Please use this identifier to cite or link to this item: http://hdl.handle.net/10397/84475
Title: Exploration of α-diazocarbonyl compounds for transition-metal catalyzed carbon-carbon bond formations : development of palladium-catalyzed stereoselective synthesis of trisubstituted alkenes and the synthesis of quaternary α, α-heterodiaryl carboxylic acids by rhodium -catalyzed multi-component coupling reactions
Authors: Tsoi, Yuk Tai
Degree: Ph.D.
Issue Date: 2012
Abstract: Transition-metal catalyzed decomposition of α-diazo carbonyl compounds are proved to be a versatile approach for carbenoid-mediated carbon-carbon bond formations. It is widely accepted that highly reactive metal-carbenoid complexes are involved to undergo cyclopropanation, C-H insertion and ylide reactions. However, due to the isoelectronic property of carbene with carbon monoxide, migratory insertion of carbene to metal-carbon bond is less established. In this research, we explored the transition-metal carbenoid for cross-coupling reactions involving migratory carbene insertion reactions as a key step. Our approach involves the formation of organometallic complexes, which can be further transformed to metal-carbene complexes. The subsequent migratory carbene insertion would afford a new organometallic complex with a new C-C bond being formed. The reactivity of the new organometallic complexes can be further exploited for C=C bond and C-C bond formations. Our investigation began by studying the stereoselective synthesis of α,β-diarylacrylates, which are common scaffolds in pharmaceutically active compounds. Perkin aldol condensation is conventionally employed for α,β-diarylacrylates synthesis; however, it suffers from limited substrate scope and low product yields. In this work, we developed a stereoselective cross-coupling reaction of benzyl bromides with α-aryldiazoesters to give (E)-α,β-diarylacrylates. Employing Pd₂(dba)₃·CHCl₃ (10 mol% Pd, dba: dibenzylideneacetone) and PPh₃ (40 mol%) as catalyst, the diarylacrylates were obtained in up to 92% yield and >20: 1 E-to-Z selectivity. Pertinent to the mechanism, we examined the stoichiometric reaction of a benzylpalladium(II) complex [BnPd(PPh₃)₂Br, 7a] with methyl phenyldiazoacetate, and (E)-methyl 2,3-diphenylacrylate was formed in 75% yield. Based on this finding, it is plausible that the cross-coupling reaction proceeded by migratory carbene insertion to the benzylpalladium complex, followed by β-hydride elimination to give the acrylate product.
In view of the medicinal value of (E)-α,β-diarylacrylates, our earlier catalytic reaction is limited by the use of reactive halides and required excess PPh₃ for operation. Thus, it is unlikely to be environmentally-sound for sustainable synthesis. In this work, we developed an oxidative cross-coupling reaction for the synthesis of (E)-α,β-diarylacrylates with O₂ as the sole oxidant. Employing Pd(OAc)₂ (5 mol%) and 1,10-phenanthroline (5.5 mol%) as catalyst, diazoesters would react with arylboronic acids (1.2 equiv) to afford (E)-α,β-diarylacrylates in up to 80% yield and >20: 1 E-to-Z selectivity. Other functionalized (E)-α,β-diarylacrylates containing chloro, bromo, trimethylsilyl, nitro, sulfonyl and acetyl have been successfully prepared. In this work, we prepared a phenylpalladium(II) complex [PhPd(1,10-phenanthroline)OAc, 10a], which has been structurally characterized by X-ray crystallography. Reacting [PhPd(1,10-phenanthroline)OAc] with methyl 2-diazo-3-phenylpropanoate produced (E)-methyl 2,3-diphenylacrylate in 72% yield. Therefore, migratory carbene insertion is probably a key step for the cross-coupling reaction. Apart from the C=C bond formation, we also succeeded in constructing a quaternary stereocenter at the carbenic carbon by forming two C-C σ bonds. In this work, we developed a one-pot rhodium-catalyzed three-component coupling reaction for the synthesis of quaternary α,α-heterodiaryl carboxylic esters. Employing [Rh(cod)OH₂ (2 mol% Rh, cod: 1,5-cyclooctadiene) as catalyst and KOtBu as base, α-aryldiazoesters would cross couple with arylboronic acids and alkyl halides to furnish quaternary α,α-heterodiaryl carboxylic esters in up to 88% yield. Various functional groups such as chloro, bromo, trifluoromethyl, trimethylsilyl, diphenylamino and sulfonyl were well tolerated in the coupling reaction. Quaternary α,α-diaryl carbonyl compounds are common scaffolds in pharmaceutical compounds such as methadone (dolophine HCl). α,α-Diaryl carbonyl compounds are commonly prepared by Friedel-Crafts reactions, which suffer from limited substrate scope and poor regioselectivity. The rhodium-catalyzed coupling reaction probably proceeded by the migratory carbene insertion of a rhodium-carbenoid species, followed by transmetallation with KOtBu and enolate alkylations.
Subjects: Transition metal compounds.
Organic compounds -- Synthesis.
Organometallic compounds.
Hong Kong Polytechnic University -- Dissertations
Pages: xxviii, 307 leaves : ill. ; 30 cm.
Appears in Collections:Thesis

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