JACS: Shihang group of West Lake University realizes amination of Ru (II) - catalyzed aryl fluoride by η 6-coordination

Nucleophilic substitution of aryl halides with heterologous nucleophiles is a common method for functionalization of aromatics, while the snar reaction is a common conversion in pharmaceutical chemistry However, the classical step-by-step snar reactions are usually limited to highly electron deficient aromatics In addition, a series of inactive aryl halides (scheme 1a) can be tolerated by using the corresponding η 6-arene-complex as the substrate for the transition metal catalyzed step-by-step snar reaction At present, transition metal catalyzed s-n-ar reactions of electron rich or neutral aryl fluorides are still to be developed In general, polar reverse aromatic substitution involves aromatic Association, nucleophilic substitution of η 6 - complex and product dissociation In the catalytic process, the combination of substrate Association and dissociation, as the aromatics exchange step, has a significant impact on the catalytic efficiency The typical obstacle of aromatics exchange is the dissociation of the double bond from the relatively stable η 6 - complex to form the corresponding η 4 - Intermediate (scheme 1b) In order to overcome this obstacle, the Shihang research group of West Lake University envisages using semi stable bidentate ligands to promote the s-n-ar catalytic reaction (scheme 1c) in two ways: 1) the side chain group L 'temporarily coordinated with TM promotes the product dissociation through spatial repulsion; 2 ）The semi stability of ligands can provide flexibility for the stabilization of reaction intermediates and reduce the space effect of coordination between substrate and catalyst Recently, Shihang research group developed a Ru diphosphonate catalyzed snar amination reaction, which can be used for the conversion of inert aryl C-F bond (scheme 1D) The result was published in J am Chem SOC (DOI: 10.1021 / JACS 9b13684) (photo source: J am Chem SOC.) firstly, the feasibility of amination of snar (Table 1) was investigated with fluorobenzene 1A as model substrate, and dichloro (p-isopropyltoluene) ruthenium dimer was used as the precursor of cationic Ru (II) - ligand complex Firstly, several representative ligands, such as cyclopentadienyl anion (CP, L1), N-heterocyclic carbene (NHC, L2) and bipyridine (L3), were investigated, but no expected products were obtained Then, the author turned his attention to phosphine ligands When using single tooth triphenylphosphine (L4) or diphenylbutylphosphone (L5), trace 2a was detected When using the half stable ligand (L6) containing methoxy side chain, the yield increased significantly (42%) After changing the flexibility of the side chain or the steric hindrance around the chelated atomic oxygen, the yield decreased or even inhibited the reaction Then, a series of strong electron donating groups such as thioether, amine, phosphine and pyridine were investigated, but all of them were ineffective, indicating the importance of matching two chelating groups on the semi stable ligand When the tridentate ligand L17 containing two methoxy groups was used, the yield decreased to 13%, while L18 did not produce the expected product Then, the aryl groups on the phosphine atom are investigated: 1) the steric hindrance and electron deficient aromatics of the ortho substituent group lead to the decrease of the yield; 2) after the introduction of the electron donor group, the yield increases to 45%, but the further increase of the electronic density of the aromatics leads to the decrease of the yield to 35% Finally, the author chose L22 as the ligand, and further optimized the conditions (including solvent and temperature) to increase the yield to 95% (photo source: J am Chem SOC.) determined the best reaction conditions, the author investigated the substrate range of aryl fluoride (Table 2) The ortho substituted aryl fluorides with and without electron, the para substituted aryl fluorides with various functional groups and the multi substituted aryl fluorides are all suitable substrates In addition, the reaction conditions can tolerate more active C-Cl bond than C-F bond, and can also tolerate a series of active segments, such as amines, amides, sulfonamides, borates and carboamides Meso substituents have a wide range, including strong donor groups such as - ome, - SME, - NH 2 and olefins, as well as electrically neutral methyl and benzyl groups The free hydroxyl will not inhibit the reaction, but the primary alcohol will be converted into corresponding amines In addition, the amination of difluoroaniline and difluorophenol showed specific regioselectivity For the substrate (1z) containing two aromatic fluoride fragments, nucleophilic substitution occurs mainly on the more electron rich aromatic hydrocarbons (2Z), showing the opposite selectivity to the classical snar reaction (2Z ') (photo source: J am Chem SOC.) next, the author examined the scope of application of amines (Table 3) Piperidine and its analogues, including hydroisoquinoline and N-methylpiperazine, are suitable nucleophiles Under this condition, the quaternary amine azacyclobutane is not stable and only trace products are observed; in contrast, both the five and seven amines can get the expected products in good yield Besides cycloamines, linear secondary amines and primary amines are also suitable nucleophiles In addition, high site selectivity was observed (photo source: J am Chem SOC.) in view of the limited understanding of phosphine loaded Ru fluoroaromatics complex, the author synthesized Ru fluoroaromatics η 6 complex 4 to further understand the reaction process (scheme 2a) It is assumed that the amination precursor 5 of S N AR is synthesized by the complex 4 Based on 1H and 31P NMR, the author considers that two semi stable ligands of intermediate 5 are asymmetric: one is double coordinated with phosphorus and oxygen, the other is single coordinated However, when morpholine was added, the fluorine peak disappeared, indicating that amination could be carried out rapidly at room temperature Finally, the reaction mixture was heated to release the free aniline product In the above study, no signal of free fluoroaromatics was detected by 19F NMR The results show that the amination reaction takes place on the η 6 - complex of ruthenium catalyst and fluorinated aromatics In addition, the author compared the biphenylbutylphosphonate ligand L5 with the semi stable ligand L6 in aromatic dissociation (scheme 2b) Under the condition of heating, aniline was completely released from the ruthenium complex 8 which coordinated with the semi stable ligand, but only trace free aniline was detected when using the ligand L5, which indicated that the weak coordination group promoted the dissociation of aromatics from the ruthenium center (photo source: J am Chem SOC.) conclusion: Shihang research group of West Lake University has developed a Ru catalyzed s-n-ar amination method of aryl fluoride by using semi stable bidentate ligands Its mild reaction conditions and wide range of substrates provide a powerful tool for the synthesis and functionalization of bioactive compounds The preliminary mechanism study shows that the substitution is carried out by η 6 - coordination, and the weak coordination group of the semi stable ligand promotes the aromatics exchange step.