Well-defined N-heterocyclic carbene/ruthenium complexes for the alcohol amidation with amines: The dual role of cesium carbonate and improved activities applying an added ligand

Article abstract of DOI:10.1002/aoc.5323

Dehydrogenative amide bond formation from alcohols and amines has been regarded as an atom-economic and sustainable process. Among various catalytic systems, N-heterocyclic carbene (NHC)-based Ru catalytic systems have attracted growing interest due to the outstanding properties of NHCs as ligands. Herein, an NHC/Ru complex (1) was prepared and its structure was further confirmed with X-ray crystallography. In the presence of Cs₂CO₃, two NHC/Ru-based catalytic systems were disclosed to be active for this amide synthesis. System A, which did not contain any added ligand, required a catalyst loading of 1.00 mol%. Interestingly, improved catalytic performance was realized by the addition of an NHC precursor (L). Optimization of the amounts of L and other conditions gave rise to system B, a much more potent system with the Ru loading as low as 0.25 mol%. Moreover, an NHC-Ru-carbonate complex 6 was identified from the refluxing toluene of 1 and Cs₂CO₃, and further investigations revealed that 6 was an important intermediate for this catalytic reaction. Based on the above results, we claimed that the role of Cs₂CO₃ was to facilitate the formation of key intermediate 6. On the other hand, it provided the optimized basicity for the selective amide formation.

Full text of DOI:10.1002/aoc.5323

Received: 8 August 2019
DOI: 10.1002/aoc.5323
Revised: 28 September 2019
Accepted: 10 October 2019
F U L L P A P E R
Well-defined N-heterocyclic carbene/ruthenium complexes
for the alcohol amidation with amines: The dual role of
cesium carbonate and improved activities applying an
added ligand
Wan-Qiang Wang1,2 | Ye Yuan2 | Yang Miao2,3 | Bao-Yi Yu4
|
Hua-Jing Wang2,5 | Zhi-Qin Wang2,3 | Wei Sang2,3 | Cheng Chen2
Francis Verpoort2,3,6,7
|
1Department of Chemical Engineering and Food Science, Hubei University of Arts and Science, 296 Longzhong Road, Xiangyang, 441053, P. R. China
2State Key Laboratory of Advanced Technology for Materials Synthesis and Processing, Wuhan University of Technology, 122 Luoshi Road, Wuhan,
430070, P. R. China
3School of Materials Science and Engineering, Wuhan University of Technology, 122 Luoshi Road, Wuhan, 430070, P. R. China
4Key Laboratory of Urban Agriculture (North China), Ministry of Agriculture, Beijing University of Agriculture, Beinong Road 7, Beijing, 102206,
P. R. China
5School of Chemistry, Chemical Engineering and Life Sciences, Wuhan University of Technology, Wuhan, 430070, P. R. China
6National Research Tomsk Polytechnic University, Lenin Avenue 30, Tomsk, 634050, Russian Federation
7Ghent University Global Campus, 119 Songdomunhwa-Ro, Yeonsu-Gu, Incheon, 21985, South Korea
Correspondence
Dehydrogenative amide bond formation from alcohols and amines has been
regarded as an atom-economic and sustainable process. Among various cata-
lytic systems, N-heterocyclic carbene (NHC)-based Ru catalytic systems have
attracted growing interest due to the outstanding properties of NHCs as
ligands. Herein, an NHC/Ru complex (1) was prepared and its structure was
further confirmed with X-ray crystallography. In the presence of Cs2CO3, two
NHC/Ru-based catalytic systems were disclosed to be active for this amide syn-
thesis. System A, which did not contain any added ligand, required a catalyst
loading of 1.00 mol%. Interestingly, improved catalytic performance was real-
ized by the addition of an NHC precursor (L). Optimization of the amounts of
L and other conditions gave rise to system B, a much more potent system with
the Ru loading as low as 0.25 mol%. Moreover, an NHC-Ru-carbonate complex
6 was identified from the refluxing toluene of 1 and Cs2CO3, and further inves-
tigations revealed that 6 was an important intermediate for this catalytic reac-
tion. Based on the above results, we claimed that the role of Cs2CO3 was to
facilitate the formation of key intermediate 6. On the other hand, it provided
the optimized basicity for the selective amide formation.
Cheng Chen and Francis Verpoort, State
Key Laboratory of Advanced Technology
for Materials Synthesis and Processing,
Wuhan University of Technology, 122
Luoshi Road, Wuhan 430070, P. R.
China.
Email: chengchen@whut.edu.cn; francis.
verpoort@ghent.ac.kr
Funding information
Tomsk Polytechnic University, Grant/
Award Number: VIU-69/2019; Tomsk
Polytechnic University Competitiveness
Enhancement Program, Grant/Award
Number: VIU-69/2019; Russian
Foundation for Basic Research, Grant/
Award Number: Nꢀ 18-29-04047; National
Natural Science Foundation of China,
Grant/Award Number: 21502062
K E Y W O R D S
amide synthesis, C-N bond formation, complex, N-heterocyclic carbene(s), ruthenium
Appl Organometal Chem. 2019;e5323.
wileyonlinelibrary.com/journal/aoc
© 2019 John Wiley & Sons, Ltd.
1 of 10
https://doi.org/10.1002/aoc.5323

2 of 10
WANG ET AL.
1 | INTRODUCTION
Considering the profound significance of the amide
linkage in organic chemistry and biological systems,[1]
numerous researchers focused on environmentally
benign and atom-economic methods for amide synthe-
sis. Among these methods, acceptorless dehydrogenative
amidation of alcohols and amines applying transition
metal-based catalytic systems has been highlighted as
an attractive strategy for constructing the amide bond.
This method features high atom economy with molecu-
lar hydrogen as the sole byproduct.[2] The generally
accepted pathway for this strategy begins with the oxi-
dation of an alcohol to form the corresponding alde-
hyde or Ru-bound aldehyde, which then reacts with an
amine to produce a hemiaminal intermediate.[2b] There
are two possible pathways after the formation of the
hemiaminal. It could be transformed to an imine,
followed by the hydrogenation of the imine to generate
an amine, the so-called hydrogen borrowing
(HB) strategy.[3] Alternatively, the hemiaminal could be
directly dehydrogenated to the corresponding amide. In
particular, ruthenium (Ru) is the most accessed
metal.[4] Originally, Murahashi and co-workers
accomplished the intramolecular amidation of 1,3- and
1,4 amino alcohols via the catalysis of RuH2(PPh3)4.[5]
A significant breakthrough was the development of a
Ru complex bearing a dearomatized PNN-type ligand,
the well-known Milstein catalyst.[6] It was worth
noting that amide synthesis could be firstly achieved in
an intermolecular manner. Inspired by these two
reports, Madsen,[7] Williams,[8] Hong,[9] Crabtree,[10]
FIGURE 1 The design strategy of this work
L, NaH led to an efficient catalytic system for this ami-
dation, and further High-Resolution Mass Spectroscopy
(HRMS) analyses of the in situ generated catalytic sys-
tem implied that NHC-Ru complex 1 was observed as a
major species (as depicted in Figure 1a). Herein, in order
to gain more mechanistic insights, we aimed to synthe-
size this Ru complex and evaluate its catalytic perfor-
mance. Through the extensive screening of various
conditions, two catalytic systems, system A (without an
added ligand) and system B (with an added ligand),
were discovered (as depicted in Figure 1b). Interestingly,
compared with system A (a Ru loading of 1.00 mol%),
system B, which contains an identical NHC precursor as
an added ligand, resulted in a much more active cata-
lytic system (a Ru loading of 0.25 mol%). Notably,
instead of NaH which was proven to be superior over
other bases in our previous in situ catalytic
systems,[20b] a milder base (Cs2CO3) was found to pro-
mote this reaction in a more efficient pattern. Further
exploration indicated that the role of Cs2CO3 was not
only to assist the formation of a NHC-Ru complex
ligated by a carbonate ligand, but also provide the opti-
mized basicity for this process.
Albrecht,[11]
Möller,[15] Bera,[16] Huynh,[17] Viswanathamurthi,[18]
Mashima,[19] Verpoort[20] Kundu[21] and their co-
Milstein,[12]
Guan,[13]
Glorius,[14]
,
workers also contributed in this area. According to the
promising properties of N-heterocyclic carbenes (NHCs)
as ligands for transition metal complexes,[22] we have
focused on the development and investigation of versa-
tile and efficient NHC-Ru catalytic systems for this
reaction.[9f, g, 20] Other groups including the
Madsen,[7] Hong,[9a–i] Glorius,[14] Möller,[15] Bera,[16]
Huynh,[17] and Viswanathamurthi[18a] groups also
explored their respective NHC-Ru systems for the same
purpose.
2 | EXPERIMENTAL SECTION
2.1 | General considerations
Previously, we developed a variety of in situ gener-
ated (p-cymene)-Ru catalytic systems comprising
benzimidazole-based NHC precursors.[20a, b] Through a
systematic investigation of the backbone and wingtip
substituents on the benzimidazole framework, 3-ethyl-
1-methyl-1H-benzo[d]imidazol-3-ium iodide (L) was
identified as an optimal NHC precursor (as shown in
Figure 1a).[20b] A combination of [RuCl2(p-cymene)]2,
All reactions were carried out using standard Schlenk
techniques or in an argon-filled glove box unless other-
wise mentioned. All the substrates and solvents were
obtained from commercial suppliers and used as received
without further purification. 1H NMR spectra were
recorded on a Bruker Avance 500 spectrometer in CDCl3
or DMSO-d6 with TMS as the internal reference, and 13C

NHC/RUTHENIUM COMPLEXES FOR THE ALCOHOL AMIDATION WITH AMINES.
3 of 10
NMR spectra were recorded in CDCl3 or DMSO-d6 on a
Bruker Avance 500 (126 MHz) spectrometer. The follow-
ing abbreviations were used to designate multiplicities:
s = singlet, brs = broad singlet, d = doublet, t = triplet,
q = quartet, dd = doublet of doublets, ddd = double of
doublets of doublets, td = triplet of doublets, tt = triplet
of triplets, m = multiplet. Melting points were taken on a
Buchi M-560 melting point apparatus and were
uncorrected. HR-MS analyses were done with a Bruker
Daltonics microTOF-QII instrument. The single crystal
structures of 1 and 6 • 2CDCl3 were obtained using a
Bruker APEX-II CCD diffractometer with Mo Kα radia-
tion (λ = 0.71073 Å). The supplementary crystallographic
data of 1 (with a deposition No. of 1864555) and 6 •
2CDCl3 (with a deposition No. of 1870478) could be
obtained free of charge from The Cambridge Crystallo-
graphic Data Centre (CCDC). NHC precursor L was
prepared according to a reported procedure.[20b]
was redissolved in dichloromethane (20 ml) and filtered
again. Concentrating the solution and subsequent precip-
itation with cold diethyl ether gave 6 as a yellow solid.
Yield: 70% (63.8 mg, 0.14 mmol). The single crystal of
6 was obtained by slow evaporation of diethyl ether into
a solution of 6 in CDCl3.
2.3 | General procedure for the amide
synthesis
2.3.1 | Catalytic reactions utilizing
system a
Inside an argon-filled glove box, 1 (2.4 mg, 0.005 mmol),
Cs2CO3 (3.3 mg, 0.01 mmol) and dry toluene (0.75 ml)
were added to an oven-dried 25 ml Schlenk flask. The
flask was taken out and heated to reflux under argon for
0.5 hr. After the reaction mixture was cooled down to
room temperature, an alcohol (0.50 mmol), an amine
(0.55 mmol) were added and the mixture was heated to
reflux for 24 hr.
2.2 | General procedure for the synthesis
of complexes 1 and 6
2.2.1 | Synthesis of NHC-Ru complex 1
2.3.2 | Catalytic reactions utilizing
A suspension of 3-ethyl-1-methyl-1H-benzo[d]imidazol-
3-ium (L, 288.1 mg, 1.00 mmol), Ag2O (115.9 mg,
0.50 mmol) in dry dichloromethane (5.0 ml) at a
refluxing temperature in dark for 12 hr. Then [Ru(p-
cymene)Cl2]2 (306.1 mg, 0.50 mmol) was added and the
resulted suspension was refluxed for an additional 6 hr.
After the reaction was complete, the mixture was filtered
through a plug of Celite and the filtrate was concen-
trated under reduced pressure. The orange residue was
then recrystallized from methanol/diethyl ether to afford
an orange solid, which was then washed with diethyl
ether for a few times to obtain analytically pure product
system B
To an oven-dried 25 ml Schlenk flask was added
1 (2.4 mg, 0.005 mmol), NHC precursor L (4.3 mg,
0.015 mmol), Cs2CO3 (11.5 mg, 0.035 mmol) and dry tol-
uene (1.00 ml) inside an argon-filled glovebox. This flask
was taken out and heated to reflux under argon for
0.5 hr. Then an alcohol (2.00 mmol), an amine
(2.20 mmol) were added and the mixture was stirred at a
refluxing temperature for 24 hr.
1
as an orange powder. Yield: 75% (355.0 mg,
2.3.3 | Catalytic reactions utilizing 6
0.75 mmol). The single crystal of 1 was obtained by slow
evaporation of diethyl ether into a solution of 1 in
dichloromethane.
without L
6 (2.3 mg, 0.005 mmol), Cs2CO3 (3.3 mg, 0.01 mmol), an
alcohol (0.50 mmol), an amine (0.55 mmol) and dry tolu-
ene (0.75 ml) were added to an oven-dried 25 ml Schlenk
flask, which was then heated to reflux under argon
for 24 hr.
2.2.2 | Synthesis of NHC-Ru-carbonate
complex 6
Since it was difficult to purify 6 directly from the mixture
of 1, Cs2CO3 and dry toluene, an alternative procedure
was utilized based on a similar procedure.[10b] Sodium
carbonate (106.0 mg, 1.00 mmol), 1 (94.0 mg, 0.20 mmol)
and ethanol (15 ml) were stirred at room temperature for
3 hr. The resulted mixture was filtered through Celite,
and the solvent was removed. Afterwards, the residue
2.3.4 | Catalytic reactions utilizing 6 in
the presence of L
The procedure was similar to that for catalytic reactions
utilizing system B, by replacing 1 with 6 and adjusting
the amount of each substance accordingly.

4 of 10
WANG ET AL.
2.3.5 | Additional information
In order to discover a more potent catalytic system,
further screening of various conditions was also con-
ducted (as shown in Table 2). If the Ru loading was
reduced from 1.00 mol% to 0.50 mol% and 0.25 mol%,
respectively, the amide percentages among product dis-
tribution were gradually decreased (entries 1–3). Since
the NHC ligand of 1 was verified as the optimum one
for the reaction, we wondered if improved catalytic per-
formance could be achieved by incorporating the precur-
sor of the identical NHC ligand (L) into the catalytic
system. With this consideration in mind, different
amounts of L were added as an extra ligand (entries
4–8). To ascertain two additional equivalents of Cs2CO3
for interacting with 1 for the above entries, the amounts
of Cs2CO3 were initially changed according to those of
L. These results indicated that a 1: 3 ratio of 1: L was
optimal (entry 6). In addition, adjustment of the base
amounts revealed that the optimal ratio of 1: L: Cs2CO3
was identified as 1: 3: 7 (entries 6, 9–12). Variation of
the solvent volume suggested that 1.00 mL of toluene
gave the highest yield of 4a (entries 11, 13–15). More-
over, adding 1.00 equiv. of degassed water resulted in a
slightly lower yield of 4a (entry 16). If the reaction was
run under an argon-filled sealed tube, an unsatisfactory
result was attained (entry 17). Finally, replacing toluene
with dioxane as the solvent led to 72% of amide 4a
(entry 18). Therefore, the optimized conditions were
illustrated in entry 13 of this table unless otherwise
noted.
Based on the above optimization processes, both sys-
tem A (without an added ligand, as listed in entry 14 of
Table 1) and system B (with an added ligand, as listed in
entry 13 of Table 2) were selected for further exploration
of the substrate scope and limitations (as depicted in
Figure 3). For both systems, good yields were given for
sterically non-hindered substrates. In addition, heterocy-
clic compounds were also tolerated for both systems.
30–66% of the desired products (4d-4 g) were given for
furan- and thiophene-containing substrates, while mod-
erate to good yields were obtained for saturated heterocy-
cles. For moderately congested reactants (2j, 2 k, 3 l,
3 m) and secondary amines (3n-3p), moderate yields
were given for both systems. Except for intermolecular
amidation of an alcohol and an amine, a six-membered
cyclic lactam (4q) was efficiently synthesized in an intra-
molecular manner. Furthermore, the electronic effects
were explored on both substrates. System A could cata-
lyze most electron-rich and electron-deficient substrates
in good to excellent yields. In the case of system B, the
desired amides (4r, 4 s, 4w, 4x) with electron-donating
groups could be afforded in high yields, but considerably
lower yields were provided for those bearing electron-
withdrawing groups (4 t-4v, 4y-4a’).
For NMR yields, 1,3,5-trimethoxybenzene (0.5 mmol,
84.0 mg) and CHCl3 (1.0 mL) were added to the reaction
mixture, and 0.1 ml of the above solution and 0.5 ml of
CDCl3 were added to an NMR tube. The NMR yields of
all the identified compounds were calculated from the
exact amount of 1,3,5-trimethoxybenzene. In terms of
the isolated yields, the reaction mixture was cooled
down to room temperature, and the solvent was
removed under reduced pressure. Finally, the residue
was purified by silica gel flash column chromatography
to afford the amides. Most amide products were identi-
fied by spectral comparison with literature data,[20a–c, 23]
while amides 4f and 4 g were fully characterized. More-
over, the characterization data and the corresponding
spectra of all the amides could be found in the
supporting information.
3 | RESULTS AND DISCUSSION
Complex 1 was synthesized by transmetallation from an
in situ generated NHC-Ag complex, and its structure was
further confirmed by X-ray crystallography (as shown in
Figure 2). Then the catalytic evaluation was initiated by
selecting the coupling of benzyl alcohol (2a) with
benzylamine (3a) as a model reaction (as shown in
Table 1). At the outset, 62–72% yields of amide 4a were
obtained if a strong base such as NaH or KOtBu was used
to promote this reaction (entries 1–2). Weaker bases
including Li2CO3, Na2CO3, K2CO3 and Cs2CO3 were also
attempted (entries 3–6). Li2CO3 and Na2CO3 produced
imine 5a as the major product (entries 3–4), and K2CO3
could result in 42% of amide 4a with concurrent forma-
tion of imine 5a in 12% yield (entry 5). To our delight,
selective amide formation (88% of 4a and only 6% of 5a)
was achieved in the case of Cs2CO3 (entry 6), which
manifested an even better result than the above-
mentioned strong bases (entry 6 vs. entries 1–2). After
establishing the ideal base, the amounts of Cs2CO3 were
screened (entries 6–10), and 2.00 mol% was demonstrated
as the optimum amount (entry 6). Furthermore, the
effects of the solvent volume were also examined (entries
6, 11–13), and 0.75 mL of toluene produced the best
result (entry 12). It was also observed that pre-heating 1,
Cs2CO3 and toluene at reflux for 0.5 hr before the addi-
tion of the substrates led to a slightly enhanced yield of
4a (entry 14 vs. entry 12). Finally, 1.00 equiv. of degassed
water as an additive could not provide a better result
(entry 15 vs. entry 14). Thus, the optimized conditions
were described in entry 14 of this table unless otherwise
noted.

NHC/RUTHENIUM COMPLEXES FOR THE ALCOHOL AMIDATION WITH AMINES.
5 of 10
(0.75 ml) was heated at reflux for 0.5 hr, then the solvent
was removed and the residue was directly dissolved in
CDCl3. From the 13C-NMR analysis of the above CDCl3
solution, two carbene signals at 190.74 and 188.68 ppm as
well as a carbonyl peak at 166.28 ppm were clearly
detected (as shown in Figure S1a of the Supporting Infor-
mation). The resonance at 188.68 ppm was from the
unreacted 1 (Figure S1a vs. S1b of the Supporting Infor-
mation), while the peaks of 190.74 and 166.28 ppm could
be assigned as an NHC-Ru complex bearing a carbonate
moiety.[10b, 24] Therefore, HRMS analysis was con-
ducted to confirm the possible Ru species for both sys-
tems (as depicted in Figure 4). The HRMS spectrum for
system A was illustrated in Figure 4a. Not surprisingly,
an isotopic peak at m/z = 431.08225 was consistent with
[1-Cl]+. Interestingly, a major peak at 457.10597 was
assigned as [6 + H]+, an NHC-Ru species coordinated
with a carbonate ligand. In the case of system B, a few
mono-carbene complexes, including [1-Cl]+, [6 + H]+
and 7 were detected from the spectrum (as shown in
Figure 4b). In addition, two poly-carbene complexes
FIGURE 2 The molecular structure of complex 1, showing
the atom labeling scheme of the heteroatoms and carbon atom C1.
The disorder of the p-cymene ligand and hydrogen atoms were
omitted for clarity. The ellipsoids of atoms were shown at a
probability level of 30%
To have a clearer understanding about the mechanis-
tic insights, more investigations were performed. A mix-
ture of 1 (0.005 mmol), Cs2CO3 (0.010 mmol) and toluene
TABLE 1 Optimization of reaction conditionsa
Yields (%)b
Entry
base
x
y
4a
72
62
0
5a
13
4
Unreacted 2a
1
NaH
2.00
2.00
2.00
2.00
2.00
2.00
1.00
3.00
4.00
5.00
2.00
2.00
2.00
2.00
2.00
0.50
0.50
0.50
0.50
0.50
0.50
0.50
0.50
0.50
0.50
0.25
0.75
1.00
0.75
0.75
4
20
59
40
35
2
2
KOtBu
Li2CO3
Na2CO3
K2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
3
38
39
12
6
4
12
42
88
18
86
84
83
73
90
88
93
85
5
6
7
50
7
25
2
8
9
7
0
10
11
12
13
14c
15[c,d]
9
0
7
13
0
7
5
5
4
0
3
7
a2a (0.50 mmol), 3a (0.55 mmol), complex 1 (1.00 mol%), base (x mol%) and toluene (y ml) at refluxing temperature were used.
bNMR yields using 1,3,5-trimethoxybenzene as an internal standard (averages of two consistent runs).
c1 and Cs2CO3 were stirred at refluxing toluene for 0.5 hr before the addition of the substrates.
dDegassed water (1.00 equiv.) was added.

6 of 10
WANG ET AL.
TABLE 2
Optimization of reaction conditions catalyzed by complex 1 with an added liganda
Yields (%)b
4a
Entry
1
w
x
y
z
5a
4
Unreacted 2a
1.00
0.50
0.25
0.25
0.25
0.25
0.25
0.25
0.25
0.25
0.25
0.25
0.25
0.25
0.25
0.25
0.25
0.25
0.00
0.00
0.00
0.25
0.50
0.75
1.00
1.25
0.75
0.75
0.75
0.75
0.75
0.75
0.75
0.75
0.75
0.75
2.00
1.00
0.50
0.75
1.00
1.25
1.50
1.75
1.00
1.50
1.75
2.00
1.75
1.75
1.75
1.75
1.75
1.75
0.75
0.75
0.75
0.75
0.75
0.75
0.75
0.75
0.75
0.75
0.75
0.75
1.00
1.25
1.50
1.00
1.00
1.00
93
57
40
52
60
71
65
67
69
76
83
80
90
78
74
88
41
72
0
32
35
25
19
16
14
12
18
7
2
10
21
16
15
9
3
4
5
6
7
11
13
11
10
10
11
8
8
9
10
11
12
13
14
15
16c
17d
18e
4
0
0
12
14
4
8
11
6
6
52
25
1
a2a (1.00 equiv.), 3a (1.10 equiv.), 1 (w mol%), L (x mol%), Cs2CO3 (y mol%), and toluene (z ml) at refluxing temperature were used.
bNMR yields using 1,3,5-trimethoxybenzene as an internal standard (averages of two consistent runs).
cDegassed water (1.00 equiv.) was added.
dIn a sealed tube instead of a Schlenk flask.
eDioxane instead of toluene as the solvent.
8 and 9, similar with our previous observation,[20c] were
also observed. Unfortunately, isolation of these poly-
carbene complexes was unsuccessful, which was proba-
bly due to the complexity of system B. Thus, in order to
ensure whether complex 6 was a key intermediate during
the catalysis, we synthesized this complex and took its
13C-NMR spectrum (as shown in Figure S1c of the
Supporting Information). The structure of the newly syn-
thesized 6 was confirmed by X-ray crystallography
(as shown in Figure 5). Comparison of the 13C-NMR
spectra between the crude mixture and pure 6 revealed
the formation of this NHC-Ru-carbonate complex, which
verified that Cs2CO3 facilitated the formation of 6 (Fig-
ure S1a vs. 1c of the Supporting Information). On the
other hand, the optimization results of 1 with various
carbonate-containing bases indicated that Cs2CO3 also
provided the optimized basicity for this reaction (as listed
in entries 3–6, Table 1).
Furthermore, the catalytic activities of 6 were deter-
mined to testify whether it was a possible catalytic inter-
mediate (as listed in Table 3). In the first place, a catalyst
loading of 1.00 mol% was used in the absence of an added

NHC/RUTHENIUM COMPLEXES FOR THE ALCOHOL AMIDATION WITH AMINES.
7 of 10
FIGURE 3 Amide
synthesis from various alcohols
and amines. The reported yields
are isolated yields obtained by
averages of two consistent runs.
[a] Complex 1 (1.00 mol%),
Cs2CO3 (2.00 mol%), and toluene
(0.75 ml) at reflux for 0.5 hr
before addition of the substrates;
[b] Complex 1 (0.25 mol%),
L (0.75 mol%), Cs2CO3
(1.75 mol%) and toluene
(1.00 ml) at reflux for 0.5 hr
before addition of the substrates;
[c] 48 hr instead of 24 hr
FIGURE 4 HRMS analyses for (a) system A and (b) system B
ligand (entries 1–5). Without Cs2CO3, 35% of amide 4a
and 15% of imine 5a were observed with 45% of
unreacted 2a (entry 1). 1.00–4.00 mol% of the base
resulted in good to excellent results (entries 2–5). In the
presence of L as an added ligand, 0.25 mol% of 6 and
0.75 mol% of L were applied. Varying the base amount
from 0.75 mol% to 1.75 mol% did not significantly affect
the reaction, producing the desired product 4a in 78–91%
yields (entries 6–10). The above results illustrated that
6 should be a key intermediate during the catalysis.
With an aim to clarify the significant role of 6 during
the catalysis, further experiments were conducted. Gener-
ally, it has been postulated that the generation of Ru
hydride species is crucial for the NHC-Ru catalyzed
amide synthesis.[9b, h, 20a, d] Therefore, Ru hydride for-
mation was monitored by two NMR reactions utilizing
6 with and without L, respectively (as shown in
Figure S2 and S3 of the supporting information). Initially,
a mixture of 6 (0.015 mmol), Cs2CO3 (0.030 mmol) and
toluene-d8 (0.6 mL) was transferred to a screw-capped

8 of 10
WANG ET AL.
intensity of the peak at −9.40 ppm gradually decreased
while another singlet resonance at −17.09 was intensified
(Figure S2c-2f). However, further elongating the period
resulted in the disappearance of this peak (Figure S2f-2i).
For the NMR reaction applying an added amount of
ligand L, a similar trend was found (as shown in
Figure S3 of the supporting information). No hydride res-
onance was observed before or after the addition of both
substrates at room temperature (Figure S3a). However, a
singlet at −7.76 ppm was originally shown upon heating
the NMR tube to reflux (Figure S3b). As the heating con-
tinued, this peak gradually disappeared and another sin-
glet at −17.09 was clearly seen (Figure S3c-f).
Interestingly, this peak persisted even after 6 hr
(Figure S3f-3i). These results implied that Ru-hydride
species, probably Ru monohydride species due to the
observation of several singlet hydrides, were involved
and regarded to be paramount in the catalytic cycle.
Moreover, the hydride peak at −17.09 ppm was ulti-
mately observed for these two systems (with or without
extra NHC precursor L), which probably implied that the
same Ru hydride species was formed for both systems
and played a key role for this catalytic process. More sig-
nificantly, the extra L presumably stabilized the catalytic
FIGURE 5 The molecular structure of 6 • 2CDCl3, showing
the atom labelling scheme of the heteroatoms and carbon atom C1.
The disorder of the p-cymene ligand, hydrogen atoms and CDCl3
molecules were omitted for clarity. The ellipsoids of atoms were
shown at a probability level of 30%
NMR tube, but no hydride peak was observed. After-
wards, 2a (0.075 mmol) and 3a (0.083 mmol) were added,
and still no hydride signal was detected (as shown in
Figure S2a). Interestingly, a singlet at −9.40 ppm was
found after heating the NMR tube at reflux for 15 min
(Figure S2b). As the heating period was elongated, the
TABLE 3 The catalytic performance of 6
Yields (%)a
Entry
w
x
y
z
n
4a
35
75
91
89
87
80
85
90
91
82
5a
15
10
3
Unreacted 2a
1
1.00
1.00
1.00
1.00
1.00
0.25
0.25
0.25
0.25
0.25
0.00
0.00
0.00
0.00
0.00
0.75
0.75
0.75
0.75
0.75
0.00
1.00
2.00
3.00
4.00
0.75
1.00
1.25
1.50
1.75
0.75
0.75
0.75
0.75
0.75
1.00
1.00
1.00
1.00
1.00
0
45
8
2
0
3
0
0
4
0
4
0
5
0
5
0
6
0.5
0.5
0.5
0.5
0.5
2
12
9
7
5
8
3
4
9
6
0
10
10
0
aNMR yields using 1,3,5-trimethoxybenzene as an internal standard (averages of two consistent runs).

NHC/RUTHENIUM COMPLEXES FOR THE ALCOHOL AMIDATION WITH AMINES.
9 of 10
4 | CONCLUSION
In summary, based on the various in situ generated
NHC-Ru catalytic systems, we synthesized a superior
NHC-Ru complex 1 and confirmed its structure by X-ray
crystallography. Through a systematic investigation of
various reaction conditions, system A (without an added
ligand) and system B (in the presence of NHC precursor
L) were identified as the optimized catalytic systems, pro-
ducing various amides from the corresponding alcohols
and amines. Without any added ligand, 1.00 mol% of
1 was required. Improved catalytic activities were
observed with different amounts of an added ligand, and
only a Ru loading of 0.25 mol% was enough to achieve
satisfactory results. Further investigations indicated the
existence of an NHC-Ru-carbonate complex 6, which was
certified as a vital catalytic intermediate from the cata-
lytic evaluation of this complex. Significantly, it was pro-
posed that Cs2CO3 not only facilitated the formation of
the Ru carbonate species, but also served as the opti-
mized base for this transformation.
ACKNOWLEDGEMENTS
FIGURE 6 The proposed mechanism for the NHC/Ru
This research was supported by the National Natural
Science Foundation of China (No. 21502062).
F.V. acknowledges the support from the Russian Founda-
tion for Basic Research (Nꢀ 18-29-04047) and the Tomsk
Polytechnic University Competitiveness Enhancement
Program grant (VIU-69/2019).
catalyzed amidation of alcohols with amines
active species since the hydride resonance of −17.09 ppm
in the presence of L persisted for much longer time than
that without L (Figure 2f-2i vs. Figure 3f-3i).
Addressing the dual role of Cs2CO3 herein is closely
related to the recent study of NHC/Pd and NHC/Ni sys-
tems, where O-NHC coupling upon the addition of simi-
lar oxygen bases,[25] so we would like to confirm whether
the occurrence of O-NHC coupling was also involved in
our catalytic systems. Accordingly, we carefully examined
and analyzed the HR-MS spectra of both system A and
system B, but no azolones were observed in both systems
(as shown in Figure S4 and S5 of the supporting informa-
tion). Based on the above experiments and previous
literature,[9b, h, 17, 20a, d] we proposed a possible path-
way for this catalytic reaction (as shown in Figure 6).
Complex 1 and Cs2CO3 at refluxing toluene, either with
or without an extra added NHC precursor L, could give
rise to the NHC-Ru-carbonate complex 6, which reacts
with alcohol 2 and Cs2CO3 to generate key Ru-alkoxide
intermediate I. I could undergo β-hydride elimination to
afford Ru monohydride species II bound with an alde-
hyde, which then reacts with 3 to deliver intermediate III
with elimination of H2. Furthermore, III is subsequently
transformed into Ru monohydride species IV via β-
hydride elimination. Finally, ligand exchange with 2 gives
amide 4 and monohydride complex V, which releases
one H2 molecule to regenerate intermediate I so that the
fulfilment of the catalytic cycle is accomplished.
ORCID
Cheng Chen https://orcid.org/0000-0001-5439-5421
Francis Verpoort https://orcid.org/0000-0002-5184-5500
REFERENCES
[1] a)J. M. Humphrey, A. R. Chamberlin, Chem. Rev. 1997, 97,
2243. b)J. W. Bode, Curr. Opin. Drug Discovery Dev. 2006, 9,
765. c)T. Cupido, J. Tulla-Puche, J. Spengler, F. Albericio,
Curr. Opin. Drug Discovery Dev. 2007, 10, 768. d)E. Valeur,
M. Bradley, Chem. Soc. Rev. 2009, 38, 606. e)M. A. Ali,
T. Punniyamurthy, Adv. Synth. Catal. 2010, 352, 288. f)
V. R. Pattabiraman, J. W. Bode, Nature 2011, 480, 471.
[2] a)C. L. Allen, J. M. J. Williams, Chem. Soc. Rev. 2011, 40, 3405.
b)C. Chen, S. H. Hong, Org. Biomol. Chem. 2011, 9, 20. c)
C. Gunanathan, D. Milstein, Science 2013, 341, 249. d)
C. Gunanathan, D. Milstein, Chem. Rev. 2014, 114, 12024. e)
R. M. de Figueiredo, J.-S. Suppo, J.-M. Campagne, Chem. Rev.
2016, 116, 12029. f)X. Q. Xiong, G. M. Fan, R. J. Zhu, L. Shi,
S. Y. Xiao, C. Bi, Prog. Chem. 2016, 28, 497. g)D. G. Gusey,
ACS Catal. 2017, 7, 6656.
[3] a)A. J. A. Watson, J. M. J. Williams, Science 2010, 329, 635. b)
G. E. Dobereiner, R. H. Crabtree, Chem. Rev. 2010, 110, 681. c)
S. Baehn, S. Imm, L. Neubert, M. Zhang, H. Neumann,
M. Beller, ChemCatChem 2011, 3, 1853. d)A. Quintard,
J. Rodriguez, ChemSusChem 2016, 9, 28. e)B. G. Reed-Berendt,

10 of 10
WANG ET AL.
K. Polidano, L. C. Morrill, Org. Biomol. Chem. 2019, 17, 1595.
f)A. K. Bains, A. Kundu, S. Yadav, D. Adhikari, ACS Catal.
2019, 9, 9051.
G. Prakash, M. Nirmala, P. Viswanathamurthi, S. Fujiwara,
A. Endo, Inorg. Chim. Acta 2017, 454, 46.
[19] T. Higuchi, R. Tagawa, A. Iimuro, S. Akiyama, H. Nagae,
K. Mashima, Chem. – Eur. J. 2017, 23, 12795.
[4] C. Chen, F. Verpoort, Q. Wu, RSC Adv. 2016, 6, 55599.
[5] T. Naota, S. I. Murahashi, Synlett 1991, 10, 693.
[6] C. Gunanathan, Y. Ben-David, D. Milstein, Science 2007,
317, 790.
[7] a)L. U. Nordstrøm, H. Vogt, R. Madsen, J. Am. Chem. Soc.
2008, 130, 17672. b)J. H. Dam, G. Osztrovszky,
L. U. Nordstrøm, R. Madsen, Chem. – Eur. J. 2010, 16, 6820. c)
I. S. Makarov, P. Fristrup, R. Madsen, Chem. – Eur. J. 2012, 18,
15683.
[20] a)H. Cheng, M.-Q. Xiong, C.-X. Cheng, H.-J. Wang, Q. Lu, H.-
F. Liu, F.-B. Yao, C. Chen, F. Verpoort, Chem. – Asian J. 2018,
13, 440. b)H. Cheng, M.-Q. Xiong, N. Zhang, H.-J. Wang,
Y. Miao, W. Su, Y. Yuan, C. Chen, F. Verpoort, ChemCatChem
2018, 10, 4338. c)C. Chen, Y. Miao, K. De Winter, H. J. Wang,
P. Demeyere, Y. Yuan, F. Verpoort, Molecules 2018, 23, 2413.
d)X.-J. Wu, H.-J. Wang, Z.-Q. Yang, X.-S. Tang, Y. Yuan,
W. Su, C. Chen, F. Verpoort, Org. Chem. Front. 2019, 6, 563.
[21] M. Maji, K. Chakrabarti, B. Paul, B. C. Roy, S. Kundu, Adv.
Synth. Catal. 2018, 360, 722.
[8] a)A. J. A. Watson, A. C. Maxwell, J. M. J. Williams, Org.
Lett.
2009,
11,
2667.
b)A.
J.
A.
Watson,
R. J. Wakeham, A. C. Maxwell, J. M. J. Williams, Tetrahedron
2014, 70, 3683.
[22] a)H. V. Huynh, Y. Han, R. Jothibasu, J. A. Yang, Organometal-
lics 2009, 28, 5395. b)C. Chen, M. H. Kim, S. H. Hong, Org.
Chem. Front. 2015, 2, 241. c)S. Kaufhold, L. Petermann,
R. Staehle, S. Rau, Coord. Chem. Rev. 2015, 304, 73. d)X. Xie,
H. V. Huynh, Org. Chem. Front. 2015, 2, 1598. e)H. Han Vinh,
Chem. Rev. 2018, 118, 9457.
[23] a)L. Gu, J. Lim, J. L. Cheong, S. S. Lee, Chem. Commun. 2014,
50, 7017. b)T. Ben Halima, J. Masson-Makdissi,
S. G. Newman, Angew. Chem. Int. Ed. 2018, 57, 12925.
[24] a)B. Demerseman, M. D. Mbaye, D. Sémeril, L. Toupet,
C. Bruneau, P. H. Dixneuf, Eur. J. Inorg. Chem. 2006, 2006,
1174. b)C. E. Ellul, O. Saker, M. F. Mahon, D. C. Apperley,
M. K. Whittlesey, Organometallics 2008, 27, 100. c)A. Azua,
S. Sanz, E. Peris, Organometallics 2010, 29, 3661. d)
B. Christian Schulte, F. E. Hahn, Eur. J. Inorg. Chem. 2015,
2015, 3227. e)C. Mejuto, M. A. Garcia-Eleno, G. Guisado-
Barrios, D. Spasyuk, D. Gusev, E. Peris, Org. Chem. Front.
2015, 2, 936. f)A. Azua, M. Finn, H. Yi, A. B. Dantas,
A. Voutchkova-Kostal, ACS Sustainable Chem. Eng. 2017, 5,
3963.
[9] a)S. C. Ghosh, S. Muthaiah, Y. Zhang, X. Y. Xu, S. H. Hong,
Adv. Synth. Catal. 2009, 351, 2643. b)Y. Zhang, C. Chen,
S. C. Ghosh, Y. Li, S. H. Hong, Organometallics 2010, 29, 1374.
c)S. Muthaiah, S. C. Ghosh, J. E. Jee, C. Chen, J. Zhang,
S. H. Hong, J. Org. Chem. 2010, 75, 3002. d)S. C. Ghosh,
S. H. Hong, Eur. J. Org. Chem. 2010, 22, 4266. e)J. Zhang,
M. Senthilkumar, S. C. Ghosh, S. H. Hong, Angew. Chem. Int.
Ed. 2010, 49, 6391. f)C. Chen, Y. Zhang, S. H. Hong, J. Org.
Chem. 2011, 76, 10005. g)C. Chen, S. H. Hong, Org. Lett. 2012,
14, 2992. h)K. Kim, B. Kang, S. H. Hong, Tetrahedron 2015,
71, 4565. i)B. Kang, S. H. Hong, Adv. Synth. Catal. 2015, 357,
834. j)S. H. Kim, S. H. Hong, Org. Lett. 2016, 18, 212.
[10] a)A. Nova, D. Balcells, N. D. Schley, G. E. Dobereiner,
R. H. Crabtree, O. Eisenstein, Organometallics 2010, 29, 6548.
b)N. D. Schley, G. E. Dobereiner, R. H. Crabtree, Organometal-
lics 2011, 30, 4174.
[11] A. Prades, E. Peris, M. Albrecht, Organometallics 2011, 30,
1162.
[12] a)B. Gnanaprakasam, E. Balaraman, Y. Ben-David,
D. Milstein, Angew. Chem. Int. Ed. 2011, 50, 12240. b)
B. Gnanaprakasam, E. Balaraman, C. Gunanathan,
D. Milstein, J. Polym. Sci., Part a: Polym. Chem. 2012, 50, 1755.
c)D. Srimani, E. Balaraman, P. Hu, Y. Ben-David, D. Milstein,
Adv. Synth. Catal. 2013, 355, 2525.
[13] a)H. Zeng, Z. Guan, J. Am. Chem. Soc. 2011, 133, 1159. b)
N. J. Oldenhuis, V. M. Dong, Z. Guan, Tetrahedron 2014, 70,
4213.
[14] N. Ortega, C. Richter, F. Glorius, Org. Lett. 2013, 15, 1776.
[15] a)J. Malineni, C. Merkens, H. Keul, M. Möller, Cat. Com.
2013, 40, 80. b)J. Malineni, H. Keul, M. Möller, Macromol.
Rapid Commun. 2015, 36, 547.
[16] B. Saha, G. Sengupta, A. Sarbajna, I. Dutta, J. K. Bera,
J. Organomet. Chem. 2014, 771, 124.
[25] V. M. Chernyshev, O. V. Khazipov, M. A. Shevchenko,
A. Y. Chernenko, A. V. Astakhov, D. B. Eremin,
D. V. Pasyukov, A. S. Kashin, V. P. Ananikov, Chem. Sci. 2018,
9, 5564.
SUPPORTING INFORMATION
Additional supporting information may be found online
in the Supporting Information section at the end of this
article.
How to cite this article: Wang W-Q, Yuan Y,
Miao Y, et al. Well-defined N-heterocyclic carbene/
ruthenium complexes for the alcohol amidation
with amines: The dual role of cesium carbonate
and improved activities applying an added ligand.
Appl Organometal Chem. 2019;e5323. https://doi.
org/10.1002/aoc.5323
[17] X. K. Xie, H. V. Huynh, ACS Catal. 2015, 5, 4143.
[18] a)M. Nirmala, P. Viswanathamurthi, J. Chem. Sci. 2016, 128, 9.
b)S. Selvamurugan, R. Ramachandran, G. Prakash,
P. Viswanathamurthi, J. G. Malecki, A. Endo, J. Organomet.
Chem. 2016, 803, 119. c)S. Selvamurugan, R. Ramachandran,