Rapid Continuous Ruthenium-Catalysed Transfer Hydrogenation of Aromatic Nitriles to Primary Amines

Article abstract of DOI:10.1055/s-0036-1589096

A continuous flow method for the selective reduction of aromatic nitriles to the corresponding amine is reported. The method is based on a ruthenium-catalysed transfer-hydrogenation process, requires no additives, and uses isopropanol as both solvent and reducing agent. The process utilizes 1 mol% of the commercially available [Ru(p -cymene)Cl ₂ ] ₂, with a residence time of ca. 9 min, and a throughput of 50 mmol/h. The method was successfully applied to a range of aromatic nitriles providing the corresponding primary amines in good yields.

Full text of DOI:10.1055/s-0036-1589096

SYNLETT
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© Georg Thieme Verlag Stuttgart · New York
2017, 28, A–D
letter
A
en
R. Labes et al.
Letter
Synlett
Rapid Continuous Ruthenium-Catalysed Transfer Hydrogenation
of Aromatic Nitriles to Primary Amines
Ricardo Labesa
[Ru(p-cymene)Cl2]2 (1mol%)
H
H
200 °C
Davir González-Calderóna
Claudio Battilocchioa
Carlos Mateos*b
Graham R. Cummingb
Oscar de Frutosb
CN
OH
NH2
O
H
R
R
+
+
(solvent)
Phosphine- and base-free
Commercial air-stable catalyst
17 examples (63–82%)
Juan A. Rincónb
Steven V. Ley*a
a Innovative Technology Centre, Department of Chemistry,
University of Cambridge, Lensfield Road, Cambridge, CB2
1EW, UK
svl1000@cam.ac.uk
b Centro de Investigación Lilly S.A., Avda. de la Industria 30,
Alcobendas-Madrid 28108, Spain
c.mateos@lilly.com
Dedicated to our friend Vic Snieckus on the occasion of his 80th birthday
Received: 23.06.2017
Accepted after revision: 18.07.2017
Published online: 21.08.2017
methodologies can, however, suffer from selectivity issues
and lead to several byproducts being formed in these reac-
tions (Scheme 1). Several recent attempts have been report-
ed to solve these selectivity problems employing catalysts
and H2 gas8 and selective TH reactions.11–13
DOI: 10.1055/s-0036-1589096; Art ID: st-2017-r0508-l
Abstract A continuous flow method for the selective reduction of aro-
matic nitriles to the corresponding amine is reported. The method is
based on a ruthenium-catalysed transfer-hydrogenation process, re-
quires no additives, and uses isopropanol as both solvent and reducing
agent. The process utilizes 1 mol% of the commercially available [Ru(p-
cymene)Cl2]2, with a residence time of ca. 9 min, and a throughput of
50 mmol/h. The method was successfully applied to a range of aromat-
ic nitriles providing the corresponding primary amines in good yields.
R
CN
1
Transfer Hydrogenation
Side reactions
Hydrogenation
Side reactions
TH
or H2
Cat.
R1
R
N
H
R2
3
R
R
R
N
R
NH
5
– NH3
6
2
Key words nitrile reduction, transfer hydrogenation, ruthenium, pri-
mary amine, continuous flow
TH
Cat.
H2/Cat.
TH
or H2
Cat.
R
R1
O
N
H
R
R1 R2
– H2O
Amines are key intermediates in the production of fine
chemicals, active pharmaceutical ingredients (APIs), agro-
chemicals, as well as many natural products.1 In particular,
primary amines are important synthetic building blocks, as
these are used in many processes such as the Buchwald–
Hartwig coupling reactions,2 hydroaminations,3 and alcohol
amination by hydrogen-borrowing strategies4–7 for example.
The reduction of nitriles is among the most common
route to generate the corresponding primary amines.8 The
use of hydrides in stoichiometric amounts such as LiAlH4 is
effective for this transformation, but catalytic hydrogena-
tion methods using Raney Nickel, for example, are often
preferred, however, these are not without problems. De-
spite being known for decades,9 transfer-hydrogenation
processes (TH) have gained in interest recently,10 also with
applications to nitrile reduction.11–14 Transfer-hydrogena-
tion techniques are attractive as they eliminate the need for
pressurized hydrogen gas typical of many catalytic meth-
ods. Both direct hydrogenation (employing H2), and TH
R
N
R2
NH2
7
4
3
Scheme 1 Side reactions for the transfer hydrogenation and hydroge-
nation of nitriles
To the best of our knowledge, while hydrogenation reac-
tions have been thoroughly investigated in continuous
flow,15–20 including nitrile reductions to the correspondent
primary amine21 and direct reductive amination,22 no con-
tinuous transfer hydrogenation of nitriles to primary
amines has been reported so far. However, we could expect
to see distinct advantages from the approach, especially in
terms of safety and selectivity.
Beller and coworkers have reported the use of 2-butanol
in the transfer hydrogenation of nitriles to obtain the corre-
sponding primary amine while simultaneously reducing
the formation of byproducts.11 The same group also report-
ed a heterogeneous TH using Pd/C and ammonium formate
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D

B
R. Labes et al.
Letter
Synlett
as a hydrogen source12 and the use of 2-propanol with
NaOH to afford the alkylated secondary amines.23 On the
other hand Zhou and Liu assessed two cobalt catalysts for
TH of nitriles that led to the selective preparation of prima-
ry, secondary, or tertiary products. Here the solvent choice
played a crucial role on the outcome of the reaction.13
Notably, three recent reports using transfer hydrogena-
tion to reduce nitriles with a ruthenium catalyst led to the
N-isopropylidene derivatives (4, Scheme 1) as the main
product through a further coupling and reduction. These
studies use KOtBu as base and relatively long reaction
times.14,24,25 Recently, the use of a nickel catalyst and 1,4-
butanediol as hydrogen source to afford N-benzylidenes as
main products of the transfer hydrogenation nitrile reduc-
tion have been observed.26
Even with all these advances, we felt there was a need
for a practical, safe, and selective method for the transfer
hydrogenation of nitriles, tolerant to a wide aromatic func-
tionality. Inspired by our recent studies towards the chemo-
selective continuous ruthenium-catalysed hydrogen-trans-
fer oxidation of secondary alcohols,27 we became interested
in expanding the application scope of the system. Among
other advantages of using a continuous-flow system is the
precise control of residence times and heating regimes.
By analogy with our previous approach to continuous
transfer hydrogenation, we devised a simple system com-
prising of a pump, a heated coil, and a backpressure regula-
tor (BPR). Initial screening was performed using a Uniqsis
FlowSyn28 unit equipped with a 20 mL stainless-steel coil
reactor operating at the temperature indicated (Table 1).
Our study began employing triethylamine as a base, as it
proved to be beneficial in our previous work employing the
same catalyst.27 It was quickly realised that triethylamine
was not in fact necessary for this transformation to proceed
(Table 1).
Interestingly, Beller’s report suggests that no conversion
was observed using the same catalyst [Ru(p-cymene)Cl2]2
and 2-butanol at 120 °C for ten minutes in batch.11 We were
pleasantly surprised to find that under the conditions de-
scribed, even at 100 °C (Table 1, entry 2), the expected pri-
mary amine could be observed in flow. By increasing the
temperature to 150 °C the yield increased to 85% in the ab-
sence of phosphine ligands or base (Table 1, entry 5). Con-
centration of the substrate in IPA was crucial to the out-
come of the reaction. By increasing either the concentration
of substrate or the amount of ruthenium catalyst, the
amount of alkylated byproduct 5 increased. Residence time
could be reduced to ten minutes maintaining the product
yield. By reducing the residence time we diminished the
amount of alkylated byproduct 5. However, we could now
observe some unreacted imine 2, while the overall yield of
primary amine was unchanged.
Table 1 Initial Optimisation for the Continuous TH of Nitriles
Flow
(mL/min)
T (°C)
CN
NH2
20 bar
20 mL
SS 1/16"
0.1 M in IPA
[Ru(p-cymene)Cl2]2
NEt3
Entry
Residence time Temp
Cat.
(mol%)
Et3N
(equiv)
Yield
(%)a
(min)
(°C)
1
2
40
40
40
40
40
40
40
40
20
10
100
0
2
2
2
2
0
2
0
0
0
0
0
50
75
85
85
0
100
125
150
150
150
150
150
150
150
1
3
1
4
1
5
1
6b
7
1
0.5
5
80
66
85
85
8
9
1
10
1
a Yield of primary amine by 1H NMR analysis (1,4-dinitrobenzene as internal
standard) of the crude mixture after solvent removal.
b Using (Ph3P)3RuCl2 as catalyst.
The reaction system was then transferred to a Phoenix
reactor platform,29 equipped with a 1/8′′ 35 mL stainless
steel coil. This gave us the opportunity to work at even
higher temperatures and pressures.
By precisely controlling the residence time of the solu-
tion we could halt the reaction at a specific equilibrium
point between 1 and 5 (Scheme 1). The residence time was
then optimized using benzonitrile as a model substrate. To
enable a suitable downstream product isolation, we opted
to isolate the primary amines as their hydrochloride salts,
which could be easily separated by filtration, also enabling
removal of any ruthenium residues. The general method
was then applied to different nitriles (Table 2).30
Notably, aromatic nitriles bearing ether, thioether, chlo-
ride, and amide functionalities were all successfully re-
duced in good yields and good degree of selectivity. A pyri-
dine derivative (Table 2, entry 16) was also converted into
the desired primary amine in good yield. A nitrile com-
pound containing an amide group (Table 2, entry 15) selec-
tively afforded the corresponding primary amine, however,
substrates bearing more reactive carbonyl groups as in
ketones or aldehydes led to a mixture of products.
Attempts to reduce aliphatic nitriles also led to poor
yields due to reduced reactivity of these substrates.31 This
expected lower reactivity has been observed by others.12,14
To further evaluate the robustness of the methodology, the
system was operated continuously for two hours and af-
forded 4 g of benzylamine (Scheme 2).
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D

C
R. Labes et al.
Letter
Synlett
Table 2 (continued)
Entry
Table 2 Substrate Scope for the Continuous TH of Nitriles
Substrate
Yield (%)a
200 °C
4 mL/min
100 bar
R
NH2
O
R
CN
CN
0.1 M in IPA
15
77
35 mL
SS 1/8"
N
H
[Ru(p-cymene)Cl2]2
(1 mol%)
CN
Yield (%)a
78
16
17
71b
70
Entry
1
Substrate
N
CN
MeS
CN
a Isolated yield as hydrochloride salts.
OMe
CN
b Yield of primary amine by 1H NMR analysis (1,4-dinitrobenzene as internal
standard).
2
3
4
5
6
71b
80
69
76
71
MeO
CN
200 °C
CN
4 mL/min
NH2
100 bar
CN
O
O
35 mL
SS 1/8"
0.1 M in IPA
4 g in 2 h
+
[Ru(p-
cymene)Cl2]2
(1 mol%)
CN
Scheme 2 Transfer hydrogenation of nitriles, 2 h continuous operation
CN
To conclude, we have developed a fast, continuous, ru-
thenium-catalysed transfer hydrogenation of aromatic ni-
triles to afford primary amines. The system uses a commer-
cial ruthenium catalyst and IPA as solvent and hydrogen do-
nor. This system was successfully applied to reduce 17
different nitriles affording their correspondent primary
amines in good yields.
CN
7
69
CN
8
9
70
72
Funding Information
CN
This work was supported by Eli Lilly & Co. through the Lilly Research
Award Program (LRAP). This work has also been funded by the EPSRC
(SVL, grants EP/K009494/1, EP/M004120/1 and EP/K039520/1).
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Supporting Information
O
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1589096. Additional data is available
from the University of Cambridge Data Repository website:
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https://doi.org/10.17863/CAM.10921.
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References and Notes
EtO
Cl
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CN
Cl
CN
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D

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R. Labes et al.
Letter
Synlett
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A solution (50 mL) containing the nitrile (5 mmol), and
dichloro(p-cymene)ruthenium(II) dimer (0.05 mmol) in IPA
(solution was sonicated until the catalyst was solubilized 10–50
min) was pumped at 4 mL/min through the reactor coil heated
at 200 °C. The Phoenix backpressure regulator was set to
manual at 30%, which correlated to approximately 100 bar. A 10
mL fraction of the solution obtained from the system in steady
state was used to prepare the hydrochloric salt. Yields are
reported as isolated hydrochloride salts, unless otherwise
stated.
(19) Mennecke, K.; Cecilia, R.; Glasnov, T. N.; Gruhl, S.; Vogt, C.;
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NMR Data for Entry 4
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1H NMR (600 MHz, MeOD): δ = 7.02–6.94 (m, 2 H), 6.90 (m, 1
H), 6.02 (s, 2 H), 4.13 (s, 2 H). 13C NMR (151 MHz, MeOD): δ =
148.81, 148.35, 124.43, 123.86, 109.54, 108.27, 101.63, 50.34.
(31) Under the conditions in Table 1, entry 5 cyclohexanecarboni-
trile was not successfully converted into considerable amounts
of the desired product.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D