Copper-catalysed C-H functionalisation gives access to 2-aminobenzimidazoles

This paper describes the development, optimisation and exemplification of a copper-catalysed C-H functionalisation to form pharmaceutically relevant 2-aminobenzimidazoles from aryl-guanidines. High throughput screening was used as a tool to identify a catalytically active copper source, DoE was used...

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Published inOrganic & biomolecular chemistry Vol. 17; no. 34; pp. 7943 - 7955
Main Authors Clark, Peter R, Williams, Glynn D, Tomkinson, Nicholas C. O
Format Journal Article
LanguageEnglish
Published CAMBRIDGE Royal Soc Chemistry 28.08.2019
Royal Society of Chemistry
Subjects
Additives
Aminobenzimidazole
Antihistamines
Aromatic compounds
Chemistry
Chemistry, Organic
Copper
Copper compounds
Design of experiments
Design optimization
Guanidines
High-throughput screening
Isotope effect
Mathematical models
NMR
Nuclear magnetic resonance
Physical Sciences
Science & Technology
Statistical models
POTENT
AMIDINES
BIOLOGICAL EVALUATION
BOND FORMATION
INHIBITORS
BENZIMIDAZOLES
DISCOVERY
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Summary:This paper describes the development, optimisation and exemplification of a copper-catalysed C-H functionalisation to form pharmaceutically relevant 2-aminobenzimidazoles from aryl-guanidines. High throughput screening was used as a tool to identify a catalytically active copper source, DoE was used for reaction optimisation and a range of aryl-guanidines were prepared and exposed to the optimum conditions to afford a range of 2-aminobenzimidazoles in moderate to good yields. The methodology has been applied to the synthesis of Emedastine, a marketed anti-histamine pharmaceutical compound, with the key cyclisation step performed on a gram-scale. This paper describes the development, optimisation and exemplification of a copper-catalysed C-H functionalisation to form pharmaceutically relevant 2-aminobenzimidazoles from aryl-guanidines.
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Electronic supplementary information (ESI) available: Copies of
C NMR spectra of all new compounds can be found, along with 1H of known compounds. Results of a high throughput screen of copper sources, additives & solvents, the kinetic isotope effect experiment and the design of experiment optimisation procedure & the statistical model. See DOI
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ISSN:1477-0520
1477-0539
DOI:10.1039/c9ob01651a