Regio- and chemoselective Csp3–H arylation of benzylamines by single electron transfer/hydrogen atom transfer synergistic catalysis

Catalyst controlled regio-, and chemo-selective C-H arylation of benzylamines.


General information
H NMR spectra were measured on a JEOL JNM-ECA-500 spectrometer at 500 MHz. 13 C NMR spectra were recorded on a JEOL JNM-ECA-500 spectrometer at 125 MHz. Chemical shifts were reported in parts per million (ppm) downfield from TMS (= 0) or CDCl 3 for 1 H NMR. For 13 C NMR, chemical shifts were reported in the scale relative to CDCl 3 . Infrared spectra were measured on a SHIMADZU IRPrestige-21 and only diagnostic absorptions are listed below. ESI-MS data were taken on a Thermo SCIENTIFIC ACCELA Exactive liquid chromatography-mass spectrometer (LC-MS). Column chromatography was performed with silica gel N-60 (40-100 µm) purchased from Kanto Chemical Co., Inc. TLC analysis was performed on Silica gel 60 F254-coated glass plates (Merck). Visualization was accomplished by means of ultraviolet (UV) irradiation at 254 nm or by spraying 12molybdo(VI)phosphoric acid ethanol solution as a developing agent. GPC purification was conducted on a Shimadzu recycling preparative HPLC system [LC-20AR; column, YMC-GPC T-2000; chloroform]. Blue light irradiation was performed with a RelyOn LED lamp (3 W, λ = 425 nm).

Preparation of amine substrates 2.1. Synthesis of (4-((dimethylamino)methyl)phenyl)methanol (1ad)
To a solution of methyl 4-(bromomethyl)benzoate (2.0 g, 8.7 mmol) in THF (50 mL) was added Me 2 NH (2 M in THF, 8.7 mL, 17.4 mmol) at 0 °C. The reaction mixture was stirred for 4 h at ambient temperature, and then H 2 O was added to the mixture. The organic material was extracted with EtOAc (15 mL × 2). The combined organic layers were washed with brine and dried over MgSO 4 . After filtration, the filtrate was concentrated in vacuo and the crude mixture was used without further purification in the next step.
To a solution of LiAlH 4 (495 mg, 13.1 mmol) in THF (30 mL) was added a solution of the crude mixture in THF (10 mL) at 0 °C. The resultant mixture was stirred for 2 h. The reaction was quenched with H 2 O (0.5 mL), and 1 N NaOH aq. (0.5 mL) and H 2 O (1.5 mL) were carefully added to the mixture. After filtration, the filtrate was concentrated in vacuo and the residue was purified by column chromatography on silica gel (n-hexane/EtOAc = 5/1) to provide 1ad (1.27 g, 88% yield in 2 steps) as a colorless oil.

Synthesis of N-benzyl-4-((dimethylamino)methyl)aniline (1ae)
To a solution of 4-nitrobenzoyl chloride (3.0 g, 16.2 mmol) in CH 2 Cl 2 (50 mL) was added Me 2 NH (2 M in THF, 16.2 mL, 32.4 mmol) at 0 °C. The reaction mixture was stirred for 2 h at ambient temperature and concentrated in vacuo. The residue was diluted with EtOAc (30 mL) and was washed with H 2 O and brine. The combined organic layers were dried over MgSO 4 . After filtration, the filtrate was concentrated in vacuo and the crude mixture (2.81 g) was used without further purification in the next step. A round-bottom flask (100 mL) equipped with a Teflon septum and a magnetic stir bar was charged with the above crude mixture (2.81 g) and 10% Pd/C (281 mg, 10 w/w%). The flask was purged with a stream of argon and MeOH (30 mL) was added to the flask via a syringe. The reaction mixture was degassed and the flask was backfilled with hydrogen. After being stirred for 18 h, the mixture was filtered through a pad of Celite. The filtrate was concentrated in vacuo and the crude mixture (2.37 g) was used without further purification in the next step.
To a solution of LiAlH 4 (1.64 g, 43.3 mmol) in THF (60 mL) was added a solution of the crude mixture in THF (50 mL) at 0 °C. The reaction mixture was stirred for 3 h and was quenched with H 2 O (1.6 mL) at 0 ˚C, followed by the addition of 1 N NaOH aq. (1.6 mL), and H 2 O (4.8 mL). After filtration through a pad of Celite, the filtrate was concentrated in vacuo and the residue (2.00 g) was used without further purification in the next step.
To a solution of the crude product in EtOH (30 mL) was added benzaldehyde (1.69 g, 16.0 mmol) at ambient temperature. The reaction mixture was stirred for 2 h at 70 ˚C, and then the reaction mixture was cooled to 0 ˚C. Subsequently, NaBH 4 (754 mg, 20 mmol) was added to the reaction mixture. After stirring for 4 h at ambient temperature, H 2 O (50 mL) was added to the mixture at 0 ˚C. The mixture was evaporated to remove EtOH. The organic material was extracted with Et 2 O (40 mL×3) and the organic layers were dried over MgSO 4 . After filtration, the filtrate was concentrated in vacuo and the residue was purified by column chromatography on silica gel (CH 2 Cl 2 /MeOH = 4/1) to provide 1ae (1.68 g, 6.99 mmol, 43% in 4 steps) as a colorless oil.

Experimental procedure
An oven-dried 5 mL Schlenk flask equipped with a Teflon septum and a magnetic stir bar was charged with Ir(ppy) 3 (tris[2-phenylpyridinato-C 2 ,N]iridium(III), 1.3 mg, 1.0 mol %), terephtharonitrile (25.6 mg, 0.2 mmol, 1.0 equiv) and K 2 HPO 4 (34.8 mg, 1.0 mmol, 1.0 equiv). The flask was purged with a stream of argon, and DMA (1.0 mL) and N,Ndimethylbenzylamine (0.6 mmol, 3.0 equiv) were added to the flask.. The reaction mixture was then degassed with a Freeze-Pump-Thaw cycling (3 cycles) and the flask was backfilled with argon. Then, the flask was sealed with a screw cap and was placed on a stirrer (approximately 2 cm away from a 3 W blue LED (425 nm)). After being stirred for 12 h at room temperature, the reaction mixture was diluted with Et 2 O (5 mL) and the organic solution was washed with H 2 O and brine. The organic layer was dried over MgSO 4 . After filtration, the filtrate was concentrated in vacuo and the residue was purified by column chromatography on silica gel (n-hexane/EtOAc = 20/1) to give 2a (3.3 mg, 7%) as a colorless solid and 3a (38.8 mg, 82%) as a colorless oil.

General experimental for cyclic voltammetry
Ferrocene was purified by recrystallisation twice from n-hexane prior to use. n-Bu 4 NPF 6 was used as supplied commercially from Aldrich. Unless otherwise stated, all solutions were prepared at 10.0 mM concentration (in 0.1 M n-Bu 4 NPF 6 /MeCN or DMA as solvent) using anhydrous CH 3 CN or DMA. Unless otherwise stated, a default scan rate of 100 mV s -1 was used and potentials are given relative to the saturated calomel electrode (vs. SCE). Peak heights are given in amps (A). Ferrocene was used as an external standard, measured both before and after running any series of analytes, to ensure consistency. Measurements performed vs. Ag/AgCl were converted to vs. SCE by subtracting 45 mV. The anodiccathodic peak separation for ferrocene ΔE p obtained was 117 mV (compared to 59 mV/n for an ideal one-electron transfer), indicating a high degree of reversibility (and so rapid kinetics) for the electron transfer process. For reductions, the sample was first degassed by Ar bubbling for 5 min. Cyclic voltammetry was conducted using a three-electrode setup consisting of a platinum wire working electrode (d = 1.60 mm) and platinum gauge counter electrode. The reference electrode was a Ag/AgCl electrode (containing 3.0 M NaCl saturated with AgCl). Electrochemical measurements were carried out in a 20 mL cell (SCV-3 Voltammetry cell) using BAS ALS660E potentiostat.

Results
The ferrocene peak height (ca. 7.0 x 10 -5 A) corresponds to a one-electron oxidation. All oxidations of analytes gave a similar peak height (ca. 3.5 x 10 -5 A to 7.0 x 10 -5 A) to ferrocene, corresponding to a one-electron oxidation (except Ir(ppy) 3 which was analyzed at 1.0 mM concentration and was not fully soluble at that concentration). No peaks were observed for electrochemical reductions of the substrates chosen.

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All CV data in CH 3 CN are summarised in Table S1 (these data have been converted from vs. Ag/AgCl as shown in Section 4.2.1. to vs. SCE in Table S1). Where possible, the data in the literature are shown for comparison (and calibrated to vs. SCE by using ferrocene, if necessary and if reported in the literature study). The reported redox potentials are quoted vs. SCE and are in good agreement with measured values herein. As far as possible, the redox potentials quoted have been obtained using the identical CV conditions (298 K, 0.1 M n-Bu 4 NPF 6 in CH 3 CN), but variations occur in some cases. Readers are referred to the literature referenced in Table S1 for details.    Relative Current

Comparison of the measured potentials of the above compounds
The above results clearly show that potassium thiobenzoate salt undergoes most facile oxidation under the reaction conditions. The N-benzyl-1,2,3,4-tetrahydroquinoline has an E p ox value almost identical to that of Ir(ppy) 3 , however the potassium thiobenzoate salt is present under the reaction conditions. The difference in the observed reaction selectivity between Nbenzyl-1,2,3,4-tetrahydroquinoline and N-benzylindoline cannot be explained by the change

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in reaction mechanism to SET only catalysis, since these compounds have almost identical E p ox values in MeCN. The SET/HAT synergistic catalytic mechanism is occurring for these substrates (not oxidation by [Ir(ppy) 3 ] 4+ ) and the change in the reaction selectivity must be attributed to either sterics, BDEs or conformation of the 5-/6-/7-membered rings to allow the formation of the 2 o α-amino radical (See, Scheme 3B). Table S3: Optimization of the reaction conditions. a a The reactions were carried out on a 0.2 mmol scale. b Yield and regioisomeric ratio were determined by 1 H NMR analysis using 1,1,2,2-tetrachloroethane as an internal standard. c Run with Ir(ppy) 3 (0.5 mol %), thiobenzoic acid (1 mol %), and 1a (2 equiv) for 2 h. d Isolated yield. e Run under the dark conditions.  S-13

Typical experimental procedure for the benzylic arylation of benzylamines
An oven-dried 25 mL Schlenk flask equipped with a Teflon septum and a magnetic stir bar was charged with Ir(ppy) 3 (tris[2-phenylpyridinato-C 2 ,N] iridium(III), 3.3 mg, 0.5 mol %), terephthalonitrile (128.1 mg, 1.0 mmol, 1.0 equiv) and K 2 HPO 4 (174.2 mg, 1.0 mmol, 1.0 equiv). The flask was purged with a stream of argon, and a DMA solution (5 mL) of ,N,Ndimethylbenzylamine (300 µL, 2 mmol, 2.0 equiv) and thiobenzoic acid (1.2 µL, 1 mol %) was added to the flask. The reaction mixture was then degassed with a Freeze-Pump-Thaw cycling (3 cycles) and the flask was backfilled with argon. Then, the flask was sealed with a screw cap and was placed on a stirrer (approximately 2 cm away from a 3 W blue LED (425 nm)). After stirring for 2 h at room temperature, the reaction mixture was diluted with Et 2 O (5 mL) and the organic solution was washed with aqueous saturated NaHCO 3 and brine. The organic layer was dried over MgSO 4 . After filtration, the filtrate was concentrated in vacuo and the residue was purified by column chromatography on silica gel (n-hexane/EtOAc = 20/1) to give 2a (205.6 mg, 87% yield) as a colorless solid.