Synthesis of 18F-difluoromethylarenes using aryl boronic acids, ethyl bromofluoroacetate and [18F]fluoride

Herein, we report the radiosynthesis of 18F-difluoromethylarenes via the assembly of three components, a boron reagent, ethyl bromofluoroacetate, and cyclotron-produced non-carrier added [18F]fluoride.


S1: General Information
All chemicals purchased from commercial sources were used without further purification prior to use. All NMR spectra were recorded at a temperature of 298.15 K on Bruker AV400, or AV500 spectrometers. Appropriate deuterated solvents were used as an internal reference depending on the compound measured. All corresponding compound peaks were referenced to the residual solvent peak and reported in parts per million (ppm) using the Bruker internal referencing procedure (edlock). 19 F NMR spectral peaks were referenced to CFCl3. All coupling constants are denoted as J and reported in Hz. The following abbreviations were used to define peak multiplicities s = singlet, d = doublet, t = triplet, q = quartet, pent = pentet, sept = septet, br = broad, m = multiplet. All NMR spectra were processed using Mestrenova 11.0 software. Mass spectra were recorded on Micromass GCT (CI) or Autospec-oaTof instruments.
IR spectra were recorded as thin films on Bruker Tensor 27 FT-IR spectrometer. IR absorption are reported in wavenumbers (cm -1 ). All reactions which required anhydrous conditions were carried out in flame-dried glassware under an inert atmosphere of nitrogen or argon. When dry solvents were used these were purified a priori on an alumina column using standard procedures. All reactions were monitored by TLC using Merck Kieselgel 60 F254 plates. High resolution mass spectra (HRMS, m/z) were recorded on a Bruker MicroTOF spectrometer using negative or positive electrospray ionization (ESI). Melting point measurements were recorded using a Griffin melting point apparatus.

S2: Optimisation of the Cu-catalysed cross coupling reaction General Screening Procedure:
To a 4 mL vial containing a magnetic stir bar was added ligand (if solid), boronic acid, copper source and base. The vial was then evacuated and refilled with N2 three times. Solvent (0.5 mL) and ligand (if liquid) were then added before heating the reaction mixture to 100 °C and stirring for 18 hours. The resulting solution was cooled to 0 °C before 0.1 mmol of PhCF3 was added as an internal standard, the corresponding sample was then diluted with CDCl3. Yields were calculated by quantitative 19 F NMR and referenced to PhCF3. Note: All screening reactions were run on a 0.1 mmol scale, isolations were performed on 0.3 mmol scale and in some cases scaled up to illustrate scalability. Screening reactions performed on 0.1 mmol scale. a Yield determined by 19 F-NMR using PhCF3 as internal standard. b Reactions with 2 equiv. of 6a and 1 equiv. of 2-bromo-2-fluoroacetate. b Reactions with 1 equiv. of 6a and 2 equiv. of 2-bromo-2-fluoroacetate d Yield of isolated product. e One-pot procedure. followed by argon degassed toluene (1.5 mL

Preparation of Boronic Acid Precursors
Boronic acid precursors used in the synthesis towards 8a-8h, 8j and 8p-8v were purchased from commercial vendors.
Boronic acid precursors used in the synthesis towards 8i and 8k-8m were kindly donated by Pfizer inc.
Boronic acid precursors used in the synthesis of 8n and 8o were synthesized according to known literature procedures.