Minisci reaction

Minisci reactions have also been applied to these compounds. formation by exposure to w-CPBA and O-methylation with Meerwein s reagent converted 54 into 55. Nucleophilic attack of the hydroxymethyl radical, generated with ammonium sulfate, provides an alternate route to 2-hydroxymethyl pyridines 56. 

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

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. 

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. 

Using a modified Minisci reaction, the 4-position of the quinoline ring in alkaloid 195 (camptothecin) was substituted to afford the highly active antitumor agent 196 (karenitecin) (Equation 105) <2001USP6194579>. 

Fig. 95 Oxalic amides in silver-catalyzed Minisci reactions...

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. 

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). 

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... 

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. 

Scheme 16.7 Minisci reactions in the semisynthesis of camptothecin-derived drug candidates.

Notably, when the same cyclisation was carried out using sodium cobalt(I)salophen, the reaction became selective for toddaquinoline methyl ether <00TL6681>. This apparent diehotomy was attributed to the formation of a Lewis acid - Lewis base complex between cobalt(II)salophen and the pyridine moiety. Loss of bromide from the radical anion 151 generates aryl radieal 152 which adds to the proximal pyridine giving 153. Dehydrocobaltation to toddaquinoline methyl ether 149 completes the sequence (Scheme 42). Notably, as the pyridine ring is activated by complexation to the Lewis acidic Co(II), the eyelisation is more akin to a Minisci reaction. Consequently, cyclisation to C6 is promoted in this case <01T4447>. 

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. 

Related reactions Fries-, Photo-Fries and Anionic Ortho-Fries rearrangement, Houben-Hoesch reaction, Minisci reaction ... 

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