| Author: | Ng, Fo Ning |
| Title: | Cross-coupling reactions of arylrhodium(III) complexes with α-diazocarbonyl compounds and N-haloamines for carbon-carbon and carbon-nitrogen bonds formation : towards development of catalytic cascade arylation-halogenation and direct arene amination reactions |
| Advisors: | Yu, Wing-yiu Michael (ABCT) |
| Degree: | Ph.D. |
| Year: | 2017 |
| Subject: | Hong Kong Polytechnic University -- Dissertations Stereochemistry Organic compounds -- Synthesis |
| Department: | Department of Applied Biology and Chemical Technology |
| Pages: | xxxv, 395 pages : illustrations |
| Language: | English |
| Abstract: | Quaternary stereocenters are important motifs found in many medicinal compounds such as Norpace, Dolophine and Imodium. However, effective routes for synthesizing quaternary stereocenters are limited. Recently, transition metal-catalyzed migratory carbene insertion was proved to be an effective strategy for C-C bond formation. It is anticipated that the σ-alkyl metal species formed after the migratory carbene insertion are active for further functionalization, thereby affording products with a quaternary stereocenters. However, the σ-alkyl metal complexes are usually decomposed through spontaneous ß-hydride elimination / protonolysis. We envisioned that these competing reactions could be suppressed by forming metallacycles. In this work, we explored a strategy involving a sequence of migratory carbene insertion - metallacycles formation - functionalization for catalytic synthesis of quaternary stereocenters by a cascade formation of C-C and C-X (X = Cl / F) bonds on the carbenic center. The RhIII-catalyzed cascade arylation and chlorination of α-diazocarbonyl compounds with arylboronic acids and N-chlorosuccinimide was initially developed. In this study, reacting arylboronic acids (0.6 mmol) with α-diazomalonates (0.2 mmol), N-chlorosuccinimide (0.6 mmol) and [Rh(Cp*)(OAc)₂] (5 mol %) (Cp* = 1,2,3,4,5-pentamethylcyclopentadienyl) afforded the desired α-aryl-α-chlorocarbonyl compounds in up to 86% yields with good functional groups tolerance. Moreover, the α-aryl-α-chlorocarbonyl compounds with an alkene side chain can be further transformed to γ-lactones by the Cu-catalyzed chlorine atom transfer radical cyclization. Analogous to the arylchlorination reaction, the cascade arylation-fluorination of the α-diazocarbonyl compounds was also achieved for the synthesis of α-fluorocarbonyl compounds. Treating arylboronic acids (0.6 mmol) with α-diazomalonates (0.2 mmol), N-fluorobenzenesulfonimide (NFSI; 0.6 mmol), K₂CO3 (0.6 mmol) and [Rh(Cp*)(OAc)₂] (5 mol %) furnished the α-aryl-α-fluorocarbonyl compounds in up to 95% yields. To identify the key steps in the catalysis, kinetic studies on the catalytic reaction of p-bromophenylboronic acid (5b), diethyl diazomalonate (6p), NFSI and [Rh(Cp*)(OAc)₂] were performed. A rate-law = k[diazomalonate][Rh(Cp*)(OAc)₂]; k = second-order rate constant was established. This result indicates that the reaction involves diazo decomposition as the turnover-limiting step. To ascertain the nature of the C-F bond formation, we have synthesized a structurally defined rhodium(III)-diketonate complex {Rh(Cp*)(Cl)[O-O'-k²-MeCOC(Ph)COMe]} (Rh-3a). The stoichiometric reaction of Rh-3a with NFSI (2 equiv) afforded the fluorinated product α-phenyl-α-fluoroacetylacetone (9al) in 73% yield. On the basis of these findings, the reaction of rhodium(III)-diketonate with NFSI should mediate the C-F bond formation process. The nature of the transition state for the fluorination step was also studied. A series of rhodium(III)-diketonate complexes carrying different electronic substituents (Rh-3a-Y) (Y = H, p-OMe, p-Me, p-CF3 and m-OMe) were synthesized. The reaction rates of stoichiometric fluorination of each rhodium(III)-diketonate complex were measured by 1H NMR spectroscopy. A linear free-energy relationship of log(kY/kH) with Hammett σ+ constant was established, and the plot displays a linear fit (R² = 0.97) with a p+ value of -0.28. Based on the above kinetic studies, the fluorination reaction should proceed via a partially positively charged transition state. Analogous to the aryl-migratory carbene insertion, a RhIII-catalyzed direct C-H amidation/amination of benzoic acids with N-chlorocarbamates / N-chloromorpholines was also achieved. Anthranilic acids were obtained in up to 85% yields. Successful benzoic acids amination was achieved with carbamates bearing various amide groups including NHCO2Me, NHCbz and NHTroc to furnish highly functionalized anthranilic acids. Secondary amines such as morpholines, piperazines and piperidines are effective coupling partners for the amination reaction. A stoichiometric reaction of a cyclometallated rhodium(III) complex of benzo[h]quinoline with a silver salt of N-chlorocarbamate afforded an amido-rhodium(III) complex, which was isolated and structurally characterized by X-ray crystallography. This finding confirmed that the C-N bond formation results from the cross-coupling of N-chlorocarbamate with the arylrhodium(III) complex. |
| Rights: | All rights reserved |
| Access: | open access |
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|---|---|---|---|---|
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