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Hypervalent Iodine Reagents in Metal-Free Arylations and Vinylations: Investigation of Suitable Coupling Partners and Synthesis of New Reagents
Stockholm University, Faculty of Science, Department of Organic Chemistry. (Berit Olofsson)
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

This thesis concerns the development of metal-free reactions to obtain carbon-heteroatom and carbon-carbon bonds. This is achieved by transferring carbon ligands from hypervalent iodine reagents to suitable nucleophiles.

The bulk of the work presented herein concerns arylation of oxygen and nitrogen nucleophiles, using the well-known diaryliodonium salts as aryl sources. In the first project, O-arylation of the oxime ethyl acetohydroxamate was studied. It was found that electron-poor as well as electron-rich aryl moieties could be transferred successfully to this nucleophile. Furthermore, the protocol could be extended to a sequential one-pot synthesis of benzo[b]furans. This method allowed for a fast synthesis of the natural product stemofuran A and formal syntheses of other natural products.

In a successive project, O-arylation of hydroxide and aliphatic alkoxides was investigated. It is known that electron-poor aryl moieties can be transferred to these nucleophiles in moderate to high yields. However, combined with more electron-rich diaryliodonium salts, a large amount of side products were formed. These were suppressed upon addition of aryne traps, suggesting that aryne pathways are competing with the desired ligand coupling. It was also observed that secondary alcohols were oxidized to the corresponding ketones. The mechanism for this oxidation was investigated and aryne pathways could be excluded. Instead we suggest that the carbinol hydrogen gets deprotonated via an internal mechanism, after the alkoxide has coordinated to the iodonium salt. Highly sterically congested alkyl aryl ethers could be obtained in high yields by combining tertiary alcohols with ortho-blocked diaryliodonium salts. 

Next, N-arylation of secondary acyclic amides was studied using acetanilide as the model substrate. This procedure was suitable for transfer of electron-poor as well as ortho-substituted aryl moieties, but attempts to transfer very electron-rich aryl groups were unsuccessful. On the other hand, the amides displayed a complementary reactivity, allowing phenylation of electron-rich amides. 

In the final project, a one-pot synthesis of the cyclic iodonium reagent vinylbenziodoxolone is presented. These compounds have not been explored as reagents earlier. Initial screenings showed that the vinyl moiety could be transferred to nitrocyclohexane with opposite regioselectivity compared to the acyclic analogue of the reagent.

Place, publisher, year, edition, pages
Stockholm: Department of Organic Chemistry, Stockholm University , 2017. , 87 p.
Keyword [en]
Diaryliodonium Salts, Benzofurans, Aryl Ethers, Secondary Amides, Vinylbenziodoxolones
National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
URN: urn:nbn:se:su:diva-141580ISBN: 978-91-7649-704-3 (print)ISBN: 978-91-7649-705-0 (electronic)OAI: oai:DiVA.org:su-141580DiVA: diva2:1088095
Public defence
2017-06-02, Magnélisalen, Kemiska Övningslaboratoriet, Svante Arrhenius väg 16 B, Stockholm, 10:00 (English)
Opponent
Supervisors
Note

At the time of the doctoral defense, the following paper was unpublished and had a status as follows: Paper 2: Manuscript.

Available from: 2017-05-10 Created: 2017-04-11 Last updated: 2017-05-03Bibliographically approved
List of papers
1. Metal-Free One-Pot Synthesis of Benzofurans
Open this publication in new window or tab >>Metal-Free One-Pot Synthesis of Benzofurans
2014 (English)In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 20, no 29, 8888-8892 p.Article in journal (Refereed) Published
Abstract [en]

Ethyl acetohydroxamate was efficiently arylated with diaryliodonium salts at room temperature under transition-metal-free conditions. The obtained O-arylated products were reacted in situ with ketones under acidic conditions to yield substituted benzo[b]furans through oxime formation, [3,3]-rearrangement, and cyclization in a fast and operationally simple one-pot fashion without using excess reagents. Alternatively, the O-arylated products could be isolated or transformed in situ to aryloxyamines or O-arylaldoximes. The methodology was applied to the synthesis of Stemofuran A and the formal syntheses of Coumestan, Eupomatenoid 6, and (+)-machaeriol B.

Keyword
arylation, aryloxyamines, cyclization, diaryliodonium salts, O-aryloximes, sigmatropic rearrangement
National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-106727 (URN)10.1002/chem.201403523 (DOI)000339386700013 ()
Funder
Wenner-Gren FoundationsCarl Tryggers foundation , 12:345
Note

AuthorCount:3;

Available from: 2014-08-18 Created: 2014-08-18 Last updated: 2017-04-27Bibliographically approved
2. Competing Pathways in O-Arylations with Diaryliodonium Salts – Mechanistic Insights
Open this publication in new window or tab >>Competing Pathways in O-Arylations with Diaryliodonium Salts – Mechanistic Insights
Show others...
(English)Manuscript (preprint) (Other academic)
National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-140795 (URN)
Available from: 2017-03-24 Created: 2017-03-24 Last updated: 2017-04-11Bibliographically approved
3. Mild Synthesis of Sterically Congested Alkyl Aryl Ethers
Open this publication in new window or tab >>Mild Synthesis of Sterically Congested Alkyl Aryl Ethers
2016 (English)In: Organic Letters, ISSN 1523-7060, E-ISSN 1523-7052, Vol. 18, no 17, 4234-4237 p.Article in journal (Refereed) Published
Abstract [en]

An efficient and transition-metal-free method is presented to access tertiary alkyl aryl ethers by arylation of tertiary alcohols with ortho-substituted diaryliodonium salts. The scope covers cyclic and acyclic aliphatic, benzylic, allylic, and propargylic tertiary alcohols as well as primary and secondary fluorinated alcohols. The methodology gives access to alkyl aryl ethers of previously unprecedented steric congestion. Furthermore, the versatility of the developed procedure was demonstrated by arylation of the pro-drug mestranol.

National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-135023 (URN)10.1021/acs.orglett.6b01975 (DOI)000382711200022 ()27586361 (PubMedID)
Funder
Swedish Research Council
Available from: 2016-11-10 Created: 2016-10-31 Last updated: 2017-06-18Bibliographically approved
4. Metal-Free N-Arylation of Secondary Amides at Room Temperature
Open this publication in new window or tab >>Metal-Free N-Arylation of Secondary Amides at Room Temperature
Show others...
2015 (English)In: Organic Letters, ISSN 1523-7060, E-ISSN 1523-7052, Vol. 17, no 11, 2688-2691 p.Article in journal (Refereed) Published
Abstract [en]

The arylation of secondary acyclic amides has been achieved with diaryliodonium salts under mild and metal-free conditions. The methodology has a wide scope, allows synthesis of tertiary amides with highly congested aryl moieties, and avoids the regioselectivity problems observed in reactions with (diacetoxyiodo)benzene.

National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-119153 (URN)10.1021/acs.orglett.5b01079 (DOI)000355962200032 ()
Funder
Swedish Research CouncilKnut and Alice Wallenberg Foundation
Available from: 2015-08-12 Created: 2015-07-29 Last updated: 2017-04-27Bibliographically approved
5. Synthesis, Characterization and Unusual Reactivity of Vinylbenziodoxolones-Novel Hypervalent Iodine Reagents
Open this publication in new window or tab >>Synthesis, Characterization and Unusual Reactivity of Vinylbenziodoxolones-Novel Hypervalent Iodine Reagents
Show others...
2016 (English)In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 22, no 45, 16066-16070 p.Article in journal (Refereed) Published
Abstract [en]

A novel type of hypervalent iodine(III) reagents, vinylbenziodoxolones (VBX), has been synthesized in a one-pot reaction from 2-iodobenzoic acid. VBX is bench stable, has been thoroughly characterized and the cyclic structure is supported by X-ray analysis. The reactivity of VBX was investigated in vinylation of nitrocyclohexane, and delivered vinylated products with opposite regioselectivity compared to acyclic vinyl(aryl) iodonium salts. The reagents could become a powerful tool in vinylation reactions under both metal-free and metal-catalyzed conditions.

Keyword
benziodoxolones, hypervalent compounds, structure analysis, synthetic methods, vinylation
National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-136921 (URN)10.1002/chem.201603955 (DOI)000387132800014 ()27629653 (PubMedID)
Funder
Swedish Research CouncilCarl Tryggers foundation
Available from: 2017-01-03 Created: 2016-12-19 Last updated: 2017-06-14Bibliographically approved

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