Organic Chemistry Portal
Organic Chemistry Highlights

Tuesday, September 5, 2006
M. Manuel B. Marques
REQUIMTE - FCT - New University of Lisbon

Novel Synthetic Approaches Toward Substituted Indole Scaffolds

The indole scaffold is a prominent and privileged structural motif found in numerous natural products and various synthetic compounds. Recently, a large number of indole-containing compounds have revealed remarkable pharmacological activity and their utility as therapeutic agents has attracted considerable attention from chemists (Angew. Chem. 2005, 44, 606, DOI: 10.1002/anie.200461864; J. Am. Chem. Soc. 2005, 127, 5342, DOI: 10.1021/ja0510616). Libraries based on the indole scaffold have been developed to address the need for novel drugs with increased potency (J. Comb. Chem. 2005, 7, 130, DOI: 10.1021/cc049922e; Tetrahedron 2006, 62, 3439, DOI: 10.1016/j.tet.2006.01.047). Subsequently, the development of efficient methods that allow rapid access to functionalized indoles with different substitution patterns (at C-2, C-3, N-atom and aromatic ring, Figure 1) constitutes an emerging area.

The most recent advances on catalytic methods to achieve the synthesis of substituted indole are highlighted herein. For a review on earlier work on indole synthesis, see J. Chem. Soc. Perkin Trans. 1 2000, 1045. DOI: 10.1039/a909834h)

I. Palladium-catalyzed methods

Senanayake and co-workers of the Boehringer-Ingelheim Pharmaceuticals (Virginia) (Org. Lett. 2006, 8, 3271. DOI: 10.1021/ol061136q) have reported on a one-pot, three-component procedure for the synthesis of 2,3-substituted indoles based on Cacchi´s protocol (Scheme 1).

Scheme 1 - One-pot, three-component procedure for accessing the 2,3-substituted indole scaffold.

This regiospecific procedure consisted of a Pd domino indolization involving a consecutive Pd-catalyzed Sonogashira coupling followed by aminopalladation and reductive elimination starting from 2-iodo-N-trifluoroacetylanilide 1, a suitable acetylene 2 and bromoarene 3. The Senanayake group optimized the reaction conditions as shown in Scheme 1: the use of trifluoroacetyl as protecting group in 1 was shown to be advantageous (readily hydrolyzable); addition of bromobenzene at the beginning simplified the procedure and enhanced the reaction rate; DMF as solvent combined with K2CO3 as base, and a temperature of 60 ēC gave better results.

The Larock group of the Iowa State University reported (J. Org. Chem. 2006, 71, 62. DOI: 10.1021/jo051549p) on the synthesis of 3-iodoindoles 8 via Pd/Cu-catalyzed coupling of N,N-dialkyl-2-iodoanilines 5 with terminal acetylenes 6 and subsequent electrophilic cyclization of 7 (Scheme 2). Due to the high reactivity of N,N-dialkyl-o-iodoanilines towards the Sonogashira coupling, a wide variety of substituted anilines and alkynes were used (with aryl, vinyl, alkyl and silyl groups). However, the authors reported that substituents on the triple bond of 7 affect the yield of the following cyclization step, since increased conjugation enhances the reaction rate and also increases the product yield. In addition, while electron-withdrawing groups enhanced cyclization, (strong) electron-donating groups slowed the reaction and led to lower yields.

Scheme 2 - Synthesis of 3-iodoindoles by Pd/Cu-catalyzed coupling followed by electrophilic cyclization.

The authors reported an interesting feature; when there are two different N-alkyl groups, the less-hindered group is more easily removed. Additionally, this procedure allows further derivatization/functionalization at C-3, since 8 might be used for cross-coupling reactions.

The Lautens group of the University of Toronto described a modular synthesis of 2-substituted indoles via a palladium-catalyzed coupling (Org. Lett. 2005, 7, 3549. DOI: 10.1021/ol051286l). This methodology involved an intramolecular Buchwald-Hartwig C-N/intermolecular Suzuki-Miyaura C-C coupling of o-gem-dihalovinylanilines with an organoboron reagent catalyzed by Pd(OAc)2/S-Phos in the presence of K3PO4.H2O (Scheme 3). Interestingly, the free aniline furnished the desired indole directly and in good yield. The strategy reported by the authors showed a wide range of applicability in terms of substituents, in particular for the challenging 4-substituted indoles. Better results were obtained for X = Cl. Moreover, the authors expanded the reaction scope to obtain 1,2,3-trisubstituted indoles by switching the order of addition of the two boronic acids.

Scheme 3 - Synthesis of 2,3-disubstituted indoles using a Pd-catalyzed C-N/C-C coupling strategy.

II. Zn(OTf)2 –Catalyzed Cyclization

The Liu group of the National Tsing-hua University published a new indole synthetic approach (J. Org. Chem. 2006, 71, 4951. DOI: 10.1021/jo0606711), using anilines 12 as starting material with the appropriately substituted propargyl alcohols 13 as the source of the C-2―C-3 unit. This method proved to be very effective in the preparation of several indoles 14 in good to high yields (Scheme 4), since Zn(OTf)2 has the advantage of activating not only the C-2-addition of the alcohol but also the subsequent cyclization step. The mechanism elucidated by the authors proposed that the isomerization of the α-amino ketone intermediate occurs through a 1,2-nitrogen shift, thus explaining the observed chemoselectivity.

Scheme 4 - Zn(OTf)2-catalyzed cyclization of propargyl alcohols 13 with anilines 12.

III. Rearrangement of Azirines via Thermolysis

D. Taber and W. Tian of the University of Delaware have reported on the synthesis of indole 17 (J. Am. Chem. Soc. 2006, 128, 1058. DOI: 10.1021/ja058026j) via the thermal rearrangement of azirines 16 that are readily available from the ketones 15 (Neber reaction) via the corresponding activated oxime (Scheme 5). The rearrangement occurred at temperatures ranging from 40 ēC up to 170 ēC. The authors suggest that the cyclization mechanism proceeds by a π-participation of the aromatic ring followed by reorganization, before the new C-N bond is formed.

Scheme 5 - Indole synthesis via rearrangement of functionalized azirines 16.
IV. N-Methoxyindoles via Alkylative Cycloaddition of Nitrosoarenes with Alkynes

The Nicholas and Penoni groups of the University of Oklahoma and of the Universitā degli Studi dell’Insubria, respectively, have reported on a pathway to N-methoxyindoles via an alkylative cycloaddition reaction (J. Org. Chem. 2006, 71, 823. DOI: 10.1021/jo051609r). The authors performed a one-pot procedure for the preparation of several substituted N-methoxyindoles 20 using as starting materials the readily available nitrosoarenes 18 and the alkyne 19 (Scheme 6). Both electron-poor and electron-rich nitrosoarenes gave good product yields and regioselectivity for the 3-position was observed. The authors obtained higher yields for 2-substituted nitrosoarenes 18 when compared to 4-substituted nitrosoarenes 18. Additionally, this method constitutes a formal synthesis of the corresponding indole (NH) since the latter can be formed by reduction of 20.

Scheme 6 - Synthesis of N-methoxyindoles 20 through alkylative cycloaddition.

Recently, a review on the synthesis of indole derivatives via the versatile isocyanides was reported by M. Gárcia-Valverde and T. Torroba groups of the Universidad de Burgos and of the Universitā degli Studi di Firenze, respectively (Org. Biomol. Chem. 2006, 4, 757. DOI: 10.1039/b514946k).

M. M. B. Marques, Org. Chem. Highlights 2006, September 5.