Optimisation and real time reaction monitoring of the synthesis of 2-fluoromalonate esters by direct fluorination using fluorine gas is reported. An assessment of green metrics including atom economy and process mass intensity factors, demonstrates that the one-step selective direct fluorination process compares very favourably with established multistep processes for the synthesis of fluoromalonates.
Scheme 2 Synthetic routes to 2-fluoromalonate esters.
|Scheme 1 2-Fluoromalonate esters used in the synthesis of Fluoxastrobin and TAK-733.|
|Fig. 1 IR spectra of the fluorination reaction at 0% (light blue), 50% (dark blue) and 100% (red) conversions.|
|Entry no.||T/°C||C malonate (mol L−1)||Catalyst (mol%)||F 2 in N2 (% v/v)||Conversion (1H NMR)||A/B/C ratio (19F NMR)||Isolated weight|
|Scheme 3 Fluorination of di-methyl and di-tert-butyl malonates.|
Diethyl fluoromalonate large scale fluorinationDiethyl malonate (40.0 g, 0.25 mol) and copper nitrate hydrate (Cu(NO3)2·2.5H2O; 5.81 g, 25 mmol) were dissolved in acetonitrile (200 mL) and placed in 500 mL fluorination vessel, cooled to 0–5 °C and stirred at 650 rpm using an overhead stirrer. After purging the system with N2 for 5 minutes, fluorine gas (20% v/v in N2, 80 mL min−1, 265 mmol) was introduced into the mixture for 6 hours and 30 minutes. The reactor was purged with nitrogen for 10 minutes, the solvent removed in vacuo and the residue partitioned between water (50 mL) and ethyl acetate (50 mL). The aqueous phase was extracted once more with ethyl acetate (50 mL) and the combined organic layers were washed with saturated NaHCO3 (25 mL) and brine (20 mL). After drying over sodium sulfate, the solvent was evaporated to leave diethyl 2-fluoromalonate (44.4 g, 99% yield, 95% purity) as a light yellow, transparent liquid. This crude product was distilled to afford high purity fluoromalonate (34.7 g, 77% yield, 99%+ purity) as a colourless liquid, bp. 102–103 °C (18 mbar), (lit.: 110–112 °C, 29 mbar), spectroscopic data as above.........N. Ishikawa, A. Takaoka and M. K. Ibrahim, J. Fluorine Chem., 1984, 25, 203–212 CrossRef CAS.
Fluorine gas for life science syntheses: green metrics to assess selective direct fluorination for the synthesis of 2-fluoromalonate esters†
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Fluorine gas for life science syntheses: green metrics to assess selective direct fluorination for the synthesis of 2-fluoromalonate esters