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Transmetallation Versus β-Hydride Elimination: The Role of 1,4 Benzoquinone in Chelation-Controlled Arylation Reactions with Arylboronic Acids
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
Department of Chemistry, University of Gothenburg.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
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2012 (English)In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 18, no 15, 4714-4722 p.Article in journal (Refereed) Published
Abstract [en]

The formation of an atypical, saturated, diarylated, Heck/Suzuki, domino product produced under oxidative Heck reaction conditions, employing arylboronic acids and a chelating vinyl ether, has been investigated by DFT calculations. The calculations highlight the crucial role of 1,4-benzoquinone (BQ) in the reaction. In addition to its role as an oxidant of palladium, which is necessary to complete the catalytic cycle, this electron-deficient alkene opens up a low-energy reaction pathway from the post-insertion sigma-alkyl complex. The association of BQ lowers the free-energy barrier for transmetallation of the s-alkyl complex to create a pathway that is energetically lower than the oxidative Heck reaction pathway. Furthermore, the calculations showed that the reaction is made viable by BQ-mediated reductive elimination and leads to the saturated diarylated product.

Place, publisher, year, edition, pages
Wiley-VCH Verlagsgesellschaft, 2012. Vol. 18, no 15, 4714-4722 p.
National Category
Organic Chemistry Theoretical Chemistry
Research subject
Chemistry
Identifiers
URN: urn:nbn:se:uu:diva-172740DOI: 10.1002/chem.201102678ISI: 000302162500033OAI: oai:DiVA.org:uu-172740DiVA: diva2:515479
Available from: 2012-04-13 Created: 2012-04-13 Last updated: 2017-12-07Bibliographically approved
In thesis
1. Palladium-Catalysed Couplings in Organic Synthesis: Exploring Catalyst-Presenting Strategies and Medicinal Chemistry Applications
Open this publication in new window or tab >>Palladium-Catalysed Couplings in Organic Synthesis: Exploring Catalyst-Presenting Strategies and Medicinal Chemistry Applications
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Palladium-catalysed coupling reactions have been embraced by synthetic chemists as one of the preferred means for smooth formation of new carbon-carbon bonds: a truly ubiquitous methodology of synthesizing complex molecules.

This thesis describes the study of a series of palladium(0)-catalysed C2-arylations of a 1-cyclopentenyl ether, equipped with a chiral (S)-N-methyl-pyrrolidine auxiliary. The investigated olefin was demonstrated to undergo Si-face insertion, providing (R)-configuration of the arylated C2-carbon.

In addition, the mild and novel palladium(II)-catalysed dominoHeck/Suzuki β,α-diarylation-reduction of a dimethylaminoethyl-substituted chelating vinyl ether was developed using arylboronic acids as arylating agents in combination with 1,4-benzoquinone (BQ). Further, highly regioselective palladium(II)-catalysed α-and β-monoarylation of the chelating vinyl ether was achieved using either a bidentate ligand or by employing ligand-less conditions. These studies demonstrate that the choice of ligands has a profound effect on the reaction outcome, as productive β,α-diarylation could only be obtained by suppressing the competing β-hydride elimination using BQ as the stabilising ligand and terminal reoxidant.

The pivotal role of BQ in the reaction was studied using computer-aided density functional theory calculations. The calculations highlight the crucial role of BQ as a Pd(II)-ligand. In addition of serving as an oxidant of palladium, the calculations support the view that the coordination of BQ to the Pd(II)-centre in the key σ-alkyl complex leads to a low-energy pathway, aided by a strong η2 Pd-BQ donation-back-donation interaction.

Furthermore, an investigation of the scope and limitations of novel stereoselective and BQ-mediated palladium(II)-catalysed domino Heck/Suzuki β,α-diarylation reactions, involving metal coordinating cyclic methylamino vinyl ethers and a number of electronically diverse arylboronic acids, conducted.

In addition, a set of 4-quinolone-3-carboxylic acids, structurally related to elvitegravir and bearing different substituents on the condensed benzene ring, was designed and synthesized as potential HIV-1 integrase inhibitors.

Finally, in an effort to identify a new class of HIV-1 protease inhibitors, four different stereopure β-hydroxy γ-lactam-containing inhibitors were synthesized, biologically evaluated, and co-crystallized with the enzyme.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2012. 90 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 162
Keyword
Mizoroki-Heck arylation, Suzuki coupling, domino reaction, stereoselective, palladium, chelation control, vinyl ether, HIV-protease inhibitors, HIV-integrase inhibitors
National Category
Organic Chemistry
Research subject
Chemistry with specialization in Organic Chemistry
Identifiers
urn:nbn:se:uu:diva-173068 (URN)978-91-554-8370-8 (ISBN)
Public defence
2012-06-08, B42, Uppsala Biomedical Centre (BMC), Husargatan 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Note
The time 12:05 for the public defense mentioned in the thesis is incorrect. It will take place at 09:15, 2012-06-08.Available from: 2012-05-16 Created: 2012-04-18 Last updated: 2012-08-01Bibliographically approved

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