A highly efficient, convergent approach to the synthesis of the angiotensin I1 receptor antagonist losartan (1) is described. Directed ortho-metalation of 2-trityl-5-phenyltetrazole provides the key boronic acid intermediate 10 for palladium-catalyzed biaryl coupling with bromide 5 obtained from the regioselective alkylation of the chloroimidazole 2. This methodology overcomes many of the drawbacks associated with previously reported syntheses.
The palladium-catalyzed coupling of aryl and heteroaryl chlorides with primary amides under mild homogeneous reaction conditions is reported. Successful C−N coupling is enabled by the use of a unique "dual-base" system consisting of DBU and NaTFA, which serve as proton acceptor and halide scavenger, respectively, using low catalyst loadings (0.5 mol %) with readily available, air-stable palladium precatalysts. The DBU/NaTFA system also enables the room-temperature coupling of primary aryl amines with aryl chlorides and is tolerant of a variety of base-sensitive functional groups.
A practical synthesis of nicotinamide mononucleotide (b-NMN) and a high yield coupling with AMP-morpholidate that also provides NAD + in an efficient manner are reported.
Investigations into nickel-catalyzed borylation reactions have led to the development of an experimental design of 24 reaction conditions for rapid lead identification. A case study on the borylation of a model aryl bromide with B 2 (OH) 4 prompted a series of mechanistic and stability studies to better understand the catalytic cycle and factors that affect robustness. HTEx was employed to study the effect of a series of scavengers on the remediation of nickel from the reaction stream. These combined results have generated an increased understanding of nickel-catalyzed borylation reactions and set the stage for their expanded use in process chemistry.
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