Synthetic Method and Condensation reaction of BOC-Glycine

BOC-Glycine is an amino acid derivative that appears as a white to off-white solid powder under normal temperature and pressure. BOC-Glycine is insoluble in water but soluble in organic solvents such as chloroform and ethyl acetate. BOC-Glycine is primarily used in the synthesis of proteins and peptides, and it finds wide application in the synthesis of various products across pharmaceutical biochemistry, food, cosmetics, and other industries. It holds significant importance in fundamental biochemical research.

Synthetic Method

Method 1

Figure1: Synthesis of BOC-Glycine

To a solution of six amino acids (20 mmol) in a mixture of water (20 mL) and acetone (40 mL) placed in a flask, triethylamine (1.5 equiv) and di-tert-butyl dicarbonate (22 mmol) are sequentially added under stirring, and the reaction is allowed to proceed for 4 hours while carefully maintaining the temperature within the range of 0°C to 40°C. The progress of the reaction is routinely monitored by thin-layer chromatography, and once deemed complete, the acetone is removed under reduced pressure. The remaining aqueous layer is then acidified with dilute hydrochloric acid to achieve a pH value of 2–3, followed by exhaustive extraction with ethyl acetate (four 60 mL portions). The combined organic extracts are subsequently washed with saturated brine (two 10 mL portions) and dried over anhydrous sodium sulfate. Finally, the crude product obtained after concentration is crystallized from a mixture of ethyl acetate and petroleum ether in a 1:2 volume ratio, yielding the desired product, BOC-Glycine. [1]

Method 2

N-tert-Butoxycarbonyl-3-azetidinone (0.2 g, 1.2 mmol) is introduced into a solution of oxone (0.72 g, 2.34 mmol) dissolved in 1 M NaOH, and the resulting mixture is allowed to stir at room temperature for a duration of 30 minutes. Upon completion, the reaction mixture is carefully acidified using 1 M HCl, followed by extraction with ethyl acetate (three portions of 10 mL each). The combined organic extracts are subsequently dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford the crude product, which is then subjected to purification via flash column chromatography on silica gel, employing a mixture of dichloromethane and methanol (95:5) as the eluent to give BOC-Glycine. [2]

Condensation reaction

Figure2: Condensation reaction of BOC-Glycine

Benzophenone oxime (5 mmol, 1.0 equiv) and an BOC-Glycine (6 mmol, 1.2 equiv) are combined in CH₂Cl₂ (20 mL), followed by the addition of DMAP (10 mol%, 0.5 mmol) and EDCI·HCl (12.5 mmol, 2.5 equiv). The resulting mixture is stirred at room temperature under an inert atmosphere, and the reaction progress is monitored by TLC until completion. Upon completion, the mixture is diluted with distilled water (25 mL), and the CH₂Cl₂ layer is separated, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude product obtained is subsequently purified by silica gel column chromatography, employing a mixture of petroleum ether and ethyl acetate (2.5:1) as the eluent. [3]

Michael addition reaction

To an oven-dried 8 mL vial equipped with a stir bar, the BOC-Glycine (105.1 mg, 0.60 mmol, 3.0 equiv), Michael acceptor (30.8 mg, 0.20 mmol, 1.0 equiv), NaHCO₃ (16.8 mg, 0.20 mmol, 1.0 equiv), and the catalyst Fe(acac)₃ (7.06 mg, 20.0 mol%, 0.1 equiv) were added, and the mixture was dissolved in 2 mL of MeCN (0.1 M) under an argon atmosphere. At this point, the acid liquid was introduced to the reaction mixture, and the vial was subsequently sealed with parafilm and placed in front of a Kessil PR160L-blue LED lamp as depicted in the reaction setup, where it was irradiated for 20 hours. Following irradiation, the reaction mixture was diluted with ethyl acetate (8 mL), stirred for 10 minutes in the presence of NaHCO₃, and then extracted with ethyl acetate three times. The combined organic phases were washed sequentially with NaHCO₃ (0.6 mmol, 3.0 equiv) and brine, after which the organic layer was dried over Na₂SO₄. Finally, the solvents were removed under reduced pressure, and the resulting crude mixture was subjected to purification by column chromatography. [4]

Reference

[1] Cao, Weiya; et al, Synthesis and antitumor evaluation of amino acid conjugates of monocarbonyl curcumin in hepatocellular carcinoma cell, Scientific Reports (2025), 15(1), 8181.

[2] Green Oxidation of Heterocyclic Ketones with Oxone in Water, Giraudo, Alessandro ; et al, rnal of Organic Chemistry (2023), 88(21), 15461-15465.

[3] Zhang, Zhongyu; et al, Photocatalytic Radical Relay Strategy for the Synthesis of Allylic gem-Difluorides via 1,4-Difunctionalization of gem-Difluorobuta-1,3-dienes, Organic Letters (2026), 28(5), 1869-1875.

[4] Perez-Maseda, Fernando; et al, Fe-Photocatalyzed Decarboxylative Giese-Type Reaction of α-N, O or S Carboxylic Acids: Insight into the Mechanism of the Radical Formation, Advanced Synthesis & Catalysis (2025), 367(21), e70114.

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