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.

asymmetric catalysis - carbenes - copper - Michael additions

References and Notes

1 Herrmanm WA. Angew. Chem. Int. Ed.  2002,  41:  1291 

2 Alexakis A. Benhaim C. Eur. J. Org. Chem.  2002,  3221 

3 Perry MC. Cui X. Powell MT. Hou D.-R. Reibenspies JH. Burgess K. J. Am. Chem. Soc.  2003,  125:  114 

4 Van Veldhuizen JJ. Garber SB. Kingsbury JS. Hoveyda AH. J. Am. Chem. Soc.  2002,  124:  4954 

5 Douthwaite RE. Coord. Chem. Rev.  2007,  251:  702 

6 Fraser PK. Woodward S. Tetrahedron Lett.  2001,  42:  2747 

7 Guillen F. Winn CL. Alexakis A. Tetrahedron: Asymmetry  2001,  12:  2083 

8 Pytkowics J. Roland S. Mangeney P. Tetrahedron: Asymmetry  2001,  12:  2087 

9 Winn CL. Guillen F. Pytkowicz J. Roland S. Mangeney P. Alexakis A. J. Organomet. Chem.  2005,  690:  5672 

10a Clavier H. Coutable L. Guillemin J.-C. Mauduit M. Tetrahedron: Asymmetry  2005,  16:  921 

10b Clavier H. Toupet L. Coutable L. Guillemin J.-C. Mauduit M. J. Organomet. Chem.  2005,  690:  5237 

10c Martin D. Kehrli S. d’Augustin M. Clavier H. Mauduit M. Alexakis A. J. Am. Chem. Soc.  2006,  128:  8416 

11a Edworthy IS. Rodden M. Mungaur SA. Davis KM. Blake AJ. Wilson C. Schroder M. Arnold PL. J. Organomet. Chem.  2005,  690:  5710 

11b Arnold PL. Rodden M. Davis KM. Scarisbrick AC. Blake AJ. Wilson C. Chem. Commun.  2004,  1612 

12a Jurkauskas V. Sadighi JP. Buchwald SL. Org. Lett.  2003,  5:  1157 

12b Kaur H. Zinn FK. Stevens ED. Nolan SP. Organometallics  2004,  23:  1157 

12c Fructos MR. Belderrain TR. Nicasio MC. Nolan SP. Kaur H. Díaz-Requejo MM. Perez PJ. J. Am. Chem. Soc.  2004,  126:  10846 

12d Díez-González S. Kaur H. Kauer Zinn F. Stevens ED. Nolan SP. J. Org. Chem.  2005,  70:  4784 

13 Nagle AS. Salvatore RN. Chong B.-D. Woon Jung K. Tetrahedron Lett.  2000,  41:  3011 

14 Larsen AO. Leu W. Oberhuber CN. Campbell JE. Hoveyda AH. J. Am. Chem. Soc.  2004,  126:  11130 

15 Gade LH. Cesar V. Bellemin-Laponnaz S. Angew. Chem. Int. Ed.  2004,  43:  1014 

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.