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Palladium(II)-Catalyzed Coupling Reactions
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Sustainable chemical processes are becoming increasingly important in all fields of synthetic chemistry. Catalysis can play an important role in developing environmentally benign chemical processes, and transition metals have an important role to play in the area of green chemistry. In particular, palladium(II) catalysis includes many key features for successful green chemistry methods, as demonstrated by a number of eco-friendly oxidation reactions catalyzed by palladium(II).

The aim of the work presented in this thesis was to develop novel and greener palladium(II)-catalyzed coupling reactions. In striving to achieve this aim, the first open-vessel, room-temperature palladium(II)-catalyzed oxidative Heck reaction, using oxygen from the air as the reoxidant of palladium, was developed.

In a further investigation of the palladium(II)-catalyzed oxidative Heck reaction, base-free conditions for the transformation were identified and suitable conditions for microwave-assisted oxidative Heck reactions were established.

A convenient and low-cost palladium(II)-catalyzed method for the synthesis of styrene derivatives, by coupling arylboranes with vinyl acetate, was developed. The reaction mechanism was studied using ESI-MS, which enabled the detection of cationic palladium intermediates in ongoing productive reactions, and a plausible catalytic cycle was proposed.

In an attempt to make the oxidative Heck and the styrene synthesis reactions more attractive from an industrial point of view, conditions for continuous flow synthesis were identified. The results were generally good and rapid synthesis of the desired products was obtained.

The first palladium(II)-catalyzed C–P bond-forming Hirao-type reaction, employing arylboranes instead of the commonly used aryl halides, was developed. An ESI-MS study was performed, and a plausible catalytic pathway was suggested.

Finally, a novel method for synthesizing aryl ketones from benzoic acids and nitriles, via palladium(II)-catalyzed decarboxylation of the benzoic acids, was established. Further, the reaction mechanism was studied by ESI-MS and a plausible catalytic route presented.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 2010. , p. 87
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 127
Keywords [en]
Palladium(II), oxidative Heck reactions, Microwaves, Styrenes, Aryl ketones, Continuous flow, ESI-MS
National Category
Medicinal Chemistry
Research subject
Medicinal Chemistry
Identifiers
URN: urn:nbn:se:uu:diva-130031ISBN: 978-91-554-7879-7 (print)OAI: oai:DiVA.org:uu-130031DiVA, id: diva2:346722
Public defence
2010-10-15, B7:101, Biomedical Centre (BMC), Husargatan 3, Uppsala, 13:15 (English)
Opponent
Supervisors
Available from: 2010-09-24 Created: 2010-08-27 Last updated: 2018-01-12
List of papers
1. Open-air oxidative Heck reactions at room temperature
Open this publication in new window or tab >>Open-air oxidative Heck reactions at room temperature
2006 (English)In: Green Chemistry, ISSN 1463-9262, E-ISSN 1463-9270, Vol. 8, no 4, p. 338-343Article in journal (Refereed) Published
Abstract [en]

Palladium(II)-catalyzed oxidative Heck arylation reactions proceed at room temperature with atmospheric air as the sole reoxidant. Using arylboronic acids as arylating agents and inexpensive 2,9-dimethyl-1,10-phenanthroline as the supporting ligand, efficient vinylic substitution reactions were obtained both with electron-poor and electron-rich olefins on a 1–50 mmol scale.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-94792 (URN)10.1039/B517152K (DOI)
Available from: 2006-09-14 Created: 2006-09-14 Last updated: 2017-12-14Bibliographically approved
2. Efficient palladium(II) catalysis under air. Base-free oxidative heck reactions at room temperature or with microwave heating
Open this publication in new window or tab >>Efficient palladium(II) catalysis under air. Base-free oxidative heck reactions at room temperature or with microwave heating
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2007 (English)In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 72, no 21, p. 7957-7962Article in journal (Refereed) Published
Abstract [en]

Scope and limitations of the base-free oxidative Heck reaction with arylboronic acids have been explored. Under our conditions, the dmphen−palladium(II)-catalyzed arylation proceeded with air or p-benzoquinone as reoxidants of palladium(0). We found that ambient temperature and mild aerobic conditions allow for the use of substrates sensitive to palladium(II)-catalyzed oxidation. Oxidative Heck couplings, employing different arylboronic acids, were smoothly and regioselectively conducted with both electron-rich and electron-poor olefins, providing high yields even with disubstituted butyl methacrylate, sensitive acrolein, and a vinylboronate ester. Controlled microwave processing was used to reduce reaction times from hours to minutes both in small scale and in 50 mmol scale batch processes.

Keywords
Acrylates/*chemistry, Aerobiosis, Benzene Derivatives/*chemistry, Boronic Acids/*chemistry, Catalysis, Chemistry; Organic/*methods, Heat, Microwaves, Oxidation-Reduction, Palladium/*chemistry, Temperature
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-16615 (URN)10.1021/jo701434s (DOI)000249986500019 ()17887706 (PubMedID)
Available from: 2008-05-29 Created: 2008-05-29 Last updated: 2018-01-12Bibliographically approved
3. Synthesis of styrenes by palladium(II)-catalyzed vinylation of arylboronic acids and aryltrifluoroborates by using vinyl acetate
Open this publication in new window or tab >>Synthesis of styrenes by palladium(II)-catalyzed vinylation of arylboronic acids and aryltrifluoroborates by using vinyl acetate
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2009 (English)In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 15, no 18, p. 4630-4636Article in journal (Refereed) Published
Abstract [en]

Reactions of aromatic and heteroaromatic boronic acids or aryltrifluoroborate salts with vinyl acetate in the presence of a palladium(II) catalyst give the corresponding styrenes in good yields. This Heck reaction proceeds with microwave heating in less than 30 min at 140 degrees C in the absence of base and tolerates a variety of substituents. No palladium reoxidant is needed and the vinylation is performed under non-inert conditions. Mass spectrometry (electrospray ionization mass spectrometry (ESIMS) and tandem mass spectrometry   (MS/MS)) was used to identify cationic palladium-containing complexes in ongoing reactions. The key intermediates that have been detected, together with experiments that used deuterated vinyl acetate, support the existence of catalytically active palladium hydride species, and that it is the arylation of ethylene, not vinyl acetate, which   generates the styrene product. The mechanism of the reaction is discussed in terms of the palladium(II) intermediates mentioned above.

Keywords
Heck reaction, mass spectrometry, mechanistic studies, palladium, styrene
National Category
Chemical Sciences
Identifiers
urn:nbn:se:uu:diva-102918 (URN)10.1002/chem.200802744 (DOI)000265955200018 ()19274694 (PubMedID)
Available from: 2009-05-13 Created: 2009-05-12 Last updated: 2017-12-13Bibliographically approved
4. Continuous Flow Palladium(II): Catalyzed Oxidative Heck Reactions with Arylboronic Acids
Open this publication in new window or tab >>Continuous Flow Palladium(II): Catalyzed Oxidative Heck Reactions with Arylboronic Acids
2010 (English)In: European Journal of Organic Chemistry, ISSN 1434-193X, E-ISSN 1099-0690, no 12, p. 2270-2274Article in journal (Refereed) Published
Abstract [en]

Palladium(II)-catalyzed oxidative Heck reactions were investigated under continuous flow conditions. Selective, fast and convenient protocols for the coupling of arylboronic acids with electron-rich and electron-poor olefins were developed by using a commercially available flow reactor.

Keywords
Continuous flow, cross-coupling, Boron, Palladium, homogeneous catalysis, organic-synthesis, base-free, coupling reactions, room-temperature, bond formation, efficient, catalysis, palladium, air, perspective
National Category
Chemical Sciences
Identifiers
urn:nbn:se:uu:diva-130028 (URN)10.1002/ejoc.201000063 (DOI)000277332500004 ()
Available from: 2010-08-27 Created: 2010-08-27 Last updated: 2017-12-12Bibliographically approved
5. Microwave-promoted palladium(II)-catalyzed C-P bond formation by using arylboronic acids or aryltrifluoroborates.
Open this publication in new window or tab >>Microwave-promoted palladium(II)-catalyzed C-P bond formation by using arylboronic acids or aryltrifluoroborates.
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2009 (English)In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 15, no 47, p. 13069-13074Article in journal (Refereed) Published
Abstract [en]

The first Pd-II-catalyzed P arylation has been performed by using palladium acetate, the rigid bidentate ligand dmphen (dmphen=2,9-dimethyl-1,10-phenanthroline), and without the addition of base or acid. Couplings of arylboronic acids or aryl trifluoroborates with H-phosphonate dialkyl esters were conducted in 30 min with controlled microwave (MW) heating under non-inert conditions. Aryl phosphites were also synthesized at room temperature with atmospheric air as the sole reoxidant. The arylated phosphonates were isolated in 44-90% yields. The excellent chemoselectivity of the method was illustrated in the synthesis of a Mycobacterium tuberculosis glutamine synthetase (MTB-GS) inhibitor. Online ESIMS was used to detect cationic palladium species in ongoing reactions directly, and a catalytic cycle has been proposed based on these results.

Place, publisher, year, edition, pages
Weinheim: Wiley-VCH Verlag GmbH, 2009
Keywords
Boronic acids, microwave chemistry, palladium, P arylation, trifluoroborates
National Category
Analytical Chemistry
Research subject
Analytical Chemistry
Identifiers
urn:nbn:se:uu:diva-113919 (URN)10.1002/chem.200901473 (DOI)000273697100021 ()19856344 (PubMedID)
Available from: 2010-02-04 Created: 2010-02-04 Last updated: 2017-12-12Bibliographically approved
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