LiAlH4: From Stoichiometric Reduction to Imine Hydrogenation Catalysis

Article abstract of DOI:10.1002/anie.201803804

Imine-to-amine conversion with catalytic instead of stoichiometric quantities of LiAlH₄ is demonstrated (85 °C, catalyst loading≥2.5 mol %, pressure≥1 bar). The effects of temperature, pressure, solvent, and catalyst modifications, as well as the substrate scope are discussed. Experimental investigations and preliminary DFT calculations suggest that the catalytically active species is generated in situ: LiAlH₄+Ph(H)C=NtBu→LiAlH₂[N(tBu)CH₂Ph]₂. A cooperative mechanism in which Li and Al both play a prominent role is proposed.

Full text of DOI:10.1002/anie.201803804

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
International Edition Chemie
www.angewandte.org
Accepted Article
Title: LiAlH4: From Stoichiometric Reduction to Imine Hydrogenation
Catalysis
Authors: Holger Elsen, Christian Färber, Gerd Ballmann, and Sjoerd
Harder
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201803804
Angew. Chem. 10.1002/ange.201803804
Link to VoR: http://dx.doi.org/10.1002/anie.201803804
http://dx.doi.org/10.1002/ange.201803804

Angewandte Chemie International Edition
10.1002/anie.201803804
LiAlH : From Stoichiometric Reduction to Imine Hydrogenation Catalysis
4
Holger Elsen, Christian Färber, Gerd Ballmann, Sjoerd Harder*
[a]
Prof. Dr. S. Harder, H. Elsen, Dr. C. Färber, G. Ballmann
Inorganic and Organometallic Chemistry, Universität Erlangen-Nürnberg, Egerlandstrasse 1, 91058
Erlangen, Germany
Fax: (+49) 9131-8527387
E-mail: sjoerd.harder@fau.de
Supporting information for this article is available on the WWW under http//:www.angewandte.chemie.org or
from the author.
Keywords: Hydrides – Aluminium – Lithium – Reduction – Sustainability
Table of Contents
Atom-economical imine reduction:
Classical imine-to-amine reduction uses stoichiometric quantities of LiAlH
salt side-products. The same reaction under an H atmosphere needs only catalytic LiAlH
2.5 mol%) and proceeds at surprisingly mild conditions (85 °C, 1 bar H ). The catalyst is an
in-situ generated complex: LiAlH (NRR’)
4
, generating Li/Al
2
4
(
2
2
2
.
Abstract: Imine-to-amine conversion with catalytic instead of stoichiometric quantities of
LiAlH is demonstrated (85 °C, catalyst loadings ≥ 2.5 mol%, pressure ≥ 1 bar). The effects of
4
temperature, pressure, solvent, catalyst modifications and substrate scope are discussed.
Experimental investigations and preliminary DFT calculations suggest that the catalytically
active species is generated in-situ: LiAlH
4
+ Ph(H)C=NtBu → LiAlH
2
[N(tBu)CH
2
Ph] . A
2
cooperative mechanism in which Li and Al both play a prominent role is proposed.
This article is protected by copyright. All rights reserved.

Angewandte Chemie International Edition
10.1002/anie.201803804
2
The simplest metal hydride, (LiH)
∞
, is an essentially inert salt[1] that is stable in air and, on
-
1 [2]
account of its high crystal lattice energy (920 kJ∙mol ) does not even react with hydrogen
chloride. However, in combination with AlH it becomes a highly useful reducing agent.
3
+
¯ in the 40’s should be regarded a milestone discovery.[3]
Schlesinger’s synthesis of Li AlH
4
Key to its fame is its fair solubility in ethereal solvents rendering it highly reactive towards a
large array of substrates.[4,5] More than 70 years after its invention, LiAlH
is still one of the
4
most potent reducing agents that developed from a laboratory reagent to bulk product,
finding large-scale industrial application.[6] Whereas stoichiometric reduction of ketones
proceeds smoothly, only exceptionally strongly activated alkenes may be reduced. Reduction
of the interjacent imines requires high temperatures but is a well-established method for
imine-to-amine conversion. Using stoichiometric quantities of LiAlH , however, inherently
4
generates copious amounts of Li/Al salts that often complicate product work-up and on a
larger industrial scale have a negative environmental impact. Societal pressure to
sustainable “green” production processes[7] is the driving force for atom-economical
catalytic imine hydrogenation using the simplest, widely accessible, reducing agent: H
2
.[8]
Catalytic imine reduction with H , however, received much less attention than alkene or
2
ketone hydrogenation and remains a challenge.[9] With few exceptions,[10,11] existing
catalysts are generally based on late transition metals (Rh, Ir).[9a] Since the platinum group
metals are scarce[12] and may on account of their high toxicity pose problems in
pharmaceutical products, it is increasingly popular to use more abundant, biocompatible,
metals.[13-15] Recently, Cp*ZnH and iBu
hydrogenation but harsh working conditions including high H
needed.[16,17] Metal-free Frustrated-Lewis-Pairs (FLP’s)[18] operate under much milder
AlH were found to be catalytically active in imine
pressures (70-100 bar) are
2
2
conditions (5 bar H
reduced by B(C
the type MN’’
mild conditions (1-6 bar H
tolerance.[21] This finding was rather unexpected since the catalyst initiation step (Scheme 1)
is formally a deprotonation of H (pK
≈ 49)[22] giving the metal hydride catalyst and amine
N’’H with a much lower pK
(25.8).[23] Also the last -bond metathesis step in the cycle
2
, 80-140 °C).[19] As the imine itself is a Lewis base, bulky imines can be
as a catalyst.[20] We recently reported simple group 2 metal catalysts of
6
F
5 3
)
2
(M = Ca, Sr, Ba; N’’ = N(SiMe
3
2
) ) that operate efficiently under surprisingly
2
, 80 °C) and show a fair substrate scope and functional group
2
a
a
seemed questionable. A comprehensive calculational study, however, demonstrated that
the metal hydride mechanism shown in Scheme 1 is feasible.[21]
This article is protected by copyright. All rights reserved.

Angewandte Chemie International Edition
10.1002/anie.201803804
3
Given the simplicity of these group 2 metal catalysts, we wondered whether LiAlH
in imine reduction is normally added stoichiometrically, could be catalytically active. Already
in the 60’s LiAlH
has been used as a catalyst for alkyne reduction,[24] however, the very
harsh conditions needed (35 mol% cat, 190 °C, 80 bar H ) did not encourage follow-up
research. A crucial step is the hydrogenolysis of the metal-C bond by H for which the rate is
known to decrease with decreasing bond ionicity: Na-C > Mg-C > Al-C.[25] As it is well-known
that RNH and R NH react smoothly with LiAlH to Al-amide products and H
,[26-31]
hydrogenolysis of Al-N bonds to give amines is anticipated to be even more cumbersome.
Substitution of H for polar borane or silane reductants was therefore a logical consequence.
4
, which
4
2
2
2
2
4
2
2
Indeed, hydroboration and hydrosilylation reactions were found to be more promising.[32]
Aluminium driven catalysis using polar activated substrates currently experiences immense
interest.[15,18,31-42] Especially noteworthy are two very recent investigations on LiAlH
catalyzed alkene and aldehyde/ketone hydroboration.[31,38] Aluminium catalyzed
hydrogenation using the simple reductant H , however, are limited to highly Lewis-acidic
tricoordinate Al catalysts,[43] often using high temperatures and H pressures.[17,24] In
contrast, the reversed reaction, aluminium catalyzed dehydrogenation, has been studied in
depth: e.g. HC(O)OH → CO + H , normally applied as a
.[15,41-42] Herein we introduce LiAlH
stoichiometric reducing agent, as a simple catalyst for imine reduction using the bulk
commodity H at a convenient 1 bar pressure (Table 1).
In a benchmark experiment using 10 mol% LiAlH catalyst, neat Ph(H)C=NtBu was within
two hours at 85 °C and 1 bar H pressure fully converted to PhCH N(H)tBu (entry 1). Catalyst
-
4
2
2
2
2
4
2
4
2
2
loadings down to 2.5 mol% are possible but longer reaction times are needed for full
conversion (entries 2-3). Slight increase of pressure, however, has an accelerating effect (cf.
entries 2 and 4 or 5-7) implying that hydrogenation is a difficult step. Decreasing the
temperature from 85 °C to 65 °C gave significantly slower conversion (entries 7-8) indicating
a high activation barrier. Interestingly, running the experiments at the higher temperature of
1
00 °C also gave less conversion (entry 9). We attribute this to thermal decomposition of
0
metastable LiAlH
4
into Li
3
AlH
6
, Al and H
2
. This reaction already proceeds slowly at room
, but is much faster
above 100 °C thus limiting its operation temperature.[45] For reproducibility, all catalytic
experiments have been performed with purified white crystalline LiAlH , however, using
temperature,[44] explaining the grey color of commercially available LiAlH
4
4
commercial grey LiAlH
4
gave, at least for entry 1, similar results.
This article is protected by copyright. All rights reserved.

Angewandte Chemie International Edition
10.1002/anie.201803804
4
Apart from low H pressures also the solvent-free nature is an attractive feature of this
2
catalytic conversion. However, in order to study the effect of solvent polarity, reactions also
have been run in benzene and THF. Conversions in THF and benzene are both slower than in
neat imine (cf. entries 1 and 10-11) but there seems to be no significant effect of solvent
polarity on conversion rate. The slower conversion is therefore simply due to dilution of
substrate and catalyst. Slight increase of the H pressure to 7 bar led also in THF and
2
benzene to full substrate conversion (entries 12-13). The addition of TMEDA and PMDTA did
not have a large influence on conversion rates (entries 5, 14, 15).
Whereas LiAlH
surprisingly low pressures, using its components LiH or AlH
conversion (entries 16-17). With Red-Al, LiAlH (OCH CH OMe)
observed (entry 18). Replacing LiAlH for NaAlH noticeably decelerated the reaction (cf.
entries 4 and 19). Expectedly, the very mild reducing agent NaBH [46]
did not give even
4
shows excellent catalytic activities for hydrogenation of Ph(H)C=NtBu at
gave no or only stoichiometric
, slow but full conversion was
3
2
2
2
2
4
4
4
stoichiometric conversion (entry 20). These observations indicate heterobimetalic
cooperativity.
Imines with Cl and MeO para-substituents in the Ph group gave significantly slower
conversions (entries 21-22). Replacing the Ph group at C in the benchmark substrate for a
tBu substituent gave very slow conversion (entry 23). This may be explained by the strong
inductive effect and significant bulk of a tBu substituent, both hindering hydridic attack at C.
Replacing the tBu group at N in the benchmark substrate for Ph inhibits catalytic conversion
(
entry 24). This may be due to formation of an intermediate PhCH
resonance-stabilized amide that in contrast to PhCH (tBu)N‾ is likely unable to deprotonate
. An imine with mesityl (Mes, entry 25) or benzyl (entry 26) at N, however, gave slightly
better conversion. This may be attributed to the higher basicity of the PhCH (Mes)N‾ anion
2
(Ph)N‾ anion, a
2
H
2
2
in which charge delocalization is partly shut off (Mes is perpendicularly oriented to the C-N-C
plane). The ketimine Ph(Me)C=NtBu gave no conversion implying that the method hitherto is
limited to certain aldimines.
To shed light on a potential mechanism for LiAlH
monitored the stoichiometric reaction between LiAlH
negligible conversion was found but after two hours at 80 °C the imine was fully converted
giving a solution of unreacted LiAlH , LiAlH [N] and LiAlH [N] ; [N] = the amide ligand
4
catalyzed imine hydrogenation, we
4
and Ph(H)C=NtBu in THF-d . At 60 °C
8
4
3
2
2
N(tBu)CH
2
Ph (see Figures S15-21). The troublesome addition of LiAlH to imine explains the
4
This article is protected by copyright. All rights reserved.

Angewandte Chemie International Edition
10.1002/anie.201803804
5
high temperatures needed for catalysis. Addition of a second equivalent of imine led to clean
conversion into LiAlH [N] . Insertion of a third imine to give LiAlH[N] is more difficult and
needs longer reaction times. This is in agreement with earlier studies in which the species
LiAl[N]
was never obtained.[26-30]
2
2
3
4
In preliminary DFT investigations (B3PW91/6-311++G**) we assessed multiple imine
insertions under the reaction conditions used in catalysis (Scheme 2). Subsequent imine
insertions become increasingly less exothermic and the fourth insertion is even
endothermic. The G values, in which entropy loss is considered, show that the third imine
insertion already becomes endergonic. It is also of interest to note that optimization of the
intermediate LiAl[N]
This is in line with observations by Stalke et al. ([N] = N(SiMe
As the second imine insertion is easier than the first and third insertions, we were able to
cleanly isolate the LiAlH [N] intermediate. The latter could be crystallized in the form of its
TMEDA and PMDTA adducts (Figure 1). H- and Li-DOSY NMR investigations on LiAlH
with either additional THF, TMEDA or PMDTA, suggest a single monomeric species in
4
led to dissociation into a Al[N]
3
species that is loosely bound to Li[N].
)
3 2
).[26]
2
2
1
7
2
[N] in
2
C D
6 6
1
7
solution (see ESI): H- and Li-DOSY gave similar diffusion constants. The complex in the
presence of TMEDA was found to be present as a single species LiAlH
2
[N] ∙TMEDA and not as
2
+
the solvent-separated-ion-pair: [Li ∙TMEDA][AlH
2
[N] ‾]. Similar as observed recently for
2
LiAlH
2
[N(SiMe
3
)
2
]
by the Mulvey group,[31] we propose intimate contact-ion-pairs with Al-H-
2
Li bridges in solution (cf. Figure 1a).
Based on these observations, we propose the following catalytic cycle (Scheme 3).
Starting from simple LiAlH
easier second insertion. The actual catalyst in the catalytic cycle is proposed to be the
double-insertion product: LiAlH [N] . Reaction of the intermediate obtained after a third
imine insertion, LiAlH[N] , with H
center in LiAlH[N]
4
as a precatalyst, a first difficult imine insertion is followed by an
2
2
3
2
regenerates the catalyst and gives the product. As the Al
+
3
is sterically congested with three amide ligands, Li may play an important
role in this hydrogenation step. We can, however, not exclude product formation by reaction
of LiAlH [N] and LiAlH [N] with H . A more detailed reaction mechanism is currently under
2
2
3
2
investigation and comprehensive calculational results will be reported in the near future.
We demonstrated imine-to-amine conversion with catalytic instead of stoichiometric
quantities of LiAlH
4
. This catalytic process, which uses the bulk commodity H at convenient
2
ambient pressure, is fully atom-economical and preferably runs without using organic
This article is protected by copyright. All rights reserved.

Angewandte Chemie International Edition
10.1002/anie.201803804
6
solvents. Variation of substrates generally needs somewhat higher H
2
pressures (6-25 bar)
and longer reaction times, limiting its scope when compared to that of group 2 metal
catalysts.[21] The results of catalytic runs with LiH or AlH
alone, or with NaAlH and NaBH
differ from the LiAlH catalyzed reaction. This indicates that the Li and Al metal centers in the
in-situ formed catalyst LiAlH [N] operate cooperatively. The simple catalytic system LiAlH ,
3
4
4
,
4
2
2
4
offers enormous potential for optimization by variation of the s-block metal Li, the p-block
metal Al or by introduction of a spectator ligand. This is the focus of our current research.
References
[
[
1]
2]
T. Ohkuma, S. Hashiguchi, R. Noyori J. Org. Chem. 1994, 59, 217-221 and references cited therein.
In CRC Handbook of Chemistry and Physics, 63rd ed.; Weast, R. C., Ed., Astle, M. J., Associate Ed.; CRC
Press: Boca Raton, FL, 1982; Section D, p. 109.
[3]
[4]
[5]
A. E. Finholt, A. C. Bond, H. I. Schlesinger, J. Am. Chem. Soc. 1947, 95, 1199-1203.
R. F. Nystrom, W. G. Brown, J. Am. Chem. Soc. 1948, 70, 3738-3740.
More recently also solubilization of CaH
2
and NaH led to highly increased reactivity: (a) S. Harder, J.
Brettar Angew. Chem. 2006, 45, 3474-3478; (b) J. Spielmann, S. Harder, Chem. Eur. J. 2007, 13, 8928-
8
3
938; (c) P. C. Too, G. H. Chan, Y. L. Tnay, H. Hirao, S. Chiba, Angew. Chem. Int. Ed. 2016, 55, 3719-
723.
[6]
[7]
[8]
J. Magano, J. R. Dunetz, Org. Process Res. Dev. 2012, 16, 1156−1184.
P. J. Dunn, Chem. Soc. Rev. 2012, 41, 1452–1461.
J. G. de Vries, C. J. Elsevier, Handbook of Homogeneous Hydrogenation: 3 Volumes. Wiley-VCH
publishers, 2007.
[9]
A. Fabrello, A. Bachelier, M. UrrutigoÏty, P. Kalck, Coord. Chem. Rev. 2010, 254, 273–287; (b) H.-U.
Blaser, C. Malan, B. Pugin, F. Spindler, H. Steiner, M. Studer, Adv. Synth. Catal. 2003, 345, 103-151. (c)
C. Wang, B. Villa-Marcos, J. Xiao, Chem. Commun. 2011, 47, 9773-9785.
[10]
[11]
[12]
[13]
C. A. Willoughby, S. L. Buchwald, J. Am. Chem. Soc. 1994, 116, 11703-11714.
Y. Obora, T. Ohta, C. L. Stern, T. J. Marks, J. Am. Chem. Soc. 1997, 119, 3745-3755.
R. B. Gordon, M. Bertram, T. E. Graedel, Proc. Natl. Acad. Sci. U. S. A. 2006, 103, 1209-1214.
Group 2 metal catalysts: (a) S. Harder, Chem. Rev. 2010, 110, 3852-3876; (b) M. S. Hill, D. J. Liptrot, C.
Weetman, Chem. Soc. Rev. 2016, 45, 972-988.
[
[
14]
15]
First row transition metal catalysts: M. S. Holzwarth, B. Plietker, ChemCatChem 2013, 5, 1650-1679.
Aluminium catalysts: (a) L. A. Berben, Chem. Eur. J. 2015, 21, 2734-2742; (b) G. I. Nikonov, ACS Catal.
2017, 7, 7257−7266. (c) W. Li, X. Ma, M. G. Walawalkar, Z. Yang, H. W. Roesky, Coord. Chem. Rev.
2
017, 350, 14-29.
[16]
(a) P. Jochmann, D. W. Stephan, Angew. Chem. Int. Ed. 2013, 52, 9831-9835. (b) P. Jochmann, D. W.
Stephan, Chem. Eur. J. 2014, 20, 8370-8378.
[
[
17]
18]
J. A. Hatnean, J. W. Thomson, P. A. Chase, D. W. Stephan, Chem. Commun. 2014, 50, 301–303.
(a) D. W. Stephan, G. Erker, Angew. Chem. Int. Ed. 2015, 54, 6400-6441. (b) D. W. Stephan, Acc. Chem.
Res. 2015, 48, 306-316.
[
[
19]
20]
P. A. Chase, G. C. Welch, T. Jurca, D. W. Stephan, Angew. Chem. Int. Ed. 2007, 46, 8050-8053.
(a) P. A. Chase, T. Jurca, D. W. Stephan, Chem. Commun. 2008, 1701-1703. (b) D. Chen, J.
Klankermeyer, Chem. Commun. 2008, 2130-2131.
[
21]
22]
H. Bauer, M. Alonso, C. Färber, H. Elsen, J. Pahl, A. Causero, G. Ballmann, F. de Proft, S. Harder, Nature
Catalysis 2018, 1, 40-47.
K. Abdur-Rashid, T. P. Fong, B. Greaves, D. G. Gusev, J. G. Hinman, S. E. Landau, A. J. Lough, R. H.
Morris J. Am. Chem. Soc. 2000, 122, 9155-9171.
[
[23]
[24]
[25]
[26]
[27]
R. R. Fraser, T. S. Mansour, S. Savard, J. Org. Chem. 1985, 50, 3232-3234.
L. H. Slaugh, Tetrahedron 1966, 22, 1741-1746.
H. E. Podall, H. E. Petree, J. R. Zietz, J. Org. Chem. 1959, 24, 1222-1226.
A. Heine, D. Stalke, Angew. Chem. Int. Ed. 1992, 31, 854-855.
M. G. Gardiner, S. M. Lawrence, C. L. Raston, Inorg. Chem. 1995, 34, 4652-4659.
This article is protected by copyright. All rights reserved.

Angewandte Chemie International Edition
10.1002/anie.201803804
7
[28]
[29]
[30]
[31]
M. L. Montero, H. Wessel, H. W. Roesky, M. Teichert, I. Usón, Angew. Chem. Int. Ed. 1997, 36, 629-630.
J. Pauls, B. Neumüller, Inorg. Chem. 2001, 40, 121-124.
G. Linti, W. Köstler, A. Rodig, Z. Anorg. Allg. Chem. 2002, 628, 1319-1326.
V. A. Pollard, S. A. Orr, R. McLellan, A. R. Kennedy, E. Hevia, R. E. Mulvey, Chem. Commun. 2018, 54,
1233-1236.
[32]
(a) M. Itoh, M. Kobayashi, J. Ishikawa, Organometallics 1997, 16, 3068-3070. (b) M. Kobayashi, M. Itoh,
Chemistry Letters 1996, 1013-1014. (c) A. J. Blake, A. Cunningham, A. Ford, S. J. Teat, S. Woodward,
Chem. Eur. J. 2000, 6, 3586-3594.
[
[
33]
34]
J. M. Blackwell, E. R. Sonmor, T. Scoccitti, W. E. Piers, Org. Lett. 2000, 2, 3921-3923.
(a) Z. Yang, M. Zhong, X. Ma, S. De, C. Anusha, P. Parameswaran, H. W. Roesky Angew. Chem. Int. Ed.
2
015, 54, 10225-10229. (b) Z. Yang, M. Zhong, X. Ma, K. Nijesh, S. De, P. Parameswaran, H. W. Roesky,
J. Am. Chem. Soc. 2016, 138, 2548-2551.
[35]
[36]
[37]
[38]
[39]
[40]
V. K. Jakhar, M. K. Barman, S. Nembenna, Org. Lett. 2016, 18, 4710-4713.
D. Franz, L. Sirtl, A. Pöthig, S. Inoue, Z. Anorg. Allg. Chem. 2016, 642, 1245-1250.
A. Bismuto, S. P. Thomas, M. J. Cowley, Angew. Chem., Int. Ed. 2016, 55, 15356-15359.
A. Bismuto, S. P. Thomas, M. J. Cowley, ACS Catal. 2018, 8, 2001-2005.
R. J. Less, H. R. Simmonds, S. B. J. Dane, D. S. Wright, Dalton Trans. 2013, 42, 6337-6343.
(a) C. Appelt, J. C. Slootweg, K. Lammertsma, W. Uhl, Angew. Chem. Int. Ed. 2012, 51, 5911-5914. (b) C.
Appelt, J. C. Slootweg, K. Lammertsma, W. Uhl, Angew. Chem. Int. Ed. 2013, 52, 4256-4259. (c) J. Chen,
E.Y.-X. Chen, Angew. Chem. Int. Ed. 2015, 54, 6842-6846. (d) D. W. Stephan, Acc. Chem. Res. 2015, 48,
306-316.
[41]
[42]
[43]
T. W. Myers, L. A. Berben, Chem. Sci. 2014, 5, 2771−2777.
Q.-Q. Lu, H.-Z. Yu, Y. Fu, Chem. Eur. J. 2016, 22, 4584-4591.
Porous organic polymers with tricoordinate (RO)
2
AlMe units are catalytically active in alkene and
) but do not catalyze imine
alkyne hydrogenation under mild conditions (75-100 °C, 5-14 bar H
2
hydrogenation: J. Camacho-Bunquin, M. Ferrandon, U. Das, F. Dogan, C. Liu, C. Larsen, A. E. Platero-
Prats, L. A. Curtiss, A. S. Hock, J. T. Miller, S. T. Nguyen, C. L. Marshall, M. Delferro, P. C. Stair, ACS
Catal. 2017, 7, 689-694.
[44]
[45]
[46]
J. Graetz, ISRN Materials Science 2012, Article ID 863025, 1-18.
J. M. Welch, V. P. Balema, V. K. Pecharsky, M. Prusk, J. Solid State Chem. 2004, 177, 648-653.
H. C. Brown, S. Krishnamurthy Aldrichimica Acta 1979, 12(1), 3-11.
Acknowledgments We thank the University Erlangen-Nürnberg for the general support of
this project.
1
13
7
27
Supporting Information Experimental procedures, selected H, C, Li and Al NMR spectra,
details for the DFT calculations and XYZ coordinates for all optimized structures. Crystal
+
structure data for the complexes LiAlH
2
[N]
2
∙PMDTA and [Li ∙TMEDA][AlH
2
[N] ‾] have been
2
deposited with the Cambridge Crystallographic Data Centre as entries 1833191-1833192,
respectively.
This article is protected by copyright. All rights reserved.

Angewandte Chemie International Edition
10.1002/anie.201803804
8
Table 1. LiAlH
catalyzed imine hydrogenation.a
4
Entry Cat. (mol%)
R1
R2
T(°C)
2
H (bar) t(h) Conv(%)
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
a
LiAlH
LiAlH
LiAlH
LiAlH
LiAlH
LiAlH
LiAlH
LiAlH
LiAlH
LiAlH
LiAlH
LiAlH
LiAlH
LiAlH
LiAlH
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
(10)
(5)
(2.5)
(5)
(5)
(5)
(5)
(5)
(5)
(10) in C
(10) in THF
(10) in C
(10) in THF
(5) + 4 TMEDA Ph
(5) + 1 PMDTA Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
Ph
85
85
85
85
85
85
85
65
100
85
85
85
85
85
85
85
85
85
85
85
85
85
85
85
1
1
1
5
1
20
1
1
1
1
1
7
7
1
1
25
25
8
6
6
2
>99
>99
>99
>99
55
85
85
39
51
60
56
>99
>99
71
54
0
12
15
66
6
2.5
2.5
6
6
6
3
3
6
6
2.5
2.5
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
6
H
6
H
6 6
LiH (20)
AlH (10)
Red-Al (10)
NaAlH (5)
NaBH
Ph
Ph
Ph
Ph
Ph
3
3
2.5d >99
6
6
24
24
4d
24
3d
3d
4
77
0
4
(5)
(10)
(10)
(5)
(5) in THF
(5) in THF
(5)
LiAlH
LiAlH
LiAlH
LiAlH
LiAlH
LiAlH
4
p-Cl-C
p-MeO-C
6
H
6 4
H
4
25
25
6
6
6
46
52
66
13
52
85
4
4
4
4
4
tBu
Ph
Ph
Ph
Mes 85
CH Ph 85
2
6
Reaction times for >99% conversion have been optimized in 15 minutes steps. For non-quantitative
1
conversions time and yield (determined by H NMR) is given. LiAlH
4
was purified by recrystallization from Et O.
2
This article is protected by copyright. All rights reserved.

Angewandte Chemie International Edition
10.1002/anie.201803804
9
Scheme 1. Catalytic cycle for imine hydrogenation with CaN’’
2
; N’’ = N(SiMe ) .
3
2
This article is protected by copyright. All rights reserved.

Angewandte Chemie International Edition
10.1002/anie.201803804
1
0
Figure 1. (a) Crystal structure of LiAlH
2
[N]
2
∙PMDTA; [N] = N(tBu)CH Ph; H atoms only partially
2
shown. Selected bond distances (Å): Al-H1 1.60(2), Al-H2 1.48(2), Al-N1 1.853(1), Al-N2
1
.856(1), Li-H1 1.85(2), Li-N3 2.110(2), Li-N4 2.115(3), Li-N5 2.107(2). (b) Crystal structure of
+
[
Li ∙TMEDA][AlH
2
[N] ‾]; H atoms only partially shown. Selected bond distances (Å): Al-H1
2
1
2
.56(2), Al-H2 1.57(2), Al-N1 1.857(1), Al-N2 1.862(1), Li-N3 2.126(2), Li-N4 2.150(3), Li-N5
.095(3), Li-N6 2.126(2).
This article is protected by copyright. All rights reserved.

Angewandte Chemie International Edition
10.1002/anie.201803804
1
1
Scheme 2. Reaction of LiAlH with subsequently one, two, three and four equivalents of
4
Ph(H)C=NtBu. E and G (85 °C, 6 bar, PCM correction for the polar solvent THF) given in
kcal/mol.
This article is protected by copyright. All rights reserved.

Angewandte Chemie International Edition
10.1002/anie.201803804
1
2
Scheme 3. Proposed mechanism for the imine hydrogenation with a LiAlH precatalyst.
4
This article is protected by copyright. All rights reserved.