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Catalytic Methods to Convert Allylic Substrates through Hydride and Proton Shifts: Transition Metal-Catalyzed and Organocatalyzed Approaches
Stockholm University, Faculty of Science, Department of Organic Chemistry.ORCID iD: 0000-0001-9774-0731
2019 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The present thesis describes the development of new catalytic protocols to transform allylic substrates into a wide variety of versatile carbonyl and vinyl organic compounds. All procedures that are described in this work have in common the existence of one or more hydrogen shifts as key steps in the mechanism of the reactions. The thesis is divided into two mayor sections depending on the strategy employed, metal catalysis or organocatalysis. 

The introductory chapter (Chapter 1) starts with an overview of the different types of catalysis and the importance of allylic substrates in organic chemistry. The chapter continues with an extensive description of the isomerization of allylic alcohols and finishes with a short introduction about hypervalent iodine chemistry. The goals of the thesis are also depicted at the end of this chapter.

Chapters 2, 3 and 4 embody the use of iridium catalysis as an effective tool to synthesize α-functionalized carbonyl compounds selectively as single constitutional isomers from allylic alcohols. The first two chapters of this section describe the employment of several electrophiles to trap enolate derivatives formed from the corresponding allylic alcohols. Chapter 2 shows the development of two new protocols for the preparation of challenging α-iodinated carbonyl compounds. In chapter 3, the synthesis of α-aminooxy and α-hydroxyketones is investigated by employing an N-oxoammonium salt as electrophilic agent. Chapter 4 describes the development of an umpolung strategy that allows the synthesis of α-functionalized carbonyls through the reaction of two formal nucleophiles: enolate derivatives and alcohols. Mechanistic investigations performed in this section point to the presence of an iridium-catalyzed hydride shift operating in the reaction pathways.

The last three chapters (5, 6 and 7) describe the development of metal-free methods for the conversion of allylic substrates into valuable products by means of base catalysis. Chapter 5 and 6 depict the stereospecific isomerization of a large scope of allylic alcohols, ethers and halides. A simple guanidine-type base, TBD (1,5,7-triazabicyclo[4.4.0]dec-5-ene), is an effective catalyst to isomerize allylic substrates with excellent levels of transfer of chirality. The mechanism of this transformation is studied in detail experimentally and computationally and it is suggested to involve a [1,3]-proton shift through the formation of a tight ion-pair. Chapter 7 shows that base-catalysis allows the isomerization of conjugated polyenyl alcohols and ethers which has been proved to be challenging with metal–catalysis. Experimental and computational investigations in this last chapter suggests that the mechanism may proceed through a series of iterative [1,3]-proton shifts or “base-walk”. 

Place, publisher, year, edition, pages
Stockholm: Department of Organic Chemistry, Stockholm University , 2019. , p. 94
Keywords [en]
Allylic substrates, Iridium catalysis, Base catalysis, Method development, Isomerization, Hydride shift, Proton shift, Mechanistic studies
National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
URN: urn:nbn:se:su:diva-175359ISBN: 978-91-7797-903-6 (print)ISBN: 978-91-7797-904-3 (electronic)OAI: oai:DiVA.org:su-175359DiVA, id: diva2:1363047
Public defence
2019-12-06, 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 6: Manuscript.

Available from: 2019-11-13 Created: 2019-10-22 Last updated: 2019-11-11Bibliographically approved
List of papers
1. 2,2-Diiododimedone: a mild electrophilic iodinating agent for the selective synthesis of alpha-iodoketones from allylic alcohols
Open this publication in new window or tab >>2,2-Diiododimedone: a mild electrophilic iodinating agent for the selective synthesis of alpha-iodoketones from allylic alcohols
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2017 (English)In: Chemical Communications, ISSN 1359-7345, E-ISSN 1364-548X, Vol. 53, no 71, p. 9842-9845Article in journal (Refereed) Published
Abstract [en]

2,2-Diiodo-5,5-dimethylcyclohexane-1,3-dione is reported as a new electrophilic iodinating agent that selectively iodinates electron-rich aromatics. In contrast to other common electrophilic iodinating reagents, its mild nature allows it to be used for the selective synthesis of alpha-iodinated carbonyl compounds from allylic alcohols through a 1,3-hydrogen shift/iodination process catalyzed by iridium(III) complexes.

National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-148095 (URN)10.1039/c7cc04823h (DOI)000409481000003 ()28809976 (PubMedID)
Available from: 2017-10-20 Created: 2017-10-20 Last updated: 2019-10-22Bibliographically approved
2. Synthesis of alpha-Iodoketones from Allylic Alcohols through Aerobic Oxidative Iodination
Open this publication in new window or tab >>Synthesis of alpha-Iodoketones from Allylic Alcohols through Aerobic Oxidative Iodination
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2018 (English)In: Advanced Synthesis and Catalysis, ISSN 1615-4150, E-ISSN 1615-4169, Vol. 360, no 20, p. 3884-3888Article in journal (Refereed) Published
Abstract [en]

An efficient method for the synthesis of alpha-iodoketones from allylic alcohols and elemental iodine is reported. We show in this paper that the isomerization of allylic alcohols catalyzed by iridium(III) complexes can be combined with an aerobic oxidative iodination protocol, resulting in a straightforward method for the synthesis of a wide range of alpha-iodoketones as single constitutional isomers and in high yields under mild reaction conditions.

Keywords
isomerization, aerobic oxidative iodination, alpha-iodoketones, alpha-aminoketones, allylic alcohol
National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-161929 (URN)10.1002/adsc.201800661 (DOI)000447633800004 ()
Available from: 2018-11-13 Created: 2018-11-13 Last updated: 2019-12-04Bibliographically approved
3. Selective Synthesis of Unsymmetrical Aliphatic Acyloins through Oxidation of Iridium Enolates
Open this publication in new window or tab >>Selective Synthesis of Unsymmetrical Aliphatic Acyloins through Oxidation of Iridium Enolates
2018 (English)In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 24, no 45, p. 11564-11567Article in journal (Refereed) Published
Abstract [en]

The first method to access unsymmetrical aliphatic acyloins is presented. The method relies on a fast 1,3-hydride shift mediated by an Ir-III complex in allylic alcohols followed by oxidation with TEMPO+. The direct conversion of allylic alcohols into acyloins is achieved in a one-pot procedure. Further functionalization of the C alpha' of the alpha-amino-oxylated ketone products gives access to highly functionalized unsymmetrical aliphatic ketones, which further highlights the utility of this transformation.

Keywords
allylic alcohols, hydride shifts, iridium, oxidation, alpha-hydroxy ketones
National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-160118 (URN)10.1002/chem.201803117 (DOI)000441126900008 ()29928782 (PubMedID)
Available from: 2018-09-18 Created: 2018-09-18 Last updated: 2019-10-22Bibliographically approved
4. An Umpolung Strategy to React Catalytic Enols with Nucleophiles
Open this publication in new window or tab >>An Umpolung Strategy to React Catalytic Enols with Nucleophiles
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(English)Manuscript (preprint) (Other academic)
National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-175354 (URN)
Available from: 2019-10-21 Created: 2019-10-21 Last updated: 2019-12-04Bibliographically approved
5. Base-Catalyzed Stereospecific Isomerization of Electron-Deficient Allylic Alcohols and Ethers through Ion-Pairing
Open this publication in new window or tab >>Base-Catalyzed Stereospecific Isomerization of Electron-Deficient Allylic Alcohols and Ethers through Ion-Pairing
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2016 (English)In: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 138, no 40, p. 13408-13414Article in journal (Refereed) Published
Abstract [en]

A mild base-catalyzed strategy for the isomerization of allylic alcohols and allylic ethers has been developed. Experimental and computational investigations indicate that transition metal catalysts are not required when basic additives are present. As in the case of using transition metals under basic conditions, the isomerization catalyzed solely by base also follows a stereospecific pathway. The reaction is initiated by a rate-limiting deprotonation. Formation of an intimate ion pair between an allylic anion and the conjugate acid of the base results in efficient transfer of chirality. Through this mechanism, stereochemical information contained in the allylic alcohols is transferred to the ketone products. The stereospecific isomerization is also applicable for the first time to allylic ethers, yielding synthetically valuable enantioenriched (up to 97% ee) enol ethers.

National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-136066 (URN)10.1021/jacs.6b08350 (DOI)000385469600048 ()
Funder
Swedish Research CouncilKnut and Alice Wallenberg FoundationVinnovaWenner-Gren Foundations
Available from: 2016-12-16 Created: 2016-11-29 Last updated: 2019-10-22Bibliographically approved
6. Selective Synthesis and Stereospecific Isomerization of Chiral Allylic Halides
Open this publication in new window or tab >>Selective Synthesis and Stereospecific Isomerization of Chiral Allylic Halides
(English)Manuscript (preprint) (Other academic)
National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-175356 (URN)
Available from: 2019-10-21 Created: 2019-10-21 Last updated: 2019-12-04Bibliographically approved
7. Base-Catalyzed [1,n]-Proton Shifts in Conjugated Polyenyl Alcohols and Ethers
Open this publication in new window or tab >>Base-Catalyzed [1,n]-Proton Shifts in Conjugated Polyenyl Alcohols and Ethers
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2019 (English)In: ACS Catalysis, ISSN 2155-5435, E-ISSN 2155-5435, Vol. 9, no 10, p. 9134-9139Article in journal (Refereed) Published
Abstract [en]

The isomerization of dienyl alcohols and polyenyl alkyl ethers catalyzed by TBD (1,5,7-triazabicyclo[4.4.0]dec-5-ene) under metal-free conditions is presented. Two reaction pathways have been observed. For dienyl alcohols, the reaction proceeds by a [1,3]-proton shift to give γ,δ-unsaturated ketones exclusively. On the other hand, the reaction with polyenyl alkyl ethers gives the corresponding conjugated vinyl ethers in good yields (up to 85%), with regioselectivities up to >20:1. Experimental and computational investigations suggest that the mechanism proceeds through consecutive “chain-walking” proton shifts (“base walk”) mediated by TBD.

Keywords
base catalysis, mechanism, superbase, isomerization, proton shift, base walk
National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-175351 (URN)10.1021/acscatal.9b02478 (DOI)000489204000032 ()
Available from: 2019-10-21 Created: 2019-10-21 Last updated: 2019-12-04Bibliographically approved

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