Low-Pressure Hydrogenation of Nitriles to Primary Amines Catalyzed by Ruthenium Pincer Complexes. Scope and mechanism

Article abstract of DOI:10.1002/cctc.201601416

The catalytic hydrogenation of nitriles to primary amines constitutes an environmentally benign and atom-economical methodology in synthetic organic chemistry. However, selective hydrogenation can be challenging, and usually elevated pressure and the use of various additives is required. Herein the hydrogenation of aromatic and aliphatic nitriles to form primary amines catalyzed by ruthenium pincer complexes is described. The reactions are conducted at low H₂ pressure, low catalytic loadings and, in case of a variety of benzonitriles, under neutral conditions and without any additives. Mechanistic insight is provided.

Full text of DOI:10.1002/cctc.201601416

Accepted Article
Title: Low-Pressure Hydrogenation of Nitriles to Primary Amines
Catalyzed by Ruthenium Pincer Complexes. Scope and
Mechanism.
Authors: David Milstein, Arup Mukherjee, Dipankar Srimani, and
Yehoshoa Ben-David
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ChemCatChem
Low-Pressure Hydrogenation of Nitriles to Primary
Amines Catalyzed by Ruthenium Pincer Complexes.
Scope and mechanism
Arup Mukherjee,† Dipankar Srimani,†,‡ Yehoshoa Ben-David,† and David Milstein†,*
†Department of Organic Chemistry, Weizmann Institute of Science, Rehovot, 76100, Israel
E-mail: david.milstein@weizmann.ac.il
Dedicated to the memory of our group member Alexander Nerush
Abstract:
The catalytic hydrogenation of nitriles to primary amines constitutes an environmentally
benign and atom-economical methodology in synthetic organic chemistry. However, selective
hydrogenation can be challenging, and usually elevated pressure and the use of various
additives is requited. Herein the hydrogenation of aromatic and aliphatic nitriles to form
primary amines catalyzed by ruthenium pincer complexes is described. The reactions are
conducted at low H2 pressure, low catalytic loadings and, in case of a variety of
benzonitriles, under neutral conditions and without any additives. Mechanistic insight is
provided.
1
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10.1002/cctc.201601416
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Introduction:
Amines and their derivatives are important building blocks for the production of dyes,
pigments, agrochemicals, pharmaceuticals and are produced annually by both the bulk and
fine chemical industries.[1] In general, they are prepared by amination of aryl halides,[2]
hydroaminations[3] and hydroaminomethylation of olefins or alkynes,[4] reductive
aminations,[5] and the direct amination of alcohols[6]. In organic synthesis, on a laboratory
scale, stoichiometric methods based on reducing agents such as metal hydrides, or
hydrosilanes are still popular. However, these methods suffer from poor atom efficiency, low
functional group tolerance, hazardous reagents and the generation of stoichiometric amounts
of waste.[7] From ecological and economic points of view hydrogenation of nitriles is a most
desirable method for the production of amines due to ultimate atom efficiency.
Selective hydrogenation of nitriles to primary amines is challenging. Often, imines
and a mixture of primary, secondary, and tertiary amines are formed (Scheme 1).[8] Imines,
produced by the partial hydrogenation of nitriles, are key intermediates on the way to primary
amines. However, imines can undergo nucleophilic attack by the formed primary or
secondary amines, with expulsion of NH3, to give N-substituted imines and enamines,
respectively (Scheme 1). Concomitant hydrogenation of these leads to formation of
secondary and tertiary amines.
B
H2
H2
NH2
R
R
NH
R C N
R
N
R
R
R
Cat
Cat
-NH3
B
C
A
D
H2 Cat
B
N
N
H
R
R
-NH3
R
F
H2 Cat
E
Scheme 1. General schematic pathway for the hydrogenation of nitriles to form primary,
secondary and tertiary amines, via imine intermediates.
2
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Hydrogenation of nitriles to amines utilizing precious-metal complexes as catalysts,[9]
and very recently, non-noble metal complex catalysts, were reported.[10] In seminal work,
Sabo-Etienne and co-workers reported in 2010 the selective hydrogenation of benzonitrile to
benzylamine at room temperature under 3 bar of H2 using a bis(dihydrogen)ruthenium
complex as catalyst,[9b] although other nitrile substrates were not reported. Following this
report, several other Ru-complexes were applied for the formation of amines from nitriles.
Very recently, Prechtl reported the controlled synthesis of imines or amines from nitriles
catalyzed by an aliphatic PNP-Ru pincer complex, under very mild conditions.[9j] In this
reaction amine formation required use of 2-propanol as solvent, and secondary acetone imine
was formed as side product (except in one case). Beller reported an imidazolylphosphine
based Ru-catalysts, which enabled the synthesis of primary amines from aromatic and
aliphatic nitriles under 50 bar or 30 bar H2 pressure.[9g,9l] Very recently, Beller and we
independently reported Fe-[10a,10b], Mn-,[10f] and Co-based[10c] homogeneous catalysts for the
selective hydrogenation of various nitriles to primary amines. Notably, these catalytic
reactions were performed at elevated hydrogen pressure (e.g., 30-75 bar) and/or in the
presence of additives, such as a base or co-catalyst, or have limited substrate scope.[9,10]
Hence, development of a suitable catalyst that selectively hydrogenates nitriles to primary
amines under low hydrogen pressure and in the absence of any additives or base, irrespective
of the solvent used, is desirable. Herein, we report such a reaction using a dearomatized Ru-
pincer complex (0.3 mol%) under mild, low pressure, and (in the case of benzonitriles), under
neutral conditions. The catalytic reaction can be performed in solvents having different
polarity, making the catalytic system broadly applicable. A plausible mechanism is proposed
based on an NMR study.
3
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Results and Discussions:
The hydrogenation reaction of benzonitrile to give benzylamine was chosen as a model
system for this study. Thus, a dry benzene solution containing benzonitrile, pincer Ru-
complexes 1-6 (Figure 1), with or without added base, was heated under 5 bar H2 pressure at
110 °C (bath temperature) for 24 h in a Fisher-Porter pressure vessel. The products were
analyzed by GC–MS and NMR spectroscopy and identified by comparison with authentic
samples.
Figure 1. PNP- and PNN-based ruthenium pincer complexes used in this study.
Hydrogenation of benzonitrile (2 mmol) with PNPtBu Ru complex 1[11] (0.1 mol%),
KOtBu (0.1 mol%) under 5 bar H2 pressure at 110 °C in benzene (2 mL) for 24 h resulted in
54% conversion, yielding a mixture of benzylamine (36%) and N-benzylidene-1-
phenylmethanamine (18%, Table 1, entry 1). However, when the reaction was carried out
with 0.3 mol% of complex 1 and 0.3 mol% KOtBu, keeping other conditions unchanged,
98% conversion to benzylamine was obtained (Table 1, entry 2). Since the base is capable of
in-situ deprotonation of complex 1 to yield the dearomatized PNPtBu complex 2[12] (Figure 1),
a catalytic reaction employing this complex (0.3 mol%) under 5 bar H2 pressure at 110 °C in
benzene with no added base was performed. Gratifyingly, benzylamine was exclusively
formed in 97% yield and no side products being observed (Table 1, entry 3). However, when
4
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the reaction was carried out at lower temperature (70 °C) using catalyst 2, only 32%
conversion of benzonitrile was obtained, yielding a mixture of benzylamine (29%) and N-
benzylidene-1-phenylmethanamine (3%, Table 1, entry 4). Interestingly, when the H2
pressure was decreased from 5 bar to 3 bar, benzylamine was obtained as the sole product in
97% yield at 110 °C (Table 1, entry 5). Further decrease of H2 pressure to 2 bar drastically
decreased the catalytic activity under similar reaction condition, yielding a mixture of 3%
benzylamine and 7% N-benzylidene-1-phenylmethanamine (Table 1, entry 6). Complexes 3-6
exhibited low activity in the hydrogenationof benzonitrile.
Table 1. Optimization of the reaction conditions for the hydrogenation of benzonitrile.a
Entry Complex Base (mol%)
(mol%)
Solvent
Conv.
(%)b
Selectivity (%,
a:b)b
1
1 (0.1)
1 (0.3)
2 (0.3)
2 (0.3)
2 (0.3)
2 (0.3)
3 (0.3)
4 (0.3)
5 (0.3)
6 (0.3)
2 (0.3)
2 (0.3)
KOtBu (0.1)
benzene
benzene
benzene
benzene
benzene
benzene
benzene
benzene
benzene
benzene
THF
54
98
97
32
97
10
3
36:18
2
KOtBu (0.3)
98:0
97:0
29:3
97:0
3:7
3
–
4c
5d
6e
7
–
–
–
KOtBu (0.3)
KOtBu (0.3)
KOtBu (0.3)
NaOH (0.3)
–
2:1
8
13
3.0
20
94
91
8:5
9
2:1
10
11
12
18:2
94:0
91:0
–
toluene
5
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13
2 (0.3)
–
1,4-dioxane
92
92:0
a
Reaction conditions: benzonitrile (2 mmol), complex 1-6, H2 (5 bar) and dry benzene (2 mL) were
b
heated in a 100 mL Fischer–Porter tube at 110 °C (bath temperature); conversions were determined
by H NMR spectroscopy with respect to toluene as an internal standard; c reaction was carried out at
1
70 °C; d reaction was carried out under 3 bar H2 pressure; e reaction was carried out under 2 bar H2.
Interestingly, using the PNPiPr complex 3[13], closely related to the catalytically active PNPtBu
complex 1, under the same conditions, only 2% of the benzylamine was obtained (Table 1,
entry 7). Thus what seems to be a relatively minor structural change (replacing PNPtBu by
PNPiPr) had such a major effect on catalysis. This may be due to the expected lower stability
of the unsaturated dearomatized complex (analogous to 2), obtained upon deprotonation of 3,
due to lower steric protection. The PNNEt complex 4[13] under similar condition produced
only 8% of benzylamine and 5% N-benzylidene-1-phenylmethanamine (Table 1, entry 8).
Using the bipyridyl-based PNN-complex 5[6b], the yield of benzylamine dropped to 2%
(Table 1, entry 9). The acridine PNP complex 6[6a] yielded 18% of benzylamine (Table 1,
entry 10).
The effect of various solvents was also examined. Using catalyst 2, the solvents
benzene, THF, 1,4-dioxane, and toluene gave similar high yields of benzylamine (Table 1,
entries 3, 11−13).
Using the optimized reaction conditions (Table 1, entries 3 and 5), the generality of
this catalytic hydrogenation of nitriles was explored. Initially, various aromatic nitriles were
tested as substrates. As shown in Table 2, nitriles bearing either electron-donating or
electron-withdrawing substituents were hydrogenated in good isolated yields. Reaction of
benzonitrile catalyzed by 2 (0.3 mol%) under 3 bar H2 at 110 °C produced selectively 97%
benzylamine, with 89% isolated yield (Table 2, entry 1). Reaction of 4-methylbenzonitrile
and 3-methylbenzonitrile using 2 (0.6 mol%) under 5 bar H2, furnished after 60 h 99% and
97% conversion, respectively, with 87% and 91% isolated yields of 4-methylbenzylamine
6
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and 3-methylbenzylamine (Table 2, entries 2 and 3). In case of 4-methylbenzylamine
formation of a small amount (<5%) of the corresponding imine was also observed. When
both reactions were carried out under 3 bar H2 pressure, lower yields of the corresponding
benzylamine were obtained (Table 2).
Next, aromatic nitriles having electron withdrawing substituents were tested. Hydrogenation
of 4-fluorobenzonitrile catalyzed by 2 (0.8 mol%) under 5 bar H2 at 110 °C, resulted after
60h in 98% conversion and 73% isolated yield of 4-fluorobenzylamine (Table 2, entry 4). It
yielded also 10% of N-(4-fluorobenzylidene)-1-(4-fluorophenyl)methaneamine and <5% of
the corresponding secondary amine. In addition, the hydrogenation of 3-fluorobenzonitrile
and 2-fluorobenzonitrile yielded under the same conditions 87% of 3-fluorobenzylamine and
88% of 2-fluorobenzylamine, respectively (Table 2, entries 5 and 6). In case of 3-
fluorobenzonitrile 7% of the corresponding secondary amine was also observed, while the
reaction of 2-fluorobenzonitrile yielded <5% of the corresponding imine as a side product.
Hydrogenation of 4-(trifluoromethyl)benzonitrile under 10 bar H2 yielded 50% of 4-
(trifluoromethyl)benzylamine and 50% of N-(4-trifluoromethylbenzylidene)-1-(4-
trifluoromethylphenyl)methaneamine, respectively after 40 h., while the hydrogenation of 4-
(trifluoromethyl)benzonitrile under 5 bar H2 yielded 28% 4-(trifluoromethyl)benzylamine
(Table 2, entry 8). The large amount of the imine product in the case of the strong electron
withdrawing CF3 substituent is presumably a result of the intermediate primary imines being
more susceptible to nucleophilic attack by the product primary amine (Scheme 1).
Hydrogenation of 1-naphthonitrile resulted after 36 h in 99% conversion and 89% isolated
yield of 1-naphthylmethylamine (Table 2, entry 9). The hydrogenation of 4-
methoxybenzonitrile yielded 94% of isolated 4-methoxybenzylamine
7
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Table 2. Catalytic hydrogenation of various aromatic and aliphatic nitriles catalyzed by 2.a
8
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(Table 2, entry 10). Under identical reaction condition, 3,4-dimethoxybenzonitrile furnished
3,4-dimethoxybenzylamine in 88% isolated yield (Table 2, entry 11).
Next, hydrogenation of aliphatic nitriles was tested. Initially, hydrogenation of
valeronitrile was attempted with catalyst 2 under 5 bar H2 pressure. Unfortunately, even after
48 h at 110 °C, no 1-pentylamine was detected and only starting material was recovered, as
evidenced from GC-MS and 1H NMR spectroscopy. Increasing H2 pressure to 10 bar also did
not give the desired 1-pentylamine. Hence, the catalytic activity of other Ru-catalysts (Figure
1) was tested. Interestingly, the acridine-based ruthenium PNP complex 6 (0.5 mol%) and
NaOH (0.5 mol%) catalyzed the hydrogenation of valeronitrile, resulting in 83% conversion,
giving 1-pentylamine in 48% yield under 10 bar H2 pressure (Table 2, entry 12). Under
similar condition, butyronitrile led to the corresponding 1-butylamine in 35% yield (Table 2,
entry 15). When the hydrogenation of both valeronitrile and butyronitrile was carried out
under 5 bar H2, the corresponding primary amine was formed in 30% and 8% yield,
respectively. In all the cases the corresponding imine was also formed.
To gain mechanistic insight, the reaction of complex 2 with benzonitrile was studied.
Complex 2 exhibits a triplet at δ –25.8 ppm (JP-H =16.3 Hz, Figure 2A) corresponding to the
1
Ru–H signal in the H NMR spectrum, and two sharp AB doublets at δ 83.6 and 74.8 ppm
(JP-P = 214.6 Hz) in the 31P{1H} NMR spectrum (Figure 2A').[14] Immediately after addition of
excess benzonitrile to a solution of complex 2 in benzene-d6, a sharp color change from
1
bluish-green to pale yellow was observed. The H NMR spectrum of the reaction mixture
revealed a downfield shift of the Ru–H signal from a triplet at δ –25.8 ppm to a broad singlet
at δ –16.7 ppm, suggesting a dynamic process (Figure 2B). This shift of the hydride signal
indicates coordination of benzonitrile trans to the Ru–H bond, forming complex 7 (Scheme
2), as observed in a previous case of coordination trans to Ru–H of 2[14]. The solution
9
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31
containing 2 and benzonitrile exhibited in the P{1H} NMR spectrum an AB spectrum with
doublets at δ 84.3 and 80.1 ppm (JP-P = 221.5 Hz, Figure 2B'), as expected from two
(1)
(2)
1
Figure 2. (1) Hydride region of H NMR spectra (benzene-d6) of (A) complex 2; (B)
complex 2 and excess benzonitrile; (C) complex 2 and benzonitrile under 5 bar H2 pressure;
10
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(2) 31P{1H} NMR spectra (benzene-d6) of (A') complex 2; (B') complex 2 and excess
benzonitrile; (C') complex 2 and benzonitrile under 5 bar H2 pressure.
magnetically inequivalent phosphorus atoms of the pincer ligand, not very different than the
spectrum of complex 2 which exhibits an AB spectrum showing two sharp doublets at δ 83.6
and 74.8 ppm (JP-P = 214.6 Hz). The IR spectrum of the reaction mixture exhibited a strong
absorption at 1906 cm-1 assignable to the CO ligand, and at 2105 cm-1 assignable to
coordinated -C≡N, which is in accordance with an earlier report[9b,9j,15]. Upon treatment of
this reaction mixture with 5 bar H2 the trans-dihydride complex (8)[15] was quantitatively
1
formed with concomitant aromatization of the pincer ligand (Scheme 2). The H NMR
spectrum of the reaction mixture exhibited the trans-dihydride signal as a sharp triplet at δ –
4.8 ppm (JP-H =17.1 Hz, Figure 2C). As expected, the 31P{1H} NMR spectrum of this reaction
mixture showed a singlet at δ 106.8 ppm (Figure 2C'), indicating that aromatization took
place, rendering the two phosphorous atoms equivalent. Apart from complexes 7 and 8, no
other complex was observable.
In line with the above NMR experiments, and with the literature regarding
hydrogenation catalysis by pyridine-based PNP-Ru complexes[16,17] a plausible mechanism of
the ruthenium catalyzed hydrogenation of nitriles to primary amines is postulated in Scheme
2. Initially, complex 2 binds with the nitrile trans to the Ru–H bond to yield intermediate 7.
In the presence of H2, 7 forms the trans-dihydride complex 8 with concomitant aromatization
of the pincer ligand and liberation of free nitrile. The saturated complex 8, which is an
intermediate in the catalytic cycle, transfers to the nitrile a hydride ligand and a proton from
the pincer arm, by an outer sphere mechanism involving metal-ligand cooperation by
aromatization-dearomatization[16,17,18], possibly via transition state 9 (or via stepwise hydride
and proton transfer), to give the de-aromatized imine complex 10. Imine release from 10
11
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followed by addition of H2 regenerates the dihydride complex 8. The primary imine thus
formed undergoes a similar catalytic cycle with 8 through transition state 11 and intermediate
12 to furnish the primary amine and regenerate catalyst 8 for the next cycle (Scheme 2).
Scheme 2. Plausible mechanism for the selective hydrogenation of nitriles to primary amines
using catalyst 2 (P = PtBu2).
In conclusion, an efficient, low pressure ruthenium-catalyzed protocol for the
reduction of nitriles is reported. The hydrogenation of aromatic nitriles having both electron-
donating and -withdrawing substituents catalyzed by the ruthenium pincer complex 2 under
neutral conditions, as well as precatalyst 1 in presence of catalytic base (generating complex
2 in situ), result in selective formation of primary amines under mild conditions, in good to
excellent isolated yields. Aliphatic nitriles undergo hydrogenation using pre-catalyst 6 in
presence of catalytic base, although at lower selectivity. A plausible mechanism for the
reactions catalyzed by 2 is proposed.
12
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Acknowledgment:
This research was supported by the Israel Science Foundation and by the Kimmel
Center for molecular design. D. M. holds the Israel Matz Professorial Chair of Organic
Chemistry. A. M. thanks the Planning and Budgeting Committee (PBC) of the Council for
Higher Education in Israel for a fellowship.
Present Address:
‡Department of Chemistry, Indian Institute of Technology Guwahati, Guwahati 781039,
Assam, India.
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10.1002/cctc.201601416
ChemCatChem
Table of Contents
Nitrile Hydrogenation: Hydrogenation of nitriles to the corresponding primary amines
under low hydrogen pressure, catalyzed by ruthenium pincer complexes is reported.
16
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