Quinolinic acid enamine

Other secondary amines such as pyrrolidine, di- -butylamine, tetrahydro-quinoline, n-benzylamine, and piperidine were also found to be capable of effecting this reduction. Interestingly, morpholine does not reduce enamines as readily (47) and its acid-catalyzed reaction with norbornanone was reported (45) to give only the corresponding enamine (93), although trace amounts of the reduction product were detected when cyclohexanone was treated with morpholine under these conditions (47a). The yield of morpholine reduction product was increased by using higher temperatures. 

In 1888, Combes described condensation of 2,4-pentadione (acetylacetone) 5 with aniline 1 to provide enamine 6. Subsequent warming in sulfuric acid provided quinoline 7. An excellent study describing scope and limitations of the Combes reaction was published in 1928 by Roberts and Turner. The authors noted that the ease of... 

Condensation of an aniline with a dione with loss of water provides enamine 16. Ketone protonation and cyclization forms 18 followed by loss of water provides quinoline 4. Some have suggested the formation of dication 19 as a requirement to cyclization. Cyclization of 19 to 20 and subsequent conversion to quinoline 4 requires loss of water and acid. Another rendering of the mechanism takes into account participation of an electron-donating group (EDG), which stabilizes intermediate 21. 

Mechanistically, the Brpnsted acid-catalyzed cascade hydrogenation of quinolines presumably proceeds via the formation of quinolinium ion 56 and subsequent 1,4-hydride addition (step 1) to afford enamine 57. Protonation (step 2) of the latter (57) followed by 1,2-hydride addition (step 3) to the intermediate iminium ion 58 yields tetrahydroquinolines 59 (Scheme 21). In the case of 2-substituted precursors enantioselectivity is induced by an asymmetric hydride transfer (step 3), whereas for 3-substituted ones asymmetric induction is achieved by an enantioselective proton transfer (step 2). 

Reduction of quinolines in acid solution at a lead cathode or by dissolving zinc leads to attack on the heterocyclic ring with the formation of 4,4-coupled products, together with the tetrahydroquinoline [82,83]. In the case of 2- and 4-methyl substituted quinolines, dimeric products are obtained in 10 90 % yields. In these processes, dimerization of the one-electron addition product is in competition with further reduction to give the 1,4-dihydroquinoline, The latter is an enamine and it... 

Trimethylquinoline. Add 6g (0.032 mol) of the above enamine, in portions, to 25 ml of concentrated sulphuric acid (d 1.84) contained in a 250-ml conical flask. Swirl the mixture occasionally to ensure thorough mixing. The first portions of the enamine dissolve rather slowly but solution occurs more rapidly with the later portions as the temperature of the mixture increases to 60-70 °C. Heat the reaction mixture on the steam bath for 30 minutes, and then cool the brown solution to room temperature and add it slowly to 250 ml of ice-water in a 1-litre beaker. Add solid sodium carbonate to the solution until it is alkaline. During this addition the quinoline salt tends to separate and the whole mixture may solidify if this happens the mass should be broken up and stirred with a stout glass rod or spatula while the sodium carbonate is added. The quinoline eventually separates as an oil from the alkaline solution. Cool the mixture in an ice-water bath until the quinoline solidifies avoid over-cooling as this will result in the separation of a large... 

In another synthesis of quinolines involving imine intermediates, o-oxazoline-substi-tuted anilines (6) react with ketones in dry butanol reflux to give 4-amino-substituted quinolines [e.g. (7)], or 4-quinolones, using tosic acid as catalyst.18 A mechanism involving ketoimine formation with subsequent tautomerization to give an enamine which attacks the oxazoline ring is discussed. 

The schemes presented below also illustrate the synthesis of various amides of substituted quinoline-and quinolonecarboxylic acids 212-214 by the reaction of isatins 7, 9, 54, and 180 with amides 215 [179], acylated amino acids 216 and isothiocyanates [182], and enamines 217 [183],... 

The reduction of isoquinolinium ions has been extensively investigated with borohydride and aluminum hydride ions. The use of boro-hydride ion in a protonic solvent normally leads to the formation of 1,2,3,4-tetrahydroisoquinolines, whereas the reduction with aluminum hydride ion in an aprotic medium generally gives a 1,2-dihydroiso-quinoline. This 1,2-dihydroisoquinoline contains an enamine system and may undergo further reaction on treatment with acid. The 1,2-and 3,4-dihydroisoquinolines as well as isoquinolinium ions are reduced by the borohydride ion in a protonic medium to the 1,2,3,4-tetrahydroisoquinolines. 

According to the work of Greenhill and Mohamed dimedone enamine is attacked by methyl vinyl ketone in propionic acid at the / -position leading to quinoline ring closure. 

The first step in the Combes reaction is the acid-catalyzed condensation of the diketone with the aromatic amine to form a Schiff base (imine), which then isomerizes to the corresponding enamine. In the second step, the carbonyl oxygen atom of the enamine is protonated to give a carbocation that undergoes an electrophilic aromatic substitution. Subsequent proton transfer, elimination of water and deprotonation of the ring nitrogen atom gives rise to the neutral substituted quinoline system. 

Trifluoromethyl-3,l-benzoxazine-4-ones (255) react rapidly with enamines (256) at low temperatures to quinoline-8-carboxylic acids (258) and a secondary amine. Nucleophilic attack of (256) on (255) has been assumed, forming an intermediate vinamidine (257) which immediately undergoes cyclization103 ... 

Quinoline 289 was obtained as a byproduct from the acid catalyzed reaction of 31 (R = H) with 3-ethoxy-2-methylacroline to give 286 whose further reaction with 31 (R = H) gave 287 that upon oxidation gave 288, which cyclized to 289 (81JCR(S)66, 84JCS(P1)287). Enamine 31 (R = H,... 

The lower temperature variation of this reaction initially forms an imine or an enamine. Friedel Crafts cyclization gives the 4-hydroxyquinoline in what is called the Conrad-Limpach reaction. xhis reaction generally gives the opposite regioisomeric product to that obtained by the Knorr quinoline synthesis. The initially formed product is usually the enamine (as in the formation of 248 from aniline and ethyl acetoacetate). 3 Under acidic conditions the iminium salt is formed and cyclized with the aromatic ring. A more efficient method simply heated 248 to 250°C in mineral oil, giving a 90% yield of 249. A variety of other functional groups can be tolerated in the molecule when this procedure is used. 

A -Quatemization increases the CH-acidity of the 2> and 4-CH3 groups in quinoline even further. The anhydrobases formed after deprotonation (e.g. 34) are usually stable and, as enamines, are subject to electrophilic attack on the CH2 group, e.g. alkylation (34 35) ... 

The preparation of the quinoline system by pericyclic reactions is less important than the previous syntheses. Some cyclization/elimination reactions of iV-phenylimines 95 and 96 with alkynes, enol ethers or enamines are of preparative interest. Although they correspond to [4+2] cycloadditions, they are likely to proceed by SeAt mechanisms and are usually catalysed by Lewis acids. In the enolether cycloaddition to imines 95 ytterbium(III)triflate proved to be particularly effective [104]. 

The particular acidity of the protons of pyridine a- and 7-alkyl groups is echoed by quinoline-2- and 4-alkyl groups and by alkyl at the isoquinoline 1-position, but to a much lesser extent by alkyl at isoquinoline C-3. Condensation reactions with alkyl groups at these activated positions can be achieved in either basic or acidic media the key nucleophilic species in the latter cases is probably an enamine, or enamide, and in the former, a side-chain carbanion. ... 

One routine method for the functionalization of quinolines is the addition of substituents to the 2-position. Further advances in the catalytic, enantioselcctive Reissert-type reaction were reported. Quinoline 63 was treated with 2-furoyl chloride and TMSCN in the presence of Lewis acid-Lewis base bifunctional catalyst 64 followed by reduction of the corresponding enamine to afford quinoline 65 in 93% ee. Quinoline 65 was subsequently converted to (-)-L-689,560, a potent NMDA receptor antagonist <01JA6801>. Additions of ally.silanes to quinolines acylated with chloroformate esters and catalyzed by various triflate salts were reported <01T109>. 

Quinolines and isoquinolines can also react with electrophiles at the pyridine side. This can be rationalized by a different reaction mechanism involving the prior introduction of a nucleophile in the heterocyclic quinoline/isoquinoline ring followed by an electrophilic substitution involving attack on the intermediate enamine. Notable is the electrophilic bromination of isoquinoline hydrobromide in a solvent like nitrobenzene that provides 81% yield of 4-bromoisoquinoline, in contrast to the bromination or chlorination of an isoquinoline-aluminum chloride complex that affords 78% of 5-bromoisoquinoline. Exhaustive bromination or chlorination under Lewis acid conditions usually yields mixtures of 5,8-halogenated isoquinolines along with 5,7,8-trisubstituted derivatives. ... 

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