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A General Route to beta-Substituted Pyrroles by Transition-Metal Catalysis
Stockholm University, Faculty of Science, Department of Organic Chemistry. Uppsala University, Sweden.
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2016 (English)In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 81, no 4, 1450-1460 p.Article 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.

Place, publisher, year, edition, pages
2016. Vol. 81, no 4, 1450-1460 p.
National Category
Chemical Sciences
Research subject
Organic Chemistry
Identifiers
URN: urn:nbn:se:su:diva-128545DOI: 10.1021/acs.joc.5b02581ISI: 000370768000013PubMedID: 26789020OAI: oai:DiVA.org:su-128545DiVA: diva2:939902
Funder
Swedish Research Council FormasStiftelsen Olle Engkvist Byggmästare
Available from: 2016-06-20 Created: 2016-03-30 Last updated: 2017-08-31Bibliographically 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: 2017-10-12Bibliographically approved

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