Palladium-Catalyzed Regioselective Hydroalkylation of 2-Fluoroallyl Acetates: Synthesis of Vinylmalonic Acid Ester Derivatives

Abstract

The palladium-catalyzed hydroalkylation of 2-fluoroallyl acetates with the malonate anion and hydride was developed. The reaction proceeded through the C–F bond activation and provided vinylmalonic acid ester derivatives by the regioselective substitutions with the carbon nucleophile and hydride.

Key words

palladium - catalysis - fluorine - regioselectivity - coupling

• References and Notes

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• 8 The olefin geometry of the major isomer was determined to be Z by the NOESY spectra. Please see the Supporting Information for details.
• 9 We also examined the reaction by Pd₂(dba)₃, Pd(OAc)₂, or Pd(acac)₂ with bpy, but those reactions resulted in lower or similar yields (<2–62%) with 31–60% Z selectivity.
• 10 Typical Procedure for the Hydroalkylation of 2-Fluoroallyl Acetates 1 with 3 and 4 To a solution of [Pd(π-allyl)Cl]₂ (4.7 mg, 0.013 mmol), 2,2′-bipyridyl (4.0 mg, 0.026 mmol), silver trifluoromethanesulfonate (6.6 mg 0.026 mmol), and (Z)-2-fluoro-3-phenylallyl acetate (1a, 50 mg, 0.26 mmol) in dioxane–DCE (1:1, 1.4 mL) was added dimethyl malonate (3a, 102 mg, 0.77 mmol) and triethylsilane (4, 60 mg 0.51 mmol), then LiHMDS (0.72 mmol, 0.7 mL of 1.0 M in THF) was also added slowly at 0 °C. The reaction mixture was heated at 60 °C and stirred for 12 h, then quenched with 2 M HCl, and extracted with Et₂O. The combined organic layers were dried over MgSO₄ and concentrated in vacuo. The Z/E ratio was determined to be 92:8 by ¹H NMR for the crude materials. The residue was chromatographed on silica gel (hexane–EtOAc, 4:1) to give 54 mg (83%) of 5aa as a colorless oil. ¹H NMR (400 MHz, CDCl₃): δ = 2.04 (d, J = 1.4 Hz, 3 H), 3.76 (s, 6 H), 4.71 (s, 1 H), 6.67 (s, 1 H), 7.19 (d, J = 6.8 Hz, 2 H) 7.28–7.36 (m, 3 H). Selected ¹H NMR data of minor isomer (E)-5aa: δ = 2.01 (d, J = 1.4 Hz, 3 H), 3.78 (s, 6 H), 4.27 (s, 1 H), 6.48 (s, 1 H), aromatic region overlaps with major isomer. ¹³C NMR (125 MHz, CDCl₃): δ = 21.0, 52.5, 53.5, 127.0, 128.4, 128.5, 130.0, 132.0, 136.7, 168.5. IR (neat): 3468, 3057, 3024, 2954, 2844, 1738 cm^–1. HRMS (DART): m/z calcd for C₁₄H₁₇O₄ [M + H]⁺: 249.1121; found: 249.1118.
• 11 We confirmed that the reaction of (E)-5aa (minor isomer) with NaH and MeI in THF at r.t. provided (E)-5ae.
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• 13 The exact stereochemistry had not been determined, and it was estimated by comparison with (Z)-5.
• 14 The stereochemistry of the major isomer was determined to be E by the NOESY spectra. See the Supporting Information for details.
• 15 The reaction using HSiEt₃ and AgOTf also provided the desired product (E)-12, but the reproducibility was low (0–72% yield).