Green Synthesis of Primary Aniline-Based Indolylmethanes via One-Pot Aza-Friedel–Crafts Reaction Catalyzed by Brønsted Acidic Ionic Liquid in Aqueous Media

Abstract

A green, convenient, and metal-free methodology for synthesizing primary aniline-based indolylmethanes has been developed through a sequential one-pot, three-component aza-Friedel–Crafts reaction. This approach employs a wide range of commercially available aldehydes, primary anilines, and indoles, catalyzed by a Brønsted acidic ionic liquid in an aqueous medium. A variety of desirable products were obtained in high yields (up to 98%). The process was successfully demonstrated on a gram scale, confirming its scalability and reproducibility while maintaining high yields. Additionally, the catalyst exhibited remarkable recyclability, retaining high catalytic efficiency over three cycles without a significant loss of activity.

Introduction

Triarylmethanes (TRAMs) are highly valuable molecules frequently found in natural products and have emerged as crucial structural motifs with broad applications in pharmaceuticals, dyes, and materials science. Additionally, TRAMs serve as essential building blocks for synthesizing versatile compounds used in various research fields. , Among these, unsymmetrical TRAMs incorporating indole and aniline frameworks, known as aniline-based indolylarylmethanes, show promising biological properties (Figure a) ,, and are recognized as critical structural motifs in organic synthesis.

1.

Examples of (a) aniline-based indolylarylmethanes and (b) aniline-based molecules.

Numerous methodologies have been developed for the synthesis of tertiary aniline-based indolylarylmethanes through Friedel–Crafts reactions under various conditions using different catalysts, including Brønsted and Lewis acids. , However, these methods suffer from limitations, including the use of organic solvents, corrosive acids, metal catalysts, and harsh reaction conditions. In particular, metal catalysts introduce some disadvantages such as toxicity, environmental harm, air and moisture sensitivity, high costs, and limited recyclability. Consequently, there is a growing need to develop more effective methods suitable for high-throughput synthesis and sustainable processes that are safer for industrial applications and consistent with green chemistry principles.

To date, Brønsted acidic ionic liquids (BAILs) have garnered significant attention as highly efficient acid catalysts in various important areas of synthetic chemistry. , These catalysts offer numerous advantages, including air stability, moisture resistance, thermal stability, nonvolatility, nontoxicity, less corrosiveness, cost efficiency, and reusability, making them highly compatible with green and sustainable processes. Furthermore, their water solubility facilitates efficient reactions in aqueous systems.

Recently, our previous studies explored the synthesis of aniline-based triarylmethanes using the BAIL, namely, [bsmim]­[NTf₂], as a reusable catalyst under solvent-free conditions. Symmetrical aniline-based triarylmethanes were successfully synthesized from primary, secondary, and tertiary anilines through double Friedel–Crafts reactions. Subsequently, unsymmetrical tertiary aniline-based indolylarylmethanes were obtained through one-pot, three-component double Friedel–Crafts reactions. Both approaches provided high to excellent yields of the corresponding products, with the catalyst being reusable and demonstrating effective performance on a gram scale. However, despite extensive efforts, the synthesis of unsymmetrical primary aniline-based indolylarylmethanes under these conditions has proven to be unsuccessful. This challenge highlights the need for further investigation to discover novel strategies for the synthesis of this compound.

Primary aniline-based triarylmethanes have attracted considerable attention due to the remarkable versatility of primary amine. The amino group on the benzene ring can be readily converted into various functional groups, making triarylmethanes bearing primary anilines valuable for preparing a diverse triarylmethanes derivatives and their application in various research fields (Figure b). ,

In the literature, primary and secondary aniline-based triarylmethanes have been synthesized using metal catalysts. For example, Hikawa’s group evaluated the use of water-soluble Au­(III)/TPPMS as a catalyst in an aqueous system through the benzylation of unprotected anthranilic acids and benzyl alcohols. Similarly, Ghorai’s group employed Re₂O₇ as a catalyst for the benzylation of unprotected aniline with benzyl alcohol (Scheme a). Another interesting approach involves the aza-Friedel–Crafts reaction, which has been explored for the synthesis of primary and secondary aniline-based indolylmethanes. This is of great interest due to the bioactivity of indoles and the broad applicability of primary anilines. Recently, Bosica’s group reported a one-pot, three-component aza-Friedel–Crafts reaction utilizing primary and secondary anilines, indoles, and aldehydes, catalyzed by a heterogeneous system comprising 30% w/w silicotungstic acid supported on Amberlyst 15 beads (WS/A15, Scheme b). Kobayashi’s group developed a strategy for the synthesis of 3-substituted indoles via a three-component aza-Friedel–Crafts reaction of aldehydes, o-anisidine, and indoles catalyzed by decanoic acid in water. This method produced N-branched amines, which were subsequently converted to 3-substituted indoles. Additionally, various catalysts, including polymer-grafted ZnO nanoparticles dispersed in water, iron­(III) phosphate (FePO₄), 2,4,6-trichloro-1,3,5-triazine (cyanuric chloride, TCT), Yb­(OTf)₃–SiO₂, and iodine have been employed for preparing N-branched amines (Scheme c).

1. Synthetic Methods for the Synthesis of Primary and Secondary Aniline-Based Indolylmethanes .

^a (a–c) Previous Works, (d) this work.

However, the method for the synthesis of primary aniline-based indolylarylmethanes under metal-free conditions remains less explored. In this study, a practical, sustainable, and metal-free methodology for synthesizing these derivatives was presented. This approach utilized a one-pot, three-component aza-Friedel–Crafts reaction catalyzed by a reusable BAIL in an aqueous medium. The reaction proceeds through an N-branched amine intermediate, employing commercially available aldehydes, primary anilines, and indoles (Scheme d).

Results and Discussion

A series of Brønsted acidic ionic liquids (BAILs) based on imidazolium cations was synthesized using a previously reported method (see Supporting Information) and employed as catalysts in this approach (Figure ).

2.

Brönsted acidic ionic liquids (BAILs) based on imidazolium cation.

The synthesis of primary aniline-based indolylarylmethanes 4a was investigated via a sequential one-pot, three-component aza-Friedel–Crafts reaction. The optimal reaction was explored using the model reaction involving commercially available 4-nitrobenzaldehyde (1a), aniline (2a), and indole (3a) under various conditions, with yields determined by HPLC analysis (Table ). Initially, the acidic ionic liquid [bsmim]­[NTf₂] (I) was evaluated as a catalyst due to its previously demonstrated high catalytic activity. , The reaction was conducted with 1a, 2a, and 3a in a 0.2:0.2:0.2 mmol ratio, using 10 mol % of [bsmim]­[NTf₂] (I) at room temperature in an aqueous medium for 1.0 h. Upon heating the reaction at 100 °C for 2 h, the desired product 4a was obtained in only 7% yield along with 17% bisindole 5a and a trace amount of leuco base 6a (entry 1). The yield of 4a was improved by increasing the amount of aniline 2a (entries 2–4). The best yield of 4a (64%, entry 3) was achieved with 0.4 mmol (2.0 equiv) of aniline 2a. However, increasing the amount of aniline 2a to 0.6 mmol did not significantly increase the yield (63%) and led to the formation of the undesirable product 6a (7%, entry 4). Heating the reaction at 100 °C for 3.0 h from the beginning led to a decrease in yield of 4a (55%, entry 5), while the amount of bisindole 5a increased to 25%. This is likely due to the more facile formation of bisindole 5a under heating conditions, either through a direct double Friedel–Crafts reaction between indole 3a and aldehyde 1a, or through a rapid reaction of indole 3a with intermediate 7a. Subsequently, various organic solvents, including solvent-free conditions, were examined (entries 6–13). The reaction proceeded slowly in both organic solvents and solvent-free conditions, with product 4a obtained in lower yields (12–48%), while unreacted intermediate 7a was detected in moderate yields (20–48%). This is attributed to the fact that BAIL catalysts are fully soluble in water, significantly enhancing their catalytic activity. Consequently, water was chosen as the optimal solvent for this approach. Additionally, under the same aqueous conditions, various catalysts were screened (entries 14–24). Imidazolium-based BAILs yielded product 4a depending on their cationic and anionic components. Catalysts II–IV (entries 14–16), with different counteranions (OTf, pTsO, and HSO₄), resulted in slower reactions, producing 4a in relatively lower yields (9–24%), compared to catalyst I with the NTf₂ anion (entry 3). Unreacted intermediate 7a also remained in moderate amounts (23–51%). These results highlight the critical role of the counteranion in this protocol, with the NTf₂ anion, derived from the traditional strong acid bis­(trifluoromethane)­imide (NHTf₂), exhibiting the highest catalytic activity. Evaluation of catalysts V–VII, which are different cationic imidazolium-based compounds with the NTf₂ anion, was also conducted (entries 17–19). Catalyst V provided a promising yield of 4a (65%, entry 17), similar to that of catalyst I (64%, entry 3). In contrast, catalysts VI and VII produced 4a in lower yields (21 and 50%, respectively), with some unreacted intermediate 7a observed (entries 18–19). For comparison, traditional acidic catalysts, including metal catalysts, were examined, such as general acid bis­(trifluoromethane)­imide (HNTf₂), cyanuric chloride, decanoic acid, Cu­(OTf)₂, and Yb­(OTf)₂ (entries 20–24). The results showed that none of these catalysts yielded better results than catalysts I and V. The control reaction conducted without a catalyst produced only trace amounts of 4a along with significant amounts of bisindole 5a and intermediate 7a (entry 25).

1. Optimization of Sequential One-Pot Reaction .

	substrate (mmol)					yield (%)
entry	1a	2a	3a	catalyst	solvent	4a	5a	6a	7a
1	0.2	0.2	0.2	[bsmim][NTf2] (I)	H2O	7	17	trace	0
2	0.2	0.3	0.2	[bsmim][NTf2] (I)	H2O	30	14	0	0
3	0.2	0.4	0.2	[bsmim][NTf2] (I)	H2O	64	18	0	0
4	0.2	0.6	0.2	[bsmim][NTf2] (I)	H2O	63	11	7	0
5	0.2	0.4	0.2	[bsmim][NTf2] (I)	H2O	55	25	0	2
6	0.2	0.4	0.2	[bsmim][NTf2] (I)	EtOH	22	16	0	42
7	0.2	0.4	0.2	[bsmim][NTf2] (I)	MeCN	48	3	0	45
8	0.2	0.4	0.2	[bsmim][NTf2] (I)	DMSO	12	5	0	25
9	0.2	0.4	0.2	[bsmim][NTf2] (I)	EtOAc	41	5	0	45
10	0.2	0.4	0.2	[bsmim][NTf2] (I)	THF	29	5	0	44
11	0.2	0.4	0.2	[bsmim][NTf2] (I)	Toluene	39	7	0	40
12	0.2	0.4	0.2	[bsmim][NTf2] (I)	1,4-Dioxane	37	21	0	20
13	0.2	0.4	0.2	[bsmim][NTf2] (I)	-	36	4	4	48
14	0.2	0.4	0.2	[bsmim][OTf] (II)	H2O	22	18	0	23
15	0.2	0.4	0.2	[bsmim][pTsO] (III)	H2O	9	13	0	51
16	0.2	0.4	0.2	[bsmim][HSO4] (IV)	H2O	24	15	0	33
17	0.2	0.4	0.2	[bsdodecim][NTf2] (V)	H2O	65	6	0	0
18	0.2	0.4	0.2	[dodecim][NTf2] (VI)	H2O	21	23	3	15
19	0.2	0.4	0.2	[mim][NTf2] (VII)	H2O	50	18	0	12
20	0.2	0.4	0.2	NHTf2	H2O	36	21	3	0
21	0.2	0.4	0.2	Cyanuric chloride	H2O	44	18	0	7
22	0.2	0.4	0.2	Decanoic acid	H2O	35	15	0	17
23	0.2	0.4	0.2	Cu(OTf)2	H2O	35	15	5	2
24	0.2	0.4	0.2	Yb(OTf)2	H2O	40	16	6	5
25	0.2	0.4	0.2	No catalyst	H2O	3	18	0	37

^aReaction conditions: (1) 1a (0.2 mmol), 2a (0.2–0.4 mmol), 3a (0.2 mmol), catalyst (10 mol %), solvent (0.6 mL), room temperature, 1.0 h; (2) 100 °C, 2.0 h.

^bHPLC yield; HPLC analysis condition: DAD detector/C18 HPLC column, solvent system 70% MeCN/H₂O, flow rate 1 mL/min, inj. Vol. Ten mL, pressure 80–90 bar, oven 30 °C, wavelength 254 nm.

^c100 °C, 3.0 h.

^dprevious condition

To confirm the best catalyst, catalysts I and V were further evaluated (Table ). The reaction was performed by using model substrates to optimize the formation of intermediate 7a, with yields determined by HPLC analysis. The results showed that catalysts I and V produced similar yields of product 7a after 1 h, 64 and 66% (entries 1 and 5, respectively). However, catalyst I yielded a significant amount of bisindole 5a, while catalyst V produced only trace amounts of 5a. These findings suggest that catalyst I promotes the formation of bisindole 5a more readily at room temperature, likely through either the direct double Friedel–Crafts reaction of indole 3a with aldehyde 1a or the rapid reaction of indole 3a with compound 7a. After 3 h, catalyst I showed a slight increase in the yield of 7a to 70% (entry 2), whereas catalyst V, with a long alkyl chain, achieved a higher yield of 7a (95%, entry 6). The yield of 7a remained consistent after 12 h for both catalysts, at 75 and 93% (entries 3 and 7, respectively). However, after 24 h, the yield of 7a declined, reaching 60 and 80% (entries 4 and 8, respectively). These results demonstrate that catalyst V provides the best performance compared to catalyst I. Additionally, the isolated yields of the products were evaluated, confirming that the high yield of product 7a was maintained at 92% (entry 6, in brackets).

2. Optimization of First Step .

		time (h)	yield (%)
entry	catalyst		7a	5a
1	[bsmim][NTf2] (I)	1.0	64	12
2	[bsmim][NTf2] (I)	3.0	70	10
3	[bsmim][NTf2] (I)	12.0	75	10
4	[bsmim][NTf2] (I)	24.0	60	19
5	[bsdodecim][NTf2] (V)	1.0	66	4
6	[bsdodecim][NTf2] (V)	3.0	95(92),	trace
7	[bsdodecim][NTf2] (V)	12.0	93	trace
8	[bsdodecim][NTf2] (V)	24.0	80	6

^aReaction conditions: 1a (0.2 mmol), 2a (0.4 mmol), 3a (0.2 mmol), catalyst (10 mol %), solvent (0.6 mL), at room temperature, 1.0–24.0 h.

^bHPLC yield; HPLC analysis condition: DAD detector/C18 HPLC column, solvent system 70% MeCN/H₂O, flow rate 1 mL/min, inj. Vol. Ten mL, pressure 80–90 bar, oven 30 °C, wavelength 254 nm,

^cThe reaction was conducted with 1a:2a:3a (1:2:1 mmol),

^dIsolated yield.

Based on the result in Table , the best-performing catalyst V was further investigated using the model reaction, with yields quantified by HPLC analysis (Table ). The reaction was carried out using 10 mol % of catalyst V in water at room temperature for 3 h, followed by heating the reaction at 100 °C for 2 h (entry 1) and 3 h (entry 2), resulting in the desired product 4a in a consistent yield of 66% for both cases. The effect of catalyst loading on the reaction efficiency was also explored (entries 3–7). Reducing the catalyst loading to 5 mol % decreased the yield of 4a to 41% (entry 3), while increasing the catalyst loading to 20–50 mol % slightly reduced the yield to 53–60% (entries 4–7). Varying the water volume to adjust the reaction concentration did not enhance the yield of 4a (entries 8–10). Interestingly, the desirable product 4a was obtained in a significantly higher yield when the reaction was performed under neat conditions in the second step. Therefore, after the first step, water was removed under reduced pressure and the reaction proceeded without solvent. This approach resulted in the highest yield of 4a in 82% yield (entry 11), which was confirmed by isolated yield (82%, entry 11, in brackets). Furthermore, lowering the temperature to 80 °C in the second step did not increase the yield of 4a, even with prolonged reaction times (entries 12–15).

3. Optimization of Sequential One-Pot Reaction .

		solvent (mL)		temp. (oC)	time (h)	yield (%)
entry	catalyst loading (mol %)	1st step	2nd step	2nd step	2nd step	4a	5a	6a
1	10	H2O (0.6)	H2O (0.6)	100	2.0	66	4	0
2	10	H2O (0.6)	H2O (0.6)	100	3.0	66	3	0
3	5	H2O (0.6)	H2O (0.6)	100	2.0	41	2	0
4	20	H2O (0.6)	H2O (0.6)	100	2.0	60	4	0
5	30	H2O (0.6)	H2O (0.6)	100	2.0	57	3	0
6	40	H2O (0.6)	H2O (0.6)	100	2.0	53	6	0
7	50	H2O (0.6)	H2O (0.6)	100	2.0	55	5	0
8	10	H2O (0.4)	H2O (0.4)	100	2.0	51	5	6
9	10	H2O (0.8)	H2O (0.8)	100	2.0	65	3	trace
10	10	H2O (1.0)	H2O (1.0)	100	2.0	66	3	trace
11	10	H2O (0.6)(3.0)	neat	100	2.0	82(82),	5(4),	4(4),
12	10	H2O (0.6)	neat	80	2.0	77	6	0
13	10	H2O (0.6)	neat	80	3.0	76	7	0
14	10	H2O (0.6)	neat	80	6.0	77	6	0
15	10	H2O (0.6)	neat	80	24.0	54	7	2

^aReaction conditions: 1a (0.2 mmol), 2a (0.4 mmol), 3a (0.2 mmol), catalyst (5–50 mol %), H₂O (0.4–1.0 mL), room temperature, 3.0 h (step 1), 80–100 °C, 2.0–24 h (step 2),

^bHPLC yield (HPLC analysis condition: DAD detector/C18 HPLC column, solvent system 70% MeCN/H₂O, flow rate 1 mL/min, inj. Vol. 10 mL, pressure 80–90 bar, oven 30 °C, wavelength 254 nm),

^cThe reaction was conducted with 1a:2a:3a (1:2:1 mmol),

^dIsolated yield.

Under the optimized reaction (Table , entry 11), the scope of the reaction was extended to include various aldehydes (1) substrates, and the results are summarized in Scheme . The results showed that the desirable product yields were influenced by the electronic effects of the aldehyde substrates. Aromatic aldehydes bearing electron-withdrawing substituents on the benzene ring, including benzaldehyde, readily participated in the reaction, furnishing the desired products (4aa–4ah) in good to high yields (72–83%). In contrast, aldehydes with electron-donating groups afforded the products (4ai–4ap) in moderate yields (50–65%). Whereas 1-naphthaldehyde was examined to afford the product 4aq in a moderate yield of 68%. Heteroaromatic aldehydes, such as pyridine-2-carbaldehyde and 2-bromopyridine-3-carbaldehyde, also provided the products 4ar and 4as in moderate yields of 67 and 63%, respectively. However, pyrrole-2-carbaldehyde failed to yield the desired product 4at, likely due to the instability of the substrate.

2. Synthesis of Unsymmetrical Triarylmethanes with Various Aldehyde Substrates,

^c Minor products 5.

^d Reaction was conducted from intermediate 7a

^a Reagents and conditions: aldehyde (1, 1.0 mmol), aniline (2a, 2.0 mmol) and indole (3a, 1.0 mmol), 10 mol % of [bsdodecim]­[NTf₂] (V) in 3.0 mL of water, room temperature, (1) 3.0 h, (2) 100 °C, 2.0 h,

^b Isolated yield,

Further investigations were conducted with various aldehyde (1), primary aniline (2), and indole (3) substrates bearing substituents on the benzene ring using the optimized reaction conditions (Scheme ). Ortho-substituted anilines, having electron-donating groups and electron-withdrawing groups, delivered the products in high to excellent yields for 4ba–4bf (o-OMe, 74–87%), 4bg (X¹ = o-Me, 95%), 4bi (X¹ = o-Br, 83%), and 4bj (X¹ = o-F, 84%). Notably, these results indicated no dependency on the electronic effects of the aromatic aldehyde substrates, including heteroaromatic aldehydes. In contrast, the ortho-hydroxy group yielded only 27% of product 4bh, likely due to the instability of the hydroxy moiety. Remarkably, ortho-methoxy aniline, which has two possible sites for C-nucleophilic addition, exhibited regioselectivity, leading to C-nucleophilic addition at the para-position of the amino group. In contrast, C-nucleophilic addition at the para-position of the methoxy group was not observed. This is likely because the amino group is more reactive than the methoxy group through strong resonance delocalization of the lone-pair electrons on the nitrogen atom. Meta-substituted anilines with either electron-donating (OMe) or electron-withdrawing (Br) groups afforded high yields of 4bk and 4bl in 78 and 88%, respectively. Interestingly, para-substituted anilines provided the products through C-nucleophilic addition at the ortho-position of the amino group. However, lower yields of 4bm (31%) and 4bn (50%) were observed, likely due to steric hindrance at the ortho-position. In contrast, anilines bearing substituents at both the ortho- and meta-positions did not affect the yields, furnishing the products in excellent (4bo, 98%) and high (4bp, 87%) yields. Subsequently, the scope of indole nucleophiles was further explored under the optimized conditions. N-substituted indoles with a methyl group gave a high yield of 4bq (89%), whereas a moderate yield of 4br (61%) was obtained with a phenyl group. The reduced yield is likely attributed to the resonance effect of the phenyl group, which diminishes the nucleophilic reactivity of the indole. Substitutions at the 5- and 6-positions of the indole ring, whether with electron-withdrawing or electron-donating groups, resulted in high to excellent yields of 4bs–4by (74–90%), indicating that these positions had no significant effect on the yields. Surprisingly, when both the 5- and 6-positions on the indole ring were substituted, the yield of 4bz was significantly reduced to only 21%.

3. Synthesis of Unsymmetrical Triarylmethanes with Various Aldehyde, Aniline, and Indole Substrates,

^c Minor products 5.

^a Reagents and conditions: aldehyde (1, 1.0 mmol), aniline (2, 2.0 mmol), indole (3, 1.0 mmol), 10 mol % of [bsdodecim]­[NTf₂] (V), 3.0 mL of water, (1) room temperature for 3.0 h, (2) 100 °C for 2.0 h,

^b Isolated yield,

In addition, the effect of sterically hindered groups on 2-substituted indoles was examined, resulting in high yields of 82 and 86% for products 4ca and 4cb, respectively. However, when additional substitutions were introduced at the 5-position along with the 2-substituted indole, lower yields were observed, with 65 and 52% for products 4cc and 4cd, respectively. Aniline and indole nucleophiles with electron-donating groups were employed, resulting in excellent yields of 4ce at 90% and high yields of 4cf and 4cg at 71 and 70%, respectively. An electron-donating group on the benzene ring of aniline and an electron-withdrawing group on the indole ring gave high yields of 87% and 77% for products 4ch and 4ci, respectively. In contrast, when an electron-withdrawing group was substituted on the aniline and an electron-donating group was substituted on the indole, a moderate yield of 4cj (41%) was obtained. Similarly, electron-withdrawing groups on both the aniline and indole led to a moderate yield of 48% for 4ck. Unfortunately, strong electron-withdrawing groups, such as the nitro group, did not produce the expected products 4cl and 4 cm.

To assess the practicality of this method, gram-scale syntheses were performed using 6.62 and 20.0 mmol of 4-nitrobenzaldehyde (1a) under the optimized conditions (Scheme ). The results showed that both reaction scales consistently afforded high yields of 4a (83 and 82%, respectively), with only minor amounts of byproducts 5a and 6a, comparable to those obtained in the small-scale reaction (Table , entry 11).

4. Gram-Scale Synthesis.

The recycling performance of catalyst V was evaluated (Scheme ). After the first reaction cycle, water (3.0 mL) was added to dissolve the water-soluble catalyst V, then organic residues were simply extracted with ethyl acetate (3 × 5 mL), leaving catalyst V in the aqueous layer. Substrates were then directly added to the water layer containing catalyst V in the same amounts for subsequent cycles (method A). The results showed a decline in the yield of 4a to 72 and 60% in the second and third cycles, respectively, accompanied by an increase in the minor byproduct 6a to 15 and 21%. This reduction in efficiency is attributed to a significant amount of aniline (2a) remaining dissolved in the aqueous layer, as it is poorly extracted by ethyl acetate. This residual aniline 2a in water readily promotes the formation of 6a. Surprisingly, this issue was effectively resolved by reducing the amount of aniline (2a) in subsequent cycles, adjusting the molar ratio of 1a, 2a, and 3a to 1.0:1.0:1.0. This modification maintained the yield of 4a consistently high over three cycles (83, 81, and 79%, respectively) with only trace amounts of byproducts 5a and 6a (method B, in brackets).

5. Recyclability.

Based on our previous studies and related reports in the literature, , a plausible mechanism for the formation of primary aniline-based indolylmethanes catalyzed by a Brønsted acidic ionic liquid (BAIL) is proposed in Scheme . The mechanism begins with the activation of the carbonyl group at the oxygen atom of the aldehyde substrate (1) by BAIL catalyst V, which then readily reacts with the aniline nucleophile (2a) via N-nucleophilic addition to form an imine intermediate. This imine, acting as an activated electrophile, then reacts rapidly with indole (3a) to generate intermediate 7. Subsequently, BAIL catalyst V back to activate intermediate 7 at nitrogen atom, and upon heating, the aniline moiety (PhNH₂) is eliminated to form an azafulvene intermediate. Finally, aniline rapidly reacts with the azafulvene intermediate through C-nucleophilic addition at the para-position, leading to the formation of the desired product 4a.

6. Proposed Mechanism for the Formation of Primary Aniline-Based Indolylmethanes.

Conclusions

In conclusion, a simple, practical, and metal-free methodology for the preparation of primary aniline-based indolylmethanes via a sequential one-pot, three-component aza-Friedel–Crafts reaction of commercially available aromatic aldehydes, primary anilines, and indoles has been successfully demonstrated. The Brønsted acidic ionic liquid (BAIL), [bsdodecim]­[NTf₂], proved to be the most efficient catalyst in a water system, achieving the corresponding products in moderate to high yields with a diverse range of substrates. The reaction proceeded smoothly, affording high yields even in gram-scale synthesis. Moreover, the catalyst was recyclable, maintaining high yields over three cycles without any significant loss of catalytic activity. Therefore, this protocol offers superior efficiency and practical advantages over conventional methods, including operation under mild aqueous conditions, elimination of metal catalysts, and broad substrate applicability. These features highlight its potential as an effective green synthetic approach.

Experimental Section

General Remarks

All chemicals were purchased from commercial sources and used without further purification. ¹H and ¹³C NMR spectra were recorded by using a BRUKER Avance (400 MHz) spectrometer from Burapha University. High-performance liquid chromatography (HPLC) was performed for the optimization using an Agilent, Infinity 1260 with an LC column 250 × 4.6 mm² (Luna 5 mm C18(2) 100 Å). HPLC conditions were DAD detector, flow rate 1.00 mL/min, eluting with MeCN/H₂O (70/30), pressure 80–90 bar, oven 30 °C, and wavelength 254 nm. High-resolution mass spectra (HRMS) data were recorded using a Bruker Daltonics-micrOTOF-Q at Mahidol University and an Agilent Technologies Q-TOF at Naresuan University. Infrared spectra were determined on a PERKIN ELMER FT/IR-2000S spectrophotometer. Analytical thin-layer chromatography (TLC) was conducted on precoated TLC plates; silica gel 60 F-254 [E. Merck, Darmstadt, Germany]. Open-column chromatography was carried out using silica gel 60 (0.063–0.200 mm) [E. Merck, Darmstadt, Germany]. Melting points were measured using a melting point apparatus (Griffin) from Burapha University.

General Procedure for Aniline-Based Indolylmethanes Synthesis

To a solution of [bsdodecim]­[NTf₂] (10 mol %) in water (3.0 mL) was added aldehyde (1) (1.0 mmol), aniline (2) (2.0 mmol), and indole (3) (1.0 mmol) at room temperature. The reaction mixture was stirred at room temperature for 3.0 h. The progress of the reaction was monitored by TLC. After completion of the first step, water was removed by a rotary evaporator. The crude residue was heated at 100 °C for 2.0 h under neat conditions. After the reaction was completed, the crude product was diluted with water (5.00 mL) and extracted with ethyl acetate (5 × 10 mL). The combined organic layer was dried over sodium sulfate anhydrous and concentrated using a rotary evaporator. The crude product was purified by column chromatography (SiO₂, 5–50% ethyl acetate/n-hexane as eluent, depending on each derivative) to give the corresponding products.

N-((1H-indol-3-yl)­(4-nitrophenyl)­methyl)­aniline (7a)

,, CAS Number 886209–34–3; 94% yield (0.3228 g) as a yellow solid; mp 138–140 °C; R _f = 0.41 (30% EtOAc/n-hexane); IR (Neat): 3394, 3366, 3051, 2843, 1600, 1500, 1338, 1271, 1095, 1069, 814, 736, 694 cm^–1; ¹H NMR (400 MHz, DMSO-d ₆): δ 11.03 (s, 1H), 8.19 (d, 2H, J = 8.8 Hz), 7.79 (d, 2H, J = 8.8 Hz), 7.56 (d, 1H, J = 7.6 Hz), 7.36 (d, 1H, J = 8.0 Hz), 7.10–6.94 (m, 5H), 6.68 (d, 2H, J = 8.0 Hz), 6.52 (t, 1H, J = 7.2 Hz), 6.45 (d, 1H, J = 6.8 Hz), 6.01 (d, 1H, J = 6.8 Hz); ¹³C NMR (100 MHz, DMSO-d ₆): δ 152.25, 147.83, 146.35, 136.52, 128.80 (2C), 128.28 (2C), 125.74, 123.72, 123.56 (2C), 121.47, 119.06, 118.85, 116.32, 116.30, 113.10 (2C), 111.69, 53.77.

4-((1H-indol-3-yl)­(4-nitrophenyl)­methyl)­aniline (4aa)

CAS Number 2149047–15–2; 82% yield (0.2850 g) as a yellow solid; mp 138–140 °C; R _f = 0.13 (30% EtOAc/n-hexane); IR (Neat): 3411, 3351, 3053, 2920, 2867, 1622, 1593, 1341, 1276, 1262, 1219, 1180, 1124, 1096 cm^–1; ¹H NMR (400 MHz, DMSO-d ₆): δ 10.92 (s, 1H), 8.14 (d, 2H, J = 8.8 Hz), 7.46 (d, 2H, J = 8.8 Hz), 7.35 (d, 1H, J = 8.0 Hz), 7.08 (d, 1H, J = 8.0 Hz), 7.04 (t, 1H, J = 8.0 Hz), 6.89 (d, 2H, J = 8.4 Hz), 6.85 (t, 1H, J = 7.2 Hz), 6.71 (d, 1H, J = 2.0 Hz), 6.49 (d, 2H, J = 8.4 Hz), 5.63 (s, 1H), 4.95 (s, 2H); ¹³C NMR (100 MHz, DMSO-d ₆): δ 153.52, 147.14, 145.75, 136.72, 129.99, 129.66 (2C), 129.10 (2C), 126.34, 124.21, 123.45 (2C), 121.23, 119.02, 118.48, 117.44, 114.00 (2C), 111.60, 47.17; HRMS (ESI) m/z C₂₁H₁₇N₃O₂ [M + H]⁺ calcd 344.1399, found 344.1397.

The data underlying this study are available in the published article and its Supporting Information.

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsomega.5c04294.

• Synthetic procedures, characterization data for all new compounds (PDF)

The authors declare no competing financial interest.