Indoles, synthesis, Fischer indole

Related reactions Bartoli indole synthesis, Fischer indole synthesis, Madelung indole synthesis, Nenitzescu indole synthesis ... 

Benzilic acid rearrangement Benzoin reaction (condensation) Blanc chloromethylation reaction Bouveault-Blanc reduction Bucherer hydantoin synthesis Bucherer reaction Cannizzaro reaction Claisen aldoi condensation Claisen condensation Claisen-Schmidt reaction. Clemmensen reduction Darzens glycidic ester condensation Diazoamino-aminoazo rearrangement Dieckmann reaction Diels-Alder reaction Doebner reaction Erlenmeyer azlactone synthesis Fischer indole synthesis Fischer-Speior esterification Friedel-Crafts reaction... 

This reaction is related to the Bucherer Carbazole Synthesis, Fischer Indole Synthesis, Graebe-Ullmann Synthesis and Piloty-Robinson Pyrrole Synthesis. 

Fischer s name is associated with a great number of important organic transformations, such as the Fischer indole synthesis, Fischer esterification, Kiliani-Fischer synthesis, and the Fischer oxazole synthesis. The Fischer oxazole synthesis was one of his first contributions in his early years in the Berlin University (currently Humboldt University). In 1896 he published a new synthesis of 2,5-diaryloxazoles using an acid-catalyzed condensation of cyanohydrins with aldehydes. 

N. Campbell, B. M. Barclay, Chem. Rev. 40, 361 (1947) W. Freudenberg, Heterocyclic Compounds 3, 298 (1952) P. Bruck, J. Org. Chem. 35,2222 (1970). Cf. Bucherer Carbazole Synthesis Fischer Indole Synthesis Pilotv-Robinson Synthesis. 

An important general method of preparing indoles, known as the Fischer Indole synthesis, consists in heating the phenylhydrazone of an aldehyde, ketone or keto-acld in the presence of a catalyst such as zinc chloride, hydrochloric acid or glacial acetic acid. Thus acrtophenone phenylhydrazone (I) gives 2-phenyllndole (I V). The synthesis involves an intramolecular condensation with the elimination of ammonia. The following is a plausible mechanism of the reaction ... 

Retrosynthesis a in Scheme 7,1 corresponds to the Fischer indole synthesis which is the most widely used of all indole syntheses. The Fischer cyclization converts arylhydrazones of aldehydes or ketones into indoles by a process which involves orf/io-substitution via a sigmatropic rearrangement. The rearrangement generates an imine of an o-aminobenzyl ketone which cyclizes and aromatizes by loss of ammonia. 

Phosphorus trichloride in benzene is reported to effect mild and fast cydization. It has been used for synthesis of 2,3-dialkyl- and 2,3-diaryl-indoles[8-ll]. Table 7.2 presents some typical Fischer indolization reactions using both the traditional and more recently developed reaction conditions. 

One of the virtues of the Fischer indole synthesis is that it can frequently be used to prepare indoles having functionalized substituents. This versatility extends beyond the range of very stable substituents such as alkoxy and halogens and includes esters, amides and hydroxy substituents. Table 7.3 gives some examples. These include cases of introduction of 3-acetic acid, 3-acetamide, 3-(2-aminoethyl)- and 3-(2-hydroxyethyl)- side-chains, all of which are of special importance in the preparation of biologically active indole derivatives. Entry 11 is an efficient synthesis of the non-steroidal anti-inflammatory drug indomethacin. A noteworthy feature of the reaction is the... 

The Fischer Indole Synthesis and Related Sigmatropic Syntheses. In the Fischer indole synthesis (26) an Ai-aryUiydra2one is cyclized, usually under acidic conditions, to an indole. The key step is a [3,3] sigmatropic rearrangement of an enehydra2one tautomer of the hydra2one. 

Unsaturated hydrazones, unsaturated diazonium salts or hydrazones of 2,3,5-triketones can be used as suitable precursors for the formation of pyridazines in this type of cyclization reaction. As shown in Scheme 61, pyridazines are obtainable in a single step by thermal cyclization of the tricyanohydrazone (139), prepared from cyanoacetone phenylhydrazone and tetracyanoethylene (76CB1787). Similarly, in an attempted Fischer indole synthesis the hydrazone of the cyano compound (140) was transformed into a pyridazine (Scheme 61)... 

The Piloty-Robinson pyrrole synthesis (74JOC2575,18JCS639) may be viewed as a monocyclic equivalent of the Fischer indole synthesis. The conversion of ketazines into pyrroles under strongly acidic conditions apparently proceeds through a [3,3] sigmatropic rearrange-... 

Formation of a 1,2-disubstituted hydrazine by acid hydrolysis of an appropriately substituted pyrazolidine has been noted (67HC(22)l), but the most interesting ring fission of pyrazolidines involves the N(l)—N(2) bond of 1-phenylpyrazolidines (421). If, instead of phenylhydrazone, compound (421) is used in the Fischer indole synthesis, N- aminopropylin-doles are formed (73T4045). Scheme 39 shows the reaction with cyclohexanone. 

FISCHER - BORSCHE - DRECHSEL Indole synthesis Indole synlhesis Irom phenylhydrazones ol ketones (Fischer), m the case ol cyclohexanone phenylhydrazones letrahydrocarbazoles are oblained (Borsche-Drechsel). 

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