JACS: Lambert group of Columbia University realizes highly regioselective C-H functionalization of ether under photocatalysis

The functionalization of the inactive C-H bond has become an important tool in organic synthesis, and the hydrogen atom transfer (HAT) has become a key step in the conversion process At present, the regioselective activation of C-H bond is still difficult to achieve Minisci reaction is a useful tool to establish molecular complexity, but most of the reactions need stoichiometric peroxides and lack of regional control (Figure 1a) In the first time, Macmillan group realized the direct α - arylation of ether through C-H activation and Minisci reaction However, asymmetric substrates such as 2-methyltetrahydrofuran have poor regioselectivity (3.5:1) Later, Singh reported the cross dehydrogenation coupling catalyzed by K 2S 2O 8, but its high temperature resulted in lower regioselectivity (1.6:1) In 2017, Wang Wei's group reported the N-hydroxysuccinimide mediated reaction, which still showed poor regional selectivity (2:1) Recently, it has been reported that Cu / selectfluor system can achieve high regioselectivity in this kind of reactions Therefore, the development of highly regioselective Minisci functional systems for ethers is still challenging Recently, Tristan h Lambert group of Columbia University developed a highly regioselective C-H functionalization method for ethers under photocatalysis, which was recently published in J am Chem SOC (DOI: 10.1021 / JACS 9b11472) (photo source: J am Chem SOC.) firstly, the author studied the photocatalysis coupling between THF (4) and 4-bromoisoquinoline (5) (Table 1) In the presence of LiClO 4, acetic acid, CF 3Co 2H and 5 mol% TAC (1), Minisci product 6 (yield 42%) was obtained by treating the substrate with 1.5V constant voltage and CFL It is found that light, electricity, catalyst and CF 3Co 2H are necessary for the reaction By increasing the catalyst loading (8 mol%) and the reaction time (36 h), the product yield was increased (82%) However, when the voltage increased (3.0 V), the by-products increased, while the lower voltage did not affect the reaction In order to prove the practicability of this method, the author has carried out an amplification reaction (8 mmol) and obtained 1.6 g product Finally, the optimized conditions are applied to asymmetric ether 2-methyltetrahydrofuran (7) and a single isomer product is obtained (photo source: J am Chem SOC.) under the best reaction conditions, the author explored the range of the reaction (Table 2) In addition to 4-bromoisoquinoline, other isoquinoline ligands were used to obtain the corresponding products in medium to good yields, and other cyclic and non cyclic ethers such as tetrahydropyran and ether were also used to obtain the corresponding coupling products in medium yields Next, the author attempts to further explore the key issues of regional selectivity (Table 2) 2-methyltetrahydrofuran, isoquinoline and other noncyclic ethers have high regioselectivity Compared with the tertiary C-H bond, the primary C-H bond is more regioselective, and only the functional products of the primary C-H bond are obtained However, in the competition of primary and secondary C-H bonds, the reaction mainly takes place in the secondary position, showing the excellent regioselectivity of the tertiary C-H bond and the secondary C-H bond However, no regioselectivity was observed for substrates with different steric hindrances In addition, 2,5-dimethyltetrahydrofuran containing the tertiary α - C-H bond did not react For other azoles, the reaction with quinoline substrate is more efficient, but the reaction with pyridine substrate is less efficient Under these conditions, pyrimidine, quinoxaline, indole and other substrates did not react (photo source: J am Chem SOC.) in order to further explore the application scope of this electro-optic catalytic reaction, the author investigated other free radical receptors (Table 3) The experimental results show that vinyl sulfones such as phenyl vinyl sulfone, 1,1-Bis (phenylsulfonyl) ethylene, acrylate and propargyl alkynyl ester can be obtained in medium yield (photo source: J am Chem SOC.) in addition to the above-mentioned C-C bond coupling, the photocatalysis system can also realize the formation of C-N bond (Table 4) In the above conditions, when acetic acid is replaced by trifluoroacetic acid and the battery potential is adjusted to 2.0 V, 4-formylpyrazol and halopurine can react smoothly with tetrahydrofuran, tetrahydropyran or 2-methyltetrahydrofuran (photo source: J am Chem SOC.) finally, the author proposed the mechanism of the photocatalysis reaction (Figure 2a) TAC cation 1 undergoes electrochemical oxidation to form free radical double cation 2 Subsequently, photoexcitation results in the amino radical cation property of intermediate 3 At last, 46 reacts with isoquinoline 5 to produce free radical 48, and then the product 12 is obtained by secondary oxidation and deproton At the same time, the deproton of double cation 47 regenerates TAC catalyst 1 to complete the catalytic cycle It can be confirmed that C-C coupling is carried out through ether radical intermediate, but the mechanism of C-N coupling is not clear Although it may be added to the same type of free radical 49 by the addition of oxazole 50 and reoxidation (Figure 2B, path a), it is an effective path (path B) after oxidation to the corresponding onium ion 52 In order to prove that path B is reasonable, the author found that the formation of acetal 54 (Figure 2C) from benzyl alcohol 53 must be carried out by oxonium ion 52 Therefore, it can be seen that the photocatalysis strategy can realize the functionalization of ether by single and double electron pathways under similar conditions (photo source: J am Chem SOC.) conclusion: Tristan h Lambert group has developed a highly regioselective C-H functionalization method for ethers under photocatalysis The combination of electrochemistry and photochemistry avoids the use of external oxidants, while the catalyst structure makes the chemical similar bond based on different space have high regioselectivity.