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15.3.1.1.1.3.2.1.1 Variation 1: Friedländer Synthesis

DOI: 10.1055/sos-SD-015-00689

Larsen, R. D.; Cai, D.Science of Synthesis, (200515398.

The Friedländer synthesis (Scheme 15)[‌83‌] consists of reacting a 2-aminobenzaldehyde[‌84‌] with a carbonyl compound 38 containing an active α-methylene group to produce the quinoline 39. The reaction is a suitable approach for introducing functionality at the 3-position.[‌85‌‌88‌] With acetoacetates the quinolin-2-one can also be formed through the amidation pathway (see Section 15.4.1.1.1.1.1.1).[‌89‌] Of particular utility is the application to the synthesis of camptothecin through coupling of aminobenzaldehydes with pyrroli­dinones.[‌90‌‌93‌] Base catalysis is traditionally used in the Friedländer reaction with alkali[‌94‌‌97‌] or alkoxides[‌98‌] in a protic solvent or dimethyl sulfoxide.[‌99‌] However, owing to the sensitivity or failure of some substrates to undergo the cyclization,[‌83‌] other bases, such as piperidine[‌88‌,‌100‌‌102‌] or Triton B,[‌103‌] are often used. The reaction affords very good yields at higher pH in water[‌104‌] or under neutral conditions in an alcoholic solvent.[‌105‌,‌106‌] An alternative substrate for the Friedländer reaction is the N-pivaloylaminobenzaldehyde 40, which reacts with aldehydes or ketones using potassium hexamethyldisilazanide as base to afford the quinolines 41.[‌107‌,‌108‌] N-Pivaloylaminobenzophenones also react under acid-catalyzed conditions to afford moderate yields of the 4-phenylquinoline derivatives.[‌109‌] In many cases the base-catalyzed conditions fail to yield any product, due in some part to the instability of the (2-acylaryl)amines. In particular, the base-catalyzed Friedländer reaction with aceto- or benzophenones is generally regarded to work only with simple methyl ketones.[‌110‌] Acid catalysis is an alternative and even provides improved yields, especially with benzophenones 42 which provide the 4-arylquinolines 43. By heating a mixture of the aniline hydrochloride directly with the ketone, very good yields of quinolines are obtained.[‌111‌,‌112‌] Hydrogen chloride in chlorobenzene is also used as a catalyst.[‌99‌] With catalytic sulfuric acid in acetic acid, good to high yields of quinolines are possible.[‌89‌,‌110‌,‌113‌‌116‌] Other acid catalysts are used, such as methanesulfonic acid,[‌87‌] 4-toluenesulfonic acid,[‌87‌,‌90‌,‌117‌,‌118‌] zinc(II) chloride,[‌119‌,‌120‌] or ion-exchange resins.[‌121‌] A microwave-assisted reaction in acetic acid[‌122‌] or in the presence of montmorillonite KSF clay is an alternative.[‌123‌] An advantage of the acid-catalyzed reactions is the ability to use the acetals or ketals of the benzaldehyde in the cyclization, imparting better stability to the starting material.[‌116‌] In some cases the Friedländer synthesis of quinolines is better run in a stepwise fashion:[‌106‌,‌124‌‌126‌] the Schiff base intermediate is formed in a separate step; subsequently, the cyclodehydration is carried out under acidic conditions.

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