One-pot aminobenzylation of aldehydes with toluenes

Amines are fundamental motifs in bioactive natural products and pharmaceuticals. Using simple toluene derivatives, a one-pot aminobenzylation of aldehydes is introduced that provides rapid access to amines. Simply combining benzaldehydes, toluenes, NaN(SiMe3)2, and additive Cs(O2CCF3) (0.35 equiv.) generates a diverse array of 1,2-diarylethylamine derivatives (36 examples, 56–98% yield). Furthermore, suitably functionalized 1,2-diarylethylamines were transformed into 2-aryl-substituted indoline derivatives via Buchwald–Hartwig amination. It is proposed that the successful deprotonation of toluene by MN(SiMe3)2 is facilitated by cation–π interactions between the arene and the group(I) cation that acidify the benzylic C–Hs.

The progress of the reactions was monitored by thin-layer chromatography using TLC plates and visualized by short-wave ultraviolet light or by treatment with ninhydrin. Flash chromatography was performed with Qingdao Haiyang flash silica gel (200-300 mesh). The NMR spectra were obtained using a Brüker 400 MHz Fourier-transform NMR spectrometer. Chemical shifts were reported in units of parts per million (ppm) downfield from tetramethylsilane (TMS), and all coupling constants were reported in hertz. Trace element/metal analysis was performed on an Thermo X series inductively coupled plasma (ICP) mass spectrometer calibrated against multi-element standard solutions. The infrared spectra were obtained with KBr plates by using a IS10 FT-IR Spectrometer (ThermoFisher Corporation). High resolution mass spectrometry (HRMS) data were obtained on a Waters LC-TOF mass spectrometer (Xevo G2-XS QTof) using electrospray ionization (ESI) in positive or negative mode. Melting points were measured using a SGW X-4 Melt-Temp apparatus and were uncorrected. ICP trace metal analysis was carried out using commercially available NaHMDS (Aldrich, 95%), CsTFA (Alfa, 98%+) and a standard reaction mixture. These data were displayed in Table 1. As a result of these quantitative analyses, there were no appreciable transition metal contaminants. Furthermore, the reactions have been conducted in two countries with different reagents from different vendors and the results are completely reproducible.
The microwave vial was sealed with a cap and removed from the glove box. The reaction mixture was heated to 110 °C in an oil bath and stirred for 12 h. The sealed vial was cooled to room temperature, opened to air, and then 5 drops of water was added. The reaction mixture was passed through a short pad of silica, washed with an additional 6 mL of ethyl acetate (3  2 mL), and the combined solutions were concentrated in vacuo. The crude material was loaded onto a column of silica gel for purification of the amine.
General Procedure B：To an oven-dried microwave vial equipped with a stir bar under an argon atmosphere inside a glove box was added NaN(SiMe 3 ) 2 (73.2 mg, 0.40 mmol), CsTFA (17.2 mg, 0.07 mmol), the toluene derivative (1 mL) and cyclohexane (1 mL). Then the corresponding aldehyde (0.20 mmol) was added via syringe. The microwave vial was sealed with a cap and removed from the glove box. The reaction mixture was heated to 110 °C in an oil bath and stirred for 12 h. The sealed vial was cooled to room temperature, opened to air, and then 5 drops of water was added. The reaction mixture was passed through a short pad of silica, washed with additional 6 mL of ethyl acetate (3  2 mL), and the combined solutions were concentrated in vacuo. The crude material was loaded onto a column of silica gel for purification of the amine.

Synthesis of 1,2-diphenylethan-1-aminium chloride salt
To   ppm. The spectroscopic data for this product match the literature data. 9

N-(1,2-Diphenylethyl)propan-2-amine (5b)
To an oven-dried flask equipped with a stir bar under argon atmosphere was added 1,2-diphenylethan-1-amine (3aa) (38.6 μL, 0.2 mmol), anhydrous Na 2 SO 4 (43 mg, 0.3 mmol) and acetone (0.8 mL) in sequence at room temperature. The reaction mixture was stirred at the same temperature for 12 h. Then the resulting mixture was filtered and the filtrate was removed in vacuo to give the crude product, which was used in the next step without further purification. To a stirred solution of the crude product in MeOH (1 mL) was added NaBH 4 (10 mg, 0.26 mmol) at room temperature. The reaction mixture was stirred at room temperature for 1 h, then 5 drops water were added.
The reaction mixture was passed through a short pad of silica gel, the silica gel rinsed with an addition 6 mL of ethyl acetate (3 × 2 mL), and the combined solutions were concentrated in vacuo.