Ruthenium(II)-Complex-Catalyzed Acceptorless Double Dehydrogenation of Primary Amines to Nitriles

Article abstract of DOI:10.1055/s-0040-1708016

Acceptorless dehydrogenative oxidation of primary amines into nitriles using an in situ complex derived from commercially available dichloro(1,5-cyclooctadiene) ruthenium(II) complex and simple hexamethylenetetramine has been demonstrated. The synthetic protocol is highly selective and yields the nitrile compounds in moderate to excellent yields and produces hydrogen as the sole byproduct.

Full text of DOI:10.1055/s-0040-1708016

SYNLETT
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© Georg Thieme Verlag Stuttgart · New York
2020, 31, 1073–1076
letter
1073
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M. Kannan, S. Muthaiah
Letter
Synlett
Ruthenium(II)-Complex-Catalyzed Acceptorless Double
Dehydrogenation of Primary Amines to Nitriles
Muthukumar Kannan
N
Senthilkumar Muthaiah*
0
0
0
0-0
0
0
2-7
0
7
3-
6
9
1
6
Cl
Cl
Ru
N
N
R
N
+
2 H2
R
NH2
N
Department of Chemistry, National Institute of Technology
Kurukshetra, Kurukshetra-136119, Haryana, India
msenthil@nitkkr.ac.in
n
no acceptor
toluene, reflux, 24 h
R = alkyl, aryl
12 examples
up to 92% yield
Received: 04.02.2020
Accepted after revision: 27.03.2020
Published online: 16.04.2020
the metal-catalyzed dehydrogenative oxidation was found
to be very superior compared to aerobic oxidation and oth-
er traditional methods as it is very clean, producing hydro-
gen as the sole byproduct, and has high atom economy
(Scheme 1). Moreover, the metal-catalyzed dehydrogena-
tive oxidation methodology was identified as a potential
candidate in the field of hydrogen storage and transporta-
tion as amines are considered as liquid organic hydrogen
carriers (LOHCs).5
DOI: 10.1055/s-0040-1708016; Art ID: st-2020-b0068-l
Abstract Acceptorless dehydrogenative oxidation of primary amines
into nitriles using an in situ complex derived from commercially avail-
able dichloro(1,5-cyclooctadiene) ruthenium(II) complex and simple
hexamethylenetetramine has been demonstrated. The synthetic proto-
col is highly selective and yields the nitrile compounds in moderate to
excellent yields and produces hydrogen as the sole byproduct.
Key words ruthenium, amine, nitrile, dehydrogenation
[Ru]/O2
[Ru]
R
N
R
N
R
NH2
H2O
Aerobic Oxidation
H2
Dehdrogenative Oxidation
Nitrile compounds play a vital role in the field of syn-
thetic chemistry for the synthesis of several industrially im-
portant products.1 As a result; several methods are avail-
able for the synthesis of nitrile compounds. Some of the im-
portant traditional methods available for the synthesis of
nitrile compounds include Sandmeyer-type reaction, am-
moxidation reaction, Rosenmund–von Braun reaction, and
other methods which use stoichiometric amounts of oxi-
dizing agents such as MnO2, HgO–I2, DDQ, IBX, S, and many
others.2,3 All the traditional methods suffer from several
drawbacks such as the use of toxic reagents/reactants, poor
atom economy, and harsh reaction conditions.2,3 Among
several existing methods for the synthesis of nitrile com-
pounds from a variety of starting materials, oxidation of
amines using transition-metal catalysts provides direct ac-
cess. The transition-metal-catalyzed oxidation of amines
involves two different pathways, namely aerobic oxidation
and dehydrogenative oxidation. The aerobic oxidation of
amines works in the presence of transition-metal catalyst
in combination with an external oxygen source and pro-
duces water as the side product.4 Though, this method is
very efficient in producing nitriles, sometimes it suffers
from selectivity issues forming other possible side product
such as amide.4a The second methodology which involves
Scheme 1 Ruthenium-catalyzed oxidation of primary amine
Notwithstanding its potential applications, the reported
catalyst systems for the dehydrogenation of amines, especial-
ly the dehydrogenation of primary amine to form nitriles,
are scarce. To the best of our knowledge only three catalyst
systems are available in the literature for the acceptorless
and dehydrogenative oxidation of primary amines to form
nitrile compounds. The complexes are pyridine-based PNN-
pincer ruthenium complex by Szymczak and co-workers,6
Ru(p-cymene) system reported by Bera and co-workers,7
and [Ru(benzene)Cl2]2 reported by our group (Scheme 2).8
In transition-metal-catalyzed organic transformations,
the role of additives is crucial in deciding the selectivity and
efficiency of the catalyst system. The added additive works
in tandem with metal catalyst by providing different reac-
tion pathway by activating catalyst and/or substrate(s).9 It
has been reported in the literature that hexamethylenete-
tramine (HMTA) upon decomposition can act as a source of
small molecules such as NH3, H2, HCN, HCHO, CO, CO2, and
many others, which makes HMTA an interesting molecule
in organic synthesis.10 Recently, we have reported the first
© 2020. Thieme. All rights reserved. Synlett 2020, 31, 1073–1076
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

1074
M. Kannan, S. Muthaiah
Letter
Synlett
Table 1 Optimization of Reaction Conditions for Catalytic Dehydroge-
nation of Benzylamine (3a)
Previous Reports
PPh3
N
[Ru(COD)Cl2]n (1)
HMTA (2)
But
NH
Cl
Cl
Cl
N
N
N
Ru
+
2 H2
N
Ru
Ph
N
N
Ru
Ph
NH2
N
toluene, 24 h
Ru
Cl
N
H
Cl
3a
4a
PPh3
Entry
[Ru]
HMTA
Solvent
Temp (°C) Time (h) Yield of
Szymczak et al. 2013
This Work
Bera et al. 2018
Our group 2019
(mol%) (mol%)
4a (%)a
N
1
2
5
–
toluene
toluene
toluene
toluene
toluene
toluene
THF
110
110
110
110
110
110
64
24
24
24
24
24
24
24
24
24
6
27
–
Cl
+
Ru
[Ru]
N
N
Cl
–
5
R
N + 2 H2
no acceptor
R
NH2
N
additive
n
3
0.5
1
0.5
1
56
70
85
97
0
commercially available
catalyst and additive
4
5
2
2
Scheme 2 Ruthenium-catalyzed double dehydrogenation of amines
6
3
3
7
3
3
example of hexamethylenetetramine (HMTA) being simul-
taneously acting as both base as well as hydride donor in
[Ru(benzene)Cl2]2-catalyzed acceptorless amine dehydro-
genation reaction.8 In view of extending the chemistry of
HMTA as a cheap and versatile additive, we explored its re-
activity in combination with other ruthenium complexes.
Herein, we report the efficient conversion of primary
amines into nitriles using the commercially available
[Ru(COD)Cl2]n as the pre-catalyst and simple HMTA as the
additive. Experimental studies proved that the oxidation of
primary amines to nitriles involves double dehydrogena-
tion pathway with the evolution of hydrogen as the sole by-
product.
8
3
3
CH2Cl2
toluene
toluene
toluene
40
2
9
3
3
80
54
42
56
10
11
3
3
80
3
3
80
12
a GC yields using dodecane as the internal standard and average of at least
two runs.
After optimizing the reaction conditions for the double
dehydrogenation of amines to form nitriles, we explored
the substrate scope of our catalyst system as shown in Table
2.
Initially, in view of testing the electronic effect on the
yield of nitrile product, a series of substituted benzylamine
substrates were tested. The presence of electron-donating
substituents such as methyl (3b) and methoxy (3c) groups
in the para position gave the corresponding nitrile products
4b and 4c, respectively, in excellent yields (Table 2, entries 2
and 3). The slight decrease in the yields of nitrile product
was observed when electron-withdrawing substituents,
namely chloro (3b), fluoro (3e), and nitro (3f), were present
in the para position (entries 4–6). Moreover, the halogen
and nitro groups were retained in the nitrile products indi-
cating the very good functional group tolerance of our cata-
lyst system. The presence of substituents such as methyl
(3g) and chloro (3h) groups in the ortho position gave the
nitrile products 4g and 4h in moderate yields, showing the
developed catalyst system is sensitive towards the steric
factor (entries 7 and 8). The dehydrogenation of few alkyl
amines was also tested and all of them gave the correspond-
ing nitrile products in very good yields (entries 9–11).
Encouraged by the activity of [Ru(benzene)Cl2]2 for the
dehydrogenative oxidation of amines, we tested the activity
of [Ru(COD)Cl2]n (1) in combination with HMTA (2) for the
dehydrogenation of amines. The dehydrogenation of ben-
zylamine (3a) to form benzonitrile (4a) was taken as the
model reaction, and several reactions were carried out to
optimize the reaction conditions as depicted in Table 1.
Initially, 5 mol% of 1 was tested for the conversion of 3a
into 4a in the absence of any additive under toluene reflux
conditions for 24 h, which resulted in the formation of ni-
trile product 4a in poor yield (Table 1, entry 1). When
HMTA (2) was employed in the absence of Ru complex, no
formation of product was observed (entry 2). However,
when the activity of 0.5 mol% of 1 combination with 0.5
mol% 2 was tested, it led to increase in the yield of 4a (entry
3). Further increase in catalyst/additive loading resulted in
the increased yield of the product, and excellent yields were
obtained while using 3 mol% both 1 and 2 (entries 4–6). Af-
ter identifying the suitable catalyst and additive ratio and
amount, other parameters such as reaction solvent, tem-
perature, and time were optimized and identified that tolu-
ene reflux conditions for 24 h were ideal for the dehydroge-
native oxidation of amine to form nitrile (entries 7–11).
[Ru(COD)Cl2]n (1)
HMTA (2)
CN
NH2
+
2 H2
toluene, 24 h
H2N
H2N
3l
4l 74%
Scheme 3 Dehydrogenation of 4-aminobenzylamine
© 2020. Thieme. All rights reserved. Synlett 2020, 31, 1073–1076

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M. Kannan, S. Muthaiah
Letter
Synlett
In order to check the selectivity and functional group
tolerance, the double dehydrogenation of 4-aminobenzyl-
amine (3l) having both H2N–CR2 and H2N–CH2– groups was
attempted using the present catalyst system (Scheme 3).
The reaction resulted in the formation of 4-aminobenzoni-
trile (4l) as the only product in good yield. This result
shows the very good selectivity of our catalyst system. In
addition, this also proves the oxidation reaction involving
the dehydrogenative pathway without forming 4-nitroben-
zonitrile, which is possible during aerobic oxidation in the
presence of any external oxygen source.
mol%), benzylamine, and cyclohexene in 1:10 equivalent
ratio were taken heated at 115 °C for 24 h using toluene as
the solvent (Scheme 4). This resulted in the formation of cy-
clohexane in 24% yield.
[Ru(COD)Cl2]n (1)
HMTA (2)
Ph
N
+
+
Ph
NH2
toluene
115 °C, 24 h
3a
4a 49%
24%
Scheme 4 Dehydrogenation of benzylamine in the presence of cyclo-
hexene
Further, to confirm the evolution of hydrogen gas and
dehydrogenative pathway, the double dehydrogenation of
benzylamine was conducted using the present catalyst sys-
tem in the presence of a hydrogen acceptor such as cyclo-
hexene. In a typical closed-vessel reaction, 1 (3 mol%), 2 (3
The above reaction suggested that the reaction involved
hydrogen evolution and followed the dehydrogenative
pathway (Scheme 4). Based on the literature report and our
experimental results, the following mechanism has been
proposed for the double dehydrogenation of primary
amines to form nitrile compounds (Scheme 5). In our previ-
ous report we proved the formation of Ru(H)2 species as the
catalytically active species during dehydrogenation of pri-
mary amines while using [Ru(benzene)Cl2]2 as the pre-cat-
alyst and HMTA as the additive.8 Further, we experimental-
ly proved that HMTA acted simultaneously as a source of
base as well as hydride donor. According to the proposed
mechanism the catalytically active species [Ru(H)2] (A) is
generated from a reaction between complex 1 and additive
2. The active catalyst A upon reaction with primary amine,
followed by elimination of hydrogen molecule lead to the
formation of amine-coordinated Ru–hydride complex B.
The complex B undergoes -elimination to form the imine-
coordinated Ru–dihydride intermediate C. The formation of
imine-coordinated Ru complex was observed in the in situ
1H NMR study of dehydrogenation of benzylamine using
the present catalyst system (Figure S13 in the Supporting
Information). The complex C upon elimination of hydrogen
molecule and -elimination resulted in the formation of ni-
trile-coordinated ruthenium complex D. The complex D
further undergoes reductive elimination to yield the nitrile
product and regenerate the active catalyst A.
Table 2 Dehydrogenative Oxidation of Amines to Nitrilesa
[Ru(COD)Cl2]n (1)
HMTA (2)
+
2 H2
R
N
R
NH2
toluene
reflux, 24 h
3
4
Entry
Substrate 3
Product 4
Isolated yield (%)b
CN
NH2
R
R
1
2
3
4
5
6
3a R = H
4a
4b
4c
4d
4e
4f
88
92
90
82
80
79
3b R = CH3
3c R = OCH3
3d R = Cl
3e R = F
3f R = NO2
CN
NH2
7
8
9
73
70
83
3g
3h
4g
CN
Cl
NH2
Cl
N
Br
4h
4i
[Ru(COD)Cl2]n
+
Ph
N
N
N
NH2
CN
NH2
H2
R
[Ru(H)2]
R
N
A
3i
3j
CN
CN
Overall Reaction
NH2
4
4
5
10
11
80
82
Ru-H
R
N Ru(H)2
2 H2
R
N
N
R
R
NH2
4j
H
D
B
3
4
H2
NH2
5
Ru(H)2
N
H
R
4k
3k
a Reactions were carried out with amine substrate (0.47 mmol),
Ru(COD)Cl2 (3 mol%), and HMTA (3 mol%) in toluene (0.6 mL) under reflux.
b Isolated yields and average of at least two runs.
C
Scheme 5 Mechanism for the oxidation of amine to nitrile
© 2020. Thieme. All rights reserved. Synlett 2020, 31, 1073–1076

1076
M. Kannan, S. Muthaiah
Letter
Synlett
In conclusion, the double dehydrogenation of several
primary amines to form nitrile products using an in situ
catalyst system generated from [Ru(COD)Cl2]n as the pre-
catalyst and HMTA as the additive was developed.11–13 The
present catalyst system is highly atom economic as it avoids
the use of any oxidizing agent/hydrogen acceptor and yield-
ed the nitrile products even in good to excellent yields. The
mechanism studies revealed that the reaction involves de-
hydrogenative pathway with the evolution of hydrogen
molecule.
42, 1480. (e) Ray, R.; Hazari, A. S. Lahiri G. K.; Maiti, D. Chem.
Asian J. 2018, 13, 2138. (f) Ray, R.; Hazari, A. S.; Chandra, S.;
Maiti, D.; Lahiri, G. K. Chem. Eur. J. 2018, 24, 1067. (g) Ray, R.;
Chandra, S.; Maiti, D.; Lahiri, G. K. Chem. Eur. J. 2016, 22, 8814.
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(6) (a) Tseng, K.-N. T.; Rizzi, A. M.; Szymczak, N. K. J. Am. Chem. Soc.
2013, 135, 16352. (b) Hale, L. V. A.; Malakar, T.; Tseng, K.-N. T.;
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W.; Bera, J. K. J. Am. Chem. Soc. 2018, 140, 8662.
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(9) (a) Ananikov, V. P. Understanding Organometallic Reaction
Mechanisms and Catalysis: Computational and Experimental
Tools; Wiley-VCH: Weinheim, 2015. (b) Hong, L.; Sun, W.; Yang,
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Świerkosz, B. Top. Catal. 2002, 21, 35.
Funding Information
The authors acknowledge TEQIP-III for financial assistance in the
form of a fellowship to M.K.()
(10) (a) Kwak, Y.; Matyjaszewski, K. Polym. Int. 2009, 58, 242.
(b) Caillault, X.; Pouillaoua, Y.; Barrault, J. J. Mol. Catal. A: Chem.
1995, 103, 117. (c) Dreyfors, J. M.; Jones, S. B.; Sayed, Y. Am. Ind.
Hyg. Assoc. J. 1989, 50, 579. (d) Cheng, C.; Gong, S.; Fu, Q.; Shen,
L.; Liu, Z.; Qiao, Y.; Fu, C. Polym. Bull. 2011, 66, 735.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0040-1708016.
S
u
p
p
orit
n
gInformati
o
n
S
u
p
p
orti
n
gInformati
o
n
(11) General Procedure for the Dehydrogenation of Amine
Ruthenium(II) chloride 1,5-cyclooctadiene 1 (3 mol%), HMTA (2,
3 mol%), amine 3 (0.25 mL), and dry toluene (1.0 mL) were
placed in a Schlenk tube. The reaction mixture was stirred
under open conditions to nitrogen and refluxed for 24 h. After
completion of the reaction all toluene were evaporated under
vacuo, the oxidized products 4 were isolated from crude
mixture with the help of column chromatography using hex-
ane/EtOAc as eluent. The formation of products was confirmed
by comparing the 1H NMR data with literature reports.
(12) General Procedure for the Dehydrogenation of Benzylamine
3 in the Presence of Cyclohexene
References and Notes
(1) (a) Pollak, P.; Romeder, G.; Hagedorn, F.; Gelbke, H. -P. Nitriles,
In Ullmann’s Encyclopedia of Industrial Chemistry; Wiley-VCH:
Weinheim, 2012. (b) Kleemann, A.; Engel, J.; Kutscher, B.;
Reichert, D. Pharmaceutical Substance: Synthesis Patents, Appli-
cations, 4th ed; Thieme: Stuttgart, 2001. (c) Larock, R. C. In Com-
prehensive Organic Transformations: A Guide to Functional Group
Preparations; Wiley-VCH: Weinheim, 1989, 819–995. (d) Layer
R, W. Chem. Rev. 1963, 63, 489. (e) Belowich, M. E.; Stoddart, J. F.
Chem. Soc. Rev. 2012, 41, 2003. (f) Martin, S. F. Pure Appl. Chem.
2009, 81, 195.
In a 50 mL closed-vessel reactor, ruthenium(II) chloride 1,5-
cyclooctadiene 1 (0.004 g, 0.013 mmol), HMTA (2, 0.002 g,
0.013 mmol), amine 3 (0.05 mL, 0.5mmol), cyclohexene (0.4
mL, 5 mmol), and dry toluene (0.6 mL) were taken. The result-
ing mixture was heated at 110 °C for 24 h. After completion of
the reaction, the solution was cooled to room temperature and
extracted with CH2Cl2 then analyzed through gas chromatogra-
phy; yield of benzonitrile 4 49% and cyclohexane 24%.
(2) (a) Grasselli, R. K. Catal. Today 1999, 49, 141. (b) Sandmeyer, T.
Ber. Dtsch. Chem. Ges. 1885, 18, 1496. (c) Sandmeyer, T. Ber.
Dtsch. Chem. Ges. 1885, 18, 1492. (d) Rosenmund, K. W.; Struck,
E. Ber. Dtsch. Chem. Ges. 1919, 52, 1749.
(3) (a) Nicolaou, K. C.; Mathison, C. J. N.; Montagnon, T. Angew.
Chem. Int. Ed. 2003, 42, 4077. (b) Aoyama, T.; Sonoda, N.;
Yamauchi, M.; Toriyama, K.; Anzai, M.; Ando, A.; Shioiri, T.
Synlett 1998, 35. (c) Ochiai, M.; Kajishima, D.; Sueda, T. Hetero-
cycles 1997, 46, 71. (d) Orito, K.; Hatakeyama, T.; Takeo, M.;
Uchiito, S.; Tokuda, M.; Suginome, H. Tetrahedron 1998, 54,
8403. (e) Fu, P. P.; Harvey, R. G. Chem. Rev. 1978, 78, 317.
(4) (a) Tang, R.; Diamond, S. E.; Neary, E. R. N.; Mares, F. J. Chem.
Soc., Chem. Commun. 1978, 13, 562. (b) Bailey, A. J.; James, B. R.
Chem. Commun. 1996, 20, 2343. (c) Ray, R.; Chandra, S.; Yadav,
V.; Mondal, P.; Maiti, D.; Lahiri, G. K. Chem. Commun. 2017, 53,
4006. (d) Yamaguchi, K.; Mizuno, N. Angew. Chem. Int. Ed. 2003,
(13) General Procedure for in situ 1H NMR Study to Show Forma-
tion of Imine Intermediate
In N2 atmosphere benzylamine 3 (0.05 mL, 0.46 mol), ruthe-
nium(II) chloride 1,5-cyclooctadiene (1, 0.004 g, 3 mol%) HMTA
(2, 0.002 g, 3 mol%), and toluene-d8 as a solvent (0.4 mL) were
taken in the NMR tube. The reaction mixture was heated at
110 °C for 12 h, and then the reaction mixture was cooled to
room temperature before collecting the NMR data.
© 2020. Thieme. All rights reserved. Synlett 2020, 31, 1073–1076