Combes synthesis of quinolines

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The Combes synthesis of quinolines (Scheme 13) has been reviewed (92CHE845). 

Pyridine ring closure on Combes synthesis of quinolines 92KGS1011. 

In an example of the Combes synthesis of quinolines, acid-catalyzed condensation of 4(7)-aminobenzimidazole with excess acetylacetone afforded 5,7-dimethylimidazo[4,5-A]quinoline (81), albeit in low yield (Equation (44)) <91T7459>. 

This reaction is employed in the Combes synthesis of quinolines (Scheme 4.16). A side-chain with a terminal carbonyl group is first attached to the benzene ring. Acid catalysis then promotes the attack of C=0 on the ring by the adding of a proton to the carbonyl oxygen to increase its electrophilicity acid also catalyzes the elimination of water from the intermediate to generate the aromatic pyridine component of quinoline. Many quinolines have been prepared by this and related methods in the search for new antimalarial dmgs. 

A very large group of syntheses in which the /3,y-bond is formed are those in which a side chain electrophile attacks the benzene ring. These include the Skraup and Doebner-von Miller syntheses (dealt with in Section 2.08.2.2.3(ii)), the Knorr, Conrad-Limpach and Combes syntheses of quinolines (dealt with here), the Pomerantz-Fritsch synthesis of isoquinolines, and many syntheses of phenanthridines and of acridines. 

Combes, A. Synthesis of quinoline derivatives from acetyl acetone. Bull. Soc. Chim. France 1883, 49, 89. 

Yamashkin, S. A., Yudin, L. G., Kost, A. N. Pyridine ring closure in synthesis of quinolines according to Combes (review). Khim. Geterotsikl. Soedin. 1992,1011-1024. 

This reaction was first reported by Combes in 1888. It is the synthesis of quinolines by the condensation of primary aromatic amines with acetoacetone or other -diketones followed by cyclization in the presence of sulfuric acid. This method provides a rapid access to the 2,4-substituted quinoline skeleton but, it suffers from low regioselectivity, such as in the case of meto-substituted anilines with two different ortho positions for ring closure. It was found that polyphosphoric acid is a better catalyst than sulfuric acid for the cyclization," and the factors that affect this reaction have been reviewed by Roberts and Turner. ... 

The synthesis of 1,8-naphthyridines using adaptations of quinoline syntheses (Knorr, Conrad-Limpach, Combs, Chichibabin, Doebner, and Doebner-Miller) has been discussed by Hauser and Weiss104 and the reader is referred to this work for details. 

Tu S, Li C, Li G et al (2007) Microwave-assisted combinatorial synthesis of polysubstituent imidazo[l, 2-a]quinoline, pyrimido[l, 2-a]quinoline and quinolino[l, 2-a]quinazoline derivatives. J Comb Chem 9 1144-1148... 

The formation of quinolines and benzoquinolines by the condensation of primary aryl amines with P-diketones followed by an acid catalyzed ring closure of the Schiff base intermediate is known as the Combes quinoline synthesis. The closely related reaction of primary aryl amines with p-ketoesters followed by the cyclization of the Schiff base intermediate is called the Conrad-Limpach reaction and it gives 4-hydroxyquinolines as products. ... 

In the laboratory of S. Gupta, the synthesis of novel heterocyclic ring systems was accomplished utilizing the Combes reaction The condensation of 1-naphthylamine with 2-acylindan-1,3-diones produced the corresponding anils in good yield. The anils were cyclodehydrated to benz[/ ]indeno[2,1-c]quinoline-7-ones in the presence of polyphosphoric acid. Subsequent Wolff-Kishner reduction gave rise to the novel 7H-benzo[/ ]indeno[2,1-c]quinolines. 

In the attempted synthesis of twisted polycycle 1,2,3,4-tetraphenylfluorenoM, 9-g/i]quinoline, R.A. Pascal Jr. et al. used the Combes quinoline synthesis to assemble the azaaceanthrene core. Oxidation with DDQ was followed by a Diels-Alder reaction with tetracyclone (tetraphenylcyclopentadienone) to afford the corresponding cycloadduct. However, the last decarbonylation step of the sequence failed to work even under forcing conditions, presumably due to steric hindrance. 

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

Combes quinoline synthesis. Formation of quinolines by condensation of (i-di ketones with primary arylamines followed by acid-catalyzed ring closure of the intermediate Schiff base. 

Some of the quinoline preparations based on intramolecular SeAt processes belong to the classics of heterocycle synthesis. For instance, primary arylamines with a free ortho position can be made to undergo cyclocondensation with (3-diketones or with p-keto aldehydes in a strongly acidic medium Combes synthesis [101]) ... 

Condensation of arylamine with 1,3-diketone, keto-aldehyde, or dialdehyde, followed by acidic Friedel-Craft type cyclization and dehydration, is well-known as the Combes reaction for quinoline synthesis. 

The last two decades of the 19th century proved to be an important era for the development of quinoline chemistry. It was during this time period that various methods for synthesizing quinolines, such as the Friedlander quinoline synthesis, Pfitzinger quinoline synthesis, Doebner-Miller quinoline synthesis, Conrad-Limpach quinoline synthesis, Combes quinoline synthesis, and Camps quinoline synthesis were first reported. In 1882, Friedlander showed that the condensation of 2-aminobenzaldehyde (4) with acetaldehyde (5) provided quinoline (6). ... 

Alternatively, several new methods were unfolded which eventirally became conventional for synthesizing the structural core of quinoline. These are (a) Combes synthesis using anilines and p-diketones (b) Conrad-Limpach synthesis employing anilines and P-ketoesters (c) Doebner-Miller reaction involving anilines and a,P-unsatmated carbonyl compotmds (d) Friedlander synthesis using 2-amino-benzaldehyde and acetaldehyde (e) Povarov reaction which involves reaction of an aniline, a benzaldehyde and an activated alkene also known as Aza-Diels-Al-... 

Some of the classical quinoline syntheses utilize intramolecular ring-closing SnAr reactions. Among them, the Combes synthesis and the Skraup-Doebner-Miller synthesis are of general relevance. 

Many substituted quinolines are intermediates for antimalarials. The 2,4-di-substituted quinolines are produced from aniline and 1,3-diketones by the Combes quinoline synthesis (28). The reaction of aniline with nitrobenzene in the presence of dry sodium hydroxide at 140°C leads to formation of phenazine [92-82-0] and by-products (Wohl-Aue synthesis) (29). 

If a 3-diketone is used rather than a 3-keto ester, the result is a 4-alkylquinoline in what is known as the Combes quinoline synthesis. Reaction of aniline with acetyl acetonate (2,5-pentanedione), for example, generated enamine 258, which is in equilibrium with the imine (259). Enolization to 260 in the presence of HE was followed by cyclization to give the quinoline (261) in 96% yield.l57,l56a... 

Thermal or acid-catalyzed condensation of anilines with P-ketoesters leads to qui-nolin-4-ones. Cf. Combes quinoline synthesis. 

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