Hydrogenation and Reductive Amination of Aldehydes using Triphos Ruthenium Catalysts

Article abstract of DOI:10.1002/cctc.201701450

An air-stable and readily accessible ruthenium dihydride complex catalyses aldehyde hydrogenation under neutral conditions. A high activity has been shown in a number of examples, and solvent-free conditions are also applicable, which favours industrial-scale applications. The catalyst has also been demonstrated to be active at low catalyst loadings for the reductive amination of aldehydes under mildly acidic conditions. A number of examples of chemoselectivity challenges are also presented in which the catalyst does not reduce carbon?halogen groups, alkene or ketone functionality. The advantage of using the pre-formed complex, Triphos-Ru(CO)H₂ (1), over in situ formed catalysts from Triphos and Ru(acac)₃ (acac=acetylacetonate) is also shown in terms of both chemoselectivity and activity, in particular this can be seen if low reaction temperatures are used.

Full text of DOI:10.1002/cctc.201701450

DOI: 10.1002/cctc.201701450
Full Papers
Hydrogenation and Reductive Amination of Aldehydes
using Triphos Ruthenium Catalysts
Francesca Christie,[b] Antonio Zanotti-Gerosa,[a] and Damian Grainger*[a]
An air-stable and readily accessible ruthenium dihydride com-
plex catalyses aldehyde hydrogenation under neutral condi-
tions. A high activity has been shown in a number of exam-
ples, and solvent-free conditions are also applicable, which fa-
vours industrial-scale applications. The catalyst has also been
demonstrated to be active at low catalyst loadings for the re-
ductive amination of aldehydes under mildly acidic conditions.
A number of examples of chemoselectivity challenges are also
presented in which the catalyst does not reduce carbonÀhalo-
gen groups, alkene or ketone functionality. The advantage of
using the pre-formed complex, Triphos-Ru(CO)H2 (1), over
in situ formed catalysts from Triphos and Ru(acac)3 (acac=ace-
tylacetonate) is also shown in terms of both chemoselectivity
and activity, in particular this can be seen if low reaction tem-
peratures are used.
Introduction
The reduction of aldehydes to alcohols is an important trans-
formation in chemical synthesis. The application of non-catalyt-
ic methods, for example NaBH4, is reliable, well established and
effective, although not without drawbacks associated with
work-up and waste management.[1] Catalytic methods have ad-
vantages in terms of atom efficiency, and if the catalyst cost
contributions are acceptable, can become viable alternatives
to established hydride-based processes. In addition, homoge-
neous catalysis used in hydrogenation can find applications in
transformations in which alternative heterogeneous catalysts
fail to deliver satisfactory chemoselective reductions. Simple
phosphine ruthenium complexes were reported to be capable
homogeneous catalysts for aldehyde hydrogenation in the late
1970s and early 1980s.[2–6] The well-established phosphine
ruthenium diamine catalysts developed by Noyori et al. gave
significant improvements in activity for carbonyl reduction
under basic reaction conditions, although the requirement of
base, in some cases, can also be regarded as a limitation of
this technology.[7,8] A number of refinements and advances
have been applied to address these limitations, for example,
the development of RuH(h1-BH4) complexes reported by
Noyori et al.[9] and the use of phenylacetylide complexes, HÀ
RuÀ(CCPh), reported by Morris et al.[10] More recently, rutheni-
um carboxylates have been developed by Dupau and co-work-
ers and are employed under neutral or weakly acidic condi-
tions.[11,12] Additionally, an efficient catalytic hydrogenation of
aldehydes using a ruthenium glycinate complex has been re-
ported by Zhang and co-workers.[13]
The large-scale industrial use of aldehydes also includes re-
ductive amination reactions. Again, non-catalytic methods are
well represented and hydride reagents can give chemoselectiv-
ity advantages over heterogeneous catalysis,[14] homogeneous
methods have the potential to provide viable alternatives to
these existing processes. The reductive amination of aldehydes
and ketones using cationic rhodium(I) complexes has been re-
ported by Bçrner et al.[15] Also with Rh catalysts, the formation
of primary amines by the reductive amination of benzaldehyde
with ammonia has been described by Beller et al.[16] Ir catalysts
were reported by Watanabe et al. and, subsequently, cyclome-
talated Ir catalysts were reported by Xiao et al. for reductive
aminations reactions under transfer hydrogenation condi-
tions.[17–20] More recently, Ru catalysts in transfer hydrogenation
have been used for this transformation by Thiel et al. and
Zhu.[21,22] Selectivity for primary amines using Ru complexes
has also been shown by Meijboom et al.[23]
Herein we describe results from recent studies in which we
used catalysts based on Triphos ruthenium complexes. Initial
catalytic studies in which a Triphos ruthenium complex was
used were performed by Elsevier et al. for the hydrogenation
of dimethyl oxalate.[24–26] Around a decade passed before a re-
surgence of publications in this area was observed, which ex-
panded the applications of Triphos-based catalysts. Generally,
earlier studies employed catalysts formed in situ from Triphos
and Ru(acac)3 (acac=acetylacetonate) and focused on carbonyl
group reductions such as esters,[27] amides[28–30] and acids.[31]
Other applications such as N-methylation using CO2 and the
amination of alcohols in the presence of ammonia have also
been reported.[32,33] More recently, a Triphos ruthenium precur-
sor complex, [Ru(Triphos)(TMM)] (TMM=trimethylenemethane)
[a] Dr. A. Zanotti-Gerosa, Dr. D. Grainger
Johnson Matthey
28 Cambridge Science Park, Milton Road, Cambridge, CB4 0FP (UK)
E-mail: damian.grainger@matthey.com
[b] F. Christie
School of Chemistry
University of St Andrews, EaStCHEM
St Andrews, Fife, KY16 9ST (UK)
Supporting information and the ORCID identification number(s) for the
author(s) of this article can be found under:
https://doi.org/10.1002/cctc.201701450.
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reported by Leitner et al.[34–37] has been used in place of the
in situ formed catalyst. The hydrosilylation of aldehydes using
a Triphos-Ru(OAc)2 complex has also been reported by Cantat
et al.[38] Our own application of Triphos ruthenium complexes
to the reduction of aldehyde substrates to some extent ap-
pears to bring about a return to more simple phosphine ruthe-
nium catalysts that find application under base-free conditions.
peratures conveys significant advantages for more challenging
aldehyde substrates in which a chemoselective reduction is re-
quired.
The advantages of the use of 1 for chemoselective aldehyde
reduction can be seen if cinnamaldehyde is used as the sub-
strate (Table 1). Catalysts formed in situ and pre-formed 1 were
compared at different reaction temperatures. The use of the
in situ formed catalyst at 1408C led to the full conversion to
the alcohol products with 83% selectivity for the unsaturated
alcohol (entries 1–2). A decrease of the temperature to 1208C
increased the selectivity for the unsaturated alcohol to 93% al-
though at the expense of conversion (78%). Temperatures
below 1208C gave very low conversions (entries 3–4). The re-
quirement of the Triphos ligand to achieve C=O versus C=C
chemoselectivity was confirmed if the reduction was attempt-
ed using only Ru(acac)3; under these conditions the selectivity
for alcohol 4 was very poor (2%), and the major reaction prod-
uct was hydrocinnamyl alcohol (5; entry 5).
With the aim to improve the reaction selectivity, the use of
pre-formed 1 at lower reaction temperatures was investigated.
At temperatures in the range of 80–1208C at catalyst loadings
of substrate/catalyst (S/C)=5000:1, 1 performed significantly
better than the in situ formed catalyst (entries 6–10). These re-
sults show clearly that in the case of cinnamaldehyde, there is
a distinct advantage of the use of the pre-formed complex, as
higher reactivity and selectivity are observed under mild reac-
tion conditions.
Results and Discussion
Attracted by the concept of using a highly active Ru catalyst
under neutral or acidic reaction conditions, the Triphos ruthe-
nium complex Triphos-Ru(CO)H2 (1) was selected as a conven-
ient precursor for these studies. The aim was to increase sub-
strate scope to include aldehyde reduction and reductive ami-
nation reactions and to demonstrate low catalyst loadings.
Complex 1 was first prepared by Bianchini and co-workers[39]
and later generated from Ru(acac)3 and Triphos under hydro-
genation conditions by the decarbonylation of propanal.[27]
Generally, 1 is considered as an inactive catalyst for the reduc-
tion of esters, amides and acids,[36] although the removal of
the CO ligand under acid conditions with H2 reportedly leads
to
a
catalytically active species, [Ru(Triphos)(solvent)(H)À
(H2)]+.[27,36] Complex 1 can be prepared easily from commercial-
ly available precursors in good yield. Ru(acac)3 and Triphos are
reacted under hydrogenation conditions (30 bar) at 1408C in
the presence of methanol (as the source of the CO ligand). The
obtained 1 is reasonably stable at room temperature and does
not need protection under inert atmosphere.[40] The structures
of 1 and Triphos (2) are shown in Figure 1.
Low catalyst loadings of S/C=10000:1, a selection of sol-
vents and solvent-free conditions were tested. Full conversion
was observed in most cases and, pleasingly, improved selectivi-
ty was observed, up to 98:2 in favour of cinnamyl alcohol (en-
tries 11–17). The low catalyst loading and high selectivity for
the allylic alcohol compare favourably with the best homoge-
nous catalysts under hydrogenation conditions, for example:
(Ir) S/C=500:1,[41] (Ru) S/C=500:1,[8] (Ru) S/C=200:1,[42] (Ru) S/
C=200:1,[43] (Ru) SC=500:1,[44] (Ru) S/C=1000:1,[45] (Fe) S/C=
200:1,[46] (Fe) S/C=500:1,[47] (Fe) S/C=20000:1,[48] (Ru) S/C=
10000:1.[49]
Figure 1. Structures of 1 and 2.
The substrate scope was then investigated using 1 (Table 2).
In most cases a loading of S/C=10000:1 was achievable with-
out the need for the significant optimisation of the reaction
conditions. Temperatures in the range of 100–1408C were
used, and solvents such as iPrOH, dioxane, heptane and tolu-
ene and solvent-free conditions are compatible in many cases.
The conversion of aldehyde to alcohol was measured by using
GC (peak area using flame ionisation detection; FID) and con-
firmed by using 1H NMR spectroscopy of the crude reaction
mixtures. Hydrogenation reactions were performed by using
Biotage Endeavor parallel screening equipment on a small
scale (16–50 mmol) or on a larger scale (100–150 mmol) by
using 50 mL Parr vessels (entries 1–5, 14–15 and 17). Benzalde-
hyde could be reduced with low catalyst loadings (S/C=
100000:1) under solvent-free conditions to give the alcohol
product in a high yield and purity (entry 1). Lower catalyst
loadings are also possible (S/C=200000:1) to give a full con-
version within a reasonable reaction time (20 h; entry 3). A cat-
alyst loading of S/C=500000:1 also led to a full conversion
Initial tests were conducted using benzaldehyde as the sub-
strate, the catalyst formed in situ from Ru(acac)3 and Triphos
was tested using iPrOH as solvent and under solvent-free con-
ditions at 90–1408C. The hydrogenation proceeded with in-
creased reaction rates in the presence of solvent (iPrOH, [S]=
5m, S=substrate). A high reaction temperature resulted in in-
creased reaction rates. The in situ formed catalyst appears to
benefit from high reaction temperatures (ꢀ1208C), presuma-
bly to generate the catalytically active species in sufficient
quantities. Although high temperatures also improved the re-
action rate of pre-formed 1, a comparison at low temperatures
(<1208C) revealed that 1 retained a good activity for the re-
duction of aldehydes. Reaction temperatures in the region of
100–1408C are relatively high compared with typical operating
temperatures for Noyori-type catalysts. However, Triphos ruthe-
nium complexes are usually used at even higher temperatures
(140–2208C) for more demanding carboxylic acid derivatives.[36]
The ability of the pre-formed complex to operate at low tem-
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Table 1. Reduction of cinnamaldehyde.[a]
Entry
Catalyst
S/C
5000
5000
5000
5000
5000
5000
5000
5000
5000
Solvent
Concentration [m]
T [8C]
Conversion [%][b]
Selectivity 4/5 [%][b]
1
2
3
4
5
6
7
8
Ru(acac)3 & 2
Ru(acac)3 & 2
Ru(acac)3 & 2
Ru(acac)3 & 2
iPrOH
iPrOH
iPrOH
iPrOH
iPrOH
iPrOH
iPrOH
iPrOH
iPrOH
iPrOH
iPrOH
iPrOH
–
5
5
5
5
5
5
5
5
5
5
4
3
–
4
3
4
3
140
120
100
90
140
120
100
100
90
99
78
9
83/17
93/7
100/0
100/0
2/98
88/12[c]
93/7[c]
95/5
96/4
97/3
96/4
97/3
5
Ru(acac)3
100
98
98
98
98
98
99
72
98
99
99
99
90
1
1
1
1
1
1
1
1
1
1
1
1
9
10
11
12
13
14
15
16
17
5000
80
10000
10000
10000
10000
10000
10000
10000
100
100
100
100
100
100
100
97/3
97/3
98/2
98/2
heptane
heptane
toluene
toluene
99/1
[a] Conditions: 16–20 mmol scale, 30 bar H2, 16 h. [b] Calculated from the GC–FID peak areas. [c] A catalyst batch of lower purity, ꢁ50% by using 31P NMR
spectroscopy, was used; for all other entries in which 1 was used the catalyst batch was of higher purity, >90% by using 31P NMR spectroscopy.
after extended reaction times (144 h), which demonstrates the
high catalyst stability under the reaction conditions
(entry 4).[50,51] A low catalyst loading (S/C=100000:1) was also
demonstrated on p-anisaldehyde if heptane was used as the
solvent (entry 5). Various substitution patterns and functionali-
ties were tolerated on the aromatic group (entries 6–9). How-
ever, some functional groups led to problems with reactivity,
for example, 4-cyanobenzaldehyde showed an incomplete con-
version and low product purity (entry 10), whereas 2-nitroben-
zaldehyde led to improved results if a higher catalyst loading
and lower reaction temperature were used (entries 11 and 12).
The efficient hydrogenation of furfural was observed under sol-
vent-free conditions and a high-purity product was obtained
with a catalyst loading of S/C=50000:1 (entry 13). The use of
a Parr vessel on a larger scale (150 mmol) gave a high product
yield but required a longer reaction time, possibly because less
efficient mixing and causes a slightly lower purity (entry 14).
Aliphatic aldehydes such as hexanal were also reduced effi-
ciently. A catalyst loading of S/C=100000:1 was demonstrated
with an improved product purity if iPrOH was used as the sol-
vent (entries 15–16). A selection of a,b-unsaturated aldehydes
was also tested to establish the substrate scope for the chemo-
selective C=O reduction. Loadings of S/C=5000:1 were used,
and high conversions and good to excellent selectivity for the
a,b-unsaturated alcohols were obtained (entries 17–21). For a
comparison of activity towards ketones, acetophenone was
tested under typical reaction conditions and a low conversion
was observed, which indicates the potential to discriminate be-
tween the ketone and aldehyde functionality (entry 22).
to be more in line with that of aldehydes on steric grounds.
Therefore, we turned our attention to reductive amination re-
actions (Table 3). The use of acid additives such as acetic acid
was explored to promote the reaction.[16] Again, the in situ
formed catalyst and pre-formed 1 were compared. The use of
Ru(acac)3 in the absence of the Triphos ligand gave only trace
amounts of reduction products, and the major reaction com-
ponent was identified as imine 22, which results from alde-
hyde and amine condensation (entry 1). The use of the biden-
tate ligand, 1,3-bis(diphenylphosphino)propane (DPPP), also
showed no reactivity (entry 2). In contrast, the in situ formed
catalyst that incorporates the Triphos ligand gave a full conver-
sion and good selectivity for the secondary amine product
(entry 3). A decrease of the catalyst loading highlights the limi-
tation of the use of the in situ system; at S/C=2000:1 the con-
version was reduced slightly, whereas the decrease in the reac-
tivity was significant at S/C=5000:1 (entries 4 and 5). In con-
trast, pre-formed 1 retained a high activity under these condi-
tions. A loading of S/C=5000:1 gave a full conversion within a
reasonably short time of approximately 5 h based on hydrogen
consumption data (entry 7). Once again these results demon-
strate a clear advantage of the pre-formed system for the re-
ductive amination reaction of benzaldehyde and benzylamine.
The presence of acetic acid (1 equivalent) had a positive effect
on the selectivity for reductive amination over the competing
aldehyde reduction. In the presence of the acid additive, 77%
product was obtained compared to 69% without acid along
with increased amounts of benzyl alcohol (11%; entries 8 and
9).
As the reactivity for aldehydes versus ketones appeared to
be very different we were interested in the evaluation of
imines as potential substrates and we expected the reactivity
The substrate scope was extended to include 2-chloroben-
zaldehyde and additional primary and secondary amines
(Table 4). 2-Chlorobenzyldimethylamine is an intermediate in
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Table 2. Reduction of aldehydes catalysed by 1.[a]
Entry
Substrate
S/C
Solvent
Concentration [m]
T [8C]
H2 uptake [h][b]
Conversion [%][c]
Purity [%][c]
1
2
3
4
5
6
7
8
6
6
6
6
7
8
8
9
10
11
12
12
13
13
14
14
3
15
16
17
18
19
100000
100000
200000
500000
100000
10000
10000
10000
10000
10000
10000
5000
50000
50000
100000
100000
10000
5000
–
–
3
3
3
4
3
4
4
4
5
4
1
–
–
–
4
–
–
–
–
–
4
140
140
140
140
140
100
140
140
140
100
140
100
120
120
140
140
100
100
100
100
100
100
11
7[e]
20
n/d
n/d
5
2
4
4
>16
6
10
9
42
6
n/d
12
16
>16
>16
40[f]
–
99.7 (98)[d]
99.7[d]
99.7[c,f]
96.9[d,g]
99.3 (98)[d]
100
100
100
100
76.0
82.3
100
99.9[h]
99.8 (96)[e,i]
100 (92)[d]
100
99.6
97.6
98.9
95.5
97.6
99.6
98.9
99.6
99.0
51.1
78.0
95.3
98.1
95.5
90.7
97.6
92.5
91.8[j]
91.0[j]
75.4
91.8[l]
–
iPrOH
iPrOH
iPrOH
n-heptane
n-heptane
iPrOH
iPrOH
1,4-dioxane
n-heptane
iPrOH
iPrOH
–
–
–
iPrOH
–
–
–
–
–
9
10
11
12
13
14
15
16
17
18
19
20
21
22
96.5 (98)[d]
98.0
96.0
78.2
>95[k]
3
5000
5000
5000
10000
iPrOH
[a] Conditions: (16–150 mmol), 30 bar H2, 16 h. [b] Approximate time for completion according to the hydrogen consumption data. [c] Calculated from GC–
FID peak areas, isolated yield given in parenthesis. [d] 100 mmol scale in Parr vessel. [e] With the use of the in situ formed catalyst, full conversion to
benzyl alcohol at S/C=100000:1 was achieved for which the consumption of hydrogen ended after ꢁ15 h. [f] Reaction run for 40 h. [g] Reaction run for
144 h. [h] 50 mmol scale by using a Biotage Endeavor. [i] 150 mmol scale by using a Parr vessel. [j] Unsaturated product confirmed by using 1H NMR spec-
1
troscopy. [k] Determined by using H NMR spectroscopy. [l] Mixture of alkene isomers.
Table 3. Reductive amination of benzaldehyde and benzylamine.[a]
Entry
Catalyst
S/C
1000
1000
1000
2000
5000
2000
5000
10000
10000
H2 uptake [h][b]
HN(Bn)2 21 [%][c]
H2NBn 20 [%][c]
PhCH=NBn 22 [%][c]
BnOH 23 [%][c]
BzH 6 [%][c]
1
2
3
4
5
6
7
8
9
Ru(acac)3
Ru(acac)3 & DPPP
Ru(acac)3& 2
Ru(acac)3 & 2
no uptake
no uptake
1
1
88
80
4
87
88
69
77
4
4
3
4
5
4
3
11
0
85
85
2
11
85
1
1
9
0
0
0
1
1
0
3
2
11
2
4
4
0
0
3
0
0
0
0
12
16
Ru(acac)3 & 2
no uptake
1
1
1
1
4
5
>40[d]
5
[a] Conditions: (5 mmol scale), AcOH additive (1 equiv.), iPrOH [S]=1m, 30 bar H2, 1008C, 16 h. [b] Approximate time for completion according to hydrogen
consumption data. [c] Calculated from GC–FID peak areas. [d] No acetic acid added, reaction run for 40 h.
the production of active agrochemical compounds and micro-
bicides of the methoximinophenylglyoxylic ester series.[52] Fur-
ther assessment of the reaction parameters was made in an
effort to improve selectivity for amine products (Supporting In-
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Table 4. Reductive amination reactions catalysed by 1.
Entry
Catalyst
Aldehyde
Amine
Product
H2 uptake [h][b]
Product [%][c]
Alcohol 23/29 [%][c]
1
2
3
4
5
6
7
1
1
1
1
1
1
1
6
6
6
9
9
BnNH2
CyNH2
HNMe2
CyNH2
BnNH2
HNMe2
BnNH2
21
24
25
27
26
28
21
6
2
2
7
12
2
93 (89)
94 (94)
99 (63)
88 (94)
78 (95)
99 (85)
0
0
0
0
2
3
[d]
[d]
9
0
58[e]
BnOH
no uptake
[a] Conditions: complex 1, S/C=10000:1, in MeOH [S]=1m, AcOH 1 equiv., 30 bar H2, 16 h. [b] Approximate time for completion according to hydrogen
consumption data. [c] Calculated from GC–FID peak areas, yield given in parenthesis (as acetic acid salt after the removal of volatile components).
[d] Added as a 2m solution in MeOH. [e] 42% amine 20 from the GC–FID peak area.
formation). A switch of the solvent to methanol gave a high
selectivity for the reductive amination products and in general
fast reaction rates, with all reactions except one complete
within 7 h according to hydrogen consumption data (en-
tries 1–6). To probe whether the reaction proceeds by reduc-
tive amination as opposed to aldehyde reduction followed by
an alkylation/hydrogen-borrowing-type process,[30] benzyl alco-
hol was subjected to the reaction conditions; no evidence of a
higher amine product was observed, which supports a reduc-
tive amination-type process (entry 7). The attempted reductive
amination of acetophenone with benzylamine also showed no
evidence of ketone reactivity, which was assessed by using GC
and seen from the lack of hydrogen uptake. Overall, reductive
amination with primary and secondary amines gave very en-
couraging results. Unfortunately, reductive amination to give
primary amines has not yet been optimised, and brief testing
indicated that selectivity for the primary amine was low but
could be improved with the addition of ammonia, although
the secondary amine persisted as the major reductive amina-
tion product (Supporting Information).
and the pre-formed complex gave higher-purity products at
lower catalyst loadings.
Experimental Section
General
All reagents were purchased from catalogue companies and used
as supplied without further purification. Triphos was purchased
from Sigma–Aldrich. Ru(acac)3 was obtained from Johnson Mat-
they. The aldehydes 3 (99%), 6 (ꢀ99%), 7 (98%), 8 (99%), 9 (99%),
10 (99%), 11 (95%), 12 (ꢀ99.0%), 14 (98%), 15 (97%), 16 (92%),
17 (97%) and 18 (95%) were purchased from Sigma–Aldrich; alde-
hyde 13 (ꢀ98%) was purchased from Alfa Aesar. Benzylamine
(99%) and cyclohexylamine (ꢀ99.9%) were purchased from
Sigma–Aldrich. Dimethylamine (2m solution in THF) was purchased
from Fisher. Dimethylamine, (2m in MeOH) was purchased from
Alfa Aesar. Acetic acid (ꢀ99.7%) was purchased from Sigma–Al-
drich. All solvents used were of anhydrous grade and purchased
from Sigma–Aldrich. NMR spectra were recorded by using a Bruker
Avance III 400 (400 MHz) spectrometer. GC analyses were per-
formed by using a Varian 3900 gas chromatograph system with an
Agilent J&W HP-1 column of 50 m of length, internal diameter of
0.20 mm, flow rate of 2 mLminÀ1, He as carrier gas and a FID. The
injector and detector temperature was 2708C. Program used: initial
T=1008C ramped to 2808C at 158CminÀ1 and then held at 2808C
for 2 min. The hydrogenation experiments were performed by
using a Biotageꢁ Endeavor and a Parr autoclave.
Conclusions
We have applied a readily available ruthenium Triphos com-
plex to aldehyde hydrogenation under neutral conditions. The
catalyst is active at low or very low catalyst loadings. A
number of examples of chemoselectivity challenges are pre-
sented in which the catalyst does not reduce carbonÀhalogen
groups, ketone or alkene functionality. The extension to reduc-
tive amination reactions demonstrates the versatility of this
complex. In this case the use of an acidic additive, acetic acid,
was found to give significant benefits. The advantage of the
pre-formed complex over an in situ formed catalyst has been
demonstrated clearly, in terms of both selectivity and activity,
Preparation of 1
A 50 mL Parr autoclave was charged with Ru(acac)3 (900 mg,
2.2 mmol) and Triphos (1.6 g, 2.6 mmol). The vessel was sealed and
purged with nitrogen by pressurising to 3 bar then releasing pres-
sure and repeating five times. To the vessel was then added iPrOH
(10 mL) followed by methanol (10 mL, 0.25 mol). Another further
five nitrogen-purge cycles at 3 bar were performed. The mixture
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was stirred at 1500 rpm and the system was again purged five
times with nitrogen. Following this, five hydrogen purges at 20 bar
were performed before stirring for 20 h under hydrogen at 30 bar
and 1408C. After cooling to RT, the reaction mixture was purged
with nitrogen for five cycles. The pale yellow precipitate was col-
lected by filtration and washed with acetone (2ꢂ4 mL). Complex 1
was obtained (1.4 g, yield 84%) and its 1H and 31P NMR spectra
were consistent with literature values.[27]
pressurising to 20 bar and releasing the pressure (five cycles). The
vials were stirred under hydrogen at 30 bar at 600 rpm and the
stated temperatures for 16 h. After the reactions had cooled to RT,
a final series of nitrogen purges was performed. The reactions
were then sampled and analysed by using GC (ꢁ20 mL, diluted to
1 mL with iPrOH). Product yields were calculated following removal
of solvent under reduced pressure and are given for un-purified
acetic acid salts. The crude reaction mixture was also analysed by
using 1H NMR spectroscopy following aqueous work-up with
CH2Cl2 and 10% NH4OH(aq) to support product identification.
Hydrogenation of aldehydes, general procedure (up to 50
mmol scale)
Conflict of interest
Catalyst 1 or that formed in situ from Ru(acac)3 and Triphos are
weighed into each vial of a Biotage Endeavor. To the vial was then
added solvent (if applicable) and the aldehyde. The vials were
loaded into a Biotage Endeavor and purged with nitrogen by pres-
surising to 3 bar and releasing the pressure (five cycles). The mix-
tures were stirred at 250 rpm, and the purge procedure was re-
peated. Subsequently, the system was purged with hydrogen by
pressurising to 20 bar and releasing the pressure (five cycles). The
vials were stirred at the relevant temperatures under hydrogen at
30 bar for 16 h. After the reactions had cooled to RT, a final series
of nitrogen purges were performed. The reactions were then sam-
pled (ꢁ20 mL, diluted to 1 mL with iPrOH) and analysed by using
The authors declare no conflict of interest.
Keywords: aldehydes · amination · homogeneous catalysis ·
hydrogenation · ruthenium
[1] J. Seyden-Penne, Reductions by the Alumino- and Borohydrides in Organ-
ic Synthesis, 2nd ed., Wiley-VCH, Weinheim, 1997.
[2] J. Tsuji, H. Suzuki, Chem. Lett. 1977, 6, 1085–1086.
[3] W. Strohmeier, L. Weigelt, J. Organomet. Chem. 1978, 145, 189–194.
[4] R. A. Sanchez-Delgado, O. L. De Ochoa, J. Mol. Catal. 1979, 6, 303–305.
[5] R. G. Sanchez-Delgado, A. Andriollo, O. L. De Ochoa, T. Suarez, N. Valen-
cia, J. Organomet. Chem. 1981, 209, 77–83.
[6] C. W. Jung, P. E. Garrou, Organometallics 1982, 1, 658–666.
[7] T. Ohkuma, H. Ooka, S. Hashiguchi, T. Ikariya, R. Noyori, J. Am. Chem.
Soc. 1995, 117, 2675–2676.
1
GC. The crude reaction mixture was also analysed by using H NMR
spectroscopy to support product identification and purity assess-
ment. Product yields were calculated after the removal of solvent
under reduced pressure and without further purification.
[8] T. Ohkuma, H. Ooka, T. Ikariya, R. Noyori, J. Am. Chem. Soc. 1995, 117,
10417–10418.
[9] T. Ohkuma, M. Koizumi, K. MuÇiz, G. Hilt, C. Kabuto, R. Noyori, J. Am.
Chem. Soc. 2002, 124, 6508–6509.
Hydrogenation of aldehydes, general procedure (50–150
mmol scale)
[10] S. E. Clapham, R. Guo, M. Zimmer-De Iuliis, N. Rasool, A. Lough, R. H.
Morris, Organometallics 2006, 25, 5477–5486.
Catalyst 1 was weighed into either a 25 or 50 mL Parr autoclave
(added either as a solid or solution in dichloromethane 1 mgmLÀ1
followed by solvent removal under a flow of nitrogen). The vessel
was sealed and purged with nitrogen by pressurising to 3 bar and
releasing the pressure (five cycles). To the reactor was added sol-
vent (6–12 mL) followed by the substrate (50–150 mmol). The
vessel was purged with nitrogen by pressurising to 3 bar and re-
leasing the pressure (five cycles). The mixture was stirred at
1500 rpm, and this purge procedure was repeated. The system was
subsequently purged with hydrogen by pressurising to 20–30 bar
and releasing the pressure (five cycles) with stirring at 1500 rpm.
The reaction heated to 1408C under hydrogen at 30 bar for 16–
144 h. After the reactions had cooled to RT, a final series of nitro-
gen purges was performed. The reactions were then sampled (
ꢁ20 mL, diluted to 1 mL with iPrOH) and analysed by using GC.
The crude reaction mixture was also analysed by using 1H NMR
spectroscopy to support product identification and purity assess-
ment. Product yields were calculated following the removal of sol-
vent under reduced pressure and without further purification.
[11] P. Dupau, L. Bonomo, L. Kermorvan, Angew. Chem. Int. Ed. 2013, 52,
11347–11350; Angew. Chem. 2013, 125, 11557–11560.
[12] L. Bonomo, L. Kermorvan, P. Dupau, ChemCatChem 2015, 7, 907–910.
[13] X. Tan, G. Wang, Z. Zhu, C. Ren, J. Zhou, H. Lv, X. Zhang, L. W. Chung, L.
Zhang, X. Zhang, Org. Lett. 2016, 18, 1518–1521.
[14] A. F. Abdel-Magid, S. J. Mehrman, Org. Process Res. Dev. 2006, 10, 971–
1031.
[15] V. I. Tararov, R. Kadyrov, A. Bçrner, T. H. Riermeier, Chem. Commun. 2000,
1867–1868.
[16] T. Gross, A. M. Seayad, M. Ahmad, M. Beller, Org. Lett. 2002, 4, 2055–
2058.
[17] S. Ogo, N. Makihara, Y. Kaneko, Y. Watanabe, Organometallics 2001, 20,
4903–4910.
[18] C. Wang, A. Pettman, J. Basca, J. Xiao, Angew. Chem. Int. Ed. 2010, 49,
7548–7552; Angew. Chem. 2010, 122, 7710–7714.
[19] Q. Lei, Y. Wei, D. Talwar, C. Wang, D. Xue, J. Xiao, Chem. Eur. J. 2013, 19,
4021–4029.
[20] D. Talwar, N. P. Salguero, C. M. Robertson, J. Xiao, Chem. Eur. J. 2014, 20,
245–252.
[21] C. Kerner, S.-D. Straub, Y. Sun, W. R. Thiel, Eur. J. Org. Chem. 2016, 22,
3060–3064.
[22] M. Zhu, Tetrahedron Lett. 2016, 57, 509–511.
[23] F. P. Malan, J.-H. Noh, G. Naganagowda, E. Singleton, R. Meijboom, J. Or-
ganomet. Chem. 2016, 825–826, 139–145.
[24] H. T. Teunissen, C. J. Elsevier, Chem. Commun. 1997, 667–668.
[25] H. T. Teunissen, C. J. Elsevier, Chem. Commun. 1998, 1367–1368.
[26] M. C. van Engelen, H. T. Teunissen, J. G. de Vries, C. J. Elsevier, J. Mol.
Catal. A 2003, 206, 185–192.
[27] F. M. A. Geilen, B. Engendahl, M. Hçlscher, J. Klankermayer, W. Leitner, J.
Am. Chem. Soc. 2011, 133, 14349–14358.
Reductive amination of aldehydes, general procedure
Catalyst 1 or that formed in situ from Ru(acac)3 and Triphos was
weighed into each vial of a Biotage Endeavor. This was followed
by the addition aldehyde (5 mmol), the appropriate volume of sol-
vent, amine (5 mmol) and acetic acid (0.3 mL, 5 mmol). The vials
were loaded into a Biotage Endeavor and purged with nitrogen by
pressurising to 3 bar and releasing the pressure (five cycles). The
mixtures were stirred at 250 rpm, and this purge procedure was re-
peated. The system was subsequently purged with hydrogen by
[28] A. A. NfflÇez Magro, G. R. Eastham, D. J. Cole-Hamilton, Chem. Commun.
2007, 3154–3156.
&
ChemCatChem 2018, 10, 1 – 8
www.chemcatchem.org
6
ꢀ 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!

Full Papers
[29] J. Coetzee, D. L. Dodds, J. Klankermayer, S. Brosinski, W. Leitner, A. M. Z.
Slawin, D. J. Cole-Hamilton, Chem. Eur. J. 2013, 19, 11039–11050.
[30] J. R. Cabrero-Antonino, E. Alberico, K. Junge, H. Junge, M. Beller, Chem.
Sci. 2016, 7, 3432–3442.
[31] X. Cui, Y. Li, C. Topf, K. Junge, M. Beller, Angew. Chem. Int. Ed. 2015, 54,
10596–10599; Angew. Chem. 2015, 127, 10742–10745.
[43] R. Liu, H. Cheng, Q. Wang, C. Wu, J. Ming, C. Xi, Y. Yu, S. Cai, F. Zhao, M.
Arai, Green Chem. 2008, 10, 1082–1086.
[44] K. E. Jolley, A. Zanotti-Gerosa, F. Hancock, A. Dyke, D. M. Grainger, J. A.
Medlock, H. G. Nedden, J. J. M. Le Paih, S. J. Roseblade, A. Seger, V. Siva-
kumar, I. Prokes, D. J. Morris, M. Wills, Adv. Synth. Catal. 2012, 354,
2545–2555.
[32] Y. Li, I. Sorribes, T. Yan, K. Junge, M. Beller, Angew. Chem. Int. Ed. 2013,
52, 12156–12160; Angew. Chem. 2013, 125, 12378–12382.
[33] E. J. Derrah, M. Hanauer, P. N. Plessow, M. Schelwies, M. K. da Silva, T.
Schaub, Organometallics 2015, 34, 1872–1881.
[45] I. Warad, H. Al-Hussain, R. Al-Far, R. Mahfouz, B. Hammouti, T. B. Hadda,
Spectrochim. Acta Part A 2012, 95, 374–381.
[46] S. Fleischer, S. Zhou, K. Junge, M. Beller, Angew. Chem. Int. Ed. 2013, 52,
5120–5124; Angew. Chem. 2013, 125, 5224–5228.
[34] T. vom Stein, T. Weigand, C. Merkens, J. Klankermayer, W. Leitner, Chem-
CatChem 2013, 5, 439–441.
[47] G. Wienhçfer, F. A. Westerhaus, K. Junge, R. Ludwig, M. Beller, Chem. Eur.
J. 2013, 19, 7701–7707.
[35] K. Beydoun, T. vom Stein, J. Klankermayer, W. Leitner, Angew. Chem. Int.
Ed. 2013, 52, 9554–9557; Angew. Chem. 2013, 125, 9733–9736.
[36] T. vom Stein, M. Meuresch, D. Limper, M. Schmitz, M. Hçlscher, J. Coet-
zee, D. J. Cole-Hamilton, J. Klankermayer, W. Leitner, J. Am. Chem. Soc.
2014, 136, 13217–13225.
[37] M. Meuresch, S. Westhues, W. Leitner, J. Klankermayer, Angew. Chem.
Int. Ed. 2016, 55, 1392–1395; Angew. Chem. 2016, 128, 1414–1417.
[38] C. Chauvier, P. ThuØry, T. Cantat, Angew. Chem. Int. Ed. 2016, 55, 14096–
14100; Angew. Chem. 2016, 128, 14302–14306.
[48] N. Gorgas, B. Stoger, L. F. Veiros, K. Kirchner, ACS Catal. 2016, 6, 2664–
2672.
[49] S. Baldino, S. Facchetti, A. Zanotti-Gerosa, H. G. Nedden, W. Baratta,
ChemCatChem 2016, 8, 2279–2288.
[50] Control reactions were performed in the absence of catalyst between
reactions at low catalyst loading (S/Cꢂ100000:1), which showed no
hydrogen uptake, and the absence of benzyl alcohol was verified by
using GC.
[51] For examples of exceptionally high catalyst turnover numbers see: a) N.
Arai, T. Ohkuma, Chem. Rec. 2012, 12, 284–289; b) J.-H. Xie, X.-Y. Liu, J.-
B. Xie, L.-X. Wang, Q.-L. Zhou, Angew. Chem. Int. Ed. 2011, 50, 7329–
7332; Angew. Chem. 2011, 123, 7467–7470.
[39] V. I. Bakhmutov, E. V. Bakhmutova, N. V. Belkova, C. Bianchini, L. M. Ep-
stein, D. Masi, M. Peruzzini, E. S. Shubina, E. V. Vorontsov, F. Zanobini,
Can. J. Chem. 2001, 79, 479–489.
[40] No significant decomposition was observed by using 31P NMR spectros-
copy during time frames of around 1–6 months although some discol-
oration was observed if the samples were stored at room temperature.
However, storage under an inert atmosphere at low temperature is still
recommended.
[52] K. Moonen, K. Dumoleijn, L. Prati, A. Villa, (Taminco Bvba, Tennessee),
WO 2016071410 A1, 2016.
ˇ
[41] E. Farnetti, M. Pesce, J. Kaspar, R. Spogliarich, M. Graziani, J. Mol. Catal.
Manuscript received: September 5, 2017
Revised manuscript received: October 5, 2017
Version of record online: && &&, 0000
1987, 43, 35–40.
[42] M. L. Clarke, M. B. Díaz-Valenzuela, A. M. Slawin, Organometallics 2007,
26, 16–19.
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F. Christie, A. Zanotti-Gerosa, D. Grainger*
Try Triphos: An air-stable and readily
accessible ruthenium dihydride complex
catalyzes aldehyde hydrogenation
under neutral conditions or reductive
amination under mildly acidic condi-
tions. Low catalyst loadings are em-
ployed, typically 10000–100000:1 sub-
strate/catalyst, which suggests that fa-
vorably low catalyst cost contributions
are achievable.
&& – &&
Hydrogenation and Reductive
Amination of Aldehydes using Triphos
Ruthenium Catalysts
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