Diketones reaction with aniline

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). 

Reaction of lithiated 3-enaminophosphonj tes of aniline and isocyanates with subsequent cyclization of the resulting amides with triphenylphosphine/triethylamine leads to the 3-phosphonyl-4-aminoquinolines (Equation 92) <1999T5947>. Aniline reaction with /3-diketones < 1999H(51 )2171 > and ethoxymethylenemalonates <1999JFC(94)7> also leads to quinoline formation. The Vilsmeier reaction conditions can also be applied to the synthesis of quinolines with the use of a-oxoketene /V -anilinoacetals (Equation 93) <2003JOC3966>. 

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... 

Reddy et al. synthesized 5-hydroxyindole derivatives via the Nenitzescu reaction by coupling of aniline, ethyl acetoacetate, and p-benzoquinone, in 1,2-dichloroethane, using montmorillonite KSF clay as catalyst (Scheme 18) [87]. The reaction was also performed using acyclic and cyclic 1,3-diketones and with aryl and alkyl amines. Among several catalysts tested in this reaction, montmorillonite KSF clay proved to be the best catalyst leading to the highest yields in a shorter reaction time. 

The first step of the Combes reaction has been reported to occur by merely mixing an aniline and diketone in an alcoholic solvent, or neat, with slight warming. Dilute aqueous acid (2 M HCl), AcOH, ZnCh as well as CaCl2, or other types of drying agents have been used to promote the first step. 

An interesting synthetic approach to cyclic enamine ketones is provided by waste-free and quantitative solid-state reaction of the anilines 236 with cyclic 1,3-diketones such as 332 or enolized 334 (Scheme 52). The enamine ketones 333c-h are quantitatively obtained in the solid state by milling at room temperature. The melt reaction (80 °C) for 333a is not quantitative, but 333b arises with 100% yield from the melt reaction [10]. All of the solid-state reactions give 100% yield, as usual. 

Other workers have concurrently developed the extensive acid-base chemistry of palladium and platinum /l-diketonates.44 452 Sequential displacement reactions also occur with Pt(CF3COCHC-OCF3)2, Pt(CF3COCHCOMe)2 and Pd(CF3COCHCOMe)2. Pdtetrakis(aniline)2+ diketonates are... 

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. ... 

Tu et al. have reported the synthesis of 4-aza-podoplyllotoxin via a three-component reaction of an aldehyde, aniline and cyclic diones in H2O under MWl. Use of tetronic acid as the cyclic diketone provided the 4-aza-podophyllotoxin derivatives (76) (Scheme 6.30). The reaction proceeded via the attack of Schiff s base, formed through the condensation between aldehyde and aniline, on tetronic acid resulting into an intermediate which underwent intramolecular cyclization and dehydration to yield the product. The scope of the strategy was enhanced by replacing tetronic acid with 1,3-indanedione to generate indenoquinoline derivatives (77) [69]. 

A simple preparation of indoles from anilines is based on a specific o-alkylation of ar. amines with sulfides in the presence of an active chlorine source such as tert-hwtyl hypochlorite . A lactamol has been obtained by double ring closure of a diketone in one operation combining 4 simple steps, all of which occur stereospecifically in high yield in the same medium . Another multiple reaction is the stereospecific rearrangement of an epoxytetrahydrofuranolactone in the course of synthetic studies on tetrodotoxin. A new riboflavin synthesis via its 5-oxide has been reported . 

Various synthetic approaches to 2-(trifluoromethyl)quinolines are based on use of the trifluoromethyl-containing reagents. In particular, 2-aminoaryl aldehydes (ketones) or ortho-v myl substituted anilines are appropriate starting materials to be condensed with readily available trifluoromethyl 1,3-diketones or aldehyde hydrates respectively. For instance, the regioselective Friedlaender reaction of unsymmetrical trifluoromethyl 1,3-diketones with 2-aminoaryl aldehydes appears to be an efficient way to 2-trifluoromethylquinolines 83a and 83b (Scheme 33) [54]. 

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