Cyclization Fischer indole

Fischer indole cyclizations incorporating functionalized substituents... 

Many aryhydrazones provide two or more isomers when subjected to the conditions of the Fischer indole cyclization. The product ratio and the direction of indolization can also be affected by different reaction conditions (i.e. catalysts and solvents), which is attributed, at least in part, to the relative stabilities of the two possible tautomeric ene-hydrazine intermediates. Generally, strongly acidic conditions favor formation of the least substituted ene-hydrazine, while cyclization carried out in weak acids favors the most substituted ene-hydrazine. Eaton s acid (10% P2O5 in MeSOsH) has been demonstrated to be an effective catalyst for the preparation of 3-unsubstituted indoles from methyl ketones under strongly acidic conditions. Many comprehensive reviews on this topic have appeared. ... 

From what was plarmed as a straightforward displacement of the chloride atom in 36 with hydrazine followed by a condensation with 2-tetralone and Fischer indolization to produce 39, dihydrazone 38 was isolated as an intermediate, resulting fi om dihydrazine 37 <99JHC441>. Subsequent Fischer indole cyclization and aminolysis of 38 produced 39 a mono-hydrazone intermediate (as opposed to 38) was ruled out by the authors on the basis of H NMR. 

Carboxy-2-pyridylthio)propionic acids, prepared by the reaction of 2-mercatopyridin-3-carboxylic acid with 3-bromopropionic acid in aqueous KOH, undergo cyclization upon treatment with anhydrous sodium acetate and acetic anhydride to afford 2,3-dihydrothiopyrano[2,3-3]pyridin-4(4//)-ones. These products undergo further reaction with phenylhydrazine to give the phenylhydrazone (isolated) and then Fischer indole cyclization to give novel 5/7,1177-pyrido[2, 3 2,3]thiopyrano[4,3-3]indoles <2000JHC379>. 

Scheme 24. Synthesis of optically pure frovatriptan ((/ )-6) utilizing 4-benzoyloxycyclohexanone in the Fischer indole cyclization.

Scheme 26. Synthesis of amine intermediate 81 utilizing 4-phthalimido cyclohexanone (78) in the Fischer indole cyclization.

Sridar, V., Rate acceleration of Fischer-indole cyclization by microwave irradiation, Indian J. Chem., Sect. B, 1996, 35B(7), 737-738. 

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... 

Annelation of steroidal dienamines with substituted phenacyl bromides (7 examples) or with benzenediazonium salts (11 examples) has been shown to lead to the corresponding furano- and indolo-steroids.89 Thus the A3,5-dienamine derived from A4-androstene-3,17-dione reacted with p-bromophenacyl bromide to yield the A5-androstano[3,4-h]furan (199) in 26% yield, and reaction of the same A3,5-dienamine with benzenediazonium fluoroborate at -45 °C led to formation of the hydrazone (200) which underwent Fischer-indole cyclization on treatment with phosphorus oxychloride to produce the A4-androstano[6,7-6]indole (201). The A3,5-dienamine derived from 17/3-acetoxyandrost-4-en-3-one has been converted into the benz[4,5,6]-steroid (202 R1 = Me, R2 = H) by reaction with methyl vinyl ketone and into the analogous benzsteroid (202 R1 = H, R2 = Me) on treatment with crotonal-dehyde.90 A route to the condensed pyrroline ring system (203) has been devised... 

Indolo-steroids have been obtained by -coupling of steroid dienamines with dia-zonium salts in dimethylformamide followed by Fischer-indole cyclization of the resulting hydrazone39 (Scheme 37). In methylene chloride the /Fcoupled product 75 was obtained, cyclization of which gave indazoles 74 and 762a. The oxidative role of dimethyl sulphoxide in the formation of 76 was attributed to nucleophilic attack by the solvent on 75 leading to intermediates 77 and 78, with elimination of dimethyl sulphide (Scheme 38). 

Lescot and co-workers (100) have described two routes to the 11//-pyrido[a]carbazoles. In the first (Scheme 36), a Fischer indole cyclization of the naphthylhydrazone 213, followed by dehydrogenation, gave the fully aromatic pyrido[a]carbazoles 215-217. Methylation or demethylation completed the preparation of the desired target compounds. A different route was used to synthesize the 5-methyl-2-aza derivatives 226 and 227 (Scheme 37) (100). Condensation of aldehyde 224 with 4-ethylpyridine gave the vinylindole 225. Deacylation and a variation of the Snieckus pyrido[c]carbazole synthesis (101) gave the desired compounds 226 and 227. 

The Beckmann rearrangement of ketoximes to the corresponding amides (31), the Fischer indole cyclization, isomerization of epoxides to the corresponding aldehydes, ketones, or alcohols, hydration and ammo-nolysis of epoxides, oxygen-sulfur interchange, formation of diaryl-ureas and -thioureas from condensation of aniline and carbonyl sulfide, and olefin carbonylation occur over zeolite catalysts (62). The oxo reaction over rhodium and cobalt containing zeolites recently has been claimed (22). 

Martin, M. J., Dorn, L. J., Cook, J. M. Novel pyridodiindoles, azadiindoles, and indolopyridoimidazoles via the Fischer-indole cyclization. Heterocycles 1993, 36,157-189. 

Condensation of the allylic alcohol 646 with methyl orthopropionate in butyric acid gave ester 647 which, after hydrolysis, was treated with methyllithium to give ketone 648. Fischer indole cyclization with poly-phosphoric acid of the phenylhydrazone of 648 gave the indole 649. The iV-oxide of 649 in trifluoroacetic anhydride at 0° gave in 92% yield the hexahydroellipticine 650, convertible with palladium-charcoal to 267 in 35% yield. The overall yield from 646 is on the order of 19% (Scheme 43). 

In the synthesis of an indoloquinolone antibacterial, the Gassman indole synthesis was explored to serve as the central operation. Therefore, difluoroaniline was selectively monobrominated. Although the Fischer indole cyclization for the resulting 2-bromo-4,5-difluoroaniline only gave the indole in poor yield, the Gassman indole synthesis worked well in one pot. Thus, treatment of the aniline with r-butyl hypochlorite was followed by addition of ethylthio-2-propanone and treatment with triethylamine to produce the indole in excellent yield. 

This reaction was first reported by Fischer and Jourdan in 1883. It is a synthesis of indole derivatives by the treatment of aryl hydrazones coupled from aromatic hydrazines and ketones or aldehydes with either a mineral or Lewis acid. Therefore, it is generally known as the Fischer indole synthesis. In addition, it is also referred to as Fischer cyclization, Fischer indole cyclization, Fischer indole reaction, Fischer indolization, Fischer reaction, and Fischer indole annulation. Although the mechanism has been extensively studied, the one formulated by Robinson and Robinson is now generally accepted. It involves the following steps (a) initial acid-catalyzed tautomerization of an aromatic hydrazone to an ene-hydrazine, b) a [3,3]-sigmatropic rearrangement of ene-hydrazine to a M-imine intermediate, (c) re-aromatization to aniline, d) intramolecular nucleophilic attack to form aminal, and (e) extrusion of an ammonia to afford the indole. 

Willoughby and coworkers reported a solid-phase strategy for the preparation of 2-arylindole combinatorial libraries in a split-and-pool format (Figure 11.61). Twenty different arylalkyl ketoacids were immobilized onto a sulfonamide resin, mixed, and separated into twenty equal portions. The Fischer indole cyclization was carried out with 20 arylhydrazines in the presence of ZnCl2 and acetic acid. The resin was mixed, separated into 80 equal portions, and finally alkylated under Mitsunobu conditions. A library of 12,800 compounds was generated, and led to the discovery of potent ligands for a variety of G-protein coupled receptors. 

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). 

Scheme 13.5 Tryptamine synthesis reported by Beller et al. The HCI generated in this process catalyzes the Fischer indole cyclization, which makes the addition of a Lewis acid such as ZnCl2 unnecessary [13].

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