H2 Activation by Non-Transition-Metal Systems: Hydrogenation of Aldimines and Ketimines with LiN(SiMe3)2

Article abstract of DOI:10.1002/chem.201805549

In recent years, H₂ activation at non-transition-metal centers has met with increasing attention. Here, a system in which H₂ is activated and transferred to aldimines and ketimines using substoichiometric amounts of lithium bis(trimethylsilyl)amide is reported. Notably, the reaction tolerates the presence of acidic protons in the α-position. Mechanistic investigations indicated that the reaction proceeds via a lithium hydride intermediate as the actual reductant.

Full text of DOI:10.1002/chem.201805549

A Journal of
Accepted Article
Title: H2 Activation by Non-Transition Metal Systems: Hydrogenation of
Aldimines and Ketimines with LiN(SiMe3)2
Authors: Andreas Pfaltz, Daniel C. Elliott, Alex Marti, and Pablo
Mauleon
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To be cited as: Chem. Eur. J. 10.1002/chem.201805549
Link to VoR: http://dx.doi.org/10.1002/chem.201805549
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COMMUNICATION
H
2
Activation by Non-Transition Metal Systems: Hydrogenation of
Aldimines and Ketimines with LiN(SiMe
)
3 2
Daniel C. Elliott,[a] Alex Marti, Pablo Mauleón,* and Andreas Pfaltz*
[a]
[b]
[a]
Abstract: In recent years, H
centers has met with increasing attention. Here, we report a system
in which H is activated and transferred to aldimines and ketimines
2
activation at non-transition metal
2), which took place upon treatment with pyridinium salt,
LiN(SiMe , and H . We found that the reaction did not proceed,
as initially assumed, via hydride transfer from a dihydropyridine
generated from pyridinium salt by deprotonation and subsequent
3
)
2
2
2
using substoichiometric amounts of lithium bis(trimethylsilyl)amide.
Notably, the reaction tolerates the presence of acidic protons in the -
position. Mechanistic investigations indicate that the reaction
proceeds via a lithium hydride intermediate as the actual reductant.
addition of H
mechanism involving solely LiN(SiMe
2
. Instead, we obtained clear evidence for a
and H . Because such a
3
)
2
2
purely base-mediated hydrogenation of imines was not known at
that time, we decided to investigate this process in more detail.
Our study shows that LiN(SiMe
amounts, induces clean reduction of imines with H
3
)
2
, even in substoichiometric
as reductant
Catalytic hydrogenations typically require the action of a transition
2
metal center to activate H
2
.[1] However, non-transition metal-
at moderate temperatures of 25–80 °C. Compared to the
application range of group 2 metal amides,[10] which is limited to
aldimines, the reaction scope is remarkably broad including
ketimines and even imines bearing acidic protons in the -
based reagents and catalysts as well are known that promote
cleavage of the strong H-H bond. Frustrated Lewis pairs (FLPs)
consisting of a highly electrophilic borane and a sterically
hindered Lewis base have been shown to cleave H
2
under mild
[11]
position.
conditions and enable catalytic hydrogenation of C=C, C=O, and
C=N bonds.[2, 3] The high Lewis acidity of the borane is the driving
force in these reactions. On the other hand, a strong base in
Approaches to H
2
activation by non-transition metal systems.
combination with a weak Lewis acid such as an alkali metal ion
a. Frustrated Lewis Pairs (Stephan, Erker)
X
can also effect H-H cleavage.[
4, 5]
In this case the reaction can be
molecule assisted by a
H
2
R
1
R
2
XH
described as a deprotonation of the H
2
BR3
base
[HBR3]
+
[base-H]
+ BR3
+
base
+
R1 R2
weakly Lewis acidic metal ion. A first example of this reactivity
was reported in 1961 by Walling and Bollyky, who found that
KO Bu catalyzes the hydrogenation of benzophenone under
forcing conditions (typically 200 °C, 100 atm H
2
).[6a, 6b] Mechanistic
studies by Berkessel indicated that the reaction proceeds by
heterolytic splitting of the H–H bond.[6c] Shortly after, Slaugh
b. Base catalyzed hydrogenation of organic substrates
t
Walling 1964
Stock 1996
H
H
2
O
H
2
O
H
Ph
Ph
tBuOK
LiN(SiMe
Alonso and Harder 2018
3 2
)
Ph
Ph
reported on the hydrogenation of dienes using metal hydrides
Harder 2008
such as NaH, KH, or LiAlH
4
as catalysts.[7] These reactions
H
tBu
tBu
H
2
H
2
H
N
N
required similarly harsh conditions and produced many side
products. 30 years later, Yang and Stock demonstrated that
lithium and potassium amides catalyze the hydrogenation of
Ph
[CaH]
3 2 2
Ca[N(SiMe ) ]
Ph
H
Ph
Ph
H
limited to aldimines
polycyclic aromatic compounds at 200-300 °C and 35-70 bar H
2
This work: LiN(SiMe3)2 catalyzed reduction of aldimines and ketimines
pressure.[8] More recently, Harder and coworkers discovered
well-defined organocalcium complexes with strongly basic benzyl
anions as ligands that catalyzed the reduction of conjugated
olefins at remarkably low temperatures of 20-60 °C.[9] During the
final stages of our work presented herein, Alonso and Harder
applicableto aldimines
and ketimines
NR
NHR
toleratesacidic
-protons
H
2
R2
R2
R1
R1
LiN(SiMe
3
)
2
H
mildtemperatures
H H
(
25-80ºC)
reported on the use of group 2 metal amides (Ca[N(SiMe
particular) as catalysts for the hydrogenation of aldimines under
mild conditions (6 bar of H
, 80 ºC).[10]
3 2 2
) ] in
2
Scheme 1. H activation by non-transition metal systems
2
During the course of our work on H
2
activation with pyridinium
Li
Ph
Ph
N
H
2
N
H
salts and base,[4b, c] we studied the reduction of imine 1 (Scheme
+
LiN(SiMe3)2
.2 equiv
+
HN(SiMe3)2
F
3
C
Ph
F
3
C
Ph
2
1
2
[
a]
b]
Dr. D. C. Elliott, Dr. A. Martí, Prof. Dr. A. Pfaltz
Department of Chemistry, University of Basel
St. Johanns-Ring 19, 4056 Basel (Switzerland)
E-mail: andreas.pfaltz@unibas.ch
3 2
Scheme 2. Imine reduction promoted by LiN(SiMe ) (ref. [4])
[
Dr. P. Mauleón
Department of Organic Chemistry, Universidad Autónoma de Madrid
c/ Fco. Tomás y Valiente 7, Cantoblanco 28049, Madrid (Spain)
E-mail: pablo.mauleon@uam.es
We initially focused our study on the reduction of aromatic
aldimines prepared from benzaldehyde derivatives and aniline,
cyclohexyl-, or benzylamine (Table 1). The reactivity of N-
phenylimines was significantly lower than that of analogous N-
cyclohexyl- or N-benzylimines. For example, at 80 °C in toluene
Supporting information for this article is given via a link at the end of
the document.
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COMMUNICATION
complete reduction of imine 3 (R1 = 4-H, entry 1) was only
could proceed via a stepwise process starting by deprotonation of
achieved using a stoichiometric amount of base. Substitution with
an electron-donating group (4, R = 4-OMe, entry 2) reduced the
H
2
to produce LiH, which subsequently transfers the hydride to
1
the C=N bond (Scheme 3b).
activity, and complete conversion of starting material was not
achieved. In contrast, the introduction of electron withdrawing
R
Li
H
1
TMS
TMS
N
TMS
TMS
groups (5 and 6, R = 4-F and 4-CF
3
, entries 3 and 4) accelerated
basicity
N
H
N
H
the reaction, and full conversion was observed with less than 1
equivalent of base. Aldimines derived from cyclohexylamine
proved to be significantly more reactive, and complete reduction
Ar
H
Ph
Ar
Li
H
Cy
Li
H
N
N
R
R
H
H
N
N
+
H2
Ar
H
H
3 2
with 0.15 to 0.4 equivalents of LiN(SiMe ) was achieved in most
Ar
LiHMDS
Ar
H
cases (entries 5-10). The presence of an electron donating group
1
in the phenyl ring (R = 4-OMe, entry 6) slightly reduced activity
a. Concerted mechanism
1
compared to the most reactive substrates 7 and 11 (R = 4-H and
R2
R2
R1
TMS
TMS
M
H
N
2
-Me, entries 5 and 9). Conversely, electron withdrawing groups
as well had a negative but more distinct effect on reactivity: While
imines 9 and 10 with p-F- and p-CF - groups still gave full
N
H
N
or
H
M
R1
H
N
H
H
TMS TMS
3
conversion with 0.4 equiv. of base, attempted reduction of a
substrate bearing a nitrile substituent (R = 4-CN, entry 12) did
not yield any product.
b. Stepwise mechanism
1
Li
N
H
H
H
“LiH”
+
N
(1)
R
R
R
R
Table 1. H
2
activation coupled with aldimine reduction
Li
N
R2
N
“LiH”
R2
R1
R1
(2)
R2
H
LiN(SiMe
3
)
2
R2
H
H
N
H2 (100 bar)
HN
H
Scheme 3. Catalytic cycle proposed and possible mechanisms for the base
R1
PhMe
R1
80 ºC
promoted reduction of imines.
LiN(SiMe
eq.][a]
3
)
2
Conv. Yield
#
R
1
R
2
Imine
t [h]
[
[%]
[%]
Although commercial LiH lacks reactivity as a reducing agent,
active forms of LiH that reduce carbonyl compounds can be
generated by reaction of tert-butyl lithium or other strongly basic
1
2
3
4
5
6
7
8
9
1
1
1
4-H
Ph
3
4
5
6
7
8
9
1.0
21
19
20
20
20
20
20
18
22
20
20
20
>99
86
90
n.d.
90
85
93
95
74
80
91
76
74
0
4-OMe Ph
1.5
4-CF
3
Ph
Ph
0.8
>99
>99
>99
>99
>99
>99
>99
>99
>99
0
reagents with hydrogen.[12] It is conceivable that LiN(SiMe
also produce active LiH species when treated with H . To test this
4-F
0.4
3 2
) could
4-H
C
C
C
C
C
C
6
H
6
H
6
H
6
H
6
H
6
H
11
11
11
0.15
0.25
0.40
0.40
0.15
0.35
0.30
1.0
2
4-OMe
4-F
1
2
hypothesis, we performed H and H NMR studies of the reactions
of LiN(SiMe
3
)
2
and the more basic Li tetramethyl piperidide
. Firstly, Li amides of “ordinary” and 15N labeled
2
4-CF
3
11 10
11 11
11 12
13
(
LiTMP) with H
2-Me
Naphth
H
TMP were treated with D
2
(75 and 100 bar) at 80 °C for 20 h
0
1
2
(
Figure 1, above). The deuterium NMR spectrum of both samples
Bn
4-CN
C
6
H
11 14
showed a strong signal at 0.1 ppm, indicative of formation of a N-
D bond.[13] Additionally, the labeled sample contained a distinct N-
[
3 2
a] Amount of LiN(SiMe ) required to achieve maximum conversion.
D doublet with a characteristic 1
J
N-D of 10.6 Hz. Secondly, we
treated a solution of LiN(SiMe
toluene-d (Figure 1, below). As a reference the spectrum of a 1:1
3
)
2
with H gas (100 bar) at 80 °C in
2
The distinctly higher reactivity of N-cyclohexyl- and N-
benzylimines compared to N-phenylimines can be rationalized by
the pK of the amines formed upon reduction. The Li amides
a
resulting from addition of hydride to the C=N bond of N-
phenylimines are significantly less basic than their N-cyclohexyl
and N-benzyl counterparts, due to electron delocalization into the
N-phenyl -system. In contrast to phenylamides, cyclohexyl and
8
8
mixture of LiN(SiMe
After 24 h at 80 °C, the H NMR spectrum showed only one signal
3
)
2
and HN(SiMe
3
)
2
in toluene-d was taken.
1
with the chemical shift of HN(SiMe
3 2
) , indicative of complete
conversion of LiN(SiMe to HN(SiMe ) .
3
)
2
3 2
In addition, a precipitate was obtained in these reactions,
which we assumed to be LiH. [14] To corroborate our assumption,
we treated phenol with an excess of the putative LiH prepared
benzylamides are sufficiently basic to deprotonate HN(SiMe
and consequently regenerate LiN(SiMe or they could act as
base for H activation. Reduced reactivity of N-phenyl- compared
3 2
)
3 2
)
and measured the 13C and
2
from LiTMP/H
2
as well as Li(SiMe
3
)
2
/H
2
8
to N-alkylimines has also been observed in the hydrogenation
7Li NMR spectra of each solution in THF-d . Both samples
matched the spectrum of a sample of lithium phenolate prepared
with Ca catalysts by Alonso and Harder, and rationalized by the
different pK
a
values of the corresponding amines.[10a]
from phenol with n-BuLi. A likely driving force for the formation
[15]
of LiH is its insolubility, resulting in irreversible precipitation from
the reaction medium.
A concerted or a stepwise mechanism may be formulated for
the hydride transfer (Scheme 3). The concerted pathway could
take place either via a cyclic transition state, as postulated for the
hydrogenation of benzophenone with NaO Bu (Scheme 1b),
or via an open-chain transition state. Alternatively, the reaction
t
[6c, d]
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COMMUNICATION
The two-step mechanism via a LiH intermediate (Scheme 3b)
is in line with the conclusions reached by Alonso and Harder, who
presented conclusive evidence for an analogous process via a
CaH intermediate, based on experimental and computational
in the reactive imine form, we thought that hydrogenation of this
type of substrates would be feasible.
Cy
Cy
results.[10a]
bis(trimethylsilyl)amides, which were less reactive than
LiN(SiMe but still showed activity in the hydrogenation of
N-cyclohexylimine (reactivity order:
Complexation of the cations with crown ethers
We
also
tested
other
alkali
metal
Li
N
N
3 2
Li[N(SiMe ) ], 1.0 equiv
+
3 2
HN(SiMe )
CH
3
CH
2
PhMe, 80 ºC
3 2
)
15
15-Li
benzaldehyde
Li>Cs>Na>K).[
15, 16]
15:15-Li ratio = 10:1
completely inhibited the reaction, indicating that the presence of
a "free" alkali metal ion that can function as Lewis acid is essential.
3 2
Scheme 4. Treatment of ketimines bearing -protons with LiN(SiMe )
Indeed, various imines derived from enolizable carbonyl
compounds such as cyclohexanecarboxaldehyde, acetophenone,
or naphthyl methyl ketone smoothly reacted with
3 2 2
substoichiometric amounts of LiN(SiMe ) and H to afford the
corresponding amines in good yields (Table 2, entries 1-4). As
observed before, imines bearing an N-cyclohexyl or N-benzyl
group were particularly reactive and gave full conversion with only
0.25-0.35 equiv. of base. Ketimine 1, with an N-Ph group, required
0.8 equiv. of base to achieve complete conversion (entry 5). Two
cyclic ketimines (entries 6 and 7) were also fully reduced using
.5-0.6 equiv. of base.
0
Table 2. Scope of base-mediated hydrogenation of imines
LiN(SiMe
3 2
)
R2
R3
R2
H
2
(100 bar)
HN
R1
N
R1
R3
PhMe, 80 ºC
H
LiN(SiMe
[
)
3 2
Conv. Yield
#
R1
R2
R3 Imine
t [h]
eq.][a]
[%]
[%]
1
2
3
4
5
C
6
H
11
C
6
H
11
H
16
0.25
0.3
18
20
21
27
20
>99
>99
>99
>99
>99
82
Naphth
Ph
C
6
H
11 Me 17
Me 18
n.d.[b]
Bn
0.35
0.35
0.8
76
Ph
C
6
H
11 Me 15
89
Ph
Ph
CF
3
1
65
6
7
19
0.5
0.6
20
20
>99
>99
78
60
20
3 2
[a] Amount of LiN(SiMe ) required to achieve maximum conversion.; [b] An
inseparable mixture of product and one or more unknown byproducts was
obtained.
2
N-cyclohexyl- and N-benzylimines also reacted well at lower
temperatures of 50 °C and in some cases even at 25 °C if the
loadings of LiN(SiMe ) were increased (Table 3). As observed
Figure 1. Above: Comparison of H NMR D-tetramethyl piperidine (bottom) and
2
H NMR of N-D tetramethyl piperidine (top). Below: 1H NMR spectra of a
solution obtained upon reaction of LiN(SiMe ) and H , at 80 °C.
3 2 2
15
3
2
before, aldimines were reduced more easily than ketimines.
Table 3. Temperature studies of the base-mediated hydrogenation of imines
We next explored the scope of this base-mediated
hydrogenation on more challenging substrates, including imines
bearing an acidic hydrogen atom in the -position. 1H NMR
experiments showed that imine 15 was deprotonated by
LiN(SiMe3)2
H2 (100 bar)
R2
R3
R2
R3
N
HN
H
R1
PhMe, T
R1
3 2
LiN(SiMe ) under typical hydrogenation conditions, but only to a
3 2 3 2
small extent (Scheme 4; equilibrium ratio LiN(SiMe ) :HN(SiMe )
T
[
LiN(SiMe
)
3 2
t
Conv. Yield
ca 10:1).[ Because the major part of the substrate was present
15]
#
R
1
R
2
R
3
Imine
7
ºC] [eq.][a]
[h] [%]
[%]
1
H
C
6
H
11
H
25 0.5
20 >99
91
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Chemistry - A European Journal
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COMMUNICATION
2
3
4
5
6
7
8
4-F
C
C
C
C
C
6
6
6
6
6
H
H
H
H
H
11
11
11
11
11
H
H
H
H
H
9
25 0.8
25 1.0
25 0.5
50 0.6
50 0.5
50 1.0
50 1.0
20 >99
20 54
20 >99
20 >99
20 >99
24 90
24 90
86
H2 (100 bar)
Ph
H
4-CF
3
10
11
8
n.d.
86
HN
>
99% conversion
62% yield
(1)
2-Me
PhMe, 80 ºC
Ph
Li
4-OMe
95
N
4-CF
3
10
84
2
3
H
Bn Me 18
n.d.
n.d.
H
C
6
H
11Me 15
Ph
Ph
D2 (100 bar)
n
N
HN
D
2
2-Li
D
D
D
D
D
(2)
9
1
19
50 1.0
50 1.0
23
43
95
n.d.
n.d.
+
PhMe, 80 ºC
D
D
D
22-d
23-d
0
20
23
Full -deuteration,
~
23% reduction
3 2
[a] Amount of LiN(SiMe ) required to achieve maximum conversion.
LiHMDS
(
0.7 equiv.)
Ph
H
HN
H2 (100 bar)
To gain more insight into the role of deprotonation equilibria
in the reduction of imines with acidic -protons, imine 15 was
>
99% conversion
83% yield
(3)
Ph
PhMe, 80 ºC
N
23
treated with D
2
gas (100 bar) and 0.5 equivalents of LiN(SiMe
3
)
2
1
(
80 °C, 20 h, Scheme 5). H NMR analysis of the crude product
LiHMDS
0.7 equiv.)
(
Ph
Ph
revealed complete conversion to the corresponding amine, and
full deuterium incorporation at the benzylic position. In addition,
N
HN
D
D2 (100 bar)
D
D
D
D
D
22
(4)
+
D
D
D
70% D incorporation at the methyl group was observed.
PhMe, 80 ºC
22-d
23-d
Deuteration at this position could either occur by deprotonation
+
and subsequent D transfer from DN(SiMe
3
)
2
, which is formed by
~
10% -deuteration
10% reduction
2
D splitting, or alternatively, the deprotonated imine could act as
~
+
2
a base and directly abstract D from D .
Scheme 6. Hydrogenation experiments conducted on 22-Li and 22
Cy LiHMDS (0.5 equiv.)
Cy
N
DN
C1
100% conversion
2
D (100 bar)
C2
full D incorporation at C1
x (3-x)
CH D
PhMe, 80 ºC
20 h
D
70% D incorporation at C2
In conclusion, LiN(SiMe3)2 has emerged as a remarkably
reactive agent for the activation coupled with imine
15
21-dx
H
2
hydrogenation. Our results together with the recent studies of
Scheme 5. Deuteration studies
Alonso and Harder[ and Stephan demonstrate considerable
10]
[11]
potential for group 1 and 2 metal amides as hydrogenation
catalysts. Compared to group 2 metal amides, LiN(SiMe
3 2
)
To examine whether an -deprotonated imine is sufficiently
basic to induce H splitting, a suspension of the lithiated imine 22-
Li, free from HN(SiMe and LiN(SiMe , was treated with H
100 bar, 80 °C in toluene). Imine 22 was chosen for these
experiments because the corresponding lithium salt 22-Li could
be isolated in pure form following a known procedure.[17] After a
reaction time of 20 h, we observed complete conversion to the
corresponding amine (Scheme 6, eq 1), as in the reaction of the
requires higher H pressure (100 bar vs. 1-6 bar) but reactions
2
2
may be conducted at lower temperatures (50 °C and in some
cases even room temperature vs. 80 °C). While group 2 metal
amides have only been applied to aldimines, the substrate scope
3
)
2
3
)
2
2
(
3 2
of LiN(SiMe ) also comprises ketimines and, notably, imines with
acidic -protons. For both lithium and calcium amides evidence
for a two-step mechanism via metal hydride intermediates has
been obtained. The mechanistic insights gained from these
studies could serve as a basis for exploring other combinations of
main group metal ions and bases as hydrogenation catalysts.
parent imine with LiN(SiMe
analogous reactions of metalloenamine 22-Li (Scheme 6, eq 2)
and imine 22 with LiN(SiMe (Scheme 6, eq 4) were conducted
under 100 bar of D . Both reactions gave very little conversion to
3 2
) (Scheme 6, eq 3). In addition, the
3 2
)
2
product, which is consistent with a strong kinetic isotope effect.
However, metalloenamine 22-Li gave back recovered starting
material with nearly complete D incorporation at the -positions.
Two conclusions can be drawn from these results: 1.
Metalloenamine 22-Li is a reactive intermediate capable of
Acknowledgements
Financial support from the Swiss National Science Foundation is
gratefully acknowledged. P.M. thanks the European Union for a
Marie Curie Career Integration Grant (CIG). We thank Prof. Daniel
Häussinger for his help with some NMR experiments.
2 2
splitting H . 2. Splitting of H is faster than hydride transfer to the
imine, otherwise deuteration of the  positions of 15 and 22 would
not occur (Scheme 5 and eq. 2 in Scheme 6).
Keywords: Catalytic hydrogenation • Main-group metal hydrides
•
H
2
activation • aldimines and ketimines.
[1]
a) The Handbook of Homogeneous Hydrogenation, Volumes 1-3. (Eds.
J. G. de Vries, J. Cornelis). Elsevier (Universiteit van Amsterdam, The
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Chemistry - A European Journal
10.1002/chem.201805549
COMMUNICATION
Netherlands). Wiley-VCH Verlag GmbH & Co. KGaA: Weinheim, 2007;
b) Handbook of Heterogeneous Catalytic Hydrogenation for Organic
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[11] Right before submission of this work, a related study on the reversible
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by alkali metal amides and phosphides which included
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For stoichiometric reactions of H
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2
, slow reduction to the
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2
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solubility issues could play a role.
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Chemistry - A European Journal
10.1002/chem.201805549
COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
Abstract
Daniel C. Elliott, Alex Martí, Pablo
Mauleon,* and Andreas Pfaltz*
LiN(SiMe
amounts, induces clean reduction of
aldimines and ketimines with as
reductant at moderate temperatures of
5–80 °C. Notably, the reaction tolerates
the presence of acidic protons in the -
position. Mechanistic investigations
3 2
) , even in substoichiometric
Page No. – Page No.
H
2
Title
2
indicate that the reaction proceeds via a
lithium hydride intermediate as the actual
reductant.
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