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. 2022 Aug;19(8):e202200327.
doi: 10.1002/cbdv.202200327. Epub 2022 Aug 3.

Cu-Catalyzed Chan-Evans-Lam Coupling Reactions of 2-Nitroimidazole with Aryl Boronic Acids: An Effort toward New Bioactive Agents against S. pneumoniae

Selvam Raju  1 , Patrick E Sheridan  1 , Alanna K Hauer  1 , Allyn E Garrett  1 , Danielle E McConnell  2   3 , Justin A Thornton  3 , Sean L Stokes  1 , Joseph P Emerson  1
Affiliations

Cu-Catalyzed Chan-Evans-Lam Coupling Reactions of 2-Nitroimidazole with Aryl Boronic Acids: An Effort toward New Bioactive Agents against S. pneumoniae

Selvam Raju et al. Chem Biodivers. 2022 Aug.

Abstract

The coupling of phenylboronic acids with poorly-activated imidazoles is studied as a model system to explore the use of copper-catalyzed Chan-Evans-Lam (CEL) coupling for targeted C-N bond forming reactions. Optimized CEL reaction conditions are reported for four phenanthroline-based ligand systems, where the ligand 4,5-diazafluoren-9-one (dafo, L2) with 1 molar equivalent of potassium carbonate yielded the highest reactivity. The substrate 2-nitroimidazole (also known as azomycin) has documented antimicrobial activity against a range of microbes. Here N-arylation of 2-nitroimidazole with a range of aryl boronic acids has been successfully developed by copper(II)-catalyzed CEL reactions. Azomycin and a range of newly arylated azomycin derivatives were screened against S. pneumoniae, where 1-(4-(benzyloxy)phenyl)-2-nitro-1H-imidazole (3d) was demonstrated to have a minimal inhibition concentration value of 3.3 μg/mL.

Keywords: C−N bond forming reactions; S. pneumoniae; azomycin; copper(II); nitroimidazole.

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Figures

Figure 1.
Figure 1.
Representative natural products and therapeutical molecules containing the imidazole heterocycles.
Figure 2.
Figure 2.
Representative growth curves of S. pneumoniae TIGR4 challenged by different N-arylated complexes in the absence of antimicrobial agent (black circles), and in the presence of 100 μM 1 (open circles), 3a (red squares), 3d (blue triangles), 3i (green squares), and 3j (pink X symbols).
Scheme 1.
Scheme 1.
CEL reactions from previously reported studies and our work herein.
Scheme 2.
Scheme 2.
Substrate Scope study of C—N coupling products. Reaction Conditions: a 0.4 mmol phenylboronic acid, 0.2 mmol imidazole, 0.016 mmol [Cu(L2)2](OTf)2, 0.2 mmol K2CO3, 1 mL MeOH. b 8.0 mmol phenylboronic acid, 4.0 mmol imidazole, 0.32 mmol [Cu(L2)2](OTf)2, 4.0 mmol K2CO3, 20.0 mL MeOH.
Scheme 3.
Scheme 3.
Substrate Scope study of C-N coupling products. Reaction Conditions: 0.4 mmol phenylboronic acid, 0.2 mmol imidazole, 0.016 mmol [Cu(L2)2](OTf)2, 0.2 mmol K2CO3, 1 mL MeOH.
Scheme 4.
Scheme 4.
Functionalization of 3a.
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