Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
H3PO2-Catalyzed Intramolecular Stereospecific Substitution of the Hydroxyl Group in Stereogenic Secondary Alcohols by N-, O-, and S-centered Nucleophiles to Generate Heterocycles
Stockholm University, Faculty of Science, Department of Organic Chemistry.
Stockholm University, Faculty of Science, Department of Organic Chemistry.
Show others and affiliations
(English)Manuscript (preprint) (Other academic)
Abstract [en]

The direct intramolecular stereospecific substitution of the hydroxyl group in stereogenic secondary alcohols was successfully accomplished by phosphinic acid catalysis. The hydroxyl group was displaced by O-, S-, and N-centered nucleophiles to provide enantioenriched five- and six-membered heterocycles in good to excellent yields and high enantiospecificity with water as the only by product. Mechanistic studies using both experiments and calculations have been performed. Rate order determination shows first-order dependences in catalyst, internal nucleophile, and electrophile concentrations, however, independence on external nucleophile and electrophile. Furthermore, phosphinic acid does not promote SN1 reactivity. Computational studies support a bifunctional role of the phosphinic acid in which activations of both nucleofuge and nucleophile occur in a bridging SN2-type transition state. 

Keyword [en]
stereospecific substitution, alcohols, phosphinic acid catalysis, heterocyclic compounds, atom economy
National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
URN: urn:nbn:se:su:diva-146488OAI: oai:DiVA.org:su-146488DiVA: diva2:1137259
Available from: 2017-08-30 Created: 2017-08-30 Last updated: 2017-09-05Bibliographically approved
In thesis
1. Direct Catalytic Nucleophilic Substitution of Non-Derivatized Alcohols
Open this publication in new window or tab >>Direct Catalytic Nucleophilic Substitution of Non-Derivatized Alcohols
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

This thesis focuses on the development of methods for the activation of the hydroxyl group in non-derivatized alcohols in substitution reactions. The thesis is divided into two parts, describing three different catalytic systems.

The first part of the thesis (Chapter 2) describes nucleophilic allylation of amines with allylic alcohols, using a palladium catalyst to generate unsymmetrical diallylated amines. The corresponding amines were further transformed by a one-pot ring-closing metathesis and aromatization reaction to afford β-substituted pyrroles with linear and branched alkyl, benzyl, and aryl groups in overall moderate to good yields.

The second part (Chapters 3 and 4) describes the direct intramolecular stereospecific nucleophilic substitution of the hydroxyl group in enantioenriched alcohols by Lewis acid and Brønsted acid/base catalysis.

In Chapter 3, the direct intramolecular substitution of non-derivatized alcohols has been developed using Fe(OTf)3 as catalyst. The hydroxyl groups of aryl, allyl, and alkyl alcohols were substituted by the attack of O- and N-centered nucleophiles, to provide five- and six-membered heterocycles in up to excellent yields with high enantiospecificities. Experimental studies showed that the reaction follows first-order dependence with respect to the catalyst, the internal nucleophile, and the internal electrophile of the substrate. Competition and catalyst-substrate interaction experiments demonstrated that this transformation proceeds via an SN2-type reaction pathway.

In Chapter 4, a Brønsted acid/base catalyzed intramolecular substitution of non-derivatized alcohols was developed. The direct intramolecular and stereospecific substitution of different alcohols was successfully catalyzed by phosphinic acid (H3PO2). The hydroxyl groups of aryl, allyl, propargyl, and alkyl alcohols were substituted by O-, N-, and S-centered nucleophiles to generate five- and six-membered heterocycles in good to excellent yields with high enantiospecificities. Mechanistic studies (both experiments and density functional theory calculations) have been performed on the reaction forming five-membered heterocyclic compounds. Experimental studies showed that phosphinic acid does not promote SN1 reactivity. Rate-order determination indicated that the reaction follows first-order dependence with respect to the catalyst, the internal nucleophile, and the internal electrophile. DFT calculations corroborated with a reaction pathway in which the phosphinic acid has a dual activation mode and operates as a bifunctional Brønsted acid/Brønsted base to simultaneously activate both the nucleophile and nucleofuge, resulting in a unique bridging transition state in an SN2-type reaction mechanism.

Place, publisher, year, edition, pages
Stockholm: Department of Organic Chemistry, Stockholm University, 2017. 76 p.
Keyword
nucleophilic substitution, catalysis, alcohols, stereospecific, Lewis acid, Brønsted acid/base, bifunctional, heterocycles
National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-146426 (URN)978-91-7649-917-7 (ISBN)978-91-7649-918-4 (ISBN)
Public defence
2017-10-05, 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 2: Manuscript. Paper 4: Manuscript.

Available from: 2017-09-12 Created: 2017-08-30 Last updated: 2017-09-11Bibliographically approved

Open Access in DiVA

Supporting Information to H3PO2-Catalyzed Intramolecular Stereospecific Substitution of the Hydroxyl Group in Stereogenic Secondary Alcohols by N-, O-, and S-centered Nucleophiles to Generate Heterocycles(15604 kB)2 downloads
File information
File name ATTACHMENT01.pdfFile size 15604 kBChecksum SHA-512
248b507185876dfbc20ab949de2001f3e0c2cdae7e0e14b0e7ba5718cce4bdbb20f5241d760a9ca37d7204e10188495068c7b04f28378670a228553a78b58d52
Type attachmentMimetype application/pdf

Search in DiVA

By author/editor
Bunrit, AnonSrifa, PemikarHimo, FahmiWatile, RahulSamec, Joseph
By organisation
Department of Organic Chemistry
Organic Chemistry

Search outside of DiVA

GoogleGoogle Scholar
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

Total: 40 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf