Ruthenium-based catalytic systems incorporating a labile cyclooctadiene ligand with N-heterocyclic carbene precursors for the atom-economic alcohol amidation using amines

Article abstract of DOI:10.3390/molecules23102413

Transition-metal-catalyzed amide-bond formation from alcohols and amines is an atom-economic and eco-friendly route. Herein, we identified a highly active in situ N-heterocyclic carbene (NHC)/ruthenium (Ru) catalytic system for this amide synthesis. Various substrates, including sterically hindered ones, could be directly transformed into the corresponding amides with the catalyst loading as low as 0.25 mol.%. In this system, we replaced the p-cymene ligand of the Ru source with a relatively labile cyclooctadiene (cod) ligand so as to more efficiently obtain the corresponding poly-carbene Ru species. Expectedly, the weaker cod ligand could be more easily substituted with multiple mono-NHC ligands. Further high-resolution mass spectrometry (HRMS) analyses revealed that two tetra-carbene complexes were probably generated from the in situ catalytic system.

Full text of DOI:10.3390/molecules23102413

molecules
Communication
Ruthenium-Based Catalytic Systems Incorporating
a Labile Cyclooctadiene Ligand with N-Heterocyclic
Carbene Precursors for the Atom-Economic Alcohol
Amidation Using Amines
Cheng Chen 1 , Yang Miao 2, Kimmy De Winter 3, Hua-Jing Wang 4, Patrick Demeyere 3,
Ye Yuan 1,* and Francis Verpoort 1,2,5,6,
*
1
State Key Laboratory of Advanced Technology for Materials Synthesis and Processing,
Wuhan University of Technology, 122 Luoshi Road, Wuhan 430070, China; chengchen@whut.edu.cn
School of Materials Science and Engineering, Wuhan University of Technology, 122 Luoshi Road,
Wuhan 430070, China; miaoyang2018@126.com
Odisee/KU Leuven Technology Campus, Gebroeders de Smetstraat 1, 9000 Ghent, Belgium;
kimmydewinter@hotmail.com (K.D.W.); patrick.demeyere@odisee.be (P.D.)
School of Chemistry, Chemical Engineering and Life Sciences, Wuhan University of Technology,
122 Luoshi Road, Wuhan 430070, China; 18772101949@163.com
National Research Tomsk Polytechnic University, Lenin Avenue 30, Tomsk 634050, Russian
Ghent University Global Campus, 119 Songdomunhwa-Ro, Yeonsu-Gu, Incheon 21985, Korea
Correspondence: fyyuanye@whut.edu.cn (Y.Y.); francis.verpoort@ghent.ac.kr (F.V.);
Tel.: +86-186-358-00380 (Y.Y.); +86-150-7117-2245 (F.V.)
2
3
4
5
6
*
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
ꢀꢁꢂꢃꢄꢅꢆ
Received: 29 August 2018; Accepted: 18 September 2018; Published: 20 September 2018
Abstract: Transition-metal-catalyzed amide-bond formation from alcohols and amines is
an atom-economic and eco-friendly route. Herein, we identified a highly active in situ N-heterocyclic
carbene (NHC)/ruthenium (Ru) catalytic system for this amide synthesis. Various substrates,
including sterically hindered ones, could be directly transformed into the corresponding amides
with the catalyst loading as low as 0.25 mol.%. In this system, we replaced the p-cymene ligand of
the Ru source with a relatively labile cyclooctadiene (cod) ligand so as to more efficiently obtain
the corresponding poly-carbene Ru species. Expectedly, the weaker cod ligand could be more
easily substituted with multiple mono-NHC ligands. Further high-resolution mass spectrometry
(HRMS) analyses revealed that two tetra-carbene complexes were probably generated from the in
situ catalytic system.
Keywords: ruthenium (Ru); N-heterocyclic carbenes (NHCs); homogeneous catalysis; in situ; amide
bonds; synthesis
1. Introduction
Amides are a series of fundamental functional structures in nature and biological systems, as well
as crucial building blocks for organic synthesis [
reported for the construction of amide bonds. However, they generally suffer from the usage of
various stoichiometric additives and the production of unfavorable equimolar byproducts [ 14].
1–6]. As of late, numerous synthetic methods were
7
–
Therefore, green and eco-friendly strategies are highly required for amide synthesis [15]. Recently,
a methodology employing transition-metal-based catalytic systems for direct amide synthesis from
alcohols and amines was proven to be far more atom-economic and environmentally friendly as the
only byproduct is hydrogen [16–22]. Throughout this research, ruthenium (Ru) was most extensively
studied [23]. Initially, the Murahashi [24] and Milstein [25] groups pioneered Ru-catalyzed amide
Molecules 2018, 23, 2413; doi:10.3390/molecules23102413
www.mdpi.com/journal/molecules

Molecules 2018, 23, 2413
2 of 10
synthesis in intramolecular and intermolecular manners, respectively. Notably, the Milstein catalyst,
a Ru complex bearing a PNN-type pincer ligand, was highly active for this reaction. With a catalyst
loading of 0.1 mol.%, various amides could be synthesized from alcohols and amines [25]. Later,
great progress was achieved by the Milstein [26
Crabtree [44 45], Albrecht [46], Guan [47 48], Glorius [49], Möller [50
Viswanathamurthi [54 56], Mashima [57], Verpoort [58 59], and Kundu [60] groups. In particular,
–28], Madsen [29
–31], Williams [32,33], Hong [34–43],
,
,
,
51], Bera [52], Huynh [53],
–
,
Ru combined with N-heterocyclic carbenes (NHCs) attracted more and more interest due to the
flexible tunability of the electronic and steric properties of NHCs, which may easily access the optimal
structures of the corresponding NHC/Ru complexes [61–63]. Accordingly, a multitude of efficient
NHC/Ru catalytic systems were discovered for this reaction. Furthermore, considering the merits of
the in situ catalytic systems, such as easy operation and convenient investigation of electronically and
sterically distinct NHCs, a number of versatile and potent in situ NHC/Ru catalytic systems recently
emerged. However, satisfactory yields could only be attained by these reported systems if relatively
high Ru loadings of 2.0–5.0 mol.% were employed [29,34,36,37,49]. Therefore, the development of
more efficient in situ NHC/Ru catalytic systems which can accomplish the formation of amide linkage
are urgently required.
In our previous work, the development of various in situ generated (p-cymene)/Ru catalytic
systems, which contain benzimidazole-based NHC precursors bearing different electronic and steric
properties, was accomplished [58]. Further experiments revealed that two mono-NHC/Ru complexes
were observed as major species and two poly-carbene complexes were detected as only minor species
(as depicted in Figure 1a) [59]. Herein, we envisioned that replacing the p-cymene ligand of the Ru
center with a relatively labile cyclooctadiene (cod) ligand could possibly give rise to poly-carbene
complexes as a major species (as shown in Figure 1b). Expectedly, the weaker cod ligand could be
more easily substituted with multiple mono-NHC ligands. Based on this, an efficient in situ NHC/Ru
catalytic system was developed through extensive screening of various conditions. Notably, this system
demonstrated excellent catalytic activity for amide synthesis with the applied catalyst loading as low
as 0.25 mol.%. Various amides, including sterically congested ones, were directly synthesized from
alcohols and amines in moderate to excellent yields. Furthermore, high-resolution mass spectrometry
(HRMS) analyses suggested several Ru species bearing multiple NHC ligands as major species, which
was in accordance with our prospection.
Figure 1. The design strategy of this work.
2. Results and Discussion
The reaction of benzyl alcohol (1a) and benzylamine (2a) was selected as a model reaction for the
optimization of the reaction conditions. Based on our previous work [59], 0.5 mol.% of [RuCl2(cod)]n,
2.00 mol.% of an NHC precursor, 3.50 mol.% of NaH, 0.5 h of catalyst generation time, and 16 h

Molecules 2018, 23, 2413
3 of 10
of reaction time were originally applied (as listed in Table 1). In the beginning, NHC precursors
L1 L6 with different backbone and wingtip substituents were prepared (entries 1–6, Table 1). The first
–
and foremost, 62% of amide 3a and 15% of imine 4a, were obtained with 18% of 1a remaining if L1
was used (entry 1). Electron-deficient precursor L2 gave rise to lower amide content in the product
distribution, demonstrating its disadvantage for amide formation (entry 2 vs. entry 1). In the case
of an electron-rich NHC precursor (L3), a similar result was obtained compared with L1 (entry 3 vs.
entry 1). Moreover, the substituents on the N-terminus of the NHC precursors were adjusted (entries 1,
4–6). With retaining Me as the substituent for one N-terminus, different groups including Et, nPr,
and iPr were introduced for the other terminus. The result was indicative that Et was the optimized
group for this reaction (entry 4 vs. entries 1, 5, and 6). After establishing the ideal NHC precursor (L4),
we continued the optimization by screening other reaction conditions. It was found that the catalyst
generation time was crucial for the catalysis (entries 4, 7–11); 57% of the amide product could be
detected if every substance was added simultaneously (entry 5). As we elongated the period for the in
situ catalyst generation from 0 h to 2.0 h, the yields of 3a gradually increased (entries 4, 7–10). A further
increment of the time led to a similar yield (entry 11 vs. entry 10). Therefore, the ideal duration for the
catalyst generation was finalized as 2 h. Next, the ratio of [Ru]: L4:NaH was varied (entries 12–17). It is
worth emphasizing that the amount of both L4 and NaH changed so as to ascertain three additional
equivalents of NaH to activate [RuCl2(cod)]n for all cases. Without L4, no amide was formed (entry
12). As the ratio increased from 1:0:3 to 1:5:8, gradually higher yields of 3a were observed (entries 10,
12–16). However, a higher ratio prompted a reduced yield of 3a (entry 17 vs. entry 16). Thus, the ratio
of 1:5:8 was recognized as the best one (entry 16), and further increasing the reaction time from 16 h to
36 h produced 3a in 93% yield (entry 18).
In order to identify a more active catalytic system, a reduced Ru loading of 0.25 mol.% was
attempted (as listed in Table 2). At the outset, 65% of 3a was afforded if the loading of the
above-optimized catalytic system was directly reduced to 0.25 mol.% (entry 1). In addition, different
bases including potassium bis(trimethylsilyl)amide (KHMDS), KOtBu, and Cs2CO3 were exploited
instead of NaH (entries 2–4). Interestingly, compared with NaH, the milder Cs2CO3 led to an increased
yield of 3a (entry 4 vs. entry 1). It was also noticed that the volume of toluene was crucial for the
reaction (entries 4–8). Either a more concentrated or diluted solution triggered a lower amide/imine
selectivity (entry 5–8 vs. entry 4). Furthermore, the adjustment of the base amounts influenced the
reaction (entries 4, 9–12), and 1.75 mol.% of Cs2CO3 was found to be optimal for the selective amide
formation (entry 10). Therefore, the optimized reaction conditions were identified as
(5.50 mmol), [RuCl2(cod)]n (0.0125 mmol), L4 (0.0625 mmol), Cs2CO3 (0.075 mmol), toluene (1.50 mL),
reflux, and 36 h unless otherwise noted.
With the optimized reaction conditions at hand, the substrate scope and limitations of this strategy
were further investigated (as depicted in Figure 2). For the sterically non-hindered substrates (1a 1e)
1 (5.00 mmol),
2
–
,
the corresponding amides could be obtained in good to excellent yields. If a secondary amine (1f) was
employed, tertiary amide 3f was also given in 80% yield with 0.5 mol.% of [Ru]. Expectedly, lactam
3g was efficiently afforded from amino alcohol 1f in an intramolecular pattern. On the other hand,
the reactions of benzyl alcohol with substituted benzylamines were evaluated. It seemed that these
substituents had no obvious influence on the reactivity, and amides 3h
yields. In the case of coupling benzylamine with various benzyl alcohols, a substituent at either the
para or meta position resulted in good yields of amides 3l 3n. However, an ortho group gave amide
–3k were synthesized in 75–85%
–
3o in a moderate yield. Apparently, aromatic amines were less reactive, and aniline (2p) produced
amide 3p in only 25% yield. To our delight, this newly developed catalytic system was not as sensitive
to steric bulks as our previous systems [58
,59]. With an Ru loading of 0.5 mol.%, several sterically
hindered substrates could be efficiently transformed into amides 3q–3t.

Molecules 2018, 23, 2413
4 of 10
Table 1. Optimization of reaction conditions with a catalyst loading of 0.5 mol.% a.
Yields (%) b
y
Entry
x
n
L
3a
4a
Unreacted 1a
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18 c
L1
L2
L3
L4
L5
L6
L4
L4
L4
L4
L4
L4
L4
L4
L4
L4
L4
L4
2.00
2.00
2.00
2.00
2.00
2.00
2.00
2.00
2.00
2.00
2.00
0.00
0.50
1.00
1.50
2.50
3.00
2.50
3.50
3.50
3.50
3.50
3.50
3.50
3.50
3.50
3.50
3.50
3.50
1.50
2.00
2.50
3.00
4.00
4.50
4.00
0.5
0.5
0.5
0.5
0.5
0.5
0.0
1.0
1.5
2.0
2.5
2.0
2.0
2.0
2.0
2.0
2.0
2.0
62
28
63
78
72
28
57
79
81
83
82
0
37
60
75
86
81
93
15
30
15
10
12
30
10
6
5
4
4
19
10
11
7
4
6
18
39
16
8
8
39
31
8
7
5
6
76
51
28
16
9
3
0
5
a
1a (2.50 mmol), 2a (2.75 mmol), [RuCl2(cod)]n (0.50 mol.%),
L
(x mol.%), NaH (y mol.%), toluene (1.25 mL), 120 ◦C,
b
n h of catalyst generation time, and 16 h of reaction time; NMR yields (average of two consistent runs) using
1,3,5-trimethoxybenzene as an internal standard; c 36 h of reaction time.
Concerning the in situ catalytic systems, it is crucial to explore the possible structures of the
generated Ru species. As a result, HRMS analyses were performed to clarify this matter (as shown in
Figure 3). In accordance with our speculation, no mono-carbene complexes were detected. Instead, two
poly-carbene Ru species were observed from the spectrum. [Ru]-
at m/z = 812.24209), consistent with an Ru species comprising four-fold NHC ligands, was observed
as a major species. Furthermore, another tetra-carbene Ru species, assigned as [Ru] with the isotopic
peak at m/z = 793.26709, was also found as a minor species. Presumably, during exposure to air and/or
the HRMS measurements, the Ru centers in [Ru] and [Ru] were oxidized to +3 and +4, respectively.
1 (corresponding to an isotopic peak
-2
-1
-2
Unfortunately, attempts to isolate these tetra-carbene complexes were unsuccessful, probably due to
the complexity of the in situ catalyst generation. Therefore, it was still unclear whether the high activity
of the current catalytic system was attributed to the observed tetra-carbene Ru species or other species.

Molecules 2018, 23, 2413
5 of 10
a
Figure 2. Amide synthesis from various alcohols and amines; isolated yields (averages of two
consistent runs); b in m-xylene at reflux; c 0.5 mol.% of [Ru].
Table 2. Optimization of reaction conditions with a catalyst loading of 0.25 mol.% a.
Yields (%) b
y
Entry
x
Base
3a
4a
Unreacted 1a
1
2
3
4
5
6
7
8
9
NaH
KHMDS
KOtBu
2.00
2.00
2.00
2.00
2.00
2.00
2.00
2.00
1.50
1.75
2.25
2.50
1.50
1.50
1.50
1.50
0.50
1.00
2.00
2.50
1.50
1.50
1.50
1.50
65
27
45
86
57
71
69
45
66
90
81
72
7
24
57
32
5
22
12
13
15
12
2
11
15
7
18
13
16
38
15
7
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
10
11
12
10
12
8
15
a 1a (5.00 mmol), 2a (5.50 mmol), [RuCl2(cod)]n (0.25 mol.%), L4 (1.25 mol.%), base (x mol.%), toluene (y mL), 120 ◦C,
b
2 h of catalyst generation time, and 36 h of reaction time; NMR yields (average of two consistent runs) using
1,3,5-trimethoxybenzene as an internal standard.

Molecules 2018, 23, 2413
6 of 10
Figure 3. The high-resolution mass spectrometry (HRMS) analyses for the identification of the possible
Ru species.
3. Experimental
3.1. General Considerations
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
1
and used as received without further purification. H-NMR spectra were recorded on a Bruker Avance
500 spectrometer (Billerica, MA, USA) 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 were used to designate multiplicities: s = singlet, brs = broad singlet,
d = doublet, t = triplet, dd = doublet of doublets, dq = doublet of quartets, td = triplet of doublets,
ddd = doublet of doublets of doublets, and m = multiplet. Melting points were taken on a Buchi
M-560 melting point apparatus (Flawil, Switzerland) and were uncorrected. HRMS analyses were
done with a Bruker Daltonics microTOF-QII instrument (Billerica, MA, USA). NHC precursors L1
–L6
were prepared according to a previous publication [58 59], and all the amide products were identified
,
1
by spectral comparison with the literature data [58,
59]. H-NMR, 13C-NMR data and original spectra
of amides 3a–3t could be found in the Supplementary Materials.
3.2. General Procedure for the Amide Synthesis
Inside an argon-filled glove box, [Ru(cod)Cl2]n (3.5 mg, 0.0125 mmol), L4 (18.0 mg, 0.0625 mmol),
Cs2CO3 (28.6 mg, 0.0875 mmol), and dry toluene (1.50 mL) were added to an oven-dried 25-mL
Schlenk flask. The tube was taken out of the glove box and heated to reflux under argon for 2 h.
Then, an alcohol (5.00 mmol) and an amine (5.50 mmol) were added, and the mixture was stirred at a
refluxing temperature for 36 h. The procedures for calculating the NMR yields were as follows: when
the reaction was complete, 1,3,5-trimethoxybenzene (0.5 mmol, 84.0 mg) and CHCl3 (1.0 mL) were
added to the reaction mixture. Afterward, to an NMR tube was added 0.1 mL of the above solution and

Molecules 2018, 23, 2413
7 of 10
0.4 mL of CDCl3. The NMR yields were obtained based on the exact amount of 1,3,5-trimethoxybenzene.
In order to obtain the isolated yields of the amides, 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.
4. Conclusions
In summary, based on the assumption that the relatively labile cod ligand could be replaced by
multiple NHC ligands to obtain versatile and active catalytic systems, we prepared several NHC
precursors with distinct electronic and steric properties, then combined them with [RuCl2(cod)]n and
a mild Cs2CO3 to obtain a series of in situ NHC/Ru catalytic systems. Through extensive screening of
these systems and other conditions, the L4-based NHC/Ru catalytic system exhibited optimal activity
for the dehydrogenative amidation of alcohols and amines. Various amides, especially sterically
hindered ones, could be afforded in an efficient manner. Notably, the applied catalyst loading was as
low as 0.25 mol.%. Further experiments revealed that the higher amount of L4 compared to Ru probably
facilitated the formation of two tetra-carbene species ([Ru]-1 and [Ru]-2), which were observed from
HRMS analyses. However, since the in situ catalytic system was relatively complicated, it is still
uncertain whether these tetra-carbene Ru species or other species were key catalytic intermediates for
this reaction.
1
Supplementary Materials: Supplementary materials, which contain H-NMR and 13C-NMR data, as well as
spectra of amides 3a–3t, are available online.
Author Contributions: C.C., Y.Y and F.V. discussed and designed the whole project together. C.C., Y.M., K.D.W.,
and H.W. performed the experiments. C.C. and Y.M. wrote the manuscript. Y.Y., F.V. and P.D. revised the
manuscript. All authors read and approved the final manuscript.
Funding: This research was supported by the National Natural Science Foundation of China (No. 21502062). F.V.
acknowledges the support from the Russian Foundation for Basic Research (No. 18-29-04047) and the Tomsk
Polytechnic University Competitiveness Enhancement Program grant (VIU-195/2018).
Conflicts of Interest: The authors declare no conflicts of interest.
References
1.
Humphrey, J.M.; Chamberlin, A.R. Chemical synthesis of natural product peptides: Coupling methods
for the incorporation of noncoded amino acids into peptides. Chem. Rev. 1997, 97, 2243–2266. [CrossRef]
[PubMed]
2.
3.
4.
5.
6.
7.
8.
9.
Bode, J.W. Emerging methods in amide- and peptide-bond formation. Curr. Opin. Drug Discov. Dev.
2006, 9, 765–775. [CrossRef]
Cupido, T.; Tulla-Puche, J.; Spengler, J.; Albericio, F. The synthesis of naturally occurring peptides and their
analogs. Curr. Opin. Drug Discov. Dev. 2007, 10, 768–783.
Valeur, E.; Bradley, M. Amide bond formation: Beyond the myth of coupling reagents. Chem. Soc. Rev.
2009, 38, 606–631. [CrossRef] [PubMed]
Ali, M.A.; Punniyamurthy, T. Palladium-catalyzed one-pot conversion of aldehydes to amides.
Adv. Synth. Catal. 2010, 352, 288–292. [CrossRef]
Pattabiraman, V.R.; Bode, J.W. Rethinking amide bond synthesis. Nature 2011, 480, 471–479. [CrossRef]
[PubMed]
Han, S.Y.; Kim, Y.A. Recent development of peptide coupling reagents in organic synthesis. Tetrahedron
2004, 60, 2447–2467. [CrossRef]
Kohn, M.; Breinbauer, R. The Staudinger ligation-A gift to chemical biology. Angew. Chem. Int. Ed.
2004, 43, 3106–3116. [CrossRef] [PubMed]
Montalbetti, C.A.G.N.; Falque, V. Amide bond formation and peptide coupling. Tetrahedron
2005, 61, 10827–10852. [CrossRef]
10. Kolakowski, R.V.; Shangguan, N.; Sauers, R.R.; Williams, L.J. Mechanism of thio acid/azide amidation. J. Am.
Chem. Soc. 2006, 128, 5695–5702. [CrossRef] [PubMed]

Molecules 2018, 23, 2413
8 of 10
11. Lang, S.; Murphy, J.A. Azide rearrangements in electron-deficient systems. Chem. Soc. Rev. 2006, 35, 146–156.
[CrossRef] [PubMed]
12. Martinelli, J.R.; Clark, T.P.; Watson, D.A.; Munday, R.H.; Buchwald, S.L. Palladium-catalyzed
aminocarbonylation of aryl chlorides at atmospheric pressure: The dual role of sodium phenoxide.
Angew. Chem. Int. Ed. 2007, 46, 8460–8463. [CrossRef] [PubMed]
13. Owston, N.A.; Parker, A.J.; Williams, J.M.J. Iridium-catalyzed conversion of alcohols into amides via oximes.
Org. Lett. 2007, 9, 73–75. [CrossRef] [PubMed]
14. Chang, J.W.W.; Chan, P.W.H. Highly efficient ruthenium (II) porphyrin catalyzed amidation of aldehydes.
Angew. Chem. Int. Ed. 2008, 47, 1138–1140. [CrossRef] [PubMed]
15. Constable, D.J.C.; Dunn, P.J.; Hayler, J.D.; Humphrey, G.R.; Leazer, J.L., Jr.; Linderman, R.J.; Lorenz, K.;
Manley, J.; Pearlman, B.A.; Wells, A.; et al. Key green chemistry research areas-a perspective from
pharmaceutical manufacturers. Green Chem. 2007, 9, 411–420. [CrossRef]
16. Allen, C.L.; Williams, J.M.J. Metal-catalysed approaches to amide bond formation. Chem. Soc. Rev.
2011, 40, 3405–3415. [CrossRef] [PubMed]
17. Chen, C.; Hong, S.H. Oxidative amide synthesis directly from alcohols with amines. Org. Biomol. Chem.
2011, 9, 20–26. [CrossRef] [PubMed]
18. Gunanathan, C.; Milstein, D. Applications of acceptorless dehydrogenation and related transformations in
chemical synthesis. Science 2013. [CrossRef] [PubMed]
19. Gunanathan, C.; Milstein, D. Bond activation and catalysis by ruthenium pincer complexes. Chem. Rev.
2014, 114, 12024–12087. [CrossRef] [PubMed]
20. de Figueiredo, R.M.; Suppo, J.S.; Campagne, J.M. Nonclassical routes for amide bond formation. Chem. Rev.
2016, 116, 12029–12122. [CrossRef] [PubMed]
21. Xiong, X.Q.; Fan, G.M.; Zhu, R.J.; Shi, L.; Xiao, S.Y.; Bi, C. Highly efficient synthesis of amides. Prog. Chem.
2016, 28, 497–506.
22. Gusey, D.G. Rethinking the dehydrogenative amide synthesis. ACS Catal. 2017, 7, 6656–6662.
23. Chen, C.; Verpoort, F.; Wu, Q.Y. Atom-economic dehydrogenative amide synthesis via ruthenium catalysis.
RSC Adv. 2016, 6, 55599–55607. [CrossRef]
24. Naota, T.; Murahashi, S.I. Ruthenium-catalyzed transformations of amino-alcohols to lactams. Synlett
1991, 10, 693–694. [CrossRef]
25. Gunanathan, C.; Ben-David, Y.; Milstein, D. Direct synthesis of amides from alcohols and amines with
liberation of H-2. Science 2007, 317, 790–792. [CrossRef] [PubMed]
26. Gnanaprakasam, B.; Balaraman, E.; Ben-David, Y.; Milstein, D. Synthesis of peptides and pyrazines from
β-Amino alcohols through extrusion of H2 catalyzed by ruthenium pincer complexes: Ligand-controlled
selectivity. Angew. Chem. Int. Ed. 2011, 50, 12240–12244. [CrossRef] [PubMed]
27. Gnanaprakasam, B.; Balaraman, E.; Gunanathan, C.; Milstein, D. Synthesis of polyamides from diols and
diamines with liberation of H2. J. Polym. Sci. Part A Polym. Chem. 2012, 50, 1755–1765. [CrossRef]
28. Srimani, D.; Balaraman, E.; Hu, P.; Ben-David, Y.; Milstein, D. Formation of tertiary amides and dihydrogen
by dehydrogenative coupling of primary alcohols with secondary amines catalyzed by ruthenium
bipyridine-based pincer complexes. Adv. Synth. Catal. 2013, 355, 2525–2530. [CrossRef]
29. Nordstrøm, L.U.; Vogt, H.; Madsen, R. Amide synthesis from alcohols and amines by the extrusion of
dihydrogen. J. Am. Chem. Soc. 2008, 130, 17672–17673. [CrossRef] [PubMed]
30. Dam, J.H.; Osztrovszky, G.; Nordstrøm, L.U.; Madsen, R. Amide synthesis from alcohols and amines
catalyzed by ruthenium N-heterocyclic carbene complexes. Chem. Eur. J. 2010, 16, 6820–6827. [CrossRef]
[PubMed]
31. Makarov,
I.S.;
Fristrup,
P.;
Madsen,
R.
Mechanistic
investigation
of
the
ruthenium-N-heterocyclic-carbene-catalyzed amidation of amines with alcohols. Chem. Eur. J.
2012, 18, 15683–15692. [CrossRef] [PubMed]
32. Watson, A.J.A.; Maxwell, A.C.; Williams, J.M.J. Ruthenium-catalyzed oxidation of alcohols into amides.
Org. Lett. 2009, 11, 2667–2670. [CrossRef] [PubMed]
33. Watson, A.J.A.; Wakeham, R.J.; Maxwell, A.C.; Williams, J.M.J. Ruthenium-catalysed oxidation of alcohols to
amides using a hydrogen acceptor. Tetrahedron 2014, 70, 3683–3690. [CrossRef]
34. Ghosh, S.C.; Muthaiah, S.; Zhang, Y.; Xu, X.Y.; Hong, S.H. Direct amide synthesis from alcohols and amines
by phosphine-free ruthenium catalyst systems. Adv. Synth. Catal. 2009, 351, 2643–2649. [CrossRef]

Molecules 2018, 23, 2413
9 of 10
35. Zhang, Y.; Chen, C.; Ghosh, S.C.; Li, Y.X.; Hong, S.H. Well-defined N-heterocyclic carbene based ruthenium
catalysts for direct amide synthesis from alcohols and amines. Organometallics 2010, 29, 1374–1378. [CrossRef]
36. Muthaiah, S.; Ghosh, S.C.; Jee, J.E.; Chen, C.; Zhang, J.; Hong, S.H. Direct amide synthesis from either
alcohols or aldehydes with amines: Activity of Ru (II) hydride and Ru (0) complexes. J. Org. Chem.
2010, 75, 3002–3006. [CrossRef] [PubMed]
37. Ghosh, S.C.; Hong, S.H. Simple RuCl3-catalyzed amide synthesis from alcohols and amines. Eur. J. Org. Chem.
2010, 4266–4270. [CrossRef]
38. Zhang, J.; Senthilkumar, M.; Ghosh, S.C.; Hong, S.H. Synthesis of cyclic imides from simple diols.
Angew. Chem. Int. Ed. 2010, 49, 6391–6395. [CrossRef] [PubMed]
39. Chen, C.; Zhang, Y.; Hong, S.H. N-heterocyclic carbene based ruthenium-catalyzed direct amide synthesis
from alcohols and secondary amines: Involvement of esters. J. Org. Chem. 2011, 76, 10005–10010. [CrossRef]
[PubMed]
40. Chen, C.; Hong, S.H. Selective catalytic sp3 C-O bond cleavage with C-N bond formation in
3-alkoxy-1-propanols. Org. Lett. 2012, 14, 2992–2995. [CrossRef] [PubMed]
41. Kim, K.; Kang, B.; Hong, S.H. N-Heterocyclic carbene-based well-defined ruthenium hydride complexes for
direct amide synthesis from alcohols and amines under base-free conditions. Tetrahedron 2015, 71, 4565–4569.
[CrossRef]
42. Kang, B.; Hong, S.H. Hydrogen acceptor- and base-free N-formylation of nitriles and amines using methanol
as C-1 Source. Adv. Synth. Catal. 2015, 357, 834–840. [CrossRef]
43. Kim, S.H.; Hong, S.H. Ruthenium-catalyzed urea synthesis using methanol as the C1 source. Org. Lett.
2016, 18, 212–215. [CrossRef] [PubMed]
44. Nova, A.; Balcells, D.; Schley, N.D.; Dobereiner, G.E.; Crabtree, R.H.; Eisenstein, O.
An experimental-theoretical study of the factors that affect the switch between ruthenium-catalyzed
dehydrogenative amide formation versus amine alkylation. Organometallics 2010, 29, 6548–6558. [CrossRef]
45. Schley, N.D.; Dobereiner, G.E.; Crabtree, R.H. Oxidative synthesis of amides and pyrroles via
dehydrogenative alcohol oxidation by ruthenium diphosphine diamine complexes. Organometallics
2011, 30, 4174–4179. [CrossRef]
46. Prades, A.; Peris, E.; Albrecht, M. Oxidations and oxidative couplings catalyzed by triazolylidene ruthenium
complexes. Organometallics 2011, 30, 1162–1167. [CrossRef]
47. Zeng, H.; Guan, Z. Direct synthesis of polyamides via catalytic dehydrogenation of diols and diamines.
J. Am. Chem. Soc. 2011, 133, 1159–1161. [CrossRef] [PubMed]
48. Oldenhuis, N.J.; Dong, V.M.; Guan, Z. Catalytic acceptorless dehydrogenations: Ru-Macho catalyzed
construction of amides and imines. Tetrahedron 2014, 70, 4213–4218. [CrossRef] [PubMed]
49. Ortega, N.; Richter, C.; Glorius, F. N-formylation of amines by methanol activation. Org. Lett.
2013, 15, 1776–1779. [CrossRef] [PubMed]
50. Malineni, J.; Merkens, C.; Keul, H.; Möller, M. An efficient N-heterocyclic carbene based ruthenium-catalyst:
Application towards the synthesis of esters and amides. Catal. Commun. 2013, 40, 80–83. [CrossRef]
51. Malineni, J.; Keul, H.; Möller, M. An efficient N-heterocyclic carbene-ruthenium complex: Application towards
the synthesis of polyesters and polyamides. Macromol. Rapid Commun. 2015, 36, 547–552. [CrossRef] [PubMed]
52. Saha, B.; Sengupta, G.; Sarbajna, A.; Dutta, I.; Bera, J.K. Amide synthesis from alcohols and amines catalyzed
by a Ru-II-N-heterocyclic carbene (NHC)-carbonyl complex. J. Organomet. Chem. 2014, 771, 124–130.
[CrossRef]
53. Xie, X.K.; Huynh, H.V. Tunable dehydrogenative amidation versus amination using a single ruthenium-NHC
catalyst. ACS Catal. 2015, 5, 4143–4151. [CrossRef]
54. Nirmala, M.; Viswanathamurthi, P. Design and synthesis of ruthenium (II) OCO pincer type NHC complexes
and their catalytic role towards the synthesis of amides. J. Chem. Sci. 2016, 128, 9–21. [CrossRef]
55. Selvamurugan, S.; Ramachandran, R.; Prakash, G.; Viswanathamurthi, P.; Malecki, J.G.; Endo, A. Ruthenium
(II) carbonyl complexes containing bidentate 2-oxo-1,2-dihydroquinoline-3-carbaldehyde hydrazone ligands
as efficient catalysts for catalytic amidation reaction. J. Organomet. Chem. 2016, 803, 119–127. [CrossRef]
56. Selvamurugan, S.; Ramachandran, R.; Prakash, G.; Nirmala, M.; Viswanathamurthi, P.; Fujiwara, S.; Endo, A.
Ruthenium (II) complexes encompassing 2-oxo-1,2-dihydroquinoline-3-carbaldehyde thiosemicarbazone
hybrid ligand: A new versatile potential catalyst for dehydrogenative amide synthesis. Inorg. Chim. Acta
2017, 454, 46–53. [CrossRef]

Molecules 2018, 23, 2413
10 of 10
57. Higuchi, T.; Tagawa, R.; Iimuro, A.; Akiyama, S.; Nagae, H.; Mashima, K. Tunable ligand effects on ruthenium
catalyst activity for selectively preparing imines or amides by dehydrogenative coupling reactions of alcohols
and amines. Chem. Eur. J. 2017, 23, 12795–12804. [CrossRef] [PubMed]
58. Cheng, H.; Xiong, M.Q.; Cheng, C.X.; Wang, H.J.; Lu, Q.; Liu, H.F.; Yao, F.B.; Chen, C.; Verpoort, F. In situ
generated ruthenium catalyst systems bearing diverse N-heterocyclic carbene precursors for atom-economic
amide synthesis from alcohols and amines. Chem. Asian J. 2018, 13, 440–448. [CrossRef] [PubMed]
59. Cheng, H.; Xiong, M.Q.; Zhang, N.; Wang, H.J.; Miao, Y.; Su, W.; Yuan, Y.; Chen, C.; Verpoort, F. Efficient
N-heterocyclic carbene/ruthenium catalytic systems for the alcohol amidation with amines: Involvement of
poly-carbene complexes? ChemCatChem 2018. [CrossRef]
60. Maji, M.; Chakrabarti, K.; Paul, B.; Roy, B.C.; Kundu, S. Ruthenium(II)-NNN-pincer-complex-catalyzed
reactions between various alcohols and amines for sustainable C-N and C-C bond formation.
Adv. Synth. Catal. 2018, 360, 722–729. [CrossRef]
61. Huynh, H.V.; Han, Y.; Jothibasu, R.; Yang, J.A. 13C-NMR spectroscopic determination of ligand donor
strengths using N-heterocyclic carbene complexes of palladium (II). Organometallics 2009, 28, 5395–5404.
[CrossRef]
62. Chen, C.; Kim, M.H.; Hong, S.H. N-heterocyclic carbene-based ruthenium-catalyzed direct amidation of
aldehydes with amines. Org. Chem. Front. 2015, 2, 241–247. [CrossRef]
63. Kaufhold, S.; Petermann, L.; Staehle, R.; Rau, S. Transition metal complexes with N-heterocyclic carbene
ligands: From organometallic hydrogenation reactions toward water splitting. Coord. Chem. Rev.
2015, 304, 73–87. [CrossRef]
Sample Availability: Samples of compounds 3a–3t are available from the authors.
©
2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access
article distributed under the terms and conditions of the Creative Commons Attribution
(CC BY) license (http://creativecommons.org/licenses/by/4.0/).