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Palladium(0)-Catalysed Carbonylative Multicomponent Reactions: Synthesis of Heterocycles and the Application of Quinolinyl Pyrimidines as Enzyme Inhibitors
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Description
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. , p. 86
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 237
Keywords [en]
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: urn:nbn:se:uu:diva-329970ISBN: 978-91-513-0083-2 (print)OAI: oai:DiVA.org:uu-329970DiVA, id: diva2:1143970
Public defence
2017-11-10, B41, BMC, Husargatan 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2017-10-20 Created: 2017-09-24 Last updated: 2018-01-13
List of papers
1. Synthesis of 4-Quinolones via a Carbonylative Sonogashira Cross-Coupling Using Molybdenum Hexacarbonyl as a CO Source
Open this publication in new window or tab >>Synthesis of 4-Quinolones via a Carbonylative Sonogashira Cross-Coupling Using Molybdenum Hexacarbonyl as a CO Source
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2015 (English)In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 80, no 3, p. 1464-1471Article 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.

National Category
Chemical Sciences
Identifiers
urn:nbn:se:uu:diva-249019 (URN)10.1021/jo502400h (DOI)000349934600019 ()25575042 (PubMedID)
Available from: 2015-04-24 Created: 2015-04-10 Last updated: 2017-12-04Bibliographically approved
2. Synthesis of 2-Aminoquinazolinones via Carbonylative Coupling of ortho-lodoanilines and Cyanamide
Open this publication in new window or tab >>Synthesis of 2-Aminoquinazolinones via Carbonylative Coupling of ortho-lodoanilines and Cyanamide
2016 (English)In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 81, no 7, p. 2966-2973Article in journal (Refereed) Published
Abstract [en]

Herein, we describe a convenient and efficient synthesis of 2-aminoquinazolin-4(3H)-ones and N1-substituted 2-aminoquinazolin-4(1H)-ones by a domino carbonylation/cyclization process. The reaction proceeds via carbonylative coupling of readily available ortho-iodoanilines with cyanamide followed by in situ ring closure of an N-cyanobenzamide intermediate. The products were easily isolated by precipitation in moderate to excellent yields for a wide range of substrates, making this a highly attractive method for the synthesis of 2-aminoquinazolinones.

National Category
Organic Chemistry
Identifiers
urn:nbn:se:uu:diva-295556 (URN)10.1021/acs.joc.6b00249 (DOI)000373520200028 ()26967689 (PubMedID)
Available from: 2016-06-22 Created: 2016-06-08 Last updated: 2017-11-28Bibliographically approved
3. Synthesis of 4H-Benzo[e][1,3]oxazin-4-ones by a Carbonylation-Cyclization Domino Reaction of ortho-Halophenols and Cyanamide
Open this publication in new window or tab >>Synthesis of 4H-Benzo[e][1,3]oxazin-4-ones by a Carbonylation-Cyclization Domino Reaction of ortho-Halophenols and Cyanamide
2017 (English)In: ChemistryOpen, ISSN 2191-1363, Vol. 6, no 5, p. 620-628Article in journal (Refereed) Published
Abstract [en]

A mild and convenient one-step preparation of 4H-1,3-benzoxazin-4-ones by a domino carbonylation-cyclization process is developed. Readily available ortho-iodophenols are subjected to palladium-catalyzed carbonylative coupling with Mo(CO)(6) and cyanamide, followed by a spontaneous, intramolecular cyclization to afford 4H-1,3-benzaxazin-4-ones in moderate to excellent yields. Furthermore, the scope of the reaction is ex tended to include challenging orthobromophenols. Finally, to highlight the versatility of the developed method, Mo(CO), is successfully replaced with a wide array of CO-releasing reagents, such as oxalyl chloride, phenyl formate, 9-methylfluorene-9-carbonyl chloride, and formic acid, making this an appealing strategy for the synthesis of 4H-benzo[e][1,3]oxazin-4-ones.

National Category
Organic Chemistry
Identifiers
urn:nbn:se:uu:diva-329967 (URN)10.1002/open.201700130 (DOI)000413038400003 ()29046856 (PubMedID)
Available from: 2017-09-24 Created: 2017-09-24 Last updated: 2018-02-05Bibliographically approved
4. Palladium(0)-Catalyzed Carbonylative Synthesis of N-Acylguanidines
Open this publication in new window or tab >>Palladium(0)-Catalyzed Carbonylative Synthesis of N-Acylguanidines
(English)In: Article in journal (Other academic) Submitted
National Category
Organic Chemistry
Identifiers
urn:nbn:se:uu:diva-329968 (URN)
Available from: 2017-09-24 Created: 2017-09-24 Last updated: 2017-09-24
5. Synthesis and in vitro biological evaluation of quinolinyl pyrimidines targeting type II NADH-dehydrogenase (NDH-2)
Open this publication in new window or tab >>Synthesis and in vitro biological evaluation of quinolinyl pyrimidines targeting type II NADH-dehydrogenase (NDH-2)
Show others...
(English)In: Article in journal (Other academic) Submitted
National Category
Medicinal Chemistry
Identifiers
urn:nbn:se:uu:diva-329969 (URN)
Available from: 2017-09-24 Created: 2017-09-24 Last updated: 2018-01-13

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