Photocatalytic Synthesis of Polycyclic Indolones

Abstract In this work, a photocatalytic strategy for a rapid and modular access to polycyclic indolones starting from readily available indoles is reported. This strategy relies on the use of redox‐active esters in combination with an iridium‐based photocatalyst under visible‐light irradiation. The generation of alkyl radicals through decarboxylative single electron reductions enables intramolecular homolytic aromatic substitutions with a pending indole moiety to afford pyrrolo‐ and pyridoindolone derivatives under mild conditions. Furthermore, it was demonstrated that these radicals could also be engaged into cascades consisting of an intermolecular Giese‐type addition followed by an intramolecular homolytic aromatic substitution to rapidly assemble valuable azepinoindolones.

Indoles are prevalent motifs in bioactive natural products and pharmaceuticals. 1 Therefore, the development of methods for the synthesis of functionalized of indoles under mild conditions is an important task in synthetic chemistry. 2 In this respect, catalytic transformations enabling the direct functionalization of indole C-H bonds are particularly valuable because they afford complex indole structures with an excellent step and atomeconomy. 3 We report herein a catalytic access to diverse polycyclic indolones starting from cheap and readily available indole precursors (Scheme 1). Importantly, such indolone motifs are found in a range of indole alkaloids 4 and are valuable intermediates in the total synthesis of related natural products. 5 Scheme 1. A photocatalytic strategy to access valuable polycyclic indolones.
Over the last decade, photoredox catalysis has emerged as a powerful tool for organic synthesis allowing the generation of reactive free radical species under mild conditions and from simple precursors. 6 Notably, photoredox catalysis can be an efficient tool for indole functionalization. 7 Redox-active esters such as N-acyloxyphthalimides (NAPs) are versatile precursors of alkyl radicals through single-electron reduction followed by decarboxylation. 8 In particular, NAPs have been used in photocatalytic Minisci-type reactions to generate nucleophilic alkyl radicals which reacts with electron deficient heterocycles such as pyridines or (iso)quinolines. 9 However, NAPs have rarely been applied to the functionalization of electron rich heterocycles like indoles. 10 We reasoned that an intramolecular cyclization could overcome the mismatch polarity of radicals with a nucleophilic character reacting with electron-rich aromatics. To this purpose, we studied the use of NAPs 2 derived from carboxylic acids obtained from the reaction of indoles and commercially available cyclic anhydrides (Scheme 2a). We expected these NAPs to undergo a single-electron transfer with an excited reducing photocatalyst leading to alkyl radical 3 after fragmentation followed by decarboxylation. Radical 3 would then undergo a 5-exo-trig cyclization leading to dearomatized intermediate 4 which after oxidation and proton elimination would afford indolone product 6 (Scheme 2b). We studied the feasibility of the envisioned process with substrate 2a, readily accessed in two steps from indole and succinic anhydride. We first evaluated the use of organic dyes as photocatalysts. 11 When 2a was reacted with 5 mol% of commonly used 4-CzIPN 12 (PC1, E red = -1.04 V vs. SCE) in DMSO under blue light irradiation, a small amount of 6a could be detected but most of the crude mixture consisted of unreacted starting material (Table 1, entry 1). Given the highly negative reduction potential of NAPs (E red = -1.3 V vs. SCE), we reasoned that a more reducing photocatalyst would facilitate a photoinduced electron transfer (PET) to the substrate, thus increasing the conversion of 2a. To this purpose we performed the reaction in the presence of PC2, a highly reducing phenoxazine photocatalyst recently developed by Miyake and coworkers (E red* = -1.93 V vs. SCE). 13 Pleasingly, the yield of 6a significantly increased to 58% (entry 2). Based on these results, we then further evaluated fac-Ir(ppy) 3 (E red* = -1.73 V vs. SCE) which proved to be a very efficient photocatalyst for the targeted transformation leading to 6a in 67% isolated yield (entry 3). The use of other common solvents such as DMA or DMF was detrimental (entry 4-5). Of note, the presence of up to ten equivalents of water does not affect the yield of the reaction so technical grade DMSO could be used as solvent for this study (entry 6). Furthermore, a control experiment revealed that the photocatalyst is required to observe the desired reactivity (entry 7). Finally, the use of a reduced catalyst loading (0.5 mol%) led to a similar yield after 14h (entry 8). With optimal conditions in hand to promote the desired cyclization, we developed a more efficient one-pot protocol enabling the synthesis of indolone 6a starting directly from carboxylic acid 7a. To this purpose, we investigated the use of coupling agents such as dicyclohexylcarbodiimide (DCC) and diisopropylcarbodiimide (DIC) ( Table 2, entry 1-2). Pleasingly, the use of DIC led to a similar yield when compared to our previously optimized two-step protocol (entry 2). The low yield obtained with DCC may be due to the formation of a poorly soluble dicyclohexylurea byproduct which might prevent a sufficient light penetration into the reaction medium. Of note, the addition of a catalytic amount of DMAP for the coupling was detrimental to the overall process (entry 3).   The scope of the reaction was then evaluated with a range of different anhydrides and indole derivatives (Scheme 3). Substrates derived from several succinic anhydrides and leading to the formation of primary, secondary and tertiary radicals afforded the desired pyrroloindolones 6a-d in good overall yields. Importantly, compounds 6b and 6c were obtained as single diastereoisomers. Pleasingly, substrates 7e-g derived from glutaric anhydrides also led to the formation of pyridoindolones through a cyclisation step which then occurs via a 6-exo-trig addition. Then, a variety of indoles with different substitution patterns were also evaluated for this process. Substrates bearing both electron-withdrawing and electrondonating groups were successfully implemented in our methodology as shown with indolones 6h-v. The use of chlorinated and brominated indoles led to the desired indolones 6m-o uneventfully and allow for further modifications through cross-coupling reactions. A pyrrole-derived substrate was also competent for this process as shown with 6p. Finally, a range of 3-substituted indoles could be used to access indolones 6q-v.
Notably, several complex substrates derived from tryptamine, melatonine and tryptophan were successfully transformed into valuable indolones 6t-v in good yields. The structure of 6v was unambiguously confirmed by X-ray crystallographic analysis. 14 Scheme 4. Gram-scale reaction and synthetic applications.
To showcase the scalability of the process, we performed a gram-scale reaction using 4.25 mmol of 2q and a reduced catalyst loading of only 0.2 mol% without impacting the outcome of the reaction (Scheme 4). Then, to further demonstrate the utility of this method we performed some transformations on compounds 6 to prove their versatility as synthetic intermediates. First, 6q was reduced with borane to access in a single step the pyrroloindole scaffold (see 8) which is found is many bioactive compounds, 15 including the flinderole alkaloids 16 and many pharmaceutically relevant small molecules. 17 Importantly, 6q could also be selectively hydrogenated with a catalytic amount of palladium on charcoal to access the important indoline scaffold quantitatively (see 10). Then, the indolone moiety was also reacted with soft nucleophiles to afford C2-alkylated free indoles as exemplified with compound 9. Finally, electrophilic bromination of compound 6v led to complex pyrroloindoline 11 which is reminiscent of many naturally occurring alkaloids exhibiting a diverse range of biological activities. 18 The commercial availability of many succinic and glutaric anhydrides enabled us to efficiently synthesize a range of pyrrolo-and pyridoindolones using our methodology. However, the scarce availability of adipic anhydrides, prevented us to access the valuable azepinoindolone scaffold. 4a-b,19 To circumvent this issue, we envisaged to intercept radical 3 with an external olefin to access radical 12 which would then add to the indole moiety to afford azepinoindolone 13 as described in Scheme 5a. As an inherent challenge to this strategy, the intermolecular Giese-type addition to the olefin must be kinetically favored over the intramolecular 5-exo-trig cyclization to the indole. After some experimentation, we discovered that the use of acrylonitrile as a trapping olefin efficiently led to the desired azepinoindolones while only traces of the corresponding pyrroloindolones could be detected. 20 This strategy allowed us to access valuable azepinoindolones 13a-f in moderate to good yields (Scheme 5b).

Scheme 5. Synthesis of azepinoindolones.
In summary, we have developed a photocatalytic C-H alkylation strategy mediated by visible light that provides an efficient access to a variety of relevant polycyclic indolones. The reaction is scalable and the indolone products can be further used as valuable synthetic intermediates to access other important scaffolds such as pyrroloindoles and (pyrrolo)indolines. Finally, the development of a challenging two-component process enabled the straightforward synthesis of functionalized azepinoindolones. We expect this methodology to find a widespread use in the synthesis of indole-containing natural products and bioactive compounds.