Green Process Synth 2014; 3: 457–461

Liang Wang*, Kai-Qiang Zhu, Qun Chen and Ming-Yang He*

Facile and green synthesis of Hantzsch derivatives

in deep eutectic solvent
Abstract: An efficient one-pot synthesis of polyhydroacri- 12], ceric ammonium nitrate (CAN) [13], organocatalyst
dines and polyhydroquinolines through the Hantzsch [14] and Brønsted acids [15, 16]. Among them, polyhy-
reaction in deep eutectic solvent choline chloride/urea droacridines (PHA) and polyhydroquinolines (PHQ) are
(1:2) has been developed. Good to excellent yields, broad two kinds of 1,4-DHPs that have received less attention
substrate compatibility as well as the reusability of the than other 1,4-DHP derivatives. PHA are usually synthe-
solvent are the major advantages of the present protocol. sized by one-pot condensation of dimedone, aldehydes
and ammonium acetate under microwave irradiation [17,
Keywords: deep eutectic solvent; green chemistry; Hantzsch 18] and solvent-free condition [19]. Ionic liquid [20] and
reaction; polyhydroacridines; polyhydroquinolines. organocatalyst [21] were also employed for such trans-
formation. PHQ are generally synthesized by an unsym-
DOI 10.1515/gps-2014-0056
metrical Hantzsch reaction, which involves the one-pot,
Received July 23, 2014; accepted September 5, 2014; previously pub- four-component condensation of dimedone, aldehydes,
lished online October 11, 2014 ethylacetoacetate and ammonium acetate, using various
catalysts or reagents such as montmorillonite K-10 [22],
Lewis acids [11, 23, 24], cerium (IV) ammonium nitrate [13]
and trifluoroethanol [25]. Syntheses of these compounds
1 Introduction using microwave irradiation [26], solar thermal energy
[7] and grinding [27] have also been reported. Although
The Hantzsch reaction is an old but very famous reaction great advances have been achieved, limitations includ-
because it offers an effective way to construct 1,4-dihy- ing expensive reagents, unsatisfactory yields, long reac-
dropyridines (1,4-DHPs) which exhibit significant bio- tion time, tedious work-up as well as unrecyclability of
logical activities [1–4]. Up until now, several commercial, the catalysts are still the major problems of the reported
clinically important drugs such as amlodipine, nifedipin, methods. Thus, a simple, efficient and eco-friendly proto-
nimodipine, felodipine, isradipine and nicardipine con- col for such useful transformation is still in demand.
taining the 1,4-DHP parent nucleus have been manufac- Recently, deep eutectic solvents (DES) have received
tured and used worldwide (Figure 1). wide attention as green solvents or catalysts in organic reac-
Traditionally, 1,4-DHPs are prepared via the three- tions due to their good properties such as low vapor pres-
component condensation of aldehyde, β-ketoester and sure, low flammability and biodegradability [28]. Moreover,
ammonia, namely the Hantzsch reaction [5]. However, the DES are usually non-toxic and inexpensive. One of the
this method suffers from some drawbacks such as long most explicit examples is the mixing one mole of choline
reaction time (∼20 h) and harsh reaction condition (in chloride (ChCl) with two moles of urea (with melting points
refluxing acetic acid or alcohol) while affords the prod- of 247°C and 133°C, respectively), which results in a DES
ucts in low yields (low to moderate yields). Recently, with a room temperature melting point [29]. It was worth
numerous efficient methods have been developed for noting that ChCl and urea are naturally occurring biocom-
the synthesis of 1,4-DHP derivatives, including the use of patible compounds and they are also commercially pro-
microwave [6], solar thermal energy [7], ultrasound irrita- duced on a large scale [30]. They also have shown potential
tion [8], autoclave [9], ionic liquids [10], Lewis acids [11, applications as both solvents and catalysts in organic reac-
tions such as epoxide hydrolysis [31], nitroaldol reaction
*Corresponding authors: Liang Wang and Ming-Yang He, School [32], C-C bond formation reaction [33], alkylation of amines
of Petrochemical Engineering, Changzhou University, Changzhou [34] and oxidative hydroxylation [35].
213164, People’s Republic of China, e-mail: [email protected]
As a part of our program for green chemistry [35],
(Liang Wang), [email protected] (Ming-Yang He)
Kai-Qiang Zhu and Qun Chen: School of Petrochemical Engineering,
herein, we wish to report a simple, efficient and reusable
Changzhou University, Changzhou 213164, People’s Republic of reaction system for one-pot synthesis of PHA and PHQ
China through the Hantzsch reaction (Scheme 1).

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458 L. Wang et al.: Hantzsch reaction in deep eutectic solvent

Cl organic layer was concentrated and the resulting crude product was
further purified by recrystallization with absolute ethanol to provide
NO2 Cl the 4a in 90% yield. 3,3,6,6-Tetramethyl-4-phenyl-3,4,6,7,9,10-hexa-
H3CO2C CO2CH3 H3CO2C CO2C2H5 hydro-2H,5H-acridine-1,8-dione (4a) [17]: white solid. M.p. > 250°C. 1H
NMR (500 Hz, CDCl3): δ 7.28–7.09 (m, 5H), 5.54 (s, 1H), 2.48–2.30 (m,
H3C N CH3 H3C N CH3
8H), 1.24 (s, 6H), 1.10 (s, 6H). ESI-MS m/z: 350 [M+H]+.
H H
Nifedipine Felodipine

NO2 2.3 Typical procedure for the synthesis of PHQ 6a

O
H3CO2C N
A mixture of 5,5-dimethylcyclohexane-1,3-dione (0.140 g, 1 mmol),
O aldehyde (1 mmol), ammonium acetate (0.077 g, 1 mmol), acetoac-
H3C N CH3 etate (0.129 g, 1 mmol) in ChCl/urea (1:1, 4 ml) was stirred at 80°C
H for 4 h. After completion of the reaction, the reaction mixture was
cooled to room temperature and extracted with EtOAc (3 × 5 ml). The
Nicardipine
organic layer was concentrated and the resulting crude product was
Figure 1 Selective examples of 1,4-dihydropyridine derivatives. further purified by recrystallization with absolute ethanol to pro-
vide the 6a in 91% yield. 2,7,7-Trimethyl-5-oxo-4-phenyl-1,4,5,6,7,8-
hexahydroquinoline-3-carboxylic acid ethyl ester (6a) [36]: white
solid. M.p. 203–205°C. 1H NMR (500 Hz, CDCl3): δ 7.31–7.08 (m, 5H),
2 Materials and methods 5.78 (br s, 1H, NH), 5.05 (s, 1H), 4.06 (q, J = 7.1 Hz, 2H), 2.32 (s, 3H),
2.24–2.14 (m, 4H), 1.19 (t, J = 7.1 Hz, 3H), 1.06 (s, 3H), 0.94 (s, 3H). ESI-
2.1 General remarks MS m/z: 340 [M+H]+.

All of the reagents and solvents are commercially available and were
used without further purification. Melting points were determined 2.4 Recovery of the DES
with a WRS-1B apparatus (Shuangxu Electronics Co., Ltd., Shanghai,
China) and were uncorrected. 1H NMR spectra were recorded in CDCl3 After completion of the reaction, ethyl acetate and water were added
using a Bruker Avance III 500-MHz spectrometer (Bruker, Germany). and the mixture was stirred for 5 min. The ethyl acetate layer contain-
Mass spectra (ESI) were measured with JMS-DX300 (Jeol, Japan) ing the starting substrates and product was separated. After remov-
and LCQ instruments (Thermo Fisher Scientific Inc., USA). All the ing the water, the DES was dried under vacuum at 80°C and then
products are known compounds and their spectroscopic data are in reused for the next cycle.
accordance with those previously presented.

3 Results and discussion

2.2 Typical procedure for the synthesis of PHA 4a
The DES ChCl/urea was readily prepared by mixing
A mixture of 5,5-dimethylcyclohexane-1,3-dione (0.280 g, 2 mmol),
ChCl (1 mol) with urea (2 mol) at 100°C until a clear
benzaldehyde (0.106 g, 1 mmol) and ammonium acetate (0.077 g,
1 mmol) in ChCl/urea (1:1, 4 ml) was stirred at 80°C for 4 h (monitored solution was obtained (30 min) which was directly
by TLC). After completion of the reaction, the reaction mixture was used without any purification. Other DES could also
cooled to room temperature and extracted with EtOAc (3 × 5 ml). The be prepared in a similar way. Initially, a mixture of

O Ar O
O
1
N
O H
PHA 4
ChCl/urea
+ Ar CHO + NH4OAc O O
O O Ar O
OEt
5 O
1 2 3
N
H
PHQ 6

Scheme 1 One-pot synthesis of PHA and PHQ derivatives in ChCl/urea.

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 L. Wang et al.: Hantzsch reaction in deep eutectic solvent 459

5,5-dimethylcyclohexane-1,3-dione (1), benzaldehyde (2a) The good results obtained for the reaction shown in
and ammonium acetate (3) was chosen as the model reac- Table 2 prompted us to extend this protocol to the synthe-
tion to examine the reaction conditions. Results are sum- sis of PHQ (Table 3). As seen from the table, the above pro-
marized in Table 1. A 61% yield of product was obtained tocol was also suitable for the synthesis of PHQ, providing
under solvent-free conditions. Other DES such as ChCl/p- the products 6a–6f in excellent yields.
TsOH (1:1), ChCl/malonic acid (1:2), ChCl/glycerol (1:2), The recyclability of ChCl/urea was also investigated
ChCl/HFIP (1:1.5) and ChCl/ZnCl2 (1:2) provided the prod- using the model reaction in Table 2. After completion
ucts in low to moderate yields. ChCl/urea was found to be of the reaction, ethyl acetate and water were added and
the best choice, giving the corresponding product 4a in the mixture was stirred for 5 min. The ethyl acetate layer
90% yield after 4 h (Table 1, entry 7). Other conventional containing the starting substrates and product was sepa-
solvents were also evaluated and low yields were obtained. rated. After removing the water, the deep eutectic solvent
A survey on the temperature also clearly showed that 80°C was dried under vacuum at 80°C and then reused for the
was the optimum temperature. next cycle. The results showed that the DES could be
Then, the scope and limitations of the current proce- reused for several runs with a gradual decrease in the
dure were examined, and a series of aromatic aldehydes yield (Table 4).
were evaluated under the optimized reaction conditions
(Table 1, entry 7). The results are summarized in Table 2.
Generally, the reactions proceeded smoothly to give the cor-
responding products in good to excellent yields (81–92%). 4 Conclusion
Aromatic aldehydes bearing both electron-withdrawing
and electron-donating groups showed good activities, In summary, we have developed a simple, efficient and
while aromatic aldehydes with nitro group at para position green procedure for the one-pot synthesis of PHA and
afforded slightly higher yield (Table 3, entry 8). The steric PHQ derivatives using ChCl/urea as a reaction medium.
hindrance was also examined and ortho-substituted alde- Mild conditions, good to excellent yields as well as wide
hydes gave relatively lower yield (Table 3, entry 10). substrate compatibility are the major advantages of this
protocol. Moreover, this deep eutectic solvent was envi-
ronmentally benign, easily available and could be recy-
Table 1 Survey on the solvent effect on the model reaction.a cled and reused for several runs.

O O Ph O

2 Eq. + PhCHO + NH4OAc

O N Table 2 Synthesis of PHA derivatives in ChCl/urea.a
H
1 2a 3 4a O O Ar O

2 Eq. + ArCHO + NH4OAc

Entry DES Temperature (°C) Yield (%)b N
O H
1 – 80 61 1 2 3 4
2 ChCl/p-TsOH (1:1) 80 76
3 ChCl/malonic acid (1:2) 80 30
Entry Ar Time (h) Yield (%)b
4 ChCl/glycerol (1:2) 80 Trace
5 ChCl/HFIP (1:1.5) 80 41 1 C6H5 4 4a (90)
6 ChCl/ZnCl2 (1:2) 80 65 2 4-CH3C6H4 4 4b (88)
7 ChCl/urea (1:2) 80 90 3 4-CH3OC6H4 4 4c (85)
8 EtOH 80 40 4 4-OHC6H4 6 4d (84)
9 Water 80 Trace 5 2-OHC6H4 6 4e (82)
10 CH3CN 80 32 6 4-ClC6H4 6 4f (90)
11 CH2Cl2 Reflux Trace 7 3-ClC6H4 4 4g (83)
12 EtOAc Reflux 20 8 4-NO2C6H4 4 4h (92)
13 ChCl/urea (1:2) 60 70 9 3-NO2C6H4 6 4i (83)
14 ChCl/urea (1:2) 40 53 10 2-NO2C6H4 6 4j (81)
15 ChCl/urea (1:2) 25 30 11 3-CH3O-4-OHC6H3 6 4k (87)
a
Reaction conditions: 1 (2 mmol), benzaldehyde 2a (1 mmol), a
Reaction conditions: dimedone 1 (2 mmol), aldehyde 2 (1 mmol),
­ammonium acetate 3 (1 mmol), DES or other solvents (4 ml), 4 h. ammonium acetate 3 (1 mmol), ChCl/urea (4 ml), 80°C.
b
Isolated yields. b
Isolated yield.

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460 L. Wang et al.: Hantzsch reaction in deep eutectic solvent

Table 3 Synthesis of PHQ derivatives in ChCl/urea.a [7] Mekheimer RA, Hameed AA, Sadek KU. Green Chem. 2008, 10,
O Ar O 592–593.
O
O O [8] Shaabani A, Rezayan AH, Rahmati A, Sharifi M. Monatsh.
O
+ ArCHO + NH4OAc +
OEt
Chem. 2006, 137, 77–81.
N
O H [9] Watanabe Y, Shiota K, Hoshiko T, Ozaki S. Synthesis 1983, 15,
1 2 3 5 6 761.
[10] Ji SJ, Jiang ZQ, Lu J, Loh TP. Synlett 2004, 15, 831–835.
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5771–5774.
1 C6H5 4 6a (91)
[12] Wang LM, Sheng J, Zhang L, Han JW, Fan Z, Tian H, Qian CT.
2 4-CH3C6H4 4 6b (88)
Tetrahedron 2005, 61, 1539–1543.
3 4-CH3OC6H4 4 6c (87)
[13] Ko S, Yao CF. Tetrahedron 2006, 62, 7293–7299.
4 4-OHC6H4 6 6d (85)
[14] Kumar A, Maurya RA. Tetrahedron 2007, 63, 1946–1952.
5 4-ClC6H4 3 6e (90)
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 L. Wang et al.: Hantzsch reaction in deep eutectic solvent 461

Qun Chen graduated from Jiangsu Polytechnic University in 1984

Liang Wang obtained his PhD degree in Applied Chemistry from
as a chemical engineer. He is a full professor and the Director
Nanjing University of Science and Technology of China in 2011. He
of the Center for Green Catalysis in the Department of Chemical
is currently working as an assistant professor at the School of Pet-
Engineering, Changzhou University. His research interests include
rochemical Engineering, Changzhou University, China. His research
the development of green methodologies for organic synthesis
is focused on the development of green methodologies for organic
and catalysis. He realized a series of stable and functional resin
synthesis and catalysis.
catalysts for industry application and he has also published more
than 100 research papers on green chemistry, organic chemistry
and inorganic chemistry.

Kai-Qiang Zhu received his BSc degree from Yancheng Teachers

University of China in 2013. He is currently pursuing his MSc degree
at the School of Petrochemical Engineering in Changzhou Univer- Ming-Yang He graduated from Jiangsu Polytechnic University in
sity under the supervision of Professor Ming-Yang He. His work is 1982. He is a full professor in the Department of Chemistry, Chang-
focused on green synthesis in an eco-friendly reaction medium. zhou University. He is also the Dean of the School of Petrochemical
Engineering. His research interests are focused on the clean synthe-
sis and heterogeneous catalysis. He has published more than 100
research papers on green chemistry, organic chemistry and material
chemistry.

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