Pyridines alkylation, homolytic

The alkylation of pyridine [110-86-1] takes place through nucleophiUc or homolytic substitution because the TT-electron-deficient pyridine nucleus does not allow electrophiUc substitution, eg, Friedel-Crafts alkylation. NucleophiUc substitution, which occurs with alkah or alkaline metal compounds, and free-radical processes are not attractive for commercial appHcations. Commercially, catalytic alkylation processes via homolytic substitution of pyridine rings are important. The catalysts effective for this reaction include boron phosphate, alumina, siHca—alurnina, and Raney nickel (122). 

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. ... 

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. 

Methylation is taken as illustrative of alkylation for comparative purposes in Table 25 however, a wide range of other alkylations have been studied (76MI20503). Photolysis of di-r-butyl peroxide in a mixture of cyclohexane and pyridine gives cyclohexylation (equation 170) (7lCR(C)(272)854>. The relative rates for homolytic substitution of pyridines by cyclic alkyl radicals have been obtained (74JCS(P2)1699). A striking contrast can be seen (Table 26)... 

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]. 

Within the limits imposed there exists a number of available procedures for introducing alkyl substituents onto the pyridine ring. All of these involve either nucleophilic or homolytic substitution since alkylation via electrophilic substitution, e.g. Friedel Crafts alkylation, is not possible with the TT-deficient pyridine nucleus. 

Free Radical Processes. Homolytic alkylation and arylation of pyridines has been studied extensively and reviewed (U ). The products are almost invariably mixtures of several Isomers depending on the nature of the pyridine substrate, the free radical (audits method of generation) and the type of medium in which the reaction is carried out. Tho gh early reports suggested 2-, and -substitution exclusively, more sensitive analytical techniques have shown the earlier claims to be erroneous 6ind studies into the various factors affecting product formation have been reported (1 6-62). 

Homolytic cleavage of oxaziridines by ferrous salts, already described by Emmons, is a useful source of alkyl radicals. From oxaziridine 28, easily accessible from cyclohexanone and Af-chloromethylamine, on the action of ferrous salt, reaction products of radical 29 are obtained In the presence of FeCl2 oj-chlorohexanoic acid methylamide (30) is formed quantitatively in the absence of reaction partners, dimerization occurs to 31. As shown in a very careful investigation by Hawkins in the case of the N-cyclohexyl compound, the dicarboxylic acid derivative is accompanied by appreciable quantities of branched-acid derivatives, formed by a radical rearrangement 29 -> 32. The radical 29 adds to pyridine and gives rise, after rearomatization, to the formation of 70-80% of 2- and 4-substituted pyridine (33). ... 

Radical cyclizations of nucleophilic N-alkyl radicals 96 onto the benzimidazole 2-position, mediated by tributyltin hydride and activated by quater-nizing the pyridine-like N-3 of imidazole with camphorsulfonic acid, have recently been reported (Scheme 20) [67]. These new five-, six- and seven-membered homolytic aromatic substitutions of nucleophilic N-alkyl radicals onto the benzimidazole-2-position occurred upon the use of large excesses of the azo-initiator, l,T-azobis(cyclohexanecarbonitrile), to supplement the non-chain reaction. The intermediate 97 aromatizes in high yields to the cy-clized benzimidazoles 98. 

The results of the Table 17 show the substrate selectivity of the homolytic alkylation of 4-substituted pyridines by the simplest types of alkyl radicals ... 

Table 17. Relative rates in the homolytic alkylation of protonated 4-X-pyridines...

The methods of homolytic alkylation of pyridine and related heterocycles developed by Minisci (73S1, 74AHC123) are used to introduce C-alkyl groups into IP molecules. 

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. 

Turning from 5 1 to a possible 5 2 process, it is observed that homolytic fission of a Co-C bond can be brought about by attack at the carbon atom by an alkyl radical. The thermal decomposition in CCI4 of hex-5-enyl(pyridine)cobaloxime and in particular its 5-methyl derivative leads to cyclopentyl products reaction (18) is though to occur (R = H or Me) ... 

The stability constants for the coordination of pyridine or substituted pyridines to various alkylcobalt porphyrin systems have been reported. This study has been done in order to observe the m-influence of hydroporphyrin macrocycles on axial position and alkyl exchange reactions. The alkyl exchange reactions of organocobalt(lll) porphyrins with a cobalt(ll) complex of a distinguishable porphyrin or tetrapyrrolc have been studied. The equilibrium constants for the alkyl transfer have been reported. The exchange of the axial ligand is reversible and it follows a bimolecular mechanism. Thermodynamic and activation parameters for homolytic Co-C bond dissociation have been obtained on the (TAP)CoC(CH3)2CN complex (TAP = tetraanisylporphirinato). ... 

An interesting synthesis of trichloroethyl-benzenes provides the first example of homolytic displacement by an alkyl group at a saturated carbon atom. In this way benzylbis(dimethylglyoximato)pyridine cobalt, with BrCCla in chloroform, leads to PhCHiCCls and PhCH2Br. 

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