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Home > Indole Synthesis Using Silver Catalysis
Indole Synthesis Using Silver Catalysis
Aimee K. Clarke+, Hon E. Ho+, James A. Rossi-Ashton+, Richard J. K. Taylor, and William P. Unsworth*
1. Introduction
The indole core is a key structural component in many natural products and pharmaceuticals and serves as a fundamental building block in organic synthesis.[1] The synthesis of indole scaffolds has therefore been the focus of much research and a myriad of methods to construct indole rings have been developed over the years.[2] Classical methods include the Fischer indole[3] and Bartoli syntheses, which are widely and routinely used by the synthetic community.[4] Nonetheless, limitations associated with these classical procedures mean that establishing novel strategies to prepare indoles is still important and continues to be actively pursued.
Many indole syntheses make use of alkyne activation approaches, typically involving coordination of a metal catalyst to the alkyne to activate it towards cyclization.[5] Silver, a member of the “coinage metal” family, can be readily obtained in the form of silver(I) salts with a variety of different counterions. These salts, which have a d10 electronic configuration at silver, are well-established as being good s-/p-Lewis acids and are recognized as being powerful catalysts in alkyne activation.[6] In addition to their ability to interact with p-systems to promote useful reactivity, the use of silver in organic transformations has important economic benefits relative to other more expensive transition metals such as gold, palladium and platinum.[5,6] Indole synthesis has been extensively reviewed previously,[2] however, a comprehensive review focusing specifically on silver-catalyzed approaches has not been reported before. As the use of silver catalysis in heterocycle synthesis is becoming more prevalent,[5] a review of this topic in the context of indole synthesis is timely. To the best of our knowledge, this Minireview summarizes all silver-catalyzed indole syntheses to date, with a cut-off period of papers published before January 2019. Note that whilst we believe that all publications that feature examples within the remit of this review are discussed, we have not reproduced all of the individual examples from these
studies.
Many indole syntheses utilize silver in mixed catalytic systems (e.g. mixed gold/silver systems),[5] but this Minieview is limited to examples in which the silver species have been shown to be competent at catalyzing the reaction without the influence of another metal species. The review is organized in chronological order and is divided based on the type of reaction used to construct the indole core, starting with the most commonly used hydroamination pathway, before moving on to other methods. Mechanisms are included and described in more detail whenever they deviate from the generally accepted hydroamination mechanism.
2. Hydroamination Strategies
Alkyne hydroamination[7] is by far the most common synthetic strategy used for silver-catalyzed indole syntheses. In such reactions, anilines 1 substituted with an alkyne at their 2-position are treated with a silver(I) species which acts as a p-acid to activate the alkyne towards attack from a pendant aniline nitrogen via a 5-endo-dig cyclization mode (3!4). Protodemetallation then liberates the silver(I) species (meaning that the reactions can be catalytic in the silver species) and deprotonation completes the synthesis of the indole product 2 (Scheme 1).
To the best of our knowledge, the earliest example of the silver-catalyzed hydroamination strategy being used to prepare indole derivatives was reported by Rutjes and co-workers in 2004.[8] This group described the transition metal-catalyzed cyclization of o-alkynylanilines to access indole 2-propargylglycine (isotryptophan) derivatives. o-Alkynylpropargylglycine anilines 5 and 6 were prepared using Sonogashira cross-coupling between o-iodoanilines and enantiopure propargylic glycine precursors. The use of 10 mol% AgOTf in MeCN at reflux for 20 h furnished the isotryptophan products 7 and 8 in good yields. By comparison, the use of a Pd II catalytic system resulted in formation of the undesired cyclization product 9, which was not observed when AgOTf was employed (Scheme 2).
In 2007, Li et al. reported a gold and silver co-catalyzed double hydroamination of o-alkynylanilines with terminal alkynes to access N-vinyl indole derivatives.[9] During the catalyst screening process, the separate use of both 5 mol% AgOTf and 5 mol% AgBF4 at 608C for 2 h under neat conditions gave the N-vinyl indole product 12 in 62% and 59% yields, respectively (Scheme 3). Although a silver(I) species can facilitate the cascade hydroamination process alone, it was later revealed that the combination of 5 mol% of AuCl3/AgOTf at RT was more efficient and hence was the main focus of the study.
In 2009, Liu et al. reported a gold and silver co-catalyzed microwave-assisted intramolecular hydroamination of o-alkynylamides to construct N1-carbamide indole derivatives.[10] Although the combination of AuI/AgI in aqueous media using microwave irradiation at 150 8C was chosen as the optimal reaction conditions, using 10 mol% AgOTf or Ag2CO3 alone displayed catalytic activity to afford the cyclized indole product 14 in 23% and 75% yields, respectively (Scheme 4A). It was also found that the reaction conditions were exclusive to o-terminal alkynes as no reaction was observed when 2-substituted o-alkynylcarbamides 15 and 16 were used as substrates(Scheme 4 B).
In 2009, Ding et al. reported a silver-catalyzed hydroamination process using (o-alkynylphenyl)guanidines 17 to access Ncarboximidamide or N-carboximidoate indole derivatives 18(Scheme 5).[11] By using 5 mol% AgNO3 at RT and MeCN as the solvent, guanidines 17 were found to selectively undergo 5- endo-dig cyclization to afford a range of indole derivatives 18 in good yields. The authors also conducted a comparison study between AgI and other commonly used p-acids such as PdII and CuI salts. It was reported that the reaction using a AgNO3 catalyst was the most effective, proceeding efficiently and in high yield; meanwhile, the analogous reactions using both PdII and CuI catalytic systems were incomplete, even after extended reaction times. Overall, this silver(I)-catalyzed cyclization provides access to N-carboximidamide or N-carboximidoate indole-2-phenyl derivatives under simple and mild reaction conditions.
In 2010, Oh et al. reported a silver(I)-catalyzed cascade process based on the reaction of o-alkynylformidates 19 and activated methylene compounds 20 to synthesize 3-vinyl indole derivatives 21(Scheme 6).[12] Typically, these reactions were performed using 5 mol% AgOTf in toluene at 808C for 12 h, enabling a range of 3-vinyl indoles 21 to be prepared in moderate to good yields.
The authors suggested a plausible mechanism for this transformation, involving an interesting 3-alkenyl migration process(Scheme 7). First, coordination of silver(I) to the alkyne facilitates enolate addition into imine 22 to form 23. This is followed by p-acid activation of the alkyne by silver(I) to induce a 5-endo-dig cyclization to form the indole core. 1,3-Alkenyl migration is then proposed to occur via a silver-carbene intermediate 26, which is followed by rapid protodemetallation under acidic conditions to furnish the 3-vinyl indole product 21. Note that similar migration patterns have also been reported by using other transition metals such as PdII, PtII, and AuIII. [5, 13]
The 1,3-alkenyl migration mechanism shown in Scheme 7 was supported by a series of control experiments. For example, when o-alkynylenamine 28 was subjected to the standard reaction conditions, only the hydroamination product 29 was isolated in 55% yield (Scheme 8). This suggested that fast protodemetallation was competing with the 1,3-alkenyl migration pathway in some instances.
In 2010 Chan et al. described a system for the synthesis of indoles via gold-catalyzed cycloisomerization reactions.[14] During this investigation, as a control experiment, 1,3-diphenyl-1-(2 (tosylamino)phenyl)prop-2-yn-1-ol 30 was treated with 5 mol% AgOTf, which yielded the corresponding indenyl-fused indole 31 in 16% yield, alongside the alcohol-tethered indole 32 in 48% yield (Scheme 9). Although it was proven that AgOTf could facilitate indole formation, a gold-catalyzed method was shown to be more efficient and was the main focus of this investigation.
Two years later, Chan et al. developed a silver-catalyzed tandem heterocyclization/alkynylation process using propargylic 1,4-diols 33 to generate o-alkynyl indoles 34, liberating two molecules of water as the sole by-products (Scheme 10).
This was the first reported indole synthesis that introduced alkyne moieties at the 2-position of the indole ring without relying on traditional cross-coupling methods. A variety of tosylprotected o-alkynyl indoles 34, bearing additional substituents in the 3-, 5- and 6-positions, were generated in good to excellent yields employing AgOTf as the catalyst. Interestingly, the reaction proceeds well in the absence of a group in the R 1 position, which leads to the formation of 3H-indole products; this is particularly noteworthy as these products cannot be formed using traditional cross-coupling approaches. The authors suggested that the silver catalyst activates the C@OH bonds in the diol substrates, rather than the alkyne moiety directly, and that this subsequently triggers cyclization/hydroamination.
In 2012, Van der Eycken et al. reported the microwave-assisted syntheses of pyrazino-quinazolines and indolyl-pyrazinones from alkyne-tethered pyrazinones using either silver or gold catalysis.[16] Treatment of alkyne-tethered pyrazinone 35 with AgOTf, using conventional heating, resulted in the synthesis of indole 36 in 18% yield, alongside quinazoline product 37 in 75% yield (Scheme 11). Ag(I) was found to be the superior catalyst for the formation of the quinazoline products, but AuCl was in fact identified as the optimum catalyst for formation of the indole products.
In 2012, Tang et al. reported a silver-catalyzed process for the synthesis of bis(indolyl)methanes 40 from o-alkynylanilines 38 and aryl aldehydes 39 (Scheme 12).[17] Their simple one-pot procedure was performed in the presence of 5 mol% AgNO3 in DMSO at 808C for 12 h. A wide range of o-alkynylanilines 38 and aryl aldehydes 39 were tolerated in this process, providing access to the corresponding bis(indolyl)methanes 40 in moderate to excellent yields. Based on previously reported mechanisms, the authors suggested that these reactions proceed via a hydroamination pathway in which the silver catalyst activates both alkyne and aldehyde starting materials.
In 2013, Liu et al. reported the synthesis of (3-indolyl)stannanes 42 via a silver-catalyzed cyclization/stannylation cascade process.[18] Starting from a series of o-alkynylanilines 41 and reacting with 5 mol% AgSbF6 and two equivalents of 2-tributylstannylfuran, a wide range of N1-protected-(3-indolyl)stannanes 42 were synthesized (Scheme 13A). The procedure was shown to tolerate both electron-donating and electron-withdrawing groups on the alkyne phenyl ring and substituents at the 4-position of the parent aniline ring. It was found that the presence of an electron-withdrawing protecting group is essential to the success of the reaction, as the non-stannylated 3H-indole product was isolated when a N-methyl aniline starting material was tested. It was also found that indoles bearing electron-withdrawing protecting groups other than sulfonyl were unstable during purification via column chromatography.
The authors showcased the utility of the 3-stannylated indole products 42 by performing a series of elaboration reactions. To probe the reaction mechanism, 3H-indole was subjected to the optimized reaction conditions and no stannylated product was observed, which indicated that the stannylation did not occur via C@H functionalization of the indole product but instead through a silver-tin transmetallation process as shown in Scheme 13B. In this mechanism, the silver is proposed to have a dual role; activating the alkyne towards attack from the amino group via the silver-coordinated alkyne 43 whilst also catalyzing the destannylation of 2-tributylstannylfuran throug a transmetallation protodemetallation pathway, thus liberating Bu3Sn+ which goes on to react with the 3-indolyl silver(I) intermediate 44.
Many indole syntheses utilize silver in mixed catalytic systems :
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