JACS: visible light catalysis and Lewis acid activation for single C (SP3) - f bond breaking of trifluoromethyl aromatic hydrocarbons

Organic fluorides have unique chemical and biological properties, which are very important in the field of pharmaceutical chemistry and agricultural chemistry With the increasing demand for novel fluorides, Organofluorine Chemistry has developed rapidly in recent years In recent years, more and more attention has been paid to the selective C-F bond breaking of PFCs Difluoromethylarene derivatives (arcf2r) are the building blocks of many bioactive compounds (Fig 1a) The derivatives of arcf2r can be directly prepared by selective C (SP 3) - f bond breaking of trifluoromethyl aromatic hydrocarbons (arcf 3) The by-product of the reaction is only f -, and the conversion process has high atomic economy and step economy However, the single C (SP 3) - f bond fracture is very challenging, because: the dissociation energy of C (SP 3) - f bond is very high, which is inert in many reaction conditions; moreover, one C (SP 3) - f bond fracture in - CF 3 will reduce the dissociation energy of the remaining C (SP 3) - f bond, that is, it is easy to get the products of all three C (SP 3) - f bonds fracture Recently, selective C (SP 3) - f bond breaking methods have been reported, such as single C (SP 3) - f bond breaking by ortho silicon cation activation or transition metal catalysis, and single electron transfer (set) strategy by active metal reduction, electrochemistry or UV irradiation (Figure 1b) However, these methods have many disadvantages, such as the use of reducing agents, the limitation of substrates, and sometimes the low selectivity of defluorination Fig 1 The source of selective C (SP 3) - f bond breaking of arcf2 R and arcf3 with biological activity: J am Chem SOC Recently, Ruth gschwind and Burkhard K ö nig from the University of Regensburg, Germany published a paper on J am Chem SOC., reporting the combined action of visible light catalysis and Lewis acid activation in the removal of single fluorine from arcf3 The team envisages that in the presence of photocatalyst and electron donor, arcf3 is first reduced by photocatalyst set and converted into free radical anion Due to the weak ability of F - to leave, the anion of free radical will slowly release F - to form aryl difluoromethyl radical (arcf2 ·) And the addition of Lewis acid can clear the F - and accelerate the process Finally, the corresponding arcf2r product can be obtained by adding the free radical trapping reagent (Fig 1c) In accordance with the requirements of reaction design, the author selected different photocatalysts, solvents, reaction time and the equivalent of each component with p-trifluoromethylbenzonitrile 1A as the substrate of Demerization and n-methyl-n-phenylmethylacrylamide 2A as the capture reagent The optimal conditions were: fac IR (PPy) 3 (1.0 mol%), 2,2,6,6-tetramethylpiperidine (TMP, 2.0 equiv.), pinacol borane (hbpin, 3.0 equiv.), 2A (2.0 equiv.), blue light (455 nm) irradiation for 24 hours in DCE Under these conditions, the reaction has a good selectivity for breaking single C (SP 3) - f bond, and the product of defluorination is less than 5% With the optimum reaction conditions, the author developed the reaction substrate arcf3 and the capture reagent methylacrylamide The expansion result of methylacrylamide 2 is shown in Figure 2 It can be seen that the yield of electron rich substrate (3b, 3C) is higher than that of electron deficient substrate (3E, 3f), which is because electron rich methylacrylamide can promote the capture process and ring closing step of electron deficient radicals; the steric effect should hinder the ring closing step, making the yield low (3D); C (SP 2) ）-The substrate (3f) of CL is compatible with the reaction, indicating that the reaction has good selectivity for C (SP 3) - f bond In addition, the reaction activity of biphenyl derivatives is low (3G), and the substrate with different N-protecting groups has good activity (3h-3j) Fig 2 Extended source of methylacrylamide substrate: J am Chem SOC On the other hand, arcf 3 shows that (Fig 3): the ortho and para position of trifluorotoluene contain cyano group, and the reaction activity is relatively good (4b), but the substituent of m-cyano group cannot react (4C); the increase of methyl and phenyl on benzene ring will lead to the decrease of yield (4D, 4e); C (SP 2) ）-The reaction activity of f-bond is much lower than that of C (SP 3) - f-bond (4F); the substrates containing different N-protected sulfonamides can react with medium to good yield (4g-4k); while the substrates containing carboxylate substituents have low reaction activity and relatively poor selectivity for monofluorination (4L, 4m) Figure 3 Source of substrate expansion of arcf3: J am Chem SOC Finally, the author studies the reaction mechanism through a series of experiments and gives the corresponding reaction mechanism See Figure 4 for details The results show that the chemical selectivity of C (SP 3) - f bond breaking is controlled by the synergism of space and electron Figure 4 Source of reaction mechanism proposed by the author: J am Chem SOC Conclusion: the team of gschwind and K ö nig realized the combined action of photo redox catalysis and Lewis acid activation of trifluoromethyl aromatic hydrocarbon C (SP 3 ）-In the process of f-bond activation, the product containing aryl difluoromethyl module was obtained with high atom economy and step economy Moreover, the reaction has good chemical selectivity and functional compatibility Paper link: http://pubs.acs.org/doi/10.1021/jacs.7b10755 research group gschwind: http://www-oc.chemie.uni-regensburg.de/gschwind/index_e.html Research Group K ö nig: http://www-oc.chemie.uni-regensburg.de/koenig/index.php burkhardk ö nig and Ruth gschwind