Difluoromethylation Reactions of Ethyl Pyruvate with the TDAE - A Mild
Approach to the Synthesis of 3,3-Difluoro-2-hydroxy-2-methyl-4-oxo-butyric Ethyl Esters Derivatives

Abstract

New 3,3-difluoro-2-hydroxy-2-methyl-4-oxo-butyric ethyl esters derivatives are easily obtained in moderate to good yields from the tetrakis(dimethylamino)ethylene (TDAE) mediated reduction of a series of RCF₂X (X = Cl or Br) starting materials in the presence of ethyl pyruvate.

Key words

electron transfer - fluorine - tetrakis(dimethylamino)ethylene - ethyl pyruvate - nucleophilic additions

References

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7

A typical procedure for the reaction between 1, CH₃COCO₂Et and TDAE is as follows:
Into a three-necked flask equipped with a calcium chloride drying tube, and a nitrogen inlet was added, under nitrogen, 5 mL of anhyd DMF and then 1 (0.50 g, 2.62 mmol) followed by ethyl pyruvate (0.91 g, 7.9 mmol, 0.87 mL). The solution was cooled down to -20 °C, stirred and maintained at this temperature for 30 min and then was added dropwise (via a syringe) the TDAE (0.63 g, 3.15 mmol). A red color immediately developed with the formation of a white fine precipitate. The solution was vigorously stirred at -20 °C for 1 h and then warmed up to r.t. for one hour (orange-red color). After this time TLC analysis [Hexane/EtOAc (60:40)] clearly showed that 1 was totally consumed. The orange-red turbid solution was filtered (to remove the octamethyloxamidinium dichloride) and hydrolyzed with 30 mL of an aq NaCl solution. The aq solution was extracted with CH₂Cl₂ (3 × 30 mL), the combined organic solutions washed with brine (3 × 30 mL), H₂O (3 × 30 mL) and dried over MgSO₄. Evaporation of the solvent left an orange viscous liquid as crude product. Purification by silica gel chromatography [Hexane/EtOAc (60:40)] gave 0.43 g (1.58 mmol, 61%) of 8 as a yellowish viscous oil.
3,3-Difluoro-2-hydroxy-2-methyl-4-oxo-4-phenyl-butyric Acid Ethyl Ester: ¹H NMR (CDCl₃): δ = 1.31 (3 H, t, -CH ₃ CH₂), 1.66 (3 H, s, -CH₃), 4.32 (2 H, m, -CH₂), 7.4-7.7 (4 H, m), 8.10 (1 H, d, J = 7.2 Hz). ¹⁹F NMR (CDCl₃/CFCl₃): δ = -103.3 (1 F, d, J = 288 Hz), -119.2 (1 F, d, J = 288 Hz). GC/MS: M⁺ = 272, M⁺ - CO₂Et: 199, 156 (PhCOCF₂), 105 (PhCO), 77 (Ph). HRMS: Calcd for C₁₃H₁₄F₂O₄: 272.0860. Found: 272.0845.