Quinolines dihydropyridine

This section is concerned with the structure of pyridines within this context we consider pyridine itself, pyridines substituted on carbon and nitrogen, including in the latter category ylide, betaine and zwitterion structures, and in the former benzo substituents. Thus quinolines and isoquinolines will receive attention as well as bipyridyls, but not, for example, cinnoline or quinoxaline. Completely saturated derivatives, such as piperidine, and partially saturated derivatives, such as dihydropyridines, will also be treated. 

Nucleophilic reagents attack pyridine at the a-position to form an adduct that rearomatizes by dissociation (Scheme 1). Only very strong nucleophiles, e.g. NH2-, RLi, LAH, Na-NH3, react, and for the second step to afford a substitution product (5), conditions that favour hydride loss are required. Adducts formed with hydride ions (from LAH) or carbanions (from lithium alkyls) are relatively more stable than the others at low temperature, and dihydropyridines (6) can be obtained by careful neutralization. Fusion of a benzene ring to pyridine increases reactivity towards nucleophiles, and attack is now found at both a- and y-positions in quinoline (7) and at C-l in isoquinoline (8). This may be attributed to a smaller loss of aromaticity in forming the initial adduct than in pyridine, and thus a correspondingly decreased tendency to rearomatize is also observed. Acridine reacts even more easily, but nucleophilic attack is now limited to the y -position (9), as attachment of nucleophiles at ring junctions is very rare. 

In a typical experiment quinoline (20 mg), catalyst (1-2 mol %) and Hantzsch dihydropyridine (2.4 equiv) were suspended in benzene (2mL) in a screw-capped vial and flushed with argon. The resulting mixture was allowed to stir at 60 °C for 12 h. The solvent was removed under reduced pressure and purification of the crude product by column chromatography on silica gel afforded the pure 1,2,3,4-tetrahydroquinoline. 

Benzo[l,3]dioxol-5-yl-ethyl)-quinoline (20.0mg 0.072 mmol), BINOL-phosphate 1 (0.5 mg, Imol %), Hantzsch dihydropyridine (43.8 mg,... 

The Brpnsted acid catalyzed hydrogenation of quinolines with Hantzsch dihydropyridine as reducing agent provides a direct access to a variety of substituted tetrahydroquinolines (Table 4.2). The mild reaction conditions of this metal-free reduction of heteroaromatic compounds, high yields, operational simplicity and practicability, broad scope, functional group tolerance and remarkably low catalyst loading render this environment-friendly process an attractive approach to optically active tetrahydroquinolines and their derivatives (Table 4.3) (see page 176). ... 

The interaction between pyridine and organolithium compounds in benzene was first reported by Ziegler and Zeiser129 and was attributed to the formation of 1 1 adducts. Indirect evidence for intermediates of this kind was based on the formation of dihydropyridines by treatment of the reaction mixture with water. More definite evidence was obtained with quinoline, isoquinoline, and acridine.130 Phenyllithium reacts quantitatively with quinoline in ether to yield an adduct as a yellow powder that can be recrystallized. In order to define the site of attachment, the adducts were hydrolyzed to dihydro derivatives and the latter dehydrogenated. Because this treatment leads mainly to 2-phenyIquinoIine and l-phenylisoquinoline from quinoline and isoquinoline, respectively, the related adducts can be assumed to have structures 80 and 81. Isolation and characterization of the dihydro derivatives have been carried out, as well as in the case of the reaction of acridine with phenyllithium. 

A-Acylpyridinium salts are more reactive than the A-alkyl derivatives and afford more stable dihydropyridine products on addition of nucleophiles. Organocuprates are utilized for entry into 2-alkynyl-substituted quinoline systems (Equation 53) <2005TL8905>. They have the advantage of superior selectivity over Grignard reagents, which yield a mixture of the 2- and 4-substituted products. The reaction has been expanded to include isoquinolines and pyridines. 

Allyl and benzyl bromides react with a,/ -unsaturated nitriles in the presence of indium(i) iodide under sonication to produce the corresponding allylated and benzylated imines, involving exclusive addition of the allyl/benzyl group to the nitrile moiety (Equation (63)).273 The reaction of allylindium reagents with methyl cyanoacetates affords the corresponding allylation-enamination products (Equation (64)).27 l-Acyl-l,2-dihydropyridines are prepared by indium-mediated allylation of 1-acylpyridinium salts (Equation (65)).275 Quinoline and isoquinoline activated by... 

In the synthesis of pyridines it proved advantageous to make a dihydropyridine and oxidize it to a pyridine afterwards. The same idea works well in probably the most famous quinoline synthesis, the Skraup reaction. The diketone is replaced by an unsaturated carbonyl compound so that the quino-y line is formed regiospecifically. 

Nina A. Nedolya was born in Irkutsk (Russia) and educated in organic chemistry at the Irkutsk State University (Diploma 1972, PhD 1982, DSc 1998). From 1995 to 1999 she was associated with Prof. L. Brandsma at the Utrecht University (The Netherlands). In 1999 she obtained her second PhD from the Utrecht University. She is presently Head of the Research Group of Chemistry of Heterocyclic Compounds at A. E. Favorsky Irkutsk Institute of Chemistry. She is the author of over 210 review articles and research papers. She is also one of the inventors for 112 patents. She is interested in the chemistry of polyfunctional unsaturated heteroatomic systems (vinyl, allenyl, and alkynyl ethers and their derivatives, linear and cyclic heteropolyenes, hetero-cumulenes), including synthesis of important heterocycles, particularly pyrroles, thiophenes, thiazoles, imidazoles, dihydrofurans, dihydropyridines, pyridines, quinolines, dihydroazepines, and azepines, based on metallated allenes or alkynes and/or heterocumulenes. 

This review deals with the formation of reduced pyridines and their benzo analogs from the parent heteroaromatic bases. Included are acridines, isoquinolines, pyridines and quinolines and their quaternary ammonium salts and N-oxides. The formation of the reduced species by other methods, e.g. Hantzsch dihydropyridine synthesis, is not addressed. 

Sodium hydride reduction of quinoline in HMPA leads to a 2 3 mixture of 1,2-dihydroquinoline (82) and 1,4-dihydroquinoline (83) isolated as the A-methoxycarbonyl derivatives. In situ produced copper hydride reagents react with pyridinium species with high regioselectivity generating 1,4-dihydropyridine... 

Heteroaromatic cations undergo reduction when treated with 1,4-dihydronicotinamide. An early study showed that the 10-methylacridinium ion (87) was rapidly reduced in a redox reaction to the 9,10-dihydro adduct by 1,4-dihydronicotinamides (M Scheme 18). A variety of systems including py-ridines, isoquinolines, quinolines and phenanthridines have been studied using this and related procedures. The selective reduction of pyridinium and quinolinium salts with 1-benzyl-1,2-dihydro-isonicotinamide (89) has been achieved. The selective conversion to the thermodynamically more stable 1,4-dihydro species (90 Scheme 18) is rationalized by the reversibility in the formation of the kinetic products (i.e. the 1,2-adducts) in the presence of pyridinium ions. In the pyridinium case 1,6-di-hydro adducts were also observed in some cases. Reactivity in such systems is sometimes hindered due to hydration of the dihydropyridine system. This is particularly so in aqueous systems designed to replicate biological activity. Dihydroazines derived from isoquinolines and 3,5-disubstituted pyridines have been reported to overcome some of these difficulties. ... 

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