Given the importance of indoles, there have been a vast amount of research dedicated to their synthesis. A few researchers who worked in the field include Leimgruber-Batcho,29 Fischer,30 Bartoli,31 Bischler-Möhlau,32 Fukuyama,33 Gassman,34 Larock,35 Madelung,36 Nenitzescu,37 Reissert,38 and Plieninger.39 Due to amount of work dedicated to this field, only a small subset will be discussed.
2.2.2.1 Fischer indole synthesis
One of the most well-known indole synthesis was developed in 1883 by Fischer and Jourdan. As seen in Scheme 2-10, they reacted pyruvic acid 1-methylphenylhydrazone (2-61, derived from ketone 2-59 and phenylhydrazine 2-60) with HCl and isolated 1- methylindole-2-carboxylic acid (2-62).40 The reaction is tolerant of many protic or Lewis acids, although Lewis acids generally allow for cooler reaction temperatures. For the indolization of unsymmetrical ketones with phenylhydrazines, when a strong acid is used indolization usually occurs at the least substituted α-carbon, and at the more substituted α-carbon under weakly acidic conditions.41 The mechanism of the reaction, originally
proposed by Robinson in 1924,42 first involves protonation of imine 2-63, which its self is
made from a condensation between a ketone and phenylhydrazine. Tautomerization of 2- 63 to form ene-hydrazine 2-65, followed by a [3,3]-sigmatropic rearrangement results in di-imine 2-66. Another tautomerization occurs to form enamine 2-67, which immediately cyclizes to aminal 2-68. Indole 2-69 is finally produced by the elimination of ammonia.
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Scheme 2-10 Fischer indole synthesis
2.2.2.2 Bartoli indole synthesis
Many naturally occurring indoles, and therapeutics, possess substitution at C7; however, synthesis of these indoles can be troublesome. In 1989, the Bartoli group developed an efficient protocol to access C7-substituted indoles through the reaction of substituted nitro groups with substituted vinyl Grignard reagents (Scheme 2-11).31 The first step of the mechanism involves a reduction of the nitro group in 2-70,by a Grignard reagent, to form nitroso 2-75. Confirmation of the initial reduction was done by obtaining 2-74 as a by-product, and also because indoles could be formed straight from nitrosoarene 2-75.
Scheme 2-11 Bartoli indole synthesis
Another Grignard addition, this time to nitrosoarene 2-75,gives intermediate 2-76 which then undergoes a [3,3] sigmatropic rearrangement to give imine 2-77. A third Grignard reagent is used to deprotonate 2-77, which results in re-aromatization of the six membered ring to give 2-79, and by product 2-78. Aniline 2-79 then undergoes a cyclization reaction, and subsequent dehydration to give indole 2-72. If X=Br then a plethora of modifications at the C7 of the indole can occur via various coupling reactions. A few more benefits of the Bartoli indole synthesis include: 1) nitroarenes are commercially available, or can be easily synthesized;43 2) the reaction is usually very fast and can easily be scaled up; and lastly, 3) nitro and nitrosoarenes are more reactive than many functional groups towards Grignard reagents, thus alleviated the necessity for protecting groups.44
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2.2.2.3 Larock indole synthesis
In 1991, Larock developed an indolization sequence from the Pd-catalyzed coupling of 2- iodoanilines (2-81) and disubstituted alkynes (2-82, Scheme 2-12).45 The reaction is
tolerant to many different substituents on the aniline, or the alkyne, and the coupling is also fairly regioselective – with larger substituents located at the 2-position of the indole.46 The rationale for the regioselectivity could be explained by sterics in
intermediate 2-85, whereby larger functional groups would avoid the arene.
The proposed mechanism is highlighted in Scheme 2-12. To begin the synthesis, the Pd(II) source is reduced to Pd(0), which then undergoes an oxidative addition with aniline 2-84. The alkyne then undergoes a ligand exchange with the palladium complex to form 2-85, followed by a syn-insertion to the arylpalladium bond (2-86). The amine then displaces the halide to form the six-membered, heteroatom-containing palladacycle 2-87, which then undergoes a reductive elimination to regenerate the Pd(0) species, and to form indole 2-83.
In 2013, the Jia group modified the Larock indole synthesis to access 3,4-fused tricyclic indole 2-90 from an intramolecular Larock indole synthesis of aniline 2-88 (Scheme 2-13).47 Various atoms in the tether (Y= C, N, or O) could be utilized, and many different sized rings (6, 9, 10, 11, 18) were synthesized.
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2.2.2.4 Huang indole synthesis
More recently, in 2013, the Huang group found that they could access indoles through a triazene-directed (2-91) C-H annulation with alkyne 2-92 (Scheme 2-14).48 During their
optimization they found that [{RhCp*Cl2}2] and methanol were required, as other
catalysts or solvents did not form the indole. Also necessary was a stoichiometric amount of copper oxidant, and catalytic amounts of a non-coordinating silver counter ion. Triazenyl arenes substituted with alkyl, EWG, and halides were able to undergo the indolization sequence, however arenes with EDG resulted in decomposition. Alkynes had either aryl or alkyl substituents, while terminal alkynes could not be used as they lead to dimerization. The proposed mechanism is seen below in Scheme 2-14. After the formation of the active Rh3+ acetate species, a directed C-H bond insertion occurs (2-94). Insertion of the alkyne results in seven-membered metallacycle 2-95, which can rearrange to the more stable six-membered metallacycle (2-96, Pathway A). Solvolysis of the triazene by methanol (2-96), followed by reductive elimination of 2-98 results in indole 2-93. Alternatively, after the formation of the seven-membered metallacycle 2-95, N=N insertion to the Rh-C bond forms intermediate 2-99 (Pathway B). Reduction of the Rh catalyst, results in an intermediate similar to 2-96, which also undergoes solvolysis to access indole 2-93.
Scheme 2-14 Huang group’s synthesis of indoles through triazene directed C-H annulation
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2.2.2.5 Plieninger indolization sequence
In 1956, the Plieninger group were able to convert dihydronaphthalenamine 2-100 to indole 2-103 through an ozonolytic cleavage/dehydration procedure (Scheme 2-15).49
Scheme 2-15 Plieninger’s indole synthesis
Despite the relative simplicity of the reaction, the indolization sequence did not build much traction within the synthetic community, likely because the indoles were obtained in low yields and dihydronaphthalenamines were not easily accessible at the time. A Birch reduction of 2-aminonaphthalene 2-104 was commonly employed to access dihydronaphthalenamines (Scheme 2-16); however, many functional groups are not tolerated by the reducing conditions. Nevertheless, the protocol was used in a total synthesis by Plieninger, 20 years later, to access (±)-chanoclavine I.50
Scheme 2-16 Accessing dihydronapthalenamine via Birch reduction
In the synthesis of (±)-chanoclavine I (Scheme 2-17, 2-111), the dihydronapthalenamine was not accessed through a Birch reaction, but instead from a Diels-Alder reaction between diene 2-106 and maleic anyhydride (2-107). After some further manipulations Plieninger had requisite dihydronapthalenamine 2-109, which underwent the Plieninger indolization sequence. After a few more synthetic steps, he was able to complete the total synthesis of (±)-chanoclavine I.
Scheme 2-17 Plieninger group’s total synthesis of (±)-chanoclavine I
The indolization sequence was also used by Maehr and Smallheer nine years later in their total synthesis of (±)-rivularin D1 (2-116a) and (±)-rivularin D3 (2-116b) (Scheme
2-18).51 A Birch reduction of aminonaphthalene hydrochloride 2-112, followed by bromination by pyridinium tribromide (2-113), and lastly tosylation of the amine gave access to dihydronaphthalenamine 2-114. Submitting 2-114 to the Plieninger indolization sequence afforded indole 2-115 in a 32% yield over two steps. The indole then underwent a Fischer indole synthesis to install the other indole moiety, followed by some final manipulations to form (±)-rivularin D1 and (±)-rivularin D3.
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