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Direct Palladium(II)-Catalyzed Synthesis of Arylamidines from Aryltrifluoroborates
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
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2012 (English)In: Organic Letters, ISSN 1523-7060, E-ISSN 1523-7052, Vol. 14, no 9, 2394-2397 p.Article in journal (Refereed) Published
Abstract [en]

A fast and convenient synthesis of arylamidines starting from readily available potassium aryltrifluoroborates and cyanamides is reported. The coupling was achieved by Pd(II)-catalysis in a one step 20 min microwave protocol using Pd(O2CCF3), 6-methyl-2,2'-bipyridyl, TFA, and MeOH, providing the corresponding arylamidines in moderate to excellent yields.

Place, publisher, year, edition, pages
2012. Vol. 14, no 9, 2394-2397 p.
National Category
Organic Chemistry
Identifiers
URN: urn:nbn:se:uu:diva-167719DOI: 10.1021/ol300813cISI: 000303492200052OAI: oai:DiVA.org:uu-167719DiVA: diva2:487810
Available from: 2012-01-31 Created: 2012-01-31 Last updated: 2017-12-08Bibliographically approved
In thesis
1. Palladium-Catalyzed Carbonylation and Arylation Reactions
Open this publication in new window or tab >>Palladium-Catalyzed Carbonylation and Arylation Reactions
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Palladium-catalyzed reactions have found widespread use in contemporary organic chemistry due to their impressive range of functional group tolerance and high chemo- and regioselectivity. The pioneering contributions to the development of the Pd-catalyzed C-C bond forming cross-coupling reaction were rewarded with the Nobel Prize in Chemistry in 2010. Today, this is a rapidly growing field, and the development of novel methods, as well as the theoretical understanding of the various processes involved are of immense importance for continued progress in this field.

The aim of the work presented in this thesis was to develop novel palladium(0)- and palladium(II)-catalyzed reactions. The work involved in achieving this aim led to the development of a Mo(CO)6-mediated carbonylative Stille cross coupling reaction for the preparation of various deoxybenzoins. The protocol utilized convenient gas-free conditions to facilitate the carbonylative coupling of benzyl bromides and chlorides with aryl and heteroaryl stannanes. Mo(CO)6-assisted conditions were then used in the development of a general protocol suitable for the aminocarbonylation of aryl triflates. Both electron-poor and electron-rich triflates were coupled with primary, secondary and aryl amines. In addition, DMAP was found to be a beneficial additive when using sterically hindered or poorly nucleophilic amines.

An efficient and convenient method for the synthesis of styrenes from arylboranes was developed, employing the relatively inexpensive vinyl acetate as the ethene source under Pd(II)-catalyzed conditions. The reaction mechanism was studied using ESI-MS, and a plausible catalytic cycle was proposed.

A method for the oxidative Heck reaction employing aryltrifluoroborates and aryl MIDA boronates was also developed. Electron-rich and electron-poor olefins were regioselectively arylated under microwave-assisted conditions. Various arylboron species were identified in an ongoing reaction using ESI-MS.   

Further investigations led to the development of a direct method for the synthesis of arylamidines from aryltrifluoroborates and cyanamides. Under Pd(II)-catalyzed conditions it was possible to insert the aryl into primary, secondary and tertiary cyanamides.

Finally, a desulfitative method for the synthesis of aryl ketones was developed. A variety of aryl sulfinates were effectively inserted into alkyl- and aryl nitriles. The mechanism was further investigated using ESI-MS and a plausible catalytic cycle was proposed.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2012. 81 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 155
Keyword
palladium, carbonylation, styrene, amidine, aryl ketones, aryl sulfinates, ESI-MS, aryltrifluoroborates
National Category
Medicinal Chemistry
Research subject
Organic Pharmaceutical Chemistry
Identifiers
urn:nbn:se:uu:diva-167720 (URN)978-91-554-8267-1 (ISBN)
Public defence
2012-03-16, B:41, BMC, Husargatan 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2012-02-21 Created: 2012-01-31 Last updated: 2012-03-01
2. Palladium(II)-Catalyzed Addition Reactions: Synthesis of Aryl Amidines and Aryl Ketones
Open this publication in new window or tab >>Palladium(II)-Catalyzed Addition Reactions: Synthesis of Aryl Amidines and Aryl Ketones
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Palladium-catalyzed reactions have become one of the most important tools in modern organic chemistry due to its ability to catalyze the formation of new carbon-carbon bonds.

The aim of the work presented in this thesis was to develop new palladium(II)-catalyzed addition reactions. In this work, cyanamides were investigated as a new substrate to give aryl amidines as products. The first protocol developed employed aryltrifluoroborates as the aryl partner, and the insertion of the aryl group into un-, mono-, and di-substituted cyanamides was successful for a wide variety of aryltrifluoroborates. An alternative method of generating the necessary intermediate for insertion into the cyanamide is the decarboxylative formation of aryl-palladium from aryl carboxylic acids. A protocol was developed for this reaction, but was unfortunately limited to a small number of ortho-substituted electron-rich aryl carboxylic acids. The mechanism was investigated by the means of DFT calculations and ESI-MS studies, and the rate-determining step was suggested to be the 1,2-carbopalladation based upon those results. A translation of the batch protocol to continuous-flow conditions was also demonstrated. The ideal method of generating the aryl-palladium species is by C-H bond activation, and this approach was demonstrated with indoles, giving a variety of 3-amidinoindoles as products. The mechanism was investigated by DFT calculations and a plausible catalytic cycle was proposed.

A continuous-flow application of a desulfitative palladium(II)-catalyzed addition to nitriles to give ketones was developed. In addition, different reactor materials were evaluated in the microwave heated reactor cavity. Thus the reaction was shown to proceed with microwave heating in a borosilicate glass and an aluminum oxide reactor, and also in conditions mimicking conventional heating in a silicon carbide reactor.

Finally, a protocol was developed for the convenient synthesis of sodium aryl sulfinates from Grignard and lithium reagents using a solid sulfur dioxide source as a safe alternative to the gas. The products of this protocol can be used as aryl-palladium precursors by a desulfitative process.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2017. 97 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 233
Keyword
Palladium, Catalysis, Palladium(II) catalysis, Synthesis, Addition Reactions, Cyanamide, Amidine, Aryl Amidine, Nitrile, Ketone, Aryl Ketone, Carbopalladation, Continuous-flow, Continuous flow, Microwave heating
National Category
Organic Chemistry
Research subject
Pharmaceutical Science
Identifiers
urn:nbn:se:uu:diva-326816 (URN)978-91-513-0012-2 (ISBN)
Public defence
2017-09-15, B22, BMC, Husargatan 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2017-08-25 Created: 2017-07-31 Last updated: 2017-09-08

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Sävmarker, JonasRydfjord, JonasGising, JohanOdell, Luke R.Larhed, Mats

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