Comb Synthesis

Combes Synthesis. When aniline reacts with a 1,3-diketone under acidic conditions a 2,4-disubstituted quinoline results, eg,... 

Comb copolymers, 7 610t Combed yarn, 11 178 Combes synthesis, of quinolines, 21 189 Combicat, 7 387, 392 Combinational libraries, 7 382 characterization, 7 404-405 composition gradient libraries, 7 407 design, 7 399-400 fabrication, 7 414-419 temperature gradient libraries, 7 407—408 thickness gradient libraries, 7 406 Combination electrodes, 14 30 Combination vaccines, 25 504-505 Combinatorial biology, 16 414 Combinatorial biosynthesis, 15 301-302, 305... 

Combes synthesis with pentan-2,4-dione that led to 157, was ascribed to unfavorable steric hindrance in the alternative orientation in the Combes synthesis. 2-Amino-l,4-dimethylcarbazole underwent the Skraup reaction in the only orientation available to it. Finally, the carbazol-1-yIhydrazone of ethyl pyruvate underwent normal Fischer indolization giving 158 its 3-isomer gave an indole by cyclization at C-4 producing 159. ... 

The Combes synthesis of quinolines (Scheme 13) has been reviewed (92CHE845). 

Pyridine ring closure on Combes synthesis of quinolines 92KGS1011. 

The Combes synthesis has been used for the preparation of fused pyridine derivatives. Thus, 2,6-diaminopyridine reacts with the fluorinated 1,3-diketone (276) and PPA giving the naphthyridine derivative (277) (95% yield) <86JHC50l>, and compound (269) reacts with acetylacetone in acetic acid yielding heterocycle (278) (52% yield) <93JHC317>. A mixture of malic and sulfuric acids... 

In an example of the Combes synthesis of quinolines, acid-catalyzed condensation of 4(7)-aminobenzimidazole with excess acetylacetone afforded 5,7-dimethylimidazo[4,5-A]quinoline (81), albeit in low yield (Equation (44)) <91T7459>. 

The Combe synthesis was applied for the synthesis of pyrrolo[3,2-p]- and pyrrolo[2,3-c/]quinolines176 (equation 120). Even during the synthesis of an enaminone from a... 

Similar to the Combe synthesis, primary aromatic amines condense with alkyl acetoacetates at lower temperatures to give / -anilinocrotonates, which can be used as precursors for cyclization to 4-hydroxyquinolines177 by action of hot sulphuric acid or hydrochloric acid in a Conrad-Limpach synthesis. 

The present procedure for the preparation of acetone-anil is described by Reddelien. A reaction at lower temperature is reported by Craig, who also describes the alkaline decomposition of the anil to 2,4-dimethylquinoline and methane and gives a method of purification of the final product. Other methods for the preparation of 2,4-dimethylquinoline involve the Beyer synthesis from aniline hydrochloride and ethylidene acetone, a modification of this synthesis, or the Combes synthesis from acetyl-acetone and aniline. 

Some of the quinoline preparations based on intramolecular SeAt processes belong to the classics of heterocycle synthesis. For instance, primary arylamines with a free ortho position can be made to undergo cyclocondensation with (3-diketones or with p-keto aldehydes in a strongly acidic medium Combes synthesis [101]) ... 

While the 2-quinolone formation is due to an SgAr process analogous to a Combes synthesis, the 4-quinolone formation is thought to be the result of an electrocyclization. The Konrad-Limpach synthesis is very flexible with regard to the arylamine and P-keto ester substituents, as well as to the use of alkoxymethylene malonic esters and dianilides of malonic aicid... 

This reaction is employed in the Combes synthesis of quinolines (Scheme 4.16). A side-chain with a terminal carbonyl group is first attached to the benzene ring. Acid catalysis then promotes the attack of C=0 on the ring by the adding of a proton to the carbonyl oxygen to increase its electrophilicity acid also catalyzes the elimination of water from the intermediate to generate the aromatic pyridine component of quinoline. Many quinolines have been prepared by this and related methods in the search for new antimalarial dmgs. 

Alternatively, several new methods were unfolded which eventirally became conventional for synthesizing the structural core of quinoline. These are (a) Combes synthesis using anilines and p-diketones (b) Conrad-Limpach synthesis employing anilines and P-ketoesters (c) Doebner-Miller reaction involving anilines and a,P-unsatmated carbonyl compotmds (d) Friedlander synthesis using 2-amino-benzaldehyde and acetaldehyde (e) Povarov reaction which involves reaction of an aniline, a benzaldehyde and an activated alkene also known as Aza-Diels-Al-... 

Some of the classical quinoline syntheses utilize intramolecular ring-closing SnAr reactions. Among them, the Combes synthesis and the Skraup-Doebner-Miller synthesis are of general relevance. 

Cacchi synthesis (indole) 140 Chichibahin reaction 352 Chichibabin synthesis (indolizine) 153 Claisen synthesis (isoxazole) 188 Combes synthesis (quinoline) 399 Cook-Heilbron synthesis (thiazole) 206 Corey synthesis (oxirane) 22 Cornforth rearrangement 171 imino-Corey reaction 36... 

The PS comb synthesis was finally achieved by adding dropwise the living PS solution onto a known amount of PCEVE in THF. Discoloration of the living PS was used as an indicator of the... 

---