Quinoline and isoquinoline A-oxides

A -Oxide chemistry in these bicyclic systems largely parallels the processes described for pyridine A -oxide, with the additional possibility of benzene ring electrophilic substitution for example, mixed acid nitration of quinoline N-oxide takes place at C-5 and C-8 via the 0-protonated species, but at C-4 at lower acid strength nitration of isoquinoline A -oxide takes place at C-5. Diethyl cyanophosphonate converts quinoline and isoquinoline A -oxides into the 1- and 2-cyanoheterocycles in high yields in a process which must have 0-phosphorylation as a first step, and in which the elimination of diethylphosphate may proceed via a cyclic transition state.  

---

Again, as expected, pyridine A-oxides are very susceptible to nucleophilic attack. Unlike the situation usually prevalent with the quaternary pyridinium salts, the elimination stage of the two-step nucleophilic substitution can occur with relative ease, the oxide grouping serving as a good sink for the leaving hydride ion electron-pair and being itself eliminated in the process. Considerably more work has been carried out on quinoline and isoquinoline A-oxides than on pyridine A-oxide derivatives. 

Quinoline and isoquinoline A-oxides, formed by the action of peracids in quinoline and isoquinoline core, are useful synthetic precursors as they possess both electrophilic and nucleophilic character. The positive charge on nitrogen or the negative charge on oxygen atom can be delocalized to the a-or y-positions, depending on demand fi-om the reagent used. 

For pyridine N- oxides, direct oxygen loss may occur, but for quinoline and isoquinoline N- oxides (118) a 1,2-shift is an alternative, giving the corresponding -one radical cation (119) (68T3139), while -one derivatives themselves readily lose CO, as shown for N-methylquinolin-2-one (120) and acridinone (121) molecular ions (67AJC1179, B-71MS364). 

The Reissert-Henze and the Feely-Beavers-Tani reactions are considered together in this section because of their similarity. The former involves cyanation of acyloxy (formed in situ) (Scheme 113), and the latter alkoxy (Scheme 114), quaternary salts. The Reissert-Henze reaction is a facile, fairly general reaction for quinoline and isoquinoline AT-oxides (Table 19) with cyanation occurring a to the ring nitrogen. Certain substituents inhibit reaction, for example a 1-methyl group (equation 125), and others undergo replacement (Scheme 130) (81H(15)98l). Reaction of 1-methylisoquinoline 2-oxide with benzoyl chloride... 

The reaction of N,N- dimethylaniline with pyridine (equation 55) should also be considered in this category. Enamines usually attack acylated N- oxides at position 2 unless it is blocked, as in 2-methylquinoline 1-oxide, when attack takes place at C-4. Methyl /3-aminocrotonate attacks quinoline and isoquinoline AT-oxides at the position a to the N- oxide function in the presence of tosyl chloride (78JHC1425). However, pyridine and 2-methylpyridine 1-oxides react at the 4-position (equation 142). A low yield of by-product (242) is formed in each case, probably as a result of self-condensation of methyl /3-aminocrotonate. 4-Hydroxyquinoline 1-oxide is exceptional in that it reacts with an enamine in the presence of tosyl chloride at the /3-position (Scheme 170) (B-71MI20500). 5-Amino-3-methylisoxazole reacts with quinoline 1-oxide at the a-position, and the product can be degraded, to afford ultimately 2-methylquinoline (Scheme 171) (78CPB2759). 

A variety of new methods for the selective reduction of pyridine Ar-oxides to the corresponding pyridine have been developed. A procedure that is limited to the reduction of relatively electron-rich pyridine Ar-oxides utilizes hexamethyldisilane in the presence of methyllithium in THF/HMPA <1999JOC2211>. This reduction can also be performed on quinoline and isoquinoline Ar-oxides. Tris(2-carboxyethyl)phosphine (TCEP) can be used to... 

Albini, A., Fasani, E. and Maggi Dacrema, L. (1980) Photochemistry of methoxy-substituted quinoline and isoquinoline N-oxides. Journal of Chemical Society, Perkin Transactions 1, (12), 2738—2742. 

It has recently been demonstrated that bromo-tns-pyrrolidino-phosphonium hexafluorophosphate (PyBroP) can be functiOTiing as a mild activator of azine N-oxide providing regioselective addition of Ai-nucleophiles (amines, sulfonamides, and NH-heterocycUc compounds) to pyridine, quinoline, and isoquinoline N-oxides (Scheme 53) [112,113]. A strong regiochemical preference for the orf/io-substitution pattern in aU these cases is likely caused by specific electrostatic attraction of nucleophilic species and the intermediate phosphonium salt 76. This synthetic procedure was successfully extended for other types of nucleophilic reagents (phenols, thiols, malonates). 

High yields of a-cyanoazines are obtained from pyridine, quinoline or isoquinoline A -oxides and TMS-CN in acetonitrile/triethylamine or in DMF, and also in THF in the presence of tetrabutylatmnoni-um fluoride. In another variation TMS-CN together with dimethylcarbamoyl chloride is used. Mechanistically these transformations should be similar to the Reissert reaction and may run through intermediates of type (18) and (19 Scheme 22). ... 

In a similar vein, quinoline and isoquinoline N-oxides react with 2-oxazolin-5-ones (2) in the presence of acetic anhydride to give (3) which upon hydrolysis yield the aminomethyl derivatives (4). ... 

The methylation of pyridine, quinoline, and isoquinoline N-oxides to afford A-methoxy salts has also been investigated. For example, treatment of quinoline A-oxide with dimethyl sulfate provides the N-methoxy methylsulfate salt in excellent yield (eq 9). The resulting salts were subsequently treated... 

This method is exemplified by its application to quinoline, isoquinoline, cinnoline, and isoquinoline 2-oxide, which are nitrated as their conjugate acids. The rate profiles for these compounds and their N- or O-methyl perchlorates show closely parallel dependences upon acidity (fig. 2.4). Quaternisation had in each case only a small effect upon the rate, making the criterion a very reliable one. It has the additional advantage of being applicable at any temperature for which kinetic measurements can be made (table 8.1, sections B and D). 

Heterocyclic N-oxides such as pyridine, quinoline, or isoquinoline N-oxides can be converted into a mixture of 2- and some 4-cyanopyridines, 2- or 4-cyanoquino-lines, or 1-cyanoisoquinolines, in 40-70% yield, in a Reissert-Henze reaction, by activation of the N-oxide function by O-acylation [1] or O-alkylation [2, 3] followed by treatment with aqueous alkali metal cyanide in H2O or dioxane. 

The oxidative degradations of binuclear azaarenes (quinoline, isoquinoline, and benzodrazines) by hydroxyl and sulfate radicals and halogen radicals have been studied under both photochemical and dark-reaction conditions. A shift from oxidation of the benzene moiety to the pyridine moiety was observed in the quinoline and isoquinoline systems upon changing the reaction from the dark to photochemical conditions. The results were interpreted using frontier-orbital calculations. The reaction of OH with the dye 3,3,6,6-tetramethyl-3,4,6,7,9,10-hexahydro-(l,8)(2//,5//)-acridinedione has been studied, and the transient absorption bands assigned in neutral solution.The redox potential (and also the pA a of the transient species) was determined. Hydroxyl radicals have been found to react with thioanisole via both electron transfer to give radical cations (73%) and OH-adduct formation (23%). The bimolec-ular rate constant was determined (3.5 x lO lmoU s ). " ... 

Oxidation of quinoline and isoquinoline under vigorous conditions with potassium permanganate results in oxidative degradation of the benzo-fused ring and formation of pyridine-2,3- and -3,4-dicarboxylic acid respectively. As expected, the presence of electron-donating substituents facilitates the reaction while electron-withdrawing substituents make oxidation much more difficult. Apart from A-oxide formation, little study has been devoted to the oxidation of other benzo-fused 7r-deficient systems. 

A hydrogen attached to a pyridine or pyridine 1-oxide nucleus cannot be replaced directly by cyanide however, addition of cyanide to various quaternary salts constitutes an important class of reactions of synthetic importance. Before surveying these reactions in detail, the four main classes are outlined. In 1905, Reissert reported the first example, the reaction of quinoline with benzoyl chloride in aqueous potassium cyanide (Scheme 111) (05CB1603). This yielded a crystalline product, C17H12N2O, a Reissert compound (176) which afforded benzaldehyde and quinaldinic acid on acid hydrolysis (Scheme 111). Kaufmann (09CB3776) treated a 1 -methylquinolinium salt with aqueous potassium cyanide and observed 1,4-rather than 1,2-addition (Scheme 112), the Reissert-Kaufmann reaction. Reissert compounds are well known in the quinoline and isoquinoline series, but only rarely have even small yields been found in the pyridine series. On the other hand, cyanide ions add 1,4 with ease to pyridinium salts that have an electron withdrawing substituent at C-3. 

Antimony pentachloride complexes of A-oxides of pyridine, quinoline and isoquinoline rearrange on heating to give the corresponding pyrid-2-one, carbostyril or isocarbostyril, e.g. Scheme 118 (81T1871). 

Similarly, the large a-CH couplings of pyridine, quinoline, and isoquinoline can be used to locate substituents or fused rings in these heterocycles [73 d, i], N-Oxidation and protonation further enhance Jcu of the a-CH bond in pyridine (Table 4.68) due to the positive charge at nitrogen. To conclude, the sites of oxidation and protonation can be derived from the magnitudes of JC I in pyridines, azines, and their fused derivatives [467]. 

Small amounts of the benzopyridines quinoline and isoquinoline are excreted as their N-oxides (41) by guinea-pigs and are also formed by guinea-pig and rabbit hepatic microsomes15,28. Moreover, the antimalarial agent chloroquine affords an N-oxide as a metabolite of the quinoline ring system104. 

---