Catalytic Asymmetric Cyano-Ethoxycarbonylation Reaction of Aldehydes Using a Novel C ₂-Symmetric Chiral N,N′-Dioxide Titanium Complex

Abstract

The asymmetric addition of ethyl cyanoformate to a range of aldehydes was efficiently catalyzed by a easily prepared C ₂-symmetric chiral N,N′-dioxide-Ti(IV) complex in high yields with up to 90% ee under mild conditions. A linear effect between the enantiopurity of the ligand and the enantiopurity of the product was observed.

C ₂-symmetric chiral N,N′-dioxide ligand - ethyl cyanoformate - aldehydes - enantioselectivity - organotitanium

References and Notes

For reviews on synthesis of cyanohydrin carbonates, see:

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9

General Procedure for the Preparation of C ₂ -Symmetric Ν , N ′-Dioxide Ligands.
(a) To a solution of (S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (2.3 g, 10.0 mmol) in CH₂Cl₂ was added Et₃N (4 mL), isobutyl carbonochloride (1.44 mL, 10.0 mmol) at 0 °C under stirring After 25 min, the amine (10.2 mmol) was added. It was allowed to warm to r.t. and stirred for 8 h. The mixture was washed with 1 M KHSO₄ (20 mL), sat. NaHCO₃ (20 mL), brine (20 mL), dried over Na₂SO₄ and concentrated. The residue in CH₂Cl₂ (25 mL) was added TFA (10 mL) and stirred for 2 h. Then, the solvent was evaporated, and H₂O (20 mL) was added. 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 (50 mL). The CH₂Cl₂ extracts were pooled, washed with brine, dried over Na₂SO₄ and evaporated in vacuo. The residue was used for next step directly.
(b) 2,6-Di(bromomethyl)-4-methylphenol (5.1 mmol) was added in one portion to a stirred and cooled solution of (S)-pyrrolidine-2-carboxamide (10.2 mmol) and K₂CO₃ (21 mmol) in dry DMF (8 mL). The ice bath was removed after the addition and the resulting solution was allowed to stir at r.t. for 12 h before it was diluted with H₂O (50 mL) and Et₂O (50 mL). The two phases were separated and the aqueous phase was extracted with Et₂O three times and the combined organic phases were washed with H₂O (20 mL), brine (20 mL), dried over Na₂SO₄, and evaporated. The residue was purified by silic gel column chromatography to give the foam product. Next, MCPBA (13 mmol) was added at -78 °C to a solution of the above product and anhyd K₂CO₃ in CH₂Cl₂. The resulting mixture was stirred at the same temperature and the reaction was monitored by TLC. After completion, the mixture was allowed to warm slowly to r.t. and filtered. The solvents were evaporated under reduced pressure. Purification of the residue by silica gel column chromatography (Et₂O-MeOH, 10:1 and Et₂O-MeOH, 6:1) to afford the corresponding (2S,2′S)-1,1′-[(2-hydroxy-5-methyl-1,3-phenylene)di(methylene)]bis[N-(2-tert-butylphenyl)pyrrolidine-2-carboxamide]-N,N′-dioxide (1c).

10

The following are the physical, NMR and HRMS data of 1c: mp 127-129 °C; [α]_D ²⁵ -7.3 (c 2.12, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ = 8.54 (s, 2 H), 7.25-7.33 (m, 4 H,), 7.07-7.15 (m, 4 H), 6.82 (s, 2 H), 3.82-3.85 (d, J = 12 Hz, 2 H), 3.59-3.62 (d, J = 12 Hz, 2 H), 3.30-3.34 (m, 2 H), 2.95-3.00 (m, 2 H), 2.39-2.46 (m, 2 H), 2.19 (s, 3H), 1.99-2.05 (m, 4 H), 1.76-1.79 (m, 4 H), 1.44 (s, 18 H,). ¹³C NMR (400 MHz, CDCl₃): δ = 20.39, 24.01, 30.16, 30.56, 34.54, 53.83, 55.78, 67.42, 123.07, 125.89, 126.34, 126.58, 127.8, 129.74, 135.08, 142.76, 153.32, 172.28. HRMS: m/z calcd for C₃₈H₅₂N₄O₅: 657.4016 [M + H]⁺; found: 657.4005 [M + H]⁺.

11

General Procedure for Asymmetric Addition of Ethyl Cyanoformate to Aldehydes. To a solution of 1c (16.4 mg, 0.025 mmol) and 4 Å MS (20 mg) in CH₂Cl₂ (0.5 mL) was added Ti(Oi-Pr)₄ (1 M in toluene, 25 µL, 0.025 mmol) at r.t., then the mixture was stirred at 35 °C for 1 h under N₂ atmosphere. To this solution aldehyde (0.25 mmol) and EtOCOCN (50 µL, 0.5 mmol) were added at -45 °C under N₂ atmosphere. After the complete conversion of the aldehyde (monitored by TLC, 48-100 h), the crude product was purified by column chromatography on silica gel (PE-Et₂O, 10:1) to give the corresponding cyanohydrin carbonates for further analysis.

12a Girard C. Kagan HB. Angew. Chem. Int. Ed.  1998,  37:  2922 

12b Avalos M. Babiano R. Cintas P. Jiménez JL. Palacios JC. Tetrahedron: Asymmetry  1997,  8:  2997