Experiments and DFT Computations Combine to Decipher Fe-Catalyzed Amidine Synthesis through Nitrene Transfer and Nitrile Insertion

Multicomponent
reactions are attracting strong interest as they
contribute to the development of more efficient synthetic chemistry.
Understanding their mechanism is thus an important issue to optimize
their operation. However, it is also a challenging task owing to the
complexity of the succession of molecular events involved. Computational
methods have recently proven to be of utmost interest to help decipher
some of these processes, and the development of integrated experimental
and theoretical approaches thus appears as the most powerful means
to understand these mechanisms at the molecular level. A good example
is given by the synthesis of amidines which are important pharmaceutical
compounds. Their synthesis requires the association of three components,
often an alkyne, a secondary amine, and an organic azide as the nitrene
precursor. We found that an alternative way is offered by an Fe-catalyzed
combination of a hydrocarbon, a nitrile, and a nitrene which gives
amidines in good yields under mild conditions. The efficiency of the
transformation and the paucity of mechanistic information on these
reactions prompted us to thoroughly investigate its mechanism. Several
mechanistic scenarios were explored using experimental techniques,
including radical trap and 15N labeling studies, combined
with density-functional theory (DFT) calculations of reaction profiles.
This allowed us to show that the amidination reaction involves the
trapping of an intermediate substrate cation by an Fe-released acetonitrile
molecule pointing to a true multicomponent reaction occurring exclusively
within the cage around the metal center. Moreover, the calculated
energy barriers of the individual steps explained how amidination
outweighs direct amination in these reactions. The perfect consistency
between DFT results and specific experiments to validate them strongly
supports these mechanistic conclusions and highlights the potency
of this combined approach.