Synthesis of Amidoalkyl Imidazol-2-ylidene Ligands and Their Application to Enantioselective Copper-Catalysed Conjugate Addition

Abstract

A small library of precursors to chiral amidoalkyl imidazol-2-ylidene ligand was synthesised via a two-step procedure starting from commercially available amino alcohols. Preliminary screening of these bidentate ligands for the enantioselective copper-catalysed conjugate addition of diethyl zinc to cyclohexenone revealed some moderate ee values. Related chiral iminoalkyl imidazole-2-ylidene ligands demonstrated much poorer enantioselectivity. The results indicate that chelation involving a covalent copper-nitrogen bond gives better selectivity than that arising from a dative copper-nitrogen co-ordination.

Key words

asymmetric catalysis - carbenes - copper - Michael additions

References and Notes

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16

Merzouk, M.; Williams, N. A. Tetrahedron Lett. submitted for publication.

17

Experimental and Spectroscopic Data for Ligand Precursors 4a-eCompound 4a: 1-methylimidazole (5 mmol, 0.4 g) and (S)-1-bromo-2-amino-4-methylpentane hydrobromide (5 mmol, 1.3 g) were dissolved in anhyd MeCN (50 mL) and heated to reflux for 20 h under a nitrogen atmosphere. On cooling, a white solid precipitated and was filtered and dried under vacuum; yield 40% (0.68 g). ¹H NMR (400 MHz, D₂O): δ = 0.91 (3 H, d, ^³ J = 6.6 Hz), 0.95 (3 H, d, ^³ J = 6.6 Hz), 1.50-1.64 (2 H, m), 1.70-1.80 (1 H, m), 3.85 (1 H, m), 3.91 (3 H, s), 4.48 (1 H, dd, ^² J = 15 Hz, ^³ J = 7.6 Hz), 4.57 (1 H, dd, ^² J = 15 Hz, ^³ J = 5 Hz), 7.56 (2 H, m), 8.90 (1 H, s). ¹³C NMR (100 MHz, D₂O): δ = 21.2, 21.9, 23.6, 36.3, 38.8, 49.5, 50.8, 122.9, 124.8, 137.2. Mp 242-244 °C. HRMS: m/z calcd for [M - 2 Br - H]⁺ 182.1652; found: 182.1651. Anal. Calcd (%): C, 35.01; H, 6.17; N, 12.25. Found: C, 34.68; H, 6.13; N, 12.13.Compound 4b: 1-benzylimidazole (8 mmol, 1.26 g) and (S)-1-bromo-2-amino-4-methylpentane hydrobromide (5 mmol, 1.3 g) were dissolved in anhyd MeCN (50 mL) and heated to reflux for 20 h under a nitrogen atmosphere. On cooling, a white solid precipitated and was filtered and dried under vacuum; yield 37% (0.79 g). ¹H NMR (400 MHz, D₂O): δ = 0.86 (3 H, d, ^³ J = 6.5 Hz), 0.90 (3 H, d, ^³ J = 6.5 Hz), 1.40-1.69 (3 H, m), 3.79-3.88 (1 H, m), 4.45 (1 H, dd, ^² J = 15 Hz, ^³ J = 7.2 Hz), 4.52 (1 H, dd, ^² J = 15 Hz, ^³ J = 5.5 Hz), 5.41 (2 H, s), 7.45 (5 H, m), 7.59 (2 H, m), 8.97 (1 H, s). ¹³C NMR (100 MHz, D₂O): δ = 21.1, 21.8, 23.8, 38.9, 49.2, 50.9, 53.5, 123.3, 123.6, 129 (2 C), 129.6 (2 C), 129.7, 133.2, 136.7; mp 238.5-240 °C. HRMS: m/z calcd for [M - 2 Br - H]⁺: 258.1968; found: 258.1965.Compound 4c: 1-phenylimidazole (5 mmol, 0.72 g, 0.63 mL) and (S)-1-bromo-2-amino-4-methylpentane hydrobromide (5 mmol, 1.3 g) were dissolved in anhyd MeCN (50 mL) and heated to reflux for 20 h under a nitrogen atmosphere. The solvent was removed under vacuum and the residue dissolved in MeCN (3 mL), and then layered with Et₂O to precipitate a white solid. The solid was recrystallised from hot EtOH; yield 21% (0.42 g). ¹H NMR (400 MHz, D₂O): δ = 0.94 (3 H, d, ³ J = 6.4 Hz), 0.97 [3 H, d, CH(CH₃)₂, ^³ J = 6.4 Hz], 1.57-1.70 (2 H, m), 1.72-1.82 (1 H, m), 3.93-3.99 (1 H, m), 4.59 (1 H, dd, ^² J = 15.0 Hz, ³ J = 7.9 Hz), 4.71 (1 H, dd, ^² J = 15.0 Hz, ³ J = 4.8 Hz), 7.63 (5 H, m), 7.79 (1 H, s), 7.99 (1 H, s), 9.45 (1 H, s). ¹³C NMR (100 MHz, D₂O): δ = 21.1, 21.8, 23.8, 38.9, 49.5, 51.2, 122.5 (2 C), 123, 123.5, 130.5 (2 C), 130.6, 137.2. Mp 260-264 °C. HRMS: m/z calcd for [M - 2 Br - H]⁺ (C₁₅H₂₂N₃): 244.1808; found: 244.1808. Anal. Calcd (%): C, 44.47; H, 5.72; N, 10.37. Found: C, 44.25; H, 5.70; N, 10.22.Compound 4d: 1-mesitylimidazole (5 mmol, 0.93 g) and (S)-1-bromo-2-amino-4-methylpentane hydrobromide (5 mmol, 1.3 g) were dissolved in anhyd MeCN (50 mL) and heated to reflux for 20 h under a nitrogen atmosphere. The solvent was removed under vacuum and the residue dissolved in MeCN (3 mL), which was layered with Et₂O to precipitate a white solid. The solid was recrystallised from hot EtOH, yield 20% (0.36 g). ¹H NMR (400 MHz, D₂O): δ = 0.88 (3 H, d, ³ J = 6.6 Hz), 0.93 (3 H, d, ^³ J = 6.4 Hz), 1.47 (1 H, m), 1.61-1.73 (2 H, m), 2.02 (3 H, s), 2.03 (3 H, s), 2.31 (3 H, s), 3.92-3.97 (1 H, m), 4.62 (1 H, dd, ^² J = 14.7 Hz, ^³ J = 6.4 Hz), 4.70 (1 H, dd, ^² J = 14.7 Hz, ^³ J = 6.0 Hz), 7.13 (2 H, s), 7.68 (1 H, m) 7.87 (1 H, m), 9.18 (1 H, s). ¹³C NMR (100 MHz, D₂O): δ = 16.6 (2 C), 20.3, 21.0, 21.9, 23.8, 39.1, 48.9, 51.5, 123.7, 125.3, 129.5 (2 C), 130.7, 134.8 (2 C), 137.7, 141.8. Mp 264-264.5 °C. HRMS: m/z calcd for [M - 2 Br - H]⁺: 286.2283; found: 286.2277. Anal. Calcd (%): C, 48.34; H, 6.54; N, 9.39. Found: C, 47.70; H, 6.51; N, 9.15.Compound 4e: 1-benzylimidazole (8 mmol, 1.26 g) and (S)-1-bromo-2-amino-3-phenylpropane hydrobromide (5 mmol, 1.48 g) were dissolved in MeCN (30 mL) and heated to reflux for 20 h. The mixture was then allowed to cool to r.t. and the product precipitated as a white solid. This was isolated by filtration and dried under vacuum; yield 32% (0.74 g). ¹H NMR (400 MHz, D₂O): δ = 3.03 (1 H, dd, ^² J = 14.2 Hz, ^³ J = 8 Hz), 3.12 (1 H, dd, ^² J = 14.2 Hz, ^³ J = 6.6 Hz), 4.10-4.40 (1 H, m), 4.40-4.55 (2 H, m), 5.26 (2 H, s), 7.20-7.50 (12 H, m), 8.72 (1 H, s). ¹³C NMR (100 MHz, D₂O): δ = 36.9, 50.7, 51.7, 53.4, 123.0, 123.3, 128.0, 129.2 (2 C), 129.3 (2 C), 129.4 (2 C), 129.6 (2 C), 129.7, 132.9, 134.1, 136.4. Mp 246-248 °C. HRMS: m/z calcd for [M - 2 Br - H]⁺ 292.1808; found: 292.1808.