Functionalization indole derivatives

It is interesting to note that this methodology allows the preparation of 4-functionalized indole derivatives starting from a simple acyclic precursor in a one-pot sequence. To prepare N-unsubstituted indoles, we choose the allyl moiety as a result to its stability to strong basic conditions and the variety of methods for its removal.[20] We therefore used an approach based on the isomerization/hydrolysis of the allyl groups with diisobutylaluminium hydride (DIBAL-H) and a... 

Table 1. Preparation of 4-functionalized indole derivatives 2 and 3 from N-(2-bromoallyl)-2-fluoroanilines (1).

Scheme 3. Synthesis of 3,4-functionalized indole derivatives 10 and 11 by Alder-ene reactions, i) X=Y, THF, 67 °C [X=Y H20=N+Me2L,...

Later, Yamamoto employed this chemistry for very efficient synthesis of functionalized indole derivatives 99 (Scheme 9.36). Substantially higher yields were achieved upon addition of CaC03, whereupon Si-substituted alkynes 98 underwent a concomitant deprotection to give C-2 unsubstituted indoles in good to excellent yields [182]. 

C. G. Neochoritis, A. Domling, Org. Biomol. Chem. 2014,12, 1649-1651. Towards a facile and convenient synthesis of highly functionalized indole derivatives based on mnlti-com-ponent reactions. 

F. Epifano, S. Genovese, O. Rosati, S. Taghapietra, C. Pelucchini, M. Curini, Tetrahedron Lett. 2011, 52, 568-571. Ytterbium triflate catalyzed synthesis of p-functionalized indole derivatives. 

One of the virtues of the Fischer indole synthesis is that it can frequently be used to prepare indoles having functionalized substituents. This versatility extends beyond the range of very stable substituents such as alkoxy and halogens and includes esters, amides and hydroxy substituents. Table 7.3 gives some examples. These include cases of introduction of 3-acetic acid, 3-acetamide, 3-(2-aminoethyl)- and 3-(2-hydroxyethyl)- side-chains, all of which are of special importance in the preparation of biologically active indole derivatives. Entry 11 is an efficient synthesis of the non-steroidal anti-inflammatory drug indomethacin. A noteworthy feature of the reaction is the... 

The aniline derivative 332, prepared from 2-fluoro-6-nitrotoluene, was transformed through successive reactions as shown in Scheme 60 to give the functionalized indole 333. It was then reduced with LiAlH4 to the dimethylaminopropyl derivative which was quaternized with Mel to the trimethyl ammonium salt 334. Subsequent cyclization and functionalization afforded the pyrroloquinoline 335. The latter could be transformed to the tetracyclic acid 336 (90JHC2151). (Scheme 60)... 

Waldmann used (R) and (5>aminoacid methyl esters and chiral amines as chiral auxiliaries in analogous aza-Diels-Alder reactions with cyclodienes.111 The diastereoselectivity of these reactions ranged from moderate to excellent and the open-chain dienes reacted similarly. Recently, the aza-Diels-Alder reaction was used by Waldmann in the asymmetric synthesis of highly functionalized tetracyclic indole derivatives (Eq. 12.45), which is useful for the synthesis of yohimbine- and reserpine-type alkaloids.112... 

Synthesis of Functionalized Indole- and Benzo-Fused Heterocyclic Derivatives through Anionic Benzyne Cyclization... 

Supercritical solutions are characterized by very low solvent densities. As a result, they possess the interesting feature that solubility is determined more by solute-solute than solute-solvent interactions. Thus we were able to express the solubilities of naphthalene and a series of indole derivatives in four different supercritical solvents (C2H4, C2H6, C02 and the highly polar CHF3) in the same functional format, only the numerical coefficients varying from one to another.57 Solute-solvent interactions do occur,58 but solubility can be represented quite... 

Various organolithium intermediates may be posmlated for the synthesis of functionalized indoles and other heterocyclic compounds, from substituted Af-allylanilines (331a-c) or the cychc analog 332, on treatment with f-BuLi. For example, in equation 81 intermediate 333, derived from 331a, was quenched with deuterium oxide. Participation of benzyne metallated intermediates, such as 334, derived from 332, is surmised in equation 82 and other processes. The products of equations 81 and 82 can be characterized by H and NMR spectra . 

Indole derivatives such as dihydroindolone are scaffolds of potentially biological interest. Thus, the development of such functionalized skeletons has been approached by a MCR involving cyclic 1,3-diketones, cyclohexyl isocyanide, aromatic aldehydes, and ammonium acetate in the presence of catalytic amount of KHSO4 in refluxing acetonitrile (Scheme 30) [117]. hi this strategy, the imine derived from the Knoevenagel adduct reacts with cyclohexyl isocyanide to give the... 

Using derivatized glycine usually lowers the yields compared with sarcosin -nevertheless various functionalized glycine derivatives have been used. Amine 245, obtained by reaction of a trimethoxy-indole functionalized amino acid with an aliphatic co-amino-aldehyde, has been coupled with an oligonucleotide to increase the affinity of Cjq conjugates to certain nucleic acids (Figure 4.13) [288]. 

The best known drugs acting as antimitotics are the vinca alkaloids, vincristine (7.90) and vinblastine (7.91). They are very complex indole derivatives that nevertheless have been synthesized. Both are quite effective in various leukemias and in Hodgkin s lymphoma, but show considerable neurotoxicity. Vinblastine and vincristine bind specifically to the microtubular protein tubulin in dimeric form, precipitating depolymerization of the microtubules and functionally acting as a mitotic poison. Vinorelbine (7.92) is a semisynthetic vinca alkaloid functionally identical to vinblastine. 

Protected and unprotected indole derivatives dissolved in hydrogen fluoride are also fluorinated by 18F-F. The relatively stable melatonin (10), a neurohormone responsible for the biological clock and other brain functions, gave only the 6-[l8F]fluoro derivative 11, but even the more fragile 5-hydroxytryptophan (12) could be fluorinated under these conditions resulting in a mixture of 4- and 6-[l8F]fluorohydroxytryptophan 13.54... 

The electrochemical oxidation of aromatic aldehydes (1) must be studied in strongly alkaline media. Acidity functions for strongly alkaline aqueous solutions of alkali metal and quaternary ammonium hydroxides, corresponding to dissociation of proton (H ), are well established (2, 3). Substituted anilines and diphenylamines (4,5) and indoles (6) were used as acid-base indicators for establishment of such scales, but whether an acidity scale based on one type of indicator can be rigorously applied to acid-base equilibria involving structurally different acidic groups for reactions in strongly alkaline media remains questionable. For substituted anilines, behavior both parallel (7) and nonparallel (8) to the H scale based on indole derivatives has been reported. The limited solubility of anilines in aqueous solutions of alkali metal hydroxides, the reactions of the aniline derivative with more than one hydroxide ion, irreversible substitution reactions (9), and the possibility of hydroxide ion addition rather than... 

The reaction of vinylindoles containing the vinyl function incorporated in a carbocyclic ring provide access to novel polycyclic indole derivatives. The reaction of 46 with DMAD under forced conditions gave a mixture of Diels-Alder (47), Michael (48), and ene (49) adducts (91LA357). 

---