Cyclization quinoline synthesis

KNORR Quinoline Synthesis Quinoline synthesis by cyclization of acetoacetanilides. 

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. ... 

The Knorr quinoline synthesis has been nicely extended by Hodgkinson and Staskun to include P-ketoesters that do not have protons at the 2 position of the starting keto-ester. 2,2 -dichloroanilides of type 14 can cyclize to provide quinolines such as 15 and 16 in good respective yields. ... 

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... 

An initial step of orthometallation probably also occurs when aniline is allowed to react with ethylene in the presence of a rhodium(I) catalyst. 2-Methylquinoline (10 turnovers relative to the metal) and JV-ethylaniline (30 turnovers) are formed after 72 h in what are probably two independent reaction pathways (Scheme 144).216 It is interesting to note that the intramolecular cyclization step in the proposed216 mechanism (Scheme 144) has precedent in the palladium-promoted quinoline synthesis reported by Hegedus et al.16 (see Scheme 142), but the transformation 118->119 is unusual in the chemistry of organometallic insertion reactions.106... 

Alkynes continue to be used as a reactive functionality in quinoline synthesis. The readily available thiocarba-mates, thioamides, and thioureas allow intramolecular cyclization of pendant alkynes to give modest to good yields of the quinolines (Equation 118) <20030L1765>. An intermolecular reaction involving a zinc-mediated alkynylation-cyclization provides an efficient route to 4-trifluoromethyl-substituted quinolines (Equation 119) <2002JOC9449>. 

The enamine will normally prefer to adopt the first configuration shown in which cyclization is i not possible, and (perhaps for this reason or perhaps because it is difficult to predict which quinoline will be formed from an unsymmetrical 1,3-dicarbonyl compound) this has not proved a very important quinoline synthesis. We shall describe two more important variants on the same theme, one for quinolines and one for qui nolo lies. 

As an example of alkylideneaminyl radical cyclization in quinoline synthesis, Forrester and colleagues reported the cyclization of (l,2,3,3-tetraphenylpropylideneaminooxy)acetic acid 91 by oxidation with KjSjOg (Scheme 43), and various heterocyclic compounds were prepared by this method. 

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. ... 

Knorr quinoline synthesis. Formation of a-hydroxyquinolines from (3-ketoesters and aryla-mines above 100C. The intermediate anilide undergoes cyclization by dehydration with concentrated sulfuric acid. 

In their quest to synthesize quinolines without the need to involve metalated species as cross-coupling partners, Banwell and coworkers have devised a two-step procedure wherein the first step is the palladium[0]-mediated Ullmann cross-coupling of 1-bromo-2-nitroarenes (e.g. 173) with p-halo-cnals [74]. The resulting p-nitroaryl enal undergoes reductive cyclization, in the style of the Friedlander quinoline synthesis, to give the corresponding quinoline. A wide range of quinolines can be accessed by this method since many l-halo-2-nitroarenes are commercially available and p-halo-cnals such as 174 can be easily prepared by Vilsmeier haloformylation of the appropriate ketones. 

Quinoline synthesis by acid catalyzed cyclization of acetoacetanilides (see 1st edition). 

ROBINSON - FOULOS Quinoline synthesis Cyclization of 2 ammo styrene derivatives to quinolines... 

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. 

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... 

It has been proven that the chiral Pd(II) complexes as transition metal catalysts vs Lewis acid catalysts bring a breakthrough in the frontier of catalytic asymmetric organic synthesis. Here we discussed the key issues based on asymmetric carbon-carbon bond formations anomalous six-membered ring formation, ene-type cyclization leading to five-membered rings, spiro cycliza-tion, alkaloid and quinoline synthesis, Suzuki-Miyaura coupling, and C-H bond activation/C-C bond formation by transition metallic Pd(II) catalysts. On the other hand, the carbonyl-ene reaction, hetero Diels-Alder reaction, and... 

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 quinoline is formed regiospecifically. The first step is conjugate addition of the amine. Under acid catalysis the ketone now cyclizes in the way we have just described to give a dihydroquinoline after dehydration. Oxidation to the aromatic quinoline is an easy step accomplished by many possible oxidants. 

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. 

This reaction was first reported by Knorr in 1886. It is the synthesis of 2-hydroxyquinolines via the cyclization and dehydration of an anilide intermediate condensed from )0-ketoesters and anilines at a relatively high temperature. Right after this report, Conrad and Limpach also reported a similar reaction between anilines and )0-ketoesters but at low temperatures, which resulted in the formation of 4-hydroxy quinolines from the intermediate of alkyl crotonate. Thus this reaction is known as the Knorr synthesis, Knorr-Limpach method, Knorr cyclization, Conrad-Limpach-Knorr reaction, or Knorr quinoline synthesis. It has been reported that the formation of an alkyl crotonate intermediate is favored at moderate or low temperature in the presence of iodine or an acid catalyst, whereas intermediate anilide is formed at high temperatures. ... 

The mechanism for the Niementowski quinoline synthesis is presumably similar to that of the closely related Friedlander reaetion. The mechanism for the Friedlander reaction has been studied extensively" and two possible mechanistic pathways exist, as illustrated below. There is support for both pathways. Most of the evidence, however, tends to favor initial formation of the SchifTs base intermediate (13) followed by cyclization to give quinoline 15 however, the reaction conditions and structures of the reactants may influence the pathway by which the reaetion proeeeds. ... 

Ichikawa J, Wada Y, Miyazaki H, Mori T, Kuroki H (2003) Ring-fluorinated isoquinoline rmd quinoline synthesis intramolecular cyclization of o-cyano- and o-isocyano- 0, 0-difluorostyrenes. Oig Lett 5 1455-1458... 

Hatano M, Mikami K (2003) Highly enantioselective quinoline synthesis via ene-type cyclization of 1,7-enynes catalyzed by a cationic BINAP-palladium(II) complex. J Am Chem Soc 125 4704-4705... 

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