Quinoline Combes synthesis

The Combes reaction is a sequence of the following reactions (a) condensation of an arylamine 1 with a 1,3-diketone, keto-aldehyde or dialdehyde 2 providing enamine 3, and (b) cyclodehydration to provide quinoline 4. 

In 1888, Combes described condensation of 2,4-pentadione (acetylacetone) 5 with aniline 1 to provide enamine 6. Subsequent warming in sulfuric acid provided quinoline 7. An excellent study describing scope and limitations of the Combes reaction was published in 1928 by Roberts and Turner. The authors noted that the ease of 

The rationale for the predominance of linear cyclization products versus angular cyclization products has been accepted as qualitative. The mechanism of the Combes reaction has been argued. It was initially proposed that cyclization to linear products was due to initial protonation of a more reactive site on the aromatic ring (1-position of 13 corrresponding to the 10-position of 15) thus, blocking cyclization to angular products. Bom showed this not to be the case for the cyclization of 2-naphthyl amino-2-penten-4-one. No 10-deutero material was observed. 

Condensation of an aniline with a dione with loss of water provides enamine 16. Ketone protonation and cyclization forms 18 followed by loss of water provides quinoline 4. Some have suggested the formation of dication 19 as a requirement to cyclization. Cyclization of 19 to 20 and subsequent conversion to quinoline 4 requires loss of water and acid. Another rendering of the mechanism takes into account participation of an electron-donating group (EDG), which stabilizes intermediate 21. 

Petrow described the formation of 3-iminoketones from 3-keto-aldehydes and aniline. Cyclization in the presence of aniline hydrochloride and ZnCh smoothly provides the desired quinoline 26. Bis-imine 24 is the proposed intermediate that undergoes cyclization. The aldimine is more reactive than the ketimine toward cyclization thus, cyclization on the aldimine occurs. When the bis-imine is not formed, partial aniline migration can occur which results in mixtures of cyclized products. 

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. 

Several conditions are used for the difficult cyclization step, avoiding the acidic hydrolytic conditions in the reaction mixture that can hydrolyze the initially formed enamine. Thus, use of concentrated inorganic acids is preferential (e.g., cone, sulfuric and hydrochloric acids), as well as chloroacetic acid,/7-toluene sulfonic acid, etc. 

Unsymmetrical diones have also been used as coupling partners for the Combes reaction, providing selectively, in some cases, otherwise difficult 

An unconventional modification of the Combes reaction was also used to access pharmacological interesting 3-formyl quinolines by treacling anilines with vinamidium salts.  

---

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). 

COMBES Quinoline Synthesis Quinoline synthesis from anilines and p-diketones... 

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 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. 

COMBES Quinoline Synthesis Qunoline synthesis from anilines and P-diketones... 

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... 

---