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Mild Synthesis of Sterically Congested Alkyl Aryl Ethers
Stockholm University, Faculty of Science, Department of Organic Chemistry.
Stockholm University, Faculty of Science, Department of Organic Chemistry.
Stockholm University, Faculty of Science, Department of Organic Chemistry.
Number of Authors: 3
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.

Place, publisher, year, edition, pages
2016. Vol. 18, no 17, 4234-4237 p.
National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
URN: urn:nbn:se:su:diva-135023DOI: 10.1021/acs.orglett.6b01975ISI: 000382711200022PubMedID: 27586361OAI: oai:DiVA.org:su-135023DiVA: diva2:1045769
Available from: 2016-11-10 Created: 2016-10-31 Last updated: 2017-04-27Bibliographically approved
In thesis
1. Metal-Free O- and C-Arylation with Diaryliodonium Salts
Open this publication in new window or tab >>Metal-Free O- and C-Arylation with Diaryliodonium Salts
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

This thesis concerns the development of metal-free applications using diaryliodonium salts. The first project describes an arylation protocol of allylic and benzylic alcohols in aqueous media. The method proceeds under mild conditions and the ether products were obtained in moderate to good yields. The methodology was also expanded to include arylation of phenols, giving diaryl ethers in good to excellent yields. In the second project, an arylation method that included a wider range of aliphatic alcohols was developed. The scope of accessible alkyl aryl ethers was studied and included a comparative study of phenylation and nitrophenylation of various alcohols. Finally, a formal metal-free synthesis of butoxycain was performed, illustrating the applicability of the developed method.

The third project focused on the limitations and side reactions occurring in Chapter 2 and 3. First, an approach to access symmetric diaryl ethers via arylation of hydroxide was presented. This reaction gave rise to a number of side products, which we hypothesized to originate from aryne-type intermediates. A mechanism for the formation of these side products was suggested, supported by trapping and deuterium labeling experiments.

Oxidation of the alcohol to the corresponding ketone was also observed and the mechanism of this interesting side reaction was investigated. The latter was suggested to proceed via an intramolecular oxidation without the involvement of radicals or arynes.

The fourth project covers a method to synthesize highly sterically congested alkyl aryl ethers via arylation of tertiary alcohols using diaryliodonium salts. The method displayed a broad scope of tertiary alcohols and was also suitable for fluorinated alcohols.

The final project detailed in this thesis deals with C-arylation with diaryliodonium salts, showcasing nitroalkanes as well as a nitro ester as suitable nucleophiles for metal-free arylation. 

Place, publisher, year, edition, pages
Stockholm: Department of Organic Chemistry, Stockholm University, 2017. 85 p.
Keyword
Hypervalent Iodine, Alkyl Aryl Ethers, Nitro Compounds, Alcohols, Diaryliodonium Salts
National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-140944 (URN)978-91-7649-702-9 (ISBN)978-91-7649-703-6 (ISBN)
Public defence
2017-05-12, 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 3: Manuscript.

Available from: 2017-04-19 Created: 2017-03-24 Last updated: 2017-04-11Bibliographically approved
2. Hypervalent Iodine Reagents in Metal-Free Arylations and Vinylations: Investigation of Suitable Coupling Partners and Synthesis of New Reagents
Open this publication in new window or tab >>Hypervalent Iodine Reagents in Metal-Free Arylations and Vinylations: Investigation of Suitable Coupling Partners and Synthesis of New Reagents
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
Diaryliodonium Salts, Benzofurans, Aryl Ethers, Secondary Amides, Vinylbenziodoxolones
National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-141580 (URN)978-91-7649-704-3 (ISBN)978-91-7649-705-0 (ISBN)
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

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