Mechanistic Insights into Fe Catalyzed α‐C−H Oxidations of Tertiary Amines

Abstract

We report detailed mechanistic investigations of an iron‐based catalyst system, which allows the α‐C−H oxidation of a wide variety of amines. In contrast to other catalysts that effect α‐C−H oxidations of tertiary amines, the system under investigation exclusively employs peroxy esters as oxidants. More common oxidants (e. g. tBuOOH) previously reported to affect amine oxidations via free radical pathways do not provide amine α‐C−H oxidation products in combination with the described catalyst system. The investigations described herein employ initial rate kinetics, kinetic profiling, DFT calculations as well as Eyring, kinetic isotope effect, Hammett, ligand coordination, and EPR studies to shed light on the Fe catalyst system. The obtained data suggest that the catalytic mechanism proceeds through C−H abstraction at a coordinated substrate molecule. This rate‐determining step occurs either through an Fe(IV) oxo pathway or a 2‐electron pathway at an Fe(II) intermediate with bound oxidant. DFT calculations indicate that the Fe(IV) oxo mechanism will be the preferred route of these two possibilities. We further show via kinetic profiling and EPR studies that catalyst activation follows a radical pathway, which is initiated by hydrolysis of PhCO3tBu to tBuOOH. Overall, the obtained mechanistic data support a non‐classical, Fe catalyzed pathway that requires substrate binding, inducing selectivity for α‐C−H functionalization.

Iron-Catalyzed α-C–H Cyanation of Simple and Complex Tertiary Amines

“…We reasoned that establishing the desired reactivity with the unactivated substrate 1 should in turn also enable C-H functionalizations of anilines and benzylic amines, and thus provide a general reaction protocol. Gratifyingly, minor changes to the reported conditions for α-C-H oxygenation 27,28 (use of MeCN as solvent; addition of NaCN as cyanide source instead of H 2 O) afforded 49% of the desired α-C-H cyanation product 1a after 24 h (Table 1, entry 1), using the reported FeCl 3 /2-picolinic acid (PA) catalyst system. Extending the reaction time to 48 h resulted in a small increase in yield (57%, entry 2).…”

“…Consistently with the discussed data, we propose a mechanistic hypothesis that enables substrate oxidation without the intermediacy of free radical species (Scheme 6). This hypothesis was formulated in analogy to detailed mechanistic studies 28 The proposed mechanism lacks the intermediacy of free radicals necessary for productive turnover. This hypothesis is consistent with the ability to tolerance double and triple bonds in the amine substrates without further reactivity at those sites; the significant remaining catalytic activity of the system in the presence of BHT; higher yields obtained with 18-crown-6; and the dealkylation products observed with i Pr 2 NH 31 and imipramine 26 as substrates.…”

Iron Catalyzed α-C-H Cyanation of Simple and Complex Tertiary Amines

“…The reaction optimization was initiated using conditions very similar to those reported for Fe catalyzed amine α-C-H oxygenation. 27,28 The one major difference we introduced for amine α-C-H cyanation was the departure from pyridine as a solvent to avoid incompatibilities caused by potential base sensitivities of complex substrates. Tri-n-butylamine (1) was chosen as a test substrate, as its α-C-H bonds do not exhibit additional activation (i.e., benzylic or in aniline-type C-H bonds).…”

“…Consistently with the discussed data, we propose a mechanistic hypothesis that enables substrate oxidation without the intermediacy of free radical species (Scheme 6). This hypothesis was formulated in analogy to detailed mechanistic studies 28 of amine α-C-H oxidation with FeCl 3 /PA/PhCO 3 t Bu.…”

Iron Catalyzed α-C-H Cyanation of Simple and Complex Tertiary Amines

“…All components of the described system are readily available, allowing implementation of the presented methodology without the need for lengthy catalyst synthesis.Recent mechanistic work in the Fe catalyzed α-C-H oxidation of tertiary amines has uncovered a radical rebound (instead of a free radical) mechanism by which tertiary aliphatic amines can undergo α-C-H functionalization. [27][28][29] We speculated that this reaction manifold could enable α-C-H cyanations with greater functional group tolerance than methods mediated by free radicals and thus be valuable for late-stage functionalization approaches in complex molecular settings (Scheme 1C). This manuscript details reaction optimizations and substrate scope studies employing this approach to establish a general catalyst system for the late-stage functionalization of tertiary amine substrates.…”