Zeolites Fischer indole synthesis

In the same domain of heterocyclic synthesis, much effort has been devoted to understanding the selectivities in the synthesis of indoles starting from phenylhydrazine and ketones, i.e. the Fischer indole synthesis. With phenyl-hydrazine, l-phenyl-2-butanone and zeolite H-Beta, the slimmer product 2-phenyl-3-methylindole dominates over the more bulky isomer (13) ... 

Other examples of zeolite-catalyzed cyclizations include the Fischer indole synthesis [80] and Diels-Alder reactions [81]. 

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. 

Fischer Indole Synthesis over Zeolite Catalysis ... 

An early, non-shape-selective, application of zeolites in the Fischer indole synthesis was reported by Venuto and Landis [18]. They employed calcium-and rare-earth-exchanged zeolite X as catalysts under continuous-flow conditions at 150 °C. Good yields of indoles were obtained with both acetone and cyclohexanone phenylhydrazones a 72.5% yield of indole was obtained from the latter with CaX catalyst. 

On the basis of the examples reviewed above, it can be concluded that heterogeneous catalysis of the Fischer Indole Synthesis provides a practical and environmentally friendly alternative to the acids traditionally employed. Although it has not yet been possible to demonstrate unambiguously the use of a zeolite to effect the shape-selective formation of a single indole isomer, new structural types of zeolite and related materials continue to be synthesized, so that catalysts offering pore access and thus enhanced activity combined with shape selectivity remain a realistic research goal. 

It was found that zeolite beta is a highly shape-selective catalyst for the Fischer indole synthesis of 2-benzyl-3-methylindole from phenylhydrazine and 1 -phenyl-2-butanone. A selectivity of 83 % for this isomer was obtained at full conversion. Combined results from catalytic experiments and sorption measurements indicated that the formation of the isomeric 2-ethyl-3-phenylindole is suppressed as a consequence of restricted transition state selectivity. 

Zeolites are known to catalyze the formation of various nitrogen-containing aromatic ring systems. Examples include the synthesis of pyridines by dehydrogenation / condensation / cyclization of C -Cg precursors [1], the formation of methylpyridines by high-temperature isomerization of anilines [2], the amination of oxygen-containing heterocyclic compounds [3] and the Fischer indole synthesis [4,5]. The latter synthesis consists (see Scheme 1) of a condensation towards a phenylhydrazone followed by an acid-catalyzed cyclization with elimination of ammonia. The two reaction steps are usually combined in a one-pot procedure. 

Kunkeler et al. (1997) reported that zeolite HNaY and zeolite-P are active and recyclable heterogeneous catalysts in the Fischer indole synthesis (Scheme 2.12). In certain cases, zeolite-P is capable of producing the linear indole isomer in excess. 

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. 

---