Photo-driven bifunctional iron-catalyzed one-pot assembling of indoles from arylamines and alkanes/carboxylic acids

Domain: chemistry
Published: 2026-01-08
Editorial outcome: minor_revision

Abstract
Indoles are privileged structural motifs in N-heterocyclic chemistry, while developing a general and facile platform capable of directly transforming commodity chemicals into multi-functionalized indoles persists as an unmet challenge. Herein, we present a photo-driven bifunctional iron-catalyzed strategy for one-pot synthesis of indoles from readily available arylamines and alkanes/carboxylic acids. By leveraging a synergistic combination of iron-based photocatalysis via ligand-to-metal charge transfer pathway and Lewis acid catalysis, the method enables efficient C(sp3)–H activation or decarboxylation followed by sigmatropic rearrangement cyclization under mild conditions. The protocol demonstrates broad substrate scope (152 examples), excellent functional group tolerance, and high yields (up to 95%), facilitating the direct construction of diverse indole scaffolds without pre-functionalization. Notably, the methodology can be successfully applied to the concise and scale-up total synthesis of several pharmacologically relevant indole derivatives, including Iprindole, Mebhydrolin, Melatonin, and A-FABP inhibitor, underscoring its practicality and potential for industrial application in pharmaceutical manufacturing.

Introduction
Indoles, as privileged structural motifs in N-heterocyclic chemistry, serve as pivotal building blocks for the construction of natural products1–3, agrochemicals, and bioactive pharmaceuticals4–6. The enduring pursuit of efficient synthetic routes for indole core construction and functionalization has driven remarkable innovations in modern organic synthesis. Early in 1883, the landmark Fischer indole synthesis was reported, which employs arylhydrazines and carbonyl compounds to form hydrazones followed by acid-mediated [3,3]-sigmatropic rearrangement under thermal conditions (Fig. 1a)7. Nevertheless, conventional protocols frequently suffer from operational limitations, including stringent acidic media, narrow substrate scope, and source-restricted substituted arylhydrazine precursors. Over a century of methodological development has yielded a multitude of synthetic approaches8–12, in which one of the most significant developments is demonstrating that aryldiazonium salts can serve as effective precursors for indole synthesis (Fig. 1b). In 2014, Matcha & Antonchick group developed a catalytic protocol for the modular synthesis of C2-CF3 CH2-substituted indole derivatives with non-activated olefins, aryldiazonium salts, and sodium triflate13. Subsequently, Xiao group advanced this strategy by photocatalysis to construct trifluoromethylated azo intermediates followed by Brønsted acid-catalyzed cyclization to access indole derivatives14. Apart from the trifluoromethyl-containing scope, organozinc reagents15, alkyl iodides16,17, and dihydropyridine-functionalized alkanes18 have been successfully employed in the construction of azo intermediates with aryldiazonium salts for subsequent indole formation, while some shortcomings, such as the essential pre-activated substrates, fussy multi-step synthesis, and poor atom economy still exist. Given the enduring importance of indoles and the aforementioned limitations, the development of a multifunctional catalytic system to realize integrated indole synthetic paradigms with improved substrate scope and mild conditions remains imperative.

Recent years have witnessed transformative developments in photochemical synthesis as an environmentally benign and atom-economical paradigm for organic transformations. Among these advancements, the photoinduced ligand-to-metal charge transfer (LMCT) strategy has emerged as a cutting-edge platform, particularly noted for its efficacy in enabling challenging bond activations and constructions through radical-mediated pathways. Mechanistically, photoexcitation of the LMCT band induces homolytic cleavage of high-valent metal-ligand bonds, generating reactive radical intermediates that drive diverse transformations, such as decarboxylation, C–H functionalization, and β-cleavage processes19–35. The strategic implementation of iron-based catalysts in LMCT systems has garnered particular interest, owing to iron’s combination of terrestrial abundance, low toxicity, and simple catalytic system35–45. These attributes position Fe-LMCT platforms as sustainable alternatives that simultaneously address economic and ecological imperatives in modern synthesis. Importantly, iron catalysts exhibit versatile catalytic capabilities in traditional thermally driven systems46–48, including redox catalysis49 and Lewis acid (LA) catalysis50,51. Integrating these multifaceted functions with their emerging photocatalytic competence enables synergistic multi-catalytic processes within a unified system, unlocking broad synthetic potential. Recently, our group pioneered the direct fusion of iron photocatalysis with traditional iron redox catalysis, achieving concurrent alkane C–H activation and stereoselective olefin construction within a single catalytic cycle43. Building upon this foundation, we next attempt to design a Swiss-Army-knife-type catalytic platform integrating iron photocatalysis and iron LA catalysis for addressing the mentioned critical challenges—notably laborious multistep protocols and narrow substrate scope—in indole synthesis (Fig. 1c). This multifunctional system is proposed to simultaneously leverage three consecutive units, including in situ diazotization of anilines, LMCT-driven C–H activation/decarboxylation, and LA-catalyzed cascade cyclization. By orchestrating these mechanistically distinct pathways within one pot, we expect to establish an integrated and streamlined route to various indoles directly from industrial feedstocks.

Building upon our design and research foundation in iron photocatalysis41–45, we herein introduce a photo-induced bifunctional iron-catalyzed strategy that orchestrates the photocatalytic cycle and LA-mediated pathway to replace classical indole synthesis (Fig. 1d). This multifunctional integration protocol enables direct, single-step/one-pot two-step construction of high-value-added indole scaffolds from inexpensive and widely available anilines and alkanes/carboxylic acids, characterized by its ease of operation, mild reaction conditions, high efficiency, low cost, and broad substrate applicability. Notably, the method facilitates the streamlined synthesis of pharmaceutically pivotal indole intermediates—such as Iprindole, Mebhydrolin, Melatonine, etc.—with significantly shortened steps and enhanced efficiency compared to conventional approaches. As a scalable and purification-friendly process, the approach demonstrates a compelling potential for industrial implementation in active pharmaceutical ingredient manufacturing.

Results
Initially, we explored the feasibility of one-step indole synthesis through photo-induced LMCT-mediated alkane activation, utilizing cyclohexane (1a) and 4-methoxyaniline (1b) as model substrates (Table 1, more details see supplementary Table S1). We were delighted to find that the reaction obtained the desired product 1c in 85% yield with FeCl3·6H2O (0.1 equiv.) as catalyst, tBuONO (1 equiv.), and HBF4 (1.0 equiv.) as diazotization reagents, and MeCN as solvent under N2 and irradiation of 30 W 405 nm LEDs for 12 h (entry 1). The influence of the amount of HBF4 and other protic acids on the yield was systematically examined (entries 1–10), revealing that HBF4 (0.7 equiv.) was optimal with an excellent isolated yield of 95% (entry 5). Moreover, FeCl2·4H2O afforded the product in a competitive yield (entry 11), presumably due to its in-situ oxidation to the active Fe(III) species by tBuONO. Other iron catalysts were investigated but failed to produce indole without chlorides (entries 12–14). Correspondingly, the incorporation of an exogenous chloride source in conjunction with Fe(NO3)3·9H2O was observed to be effective (entry 15), suggesting the chlorine species to be an essential additive for alkane activation. Furthermore, a copper catalyst CuCl2 (entry 16), which has been reported to have similar photocatalytic activity to FeCl352, and a variety of common Lewis acid catalysts (details see Table S1) were evaluated; however, none produced the desired product under the reaction conditions, demonstrating that the iron catalyst exhibits more than one catalytic property in this system. The solvent screening revealed that different solvent choices significantly impacted reaction yields, with DMSO, DCE, and DMF failing to initiate the reaction (entry 17, details see Table S1). Meanwhile, acetone proved to be suitable for this transformation but afforded lower yields than MeCN (entry 18). Various light sources with different wavelengths, including 365 nm, 395 nm, 455 nm, and CFL, were tested next. The results indicated that the reaction efficiency was not as optimal as that achieved with 405 nm LEDs (entries 19–22). In addition, the yield of 1c slightly decreased when the reaction was performed by employing 0.05 equivalent of FeCl3·6H2O (entry 23). Notably, the addition of TBACl to increase the chloride ion concentration resulted in an improved reaction efficiency with a slightly reduced yield (entry 24). Control experiments revealed that no product was observed in the absence of an iron catalyst (entry 25), light (entry 26), or under air (entry 27).

With the optimal reaction conditions for the one-step iron-catalyzed construction of indole skeletons in hand, we proceeded to systematically investigate the reaction scope using diverse alkane and arylamine substrates (Fig. 2). Preliminary investigations employing a series of cycloalkanes (5-, 6-, 7-, 8-, and 12-membered rings; 1c–6c) demonstrated consistently excellent reactivity (>90% yields). Notably, cyclooctane (5c) exhibited extraordinary reactivity, and its derived indole product constitutes a pivotal synthetic intermediate for Iprindole, a finding that significantly streamlines the preparation of this pharmacologically important scaffold. When we applied a linear n-pentane instead, only 2° C–H activation products were acquired with no 1° C–H activation observed in this system (7c). We next investigated the substrate scope of this multi-step cyclization reaction with various aniline derivatives. The experimental results demonstrated that structurally diverse substituted anilines could efficiently react with cyclohexane to construct indole frameworks in good to excellent yields (51–95%, 8c–50c). The transformation showed remarkable functional group tolerance, accommodating both electron-donating and electron-withdrawing substituents with high efficiency. Firstly, anilines with electron-donating groups including alkyls (Me, Et, tBu, iPr, 8c–11c) and ethers (OEt, OPh, OCF3, 12c–14c) performed particularly well (almost around 90%). Moreover, the reaction also exhibited good to excellent compatibility towards various electron-withdrawing groups, including halogens (F, Cl, Br, I, 18c–21c), trifluoromethyl (22c), cyano (24c), esters (COOMe, COOEt, 24c, 25c), carbonyls (Ac, COPh, 26c, 27c), and sulfonyl derivatives (SO2Me, SO2NH2, 28c, 29c). Remarkably, hydroxyl-containing moieties, including phenolic (81%, 16c) and aliphatic alcohol groups (87%, 15c), and drug-relevant sulfamide units (61%, 29c) remain intact without protective strategies, providing a wide chemical space for further diversification. Following steric evaluation revealed that meta-substituted anilines (30c–34c) afforded slightly lower yields (59–73%) relative to their para-substituted counterparts. Multi-substituted substrates performed well regardless of electronic properties, with both mixed electron-donating/withdrawing combinations (35c, 36c, 38c, 41c) and bis-electron-withdrawing systems (37c, 39c, 40c, 42c, 43c) maintaining moderate to good reaction efficiency. Notably, the indole product (48c, 52%) obtained from the reaction of a free carboxylic acid-containing aniline with cycloheptane serves as a key intermediate for A-FABP inhibitors, demonstrating the practical utility of this transformation in medicinal chemistry. Heteroaromatic amines involving quinoline and benzofuran motifs were also compatible, affording the corresponding indole product in moderate yields (49c, 50c). The transformation’s remarkable substrate versatility and functional group tolerance prompted our exploration of its applications in complex molecular settings. Impressively, the commercially available sulfonamide antibiotic Sulfamethazine was directly converted to its corresponding indole derivative (51c) in 65% yield under standard conditions, without requiring protection of the pharmacophoric sulfonamide group. Furthermore, a series of representative natural products and pharmaceutical molecules, including Borneol (52c), DL-Menthol (53c), Carvacrol (54c), Thymol (55c), Naproxen (56c), Propafenone (57c), Vanillylacetone (58c), and Vitamin E (59c), were selected for derivatization studies. These substrates could be readily converted into corresponding arylamines under mild conditions, followed by successful photoinduced cross-coupling and cyclization to afford the desired indole derivatives in good to excellent yields (65–85%). These successful examples not only broadens synthetic access to medicinally relevant indole scaffolds but also provide a general platform for the structural diversification of bioactive natural products and pharmaceuticals through photo-driven C(sp3)–H activation of alkanes. Moreover, we executed a gram-scale synthesis employing 4-methoxyaniline 1b (10.0 g, 81.2 mmol), achieving product 1c in 91.9% isolated yield with no obvious efficiency loss (more details see Fig. S12). To further increase the light utilization efficiency, a well-designed continuous-flow photocatalytic micro-reactor was used, capable to afford similar results to those of the batch reaction with a reduced time and attenuated light irradiation (more details see Fig. S13). This successful scale-up and flow synthesis not only confirms the robustness of our methodology but also highlights its potential for industrial manufacturing applications.

Delightfully, a noticeable advance in constructing the indole skeleton has been achieved through an iron-catalyzed photoredox one-step coupling of alkanes with arylamines, although some limitations, including the difficult activation of the primary C–H bonds of alkanes and the exclusive formation of 2,3-disubstituted indoles, still exist. Meanwhile, carboxylic acids serve as versatile radical precursors due to their advantageous properties: environmental benignity, cost efficiency, general stability in air and moisture, ease of storage and handling, and natural abundance (such as amino acids, fatty acids, etc.). The decarboxylation process exhibits thermodynamic driving force with CO2 as a byproduct, making it a powerful strategy for constructing C–C, C–N, C–O, and C–X bonds53–56. Significantly, the Fe-LMCT process demonstrates remarkable versatility, proving effective not only for alkane activation but also for facilitating efficient carboxylic acid transformations57–59. In order to break through the above limitations and expand the application scope of this bifunctional iron-catalyzed system, we then broadened our focus to include carboxylic acids with wider sources and varieties than alkanes as substrates.

At the outset of our investigation, we selected the reaction between cyclohexanecarboxylic acid (1a′) and 4-methoxybenzenediazonium tetrafluoroborate (1b′) as the model system for condition optimization of the decarboxylative indole construction process (more details see Supplementary Tables S2 and S3). After systematic investigation of catalysts, ligands, additives, and solvents, we successfully established the following optimal reaction conditions. The combination of FeCl3·6H2O (0.1 equiv.) as an inexpensive photocatalyst as well as a Lewis-acid catalyst, di-(2-picolyl)amine L1 (0.2 equiv.) as the ligand, and DABCO (1 equiv.) and KHSO4 (5 equiv.) as additives in MeCN under 30 W 405 nm LED irradiation provided the target indole product 1c in 88% yield (Table S2, entry 15). Various iron catalysts, including FeBr3, Fe(OTf)3, Fe(NO3)3·9H2O, FeSO4·7H2O, and Fe(acac)3, all showed limited activity (entries 35–42). Interestingly, CeCl3 exhibited moderate catalytic efficiency (67% yield, entry 44), while other metal chlorides, including ZrCl4 and CuCl2, presented no activity (entries 45−48). Control experiments established the essential roles of each kind of reaction component for successful transformation (entries 55–59). Furthermore, the stoichiometric ratio between carboxylic acids and aryldiazonium salts critically influenced the reaction outcome, as a molar ratio lower than 2:1 led to diminished yields compared to the optimal conditions (Table S3). Building upon our target to establish a Swiss-Army-knife-type catalytic platform for one-pot synthesis of indoles, we further sought to expand this methodology to a direct one-pot coupling between arylamines and carboxylic acids (Tables S4 and S5). Initial one-step studies revealed limited efficiency, with the transformation yielding only 54% even after extensive condition optimization (Table S4, entry 3). To address this issue, we devised an improved one-pot two-step strategy involving an initial arylamine diazotization at 0 °C and a following iron-catalyzed decarboxylative cyclization in situ without intermediate purification. This optimized protocol significantly promoted the yield of target indole product 1c to 86% (Table S5, entry 2).

With the optimized one-pot two-step protocol established, we next evaluated the reaction scope using various carboxylic acids and arylamines (Fig. 3). The investigation first focused on secondary carboxylic acids. Cyclic substrates involving substituted cyclohexanecarboxylic acids (bearing methyl, propyl, ester, hydroxy, amide, and fluoro groups; 60c–65c) and carbocyclic acids of varying ring sizes (5- to 7-membered rings; 1c, 66c, 67c) were all proved to be effective substrates, affording the corresponding indole products in 68–87% yields. Notably, with 1-methylpiperidine-4-carboxylic acid as a substrate, our optimized decarboxylation protocol enabled the robust and efficient construction of a pharmacologically valuable piperidine-fused indole scaffold (68c–70c). This privileged scaffold serves as a versatile synthetic intermediate and has been strategically employed in the concise synthesis of biologically active compounds, such as Dimebolin (69c) and Mebhydrolin (70c). Similarly, a series of secondary carboxylic acids with varying carbon chain lengths (71c–77c, C4–C9) and their phenyl-substituted analogs (78c–82c) efficiently delivered indole frameworks in 74–84% yields. Subsequent investigation of phenylpropanoic acid substrates demonstrated that aromatic analogs bearing diverse substituents (OMe, Cl, Br, I, CN) could be transformed into corresponding indole derivatives (83c–89c) in good yields. Nevertheless, comparative studies revealed a little lower reactivity of general primary carboxylic acids relative to their secondary counterparts. To overcome this obstacle, we developed an optimized protocol (details see Table S6) by modulating the catalyst and additive loading and adjusting their radiation wavelength to 365 nm. Through condition screening, the reaction efficiency using primary carboxylic acids as the substrate was improved by three times (21%→61%). Depending on these efforts, linear primary carboxylic acids with different carbon chain lengths (C4–C15) all participated effectively in the reaction, affording C3-substituted indole derivatives (93c–104c) in moderate yields. As the alkyl chain length increased (>C11), the yields showed a slight decrease due to the markedly reduced solubility of acid substrates in MeCN solvent. More propionic acid derivatives bearing diverse functional groups, including alkyl (91c, 92c), halogens (105c, 106c), esters (107c–109c), thioesters (110c), and amides (111c), were also converted to the corresponding indole derivatives in satisfactory yields, showing the excellent functional group compatibility of this method. To evaluate the synthetic utility of this one-pot two-step methodology, we then investigated its application to structurally diverse natural products and bioactive pharmaceutical compounds. The reaction demonstrated remarkable versatility in accommodating various natural fatty acids, including saturated (Lauric acid 113c, Myristic acid 114c, and Palmitic acid 115c) and unsaturated (Oleic acid 116c) variants, as well as the therapeutic agent Azelaic acid (117c), all of which were efficiently converted to their corresponding indole derivatives. The methodology was further extended to primary carboxylic acid derivatives derived from biologically relevant scaffolds and drugs, including Geraniol (118c), Vanillylacetone (119c), Triclosan (120c), Procaine (121c), and Estrone (122c), and the results demonstrated the success of the cross-conjugation between these functional molecules with the indole motif under mild conditions and convenient operation.

The seven-membered ring fused with an indole core is known as cyclohepta[b]indole, a privileged scaffold in medicinal chemistry. Compounds containing this structural motif exhibit diverse pharmacological activities, including: A-FABP inhibitor, LTB4 inhibitor, SIRT1 inhibitor IV, and anti-tubercular agent60. Building upon these significant medicinal properties, cycloheptanecarboxylic acid was chosen as a model substrate to evaluate the compatibility of the decarboxylative indolization protocol with various aromatic amines, and meanwhile, construct an abundant molecular library for the functionalized cyclohepta[b]indole derivatives (Fig. 4). Gratifyingly, cycloheptanecarboxylic acid exhibited excellent reactivity in this bifunctional iron-catalyzed photoredox system, efficiently affording the corresponding cyclohepta[b]indoles (123c–152c) in moderate to excellent yields (43–84%). This transformation exhibited remarkable versatility by readily accommodating both para- and ortho-substituted arylamines containing diverse functional groups, including alkyl (123c, 124c), ether (125c–129c), phenolic (128c), alcohol (129c), fluoro (130c, 133c), chloro (131c, 134c), bromo (132c, 135c), trifluoromethyl (136c), nitrile (137c), ester (138c–140c), sulfone (141c), sulfonamide (142c) and carbonyl (143c, 144c). A particularly noteworthy example was the successful application to ester-substituted aniline (139c), as the resulting indole derivatives serve as key intermediates for adipocyte fatty acid-binding protein (A-FABP) inhibitors, underscoring the methodology’s medicinal chemistry relevance. The protocol also proved effective for disubstituted arylamines (145c–147c), enabling access to highly substituted indole scaffolds in competitive yields. 8-Aminoquinoline as a heteroaromatic substrate was tried next, furnishing the corresponding indole in 43% yield (148c). A clear electronic effect was observed in this library, with electron-donating groups presenting enhanced reactivity relative to electron-withdrawing substituents. Furthermore, the methodology successfully incorporated other bioactive motifs from natural products and pharmaceuticals with the valuable cyclohepta[b]indole core, including Borneol (149c), Carvacrol (150c), Thymol (151c), and Naproxen (152c), endowing this molecular library with additional potential value for new drug discovery.

Depending on the convenience, practicality, and great functional group tolerance of our method, we next implemented this Swiss-Army-knife-type catalytic strategy for the route improvement of the total synthesis of four pharmaceutically valuable indole-containing drugs (Fig. 5). Initially, the antidepressant Iprindole61,62 (5d), traditionally prepared via a four-step sequence under harsh reaction conditions, was efficiently synthesized through our streamlined two-step protocol under mild conditions, achieving 75% isolated yield (vs 43% overall yield for the 4-step route) with significantly enhanced operational efficiency. Mebhydrolin63,64 (70d), a clinically used antihistamine for histamine-mediated allergic diseases, was efficiently synthesized via our one-pot decarboxylation/cyclization protocol using commercially available aniline and 1-methylpiperidine-4-carboxylic acid as starting materials. This optimized approach afforded the target compound in 56% total yield, representing a substantial improvement over the conventional multi-step synthesis (47% overall yield after four steps) and simultaneously enhancing both operational safety and atom economy. Melatonin65,66 (112c), as an important endogenous compound with multiple biological activities, has been scientifically demonstrated to possess various pharmacological effects, including anti-inflammatory, antioxidant, energy metabolism regulation, skin barrier protection, and glucose metabolism improvement. Although several synthetic routes have been developed for industrial production, these methods are generally limited by their multi-step procedures and toxic reagent usage. In our work, the target molecule was efficiently constructed in just one step from readily available starting materials, achieving a yield of 57% with notably improved synthetic efficiency and cost-effectiveness. Finally, the A-FABP inhibitor67,68 (139d) acts on a therapeutic target with dual mechanisms of action that regulate fatty acid transport and suppress inflammatory responses. However, its traditional synthetic methods require six laborious steps: hydrolysis, diazotization, reduction, cyclization, esterification, and hydrolysis. In contrast, an innovative synthetic route provided herein could prepare the target molecule in just two steps: initial construction of the indole core via decarboxylation or alkane activation, followed by benzyl protection/hydrolysis to afford the final product. This streamlined protocol achieves a 50% overall yield—nearly doubling the yield compared to traditional methods—while eliminating hazardous diazotization reactions and multiple purification steps, thereby significantly enhancing both synthetic efficiency and operational safety. To further demonstrate the application potential for this methodology, we attempted and smoothly accomplished decagram-scale production of both Iprindole (73.3%) and Melatonin (54.7%), exhibiting scalability and process robustness with minimal yield variation compared to small-scale reactions. This breakthrough strategy effectively addresses critical industrialization challenges through the complete elimination of hazardous diazotization steps while rigorously adhering to green chemistry principles, thereby offering a sustainable and industrially viable solution for large-scale pharmaceutical manufacturing.

To gain insights into the bifunctional iron-catalyzed photoredox indolization pathway, we systematically conducted a series of mechanistic experiments (Fig. 6). Firstly, the radicals produced in the iron-catalyzed system were surveyed by electron paramagnetic resonance (EPR) in the presence of 5,5-dimethyl-1-pyrroline N-oxide (DMPO) as the spin trapping agent. As shown in Fig. 6a, irradiation of the 1a/FeCl3·6H2O/DMPO system generated a sextet signal (AN = 14.51 G, AH = 21.52 G, and g = 2.0053) which was attributable to a carbon-centered radical69. Only a ferric signal could be observed without light, indicating that cyclohexane 1a was activated to a cyclohexyl radical through iron photocatalysis. Furthermore, after the addition of substrate 1b′ into this mixture, a triplet signal (AN = 14.39 G, AH = 14.59 G, and g = 2.0086) ascribed to a nitrogen-centered radical70 was detected instead under irradiation, suggesting the rapid radical-trapping nature between the cyclohexyl radical and 1b′ (more details see Figs. S3 and S4). Assisted by L1 and DABCO, the same carbon-centered and the following nitrogen-centered radicals were both acquired via photoinduced LMCT pathway with cyclohexanecarboxylic acid 1a′ as substrate, demonstrating similar radical generation and capturing processes as 1a (more details see Figs. S5 and S6). Subsequent radical trapping experiments using superstoichiometric 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) produced the adducts of carbon radicals and TEMPO and were verified by GC-MS analysis, further indicating the achievement of radical-mediated C(sp3)–H activation/decarboxylation steps (Fig. 6b, more details see Figs. S1 and S2). Kinetic isotopic effect (KIE) studies with separate kinetic experiments were next carried out to gain insights into the C(sp3)–H cleavage step (Fig. 6c). The KIE values given by KH/KD and PH/PD were measured as 3.10 and 3.19 by using (1) 1a/1a-d12 respectively as substrates or (2) a 1:1 mixture of 1a and 1a-d12 as substrates to produce 1c (more details see SI, part IV, iii). These results implied one of the alkyl C(sp3)–H activation processes to be the “rate-determining step” for this system. Moreover, the quantum yield of the model reaction was calculated as 0.019 (more details see SI, part IV, vii), reflecting that radical chain processes made little contribution in the indole construction strategy.71

To further elucidate the mechanism of the cyclization reaction, we designed and performed a series of control experiments. Initial experiments replacing the in situ diazotization system (aniline/tert-butylnitrite/HBF4) with pre-formed diazonium salt 1b′ demonstrated efficient indole synthesis using only FeCl3·6H2O as the catalyst without Brønsted acid additives (Fig. 6d-1). This preliminarily confirmed iron’s dual role beyond photocatalysis: as a Lewis acid catalyst for cyclization. Subsequent substitution of diazonium salts with putative azo intermediates (1g) proceeded smoothly for indole construction under iron-mediated Lewis acid catalysis, with negligible dependence on cyclohexane presence (Fig. 6d-2, 6d-3). Further investigation with hydrazone isomer 1h (double-bond migrated derivative of 1g) also afforded the indolization product in an excellent yield (87%) (Fig. 6d-4). Collectively, these experiments robustly demonstrate iron’s bifunctionality: enabling both photocatalytic C(sp3)–H activation and Lewis acid-driven sigmatropic rearrangement cyclization within a unified system. Building upon these findings, parallel conclusions were substantiated when employing carboxylic acids as alternative substrates to alkanes (Fig. 6e). Through analogous control experiments, we confirmed iron’s dual catalytic functionality in simultaneously enabling photocatalytic decarboxylation and Lewis acid-mediated indolization. Importantly, the acidic (HBF4 and KHSO4) or alkaline (DABCO) additives present in the system were excluded from participating in the cyclization stage. To further elucidate the role of these additives in the decarboxylation regime, we conducted subsequent mechanistic investigations with a pre-synthesized Fe(III)-carboxylate complex [Fe]-1 through Guérinot’s method72. As presented in Fig. 6f-1, spectroscopic analysis revealed that complex [Fe]-1 exhibits strong absorption at 405 nm, identifying it as the putative photosensitizer responsible for generating alkyl radicals via a LMCT process (more details see Figs. S8 and S9). Reaction of [Fe]-1 with diazonium salt 1b′ afforded the radical-trapped azo product 1g in a moderate yield (Fig. 6f-2). In this system, stoichiometric Lewis base DABCO masks iron’s Lewis acidity, almost inhibiting the cyclization step. Notably, even excess Brønsted acid KHSO4 failed to promote cyclization under these conditions. Removal of DABCO partially restored iron’s Lewis acidity, resulting in enhanced indolization efficiency (Fig. 6f-3). Further supplementation with FeCl3·6H2O as an exogenous Lewis acid catalyst quantitatively converted intermediate 1g into the target indole product (Fig. 6f-4). These control experiments definitively establish that: 1. The sigmatropic rearrangement cyclization is exclusively driven by iron’s Lewis acidity; 2. DABCO functions solely to facilitate carboxylate-iron coordination; 3. Brønsted acids primarily mediate diazonium formation and pH modulation. Overall, neither additive participates in the cyclization process, further confirming iron’s dual catalytic functionality as we design.

Integrating our mechanistic investigations with prior literature reports7,41,43,73,74, we propose a plausible bifunctional iron-catalyzed indolization pathway for C(sp3)–H/decarboxylative functionalization via a photoinduced LMCT and Lewis acid-driven mechanism (Fig. 7). In the decarboxylation system, the coordination of the carboxylic acid a′ to Fe(III) species A is proposed to form a Fe(III)−carboxylate complex B (similar to complex [Fe]-1) Photoexcitation of the iron complex B generates its excited state C and renders an intramolecular LMCT event to afford the reduced Fe(II) complex D and a carboxyl radical, which will produce the desired alkyl radical E after CO2 extrusion. When using alkane a as substrate, irradiation of the Fe(III)–Cl complex I gives the excited state II, and a subsequent LMCT generates an intermediate Fe(II) complex III and a highly active chlorine radical IV. A following hydrogen atom transfer (HAT) from alkane a to IV results in the same alkyl radical E. The radical E provided by both cycles selectively couples with aryldiazonium salt b′, delivering a highly reactive azo radical cation intermediate F. Within the Fe(II)/Fe(III) redox catalytic cycle, F undergoes facile single-electron transfer (SET) with Fe(II) to afford the neutral Fe(III)−diazene complex G. Sequential tautomerization via intramolecular proton transfer converts G to a hydrazone derivative H and a reactive enamine intermediate I, which subsequently proceeds a Fischer-type [3,3]-sigmatropic rearrangement to afford the diimine intermediate J through iron catalysis. Finally, J undergoes successive isomerization and aromatization-driven cyclization to form hemiaminal intermediate M after releasing Fe(III)-NH3, finally affording the target indole product c.

Methods
General procedure for one-step indole synthesis using arylamine and alkane
Arylamine b (0.2 mmol), alkane a (10 equiv.), FeCl3·6H2O (10 mol%, 5.4 mg), MeCN (2 mL), tert-butyl nitrite (0.2 mmol, 1 equiv., 20.6 mg), and HBF4 (48 wt% in H2O, 0.7 equiv., 25.6 mg) were added into a 10 mL Schlenk tube with a magnetic stir bar in sequence. The mixture was allowed to stir under N2 with the irradiation of a 30 W 405 nm LED at room temperature for 12 h. Upon completion, the reaction solution was diluted with 25 mL of EtOAc and washed with deionized water. The organic layer was concentrated under reduced pressure and the residue was purified by silica gel flash column chromatography (PE/EtOAc = 10:1–1:1) to give the desired product.

General procedure for one-pot two-step indole synthesis using arylamine and carboxylic acid
Arylamine b (0.2 mmol), EtOH (50 μL), and HBF4 (48 wt.% in H2O, 0.7 equiv., 25.6 mg) were added into a 10 mL Schlenk tube with a magnetic stir bar in sequence. The mixture was cooled to 0 °C, and tert-butyl nitrite (0.2 mmol, 1 equiv., 20.6 mg) was added dropwise. After stirring at 0 °C for 30 min, carboxylic acids a′ (3 equiv. for secondary carboxylic acids and 4 equiv. for primary carboxylic acids), FeCl3·6H2O (10 mol% for secondary carboxylic acids and 20 mol% for primary carboxylic acids), L1 (20 mol%, 8.0 mg), DABCO (1 equiv. for secondary carboxylic acids and 1.5 equiv. for primary carboxylic acids), KHSO4 (1 mmol, 5 equiv., 136.1 mg), and MeCN (2 mL) were added. The mixture was allowed to stir under N2 with the irradiation of a 30 W 405 nm LED at room temperature for 12 h. Upon completion, the reaction solution was diluted with 25 mL of EtOAc and washed with deionized water. The organic layer was concentrated under reduced pressure and the residue was purified by silica gel flash column chromatography (PE/EtOAc = 10:1–1:1) to give the desired product.

Peer review rounds
[{"round": 1, "reviewer_comments": {"reviewer_1": "General Comments\nThe manuscript by Jin and co-workers reports a new and elegant method for the synthesis of indoles through a photo-driven, bifunctional, iron-catalyzed one-pot process starting from arylamines and alkanes or carboxylic acids. The work is well written and clearly presented. The authors describe in detail a clever strategy for assembling indoles in a single step, achieving yields ranging from good to high, and in some cases, performing the reactions on a multigram scale.\nThe work was carried out in a competent and systematic manner. Each step is described thoroughly, covering the reactions of arylamines, cyclic and acyclic alkanes, and carboxylic acids. The transformation of arylamines into the corresponding aryldiazonium salts and the generation of radicals from alkanes and carboxylic acids under iron photocatalysis are both clearly explained. The scope of the reaction is impressive, encompassing over 140 examples.\nSeveral examples are particularly noteworthy, including substrates bearing long alkyl chains with tertiary centers (e.g., compound 57c derived from vitamin E) and carboxylic acids containing double bonds (e.g., compound 116c derived from geraniol), which, in principle, might be prone to side reactions with alkyl radicals generated in situ. Remarkably, these transformations proceeded smoothly, highlighting the robustness of the protocol.\nThe authors also demonstrate the synthetic utility of the method through the preparation of several pharmacologically relevant compounds, such as iprindole, mebhydrolin, melatonin (also referred to as melatonine in the text), and an A-FABP inhibitor, all obtained in essentially one step and with good overall yields. The scalability of the procedure to the multigram level further illustrates its potential for practical application.\nThe mechanistic studies are thorough and well-designed. The authors employed EPR analysis, control experiments, and kinetic isotope effect measurements to support their mechanistic proposal. The rationale includes several intriguing steps, particularly regarding the role of iron throughout the catalytic cycle, which the authors discuss convincingly. However, it is not clear to this reviewer whether DFT calculations were performed to substantiate the proposed mechanism. Inclusion of such computational data could further strengthen the mechanistic understanding, although it does not seem critical at this stage.\nOne minor but noteworthy point concerns the authors’ claim that the method is suitable for industrial application. Although the scalability and comparison with existing multistep routes are interesting, the authors do not discuss the economic aspects of the process. For instance, the reactions are performed under a nitrogen atmosphere, require light of a specific wavelength (405 nm) for 72 hours, and employ tert-butyl nitrite for diazotization. These factors may impact the industrial feasibility and should at least be acknowledged in the discussion.\n________________________________________\nMinor Issues\n• Please verify the pagination of references 11, 17, 22, 43, 56, and 61.\n• Some references appear incomplete:\no Ref. 22: Chem. Phys. Rev. 3 (2022).\no Ref. 70: Blank, O.; Heinrich, M. R. Carbodiazenylation of olefins by radical iodine transfer and addition to arenediazonium\nsalts. Wiley Online Library (2006).\nRecommendation:\nThe manuscript presents a valuable and innovative contribution to the field of photocatalytic C–C bond formation and heterocycle synthesis. With very minor revisions, it will be suitable for publication in the journal.", "reviewer_2": "In the present submission by Jin and coworkers, a photoredox driven strategy is involving bifunctional iron catalyst is developed to synthesize a variety of indoles through a modified Fischer Indole route. The authors claim role of iron as a photocatalyst through ligand to metal charge transfer for the early part of the mechanism and Lewis acid for the Sigmatropic rearrangement. The reaction has utilized arylamines converting them into diazonium salts and reacting them for the follow up reaction in the same pot. In one set, these substrates have been reacted with a variety of alkanes and in another, a variety of carboxylic acids have been involved. Overall, 148 exmaples have been generated, upscaling to the level of multi gram scale is successfully conducted, and several biological molecules including a few drugs as Iprindole, Mebhydrolin, etc. have been synthesized in better yields and fewer steps than the known methods, implying the usefulness of the work. Moreover, a detailed mechanistic evaluation has been undertaken using EPRs, UV-vis spectroscopy, KIE studies, and several other mechanistic experiments, which led the authors to strongly substantiate their proposed mechanism.\nOverall, the approach of this method is novel, the quality of the work is high, and the substrate scope is very broad. Based upon that, I recommend this work for publication in nature communications.\nHowever, I have the following minor queries:\n1. Table 1: Did the authors try an auxiliary such as TBACl to increase the Cl radical concentration? It would be prudent to try this in the present reaction.\n2. Table 1, entry 13: The fact that FeCl2 works equally well is likely because it gets oxidized to Fe(III) immediately. However, it may be spelled out in the text.\n3. Scheme 2: What if the arylamine has an addition thiolic or phenolic substitution?\n4. Scheme 2: What can be a possible explanation for the predominant regioisomer in 7c?\n5. Scheme 4: If possible, the authors may try a heterocyclic amine as a substrate in a few examples to see the effect of other heteroatoms.\n6. Scheme 7: For conversion of I to J, is light necessary?\n7. Why 1b’ hasn’t been optimized against constant 1a’ as in Table S3?\n8. Compounds such as 10c, 21c, 43c, 45c, 127c, etc have minor extraneous peaks in HNMR spectra. If possible, such compounds should be repurified.", "reviewer_3": "In this manuscript, Jin and co-workers reported a light-driven iron-catalyzed one-pot two-step indole synthesis from arylamines and alkanes or carboxylic acids. The protocol features broad substrate scope, excellent functional-group tolerance, and high efficiency. The synthetic utility was further demonstrated by gram-scale synthesis of several pharmacologically relevant indole derivatives. This work represents a very important contribution to photoredox catalysis, radical chemistry and indole synthesis. More importantly, the bifunctional role played by iron catalyst is intriguing and could inspire future efforts for new reaction development. The study is well conceived, carefully executed, and clearly presented. The conclusions are convincingly supported by the experimental data. The supporting information is also a good put-tegether. Overall, publication of this bueatiful work in Nature Communications in highly recommended pending the following minor considerations:\n1. How does the reaction work using NaNO2 instead of tBuONO?\n2. It is interesting to see the reaction with heteroaryl amines, such as aminopyridines, for the synthesis of aza-indoles.\n3. Relevant references on Fe-catalyzed C–N bond formation should be cited, such as Angew. Chem. Int. Ed. 2025, 64, e202417414; ACS Catal. 2024, 14, 4968; CCS Chem. 2025, doi/10.31635/ccschem.025.202506113.\n4. Typos:\n4.1 “field” in Scheme 6a is misspelled as “filed”\n4.2 In the SI, part X, the 13C NMR frequency is incorrectly given as “126 MHz”."}, "author_response": "Response: We sincerely thank the reviewer for the meticulous review and highly constructive feedback, particularly regarding the industrial potential of our method. We fully agree with the reviewer's point that a long-duration batch reaction may impact the industrial feasibility. To further enhance process efficiency and address the feasibility concerns, we implemented the reaction using a carefully designed continuous-flow photocatalytic microreactor that is closer to industrial production processes. This approach significantly reduced the reaction time and attenuated the essential light irradiation, while still maintaining yields comparable to those achieved in the batch process. Accordingly, the corresponding data has been added in the revised supporting information (page S29, Part VII) and discussed in the main text (lines 176-180).\n\nResponse: We sincerely apologize for this oversight. As noted by the reviewer, all the cited references have been carefully checked, and the necessary corrections have been made in the revised manuscript.\n\nResponse: We sincerely thank the reviewer for this insightful suggestion. Following the recommendation, we systematically evaluated the effect of adding tetrabutylammonium chloride (TBACl) to the standard reaction conditions. As summarized in the table below, the addition of TBACl led to an improved reaction efficiency with a slightly reduced isolated yield of the desired product 1c. These results support the reviewer’s suggestion that the addition of an auxiliary such as TBACl can increase the chlorine radical concentration. However, in order to ensure a higher yield of the reaction, we still preferred to keep the original reaction conditions unchanged. The corresponding data have been added in Table 1 (Entry 24) and discussed in the revised manuscript (lines 121-123).\n\nResponse: Many thanks to the reviewer for this insightful comment. As suggested by the reviewer, we have added the explanation regarding the in-situ oxidation of FeCl2 to the active Fe(III) species in the revised manuscript (lines 102-104).\n\nResponse: Many thanks to the reviewer for this important comment regarding substrate scope. Following the suggestion, we respectively evaluated arylamines containing additional phenolic and thiolic substituents in both reaction systems. As shown in the revised Figures 2 and 4, phenolic-substituted arylamines reacted smoothly under standard conditions, affording product 16c in 81% yield in the alkane system (revised Figure 2, page 16) and product 128c in 50% yield in the carboxylic acid system (revised Figure 4, page 18). In contrast, thiolic-substituted anilines failed to produce the desired indole products in either reaction system. The corresponding results and discussion were added to the revised paper (Figures 2 and 4; lines 146-147, 280) and supporting information (page S35, S101, and S74, S213; part VIII and XI).\n\nResponse: Many thanks to the reviewer for this insightful question regarding the regioselectivity observed for product 7c. Since the activation capability of chlorine radicals toward methylene groups is essentially identical, the regioselectivity of the reaction is determined by the number of equivalent hydrogen atoms at each site. For n-pentane, the number of equivalent hydrogens at the C2 position is twice that at the C3 position, resulting in predominant functionalization at C2 for product 7c. This regioselectivity trend is essentially consistent with our previous study (Green Chem. 2021, 23, 6984–6989).\n\nResponse: Heartfelt thanks to the reviewer for this valuable suggestion. Following the recommendation, we evaluated several heterocyclic amines as substrates in both the alkane and carboxylic acid reaction systems. As summarized in Figure R2, we examined a series of heteroaromatic amines, including pyridine-, quinoline-, benzofuran-, and benzo[b]thiophene-based analogues. Among these substrates, 8-aminoquinoline and benzofuran-5-amine gave trace products with cyclohexane at room temperature and afforded the corresponding indoles 49c and 50c in 48% and 16% yield under elevated temperature (80 °C), respectively. However, no desired product was detected with 4-aminopyridine and benzo[b]thiophen-5-amine under both conditions. The corresponding results and discussion were added to the revised paper (Figure 2; lines 157-159) and supporting information (pages S45–S46, S134–S135; part VIII and XI). In the carboxylic acid system, a similar trend was observed. 8-Aminoquinoline participated effectively, yielding indole 148c in 43% yield at 80 °C, while both benzofuran-5-amine and benzo[b]thiophen-5-amine afforded only trace amounts of the corresponding products. The corresponding results and discussion were added to the revised paper (Figure 4; lines 288-289) and supporting information (pages S80–S81, S233; part VIII and XI).\n\nResponse: Many thanks to the reviewer for raising this thoughtful mechanistic question. To determine whether light is required for the conversion of intermediate I to J, we conducted additional control experiments in the dark using substrates 1g and 1h under otherwise standard conditions. In both cases, the reaction failed to deliver the indole product 1c, confirming that the transformation from G to c is indeed light-dependent. Based on previous experience with Fischer indole synthesis studies, the 3,3-sigmatropic rearrangement from I to J is likely the step with the relatively highest energy barrier in the overall process from G to c. Therefore, we speculate that the step requiring photoexcitation in this process should be this one. The corresponding data are added in the revised supporting information (page S15).\n\nResponse: Many thanks to the reviewer for this pertinent question. In our original submission, the optimization of the stoichiometric ratio (Table S3) was performed with a fixed amount of aryldiazonium salt 1b’ (0.2 mmol) while varying the equivalents of carboxylic acid 1a’. Following the reviewer's suggestion, we have now systematically evaluated the reverse scenario by fixing the amount of carboxylic acid 1a’ (0.2 mmol) and varying the equivalents of aryldiazonium salt 1b’ from 1 to 5 equivalents. These additional results have been incorporated as entries 6–9 in Table S3 of the revised supporting information (page S3). As shown in Table R2, increasing the amount of 1b’ leads to a sharp decrease in reaction efficiency, with only trace amounts of product being detected.\n\nResponse: We sincerely thank the reviewer for the careful review. As suggested by the reviewer, we have repurified compounds 10c, 21c, 43c, 45c, and 127c (new number 130c). The updated NMR spectra demonstrate significantly improved purity, with the corresponding extraneous peaks eliminated. The newly purified spectra have been replaced in the revised supplementary information (page S95, S106, S128, S130, S215; part XI).\n\nResponse: Many thanks to the reviewer for the professional inquiry. As the reviewer suggested, NaNO2 was employed to replace tBuONO as the diazotizing reagent in both reaction systems. In both cases, lower yields were observed: 63% for the alkane system (Table S1, Entry 32, Page S2) and 57% for the carboxylic acid system (Table S5, Entry 7, Page S3).\n\nResponse: Heartfelt thanks to the reviewer for this valuable suggestion. Following the recommendation, we evaluated several heterocyclic amines as substrates in both the alkane and carboxylic acid reaction systems. As summarized in Figure R2, we examined a series of heteroaromatic amines, including pyridine-, quinoline-, benzofuran-, and benzo[b]thiophene-based analogues. Among these substrates, 8-aminoquinoline and benzofuran-5-amine gave trace products with cyclohexane at room temperature and afforded the corresponding indoles 49c and 50c in 48% and 16% yield under elevated temperature (80 °C), respectively. However, no desired product was detected with 4-aminopyridine and benzo[b]thiophen-5-amine under both conditions. The corresponding results and discussion were added to the revised paper (Figure 2; lines 157-159) and supporting information (pages S45–S46, S134–S135; part VIII and XI). In the carboxylic acid system, a similar trend was observed. 8-Aminoquinoline participated effectively, yielding indole 148c in 43% yield at 80 °C, while both benzofuran-5-amine and benzo[b]thiophen-5-amine afforded only trace amounts of the corresponding products. The corresponding results and discussion were added to the revised paper (Figure 4; lines 288-289) and supporting information (pages S80–S81, S233; part VIII and XI).\n\nResponse: Many thanks to the reviewer for the enlightening comments. As suggested by the reviewer, the mentioned reports for Fe-catalyzed C–N bond formation have been added in the revised manuscript as ref 46-48.\n\nResponse: We highly apologize for this mistake. As the reviewer suggested, we have carefully checked and corrected the misspelled word \"filed\" in Figure 6a.\n\nResponse: We highly apologize for this mistake. As the reviewer suggested, we have carefully checked and corrected the frequency of 13C NMR to \"125 MHz\" (pages S86-S240, part XI)."}, {"round": 2, "reviewer_comments": {"reviewer_1": "All the suggestions and corrections I have made during the reviewer process were incorporated into the revised manuscript, including a new scale-up flow experiment. The authors have also increased the number of examples to illustrate its robustness.\nMy congratulations to all the authors for their excellent work.", "reviewer_2": "The authors have done a great work to address all the queries raised in the previous version of the manuscript. I have no reservations in accepting this work for publication now.", "reviewer_3": "I consider that all the points raised by me and other referees were suitably reflected in the revised manuscript. I thus support publication of this work in Nat. Commun."}, "author_response": ""}]

Decision letter