1. Introduction
The direct installation of an amino group into an indole skeleton is a very important strategy to generate amino indole derivatives, which are key building blocks for indole-based natural products and biologically active compounds [1,2,3,4,5,6]. The novel 3-selective amination of indole derivatives has attracted considerable attention from synthetic organic chemists. Regarding previous work on the 3-selective amination of indole derivatives, the nitration of protecting-group-free and N-protected indoles with metal nitrate or nitric acid is well known (Scheme 1A) [7,8,9,10,11,12]. Sudalai and coworkers reported an azidation of indole derivatives with a stoichiometric amount of I2 and NaN3 to give 3-azide indole derivatives (Scheme 1B) [13]. Wang and coworkers developed an electrophilic amidation of indoles with N-[(benzenesulfonyl)oxy]amide as the electrophilic nitrogen agent in the presence of ZnCl2 (Scheme 1C) [14]. As examples of the C–N coupling reaction of indoles with a nucleophilic nitrogen source, the azidation with NaN3 via the formation of indolyl(phenyl)iodonium azide (Scheme 1D) [15], and the amination of alkylamines via the formation of indolyl(Mes)iodonium tosylate (Scheme 1E) [16] from electron-donating group protected 2-substituted indoles using hypervalent iodine compounds were developed by Suna and coworkers. Regarding the 3-amination of electron-withdrawing group protected indoles, the 3-imidation of N-acetyl indoles with (PhSO2)2NF under transition-metal-free conditions was developed by Yang and coworkers (Scheme 1F) [17].
On the other hand, we were able to prepare indolyl(aryl)iodonium imides, which are related to I–N bonding hypervalent iodine compounds, from N-electron-withdrawing group protected indoles, bissulfonimides, and (diacetoxyiodo)arenes [18,19], and to achieve the dual functionalization of indoles via halo-amination with halogen reagents using the indolyl(aryl)iodonium imides [18,20].
We report herein a 3-selective C–N coupling reaction of N-electron-withdrawing group protected indoles with various bissulfonimides using hypervalent iodine compounds (Scheme 1G). In our previous work, the indole-selective C–N coupling reaction of indolyl(aryl)iodonium imides promoted by a copper catalyst gave 3-amino indole derivatives [21]. Furthermore, in the copper-catalyzed C–N coupling reaction, indolyl(2-butoxyphenyl)iodonium bistosylimide showed high indole selectivity whereas indolyl(phenyl)iodonium bistosylimide showed aryl selectivity (Scheme 2). From the results, we envisioned that (diacetoxy)iodoarene bearing an o-substituted phenyl group would promote the copper-catalyzed C–N coupling reaction of indoles with bissulfonimides via the formation of indolyl(aryl)iodonium imides. To obtain the corresponding 3-amino indole derivatives using this method, the formation of indolyl(aryl)iodonium imides should proceed effectively other than indole selectivity in the C–N coupling reaction of indolyl(aryl)iodonium imides. However, it is possible that steric hindrance by o-substituted bissulfonimidoiodoarene (ArI(OAc)(N(SO2R2)2) or ArI(N(SO2R2)2)2), which is generated in situ from the reaction of (diacetoxyiodo)arene with bissulfonimides, would suppress the formation of indolyl(aryl)iodonium imides. The necessity of appropriate steric hindrance and the electronic effect of o-alkoxy group substituted iodoarene moiety on hypervalent iodine(III) compounds in the 3-amination of N-electron-withdrawing group protected indoles were evaluated on the basis of comparisons with other o-substituted (diacetoxyiodo)arenes.
2. Results and Discussion
First, we conducted screening for (acetoxy)iodoarene, copper catalyst, and solvent for the 3-amination of indoles on the basis of previously reported reaction conditions (Table 1). It is important to use MeCN as a solvent in the formation of indolyl(aryl)iodonium imides (in the first step) and toluene-related solvent (i.e., toluene and xylene) in the copper-catalyzed C–N coupling reaction (in the second step) to progress each reaction efficiently [18,20,21]. Treatment of N-pivaloyl indole (1a) with Ts2NH (1.6 equiv.) and PhI(OAc)2 (1.2 equiv.) in MeCN at 40 °C for 7 h, followed by the addition of Cu(MeCN)4BF4 (5 mol%) in toluene under reflux conditions for 1 h provided N-pivaloyl-3-bistosylimido indole (2a) in 26% yield together with N,N-bistosylaniline in 58% yield as a byproduct (Entry 1). When (diacetoxyiodo)2-butoxybenzene (A), (diacetoxyiodo)2,4,6-trimethylbenzene (B), and (diacetoxyiodo)2,6-dimethoxybenzene (D) were used instead of PhI(OAc)2, the C–N coupling reaction showed high indole selectivity to obtain the desired product (2a) in high yields (76–82% yield) (Entries 2, 3, and 5). The use of (diacetoxyiodo)2,4,6-triisopropylbenzene (C) and 1-acetoxy-1,2-benziodoxol-3-(1H)-one (E) gave 2a in moderate to low yields (Entries 4 and 6). (Diacetoxyiodo)arenes (A, B, and D) as o-substituted hypervalent iodine compounds were adopted for use in xylene at 130 °C for the 3-amination of indoles, and similar reactivity to that in toluene under reflux conditions was realized (Entries 7–9). By contrast, the reaction with (diacetoxyiodo)arenes A, B, and D in the absence of copper catalyst gave 2a in low yields (16–42% yield) (Entries 10–12).
Then, (diacetoxyiodo)arenes A, B, and D were utilized in the reaction with N-pivaloyl 5-chloroindole (1b) under two conditions (in toluene under reflux conditions and in xylene at 130 °C) to clarify substrate generality for the 3-amination of indoles (Scheme 3). Treatment of 1b with (diacetoxyiodo)2-butoxybenzene (A) in xylene at 130 °C in the second step provided the desired product (2b) in 75% yield. However, when (diacetoxyiodo)2,4,6-trimethylbenzene (B) was used under similar conditions to those in the reaction with A, the reactivity of B with 1b declined to give 2b in 48% yield. (Diacetoxyiodo)2,6-dimethoxybenzene (D) showed similar reactivity to A (68% yield). It is noteworthy that the reaction of 1b in toluene under reflux conditions in the second step using the three (diacetoxyiodo)arenes (A, B, and D) generated small quantities of 2-aminated indole derivative as byproduct (5–9% yield). Therefore, we determined that the reaction in xylene at 130 °C in the presence of Cu(MeCN)4BF4 catalyst was the best option for the second step in the 3-amination of indoles using (diacetoxyiodo)arenes.
To compare the reactivities of (diacetoxyiodo)arenes (A, B, and D) in the copper-catalyzed 3-amination of indoles, N-protected indoles (1) were examined under optimum conditions (Scheme 4). Treatment of N-pivaloyl indole (1a) with various bissulfonimides, containing an aromatic group, an aliphatic group, or a dissymmetric functional group provided corresponding 3-amino indole derivatives (2c–f) in 51–81% yields, respectively. Unfortunately, the reaction with Ms2NH gave N-pivaloyl-2-dimesylimido-indole derivative (3f) in 10–14% yields as the by-product. The reaction of 5- and 6-substituted indoles bearing an alkyl group (1g and 1o), a halogen (1h, 1i, and 1p–r), an ether (1j and 1s), an ester (1k and 1l), and a phthalimide (1n) also produced corresponding products (2g–l, 2n–s) in 39–84% yields, respectively. Use of 7-substituted indole (1u) and 2-substituted indole (1w) derivatives in the present reaction also furnished the desired products (2u and 2w) in good yields (60–76%). Other indole protecting groups, such as benzoyl (1x) and tosyl (1y) groups, instead of a pivaloyl group also enhanced the reactivities of (diacetoxyiodo)arenes in the present reaction to give 3-amino indole derivatives (2x and 2y) in high yields (72–91%). In the reaction of 5-cyano (1m), 4-fluoro (1t), and 5,6-dichloro indole (1v) derivatives, (diacetoxyiodo)2-butoxybenzene (A) or (diacetoxyiodo)2,6-dimethoxybenzene (D) improved the yields of 3-amino indole derivatives (2m, 2t, and 2v) to 50–59% yield, whereas other (diacetoxyiodo)arenes showed low reactivity (20–36% yield). It is noteworthy that (diacetoxyiodo)arenes A and D are superior to (diacetoxyiodo)2,4,6-trimethylbenzene (B) in the one-pot 3-amination of indoles.
Furthermore, we examined the reaction of N-pivaloyl-5-chloroindole (1b) with Ts2NH and (diacetoxyiodo)arene (A, B, and D) in MeCN at 40 °C, which forms indolyl(aryl)iodonium imide (4b) (in the first step), to elucidate the reason why the reactivities of (diacetoxyiodo)arenes differ in the 3-amination of indole derivatives (Scheme 5). When (diacetoxyiodo)2-butoxybenzene (A) and (diacetoxyiodo)2,6-dimethoxybenzene (D) were used in this reaction, indolyl(aryl)iodonium imide (4b) was obtained in good yields (54% and 65%) together with 3-amino indole derivative (2b) (14% and 19%) and 2-amino indole derivative (3b) (12% and 13%). In contrast, (diacetoxyiodo)2,4,6-trimethylbenzene (B) showed lower reactivity than ArI(OAc)2 A and D (25% yield of 4b and 15% recovery of 1b). From the results, we suggest that the difference in reactivity among the (diacetoxyiodo)arenes in the 3-amination of indoles is strongly dependent on the reactivity in the formation of indolyl(aryl)iodonium imide in the first step.
In addition, it is possible that 3b is converted into 2b via rearrangement by a copper catalyst, based on the results that 3b was not generated in xylene at 130 °C, but was obtained in toluene under reflux conditions (Scheme 3). The reaction of N-pivaloyl 2-bistosylimido-5-chloroindole (3b) in the presence of Cu(MeCN)4BF4 catalyst in xylene at 130 °C provided a complex mixture without the formation of 2b (Scheme 6).
Based on the results of mechanistic studies, we propose a reaction mechanism for the 3-amination of indole derivatives, as shown in Scheme 7. The reaction of indole derivatives (1) with (diacetoxyiodo)arenes (ArI(OAc)2) and bissulfonimides ((R2SO2)2NH) in MeCN, which generates (sulfonimidoiodo) arene intermediates (ArI(OAc)(N(SO2R2)2) or ArI (N(SO2R2)2)2) in situ, provides indolyl(aryl)iodonium imides (4) together with 3-amino indole derivatives (2) and 2-amino indole derivatives (3) in the first step. The alkoxy groups at o-positions of iodoarenes result in higher reactivity than the alkyl groups to induce the formation of amino group-containing products. Subsequently, indolyl(aryl)iodonium imides (4) are converted into 3-amino indole derivatives (2) through an oxidative C–N coupling reaction using Cu(MeCN)4BF4 catalyst [21]. It is noteworthy that the o-substituent on iodoarene is essential to prompt the indole selectivity for the C–N coupling reaction of 4. In contrast, 2-amino indole derivatives (3) are decomposed in the presence of a copper catalyst under heating conditions.
3. Materials and Methods
3.1. General Procedure
1H NMR spectra were measured on a JEOL ECS-500 (500 MHz) spectrometer at ambient temperature. Data were recorded as follows: chemical shift in ppm from internal tetramethylsilane on the δ scale, multiplicity (s = singlet; d = doublet; t = triplet; q = quartet; sep = septet; m = multiplet; br = broad), coupling constant (Hz), integration, and assignment. 13C NMR spectra were measured on a JEOL ECS-500 (125 MHz) spectrometer (see Supplementary Materials). Chemical shifts were recorded in ppm from the solvent resonance employed as the internal standard (deuterochloroform at 77.0 ppm). High-resolution mass spectra were recorded by Thermo Fisher Scientific Exactive Orbitrap mass spectrometers. Infrared (IR) spectra were recorded on a JASCO FT/IR 4100 spectrometer. Single crystal X-ray diffraction data were collected at 173K on a Bruker SMART APEX II ultra CCD diffractometer with Cu Kα (λ = 1.54178) radiation and graphite monochromator. For thin-layer chromatography (TLC) analysis throughout this work, Merck precoated TLC plates (silica gel 60GF254 0.25 mm) were used. The products were purified by neutral column chromatography on silica gel (Kanto Chemical Co., Inc. silica gel 60N, Prod. No. 37560-84; Merck silica gel 60, Prod. No. 1.09385.9929). Visualization was accomplished by UV light (254 nm), anisaldehyde, KMnO4, and phosphomolybdic acid. In experiments that required dry solvents such as MeCN, toluene, and xylene (mixed isomers), these were distilled in prior to use.
3.2. General Procedure for 3-Amination of Indoles 1
A mixture of 1-(diacetoxyiodo)-2-butoxybenzene (94.6 mg, 0.24 mmol) and Ts2NH (104.1 mg, 0.32 mmol) in MeCN (2.0 mL) was stirred at room temperature for 30 min under argon atmosphere. Then, N-pivaloylindole (1a) (40.3 mg, 0.20 mmol) was added, and the solution was stirred at 40 °C for 7 h under argon atmosphere. The reaction mixture was concentrated under reduced pressure and the crude product was dissolved xylene (mixed isomers) (2.0 mL). Cu(MeCN)4BF4 (3.1 mg, 0.01 mmol) was added to the reaction mixture at room temperature, and further stirred at 130 °C for 1 h under argon atmosphere. Saturated NaHCO3 aqueous solution (10 mL) was added to the reaction mixture, and the product was extracted with AcOEt (15 mL × 3). The combined extracts were washed with brine (10 mL) and dried over Na2SO4. The organic phase was concentrated under reduced pressure and the crude product was purified by silica gel column chromatography (eluent: hexane/AcOEt = 5/1), to give the desired product 2a (82.3 mg, 78% yield).
4-Methyl-N-(1-pivaloyl-1H-indol-3-yl)-N-tosylbenzenesulfonamide (2a). White solid, mp 214.0–214.5 °C, 1H NMR (500 MHz, CDCl3) δ 1.40 (s, 9H), 2.46 (s, 6H), 7.07 (d, J = 7.8 Hz, 1H), 7.14–7.19 (m, 1H), 7.30–7.37 (m, 1H), 7.32 (d, J = 8.2 Hz, 4H), 7.46 (s, 1H), 7.87 (d, J = 8.2 Hz, 4H), 8.46 (d, J = 8.3 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ 21.7 (2C), 28.5 (3C), 41.3, 115.8, 117.3, 118.6, 124.1, 126.0, 126.8, 127.7, 128.6 (4C), 129.6 (4C), 135.7, 136.2 (2C), 145.2 (2C), 176.7. IR (neat) 1702, 1374, 1357, 1316, 1165 cm–1. MS (ESI) calcd for C27H29N2O5S2 [M + H]+ 525.1512, found 525.1501. Crystal data for 2a: Formula C27H28N2O5S2, colorless, crystal dimensions 0.30 × 0.20 × 0.20 mm3, Triclinic, space group P −1, a = 9.475(2) Å, b = 10.144(2) Å, c = 13.660(3) Å, α = 98.118(3) °, β = 91.348(3) °, γ = 100.871(3) °, V = 1274.7(5) Å3, Z = 2, ρcalc = 1.367 g cm−3, F(000) = 552, μ(MoKα) = 0.250 mm−1, T = 173 K. 7413 reflections collected, 5602 independent reflections with I > 2σ(I) (2θmax = 27.572°), and 330 parameters were used for the solution of the structure. The non-hydrogen atoms were refined anisotropically. R1 = 0.0508 and wR2 = 0.1031. GOF = 1.015. Crystallographic data (excluding structure factors) for the structure reported in this paper have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication no. CCDC-1860598. Copies of the data can be obtained free of charge on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [Fax: int. code + 44(1223)336-033; E-mail:
N-(5-Chloro-1-pivaloyl-1H-indol-3-yl)-4-methyl-N-tosylbenzenesulfonamide (2b): White solid, mp 205.5–206.0 °C, 1H NMR (500 MHz, CDCl3) δ 1.41 (s, 9H), 2.48 (s, 6H), 6.81 (d, J = 2.0 Hz, 1H), 7.27 (d, J = 8.9, 2.0 Hz, 1H), 7.33 (d, J = 8.5 Hz, 4H), 7.52 (s, 1H), 7.85 (d, J = 8.5 Hz, 4H), 8.38 (d, J = 8.9 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ 21.7 (2C), 28.4 (3C), 41.3, 115.2, 118.2, 118.4, 126.2, 128.0, 128.6 (4C), 128.7, 129.7 (4C), 130.0, 133.9, 136.0 (2C), 145.6 (2C), 176.6. IR (neat) 1708, 1379, 1351, 1307, 1163, 1085 cm–1. MS (ESI) calcd for C27H28ClN2O5S2 [M + H]+ 559.1123, found 559.1119.
N-(Phenylsulfonyl)-N-(1-pivaloyl-1H-indol-3-yl)benzenesulfonamide (2c). White solid, mp 182.0–183.0 °C, 1H NMR (500 MHz, CDCl3) δ 1.39 (s, 9H), 7.01 (d, J = 8.0 Hz, 1H), 7.12–7.18 (m, 1H), 7.31–7.37 (m, 1H), 7.48 (s, 1H), 7.50–7.56 (m, 4H), 7.67 (t, J = 7.5 Hz, 2H), 7.97–8.02 (m, 4H), 8.47 (d, J = 8.5 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ 28.5 (3C), 41.3, 115.5, 117.3, 118.5, 124.2, 126.1, 126.6, 127.7, 128.5 (4C), 129.0 (4C), 134.1 (2C), 135.6, 139.0 (2C), 176.7. IR (neat) 1704, 1381, 1344, 1315, 1159 cm–1. MS (ESI) calcd for C25H25N2O5S2 [M + H]+ 497.1199, found 497.1205.
4-Methyl-N-(methylsulfonyl)-N-(1-pivaloyl-1H-indol-3-yl)benzenesulfonamide (2d). White solid, mp 221.5–22.0 °C, 1H NMR (500 MHz, CDCl3) δ 1.44 (s, 9H), 2.43 (s, 3H), 3.56 (s, 3H), 7.23–7.30 (m, 3H), 7.30–7.34 (m, 1H), 7.34–7.40 (m, 1H), 7.62 (s, 1H), 7.79 (d, J = 8.3 Hz, 2H), 8.48 (d, J = 8.3 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ 21.7, 28.5 (3C), 41.4, 44.0, 115.2, 117.4, 118.2, 124.4, 126.2, 126.7, 127.2, 128.8 (2C), 129.6 (2C), 135.1, 135.7, 145.6, 176.7. IR (neat) 1704, 1366, 1349, 1317, 1157 cm–1. MS (ESI) calcd for C21H25N2O5S2 [M + H]+ 449.1199, found 449.1198.
N-(1-Pivaloyl-1H-indol-3-yl)-N-(propylsulfonyl)propane-1-sulfonamide (2e). White solid, mp 190.0–191.0 °C, 1H NMR (500 MHz, CDCl3, 60 °C) δ 1.07 (t, J = 7.3 Hz, 6H), 1.52 (s, 9H), 1.88–2.01 (m, 4H), 3.37–3.55 (m, 2H), 3.55–3.75 (m, 2H), 7.31–7.41 (m, 2H), 7.62 (d, J = 7.5 Hz, 1H), 7.88 (s, 1H), 8.50 (d, J = 8.0 Hz, 1H). 13C NMR (125 MHz, CDCl3, 60 °C) δ 12.8 (2C), 17.1 (2C), 28.7 (3C), 41.5, 57.7 (2C), 115.5, 117.6, 118.5, 124.5, 126.2, 126.9, 127.2, 135.9, 176.7. IR (neat) 1703, 1370, 1347, 1316, 1151 cm–1. MS (ESI) calcd for C19H29N2O5S2 [M + H]+ 429.1512, found 429.1512.
N-(Methylsulfonyl)-N-(1-pivaloyl-1H-indol-3-yl)methanesulfonamide (2f). White solid, mp 205.0–207.0 °C, 1H NMR (500 MHz, CDCl3) δ 1.54 (s, 9H), 3.44 (s, 6H), 7.35–7.40 (m, 1H), 7.40–7.45 (m, 1H), 7.58–7.63 (m, 1H), 7.94 (s, 1H), 8.53 (d, J = 8.3 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ 28.6 (3C), 41.5, 42.9 (2C), 114.6, 117.7, 118.0, 124.7, 126.3, 126.4, 127.1, 135.8, 176.8. IR (neat) 1703, 1349, 1317, 1159 cm–1. MS (ESI) calcd for C15H20ClN2O5S2 [M + Cl]− 407.0508, found 407.0515.
4-Methyl-N-(5-methyl-1-pivaloyl-1H-indol-3-yl)-N-tosylbenzenesulfonamide (2g). White solid, mp 217.0–217.5 °C, 1H NMR (500 MHz, CDCl3) δ 1.39 (s, 9H), 2.28 (s, 3H), 2.47 (s, 6H), 6.71–6.73 (m, 1H), 7.12–7.16 (m, 1H), 7.32 (d, J = 8.2 Hz, 4H), 7.42 (s, 1H), 8.87 (d, J = 8.2 Hz, 4H), 8.31 (d, J = 8.6 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ 21.2, 21.7 (2C), 28.5 (3C), 41.2, 115.6, 116.9, 118.4, 126.9, 127.4, 127.6, 128.7 (4C), 129.5 (4C), 133.8, 133.9, 136.3 (2C), 145.2 (2C), 176.6. IR (neat) 1701, 1379, 1353, 1308, 1156 cm–1. MS (ESI) calcd for C28H31N2O5S2 [M + H]+ 539.1669, found 539.1672.
N-(5-Fluoro-1-pivaloyl-1H-indol-3-yl)-4-methyl-N-tosylbenzenesulfonamide (2h). White solid, mp 214.5–215.2 °C, 1H NMR (500 MHz, CDCl3) δ 1.40 (s, 9H), 2.47 (s, 6H), 6.66 (dd, J = 8.5, 2.5 Hz, 1H), 7.05 (td, J = 9.0, 2.5 Hz, 1H), 7.33 (d, J = 8.5 Hz, 4H), 7.51 (s, 1H), 7.86 (d, J = 8.5 Hz, 4H), 8.43 (dd, J = 9.0, 4.5 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ 21.7 (2C), 28.5 (3C), 41.3, 104.3 (d, JC–F = 25.0 Hz), 113.9 (d, JC–F = 25.0 Hz), 115.5 (d, JC–F = 3.5 Hz), 118.6 (d, JC–F = 9.5 Hz), 128.1 (d, JC–F = 9.5 Hz), 128.5 (4C), 129.0, 129.7 (4C), 131.9, 136.1 (2C), 145.5 (2C), 159.9 (d, JC–F = 240.8 Hz), 176.5. 19F NMR (471 MHz, CDCl3) δ −117.9. IR (neat) 1708, 1376, 1359, 1311, 1237, 1169 cm–1. MS (ESI) calcd for C27H28FN2O5S2 [M + H]+ 543.1418, found 543.1422.
N-(5-Bromo-1-pivaloyl-1H-indol-3-yl)-4-methyl-N-tosylbenzenesulfonamide (2i). White solid, mp 215.0–216.0 °C, 1H NMR (500 MHz, CDCl3) δ 1.41 (s, 9H), 2.48 (s, 6H), 6.09 (d, J = 1.8 Hz, 1H), 7.31–7.35 (m, 4H), 7.40 (dd, J = 9.0, 1.8 Hz, 1H), 7.51 (s, 1H), 7.82–7.86 (m, 4H), 8.32 (d, J = 9.0 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ 21.7 (2C), 28.4 (3C), 41.3, 115.0, 117.7, 118.7, 121.3, 128.4, 128.50, 128.55 (4C), 128.8, 129.7 (4C), 134.3, 136.0 (2C), 145.6 (2C), 176.6. IR (neat) 1703, 1382, 1348, 1306, 1164, 659 cm–1. MS (ESI) calcd for C27H28BrN2O5S2 [M + H]+ 603.0618, found 603.0620.
N-(5-Methoxy-1-pivaloyl-1H-indol-3-yl)-4-methyl-N-tosylbenzenesulfonamide (2j). White solid, mp 220.0–221.0 °C, 1H NMR (500 MHz, CDCl3) δ 1.39 (s, 9H), 2.46 (s, 6H), 3.62 (s, 3H), 6.37 (d, J = 2.6 Hz, 1H), 6.92 (dd, J = 9.1, 2.6 Hz, 1H), 7.32 (d, J = 8.2 Hz, 4H), 7.43 (s, 1H), 7.88 (d, J = 8.2 Hz, 4H), 8.34 (d, J = 9.1 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ 21.7 (2C), 28.6 (3C), 41.2, 55.2, 100.1, 115.4, 115.6, 118.3, 127.8, 128.0, 128.6 (4C), 129.6 (4C), 130.2, 136.4 (2C), 145.2 (2C), 156.7, 176.4. IR (neat) 1701, 1380, 1358, 1312, 1162, 1086 cm–1. MS (ESI) calcd for C28H31N2O6S2 [M + H]+ 555.1618, found 555.1621.
3-((4-Methyl-N-tosylphenyl)sulfonamido)-1-pivaloyl-1H-indol-5-yl pivalate (2k): White solid, mp 225.0 °C (dec.), 1H NMR (500 MHz, CDCl3) δ 1.35 (s, 9H), 1.40 (s, 9H), 2.45 (s, 6H), 6.64 (d, J = 2.5 Hz, 1H), 7.02 (dd, J = 9.0, 2.5 Hz, 1H), 7.33 (d, J = 8.3 Hz, 4H), 7.48 (s, 1H), 7.88 (d, J = 8.3 Hz, 4H), 8.46 (d, J = 9.0 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ 21.7 (2C), 27.1 (3C), 28.5 (3C), 38.9, 41.3, 113.3, 115.7, 118.1, 120.0, 127.6, 128.58 (4C), 128.63, 129.7 (4C), 133.2, 136.2 (2C), 145.3 (2C), 147.7, 176.5, 176.8. IR (neat) 1750, 1708, 1377, 1358, 1311, 1167, 1119 cm–1. MS (ESI) calcd for C32H37N2O7S2 [M + H]+ 625.2037, found 625.2937.
Methyl 3-((4-methyl-N-tosylphenyl)sulfonamido)-1-pivaloyl-1H-indole-5-carboxylate (2l). White solid, mp 221.0–221.5 °C, 1H NMR (500 MHz, CDCl3) δ 1.41 (s, 9H), 2.46 (s, 6H), 3.89 (s, 3H), 7.33 (d, J = 8.3 Hz, 4H), 7.54 (s, 1H), 7.63 (d, J = 1.5 Hz, 1H), 7.86 (d, J = 8.3 Hz, 4H), 8.02 (d, J = 8.9, 1.5 Hz, 1H), 8.50 (d, J = 8.9 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ 21.7 (2C), 28.4 (3C), 41.4, 52.0, 116.2, 117.1, 120.7, 126.1, 126.6, 127.2, 128.6 (4C), 128.8, 129.7 (4C), 136.0 (2C), 138.1, 145.5 (2C), 166.7, 176.7. IR (neat) 1717, 1379, 1360, 1313, 1165 cm–1. MS (ESI) calcd for C29H31N2O7S2 [M + H]+ 583.1567, found 583.1571.
N-(5-Cyano-1-pivaloyl-1H-indol-3-yl)-4-methyl-N-tosylbenzenesulfonamide (2m). White solid, mp 214.0–215.0 °C, 1H NMR (500 MHz, CDCl3) δ 1.42 (s, 9H), 2.49 (s, 6H), 7.17 (d, J = 1.5 Hz, 1H), 7.34 (d, J = 8.0 Hz, 4H), 7.55 (dd, J = 9.0, 1.5 Hz, 1H), 7.64 (s, 1H), 7.83 (d, J = 8.0 Hz, 4H), 8.55 (d, J = 8.5 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ 21.7 (2C), 28.2 (3C), 41.5, 107.6, 115.5, 118.2, 118.8, 123.4, 126.9, 128.5 (4C), 128.7, 129.5, 129.8 (4C), 135.7 (2C), 137.2, 145.8 (2C), 176.6. IR (neat) 2221, 1715, 1363, 1348, 1308, 1169, 1086 cm–1. MS (ESI) calcd for C28H28N3O5S2 [M + H]+ 550.1465, found 550.1470.
N-(5-(1,3-Dioxoisoindolin-2-yl)-1-pivaloyl-1H-indol-3-yl)-4-methyl-N-tosylbenzenesulfonamide (2n). White solid, mp 227.5–228.0 °C, 1H NMR (500 MHz, CDCl3) δ 1.39 (s, 9H), 2.44 (s, 6H), 7.23 (d, J = 2.0 Hz, 1H), 7.38 (d, J = 8.3 Hz, 4H), 7.42 (dd, J = 9.0, 2.0 Hz, 1H), 7.47 (s, 1H), 7.80 (dd, J = 5.5, 3.0 Hz, 2H), 7.92 (d, J = 8.3 Hz, 4H), 7.96 (dd, J = 5.5, 3.0 Hz, 2H), 8.61 (d, J = 9.0 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ 21.7 (2C), 28.4 (3C), 41.3, 115.6, 117.5, 118.0, 123.6 (2C), 124.7, 127.3, 127.9, 128.6 (4C), 128.9, 129.8 (4C), 131.8 (2C), 134.3 (2C), 134.9, 136.0 (2C), 145.3 (2C), 167.1 (2C), 176.6. IR (neat) 1727, 1705, 1375, 1355, 1308, 1167, 1080 cm–1. MS (ESI) calcd for C35H32N3O7S2 [M + H]+ 670.1676, found 670.1678.
4-Methyl-N-(6-methyl-1-pivaloyl-1H-indol-3-yl)-N-tosylbenzenesulfonamide (2o). White solid, mp 203.5–204.2 °C, 1H NMR (500 MHz, CDCl3) δ 1.38 (s, 9H), 2.45 (s, 3H), 2.46 (s, 6H), 6.95 (d, J = 8.0 Hz, 1H), 7.01 (d, J = 8.0 Hz, 1H), 7.29–7.35 (m, 4H), 7.37 (s, 1H), 7.84–7.89 (m, 4H), 8.32 (s, 1H). 13C NMR (125 MHz, CDCl3) δ 21.7 (2C), 21.9, 28.4 (3C), 41.3, 115.8, 117.4, 118.2, 124.6, 125.6, 127.0, 128.6 (4C), 129.6 (4C), 136.1, 136.26, 136.28 (2C), 145.2 (2C), 176.9. IR (neat) 1704, 1371, 1339, 1313, 1163 cm–1. MS (ESI) calcd for C28H30ClN2O5S2 [M + Cl]– 573.1290, found 573.1303.
N-(6-Fluoro-1-pivaloyl-1H-indol-3-yl)-4-methyl-N-tosylbenzenesulfonamide (2p). White solid, mp 215.0–215.5 °C, 1H NMR (500 MHz, CDCl3) δ 1.40 (s, 9H), 2.46 (s, 6H), 6.89–7.02 (m, 2H), 7.32 (d, J = 8.0 Hz, 4H), 7.46 (s, 1H), 7.85 (d, J = 8.0 Hz, 4H), 8.22 (dd, J = 10.3, 2.0 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ 21.7 (2C), 28.4 (3C), 41.3, 104.7 (d, JC–F = 29.8 Hz), 112.6 (d, JC–F = 23.9 Hz), 115.7, 119.4 (d, JC–F = 9.5 Hz), 123.1, 127.8 (d, JC–F = 3.5 Hz), 128.5 (4C), 129.7 (4C), 135.7 (d, JC–F = 13.1 Hz), 136.1 (2C), 145.4 (2C), 161.7 (d, JC–F = 240.9 Hz), 176.6. 19F NMR (471 MHz, CDCl3) δ –115.1. IR (neat) 1707, 1382, 1345, 1315, 1230, 1162 cm–1. MS (ESI) calcd for C27H27ClFN2O5S2 [M + Cl]– 577.1039, found 577.1055.
N-(6-Chloro-1-pivaloyl-1H-indol-3-yl)-4-methyl-N-tosylbenzenesulfonamide (2q). White solid, mp 212.5–213.0 °C, 1H NMR (500 MHz, CDCl3) δ 1.40 (s, 9H), 2.47 (s, 6H), 6.94 (d, J = 8.6 Hz, 1H), 7.14 (dd, J = 8.6, 1.7 Hz, 1H), 7.30–7.35 (m, 4H), 7.46 (s, 1H), 7.82–7.87 (m, 4H), 8.54 (d, J = 1.7 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ 21.7 (2C), 28.4 (3C), 41.3, 115.7, 117.6, 119.4, 124.8, 125.4, 128.1, 128.5 (4C), 129.7 (4C), 132.1, 135.8, 136.1 (2C), 145.4 (2C), 176.6. IR (neat) 1706, 1381, 1360, 1337, 1160, 1083 cm–1. MS (ESI) calcd for C27H28ClN2O5S2 [M + H]+ 559.1123, found 559.1123.
N-(6-Bromo-1-pivaloyl-1H-indol-3-yl)-4-methyl-N-tosylbenzenesulfonamide (2r). White solid, mp 214.0–214.8 °C, 1H NMR (500 MHz, CDCl3) δ 1.39 (s, 9H), 2.47 (s, 6H), 6.90 (d, J = 8.5 Hz, 1H), 7.29 (dd, J = 8.5, 1.5 Hz, 1H), 7.32 (d, J = 8.5 Hz, 4H), 7.44 (s, 1H), 7.85 (d, J = 8.5 Hz, 4H), 8.71 (d, J = 1.5 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ 21.7 (2C), 28.3 (3C), 41.3, 115.7, 119.7, 119.9, 120.4, 125.7, 127.5, 128.0, 128.5 (4C), 129.7 (4C), 136.06 (2C), 136.11, 145.4 (2C), 176.6. IR (neat) 1705, 1380, 1336, 1308, 1159, 658 cm–1. MS (ESI) calcd for C27H27BrClN2O5S2 [M + Cl]– 637.0239, found 637.0256.
N-(6-Methoxy-1-pivaloyl-1H-indol-3-yl)-4-methyl-N-tosylbenzenesulfonamide (2s). White solid, mp 201.0–201.8 °C, 1H NMR (500 MHz, CDCl3) δ 1.40 (s, 9H), 2.46 (s, 6H), 3.86 (s, 3H), 6.80 (dd, J = 8.5, 2.3 Hz, 1H), 6.90 (d, J = 8.5 Hz, 1H), 7.29–7.34 (m, 4H), 7.36 (s, 1H), 7.84–7.89 (m, 4H), 8.07 (d, J = 2.3 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ 21.7 (2C), 28.4 (3C), 41.3, 55.6, 100.8, 114.1, 115.9, 119.1, 120.5, 126.2, 128.5 (4C), 129.6 (4C), 136.3 (2C), 136.7, 145.2 (2C), 159.0, 177.1. IR (neat) 1703, 1378, 1346, 1312, 1286, 1162 cm–1. MS (ESI) calcd for C28H30ClN2O5S2 [M + Cl]– 589.1239, found 589.1257.
N-(4-Fluoro-1-pivaloyl-1H-indol-3-yl)-4-methyl-N-tosylbenzenesulfonamide (2t). White solid, mp 220.0–222.6 °C, 1H NMR (500 MHz, CDCl3) δ 1.42 (s, 9H), 2.46 (s, 6H), 6.85 (dd, J = 10.0, 8.0 Hz, 1H), 7.24–7.30 (m, 1H), 7.30–7.34 (m, 4H), 7.50 (s, 1H), 7.84–7.88 (m, 4H), 8.28 (d, J = 8.5 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ 21.7 (2C), 28.4 (3C), 41.4, 110.2 (d, JC–F = 19.0 Hz), 112.9, 113.3 (d, JC–F = 3.6 Hz), 115.7 (d, JC–F = 17.9 Hz), 126.7 (d, JC–F = 7.3 Hz), 128.0, 128.6 (4C), 129.5 (4C), 136.1(2C), 137.7 (d, JC–F = 7.1 Hz), 145.1 (2C), 154.7 (d, JC–F = 249.1 Hz), 176.7. 19F NMR (471 MHz, CDCl3) δ –122.8. IR (neat) 1707, 1375, 1359, 1309, 1251, 1176 cm–1. MS (ESI) calcd for C27H27ClFN2O5S2 [M + Cl]– 577.1039, found 577.1053.
4-Methyl-N-(7-methyl-1-pivaloyl-1H-indol-3-yl)-N-tosylbenzenesulfonamide (2u). White solid, mp 190.0–191.0 °C, 1H NMR (500 MHz, CDCl3) δ 1.41 (s, 9H), 2.30 (s, 3H), 2.45 (s, 6H), 6.94 (dd, J = 7.5, 1.5 Hz, 1H), 7.06–7.12 (m, 2H), 7.20 (s, 1H), 7.29–7.33 (m, 4H), 7.84–7.89 (m, 4H). 13C NMR (125 MHz, CDCl3) δ 21.2, 21.7 (2C), 28.9 (3C), 42.1, 114.8, 116.6, 123.8, 125.4, 127.5, 128.00, 128.03, 128.6 (4C), 129.5 (4C), 134.9, 136.3 (2C), 145.1 (2C), 178.2. IR (neat) 1715, 1377, 1361, 1303, 1171 cm–1. MS (APCI) calcd for C28H31N2O5S2 [M + H]+ 539.1669, found 539.1670.
N-(5,6-Dichloro-1-pivaloyl-1H-indol-3-yl)-4-methyl-N-tosylbenzenesulfonamide (2v). White solid, mp 223.5–224.2 °C, 1H NMR (500 MHz, CDCl3) δ 1.41 (s, 9H), 2.48 (s, 6H), 6.87 (s, 1H), 7.32–7.36 (m, 4H), 7.52 (s, 1H), 7.82–7.86 (m, 4H), 8.65 (s, 1H). 13C NMR (125 MHz, CDCl3) δ 21.7 (2C), 28.3 (3C), 41.3, 115.0, 119.1, 119.5, 126.4, 128.5 (5C), 129.0, 129.8 (4C), 130.1, 134.0, 135.9 (2C), 145.7 (2C), 176.4. IR (neat) 1710, 1382, 1361, 1330, 1158, 1084 cm–1. MS (ESI) calcd for C27H27Cl2N2O5S2 [M + H]+ 593.0733, found 593.0732.
4-Methyl-N-(2-methyl-1-pivaloyl-1H-indol-3-yl)-N-tosylbenzenesulfonamide (2w). White solid, mp 158.0–159.0 °C, 1H NMR (500 MHz, CDCl3) δ 1.34 (s, 9H), 1.79 (s, 3H), 2.45 (s, 6H), 6.99–7.06 (m, 2H), 7.12–7.18 (m, 1H), 7.21 (d, J = 8.0 Hz, 1H), 7.30 (d, J = 8.5 Hz, 4H), 7.85 (d, J = 8.5 Hz, 4H). 13C NMR (125 MHz, CDCl3) δ 10.8, 21.6 (2C), 28.0 (3C), 44.4, 110.5, 111.7, 118.7, 121.7, 122.8, 125.8, 128.6 (4C), 129.5 (4C), 133.8, 136.7 (2C), 137.9, 145.0 (2C), 185.8. IR (neat) 1710, 1384, 1360, 1313, 1165, 1084 cm–1. MS (APCI) calcd for C28H31N2O5S2 [M + H]+ 539.1669, found 539.1671.
N-(1-Benzoyl-1H-indol-3-yl)-4-methyl-N-tosylbenzenesulfonamide (2x). White solid, mp 214.0–215.0 °C, 1H NMR (500 MHz, CDCl3) δ 2.47 (s, 6H), 7.10 (d, J = 8.0 Hz, 1H), 7.12 (s, 1H), 7.19–7.24 (m, 1H), 7.32 (d, J = 8.5 Hz, 4H), 7.36–7.41 (m, 1H), 7.45–7.51 (m, 2H), 7.59–7.65 (m, 3H), 7.87 (d, J = 8.5 Hz, 4H), 8.37 (d, J = 8.0 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ 21.7 (2C), 116.2, 116.3, 119.0, 1124.5, 125.8, 128.0, 128.59 (4C), 128.64 (2C), 129.3, 129.4 (2C), 129.6 (4C), 132.5, 133.4, 135.0, 136.2 (2C), 145.2 (2C), 168.1. IR (neat) 1694, 1376, 1359, 1325, 1166 cm–1. MS (ESI) calcd for C29H25N2O5S2 [M + H]+ 545.1199, found 545.1205.
4-Methyl-N-tosyl-N-(1-tosyl-1H-indol-3-yl)benzenesulfonamide (2y). White solid, mp 182.0–183.0 °C, 1H NMR (500 MHz, CDCl3) δ 2.35 (s, 3H), 2.44 (s, 6H), 7.04 (d, J = 8.0 Hz, 1H), 7.08–7.13 (m, 1H), 7.23–7.30 (m, 7H), 7.43 (s, 1H), 7.70–7.77 (m, 6H), 7.92 (d, J = 8.5 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ 21.5, 21.7 (2C), 113.5, 116.8, 119.4, 123.9, 125.4, 126.9 (2C), 128.2, 128.3, 128.5 (4C), 129.5 (4C), 130.0 (2C), 133.7, 134.5, 136.0 (2C), 145.3 (2C), 145.5. IR (neat) 1595, 1372, 1355, 1283, 1168, 1086 cm–1. MS (ESI) calcd for C29H27N2O6S3 [M + H]+ 595.1026, found 595.1027.
4. Conclusions
In conclusion, we developed a 3-amination of indole derivatives using a hypervalent iodine(III) compound that promotes the formation of indolyl(aryl)iodonium imides. This reaction was followed by a copper-catalyzed oxidative C–N coupling reaction to obtain the 3-amino indole derivatives regioselectively. The o-alkoxy groups on (diacetoxy)iodoarenes resulted in higher reactivity than the o-alkyl groups in the formation of indolyl(aryl)iodonium imides (first step). In addition, the 3-amino indole derivatives were given as a single isomer product by a decomposition of 2-amino indole derivatives under copper-catalyzed reaction conditions (second step). The design of substituted iodoarene as a high-performance hypervalent iodine compounds and the combined use of hypervalent iodine compound and a transition-metal catalyst for the unique transformation are underway in our laboratory.
Supplementary Materials
The following are available online. The 1H and 13C NMR spectra of compounds in 3-amination of indole derivatives, and crystal data of 2a can be found in the Supporting Information.
Author Contributions
Conceptualization, K.M.; Methodology, K.M.; Validation, K.M; Investigation and Analyses, K.W. and K.M.; Writing—original draft preparation, K.M.; Writing—review and editing, K.M.; Visualization, K.M.; Supervision, K.M.; Project Administration, K.M.; Funding Acquisition, K.M.
Funding
Financial support in the form of a Grant-in-Aid for Scientific Research (No. G15K17819) from the Ministry of Education, Culture, Sports, Science and Technology in Japan is gratefully acknowledged.
Conflicts of Interest
The authors declare no conflict of interest.
Footnotes
Sample Availability: Samples of the compounds are not available from the authors.
Schemes and Table
Enlarge this image.Scheme 1. 3-Installation of amino group into indole skeleton. (A) Nitration. 3-Amination of electron-donating group protected indoles: (B) Azidation, (C) Electrophilic amidation, (D) Azidation via formation of indolyl(phenyl)iodonium azide, (E) Amidation via formation of indolyl(Mes)iodonium tosylate. 3-Amination of electron-withdrawing group protected indoles: (F) Electrophilic amidation, (G) Amidation via formation of indolyl(aryl)iodonium imide.
Enlarge this image.Scheme 2. Effect of substituent on iodoarene in copper-catalyzed C–N coupling reaction of indolyl(aryl)iodonium imides.
Enlarge this image.Scheme 3. Copper-catalyzed 3-amination of 1b with o-substituted (diacetoxyiodo)arenes. a Numbers in parentheses indicate yield of N-pivaloyl-2-bistosylimdo-5-chloroindole (3b).
Enlarge this image.Scheme 4. Copper-catalyzed 3-amination of N-protected indoles (1). a Numbers in parentheses indicate yield of N-pivaloyl-2-bismesylimdo-chloroindole (3f). b For 24 h (in the first step). c At 100 °C (in the second step).
Enlarge this image.Scheme 5. Comparison of (diacetoxyiodo)arenes in the formation of indolyl(aryl)iodonium imide.
Enlarge this image.Scheme 6. Reaction of 2-amino indole derivatives (3b) in the presence of copper-catalyst.
Screening for ArI(OAc)2 and solvent for 3-amination of indole (1a).
| Entry | ArI(OAc)2 | Temp. 1 (°C) | Solvent | Temp. 2 (°C) | Yield (%) |
|---|---|---|---|---|---|
| 1 | PhI(OAc)2 | 40 | Toluene | Reflux | 26 (58) a |
| 2 | A | 40 | Toluene | Reflux | 76 |
| 3 | B | 60 | Toluene | Reflux | 82 |
| 4 | C | 60 | Toluene | Reflux | 55 (19) b |
| 5 | D | 60 | Toluene | Reflux | 81 |
| 6 | E | 60 | Toluene | Reflux | 2 (76) b |
| 7 | A | 40 | Xylene | 130 | 78 |
| 8 | B | 60 | Xylene | 130 | 76 |
| 9 | D | 60 | Xylene | 130 | 78 |
| 10 c | A | 40 | Xylene | 130 | 16 (67) d |
| 11 c | B | 60 | Xylene | 130 | 42 (9) d |
| 12 c | D | 60 | Xylene | 130 | 32 (64) d |
a Number in parentheses indicates yield of N,N-bistosylaniline. b Numbers in parentheses indicate recovery of 1a. c The reaction was carried out in the absence of Cu(MeCN)4BF4. d Numbers in parentheses indicate yield of indolyl(aryl)iodonium imide (4).
© 2019 by the authors.