Bismuth(III)-Catalyzed Regioselective Selenation of Indoles with Diaryl Diselenides: Synthesis of 3-Selanylindoles

Heterocyclic aryl selenides have recently attracted considerable research interest owing to their applications in biological and pharmaceutical fields. Herein, we describe a simple and general synthesis of 3-selanylindoles via a novel regioselective C–H selenation of indoles using a bismuth reagent as a catalyst. The reactions of indoles with diselenides in the presence of 10 mol% BiI3 at 100 °C in DMF afforded the corresponding 3-selanylindoles in moderate-to-excellent yields. The reaction proceeded efficiently under aerobic conditions by adding only a catalytic amount of BiI3, which was non-hygroscopic and less toxic, and both selanyl groups of the diselenide were transferred to the desired products.


Introduction
Organoselenium compounds have received considerable attention in organic chemistry, as well as in biological and pharmaceutical sciences [1][2][3][4][5][6][7][8][9][10][11][12][13][14], and there is growing interest in biologically active unsymmetrical diaryl selenides containing heterocyclic rings (i.e., aryl heteroaryl selenides).For example, 3-selanylindoles, compounds with a selenium side chain substituted at the 3-position of indoles, which are widely used as a basic skeleton in natural products and medicines, have been reported to have biological activities, such as the inhibition of tubulin polymerization, antiproliferative activity, anti-inflammatory properties, and antioxidant activity, and are expected to be used as drug discovery resources (Figure 1) [15][16][17][18][19][20].Therefore, the development of synthetic methods for these compounds has attracted attention.Direct selenation into indoles has been reported since the 2010s and is a powerful and commonly used method involving the reaction of available indole derivatives with stable and easy-to-handle diselenides as selenium sources.These reactions can be broadly classified into those involving the addition of oxidants [21][22][23] or bases [24][25][26], radical reactions using photoreactors [27][28][29][30][31][32][33][34] or electrolytic devices [35,36], and those using transition metal catalysts containing Pd, Cu, Ag, and Fe [37][38][39][40][41][42].However, these reactions use excessive reagents, additives, and transition metal catalysts of toxicological concern even in catalytic reactions, and require special equipment and expensive photocatalysts or supporting electrolytes for the photoreactions and electrolytic reactions, respectively.Recently, four transition metal-free catalytic reactions were reported (Scheme 1).Braga et al. developed a catalytic reaction using DMSO as the oxidant in the presence of a catalytic quantity of I 2 ; however, the reaction required microwave irradiation [43].The researchers also used KIO 3 as a catalyst, but this reaction required an excess (4 equiv.) of glycerol [44].Roehrs et al. reported an I 2 -catalyzed reaction that required the addition of stoichiometric amounts of urea hydrogen peroxide as an oxidant [45].Jana et al. developed a reaction using Cs 2 CO 3 as a catalyst, albeit in an oxygen atmosphere [46].As mentioned above, catalytic reactions require additives; otherwise, the reaction conditions are restrictive.
atmosphere [46].As mentioned above, catalytic reactions require additives; otherwise, the reaction conditions are restrictive.Inorganic bismuth compounds have attracted attention in the field of organic synthesis since the 1980s because of their excellent reactivity as mild Lewis acids, nontoxicity, and environmental friendliness [47][48][49][50][51][52].For example, BiCl3, a trivalent bismuth halide, has been reported to act as a catalyst for the following reactions: the Mukaiyama aldol reaction [53,54], the nucleophilic opening of epoxide [55], deoxygenative allylation [56], the Diels-Alder reaction [57,58], the three-component reaction of aldehydes, amines, and ketones or trimethylsilyl cyanide [59,60], the Friedel-Crafts reaction [61], the oxy-Michael addition [62], the aminooxygenation of propargyl amidine [63], and the tandem cyclization of tryptamine-ynamide [64].More recently, BiCl3 has been utilized in the catalytic coupling reactions of aryl iodides or aminobenzimidazoles with arylboronic acids for C(Ar)-C(Ar) and C(Ar)-N bond formation [65,66].By contrast, bismuth iodide (BiI3) is widely used in semiconductors and solar cell devices [67,68].However, its chemical reactivity in organic reactions is largely unknown, and its use in catalytic reactions has been limited to the deprotection of acetals, guanylation with desulfurization using thioureas and amines, and S,S-acetalization of benzaldehyde [69][70][71].Inspired by these reports, we present a facile Bi(III)-catalyzed regioselective C(Ar)-Se bond formation reaction of indoles with diaryl diselenides using BiI3 as the catalyst for the synthesis of 3-selanylindoles under mild conditions.The system was simple, containing only substrates and a Bi catalyst.

Results and Discussion
We initially focused on determining the optimal experimental conditions, including screening for suitable catalysts and solvents, for the synthesis of 3-selanylindole 3aa using N-methylindole 1a and diphenyl diselenide 2a as model substrates, the results of which, are summarized in Table 1.N-methylindole 1a (0.5 mmol) was reacted with 2a (0.25 mmol) in the presence of several Bi catalysts (0.05 mmol) in DMF at 100 °C under aerobic conditions (entries 1-7).BiCl3, BiBr3, BiI3, and Bi(OTf)3, which function as Lewis acids, afforded the corresponding 3-selanylindole 3aa in good-to-excellent yields (77-97%).BiI3 displayed the best yield and reaction time, and both selanyl groups were efficiently transferred from the diselenide to product 3aa (entry 3).Furthermore, although bismuth atmosphere [46].As mentioned above, catalytic reactions require additives; otherwise, the reaction conditions are restrictive.Inorganic bismuth compounds have attracted attention in the field of organic synthesis since the 1980s because of their excellent reactivity as mild Lewis acids, nontoxicity, and environmental friendliness [47][48][49][50][51][52].For example, BiCl3, a trivalent bismuth halide, has been reported to act as a catalyst for the following reactions: the Mukaiyama aldol reaction [53,54], the nucleophilic opening of epoxide [55], deoxygenative allylation [56], the Diels-Alder reaction [57,58], the three-component reaction of aldehydes, amines, and ketones or trimethylsilyl cyanide [59,60], the Friedel-Crafts reaction [61], the oxy-Michael addition [62], the aminooxygenation of propargyl amidine [63], and the tandem cyclization of tryptamine-ynamide [64].More recently, BiCl3 has been utilized in the catalytic coupling reactions of aryl iodides or aminobenzimidazoles with arylboronic acids for C(Ar)-C(Ar) and C(Ar)-N bond formation [65,66].By contrast, bismuth iodide (BiI3) is widely used in semiconductors and solar cell devices [67,68].However, its chemical reactivity in organic reactions is largely unknown, and its use in catalytic reactions has been limited to the deprotection of acetals, guanylation with desulfurization using thioureas and amines, and S,S-acetalization of benzaldehyde [69][70][71].Inspired by these reports, we present a facile Bi(III)-catalyzed regioselective C(Ar)-Se bond formation reaction of indoles with diaryl diselenides using BiI3 as the catalyst for the synthesis of 3-selanylindoles under mild conditions.The system was simple, containing only substrates and a Bi catalyst.

Results and Discussion
We initially focused on determining the optimal experimental conditions, including screening for suitable catalysts and solvents, for the synthesis of 3-selanylindole 3aa using N-methylindole 1a and diphenyl diselenide 2a as model substrates, the results of which, are summarized in Table 1.N-methylindole 1a (0.5 mmol) was reacted with 2a (0.25 mmol) in the presence of several Bi catalysts (0.05 mmol) in DMF at 100 °C under aerobic conditions (entries 1-7).BiCl3, BiBr3, BiI3, and Bi(OTf)3, which function as Lewis acids, afforded the corresponding 3-selanylindole 3aa in good-to-excellent yields (77-97%).BiI3 displayed the best yield and reaction time, and both selanyl groups were efficiently transferred from the diselenide to product 3aa (entry 3).Furthermore, although bismuth Inorganic bismuth compounds have attracted attention in the field of organic synthesis since the 1980s because of their excellent reactivity as mild Lewis acids, nontoxicity, and environmental friendliness [47][48][49][50][51][52].For example, BiCl 3 , a trivalent bismuth halide, has been reported to act as a catalyst for the following reactions: the Mukaiyama aldol reaction [53,54], the nucleophilic opening of epoxide [55], deoxygenative allylation [56], the Diels-Alder reaction [57,58], the three-component reaction of aldehydes, amines, and ketones or trimethylsilyl cyanide [59,60], the Friedel-Crafts reaction [61], the oxy-Michael addition [62], the aminooxygenation of propargyl amidine [63], and the tandem cyclization of tryptamine-ynamide [64].More recently, BiCl 3 has been utilized in the catalytic coupling reactions of aryl iodides or aminobenzimidazoles with arylboronic acids for C(Ar)-C(Ar) and C(Ar)-N bond formation [65,66].By contrast, bismuth iodide (BiI 3 ) is widely used in semiconductors and solar cell devices [67,68].However, its chemical reactivity in organic reactions is largely unknown, and its use in catalytic reactions has been limited to the deprotection of acetals, guanylation with desulfurization using thioureas and amines, and S,S-acetalization of benzaldehyde [69][70][71].Inspired by these reports, we present a facile Bi(III)-catalyzed regioselective C(Ar)-Se bond formation reaction of indoles with diaryl diselenides using BiI 3 as the catalyst for the synthesis of 3-selanylindoles under mild conditions.The system was simple, containing only substrates and a Bi catalyst.

Results and Discussion
We initially focused on determining the optimal experimental conditions, including screening for suitable catalysts and solvents, for the synthesis of 3-selanylindole 3aa using N-methylindole 1a and diphenyl diselenide 2a as model substrates, the results of which, are summarized in Table 1.N-methylindole 1a (0.5 mmol) was reacted with 2a (0.25 mmol) in the presence of several Bi catalysts (0.05 mmol) in DMF at 100 • C under aerobic conditions (entries 1-7).BiCl 3 , BiBr 3 , BiI 3 , and Bi(OTf) 3 , which function as Lewis acids, afforded the corresponding 3-selanylindole 3aa in good-to-excellent yields (77-97%).BiI 3 displayed the best yield and reaction time, and both selanyl groups were efficiently transferred from the diselenide to product 3aa (entry 3).Furthermore, although bismuth halides such as BiCl 3 and BiBr 3 are hygroscopic, BiI 3 can be easily handled in air without such concerns.By contrast, antimony catalysts with the same group of atoms as bismuth and other Lewis acid catalysts were less effective than BiI 3 (entries 8-12).A comparison to iodine (I 2 ) was also attempted; however, the reaction barely progressed (entry 13).Solvent screening indicated that the reaction proceeded efficiently in DMF (97%), DMSO (89%), and THF (60%), whereas CH 3 CN, MeOH, dioxane, 1,2-DCE, and toluene were inefficient (entries 3 and 14-20).When the reaction was performed at 60 • C, the reaction time increased markedly to 8 h (entry 21).The reaction performed under oxygen produced 3aa in a high yield (94%), which was almost identical to that obtained under aerobic conditions (entries 3 and 22).However, the yield was notably suppressed (9%) under an argon atmosphere (entry 23).Decreasing the BiI 3 loading from 10 to 5 and 1 mol% markedly prolonged the reaction time, although the reaction afforded the desired product (entries 24 and 25).The best result was obtained under aerobic conditions at 100 • C when 1a was treated with 0.5 equivalents of diselenide 2a in the presence of BiI 3 (10 mol%) in DMF (entry 3).This selenation could also be scaled up to 10 mmol.The desired product 3aa was obtained in an excellent yield (99%), generating up to 2.84 g of the product.Furthermore, the reaction of 1a and 2a with 1 equivalent of TEMPO [(2,2,6,6-tetramethylpiperidin-1-yl)oxyl] or 1,1diphenylethylene as radical scavengers afforded 3aa in yields of 94% and 96%, respectively (entries 26 and 27).These results indicate that the reaction system does not follow a radical mechanism.The regiochemistry of 3-selanylindole 3aa was elucidated using 1 H-NMR and single-crystal X-ray analyses (Figure 2).The 1 H-NMR spectrum of 3aa was consistent with that of the standard sample [41].
Table 1.Optimization of the reaction conditions [a] .
[h] TEMPO (0.5 mmol). [i] Diphenylethylene (0.5 mmol).To understand the scope and limitations of the developed regioselective selenation reaction, various indoles 1 (0.5 mmol) were reacted with diselenides 2 (0.25 mmol) under the optimized conditions (Figure 3).The reaction of N-methylindole 1a with diaryl diselenides 2b-i afforded the corresponding products, i.e., 3ab-ai, in good-to-excellent yields, except for 3ah.For 3ab-ae, the presence of an electron-donating or electronwithdrawing group at the 4-position of the benzene ring of diselenides 3b-e did not affect the reaction progression, although the reaction time was slightly prolonged when electron-donating groups were substituted.Sterically hindered ortho-substituted diselenides 2f and 2g reacted to give selenides 3af and 3ag, respectively.By contrast, for 2h, which comprises a benzylamino group, the reaction did not proceed, and the starting materials were recovered.For the reaction using diaryl diselenide 2i, which bears a heterocyclic ring, 3ai was afforded in a good yield.Dibenzyl diselenide 2j, which contains a benzyl moiety as the alkyl group, also afforded 3aj in a good yield (82%).Next, the reaction of diphenyl diselenide 2a with various N-methylindoles, i.e., 1b-i, bearing electron-donating or electron-withdrawing groups on the benzene ring afforded the desired products 3ba-3ia in satisfactory yields (75-99%).The reaction proceeded smoothly from the unsubstituted indoles 1j-l to obtain the parent 3-selanylindoles 3ja-la (79-93%).Furthermore, the reaction of the N-substituted indoles 1m and 1n with benzyl or phenyl groups on the nitrogen also gave the corresponding products 3ma and 3na; however, N-acetylindole 1o with an electron-withdrawing group did not give 3oa, and the starting materials were recovered.These results suggest that the reaction is electrically influenced by the substituents on the indole nitrogen.2-Phenyl-and 2-methylindoles 1p and 1q were treated with 2a to afford the 3-selanyl-2-substituted indoles 3pa and 3qa, respectively.The attempted double selenation of 1a using two equivalents of diphenyl diselenide 2a did not yield the corresponding 2,3-diselanylindole 3ra; instead, 3selanylindole 3aa was isolated in a yield of 98%.These results suggest that this reaction proceeds only at the 3-position of the indole.Finally, the reaction of 1a with dichalcogenides containing sulfur and tellurium was attempted.The reaction with To understand the scope and limitations of the developed regioselective selenation reaction, various indoles 1 (0.5 mmol) were reacted with diselenides 2 (0.25 mmol) under the optimized conditions (Figure 3).The reaction of N-methylindole 1a with diaryl diselenides 2b-i afforded the corresponding products, i.e., 3ab-ai, in good-to-excellent yields, except for 3ah.For 3ab-ae, the presence of an electron-donating or electron-withdrawing group at the 4-position of the benzene ring of diselenides 3b-e did not affect the reaction progression, although the reaction time was slightly prolonged when electron-donating groups were substituted.Sterically hindered ortho-substituted diselenides 2f and 2g reacted to give selenides 3af and 3ag, respectively.By contrast, for 2h, which comprises a benzylamino group, the reaction did not proceed, and the starting materials were recovered.For the reaction using diaryl diselenide 2i, which bears a heterocyclic ring, 3ai was afforded in a good yield.Dibenzyl diselenide 2j, which contains a benzyl moiety as the alkyl group, also afforded 3aj in a good yield (82%).Next, the reaction of diphenyl diselenide 2a with various N-methylindoles, i.e., 1b-i, bearing electron-donating or electron-withdrawing groups on the benzene ring afforded the desired products 3ba-3ia in satisfactory yields (75-99%).The reaction proceeded smoothly from the unsubstituted indoles 1j-l to obtain the parent 3-selanylindoles 3ja-la (79-93%).Furthermore, the reaction of the N-substituted indoles 1m and 1n with benzyl or phenyl groups on the nitrogen also gave the corresponding products 3ma and 3na; however, N-acetylindole 1o with an electron-withdrawing group did not give 3oa, and the starting materials were recovered.These results suggest that the reaction is electrically influenced by the substituents on the indole nitrogen.2-Phenyland 2-methylindoles 1p and 1q were treated with 2a to afford the 3-selanyl-2-substituted indoles 3pa and 3qa, respectively.The attempted double selenation of 1a using two equivalents of diphenyl diselenide 2a did not yield the corresponding 2,3-diselanylindole 3ra; instead, 3-selanylindole 3aa was isolated in a yield of 98%.These results suggest that this reaction proceeds only at the 3-position of the indole.Finally, the reaction of 1a with dichalcogenides containing sulfur and tellurium was attempted.The reaction with diphenyl disulfide afforded the desired 3-sulfanylindole 4 in an excellent yield (99%), although the reaction time (24 h) was longer than that with diselenide, which is a selenium reagent.By contrast, the reaction proceeded to a certain extent with diphenyl ditelluride, and indole 5 was obtained in a yield of 26%.
diphenyl disulfide afforded the desired 3-sulfanylindole 4 in an excellent yield although the reaction time (24 h) was longer than that with diselenide, which is a sele reagent.By contrast, the reaction proceeded to a certain extent with diphenyl ditell and indole 5 was obtained in a yield of 26%. [a] 1 (0.5 mmol), 2 (0.25 m BiI3 (0.05 mmol), and DMF (2 mL). [b] Yield of isolated products. [c] 2a (0.5 mmol); 3aa was is in a yield of 98%.
However, the reaction mechanism for this selenation remains unclear.Circumst evidence indicates that the reaction was affected by the gaseous atmospher proceeded smoothly in the presence of a molecular oxygen atmosphere while notably suppressed in an inert gas atmosphere (Table 1: entries 3, 22, and 23).BiI3 fo pentacoordinated complex with bismuth, the central atom, and the oxygen ato reagents and solvents such as Mo8O26 and THF [72,73].Therefore, a possible mech for this reaction is illustrated in Scheme 2. The initial step was the generation pentacoordinated Bi-peroxo complex A from BiI3 and oxygen.While the selenium of the diselenide coordinates with complex A, the 3-position of the indole nucleophi attacks another selenium atom, forming complex B and intermediate C.  [a] 1 (0.5 mmol), 2 (0.25 mmol), BiI 3 (0.05 mmol), and DMF (2 mL). [b] Yield of isolated products. [c] 2a (0.5 mmol); 3aa was isolated in a yield of 98%.
However, the reaction mechanism for this selenation remains unclear.Circumstantial evidence indicates that the reaction was affected by the gaseous atmosphere and proceeded smoothly in the presence of a molecular oxygen atmosphere while being notably suppressed in an inert gas atmosphere (Table 1: entries 3, 22, and 23).BiI 3 forms a pentacoordinated complex with bismuth, the central atom, and the oxygen atoms of reagents and solvents such as Mo 8 O 26 and THF [72,73].Therefore, a possible mechanism for this reaction is illustrated in Scheme 2. The initial step was the generation of the pentacoordinated Biperoxo complex A from BiI

Conclusions
Herein, we report a simple Bi-catalyzed regioselective selenation protocol for the synthesis of 3-selanylindoles under mild reaction conditions.The reaction is atomeconomical, with the participation of both selanyl groups of the diaryl diselenide.Indoles and diselenides bearing different functional groups afforded the corresponding products in satisfactory yields.This reaction is the first example of the Bi-catalyzed C-H selenation of aromatic heterocycles.Detailed studies on the exact mechanism of this reaction and the synthesis of asymmetric selenides containing other heterocyclic rings using this protocol are currently underway.

Conclusions
Herein, we report a simple Bi-catalyzed regioselective selenation protocol for the synthesis of 3-selanylindoles under mild reaction conditions.The reaction is atom-economical, with the participation of both selanyl groups of the diaryl diselenide.Indoles and diselenides bearing different functional groups afforded the corresponding products in satisfactory yields.This reaction is the first example of the Bi-catalyzed C-H selenation of aromatic heterocycles.Detailed studies on the exact mechanism of this reaction and the synthesis of asymmetric selenides containing other heterocyclic rings using this protocol are currently underway.

Single-Crystal X-ray Diffraction Experiment of 3aa
A suitable crystal was selected and measured on an XtaLAB Synergy, Single source at home/near, HyPix3000 diffractometer.The crystal was kept at 103 K in an N 2 cold stream during data collection.Using Olex2 [77], the structure was solved with the SHELXT [78] structure solution program using Intrinsic Phasing and refined with the SHELXL [79] refinement package using Least Squares minimization.Crystal Data for 3aa: C 15 H 13 NSe (M = 286.22g/mol), monoclinic, space group P2 1 /n (no.14), a = 7.73810 (10) Å, b = 9.03610(10) Å,
The aryl se anion formed during the interconversion between complexes B and A a intermediate C to form 3-selanylindole 3 and selenol D. Selenol D is convert diselenide 2 via oxidation in air.Therefore, the reaction proceeds with 0.5 equivale
3 and oxygen.While the selenium atom of the diselenide coordinates with complex A, the 3-position of the indole nucleophilically attacks another selenium atom, forming complex B and intermediate C. The aryl selenide anion formed during the interconversion between complexes B and A attacks intermediate C to form 3-selanylindole 3 and selenol D. Selenol D is converted to diselenide 2 via oxidation in air.Therefore, the reaction proceeds with 0.5 equivalents of diselenide, and both selanyl groups are used for the reaction.Bismuth complexes A and B, which are expected to form during this process, have not yet been confirmed or isolated.

Table 1 .
Optimization of the reaction conditions[a].