Chiral Bifunctional NHC–Guanidine Ligands for Asymmetric Hydrogenation

Abstract

We report the synthesis of chiral N-heterocyclic carbene/guanidine bifunctional ligands from readily available amino alcohols. The resulting chiral bifunctional copper(I) complexes are active catalysts in an asymmetric hydrogenation of ketones. We show that the chiral linker unit can be employed for the transfer of stereoinformation.

Key words

N-heterocyclic carbenes - guanidines - bifunctional catalysts - hydrogenation - asymmetric catalysis - copper catalysis

• References and Notes

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• 17 Ligand Precursor 6 Brown solid; yield: 312 mg (63%). ¹H NMR (600 MHz, CDCl₃): δ = 9.15 (s, 1 H, H-14), 8.40 (s, 1 H, H-15)*, 7.39–7.34 (m, 4 H, H-6, H-11), 7.21–7.19 (m, 7 H, H-16*, H-7, H-8, H-12, H-13), 7.02 (s, 1 H, H-20), 6.98 (s, 1 H, H-20′), 6.92 (d, ³ J _N–Ha,₄ = 8.4 Hz, 1 H, N–Ha), 6.36 (d, ³ J ₉,₄ = 11.1 Hz, 1 H, H-9), 5.99 (br s, 1 H, N–Hb), 5.90 (dd, ³ J ₄,₉ = 11.1 Hz, ³ J ₄,_N–Ha= 8.2 Hz, 1 H, H-4), 3.77 (m, 2 H, H-2), 2.33 (s, 3 H, H-22), 2.05 (s, 3 H, H-19), 1.88 (s, 3 H, H-19′), 1.20 (d, ³ J ₁,₂ = 6.6 Hz, 6 H, H-1), 1.10 (d, ³ J ₁,₂ = 6.4 Hz, 6 H, H-1′). ¹³C NMR (151 MHz, CDCl₃): δ = 153.9 (C-3), 141.9 (C-21), 136.6 (C-14), 135.2 (C-10), 134.5 (C-18), 133.9 (C-18′), 133.7 (C-5), 130.5 (C-17), 130.2 (C-20′), 130.0 (C-20), 129.9 (Ar-C), 129.4 (Ar-C), 129.3 (Ar-C), 127.9 (Ar-C), 127.8 (Ar-C), 123.9 (C-16)*, 123.3 (C-15)*, 68.1 (C-9), 59.1 (C-4), 46.0 (C-2), 23.2 (C-1′), 22.1 (C-1), 21.2 (C-22), 17.1 (C-19), 17.0 (C-19′). ¹⁹F NMR (471 MHz, CDCl₃): δ = –71.7 (d, ¹ J _F,_P = 713.2 Hz). ³¹P NMR (202 MHz, CDCl₃): δ = –143.9 (sept, ¹ J _P,_F = 713.2 Hz). HRMS (ESI): m/z [M – PF₆]⁺ calcd for C₃₃H₄₂N₅: 508.3435; found: 508.3435.
• 18 Ligand Precursor 7 Yellow solid; yield: 178 mg (70%). ¹H NMR (600 MHz, CDCl₃): δ = 8.84 (s, 1 H, H-8), 8.13 (app t, ³ J = 1.6 Hz, 1 H, H-9)*, 7.24 (app t, ³ J = 1.6 Hz, 1 H, H-10)*, 7.04 (s, 2 H, H-14, H-14′), 5.71 (br s, 1 H, N–Ha), 4.91 (dd, ³ J ₅,_4b= 10.8 Hz, ³ J ₅,_4a =3.0 Hz, 1 H, H-5), 4.05 (m, 1 H, H-4a), 3.87 (d, ³ J _4b,₅ = 11.2 Hz, 1 H, H-4b), 4.03–3.58 (m, 3 H, N–Hb, H-1), 2.36 (s, 3 H, H-16), 2.03 (s, 3 H, H-13), 2.00 (s, 3 H, H-13′), 1.33 (d, ³ J ₂,₁ = 6.3 Hz, 6 H, H-2), 1.24 (d, ³ J ₂′,₁= 6.3 Hz, 6 H, H-2′), 1.09 (s, 9 H, H-7). ¹³C NMR (151 MHz, CDCl₃): δ = 153.4 (C-3), 141.9 (C-15), 137.5 (C-8), 134.2 (C-12), 133.8 (C-12′) 130.3 (C-14), 130.2 (C-14′), 130.1 (C-11), 124.1 (C-9)*, 121.4 (C-10)*, 68.7 (C-5), 45.2 (C-1), 41.5 (C-4), 34.7 (C-6), 26.4 (C-7), 22.2 (C-2), 22.0 (C-2′), 21.2 (C-16), 17.3 (C-13), 17.0 (C-13′). ¹⁹F NMR (471 MHz, CDCl₃): δ = –71.7 (d, ¹ J _F,_P = 714.2 Hz). ³¹P NMR (202 MHz, CDCl₃): δ = –144.2 (sept, ¹ J _P,_F = 714.2 Hz). HRMS (ESI): m/z [M – PF₆]⁺ calcd for C₂₅H₄₂N₅: 412.3435; found: 412.3132.
• 19 (1S)-1-Phenylethanol (16): Typical Procedure for Asymmetric Hydrogenation By following the reported procedure,⁶ in an Ar-filled glove box, a 5 mL vial equipped with a stirrer bar was charged with CuCl (1.98 mg, 2.00 μmol, 10.0 mol%), the appropriate ligand precursor 6 or 7 (2.4 μmol, 12 mol%), and t-BuONa (24.9 mg, 0.26 mmol, 1.30 equiv). The vial was capped inside the glovebox and then transferred outside. The solids were dissolved in THF (1.00 mL), and the resulting mixture was stirred for 15 min at 40 °C. 15-Crown-5 (25.0 μL, 0.260 mmol, 1.30 equiv) was added to the mixture. Acetophenone (15; 24.0 mg, 0.20 mmol, 1.00 equiv) was dissolved in THF (1.00 mL) and the solution was transferred to the reaction vial. The vial was placed in an autoclave and the septum was pierced with a needle under a N₂ counterflow. The autoclave was purged with H₂ (3 × 10 bar), and the mixture was stirred at the appropriate temperature for 72 h under a H₂ atmosphere (100 bar). After removal of the H₂ atmosphere and equilibration of the mixture to r.t., the crude mixture was filtered through a small plug of silica gel [1 × 5 cm; eluent: CH₂Cl₂ (20 mL)] and then all the volatiles were removed under reduced pressure. The conversion of the product 16 was determined by ¹H NMR and/or HPLC. The ee of the crude product 16 was determined by HPLC analysis. The crude mixture could be further purified by flash column chromatography [silica gel, EtOAc–cyclohexane (1:5)] for more precise analysis.

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