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  Synthesis of Benzopyrrole, Chemistry tutorial

Introduction:

Indole is the main constituent of coal-tar, and the 220 to 260°C distillation fraction is the most important industrial source of the material. Indole and its derivatives can as well be synthesized by a variety of methods. The major industrial routes begin from aniline. The other methods of synthesizing indole comprise the Fischer Indole, the Reissert, Wender and the Leimgruber-Batcho synthesis.

Industrial Synthesis of Indole:

Descriptive of such large-scale syntheses, indole (and replaced derivatives) forms through vapor-phase reaction of aniline by ethylene glycol in the presence of catalysts (figure shown below).

1498_Industrial Synthesis of Indole.jpg

Fig: Industrial Synthesis of Indole

In common, synthesis is conducted between 200 and 500°C. Results can be as high as 60%. Other precursors to indole comprise formyltoluidine, 2-ethylaniline and 2-(2-nitrophenyl) ethanol, all of which experience cyclization. Most of the other methods have been developed that are applicable.

Fischer-Indole Synthesis:

One of the oldest and most reliable techniques for synthesizing substituted Indoles is the Fischer indole synthesis, developed in the year 1883 by Emil Fischer (figure shown below). However, the synthesis of indole itself is problematic by using the Fischer indole synthesis, it is often employed to form Indoles replaced in the 2- and/or 3-positions. Indole can still be synthesized, though, by employing the Fischer indole synthesis by reacting phenylhydrazine by pyruvic acid followed by decarboxylation of the formed indole-2-carboxylic acid. This has as well been achieved in a one-pot synthesis by using microwave irradiation.

405_Fischer Indolisation Reaction.jpg

Fig: Fischer Idolization Reaction

Phenylhydrazine is initially reacted by an aldehyde, or ketone carrying α-methylene group (that is, not acetaldehyde). The corresponding hydrazone is heated by an acid catalyst like boron trifluoride, zinc chloride or polyphosphoric acid. The reaction is analogous to the benzidine rearrangement. Ring closure takes place via a [3,3]-sigmatropic change and ammonia (as the ammonium cation ) is lost. For illustration, acetaphenone phenylhydrazone (R1-Ph, R2=H), treated by zinc chloride at 170°C provides 2-phenylindole in up to 80% result though, the reaction fails by acetaldehyde phenyl hydrazone (R1,R2 = H) in such a way that indole itself should be made indirectly. A simple process is to carry out the Fischer reaction on the phenylhydrazone of pyruvic acid (R1 = COOH, R2 = H) and to decarboxylate the resultant indole-2-carboxylic acid thermally.

Substituent on the phenyl ring of the hydrazone affect the regiochemistry of the [3,3-rearrangement. For illustration, electron-discharging meta-substituents give mostly 6-substituted Indoles (that is, para ring closure) while electron-attracting substituents provide mostly 4-substituted Indoles (that is, ortho ring closure).

The Reissert Synthesis:

The o-nitrotoluene is reacted by diethyl oxalate in the presence of a base. The nitro group of the resultant α-keto-ester is reduced to amino and cyclisation then takes place spontaneously. The ester substituent in the indole might be eliminated, if needed by hydrolysis and thermal decarboxylation (figure shown below).

1274_Reissert Synthesis.jpg

Fig: Reissert Synthesis

The Wender Synthesis:

In this synthesis, the 2-bromo-N-(trifluoroacetyl) aniline in THF is deprotonated through butyllithium and then in the same pot, reacted by tert-butyllithium to affect halogen metal exchange to provide the dilithiated derivative. To this intermediate is added α-bromo ketone. A carbon-carbon bond is established first between the reactants and then cyclisation takes place to form a hydroxyindoline. Ultimately, dehydration produces the indole (figure shown below).

1701_Wender Synthesis.jpg

Fig: Wender Synthesis

Leimgruber-Batcho indole Synthesis:

689_Leimgruber-Batcho indole Synthesis.jpg

Fig: Leimgruber-Batcho indole Synthesis

The Leimgruber-Batcho indole synthesis is the effective process of synthesizing indole and substituted Indoles (figure shown above). Originally disclosed in a patent in the year 1976, this process is high-yielding and can produce substituted Indoles. This process is particularly popular in the pharmaceutical industry, where most of the pharmaceutical drugs are made up of particularly substituted Indoles. The process utilizes o-nitrotoluene, which whenever heated in a mixture having the base pyrrolidine and N,N-dimethylformamide dimethyl acetal (DMFDMA) provides the corresponding  β-(N,N-dimethylaminophenylethene. Reduction of this product form the suitable indole.

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