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Aminocarbonylations Employing Mo(CO)(6) and a Bridged Two-Vial System: Allowing the Use of Nitro Group Substituted Aryl Iodides and Aryl Bromides
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.
2012 (English)In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 77, no 24, 11393-11398 p.Article in journal (Refereed) Published
Abstract [en]

A bridged two-vial system aminocarbonylation protocol where Mo(CO)(6) functions as an external in situ solid source of CO has been developed. For the first time both nitro group containing aryl/heteroaryl iodides and bromides gave good to excellent yields in the Mo(CO)(6)-mediated and palladium(0)-catalyzed conversion to benzamides, while the identical one-vessel protocol afforded extensive reduction of the nitro functionality. The above-mentioned bridged two-compartment protocol furnished good results with both primary amines and secondary amines and sluggish aniline nucleophiles at 65-85 °C reaction temperatures.

Place, publisher, year, edition, pages
2012. Vol. 77, no 24, 11393-11398 p.
National Category
Medicinal Chemistry Natural Sciences
Identifiers
URN: urn:nbn:se:uu:diva-189519DOI: 10.1021/jo302322wISI: 000312564900046PubMedID: 23205569OAI: oai:DiVA.org:uu-189519DiVA: diva2:581754
Funder
Knut and Alice Wallenberg FoundationSwedish Research Council
Available from: 2013-01-02 Created: 2013-01-02 Last updated: 2017-12-06Bibliographically approved
In thesis
1. Development of Palladium-Promoted 11C/12C-Carbonylations and Radiosynthesis of Amyloid PET Ligands
Open this publication in new window or tab >>Development of Palladium-Promoted 11C/12C-Carbonylations and Radiosynthesis of Amyloid PET Ligands
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

In the first part of this thesis, palladium(0)-catalyzed and -mediated carbonylations are discussed. Paper I describes a new method for the safe, efficient use of a solid carbon monoxide source in the synthesis of primary and secondary benzamides. In total, 35 benzamides were synthesized from aryl iodides (20 examples, 69-97% yield) and aryl bromides (15 examples, 32-93% yield). Reduction-prone groups were used successfully in the reactions. In paper II, the same protocol was adopted for the palladium(0)-catalyzed synthesis of N-cyanobenzamides from aryl iodides/bromides, carbon monoxide and cyanamide. In total, 22 N-cyanobenzamides were synthesized (42-88% yield). The radiosynthesis of [11C]N-cyanobenzamides is discussed in paper III. In total, 22 compounds were synthesized from various aryl halides in 28-79% decay corrected radiochemical yield. The protocol was then applied to the radiosynthesis of [11C]N-cyanobenzamide analogs of flufenamic acid and dazoxibene.

In the second part of this thesis, compounds of interest in relation to amyloid diseases are discussed. Paper IV describes the solid-phase synthesis of BACE-1 enzyme inhibitors containing secondary and tertiary hydroxyl as the transition state isostere. In total, 22 inhibitors were synthesized. The most potent compound (IC50= 0.19 µM) was co-crystallized at the active site of the enzyme to reveal a new binding mode. In paper V, the evaluation of a potent BACE-1 inhibitor as a potential radiotracer for use in PET is described. The radiolabeled [11C]BSI-IV was obtained in 29±12% decay corrected radiochemical yield by a three-component palladium(0)-mediated aminocarbonylation. Its properties as a potential PET tracer were investigated in vitro by autoradiography and in vivo in rats using small animal PET-CT. A new class of amyloid-binding PET ligands is described in paper VI. Three polythiophenes were labeled with carbon-11 or fluorine-18 (26-43% decay-corrected radiochemical yield). The in vitro studies showed that these ligands bind specifically to amyloid deposits. In vivo PET showed low uptake in the organs of interest in healthy rats and a monkey. These results suggest the labeled thiophenes derivatives could be useful as PET tracers for the study of amyloid diseases.

Place, publisher, year, edition, pages
Uppsala: Uppsala universitet, 2014. 76 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 183
Keyword
Palladium, Carbonylation, Positron emission tomography, PET, Carbon-11, Fluor-18, Radiochemistry, Amyloidosis, Palladium, Karbonyleringar, Positronemissionstomografi, PET, Kol-11, Fluor-18, Radiokemi, Amyloidos
National Category
Pharmaceutical Chemistry Medicinal Chemistry
Research subject
Pharmaceutical Science; Chemistry with specialization in Organic Chemistry; Medicinal Chemistry
Identifiers
urn:nbn:se:uu:diva-213863 (URN)978-91-554-8843-7 (ISBN)
Public defence
2014-02-21, B21, BMC, Husargatan 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2014-01-30 Created: 2014-01-05 Last updated: 2014-02-10

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Nordeman, PatrikOdell, Luke RLarhed, Mats

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