Asymmetric Cyanosilylation of Aldehydes Catalyzed by Novel Organo­catalysts

Abstract

A novel proline-based N,N′-dioxide, which is easily prepared from inexpensive chemicals, serves as an effective catalyst for enantioselective cyanosilylation of aldehydes in up to 73% ee.

Key words

proline-based N,N′-dioxide - aldehydes - organocatalyst - cyanosilylation - enantioselectivity

References

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• 18 General Procedure for the Preparation of N , N ′-Dioxides. To a solution of (S)-1-(tert-butoxycarbonyl) pyrrolidine-2-carboxylic acid (1.183 g, 5.5 mmol) in CH₂Cl₂ was added Et₃N (2 mL), isobutyl carbonochloridate (0.72 mL, 5.5 mmol) at 0 °C under stirring. After 15 min, cyclohexanamine (0.57 mL, 5 mmol) was added. It was allowed to warm to r.t. and stirred for 3 h. The mixture was washed with 1 M KHSO₄, sat. NaHCO₃, brine, dried over anhyd Na₂SO₄ and concentrated. The residue in CH₂Cl₂ (20 mL) was added TFA (5 mL) and stirred for 1 h. Then, the solvent was evaporated, and H₂O was added (10 mL). The pH of the mixture was brought into the range of 8-10 by the addition of 2 M NaOH. The aqueous phase was extracted with CH₂Cl₂. The CH₂Cl₂ extracts were pooled, washed with brine, dried over anhyd Na₂SO₄ and evaporated in vacuo. The residue was used for next step directly.To a solution of N-cyclohexylpyrrolidine-2-carboxamide (980 mg, 5 mmol) in MeCN was added K₂CO₃ (691 mg, 5 mmol) and 1, 3-dibromopropane (0.26 mL, 2.5 mmol) under stirring. It was kept at 80 °C, and monitored by TLC after 10 h. Then, K₂CO₃ was removed by filtration. The residue was purified by silica gel column chromatography (EtOAc) to give 1,1′-(propane-1,3-diyl)bis(N-cyclohexylpyrrolidine-2-carboxamide) (974 mg, 90%) as a white solid.For the oxidation step and stereochemistry of the N-oxide, see: O’Neil IA. Miller ND. Peake J. Barkley JV. Low CMR. Kalindjian SB. Synlett  1993,  515 

17

Only 10% to 30% ee was obtained using the N-monoxide.

19

The following are the NMR data of 2f: ¹H NMR (400 MHz, CDCl₃): δ = 10.59 (2 H, d, J = 6.8 Hz, NH), 3.77 (2 H, m), 3.62 (2 H, m), 3.32-3.60 (8 H, m), 2.39-2.64 (8 H, m), 1.57-2.03 (12 H, m), 1.27-1.35 (10 H, m) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 19.73, 24.39, 25.32, 27.42, 32.26, 32.73, 47.26, 64.72, 67.55, 76.45, 166.28 ppm. HRMS (ESI): m/z calcd for C₂₅H₄₄N₄O₄: 465.3435 [M + H]⁺; found: 465.3428 [M + H]⁺.

20

Typical Procedure for the Trimethylsilylcyanation of Aldehydes.
To a solution of 2f (4.7 mg, 0.01 mmol) in CH₂Cl₂ (0.4 mL) was added freshly distilled benzaldehyde (42 µL, 0.4 mmol) under N₂ atmosphere, then TMSCN (68 µL, 0.52 mmol) was added at -78 °C. After stirring for 80 h at this temperature, the reaction was quenched. Further purification was performed by silica gel column chromatography to give the product (76 mg, 92%) as a colorless oil. To the product was added a mixture of 1 M HCl (5 mL) and EtOAc (10 mL) and stirred for 3 h at r.t., the organic layer was washed with distilled H₂O, and dried over anhyd Na₂SO₄. The cyanohydrin was converted into the corresponding acetate by reaction with two equiv of Ac₂O and pyridine in CH₂Cl₂ (5 mL) at r.t. for 1 h. The organic layer was washed with distilled H₂O, dried over anhyd Na₂SO₄ and concentrated. The crude was purified by flash chromatography on silica gel (PE-EtOAc, 10:1) to yield the corresponding acetylated cyanohydrin for further analysis.