Synthesis, characterization, catalytic and biological application of half-sandwich ruthenium complexes bearing hemilabile (κ2-: C, S)-thioether-functionalised NHC ligands

Article abstract of DOI:10.1039/c9dt04825a

A series of cationic Ru(ii)(η⁶-p-cymene) complexes with thioether-functionalised N-heterocyclic carbene ligands have been prepared and fully characterized. Steric and electronic influence of the R thioether substituent on the coordination of the sulfur atom was investigated. The molecular structure of three of them has been determined by means of X-ray diffractrometry and confirmed the bidentate (κ²-C,S) coordination mode of the ligand. Interestingly, only a single diastereomer, as an enantiomeric couple, was observed in the solid state for complexes 1c, 1i and 1j. DFT calculations established a low energy inversion barrier between the two diastereomers through a sulfur pyramidal inversion pathway with R donating group while a dissociative/associative mechanism is more likely with R substituents that contain electron withdrawing group, thus suggesting that the only species observed by the ¹H-NMR correspond to an average resonance position of a fluxional mixtures of isomers. All these complexes were found to catalyse the oxydant-free double dehydrogenation of primary amine into nitrile. Ru complex bearing NHC-functionalised S-tBu group was further investigated in a wide range of amines and was found more selective for alkyl amine substrates than for benzylamine derivatives. Finally, preliminary results of the biological effects on various human cancer cells of four selected Ru complexes are reported.

Full text of DOI:10.1039/c9dt04825a

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Bellemin-Laponnaz, A. I. I. Poblador Bahamonde, W. Chen, J. Egly and A. Maisse-François, Dalton Trans.,
2020, DOI: 10.1039/C9DT04825A.
Volume 46
Number 10
March 2017
Pages 3073-3412
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ISSN 0306-0012
COMMUNICATION
Douglas W. Stephen et al.
N-Heterocyclic carbene stabilized parent sulfenyl, selenenyl,
and tellurenyl cations (XH , X = S, Se, Te)
+
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DOI: 10.1039/C9DT04825A
Dalton Transactions
ARTICLE
Synthesis, characterization, catalytic and biological application of
half-sandwich ruthenium complexes bearing hemilabile (κ2–C,S)-
thioether-functionalised NHC ligands.
Received 00th January 20xx,
Accepted 00th January 20xx
a
a
*b
a
DOI: 10.1039/x0xx00000x
Weiguang Chen, Julien Egly, Amalia I. Poblador-Bahamonde, Aline Maisse-Francois, Stéphane
*a
*a
Bellemin-Laponnaz, Thierry Achard,
6
A series of cationic Ru(II)(η -p-cymene) complexes with thioether-functionalised N-heterocyclic carbene ligands have been
prepared and fully characterized. Steric and electronic influence of the R thioether substituent on the coordination of the
sulfur atom was investigated. The molecular structure of three of them has been determined by means of X-ray
2
diffractrometry and confirmed the bidentate (κ -C,S) coordination mode of the ligand. Interestingly, only a single
diastereomer, as an enantiomeric couple, was observed in the solid state for complexes 1c, 1i and 1j. DFT calculations
established a low energy inversion barrier between the two diastereomers through a sulfur pyramidal inversion pathway
with R donating group while a dissociative/associative mechanism is more likely with R substituents that contain electron
1
withdrawing group, thus suggesting that the only species observed by the H-NMR correspond to an average resonance
position of a fluxional mixtures of isomers. All these complexes were found to catalyse the oxydant-free double
dehydrogenation of primary amine into nitrile. Ru complex bearing NHC-functionalised S-tBu group was further
investigated in a wide range of amines and was found more selective for alkyl amine substrates than for benzylamine
derivatives. Finally, preliminary results of the biological effects on various human cancer cells of four selected Ru
complexes are reported.
effectiveness to amination reaction as recently disclose by
9
Introduction
Huynh et al. Interestingly, addition of PPh3 is frequently
required with monodentate NHC-based systems to enhance
the catalytic activity.
an additional donor group (typically P, O or N) have become an
important class of bidentate ligand due to the possible
hemilabile behaviour of their Lewis base moiety. Few
7
a, 7e, 8a, 8c, 8e, 8f
N-functionalized NHCs with
1
2
Since the pioneering work of Murahashi and Milstein on
acceptorless dehydrogenation (AD) type amidation, numerous
groups have explored this exciting catalytic-type reaction.
Ruthenium has been established as the metal of choice for this
highly atom-economic and environmentally friendly
transformation.4 Consequently, a wide-array of Ru-based
catalyst systems have been developed for the
dehydrogenation of alcohol.
complexes bearing N-Heterocyclic carbenes (NHCs), as
synthetically accessible and highly tuneable ligand, either
3
1
0
1
1
successful examples of bidentate NHC-pyrimidine,
-
naphtylridine, -picolyl,13 -phosphine and phenyl (CNHCC)8l, 15
Ru(arene) complexes have been reported for such
acceptorless/borrowing hydrogen reactions.
1
2
14
3
a, 3b, 3d, 5
In this context, Ru-
Applying this AD strategy on amine is providing access to very
important class of molecule namely: imine and nitrile.
contrast with alcohols, highly selective dehydrogenations of
amine mediated by transition metal are rare.
the double dehydrogenation of primary amines to produce
2
nitriles and H gas as the sole by-product are even scarcer.
1
6
17, 18
In
6
7
8
generated in situ or well-defined, are particularly interesting
for this process. It is noteworthy to mention that NHC-Ru
catalytic system has been successfully applied with great
3
e, 19
Reports on
1
9
Among those examples, catalysts achieve either low
a) Institut de Physique et Chimie des Matériaux de Strasbourg, Université de
Strasbourg-CNRS UMR7504, 23 rue du Loess, BP 43, 67034 Strasbourg Cedex 2,
France. E-mail: thierry.achard@ipcms.unistra.fr; bellemin@unistra.fr
20
conversion or require exogenous additives (bases and/or
2
1
sacrificial hydrogen acceptor) with high reaction temperature
b) Department of Organic Chemistry, University of Geneva, 30 Quai Ernest and only few avoid the use of excess oxidant or aerobic
Ansermet, 1211 Geneva, Switzerland. E-mail:
Amalia.pobladorbahamonde@unige.ch
22
conditions. Furthermore, the competition between the
†
Electronic Supplementary Information (ESI) available: General experimental second dehydrogenation and the transamination pathway
procedures, additional schemes and figures, characterization data and NMR
spectra. crystallographic information, and atomic coordinates of the optimized
species. CCDC 1957068 (1c), 1957070 (1i) and 1957069 (1j). For ESI and
3e,
4
often lead to selectivity issues.
Nevertheless, this
straightforward strategy represents a much delicate and
crystallographic data in CIF or other electronic format, see greener alternative to classic nitrile syntheses which often
DOI: 10.1039/x0xx00000x
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Pleas eD da lot o nn oT tr aa nd sj au c st ti o mn sa rgins
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Journal Name
suffer from certain limitation such as harsh reaction condition, thiolate (see ESI for details). NHC-ruthenium complexes 1a-l
View Article Online
2
2-23
DOI: 10.1039/C9DT04825A
were obtained from corresponding imidazolium salts a-l by a
use of toxic agent, poor selectivity or poor atom economy.
So far, we are aware of only two examples for selective base- classic transmetalation pathway between the silver-carbene
and oxidant-free acceptorless double dehydrogenation of intermediate and [Ru(p-cym)Cl
2
]
2
. Subsequently, the anion
-
-
primary amines. The first example, developed by Szymczak and exchange between Br and PF
6
was followed by purification by
II
co-workers, is implying a Ru -(NNN) pincer complex which chromatography on silica gel to afford complexes 1a-j in good
2
4
highly favoured the nitrile pathway. The second one, recently yields (Figure 1).
expose by our group, is describing the use of simple [Ru(p- All complexes were obtained as orange to dark orange
2
5
2 2
cym)Cl ] as pre-catalyst. The addition of a strong base was microcrystalline powder and are air-stable in solid state. The
found necessary to achieve both high reactivity and selectivity formation of the [(NHC)Ru(p-cym)Cl][PF
6
] complexes 1a-l was
II
for the Ru -pyrazole/t-BuOK catalytic system described by Bera established by the disappearance of the typical proton signal
and co-workers.26 Very recently, the combination of an between δ 9–11 ppm assigned to the 2H-imidazolium in the H
external base/hydride source (hexamethylenetetramine) and NMR spectrum and also by the appearance of a signal between
1
1
3
2 2
the [Ru(p-cym)Cl ] pre-catalyst, reported by Mathaiah et al., δ 165–170 ppm in the C-NMR spectrum, which corresponds
generate good nitrile selectivity even for benzylamine to the ruthenium carbene carbon. The analytical data (HRMS,
derivatives.27 Finally, various well defined monodentate NHC-
1
H-NMR) advocated for the coordination of NHC in a chelate
2
Ru catalysts have been developed by Mata et al. for this κ -(C,S) fashion which was later unambiguously confirmed by
2
8
36
transformation albeit with moderate nitrile selectivity.
X-ray analysis on single crystal (vide infra).
In this context, we wondered if the straight formation of
coordinatively more rigid cationic complexes using bidentate
NHC ligands instead of triphenylphosphine could generate
more active and robust catalysts. Among the different types of
donor-functionalized NHC hybrids ligands (N, O, and P), S-
Figure 1. Synthesis of cationic chelated ruthenium complexes 1a-l.
PF6
Me
iPr
R
S
1) Ag2O (0.5 equiv.)
CH Cl
N
N
2
2
Ru
N
functionalized NHCs still remain an undeveloped class of
Cl
Br
2) [Ru( -cymene)Cl ]
p
2 2 Bn
S
R
ligands.1
0e, 29
Interestingly, thioether-functionalized NHCs,
C
3) KPF6, SiO2
N
3
0
31
32
33
31a, 34
associated to transition metal (Cu, Ni, Pd, Pt, Rh
&
Ph
3
4b
Ru ), have proven to be efficient in several catalytic
a-l
1a-l
system.3
0-31, 32c, 32e, 32j, 32l, 33c
Among these, only one NHC-
Ru(cym) thioether catalyst was reported and applies to the
catalytic hydrogenation of styrene and 1-dodecene.
Herein we report the synthesis of a series of bidentate
thioether-functionalized N-heterocyclic carbenes precursors
with various –SR substituents. The corresponding cationic
R = -Et 1a (90%)
R =
OMe
Br
(95%)
(97%)
1
h
3
5
R = -Cy 1b (60%)
R = -tBu 1c (82%)
R = -Ad 1d (65%)
R = -C H 1e (64%)
R =
R =
R =
1
i
8
17
NHC-ruthenium complexes were prepared from [Ru(p-
NO2 1j (95%)
CF3 1k (88%)
R = -Ph 1f (73%)
2
cym)Cl ]
2 2
generating exclusively chelate complexes with a κ -
(C,S) coordination mode. The stereochemistry issue of
R =
Me
complexes were studied by a combination of variable
1
temperature (VT) H-NMR experiments, X-ray diffraction
CF3
1
g (95%)
studies and DFT calculations. Studies on the catalytic activity
and selectivity of these NHC-Ru complexes have been
conducted on the double dehydrogenation of amine without
the use of any additional oxidant. Under optimized conditions,
alkyl amines were transformed into nitrile with good
selectivity. Finally, the cytotoxicity of relevant NHC-Ru
complexes was evaluated on various cancer cell-lines.
R =
l (90%)
1
CF3
1
The H-NMR spectra of all complexes compared to the spectra
of imidazolium precursors display a marked difference in the
region between 2.4 and 4.9 ppm which correspond to the -
Results and discussion
NCH
2
CH
2
S- moiety. This observation is consistent with ligands
Synthesis and characterization of the cationic C,S-chelated
ruthenium complexes (1a-l)
2
that bind in a κ -(C,S)-chelating fashion, rendering the -CH
2
N-
and -CH
2
S- protons diastereotopic in the newly formed
and
are now split into two sets of two different multiplets. It
Reaction of benzyl imidazole with 1,2-dibromoethane provided is observed, for each case, that one of the methylene N-CH
The S-functionalized imidazolium precursors a-l have been metallacycle. The signals of the two protons of each N-CH
synthesized in two steps starting from benzyl imidazole. S-CH
2
2
2
1
-benzyl-3-bromoethylimidazolium bromide, which was next and S-CH
2
protons is slightly deshielded while the other one is
quantitatively functionalized by reacting with the desired
2
| J. Name., 2012, 00, 1-3
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ARTICLE
strongly shielded compared to imidazolium precursor (Δδ (b)
0.07/-0.8 ppm for S-CH and Δδ +0.11/-0.65 ppm for N-CH ).
View Article Online
DOI: 10.1039/C9DT04825A
+
2
2
Surprisingly, instead of a complex diastereomeric mixture that
would result of the presence of two stereogenic centers on the
sulfur and the metal center and associated to possible dynamic
3
3a, 37,38
processes namely sulphur inversion or its hemilability,
in all cases only one set of signals is observed in solution by the
1
H-NMR. The situation could be even more complicated
considering the formation of the six-membered ring between
metal and ligand whose different conformations could
3
9
generate as well a dynamic process in solution.
(c)
X-ray analyses
Single crystals suitable for X-ray diffraction analysis of 1c, 1i
and 1j were obtained by slow diffusion of diethyl ether into
concentrated solution of complexes in dichloromethane (1/3).
The molecular structure of the three complexes are depicted
in Figure 2 along with key bond lengths and bond angles.40 All
these complexes display the expected three-legged piano-stool
geometry around the ruthenium center. As a result of the
coordination of the pro-chiral thioether, two stereocenters are
present and consequently a diastereomeric mixture may be
expected. For the three structures, only one enantiomeric pair
Ru s S
(R S /SRuR
) of complex was found in the solid state.41 The R
group of the thioether is oriented in anti-position with respect Figure 2. Molecular structure of ruthenium NHC complexes 1c, 1i and 1j. Selected bond
distances (Å) and angles (°): 1c (a) CCDC n° 1957068 : Ru(1)-C(1), 2.075(7); Ru(1)-S(1),
to the p-cymene ligand as a consequence of steric repulsions.
This geometry forces the thioether to adopt a single
2
.398(2); R(1)-Cl(1), 2.407(2); Ru-Cymcent(1.721); Cl(1)-Ru(1)-S(1), 95.27(7); S(1)-Ru(1)-
C(1), 90.3(2); C(1)-Ru(1)-Cl(1), 86.8(2). 1i (b) CCDC n° 1957070: Ru(1)-C(1), 2.050(2);
configuration and thus disfavoured the formation of the Ru(1)-S(1), 2.384(4); R(1)-Cl(1), 2.395(3); Ru-Cymcent(1.720); Cl(1)-Ru(1)-S(1), 91.2(1);
S(1)-Ru(1)-C(1), 89.1(4); C(1)-Ru(1)-Cl(1), 87.6(4). 1j (c) CCDC n°1957069 : Ru(1)-C(1),
s S
enantiomeric couple RRuR /SRuS in the solid state. The Ru-
2
8
.059(1); Ru(1)-S(1), 2.389(1); R(1)-Cl(1), 2.4061(5); Ru-Cymcent(1.724); Cl(1)-Ru(1)-S(1),
7.77(1); S(1)-Ru(1)-C(1), 84.62(4); C(1)-Ru(1)-Cl(1), 92.16(4).
Carbene bond distance of complexes 1c, 1i and 1j are in the
range of other NHC-Ru(p-cymene) complexes which are in
between 2.02-2.09 Å.8d, 13, 28, 34b, 35a, 42 Ru-S bond distances are
in the range to those describe in the literature for thioether-
Ru(p-cymene) complexes.37f, 43 However, these bonds lengths
are longer compared to the one observed for the two chelates
NHC/thioether ruthenium complexes reported so far.34b, 35a
Considering the standard deviation calculated for these Ru-
Carbene and Ru-S bonds lengths (see figure 2), no significant
differences can be drawn from these value. The larger value
observed in complexes 1c-1i for the <S-Ru-C> angle (89.1-
DFT Calculation
1
All signals in the H-NMR were sharp and well-defined which
was not expected thinking about the possible dynamic
isomeric mixtures in solution. These analyses suggest either
that, in solution, these Ru-species might a display dynamic
stereochemical rearrangement, or that the Ru complex
formation is diastereoselective. In order to gather insight into
the system, computational studies were conducted. Three
substituents were chosen for this study (-tBu, 1c, -Ph, 1f and -
9
0.3°) compared to 84.6° in complex 1j is most likely related to
the difference in conformation of the 6-membered chelate
ring which is half-chair when R = tBu or p-Br-C and boat
conformation when R = p-NO -C
3 S
CF , labelled as 1CF3). First, we optimized the RRu/S
6 4
H
configuration corresponding to complex 1c base on the solid
state structure. Energy optimizations for 1c and 1CF3 were
performed using the same starting point (See ESI for
computational details). Optimized structures were also
2
6 4
H .
(a)
S
computed for the RRu/R diastereomers corresponding to the
inversion of configuration at the sulfur atom. Such
configuration was found more stable for complexes 1c and 1CF3
and slightly less stable for complex 1f (Figure 3).
The next step, was the search of the inversion path at the
sulfur atom throughout two possible processes: i) an
intramolecular pyramidal inversion mechanism without bond
rupture (Figure 3) or ii) a dissociative/associative mechanism
(Figure 4). Both pathways were investigated and they are
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1
discussed below. In addition, the influence of the substituents solution by the H-NMR which would correspond to an average
on the thioether group was also analyzed.
View Article Online
DOI: 10.1039/C9DT04825A
signals of different species/isomers. Nevertheless, studies on
the relative higher activation barrier computed for 1f (ΔG‡ =
‡
+11.3 kcal mol−1), suggests the possible experimental
observation of two diastereoisomers by the variable
temperature NMR (details discussed in the following section).
(
R)
Ru
Cl
R
Bn
S
C
N
(TS-inversion)
‡
N
+
7.6
‡
+
+
11.3
16.4
Ru
Cl
Bn
S
R
Ru
C
N
Cl
Bn
S
R
N
C
N
N
(TS2-coordination)
-
4.6
+0.9
1.8
+
+
+
15.8
18.2
4.4
0
.0
(TS1-decoordination)
-
+
+
+
9.7
15.9
6.1
RRu, SS
RRu, RS
+
+
+
7.5
11.5
0.8
(
R)
Ru
(
R)
intermediate
Cl
Ru
Bn
S
R
Cl
C
(S)
Bn
S
R
-4.6
+0.9
-1.8
N
C
(R)
N
0.0
N
N
RRu, SS
Ru
Cl
R = tBu, Ph, CF3
RRu, RS
Bn
C
N
Figure 3. Calculated sulfur pyramidal inversion pathway for 1c (red), 1f (green) and 1CF3
black) (values in Kcal mol . The PF anion was omitted for clarity).
6
N
(
R)
-1
-
Ru
(R)
(
Cl
Ru
Bn
S
R
S
Cl
N
C
(S)
R
Bn
S
(R)
R
N
C
N
The calculations established that sulfur inversion trough
pyramidal inversion might be favored and relatively easy for S-
N
R = tBu, Ph, CF3
‡
−1
tBu and S-Ph groups (+7.6 ≤ ΔG ≤ +11.3 kcal.mol ) (Figure 3) Figure 4. Calculated dissociative/associative pathway for 1c, 1f and 1CF3 (values in Kcal
-1
-
6
mol . The PF anion was omitted for clarity).
compared to the dissociative/associative pathway in which the
second step, recoordination of the sulphur atom, is the limiting
VT-NMR experiments
‡
step of the reaction and an unfavorable process (+15.8 ≤ ΔG ≤
−1
More insights in the possible dynamic processes were
Interestingly, this trend is reversed in the presence of the obtained by variable-temperature H-NMR studies of the
+
18.2 kcal mol ) (Figure 4).
1
strong electron withdrawing group as -CF
3
2 2
for which the compounds in CD Cl in the range of 298-198 K and in 1,2-
‡
−1
dichlorobenzene-d in the range of 298-378 K.
dissociative/associative pathway (ΔG = 6.1 kcal mol ) is now
4
-1
For complex 1c (-t-Bu), increasing (up to 378 K) or decreasing
favored by more than 10.3 kcal mol compared to the
pyramidal inversion. The presence of this strong electron- (up to 198 K) the temperature did not display any additional
withdrawing group at the sulfur atom further weakens the S- signals. These results may indicate that compound 1c has a
Ru bond favoring the dissociative/associative mechanism.
fixed stereochemical arrangement around Ru without
This counterintuitive result might be explained by the analysis decoordination of the thioether, but with a low activation
of the Ru-S distances on the intermediate and TS2- barrier for Sulphur inversion in agreement with the DFT
1
coordination. The optimized geometry on the intermediate calculations. In consequence, the variable-temperature H-MR
features Ru-S distances over 5 Å for R = t-Bu and Ph (5.51 Å experiments of complex 1f (-Ph) now display a different
and 5.20 Å, respectively) with the substituent placed far from feature at low temperature. Four multiplets corresponding to
2 2
the p-cym ligand in order to minimize steric hindrance. In the the N-CH -CH -S chain which integrate for one proton and the
case of R = CF
3
, the Ru-S distance is 4.92 Å and the substituent CH peaks of cymene integrating for three protons became
3
is closer to the p-cym ligand. The second step, TS2- broader as the temperature decreased and de-coalesced at
coordination, model for R = t-Bu and Ph the shortening of the 248 K, before splitting into sharp signals. At 193 K, we
Ru-S distance by 1.97 Å (R = t-Bu) and 1.56 Å (R =Ph) plus the observed a 2/1 diastereomeric mixture and no triplet signals
rotation of the substituent away from the p-cym ligand while R corresponding to uncoordinated thioether species were
=
CF
3
mainly model a shortening of 1.35 Å. This observation observed (see ESI for details). These results are consistent with
highlight that the re-coordination step seems to depend on the previous DFT calculations (see Figure 3). Finally, the free
‡
both, the shortening of the Ru-S distance and the minimization energy of activation (ΔG ) for this process based on the
of the steric hindrance between the substituent and the p-cym coalescence temperature of the SCH
2
group is of ca. 11.2 kcal
ligand being more demanding for R = t-Bu and Ph than for R = mol and 11.9 kcal mol based on the CH of the cymene
CF
group which is also in agreement with the theoretical studies
Overall, the calculations predict a fast and easy dynamic sulfur (i.e. 11.3 kcal mol , Figure 3).
inversion, which is too fast for the NMR timescale at 298K The low temperature VT-NMR was also carried out on complex
what is coherent with the observation of only set of signals in 1l which contains 2 -CF withdrawing groups and could be
−1
−1
3
3
.
−1
44
3
4
| J. Name., 2012, 00, 1-3
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Journal Name
compared with the computed -SCF
Once again, no de-coalescence was noticed even at 193 K for
this complex. The only mechanism fairly consistent with
experimental and theoretical data appears to be the pyramidal
inversion without any Ru-S bond dissociation for both 1c and
ARTICLE
3
group by the calculation.
View Article Online
DOI: 10.1039/C9DT04825A
Table 1. Evaluation of benzylamine oxidation in presence of NHC-Ru
1
f complexes.
a
complexes.
Application to catalysis: oxidation of primary amine to nitrile
under oxidant free conditions
CN
2
.5 mol% [Ru]
+
Ph
N
Ph
PhCH NH
2
2
1
10 °C, 24 h
1
,2-dichlorobenzene
In a first set of experiments, the dehydrogenation of
benzylamine into benzonitrile was chosen as benchmark
reaction and complex 1c was originally selected for optimizing
the experimental conditions. The best conditions were
obtained by varying the temperature, solvents and additives
2
3
Entry
Ru
R1
R2
Conv.
Selectivity (%)[b]
(
%)[b]
77
92
90
90
84
89
88
70
72
72
88
92
98
90
2
3
1
2
3
5
6
7
8
9
1a
1b
1c
1d
1e
1f
1g
1h
1i
Et
Cy
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
55
57
60
50
48
40
50
40
37
44
54
50
65
39
45
43
40
50
52
60
50
60
63
56
46
50
35
61
(See ESI table S1). Finally, the reactions were performed using
2
.5 mol% of Ru-complex and 0.2 mmol of benzylamine in 0.2
mL of 1,2-dichlorobenzene (ODCB) at 110 °C in an open vessel
under inert atmosphere. With this combination, high
conversion was observed after 24h and the benzonitrile was
generated as the major compound with some imine product
t-Bu
Ad
n-Oct
Ph
1
both confirmed by the H-NMR and GC analysis (see ESI table
S1). Control experiments showed that in absence of the
catalyst no reaction occurred and that only traces of imine
p-Me(C H )
6
4
p-OMe(C
6 4
H )
8
e
were detected in a close system under these experimental
1
1
0
1
p-Br(C
6 4
H )
conditions.2
5, 45
In contrast to previous reports,26-27, the
1j
p-NO (C H )
2
6 4
presence of either weak or strong base have no or slight effect
2
8
on both the nitrile/imine ratio and reactivity.
12
1k
1l
p-CF (C H )
3
6
4
1
1
1
3
4
5
3,5-CF
3
(C
6 3
H )
The NHC-Ru complexes 1a-l bearing thioether groups with
different electronic and steric properties, that may affect
coordination with the ruthenium center, were next evaluated
4
t-Bu
t-Bu
CH
CH
3
5
3
4
6
[a] Reaction conditions: benzylamine (0.2 mmol), 2.5 mol% cat. based on Ru and 1,2-
dichlorobenzene (0.2 mL), 110 °C, 24h, open vessel under argon atmosphere;
Conversion and selectivity were determined by 1H RMN hexadecane as internal
under the optimized standard conditions (Table 1). All
cationic catalysts were found active generating a mixture of
nitrile and imine products. Overall, it emerges that catalysts
bearing an electron donating alkyl group are more active than
those having aryl groups. Only the aryl-complex 1l reaches the
same level of reactivity of bulky alkyl type complexes (Entry
[
b]
reference.
In the dehydrogenative amidation of alcohol and amine
catalyzed by NHC-Ru systems, it has been shown that the
reactivity and the selectivity are sensitive to the N-
4
7
1
3). The same trend was observed for the selectivity of the
reaction for which complex 1c (S-tBu) displayed the highest
nitrile ratio (Entry 3) and complex 1i (p-Br) the highest imine
ratio (Entry 10). Either, bulky or long alkyl chains have a
detrimental effect on the formation of nitriles. In addition,
aromatic substitutions by strong electron donating or
withdrawing groups are both unpropitious for nitrile selectivity
7a, 7b
8g, 8k, 8l, 9
substitution
of the NHCs and that benzimidazole
core displays often better activity than imidazole counterpart.
A second generation catalysts were synthesized and evaluated,
under our catalytic conditions, to address these two points
(
Figure 5). First, steric effect on the nitrogen of the NHCs was
(Entries 8-13). Finally, alkyl groups with the strongest σ-
assessed through the complex 4, which has a methyl group
instead of the benzyl group. The catalyst showed the highest
reactivity and selectivity (entry 14). Secondly, the
corresponding benzimidazole complex 5 also promotes this
transformation but in contrast to its imidazole analogue 1c,
catalyst 5 favors the formation of imine rather than nitrile
products (Entry 15). This outcome indicates that the electron-
donating properties of the NHCs are crucial for imparting high
selectivity of nitrile. This observation is in the line of a recent
donating power generate the nitrile as major product of the
reaction (Entries 1-3).
II
publication which uses a strong electron-donating Ru -(1,2,3-
triazolyllidene-pyridine) bidentate complex system in the
4
8
2 3
presence of both O and NH .
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 5
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Pleas eD da lot o nn oT tr aa nd sj au c st ti o mn sa rgins
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ARTICLE
Journal Name
2
.5 mol% [1c]
PF6
PF6
View Article Online
+
R N R
DOI: 10.1039/C9DT04825A
C N
R
NH2
R
1
10 °C, 24-120 h
,2-dichlorobenzene
Ru
Ru
N
A
:
B
1
Cl
Cl
H C
3
S
tBu
H C
3
S
tBu
C
C
N
N
N
CN
6
, n = 4, n.d., 24 h (1:0)
H C
n CN
3
7
, n = 6, 80%, 30 h (1:0)
8
, n = 10, 65%, 35 h (1:0)
9
, n = 12, 71%, 48h (1:0)
1
0, n = 16, 50%, 120h (1:0)
4
5
1
1, 30%
Figure 5. Steric and electronic variations: molecular structure of complexes 4 and 5.
24 h (1:0)
We then decided to further use complex 1c to investigate the
scope and limitations of the catalytic double dehydrogenation
of primary amines (Figure 6). On primary amines, irrespective
of the nature of the alkyl chain (long, branched or saturated),
the formation of the corresponding nitrile was formed
exclusively. Thereby good yields were obtained after
Ph CN
2, 50%
6CN
CN
6
1
2, 56%
4 h (1:0)
13
24 h (1:0)
, 60%
24 h (1.5:1)
2
2
purification on SiO . Substrates with unsaturated alkene
Cl
F3C
CN
MeO
CN
CN
functions were also used and the corresponding products were
obtained in good yield. However the kinetic of the reaction
was dependent on the length of the alkyl chain; for example
the octadecylamine required 120 h of reaction time to achieve
full conversion. Benzylamine derivatives were also investigated
albeit with low selectivity and formation of imines. Electron-
rich benzylamine derivative 16 showed the best nitrile
1
4
, 37%
15
24 h (1:1)
, 30%
16
, 45%
32 (1.7:1)
30 h (1:1)
[
a]
Isolated yields; A:B ratio in parenthesis.
selectivity
compared
to
electron-poor
substrates. To gain more insight into the reaction mechanism, an
Consequently the lower yields obtained for these benzylic equimolar mixture of benzylamine and complex 1c was
derivatives are mainly due to poorest selectivity and also
dissolved in CD
2
Cl
2
at room temperature, and followed by the
4
9
issues during the purification step. Globally, these results
show the difficulty to control the factors that govern the
selectivity of the reaction with benzylamine derivatives. The
uses of several NHC-S ligands were found quasi-ineffective for
the discrimination of the two products formed. Even if those
cationic complexes display slight better nitrile selectivity for
aliphatic amines than neutral monodentate NHCs their
presence on the coordination sphere of the metal inhibit
1
H-NMR experiments. Interestingly, the spectra displayed no
change after 24 hours, even in the presence of 10 equivalents
of amine and heating up to 60 °C for 6 hours. In order to be
closer than the reaction conditions, complex 1c was heated at
1
10 °C in the presence of two equivalents of benzylamine in
deuterated ODCB (in a closed system). After two hours no
changes were observed. Interestingly however after longer
somehow the catalytic reactivity and selectivity compared to time (18 h), free cymene was identified with a ratio Ru-p-
2
5, 27
the simple [Ru(p-cym)Cl
2
]
2
complex.
However Szymczak cym/free cym of 4/1 in solution. When the reaction was set up
showed that the presence of an appropriate ligand on with ten equivalents of benzylamine at 110 °C for 24 h, we
ruthenium could achieved, under oxidant-free conditions, high
level of both reactivity and selectivity for activated amines.
Therefore, further efforts onto the design of more active and
selective ligands are thus required for such challenging
substrates.
observed an almost complete dissociation of the cymene (see
ESI fig. S13), and the NHC ligand remained attached to the
metal center (see ESI). This observation, in line with previous
reports, indicates that the p-cymene complex is probably not
2
4
50
8
f, 9, 13, 48
involved in the catalytic cycle.
Even if, no clear
Figure 6. Reaction scope of primary amines double hydrogenation with
1
a
evidence of amine coordination was detected in the H-NMR
spectrum, the observation of imine suggests that this process
should take place (see ESI). In the presence of the only imine
product and the ruthenium complex 1c, under our standard
conditions, no reaction occurred after 24h.
catalyst 1c.
To avoid the dehydrogenation pathway the tert-octylamine,
which cannot undergo the elimination process, was also used.
-
Once again, no displacement of either -StBu or Cl was
observed even after 24h at 110 °C in ODCB, suggesting that the
starting complex is a highly stable resting state.
In vitro activity of selected Ru NHC complexes
Ruthenium complexes are of great attention in the
5
1
development of metal-based anticancer compounds. Some
ruthenium(II) p-cymene have shown good antiproliferative
activities against various cancer cell lines and also low systemic
6
| J. Name., 2012, 00, 1-3
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Dalton Transactions
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Journal Name
toxicity.51 In addition, N-heterocyclic carbene ligands are of dissociative/associative pathway. Through
ARTICLE
a
systematic
View Article Online
DOI: 10.1039/C9DT04825A
particular interest in the field of medicinal inorganic chemistry. investigation of the ligand structures and various reaction
3
3d, 52
They allowed generating robust complexes even in the conditions, the cationic ruthenium complex 1c was found to be
presence of water and they fit many prerequisites for easy the most active catalyst for the double dehydrogenation of
optimization. primary amine to give the corresponding nitrile under oxidant-
Antiproliferative activities of some representative ruthenium and base-free conditions. With these bidendate NHCs, high
complexes described here, namely 1a, 1d, 1f and 1l, were selectivity has been achieved using aliphatic amines and only a
measured on a panel of three different human tumor cell lines poor to no selectivity was obtained with benzylamine
(
namely MCF7, HCT116 and PC3) (IC50, Entries 1-4, Table 2). derivatives. Investigation on the active species clearly
Complexes 1a (-Et) and 1f (-Ph) displayed activities in the range indicated the decoordination of p-cymene. Finally, these
0-75 µM. On the other hand, complexes 1d (-Ad) and 1l (-3,3’- ruthenium complexes showed promising cytotoxic activities on
CF -C ) showed good activities (up to 3.5 µM). These results several human cancer cells. We are currently further
are most likely connected with the lipophilicity of the evaluating their biomedical properties varying the nature and
5
3
6 3
H
5
3
5
4
55
complexes since adamantane
or fluorine-containing
the complexity of the systems in order to improve the
substituents are known to enhance the overall lipophilicity of cytotoxic profile and selectivity of the resulting complexes.
the molecule. Since the mode of action is not yet known, the
steric bulk might be as well a potential factor that influences
the cytotoxicity observed. Indeed, it also appears that
Conflicts of interest
increasing the steric bulk of the substituent at sulfur atom
increases activity.
There are no conflicts to declare.
Table 2 Half inhibitory concentrations IC50 (in µM) of the selected Ru
compounds against human cancer cell lines.
a
Acknowledgements
This research was funded in part by La Ligue Contre le
Entry Compound
HCT116
56.9±11.2
4.90±0.19
49.1±1.77
9.79±0.19
MCF7
PC3
Cancer—Grand-Est
and
by
the
University
of
1
2
3
1a
1d
1f
1l
75.9±3.05
14.3±0.94
57.2±6.96
12.8±2.23
74.3±10.8
3.54±0.23
65.7±13.8
10.01±1.02
Strasbourg/CNRS—Program IDEX Interdisciplinaire. We will
also like to thank the University of Geneva (U of G) for financial
support and Carmine Chiancone (U of G) for technical support.
4
a
after 72 h of incubation; stock solutions in DMSO for all complexes.
Stability in solution of the compounds is an important
requirement in medicinal chemistry. Because solutions were
prepared in DMSO/water, these results should be correlated
with the stability of the ruthenium complexes in solution,
Notes and references
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32 (a) H. V. Huynh, C. H. Yeo and G. K. Tan, Chem.
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41 Modified CIP rules were used, here the polyhapto
ligand (p-cym) is considered pseudo-atoms of atomic
weight equal to the sum of the atomic weights of all
the atoms bonded to the metal atom (molecular
weight 72). As a consequence, the following priority
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The crystallographic data for complexes 1c (CCDC
957068), 1i (CCDC 1957070), and 1j (CCDC 1957069)
(
1
3
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9
0
1
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1
have been deposited with the Cambridge
Crystallographic Data Centre. These data can be
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 9
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Pleas eD da lot o nn oT tr aa nd sj au c st ti o mn sa rgins
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ARTICLE
Journal Name
4
4
6
7
The reaction time has been set at 24 h for which the
View Article Online
DOI: 10.1039/C9DT04825A
complex 1c generates only 90% conversion.
(a) M. J. Wiester, A. B. Braunschweig, H. Yoo and C. A.
Mirkin, Inorg. Chem., 2010, 49, 7188-7196; (b) M. S.
Rosen, A. M. Spokoyny, C. W. Machan, C. Stern, A.
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1
419.
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4
8
9
2
Imines are easily hydrolysed into aldehyde derivatives
during the purification on column chromatography and
therefor are difficult to separate from the desired
nitrile products.
5
5
0
1
The reaction has been purposely conducted in a closed
system to shut down the formation of nitrile.
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