A sustainable approach to the Ugi reaction in deep eutectic solvent

Article abstract of DOI:10.1016/j.crci.2013.05.013

The Ugi reaction goes fast with high yields in a recyclable and biodegradable low-melting mixture of choline chloride and urea (DES) as a novel and efficient reaction medium. The DES is applicable to a wide range of aldehydes, amines, isocyanides, and aci

Full text of DOI:10.1016/j.crci.2013.05.013

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Full paper/Memoire
A sustainable approach to the Ugi reaction in deep eutectic solvent
b
c
Najmedin Azizi a, , Sahar Dezfooli , Mohammad Mahmoodi Hashemi
*
a Chemistry and Chemical Engineering Research Center of Iran, PO Box 14335-186, Tehran, Iran
b Young Researchers and Elites club, Science and Research Branch, Islamic Azad University, Tehran, Iran
c Sharif University of Technology, PO Box 11365-9516 Tehran, Iran
A R T I C L E I N F O
A B S T R A C T
Article history:
The Ugi reaction goes fast with high yields in a recyclable and biodegradable low-melting
mixture of choline chloride and urea (DES) as a novel and efficient reaction medium. The
DES is applicable to a wide range of aldehydes, amines, isocyanides, and acids in good to
excellent isolated yields (60–92%) and short reaction times (2–5 h) and can be reused four
times without any loss of activity.
Received 3 March 2013
Accepted after revision 27 May 2013
Available online xxx
Keywords:
´
ß 2013 Academie des sciences. Published by Elsevier Masson SAS. All rights reserved.
Ugi reaction
Green chemistry
Deep eutectic solvent
Choline chloride
Urea
1. Introduction
naturally occurring biocompatible compounds that are not
hazardous if they are released back into nature separately.
In the context of green chemistry, room-temperature
ionic liquids (RTILs), also called molten salts, are green
alternatives to organic solvents, because of their unique
properties, such as negligible vapor pressure, large liquid
range, high thermal stability, more solvation capacity, and
non-flammability. Expected cheaper and greener alter-
natives to RTILs are room-temperature deep eutectic
solvents (DESs). DESs are obtained by complexion of
quaternary ammonium salts with hydrogen bond donors,
such as urea, carboxylic acid, sugar and amide or Lewis
acids. DESs have many characteristics of conventional ILs
(e.g., high thermal stability, excellent solubility of organic
and inorganic substances, low toxicity and non-volatility),
while they offer certain advantages. For instance, the
preparation of DES in a pure state is easy and economically
viable as it shows 100% atom economy, with no need for
the post-synthesis purification that was used for the ILs.
Furthermore, choline chloride (ChCl) and urea are both
Although there are only a limited amount of research in the
field of toxicity and biodegradability of DESs, to the best of
our knowledge, there is no reversal report so far. Besides,
they are cheap and the processes that use these deep
eutectic solvents are economically viable and green [1–12].
A major challenge of modern chemistry is the design of
new artificial chemical reaction sequences that provide
novel compounds in high yields and short reaction times.
Undoubtedly, one-pot multicomponent reactions (MCRs)
from low-cost materials are convergent reactions with
high atom efficiency, and higher yields in comparison to a
similar multistep reaction. They are faster and cheaper
than classical reactions, since they are done by just mixing
compounds together in one vessel, without isolating any
intermediate. The additional benefits of this resource-
effective and ecologically benign process are readily
available starting materials, operational simplicity, easy
automation, atom economy, with minimization of reaction
time, labor, cost, and waste production [13–19].
A large and important class of MCRs is constituted by
the isocyanide-based Passerini and Ugi four-component
reactions [20–24]. These reactions have become one of the
*
Corresponding author.
E-mail addresses: azizi@ccerci.ac.ir, azizin618@yahoo.com (N. Azizi).
1631-0748/$ – see front matter ß 2013 Acade´mie des sciences. Published by Elsevier Masson SAS. All rights reserved.
http://dx.doi.org/10.1016/j.crci.2013.05.013
Please cite this article in press as: Azizi N, et al. A sustainable approach to the Ugi reaction in deep eutectic solvent. C. R.
Chimie (2013), http://dx.doi.org/10.1016/j.crci.2013.05.013

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most investigated transformations during the past decade,
in conjunction with the enabling technologies, such as
high-throughput screening, combinatorial and assembling
complex pharmacologically important structures. The
classical Ugi reaction is carried out in solvents, such as
methanol and dichloromethane under stirring at room
temperature overnight [25–30]. In order to further comply
with the green chemistry, alternative green solvents, such
as water and trifluoroethanol or ionic liquids, were used in
an isocyanide-based multicomponent reaction [31–34].
complete. To consider the efficiency of DES relative to
conventional organic solvents, some protic and aprotic
solvents were performed with the optimized conditions of
DES; the results are summarized in Table 1. The results
confirmed that DES is the best solvent and catalyst for the
one-pot multicomponent Ugi reaction.
Under these reaction conditions, the evaluation of DESs
as solvents was tested for a wide range of carbonyl
compounds. A variety of structurally diverse aldehydes
and ketones, including saturated, unsaturated, aromatic
and heteroaryl aldehydes underwent green reaction
smoothly, without using any catalyst to afford the
corresponding Ugi products in good to excellent yields.
The results are summarized in Table 2. Aryl aldehydes
substituted with various electron-withdrawing and elec-
tron-donating groups, as well as heteroaryl aldehydes,
aliphatic aldehydes and simple ketones did not seem to
influence the reaction time and yields, as revealed by the
similarity of the results, and all the carbonyl groups readily
converted into their corresponding Ugi products in the
presence of a variety of functional groups.
Encouraged by this success, the reaction is also studied
for various aromatic amines, isocyanides, and carboxylic
acid. Benzaldehyde was reacted with aromatic amines,
such as 4-methylaniline, 4-methoxyaniline, 2-methylani-
line, 4-chloroaniline, and 4-bromoaniline in DES at room
temperature, giving good to excellent yields. To further
increase the diversity at this point, we next tested other
benzoic acid derivatives, which also produced the desired
2. Results and discussion
Throughout our investigations to develop green chem-
istry by using water and deep eutectic solvent as reaction
medium [35–39], in the present work, we report the first
example of an efficient and green procedure for a one-pot
multicomponent Ugi reaction in DES based on choline
chloride and urea as a novel and green catalyst and
reaction medium.
The experimental procedure is very simple and easy.
The deep eutectic solvent DES was prepared by simply
mixing choline chloride (100 mmol) with urea (200 mmol),
and heated to ca. 80 8C in air with stirring till a clear
solution was obtained, which was used without any
purification. Since this method forms eutectic mixture
with no by-product formation, it provides 100% atom
economy.
In a typical experiment, benzaldehyde (0.5 mmol),
aniline (0.5 mmol), benzoic acid (0.5 mmol), cyclohexyli-
socyanide (0.5 mmol) and deep eutectic solvent (1 mL)
were stirred at room temperature. After completion
(180 min), the reaction mixture was diluted with water,
and the white solid mass was separated by simple
filtration. The corresponding Ugi product 5 was formed
as the only detectable product and isolated in 90% yield
after washing with water and ethanol (Table 1).
The DES was recovered easily from the filtrate by
evaporating water under vacuum and reused for three
successions of the reaction without much loss in the
product yields. Furthermore, it was possible to monitor the
a
-aminoacyl amide derivatives in good yields. The scope of
the isocyanide component was then examined. The
reaction of benzaldehyde, aniline, benzoic acid and t-butyl
isocyanide, tosylmethyl isocyanide (TOSMIC) also gave the
desired products in moderate to good yields in this type of
process (Fig. 1).
The experimental procedure is easy and the reactions
went to completion at room temperature, within 2–5 h,
depending on the reactivity of the aldehydes and
carboxylic acids. The products were easily separated by
easy extraction of the deep eutectic solvent with water,
and were usually obtained in high purity.
reaction visually.
A
white suspension solution was
In general, the reactions are very mild and clean, and no
side-products were obtained between the starting materi-
als of the Ugi reaction with DES in any run. Furthermore, in
the separated model reaction, aniline as well as benzoic
obtained after addition of all the components to the deep
eutectic solvent, and the reaction mixture became an
orange viscous liquid or solid after the reaction is
Table 1
Comparison of conventional organic solvents with DES.
O
Ph
PhNH2
2
PhCHO
1
H
Solvent (1 mL)
rt, 3h
N
+
Ph
N
C6H11
H11C6-NC
PhCO2H
Ph
O
4
5
3
Entry
Solvent (1 mL)
Yields (%)
1
2
3
4
5
6
Urea–choline chloride
90
60
40
45
30
45
Neat (solvent free condition)
CH3OH
H2O
CH2Cl2
CH3CN
Please cite this article in press as: Azizi N, et al. A sustainable approach to the Ugi reaction in deep eutectic solvent. C. R.
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3
Table 2
Green Ugi reaction in deep eutectic solvent.
O
R1
CO2H
Urea/ChCl (1 mL)
N
NC
N
R2NH2
R1CHO
+
+
+
R2
O
rt, 2-5 h
68-95%
2
3
4
5
1
Entry
R1CHO (1)
R2NH2 (2)
Yields (%)a
90
Entry
R1CHO (1)
R2NH2(2)
Yields (%)a
72
5a
5j
CHO
NH2
NH2
O
5b
85
92
88
84
5k
5l
70
72
88
90
CHO
NH2
NH2
NH2
NH2
CHO
NH2
MeO
MeO
5c
5d
5e
CHO
CHO
CHO
NH2
Cl
MeO
Me
5m
5n
CHO
NH2
Cl
CHO
CHO
NH2
Cl
Me
OMe
5f
85
82
5o
5p
92
86
CHO
Cl
CHO
CHO
NH2
NH2
NH2
NH2
Cl
Cl
Br
5g
CHO
O2N
O2N
5h
5i
75
60
5q
5r
80
76
NH2
NH2
CHO
CHO
CHO
NH2
Me
N
NH2
CHO
Cl
Cl
a
NMR yields
acid was stirred in DES for 5 h, and only aniline and benzoic
acid were recovered without any reaction with DES; so,
these results will completely contradict any possibility of
DES’ participation in the reaction.
3. Experimental
1H NMR spectra were recorded with a 500 MHz NMR
spectrometer using CDCl3 or DMSO as a solvent; chemical
shifts have been expressed in (ppm) downfield from TMS.
Finally, the recycling of DES was examined using the
Ugi reaction under optimized conditions. The recovered
DES was then reused for three runs without obvious
loss of activity. After completion, water (3 mL) was
added to the reaction mixture, which was shaken
vigorously, and a solid or viscous liquid was separated
by filtration. The deep eutectic solvent was recovered
from the filtrate by evaporating the water phase at 80 8C
under vacuum and reused for the next batch and
recycled again (Table 3).
Table 3
Recycling of deep eutectic solvent.
Entry
Cycle
Yields (%)
1
2
3
4
Fresh
90
90
88
80
First recycle
Second recycle
Third recycle
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obtained ion liquid was used without any further
purification (Fig. 2).
O
O
H
N
H
N
N
3.2. General procedure for the Ugi reaction
N
O
O
Cl
Cl
The aldehyde (0.50 mmol), the carboxylic acid
(0.50 mmol), the amine (0.50 mmol) and the cyclohexyl
5t, 75%
5s, 72%
Me
isocyanide (0.50 mmol) were dissolved in
a choline
chloride–urea-based deep eutectic solvent (1 mL), and
were mixed and vigorously stirred at room temperature.
After completion of reaction, water was added. The DES is
soluble in water and comes into the water layer. The white
solid was separated by filtration and was purified with
water then with ethanol to give the pure compounds.
O
H
O
N
H
N
N
N
O
Br
O
5u, 82%
Cl
5v, 74%
3.3. Selected data
O
3.3.1. N-(2-(Cyclohexylamino)-2-oxo-1-phenylethyl)-N-
phenylbenzamide (5a)
O
H
H
N
N
N
N
Mp = 163–169 8C, 1H NMR (500 MHz, CDCl3):
d = 1.12–
O
O
1.22 (m, 3H), 1.38–1.43 (m, 3H), 1.95–2.03 (m, 3H), 2.23 (s,
2H), 3.90 (m, 1H), 5.84 (d, J = 5 Hz, 1H), 6.20 (s, 1H), 7.05 (s,
5H), 7.15 (t, J = 10 Hz, 2H), 7.21 (t, J = 10, 5 Hz, 1H), 7.29 (s,
3H), 7.30–7.31 (m, 1H), 7.35 (d, J = 5 Hz, 2H).
Me
5x, 70%
5y, 76%
OMe
O
H
N
N
3.3.2. 2-(4-Chlorophenyl)-N-cyclohexyl-4-oxo-3,4 diphenyl-
butanamide (5c)
O
Me
Mp = 107 8C, 1H NMR (500 MHz, CDCl3):
d = 1.12–1.30
(m, 3H), 1.36–1.46 (m, 2H), 1.62–1.76 (m, 4H), 1.94–2.03
(m, 2H), 3.89–3.94 (m, 1H), 5.94 (d, J = 5 Hz, 1H), 6.17 (s,
1H), 7.02–703 (m, 1H), 7.08–7.10 (m, 3H), 7.16 (t, J = 5 Hz,
2H), 7.22–7.30 (m, 5H), 7.33 (d, J = 5 Hz, 2H).
5z, 84%
Br
Fig. 1. Green synthesis of Ugi products in urea–choline chloride.
All the amines, aldehydes, isocyanides and acids are
commercially available. Water and ethanol were distilled
before use. All the reactions are monitored by thin layer
chromatography (TLC), carried out on 0.25 mm silica gel
with UV light as the detecting agent. The melting points
were recorded with a Buchi 535 melting point apparatus
and are uncorrected.
3.3.3. N-(2-(cyclohexylamino)-1-(2,4-dichlorophenyl)-2-
oxoethyl)-N-phenylbenzamide (5f)
Mp = 292 8C, 1H NMR (500 MHz, CDCl3):
d = 1.17–1.29
(m, 3H), 1.38–1.43 (m, 2H), 1.63–1.69 (m, 1H), 1.72–1.79
(m, 2H), 1.90 (d, J = 5 Hz, 1H), 2.03 (d, J = 10 Hz, 2H), 3.83–
3.90 (m, 1H), 6.11 (d, J = 10 Hz, 1H), 6.57 (s, 1H), 7.33 (q,
1H), 7.41 (q, 2H), 7.48 (d, J = 2 Hz, 1H), 7.48–7.52 (m,
4H),7.60 (d, J = 10 Hz, 1H), 7.64 (t, J = 5, 10 Hz, 1H), 7.91 (d,
J = 5 Hz, 1H), 8.11 (d, J = 10 Hz, 1H).
3.1. Deep eutectic solvent preparation
The choline chloride–urea ionic liquid was prepared
according to the literature [2]. For DES preparation, urea
(200 mmol) and choline chloride (100 mmol) were mixed,
stirred and heated until a clear liquid appeared. The
3.3.4. N-cyclohexyl-2-(4-nitrophenyl)-4-oxo-3,4-
diphenylbutanamide (5g)
Mp = 213 8C, 1H NMR (500 MHz, CDCl3):
d
= 1.18–1.26
(m, 3H), 1.41–1.46 (m, 2H), 1.63–1.66 (m, 2H), 1.71–1.78
Fig. 2. Deep eutectic solvent preparation.
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[4] A. Vioux, L. Viau, S. Volland, J. Le Bideau, C. R. Chimie 13 (2010) 242.
[5] E. Da Silva, W. Dayoub, N. Duguet, E. Me tay, F. Popowycz, M. Lemaire,
C.R. Acad. Sci., Ser. IIc: Chim. 16 (2013) 343.
[6] Z. Chen, B. Zhou, H. Cai, W. Zhu, X. Zou, Green Chem. 11 (2009) 275.
[7] Y. Gu, F. Je´roˆme, Green Chem. 12 (2010) 1127.
[8] Q. Zhang, K. De Oliveira Vigier, S. Royer, F. Je´roˆme, Chem. Soc. Rev. 41
(2012) 7108.
(m, 2H), 1.95–2.05 (m, 2H), 3.91–3.97 (m, 1H), 6.28 (s, 2H),
7.03–7.05 (m, 1H), 7.11–7.12 (m, 3H), 7.18 (t, J = 10, 5 Hz,
2H), 7.23–7.30 (m, 1H), 7.34 (d, J = 5 Hz, 1H), 7.56 (d,
J = 5 Hz, 2H), 8.13 (d, J = 10 Hz, 2H).
3.3.5. 3-Cyclohexyl-1-(1-(4-methoxyphenyl)-2-oxo-2
[9] C. Rub, B. Ko¨nig, Green Chem. 14 (2012) 2969.
[10] S. Tang, G.A. Baker, H. Zhao, Chem. Soc. Rev. 41 (2012) 4030.
[11] J. Zhu, H. Bienayme, Multicomponent Reactions, Verlag GmbH & Co.,
Weinheim, 2005.
phenylethyl)-1-phenylurea (5l)
Mp = 182–184 8C, 1H NMR (500 MHz, CDCl3):
d = 1.11–
1.17 (3H, m), 1.38 (2H, m), 1.62–1.69 (3H, m), 1.94–1.99
(2H, m), 3.78 (3H, s), 5.80 (1H, s), 6.16 (1H, s), 6.77 (2H, d,
J = 7.19 Hz), 7.03 (5H, s), 7.14 (2H, d, J = 6.4 Hz), 7.20 (3H, d,
J = 7 Hz), 7.29–7.33 (3H, m).
[12] A. Do¨mling, Chem. Rev. 106 (2006) 17.
[13] C.L. Jeannin, M. Boisbrun, C. Nemes, F. Cochard, M. Laronze, E. Dar-
´
´
dennes, A. Kovacs, J. Kulyassa, J.-Y. Sapi, Laronze, C. R. Chimie 6 (2003)
517.
[14] B.B. Toure, D.G. Hall, Chem. Rev. 109 (2009) 4439.
[15] M. Hayyan, M. Ali Hashim, A. Hayyan, M.A. Al-Saadi, I.M. Al Nashef,
M.E.S. Mirghani, O.K. Saheed, Chemosphere 90 (2013) 2193.
4. Conclusion
´
ˆ
[16] Y. Gu, R. De Sousa, G. Frapper, C. Bachmann, J. Barrault, F. Jerome, Green
Chem. 11 (2009) 1968.
In summary, we have developed an environmentally
benign and green Ugi reaction using bio-based and
biodegradable deep eutectic solvents based on a choline
chloride–urea mixture as a novel and efficient reaction
medium. Further studies in our laboratory are under way
to develop isocyanide-based multicomponent reactions in
this green reaction media.
[17] A. Do¨mling, Comb. Chem. High Troughput Screening 1 (1998) 1.
[18] A. Do¨mling, I. Ugi, Angew. Chem. Int. Ed. 39 (2000) 3168.
[19] J. Zhu, Eur. J. Org. Chem. (2003) 1133.
[20] O.E. Vercillo, C.K.Z. Andrade, L.A. Wessjohann, Org. Lett. 10 (2008) 205.
[21] S.E. Denmark, Y. Fan, J. Am. Chem. Soc. 125 (2003) 7825.
[22] B. Henkel, B. Beck, B. Westner, B. Mejat, A. Domling, Tetrahedron Lett.
44 (2003) 8947.
[23] S.-X. Wang, M.-X. Wang, D.-X. Wang, J. Zhu, Angew. Chem. Int. Ed. 47
(2008) 388.
[24] A. Do¨mling, W. Wang, K. Wang, Chem. Rev. 112 (2012) 3083.
[25] K. Sung, F.-L. Chen, P.-C. Huang, Synlett (2006) 2667.
[26] U. Kazmaier, S. Ackermann, Org. Biomol. Chem. 3 (2005) 3184.
[27] L. El Kaim, L. Grimaud, J. Oble, Angew. Chem. Int. Ed. 44 (2005) 7961.
[28] Y. Tanaka, T. Hasui, M. Suginome, Org. Lett. 9 (2007) 4407.
[29] H. Tye, M. Whittaker, Org. Biomol. Chem. 2 (2004) 813.
[30] B.O. Okandeji, J.R. Gordon, J.K. Sello, J. Org. Chem. 73 (2008) 5595.
[31] M.C. Pirrung, V. Sarma, J. Am. Chem. Soc. 126 (2004) 444.
[32] A.F.S. Barreto, O.E. Vercillo, M.A. Birkett, J.C. Caulfield, L.A. Wessjohann,
C.K.Z. Andrade, Org. Biomol. Chem. 9 (2011) 5024.
Acknowledgements
The financial support of this work provided by the
Chemistry and Chemical Research Center of Iran, and Iran
National Science Foundation (INSF) is gratefully appre-
ciated.
[33] M.C. Pirrung, K.D. Sarma, Tetrahedron 61 (2005) 11456.
[34] T.-F. Niu, G.-P. Lu, C. Cai, J. Chem. Res. 35 (2011) 444.
[35] N. Azizi, E. Gholibeglo, M. Babapour, H. Ghafuri, S.M. Bolourtchian, C.R.
Acad. Sci., Ser. IIc: Chim. 15 (2012) 768.
[36] N. Azizi, E. Batebi, S. Bagherpour, H. Ghafuri, RSC Adv. 2 (2012) 2289.
[37] N. Azizi, E. Gholibeglo, RSC Adv. 2 (2012) 7413.
References
[1] P. Abbott, G. Capper, D.L. Davies, R.K. Rasheed, V. Tambyrajah, Chem.-
Commun. (2003) 70.
[2] I. Mamajanov, A.E. Engelhart, H.D. Bean, N.V. Hud, Angew. Chem. Int. Ed.
49 (2010) 6310.
[38] N. Azizi, E. Batebi, Catal. Sci. Technol. 2 (2012) 2445.
[39] N. Azizi, E. Saki, M. Edrisi, C. R. Chimie 14 (2011) 973.
[3] A.P. Abbott, J. Barron, K. Ryder, D. Wilson, Chem. Eur. J. 13 (2007) 6495.
Please cite this article in press as: Azizi N, et al. A sustainable approach to the Ugi reaction in deep eutectic solvent. C. R.
Chimie (2013), http://dx.doi.org/10.1016/j.crci.2013.05.013