Advertisement
Browse Subject Areas
?

Click through the PLOS taxonomy to find articles in your field.

For more information about PLOS Subject Areas, click here.

  • Loading metrics

Open Access

Peer-reviewed

Research Article

Development of an imidazole salt catalytic system for the preparation of bis(indolyl)methanes and bis(naphthyl)methane

  • Xu Wang ,

    Roles Conceptualization, Data curation, Methodology, Project administration, Writing – original draft

    norowangxu@imm.ac.cn

    Affiliation Department of Synthetic Medicinal Chemistry, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

    ⨯
  • Courtney C. Aldrich

    Roles Funding acquisition, Writing – review & editing

    Affiliations Department of Synthetic Medicinal Chemistry, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China, Department of Medicinal Chemistry, University of Minnesota, Minneapolis, Minnesota, United States of America

    ⨯

Abstract

Imidazolium salts are shown to catalyze the rapid room temperature reaction of indoles or naphthol with aldehydes to provide bis(indolyl)methanes or bis(naphthol)methane in excellent yields and the reaction proceeds optimally in dichloromethane with no base additives. The reaction exhibits a broad substrate tolerance and occurs through nucleophilic activation of the indoles and naphthols through a cation–π interaction.

Citation: Wang X, Aldrich CC (2019) Development of an imidazole salt catalytic system for the preparation of bis(indolyl)methanes and bis(naphthyl)methane. PLoS ONE 14(4): e0216008. https://doi.org/10.1371/journal.pone.0216008

Editor: Andrew C. Marr, Queen's University Belfast, UNITED KINGDOM

Received: February 1, 2019; Accepted: April 12, 2019; Published: April 25, 2019

Copyright: © 2019 Wang, Aldrich. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: All relevant data are within the manuscript and its Supporting Information files.

Funding: This work was supported by the grant of The State Key Laboratory of Bioactive Substance and Function of Natural Medicines (SKLBSFNM) and by the Union Scholar Chair Professor in Institute Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College (PUMC) to C.C.A. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist.

Introduction

Bis(indolyl)methane and its derivatives constitute a structurally fascinating and important class of heterocyclic compounds present in many natural products isolated from marine and terrestrial organisms (Fig 1).[1, 2] These compounds are a rich source of antitumor and antibacterial agents.[3–5] For instance, Gu and co-workers isolated two new indole alkaloids, arsindoline A and B with promising antitumor activities from a marine-derived Aeromonas bacterial strain CB101.[6] In 1994, Kobayashi and co-workers isolated trisindoline, an antibiotic indole trimer from a Vibrio sp. living symbiotically within the marine sponge Hyrtios altum.[7] Though vibrindole A was isolated from a natural source in 1994, it has been known as a synthetic product since 1963.[8, 9] Recently, Li and co-workers found the tetraindole compound, FCW81, which displayed efficacy in a xenograft model of human breast cancer by inhibiting growth and more importantly blocking cancer cell metastasis.[10, 11] In 2017, Müller and co-workers reported the bis(indolyl)methane alkaloid, PTS-16671 as a potent GPR84 agonist (EC50 41 nM) that demonstrated increased stability relative to their initial lead compound.[12]

thumbnail
Download:
Fig 1. Structures of biologically active bis(indolyl)methane alkaloids.

https://doi.org/10.1371/journal.pone.0216008.g001

Motivated by the above-mentioned pharmacological activities of bis(indolyl)methanes, many synthetic methods have been described in the literature for preparing this class of compounds. The traditional methods of synthesizing bis(indolyl)methanes involve the activation of aldehydes using Brønsted acids [13, 14] or Lewis acids [15–21]. However, the catalysts employed are moisture sensitive and are easily decomposed or deactivated in the presence of even a small amount of water. In recent years, many new catalysts have been used to synthesize bis(indolyl)methanes including ammonium salt or borate salts [22, 23], ionic liquids [24, 25], iodine [26], heterogeneous nanoparticles [27–29] and enzymes [30]. However, these methods involve use of harsh reaction conditions as well as toxic or expensive reagents. Moreover, the substrate scope was not thoroughly explored for many of the reported reaction conditions. Development of a waste-free synthetic protocol would be of great use for the economical and practical laboratory synthesis of these compounds. In particular, any new method should ideally demonstrate a broad substrate scope in order to explore the medicinal chemistry of this scaffold.

On the other hand, to the best of our knowledge, the reaction mechanism of bis(indolyl)methanes synthesis described is based on the activation of the electrophile aldehyde rather than the nucleophile indole. If the synthesis of such compounds can be achieved by activation of the nucleophile, then we hypothesize the substrate scope can be expanded to include other electron-rich aromatics such as naphthol.

Imidazolium salts (and analogues) have been studied as organocatalysts for the double addition of alcohol to an aldehyde.[31, 32] In 2014, Tamamura and co-workers reported a simple method to access 3-substituted indoles employing an imidazolium salt that catalyzed Friedel-Crafts type conjugate additions.[33] The reactions were carried out under mild condition, without bases, solvents or formation of N-heterocyclic carbenes (NHCs). Through detailed mechanistic studies, the potential mechanism was explained through the dual activation of indole by the cation-π interaction of imidazolium cation with indoles and Lewis base activation by the chloride anion derived from the imidazolium salts. Although acidic imidazolium species have been used as catalysts to afford bis(indolyl)methanes, the mechanism is likely Brønsted acid mediated.[24, 34–36] To the best of our knowledge, the imidazolium salt-catalyzed direct addition process to simple ketones or aldehydes has not yet been reported by cation-π interactions. We thus set out to extend this reaction to efficiently construct bioactive bis(indolyl)methanes employing aldehydes as electrophiles (Fig 2).

thumbnail
Download:
Fig 2. Our strategy for bis(indolyl)methane synthesis.

https://doi.org/10.1371/journal.pone.0216008.g002

Results and discussion

We first undertook the screening of the azolium catalysts, including imidazolium, triazolium and thiazolium salts. Results from our catalyst evaluation are shown in Fig 3. In the absence of base, catalyst 1a and 1e afforded the desired product 4a in moderate yields (entries 1, 5), while only trace amounts of product were obtained with triazolium catalysts 1b, 1c and 1d (entries 2, 3, 4). The result shows that the nature of the azolium salts is critical: imidazolium and thiazolium salts are effective catalysts, whereas the triazolium salt proved to be unproductive. Based on these findings, we further investigated other reaction parameters, such as ammonium salts, solvent and base, in order to achieve a higher chemical yield. Examination of a range of ammonium salts revealed that ammonium chloride and tetrabutylammonium fluoride did not promote the reaction (entries 6, 7). The use of other solvents, such as tetrahydrofuran and dichloromethane, resulted in enhanced yields with dichloromethane affording the desired compound 4a in an impressive 95% isolated yield (entries 8, 10). The equivalent ratio of compounds 2 and 3 was adjusted to 2:1 that is a more proper condition for maximizing the usage of reagents and the yield remained unchanged (entry 11). The yield was greatly reduced under neat conditions (entry 9). The reaction was also found to be incompatible with an amine base such as 1,8-diazabicyclo [5.4.0]undec-7-ene (DBU), which led to generation of the N-heterocyclic carbene of 1a and provided 2-hydroxy-1,2-diphenylethanone as a major product through the process of benzoin reaction as reported previously and only trace amounts of the desired product (entry 12).[37] This result indicates that the weak alkalinity of indole does not induce NHC formation, unlike other organic bases. Thus the product is formed by a direct addition reaction (conjugate acid of DBU: pKa 12.0, conjugate acid of indole: pKa 0.4). As a negative control, we confirmed the reaction did not occur in the absence of the catalyst 1a (entry 14). Decreasing the catalyst loading from 10 mol% to 5 mol% reduced the yield from 95% to 83% (entry 15) demonstrating 10 mol% is required to achieve optimal conversion.

thumbnail
Download:
Fig 3. Optimization of the reaction conditionsa.

https://doi.org/10.1371/journal.pone.0216008.g003

a Reaction conditions: A mixture of aldehyde (0.11 mmol, 1.1 equiv), catalyst (10 mol%, 0.2 equiv), indole (0.20 mmol, 2.0 equiv), base (0.11 mmol, 1.1 equiv) in solvent (1.0 mL) was stirred at room temperature for 1h. b Isolated yield after flash chromatography (the yields were calculated based on the equivalent of indole). c The amount of aldehyde used is 0.10 mmol (1.0 equiv). d The yield in parentheses is the yield of the benzoin reaction. e The amount of catalyst 1a is 5 mol%.

With the optimal conditions in hand, we next sought to explore the scope of the aldehydes in this new imidazolium salt-catalyzed Friedel-Crafts type reaction. As shown in Fig 4, a diverse array of electron-donating and electron-withdrawing benzaldehydes with a variety of functional groups (ethyl, phenyl, halide, hydroxyl, methoxy, phenoxy, nitro and cyano) performed well in this dual-addition reaction. The corresponding products (4b–4g) were isolated in excellent yields ranging from 85–96%. Notably, this method was compatible with aliphatic aldehydes (heptanal, cyclohexylcarbaldehyde, pyruvaldehyde), giving the desired products in moderate yields (4k–4m). Moreover, even unsaturated aldehyde substrates (cinnam aldehyde, citral) reacted through selective addition to carbonyl groups over conjugate addition (4n and 4o). However, acrolein can give a triindole substituted product through conjugate addition and direct addition. While our method is effective for alkyl and aromatic/heterocyclic aldehydes, it fails for formaldehyde, acetaldehyde and acetophenone.

thumbnail
Download:
Fig 4. Scope of aldehydesa.

https://doi.org/10.1371/journal.pone.0216008.g004

a Reaction conditions: A mixture of aldehyde (0.5 mmol, 1.0 equiv), catalyst (10 mol%, 0.2 equiv), indole (1.0 mmol, 2.0 equiv), in solvent (5.0 mL) was stirred at room temperature for 1h. b Isolated yield after flash chromatography. c The amount of indole used is 1.5 mmol.

The generality of the reaction with respect to the substituents on the indoles was also investigated (Fig 5). The methyl-substituted indoles at the 1- or 2-position did not affect the reaction due to the protection of the nitrogen or steric hindrance. On the contrary, the corresponding products were afforded in high yields (5a and 5b). Surprisingly, the 3-methyl indole provided an addition product at the 1-position in a moderate yield (5c). The result differs from the known method of regioselectively producing (2,2′-bis-3-methylindolyl)methanes using ionic liquids under microwave irradiation condition, [38] possibly due to the catalytic process mediated by the cation-π interaction of an indole/imidazolium complex. The structure of 5c was determined by two dimensional NMR (HSQC, HMBC. S1 File). Both electron-donating and electron-withdrawing substituents were accommodated on the indole ring furnishing excellent yields (5d–5f). 1-Naphthol was also explored as alternate nucleophilic substrate and yielded 5g through a dual-addition reaction at the C2 and C4 of 2-naphthol, respectively. The product was confirmed by comparison to the reported NMR data for this compound, prepared through an alternate route.[39]

thumbnail
Download:
Fig 5. Scope of indoles and naphtholsa, b.

https://doi.org/10.1371/journal.pone.0216008.g005

a Reaction conditions: A mixture of aldehyde (0.5 mmol, 1.0 equiv), catalyst (10 mol%, 0.2 equiv), indole (1.0 mmol, 2.0 equiv), in solvent (5.0 mL) was stirred at room temperature for 1h. b Isolated yield after flash chromatography.

Meanwhile, we used this method to synthesize the natural product arsindoline A. Although the reaction time was prolonged and the yield was moderate, this effectively expands the scope of heterocyclic substrate. (Fig 6)

thumbnail
Download:
Fig 6. Synthesis of arsindoline A.

https://doi.org/10.1371/journal.pone.0216008.g006

In their previous report, Tamamura and co-workers showed that imidazolium salts activated indoles through a cation-π interaction by 1H NMR and deuterium labeling studies.[33] To confirm the imidazolium salts were not activating benzaldehyde, we monitored the chemical shift of the C2 proton of the imidazolium salt and the CHO proton of the aldehyde. However, a significant change was not observed by 1H NMR (Fig 7) indicating the aldehyde did not interact with the imidazolium salts.

thumbnail
Download:
Fig 7.

1H-NMR investigation of the interaction of IMesCl (1a) and benzaldehyde (3) in CDCl3.

https://doi.org/10.1371/journal.pone.0216008.g007

A plausible reaction mechanism is shown in Fig 8. Based on the results of Tamamura’s mechanistic studies, we propose a catalytic process involving cation–π interaction of an indole/imidazolium complex, which increases the acidity of the indole, enabling deprotonating of the complex by the chloride anion. The intermediate (1H-indol-3-yl)(aryl)methanol is expected to ionize to an indolylphenylmethyl cationic species based on literature precedent,[40–42] which rapidly reacts with another molecule of indole to furnish the isolated bis(indolyl)methanes products. The inability to isolate the intermediate (1H-indol-3-yl)(aryl)methanol suggests the second step is very rapid.

thumbnail
Download:
Fig 8. Proposed reaction mechanism.

https://doi.org/10.1371/journal.pone.0216008.g008

Conclusions

Although imidazolium salts are often used as precursors for NHC catalysts, the reaction of imidazolium salts as organocatalysts has rarely been applied. Herein, we have shown imidazolium salts provide a mild and efficient catalytic system for the electrophilic substitution reactions of indoles with a variety of carbonyl compounds to afford bis(indolyl)methanes. Furthermore, this method tolerates a wider substrate scope than other reactions to this important class of compounds and even allows utilization of 3-methyl-1H-indole and 1-naphthol nucleophiles. In summary, we have further expanded the reaction scope of imidazolium salt catalyzed dual activation addition reactions.

Materials and methods

4.1. General information

Chemicals, catalysts and solvents were purchased from commercial suppliers and used as received. 1H, 13C spectra were recorded on a Bruker AVANCE III 400 (400 MHz), JEOL ECZ 400S (400 MHz) spectrometer. Chemical shifts were reported in parts per million (ppm), and the residual solvent peak was used as an internal reference: proton (CDCl3 δ 7.26), carbon (CDCl3 δ 77.16) was used as a reference. Multiplicity was indicated as follows: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), dd (doublet of doublet), br s (broad singlet). Coupling constants were reported in Hertz (Hz). Coupling constants, J, are quoted in Hz and recorded to the nearest 0.1 Hz. Assignments (detailed in the supporting information) were confirmed using Distortionless Enhanced Polarisation Transfer NMR (DEPT 135) and two dimensional NMR Heteronuclear Single Quantum Coherence (HSQC) and Hetero-nuclear Multiple Bond Correlation (HMBC)) experiments gave information used to assign both the 1H NMR and 13C NMR spectra. High resolution mass spectrometry (HRMS) was performed using positive/negative electrospray ionisation (ESI+/ESI-), on Thermofisher Exactive Plus mass spectrometer. All m/z values are reported to 4 decimal places and are within ±5 ppm of theoretical values. Melting points were recorded on a Kofler hot block and are uncorrected. For thin layer chromatography (TLC), Merck pre-coated TLC plates (Merck 60 F254) were used, and compounds were visualized with a UV light at 254 nm. Flash chromatography separations were performed on Merck 60 (0.040–0.063 mm) mesh silica gel.

4.2. General procedure for the synthesis of bis(indolyl)methanes and bis(naphthyl)methane

An oven-dried 20 mL Schlenk flask was charged with triazolium salt (0.1 mmol, 0.2 equiv), indole derivatives or naphthol (1.0 mmol, 2.0 equiv). A solution of the aldehyde (0.5 mmol, 1.0 equiv, 5.0 mL, 0.1 M in CH2Cl2) was then added via syringe. The reaction mixture was stirred at room temperature for 1 h. Next, the reaction was quenched with water and the aqueous mixture was extracted with EtOAc (10 mL × 3). The extracts were combined, dried with MgSO4, and concentrated to afford the residue, which was chromatographed on silica gel (15 g, 20:1–3:1 PE/EA) to give bis(indolyl)methanes or bis(naphthyl)methane.

3,3'-(Phenylmethylene)bis(1H-indole) (4a). Condensation of indole and benzaldehyde using the general method afforded the title compound (154 mg, yield 95%) as a red solid. Rf = 0.30 (40:10 PE:EA); mp 139–140 oC, lit. mp 141–142 oC [43]; 1H NMR (400 MHz, CDCl3) δ 5.89 (1H, s), 6.67 (2H, dd, J = 2.4, 0.9 Hz), 7.00 (2H, td, J = 7.5, 1.0 Hz), 7.19 (2H, t, J = 7.9 Hz), 7.22–7.25 (1H, m), 7.28–7.30 (2H, m), 7.34–7.39 (4H, m), 7.40–7.43 (2H, m), 7.90 (2H, br s); 13C NMR (100 MHz, CDCl3) δ 40.2, 111.0, 119.3, 119.8, 120.0, 121.9, 123.6, 126.2, 127.1, 128.2, 128.7, 136.7, 144.0; HRMS (ESI+) calcd for C23H19N2 [M+H]+ 323.1543, found 323.1531 (error 3.7 ppm). All spectroscopic data were in agreement with the literature values. [20]

3,3'-((4-Ethylphenyl)methylene)bis(1H-indole) (4b). Condensation of indole and benzaldehyde using the general method afforded the title compound (168 mg, yield 96%) as a white solid. Rf = 0.33 (40:10 PE:EA); mp 161–163 oC; 1H NMR (400 MHz, CDCl3) δ 1.22 (3H, t, J = 8.5 Hz), 2.61 (2H, q, J = 8.5 Hz), 5.86 (1H, s), 6.66 (2H, s), 7.00 (2H, t, J = 7.5 Hz), 7.11 (2H, d, J = 9.0 Hz), 7.18 (2H, t, J = 7.5 Hz), 7.26 (2H, d, J = 9.0 Hz), 7.35 (2H, d, J = 7.5 Hz), 7.40 (2H, d, J = 7.5 Hz), 7.86 (2H, br s); 13C NMR (100 MHz, CDCl3) δ 15.5, 28.5, 39.8, 111.0, 119.2, 119.99, 120.01, 121.9, 123.6, 127.1, 127.7, 128.6, 136.7, 141.2, 141.9; HRMS (ESI+) calcd for C25H23N2 [M+H]+ 351.1840, found 351.1855 (error 4.3 ppm).

3,3'-([1,1'-Biphenyl]-4-ylmethylene)bis(1H-indole) (4c). Condensation of indole and benzaldehyde using the general method afforded the title compound (183 mg, yield 92%) as a pink solid. Rf = 0.34 (40:10 PE:EA); mp 230–232 oC, lit. mp 241–243 oC [44]; 1H NMR (400 MHz, CDCl3) δ 5.94 (1H, s), 6.62–6.67 (2H, m), 7.02 (2H, t, J = 8.0 Hz), 7.18 (2H, t, J = 7.6 Hz), 7.32 (1H, t, J = 7.3 Hz), 7.34–7.39 (3H, m), 7.40–7.48 (5H, m), 7.52 (2H, d, J = 8.9 Hz), 7.59 (2H, d, J = 8.9 Hz), 7.92 (2H, br s); 13C NMR (100 MHz, CDCl3) δ 39.9, 111.1, 119.3, 119.7, 120.0, 122.0, 123.6, 126.95, 126.99 (2C), 127.1, 128.7, 129.1, 136.7, 138.9, 141.1, 143.2; HRMS (ESI-) calcd for C29H21N2 [M−H]− 397.1684, found 397.1699 (error 3.8 ppm). All spectroscopic data were in agreement with the literature values. [44]

3,3'-((2-Fluorophenyl)methylene)bis(1H-indole) (4d). Condensation of indole and benzaldehyde using the general method afforded the title compound (157 mg, yield 92%) as a red solid. Rf = 0.35 (40:10 PE:EA); mp 80–81 oC, lit. mp 77 oC [28]; 1H NMR (400 MHz, CDCl3) δ 6.24 (1H, s), 6.70 (2H, s), 6.98–7.04 (3H, m), 7.08 (1H, t, J = 9.2 Hz), 7.16–7.22 (4H, m), 7.36 (2H, d, J = 8.2 Hz), 7.41 (2H, d, J = 7.9 Hz), 7.89 (2H, br s); 13C NMR (100 MHz, CDCl3) δ 32.5(d, J = 4.1 Hz), 111.1, 115.3 (d, J = 22.4 Hz), 118.3, 119.3, 119.8, 122.0, 123.6, 123.9 (d, J = 3.5 Hz), 126.9, 127.8 (d, J = 8.1 Hz), 130.4 (d, J = 3.5 Hz), 130.9 (d, J = 14.0 Hz), 136.7, 160.7 (d, J = 245.9 Hz); HRMS (ESI+) calcd for C23H18FN2 [M+H]+ 341.1449, found 341.1437 (error 3.5 ppm). All spectroscopic data were in agreement with the literature values. [28]

3,3'-((2-Bromo-6-fluorophenyl)methylene)bis(1H-indole) (4e). Condensation of indole and benzaldehyde using the general method afforded the title compound (194 mg, yield 93%) as a red solid. Rf = 0.32 (40:10 PE:EA); mp 113–115 oC; 1H NMR (400 MHz, CDCl3) δ 6.27 (1H, s), 6.64 (2H, dd, J = 2.3, 1.0 Hz), 6.83 (1H, ddd, J = 8.7, 7.8, 3.1 Hz), 6.95 (1H, dd, J = 9.8, 3.1 Hz), 7.04 (2H, t, J = 7.2 Hz), 7.21 (2H, t, J = 7.2 Hz), 7.41–7.39 (4H, m), 7.51–7.61 (1H, m), 7.95 (2H, br s); 13C NMR (100 MHz, CDCl3) δ 39.8, 111.2, 115.2 (d, J = 22.4 Hz), 117.8 (d, J = 23.5 Hz), 117.9, 118.8 (d, J = 3.0 Hz), 119.5, 119.8, 122.2, 123.8, 126.9, 133.9 (d, J = 7.8 Hz), 136.8, 145.5 (d, J = 6.6 Hz), 162.1 (d, J = 245.8 Hz); HRMS (ESI+) calcd for C23H17FBrN2 [M+H]+ 419.2889, found 419.2894 (error 1.2 ppm).

3,3'-((3-Hydroxyphenyl)methylene)bis(1H-indole) (4f). Condensation of indole and benzaldehyde using the general method afforded the title compound (152 mg, yield 90%) as a red solid. Rf = 0.20 (40:10 PE:EA); mp 105–107 oC, lit. mp 100 oC [21]; 1H NMR (400 MHz, CDCl3) δ 5.35 (1H, s), 6.00 (1H, s), 6.78 (2H, d, J = 2.4 Hz), 6.86 (2H, t, J = 7.5 Hz), 7.02 (2H, t, J = 7.5 Hz), 7.13–7.23 (4H, m), 7.28 (4H, dd, J = 10.8, 8.4 Hz), 7.99 (2H, br s); 13C NMR (100 MHz, CDCl3) δ 35.9, 111.2, 116.7, 117.2, 119.6, 119.9, 120.8, 122.4, 123.6, 126.9, 128.1, 129.1, 130.0, 136.9, 154.6; HRMS (ESI+) calcd for C23H19N2O [M+H]+ 339.1483, found 339.1492 (error 2.7 ppm). All spectroscopic data were in agreement with the literature values. [21]

3,3'-((4-Methoxyphenyl)methylene)bis(1H-indole) (4g). Condensation of indole and benzaldehyde using the general method afforded the title compound (149 mg, yield 85%) as a pink solid. Rf = 0.35 (40:10 PE:EA); mp 213–215 oC, lit. mp 217–219 oC [28]; 1H NMR (400 MHz, CDCl3) δ 3.79 (3H, s), 5.84 (1H, s), 6.65 (2H, dd, J = 2.4, 1.0 Hz), 6.81–6.84 (2H, m), 6.97–7.02 (2H, m), 7.14–7.20 (2H, m), 7.24–7.27 (2H, m), 7.34–7.36 (2H, m), 7.38–7.41 (2H, m), 7.88 (2H, br s); 13C NMR (100 MHz, CDCl3) δ 39.4, 55.2, 111.0, 113.6, 119.2, 120.0, 120.1, 121.9, 123.5, 127.1, 129.6, 136.2, 136.7, 157.9; HRMS (ESI-) calcd for C24H19N2O [M−H]− 351.1491, found 351.1482 (error 2.6 ppm). All spectroscopic data were in agreement with the literature values.[28]

3,3'-((3-Phenoxyphenyl)methylene)bis(1H-indole) (4h). Condensation of indole and benzaldehyde using the general method afforded the title compound (182 mg, yield 88%) as a red solid. Rf = 0.34 (40:10 PE:EA); mp 82–83 oC, lit. mp 84–86 oC [13]; 1H NMR (400 MHz, CDCl3) δ 5.87 (1H, s), 6.68 (2H, d, J = 2.4 Hz), 6.86 (1H, dd, J = 8.0, 2.4 Hz), 6.92 (2H, d, J = 8.0 Hz), 6.98–7.08 (4H, m), 7.09–7.22 (3H, m), 7.23–7.27 (3H, m), 7.35 (2H, d, J = 8.1 Hz), 7.40 (2H, d, J = 7.9 Hz), 7.89 (2H, br s); 13C NMR (100 MHz, CDCl3) δ 40.2, 111.1, 116.9, 118.3, 119.3, 119.4, 119.8, 119.9, 122.0, 122.8, 123.5, 124.0, 127.0, 129.5, 129.6, 136.7, 146.3, 156.9, 157.5; HRMS (ESI+) calcd for C29H23N2O [M+H]+ 415.1787, found 415.1805 (error 4.3 ppm). All spectroscopic data were in agreement with the literature values. [13]

3,3'-((4-Nitrophenyl)methylene)bis(1H-indole) (4i). Condensation of indole and benzaldehyde using the general method afforded the title compound (174 mg, yield 95%) as a red solid. Rf = 0.30 (40:10 PE:EA); mp 208–210 oC, lit. mp 222–224 oC [29]; 1H NMR (400 MHz, CDCl3) δ 6.00 (1H, s), 6.69 (2H, d, J = 2.4 Hz), 7.03 (2H, t, J = 7.5 Hz), 7.20 (2H, t, J = 7.6 Hz, 2H), 7.34 (2H, d, J = 8.0 Hz), 7.39 (2H, d, J = 8.1 Hz), 7.51 (2H, d, J = 8.3 Hz), 8.00 (2H, s), 8.14 (2H, d, J = 8.3 Hz); 13C NMR (100 MHz, CDCl3) δ 40.2, 111.3, 118.2, 119.58, 119.64, 122.4, 123.7 (2C), 126.7, 129.5, 136.7, 146.6, 151.8; HRMS (ESI-) calcd for C23H16N3O2 [M−H]− 366.1226, found 366.1237 (error 3.0 ppm). All spectroscopic data were in agreement with the literature values. [29]

3,3'-((4-Cyanophenyl)methylene)bis(1H-indole) (4j). Condensation of indole and benzaldehyde using the general method afforded the title compound (163 mg, yield 94%) as an orange solid. Rf = 0.32 (40:10 PE:EA); mp 209–210 oC, lit. mp 213–215 oC[29]; 1H NMR (400 MHz, CDCl3) δ 6.94 (1H, s), 6.66 (2H, d, J = 2.4 Hz), 7.03 (2H, t, J = 7.5 Hz), 7.20 (2H, t, J = 7.6 Hz, 2H), 7.33 (2H, d, J = 8.0 Hz), 7.38 (2H, d, J = 8.2 Hz), 7.45 (2H, d, J = 8.0 Hz), 7.57 (2H, d, J = 8.0 Hz), 7.98 (2H, s); 13C NMR (100 MHz, CDCl3) δ 40.4, 110.1, 111.3, 118.3, 119.2, 119.60, 119.63, 122.3, 123.7, 126.7, 129.5, 132.2, 136.7, 149.8; HRMS (ESI-) calcd for C24H16N3 [M−H]− 346.1324, found 346.1339 (error 4.3 ppm). All spectroscopic data were in agreement with the literature values. [16]

3,3'-(Heptane-1,1-diyl)bis(1H-indole) (4k). Condensation of indole and benzaldehyde using the general method afforded the title compound (140 mg, yield 85%) as a white solid. Rf = 0.33 (40:10 PE:EA); mp 74–75 oC, lit. mp 71–72 oC [45]; 1H NMR (400 MHz, CDCl3) δ 0.80–0.90 (3H, m), 1.24–1.44 (8H, m), 2.20–2.38 (2H, m), 4.48 (1H, t, J = 6.0 Hz), 6.99 (2H, d, J = 2.2 Hz), 7.04 (2H, t, J = 7.5 Hz), 7.15 (2H, t, J = 7.6 Hz), 7.33 (2H, d, J = 8.0 Hz), 7.61 (2H, d, J = 7.9 Hz), 7.86 (2H, br s); 13C NMR (100 MHz, CDCl3) δ 22.7, 28.3, 29.5, 31.8, 31.9, 34.0, 111.0, 119.0, 119.7, 120.7, 121.4, 121.7, 127.7, 136.6; HRMS (ESI-) calcd for C23H25N2 [M−H]− 329.1999, found 329.2012 (error 3.9 ppm). All spectroscopic data were in agreement with the literature values. [45]

3,3'-(Cyclohexylmethylene)bis(1H-indole) (4l). Condensation of indole and benzaldehyde using the general method afforded the title compound (136 mg, yield 83%) as a white solid. Rf = 0.35 (40:10 PE:EA); mp 115–117 oC, lit. mp 117–119 oC [23]; 1H NMR (400 MHz, CDCl3) δ 1.10–1.20 (3H, m), 1.22–1.26 (2H, m), 1.61–1.70 (3H, m), 1.79–1.86 (2H, m), 2.22–2.29 (1H, m), 4.48 (1H, d, J = 8.8 Hz), 7.05 (2H, t, J = 7.6 Hz), 7.10 (2H, d, J = 2.3 Hz), 7.13 (2H, t, J = 7.6 Hz), 7.31 (2H, d, J = 8.1 Hz), 7.66 (2H, d, J = 7.9 Hz), 7.88 (2H, br s); 13C NMR (100 MHz, CDCl3) δ 26.7, 26.7, 32.4, 40.2, 43.0, 111.0, 119.0, 119.69, 119.72, 121.5, 121.6, 127.8, 136.3; HRMS (ESI-) calcd for C23H23N2 [M−H]− 327.1842, found 327.1856 (error 4.3 ppm). All spectroscopic data were in agreement with the literature values. [23]

3,3'-(Acetylmethylene)bis(1H-indole) (4m). Condensation of indole and benzaldehyde using the general method afforded the title compound (93 mg, yield 65%) as a yellow solid. Rf = 0.31 (40:10 PE:EA); mp 111–113 oC; 1H NMR (400 MHz, CDCl3) δ 2.33 (3H, s), 5.57 (1H, s), 7.08–7.12 (4H, m), 7.20 (2H, t, J = 7.6Hz), 7.37 (2H, d, J = 8.1Hz), 7.55 (2H, d, J = 8.0Hz), 8.07 (2H, br); 13C NMR (100 MHz, CDCl3) δ 28.9, 48.1, 111.2, 113.6, 119.2, 119.7, 122.3, 123.3, 126.8, 136.3, 207.0; HRMS (ESI+) calcd for C19H17N2O [M+H]+ 289.1324, found 289.1335 (error 3.8 ppm). All spectroscopic data were in agreement with the literature values. [46]

(E)-3,3'-(3-(4-Fluorophenyl)prop-2-ene-1,1-diyl)bis(1H-indole) (4n). Condensation of indole and benzaldehyde using the general method afforded the title compound (159 mg, yield 87%) as a yellow solid. Rf = 0.33 (40:10 PE:EA); mp 125–127 oC; 1H NMR (400 MHz, CDCl3) δ 5.40 (1H, dd, J = 7.0, 1.2 Hz), 6.50 (1H, dd, J = 15.8, 1.2 Hz), 6.72 (1H, ddd, J = 15.8, 7.0, 0.5 Hz), 6.87–7.00 (4H, m), 7.09 (2H, t, J = 8.0 Hz), 7.19 (2H, t, J = 8.2 Hz), 7.27–7.36 (2H, m), 7.38 (2H, dt, J = 8.0, 0.9 Hz), 7.59 (2H, dq, J = 8.0, 0.9 Hz), 7.96 (2H, br s); 13C NMR (100 MHz, CDCl3) δ 37.5, 111.1, 115.3 (d, J = 21.4 Hz), 118.4, 119.3, 112.0, 122.0, 122.5, 127.0, 127.8 (d, J = 8.0 Hz), 128.8, 132.1 (d, J = 2.1 Hz), 133.9 (d, J = 3.0 Hz), 136.7, 162.0 (d, J = 245.9 Hz); HRMS (ESI-) calcd for C25H18N2F [M−H]− 365.1439, found 365.1449 (error 2.7 ppm).

(E/Z)-3,3'-(3,7-Dimethylocta-2,6-diene-1,1-diyl)bis(1H-indole) (4o). Condensation of indole and benzaldehyde using the general method afforded the title compound (149 mg, yield 81%, E/Z 3:2) as a yellow solid. Rf = 0.35 (40:10 PE:EA); mp 101–103 oC; 1H NMR (400 MHz, CDCl3) δ 1.56 and 1.60 (3H, s), 1.62 and 1.68 (3H, s), 1.80 and 1.85 (3H, s), 2.12–2.33 (4H, m), 5.12–5.15 (1H, m), 5.37–5.42 (1H, m), 5.72–5.77 (1H, m), 6.86–6.95 (2H, m), 7.01–7.08 (2H, m), 7.12–7.19(2H, m), 7.31–7.38 (2H, m), 7.52–7.58 (2H, m), 7.86 (2H, br s); 13C NMR (100 MHz, CDCl3) δ 16.4 and 17.8, 17.9 and 18.4, 23.5 and 25.9, 25.8 and 26.7, 32.4 and 33.3, 33.1 and 39.8, 111.2, 119.06 and 119.08, 119.8 and 120.0, 120.0 and 120.2, 121.78 and 121.81, 122.15 and 122.17, 124.5 and 124.6, 127.1 and 127.2, 128.1 and 128.6, 131.5 and 131.8, 134.6 and 134.8, 136.80 and 136.82; HRMS (ESI+) calcd for C26H29N2 [M+H]+ 369.2311, found 369.2325 (error 3.8 ppm).

3,3',3''-(Propane-1,1,3-triyl)tris(1H-indole) (4p). Condensation of indole and benzaldehyde using the general method afforded the title compound (177 mg, yield 83%) as a yellow solid. Rf = 0.31 (40:10 PE:EA); mp 179–181 oC, lit. mp 180–185 oC [47]; 1H NMR (400 MHz, CDCl3) δ 2.63–2.70 (2H, m), 2.86–2.91 (2H, m), 4.58–4.63 (1H, m), 6.93–6.94 (1H, m), 7.00–7.11 (5H, m), 7.14–7.20 (3H, m), 7.32–7.36 (3H, m), 7.50–7.58 (3H, m), 7.86 (1H, br s), 7.90 (2H, br s); 13C NMR (100 MHz, CDCl3) δ 23.8, 33.7, 35.9, 110.95, 111.00, 116.8, 119.00, 119.02, 119.1, 119.7, 120.2, 121.1, 121.5, 121.7, 121.8, 127.1, 127.6, 136.3, 136.6; HRMS (ESI+) calcd for C27H24N3 [M+H]+ 390.1951, found 390.1964 (error 3.3 ppm). All spectroscopic data were in agreement with the literature values.[47]

3,3'-(Phenylmethylene)bis(1-methyl-1H-indole) (5a). Condensation of indole and benzaldehyde using the general method afforded the title compound (146 mg, yield 83%) as a pink solid. Rf = 0.61 (40:10 PE:EA); mp 181–183 oC, lit. mp 180–183 oC [48]; 1H NMR (400 MHz, CDCl3) δ 3.69 (6H, s), 5.90 (1H, s), 6.55 (2H, s), 6.99–7.03 (2H, m), 7.18–7.25 (3H, m), 7.27–7.32 (4H, m), 7.32–7.42 (4H, m); 13C NMR (100 MHz, CDCl3) δ 32.7, 40.1, 109.1, 118.3, 118.7, 120.1, 121.4, 126.0, 127.5, 128.2, 128.3, 128.7, 137.4, 144.5; HRMS (ESI-) calcd for C25H21N2 [M−H]− 349.1690, found 349.1699 (error 2.6 ppm). All spectroscopic data were in agreement with the literature values. [48]

3,3'-(Phenylmethylene)bis(2-methyl-1H-indole) (5b). Condensation of indole and benzaldehyde using the general method afforded the title compound (161 mg, yield 92%) as a pink solid. Rf = 0.39 (40:10 PE:EA); mp 249–250 oC, lit. mp 257–258 oC [49]; 1H NMR (400 MHz, CDCl3) δ 2.06 (6H, s), 6.01 (1H, s), 6.82–6.88 (2H, m), 6.98 (2H, d, J = 8.7Hz), 7.02–7.08 (2H, m), 7.20–7.30 (8H, m), 7.72 (2H, br s); 13C NMR (100 MHz, CDCl3) δ 12.5, 39.2, 110.0, 113.4, 119.1, 119.4, 120.6, 126.0, 128.1, 129.0, 129.1, 131.8, 135.0, 143.7; HRMS (ESI-) calcd for C25H21N2 [M−H]− 349.1690, found 349.1699 (error 2.6 ppm). All spectroscopic data were in agreement with the literature values. [49]

1,1'-(Phenylmethylene)bis(3-methyl-1H-indole) (5c). Condensation of indole and benzaldehyde using the general method afforded the title compound (110 mg, yield 63%) as a white solid. Rf = 0.55 (40:10 PE:EA); mp 110–112 oC; 1H NMR (400 MHz, CDCl3) δ 2.26 (6H, s), 6.58 (2H, s), 7.03–7.10 (2H, m), 7.12–7.18 (4H, m), 7.20–7.24 (2H, m), 7.26–7.27 (1H, m), 7.30–7.37 (3H, m), 7.56–7.62 (2H, m), 7.87 (1H, s); 13C NMR (100 MHz, CDCl3) δ 9.8, 68.5, 109.5, 112.0, 119.3, 119.8, 122.3, 123.0, 127.3, 129.0, 129.1, 129.5, 136.4, 137.1; HRMS (ESI+) calcd for C25H23N2 [M+H]+ 351.1843, found 351.1855 (error 3.4 ppm).

3,3'-(Phenylmethylene)bis(7-bromo-1H-indole) (5d). Condensation of indole and benzaldehyde using the general method afforded the title compound (228 mg, yield 95%) as a pink solid. Rf = 0.32 (40:10 PE:EA); mp 239–241 oC; 1H NMR (400 MHz, CDCl3) δ 5.80 (1H, s), 6.63 (2H, dd, J = 2.3, 1.3 Hz), 7.03–7.11 (2H, m), 7.20 (2H, d, J = 8.3Hz), 7.27–7.30 (5H, m), 7.51 (2H, d, J = 2.3Hz), 7.93 (2H, br); 13C NMR (100 MHz, CDCl3) δ 40.0, 114.0, 115.7, 119.7, 121.1, 122.7, 124.1, 125.9, 126.5, 128.4, 128.6, 137.5, 143.3; HRMS (ESI+) calcd for C25H15N2Br2 [M+H]+ 478.9568, found 478.9576 (error 1.7 ppm).

3,3'-(Phenylmethylene)bis(5-methoxy-1H-indole) (5e). Condensation of indole and benzaldehyde using the general method afforded the title compound (177 mg, yield 93%) as a white solid. Rf = 0.35 (40:10 PE:EA); mp 213–215 oC, lit. mp 218–220 oC [20]; 1H NMR (400 MHz, CDCl3) δ 3.69 (6H, s), 5.77 (1H, s), 6.66–6.67 (2H, m), 6.79–6.80 (2H, m), 6.82 (1H, d, J = 2.5 Hz), 6.84 (1H, d, J = 2.5 Hz), 7.20–7.22 (1H, m), 7.23–7.25 (2H, m), 7.27–7.30 (2H, m), 7.32–7.36 (2H, m), 7.81 (2H, br s); 13C NMR (100 MHz, CDCl3) δ 40.3, 55.9, 102.0, 111.7, 111.9, 119.3, 124.4, 126.1, 127.5, 128.2, 128.7, 131.9, 143.9, 153.7; HRMS (ESI+) calcd for C25H23N2O2 [M+H]+ 383.1740, found 383.1754 (error 3.7 ppm). All spectroscopic data were in agreement with the literature values. [20]

3,3'-(Phenylmethylene)bis(1H-indole-5-carbonitrile) (5f). Condensation of indole and benzaldehyde using the general method afforded the title compound (171 mg, yield 94%) as a pink solid. Rf = 0.32 (40:10 PE:EA); mp 243–244 oC, lit. mp 241–243 oC [27]; 1H NMR (400 MHz, CDCl3) δ 5.83 (1H, s), 6.81 (2H, dd, J = 2.5, 1.2 Hz), 7.26–7.30 (5H, m), 7.40–7.46 (4H, m), 7.66 (2H, d, J = 2.5 Hz), 8.41 (2H, br s); 13C NMR (100 MHz, CDCl3) δ 40.0, 102.6, 112.2, 119.9, 120.7, 125.2, 125.5, 125.6, 126.6, 127.0, 128.4, 128.7, 138.4, 142.3; HRMS (ESI+) calcd for C25H17N4 [M+H]+ 373.1442, found 373.1448 (error 1.6 ppm).

2-((4-Hydroxynaphthalenyl)(phenyl)methyl)naphthalen-1-ol (5g). Condensation of 1-naphthanol and benzaldehyde using the general method afforded the title compound (126 mg, yield 67%) as a white solid. Rf = 0.37 (10:10 PE:EA); mp 201–203 oC, lit. mp 205–206 oC [39]; 1H NMR (400 MHz, CDCl3) δ 5.34 (1H, br s), 5.64 (1H, br s), 6.42 (1H, s), 6.70 (1H, d, J = 7.8 Hz), 6.87 (1H, d, J = 7.8 Hz), 6.97 (1H, d, J = 9.5 Hz), 7.19–7.23 (2H, m), 7.25–7.38 (4H, m), 7.39–7.42 (1H, m), 7.44–7.50 (3H, m), 7.75–7.80 (1H, m), 7.90 (1H, d, J = 9.5 Hz), 8.13–8.17 (1H, m), 8.28 (1H, d, J = 11.4 Hz); 13C NMR (100 MHz, CDCl3) δ 48.0, 107.9, 120.4, 121.6, 122.5, 123.6, 124.2, 125.1, 125.1, 125.2, 125.4, 126.0, 127.1 (2C), 127.4, 127.6, 128.1, 128.9, 129.7, 130.1, 133.0, 133.7, 142.3, 148.8, 151.3; HRMS (ESI+) calcd for C27H21O2 [M+H]+ 377.1527, found 377.1536 (error 2.4 ppm). All spectroscopic data were in agreement with the literature values. [39]

4-(di(1H-indol-3-yl)methyl)quinoline (arsindoline A). Condensation of quinoline-4-carbaldehyde and indole using the general method afforded the title compound (114 mg, yield 61%) as a yellow solid. Rf = 0.54 (10:20 PE:EA); mp 169–170 oC, lit. mp 164–168 oC [50]; 1H NMR (500 MHz, CDCl3) δ 6.55 (s, 2H), 6.66 (s, 1H), 7.03 (t, J = 7.7 Hz, 2H), 7.15 (d, J = 4.5 Hz, 1H), 7.20 (t, J = 7.7 Hz, 2H), 7.35–7.40 (m, 4H), 7.43 (t, J = 7.7 Hz, 1H), 7.67 (t, J = 7.7 Hz, 1H), 8.13–8.17 (m, 4H), 8.73 (d, J = 4.5 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 35.6, 111.4, 117.6, 119.5 (2C), 121.1, 122.3, 124.3, 124.5, 126.7, 126.8, 127.5, 129.1, 129.9, 136.8, 148.4, 150.0, 150.4.; HRMS (ESI+) calcd for C26H20N3 [M+H]+ 374.1652, found 374.1658 (error 1.6 ppm). All spectroscopic data were in agreement with the literature values. [50]

Supporting information

S1 File. The file includes both the 1H NMR and 13C NMR spectra of all compounds and the two dimensional NMR spectra of compound 5c.

https://doi.org/10.1371/journal.pone.0216008.s001

(DOCX)

Acknowledgments

The authors would like to thank Professor Wenyi He for use of NMR instrumentation, Professor Leilei Zhang for help on HRMS instrumentation.

References

  1. 1. Shiri M, Zolfigol MA, Kruger HG, Tanbakouchian Z. Bis- and Trisindolylmethanes (BIMs and TIMs). Chem Rev. 2010;110(4):2250–93. pmid:20041637
  2. 2. Gupta L, Talwar A, Chauhan PM. Bis and tris indole alkaloids from marine organisms: new leads for drug discovery. Curr Med Chem. 2007;14(16):1789–803. pmid:17627517.
  3. 3. Afzali MF, Popichak KA, Burton LH, Klochak AL, Wilson WJ, Safe S, et al. A novel diindolylmethane analog, 1,1-bis(3'-indolyl)-1-(p-chlorophenyl) methane, inhibits the tumor necrosis factor-induced inflammatory response in primary murine synovial fibroblasts through a Nurr1-dependent mechanism. Mol Immunol. 2018;101:46–54. pmid:29870816.
  4. 4. Caspar Y, Jeanty M, Blu J, Burchak O, Le Pihive E, Maigre L, et al. Novel synthetic bis-indolic derivatives with antistaphylococcal activity, including against MRSA and VISA strains. J Antimicrob Chemother. 2015;70(6):1727–37. pmid:25691323.
  5. 5. Gul W, Hamann MT. Indole alkaloid marine natural products: an established source of cancer drug leads with considerable promise for the control of parasitic, neurological and other diseases. Life Sci. 2005;78(5):442–53. pmid:16236327; PubMed Central PMCID: PMCPMC4918921.
  6. 6. Cai SX, Li DH, Zhu TJ, Wang FP, Xiao X, Gu QQ. Two New Indole Alkaloids from the Marine-Derived Bacterium Aeromonas sp. CB101. Helvetica Chimica Acta. 2010;93(4):791–5.
  7. 7. Kobayashi M, Aoki S, Gato K, Matsunami K, Kurosu M, Kitagawa I. Marine natural products. XXXIV. Trisindoline, a new antibiotic indole trimer, produced by a bacterium of Vibrio sp. separated from the marine sponge Hyrtios altum. Chem Pharm Bull (Tokyo). 1994;42(12):2449–51. pmid:7697760.
  8. 8. Bell R, Carmeli S, Sar N. Vibrindole A, a metabolite of the marine bacterium, Vibrio parahaemolyticus, isolated from the toxic mucus of the boxfish Ostracion cubicus. J Nat Prod. 1994;57(11):1587–90. pmid:7853008.
  9. 9. Kamal A, Ali Qureshi A. Syntheses of some substituted di-indolylmethanes in aqueous medium at room temperature. Tetrahedron. 1963;19(4):513–20.
  10. 10. Li WS, Wang CH, Ko S, Chang TT, Jen YC, Yao CF, et al. Synthesis and evaluation of the cytotoxicities of tetraindoles: observation that the 5-hydroxy tetraindole (SK228) induces G(2) arrest and apoptosis in human breast cancer cells. J Med Chem. 2012;55(4):1583–92. pmid:22277074.
  11. 11. Fu C-W, Hsieh Y-J, Chang TT, Chen C-L, Yang C-Y, Liao A, et al. Anticancer efficacy of unique pyridine-based tetraindoles. Eur J Med Chem. 2015;104:165–76. pmid:26457743
  12. 12. Pillaiyar T, Köse M, Sylvester K, Weighardt H, Thimm D, Borges G, et al. Diindolylmethane Derivatives: Potent Agonists of the Immunostimulatory Orphan G Protein-Coupled Receptor GPR84. J Med Chem. 2017;60(9):3636–55. pmid:28406627
  13. 13. Yadav JS, Gupta MK, Jain R, Yadav NN, Reddy BVS. A practical synthesis of bis(indolyl)methanes employing boric acid. Monatsh Chem—Chemical Monthly. 2010;141(9):1001–4.
  14. 14. Ganesan A, Kothandapani J, Nanubolu JB, Ganesan SS. Oleic acid: a benign Bronsted acidic catalyst for densely substituted indole derivative synthesis. RSC Advances. 2015;5(36):28597–600.
  15. 15. Kamal A, Khan MN, Srinivasa Reddy K, Srikanth YV, Kaleem Ahmed S, Pranay Kumar K, et al. An efficient synthesis of bis(indolyl)methanes and evaluation of their antimicrobial activities. J Enzyme Inhib Med Chem. 2009;24(2):559–65. pmid:18951276.
  16. 16. Shaikh AC, Chen C. An Easy and Efficient Synthesis of Bisindolylmethanes and Tetraindolylmethane Tröger's Base Catatlyzed by AgBF4. J Chin Chem Soc. 2011;58(7):899–905.
  17. 17. Armstrong EL, Grover HK, Kerr MA. Scandium triflate-catalyzed nucleophilic additions to indolylmethyl Meldrum's acid derivatives via a gramine-type fragmentation: synthesis of substituted indolemethanes. J Org Chem. 2013;78(20):10534–40. pmid:24066671.
  18. 18. Roy S, Gajbhiye R, Mandal M, Pal C, Meyyapan A, Mukherjee J, et al. Synthesis and antibacterial evaluation of 3,3′-diindolylmethane derivatives. Med Chem Res. 2014;23(3):1371–7.
  19. 19. Merinos JP, Ruiz HL, Lopez Y, Lima SR. Synthesis of bis(indolyl)methanes Catalyzed by Triethylborane. Lett Org Chem. 2015;12(5):332–6. pmid:26120289; PubMed Central PMCID: PMCPMC4475781.
  20. 20. Mohapatra SS, Wilson ZE, Roy S, Ley SV. Utilization of flow chemistry in catalysis: New avenues for the selective synthesis of Bis(indolyl)methanes. Tetrahedron. 2017;73(14):1812–9.
  21. 21. Noland WE, Kumar HV, Flick GC, Aspros CL, Yoon JH, Wilt AC, et al. Hydrated ferric sulfate-catalyzed reactions of indole with aldehydes, ketones, cyclic ketones, and chromanones: Synthesis of bisindoles and trisindoles. Tetrahedron. 2017;73(27):3913–22.
  22. 22. Azizian J, Teimouri F, Mohammadizadeh MR. Ammonium chloride catalyzed one-pot synthesis of diindolylmethanes under solvent-free conditions. Catal Commun. 2007;8(7):1117–21.
  23. 23. Liao B-S, Chen J-T, Liu S-T. An Efficient Preparation of Bis(indole)methanes Catalyzed by Tetrakis[3,5-bis(trifluoromethyl)phenyl]borate Salts in Aqueous Medium. Synthesis. 2007;2007(20):3125–8. Epub 21.09.2007.
  24. 24. Yadav SJ, Reddy BVS, Sunitha S. Efficient and Eco‐Friendly Process for the Synthesis of Bis(1H‐indol‐3‐yl)methanes using Ionic Liquids. Adv Synth & Catal. 2003;345(3):349–52.
  25. 25. Mi X, Luo S, He J, Cheng J-P. Dy(OTf)3 in ionic liquid: an efficient catalytic system for reactions of indole with aldehydes/ketones or imines. Tetrahedron Lett. 2004;45(23):4567–70.
  26. 26. Bandgar BP, Shaikh KA. Molecular iodine-catalyzed efficient and highly rapid synthesis of bis(indolyl)methanes under mild conditions. Tetrahedron Lett. 2003;44(9):1959–61.
  27. 27. Rahimizadeh M, Bakhtiarpoor Z, Eshghi H, Pordel M, Rajabzadeh G. TiO2 nanoparticles: an efficient heterogeneous catalyst for synthesis of bis(indolyl)methanes under solvent-free conditions. Monatsh Chem—Chemical Monthly. 2009;140(12):1465–9.
  28. 28. Vaid R, Gupta M, Chambyal OS, Gupta R. SiO2-Diphenic acid: An efficient and recyclable heterogeneous catalyst for one-pot synthesis of bis-(indolyl)methane derivatives in liquid phase. J Chem Sci. 2015;127(6):987–97.
  29. 29. Chhattise P, Handore K, Horne A, Mohite K, Chaskar A, Dallavalle S, et al. Synthesis and characterization of Polyindole and its catalytic performance study as a heterogeneous catalyst. J Chem Sci. 2016;128(3):467–75.
  30. 30. Xie ZB, Sun DZ, Jiang GF, Le ZG. Facile synthesis of bis(indolyl)methanes catalyzed by alpha-chymotrypsin. Molecules. 2014;19(12):19665–77. pmid:25438078.
  31. 31. Myles L, Gathergood N, Connon SJ. The catalytic versatility of low toxicity dialkyltriazolium salts: in situ modification facilitates diametrically opposed catalysis modes in one pot. Chem Commun. 2013;49(46):5316–8. pmid:23646348
  32. 32. Myles L, Gore RG, Gathergood N, Connon SJ. A new generation of aprotic yet Brønsted acidic imidazolium salts: low toxicity, high recyclability and greatly improved activity. Green Chem. 2013;15(10):2740–6.
  33. 33. Narumi T, Tsuzuki S, Tamamura H. Imidazolium Salt‐Catalyzed Friedel–Crafts‐Type Conjugate Addition of Indoles: Analysis of Indole/Imidazolium Complex by High Level ab Initio Calculations. Asian J Org Chem. 2014;3(4):497–503.
  34. 34. Gu D-G, Ji S-J, Jiang Z-Q, Zhou M-F, Loh T-P. An Efficient Synthesis of Bis(indolyl)methanes Catalyzed by Recycled Acidic Ionic Liquid. Synlett. 2005;2005(06):0959–62.
  35. 35. Sadaphal SA, Shelke KF, Sonar SS, Shingare MS. Ionic liquid promoted synthesis of bis(indolyl) methanes. Cent Eur J Chem. 2008;6(4):622–6.
  36. 36. Choudhary S, Pandey K, Budania S, Kumar A. Functionalized ionic liquid-assisted chromatography-free synthesis of bis(indolyl)methanes. Mol Divers. 2017;21(1):155–62. pmid:28078549.
  37. 37. Flanigan DM, Romanov-Michailidis F, White NA, Rovis T. Organocatalytic Reactions Enabled by N-Heterocyclic Carbenes. Chem Rev. 2015;115(17):9307–87. pmid:25992594
  38. 38. Das PJ, Das J. Synthesis of aryl/alkyl(2,2′-bis-3-methylindolyl)methanes and aryl(3,3′-bis indolyl)methanes promoted by secondary amine based ionic liquids and microwave irradiation. Tetrahedron Lett. 2012;53(35):4718–20.
  39. 39. Koyama M, Takada A, Ueda T. Color Reaction of Benzaldehyde with 1-Naphthol in Concentrated Sulfuric Acid. Chem Pharm Bull (Tokyo). 1982;30(9):3239–43.
  40. 40. Guo QX, Peng YG, Zhang JW, Song L, Feng Z, Gong LZ. Highly enantioselective alkylation reaction of enamides by Bronsted-acid catalysis. Org Lett. 2009;11(20):4620–3. pmid:19746916.
  41. 41. Kogan NA. Stability of indolyphenylmethyl cations. Chemi Heterocyc Compd. 1980;16(4):373–6.
  42. 42. Kogan NA, Kul'bitskii GN. Structure of indolylphenylmethyl cations. Chem Heterocyc Compd. 1978;14(1):46–8.
  43. 43. Badigenchala S, Ganapathy D, Das A, Singh R, Sekar G. Iron(II) Chloride–1,1′-Binaphthyl-2,2′-diamine (FeCl2–BINAM) Complex Catalyzed Domino Synthesis of Bisindolylmethanes from Indoles and Primary Alcohols. Synthesis. 2014;46(01):101–9. Epub 04.11.2013.
  44. 44. Khazaei A, Zolfigol MA, Faal-Rastegar T. Ionic liquid tributyl (carboxymethyl) phosphonium bromide as an efficient catalyst for the synthesis of bis(indolyl)methanes under solvent-free conditions. J Chem Res. 2013;37(10):617–9.
  45. 45. Gopalaiah K, Chandrudu SN, Devi A. Iron-Catalyzed Oxidative Coupling of Benzylamines and Indoles: Novel Approach for Synthesis of Bis(indolyl)methanes. Synthesis. 2015;47(12):1766–74. Epub 13.02.2015.
  46. 46. Tang Q, Chen X, Tiwari B, Chi YR. Addition of Indoles to Oxyallyl Cations for Facile Access to α-Indole Carbonyl Compounds. Org Lett. 2012;14(7):1922–5. pmid:22455439
  47. 47. Shiri M, Zolfigol MA, Ayazi-Nasrabadi R. AlCl3 as a powerful catalyst for the one-pot preparation of 1,1,3-triheteroaryl compounds. Tetrahedron Lett. 2010;51(2):264–8.
  48. 48. Chinta BS, Baire B. Reactivity of indole-3-alkoxides in the absence of acids: Rapid synthesis of homo-bisindolylmethanes. Tetrahedron. 2016;72(49):8106–16.
  49. 49. Xiang J, Wang J, Wang M, Meng X, Wu A. One-pot total synthesis of streptindole, arsindoline B and their congeners through tandem decarboxylative deaminative dual-coupling reaction of amino acids with indoles. Org Biomol Chem. 2015;13(14):4240–7. pmid:25744588.
  50. 50. Jella RR, Nagarajan R. Synthesis of indole alkaloids arsindoline A, arsindoline B and their analogues in low melting mixture. Tetrahedron. 2013;69(48):10249–53.