Letter
Quaternary Ammonium Trifluoromethoxide Salts as Stable Sources
of Nucleophilic OCF3
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ABSTRACT: The reaction of nucleophilic tertiary amines with trifluoromethyl and pentafluoroethyl methyl ethers provides
quaternary ammonium trifluoromethoxide (NR4OCF3) and pentafluoroethoxide (NR4OCF2CF3) salts, respectively, in good yields.
The new trifluoromethoxide salts disclosed herein are uniquely stable for extended periods of time in both the solid state and in
solution, which complements contemporary reagents. Here we describe the preparation of a range of NR4OCF3 salts, their long-term
stability, and utility in substitution reactions.
he trifluoromethoxide group has become an emerging
feature in pharmaceuticals, agrochemicals, and materi-
trifluoromethoxide (TAS-OCF3, 10)18,26 can be prepared from
the reaction of tris(dimethylamino)sulfonium difluorotrimethyl-
silicate and fluorophosgene. While this reagent is isolable, it was
found to decompose entirely after brief heating (0.25 h, 45 °C,
MeCN).27 The preparation of tetramethylammonium trifluoro-
methoxide has previously been reported using tetramethyl-
ammonium fluoride and 9.28 Several additional isolable
trifluoromethoxide salts have been prepared, including NHC-
stabilized gold and copper trifluoromethoxides, although these
reagents also suffer from poor thermal stability and generally
decompose at room temperature.29 More recently silver(I)
trifluoromethoxide reagents have been reported that are
stabilized by imine or pyridine ligands (e.g., 11, 12; Figure 1B,
Type II reagents).27,30 These later reagents have demonstrated
utility in reactions with benzyl bromides30 and alkyl 4-
nitrobenzenesulfonates.27 However, the cost, multistep prepara-
tion, and low atom economy27 (OCF3 ≈ 20% of MW) may limit
their general utility. Notably, among these reagents 12
demonstrates the best stability (<10% decomposition after 2
daysinvarioussolvents)andcanbeusedattemperaturesupto80
°C.27 Recently, a method for the preparation of pure solutions of
silver(I) trifluoromethoxide from triphosgene was reported.31
Despite intense efforts, preparation of isolable trifluorometh-
oxide salts remains a significant synthetic challenge.
T
als.1−9 In pharmaceuticals, trifluoromethyl ethers often exhibit
improved drug properties including increased lipophilicity10 and
metabolic stability,11 and can adopt unique conformations when
compared with aliphatic ethers.1 The inclusion of a trifluor-
omethyl ether can also increase the potency of a drug lead.12 For
example, the CGPR receptor antagonist 1, a lead candidate for
the treatment of migraines,12 and the CB2 agonist 213 both
incorporate aliphatic trifluoromethyl ethers as key structural
elements. Likewise, several commercial pesticides also incorpo-
rate trifluoromethyl ethers (e.g., 3 and 4).14
The introduction of a trifluoromethyl ether into a target
molecule can be accomplished via one of several methods that
include fluorination,15 electrophilic trifluoromethylation,16 or
nucleophilic or electrophilic trifluoromethoxylation.17 Nucleo-
philic trifluoromethoxylation is generally accomplished with the
use of trifluoromethoxide salts generated in situ using one of
several processes.18,19 Notably, it was recently reported that a
diverse range of aryl and heteroaryl diazoniums could be
transformed into aryl and heteroaryl trifluoromethyl ethers using
silver(I)trifluoromethoxide.20 Early efforts relied on the reaction
of a fluoride source (e.g., KF, RbF, and CsF) with carbonyl
fluoride (COF2, fluorophosgene 5), a highly toxic gas.19 More
recently, trifluoromethoxide has been prepared in situ from
OCF3-containing reagents such as trifluoromethyl benzoate
(6),21 trifluoromethyl triflate (9),6,22,23 trifluoromethylbenzene-
sulfonates (e.g., trifluoromethyl tosylate, 7),24 and trifluor-
omethyl dinitrophenyl ether (8)25 (Figure 1B, Type I reagents).
Each of these reagents generate trifluoromethoxide upon
treatment with a fluoride source, forming benzoyl fluoride,
sulfonyl fluorides, or aryl fluorides, respectively, as reactive
byproducts. As an alternative, tris(dimethylamino)sulfonium
Recently, tetramethylammonium trifluoromethylthiolate has
been explored as a stable SCF3 source, and it has been used in a
Received: January 8, 2020
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
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