Preparation of quinolines

Furthermore, a novel hydrothermal aromatic alkylation of anilines with cyclic ketones and acyclic ketones was presented. Though the yields were low for this system, the fact that these 

Rossi et al. have reported a palladium-assisted multicomponent reaction involving 2-ethynylarylamines 106, aryl iodides 107, primary amines 108, and carbon monoxide that lead to a variety of substituted quinoline derivatives 109 as shown by the example in Seheme 30 05JOC6454 . This is the first time this type of multicomponent caseade reaetion was successful using primary amines previously, only secondary amines were successful. 

Additionally the authors were able to optimize their conditions to provide good to high yields of both isomers (113 and 114) and moderate to high diastereomeric ratios of 113 114. 

In this method the initial iodocyolization of a variety of propargylic anilines can be accomplished and followed by palladium-catalyzed substitution reactions to provide further elaboration of the 

In a similar manner a series of substituted tetrahydroquinolines were synthesized using a Lewis acid catalyzed intramolecular halo-arylation. This process was shown to be a regio- and stereoselective method that provided products in moderate to high yield 05TL8599 . 

Mulvihill et al. developed a novel one-pot synthesis of 2- or 3-mono-substituted or 2,3-disubstituted quinolines 07OBC61 . In this one-pot reaction, o-nitroaryl-carbaldehydes 80 were reduced with iron and catalytic HC1 to o-aminoarylcarbaldehydes 81 followed by in situ condensation with aldehydes or ketones to form mono- or di-substituted quinolines 82 in good yields. 

Using an environmentally benign Friedlander synthesis, Yang and co-workers synthesized 11 //-indeno[ l, 2,/)Jquinolincs in refluxing ethanol and a catalytic amount of sodium ethoxide 07T7654 . This method provided a very nice complement to quinoline synthesis through the Friedlander reaction while avoiding harsh reaction conditions. 

A variety of other environmentally friendly strategies for the synthesis of quinolines were also reported. Goswami et al. developed a one-pot approach for the synthesis of quinolines from aromatic amines and P-aryl vinyl ketones under solvent and catalyst free conditions 07JHC1191 . In another solvent free one-pot method, Nagarajan et al. synthesized 3-quinolylcarbazoles from P-nitrovinylcarbazole and 2-amino acetophenone in moderate yields 07TL2489 . 

A new approach for the synthesis of functionalized 4-alkylquinolines was developed utilizing electrogenerated carbanions 07SL1031 . The desired 4-alkylquinolines 83 were synthesized through a sequential alkylation/heterocyclization of p-(2-aminophenyl)-a,p-ynones 84 and the electrogenerated carbanions of nitroalkanes 85. This novel approach avoided metal and base catalysts and is performed under solvent free conditions. 

Additionally, Arcadi and co-workers developed an electrochemical approach for the synthesis of 3,4-disubstituted-2(l//)-quinolones in moderate yields through an intramolecular cyclization of alkynes and malonyl moieties 07EJ02430 . 

Wang et al. reported two different reaction conditions for a solvent free Friedlander quinoline synthesis. Initially, they reported the reaction of 2-acetyl anilines 73 with a variety of P-diketoesters 74 using / -Ts()H as the catalyst under microwave conditions to form substituted quinolines 75 060BC104 . They also reported the same reaction using BiCl3 as the catalyst under thermal conditions 06LOC289 . Both sets of conditions afford high yields and simpler experimental procedures. 

In addition to their work with solvent free systems, Wang and co-workers reported a water mediated Friedlander quinoline synthesis using hydrochloric acid and conventional heating to synthesize a variety of substituted quinolines in high yields 06TL1059 . 

R3 = CH3, CH2CH3, CH2OCH2CH2NPht R2 - R3 = COCH2C(CH3)2CH2, (CH2)6i CH2CH(f-butyl) CH2CH2 

Xie and co-workers developed a simple route for the synthesis of 3-aryl-l,2,3,4-tetrahydroquinolines 79 using a direct intramolecular reductive ring closure strategy 06TL7191 . The yields for the key reductive ring closure were moderate however, the simplicity of their route leads to an efficient synthesis of a variety of tetrahydroquinolines 79. 

A novel reaction for the synthesis of 4-amino-substituted quinolines 80 or 4-quinolones 81 was reported. Reaction of various ketones, such as 82 and 83, with o-oxazoline-substituted anilines 84 and 85 in the presence of a catalytic amount of /Mol ucncsul tonic acid (p-TSA) in dry w-butanol led to 80 and 81, respectively 06T9365 . To the authors surprise, the reaction of acetophenones 82 lead to a different outcome than that of the cyclic or acyclic ketones 83 containing more than one carbons a to the ketone. 

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The reaction is best carried out in the apparatus used in the preparation of quinoline, a 1500 ml. flask being fitted with a wide-bore air-condenser carrying in turn a water-condenser a still-head to fit the flask for subsequent steam-distillation should be assembled in advance. 

Oxidation. The synthesis of quinolinic acid and its subsequent decarboxylation to nicotinic acid [59-67-6] (7) has been accompHshed direcdy in 79% yield using a nitric—sulfuric acid mixture above 220°C (25). A wide variety of oxidants have been used in the preparation of quinoline N-oxide. This substrate has proved to be useful in the preparation of 2-chloroquinoline [612-62-4] and 4-chloroquinoline [611 -35-8] using sulfuryl chloride (26). The oxidized nitrogen is readily reduced with DMSO (27) (see Amine oxides). 

The preparation of quinolines using Skaup reaction uses the following scheme ... 

The traditional unpredictably violent nature of the Skraup reaction (preparation of quinoline and derivatives by treating anilines with glycerol, sulfuric acid and an oxidant, usually nitrobenzene) is attributed to lack of stirring and adequate temperature control in many published descriptions [1], A reaction on 450 1 scale, in which sulfuric acid was added to a stirred mixture of aniline, glycerol, nitrobenzene, ferrous sulfate and water, went out of control soon after the addition. A 150 mm rupture disk blew out first, followed by the manhole cover of the vessel. The violent reaction was attributed to doubling the scale of the reaction, an unusually high ambient temperature (reaction contents at 32°C) and the accidental addition of excess acid. Experiment showed that a critical temperature of 120°C was attained immediately on addition of excess acid under these conditions [2],... 

The preparation of quinoline and tetrahydroquinoline derivatives from metal carbonyl-catalyzed reactions of Schiff bases with alkyl vinyl ethers in... 

It is of primary interest to avoid corrosive mineral acids in synthetic processes. This can easily be achieved by use of acidic solid supports coupled with microwave irradiation. This has been applied to the preparation of quinolines [53] (Scheme 8.35). This procedure is a safe, green alternative to the use of H2S04 at more than 150 °C. In the same way, quinoxaline-2,3-diones were prepared [54] by use of single-mode irradiation. Previous attempts in solution led to explosions, but the authors successfully used solvent-free conditions with acidic supports or catalysts (the best being p-toluenesulfonic acid) and irradiation times of 3 min (Scheme 8.36). 

The formation of thietanes from thiones and olefins has been less exploited for synthetic purposes than the corresponding oxetane-forming reaction. It should be remarked that thiocarbonyl compounds very often undergo efficient photoreactions from the second excited singlet state S2 U4). One interesting synthetic application is found in the photochemical preparation of quinolines from N-thioamides (4.84)498). The primary photochemical step is assumed to be the intramolecular thietane formation. 

The method above described is the most satisfactory for the preparation of quinoline itself, but for the preparation of homo-logues of quinoline, the use of arsenic acid is preferable, since the yields are somewhat greater. 

Akiyama et al. extended this reaction to alkynylimines for the preparation of quinoline derivatives [28]. Treatment of N-aryl(alkynyl)imines 99 with 20 mol% W (CO)5(thf) in THF at reflux followed by oxidative work-up using NMO gave 2-arylquinolines 100 in reasonable yield through electrocydization of the vinylidene intermediate (Scheme 5.31). 

The majority of the methods for obtaining the naphthyridines (l)-(4) are similar to the methods employed for the preparation of quinolines, and aminopyridines are therefore the required starting compounds. Thus, 1,5-naphthyridines (1) may be obtained, sometimes together with the isomeric 1,7-naphthyridines (3), starting from 3-aminopyridine, 1,6-naphthyridines (2) are synthesized from 4-aminopyridines, and the 1,8-naphthyridines (4) are best obtained from 2-aminopyridine or its derivatives. 

The synthesis of quinolinic acid and its subsequent decarboxylation to nicotinic acid has been accomplished directly in 79% yield using a nitric-sulfuric acid mixture above 220°C. A wide variety of oxidants have been used in the preparation of quinoline iV-oxice. 

A preparation of quinoline-3-thiol from the diazonium salt, according to prior literature, and using potassium ethyl xanthate, abnormally threw down a solid during extraction of the product into ether. This solid, filtered and dried, exploded on prodding with a metal spatula. The solid had an nmr spectrum consistent with the expected product, an 5-aryl-O-ethyl xanthate. Although the author appears aware of only the arenediazosulfide hazard, this must have been the 5 -arenediazoxanthate. A misprint renders quinoline as quinine. 

Aniline, Glycerol, and Sulfuric Acid. The preparation of quinoline by the Skraup reaction may be violent unless adequate stirring and temperature control are maintained. 

Adams, R. and Sloan, A.W. (1941). Organic syntheses, Coll. Vol. I, 478 (a real blood-and-thunder preparation of quinoline). 

Many synthetic methods have been developed for the preparation of quinolines and 1,2,3,4-tetrahydroquinolines due to the interesting biological properties of quinoline-type alkaloids. Most of the synthetic methods are based on the elaboration of aniline derivatives and, as for the synthesis of tetrahydroquinolines, reduction of the corresponding quinolines is the main approach. Only a few methods have been reported for the construction of the quinoline skeleton by N-C(8a) bond formation as the key step, such as oxidative cyclization of 2-(3-aminopropyl)benzene-1,4-diol 89 with K2[Fe(CN)e] (Scheme 42)... 

The present one-electron reduction method thus provides an alternative route for the construction of the quinoline framework by forming the N-C(8a) bond starting from oxime derivatives. It is also noteworthy from a synthetic point of view that the present cyclization exhibits a wide generality for the preparation of quinolin-8-ols and l,2,3,4-tetrahydroquinolin-8-ols having various substituents. 

Reactions of 4-aryl-5(2f/)-isoxazolones with 1,2-dibromoethane in acetonitrile in the presence of 1 equiv of triethyl-amine gave 2-bromoalkyl-4-aryl-5(2/f)-isoxazolones as major products that were converted to heterocyclic ketene AjO-acetals by treatment with sodium methoxide in boiling methanol <1997T10433>. The preparation of quinoline derivatives was achieved by catalytic hydrogenation of 2-(2-formylaryl)-5(2//)-isoxazolones <2003T9887>. 

B) Preparation of Quinoline (M.). The results are generally better by the macro method. Use five times the amount of reagents, and a 500-ml reaction flask. The condenser should be very efficient. Use same precautions given for the micro method in starting the reaction, and allow it to proceed without external application of heat for 15-20 minutes. Boil for four hours. Transfer the mixture to a two-liter Florence flask for steam distillation. Steam-distill until about 1500-1700 ml of distillate has been collected. Use three 60-ml portions of ether with a separatory funnel to extract the distillate, and for the remainder of the experiment proportionate amounts of reagents. After the final extraction and recovery of ether use a small flask for the final distillation. If a vacuum pump is available, use a small Claisen flask and distill under diminished pressure. Collect the fraction which boils at 116-122 at 20 mm pressure. 

Combes Quinoline synthesis Preparation of quinolines from aryl amines and 1,3-diketones. 94... 

Matsugi, M., Tabusa, F., Minamikawa, J.-l. Doebner-Miller synthesis in a two-phase system practical preparation of quinolines. 

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