Bischler synthesis

A large number of carbazole syntheses have involved the preparation and dehydrogenation of hydrocarbazoles, mainly 1,2,3,4-tetrahydrocarbazoles, which are 2,3-disubstituted indoles. These, in turn, are usually prepared by the Fischer indole synthesis or the Bischler synthesis. This section will not deal with the preparation of the tetrahydrocarbazole, because... 

In the second classical method (Bischler synthesis), an aromatic primary or secondary (arylalkyl, but not diaryl) amine is condensed with an obromo (or better, hydroxy) ketone to give a 2,3-dialkylindole. This in turn is alkylated directly to the 1,2,3,3-tetraalkylindoleninium salt. Use of acetoin gives 2,3-dimethylindole, which is easily isolated and purified. The Bischler synthesis from a substitued aniline, and especially from anilines bearing one or more alkoxy groups, is much preferred in practice for indoles substitued in the 4-7-positions, since the substituted aiylhy-drazines needed for the Fischer synthesis are costly, unstable, or unavailable. 

A Bischler synthesis can be monitored best by IR,following the disappearance of the sharp, single N-H absorption of the indole, or also by the appearance of N-alkyl peaks in the NMR spectrum. 

Catalytic hydrogenation of a nitro-(formyimethyl)pyrimidine is accompanied by cyciization and formation of a fused pyrrole ring. The report on page 8 of Part I of a paper which describes the cyciization of 2-(2-aminophenyl)acetalde-hyde acetals is not cited in a 1986 paper [3189] which extends the method to the synthesis of 6-substituted indoles in which the substituent is electron-withdrawing this type of indole is not easily accessible by the Fischer or Bischler synthesis. 

In the original method, the Bischler synthesis, harsh acidic treatment of 2-arylamino-ketones (produced from a 2-halo-ketone and an arylamine) was used to bring about electrophilic cyclisation onto the aromatic ring these conditions often result in mixtures of products via rearrangements.However, iV-acylated... 

Intramolecular cyclization of 3-(acylhydrazino)pyridin-2-amines with polyphosphoric acid affords pyrido[2,3-c]-l, 2,4-triazines 7.144 This reaction is an extension of the Bischler synthesis of 1,2,4-benzotriazines.149... 

Quinazolines can be prepared by several methods. AT-Acylanthranilic acids undergo cyclization with ammonia or primary amines via amides 14 forming quinazolin-4(3ii0-ones 15 (Niementowski synthesis). Alternatively o-(acylamino)benzaldehydes or -acetophenones react with ammonia producing quinazolines 16 (Bischler synthesis) ... 

Among other classic but useful indole syntheses are those of Bis-chler (1892) and Madelung (1912). In the Bischler synthesis, an aniline derivative is alkylated by an alpha-haloketone. Heating the product (9.81) effects the electrophilic attack of the carbonyl group on the benzene ring the loss of water from the product gives the indole structure (Scheme 9.38). 

The Bischler and Niementowski syntheses are the most important methods for the synthesis of quinazolines and quinazolinones, with the latter and more well-known reaction being m improvement on the Bischler synthesis. Additional methods for the synthesis of quinazoline and quinazolinone ring systems involve various rearrangement reactions and metal-mediated processes. Examples of these reactions are illustrated below. 

The Bischler synthesis, first described in 1893, involves the fusion of A-acylanthranilic acid and ammonia to generate the corresponding 2-substituted quinazolinone, which exists in equilibrium with the 4-hydroxy quinazoline tautomer. Bischler s original synthesis, shown below, involved direct conversion of ammonium-A-acetylanthranilate to the corresponding 2-alkyl-2,3,4-dihydro-4-quinazolinone under thermal conditions. 

The mechanism of the Bischler synthesis is illustrated below. Fusion of ammonium-iV-acetylanthranilate generates the diamide, which then undergoes cyclodehydration to form tiie corresponding quinazolinone. The quinazolinone then tautomerizes to the 4-hydroxyquinazoline. ... 

The Bischler synthesis is still practical today for the synthesis of 2-substituted quinazolines and quinazolinones. However, it has been largely replaced by the Neimentowksi reaction, which can be conducted under milder conditions and is therefore more practical for synthesis highly functionalized quinazolines and quinazolinones. 

Mdhlau-Bischler Indole Synthesis, Mohlau-Bischler Synthesis)... 

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