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Palladium(II)-Catalyzed Heck Reactions: Domino Reactions, Decarboxylations, Mechanistic Studies & Continuous Flow Applications
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

This thesis describes research efforts dedicated to the development of palladium(II)-catalyzed oxidative Heck and Heck/Suzuki domino reactions, and the applications of a new microwave heating technology, purpose-built for continuous flow in organic synthesis.

Paper I describes the development of a ligand-modulated approach for attaching aryl groups to a chelating vinyl ether. By switching the ligand being used, selectivity for the arylation could be shifted to obtain three different outcomes: internal α- or terminal β-arylation, as well as a serendipitously discovered domino α,β-diarylation process. The latter was proposed to be an effect of para-benzoquinone, effectively acting as a stabilizing π-acidic ligand with the ability to suppress β-hydride elimination.

Paper II explores the performance of a new microwave heating technology in combination with continuous flow. The novel nonresonant microwave applicator allowed rapid heating of common laboratory solvents and reaction mixtures above their boiling points with stable and reproducible temperature profiles. The technology was successfully applied to small-scale method development and subsequent scale-out of palladium-catalyzed reactions, heterocycle synthesis and classical organic transformations such as the Fischer indole synthesis.

Paper III focuses on developing regioselective oxidative decarboxylative Heck reactions with electron-rich olefins. Successful internal α-arylations were achieved using various olefins and ortho-substituted aromatic acids. The mechanism was also studied by ESI-MS analysis. Key cationic organopalladium intermediates were identified, as well as an unexpected palladium(II)-complex which was isolated and characterized. Its experimentally deduced structure was in accordance with the lowest energy minimum found by DFT calculations. Preliminary findings suggested that the complex acts as a catalyst trap.

Paper IV studies the mechanism of the reaction in Paper III by means of DFT calculations. Reductive elimination was identified as the rate-determining step when using a linear enamide as the olefin, due to its propensity to form low energy chelates. Its chelating properties also played a key role in the stability of the isolated palladium(II)-complex. The complex, which can act as a catalyst trap, was characterized by X-ray crystallography.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2015. , 78 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 194
Keyword [en]
palladium(II), dft, reaction mechanisms, esi-ms, heck, decarboxylation, microwave, continuous flow
National Category
Organic Chemistry
Identifiers
URN: urn:nbn:se:uu:diva-242259ISBN: 978-91-554-9149-9 (print)OAI: oai:DiVA.org:uu-242259DiVA: diva2:782904
Public defence
2015-03-13, B41, Uppsala Biomedical Centre (BMC), Husargatan 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2015-02-19 Created: 2015-01-22 Last updated: 2015-03-11
List of papers
1. Palladium(II)-catalyzed coupling reactions with a chelating vinyl ether and arylboronic acids: a new Heck/Suzuki domino diarylation reaction
Open this publication in new window or tab >>Palladium(II)-catalyzed coupling reactions with a chelating vinyl ether and arylboronic acids: a new Heck/Suzuki domino diarylation reaction
2009 (English)In: Chemical Communications, ISSN 1359-7345, E-ISSN 1364-548X, Vol. 48, 7587-7589 p.Article in journal (Refereed) Published
Abstract [en]

A mild and novel palladium(II)-catalyzed domino Heck/Suzuki alpha,beta-diarylation-reduction of a dimethylaminoethyl substituted chelating vinyl ether was developed by using electron-rich arylboronic acids in combination with p-benzoquinone. Based on the preparative results, a catalytic cycle is proposed. Further, highly regioselective palladium(II)-catalyzed alpha- or beta-monoarylation of the chelating vinyl ether was achieved using either a bidentate ligand or by employing ligand-less conditions.

National Category
Pharmaceutical Sciences
Research subject
Organic Pharmaceutical Chemistry
Identifiers
urn:nbn:se:uu:diva-124718 (URN)10.1039/b918358b (DOI)000272238900039 ()20024288 (PubMedID)
Available from: 2010-05-05 Created: 2010-05-05 Last updated: 2017-12-12Bibliographically approved
2. Evaluation of a Nonresonant Microwave Applicator for Continuous-Flow Chemistry Applications
Open this publication in new window or tab >>Evaluation of a Nonresonant Microwave Applicator for Continuous-Flow Chemistry Applications
Show others...
2012 (English)In: Organic Process Research & Development, ISSN 1083-6160, E-ISSN 1520-586X, Vol. 16, no 5, 1053-1063 p.Article in journal (Refereed) Published
Abstract [en]

The concept of a nonresonant microwave applicator for continuous-flow organic chemistry is introduced and evaluated. The frequency of the incident microwave radiation can be adjusted between 2.4 and 2.5 GHz to optimize the energy absorbance. The temperature of the reaction is monitored by five IR sensors, and their signals can be used to automatically adjust the power output from the microwave generator. The heating of several different solvents up to 20 degrees C above the standard boiling point has been explored. Several different organic reactions have been successfully carried out using a 200 mm X (sic) 3 mm tubular borosilicate reactor and a flow between 47 and 2120 mu L/min. The microwave heating pattern was visualized with an IR camera. The transformations include palladium-catalyzed coupling reactions (oxidative Heck and Suzuki reactions), heterocyclic chemistry (oxathiazolone and Fischer indole synthesis), rearrangement (Claisen), and a Diels-Alder cycloaddition reaction. A scale-out to 57 mmol/h was performed with the Fischer indole reaction.

Keyword
non-resonant, microwave, Continuous-Flow, MAOS, CF-MAOS
National Category
Medicinal Chemistry Organic Chemistry
Research subject
Medicinal Chemistry
Identifiers
urn:nbn:se:uu:diva-160187 (URN)10.1021/op300003b (DOI)000304129100036 ()
Available from: 2011-10-17 Created: 2011-10-17 Last updated: 2017-12-08Bibliographically approved
3. Palladium(II)-Catalyzed Decarboxylative Heck Arylations of Acyclic Electron-Rich Olefins with Internal Selectivity
Open this publication in new window or tab >>Palladium(II)-Catalyzed Decarboxylative Heck Arylations of Acyclic Electron-Rich Olefins with Internal Selectivity
2014 (English)In: Advanced Synthesis and Catalysis, ISSN 1615-4150, E-ISSN 1615-4169, Vol. 356, no 4, 870-878 p.Article in journal (Refereed) Published
Abstract [en]

Despite the recent emergence of decarboxylative CC bond forming reactions, methodologies providing internally arylated electron-rich olefins are still lacking. We herein report on palladium(II)-catalyzed decarboxylative Heck arylations of linear electron-rich olefins with excellent selectivity for the internal position. The method allows a variety of electron-rich linear olefins to undergo arylation with ortho-functionalized aromatic carboxylic acids, including heterocycles. The reaction mechanism has been explored with ESI-MS studies to confirm previous findings, and to reveal the formation of a highly stable palladium complex as a result of the Heck product reacting with the catalyst.

National Category
Nano Technology
Research subject
Engineering Science with specialization in Nanotechnology and Functional Materials
Identifiers
urn:nbn:se:uu:diva-234902 (URN)10.1002/adsc.201301004 (DOI)000332929000028 ()
Funder
Swedish Research CouncilKnut and Alice Wallenberg Foundation
Available from: 2014-10-25 Created: 2014-10-25 Last updated: 2017-12-05Bibliographically approved
4. Theoretical Mechanistic Investigation of a Decarboxylative Heck Reaction with an Electron-Rich Olefin and Possible Catalyst Entrapment by the Heck Product
Open this publication in new window or tab >>Theoretical Mechanistic Investigation of a Decarboxylative Heck Reaction with an Electron-Rich Olefin and Possible Catalyst Entrapment by the Heck Product
(English)Manuscript (preprint) (Other academic)
Keyword
palladium(II), dft, reaction mechanisms, heck, decarboxylation
National Category
Chemical Sciences
Identifiers
urn:nbn:se:uu:diva-242258 (URN)
Available from: 2015-01-22 Created: 2015-01-22 Last updated: 2015-03-11

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