Pyridines reactions with alkyl radicals

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]. 

In spirooxaziridines like (114), /3-scission proceeds with ring opening. Stoichiometric amounts of iron(II) salt in acidic solution lead to the dicarboxylic acid derivative (115). The radical undergoes some interesting reactions with added unsaturated compounds. For example, pyridine yields a mixture of 2- and 4-alkylation products in 80% yield. Catalytic amounts of iron(II) ion are sufficient here since the adduct of the radical with pyridine is oxidized by iron(III) ion to the final product (116), thus regenerating iron(II) ion (68TL5609). 

Reactions of pyridine with a number of alkyl radicals generated by this method have been studied (Section... 

Homolytic aromatic substitution often requires high temperatures, high concentrations of initiator, long reaction times and typically occurs in moderate yields.Such reactions are often conducted under reducing conditions with (TMSlsSiH, even though the reactions are not reductions and often finish with oxidative rearomatization. Reaction (68) shows an example where a solution containing silane (2 equiv) and AIBN (2 equiv) is slowly added (8h) in heated pyridine containing 2-bromopyridine (1 equiv) The synthesis of 2,3 -bipyridine 75 presumably occurs via the formation of cyclohexadienyl radicals 74 and its rearomatization by disproportionation with the alkyl radical from AIBN. ... 

A mixture of water/pyridine appears to be the solvent of choice to aid carbenium ion formation [246]. In the Hofer-Moest reaction the formation of alcohols is optimized by adding alkali bicarbonates, sulfates [39] or perchlorates. In methanol solution the presence of a small amount of sodium perchlorate shifts the decarboxylation totally to the carbenium ion pathway [31]. The structure of the carboxylate can also support non-Kolbe electrolysis. By comparing the products of the electrolysis of different carboxylates with the ionization potentials of the corresponding radicals one can draw the conclusion that alkyl radicals with gas phase ionization potentials smaller than 8 e V should be oxidized to carbenium ions [8 c] in the course of Kolbe electrolysis. This gives some indication in which cases preferential carbenium ion formation or radical dimerization is to be expected. Thus a-alkyl, cycloalkyl [, ... 

The fact that such selectivity was not found with homolytic alkylation of nonprotonated heteroaromatics (Table I) or with homocyclic aromatics indicates that polar factors play a major role in the reactivity of alkyl radicals with protonated bases. These effects were determined by the study of the relative reaction rates in the alkylation of 4-substituted pyridines in acidic medium. The results obtained with methyl, n-propyl, w-butyl, sec-butyl, i-butyl, and benzyl radicals are summarized in Table III. 

Alkyl radicals, prepared in situ, react with pyridine to form mainly 2-alkyl derivatives and this regioselectivity is shown in the free radical reactions of alkylmercurial compounds with pyridines (Scheme 37). 

As a model study of methyl cobalamine (methyl transfer) in living bodies, a methyl radical, generated by the reduction of the /s(dimethylglyoximato)(pyridine)Co3+ complex to its Co1+ complex, reacts on the sulfur atom of thiolester via SH2 to generate an acyl radical and methyl sulfide. The formed methyl radical can be trapped by TEMPO or activated olefins [8-13]. As a radical character of real vitamin B12, the addition of zinc to a mixture of alkyl bromide (5) and dimethyl fumarate in the presence of real vitamin B12 at room temperature provides a C-C bonded product (6), through the initial reduction of Co3+ to Co1+ by zinc, reaction of Co1+ with alkyl bromide to form R-Co bond, its homolytic bond cleavage to form an alkyl radical, and finally the addition of the alkyl radical to diethyl fumarate, as shown in eq. 11.4 [14]. 

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