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O-alkynylanilines
In an extension to their previous work, Fan and co-workers went on to report another ox- idative dearomatization/silver-catalyzed cyclization domino process, this time involving an interesting [3+3]-dipolar cyclo- addition reaction.[22] This procedure afforded 3,4-fused indoles directly in a one-pot process from o-alkynylanilines and o-alkynylbenzaldoximes. The reaction was shown to tolerate an extensive range of N-protecting groups, aniline ring substituents, alkynyl phenyl ring substituents and a variety of o-alkynylbenzaldoximes 62.
The mechanism of this process (shown in Scheme 19) is thought to proceed via an oxidative dearomatization of a para-substituted o-alkynylaniline 61, which furnishes inter- mediate 64 following a silver-catalyzed cyclization (see Scheme 17 for details of these steps). This species is then pro- posed to undergo a [3+3]-dipolar cycloaddition (this step is best thought of as operating on resonance form 65) to for an unstable cycloadduct product 66. The authors then suggest two possible radical pathways (not shown) for the thermal re- arrangement of cycloadduct 66 resulting in the formation of 3,4-fused indole 63.
In 2014, Bi et al. reported silver-catalyzed heteroaromatiza- tion of propargylic alcohols to form a range of 3-tosyl benzo- furans, benzothiophenes and indoles.[23] Key to this work is the dual role of p-toluenesulfonylmethyl isocyanide, which serves as both the sulfonyl source and the ligand for the silver catalyst. An extensive mechanistic study was conducted on the silver-catalyzed benzofuran forming part of this work, resulting in the proposal of a deoxysulfonylation/hydration/condensa- tion reaction pathway, which was extended to the analogous indole formation. While the main focus of this investigation was on benzofuran synthesis, a smaller series of indoles 68 were synthesized from propargylic alcohols 67 with a variety of aryl and heteroaryl functionality on the C2 indole tether (Scheme 20). The scope of the investigation was expanded to isomeric propargylic alcohols 69, which resulted in the forma- tion of 3H-indoles 70 with tosyl functionality on the C2 indole tether. A similar reaction pathway was proposed to operate when isomeric propargylic alcohols 69 were reacted under broadly the same reactions conditions.
In 2016, Michelet and co-workers described the synthesis of benzoxazinone and benzisoxazole derivatives using silver or gold catalysts in the presence of oxone.[24] During optimization studies, the formation of an indole side product 71 was ob- served when reacting o-alkynylaniline 10 with catalytic quanti- ties of AgNO3 under an oxygen atmosphere (A) or in the pres- ence of 2,6-lutidine N-oxide (B). There were just two examples of the 2-phenylindole side product 71 being formed in low yield (15 % and 20 %, Scheme 21). These were the only report- ed examples of silver-catalyzed indole formation in the publi- cation but note that this was not the main focus of the study. The oxidants themselves are not involved in the formation of the indole product 71, but they were added in an attempt to promote subsequent oxidation reactions.
The authors also observed the same silver-catalyzed intra- molecular hydroamination reaction in a follow-up paper; this time indole 71 was isolated in a 37% yield when aniline 10 was heated in the presence of AgNO3 and a large excess of H2O2 in a methanol/water solvent system (Scheme 22).
Again, the oxidant appears not to be involved in this reaction. A silver-catalyzed indolization of o-alkynylanilines 72 fol- lowed by ring-opening of donor-acceptor cyclopropanes (DACs) 73 in one-pot was reported by Singh et al. in 2016 (Scheme 23).[26] This cascade process features an initial intramolecular hydroamination reaction catalyzed by AgSbF6 and is fol- lowed by an unprecedented AgI-mediated ring-opening/trap- ping of DAC 73, which functionalizes the resulting indole at the C3 position. When unprotected anilines were used, most DACs tested underwent ring-opening prior to cyclization lead- ing to a diminished indole product yield, therefore protection of the free amine is necessary for these reactions to proceed successfully. This methodology tolerates a wide range of DACs incorporating aryl, heteroaryl and vinyl functionalities as well as a variety of substituted o-alkynylaniline partners, furnishing 2,3-disubstituted indole derivatives 74 in good to excellent yields. The authors also described the elaboration of their cas- cade products into useful intermediates, further showcasing their synthetic utility.
Following on from the work reported by Tang et al. in 2012 on the preparation of bis(indolyl)methanes 40 (see Scheme 12), a similar procedure was reported by Chattopad- hyay et al. in 2016.[27] An efficient one-pot domino process for the formation of symmetrical bis(indolyl)methanes 40 from o- alkynylanilines 38 and aldehydes 39 using silver catalysis was described (Scheme 24). Although conceptually similar to Tang’s work, this paper did significantly extend the scope of this reac- tion; in particular, this study focused on exploring substituents on the pyrrole ring to include aryl, heteroaryl and alkyl groups, which were limited to aryl moieties in Tang’s earlier work. Inter- estingly, substrates featuring a n-butyl or an ester group on their alkyne unit proceeded particularly well in this transformation, which is surprising given that a hexyl substituted alkyne in Tang’s work did not generate any of the desired bis(indolyl)- methane.
In view of the importance of 2-substituted indoles in medici- nal applications, a facile silver-catalyzed route towards N- cyano-2-substituted indole derivatives was developed by Trive- di et al. and reported in 2017.[28] Hydroamination reactions commonly use o-alkynylanilines as starting substrates for indole formation but, in contrast, Trivedi and co-workers uti- lized a unique intramolecular cyclization of alkynyl tetrazoles 75 instead, which was catalyzed by AgOAc under ambient con- ditions (Scheme 25). Linear alkyl, cycloalkyl and aryl substituted alkynes are tolerated in the starting tetrazoles 75, with this method used to prepare a range of 2/7-substituted N-cyanoin- doles 76 in high yields. The authors propose that the mecha- nism proceeds via a typical AgI-alkyne activation pathway fol- lowed by nucleophilic intramolecular cyclization, whereby the nucleophilic nitrogen is generated from deprotonation of the acidic tetrazole proton and subsequent loss of N2 produces an N-phenylcyanamide species.
A “greener” AgNO3-catalyzed approach to indole and 7-aza- indole derivatives 78 using water as the reaction solvent has been reported by Shao et al. (Scheme 26).[29] The majority of the indoles and aza-indoles 78 obtained using this method were isolated in excellent yields following a simple filtration and drying process. The authors also explored recycling the aqueous AgNO3 medium, whereby the product from each cycle was obtained by filtration and the resulting aqueous filtrate (containing AgNO3) could be used in the next reaction immediately; three reaction cycles were successfully achieved in yields of 93 % and above, although a prolonged reaction time of 36 h compared to 10 h was required for the third cycle. Interestingly, none of the desired indole products were formed when the reactions were carried out in organic solvents such as DMF, toluene or ethanol. The authors suggested that this was because their process belonged to the “on-water” reaction class, which requires a water-oil phase boundary for the chemi- cal transformation to take place. They proposed that a cooper- ative hydrogen bond network forms at the water-oil interface between the substrate and solvent which helps to lower the energy of the cyclization transition state and hence promote hydroamination.
In 2018, Samanta and co-workers reported a one-pot silver- catalyzed intramolecular hydroamination of o-alkynylanilines 49 to construct complex 2,3-substituted indole derivatives 81 and 82 (Scheme 27).[30] Various additives including AuIII, CuI, ZnII, FeIII reagents as well as TfOH and HBF4 were screened in the optimization studies; 2 mol% AgSbF6 in DCE at 45 8C was found to be optimal for the synthesis of indoles 81 and 82. A wide range of substituents were tolerated on o-alkynylanilines 49, as well as the o-alkynyl cyclic enynones 79 and 80, to afford the 2,3-disubstituted indoles 81 and 82 in moderate to excellent yields.
A mechanism involving a silver(I)-catalyzed intramolecular hydroamination and Friedel–Crafts alkylation/oxacyclization cascade was proposed, as depicted in Scheme 28. First electro- philic activation of the alkynylaniline by AgI occurs to form species 83 which then undergoes hydroamination (83!84) followed by fast protodemetallation to furnish indole inter- mediate 85 whilst regenerating the silver catalyst. Then, indole 85, generated in situ, undergoes a C3 Friedel–Crafts type alky- lation at the b-position of enynone-Ag complex 86, followed by a 5-endo-dig oxacyclization in a concerted fashion to form the vinyl-Ag species 87. Finally, fast protodemetallation of 87 produces the 2,3-disubstituted indole 81.
In 2018, a silver-catalyzed “anti-Michael” hydroamination procedure to access 2-acylindoles 89 was developed by Ma- rinelli and co-workers (Scheme 29).[31] This method comple- ments existing procedures for the synthesis of 2-acylindoles and the fact that it is fully atom-economical and does not require any additional protection/deprotection strategies is par- ticularly advantageous. Other coinage metals were explored in this procedure; CuOTf also promoted the desired transforma- tion, albeit with lower efficiency and interestingly, AuI salts were completely ineffective. Silver(I) salts, in particular AgOTf, were the best catalysts for this transformation. A variety of 2- acylindoles 89 bearing aryl, heteroaryl, vinyl and alkyl groups were prepared in good to excellent yields. Thienyl and cyclo- hexyl substituted products unfortunately led to lower isolated yields and propargyl alcohols and alkynoate esters were not suitable substrates for this cyclization.
Other Examples
Although most of the procedures featured in this Minireview involve hydroamination of alkynes, this section includes rare examples of silver(I)-catalyzed indole synthesis via other meth- ods.
One of these methods was developed in our laboratory,[32] as part of a wider programme of research into silver-catalyzed alkyne activation[33] and indole dearomatization reactions.[34] This work is based on the use of pyrrole-tethered alkyne pre- cursors (Scheme 30). A variety of substituted indole derivatives were prepared via an unusual “back-to-front” approach, where- by pyrrole-based starting materials (90 and 92) were used in- stead of anilines or related benzene derivatives, which are more typically employed in indole synthesis. Both AgNO3 (sometimes with a Ag2O additive) and a silica-supported silver catalyst (1 weight% AgNO3·SiO2)[35] were shown to catalyze the formation of a variety of substituted indole products under mild conditions. Both propargyl alcohols 90 and ynones 92 were suitable substrates generating indoles 91 and 5-hydroxy indoles 93 respectively in good to excellent yields. The range of substitution patterns achieved on the benzene ring portion of the indole products is noteworthy; a range of starting mate- rials can be employed in this procedure, allowing a variety of substitution patterns to be obtained that are difficult to access using traditional indole syntheses. DFT studies were also per- formed as part of this study, and these revealed that the reac- tions are likely to proceed via initial nucleophilic attack through the pyrrole C3 position before migrating, which goes against the generally accepted view that pyrroles are more nu- cleophilic through their C2 position in such systems.
Another non-hydroamination method, published in 2015 by Youn and co-workers, concerns the silver(I)-mediated C@H ami- nation of o-alkenyl anilines 94 to access 2,3-substituted indole derivatives 95 and 96 (Scheme 31).[36] The authors report the use of 1.3 equivalents of Ag2CO3 as an oxidant and heating to 150 8C in DMF for 0.5 h as being optimal reaction conditions for this transformation. It was noted that relatively high dilu- tion (0.025 m) was needed to achieve good yields and short reaction times. Interestingly, changing the solvent from DMF to heptane (0.05 m) promoted 2,3-migration of the aryl/alkyl sub- stituents, which suggests that a rearrangement process is in- volved in the mechanism. The use of N-nosyl o-alkenyl anilines and heptane as the solvent gave a mixture of 2- or 3-substitut- ed indole products, with a ratio of up to 4.5:1 in favour of the 3-substituted indole.
Reducing the loading of Ag2CO3 resulted in lower yields, hence a catalytic protocol was not pursued further. Despite the process requiring a stoichiometric loading of silver, the authors demonstrated that the Ag2CO3 can be partially recovered after the completion of the reaction and reused in up to 4 cycles without any significant loss in activity. A mechanism as depict- ed in Scheme 32 was proposed. A nitrogen-centered radical cation 98 is believed to be generated from the AgI reagent via a single-electron transfer (SET) mechanism. This is followed by electrophilic radical addition to the tethered alkene coupled with deprotonation to afford a benzylic radical species 99. Sub- sequent oxidation of 99 to form benzylic carbocation inter- mediate 100, followed by rearomatization via deprotonation, then affords the 2-substituted indole 101.
In 2018, Liang et al. reported the isolation of phosphonoalkyl indole 104 from allylphenylacetamide 102 in 9% yield as a minor side-product from a silver-catalyzed radical phosphoryla- tion/cyclization cascade (Scheme 33).[37] This is the only exam- ple of indole formation in this report, with the focus of the paper being the formation of 3-phosphonoalkyl indolines 103. The authors hypothesized that the indole product was formed via oxidation of the initial indoline product 103 under the reac- tion conditions.
Summary
In view of the variety and number of silver-mediated indole forming reactions described in this review, it should be clear that silver chemistry has an important role to play in the syn- thesis of indole derivatives. Most of these procedures involve silver(I) catalysis and alkyne hydroamination, starting from an aniline precursor. Silver(I) species are well suited to promote this chemistry in view of their usually high p-acidity, which en- ables the alkyne to be activated under relatively mild condi- tions in many cases. The resulting vinyl silver species typically undergo fast protodemetallation, which is also important as this can facilitate faster catalyst turnover. Another important feature of silver(I) species in general is that these reagents are typically easy to handle, readily available and moderately priced in most cases (at least compared with other precious metal reagents). They are also compatible with a range of reac- tion conditions, solvents and other reagents, which is crucial in terms of them being applied in the wide range of silver-medi- ated processes described herein, particularly in the cascade processes that go beyond simple hydroamination/protodeme- tallation. The fact that suitable alkyne substituted aniline start- ing materials are usually relatively easy to prepare (e.g. via So- nogashira reactions or other cross-coupling processes) is also likely to be have contributed to the utility and popularity of these methods.
By bringing all this science together in a Minireview, we hope to facilitate the development of more efficient and ambi- tious silver(I)-mediated methods for the synthesis of important indole derivatives.
Acknowledgements
The authors would like to thank the EPSRC (A.K.C. EP/R013748/ 1, H.E.H. EP/N035119/1), the University of York, and the Lever- hulme Trust (for an Early Career Fellowship, ECF-2015-013,
W.P.U.) for financial support.
Conflict of interest
The authors declare no conflict of interest.
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