An ion-pair as a superacidic precatalyst for the synthesis of indole alkaloids: a novel entry into the Fischer indole synthesis

Abstract

We report the first application of [Ph₃C]⁺[B(C₆F₅)₄]⁻ in ion-pair catalysis to the Fischer indole synthesis, enabling efficient construction of structurally diverse indole frameworks under mild conditions. Using the [Ph₃C]⁺[B(C₆F₅)₄]⁻ ion pair as a highly active and selective catalyst, a broad range of substrates, including sterically hindered and electronically diverse partners, were converted to indoles in good to excellent yields. The method delivers high regioselectivity even in structurally complex settings, as demonstrated in concise total syntheses of paullone, (±)-desbromoarborescidine A, tjipanazole D, and tjipanazole I. Scale-up synthesis was also achieved without loss of efficiency, highlighting the operational simplicity of the protocol. This work establishes ion-pair-catalysed Fischer indole synthesis as a versatile and scalable platform for rapid access to bioactive heterocyclic scaffolds.

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Green foundation

1. This study introduces a rare example of ion-pair catalysis enabling the rapid construction of carbazole scaffolds under mild, metal-free conditions. The protocol proceeds efficiently in short reaction times and delivers high yields with excellent selectivity, demonstrating operational simplicity and improved environmental compatibility compared to conventional methods.

2. Carbazole frameworks are privileged in pharmaceuticals, materials, and natural product synthesis, yet conventional routes often rely on metals, harsh reagents, or prolonged reaction times. This work offers a more practical and sustainable alternative that is scalable and broadly applicable, reinforcing the growing relevance of ion-pair catalysis in heterocyclic synthesis.

3. Looking ahead, further advances in green synthesis will emphasize catalyst economy, energy efficiency, and waste minimization. By integrating ion-pair catalysis with metal-free aqueous conditions, this study contributes a meaningful step toward developing greener carbazole chemistry and motivates continued innovation in sustainable catalytic design.

Introduction

A defining chapter in the understanding of reactive intermediates was initiated by Gomberg's landmark discovery of the triphenylmethyl radical in 1900.^1–3 Subsequent investigations by Norris, Kehrmann, and Wentzel extended this work by demonstrating that the triphenylmethyl system could undergo heterolytic cleavage, generating a stabilized carbocation and revealing its latent ionic nature.^4,5 While Gomberg's work firmly established the existence of a persistent organic radical, the pioneering investigations of Norris and Kehrmann provided the first compelling evidence for the generation of carbocations from this system, which was further substantiated by Wentzel's studies on ionic behaviour in solution. Beyond this triad, further mechanistic and spectroscopic explorations by numerous researchers have since deepened the understanding of ion-pair formation, stability, and reactivity.^6–9

However, it was not until much later that triaryl carbenium ion pairs emerged as effective catalysts in organic synthesis. A notable turning point came with their application in promoting carbon–carbon bond-forming reactions by Mukaiyama and co-workers, such as the aldol reaction, which demonstrated their potential beyond mere reactive intermediates (Fig. 1-I).^10,11 This breakthrough catalysed growing interest in exploiting ion-pair systems for broader catalytic purposes. More recently, the field has witnessed rapid expansion, particularly in asymmetric catalysis by Chen and co-workers, where chiral carbocation catalysts have been engineered to impart high levels of enantioselectivity.¹² Innovations in this domain by Siegel and Nelson involved the activation of strong C–H and C–F bonds through highly electrophilic ion pairs, significantly expanding the reactivity landscape of traditionally inert bonds.^13,14 In parallel, Luo's group demonstrated that the incorporation of chiral phosphate counterions could unlock asymmetric Friedel–Crafts reactions,¹⁵ while Oestreich and collaborators extended the scope of this platform to include carbenium-ion-mediated [5 + 1] cycloadditions.¹⁶

Fig. 1 (I) Triaryl carbenium ion-pair catalysis in organic synthesis: previous reports and current innovation work. (II) Previous reported work using a triaryl carbenium ion ion-pair as a catalyst. (III) Previous reported work for Fischer-indole synthesis.

Of the various ion pair systems explored to date, [Ph₃C]⁺[B(C₆F₅)₄]⁻ stands out as exceptionally versatile and adaptable in mediating diverse organic transformations.^17–20 Its weakly coordinating, non-nucleophilic borate counterion enables the generation of highly reactive triaryl carbenium species, unlocking a wide array of catalytic applications.²¹ Hou and co-workers employed this ion pair in combination with transition metal complexes to facilitate polymerization reactions.^22,23 Jutzi demonstrated its utility in stabilizing reactive zirconocene intermediates via a crystalline Brønsted acid form.²⁴ Bergman highlighted its influence on intermolecular hydroamination and hydroarylation processes.²⁵

Building on this, Stokes used the same ion pair to achieve intramolecular hydroarylation of sterically hindered styrenes,²⁶ while Yao extended the method to hydroarylations involving aromatic amines.²⁷ Also, Hashmi harnessed this system for oxidative [2 + 2 + 1] cycloadditions of ynamides,²⁸ and Luo and Loh showcased its ability to activate carbonyl groups through LUMO-lowering interactions, catalysing Diels–Alder reactions with anthracenes.^29,30 Building on this momentum, Jia's group has also significantly advanced this field, with several reports demonstrating the catalytic potential of ion pairs across a broad range of C–C and C-heteroatom bond-forming reactions.^31,32 Most recently, they developed a rapid and efficient C–S coupling protocol in water using the [Ph₃C]⁺[B(C₆F₅)₄]⁻ ion pair to catalyse dehydrative couplings of thiols and alcohols under metal-free conditions (Fig. 1-II).³³

Motivated by these seminal advances, we turned our attention to re-evaluating classical name reactions through the lens of ion-pair catalysis. One such transformation is the Fischer indole synthesis, a well-established method for assembling indole-based frameworks.^34–36 Numerous methodologies have been developed for the synthesis of carbazoles,^37–41 reflecting the enduring interest in this privileged heterocyclic scaffold. Several ionic-liquid-mediated protocols have also been described,⁴² highlighting the potential of ionic environments in facilitating such transformations. However, no catalytic protocol employing the discrete ion pair [Ph₃C]⁺[B(C₆F₅)₄]⁻ under aqueous conditions has been reported; herein, we introduce this ion pair as a superacidic precatalyst enabling the efficient synthesis of carbazoles. Given its relevance in constructing diverse heterocycles,⁴³ we envisioned harnessing the reactivity of discrete ion pairs to achieve this transformation under metal-free and mild conditions. To highlight advancements achieved, Fig. 1-III summarizes prior ion-pair-catalysed transformations reported in the literature alongside our novel application of ion-pair catalysis to the Fischer indole synthesis, demonstrating a significant expansion of this catalytic strategy to heterocyclic construction.

In this work, we disclose the first such approach enabled by the [Ph₃C]⁺[B(C₆F₅)₄]⁻ system, which facilitates smooth dehydrative cyclization under aqueous conditions (Scheme 1).

Scheme 1 Our novel approach towards synthesis of carbazole derivatives.

Our efforts are situated within the broader context of heterocyclic synthesis^44–46 and thereby stem from the synthetic and pharmacological significance of the resulting carbazole derivatives,⁴⁷ which are frequently encountered in natural products and medicinally relevant scaffolds due to their diverse biological activities, including anticancer, antimicrobial, and anti-inflammatory effects.^48–50 Examples include eburnamonine (1), desbromoarborescidine A (2), carprofene (3), tjipanazole I (4), tjipanazole D (5), and paullone (6) (Fig. 2).

Fig. 2 Representative natural products and bioactive molecules containing the indole core.

In alignment with this, we previously demonstrated a successful application of the Fischer indole synthesis using pentafluorophenol,⁵¹ further inspiring us to probe the potential of ion-pair catalysis for a more sustainable approach in this domain. This study employs water as a green solvent and utilizes the ion pair as a superacidic Brønsted acid precatalyst, providing an efficient and environmentally friendly method to access valuable carbazole scaffolds.

Results and discussion

We commenced our investigation into the ion-pair-catalysed Fischer indole synthesis using phenylhydrazine hydrochloride and cyclohexanone as model substrates, with the optimization results summarized in Table 1. Using 10 mol% catalytic loading of ion-pair-1 in HFIP at 80 °C furnished 7a in only 9% yield, and substitution of HFIP with TFE or PhMe similarly gave poor outcomes (entries 1–3, ≤21%). A similar catalytic loading of ion-pair-2 in TFE afforded 7a in just 18% yield (entry 4), whereas switching to ion-pair-3 under the same conditions improved the yield to 51% at the same catalytic loading (entry 5). Replacing TFE with water at 100 °C under otherwise identical conditions dramatically enhanced the efficiency, delivering 7a in 92% yield (entry 6). Shorter reaction times led to reduced yields (entry 7), while extending the reaction time offered no significant improvement from the enhanced yield (entry 8).

Table 1 Screening of optimal reaction conditions for 7a ^a

S. no.	Change from “standard conditions”	7a yield^a (%)
Reaction conditions: phenylhydrazine hydrochloride (0.25 mmol; 1.0 equiv.) and cyclohexanone (0.26 mmol; 1.05 equiv.) in 2.0 ml of solvent at 100 °C. The reactions were carried out in a 15 ml sealed tube.a Isolated yields from column chromatography.
1	10 mol% of ion-pair-1 in HFIP at 80 °C	09
2	10 mol% of ion-pair-1 in TFE at 80 °C	21
3	10 mol% of ion-pair-1 in PhMe at 80 °C	10
4	10 mol% of ion-pair-2 in TFE at 80 °C	18
5	10 mol% catalytic loading in TFE at 80 °C instead of H2O	51
6	10 mol% catalytic loading	92
7	10 mol% catalytic loading for 1 h	72
8	10 mol% catalytic loading for 3 h	91
9	5 mol% catalytic loading	92
10	Not any	93
11	1 mol% catalytic loading for 5 h	61
12	Ion-pair-4 instead of ion-pair-3	26
13	Ion-pair-5 instead of ion-pair-3	06
14	Ion-pair-6 instead of ion-pair-3	40
15	Open flask conditions instead of N2	18
16	O2 atmosphere instead of N2	20

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Catalyst loading studies revealed that 5 mol% of ion-pair-3 maintained high reactivity (entry 9, 92%), but reducing the loading to 2 mol% unexpectedly furnished the highest yield of 93%, identifying this as the optimal condition (entry 10). Further lowering to 1 mol% resulted in diminished conversion (entry 11, 61%). Screening of alternative ion pairs confirmed the privileged performance of [Ph₃C]⁺[B(C₆F₅)₄]⁻, which delivered 7a in 93% yield under the optimized aqueous conditions, while SnCl₅⁻ (ion-pair-1), SbCl₅⁻ (ion-pair-2), PF₆⁻ (ion-pair-4), BF₄⁻ (ion-pair-5), and ion-pair-6 were markedly less effective (entries 12–14).

Subsequently, we performed the reaction under open-flask and O₂ conditions. Although the product formation was detectable, only a modest conversion of about 20% was observed, indicating the critical role of the inert atmosphere in sustaining catalytic efficiency. These findings establish [Ph₃C]⁺[B(C₆F₅)₄]⁻ in water as a uniquely potent and sustainable catalytic platform, combining high efficiency with environmentally benign conditions for the synthesis of heterocycles.

With the optimal reaction parameters in hand, we turned our focus toward evaluating the scope and functional group tolerance of the ion-pair-catalysed Fischer indole synthesis.

Given the privileged reactivity of [Ph₃C]⁺[B(C₆F₅)₄]⁻ under aqueous conditions, we anticipated that this protocol would accommodate a broad range of hydrazine and ketone substrates, thereby enabling streamlined access to structurally diverse carbazole derivatives. To test this, we examined various substitution patterns on both reaction partners under the optimized conditions (Scheme 2).⁵²

Scheme 2 Substrate scope for synthesis of various carbazole scaffolds. Substrate scope: aliphatic cyclic ketone substrates, heterocyclic ketone substrates, aliphatic ketone substrates and interrupted Fischer-indole substrates. Under standard conditions. All the yields are isolated yields after column chromatography.

We commenced our investigations by fixing the arylhydrazine hydrochloride component as unsubstituted phenylhydrazine hydrochloride and varying the ketone partner. Cyclopentanone furnished the corresponding carbazole 7b in 92% yield, cycloheptanone provided 7c in 91% yield, and 4-methylcyclohexanone was efficiently transformed into 7d in 90% yield, while the 1,3-cyclohexanone partner yielded 7e in 86% yield. Subsequently, 2-chlorophenylhydrazine hydrochloride was employed with cyclopentanone, cyclohexanone, and 3,3-dimethylcyclohexanone to afford 7f–7h in 87–90% yields. Reaction with 1-indanone yielded 7i in 81% yield, while 4-chlorophenylhydrazine hydrochloride with the same ketones furnished 7j–7l in 86–89% yields, demonstrating the broad applicability of the protocol across diverse arylhydrazine and cyclic ketone substrates.

Further studies with electron-withdrawing arylhydrazine hydrochloride revealed similar trends. 2-Bromophenylhydrazine hydrochloride reacted smoothly with cyclohexanone, cycloheptanone, and 3,3-dimethylcyclohexanone to afford 7m–7o in 88–91% yields. Likewise, 4-bromophenylhydrazine hydrochloride provided 7p–7s in 84–92% yields with cyclopentanone, cyclohexanone, cycloheptanone, and 4-methylcyclohexanone, highlighting the method's tolerance toward sterically and electronically varied hydrazine hydrochloride and ketones.

The scope was further extended to electron-donating arylhydrazines. 4-Methylphenylhydrazine hydrochloride furnished 7t and 7u in 91% and 88% yields with cyclopentanone and 3,3-dimethylcyclohexanone, respectively, while 1-indanone delivered 7v in 83% yield. 4-Methoxyphenylhydrazine hydrochloride reacted with cyclopentanone to provide 7w in 86% yield. In our efforts to access interrupted Fischer indole products, the non-aromatic keto ester ethyl 2-oxocyclohexanecarboxylate was examined. Reaction with phenylhydrazine hydrochloride furnished 7x in 87% yield, and 4-bromophenylhydrazine hydrochloride afforded 7y in 89% yield.

Heterocyclic ketones were also well tolerated. Phenylhydrazine hydrochloride reacted with dihydro-3(2H)-thiophenone and tetrahydro-4H-thiopyran-4-one to give 7z and 7aa in 83% and 85% yields, respectively, while 2-chlorophenylhydrazine hydrochloride afforded 7ab and 7ac in 79% and 77% yields. Tetrahydro-4H-thiopyran-4-one, thiochroman-4-one, and dihydro-3(2H)-thiophenone were further coupled with substituted phenylhydrazines (4-Cl, 4-Br, 4-Me, 4-OMe) to furnish 7ad–7aj in 71–91% yields, highlighting the broad tolerance of heterocyclic ketones under the standard conditions. Finally, various aliphatic ketones were explored with phenylhydrazine hydrochloride. Propionaldehyde afforded 7ak in 92% yield, propanone and 2-butanone gave 7al and 7am in 93% and 91% yields, respectively, and the aromatic ketone 4-phenylbutan-2-one furnished 7an in 90% yield. Aliphatic hydroxyaldehydes, including 4-hydroxybutanal and 5-hydroxypentanal, yielded tryptophan-derived products 7ao and 7ap in 89% and 90% yields. Additionally, N-methylphenylhydrazine hydrochloride reacted with pyruvic acid to deliver the corresponding indole derivative 7aq in 72% yield.

Collectively, these results highlight the broad substrate scope and remarkable functional group tolerance of the ion-pair-catalysed Fischer indole protocol, enabling efficient access to a diverse array of carbazole and indole derivatives from aromatic and aliphatic ketones, heterocyclic ketones, and substituted hydrazine hydrochlorides.

Encouraged by the efficiency and breadth of the ion-pair-catalysed Fischer indole synthesis across diverse substrates, we next sought to demonstrate its utility in the streamlined preparation of complex, bioactive targets. In particular, we targeted the concise synthesis of selected carbazole-based natural products and bioactive analogues, thereby underscoring the method's applicability beyond simple substrates and highlighting its potential as a versatile platform for heterocyclic natural product synthesis. As an initial demonstration, we targeted paullone (6), a bioactive scaffold of notable pharmacological relevance. The required precursor, 3,4-dihydro-1H-benzo[b]azepine-2,5-dione (10), was obtained following a well-established literature protocol.⁵³ Subjecting this intermediate to our optimized ion-pair-catalysed Fischer indole conditions with phenylhydrazine hydrochloride furnished paullone (6) in 47% yield after 8 hours (Scheme 3a). This example underscores the capacity of our strategy to streamline the construction of complex natural products, like heterocycles in a late-stage fashion.⁵²

Scheme 3 Synthesis of natural products. (a) Synthesis of paullone. (b) Synthesis of (±)-desbromoarborescidine A. (c) Synthesis of tjipanazole I. (d) Synthesis of tjipanazole D. (e) One-pot synthesis of tjipanazole D. Reaction conditions: under the "standard conditions" except for the mentioned reaction duration.

Building on this success, we applied the optimized ion-pair-catalysed Fischer indole protocol to the synthesis of the natural product (±)-desbromoarborescidine A (2). The required ketone precursor, hexahydro-2H-quinolizin-1(6H)-one ((±)-11), was subjected to phenylhydrazine hydrochloride under the same conditions (Scheme 3b). The reaction proceeded cleanly to afford the desired indolocarbazole framework as a single regioisomer (2), which was isolated in a good yield of 59% and fully characterized.⁵² The high regioselectivity observed in this transformation underscores the capacity of the [Ph₃C]⁺[B(C₆F₅)₄]⁻ system to direct dehydrative cyclization in structurally complex settings, validating the method's utility for concise access to bioactive carbazole alkaloids.

Following these successes, we further extended the utility of our ion-pair-catalyzed Fischer indole protocol to the synthesis of the natural products tjipanazole I (4) and tjipanazole D (5), underscoring the method's broad applicability to structurally diverse carbazole alkaloids. The respective phenylhydrazine hydrochlorides were initially reacted with 1,2-cyclohexanedione under the optimized conditions, delivering the carbazole intermediates 7ar and 7as in excellent yields of 86% and 79%, respectively. Subsequent treatment of these intermediates with an additional batch of arylhydrazine hydrochloride afforded the natural products tjipanazole I (5) and tjipanazole D (4) in 47% and 49% yields, respectively, accompanied by the corresponding imine side products in 36% and 34% yields, highlighting the efficiency and modularity of the stepwise strategy (Scheme 3c & d). Building on the efficiency of the stepwise protocol, we further investigated a one-pot synthesis of tjipanazole D. In this approach, two equivalents of 4-chlorophenylhydrazine hydrochloride were reacted with one equivalent of 1,2-cyclohexanedione over 12 h, providing tjipanazole D in 49% yield along with the corresponding imine side product in 34%, thereby demonstrating that the transformation can be achieved in a single operational step while maintaining comparable efficiency (Scheme 3e).

We also measured the pH of the solution of the ion pair in water at a molarity of 1.08 × 10⁻⁴ M, prior to initiating the reaction. The observed value of 2.92 clearly reflects its superacidic nature, supporting the notion that it generates highly acidic species in situ to drive the catalytic process.

We have proposed a plausible mechanism in which the catalytically active (H₂O)_nH⁺[B(C₆F₅)₄]⁻ species is generated in situ under the reaction conditions and is essential for facilitating the Fischer indole synthesis. As depicted in Scheme 4, hydrolysis of the triaryl-carbenium ion pair in water furnishes hydrated (H₂O)_nH⁺[B(C₆F₅)₄]⁻ along with triphenylmethanol.

Scheme 4 Plausible mechanism for the (H₂O)_nH⁺[B(C₆F₅)₄]⁻ catalysed pathway of indole derivative synthesis. The non-coordinating anion [B(C₆F₅)₄] stabilizes cationic intermediates without interfering with the reaction.

The resulting Brønsted acidic ion pair, containing the weakly coordinating [B(C₆F₅)₄]⁻ counter anion, acts as a strong yet non-nucleophilic proton source that efficiently activates the arylhydrazone intermediate through protonation at nitrogen. This activation promotes tautomerization to the reactive ene-hydrazine species, which undergoes the key [3,3]-sigmatropic rearrangement to generate the cyclohexadienyl iminium intermediate. Stabilization of this highly electrophilic species by the ion pair enables intramolecular electrophilic cyclization to form the indolenine scaffold. Subsequent N–N bond cleavage, accompanied by proton transfers and re-aromatization, affords the indole product while regenerating the (H₂O)_nH⁺[B(C₆F₅)₄]⁻ catalyst to complete the cycle.

To further validate the practicality of our ion-pair-catalysed Fischer indole protocol, we performed a scale-up reaction using 4-bromophenyl hydrazine hydrochloride (6.71 mmol, 1.0 equiv.) and 3-methylcyclohexanone (7.05 mmol, 1.05 equiv.) as representative substrates using 2 mol% of [Ph₃C]⁺[B(C₆F₅)₄]⁻ as the catalyst (Scheme 5).⁵²

Scheme 5 Scale-up synthesis of 6-bromo-2-methyl-2,3,4,9-tetrahydro-1H-carbazole (7at). Reaction conditions: 4-bromophenylhydrazine hydrochloride (6.71 mmol; 1.0 equiv.) and 3-methylcyclohexanone (7.05 mmol; 1.05 equiv.); catalyst loading – 2 mol% in 15 ml of solvent at 100 °C.

Under the optimized conditions, the reaction was carried out on a gram scale, affording the corresponding carbazole derivative 6-bromo-2-methyl-2,3,4,9-tetrahydro-1H-carbazole (7at) in an excellent yield of 1.4 g (79%) with no compromise in reaction efficiency or selectivity. This successful scale-up highlights the robustness and operational simplicity of the catalytic system, demonstrating its suitability for larger-scale synthesis and potential applicability in preparative and industrial contexts.

Conclusion

We report the first application of the ion pair [Ph₃C]⁺[B(C₆F₅)₄]⁻ in the Fischer indole synthesis, enabling the efficient and regioselective formation of diverse indole and carbazole frameworks under mild, aqueous, metal-free conditions. The method shows broad functional group tolerance, enables concise total syntheses of bioactive targets, and scales efficiently without loss of performance. Using water as a green solvent and operating via an in situ generated Brønsted acidic ion pair, this protocol offers a practical, sustainable platform for rapid access to valuable heterocycles.

Conflicts of interest

There are no conflicts to declare.

Data availability

Supplementary information (SI): experimental procedures and characterization data (NMR, IR & HRMS) for all synthesized compounds. Additional spectral images are included to support the findings discussed in the paper. See DOI: https://doi.org/10.1039/d5gc04707b.

Acknowledgements

The authors sincerely acknowledge CSIR-CLRI for the infrastructure, facilities, and consistent institutional support that enabled this research. The authors are deeply grateful to the Director, CSIR-CLRI, for his continued encouragement and valuable guidance throughout the course of this work. SC likes to gratefully acknowledge the financial support from ANRF-PMECRG (Anusandhan National Research Foundation), Govt. of India, File No. ANRF/ECRG/2024/002259/CS (GAP2504). MKD gratefully acknowledges the KPDC for providing essential research infrastructure. The CSIR-CLRI communication number allotted for this work is 2187.

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Footnote

† These authors have contributed equally.

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