Hexamethyldisilazane Sodium Salt as Highly Active Lewis Base Catalyst for the Staudinger Reaction

Abstract

Hexamethyldisilazane sodium salt (NaHMDS) has been found to be a highly active Lewis base catalyst for the Staudinger reaction with disubstituted ketenes and imines. This organocatalyst gave highly substituted β-lactams in nearly quantitative yield in a very short time of five minutes even at temperatures as low as -78 °C.

catalysis - cycloadditions - lactams - hexamethyldisilazane salts - organocatalysis - Staudinger reaction

References and Notes

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26

General Experimental Procedure An imine^30,31 (0.1 mmol) and a ketene^4,5,32 (0.25 mmol) were dissolved in dry THF (1 mL) and cooled down to -78 °C. Then, KHMDS (0.01 mmol) was added, and the reaction was monitored by TLC. After total conversion the reaction mixture was applied to column chromatography on silica gel and products were eluted with 1:8 EtOAc-PE mixture to give the desired compounds as white solids (yields: 48-99%).
Compound 5a (trans-isomer): white crystals, mp 144 °C. ¹H NMR (200 MHz, CDCl₃): δ = 0.57 (t, J = 7.4 Hz, 3 H), 1.25-1.43 (m, 1 H), 1.64-1.89 (m, 1 H), 5.24 (s, 1 H), 7.21-7.44 (m, 10 H), 8.12 (d, J = 8.9 Hz, 2 H), 8.34 (d, J = 8.98 Hz, 2 H). ¹³C NMR (50 MHz, CDCl₃): δ = 8.65, 27.14, 68.07, 69.92, 124.57, 126.23, 127.21, 128.13, 128.92, 129.19, 129.26, 133.59, 137.42, 143.94, 151.03, 168.60. IR (KBr): ν = 1792 (C=O) cm^-1. MS (ES⁺): m/z = 459.1 [M + Na]⁺, 895.0 [2 M + Na]⁺. Anal. Calcd (%) for C₂₃H₂₀N₂O₅S: C, 63.29; H, 4.62; N, 6.42. Found: C, 63.20; H, 4.67; N, 6.35.
Compound 5a (cis-isomer): white crystals, mp 144-145 °C. ¹H NMR (200 MHz, CDCl₃): δ = 0.94 (t, J = 7.4 Hz, 3 H), 2.20 (q, J = 7.4 Hz, 2 H), 5.15 (s, 1 H), 6.70-6.76 (m, 2 H), 6.82-6.91 (m, 2 H), 6.94-7.16 (m, 6 H), 7.95 (d, J = 8.9 Hz, 2 H), 8.26 (d, J = 8.9 Hz, 2 H). ¹³C NMR (50 MHz, CDCl₃): δ = 9.31, 32.61, 69.14, 70.26, 124.40, 127.24, 127.41, 128.16, 128.19, 128.28, 128.88, 129.01, 133.66, 134.47, 144.36, 150.84, 167.80. IR (KBr): ν = 1792 (C=O) cm^-1. MS (ES⁺): m/z = 459.1 [M + Na]⁺, 895.0 [2 M + Na]⁺. Anal. Calcd (%) for C₂₃H₂₀N₂O₅S: C, 63.29; H, 4.62; N, 6.42. Found: C, 63.38; H, 4.73; N, 6.28.
Compound 5b: Analytical data were consistent with those for 5a.
Compound 5c (trans-isomer): white crystals, mp 107 °C. ¹H NMR (400 MHz, CDCl₃): δ = 0.83 (t, J = 8.0 Hz, 3 H), 2.09-2.17 (m, 1 H), 2.24-2.33 (m, 1 H), 5.64 (s, 1 H), 6.70-6.72 (m, 1 H), 6.81-6.84 (m, 1 H), 6.95-6.98 (m, 2 H), 7.03-7.07 (m, 3 H), 7.29-7.23 (m, 2 H), 8.22 (d, J = 8.8 Hz, 2 H), 8.43 (d, J = 8.8 Hz, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 9.31, 30.74, 64.74, 71.53, 124.78, 126.89, 128.51, 129.32, 129.41, 129.66, 132.29, 133.12, 134.10, 143.82, 151.19, 168.44. IR (KBr): ν = 1787 (C=O) cm^-1. MS (ES⁺): m/z = 493.1 [M + Na]⁺. Anal. Calcd (%) for C₂₃H₁₉ClN₂O₅S: C, 58.66; H, 4.07; N, 5.95. Found: C, 58.45; H, 4.05; N, 5.97.
Compound 5c (cis-isomer): white crystals, mp 107 °C. ¹H NMR (200 MHz, CDCl₃): δ = 0.59 (t, J = 7.4 Hz, 3 H), 1.70 (q, J = 7.3 Hz, 2 H), 5.56 (s, 1 H), 7.03-7.07 (m, 5 H), 7.34-7.48 (m, 4 H), 8.15 (d, J = 8.8 Hz, 2 H), 8.37 (d, J = 8.8 Hz, 2 H). ¹³C NMR (50 MHz, CDCl₃): δ = 8.62, 25.4, 64.69, 69.50, 124.68, 126.65, 127.84, 128.29, 129.96, 129.22, 132.16, 133.08, 133.96, 143.60, 151.14, 168.13. IR (KBr): ν = 1793 (C=O) cm^-1. MS (ES⁺): m/z = 493.1 [M + Na]⁺. Anal. Calcd (%) for C₂₃H₁₉ClN₂O₅S: C, 58.66; H, 4.07; N, 5.95. Found: C, 58.71; H, 4.09; N, 5.81.
Compound 5d (trans-isomer): white crystals, mp 142 °C. ¹H NMR (200 MHz, CDCl₃): δ = 0.57 (t, J = 7.4 Hz, 3 H), 1.25-1.43 (m, 1 H), 1.59-1.83 (m, 1 H), 2.39 (s, 3 H), 5.21 (s, 1 H), 7.21-7.43 (m, 9 H), 8.12 (d, J = 9.0 Hz, 2 H), 8.35 (d, J = 9.04 Hz, 2 H). ¹³C NMR (50 MHz, CDCl₃): δ = 8.67, 21.36, 27.17, 67.96, 69.90, 124.55, 126.24, 127.16, 128.06, 129.16, 130.50, 137.51, 139.24, 143.99, 151.06, 168.71. IR (KBr): ν = 1785 (C=O) cm^-1. MS (ES⁺): m/z = 473 [M + Na]⁺, 923.0 [2 M + Na]⁺. Anal. Calcd (%) for C₂₄H₂₂N₂O₅S: C, 63.98; H, 4.92; N, 6.22. Found: C, 64.05; H, 5.17; N, 6.02.
Compound 5d (cis-isomer): white crystals, mp 147 °C. ¹H NMR (200 MHz, CDCl₃): δ = 0.93 (t, J = 8.0 Hz, 3 H), 2.18 (q, J = 7.2 Hz, 2 H), 2.20 (s, 3 H), 5.11 (s, 1 H), 6.60 (d, J = 8.0 Hz, 2 H), 6.78 (d, J = 8.0 Hz, 2 H), 6.85-6.89 (m, 2 H), 7.02-7.09 (m, 3 H), 7.87 (d, J = 9.0 Hz, 2 H), 8.18 (d, J = 9.0 Hz, 2 H). ¹³C NMR (50 MHz, CDCl₃): δ = 9.31, 21.23, 32.76, 69.15, 69.98, 124.34, 127.27, 127.38, 128.17, 128.27, 128.87, 129.00, 130.54, 134.63, 138.87, 144.41, 150.76, 167.92. IR (KBr): ν = 1781 (C=O) cm^-1. MS (ES⁺): m/z = 473 [M + Na]⁺, 923.0 [2 M + Na]⁺. Anal. Calcd (%) for C₂₄H₂₂N₂O₅S: C, 63.98; H, 4.92; N, 6.22. Found: C, 63.99; H, 5.02; N, 6.21.
Compound 5e (trans-isomer): white crystals, mp 116 °C. ¹H NMR (200 MHz, CDCl₃): δ = 0.64 (t, J = 7.6 Hz, 3 H), 1.50-1.68 (m, 1 H), 1.85-2.03 (m, 1 H), 5.53 (s, 1 H), 7.04-7.11 (m, 2 H), 7.24-7.37 (m, 6 H), 8.10 (d, J = 9.0 Hz, 2 H), 8.34 (d, J = 9.2 Hz, 4 H). ¹³C NMR (50 MHz, CDCl₃): δ = 8.74, 27.65, 65.81, 68.34, 124.52, 126.24, 126.72, 127.53, 127.86, 128.24, 129.18, 129.21, 136.52, 137.08, 143.98, 168.17. IR (KBr): ν = 1782 (C=O) cm^-1. MS (ES⁺): m/z = 465.0 [M + Na]⁺, 907.0 [2 M + Na]⁺, 332.1, 641.2, 774.0. Anal. Calcd (%) for C₂₁H₁₈N₂O₅S₂: C, 57.00; H, 4.10; N, 6.33. Found: C, 56.99; H, 4.10; N, 6.30.
Compound 5e (cis-isomer): white crystals, mp 124 °C. ¹H NMR (200 MHz, CDCl₃): δ = 0.97 (t, J = 7.2 Hz, 3 H), 2.25 (q, J = 8.0 Hz, 2 H), 5.49 (s, 1 H), 6.73-6.75 (m, 2 H), 6.97-7.04 (m, 3 H), 7.11-7.18 (m, 3 H), 7.93 (d, J = 9.04 Hz, 2 H), 8.25 (d, J = 9.04 Hz, 2 H). ¹³C NMR (50 MHz, CDCl₃): δ = 9.33, 32.35, 64.91, 70.50, 124.35, 126.40, 127.17, 127.92, 128.54, 128.90, 129.08, 134.51, 137.21, 144.38, 150.79, 167.23. IR (KBr): ν = 1790 (C=O) cm^-1. MS (ES⁺): m/z = 465.0 [M + Na]⁺, 907.0 [2 M + Na]⁺, 332.1, 641.2, 774.0. Anal. Calcd (%) for C₂₁H₁₈N₂O₅S₂: C, 57.00; H, 4.10; N, 6.33. Found: C, 57.13; H, 4.15; N, 6.26.
Compound 5f (trans-isomer): white crystals, mp 182 °C. ¹H NMR (200 MHz, CDCl₃): δ = 0.66 (t, J = 7.4 Hz, 3 H), 1.26-1.43 (m, 1 H), 1.58-1.78 (m, 1 H), 5.82 (s, 1 H), 7.05-7.10 (m, 2 H), 7.34-7.38 (m, 3 H), 7.43-7.63 (m, 5 H), 7.87-7.97 (m, 2 H), 8.27 (d, J = 9.0 Hz, 2 H), 8.46 (d, J = 9.0 Hz, 2 H). ¹³C NMR (50 MHz, CDCl₃): δ = 8.93, 24.11, 68.46, 68.84, 122.90, 124.75, 125.08, 125.17, 126.47, 126.90, 128.55, 129.45, 129.50, 129.58, 129.67, 130.91, 133.89, 136.62, 143.99, 169.70. IR (KBr): ν = 1787 (C=O) cm^-1. MS (ES⁺): m/z = 518.8 [(2 M + 3 Na)/2]⁺. Anal. Calcd (%) for C₂₇H₂₂N₂O₅S: C, 66.65; H, 4.56; N, 5.76. Found: C, 66.77; H, 4.78; N, 5.59.
Compound 5f (cis-isomer): white crystals, mp 186 °C. ¹H NMR (200 MHz, CDCl₃): δ = 0.97 (t, J = 7.6 Hz, 3 H), 2.26-2.47 (m, 2 H), 6.05 (s, 1 H), 6.69-6.99 (m, 6 H), 7.50-7.69 (m, 4 H), 7.83 (d, J = 7.8 Hz, 1 H), 8.02 (d, J = 8.2 Hz, 1 H), 8.15 (d, J = 9.0 Hz, 2 H), 8.38 (d, J = 9.0 Hz, 2 H). ¹³C NMR (50 MHz, CDCl₃): δ = 9.47, 31.21, 64.86, 71.61, 121.70, 124.65, 125.05, 126.08, 126.80, 127.17, 127.58, 128.08, 128.96, 129.34, 129.49, 129.64, 131.32, 133.45, 134.12, 138.28, 144.41, 168.62. IR (KBr): ν = 1782 (C=O) cm^-1. MS (ES⁺): m/z = 518.8 [(2 M + 3 Na)/2]⁺. Anal. Calcd (%) for C₂₇H₂₂N₂O₅S: C, 66.65; H, 4.56; N, 5.76. Found: C, 66.58; H, 4.87; N, 5.54.
Compound 5g (trans-isomer): light yellow crystals, mp 143 °C. ¹H NMR (200 MHz, CDCl₃): δ = 0.59 (t, J = 7.4 Hz, 3 H), 1.26-1.49 (m, 1 H), 1.69-1.87 (m, 1 H), 3.86 (s, 3 H), 3.92 (s, 3 H), 5.16 (s, 1 H), 6.84 (s, 1 H), 6.88-6.89 (m, 2 H), 7.18-7.39 (m, 5 H), 8.13 (d, J = 9.0 Hz, 2 H), 8.35 (d, J = 9.0 Hz, 2 H). ¹³C NMR (50 MHz, CDCl₃): δ = 8.73, 27.05, 56.13, 56.19, 68.15, 69.92, 110.21, 111.25, 119.92, 124.58, 125.88, 126.18, 128.13, 129.22, 137.48, 143.91, 149.33, 149.81, 151.06, 168.80. IR (KBr): ν = 1793 (C=O) cm^-1. MS (ES⁺): m/z = 518.8 [M + Na]⁺, 829.0. Anal. Calcd (%) for C₂₅H₂₄N₂O₇S: C, 60.47; H, 4.87; N, 5.64. Found: C, 60.41; H, 4.83; N, 5.63.
Compound 5g (cis-isomer): yellow crystals, mp 146 °C. ¹H NMR (200 MHz, CDCl₃): δ = 0.94 (t, J = 7.4 Hz, 3 H), 2.18 (q, J = 7.4 Hz, 2 H), 3.21 (s, 3 H), 3.79 (s, 3 H), 5.08 (s, 1 H), 5.82 (s, 1 H), 6.57-6.59 (m, 2 H), 6.84-6.92 (m, 2 H), 7.06-7.09 (m, 3 H), 7.93 (d, J = 9.0 Hz, 2 H), 8.26 (d, J = 9.0 Hz, 2 H). ¹³C NMR (50 MHz, CDCl₃): δ = 9.33, 32.59, 55.43, 55.93, 69.16, 69.94, 110.29, 110.62, 121.84, 124.30, 125.72, 127.24, 127.50, 128.44, 128.99, 129.18, 134.91, 144.42, 148.52, 149.53, 150.78, 167.89. IR (KBr): ν = 1787 (C=O) cm^-1. MS (ES⁺): m/z = 518.8 [M + Na]⁺, 829.0. Anal. Calcd (%) for C₂₅H₂₄N₂O₇S: C, 60.47; H, 4.87; N, 5.64. Found: C, 60.47; H, 4.90; N, 5.67.
Compound 7a (trans-isomer): white crystals, mp 163 °C. ¹H NMR (200 MHz, CDCl₃): δ = 1.18 (s, 3 H), 5.28 (s, 1 H), 7.20-7.42 (m, 10 H), 8.15 (d, J = 9.0 Hz, 2 H), 8.37 (d, J = 9.0 Hz, 2 H). ¹³C NMR (50 MHz, CDCl₃): δ = 19.95, 64.13, 70.04, 124.61, 125.41, 126.99, 128.22, 128.98, 129.20, 129.25, 129.38, 133.58, 139.55, 143.98, 151.05, 169.08. IR (KBr): ν = 1787 (C=O) cm^-1. MS (ES⁺): m/z = 445.1 [M + Na]⁺, 867.0 [2 M + Na]⁺. Anal. Calcd (%) for C₂₂H₁₈N₂O₅S: C, 62.55; H, 4.29; N, 6.63. Found: C, 63.19; H, 4.64; N, 6.63.
Compound 7a (cis-isomer): white crystals, mp 142 °C. ¹H NMR (200 MHz, CDCl₃): δ = 1.81 (s, 3 H), 5.12 (s, 1 H), 6.71-6.77 (m, 2 H), 6.86-6.93 (m, 2 H), 6.95-7.16 (m, 6 H), 7.98 (d, J = 9.0 Hz, 2 H), 8.29 (d, J = 9.0 Hz, 2 H). ¹³C NMR (50 MHz, CDCl₃): δ = 25.44, 65.97, 71.10, 124.49, 126.75, 127.57, 127.91, 128.26, 128.48, 128.95, 129.08, 133.62, 135.84, 144.15, 150.94, 168.47. IR (KBr): ν = 1791 (C=O) cm^-1. MS (ES⁺): m/z = 445.1 [M + Na]⁺, 867.0 [2 M + Na]⁺. Anal. Calcd (%) for C₂₂H₁₈N₂O₅S: C, 62.55; H, 4.29; N, 6.63. Found: C, 63.14; H, 4.60; N, 6.50.
Compound 7b: Analytical data were consistent with those for 5a.
Compound 7c: white crystals, mp 156 °C. ¹H NMR (200 MHz, CDCl₃): δ = 5.86 (s, 1 H), 6.87-7.21 (m, 10 H), 7.28-7.48 (m, 5 H), 8.00 (d, J = 9.0 Hz, 2 H), 8.26 (d, J = 9.0 Hz, 2 H). ¹³C NMR (50 MHz, CDCl₃): δ = 69.6, 73.30, 124.44, 126.91, 127.58, 127.80, 128.03, 128.30, 128.36, 129.03, 129.07, 129.22, 133.40, 135.58, 138.72, 143.87, 150.90, 166.71. IR (KBr): ν = 1781 (C=O) cm^-1. MS (ES⁺): m/z = 507.0 [M + Na]⁺. Anal. Calcd (%) for C₂₇H₂₀N₂O₅S: C, 66.93; H, 4.16; N, 5.78. Found: C, 66.97; H, 4.31; N, 5.77.
Compound 7d: white crystals, mp 168 °C. ¹H NMR (200 MHz, CDCl₃): δ = 1.06-1.38 (m, 4 H), 1.46-1.66 (m, 6 H), 1.72-2.02 (m, 2 H), 4.85 (s, 1 H), 7.11-7.33 (m, 5 H), 8.12 (d, J = 8.8 Hz, 2 H), 8.38 (d, J = 8.8 Hz, 2 H). ¹³C NMR (50 MHz, CDCl₃): δ = 22.83, 23.71, 28.98, 29.08,29.98, 35.42, 64.28, 70.50, 124.60, 127.11, 128.79, 128.98, 129.15, 134.09, 144.19, 150.99, 171.32. IR (KBr) ν = 1787 (C=O) cm^-1. MS (ES⁺): m/z = 437.2 [M + Na]⁺. Anal. Calcd (%) for C₂₁H₂₂N₂O₅S: C, 60.85; H, 5.35; N, 6.76. Found: C, 60.71; H, 5.47; N, 6.69.

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