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New C-C coupling Reactions Enabled by Main-group Organometallics
Stockholm University, Faculty of Science, Department of Organic Chemistry.ORCID iD: 0000-0002-1964-9243
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The carbon-carbon bond has always been at the very core of chemical research. Strategies for the creation of C−C bonds are one of the keys to the construction game that organic chemists play with the building blocks provided by Nature, with the ultimate goal of producing useful molecular structures that will serve society as medicines, materials, imaging tools, catalysts, and ligands (to mention but a few). While very different in their structure, all of these molecules are often prepared by the same methods. However, efficiency could be improved with tailored chemical strategies that would serve an individual purpose. Ideally, these chemical manipulations should be efficient, selective, environmentally friendly and economic, in order to truly fulfill their final objective.

However, despite the ever-expanding rule-book of chemical reactions, target molecules of increasing complexity often face chemists with daunting challenges, whose success rely on multi-step synthetic sequences. There is therefore a permanent need for new, specific methods and strategies that are capable of seamlessly creating C−C bonds, evading the synthesis of difficult or expensive substrates. In this regard, common organometallic reagents display a unique behavior as carbon precursors, in particular as powerful nucleophiles. Reagents based on main-group elements such as lithium or magnesium have therefore played a central role in organic synthesis ever since their discovery. The challenge often lies in controlling their high reactivity, as well as their basic character. Tuning and taming these properties provides chemists with a wide range of unique strategies for the selective synthesis of countless molecular targets.

In the first part of this thesis, a scalable and stereoselective [3+3] homocoupling of imines in which two C−C bonds are formed in a single step is reported. This reaction relies on an unusual combination of visible-light irradiation and aluminum organometallics. This photochemical process enables the circumvention of the native [3+2] reactivity of these readily available starting materials, thus enabling rapid access to densely functionalized piperazines. Thanks to the congested environment they provide, these heterocyclic scaffolds can be used as ligands to prevent catalyst deactivation through oligomerization.

The next chapter presents a novel Pummerer-type redox-neutral coupling of sulfoxides and Grignard reagents. This reaction is enabled by a unique turbo-magnesium amide base, and allows the use of a wide range of carbon nucleophiles in intermolecular Pummerer C−C coupling for the streamlined preparation of thioethers. Given the central character of sulfur in organic chemistry, these compounds can then be converted to a variety of unrelated functional groups for the streamlined preparation of diverse building blocks.

In the final two chapters, the development of a method for the direct conversion of carboxylic acids to ketones with Grignard reagents is described. Using the above-mentioned combination of organometallics, a wide variety of carboxylic acids substrates and Grignard reagents can be coupled in a convenient, scalable and highly selective method that suppresses the need for activation and offers a straightforward approach to ketones from readily available starting materials.

Place, publisher, year, edition, pages
Stockholm: Department of Organic Chemistry, Stockholm University , 2018. , p. 82
Keywords [en]
C-C coupling, organometallics, aluminum, magnesium, Grignard, turbo-Hauser-bases, piperazines, sulfur, ketones
National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
URN: urn:nbn:se:su:diva-160658ISBN: 978-91-7797-418-5 (print)ISBN: 978-91-7797-419-2 (electronic)OAI: oai:DiVA.org:su-160658DiVA, id: diva2:1252372
Public defence
2018-11-16, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 16 B, Stockholm, 10:00 (English)
Opponent
Supervisors
Note

At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 4: Manuscript. Paper 5: Manuscript.

Available from: 2018-10-24 Created: 2018-10-01 Last updated: 2018-10-24Bibliographically approved
List of papers
1. Scalable Synthesis of Piperazines Enabled by Visible-Light Irradiation and Aluminum Organometallics
Open this publication in new window or tab >>Scalable Synthesis of Piperazines Enabled by Visible-Light Irradiation and Aluminum Organometallics
2015 (English)In: Angewandte Chemie International Edition, ISSN 1433-7851, E-ISSN 1521-3773, Vol. 54, no 47, p. 14094-14098Article in journal (Refereed) Published
Abstract [en]

The development of more active C-H oxidation catalysts has inspired a rapid, scalable, and stereoselective assembly of multifunctional piperazines through a [3+3] coupling of azomethine ylides. A combination of visible-light irradiation and aluminum organometallics is essential to promote this transformation, which introduces visible-light photochemistry of main-group organometallics and sets the basis for new and promising catalysts.

Keywords
aluminum, cycloaddition, heterocycles, oxidation, photochemistry
National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-126408 (URN)10.1002/anie.201505608 (DOI)000367722500046 ()26337253 (PubMedID)
Funder
Swedish Research CouncilBerzelii Centre EXSELENT
Available from: 2016-02-08 Created: 2016-02-01 Last updated: 2019-05-27Bibliographically approved
2. Intermolecular Pummerer Coupling with Carbon Nucleophiles in Non-Electrophilic Media
Open this publication in new window or tab >>Intermolecular Pummerer Coupling with Carbon Nucleophiles in Non-Electrophilic Media
2017 (English)In: Angewandte Chemie International Edition, ISSN 1433-7851, E-ISSN 1521-3773, Vol. 56, no 50, p. 16042-16046Article in journal (Refereed) Published
Abstract [en]

A new Pummerer-type C-C coupling protocol is introduced based on turbo-organomagnesium amides, which unlike traditional Pummerer reactions, does not require strong electrophilic activators, engages a broad range of C(sp(3))-, C(sp(2))-, and C(sp)-nucleophiles, and seamlessly integrates with C-H and C-X magnesiation. Given the central character of sulfur compounds in organic chemistry, this protocol allows access to unrelated carbonyls, olefins, organometallics, halides, and boronic esters through a single strategy.

Place, publisher, year, edition, pages
Wiley-VCH Verlagsgesellschaft, 2017
Keywords
C-C coupling, magnesium, main group elements, Pummerer reaction, sulfur
National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-150977 (URN)10.1002/anie.201709715 (DOI)000417200600045 ()29053208 (PubMedID)
Funder
Knut and Alice Wallenberg FoundationSwedish Research CouncilVINNOVA
Available from: 2018-01-12 Created: 2018-01-12 Last updated: 2018-12-05Bibliographically approved
3. Iterative Synthesis of Pluripotent Thioethers through Controlled Redox Fluctuation of Sulfur
Open this publication in new window or tab >>Iterative Synthesis of Pluripotent Thioethers through Controlled Redox Fluctuation of Sulfur
2018 (English)In: Synlett: Accounts and Rapid Communications in Synthetic Organic Chemistry, ISSN 0936-5214, E-ISSN 1437-2096, Vol. 29, no 10, p. 1329-1333Article in journal (Refereed) Published
Abstract [en]

Target- and diversity-oriented syntheses are based on diverse building blocks, whose preparation requires discrete design and constructive alignment of different chemistries. To enable future automation of the synthesis of small molecules, we have devised a unified strategy that serves the divergent synthesis of unrelated scaffolds such as carbonyls, olefins, organometallics, halides, and boronic esters. It is based on iterations of a nonelectrophilic Pummerer-type C-C coupling enabled by turbo -organomagnesium amides that we have recently reported. The pluripotency of sulfur allows the central building blocks to be obtained by regulating C-C bond formation through control of its redox state.

Keywords
sulfur, Pummerer coupling, iterative synthesis, Grignard reagents
National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-157695 (URN)10.1055/s-0036-1591864 (DOI)000433554100012 ()
Available from: 2018-07-31 Created: 2018-07-31 Last updated: 2018-10-01Bibliographically approved
4. Synthesis of Ketones from Carboxylic Acids Using Grignard Reagents and turbo-Hauser Bases
Open this publication in new window or tab >>Synthesis of Ketones from Carboxylic Acids Using Grignard Reagents and turbo-Hauser Bases
(English)Manuscript (preprint) (Other academic)
National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-160652 (URN)
Available from: 2018-10-01 Created: 2018-10-01 Last updated: 2018-10-01Bibliographically approved
5. One-pot Synthesis of Ketones from Aliphatic Carboxylic Acids Using Grignard Reagents and an in situ generated turbo-Hauser Base
Open this publication in new window or tab >>One-pot Synthesis of Ketones from Aliphatic Carboxylic Acids Using Grignard Reagents and an in situ generated turbo-Hauser Base
(English)Manuscript (preprint) (Other academic)
National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-160656 (URN)
Available from: 2018-10-01 Created: 2018-10-01 Last updated: 2018-10-01Bibliographically approved

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