| Author: | Ling, Cho Hon |
| Title: | Regioselective and enantioselective Pd(II)- and Ru(Il)-catalyzed sp² and sp³ C-H bonds intramolecular and intermolecular amidation reactions |
| Advisors: | Yu, Wing-yiu Michael (ABCT) |
| Degree: | Ph.D. |
| Year: | 2021 |
| Subject: | Palladium catalysts Organic compounds -- Synthesis Hong Kong Polytechnic University -- Dissertations |
| Department: | Department of Applied Biology and Chemical Technology |
| Pages: | [296] pages : color illustrations |
| Language: | English |
| Abstract: | N-Aryl amides are very important because it can be found in many pharmaceutical compounds. Regioselective amidation reactions of simple arenes is very challenging as the selectivity of the reaction depends on electronic properties of the substituents. Recently, the ortho-selective transition metals catalyzed (e.g. Pd(II), Rh(III), Ru(II) and Cu(II) etc.) amidation reactions are well established. The functional groups (e.g. pyridyls, ketos, amides and carboxylic acids etc.) act as directing groups for coordination of catalysts and then perform C-H activation to form cyclometallated complexes. The chelation strategy achieves high regioselective at ortho-position of arenes. The Pd(II)-catalyzed regioselective amidation reaction with non-chelation strategy necessities the use of pre-functionalized arenes. Our group was investigated Pd(II)-catalyzed regioselective amidation reaction of simple arenes to afford N-arylphthalimides. The steric repulsion offered by the bulky N-heterocyclic carbene ligand controls regioselective C-H bond activation to form aryl-palladium intermediate for the further functionalization. In this work, employing the phthalimide (0.1 mmol) with [(IPr)Pd(OAc)2(OH2)] (10 mol %) (IPr = 1,3-bis(2,6-diisopropylphenyl)-2,3-dihydro-1H-imidazole) as a catalyst and PhI(OAc)2 (10 equiv, 1 mmol) as an oxidant in neat arenes at 100 °C gave 50 – 70 % isolated yields of desired N-arylphthalimides formation. The amidation product of electron-deficiency arenes such as α,α,α-trifluorotoluene is meta-isomer in dominant (o:m:p = 1:16:5). For the electron-rich arenes such as toluene, the amidation product is meta- and para-isomers in mixture (o:m:p = 1:22:29). To explore the mechanism of the reaction, the kinetic studies on the catalytic reaction of phthalimide, benzene-d6, PhI(OAc)2 and [(IPr)Pd(OAc)2(OH2)] were conducted in 1H NMR spectroscopic analysis. A rate law = k[PhI(OAc)2][(IPr)Pd(OAc)2(OH2)][phthalimide]0.3 was obtained. It is the first order of reaction with respect to PhI(OAc)2 indicating that the resting state is Pd(IV) intermediate before the C-H bond activation step. While, the enantioselective Ru(II)-catalyzed intramolecular C(sp2)-H bond amidation reaction of 3-(2,2-diphenylethyl)-1,4,2-dioxazol-5-one (1i) examined. By employing 1i (0.1 mmol) with catalytic amounts of [Ru(p-cymene)(L-proline)Cl] ([Ru4], 10 mol %) and AgSbF6 (10 mol %) in TFE (1 mL) at 50 °C to afford 4-phenyl3,4-dihydroquinolin-2(1H)-one (2i) in 76 % yield with 30 % ee. Based on the HPLC analysis of product mixture obtained from Ru(II)-catalyzed reaction of 1i, (S)-4phenyl-3,4-dihydroquinolin-2(1H)-one (peak at retention time = 21.4 mins) was found to be the major enantiomer. At the same time, the regioselectivity of the amidation reaction between C(sp2)-H bond and C(sp3)-H bond was studied. Employing the 3-(2,3-diphenylpropyl)-1,4,2-dioxazol-5-one (1a) with Ru(II) catalysts ([Ru1] – [Ru5], 10 mol %) and AgSbF6 (10 mol %) in dry solvent (either DCE or TFE, 1 mL) at 50 °C, L-proline ([Ru4]) gave 4-benzyl-3,4-dihydroquinolin-2(1H)-one 2a (sp2 amidation product) in 78 % and trace amount of (5R)-4,5-diphenylpyrrolidin-2-one 2a' (sp3 amidation product) formation in TFE as a solvent. Several products formation in substrate scope studies demonstrated the mechanism of the reaction goes through spirocyclization followed by C-C migration rather than electrophilic aromatic substitution (SEAr). Enantioselective intramolcular Ru(II)-catalyzed nitrenoid insertion of arenes established the chiral ligand produces enantio-pure amidation products. The enantioselective intermolecular Ru(II)-catalyzed nitrenoid insertion of unactivated terminal alkenes was investigated. Treatment of terminal alkenes (0.2 mmol) with 1,4,2-dioxazol-5-ones (0.1 mmol) in the presence of [Ru(p-cymene)Cl2]2 (10 mol %), AgSbF6 (15 mol %), LiOAc (20 mol %) and HOAc (0.1 mmol) in distillated DCE (0.5 mL) at 35 °C to afford desired allylamides formation in 11 – 61 % isolated yields. By designing a chiral cymene ligand, the chiral cymene is a 10-membered ring structure with the axial chirality. After the coordination of the Ru(II) metal center, the chiral [Ru2] was characterized by 1H NMR, 13C NMR and X-ray crystalline spectrometers. By repeating the amidation reaction of terminal alkene, it gave 60 % isolated yield of the desired allylamide product but the enantiomeric excess of the product is 10 % ee. |
| Rights: | All rights reserved |
| Access: | open access |
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