Fischer indole transform

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)... 

In order to allow further transformation to an indole, the carbonyl compound 8 must contain an a-methylene group. The hydrazone 1 needs not to be isolated. An equimolar mixture of arylhydrazine 7 and aldehyde or ketone 8 may be treated directly under the reaction conditions for the Fischer indole synthesis. ... 

The Fischer indolization of bicycloketones of the morphane series often has been used for the synthesis of the corresponding azocinoindoles (89TL3841, 90TL2449, 92LA461). Thus, bicyclic ketone 44, under Fischer conditions, has been transformed into azocinoindole 45 in moderate yields (94JOC3939 Scheme 11). 

Five years later, the same authors reported an improved total synthesis of arcyriaflavin A (345) starting from the TBS enol ether 1490 (for the synthesis see Scheme 5.252). This route involves two indolizations based on silyl enol ether nucleophilic attack and Fischer processes. Using Cadogan s procedure by heating in triethyl phosphite, the TBS enol ether 1490 was transformed into the ketone ( + )-1495, involving silyl enol ether-mediated indolization. Finally, Fischer indolization of (+ )-1495 by reacting with phenylhydrazine (524) led directly to arcyriaflavin A (345) in 57% yield (794) (Scheme 5.253). 

Fischer indole cyclization and transformation of a nitrile to an ester (Pinner synthesis) to yield diethyl 5-hydroxy-1 T/-pyrrolo[2,3-/]quinoline-2,7-dicarboxylate (183) was performed in one step by... 

The most prominent examples of this type of reaction are the Fischer Indole synthesis, the Beckmann rearrangement and the benzylamine rearrangement. For all three reactions rather complex mechanisms have been proposed. On comparing the structure- activity relationships for these transformations, it becomes clear that generalisations are difficult and that a complex interplay between pore shape and size, the acid strength and the polarity of the zeolite lattice seems to control the activity and selectivity for a given reaction. 

After evaluating each of the proposed routes, we came to the conclusion that the one-step Fischer indole-type reaction b was the most promising as a scalable process despite a low yield. Ready availability of the starting raw materials (p-tolylhydrazine and 4,4-diethoxy-butylamine) at low cost compensates for the low productivity of that transformation. 

The mechanism of the Gassman indole synthesis bears some resemblance to that of the Fischer indole reaction. An Sn2 displacement of the TV-chlorinated aniline with the a-keto sulfide gives rise to a sulfonium ion. After deprotonation, a [2,3]-sigmatropic rearrangement (Sommelet-Hauser rearrangement) takes place where the weak N-S bond is broken and a strong C-C bond is formed. Similar to the Fischer indole reaction, the resulting imine was transformed into indole after re-aromatization and cyclization. 

A similar strategy was applied in the synthesis of aryl-substituted 5-(3-indolyl)oxazoles 43. Here, propatgyl amides 5 were reacted with acid chlorides 4 in a modified Sonogashira cross-coupling I followed by the above described add-catalyzed cycloisomerization. The remaining methylene ketone was then transformed via Fischer indole synthesis with different aryl hydrazine hydrochlorides to form the indole ring (Scheme 24) (20110BC(9)8130). 

Bergman and Yudina have effected a route to several indolo[3,2- 7]carbazoles, such as 175 (equation 2) via a double Fischer indolization [356]. Such compounds are of biological interest because 175 is formed in vivo after the consumption of cruciferous vegetables. It has a strong affinity for the dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin) (TCDD) Ah-receptor. Moreover, the 6-formyl derivative 176 binds more strongly to the Ah-receptor than TCDD itself [357, 358]. Saracoglu and Talaz have transformed cyclooctanone into tetrameric indole 177 by stepwise Fischer indolization steps [359]. 

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. 

Catalytic hydrohydrazinations, in which the amine substrate is replaced by hydrazine derivatives, are much less developed to date [11]. However, it is now well established that the hydrohydrazination of alkynes provides an atom-economical access to hydrazones [12], which are potentially valuable reagents for further transformations. Homogeneous catalysts employed for this reaction are titanium- or zinc-based, the latter allowing the tandem combination of hydrohydrazination and subsequent Fischer indole cyclization (Scheme 13.4). 

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