Science of Synthesis

Kim, S.; Yoon, J.-Y., Science of Synthesis, (2004) 27, 686.

The Fischer indole synthesis involves the cyclization of enolizable N-arylhydrazones normally in the presence of an acid catalyst. Mechanistically, a typical Fischer indole synthesis leading to 2-phenylindole (‌61‌) from the hydrazone ‌60‌ of acetophenone[‌52‌] involves tautomerization of the hydrazone to an ene–hydrazine. The ene–hydrazine then undergoes a [3,3]-sigmatropic rearrangement and subsequent aromatization to afford an aniline intermediate ‌62‌. An intramolecular nucleophilic attack and the loss of ammonia then affords the indole (‌Scheme 15‌). Experimental conditions employed in the Fischer reaction vary greatly since the ease of cyclization depends on the nature of the arylhydrazone, the catalyst, and the temperature. Although the first indole synthesis by Fischer and Jourdan utilized alcoholic hydrochloric acid,[‌72‌] a variety of other acids and Lewis acids have since been used; these include sulfuric, acetic, and phosphoric acids, zinc chloride, boron trifluoride, and cation-exchange resins.[‌70‌] Furthermore, the isolation of arylhydrazones is often bypassed by subjecting an equimolar mixture of the arylhydrazine and an aldehyde or a ketone directly to Fischer indolization conditions. This is especially useful as enolizable N-arylhydrazones can be difficult to purify and often decompose on column chromatography. A general problem in this indole synthesis arises with N-arylhydrazones of unsymmetrical ketones, which can give two isomeric products. Generally, the indole derived from the more highly substituted ene–hydrazine predominates. Thus, cyclization of the hydrazone ‌63‌ in refluxing hydrochloric acid furnishes the indole ‌65‌ via the ene–hydrazine ‌64‌, but the yield is modest (‌Scheme 15‌).[‌73‌] The regiochemistry can be controlled to some extent by the reaction conditions such as the strength and the amount of acid catalyst. Indeed, the use of very strongly acidic conditions can shift the reaction to favor cyclization through the less stable ene–hydrazine. For example, treatment of the hydrazone of isopropyl methyl ketone with 70% sulfuric acid (1 equiv) gives a 96% yield of the 3H-indole ‌66‌ and only 1% of the 1H-indole ‌67‌, but with 5 equivalents of the same acid the proportion of the 3H-isomer is reduced to 27% and the yield of the 1H-indole is raised to 67% (‌Scheme 15‌).[‌74‌] A useful route to 2-acyl-substituted indoles involves the coupling of active methylene compounds with diazonium salts, which provides access to many α-acylhydrazones unobtainable by direct methods.[‌75‌]

‌Meeeee 88‌ Meeeeee Meeeee Meeeeeeee[‌88‌,‌88‌–‌88‌]

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8-Meeeee-8M-eeeeee (‌88‌); Meeeeee Meeeeeeee:[‌88‌]

Meeeeeeee eeee (Meeeeee; Meeeee; Meeee, Meeeeee Meeeeeeee, Meeeeeeeee Meeeee MMM), Meeeeeeee (8888), e 888, eeee eeeeeeeeee eeee Meee Meeee&Meee, Mee.

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References

Meeeeee Meeeeeeeeee

• 8.Meeeee-Meee, (8888) 8/8e8, 888.
• 8.Meeeee-Meee, (8888) M 88e8, 888.