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Iron (III)-Catalyzed Intramolecular Stereospecific Substitution of the OH Group in Stereogenic Secondary and Tertiary Alcohols
Stockholm University, Faculty of Science, Department of Organic Chemistry.
Stockholm University, Faculty of Science, Department of Organic Chemistry.
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

We herein report a Fe(OTf)3-catalyzed stereospecific substitution of the hydroxyl (OH) group in secondary and tertiary alcohols by N-, and O-centered nucleophiles to generate synthetically precious enantioenriched pyrrolidines, tetrahydrofuran, 1,2,3,4-tetra-hydroquinolines, and chromanes. The substitution of the OH group in benzylic, allylic, and aliphatic alcohols proceed with high yields and high degree of enantiospecificity to give saturated five- and six-membered heterocyclic products and water as the only by-product. Mechanistic studies revealed that the intramolecular substitution reaction proceeds through an SN2 reaction with secondary alcohols and an SN1 reaction, comprising a tight ion pair, with tertiary alcohols giving products with inversion of configuration at the stereogenic carbon in both cases. The iron interacts with both nucleofile and nucloefuge, where the latter leads to a controlled carbon−oxygen (C–O) bond cleavage. The procedure opens up new atom efficient technique for catalytic stereospecific reactions that allow easily accessible stereogenic secondary and tertiary alcohols to be considered as substrates in substitution reactions. 

Keyword [en]
Stereospecific substitution, alcohols, iron catalysis, heterocyclic compounds, atom economy
National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
URN: urn:nbn:se:su:diva-146489OAI: oai:DiVA.org:su-146489DiVA: diva2:1137263
Available from: 2017-08-30 Created: 2017-08-30 Last updated: 2017-09-05
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

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