6-Halo-2-pyridone as an efficient organocatalyst for ester aminolysis

It was found that 6-halo-2-pyridones catalysed ester aminolysis in which not only reactive aryl esters but also relatively less reactive methyl and benzyl esters could be used as a substrate. The reaction could be performed without strictly dry and anaerobic conditions and the 6-chloro-2-pyridone catalyst could be recovered quantitatively after reaction. The method could be applied to dipeptide synthesis from methyl or benzyl esters of amino acids, where a high enantiomeric purity of the products was maintained. The mechanism involving dual activation of ester and amine substrates through hydrogen bonding between catalyst and substrates is proposed where 6-halo-2-pyridones act as a bifunctional Brønsted acid/base catalyst.


General Information
All reagents and solvents were purchased from either Tokyo Chemical Industry Co., Ltd., or FUJIFILM Wako Pure Chemical Corporation, Kanto Chemical Co., Ltd., Sigma-Aldrich Co. LLC, and were used without further purification. Unless otherwise noted, all reactions were conducted without any inert gas.
Chromatography was carried out with Wakogel ® C-200 silica gel (FUJIFILM Wako Pure Chemical Corporation, granule, 0.075-0.150 mm). NMR spectra were recorded at 400 MHz for 1 H and 100 MHz for 13 C on JEOL JNM-ECZ400R spectrometer. Chemical shifts are reported in part per million (ppm, δ) relative to residual solvent peaks of CDCl 3 (7.26 ppm for 1 H NMR, 77.0 ppm for 13 C NMR) and coupling constant (J values) are given in Hertz. IR spectra were recorded on a JASCO IR FT/IR 4100 spectrometer. High-resolution mass spectra (HRMS) were measured on a JEOL Accu TOF T-100 equipped with an ESI ionization unit. High performance liquid chromatography was carried out with PU-2089 plus HPLC pump (JASCO), LC-NetⅡ/ADC (JASCO), UV-2075 plus UV/Vis detector (JASCO).

Preparation of 5-methoxy-2-pyridone (12c)
To a stirred BnOH (12 mL) was added Na (304 mg, 13.2 mmol) at 0 o C under Ar atmosphere. The reaction mixture was warmed to 100 o C, then 2-bromo-5-methoxypyridine (2.26 g, 12.0 mmol) was added to the mixture. After stirring the mixture at 120 o C for 24 h, the reaction mixture was cool to rt, then the mixture was put on a silica gel and purified by column chromatography to give a 2-(benzyloxy)-5-methoxypyridine (251 mg, 10%). To a stirred solution of 2-(benzyloxy)-5-methoxypyridine (251 mg, 1.2 mmol) in AcOEt (6 mL) was added 10 wt% Pd/C (25 mg) under Ar atmosphere. Ar was replaced by H 2 , then the mixture was stirred at room temperature for 30 min. The suspension was filtered through a pad of celite® and the filtrate was concentrated in vacuo. to provide a 5-methoxy-2-pyridone (12c) (135 mg, 92%). The characteristic data was consistent with   To a stirred solution of 2-bromo-6-methoxypyridine (0.86 mL, 7.1 mmol) in THF (11 mL) was added n-BuLi (1.56 M in hexane, 5 mL, 7.8 mmol) at -78 o C under Ar atmosphere. The reaction mixture was stirred at same temperature for 1 h, then a solution of I 2 (2.16 g, 8.5 mmol) in THF (10 mL) was added. The reaction mixture was gently warm to room temperature. The reaction was quenched with a saturated aqueous NH 4 Cl (40 mL) and extracted by AcOEt (30 mL x 3). Combined organic layers were washed with brine (40 mL) and dried over anhydrous Na 2 SO 4 . The mixture was filtered and concentrated in vacuo. To a stirred suspension of crude mixture and NaI (3.2 g, 21 mmol) in MeCN (36 mL) was added TMSCl (4.5 mL, 35.6 mmol) at room temperature under Ar atmosphere. After the reaction mixture was stirred at same temperature for 13 h, the reaction was quenched with a saturated aqueous NaS 2 O 3 (40 mL) and extracted by CH 2 Cl 2 (30 mL x 3).
Combined organic layers were washed with brine (40 mL) and dried over anhydrous Na 2 SO 4 . The mixture was filtered and concentrated in vacuo. A Et2O (5 mL) was added the residue and the insoluble material was filtered off and washed with Et2O (5 mL x 2). The combined Et2O solution was concentrated in vacuo. and the residue was purified by flash column chromatography on silica gel (Hexane : AcOEt = 10 : 1) to give a 6-iodo-2-

Preparation of 4-phenylbutanoic acid phenylester (15)
To a stirred solution of phenol (564 mg, 6.0 mmol) and 4-phenylbutanoic acid (985 mg, 6.0 mmol) in CH 2 Cl 2 (60 mL) was added DCC (1.36 g, 6.6 mmol) and DMAP (73.3 mg, 0.6 mmol) at 0 o C under Ar atmosphere. After stirring the mixture at room temperature for 13 h, the reaction was quenched with a saturated aqueous NH 4 Cl (40 mL) and extracted by AcOEt (30 mL x 3). Combined organic layers were washed with brine (50 mL) and dried over anhydrous Na 2 SO 4 . The mixture was filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (Hexane : AcOEt = 20 : 1) to give a phenyl ester 15 (1.27 g, 88%) as a colorless solid. The characteristic data were consistent with reported value. 13

Preparation of benzylester (21b)
To a stirred solution of benzyl alcohol (0.62 mL, 6.0 mmol) and 4-phenylbutanoic acid (985 mg, 6.0 mmol) in CH 2 Cl 2 (60 mL) was added DCC (1.36 g, 6.6 mmol) and DMAP (73.3 mg, 0.6 mmol) at 0 o C under Ar atmosphere. After stirring the mixture at room temperature for 13 h, the reaction was quenched with a saturated aqueous NH 4 Cl (40 mL) and extracted by AcOEt (30 mL x 3). Combined organic layers were washed with brine (50 mL) and dried over anhydrous Na 2 SO 4 . The mixture was filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (Hexane : AcOEt = 20 : 1) to give a phenyl ester 2ab (1.27 g, 84%) as a colorless solid. The characteristic data were consistent with reported value. 14

Preparation of Boc-Gly-OBn (24a)
To a stirred solution of Boc-Gly-OH (1.75 g, 10.0 mmol) and NEt 3 (1. mL) was added benzyl bromide (2.4 mL, 20 mmol) at 0 o C under Ar atmosphere. After stirring the mixture at room temperature for 17 h, the reaction was quenched with a saturated aqueous NH 4 Cl (30 mL) and extracted by Et 2 O (20 mL x 3). Combined organic layers were washed with brine (30 mL) and dried over anhydrous Na 2 SO 4 . The mixture was filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (Hexane : AcOEt = 9 : 1) to give a benzyl ester 24a (2.41 g, 91%) as a colorless oil. The characteristic data were consistent with reported value. 15

Preparation of Boc-L-Leu-OBn (25)
To a stirred solution of Boc-Leu-OH (2.31 g, 10.0 mmol) and NEt 3 (1.7 mL, 12.0 mmol) in DMF (40 mL) was added benzyl bromide (2.4 mL, 20 mmol) at 0 o C under Ar atmosphere. After stirring the mixture at room temperature for 17 h, the reaction was quenched with a saturated aqueous NH 4 Cl (30 mL) and extracted by Et 2 O (20 mL x 3). Combined organic layers were washed with brine (30 mL) and dried over anhydrous Na 2 SO 4 . The mixture was filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (Hexane : AcOEt = 15 : 1) to give a benzyl ester 25 (2.96 g, 92%) as a colorless oil. The characteristic data were consistent with reported value. 16

General Procedure for Ester Aminolysis catalyzed by 2-Pyridone
A mixture of an ester (0.1 mmol), amine (0.12 mmol) and 6-chloro-2-pyridone 13a (20 mol%) in toluene (0.1 mL) was stirred. The reaction was monitored by TLC. After completion of the reaction, the mixture was put on silica gel and purified by column chromatography to give the corresponding amide. The catalyst 13a could be recovered quantitatively at the purification of silica gel column chromatography (hexane : AcOEt = 10 : 1