Three-Component One-Pot Synthesis of Highly Functionalized Bis-Indole Derivatives.

In this study, we detail the development of a concise and efficient three-component protocol for the regioselective synthesis of highly functionalized bis-indoles through a one-pot, two-step sequential process starting from enaminones 1, indoles 2, and acenaphthylene-1,2-dione 3 that is catalyzed by piperidine and p-methyl benzenesulfonic acid. This protocol has several advantages including simplicity of experimental operation, high efficiency of bond formation, ready availability and low cost of starting materials, environmentally benign conditions, and target molecular diversity.

Introduction

Indole and its derivatives belong to a fascinating and important class of nitrogen heterocyclic compounds that have been regarded as privileged scaffolds found in many biologically active pharmaceuticals and natural products.[1] They can also be used as nucleophiles for organic synthesis,[2] and of these, the molecularly diverse bis-indole skeletons are frequently found in natural products and possess broad spectrum biological activities. For example, topsentin and its analogue, (R)-6′-debromohamacanthin B (Figure ), were originally isolated from the marine sponge and have shown antitumor, antiviral, antimicrobial, and anti-inflammatory activities.[3] Another analogue, isoborreverine[4] (Figure ) has exhibited antimalarial activity.[5] Whereas indirubin (Figure ), a potent and selective cyclin-dependent kinase inhibitor[6] and dioxin receptor,[7] was found as glycogen synthase kinase-3[8] and aurora kinases[9] and possesses antitumor activity.[10] Therefore, in the effort to develop novel and efficient methodologies for synthesis, these bis-indole and simple bis-indole alkaloids have attracted our attention.

Figure 1

Representative examples of natural bis-indoles and the target molecule.

Multicomponent reactions (MCRs)[11] are powerful tools for the construction of multi-C–C and C–hetero bonds. They can generate high levels of diverse and complex molecules where at least three polyfunctional raw materials react in an ordered fashion via tandem processes. These reactions can avoid purification intermediates and allow savings of both solvents and reagents. Other inherent characteristics of MCRs include regio- and chemo-selectivity, atom and step economy, step efficiency, target molecular diversity, and operational simplicity.[12]

On the other hand, diversity-oriented synthesis is an application that is widely used in biological and medical research and has led to the rapid development of broadly used synthons.[13] Enaminones are powerful and versatile building blocks that have been widely used in the synthesis of pharmacologically interesting heterocyclic and fused heterocyclic compounds, including acridines, indoles, naphthyridines, quinolones, pyrroles, thiazines, pyridines, and thiazoles.[14] Some of these heterocycles demonstrate to have promising biological activity, such as antimicrobial activity,[15] and have potential as protein kinase CK2 inhibitors.[16]

Recently, our group has developed several novel MCRs based on enaminones that can offer convenient and efficient access to heterocycles and fused heterocycles.[17] For the purpose of continuing our previous endeavors in and furthering our knowledge of the fabrication of aza heterocycles, we set out to develop a new synthetic protocol for efficient synthesis of polycyclic bis-indoles through a one-pot, two-step, three-component reaction of enaminones 1 and indoles 2, with acenaphthylene-1,2-dione 3, and report it herein (Scheme ).

Scheme 1

Pathways for the Synthesis of Bis-Indoles

Results and Discussion

Acenaphthenequinones have proven to be an appealing building block for the reaction of their 1,2-biselectrophilic centers and have thus been widely used for the detection of the nucleophilic group. Indole specifically possesses three nucleophilic centers. Several reports have detailed the utilization of its C-3 position as a nucleophilic center for the construction of 3-substituted indole derivatives. Acenaphthenequinone can provide two active sites, which can be reacted with the electron-rich C-3 atom of indoles. A recent report has found that the reaction of two indole molecules with acenaphthenequinone that is catalyzed by acid can afford the symmetrical bisindoly acenaphthylen-1(2H)-one 6.[18] However, a report describing the use of acenaphthenequinone and indole for the formation of indoyl-acenaphthylen-1(2H)-one 5 has yet to be realized (Scheme ). Accordingly, we focused our efforts on searching for potential catalysts and suitable reaction conditions for the synthesis of indoyl-acenaphthylen-1(2H)-one 5, which serves as a bis-electrophile (C=O and C–OH as electrophilic sites) and reacts with bis-nucleophile enaminones to produce polycyclic bis-indoles 4 via [3 + 2] annulation reaction.

Scheme 2

Acenaphthenequinone and Indoles React in Different Ways

On the basis of the above analysis, we began our investigation by performing the reaction of indole 2a and 3 in the presence of different catalysts (0.2 equiv) in ethanol at reflux. First, we investigated the organic bases, which included piperidine, DBU, and Et3N, and then obtained the corresponding indole-3-yl products 5 with 92, 79, and 85% yields, respectively. Next, we tested some acidic catalysts, which included HOAc, TsOH, and trifluoroacetyl, and found that only bisindoly acenaphthylen-1(2H)-one 6 was formed even when using a molar ratio of 1:1 of 2a:3. Finally, several solvents (CH3OH, dioxane, CH2Cl2, and CH3CN) were used in our experiments, and the yields did not show obvious affection. These results indicated that the best conditions for the synthesis of 5 could be the use of piperidine as a base at reflux.

The subsequent reaction of intermediate 5 with enaminones 1 requires a suitable acid to eliminate the hydroxyl and generate carbocation. Based on this, we decided to screen different acidic catalysts and solvents (Table ). Initially, this reaction was performed in the presence of p-TsOH for an hour at room temperature in ethanol, but the reaction did not occur (Table , entry 1). However, when the reaction temperature was raised to reflux, we obtained a 72% yield of bis-indole derivative 4a (Table , entry 2). After that, we employed several other Brønsted acids, such as KHSO4, HOAc, CF3COOH, CF3SO3H, and l-proline, as well as Lewis acids, such as AlCl3 and ZnCl2, in an effort to improve the yield, but the results showed that these catalysts could not promote this reaction efficiently (Table , entries 3–9). Next, we optimized different solvents and examined a variety of both polar and nonpolar solvents. We found that methylene chloride/methanol (CH2Cl2/CH3OH) was a more suitable solvent than ethanol for this reaction. Despite this, because of the volatility and toxicity of methylene chloride and methanol, we ultimately chose ethanol as the solvent for our future reactions. Finally, when we carried out the three-component in one-step reaction of 1 with 2 and 3 under similar conditions, we did not observe the expected product 4, instead we saw that only intermediate 6 was afforded. These findings indicate that the steric hindrance of 1 and the nucleophilicity of the substrates might control the reaction pathway.

Table 1

Screening Optimum Reaction Conditions for the Model Reactiona

entry	solvent	catalyst	temp (°C)	yield %b
1	EtOH	p-TSA	r.t	n.r
2	EtOH	p-TSA	reflux	72
3	EtOH	KHSO4	reflux	63
4	EtOH	HOAc	reflux	n.r
5	EtOH	CF3COOH	reflux	68
6	EtOH	CF3SO3H	reflux	57
7	EtOH	l-proline	reflux	n.r
8	EtOH	ZnCl2	reflux	n.r
9	EtOH	AlCl3	reflux	n.r
10	CH2Cl2	p-TSA	reflux	76
11	CH3CN	p-TSA	reflux	75
12	dioxane	p-TSA	reflux	20
13	CH3OH	p-TSA	reflux	63
14	H2O	p-TSA	reflux	n.r
15c	EtOH	p-TSA	reflux	n.r

Reaction conditions, unless stated otherwise, step 1: indole 2a (1.0 mmol), acenaphthenequinone 3 (1.0 mmol), and piperidine (0.2 mmol) in solvent (15 mL); step 2: enaminone 1a (1.0 mmol), catalyst (0.5 mmol).

Values are the isolated products.

Reaction was conducted by one-step, one-pot; only intermediate 6 was obtained.

Having established the optimum reaction conditions, we set out to explore the generality of the substrate of this transformation, the results of which are presented in Figure . At the start, we tested the substrate scope of enaminones 1 and found that, whether or not the substituent with diverse substitution patterns (para, ortho, and meta) on the aromatic ring of enaminones 1 was electron-donating or electron-withdrawing, the reaction could afford the corresponding bis-indoles 4 with good to excellent yield. Additionally, when including N-substituted 3-amino-5,5-dimethylcyclohex-2-enones and N-substituted 3-aminocyclohex-2-enonephenyls, all reactions proceeded well and yielded the corresponding bis-indoles derivatives (Figure , 4a–4x).

Figure 2

Substrate scope of the reaction for bis-indoles 4. Reaction conditions: indoles 2 (1.0 mmol), acenaphthenequinone 3 (1.0 mmol), and piperidine (0.2 mmol) in ethanol (15 mL) under reflux, and then the addition of enaminone 1 (1.0 mmol) and p-TSA (0.5 mmol). Isolated yield based on enaminone 1.

In order to explore the application of the present approach, we also evaluated the scope of the indoles. The 6-fluoroindole, 6-chloroindole, and 5-methylindole were used as substrates under the optimal conditions and generated the desired products (Figure , e.g., 4c, 4i, and 4x) with moderate and excellent yields, respectively.

The chemical structures of bis-indoles 4 were fully characterized by infrared spectroscopy (IR), 1H NMR, 13C NMR, and high-resolution mass spectrometry (HRMS) spectra. The intermediates 5 and 6 were isolated and identified using 1H NMR and 13C NMR (see the Supporting Information). In order to propose a plausible reaction mechanism, we tested the reaction of intermediates 5a and 1a in ethanol in the presence of p-TSA and obtained the expected target molecule 4 with the consumption of 5a.

Based on the above results and previous literature,[19] a tentative mechanism for the three-component reaction was proposed, as outlined in Scheme . First, indoles 2 reacted with acenaphthylene-1,2-dione 3 via aza-ene addition reaction to generate intermediate [A] prompted by the piperidine; meanwhile, [A] undergoes a process of imine-enamine tautomerization to give intermediate 5. Then, intermediate 5 accepts one proton to form [C], and losing one molecule water to form intermediate [C] gives iminium ion [D]. Intermediate [D] reacted with enaminone 1 to form intermediate [E] via a Michael addition. Finally, intermediate [E] underwent an intramolecular N-cyclization mediated by acidic that affords the bis-indoles 4.

Scheme 3

Postulated Mechanisms for the Formation of Bis-Indoles 4

Conclusions

In conclusion, we have successfully disclosed a novel, efficient, simple route for the synthesis of highly functionalized bis-indoles by a one-pot, two-step, three-component reaction of indoles, acenaphthylene-1,2-dione, and enaminones. The simplicity of operation, ready availability of starting materials, target molecular diversity, environmental sustainability with high atom economy, and excellent regioselectivity make this method a valuable complementary tool in the construction of bis-indoles. We therefore believe that such an efficient and simple methodology could have great potential for many applications as well as for the optimization of the synthetic production of bis-indoles, which has peaked interest and held the attention of the organic chemistry and medicinal communities.

Experimental Section

General Methods

All chemicals and solvents were directly used, without further purification unless otherwise stated. Materials 2 and 3 were ordered from Adamas Reagent Ltd. The silica gel (200–300 mesh) was used to perform column chromatography. All synthesized chemical molecules were characterized by full spectroscopic data. A Bruker AVANCE III 400 MHz (1H NMR: 400 MHz, 13C NMR: 100 MHz) was used to characterize the 1H and 13C nuclear magnetic resonance (NMR) spectra with DMSO-d6 as a solvent and tetramethylsilane as the internal standard. J values are given in Hz, and chemical shifts (δ) are expressed in ppm. A Fourier transform infrared Thermo Nicolet Avatar 360 was used to characterize IR spectra by using a KBr pellet. The whole process of each reaction was monitored in real time by the thin-layer chromatography (TLC) with silica gel GF254. A XT-4A melting point apparatus was used to detect the melting points without further correction. HRMS was characterized on an Agilent LC/Msd TOF and monoisotopic mass instrument.

General Procedure for Synthesis of Bis-Indoles 4

The chemical of indoles 2 (1.0 mmol), acenaphthylene-1,2-dione 3 (1.0 mmol), and piperidine (0.2 mmol) was first dissolved in ethanol (15 mL) together. The reaction mixture was then refluxed for a certain period of time by monitoring with TLC. Enaminone 1 (1.0 mmol) and p-TSA (0.5 mmol) were further added into the mixture and stirred at reflux temperature. At the end of the reaction, as monitored by TLC, the reaction mixture was terminated by diluting with 50 mL of water and cooled to room temperature. Afterward, the mixture was extracted with 50 mL of EtOAc two times. Then, the organic phase was dried over anhydrous Na2SO4 and concentrated under a vacuum. Finally, flash chromatography with petroleum ether–ethyl acetate (1:2, v/v) was used for the purification of the residue and giving a white compound solid 4 with high purification.

7-(4-Fluorophenyl)-6b-hydroxy-11b-(1H-indol-3-yl)-8,9,10,11b-tetrahydro-6bH-acenaphtho[1,2-b]indol-11(7H)-one (4a)

White solid; mp 221–223 °C; IR (KBr): 3477, 3061, 1591, 1553, 1222, 1157, 1024, 788 cm–1; 1H NMR (400 MHz, DMSO-d6): δ 10.89 (br, 1H, NH), 7.80 (d, J = 8.0 Hz, 1H, ArH), 7.73 (d, J = 8.0 Hz, 1H, ArH), 7.56–7.58 (m, 1H, ArH), 7.50 (s, 1H, ArH), 7.38 (t, J = 8.0 Hz, 1H, ArH), 7.30–7.50 (m, 5H, ArH), 6.85–6.93 (m, 2H, ArH), 6.44 (d, J = 8.0 Hz, 1H, ArH), 6.26 (s, 1H, ArH), 5.64 (br, 1H, OH), 2.09–2.20 (m, 1H, CH2), 1.85–2.00 (m, 3H, CH2); 13C NMR (100 MHz, DMSO-d6): δ 189.9, 162.9, 161.7 (d, 1JC–F = 244.0 Hz), 141.7, 137.3, 136.3, 133.6, 132.1 (d, 3JC–F = 9.0 Hz), 131.9 (d, 3JC–F = 9.0 Hz), 131.2, 128.9, 127.7, 125.3, 123.0, 122.4, 120.8, 120.4, 119.9, 118.2, 116.2 (d, 2JC–F = 22.0 Hz), 116.0 (d, 2JC–F = 22.0 Hz), 111.6, 106.2, 64.3, 37.5, 24.3, 22.6; HRMS (ESI-TOF): m/z calcd for C34H24FN2O2+ [(M + H)+], 487.1816; found, 487.1814.

7-(4-Chlorophenyl)-11b-(6-fluoro-1H-indol-3-yl)-6b-hydroxy-8,9,10,11b-tetrahydro-6bH-acenaphtho[1,2-b]indol-11(7H)-one (4b)

White solid; mp > 300 °C; IR (KBr): 3472, 2959, 1559, 1400, 1322, 1140, 1092, 789 cm–1; 1H NMR (400 MHz, DMSO-d6): δ 10.98 (br, 1H, NH), 7.80 (d, J = 8.0 Hz, 1H, ArH), 7.73 (d, J = 8.0 Hz, 1H, ArH), 7.62–7.72 (m, 1H, ArH), 7.50 (d, J = 8.0 Hz, 3H, ArH), 7.40–7.49 (m, 2H, ArH), 7.39 (t, J = 8.0 Hz, 1H, ArH), 7.28 (d, J = 8.0 Hz, 1H, ArH), 7.07 (d, J = 8.0 Hz, 3H, ArH), 6.49 (d, J = 8.0 Hz, 1H, ArH), 6.44 (s, 1H, ArH), 6.22–6.30 (m, 1H, ArH), 5.49 (br, 1H, OH), 2.34–2.46 (m, 1H, CH2), 2.08–2.20 (m, 4H, CH2), 1.94–1.97 (m, 1H, CH2); 13C NMR (100 MHz, DMSO-d6): δ 190.2, 163.1, 158.6 (d, 1JC–F = 233.0 Hz), 146.4, 141.7, 137.1 (d, 3JC–F = 12.0 Hz), 136.4, 136.2, 132.5, 131.4, 131.2, 129.4, 128.9, 127.8, 125.4, 123.2, 122.4, 119.9, 106.3, 97.5 (d, 2JC–F = 25.0 Hz), 97.3 (d, 2JC–F = 25.0 Hz), 64.3, 37.5, 24.3, 22.7; HRMS (ESI-TOF): m/z calcd for C32H23ClFN2O2+ [(M + H)+], 521.1427; found, 521.1427.