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Palladium(II)-catalyzed coupling reactions with a chelating vinyl ether and arylboronic acids: a new Heck/Suzuki domino diarylation reaction
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.
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.
2009 (English)In: Chemical Communications, ISSN 1359-7345, E-ISSN 1364-548X, Vol. 48, 7587-7589 p.Article in journal (Refereed) Published
Abstract [en]

A mild and novel palladium(II)-catalyzed domino Heck/Suzuki alpha,beta-diarylation-reduction of a dimethylaminoethyl substituted chelating vinyl ether was developed by using electron-rich arylboronic acids in combination with p-benzoquinone. Based on the preparative results, a catalytic cycle is proposed. Further, highly regioselective palladium(II)-catalyzed alpha- or beta-monoarylation of the chelating vinyl ether was achieved using either a bidentate ligand or by employing ligand-less conditions.

Place, publisher, year, edition, pages
2009. Vol. 48, 7587-7589 p.
National Category
Pharmaceutical Sciences
Research subject
Organic Pharmaceutical Chemistry
Identifiers
URN: urn:nbn:se:uu:diva-124718DOI: 10.1039/b918358bISI: 000272238900039PubMedID: 20024288OAI: oai:DiVA.org:uu-124718DiVA: diva2:317917
Available from: 2010-05-05 Created: 2010-05-05 Last updated: 2017-12-12Bibliographically 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
2. Palladium(II)-Catalyzed Heck Reactions: Domino Reactions, Decarboxylations, Mechanistic Studies & Continuous Flow Applications
Open this publication in new window or tab >>Palladium(II)-Catalyzed Heck Reactions: Domino Reactions, Decarboxylations, Mechanistic Studies & Continuous Flow Applications
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

This thesis describes research efforts dedicated to the development of palladium(II)-catalyzed oxidative Heck and Heck/Suzuki domino reactions, and the applications of a new microwave heating technology, purpose-built for continuous flow in organic synthesis.

Paper I describes the development of a ligand-modulated approach for attaching aryl groups to a chelating vinyl ether. By switching the ligand being used, selectivity for the arylation could be shifted to obtain three different outcomes: internal α- or terminal β-arylation, as well as a serendipitously discovered domino α,β-diarylation process. The latter was proposed to be an effect of para-benzoquinone, effectively acting as a stabilizing π-acidic ligand with the ability to suppress β-hydride elimination.

Paper II explores the performance of a new microwave heating technology in combination with continuous flow. The novel nonresonant microwave applicator allowed rapid heating of common laboratory solvents and reaction mixtures above their boiling points with stable and reproducible temperature profiles. The technology was successfully applied to small-scale method development and subsequent scale-out of palladium-catalyzed reactions, heterocycle synthesis and classical organic transformations such as the Fischer indole synthesis.

Paper III focuses on developing regioselective oxidative decarboxylative Heck reactions with electron-rich olefins. Successful internal α-arylations were achieved using various olefins and ortho-substituted aromatic acids. The mechanism was also studied by ESI-MS analysis. Key cationic organopalladium intermediates were identified, as well as an unexpected palladium(II)-complex which was isolated and characterized. Its experimentally deduced structure was in accordance with the lowest energy minimum found by DFT calculations. Preliminary findings suggested that the complex acts as a catalyst trap.

Paper IV studies the mechanism of the reaction in Paper III by means of DFT calculations. Reductive elimination was identified as the rate-determining step when using a linear enamide as the olefin, due to its propensity to form low energy chelates. Its chelating properties also played a key role in the stability of the isolated palladium(II)-complex. The complex, which can act as a catalyst trap, was characterized by X-ray crystallography.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2015. 78 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 194
Keyword
palladium(II), dft, reaction mechanisms, esi-ms, heck, decarboxylation, microwave, continuous flow
National Category
Organic Chemistry
Identifiers
urn:nbn:se:uu:diva-242259 (URN)978-91-554-9149-9 (ISBN)
Public defence
2015-03-13, B41, Uppsala Biomedical Centre (BMC), Husargatan 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2015-02-19 Created: 2015-01-22 Last updated: 2015-03-11

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Fardost, AshkanLarhed, Mats

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