Deep eutectic solvent promoted highly efficient synthesis of N, N'-diarylamidines and formamides

Article abstract of DOI:10.1016/j.crci.2012.06.011

A deep eutectic solvent was used as a dual catalyst and reaction medium for the efficient N-formylation of aromatic amines without hazardous organic solvent and catalyst. Treatment of aromatic amines with trimethyl orthoformate and formic acid in deep eutectic solvent at 70 °C gives the corresponding N-formyl derivatives in good to excellent yields. This simple ammonium deep eutectic solvent, easily synthesized from choline chloride and SnCl₂, with 100% atom economy and making it applicable to industry and laboratory. Furthermore, heating the trimethyl orthoformate and aromatic primary amines in the deep eutectic solvent results in formation of the corresponding N,N'-diarylamidines in high yields.

Full text of DOI:10.1016/j.crci.2012.06.011

C. R. Chimie 15 (2012) 768–773
Contents lists available at SciVerse ScienceDirect
Comptes Rendus Chimie
www.sciencedirect.com
´
Full paper/Memoire
Deep eutectic solvent promoted highly efficient synthesis of
N, N’-diarylamidines and formamides
*
Najmadin Azizi , Elham Gholibeglo, Mahbobe Babapour, Hossein Ghafuri,
Seyed Mohammad Bolourtchian
Chemistry and Chemical Engineering Research Center of Iran, PO Box 14335-186, Tehran, Iran
A R T I C L E I N F O
A B S T R A C T
Article history:
A deep eutectic solvent was used as a dual catalyst and reaction medium for the efficient N-
formylation of aromatic amines without hazardous organic solvent and catalyst. Treatment
of aromatic amines with trimethyl orthoformate and formic acid in deep eutectic solvent at
70 8C gives the corresponding N-formyl derivatives in good to excellent yields. This simple
ammonium deep eutectic solvent, easily synthesized from choline chloride and SnCl2, with
100% atom economy and making it applicable to industry and laboratory. Furthermore,
heating the trimethyl orthoformate and aromatic primary amines in the deep eutectic
solvent results in formation of the corresponding N,N’-diarylamidines in high yields.
ß 2012 Acade´mie des sciences. Published by Elsevier Masson SAS. All rights reserved.
Received 13 March 2012
Accepted after revision 26 June 2012
Available online 11 August 2012
Keywords:
Aromatic amine
Diarylamidine
Deep eutectic solvent
Formamides
Trimethyl orthoformate
1. Introduction
Protection of amines as formamides is an important
reaction in synthetic organic chemistry [8]. Formamides
In recent years, utilization of ionic liquids (ILs) in
organic synthesis and industry received great attention as
alternative green solvents due to their unusual properties
compared with traditional organic solvents, such as lower
vapor pressure, thermal stability; broad rang of solubility
for many organic or inorganic compounds, and favorable
environments. However, most ILs have the disadvantage of
high cost for large-scale production and are environmen-
tally unsafe. Recently, a new versatile reaction medium has
emerged, known as deep eutectic solvents (DESs). They are
made by simple heating of a quaternary ammonium salt
and a metal halide or hydrogen bond donor, with 100%
atom economy. Relative to conventional ILs, DESs have
significant advantages, such as being easier and cheaper to
prepare, nonreactive with water and many are biodegrad-
able, but still exhibit chemical stability, non-flammability
and conductivity [1–7].
have wide applications as intermediates in the preparation
of pharmaceuticals and as important reagents for Vilsme-
ier formylation [9–11]. They are also in use as Lewis base
catalysts in organic transformations of carbonyl com-
pounds [12,13].
In the literature, various approaches with some of the
useful formylation reagents have been reported on N-
formylation of amines [14–26]. Many of the N-formylation
methods have disadvantages such as expensive reagents,
formation of side products, thermal instability and difficult
accessibility to reagents.
2. Experimental
Reactions were monitored by TLC and GC. FT-IR spectra
were recorded using KBr disks on a Bruker Vector 22 FT-IR
Spectrometer, 1H NMR spectra were recorded on 500 MHz
NMR spectrometer and 13C NMR spectra were recorded on
125 MHz NMR spectrometer using CDCl3 or DMSO as a
solvent, and chemical shifts have been expressed in ppm
downfield from TMS. Melting points were recorded on
* Corresponding author.
E-mail address: azizi@ccerci.ac.ir (N. Azizi).
1631-0748/$ – see front matter ß 2012 Acade´mie des sciences. Published by Elsevier Masson SAS. All rights reserved.
http://dx.doi.org/10.1016/j.crci.2012.06.011

N. Azizi et al. / C. R. Chimie 15 (2012) 768–773
769
Buchi 535 melting point apparatus and are uncorrected. All
2.3. General procedure for the preparation of symmetric
formamidines
starting materials, choline chloride and Tin chloride are
commercially available and were purchased and used
without further purification. Water and other solvent were
distilled before used.
To a mixture of aniline (2 mmol), trimethyl orthofor-
mate (1 mmol), in a test tube with magnetic stirring, tin (II)
chloride–choline chloride (2:1) (30 mol %) ionic liquid was
added. The test tube was heated in an oil bath at 90 8C for
20 minutes and then was cooled to room temperature and
ethyl acetate (20 mL) was added slowly and filtered off to
extract the product from the deep eutectic solvent. Then
the solvent and other volatile compounds were removed
under reduced pressure to give solid crude products.
Further purification was carried out by simple silica gel
with the mixture of ethyl acetate and hexane (4:1) or
recrystallization in hexane or the mixture of acetone and
tert-butylmethylether providing a colorless or yellow
powder.
2.1. General procedure for preparation of deep eutectic
solvent
Choline chloride (100 mmol) was mixed with tin (II)
chloride (200 mmol) and heated to ca. 130 8C in air with
stirring until a clear liquid was obtained1.
2.2. General procedure for N-formylation of amine
To a mixture of aniline (2 mmol) and formic acid
(3 mmol) or trimethyl orthoformate (3 mmol) in water
(0.5 mL), tin (II) chloride–choline chloride (2:1) (30 mol
%) was added into a test tube with magnetic stirring. The
test tube was heated in an oil bath at 70 8C for 20 min and
then was cooled to room temperature slowly and, ethyl
acetate (20 mL) was added and filtered off to extract the
product from the deep eutectic solvent. In some cases,
purification was not necessary and the products were
analyzed by 1H NMR spectroscopy; however, where
appropriate, short flash column chromatography and
recrystallization in an appropriate solvent was used for
further purification. All compounds are known and
characterized on the basis of their spectroscopic data
(IR, NMR) and melting point by comparison with those
reported in the literature.
3. Results and discussion
During the course of our study aimed for improving the
ecocompatibility of certain organic processes, we evaluat-
ed the possibility of performing basic organic transforma-
tions by using water and a deep eutectic solvent as green
solvent to develop environmentally benign reactions [27–
31]. Herein, we report, a simple and practical synthesis of
Formamides and N,N’-diarylamidines promoted by deep
eutectic solvent under mild reaction conditions.
First, we embarked upon a series of experiments to
establish the optimum conditions. In the initial study, five
deep eutectic solvents were screened under different
H
N
N
3
90%
HC(OMe)3, 90 oC
20 min
ChCl/SnCl2
NH2
NHCHO
NHCHO
HCOOH, 70 0C
HC(OMe)3, 70 oC
ChCl/SnCl2
water (0.5 mL)
20 min
ChCl/SnCl2
20 min
2
98%
2
1
80%
DESa
Ch/SnCl2 Ch/Urea Ch/ZnCl2 Ch/ZnCl2/SnCl2 Ch/Gly
Molar ratio
Yields (%)
1:2
98
1:2
40
1:2
80
1:1:1
90
1:3
15
a Reaction of aniline and formic acid in different DES. Ch= Choline chloride
Scheme 1. Optimization of reaction condition.

770
N. Azizi et al. / C. R. Chimie 15 (2012) 768–773
Table 1
Synthesis of Formamides (2) in DESs.
HCOOH
or
HC(OMe)3/ H2O
SnCl2/ChCl
Ar
CHO
ArNH2
+
N
70 oC, 20−160 min
H
30−98 %
Yields (%)a
HCO2H
98
Entry
Product (2)
HC(OMe)3
80
1
X = H
X
N H C H O
2
X = Cl
95
90
92
95
95
90
97
97
90
78
72
74
70
68
64
60
72
40
3
X = Br
4
X = I
5
X = OH
X = CH3
X = n-Bu
X = OMe
X = Me2CH
X = NO2
6
7
8
9
10
11
X = Cl
90
58
NHCHO
X
12
13
14
15
16
X = Br
82
88
90
92
88
62
60
74
76
68
X = OH
X = CH3
X = OMe
X = C2H5
17
X = Cl
95
55
X
NHCHO
18
19
20
X = Br
90
92
85
60
70
72
X = CH3
X = C2H5
21
88
50
Cl
NHCHO
NHCHO
Cl
22
72
40
23
24
80
70
45
30
CHO
N
CHO
Ph
Ph
N
25
26
72
90
35
60
N
NHCHO
H
N
N
ChCl: Choline Chloride.
a
Isolated yields.

N. Azizi et al. / C. R. Chimie 15 (2012) 768–773
771
reaction conditions (Scheme 1). First findings indicated
that simply mixing aniline (2 mmol), formic acid (3 mmol)
and choline chlorideꢀ2SnCl2 (30 mol %) at 70 8C provided
N-formyl aniline 3 in 98% yield within 20 minutes.
Among different deep eutectic solvents tested in this
reaction system, choline chloride ChCl and urea are both
the naturally occurring biocompatible compound as they
are easily biodegradable and are not hazardous if they are
released back into nature. Thus, we further optimized the
reaction condition (temperature, time and amount of
reagent) in urea-based deep eutectic solvent. So we
prolonged the reaction time to 4 h and 12 h and obtained
N-formyl aniline, with 78% and 85% yields respectively.
Then the reaction was performed at different tempera-
tures. We next investigated the effect of temperature on
the yields of reaction. At room temperature only starting
Table 2
Simple ppreparation of symmetric formamidines in deep eutectic solvent.a
SnCl2/ChCl
Ar
Ar
ArNH2
HC(OMe)3
+
N
N
H
90 oC, 20-100 min
45-90 %
Entry
Products
Yields (%)a,b
Entry
10
Products
Yields (%)a,b
80
1
90
H
H
Cl
N
N
N
N
Cl
2
80
82
78
11
12
13
75
88
90
Br
Br
H
N
H
N
N
N
Cl
Br
I
Cl
3
4
H
H
N
N
N
N
MeO
OMe
Br
OMe
H
N
H
N
N
N
I
OMe
5
6
85
85
14
15
78
72
H
N
H
N
N
N
H3C
CH3
H3C
CH3
Cl
Cl
H
H
N
N
N
N
N
Cl
Cl
Cl
Cl
7
8
80
78
16
17
45c
H
H
N
N
N
F3C
CF3
64c
H
N
H
N
N
N
NO2
NO2
9
74
18
66c
Cl
H
H
N
N
N
N
N
N
Cl
a
b
c
Isolated yields.
Reaction condition: amine (2 mmol), trimethyl orthoformate (1 mmol) and tin (II) chloride–choline chloride (2:1) (30 mol %) at 90 8C.
Reaction run at 130 8C for 4 h.

772
N. Azizi et al. / C. R. Chimie 15 (2012) 768–773
materials were recovered. When, the reaction was carried
at higher temperatures, i.e., 60 8C, 80 8C, 100 8C and 140 8C.
The yield was improved to 90% when the reaction was run
at 100 8C. However, increasing the temperature to 140 8C
failed to enhance the reaction rate substantially. In point of
fact, higher temperatures lowered the product yield
slightly, accompanied by some impurities. Furthermore,
4-nitroaniline did not give any products at choline
chloride/urea based deep eutectic solvent.
To demonstrate the versatility of this green method, we
next investigated the scope of this reaction under the
optimized conditions with the orthoformate as protecting
group in deep eutectic solvent. In DES, reaction of aniline
with trimethyl orthoformate, depending on the reaction
conditions, provided either compound 2 or 3 as the major
product with satisfactory yield. Under anhydrous condi-
tions in the presence of DES (30 mol %), reaction of aniline
(2 mmol) and trimethyl orthoformate (1 mmol) at 90 8C
gave N,N’-diarylamidines 3 at 90% yields within 20 min-
utes. When same reaction condition was carried out in the
presence of water (0.5 mL), formamide 2 were obtained in
80% yields (Scheme 1).
This finding has encouraged us to investigate the N-
formylation of a variety of aryl, and heteroaryl amines with
formic acid and trimethyl orthoformate under similar
conditions using DES as a catalyst and reaction condition
and the results of this investigation are shown in Table 1.
All the reactions with substituted aromatic amines
proceeded very cleanly, and no undesirable side-reactions
were observed, although the yields were highly dependent
on the substituents and formylating agent. Anilines
containing either electron-donating or electron-withdraw-
ing groups such as chloro, fluoro, bromo and iodo favored
the formation of product with formic acid and orthoester.
In contrast, strong electron-withdrawing group and
deactivated amines gave the slightly lower yield with
longer reaction times (Table 1). Secondary aromatic
amines, such as N-ethyl aniline gave excellent yields with
both formyl sources. With aliphatic amines no N-formyla-
tion occurred with both formyl sources whereas diphenyl-
amine gave moderate yield with formic acid. When o-
phenylenediamine was used, instead of N-formylation,
cyclization occurred to give benzimidazole as a sole
product with formic acid and orthoester. In the all cases
formic acid is more efficient formylating agent when
compared to orthoester.
Amidines and their derivatives have important indus-
trial applications in catalyst chemistry [31], material
science [32], biological chemistry [33–35], nitrogen based
superbase [36] promoted organic reactions and switchable
solvents [37–41]. A review of synthetic methods in the
literature indicates that nitriles, amides and dithiocarba-
mates in the presence of either protic acid or Lewis acid are
the most common building blocks for the synthesis of
unsymmetrical amidines. Furthermore, the condensation
of primary amine with carboxylic acids and their
derivatives or ortho-esters can be used for the synthesis
of symmetrical amidines in low yields and long reaction
time [42,43].
anhydrous eutectic salts was carried out with a primary
aryl amine and orthoformate (Table 2). Notably, most
aromatic amines performed very well and led to symmet-
rical formamidines in good yields. As shown in Table 2, a
series of aromatic amines bearing either electron-donating
or electron-withdrawing groups on the aromatic ring was
investigated. In general, electron-rich arylamines and mild
electron-withdrawing groups such as halides afforded
good to excellent yields of products in short reaction times.
However, when strongly electron-withdrawing groups
(such as CF3) were placed in the ortho-, meta- and
parapositions, higher reaction temperatures and longer
reaction times were required to access the products in
reasonable yields. Furthermore, heteroaromatic amine
such as 4-aminopyridine in deep eutectic solvent gives
the desired products within prolonged reaction time in
good yields (Table 2).
4. Conclusion
In summary, we have developed that an environmen-
tally friendly, and practical procedure for the synthesis of
N,N’-diarylamidines and formamides in the presence of
deep eutectic solvent and readily available starting
material in high yields. We believe that originality, time/
cost savings and experimental simplicity, concepts that are
considered by modern academic and industrial synthetic
chemists in reaching the maximum efficiency of a process,
are clearly represented this very simple catalytic transfor-
mation that provides an appealing methodology for the
synthesis of amidine derivatives. Exploitation of this novel
reaction media for the other organic synthesis is currently
under way in our laboratory.
Acknowledgments
The financial support of this work provided by
Chemistry and Chemical Research Center of Iran and Iran
National Science Foundation (INSF) is gratefully appre-
ciated.
References
[1] A.P. Abbott, G. Frisch, J. Hartley, K.S. Ryder, Green Chem. 13 (2011) 471.
[2] A.P. Abbott, R.C. Harris, K.S. Ryder, C.D. Agostino, L.F. Gladden, M.D.
Mantle, Green Chem. 13 (2011) 82.
[3] Z. Chen, W. Zhu, Z. Zheng, X. Zou, J. Fluorine Chem. 131 (2010) 340.
[4] Z. Maugeri, P. Domı´nguez de Marı´a, RSC Adv. 2 (2012) 421.
[5] Z. Chen, B. Zhou, H. Cai, W. Zhu, X. Zou, Green Chem. 11 (2009) 275.
[6] B. Singh, H. Lobo, G. Shankarling, Catal. Lett. 141 (2011) 178.
[7] P. Domı´nguez de Marı´a, Z. Maugeri, Curr. Opin. Chem. Biol. 15 (2011)
220.
[8] T.W. Green, P.G.M. Wuts, Protective Groups in Organic Synthesis, 4th
ed, Wiley Interscience, New York, 2007.
[9] B.C. Chen, M.S. Bendarz, R. Zhao, J.E. Sundeen, P. Chen, Z. Shen, A.P.
Skoumbourdis, J.C. Barrish, Tetrahedron Lett. 41 (2000) 5453.
[10] J.G. Kim, D.O. Jang, Synlett (2010) 2093.
[11] I.M. Downie, M.J. Earle, H. Heaney, K.F. Shuhaibar, Tetrahedron 49
(1993) 4015.
[12] S. Kobayashi, K. Nishio, J. Org. Chem. 56 (1994) 6620.
[13] S. Kobayashi, M. Yasuda, I. Hachiya, Chem. Lett. 25 (1996) 407.
[14] A.C. Shekhar, A.R. Kumar, G. Sathaiah, L. Paul, M. Sridhar, P.S. Rao,
Tetrahedron Lett. 50 (2009) 7099.
[15] M. Mihara, Y. Ishino, S. Minakara, M. Komatsu, Synthesis (2003) 2317.
[16] B. Das, M. Krishnaiah, P. Balasubramanyam, B. Veeranjaneyulu, D.N.
kumar, Tetrahedron Lett. 49 (2008) 2225.
To expand the scope of this reaction further, eco-
friendly preparation of symmetrical amidines using

N. Azizi et al. / C. R. Chimie 15 (2012) 768–773
773
[17] P.G. Reddy, G.D.K. Kumar, S. Bhaskaran, Tetrahedron 41 (2000) 9149.
[18] M. Hosseini-Sarvari, H. Sharghi, J. Org. Chem. 71 (2006) 6652.
[19] M. Suchy´, A.A.H. Elmehriki, R.H.E. Hudson, Org. Lett. 13 (2011) 3952.
[20] B. Kaboudin, M. Khodamorady, Synlett (2010) 2905.
[21] S.H. Jung, J.H. Ahn, S.K. Park, J.K. Choi, Bull. Korean Chem. Soc. 23 (2002)
149.
[22] K. Bao, W. Zhang, X. Bu, Z. Song, L. Zhang, M. Cheng, Chem. Commun. 42
(2008) 5429.
[23] J.G. Kim, D.O. Jang, Synlett (2010) 2093.
[33] S.D. Guile, L. Alcaraz, T.N. Birkinshaw, K.C. Bowers, M.R. Ebden, M.
Furber, M.J. Stocks, J. Med. Chem. 52 (2009) 3123.
[34] U.E.W. Lange, B. Scha¨fer, D. Baucke, E. Buschmann, H. Mack, Tetrahe-
dron Lett. 40 (1999) 7067.
[35] S. Caron, L. Wei, J. Douville, A. Ghosh, J. Org. Chem. 75 (2010) 945.
[36] K. Nagasawa, Superbases for Organic Synthesis, John Wiley & Sons
Limited, Chichester, U.K, 2009pp. 211–250.
[37] D.J. Heldebrant, P.K. Koech, T. Ang, C. Liang, J.E. Rainbolt, C.R. Yonker,
P.G. Jessop, Green Chem. 12 (2010) 713.
[24] J.G. Kim, D.O. Jang, Bull. Korean Chem. Soc. 31 (2010) 2989.
[25] B. Krishnakumar, M. Swaminathan, J. Mol. Catal. A: Chem. 334 (2011)
98.
[26] T. Cochet, V. Bellosta, A. Greiner, D. Roche, J. Cossy, Synlett (2011)
1920.
[27] N. Azizi, M.R. Saidi, Organomet. 23 (2004) 1457.
[28] N. Azizi, M.R. Saidi, Org. Lett. 7 (2005) 3649.
[29] N. Azizi, E. Saki, M. Edrisi, C. R. Chimie 14 (2011) 973.
[30] N. Azizi, R. Baghi, H. Ghafuri, M. Bolourtchian, M. Hashemi, Synlett
(2010) 379.
[38] P.G. Jessop, D.J. Heldebrant, L. Xiaowang, C.A. Eckert, C.L. Liotta, Nature
436 (2005) 1101.
[39] L. Phan, J.R. Andreatta, L.K. Horvey, C.F. Edie, A.L. Luco, A. Mirchandi, D.J.
Darensbourg, P.G. Jessop, J. Org. Chem. 73 (2008) 127.
[40] L. Phan, X. Li, D.J. Heldebrant, R. Wang, D. Chiu, E. John, H. Huttenhower,
P. Pollet, C.A. Eckert, C.L. Liotta, P.G. Jessop, Ind. Eng. Chem. Fundam. 47
(2008) 539.
[41] D.J. Heldebrant, C.R. Yonker, P.G. Jessop, L. Phan, Energ. Environ. Sci. 1
(2008) 487.
[42] K. Ostrowska, A. Kolasa, Science of Synthesis, Georg Thieme Verlag,
Germany, 2005, Vol. 22, pp. 379–488.
[31] F.T. Edelmann, Chem. Soc. Rev. 38 (2009) 2253.
[32] F.T. Edelmann, Adv. Organomet. Chem. 57 (2008) 183.
[43] J.R. Harjani, C. Liang, P.G. Jessop, J. Org. Chem. 76 (2011) 1683.