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Palladium-Catalysed Carbon–Carbon Coupling Reactions: Focusing on Microwave Heating, Low Catalyst Concentrations, Aqueous Conditions, Regioselectivity and Medicinal Chemistry Applications
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
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. , p. 77
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 93
Keywords [en]
Suzuki coupling, Heck reaction, palladium, microwave heating, water, vinyl ethregioselective, HIV-1 integrase inhibitor
National Category
Medicinal Chemistry
Research subject
Pharmaceutical Biochemistry
Identifiers
URN: urn:nbn:se:uu:diva-99776ISBN: 978-91-554-7475-1 (print)OAI: oai:DiVA.org:uu-99776DiVA, id: diva2:209585
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: 2018-01-13Bibliographically approved
List of papers
1. A reassessment of the transition-metal free suzuki-type coupling methodology.
Open this publication in new window or tab >>A reassessment of the transition-metal free suzuki-type coupling methodology.
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2005 (English)In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 70, no 1, p. 161-168Article in journal (Refereed) Published
Abstract [en]

We present here a reassessment of our transition-metal free Suzuki-type coupling protocol. We believe that, although the reaction can be run without the need for addition of a metal catalyst, palladium contaminants down to a level of 50 ppb found in commercially available sodium carbonate are responsible for the generation of the biaryl rather than, as previously suggested, an alternative non-palladium-mediated pathway. We present a revised methodology for Suzuki couplings using ultralow palladium concentrations for use with aryl and vinyl boronic acids and discuss the effects of the purity of the boronic acid on the reaction.

National Category
Natural Sciences
Identifiers
urn:nbn:se:uu:diva-99771 (URN)10.1021/jo048531j (DOI)000226508600019 ()15624918 (PubMedID)
Available from: 2009-03-19 Created: 2009-03-19 Last updated: 2017-12-13Bibliographically approved
2. Microwave-promoted Heck coupling using ultralow metal catalyst concentrations.
Open this publication in new window or tab >>Microwave-promoted Heck coupling using ultralow metal catalyst concentrations.
2005 (English)In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 70, no 5, p. 1786-1790Article in journal (Refereed) Published
Abstract [en]

We show that Heck couplings can be performed in water using microwave heating and Pd catalyst concentrations as low as 500 ppb. The methodology is simple; all that is required as the catalyst is a stock solution of palladium.

National Category
Natural Sciences
Identifiers
urn:nbn:se:uu:diva-99770 (URN)10.1021/jo048052k (DOI)000227246800035 ()15730302 (PubMedID)
Available from: 2009-03-19 Created: 2009-03-19 Last updated: 2017-12-13Bibliographically approved
3. Automated batch scale-up of microwave-promoted Suzuki and Heck coupling reactions in water using ultra-low catalyst concentrations
Open this publication in new window or tab >>Automated batch scale-up of microwave-promoted Suzuki and Heck coupling reactions in water using ultra-low catalyst concentrations
2005 (English)In: Tetrahedron, ISSN 0040-4020, E-ISSN 1464-5416, Vol. 61, no 39, p. 9349-9355Article 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.

National Category
Natural Sciences
Identifiers
urn:nbn:se:uu:diva-99772 (URN)10.1016/j.tet.2005.07.063 (DOI)000231782100017 ()
Available from: 2009-03-19 Created: 2009-03-19 Last updated: 2017-12-13Bibliographically approved
4. Suzuki coupling of aryl chlorides with phenylboronic acid in water, using microwave heating with simultaneous cooling
Open this publication in new window or tab >>Suzuki coupling of aryl chlorides with phenylboronic acid in water, using microwave heating with simultaneous cooling
2005 (English)In: Organic Letters, ISSN 1523-7060, E-ISSN 1523-7052, Vol. 7, no 11, p. 2101-2104Article in journal (Refereed) Published
Abstract [en]

We present here a methodology for the Suzuki coupling of aryl chlorides with phenylboronic acid using Pd/C as a catalyst, water as a solvent, and microwave heating. We show that simultaneous cooling in conjunction with microwave heating prolongs the lifetime of the aryl chloride substrates during the course of the reaction and, as a result, yields of the desired biaryl as well as overall recovery of material can be increased.

National Category
Natural Sciences
Identifiers
urn:nbn:se:uu:diva-99768 (URN)10.1021/ol0503384 (DOI)000229420400006 ()15901144 (PubMedID)
Available from: 2009-03-19 Created: 2009-03-19 Last updated: 2017-12-13Bibliographically approved
5. Highly regioselective internal heck arylation of hydroxyalkyl vinyl ethers by aryl halides in water
Open this publication in new window or tab >>Highly regioselective internal heck arylation of hydroxyalkyl vinyl ethers by aryl halides in water
2007 (English)In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 72, no 17, p. 6390-6396Article 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.

National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-16616 (URN)10.1021/jo0705768 (DOI)000248793400007 ()17658848 (PubMedID)
Available from: 2008-05-29 Created: 2008-05-29 Last updated: 2018-01-12Bibliographically approved
6. Investigations on the 4-quinolone-3-carboxylic acid motif. 1. Synthesis and structure-activity relationship of a class of human immunodeficiency virus type 1 integrase inhibitors
Open this publication in new window or tab >>Investigations on the 4-quinolone-3-carboxylic acid motif. 1. Synthesis and structure-activity relationship of a class of human immunodeficiency virus type 1 integrase inhibitors
Show others...
2008 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 51, no 16, p. 5125-9Article in journal (Refereed) Published
Abstract [en]

A set of 4-quinolone-3-carboxylic acids bearing different substituents on the condensed benzene ring was designed and synthesized as potential HIV-1 integrase inhibitors structurally related to elvitegravir. Some of the new compounds proved to be able to inhibit the strand transfer step of the virus integration process in the micromolar range. Docking studies and quantum mechanics calculations were used to rationalize these data.

National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-99766 (URN)10.1021/jm8003784 (DOI)000258637400032 ()18665580 (PubMedID)
Available from: 2009-03-19 Created: 2009-03-19 Last updated: 2018-01-13Bibliographically approved

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