Mechanistic Studies of Hydride Transfer to Imines from a Highly Active and Chemoselective Manganate Catalyst

Article abstract of DOI:10.1021/jacs.9b05024

We introduce a highly active and chemoselective manganese catalyst for the hydrogenation of imines. The catalyst has a large scope, can reduce aldimines and ketimines, and tolerates a variety of functional groups, among them hydrogenation sensitive examples such as an olefin, a ketone, nitriles, nitro groups, and an aryl iodo substituent or a benzyl ether. We could investigate the transfer step between imines and the hydride complex in detail. We found that double deprotonation of the ligand is essential and excess base does not lead to a higher rate in the transfer step. We identified the actual hydrogenation catalyst as a K-Mn-bimetallic species and could obtain a structure of the K-Mn complex formed after hydride transfer by X-ray analysis. NMR experiments indicate that the hydride transfer is a well-defined reaction, which is first order in imine, first order in the bimetallic (K-Mn) hydride, and independent in rate from the concentration of the potassium base. We propose an outer-sphere mechanism in which protons do not seem to be involved in the rate-determining step, leading to a transiently negatively charged nitrogen atom in the substrate which reacts rapidly with HO^tBu (2-methylpropan-2-ol) to produce the amine. This is based on several observations, such as no dependency of the reaction rate on the HO^tBu concentration, no observable manganese amide complex, and a high reaction constant in a conducted Hammett study. Furthermore, hydrogen transfer of the catalytic cycle was experimentally probed and monitored by NMR with subsequent quantitative regeneration of the catalyst by H₂.

Full text of DOI:10.1021/jacs.9b05024

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Article
Mechanistic Studies of Hydride Transfer to Imines from
a Highly Active and Chemoselective Manganate Catalyst
Frederik Freitag, Torsten Irrgang, and Rhett Kempe
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b05024 • Publication Date (Web): 28 Jun 2019
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Mechanistic Studies of Hydride Transfer to Imines from a Highly Active
and Chemoselective Manganate Catalyst
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Frederik Freitag, Torsten Irrgang, Rhett Kempe*
Inorganic Chemistry II – Catalyst Design, University of Bayreuth, 95440 Bayreuth, Germany.
KEYWORDS: Hydride Transfer – Hydrogenation – Imines – Manganese – Mechanism
ABSTRACT: We introduce a highly active and chemoselective manganese catalyst for the hydrogenation of imines. The
catalyst has a large scope, can reduce aldimines and ketimines, and tolerates a variety of functional groups, among them
hydrogenation sensitive examples such as an olefin, a ketone, nitriles, nitro groups and an aryl iodo substituent or a benzyl
ether. We could investigate the transfer step between imines and the hydride complex in detail. We found that double
deprotonation of the ligand is essential and excess base does not lead to a higher rate in the transfer step. We identified the
actual hydrogenation catalyst as a K-Mn-bimetallic species and could obtain a structure of the K-Mn complex formed after
hydride transfer by X-ray analysis. NMR experiments indicate that the hydride transfer is a well-defined reaction, which is
first order in imine, first order in the bimetallic (K-Mn) hydride and independent in rate from the concentration of the
potassium base. We propose an outer-sphere mechanism in which protons do not seem to be involved in the rate-determining
step, leading to a transiently negatively charged nitrogen atom in the substrate which reacts rapidly with HOtBu (2-
methylpropan-2-ol) to produce the amine. This is based on several observations, such as no dependency of the reaction rate
on the HOtBu concentration, no observable manganese amide complex and a high reaction constant in a conducted Hammett
study. Furthermore, hydrogen transfer of the catalytic cycle was experimentally probed and monitored by NMR with
subsequent quantitative regeneration of the catalyst by H2.
Introduction
of a variety of classes of unsaturated substrates with
molecular hydrogen (ketones/aldehydes11–20, esters21–23
,
Hydrogenation catalysis employing manganese catalysts
was essentially unknown until 2016.1–11 Beller´s group
described the hydrogenation of nitriles and ketones or
aldehydes employing precatalyst A12 and proposed a
catalytically active manganese hydride complex. Our group
used precatalyst B13 to hydrogenate ketones and aldehydes
(Figure 1).
amides24, 25, CO2/carbonates26–28, nitriles12, 18, 29, imines30, 31).
The multi-dentate ligands used to stabilize these Mn
hydrogenation catalysts can be (de)protonated (Figure 2).
Experimental mechanistic investigations regarding the key
step in such hydrogenation reactions, the manganese
hydride transfer towards the corresponding (polar)
unsaturated substrate, are rare. Kirchner and coworkers
reported in 2017 that the stoichiometric reaction between
a pyridine-based manganese hydride complex and CO2 or
formic acid leads to the formation of a manganese formate
complex, which is evidence for the reduction of CO2
proceeding via a formate complex as an intermediate.
(Figure 2, C).32 Liu and coworkers investigated the hydride
transfer step in the Guerbet reaction with ethanol using a
manganese hydride complex and crotonaldehyde (Figure 2,
D).33 Full conversion of the hydride complex was achieved
after 3 h and manganese complexes bearing an ethoxido,
acetate or hydroxido substituent were detected as products.
The Mn catalyzed Guerbet reaction was also investigated by
Jones and coworkers.34 In 2018, Milstein and coworkers
conducted experiments with a manganese hydride complex
prepared in-situ, which was reacted with dimethyl
carbonate and methyl formate in tolueneD8 (Figure 2, E).27
They found signals in 1H and 31P NMR, which were assigned
to a methyl formate manganese complex for the reaction
with dimethylcarbonate and a formaldehyde complex for
the reaction using methyl formate. These results indicate
NH
N
N
H
N
HN
(iPr)2P
N
NH
Br
Br
(iPr)2P
OC
P(iPr)2
P(iPr)2
Mn
Mn
OC
CO
CO
A
B
Beller and coworkers
2016
Kempe and coworkers
2016
Figure 1. Mn precatalysts A and B used in hydrogenation
catalysis.12, 13
We employed milder reaction conditions, and the catalyst
tolerated a variety of hydrogenation-sensitive functional
groups, among them nitriles, and emphasized the
importance of the multidentate ligand, the ancillary
carbonyl ligands, and the oxidation state of Mn (Figure 2,
left). These initial publications inspired many groups to
develop Mn catalysts (Figure 2, right) for the hydrogenation
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that the complexes are intermediates in the reduction of Regarding the mechanism, deprotonation of the acidic
protons of the ligand backbone by KOtBu is essential to
observe hydride transfer activity. A bimetallic (potassium
and manganese) outer-sphere mechanism is very likely and
no amido-manganese intermediate could be observed. The
catalytically active bimetallic hydride complex is unusually
stable, but efficient hydride transfer to aldimines and
ketimines takes place under mild conditions, permitting an
impressive functional group tolerance. The hydride transfer
is a defined reaction as is the dihydrogen activation at the
K-Mn bimetallic catalyst.
1
2
3
4
5
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7
8
carbonates described. In the same year, Leitner´s group
reported on reactions of a hydride complex produced in-situ
with ethylene carbonate in toluened8 (1) and, in a second
experiment, with methyl formate (2).28 Signals of the
resulting mixtures were assigned to
a manganese
methoxido complex (Figure 2, F), a manganese complex
without bound H2 (1 and 2), partially hydrogenated
carbonate (1), free formaldehyde (1 and 2) and free
methanol (2). Kirchner and his group recently reported a
base-free hydrogenation of aldehydes with a pyridine-
based manganese hydride complex.19 By adding p-
fluorobenzaldehyde to the manganese hydride complex in
C6D6, new minor signals in 19F and 31P NMR spectra
appeared, which could be fully interconverted with a
required excess of 20 eq. of the aldehyde. The new signals
were assigned to a manganese alkoxido species, probably as
a result of an insertion into the C=O-bond, which could not
be isolated.
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Results and discussion
Optimization of the reaction conditions
The hydrogenation of N-benzylideneaniline (1a) was used
to find optimal reaction conditions and identify the most
active catalyst, also to be used for mechanistic studies.
Optimization of the parameters regarding solvent (thf,
1,4-dioxane, toluene, 2-methyl-2-butanol, diglyme,
dimethoxyethane, 2-methyl-thf), base (LiOtBu, NaOtBu,
KOtBu, NaHMDS, KHMDS, Cs2CO3, KOH, NaOH, KH), and base
loading (1, 2, 5, 8, 10, 12 eq.), resulted in thf as the solvent
of choice and 10 eq. of KOtBu with respect to the precatalyst.
After that, we evaluated the effect of the different
precatalysts as depicted in Table 1 at lower catalyst and
base loadings. Neither a precatalyst with pyridine backbone
H
HN
(iPr)2P
N
NH
P(iPr)2
N
CO
CO
(iPr)2P
RO
P(iP)2
Mn
Mn
CO
O
CO
R
R = H, Et, Ac
R = C(O)H, 4-F-C6H4
Kirchner
2017, 2018
C
Liu
2017
D
N
CO/D Mn
CO
D
H
nor
a Mn(II)-based precatalyst nor the precursor
CO
H
[Mn(CO)5Br] showed significant activity in the
hydrogenation of 1a under the conditions chosen. The
reactions in which triazine-based manganese(I) complexes
were used, resulted in yields from 11 to 37 % of 2a. The
precatalyst with R = phenyl ([Mn-Br]H2) showed the
highest activity. This is consistent with our findings for the
amine alkylation with alcohols, which can also include an
imine-reduction step.35 Complete hydrogenation was
achieved by extending the reaction time to 4 h, raising the
temperature to 50 °C, and with 0.4 mol% precatalyst
loading.
N
N
CO
CO
Mn NtBu
(iPr)2P
MeO
P(iPr)2
(tBu)2P
R
Mn
O
CO
CO
H
Leitner
2018
F
R = H, OMe
Milstein
2018
E
Figure 2. General structure of manganese complexes used in
hydrogenation catalysis (left).1-11 D is a donor unit, for example,
a dialkyl phosphine. When a bidentate ligand is used,17, 31 three
CO ligands coordinate. Multidentate ligands contain an acidic
proton. Right (C-F): Detected key intermediates in hydride
transfer investigations. 19, 27, 28, 32, 33
Despite these highly interesting experiments, no
stoichiometric, byproduct-free, and defined hydride
transfer of any of the proposed catalytically active
manganese complexes to one of the unsaturated substrates
in combination with quantitative dihydrogen activation
could be observed. Therefore, the transfer could not be
studied in detail. In addition, manganese catalyst-based
imine hydrogenation has not yet been investigated
mechanistically.
Herein, we report on mechanistic insights into hydride
transfer from a manganese hydrogenation catalyst to
imines. Our catalyst permits the general and highly
chemoselective hydrogenation of imines. Efficient
hydrogenation of ketimines and aldimines and tolerance of
numerous functional groups were observed, among them,
hydrogenation-sensitive examples such as an olefin, a
ketone, nitriles, as well as nitro and aryl iodo substituents,
or a benzyl ether. Upscaling was easily accomplished.
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Table 1. Precatalyst screening for the hydrogenation of
Ph
imine 1a.a
1
2
3
4
5
6
(thf)x
N
N
H
K
+1 KOtBu
-1 HOtBu
1 eq. base
[Mn-H]HK
HN
(iPr)2P
N
N
P(iPr)2
Mn
R
Ph
OC
CO
X
X
N
N
[Mn-H]HK
Ph
[Mn]
HN
(iPr)2P
N
NH
P(iPr)2
Ph
HN
(iPr)2P
N
NH
P(iPr)2
Br
Ph
KOtBu
H2
N
N
H
N
Ph
N
Ph
Mn
0 eq. base
[Mn-H]H2
H
Mn
thfD8
OC
HN
(iPr)2P
N
NH
P(iPr)2
1a
2a
Cl
Cl
CO
Mn
7
8
9
OC
CO
[Mn-H]H2
Entry
Precatalyst
Yield 2a [%]b
Ph
(thf)x
(thf)x
N
N
H
K
2 eq. base
[Mn-H]K2
K
1
2
3
4
5
6
7
8
R = Ph, X = N ([Mn-Br]H2)
R = 4-F3C-C6H4, X = N
R = NH-cyclopropyl, X = N
R = NEt2, X = N
37
11
20
14
28
2
+2 KOtBu
-2 HOtBu
N
N
N
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
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60
(iPr)2P
P(iPr)2
Mn
OC
CO
[Mn-H]K2
31P NMR
R = Me, X = N
Figure 3. Deprotonation of hydride complex [Mn-H]H2 with 1
and 2 eq. of KOtBu and corresponding signals in 31P NMR
spectra.
R = H, X = CH
PN5P[MnCl2]
0
[Mn(CO)5Br]
1
a 1a (1.0 mmol), KOtBu (1.6 mol%), 0.2 mol% precatalyst,
thf (2 mL), 40 °C, 20 bar H2, 2 h. Determined by GC with
dodecane as internal standard.
This indicates that the actual active hydride species is
[Mn-H]K2. The reaction starts as soon as a small percentage
of [Mn-H]HK is deprotonated a second time, to produce
[Mn-H]K2 and the increase in reaction rate stops as soon as
the whole complex is transformed into [Mn-H]K2.
Considering the inactivity of the neutral and the mono
deprotonated complex, the driving force of the hydride
transfer may be the double anionic nature of the catalyst
which results in two negatively charged N-atoms. These are
in conjugation with the hydride via the triazine ring and,
thus, the hydride is electron-richer. This aspect makes the
triazine backbone unique, considering that for other
b
Mechanistic studies
Base-dependent activation and intermediates
After optimization of the reaction conditions for the imine
reduction, we tried to identify the catalytically active
hydride species. [Mn-H]H2, a hydride complex readily
available by the reaction of [Mn-Br]H2 with 1 eq. of KOtBu
and H2,36 was reacted with 1, 2, and 10 eq. of KOtBu (Figure
3), the base also employed in the hydrogenation catalysis
(Table 1). As can be seen from NMR spectra, 1 eq. leads to
instantaneous deprotonation of one NH proton
([Mn-H]HK;  symbolizes a reaction to a specific
component shown after the arrow). The phosphorus atoms
are no longer magnetically equivalent, therefore, two
doublets are observed. The addition of 2 eq. of KOtBu leads
to fast and quantitative deprotonation of the remaining
acidic proton ([Mn-H]K2), resulting in one single peak in
31P NMR, due to the recovery of magnetic equivalence in
both phosphorus atoms. Addition of 10 eq. of base did not
lead to further deprotonation (see SI).
manganese hydrogenation catalysts.12,
Metalation of pincer ligands, as used here, or related ligands
with a pyridine backbone, except the compounds described
19, 22, 23, 24, 32,
here, are rare. The groups of Gambarotta and Korobkov
reported Al-Cr complexes.37,
These complexes were
38
employed in the oligomerization of ethylene.
Ph
Ph
(thf)x
N
N
N
N
H
+KOtBu
K
N
Ph
+
N
Ph
+
Ph
Ph
HN
(iPr)2P
N
NH
N
N
N
H
-HOtBu
thfD8
H
P(iPr)2
Mn
(iPr)2P
P(iPr)2
Mn
OC
1a
2a
OC CO
CO
[Mn-H]H2
23 °C
n
[Mn]K
With the knowledge about the base-dependent formation of
the different species [Mn-H]HK and [Mn-H]K2 in hand, the
next step was to evaluate the effect of the protonation stage
on the hydride transfer to imine 1a. Therefore, NMR
experiments in thfD8 were performed with [Mn-H]H2 and 1a
in an equimolar ratio using various amounts of KOtBu added
to the reaction (2a + [Mn]K) (Figure 4). Interestingly, no
hydride was transferred with less than 1 eq. of base, which
is consistent with the hypothesis of base-dependent
activation of the precatalyst. Moreover, there is a steep
increase in the initial rate between 1 eq. and 2 eq. of KOtBu,
which stagnates thereafter.
Figure 4. Base dependency of the initial rate (ri) of the hydride
transfer reaction from [Mn-H]H2 to 1a. Imine consumption
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was monitored via 1H NMR spectroscopy.a
Scheme 1. Stoichiometric transfer of hydride to 1a and
subsequent regeneration of [Mn-H]K2.
a
1a (30 µmol), [Mn-H]H2 (30 µmol), KOtBu, thfD8 (700 µL),
1
2
3
4
5
6
7
8
23 °C.
Ph
Ph
Ph
(thf)x
(thf)x
(thf)x
N
N
H
N
N
H
K
K
N
N
K
KOtBu (2 eq.)
Reaction order
HN
(iPr)2P
N
NH
P(iPr)2
N
N
N
N
N
N
(iPr)2P
P(iPr)2
Mn
(iPr)2P
P(iPr)2
Mn
Mn
thfD8
23 °C, 4 d
thfD8, rt
immediately
OC
After having evaluated the influence of the base on the
reaction, we further explored the influence of reactants for
the stoichiometric reduction of 1a with [Mn-H]H2. The
results suggest that rapid deprotonation of the complex
takes place first to yield [Mn-H]K2 and 2 eq. of HOtBu. After
that, the actual hydrogenation occurs between the activated
complex [Mn-H]K2, imine 1a, and probably HOtBu. The
reaction orders, with respect to the components, were
evaluated by varying their concentrations and detecting the
corresponding initial rates of the imine consumption. We
found a first-order dependency on 1a and [Mn-H]K2. The
reaction shows a zero-order dependency on HOtBu and on
OC
OC CO
[Mn]K
CO
[Mn-H]H2
CO
[Mn-H]K2
n
Ph
Ph
N
Ph
+
N
Ph
+
Ph
Ph
N
H
+ 2 HOtBu
1a
+ 2
2a
+ KOtBu
N
Ph
Ph
+ 2
+ HOtBu
1a
1a
9
Ph
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(thf)x
(thf)x
N
N
K
K
20 bar H2
N
N
N
H
thfD8
40 °C
over night
(iPr)2P
P(iPr)2
Mn
OC
CO
[Mn-H]K2
Ph
+ 2
+ 2 HOtBu
N
Ph
H
2a
1
1
KOtBu. Furthermore, plotting of
([A] is the time-
―
[퐴]
[퐴]0
These results led to the following conclusions concerning
the catalytic cycle (Figure 5): At first, precursor [Mn-Br]H2
is activated via an excess of KOtBu in the reaction mixture of
the hydrogenation and produces [Mn-H]K2 in reaction with
KOtBu and H2. [Mn-H]K2 transfers a hydride to imine 1a
under consumption of 1 eq. HOtBu and reproduction of 1 eq.
KOtBu. Amine 2a and [Mn]K are formed in this way. This
complex reacts again with H2 and KOtBu to regenerate
hydride complex [Mn-H]K2 and 1 eq. of HOtBu to close the
catalytic cycle. In order to investigate this hypothesis, we
conducted a hydrogenation reaction at 50 °C with 0.4 mol%
of the isolated complex [Mn-H]K2 (leads to full conversion
after 4h with [Mn-Br]H2 and 10 eq. of KOtBu instead) and
1 eq. HOtBu. As expected, the rate was much lower, but after
24 h, a yield of 28 % was achieved. The lower activity with
less base is probably due to the generated acidic protons of
the amine. These are in high excess compared to the catalyst
and compete with the NH protons of the triazine for
deprotonation.
dependent concentration of 1a and [A]0 is the
corresponding starting concentration) against time t, as a
typical plot for a second-order reaction with an equimolar
ratio of both components (1a and [Mn-H]K2), resulted in a
straight line with R2 = 0.999 (R = Pearson correlation
coefficient) (see SI). This is further evidence that the
hydride transfer is a second-order reaction, as expected
from the individual reaction orders of the components.
Comparable reactions of imines and a ruthenium hydride
complex under stoichiometric conditions were found to
also proceed with a second order kinetic (first order with
respect to the ruthenium complex and the imine).39 In
addition, we conclude that only the activated complex
[Mn-H]K2 and imine 1a seem to be involved in the rate-
determining step. Under catalytic conditions, the rate-law
probably collapses to a pseudo-first order reaction, due to
the large excess of imine (1).
Investigation of the catalytic cycle
Ph
Subsequently, the catalytic cycle was probed
experimentally (Scheme 1). A mixture of 1 eq. [Mn-H]H2,
2 eq. KOtBu ( 1 eq. of [Mn-H]K2 + 2 eq. of HOtBu), and
2 eq. of 1a was prepared for this purpose. Full conversion of
[Mn-H]H2 to [Mn-H]K2 was observed immediately and the
mixture was left to react over 4 d at room temperature and
monitored via 1H NMR spectroscopy (see SI). The
production of amine 2a and consumption of 1a and
[Mn-H]K2 were detected in 1H NMR as well as the formation
of KOtBu. As expected, almost all the hydride complex was
consumed after the reaction and the corresponding mixture
of 1a and 2a (nearly 1:1) was obtained. After that, the
mixture was pressurized with 20 bar H2 in an autoclave at
40 °C over night to ensure full conversion (Scheme 1).
Herewith, [Mn]K was converted back to [Mn-H]K2, which
then hydrogenated the rest of imine 1a into amine 2a. After
that, [Mn-H]K2 and HOtBu were regenerated again with H2
(still with the right stoichiometry of 2a:[Mn-H]K2 of 2:1).
N
N
HN
N
NH
Br
Mn
(iPr)2P
P(iPr)2
OC
CO
[Mn-Br]H2
excess
-KBr
-3 HOtBu
KOtBu
thf, H2
Ph
(thf)x
(thf)x
N
N
K
K
N
Ph
Ph
t
H
O Bu
1a
N
N
N
H
(iPr)2P
P(iPr)2
t
Mn
H
O Bu
+
OC
CO
[Mn-H]K2
Ph
(thf)x
K
N
N
H
H H
-
N
Ph
N
N
N
t
K
O Bu
+
Ph
(iPr)2P
P(iPr)2
Mn
2a H
OC CO
t
K
+
O Bu
n
[Mn]K
Figure 5. Proposed catalytic cycle for the hydrogenation of
imines.
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[Mn]K, which has a key role in this suggested catalytic cycle, significantly lower activity in imine hydrogenation (Table 1,
1
2
3
4
5
6
7
8
was obtained as dark green crystals either by crystallization
of a hydride transfer reaction after full conversion or by
adding 2 eq. of KOtBu to [Mn-Br]H2 in thf (see SI). In the
second reaction, 1 eq. of KOtBu leads to the elimination of
KBr and the second eq. metalates the complex, with 2 eq. of
HOtBu as byproduct in total.
Entry 6).
Hammett study
A series of competition experiments (Hammett study) was
conducted to gain further insight into the rate-determining
step of the hydride transfer. We explored the reactions
between [Mn-H]K2 and 1a and imines with various
substituents in para-position of the phenyl ring adjacent to
the nitrogen atom (1). It resulted that the reaction was
much faster with electron-withdrawing functional groups
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(see SI). The next step was to plot the relative reaction rate
푘푋
푘
(
=
constants krel
with kX as the reaction constant for
푟푒푙
푘퐻
the reaction with reactant 1 with a substituent other than H
and kH for the reaction with 1a) against various -values
42
(see SI).41, It was found that R2 for the plot against -
values optimized for radical reactions was only 0.11,
excluding a radical pathway. The only almost perfectly
fitting values with R2 = 0.94 (see Figure 7) were those
optimized for reactions with an evolving negative charge
(or decreasing positive charge), which is in conjugation
with the substituent in para-position. Taking the high slope
into consideration, which equals the reaction constant of
 = 5.85, it is most likely that a negative charge at the imine
is built-up during the reaction, which is in conjugation with
the varied substituents. This is consistent with the hydride
transfer to the imine, resulting in a negatively charged
nitrogen atom, being the rate-determining step. These
results and the fact that the concentration of HOtBu is not
relevant for the reaction rate are strong indications that no
alcohol or proton is involved in the rate-determining step.
Figure 6. Molecular structure of [Mn]K with 50% probability of
thermal ellipsoids.40 Hydrogen atoms are omitted for clarity.
Selected bond lengths [Å] and angles [°]: Mn1-P2 2.272 (15),
Mn1-P1 2.252(15), Mn1-N1 1.973 (4), Mn1-C2 1.753 (6), Mn1-
C1 1.729 (6), K2-N5 2.779 (4), K2-N4 2.889 (4), P2-N5 1.677
(4), P1-N2 1.675 (4), K1-N2 2.744 (4), K1-N3 2.855 (4), Mn2-
P3 2.269 (15), Mn2-P4 2.259 (15), C1-O1 1.170 (7), C2-O2
1.164 (7); P1-Mn1-N1 79.30 (12), P2-Mn1-N1 79.50 (12), P1-
Mn1-P2 158.32 (6), C1-Mn1-C2 85.80 (3), C1-Mn1-P1 99.12
(19), C1-Mn1-P2 96.70 (2), C1-Mn1-N1 125.00 (3), C2-Mn1-P2
100.19 (19), C2-Mn1-P1 95.65 (19), C2-Mn1-N1 149.10 (2),
N2-K1-N3 48.30 (11), N4-K2-N5 47.85 (11), P3-Mn2-P4 158.95
(6).
X
X
+
KOtBu (2 eq.)
Ph
Ph
+
[Mn]K
+
+
Ph
[Mn-H]H2
N
N
Ph
H
-HOtBu
N
H
Ph
N
Ph
thfD8, 23 °C
X = OMe, Me,
C6H5CH=CH,
X = OMe, Me,
C6H5CH=CH,
Cl, I
Cl, I
1a
1
2a
2
The molecular structure of [Mn]K was determined by X-ray
crystal structure analysis and is shown in Figure 6,
including selected bond lengths and angles. [Mn]K
crystallizes as a coordination polymer with a Mn to K ratio
of 1 to 1. Manganese is coordinated in a slightly distorted
trigonal bipyramidal geometry, with both phosphorus
atoms as axial ligands and both carbonyl substituents and
the triazine nitrogen as equatorial ligands. The Namido-Ctriazine
bonds in [Mn]K (average 1.318 Å) which are directly
impacted by the potassium coordination are slightly shorter
than the corresponding Namino-Ctriazine bonds in [Mn-H]H2
(average 1.345 Å)36. The Ctriazine-Ntriazine bond length
 = 5.85
R2 = 0.94
(average 1.366 Å) of the 4-ring chelate K-Ntriazine-Ctriazine
-
Namido is slightly longer than in [Mn-H]H2 (average 1.334
Å)36. The bond length and the planarity of the triazine motif
indicate that the complex is still aromatic. Each potassium
atom is coordinated by two triazine complexes with two
nitrogen atoms, respectively, and two thf molecules
resulting in a coordination number of six. Furthermore, one
potassium atom is pushed slightly behind and one in front
of the triazine plane. The cavity provided by the triazine
motif could be a reason for the stability and the activity of
the bimetallic catalyst system. Note that a related catalyst,
having a pyridine instead of a triazine backbone, shows
Figure 7. Hammett plot for the reaction of [Mn-H]K2
([Mn-H]H2 + 2 KOtBu) and 1.a
a[Mn-H]H2 (30 µmol), 1a (15 µmol), 1 (15 µmol), KOtBu
(60 µmol), thfD8 (700 µL), 23 °C.
Imine precoordination and effect of potassium
ACS Paragon Plus Environment

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However, precoordination of 1 at the manganese atom of Proposed catalytic cycle
Page 6 of 11
1
[Mn-H]K2 had to be excluded in order to differentiate
between an inner- and an outer-sphere mechanism. We
could not see any evidence in the NMR for imine
coordination at [Mn-H]K2. Considering that the isopropyl
substituents at the phosphorus atoms are highly sterically
demanding, an additional coordination of 1 to manganese,
with two carbonyl and one hydride ligands already bound
to the metal center, is highly unlikely. Thus, a ligand would
have to decoordinate to create a free coordination site if the
hydrogenation proceeds via an inner-sphere mechanism.
Because of the bimetallic nature of the double deprotonated
hydride complex, the PN5P ligand is even more rigid and,
therefore, can almost certainly not decoordinate. The CO-
ligands, however, could undergo ligand exchange with
imine in an equilibrium, followed by insertion and
recoordination of CO. A CO atmosphere should influence the
reaction rate strongly in such a scenario. We carried out a
stoichiometric reaction between 1a and [Mn-H]K2 with
1.5 bar absolute CO pressure (see SI). However, no
significant change in the initial reaction rate was observed.
Consequently, CO-imine ligand exchange is unlikely.
All these results led to a proposed catalytic cycle, as shown
in Figure 8. The catalytically active hydride for
hydrogenation is [Mn-H]K2 (I, black circle), for which we
postulate a coordination of both potassium atoms in the
triazine cavities, similar to [Mn]K. Imine 1 approaches the
hydride in an outer-sphere manner (II). The
rate-determining step is now the transfer of the hydride to
the imine ( III), which is in accordance with the Hammett
study. This step (I  II) could be supported by potassium
coordination. The equilibrium between I and III tends
strongly towards I considering the conversion of [Mn]K to
[Mn-H]K2 when reacted with K•2a (Scheme 2). Formation
of a manganese amido complex also seems unlikely. The
high slope of the Hammett plot (Figure 7) indicates an
evolving negative charge, most likely at the nitrogen atom,
which is in conjugation with the varied substituents. Such a
negative charge can be built-up in an outer-sphere
mechanism. A partial compensation of the negative charge
when in mesomerization with the ligand would lead to a
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
significantly less charged
N atom. Subsequently, the
transient potassium amide (III) reacts rapidly with HOtBu
to yield KOtBu, amine 2, and complex [Mn]K (IV). After that,
H2 is activated by [Mn]K ( V) and KOtBu deprotonates the
resulting NH proton to reproduce [Mn-H]K2 and, hereby,
close the catalytic cycle. The group of Casey found that the
stoichiometric reduction of aldehydes with Shvo’s complex
Furthermore, approaches of synthesizing an amido complex
with a small excess of the potassium salt of 2a (K•2a) and
[Mn]K or [Mn-Br]H2 (2 eq. for the deprotonation and the
third eq. for the reaction with the [Mn]K produced in-situ)
in thfD8, resulted in almost complete conversion of the
manganese complex to the activated hydride complex [Mn-
H]K2 with no observable amido complex (Scheme 2). Imine
1a was found as the byproduct, due to the hydride transfer
to the manganese complex (see SI).
derivatives proceed via
a
concerted outer-sphere
mechanism.43, 44 Comparable results were obtained with an
iron-based hydride complex.45 In contrast to that, Bäckvall
and coworkers reported that the precoordination of the
imine to the metal center is the rate-determining step in the
hydride transfer to imines from
a
Shvo´s catalyst
Scheme 2. Reaction of [Mn-Br]H2 and [Mn]K with K•2a
results in the activated complex [Mn-H]K2.a
derivative.46
thfD8
3 eq.
Ph
K
N
Ph
H
H
N
N
Ph
Ph
2a
K•
N
P
(thf)x
N
N
(thf)x
HN
(iPr)2P
N
NH
P(iPr)2
Br
N
N
H
K
K
Ph
N
Mn
CO
H
N
R2
Mn
R1
N
N
N
OC
N
P
2
CO
[Mn-Br]H2
(iPr)2P
P(iPr)2
K
CO
Mn
[Mn-H]HK
V
OC
CO
thfD8
5 eq.
Ph
K
Ph
H
[Mn-H]K2
(thf)x
N
R2
P
R1
N
Ph
N
N
N
Ph
+
K
Ph
H H
-
2a
K•
H
H
K
N
1a
N
N
N
N
N
P
(iPr)2P
P(iPr)2
N
N
CO
CO
Mn
N
N
Ph
N
Mn
Ph
N
Mn
CO
t
OC CO
K
O Bu
N
P
P
t
n
H
O Bu
K
K
CO
[Mn]K
IV
[Mn]K
[Mn-H]K2
I
a [Mn-Br]H2 or [Mn]K (1 eq.), K•2a (3 or 5 eq.), thfD8, rt.
fast
N
R2
R1
1
N
R2
R1
K
N
R2
R1
H
K
We conducted further hydride transfer experiments in
order to explore the influence of the alkali metal ion. We
activated [Mn-H]H2 with 2 eq. of KOtBu, NaOtBu or LiOtBu,
respectively, and compared the initial rates of the hydride
transfer to imine 1a at 50 °C. The rate of amine formation
H
N
P
N
P
N
N
N
N
Mn
CO
Ph
N
Mn
CO
Ph
N
N
P
N
P
CO
K
CO
K
II
III
increased heavily from Li (0.68 푚푀), over Na (5.50 푚푀), to K
Figure 8. Proposed mechanism for the hydrogenation of imines
via an outer-sphere mechanism. Complex [Mn]K is simplified
as a monomeric dearomatized structure and thf is omitted for
clarity. P = P(iPr)2.
ℎ
ℎ
(48.1 푚푀) and correlates with the size of the Group 1 metal
ℎ
cation. In addition, we added 18-crown-6 to an imine
hydrogenation at standard conditions. The activity was
significantly lower with a yield of only 38 % in comparison
to full conversion without crown ether (see SI for details).
Imine hydrogenation catalysis
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Journal of the American Chemical Society
A series of imines with various substituents at the phenyl
Table 2. Substrate scope for the variation of
substituents attached to the nitrogen atom.a Substrates
carrying functional groups sensitive to hydrogenation
are shown in blue.
1
2
3
4
5
6
7
8
ring attached to the nitrogen atom were tested to evaluate
the substrate scope of the imine hydrogenation (Table 2).
Standard substrate 2a was isolated in 98 % yield.
Substrates 2b-f with one or two halide substituents (F, Cl,
Br, and I) were also isolated in nearly quantitative yields. A
3,5-CF3-substrate was converted into 95 % of 2g. Nitrile
(2h, 2i) and nitro (2j, 2k), which are substituents sensitive
to hydrogenation, were tolerated in different positions of
the phenyl ring with high yields of up to 94 %. Furthermore,
amines with ketone- (2l) and C-C double bond functionality
(2m) were isolated in 77 % and 94 % yields, respectively.
The substrate class of the latter (2m), known as Resveratrol
amine derivatives, are investigated as drugs for the
treatment of Alzheimer’s disease.47 The electron-donating
Ph
[Mn-Br]H
2 (0.4 mol%)
N
N
KOtBu (4 mol%)
HN
(iPr)2P
N
NH
P(iPr)2
R
Br
R
N
Ph
thf, 20 bar H2
50 °C, 4 h
N
Ph
Mn
H
OC
1
2
CO
[Mn-Br]H2
9
F
Cl
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
N
N
N
H
98 %
H
H
98 % (98 %b)
95 %
2b
2c
2a
Cl
Br
I
i
N
H
96 %
N
H
Cl
N
H
substituents Me (2n), Pr (2o), and OMe (2p) were also
99 % (98 %b)
94 %
2f
tolerated in the reaction with yields of the isolated products
of 85–94 %. The heterocyclic der ivative 2q was obtained in
92 % yield. Upscaling to multigram scale of 1a and even of
substrates sensitive to hydrogenation (2e, 2h) was easily
accomplished with yields of at least 90 %.
2d
2e
CF3
NC
CN
F3C
O2N
N
H
95 %
N
H
N
H
86 %
94 % (90 %b)
2g
2i
2h
O
NO2
Ph
Next, the substituents attached to the -carbon atom were
varied (Table 3). F-, Br-, and Cl-phenyl were used as halide
substituents (2r–2t), yielding the products in 93–95 %. A
hydrogen-sensitive methyl ester was tolerated with 74 %
yield of the isolated amine 2u. As an aliphatic substrate,
cyclopropyl was used as a substituent (2v) and transformed
into the corresponding amine in 81 % yield. Moreover,
amines with OBn (2w), OMe (2x), and Me (2y), as examples
of electron-donating functional groups, were produced with
up to 97 % yield. In addition, sulfur-containing imines were
transformed almost quantitatively into the corresponding
products 2z and 2aa with 93–97 % yield. These are
potentially catalyst-inhibiting substrates, because they
could coordinate to the free coordination site at one of the
two key catalytic intermediates [Mn]K.
N
H
N
H
N
H
77 %
85 %c,d
81 %c,d
2l
2j
2k
Ph
Me
N
N
H
N
H
H
94 %c
85 %
93 %
2n
2o
2m
MeO
N
H
N
N
H
94 %c
92 %
2q
2p
a
1 (1 mmol), KOtBu (10 eq. with respect to [Mn-Br]H2),
[Mn-Br]H2 (0.4 mol%), 20 bar H2, 50 °C, 4 h. Yields of isolated
products are given. b 20 mmol 1. c 0.6 mol% [Mn-Br]H2. d 18 h
reaction time.
Furthermore, substrates were synthesized with a variation
of substituents on both sides of aldimine 1 (Table 4). Two
amines (2ab and 2ac) which have not been described in
literature so far, were obtained in 93 % and 97 % yield.
Furthermore, two thiophene derivatives were produced.
2ad, with a sensitive nitrile group, and 2ae, with a pyridine
substituent, were obtained in 96 % and 73 % yields,
respectively.
After the hydrogenation of aldimines, we became interested
in the reduction of ketimines (3) (Table 4). Especially
substituents which are sensitive to hydrogenation are of
broad interest, due to the generally harsher reaction
conditions needed for this substrate class. To our delight, it
was possible to transform nitrile-substituted ketimines into
the corresponding amines 4a and 4b with yields of 71 %
and 73 %. In addition, aromatic N-heterocycles were
tolerated. We were able to incorporate the pyridine (4c)
and the pyridazine motif (4d, 4e) into products 4c–4e with
79–85 % of the isolated products. This is the first report of
aromatic N-heterocycles being tolerated in the
hydrogenation of ketimines using a base metal catalyst. In
comparison to the work of the groups of Jacobi von
Wangelin30 and Sortais,31 our catalyst system has a broad
scope and an interesting functional group tolerance. Jacobi
von Wangelin and coworker were able to hydrogenate
aldimines and ketimines but their functional group
tolerance was very limited. Sortais and coworkers observed
an impressive functional group tolerance but could only
hydrogenate aldimines.
ACS Paragon Plus Environment

Journal of the American Chemical Society
Conclusion
Page 8 of 11
Table 3. Substrate scope for the variation of
substituents attached to the -carbon.a Substrates
carrying functional groups sensitive to hydrogenation
are shown in blue.
1
2
3
4
5
6
7
8
We developed a highly active and chemoselective catalyst
system for the reduction of aldimines and ketimines with
molecular H2. We investigated the mechanism using NMR
spectroscopy and stoichiometric reactions between imine
(1) and hydride complex [Mn-H]H2. NMR experiments
Ph
N
N
[Mn-Br]H
2 (0.4 mol%)
KOtBu (4 mol%)
indicate that the actual hydrogenation catalyst is
a
HN
(iPr)2P
N
NH
P(iPr)2
Ph
Br
Ph
N
R
thf, 20 bar H2
50 °C, 4 h
N
R
Mn
H
bimetallic K-Mn complex ([Mn-H]K2) produced by reaction
of [Mn-H]H2 and 2 eq. KOtBu. Potassium is coordinated in
the triazine cavity of the ligand, which is supported by X-ray
crystal analysis of the catalyst after transfer of H- ([Mn]K]).
The reaction rate for the stoichiometric hydride transfer to
imines was found to depend only on the concentration of
the imine (1) and [Mn-H]K2 (first order in each substrate)
and the transfer is most probably a second-order reaction.
We propose a mechanism in which the hydride transfer
proceeds via an outer-sphere mechanism without
involvement of protons in the rate-determining step. A
transiently negatively charged nitrogen atom at the former
imine reacts rapidly with protons of HOtBu to yield amine 2.
This is consistent with several observations, such as no
HOtBu concentration dependency of the reaction rate, no
observable manganese amide complex, and a relatively high
reaction constant in the Hammett study. The catalytic cycle
was experimentally probed and monitored via NMR and
[Mn-H]K2 could be fully recovered after the reaction by
treating the mixture with H2. The catalytic system was
applicable to over 30 aldimines and several ketimines with
a variety of challenging functional groups. The tolerance of
functional groups sensitive to hydrogenation, such as an
olefin, a ketone, nitriles, as well as nitro groups, an aryl iodo
substituent, or a benzyl ether is particularly interesting. We
were able to employ mild reaction conditions and a catalyst
loading as low as 0.4 mol%. Upscaling of the hydrogenation
to a multigram scale was easily achievable.
OC
1
2
CO
[Mn-Br]H2
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
N
N
N
H
H
H
F
Cl
Br
93 %
95 %
94 %
2t
2r
2s
N
H
N
O
O
H
N
H
81 %
OBn
74 %
2u
97 %
2w
2v
N
N
H
S
N
H
93 %b
H
OMe
SMe
Me
86 %
2y
91 %
2x
2z
N
H
97 %
2aa
1 (1 mmol), KOtBu (10 eq. with respect to [Mn-Br]H2),
[Mn-Br]H2 (0.4 mol%), 20 bar H2, 50 °C, 4 h. Yields of isolated
a
products are given. b 0.6 mol% [Mn-Br]H2.
Table 4. Substrate scope for the variation of both
substituents at the aldimine (1) and ketimine (3)
hydrogenation.a Substrates carrying functional groups
sensitive to hydrogenation are shown in blue.
Ph
N
N
[Mn-Br]H2
R2
R2
KOtBu
R1
ASSOCIATED CONTENT
Supporting Information.
HN
(iPr)2P
N
NH
P(iPr)2
R1
Br
N
R3
N
R3
thf, 20 bar H2
50 °C
Mn
H
OC
: R2 = H
: R2 = Me
: R2 = H
: R2 = Me
1
2
CO
[Mn-Br]H2
3
4
The Supporting Information is available free of charge on the
ACS Publication Website at DOI:
Experimental details, kinetics, detailed Hammett study,
spectroscopic data (PDF)
O
CF3
Ph
NC
N
H
F3C
Br
N
S
Crystallographic data (CIF)
N
H
H
SMe
93 %
97 %
96 %
2ab
2ac
2ad
AUTHOR INFORMATION
Corresponding Author
S
N
N
H
73 %
2ae
*kempe@uni-bayreuth.de
F
ORCID
N
N
N
H
Rhett Kempe: 0000-0002-9138-4155
Notes
H
H
N
CN
CN
73 %b,c
71 %b,c
79 %b,c
4c
4a
4b
F
The authors declare no competing financial interest.
N
N
N
N
H
N
H
N
ACKNOWLEDGMENT
85 %b,d
4d
81 %b,e
4e
We thank the Deutsche Forschungsgemeinschaft, DFG, KE
756/31-1, for financial support, Robin Fertig for X-ray crystal
structure analysis and Max Mörtel of the group of Marat
Khusniyarov of the Friedrich-Alexander University Erlangen-
Nuremberg for IR measurements.
a 1 or 3 (1 mmol), KOtBu (10 eq. with respect to [Mn-Br]H2),
[Mn-Br]H2 (0.4 mol%), 20 bar H2, 50 °C, 4 h. Yields of isolated
products are given. b 5 eq. KOtBu with respect to the precatalyst
and 18 h reaction time. c 3 mol% [Mn-Br]H2. d 1 mol%
[Mn-Br]H2. e 2 mol% [Mn-Br]H2.
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Journal of the American Chemical Society
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