1. Introduction

The name indole is portmanteau of the words indigo and oleum since indole was first isolated by treatment of the indigo dye with oleum. The word indole is coined from the word India, a blue dye imported from India known as Indigo. Indigo can be converted to isatin, and then to oxindole [1]. Indole derivatives represent one of the most important heterocyclic rings which provide privileged scaffolds in drug discovery and medicinal chemistry. The substituted indole nucleus [2-4] is an important structural component of vast number of biologically active natural products such as heteroauxin [5-8], tryptophan [9-15], hypaphorine [16, 17], bufotenin [18], and gramine [19,20], etc. Indole derivatives are also found widely in plants, animals, and marine organisms [21]. Moreover, the structure and activity of bisindole alkaloids have been reported and the investigation of isolated bisindole alkaloids are increasing day by day [22-27]. Bisindole natural products [28-32] consists of two monomeric indole alkaloid scaffolds as their necessitate ingredients and are more effective with regard to their respective monomeric units. In addition, establishing new protocols towards the bisindoles synthesis are more challengeable than the synthesis of monomeric indole alkaloids [33-35]. Among bisindoles, the N, N’-bisindoles are extremely rare and still there is a need to be explored in this area as very few synthetic methodologies have been reported. As the isolated alkaloids containing rare N, N’-bisindoles motif (2, 3) are increasing (Figure 1) [36, 37], we have decided to review the literature reports on the synthesis of N, N’-bisindoles. The review cited the references till September 2022.

Figure 1. N, N’-bisindole nucleus containing natural products

2. Synthesis and Bioactivity

Although the N, N’-bisindole moiety was observed in a hypothetical intermediate during the oxidation of 3-indoleacetic acid over 60 years ago [38], synthesis for making this heterocyclic motif is not widely explored. In 2005, an anti-cancer bisindole natural product Schischkiniin (1) was isolated from seeds of the thistle Centaurea schischkinii by Sarker and co-workers [36]. This natural product possesses an extremely rare N, N’-linked bisindole motif embedded within a 14-membered macrocycle proposed to arise from dehydration of two Trp-Glydiketo piperazines followed by [2+2]-cycloaddition [39]. Schischkiniin (1) is assessed in DPPH assay for free radical scavenging properties, the general toxicity by brine shrimp lethality and cytotoxicity in MTT cytotoxicity assays using CaCo-2 colon cancer cell lines. It exhibited promising in vitro anticancer activity (IC₅₀=76 mM).

3. Miscellaneous Method of N, N’-Bisindole Synthesis

Koelsch [40] reported the formation of a compound, C₄₀H₂₈N₂O+C₆H₆ (from benzene-ethanol), m.p. 199-200 °C in 1944 by reacting 2, 3-diphenylindole (4) and potassium permanganate. However, no structure was assigned to that novel compound (Scheme 1). Almost a quarter century later Dave [41] characterized the product’s structure as a N, N’-dimer based on the analytical data, spectroscopic, and chemical evidence. The spectroscopic data of the compound (molecular ion m/e 536) included the diphenylindole chromophore (UV), only aromatic hydrogen atoms (NMR) and no NH group (IR). These spectral data suggested the probable linking of two diphenylindole molecules 5 by the nitrogen atoms. This was definitely the case revealed by reductive cleavage of nitrogen-nitrogen single bond by lithium aluminum hydride to afford only 2, 3-diphenylindole (7) as a product. The dimeric indole structure 5 was further supported by the reaction with m-chloroperbenzoic acid (m-CPBA) which gave the N-benzoyl-o-aminobenzophenone derivative 6.

Scheme 1. Characterization of structure of N, N′-dimer

Goyal et al. [42] have developed the synthesis of 3-carbaldehydebisindole (11) (Scheme 2) from the electrochemical oxidation of indole-3-methanol in persulfate-medium and phosphate buffers. In this oxidation, pyrolytic graphite electrode (PGE) was used and the electrode reaction underwent the ECE (Electron transfer -Chemical reaction- Electron transfer) mechanism. The following mechanism can be proposed for the oxidation of indole-3-methanol (9) using PGE on the basis of voltammetric behavior, spectral behavior, coulometry and product characterization. In the first step, a radical cation moiety (I) was formed from the oxidation of indole-3-methanol by losing 1e (single electron) step as depicted in Scheme 2. However, one electron was removed from the pyrrole -NH of indole which was already reported in oxidation of indole [43]. The cation radical (I) further deprotonated to give neutral free radical II as well as dimerized by losing two protons to afford a dimer 10. The participation of the free indolyl radical in this step was not completely ruled out in view of the pKa of the indolyl radical cation which is ~5.0 as reported in the literature [44]. Consequently, N–N linked dimer 10 was formed from the dimerization of radical cation. Then, the methanol group was oxidized via the ECE mechanism in a 2e, 2H⁺ process to provide the aldehydic dimer 11, which has been characterized by its mass and NMR spectra.

Scheme 2. Electrochemical synthesis of 3-carbaldehyde bisindole

Zang et al. [45] have established a novel N-N coupling reaction by treatment of the easily available rare-earth-metal (RE) amides [(Me₃Si)₂N]₃RE(μ-Cl)Li(THF)₃ with aromatic primary or secondary amines via oxidation of rare-earth-metal-nitrogen bonds produced. In this reaction, the symmetrical or unsymmetrical azo compounds and hydrazine derivatives were afforded under the mild conditions in good to high yields within a very short time. Using the yttrium amides [(Me₃Si)₂N]₃Y(μ-Cl)Li(THF)₃ complex N,N’-bisindole was synthesized via oxidation of yttrium-nitrogen bonds in good yield (Scheme 3).

The amino radical obtained from the oxidation of rare-earth-metal-nitrogen (RE-N) bonds is responsible for the N-N coupling reaction. This experiment is supported on the basis of isolation of the amido complex, characterized by using NMR and ESR probes of the intermediates.

Scheme 3. Synthesis of N, N’-bisindole through oxidation

In an another important invention, Kushmaro et al. [46] reported bisindole13 or a combination of 13 for the use in inhibiting biofilm [47-50] formation by bacteria on a surface or disrupting existing biofilm in medical and environmental settings.

An efficient palladium catalyzed one-pot domino reaction was reported by Halland et al. [51] with2-bromo phenyl acetylene and indol-1-amine gave N-indole substituted 2-phenylindoles in excellent yield (82%) (Scheme 4).

Scheme 4. Palladium catalyzed one-pot domino reaction to synthesize substituted N, N’-bisindole

Initially, N^’-aryl-N,N’-indole was formed through palladium catalyzed coupling between 2-bromo phenyl acetylene (14) and indol-1-amine (15), in this reaction which further underwent in situ “5-endo-dig” cyclization to obtain the desired 1-indol-1-yl-3-phenyl-indole (16). One of the synthetic precursor 1-aminoindoles of this palladium catalyzed domino synthesis was obtained from the reaction of readily available 2-halophenylacetylenes and N, N’-disubstituted hydrazines in good to excellent yields in just a few hours under mild reaction conditions with high functional group tolerance.

Recently, the first general synthetic approach to N, N’-bisindoles was reported by Wang et al. [52] using double Mori-Ban cyclization. Bisindolization of several diallylated hydrazobenzenes were affected by using simultaneous Mori–Ban reactions twice with minimal cleavage of the N–N bond (Scheme 5) under ambient temperature. The iodohydrozobenzene 18 was prepared from 2-iodonitrobenzene 17 by reduction with zinc metal. A series of diallylatedhydrazobenzenes 20 were afforded from two-steps allylation of 18 with various allyl bromides via monoallylated 19 that was later subjected to intramolecular, base-free, reductive Heck reaction condition produced bisindolization 21 in 24-63% yields. The methodology was used to access different 3,3’-dialkyl-N,N’-bisindoles (Figure 2, 21a-e), 3,3’-dibenzyl-N,N’-bisindoles (21f), and along with an unsymmetrical N,N’-bisindole (21e) in moderate to good yields which can be beneficial in future for synthesizing similar scaffolds.

Scheme 5. Synthetic approach to N, N’-bisindoles

Owing to its promising methodology, several attempts were made to the formal synthesis of Schischkiniin (1) [39], but the efforts went unsuccessful on final photochemical [2+2] cyclization step (Scheme 6).

Scheme 6. Synthetic Scheme of Schischkiniin (1)

Figure 2. N, N’-Bisindole derivatives synthesized by double Mori-Ban cyclization

The N, N’-bisindole 23 was constructed from diallylated hydrazobenzene (22) using two simultaneous Sakamoto’s modified Mori-Ban indolization reaction condition which gave access to the non-isomerized product in preference to the 3-substituted indole. Bromination of the N, N’-bisindoline with NBS produced the desired dibromide compound 24. Because of the associated instability of 24, the compound was subjected for hydrolysis as such without isolation to yield a stable 3, 3^’-dimethanol-N, N’-bisindole (25). The straightforward oxidation of 25 gave the desired dicarbaldehyde 26 followed by a double Horner-Wadsworth-Emmons (HWE) reaction using methyl 2-dimethoxyphosphorylpropanoate in the DBU presence and an excess of lithium chloride, produced the N,N’-bisdehydrotryptophan (27) in good yield. The palladium catalyzed hydrogenationin a non-stereoselective manner delivered N, N’-bistryptophan (28) in excellent yield as an inseparable 1:1 mixture of diastereomers. The amidation of bistryptophan compound was achieved using excess of amino acetaldehyde to give the desired bisamide 29 in 56% yields. After the successful synthesis of 29, several attempts were made to synthesize the bis cyclized intermediate 30 using various acids (HCl, H₂SO₄,TFA, and acetic acid) did not yield the desired product 30, rather it led to the extensive degradation of starting material 29. However, para-toluenesulfonicacid (p-TSA) did affect the cyclization of 29, affording bis-dihydropyrazinone (30) that had surprisingly retained the Boc groups. As such, a separate set of conditions was sought to cleave the Boc groups to the desired bis-dihydropyrazinone. Unfortunately, treatment of 30 with various acids gave none of the desired product 31 but led to extensive degradation. Similar attempts were made to cleave the Boc protecting group under thermal conditions failed to deliver 31. Finally, the focus was turned to conduct the [2+2]-cycloaddition on compound 30, which followed the deprotection of Boc, expected to give 1. However, the attempted photocycloaddition of 30 failed due to the restriction of free rotation about the N-N bond due to the inherent Boc groups, hence preventing the two alkenes aligning into the close proximity required for the [2,2]-cycloaddition to occur. Although the methodology was esthetically planned to construct the N,N’-bisindole core during final photochemical [2+2] cyclization step did not yield any success due to unforeseen complications in the molecular orientations of the molecule which resisted the molecule cyclization.

Recently, Ludvikova et al. [53] reported photosensitized cross-linking of N-acetyl derivatives of Tryptophan 32 using rose bengal in phosphate buffer saline (Scheme 7). Dimeric and higher oligomeric products [54, 55] were formed by cross-linking the amino acid 32 under anoxic conditions in the presence of rose bengal sacrificial oxidant. Here, they react predominantly with singlet oxygen fabricated by rose bengal in aerated solutions. In this investigation, a comprehensive view was obtained for the first steps of rose bengal photosensitized cross-linking of this amino acid. The postulated mechanisms for the observed photosensitized cross-linking reactions of 32 was that the rose bengal singlet excited state upon irradiation efficiently intersystem crosses (Φisc≈ 1 in water) to give the triplet excited state ³RB²⁻. One electron is accepted by this species from the amino acid derivative to furnish a rose bengal anion radical (RB^•3−) and the cation radical of 32 (32^•+), and also RB^•3−is directly detected by nanosecond transient spectroscopy. The cation radical was subsequently deprotonated to give the neutral radical 32^• (Scheme 7). The results achieved in this work illustrated that N1−N1 dimer is very likely among the observed products, whereas C2−C2 product is obtained in trace amount. Consequently, the recombination of 32^• appears to be a plausible major reaction pathway towards the formation of bisindole derivative 33. These reported results can be helpful for future applications of rose bengal and related dyes, such as photochemical tissue bonding or visible light photocatalysis.

Scheme 7. Pathway of complex photosensitized cross-linking of 32 by Rose Bengal

Very recently, Zhang et al. [56] have developed a protocol for the enantioselective synthesis of N-N bisindole atropisomers 37 (Scheme 8). In the first step, enamine is formed from their corresponding α-arylketones 34 and 1-amine indole 35 in presence of TsOH.H₂O (20 mol%) and toluene. The enamine 36 was further reacted with Chiral biphosphines (DTBM-SEGPHOS) using Pd(OAc)₂  (5.0 mol%) and Cs₂CO₃ (1.2 equiv) in toluene (2.0 mL) to afford the corresponding enantioselective N-N bisindole atropisomers 37. A broad range of axially chiral bisindoles were conveniently accessed via the de novo construction of one indole ring in high yields and with excellent enantioselectivities. Moreover, structurally diverse indole-pyrrole, indole-carbazole, and non-biaryl-indole atropisomers possessing a chiral N-N axis were reported. The utility of the current protocol was highlighted by successful gram-scale experiments and further product conversion into synthetically useful molecules containing N-N atropisomeric skeletons. Furthermore, mechanistic investigations through DFT calculations revealed the details of the reaction pathways, and the enantioselectivity was shown to be determined by the steric repulsion in the rearrangement transition states.

In summary, the synthetic sequence demonstrates that N, N’-bisindoles are capable of participating in diverse synthetic transformations exhibiting the sustenance to various reagents and keen participants in lengthy synthetic sequences. This brief review emphasizes the importance of bisindole scaffolds in the field of organic synthesis and medicinal chemistry, and also provides a new challenges and opportunities to explore their chemistry.

Scheme 8. Enantioselective synthesis of N-N bisindole atropisomers

4. Conclusion

In this review, we have tried to be inclusive and attempts were made to summarize the recent developments in N, N’-bisindole chemistry, its biological and other industrial applications. We hope that the synthetic methodologies outlined here for the N, N’-bisindole synthesis will be useful to the chemists and will stimulate new thinking in the field of bisindole. A detailed discussion has been confined to the literature published till September 2022. To our knowledge, this is the first review article on N,N’-bisindole motif.

 Acknowledgments

Authors thank to School of Chemistry, Sambalpur University, Burla, Odisha, India for support to this research.

Orcid:

Hari Narayan Pati

https://www.orcid.org/0000-0003-0138-2680

Prajna Parimita Mohanta

https://www.orcid.org/0000-0001-6153-0185

Ajaya Kumar Behera

https://www.orcid.org/0000-0001-8466-9251

Citation: H. N. Pati*, P. P. Mohanta, A. K. Behera, A Brief Review on Exceedingly Rare N, N′-Bisindole. J. Chem. Rev., 2023, 5(1), 83-95.