An efficient, green and scale-up synthesis of amides from esters and amines catalyzed by Ru-MACHO catalyst under mild conditions

Article abstract of DOI:10.1016/j.catcom.2014.08.036

An efficient, green and scale-up synthesis of amides from esters and amines has been developed using Ru-MACHO as a readily available catalyst. A diverse range of amides were obtained in moderate to excellent yields (55-98%). Furthermore, when the scale of the amidation reaction was increased to 240.0 mmol, the desired amide still could be obtained in high yield (48.2 g of N-benzylbenzamide, 95%).

Full text of DOI:10.1016/j.catcom.2014.08.036

An efficient, green and scale-up synthesis of amides from esters and amines
catalyzed by Ru-MACHO catalyst under mild conditions
Qian Han, Xingquan Xiong, Sizhong Li
PII:
DOI:
Reference:
S1566-7367(14)00348-3
doi: 10.1016/j.catcom.2014.08.036
CATCOM 4035
To appear in:
Catalysis Communications
Received date:
Revised date:
Accepted date:
18 June 2014
26 August 2014
28 August 2014
Please cite this article as: Qian Han, Xingquan Xiong, Sizhong Li, An efficient,
green and scale-up synthesis of amides from esters and amines catalyzed by Ru-
MACHO catalyst under mild conditions, Catalysis Communications (2014),
doi:
10.1016/j.catcom.2014.08.036
This is a PDF file of an unedited manuscript that has been accepted for publication.
As a service to our customers we are providing this early version of the manuscript.
The manuscript will undergo copyediting, typesetting, and review of the resulting proof
before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that
apply to the journal pertain.

ACCEPTED MANUSCRIPT
An efficient, green and scale-up synthesis of amides from
esters and amines catalyzed by Ru-MACHO catalyst under
mild conditions
Qian Han, Xingquan Xiong*, Sizhong Li
College of Materials Science and Engineering, University of Huaqiao, Xiamen
361021, China.
*Corresponding author. E-mail address: xxqluli@hqu.edu.cn.
Abstract: An efficient, green and scale-up synthesis of amides from esters and amines
has been developed using Ru-MACHO as a readily available catalyst. A diverse range
of amides were obtained in moderate to excellent yields (55-98%). Furthermore, when
the scale of the amidation reaction was increased to 240.0 mmol, the desired amide
still could be obtained in high yield (48.2 g of N-benzylbenzamide, 95%).
Keywords: Amides, Esters, Amines, Ru-MACHO, Green synthesis
1. Introduction
Amides are important chemicals in organic synthesis and in pharmaceutical
chemistry and they play important roles in agrochemicals, pharmaceuticals and
polymeric materials [1-5]. Therefore, the synthesis of amides is one of the hot topics
in modern synthetic chemistry, which have received widespread attention not only
from academic research but also from industrial application.
Up to now, lots of synthetic methods have been applied to synthesize them (Scheme
1) [6-8]. Traditionally, the reactions of carboxylic acids or their derivatives (such as
acid anhydrides and acyl halides) with amines are applied for the synthesis of amides.
1

ACCEPTED MANUSCRIPT
However, all these synthetic methods involve harsh reaction conditions and/or
produce stoichiometric amount of toxic wastes during the reaction processes [9]. In
addition, labile substrates and a limited substrate scope are also restricted. Thus, the
development of the environmentally benign, waste-free, efficient and cost-effective
methods is in high demand.
In 2007, Milstein and co-workers reported the direct synthesis of amides with high
yields via catalytic dehydrogenation of alcohols and amines. These amidation
reactions were catalyzed by a ruthenium complex based on an electron rich hemilabile
PNN ruthenium-pincer catalyst (the Milstein catalyst) [10]. Subsequently, other
groups also reported the direct and highly efficient amidation of amines/organic
azides with alcohols for the synthesis of amides, respectively [11-17]. Mainly, the
amidation reactions were performed with a complex catalytic system, which
constructed with a ruthenium precursor, an N-heterocyclic carbene and a phosphine
ligand. Unfortunately, high concentrations of catalysts in their work were normally
required (3-5 mol % of [Ru]).
Aminolysis of esters has also been used for the synthesis of amides. So far, only
few papers are available in scientific literature on the application of aminolysis of
esters to synthesize amides [18-21]. For example, in 2011, the Milstein group reported
an efficient synthesis of amides directly from esters and amines with high yields
under mild, neutral conditions with the liberation of H2 via the Milstein catalyst [21].
However, the Milstein catalyst was highly sensitive towards air and moisture.
Furthermore, the complicated molecule structure and high price of the Milstein
2

ACCEPTED MANUSCRIPT
catalyst limited its practical application in the industry. Therefore, the development of
an efficient and practical catalyst system for the production of amides from esters and
amines is in urgent demand.
As a currently commercialized and thus readily available (PNP) Ru-based catalyst,
Ru-MACHO has played important roles in hydrogenation [22], dehydrogenation [23,
24], amidation [25] and other areas [26, 27]. For example, Guan’s group reported an
efficient synthesis of amides directly from alcohols and amines with high yields by
Ru-MACHO in 2014 [25]. As a part of our continuing interest in the further
improvement the practicability and eco-friendliness of the amidation reaction, in this
work we report our preliminary results on the use of Ru-MACHO for the
cost-effective, highly efficient and scale-up synthesis of amides from readily available
esters and amines, to give the corresponding amides with moderate to excellent yields.
Compared with the Milstein catalyst, Ru-MACHO was more stable and could be
prepared in lower cost, simpler synthetic steps and larger scale.
[Insert Scheme 1]
2. Experimental
2.1 General
All chemicals were purchased from Aladdin. All solvents were purified according
to the methods in the literature [28] and were kept with 4Å molecular sieves. All
reactions were carried out under an atmosphere of nitrogen. RuHCl(CO)(PPh3)3 [29],
bis[2-(diphenylphosphino)ethyl]amine hydrochloride [30] and Ru-MACHO [31] were
3

ACCEPTED MANUSCRIPT
prepared according to the literature procedures. The progress of the reaction was
monitored by thin layer chromatography using silica gel plates.
The IR spectra were obtained using a FT-IR (4000~400 cm-1) spectrometer (Nicolet
Nexus FT-IR spectrometer, USA) at 4 cm-1 resolution and 32 scans. Samples were
prepared using the KBr disc method. NMR spectra were acquired in CDCl3 on a
1
Bruker DMX-400 spectrometer at 400 MHz for H NMR, the chemical shifts are
given in δ values from TMS as an internal standard.
2.2 General procedure for synthesis of amides
A mixture of amine (6.0 mmol), ester (3.0 mmol) and Ru-MACHO (1% mol) in
toluene (3.0 mL) was placed in a flask and replaced with nitrogen gas. Then, t-BuOK
(20% mol) was added in the mixture in the nitrogen gas flowing. The mixture was
heated by reflux under the nitrogen atmosphere. During this time, the nitrogen gas
was passed through the Schlenk line allowing the hydrogen gas evolved from the
reaction to escape the reactor. After the 48 h, the solvent was evaporated and the crude
product was purified by flash chromatography on silica-gel to give the desired amides
in 55–98% yields. The structures of the obtained amides were determined by FT-IR
and 1H NMR.
3. Results and discussion
3.1 Attempt to synthesize amides from alcohols and amines
Some attempts to synthesize amides from alcohols and amines were conducted
using ethylene glycol monomethyl ether and benzylamine. This model reaction
carried out with Ru-MACHO (1% mol) and base (20% mol) under solvent reflux
4

ACCEPTED MANUSCRIPT
under nitrogen atmosphere for 48 h (Table S1). Unfortunately, we found that the
desired product could be obtained with a maximal yield of 41% when KOH was used
as base and toluene as solvent.
3.2 Screening of bases for synthesis of amides
With the further research on the synthesis of amides, it was found that the amides
could be prepared in good yields from esters and amines. Therefore, we focus on the
synthesis of amides from esters and amines in the following study.
In order to determine the optimal base for the synthesis of amides from esters and
amines, the different bases were examined in a model reaction using benzyl benzoate
and benzylamine. The results are summarized in Table 1. The results given in Table 1
show the screening of bases as initiators of the catalytic reaction. Weak bases such as
Na2CO3 and K2CO3, strong bases such as NaOH and KOH were not effective (entries
1−4). Additionally, the desired amide could be obtained in moderate yield using
EtONa as base (56%, entry 5). To our delight, t-BuOK was found to be the most
effective initiator of the catalytic reaction in terms of isolated yield of the
corresponding product (94%, entry 6).
[Insert Table 1]
3.3 Screening of solvents for synthesis of amides
Solvents play an important role in aminolysis of esters with amines. To check the
solvent effect on the outcome of the aminolysis reaction, the above model reaction
was performed with Ru-MACHO in various solvents such as toluene, anisole, DMF
o
and DMSO at 120 C (Figure 1). As shown in Figure 1, it was obvious that toluene
5

ACCEPTED MANUSCRIPT
was the best solvent (94%), whereas DMF and DMSO afforded very low yields (30
and 15%). Moderate yield of N-benzylbenzamide could be obtained when the reaction
was performed in anisole (61%). In addition, the reaction under solvent-free
conditions led only to a moderate yield (65%)
[Insert Figure 1]
We continued the aminolysis reaction optimization process after finding the need
for a strong base t-BuOK to activate Ru-MACHO in toluene. The following step was
to study the influence of Ru-MACHO and t-BuOK dosage on the catalytic reaction.
The results given in Table 2 indicated that lower dosage of catalyst and initiators led
to lower yields (entries 1−3). As expected, higher dosage of catalyst and initiators led
to higher yields (entries 4−6). Thin-layer chromatography (TLC) showed the
aminolysis reaction was completed within 48 h in quantitative conversion rate and
94% isolated yield was obtained when the catalyst and initiator were used in amount
of 1.0 and 20.0 mol%, respectively. However, the isolated yield of product was
increased by only 1% when the catalyst and initiator were used in amount of 1.0/1.5
and 20.0 mol%, respectively (entries 4−6). Therefore, the following aminolysis of
esters with amines were carried out in the presence of 1.0 mol % of Ru-MACHO and
20.0 mol % of t-BuOK.
[Insert Table 2]
3.4 Synthesis of amides from esters and amines
To expand the scope of the aminolysis reactions, various esters and amines were
used as starting substrates and the results are summarized in Table 3. The obtained
6

ACCEPTED MANUSCRIPT
results showed that both aliphatic/aromatic esters and aromatic/aliphatic amines
underwent the aminolysis reactions smoothly to provide the corresponding amides in
moderate to excellent yields (55-98%). The structure of amines has an obvious effect
on the aminolysis reactions. Good to excellent yields were observed when primary
amines, such as benzylamine, aniline, n-butylamine and ethylenediamine were used
(entries 1-4, 8-11 and 13-16). Lower yields were obtained when secondary amines,
such as morpholine, diethylamine and dibutylamine were used (entries 5-7).
Compared to the aromatic esters, aliphatic esters have the lower yields. All products
1
listed in Table 3 have been characterized by FT-IR and H NMR spectroscopy.
However, the aminolysis reaction also suffers from a limitation. In order to obtain a
single product in this reaction, the corresponding symmetric ester must be used.
[Insert Table 3]
3.5 Scale-up synthesis of amides
Amides are important molecules in organic chemistry, so it is significant for the
aminolysis reaction to be achievable on multi-gram scale. To clearly demonstrate the
potential of the method for preparative purposes, the scale-up synthesis of the amides
was investigated in the case of N-benzylbenzamide as a model reaction. The detailed
results were shown in the Table 4. As demonstrated in Table 4, we have shown that
N-benzylbenzamide could be synthesized on 5.0 mmol, 15.0 mmol, 60.0 mmol and
240.0 mmol scales to afford excellent yields. Most importantly, when the scale of the
amidation reaction was increased to 240.0 mmol, the aminolysis reaction was found to
proceed successfully and N-benzylbenzamide was still obtained in 95% yield.
7

ACCEPTED MANUSCRIPT
[Insert Table 4]
4. The plausible mechanism
On the basis of the above results, the proposed mechanism was illustrated in Figure
S1. The initial step was activation of the Ru-MACHO catalyst by the elimination of
HCl under t-BuOK condition to afford the more active specie INT1 [27], which was
able to form the intermediate INT2 when reacted with amines via N-H activation.
When the INT2 reacted with ester via intermolecular nucleophilic attack, the desired
amide was obtained and at the same time the alkoxy intermediate INT3 was formed.
Then, the alkoxy intermediate is oxidized to an aldehyde intermediate INT4 through a
dehydrogenation. Subsequently, after nucleophilic reaction between the amine and the
aldehyde intermediate INT4 and β-H elimination reaction, another molecule of the
amide was obtained.
5. Conclusions
In conclusion, we have successfully developed a readily available (PNP) Ru-based
catalyst Ru-MACHO for the efficient, green and scale-up synthesis of amides from
esters and amines. A wide range of esters and amines were tested and gave moderate
to excellent yields. When the scale of the acylation of benzylamine was increased to
240.0 mmol, the desired product was still obtained in 95% yield. The low-cost
catalyst, good yields of products and scale-up synthesis will make the present method
a practical and important addition for the construction of amides from readily
available esters and amines.
Acknowledgements
8

ACCEPTED MANUSCRIPT
National Natural Science Foundation of China (21004024), Natural Science
Foundation of Fujian Province (2011J01046), the Program for New Century Excellent
Talents in Fujian Province (2012FJ-NCET-ZR03), Promotion Program for Young and
Middle-aged Teacher in Science and Technology Research of Huaqiao University
(ZQN-YX103) and Special Foundation for Young Scientists of Fujian Province
(2011J05131) are appreciated.
References
[1] N. Sewald, H.-D. Jakubke, Peptides: Chemistry and Biology (Wiley-VCH,
Weinheim, Germany, 2002).
[2] A. Greenberg, C. M. Breneman, J.F.Eds. Liebman, The Amide Linkage: Selected
Structural Aspects in Chemistry, Biochemistry, and Materials Science
(Wiley-Interscience, New York, 2000).
[3] B. L. Bray, Nat. Rev. Drug Discov. 2 (2003) 587–593.
[4] T. Cupido, J. Tulla-Puche, J. Spengler, F. Albericio, Curr. Opin. Drug Discovery
Dev. 10 (2007) 768–783.
[5] J.M. García, F.C. García, F. Serna, J.L. de La Peňa, Prog. Polym. Sci. 35 (2010)
623–686.
[6] C. L. Allen, J.M.J. Williams, Chem. Soc. Rev. 40 (2011) 3405–3415.
[7] S.T. Gadge, B.M. Bhanage, RSC Adv. 4 (2014) 10367–10389.
[8] R. García-Álvarez, P. Crochet, V. Cadierno, Green Chem. 15 (2013) 46–66.
[9] M.B. Smith, Compendium of Organic Synthetic Methods (Wiley, New York, vol.
9, 2001), pp. 100.
9

ACCEPTED MANUSCRIPT
[10] C. Gunanathan, Y. Ben-David, D. Milstein, Science 317 (2007) 790–792.
[11] L.U. Nordstrøm, H. Vogt, R. Madsen, J. Am. Chem. Soc. 130 (2008)
17672–17673.
[12] J.H. Dam, G. Osztrovszky, L.U. Nordstrøm, R. Madsen, Chem. Eur. J. 16 (2010)
6820–6827.
[13] S.C. Ghosh, S. Muthaiah, Y. Zhang, X.Y. Xu, S.H. Hong, Adv. Synth. Catal. 351
(2009) 2643–2649.
[14] S. Muthaiah, S.C. Ghosh, J-E. Jee, C. Chen, J. Zhang, S.H. Hong, J. Org. Chem.
75 (2010) 3002–3006.
[15] J. Malineni, C. Merkens, H. Keul, M. Möller, Catal. Commun. 40 (2013) 80–83.
[16] Z.Q. Fu, J. Lee, B. Kang, S.H. Hong, Org. Lett. 14 (2012) 6028–6031.
[17] X.F. Guo, L. Tang, Y. Yang, Z.G. Zha, Z.G. Wang, Green Chem. 16 (2014)
2443–2447.
[18] C. Sabot, K.A. Kumar, S. Meunier, C. Mioskowski, Tetrahedron Lett. 48 (2007)
3863–3866.
[19] E.C. de Lima, C.C. de Souza, R.D. Soares, B.G. Vaz, M.N. Eberlin, A.G. Dias,
P.R.R. Costa, J. Brazil. Chem. Soc. 22 (2011) 2186–2190.
[20] C. Han, J.P. Lee, E. Lobkovsky, J.A.P. Jr, J. Am. Chem. Soc. 127 (2005)
10039–10044.
[21] B. Gnanaprakasam, D. Milstein, J. Am. Chem. Soc. 133 (2011) 1682–1685.
[22] C. Ziebart, R. Jackstell, M. Beller, ChemCatChem 5 (2013) 3228–3231.
10

ACCEPTED MANUSCRIPT
[23] M. Bertoli, A. Choualeb, A. J. Lough, B. Moore, D. Spasyuk, D. G. Gusev,
Organometallics 30 (2011) 3479–3482.
[24] M. Nielsen, H. Junge, A. Kammer, M. Beller, Angew. Chem. Int. Ed. 51 (2012)
5711–5713.
[25] N.J. Oldenhuis, V.M. Dong, Z.B. Guan, Tetrahedron 70 (2014) 4213–4218.
[26] A. Monney, E. Barsch, P. Sponholz, H. Junge, R. Ludwig, M. Beller, Chem.
Commun. 50 (2014) 707–709.
[27] M. Nielsen, E. Alberico, W. Baumann, H.J. Drexler, H. Junge, S. Gladiali, M.
Beller, Nature 495 (2013) 85–89.
[28] W.L.F. Armarego, C.L.L. Chai, Purification of Laboratory Chemicals, fifth
edition, Elsevier Science, Great Britain, 2003.
[29] G.W. Parshall, M. Hill, Inorganic Syntheses, Volume XV, USA, 1974.
[30] R.G. Nuzzo, S.L. Haynie, M.E. Wilson, G.M. Whitesides, J. Org. Chem. 46 (1981)
2861–2867.
[31] W. Kuriyama, T. Matsumoto, O. Ogata, Y. Ino, K. Aoki, S. Tanaka, K. Ishida, T.
Kobayashi, N. Sayo, T. Saito, Org. Process Res. Dev. 16 (2012) 166−171.
Captions
Scheme 1. Different strategies for synthesis of amides.
Figure 1. Screening of solvents for synthesis of amides.
Table 1. Screening of bases for synthesis of amides.a
11

ACCEPTED MANUSCRIPT
Table 2. Optimization of the reaction conditions.a
Table 3. Amide synthesis from benzyl benzoate and amine.a
Table 4. Scale-up synthesis of N-benzylbenzamide.
Scheme 1. Different strategies for synthesis of amides.
12

ACCEPTED MANUSCRIPT
Traditional synthesis of amides
O
O
H
R2
N
Coupling reagent
Base
R1
+
R1 NH2
+
Wastes
(1)
(2)
+
R2
OH
O
H
N
R2
R1 NH2
+
R2
X
R1
Wastes
O
X = Cl, Br, I
Synthesis of amides via catalytic dehydrogenation
H
R2
N
the Milstein catalyst
R2
OH
(3)
R1 NH2
+
R1
+
H2
O
This work
PPh2
O
O
Cl
Ru
R2
t-BuOK
Ru-MACHO
H2N R2
R1
O
R1
+ 2
R1
N
HN
H
CO
2
H
PPh2
Ru-MACHO
Figure 1. Screening of solvents for synthesis of amides.
13

ACCEPTED MANUSCRIPT
Table 1. Screening of bases for synthesis of amides.a
14

ACCEPTED MANUSCRIPT
O
O
20 % mol base
N
O
NH2
2
H
+
2
1 % mol Ru-MACHO
toluene, reflux
Entry
Base
Na2CO3
K2CO3
NaOH
KOH
Yield (%)b
<10
1
2
3
4
5
6
<10
<10
<10
EtONa
t-BuOK
56
94
a benzyl benzoate (3.0 mmol), benzylamine (6.0 mmol), toluene (3.0 mL), 1 mol % catalyst, 120
oC, nitrogen atmosphere, 48 h. b Isolated yields.
Table 2. Optimization of the reaction conditions.a
15

ACCEPTED MANUSCRIPT
O
O
t-BuOK
N
NH2
O
2
+
H
2
Ru-MACHO
toluene, reflux
Entry Catalyst/% mol t-BuOK/% mol Yield (%)b
1
2
3
4
5
6
0.01
0.5
1
2
<10
46
54
94
95
95
10
10
20
30
30
1
1
1.5
o
abenzyl benzoate (3.0 mmol), benzylamine (6.0 mmol), toluene (3.0 mL), 120 C, nitrogen
atmosphere, 48 h. bIsolated yields.
Table 3. Amide synthesis from benzyl benzoate and amine.a
16

ACCEPTED MANUSCRIPT
O
O
20 % mol base
R2
H2N R2
R1
2
N
R1
O
R1
2
+
1 %mol Ru-MACHO
toluene, reflux
H
Entry
Ester
Amine
Product
Yield (%)b
94
O
O
NH2
O
N
H
1
2
O
O
O
NH2
86
80
98
68
75
77
82
80
70
76
57
82
80
74
78
55
HN
O
O
O
NH2
N
H
3
O
O
O
H
N
H2N
N
H
NH2
4
O
O
N
O
O
H
N
5
O
O
O
O
O
N
H
N
6
O
O
O
H
N
N
7
O
O
O
NH2
NH
8
O
NH2
O
O
9
N
H
O
O
O
NH2
NH2
10
11
12
13
14
15
16
17
N
H
O
O
H2N
H
N
O
O
O
NH2
NH2
NH2
NH2
H2N
H
N
O
o
aester (3.0 mmol), amine (6.0 mmol), toluene (3.0 mL), 120 C, nitrogen atmosphere, 48 h.
bIsolated yields.
17

ACCEPTED MANUSCRIPT
Table 4. Scale-up synthesis of N-benzylbenzamide.
18

ACCEPTED MANUSCRIPT
O
O
20 % mol base
N
NH2
O
2
H
+
2
1 % mol Ru-MACHO
toluene, 120 oC, 48 h
Entry amine/mmol Cat./% mol Isolated Yield (%)
1
2
3
4
5
1
1
1
1
94
95
95
95
15
60
240
19

ACCEPTED MANUSCRIPT
Highlights
 An efficient, green and scale-up synthesis of amides has been developed.
 Amides are readily obtained from esters and amines.
 Ru-MACHO is used as a readily available catalyst.
 Amides are prepared in moderate to excellent yields and on multi-gram scale.
20