Pyridines radical substitution, regioselectivity

Pyridines undergo radical substitution reactions preferentially at the 2-position. Yields and regioselectivity are generally higher if the reaction is carried out in an acid medium. The presence of a strongly electron-donating substituent (OH, OR, NR2) on the pyridine ring can alter the reactivity pattern of electrophilic and radical substitution. 

Regioselective nucleophilic, electrophilic, and radical substitution in pyridines, di-, tri-, and tetrazines 88AHC(44)199. 

The reaction of nucleophilic radicals, under acidic conditions, with heterocycles containing an imine unit is by far the most important and synthetically useful radical substitution of heterocyclic compounds. Pyridines, quinolines, diazines, imidazoles, benzothiazoles, and purines are amongst the systems which have been shown to react with a wide range of nucleophilic radicals, selectively at positions a and 7 to the nitrogen, with replacement of hydrogen. Acidic conditions are essential because N-protonation of the heterocycle both greatly increases its reactivity and promotes regioselectivity towards a nucleophilic radical, most of which hardly react at all with... 

Radical alkylations of pyridines and quinolines preferentially occur at positions 2 and 4. Protonation of the ring nitrogen influences the regioselectivity by favoring C-4 substitution. 

As mentioned before, alkyl radicals and acyl radicals have a nucleophilic character therefore, radical alkylation and acylation of aromatics shows the opposite reactivity and selectivity to polar alkylation and acylation with the Friedel-Crafts reaction. Thus, alkyl radicals and acyl radicals do not react with anisole, but may react with pyridine. Eq. 5.1 shows the reaction of an alkyl radical with y-picoline (1). The nucleophilic alkyl radical reacts at the 2-position of y-picoline (1), where electron density is lower than that of the 3-position. So, 2-alkyl-4-methylpyridine (2) is obtained with complete regioselectivity. When pyridine is used instead of y-picoline, a mixture of 2-alkylpyridine and 4-alkylpyridine is obtained. Generally, radical alkylation or radical acylation onto aromatics is not a radical chain reaction, since it is just a substitution reaction of a hydrogen atom of aromatics by an alkyl radical or an acyl radical through the addition-elimination reaction. Therefore, the intermediate adduct radical (a complex) must be rearomatized to form a product and a hydrogen atom (or H+ and e ). Thus, this type of reactions proceeds effectively under oxidative conditions [1-6]. 

When more than one reactive position is available in a heterocyclic substrate, as is often the case for pyridines for example, there are potential problems with regioselectivity or/and disubstitution (since the product of the first substitution is often as reactive as the starting material). Regioselectivity is dependent to a certain extent on the nature of the attacking radical and the solvent, but may be difficult to control satisfactorily. ... 

A-Azinylpyridinium A-aminides 73 have been shown to be convenient precursors for the regioselective synthesis of 3-fluoro-2-aminopyridines 76" " (Scheme 6.25). First, compound 73 was treated with xenon difluoride, which resulted in the regioselective introduction of fluorine in 3 of substituted pyridine ring leading to compounds 74, which were further alkylated to give compounds 75 and finally, the radical reduction was used to form 3-fluoropyridines 76. 

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. 

As a mechanistic explanation, change to a radical process is thought to be responsible for the reversal of regioselectivity observed in alkylation. A SET from the metal to pyridine generates a radical anion 40, which adds RMgX to give the dihydropridine 41 and finally the 4-substitution product 39 [90]. 

---