Quinoline radical substitution

As for radical substitutions in compounds XV, XVII, XXV, and some other compounds, the F values (hence also Ar and Sr values, cf. section V, A) correctly predict the experimental reactivity order. The calculated and experimental orders disagree in the case of compounds XXI and, particularly, XVI the latter case (radical phenylation of quinoline) represents a serious failure of the theory, for the experimental study was very thorough.160 It is worth noting that in the compounds which have no meso-position the center of radical reactivity is the position adjacent to the nitrogen atom (with the exception of the just mentioned phenylation of quinoline). 

Quinoline derivatives have been substituted by nucleosides <94JCS(P1)2931> and by ert-butyl groups <95JOC(60)5390> via radical substitution reactions. Palladium-catalyzed cross coupling method has been used to couple quinoline triflates with acetylene <95T(51)3737>. 4-Quinolones, in contrast to 2-quinolones, react with peroxodisulfate anions in aqueous base to form 3-hydroxyquinolines via the 3-sulfate ester <95JCR(S)164>. 

The reaction of nucleophilic radicals, under acidic conditions, with heterocycies containing an imine unit is by far the most important and synthetically useful radical substitution of heterocyclic compounds. Pyri-dines, quinolines, diazines, imidazoles, benzothiazoles and purines are amongst the systems that have been shown to react with a wide range of nucleophilic radicals, selectively at positions a and y to the nitrogen, with replacement of hydrogen. Acidic conditions are essential because A-protonation of the heterocycle... 

This chapter describes in general terms the types of reactivity found in the typical six-and five-membered aromatic heterocycles. In addition to discussions of classical substitution chemistry, considerable space is devoted to radical substitution, metallation and palladium-catalysed reactions, since these areas have become very important in heterocyclic manipulations. In order to gain a proper appreciation of their importance in the heterocyclic context we provide an introduction to these topics, since they are only poorly covered in general organic text-books. Emphasis on the typical chemistry of individual heterocyclic systems is to be found in the summary/revision chapters (4, 7, 10, 12, 16, and 20) and a more detailed examination, of typical heterocyclic reactivity, and many more examples for particular heterocyclic systems are to be found in the chapters - Pyridines reactions and synthesis etc. For the advanced student, it is recommended that this present chapter should be read in its entirety before moving on to the later chapters, and that the introductory summary/revision chapters, like Typical reactivity of pyridines, quinolines and isoquinolines should be read before the more detailed discussions. 

Stabilization will be greater, the greater the NBMO coefficient at that point. Radical substitution consequently takes place more easily in the a and y positions in pyridine than in the jS position, while quinoline reacts most easily in the 2,4 positions and isoquinoline in the 1 position. Similar directing effects are shown by +/ and —1 substituents for the same reason. 

Chlorination. Electrophilic chlorination of quinoline (66) in neutral medium showed a positional selectivity order of 3 > 6 > 8. The 5- and 8-positions should be sterically hindered to some extent. Hammett cr+ values predict an order for electrophilic substitution of 5 > 8 = 6 > 3. Treatment with chlorine at 160-190°C converted quinoline into a mixture of 3-chloro-, 3,4-dichloro-, 3,4,6- and 3,4,8-trichloro-, 3,4,6,8-tetrachloro-, and 3,4,6,7,8-pentachloro-quinolines. At lower temperatures ( 100°C) the major product was 3-chloroquinoline, albeit in low yield. The 4-substituted species may have arisen from an addition-elimination or radical process (70JHC171). 

Other quinoline A-oxide derivatives have been examined. A 1,3-oxazepine is the major product of irradiation of 2-cyanoquinoline A-oxide whereas lactam formation predominates on irradiation of 4-methylquinoline N-oxide in aqueous ethanol.60 Lactam formation has been shown to be influenced by an external magnetic field and on this basis it has been proposed that the first step in this transformation is the formation of an excited radical-ion pair.61 1,3-Oxazepines undergo further reaction on prolonged irradiation. The synthesis of 4-substituted indoles, for example, has been accomplished in this way by irradiation of 5-substituted quinoline A-oxides.62... 

Zoltewicz and Oestreich (1973) employed sodium methylate to accelerate the reaction between 4-bromo-iso-quinoline and sodium thiophenolate. In this case, the CHjO ion acts as a competing electron donor with respect to the PhS ion. On electron transfer to the substrate, thiophenolate converts into the phenylthiyl radical and then to diphenyldisulhde. Diphenyldisulfide is inactive in further transformations. The methylate ions generate the anion-radicals of the substrate, thus preserving the greater part of the thiophenolate for use in substitution. The observed rate of thioarylation and the yield of 4-phenylthio-iso-quinoline increase in the presence of sodium methylate. Azobenzene inhibits the action of sodium methylate. Scheme 5.7 summarizes what has been mentioned. 

It is important to note that sodium methylate initiates only the formation of 4-phenylthio-iso-quinoline the product of the competing substitution, 4-methoxy-iso-quinoline, is produced only in traces. The methylate ion, however, converts a part of the iso-quinolyl a-radicals into the unsubstituted iso-quinoline and produces formaldehyde. 

A study of substituent effects in the homolytic acylation of 2- and 4-substituted quinolines with acetyl and benzoyl radicals has confirmed this character of the reaction. The benzoyl radical shows a higher nucleophilic character than the acetyl. This has been explained by the fact that the polar character originates in the contribution of the polar form (7) in the transition state. 

The synthetic interest in direct substitution of protonated heteroaromatic bases by carbamoyl and a-amidoalkyl radicals arises because the reaction is applicable to a variety of heteroaromatic bases having highly reactive nucleophilic positions and because a variety of amides can be used. The selectivity of attack is complete at the a- and y-positions of the heterocyclic system owing to the nucleophilic character of both carbamoyl and a-amidoalkyl radicals, The results with formamide are shown in Table VI. Quinoline with dimethylformamide gave a variety... 

Radical attack on isoquinoline, as either free base or isoquinolinium cation, always occurs at position 1 and the method is not suitable for the preparation of benzo ring-substituted products. The same can be said of radical attack on the JV-oxides of quinoline and isoquinoline. 

A series of acridine antimalarial compounds was developed almost simultaneously with the quinolines. For example, quinacrine (59) (38USP2113357), almost a composite of the quinoline synthetics, was used extensively in World War II under the trade name Atabrine . Dimethacrine (60), an acridine with a radically different substitution pattern, still exhibits antimalarial activity (63BRP933875). 

Alkyl radicals for such reactions are available from many sources such as acyl peroxides, alkyl hydroperoxides, particularly by the oxidative decarboxylation of carboxylic acids using peroxy-disulfate catalyzed by silver. Pyridine and various substituted pyridines have been alkylated in the 2-position in high yield by these methods. Quinoline similarly reacts in the 2-, isoquinoline in the 1-, and acridine in the 9-position. Pyrazine and quinoxaline also give high yields of 2-substituted alkyl derivatives <74AHC(16)123). 

---