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Title: Catalytic carbon-hydrogen bond cross coupling reactions for carbon-carbon bond formations : development of ruthenium-, rhodium- and palladium-catalyzed (hetero)arene C-H bond functionalizations by {220}-diazocarbonyl compounds and carboradicals
Authors: Chan, Wai Wing
Degree: Ph.D.
Issue Date: 2014
Abstract: Alkylation of arenes is an important route for aromatic hydrocarbons synthesis. Currently, Friedel-Crafts alkylation remains a widely adopted method for aromatic alkylations. Apart from poor regioselectivity, Freidel-Crafts alkylation is limited by the use of over-stoichiometric Lewis acids (e.g. AlCl₃) as catalyst. Recently, Pd-catalyzed cross coupling reactions of aryl halides with enolates constitute a highly regioselective route to α-aryl carbonyl compounds. However, the Pd-catalyzed reactions necessitate the use of pre-functionalized arenes. It is anticipated that regioselective direct alkylation of arene C-H bonds would be highly favorable for development of atom-economical and sustainable chemical synthesis. Our investigation began with the Ru(II)-catalyzed intramolecular cyclization of diazo-β-ketoanilides to form 3-alkylideneoxindoles, which are important motifs of some pharmaceutical products (e.g. Tenidap). Diazo compounds are versatile carbenoid reagents for C-C bond formations. Dirhodium (II, II) carboxylates and analogues are well-known catalysts for carbenoid C-H insertions with excellent regio- and enantiocontrol being achieved. Related studies with other transition metal catalysts such as ruthenium are sparse in literature. In this work, treatment of diazo-β-ketoanilides with [RuCl₂(p-cymene)]₂ (2.5 mol%) in toluene at 40 °C afforded 3-alkylideneoxindoles in up to 92% yields. Dirhodium (II, II) tetraacetate was also known to effect similar carbenoid cyclization; however, higher temperature (80 90 °C) was needed for success. While the cyclization of diazo-β-ketoanilides involved formally intramolecular carbenoid arene C-H insertion, the intermolecular carbenoid insertion to heteroarenes has been examined. When NH-free indoles were treated with [RuCl₂(p-cymene)]₂ (2 mol%) and α-aryldiazoacetates in dichloromethane at room temperature, C2-alkylated indoles were formed in up to 96% yields and N-alkylation products were not obtained. According to the literature, the analogous dirhodium-catalyzed reactions were featured predominantly by C3-and N-alkylations. Functional groups such as halogens and nitro are well tolerated for the Ru-catalyzed reactions. Likewise, highly selective C2-alkylation of pyrroles has also been achieved.
The [RuCl₂(p-cymene)]₂-catalyzed intra- and intermolecular carbenoid arene C-H functionalizations did not exhibit significant primary kinetic isotope effect (kH/ kD ~ 1) at the C-H bonds involved in the carbenoid reactions. Assuming reactive ruthenium-carbene intermediates, the lack of primary kinetic isotope effect is not compatible with direct C-H bond insertion mechanism. Alternatively, mechanism involving cyclopropanation of the arene was proposed. Reactive metal-carbene complexes are known to insert aliphatic C-H bonds with the order of reactivity being tertiary C-H bond > secondary C-H bond >> primary C-H bond. Direct carbene insertions to arene C-H bonds are rare. In this work, [Cp*RhCl₂]₂ was found to catalyze intermolecular carbenoid arene C-H functionalization with diazomalonates. For example, treating acetophenone oximes with [Cp*RhCl₂]₂ (1.25 mol%), AgOAc (7.5 mol%) and diazomalonates in methanol at 60 °C for 12 h afforded the corresponding aryl malonates in up to 98% yields. With the oxime substituent as directing group, the ortho-C-H bond was selectively alkylated. Arenes with carboxylic acid, amine and pyridine groups were also alkylated regioselectively at the ortho position. The [Cp*Rh]-catalyzed reactions were found to tolerate many functional groups such as halogens, sulfone and amide. The reaction is probably initiated by electrophilic C-H rhodation to form arylrhodium(III) complexes, followed by coupling reaction with the diazomalonate. With benzo[h]quinoline as substrate, the σ-alkylrhodacycle intermediate has been isolated and structurally characterized by X-ray crystallography. We also explored the intermolecular oxidative coupling of anilides with β-ketoesters for direct arene C-H alkylations. Construction of new C-C bonds directly through coupling of two C-H bonds is an attractive goal in catalysis. In this work, treating N-pivalanilides with Pd(OAc)₂ (10 mol%), Mn(OAc)3·2H₂O (1.5 equiv), trifluoroacetic acid (TFA) and β-ketoesters in toluene at room temperature furnished the ortho-alkylated products in up to 94% yields. With Mn(OAc)3·2H2O as one-electron oxidant, β-ketoesters would be oxidized to generate β-ketoester radicals. To probe the nature of C-H functionalization, the dinuclear Pd cyclometalated complex [Pd(C~O)(μ-OAc)]₂ (C~O = N-acetyl-3-methylaniline) was prepared and reacted with dimethyl malonate in presence of Mn(OAc)3·2H₂O (1.5 equiv) and TFA in toluene at room temperature; the α-aryl malonate was obtained in 44% yield. Thus the principal step of the direct anilide-ketoester coupling reaction should involve carboradical coupling with arylpalladium (II) complexes.
Subjects: Friedel-Crafts reaction.
Hydrocarbons -- Synthesis.
Hong Kong Polytechnic University -- Dissertations
Pages: xxxviii, 548 p. : ill. ; 30 cm.
Appears in Collections:Thesis

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