Transfer Hydration of Dinitriles to Dicarboxamides

Published as part of the Cluster Metathesis beyond Olefins

Abstract

We present a robust method for double transfer hydration of dinitriles to afford diamides. The transfer hydration of 1,n-dinitriles (n = 1–6) proceeds smoothly in the presence of a palladium(II) catalyst with acetamide as a water donor, affording the corresponding diamides in moderate to high yields, without involving significant side reactions such as monohydration or cyclization. The equilibrium was shifted in the forward direction by removing coproduced acetonitrile under reduced pressure.

Keywords

hydration - nitriles - palladium - amides - diamides

• References and Notes

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• 11 Reactor A was used throughout the experiments unless otherwise noted.
• 12 Typical Procedure for Double Transfer Hydration To a 500 mL round-bottom flask equipped with a stirring bar and a 2-necked Teflon stopcock were added glutaronitrile (1a, 942.1 mg, 10.0 mmol), acetamide (5900.5 mg, 99.9 mmol), and acetic acid (20 mL). The mixture was stirred at 50 °C for 30 min under open air (760 mmHg). Pd(CH₃CN)₄(BF₄)₂ (4.52 mg, 0.0102 mmol) was added to start the reaction, and the mixture was stirred at 50 °C for 2 h under reduced pressure (1–3 mmHg). The internal pressure was continuously reduced by means of a belt drive rotary vane vacuum pump (SATO VAC INC. USW-50) equipped with a 450 mL liq. nitrogen trap (for acetonitrile and acetic acid). The resulting pale-yellow crude mixture was washed with acetonitrile (50 mL) with sonication for 1 h to remove acetamide. The precipitate was collected by filtration on a membrane filter (Merck Millipore JHWP04700 0.45 μm pore size, hydrophilic PTFE membrane, 47 mm diameter) and dried in vacuo at 120 °C overnight to afford glutaramide (2a, 1043.3 mg, 80% yield) with minor contamination with acetamide (27.0 mg, as determined by ¹H NMR spectroscopy). The product (499.7 mg) was recrystallized from methanol to give analytically pure 2a (418.9 mg, 69% overall yield).
• 13 Analytical Data of Selected Products Compound 2a: white solid; mp 181–182 °C. ¹H NMR (600 MHz, DMSO-d ₆): δ = 1.67 (quin, J = 7.6 Hz, 2 H), 2.03 (t, J = 7.6 Hz, 4 H), 6.69 (br s, 2 H), 7.24 (br s, 2 H). ¹³C{¹H} NMR (150 MHz, DMSO-d ₆): δ = 21.3, 34.6, 174.5. IR (KBr): 3381 (NH), 3190 (NH), 1650 (CO) cm^–1. HRMS (FAB): m/z calcd for [C₅H₁₀N₂O₂Na⁺] [M + Na⁺]: 153.0640; found: 153.0633. Compound 2d: white solid; mp 153–154 °C. ¹H NMR (600 MHz, DMSO-d ₆): δ = 0.98 (d, J = 6.9 Hz, 3 H), 1.45–1.51 (m, 1 H), 1.62–1.69 (m, 1 H), 1.95–2.09 (m, 2 H), 2.19 (sext, J = 6.9 Hz, 1 H), 6.69 (br s, 2 H), 7.23 (br s, 2 H). ¹³C{¹H} NMR (150 MHz, DMSO-d ₆): δ = 17.8, 29.3, 32.9, 39.0, 174.0, 177.5. IR (KBr): 3396 (NH), 3210 (NH), 1660 (CO) cm^–1. HRMS (FAB): m/z calcd for [C₆H₁₂N₂O₂Na⁺] [M + Na⁺]: 167.0796; found: 167.0796. Compound 2e: white solid; mp 157–159 °C. ¹H NMR (600 MHz, DMSO-d ₆): δ = 2.16–2.17 (m, 4 H), 4.15 (dquin, J = 6.1, 4.8 Hz, 1 H), 4.87 (d, J = 4.8 Hz, 1 H), 6.81 (br s, 2 H), 7.28 (br s, 2 H). ¹³C{¹H} NMR (150 MHz, DMSO-d ₆): δ = 42.8, 65.1, 172.8. IR (KBr): 3411 (NH), 3184 (NH), 1651 (CO) cm^–1. HRMS (FAB): m/z calcd for [C₅H₁₀N₂O₃Na⁺] [M + Na⁺]: 169.0589; found: 169.0581. Compound 2f: white solid; mp decomp. >150 °C. ¹H NMR (600 MHz, DMSO-d ₆): δ = 3.59 (s, 2 H), 6.99 (br s, 1 H), 7.27–7.30 (m, 2 H), 7.38 (dt, J = 7.6, 1.4 Hz, 1 H), 7.43 (br s, 1 H), 7.47 (dd, J = 7.9, 1.7 Hz, 1 H), 7.68 (br s, 1 H), 8.22 (br s, 1 H). ¹³C{¹H} NMR (150 MHz, DMSO-d ₆): δ = 39 (overlapped with DMSO-d ₆), 126.4, 128.0, 129.6, 130.4, 134.0, 136.8, 170.7, 172.8. IR (KBr): 3394 (NH), 3195 (NH), 1650 (CO) cm^–1. HRMS (FAB): m/z calcd for [C₉H₁₀N₂O₂Na⁺] [M + Na⁺]: 201.0640; found: 201.0632.