1.19a). The most prominent feature using heteroaryl sulfones as fluoroalkyl radical precursors is that they are reactivity‐tunable. By slightly changing the heteroaryl rings, the redox potential of fluorinated heteroaryl sulfones can be varied, ensuring the efficient generation of various fluoroalkyl radicals (Scheme 1.19b).
Scheme 1.18 The preparation and application of sodium fluoroalkanesulfinates.
Scheme 1.19 Heteroaryl sulfones as fluoroalkyl radical precursors.
The combination of gem‐difluoroolefination and fluorination can also be used as a good synthetic strategy for fluoroalkylation. In 2015, we reported an AgF‐mediated fluorination of gem‐difluoroolefination, followed by subsequent cross‐coupling with a non‐fluorinated olefin, to access α‐CF3 alkenes and β‐CF3 ketones [32] (Scheme 1.20a). Mechanistic studies revealed that α‐CF3‐substituted benzyl radicals are involved, concluded by 2, 2,6, 6‐tetramethylpiperidine 1‐oxyl (TMEPO) trapping and radical clock experiments. A proposed mechanism is shown in Scheme 1.20b: addition of AgF to gem‐difluoroolefination gives rise to α‐CF3‐benzylsilver intermediate, which can undergo C—Ag bond homolysis to give α‐CF3‐substituted benzyl radical. Addition of this radical to non‐fluorinated alkene generates a new radical, which is oxidized to a carbocation followed by deprotonation to afford α‐CF3 alkene.
Scheme 1.20 AgF‐mediated cross‐coupling of gem‐difluoroolefins and non‐fluorinated olefins.
1.3.3 From Fluoroalkylation to Fluorination
3, 3‐Difluorocyclopropenes are readily available by the reaction of alkynes and difluorocarbene reagents, such as TMSCF3, TMSCF2Cl, and TMSCF2Br [8d–f]. Based on the fact that 3, 3‐difluorocyclopropenes can be hydrolyzed to cyclopropenones in wet atmosphere and Lambert's elegant work in deoxychlorination of alcohols using 3, 3‐dichlorocyclopropenes [33], we successfully realized the use of safe and readily available difluorocarbene reagents for fluorination by means of 3, 3‐difluorocyclopropenes [11] (Scheme 1.21). To ensure the high efficiency of deoxyfluorination of aliphatic alcohols with 3, 3‐difluorocyclopropenes, the reaction should be carried out in a non‐glass vessel because the in situ‐generated HF will be consumed by the glassware (mainly SiO2), thereby retarding the desired reaction.
The electronic nature of CpFluors is critical. For monoalcohols, utilizing electron‐rich aryl substituent on CpFluors to stabilize the cyclopropenium cation intermediate is a key issue (Scheme 1.21, path a). However, for 1, 2‐ and 1, 3‐diols, the reaction proceeds through cyclopropenone acetal intermediates, and is thus less dependent on the electronic nature of CpFluors (Scheme 1.21, path b). The most intriguing feature of CpFluors is that they are more sensitive to the electronic nature of alcohols than many other deoxyfluorination reagents; hence, selective fluorination of electron‐rich OH groups of longer diols (non‐1, 2‐ and 1,3‐diols) can be realized (Scheme 1.22).
Scheme 1.21 Deoxyfluorination of alcohols with 3,3‐difluorocyclopropenes.
Scheme 1.22 Selective deoxyfluorination of longer diols.
Based on our work on fluoroalkylation chemistry using fluorinated sulfones and sulfoximines, and also inspired by Doyle's work [34], we developed N‐tosyl‐4‐chlorobenzenesulfonimidoyl fluoride (SulfoxFluor) as a new bench‐stable and highly reactive deoxyfluorination reagent [12] (Scheme 1.23). The prominent features of SulfoxFluor include a rapid fluorination rate, fluorine economy, selective monofluorination at the least steric hindered site of diols, and high fluorination/elimination selectivity.
Scheme 1.23 Development of SulfoxFluor for deoxyfluorination.
1.4 Conclusions
Our efforts in the development of novel reagents for fluoroalkylation, fluoroolefination, and fluorination by probing the unique fluorine effects have been summarized. During our research work, we realized that (i) there are often unique fluorine effects in organic reactions, (ii) tackling the unique fluorine effect and unveiling the relationships among fluoroalkylation, fluoroolefination, and fluorination enable us to develop various reagents for synthetic organofluorine chemistry, and (iii) organofluorine reactions are not only practically useful but also provide fundamentally intriguing insights into generally organic reactions.
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