Combes reaction

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. 

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. 

The Combes reaction has been applied to the preparation of carbazoles related to eJJipticine. In that case, the imine was not formed separately nor purified yet the desired product 57 was isolated in 35%. ... 

A retrosynthetic analysis for 2,4,6-trimethylquinoline (102) reveals p-toluidine and pentane-2,4-dione. This is an example of the Combes reaction. 

The first step in the Combes reaction is the acid-catalyzed condensation of the diketone with the aromatic amine to form a Schiff base (imine), which then isomerizes to the corresponding enamine. In the second step, the carbonyl oxygen atom of the enamine is protonated to give a carbocation that undergoes an electrophilic aromatic substitution. Subsequent proton transfer, elimination of water and deprotonation of the ring nitrogen atom gives rise to the neutral substituted quinoline system. 

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. 

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. 

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. ... 

D Combes. Reaction/separation process in supercritical C02 using lipases, NATO ASI Ser., Ser. E, 317(Engineering of/with Lipases), 613-618, 1996. 

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). 

The most commonly used combination of chemicals to produce a polyacrylamide gel is acrylamide, bis acrylamide, buffer, ammonium persulfate, and tetramethylenediarnine (TEMED). TEMED and ammonium persulfate are catalysts to the polymerization reaction. The TEMED causes the persulfate to produce free radicals, causing polymerization. Because this is a free-radical driven reaction, the mixture of reagents must be degassed before it is used. The mixture polymerizes quickly after TEMED addition, so it should be poured into the gel-casting apparatus as quickly as possible. Once the gel is poured into a prepared form, a comb can be appHed to the top portion of the gel before polymerization occurs. This comb sets small indentations permanently into the top portion of the gel which can be used to load samples. If the comb is used, samples are then typically mixed with a heavier solution, such as glycerol, before the sample is appHed to the gel, to prevent the sample from dispersing into the reservoir buffer. 

The use of an acidic solution of p-anisaldehyde in ethanol to detect aldehyde functionalities on polystyrene polymer supports has been reported (beads are treated with a freshly made solution of p-anisaldehyde (2.55 mL), ethanol (88 mL), sulfuric acid (9 mL), acetic acid (1 mL) and heated at 110°C for 4 min). The colour of the beads depends on the percentage of CHO content such that at 0% of CHO groups, the beads are colourless, -50% CHO content, the beads appear red and at 98% CHO the beads appear burgundy [Vdzquez and Albericio Tetrahedron Lett 42 6691 200]]. A different approach utilises 4-amino-3-hydrazino-5-mercapto-1,2,4-triazole (Purpald) as the visualizing agent for CHO groups. Resins containing aldehyde functionalities turn dark brown to purple after a 5 min reaction followed by a 10 minute air oxidation [Coumoyer et al. J Comb Chem 4 120 2002]. 

Synthesis of comb (regular graft) copolymers having a PDMS backbone and polyethylene oxide) teeth was reported 344). These copolymers were obtained by the reaction of poly(hydrogen,methyl)siloxane and monohydroxy-terminated polyethylene oxide) in benzene or toluene solution using triethylamine as catalyst. All the polymers obtained were reported to be liquids at room temperature. The copolymers were then thermally crosslinked at 150 °C. Conductivities of the lithium salts of the copolymers and the networks were determined. 

Potter, A.E., Jr., and Anagnostou, E., Reaction order in the hydrogen-bromine flame from the pressure dependence of quenching diameter, Proc. Comb. Inst., 7 347,1959. 

Top view of a piston engine at a crank angle of 10°. Cross-section colored by the reaction rate for four different cycles. (From Richard, S., Colin, O., Vermorel, O., Benkenida, A., Angelberger, C., and Veynante, D., Proc. Comb. Inst., 31,3059,2007.)... 

The present volume continues the tradition. Once again the recent literature has been combed for new examples the better to exemplify principles of reactions. Of particular interest is an admirable chapter dealing with reactions controlled by orbital symmetry. Until I read it I was not convinced that this very important new development in the theory of organic reactions could be simply yet usefully communicated to students at an elementary level. To have succeeded in doing so only u nderlines further Dr. Sykes gifts as a teacher and writer and I am sure that this new edition of the Guidebook will more than equal the success of its predecessors. 

An alternative route for the preparation of styrenic macromonomers is the reaction of living chains with 4-(chlorodimethylsilyl)styrene (CDMSS) [192]. The key parameter for the successful synthesis of the macromonomers is the faster reaction of the living anionic chain with the chlorosilane group rather than with the double bond of the CDMSS. Anionic in situ copolymerization of the above macromonomers (without isolation) with conventional monomers leads, under appropriate conditions, to well-defined comb-like chains with a variety of structures. 

R. J. Pieters, D. T. S. Rijkers, and R. M. J. Liskamp, Application of the 1,3-dipolar cycloaddition reaction in chemical biology Approaches toward multivalent carbohydrates and peptides and peptide-based polymers, QSAR Comb. Sci., 26 (2007) 1181-1190. 

The first examples of microwave-mediated solid-phase carbon-nitrogen cross-coupling reactions were reported in 1999 by the group of Combs [16], using a boronic... 

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