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

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.


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 Recently, the original procedure (for which stoichiometric amounts of a Lewis acid were required) has been replaced by catalytic Friedel-Crafts-type reactions for the alkylation and acylation of aromatic and heteroarene compounds [3,4].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.

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)-1Hindole (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 C3alkylation 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.

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 Et 3 N (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 Et 3 N 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-phenanthrolinepalladium catalyzed alkylation of several indoles, and the results are summarized in Table 2. The 2methylindole 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-1Hindole 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-1Hindole 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).  With the optimal conditions in hand, we examined the polymer-supported 1,10-phenanthrolinepalladium catalyzed alkylation of several indoles, and the results are summarized in Table 2. The 2methylindole 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-1Hindole 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-1Hindole 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).  With the optimal conditions in hand, we examined the polymer-supported 1,10-phenanthrolinepalladium catalyzed alkylation of several indoles, and the results are summarized in Table 2. The 2methylindole 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-1Hindole 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-1Hindole 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).  With the optimal conditions in hand, we examined the polymer-supported 1,10-phenanthrolinepalladium catalyzed alkylation of several indoles, and the results are summarized in Table 2. The 2methylindole 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-1Hindole 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-1Hindole 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 C3allylindole 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 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 C3allylindole 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 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 C3allylindole 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 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 C3allylindole 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 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 C3allylindole 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 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 C3allylindole 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 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 C3allylindole 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 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 C3allylindole 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 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 C3allylindole 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 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 C3allylindole 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 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 C3allylindole 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 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 C3allylindole 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 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 C3allylindole 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 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 C3allylindole 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 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 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.

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 1 H and 100 MHz for 13 C); 1 H and 13 C spectra were recorded in CDCl3, CD3OD, and DMSO-d6 at 25 °C. Chemical shifts of 13 C 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.

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. 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. 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.

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 1 H and 100 MHz for 13 C); 1 H and 13 C spectra were recorded in CDCl3, CD3OD, and DMSO-d6 at 25 °C. Chemical shifts of 13 C 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.

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 1 H and 100 MHz for 13 C); 1 H and 13 C spectra were recorded in CDCl 3 , CD 3 OD, and DMSO-d 6 at 25 • C. Chemical shifts of 13 C are given relative to CDCl 3 , CD 3 OD, and DMSO-d 6 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.

Synthesis of Polymer-Supported Ligand
First, 5-methyl-1,10-phenanthroline (99 mg, 0.51 mmol) and SeO 2 (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 MgSO 4 . The solvent was removed by an evaporator and dried in vacuum to give a 76% yield of 1,10-phenanthroline-5-carbaldehyde. 1  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 NaClO 2 (105 mg, 1.2 mmol) and NaH 2 PO 4 ·2H 2 O (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 CH 2 Cl 2 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.  (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 CH 2 Cl 2 . The resin was dried under reduced pressure to provide the polymer-supported phenanthroline.

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 H 2 O (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.