Indoles 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 a-arylaminoketones (produced from the 2-haloketone and an arylamine) was used to bring about electrophilic cyclisation onto the aromatic ring these conditions often resulted in mixtures of products via rearrangements. It is now known that N-acylated-Q-arylaminoketones can be cyclised under much more controlled conditions, and in contrast to early work, this approach to indoles can even be used to produce hetero-ring-unsubstituted indoles. ... 

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). 

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

Wender and White published a very simple indole ring synthesis that involves the generation of a bis-lithio anion 1 and its reaction with an a-halo carbonyl compound 2, followed by acid- or base-catalyzed dehydration [1,2], The overall transformation is shown in Scheme 1, along with three examples. This chemistry illustrates yet another indole ring synthesis that uses a-halo carbonyl compounds [3]. We will encounter these compounds again with the venerable Bischler indole synthesis in Chapter 23. A summary of several Wender indole ring syntheses is tabulated in Table 1 [1, 2, 4-7], Entry 5 features a directed lithiation method to the bis-lithio nucleophile [5], a modification also described by Wender and White [2], Sainsbury and... 

Aromatic amines react with 1-haloketones or 1-hydroxyketones to yield substituted indoles. This reaction is known as the Bischler indole synthesis (30). 

Wender and Aube have independently described the use of the Bischler-Napieralski reaction in the synthesis of Yohimban alkaloids. Aube s approach involved the cyclization of indole 50 followed by reduction of the resulting dihydroisoquinoline... 

A synthetic approach to the same tetracyclic y-carboline nucleus (235) is the consecutive Fischer indole and Bischler-Napieralski ring closure of o-acetamidoacetophenone methylphenyUiydrazone (234). The Bischler-Napieralski reaction has also been used in the synthesis of 3,4-benz-j8-carbolines (236) and 3,4-benz-3-carbolines, e.g. 237... 

The Yao group has made use of a Ic type intramolecular Heck reaction to prepare the C2-symmetric dimeric indole core of chloptosin <06OL4919>. A solvent-free variation of the Bischler indole synthesis, electrophilic cyclization of a-arylamino imine tautomers prepared from aniline derived a-arylamino ketones, has been used by Menendez and co-workers for the preparation of 2-arylindoles <06SL91>. 

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