Indole formation

It has been proposed that protonation or complex formation at the 2-nitrogen atom of 14 would enhance the polarization of the r,6 -7i system and facilitate the rearrangement leading to new C-C bond formation. The equilibrium between the arylhydrazone and its ene-hydrazine tautomer is continuously promoted to the right by the irreversible rearomatization in stage II of the process. The indolization of arylhydrazones on heating in the presence of (or absence of) solvent under non-catalytic conditions can be rationalized by the formation of the transient intermediate 14 (R = H). Under these thermal conditions, the equilibrium is continuously pushed to the right in favor of indole formation. Some commonly used catalysts in this process are summarized in Table 3.4.1. 

Studies on the Bischler-Napieralski cyclization of A -acetyltryptamine in the presence of indole have led to the isolation of numerous products, among which the indolocarbazole 186 could be found in 3.5% yield. This outcome was rationalized as a result of the intermediacy of a spiroindolenine species formed under these conditions [89H(28)175]. During detailed studies on the polymerization of indole, formation of a low yield of the related indolo[3,2-h]carbazole 187 was discovered in the product mixture originating from the treatment of indole with p-toluenesulfonic acid at elevated temperature [88JCS(P1)2387]. In an investigation of the condensation of p-benzoquinone with 4-substituted anilines, an indolo[3,2-h]carbazole derivative has been reported to be formed in 2% yield (80JOC1493). 

Indol-bildung, /. indole formation, -gruppe, /. Indole group, -korper, m. indole substance, member of the indole group. 

Fig. 8 Long range charge transport between dppz complexes of Ru(III) and an artificial base, methyl indole, in DNA. The methyl indole is paired opposite cytosine and separated from the intercalating oxidant by distances up to 37 A. In all assemblies, the rate constant for methyl indole formation was found to be coincident with the diffusion-controlled generation of Ru(III) (> 107 s )> indicating that charge transport is not rate limiting over this distance regime...

Transition metal catalysis on solid supports can also be applied to indole formation, as shown by Dai and coworkers [41]. These authors reported a palladium- or copper-catalyzed procedure for the generation of a small indole library (Scheme 7.23), representing the first example of a solid-phase synthesis of 5-arylsulfamoyl-substituted indole derivatives. The most crucial step was the cydization of the key polymer-bound sulfonamide intermediates. Whereas the best results for the copper-mediated cydization were achieved using l-methyl-2-pyrrolidinone (NMP) as solvent, the palladium-catalyzed variant required the use of tetrahydrofuran in order to achieve comparable results. Both procedures afforded the desired indoles in good yields and excellent purities [41]. 

Scheme 7.23 Transition metal-catalyzed indole formation on a solid phase.

The mechanism for the Mori-Ban indole formation is representative of many Pd-catalyzed pyrrole annulation processes [123], Reduction of Pd(OAc)2 by PPh3 generates Pd(0) species accompanied by triphenylphosphine oxide and acetic anhydride. 

The fact that benzene derivatives are much more generally accessible than pyrroles has relegated pyrrole annelation to a relatively minor role in indole synthesis. Nevertheless the concept provides a viable synthetic approach and the existing methods serve as useful prototypes. One strategy is to build up an appropriately functionalized side-chain and complete indole formation by electrophilic substitution-aromatization. Reactions (135)-(137) illustrate this type of approach (79TL3477, 79JA257, 73JPR295). 

Reactivity of Diazaphosphole Derivatives Unexpected Indole Formation... 

In such cases the most thermodynamically stable ene hydrazine, i.e. the one with the more highly substituted double bond, forms preferentially. In this particular example there is also extra stabilisation derived from conjugation of the lone pairs of electrons on the sulphur atom with the double bond. This regioselectivity in ene hydrazine formation is then reflected in the regioselectivity of indole formation. 

Although serotonin is a somewhat stronger donor than indole, or some of its derivatives such as tryptamine, this extraordinary reactivity is characteristic for the indole formation in general and is in no way explained by the energy values of the highest filled molecular orbital.. . There seem to be other hitherto unknown molecular... 

The total synthesis of (+)-deethylibophyllidine was accomplished by J. Bonjoch and co-workers, who applied a regioselective Fischer indole synthesis as one of the key steps to obtain octahydropyrrolo[3,2-c]carbazoles. The indole formation was followed by a tandem Pummerer rearrangement-thionium ion cyclization to generate the quaternary spiro stereocenter. 

During the total synthesis of (+)-aspidospermidine by J. Aube et al., the final steps involved an efficient Fischer indolization of a complex tricyclic ketone." This ketone was unsymmetrical and the indole formation occurred regioselectively at the most substituted a-carbon in a weakly acidic medium (glacial AcOH). 

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