The Minisci Reaction

The Friedel-Crafts reaction requires electron-rich aromatic rings for the reaction to occur. Friedel-Crafts reaction, with electron-poor rings under ionic conditions, is difficult to achieve. Minisci showed that by generating a nucleophilic carbon-centered radical, HAS with electron-poor heteroaromatic rings affects the same net transformation. Activation of the ring through protonation is necessary. 

The scope of the reaction is quite broad, and a number of functional groups are tolerated in the reaction. Radicals generated at the carbonyl of an amide or a to an alcohol, ether (45) or amine can be utilized in the Minisci reaction. Minisci, later, showed homolysis of sugar-derived alkyl iodides 46 under thermal conditions to give carbon-centered radicals. These radicals undergo HAS to quinoline derivatives 47 and other heteroaromatics in good yields. Cowden showed that decarboxylation of commercially available a-amino acids 48 can form a carbon-centered radical for use in the Minisci reaction.  

Biaryls are ubiquitous substructures in biologically active molecules. The direct synthesis of biaryls is well known, and a focus on environmentally friendly methods 

A 2008 paper from the Kami group noted the direct coupling of an aryl iodide to an unactivated aryl ring in the absence of transition metals typically employed for this purpose. The Itami group was attempting biaryl formation through the use of iridium catalysis with potassium t-butoxide as base, but control reactions found the reaction occurred solely in the presence of potassium t-butoxide. Optimized conditions of an aryl iodide with a variety of electron deficient heteroaromatic rings and potassium t-butoxide for 5 min under microwave conditions provided a number of successfully coupled biaryls. 

The mechanism is believed to begin by SET from the base to the aryl iodide to form a radical anion. Inter-molecular reaction can occnr through a HAS, the radical variant of the more commonly known EAS reaction. For intermolecular reaction, addition of the radical to the coupling partner resnlts in a resonance-stabilized radical. Deprotonation with base forms a biaryl radical anion which propagates the mechanism by donating an electron to another aryl haUde. For intra-molecular reaction, the aryl radical likely adds to the ipso position of the tether. Subsequent ring expansion and re-aromatization yields the prodnct.  

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Addition of nucleophilic radicals to protonated heteroaromatics (the Minisci reaction) 768... 

More recently, Porta and co-workers [6] applied similar considerations of the polar effects to a new one-pot multicomponent process for the addition of nucleophilic radicals to aldimines, generated in situ in the presence of Ti(IV). In analogy with the Minisci reaction, Ti(IV), which acts as a Lewis acid, coordinates the nitrogen of the imine, strongly increasing the electron-deficient character of the carbon in the a-posilion and thus the reactivity of the imine toward nucleophilic radicals. This reaction, as well as the Minisci one, represents a useful route for the synthesis of a variety of poly-functionalized derivatives of chemical and biochemical relevance. 

Pyridines undergo a variety of reactions with radical reagents, and at surfaces many of these parallel the corresponding reactions of benzenes however, the reaction of nucleophilic radicals with protonated pyridines is important (the Minisci reaction). Electron uptake from a metal to form a radical anion occurs readily. 

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). 

The Minisci reactions referred to above can also employ /-butyl hydroperoxide (TBHP), perdisulfate or dibenzoyl peroxide in the presence of hydrogen peroxide.493... 

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... 

An interesting example of carbon-carbon bond formation represents the reaction between 3(2//)-pyridazinone and pyridine A -oxide in the presence of platinized palladium-carbon catalyst at 150°C to give, in 2% yield, 6-(pyridyl-2 )-3(2//)-pyridazinone. Pyridazine itself did not react (78YZ67). 4,5-Diacylpyridazines were prepared from pyridazine and the corresponding aldehydes according to the Minisci reaction (78M63). 

In the laboratory of D.W. Cameron the total synthesis of the azaanthraquinone natural product bosttycoidin was undertaken using the Minisci reaction and the intramolecular Houben-Hoesch reaction as the key steps. It is worth noting that the synthesis of specific di- and trihydroxyazaanthraquinones by the Friedel-Crafts acylation is very limited due to the lack of orientational specificity and the lack of reactivity of pyridine derivatives in acylation reactions. 

Although much less well developed than the Minisci reaction, substitution with electrophihc radicals can be used in some cases to achieve selective reaction in electron-rich heterocycles. ... 

Of more preparative value are the reactions of nucleophilic radicals, such as HOCHa and RaNCO, which can be easily generated under mild conditions, for example HOCH2 from ethylene glycol by persulfate oxidation with silver nitrate as catalyst. These substitutions are carried out on the pyridine protonic salt, which provides both increased reactivity and selectivity for an a-position the process is known as the Minisci reaction (cf. 3.4.1). It is accelerated by electron-withdrawing substituents on the ring. 

Regioselective substitutions can be achieved a to the nitrogen, with nucleophilic radicals, in acid solution - the Minisci reaction (3.4.1). 

An interesting variant of the Minisci reaction has been reported for 1,2,3-triazine, which is unstable to the usual acidic conditions here, activation of the heterocycle to attack by the nucleophilic radical is brought... 

This persuasive evidence for homolytic chemistry occurring in the PFL reaction has led Kozarich and co-workers to propose a working hypothesis for the overall enzymic reaction (787). A chemical precedent exists in the H202/Fe(II)-mediated homolytic cleavage of ethyl pyruvate to ethyl formate radical and acetate. This is the Minisci reaction, which has been employed in the selective carboxylation of heteroaromatic bases (Scheme 40) (796-798). The initial step in this process is the formation of a hydroperoxy hemiketal with ethyl pyruvate and H2O2, followed by Fe(II) reduction of the hemiketal to the alkoxy radical. 

Scheme 41. Postulated mechanism of pynivate formate-lysase based on the Minisci reaction (187).

The Minisci reaction has successfully been applied for the alkylation of various heteroarenes, i. e. lepidine, pyrazine, quinoline and quinoxaline [2e, 2g, 10]. Organic compounds such as alkanes, alkenes, carboxylic acids, esters, amides, amines, alcohols, ethers, aldehydes, ketones, halides etc. have been successfully used as radical precursors in the Minisci reaction. A good overview of the different methods which have been applied to generate the alkyl radicals in these processes is summarized in [10b]. 

Reactions of heterocycles with nucleophilic radicals The Minisci reaction" ... 

Later, professor Minisci made a great contribution to this field demonstrating a benefit of acidic conditions, which enabled chemists to improve both reaction rates and positional selectivity for radical additions to heteroaromatic bases (Scheme 43) [91]. Minisci and other organic chemists refined the radical reactions to the point where they constitute the effective set of distinct transformations. This is why the radical additions to heteroaromatic bases are sometimes referred in the literature as the Minisci reactions. Indeed, the Minisci reactions represent a powerful tool for the C-H functionalization of heteroaromatic compounds [92]. The reactions are... 

Reactions with Radicals. Isoquinoline does react with radicals to give addition to the 1-position with subsequent loss of hydrogen. The Minisci reaction is a well-known example of this transformation. It is an effective reaction for the addition of hydroxymethyl, alkyl, and acyl radicals. Formyl and carbamoyl groups have also be added using this method. Acidic conditions help to promote the reaction. Alkylation is effective when carried out with alkyl iodides or alkyl xanthates. Hydroxymethyla-tion can also be carried out. Photochemical-induced free radical reactions have also been reported. Alkylation is possible using ethanol or propanoic acid but low yields are often obtained. Addition of a phenyl group can be achieved in 81% yield. ... 

Dou and Lynch first, and Minisci himself later on [5], also emphasized tiie beneficial effect of acidic conditions to reaction rates and positional selectivity, rendering the radical addition to heteroaromatic bases a valuable tool for selective organic synthesis. As a consequence, since 1970s up to the present days a tremendous amount of catalytic systems has been developed, capable to promote the Minisci reaction under different operative conditions [5]. In... 

The use of organotrifluoroborate building blocks as sources of nucleophilic radicals for the Minisci reaction [7]. The most traditional catalytic systems will be discussed in detail in Section 3. 

In subsequent efforts, we succeeded in introducing significantly improved variants of the Minisci reaction. Pyridine-N-oxide proved to be reactive enough to undergo radical allqrlation with cyclic hydrocarbons even in the absence of an activator (Scheme 1.20). ... 

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