Biorenewable deep eutectic solvent for selective and scalable conversion of furfural into cyclopentenone derivatives

Article abstract of DOI:10.3390/molecules23081891

The development of novel synthetic routes to produce bioactive compounds starting from renewable sources has become an important research area in organic and medicinal chemistry. Here, we present a low-cost procedure for the tunable and selective conversion of biomass-produced furfural to cyclopentenone derivatives using a mixture of choline chloride and urea as a biorenewable deep eutectic solvent (DES). The proposed medium is a nontoxic, biodegradable, and could be reused up to four times without any unfavorable effect on the reaction yield. The process is tunable, clean, cheap, simple and scalable and meets most of the criteria; therefore, it can be considered as an environmental sustainable process in a natural reaction medium.

Full text of DOI:10.3390/molecules23081891

molecules
Article
Biorenewable Deep Eutectic Solvent for Selective and
Scalable Conversion of Furfural into
Cyclopentenone Derivatives
Maria Luisa Di Gioia 1 , Monica Nardi
ID
2,3,
* ID , Paola Costanzo 4 , Antonio De Nino 2
ID
ID
,
2
4
ID
and Antonio Procopio 4
Loredana Maiuolo , Manuela Oliverio
1
Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Arcavacata di Rende,
7036 Cosenza, Italy; ml.digioia@unical.it
Department of Chemistry and Chemical Technologies of the University of Calabria, Cubo 12C,
Arcavacata di Rende, 87036 Cosenza, Italy; antonio.denino@unical.it (A.D.N.);
loredana.maiuolo@unical.it (L.M.)
Agrarian Department, San Raffaele Telematic University, Via di Val Cannuta, 247, 00166 Roma, Italy
Department of Health Sciences, Magna Graecia University, Viale Europa, 88100 Germaneto CZ, Italy;
pcostanzo@unicz.it (P.C.); m.oliverio@unicz.it (M.O.); procopio@unicz.it (A.P.)
Correspondence: monica.nardi@unical.it; Tel.: +39-098-449-2850
8
2
3
4
*
ꢀ
ꢁꢂꢀꢃꢄꢅꢆꢇ
ꢀ
ꢁꢂꢃꢄꢅꢆ
Received: 22 June 2018; Accepted: 26 July 2018; Published: 28 July 2018
Abstract: The development of novel synthetic routes to produce bioactive compounds starting from
renewable sources has become an important research area in organic and medicinal chemistry. Here,
we present a low-cost procedure for the tunable and selective conversion of biomass-produced
furfural to cyclopentenone derivatives using a mixture of choline chloride and urea as a biorenewable
deep eutectic solvent (DES). The proposed medium is a nontoxic, biodegradable, and could be reused
up to four times without any unfavorable effect on the reaction yield. The process is tunable, clean,
cheap, simple and scalable and meets most of the criteria; therefore, it can be considered as an
environmental sustainable process in a natural reaction medium.
Keywords: biomass conversion; cyclopentenones; deep eutectic solvents; furfural; green chemistry
1
. Introduction
In recent years, green chemistry has gained a great deal of attention, due to its ability to provide
new processes that minimize the use or generation of harmful substances, focusing the attention on the
use of cheap, renewable, and environmentally safe starting materials. In this regard, bio-based
materials have attracted many attentions in the last two decades; therefore, a list of top value
added chemicals from biomass has been drafted by the U.S. Department of Energy. Furfural, easily
obtained from xylose, is considered in that list as a valuable chemical building block to synthesize
other functionalized compounds [1–7]. One important class of new products derived from furfural
are cyclopentenones, which are distinguished structural motifs present not only in notable natural
molecules but also versatile as synthetic intermediates.
The introduction of the cyclopentenone moiety into molecules, such as (2)-cephalotaxine ester
derivatives
this five-membered ring structure is found in many compounds used in the perfumery industry,
such as dihydrojasmones and cis-jasmones , as well as in biologically active compounds, including
rethrolones employed in the synthesis of pyrethrines, prostanoids, methylenomycins (Figure 1) [ 10].
1 and (+)-nakadomarin 2, has been shown to boost their anticancer potential. Furthermore,
3
4
5
8–
Molecules 2018, 23, 1891; doi:10.3390/molecules23081891
www.mdpi.com/journal/molecules

Molecules 2018, 23, 1891
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Figure 1. The cyclopentenone moiety into biologically active molecules: (2)-cephalotaxine ester
derivatives 1, (+)-nakadomarin 2, dihydrojasmones 3, cis-jasmones 4 and rethrolones 5.
Numerous conventional synthetic approaches reported on the construction of the cyclopentenone
framework suffer from disadvantages, such as requirement of expensive catalysts, excess of toxic
solvents, harsh reaction conditions, undesirable wastes, unsatisfactory yields, and cumbersome
product isolation procedures [11–14]. Therefore, in the last decade, considerable research has
been devoted to the use of catalytic systems, such as Sc(OTf) and Dy(OTf) , for the synthesis of
3
3
trans-4,5-diaminocyclopent-2-enones [15]. In this context, erbium(III) chloride has found to act as a
powerful catalyst to convert biorenewable furfural derivatives into bifunctionalized cyclopentenones
in a green solvent, such as ethyl lactate [16], as well as in heterogeneous catalysts [17,18].
Within the framework of green chemistry, solvents occupy a strategic place, and in the literature,
novel approaches have also been proposed, addressing the use of safer alternative media for this
kind of transformation. Ramesh et al. employed an acidic ionic liquid as a reusable catalyst for the
reaction of furfural and secondary amines to yield trans-4,5-diaminocyclopent-2-enones [19], and our
group recently demonstrated the successful use of water as a reaction medium for the preparation
of cyclopentenone derivatives under microwave irradiation [20,21]. In addition, a very recent paper
from Afonso’s group described the use of Cu(OTf) as a very efficient catalyst for the synthesis of
2
cyclopentenones in water at room temperature for only 1 min [22]. Water is undoubtedly the cleanest
solvent on the Earth, as it is cheap, nontoxic, nonflammable, biorenewable, and safe for humans
and the environment [23–26]. Nevertheless, pure water is precious, and when it is contaminated by
chemicals, its purification is difficult and expensive [27], indicating that water can be considered to
be a truly green solvent only if it can be directly discharged to a biological effluent treatment plant.
Meanwhile, the use of water in various applications is limited. Therefore, the promising approach is to
seek more solvents, identify their characteristics that promote the selected process, and then choose a
suitable green solvent with required properties. For this purpose, a large set of solvents could be the
best alternative to the ideal “solvent-free condition”.
Deep eutectic solvents (DESs) are promising sustainable alternatives to traditional solvents and
ionic liquids. They are generally composed of two or three safe and inexpensive components, which are
involved in hydrogen bond interactions with each other to obtain a eutectic mixture with a melting
point much lower than that of each component species [28]. Since their typical components (e.g., choline
chloride (ChCl), urea, glycerol (Gly), natural carboxylic acids, amino acids and carbohydrates,
polyalcohols, etc.) come from natural sources, DESs display low toxicity, high thermal stability,
high biodegradability, high recyclability, low inflammability and volatility [29
the preparation of DES is easy and cost-effective and does not involve any post purification or
disposal problems [31 32]. DESs have been used for a variety of applications, including metal
deposition, metal oxide processing, metal dissolution, extractions and a variety of synthetic processes.
,30]. In addition,
,

Molecules 2018, 23, 1891
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New emerging fields of applications of DESs are represented by metal-, bio-, and organocatalysis,
and by organometallics [33 41]. All of these benefits prompted us to use DESs in our research.
–
Herein, we reported an experimentally and environmentally convenient method for the synthesis of
bifunctionalized cyclopentenones from furfural and amines using a biorenewable ChCl-based DES.
2
. Results and Discussion
Our investigation started with the model reaction between 2-furaldehyde and morpholine in
different ChCl-based DESs in order to optimize the reaction conditions. Initially, the effect of these
media on the system furfural/morpholine was studied performing the reaction in the DES formed by
ChCl and glycerol (Table 1, entries 1 and 2). Although no reaction was observed at room temperature,
evidence that the system could work well was registered when the same reaction was performed at
◦
8
0 C. Therefore, other ChCl-based DESs were examined as media of the reaction (Table 1, entries 3–9).
Thus, the yields of product A in ChCl:citric acid or in ChCl:lactic acid DES (Table 1, entries 3 and 4)
were lower compared to those obtained using the ChCl–urea mixture as the reaction medium. Indeed,
although no reaction occurred at room temperature in this system (Table 1, entry 5), increasing the
◦
temperature up to 60 C resulted in very high yields, indicating that the best results was generated
with the use of the DES composed of ChCl and urea (molar ratio) (Table 1, entry 6). Noteworthy,
increasing the reaction temperature did not change the result in terms of reaction yields (Table 1,
entry 7).
Table 1. Optimization of the reaction conditions in model reaction 1,2
.
◦
Yield 3 (%)
Entry
DES (Molar Ratio)
Temp ( C)
Time (min)
Product
1
1
2
3
4
5
6
7
8
ChCl:glycerol (1:2)
ChCl:glycerol (1:2)
ChCl:citric acid (1:1)
ChCl:lactic acid (1:1)
ChCl:urea (1:2)
rt
80
80
80
rt
60
80
60
60
60
5
5
5
60
5
5
5
240
30
60
1A
1A
1A
1A
1A
1A
1A
1B
1B
1B
1B
-
1
20
35
45
-
1
1
1
1
ChCl:urea (1:2)
ChCl:urea (1:2)
ChCl:urea (1:2)
ChCl:urea (1:2)
ChCl:urea (1:2)
ChCl:urea (1:2)
95
95
1
2
4
0
2
9
1
1
98
45
45
0 2
5
60 (MW)
60 (MW)
2
5
1
1
General reaction conditions for the synthesis of trans-4,5-dimorpholinocyclopent-2-enone 1A: furfural (1 mmol)
2
and morpholine (2 mmol) are dissolved in a DES and stirred for 5–60 min at different temperatures. General
reaction conditions for the synthesis of 2,4-dimorpholinocyclopent-2-enone 1B: furfural (1 mmol) and morpholine
3
(
2.2 mmol) were dissolved in a DES and stirred for 5–240 min at different temperatures. Yield (%) calculated from
4
5
GC/MS data of conversion of furfural. Compound 1A is obtained as the only product (97% yield). GC/MS
analysis shows the formation of both product 1A (55% yield) and product 1B (45% yield).

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As shown in Table 1, it was shown that heating 2-furaldehyde (1 mmol) and morpholine
◦
(
2 mmol) in the ChCl–urea mixture at 60 C was considered as the optimum conditions for the
synthesis of 4,5-dimorpholinocyclopent-2-enone (1A). An important advantage of this solvent system
is that the use of ChCl/urea is beneficial for the easy reaction mechanism without using any
chromatographic or other purification methods in addition to reduction in reaction times. In fact,
compound A was recovered by simple extraction with diethyl ether, followed by separation and
removal of the solvent under reduced pressure. A crucial factor in the development of a total full
green protocol is the environmental impact of the disposal of huge amounts of industrial solvents,
which must match the requirements of the “Green Chemistry Principles” [42]. Therefore, the possibility
to use a green solvent not only during the reaction but also during the final extraction of the
cyclopentenone derivatives was taken into account. The following green biosolvents [43] were
evaluated: ethyl lactate, ethyl acetate, 2-methyltetrahydrofuran, cyclopentyl methyl ether, dimethyl
carbonate, diethyl carbonate. The performance of all these media during the extraction of compound
A was comparable to diethyl ether. Therefore, taking into account the solvent selection guides that are
available [44,45], we decided to develop our protocol choosing ethyl acetate as the “greenest” solvent
for the extraction of compound 1A from the DES.
In a recent report by our group, we observed that using a slight excess of amine (2.2 mmol)
with respect to furfural in water, compound 1A was converted into the thermodynamically stable
2
,4-derivative 1B [20]. As a result, we decided to extend the scope of the present protocol further. Thus,
we performed the model reaction heating furfural with 2.2 mmol of morpholine in the ChCl–urea
◦
mixture. After 5 min of reaction at 60 C, compound 1A was still afforded in 97% (Table 1, entry 8),
but increasing the reaction time beyond 4 h, product 1A was totally converted into 1B (Table 1, entry 9).
The application of microwave irradiation with the aim to provide the enhanced reaction rate of this
second process [46–53] failed, as it furnished a mixture of both products 1A and 1B even after prolonged
reaction time (entry 10, 11). Therefore, the best synthesis of 2,4-dimorpholino cyclopentenone 1B
◦
occurred at 60 C for four hours with the use of ChCl–urea DES (Table 1, entry 9). These experimental
conditions were applied to widely enlarge the application field of the method (Table 2). The reaction
gave excellent results for different secondary amines, allowing the isolation of products 1A–10A in
high yields (Table 2, entries 1–10). Treatment of furfural with excess of aniline under our reaction
conditions did not afford the expected result (Table 2, entry 11) but in that case, the reaction furnished
a mixture of the corresponding imine and product 11A (see Supplementary Materials).
The reaction with primary aliphatic amines, such as benzylamine, produced the corresponding
imine as the only product even after prolonged reaction time (Table 2, entry 12). When a slight
excess of the appropriate secondary amine was used for a prolonged period of time, the formation of
2
,4-bisubstituted cyclopentenone derivatives 1B–2B was detected. The ChCl–urea DES was found to be
very effective in this kind of synthesis, since reaction time was not longer than four hours, and purity
of final compound, as well as the yields, was satisfied (Table 2, entries 13, 14). As already reported [20],
the importance of the nucleophilic character of the functional group was evidenced in this new DES
assisted protocol. Accordingly, when cysteine was added to the reaction system, the 4-thio derivative
was the major product of the reaction (Table 2, entry 15).
The observed ability of DES to rapidly form the imine functionality when furfural is treated with
a primary amine (Table 2, entries 11, 12) prompted us to exploit the reactivity of the free primary
amino group in compound 1C. On the other hand, the synthesis of Schiff bases in DESs is also a
well-known reaction [54
of amino acids [59 63] are one of the most important issues in the synthesis of biologically active
compounds and particularly in the synthesis of peptidomimetics [64 69]. For this aim, after the
–58]. Moreover, the protection and/or modification of the amino function
–
–
formation of 1C in DES, the simple addition of 1 mmol of furfural to the reaction mixture furnished the
corresponding imine 1D in a one-pot protocol (Scheme 1). The entire process afforded a compound
with potential pharmacological interest in excellent yields and short reaction time.

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Table 2. Synthesis of bifunctionalized cyclopentenones from furfural a.
Yields b (%)
Entry
Amine
Products
1
1A
9595
2
3
4
2A
3A
4A
90
92
95
5
6
5A
6A
96
89
7
7A
91

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Table 2. Cont.
Yields b (%)
Entry
Amine
Products
8
8A
9A
93
9
94
94
1
0
10A
1
1
1
2
11A
12A
40 c
0 d
1
3
4
1B
2B
98
94
O
NPh
1
N
Ph

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Table 2. Cont.
Yields b (%)
Entry
Amine
Products
1
5
1C
85
a
General reaction conditions: 1 mmol of furfural and 2 mmol/2.2 mmol of amine are dissolved under stirring in the
◦
b
DES (1 mL) at 60 C for 5 min/4 h to afford the corresponding products
A/B. Yield (%) calculated from GC/MS
data. c The corresponding imine derivative is afforded in 60% yield. d The corresponding imine is recovered as the
sole product.
The reusability of green solvents, such as ionic liquids (ILs) and DES, is always an advantage
for viable commercial and industrial processes, so we have evaluated the recyclability of the DESs in
the reaction of furfural with morpholine. The reaction mixture, including ChCl–urea and products,
was extracted with ethyl acetate. This extractive procedure was repeated two more times, and the
combined organic extracts were washed with water, dried, filtered and evaporated under reduced
pressure to afford the crude reaction product. The residual volatile organic solvent present in the
DES phase was removed under vacuum evaporation. Then, the next reaction cycle was performed by
simply adding new fresh reagents to the same DES. This reaction mixture was again subjected to the
above-described procedure, and further reaction cycles were repeated using the recycled DES phase.
2
H N
SH
O
O
O
O
3
H CO
O
HN
O
N
N
O
O
O
H
H2N
N
S
ChCl/Urea
ChCl/Urea
O
3
H CO
O
O
1
A
1C
H
O
ChCl/Urea
5
min
O
N
O
N
O
S
3
H CO
1D (75% yield)
Scheme 1. One-pot synthesis of cyclopentenone derivative 1D.
The ChCl–urea DES could be recovered and reused for four consecutive cycles in the synthesis
of A obtaining high yields (Figure 2). A slight decrease observed in the last cycle might be due to a
modification of the initial DES structure, thus reducing the initial beneficial solvent effects.

Molecules 2018, 23, 1891
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◦
Figure 2. Recyclability of DES. Isolated yields from reaction in the ChCl–urea mixture at 60 C.
Then, in order to demonstrate the potential practical applicability of this green procedure,
the model reaction to afford 1A was carried out in a scale of 10 mmol using 10 mL of DES. The reaction
was completed in 30 min with an 87% isolated yield after simple water addition and extraction with
ethyl acetate.
In Figure 3, we tentatively proposed the mechanism of the reaction. Hydrogen bonding is
the main factor that influences the reactivity and selectivity of the process [70–73]. The reversible
hydrogen bonding between urea and carbonyl groups giving substrate–solvent complex and activated
aldehyde are shown. The initial condensation of activated carbonyl group with the secondary
amine in the DES leads to the formation of an enamine intermediate with the loss of a water
molecule. Then, this intermediate via a 4π-electrocyclic rearrangement furnishes compound A [15,20].
The hydrogen-bond donating character of urea is also involved in the formation of an enolic
intermediate that successively leads to the thermodynamically stable regioisomer B.
Figure 3. Proposed mechanism of the reaction in DES.

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3
. Materials and Methods
3
.1. General Information
All chemicals and solvents were purchased from common commercial sources and were used as
received without any further purification. All reactions were monitored by GC/MS analysis (Shimadzu,
Kyoto, Japan) and thin-layer chromatography TLC on silica Merck 60 F254 pre-coated aluminum plates
and were developed by spraying with sulphuric acid in ethanol solution when possible. The GC-MS
Shimadzu workstation was constituted by a GC 2010 (equipped with a 30 m-QUADREX 007-5MS
capillary column, operating in the “split” mode, 1 mL min-1 flow of He as carrier gas) and a 2010
1
quadrupole mass-detector. Proton nuclear magnetic resonance ( H-NMR) spectra were recorded on
a Brüker spectrometer (Bruker Instrument, Inc., Zurich, Switzerland) at 300 MHz. Chemical shifts
were reported in
δ units (ppm) with tetramethylsilane (TMS) as a reference (δ 0.00). All coupling
constants (J) were reported in Hertz. Multiplicity was indicated by one or more of the following:
s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet). Carbon nuclear magnetic resonance
13
(
C-NMR) spectra were recorded on a Brüker at 75 MHz. Chemical shifts were reported in
δ units
(
ppm) relative to CDCl3 ( 77.0). LC-MS analysis were carried using an Agilent 6540 UHD Accurate
δ
Mass Q-TOF LC–MS (Agilent, Santa Clara, CA, USA) fitted with an electrospray ionization source
(
Dual AJS ESI) operating in the positive ion mode. Chromatographic separation was achieved using
◦
a C18 RP analytical column (Poroshell 120, SB-C18, 50
gradient from 5% to 95% of B over 13 min, A being H O (0.1% FA) and B CH CN (0.1% FA). The flow
×
2.1 mm, 2.7
µ
m) at 30 C with an elution
2
3
rate was 0.4 mL/min.
3
.2. General Procedure for the Deep Eutectic Solvent Preparation
A mixture of ChCl (6.98 g, 50 mmol) and urea (6.00 g, 100 mmol) was added in a round-bottom
◦
flask under inert atmosphere. The mixture was magnetically stirred for 60 min at 80 C until a clear
colourless liquid was obtained. The obtained DES was used without purification.
3
.3. General Procedure for the Formation of 4,5-Difunctionalized Cyclopentenones (1A–12A)
The amine (1–12, 2 mmol) was added to a stirred solution of furfural (1 mmol) in ChCl–urea
◦
eutectic mixture (1 mL). The resulting mixture was stirred at 60 C for 5 min. The reaction was
monitored by TLC and GC/MS analysis. After this time, the reaction was quenched with water and
extracted with AcOEt (3
×
2 mL). The organic phases were dried over Na SO , followed by evaporation
2 4
under reduced pressure to remove the solvent to give the corresponding products 1A–12A. Spectral
data were in accordance with the literature [10].
The reaction of morpholine with furfural was scaled up to grams using 10 mL of DES.
After completion of the reaction, 10 mL of water was added. The resulting mixture was stirred
for 30 min, and after that, the obtained solution was extracted with ethyl acetate (3
A was afforded with a yield of 87%.
×
10 mL). Product
1
3
.4. General Procedure for the Formation of 2,4-Bifunctionalized Cyclopentenones (1B–2B)
The amine (1–2, 2.2 mmol) was added to a stirred solution of furfural (1 mmol) in ChCl–urea
◦
eutectic mixture (1 mL). The resulting mixture was stirred at 60 C for 4 h. The reaction was monitored
by TLC and GC/MS analysis. After this time, the reaction was quenched with water and extracted
with AcOEt (3
×
5 mL). The organic phases were dried over Na SO , followed by evaporation under
2 4
reduced pressure to remove the solvent to give the corresponding products 1B–2B. Spectral data were
in accordance with the literature [14].

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3
.5. Procedure for the Formation of Methyl (2R)-2-(furan-2- ylmethylene) amino)-3-((3-morpholino-4-
oxocyclopent-2-en-1-yl)thio]propanoate (1D)
Morpholine (2.2 mmol) was added to a stirred solution of furfural (1 mmol) in ChCl–urea eutectic
◦
mixture (1 mL). The resulting mixture was stirred at 60 C for 5 min. After this time, cysteine
methyl ester hydrochloride (1 mmol) was added to the reaction mixture and stirred for further 4 h to
obtain 4-(methyl-L-cysteinate)-2-morpholino cyclopent-2-enone 1C [14]. In order to obtain the imine
derivative of 1C, 1 mmol of furfural was added to the reaction mixture described above and maintained
under stirring for 5 min and monitored by GC/MS analysis. The reaction was quenched with water
and extracted with AcOEt (3
evaporation under reduced pressure to remove the solvent to give the corresponding product 1D in
×
2 mL). The organic phases were dried over Na SO , followed by
2 4
7
5% yield.
1
H-NMR (300 MHz, CDCl ): 2.47 (dd, 1H, J = 8.4 Hz, J = 4.5 Hz, COCHN=), 2.56 (m, 1H, SCH ), 2.85 (m,
3
2
1
H, SCH ), 3.13–3.16 (m, 4H, morpholine), 3.44 (dd, 1H, J = 8.1 Hz, J = 3.3 Hz, COCH ), 3.50 (dd, 1H,
2
2
J = 5.1 Hz, J = 3.0 Hz, COCH ), 3.03 (s, 3H, CH ), 3.63 (t, 1H, SCH), 3.71–3.82 (m, 4H, morpholine),
2
3
6
.23 (d, J = 3.0 Hz, 1H, COC=CH), 6.27 (dd, J = 3.0 Hz, J = 2.1 Hz, 1H, OCH=CH), 6.31 (d, J = 2.1 Hz,
13
1H, OC=CH) 6.38 (d, J = 3.0 Hz, 1H, OCH=C), 7.33 (s, 1H, CH=N); C-NMR (75 MHz, CDCl ) 29.7,
3
3
0.4, 44.2, 47.3, 53.1, 66.5, 78.6, 108.9, 110.0, 129.2, 141.8, 142.4, 151.6, 152.9, 174.9, 201.8. MS(EI): m/z
+
.
(%) = 378 (4) [M] , 319 (3), 277 (2), 245 (3), 212 (18), 180 (100), 166 (47), 146 (4), 138 (13), 120 (16),
+
+
111 (17), 93 (13), 44(8). HRMS (ESI) for ([C H N O S] + H) 378.1249, found 379.1328 [M + H] ,
18
22
2
5
+
4
01.1143 [M + Na] .
3
.6. Recycling of Deep Eutectic Solvent
The recycling of DES was examined in the reaction of furfural and morpholine in the ChCl–urea
mixture under optimized conditions. After the reaction was completed, AcOEt (3 mL) was added
to the reaction mixture, and stirred for 5 min. The stirring was stopped to allow phase separation,
and the upper organic layer was removed. This extractive procedure was repeated two more times
and the combined organic extracts were washed with water (3
×
5 mL), dried (Na SO ), filtered,
2 4
and evaporated under reduced pressure to afford the crude reaction product. The residual volatile
organic solvent present in the DES phase was removed under vacuum evaporation. Then, the next
reaction cycle was performed with the DES, adding fresh furfural and morpholine. This reaction
mixture was again subjected to the above-described procedure, and further reaction cycles were
repeated using the recycled DES phase.
4
. Conclusions
In conclusion, we have described an effective and rapid method for the synthesis of
bifunctionalized cyclopentenones in an eco-friendly and biodegradable DES based on the ChCl–urea
mixture. The advantages of this method are operational simplicity, green medium, DES recoverability,
short reaction time, high yields and no chromatographic purification procedures. The recyclability of
the DES (up to four reaction runs) and its synergistic effect on the reaction outcome have also been
demonstrated. Furthermore, the DES can be used as a low-cost, safe and efficient solvent with feasible
large-scale preparation.
To the best of our knowledge, this is the first report on the synthesis of trans-4,5-diaminocyclopent-
2
-enones derivatives and 2,4-diaminocyclopent-2-enones in DESs.
Moreover, this synthetic strategy can be utilized for the construction of many other novel
cyclopentenone derivative compounds of pharmaceutical importance.
Supplementary Materials: The HR-MS, GC/MS, 1H- and 13C-NMR spectra of new synthesized compounds are
available online.

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Author Contributions: M.N. conceived and designed the experiments; M.L.D.G. performed the experiments;
A.D.N. and L.M. analyzed the data; M.O. and P.C. helped with experiment feasibility; M.N. and M.L.D.G. wrote the
text. The whole work was co-ordinated by A.P. All authors have approved for the final version of the manuscript.
Funding: This research received no external funding.
Acknowledgments: The authors would like to acknowledge the University of Calabria, and the University of
Magna Graecia for supporting this work.
Conflicts of Interest: The authors declare no conflict of interest.
References
1
.
Bozell, J.J.; Petersen, G.R. Technology development for the production of biobased products from biorefinery
carbohydrates—The US Department of Energy’s “Top 10” revisited. Green Chem. 2010, 12, 539–554.
[CrossRef]
2
3
.
.
Peters, F.N. Industrial uses of furans. Ind. Eng. Chem. 1939, 31, 178–180. [CrossRef]
Lukes, R.M.; Wilson, C.L. Reactions of furan compounds. XI. Side chain reactions of furfural and furfuryl
alcohol over nickel-copper and iron-copper catalysts. J. Am. Chem. Soc. 1951, 73, 4790–4794. [CrossRef]
Hashmi, S.K.; Wölfle, M.; Teles, J.H.; Frey, W. Bisphenols from furfurals by organocatalysis and gold catalysis.
Synlett 2007, 11, 1747–1752. [CrossRef]
4.
5.
6.
Tšupova, S.; Rominger, F.; Rudolpha, M.; Hashmi, A.S.K. Synthesis of phenols from hydroxymethylfurfural
(HMF). Green Chem. 2016, 18, 5800–5805. [CrossRef]
Hashmi, S.K.; Rudolph, M.; Siehl, H.U.; Tanaka, M.; Bats, J.W.; Frey, W. Gold catalysis: Deuterated
substrates as the key for an experimental insight into the mechanism and selectivity of the phenol synthesis.
Chem. Eur. J. 2008, 14, 3703–3708. [CrossRef] [PubMed]
7
8
9
1
1
1
1
1
1
.
.
.
Hashmi, A.S.K.; Frost, T.M.; Bats, J.W. Highly selective gold-catalyzed arene synthesis. J. Am. Chem. Soc.
2
000, 122, 11553–11554. [CrossRef]
Takano, I.; Yasuda, I.; Nishijima, M.; Hitotsuyanagi, Y.; Takeya, K.; Itokawa, H. New cephalotaxus alkaloids
from cephalotaxus harringtonia var. drupacea. J. Nat. Prod. 1996, 59, 965–967. [CrossRef]
Inagaki, F.; Kinebuchi, M.; Miyakoshi, N.; Mukai, C. Formal Synthesis of (+)-Nakadomarin A. Org. Lett. 2010
,
1
2, 1800–1803. [CrossRef] [PubMed]
0. Magnus, P.; Fielding, M.R.; Wells, C.; Lynch, V. Stereoselective synthesis of the tricyclic core ABC-rings of
nakadomarin and manzamine from a common intermediate. Tetrahedron Lett. 2002, 43, 947–950. [CrossRef]
1. McGowan, J.C. The preparation of bases from the coloured compounds formed by condensation of
furfuraldehyde with aromatic amines. J. Chem. Soc. 1949, 777–779. [CrossRef]
2. Lewis, K.G.; Mulquiney, C.E. Aspects of the formation and use of stenhouse salts and related compounds.
Tetrahedron 1977, 33, 463–475. [CrossRef]
3. Lewis, K.G.; Mulquiney, C.E. Rearrangements in the furan series. ii. The reaction between furfuraldehyde
and aromatic amines. Aust. J. Chem. 1979, 32, 1079–1092. [CrossRef]
4. Hofmann, T. Characterization of the chemical structure of novel colored maillard reaction products from
furan-2-carboxaldehyde and amino acids. J. Agric. Food Chem. 1998, 46, 932–940. [CrossRef]
5. Li, S.W.; Batey, R.A. Mild lanthanide(III) catalyzed formation of 4,5-diaminocyclopent-2-enones from
2-furaldehyde and secondary amines: A domino condensation/ring-opening/electrocyclization process.
Chem. Commun. 2007, 3759–3761. [CrossRef] [PubMed]
1
6. Procopio, A.; Costanzo, P.; Curini, M.; Nardi, M.; Oliverio, M.; Sindona, G. Erbium(III) chloride
in ethyl lactate as a smart ecofriendly system for efficient and rapid stereoselective synthesis of
trans-4,5-diaminocyclopent-2-enones. ACS Sustain. Chem. Eng. 2013, 1, 541–544. [CrossRef]
7. Nunes, J.P.M.; Afonso, C.A.M.; Caddick, S. Synthesis of 2,4-bifunctionalised cyclopentenones from
1
1
1
2
-furaldehyde. RSC Adv. 2013, 3, 14975–14978. [CrossRef]
8. Estevão, M.S.; Afonso, C.A.M. Synthesis of trans-4,5-diaminocyclopent-2-enones from furfural catalyzed by
Er(III) immobilized on silica. Tetrahedron Lett. 2017, 58, 302–304. [CrossRef]
9. Ramesh, D.; Reddy, T.S.; Narasimhulu, M.; Rajaram, S.; Suryakiran, N.; CMahesh, K.; Venkateswarlu, Y.
Efficient and rapid stereoselective synthesis of trans-4,5-diaminocyclopent-2-enones by acidic ionic liquid
under solvent-free conditions. Chem. Lett. 2009, 38, 586–587. [CrossRef]

Molecules 2018, 23, 1891
12 of 14
2
2
2
0. Nardi, M.; Costanzo, P.; De Nino, A.; Di Gioia, M.L.; Olivito, F.; Sindona, G.; Procopio, A. Water excellent
solvent for the synthesis of bifunctionalized cyclopentenones from furfural. Green Chem. 2017, 19, 5403–5411.
CrossRef]
1. Messa, F.; Perrone, S.; Capua, M.; Tolomeo, F.; Troisi, L.; Capriati, V.; Salomone, A. Towards a sustainable
synthesis of amides: Chemoselective palladium-catalysed aminocarbonylation of aryl iodides in deep
eutectic solvents. Chem. Commun. 2018. [CrossRef] [PubMed]
2. Gomes, R.F.A.; Esteves, N.R.; Coelho, J.A.S.; Afonso, C.A.M. Copper(II) triflate as a reusable catalyst for the
synthesis of trans-4,5-diamino-cyclopent-2-enones in water. J. Org. Chem. 2018. [CrossRef] [PubMed]
3. Lindström, U.M. Stereoselective Organic Reactions in Water. Chem. Rev. 2002, 10, 2751–2772. [CrossRef]
4. Procopio, A.; Gaspari, M.; Nardi, M.; Oliverio, M.; Tagarelli, A.; Sindona, G. Simple and efficient MW-assisted
cleavage of acetals and ketals in pure water. Tetrahedron Lett. 2007, 48, 8623–8627. [CrossRef]
[
2
2
2
5. Procopio, A.; Gaspari, M.; Nardi, M.; Oliverio, M.; Rosati, O. Highly efficient and versatile chemoselective
addition of amines to epoxides in water catalyzed by erbium(III) triflate. Tetrahedron Lett. 2008, 49, 2289–2293.
[
CrossRef]
6. Nardi, M.; Di Gioia, M.L.; Costanzo, P.; De Nino, A.; Maiuolo, L.; Oliverio, M.; Olivito, F.; Procopio, A.
Selective acetylation of small biomolecules and their derivatives catalyzed by Er(OTf) . Catalysts 2017, 7, 269.
2
3
[
CrossRef]
7. Simon, M.O.; Li, C.J. Green chemistry oriented organic synthesis in water. Chem. Soc. Rev. 2012, 41, 1415–1427.
CrossRef] [PubMed]
8. Abbott, A.P.; Davies, D.L.; Capper, G.; Rasheed, R.K.; Tambyrajah, V. Ionic Liquids and Their Use As solvents.
U.S. Patent 7,183,433, 27 February 2007.
9. Paiva, A.; Craveiro, R.; Aroso, I.; Martins, M.; Reis, R.L.; Duarte, A.R.C. Natural deep eutectic
solvents—Solvents for the 21st century. ACS Sustain. Chem. Eng. 2014, 2, 1063–1071. [CrossRef]
0. Zhang, Q.; Vigier, K.D.O.; Royer, S.; Jérôme, F. Deep eutectic solvents: Syntheses, properties and applications.
Chem. Soc. Rev. 2012, 41, 7108–7146. [CrossRef] [PubMed]
1. Abbott, A.P.; Capper, G.; Davies, D.L.; Rasheed, R.K.; Tambyrajah, V. Novel solvent properties of choline
chloride/urea mixtures. Chem. Commun. 2003, 70–71. [CrossRef]
2
2
2
3
3
3
3
3
3
[
2. Gorke, J.T.; Srienc, F.; Kazlauskas, R.J. Hydrolase-catalyzed biotransformations in deep eutectic solvents.
Chem. Commun. 2008, 10, 1235–1237. [CrossRef] [PubMed]
3. Smith, E.L.; Abbott, A.P.; Ryder, K.S. Deep Eutectic Solvents (DESs) and their applications. Chem. Rev. 2014
14, 11060–11082.
,
1
4. Abo-Hamad, A.; Hayyan, M.; AlSaadi, M.A.; Hashim, M.A. Potential applications of deep eutectic solvents
in nanotechnology. Chem. Eng. J. 2015, 273, 551–567. [CrossRef]
5. Del Monte, F.; Carriazo, D.; Serrano, M.C.; Gutierrez, M.C.; Ferrer, M.L. Deep eutectic solvents in
polymerizations: A greener alternative to conventional syntheses. ChemSusChem 2014, 7, 999–1009.
[CrossRef] [PubMed]
3
3
3
3
6. García-Álvarez, J. Deep eutectic mixtures: Promising sustainable solvents for metal-catalysed and
metal-mediated organic reactions. Eur. J. Inorg. Chem. 2015, 31, 5147–5157. [CrossRef]
7. Alonso, D.A.; Baeza, A.; Chinchilla, R.; Guillena, G.; Pastor, I.M.; Ramón, D.J. Deep eutectic solvents:
The organic reaction medium of the century. Eur. J. Org. Chem. 2016, 4, 612–632. [CrossRef]
8. Khandelwal, S.; Tailor, Y.K.; Kumar, M. Deep eutectic solvents (DESs) as eco-friendly and sustainable solvent/
catalyst systems in organic transformations. J. Mol. Liq. 2016, 215, 345–386. [CrossRef]
9. Chen, J.; Liu, M.; Wang, Q.; Du, H.; Zhang, L. Deep eutectic solvent-based microwave-assisted method for
extraction of hydrophilic and hydrophobic components from radix salviae miltiorrhizae. Molecules 2016, 21,
1
383. [CrossRef] [PubMed]
4
4
4
0. Li, T.; Lyu, G.; Liu, Y.; Lou, R.; Lucia, L.A.; Yang, G.; Chen, J.; Saeed, H.A.M. Deep eutectic solvents (DESs)
for the isolation of willow lignin (salix matsudana cv. zhuliu). Int. J. Mol. Sci. 2017, 18, 2266. [CrossRef]
[PubMed]
1. Piemontese, L.; Perna, F.M.; Logrieco, A.; Capriati, V.; Solfrizzo, M. Deep Eutectic Solvents as novel and
effective extraction media for quantitative determination of ochratoxin a in wheat and derived products.
Molecules 2017, 22, 121. [CrossRef] [PubMed]
2. Anastas, P.T.; Warner, J.C. Green Chemistry: Theory and Practice; Oxford University Press: Oxford, UK, 1998;
ISBN 0-19-850234-6.

Molecules 2018, 23, 1891
13 of 14
4
4
4
4
4
4
4
3. Alder, C.M.; Hayler, J.D.; Henderson, R.K.; Redman, A.M.; Shukla, L.; Shuster, L.E.; Sneddon, H.F. Updating
and further expanding GSK s solvent sustainability guide. Green Chem. 2016, 18, 3879–3890. [CrossRef]
4. Prat, D.; Haylerb, J.; Wellsc, A. A survey of solvent selection guides. Green Chem. 2014, 16, 4546–4551.
0
[CrossRef]
5. Prat, D.; Wells, A.; Hayler, J.; Sneddon, H.; McElroy, C.R.; Abou-Shehadad, S.; Dunne, P.J. CHEM21 selection
guide of classical- and less classical-solvents. Green Chem. 2016, 18, 288–296. [CrossRef]
6. Desai, K.R. Green Chemistry Microwave Synthesis, 1st ed.; Himalaya Publication House: New Delhi, India,
2
005; p. 20.
7. Kappe, O. Controlled microwave heating in modern organic synthesis. Angew. Chem. Int. Ed. 2004, 43,
250–6284. [CrossRef] [PubMed]
8. Dallinger, D.; Kappe, O. Microwave-assisted synthesis in water as solvent. Chem. Rev. 2007, 107, 2563–2591.
CrossRef] [PubMed]
9. Oliverio, M.; Costanzo, P.; Nardi, M.; Calandruccio, C.; Salerno, R.; Procopio, A. Tunable microwave-assisted
method for the solvent-free and catalyst-free peracetylation of natural products, Beilstein. J. Org. Chem. 2016
2, 2222–2233.
6
[
,
1
5
5
0. Nardi, M.; Bonacci, S.; Cariati, L.; Costanzo, P.; Oliverio, M.; Sindona, G.; Procopio, A. Synthesis and
antioxidant evaluation of lipophilic oleuropein aglycone derivatives. Food Funct. 2017, 8, 4684–4692.
[CrossRef] [PubMed]
1. Maiuolo, L.; Merino, P.; Algieri, V.; Nardi, M.; Di Gioia, M.L.; Russo, B.; Delso, I.; Tallarida, M.A.; De Nino, A.
Nitrones and nucleobase-containing spiro-isoxazolidines derived from isatin and indanone: Solvent-free
microwave-assisted stereoselective synthesis and theoretical calculations. RSC Adv. 2017, 7, 48980–48988.
[CrossRef]
5
2. Mingos, D.M.P. Microwave in chemical syntheses. Chem. Ind. 1994, 596–599.
5
3. De la Hoz, A.; Díaz-Ortiz, A.; Moreno, A. Microwaves in organic synthesis. Thermal and non-thermal
microwave effects. Chem. Soc. Rev. 2005, 34, 164–178. [CrossRef] [PubMed]
5
5
5
5
4. Dalpozzo, R.; De Nino, A.; Nardi, M.; Russo, B.; Procopio, A. Erbium(III) triflate: A valuable catalyst for the
synthesis of aldimines, ketimines, and enaminones. Synthesis 2006, 31, 1127–1132. [CrossRef]
5. Nardi, M.; Cozza, A.; De Nino, A.; Oliverio, M.; Procopio, A. One-pot synthesis of dibenzo[b,e][1,4]diazepin-
1
-ones. Synthesis 2012, 44, 800–804. [CrossRef]
6. Oliverio, M.; Costanzo, P.; Nardi, M.; Rivalta, I.; Procopio, A. Facile ecofriendly synthesis of monastrol and
its structural isomers via biginelli reaction. ACS Sustain. Chem. Eng. 2014, 2, 1228–1233. [CrossRef]
7. Nardi, M.; Oliverio, M.; Costanzo, P.; Sindona, G.; Procopio, A. Eco-friendly stereoselective reduction of
α,β-unsaturated carbonyl compounds by Er(OTf) /NaBH in 2-MeTHF. Tetrahedron 2015, 71, 1132–1135.
3 4
[CrossRef]
5
8. Molnar, M.; Komar, M.; Brahmbhatt, H.; Babi c´ , J.; Joki c´ , S.; Rastija, V. Deep Eutectic Solvents as convenient
media for synthesis of novel coumarinyl schiff bases and their QSAR studies. Molecules 2017, 22, 1482.
[CrossRef] [PubMed]
5
6
9. De Marco, R.; Di Gioia, M.L.; Leggio, A.; Liguori, A.; Viscomi, M.C. Deprotection of N-Nosyl-α-amino Acids
by using solid-supported mercaptoacetic acid. Eur. J. Org. Chem. 2009, 22, 3795–3800. [CrossRef]
0. Di Gioia, M.L.; Barattucci, A.; Bonaccorsi, P.; Leggio, A.; Minuti, L.; Romio, E.; Temperini, A.; Siciliano, C.
Deprotection/reprotection of the amino group in
α-amino acids and peptides. A one-pot procedure in
[Bmim][BF4] ionic liquid. RSC Adv. 2014, 4, 2678–2686. [CrossRef]
6
6
6
6
1. Di Gioia, M.L.; Gagliardi, A.; Leggio, A.; Leotta, V.; Romio, E.; Liguori, A. N-Urethane protection of amines
and amino acids in an ionic liquid. RSC Adv. 2015, 5, 63407–63420. [CrossRef]
2. Nardi, M.; Herrera Cano, N.; Costanzo, P.; Oliverio, M.; Sindona, G.; Procopio, A. Aqueous MW eco-friendly
protocol for amino group protection. RSC Adv. 2015, 5, 18751–18760. [CrossRef]
3. Di Gioia, M.L.; Costanzo, P.; De Nino, A.; Maiuolo, L.; Nardi, M.; Olivito, F.; Procopio, A. Simple and efficient
Fmoc removal in ionic liquid. RSC Adv. 2017, 7, 36482–36491. [CrossRef]
4. Di Gioia, M.L.; Leggio, A.; Le Pera, A.; Siciliano, C.; Sindona, G.; Liguori, A. An efficient and highly selective
deprotection of N-Fmoc-a-amino acid and lipophilic N-Fmocdipeptide methyl esters with aluminium
trichloride and N,N-dimethylaniline. J. Pept. Res. 2004, 63, 383–387. [CrossRef] [PubMed]

Molecules 2018, 23, 1891
14 of 14
6
6
6
6
6
5. De Marco, R.; Di Gioia, M.L.; Leggio, A.; Liguori, A.; Perri, F.; Siciliano, C.; Viscomi, M.C. A new non-natural
arginine-like amino acid derivative with a sulfamoyl group in the side-chain. Amino Acids 2010, 38, 691–700.
CrossRef] [PubMed]
6. De Marco, R.; Di Gioia, M.L.; Liguori, A.; Perri, F.; Siciliano, C.; Spinella, M. N-Alkylation of
N-Arylsulfonyl- -amino Acid Methyl Esters by Trialkyloxonium Tetrafluoroborates. Tetrahedron 2011
7, 9708–9714. [CrossRef]
[
α
,
6
7. Di Gioia, M.L.; Belsito, E.L.; Leggio, A.; Leotta, V.; Romio, E.; Siciliano, C.; Liguori, A. Reduction of amide
carbonyl group and formation of modified amino acids and dipeptides. Tetrahedron Lett. 2015, 56, 2062–2066.
[
CrossRef]
8. Di Gioia, M.L.; Leggio, A.; Malagrinò, F.; Romio, E.; Siciliano, C.; Liguori, A. N-Methylated
And Peptides: Synthesis And Biological Activity. Mini-Rev. Med. Chem. 2016, 16, 683–690. [CrossRef]
PubMed]
9. Nardi, M.; Cano, N.H.; De Nino, A.; Di Gioia, M.L.; Maiuolo, L.; Oliverio, M.; Santiago, A.; Sorrentino, D.;
Procopio, A. An eco-friendly tandem tosylation/Ferrier N-glycosylation of amines catalyzed by Er(OTf) in
α
-Amino Acids
[
3
2
-MeTHF. Tetrahedron Lett. 2017, 58, 1721–1726. [CrossRef]
7
0. Yadav, U.N.; Shankarling, G.S. Room temperature ionic liquid choline chloride–oxalic acid: A versatile
catalyst for acid-catalyzed transformation in organic reactions. J. Mol. Liq. 2014, 191, 137–141. [CrossRef]
1. Capua, M.; Perrone, S.; Perna, F.M.; Vitale, P.; Troisi, L.; Salomone, A.; Capriati, V. An Expeditious and
Greener Synthesis of 2-Aminoimidazoles in deep eutectic solvents. Molecules 2016, 21, 924. [CrossRef]
7
[PubMed]
7
7
2. Shaabani, A.; Hooshmand, S.E. Choline chloride/urea as a deep eutectic solvent/organocatalyst promoted
three-component synthesis of 3-aminoimidazo-fused heterocycles via Groebke–Blackburn–Bienayme process.
Tetrahedron Lett. 2016, 57, 310–313. [CrossRef]
3. Dilauro, G.; Cicco, L.; Perna, F.M.; Vitale, P.; Capriati, V. Solvent-catalyzed umpolung carbonesulfur
bond-forming reactions by nucleophilic addition of thiolate and sulfinate ions to in situ derived
nitrosoalkenes in deep eutectic solvents. C. R. Chim. 2017, 20, 617–623. [CrossRef]
Sample Availability: samples of the compounds 1–5, dry preserved, are available from the authors.
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2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access
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(