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Article

Friedel–Crafts-Type Alkylation of Indoles in Water Using Amphiphilic Resin-Supported 1,10-Phenanthroline–Palladium Complex under Aerobic Conditions

by
Toshimasa Suzuka
*,
Yuto Ooshiro
and
Kazuhito Ogihara
Department of Chemistry, Biology and Marine Science, University of the Ryukyus, Nishihara, Okinawa 903-0213, Japan
*
Author to whom correspondence should be addressed.
Catalysts 2020, 10(2), 193; https://0-doi-org.brum.beds.ac.uk/10.3390/catal10020193
Submission received: 20 January 2020 / Revised: 3 February 2020 / Accepted: 4 February 2020 / Published: 5 February 2020
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Abstract

:
The palladium-catalyzed Friedel-Crafts-type alkylation of indoles in water has been achieved using amphiphilic polystyrene-poly(ethylene glycol) (PS-PEG) resin-supported phenanthroline-palladium complexes in water under aerobic conditions, affording the corresponding products with good-to-high yield. The polymeric catalyst was also found to promote the C3-alkylation reaction to give a thermodynamic alkylation product with high selectivity. The polymeric catalyst was recovered and reused several times without any loss of catalytic activity.

1. Introduction

The Friedel-Crafts reaction is one of the considerably important carbon–carbon bond forming reactions to employ Lewis acids as promoters since the pioneering study by Friedel and Crafts [1,2]. Recently, the original procedure (for which stoichiometric amounts of a Lewis acid were required) has been replaced by catalytic Friedel-Crafts-type reactions for the alkylation and acylation of aromatic and heteroarene compounds [3,4]. While widespread research has been devoted to the catalytic Friedel-Crafts reactions of allyl compounds with electron-rich aromatics, research on the catalytic Friedel-Crafts reactions has took place in organic solvent [5,6,7,8,9,10,11,12,13,14,15] or in water solvent [16,17] under homogeneous conditions. If the Friedel-Crafts reactions were performed in water with recyclable palladium catalysts, where neither aqueous-organic solvent wastes nor metal-contaminated wastes were yielded, this would go a long way to meeting green chemical requirements.
Nowadays, we have developed amphiphilic polystyrene-poly(ethylene glycol) (PS-PEG) resin-supported terpyridine-palladium complexes that promote varied catalytic transformations [18,19,20,21,22,23,24,25,26,27,28] smoothly in water [29,30,31,32] under heterogeneous conditions [33,34,35,36]. Herein, we aimed for the Friedel-Crafts reaction of π-allylic palladium intermediates with indoles in water under aerobic conditions in the presence of amphiphilic PS-PEG resin-bound pyridine skeleton ligand-palladium complexes 1a–c (Scheme 1).

2. Results

Alkylation Reaction

First, the polymeric catalyst 1b was prepared from phenanthroline carboxylic acid, PS-PEG resin, and palladium in accordance with previously reported procedures [26], and we then examined different bases and catalysts in the alkylation reaction in water to distinguish which bases and catalysts were most suitable for use in the reaction (Table 1). Thus, the alkylation reaction of indole (2a) and 1,3-diphenyl-2-propenyl acetate (3a) was carried out in water with Et3N (3.0 equivalent) in the presence of the polymeric catalyst 1b (5 mol.% to Pd) at 40 °C for 24 h. After completion of the reaction, the reaction mixture was filtered, and the recovered resin beads were rinsed with a small portion of water and extracted with EtOAc to give an 88% yield of 3-(1,3-diphenyl-2-propenyl)-1H-indole (4a) (entry 2, Table 1). The scope of suitable bases for the C3-alkylation of indole in water using catalyst 1b was examined. lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogen carbonate, and DBU gave 27%, 12%, 13%, 16%, 28%, and 30% yields, respectively (entries 4–9, Table 1). Next, we tested several catalysts using Et3N as a base for the C3-alkylation reaction, which produced 4a with 43%–88% yields (entries 1–3, Table 1). The most effective catalyst proved to be polymer-supported 1,10-phenanthroline-palladium complex 1b, which gave 4a in an impressive 88% yield (entry 2, Table 1). In addition, these reaction conditions were applicable to scale up the reaction (entry 10, Table 1). Thus, the reaction was performed using 20 times the amount of indole of entry 2 to give the corresponding product in 94% yield.
With the optimal conditions in hand, we examined the polymer-supported 1,10-phenanthroline-palladium catalyzed alkylation of several indoles, and the results are summarized in Table 2. The 2-methylindole gave a 78% yield of 3-allyl-2-methyl-1H-indole 4b (entry 2, Table 2). Due to the low dissolubility of 2-phenylindole (2c), the reaction of the 2c with 3a afforded the 3-allyl-2-phenyl-1H-indole 4c in only a 27% yield (entry 3, Table 2). The 5-methylindole (2d) and 7-methylindole (2e) also underwent the alkylation to give 4d and 4e in 91% and 77% yields, respectively (entries 4 and 5, Table 2). The alkylation of indoles 2f and 2g having an electron withdrawing group at the 5-position afforded the 3-allyl-5-bromo-1H-indole 4f and 3-allyl-2-chloro-1H-indole 4g in 74% and 64% yields, respectively (entries 6 and 7, Table 2). The 5-substituted indoles 2h and 2i having an electron donating group (OCH3 or OBn) furnished the 3-allyl-5-methoxy-1H-indole 4h and 3-allyl-2-benzyloxy-1H-indole 4i in 52% and 33% yields, respectively (entries 8 and 9, Table 2). The cyclic substrate was also examined, but the alkylation reaction did not proceed at all (entry 10).
Recycling experiments were tested for alkylation of indole (2a) with the allyl ester 3a. After the first use of the polymeric palladium catalyst 1b (Table 1, entry 1) to give an 88% yield of the C3-allylindole 4a, the recovered catalyst beads were taken on for a 3rd reuse and exhibited stable catalytic activity (Scheme 2). After the recycling experiments, inductively coupled plasma-atomic emission spectrometry (ICP-AES) analysis showed that the concentration of Pd leached into the aqueous solution was <0.3 ppm.
Bandini and co-workers reported that while low coordinating solvents would favor the generation of C3-alkylation product 4a, the use of highly coordinating solvents would drive the regiochemistry toward the formation of N-alkylation product 5 (Scheme 3) [9]. It is noteworthy that the C3-allylindole 4a was obtained as a sole product using polymeric catalyst 1b with triethylamine in water. These results suggested that the Friedel–Crafts-type reaction of indole in water with polymeric catalyst 1b proceeded in the polystyrene moiety of the polystyrene-poly(ethylene glycol) matrix to give thermodynamic alkylation product 4a in 88% yield.

3. Materials and Methods

3.1. General Methods

All manipulations were conducted under aerobic conditions. Water was deionized with a Millipore Milli-Q Gradient A10 system. NMR spectra were recorded on a Bruker AVANCE spectrometer (400 MHz for 1H and 100 MHz for 13C); 1H and 13C spectra were recorded in CDCl3, CD3OD, and DMSO-d6 at 25 °C. Chemical shifts of 13C are given relative to CDCl3, CD3OD, and DMSO-d6 as internal standards (δ77.0, δ49.0, δ39.7 ppm). Mass spectra were measured on a JEOL JMS-T100GCv MS detector (gas chromatography (GC)-MS) and a JEOL JMS-T100LP MS detector (LC-MS); the base peak is denoted as “bp.” GC and IR analyses were performed on a Shimadzu GC-2014 instrument and a Jasco FTIR-410 detector, respectively. ICP-AES spectra were measured on a Shimadzu ICPE-9000 instrument.

3.2. Materials

The PS-PEG-supported phenanthroline-palladium complex (PS-PEG-phenanthroline-Pd; 1b) was prepared from a PS-PEG amino-resin (TentaGel S NH2, average diameter 90 µm, 1% divinylbenzene cross-linked, loading value of amino residue 0.29 mmol/g; purchased from Rapp Polymer), a polymeric phenanthroline ligand, and (C6H5CN)2PdCl2 in accordance with previously reported procedures [26]. The loading level of Pd in polymeric catalyst 1b was 0.26 mmol/g.

3.3. Synthesis of Polymer-Supported Ligand

First, 5-methyl-1,10-phenanthroline (99 mg, 0.51 mmol) and SeO2 (115 mg, 1.0 mmol) were suspended in ortho-dichlorobenzene (20 mL) and the mixture was heated at reflux for 6 h, and then cooled to room temperature. Filtration was followed by the addition of 5M aqueous citric acid (10 mL) to the filtrate. The aqueous phase was collected and washed with dichloromethane and then neutralized by the addition of 10M NaOHaq (15 mL). Dichloromethane was added, and extraction was repeated 5 times with dichloromethane. The corrected organic layers were washed with saturated NaCl and dried over MgSO4. The solvent was removed by an evaporator and dried in vacuum to give a 76% yield of 1,10-phenanthroline-5-carbaldehyde. 1H NMR (CDCl3): δ10.42 (s, 1H), 9.81 (dd, J = 8.1, 1.3 Hz, 1H), 9.38 (dd, J = 3.9, 1.3 Hz, 1H), 9.33 (d, J = 2.7 Hz, 1H), 8.47 (dd, J = 8.0, 1.4 Hz, 1H), 8.41 (s, 1H), 7.83–7.79 (m, 2 H); 13C NMR (CDCl3): δ192.6, 153.4, 151.1, 148.0, 146.0, 139.7, 137.5, 134.2, 130.4, 126.8, 125.5, 124.4, 123.9; IR (ATR) (cm−1): v 2970, 1681, 1506; HR-EI-MS: Calculated for C13H9N2O (M+) 208.0636, found 208.0637.
To a solution of the crude 1,10-phenanthroline-5-carbaldehyde (81 mg, 0.39 mmol) in THF (9.0 mL) and t-BuOH (9.0 mL), 2-methyl-2-butene (318 mg, 4.5 mmol) was added. The solution of NaClO2 (105 mg, 1.2 mmol) and NaH2PO4·2H2O (182 mg, 1.2 mmol) in 3.0 mL water was added to the reaction mixture and the mixture was stirred vigorously at 25 °C for 24 h, after which a white suspension was obtained. To a reaction mixture, 43 mL of 0.70 M NaOH was added, and the combined reaction mixture was washed with CH2Cl2 to remove residual starting materials. The water layers were neutralized with 10 mL of 0.5 M critic acid to generate a white precipitate via crystallization at 0 °C. The precipitate was filtered and washed with water. The precipitate was further purified by heating under reflux for 1 h in MeOH. The 5-carboxy-1,10-phenanthroline (13.7 mg, 16% yield) was collected by filtration. 1H-NMR (CD3OD): δ9.52 (dd, J = 8.5, 1.6 Hz, 1H), 9.17 (dd, J = 4.4, 1.6 Hz, 1 H), 9.11 (dd, J = 4.2, 1.6 Hz, 1H), 8.72–8.69 (m, 1H), 8.59 (dd, J = 8.0, 1.6 Hz, 1H), 7.85–7.82 (m, 2H); 13C-NMR (DMSO-d6): δ.168.0, 152.5, 150.4, 147.2, 146.0, 138.1, 134.8, 132.1, 127.1, 126.8, 126.6, 124.3, 124.0; IR (ATR) (cm−1): v 3669 (br), 2997, 1683, 1508; HR-ESI-MS: Calculated for C13H9N2O2 (M + H) 225.0664, found 225.0665.

3.4. Preparation of PS–PEG Resin-Supported Phenanthroline–Palladium Complex 1b

A Merrifield vessel was charged with PS-PEG-NH2 (348 mg, 0.10 mmol), phenanthroline-COOH ligand (35.0 mg, 0.16 mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (39.4 mg, 0.21 mmol), 1-hydroxybenzotriazole (27.4 mg, 0.2 mmol), and DMSO (6 mL). The reaction mixture was shaken at 25 °C for 17 h. The consumption of the primary amino residue of the resin was monitored by the Kaiser negative test. The reaction mixture was filtered, and the resin was washed with DMSO and CH2Cl2. The resin was dried under reduced pressure to provide the polymer-supported phenanthroline.
Another Merrifield vessel was charged with the obtained resin-supported phenanthroline ligand (0.10 mmol) and toluene (6 mL). To a suspension, (C6H5CN)2PdCl2 (45.9 mg, 0.12 mmol) was added, and the mixture was shaken (CM-1000) at 25 °C for 2 h. The mixture was filtered, and the resin was washed with toluene and CH2Cl2. The resulting resin was dried under reduced pressure to provide the polymer-supported palladium complex 1b (loading value of Pd: 0.26 mmol/g). IR (ATR) (cm−1); 1; v 2868, 1683, 1102, 700.

3.5. Palladium-Catalyzed Friedel-Crafts-Type Alkylation of Indoles with Allyl Esters

The reaction conditions and results are shown in Table 1. A typical procedure is given for the reaction with indole 2a and 1,3-diphenyl-2-propenyl acetate 3a in water in entry 1. To a solution of catalyst 1 (38.0 mg, 0.01 mmol), 1,3-diphenyl-2-propenyl acetate (75 mg, 0.30 mmol), and indole 2a (23.4 mg, 0.2 mmol) in H2O (1.5 mL), triethylamine (60.7 mg, 0.60 mmol) was added, and the mixture was stirred at 40 °C for 24 h. The reaction mixture was filtered and the recovered resin beads were rinsed three times with AcOEt. The combined filtrate was extracted with AcOEt. The combined extracts were washed with aqueous sodium chloride and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was chromatographed on silica gel (hexane/ethyl acetate = 95/5) to give a mixture of the corresponding substituted products and indole. The indole was removed from a mixture of products and indole by distillation to give 3-(1,3-diphenyl-2-propenyl)-1H-indole in 88% yield (54.5 mg, 0.18 mmol). (To remove the other indoles 2b–h, the mixture of products and indoles was separated by recycle HPLC (JAI LC-9201)).
The compounds and CAS registry numbers are as follows: 3-(1,3-diphenyl-2-propenyl)-1H-indole (4a), 3-(1,3-diphenyl-2-propenyl)-2-methyl-1H-indole (4b), 3-(1,3-diphenyl-2-propenyl)-2-phenyl-1H-indole (4c), 3-(1,3-diphenyl-2-propenyl)-5-methyl-1H-indole (4d), 3-(1,3-diphenyl-2-propenyl)-7-methyl-1H-indole (4e), 3-(1,3-diphenyl-2-propenyl)-5-bromo-1H-indole (4f), 3-(1,3-diphenyl-2-propenyl)-5-chloro-1H-indole (4g), 3-(1,3-diphenyl-2-propenyl)-5-methoxy-1H-indole (4h), 3-(1,3-diphenyl-2-propenyl)-5-benzyloxy-1H-indol (4i); and 1265313-04-9, 956480-06-6, 769929-40-0, 1264750-28-8, 1264750-28-8, 769929-44-4, 1264750-26-6, 957777-42-3, 769929-42-2, respectively.
Spectral and analytical data for the 4 are shown below:
(R)-3-(1,3-diphenyl-2-propenyl)-1H-indole (4a): 1H NMR (CDCl3): δ8.01 (br, 1 H), 7.27–7.44 (m, 14 H), 7.16–7.24 (m, 1 H), 6.73 (dd, J = 7.4, 15.8 Hz, 1 H), 6.45 (d, J = 15.1 Hz, 1 H), 5.13 (d, J = 7.3 Hz, 1 H). 13C NMR (CDCl3): δ143.3, 137.5, 136.6, 132.5, 130.5, 128.5 (2C), 128.4 (2C), 127.1 (2C), 126.7 (2C), 126.4 (2C), 126.3, 122.6, 122.1, 119.9, 119.4, 118.7, 111.1, 46.2. MS (EI): m/z (rel%) 309 (bp, M+), 232 (36), 130 (30), 130 (29), 77 (16). IR (ATR): (cm–1) v 3419 (br), 3056, 3024. EI-HRMS: Calcd for C23H19N 309.1517, found 309.1516.
3-(1,3-diphenyl-2-propenyl)-2-methyl-1H-indole (4b): 1H NMR (CDCl3): δ7.62 (br, 1 H), 7.36–7.31 (m, 5 H), 7.26–7.20 (m, 4 H), 7.18–7.14 (m, 3 H), 7.05 (td, J = 7.1, 1.1 Hz, 1 H), 6.95 (td, J = 7.1, 1.1 Hz, 1 H), 6.81 (dd J = 15.8, 7.2 Hz, 1 H), 6.39 (d, J = 15.8 Hz, 1 H), 5.11 (d, J = 7.2 Hz, 1 H), 2.27 (s, 3 H). 13C NMR (CDCl3): δ143.4, 137.4, 135.2, 132.1, 131.5, 130.5, 128.4 (2C), 128.2 (2C), 127.8 (2C), 127.0 (2C), 126.2 (2C), 126.0, 120.8, 119.3, 119.1, 112.7, 110.2, 45.0, 12.2. MS (EI): m/z (rel%) 323 (bp, M+), 308 (67), 246 (38), 218 (36), 144 (42), 77 (14). IR (ATR): (cm–1) v 3379 (br), 2982. EI-HRMS: Calcd for C24H21N 323.1674, found 323.1682.
3-(1,3-diphenyl-2-propenyl)-2-phenyl-1H-indole (4c): 1H NMR (CDCl3): δ8.05 (br, 1 H), 7.53–7.51 (m, 2 H), 7.45–7.41 (m, 3 H), 7.38–7.31 (m, 6 H), 7.27–7.23 (m, 4 H), 7.20–7.14 (m, 3 H), 6.99 (td, J = 8.0, 1.0 Hz, 1 H), 6.88 (dd, J = 15.8, 7.2 Hz, 1 H), 6.39 (dd, J = 15.8, 1.0 Hz, 1 H), 5.27 (d, J = 7.2 Hz, 1 H). 13C NMR (CDCl3): δ143.4, 137.4, 136.2, 135.5, 132.9, 132.2, 131.0, 128.7 (2C), 128.5 (2C), 128.4 (2C), 128.2 (2C), 128.2, 128.0, 127.9, 127.0, 126.2 (2C), 126.0, 122.0, 121.2, 119.6, 113.8, 110.9, 45.1. MS (EI): m/z (rel%) 385 (bp, M+), 294 (89), 206 (41), 91 (13). IR (ATR): (cm–1) v 3408 (br), 3056, 3023. EI-HRMS: Calcd for C29H23N 385.1830, found 385.1835.
3-(1,3-diphenyl-2-propenyl)-5-methyl-1H-indole (4d): 1H NMR (CDCl3): δ7.74 (br, 1 H), 7.35–7.16 (m, 12 H), 6.97 (dd, J = 8.2, 1.4 Hz, 1 H), 6.77 (dd, J = 2.3, 0.6 Hz, 1 H), 6.69 (dd, J = 15.8, 7.2 Hz, 1 H), 6.39 (dd, J = 16.4 Hz, 1 H), 5.07 (d, J = 7.2 Hz, 1 H), 2.35 (s, 3 H). 13C NMR (CDCl3): δ143.4, 137.5, 134.9, 132.6, 130.4, 128.5 (2C), 128.4 (2C), 128.4, 128.3 (2C), 127.0, 127.0, 126.2, 126.2 (2C), 123.7, 122.7, 119.3, 118.0, 110.7, 46.0, 21.5. MS (EI): m/z (rel%) 323 (bp, M+), 246 (42), 220 (28), 191 (20), 144 (14), 91 (8). IR (ATR): (cm–1) v 3404 (br), 2982. EI-HRMS: Calcd for C24H21N 323.1674, found 323.1679.
3-(1,3-diphenyl-2-propenyl)-7-methyl-1H-indole (4e): 1H NMR (CDCl3): δ7.69 (br, 1 H), 7.33–7.10 (m, 11 H), 6.95–6.91 (m, 2 H), 6.76 (dd, J = 2.4, 0.8 Hz, 1 H), 6.69 (dd, J = 15.8, 7.3 Hz, 1 H), 6.40 (dd, J = 15.8, 0.5 Hz, 1 H), 5.07 (d, J = 7.3 Hz, 1 H), 2.37 (s, 3 H). 13C NMR (CDCl3): δ143.4, 137.4, 136.1, 132.5, 130.4, 128.4 (2C), 128.4 (2C), 128.3 (2C), 127.0, 126.3, 126.3, 126.2 (2C), 122.5, 122.2, 120.1, 119.6, 119.0, 117.5, 46.2, 16.4. MS (EI): m/z (rel%) 323 (bp, M+), 246 (38), 220 (28), 191 (20), 144 (22), 91 (7). IR (ATR): (cm–1) v 3429 (br), 3024. EI-HRMS: Calcd for C24H21N 323.1674, found 323.1670.
3-(1,3-diphenyl-2-propenyl)-5-bromo-1H-indole (4f): 1H NMR (CDCl3): δ7.84 (br, 1 H), 7.52 (d, J = 1.8 Hz, 1 H), 7.33–7.16 (m, 11 H), 7.10 (d, J = 8.8 Hz, 1 H), 6.79 (d, J = 2.4 Hz, 1 H), 6.64 (dd, J = 15.8, 7.3 Hz, 1 H), 6.37 (d, J = 15.8 Hz, 1 H), 5.00 (d, J = 7.2 Hz, 1 H). 13C NMR (CDCl3): δ142.8, 137.2, 135.1, 132.0, 130.0, 128.4 (2C), 128.4, 128.4 (2C), 128.3 (2C), 127.2, 126.5, 126.2 (2C), 124.9, 123.7, 122.1, 118.2, 112.6, 112.5, 45.8. MS (EI): m/z (rel%) 389 (42), 387 (M+, 47), 231 (25), 233 (25), 130 (45), 68 (bp). IR (ATR): (cm–1) v 3364 (br), 2982. EI-HRMS: Calcd for C23H1879BrN 387.0622, found 387.0638.
3-(1,3-diphenyl-2-propenyl)-5-chloro-1H-indole (4g): 1H NMR (CDCl3): δ7.84 (br, 1 H), 7.37–7.14 (m, 12 H), 7.07 (dd, J = 8.6, 1.9 Hz, 1 H), 6.81 (dd, J = 2.2, 0.5 Hz, 1 H), 6.64 (dd, J = 15.8, 7.3 Hz, 1 H), 6.38 (d, J = 15.8 Hz, 1 H), 5.01 (d, J = 7.3 Hz, 1 H). 13C NMR (CDCl3): δ142.8, 137.2, 134.9, 132.0, 130.7, 128.4 (2C), 128.4 (2C), 128.3 (2C), 127.8, 127.2, 126.5, 126.2 (2C), 125.0, 123.9, 122.3, 119.1, 118.3, 112.1, 45.8. MS (EI): m/z (rel%) 343 (bp, M+), 266 (35), 240 (29), 191 (27), 115 (26). IR (ATR): (cm–1) v 3853 (br), 3025. EI-HRMS: Calcd for C23H1835ClN 343.1127, found 343.1131.
3-(1,3-diphenyl-2-propenyl)-5-methoxy-1H-indole (4h): 1H NMR (CDCl3): δ7.75 (br, 1 H), 7.34–7.11 (m, 12 H), 6.84–6.65 (m, 4 H), 6.41 (d, J = 15.8, 1 H), 5.03 (d, J = 7.2 Hz, 1 H), 3.67 (s, 3 H). 13C NMR (CDCl3): δ153.7, 143.2, 137.4, 132.4, 131.7, 130.4, 128.4 (2C), 128.3 (3C), 127.1 (2C), 126.3 (2C), 126.2 (2C), 123.4, 118.1, 112.0, 111.7, 101.8, 55.7, 46.1. MS (EI): m/z (rel%) 339 (bp, M+), 262 (38), 236 (25), 115 (12). IR (ATR): (cm–1) v 3420 (br), 3024. EI-HRMS: Calcd for C24H21NO 339.1623, found 339.1624.
3-(1,3-diphenyl-2-propenyl)-5-benzyloxy-1H-indole (4i): 1H NMR (CDCl3): δ7.66 (br, 1 H), 7.34–7.13 (m, 15 H), 7.06 (d, J = 8.8 Hz, 1 H), 6.92 (d, J = 2.3 Hz, 1 H), 6.85 (dd, J = 8.7, 2.4 Hz, 1 H), 6.99 (d, J = 2.0 Hz, 1 H), 6.64 (dd, J = 15.8, 7.3 Hz, 1 H), 6.38 (d, J = 15.8 Hz, 1 H), 4.99 (d, J = 7.3 Hz, 1 H), 4.90 (s, 2 H). 13C NMR (CDCl3): δ152.8, 143.2, 137.5, 137.4, 132.4, 131.8, 130.4, 128.4 (2C), 128.3 (2C), 128.3, 127.6 (2C), 127.5 (2C), 127.0 (2C), 127.0 (2C), 126.3, 126.2 (2C), 123.4, 118.0, 112.8, 111.7, 103.3, 70.8, 46.1. MS (ESI): m/z (rel%) 438 (bp, M+Na). IR (ATR): (cm–1) v 3426 (br), 3025. ESI-HRMS: Calcd for C30H25NONa 438.1833, found 438.1836.

4. Conclusions

In summary, we have developed a practical protocol for the Friedel-Crafts-type alkylation of indoles with allylic ester using the PS-PEG resin-supported phenanthroline-palladium complex to give the 3-allyl-1H-indoles with up to 91% yield. This polymeric catalyst was also found to promote the C3-alkylation reaction to give a thermodynamic alkylation product with high selectivity. This catalyst was recovered and reused several times without any loss of activity.

Author Contributions

T.S. designed and performed the research and experiments and did the data analysis, manuscript writing, and revision. Y.O. performed the experiments and analyzed the data. K.O. advised us for this research. All authors have read and agreed to the published version of the manuscript.

Acknowledgments

We are grateful for financial support from the Steel Foundation for Environmental Protection Technology. We thank Hiromu Sueyoshi for assistance with some of the lab works.

Conflicts of Interest

The authors declare no conflict of interest.

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Catalysts 10 00193 sch001 550
Scheme 1. Friedel-Crafts-type alkylation of indole in water using polymeric catalysts 1.
Scheme 1. Friedel-Crafts-type alkylation of indole in water using polymeric catalysts 1.
Catalysts 10 00193 sch001
Catalysts 10 00193 sch002 550
Scheme 2. Recycling experiments.
Scheme 2. Recycling experiments.
Catalysts 10 00193 sch002
Catalysts 10 00193 sch003 550
Scheme 3. Regioselective alkylation of indole.
Scheme 3. Regioselective alkylation of indole.
Catalysts 10 00193 sch003
Table
Table 1. Friedel–Crafts-type alkylation of indole in water using catalysts 1 and several bases a.
Table 1. Friedel–Crafts-type alkylation of indole in water using catalysts 1 and several bases a.
Catalysts 10 00193 i001
EntryCatalystBases (3 equiv.)Yield of 4a (%)
11aEt3N43
21bEt3N88
31cEt3N53
4 1bLi2CO327
5 1bNa2CO312
6 1bK2CO313
7 1bCs2CO316
81bNaHCO328
91bDBU30
10 b1bEt3N94 c
a: All reactions were performed in water at 40 °C for 24 h. The ratio of 3 (mol)/indoles (mol)/base (mol)/Pd (mol)/H2O (mL) = 1.5/1/3/0.05/1.5. Yields were determined by gas chromatography (GC) based on n-dodecane as an internal standard. b: This reaction was performed under scaled-up conditions (3 (3 mmol)/indoles (2 mmol)/base (6 mmol)/Pd (0.1 mmol)/H2O (15 mL). c: One day later, the yield of 4a in extract was the same. It means that the reaction did not proceed without the polymeric catalyst.
Table
Table 2. Friedel–Crafts-type alkylation of indoles 2 with allyl esters 3 in H2O.
Table 2. Friedel–Crafts-type alkylation of indoles 2 with allyl esters 3 in H2O.
Catalysts 10 00193 i002
Entry24Yield (%) a
1 Catalysts 10 00193 i003
2a		 Catalysts 10 00193 i004
4a		88
2 Catalysts 10 00193 i005
2b		 Catalysts 10 00193 i006
4b		78
3 Catalysts 10 00193 i007
2c		 Catalysts 10 00193 i008
4c		27
4 Catalysts 10 00193 i009
2d		 Catalysts 10 00193 i010
4d		91
5 Catalysts 10 00193 i011
2e		 Catalysts 10 00193 i012
4e		77
6 Catalysts 10 00193 i013
2f		 Catalysts 10 00193 i014
4f		74
7 Catalysts 10 00193 i015
2g		 Catalysts 10 00193 i016
4g		64
8 Catalysts 10 00193 i017
2h		 Catalysts 10 00193 i018
4h		52
9 Catalysts 10 00193 i019
2i		 Catalysts 10 00193 i020
4i		33
10 Catalysts 10 00193 i021
2j		 Catalysts 10 00193 i022
4j		0
a: All reactions were performed in water at 40 °C for 24 h. The ratio of 3 (mol)/indoles (mol)/triethylamine (mol)/Pd (mol)/H2O (mL) = 1.5/1/3/0.05/1.5.

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Suzuka, T.; Ooshiro, Y.; Ogihara, K. Friedel–Crafts-Type Alkylation of Indoles in Water Using Amphiphilic Resin-Supported 1,10-Phenanthroline–Palladium Complex under Aerobic Conditions. Catalysts 2020, 10, 193. https://0-doi-org.brum.beds.ac.uk/10.3390/catal10020193

AMA Style

Suzuka T, Ooshiro Y, Ogihara K. Friedel–Crafts-Type Alkylation of Indoles in Water Using Amphiphilic Resin-Supported 1,10-Phenanthroline–Palladium Complex under Aerobic Conditions. Catalysts. 2020; 10(2):193. https://0-doi-org.brum.beds.ac.uk/10.3390/catal10020193

Chicago/Turabian Style

Suzuka, Toshimasa, Yuto Ooshiro, and Kazuhito Ogihara. 2020. "Friedel–Crafts-Type Alkylation of Indoles in Water Using Amphiphilic Resin-Supported 1,10-Phenanthroline–Palladium Complex under Aerobic Conditions" Catalysts 10, no. 2: 193. https://0-doi-org.brum.beds.ac.uk/10.3390/catal10020193

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