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Synthesis of 4-Quinolones via a Carbonylative Sonogashira Cross-Coupling Using Molybdenum Hexacarbonyl as a CO Source
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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2015 (English)In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 80, no 3, 1464-1471 p.Article in journal (Refereed) Published
Abstract [en]

A palladium-catalyzed CO gas-free carbonylative Sonogashira/cyclization sequence for the preparation of functionalized 4-quinolones from 2-iodoanilines and alkynes via two different protocols is described. The first method (A) yields the cyclized products after only 20 min of microwave (MW) heating at 120 degrees C. The second method (B) is a gas-free one-pot two-step sequence which runs at room temperature, allowing the use of sensitive substituents (e.g., nitro and bromide groups). For both protocols, molybdenum hexacarbonyl was used as a solid source of CO.

Place, publisher, year, edition, pages
2015. Vol. 80, no 3, 1464-1471 p.
National Category
Chemical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-249019DOI: 10.1021/jo502400hISI: 000349934600019PubMedID: 25575042OAI: oai:DiVA.org:uu-249019DiVA: diva2:807808
Available from: 2015-04-24 Created: 2015-04-10 Last updated: 2017-12-04Bibliographically approved
In thesis
1. Palladium(0)-Catalysed Carbonylative Multicomponent Reactions: Synthesis of Heterocycles and the Application of Quinolinyl Pyrimidines as Enzyme Inhibitors
Open this publication in new window or tab >>Palladium(0)-Catalysed Carbonylative Multicomponent Reactions: Synthesis of Heterocycles and the Application of Quinolinyl Pyrimidines as Enzyme Inhibitors
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Palladium-catalysed carbonylative multicomponent reactions have proven useful for the synthesis of structurally diverse compounds. Carbon monoxide serves as an atom-efficient, one-carbon building block, which allows for further structural elaboration of the carbonyl compound. By varying the components of the carbonylative multicomponent reaction, considerable product diversity can readily be attained. However, due to the reluctance to use toxic CO gas, considerable efforts have been directed at exploring non-gaseous approaches. The work described in this thesis has mainly focused on the development of palladium(0)-catalysed, carbonylative multicomponent synthetic methodology, using the non-gaseous CO source molybdenum hexacarbonyl, in the synthesis of heterocycles and other biologically relevant functional groups.

The first part of this work describes the development of a non-gaseous carbonylative Sonogashira cross-coupling of bifunctional ortho-iodoanilines and terminal alkynes. Where 4-quinolones were synthesised via a carbonylation/cyclisation sequence. Using a similar synthetic strategy, three different N-cyanobenzamide intermediates were prepared by palladium-catalysed carbonylative couplings of various aryl halides and bromides and cyanamide. The formed intermediates provided a basis for further chemical transformations. First, ortho-iodoanilines were carbonylatively coupled with cyanamide and subsequently cyclised to yield heterocyclic 2-aminoquinazolinones. Next, building on those findings, the same synthetic strategy was applied to ortho-halophenols to provide a highly convenient domino carbonylation/cyclisation method for the preparation of benzoxazinones. The developed method was used to evaluate the efficiency of various non-gaseous CO sources. Third, the palladium-catalysed carbonylative synthesis of N-cyanobenzamides, was used to produce biologically relevant N-acylguanidines with considerable product diversity. Finally, one of the developed carbonylative methodologies was used in the preparation of potential NDH-2 inhibitors based on a quinolinyl pyrimidine scaffold. The prepared compounds were biologically evaluated in terms of inhibition of oxidoreductase NDH-2 and antibacterial activity on Gram-negative bacteria, S. aureus and Mtb. The biological evaluation revealed that some of the quinolinyl pyrimidines exerted inhibitory activity on the NDH-2 enzyme and possessed antibacterial properties.

The work described in this thesis has been devoted to the development of non-gaseous one-pot, multicomponent carbonylation/cyclisation and carbonylation/amination reactions. The described methods offer highly attractive synthetic strategies that can be of great value to synthetic and medicinal chemists.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2017. 86 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 237
Keyword
Palladium catalysis, Carbonylation, Multicomponent reactions, Domino reactions, Heterocycles, 4-Quinolones, 2-Aminoquinazolinones, Benzoxazinones, N-Acylguanidines, Type II NADH dehydrogenase, NDH-2
National Category
Organic Chemistry Medicinal Chemistry
Identifiers
urn:nbn:se:uu:diva-329970 (URN)978-91-513-0083-2 (ISBN)
Public defence
2017-11-10, B41, BMC, Husargatan 3, Uppsala, 09:15 (English)
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Supervisors
Available from: 2017-10-20 Created: 2017-09-24 Last updated: 2017-10-20

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Åkerbladh, LindaNordeman, PatrikOdell, Luke R.Larhed, Mats

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