Tetrafluoropyridyl (TFP): a general phenol protecting group readily cleaved under mild conditions† †Electronic supplementary information (ESI) available. CCDC 1856218–1856219. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c8ob02899k

Herein we introduce tetrafluoropyridyl (TFP) as a new general protecting group for phenols. The TFP protecting group is readily cleaved under mild conditions.

collected on a Waters TQD mass spectrometer and accurate mass spectra were collected on a Waters LCT Premier XE mass spectrometer. Optical rotations were measured with a Jasco P-1020 polarimeter. Melting points were carried out in triplicate and an average of the values taken and reported as a range using a Stuart SMP10 melting point apparatus. Melting points were carried out directly on material purified by flash column chromatography

General procedure for the synthesis of tetrafluoropyridyl ethers
To a stirred solution of phenol (1 equiv.) in acetonitrile (20 mL) was added pentafluoropyridine (1.05 equiv.) and potassium carbonate (1.05 equiv.). The reaction mixture was stirred at room temperature for 16 h. After this time the reaction mixture was concentrated under reduced pressure and the resulting residue was purified directly by flash column chromatography.

General procedure for the deprotection of tetrafluoropyridyl ethers
To a stirred solution of TFP ether (1 equiv.) in acetonitrile (5 mL) and water (0.1 mL) was added potassium fluoride (2 equiv.), 18-Crown-6 (3 equiv.) and methyl thioglycolate (10 equiv.). The reaction mixture was stirred for 2 h at 50 °C. After this time the reaction mixture was concentrated under reduced pressure and the resulting residue purified directly by flash column chromatography.

Synthesis of 2,3,5,6-tetrafluoro-4-(m-tolyloxy)pyridine 2a
The title compound was synthesised according to the general procedure for the synthesis of tetrafluoropyridyl ethers from 4.63 mmol of the corresponding phenol as a white solid (1.16 g) in 97% yield.

Synthesis of 2,3,5,6-tetrafluoro-4-(o-tolyloxy)pyridine 2b
The title compound was synthesised according to the general procedure for the synthesis of tetrafluoropyridyl ethers from 4.63 mmol of the corresponding phenol as a clear oil (0.980 g) in 83% yield.

Synthesis of 4-((perfluoropyridin-4-yl)oxy)benzonitrile 2g
The title compound was synthesised according to the general procedure for the synthesis of tetrafluoropyridyl ethers from 4.20 mmol of the corresponding phenol as a clear oil (0.991 g) in 88% yield.

Synthesis of 2,3,5,6-tetrafluoro-4-(4-methoxyphenoxy)pyridine 2j
The title compound was synthesised according to the general procedure for the synthesis of tetrafluoropyridyl ethers from 4.03 mmol of the corresponding phenol as a white solid (1.08 g) in 98% yield.

Synthesis of 4-(3-ethynylphenoxy)-2,3,5,6-tetrafluoropyridine 2m
The title compound was synthesised according to the general procedure for the synthesis of tetrafluoropyridyl ethers from 2.11 mmol of the corresponding phenol as a clear oil (0.500 g) in 89% yield.

Deprotection Reactions Monitored by NMR General Procedure for TFP Ether Cleavage monitored by 1 H NMR
To a solution of TFP Ether (0.022 mmol, 1 equiv.) in CD 3 CN (0.7 mL) was added KF (0.044 mmol, 2 equiv.), 18-C-6 (0.066 mmol, 3 equiv.) and methyl thioglycolate (0.22 mmol, 10 equiv.) and finally D 2 O (0.1 mL). The reaction mixture was gently heated until all components were dissolved. The resulting mixture was transferred to a NMR tube and suspended in a water bath at 50 °C for 1 h. After this time the tube was removed from the water bath and a 1 H NMR spectrum of the reaction mixture recorded. In cases where full conversion was not reached after 1 h the NMR tube was returned to the water bath and heated until full conversion was reached. KI (2 equiv.), 18-C-6 (3 equiv.) 24 <1 6 KF (2 equiv.), 18-C-6 (3 equiv.) 24 1 7

90
Conversion was determined by 1 H NMR analysis of the reaction mixture (see SI).
All reactions were carried out in a water bath set to 50 °C. S-100

S-101
General Procedure for stability testing using 1 H NMR To a solution of TFP ether (10 mg) in deuterated solvent (0.7 mL) was added the desired reagent to be tested. The reaction mixture was transferred to an NMR tube and the reaction mixture left at rt for 24 h. After this time the reaction mixture was analysed by 1 H NMR spectroscopy.

X-ray Crystallography
The X-ray single crystal data for 2r and 2i have been collected using λMoKα radiation (λ =0.71073Å) on a Bruker D8Venture diffractometer (Photon100 CMOS detector, IμSmicrosource, focusing mirrors) equipped with a Cryostream (Oxford Cryosystems) open-flow nitrogen cryostats at the temperature 120.0(2) K. Both structures were solved by direct method and refined by full-matrix least squares on F 2 for all data using Olex2 [1] and SHELXTL [2] software. All non-hydrogen atoms were refined anisotropically, hydrogen atoms in structure 2r were refined isotropically, while in the structure 2i they were placed in the calculated positions and refined in riding mode. Crystal data and parameters of refinement are listed in