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Palladium(II)-Catalyzed Addition Reactions: Synthesis of Aryl Amidines and Aryl Ketones
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.ORCID iD: 0000-0002-8037-3741
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 [en]
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: urn:nbn:se:uu:diva-326816ISBN: 978-91-513-0012-2 (print)OAI: oai:DiVA.org:uu-326816DiVA: diva2:1128867
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
List of papers
1. Direct Palladium(II)-Catalyzed Synthesis of Arylamidines from Aryltrifluoroborates
Open this publication in new window or tab >>Direct Palladium(II)-Catalyzed Synthesis of Arylamidines from Aryltrifluoroborates
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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.

National Category
Organic Chemistry
Identifiers
urn:nbn:se:uu:diva-167719 (URN)10.1021/ol300813c (DOI)000303492200052 ()
Available from: 2012-01-31 Created: 2012-01-31 Last updated: 2017-07-31Bibliographically approved
2. Decarboxylative Palladium(II)-Catalyzed Synthesis of Aryl Amidines from Aryl Carboxylic Acids: Development and Mechanistic Investigation
Open this publication in new window or tab >>Decarboxylative Palladium(II)-Catalyzed Synthesis of Aryl Amidines from Aryl Carboxylic Acids: Development and Mechanistic Investigation
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2013 (English)In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 19, no 41, 13803-13810 p.Article in journal (Refereed) Published
Abstract [en]

A fast and convenient synthesis of aryl amidines starting from carboxylic acids and cyanamides is reported. The reaction was achieved by palladium(II)-catalysis in a one-step microwave protocol using [Pd(O2CCF3)(2)], 6-methyl-2,2-bipyridyl and trifluoroacetic acid (TFA) in N-methylpyrrolidinone (NMP), providing the corresponding aryl amidines in moderate to excellent yields. The protocol is very robust with regards to the cyanamide coupling partner but requires electron-rich ortho-substituted aryl carboxylic acids. Mechanistic insight was provided by a DFT investigation and direct ESI-MS studies of the reaction. The results of the DFT study correlated well with the experimental findings and, together with the ESI-MS study, support the suggested mechanism. Furthermore, a scale-out (scale-up) was performed with a non-resonant microwave continuous-flow system, achieving a maximum throughput of 11mmolh(-1) by using a glass reactor with an inner diameter of 3mm at a flow rate of 1mLmin(-1).

Keyword
decarboxylation, density functional calculations, mass spectrometry, microwave chemistry, palladium
National Category
Natural Sciences
Identifiers
urn:nbn:se:uu:diva-210180 (URN)10.1002/chem.201301809 (DOI)000325135800026 ()
Available from: 2013-11-04 Created: 2013-11-04 Last updated: 2017-07-31Bibliographically approved
3. Route to 3-Amidino Indoles via Pd(II)-Catalyzed C-H Bond Activation.
Open this publication in new window or tab >>Route to 3-Amidino Indoles via Pd(II)-Catalyzed C-H Bond Activation.
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2017 (English)In: Organic Letters, ISSN 1523-7060, E-ISSN 1523-7052Article in journal (Refereed) Epub ahead of print
Abstract [en]

We report a facile synthesis of 3-amidino indoles from indoles and cyanamides. The reaction is Pd(II)-catalyzed and proceeds via C-H bond activation of the indole in its 3-position followed by a 1,2-addition of the resulting indole-palladium σ-complex to a cyanamide, which provides the corresponding amidine. The preference for 4,5-diazafluoren-9-one (DAF) as the ligand is investigated using DFT calculations, and a plausible reaction pathway is presented.

National Category
Pharmaceutical Sciences
Research subject
Pharmaceutical Science
Identifiers
urn:nbn:se:uu:diva-326815 (URN)10.1021/acs.orglett.7b01836 (DOI)28741950 (PubMedID)
Available from: 2017-07-31 Created: 2017-07-31 Last updated: 2017-09-19
4. Microwave Heated Continuous Flow Palladium(II)-Catalyzed Desulfitative Synthesis of Aryl Ketones
Open this publication in new window or tab >>Microwave Heated Continuous Flow Palladium(II)-Catalyzed Desulfitative Synthesis of Aryl Ketones
2016 (English)In: Organic Process Research & Development, ISSN 1083-6160, E-ISSN 1520-586X, Vol. 20, no 11, 2005-2011 p.Article in journal (Refereed) Published
Abstract [en]

A protocol for Pd(II)-catalyzed desulfitative synthesis of aryl ketones from sodium aryl sulfinates and nitriles in continuous flow has been developed. The reactions proceed with microwave heating using microwave transparent tube reactors, affording the desired aryl ketones in fair to good yields. Microwave transparent aluminum oxide reactors were identified as a safe and thermostable alternative to borosilicate glass reactors.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2016
Keyword
Heck-Type Reaction, Direct Esi-Ms, Organic-Synthesis, Sulfinic Acids, High-Speed, Chemistry, Arylation, Nitriles, Hydrogenation, Temperature
National Category
Organic Chemistry
Identifiers
urn:nbn:se:uu:diva-304719 (URN)10.1021/acs.oprd.6b00306 (DOI)000388430300017 ()
Available from: 2016-10-08 Created: 2016-10-08 Last updated: 2017-07-31Bibliographically approved
5. Synthesis of sodium aryl sulfinates from aryl bromides employing 1,4-diazabicyclo[2.2.2]octane bis(sulfur dioxide) adduct (DABSO) as a bench-stable, gas-free alternative to SO2
Open this publication in new window or tab >>Synthesis of sodium aryl sulfinates from aryl bromides employing 1,4-diazabicyclo[2.2.2]octane bis(sulfur dioxide) adduct (DABSO) as a bench-stable, gas-free alternative to SO2
2016 (English)In: Tetrahedron Letters, ISSN 0040-4039, E-ISSN 1359-8562, Vol. 57, no 5, 533-536 p.Article in journal (Refereed) Published
Abstract [en]

Abstract A convenient two-step protocol for the synthesis of sodium aryl sulfinates from aryl bromides and the SO2 surrogate 1,4-diazabicyclo[2.2.2]octane bis(sulfur dioxide) adduct (DABSO) has been developed. A wide range of aryl bromides with respect to electronic properties were employed to give the corresponding sodium arylsulfinates in good to excellent yields. The protocol is especially efficient for electron poor aryl bromides which are often difficult to prepare using existing methods.

Keyword
Sodium sulfinate, Sulfur dioxide surrogate, DABSO
National Category
Organic Chemistry
Identifiers
urn:nbn:se:uu:diva-276924 (URN)10.1016/j.tetlet.2015.12.073 (DOI)000369557300007 ()
Funder
Knut and Alice Wallenberg Foundation
Available from: 2016-02-16 Created: 2016-02-16 Last updated: 2017-07-31Bibliographically approved

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