uu.seUppsala University Publications
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Highly regioselective internal heck arylation of hydroxyalkyl vinyl ethers by aryl halides in water
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
Università degli Studi di Siena, Dipartimento Farmaco Chimico Tecnologico.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
2007 (English)In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 72, no 17, 6390-6396 p.Article in journal (Refereed) Published
Abstract [en]

Highly regioselective and fast Pd(0)-catalyzed internal α-arylation of ethylene glycol vinyl ether with aryl halides was shown to be possible in water without the need for any halide scavengers or ionic liquid additives. This presents, to our knowledge, the first case of water being utilized in the selective arylation of electron-rich olefins. Resulting α-products were hydrolyzed and isolated as corresponding acetophenones in good to excellent yields when using aryl bromides and with good to moderate yields in the case of aryl iodides. Microwave irradiation was shown to be beneficial in activation of aryl chlorides toward the internal Heck arylation. The scope of the protocol was further increased to include different hydroxyalkyl vinyl ethers, these all giving selectively only branched α-products. Finally, the active role of the hydroxy group in directing the regioselectivity toward internal arylation of electron-rich olefins, even in nonpolar toluene, was revealed.

Place, publisher, year, edition, pages
2007. Vol. 72, no 17, 6390-6396 p.
National Category
Pharmaceutical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-16616DOI: 10.1021/jo0705768ISI: 000248793400007PubMedID: 17658848OAI: oai:DiVA.org:uu-16616DiVA: diva2:44387
Available from: 2008-05-29 Created: 2008-05-29 Last updated: 2017-12-08Bibliographically approved
In thesis
1. Palladium-Catalysed Carbon–Carbon Coupling Reactions: Focusing on Microwave Heating, Low Catalyst Concentrations, Aqueous Conditions, Regioselectivity and Medicinal Chemistry Applications
Open this publication in new window or tab >>Palladium-Catalysed Carbon–Carbon Coupling Reactions: Focusing on Microwave Heating, Low Catalyst Concentrations, Aqueous Conditions, Regioselectivity and Medicinal Chemistry Applications
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

It is widely accepted that palladium is one of the most useful catalysts in organic chemistry, and many palladium(0)-catalysed carbon–carbon bond-forming reactions have been developed over the years. In addition, the ever-growing need for more environmentally benign processes in the chemical industry has driven scientists to look for greener options while developing new methodologies for organic synthesis. This thesis describes a series of studies on Suzuki and Heck coupling reactions in water and the application of palladium(0) catalysis to the development of new HIV-1 integrase inhibitors.

The previously described 'transition-metal-free Suzuki-type coupling' reaction was shown to take place due to sub-ppm levels of palladium contaminants present in the commercially available sodium carbonate base. Based on this finding, a new, microwave-assisted Suzuki protocol utilizing ppb/ppm levels of palladium in water was developed. This methodology was adapted to terminal Heck coupling, although the scope of the protocol was found to be rather limited. Finally, both Suzuki and Heck reaction processes were successfully scaled up to 100 mmol using an automated batch stop-flow microwave apparatus.

As the methodologies utilizing ultralow palladium concentrations were not applicable to aryl chlorides, attention was shifted towards palladium on carbon. This simple catalyst, together with microwave heating employing simultaneous cooling, was found to be beneficial in the Suzuki coupling of aryl chlorides with phenylboronic acid in water.

Ligand-controlled internal arylation of ethylene glycol vinyl ether with aryl halides was shown to be possible in water alone without any additives. Reactions were run under air, using conventional heating and the products formed were isolated as aryl methyl ketones in good to excellent yields. The electron-rich (dippp)2Pd complex was shown to be beneficial for the microwave-assisted internal arylation of some aryl chlorides. Furthermore, the active role of the hydroxyl group of ethylene glycol vinyl ether in the formation of a cationic intermediate leading to internal Heck coupling product was elucidated.

Finally, to demonstrate the usefulness of palladium(0) catalysis in the development of new pharmaceutical entities, a series of HIV-1 integrase inhibitors was synthesised and evaluated in strand transfer assays and in vitro. Based on the results and docking studies performed, valuable information related to the structure–activity relationship was obtained.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2009. 77 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 93
Keyword
Suzuki coupling, Heck reaction, palladium, microwave heating, water, vinyl ethregioselective, HIV-1 integrase inhibitor
National Category
Medicinal Chemistry
Research subject
Pharmaceutical Biochemistry
Identifiers
urn:nbn:se:uu:diva-99776 (URN)978-91-554-7475-1 (ISBN)
Public defence
2009-05-08, B22, BMC, Husargatan 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2009-04-16 Created: 2009-03-19 Last updated: 2009-04-16Bibliographically approved

Open Access in DiVA

No full text

Other links

Publisher's full textPubMed

Authority records BETA

Larhed, Mats

Search in DiVA

By author/editor
Larhed, Mats
By organisation
Department of Medicinal Chemistry
In the same journal
Journal of Organic Chemistry
Pharmaceutical Sciences

Search outside of DiVA

GoogleGoogle Scholar

doi
pubmed
urn-nbn

Altmetric score

doi
pubmed
urn-nbn
Total: 385 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf