2.3 Direct Fluorination
2.3.1 Nucleophilic
There are multiple fluorination approaches that employ nucleophilic transformation pathway. Most frequently occurring among them are deoxofluorination, (di)hydrofluorina-tion of unsaturated compounds, desulfurative fluorina(di)hydrofluorina-tion, and halogen exchange. These transformations are generalized in Scheme2.1.
R
Scheme 2.1 Generalized nucleophilic transformations into mono- and difluoro compounds
Halogen exchange was chronologically the first pathway of selective direct fluorina-tion. SbF3has been used as a fluorinating agent in organic chemistry since 1892, when Frederic Swarts discovered its ability to transform organic chlorides into fluorides [19].
This method allows introducing fluorine atoms into various chlorine-containing organic substrates quite selectively and with a high yield (Scheme2.2).
ClCl
Scheme 2.2 Swarts fluorination
Halogen exchange using ionic fluorides is also widespread and is applied in cases where an unassisted displacement process is feasible, sometimes by forcing it with
el-2
evated temperatures [8]. KF is the most common of such fluoride salts, due to its bene-ficial reactivity/economy ratio, and the possibility to control halogen exchange ratio by varying reaction conditions. When extensive fluorination has to be reached (e.g., full re-placement of halogens, hydrogens, and saturation of double and aromatic bonds), then high-valency fluorides (mainly CoF3) are being used. Meanwhile, for partial, more se-lective halogen exchange (often when one or two atoms of fluorine need to be intro-duced), AgF or AgBF4have been frequently employed [8].
The next important milestone – the Balz-Schiemann reaction was developed in 1927 and is a Sandmeyer-like diazotization [20]. This method is considered a traditional route toward fluorobenzene and related derivatives, including 4-fluorobenzoic acid (Scheme 2.3).
NH2 HBF4 HNO2
N N BF4
hν
∆
F
Scheme 2.3 Balz-Schiemann reaction
Later developments demonstrated, that HBF4in this reaction can be replaced with Olah’s reagent (PPHF). PPHF is often employed in other nucleophilic fluorination reac-tions, mainly (di)hydrofluorination and desulfurative fluorination[21].
Achieving (di)hydrofluorination of alkenes or alkynes, while seemingly straightfor-ward and simple task on paper (it should follow Markovnikov’s rule, and be analogous to HBr or HCl), is often not easily implemented, and is substrate-specific. In an original report by Olah et al. [21], simple linear and cyclic alkenes were successfully hydrofluor-inated, halofluorinated (by addition of halosuccinimides), nitrofluorinated (by addition of NOBF4), and fluorinated in situ to form vicinal difluorides (by addition of AgF) [21].
In the case of (di)hydrofluorination of alkynes, examples are more scarce. Reports on di-hydrofluorination of terminal alkynes use PPHF or its polymer-based analogs, and while achieving similar transformation for internal alkynes, the substrate scope is often lim-ited, and partial (hydrofluorination) is often observed [14] (Scheme2.4).
R
R'
R R'
F F R
F R' PPHF, PVPHF
or DMPU•HF, Au(I)
TEA•HF E+
DMPU•HF Au(I) Scheme 2.4 Limitations of hydrofluorination of alkynes
Control over the extent of hydro- and halo-fluorination of alkynes can be done by replacing PPHF with TEA·3HF along with Lewis acid additive (e.g., BF3, for hydrofluor-ination) or halosuccinimide (e.g., NIS, NBS, for halofluorhydrofluor-ination) [22]. These reactions are often inefficient and non-selective, and to improve the scope of possible applications recent investigations draw attention to the use of Au(I) additives [23–25]. As a pinnacle
2
of such approach, group of Gerrard Hammond developed the DMPU·HF reagent, which when used along with JohnPhos imidogold precatalyst demonstrated versatile and con-trollable mono- and dihydrofluorination over a variety of substrates, as demonstrated in the work by Okoromoba et al. [26].
Desulfurative fluorination uses similar reagents mixed with electrophilic sources (usually succinimides and their analogs, e.g., NIS, NBS, or DBDMH), to generate IF or BrF in situ. This approach was successfully implemented by Olah et al. [21], and later by Sondej and Katzenellenbogen [27]. In our experience, the latter protocol has proven to be superior, and with slight optimization was implemented for substrates of interest [10].
R R'
S
R R'
F F
R R'
O
RS S R'
n
PPHF
AgF E+
[S]
HS
SH
n
Scheme 2.5 Two-step transformation of carbonyl groups into CF2through desulfurative fluorination
Another honorable mention is the report by Newton et al., where mild synthesis of di-fluoroalkyl ethers was achieved from thionoesters using AgF [28]. This non-toxic, shelf-stable and mild reagent does not require anhydrous conditions, can be applied in con-ventional glassware, and opens up the way to a variety of substrates. What distinguishes this method from its counterparts (both for the synthesis of thionoesters and difluoro-methyl compounds), is a high functional group tolerance, which surpasses that of PPHF, DAST, and XeF2. Both pathways are sketched in Scheme2.5.
Despite continuous developments of new reagents and improvements described for above-mentioned reactions, deoxofluorination remains one of the most versatile and widespread approaches in organofluorine chemistry.
Sulfur tetrafluoride (SF4) was first synthesized in 1929 by Fisher and Jaenckner, but it took until 1959 when Smith et al. reported the first examples of fluorination of carbonyl compounds with SF4, which sparkled rapid development of deoxofluorination [29]. SF4 is still widely used in organic synthesis to convert alcohol and carbonyl into CF and CF2groups, respectively. Ketones and aldehydes form geminal difluorides. Carboxylic acids are converted into trifluoromethyl derivatives, while esters break down into two trifluoromethyl derivatives (Scheme2.6). In case of slow or troublesome transforma-tion, SF4is often used along with HF, which increases its reactivity. By-products of SF4 reactions (SOF2and SO2) are toxic, but can be eliminated by alkali neutralization [30–
35].
Dialkylaminosulfurtrifluorides (e.g., DAST, MOST, BAST, XtalFluor salts) are used to convert alcohols into the corresponding alkyl fluorides, as well as aldehydes and ketones into geminal difluorides. These reagents are easier to handle than SF4, which however
2
R R'
[F
-] = All deoxofluorinating reagents
[F
-] = SF
4, DAST,
MOST, BAST, XtalFluor, Fluolead, DFI
Scheme 2.6 Generalized scope of deoxofluorination reagents
comes at a price of decreased reactivity, and as a consequence, the scope of deoxofluor-ination is often substrate-dependent [34,36]. DAST was first reported by Middleton in 1974 [36], who later introduced Morph-DAST (MOST), as a more temperature-stable analog [37]. Later developments of shelf-stable reagents, which can be used at elev-ated temperatures, brought Deoxofluor (BAST)[38], and the solid derivatives of DAST and MOST – XtalFluor salts [39]. In contrast to SF4, the interaction of carboxylic acids with dialkylaminosulfurtrifluorides stops at the stage of formation of acyl fluoride, while esters are generally perceived as unreactive [14] (except rare cases[40]) (Scheme2.6).
The development of deoxofluorination reagents is continuous, and not limited to
2
dialkylaminosulfurtrifluorides, or even to SF4derivatives. In 2010, Umemoto reported a novel reagent – Fluolead, which shows similar to improved reactivity to DAST, MOST, and BAST, while possessing higher thermal stability and stereoselectivity[41]. The most notable difference between Fluolead and dialkylminosulfurtrifluorides, is the ability of the former to convert carboxylic acids to CF3groups, which was previously only achiev-able with SF4.
Another sulfur-free reagent used for deoxofluorination of hydroxyl and carbonyl com-pounds – DFI was developed in 2002 by Hayashi et al.[42]. The most noteworthy feature of DFI is it’s ability to deoxofluorinate phenolic -OH group [15,42]. Meanwhile, in 2015, Nielsen et al. reported PyFluor – a new low-cost, and stable reagent, which can be se-lectively applied for the transformation of alcohols into fluorides [43].
Two of more classic alternatives used for deoxofluorination of alcohols, while being significantly more impartial to other carbonyl compounds are reagents of Yarovenko and Ishikawa.
Yarovenko’s reagent is a product of the interaction between chlorotrifluoromethylene and diethylamine [44]. This reagent must be prepared in an airtight container, and af-terward, it can be stored for only a couple of days, even in the refrigerator. Yarovenko’s reagent is most commonly used to convert primary alcohols into alkyl fluorides under mild conditions and in high yields. However, secondary and tertiary alcohols form only significant amounts of by-products, in particular alkenes and ethers [13,44].
Twenty years after the report by Yaroveko, the Ishikawa group made an improved ver-sion of this reagent, by changing chlorine to CF3group (see Figure2.3). The Ishikawa’s reagent is widely used for the conversion of alcohols into alkyl fluorides and carboxylic acids into acyl fluorides. Another important feature is that it does not react with alde-hydes and ketones. Ishikawa reagent is a popular alternative to DAST because it can be stored for a long time and is inexpensive, as it can be easily prepared from available and safe substances [45–47].