The archetypal reductant in organic chemistry is undeniably LiAlH4, which most often finds use in stoichiometric conversions of polar unsaturated substrates into saturated species. This methodology remains widespread despite its poor atom efficiency — the net addition of H2 to a substrate first requires delivery of H− from LiAlH4 and then H+ from a protic solvent. The environmental and economic consequences of this poor efficiency beg the question: can LiAlH4 also serve as a catalyst for the addition of H2 to organic molecules? LiAlH4 catalytically hydrogenates alkynes and 1,3-dienes to their corresponding alkenes, but does so only under forcing conditions. More recent work has shown that LiAlH4 is also a catalyst for the hydroboration of alkenes, ketones and aldehydes. Imines are of intermediate polarity, and a group led by Sjoerd Harder now describes in Angewandte Chemie International Edition a disarmingly mild methodology for their catalytic hydrogenation using LiAlH4.

Credit: David Schilter/Rachael Tremlett/Macmillan Publishers Limited

The catalytic reduction of imines is typically the domain of precious metal catalysts, which can oxidatively add H2 and transfer it to a substrate. Such H2 homolysis contrasts the H2 heterolysis that takes place between imines and the Lewis acid B(C6F5)3, with the former first accepting H+ and then H− before becoming an amine. However, the search for another non-transition-metal hydrogenation catalyst continued because B(C6F5)3 is neither cheap nor compatible with many nucleophiles. Amido hydrides MH[N(SiMe3)2] (M=Mg, Ca, Sr, Ba) are catalysts for imine hydrogenation, so it seemed conceivable that LiAlH4 — long known as a stoichiometric imine reductant — may also be a useful precatalyst. Harder’s team found that catalytic amounts of LiAlH4, under merely 1 bar of H2 pressure, convert neat aldimine substrates Ar(H)C=NR into the amines Ar(H)2C–NHR.

The team monitored reaction mixtures and performed independent syntheses of putative intermediates to support their proposed catalytic mechanism. “It is likely that two imine insertions into LiAlH4 afford Li(μ-H)2Al[Ar(H)2CNR]2, an active species belonging to a well-studied class of diamido dihydrides,” notes Harder. The Lewis acidic Li can bind the N atom of an imine substrate, with concomitant attack of a bridging hydride ligand on the imine C atom resulting in a six-membered transition state. The resulting triamido hydride Li(μ-H)Al[Ar(H)2CNR]3 is thought to heterolyze H2 through a frustrated Lewis pair mechanism. In this key step, H2 binds both the Lewis acidic Li centre and the lone pair of an amido ligand, after which σ-bond metathesis liberates the amine product Ar(H)2C–NHR and regenerates the diamido dihydride.

A heterobimetallic mechanism for LiAlH4 catalysis would be exciting in that the matrix for catalyst optimization could be enormous

Of the substrates tested, it was Ph(H)C=NtBu that underwent hydrogenation the most smoothly, with Harder and colleagues using just 2.5 mol% LiAlH4 to achieve >99% conversion in 2 h at 85 °C. Replacing Ph with electron-rich or electron-deficient aryls (or a bulky electron-releasing tBu group) resulted in lower yields. Similarly, the aliphatic tBu N-substituent proved crucial, and its replacement with Ph caused the reaction to be much slower because the amido ligands in the triamido hydride Li(μ-H)Al[Ar(H)2CNPh]3 are insufficiently basic to deprotonate H2 and effect σ-bond metathesis. The methodology is presently limited to N-alkyl aldimines, with preliminary testing on alkene substrates being unsuccessful. Likewise, Harder admits that the conditions are unlikely to work for ketones because alkoxo intermediates are unlikely to deprotonate H2. Far from being discouraged, the team is conducting further in silico studies to unravel details of the imine hydrogenation. The cooperativity between one metal and a proximal metal amido might be generalizable. “A heterobimetallic mechanism for LiAlH4 catalysis would be exciting in that the matrix for catalyst optimization could be enormous,” says Harder.