We report an investigation of the Chan-Lam amination reaction. A combination of spectroscopy, computational modeling, and crystallography has identified the structures of key intermediates and allowed a complete mechanistic description to be presented, including off-cycle inhibitory processes, the source of amine and organoboron reactivity issues, and the origin of competing oxidation/protodeboronation side reactions. Identification of key mechanistic events has allowed the development of a simple solution to these issues: manipulating Cu(I) → Cu(II) oxidation and exploiting three synergistic roles of boric acid has allowed the development of a general catalytic Chan-Lam amination, overcoming long-standing and unsolved amine and organoboron limitations of this valuable transformation.
1. INTRODUCTION 1.1 Generalities and Context 1.2 C-N Bond Formation via Cross-Coupling Reactions 1.3 C-N Bond Formation via Nucleophile-Electrophile Cross-Coupling 1.4 C-N Bond Formation via Nucleophile-Nucleophile Cross-Coupling 2. DISCUSSION 2.1 Discovery 2.2 Development of Reaction Conditions 2.3 A General Mechanistic Description of the Chan-Lam Reaction 2.4 Reactions Variables and Selection of Reaction Conditions 3. SCOPE OF THE CHAN-LAM AMINATION 3.1 Organoboron Variation 3.2 Aryl Amines (Anilines) 3.3 Heteroaryl Amines (Heterocyclic Anilines) 3.4 Alkyl Amines 3.5 Amides 3.6 NH-Heterocycles 3.7 C-N Bond Formation to non-NH-Nucleophiles 3.8 Sulfonamides and Sulfoximes 3.9 Sequential Processes 3.10 C-N Bond Formation on Nucleobases and Peptides 4. MECHANISM 4.1 Historical Context 4.2 Mechanistic Investigations in the Etherification Reaction 4.3 Mechanistic Investigations in the Amination Reaction 4.4 Mechanistic Investigations in the Amination Reaction: Ligand-based Systems 4.5 Mechanism Summary
A range of alternative solvents have been evaluated within amidation reactions employing common coupling reagents with a view to identifying suitable replacements for dichloromethane and N,N-dimethylformamide. Results and discussion Methods For our study, we elected to use five of the most common amide coupling reagents or reagent combinations: (1-cyano-2ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate (COMU), 12 N,N′-diisopropylcarbo-† Electronic supplementary information (ESI) available: Experimental procedures, analytical data, charts of conversion vs. time for all substrates in all solvents and for all coupling agents. See
The bromodomain and extra-terminal domain (BET) family of proteins bind acetylated lysine residues on histone proteins. The four BET bromodomains-BRD2, BRD3, BRD4, and BRDT-each contain two bromodomain modules. BET bromodomain inhibition is a potential therapy for various cancers and immunoinflammatory diseases, but few reported inhibitors show selectivity within the BET family. Inhibitors with selectivity for the first or second bromodomain are desired to aid investigation of the biological function of these domains. Focused library screening identified a series of tetrahydroquinoxalines with selectivity for the second bromodomains of the BET family (BD2). Structure-guided optimization of the template improved potency, selectivity, and physicochemical properties, culminating in potent BET inhibitors with BD2 selectivity.
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