Angelw: nickel catalyzed intermolecular and intramolecular metathesis of aryl thioethers via reversible arylation

Aryl thioethers are common in natural products, drugs, materials, photoinitiators and perfumes Therefore, the conversion of C (SP 2) - s bond has become an important research field in transition metal catalysis The emergence of cross coupling reactions catalyzed by various metals (such as PD, Cu and CD) has greatly promoted the development of C-S bond formation, and various electrophilic precursors can be used to construct complex aryl thioethers (scheme 1a) However, there are few studies on the catalytic cracking of C-S bond (scheme 1b) Recently, the bill Morandi group of the Federal Institute of technology in Zurich realized the formation and cleavage of C-S bond (scheme 1c) through reversible single bond decomposition However, there are many limitations in palladium catalytic system, such as high cost, not suitable for mass production, limited range of substrates, unclear reaction mechanism and so on Recently, Morandi group developed a nickel catalyzed scheme 1D of intermolecular and intramolecular thioethers, which was recently published in angew Chem Int ed (DOI: 10.1002 / anie 201910436) (picture source: angelw Chem Int ed.) firstly, the author studied Ni (COD) 2 as pre catalyst, thioanisole and cyclohexanethiol as model substrate (Table 1) It was found that when 1,2-bis (dicyclohexylphosphine) ethane (dcype) ligand was combined with Ni (COD) 2 (5%), 95% yield of the product was obtained Then, the scope of application of thioanisole substrate catalyzed by nickel was investigated Under the standard conditions, the aromatics which are neutral, electron rich and electron deficient can get the expected products with high yield Aromatic compounds, heterocyclic compounds, bicyclic compounds such as naphthalene, quinoline, benzoxazole and alkene bases containing ortho substituents are suitable substrates The reaction was also applied to the structural modification of some thioanisole containing drug molecules, which proved the potential of derivatization of active molecules with ArsR structure In addition, the lower catalyst loading (0.5 mol%) can increase the yield to 86%, indicating that the more sustainable nickel system can have the same activity as palladium system (picture source: angel Chem Int ed.) next, the author investigated the substrate range related to the thiol spouse (Table 2): the easily obtained alkylmercaptan, such as primary, secondary and tertiary mercaptan, can be more than 80% of the yield to obtain the decomposition products; thiocitronellol containing olefins and (s) - thioprolol containing basic amines can also get the expected products in good yield In addition, alkylmercaptan substrates have a wide range of functional group tolerance, such as ether, nitrile, thioether, amide, sulfone, tetrahydropyran and azacyclobutane (photo source: angelw Chem Int ed.) later, the author optimized the reaction conditions for macrocyclization (Table 3) The yield of macrocyclic 3CA was 68% by the double decomposition reaction of sulfur bond closing, while the yield of PD singacycle A1 catalyst system (10% loading) was less than 20% The results show that the macrocyclization must be carried out under the condition of high dilution, and the activity of palladium catalyst is not enough to catalyze the metathesis The macrocyclic compounds can be obtained from the substrates with different chain lengths (such as 15, 16 and 18 CH2) between phenol and mercaptan in medium yields In addition, 3CB dimerization can obtain rare 40 membered macrocycles with 22% separation yield and 3ce with 16 CH 2 in 44% yield (picture source: angelw Chem Int ed.) palladium catalyzed cross coupling is generally carried out through PD 0 / PD II pathway, but due to the higher stability of Ni I and Ni III, nickel catalysis can be carried out in different ways Although the oxidation addition of Ni0 → NiII has been reported, the reduction elimination of C-X (n, O, s) is usually carried out by niiii / NII route Indirect evidence is also provided by calculation and free radical capture experiments However, it is extremely rare to observe the elimination of C-X reduction directly from NiII Therefore, stoichiometric experiments and potential separation of organometallic intermediates were carried out Subsequently, Ni (dcype) (COD) complex was synthesized and its stoichiometric reactivity to aryl thioether was investigated by using thioanisole 1n and adamantane mercaptan 2H as model substrates Next, the author evaluated the reaction of complex 4 with thioanisole derivative 1n (scheme 2a) After reaction at 75 ℃ for 2 h, the formation of complex 5 was observed by 31 P {h} NMR, and its structure was confirmed by single crystal X-ray diffraction Next, the author studied the putative scheme 2B through the stoichiometric experiment between complex 5 and the separated lithium adamantyl mercaptan At room temperature, the reaction was very slow, and the conversion reached 30% at 90 ℃ Then, the complex 4 was oxidized with adamantyl s-phenyl to give 6 (50%), and its 31 P {h} NMR was consistent with that of the previous compound (scheme 2b) This proves the feasibility of transition metallization In addition, the reduction elimination of Ni II complex 6 provides a more reasonable way (scheme 2C) to shut down the catalytic cycle In the presence of 2 equivalent cod, the complex 6 can be reduced and eliminated, while the catalytic reaction only needs the sub stoichiometric cod Next, the author confirmed the catalytic ability of complexes 4, 5 and 6 (scheme 3a) under the standard reaction conditions (picture source: angelw Chem Int ed.) (picture source: angelw Chem Int ed.) based on the above research, the author proposes a reversible catalytic cycle (scheme 3b) based on Ni 0 / Ni II pathway: firstly, Ni catalyst and s-ph bond are oxidized to form 5; then, Ni SME and alkyl s-li are transformed to metallization to form 6 Finally, 6 is eliminated by reduction and the product is released Conclusion: Bill Morandi group has developed a nickel catalyzed aryl sulfide decomposition reaction, which can synthesize macrocyclic compounds in high yield and has a wide range of functional group tolerance In addition, the mechanism of reversible Ni 0 / Ni II pathway to form products was supported by the in-depth study on the separation of organometallic intermediates.