KHF₂: A Mild and Selective Desilylating Agent for Phenol tert-Butyldimethylsilyl (TBDMS) Ethers

^◊ Undergraduate research participants
^§ Equal contributions from these authors

Abstract

TBDMS (t-BuMe₂Si, tert-butyldimethylsilyl) ethers of a variety of phenols have been deprotected with KHF₂ in MeOH, at room temperature. Carboxylic ester and labile phenolic acetate were unaffected under these conditions. In competition reactions between TBDMS ethers of a phenol and two primary benzylic alcohols, the phenolic ether underwent cleavage whereas the alcohol ethers remained intact. From a substrate containing both a phenolic hydroxyl group and a secondary, doubly benzylic hydroxyl group protected as TBDMS ethers, the phenol was rapidly and selectively released. Cleavage of TBDMS, TBDPS, and TIPS ethers of a phenol was also compared. TBDMS and TBDPS ethers underwent cleavage at room temperature within 30 minutes, whereas removal of the TIPS ether required 2.5 hours. Ease of cleavage appears to be TBDMS ≈ TBDPS > TIPS. At 60 °C, TBDMS ethers of primary benzylic, allylic, and unactivated alcohols can be efficiently desilylated over a prolonged period (13–17 h). Thus, KHF₂ proves to be a mild and effective reagent for the selective desilylation of phenol TBDMS ethers at room temperature.

Key words

deprotection - desilylation - silicon - fluoride - potassium bifluoride

• References and Notes

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• 30 Caution! KHF₂ can produce HF upon contact with water and MeOH. It has been shown to etch glass in repeated use of glassware for the synthesis of organotrifluoroborates.³¹ Representative Procedure for Desilylation of Phenol TBDMS Ethers: 4-Hydroxyphenyl Acetate (13) ²⁹ In an oven-dried 25 mL round-bottom flask, a mixture of silyl ether 12 (0.266 g, 1 mmol) and KHF₂ (0.195 g, 2.5 mmol) in anhydrous MeOH (10.0 mL) was stirred at r.t. The reaction was monitored by TLC using 40% EtOAc in hexanes and was found to be complete within 1 h. The mixture was evaporated under reduced pressure and loaded onto a silica column (100–200 mesh) packed with hexanes (adequate caution was exercised to ensure complete transfer of the crude material). Elution with hexanes, followed by 30% EtOAc in hexanes gave 0.148 g (97% yield) of 4-hydroxyphenyl acetate (13) as a white powder. R_f = 0.37 (40% EtOAc in hexanes). ¹H NMR (500 MHz, CDCl₃): δ = 6.95 (d, J = 8.8 Hz, 2 H, ArH), 6.81 (d, J = 8.8 Hz, 2 H, ArH), 4.69 (br s, 1 H, OH), 2.28 (s, 3 H, CH₃). ¹³C NMR (125 MHz, CDCl₃): δ = 170.4, 153.7, 144.5, 122.6, 116.3, 21.2. ESI-HRMS (TOF): m/z calcd for C₈H₈O₃Na [M + Na]⁺: 175.0366; found: 175.0380.
• 31 Lennox AJ. J. PhD Dissertation: Organotrifluoroborate preparation, coupling and hydrolysis. University of Bristol; UK: 2013
• 32 Comparison based upon catalogue prices of a leading chemicals supplier.