Catalytic coupling of nitriles with amines to selectively form imines under mild hydrogen pressure

Article abstract of DOI:10.1039/c2cc36639h

Imines are selectively formed by coupling of nitriles and amines under mild hydrogen pressure. The reaction is catalyzed by a bipyridine-based PNN Ru(ii) pincer complex and proceeds under mild, neutral conditions at 4 bar of H ₂.

Full text of DOI:10.1039/c2cc36639h

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COMMUNICATION
Catalytic coupling of nitriles with amines to selectively form imines under
mild hydrogen pressurew
Dipankar Srimani, Moran Feller, Yehoshoa Ben-David and David Milstein*
Received 12th September 2012, Accepted 12th October 2012
DOI: 10.1039/c2cc36639h
Imines are selectively formed by coupling of nitriles and amines
under mild hydrogen pressure. The reaction is catalyzed by a
bipyridine-based PNN Ru(II) pincer complex and proceeds under
mild, neutral conditions at 4 bar of H2.
The selective catalytic hydrogenation of nitriles to form imines is
challenging.1 Hydrogenation of nitriles generally results in mixtures
of primary, secondary and tertiary amines as well as imines as side
products.2 The imines are key intermediates of this reaction,
produced by the partial reduction of nitriles. The initially formed
primary imine undergoes nucleophilic attack on the electron-
deficient imine carbon by the product primary amine to produce
a gem-diamine; the latter could undergo either direct hydro-
genolysis or elimination of NH3 (via dialkylated imines), followed
by hydrogenation to form the corresponding secondary amine.2i It
was proposed that tertiary amines are formed by addition of the
secondary amine to the imine and subsequent hydrogenolysis of
the gem-diamine intermediate,2a,i or by first elimination of NH3
from the gem-diamine to form an enamine intermediate that is
subsequently hydrogenated to the tertiary amine (Scheme 1).2b,i
The composition of the products formed markedly depends on
the nature of the catalysts, reaction temperature, hydrogen
pressure and on the structure of the nitriles,3 and examples of
selective formation of primary amines4 or secondary amines5 were
reported. Nitriles can also be hydrogenated in the presence of
amines to give unsymmetrical amines.6 Selective formation of an
imine product by the hydrogenation of nitriles was reported in
only one case.4d Sabo-Etienne et al. observed formation of
N-benzylidene-1-phenylmethanamine during the hydrogenation
of benzonitrile to benzylamine and were able to obtain it
selectively when the reaction was performed in the absence of
solvent; using a solvent (THF), a mixture of benzylamine and
benzylidene-1-phenylmethanamine was obtained.4d We present here
a new method for the synthesis of imines. It is based on cross-
hydrogenative coupling of nitriles with amines under mild hydrogen
pressure. Imines have widespread applications in laboratory and
industrial synthetic processes due to their diverse reactivity.7 We
believe that the selective formation of imines from readily available
nitriles and amines has considerable synthetic potential.
Scheme 1 Mechanism of the hydrogenation of nitriles to primary,
secondary and tertiary amines, via imine intermediates.
We reported the efficient dehydrogenative coupling of alcohols
with amines to give imines catalysed by a pyridine-based PNP Ru
pincer complex.8h This reaction occurs with liberation of H2 and
water, with high turnover numbers, and no waste products are
formed. Several other environmentally benign reactions catalyzed
by tridentate PNN and PNP Ru(II) pincer complexes based on
pyridine-8 and acridine-9 backbones were developed. Recently,
the hydrogenation of amides to the corresponding alcohols and
amines catalyzed by the bipyridine-based pincer complex 1 was
reported.10 This complex also catalyzes the hydrogenation of urea
derivatives,11a organic carbonates, carbamates and formates11b
and the hydrogenation of cyclic di-esters to 1,2-diols.11c
Here we report on the hydrogenation of nitriles in the
presence or absence of added amine, catalyzed by complex 1
under mild, neutral conditions (Scheme 2).
Department of Organic Chemistry, The Weizmann Institute of Science,
Rehovot 76100, Israel. E-mail: david.milstein@weizmann.ac.il;
Fax: +972 9346569; Tel: +972 934259
w Electronic supplementary information (ESI) available: Experimental
details and spectral data. See DOI: 10.1039/c2cc36639h
Scheme 2 Hydrogenative coupling of nitriles with amines catalyzed
by complex 1.
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 11853–11855 11853

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Reaction of benzonitrile with H2 (10 bar) at 110 1C (bath
temperature) in dry THF for 24 h catalyzed by 1 (1 mol%)
resulted in complete conversion, yielding a mixture of benzylamine
(65%) and dibenzylamine (30%). Significantly, upon lowering the
temperature and pressure, selective imine formation took place.
Thus, stirring benzonitrile (2 mmol) at 70 1C in 2 mL dry THF
under 4 bar H2 in the presence of 0.6 mol% catalyst 1 resulted
after 16 h in formation of N-benzylidene-1-phenylmethanamine in
88% yield and no benzylamine or dibenzylamine was detected by
GC-MS (entry 1). Apparently, the amine formed by the reduction
of the nitrile attacks the intermediate imine and gives rise to a gem-
diamine, which liberates ammonia to yield the desired imine. It is
noteworthy that no hydrogenation of the product imine took
place. Exploring further the scope with regard to different nitriles,
reaction of 4-methyl benzonitrile and 4-methoxy benzonitrile
under the same conditions resulted in N-(4-methylbenzylidene)-1-
(p-tolyl)methanamine and N-(4-methoxybenzylidiene)-1-(4-ethoxy-
phenyl)methanamine, respectively, in excellent yields (81% and
92%, respectively; entries 2 and 3). Encouraged by these results we
explored the possibility of coupling of amines with the intermediate
imines produced by partial hydrogenation of nitriles, to obtain the
cross-imines. Thus, upon 15 h stirring equimolar amounts of
benzonitrile and hexylamine in THF under 4 bar of hydrogen at
70 1C in the presence of 0.6 mol% catalyst, complete conversion of
the nitrile to form N-benzylidenehexan-1-amine in 85% yield took
place (entry 4), in addition to a minor amount of the self-coupled
product N-benzylidene-1-phenylmethanamine (12% yield). For
comparison, reaction of benzonitrile with hexylamine under
similar conditions as in entry 4 using 0.6 mol% of RuCl2(PPh3)3
did not result in any product formation. Increasing the reaction
temperature to 110 1C, the H2 pressure to 10 bars and the
reaction time to 40 h resulted in the formation of a mixture
of N-benzylhexan-1-amine (38% yield), N-benzylidenehexan-1-
amine (14% yield), dibenzylamine (18% yield), N-benzylidene-1-
phenylmethanamine (9% yield) and benzylamine (21% yield)
(Table 1).
Table 1 Hydrogenation of nitriles in the absencea or presenceb of
added amines
Con-
Time version Yieldc
Entry Nitrile Amine
Product
(h) (%)
(%)
1
2
3
4
5
6
None
None
None
16
49
48
15
35
72
99
85
99
99
99
55
88
81
92
85
84
50
7
23
27
27
54
60
50
99
99
99
86
99
15d
90
8
91
9
85
10
11
12
81d
71d
—
13
14
27
20
99
99
80
74
15
16
20
70
99
55
69
30d,e
None
a
Complex 1 (0.6 mol%), nitrile (2 mmol), H2 (4 bar) and dry THF
(2 mL) were heated in a 100 mL Fischer–Porter tube at 70 1C (bath
temperature). Complex 1 (0.6 mol%), nitrile (2 mmol), amine
b
Studying the scope of this new reaction with regard to
different nitriles and amines, the reaction of hexylamine with
4-methylbenzonitrile in the presence of 0.6 mol% catalyst 1
was carried out under 4 bar of hydrogen to give after 35 h
N-(4-methylbenzylidene)hexan-1-amine in 84% yield and the self-
coupling product N-(4-methylbenzylidene)-1-(p-tolyl)methanamine
in 10% yield (entry 5). Likewise the reaction between the electron
poor nitrile 4-fluorobenzonitrile and hexylamine gave 55% con-
version of the nitrile with 50% yield of N-(4-fluorobenzylidene)-
hexan-1-amine (entry 6). No self-coupling or reduction products of
the imine were observed by GC-MS. Similarly, 90% yield of
N-(4-methoxybenzylidene)hexan-1-amine was obtained after
23 h stirring of equimolar amounts of 4-methoxy benzonitrile and
hexylamine under the same conditions (entry 7). N-(4-Methoxy-
benzylidiene)-1-(4-methoxyphenyl)methanamine was also obtained
in 7% yield due to self-condensation. Exploring further the scope
with regard to the amine, we studied also the reaction of nitriles
with heptylamine under 4 bar of hydrogen. Thus, 27 h stirring of
heptylamine with benzonitrile and 4-methoxybenzonitrile gave
the corresponding cross products in 91% and 85% yields,
respectively (entries 8 and 9), while only 14% and 4% yields,
respectively, of N-benzylidene-1-phenylmethanamine and
N-(4-methoxybenzylidene)-1-(4-methoxyphenyl)methanamine were
(2 mmol), H2 (4 bar) and dry THF (2 mL) were heated in a 100 mL
c
Fischer–Porter tube at 70 1C (bath temperature). Yields of the
product and conversion of nitriles were determined by gas chromato-
d
graphy (GC) using toluene as an internal standard. 0.8 mol%
e
catalyst was used. Isolated yield.
obtained, due to self-condensation of the corresponding
nitriles. The optimized reaction conditions were applied also
to heterocyclic nitriles. Thus, reaction of 3-cyanopyridine with
hexylamine under 4 bar of hydrogen using 0.6 mol% catalyst
was somewhat sluggish, yielding after 30 h 40% N-(pyridine-3-
ylmethylene)hexan-1-amine. The yield was improved to 81%
(entry 10) by use of 0.8 mol% catalyst and a longer reaction
time (54 h). No self-coupled product was observed. Similarly
after 60 h stirring with heptylamine complete conversion of
3-cyanopyridine was observed, forming N-(pyridine-3-yl-
methylene)heptan-1-amine in 71% yield (entry 11) with 20%
yield of N-(pyridine-3-ylmethyl)heptan-1-amine as the reduced
product of the corresponding imine. No self-coupled product was
obtained in this case. Trying to couple 2-cyanopyridine with
hexylamine using 0.8 mol% of 1 resulted in only 15% conver-
sion to N-(pyridine-2-ylmethylene)hexan-1-amine (entry 12).
c
11854 Chem. Commun., 2012, 48, 11853–11855
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Scheme 3 Possible mechanism for cross coupling between nitriles
and amines under mild H2 pressure catalyzed by complex 1.
This may be due to the chelating nature of 2-iminopyridine
which might deactivate the catalyst.
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yield of N-benzylidenecyclohexanamine (entry 13) and 18%
yield of N-benzylidene-1-phenylmethanamine as self-coupled
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The mechanism illustrated in Scheme 3 might be possible,
although other mechanisms cannot be excluded at this stage.
Initially, coordination of the nitrile to the unsaturated
complex 1 gives rise to the coordinatively saturated complex
A which can undergo de-coordination of the bipyridine ‘‘arm’’
followed by addition of dihydrogen by metal–ligand cooperation
to generate complex B. Subsequent hydride transfer to the
nitrile group leads to the imine intermediate C. Nucleophilic attack
by the amine on the coordinated imine can give intermediate D,
which liberates a diamine with regeneration of the catalyst. NH3
liberation from the diamine gives rise to the desired imine.
In conclusion, for the first time imines can be selectively formed
by hydrogenative coupling of nitriles and amines. The reaction
proceeds at relatively low temperature and under neutral, homo-
geneous conditions using the pincer catalyst 1, under mild hydrogen
pressure. This new, environmentally benign atom economical
catalytic protocol exhibits a broad substrate scope, providing a
variety of imines from amines and nitriles in good to excellent yields.
This research was supported by the European Research
Council under the FP7 framework (ERC No. 246837) and
by the Kimmel Center for Molecular Design. D. M. holds the
Israel Matz Professorial Chair of Organic Chemistry.
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Notes and references
1 L. A. Oro, D. Carmona and J. M. Fraile, in Metal-Catalysis in
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RSC Publishing London, 2006, pp. 79–113.
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 11853–11855 11855