Efficient N-Heterocyclic Carbene/Ruthenium Catalytic Systems for the Alcohol Amidation with Amines: Involvement of Poly-Carbene Complexes?

Article abstract of DOI:10.1002/cctc.201800945

The atom-economic direct amidation of alcohols with amines has been recently highlighted as an attractive and promising transformation. Among the versatile reported catalytic systems, in situ generated N-heterocyclic carbene (NHC)/ruthenium (Ru) catalytic systems have demonstrated their advantages such as easy operation and use of commercial Ru compounds. However, the existing catalyst loadings are relatively high, and additional insights for the in situ catalyst generation are still not well-documented. In this work, a variety of benzimidazole-based NHC precursors were initially synthesized. Through the screening of various NHC precursors and other reaction conditions, active in situ catalytic systems were discovered for the efficient amide synthesis. Notably, the catalyst loading is as low as 0.5 mol %. Furthermore, additional experiments were performed to validate the rationale for the superiority of the current catalytic systems over our previous system. It was observed that the ligand structure is one of the reasons for the higher activity. In addition, the higher ratio of the NHC precursor/[Ru] is another important factor for the improvement. Further HR-MS analysis identified the formation of two mono-NHC-Ru species as major species and two Ru species bearing multiple NHC ligands as minor species. Hopefully, the efficient and readily-accessible catalytic systems reported herein could demonstrate great potential for further practical applications.

Full text of DOI:10.1002/cctc.201800945

Accepted Article
Title: Efficient N-heterocyclic carbene/ruthenium catalytic systems for
the alcohol amidation with amines: Involvement of poly-carbene
complexes?
Authors: Hua Cheng, Mao-Qian Xiong, Ni Zhang, Hua-Jing Wang,
Yang Miao, Wei Su, Ye Yuan, Cheng Chen, and Francis
Verpoort
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To be cited as: ChemCatChem 10.1002/cctc.201800945
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10.1002/cctc.201800945
ChemCatChem
FULL PAPER
Efficient N-heterocyclic carbene/ruthenium catalytic systems for
the alcohol amidation with amines: Involvement of poly-carbene
complexes?
Hua Cheng,[b] Mao-Qian Xiong,[a] Ni Zhang,[f] Hua-Jing Wang,[c] Yang Miao,[d] Wei Su,[d] Ye Yuan,[a]
Cheng Chen*[a] and Francis Verpoort*[a, d, e]
Abstract: The atom-economic direct amidation of alcohols with
amines has been recently highlighted as an attractive and promising
transformation. Among the versitile reported catalytic systems, in situ
generated N-heterocyclic carbene (NHC)/ruthenium (Ru) catalytic
systems have demonstrated their advantages such as easy operation
and use of commercial Ru compounds. However, the existing catalyst
loadings are relatively high, and additional insights for the in situ
catalyst generation are still not well-documented. In this work, a
variety of benzimidazole-based NHC precursors were initially
synthesized. Through the screening of various NHC precursors and
other reaction conditions, active in situ catalytic systems were
discovered for the efficient amide synthesis. Notably, the catalyst
loading is as low as 0.5 mol%. Furthermore, additional experiments
were performed to validate the rationale for the superiority of the
current catalytic systems over our previous system. It was observed
that the ligand structure is one of the reasons for the higher activity.
In addition, the higher ratio of the NHC precursor/[Ru] is another
important factor for the improvement. Further HR-MS analysis
identified the formation of two mono-NHC-Ru species as major
species and two Ru species bearing multiple NHC ligands as minor
species. Hopefully, the efficient and readily-accessible catalytic
systems reported herein could demonstrate great potential for further
practical applications.
The amide bond is a key functional group in organic chemistry
and biological systems.[1] Recently, ruthenium (Ru)-catalyzed
amide synthesis directly from alcohols and amines has been
demonstrated as a hot research area, showing a promising
prospect for synthetic applications. This method is an atom-
economic and environmental-benign transformation which
generates hydrogen as the sole byproduct.[2] Initially, Murahashi
and co-workers reported the pioneering work in which five- and
six-membered lactams were synthesized from amino alcohols in
an intramolecular process.[3] The major breakthrough of this area
is the development of the Milstein catalyst, which drove the amide
synthesis in a highly efficient and intermolecular manner.[4]
Inspired by the above reports, numerous researchers have
developed their catalytic systems for this reaction.[5] Particularly,
N-heterocyclic carbenes (NHCs) have been regarded as
attractive ligands because flexible tuning of their chemical
structures could be easily realized to achieve the optimal catalytic
performance depending on their metal complexes.[6] Hence,
various NHC-based Ru (NHC-Ru) catalytic systems with good
catalytic performance have also been developed.[5a, 5c, 5d, 5f-j, 5n, 5q,
5r, 5t, 5w, 5y, 5z, 5ab]
Although well-defined NHC-Ru complexes have been reported
to be active for this reaction, the respective in situ catalytic
systems attracted our great interest due to their easy operation
and use of commercially-available Ru sources. Moreover, it is
convenient to systematically investigate a multitude of NHC-Ru
catalytic systems by avoiding the isolation and purification of the
NHC-Ru and/or the NHC-Ag complexes. Among the reported in
situ NHC-Ru catalytic systems, imidazole-based ones with the
catalyst loadings of 2.0-5.0 mol% were extensively studied, and
satisfactory results were attained with[5a, 5c, 5g, 5h] or without[5q] an
additional ligand (Figure 1a). Previously, our work revealed that
Ru catalytic systems incorporating a benzimidazole-derived NHC
precursor could exhibit promising catalytic efficiency in the
absence of an additional ligand (Figure 1b).[7] However, the
catalyst loading is still quite high (5.0 mol%), and insufficient
insights concerning the in situ catalyst generation were provided.
Herein, we envisioned that efficient catalytic systems could be
obtained by a systematic investigation of variable parameters on
the benzimidazole-based NHC-Ru catalytic systems. Firstly,
varied substituents could be introduced on R1-R4 and X1 to tune
the electronic and steric properties of the in situ generated NHC-
Ru complexes (Figure 1c). In addition, other parameters would
also be screened to further optimize the reaction conditions.
Herein, a variety of NHC precursors were synthesized by
structural modifications from the benzimidazole backbone.
Through extensive screening of various conditions, active in situ
NHC-Ru catalytic systems, with a catalyst loading of 0.5 mol%,
were developed for the efficient amide synthesis. Furthermore,
Introduction
[a]
Mr. Mao-Qian Xiong, Dr. Ye Yuan, Dr. Cheng Chen, Prof. Dr. 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
E-mails: chengchen@whut.edu.cn; francis.verpoort@ghent.ac.kr
Dr. Hua Cheng
Department of Chemical Engineering and Food Science
Hubei University of Arts and Science
296 Longzhong Road, Xiangyang 441053, P. R. China
Miss. Hua-Jing Wang
School of Chemistry, Chemical Engineering and Life Sciences
Wuhan University of Technology
[b]
[c]
[d]
122 Luoshi Road, Wuhan 430070, P. R. China
Mr. Yang Miao, Dr. Wei Su
School of Materials Science and Engineering
Wuhan University of Technology
122 Luoshi Road, Wuhan 430070, P. R. China
Prof. Dr. Francis Verpoort
National Research Tomsk Polytechnic University
Lenin Avenue 30, 634050, Tomsk, Russian Federation
Mrs. Ni Zhang
[e]
[f]
Hubei University of Technology Engineering and Technology College
28 Nanli Road, Wuhan 430068, P. R. China.
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10.1002/cctc.201800945
ChemCatChem
FULL PAPER
that the amount of both L12 and NaH changed so as to ensure
three additional equivalents of NaH to activate [RuCl2(p-
cymene)]2 for all the cases. In addition, elongating the reaction
time from 16 h to 36 h could give 3a in 93% yield with 5% of 4a
(entry 6), and a slightly better result was obtained for L25 (entry
7). Furthermore, reducing the catalyst loading to 0.25 mol%
resulted in lower yields of product 3a for both L12 and L25 (entries
8-9). Therefore, the optimized reaction conditions were identified
as 1 (2.50 mmol), 2 (2.75 mmol), [RuCl2(p-cymene)]2 (0.00625
mmol), L12 or L25 (0.05 mmol), NaH (0.0875 mmol), toluene
(1.25 mL), reflux, 36 h unless otherwise noted.
Figure 1. The design strategy of this work.
With the optimized reaction conditions in hand, the substrate
scope and limitations were investigated (as depicted in Figure 2).
Good to excellent yields were given for sterically nonhindered
substrates (1a-1f). In particular, the amino alcohol 1f afforded a
six-membered cyclic lactam (3f) intramolecularly in 76% yield. To
our delight, cyclic secondary amines (2g and 2h) and N-methyl-
1-phenylmethanamine (2i) also reacted smoothly, producing the
corresponding amides (3g-3i) with 75-82% yields. Besides, with
L12 as the NHC precursor, heterocyclic substrates 1j and 1k
could be transformed into the amides 3j and 3k in 65-75% yields,
which is analogous to our previous work.[7] In contrast, L25 can
catalyze the same reactions in more than 90% yields. Apparently,
our catalytic systems are also sensitive to steric bulks and
aromatic amines, and the modestly congested substrates (1l-1n)
and less basic aniline (2o) produced amides 3l-3o in moderate
yields. However, it is worth noting that only 1.00 mol% catalyst
loading was used for these challenging substrates. Furthermore,
the electronic effects were explored on both substrates. The L12-
and L25-containing catalytic systems could catalyze most
electron-rich and electron-deficient substrates (1p-1c') efficiently.
To understand the rationale for the improvement of the L12-
and L25-containing catalytic systems ([Ru] = 0.5 mol%) over our
previously reported L1-based system ([Ru] = 5.0 mol%), we firstly
studied the influences of different NHC precursors on the catalytic
activities at a catalyst loading of 1.0 mol% (as shown in Figure 3).
L1, L2, L3, L7 and L9 were selected for exploring the electronic
effects. The results indicated that the electron-poor precursors
triggered lower reaction rates and comparable (or insignificantly
lower) amide/imine selectivity. For the electron-rich NHC
precursors, L7 manifested similar activities as L1. However, L9,
which bears a bulkier tBu group as R1, resulted in low amide
percentage among the three products. Additionally, L1, L12-L16
were chosen for studying the steric effects. Unlike imidazole-
based NHC precursors in which a bulkier iPr group as both wingtip
groups is beneficial for the selective amide formation,[5c] the
additional investigations were performed to reveal the rationale
for the superiority of the present catalytic systems over our
previous system.
Results and Discussion
Since the electronic and steric properties of NHCs could affect
their coordination with Ru, a series of benzimidazole derivatives
were prepared as the NHC precursors. The coupling of benzyl
alcohol (1a) with benzylamine (2a) was used as a benchmark, and
the influence of the backbone and wingtip substituents on catalytic
activities was thoroughly examined (as listed in Table 1). In
anticipation of clearly comparing product distribution among
amide 3a, imine 4a and unreacted 1a, 1.00 mol% of the catalyst
loading and 16 h of the reaction time were applied. The first and
foremost, 61% of 3a and 6% of 4a were obtained with 30% of 1a
remaining when L1 was used (entry 1). In order to explore the
electronic effects of NHCs on the catalysis, employment of
different substituents on R1 and R2 were attempted (entries 2-11).
Electron-withdrawing groups gave rise to lower amide content in
the product distribution, demonstrating their disadvantages for the
selective amide formation (entries 2-6 vs. entry 1). Nevertheless,
compared with L1, most electron-rich analogs exhibited
comparable yields of all the three products (entries 7-8, 10-11 vs.
entry 1). However, a bulkier tBu group provided a low amide/imine
selectivity (entry 9 vs. entry 1). Next, a number of R3 and R4
groups were introduced to understand the steric effects on the
catalytic performance (entries 12-18). Extensive screening data
implied that R3 and R4 groups were optimized as Me and Et,
respectively (entries 1, 12-18). Moreover, different anions of the
NHC precursors were evaluated and an iodide was recognized as
the best one (entries 12, 19-21). Finally, replacement of the H
atoms on R1 and R2 with one or two electron-donating groups
resulted in comparable or inconsiderably better results (entries 12,
22-26). From the perspectives of the amide/imine selectivity and
synthetic simplicity, both L12 and L25 were chosen for further
investigations.
benzimidazole counterparts bearing
a bulky iPr or Cyp
(cyclopentyl) group at R4 resulted in low amide/imine selectivity.
The above results implied that electronic properties affected both
reaction rates and the amide/imine selectivity, while sterics mainly
play paramount roles in the amide/imine selectivity. Consequently,
the L12-containing catalytic system showed better catalytic
activity than the L1-based system under identical reaction
conditions. However, the undramatic difference between these
two systems is indicative of other reasons for the enhancement of
the catalyst performance.
After setting up the ideal NHC precursors, we continued the
optimization by screening other reaction conditions (as listed in
Table 2). When the catalyst loading was decreased to 0.50 mol%,
the yield of 3a dropped dramatically (77% for entry 1 and 45% for
entry 2). Interestingly, if the ratio of [Ru]: L12: NaH was changed
from 1:1:4 to 1:2:5, 1:3:6 and 1:4:7, the yields of 3a increased
gradually from 45% to 84% (Entries 2-5). It is worth mentioning
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Table 1. Amide synthesis applying various benzimidazole-based NHC precursors.[a]
Yield (%)[b]
Entry
L
R1
R2
R3
R4
X1
3a
4a
Unreacted 1a
1
L1
H
H
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
I
61
50
45
42
31
30
62
61
21
65
64
77
60
58
34
36
57
63
62
64
68
80
76
79
83
72
6
30
35
40
42
60
62
28
27
45
25
25
16
25
28
34
32
20
30
26
24
20
3
2
L2
F
H
I
7
3
L3
Cl
H
I
6
4
L4
Br
H
I
5
5
L5
F
F
I
8
6
L6
Cl
Cl
H
I
7
7
L7
Me
OMe
tBu
Me
OMe
H
I
6
8
L8
H
I
6
9
L9
H
I
31
6
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
L10
L11
L12
L13
L14
L15
L16
L17
L18
L19
L20
L21
L22
L23
L24
L25
L26
Me
OMe
H
I
I
5
I
5
H
H
nPr
nBu
iPr
Cyp
Bn
Et
I
10
9
H
H
I
H
H
I
27
29
10
5
H
H
I
H
H
I
H
H
I
H
H
Me
Me
Me
Me
Et
Et
Br
10
5
H
H
Et
BF4
H
H
Et
PF6
5
Me
Me
OMe
Me
OMe
H
Et
I
I
I
I
I
9
H
Me
Et
6
8
H
Me
Me
Me
9
5
Me
OMe
Et
5
10
18
Et
6
[a] 1a (2.50 mmol), 2a (2.75 mmol), [RuCl2(p-cymene)]2 (0.50 mol%), L (1.00 mol%), NaH (4.00 mol%) and toluene (1.50 mL) were used; [b] NMR yields (average
of two consistent runs) using 1,3,5-trimethoxybenzene as an internal standard.
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Table 2. Optimization of reaction conditions based on L12 or L25.[a]
Yield (%)[b]
Reaction
Time
Entry
L
x
y
z
3a
4a
Unreacted 1a
1
2
3
4
5
6
7
8
9
L12
L12
L12
L12
L12
L12
L25
L12
L25
1.00
0.50
0.50
0.50
0.50
0.50
0.50
0.25
0.25
1.00
0.50
1.00
1.50
2.00
2.00
2.00
1.00
1.00
4.00
2.00
2.50
3.00
3.50
3.50
3.50
1.75
1.75
16 h
16 h
16 h
16 h
16 h
36 h
36 h
48 h
48 h
77
45
68
83
84
93
94
48
60
5
16
42
25
11
10
0
8
6
4
4
5
4
0
14
12
32
25
[a] 1a (1.00 equiv.), 2a (1.10 equiv.), [RuCl2(p-cymene)]2 (0.5x mol%), L12 or L25 (y mol%), NaH (z mol%) and toluene were used; [b] NMR yields
(average of two consistent runs) using 1,3,5-trimethoxybenzene as an internal standard.
Figure 2. Amide synthesis from various alcohols and amines.
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Interestingly, isotopic peaks at m/z = 617.1733 and 743.3137,
consistent with Ru ions comprising three or four NHC ligands
([Ru]-3 and [Ru]-4, respectively), were also observed, which
might be possible intermediates of the catalytic cycle (as shown
in Figure 5). The HR-MS spectra of the proposed [Ru]-3 and [Ru]-
4 species could be clearly seen in Figure S1 of the supporting
information. Unfortunately, we failed to isolate these poly-carbene
complexes probably due to the tiny amount of these complexes
and the complexity of the in situ catalyst generation. Therefore, it
is still unclear whether the higher catalytic performance from the
increased ratio of L12/[Ru] is either attributed to the more efficient
generation of the expected mono-NHC-Ru species, or due to the
formation of the observed poly-carbene species.
Based on the above experiments and our previous
publication,[7] we proposed possible pathways for the formation of
key [Ru]H2 species IV (as illustrated in Figure 6). In situ catalyst
generation affords mono-NHC-Ru intermediates Ia and poly-
carbene complexes Ib-Ic. Apparently, with the aid of NaH, Ia or Ib
could react with an alcohol to generate Ru alkoxide species II,
which could be subsequently transformed into Ru monohydride
species III via β-hydrogen elimination. Finally, Treatment of III
with an alcohol and NaH yields IV. In the case of intermediate Ic,
its reaction with an alcohol and NaH could give the corresponding
alkoxide V, which might be further transformed into IV.
Figure 3. Electronic and steric effects of NHCs on the catalytic performance.
Next, with regard to the in situ generated catalytic systems, the
efficiency of the catalyst generation is crucial for the catalysis. In
the first place, the duration for the in situ catalyst generation was
adjusted (as depicted in Figure 4a). If all substances were added
simultaneously, only a trace amount of 3a, 30% of 4a and 60% of
unreacted 1a were detected. However, the catalytic performance
almost persisted with the period for the catalyst formation
spanning from 0.5-2.5 h. Besides, it was noticed that the
increased ratio of L12/[Ru] was indispensable to achieve the
desired results at a low catalyst loading. Therefore, the catalytic
performance with different ratios of L12/[Ru] were evaluated (as
shown in Figure 4b). In the absence of L9, no amide 3a was
formed. Excitingly, significantly higher amide selectivity and
conversion were obtained as the ratio of L12/[Ru] increased from
1:1 to 4:1. The detailed procedures of these experiments can be
found in the supporting information. As bis-NHC-Ru complexes
were previously detected and proposed in the literature,[7-8] there
are two feasible reasons behind the above phenomenon. A higher
L12/[Ru] ratio might either be attributed to more efficient formation
of the expected mono-NHC-Ru species, and/or facilitate the
generation of new Ru complexes bearing multiple NHC ligands.
With the aim to clarify this matter, the possible structures of the
generated Ru species were analyzed by HR-MS. Not surprisingly,
two mono-NHC-Ru species, assigned as [Ru]-1 and [Ru]-2, were
detected from the catalytic system (as shown in Figure 5).
Figure 4. Efficiency of generating the L12-based catalytic system.
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431.0827
100
90
80
70
60
50
40
436.0837
425.0861
30
20
10
0
523.0188
517.0217
743.3137
722.8470
683.1184
413.1167
400
617.1733
455.1270
450
641.2177
650
563.0483 594.1321
500
550
600
m/z
700
750
Figure 5. The HR-MS analysis for the identification of the possible Ru species.
Conclusions
In summary, we have developed a variety of in situ generated
NHC-Ru catalytic systems by introducing different substituents on
the benzimidazole-based NHC precursors. Through a systematic
investigation of the ligand structures and various reaction
conditions, the L12- and L25-based NHC-Ru catalytic systems
were found to be active for the atom-economic alcohol amidation
with amines, which yielded a number of amides in moderate to
excellent yields. Notably, the catalyst loading is at a low level of
0.5 mol%. Furthermore, we attempted to rationalize the
enhancement of the L12-based catalytic system over our
previous L1-based system. Electronic and steric effects of NHC
precursors on the catalytic performance were thoroughly explored,
and the results suggested that the ligand structure is one of the
reasons for the improvement. Moreover, it seems that the
increased ratio of L12/[Ru] should be another important factor for
the enhanced catalytic activities. Further experiments indicated
that the relatively higher ratio not only resulted in the expected
mono-NHC-Ru complexes as major species, but also two
(poly)NHC-Ru intermediates as minor species. Probably, the
current catalytic systems, featuring high efficiency and ready
accessibility, could be valuable for more interesting applications.
Figure 6. The proposed pathways for the generation of key [Ru]H2 species IV.
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under reduced pressure, and the residue was washed a few times with
EtOAc to provide pure compound L2 (or L5-L6, L8-L9, L11).
Experimental Section
General considerations
General procedure for preparing L16, L22-L26 (Scheme 2).
All reactions were carried out using standard Schlenk techniques or in an
argon-filled glove box unless otherwise 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 NMR spectra were recorded in CDCl3 or DMSO-d6 on
a Bruker Avance 500 (126 MHz) spectrometer. The following abbreviations
are used to designate multiplicities: s = singlet, brs = broad singlet, d =
doublet, t = triplet, q = quartet, dd = doublet of doublets, m = multiplet.
Melting points were taken on a Buchi M-560 melting point apparatus and
are
uncorrected.
HR-MS
analysis
was
done
with
a Bruker Daltonics microTOF-QII instrument or
a
Thermo Fisher
Q
Exactive Mass Spectrometer. The known benzimidazole-based NHC
precursors, including 1,3-dimethyl-1H-benzo[d]imidazol-3-ium iodide
(L1)[7] 6-chloro-1,3-dimethyl-1H-benzo[d]imidazol-3-ium iodide (L3),[9] 6-
bromo-1,3-dimethyl-1H-benzo[d]imidazol-3-ium iodide (L4),[10] 1,3,6-
trimethyl-1H-benzo[d]imidazol-3-ium iodide (L7),[9] 1,3,5,6-tetramethyl-1H-
Scheme 2. The synthetic procedure of L16, L22-L26.
In an oven-dried 25 mL Schlenk tube, 6a (or 6b-6f, 6.00 mmol) was
dissolved in dry DMF (2 mL). While stirring at 0 °C, NaH (60% dispersion
in mineral oil) (264 mg, 6.60 mmol) was added carefully and the
suspension was stirred at room temperature for 0.5 h. Then methyl iodide
or ethyl iodide (6.60 mmol) was added dropwise, and the white suspension
was stirred at room temperature for 4-8 h, as monitored by TLC to confirm
complete conversion. The reaction mixture was poured into ice-cold water
in one portion, and extracted with ethyl acetate (3 x 30 mL). The combined
organic layers were washed with brine (3 x 50 mL), dried over Na2SO4,
filtrated and concentrated under reduced pressure to afford the crude
product 7a (or 7b-7f), which was used directly for the next step. Afterwards,
7a (or 7b-7f, 2.00 mmol) and an iodide (4.00 mmol) were dissolved in
acetonitrile (20 mL) and refluxed for 16-36 h. The solvent was then
removed under reduced pressure, and the residue was washed a few
times with EtOAc to provide pure compound L16 (or L22-L26).
benzo[d]imidazol-3-ium
benzo[d]imidazol-3-ium
benzo[d]imidazol-3-ium
benzo[d]imidazol-3-ium
benzo[d]imidazol-3-ium
iodide
iodide
iodide
iodide
iodide
(L10),[7]
(L12),[11]
(L13),[12]
(L14),[13]
(L15),[11]
3-ethyl-1-methyl-1H-
1-methyl-3-propyl-1H-
3-isopropyl-1-methyl-1H-
3-butyl-1-methyl-1H-
3-benzyl-1-methyl-1H-
benzo[d]imidazol-3-ium iodide (L17),[13] 1,3-diethyl-1H-benzo[d]imidazol-
3-ium iodide (L18),[13] 3-ethyl-1-methyl-1H-benzo[d]imidazol-3-ium
bromide
(L19),[10]
3-ethyl-1-methyl-1H-benzo[d]imidazol-3-ium
hexafluorophosphate (L21)[13] were prepared using the procedures
reported in the literature. Other NHC precursors were prepared by the
methods shown in the following sections.
General procedure for synthesizing L2, L5-L6, L8-L9, L11
(Scheme 1).
General procedure for the synthesis of L20
To a 50 mL round bottom flask were added L12 (0.288 g, 1.00 mmol)
and silver tetrafluoroborate (0.204 g, 1.05 mmol) and acetone (20 mL), and
the reaction mixture was stirred at room temperature for 3 hours. After the
completion of the reaction, the mixture was then filtered. The acetone of
the filtrate was removed under reduced pressure, and the residue was
washed a few times with diethyl ether to afford pure L20 (0.191 g, 77%).
General procedure for the amide synthesis
To an oven-dried Schlenk tube was added [Ru(p-cymene)Cl2]2 (3.9 mg,
0.00625 mmol), L12 (14.4 mg, 0.05 mmol) or L25 (15.1 mg, 0.05 mmol),
NaH (60 % dispersion in mineral oil, 3.5 mg, 0.0875 mmol) and dry toluene
(1.25 mL) inside an argon-filled glovebox. The tube was taken out of the
glovebox and heated to reflux under argon for 0.5 h. After the reaction
mixture was cooled down to room temperature, an alcohol (2.50 mmol), an
amine (2.75 mmol) were added and the mixture was heated to reflux in an
open condition under an argon atmosphere for 36 h. Afterwards, the
solvent was removed under reduced pressure, and the residue was
purified by silica gel flash column chromatography to afford the amide
products. Amide products, including N-benzylbenzamide (3a),[14] N-
benzyl-2-phenylacetamide (3b),[5i] N-benzylhexanamide (3c),[14] N-
phenethylbenzamide (3d),[15] N-hexylbenzamide (3e),[16] Piperidin-2-one
Scheme 1. The synthetic procedure of L2, L5-L6, L8-L9, L11.
4-Fluorobenzene-1,2-diamine (4,5-difluorobenzene-1,2-diamine or 4,5-
dichlorobenzene-1,2-diamine, 6.00 mmol) and formic acid (20 mL) were
added to a 100 mL flask and refluxed for 4 h. The mixture was cooled to
0 °C, and the product was precipitated by neutralization with concentrated
ammonia. The precipitant was collected and washed twice with water, and
dried to give the resulted compound 5a (or 5b-5f), which was used directly
for the next step. Afterwards, 5a (or 5b-5f, 2.00 mmol), K2CO3 (0.414 g,
3.00 mmol), and methyl iodide (0.500 mL, 8.00 mmol) were dissolved in
acetonitrile (20 mL) and refluxed for 16 h. The solvent was removed under
reduced pressure, and the resultant solid was resuspended in
dichloromethane and filtered. Then the solvent of the filtrate was removed
(3f),[5d]
Morpholino(phenyl)methanone (3h),[16] N-benzyl-N-methylbenzamide
(3i),[17] (3j),[14]
N-benzylfuran-2-carboxamide N-(furan-2-
Phenyl(piperidin-1-yl)methanone
(3g),[14]
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10.1002/cctc.201800945
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ylmethyl)benzamide (3k),[18] N-benzyl-2-phenylpropanamide (3l),[19] N-
phenylbenzamide (3o),[14] N-benzyl-4-methylbenzamide (3p),[5p] N-benzyl-
4-fluorobenzamide (3t),[5p] N-benzyl-4-chlorobenzamide (3s),[5g] N-benzyl-
3-fluorobenzamide (3u),[5p] N-benzyl-2-fluorobenzamide (3v),[5p] N-(4-
methylbenzyl)benzamide (3w),[20] N-(4-fluorobenzyl)benzamide (3a'), N-
(4-chlorobenzyl)benzamide (3z),[14] N-(3-fluorobenzyl)benzamide (3b')[21]
and N-(2-fluorobenzyl)benzamide (3c')[22] were identified by spectral
comparison with literature data. Other amides were fully characterized,
data and spectra were shown in the supporting information.
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Acknowledgements
This research was supported by the National Natural Science
Foundation of China (No. 21502062), Hubei Provincial
Department of Education (No. Q20102606), Xiangyang Science
and Technology Bureau (No. 2010GG1B33), and an open project
of electromechanical-automobile discipline of Hubei province (No.
XKQ2017027). F.V. acknowledges the support from the Russian
Foundation for Basic Research (N° 18-29-04047) and the Tomsk
Polytechnic University Competitiveness Enhancement Program
grant (VIU-195/2018).
Keywords: In situ • ruthenium • N-heterocyclic carbene(s) •
atom-economic • amide synthesis
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Entry for the Table of Contents (Please choose one layout)
Layout 1:
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In situ generated N-heterocyclic
carbene (NHC)-based Ru catalytic
systems, with a low catalyst
loading of 0.5 mol%, are reported
to be active for the atom-economic
alcohol amidation with amines.
Moreover, additional experiments
were performed to rationalize the
superiority of the current system
over previously reported ones.
Hua Cheng,[b] Mao-Qian Xiong,[a] Ni
Zhang,[f] Hua-Jing Wang,[c] Yang
Miao,[d] Wei Su,[d] Ye Yuan,[a] Cheng
Chen*[a] and Francis Verpoort*[a, d, e]
Page No. – Page No.
Efficient N-heterocyclic
carbene/ruthenium catalytic
systems for the alcohol amidation
with amines: Involvement of poly-
carbene complexes?
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