Scheme 1: Examples of BIMs used for their medicinal properties.

In 2017, Müller and her research team showcased the ability of BIMs to operate as anti-inflammatory drugs by acting as GPR84 agonists . GPR84 is a protein-coupled receptor found in immune cells, which regulates a number of inflammatory processes, which can lead to inflammatory bowel disease or Alzheimer’s disease. Therefore, GPR84 agonists are used as medicine for the treatment of various inflammatory diseases, but they have been also linked to the reduction of leukemia cells, since the continuous expression of the GPR receptor can aggravate the symptoms of myeloid leukemia. In contrast to most GPR84 agonists which contain long alkyl chains, BIMs are not lipophilic molecules, which allow them to bind to the GPR receptor via an allosteric binding site and modulate GPR84’s rate of expression .

One application of BIMs, as referenced above, that is gaining attraction is the treatment of Crohn’s disease, which is an inflammatory bowel disease (IBD). Kang and his research team monitored the production of IL-8 and IL-1β, which are cytokines produced in response to inflammation, and they observed the reduction in the concentration of these cytokines, as well as, increased intestinal permeability and improved expression of tight junction proteins that control the polarity of cells when using DIM in Caco-2 human cells .

BIMs have also been linked with the therapy of various cancers with one of their most common applications being the treatment of breast cancer. Studies have shown that breast cancer is tied to the ratio of 16α-hydroxyestrone (16αOHE1) and 2-hydroxyestrone (2OHE1), which are products of the metabolism of the estrogen 17β-estradiol. BIMs can shift the process of estrogen metabolism towards the production of 2OHE1, thus reducing the risk for estrogen-sensitive cancers, especially in combination with tamoxifen, which is an estrogen receptor modulator used in the treatment of breast cancer . BIMs increase the efficacy of the antitumor activity of tamoxifen and reduce the side-effects that it can cause in the more sensitive subgroups of patients. Specifically, when DIM was used in tandem with tamoxifen, the ratio between 2OHE1/16αOHE1 increased up to 229%, as well as the concentration of the sex hormone binding globulin (SHBG) that inhibits the growth of breast cancer cells . DIM has also been found to initiate the expression of tumor suppressing proteins (ATM, p21, p27kip), which control cell growth and protect cells against ionizing radiation, which can cause DNA mutations, decreasing the overall risk of breast cancer .

The cytotoxicity of DIM and BIMs in general extends to other types of cancers as well, such as prostate cancer by being an androgen receptor (AR) agonist in LNCaP prostate cancer cells . DIM controls cell growth rates in AR-negative cells, while also targeting the mitochondria inducing apoptosis, which alleviates some of the symptoms of prostate cancer. The same apoptotic function can be observed in colon and pancreatic cancer, since BIMs (specifically DIM-C-pPhOCH3 (5)) can act as a Nur77 (Nuclear Receptor 4A1) antagonist, which modulates the life cycle of cells . The correlation between lower lung cancer risk and the consumption of cruciferous vegetables has also been showcased, due to the function of BIMs as oxidative stress inhibitors; however, the specific mechanism of action has yet to be determined .

This capability of BIMs to act as Nur77 antagonists, has resulted in their examination as potential anti-Parkinson’s disease drugs by halting the growth of brain tumor cells and inhibiting the expression of inflammatory genes . Since they can be administered orally, and they display satisfying distribution to the brain and plasma without leading to serious unwanted side effects, they have entered advanced stages of clinical trials as neuroprotective agents, presenting an attractive alternative to traditional anti-inflammatory and anti-Parkinson’s disease drugs .

With the increased drug resistance of bacteria to modern medicine, BIMs have emerged as an interesting alternative, due to their antibacterial and antiviral properties. BIMs function as selective antibacterial agents against several virulent Escherichia coli (E. coli) strains, which can cause many gut and urinary tract infections. They act by damaging DNA molecules and inhibiting their replication in bacteria, while also targeting the proteins that are responsible for bacterial cell division, such as FtsZ, which reduces the rate of bacterial growth in a reversible manner. BIMs have also been implemented against methicillin-resistant Staphylococcus aureus (MRSA), which is a drug-resistant bacterium that is usually encountered in health-care related environments . The mechanism of action involves the binding of BIMs to the penicillin-restricting protein PBP2a which inhibits the biosynthesis of the bacterial cell wall, making the treatment feasible without any toxicity to human cells .

The applications of BIMs have also been extended to agriculture, since there is a need for the development of new greener fungicidal and antiviral agents that can combat the more common plant diseases . One instance of their antiviral property being implemented in drug development involves the treatment of tobacco mosaic virus (TMV), which infects a great number of agricultural plants, causing great harm to production by evolving to resist most of the existing drugs. Thus, BIMs have emerged as a new natural alternative class of antiviral agents, surpassing commonly used drugs such as ribavirin that has been observed to damage the DNA strands of TMV, inhibiting their ability to multiply and cause damage to the plant. At the same time, they also display fungicidal activities against more than fourteen types of common fungi, such as Phytophthora alternaria, based on their DNA damaging properties with the thiourea derivative, showing the highest fungicidal activity .

The indole moiety is part of many natural products, agrochemicals, and pharmaceuticals. In medicinal chemistry, indole and its derivatives are considered important compounds, since they exhibit valuable pharmaceutical and biological activities. Among indole derivatives, bis(indolyl)methanes (BIMs) are profoundly interesting, due to their wide range of pharmaceutical properties. The most common approach involves the electrophilic substitution of various aldehydes and ketones by indoles, utilizing either protic or Lewis acids as catalysts. In 2010, Shiri published a review, where the majority of the acidic catalysts that have been employed for the synthesis of these compounds were presented . Since then, various alternative acids have been applied including protic acids, such as silica-bonded S-sulfonic acid , polyvinylsulfonic acid (PVSA) , kaolin-supported H2SO4, polyvinylpolypyrrolidone-supported triflic acid (PVPP.OTf) , ascorbic acid , phosphoric acid , benzenesulfonic acid , chitosan–SO3H (CTSA) , phthalimide-N-sulfonic acid (PISA) and SiO2-KHSO4 as well as Lewis acids, such as FeCl3, RuCl3·3H2O , AgNO3, glycerol and [Fe(III)-(salen)]Cl , Fe(DS)3·nH2O , Sc(OTf)3, B(C6F5)3 or PhSiCl3 and Cp2TiCl2. However, most of these reactions face some serious drawbacks, such as the requirement of large quantities of the catalyst due to present moisture or formation of adducts with the substrate, long reaction times, lower yields, and production of large amounts of toxic waste during work-up.

Scheme 2: Mechanisms for the synthesis of BIMs using protic or Lewis acids as catalysts.

Alternative processes, that limit environmental pollution and toxic byproducts, came to the forefront of research for the introduction of novel synthetic pathways in organic chemistry . Common organic syntheses require the use of harmful chemicals, such as toxic solvents, hazardous reagents, catalysts and reaction conditions, which contribute to environmental pollution and soil degradation . Wanting to enhance the sustainability and viability of these synthetic protocols, organic chemists have been opting towards the use of greener catalysts and solvents in drug development.

Chemists dream to perform reactions under solvent-free conditions, which provide a greener approach towards organic transformations. Nowadays, the use of solvent-free reaction conditions has been introduced as a popular alternative to common organic solvents for many different organic transformations. The lack of an organic solvent can result in improved yields and reaction rates, more facile work-up processes and reduced waste, which are among the goals of green chemistry.

Organocatalysis is the acceleration of chemical reactions with the use of small organic compounds, which do not contain any amounts of enzyme or inorganic elements . The benefits of solid acid catalysis render them as an appealing choice, compared to their liquid counterparts, due to their recyclability, ease of handling, and low cost . Carbon-based solid acid catalysts especially are an interesting catalyst class, because they display low corrosiveness, toxicity, and higher catalytic activity, while also being insoluble in most organic solvents. The large amount of strong acidic sites that are on the carbon-based solid acids enhance their catalytic ability, compared to traditional Lewis and protic acids .

The most common examples in literature for the reaction of the synthesis of BIMs under solvent-free conditions utilize either protic acids, such as camphorsulfonic acid (CSA) , diammonium hydrogen phosphate (DAHP) , Amberlyst 15 , P2O5/MeSO3H , p-sulfonic acid calix[4]arene , xanthan sulfuric acid (XSA) , H5PW10V2O40/pyridino-santa barbara amorphous-15 (SBA-15) , TiO2-SO42−, humic acid or Lewis acids, such as N-bromosuccinimide (NBS) , silica chloride , Ph3CCl , ZnO , La(NO3)3·6H2O , V(HSO4)3, Cu(ClO4)2·6H2O , Fe/Al pillared clay , trimethylsilyl chloride (TMSCl) , BiCl3-loaded montmorillonite K10 , ZrO2-MgO or CaO . Silica gel is an intriguing solid support, since it is a low cost, commercially available and non-hazardous support, that can be employed in tandem with various traditional catalysts . Some examples in literature are ZrOCl2·8H2O/SiO2, P2O5/SiO2, LiHSO4/SiO2, (PhCH2PPh3)+Br−/SiO2, H2SO4/SiO2, ZnCl2/SiO2, heteropoly-11-tungsto-1-vanadophosphoric acid, H4[PVV W11O40] (HPV) (20%) supported on natural clay (HPVAC-20) , V2O5/SiO2, strongly acidic cation exchange resin (Seralite SRC-120) or HCl/SiO2.

Scheme 3: Synthesis of bis(indolyl)methanes using DBDMH.

Scheme 4: Competition experiments and synthesis of bis(indolyl)methanes using DBDMH.

Scheme 5: Proposed mechanism for formation of BIM of using DBDMH.

Recently, halogen bonding (XB) interactions have emerged as an interesting alternative to hydrogen bonding, which constitute an indispensable type of non-covalent interaction utilized in several catalytic approaches . In 2008, Bolm introduced the use of perfluoroiodoalkanes as XB catalysts and the field gained widespread attention as an intriguing tool in the catalysis of various organic transformations that were previously considered unfeasible .

Scheme 6: Synthesis of bis(indolyl)methanes using I2.

Scheme 7: General reaction mechanism upon halogen bonding.

Scheme 8: Synthesis of bis(indolyl)methanes using I2, introduced by Ji.

Scheme 9: Synthesis of bis(indolyl)methanes using Br2 in CH3CN.

Scheme 10: Βidentate halogen-bond donors.

Scheme 11: Synthesis of bis(indolyl)methanes using bidentate halogen-bond donor 26.

Scheme 12: Proposed reaction mechanism.

Scheme 13: Synthesis of bis(indolyl)methanes using iodoalkyne as catalyst.

Scheme 14: Proposed reaction mechanism.

The most recent application of halogen bonding in the synthesis of BIMs was introduced in 2023 by Galathri et al., who employed an N-heterocyclic iod(az)olium salt as the monodentate catalyst . This approach utilized water as the reaction solvent and employed a low catalyst loading of just 0.5 mol %, while providing satisfying yields (60–96%) in just 1 hour. The employment of a green aqueous medium, the mild reaction conditions and the relatively broad substrate scope are some of the benefits that render this protocol more efficient than previous halogen-bonding methodologies .

Nanocatalysis has emerged over the last decades as a sustainable and green field of organic catalysis that offers unparalleled opportunities for chemical transformations that were previously deemed unfeasible. The use of nanoparticles, compounds with a cross section of less than 100 nm, exhibit various benefits, such as tailoring the scaffold of the catalyst, the recyclability of the nanocompounds, as well as the elevated catalytic activity offered. These benefits stem from their high surface area, that provides more active sites for the reactants to absorb into and collide with one another. With the new avenues offered by the advent of nanocatalysis, it did not take long for its application in the Friedel–Crafts arylation of indoles with aldehydes, since the development of more resource-efficient catalytic pathways for the synthesis of BIMs had received great interest from the scientific world .

In 2008, the first application of nanocatalysis for the synthesis of BIMs was introduced by Shailaja and her research group, utilizing a ceria/vinylpyridine nanocomposite as the catalyst . After repeated studies and experiments on the reaction between indole (11) and benzaldehyde (31), methanol emerged as the optimum solvent with the isolated product yield approaching 98%, after 1 hour, when 69 mg of the nanocomposite were added to the reaction mixture . The recovery of the nanocatalyst was feasible by simple filtration and it was found that its catalytic efficiency would not diminish even after 3 cycles . Several substituted indoles, aldehydes and ketones reacted in good yields (74–98%), with ketones requiring longer reaction rates of 3 hours, due to their lower reactivity. The electron-donating or withdrawing effects of the substituents of the benzene ring of the carbonyl groups did not affect this protocol, rendering its generality superior to many traditional approaches. However, the high catalyst loading raised some concerns over the environmental impact of this methodology and left room for improvements for newer approaches .

In 2009, Rahimizadeh et al. proposed the use of the nanometal oxide TiO2, which was already reported as an effective nanocatalyst for the promotion of various organic transformations . TiO2 nanoparticles are non-toxic, inexpensive and reusable compounds that are synthesized through a sol–gel method. This method involves gradually adding titanium tetra-n-butoxide to a solution of deionized water in ethanol and calcinating it to form the desired nanocompounds. 10 mol % of the nano-TiO2 heated at 80 °C, provided an optimum yield of 95% for the reaction of indole with benzaldehyde, under solvent-free conditions after just 3 minutes . With the optimum reaction conditions in hand, both aromatic and aliphatic aldehydes reached promising conversion rates of formed BIMs of 77–95%. Sterically hindered substituted aldehydes exhibited longer reaction times, while substituted indoles also showed no issue, reaching yields of 85% after 20 minutes of stirring. The nano-TiO2 catalyst was easily recovered by centrifugation, where it could be reused up to four times, without any reductions in product conversion. What holds back the efficiency of this nanocatalytic protocol is the application of conventional heating, as well as the use of a metal oxide at a significant quantity, which can be a water and soil pollutant .

Scheme 15: Optimized reaction conditions used by Ramshini.

Scheme 16: Activation of the carbonyl group by HPA/TPI-Fe3O4.

Both aliphatic and aromatic aldehydes faced no problems, reaching yields ranging from 65–98% of formed products with substituted indoles also showing exceptional reactivity, albeit no ketones were reported forming the respective BIMs, limiting the substrate scope. Therefore, the solvent-free conditions of the reaction, the low catalyst loading and the ability of its retrieval rendered this methodology a green alternative to traditional protocols, however, the costly requirement of conventional heating hinders industrial applications.

At the same time that Ramshini published her approach, Jahanshahi also introduced nano n-propylsulfonated γ-Fe2O3 (NPS-γ-Fe2O3), which constitutes a magnetically recyclable heterogeneous catalyst that works in the exact same manner as HPA/TPI-Fe3O4. Some small differences between the two methods were the ability of ketones to form the respective BIMs, when NPS-γ-Fe2O3 was employed in contrast to HPA/TPI-Fe3O4, while also using a milder heating at 80 °C. However, Ramshini’s protocol had shorter reaction times of 25 minutes instead of 1 to 5 hours and also the catalyst loading was significantly decreased at 0.06 mol %, instead of the 0.5 mol % needed for NPS-γ-Fe2O3. Other than these differences the mechanism of action, the received yields, the absence of solvent and the recoverability of the nanocompound were identical between these two studies .

In the same year, another solvent-free approach was introduced by Chen et al. that utilized sulfated zirconia nanoparticles to conduct the Friedel–Crafts reaction between indoles and aldehydes . In an effort to synthesize the sulfated zirconia nanocompounds, a new two-step precipitation method was developed. The first step involved the employment of zirconium oxychloride and its precipitation with ammonium hydroxide. In the second step, the formed zirconium hydroxide undergoes a sulfate impregnation, utilizing sulfuric acid in the presence of polyvinylpyrrolidone (PVP) as the surfactant, to prevent particle agglomeration, leading to the formation of the desired sulfated zirconia nanoparticles after a last calcination step. After obtaining the nanocompound, its catalytic activity was evaluated for several organic transformations, including the synthesis of BIMs. Diindolylphenylmethane (DIM) was obtained in a yield of 97%, when 30 mol % of the nanocatalyst was added after 24 hours of reaction time in solvent-free and room temperature conditions. In these optimized conditions, several aromatic aldehydes and indoles formed the respective BIMs in excellent yields (84–95%), without any noteworthy differences between the various carbonyl substrates. Indoles, substituted at the 2’ position, were much more reactive, leading to isolated product yields of around 95% just after 6 h. This protocol addressed the issue of conventional heating that the previous methodologies employed, while also maintaining the solvent-free character of the reaction, with the disadvantage of longer reaction times, a high amount of nanocatalyst utilized and a more restricted substrate scope .

Scheme 17: Synthesis of BIMs in the presence of nanoAg-Pt/SiO2-doped silicate.

In 2014, Chabukswar and his research group explored the activity of cadmium sulfide (CdS) nanotubes as heterogeneous nanocatalysts for the electrophilic condensation between aldehydes and indoles . The nanorods were obtained with a solvothermal technique, where thiourea and cadmium nitrate were mixed in ethylenediamine for 10 minutes and subsequently heated at 200 °C for 12 hours. After being centrifuged, washed with water and grinded in a mortar, they were ready to be tested in the model reaction of benzaldehyde with indole. The optimum product yield was reached with a catalyst amount of 5 mol %, as a further increase did not show any further enhancement, in reflux temperature (65 °C) conditions, with methanol emerging as the superior medium over other polar solvents. A wide range of aromatic aldehydes containing both electron-withdrawing and electron-donating substituents were employed with the former, improving the conversion rate of the formed BIM product to 90–95%, compared to the 85–87% of the latter after 15 minutes of reflux. The nanotube catalyst was retrieved with a simple filtration, utilizing ethyl acetate and was reused for four synthetic cycles, before there was a decrease in catalytic activity, which was attributed to deactivation of active sites of the nanorod. Once again, this method provided short reaction times with an efficiently recovered catalyst with the handicap of the necessity of conventional heating and an unfavorable solvent .

Scheme 18: Mechanism of action proposed by Khalafi-Nezhad et al.

In an effort to replace the widespread use of nano-iron oxides, which present issues, such as aggregation, and requires large amounts of capping agents to combat, Pratihar and his research group offered the alternative of iron oxalates for the nanocatalysis of BIMs, which, after thermal decomposition form Fe(ox)-Fe3O4 oxides . Metal oxalates in general are more stable nanoparticles than their oxide counterparts, while retaining their magnetic and catalytic properties preventing the aforementioned drawbacks. Compared to Ramshini’s protocol for the synthesis of BIMs however, a higher catalytic loading was required (5 mol %) and water was added as the solvent, with both approaches also requiring conventional heating of the resulting mixture at 100 °C. Reaction rates were also slightly lower, requiring 1 hour for aromatic aldehydes containing electron-withdrawing groups and upwards of 4 hours for electron-donating substituents compared to the 25 minute Ramshini’s protocol with the additional holdback of the lack of reactivity of aliphatic aldehydes and substituted indoles. The recyclability of the nanocompound was satisfactory, since it could be reused for at least 5 times, before a slight drop in conversion rates was observed. However, due to the choice of water as the solvent, insoluble product clamps were formed, which led to a more complex recovery of the catalyst as firstly the water needed to be removed by decantation and next acetone was added so that the BIMs were dissolved and the nanoparticles could be retrieved with the use of a tiny magnet. All in all, while the iron oxalates combatted some disadvantages of the use of iron oxides, the catalytic approach presented had handicaps that held back its broader applications .

Scheme 19: Activation of the carbonyl group by the Cu–isatin Schiff base complex.

At the same time, Yavari and his research group also studied the use of hexamine, in place of NPS-γ-Fe2O3, immobilized on Fe3O4 and coated with SiO2. This protocol, while employing the identical optimum reaction conditions with Ramshini’s method, managed to reduce the reaction times to 10 minutes with 10 mg of the catalyst and could also facilitate the reaction of ketones. This improved upon the previously known nano-iron oxide methodologies without sacrificing their already satisfying product yields, the recyclability of the nanocatalyst or their environmentally benign aspects, such as the solvent-free conditions without, however, addressing the need for conventional heating that still presented an issue .