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

Abstract

Multicomponent reactions are attracting strong interest as they contribute to develop 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 of utmost interest to help deciphering some of these processes and the development of integrated experimental and theoretical approaches thus appear as most powerful 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 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 scenarii were explored using experimental techniques including radical trap and 15 N labeling studies combined to 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 outweigh direct amination in these reactions. The perfect consistency between DFT results and specific experiments to validate them strongly support these mechanistic conclusions and highlights the potency of this combined approach.

Imidazoline synthesis: mechanistic investigations show that Fe catalysts promote a new multicomponent redox reaction

“…Our study of the mechanism of amidine formation through MeCN insertion revealed that in similar conditions THF abolished amidine formation by blocking acetonitrile binding to 1b, thereby demonstrating that MeCN binds to the Fe catalyst. 34 To investigate whether MeCN binding is required to form imidazoline, we performed a fourth series of experiments (Table 4) in which the reaction medium was MeCN/THF mixtures of variable compositions.…”

“…Furthermore, using the same approach, we analyzed very recently the far more complex mechanism of amidination 34 combining nitrene transfer and nitrile insertion, which is especially relevant to the present purpose. Such reactivity calculations using the hybrid B3LYP functional are impracticable for catalyst 1b because of the size of the system combined to the multiplicity of spin states of both Fe.…”

“…This was taken into account in the computations by considering both Fe IV (=NTs) and Fe V (=NTs) active species derived from 1a as in our investigation of amidine formation. 34 Such highvalent Fe-imido species are well known to exhibit some radical character on the nitrogen atom, 26,29,35,36 but for the sake of clarity we prefer this notation based on Fe oxidation state. Accordingly, we used the same computational approach as developed in these latter mechanistic studies.…”

“…To summarize, our mechanistic studies have revealed that imidazoline can be accessed through an unprecedented multicomponent redox reaction where free acetonitrile traps an intermediate benzylic radical. Acetonitrile insertion into a product of nitrene transfer has been described only in a very limited number of cases: allylic amination catalyzed by Mn or Fe porphyrins, 39 and aliphatic aminations catalyzed by copper 40 and iron 34 complexes. In all cases these reactions led to an amidine derivative.…”

“…As far as mechanisms are concerned, it is clear that acetonitrile insertion through formation of metallacyclobutane (Scheme 4) is possible but it is generally unfavorable with respect to other pathways. 34,38 Albeit acetonitrile insertions to form imidazoline and amidine bear overall resemblance, their mechanisms depart in many respects as highlighted in Scheme 6.…”