Brønsted Acidic Ionic Liquid: An Efficient Organocatalyst for the Synthesis of Pyrrolo[1,2-a]indoles under Neat Conditions

Abstract

A new synthetic approach has emerged for constructing 9H-pyrrolo[1,2-a]indole scaffolds by the reactions between indoles and chalcones under metal- and solvent-free conditions at 80 °C. The reaction occurs smoothly in the presence of a Brønsted acidic ionic liquid, 1-methyl-3-(4-sulfobutyl)-1H-imidazol-3-ium tosylate, as a catalyst, permitting the synthesis of the desired products with satisfactory yields. The developed protocol is applicable to the construction of biologically important pyrrolo[1,2-a]indole derivatives from easily accessible chalcones having various substituents. The process commences with Michael addition to chalcones, followed by annulations induced by the elimination of a water molecule, yielding the 9H-pyrrolo[1,2-a]indole scaffolds. Several control experiments were carried out to achieve a better understanding of the reaction pathway. The feasibility of recycling the catalyst was also demonstrated. This method produces water as the sole byproduct and represents a green synthetic protocol. The clean reaction, easily accessible reactants, and the metal- and solvent-free and environmentally friendly reaction conditions are the notable advantages of this procedure.

Fused N-heterocyclic compounds have garnered significant interest from synthetic and medicinal chemists due to their extensive applications in diverse organic functional materials and pharmaceutically active molecules.[1] [2] [3] [4] [5] Substrates containing 9H-pyrrolo[1,2-a]indoles and their analogues constitute a crucial class of privileged structural units commonly encountered in natural products and pharmaceuticals.[6] For instance, mitomycin-C[7] [8] (II) (Figure [1]), a commonly studied natural product, exhibits strong antibacterial and anticancer properties, whereas compound I is a potent antitumor bifunctional DNA alkylating agent.[9] Furthermore, 9H-pyrrolo[1,2-a]indoles are important intermediates for synthesizing biologically significant compounds with more complicated and diverse structures. Those properties make them versatile in medicinal chemistry and organic synthesis, with particular significance in drug research and development.[10] [11] [12] Furthermore, 9H-pyrrolo[1,2-a]indoles display distinctive electrical and optical properties, adding to their significance in various fields such as materials science, electronics, and photonics.[13]

Over the past few years, many efforts have been devoted to developing strategies for synthesizing 9H-pyrrolo[1,2-a]indole scaffolds. In recent years, pyrroloindole skeletons have gained prominence as substrates in organic reactions in various fields, due to their notable reactivity.[14] Several researchers have synthesized this moiety. In 1966, Schweizer and Light introduced a synthesis of unsubstituted 9H-pyrrolo[1,2-a]indole from indole-2-carboxaldehyde and triphenyl(vinyl)phosphonium bromide in the presence of sodium hydride.[15] Later, 9H-pyrrolo[1,2-a]indoles were synthesized by using a Cu(OTf)₂-catalyzed Friedel–Crafts alkylation/annulation cascade reaction between indoles and 1,2-dicarbonyl-3-enes (Scheme [1a]).[16] In 2016, Zhang and co-workers developed a protocol involving a Michael addition–condensation of 3-substituted indoles with α,β-unsaturated ketimines for the synthesis of 9H-pyrrolo[1,2-a]indoles under copper catalysis (Scheme [1b]).[17] The corresponding moiety was also synthesized by an acid-promoted reaction. First, it was synthesized under reflux conditions using hydrochloric acid (Scheme [1c]).[18] Secondly, it was synthesized in the presence of p-toluenesulfonic acid (Scheme [1c]).[19] All these methods suffer from a lack of environmentally friendly aspects as they involve the use of metal catalysts, organic solvents, mineral acids, etc.

Ionic liquids, specifically Brønsted acidic ionic liquids (BAILs), have gained attention for their diverse applications in chemistry and potential low environmental impact. Some ecologically significant aspects associated with ionic liquids are their low volatility, recyclability, biodegradability, lack of toxicity, and applications in green synthesis. Although ionic liquids offer many advantages in terms of their unique properties and versatility, their environmental impact must be carefully considered to ensure sustainable use and minimize adverse effects on the environment and human health.[20]

Solvent-free and neat conditions refer to reaction conditions in which no solvent is added to the system. Instead, the reactants are combined and allowed to react without a solvent medium. The main advantages of this approach are environmental friendliness, economic benefits, improved reaction efficiency, and fewer purification steps.[21] In considering the green aspects of a reaction, we have to focus on byproducts, and if the byproducts are nonhazardous, the reaction is environmentally acceptable. Over the last few years, our groups have explored environmentally benign organic methodologies with the help of organocatalysis,[22] [23] photocatalysis,[24,25] and catalyst-free reactions.[26,27] Here, we are pleased to report a one-pot, green, and efficient approach for synthesizing the 9H-pyrrolo[1,2-a]indole scaffold. This scaffold was synthesized by reacting indoles with chalcones under metal-free and solvent-free conditions in the presence of a BAIL catalyst.

To identify the optimal condition for our current protocol, we carried out an initial investigation using 3-methylindole (1a) and chalcone (2a) as model substrates with 10 mol% of 1-methyl-3-(4-sulfobutyl)-1H-imidazol-3-ium tosylate ([BSMIM]OTs; BAIL-1) as the catalyst (Table [1]). For the screening of solvents, we performed our reaction in various solvents (MeCN, DCE, toluene, 1,4-dioxane, DMSO, EtOH, and H₂O) (Table [1], entries 1–7). We obtained only trace yields of the desired product 3a in the cases of DMSO and H₂O, whereas the other organic solvents gave comparable yields of 70–75%. Ethanol gave a better yield than water, possibly because of the greater solubility of the reactants in this solvent. We then performed the reaction under solvent-free (neat) conditions, considering the concepts of green chemistry. Surprisingly, we obtained an 83% yield of 3a under neat conditions, probably, due to the close contact between the reactants and catalyst (entry 8). We therefore consider the neat reaction to provide the optimal conditions.

Table 1 Screening of Solvent Effects^a

Entry	Solvent	Yieldb (%)
1c	MeCN	75
2c	DCE	71
3	toluene	72
4	1,4-dioxane	70
5	DMSO	trace
6c	EtOH	74
7c	H2O	trace
8	(neat)	83

^a Reaction conditions: 1a (0.6 mmol), 2a (0.5 mmol), solvent (2 mL), 100 °C, 4 h.

^b Isolated yield.

^c Under reflux.

Next, the optimal reaction temperature and time were determined by performing the reaction with various combinations of time and temperature (Table [2]). First, we performed the reaction at a constant temperature of 100 °C for times between four hours and one hour (Table [2], entries 1–4) and we found that at a temperature of 100 °C, a reaction time of two hours gave the highest yield (82%). We then performed the reaction at various temperatures (80 °C, 50 °C, 35 °C, and room temperature) for a constant time of two hours (entries 5–8), and we found that at 80 °C, we obtained a high yield of 82% (entry 5).

Table 2 Temperature Effect on the Tandem Cyclization Reaction^a

Entry	Temp (°C)	Time (h)	Yieldb (%)
1	100	4	83
2	100	3	82
3	100	2	82
4	100	1	55
5	80	2	82
6	50	2	44
7	35	2	27
8	RT	2	21

^a Reaction conditions: 1a (0.6 mmol), 2a (0.5 mmol), BAIL-1 (10 mol%), neat.

^b Isolated yield.

Several other ionic liquids (ILs) were then synthesized in our laboratory by the previously reported method,[27] and these were used to optimize the catalyst. The ILs BAIL-2, BAIL-3, BAIL-4, and IL-2 were less effective than BAIL-1 for this tandem cyclization process (Table [3], entries 1–5). On decreasing the amount of BAIL-1 catalyst, the yield decreased (entry 6); however, increasing the catalyst loading did not improve the yield markedly (entry 7). The model reaction was also carried out using TsOH and H₂SO₄ as acid catalysts, but we could not determine their effectiveness (entries 8 and 9). In addition, we also used several other existing catalysts [HCl, Cu(OTf)₂ and CuBr₂], but these were not as effective as BAIL-1 for this conversion (entries 10–12). The absence of any product conversion without a catalyst underscored the essential role of the catalyst in facilitating the reaction (entry 13). Therefore, the reaction that gave the optimal yield (82%) used 10 mol% of BAIL-1 at 80 °C for two hours without any solvent.

Table 3 Effect of Various Ionic Liquids and Catalyst Loadings^a

Entry	Catalyst	Catalyst (mol%)	Yieldb (%)
1	BAIL-1	10	82
2	BAIL-2	10	50
3	BAIL-3	10	75
4	BAIL-4	10	70
5	IL-2	10	25
6	BAIL-1	5	73
7	BAIL-1	15	82
8	TsOH	15	80
9	H2SO4	15	trace
10	HCl	15	68
11	Cu(OTf)2	10	76
12	CuBr2	10	71
13	No catalyst	--	NDc

^a Reaction conditions: 1a (0.6 mmol), 2a (0.5 mmol) of 2a , 80 °C, 2 h.

^b Isolated yield.

^c ND = not detected by TLC.

Using the optimized reaction conditions, we then investigated the substrate scope of this tandem cyclization reaction with various 3-substituted indoles and various chalcones to assess the generality of this reaction (Scheme [2]). We found that 3-methylindole (1a) gave the desired 9H-pyrrolo[1,2-a]indole (3a) in 82% yield when it reacted with chalcone (2a). Subsequently, upon altering the aldehyde component of the chalcone, products 3b–d were obtained in high yields of 78–83% across various substituents, including halo, electron-withdrawing, and naphthyl moieties. Following this, diverse chalcones and acetophenone moieties incorporating such substituents as 4-methyl, 4-methoxy, 2-chloro, and 4-chloro gave products 3e–i in moderate to good yields. We then obtained the products 3j–l in good yields (75–82%) by modifying both parts of the chalcone with various substituents. Heterocyclic chalcones 3m and 3n were also obtained in good yields. Various 3-substituted indoles reacted smoothly under the optimized conditions to give products 3o–r in yields of 78–83%. Finally, a fluorine-substituted indole moiety also gave the desired product 3s in 84% yield under the optimal reaction conditions. All these reactions were conducted under an open atmosphere and were tolerant of air and moisture.

In the next step, we tested the reusability of the catalyst. We selected the reaction between 3-methylindole (1a) and chalcone (2a) in the presence of 10 mol% of the acidic ionic liquid BAIL-1 at 80 °C as our experimental model. After completion of the reaction, water was added and the mixture, was filtered to separate the reaction components. The ionic liquid was reclaimed by evaporating the water, and the pure product was isolated from the organic phase. Remarkably, the catalyst maintained its high activity even after five cycles of reaction in the synthesis of 3a (Table [4]).

Two control experiments were then conducted in a mechanistic investigation to identify the probable reaction pathway (Scheme [3]). In the first experiment, the reaction yield did not drop significantly in the presence of the radical scavengers 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) and 2,6 di-tert-butyl-4-methylphenol (BHT) (Scheme [3a]). From this result, we concluded that the reaction follows a polar pathway. Secondly, we performed a reaction of 1,3-dimethyl-1H-indole (4) and (2E)-3-phenyl-1-(4-tolyl)prop-2-en-1-one (2e) under the standard conditions (Scheme [3b]), and we obtained the indole 5, the Michael adduct of indole 4 and chalcone 2e.

A plausible mechanistic pathway for the formation of the pyrrolo[1,2-a]indoles scaffold was elucidated through these meticulous control experiments and a thorough review of the literature[16] [22] ^, [29] [30] [31] (Scheme [4]). The first step is a Michael addition of the 3-substituted indole 1 to the α,β-unsaturated ketone 2 to give intermediate A. Here, we assume that the acidic ionic liquid activates the unsaturated ketone by protonating its carbonyl group, thereby enhancing the electrophilic nature of the β-carbon, which is helpful in forming the Michael adduct.[32] [33] [34] In the second step, intermediate A undergoes an intramolecular cyclization to afford intermediate B. The acidic ionic liquid assists the intermolecular cyclization of intermediate B and protonation. Next, water is eliminated from intermediate B in the presence of the acidic ionic liquid to form intermediate D via intermediate C. Finally, D isomerizes to the final product, the pyrrolo[1,2-a]indole 3.

In conclusion, our motivation for this study stemmed from an initial design and concept to synthesize the 9H-pyrrolo[1,2-a]indole scaffold directly from 3-substituted indoles and chalcones by using a Michael addition and cyclization.[35] We have developed a metal- and solvent-free protocol that proceeds under mild reaction conditions and uses a recyclable organic catalyst. Key to this protocol was identifying parameters that synergistically generate the 9H-pyrrolo[1,2-a]indole scaffold reliably. With these species, numerous synthetic applications can be explored, particularly in organocatalysis. Ongoing advances will be pursued and shared as they develop.

Conflict of Interest

The authors declare no conflict of interest.

Acknowledgment

We are grateful to the DST-FIST and UGC-SAP program of the Department of Chemistry, Visva-Bharati.

• References and Notes

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• 35 Pyrrolo[1,2-a]indoles 3a–s; General Procedure An oven-dried tube equipped with a magnetic stirrer bar was charged with the appropriate 3-substituted indole 1 (0.6 mmol), chalcone 2 (0.5 mmol), and BAIL-1 (10 mol%), and the mixture was stirred at 80 °C under open-air conditions for two hours until the substrates were completely consumed (TLC). H₂O was added, and the mixture was extracted with EtOAc (×3). The extracts were dried (Na₂SO₄) and concentrated under vacuum, and the crude product was purified by column chromatography (silica gel). 1-(2,6-Dichlorophenyl)-9-methyl-3-phenyl-9H-pyrrolo[1,2-a]indole (3b) Red gummy material; yield: 158 mg (81%); R_f = 0.40 (PE–EtOAc, 98:4). ¹H NMR (400 MHz, CDCl₃): δ = 7.64 (d, J = 7.2 Hz, 2 H), 7.48–7.34 (m, 6 H), 7.19 (t, J = 8 Hz, 2 H), 7.15–7.06 (m, 2 H), 6.37 (s, 1 H), 4.20–4.14 (m, 1 H), 1.26 (d, J = 7.2 Hz, 3 H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 141.3, 141.2, 141.0, 136.3, 135.7, 133.9, 132.9, 129.1, 128.4 (2 C), 128.2, 128.0, 127.7, 127.4, 127.2, 124.6, 123.3, 115.7, 112.9, 112.0, 36.4, 17.2. HRMS (ESI-TOF): m/z [M + Na]⁺ calcd for C₂₄H₁₇Cl₂NNa: 412.0630; found: 412.0639.

Corresponding Author

Publication History

Received: 13 July 2024

Accepted after revision: 10 September 2024

Accepted Manuscript online:
10 September 2024

Article published online:
01 October 2024

© 2024. Thieme. All rights reserved

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• References and Notes

• 1 Eicher T, Hauptmann S, Speicher A. The Chemistry of Heterocycles: Structure, Reactions Synthesis and Applications, 2nd ed. Wiley-VCH; : 2003
  CrossrefSearch in Google Scholar
• 2 Comprehensive Heterocyclic Chemistry III. Katritzky AR, Ramsden CA, Scriven EF. V, Taylor RJ. K. Elsevier; Oxford: 2008
  Search in Google Scholar
• 3 Sanda F, Nakai T, Kobayashi N, Masuda T. Macromolecules 2004; 37: 2703
  CrossrefSearch in Google Scholar
• 4 Häussler M, Liu J, Zheng R, Lam JW. Y, Qin A, Tang BZ. Macromolecules 2007; 40: 1914
  CrossrefSearch in Google Scholar
• 5 Martins MA. P, Frizzo CP, Moreira DN, Buriol L, Machado P. Chem. Rev. 2009; 109: 4140
  CrossrefPubMedSearch in Google Scholar
• 6 Kakadiya R, Dong H, Lee P.-C, Kapuriya N, Zhang X, Chou T.-C, Lee T.-C, Kapuriya K, Shah A, Su T.-L. Bioorg. Med. Chem. 2009; 17: 5614
  CrossrefPubMedSearch in Google Scholar
• 7 Galm U, Hager MH, Van Lanen SG, Ju J, Thorson JS, Shen B. Chem. Rev. 2005; 105: 739
  CrossrefPubMedSearch in Google Scholar
• 8 Bradner WT. Cancer Treat. Rev. 2001; 27: 35
  CrossrefPubMedSearch in Google Scholar
• 9 Tomasz M, Palom Y. Pharmacol. Ther. 1997; 76: 73
  CrossrefPubMedSearch in Google Scholar
• 10 Calvert MB, Sperry J. Org. Biomol. Chem. 2016; 14: 5728
  CrossrefPubMedSearch in Google Scholar
• 11 Dethe DH, Erande RD, Ranjan A. J. Org. Chem. 2013; 78: 10106
  CrossrefPubMedSearch in Google Scholar
• 12 Colandrea VJ, Rajaraman S, Jimenez LS. Org. Lett. 2003; 5: 785
  CrossrefPubMedSearch in Google Scholar
• 13 Yoshihara T, Druzhinin SI, Zachariasse KA. J. Am. Chem. Soc. 2004; 126: 8535
  CrossrefPubMedSearch in Google Scholar
• 14 Shelke YG, Hande PE, Gharpure SJ. Org. Biomol. Chem. 2021; 19: 7544
  CrossrefPubMedSearch in Google Scholar
• 15 Schweizer EE, Light KK. J. Org. Chem. 1966; 31: 870
  CrossrefSearch in Google Scholar
• 16 Sun Y, Qiao Y, Zhao H, Li B, Chen S. J. Org. Chem. 2016; 81: 11987
  CrossrefPubMedSearch in Google Scholar
• 17 Zhang M, Liao L, Yu S, Liao Y, Xu X, Yuan W, Zhang X. J. Heterocycl. Chem. 2017; 54: 965
  CrossrefSearch in Google Scholar
• 18 Wood K, Black DStC, Kumar N. Tetrahedron Lett. 2009; 50: 574
  CrossrefSearch in Google Scholar
• 19 Li H, Wang Z, Zu L. RSC Adv. 2015; 5: 60962
  CrossrefSearch in Google Scholar
• 20 Wei P, Pan X, Chen C.-Y, Li H.-Y, Yan X, Li C, Chu Y.-H, Yan B. Chem. Soc. Rev. 2021; 50: 13609
  CrossrefPubMedSearch in Google Scholar
• 21 Sarkar A, Santra S, Kundu SK, Hajra A, Zyryanov GV, Chupakhin ON, Charushin VN, Majee A. Green Chem. 2016; 18: 4475
  CrossrefSearch in Google Scholar
• 22 Mahato S, Santra S, Chatterjee R, Zyryanov GV, Hajra A, Majee A. Green Chem. 2017; 19: 3282
  CrossrefSearch in Google Scholar
• 23 Samanta S, Chatterjee R, Sarkar S, Pal S, Mukherjee A, Butorin II, Konovalova OA, Choudhuri T, Chakraborty K, Santra S, Zyryanov GV, Majee A. Org. Biomol. Chem. 2022; 20: 9161
  CrossrefPubMedSearch in Google Scholar
• 24 Sarkar S, Pal S, Santra S, Zyryanov GV, Majee A. J. Org. Chem. 2024; 89: 8137
  CrossrefPubMedSearch in Google Scholar
• 25 Sarkar S, Pal S, Mukherjee A, Santra S, Zyryanov GV, Majee A. J. Org. Chem. 2024; 89: 1473
  CrossrefPubMedSearch in Google Scholar
• 26 Pal S, Sarkar S, Mukherjee A, Kundu A, Sen A, Rath J, Santra S, Zyryanov GV, Majee A. Green Chem. 2023; 25: 9847
  CrossrefSearch in Google Scholar
• 27 Du Z, Li Z, Deng Y. Synth. Commun. 2005; 35: 1343
  CrossrefSearch in Google Scholar
• 28 Pal S, Chatterjee R, Santra S, Zyryanov GV, Majee A. Adv. Synth. Catal. 2021; 363: 5300
  CrossrefSearch in Google Scholar
• 29 Lorton C, Voituriez A. Eur. J. Org. Chem. 2019; 2019: 5133
  CrossrefSearch in Google Scholar
• 30 Zhao Y, Li S, Fan Y, Guo X, Jiao X, Tian L, Sun X. Eur. J. Org. Chem. 2021; 2021: 4358
  CrossrefSearch in Google Scholar
• 31 Zhu Y.-S, Yuan B.-B, Guo J.-M, Jin S.-J, Dong H.-H, Wang Q.-L, Bu Z.-W. J. Org. Chem. 2017; 82: 5669
  CrossrefPubMedSearch in Google Scholar
• 32 Rádai Z, Kiss NZ, Keglevich G. Curr. Org. Chem. 2018; 22: 533
  CrossrefSearch in Google Scholar
• 33 Gu D.-g, Ji S.-j, Wang H.-x, Xu Q.-y. Synth. Commun. 2008; 38: 1212
  CrossrefSearch in Google Scholar
• 34 Yu C.-J, Liu C.-J. Molecules 2009; 14: 3222
  CrossrefPubMedSearch in Google Scholar
• 35 Pyrrolo[1,2-a]indoles 3a–s; General Procedure An oven-dried tube equipped with a magnetic stirrer bar was charged with the appropriate 3-substituted indole 1 (0.6 mmol), chalcone 2 (0.5 mmol), and BAIL-1 (10 mol%), and the mixture was stirred at 80 °C under open-air conditions for two hours until the substrates were completely consumed (TLC). H₂O was added, and the mixture was extracted with EtOAc (×3). The extracts were dried (Na₂SO₄) and concentrated under vacuum, and the crude product was purified by column chromatography (silica gel). 1-(2,6-Dichlorophenyl)-9-methyl-3-phenyl-9H-pyrrolo[1,2-a]indole (3b) Red gummy material; yield: 158 mg (81%); R_f = 0.40 (PE–EtOAc, 98:4). ¹H NMR (400 MHz, CDCl₃): δ = 7.64 (d, J = 7.2 Hz, 2 H), 7.48–7.34 (m, 6 H), 7.19 (t, J = 8 Hz, 2 H), 7.15–7.06 (m, 2 H), 6.37 (s, 1 H), 4.20–4.14 (m, 1 H), 1.26 (d, J = 7.2 Hz, 3 H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 141.3, 141.2, 141.0, 136.3, 135.7, 133.9, 132.9, 129.1, 128.4 (2 C), 128.2, 128.0, 127.7, 127.4, 127.2, 124.6, 123.3, 115.7, 112.9, 112.0, 36.4, 17.2. HRMS (ESI-TOF): m/z [M + Na]⁺ calcd for C₂₄H₁₇Cl₂NNa: 412.0630; found: 412.0639.

• Supplementary Material