Indole

The Leimgruber–Batcho indole synthesis is an efficient method of synthesizing indole and substituted indoles.[23] Originally disclosed in a patent in 1976, this method is high-yielding and can generate substituted indoles. This method is especially popular in the pharmaceutical industry, where many pharmaceutical drugs are made up of specifically substituted indoles.

One-pot microwave-assisted synthesis of indole from phenylhydrazine and pyruvic acid

One of the oldest and most reliable methods for synthesizing substituted indoles is the Fischer indole synthesis, developed in 1883 by Emil Fischer. Although the synthesis of indole itself is problematic using the Fischer indole synthesis, it is often used to generate indoles substituted in the 2- and/or 3-positions. Indole can still be synthesized, however, using the Fischer indole synthesis by reacting phenylhydrazine with pyruvic acid followed by decarboxylation of the formed indole-2-carboxylic acid. This has also been accomplished in a one-pot synthesis using microwave irradiation.[24]

• Bartoli indole synthesis
• Bischler–Möhlau indole synthesis
• Cadogan-Sundberg indole synthesis
• Fukuyama indole synthesis
• Gassman indole synthesis
• Hemetsberger indole synthesis
• Larock indole synthesis
• Madelung synthesis
• Nenitzescu indole synthesis
• Reissert indole synthesis
• Baeyer–Emmerling indole synthesis
• In the Diels–Reese reaction[25][26] dimethyl acetylenedicarboxylate reacts with 1,2-diphenylhydrazine to an adduct, which in xylene gives dimethyl indole-2,3-dicarboxylate and aniline. With other solvents, other products are formed: with glacial acetic acid a pyrazolone, and with pyridine a quinoline.

Unlike most amines, indole is not basic: just like pyrrole, the aromatic character of the ring means that the lone pair of electrons on the nitrogen atom is not available for protonation.[27] Strong acids such as hydrochloric acid can, however, protonate indole. Indole is primarily protonated at the C3, rather than N1, owing to the enamine-like reactivity of the portion of the molecule located outside of the benzene ring. The protonated form has a pK_a of −3.6. The sensitivity of many indolic compounds (e.g., tryptamines) under acidic conditions is caused by this protonation.

The most reactive position on indole for electrophilic aromatic substitution is C3, which is 10¹³ times more reactive than benzene. For example, it is alkylated by phosphorylated serine in the biosynthesis of the amino acid tryptophan. Vilsmeier–Haack formylation of indole[28] will take place at room temperature exclusively at C3.

Since the pyrrolic ring is the most reactive portion of indole, electrophilic substitution of the carbocyclic (benzene) ring generally takes place only after N1, C2, and C3 are substituted. A noteworthy exception occurs when electrophilic substitution is carried out in conditions sufficiently acidic to exhaustively protonate C3. In this case, C5 is the most common site of electrophilic attack.[29]

Gramine, a useful synthetic intermediate, is produced via a Mannich reaction of indole with dimethylamine and formaldehyde. It is the precursor to indole-3-acetic acid and synthetic tryptophan.

The N–H center has a pK_a of 21 in DMSO, so that very strong bases such as sodium hydride or n-butyl lithium and water-free conditions are required for complete deprotonation. The resulting organometalic derivatives can react in two ways. The more ionic salts such as the sodium or potassium compounds tend to react with electrophiles at nitrogen-1, whereas the more covalent magnesium compounds (indole Grignard reagents) and (especially) zinc complexes tend to react at carbon 3 (see figure below). In analogous fashion, polar aprotic solvents such as DMF and DMSO tend to favour attack at the nitrogen, whereas nonpolar solvents such as toluene favour C3 attack.[30]

After the N–H proton, the hydrogen at C2 is the next most acidic proton on indole. Reaction of N-protected indoles with butyl lithium or lithium diisopropylamide results in lithiation exclusively at the C2 position. This strong nucleophile can then be used as such with other electrophiles.

Bergman and Venemalm developed a technique for lithiating the 2-position of unsubstituted indole,[31] as did Katritzky.[32]

Due to the electron-rich nature of indole, it is easily oxidized. Simple oxidants such as N-bromosuccinimide will selectively oxidize indole 1 to oxindole (4 and 5).

Only the C2–C3 pi bond of indole is capable of cycloaddition reactions. Intramolecular variants are often higher-yielding than intermolecular cycloadditions. For example, Padwa et al.[33] have developed this Diels-Alder reaction to form advanced strychnine intermediates. In this case, the 2-aminofuran is the diene, whereas the indole is the dienophile. Indoles also undergo intramolecular [2+3] and [2+2] cycloadditions.

Despite mediocre yields, intermolecular cycloadditions of indole derivatives have been well documented.[34][35][36][37] One example is the Pictet-Spengler reaction between tryptophan derivatives and aldehydes,[38] which produces a mixture of diastereomers, leading to reduced yield of the desired product.

Indoles are susceptible to hydrogenation of the imine subunit.[39]

• Houlihan, W. J., ed. (1972). Indoles Part One. New York: Wiley Interscience.
• Sundberg, R. J. (1996). Indoles. San Diego: Academic Press. ISBN 978-0-12-676945-6.
• Joule, J. A.; Mills, K. (2000). Heterocyclic Chemistry. Oxford, UK: Blackwell Science. ISBN 978-0-632-05453-4.
• Joule, J. (2000). E. J., Thomas (ed.). Science of Synthesis. Vol. 10. Stuttgart: Thieme. p. 361. ISBN 978-3-13-112241-4.
• Schoenherr, H.; Leighton, J. L. (2012). "Direct and Highly Enantioselective Iso-Pictet-Spengler Reactions with α-Ketoamides: Access to Underexplored Indole Core Structures". Org. Lett. 14 (10): 2610–3. doi:10.1021/ol300922b. PMID 22540677.