Quinolines 4-aryl

In 1883, Bottinger described the reaction of aniline and pyruvic acid to yield a methylquinolinecarboxylic acid. He found that the compound decarboxylated and resulted in a methylquinoline, but made no effort to determine the position of either the carboxylic acid or methyl group. Four years later, Doebner established the first product as 2-methylquinoline-4-carboxylic acid (8) and the second product as 2- methylquinoline (9). Under the reaction conditions (refluxing ethanol), pyruvic acid partially decarboxylates to provide the required acetaldehyde in situ. By adding other aldehydes at the beginning of the reaction, Doebner found he was able to synthesize a variety of 2-substituted quinolines. While the Doebner reaction is most commonly associated with the preparation of 2-aryl quinolines, in this primary communication Doebner reported the successful use of several alkyl aldehydes in the quinoline synthesis. 

In a model study [50], 2-[2-(4-phenyl-3-amino)-pyridyl]quinoline 119 was derived from the Stille coupling of 2-trimethylstannylquinoline 41 and pyridyl triflate 118. As an extension of the aforementioned method, decorated 2-trimethylstannylquinoline 120 was coupled with a more intricate pyridyl triflate 121 in the presence ofY C, to assemble adduct 122 in 68% yield [49]. Addition of Cu2Br2 is supposed to promote the rate of transmetalation. 2-Aryl-quinoline 122 was an advanced intermediate for the total syntheses of Streptonigrin [51 ] and Lavendamycin [52], which have been shown to possess antitumor and antiviral activities [51]. 

Recently, Phan et al. (2013) prepared an open metal site MOF Cu(BDC) and successfully applied it to the modified Friedlander reaction. In the presence of 3-5 mol% Cu(BDC), several 2-aryl quinolines were efficiently synthesized from 2-aminobenzyl alcohol and methyl ketones (Scheme 4.42). Different from the previous reports, the reaction of p-methoxyacetophenone or p-nitroacetophenone did not occur in this catalytic system. 

Cenini, S. Bettettini, E. Fedele, M. Tollari, S. (1996) Intramolecular amination catalyzed by ruthenium and palladium synthesis of 2-acyl indoles and 2-aryl quinolines by carbon-ylation of 2-nitrochalcones, J. Mol Catal A-Chem., Ill, 37-41. 

Arylated quinolines were selectively accessed without diary-lated by-products in good to excellent yields using arylzinc species bearing ether, amine, and chloro functionalities (eq 17). 

T.R. Reddy, L.S. Reddy, G.R. Reddy, K. Yarbagi, Y. Lingappa, D. Rambabu, G.R. Krishna, C.M. Reddy, K.S. Kumar, M. Pal, Construction of a quinoline ring via a 3-component reaction in water crystal structure analysis and H-bonding patterns of a 2-aryl quinoline, Green Chem. 14... 

In an analogous manner, novel 2-(2-hydroxyaryl)quinolines can be prepared via a one-pot synthesis from intramolecular reductive coupling reactions of 2 -hydroxy-2-nitro-chalcones [75]. Accordingly, 2 -hydroxy-2-nitrochalcones 177a-b were treated with ammonium formate and Pd/C at room temperature to give a mixture of 2-(2-hydroxy-aryl)quinolines 178a-b and 2-(2-hydroxyaryl)quinoline-N-oxides 179a-b. 

Monographs on Contemporary Heterocyclic Chemistry and quinoline chemistry have appeared. The latter work contains reviews on alkyl- and aryl-quinolines, Reissert compounds and related dihydroquinolines, and quinoline N-oxides. The chemistry of quinolizines, 0 1, 7-naphtliyridines, azaphenalenes, 2... 

Arylation of Quinoline N-Oxides and Pyridines N-Oxides. An efficient protocol to directly arylate quinoline A-oxides was developed using palladium acetate as the catalyst and potassium carbonate as the hase. A survey of different phosphines demonstrated that the sterically less encumbered di-tert-butyl(methyl)phosphonium tetrafluoroborate provides higher yields relative to tri-iert-hutylphosphine. Using this protocol, 15 quinohne A-oxides were arylated in good to excellent yields (eq 1). ... 

SCHEME 31.46. Biomimetic reduction of 3-aryl-quinolines 140a-e. 

The reaction between aryl Grignard compounds and 5-methoxy-6-nitroquinoline derivatives in THF has been found to proceed in a chemodivergent mode that depended on the functional groups present in the heterocyclic ring. Thus, the reactions that started from carbostyril derivatives afforded 6-(arylamino)carbostyrils as the major products, whereas those that started with 2-alkoxyquinolines gave exclusively 5-aryl-quinolines. 

Synthesis and Properties. Polyquinolines are formed by the step-growth polymerization of o-aminophenyl (aryl) ketone monomers and ketone monomers with alpha hydrogens (mosdy acetophenone derivatives). Both AA—BB and AB-type polyquinolines are known as well as a number of copolymers. Polyquinolines have often been prepared by the Friedlander reaction (88), which involves either an acid- or a base-catalyzed condensation of an (9-amino aromatic aldehyde or ketone with a ketomethylene compound, producing quinoline. Surveys of monomers and their syntheses and properties have beenpubhshed (89—91). 

The wide variety of ketomethylene and amino ketone monomers that could be synthesized, and the abiUty of the quinoline-forming reaction to generate high molar mass polymers under relatively mild conditions, allow the synthesis of a series of polyquinolines with a wide stmctural variety. Thus polyquinolines with a range of chain stiffness from a semirigid chain to rod-like macromolecules have been synthesized. Polyquinolines are most often prepared by solution polymerization of bis(i9-amino aryl ketone) and bis (ketomethylene) monomers, where R = H or C H, in y -cresol with di-y -cresyl phosphate at 135—140°C for a period of 24—48 h (92). 

The Lewis acid-catalyzed cyclization of 3-anaino-2-alkerLirnines (21) leads to a wide variety of alkyl- and aryl-substituted quinolines (59). The high regiospecificity and the excellent yields obtained make this process promising. 

Phenols. Phenols are unreactive toward chloroformates at room temperature and at elevated temperatures the yields of carbonates are relatively poor (< 10%) in the absence of catalysis. Many catalysts have been claimed in the patent Hterature that lead to high yields of carbonates from phenol and chloroformates. The use of catalyst is even more essential in the reaction of phenols and aryl chloroformates. Among the catalysts claimed are amphoteric metals or thek haUdes (16), magnesium haUdes (17), magnesium or manganese (18), secondary or tertiary amines such as imidazole (19), pyridine, quinoline, picoline (20—22), heterocycHc basic compounds (23) and carbonamides, thiocarbonamides, phosphoroamides, and sulfonamides (24). 

Friedlander synthesis, 2, 444 Quinoline, 2-aryl-4-phenyl-synthesis... 

Me3SiI, CHCI3, 25-50°, 12-140 h. lodotrimethylsilane in quinoline (180°, 70 min) selectively cleaves an aryl methyl group, in 72% yield, in the presence of a methylenedioxy group. Me3SiI cleaves esters more slowly than ethers and cleaves alkyl aryl ethers (48 h, 25°) more slowly than alkyl alkyl ethers (1.3-48 h, 25°), but benzyl, trityl, and /-butyl ethers are cleaved quite rapidly (0.1 h, 25°). ... 

Condensation of Af-aryliminochlorides with malonic ester followed by thermal cyclization, as initially reported by Just, was found to be a general method for the preparation of 2, 3, 4-substituted quinolines. Various substituents on the aryl ring of the iminochloride proved uneventful, even though the conditions required to generate the iminochloride utilized PCI5. 

The Knorr quinoline synthesis refers to the formation of a-hydroxyquinolines 4 from P-ketoesters 2 and aryl amines 1. The reaction usually requires heating well above 100°C. However, some cases do exist when the cyclization takes place in the presence of a catalytic amount of mineral acid at temperatures as low as -10 °C. The intermediate anilide 3 undergoes cyclization by dehydration with concentrated sulfuric acid. The reaction is conceptually close to the Doebner-Miller and Gould-Jacobs reactions. ... 

A variety of aryl systems have been explored as substrates in the Knorr quinoline synthesis. Most notable examples are included in the work of Knorr himself who has demonstrated the high compatibility of substituted anilines as nucleophilic participants in that reaction. In the case of heteroaromatic substrates however, the ease of cyclization is dependent on the nature and relative position of the substituents on the aromatic ring." For example, 3-aminopyridines do not participate in ring closure after forming the anilide... 

Alteration of the relative reactivity of the ring-positions of quinoline is expected and observed when cyclic transition states can intervene. Quinoline plus phenylmagnesium bromide (Et20,150°, 3 hr) produces the 2-phenyl derivative (66% yield) phenyllithium gives predominantly the same product along with a little of the 4-phenylation product. Reaction of butyllithium (Et 0, —35°, 15 min) forms 2-butylquinoline directly in 94% yield. 2-Aryl- or 6-methoxy-quinolines give addition at the 2-position with aryllithium re-agents, and reaction there is so favored that appreciable substitution (35%) takes place at the 2-position even in the 4-chloroquinoline 414. Hydride reduction at the 2-position of quinoline predominates. Reaction of amide ion at the 2-position via a cyclic... 

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