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DOI: 10.1039/D3CC02294C (Communication) Chem. Commun., 2023, 59, 8719-8722

An electrochemical cascade process: synthesis of 3-selenylindoles from 2-alkynylanilines with diselenides†

Anil Balajirao Dapkekar and Gedu Satyanarayana *
Department of Chemistry, Indian Institute of Technology Hyderabad (IITH) Kandi, 502284, Sangareddy, Telangana, India. E-mail: gvsatya@chy.iith.ac.in; Fax: +(040) 2301 6003/32

Received 11th May 2023 , Accepted 18th June 2023

First published on 19th June 2023

Abstract

Substituted organoselenium compounds are crucial structural motifs in pharmaceutical molecules. Herein, we report a metal, oxidant, and base-free electrochemical approach to access 3-selenylindoles through an oxidative cyclization of 2-alkynylanilines with diselenides. This environmentally friendly approach demonstrates a wide range of substrate scope under mild reaction conditions in an electrochemical undivided cell setup.

Over the past few years, the electrochemical organic synthesis approach has gained significant interest from scientists worldwide as well as industry due to its environmentally friendly and cost-effective features.1 As a result, numerous methodologies have emerged,2–4 and electro-organic synthesis is becoming increasingly common and opening novel pathways in organic synthesis.5–9 Electro-organic synthesis is the process of synthesizing organic compounds with the use of simple electricity via a one-electron transfer process. Effective and selective molecular syntheses by electrochemical organic synthesis are critical in biomolecular material sciences and chemistry, as well as in the chemical, agrochemical, and pharmaceutical industries.

The substituted indoles are a privileged scaffold comprising heterocycles commonly present in natural products and serve as the skeleton assemblies for many biologically active compounds such as agrochemicals, pharmaceuticals, and alkaloids.10–12 In particular, the selenium-bearing indole moiety (3-selenylindoles) has attracted a lot of interest for its ability to treat ailments. Organoselenium compounds are crucial for organic synthesis, as well as for applications in medicine,13 biology,14 and materials.15 These compounds, especially heterocyclic selenium-containing indole cores, have distinct biological and medical properties, including anti-bacterial, anti-cancer, anti-tumor, anti-viral, anti-inflammatory, immunological modulation, cardiovascular protection, etc. The combination of heterocycles with organoselenium clusters has been magnificently used in several drug candidates from the perspective of drug design.16–18 Some of the delegate examples of 3-selenylindoles are depicted in Fig. 1.19


image file: d3cc02294c-f1.tif
Fig. 1 Examples of biologically significant 3-selenylindoles.

In this context, several sophisticated methods were disclosed for accomplishing indoles from 2-vinylanilines using an oxidant, with or without a transition metal-catalyzed approach [TM = Pd, Ru, Cu, Rh, Co, etc.].20–23 Later, the same approach described above was used to synthesize 3-selenylindoles from 2-alkynylanilines.24–26 Recently, Lei wang et al. demonstrated that the cyclization of 2-alkynylanilines could lead to the construction of 3-selenylindoles under photolytic conditions (Scheme 1a).27 Owing to the important structural features and significant biological properties of 3-selenylindoles as well as our interest in establishing novel electrochemical-based organic synthetic transformations,28,29 and in contrast to early methods, we hypothesized that the synthesis of 3-selenylindoles might be accomplished under electrochemical conditions. Thus, herein, we demonstrate an efficient, oxidant and metal-free oxidative electrochemical cyclization pathway to accomplish the synthesis of 3-selenylindoles starting from readily accessible 2-alkynylanilines with diaryldiselenides under trivial and environmentally benign reaction conditions (Scheme 1b). Importantly, this metal free technique showed a broader substrate scope and furnished the 3-selenylindole products with acceptable to exceptional yields.


image file: d3cc02294c-s1.tif
Scheme 1 Reported works vs. current approach.

To begin with, it was supposed that the synthesis of 3-selenylindoles 3 would be feasible through the oxidative cyclization of 2-alkynylanilines 1 with diaryldiselenides 2 in the presence of a suitable electrolyte. To find the ideal reaction conditions, we screened various reaction parameters for synthesizing 3-selenylindole 3aa, as depicted in Table 1. Initially, the optimization commenced with 1a and 2a as model substrates in an undivided cell setup. The reaction was conducted in an IKA Electrosyn 2.0 undivided cell with platinum as the counter electrode and graphite serving as the working electrode using LiClO4 as the electrolyte in solvent CH3CN (6 mL) at a constant current of 10 mA, which gratifyingly, resulted in the formation of 3-selenylindole 3aa in a 90% yield (Table 1, entry 1). Furthermore, the reaction was screened by changing the electrode pairs, such as “Cgr (+)/Ni (−),” “Cgr (+)/Cgr (−),” and “Pt (+)/Pt (−),” which were found to be less efficient and delivered the selenylated cyclized product 3aa in 85%, 81%, and 75% isolated yields, respectively (Table 1, entries 2–4). In addition, various electrolytes were screened to boost the yield of 3aa, including TBAPF6, TBABF4, TBAB, TBACl, TBAI, and nEt4BF4; however, none of them were found to be more effective than LiClO4 (Table 1, entries 4–5). Furthermore, the reaction parameters were screened using different solvents (or combination of solvents), namely, DCE, DCM, DMF and CH3CN/H2O resulting in 60%, 40%, 15%, and 30% yields, respectively (Table 1, entries 6–7). No reaction occurred without electricity, proving that electricity was essential for this process [(Table 1, entry 8), for details, see Table S3, ESI†].

Table 1 Optimization study to synthesize 3aaab

image file: d3cc02294c-u1.tif
Entrya Variation from standard conditions Yieldb (%)
a Standard reaction conditions: Graphite anode (Cgr), platinum cathode (Pt), I = 10 mA, 1a (0.25 mmol), 2a (0.25 mmol, 1 equiv.), LiClO4 (0.1 M), CH3CN (6 mL), RT, 3.25 h (4.85 F mol−1), undivided cell. b Isolated yields of the product 3aa.
1 None 90%
2 Cgr (+) and Ni (−) 85%
3 Cgr (+) and Cgr (−) 81%
4 Pt (+) and Pt (−) 75%
4 TBAPF6, TBABF4, TBAB 88%, 75%, 38%
5 TBACl, TBAI, nEt4BF4 36%, 30%, 25%
6 DCE, DCM, DMF 60%, 40%, 15%
7 CH3CN/H2O (5/1) 30%
8 No electricity 0%

After establishing the optimized reaction conditions (Table 1, entry 1), next, the substrate scope of 2-alkynylanilines 1 was examined, as illustrated in Scheme 2. Outstandingly, the reaction displayed a broad substrate scope with 2-alkynylanilines 1a–1u and 1,2-diphenyldiselane 2a and delivered the products 3aa–3ua in good to outstanding yields. For example, the reaction with 1a and diphenyl diselenide 2a afforded the anticipated product 3aa in 90% isolated yield. To further showcase the practicability of this electrochemical selenocyclization technique, scale up of the reaction between 1a (500 mg, 1.44 mmol) and 2a (449 mg, 1 equiv.) was performed under standard electrolytic conditions, which delivered 3aa in 87% yield. Besides, the reactions were compatible with aromatic substituents (i.e., R2 originated from acetylene moiety) ranging from weak to strong electron-donating groups, such as p-Me (1b), p-Et (1c), p-OMe (1d) and p-tBu (1e) and furnished the corresponding cyclized products 3ba–3ea in very good to excellent yields (84%–95%). Notably, the halo-substituents (R2 = Cl & F) were well tolerated and gave 3fa and 3ga in 82% and 85% yield, respectively. This method was also compatible with different substituents that flanked the aromatic ring aniline moiety of 1 (i.e., R1), such as p-Me (1h), p-Cl (1i), and p-CF3 (1j) with respect to the position of the amino functional group, and it delivered the target products 3ha (87%), 3ia (80%), and 3ja (85%).


image file: d3cc02294c-s2.tif
Scheme 2 The substrate scope of 2-alkynylanilines 1a–1u and diaryldiselenides 2a–2i. Reaction conditions: a[thin space (1/6-em)]Cgr anode, Pt cathode, I = 10 mA, 1 (0.25 mmol), 2 (0.25 mmol), LiClO4 (0.1 M), CH3CN (6 mL), RT, 3.25 h (4.85 F mol−1), undivided cell. b[thin space (1/6-em)]Isolated yields of 3, c[thin space (1/6-em)]Scale up reaction. d6 h (8.96 F mol−1).

Also, the reaction was smooth with 1k and afforded 3ka in 90% isolated yield. Significantly, this protocol was found to be flexible with aliphatic alkynes having 2-alkynylanilines 1l–1n under standard conditions and generated the corresponding products 3la–3na in 94%, 95% and 92% yields, respectively. The 2-alkynylaniline bearing EWG (–CN) 1o was also amenable for constructing 3-selenylindoles 3oa (70%). Moreover, the present technique was extended to synthesize various functionalized heterocycles by subjecting different anilines 1p–1s to 2a. To our delight, the strategy showed a broad substrate scope and afforded 3pa–3sa (80%–88%) regardless of the substituent pattern on the aromatic rings. Noteworthily, the reaction was unsuccessful in furnishing 3ta with protecting group free 2-(phenylethynyl)aniline 1t. In addition, the reaction was feasible with 1u, and 3ua was obtained in an 85% yield.

However, after successfully establishing the scope of 2-alkynylanilines 1a–1u, we have focused on investigating the substrate scope using different diaryldiselenides 2a–2i. Initially, 2-alkynylanilines 1a–1e were subjected to the reactions with 1,2-di-p-tolyldiselane 2b under standard conditions, which to our delight, afforded the products 3ab–3eb with yields ranging from 80% to 90%. Substrates 1a and 1m–1o treated with 1,2-bis(4-ethylphenyl)diselane 2c could smoothly furnish the corresponding products 3ac–3oc [3ac (85%), 3mc (89%), 3nc (92%), & 3oc (75%)]. Formation of 3ad (86%) and 3id (82%) proceeded well with 1,2-bis(4-methoxyphenyl)diselane 2d. Significantly, the halo group flanked diaryldiselenides, such as 2e–2h, worked smoothly under the standard conditions and furnished the anticipated products in good to very good yields [3ae (78%), 3ce (78%), 3fe (77%), 3ie (80%), 3je (75%), 3le (85%), 3bf (82%), 3if (80%), 3ag (70%), & 3dh (75%)], as portrayed in Scheme 2. In addition, the reaction was found to be smooth for 1e with 1,2-bis(3-(trifluoromethyl)phenyl)diselane 2i and gave the expected product 3ei in 70% isolated yield. Under typical electrochemical conditions, the substituted 2-alkynylaniline derivatives, such as 1r, 1s, and 1q, underwent smooth electrochemical transformations to give the corresponding products 3rb, 3sb, and 3qd. The reactions were also compatible with disubstituted, trisubstituted, heterocyclic, and aliphatic selenides (1j–1n), and delivered the products 3aj–3en in good to exceptional yields. The structures of 3aa (CCDC: 2256835†) and 3ab (CCDC: 2244978†) were confirmed by single crystal X-ray analysis.

Moreover, some control experiments were conducted to shed light on the electrochemical process's mechanistic aspects, as illustrated in Scheme 3. Therefore, initially, an electrolytic reaction of 1a with 2a in the presence of TEMPO (2 equiv.) led to the formation of 3aa in 55% yield. The intended product 3aa was also produced in 70% and 60% isolated yields, respectively, when the reaction was carried out using BHT and DPE as radical scavengers. This demonstrates that the transformation might not be passing through solely radical pathways. Furthermore, the anticipated product 3aa was isolated in 70% yield when 1a reacted with PhSeCl 4 under the established conditions (Scheme 3a), suggesting that the radical pathway could not be feasible. Without electricity, the anticipated product 3aa was not formed, indicating that electricity was required for the reaction (Scheme 3b). Besides, it could not isolate the anticipated radical trapped product 5 when the reaction was performed between 1a and TEMPO (Scheme 3c). This indicates that the reaction does not occur via an N-radical center pathway. This suggests that the reaction might be possible through an ionic pathway. Furthermore, we performed cyclic voltammetry (CV) experiments to understand more about the potentials of the substrates, as depicted in Fig. S1 (ESI†). Substrates 1a and 2a showed oxidation peaks in acetonitrile at 1.72 and 1.41 V, respectively. According to this CV data, diselenide 2a will oxidize preferentially to produce a reactive seleno molecule to start the cascade cyclization (for details, see ESI†).


image file: d3cc02294c-s3.tif
Scheme 3 Control experiments.

Based on our mechanistic studies, cyclic voltammetry, control experimentations, and previous literature backgrounds, a plausible reaction pathway for the electrochemical cascade cyclization was outlined in Scheme 4.30 Initially, at the anode, 2a undergoes anodic oxidation and is converted into phenylselenium radical B and phenylselenium cation Cvia radical cation intermediate A. Also, it might be possible that 2a will undergo cathodic reduction, producing radical B and anion D. Afterwards, the addition of phenylselenyl radical B to the alkyne moiety of 1a forms a radical intermediate E. Subsequently, the intermediate E undergoes one-electron oxidation followed by nucleophilic addition and deprotonation to produce 3aa through intermediate G (path a, probably a minor pathway). Another hypothesis is that 1a was attacked by the phenylselenium cation C generating the alkenyl cation G. Finally, the cyclization of G occurred, followed by deprotonation to synthesize the desired product 3aa (path b, could be a major pathway).


image file: d3cc02294c-s4.tif
Scheme 4 Plausible reaction pathway for the synthesis of 3aa.

In conclusion, we have developed an effective environmentally friendly procedure for the electrochemical oxidative cyclization-based synthesis of 3-selenylindoles. A broad range of 3-selenylindoles were accomplished in good to excellent yields by combining various functionalized 2-alkynylanilines with different diaryldiselenides. To comprehend the reaction mechanism, several mechanistic experiments were conducted. Significantly, this metal-free technique was demonstrated using affordable and environmentally benign materials. In our laboratory, research works on using more electrochemically generated reactive organoselenium compounds for various synthetic processes are in progress.

The authors sincerely acknowledge the financial support from the Indian Institute of Technology, Hyderabad (IITH), India. A. B. D. sincerely thanks to MHRD and PMRF for providing the fellowship.

Conflicts of interest

There are no conflicts of interest.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. CCDC 2244978 and 2256835. For ESI and crystallographic data in CIF or other electronic format see DOI: https://doi.org/10.1039/d3cc02294c
This journal is © The Royal Society of Chemistry 2023
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