Intramolecular alkyne hydroamidation
represents a straightforward
approach for the access to synthetically valuable cyclic enamides.
Despite some advances made in this realm, the ability to attain a
precise regiocontrol still remains challenging, especially for endo cyclization that leads to six-membered and larger azacyclic
rings. Herein, we report a NiH-catalyzed intramolecular hydroamidation
of alkynyl dioxazolones that allows for an excellent endo selectivity, thus affording a range of six- to eight-membered endocyclic
enamides with a broad scope. Mechanistic investigations revealed that
Ni(I) catalysis is operative in the current system, proceeding via
regioselective syn-hydronickelation, alkenylnickel E/Z isomerization, and Ni-centered inner-sphere
nitrenoid transfer. In particular, the key alkenylnickel isomerization
step, which previously lacked mechanistic understandings, was found
to take place through the η2-vinyl transition state.
The synthetic value of this protocol was demonstrated by diastereoselective
modifications of the obtained endocyclic enamides to highly functionalized
δ-lactam scaffolds.
Synthesis of heteroaryl amines has been an important topic in organic chemistry because of their importance in smallmolecule discovery. In particular, 2-aminopyrimidines represent a highly privileged structural motif that is prevalent in bioactive molecules, but a general strategy to introduce the pyrimidine C2−N bonds via direct functionalization is elusive. Here we describe a synthetic platform for site-selective C−H functionalization that affords pyrimidinyl iminium salt intermediates, which then can be transformed into various amine products in situ. Mechanism-based reagent design allowed for the C2-selective amination of pyrimidines, opening the new scope of site-selective heteroaryl C−H functionalization. Our method is compatible with a broad range of pyrimidines with sensitive functional groups and can access complex aminopyrimidines with high selectivity.
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