Transition metal-mediated formation of C–N bonds is an essential synthetic methodology. The discovery of the Chan–Lam amination provided a C–N bond forming process that was mild, convenient, and ...inexpensive, offering an alternative to complementary methods using other transition metals (TMs). Over the past 20 years, this reaction has seen considerable development in its scope of application, uptake into industry, and understanding of its mechanism. This review provides an account of the development of the Chan–Lam amination, highlighting progress and notable examples of application since 2011. Focus is given to evolution in mechanistic understanding and selected applications of the methodology within medicinal and process chemistry.
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.
Designing strategies to access stereodefined olefinic organoboron species is an important synthetic challenge. Despite significant advances, there is a striking paucity of routes to Z‐α‐substituted ...styrenyl organoborons. Herein, this strategic imbalance is redressed by exploiting the polarity of the C(sp2)−B bond to activate the neighboring π system, thus enabling a mild, traceless photocatalytic isomerization of readily accessible E‐α‐substituted styrenyl BPins to generate the corresponding Z‐isomers with high fidelity. Preliminary validation of this contra‐thermodynamic E→Z isomerization is demonstrated in a series of stereoretentive transformations to generate Z‐configured trisubstituted alkenes, as well as in a concise synthesis of the anti‐tumor agent Combretastatin A4.
It's EZ: Exploitation of the polarity of the C(sp2)−B bond to activate the neighboring π system enables a mild, traceless photocatalytic isomerization of readily accessible E‐α‐substituted styrenyl BPins to generate the corresponding Z‐isomers with high fidelity. The method is used for a series of stereoretentive transformations to generate Z‐configured trisubstituted alkenes, as well as in a concise synthesis of the anti‐tumor agent combretastatin A4.
The Chan–Evans–Lam reaction is a valuable C–N bond forming process. However, aryl boronic acid pinacol (BPin) ester reagents can be difficult coupling partners that often deliver low yields, in ...particular in reactions with aryl amines. Herein, we report effective reaction conditions for the Chan–Evans–Lam amination of aryl BPin with alkyl and aryl amines. A mixed MeCN/EtOH solvent system was found to enable effective C–N bond formation using aryl amines while EtOH is not required for the coupling of alkyl amines.
Control of boronic acid speciation is presented as a strategy to achieve nucleophile chemoselectivity in the Suzuki–Miyaura reaction. Combined with simultaneous control of oxidative addition and ...transmetalation, this enables chemoselective formation of two CC bonds in a single operation, providing a method for the rapid preparation of highly functionalized carbogenic frameworks.
Breaking the limit: Chemoselective Suzuki–Miyaura cross‐coupling has previously been limited to single CC bond formation due to a lack of nucleophile selectivity. Manipulation of boron speciation enables complete chemoselective control of the Suzuki–Miyaura reaction, allowing harmonized sequential cross‐coupling in a single operation.
The bromodomain and extra-terminal domain (BET) family of proteins bind acetylated lysine residues on histone proteins. The four BET bromodomainsBRD2, BRD3, BRD4, and BRDTeach 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.
Ligand metathesis of Pd(II) complexes is mechanistically essential for cross-coupling. We present a study of halide→OH anion metathesis of (Ar)PdII complexes using vinylBPin as a bifunctional ...chemical probe with Pd(II)-dependent cross-coupling pathways. We identify the variables that profoundly impact this event and allow control to be leveraged. This then allows control of cross-coupling pathways via promotion or inhibition of organoboron transmetalation, leading to either Suzuki–Miyaura or Mizoroki–Heck products. We show how this transmetalation switch can be used to synthetic gain in a cascade cross-coupling/Diels–Alder reaction, delivering borylated or non-borylated carbocycles, including steroid-like scaffolds.
An investigation into the mechanism of Cu-catalyzed aryl boronic acid halodeboronation using electrophilic halogen reagents is reported. Evidence is provided to show that this takes place via a ...boronate-driven ipso-substitution pathway and that Cu is not required for these processes to operate: general Lewis base catalysis is operational. This in turn allows the rational development of a general, simple, and effective base-catalyzed halodeboronation that is amenable to the preparation of 125I-labeled products for SPECT applications.
A catalytic amidation method has been developed, employing 2,2,2-trifluoroethanol to facilitate condensation of unactivated esters and amines, enabling the synthesis of a range of amide products in ...good to excellent yields. Mechanistic studies indicate the reaction proceeds through a trifluoroethanol-derived active ester intermediate.
Chemoselective Suzuki–Miyaura cross‐coupling generally requires a designed deactivation of one nucleophile towards transmetallation. Here we show that boronic acids can be chemoselectively reacted in ...the presence of ostensibly equivalently reactive boronic acid pinacol (BPin) esters by kinetic discrimination during transmetallation. Simultaneous electrophile control allows sequential chemoselective cross‐couplings in a single operation in the absence of protecting groups.
Set phases to stun: Chemoselective Suzuki–Miyaura cross‐coupling can be achieved by kinetic discrimination of boronic acids and BPin esters during transmetallation. Simultaneous electrophile control allows sequential chemoselective cross‐couplings in a single operation in the absence of protecting groups.
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