David C. Leitch

Broadening the scope of group 4 hydroamination catalysis using a tethered ureate ligand.

A broadly applicable group-4-based precatalyst for the hydroamination of primary and secondary amines was developed. Screening experiments involving a series of amide and urea proligands led to the discovery of a tethered bis(ureate) zirconium complex with unprecedented reactivity in the intermolecular hydroamination of alkynes and the intramolecular hydroamination of alkenes. This catalyst system is effective with primary and secondary amines, 1,2-disubstituted alkenes, and heteroatom-containing functional groups, including ethers, silanes, amines, and heteroaromatics. The gem-disubstituent effect is not required for cyclization. The catalyst is generally regioselective for the anti-Markovnikov product of intermolecular alkyne hydroamination, and chemoselective for hydroamination over alpha-alkylation when forming 6- and 7-membered rings from aminoalkenes.

Selective C−H Activation α to Primary Amines. Bridging Metallaaziridines for Catalytic, Intramolecular α-Alkylation

Selective alpha-C-H activation results in the synthesis of the first bridging metallaaziridine complex for the catalytic alpha-alkylation of primary amines. Reaction development led to the preparation of new Zr 2-pyridonate complexes for this useful transformation. No nitrogen protecting groups are required for this reaction, which is capable of assembling quaternary chiral centers alpha to nitrogen. Preliminary mechanistic investigations suggest bridging metallaaziridine species are the catalytically active intermediates for this alpha-functionalization reaction, while monomeric imido complexes furnish azepane hydroamination products.

Mechanistic Elucidation of Intramolecular Aminoalkene Hydroamination Catalyzed by a Tethered Bis(ureate) Complex: Evidence for Proton-Assisted C–N Bond Formation at Zirconium

A broad mechanistic investigation regarding hydroamination reactions catalyzed by a tethered bis(ureate) zirconium species, [ureate(2-)]Zr(NMe(2))(2)(HNMe(2)), is described. The cyclization of both primary and secondary aminoalkene substrates gives similar kinetic profiles, with zero-order dependence on substrate concentration up to ∼60-75% conversion, followed by first-order dependence for the remainder of the reaction. The addition of 2-methylpiperidine changes the observed substrate dependence to first order throughout the reaction, but does not act as a competitive inhibitor. The reactions are first order in precatalyst up to loadings of ∼0.15 M, indicating that a well-defined, mononuclear catalytic species is operative. Several model complexes have been structurally characterized, including dimeric imido and amido species, and evaluated for catalytic performance. These results indicate that imido species need not be invoked as catalytically relevant intermediates, and that the mono(amido) complex [ureate(2-)]Zr(NMe(2))(Cl)(HNMe(2)) is much less active than its bis(amido) counterpart. Structural evidence suggests that this is due to differences in coordination geometry between the mono- and bis(amido) complexes, and that an equatorial amido ligand is required for efficient catalytic turnover. On the basis of the determination of kinetic isotope effects and stoichiometric reactivity, the catalytic turnover-limiting step is proposed to be a concerted C-H, C-N bond-forming process with a highly ordered, unimolecular transition state (ΔS(‡) = -21 ± 1 eu). In addition to this key bond-forming step, the catalytic cycle involves an on-cycle pre-equilibrium between six- and seven-coordinate intermediates, leading to the observed switch from zero- to first-order kinetics.

Bis(amidate)bis(amido) titanium complex: a regioselective intermolecular alkyne hydroamination catalyst.

An efficient and selective bis(amidate)bis(amido) titanium precatalyst for the anti-Markovnikov hydroamination of alkynes is reported. Hydroamination of terminal and internal alkynes with primary alkylamines, arylamines, and hydrazines is promoted by 5-10 mol % of Ti catalyst. Various functional groups are tolerated including esters, protected alcohols, and imines. The in situ generated complex shows comparable catalytic activity, demonstrating its synthetic versatility for benchtop application. Applications of this catalyst for the synthesis of amino alcohols and a one-pot procedure for indole synthesis are described. A mechanistic proposal that invokes turnover-limiting protonolysis is presented to rationalize the observed regioselectivities.

Upgrading light hydrocarbons via tandem catalysis: a dual homogeneous Ta/Ir system for alkane/alkene coupling.

Light alkanes and alkenes are abundant but are underutilized as energy carriers because of their high volatility and low energy density. A tandem catalytic approach for the coupling of alkanes and alkenes has been developed in order to upgrade these light hydrocarbons into heavier fuel molecules. This process involves alkane dehydrogenation by a pincer-ligated iridium complex and alkene dimerization by a Cp*TaCl2(alkene) catalyst. These two homogeneous catalysts operate with up to 60/30 cooperative turnovers (Ir/Ta) in the dimerization of 1-hexene/n-heptane, giving C13/C14 products in 40% yield. This dual system can also effect the catalytic dimerization of n-heptane (neohexene as the H2 acceptor) with cooperative turnover numbers of 22/3 (Ir/Ta).

Convergent Synthesis of the NS5B Inhibitor GSK8175 Enabled by Transition Metal Catalysis

A convergent eight-stage synthesis of the boron-containing NS5B inhibitor GSK8175 is described. The previous route involves 13 steps in a completely linear sequence, with an overall 10% yield. Key issues include a multiday SNAr arylation of a secondary sulfonamide using HMPA as solvent, multiple functional group interconversions after all of the carbon atoms are installed (including a Sandmeyer halogenation), use of carcinogenic chloromethyl methyl ether to install a protecting group late in the synthesis, and an unreliable Pd-catalyzed Miyaura borylation as the penultimate step. We have devised an orthogonal approach using a Chan-Lam coupling between a halogenated aryl pinacol boronate ester and an aryl methanesulfonamide. This reaction is performed using a cationic Cu(I) precatalyst, which can be easily generated in situ using KPF6 as a halide abstractor. High-throughput screening revealed a new Pd catalyst system to effect the penultimate borylation chemistry using simple monodentate phosphine ligands, with PCyPh2 identified as optimal. Reaction progress analysis of this borylation indicated likely mass-transfer rate limitations under standard conditions using KOAc as the base. We have devised a K2CO3/pivalic acid system as an alternative, which dramatically outperforms the standard conditions. This new synthesis proceeds in eight stages with a 20% overall yield.