Physicochemical properties of a urea/zinc chloride eutectic mixture and its improved effect on the fast and high yield synthesis of indeno[2,1-: C] quinolines

Article abstract of DOI:10.1039/d0nj01342k

In this contribution, a low melting mixture of urea-zinc chloride was prepared and characterized using FTIR, RAMAN and TGA. In addition, the physicochemical properties, such as electrical conductivity, density, pH and refractive index were measured and analysed as a function of temperature. To further expand the use of this DES as a valuable reaction medium, the three-component Povarov reactions between aromatic aldehydes, anilines and indene were studied obtaining a series of pharmacologically important indeno[2,1-c]quinolines in high yields with short reaction times. All the reactions proceeded efficiently using the eutectic mixture as an environmentally friendly solvent, which was reused up to three cycles. Moreover, green metrics analysis showed that this protocol offers a green and very efficient alternative to the traditionally reported methods for constructing the same heterocyclic system.

Full text of DOI:10.1039/d0nj01342k

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Physicochemical properties of Urea/Zinc chloride eutectic mixture
and its improved effect on the fast and high yield synthesis of
indeno[2,1-c]quinolines
Received 00th January 20xx,
Accepted 00th January 20xx
Diana Peña-Solórzano, a Vladimir V. Kouznetsov b and Cristian Ochoa-Puentes *a
DOI: 10.1039/x0xx00000x
In this contribution, the low melting mixture urea-zinc chloride was prepared and characterized by FTIR, RAMAN and TGA.
In addition, the physicochemical properties such as electrical conductivity, density, pH and refractive index were measured
and analysed as function of temperature. To further expand the use of this DES as a valuable reaction medium, the three-
component Povarov reaction between aromatic aldehydes, anilines and indene was studied obtaining a series of
pharmacologically important indeno[2,1-c]quinolines in high yields with short reaction times. All reactions proceeded
efficiently using the eutectic mixture as environmentally friendly solvent which was reused up to three cycles. Moreover,
green metrics analysis showed that this protocol offers a green and very efficient alternative to the traditional reported
methods for constructing the same heterocyclic system.
15
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19
chemosensors,11-13 MOF´s,14,
dyes16,
and polymers18,
also
Introduction
contain this heterocycle in the structure.
Deep eutectic solvents (DES) have shown a great capability to
perform different chemical processes in which organic solvents are
commonly employed. Their particular physicochemical properties
together with the low cost and availability of many chemicals used in
their formation have allowed finding new applications in organic
synthesis, metal and natural products extraction, electrochemistry,
nanomaterials, trace metal analysis and biochemistry.1-3 The
versatility of these new alternative solvents has been widely
demonstrated in the synthesis of several organic compounds where
the eutectic mixture allows performing organic transformations such
as brominations, reductions, condensations, addition of
organometallic reagents to carbonyl compounds, palladium
catalysed cross coupling reactions, among others.4-6 Nevertheless,
new and practical applications for these solvents aimed to synthesize
diversely functionalized organic compounds with a broad spectrum
of applications are highly desirable and challenging.
Figure 1. Structure of representative quinoline alkaloids and
synthetic drugs.
Different and well-known synthetic strategies for the construction of
diversely substituted quinolines are reported in literature. The classic
Skraup synthesis, Doebner, Doebner-Von Miller, Conrad-Limpach,
21
Friedlander, Pfitzinger and Combe´s reactions,20, together with
Quinoline and its derivatives are among the most common
heterocyclic units found in nature. This nitrogenated scaffold takes
part of the structure of complex and bioactive natural products such
as benzastatin D 1, camptothecin 2, orixine 3 and cinchonine 4,7 and
the synthetic drugs chloroquine 5, pyronaridine 6, lenvatinib 7
among others (Figure 1). In addition, materials with a broad scope of
applications including harvesting and emitting complexes,8-10
modern methods such as transition-metal mediated synthesis22 and
photoinduced synthesis23-25 have allowed the obtention of multiple
compounds bearing different substituents on all positions of the
quinoline skeleton. However, and despite the large number of
methods for the synthesis of substituted quinolines, the construction
of polycyclic derivatives through new efficient convergent strategies
is still required.
As a representative class of polycyclic derivatives, indenoquinolines
have riced great interest due to their diverse applications. In
particular, indeno[2,1-c]quinolines exhibited significant biological
activities such as topoisomerase I/II inhibitors,26-28 anti-
mycobacterial,29-31 antitumor,32 antiprotozoal33 and anti-
inflammatory.34 The current methods found in literature for the
a.Laboratorio de Síntesis Orgánica Sostenible, Departamento de Química,
Universidad Nacional de Colombia–Sede Bogotá, Carrera 45 # 26-85, A.A 5997,
Bogotá, Colombia.
b.Laboratorio de Química Orgánica y Biomolecular, CMN, Universidad Industrial de
Santander. Parque Tecnológico Guatiguará, Km 2 Vía Refugio, Piedecuesta 681011,
Colombia.
Electronic Supplementary Information (ESI) available: TGA, characterization data for
all compounds and selected 1H and 13C-NMR spectra. See DOI: 10.1039/x0xx00000x
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construction of this tetracyclic system are very limited and most of The eutectic mixture urea/zinc chloride (3.5:1 molar ratio), first
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them are based on linear multistep synthesis;35-37 however, several reported by Abbott et al,43 has been already employed for the
DOI: 10.1039/D0NJ01342K
authors have recently reported more efficient straightforward synthesis of imidazoles,44 dihydroquinazolinones,45 imidazolones,46
methods involving the reaction of propargylanilines with diethyl and bis(indolyl)methanes;47 however a detailed physicochemical
benzaldehyde acetals through a tandem carboarylation/cyclization characterization has not been yet reported. Therefore, before
procedure,38 or the reaction of anilines, aldehydes and indane exploring its potential in the synthesis of indenoquinolines, we
derivatives such as 1-indanone, 2-indanol and indene (Scheme 1).32, focused our efforts on studying the FTIR and Raman spectra as well
39-42
as the TGA analysis and some physicochemical properties as function
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of temperature and thus, understand its behaviour and role in this
and future diverse applications.
The FTIR characterization of the synthesized DES was conducted in
order to study the functional groups of the components present in
the DES, and to analyse the possible changes in the structure. The
FTIR spectra of pure urea (a), ZnCl2 (b) and the DES Urea/ZnCl2 (c) are
presented in Figure 2.
Scheme 1. Straightforward synthetic methods reported for the
construction of indeno2,1-cquinolines.
The developed synthetic methods depicted in Scheme 1 show that
Figure 2. FTIR spectra for the urea/ZnCl2 DES and the corresponding
constituents.
the target heterocyclic compound can be obtained in moderate to
excellent yields in one or two synthetic steps starting from readily
available starting materials, but some drawbacks such as long
reaction times, harsh reaction conditions, use of costly, air sensitive
or toxic solvents and catalysts, and the generation of waste are also
associated. The advantages and limitations found in the
aforementioned synthetic methods have motivated us to study the
obtention of this important heterocyclic scaffold employing the
eutectic mixture urea/zinc chloride as reaction media and herein we
report the results obtained.
It can be seen in Figure 2a that the IR spectrum of pure urea shows
the vibrational bands of the NH2 group at 3500-3200 cm-1, while the
band in 1678 cm-1 is attributed to the C=O stretching. The vibrational
bands at 1623 and 1461 cm-1 correspond to the NH and C-N bending
respectively, and the C-N stretch appears at 1100 cm-1. Similarly, the
FTIR spectrum of pure ZnCl2 (Figure 2b) exhibited an absorption peak
at 3519 cm-1 (O-H stretching) and 1605 cm-1 (H-O-H bending
vibration) indicating the presence of water molecules, which might
come from the trapped moisture in the sample during the analysis.
Results and discussion
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The hygroscopic nature of zinc chloride allows the formation of
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hydrates (ZnCl2 [H2O]n;) on exposure to water molecules.48 The metal
halides (Zn–Cl) show IR peaks below 900 cm-1. The FTIR spectrum for
the DES (Figure 2c) displays all bands corresponding to the functional
groups of both constituents; however, a new peak at 2224 cm-1
appeared which might suggest that new bonds are formed by
coordination between urea and Zinc chloride. Moreover, the
carbonyl vibration in urea showed a red shift from 1678 cm-1 to 1622
cm-1, indicating that the coordination bonds were mainly formed
between oxygen of carbonyl in urea and the metal ion.49
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The Raman spectra for urea, zinc chloride and the DES are depicted
in Figure 3.
Figure 4. Density (ρ) of urea/zinc chloride DES as a function of
temperature.
As can be seen, the densities of DES have a temperature-dependent
behaviour where the densities gradually decrease with increase in
temperature. The variation of density with temperature was
modelled according to equation 1 where ρ is the density, t is the
temperature, a and b are constants (Table 1).
ρ(g/cm3) = a(t/oC) + b
(1)
Figure 3. Raman spectra of urea, zinc chloride and the urea/zinc
chloride DES.
At the same range of temperatures, the refractive index of the DES
lies within the range of 1.511 ‐ 1.528 showing a decrease with
increasing temperature (Figure 5). Considering that low values for
density are obtained at high temperatures this behaviour was the
expected.
The Raman spectrum of urea show bands between 1500-1700 cm-1
which are assigned to the NH2 deformation vibration (1649 cm-1) and
the CO stretching vibration (1540 cm-1). The bands at 1478 cm-1 and
1014 cm-1 are assigned to the antisymmetrical and symmetrical CN
stretching vibrations respectively.50 The most intense band observed
in ZnCl2 spectra at 252 cm-1 was assigned to Zn-Cl stretching mode of
symmetry Ag.51 The same band is observed at 250 cm-1 in the DES
while the band observed in 1014 cm-1 in urea appears at lower
wavenumber at 1010 cm-1. From above data analysis given by FTIR
and Raman, it is notorious that the coordination of metal ions
through the oxygen atom of urea is confirmed by the change in
nature of C=O and C–N bonds.
The thermogravimetric analysis (see supporting information) is
congruent with the observations made by Lian et al.52 and shows that
before 158 oC the DES loses 3.4 wt% which is attributed to the
inherent moisture content in ZnCl2. No decomposition of urea is
observed at this temperature which indicates that this DES can be
used as reaction media at temperatures between 9 and 150 °C.
Next, several physicochemical properties such as density (ρ),
refractive index (nD), pH and electrical conductivity (k) were studied
as function of temperature.
Figure 5. Refractive index (nD) of urea/zinc chloride DES as a function
of temperature.
Density measurements for the urea/ZnCl2 DES (Figure 4) were
performed at temperatures ranging from 35 to 80 °C.
The variation of refractive index with temperature was fitted linearly
according with the equation 2 where nD is the refractive index, t is
the temperature, a and b are unitless parameters shown in Table 1.
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nD = a(t/oC) + b
(2)
The correlation between temperature and conductivity can be
modelled with the Arrhenius-like equation 4.
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On the other hand, changes in pH are also observed with the
variation of temperature: an increase of temperature decreases the Ln k = ln k0 - (Ek/RT)
pH in the DES showing values in the range of 5.34 to 4.20 (Figure 6).
(4)
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Table 1. Values of parameters a, b, c, k0, Ek/R and correlation
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coefficient for equations 1-4.
Physical properties
Parameters
and
correlation
coefficient
ρ
nD
pH
k
a
-5.7x10-3
1.835
-4x10-4
1.541
-3x10-4
0.0104
5.3453
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k0
Ek/R
R2
1631.2
4102.8
0.9955
0.9994
0.9995
0.9961
Figure 6. pH for urea/zinc chloride DES as a function of temperature.
Having studied the physicochemical properties of the urea/zinc
chloride DES as function of temperature, our efforts were directed
toward the synthesis of indeno[2,1-c]quinolines employing the
eutectic mixture as reaction media. Taking into account the results
obtained from TGA and the physicochemical measurements, we
conclude that the urea/zinc chloride DES might be used as a reaction
medium at high temperatures (up to 150 oC) without showing
decomposition of its components and thus, favouring the mobility of
substrates (DES components and starting materials). Among the
reported synthetic methods depicted in Scheme 1, we envisaged that
the Povarov reaction between anilines, aldehydes and indene41, 42, 53
could be the most convenient method to obtain the target
compounds because it offers some advantages over the other
methods such as the easy access to a wide source of commercially
available aldehydes and anilines, the low cost of indene compared to
1-indanone, 2-indanol and the superior atom economy. In addition,
our recent report about the use of DES in the Povarov reaction has
showed that this alternative reaction media drastically reduces the
reaction time and improve the yield.54 To start our synthetic studies,
the reaction between p-toluidine, benzaldehyde and indene was
selected as model reaction with the aim of obtains the
indenoquinoline 9. Results are summarized in Table 2.
The variation of pH with temperature was fitted by the general
second‐order polynomial equation 3 where t is the temperature, a,
b and c are unitless parameters shown in Table 1.
pH = a(t/oC)2 + b(t/oC) + c
(3)
Unlike the other physicochemical properties, the ionic conductivity
increases with temperature as a result of the enhanced kinetic
energy of all species present in the DES (Figure 7).
As seen in Table 2, the eutectic mixture ChCl/ZnCl2, previously
reported for us for the diastereoselective synthesis of
tetrahydroquinolines,54
yielded
a
mixture
of
the
tetrahydroindenoquinoline 8 and its aromatic analogue 9 (entries 1-
4). It was observed that the desired indenoquinoline 9 was the major
product in all reactions, and the increase in temperature favours the
obtention of this compound reaching an 84 % yield after 3 h (entry
4). The structure of the diastereomeric tetrahydroquinoline 8 was
established on base of some representative 1H-NMR signals.32
Figure 7. Conductivity as a function of temperature for urea/zinc
chloride DES.
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aldehydes and amines bearing electro donatingVieawnAdrticeleleOcntlirnoe
withdrawing substituents with indene. Results are shown in Figure 8.
DOI: 10.1039/D0NJ01342K
Table 2. Optimization of the reaction conditions for the synthesis of
compound 9
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Entry Conditionsa
Conv. (%)b
Yield (%) 8:9c
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ChCl/ZnCl2, 60 0C, 3 hd
100
100
100
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100
17:38
15:52
13:66
11:84
<1:98
10:67
12:82
0
ChCl/ZnCl2, 80 0C, 3 hd
ChCl/ZnCl2, 110 0C, 1 hd
ChCl/ZnCl2, 110 0C, 3 hd
Urea/ZnCl2, 110 0C, 1 he
Urea/ZnCl2, 110 0C, 0.5 he 100
Urea/ZnCl2, 80 0C, 1 he
Urea, 110 0C, 1 hf
ZnCl2, 110 0C, 1 hg
110 0C, 1 h
100
67
81
9:23
0
78
a All reactions were performed with 1 mmol of p-toluidine, 1 mmol
of benzaldehyde and 1 mmol of indene in an open 2 mL headspace
vial. b Based on unreacted p-toluidine recovered after purification.
c Isolated yield. d 1.6 g of choline chloride/zinc chloride (ChCl/ZnCl2
e
f
1.5:1) was used. 1.6 g of urea/zinc chloride (3.5:1) was used.
g
The same amount of urea as in entry 5 was used. The same
amount of ZnCl2 as in entry 5 was used.
With these results in our hands, we hypothesize that this DES can
promote
the
Povarov
reaction
forming
the
initial
tetrahydroquinoline 8, which is oxidized in-situ by the oxygen
present in the atmosphere giving the corresponding quinoline 9.
Analogously, the performance of the urea/ZnCl2 DES was also
evaluated on the model reaction (entries 5-7). To our delight, it was
found that after 1 hour of reaction the desired indenoquinoline 9 was
obtained in an excellent yield (entry 5) and only trace amounts of the
corresponding tetrahydroquinoline were detected (according to GC–
MS and crude 1H NMR). A reduction on the reaction time or
temperature give lower yields of the aromatic compound and the
amount of tetrahydroquinoline found was about 10-12 % (entry 6
and 7). The reaction carried out with urea or under solvent free
conditions yielded no product (entries 8 and 10) while the use of zinc
chloride only afforded the product 9 in 23 % together with 9 % of
compound 8. It was also observed that high conversion of p-toluidine
is obtained when DES are used as reaction medium (entries 1-7) and
lower values are found for reactions performed in urea, zinc chloride
or solvent free conditions (entries 8-10). The conversion of p-
toluidine is attributed to the formation of the imine intermediate (by
reaction with benzaldehyde) which react with indene to afford
compounds 8 and 9. With the optimal reaction conditions already
established, we next study the scope of this cycloaddition-oxidative
aromatization tandem reaction by reacting different aromatic
Figure 8. Substrate scope for the one-pot multicomponent synthesis
of indeno[2,1-c]quinolines 9-44.
Indenoquinolines 9-44 were obtained in excellent yields ranging
from 89 to 99 %. Aniline and its derivatives bearing electron donating
(p-methyl and p-methoxy) and electron withdrawing groups (p-
chloro, p-nitro and 2,4-dichlororo) react smoothly with
benzaldehyde and indene giving the corresponding tetracyclic
compounds 14, 19, 24, 29 and 34 in 98, 89, 94, 97 and 92 % yield
respectively. On the other hand, it was observed that the electronic
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nature of aldehydes used along each series does not influence the bands indicating decomposition or the appearance of new functional
outcome of the reaction; for example, the yields obtained in the groups are not present (Figure 9).
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series synthesized from aniline are 98(14), 95(15), 98(16), 96(17) and
98 % (18) when benzaldehyde and its o-chloro, p-chloro, m-nitro and
p-methoxy derivatives are employed. In addition to the examples
given earlier, heteroaromatic aldehydes such as pyridine-based
aldehydes also afforded the target compounds 39-44 in 90-96 %
yield. However, the aliphatic aldehydes heptanal and decanal did not
react as expected and a complex mixture of products was obtained.
This result might be explained by the enolizable character of these
aldehydes which can also react affording tetrahydroquinolines and
quinolines.55-57
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A comparison of the available methods for the synthesis of
compounds 9, 21-23 and 39-44 (Scheme 1) reveals that our
methodology is superior allowing the synthesis of the target
compounds in one step with very short reaction times and excellent
yields avoiding the need of expensive, air sensitive or laborious
heterogeneous catalysts and oxidizing agents such as Sulphur or
chloranil (Table 3).
Table 3. Comparison of reported synthetic methods and this work for
the obtention of indeno[2,1-c]quinolines.
Yield (%)a
Entry Comp.
Reaction conditions
Reported
This
work
1
9
AgOTf (5 mol%), HOTf
(10 mol%) toluene, air
120 °C, 12 h40
86
98
2
21
22
23
39
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44
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92
94
92
90
92
95
91
94
96
LDHs@Propyl–ANDSA,
3
94
CH3CN, 60oC, 1.7-3.7 h39
4
88
Figure 9. FTIR spectra of freshly prepared DES and after each reaction
cycle.
5
40b
60b
82b
63b
62b
92b
Considering the structure of the intermediates involved in this
reaction, a plausible mechanism for the obtention of compounds 9-
44 is proposed in Scheme 2.
6
.
1. BF3 OEt2, CH3CN, 80
7
oC, 2-10 h; 2. S8/220-
240 oC, 5-10 min32, 41
8
According to the proposed mechanism, the reaction is initiated by
the condensation of the aromatic aldehyde and the aniline resulting
on the formation of the imine A. Here, the electrophilic character of
the carbonyl group of the aldehyde might be enhanced by the
different zinc species that coexist in the DES favouring the obtention
of the 2-azadiene.52, 58 Next, the addition of indene to yield the
tetrahydroindenoquinoline might follow two mechanistic pathways:
a concerted mechanism or a stepwise cycloaddition. For the
concerted mechanism, the activated imine B follow a [4+2]
cycloaddition over an endo favoured transition state C followed by a
1,3-hydrogen shift forming thus the diastereoisomer D which then
undergo an aerobic oxidative dehydrogenation yielding the
indenoquinoline E. On the other hand, the stepwise mechanism
starts with the addition of indene to the azomethine carbon in the
imine B yielding a zwitterionic intermediate F which, in its more
stable form G, may follow a Friedel-Crafts alkylation forming the
diastereoisomer D (cis-isomer) that after an aerobic oxidation yields
the indenoquinoline E. Recent theoretical studies of the Povarov
reaction have suggested that this reaction involves a multistep
9
10
a Isolated yield. b Overall yield.
In order to validate this new methodology for practical applications,
a gram scale synthesis (10 mmol) of the model reaction was carried
out yielding the indenoquinoline 9 in 90 %. In addition, the
recyclability and reuse of the eutectic mixture was evaluated; and for
this, after the model reaction was completed, water was added, and
the crude solid product was filtered and washed with water. The
filtrate was concentrated by lyophilization and new fresh reactants
(indene, p-toluidine and benzaldehyde) were added and the reaction
was run completing thus the first cycle. After three cycles (four
reactions) the target indeno[2,1-c]quinoline 9 was obtained in 97, 96,
94 and 91 % yield, respectively. FTIR spectra taken after each cycle
reveal that all characteristic bands found for the freshly prepared
eutectic mixture are present in the DES employed in all reactions and
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processes where the nucleophilic attack of the electron rich stepwise mechanism is more probable for electron-rich dienophiles
dienophile on the imine carbon atom yield a cationic intermediate such as indene, we can speculate that the obtention of the
View Article Online
DOI: 10.1039/D0NJ01342K
which undergoes a fast intramolecular Friedel-Crafts reaction intermediate tetrahydroindenoquinolines might follow a stepwise
60
generating thus the tetrahydroquinoline.59,
Considering that a cycloaddition.
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Scheme 2. Proposed reaction mechanism for the synthesis of indeno[2,1-c]quinolines 9-44.
Finally, in order to evaluate the environmental impact of the B, entry 3 for method C and entry 10 for method D). The calculated
methodology here reported for the synthesis of indeno[2,1- green metrics are: atom economy (AE), atom efficiency (AEf), carbon
c]quinolines (method A), we decided to calculate several green efficiency (CE), reaction mass efficiency (RME), optimum efficiency
metrics for compounds 9, 22 and 44 and the results were compared (OE), process mass intensity (PMI), E-factor (E), solvent intensity (SI),
to the experimental procedures already reported for the same and water intensity (WI) (see Supporting information for the detailed
compounds as depicted in Scheme 1 and Table 3 (entry 1 for method calculations).61-63
Table 4. Green metrics (AE, AEf, CE, RME, OE, MP) for the synthesis of compounds 9, 22 and 44 in methods A, B, C and Da
Process
Number of
steps
Yield (%)
AE (%)
AEf (%)
CE (%)
RME (%)
OE (%)
MP (%)
Compound 9
A (this work)
B (ref. 40)
1
1
98
86
93
88
91
53
98
72
91
62
98
70
4.34
0.25
100
80
60
40
20
0
A (this work)
B (ref. 40)
Yield (%)
AE (%)
AEf (%)
CE (%)
Green metrics
RME (%)
OE (%)
MP (%)
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Compound 22
View Article Online
DOI: 10.1039/D0NJ01342K
A (this work)
C (ref. 39)
1
1
94
94
94
91
87
85
94
94
87
85
94
94
4.95
4.69
100
80
60
40
20
0
6
7
8
9
A (this work)
C (ref. 39)
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Yield (%)
AE (%)
AEf (%)
CE (%)
RME (%)
OE (%)
MP (%)
Green metrics
Compound 44
A (this work)
D (ref. 32, 41)
1
2
96
92
94
94
90
88
96
87
90
82
96
88
4.54
2.08
100
80
60
40
20
0
A (this work)
D (ref. 32, 41)
Yield (%) AE (%) AEf (%) CE (%) RME (%) OE (%) MP (%)
Green metrics
a Values closer to 100% represent a more greener reaction process
Table 5. Green metrics (PMI, E factor, SI and WI) for the synthesis of compounds 9, 22 and 44 in methods A, B, C and Da
Method
PMI (g/g)
E Factor (g/g)
Compound 9
22
SI (g/g)
WI (g/g)
A (this work)
B (ref. 40)
23
392
5
315
17
76
391
500
400
300
200
100
0
A (this work)
B (ref. 40)
PMI (g/g) E Factor (g/g)
SI (g/g)
WI (g/g)
Green metrics
Compound 22
19
20
A (this work)
C (ref. 39)
20
21
5
20
14
0
25
20
15
10
5
A (this work)
C (ref. 39)
0
PMI (g/g) E Factor (g/g)
SI (g/g)
WI (g/g)
Green metrics
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Compound 44
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View Article Online
DOI: 10.1039/D0NJ01342K
A (this work)
D (ref. 32, 41)
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5
19
16
27
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30
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10
0
6
7
8
9
A (this work)
D (ref. 32, 41)
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PMI (g/g)
E Factor (g/g)
SI (g/g)
WI (g/g)
Green metrics
a Better reaction processes have lower values.
As seen in Scheme 1, the target compounds are obtained in good to line of 780 nm wavelength from a frequency-stabilized single mode
excellent yields employing synthetic methods that involve a one-pot diode laser. The incident power was about 20 mW at the sample
three component reaction; and therefore, high values for atom point. TGA analysis for the DES was run in nitrogen (40 mL/min)
economy (AE) are observed in Table 4. Close values for the other atmosphere using
a TGA 1
STARe System (Mettler Toledo).
metrics (AEf, CE, RME, OE and MP) are found when comparing our Programmed heating rate was 15oC/min starting from 30oC until
method (method A) with the method C. However, the method A 300oC. The density of the DES was measured using a liquid
showed to be superior to method B and D for the same metrics (Table densitometer (Anton Paar DMA4500M). An Abbe type refractometer
4).
(model 2WAJ equipped with a sodium D1 line) was used to measure
the DES refractive. The pH of the synthesized DES was measured at
different temperatures using Jenway 370 pH/mV hand-held meter.
The conductivity and its temperature dependence were determined
using a Jenway 470 portable conductivity/TDS meter calibrated by
measuring the conductivities of aqueous solutions of KCl at different
concentrations. The variation of the temperature for the
determination of the physical properties was done by using a Lauda
Alpha water circulator.
Major differences between our method and methods B, C and D are
found for parameters such as PMI, E factor, SI and WI (Table 5). In
general, all values for these parameters are much worse in method
B compared to method A, while values for method D are close two-
fold higher. On the other hand, method A and C show similar values
for PMI and E factor while solvent intensity is better in method A and
water intensity in method B. The results found for all green metrics
in method C, which are similar to those in method A, might be
explained by the fact that all reagents and solvents used in the General procedure for the synthesis of indeno2,1-cquinolines (9-
synthesis of the heterogeneous catalyst (LDHs@Propyl–ANDSA) 44).
were not considered for the calculation due to this information was
1.6 g of urea/zinc chloride DES (3.5:1) (970.7 mg; 16.16 mmol of urea
and 629.3 mg; 4.61 mmol of ZnCl2) was heated to 60 C to obtain a
not available.
o
The green metric analysis described before evidenced the clear melt (2-3 minutes). To this melt a mixture of amine (1 mmol),
environmental benefits of the synthetic method here developed
over the available methods reported in literature.
aldehyde (1 mmol) and indene (1 mmol) was added and the reaction
mixture was stirred at 110 oC for 60 minutes. After completion of the
reaction (monitored by TLC), the mixture was quenched by adding
water while still hot, cooled to room temperature and the crude
mixture was filtered. The resulting solid was purified by flash column
chromatography on silica gel using petroleum ether–ethyl acetate
mixtures (2:1 to 1:2 v/v) as eluent to afford the pure product.
Experimental
Materials and methods.
All the chemicals and solvents were purchased from commercial
suppliers (Aldrich, Merck). Melting points, reported without
correction, were measured using a Stuart SMP10 apparatus. The FT-
2-Methyl-6-phenyl-7H-indeno[2,1-c]quinolone (9). White solid; mp:
Shimadzu IR prestige 21 215 - 218 °C, IR νmax/cm-1: 3429, 1654, 1354. 1H-NMR (400 MHz,
IR spectra were obtained with
a
spectrophotometer (Columbia, MD, USA). H and 13C NMR spectra
were recorded with a Bruker AVANCE III system operating at 400
MHz, using residual and deuterated solvent peaks of CDCl3 (δH 7.26;
δC 77.0) and DMSO (δH 2.50; δC 39.5) as reference standards.
Elemental analyses were performed on a Thermo Scientific Flash
2000 CHNS/O analyser and their results agreed with the calculated
values. Raman spectra was acquired with Thermo Scientific DXR
Raman Microscope, excitation was accomplished by using a single
1
CDCl3): δ (ppm) 8.52 (d, J = 7.9 Hz, 2H), 8.28 (d, J = 7.9 Hz, 1H), 7.95
(d, J = 8.3 Hz, 2H), 7.69 (d, J = 7.3 Hz, 1H), 7.64 (d, J = 8.5 Hz, 1H), 7.58
(t, J = 7.9 Hz, 3H), 7.56 (m, 2H), 4.18 (s, 2H), 2.70 (s, 3H). 13C-NMR
(100 MHz, CDCl3): δ (ppm) 145.1, 140.8, 136.7, 134.3, 131.1, 130.0,
128.8, 128.6, 128.2, 127.3, 125.1, 124.4, 123.9, 122.4, 37.6, 22.1.
Anal. calcd for C23H17N: C, 89.87; H, 5.57; N, 4.56; found: C, 89.73; H,
5.48; N, 4.52.
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6-Phenyl-7H-indeno[2,1-c]quinoline (14). Light brown solid, mp: 197
- 199 °C, IR νmax/cm-1: 3429, 1648, 1354. 1H-NMR (400 MHz, CDCl3): δ
(ppm) 8.13 (s, 1H), 7.45 (d, J = 8.2 Hz, 1H), 7.38 (m, 4H), 7.28 (m, 4H),
6.95 (t, J = 7.4 Hz, 2H), 4.06 (s, 2H). 13C-NMR (100 MHz, CDCl3): δ
(ppm) 150.4, 137.4, 136.0, 134.8, 131.8, 129.7, 128.0, 126.6, 126.3,
125.8, 125.1, 124.4, 124.1, 121.3, 120.3, 117.6, 117.1, 117.0, 116.8,
21.9. Anal. calcd for C22H15N: C, 90.07; H, 5.15; N, 4.77; found: C,
90.01; H, 5.08; N, 4.74.
aldehydes and indene. It was found that this solvent efficiently
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promotes the cycloaddition formingDOIt: h10e.103i9n/tDe0rNmJe0d13ia42teK
tetrahydroindeno2,1-cquinolines which undergo a fast-
aerobic oxidation yielding the target compounds in good to
excellent yields within short reaction times avoiding the use of
oxidizing agents. The green metric analysis performed with
three compounds showed that the synthetic methodology here
developed offers an environmentally friendly alternative for the
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access to indeno2,1-cquinolines using a benign, inexpensive,
recyclable and reusable solvent.
6-(4-Chlorophenyl)-2-methoxy-7H-indeno[2,1-c]quinolone
(21).
Light purple solid; mp: 126 – 129 °C, IR νmax/cm-1: 3429, 1653, 1349.
1H NMR (400 MHz, CDCl3): δ 7.85 (d, J = 8.5 Hz, 2H), 7.59 (m, 1H), 7.46
(d, J = 8.5 Hz, 2H), 7.29 (m, 3H), 6.96 (d, J = 8.9 Hz, 3H), 4.24 (s, 2H),
3.86 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 156.7, 147.7, 144.5, 142.2,
139.4, 136.9, 135.2, 133.1, 130.8, 129.7, 129.0, 128.8, 126.1, 124.4,
122.2, 120.2, 118.3, 114.4, 55.5, 33.7. Anal. calcd for C23H16ClNO: C,
77.20; H, 4.51; N, 3.91; found: C, 77.05; H, 4.47; N, 3.83.
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
C. O-P. wishes to thank Professor Humberto Zamora for
providing some research facilities. D. P-S thanks COLCIENCIAS
(grant FP44842-155-2018) We would also like to thank the
Universidad Nacional de Colombia and the Universidad
Industrial de Santander for financial support.
6-(2-Chlorophenyl)-2-nitro-7H-indeno[2,1-c]quinoline (30). Yellow
solid; mp: 183 - 185 °C, IR νmax/cm-1: 3495, 1654, 1360. 1H NMR (400
MHz, CDCl3): δ 8.71 (s, 1H), 8.12 (d, J = 9.2 Hz, 2H), 7.93 (d, J = 8.5 Hz,
2H), 7.71 (m, 2H), 7.21 (m, 4H), 4.14 (s, 2H). 13C NMR (100 MHz,
CDCl3): δ 144.6, 142.6, 141.3, 140.0, 138.2, 136.7, 135.5, 133.2,
131.1, 129.3, 127.8, 126.4, 124.7, 122.7, 120.7, 118.3, 117.1, 115.3,
33.7. Anal. calcd for C22H13ClN2O2: C, 70.88; H, 3.51; N, 7.51; found:
C, 70.59; H, 3.45; N, 7.47.
Notes and references
1.
2.
3.
4.
5.
6.
B. Tang and K. H. Row, Monatsh. Chem., 2013, 144, 1427-
1454.
Y. Liu, J. B. Friesen, J. B. McAlpine, D. C. Lankin, S.-N. Chen
and G. F. Pauli, J. Nat. Prod., 2018, 81, 679-690.
E. L. Smith, A. P. Abbott and K. S. Ryder, Chem. Rev., 2014,
114, 11060-11082.
Q. Zhang, K. De Oliveira Vigier, S. Royer and F. Jérôme,
Chem. Soc. Rev., 2012, 41, 7108-7146.
C. Vidal, J. García-Álvarez, A. Hernán-Gómez, A. R. Kennedy
and E. Hevia, Angew. Chem., Int. Ed., 2014, 53, 5969-5973.
C. Vidal, J. García-Álvarez, A. Hernán-Gómez, A. R. Kennedy
and E. Hevia, Angew. Chem., Int. Ed., 2016, 55, 16145-
16148.
2,4-Dichloro-6-(4-chlorophenyl)-7H-indeno[2,1-c]quinoline
(36).
White solid; mp: 254 - 256 °C, IR νmax/cm-1: 3496, 1652, 1360. 1H NMR
(400 MHz, CDCl3): δ 8.28 (d, J = 9.0 Hz, 2H), 7.76 (s, 2H), 7.71 (s, 1H),
7.40 (m, 2H), 7.33 (s, 1H), 7.20 (m, 2H), 4.15 (s, 2H). 13C NMR (100
MHz, CDCl3): δ 144.8, 143.5, 142.5, 140.8, 139.6, 137.7, 136.3, 134.5,
133.5, 131.9, 131.3, 129.9, 128.2, 126.2, 125.3, 124.0, 122.0, 120.3,
119.8, 33.7. Anal. calcd for C22H12Cl3N: C, 66.61; H, 3.05; N, 3.53;
found: C, 66.53; H, 2.99; N, 3.50.
2-Chloro-6-(pyridin-3-yl)-7H-indeno[2,1-c]quinoline (43). Light
yellow solid; mp: 258-259 °C, IR νmax/cm-1: 3491, 1650, 1359. 1H NMR
(500 MHz, DMSO): δ 8.86-8.84 (m, 2H), 8.63 (d, J = 7.1 Hz, 1H), 8.59
(d, J = 8.0 Hz, 1H), 8.28 (d, J = 9.0 Hz, 1H), 8.07 (dt, J = 7.5, J = 1.8 Hz,
1H), 7.89 (dd, J = 8.9, 2.2 Hz, 1H), 7.85 (d, J = 7.8 Hz, 1H), 7.62-7.56
(m, 4H), 4.66 (s, 2H). 13C NMR (126 MHz, DMSO): δ 152.2, 149.0,
144.4, 142.7, 139.3, 139.1, 136.6, 135.3, 133.3, 132.4, 130.2, 127.9,
126.1, 123.3, 122.5, 121.8, 121.3, 30.7. Anal. calcd for C21H13ClN2: C,
76.71; H, 3.99; N, 8.52; found: C, 76.68; H, 3.93; N, 8.42.
7.
8.
M. Sainsbury, in Rodd's Chemistry of Carbon Compounds
(Second Edition), ed. S. Coffey, Elsevier, Amsterdam, 1964,
DOI: https://doi.org/10.1016/B978-044453345-6.50764-1,
pp. 171-255.
C. A. Echeverry-Gonzalez, C. E. Puerto-Galvis, C. H. Borca,
M. A. Mosquera, A. F. Luis-Robles and V. V. Kouznetsov,
Org. Chem. Front., 2019, 6, 3374-3382.
9.
B. Jiang, X. Ning, S. Gong, N. Jiang, C. Zhong, Z.-H. Lu and C.
Yang, J. Mater. Chem. C, 2017, 5, 10220-10224.
H. K. Dahule, N. Thejokalyani and S. J. Dhoble,
Luminescence, 2015, 30, 405-410.
X. Meng, D. Cao, Z. Hu, X. Han, Z. Li and W. Ma, RSC Adv.,
2018, 8, 33947-33951.
10.
11.
Conclusions
12.
13.
A. Kim and C. Kim, New J. Chem., 2019, 43, 7320-7328.
Z.-J. Jiang, H.-S. Lv, J. Zhu and B.-X. Zhao, Synth. Met., 2012,
162, 2112-2116.
In conclusion, we have characterized and study different
physical properties of the low melting mixture urea/zinc
chloride as function of temperature. This deep eutectic solvent
was used as alternative green mildly acidic media for the
14.
C. Gogoi and S. Biswas, Dalton Trans., 2018, 47, 14696-
14705.
synthesis
of
indeno

2,1-c

quinolines
through
the
multicomponent Povarov reaction between aromatic amines,
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Please do not adjust margins
Journal Name
ARTICLE
1
2
3
4
5
6
7
8
9
15.
16.
C. Gogoi, M. Yousufuddin and S. Biswas, Dalton Trans., 42.
2019, 48, 1766-1773.
P.-l. Lam, C.-w. Kan, M. C.-w. Yuen, S.-y. Cheung, R.
Gambari, K.-h. Lam, J. C.-o. Tang and C.-h. Chui, Color. 43.
Technol., 2012, 128, 192-198.
J.-Y. Li, C.-Y. Chen, W.-C. Ho, S.-H. Chen and C.-G. Wu, Org. 44.
Lett., 2012, 14, 5420-5423.
S. Concilio, P. M. Pfister, N. Tirelli, C. Kocher and U. W. 45.
Suter, Macromolecules, 2001, 34, 3607-3614.
İ. Kaya, G. Er and K. Temizkan, Polym. Bull. , 2018, 75, 1809- 46.
1822.
P. M. Khaja Mohinuddin, R. Dada, A. I. Almansour, N.
Arumugam and S. Yaragorla, Tetrahedron LVeitetw.,A2rti0c1le9O,n6lin0e,
DOI: 10.1039/D0NJ01342K
1043-1048.
A. P. Abbott, J. C. Barron, K. S. Ryder and D. Wilson, Chem.
- Eur. J., 2007, 13, 6495-6501.
N. L. Higuera, D. Peña-Solórzano and C. Ochoa-Puentes,
Synlett, 2019, 30, 225-229.
D. Peña-Solórzano, C. E. González Guilombo and C. Ochoa-
Puentes, Sustainable Chem. Pharm., 2019, 14, 100167.
K. Aghapoor, F. Mohsenzadeh, H. R. Darabi, H. Sayahi and
M. R. Jalali, ChemistrySelect, 2019, 4, 11093-11097.
N. Seyedi, H. Khabazzadeh and S. Saeednia, Synth. React.
Inorg., Met.-Org., Nano-Met. Chem., 2015, 45, 1501-1505.
M. K. Trivedi, K. K. Sethi, P. Panda and S. Jana, Int J Pharm
Investig., 2017, 7, 33-40.
Q. Wang, X. Yao, Y. Geng, Q. Zhou, X. Lu and S. Zhang, Green
Chem., 2015, 17, 2473-2479.
R. Keuleers, H. O. Desseyn, B. Rousseau and C. Van Alsenoy,
J. Phys. Chem. A, 1999, 103, 4621-4630.
D. W. James, R. M. Parry and W. H. Leong, J. Raman
Spectrosc., 1978, 7, 71-73.
H. Lian, S. Hong, A. Carranza, J. D. Mota-Morales and J. A.
Pojman, RSC Adv., 2015, 5, 28778-28785.
V. V. Kouznetsov, C. O. Puentes, A. R. R. Bohorquez, S. A.
Zacchino, M. Sortino, M. Gupta, Y. Vazquez, A. Bahsas and
J. Amaro-Luis, Lett. Org. Chem., 2006, 3, 300-304.
A. Peñaranda Gómez, O. Rodríguez Bejarano, V. V.
Kouznetsov and C. Ochoa-Puentes, ACS Sustainable Chem.
Eng., 2019, 7, 18630-18639.
D. Shahabi and H. Tavakol, J. Mol. Liq., 2016, 220, 324-328.
Y.-F. Yang, X.-Z. Shu, H.-L. Wei, J.-Y. Luo, S. Ali, X.-Y. Liu and
Y.-M. Liang, Org. Biomol. Chem., 2011, 9, 5028-5033.
S. Talukdar, C.-T. Chen and J.-M. Fang, J. Org. Chem., 2000,
65, 3148-3153.
R. B. Penland, S. Mizushima, C. Curran and J. V. Quagliano,
J. Am. Chem. Soc., 1957, 79, 1575-1578.
L. R. Domingo, M. J. Aurell, J. A. Sáez and S. M. Mekelleche,
RSC Adv., 2014, 4, 25268-25278.
L. R. Domingo, M. Ríos-Gutiérrez and S. Emamian, RSC Adv.,
2016, 6, 17064-17073.
D. J. C. Constable, A. D. Curzons and V. L. Cunningham,
Green Chem., 2002, 4, 521-527.
17.
18.
19.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
20.
21.
G. A. Ramann and B. J. Cowen, Molecules, 2016, 21, 986.
S. M. Prajapati, K. D. Patel, R. H. Vekariya, S. N. Panchal and
H. D. Patel, RSC Adv., 2014, 4, 24463-24476.
R. Sharma, P. Kour and A. Kumar, J. Chem. Sci., 2018, 130,
73.
X. Yang, L. Li, Y. Li and Y. Zhang, J. Org. Chem., 2016, 81,
12433-12442.
A. K. Chaturvedi and N. Rastogi, Org. Biomol. Chem., 2018,
16, 8155-8159.
47.
48.
49.
50.
51.
52.
22.
23.
24.
25.
26.
X.-F. Zhou, Y.-Y. Sun, J.-J. Dai, J. Xu and H.-J. Xu, J.
Photochem. Photobiol., A, 2018, 355, 186-193.
T. Utsugi, K. Aoyagi, T. Asao, S. Okazaki, Y. Aoyagi, M. Sano,
K. Wierzba and Y. Yamada, Jpn. J. Cancer Res., 1997, 88, 53.
992-1002.
27.
28.
Y. Aoyagi, T. Kobunai, T. Utsugi, T. Oh-hara and Y. Yamada,
Jpn. J. Cancer Res., 1999, 90, 578-587.
54.
A. Ryckebusch, D. Garcin, A. Lansiaux, J.-F. Goossens, B.
Baldeyrou, R. Houssin, C. Bailly and J.-P. Hénichart, J. Med.
Chem., 2008, 51, 3617-3629.
55.
29.
R. S. Upadhayaya, P. D. Shinde, S. A. Kadam, A. N. Bawane, 56.
A. Y. Sayyed, R. A. Kardile, P. N. Gitay, S. V. Lahore, S. S.
Dixit, A. Földesi and J. Chattopadhyaya, Eur. J. Med. Chem., 57.
2011, 46, 1306-1324.
R. S. Upadhayaya, P. D. Shinde, A. Y. Sayyed, S. A. Kadam, 58.
A. N. Bawane, A. Poddar, O. Plashkevych, A. Földesi and J.
Chattopadhyaya, Org. Biomol. Chem., 2010, 8, 5661-5673. 59.
R. S. Upadhayaya, S. V. Lahore, A. Y. Sayyed, S. S. Dixit, P.
D. Shinde and J. Chattopadhyaya, Org. Biomol. Chem., 60.
2010, 8, 2180-2197.
30.
31.
32.
33.
A. Bahsas, J. Amaro-Luis, Y. Vazquez, M. Gupta, M. Sortino, 61.
S. Zacchino, V. V. Kouznetsov, C. Ochoa Puentes and A.
Bohorquez, Lett. Org. Chem., 2006, 3, 300-304.
62.
J. Augé, Green Chem., 2008, 10, 225-231.
C. Jiménez-González, D. J. C. Constable and C. S. Ponder,
Chem. Soc. Rev., 2012, 41, 1485-1498.
R. S. Upadhayaya, S. S. Dixit, A. Földesi and J. 63.
Chattopadhyaya, Bioorg. Med. Chem. Lett., 2013, 23, 2750-
2758.
C.-H. Tseng, C.-W. Tung, C.-H. Wu, C.-C. Tzeng, Y.-H. Chen,
T.-L. Hwang and Y.-L. Chen, Molecules, 2017, 22, 1001.
M. A. Quraishi and S. N. Dhawan, J. Chem. Eng. Data, 1989,
34, 134-135.
M. Anzini, A. Cappelli and S. Vomero, J. Heterocycl. Chem.,
1991, 28, 1809-1812.
X. Liu, Q. Zhang, D. Zhang, X. Xin, R. Zhang, F. Zhou and D.
Dong, Org. Lett., 2013, 15, 776-779.
Q. Yang, T. Xu and Z. Yu, Org. Lett., 2014, 16, 6310-6313.
Z. Karamshahi, R. Ghorbani-Vaghei and N. Sarmast, Mater.
Sci. Eng., C, 2019, 97, 45-54.
X. Zhang, W. Liu, R. Sun, X. Xu, Z. Wang and Y. Yan, Synlett,
2016, 27, 1563-1568.
V. V. Kouznetsov, A. R. R. Bohórquez and L. A. Saavedra,
Synthesis, 2009, 2009, 4219-4225.
34.
35.
36.
37.
38.
39.
40.
41.
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New Journal of Chemistry
Page 12 of 12
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DOI: 10.1039/D0NJ01342K
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An environmentally friendly and efficient method for the synthesis of indeno[2,1-c]quinolines is
developed using the urea/zinc chloride eutectic mixture as a green mildly acidic medium.
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O
Urea/ZnCl2
110oC, 1 h
R
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+
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R
Ar
NH2
N
Ar
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