Selective Hydrogenation of Nitriles to Secondary Imines Catalyzed by an Iron Pincer Complex

Article abstract of DOI:10.1021/acscatal.7b00906

Selective hydrogenation of nitriles to secondary imines catalyzed by an iron complex, the pincer complex (iPr-PNP)Fe(H)Br(CO), in the presence of catalytic base, is reported. A wide range of (hetero)aromatic and aliphatic nitriles are hydrogenated to the corresponding secondary imines under mild conditions.

Full text of DOI:10.1021/acscatal.7b00906

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Letter
Selective Hydrogenation of Nitriles to Secondary
Imines Catalyzed by an Iron Pincer Complex
Subrata Chakraborty, and David Milstein
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ACS Catalysis
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Selective Hydrogenation of Nitriles to Secondary Imines Catalyzed
by an Iron Pincer Complex
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Subrata Chakraborty and David Milstein*
Department of Organic Chemistry, Weizmann Institute of Science, Rehovot, 76100, Israel
ABSTRACT: Selective hydrogenation of nitriles to secondary imines catalyzed by an iron complex, the pincer complex
(iPr-PNP)Fe(H)Br(CO), in the presence of catalytic base, is reported. A wide range of (hetero)aromatic and aliphatic ni-
triles are hydrogenated to the corresponding secondary imines under mild conditions.
KEYWORDS: Iron, nitriles, secondary imines, hydrogenation, pincer.
Catalytic hydrogenation of nitriles constitutes an important
methodology in industry and academia. Imines and amines that
are generally formed serve as important intermediates and pre-
cursors in the synthesis of various natural products, agrochemi-
cals, dyes, pigments, polymers and pharmaceuticals.1 However,
nitrile hydrogenation often leads to mixtures of primary-, sec-
ondary- and even tertiary- amines via imine intermediates, pre-
senting crucial selectivity issues (Scheme 1).2 Therefore the dis-
covery of a catalyst for selective hydrogenation of nitrile to either
of these products is desirable.
Berke’s group reported homogeneous hydrogenation of nitriles
to form secondary imines as major products using molybdenum
and tungsten amides bearing the so-called “MACHO” PNP pin-
cer ligand.18 These reactions proceed at high temperature and
pressure (140 0C, 60 bar H2), and high catalyst loadings (5 mol%),
resulting in a mixture of primary amine, intermediate imine and
secondary imine (major) products, while selectivity towards
secondary imine was obtained only at low conversions. The only
hydrogenation of nitriles to secondary imines catalyzed by a
base-metal complex was reported by García using a nickel cata-
lyst.19 That system requires high temperatures (140-180 0C) and is
limited to mono- and dicyano- benzene derivatives. To our
knowledge, homogeneous hydrogenation of nitriles to selectively
form secondary imines catalyzed by iron was not reported so far.
Scheme 1. Possible products in nitrile hydrogenation.
Conventional methods for reduction of nitriles involve stoichio-
metric amounts of metal hydrides, or hydrosilanes.3 Unfortu-
nately, these routes are not environmentally benign as they pro-
duce copious waste. Heterogeneous catalysts based on Co, Ni
and Pd, commonly used for nitrile hydrogenation in industry,4
suffer from low selectivity towards a particular product and low
functional group tolerance. Typically, homogeneous catalysts
based on precious metals such as Ru, Rh, Ir, and Re are applied
in the hydrogenation of nitriles.5-7
Figure 1. Fe-based catalysts for homogeneous nitrile hydrogena-
tion/hydrogenative cross-coupling with amine.
Replacement of precious metal-based catalysts by complexes of
earth abundant, low-toxicity first row base-metals is a topic of
much current interest.8 Indeed, recent years have witnessed
much progress in the development of homogeneous catalysts
based on earth-abundant base-metals.9-12 Of prime interest is the
use of iron complexes since iron is generally less toxic than noble
metals and it is the most abundant metal on the earth crust.
Iron catalyzed hydrogenation of various substrates13 including
esters14 and amides15 was reported by a few groups, including
ours. Selective catalytic hydrogenation of nitriles to primary
amines by iron complexes (Figure 1)16, as well as by Mn10a and
Co12i complexes, was also demonstrated.
The nitrile group is an important functionality in various natural
and synthetic organic compounds, including pharmaceuticals,
and it can be further processed by catalytic hydrogenation or
hydrolysis.17 In addition to the possibility of its hydrogenation to
form primary amines, an interesting but challenging goal is the
direct hydrogenation to selectively form secondary imines.
In fact, even reports on precious metal-catalyzed selective hy-
drogenation of nitriles to secondary imines are rare. Sabo-
Etienne
observed
formation
of
N-benzylidene-1-
phenylmethaneamine during the hydrogenation of benzonitrile
in the absence of a solvent catalyzed by a Ru system.5b Our
group, and recently Prechtl and coworkers, reported hydrogena-
tion and hydrogenative coupling of nitriles and amines to give
secondary self-coupled imines and cross-imines as major prod-
ucts, by Ru-PNN20a and Ru-PNP20b catalysts, respectively.
Very recently we reported the hydrogenative cross-coupling of
nitriles and amines to form secondary aldimines under mild
conditions (10-20 bar H2, 60 °C) using the complex Fe(iPr-
PNP)(H)Br(CO) (1) in the presence of a catalytic amount of base
(Figure 1).21 Herein we employ complex 1 and catalytic base for
the selective hydrogenation of nitriles to secondary aldimines.
The reaction proceeds under relatively mild conditions (90°C, 30
bar H2).
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Page 2 of 6
Catalytic hydrogenation of benzonitrile using complex 1 to give
shown in Scheme 1. It is also noteworthy that no hydrogenation
of the product imine took place. The selectivity towards the sec-
ondary imine depends strongly on the reaction temperature and
pressure. At higher temperature (135 °C) the selectivity dropped
and a lower yield of N-benzylidenebenzylamine (71%) was ob-
tained (Table 1, entry 3) under otherwise the same conditions.
Exploring the effect of various additives, KHMDS and tBuOK
were employed under similar reaction conditions. Using the base
KHMDS (1 mol%), a lower yield of N-benzyl benzaldimine (40%)
was obtained, in comparison to when NaHBEt3 was used (Table
1, entry 4). tBuOK turned out to be the best additive, resulting in
97% yield of N-benzyl benzaldimine after just 10 h under analo-
gous conditions (Table 1, entry 5). In the absence of base, em-
ploying pre-catalyst 1 (1 mol%) no hydrogenation of benzonitrile
took place (Table 1, entry 7), indicating that one equivalent of
selectively N-benzyl benzaldimine was initially chosen as a mod-
el system. The influence of temperature, hydrogen pressure,
various additives, and different solvents was examined. Selected
optimization experiments are shown in Table 1. Using NaHBEt3
(1 mol%), and complex 1 (1 mol%) under 60 bar H2 at 65 °C in
THF, complete conversion of benzonitrile was observed after 38h
1
2
3
4
5
6
7
8
Table 1. Optimization of the reaction conditions for the
hydrogenation of benzonitrile catalyzed by 1.
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En-
trya
Solvent
Additives
(mol%)
Time
(h)
Tem
p
(°C)
H2
(ba
r)
Convb
(%)
Yield
b
(%)
64
98
71
40
97
53
00
96
98
98
97
98
46
93
Table 2. Hydrogenation of nitriles to secondary imines cat-
alyzed by 1.
1
2
3
4
5
6
7
8
9
10
11
12
13c
14
THF
THF
THF
THF
THF
NaHBEt3 (1)
NaHBEt3 (1)
NaHBEt3 (1)
KHMDS (1)
tBuOK(1)
tBuOK(1)
-
tBuOK (1)
tBuOK (1)
tBuOK (1)
tBuOK(1)
tBuOK(1)
tBuOK (1)
tBuOK(1)
38
20
20
10
10
5
10
10
10
10
5
65
60
>99
>99
>99
84
>99
>99
00
>99
>99
>99
>99
>99
>99
>99
90
135
90
90
90
90
90
90
90
90
90
90
90
60
60
60
60
60
60
60
60
60
60
60
60
30
En-
trya
Substrate
Product
1
mol
%
Time
(h)
Convb
(%)
Yieldb
(%)
THF
THF
Dioxane
C6H6
EtOH
EtOH
C6H6
iPrOH
C6H6
1
1
<36
<36
<36
18
>99
>99
>99
81
97
93
91
2c
3c
4d
5d
6d
7d
8
2
1
5
5
18
aConditions: benzonitrile (1 mmol), 1 (0.01 mmol) additive (1 equiv.
relative to 1), and solvent (2 mL), heated in an autoclave. byields and
conversions determined by GC-MS analysis using m-xylene as inter-
nal standard. Differences in conversions of benzonitrile and yields of
N-benzylidenebenzylamine indicate formation of benzaldimine and
its trimerised N,N-di(phenylmethylidene)phenylmethanediamine
product. C53% benzylamine formation was observed.
2
1
52
79
56
28
99
24
>99
>99
59
4
4
4
36
(Table 1, entry 1) as revealed by GC-MS. Surprisingly, no primary
benzylamine, or dibenzylamine were detected by GC-MS. N-
benzyl benzaldimine was obtained in 64% yield. The partially
hydrogenated product benzaldimine was also detected by GC-
MS, appearing as a broad signal along with its trimerized prod-
uct N,N-di(phenylmethylidene)phenylmethanediamine (hydro-
benzamide) (Scheme 2).22 The hydrobenzamide was character-
ized by 1H NMR, showing a typical resonance shift at δ = 5.7 ppm
for the methyne proton and at 8.3 ppm for the imine CH proton
in a 1:2 ratio. In the 13C{1H} NMR spectra, the methyne carbon
resonates at δ = 92.7 ppm and the imine carbon at δ = 160.7 ppm
(see Supporting Information (SI)).
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14
>99
9
4
4
12
16
>99
>99
99
70
10d
11d
4
14
80
61
12
13
14
15
8
8
8
8
36
36
36
36
61
32
69
11
61
32
69
11
1
Scheme 2. Products detected by GC-MS and H NMR in the
hydrogenation of benzonitrile at 65°C catalyzed by 1 (Table 1,
entry 1).
aConditions: benzonitrile (1-0.125 mmol), 1 (0.01 mmol), tBuOK (1
equiv. relative to 1), and 2 ml C6H6 (1 mL for 4 mol% and 8 mol% cat
loading), heated in an autoclave at 90 °C under 30 bar H2. byields and
Significantly, increasing the temperature to 90 °C under analo-
gous reaction conditions resulted in 99% consumption of ben-
zonitrile, yielding 98% of N-benzyl benzaldimine after 20 h (Ta-
ble 1, entry 2). Although benzylamine was not detected, it is like-
ly formed as an intermediate, followed by its attack on the in-
termediate imine to form a gem-diamine intermediate which
liberates ammonia to yield the desired secondary aldimine, as
1
conversions determined by GC-MS and H NMR analysis using m-
xylene, or toluene as internal standard. isolated yield. dDifferences
c
in conversions of nitriles and yields of secondary imines indicate
formation of partially hydrogenated intermediate imines and their
trimerised products.
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base (or NaHBEt3) (relative to 1) is required to generate the ac-
not react with benzonitrile at room temperature in C6D6, where-
as 3 did react with benzonitrile, regenerating the amido complex
2 and benzaldimine. Based on these previously observed detailed
mechanistic results,21 a plausible outer-sphere mechanism is
depicted in Scheme 3.
tive catalyst. Regarding solvent optimization, dioxane, benzene
or EtOH all gave exclusively N-benzylidenebenzylamine (98%)
in less than 10 h using 1 (1 mol%) and, tBuOK (1 mol%) at 90 °C
and 60 bar H2 (Table 1, entries 8-12). However, using isopropanol
as solvent, 53% of benzylamine formation was observed along
with N-benzylbenzaldimine (46%) (Table 1, entry 13) after 5 h
under otherwise similar conditions. Gratifyingly, lowering the H2
pressure to 30 bar in the presence of tBuOK (1 mol%) and 1 (1
mol%) using benzene as solvent furnished 93% N-benzyl ben-
zaldimine (Table 1, entry 14) in less than 18 h at 90 °C.
Using the optimized reaction conditions (C6H6, 90 °C, 30 bar H2,
1 mol% tBuOK and 1 mol% 1), the generality of this iron-
catalysed hydrogenation of nitriles was explored. As shown in
Table 2, benzonitriles bearing electron-donating substituents at
the para positions, including 4-methoxybenzonitrile, 4-
methylbenzonitrile, 4-N,N- dimethylbenzonitrile, and meta-
substituted 3-methylbenzonitrile were hydrogenated to their
corresponding secondary aldimines in excellent conversions
with good selectivities (Table 2, entries 1-4). Catalytic hydro-
genation of benzonitriles bearing electron withdrawing substitu-
ents at the para positions, including 4-fluorobenzonitrile and 4-
chlorobenzonitrile, also afforded selectively the corresponding
secondary imines, although higher catalyst loading (4 mol%) was
required in the case of the latter. No hydro-dehalogenation was
observed (Table 2, entries 5 and 8).
1
2
3
4
5
6
7
8
Initially, complex 2, formed by reaction of base with complex 1,
adds dihydrogen by metal–ligand cooperation to generate the
cis-dihydrido complex 3, as previously reported.21 Complex 3 is
likely in equilibrium with the unobserved trans dihydride com-
plex 3’, which is believed to be the active species. The imine in-
termediate is generated by hydride and proton transfer from 3’
to the nitrile group, either in a concerted or stepwise fashion and
3’ is converted to the amido complex 2. Similarly, in another
catalytic cycle H2 is transferred to the imine intermediate to
form the primary amine. This step is likely the rate limiting step,
otherwise full hydrogenation to the amine would have taken
place. As soon as the primary amine is formed, nucleophilic at-
tack by the amine on the reactive imine intermediate produces a
gem-diamine, which liberates NH3 to give the desired secondary
imine (Scheme 3).
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However, the meta- and ortho- substituted 3-fluorobenzonitrle
and 2-fluorobenzonitrile yielded the corresponding secondary
imines in moderate yields (Table 2, entries 6 and 7) along with
the formation of 43% and 31% of partially hydrogenated inter-
mediate 3-fluorobenzaldimine and 2-fluorobenzaldimine, re-
spectively which appeared as their trimeric products, as shown
1
by H NMR. Hydrogenation of p-bromobenzonitrile, applying 1
(4 mol %) as pre-catalyst and 4 mol% tBuOK in THF resulted in
99%
yield
of
N-(4-
bromobenzylidene)-1-(4-
bromophenyl)methaneamine (Table 2, entry 9), showing that
even bromo substituents are tolerated. Hydrogenation of 2-
naphthonitrile resulted in the formation of N-(naphthylidene)-1-
(naphthyl)methanamine in70% yield after 16 h (Table 2, entry
10).
The scope of the reaction was further probed by employing the
heterocyclic nitrile 3-pyridinecarbonitrile, furnishing N-(3-
pyridinylmethylene)-3-pyridinemethanamine in 61% yield after
14 h (Table 2, entry 11).
Catalytic hydrogenation of aliphatic nitriles bearing alpha hy-
drogen atoms is more challenging due to potential base-induced
condensation side reactions. In addition, aliphatic imines are
inherently less stable. Employing the Fe-PNP complex 1, catalytic
hydrogenation of aliphatic nitriles progressed sluggishly com-
pared to aromatic nitriles, and catalyst loading had to be in-
creased. Thus, valeronitrile and butyronitrile were hydrogenated
to the corresponding secondary imines in 61% and 32% yield,
respectively, using 8 mol% catalyst 1 and NaHBEt3 (8 mol%)
under 30 bar H2 at 90 °C (Table 2, entries 12 and 13). Hydrogena-
tion of the secondary alkyl nitrile cyclohexylcarbonitrile resulted
in formation of the corresponding secondary imine in 69% yield
(Table 2, entry 14). Using isobutyronitrile under similar condi-
tions, only 11% conversion to the corresponding secondary imine
was noticed (Table 2, entry 15). The expected lower stability of
the generated alkyl imine intermediate might be a reason for the
inferior performance.
Scheme 3. Plausible mechanism for the hydrogenation of
nitriles to secondary imine catalyzed by iron.
In conclusion, we have presented the first iron-catalyzed hydro-
genation of nitriles to selectively form secondary imines. The
reaction proceeds at relatively low temperature and pressure (90
°C, 30 bar H2), under apparently neutral, homogeneous condi-
tions, using the pincer complex (iPr-PNP)Fe(H)Br(CO) 1 and a
base (in an equimolar amount to Fe). No products of full hydro-
genation (primary or secondary amines) were observed. In con-
trast, nitrile hydrogenation catalyzed by a related “MACHO”
ligand-based iron system developed by Beller16a afforded selec-
tively primary amines, providing another example as to the criti-
cal role that ligand modification may have.
AUTHOR INFORMATION
Corresponding Author
*E-mail: david.milstein@weizmann.ac.il.
Notes
The authors declare no competing financial interests.
Regarding the mechanism of the nitrile hydrogenation, we have
previously reported21 that complex 1 reacted with 1 equiv. of
tBuOK in THF at room temperature forming a deprotonated
amido complex (iPr-PNP)Fe(H)(CO) 2 (Scheme 3) and reaction
with 1 equiv. NaHBEt3 gives the cis-dihydridocarbonyl complex
(iPr-PNP)Fe(H)2(CO) 3. The deprotonated amido complex 2 did
ASSOCIATED CONTENT
Experimental details of the catalytic experiments, GC-MS data of
hydrogenation products, and NMR spectra.
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(10) Mn catalyzed hydrogenation: (a) Elangovan, S.; Topf, C.;
“This material is available free of charge via the Internet at
http://pubs.acs.org.”
Fischer, S.; Jiao, H.; Spannenberg, A.; Baumann, W.; Ludwig, R.;
Junge, K.; Beller, M. J. Am. Chem. Soc. 2016, 138, 8809-8814. (b) Kall-
meier, F.; Irrgang, T.; Dietel , T.; Kempe, R. Angew. Chem. Int. Ed.
2016, 55, 11806-11809. (c) Elangovan, S.; Garbe, M.; Jiao, H.; Spannen-
berg, A.; Junge, K.; Beller, M. Angew. Chem. Int. Ed. 2016, 55, 15364-
15368. (d) Espinosa-Jalapa, N. A.; Nerush, A.; Shimon, L. J. W.; Leitus,
G.; Avram, L.; Ben-David, Y.; Milstein, D. Chem. Eur. J. 2016, 22, DOI:
10.1002/chem.201604991.
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ACKNOWLEDGMENT
This research was supported by the European Research Council
(ERC AdG 692775) and by the Kimmel Center for Molecular
Design. D.M. holds the Israel Matz Professorial Chair of Organic
Chemistry. S.C. thanks the Swiss Friends of the Weizmann Insti-
tute of Science for a generous postdoctoral fellowship.
(11) Mn catalyzed conjugate addition of non-activated nitriles: Ne-
rush, A.; Vogt, M.; Gellrich, U.; Leitus, G.; Ben-David, Y.; Milstein, D.
J. Am. Chem. Soc. 2016, 138, 6985-6997.
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