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A directing group switch in copper-catalyzed electrophilic C-H amination/migratory annulation cascade: divergent access to benzimidazolone/benzimidazole.

ABSTRACT: We present here a copper-catalyzed electrophilic ortho C-H amination of protected naphthylamines with N-(benzoyloxy)amines, cyclization with the pendant amide, and carbon to nitrogen 1,2-directing group migration cascade to access N,N-disubstituted 2-benzimidazolinones. Remarkably, this highly atom-economic tandem reaction proceeds through a C-H and C-C bond cleavage and three new C-N bond formations in a single operation. Intriguingly, the reaction cascade was altered by the subtle tuning of the directing group from picolinamide to thiopicolinamide furnishing 2-heteroaryl-imidazoles via the extrusion of hydrogen sulfide. This strategy provided a series of benzimidazolones and benzimidazoles in moderate to high yields with low catalyst loading (66 substrates with yields up to 99%). From the control experiments, it was observed that after the C-H amination an incipient tetrahedral oxyanion or thiolate intermediate is formed via an intramolecular attack of the primary amine to the amide/thioamide carbonyl. It undergoes either a 1,2-pyridyl shift with the retention of the carbonyl moiety or H₂S elimination for scaffold diversification. Remarkably, inspite of a positive influence of copper in the reaction outcome, from our preliminary investigations, the benzimidazolone product was obtained in good to moderate yields in two steps under metal-free conditions. The N-pyridyl moiety of the benzimidazolone was removed for further manipulation of the free NH group.

SUBMITTER: Begam HM

PROVIDER: S-EPMC9116329 | biostudies-literature | 2022 May

REPOSITORIES: biostudies-literature

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A directing group switch in copper-catalyzed electrophilic C-H amination/migratory annulation cascade: divergent access to benzimidazolone/benzimidazole.

Begam Hasina Mamataj HM Nandi Shantanu S Jana Ranjan R

Chemical science 20220414 19

We present here a copper-catalyzed electrophilic ortho C-H amination of protected naphthylamines with N-(benzoyloxy)amines, cyclization with the pendant amide, and carbon to nitrogen 1,2-directing group migration cascade to access N,N-disubstituted 2-benzimidazolinones. Remarkably, this highly atom-economic tandem reaction proceeds through a C-H and C-C bond cleavage and three new C-N bond formations in a single operation. Intriguingly, the reaction cascade was altere ...[more]

PMID: 35694354

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Project description:BackgroundChitin, the main form of aminated polysaccharide in nature, is a biocompatible, polycationic, and antimicrobial biopolymer used extensively in industrial processes. Despite the abundance of chitin, applications thereof are hampered by difficulties in feedstock harvesting and limited structural versatility. To address these problems, we proposed a two-step cascade employing carbohydrate oxidoreductases and amine transaminases for plant polysaccharide aminations via one-pot reactions. Using a galactose oxidase from Fusarium graminearum for oxidation, this study compared the performance of CvATA (from Chromobacterium violaceum) and SpATA (from Silicibacter pomeroyi) on a range of oxidized carbohydrates with various structures and sizes. Using a rational enzyme engineering approach, four point mutations were introduced on the SpATA surface, and their effects on enzyme activity were evaluated.ResultsHerein, a quantitative colorimetric assay was developed to enable simple and accurate time-course measurement of the yield of transamination reactions. With higher operational stability, SpATA produced higher product yields in 36 h reactions despite its lower initial activity. Successful amination of oxidized galactomannan by SpATA was confirmed using a deuterium labeling method; higher aminated carbohydrate yields achieved with SpATA compared to CvATA were verified using HPLC and XPS. By balancing the oxidase and transaminase loadings, improved operating conditions were identified where the side product formation was largely suppressed without negatively impacting the product yield. SpATA mutants with multiple alanine substitutions besides E407A showed improved product yield. The E407A mutation reduced SpATA activity substantially, supporting its predicted role in maintaining the dimeric enzyme structure.ConclusionsUsing oxidase-amine transaminase cascades, the study demonstrated a fully enzymatic route to polysaccharide amination. Although the activity of SpATA may be further improved via enzyme engineering, the low operational stability of characterized amine transaminases, as a result of low retention of PMP cofactors, was identified as a key factor limiting the yield of the designed cascade. To increase the process feasibility, future efforts to engineer improved SpATA variants should focus on improving the cofactor affinity, and thus the operational stability of the enzyme.

Dataset Information

A directing group switch in copper-catalyzed electrophilic C-H amination/migratory annulation cascade: divergent access to benzimidazolone/benzimidazole.

Publications

A directing group switch in copper-catalyzed electrophilic C-H amination/migratory annulation cascade: divergent access to benzimidazolone/benzimidazole.

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