Preparation of Diglycolamides via Schotten–Baumann Approach and Direct Amidation of Esters

Abstract

Diglycolyl chlorides, commercially available or obtained from the corresponding dicarboxylic acids, have been converted into the corresponding diamides by reaction with a wide range of amines in an organic-aqueous biphasic system (Schotten–Baumann approach) in high yields. Treatment with poly(4-styrenesulfonic acid) afforded the pure compounds. Substituted diglycolyl diesters, obtained by coupling of commercial monoesters, were transformed directly in the corresponding diamides in the presence of aluminum trichloride as catalyst in good yields.

Key words

diglycolamides - Schotten–Baumann - direct amidation - ­ligand - aluminum

• References and Notes

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• 10 General Procedure 1: Synthesis of Diglycolamides by Schotten–Baumann Reaction Diglycolyl chloride (0.85 g, 5 mmol) in Et₂O (30 mL) was added dropwise to a solution of amine (30 mmol) and NaOH (1.2 g, 30 mmol) in water (36 mL) at 0 °C over 30 min. The mixture was stirred at 0 °C for 2 h, and then the phases were separated. The aqueous layer was saturated with NaCl and extracted with Et₂O (3 × 30 mL). An aqueous solution of 10% HCl (20 mL) was added to the combined organic layers. The mixture was shaken vigorously to facilitate formation of clumps of ammonium salts, floating between the two phases. The organic layer was washed two more times with HCl solution (20 mL) and then filtered through a glass frit (G3). A poly(4-styrenesulfonic acid) solution (4 wt%, 25 mL) in water was added to the organic layer. The mixture was shaken vigorously to facilitate formation of polymeric salts as an amorphous material floating between the layers. The organic layer was washed with water and then separated from the polymeric salt. It was dried with MgSO₄, whereupon the solvent was removed by vacuum evaporation to afford the DGAs, which had a purity of ≥97% according to the ¹H NMR spectra.
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• 13 In the case of bis(2-ethylhexyl)amine, after the separation of the phases, the organic layer was evaporated. Poly(4-styrenesulfonic acid) solution (18 wt%, 3 mL) was added directly to the crude material. The mixture was shaken to facilitate formation of polymeric salts and then extracted with Et₂O (3 × 50 mL). The combined organic layers were washed with water (30 mL), dried with MgSO₄, whereupon the solvent was removed by vacuum evaporation to afford the DGA.
• 14 General Procedure 2: In situ Preparation of Diacyl Chlorides DMF (5 drops) was added to a solution of a substituted dicarboxylic acid (1 mmol) in pure oxalyl chloride (2 mL). The reaction mixture was stirred under argon for 2 h and then oxalyl chloride was removed by vacuum evaporation. The diacyl chloride obtained was immediately dissolved in Et₂O (6 mL) and used for the synthesis of DGAs according to General Procedure 1. The DGA had a purity of ≥97% according to the ¹H NMR spectra.
• 15 ¹H NMR (400 MHz, CDCl₃): δ = 4.52 (q, J = 6.6 Hz, 1 H, CH₃CHO), 4.28 and 3.95 [AB-q, J = 13.5 Hz, 1 H, OCH₂ C(O)], 3.50–3.25 (m, 8 H, NCH₂ CH₃), 1.41 (d, J = 6.6 Hz, 3 H, CH₃ CHO), 1.18, 1.16, 1.13, and 1.12 (t, J = 7.1 Hz, 3 H, NCH₂CH ₃). ¹³C NMR (101 MHz, CDCl₃): δ = 171.9, 169.3, 73.5, 67.5, 66.0, 41.9, 41.8, 40.8, 18.5, 15.4, 14.5, 14.3, 13.0, 12.9. ESI-MS: m/z = 259.3 [M + H]⁺. HRMS: m/z calcd for C₁₃H₂₇N₂O₃: 259.1943 [M + H]⁺; found: 259.1992.
• 16 ¹H NMR (400 MHz, CDCl₃): δ = 4.29 (q, J = 6.7 Hz, 2 H, CH₃CHO), 3.54–3.44 (m, 2 H, NCH₂ CH₃), 3.41–3.20 (m, 6 H, NCH₂ CH₃), 1.41 (d, J = 6.7 Hz, 6 H, CH₃ CHO), 1.14 and 1.12 (t, J = 7.1 Hz, 6 H, NCH₂CH ₃). ¹³C NMR (101 MHz, CDCl₃): δ = 171.6, 71.8, 41.2, 40.5, 19.2, 14.7, 13.0. ESI-MS: m/z = 273.2 [M + H]⁺. HRMS: m/z calcd for C₁₄H₂₉N₂O₃: 272.2153 [M + H]⁺; found: 272.2173.
• 17 General Procedure 3: Synthesis of Diglycolamides by Direct Amidation of Diesters Et₃N (2.13 g, 21.05 mmol) in CH₂Cl₂ (5 mL) was added dropwise to a suspension of AlCl₃ (2.1 g, 15.79 mmol) in CH₂Cl₂ (8 mL) at 0 °C. The reaction mixture was stirred for 15 min and then warmed to room temperature. A solution of diester (5.26 mmol) and amine (13.68 mmol) in CH₂Cl₂ (3 mL) was added dropwise to the reaction mixture over a period of 30 min. After stirring for 2 h, the reaction mixture was quenched with a solution of Na₂CO₃ (14 g) in water (50 mL), and then EtOAc (60 mL) was added. The aqueous phase was extracted with EtOAc (3 × 100 mL) and the combined organic layers were dried with MgSO₄. After evaporation of the solvent, the compound was purified by flash column chromatography [SiO₂, hexanes–EtOAc (3:1 to 1:1) for long-chain amines; SiO₂, CH₂Cl₂–EtOH (95:5 to 80:20) for intermediate and small amines]. The DGA had a purity of ≥99% according to the ¹H NMR spectra.
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