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Microwave Heated Continuous Flow Palladium(II)-Catalyzed Desulfitative Synthesis of Aryl Ketones
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.ORCID iD: 0000-0002-8014-5757
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. (The Beijer Laboratory for Drug Discovery)
Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
2016 (English)In: Organic Process Research & Development, ISSN 1083-6160, E-ISSN 1520-586X, Vol. 20, no 11, 2005-2011 p.Article in journal (Refereed) Published
Abstract [en]

A protocol for Pd(II)-catalyzed desulfitative synthesis of aryl ketones from sodium aryl sulfinates and nitriles in continuous flow has been developed. The reactions proceed with microwave heating using microwave transparent tube reactors, affording the desired aryl ketones in fair to good yields. Microwave transparent aluminum oxide reactors were identified as a safe and thermostable alternative to borosilicate glass reactors.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2016. Vol. 20, no 11, 2005-2011 p.
Keyword [en]
Heck-Type Reaction, Direct Esi-Ms, Organic-Synthesis, Sulfinic Acids, High-Speed, Chemistry, Arylation, Nitriles, Hydrogenation, Temperature
National Category
Organic Chemistry
Identifiers
URN: urn:nbn:se:uu:diva-304719DOI: 10.1021/acs.oprd.6b00306ISI: 000388430300017OAI: oai:DiVA.org:uu-304719DiVA: diva2:1033684
Available from: 2016-10-08 Created: 2016-10-08 Last updated: 2017-11-30Bibliographically approved
In thesis
1. Palladium(II)-Catalysed Heck and Addition Reactions: Exploring Decarboxylative and Desulfitative Processes
Open this publication in new window or tab >>Palladium(II)-Catalysed Heck and Addition Reactions: Exploring Decarboxylative and Desulfitative Processes
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Palladium complexes have the ability to catalyse cross-coupling of two organic moieties through the formation of transient metal-carbon bonds, thus bringing them closer to each other to facilitate the formation of a new bond. Palladium-catalysed coupling reactions are one of the most important carbon-carbon forming reactions available to organic chemists and many of these reactions rely on the reactivity of aryl-palladium complexes. The investigation of new aryl-palladium precursors is thus of great interest, especially as more sustainable and economic methods can be developed.

This thesis describes the use of carboxylic acids and sodium arylsulfinates as such new arylating agents. Protocols for microwave-assisted palladium(II)-catalysed decarboxylative synthesis of electron-rich styrenes and 1,1-diarylethenes were developed. However, these transformations had very limited substrate scopes which prompted the investigation of sodium arylsulfinates as alternative arylating agents. These substrates were employed in the microwave-assisted palladium(II)-catalysed desulfitative addition to nitriles, and the substrate scope was demonstrated by combining a wide array of sodium arylsulfinates and nitriles to yield the corresponding aryl ketones. The application of the desulfitative reaction in a continuous flow setup was demonstrated, and aluminium oxide was identified as safe alternative to borosilicate glass as a reactor material. The mechanisms of the decarboxylative and desulfitative transformations were investigated by density functional theory (DFT) calculations. The desulfitative reaction was also investigated by direct electrospray ionization mass spectrometry (ESI-MS), providing further mechanistic insight. Finally, a protocol for the safe and convenient synthesis of a wide range of sodium arylsulfinates was developed.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2016. 100 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 221
Keyword
Palladium, catalysis, palladium(II) catalysis, synthesis, Heck, carboxylic acid, sulfinic acid, sodium sulfinate, nitrile, styrene, ketone, aryl ketone, electrospray ionization mass spectrometry, density functional theory, microwave heating, continuous flow
National Category
Organic Chemistry
Research subject
Chemistry with specialization in Organic Chemistry
Identifiers
urn:nbn:se:uu:diva-304746 (URN)978-91-554-9717-0 (ISBN)
Public defence
2016-11-25, B21, BMC, Husargatan 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2016-11-04 Created: 2016-10-10 Last updated: 2016-11-16
2. Palladium(II)-Catalyzed Addition Reactions: Synthesis of Aryl Amidines and Aryl Ketones
Open this publication in new window or tab >>Palladium(II)-Catalyzed Addition Reactions: Synthesis of Aryl Amidines and Aryl Ketones
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Palladium-catalyzed reactions have become one of the most important tools in modern organic chemistry due to its ability to catalyze the formation of new carbon-carbon bonds.

The aim of the work presented in this thesis was to develop new palladium(II)-catalyzed addition reactions. In this work, cyanamides were investigated as a new substrate to give aryl amidines as products. The first protocol developed employed aryltrifluoroborates as the aryl partner, and the insertion of the aryl group into un-, mono-, and di-substituted cyanamides was successful for a wide variety of aryltrifluoroborates. An alternative method of generating the necessary intermediate for insertion into the cyanamide is the decarboxylative formation of aryl-palladium from aryl carboxylic acids. A protocol was developed for this reaction, but was unfortunately limited to a small number of ortho-substituted electron-rich aryl carboxylic acids. The mechanism was investigated by the means of DFT calculations and ESI-MS studies, and the rate-determining step was suggested to be the 1,2-carbopalladation based upon those results. A translation of the batch protocol to continuous-flow conditions was also demonstrated. The ideal method of generating the aryl-palladium species is by C-H bond activation, and this approach was demonstrated with indoles, giving a variety of 3-amidinoindoles as products. The mechanism was investigated by DFT calculations and a plausible catalytic cycle was proposed.

A continuous-flow application of a desulfitative palladium(II)-catalyzed addition to nitriles to give ketones was developed. In addition, different reactor materials were evaluated in the microwave heated reactor cavity. Thus the reaction was shown to proceed with microwave heating in a borosilicate glass and an aluminum oxide reactor, and also in conditions mimicking conventional heating in a silicon carbide reactor.

Finally, a protocol was developed for the convenient synthesis of sodium aryl sulfinates from Grignard and lithium reagents using a solid sulfur dioxide source as a safe alternative to the gas. The products of this protocol can be used as aryl-palladium precursors by a desulfitative process.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2017. 97 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 233
Keyword
Palladium, Catalysis, Palladium(II) catalysis, Synthesis, Addition Reactions, Cyanamide, Amidine, Aryl Amidine, Nitrile, Ketone, Aryl Ketone, Carbopalladation, Continuous-flow, Continuous flow, Microwave heating
National Category
Organic Chemistry
Research subject
Pharmaceutical Science
Identifiers
urn:nbn:se:uu:diva-326816 (URN)978-91-513-0012-2 (ISBN)
Public defence
2017-09-15, B22, BMC, Husargatan 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2017-08-25 Created: 2017-07-31 Last updated: 2017-09-08

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Skillinghaug, BoboRydfjord, JonasSävmarker, JonasLarhed, Mats

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