Deoxyfluorination: A Detailed Overview of Recent Developments

Abstract

Fluorine organic compounds have been a predominant force of pharmaceutical chemistry for modern drug design, with an increasing amount of fluorine-containing compounds entering the market. Methodologies for fluorine atom incorporation into organic molecules are still challenging to date and thus represent an important research area. Deoxyfluorination serves as a useful tool for the construction of carbon–fluorine bonds in biologically active molecules by converting a common hydroxyl group into the corresponding fluoride. In this review, we have summarized and categorized deoxyfluorination reaction protocols developed over the last decade (2015–2024) by the structural type of C–O bond deoxyfluorination, including substrates like alcohols, phenols, ketones, aldehydes, and carboxylic acids.

1 Introduction

2 Deoxyfluorination of C(sp³)–O Bonds

2.1 Alcohols

2.2 Alcohol Derivatives

3 Deoxyfluorination of C(sp²)–O Bonds

3.1 Phenols

3.2 Phenol Derivatives

3.3 Aldehydes and Ketones

3.4 Carboxylic Acids

4 Conclusions

Key words

deoxyfluorination - photochemical conditions - alcohols - phenols - carboxylic acids

Biographical Sketches

Gašper Tavčar studied chemistry at the University of Ljubljana, earning a B.Sc. in 2000. He then studied inorganic chemistry with Professor Boris Žemva at the Jožef Stefan Institute in Ljubljana, graduating in 2005. After postdoctoral research with Prof. Herbert Roesky at Georg August University in Goettingen, Germany, he returned to Slovenia in 2010 to begin his independent career at Jožef Stefan Institute. In 2011 he was appointed head of the Department of Inorganic Chemistry and Technology. He habilitated at the Jožef Stefan International Postgraduate School and was appointed an associate professor in 2023. His research interests include synthesis, fluorine chemistry, coordination chemistry, and crystallography.

Jan Jelen was born in Ljubljana, Slovenia. He studied chemistry at the University of Ljubljana, obtaining his M.Sc. in 2022 under the supervision of Gašper Tavčar, working as a project student­ at the Department of Inorganic Chemistry and Technology, Jožef Stefan Institute. He is continuing his postgraduate studies at Jožef Stefan International Postgraduate School, working in the same department. His research interests include organic chemistry, fluorine chemistry, synthetic strategies, catalysis, and photocatalysis.

1

Introduction

The significance of carbon–fluorine bonds lies in their exceptional strength and effects on biological processes. These bonds play a pivotal role in enhancing the stability of molecules and have become indispensable in pharmaceuticals, where stability is the linchpin for drug safety and efficacy. However, the influence of C–F bonds is not limited to stability. Since they possess lipophilic character, they are adept at improving a compound’s bioavailability, affecting its absorption, distribution, metabolism, and excretion – key factors in drug design. Furthermore, they bring an element of diastereoselectivity particularly useful in medicinal chemistry.[1] [2] [3] [4] [5] [6] [7] [8] One of the means of introducing carbon–fluorine bonds is the deoxyfluorination reaction. In these one-step nucleophilic substitution reactions, oxygen atoms, often derived from hydroxyl groups, are displaced by fluoride anions.

In this article, we explore the pivotal role of deoxyfluorination reactions developed over the last decade, covering key literature findings published between January 2015 and March 2024. There are several previously published review articles that cover deoxyfluorination reactions;[4] [9] [10] in particular, the reviews by Hunter[11] in 2017 and Verma[12] in 2021 have discussed this topic in great detail. However, many novel deoxyfluorination protocols have been developed since. While those reviews are mostly categorized by structural types of reagents, our goal is to address deoxyfluorination in a different systematic way, by dividing the sections by the type of C–O bond participating in the deoxyfluorination reaction and strategies used for achieving such a transformation, providing more mechanistic insights. We pay particular attention to novel recently developed photochemical deoxyfluorination reactions, as they often rely on milder reaction conditions. Deoxyfluorination reagents or nucleophilic fluoride sources discussed in the presented review are listed in Figure [1]. Below each compound is listed its molar mass (in g mol^–1) along with information on whether the compound is commercially available from common worldwide chemical suppliers.

Figure 1 Deoxyfluorination reagents discussed in this review article

2

Deoxyfluorination of C(sp³)–O Bonds

2.1

Alcohols

The most abundant and cheapest starting materials containing C(sp³)–O bonds are alcohols, due to their extensive presence in nature. In the last decade, numerous reaction protocols using various structural types of reagents have been developed to convert alcohols into the corresponding alkyl fluorides. In addition to the newly discovered strategies, a brief summary of reagents and methodologies already discussed in several other review articles is given below.

2.1.1

PyFluor, AlkylFluor, and CpFluor

In 2015, Doyle’s group reported a stable low-cost sulfonyl fluoride-based reagent PyFluor (I) that exhibits high chemical and thermal stability with excellent selectivity against elimination side products, allowing for straightforward purification.[13] It is a low-melting solid (mp 23–26 °C) and can be readily prepared on a multigram scale via a two-step synthesis from 2-mercaptopyridine (1) by aqueous sodium hypochlorite oxidation followed by fluoride anion exchange with potassium bifluoride in MeCN to afford PyFluor in 73% overall yield on 10 g scale. It acts as a deoxyfluorination agent for primary and secondary aliphatic or benzylic alcohols 3 with wide functional group tolerance and substrate scope, including amino acid derivative 4d, carbohydrate 4a, and steroid derivative 4c, demonstrating a high yielding late-stage deoxyfluorination potential (Scheme [1]).[13] The reaction requires the use of strong amidine or guanidine bases such as DBU and 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene (MTBD) for high conversion to the deoxyfluorination product and minimization of side product formation. The reaction mechanism involves rapid formation of a sulfonate ester intermediate 6, which is then gradually converted into the alkyl fluoride product by base-assisted fluoride attack. The only side product detected by LC-MS was alkylated DBU cation 8 arising from DBU nucleophilic attack on the sulfonate ester intermediate and accounts for the mass balance. Blind experiments with PyFluor and DBU base showed observation of complex 9, but it forms several orders of magnitude slower than the sulfonate ester intermediate 8 and is incompetent for deoxyfluorination reactions. Additionally, deoxyfluorination with PyFluor is not highly solvent dependent (toluene and cyclic ethers perform best) and proceeds with inversion of stereochemistry (Scheme [1]).[13]

Scheme 1 Deoxyfluorination of primary and secondary alcohols with PyFluor

Ritter’s group later in 2016 reported the development of AlkylFluor (II), a derivative of a PhenoFluor-type reagent, suitable for deoxyfluorination of alcohols (Scheme [2]).[14] It is a bench-stable reagent and can be prepared by treating 2-chloro-1,3-bis(2,6-diisopropylphenyl)imidazolium chloride (11) with potassium fluoride and potassium tetrafluoroborate in MeCN under an inert atmosphere. It is capable of efficient and practical deoxyfluorination of primary and secondary aliphatic or benzylic alcohols, including carbohydrates (13b), amino acids (13d), steroids (13a), and pharmaceutical compounds (13c). The reaction requires the use of potassium fluoride as an additional fluoride source in 1,4-dioxane as a solvent and tolerates many useful functional groups, including ketones, esters, amides, carbamates, protected or unprotected amines, acetals, and heterocyclic compounds. Although deoxyfluorination with AlkylFluor generally proceeds cleanly with minor elimination side products, certain substrates required AlkylFluor to be converted into PhenoFluor in situ, by preheating it with cesium fluoride at 100 °C in toluene beforehand (Scheme [2]).[14]

Scheme 2 Deoxyfluorination of primary and secondary alcohols with AlkylFluor

In 2016, Hu and coworkers reported 3,3-difluoro-1,2-diarylcyclopropenes, CpFluors III, as useful bench-stable deoxyfluorination reagents.[15] CpFluor IIIb performed best at facilitating deoxyfluorination of primary, secondary, and tertiary aliphatic or benzylic alcohols 16, while CpFluor IIIa allowed for monodeoxyfluorination of 1,2- or 1,3-diols 18, due to unique sensitivity to the electronic character of the substrates (Scheme [3]). Deoxyfluorination proceeds through the formation of an alkoxycyclopropenium cation intermediate 22 stabilized by electron-rich aryl groups (Scheme [3]). Therefore, the electronic nature of the aryl substituents was a crucial selection factor to achieve high reaction yields with minimal formation of the byproduct 2,3-diarylacrylate 26 alongside 2,3-diarylcyclopropanone 23. On the other hand, monodeoxyfluorination of diols occurs through formation of nonconjugated cyclopropenone acetals, which in turn makes them less sensitive to electronic effects of substituents. CpFluors react readily with glass and Lewis basic solvents such as THF and MeCN, consequently requiring a PTFE reaction vessel and solvents such as toluene, DCM, DCE, or chlorobenzene. CpFluors can be prepared by a single-step synthesis from 1,2-diarylacetylene and difluorocarbene generated in situ via TMSCF₂Br in toluene at 110 °C under an inert atmosphere (Scheme [3]).[15]

Scheme 3 Deoxyfluorination of primary, secondary, and tertiary alcohols with CpFluor

2.1.2

SO₂F₂ and Other Sulfonyl Fluorides

Recently, a protocol for SO₂F₂-mediated deoxyfluorination of primary and secondary alcohols was developed by Sammis’s group.[16] The optimal reaction conditions required the use of an external fluoride source (KF in combination with 18-crown-6) together with the base DBU for efficient HF abstraction in THF at room temperature under an anhydrous inert atmosphere (Scheme [4]). The reaction protocol employs the reverse addition strategy, in which the alcohol solution is slowly added to the SO₂F₂ solution prepared in situ to prevent the formation of a dialkyl sulfate (31) side product (Scheme [4]). This effectively promoted the deoxyfluorination of many primary (28a–d) and some secondary aliphatic (28e–h) or allylic alcohols (28c), tolerating a handful of functional groups such as esters, olefins, halides, nitro group, and phthalimide. The elimination side reaction was problematic for several substrates and required a reduction in the amount of base added to achieve higher yields. Benzylic alcohols were generally not effective under these reaction conditions, the only exception being 4-trifluoromethylbenzyl alcohol (28a). Finally, the method was applied to a steroid derivative (28d) in good yield and dr with inversion of the stereocenter (Scheme [4]).[16]

Scheme 4 Deoxyfluorination of primary and secondary alcohols with SO₂F₂

Doyle’s group explored the reaction space of deoxyfluorination with sulfonyl fluorides V (Scheme [5]).[17] They screened five structurally different sulfonyl fluorides Va–e with different electronic properties. They demonstrated that the flexibility of the sulfonyl fluoride scaffolds allows for deoxyfluorination of a wide range of alcohol substrates, including cyclic alcohols (34c), unactivated (primary, secondary and tertiary) alcohols (34a), activated (benzylic and allylic) alcohols (34b), homobenzylic alcohols, hemiacetals (34d), and α/β-hydroxy carbonyl compounds. Furthermore, they employed a random forest model to accurately predict reaction outcomes and help assessing optimal reaction conditions for new alcohols (Scheme [5]).[17]

Scheme 5 Deoxyfluorination of alcohols with different sulfonyl fluorides

2.1.3

Deoxytrifluoromethylation by Bromodifluoroacetate

Scheme 6 Deoxytrifluoromethylation of allylic, propargylic, and (hetero)benzylic alcohols with phenyl difluorobromoacetate and Cu(I) catalyst

In 2019, Altman’s group reported a rare example of catalytic one-step deoxytrifluoromethylation of alcohols.[18] Using phenyl bromodifluoroacetate (VI) and a Cu(I)-based catalyst, they were able to efficiently convert benzylic, allylic, and propargylic alcohols to their corresponding trifluoromethyl counterparts in moderate to good yields (Scheme [6]). The reaction mechanism involves the transesterification of phenyl bromodifluoroacetate (VI) with an alcohol that replaces the phenolate leaving group, leading to the formation of an active intermediate 41, which participates in the final decarboxylative copper catalytic trifluoromethylation cycle (Scheme [6]). The reaction can be carried out as either a one-pot or a two-pot synthesis involving the formation and purification of intermediate bromodifluoroacetic esters 41. For most allylic and propargylic alcohols (40a,b,c,e,f), a one-pot deoxytrifluoromethylation gave higher yields, since many allylic and propargylic bromodifluoroacetates were unstable to basic conditions, silica gel, and even cold storage. A handful of (hetero)benzylic alcohols proved to be more challenging substrates, requiring higher temperatures and copper catalyst loading to achieve useful yields. The reaction is compatible with many heterocycles and tolerates many useful functional groups including halides, olefins, esters, amides, tosylated amines, and the nitro group. In addition, it afforded synthetic intermediate of L-784,512 (COX-2 inhibitor) and a fluorinated analogue of Tebufenpyrad in one step with comparable yields. The reagent aryl bromodifluoroacetate is synthesized by mixing the corresponding phenol 37 with bromodifluoroacetyl chloride, prepared in situ from oxalyl chloride and bromodifluoroacetic acid (38), in DCM under an inert atmosphere (Scheme [6]).[18]

2.1.4

SulfoxFluor

Scheme 7 Deoxyfluorination of alcohols with SulfoxFluor

Hu and coworkers reported an alternative sulfonyl fluoride deoxyfluorination reagent called SulfoxFluor (VII) in 2019.[19] Like its structural relative PyFluor, it is capable of converting primary, secondary, and even tertiary alcohols into their corresponding alkyl fluorides in fair to excellent yields, with broad functional group tolerance, including ketones, aldehydes, esters, amides, sulfonamides, carbamates, olefins, and heterocycles, including natural compounds such as carbohydrates (49f), steroids (49h), and amino acids (49i) (Scheme [7]). It also exhibits a high selectivity against elimination reactions. For example, deoxyfluorination of primary alcohols rarely produces elimination side products, even in the case of homobenzylic alcohols (49g) that tend to undergo elimination. The deoxyfluorination reaction requires DBU as a base to effectively abstract HF, similarly to PyFluor, but, in comparison, usually proceeds much faster in the order of minutes. Some difficult substrates (49a,g) required the addition of TBAF(tBuOH)₄ (1.0 equiv.) to achieve higher yields (Scheme [7]). Deoxyfluorination with SulfoxFluor occurs with inversion of stereochemistry on chiral alcohols with high enantiospecificity. Monitoring of the reaction mechanism by ¹⁹F NMR spectroscopy at various reaction conditions showed the formation of a sulfonimidate intermediate (40a), resulting from nucleophilic attack of alcohol 48 on Sulfoxfluor (VII), which slowly converted into the corresponding alkyl fluoride 49 in the presence of DBU·HF (Scheme [7]).[19] [20]

2.1.5

Radical Deoxyfluorination with Selectfluor

An alternative radical deoxyfluorination reaction of tertiary alcohols was discovered by Xiao and colleagues, reported in 2020, using Selectfluor (VIII) as a fluorine source for efficient formation of tertiary C–F bonds under mild conditions (Scheme [8]).[21] It relies on the activation of the hydroxyl group by the Ph₂PCH₂CH₂PPh₂/ICH₂CH₂I reagent system, which generates iodophosphonium salt 58 in situ, detected by ³¹P NMR spectroscopy, and is capable of converting alcohols 52 into the corresponding alkyl iodides 54 (Scheme [8]). Under the reaction conditions, iodide anions (from 58) promote a redox reaction with Selectfluor, generating intermediate radical species 61 and alkyl radicals 63 by XAT (halogen atom transfer), which in turn capture the electrophilic fluorine atom of Selectfluor, closing a radical cycle. Nucleophilic fluoride substitution of tertiary alkyl iodides could be ruled out, since no fluorination occurs when CsF is used as the fluorine source. The reaction is usually completed in less than 15 minutes and is carried out in MeCN as a solvent at room temperature. Various functional groups were tolerated, such as carbonyl, esters, sulfonate, sulfonamide, aryl, and primary alkyl halides, including more complex molecules such as steroids. Bulkier substituents on tertiary alcohols (53e,f) resulted in lower yields, indicating steric effects greatly affect reaction efficiency. The deoxyfluorination protocol was also applicable on gram scale without a noticeable decrease in yield (53a) (Scheme [8]).[21]

Scheme 8 Radical deoxyfluorination of tertiary alcohols using Selectfluor

2.1.6

CuF₂/DIC System

In 2020, Watson and coworkers succeeded in deoxyfluorinating primary and secondary alkyl, benzyl, or allyl alcohols with CuF₂ and a Lewis base activating group, overcoming previous difficulties in using transition metal fluorides (MF_n) as fluorinating agents.[22] The procedure utilizes the DIC-derived O-alkylisourea chelate 67 as an auxiliary that drives fluoride transfer from a hydrated Cu^IIF species that displaces the urea leaving group 68 (Scheme [9]). The reaction requires Cu^I-catalyzed formation of O-alkylisourea 67 prior to the addition of CuF₂. Furthermore, the addition of H₂O to anhydrous CuF₂ was essential, since removal of H₂O or use of a hydrate salt resulted in lower yields. Powder XRD and solid-state NMR suggested a superposition of two phases different from the hydrate form of CuF₂. The reaction was effective for both primary and secondary alcohols 64 in moderate to good yields, tolerating a variety of common functional groups such as aryl or alkyl halides, amines, esters, heterocycles, and even tertiary hydroxyl groups (Scheme [9]). This method also showed high stereospecificity for various substrates such as steroid compounds (65h), carbohydrates (65e), and other bioactive molecules (65f,g) (Scheme [9]). The method was also used to enable effective ¹⁸F installation when using Cu(OTf)₂ and the [¹⁸F]F^–/K222/ K₂CO₃ system.[22]

Scheme 9 Deoxyfluorination of primary and secondary alcohols with CuF₂/DIC

Scheme 10 Deoxyfluorination of alcohols with PFECAs

2.1.7

Perfluoroalkyl Ether Carboxylic Acids (PFECAs)

Chen and colleagues successfully used perfluoroalkyl substances (PFAS) to deoxyfluorinate primary, secondary, and tertiary alcohols containing alkyl or (hetero)aryl substituents (Scheme [10]).[23] They used thermal decomposition of perfluoroalkyl ether carboxylic acids (PFECAs), namely CF₃(OCF₂)₂COOK, to generate carbonyl fluoride (COF₂) in situ, capable of mediating deoxyfluorination reactions. Addition of the external fluoride salt TMAF and heating to 150 °C in DMPU as solvent under inert atmosphere were required to achieve optimal yields. Many functional groups were tolerated, including carbonyls, esters, nitriles, halides, sulfones, olefins, the methoxy group, and several heterocyclic systems, and provided alkyl fluoride products in moderate to excellent yields (79–94%). The substrate scope included bioactive compounds such as steroid (70h) and rosuvastatin impurity derivative (70g). Investigation of the reaction mechanisms with GC-MS confirmed formation of COF₂. They proposed an intermediate (71) formation between alcohol (69) and carbonyl fluoride (COF₂), which is susceptible to nucleophilic attack by fluoride ion, realizing the alkyl fluoride product and gaseous CO₂. Tracking of stereoselectivity showed an inversion of the configuration, suggesting an S_N2 reaction pathway of fluoride attack on intermediate 71 (Scheme [10]).[23]

2.1.8

Sulfur Hexafluoride (SF₆)

Sulfur hexafluoride (SF₆) was found to be an important fluorinating agent for photocatalytic C–F bond construction of alcohols, as suggested by recent findings in literature. Jamison’s group used SF₆ for the deoxyfluorination of allylic alcohols 72 (Scheme [11]).[24] They utilized an Ir(III)-based photocatalyst together with a sacrificial electron-donor amine DIPEA to effectively reduce SF₆ under visible light. The resulting species act as a deoxyfluorinating agent that activates the alcohols by forming RO-SF_x intermediates, in a manner similar to the chlorination of allyl alcohols by thionyl chloride. Moreover, this deoxyfluorination reaction proceeds with complete overall retention of stereochemistry. The presence of an adjacent π-bond enables unique reactivity under these conditions. The deoxyfluorination reaction tolerates a handful of functional groups, including amides, protected amines (73d), carbonyls, or the pyridine ring (73b), and gives moderate to good yields (Scheme [11]).[24]

Scheme 11 Photocatalyzed deoxyfluorination of allyl alcohols with SF₆ and an Ir(III) photocatalyst

Kemnitz and coworkers showed in 2018 that SF₆ could be successfully activated by N-heterocyclic carbenes (NHCs) to provide a deoxyfluorination reagent for alcohols by irradiation with UV light at 311 nm (Scheme [12]).[25] Mechanistically, excited state NHC 76* enables a single-electron transfer (SET) event reducing SF₆. The formed reactive sulfur pentafluoride radical species 78 oxidizes NHC radical cation 77 and 79 to the 2-fluoroimidazolidinium cation 80, producing PhenoFluor-type compound 2,2-difluoroimidazolidine 81, detected by ¹H, ¹³C, and ¹⁹F NMR spectroscopy and LIFDI-MS. During the deoxyfluorination reaction, the formed active deoxyfluorination reagent 2,2-difluoroimidazolidine 81 is able, in combination with CsF, to effectively convert aliphatic, benzylic, and allylic alcohols into their corresponding fluoride counterparts. Testing of three different NHCs (SIMes, IMes, and IPr) revealed that SIMes (76) performed the best and gave the highest yield of 2,2-difluoroimidazolidine intermediate 81 (Scheme [12]).[25]

Scheme 12 Photocatalyzed deoxyfluorination of alcohols with SF₆ and an NHC

Another successful activation of SF₆ was reported by Nagorny’s group in 2021, using benzophenone derivatives as photocatalysts, which facilitate deoxyfluorination of glycosylic hydroxyl groups to afford glycosyl fluorides (Scheme [13]).[26] This photocatalytic reaction is similar to that of Jamison’s group discussed earlier, relying on a sacrificial amine electron donor DIPEA using the same reaction conditions, only with a UV-A light source (365 nm) and 4,4′-dimethoxybenzophenone (DMBP) as the optimal photocatalyst. Preliminary mechanistic studies suggested that the deoxyfluorination reaction proceeds through the formation of SF₄ active reagents. They proposed that photoexcitation of DPMB (86) leads to the formation of a triplet state capable of oxidizing DIPEA to generate a ketyl radical 87, which in turn reduces SF₆ to an SF₆ ^•– radical anion 84, leading to the formation of SF₄ upon reaction with DIPEA radical cation 88. The substrate scope includes glycosyl fluorides such as glucose (83a), galactose (83b), mannose (83c), and ribose (83d) derivatives with various protecting groups (Scheme [13]).[26]

Scheme 13 Photocatalyzed deoxyfluorination of glycosides with SF₆

2.1.9

MsOH/KHF₂ Deoxyfluorination of Tertiary Alcohols

A novelty added by Paquin and coworkers in 2023 is deoxyfluorination of tertiary alcohols mediated by mesylic acid (MsOH) and potassium bifluoride (KHF₂) as a nucleophilic fluoride source (Scheme [14]).[27] The reaction is performed in DCM as a solvent at 0 °C, usually under an hour and averages 85% isolated yield on a broad scope of 23 substrate examples, including a steroid derivative 91g. Many common functional groups are tolerated, such as protected primary alcohols (91a,b,d), esters (91e,f), amides (91c), olefins, (hetero)aromatics, and more. Mechanistic investigations showed that the deoxyfluorination reaction proceeds, in part, through an elimination/hydrofluorination pathway generating a carbocation intermediate 93, with no alkene elimination side product 94 observed after the reaction, probably due to the extreme acidic environment. Furthermore, they demonstrated examples of alkyl ether and alkyl acetate ester deoxyfluorination under the same reaction conditions (Scheme [14]).[27]

Scheme 14 Deoxyfluorination of tertiary alcohols with MsOH/KHF₂

2.1.10

2-Chloro-1,3-bis(aryl)imidazolium Dihydrogen Trifluoride

Tavčar and Iskra’s group recently reported a protocol for deoxyfluorination of benzylic and some aliphatic alcohols to the corresponding alkyl fluorides using a benchtop-stable, moisture-insensitive deoxyfluorination reagent, 2-chloro-1,3-bis(2,6-diisopropylphenyl)imidazolium dihydrogen trifluoride (Scheme [15]).[28] It can be easily prepared in a two-step synthesis starting from readily accessible imidazolium chloride 95 by chlorination with hypochlorite in aqueous solution, followed by an anion exchange with an aqueous hydrofluoric acid. Deoxyfluorination requires TTMG as an appropriate base for deprotonation of the alcohol and activation of the poly[hydrogen fluoride] anionic species in order to generate nucleophilic fluoride (Scheme [15]). The reaction is performed in an autoclave reactor at 100 °C in MeCN as a solvent and usually proceeds within 3 hours. Benzylic alcohols provided moderate to excellent yields with good functional group tolerance, including ethers (98a), nitro group (98b), halides (98c,d), trifluoromethyl thioethers (98f), and (hetero)aromatics. The usefulness of the described method was demonstrated on two examples of bioactive aliphatic substrates, namely metronidazole (98g) and glucose (98h) derivatives (Scheme [15]).[28]

Scheme 15 Deoxyfluorination of benzylic alcohols with 1,3-bis(aryl)-2-chloroimidazolium dihydrogen trifluoride

2.2

Alcohol Derivatives

2.2.1

Photoredox Deoxyfluorination of Oxalate Derivatives

In recent years, an increasing number of deoxyfluorination protocols have been developed utilizing photocatalysis as milder and more environmentally friendly conditions. They are mostly applicable to secondary, tertiary, and allylic alcohol derived compounds that form stable radical species, which participate in the photocatalytic cycles. One such example was published by Brioche in 2018.[29] They developed a photoredox deoxyfluorination of tertiary alcohol derived oxalate esters 101 (Scheme [16]). This process is based on the preformation of a cesium oxalate salt, followed by a photocatalytic cycle using an Ir(III)-based photocatalyst and Selectfluor in an acetone/H₂O solvent system. Although the substrate scope is predominantly limited to tertiary alcohols, the deoxyfluorination reaction still shows very broad tolerance to different functional group such as esters, nitriles, tosylates, alcohols, carbonyls, halides, and compounds of biological interest such as steroid 102e (Scheme [16]).[29] Interestingly, in 2019, Gómez-Suárez and co-workers independently discovered the same reaction protocol without using a photocatalyst (Scheme [17]).[30] Under the same reaction conditions, they were able to convert aliphatic, (hetero)benzylic, and propargylic tertiary alcohol oxalate esters 104 to the corresponding alkyl fluorides 105 under catalyst-free conditions, exhibiting very similar tolerance to functional groups. Mechanistic studies shed some light on the photocatalytic radical cycle, which showed two possible distinct reaction pathways. In both cases, TEDA^2+• radicals 108 are generated either by direct irradiation of Selectfluor (pathway B) or by formation of EDA complex 106 between Selectfluor and the corresponding oxalate derivative 104, followed by a subsequent excitation of the formed species. Quantum yield measurements (Φ = 2185.4) showed that a very efficient radical chain mechanism is in operation, suggesting TEDA^2+• radicals 106 as chain carriers that convert several oxalate molecules 104 to the corresponding alkyl radicals 107, which capture a fluorine atom from Selectfluor, closing the radical cycle (Scheme [17]).[30] Later, in 2021, Brioche’s group reported a similar deoxyfluorination protocol by using silver(I) nitrate as an effective catalyst generating the alkyl radical. Combination with Selectfluor as a fluorine source produces corresponding alkyl fluorides, showing similar preference for tertiary alcohol oxalate derivatives.[31]

Scheme 16 Photochemical deoxyfluorination of methyl oxalate esters

Scheme 17 Photochemical deoxyfluorination of oxalate esters

Another example of radical photoredox deoxyfluorination of oxalate derivatives was independently reported in 2019 by MacMillan’s group (Scheme [18]).[32] They developed a photoredox-catalyzed deoxyfluorination of secondary and tertiary alcohols via alcohol oxalate salt derivatives. Their catalytic system also relies on an Ir(III)-based photocatalyst and Selectfluor as an electrophilic fluorine source. Prior to the photocatalyzed fluorination reaction cycle, alcohols 110 are converted into their oxalate analogues 112 by reaction with oxalyl chloride and sequential hydrolysis without purification (Scheme [18]). The mechanism involves a SET reaction between photoexcited Ir(III) catalyst and oxalate derivative 112 generating alkyl radicals 113, which capture a fluorine atom of Selectfluor in a similar fashion to previous findings of Brioche and Gómez-Suárez. The formed TEDA^2+• radicals 114 are responsible for reduction of the Ir(IV) species, regenerating the Ir(III) photocatalyst. A wide range of differentially substituted secondary and tertiary alcohols/oxalate derivatives were readily converted into their corresponding alkyl fluorides in good to excellent yields including motifs such as benzylic, homobenzylic, propargylic, and β-benzyl-substituted alcohols. The reaction is compatible with many functional groups, such as amines, amides, phthalimides, olefins, halides, carbonyl, and cyanide groups. The substrate scope includes a steroidal compound and several natural compounds such as isomenthol (111d), nortropine (111c), cedrol, and sclareolide. Deoxyfluorination of primary alcohols resulted in lower yields (111i) due to the instability of the primary alkyl radicals. It should also be emphasized that the acetone/H₂O solvent system proved to be the most efficient. Organic co-solvents other than acetone resulted in poorer yields (Scheme [18]).[32] [33]

Scheme 18 Photochemical deoxyfluorination of oxalic acids

2.2.2

Electrochemical Deoxyfluorination of Oxalates

In 2023, Lam and coworkers reported a practical electrochemical deoxyfluorination method for accessing tertiary, secondary alkyl, and primary benzylic fluorides under mild reaction conditions from activated alcohol oxalate esters 116 (Scheme [19]).[34] This provides a useful green alternative to previous photochemical methods. Their protocol uses collidinium tetrafluoroborate as a fluoride source and a supporting electrolyte, together with a carbon graphite as both cathode and anode electrode material. The reaction proceeds in DCM as solvent at room temperature and tolerates many useful functional groups such as esters, olefins, protected amines, boronic esters, aromatics, and even silyl ethers. The substrate scope includes several examples of tertiary and secondary oxalate derivatives in moderate yields. The reaction mechanism likely involves an anodic oxidation of oxalate derivatives 116 to afford hemioxalate radical 118, which undergoes two subsequent decarboxylation reactions (via 119), generating alkyl radical 120. The formed alkyl radicals rapidly undergo another anodic oxidation, generating alkyl cations 121, which capture fluoride from tetrafluoroborate anion, affording alkyl fluorides 117 (Scheme [19]).[34]

Scheme 19 Electrochemical deoxyfluorination of oxalate esters

3

Deoxyfluorination of C(sp²)–O Bonds

3.1

Phenols

Phenols are a great source of naturally occurring species containing a hydroxyl group at the C(sp²) atom, making them prominent precursors for the synthesis of aryl fluorides. In comparison to deoxyfluorination reactions of alcohols, phenols usually require harsher reaction conditions. Reagents that facilitate deoxyfluorination of phenols often rely on the concerted mechanism of the aromatic nucleophilic substitution reaction (CS_NAr), rather than the typical nucleophilic aromatic substitution proceeding stepwise through the Meisenheimer complex. This allows for lower reaction temperatures than those for typical aromatic nucleophilic aromatic substitution, with less solvent dependence and wider substrate scope, since substituents have a marginal effect due to minor charge buildup during the transition state.[35] [36] [37] [38] [39]

3.1.1

PhenoFluor/PhenoFluorMix

In 2015, Ritter’s group reported the PhenoFluorMix reagent mixture, a bench-stable moisture-insensitive version of PhenoFluor, for deoxyfluorination of electron-poor and electron-rich phenols to corresponding aryl fluorides (Scheme [20]).[40] [41] PhenoFluorMix is based on 2-chloro-1,3-bis(aryl)imidazolium salt 122, which can be synthesized on a decagram scale from easily accessible imidazolium chloride through formation of NHC under inert atmosphere, followed by chlorination with C₂Cl₆ as a chlorinating agent (Scheme [20]). The reaction conditions tolerate many synthetically useful functional groups (aldehydes, ketones, esters, olefins, sulfides, halides, etc.), with broad substrate scope, including heterocycles containing oxazole, pyridine, pyrimidine, quinoline, or imidazole rings. Additionally, natural compounds such as estrone and a quinine derivative were successfully deoxyfluorinated in high isolated yields. Furthermore, the use of a ruthenium complex allowed for ¹⁸F-deoxyfluorination with high radiochemical (RCY) and activity (AY) yields on electron-deficient and electron-rich phenols with several representable biological compounds. ¹⁸F-Deoxyfluorination of phenols bearing electron-withdrawing groups or electron-poor ring systems was also feasible without the use of a ruthenium catalyst, with similar yields. Mechanistic investigations conducted by Ritter’s group employing Eyring plot, Hammet plot, and kinetic isotope effect showed that the deoxyfluorination reaction proceeds through a concerted transition state (CS_NAr), rather than a classic two-step mechanism, with much lower activation energies due to minimal charge buildup during a transition state. This allows for nucleophilic displacement even on electron-rich arenes. Formation of tetrahedral intermediate 126 was evident from a ¹⁹F–¹³C HSQC experiment of the reaction mixture. Additionally, all was supported by DFT calculations (B3LYP/6-31G(d), toluene solvent model) of intermediates, transition state, and intrinsic reaction coordinate (IRC), providing ΔG^‡ values of 20–25 kcal mol^–1, in close agreement with experimental values (Scheme [20]).[35] [40] [41]

Scheme 20 Deoxyfluorination of phenols with PhenoFluorMix

3.1.2

SO₂F₂/TMAF System

Sanford and coworkers published in 2017 a promising alternative method for deoxyfluorination of phenols by using combination of sulfuryl fluoride (SO₂F₂) and tetramethylammonium fluoride (TMAF) as an additional nucleophilic fluoride source (Scheme [21]).[36] The reaction proceeds via formation of aryl fluorosulfonate intermediates at room temperature for electron-poor phenols and requires heating to 80–100 °C for electron-neutral or electron-rich phenols. The reaction conditions display broad functional group tolerance, including carbonyls, esters, amides, nitriles, tertiary amines, and various heterocyclic compounds. Kinetic and computational studies revealed a similar mechanistic feature as for deoxyfluorination with PhenoFluor reagents – a concerted reaction pathway of a rate-determining step. Fluorosulfonate intermediate 130 formed by nucleophilic attack of phenol onto the SO₂F₂ molecule sequesters fluoride anion, forming anionic intermediate 131 and allowing for rearrangement via a concerted transition state. Low activation enthalpy (ΔH^‡) of 13.2 kcal/mol is consistent with the fast reaction rate measured experimentally (Scheme [21]). Further mechanistic investigations revealed that reversible formation of a diaryl sulfate side product accompanies the deoxyfluorination reaction. While diaryl sulfates are capable of converting into the aryl fluoride deoxyfluorination product by the action of SO₂F₂, their conversions are significantly lower and greatly impede the productive deoxyfluorination, especially with phenols bearing electron-donating substituents. In order to prevent formation of diaryl sulfates, aryl triflate and aryl nonaflate derivatives were explored, since these compounds are incapable of forming diaryl sulfates. They proved to be more efficient for electron-rich phenols.[36] [37] [38]

Scheme 21 Deoxyfluorination of phenols with SO₂F₂/TMAF

3.1.3

2-Chloro-1,3-bis(aryl)imidazolium Poly[hydrogen fluorides]

Scheme 22 Deoxyfluorination of electron-deficient phenols

Recently, in 2023, Tavčar’s group reported a derivative of PhenoFluorMix reagent based on dihydrogen trifluoride salt of 2-chloro-1,3-bis(aryl)imidazolium cation moiety (Scheme [22]).[43] It can be easily prepared in a two-step synthesis from accessible 1,3-bis(2,6-diisopropylphenyl)imidazolium chloride (133) by using bleach solution as a chlorinating agent and hydrofluoric acid as a fluoride source without the need of organic solvents or inert conditions, providing a far cheaper alternative with easier operation (Scheme [22]). This deoxyfluorination reagent is capable of converting electron-deficient phenols 135 into the corresponding aryl fluorides 136 by using similar reaction conditions and functional group tolerance. The use of external fluoride (CsF) is unnecessary, since the reagent already contains a nucleophilic fluoride source. As previous research indicated, the poly[hydrogen fluoride] anion can be efficiently activated by addition of base;[13] [42] in this case, the amidine base DBU proved to be the most effective. The substrate scope includes natural compounds 136b,c, dyes 136d,h, and compounds 136e–g of pharmaceutical relevance. Mechanistic studies revealed that DBU acts as hydrogen fluoride abstraction agent, generating nucleophilic fluoride anions 137 and 138 (Scheme [22]).[43] Formation of the aryl fluoride product then proceeds similarly to deoxyfluorination with PhenoFluor reagents.

3.2

Phenol Derivatives

3.2.1

Photochemical Deoxyfluorination of Aryl Ethers

In 2020, Nicewicz’s group demonstrated a polarity-reversed photoredox-catalyzed deoxyfluorination, which operates via cation-radical-accelerated SNAr and enables deoxyfluorination of electron-rich aryl ethers with ¹⁹F^– and ¹⁸F^– under mild reaction conditions.[44] This methodology thus complements the traditional arene polarity requirements (electron-withdrawing groups) necessary for S_NAr-based fluorination. After extensive optimization, it was found that using an acridinium-based photooxidant, CsF, and TBAHSO₄ with a biphasic DCM/water solvent system provided optimized yields for most substrates (Scheme [23]). The reaction tolerates many useful functional groups such as esters, ethers, protected amines, amides, sulfonates, olefins, halides, and several (hetero)aromatic compounds. The substrate scope includes natural (143b) and pharmaceutical compounds, such as nateglinide (143h) (Scheme [23]). This reaction can be performed under air or N₂ without significant difference. At the outset, it was determined that light-emitting diodes (LEDs) with λ = 427 nm were interchangeable with 455 nm LEDs. The reaction mechanism involves a SET reaction between excited acridinium photocatalyst 144 and aryl ether 142. This generates aryl cation radical 146 on a more oxidizable aromatic ring with lower reduction potential (Scheme [23]). By careful design of sacrificial aromatic ring (4-chlorophenyl, E _p/2 = 1.78 V) this process was made selective for most substrates. The utility of the presented method was furthermore complemented by application as a radiofluorination strategy, which is highlighted with short reaction times, compatibility with multiple nucleofuges and high radiofluorination yields.[44]

Scheme 23 Photochemical deoxyfluorination of electron-rich aryl ethers

3.3

Aldehydes and Ketones

A carbonyl group in aldehydes or ketones could also be subjected to deoxyfluorination reactions resulting in gem-difluoro compounds by displacement of the carbon–oxygen double bond. In general, this type of deoxyfluorination reactions usually requires the use of unstable aminodifluorosulfinium salts as deoxyfluorination reagents, e.g. DAST or DeoxoFluor. More stable analogues, such as XtalFluor-E or XtalFluor-M were also explored in developing deoxyfluorination protocols. Typical reaction conditions involve stirring the ketone or aldehyde substrate at room temperature in DCM with the addition of Et₃N·3HF and Et₃N under an inert atmosphere; common functional groups such as protected amines and esters are tolerated (Scheme [24]). Although not supported by conclusive experimental proof, the first step towards geminal difluorination is generally considered to be the addition of HF across the carbonyl group to provide a fluorohydrin 151, which then partakes in deoxyfluorination with the reagent (Scheme [24]). In the case of DAST and DeoxoFluor, the initial source of free HF arises by hydrolysis of the reagents with trace amounts of water or by the deliberate addition of ethanol. On the other hand, exogenous HF is required to initiate deoxyfluorination of carbonyls using dialkylaminodifluorosulfinium salts (Scheme [24]).[45] [46] [47] Recently, in 2023, Paquin and coworkers reported a protocol for deoxyfluorination of aromatic aldehydes 154 using XtalFluor-E as deoxyfluorination agent at room temperature and without added solvent. A wide range of gem-difluoride compounds was obtained in 21–87% isolated yield with broad functional group tolerance, including nitro group, halides, esters and several (hetero)aromatic compounds (Scheme [24]).[48]

Scheme 24 Deoxyfluorination of aldehydes and ketones with XtalFluor

3.4

Carboxylic Acids

The carboxylic group (COOH) is another example of a functional motif possessing a hydroxyl group on a C(sp²) atom and is abundantly present in naturally occurring compounds. Deoxyfluorination of derivatives of carboxylic acids most commonly result in acyl fluorides, although fluorine products such as trifluoromethyl ketones[49] or trifluoromethyl thioesters[50] can also be obtained. This provides a great platform for diversification of the carboxylic group to other synthetically and biologically relevant functional groups. For example, acyl fluorides, when reacted with various nucleophiles, provide straightforward access to high-value products such as esters, amides (peptides), or thioesters and exhibit reactivity towards a broad spectrum of nucleophiles with diverse electronic and steric properties. Compared to the traditionally used acyl chlorides, corresponding acyl fluorides demonstrate a superior stability to reactivity ratio, allowing for greater reaction yields. The former are notorious for their instability towards moisture and air, while the latter are sufficiently stable to be isolated and withstand column chromatography on silica gel and even wet solvents. Their reactivity is comparable to activated esters, while not suffering from steric constraints.[51] [52] Consequently, acyl fluorides provide good acyl synthons in acyl cross-coupling reactions.[53,54]

3.4.1

Deoxyfluorination of Carboxylic Acids to Acyl Fluorides

Acyl fluorides can be prepared from carboxylic acids in the same mechanistic manner as their corresponding chloride counterparts by using different deoxyfluorination reagents. Since the hydroxyl group (OH) is attached to the significantly electron-deficient carbon atom of the carbonyl group, deoxyfluorination (nucleophilic substitution with fluoride) proceeds rapidly, usually at room temperature in a manner of minutes to a few hours for complete conversion. In the last decade an increasing amount of useful reaction protocols have been developed, generally relying on very mild ambient reaction conditions.

In 2017, Schoenebeck and coworkers reported a bench-stable solid reagent (Me₄N)SCF₃ capable of converting aliphatic or (hetero)aromatic carboxylic acids 156 into corresponding acyl fluorides 157 in up to excellent yields and with broad functional group tolerance, e.g. of ethers, esters, amides, protected amines, the nitro group, halides, olefins, and (hetero)aromatics (Scheme [25]).[51] The substrate scope includes biologically active compounds such as the pharmaceuticals indomethacin (157f) and ofloxacin (157i). The reaction proceeds cleanly at room temperature with DCM or MeCN as a solvent. Products can be easily isolated by low-polarity solvent addition and separation of insoluble byproducts by simple filtration. Mechanistic studies based on in situ FTIR and NMR spectroscopy showed that deoxyfluorination likely proceeds through in situ generated carbonyl fluoride COF₂, which rapidly reacts with carboxylic acids 156, forming two distinct active intermediates 160 and 161, which are transformed into acyl fluoride 157 under release of gaseous carbonyl sulfide (COS) (Scheme [25]). The authors additionally managed to prepare a vitamin B7 amide derivative 158-1 by a subsequent one-pot deoxyfluorination/amidation strategy utilizing acyl fluoride as a synthetic intermediate, furthermore showing the usefulness of acyl fluorides. The most problematic challenge is the synthesis of the (Me₄N)SCF₃ reagent and, accordingly, its high price (Scheme [25]).[51] Additionally, in 2023, Maruoka and Nagano reported a protocol for the efficient one-pot amide/peptide synthesis via acyl fluorides by utilizing the AgSCF₃/KI system that functions similarly to (Me₄N)SCF₃.[55]

Scheme 25 Deoxyfluorination of carboxylic acids with (Me₄N)SCF₃

Prakash and colleagues reported in 2019 a convenient deoxyfluorination protocol using triphenylphosphine (PPh₃), NBS as an oxidant, and an acidic fluoride source such as triethylamine trifluoride (Et₃N·3HF) or potassium bifluoride (KHF₂) with trifluoroacetic acid (TFA) (Scheme [26]).[56] The reaction proceeds at room temperature in DCM or MeCN as a solvent and requires premixing of PPh₃ and NBS with carboxylic acids 162, followed by fluoride addition. It demonstrates good functional group tolerance twoards esters, ethers, amides, sulfonamides, nitriles, halides, and even the hydroxyl group, with generally high reaction yields for both aliphatic and (hetero)aromatic carboxylic acids. The substrate scope includes several pharmaceutical compounds such as naproxen (163g), ibuprofen, probenecid (163f), febuxostat (163h) and indomethacin (163i). Notably, the reaction exhibits chemoselectivity towards the carboxylic acid OH group, as shown by the example of 4-hydroxybenzoic acid (163d; 52% isolated yield). Furthermore, the authors managed to prepare three different amide derivatives of nicotinic acid 164 in a tandem deoxyfluorination/amidation reaction in good to high yields, furthermore demonstrating the utility of the presented method (Scheme [26]). Mechanistic investigation by ³¹P and ¹⁹F NMR spectroscopy revealed that the reaction proceeds through bromophosphonium ion 165 reacting with carboxylic acid 162 and forming acyloxyphosphonium ion intermediate 167. Upon addition of fluoride, this intermediate quickly reacts, forming acyl fluoride 163 under acidic conditions (HF) or Ph₃PF₂ (168) with basic fluoride anion (F^–) (Scheme [26]).[56]

Scheme 26 Deoxyfluorination of carboxylic acids with PPh₃/NBS

A year later Sun’s group reported a deoxyfluorination protocol utilizing electron-deficient fluoroarenes, namely tetrafluorophthalonitrile (TFPN) and spray-dried potassium fluoride (KF) as an additional fluoride source (Scheme [27]).[57] The reaction proceeds under heating to 80 °C in anhydrous MeCN for both aliphatic and aromatic carboxylic acids, in moderate to excellent yields, with good functional group tolerance, including functionalities such as esters, ethers, the nitro group, sulfonamides, and (hetero)aromatics. The substrate scope also includes several pharmaceutical compounds such as probenecid (171f), naproxen (171g), febuxostat (171h), and indomethacin (171i), providing moderate to good isolated yields of the corresponding acyl fluorides. NMR mechanistic and computational studies suggest formation of an ester intermediate 172 by nucleophilic substitution of carboxylate nucleophile (170′) onto TFPN. The strongly acidic phenol leaving group 173 is further easily displaced by a fluoride nucleophile (Scheme [27]).[57]

Scheme 27 Deoxyfluorination of carboxylic acids with TFPN/KF

CpFluor can also be successfully employed for deoxyfluorination of aliphatic and (hetero)aromatic carboxylic acids as demonstrated by Hu’s group in 2021 (Scheme [28]).[58]. The reaction requires heating to 50 °C for 4 hours in DCM as a solvent and a slight excess of CpFluor III-a reagent (1.6 equiv.), affording moderate to excellent yields of the corresponding acyl fluorides. The deoxyfluorination displays good functional group tolerance and a broad substrate scope, including natural compounds and pharmaceuticals such as probenecid (175h). Additionally, a one-pot synthesis of amides 176 by deoxyfluorination/amidation of several carboxylic acids with benzylamine was demonstrated in moderate to good yields. Reaction mechanistic studies showed formation of carboxylate–cyclopropenium derived intermediates 178 and 179, susceptible to an acyl nucleophilic substitution reaction with a fluoride nucleophile, providing acyl fluorides 175 and cyclopropenone 180 as side product (Scheme [28]).[58]

Scheme 28 Deoxyfluorination of carboxylic acids with CpFluor

Deoxyfluorination of aliphatic and aromatic carboxylic acids with trifluoromethyl triflate (CF₃SO₂OCF₃) and DMAP as a tertiary amine base was reported by Zhang and coworkers in 2020 (Scheme [29]).[59] The reaction proceeds at room temperature with a slight excess of trifluoromethanesulfonate (1.2 equiv.) under an inert atmosphere and is usually complete under an hour. For substrates bearing electron-withdrawing substituents, longer reaction times were required, as this appears to slow down the transformation. This deoxyfluorination method affords high isolated yields and displays good functional group tolerance, demonstrated on a broad substrate scope including pharmaceutical compounds such as oxaprozin (182d), probenecid (182f), naproxen (182g), febuxostat (182h), and indomethacin (182i). The reaction mechanism involves two possible distinct pathways of generating the CF₃O^– anion (183), which rapidly decomposes in an acidic environment to active carbonyl difluoride (184), capable of deoxyfluorination of carboxylic acids with the release of CO₂ gas (Scheme [29]).[59]

Scheme 29 Deoxyfluorination of carboxylic acids with trifluoromethyl triflate

This year a comprehensive guide to the synthesis of acyl fluoride by utilizing different CF₃X^– anions was reported by Billard’s group.[60] They developed a novel reagent based on DMAP and the OCF₃ ^– anion, working similarly to Zhang’s deoxyfluorination method. Additionally, they showed its usefulness in the synthesis of amides and esters via a one-pot deoxyfluorination/amidation strategy with different amines or alcohols.

Scheme 30 Deoxyfluorination of carboxylic acids with TCCA/CsF

In 2021, two additional deoxyfluorination strategies were reported. Shibata’s group reported deoxyfluorination of aromatic and aliphatic carboxylic acids under oxidative fluorination conditions using TCCA as an oxidation/chlorination agent and CsF as a fluoride source (Scheme [30]).[61] This method closely resembles Prakash’s PPh₃/NBS/ Et₃N·3HF method. The reaction relies on oxidative activation of carboxylic acids 186 by chlorination with TCCA to generate reactive hypochlorous anhydrides 188. The formed hypochlorous anhydrides 188 react with CsF to afford acyl fluoride 187 and molecular oxygen. Evolution of gaseous oxygen was confirmed experimentally using the Fe(OH)₂ test. This deoxyfluorination reaction proceeds at room temperature overnight with moderate yields and tolerates many useful functional groups. The substrate scope includes bioactive compounds such as estrone derivative 187g and pharmaceuticals such as probenecid (187h). In some cases, evidently for substrates with electron-donating groups, the reaction provides very poor conversions or no product at all (187a,e–h). Addition of PPh₃ (2.0 equiv.) was found to be very effective at improving reaction yields by changing the reaction mechanism analogously to the previous NBS method – with formation of acyloxyphosphonium ion intermediate 189 (Scheme [30]).[61]

Cobb and colleagues managed to develop a method using cheap, commercially available and bench-stable pentafluoropyridine (PFP) as an active deoxyfluorination reagent together with DIPEA as a base (Scheme [31]).[62] This deoxyfluorination reaction proceeds at room temperature in MeCN as a solvent of choice for both aliphatic and aromatic carboxylic acids providing acyl fluorides in moderate to excellent yields on a broad substrate scope and functional group tolerance. Additionally, a one-pot amide synthesis using deoxyfluorination/amidation protocol was developed by the authors on a wide range of carboxylic acids and amines in generally high isolated yields. They concluded that a preactivation period of at least 30 minutes is required for the in situ formation of acyl fluorides, before the addition of amines, to achieve higher reaction yields. Mechanistic studies with LC-MS and NMR spectroscopy suggest that the reaction proceeds through nucleophilic attack of carboxylate 190′ on the electron-poor pyridine ring of PFP, forming an acyloxypyridine intermediate 194. This intermediate rapidly reacts with the fluoride anion in an aromatic nucleophilic substitution reaction, displacing pyridone leaving group 195 and affording acyl fluorides 191 (Scheme [31]).[62]

Scheme 31 Deoxyfluorination of carboxylic acids with pentafluoropyridine

In 2020, Paquin and coworkers reported a deoxyfluorination protocol of carboxylic acids by utilizing a sulfur-based reagent XtalFluor-E with a catalytic amount of added external fluoride (Scheme [32]).[63] The reaction proceeds at room temperature in EtOAc as a solvent on a wide range of aliphatic or (hetero)aromatic carboxylic acids 196 to afford the corresponding acyl fluorides 197 in moderate to excellent yields. The reaction tolerates many useful functionalities such as carbonyls, amides, ethers, halides, olefins, and even a phenolic hydroxyl group. The substrate scope also includes the pharmaceutical compound indomethacin (197i). The reaction mechanism likely involves formation of an activated carboxylic acid intermediate 199 followed by a fluoride–acyl nucleophilic substitution reaction resulting in acyl fluoride 197 along with a fluoride ion, which re-enters the acyl nucleophilic substitution reaction forming a catalytic cycle. They additionally showed a one-pot sequential deoxyfluorination/amidation reaction protocol for amide 198, by addition of amine and DIPEA as a base, providing amides 198 in good to excellent isolated yields (Scheme [32]).[63]

Scheme 32 Deoxyfluorinaation of carboxylic acids with XtalFluor-E

Recently, in 2023, a new sulfur-based deoxyfluorination method to acyl fluorides via electrophilic fluorine source was reported (Scheme [33]).[64] Direct transformation of aliphatic and aromatic carboxylic acids 201 is mediated with a slight excess of Selectfluor (1.5 equiv.) and elemental sulfur (S₈). The reaction conditions involve heating to 80 °C for 4 hours in MeCN as a solvent and tolerates a handful of functional groups on a broad range of substrates, including pharmaceuticals such as ibuprofen (202f), probenecid (202h) and febuxostat (202g) in moderate to excellent yields. The reaction mechanism involves in situ generation of two types of sulfur–fluorine fluorination agents by action of Selectfluor; an S₈–fluoro sulfonium species 205 and S₈ difluoride 206, where both facilitate direct formation of acyl fluoride product 202, SO₂ gas, and polymeric sulfur (Scheme [33]).[64]

Scheme 33 Deoxyfluorination of carboxylic acids with S₈/Selectfluor

Tavčar and Iskra’s group demonstrated that the 2-chloro-1,3-bis(2,6-diisopropylphenyl)imidazolium dihydrogen trifluoride reagent is applicable not just for deoxyfluorination of electron-deficient phenols and benzylic alcohols, but also for deoxyfluorination of aliphatic and (hetero)aromatic carboxylic acids 209 to the corresponding acyl fluorides 210 (Scheme [34]).[28] The reaction proceeds under mild conditions (room temperature, 1 hour) in MeCN as a solvent in good to excellent yields, tolerating a wide variety of functional groups, similar to previous findings.[43] The substrate scope includes several bioactive compounds, such as amino acid derivatives 210h,i, naproxen derivative 210g, aspirin and ibuprofen derivatives (210f), and nicotinic acid. Mechanistic studies based on Hammett correlation (ρ = –2.6) revealed that electron-donating groups present on the carboxylic acid accelerate the reaction rate, indicating a carboxylate (209′) attack on 2-chloroimidazolium ion of the reagent as a rate-determining step. The resulting 2-acyloxyimidazolium intermediate 211 then undergoes a rapid fluoride nucleophilic acyl substitution reaction, converting into the corresponding acyl fluoride 210 and imidazol-2-one 212 as side product (Scheme [34]).[28]

Scheme 34 Deoxyfluorination of carboxylic acids with 2-chloro-1,3-bis(aryl)imidazolium dihydrogen trifluoride

4

Conclusions

This review summarizes and emphasizes recent developments of deoxyfluorination methods in the previous decade. We delve deep into the topics of both C(sp³)–O and C(sp²)–O bond deoxyfluorination reactions categorized by different types of substrates. The review includes several different strategies for the synthesis of aryl fluorides, alkyl fluorides, gem-difluorides, and acyl fluorides obtained from the corresponding phenols, alcohols, ketones and carboxylic acids. Many discussed deoxyfluorination reactions lead to the formation of useful organofluorine compounds, which contribute to promising pharmaceutical applications. The described protocols are highly versatile and tolerate a wide range of functional groups to afford diversely substituted fluorine products in up to excellent yields.

Conflict of Interest

The authors declare no conflict of interest.

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Publication History

Received: 09 May 2024

Accepted after revision: 28 August 2024

Accepted Manuscript online:
09 September 2024

Article published online:
08 October 2024