Oxidation of quinolines and isoquinolines

Ochiai and Ohta have used lead tetraacetate in benzene to convert aromatic iV-oxides (67) to the corresponding acetylated hydroxamic acids (68). Similar oxidation of quinoline and isoquinoline JV-oxides... 

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. 

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. 

Deoxygenation of N-oxides,4 TiCl4 -NaBH4 (1 2) in DME reduces the N-oxide of pyridine and mcthylpyridines (picolines) to the corresponding heterocycles in high yield. However the N-oxide of quinolines and isoquinolines is reduced further to dihydro derivatives of the hetcrocyclcs. Pyridine, quinoline, and isoquinoline themselves are not reduced by this low-valent titanium species. Reduction of heterocyclic N-oxides with TiCI, has been reported (6, 588). 

An efficient procedure for the reduction of pyridine iV-oxides to piperidines using ammonium formate and palladium on carbon has been developed (Equation 98) <2001JOC5264>. The reaction conditions are mild and can also be applied to the iV-oxides of quinoline and isoquinoline. 

The classic SsAi substitution of activated aryl halides by protected cyanohydrin anions provides substituted benzophenones. Another procedure for the arylation of protected cyanohydrin anions involves the use of aromatic substrates activated as their rr-chromium tricarbonyl complexes. - Addition of the anion of (32) to the 1,3-dimethoxybenzene complex, for example, leads principally to the meta-suh-stituted isomer (33 equation 20). Preferential meta regioselectivity is also noted with other -rr-chromium tricarbonyl complexes of arenes. Other arylations of cyanohydrin anions include interesting but synthetically limited additions at the a-position of quinoline N-oxides. In a similar manner, cyanohydrin carbonates of aromatic aldehydes react with A -oxides of quinoline and isoquinoline. ... 

A -Oxides of quinolines and isoquinolines also undergo this type of reaction [56]. 

A number of publications also describe the air oxidation of the same pyridine substrates in the presence of cupric nitrate. Extensive work has also been reported on the fixed or fluidized bed vapor phase of alkylpyridines using vanadium catalysts. " The intermediate aldehydes can be isolated, but usually the conditions are set to minimize this side reaction. Vanadates, molybdates, and tin salts of these two oxyacids are also described as efTective catalysts in the high temperature oxidation of quinolines and isoquinolines. " ... 

The most reactive position for base-catalyzed hydrogen exchange of the 1-oxide derivatives of quinoline and isoquinoline is the position adjacent to the heteroatom and nearest the fused benzene ring. Thus for isoquinoline 1-oxide the positionalreactivity is given by 1 > >3 > > 4,... 

Examples of this cyclisation-oxidation strategy include the synthesis of pyridotriazine 5.32 (page 42) and syntheses of quinolines and isoquinolines (Chapter 6). Some examples of nucleophilic and electrophilic fragments are shown in Table 1.1. Several points arise from the table. 

TABLE 12.7 Selective Hydrogenation of Quinolines and Isoquinoline in the Benzene Ring over Platinum Oxide Catalyst... 

Cyanadons. Aluminum complexes of BINOLs (1) that are armed at C-3 and C-3 with diarylphosphine oxide groups possess both Lewis acid and base centers. Asymmetric cyanation of aldehydes and mines with MeaSiCN, and of quinolines and isoquinolines in a manner analogous to the Reissert reaction is successful (ee 70-90%). The asymmetric Strecker synthesis is applicable to conjugated aldimines and the higher reactivity of Me SiCN than HCN in the presence of 10 mol% of PhOH enables its use in catalytic amount while supplying stoichiometric HCN as the cyanide source. 

Selective hydrogenation of quinolines and isoquinolines. Catalytic hydrogenation of quinolines and isoquinolines usually occurs preferentially in the pyridine ring. However, if the hydrogenation is conducted in trifluoroacetic acid, the reverse situation obtains and the benzene ring is reduced more rapidly. The same result can be obtained with mineral acids, but such hydrogenations are much slower. Both 2- and 4-phenylpyiidine can also be reduced preferentially in the benzene ring. Platinum oxide or palladium or rhodium catalysts can be used. Further reduction of 5,6,7,8-tetrahydroquinolines with sodium and ethanol provides a convenient route to rrans-decahydroquinolines. 

A number of recently described routes take rather different approaches to the synthesis of quinolines and isoquinolines, for example ozonolyses of indenes, as shown below provides homophthalaldehydes which are at exactly the right oxidation level for aromatic pyridine ring closure with ammonia. Another method for the generation of equivalent species depends on the side-chain lithiation of ortho-methylaraldehyde cyclohexylamine imines, then acylation with a Weinreb amide. 

On the other hand, the pyridine ring portion of quinolines and isoquinolines can be oxidized to various hydroxyl-derivatives by enzymes. 1,2,3,4-Tetrahydroquinoline and 1,2,3,4-tetrahydroisoquinoline derivatives are easily aromatized to quinolines and isoquinolines, respectively, by using hypervalent iodine reagents or DDQ. ... 

As described in Section 7.4, hexamethyldisilane 857 reduces, analogously, pyridine, quinoline and isoquinoline N-oxides to the free bases [17] and converts aromatic nitro groups to azo compounds [12]. Likewise, as already discussed allyltti-methylsilane 82 and benzylttimethylsilane 83 will gradually dehydrate and activate BU4NF-2-3H20 in situ to catalyze the addition of 82 and 83 to pyridine, quinoline, and isoquinoline N-oxides [13] (cf Section 7.2). 

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 ). " ... 

Azine A1-Oxides. Quinoline and isoquinoline 7/-oxides react readily with 2-phenyl-5(47/)-oxazolone 209 (Rj = Ph) and 2-methyl-5(47/)-oxazolone 209 (Ri = Me) in the presence of acetic anhydride to afford 2-substituted 4-(quinol-2-yl)- 210 and 4-(isoquinol-l-yl)-5(4//)-oxazolones 211, respectively, in good yields... 

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. 

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). 

---