A Biphasic Medium Slows Down the Transfer Hydrogenation and Allows a Selective Catalytic Deuterium Labeling of Amines from Imines Mediated by a Ru?H/D+ Exchange in D2O

Article abstract of DOI:10.1002/cctc.201801343

The transfer hydrogenation (TH) of several aldimines has been studied using [RuCl(p-cymene)(dmbpy)]BF₄, 1, (dmbpy=4,4′-dimethyl-2,2′-bipyridine) as a precatalyst. Both neat water and a biphasic water/toluene mixture (w/t) have been successfully used as solvents. In the w/t medium the corresponding precursors, amine and aldehyde, were also used as substrates for a transfer hydrogenative reductive amination. Selective deuterium labeling of the resulting alkylated amines was the main goal of this work. On using D₂O the D-content in the amine was negligible but a high level of D-incorporation was achieved in D₂O/toluene. According to calculations, this is due to the effect of the relative rates of the hydride transfer and that of the RuH/D⁺ exchange. The incorporation of deuterium increases with time as a consequence of the reduction in the hydride transfer rate as the substrate concentration diminishes. The recyclability assays performed reflect the importance of pH in the selectivity of the TH towards the imine or the aldehyde resulting from imine hydrolysis.

Full text of DOI:10.1002/cctc.201801343

Accepted Article
Title: A Biphasic Medium slows down the Transfer Hydrogenation and
allows a Selective Catalytic Deuterium Labeling of Amines from
Imines mediated by a Ru-H/D+ Exchange in D2O
Authors: Felix Angel Jalon, Margarita Ruiz-Castañeda, M. Carmen
Carrión, Lucía Santos, Blanca R. Manzano, and Gustavo
Espino
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To be cited as: ChemCatChem 10.1002/cctc.201801343
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ChemCatChem
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FULL PAPER
A Biphasic Medium slows down the Transfer Hydrogenation and
allows a Selective Catalytic Deuterium Labeling of Amines from
+
Imines mediated by a Ru-H/D Exchange in D
2
O.
[
a]
[a]
[a]
[a]
Margarita Ruiz-Castañeda, M. Carmen Carrión, Lucía Santos Blanca R. Manzano, Gustavo
Espino,*, Félix A. Jalón*
[b]
,[a]
Dedicated to Professor Pascual Royo (in memoriam)
The transfer hydrogenation (TH) of several aldimines has been
content in the amine was negligible but a high level of D-incorporation
was achieved in D O/toluene. According to calculations, this is due to
studied using [RuCl(p-cymene)(dmbpy)]BF
4
,
1, (dmbpy
=
4,4'-
2
dimethyl-2,2'-bipyridine) as a precatalyst. Both neat water and a
biphasic water/toluene mixture (w/t) have been successfully used as
solvents. In the w/t medium the corresponding precursors, amine and
aldehyde, were also used as substrates for a transfer hydrogenative
reductive amination. Selective deuterium labeling of the resulting
the effect of the relative rates of the hydride transfer and that of the
+
RuH/D exchange. The incorporation of deuterium increases with time
as a consequence of the reduction in the hydride transfer rate as the
substrate concentration diminishes. The recyclability assays
performed reflect the importance of pH in the selectivity of the TH
towards the imine or the aldehyde resulting from imine hydrolysis.
2
alkylated amines was the main goal of this work. On using D O the D-
Introduction
use of water as an alternative solvent in complex-catalyzed
Deuterium-labeled compounds are valuable chemicals that very
often are obtained by non-selective and/or energetically exigent
methods with expensive or non-ecofriendly deuterium sources[1]
reactions is of great interest due to its safety, non-toxicity, simpler
product separation and the possibility of catalyst recycling.[ 11]
Another important factor is that D
cheapest sources of deuterium.
2
O is currently one of the
[
2]
[3]
such as, for example, NaBD
4
or LiAlD
4
that are used in
stoichiometric amounts. However, deuterated substrates are
required for the determination of structures[ 4 ] and reaction
pathways,[ 5] as stable isotope tracers,[ 6] as stable isotopically
labeled internal standards in mass spectrometry,[ 7 ] for the
synthesis of drug compounds with improved metabolic stability,[8]
and to provide enhanced contrast in neutron scattering studies.[9]
The approaches established for deuterium labeling can be
extrapolated to tritium to give a new range of applications.[10]
In addition to the above, as consequence of the increasing
demand for environmentally friendly methods in chemistry, the
Amines are desirable organic compounds in a range of applied
fields such as medicine, agrochemistry and materials
chemistry.[ 12 ] Homogeneous transition metal catalysts are
commonly used for the deuteration of amines by H/D exchange
via C–H bond activation,[13] even in D O,[14] although this usually
2
requires harsh conditions and a low level of selectivity is generally
achieved.[15] A potential way to obtain deuterated amines is the
transfer hydrogenation (TH) of imines[ 16 ] or the transfer
hydrogenative reductive amination of aldehydes or ketones, both
2
in D O. In the reductive amination the amine and aldehyde
precursors of an imine are used as starting materials.[17] However,
the TH or reductive amination approaches do suffer from some
drawbacks such as the scarce incorporation of deuterium (vide
infra).
[
a]
b]
M. Ruiz-Castañeda, Dr. M. C. Carrión, Dr. L. Santos, Prof. Dr. B. R.
Manzano, Prof. Dr. F. A. Jalón
University of Castilla-La Mancha,
Facultad de Ciencias y Tecnologías Químicas-IRICA,
Avda. C. J. Cela, 10, 13071, Ciudad Real, Spain.
E-mail: Felix.Jalon@uclm.es
Metal-catalyzed hydrogenations in water, including transfer
hydrogenation (TH) processes,[18] have been reported in recent
years.[ 19] However, when these reactions are carried out in a
[
Dr. Gustavo Espino
University of Burgos,
Departamento de Química, Facultad de Ciencias,
Plaza Misael Bañuelos s/n, 09111, Burgos, Spain.
single phase, they generally require functionalized catalysts to
facilitate their solubility in water[20] or the use of phase transfer
catalyst under biphasic conditions.[21] In addition to the problems
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outlined above, the low solubility of molecular hydrogen and the
easy hydrolysis of imines are additional limitations. The former
problem can be circumvented by using transfer hydrogenation
computational calculations indicated that the Ru-H/D+
interchange has a slower rate than that of the hydride transfer to
N-benzylideneaniline and comparable to the hydride transfer to
cyclohexanone. This fact could explain the incorporation of
deuterium into cyclohexanol but a low deuteration level into the
amine (see Scheme 2).
(
TH) agents such as the systems HCOOH/HCOONa or
HCOOH/HCOONH
4
.[22] The ready hydrolysis of imines in water or
alcohols led to the opinion that they are not suitable substrates for
protic solvents.[23] However, Wu et al. successfully investigated
the asymmetric TH of aromatic cyclic imines and iminiums salts
catalyzed by a water-soluble catalyst in water. A metallacycle
system of Ir has been reported by Xiao et al. as active in the
hydrogenation of imines in methanol.[24]
+
2
1
D O
3
R CH=NR
2
R CHD-NDR1
[Ru]-H
[Ru]-D
slow
H/D exchange
2
1
R CH=NR
2
1
R CH -NDR (Main product in D O)
2
2
fast
In the work described here we aimed to obtain deuterated amines
by TH (or by reductive amination) of the aldimines Ia−VIa depicted
hydride transfer
Scheme 2. Scarce deuterium incorporation in the methylene position of the
amine in neat D O due to the fast hydride transfer.
2
in Scheme 1 using catalyst 1 in biphasic D O/toluene media and
2
with HCOOH/HCOONa as the hydrogen source. The
incorporation of deuterium will be the result of a metal-H/D+
Considering these ideas, we decided to attempt to slow down the
TH rate by using toluene as a second phase (w/t biphasic media)
in the absence of a phase-transfer catalyst, which could
accelerate the TH process. We have previously demonstrated
that the precatalyst and its derivatives are soluble in water at 80
ºC but practically insoluble in toluene, while the imine and amine
derivatives are mainly soluble in toluene. In this way, key steps
such as the decarboxylation of the formate anion and the Ru-H/D+
exchange could operate similarly in water and the presence of
toluene will not hamper them. However, the rate of hydride
transfer to the substrate should be decreased in this medium
since the substrate is mainly present in the organic phase. We
aimed to show that the use of this strategy would lead to a high
level of deuterium incorporation in the resulting amines and that it
is a concept that could be applicable to the preparation of labeled
2
exchange with acidic D O, provided that the deuteron will undergo
an inversion of polarity (umpolung). This route has barely been
explored for unsaturated substrates[25] and, to the best of our
knowledge, this methodology has never previously led to the
incorporation of deuterium in amines. It has been reported that
the main problem associated with deuterium incorporation in
unsaturated substrates is the control of the hydride transfer rate,
+
[26]
which must not exceed that of the metal-hydride/D exchange.
3
2
BF
4
4
1
5
6
N
Ru
cat =
N
Z
Cl
2
N
6
5
N
VIa
3
1
Z = C-OMe (Ia), C-Me (IIa),
4
3
C-H (IIIa), C-CF (IVa), N (Va)
(
deuterium or tritium) organic substrates.
Scheme 1.
Results and Discussion
This statement inspired this work, since in
a previous
Catalytic TH of imines in water versus water/toluene. In order
to demonstrate the ability of our precatalyst 1 to hydrogenate N-
benzylideneanilines in neat water, experiments were carried out
with four differently substituted para-N-benzylideneanilines. The
results and conditions are provided in Table S2. A starting pH of
publication[27] we reported the TH of N-benzylideneaniline with
good TON and TOF values in neat water using 1 as a precatalyst
and HCOOH/HCOONa as the hydrogen source. However, our
catalytic conditions led to a low level of deuterium incorporation in
the α-position of the resulting alkylated amine on using D
2
O as
.4 was chosen considering the results of our previous work.[27]
4
the deuterating agent. This fact contrasted with the TH of ketones,
such as cyclohexanone, which led to cyclohexanol with a
deuterium incorporation in the α-position of over 90%. In
accordance with the experimental observations, the results of
Besides the expected alkylated amine, variable amounts of para-
substituted benzaldehyde (resulting from hydrolysis of the
substrates) and of para-substituted benzylalcohols (resulting from
hydrogenation of the aldehydes) were also obtained (see Scheme
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3
a). The highest yield of the alkylated amine was obtained for the
Considering the yield of the amine product at 7 hours as
indicative (2 hours in the case of the unsubstituted and more
reactive IIIa), the expected decrease in the rate of TH when the
reaction was carried out in the w/t biphasic medium was
observed for aldimines IIa–IVa (entries 10, 14 and 24). A
homogeneous pattern was not observed for the hydrolysis
(sum of alcohol and aldehyde): for IIa and IIIa there were no
clear differences between the two media while in the case of
IVa a higher level of hydrolysis was unexpectedly observed in
the biphasic medium. The behavior of substrate Ia with OMe
was different as it showed an increase in the TH rate in w/t
media (entry 4, Table 1) with a noticeable amount of alkylated
amine at this time of 72% (34% in water). The observed partial
inhibition of the imine hydrolysis (39% in w and 10% in w/t)
probably explains this apparent discrepancy, suggesting a
possible competition between the two processes. This
competition can be extended to the benzylamine derivative
VIa, for which the alcohol produced reached high levels (see
entries 29–30) with a low yield of the alkylated amine (33% at
unsubstituted substrate IIIa (77% after two hours, TOF = 308).
The yield of the other three amines reflects the following favorable
effect of the substituent in the para position of the benzylidene
3 3
group: H > Me > CF > OMe. The imine with the CF group is
probably less reactive due to a lower polarity of the −N=C−
bond.[28] The explanation for the low yield of alkylated amine in
the case of OMe seems to be related to the degree of hydrolysis
(
39% of aldehyde at 7 hours).
Transfer hydrogenation of imines
OX
XHC
O
XHC
NX
Z
Z
Z
+
HC
Z
(a)
+
N
solvent, 1
8
0 ºC, H-donor
Z = C-OMe (Ia), C-Me (IIa),
C-H (IIIa), C-CF (IVa), N (Va)
3
OX
XHC
O
N
XN CHX
solvent, 1
0 ºC, H-donor
+
HC
(b)
+
8
(
VIa)
Transfer hydrogenative reductive amination of aldehydes
O
OX
XHC
Z
XHC
Z
Z
(
c)
solvent, 1
+
(
CH
2
)
n
N
2 n
(CH )
NH
2
80 ºC, H-donor
X
n = 0 Z = C-OMe (Ib), C-Me (IIb), C-H (IIIb),C-CF
n = 1 Z = CH (VIb)
3
(IVb)
7
hours). The case of imine Va, with a 4-pyridyl fragment, is
solvent = X
2 2
O or X O/toluene; X = H, D
H-donor = HCOOH/HCOONa
different and reflects a low reactivity: hydrolysis did not take
place and, although the alkylated amine was the only product
Scheme 3.
(
entries 32–33), the conversion was rather low (31% in 48 h).
Our aim was to increase the incorporation of deuterium in the
amines applying the strategy outlined in the introduction. As a
consequence, it was decided to demonstrate that the TH of imines
was also possible in a water/toluene biphasic medium (w/t) but
was slowed down with respect to the rate in neat water. The
general experimental conditions used in the catalytic assays in w/t
medium are indicated in Scheme 3.
According to the information in Table 1 for the aniline
derivatives (I–IV), similar production of the final alkylated
amine and also a similar degree of hydrolysis were obtained
on starting from the imine or its corresponding aldehyde and
aniline precursors (Scheme 3c, cf. entries 5 vs 8, 11 vs 13, 17
vs 22 and 25 vs 28 in Table 1, for example). However, in the
case of the benzylamine derivative (VI) it was advantageous to
start from the precursors (entries 29 vs 31).
Entries 1–28 in Table 1 concern the results obtained for the TH of
the N-benzylidenealdimines Ia–IVa, previously tested in water, as
well as the reductive amination of their precursors (substituted
benzaldehyde + aniline, Ib–IVb). Entries 29–30, 31 and 32-33
concern substrates VIa, VIb and Va, respectively.
It is interesting to analyze the data obtained after short reaction
times in the case of IIIb (entries 18 and 19). After 2 and 4 hours
there were 17% and 2% of aldehyde present, respectively,
while the corresponding alcohol was not detected. This finding
indicates that at such short times the aldehyde had not been
hydrogenated. The amount of alkylated amine increased from
The cat/S/HCOONa ratio of 1/200/6000 was considered to be
suitable in a previous study.[27] Experiments in which the
cat/substrate/formate ratio was varied did not give better results
24% to 63% on going from 2 to 4 hours. This indicates that the
(
compare entries 1 with 2 or 3).
imine was hydrogenated selectively over the aldehyde and that
the aldehyde reacted with aniline to give the imine as its
concentration is reduced with time.
For the N-benzylidenealdimines, with the exception of IVa
3
where the para substituent is the electron-acceptor CF group,
the yields of the alkylated amine were around 72–86% in 24
hours (58% for IVa) and a negligible increase was observed
after a further 24 hours (cf. entries 5 vs 6 and 25 vs 26).
Selective deuterium labeling of amines by TH of imines in
D
2
O/toluene (dw/t). Once it had been verified that the TH of
imines in the biphasic medium was possible, and took place at
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Table 1. Catalytic transfer hydrogenation results for different substrates
a lower rate than in water (with the apparent exception of Ia),
we evaluated whether this could lead to a higher level of
selective deuterium incorporation in the resulting amine on
[
a]
using 1 in biphasic medium (water/toluene).
Entry
Substrate
Time
h)
Alkylated
amine (%)
Alcohol
(%)
Aldehyde
(%)
Imine
(%)
(
[b]
1
2
3
4
5
6
7
8
2
20
31
3
16
1
7
6
70
47
76
18
2
2[c]
using D O as the deuterium source. A reaction time of 24 hours
2
OMe
2[d]
7
12
11
2
was selected since at this time a high yield of amine was
obtained (Table 2). Substrate Va was excluded from the study
due to the ineffective TH.
N
72(34)
84
8
Ia
24
48
7
14
12
3
-
88
-
-
OMe
77
2
18
O
Table 2. Deuterium labeling of alkylated amines using 1 in D
2
O/toluene
H
2
N
(dw/t) by TH of imines.[a]
H
24
85
15
-
-
Ib
x
y
DHC
R
9
2
7
16
5
4
7
75
24
R
D O/tol., cat
+
DHC
DO
R
2
N
ND
1
0
1
59(76)
10
N
R = OMe (Ia), Me (IIa), H (IIIa), CF
(IVa)
3
1
24
72
56
80
28
12
20
-
9
-
-
24
-
IIa
Time
(h)
Alkyl.
amine
(%)
x (%)
Alcohol
(%)
y (%)
Amine/
Alcohol
ratio
Imine
(%)
Entry
Subs.
1
2
3
7
O
1
H
2
H N
1
2
3
Ia
Ia
Ia
24
24[b]
82
89
84
87
7
18
11
21
89
80
97
4.5
8.1
4.0
8.1
2
IIb
24
--
--
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
2
7
23(77)
79
3
11
16
14
-
13
2
-
61
8
48
91
N
4
Ib
24
89
38
11
89
--
14
24
2
84
-
IIIa
5
6
7
8
9
IIa
24
80
86
87
88
90
91
90
77
73
78
62
5
20
14
8
70
90
74
92
96
89
86
33
37
4.0
6.1
10.9
7.3
9.0
11.4
9.0
3.3
2.7
--
--
5
86
-
-
IIb
24
24
17
2
5
-
59
35
8
IIb
24[b]
4
63
-
O
IIIa
IIIa
IIIb
IIIb
IVa
IVb
24
93
91
38
48
51
51
12
10
8
--
--
1
H
2
N
7
80
7
H
48
14
24
2
89
11
11
8
-
IIIb
10
11
12
13
24
89
-
-
24[c]
10
23
27
--
--
--
CF
3
19
4
1
-
69
21
2
24
7
49(66)
58
29
40
42
32
N
24
24
48
7
IVa
58
-
-
x
D
2
O/tol., cat
y
DHC
DO
CF
3
DHC
49
1
18
+
O
VIa
N
ND
2
H N
H
24
7
62
33
38
58
-
-
IVb
1
4
5
VIa
VIb
24
24
40
46
76
74
59
50
72
70
0.8
0.9
1
4
2
9
0
7
2
1
N
3
[a] Experiments were repeated at least twice to corroborate
2
4
31
65
-
4
2
VIa
reproducibility. T = 80 °C. Unless otherwise stated, cat/S/HCOONa =
1/200/6000, cat = 0.626 μmols, cat = 0.5 mol%., biphasic conditions (2 mL
31
O
2
D O:1 mL toluene), initial pD = 4.8 adjusted with HCOOH, 500 rpm; x and
H
7
50
43
5
H
2
N
y are the % of deuterium incorporation in the alfa-position of the alkylated
VIb
amine or the alcohol respectively. [b] Monophasic condition (2 mL D O)
2
maintaining the rest of conditions. [c] cat/S/HCOONa = 1/100/6000, cat =
1 mol%., rest of the conditions as in [a]. Conversion was determined by
1H NMR spectroscopy.
N
3
2
3
24
23
31
-
-
-
-
77
69
3
N
48
Va
[
a] Experiments were repeated at least twice to corroborate
reproducibility. T = 80 °C, unless otherwise stated, cat/S/HCOONa =
/200/6000, cat = 0.64 μmols, cat = 0.5 mol%. Biphasic conditions (2 mL
O:1 mL toluene), initial pH = 4.4 adjusted with HCOOH, 500 rpm. [b]
To our delight, a high level of deuterium incorporation in the α-
alkyl position of the amine was generally obtained (x%) and
variable amounts of the alcohol deuterated in the α position
1
H
2
Values in parenthesis correspond to the processes in neat water. [c]
Experiment with cat/S/HCOONa = 2/200/6000, cat = 1.252 μmols. [d]
Experiment with cat/S/HCOONa = 1/400/6000, cat = 0.626 μmols.
(
y%) were also obtained (Table 2).
Deuterium incorporation was markedly higher than the
negligible amounts obtained in neat D O (entries 1 vs 2 and 6
1
Conversions were determined by H NMR spectroscopy.
2
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vs 7). As one would expect,[25][29] in the alcohols obtained from
the respective aldehyde, the deuterium was incorporated at an
excellent level in both media. When the deuterium levels of the
resulting alkyl amines were compared, a dependence of the
deuterium incorporation with the substrate was observed. While
the unsubstituted benzylaniline and that with the OMe
substituent reached levels of around 90%, the amine with a Me
substituent and the dibenzylamine led to values in the range 76–
1
00
9
8
7
6
5
4
0
0
0
0
0
0
30
2
0
10
0
0
5
10
15
20
25
30
Time / h
78%. The alkyl amine that exhibited the lowest incorporation
was the benzylaniline with the CF
incorporation was only 51%.
3
substituent, for which the
D-incorp. amine
D-incorp. alcohol
Figure 1. Variation with time of the deuterium incorporation in N-
benzylideneaniline (―) and benzyl alcohol (―).
From the point of view of deuterium incorporation (x%), the use
of the imine as the substrate was clearly advantageous when
compared to the use of a mixture of their precursors amine and
alcohol (entries 1 vs 4, 5 vs 6 and 8 vs 10) with the exception of
the easily hydrolyzed imines (entries 12 vs 13 and 14 vs 15),
which gave similar results.
+
on the one hand, and of the RuH/D exchange, on the other. It
has previously been stated that imines are more easily
hydrogenated than aldehydes in acidic media (kHyd.T. imine > kHyd.T.
aldehyde, Hyd.T. = hydride transfer).[27] The low D content in the
alkylated amine must be an indication of the following order in
A control experiment, in the absence of catalyst, was carried
out, consisting in the use of the imine IIIa (Fig. S1) in the
standard catalytic conditions. Only non-deuterated IIIa and the
corresponding benzaldehyde (18%, consequence of hydrolysis)
were obtained. This experiment indicates that the TH is not
operative without catalyst and that the deuterium incorporation
is a catalytic process as well. Also experiments with N-
benzylphenylamine or benzyl alcohol were performed in the
+
rate constants: kHyd.T imine > kRuH/D exchange and the deuterium
incorporation increases when the concentration of the imine is
low enough to slow down the rate of hydride transfer process, a
situation that occurs after long reaction times. In the case of the
aldehyde, the similar rates of hydride transfer and RuH/D+
exchange allowed D incorporation from the beginning but, in
any case, a decrease in the concentration of aldehyde favored
deuteration of the alcohol. To support this hypothesis the
correlation of the deuterium incorporation vs the remaining
substrate (imine Ia or the corresponding aldehyde) with time
was analyzed (see Figure 2). According to the symmetric
evolution of these plots, it is clear that the lower the amount of
substrate that remains the higher the deuterium incorporation.
In line with this statement, it has been verified that by
decreasing the initial concentration of the substrate (entry 10 vs
entry 11, Table 2), the incorporation of deuterium in the alkyl-
amine was increased from 38 to 48%.
2
presence of 1 in D O/toluene and no deuterium incorporation
was observed (Fig. S2 and S3) indicating that the D-
incorporation takes place in the TH process.
It was decided to study the evolution with time of the D
incorporation both in the amine and in the alcohol. This study
was carried out with the pair aniline-benzaldehyde (IIIb) in the
biphasic medium dw/t (see Figure 1). After 24 hours a high yield
of alkylated amine (91%) with a low level of D incorporation
(
38%) and 9% of alcohol with 89% D incorporation were
obtained. The aim was to evaluate if the high rate of the
reductive amination was associated with a low D content in the
alkylated amine. After short reaction times (2–7 h) the
percentage of deuterium incorporation in the amine was low and
this increased with time until a stable level of around 40% was
reached after longer times (14–24 h). A similar evolution was
observed for the alcohol but higher levels of D incorporation
were observed from the beginning.
In accordance with the interpretation of relative rates, the Gibbs
energy barriers for the hydride transfer to the N-
+
benzylideneaniline (IIIa) and for the RuH/D exchange were
theoretically calculated[27] in neat water as 2.3 and 12.7 kcal
−
1
mol , respectively (Figure 3).
In this work we calculated that the Gibbs energy barrier for the
−1
hydride transfer to the benzaldehyde is 8.2 kcal mol . As stated
above, in the w/t medium the hydride transfer processes slow
down and the barriers should be higher.
All of these observations could be a consequence of the
different rates of the hydride transfer of imines and aldehydes,
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ChemCatChem
10.1002/cctc.201801343
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indicates the absence of a significant isotopic effect with this
substrate.
70
60
50
40
30
20
10
0
Catalytic recycling trials. Catalyst recycling experiments were
carried out with equimolar amounts of aniline and benzaldehyde
(
IIIb) as substrates, in the w/t biphasic medium, at the standard
described catalytic conditions for four cycles of 24 hours each.
Two recycling experiments were performed with and without the
addition of formic acid at the beginning of each new cycle and
the results were clearly different (see Figure 4). When formic
acid was not added (Figure 4a) the formation of the alkylated
amine decreased markedly in the second cycle (55%) and it was
only 5% in the next two cycles. This decrease in the yield of
alkylated amine is not related to the loss of catalytic activity,
since in fact benzaldehyde is reduced to the corresponding
alcohol with a high yield. This result can be interpreted in terms
on the effect that the pH has on the selectivity of the catalyst.
The initial pH was 4.4 but it was 8 at the end of the fourth cycle
as a consequence of the consumption of formic acid in the TH
process. The catalyst is therefore very active towards the
hydrogenation of the imine in the first cycle at the initial pH but,
according to the data, it is increasingly selective towards the TH
of the benzaldehyde when the number of cycles and the pH
have increased. It is known that the protonation is an essential
requirement for an efficient TH in imines[30] but this is not the
case for aldehydes.[31] The small amount of remaining imine in
cycles 3 and 4 is probably a consequence of the extensive
hydrogenation of the aldehyde, which in turn promotes the
hydrolysis of the imine.
0
2
4
6
8
10
12
14
16
Time / h
%
D incorporation
Remaining imine
(
a)
1
00
8
6
4
2
0
0
0
0
0
0
2
4
6
8
10
12
14
16
Time / h
%
D incorporation
Remaining aldehyde
(b)
Figure 2. Graphical correlation between the percentage of deuterium
incorporation in the substrate and that of the remaining substrate with time.
a) Imine Ia to alkylated amine (b) Aldehyde in Ib to alcohol.
(
H
2
[Ru]
H
D
1
5
0
5
0
5
O
H
[Ru]
H
R
u
]
[
[
Ru]
H
O
1
H
H
H
O
H
Ph
H
N
Ph
H
H
[
Ru]
[Ru]
In an attempt to overcome these problems fresh formic acid was
also added at the beginning of each cycle (see Figure 4b). The
optimum amount of formic acid was estimated to be that
consumed in the TH of each cycle, which means an equimolar
amount with respect to the added substrate (assuming 100%
conversion). Conversion to the amine was clearly improved.
However, a progressive increase in the amount of unreacted
imine and alcohol was observed with the number of cycles.
Aldehyde was not observed in any cycle.
D
H
H
H
2
H
O
D
O
[Ru]
H
R
u
]
[
H
H
H
HO
H
∆
-
R
u
]
[
H
·
·
·H
2
Ph
[
R
u
]
Ph
N
H
-
-
10
15
H
H
N
Ph
Ph
H
Figure 3. Reaction coordinate for the hydride transfer on the N-
benzylideneaniline (―) or benzaldehyde (―) and for the Ru-H/D exchange
in 1 (―). Some data are taken from ref 27.
+
Proposed mechanism for the imine TH. Before proposing a
catalytic cycle, we tried to detect some of the intermediates. An
experiment consisting on the addition of 10 eq. of HCOONa
Aniline and benzaldehyde (IIIb) were chosen as substrates for
a comparative study of the progression of the different species
in w/t and in dw/t. It was found that the kinetic evolution of the
species (imine, alkylated amine, alcohol and aldehyde) was
very similar in w/t and in dw/t (see Figure S5), a fact that
2
over a D O solution (0.5 mL) of precatalyst 1 at r.t. in an NMR
tube was performed (see Figure S6). Interestingly, the chlorido-,
aquo- and formato-complexes were detected in the 1H NMR
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ChemCatChem
10.1002/cctc.201801343
FULL PAPER
spectrum (the aqua-complex could be detected as a single
species in solution by the reaction of the chloride-complex with
R1
(i)
[Ru]-Cl
D O
2
ND
O
4
a slight excess of AgBF , see experimental section). In addition,
Cl-
DHC
H
O
(vii) R2
2
a new species appeared slowly which was assigned to the
hydrido-complex, although the resonance of the Ru-H group
was absent. However, the corresponding Ru-D resonance was
D
D
[
Ru] O
aquo complex
D O
2
H O
2
(
ii)
D
R1
2
N
detected in the H NMR spectrum (Fig. S9). To ensure that this
[
Ru] OOCH
HC
new species was the hydrido-complex, H
2
O (0.2 mL) was added
formato complex (iii)
[Ru]
R
2
D
to the solution. A new resonance at - 6.3 ppm appeared
1
immediately in the H NMR spectrum (Fig. 8c) reflecting a Ru-H
R1
D
R1
D
N
↔
Ru-D exchange. The proposed catalytic cycle (Figure 5) for
N
CO2
HC
HC
(vi) R2
[Ru] H/D
the hydrogenation of imines is based on these findings and on
the theoretical calculations performed in our previous work.[27]
The hydrido-complex (iv) that can be considered the key form
in the catalytic cycle and is formed by decarboxylation of the
formato species. The aforementioned Ru-H ↔ Ru-D exchange
must take place through a dicationic dihydrogen ([Ru](HD))
compound (v) formed by the reaction of the hydride with D+
although this species has not been identified.
R2
hydride complex
(
iv)
D
H
D
2
H
[Ru]-
D
(v)
R1
R1
N
ND
DHC
HCO
2
D
+
2
CO +
HC
R2
H
R2
Figure 5. Proposed mechanism for the hydrogenation of imines in an acidic D
2
O
media.
9
2
90
8
9
100
+
8
6
4
2
0
0
0
0
0
55
This species must be acidic enough to liberate H . In this way, the
3
2
incoming D+ is transformed into a Ru-D(δ–) group that is
1
1
+
5
5
Alcohol
transferred to the substrate. Such a change of polarity of the D is
1
3
3
5
Alkylated amine
0
named an “umpolung” process.[29b] The hydride transfer to the
imine is a process that takes place easily but needs the prior
protonation of this substrate, which is transformed into an iminium
salt (vi). This transfer can be of a deuteride if the umpolung
process is fast enough. The resulting alkylated amine (vii) is
liberated to the medium and substituted by a water molecule and
the cycle starts again. The limiting step is the decarboxylation of
the formate anion.[27] The total catalytic process is included in the
lower part of Figure 5 and it involves the transfer of a hydride (or
deuteride if the umpolung is operating) and a deuteron from an
HCOOD molecule to the imine, which is transformed into the
imine
1
2
3
4
Number of cycle
(
a)
8
9
89
1
00
5
1
8
6
4
2
0
0
0
0
0
3
7
4
1
39
1
1
2
11
3
2
4
Alcohol
Alkylated amine
imine
8
0
0
2
alkylated amine and a molecule of CO is released. According to
1
4
this cycle and the overall reaction, the pH must be decisive in the
hydride transfer step due to the necessary imine protonation and
since a formic acid is consumed in the formation of the alkylated
amine. Besides, the acid pH is also important in the umpolung
process where a deuteron is also necessary. The TH process of
the aldehydes can procced in a similar way, with the difference
that the protonation of the substrate is not a necessary step.[31]
Number of cycle
(b)
Figure 4. Recycling experiments for the TH of benzaldehyde + aniline (IIIb) in
a biphasic w/t medium without (a) and with (b) the addition of 4.9 µL of formic
acid at the beginning of each cycle. See discussion for further details
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FULL PAPER
Besides, a deuteration experiment of N-benzylideneaniline under
standard conditions (those indicated as [a] in the footnotes of
Table 2) in dw/t was carried out and the absence of DCOOD in
the aqueous phase was verified (Fig. S4). This fact allows to
Experimental Section
Experimental Details. All reactions were carried out under an
atmosphere of dry oxygen-free nitrogen, using Schlenk-vacuum
line techniques. Complex
1 was prepared as previously
discard a process involving deuteration of the formate anion
described.[27] Solvents were distilled from the appropriate drying
agents and degassed before use. The HCOONa/HCOOH buffer
solution was prepared from HCOONa (6.53 g, 96.0 mmol) and
HCOOH (650 μL, 17.2 mmol) in water (HPLC grade). The volume
was adjusted to 25 mL in a volumetric flask. The precatalyst
solution was prepared by dissolving the precatalyst (8.5 mg of
complex 1, 15.65 μmol) in water (HPLC grade) and adjusting the
volume in a 25 mL volumetric flask. Once the solutions had been
prepared, nitrogen was bubbled through for several minutes and
they were stored under an inert atmosphere.
-
(
DCOO ) and a consecutive deuterium transfer to the metal (as an
alternative to the umpolung process).
Conclusions
A
set of five aldimines of the type para-substituted N-
benzylideneaniline and N-benzylidenebenzylamine have been
successfully hydrogenated by a TH process using buffered
HCOONa/HCOOH solutions, as the hydrogen source, in neat
water or a water/toluene biphasic medium. The conversion of
substrates is not related to an electronic effect of the substituents
in the para position of the benzaldehydes used. The activity for
the formation of the alkylated amines follows the order H > Me >
General synthesis of imines used as substrates in the
catalytic process. In the synthesis of the imines the starting
materials were aniline or benzylamine and the corresponding
aldehyde, with the exception of the N-benzylideneaniline, which
was used as a commercial product. All these reactive were
obtained from Aldrich and used in commercial degree.
3
CF while the yield with the substrate containing OMe depends
strongly on the solvent medium. Conversions from the imine or
from the respective aldehyde and amine precursors (transfer
hydrogenative reductive amination) gave similar results
To a round-bottomed flask the corresponding aldehyde (5.12
mmol) and aniline (467.1 µL, 5.11 mmol) or benzylamine (712.5
µL, 6.52 mmol) were added. Vacuum cycles were performed in
order to remove the water produced in the reaction. The mixture
was left overnight without stirring at room temperature. The
products were purified by recrystallization from methanol. The
solids were dried under vacuum. In all cases a yellow solid was
obtained in high yield (84–99%). 1H and 13C{ H}-NMR spectra
were consistent with data from the bibliography.[32]
Calculations at the DFT level for the non-substituted N-
benzylideneaniline show that the hydride transfer to imines and
+
aldehydes in water is faster than the Ru-H/D exchange, and thus
any strategy that reduces the rate of hydride transfer may favor
the incorporation of deuterium in the final product. In line with this
idea, we have experimentally shown that the use of
a
1
water/toluene two-phase medium slows down the TH process and
makes it feasible to achieve high levels of deuterium incorporation
in the α position of the resulting amines. In relation to this effect,
it has been shown in one example with using a reductive
amination procedure that the degree of incorporation of deuterium
increases at long reaction times, when the rate of the reductive
amination process is reduced due to the decrease in the substrate
concentration. This opens a new strategy, verified with one
experiment, for the incorporation of deuterium in amines (or other
products) due to a lower initial concentration of the substrate.
The main achievement in this work is the proof of concept that
reducing the rate of TH of imines with two different strategies
leads to a higher level of deuterium incorporation in the resulting
amine. This could open new ways to label a diverse range of
General procedure for catalytic hydrogenation of imines in
®
biphasic medium. For the catalytic runs, a Teflon -capped 10
mL ampoule sealed with a Young valve was charged with 1 mL of
the buffer solution (HCOONa/ HCOOH) and 1 mL of the catalyst
solution, with 0.128 mmol of different substrates (27 mg of N-(4-
methoxybenzylidene)aniline,
methylbenzylidene)aniline, 23.2 mg of N-benzylideneaniline and
1.9 mg of N-(4-trifluoromethylbenzylidene)aniline) dissolved in 1
25
mg
of
N-(4-
3
mL of toluene. Nitrogen was bubbled through the mixture for
several minutes. The cat/substrate/HCOONa ratio was 0.64
μmol/0.128 mmol/3.84 mmol = 1/200/6000, and the precatalyst
concentration was 0.32 mM. For each experiment, two ampoules
with identical concentrations were introduced simultaneously into
a homemade multi-hole reactor preheated at 80 °C (mineral oil
bath and temperature sensor control), and the mixtures were
2 2
substrates with hydrogen isotopes from D O or T O.
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ChemCatChem
10.1002/cctc.201801343
FULL PAPER
magnetically stirred for the corresponding reaction time. The
ampoules were then cooled in an ice/water bath and the solutions
were transferred to a 5 mL vial and kept refrigerated until analysis.
The toluene phase was separated from the aqueous phase. The
resulting aqueous phase was extracted with diethyl ether (2 × 5
mL). The organic phases were combined and then evaporated in
and decanted into the ampoule. Pasteur pipettes were used to
separate the organic phases. The yield was calculated from the
1H NMR spectrum in CDCl
. Fresh benzaldehyde, aniline, toluene
3
and HCOOH (4.8 μL, 0.128 mmol) were then added to the
aqueous phase and a new cycle was run. A total of four cycles
were studied.
air. Samples were placed in an NMR tube containing CDCl
3
(0.5
Catalysis recycling without addition of HCOOH. In this case,
the experiment was carried out as described above without the
addition of HCOOH at the end of each cycle. A total of four cycles
mL) and the signals were referenced to TMS. Conversion and
1
yields were determined by integration of the H NMR spectra.
General procedure for catalytic hydrogenation of imines in
monophasic medium. In this case, the same procedure as
described previously was followed but without adding toluene.
Different substrates were charged into the ampoule directly and
the same cat/substrate/HCOONa ratio was used. The resulting
aqueous phase was extracted with diethyl ether (2 × 5 mL). The
organic phases were combined and then evaporated in air.
were studied.
+
Detection in solution of [(p-cymene)Ru(OD
light-preserved NMR tube, containing
cymene)RuCl(dmbpy)]BF
(1) (5 mg, 9.22·10-3 mmol) in 0.5 mL of
O, 1.2 equivalents of AgBF
(2.2 mg, 11.3·10-3 mmol) were
added. 1H RMN (300 MHz, D
O, 298K, see Scheme 1 for
numbering): δ = 0.80 (d, J = 7.68 Hz, 6H, MeiPr(p-cym)); 2.09 (s,
H, MeTol (p-cym)); 2.34 (sept, 1H, CHiPr (p-cym)); 2.47 (s, 6H, Me
2
)(dmbpy)] . In a
[(p-
4
D
2
4
2
3
3
Samples were placed in an NMR tube containing CDCl (0.5 mL)
(
bpy)); 5.87 (d, J = 6.5 Hz, 2H, H3/5 (p-cym)); 6.10 (d, J = 6.5 Hz,
and the signals were referenced to TMS. Conversion and yields
2H, H2/6 (p-cym)); 7.52 (d, J = 5.8 Hz, 2H, H (bpy)); 8.10 (s, 2H,
5
1
were determined by H NMR spectroscopy.
3
6
13
1
H (bpy)); 9.26 (d, J = 5.8 Hz, 2H, H (bpy)), ppm. C{ H}-RMN
125 MHz, D O) δ = 20.56 (MeTol); 23.52 (Mebpy); 23.89 (MeiPr);
3.15 (CHiPr); 85.89 (C3/5(p-cym)); 90.18 (C2/6(p-cym)); 102.62
General procedure for catalytic reductive amination of
carbonyl compounds with amines in biphasic medium. For
the catalytic runs, a 10 mL ampoule sealed with a Young valve
was charged with 1 mL of the buffer solution (HCOONa/HCOOH)
and 1 mL of the catalyst solution, with 0.128 mmol of amine
dissolved in 1 mL of toluene (11.67 μL of aniline) and 0.128 mmol
of different substrates (15.54 μL of 4-methoxybenzaldehyde,
(
2
3
(
(
C
1
/C
4
(p-cym)); 107.61 (C
1
/C
4
(p-cym)); 127.68 (C
3
(bpy)); 131.89
(bpy)),
C
5
(bpy)); 157.27 (C
6
(bpy)); 157.41 (C
2
(bpy)); 157.49 (C
4
ppm. Signals were referenced to (4,4-dimethyl-4-silapentane-1-
sulfonic acid) (DSS).
Solubility tests. The data are included in the SI.
13.01
μL
of
benzaldehyde,
17.55
μL
of
4-
Computational Details. Calculations were performed at the DFT
level using the M06 functional including an ultrafine integration
grid, as implemented in Gaussian 09.[ 33 ] The Ru atom was
described using the scalar-relativistic Stuttgart-Dresden SDD
pseudopotential and its associated double-ζ basis set,[ 34 ]
complemented with a set of f-polarization functions.[35] The 6-
trifluoromethylbenzaldehyde, 15.15 μL of 4-methylbenzaldehyde)
were added.
Selective deuteration experiments. The buffer and precatalyst
solutions were both prepared in D
way as described previously. It is noteworthy that other reagents
HCOONa, HCOOH and toluene) were not deuterated. For the
2 2
O (instead of H O) in the same
(
3
1G(d,p) basis set was used for the H,[36] C, N, O and Cl atoms.[37]
catalytic runs, the same procedure as described above was
followed.
To take into account both nonspecific and specific interactions
with the solvent, a mixed continuum/discrete solvent model was
used.[38] In this model, in addition to the continuum description of
the solvent (SMD continuum model)[ 39 ] three explicit water
molecules, able to establish hydrogen-bonding interactions with
the catalyst and the substrate, have been included. The structures
of the reactants, intermediates, transition states and products
were optimized in water solvent (ε = 78.35) using this cluster-
continuum model. Frequency calculations were carried out for all
the optimized geometries to characterize the stationary points
Catalyst recycling with addition of HCOOH. This study was
carried out using benzaldehyde and aniline as substrates. All of
the procedures were performed under an inert atmosphere. After
the first catalytic cycle, following the same procedure as described
above at 80 °C for 24 h, the reaction was stopped in an ice/water
bath. Once the solution was at room temperature, the organic
phase was separated. The resulting aqueous phase was
extracted by adding diethyl ether (2 × 5 mL). For this extraction,
the mixture was vigorously stirred for several minutes, left to stand,
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ChemCatChem
10.1002/cctc.201801343
FULL PAPER
(
zero imaginary frequency) as either minima or transition states
funds and Plan Propio of I+D+i-UCLM (2014/10340) for a
(
one imaginary frequency). Intrinsic reaction coordinate (IRC)
predoctoral contract.
calculations[40] were computed for the transition states to confirm
they connect with the corresponding intermediates. All the
energies collected in the text are Gibbs energies in water at 298K. Conflict of interest
Authors declare no conflict of interest
Acknowledgements
Keywords: Ruthenium • Deuterium labeling • Transfer
hydrogenation • Reductive amination • Imine
This work was supported by the MINECO of Spain (Grant project
CTQ2014-58812-C2-1-R, FEDER funds). MRC thanks FEDER
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Entry for the Table of Contents
FULL PAPER
Text for Table of Contents
Margarita Ruiz-Castañeda,[a] M. Carmen Carrión,
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Page No. – Page No.
D
In D
2
O/toluene
A Biphasic Medium slows down the Transfer
Hydrogenation and allows
a
Selective
+
In neat D
2
O
Catalytic Deuterium Labeling of Amines from
Imines mediated by a Ru-H/D+ Exchange in
H
2
D O.
This article is protected by copyright. All rights reserved.