Deoxyfluorination of Carboxylic Acids via an in situ Generated Trifluoromethoxide Salt

Abstract

An in situ generated pyridinium trifluoromethoxide salt (PyOCF₃) is a highly effective deoxyfluorination reagent for the synthesis of acid fluorides. PyOCF₃ is formed at room temperature from the reaction of 2,4-dinitro(trifluoromethoxy)benzene with 4-dimethylaminopyridine. PyOCF₃ undergoes slow release of fluorophosgene and fluoride, serving as the electrophile and nucleophile, respectively, for deoxyfluorination. A wide substrate scope and high functional group tolerance are demonstrated. Furthermore, the acid fluorides can be purified by filtration and telescoped to various known reactions.

Graphical Abstract

Acid fluorides are valuable intermediates in organic synthesis. They are widely used as electrophiles in acyl transfer¹ and electrophilic aromatic substitution,² serve as anhydrous fluoride sources for nucleophilic fluorination reactions,^3–5 and are versatile coupling partners for various transition metal-catalyzed cross-couplings.^6–10 Although numerous methods involving different classes of substrates have been developed,¹¹ traditional synthetic routes to acid fluorides involve halide exchange with the corresponding acid chloride.⁶ An attractive alternative is to access acid fluorides from readily available, stable, and inexpensive carboxylic acids via deoxyfluorination. Sulfur-based deoxyfluorination reagents (e.g., DAST and derivatives thereof) are highly effective for converting carboxylic acids to acid fluorides.^{12 15} However, there remains strong interest in identifying mild and easy-to-handle deoxyfluorinating reagents for acid fluoride synthesis.¹⁶

In 2017, Schoenebeck pioneered the use of CF₃X⁻ salts (X = S or O) for the deoxyfluorination of carboxylic acids (Figure 1A). In this work, tetramethylammonium trifluoromethylthiolate (NMe₄SCF₃) was used to achieve base-and additive-free deoxyfluorination at room temperature.¹⁷ A subsequent report by Zhang and co-workers leveraged the combination of trifluoromethyl trifluoromethanesulfonate (CF₃SO₂OCF₃) and 4-dimethylaminopyridine (DMAP) for an analogous transformation.¹⁸ The proposed mechanism is summarized in Figure 1B. Initial reaction between the carboxylic acid and CF₃X⁻ generates carboxylate salt I along with fluoro(thio)phosgene and HF. I then reacts with the fluoro(thio)phosgene to form fluoroanhydride intermediate II. Finally, acyl transfer between II and fluoride releases the acid fluoride product along with CO₂.

Figure 1.

(A) Reported CF₃S⁻-based deoxyfluorination reagents. (B) Proposed deoxyfluorination mechanism with OCF₃ anion. Cation omitted for clarity. (C) This work.

While these CF₃X⁻-based methods are mild and high yielding, a key disadvantage is the requirement for independent synthesis of the reagent [either NMe₄SCF₃ (a solid) or CF₃SO₂OCF₃ (a gas)]. We sought to address these limitations by leveraging commercially available, inexpensive, and easy-to-handle reagents to achieve deoxyfluorination via an analogous pathway. Previous work from our group showed that a pyridinium trifluoromethoxide salt (PyOCF₃) can be accessed at room temperature from two commercial molecules: 2,4-dinitro(trifluoromethoxy)benzene (DNTFB) and 4-dimethylaminopyridine (DMAP).^19,20 We report herein that performing the in situ formation of PyOCF₃ in the presence of a carboxylic acid results in high yielding deoxyfluorination within minutes at room temperature (Figure 1C). These reactions proceed on the benchtop (without exclusion of air or moisture) and in a wide array of common organic solvents. The optimization, scope, and telescoping of the acid fluoride products on to further transformations are described herein.

Our initial experiments focused on the reaction of DNTFB with DMAP to afford a solution of PyOCF₃ in MeCN (Scheme 1A, step 1) and subsequent use of this reagent for the deoxyfluorination of 4-biphenylcarboxylic acid (1a) (Scheme 1A, step 2). Over 1 h at room temperature (30 min per step), this sequence afforded acid fluoride 2a in 94% yield. An even more convenient protocol would involve the direct combination of DMAP, DNTFB, and the carboxylic acid in a single pot. In the event, dissolving a mixture of 1a, DNTFB, and DMAP in MeCN and stirring at 25 °C for 30 min resulted in the formation of 2a in a comparable yield to the two-step sequence (95%, Scheme 1B).²¹ Furthermore, this in situ transformation proceeded in good to excellent yield in a wide range of common organic solvents (DCM, DMF, acetone, ethyl acetate, and toluene). Flexibility in the solvent is particularly valuable for transformations in which the acid fluoride product is carried forward to subsequent transformations.

Scheme 1.

Deoxyfluorination of 2a with PyOCF₃ either (A) preformed or (B) generated in situ

^aReactions at 0.1 mmol scale (c = 0.2 M). Yields determined by ¹⁹F NMR spectroscopy with trifluorotoluene as internal standard.

We next investigated the fate of the pyridinium cation following decomposition of the trifluoromethoxide anion. A combination of control studies revealed that 4-(dimethylamino)-1-(2,4-dinitrophenyl)pyridinium bifluoride (PyHF₂) is the initial by-product (Scheme 2A, Figure S2). This salt is readily separated from the acid fluoride by precipitation with pentane followed by filtration. In CD₂Cl₂, PyHF₂ slowly decomposes via S_NAr to form a mixture of 1-fluoro-2,4-dinitrobenzene²² and DMAP•HF (Scheme 2A), and this decomposition is accelerated by the addition of base (Figure S3). This observation led us to hypothesize that the reaction could be carried out using catalytic DMAP in conjunction with an exogeneous base (Scheme 2B). Indeed, using 20 mol % of DMAP and 1.5 equiv of NEt₃, the deoxyfluorination of 1a proceeded to afford 2a in 84% yield (Scheme 2C). The ability to conduct this transformation with different stoichiometries and to form different side products facilitates identifying the ideal conditions to isolate/purify products with varied functional groups and properties.

Scheme 2.

(A) Balanced equation for deoxyfluorination with PyOCF₃. (B) Catalytic DMAP hypothesis. (C) Deoxyfluorination with catalytic DMAP

^aReactions at 0.1 mmol scale (0.2 M). Yields determined by ¹⁹F NMR spectroscopy with trifluorotoluene as internal standard.

We next explored the scope of this deoxyfluorination reaction using the in situ conditions from Scheme 1B.²³ As summarized in Scheme 3, the reaction proceeded in ≥90% crude yield with benzoic acid derivatives bearing both electrondonating (i.e., phenyl 2a-b, phenoxy 2c) and electronwithdrawing (i.e., benzoyl 2d, methoxycarbonyl 2e, and pentafluorosulfanyl 2f) substituents. Sterically hindered 2,4,6-trimethylbenzoic acid 2g underwent deoxyfluorination in 84% yield under analogous conditions. Vinyl and alkyl carboxylic acids reacted to afford acid fluorides 2h-l in ≥90% yield. Both electron-rich and electron-deficient heterocycles, including benzothiophene, indole, pyrazole, and quinoline derivatives were also well tolerated. The deoxyfluorination of benzyloxycarbonyl (CBz)-protected valine (2q) proceeded in 95% yield with minimal erosion of enantiopurity (Figure S5). The acid fluoride can be easily separated from the pyridinium salt byproducts via filtration, affording >90% pure products that can be telescoped to other transformations (vide infra).²⁴ Alternatively, analytically pure acid fluorides can be isolated via flash chromatography, albeit in lower isolated yields. As a representative example, 2d was obtained in 96% yield and ~90% purity following filtration and in 69% yield and >99% purity following chromatography. Lastly, examples of substrates that afforded low yields are provided in Scheme 3 and Figure S4. In general, these feature nucleophilic functional groups such as unprotected alcohols and amines, which likely undergo side reactions with fluorophosgene.^20b

Scheme 3.

Substrate scope of deoxyfluorination with PyOCF₃^a

^aYields determined by ¹⁹F NMR spectroscopy with trifluorotoluene as internal standard. Isolated yields in parentheses were obtained following purification via flash chromatography. ^bee determined after telescoped amidation reaction (ee SI for details).

Finally, the acid fluorides generated via PyOCF₃-promoted deoxyfluorination were telecoped to additional organic or transition metal-catalyzed transformations. 4-(Methoxycarbonyl)benzoic acid (1e) was used as a model substrate for these studies. Following deoxyfluorination with in situ generated PyOCF₃, the crude reaction mixtures were filtered and then carried directly forward. As shown in Scheme 4b and c, amidation with adamantyl amine²⁵ and esterification with 4-fluorobenzyl alcohol proceeded smoothly to afford 3e and 4e, respectively. An analogous sequence was effective for achieving palladium-catalyzed cross-coupling with 2-thiophenylboronic (affording diarylketone 5e in 72% yield) as well as Ni-catalyzed decarbonylative coupling with 4-methoxyphenylboronic acid or bis(pinacolato)diboron (affording 6e and 7e in 64% and 55% yield, respectively). Overall, these results show the compatibility of our deoxyfluorination method with various subsequent reactions of the acid fluoride products.

Scheme 4.

Telescoping acid fluorides from PyOCF₃-promoted deoxyfluorination to subsequent transformations.

Conditions: ^aDNTFB, DMAP, DCM, 25 °C, 1 h. ^badamantyl amine, DIPEA, DCM, 25 °C, 2 h. ^c4-fluorobenzyl alcohol, DIPEA, DCM, 25 °C, 2 h. ^dPd(OAc)₂, P(p-OMePh)₃, ArB(OH)₂, KF, toluene, 120 °C, 16 h. ^eNi(cod)₂, PPh₂Me, ArB(OH)₂, THF, 100 °C, 20 h. ^fNi(cod)₂, PCy₃, B₂pin₂, toluene, 115 °C, 20 h. Isolated yields.

In conclusion, this report describes the development of a mild and practical deoxyfluorination of diverse carboxylic acid derivatives. This method leverages commercially available and relatively inexpensive reagents (4-dimethylaminopyridine and 2,4-dinitro(trifluoromethoxy)benzene) for the in situ generation of a trifluoromethoxide-based deoxyfluorination reagent, PyOCF₃. This deoxyfluorination protocol is compatible with a wide array of functional groups, and the products can be telescoped to subsequent C–C and C–heteroatom coupling reactions.

Data Availability Statement

The data underlying this study are available in the published article and its Supporting Information.