Indole formation Fischer synthesis

With this tandem hydroformylation/hydrazone formation/Fischer indolization 3-substituted indoles such as valuable intermediates for the synthesis of pharmaceuticals as well as pharmaceuticals can be obtained in a very... 

Construction of the indole ring via Fischer synthesis. Starting from a variety of 3,4-dihydro-lH-benzo[l ]azepine-2,5-diones 40 and arylhydrazines Fischer syntheses of indolo benzazepinones 41 have been reported (Scheme 8 (1999JMC2909)). Usually, the reaction comprises a two-step one-pot procedure with the formation of intermediate arylhydrazones in warm acetic acid followed... 

It is also possible to use the Fischer synthesis for crafting indoles fused to other heterocyclic rings. This has been nicely demonstrated by initial formation of the enehydrazines 344, which were subsequently cyclized to the /3-carboline derivatives 345 (Scheme 42). An additional dehydrogenation step provided access to the corresponding... 

The total synthesis of (+)-deethylibophyllidine was accomplished by J. Bonjoch and co-workers, who applied a regioselective Fischer indole synthesis as one of the key steps to obtain octahydropyrrolo[3,2-c]carbazoles. The indole formation was followed by a tandem Pummerer rearrangement-thionium ion cyclization to generate the quaternary spiro stereocenter. 

During the total synthesis of (+)-aspidospermidine by J. Aube et al., the final steps involved an efficient Fischer indolization of a complex tricyclic ketone." This ketone was unsymmetrical and the indole formation occurred regioselectively at the most substituted a-carbon in a weakly acidic medium (glacial AcOH). 

Zimmermann, T. Afacile synthesis of 3H-indolium perchlorates by one-pot hydrazone formation/Fischer indolization. J. Heterocycl. Chem. 2000, 37, 1571-1574. 

Heterocycle formation (Hantzsch condensation, Pictet-Spengler, Fischer synthesis of indoles, Pd-heteroannulation)... 

Using a-acetyl-y-butyrolactone as the carbonyl component in the Fischer synthesis, decarboxylation occurs and it is thus possible to prepare a 1,2-disub-stituted indol-3-ylethanol [2637]. In a related reaction, a y-haloaldehyde or a y-haloketone reacts with an arylhydrazine to give a tryptamine in which the side-chain nitrogen is derived from the terminal nitrogen of the reacting phenylhydrazine this and related reactions were reviewed in 1974 and 1988 [2641,3461). The course of Fischer indolization of the preformed monophenyl-hydrazone of cyclohexane-1,3-dione changes when the reaction is allowed to proceed under conditions which encourage ketal formation [2565]. 

Appreciable formation of the linear 2-benzyl-3-/f-indole by the Fischer synthesis with 1-phenyl-2-propanone was only observed with polyphosphoric acid and not at all with zeolite beta, although this product resembles, in bulkiness, 2-benzyl-3-methylindole, the linear indole isomer obtained from 1-phenyl-2-buta-none. If the production of the linear isomer depended solely on suppression of the formation of the bulky product, then the trends in the selectivities for 1-phenyl-... 

As was mentioned before, isomerisation of the substituted indoles does not occur under the conditions used in this study. The selectivity of the catalytic reaction should therefore only depend on the relative rates of formation of the enehydrazines 2 and 3 in the conformation which aliows their [3,3]-sigmatropic rearrangement to occur (which is the conformation drawn in Scheme 1). The sorption data and molecular geometries indicate that the formation of both enehydrazines 2 and 3 inside the channels of zeolite beta should be possible, but 2 is probably severely hindered in adopting the conformation required for indolization, given the fact that this conformation is even bulkier than the indole isomer 4 which is formed from it. The selective Fischer synthesis of 2-benzyl-3-methylindole 5 catalyzed by zeolite beta is therefore a true example of transition state selectivity. 

Indoles.—Formation. Intermediates in the Fischer indole synthesis have been detected by N n.m.r. spectroscopy. The formation of the indole (170) from the arylhydrazone (169) indicates preferential migration of the methyl group. ... 

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)... 

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. 

A large number of Brpnsted and Lewis acid catalysts have been employed in the Fischer indole synthesis. Only a few have been found to be sufficiently useful for general use. It is worth noting that some Fischer indolizations are unsuccessful simply due to the sensitivity of the reaction intermediates or products under acidic conditions. In many such cases the thermal indolization process may be of use if the reaction intermediates or products are thermally stable (vide infra). If the products (intermediates) are labile to either thermal or acidic conditions, the use of pyridine chloride in pyridine or biphasic conditions are employed. The general mechanism for the acid catalyzed reaction is believed to be facilitated by the equilibrium between the aryl-hydrazone 13 (R = FF or Lewis acid) and the ene-hydrazine tautomer 14, presumably stabilizing the latter intermediate 14 by either protonation or complex formation (i.e. Lewis acid) at the more basic nitrogen atom (i.e. the 2-nitrogen atom in the arylhydrazone) is important. 

The formation of the indole moiety has found immense attention, since it exists in many bioactive compounds such as the indole alkaloids [302]. Whilst the Fischer indole synthesis remains the most important procedure, during the past few years several transition metal-catalyzed syntheses have been developed. Recently, a Cu11-catalyzed cyclization of anilines containing an ortho-alkynyl group was published by Hiroya and coworkers [303], which allows a double cyclization in domino fashion to provide annulated indoles. Thus, reaction of 6/4-92 in the presence of... 

With conventional methods, the formation of indole derivatives from anilines proceeds at the expense of both unsubstituted ortho positions in the phenyl ring. This leads to undesirable by-products. Particularly, the formation of by-products takes place during Fischer s synthesis of benzohet-erocycles. In the previously described ion-radical variant of the synthesis, only one indole isomer is formed—the isomer that corresponds strictly to the structure of the starting haloaniline. 

About the same time a number of publications appeared on the complete synthesis of 7a, 7b, 30 and 31 using a different approach to build the alkaloid framework (Scheme 5 68M1364, 68M1584, 69JCA(C)2738). Phenylhydrazone 34 under Fischer reaction conditions was converted into indole 34a with subsequent successive transformations to pentacyclic derivative 35. Its acid-initiated rearrangement led to the formation of 7b and 30 in a ratio of 1 5. While 7b and... 

A Neber route to substituted indoles 532, complementary to the Fischer indole synthesis, was recently developed (equation 235). Formation of azirine 531 from the oxime was smoothly induced, for example using MsCl/DBU or DIAD/BU3P or PhsP, and the intermediate was isolated. Thermal rearrangement of the azirine (40 to 170 °C, depending on the azirine structure) produced the indoles 532 directly in usually good yields (84-88% from the azirine). 

Heating of an aryl hydrazone 1 in the presence of a catalyst leads to elimination of anunonia and formation of an indole 2. This reaction is known as the Fischer indole synthesis,and is somewhat related to the Benzidine rearrangement. 

Figure 6.23 Formation of indoles from dissymmetric ketones by the Fischer indole synthesis.

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