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Direct Catalytic Nucleophilic Substitution of Non-Derivatized Alcohols
Stockholm University, Faculty of Science, Department of Organic Chemistry. Stockholm University. (Joseph Samec)
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. , p. 76
Keywords [en]
nucleophilic substitution, catalysis, alcohols, stereospecific, Lewis acid, Brønsted acid/base, bifunctional, heterocycles
National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
URN: urn:nbn:se:su:diva-146426ISBN: 978-91-7649-917-7 (print)ISBN: 978-91-7649-918-4 (electronic)OAI: oai:DiVA.org:su-146426DiVA, id: diva2:1137254
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: 2017-10-12Bibliographically approved
List of papers
1. A General Route to beta-Substituted Pyrroles by Transition-Metal Catalysis
Open this publication in new window or tab >>A General Route to beta-Substituted Pyrroles by Transition-Metal Catalysis
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2016 (English)In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 81, no 4, p. 1450-1460Article in journal (Refereed) Published
Abstract [en]

An atom-efficient route to pyrroles substituted in the beta-position has been achieved in four high yielding steps by a combination of Pd, Ru, and Fe catalysis with only water and ethene as side-products. The reaction is general and gives pyrroles substituted in the beta-position with linear and branched alkyl, benzyl, or aryl groups in overall good yields. The synthetic route includes a Pd-catalyzed monoallylation step of amines with substituted allylic alcohols that proceeds to yield the monoallylated products in moderate to excellent yields. In a second step, unsymmetrical diallylated aromatic amines are generated from the reaction of a second allylic alcohol with high selectivity in moderate to good yields by control of the reaction temperature. Ru-catalyzed ring-closing metathesis performed on the diallylated aromatic amines yields the pyrrolines substituted in the beta-position in excellent yields. By addition of ferric chloride to the reaction mixture, a selective aromatization to yield the corresponding pyrroles substituted in the beta-position was achieved. A reaction mechanism involving a palladium hydride, generated from insertion of palladium to O-H of an allyl alcohol, that is responsible for the C-O bond cleavage to generate the pi-allyl intermediate is proposed.

National Category
Chemical Sciences
Research subject
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-128545 (URN)10.1021/acs.joc.5b02581 (DOI)000370768000013 ()26789020 (PubMedID)
Funder
Swedish Research Council FormasStiftelsen Olle Engkvist Byggmästare
Available from: 2016-06-20 Created: 2016-03-30 Last updated: 2017-08-31Bibliographically approved
2. Iron (III)-Catalyzed Intramolecular Stereospecific Substitution of the OH Group in Stereogenic Secondary and Tertiary Alcohols
Open this publication in new window or tab >>Iron (III)-Catalyzed Intramolecular Stereospecific Substitution of the OH Group in Stereogenic Secondary and Tertiary Alcohols
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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. 

Keywords
Stereospecific substitution, alcohols, iron catalysis, heterocyclic compounds, atom economy
National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-146489 (URN)
Available from: 2017-08-30 Created: 2017-08-30 Last updated: 2017-09-05
3. Brønsted Acid-Catalyzed Intramolecular Nucleophilic Substitution of the Hydroxyl Group in Stereogenic Alcohols with Chirality Transfer
Open this publication in new window or tab >>Brønsted Acid-Catalyzed Intramolecular Nucleophilic Substitution of the Hydroxyl Group in Stereogenic Alcohols with Chirality Transfer
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2015 (English)In: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 137, no 14, p. 4646-4649Article in journal (Refereed) Published
Abstract [en]

The hydroxyl group of enantioenriched benzyl, propargyl, allyl, and alkyl alcohols has been intramolecularly displaced by uncharged O-, N-, and S-centered nucleophiles to yield enantioenriched tetrahydrofuran, pyrrolidine, and tetrahydrothiophene derivatives with phosphinic acid catalysis. The five-membered heterocyclic products are generated in good to excellent yields, with high degree of chirality transfer, and water as the only side-product. Racemization experiments show that phosphinic acid does not promote S(N)1 reactivity. Density functional theory calculations corroborate a reaction pathway where the phosphinic acid operates as a bifunctional catalyst in the intramolecular substitution reaction. In this mechanism, the acidic proton of the phosphinic acid protonates the hydroxyl group, enhancing the leaving group ability. Simultaneously, the oxo group of phosphinic acid operates as a base abstracting the nucleophilic proton and thus enhancing the nucleophilicity. This reaction will open up new atom efficient techniques that enable alcohols to be used as nucleofuges in substitution reactions in the future.

National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-117729 (URN)10.1021/jacs.5b02013 (DOI)000353177100014 ()
Funder
Swedish Research CouncilStiftelsen Olle Engkvist ByggmästareThe Wenner-Gren FoundationGöran Gustafsson Foundation for Research in Natural Sciences and MedicineKnut and Alice Wallenberg Foundation
Available from: 2015-06-09 Created: 2015-06-01 Last updated: 2017-08-31Bibliographically approved
4. H3PO2-Catalyzed Intramolecular Stereospecific Substitution of the Hydroxyl Group in Stereogenic Secondary Alcohols by N-, O-, and S-centered Nucleophiles to Generate Heterocycles
Open this publication in new window or tab >>H3PO2-Catalyzed Intramolecular Stereospecific Substitution of the Hydroxyl Group in Stereogenic Secondary Alcohols by N-, O-, and S-centered Nucleophiles to Generate Heterocycles
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(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. 

Keywords
stereospecific substitution, alcohols, phosphinic acid catalysis, heterocyclic compounds, atom economy
National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-146488 (URN)
Available from: 2017-08-30 Created: 2017-08-30 Last updated: 2017-09-05Bibliographically approved

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