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Synthesis 2022; 54(07): 1671-1683
DOI: 10.1055/a-1684-0121
review

A Review on the Halodefluorination of Aliphatic Fluorides

Richa Gupta
,
Rowan D. Young  ∗

We thank the Singapore Agency for Science, Technology and Research (A*STAR grant No. A1983c0033) for financial support.
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Abstract

Halodefluorination of alkyl fluorides using group 13 metal halides has been known for quite some time (first reported by Newman in 1938) and is often utilized in its crude stoichiometric form to substitute fluorine with heavier halogens. However, recently halodefluorination has undergone many developments. The reaction can be effected with a range of metal halide sources (including s-block, f-block, and p-block metals), and has been developed into a catalytic process. Furthermore, methods for monoselective halodefluorination in polyfluorocarbons have been developed, allowing exchange of only a single fluorine with a heavier halogen. The reaction has also found use in cascade processes, where the final product may not even contain a halide, but where the conversion of fluorine to a more reactive halogen is a pivotal reaction step in the cascade. This review provides a summary of the developments in the reaction from its inception until now.

1 Introduction

2 Stoichiometric Halodefluorination

2.1 Group 13 Halodefluorination Reagents

2.2 Other Metal Halide Mediated Halodefluorination

3 Catalytic Halodefluorination

4 Monoselective Halodefluorination

5 Cascade Reactions Involving Halodefluorination

6 Summary and Outlook


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Key words

halodefluorination - halogen exchange - Finkelstein reaction - C–F activation - fluoroalkanes

Biographical Sketches

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Richa Gupta completed her undergraduate studies at Miranda House, University of Delhi, India. After that she moved to Hyderabad to pursue an MSc in chemical science from Hyderabad Central University, India. Then she moved to Delhi to take an industrial position as a technical consultant chemist at Scube Scientific, India. She joined Prof. Rowan Young’s group at the National University of Singapore as a graduate student in January 2018. She is working on selective C–F bond functionalization in polyfluorocarbons employing a frustrated Lewis pair approach. In her spare time, she enjoys playing badminton.

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Rowan Young obtained his BSc (Hons) from the University of New South Wales in Australia, then went on to pursue his PhD at the Australian National University’s Research School of Chemistry under the supervision of Professor Anthony Hill. After stints at the University of Oxford and the University of Edinburgh as a research fellow in the groups of Andrew Weller and Polly Arnold, respectively, he began his independent career at the National University of Singapore in 2014. Since then he has focused on methodology development using pincer complexes and frustrated Lewis pairs to address challenges in small molecule activation, in particular the selective activation of carbon–halogen and carbon–chalcogen bonds. His achievements have been recognized with research awards including Asian Chemistry Prizes from Japan and China (2018) and the Thieme Chemistry Journal Award in 2019.

1

Introduction

Fluorocarbons are becoming increasingly abundant in materials, pharmaceuticals, agrochemicals, and fine chemicals.[1] This is primarily due to the desirable stability, solubility, biomimicry, and detectability properties that fluorine imparts to organic compounds. As such, many methods for the incorporation of fluorine into organic compounds have been developed.[2] However, as fluorine becomes more prominent in organic compounds, opportunities to derivatize or construct molecules arise from the ability to functionalize carbon–fluorine (C–F) positions. Indeed, C–F activation chemistry is an active research field, driven not only by the practical outcomes of C–F functionalization, but from the academic challenges associated with breaking the strongest carbon–element single covalent bond in high selectivity.

Many strategies have been developed for the direct functionalization of C–F bonds based on oxidative cleavage with transition metals, homolytic cleavage driven by radical chemistry, and heterolytic cleavage dominated by Lewis acid chemistry.[3] In most cases, the chemistry under development mirrors the well-established coupling chemistry of the heavier halogen congeners of the fluorocarbons being targeted. A reasonable synthetic strategy therefore might pivot on an ability to readily convert selected C–F positions in fluorocarbons to more reactive C–X bonds (X = Cl, Br, I) that are able to undergo further functionalization using established synthetic protocols. This reaction, termed halodefluorination, is indeed possible, and despite its discovery almost 80 years ago, methods allowing efficient halodefluorination are still being developed.

The reasons for developing halodefluorination go beyond a means of circumventing difficulties in functionalizing C–F bonds. Selective halodefluorination offers a means to impart orthogonal reactivity to a molecule, allowing divergent functionalization possibilities for an otherwise symmetric starting material. Conversely, selective halodefluorination also offers the ability to retain a level of fluorine in post-functionalization products when starting from polyfluorocarbons.[4]

Halodefluorination may not always act as a bridging reaction, but may provide products of value directly. Given the diversity and availability of fluorocarbons, access to heavier polyhalocarbons is frequently more convenient via a halodefluorination approach. Additionally, the byproducts of halodefluorination may be of value, for example when access to mixed aluminum chlorofluorides and aluminum bromofluorides is enabled via a halodefluorination reaction.

Despite the history, utility, and ongoing research into halodefluorination, there has yet to be a dedicated review of the chemistry concerning this reaction in aliphatic fluorides.[5] Rather, halodefluorination has been examined and summarized in more general functional defluorination reviews, or in summaries focused on more general Finkelstein, Swarts, or Halex reactions.[3b] [c] [6] This review hopes to collect reports on the halodefluorination reaction, and describe the progress and developments in this field (Scheme [1]).

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Scheme 1 Halodefluorination, the conversion of a C–F bond into a C–X (X = Cl, Br, I) bond, can occur stoichiometrically, catalytically, and selectively, and can be used to generate intermediates (isolable or otherwise) en route to more complex functionalization

# 2

Stoichiometric Halodefluorination

2.1

Group 13 Halodefluorination Reagents

The first recognized halodefluorination reaction was reported by Henne and Newman in 1938.[7] They discovered that benzotrifluoride can be converted into α,α,α-trichlorotoluene when reacted with equimolar amounts of AlCl3 in the presence of acetyl chloride. In the absence of acetyl chloride or when employing mixed chlorofluoromethanes and ethanes in a benzene solution, intractable tarry mixtures were obtained, likely the result of subsequent Friedel–Crafts alkylation.

Boron trihalides were also discovered to facilitate halogen-exchange reactions of various fluoroalkanes to give the corresponding halides.[8] For instance, Satyamurthy and co-workers developed an efficient method for converting alkyl fluorides into their corresponding alkyl halides by utilizing commercially available BX3 (X = Cl, Br, I) reagents in stoichiometric quantities (Scheme [2]A).[8a] In the case of 1-fluoroheptane, isomeric mixtures were observed due to a classical 1,2-hydride shift. For exo-2-norbornanyl fluoride, the substrate reaction was stereospecific as no endo product was formed in the reaction.

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Scheme 2 (A) Halodefluorination scope using BX3 (X = Cl, Br, I); (B) mechanistic studies using isotopic labelling suggest a phenonium intermediate

A mechanistic evaluation utilizing the deuterium-labelled­ substrate 1-fluoro-1-deutero-2-phenylethane suggested the formation of a phenonium cation when employing 1-fluoro-2-phenylethane. This was formed by direct fluoride abstraction prior to nucleophilic attack (i.e., an SN1 pathway). Nucleophilic chloride attack by the counteranion could occur at position A or B, resulting in the two observed isotopomers A and B (Scheme [2]B).

Prakash and Olah also reported halodefluorination of a C(sp3)–F bond by using stoichiometric amounts of BBr3.[8b] The product distribution could be controlled under different reaction conditions to give α,α,α-bromodifluoro-, dibromofluoro-, and tribromotoluenes (Scheme [3]). It must be noted that in these reactions, the yields are reported based on BBr3 as the limiting reagent, and the reactions are thus inefficient in the use of benzotrifluoride.

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Scheme 3 Optimization of bromodefluorination reaction conditions to obtain mono-, di-, and tribromomethyl-substituted products from benzotrifluorides; a yield based on BBr3; b yield based on PhCF3

With aluminum and boron halide mediated halodefluorination of aliphatic fluorides established, little advancement was made in halodefluorination reactions until the most recent 20 years. Chemists using the crude form of this reaction were forced to control their conditions and reagents to avoid unwanted Friedel–Crafts alkylations. Stoichiometric halodefluorination reactions were often run at cryogenic temperatures, and were carried out using electrophilic solvents or with deactivated benzotrifluorides to avoid unwanted side reactions (Scheme [4]).[9]

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Scheme 4 Halodefluorination carried out at cryogenic temperatures or in electrophilic solvents to avoid unwanted side products

Other stoichiometric approaches have used dialkylaluminum halides for halodefluorination, allowing the reactions to be run in inert alkane solvents due to the high solubility of dialkylalane reagents. Terao and Kambe were able to utilize diethylaluminum chloride for the chlorodefluorination of a range of alkyl fluorides (Scheme [5]).[10] This reaction showed a strong chemoselectivity towards alkyl fluorides, with other alkyl halides unaffected under the reaction conditions. Competition experiments revealed that the order of reactivity for chlorodefluorination follows tertiary > secondary > primary alkyl fluorides.

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Scheme 5 Terao and Kambe used Et2AlCl as an n-hexane-soluble chlorodefluorination reagent

Takahashi extended the work of Terao and Kambe, using stoichiometric trialkylalanes to induce halodefluorination (Scheme [6]).[11] In this instance, dihalomethanes acted as the halide source, presumably via metathesis with the trialkylaluminum species to generate aluminum halides that then mediated the halodefluorination reaction, and side reactions were avoided by the use of n-hexane as solvent. In the cases of chlorodefluorination and bromodefluorination, catalytic amounts of titanocene halides were found to improve the reaction, although no catalyst was required for iododefluorination. Control reactions suggested that the titanocene halide may catalyze the alkyl–halo metathesis between the trialkylalanes and the dihalomethanes. Direct transfer of halide from titanocene to the alkyl fluoride substrate was ruled out by a control reaction that failed to produce any halodefluorination product in the absence of aluminum. This is despite a previous report by Satyamurthy on the efficacy of titanium tetrahalides at effecting halodefluorination.[8a]

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Scheme 6 Halodefluorination of alkyl fluorides mediated by trialkylalanes and dihalomethanes as the halide source; titanocene dihalide was used to improve reactivity in the cases of chloro- and bromodefluorination

Halodefluorination mediated by aluminum halides has also served as a convenient synthetic route to generate the heterogeneous catalysts aluminum chlorofluoride (AlClxF3-x) and aluminum bromofluoride (AlBrxF3-x).[12] Aluminum fluoride is a surprisingly poor Lewis acid, which can be attributed to its high lattice energy. This results in poor solubility of aluminum fluoride in almost any solvent, and a lack of vacant Lewis acid sites on aluminum. Mixed aluminum halides overcome this limitation with the inclusion of defects or disorder to the local structure around the aluminum centers that provide highly Lewis acidic sites. Exactly which aliphatic fluorocarbons are used to generate the amorphous aluminum mixed halides plays a large role in the resultant activity of the heterogeneous catalyst, with trichlorofluorocarbon proving the most utilized fluorocarbon.


# 2.2

Other Metal Halide Mediated Halodefluorination

In addition to group 13 metal halides mediating halodefluorination, other metal halides have been shown capable to perform this reaction. Barrio and co-workers described a classical Finkelstein-type reaction for fluoroalkanes under acidic conditions (Scheme [7]).[13] The conversion of alkyl fluorides to the corresponding bromo and iodoalkanes was achieved at 105–130 °C in the presence of aqueous HX (X = Br, I).[14] The conversion of alkyl fluoride to alkyl chlorides required concentrated HCl. Notably, this reaction also allowed for halodefluorination of aromatic fluorides, presumably via an SNAr mechanism. The process of halogen exchange between fluoroalkanes and aqueous hydrogen halide was later shown to be accelerated by employing phase-transfer catalysis.[15]

Olah demonstrated that trimethylsilyl iodide was able to enact halodefluorination directly when used in superstoichiometric quantities (Scheme [8]).[16] The reaction worked best with tertiary and secondary fluorides where good yields could be obtained after 16 hours at 25 °C. Reactions with primary fluorides were slow, even at elevated temperatures, and led to elimination products in addition to the desired halodefluorination product. Olah suggested an associative mechanism involving pentacoordinate silicon, but no mechanistic studies were undertaken to support this postulate.

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Scheme 7 Finkelstein reaction of alkyl and aryl fluorides using hydrohalide acids as halide source
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Scheme 8 Iododefluorination of alkylfluorides using TMSI

Stoichiometric halodefluorination of benzotrifluoride by employing BeBr2, BeI2, ThI4, and HfI4 under mild conditions was reported by von Hänisch and co-workers.[17] The group was able to fully characterize the iododefluorination product α,α,α-triiodotoluene, despite its air- and light-sensitivity (Scheme [9]A).

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Scheme 9 (A) Halodefluorination using beryllium, thorium, and hafnium halides; (B) chlorodefluorination using magnesium chloride reagents; (C) chlorodefluorination using molybdenum(V) chloride

Matsubara reported the formation of 1-chlorooctane from attempts to react 1-fluorooctane with methylmagnesium chloride (Scheme [9]B).[18a] Small amounts of the chlorodefluorination product was also observed in addition to the desired coupling product 1-phenyloctane when the phenyl Grignard reagent was used. The halodefluorination product was also obtained exclusively, albeit in a lower yield of 40%, when using MgCl2. Kambe also used magnesium iodide for a related iododefluorination reaction.[18b]

The conversion of alkyl fluoride to alkyl chloride was also achieved by using molybdenum(V) chloride (Scheme [9]C).[19] The reaction conditions are comparatively milder than those required for similar conversions involving SN2 displacement. The methodology can be applied to primary, secondary, and tertiary fluorides.

The Hilmersson group reported that Sm(HMDS)2 (HMDS = hexamethyldisilazide) can be employed for reductive cleavage of aliphatic C–F bonds.[20] They extended the lanthanide-catalyzed selective C–F bond activation by utilizing YbI3, whereby alkyl fluorides could be selectively substituted with iodide (Scheme [10]A).[21] They also tested other lanthanide iodides, including LaI3, SmI3, and DyI3, but found their efficacy at iododefluorination to be inferior to that of YbI3.

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Scheme 10 (A) Iododefluorination of alkyl fluorides using ytterbium iodide; (B) proposed mechanism for YbI3 mediated iododefluorination that proceeds via competing SN2 and SNi pathways

The reaction follows an SN2 mechanism (via intermediate I) with a competing SNi pathway (via intermediates II and III) (Scheme [10]B). The reaction is stereospecific and compatible with a large range of functional groups. This methodology provides a direct route for late-stage incorporation of iodine to give a highly reactive C–I bond, which can be converted into other functional groups. The reaction did not work for di- or trifluorides or on sp2-hybridized carbon atoms, due to the higher bond strengths of CF2, CF3, and sp2-carbon atoms when compared to the monofluorinated sp3-carbon atom.


#
# 3

Catalytic Halodefluorination

Many stoichiometric reagents capable of halodefluorination are both commercially available and affordable. However, they suffer from a number of setbacks, primarily that they are too reactive resulting in highly exothermic halodefluorination reactions and hydrolysis with atmospheric water. To avoid this, halodefluorination reactions are often run under cryogenic conditions and the metal halides mediating the reaction are kept away from moisture to avoid hydrolysis.

More recently, a number of reports on the development of catalytic halodefluorination have emerged that circumvent the shortcomings of stoichiometric approaches. Firstly, the use of a catalyst allows the use of more benign halogen sources that are less prone to hydrolysis. Indeed, in some cases the halogen source is even capable of regenerating the catalyst after its reaction with water (for example, silicon halides react with alumina to regenerate aluminum chloride).[22] Secondly, the lower concentration of active catalyst often results in a more controlled reaction and less need for preventative safety controls such as cryogenic temperatures.

In an extension of group 13 halodefluorination, Young reported aluminum-catalyzed halodefluorination (Scheme [11]).[23] This catalytic process that converts carbon–fluorine bonds into carbon–halogen bonds utilizes halosilanes as the halogen source. It was found that regeneration of the aluminum halide catalysts, from reaction with silicon halides and formation of silicon fluorides, was an exergonic process and that the catalytic cycle was most likely a tandem process, where the aluminum halide mediated halodefluorination independently, and the silicon halide simply acted to regenerate the catalyst. Apart from trimethylsilyl halides, Young was able to show that industrially relevant silicon halides such as SiCl4 performed well in the reaction and that unwanted Friedel–Crafts reactions could be largely avoided, even in arene solvents.

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Scheme 11 Aluminum-catalyzed halodefluorination of alkyl fluorides using silicon halides as halogen source

Young extended this protocol to pseudohalides such as the sulfonates mesylate and triflimide (Scheme [12]).[24] Given that in most instances sulfonates serve as better leaving groups than halides, Young was able to show that alkyl fluorides could undergo selective nucleophilic substitution in the presence of alkyl halides via pseudohalide intermediates. This catalytic reaction was mediated by the prototypical Lewis acid tris(pentafluorophenyl)borane (BCF) and used trimethylsilyl sulfonates as the pseudohalide source. The two-step protocol that generates the pseudohalide intermediates also allows substitution of fluorides with Lewis bases such as alcohols and primary amines, which otherwise poison Lewis acid catalysts used in C–F activation chemistry. Traditional halodefluorination products were also accessible through substitution of the pseudohalide with latent sources of a nucleophilic halide, such as [NBu4]Br.

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Scheme 12 Pseudohalodefluorination catalyzed by B(C6F5)3 (BCF); the pseudohalo sulfonates used (i.e., OMs, NTf2) were subsequently easily displaced by other nucleophiles, including halides (Cl, Br, I)

The stoichiometric halodefluorination reaction mediated by ytterbium iodide reported by Hilmersson[21] (described above) was also rendered catalytically by employing TMSI as a halide source (Scheme [13]).[25] TMSI acts as a stoichiometric fluoride trapping reagent that allows regeneration of the YbI3(THF)3 catalyst. A mechanistic investigation supported the two-step catalytic cycle, where TMSI regenerates the active catalyst. It was found that in the presence of TMSI, YbI3(THF)3 undergoes ring opening over time, resulting in the generation of solvent-free YbI3. This was found to greatly affect the stereochemical outcome of the reaction (Scheme [13]), implying that THF plays an important role in the halodefluorination mechanism.

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Scheme 13 Iododefluorination of alkyl fluorides catalyzed by ytterbium iodide; the presence of THF greatly affected the stereochemical outcome of the reaction, suggesting that a change in mechanism from SN1 to SN2 or SNi occurs in THF-solvated ytterbium
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Scheme 14 Iron(III) halide catalyzed halodefluorination of benzotrifluorides; a statistical approach was employed to optimize the yield of the monohalogenated products

Williams and co-workers demonstrated facile halodefluorination using catalytic iron(III) halides as Lewis acids (Scheme [14]).[26] This is the first example of iron-catalyzed halogen exchange of non-aromatic C–F bonds, and employed boron trihalides as the halogen source. Although boron halides can be used as halodefluorination reagents independently, it was found that the use of the Fe(III) halide greatly improved the efficiency of the reaction, and theoretical analysis suggested that the iron halides may be directly activating the C–F bond. In this system ‘over-reaction’ (where multiple fluorides react in a polyfluorocarbon substrate) was preferred, but monohalogen exchange was optimized through a statistical method called Design of Experiment (DOE) analyses. This allowed the generation of ArCF2X products in low to moderate yields.

Lastly, halofluorination has been reported in the form of catalytic scrambling of fluorine/chlorine positions in mixed chlorofluoroalkanes.[27] Such scrambling can be mediated by aluminum halides or mixed aluminum halide heterogeneous catalysts. For example, Winfield has reported the use of aluminum fluoride (β-AlF3) for the conversion of CClF2CCl2F into CF3CCl3 at high temperature (593–693 K).


# 4

Monoselective Halodefluorination

The conversion of fluorine into other halides offers opportunities for a range of diverse functionalizations. In the case of polyfluorocarbons the ability to selectively convert a single fluoride to a heavier halogen would allow retention of fluorine in the product (something that may offer desirable chemical properties) and it would allow even more diverse functionalization, especially if the product is capable of orthogonal reactivity (where both the remaining fluorine(s) or the introduced halide may be further functionalized as desired).

The simple premise of monoselective halodefluorination in polyfluorocarbons is complicated by the effect that fluorine has on a substrate’s stability. The C–F bond is highly polarized, leading to a significant ionic contribution to its bond strength.[2a] As such, neighboring fluorine atoms tend to stabilize one another, most prominently in the case of geminal polyfluorocarbon positions. For example, the C–F bond dissociation energy (BDE) of tetrafluoromethane is 131 kcal·mol–1, while trifluoromethane has a C–F BDE of 127.5 kcal·mol–1. The trend of lowering C–F BDE with F/H substitution continues with difluoromethane having a C–F BDE of 119.5 kcal·mol–1 and fluoromethane having a C–F BDE of just 109.9 kcal·mol–1. The phenomenon of a decreasing C–F BDE with the substitution of fluorine with any other X type atom holds true for all of the halides, and thus halodefluorination of polyfluorocarbons with chemically equivalent sites tends to lead to ‘over-reaction’, where exhaustive halodefluorination dominates the reaction products mixture. Several groups have reported strategies to overcome this problem, relying either upon kinetic or thermodynamic controls.

Yoshida and Hosoya reported on the selective functionalization of benzotrifluorides bearing ortho hydrosilane groups (Scheme [15]).[28] Activation of the hydrosilane by stoichiometric trityl borate resulted in the formation of a silylium intermediate that readily attacked the most accessible fluorine (i.e., the ortho CF3 group). Thereafter, a suitable nucleophile concurrently present in the reaction mixture was able to attack the intermediate difluorocarbocation, resulting in the selectively functionalized product. Their initial report focused on allyl nucleophiles, but did include a single example that utilized HCl in diethyl ether as the nucleophile, resulting in a moderate yield of the chlorodefluorination product.[28a]

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Scheme 15 Monoselective chlorodefluorination of ortho-silylbenzotrifluoride
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Scheme 16 (A) Monoselective halodefluorination of ortho-silyl di- and trifluoromethylbenzenes; (B) post-functionalization of halodefluorination products at the halomethyl and silyl sites

Yoshida further expanded upon this methodology combining the halide nucleophile with the trityl activation reagent (Scheme [16]A).[28b] He found that trityl halides dissolved in mixtures of dichloromethane or chlorobenzene and 1,1,1,3,3,3-hexafluoropropan-2-ol (HFIP) exhibited significant ionization. Thus, treatment of benzotrifluorides possessing ortho hydrosilane groups resulted in high yields of the selective halodefluorination products. This protocol was successful for the selective substitution of fluoride with chloride, bromide, and tosylate groups, and was extended to benzodifluorides. The protocol was restricted to benzofluorides that contained ortho hydrosilyl groups. However, Yoshida demonstrated that further functionalization of both the introduced halide and the requisite ortho silyl group was feasible (Scheme [16]B).

Young developed a method for selective activation of polyfluorocarbons using frustrated Lewis pairs.[29] When utilizing 2,4,6-triphenylpyridine (TPPy) as the base partner, selective activation of trifluoromethyl groups was possible using catalytic B(C6F5)3 (BCF) as the Lewis acid partner, and TMSNTf2 to sequester the liberated fluoride (Scheme [17]).[29b] The resulting pyridinium salts reacted with a range of nucleophiles including chloride, bromide, and iodide to generate the mixed difluorohalomethyl salts in good yields. This protocol allowed the selective halodefluorination of non-activated benzotrifluorides, including the parent benzotrifluoride. It was also shown to work for non-aromatic trifluoromethyl groups including trifluoromethoxy and trifluorothiomethoxy groups.

Young extended this reaction to a generic reaction that could work for a wide range of polyfluorocarbons, including distal polyfluorides, where chemically equivalent fluorides that were not on the same carbon site (i.e., non-geminal) could be selectively halodefluorinated (Scheme [18]).[29c] Further, sulfides such as tetrahydrofuran and dimethyl sulfide) were introduced as base partners. It was found that the intermediate sulfonium salts were thermodynamically less stable than the pyridinium salts, but that sulfide displacement by any incoming nucleophile (e.g., a halide) was a more facile process.

Lastly, a two-step protocol was developed by Welch for the selective halodefluorination of trifluoromethyl groups α to carbonyl positions (Scheme [19]).[30] Treatment of such trifluoromethyl ketones with zerovalent magnesium induced a reductive C–F bond cleavage, with the resulting enolate trapped by treatment with TMSCl. The trapped silyl enolate reacted with elemental halogens or N-halosuccinimide reagents to provide difluorohalomethyl ketones, where a formal selective halodefluorination had occurred. More recently Szabó employed this approach to generate difluorobromomethyl ketones that underwent Halex substitution with [18F]F– and were utilized to synthesize radiotracers with possible application in positron emission tomography (PET).[31]

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Scheme 17 Monoselective activation of benzotrifluorides catalyzed by frustrated Lewis pairs (FLPs) and subsequent nucleophilic substitution, including by halides; the two-step, one-pot reaction constitutes a formal monoselective halodefluorination
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Scheme 18 Monoselective halodefluorination of difluoromethyl, difluoromethylene, and distal fluoroalkyl positions by using a sulfide-based FLP system
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Scheme 19 Formal monoselective halodefluorination of trifluoromethyl ketones by reduction with magnesium to form the difluoroenolate, followed by oxidation with N-halosuccinimide (NXS) or elemental halogen

# 5

Cascade Reactions Involving Halodefluorination

Intermediates and products in halodefluorination reactions are often unstable. Indeed, this can be seen as detrimental for high yielding halodefluorination reactions, where reactions need to be carried out under controlled conditions (inert solvent, cryogenic temperatures) or catalytically to avoid unwanted side reactions such as dehydrohalogenations and Friedel–Crafts alkylations. However, embracing alternative reaction pathways (to simple halodefluorination) allows for the possibility of quickly generating diverse functionalization at the C–F position.

Wakharkar and Sudalai reported that superstoichiometric aluminum chloride can be used in combined halodefluorination/carbodefluorination Friedel–Crafts alkylation reactions of benzotrifluorides.[32] The aluminum chloride serves two purposes, as a halodefluorination reagent and a Friedel–Crafts catalyst, where initial chlorodefluorination is followed by subsequent chloride abstraction from the benzotrichloride, and then attack by arene. In this manner, the combined halogenation and arylation of 1-chloro-4-(trifluoromethyl)benzene with aromatic compounds gave 1,1-dichlorodiphenylmethanes (Scheme [20]A).

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Scheme 20 (A) Cascade chlorodefluorination and Friedel–Crafts alkylation between 1-chloro-4-(trifluoromethyl)benzene and toluene induced by aluminum chloride; (B) cascade chlorodefluorination, Friedel–Crafts alkylation, and Friedel–Crafts acylation between 4-(trifluoromethyl)benzoyl chloride and fluorobenzene.

Later, in 2010, Yonezawa and co-workers also utilized aluminum-mediated Friedel–Crafts alkylation using the CF3 group in 4-(trifluoromethyl)benzoyl chloride.[33] However, in this case, disubstitution of the trifluoromethyl group by fluorobenzene was observed, and the remaining chloride was hydrolyzed to a hydroxyl group. Thus, although the reaction likely proceeds via an initial chlorodefluorination, no chloro groups are observed in the product (Scheme [20]B).

Similarly, Yoshida used boron tribromide to facilitate halodefluorination followed by coupling to arenes.[34] As in the reaction reported by Yonezawa, no halide was carried through to the final product, with workup in methanol affording diaryl ketone products (Scheme [21]A). Indeed, methanol was found to be pivotal to the success of the reaction, with no product observed when water was added after the halodefluorination reaction. The authors postulated that either the formation of an acid bromide intermediate was needed for the reaction to proceed via a Friedel–Crafts acylation mechanism (path a), or that the formation of a mixed bromofluoroborane Lewis acid was required for the reaction to proceed via a Friedel–Crafts alkylation mechanism (path b) (Scheme [21]B). In support of pathway b, control experiments showed that boron tribromide was insufficiently acidic to induce Friedel–Crafts alkylation between mesitylene and 1-methyl-4-(tribromomethyl)benzene.

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Scheme 21 (A) Coupling of benzotrifluorides with arenes mediated by boron tribromide and methanol to give diaryl ketone products; (B) the proposed mechanism was postulated to occur via initial bromodefluorination, and then through either Friedel–Crafts acylation (path a) or Friedel–Crafts alkylation (path b)

Shibata and co-workers reported the synthesis of alkenyl chlorides via the cleavage of C(sp3)–F bonds in gem-difluoroalkanes utilizing AlEt2Cl as a fluoride scavenger and a chloride source (Scheme [22]).[35] The selectivity of the reaction can be controlled by changing the substituents on the central aluminum atom of the promoter. They observed high yields and good Z/E stereoselectivity in long-chain acyclic­ substrates, but poorer selectivity for the chlorodefluorination–dehydrochlorination reaction in large cyclic systems, generating internal alkenes in moderate regio­selectivity.

When the stronger Lewis acid AlCl3 was employed, Friedel­–Crafts double cyclization was observed, resulting in spirobiindane products (Scheme [22]).[35] The authors attributed the vastly different reaction outcomes to the acidity of the Lewis acid used and the nucleophilicity of the aluminate chloride counteranion present after chloride abstraction from the intermediate chlorodefluorination product. The stronger Lewis acid AlCl3 allowed intramolecular attack of the intermediate carbocation by one of the aryl substituents. However, the more nucleophilic [AlEt2Cl2]– counteranion more readily recombined with the carbocation, preventing this pathway, but allowing the more facile dehydrochlorination reaction.

McLeod observed the halodefluorination and dehydrochlorination of 1,1,1-trifluoroalkanones using superstoichiometric aluminum chloride (Scheme [23]).[36] Trifluoroalkyl substrates not supported by a conjugated electronic system have much higher barriers toward C–F activation as compared to the gem-difluoroalkane systems utilized by Shibata (see above),[35] and it was found that the presence of the ketone group was essential for generation of the desired product. The reaction was hindered in the presence of strong donors, such as pyridines, and the alkyl chain length between the trifluoromethyl group and the carbonyl group affected the product yield greatly. McLeod postulated that a cyclized intermediate where the keto group stabilized intermediate carbocations during the chlorodefluorination process was pivotal for the reaction to proceed. Indeed, similar 1,1,1-trifluoroalkylbenzene substrates were shown to undergo intramolecular Friedel–Crafts alkylation, resulting in carbocyclic products and demonstrating the importance of the keto–carbocation interaction. Subsequent dehydrochlorination of the resultant 1,1,1-trichloroalkanone intermediates induced by the excess aluminum chloride resulted in the observed terminal 1,1-dichloroalkene products.

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Scheme 22 Diethylaluminum chloride mediated cascade chlorodefluorination followed by dehydrochlorination to give chloroalkene products; when the reaction was attempted using aluminum chloride, spirobi­indane products were obtained (see reaction below)
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Scheme 23 Cascade chlorodefluorination and dehydrochlorination of trifluoroalkanones mediated by aluminum chloride to give terminal 1,1-dichloroalkenes

Wang demonstrated selective halodefluorination in α-difluoromethylene and α-(trifluoromethyl) styrenes (Scheme [24]).[37] Depending upon the reaction conditions, monohalodefluorination, dihalodefluorination and trihalodefluorination haloalkene products were accessible. TMSX (X = Cl, Br, I) was used as a halide source in conjunction with [Al(C6F5)3(tol)0.5] (ACF) as precatalyst. Studies by Chen have shown that ACF is unstable in the presence of chloroalkanes and quickly undergoes metathesis to generate a range of aluminum chloride products.[38] As such, the speciation of the active catalyst that Wang used in 1,2-dichloroethane solvent is unlikely to have been ACF.

Through a number of control experiments, the authors found that the reaction likely proceeds via an initial SN2′ substitution to generate a γ-halo-1,1-difluoroalkene (product from conditions A) that can isomerize to a mixed α-halodifluoromethylstyrene intermediate. This can undergo a second SN2′ reaction with TMSX to generate products from conditions B. The same sequence of reactions would then also give rise to products of conditions C under more forcing conditions.

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Scheme 24 Selective halodefluorination followed by dehydrohalogenation to give 1,1-dihalostyrene products. Reagents and conditions: A: fluorocarbon substrate/TMSBr (3:1), ACF (9.0 mol%), 60 °C, 48 h; B: fluorocarbon substrate/TMSBr (1:4), ACF (4.5 mol%), 120 °C, 24 h; C: fluorocarbon substrate/TMSCl (1:7), ACF (9.0 mol%), 120 °C, 24 h; ACF = [Al(C6F5)3(tol)0.5].

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Summary and Outlook

As fluorocarbons become increasingly used as feedstocks for the synthesis of more complex hydrocarbon and/or fluorocarbon molecules, halodefluorination reactions will become further utilized and developed. Halodefluorination has advanced from a crude reaction used to obtain desired halocarbon products in poor yield and selectivity from alkyl fluorides to a reaction that can be performed catalytically and with high selectivity in challenging aliphatic polyfluorocarbons. Despite the concurrent drive in the area of C–F activation chemistry for direct carbodefluorination catalyzed by transition metals, initial conversion of fluorides to heavier halides that have more developed functionalization routes is attractive as a means for diverse functionalization. This is especially true where orthogonal reactivity is possible after selective halodefluorination.

Despite recent advances in the field, halodefluorination reactions are still less economical and practical than Finkelstein and Halex reactions that typically utilize cheap metal halides as their halogen source and are water tolerant. In contrast, most of the halodefluorination reactions described above utilize Lewis acidic reagents and/or catalysts that are water intolerant and they use group 13 or group 14 halides that are more expensive than metal halides. As such, an obvious area of development in the halodefluorination reaction might focus on the use of more robust catalysts and more affordable halide sources.

The ability of halodefluorination reactions to be selective and to undergo further cascade reactions has begun to be explored. The combination of these two features offers the ability to quickly generate stereospecific products of high complexity. The extension of this chemistry to incorporate multicomponent reactions will allow even greater potential in possible products arising from halodefluorination initiated cascade reactions.


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Conflict of Interest

The authors declare no conflict of interest.


Corresponding Author

Rowan D. Young
Department of Chemistry, National University of Singapore
12 Science Drive 2, Singapore 117543
Singapore   

Publication History

Received: 03 October 2021

Accepted after revision: 02 November 2021

Accepted Manuscript online:
02 November 2021

Article published online:
04 January 2022

© 2021. Thieme. All rights reserved

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Scheme 1 Halodefluorination, the conversion of a C–F bond into a C–X (X = Cl, Br, I) bond, can occur stoichiometrically, catalytically, and selectively, and can be used to generate intermediates (isolable or otherwise) en route to more complex functionalization
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Scheme 2 (A) Halodefluorination scope using BX3 (X = Cl, Br, I); (B) mechanistic studies using isotopic labelling suggest a phenonium intermediate
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Scheme 3 Optimization of bromodefluorination reaction conditions to obtain mono-, di-, and tribromomethyl-substituted products from benzotrifluorides; a yield based on BBr3; b yield based on PhCF3
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Scheme 4 Halodefluorination carried out at cryogenic temperatures or in electrophilic solvents to avoid unwanted side products
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Scheme 5 Terao and Kambe used Et2AlCl as an n-hexane-soluble chlorodefluorination reagent
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Scheme 6 Halodefluorination of alkyl fluorides mediated by trialkylalanes and dihalomethanes as the halide source; titanocene dihalide was used to improve reactivity in the cases of chloro- and bromodefluorination
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Scheme 7 Finkelstein reaction of alkyl and aryl fluorides using hydrohalide acids as halide source
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Scheme 8 Iododefluorination of alkylfluorides using TMSI
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Scheme 9 (A) Halodefluorination using beryllium, thorium, and hafnium halides; (B) chlorodefluorination using magnesium chloride reagents; (C) chlorodefluorination using molybdenum(V) chloride
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Scheme 10 (A) Iododefluorination of alkyl fluorides using ytterbium iodide; (B) proposed mechanism for YbI3 mediated iododefluorination that proceeds via competing SN2 and SNi pathways
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Scheme 11 Aluminum-catalyzed halodefluorination of alkyl fluorides using silicon halides as halogen source
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Scheme 12 Pseudohalodefluorination catalyzed by B(C6F5)3 (BCF); the pseudohalo sulfonates used (i.e., OMs, NTf2) were subsequently easily displaced by other nucleophiles, including halides (Cl, Br, I)
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Scheme 13 Iododefluorination of alkyl fluorides catalyzed by ytterbium iodide; the presence of THF greatly affected the stereochemical outcome of the reaction, suggesting that a change in mechanism from SN1 to SN2 or SNi occurs in THF-solvated ytterbium
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Scheme 14 Iron(III) halide catalyzed halodefluorination of benzotrifluorides; a statistical approach was employed to optimize the yield of the monohalogenated products
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Scheme 15 Monoselective chlorodefluorination of ortho-silylbenzotrifluoride
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Scheme 16 (A) Monoselective halodefluorination of ortho-silyl di- and trifluoromethylbenzenes; (B) post-functionalization of halodefluorination products at the halomethyl and silyl sites
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Scheme 17 Monoselective activation of benzotrifluorides catalyzed by frustrated Lewis pairs (FLPs) and subsequent nucleophilic substitution, including by halides; the two-step, one-pot reaction constitutes a formal monoselective halodefluorination
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Scheme 18 Monoselective halodefluorination of difluoromethyl, difluoromethylene, and distal fluoroalkyl positions by using a sulfide-based FLP system
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Scheme 19 Formal monoselective halodefluorination of trifluoromethyl ketones by reduction with magnesium to form the difluoroenolate, followed by oxidation with N-halosuccinimide (NXS) or elemental halogen
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Scheme 20 (A) Cascade chlorodefluorination and Friedel–Crafts alkylation between 1-chloro-4-(trifluoromethyl)benzene and toluene induced by aluminum chloride; (B) cascade chlorodefluorination, Friedel–Crafts alkylation, and Friedel–Crafts acylation between 4-(trifluoromethyl)benzoyl chloride and fluorobenzene.
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Scheme 21 (A) Coupling of benzotrifluorides with arenes mediated by boron tribromide and methanol to give diaryl ketone products; (B) the proposed mechanism was postulated to occur via initial bromodefluorination, and then through either Friedel–Crafts acylation (path a) or Friedel–Crafts alkylation (path b)
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Scheme 22 Diethylaluminum chloride mediated cascade chlorodefluorination followed by dehydrochlorination to give chloroalkene products; when the reaction was attempted using aluminum chloride, spirobi­indane products were obtained (see reaction below)
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Scheme 23 Cascade chlorodefluorination and dehydrochlorination of trifluoroalkanones mediated by aluminum chloride to give terminal 1,1-dichloroalkenes
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Scheme 24 Selective halodefluorination followed by dehydrohalogenation to give 1,1-dihalostyrene products. Reagents and conditions: A: fluorocarbon substrate/TMSBr (3:1), ACF (9.0 mol%), 60 °C, 48 h; B: fluorocarbon substrate/TMSBr (1:4), ACF (4.5 mol%), 120 °C, 24 h; C: fluorocarbon substrate/TMSCl (1:7), ACF (9.0 mol%), 120 °C, 24 h; ACF = [Al(C6F5)3(tol)0.5].