Pyridines radical reactions

Recently, Nadin and Harrison [70] made a similar observation with pyridones, employing a rare example of a pyridine radical. Reaction of the 3-bromopyridine derivative 278 with BusSnH and AIBN furnished the 1-exo trig cyclized product 279 along with 10% of uncyclized reduction product. It is worth noting that the same reaction failed under the Heck conditions. 

Ha.logena.tlon, One review provides detailed discussion of direct and indirect methods for both mono- and polyhalogenation (20). As with nitration, halogenation under acidic conditions favors reaction in the benzenoid ring, whereas reaction at the 3-position takes place in the neutral molecule. Radical reactions in the pyridine ring can be important under more vigorous conditions. 

The reactivity of pyridine relative to that of benzene has been measured using the competitive technique developed by Ingold and his schoool for corresponding studies of electrophilic aromatic substitution. The validity of the method applied to free-radical reactions has been discussed. Three sources of the phenyl radical have been used the results obtained are set out in Table II. 

Direct perfluoroalkylation of heteroaromatics occurs with RFI when sodium hydroxymethane sulfinate (Rongalite) is present. 3-Perfluoroal-kylcoumarins can be obtained (90CC1781). The distribution of isomers from substituted pyridines is compatible with a radical reaction (90TL2711). 

Cobaloxime(I), electrochemically regenerated from chloro(pyridine)-cobaloxime (III) (232), has been employed as a mediator in the reductive cleavage of the C—Br bond of 2-bromoalkyl 2-alkynyl ethers (253), giving (254) through radical trapping ofthe internal olefin (Scheme 95) [390]. An interesting feature of the radical cyclization (253) (254) is the reaction in methanol, unlike the trialkyltin hydride-promoted radical reactions that need an aprotic nonpolar solvent. An improved procedure for the electroreductive radical cyclization of (253) has been attained by the combined use of cobaloxime(III) (232) and a zinc plate as a sacrificial anode in an undivided cell [391]. The procedure is advantageous in terms of the turnover of the catalyst and the convenience of the operation. 

The most important synthesis of 4,4 -bipyridine involves the reaction of sodium on pyridine. This reaction was discovered as long ago as 1870, although the product was not deduced to be 4,4 -bipyridine until later. " 4,4 -Bipyridine is the predominant isomer formed, although varying amounts of other isomeric bipyridines, especially 2,2 -bipyridine and 2,4 -bipyridine, may be formed, depending on the reaction conditions. The reaction involves formation of the sodium derivative of pyridine, which is formulated as the radical 67. It then couples predominantly in the 4 positions to afford 68, which with water hydrolyzes to l,T,4,4 -tetrahydro-4,4 -bipyridine. Facile oxidation then gives 4,4 -bipyridine. ° If the reaction is carried out at the temperature of boiling pyridine (IIS C) instead of at lower temperatures, the proportion of bipyridines other than 4,4 -bipyridine increases, and some terpyridines may be formed as vvell. Oxidants... 

Distonic ions reacting primarily at the radical center provide the opportunity to study free radical reactions in the gas phase by MS. For example, 4-dehydroanilin-ium ions (37 +, m/z = 93) were generated by multiple low-energy collisions of chloro-, bromo-, or iodoanilinium ions (36+, m/z = 220) with argon. This distonic species reacted with dimethyl sulfide by abstraction of thiomethyl (MeS ), that is, as a reactive radical with an inert charge site. However, 37 + can be deprotonated by pyridine. 2° ... 

The preceding results and Ashby s observation (81JOC2429) that LDA acts as the single-electron donor towards aromatic hydrocarbons, stimulated Newkome (82JOC599) to study the reaction of pyridine with LDA (HMPA at 0°C) (Scheme 149). The products of this reaction, 2,4 - (77) and 4,4 - (494) bipyridines, obtained in the ratio 1 8, were rationalized as being formed from a pyridine radical-anion 493. In support of this proposal, complex ESR signals corresponding to both pyridine radical-anion and the diisopropylamino radical were observed under these conditions. 

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). 

Bipyridyl (20) (63AHC(2)179) is synthesized by oxidative dimerization of pyridine over hot Raney nickel, while 4,4 -bipyridyl (21) (B-79MI10705) is made by free radical coupling of the pyridine radical anion generated by sodium in liquid ammonia, followed by air oxidation (Scheme 6). Quaternization of (21) with methyl chloride gives paraquat while reaction of (20) with 1,2-dibromoethane gives diquat. 

OH radical reaction with chloropyrofos is anticipated to proceed via OH radical addition to the pyridine ring, OH radical "interaction" with the P=S group [with a group rate constant k >P=S (Table 14.4)], and H-atom abstraction from the two -OCH2CH3 groups bonded to the P atom. The total OH radical reaction rate constant is given by ... 

The rate constant for OH radical addition cannot be calculated because the effect of the -OP(=S)(OCH2CH3)2 substituent is not known. However, because the rate constant for OH radical addition to pyridine is -3.7 x 10-13 cm3 molecule-1 s-1 (Atkinson, 1989) and the three Cl atom sustituents will markedly deactivate the ring (Brown and Okamoto, 1958) [as observed, for example, for the OH radical reactions with chlorobenzene, 1,2-, 1,3- and 1,4-dichlorobenzene, and for 1,2,4-trichlorobenzene relative to that for benzene (Atkinson, 1989)], OH radical addition to the pyridine ring is expected to be minor, and its neglect will lead to an estimated lower limit to the total reaction rate constant. 

Various intramolecular aryl radical reactions of pyridine derivatives have been developed <2004COR757, 2001J(P 1 )2885>. An early example of this type is found in a short synthesis of camptothecin 195. The tetracyclic intermediate 197 was cyclized by a free radical reaction to afford the natural product (Equation 106) <1994TL5331>. 

Pyridines and their benzo-derivatives have played an important role in the synthesis of biologically active synthetic and natural substances. As a result, the construction of this molecular architecture has attracted the attention of a diverse array of synthetic methodologies. Notably, transition metal catalysis, radical reactions and cycloaddition chemistry-based methods have been developed for the construction of this important ring system. Detailed herein is a summary of the methods developed for the synthesis of pyridines, quinolines, isoquinolines and piperidines that were disclosed in the literature in 2002. Rather than survey all existing methods for the construction of these compound classes, this review will serve as a supplement and update to the review published last year in this series. 

Pyridine or picolinic acid chloride (66 R = H, COCI) reacts presumably with thionyl chloride to form a o--complex (67) that is attacked by a chloride ion to give 68. Elimination of HCI and SO, which disproportionate to sulfur and sulfur dioxide, ultimately furnishes the corresponding 4-chloropyridine hydrochloride (69). In the case of pyridine, the intermediate 4-chloropyridine (41) reacts with additional pyridine to form 65. The sometimes long initiation periods of these conversions (61 — 62 and 64— 65) indicate they may in reality be complicated radical reactions (cf. 8IS66I). 

The rate of the ring-opening reaction of 5, " and other substrates have been determined using an indirect method for the calibration of fast radical reactions, applicable for radicals with lifetimes as short as 1 ps/ This radical clock method is based on the use of Barton s use of pyridine-2-thione-Al-oxycarbonyl esters as radical precursors and radical trapping by the highly reactive thiophenol and benzeneselenol/ A number of radical clock substrates are known/ Other radical clock processes include racemization of radicals with chiral conformations, one-carbon ring expansion in cyclopentanones, norcarane and sprro[2,5]octane, a-and p-thujone radical rearrangements, and cyclopropylcarbinyl radicals or... 

Stereoselective radical reactions of carbonyl derivatives of heterocycles 00MI12. Suzuki-Miyaura cross-coupling reaction in organic synthesis (review contains many examples of reactions with participation of heterocycles) 02T9633. Tautomerism in diazoles, pyridines, and nucleic bases 02UK1120. 

Radical intermediates in electron-transfer reactions of pyridines 85ACR22. Radical reactions of thiopyridones 84SR(3)289. 

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