Synthesis of Fluorinated Amide Derivatives via a Radical N-Perfluoroalkylation–Defluorination Pathway

A one-pot approach to fluorinated hydroxamic acid, amide, and thioamide derivatives is reported. The reaction proceeds via an N-perfluoroalkylation of nitrosoarenes with perfluoroalkanesulfinates, resulting in labile N-perfluoroalkylated hydroxylamines. By the addition of suitable additives, a controllable oxy/thiodefluorination of the fluorinated hydroxylamine intermediates was achieved. The method highlights N-perfluoroalkylated amines as versatile intermediates for further synthesis.


General Information
All reactions were carried out under air unless otherwise stated. Nitrosoarenes 1c-l and 1n-q, and the sodium perfluoroalkanesulfinates were prepared according to literature procedures using commercial reagents (Section 2.1). All other starting materials and solvents were purchased from commercial suppliers and were used as received. 1 H NMR, 13 C NMR and 19 F NMR spectra were recorded at room temperature in CDCl 3 on a Bruker 400 or 500 MHz spectrometer unless otherwise stated. Chemical shifts (δ) are reported in ppm with the following abbreviations used for the observed multiplicities: s (singlet), d (doublet), t (triplet), q (quartet), bs (broad singlet), m (multiplet for unresolved lines). 1 H NMR chemical shifts were referenced to the residual solvent signal in CDCl 3 (7.26 ppm), DMSO-d 6 (2.50 ppm) or acetone-d 6 (2.05 ppm). 13 C NMR chemical shifts were referenced to the solvent signal of CDCl 3 (77.16 ppm) or acetone-d 6 (29.84 ppm) and 19 F NMR chemical shifts were referenced to the external standard α,α,α-trifluorotoluene (-63.72 ppm). Analytical TLC was performed on pre-coated silica gel plates. After elution, the plates were visualized by UV illumination at 254−360 nm, and by staining with ethanolic KMnO 4 . Column chromatography was performed using Davisil or Merck 60 Å silica gel (35-70 μm). HRMS data were recorded on a Bruker micrOTOF instrument using ESI technique. GC/MS analyses were performed on a Shimadzu GCMS-QP2020 equipped with an HP-5MS column (30m×0.25mm×0.25μm) with a quadrupole mass analyzer using helium as the carrier gas.

O-Acetyl-N-(4-nitrophenyl)-N-(perfluorobutyl)hydroxylamine (6q)
Compound 6q was obtained by a sequential one-pot reaction from 1q. The perfluoroalkylation of 1q was performed on 0.5 mmol scale according to the general procedure using Method A. Subsequently, acetic anhydride (1.0 mL) and NaHCO 3 (252.0 mg, 3.00 mmol, 6.0 equiv) were added, and the reaction mixture was allowed to stir for 24 h at room temperature before water (30 mL) and EtOAc (30 mL) were added. The layers were separated and the organic layer was washed with water (2 x 30 mL) and the combined aqueous layers were extracted with EtOAc (1 x 30 mL). The combined organic layers were dried (MgSO 4 ) and reduced in vacuo and the crude product was purified by column chromatography (pentane:DCM = 2:1) to obtain product 6q as a white solid in 61% yield.

N-(tert-Butyl)-2,2,3,3,4,4,4-heptafluoro-N-hydroxybutanamide (7r)
The perfluoroalkylation of 1r was performed on 0.5 mmol scale according to the general procedure using Method A. The reaction mixture was stirred for 24 h. Thereafter, water (30 mL) and EtOAc (30 mL) were added and the layers separated. The organic layer was washed with water (2 x 30 mL) and the combined aqueous layers were extracted with EtOAc (1 x 30 mL). The combined organic layers were dried (MgSO 4 ) and reduced in vacuo. The crude product was purified by column chromatography (pentane:DCM = 1:1) to obtain product 7r as a white solid in 54% yield.

Screening of reaction conditions for the oxydefluorination of 2b
Scheme S-3: Screening of reaction conditions for the oxydefluorination of hydroxylamine 2b.
The perfluoroalkylation of 1b was performed on 0.1 mmol scale according to the general procedure using Method A or Method B described in section 2.2. Subsequently, additional reagents were added to the reaction mixture and stirring was continued according to the conditions in Table S-2. Hexafluoroisopropanol was added as an internal standard and the crude sample was analyzed by 19 F NMR to determine the yields of 7b, 4b and 3b in CDCl 3 .
Hydroxylamine 2b was prepared in situ on 0.5 mmol scale according to the general procedure of Method A described in section 2.2. Subsequently, the reaction mixture was cooled to 0 °C (ice bath) before acetic acid (1.0 mL) and HCl (37%, 0.83 mL, 10.0 mmol, 20.0 equiv) were added. The mixture was stirred at 0 °C for 6 h. Water (20 mL) was added and the mixture was extracted with EtOAc (10 mL) five times. The combined organic layers were washed with a saturated aqueous solution of NaHCO 3 , dried over anhydrous NaSO 4 , and concentrated under reduced pressure. The crude product was purified by column chromatography (pentane:EtOAc: ormic acid = 5:1:0.1) to yield hydroxamic acid 7b.

General procedure for the oxydefluorination and N-O bond reduction with Zn/HCl (Scheme 3)
Scheme S-5: Synthesis of amides 3.

2.8
Coalescence experiment of acylated hydroxamic acid 4c 1 H NMR spectra of 4c in CDCl 3 were recorded at 25, 50, 75, 90, and 25 °C again, and the results are shown in Figure S-1. At 25 °C two sets of signals were observed, while at higher temperatures (75 and 90 °C) one set of signals was observed. Upon cooling down the sample to 25 °C again, the two original sets of signals were observed. These results indicate that the two sets of signals originate from two rotamers of 4c.

Figure S-1:
Coalescence of the aromatic signals of 4c at higher temperatures.
Hydroxylamines 2 were prepared in situ on 0.5 mmol scale according to the general procedure using Method B described in section 2.2. Subsequently, KSAc (342.6 mg, 3.00 mmol, 6.0 equiv) was added. For products 5a, 5j, 5k, and 5o, dichloromethane (4 mL) was added as co-solvent to improve the yields. The resulting reaction mixture was stirred for 16 h at room temperature before water (20 mL) and EtOAc (20 mL) were added. The layers were separated and the organic layer was washed with water (2 x 20 mL) and the combined aqueous layers were extracted with EtOAc (2 x 20 mL). The combined organic layers were dried (MgSO 4 ) and reduced in vacuo and the crude products were purified by column chromatography (pentane:DCM and/or pentane:EtOAc) to yield thioamides 5a-c, 5j, 5k, and 5o. To a solution of 3b (60.6 mg, 0.20 mmol, 1.0 equiv) in anhydrous THF (3 mL) was added LiAlH 4 (34.2 mg, 0.90 mmol, 4.5 equiv) at 0 °C (ice bath) and the mixture was refluxed (oil bath) under stirring for 12 h, After cooling to 0 °C again, an additional portion of LiAlH 4 (11.4 mg, 0.30 mmol, 1.5 equiv) was added and the mixture was refluxed for 18 h. After cooling to room temperature, water (10 mL) was added carefully. The resulting mixture was extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4 , and concentrated under reduced pressure. The crude product was purified by column chromatography (pentane:DCM = 10:1) to yield amine 9. Benzothiazole 10 was synthesized using a literature method [19] : A mixture of thioamide 5c (59.7 mg, 0.16 mmol, 1.0 equiv), CAN (184.2 mg, 0.34 mmol, 2.1 equiv) and NaHCO 3 (56.5 mg, 0.67 mmol, 4.2 equiv) in MeCN (2 mL) was stirred at 80 °C (oil bath) for 2 h. Then water (10 mL) was added and the mixture was extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4 , and concentrated under reduced pressure. The residue was then purified by column chromatography (pentane:DCM = 5:1) to yield benzothiazole 10.

GC-MS (EI) analysis of hydroxylamines 2a and 2b
Hydroxylamines 2a and 2b were prepared in situ on 0.1 mmol scale according to the general procedure using Method B described in section 2.2. Subsequently, the resulting mixture were diluted 10 times with anhydrous EtOAc and filtered. The solutions of the filtrates were used freshly for GC-MS analysis (GC-MS conditions: 60 °C for 2 min; gradient from 60 °C to 260 °C during 10 min; 260 °C for 4 min. Column: HP-5MS (30m×0.25mm×0.25μm). The results are shown in Figure

GC-MS traces of the defluorination of hydroxylamines 2a and 2b by KSAc
Hydroxylamines 2a and 2b were prepared in situ on 0.1 mmol scale according to the general procedure using Method B described in section 2.2. Subsequently, KSAc (68.5 mg, 0.6 mmol, 6.0 equiv) was added. For hydroxylamine 2a, dichloromethane (0.8 mL) was added as co-solvent. The resulting reaction mixtures were stirred for 4 h at room temperature. The suspensions were diluted 10 times with anhydrous EtOAc and filtered. The filtrates were directly used for GC-MS analysis (GC-MS conditions: 60 °C for 2 min; gradient from 60 °C to 260 °C during 10 min; 260 °C for 4 min. Column: HP-5MS (30m×0.25mm×0.25μm)). The results are shown in Figure S