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Automated batch scale-up of microwave-promoted Suzuki and Heck coupling reactions in water using ultra-low catalyst concentrations
University of Connecticut, Department of Chemistry.
University of Connecticut, Department of Chemistry.
CEM Microwave Technology.
2005 (English)In: Tetrahedron, ISSN 0040-4020, E-ISSN 1464-5416, Vol. 61, no 39, 9349-9355 p.Article in journal (Refereed) Published
Abstract [en]

Representative Suzuki and Heck couplings in water using ultra-low catalyst concentrations have been scaled-up using an automated batch stop-flow microwave apparatus. Our scale-up methodology shows proof of concept and is easy, fast and cheap to run.

Place, publisher, year, edition, pages
2005. Vol. 61, no 39, 9349-9355 p.
National Category
Natural Sciences
Identifiers
URN: urn:nbn:se:uu:diva-99772DOI: 10.1016/j.tet.2005.07.063ISI: 000231782100017OAI: oai:DiVA.org:uu-99772DiVA: diva2:208727
Available from: 2009-03-19 Created: 2009-03-19 Last updated: 2017-12-13Bibliographically 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

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