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Chiral Sulfinamide Ligands and Pd-Catalyzed Asymmetric Allylic Alkylations of Ethyl 2-Fluoroacetoacetate

Abstract

New chiral sulfinamide ligands made from salicylic acids and chiral tert-butanesulfinamide was utilized in Pd-catalyzed asymmetric allylic substitutions of ethyl 2-fluoroacetoacetate, which afforded the fluorinated allyl products with up to 98% yield, 94% ee, and 2.2:1 dr. Both sulfoxide and hydroxyl group on the sulfanilamide ligands are ­crucial for enantiocontrol in the Pd-catalyzed allylic alkylations of ethyl 2-fluoroacetoacetate.

Key words

sulfinamide ligand - allylation - palladium - enantioselectivity - fluorinated allylproduct

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• 22 Typical Procedure for the Synthesis of (R)-L1 To a solution of salicylic acid (1.0 mmol) in THF (2.0 mL) was added 1,1′-carbonyldiimidazole (CDI; 1.0 mmol, 1.0 equiv) slowly at room temperature, then the reaction mixture was heated to 50 °C for 1.0 h. The solution was cooled to room temperature and concentrated to give the active amide. To a suspension of KH (30% in oil, 2.0 mmol, 2.0 equiv) in THF (5.0 mL) was added (R)-tert-butanesulfinamide (1.0 mmol) under argon at room temperature and the mixture was stirred for 0.5 h. The active amide was added and the mixture was stirred at 50 °C for 1.0 h. The reaction mixture was cooled to room temperature and acidified with aqueous HCl to pH >7, then the mixture was diluted with EtOAc (10 mL), washed with H₂O (3 × 10 mL) and brine (10 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by column chromatography on silica gel (EtOAc) to give the desired product (R)-L1 (149.4 mg, 62% yield) as a white solid; mp 144.6–145.9 °C; [α] _d ²⁵ –73.8 (c = 1.0, MeOH). ¹H NMR (400 MHz, CDCl₃): δ = 7.78 (d, J = 7.8 Hz, 1 H), 7.39 (t, J = 7.4 Hz, 1 H), 7.01 (d, J = 8.1 Hz, 1 H), 6.88 (t, J = 7.5 Hz, 1 H), 1.36 (s, 9 H). ¹³C NMR (100 MHz, CDCl₃): δ = 168.94, 159.16, 135.22, 129.55, 119.79, 118.01, 115.40, 57.05, 22.26. IR (KBr): 3259, 2963, 2930, 2854, 1677, 1605, 1464, 1408, 1393, 1304, 1232, 1107, 1032 cm^–1. HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₁₁H₁₆NO₃S: 242.0845; found: 242.0841
• 23 CCDC-1499293, (R)-L1, contains the supplementary crystallographic data for this paper. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/getstructures
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• 27 Typical Procedure for Pd-Catalyzed Allylic Alkylation Reaction [Pd(C₃H₅)Cl]₂ (0.004 mmol, 4 mol%), (R)-L1 (0.008 mmol, 8 mol%), and (E)-1,3-disubstituted allyl acetate 1 (0.1 mmol) were dissolved in THF/dioxane (2.0 mL, 1:1) in a dry Schlenk tube filled with argon. The reaction mixture was stirred for 30 min at room temperature, then ethyl 2-fluoroacetoacetate (2a; 0.3 mmol, 3.0 equiv) and K₃PO₄ (0.3 mmol, 3.0 equiv) were added. The reaction mixture was stirred at room temperature and the progress of the reaction was monitored by TLC. Upon completion, the mixture was filtered through Celite and the solvent was evaporated under vacuum. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate) to give the desired products 3a–i. (E)-Ethyl 2-Acetyl-3,5-bis(3-chlorophenyl)-2-fluoropent-4-enoate (3a): Colorless oil (39.8 mg, 98% yield). The diastereomeric ratio was 1.6:1 determined by ¹H NMR spectroscopic analysis. The ee value of the major diastereomer was 80%, the minor diastereomer was 78%, determined by chiral HPLC [Daicel CHIRALCEL OJ-H (0.46 cm × 25 cm); hexane/i-PrOH = 98:2; flow rate = 1.0 mL/min; detection wavelength = 254 nm; t_R (major) = 16.984, 19.423 min; t_R (minor) = 21.968, 25.166 min]. ¹H NMR (400 MHz, CDCl₃, stereoisomeric mixture): δ = 7.42–7.17 (m, 13 H), 6.61–6.21 (m, 3.3 H), 4.52 (dd, J = 32.6, 8.8 Hz, 1.6 H), 4.37–4.16 (m, 2 H), 4.06 (m, 1.3 H), 2.32 (d, J = 5.7 Hz, 1.9 H), 2.01 (d, J = 5.6 Hz, 3 H), 1.27 (t, J = 7.1 Hz, 3 H), 1.06 (t, J = 7.1 Hz, 1.9 H). ¹³C NMR (100 MHz, CDCl₃, stereoisomeric mixture): δ = 201.32 (d, J = 29.8 Hz), 201.14 (d, J = 29.9 Hz), 164.66 (d, J = 25.7 Hz), 164.26 (d, J = 25.9 Hz), 139.01, 138.42, 138.10, 138.03, 134.60, 134.46, 133.61, 133.30, 130.04, 130.02, 129.85, 129.52 (d, J = 2.5 Hz), 129.19 (d, J = 2.6 Hz), 128.11, 128.06, 128.05, 128.00, 127.70 (d, J = 2.2 Hz), 127.12 (d, J = 2.6 Hz), 126.38, 126.33, 125.79, 125.75, 125.60, 125.55, 124.89, 124.80, 102.68 (d, J = 206.1 Hz), 102.52 (d, J = 207.9 Hz), 63.09, 62.84, 52.88 (d, J = 18.1 Hz), 52.82 (d, J = 18.2 Hz), 26.85, 26.84, 14.18, 13.77. ¹⁹F NMR (376 MHz, CDCl₃, stereoisomeric mixture): δ = –174.49, –175.05. IR (KBr): 3064, 2982, 2932, 2854, 1754, 1734, 1594, 1570, 1476, 1431, 1356, 1246, 1205, 967, 913, 781, 742 cm^–1. HRMS (ESI-TOF): m/z [M + Na]⁺ calcd. for C₂₁H₁₉Cl₂FNaO₃: 431.0587; found: 431.0592

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