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Ru-Catalysed C-H Arylation of Indoles and Pyrroles with Boronic Acids: Scope and Mechanistic Studies
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC.
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC.
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Molecular Biomimetics.
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2015 (English)In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 21, no 14, 5380-5386 p.Article in journal (Refereed) Published
Abstract [en]

The Ru-catalysed C2-H arylation of indoles and pyrroles by using boronic acids under oxidative conditions is reported. This reaction can be applied to tryptophan derivatives and tolerates a wide range of functional groups on both coupling partners, including bromides and iodides, which can be further derivatised selectively. New indole based ruthenacyclic complexes are described and investigated as possible intermediates in the reaction. Mechanistic studies suggest the on-cycle intermediates do not possess a para-cymene ligand and that the on-cycle metalation occurs through an electrophilic attack by the Ru centre.

Place, publisher, year, edition, pages
2015. Vol. 21, no 14, 5380-5386 p.
Keyword [en]
catalysis, C-H activation, heterocycles, reaction mechanisms, ruthenium
National Category
Chemical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-252711DOI: 10.1002/chem.201405931ISI: 000352504500017PubMedID: 25689052OAI: oai:DiVA.org:uu-252711DiVA: diva2:812286
Funder
Swedish Research Council
Available from: 2015-05-18 Created: 2015-05-11 Last updated: 2017-12-04Bibliographically approved
In thesis
1. Ruthenium-catalyzed C-H Functionalization of (Hetero)arenes
Open this publication in new window or tab >>Ruthenium-catalyzed C-H Functionalization of (Hetero)arenes
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

This thesis concerned about the Ru-catalyzed C-H functionalizations on the synthesis of 2-arylindole unit, silylation of heteroarenes and preparation of aryne precursor.

In the first project, we developed the Ru-catalyzed C2-H arylation of N-(2-pyrimidyl) indoles and pyrroles with nucleophilic arylboronic acids under oxidative conditions. Wide variety of arylboronic acids afforded the desired product in excellent yield regardless of the substituents or functional group electronic nature. Electron-rich heteroarenes are well suited for this method than electron-poor heteroarenes. Halides such as bromide and iodide also survived, further derivatisation of the halide is shown by Heck alkenylation. In order to find catalytic on-cycle intermediate extensive mechanistic experiments have been carried out by preparing presumed ruthenacyclic complexes and C-H/D exchange reactions. It suggested that para-cymene ligand is not present in the catalytic on-cycle intermediate and we suspect that metalation occurs with electrophilic ruthenium center via SEAr mechanism.

In the second project, we developed the Ru-catalyzed silylation of gramine, tryptamine and their congeners using silanes as coupling partner. The transformation worked well with many different silanes. Regarding directing group, nitrogen atom containing directing groups are more favoured than the oxygen containing directing groups. Wide range of gramines and tryptamines also yielded the desired product in poor to excellent yield. At higher temperature, albeit in low yield, undirected silylation occurred. In order to get some insights about the reaction pathway of the silylation C-H/D exchange experiments were performed, and it revealed the possibility of C4-H activation of gramines by an electron rich metal- Si-H/D experiments showed Si-H activation by Ru is easy.

In the final project, we presented the closely related aryne precursors from arylboronic acids via Ru-catalyzed C-H silylation of arylboronates and their selective oxidation. Worthy of note, the aryne capture products obtained from arylboronic acids in a single purification.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2017. 59 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 1465
Keyword
catalysis, C-H activation, heterocycles, ruthenium, aryne precursor, silylation, gramine
National Category
Organic Chemistry
Identifiers
urn:nbn:se:uu:diva-310998 (URN)978-91-554-9783-5 (ISBN)
Public defence
2017-02-24, B22, BMC, Husargatan 3, Uppsala, Uppsala, 09:30 (English)
Opponent
Supervisors
Available from: 2017-02-03 Created: 2016-12-20 Last updated: 2017-02-07
2. New Arylation Strategies Based on Organomain Group Reactivity
Open this publication in new window or tab >>New Arylation Strategies Based on Organomain Group Reactivity
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The work in this thesis describes the development of new heteroarylation methodology based on transition metal-catalysed C-H functionalisation and the properties of organomain group compounds. The underlying reaction mechanisms and reactivity patterns of the (hetero)arene substrates are also investigated. The selective C2-H arylation indoles, which are key pharmaceutically-relevant units, was achieved using N-pyrimidyl directing groups, RuII catalysis and arylboronic acids as the coupling reagents (paper I). The use of this set of conditions enabled a remarkable functional group tolerance, highlighted by the preservation of halide substituents on both coupling partners. Mechanistic experiments suggest that cleavage of the C2-H bond occurs through an electrophilic aromatic substitution type pathway. The dehydrogenative C2-H silylation of unprotected gramine and tryptamine alkaloids and other related heteroarenes using hydrosilanes under Ru0 catalysis is described in paper II. The protocol does not require protecting groups and undirected C2-H silylation of heteroarenes is possible at higher temperatures. Significantly, H/D-exchange studies revealed deuterium incorporation at the C4 and C7 positions of the indole unit, apart from C2-H silylation. This study represents the first account of C4-H activation using an electron-rich metal catalyst. Paper III describes an unexpected and profound influence of boronate substituents on the regioselectivity of aryne trapping reactions. The boronates may be introduced easily to the backbone of established fluoride-activated precursors via Ir-catalysed C-H functionalisation. Optimisation and mechanistic studies on the unprecedented level of regioselectivity control these substituents permit using external additives is presented.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2017. 80 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 1552
Keyword
C-H functionalisation, catalysis, ruthenium, indole, silylation, boronate, boryl aryne, aryne distortion
National Category
Chemical Sciences
Research subject
Chemistry with specialization in Organic Chemistry
Identifiers
urn:nbn:se:uu:diva-328750 (URN)978-91-513-0055-9 (ISBN)
Public defence
2017-10-20, B21, Biomedical Centre (BMC), Husargatan 3, Uppsala, 13:30 (English)
Opponent
Supervisors
Available from: 2017-09-29 Created: 2017-08-31 Last updated: 2017-10-17

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Sollert, CarinaDevaraj, KarthikOrthaber, AndreasPilarski, Lukasz T.

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