidic hydrolysis of the ether derivative [24]. 

But before 1980, the foundations for essentially all modern synthetic radical reactions had been laid, sometimes by synthetic organic chemists but more often by physical organic chemists. Kharasch reactions (now often called atom transfer reactions) were known since the 1930s and 1940s, and tributyltin hydride was introduced in the 1960s. In the 1970s, SnAc reactions and redox chain aromatic substitutions (Minisci reactions) were already topical, and allylations with allyl-tributylstannane were first described. In short, there were a number of ways to generate and trap radicals on the one hand, and a number of fundamental transformations of radicals such as addition and cyclization to multiple bonds on the... 

Bravo A, Bjprsvik HR, Fontana F, Liguori L, Mele A, Minisci F (1997) New methods of free-radical perfluoroalkylation of aromatics and alkenes. Absolute rate constants and partial rate factors for the homolytic aromatic substitution by n-perfluorobutyl radiceil. J Org Chem 62 7128-7136... 

The question of ami nation of aromatics by protonated amino radicals has been examined extensively by Minisci and co-workers (16). Benzene is aminated in good yields by a variety of N-chloroamines in acidic solutions, catalyzed by Iron(II) sulfates. With activated aromatics competing chlorination and sulfonation complicates the reactions, but In many cases good yields of the substituted anilines are obtained. In the case of a1kylbenzenes, benzylic chlorination competes with nuclear amlnatlon. The latter is favored by high acid concentrations. Thus, the reaction of toluene with N-chlorodimethyl amine (17) gives 95 percent amination and 6 percent benzylic chlorination in neat H SO., but 100 percent benzylic chlorination In neat acetic acid. The amount of nuclear amination increases with the concentration of H2SO4 in acetic acid. 

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