Pyridine radical attack

There appear to be no reports of direct radical attack on the pyridopyrimidine ring system, but radical bromination of methyl substituents in the 7-position of the pyridine ring has been utilized in the synthesis of deaza analogues of natural products (62JCS4678, 79JHC133). 

The classical syntheses of phenanthrene and fluorenone fit well into the electron transfer scheme discussed in Section 8.6 and in this chapter. The aryl radical is formed by electron transfer from a Cu1 ion, iodide ion, pyridine, hypophosphorous acid, or by electrochemical transfer. The aryl radical attacks the neighboring phenyl ring, and the oxidized electron transfer reagent (e. g., Cu11) reduces the hexadienyl radical to the arenium ion, which is finally deprotonated by the solvent (Scheme 10-76). 

One possible solution of this problem is to differentiate a radical first as electrophilic or nucleophilic with respect to its partner, depending upon its tendency to gain or lose electron. Then the relevant atomic Fukui function (/+ or / ) or softness f.v+ or s ) should be used. Using this approach, regiochemistry of radical addition to heteratom C=X double bond (aldehydes, nitrones, imines, etc.) and heteronuclear ring compounds (such as uracil, thymine, furan, pyridine, etc.) could be explained [34], A more rigorous approach will be to define the Fukui function for radical attack in such a way that it takes care of the inherent nature of a radical and thus differentiates one radical from the other. 

Free radical attack at the pyridine ring is noted for its low selectivity and substituents have little effect. Arylation takes place at all three positions, but halogen atoms preferentially attack the a-, and alkyl radicals the a- and y-positions. Metals such as sodium and zinc transfer a single electron to pyridine to form anion radicals. These can dimerize by reaction at the a- or y-position to yield dipyridyls by loss of hydride ion. Thus, reduction of pyridine by chemical and catalytic means is easier than reduction of benzene. 

Bromination of pyridine is much easier than chlorination. Vapour phase bromination over pumice or charcoal has been studied extensively (B-67MI20500) and, as with chlorination, orientation varies with change in temperature. At 300 °C, pyridine yields chiefly 3-bromo-and 3,5-dibromo-pyridine (electrophilic attack), whilst at 500 °C 2-bromo- and 2,6-dibromo-pyridine predominate (free radical attack). At intermediate temperatures, mixtures of these products are found. Similarly, bromination of quinoline over pumice at 300 °C affords the 3-bromo product, but at higher temperatures (450 °C) the 2-bromo isomer is obtained (77HC(32-1)319). Mixtures of 3-bromo- and 3,5-dibromo-pyridine may be produced by heating a pyridine-bromine complex at 200 °C, by addition of bromine to pyridine hydrochloride under reflux, and by heating pyridine hydrochloride perbromide at 160-170 °C (B-67MI20500). 

In sharp contrast, homolytic arylation is unselective and gives low yields. Phenyl radicals attack pyridine unselectively to form a mixture of 2-, 3- and 4-phenylpyridines in proportions of ca. 53, 33 and 14%, respectively. The phenyl radicals may be prepared from the normal precursors PhN(NO)COMe, Pb(OCOPh)4, (PhC02)2 or PhI(OCOPh)2. Substituted phenyl radicals react similarly. 

A tin-free radical cyclization of the xanthate 272 using dilauroyl peroxide (DLP), as the radical initiator, in chlorobenzene was used to give the 5//-pyrido[2,3-A azepin-8-one 273 (Scheme 35) <20040L3671>. The xanthate 272 was also made by an intermolecular free radical addition to allyl acetate, using the xanthate 271, as the radical precursor. Somewhat surprisingly in this latter case, intramolecular free radical attack on the pyridine ring did not take place. 

Pyridine is attacked by the adamantyl radical to give a mixture of C-2 and C-4 isomers (Equation 104) <1995ZOR670>. The analogous reaction of ethyl isonicotinate gave mainly the 2-substituted derivative. 

The first reaction was found by Levy and Szwarc to be predominant when methyl radicals attacked isooctane. The second reaction is predominant, however, for aromatic hydrocarbons. The free radicals formed in the above two reactions will react with each other, with other free radicals, or with impurities. The affinity of the methyl radical to attack an aromatic increases in the following order benzene, diphenyl ether, pyridine, diphenyl, benzophenone, naphthalene, quinoline, phenanthrene, pyrene, and anthracene. The ability of free alkyl radicals to interact with isopropylbenzene and cyclohexene decreases in the following order methyl, ethyl, propyl, butyl, isopropyl, sec-butyl, and tertiary butyl. 

Pincock [Pi 64] characterized solvents on the basis of the solvent dependence of the ionic decomposition of t-butyl peroxyformate. However, not only the rate, but also the mechanism of decomposition of this compound is solvent-dependent. For example, in chlorobenzene it decomposes in a slow unimolecular reaction in which the peroxide bond is split in n-butyl ether the decomposition proceeds via radical attack on the peroxide oxygen atoms and in the presence of pyridine a bimolecular elimination reaction occurs, with the formation of t-butanol and carbon dioxide. Pincock used the solvent dependence of the rate of this latter reaction to characterize the solvent. 

These results show that in the phenylation of thiazole with benzoyl peroxide two secondary reactions enter in competition the attack of thiazole by benzoyloxy radicals, leading to a mixture of thiazolyl benzoates, and the formation of dithiazolyle through attack of thiazole by the thiazolyl radicals resulting from hydrogen abstraction on the substrate and from the dimerization of these radicals. This last reaction is less important than in the case of thiophene but more important than in the case of pyridine (398). 

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. 

It is difficult to treat the effect of a heteroatom on the localization energies of aromatic systems, but Brown has derived molecular orbital parameters from which he has shown that the rates of attack of the phenyl radical at the three positions of pyridine relatively to benzene agree within 10% with the experimental results. He and his co-workers have shown that the formation of 1-bromoisoquinoline on free-radical bromination of isoquinoline is in agreement with predictions from localization energies for physically reasonable values of the Coulomb parameters, but the observed orientation of the phcnylation of quinoline cannot be correlated with localization ener-... 

Protonated nitrogen heterocycles can be carbalkoxylated" by treatment with esters of a-keto acids and Fenton s reagent. Pyridine is carbalkoxylated at C-2 and C-4, for example. The attack is by "COOR radicals generated from the esters ... 

For unsubstituted PAH, such as benzo[a]pyrene (BP), pyridinium or acetoxy derivatives are formed by direct attack of pyridine or acetate ion, respectively, on the radical cation at C-6, the position of maximum charge density (Scheme 1). This is followed by a second one-electron oxidation of the resulting radical and loss of a proton to yield the 6-substituted derivative. For methyl-substituted PAH in which the maximum charge density of the radical cation adjacent to the methyl group is appreciable, as in 6-methylbenzo[a]-pyrene (6-methylBP) (Scheme 2), loss of a methyl proton yields a benzylic radical. This reactive species is rapidly oxidized by iodine or MnJ to a benzylic carbonium ion with subsequent trapping by pyridine or acetate ion, respectively. 

As depicted in Scheme 11, ylides 39 derived from 4-methyl-[l,2,3]triazolo[l,5- ]pyridine react with Michael acceptors, which, upon nucleophilic attack at C3 and ring opening, lead to nucleophilic displacement of nitrogen. The intermediate diradical led to a mixture of compounds, including alkenes and a cyclobutane derivative when methyl acrylate was used, and the indolizine 40 with methyl propiolate as the electrophile <1998T9785>. Heating 4-methyl triazolopyridine with benzenesulfonyl chloride in acetone also confirmed decomposition via a radical pathway. 

The adduct of silyl radicals to 4-substituted pyridines and pyrazine monitored by EPR results from the attack at the nitrogen atom to give radicals 52 and 53, respectively [68,69]. The rate constant for the addition of Et3Si radical to pyridine is about three times faster than for benzene (Table 5.3) [24]. 

The ethyl radical directly attacks the heteroaromatic base, while the acetaldehyde acts as a source of acetyl radical. Photochemical oxy-alkylation has also been tried with ethers. The reaction has been successfully carried out with pyridines, quinolines, isoquinolines,cinno-lines, and quinoxalines. Particularly good yields were obtained with caffeine (16) (Scheme 14). ... 

---