A third Generation of Radical Fluroinating Agents

A third Generation of Radical Fluroinating Agents Based on N-Fluoro-N-Arylsulfonamides

Meyer et al.

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Supplementary Methods ......................................................................................................4 Experimental work ..............................................................................................................4 General Information .........................................................................................................4 Synthesis of Reagents.....................................................................................................4 Synthesis of Alkenes .......................................................................................................7 Synthesis of Peresters................................................................................................... 14 Synthesis of Amides and Sulfonamides ......................................................................... 18 Synthesis of N-fluoro-N-alkyl amides/sulfonamides ....................................................... 25 Crystal structures of NFASs22,23 ..................................................................................... 31 Hydrofluorination ........................................................................................................... 34 Kinetic Experiments ....................................................................................................... 46 Decarboxylative Fluorination ......................................................................................... 47 NMR-Spectra................................................................................................................. 51 Theoretical calculations ................................................................................................... 155 Methodology ................................................................................................................... 155 Structural Comparison (X-Ray vs QM) ............................................................................ 156 Bond Strengths (F—NR2) ................................................................................................ 157 (U)B3LYP/6-31G(d) ..................................................................................................... 157 (RO)B2PLYP/B2PLYP/G3MP2Large ........................................................................... 158 G3(MP2)-RAD ............................................................................................................. 159 Bond Strengths (H—NR2) ............................................................................................... 162 QM Data (For Bond Strengths) ....................................................................................... 163 Free Energy (ΔG) & Enthalpy (ΔH) Surfaces .................................................................. 169 Free Energy & Enthalpy Surfaces in Gas Phase at (U)B3LYP/6-31G(d)...................... 172 Free Energy Surfaces in DMF Solution (Gas Phase Optimized) .................................. 174 Charge and Spin Analysis (Gas Phase Optimized) ...................................................... 175 Free Energy & Enthalpy Surfaces at (RO)B2PLYP/G3MP2Large (Gas Phase Optimized) .................................................................................................................................... 176 Free Energy & Enthalpy Surfaces in DMF Solution (Solution Phase Optimized) .......... 177 2

Charge and Spin Analysis (Solution Phase Optimized) ............................................... 180 (U)B3LYP/6-31G(d) - Energy Surfaces with Conformational Details (Gas) .................. 181 (U)B3LYP/6-31G(d) - Energy Surfaces with Conformational Details (DMF) ................. 182 (U)B3LYP/6-31G(d) - Energy Surfaces with Conformational Details (DMF,opt) ........... 184 QM Data (For Free Energy & Enthalpy Surfaces) ........................................................... 186 References ........................................................................................................................ 192

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Supplementary Methods Experimental work General Information Starting materials were provided from Sigma Aldrich and Fluorochem. All reactions involving oxygen- or moisture-sensitive compounds were carried out under a dry argon atmosphere. Column chromatography was performed with silica gel (pore size 60 Å, 230-400 mesh particle size) packed in glass columns or using an automated CombiFlash-system. Reactions were monitored by thin layer chromatography (TLC) using Silicycle silica gel 60 F254 plates (0.2 mm thickness). Visualization was performed by ultraviolet light or by PMA- or bromocresol green stain, followed by gentle heating. NMR spectra were recorded at 300 MHz (for 1H-NMR), 75/100 MHz (for

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C-NMR), 282 MHz (for

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F-NMR) and 96 MHz (for

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B-NMR) in CDCl3 or

C6D6. Chemical shifts are reported as δ (ppm) downfield from tetramethylsilane (δ = 0.00) using residual solvent signal as an internal standard: δ singlet 7.26 (1H), triplet 77.0 (13C). IR spectra were obtained on neat samples (ATR probe). High-resolution mass spectra were recorded on an ESI-Orbitrap MS or a two sector field high-resolution mass analyzer. Gas chromatographic (GC) analyses were carried out with a Macherey-Nagel Optima delta-3-0.25 μm capillary column (20 m or 30 m, 0.25 mm). Gas carrier: He 1.4 mL/min; injector: 220 °C split mode; detector: FID 280 °C, H2 35 mL/min, air 350 mL/min. Enantiomeric purity was determined by HPLC on a CHIRALPAK IB-3 (250 mm, 4.6 mm, 3 μm).

Synthesis of Reagents Di-tert-butylhyponitrite (DTBHN) According to the literature procedure1, sodium trans-hyponitrite hydrate was dried under high vacuum for 3 days to a constant weight. The dry sodium trans-hyponitrite (5.37 g, 50.7 mmol) was added to tert-butyl bromide (45.5 mL, 405 mmol) followed by the addition of dry Et 2O (25 mL) and cooled to −5 °C. A suspension of ZnCl2 (2 M in Et2O, 30.4 mL, 60.8 mmol) was cannulated to the reaction mixture at