Easy Ruthenium-Catalysed Oxidation of Primary Amines to Nitriles under Oxidant-Free Conditions

Article abstract of DOI:10.1002/chem.201902557

A dehydrogenation of primary amine to give the corresponding nitrile under oxidant- and base-free conditions catalysed by simple [Ru(p-cym)Cl₂]₂ with no extra ligand is reported. The system is highly selective for alkyl amines, whereas benzylamine derivatives gave the nitrile product together with the imine in a ratio ranging from 14:1 to 4:1 depending on the substrate. Preliminary mechanistic investigations have been performed to identify the key factors that govern the selectivity.

Full text of DOI:10.1002/chem.201902557

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Accepted Article
Title: Easy ruthenium-catalysed oxidation of primary amines to nitriles
under oxidant free conditions
Authors: Thierry ACHARD, Julien Egly, Michel Sigrist, Aline Maisse-
François, and Stéphane Bellemin-Laponnaz
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To be cited as: Chem. Eur. J. 10.1002/chem.201902557
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Easy ruthenium-catalysed oxidation of primary amines to nitriles
under oxidant free conditions
Thierry Achard,*a Julien Egly,a Michel Sigrist,a Aline Maisse-François,a Stéphane Bellemin-Laponnaz*a
Abstract:
A
dehydrogenation of primary amine to give the
selectivity however it requires the addition of a strong base to
achieve high reactivity.17e
corresponding nitrile under oxidant- and base-free conditions
catalysed by simple [Ru(p-cym)Cl2]2 with no extra ligand is reported.
The system is highly selective for alkyl amine whereas benzylamine
derivatives gave the nitrile product together with the imine in ratio
ranging from 14:1 to 4:1 depending on the substrate. Preliminary
mechanistic investigations have been performed to identify the key
factors that govern the selectivity.
Nitrile is a valuable functional group which gives rise to
different class of organic molecules.1 Structurally diverse nitrile-
containing compounds are present in many natural products,2
medicinal drugs,3 and involved in industrial processes.4
Conventional approaches for nitrile synthesis1b such as
Sandmeyer reaction,5 the Rosenmund-von Braun reaction,6 the
dehydration of amides/oximes,7 metal-catalysed cyanation,7
oxidation of primary amine using iodine based-8 or metal-
11
catalysts9,10 and others7,
generally involve complicated
operations, heavy metal waste, toxic reagents (e.g., KCN or
CuCN), with restricted reactivity and poor selectivity12 or harsh
reaction conditions.
Acceptorless Dehydrogenation (AD)13 of primary amine has
emerged as an elegant alternative in which
a double
dehydrogenation takes place, producing H2 gas as the sole by-
product and thus produces non-toxic waste. However, relatively
few catalysts have been reported for the dehydrogenation of
amine13a, 14 in contrast to alcohol.13, 15 Among those, only few
avoid the use of excess oxidant and they achieve either low
conversion or require exogenous additives (bases and/or
sacrificial hydrogen acceptor) under harsh conditions.14 Beside
this, the reaction selectivity remains an issue due to the
competition between the second dehydrogenation and the
transamination pathway.13, 16
Scheme 1. Selective formation of nitrile without hydrogen acceptor additive
and under oxidant free condition.
While evaluating ruthenium complexes with various ancillary
ligands for this reaction, we found that a simple Ru(II) precursor
(i.e. [Ru(p-cym)Cl2]2) may act as an efficient catalyst. Indeed, in
some metal-catalysed reactions the addition of ancillary ligands
is unnecessary, since the substrate itself can serve as a
ligand.19 Herein, we explored the amine dehydrogenation under
oxidant- and base-free conditions with [Ru(p-cym)Cl2]2 as
precatalyst. Under optimised conditions alkyl amines were
selectively converted into the nitrile derivatives. Benzyl amine
substrates also gave the expected product albeit together with
little of the imine. We also conducted some experiments to have
better insight into the active species.
So far, only a few rare examples are known in the literature
for the highly selective transformation of primary amine into
nitrile under acceptorless and oxidant-free conditions (Scheme
1).17 The first example was reported in 2013 by Szymczak17a
with bis(2-pyridylimino)isoindolate Ru(II) hydride derivative 1 as
catalyst. Ru p-cymene NHC complexes 2 were found active
albeit with moderate selectivity,17d however the catalyst can be
recycled for alternative hydrogen storage purpose.18 Finally, very
recently Ru(II) p-cymene pyrazole 3 system displayed good
Initially, we studied the model reaction using benzylamine20
to establish an efficient catalytic system for benzonitrile
synthesis (Table 1). The reactions were conducted for 24h at
110 °C in 1,2-dichlorobenzene (ODCB) in an open vessel under
inert atmosphere.21 Several classical Ru precursors were then
evaluated and a complete disappearance of the amine was
observed in all cases (5 mol% cat., Entries 1-5). However,
among them only [Ru(p-cym)Cl2]2 was found to selectively
generate the benzonitrile as the sole product thanks to the
[a]
Dr. T. Achard, J. Egly, M. Sigrist, Dr. A. Maisse-Francois, Dr. S.
Bellemin-Laponnaz
Département des Matériaux Organiques
Institut de Physique et Chimie des Matériaux de Strasbourg
(IPCMS) Université de Strasbourg, CNRS UMR-7504
23 rue du Loess, BP 43, 67034 Strasbourg Cedex 2, France
E-mail: thierry.achard@ipcms.unistra.fr; bellemin@unistra.fr
Supporting information, including general experimental procedures,
additional schemes and figures, characterization data and NMR
spectra for this article, is given via a link at the end of the document.
1
analysis of both H NMR and GC spectra of reaction mixtures.
Consistent with Szymczak observation,17a-c only trace of nitrile
was observed in a closed system under our conditions (Entry 6).
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In addition, under our conditions with an atmosphere of O2, in a
closed system, the reaction is less selective producing
undesired benzaldehyde (ca. 10%) as by-product.8b, 12e-g Further
optimisation studies showed that dry 1,2-dichlorobenzene, 1M
concentration of amine and 2.5 mol% of ruthenium was the best
combination among a variety of solvents, concentrations and
catalyst loadings (see SI). 22
notably for the most electron attractive p-CF3 group (26) that
gave a 4/1 nitrile/imine ratio.
Table 2. Substrate scope for [Ru(p-cym)Cl2]2 catalyzed oxidation of primary
alkyl amine to nitrile.[a]
Table 1. Evaluation of benzylamine oxidation under varying conditions.[a]
Entry 1[a]
[Ru]
Conv
(%)[b]
Selectivity (%)[b]
4
5
1
Ru(acac)3
100
100
100
100
100
5%<
100
80
75
73
86
100
0
20
2
[CpRu(CH3CN)3][PF6]
Ru3(CO)12
25
3
27
4
[Ru(benzene)Cl2]2
[Ru(p-cym)Cl2]2
[Ru(p-cym)Cl2]2
[Ru(p-cym)Cl2]2
14
5
0
6[c]
7[d]
100
11 [e]
[a] Reaction conditions: amine (0.2 mmol), 1.25 mol% [Ru(p-cym)Cl2]2, and
1,2-diclhorobenzene (0.2 mL), 110 °C, 24h in open vessel under argon
atmosphere. Yields refer to isolated products.
86
[a] Reaction conditions: benzylamine (0.2 mmol), 5 mol% cat. based on Ru
and 1,2-dichlorobenzene (0.2 mL), 110 °C, 24h, open vessel under argon
atmosphere; [b] Conversion and selectivity were determined by 1H RMN,
internal reference hexadecane; [c] Closed system under argon atmosphere.
[d] H2O (0.2 mmol). [e] presence of 3% of benzaldehyde
Table 3. Substrate scope for [Ru(p-cym)Cl2]2 catalyzed oxidation of benzylic
amines to nitriles.[a]
Next, a series of amine substrates was examined under the
optimized conditions (Tables 2 and 3). Non-benzylic amines
generated corresponding nitriles as the exclusive product in
good yield after chromatographic purification on SiO2 (6-15).
Only the crowded adamantylamine was found less selective by
producing small amount of non-desired imine in a ratio of 6 to 1
in the crude product. Nonetheless, the expected product (16)
was isolated in 65% yield. Aliphatic amines showed good
reactivity, whether for short or long carbon chains. Both
geranylamine and oleylamine gave geranylnitrile (11) and
oleonitrile (12) in 50 and 67% yield, respectively, where double
bonds remained unaltered.
Electronic and steric effects were evaluated trough different
substitution pattern on benzylic substrates (Table 3). Whereas
benzylamine gave benzonitrile as a sole product, introduction of
substituents onto the phenyl ring induced the formation of imines
as secondary product. In all cases, amines were totally
consumed to generate nitriles together with imines at different
ratios. The presence of a substituent in para is well tolerated by
the system giving good level of selectivity. In contrast, the
presence of a substituent in ortho- or meta-position led to a
decrease of selectivity (compare 17 with 18, 19 with 20 and 21
or 22 with 23). This lower selectivity can be attributed either to
the coordinating nature or the steric bulk of the ortho-groups,
which might interfere with the metallic centre. Electron-
withdrawing groups cause a greater loss of nitriles selectivity,
[a] Reaction conditions: amine (0.2 mmol), 1.25 mol% [Ru(p-cym)Cl2]2, and
1,2-diclhorobenzene (0.2 mL), 110 °C, 24h in open vessel under argon
atmosphere. Yields refer to isolated products.
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The reactivity of dibenzylamine and indoline has also been
studied under our experimental conditions (SI, Figure S8). The
use of [Ru(p-cym)Cl2]2 complex afforded the selective imine
product for dibenzylamine however the reaction was rather slow
compared to primary amine as only 25% conversion was
achieved after 24h of reaction. On the other hand, indoline was
Finally, NMR experiments were achieved by the sequential
addition of benzylamine to a CD2Cl2 solution of [Ru(p-cym)Cl2]2
and evolution was followed by 1H NMR over the time. After
addition of 2.4 equiv. of BnNH2, a rapid formation of neutral
complex Ru(p-cym)Cl2(BnNH2) was observed (Figure 1, c).25
The slight excess of benzylamine (signal at 3.88 ppm) allows the
system to evolve slowly towards the formation of a new species
1
cleanly converted into the sole indole as shown by both H NMR
and GC analyses.
1
(see d). H NMR spectra shows appearance of two new sets of
characteristic signals of coordinated benzylamine respectively at
δ 4.20 and 3.98 ppm for the benzylic protons and at 6.35 and
2.32 ppm for those of the NH2. In other hands, typical signals of
coordinated p-cymene were shifted downfield. The mixture of
the two complex did not evolved even after 4 days for which
[(BnNH2)Ru(p-cym)Cl2] is the major specie (see d). Finally,
addition of two more equivalents of amine lead to the total
conversion of the remaining [(BnNH2)Ru(p-cym)Cl2] in a new
ruthenium complex (Figure 1, e) and the complex did not
evolved even after 48h. 2D NMR analyses of the mixture
advocate the formation of a cationic [Ru(p-cym)Cl(BnNH2)2]+Cl-
complex on which two BnNH2 molecules are coordinated.
Noteworthy, doing the same experiment with octylamine
provided similar ruthenium cationic species (see SI).
To shed light on the reaction mechanism, we conducted
various experiments. First, the reaction profile of benzylamine
dehydrogenation catalysed by [Ru(p-cym)Cl2]2 followed over
time shows that the system requires a 3h induction period likely
to form the catalytic active species (see SI). This is also
consistent with our observation that in each catalytic test,
immediately after adding the amine substrate, the solution
turned yellow and then gradually dark-red after a few hours at
110 °C.
The homogeneous nature of the catalytic system was
confirmed by the addition of ≈ 300 equivalents of Hg(0) which
did not affected the formation of benzonitrile.23 In addition, a
poisoning experiment using 0.5 equivalent of 1,10-
phenanthroline vs. [Ru] induced an increase of imine formation
with a product distribution of 3/1 nitrile/imine. However, addition
of up to 50 equivalents of 1,10-phenanthroline did not poison the
reaction, but instead promoted the formation of the sole imine
product.
(f)
2eq BnNH2
(e)
(d)
Nitrile functional groups are well known in coordination
chemistry to be good ligand for transition metals thereby they
can contribute to the activity of the catalyst or compete with the
substrate and inhibit the system. Addition of 4 equivalents of
benzonitrile vs. [Ru] in the media led to a slight increase of the
reaction rate of benzylamine (51% conv. after 6h instead of 33%
conv.). However, competitive binding of nitrile to active Ru
species appeared while using a large excess of benzonitrile
(2000 equivalents vs. [Ru]) where only 62% conversion was
observed after 24h.
2.4 eq BnNH2
(c)
(b)
(a)
[Ru(cym)Cl2]2
In the presence of the only N-Benzylidenebenzylamine 5 and
the ruthenium complex, no reaction occurred. Additionally, the
reaction carried out in presence of imine 5 and n-octylamine
showed total consumption of the amine after 24h and produced
benzonitrile 4, n-octylnitrile 7 and the transimination product 27
(confirmed by both GC and 1H NMR spectra analysis) along
unreacted 5 (scheme 2).24 Other cross coupling imine and auto-
coupling products from n-octylamine were never observed. This
cross experiment indicates that the short-lived intermediate
Figure 1. In situ formation of [Ru(p-cym)Cl(BnNH2)2]+Cl-. (a) isolated complex
[Ru(p-cym)Cl2(BnNH2)]; (b) complex [Ru(p-cym)Cl2)]2; (c) addition of 2.4 equiv
of BnNH2; (d) after 19h; (e) after 4 days; (f) addition of 2 equiv of BnNH2,
spectrum after 19 h..
At 110°C, the well-defined complex [(BnNH2)Ru(p-cym)Cl2]
stayed totally unchanged. However, addition of 10 equivalents of
BnNH2 to reaction mixture lead to the total consumption of both
the [(BnNH2)Ru(p-cym)Cl2] complex and BnNH2; no more Ru(p-
aldimine
from
n-octylamine
undergo
quick
second
1
dehydrogenation step rather than the transamination process.
cym) species were detected by H NMR and we observed free
cymene ligand in solution along the formation of benzonitrile.
Same result was obtained starting with the [Ru(p-cym)Cl2]2
precursor. In each case, the characteristic N-H and C-H signals,
around 9-8 ppm, for the coordinated aldimine intermediate has
never been observed.26 We suggest that the coordination of the
amine is directly followed by a loss of H2 to afford an aldimine
intermediate which remains bound to the ruthenium center. This
species presumably undergoes a fast dehydrogenation reaction
Scheme 2. Competition experiment between imine 3 and octylamine under
oxidant free condition
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[15] (a) T. C. Johnson, D. J. Morris, M. Wills, Chem. Soc. Rev. 2010, 39, 81-
88; (b) S. Siddiki, T. Toyao, K. Shimizu, Green Chem. 2018, 20, 2933-
2952.
to afford a Ru-nitrile adduct. Alternatively, the aldimine may
react with free benzylamine to generate the imine by-product.
[16] A. Corma, J. Navas, M. J. Sabater, Chem. Rev. 2018, 118, 1410-1459.
[17] (a) K. N. T. Tseng, A. M. Rizzi, N. K. Szymczak, J. Am. Chem. Soc.
2013, 135, 16352-16355; (b) K. N. T. Tseng, N. K. Szymczak, Synlett
2014, 25, 2385-2389; (c) L. V. A. Hale, T. Malakar, K.-N. T. Tseng, P.
M. Zimmerman, A. Paul, N. K. Szymczak, Acs Catalysis 2016, 6, 4799-
4813; (d) D. Ventura-Espinosa, A. Marza-Beltran, J. A. Mata, Chem.
Eur. J 2016, 22, 17758-17766; (e) I. Dutta, S. Yadav, A. Sarbajna, S.
De, M. Holscher, W. Leitner, J. K. Bera, J. Am. Chem. Soc. 2018, 140,
8662-8666.
In summary, we have developed a straightforward access to
nitrile from amine by employing a commercially available
ruthenium precursor with no need of additional ligand. This
reaction features no oxidant or base and is highly selective with
alkylamine derivatives. Good activity was also observed with
benzyl amine albeit with some imine as by-product. Further
studies to improve the system are currently underway in our
laboratory.
[18] M. Grellier, S. Sabo-Etienne, Dalton Trans. 2014, 43, 6283-6286.
[19] (a) G. Franc, A. Jutand, Dalton Trans. 2010, 39, 7873-7875; (b) L. A.
Perego, R. Blieck, A. Groue, F. Monnier, M. Taillefer, I. Ciofini, L.
Grimaud, Acs Catalysis 2017, 7, 4253-4264.
Acknowledgements
[20] Reproducibility of the reaction selectivity requires well dried amine.
[21] The schlenk valve is put in the open position and connects to an argon
inlet via the vacuum ramp to allow the evacuation of the H2 formed
during the reaction
We gratefully acknowledge the funding from Région Grand Est.
Keywords: dehydrogenation • nitrile • acceptorless
dehydrogenation • ruthenium • homogenous catalysis
[22] The ODBC polar solvent improved the solubility of the active species
compared to toluene for which the formation of a black solid is always
observed during the reaction. 0.2 mL of ODCB was chosen as a
standard volume in part because it allowed better purification of the
product by chromatography compared to larger solvent volumes.
[23] (a) J. A. Widegren, R. G. Finke, J. Mol. Catal. A: Chem 2003, 198, 317-
341; (b) R. H. Crabtree, Chem. Rev. 2012, 112, 1536-1554.
[24] M. Ciaccia, S. Di Stefano, Org. Biomol. Chem. 2015, 13, 646-654.
[25] P. Govindaswamy, Y. A. Mozharivskyj, M. R. Kollipara, Polyhedron
2004, 23, 3115-3123.
[1]
(a) R. C. Larock, in: Comprehensive Organic Transformations: a Guide
to Functional Group Preparations, Wiley-VCH, Weinheim, 1989, pp
819–995. (b) A. J. Fatiadi, in: Preparation and Synthetic Applications of
Cyano Compounds, (Eds.: S. Patai, Z. Rappoport), Wiley-VCH, New
York, 1983.
[2]
[3]
[4]
(a) F. F. Fleming, Nat. Prod. Rep. 1999, 16, 597-606; (b) F. F. Fleming,
L. Yao, P. C. Ravikumar, L. Funk, B. C. Shook, J. Med. Chem. 2010, 53,
7902-7917.
[26] G. Albertin, S. Antoniutti, J. Castro, J. Organomet. Chem. 2010, 695,
574-579.
A. Kleemann, J. Engel, B. Kutscher, D. Reichert, in Pharmaceutical
Substance: Synthesis Patents, Applications, 4th edn., Georg Thieme
Verlag, Stuttgart, 2001
Pollak, P.; Romeder, G.; Hagedorn, F.; Gelbke, H.-P. Nitriles. In
Ullmann’s Encyclopedia of Industrial Chemistry; Wiley-VCH: Weinheim,
Germany, 2012
[5]
[6]
T. Sandmeyer, Ber. Dtsch. Chem. Ges. 1884, 17, 1633–1635.
K. W. Rosenmund, E. Struck, Ber. Dtsch. Chem. Ges. 1919, 2, 1749–
1756
[7]
[8]
G. B. Yan, Y. Zhang, J. B. Wang, Adv. Synth. Catal. 2017, 359, 4068-
4105.
(a) V. V. Zhdankin, P. J. Stang, Chem. Rev. 2008, 108, 5299-5358; (b)
T. Najam, S. S. A. Shah, K. Mehmood, A. U. Din, S. Rizwan, M. Ashfaq,
S. Shaheen, A. Waseem, Inorg. Chim. Acta 2018, 469, 408-423.
Sheldon, R. A.; Kochi, J. K. in Metal-Catalyzed Oxidations of Organic
Compounds; Academic Press: San Diego, 1981; pp 387-397
[9]
[10] M. T. Schumperli, C. Hammond, I. Hermans, Acs Catalysis 2012, 2,
1108-1117.
[11] (a) J. Kim, H. J. Kim, S. Chang, Angew. Chem. Int. Ed. 2012, 51,
11948-11959; (b) R. Ray, A. S. Hazari, G. K. Lahiri, D. Maiti,
Chemistry-an Asian Journal 2018, 13, 2138-2148.
[12] (a) F. Porta, C. Crotti, S. Cenini, G. Palmisano, J. Mol. Catal. 1989, 50,
333-341; (b) W. P. Griffith, B. Reddy, A. G. F. Shoair, M. Suriaatmaja, A.
J. P. White, D. J. Williams, J. Chem. Soc., Dalton Trans. 1998, 2819-
2825; (c) S. Yamazaki, Y. Yamazaki, Bull. Chem. Soc. Jpn. 1990, 63,
301-303; (d) S. Aiki, A. Taketoshi, J. Kuwabara, T.-a. Koizumi, T.
Kanbara, J. Organomet. Chem. 2011, 696, 1301-1304; (e) J. Kim, S. S.
Stahl, Acs Catalysis 2013, 3, 1652-1656.
[13] (a) G. E. Dobereiner, R. H. Crabtree, Chem. Rev. 2010, 110, 681-703;
(b) C. Gunanathan, D. Milstein, Science 2013, 341; (c) C. Chen, F.
Verpoort, Q. Y. Wu, RSC Advances 2016, 6, 55599-55607; (d) P.
Pandey, I. Dutta, J. K. Bera, Proc. Natl. Acad. Sci., India, Sect. A Phys.
Sci. 2016, 86, 561-579; (e) R. H. Crabtree, Chem. Rev. 2017, 117,
9228-9246.
[14] D. L. J. Broere, Physical Sciences Reviews 2018, 3.
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COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
Thierry Achard*, Julien Egly, Michel
Sigrist, Aline Maisse-Francois, Stéphane
Bellemin-Laponnaz*
Oxidant free conditions
[
R
]
Page No. – Page No.
2
u
(
p
l2
C
)
-
c
m
R
NH2
y
y
m
c
-
)
p
C
l2
]
(
u
R
[
2
Easy ruthenium-catalysed oxidation
of primary amines to nitriles under
oxidant free conditions
R
l
=
y
k
A
r
l
A
o
m
=
a
R
t
i
c
Alk CN
Ar CN
Oxidant- and base-free system: [Ru(p-cym)Cl2]2 is able to catalyse the transformation of primary amines into nitriles via a double
dehydrogenation under mild conditions and without extra ligand, oxidant or base.
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