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Scientific Reports volume 13, Article number: 14251 (2023) Cite this article

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In this paper, we report an eco-friendly approach for the C(sp2)–H bond selenylation of imidazopyridines and other N-heteroarenes as well as simple arenes at ambient temperature. This new protocol consists of the reaction between (N-hetero)-arenes and the diorganyl-diselenides and trichloroisocyanuric acid (TCCA)-ethanol reagent system. In a short reaction time, the desired selenylated products were obtained regioselectively in good yields, with tolerance for a wide range of functional groups.

The construction of the C–Se bond is gaining increasing interest in organic synthesis, as these compounds exhibit fascinating biological characteristics1,2,3,4. In this regard, diorganyl-selenides are well-known for their diverse biological properties, mainly their antioxidant, anti-inflammatory, anti-Alzheimer and anticancer activities5,6,7,8,9. These ubiquitous structures play a fundamental role in modern organic synthesis and are employed in several reactions as catalysts, ligands and synthetic intermediates in total synthesis, as well as in ionic liquids10, 11. They are also applied in materials science12. Therefore, research studies have led to important discoveries regarding selective C-Se bond formation and in this context, a notable approach is direct selenylation reactions2, 3, 10, 13,14,15,16,17.

Similarly, N-heteroarenes, e.g., imidazo[1,2-a]pyridine (IP), imidazo[2,1-b]thiazole and indole are privileged scaffolds18,19,20, given their pharmaceutical, biological and materials science applications18, 20,21,22. These motifs are present in several commercially-available drugs (Fig. 1), highlighting the importance of these nuclei19,20,21. Therefore, they are considered as structures of interest in organic synthesis23,24,25,26,27,28.

Biologically-relevant imidazo[1,2-a]pyridine (IP), indole and selenylated N-heteroarenes.

Considering the therapeutic properties of (N-hetero)arenes and the biological relevance of organoselenium compounds, molecular hybridization of these structures could lead to molecules with promising biological properties (Fig. 1)29,30,31. In this regard, a new synthetic methodology to the construct the C–Se bond in (N-hetero)arenes has become a research hotspot2,3,4, 36,37,38,39,40,41,42,43.

In contrast to cross-coupling reactions, the formation of N-heteroarene containing organoselenides via C(sp2)−H bond functionalization provides a straightforward one-step bond formation route. This approach remains underexplored, although direct C–H functionalization is an atom-economical and greener alternative. For this type of direct C(sp2)−H bond selenylation of (N-hetero)arenes with diorganyl diselenides, there are two possible pathways: (a) nucleophilic species from arenes, generated in situ44, 45 and (b) electrophilic species from diselenides, generated in-situ46, 47. In terms of practicality, the former pathway is limited due to narrow substrate scope, while the development of a new method involving the activation of diselenides through the later pathway is highly desirable.

Although they offer good features, some of the previously used methods are associated with limitations in terms of applicability/sustainability, e.g., pre-functionalized coupling partners, non-green solvents, excess of organoselenium source, limited substrate scope, long reaction time and high temperature, low atom economy, transition metal catalyst, malodorous reagents, and multi-step processes.

On the other hand, trichloroisocyanuric acid (TCCA), a green chlorination agent48, is a stable and inexpensive reagent, commonly found in commercial products for swimming-pool disinfection49. Due to its highly electrophilic chlorine content and ease of handling, it is used as an efficient chlorine source in several reactions for the chlorination of organic compounds as well as in oxidation reactions50.

The development of a new alternative and benign method for the synthesis of organoselenyl containing IPs and other N-heteroarene hybrid structures with a broad scope, involving the use of a greener solvent at room temperature and ease of handling, which could provide high efficiency under neutral reaction conditions, would be highly desirable and advantageous.

Continuing our research on direct organochalcogen functionalization and the development of eco-friendly processes23, 27, 48, 51,52,53, herein we describe, for the first time, the TCCA-mediated synthesis of biologically-relevant organoselenyl-indoles, -imidazoles and -arenes through C(sp2)–H bond selenylation, using diselenide. This new transition-metal free, alternative, and sustainable protocol offers ease of reagent handling and is operated in a short time at room temperature. It is applicable to a very broad scope of substrates, using EtOH as the solvent, and the procedure can be scaled up to the multi-gram scale (Fig. 2).

TCCA mediated C(sp2)–H bond selenylation of (N-hetero)-arenes using diselenides.

In a Schlenk tube equipped with a stirring bar was charged with the TCCA (0.35 mol equiv.) and diselenide 2 (0.55 mol equiv.) in 1.0 mL of anhydrous ethanol and let to react for 5 min. After that, was added the respective (N-hetero)-arenes (0.25 mmol) and 1.0 mL of anhydrous ethanol. After the total consumption of starting materials, the reactional contend was diluted with 25.0 mL of ethyl acetate followed of extraction with distilled water (2 × 10 mL) and brine (1 × 10.0 mL). The organic phase was dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was then subjected to purification on column chromatography of silica gel as stationary phase and eluate with appropriate solvent to afford the desired product.

Obtained as pale yellow solid (84.7 mg, 97%); Purified using hexane/ethyl acetate (80:20); mp:77–79 °C; 1H NMR (400 MHz, CDCl3) δ: 8.32 (d, J = 7.0 Hz, 1H), 8.18–8.12 (m, 2H), 7.71 (d, J = 9.0 Hz, 1H), 7.47–7.35 (m, 5H), 7.30–7.25 (m, 1H), 7.18–7.06 (m, 5H), 6.81 (t, J = 6.5 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ: 151.8, 147.8, 133.8, 130.9, 129.7, 128.8, 128.5, 128.36, 128.3, 126.7, 126.5, 125.6, 117.5, 113.0, 102.9.

Obtained as yellow solid (78.8 mg, 82%); Purified using hexane/ethyl acetate (70:30); mp: 159–160 °C; 1H NMR (400 MHz, CDCl3) δ: 8.28 (d, J = 6.8 Hz, 1H), 8.17–8.09 (m, 2H), 7.71 (d, J = 9.0 Hz, 1H), 7.43 (t, J = 7.5 Hz, 2H), 7.37 (d, J = 7.0 Hz, 1H), 7.32–7.26 (m, 1H), 7.11 (d, J = 8.5 Hz, 2H), 7.00 (d, J = 8.5 Hz, 2H), 6.83 (t, J = 7.0 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ: 151.96, 147.82, 133.62, 132.89, 129.81, 129.57, 129.13, 128.75, 128.62, 128.40, 126.67, 125.45, 117.64, 113.21, 102.48.

Obtained as yellow solid (66.2 mg, 72%); Purified using hexane/ethyl acetate (70:30); mp: 97–100 °C; 1H NMR (200 MHz, CDCl3) δ: 8.34 (d, J = 7.0 Hz, 1H), 8.14 (dd, J = 8.0, 1.5 Hz, 2H), 7.72 (d, J = 9.0 Hz, 1H), 7.52–7.22 (m, 5H), 7.16–7.03 (m, 2H), 6.93–6.80 (m, 3H). 13C NMR (50 MHz, Chloroform-d) δ: 151.66, 147.67, 133.62, 130.37 (d, J = 7.7 Hz), 128.73, 128.51, 128.31, 126.51, 125.41, 117.58, 116.84 (d, J = 22.0 Hz), 113.08.

Obtained as yellow solid (66.9 mg, 64%); Purified using hexane/ethyl acetate (70:30); mp: 99–101 °C;1H NMR (300 MHz, CDCl3) δ 8.28 (d, J = 6.9 Hz, 1H), 8.11 (d, J = 6.9 Hz, 2H), 7.71 (d, J = 9.0 Hz, 1H), 7.46–7.26 (m, 6H), 7.19 (t, J = 7.9 Hz, 1H), 7.07 (d, J = 8.0 Hz, 1H), 6.83 (t, J = 6.8 Hz, 1H). 13C NMR (50 MHz, CDCl3) δ: 152.25 (s), 147.86 (s), 133.34 (s), 132.27 (s), 131.04 (s), 129.96 (s), 128.64 (s), 128.30 (s), 126.75 (s), 125.74–124.63 (m), 124.81 (q, J = 3.5 Hz), 123.47 (q, J = 3.5 Hz), 117.60 (s), 113.27 (s), 101.73 (s).

Obtained as yellow solid (83.7 mg, 92%); Purified using hexane/ethyl acetate (70:30); mp: 110–113 °C; 1H NMR (300 MHz, CDCl3) δ 8.24 (d, J = 6.9 Hz, 1H), 8.08 (d, J = 8.3 Hz, 2H), 7.60 (d, J = 9.0 Hz, 1H), 7.39–7.25 (m, 3H), 7.21–7.14 (m, 1H), 6.97–6.83 (m, 4H), 6.72 (t, J = 6.8 Hz, 1H), 2.14 (s, 3H).13C NMR (75 MHz, CDCl3) δ 151.63, 147.71, 136.76, 133.92, 130.54, 128.86, 128.60, 128.47, 128.36, 127.03, 126.43, 125.70, 117.54, 113.00, 103.35, 21.00.

Obtained as yellow solid (81.0 mg, 89%); Purified using hexane/ethyl acetate (70:30); mp: 84–82 °C; 1H NMR (300 MHz, CDCl3) δ 8.12 (d, J = 6.9 Hz, 1H), 8.01 (d, J = 6.9 Hz, 2H), 7.61 (d, J = 9.0 Hz, 1H), 7.28 (dt, J = 14.9, 7.1 Hz, 3H), 7.19–7.10 (m, 1H), 7.04 (d, J = 7.8 Hz, 1H), 6.94 (t, J = 6.7 Hz, 1H), 6.82–6.62 (m, 2), 6.43 (d, J = 7.9 Hz, 1H), 2.34 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 152.33, 147.98, 136.48, 133.81, 131.41, 130.68, 128.76, 128.46, 128.31, 127.17, 126.84, 126.45, 125.66, 117.52, 113.01, 101.83, 21.14.

Obtained as yellow solid (91.1 mg, 96%); Purified using hexane/ethyl acetate (70:30); mp: 97–98 °C; 1H NMR (400 MHz, CDCl3) δ: 8.37 (d, J = 7.0 Hz, 1H), 8.24–8.12 (m, 2H), 7.69 (d, J = 9.0 Hz, 1H), 7.45 (t, J = 7.5 Hz, 2H), 7.38 (t, J = 7.5 Hz, 1H), 7.31–7.24 (m, 1H), 7.09 (d, J = 9.0 Hz, 2H), 6.86–6.80 (m, 1H), 6.71 (d, J = 9.0 Hz, 2H), 3.69 (s, 3H). 13C NMR (100 MHz, CDCl3) δ: 159.13, 151.19, 147.53, 133.91, 130.80, 128.90, 128.47, 128.37, 126.41, 125.66, 120.54, 117.52, 115.49, 112.99, 104.17, 55.35.

Obtained as yellow solid (81.0 mg, 86%); Purified using hexane/ethyl acetate (70:30); mp: 154–155 °C; 1H NMR (400 MHz, CDCl3) δ: 8.31 (d, J = 7.0 Hz, 1H), 8.17–8.06 (m, 2H), 7.73 (d, J = 9.0 Hz, 1H), 7.44–7.27 (m, 4H), 7.17–7.10 (m, 1H), 6.89–6.76 (m, 2H), 6.72–6.59 (m, 1H), 6.42 (dd, J = 7.5, 1.5 Hz, 1H), 3.92 (s, 2H). 13C NMR (100 MHz, CDCl3) δ: 156.72, 152.51, 148.12, 133.93, 128.80, 128.43, 128.34, 127.54, 127.39, 126.45, 125.98, 122.11, 119.97, 117.53, 112.94, 110.72, 101.28, 55.95.; IR νmax: 3058, 2830, 1471, 1342, 1232, 1235, 752.; HRMS-ESI: m/z [M+H]+ calcd. for C20H17N2OSe 381.0501, found: 381.0505.

Obtained as yellow solid (63.0 mg, 64%); Purified using hexane/ethyl acetate (70:30); mp: 158–160 °C; 1H NMR (300 MHz, CDCl3) δ 8.25 (d, J = 6.9 Hz, 1H), 8.15 (dd, J = 15.4, 7.8 Hz, 3H), 7.83 (d, J = 7.9 Hz, 1H), 7.73 (d, J = 9.0 Hz, 1H), 7.64 (d, J = 8.1 Hz, 1H), 7.60–7.48 (m, 2H), 7.47–7.31 (m, 3H), 7.30–7.22 (m, 1H), 7.11 (t, J = 7.7 Hz, 1H), 6.87 (d, J = 7.3 Hz, 1H), 6.74 (t, J = 6.8 Hz, 1H). 13C NMR (75 MHz, CDCl3) δ 152.57, 148.12, 134.34, 133.84, 132.31, 129.27, 128.83, 128.59, 128.41, 127.25, 126.70, 126.55, 126.51, 126.34, 125.79, 125.63, 125.21, 117.61, 113.08, 101.67.

Obtained as yellow oil (80.0 mg, 90 %); Purified using hexane/ethyl acetate (70:30); 1H NMR (400 MHz, CDCl3) δ 8.56 (d, J = 7.0 Hz, 1H), 8.23–8.18 (m, 2H), 7.66 (d, J = 9.0 Hz, 1H), 7.50 (t, J = 7.5 Hz, 2H), 7.41 (t, J = 7.5 Hz, 1H), 7.31–7.26 (m, 1H), 7.26–7.23 (m, 1H), 7.13 (dd, J = 3.5, 1.0 Hz, 1H), 6.93–6.87 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 150.88, 147.36, 133.94, 132.89, 129.87, 129.15, 129.12, 128.55, 128.40, 128.07, 126.45, 125.62, 124.44, 117.68, 113.05.

Obtained as yellow oil (79.1 mg, 96%); Purified using hexane/ethyl acetate (90:10); 1H NMR (400 MHz, CDCl3) δ: 8.54 (d, J = 7.0 Hz, 1H), 8.23 (d, J = 7.0 Hz, 2H), 7.68 (d, J = 9.0 Hz, 1H), 7.47 (t, J = 7.5 Hz, 3H), 7.37 (t, J = 7.5 Hz, 1H), 7.31–7.22 (m, 1H), 6.90 (t, J = 7.0 Hz, 1H), 2.66 (t, J = 7.5 Hz, 2H), 1.46 (dt, J = 15.0, 7.0 Hz, 3H), 1.28 (dq, J = 14.5, 7.5 Hz, 4H), 0.75 (t, J = 7.5 Hz, 3H).; 13C NMR (100 MHz, CDCl3) δ 150.12, 147.12, 134.10, 128.83, 128.27, 128.23, 126.00, 125.68, 117.42, 112.78, 104.46, 32.16, 29.29, 22.73, 13.48; IR νmax: 3065, 2958, 2929, 1463, 1343, 755, 694; HRMS-ESI: m/z [M+H]+ calcd. for C17H19N2OSe 331.0709, found: 331.0705.

Obtained as yellow solid (65.7 mg, 70 %); Purified using hexane/ethyl acetate (80:20); mp: 93–95 °C; 1H NMR (400 MHz, CDCl3) δ: 8.31 (d, J = 7.0 Hz, 1H), 8.12 (d, J = 9.0 Hz, 2H), 7.69 (d, J = 9.0 Hz, 1H), 7.27 (ddd, J = 9.0, 7.0, 1.0 Hz, 1H), 7.18–7.12 (m, 3H), 7.12–7.06 (m, 2H), 6.96 (d, J = 9.0 Hz, 2H), 6.85–6.75 (m, 1H), 3.82 (s, 3H).; 13C NMR (100 MHz, CDCl3) δ: 159.99, 151.72, 147.74, 131.09, 130.06, 129.73, 128.22, 126.69, 126.41, 125.58, 117.33, 113.83, 112.89, 102.07, 55.34.

Obtained as White solid (96.7 mg, 95%); Purified using hexane/ethyl acetate (70:30); mp: 103–105 °C; 1H NMR (400 MHz, CDCl3) δ: 8.35–8.30 (m, 1H), 7.81–7.66 (m, 3H), 7.33 (t, J = 8.0 Hz, 1H), 7.29–7.22 (m, 1H), 7.16–7.05 (m, 5H), 6.91 (dd, J = 8.0, 2.6 Hz, 1H), 6.83–6.74 (m, 1H), 3.77 (s, 3H). 13C NMR (100 MHz, CDCl3) δ: 159.52, 151.56, 147.63, 135.09, 130.96, 129.67, 129.30, 128.23, 126.68, 126.46, 125.58, 121.22, 117.50, 114.88, 113.60, 113.02, 103.05, 55.23; IR νmax: 3035, 2835, 1476, 1344, 1215, 1051, 734, 687, 459; HRMS-ESI: m/z [M+H]+ calcd. for C20H17N2OSe 381.0501, found: 381.0506.

Obtained as a yellow oil (73.8 mg, 72%); Purified using ethyl acetate/hexane (1:1); 1H NMR (200 MHz, CDCl3) δ: 8.37 (d, J = 7.0 Hz, 1H), 7.84–7.65 (m, 3H), 7.35–7.07 (m, 6H), 6.93 (d, J = 8.0 Hz, 1H), 6.84 (t, J = 7.0 Hz, 1H), 3.91 (s, 3H), 3.85 (s, 3H). 13C NMR (50 MHz, CDCl3) δ: 151.60, 149.45, 148.76, 147.69, 131.20, 129.75, 128.15, 126.73, 126.55, 125.57, 121.42, 117.32, 113.02, 111.95, 110.98, 102.27, 55.94, 55.85; IR νmax : 3380, 2935, 1707, 1479, 1340, 891, 812, 577, 461; HRMS-ESI: m/z [M+H]+ calcd. for C21H19N2O2Se 411.0612, found 411.0629.

Obtained as Off White solid (78.6 mg, 74%); Purified using hexane/ethyl acetate (80:20); mp: 135–137 °C; 1H NMR (400 MHz, CDCl3) δ: 8.38–8.29 (m, 1H), 8.06 (d, J = 8.5 Hz, 2H), 7.70 (d, J = 9.0 Hz, 1H), 7.59–7.50 (m, 2H), 7.30 (ddd, J = 9.0, 7.0, 1.0 Hz, 1H), 7.16 (dd, J = 5.0, 1.5 Hz, 3H), 7.07 (dd, J = 6.5, 3.5 Hz, 1H), 6.85 (td, J = 7.0, 1.0 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ: 150.59, 147.82, 132.81, 131.56, 130.69, 130.32, 129.85, 128.35, 126.94, 126.80, 125.71, 122.91, 117.62, 113.28, 103.16.

Obtained as pale yellow solid (104.8 mg, 94%); Purified using ethyl acetate; mp: 142–148 °C; 1H NMR (400 MHz, CDCl3) δ: 8.42 (d, J = 8.5 Hz, 2H), 8.38 (d, J = 7.0 Hz, 1H), 7.99 (d, J = 8.5 Hz, 2H), 7.72 (d, J = 9.0 Hz, 1H), 7.35 (ddd, J = 9.0, 7.0, 1.0 Hz, 1H), 7.18 (dd, J = 5.0, 1.5 Hz, 3H), 7.08 (dd, J = 6.5, 3.0 Hz, 2H), 6.90 (td, J = 7.0, 1.0 Hz, 1H), 3.07 (s, 3H).; 13C NMR (100 MHz, CDCl3) δ: 149.19, 147.84, 139.80, 139.27, 130.24, 129.85, 129.34, 128.35, 127.32, 127.13, 127.07, 125.71, 117.77, 113.61, 104.39, 44.55; IR νmax: 3071, 2921, 1573, 1301, 1159, 1142, 773, 544, 530; HRMS-ESI: m/z [M+H]+ calcd. for C20H17N2O2SSe 429.0171, found: 429.0176.

Obtained as white solid (45.1 mg, 45%); Purified using hexane/ethyl acetate (80:20–70:30); mp: 140–141 °C; 1H NMR (200 MHz, CDCl3) δ: 8.66 (s, 1H), 8.42–8.29 (m, 2H), 7.92–7.81 (m, 3H), 7.76 (d, J = 9.0 Hz, 1H), 6.90–6.81 (m, 1H). 13C NMR (50 MHz, CDCl3) δ: 151.72, 147.93, 133.45, 131.32, 131.04, 129.83, 128.76, 128.61, 128.33, 127.93, 127.74, 126.92, 126.68, 126.51, 126.43, 126.17, 125.75, 117.65, 113.18, 103.55.

Obtained as white solid (86.8 mg, 89%); Purified using hexane/ethyl acetate (80:20–70:30); mp: 134–135 °C; 1H NMR (200 MHz, CDCl3) δ: 8.28 (d, J = 6.5 Hz, 1H), 7.76 (d, J = 4.0 Hz, 1H), 7.63 (d, J = 9.0 Hz, 1H), 7.31–7.13 (m, 6H), 6.89 (d, J = 4.0 Hz, 1H), 6.81 (t, J = 7.0 Hz, 1H); 13C NMR (50 MHz, CDCl3) δ: 147.64, 146.10, 135.42, 131.42, 130.21, 129.79, 128.78, 127.12, 126.93, 126.79, 125.94, 125.40, 117.25, 113.24, 102.23.

Obtained as yellow solid (19.5 mg, 29%); Purified using hexane/ethyl acetate (75:25); mp: 60–61 °C; 1H NMR (400 MHz, CDCl3) δ: 8.27 (d, J = 7.0 Hz, 1H), 7.98 (s, 1H), 7.70 (d, J = 9.0 Hz, 1H), 7.31–7.26 (m, 1H), 7.17 (tt, J = 5.5, 2.5 Hz, 5H), 6.89–6.83 (m, 1H).; 13C NMR (100 MHz, CDCl3) δ: 148.39, 143.12, 130.66, 129.63, 129.12, 126.98, 125.88, 125.35, 118.04, 113.18, 106.61.

Obtained as white off solid (84.6 mg, 93%); Purified using hexane/ethyl acetate (8:2); mp: 154–157 °C; 1H NMR (200 MHz, CDCl3) δ: 8.23–8.08 (m, 3H), 7.50–7.33 (m, 4H), 7.19–7.04 (m, 5H), 6.70–6.60 (m, 1H), 2.41 (s, 3H). 13C NMR (50 MHz, CDCl3) δ: 151.71, 148.15, 137.79, 133.93, 131.24, 129.72, 128.78, 128.42, 128.34, 128.23, 126.67, 124.81, 116.06, 115.72, 102.11, 21.41.

Obtained as a white solid (73.7 mg, 81%); Purified using hexane/ethyl acetate (8:2); mp:148–149 °C; 1H NMR (200 MHz, CDCl3) δ: 8.29–8.01 (m, 3H), 7.62 (d, J = 9.0 Hz, 1H), 7.48–7.31 (m, 3H), 7.20–7.01 (m, 6H), 2.28 (s, 3H). 13C NMR (50 MHz, CDCl3) δ: 151.66, 146.83, 133.94, 131.31, 129.71, 128.73, 128.31, 128.12, 126.62, 123.35, 122.87, 116.90, 102.41, 18.42.

Obtained as Off White solid (81.5 mg, 90 %); Purified using hexane/ethyl acetate (85:15); mp: 130–132 °C; 1H NMR (400 MHz, CDCl3) δ: 8.18 (d, J = 7.0 Hz, 1H), 8.15–8.11 (m, 2H), 7.42 (t, J = 7.5 Hz, 2H), 7.37–7.32 (m, 1H), 7.15–6.99 (m, 6H), 6.71 (t, J = 7.0 Hz, 1H), 2.70 (s, 3H). 13C NMR (100 MHz, CDCl3) δ: 151.54, 148.12, 134.19, 131.26, 129.68, 128.97, 128.34, 128.29, 127.63, 126.63, 125.22, 123.49, 112.97, 103.20, 16.95.

Obtained as yellow solid (42.0 mg, 44%); Purified using hexane/ethyl acetate (75:25); mp: 146–148 °C; 1H NMR (400 MHz, CDCl3) δ: 8.40 (s, 1H), 8.17–8.11 (m, 2H), 7.66 (d, J = 9.5 Hz, 1H), 7.44 (t, J = 7.5 Hz, 2H), 7.38 (d, J = 7.0 Hz, 1H), 7.26 (d, J = 8.0 Hz, 1H), 7.22–7.16 (m, 3H), 7.13–7.07 (m, 2H). 13C NMR (100 MHz, CDCl3) δ: 152.53, 146.09, 133.36, 130.47, 129.92, 128.83, 128.77, 128.50, 128.49, 127.99, 127.08, 123.68, 121.56, 117.98, 103.86.; IR νmax: 3067, 1574, 1439, 1315, 1077, 804, 747, 696, 456.; HRMS-ESI: m/z [M+H]+ calcd. for C19H14ClN2OSe 385.0003, found: 385.0004.

Obtained as yellow solid (77.7 mg, 78 %); Purified using hexane/ ethyl acetate (70:30); mp: 100–101 °C; 1H NMR (400 MHz, CDCl3) δ 8.16 (d, J = 7.0 Hz, 1H), 8.10 (d, J = 9.0 Hz, 2H), 7.44 (s, 1H), 7.13 (d, J = 6.5 Hz, 3H), 7.07 (dd, J = 7.5, 2.0 Hz, 2H), 6.95 (d, J = 9.0 Hz, 2H), 6.62 (d, J = 7.0 Hz, 1H), 3.80 (s, 3H), 2.39 (s, 3H).; 13C NMR (100 MHz, CDCl3) δ: 159.87, 151.46, 148.00, 137.60, 131.33, 129.94, 129.64, 128.10, 126.56, 126.48, 124.67, 115.80, 115.46, 113.75, 101.17, 55.28, 21.34.

Obtained as yellow solid (83.4 mg, 80 %); Purified using hexane/ethyl acetate (70:30); mp: 146–148 °C; 1H NMR (400 MHz, CDCl3) δ 8.40 (d, J = 1.5 Hz, 1H), 8.10 (d, J = 8.5 Hz, 2H), 7.69 (d, J = 9.5 Hz, 1H), 7.44–7.33 (m, 2H), 7.29 (dd, J = 9.5, 2.0 Hz, 1H), 7.19 (dd, J = 6.5, 3.5 Hz, 3H), 7.10 (dt, J = 6.0, 3.0 Hz, 2H). 13C NMR (50 MHz, CDCl3) δ 150.77, 145.73, 134.85, 131.40, 129.86, 129.83, 128.60, 128.39, 127.14, 123.54, 121.81, 117.76, 77.00. IR νmax: 3047, 2362, 1738, 1452, 1323, 1073, 851, 732.; HRMS-ESI: m/z [M+H]+ calcd. for C19H13Cl2N2Se 418.9621, found: 418.9630.

Obtained as yellow solid (72.2 mg, 77 %); Purified using hexane/ethyl acetate (85:15); mp: 97–99 °C; 1H NMR (300 MHz, CDCl3) δ 8.35–8.24 (m, 3H), 7.72–7.59 (m, 3H), 7.32–7.26 (m, 1H), 7.07–6.99 (m, 3H), 6.84 (t, J = 7.4 Hz, 2H) 6.87–6.79 (m, 1H). δ 13C NMR (75 MHz, CDCl3) δ 149.08, 147.76, 138.26, 131.99, 130.14, 129.81, 128.95, 128.25, 127.07, 127.02, 125.62, 118.92, 117.70, 113.54, 111.57, 104.17.

Obtained as white solid (83.1 mg, 88%); Purified using hexane/ethyl acetate (80:20–70:30); mp: 109–110 °C; 1H NMR (200 MHz, CDCl3) δ: 8.13 (s, 1H), 8.02 (d, J = 8.0 Hz, 2H), 7.61 (d, J = 9.0 Hz, 1H), 7.26–7.09 (m, 8H), 2.37 (s, 3H), 2.30 (s, 3H); 13C NMR (50 MHz, CDCl3) δ: 151.83, 146.83, 138.24, 131.45, 131.13, 129.70, 129.55, 129.08, 128.61, 128.13, 126.58, 123.35, 122.74, 116.83, 102.09, 21.39, 18.42. IR νmax: 2919, 2356, 1534, 1332, 969, 687.; HRMS-ESI: m/z [M+H]+ calcd. for C21H19N2Se 379.0713, found: 379.0703.

Obtained as yellow solid (70.1 mg, 81%); Purified using hexane/ethyl acetate (1:1); mp: 98–99 °C; 1H NMR (400 MHz, CDCl3) δ: 8.64–8.57 (m, 2H), 8.31–8.27 (m, 2H), 7.48–7.38 (m, 3H), 7.20–7.17 (m, 3H), 7.11 (dd, J = 6.5, 3.0 Hz, 2H), 6.92 (dd, J = 7.0, 4.0 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ: 153.07, 151.49, 150.81, 133.21, 130.05, 129.93, 129.06, 128.99, 128.55, 128.44, 127.15, 109.45, 101.73.

Obtained as White solid (92.8 mg, 83%); Purified using hexane/ethyl acetate (95:5); mp: 138–139 °C; 1H NMR (400 MHz, CDCl3) δ 8.08–8.04 (m, 2H), 7.38 (t, J = 7.5 Hz, 2H), 7.29 (t, J = 7.5 Hz, 1H), 7.20–7.14 (m, 6H), 2.35 (d, J = 1.5 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ: 151.74, 151.02, 134.06, 131.78, 129.70, 128.40, 128.33, 127.88, 127.69, 126.69, 115.37, 102.03, 14.21.

Obtained as Yellow solid (105.3 mg, 97 %); Purified using hexane/ethyl acetate (9:1); mp: 88–89 °C; 1H NMR (400 MHz, CDCl3) δ: 7.99 (d, J = 9.0 Hz, 2H), 7.23–7.11 (m, 6H), 6.92 (d, J = 9.0 Hz, 2H), 3.81 (s, 3H), 2.37 (s, 2H).; 13C NMR (100 MHz, CDCl3) δ: 159.49, 151.79, 150.93, 131.98, 129.71, 128.98, 128.32, 126.78, 126.64, 126.38, 115.41, 113.79, 101.10, 55.36, 14.22.; IR νmax: 3107, 2831, 1608, 14668, 1246, 1031, 836, 727, 686, 453; HRMS-ESI: m/z [M+H]+ calcd. for C19H17N2OSSe 401.0221, found: 401.0218.

Obtained as White solid (94.4 mg, 97 %); Purified using hexane/ethyl acetate (9:1); mp: 159–162 °C; 1H NMR (400 MHz CDCl3) δ: 8.06–8.01 (m, 2H), 7.21–7.14 (m, 6H), 7.06 (t, J = 8.5 Hz, 2H), 2.39–2.33 (m, 3H).; 13C NMR (100 MHz, CDCl3) δ: 162.65 (d, JC-F = 247.16 Hz), 150.97 (d, JC-F = 15.81), 131.63, 130.26 (d, JC-F = 3.27 Hz), 129.77, 129.43 (d, JC-F = 8.0 Hz), 128.38, 126.81, 126.80, 115.37, 115.36, 115.14, 101.82, 14.22.; IR νmax: 3056, 2909, 1527, 1465, 1218. 840, 728, 555, 408.; HRMS-ESI: m/z [M+H]+ calcd. for C18H14FN2SSe 389.0021, found: 389.0023.

Obtained as Brown Oil (33.9 mg, 39%);Purified using hexane/ethyl acetare (95:5); 1H NMR (400 MHz, CDCl3) δ: 8.59 (s, 1H), 7.73 (dd, J = 8.0, 1.5 Hz, 2H), 7.65 (d, J = 8.0 Hz, 1H), 7.46–7.37 (m, 4H), 7.29–7.17 (m, 4H), 7.15–7.07 (m, 3H).; 13C NMR (100 MHz, CDCl3) δ: 142.21, 136.30, 132.22, 132.17, 131.66, 129.18, 128.77, 128.65, 128.43, 127.39, 125.55, 123.42, 121.25, 121.07, 111.12.

Obtained as Orange solid (44.8 mg, 60%); Purified using hexane/ethyl acetate (95:5); mp: 75–77 °C; 1H NMR (400 MHz, CDCl3) δ 8.27 (d, J = 8.5 Hz, 1H), 7.87 (d, J = 9.0 Hz, 1H), 7.78 (d, J = 8.0 Hz, 1H), 7.51–7.45 (m, 1H), 7.40–7.31 (m, 2H), 7.12 (s, 6H).; 13C NMR (100 MHz, CDCl3) δ: 156.34, 135.92, 132.90, 130.66, 129.56, 129.19, 128.59, 128.03, 127.04, 126.71, 123.89, 116.68, 109.11.

Obtained as Brown solid (41.3 mg, 53%); Purified using hexane/ethyl acetate (95:5); mp: 57–58 °C; 1H NMR (400 MHz, CDCl3) δ: 8.28 (d, J = 8.5 Hz, 1H), 7.86 (d, J = 9.0 Hz, 1H), 7.78 (d, J = 8.0 Hz, 1H), 7.52–7.44 (m, 1H), 7.39–7.31 (m, 2H), 7.16 (s, 1H), 7.07 (d, J = 8.0 Hz, 2H), 6.94 (d, J = 8.0 Hz, 2H), 2.22 (s, 3H).; 13C NMR (100 MHz, CDCl3) δ: 156.20, 136.73, 135.90, 132.73, 130.36, 129.52, 128.57, 127.96, 127.08, 126.82, 123.82, 116.65, 109.63, 21.07.

Obtained as Brown solid (36.4 mg, 50%); Purified using hexane/ethyl acetate (95:5); mp: 108–109 °C; 1H NMR (400 MHz, CDCl3) δ: 8.21 (d, J = 8.5 Hz, 1H), 7.88 (d, J = 9.0 Hz, 1H), 7.79 (d, J = 8.0 Hz, 1H), 7.53–7.43 (m, 1H), 7.36 (td, J = 9.0, 8.5, 3.0 Hz, 2H), 7.12–7.02 (m, 5H). 13C NMR (100 MHz, CDCl3) δ: 156.34, 135.68, 133.17, 132.88, 130.48, 129.66, 129.60, 128.86, 128.69, 128.20, 126.78, 124.02, 116.74, 108.82.

The optimization of the reaction conditions was conducted using IP 1a and diphenyl diselenide 2a as model substrates, in the presence of TCCA at room temperature. Screening under various conditions was carried out (Table 1). Initially, the reactions were performed for a duration of 1 h. Considering that TCCA has 3 chlorine atoms, we focused on the stoichiometric quantity of TCCA (entries 1–5). On using 0.6 molar equiv. of TCCA, the selenylated product 3a was obtained in 74% isolated yield (entry 1). There was an improvement in the yield of the reaction when we further decreased the quantity of TCCA (entry 2–3). The yield of 3a remained constant when 0.35 molar equiv. of TCCA was used (entry 4), while a further decrease in the quantity of TCCA had a negative impact on the reaction (entry 5).

After determining the appropriate quantity of TCCA, in the next step the stoichiometric quantity of diselenide 2a was screened for this transformation (entries 5–8) and the ideal quantity of 0.55 molar equiv. of 2a was obtained (entry 7). With regard to the influence of the solvent on the selenylation of 1a (Table 1, entries 9–16), EtOH was found to be the most effective solvent. Increasing the reaction temperature to 50 °C (entry 17) or applying reflux (entry 18) had a negative impact on the yield of 3a. Subsequently, when the reaction was performed under an inert atmosphere, no influence on the yield of selenylated product was observed (entry 7 vs. 16).

To minimize the quantity of solvent used, we then screened the effect of the solvent quantity, 1 mL (entries 7, 17–18) and 2 mL of EtOH (entries 7, 17–18) resulted in the best yield of 3a (entry 17). Lastly, the effect of the reaction time was screened for this transformation (entries 7, 20–23). On decreasing the reaction time from 60 to 15 min, the desired product 3a was isolated in almost constant yields. However, with a further decrease in the reaction time from 15 to 10 min, a significant decrease in the yield of 3a was observed (entry 22 vs. 23).

After ascertaining the best reaction parameters (Table 1, entry 22), the generality and scope of the C(sp2)–H bond selenylation of various other diorganyl diselenides 2 (Fig. 3) and IPs 1 (Fig. 4) were investigated. We first evaluated the efficiency of different diorganyl diselenides 2 while keeping IP 1a constant (Fig. 3).

Scope of diorganyl diselenides 3. Conditions: 1a 0.25 mmol, 2a–k (0.55 molar equiv), TCCA (0.35 molar equiv); EtOH (2.0 mL), time is shown for each example, r.t., room temperature; NR, No reaction.

Scope of IP 1. Conditions: 1a–o (0.25 mmol), 2a (0.55 molar equiv), TCCA (0.34 molar equiv); EtOH (2.0 mL), time is shown for each example, r.t., room temperature.

The reaction worked well for several diorganyl diselenides containing both electron-donating (EDG) (Me, OMe) and electron-withdrawing (EWG) (F, Cl, CF3) groups as well as bulky groups, verifying the tolerance and broad scope regarding the electronic and steric effects of several different substituents. All of the desired selenylated products were obtained in good to excellent yields. In general, EWGs at the phenyl ring afforded the respective product in a slightly lower yield as compare to the EDGs (3b–d vs. 3e,g). These results revealed a small dependence on the electronic effect of the substituents bonded to the aromatic ring at the selenium atom. A greater stability of the electrophilic species generated can explain the higher yields when substituted rings with electronic density donor groups were used. In order to investigate the effect of steric hindrance, ortho-substituted aryl substrates were used and a weaker influence on the yields was observed as compared to the respective para derivatives (3e,g vs. 3f,h respectively). Sterically-bulkier substrates (2-napthyl) resulted in the desired product 3i in 64% yield. It should be noted that the reaction demonstrated a great tolerance to heteroaromatic diselenide and C-2 heteroaryl diselenide afforded the desired product 3j with 90% yield.

Considering the importance of aliphatic selenides, the protocol was then extended to butylated organoselenides, since they play an important role in cross-coupling reactions54. Gratifyingly, diselenides with n-butyl groups directly bonded to the selenium atom, producing the corresponding products 3k in excellent yield. Lastly, when diphenyl disulfide and ditelluride were tested as substrates under the optimized reaction conditions, no reaction was observed. Similarly, when thiophenol was used as the source of chalcogen, the expected product was not observed.

To further broaden the scope in relation to the substrate, the influence of the IP 1 moiety was evaluated with 2a (Fig. 4), under the optimized reaction conditions. The IP nucleus was tested with different functionalities, e.g., Cl, Br, Me, MeO, attached at the aryl moiety as well as the heteroaryl substituent. It should be noted that the compounds 1b–p are well tolerated in this transformation and resulted in the respective products 4a–o with up to 95% yield. Electronics effects of the substituents attached to the aryl moiety at position C-2 demonstrate great tolerance for the selenylation reaction. OMe (EDG) at the para, meta and para and meta positions, for example, can be tolerated with short reaction times and satisfactory yields. In the case of an EWG at the aromatic ring, attached to the C-2, elevated yields were obtained for products 4d–e and 4p. Selenylated products with the bromo-substituent attached are important as they can be post-functionalized in other organic transformations. Moderate yields were obtained in the synthesis of 4f and 4h. In the case of 4f, we postulate that steric hindrance by the naphthyl ring contributed to the decrease in the yield. Even when a longer reaction time was applied (720 min), there was no increase in the yield of the respective product. Notably, the product containing the heteroaromatic group at the C-2 position (4g) was also synthesized in high yield (88%), demonstrating the versatility of our protocol.

In the next step, the effect due to a variation in the functionalization of positions 6, 7 and 8 of IP was tested. The reaction tolerated the electronic effect and resulted in the selenylated product 4i–l in 74-93% yields. In addition, on exploring the double electronic effects of the substituent on IP, the products 4m and 4n were also achieved in good yields. Encouraged by the results obtained from the selenylation of IP, we applied this transformation to the IP 1o, which is the core for a commercially available drug with the trade name “Zolpidem”, affording the corresponding selenylated product 4o with high efficiency and high yield. Similarly, it is also noteworthy to mention that by using Zolmidine (commercial drug, used in the treatment of peptic ulcer and gastro-oesophageal reflux disease) as substrate, afforded the desired selenylated product 4e in 94% yield. These products are extremely relevant since it contains the same molecular scaffolds as Zolpidem and Zolmidine, which could have importance regarding the pharmacophoric characteristics of a possible newly discovered drug.

Following the success in the TCCA-mediated C(sp2)–H bond selenylation of the IP indole 2, this method was extended to structurally diverse N-heteroarenes 5a–e, using diselenide 2a under ideal reaction conditions (Fig. 5). It was observed that 2-phenylimidazo[1,2-a]pyrimidine 5a furnished the corresponding C-3 selenylated product in 81% yield. When imidazo[2,1-b]thiazoles 5b–d were tested as substrates, the respective products 6b–d were achieved in very good to excellent yields. Furthermore, to extend the scope of the work to other heteroarenes, we tested indole 5c as the substrate for selenylation, resulting in 6c in 39% isolated yields. These findings demonstrate the potential application of this methodology to a diversity of heteroaromatics.

Synthesis of selenylated N-aromatic products 6a–e. Conditions: 5a–e 0.25 mmol, 2a (0.55 molar equiv), TCCA (0.35 molar equiv); EtOH (2.0 mL) time is shown for each example r.t., room temperature.

Following the success in the TCCA-mediated C(sp2)–H bond selenylation of N-heteroarenes, this method was extended to 2-naphthol 5f and diorganyl diselenides 2 as the coupling partner (Fig. 6). To our delight, the reaction furnished the corresponding selenylated products 6f–h in moderate to good yields, highlighting the potentially broad scope of this methodology.

Scope of selenylated naphthol 6f–h. Conditions: 5f (0.25 mmol), 2 (0.55 molar equiv), TCCA (0.35 molar equiv); EtOH (2.0 mL), time is shown for each example, r.t., room temperature.

To demonstrate the potential and the synthetic utility of our methodology, a series of reactions was performed at different scales in a normal laboratory set-up (Fig. 7; up to 10 mmol). For this, IP 1a and diselenide 2a were selected as substrates and were tested under optimized conditions, affording 3a with no major decrease in yield. Thus, this protocol represents a practical synthetic method for the synthesis of biologically-relevant lead compounds on a larger scale.

Results for the reaction at different scales.

Lastly, in order to gain further insights regarding the reaction and to tentatively propose a mechanism, some control experiments were conducted (Fig. 8). Firstly, the standard reaction was conducted in the presence of 3.0 molar equiv. of radical inhibitor (TEMPO, hydroquinone, BHT). It was found that radical scavengers did not hamper the reaction (Fig. 8a), excluding the possibility of a radical pathway. In the next step, some reactions were carried out in order to ascertain if a chlorinated species is involved in the reaction. In this experiment, 3-chloro-2-phenylimidazo[1,2-a]pyridine 7 was used as the substrate together with 2a, without the presence of TCCA (Fig. 8b). In this case, no reaction was observed, eliminating the possibility of 7 as the intermediate.

Investigation of the reaction mechanism.

Subsequently, when 1a was treated PhSeCl 8, under the optimized reaction conditions, the desired product was obtained in 30% isolated yield (Fig. 8c). In case of reaction with the selenium derivative of isocyanuric acid 9, the selenylated product 3a was obtained in 86% yield (Fig. 8d). This indicates that the electrophilic selenium species 9 could be involved in the reaction. These results, clearly highlights the active involvement of 9 as an intermediate.

Based on the results obtained from the control experiments and reported in the literature55, a possible mechanism was proposed using 1a and 2a as examples (Fig. 9). In the first step the electrophilic species I is most likely formed from the reaction of diselenide 2a and TCCA. Subsequently, species I could react with IP 1a via a canonical structure II at the C-3 position, generating the species III. Ethanol, used as a solvent, could play an important role in the reaction, by stabilizing species II. The selenylated species III would undergo deprotonation and restoration of the aromaticity, resulting in the desired product 3a.

Proposed mechanism for the reaction.

In conclusion, we have developed a robust and straightforward method for the preparation of selenylated-imidazopyridines from the corresponding imidazopyridines and diorganyl diselenides in a very short reaction time. Under the optimized reaction conditions, which involve the use of a trichloroisocyanuric acid (TCCA)-ethanol system, this eco-friendly approach afforded the desired products in good yields. The reaction demonstrated tolerance for the electronic and steric effects of substituents, without the need for the exclusion of air and moisture. Moreover, this method could be applied to other N-heteroarenes as substrates. This is an important contribution considering the potential therapeutic application of these hybrid compounds.

The important features of this benign protocol are: (1) open to the air atmosphere; (2) very short reaction time; (3) inexpensive reagents; (4) gram-scalable; (5) green oxidant (6) greener solvent; and (7) applicability to structurally diverse N-heteroarenes.

All data generated or analyzed during this study are included in this published article and its supplementary information file.

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We gratefully acknowledge CAPES (001), CNPq, INCT-Catálise/CNPq/FAPESC and UFMS for financial support. J.S.S.N. (Postdoctoral fellow) and M.R.S. (Ph.D. fellow) are grateful to CAPES and CNPq for the fellowships. S.S., D.P.L., and J.R. would like to acknowledge CNPq (315399/2020-1, 422645/2021-4, 309975/2022-0, and 403210/2021-6) and FUNDECT—MS Grant No. 266/2022 (SIAFEM 32184—DPL), Grant No. 266/2022 and Process No. 71/020.168/2021. The authors also acknowledge CEBIME for the HRMS analysis.

Departamento de Química, Universidade Federal de Santa Catarina–UFSC, Florianópolis, SC, 88040-970, Brazil

José S. S. Neto, Marcos R. Scheide, Marcelo S. Franco & Antonio L. Braga

Instituto de Química, Universidade Federal de Goiás–UFG, Goiânia, GO, 74690-900, Brazil

José S. S. Neto, Isis J. A. Granja, Sumbal Saba & Jamal Rafique

Instituto de Química, Universidade Federal do Mato Grosso do Sul–UFMS, Campo Grande, MS, 79074-460, Brazil

Cassio A. O. Moraes, Adilson Beatriz, Dênis P. de Lima & Jamal Rafique

Departamento de Química, Universidade Estadual do Centro-Oeste–UNICENTRO, Guarapuava, PR, 85819-110, Brazil

Giancarlo V. Botteselle

Universidade Federal de Santa Catarina–UFSC, Campus Araranguá, Araranguá, SC, 88905-120, Brazil

Tiago E. A. Frizon

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Conceptualization: J.S.S.N., S.S., J.R., and A.L.B.; Methodology: J.S.S.N., I.J.A.G., M.R.S., M.S.F., and C.A.O.M.; Validation: J.S.S.N., M.R.S., A.B., D.P.L. G.V.B., S.S., and T.E.A.F.; Formal analysis: J.S.S.N., M.R.S., A.B., D.P.L. G.V.B., T.E.A.F., S.S., and J.R.; Investigation: J J.S.S.N., I.J.A.G., M.R.S., M.S.F., and C.A.O.M.; Resources: S.S., J.R., and A.L.B.; Data curation: J.S.S.N., M.R.S., and M.S.F.; Writing—Original draft: J.R.; Writing—Review & Editing: J.R. and A.L.B.; Visualization: J.R. and A.L.B.; Supervision: S.S., J.R., and A.L.B.; Project administration: J.R. and A.L.B.; Funding acquisition: J.R. and A.L.B. All authors read and approved the final draft of the manuscript.

Correspondence to Jamal Rafique or Antonio L. Braga.

The authors declare no competing interests.

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Neto, J.S.S., Granja, I.J.A., Scheide, M.R. et al. Catalyst- and metal-free C(sp2)–H bond selenylation of (N-hetero)-arenes using diselenides and trichloroisocyanuric acid at room temperature. Sci Rep 13, 14251 (2023). https://doi.org/10.1038/s41598-023-41430-9

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Received: 05 May 2023

Accepted: 26 August 2023

Published: 31 August 2023

DOI: https://doi.org/10.1038/s41598-023-41430-9

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