There are three main routes utilised for introducing fluorine to organic scaffolds: nucleophilic, electrophilic and radical fluorination (Scheme 2.5).228 In nucleophilic fluorination, the substrate behaves as an electrophile while an F– source acts as a nucleophile. In these reactions, a suitable leaving group on the substrate is replaced with fluoride in what is generally an SN2 reaction,
with inversion of stereochemistry at the site of substitution (Scheme 2.5). A particular example of these nucleophilic reactions is where an alcohol is substituted is called deoxyfluorination, discussed in in section 2.4.2.
Compound GABAA Activity GABAB Activity GABAC Activity
196 Agonist Agonist Agonist
197 Weak agonist N/A Agonist
198 Weak agonist N/A Agonist
199 nil nil Agonist
200 nil Agonist Antagonist
201 Weak antagonist Weak agonist Weak antagonist
67 Scheme 2.5 General schemes for fluorination reactions
The more traditional reagents in nucleophilic fluorination include complexes of HF, such as HF/pyridine, tetrabutylammonium fluoride (TBAF) and tetrabutylammonium difluorotriphenylsilicate (TBAT). Hypervalent iodine and bromine reagents have also been reported, such as IPyBF4, para-
iodotoluene difluoride and para-trifluoromethylphenylbromine difluoride (203,
204, and 205, Figure 2.7).229-231 A number of more recently developed reagents aim to improve on issues associated with these, such as poor air stability and hygroscopicity. For example, to circumvent the issue of TBAF’s hygroscopicity, which can lead to unwanted side reactions of hydroxide, Sun and colleagues developed an approach for preparing and then using anhydrous TBAF in situ, through a fluoride shuttling approach starting from KF. They tested this successfully on a range of alkyl halides, nitro groups and activated alcohols.232,233 Kim and co-workers developed an alternative approach to circumvent TBAF’s hygroscopicity, by synthesising a non- hygroscopic reagent, TBAF (t-BuOH)4, that also performed well in
substituting bromides, tosylates, mesylates and silyl ethers.234
In a similar vein, Hammond and colleagues sought to develop new versions of the more established hydrogen-bonded HF complexes to give stable and selective reagents, which gave rise to a DMPU/HF complex (206, Figure 2.7). This proved to be useful for the selective mono or difluorination of alkynes.235
R R'
X F–
SN2 R R'
F X F– F
X = halide, activated alcohol, etc Nucleophilic: Electrophilic: Radical: R3C- "F+" X F R3C F "F+" X = SiR3, SnR3, BR2 or BR3- R3C F R3C F SNAr
68 Hara and co-workers developed an alternative to the older reagent IF5, by
mixing it with a 50:50 mix of pyridine:HF to produce IF5-pyridine-HF.236 This
reduced issues of rearrangements and overfluorination for a number of
fluorinations of α-(arylthio)carbonyl compounds, and
desulfurisation/difluorination, in good to excellent yields. An obvious disadvantage is the use of significant amounts of HF in preparation of the reagent, although the reagent itself is more stable than IF5. They found
similar results working with BrF3-KHF2.237
Figure 2.7: Some nucleophilic fluorination reagents
In electrophilic fluorination the roles are reversed, with the reagent designed to act as an equivalent for F+ (Scheme 2.5). The substrate is most often an
electron rich system such as an alkene, alkyne or arene; although it can also be a carbon site with a nucleophilic labile substituent such as C–Si, C–B or C–Sn.238 The most common reagents deployed are those with N–F bonds,
such as NFPy salts (207),239 NFSI (208),240 and the popular reagents Selectfluor® (209) and Accufluor™ (210, Figure 2.8).241-244 Newer reagents again tend to build on their predecessors, such as in Yasui and colleagues development of NFSBI (211), a sterically demanding variant of NFSI that allowed for modest improvement in the enantioselectivity of fluorination reactions.245 Zhu and co-workers achieved better results through preparation of a chiral NFSI analogue.246
Likewise, Wolstenhulme and colleagues developed a chiral F+ source based on Selectfluor®, with a DABCO-based dication skeleton (213), which proved effective in fluorocyclisation of alkenes.247
Other researchers have looked into adding chiral metal complex catalysts to improve the enantioselectivity of fluorination.248 Geary and colleagues synthesised an interesting iodane species, a fluorinated hypervalent iodine reagent used for electrophilic fluorination (212).249
I N N BF4- 203 I F F 204 F3C Br F F 205 N N O H3C CH3 H F 206
69 Figure 2.8: Common and newer electrophilic fluorination reagents
Cases of radical fluorination are rarer, but do exist. The standard approach in these cases is to use a carbon-centred radical as the substrate, and then a source of molecular fluorine (Scheme 2.5).250 Early examples of the fluorine
sources used were fluorine itself, hypofluorite sources, or XeF2.251-253 More
recently N–F electrophilic fluorine reagents have also proven to be good sources,254-256 along with a couple of recent reports of using fluorinated solvents.257,258
2.4.2 Reagents and Methods for Deoxyfluorination
Deoxyfluorination is a particular case of nucleophilic fluorination, although it has developed its own particular subset of popular reagents. In general terms, deoxyfluorination proceeds via nucleophilic attack of the alcohol on to the electrophilic reagent, which converts the alcohol into a good leaving group and generates F– (Scheme 2.6). The F– then normally undergoes SN2
substitution of the activated alcohol to give fluorination with inversion of stereochemistry.