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Selective activation of an sp³ hybridized C-H bond adjacent to an amine, and the subsequent functionalization of this bond, is an attractive approach for the synthesis of a-chiral amines.  When mediated in a catalytic fashion, this strategy results in the 100% atom economic preparation of structurally diverse amines from primary amine and alkene starting materials in one C-C bond forming reaction.  Preliminary results in our laboratory have attained such a transformation (the cyclization of an aminoalkene to give a substituted cyclohexylamine) in up to 80% yield.  Preliminary investigations suggest that multi-metallic species are responsible for the interesting reactivity observed and we have postulated a bridging imido as a “metal-protected amine” to permit C-H activation adjacent to the nitrogen. 

Since submission of the proposal we have disclosed a Zr pyridonate complex for this emerging catalytic technology that has been coined hydroaminoalkylation (preliminary work funded from other sources).  Notably the Ti congener of the same pyridonate complex is not catalytically viable for the same transformations.  Indeed, the complexes from our program that are capable of mediating this C-C bond forming transformation were initially developed for catalytic hydroamination.  Since the submission and funding of this proposal Prof. Sven Doye has shown that other Ti hydroamination catalysts, including the commercially available Ti(NMe₂)₄ and Ti(Bn)₄ complexes can be used for this transformation in an intramolecular and intermolecular fashion.  We have established Zr(NMe₂)₄ can mediate this transformation with select substrates, however, it is not broadly useful for this transformation.  We have also verified that our Zr pyridonate complexes are only useful for the intramolecular version of this reaction and importantly, they are selectively reactive with primary amines substrates.  Thus, initial work on this project, which has been undertaken by two doctoral students, has focused on what features control intramolecular hydroaminoalkylation reactivity, including metal, ligand structure, concentrations, solvents and reaction temperatures.  These investigations have been pursued using a 2 pronged approach.  One student has focused on mechanistic investigations, which includes the stoichiometric preparation of reactive intermediate and reactions kinetics.  This work is presently being prepared for publication.  In our second approach we are methodically varying the ligand environment about the reactive metal center, to test our current working hypothesis that sterically accessible metal complexes must be used to promote the formation of reactive dimers.  Furthermore, the electronic impact of metal complex upon reactivity is an area of on-going investigation.   

Various group 4 bis(amidate) complexes have been screened for 6-membered ring formation via intramolecular hydroaminoalkylation. Of the complexes screened, Ti complexes are preferred over Zr counterparts, which show no sign of hydroaminoalkylation.  This observation for bis(amidates) is in contrast to the bis(pyridonate) system. The most suitable complex was that of Ti bis(N-(2,6-dimethylphenyl)pivalamidate) complex with a starting material consumption of 55.4% with no hydroamination products observed by ¹H NMR spectroscopy. It seems that less sterically bulky amidate ligands are preferred for hydroaminoalkylation, in contrast to hydroamination catalysis. However, these group 4 bis(amidate) complexes are not as reactive as commercially available Ti(NMe₂)₄.

Thus, less bulky titanium bis(pyridonate) complexes were synthesized from commercially available pyridones and screened with three different primary aminoalkene substrates making 5- and 6-membered rings.  Electron-withdrawing groups such as –Cl and –CF₃ groups did not favour hydroaminoalkylation, and it seems that substituents at the 6-position of pyridones are unfavourable for hydroaminoalkylation. The most promising pyridone ligands are those with substituents at the 3-position (a-to carbonyl). Such ligands show promise for 5-membered ring formation via hydroaminoalkylation, however, their reactivity for 6-membered cyclization is not yet satisfactory.

Mono(η⁵-cyclopentadienyl)-mono(amidate)-bis(dimethylamido) Ti precatalysts for intramolecular hydroaminoalkylationhave been prepared.  These systems have the potential to exploit the bridging nature of the amidate ligands and could form a binuclear complex with Cp (η⁵-C₅H₅) capping ligands on the “ends”. Various amidate ligands were screened, however, CpTi(NMe₂)₃ had the highest reactivity. For all the systems shown above no hydroamination was observed. Furthermore, mono(η⁵-cyclopentadienyl)-mono(pyridonate)-bis(dimethylamido) Ti precatalysts were screened, but their reactivity and selectivity were not as promising as bis(pyridonate) Ti complexes.

To date, we have found that in the presence of less sterically demanding ligands, Ti is indeed the metal of preference for this transformation.  We have also established that recently disclosed ureate catalyst systems are completely selective for hydroamination and there is no observed hydroaminoalkylation. Kinetic investigations show a first order dependence upon substrate and non-linear dependence upon catalyst concentration.  Using KIE of deuterated substrates a turnover limiting C-H activation step is presently postulated.  Not surprisingly an Eyring analysis reveals a very large and negative entropy of activation, consistent with an highly order transition state.  At present we favour a catalytic mechanism that procedes via formation of bridged species and on-going efforts target the discrete preparation of organometallic reactive intermediates.   

Future directions include the development of a new class of N,O bridged, dinuclear catalysts for this C-H functionalization reaction to give new C-C bonds a to nitrogen.  The amidate N,O chelating ligands that we have been using for the preparation of monomeric metal complexes are also well known to promote bridging interactions between metal centers.  The proposed N,O bridged dinuclear complexes will be investigated for substrate scope and will be probed mechanistically to better understand the catalytic cycle.  Initial investigations will focus on intramolecular versions of this reaction, with the development of systems that can mediate intermolecular reactions as a long term objective.  Ultimately, this project may result in the development of asymmetric catalysts to give enantiopure a-chiral amines.