L-1-Phenylethylamine (1-PEA or α-PEA), is the organic compound with the formula C6H5CH(NH2)CH3.This primary amine is a colorless liquid is often used in chiral resolutions. Like benzylamine, L-1-Phenylethylamine is relatively basic and forms stable ammonium salts and imines.

Synthesis of L-1-Phenylethylamine

In an argon atmosphere, acetophenone (1 mmol, 120 mg),RuX2L, NH4X (2mmol) was added to a 5mL ampule, The corresponding solvent (2 mL) was added and the reaction flask was placed in an autoclave. Charge hydrogen three times, each charge 10atm hydrogen, The hydrogen pressure required for the last flush, The autoclave is placed in an oil bath which is preheated to a corresponding temperature in advance. Stir under heating for 24 hours, cool to room temperature, and slowly release hydrogen. Take out the reaction flask and add 3 mL of 6M hydrogen chloride solution. Heat at 80 °C for 6 hours, cool, wash twice with ether. Neutralize to pH 10 with 4M sodium hydroxide solution and extract three times with diethyl ether. The organic phases were combined, dried over anhydrous sodium sulfate and dried in vacuo. Obtaining pure 1-phenylethylamine, The enantioselective determination of the product L-1-Phenylethylamine requires first acetylation of the product. The corresponding yield is 80%.[1]

Clathrates with Both Enantiomers of L-1-Phenylethylamine

2,7,10,15-Tetrahydroxytetraphenylene (THTP) was synthesized in two steps by the homo-coupling reaction of 2,2′-dibromo-5,5′-dimethoxybiphenyl. Optical resolution of racemic THTP was achieved by complexation with (S)-1-phenylethylamine in toluene to afford (S,S)-THTP in good yield. (R,R)-THTP was also obtained using L-1-Phenylethylamine. In the course of these studies, (S,S)-THTP constituted an inclusion compound even with L-1-Phenylethylamine. Both complexes were characterized by X-ray structural analyses and the thermal analyses (DSC and TGA). The hydrogen bonding networks of the complex with L-1-Phenylethylamine are more complicated than those of the complex with (S)-1-phenylethylamine. The thermal analysis suggests that the complex with (S)-1-phenylethylamine is a less stable clathrate than the complex with L-1-Phenylethylamine.[2]

To prepare enantiomerically pure THTP, we tried optical resolution based on inclusion complexation with various chiral amines and alcohols such as (–)-sparteine, brucine, 1-phenylethylalcohol, TADDOL-type host molecules, ethyl lactate and so on. Fortunately, when (±)-THTP was dissolved in an excess of (S)-1-phenylethylamine at 70 °C and then toluene was added, colorless crystals precipitated as needles from the toluene solution. X-ray analysis revealed that the crystals consisted of a 1:2:1 inclusion complex of (S,S)-THTP, (S)-1-phenylethylamine and toluene, termed the SS-S complex, as described later in detail. After the crystals were dissolved in an alkali solution, the aqueous solution was washed with CH2Cl2, acidified (6 m HCl aq.) and extracted with EtOAc. From the EtOAc layer, (S,S)-(–)-THTP was obtained in 37?%. The optical purity of the obtained (–)-THTP was determined as 99?% ee by HPLC analysis using a chiral column. From the mother liquor (the toluene solution), 61?% ee of (R,R)-(+)-THTP was recovered in 61?% yield, which was treated with L-1-Phenylethylamine to convert it to highly optically pure (+)-THTP. Thus, gram scale of both enantiomers of THTP were obtained with highly enantiomeric purity without the formation of diastereomeric mixtures that require tedious column chromatographic separation, or chiral preparatory column chromatographic separation.

96?% ee of (S,S)-THTP (1.23 g, 3.34 mmol) was dissolved in excess L-1-Phenylethylamine (3.4 mL, 26.4 mmol) at 70 °C. To this solution was added toluene (3?×?6.7 mL), and the mixture was allowed to stand at room temperature to give colorless prisms, which was the 1:2:1 inclusion complex of (S,S)-THTP, L-1-Phenylethylamine and toluene (the SS-R complex, used for X-ray analysis). The crystalline solid was dissolved in 1 m NaOH aq. (20 mL), and extracted with diethyl ether (3?×?30 mL). The alkaline aqueous layer was acidified with 6 m HCl aq. (pH = 1.0), then extracted with diethyl ether (3?×?50 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated in vacuo to afford 1.00 g of pure (S,S)-THTP (82?%, >99?% ee). With the same aqueous treatment, 225.4 mg of (S,S)-THTP was obtained (18?%, 80?% ee) from the filtrate.[3]

Scientists synthesized (±)-2,7,10,15-tetrahydroxytetraphenylene (THTP) in short steps by homo-coupling reaction. To obtain the chiral THTP, we carried out the optical resolution of (±)-tetrahydroxytetraphenylene using (S)-phenethylamine in toluene. In the process, we obtained two unique diastereotopic clathrates, the SS-S and SS-R complexes, which were generated with THTP and (S)- or L-1-Phenylethylamine and toluene in the ratio of 1:2:1. Furthermore, detailed X-ray analyses of both complexes revealed that the hydrogen bonding networks were quite different between them. Finally, the thermal analyses (TGA and DSC) suggested that the SS-S complex was a less stable clathrate than the SS-R complex.

References

[1] SHENZHEN CATALYS TECH - CN109851506, 2019, A

[2] Kaku, H., Mitarai, A., Okamoto, N., Tanaka, K., Ichikawa, S., Yamamoto, T., Inai, M., Nishi, T., Horikawa, M., & Tsunoda, T. (2018). Optically Active 2,7,10,15-Tetrahydroxytetraphenylene: Clathrates with Both Enantiomers of 1-Phenylethylamine and Their Stability. European Journal of Organic Chemistry, 2018(48), 6991–6999.

[3] T. C. W. Mak and H. N. C Wong, in: Comprehensive Supramolecular Chemistry (Eds.: D. D. MacNicol, F. Toda and R. Bishop), Pergamon Press: Oxford, 1996, Vol. 6, pp. 351–369.