Methods to incorporate deuterium atoms into organic molecules are valuable for the pharmaceutical industry. The introduction of deuterium atoms by a synthetic method enables the direct tracing of the drug molecule without substantially altering its structure or function. The methyl group is one of the most commonly occurring carbon fragments in biologically active molecules. Here, a biomimetic design reagent, 5-(methyl-d3)-5H-dibenzo[b,d]thiophen-5-ium trifluoromethane sulfonate (DMTT), as an analog of S-adenosylmethionine (SAM), has been developed for the selective d3-methylation of complex molecules bearing several possible reactive sites with excellent selectivity and high-level deuterium incorporation. A series of d3-methylated organic molecules and deuterated pharmaceuticals were synthesized under the mild system with excellent functional group compatibility.

The widespread use of phosphine ligand libraries is frequently hampered by the challenges associated with their modular preparation. Here, we report a protocol that appends arenes to arylphosphines to access a series of biaryl monophosphines via rhodium-catalyzed P(III)-directed ortho C–H activation, enabling unprecedented one-fold, two-fold, and three-fold direct arylation. Our experimental and theoretical findings reveal a mechanism involving oxidative addition of aryl bromides to the Rh catalyst, further ortho C–H metalation via a four-membered cyclometalated ring. Given the ready availability of substrates, our approach opens the door to developing more general methods for the construction of phosphine ligands.

Enantioenriched phosphorus compounds play crucial roles in many fields ranging from catalyst to materials science to drug development. Despite advances in the construction of phosphacycles, incorporation of a P-chirogenic center into heterocycles remains challenging. Here, we report an effective method for the preparation of phosphacycles through nickel-catalyzed [4+2] heteroannulation of internal alkynes with aminophosphanes derived from o -haloanilines. Notably, chiral 2-λ5-phosphaquinolines can be prepared from P-stereogenic substrates via NH/PH tautomeric equilibrium without loss of stereochemical integrity. The strategy is found to exhibit a broad scope in terms of both reaction components, enabling modular construction of libraries of 2-λ5-phosphaquinolines with different steric and electronic properties for fine-tuning photophysical properties, where some of these compounds showed distinct fluorescence with high quantum yields. A series of mechanistic studies further shed light on the pathway of the heteroannulation and reasons for stereospecificity.

The precise activation of C–H bonds will eventually provide chemists with transformative methods to access complex molecular architectures. Current approaches to selective C–H activation relying on directing groups are effective for the generation of five-membered, six-membered and even larger ring metallacycles but show narrow applicability to generate three- and four-membered rings bearing high ring strain. Furthermore, the identification of distinct small intermediates remains unsolved. Here, we developed a strategy to control the size of strained metallacycles in the rhodium-catalysed C−H activation of aza-arenes and applied this discovery to tunably incorporate the alkynes into their azine and benzene skeletons. By merging the rhodium catalyst with a bipyridine-type ligand, a three-membered metallacycle was obtained in the catalytic cycle, while utilizing an NHC ligand favours the generation of the four-membered metallacycle. The generality of this method was demonstrated with a range of aza-arenes, such as quinoline, benzo[f]quinolone, phenanthridine, 4,7-phenanthroline, 1,7-phenanthroline and acridine. Mechanistic studies revealed the origin of the ligand-controlled regiodivergence in the strained metallacycles.