Effective and Sustainable Access to Quinolines and Acridines: A Heterogeneous Imidazolium Salt Mediates C–C and C–N Bond Formation

Article abstract of DOI:10.1002/ejoc.201900880

Quinoline and acridine derivatives have been prepared using a functionalized imidazolium salt as heterogeneous catalyst. Different ketones have been coupled with 2-aminobenzaldehydes and 2-aminoaryl ketones under solvent-free conditions, employing 1,3-bis(carboxymethyl)-imidazolium chloride as a catalyst. The protocol is simple and effective for the synthesis of a variety of nitrogen containing heterocycles (> 35 examples) with moderate to excellent yields (up to 96 %), being possible to perform the reaction in preparative scale. Additionally, 3-acetylquinolines have been transformed, under solvent-free conditions, into quinolyl chalcone derivatives by means of the same catalyst. Thus, the catalytic system mediates both reactions effectively in a tandem procedure. Furthermore, the catalyst is easily separated from the reaction mixture and can be reused without loss of activity (up to 8 cycles) which remarks its sturdiness. The E-factors are in the range of 14–23, both for the formation of quinolines and for the tandem reaction, which demonstrates the sustainability of the protocols described.

Full text of DOI:10.1002/ejoc.201900880

A Journal of
Accepted Article
Title: Metal-free robust catalyst mediated C-C and C-N bond formation:
an effective and sustainable access to quinoline and acridine
derivatives
Authors: Patricia Gisbert, María Albert-Soriano, and Isidro Manuel
Pastor
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201900880
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10.1002/ejoc.201900880
European Journal of Organic Chemistry
FULL PAPER
Metal-free robust catalyst mediated C-C and C-N bond formation:
an effective and sustainable access to quinoline and acridine
derivatives
Patricia Gisbert,‡[a] María Albert-Soriano,‡[a] and Isidro M. Pastor*[a]
Abstract: Quinoline and acridine derivatives have been prepared
using a functionalized imidazolium salt as heterogeneous catalyst.
Different ketones have been coupled with 2-aminobenzaldehydes
and 2-aminoaryl ketones under solvent-free conditions, employing
1,3-bis(carboxymethyl)-imidazolium chloride as catalyst. The
protocol is simple and effective for the synthesis of a variety of
nitrogen containing heterocycles (> 35 examples) with moderate to
excellent yields (up to 96%), being possible to perform the reaction
in preparative scale. Additionally, 3-acetylquinolines have been
transformed, under solvent-free conditions, into quinolyl chalcone
derivatives by means of the same catalyst. Thus, the catalytic
system results effective performing both reactions in a tandem
procedure. Furthermore, the catalyst is easily separated from the
reaction mixture and can be reused without loss of activity (up to 8
cycles) which remarks its sturdiness. The E-factors are in the range
of 14-23, both for the formation of quinolines and for the tandem
reaction, which demonstrates the sustainability of the protocols
described.
catalyst concepts have been identified as the main development
strategies in the area of catalysis.[3] Therefore, the search for
new catalytic systems is a fundamental line of work within the
sustainable development of organic synthesis, and our
laboratory has been working in this direction during the last
decade. Moreover, we can pay attention to other types of
sustainable modifications, such as the use of environmentally
benign solvents. Thus, the need for a dispersion medium when
using homogeneous catalysis makes the use of alternative
solvents, such as deep eutectic solvents (DES),[4] an important
strategy. For such cases, it may be necessary to design new
catalysts that are compatible with the reaction medium,[5] albeit
metal-catalyzed reactions in DES using cheap and commercially
available catalysts [e.g. Pd/C or Pd(OAc)2] have been
reported.[6] Even though solvents are important in some
reactions modulating or even influencing their outcome,[7] if
possible carrying out chemical transformations in the absence of
solvent is convenient from an environmental point of view.[8]
Therefore, it is possible to carry out processes with
heterogeneous catalysts in the absence of solvents using for
example metal-organic frameworks (MOFs).[9] In this sense our
research group has described, under solvent-free conditions, the
use of MOFs based on copper to synthesize amides[10] and
MOFs based on calcium or barium to prepare quinoline
derivatives.[11] Iron based Lewis acidic ionic liquids (IBLAILs),
which are obtained by combining imidazolium salts with iron(III)
halides, have also been used as catalysts in the absence of
solvents to carry out the preparation of 2-allylanilines, 4-
allylanilines, quinolines[12] and thioamides.[13]
Introduction
Society faces the important challenge of sustainable
development, for which basic science and engineering must
come together. As far as chemistry is concerned, sustainability
is well reflected in the twelve principles of Green Chemistry.[1] In
this regard, efforts to improve the use of natural resources, to
develop new chemical products and materials, to reduce energy
consumption in chemical processes through better catalysis and
to improve the procedures for recycling, reuse and recovery of
chemical products are important.[2] Thus, catalysis plays, and will
The quinoline moiety is present in many natural occurring
compounds, mainly alkaloids, many of which are known to
present biological activity.[14] This type of natural products has
served as inspiration to consider the study of quinoline
derivatives in the field of pharmacology. The traditional use of
quinine in the treatment of malaria may have led to the
development of other antimalarial agents with a quinoline
moiety,[15] such as chloroquine, piperaquine and pyronaridine.[16]
Moreover, an important number of quinoline derivatives present
antifungal,[17] antioxidant[18] and antibiotic activities,[18a,19] such as
continue to play,
a fundamental role in the sustainable
development of different areas of chemistry and energy, possibly
being the key to achieve certain socio-economic objectives.
Consequently, further developments in catalysis are necessary.
The study of catalytic processes at different levels for better
understanding, the design of new catalysts and the expansion of
ciprofloxacin[20]
or
the
antitubercular
bedaquiline.[21]
[a]
P. Gisbert, M. Albert-Soriano, Dr. I. M. Pastor
Organic Chemistry Department and Instituto Síntesis Orgánica
(ISO)
Antineoplastic agents having quinoline moiety in their
structure[22] have also been successfully employed, such as
tipifarnib[23] and bosutinib.[24] Furthermore, small molecules with
a quinoline ring (such as quinine, mefloquine and MS-209) have
been considered to overcome multidrug resistance during the
chemotherapy.[25] Therefore, the development of new processes
for the preparation of quinoline derivatives is of continuing
interest, both at the fundamental and applied level. There are
several ways to build the quinoline ring, most approaches being
University of Alicante
Apdo. 99, 03080 Alicante (Spain)
E-mail: patricia.gisbert@ua.es; maria.albert@ua.es; ipastor@ua.es
Homepage: http://www.researcherid.com/rid/K-7784-2014
These authors contributed equally to this work.
[‡]
Supporting information for this article is given via a link at the end of
the document.
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10.1002/ejoc.201900880
European Journal of Organic Chemistry
FULL PAPER
made from anilines. Thus, the reactions of Skraup,[26]
bond acceptor with the chloride ion (like choline chloride in a
DES formation). Herein, we report our findings in the use of an
IOS as heterogeneous catalyst under solvent-free conditions for
the synthesis of quinoline derivatives. It was also explored the
use of the catalytic system in a tandem reaction for the further
functionalization of the quinoline core. The fact of studing
solventless protocols and the ease recovery of the catalyst can
have very interesting considerations for the environmental
impact of the synthesis.
Combes,[27]
Conrad-Limpach,[28]
Gould-Jacobs[29]
and
Doebner[26] carry out the coupling between anilines and different
carbonyl derivatives. In another type of approach, different
anilides are cycled under different reaction conditions, as occurs
in the Knorr,[30] Meth-Cohn[31] and Camps[32] reactions. In
addition, the reaction of carbonyl compounds with 2-
aminobenzaldehydes, 2-aminophenyl ketones or anthranilic
acids, as in the processes described by Friedländer[33] and
Niementowski,[34] is another type of method. In recent years, the
development of synthetic methods catalyzed by transition metals
has occupied a noteworthy place,[35] although more sustainable
methodologies have also been described for the preparation of
heterocyclic compounds with quinoline moieties.[36] In any case,
it has been stated it is preferable to explore the use of more
atom economy strategies, such as multicomponent reactions
(MCR) or the Friedländer reaction, trying to search for new
methodologies in more benign solvents (such as DES, water or
ionic liquids) or solvent-free conditions to reduce waste
production.[36a] Regarding the Friedländer reaction, the instability
of 2-aminobenzaldehyde derivatives, as well as the tendency of
2-aminoaryl ketones to undergo self-condensation, cause
difficulties when these compounds are used as substrates,
especially with less reactive carbonyl compounds. These
drawbacks particularly limit the preparation of certain quinoline
derivatives, mainly on a larger scale.[33]
Results and Discussion
The reaction of 2-aminobenzaldehyes give access to a variety of
quinoline derivatives without substituent in the position C-4 and
acridine derivatives, which are of interest due to their potential
bioactivity. This type of substrates has been less considered in
previous studies, so we conducted our initial tests using 2-
amino-3,5-dibromobenzaldehyde (1a). The aminobenzaldehyde
1a was reacted, at 80 ºC, with cyclohexanone (2a) employing
the imidazolium salt bcmim-Cl (10 mol%) as catalyst and in the
absence of any solvent. After 16 h, the expected 5,7-dibromo-
1,2,3,4-tetrahydroacridine (3aa) was observed with only an 8%
conversion (Table 1, entry 1). Increasing the amount of the
ketone 2a, the conversion of the 2-aminobenzaldehyde to the
final tetrahydroacridine improved significantly according to GC
analysis of the crude (Table 1, entries 2 and 3). To prove that
there is not a solubility effect using higher amount of ketone, the
Table 1. Optimization of the reaction conditions between 1a and 2a.[a]
Figure 1. Possible interactions of 1,3-bis(carboxymethyl)imidazolium chloride
with the reactants.
Entry
Heating
Time (h)
16
Temp. (ºC)
Equiv. 2a
Conv. (%)
1
Conventional
Conventional
Conventional
Conventional
Conventional
MW
80
1
8
To achieve more sustainable and cost-effective processes to
access highly functionalized and structurally diverse quinolines,
the use of appropriate catalyst is crucial. According to our
research work on the use of catalytic systems based on
2
16
80
5
66
3
16
80
10
1
77
carboxy-functionalized
imidazole
derivatives,[10-13,37]
we
4[b]
5
16
80
<1
considered the possibility of using 1,3-bis(carboxymethyl)-
imidazolium chloride (bcmim-Cl) as a heterogeneous catalyst in
the coupling of 2-aminophenyl-carbonyl compounds with
ketones for the synthesis of quinolines. This salt bcmim-Cl is an
ionic organic solid (IOS), which can be then more easily
separated from the reaction mixture.[38] Moreover, we
hypothesized that the functionalized imidazolium salt can
establish favorable interactions with the reactants, in a similar
way that occurs with the components of a low transition
temperature mixtures (LTTM) or deep eutectic solvents
(DES),[39] favoring the reaction between reactants in the absence
of any solvent (Figure 1). Catalytic IOS can act as a hydrogen
bond donor, with the carboxylic moieties, and as a hydrogen
16
100
80
5
96 (72)[C]
6
0.5
1
1
7
MW
0.5
80
5
4
8
MW
0.5
80
10
5
8
9
MW
0.33
150
86
[a] Reaction conditions: 1a (0.5 mmol), 2a (x mmol) and bcmim-Cl (10 mol%).
Conversion determined by GC analysis. [b] Reaction performed in 2-
methyltetrahydrofuran as solvent. [c] In brackets, yield of isolated product after
purification by column chromatography.
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10.1002/ejoc.201900880
European Journal of Organic Chemistry
FULL PAPER
reaction was performed, with 1 equivalent of ketone, in 2-
methyltetrahydrofuran as solvent, resulting in no conversion to
the product (Table 1, entry 4). Then, a slight increase in
temperature (100 °C) resulted in the exclusive obtaining of the
desired product 3aa with high conversion (96%). The acridine
3aa was isolated with 72% yield (Table 1, entry 5). The catalyst
resulted effective in the transformation, despite of being
heterogeneous, since the non-catalyzed reaction gave only ca.
10% of conversion. Next, we decided to test the reaction using
under microwave heating, was tested at 150 ºC for 20 minutes,
to avoid degradation,[40] resulting in an 86% conversion (Table 1,
entry 9).
With the optimized conditions, we next studied the scope of the
reaction changing both the 2-aminobenzaldehyde[41] and the
ketone. In general, non-substituted aminoaryl aldehydes (phenyl
and naphthyl derivatives) provided the corresponding acridines
3ba, 3cd and 3ce in good yields (Scheme 1) in their reaction
with cyclic ketones and quinoline 3bc when methyl acetylacetate
was employed (Scheme 1). The use of cyclopentanone gave the
corresponding compound 3bb, although in lower yield (Scheme
1). 2-Aminobenzaldehydes bearing electron withdrawing groups
(i.e., Cl and Br) afforded the corresponding quinoline 3ef and
acridine derivatives 3aa, 3de and 3ea in good to excellent yields
(Scheme 1). Finally, we explored the use of more electron-rich
aminobenzaldehydes, having access to a variety of quinolines
with methoxy substituents and fused 1,3-dioxole motif. Thus, 6-
amino-1,3-benzodioxole-5-carboxaldehyde led to the formation
of the corresponding products in yields from 46 to 93%
depending on the ketone (Scheme 1, compounds 3fb, 3fc, 3fe
and 3fg). Moreover, 2-amino-4,5-dimethoxy-1-benzaldehyde
gave rise to the desired products in moderate to good yields
(Scheme 1, compounds 3ga, 3gd and 3gf). Remarkably, the
protocol has resulted efficient in the preparation of acridinone
microwave heating since it has been described to be
a
sustainable alternative in this type of transformations.[36] After
irradiating the reaction mixture (80 ºC) for 30 minutes, the
conversions observed were low (<10%), regardless of the
amount of 2a (Table 1, entries 6-8). Additionally, the reaction,
Scheme 2. Scope evaluation of 2-aminoacetophenones and ketones using
bcmim-Cl. Reaction conditions: 2-aminophenone 4 (0.5 mmol), ketone 2 (2.5
mmol), catalyst (10 mol%), 100 °C, 16 hours. In parenthesis: yield of isolated
product after column chromatography or preparative TLC. [a] Reaction carried
out at 80 °C during 6 h.
Scheme 1. Scope evaluation of 2-aminoabenzaldehydes and ketones using
bcmim-Cl. Reaction conditions: 2-aminobenzaldehyde 1 (0.5 mmol), ketone 2
(2.5 mmol), catalyst (10 mol%), 100 °C, 16 hours. In parenthesis: yield of
isolated product after column chromatography or preparative TLC.
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10.1002/ejoc.201900880
European Journal of Organic Chemistry
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derivatives, such as 3ce, 3de and 3fe, which are interesting as
starting compounds for the preparation of antitumor active 4-
azapodophyllotoxin analogs.[42]
To corroborate the versatility of the readily available catalytic
system, a variety of aminoaryl ketones and ketones, both acyclic
and cyclic, have been considered as more challenging reactants
versatility of this methodology, the reaction was performed with
more challenging substrates, such as α-tetralone (2m), being
possible to obtain as single products the tetracyclic compounds
5bm and 5cm in moderate yield (Scheme 3).
(Schemes
2
and 3). Firstly, the reaction of 2-
aminoacetophenone (4a) with propiophenone (2k) was carried
out using bcmim-Cl (10 mol%) as catalyst at 80 °C and under
solvent-free conditions, producing, after 6 h, the expected
quinoline 5ak but in low conversion (< 5%). As previously
observed with the aminobenzaldehydes, a slight increase in the
temperature and reaction time could improve significantly the
yield. Indeed, we augmented the temperature up to 100 °C,
resulting in the increase of the final conversion, up to 45%, of
the corresponding quinoline. Moreover, extending the reaction
time to 16 hours gave double amount of the expected quinoline
5ak (91% conversion), being the unique product formed during
the reaction. Satisfactorily, the product 5ak was easily isolated
from the reaction crude in 86% yield (Scheme 2). Next, different
cyclic and acyclic ketones were reacted to form the
corresponding expected products 5 in all the cases in moderate
to excellent yields (Scheme 2). Thus, 3-heptanone and
acetophenone gave the quinolines 5ai and 5aj respectively
(Scheme 2). Non-symmetrically substituted ketone, such as 2-
hexanone (2h), can proceed via two modes of cyclizations,
providing two regioisomers whose ratio depends on the nature
of the catalyst.[43] The reaction between 4a and 2h led to the
formation of the isomers 5ah and 5ah’ in ca. 4:1 ratio (Scheme
2), the main product being the expected under acidic catalysis.
Both regioisomers could be isolated, in 58% and 15% yields
respectively. Interestingly, the reaction of aminoketone 4a with
cyclic ketones (i.e. cyclohexanone, cyclopentanone and 4-
methylcyclohexanone) and β-dicarbonyl compounds (i.e.
acetylacetone and methyl acetylacetate) could be performed
with milder reaction conditions (80 °C) and shorter reaction
times (6 h) yielding the corresponding quinolines (5ab, 5ac and
5af) and acridines (5aa and 5ad, Scheme 2). On the contrary,
the reaction of cyclohexane-1,3-dione with 4a required 100 ºC
and longer reaction time to give the acridinone 5ae in 81% yield,
probably due to the interaction between the substituents phenyl
and carbonyl (Scheme 2). In this case, the reaction took place
between two compounds which are in solid state (i.e. 4a and
cyclohexane-1,3-dione), proving the effectiviness of the catalyts.
Following the study, carbonyl compounds reacted smoothly with
substituted 2-aminobenzophenones, such as 2-amino-5-
Scheme 3. Scope evaluation of 2-aminoacetophenones and ketones using
bcmim-Cl. Reaction conditions: 2-aminophenone 4 (0.5 mmol), ketone 2 (2.5
mmol), catalyst (10 mol%), 100 °C, 16 hours. In parenthesis: yield of isolated
product after column chromatography or preparative TLC.
We envisioned, as commented above, that the catalyst would
establish interactions with the reactants allowing a close contact.
The presence of a chloride is probably important during this
catalytic process. To prove that, we performed the reaction
between the aminophenone 4a and acetylacetone (2f) in the
presence of the zwitterionic imidazole derivative bcmim,
observing only a 9% conversion to the quinoline 5af (Scheme 4),
which is in the level of the uncatalyzed reaction. This fact is in
sharp contrast with the full conversion obtained for the same
transformation catalyzed with bcmim-Cl (Scheme 4). Moreover,
another interesting feature of the catalyst is the presence of
different hydrogens in its structure, which can participate in
hydrogen bonding to gather the reactants. In this sense, the use
of imidazolium salts lacking an acid moiety, such as 1-
chlorobenzophenone
(4b)
and
2-amino-2’,5-dichloro-
benzophenone (4c), under solvent-free conditions at 100 ºC.
The expected quinolines and acridines were obtained with
moderate to excellent yields (Scheme 3). Thus, cyclic ketones,
such as cyclopentanone (2b), 4-methylcyclohexanone (2d), 1,3-
cyclohexanedione (2e) and cycloheptanone (2l), gave access to
the corresponding acridines 5be, 5cd and 5ce, and to the
quinolines 5bb, 5bl and 5cl (Scheme 3). In a like manner,
acyclic 3-heptanone, propiophenone, methyl 3-oxobutanoate
and pentane-2,4-dione were used to obtain the quinolines 5bi,
5bk, 5cc and 5cf (Scheme 3). Finally, to explore further the
(methoxycarbonylmethyl)-3-methylimidazolium
chloride
[(mocm)mim-Cl] and 1-methyl-3-(2-phenyl-2-oxoethyl)-
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10.1002/ejoc.201900880
European Journal of Organic Chemistry
FULL PAPER
imidazolium chloride [m(poe)im-Cl], resulted less effective,
giving lower converesion (Scheme 4). Next, we observed that
the hydrogen present in the C-2 of the imidazolium ring could
also provide helpful interactions since the conversion decreased
when
1-(methoxycarbonylmethyl)-2,3-dimethylimidazolium
chloride [(mocm)dmim-Cl] or 1-(carboxymethyl)-2,3-dimethyl-
imidazolium chloride [(cm)dmim-Cl] were employed as catalysts
(Scheme 4). For comparison, we tested the choline chloride
(ChCl), which can provide similar type of interactions, as
catalyst, observing a conversion of 37% (Scheme 4). Moreover,
if the reaction is performed in eutectic mixtures, such as choline
chloride/glycerol (1:2) of choline chloride/urea (1:2), results in
almost no formation of the corresponding quinoline with
conversions lower than 4%. This suggests that the interactions
of choline chloride with the other component of the eutectic
mixture (i.e. glycerol or urea) are more effective, lessening the
interactions with the reactans.
Scheme 5. Proposed interactions during the formation of quinolines.
At this point, we have proved that the catalyst is effective and
robust for different substrates under the protocol assayed.
Catalyst reuse is a fundamental point towards sustainability for
many industrial processes.[45] Having this in mind and taking the
advantage that the catalyst is insoluble in organic solvents, such
as ethyl acetate, we decided to study the recyclability of our
catalytic system. Thus, when the reaction between 2-
aminoacetophenone 4a and pentane-2,4-dione 2f was
completed, the catalyst was easily separated by centrifugation
using ethyl acetate to remove the product. The catalyst was
recovered completely, no traces being observed in the filtrate
(1H NMR). Then, the reaction was set again by only adding the
starting materials and we were glad to observe that the desired
product was obtained with the same excellent conversion. The
catalytic system could be recycled up to 8 consecutive cycles
without any decrease in its catalytic activity (Figure 2). The atom
economy efficiency of the transformation is high since only 2
equivalents of H2O are generated during the formation of the
final product, the conversion being high in most of the cases.
However, to know better the environmental impact of the
process, the E-factor was calculated taking into account that
only 2 mL of ethyl acetate were necessary to separate the
product from the catalyst. Pleasingly, an E-factor of 16.5 was
obtained in the preparation of compound 5af (Figure 2), which is
within the numbers of Fine Chemical production in the
industry.[46]
Scheme 4. Evaluation of different salts as catalyst. Reaction conditions: 4a
(0.5 mmol), 2f (2.5 mmol), catalyst (10 mol%), 80 °C, 6 hours. Conversion
determined by GC analysis.
Consequently, the synergic action of the different moieties
present in the imidazolium salt resulted in a more active and
robust catalyst. Based on these results and taking into
consideration that most of the evidences favored a pathway
involving the imine formation,[44] we postulated the possible
mechanism depicted in Scheme 5. Thus, the catalyst interacts
with both components of the reaction favoring the condensation
to the corresponding imine, which would be in equilibrium with
the enamine. Then, the intramolecular reaction of the enamine
with the carbonyl compound gives the quinoline after elimination
of water (Scheme 5). However, we cannot rule out the other
pathway via an aldol type reaction as the first step forming the
corresponding enone, which via condensation forms the
quinoline.[44]
Figure 2. Recyclability of the catalyst and E-factor in the preparation of 5af.
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10.1002/ejoc.201900880
European Journal of Organic Chemistry
FULL PAPER
potential bioactivities as antitumoral, anti-HIV, antioxidant and
antituberculosis, among others.[48] In this sense, quinolyl
chalcones represent a type of family compounds which is of
interest to be considered in pharmacological studies.[49] To
explore further the versatility of our catalytic system, we
envisioned the possibility of performing an aldol coupling in the
presence of bcmim-Cl, allowing the preparation of quinolyl
chalcones starting from the 3-acetylquinoline 5af. Satisfyingly,
the corresponding products 7a-c were obtained reacting 5af with
different benzaldehydes under solvent free conditions at room
temperature (Scheme 7). Consequently, the catalyst provided a
new methodology to prepare these quinoline derivatives
following a high sustainable process. Next, the fact that the
catalyst is capable of carrying out both transformations in the
absence of solvent raised the possibility of synthesizing the
derivatives 7 through a tandem process. Thus, the product 7a
was obtained with a yield of 66%, starting from 2-aminophenone
4a, ketone 2f and aldehyde 6a, without the need to isolate the
quinoline 5 (Scheme 7). The yield of 7a is comparable to the one
obtained by the two steps method, with a 94% for first step
(Scheme 2) and 74% for the second (Scheme 7). As before, at
the end of the reaction, the catalyst was separated by simple
filtration and the product obtained pure by recrystallization. The
same protocol allowed the isolation of 7d with 58% yield
(Scheme 7). To compare both approaches from their
environmental impact, the E-factor for the two-step method in
the preparation of 7a is slightly higher (31.3) than that observed
for the tandem process (22.9), since in the latter it is only
necessary to separate the catalyst using solvent at the end of
the whole process.
Scheme 6. Gram-scale reaction. Yield and E-factor in the synthesis of
products 5ac and 5af.
Furthermore, to demonstrate the applicability of the process, the
reaction was performed on a preparative scale (Scheme 6). The
methodology proved to be effective for obtaining enough
amounts of potential interesting compounds. For these
experiments, 2-aminoacetophenone 4a (2.00 g, 10.1 mmol) and
ketone 2c or 2f (50.1 mmol) were stirred at 60 °C for 6 hours,
cooled to room temperature and filtered using ethyl acetate to
afford exclusively the corresponding quinolines (Scheme 6).
After recrystallization, 2.14 g and 2.18 g of pure products 5ac
and 5af (83% and 77% yield, respectively) were obtained. It is
worthy to mention that the E-factor for these processes,
including the recrystallization step, stay in the same rank (14.3
and 16.1, respectively) as previously commented.
Conclusions
To conclude, the 1,3-bis(carboxymethyl)imidazolium chloride,
bearing two carboxylic acid moieties, has resulted an efficient
and robust catalyst in the preparation of different quinoline and
acridine derivatives. The catalytic system studied for this
transformation offers remarkable characteristics that make it
more sustainable and robust than others previously reported do.
The novelty of this catalytic system is that the imidazolium salt is
“solid” and stays like that during the whole process, it is not an
Ionic Liquid, being the reaction performed under solvent-free
conditions. Thus, the catalytic system is used in 10 mol% and it
is recycled by simple filtration, being an improvement in the
performance compare with previous reported protocols.
Moreover, the recovered catalyst is reused without loss of
activity. Importantly, the same catalyst allows to chain reactions
(tandem protocol) for further functionalization giving quinolyl
chalcone derivatives, expanding the applicability of this
methodology. This novel catalytic protocol works in preparative
scale, giving access to potential bioactive compounds in
multigram amounts. Regarding the environmental impact, the
methodology reported is appropriate for fine chemical production,
with E-factors below 17 for a single reaction or below 23 for
tandem transformations. The catalytic activity of the imidazolium
Scheme 7. Preparation of quinolyl chalcones using bcmim-Cl as catalyst.
Reagents and conditions (a): quinoline 5af (0.5 mmol), benzaldehyde 6 (0.5
mmol), bcmim-Cl (10 mol%), room temperature, 3 hours. Reagents and
conditions (b): i) 2-aminophenone (0.5 mmol), pentane-2,4-dione (2.5 mmol),
bcmim-Cl (10 mol%), 80 °C, 6 h; ii) benzaldehyde 6 (0.5 mmol), room
temperature,
3 hours. In parenthesis: yield of isolated product after
recrystallization.
The quinoline heterocycle is present in a vast diversity of natural
and synthetic compounds, being discovered constantly new
quinoline based alkaloids with potential bioactivities.[47] In
addition, quinoline derivatives are versatile and interesting
synthetic building blocks in drug discovery or development.
Moreover, chalcone derivatives are also interesting due to their
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10.1002/ejoc.201900880
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General procedure for the synthesis of quinolines and acridines. A
mixture of the corresponding 2-aminobenzaldehyde or 2-aminoarylketone
(0.5 mmol), the corresponding ketone 2 (5 equivalents) and bcmim-Cl
(10 mol%) were stirred at 80 or 100 ºC during 6 or 16 hours. After cooling
down, the mixture was filtered through celite to remove the catalyst,
eluting with ethyl acetate. Then, the solvent was evaporated under
reduced pressure, and the excess of starting ketone was distilled off (10-5
mbar, 55-90 °C). The corresponding products were purified using
preparative TLC or column chromatography and mixtures of hexane and
ethyl acetate as eluent.
salt lies on the presence of carboxylic acid moieties and chloride
counterion, which helped in favorable interactions with the
reactants.
Experimental Section
Instruments and reagents.
All commercially available reagents and solvents were purchased (Acros,
Aldrich, Fluka, Fluorochem, Merck) and used without further purification.
1H NMR and 13C NMR spectra were recorded at the technical service of
the University of Alicante (SSTTI-UA), employing a Bruker AC-300 or a
Bruker Advance-400. Chemical shifts (δ) are given in ppm and the
coupling constants (J) in Hz. Melting points were determined using a
Gallenkamp capillary melting point apparatus (model MPD 350 BM 2.5)
and are uncorrected. Low-resolution mass spectra (EI) were obtained at
70 eV with and Agilent 5973 Network spectrometer, with fragment ions
m/z reported with relative intensities (%) in parentheses. Low-resolution
HPLC with electrospray ionization (HPLC-ESI) mass spectra were
recorded at the technical service of the University of Alicante (SSTTI-UA),
employing an Agilent 1100 series apparatus with the possibility of MS/MS.
Infrared spectra were recorded with an FT-IR/4100 LE (JASCO, Pike
Miracle ATR) spectrometer. Spectra were recorded from neat samples
and results are given in cm-1. Analytical TLC was performed on Merck
aluminium sheets with silica gel 60 F254, 0.2 mm thick. Silica gel 60
(0.04-0.06 mm) was employed for column chromatography. P/UV254
silica gel with CaSO4 supported on glass plates was employed for
preparative TLC. The conversion of the reactions and purity of the
products were determined by GC analysis using a Younglin 6100GC,
equipped with a flame ionization detector and a Phenomenex ZB-5MS
column (5% PH-ME siloxane): 30 m (length), 0.25 mm (inner diameter)
and 0.25 µm (film).
5,7-Dibromo-1,2,3,4-tetrahydroacridine (3aa).[51] Pale yellow solid;
purification by column chromatography (hexane/ethyl acetate 9.5/0.5),
72% yield; m.p.: 104-106 °C (AcOEt) (Lit.:[51] 106-108 °C); IR (ATR): ν =
2935, 2865, 1730, 1714, 1671, 1587, 1541, 1460, 1396, 1307, 1232,
1183, 1162, 1128, 1079, 979, 924, 866, 844, 817, 776, 739, 704, 674 cm-
1; 1H NMR (400 MHz, CDCl3): δH = 8.01 (d, J = 2.1 Hz, 1H, CHAr), 7.78 (d,
J = 2.1 Hz, 1H, CHAr), 7.65 (s, 1H, CHAr), 3.17 (t, J = 6.5 Hz, 2H, CCH2),
2.98 (t, J = 6.2 Hz, 2H, CCH2), 2.04-1.86 (m, 4H, CH2CH2CH2CH2) ppm;
13C NMR (101 MHz, CDCl3): δC = 161.4, 142.4, 134.6, 134.3, 133.1,
129.0, 128.9, 125.0, 118.4, 33.9, 29.1, 23.0, 22.7 ppm; MS (EI): m/z 343
(M++4, 11%), 342 (33), 341 (M++2, 100), 340 (48), 339 (M+, 52), 338 (24),
260 (12), 180 (15), 153 (14).
1,2,3,4-Tetrahydroacridine (3ba).[52] Yellow solid; purification by column
chromatography (hexane/ethyl acetate 5.0/5.0), 80% yield; m.p.: 48-
50 °C (AcOEt) (Lit.:[52] 52-53 °C); IR (ATR): ν = 2935, 2859, 1716, 1622,
1599, 1560, 1491, 1437, 1415, 1243, 1153, 1136, 949, 924, 858, 821,
1
778, 749 cm-1; H NMR (300 MHz, CDCl3): δH = 7.98 (d, J = 8.5 Hz, 1H,
CHAr), 7.79 (s, 1H, CHAr,), 7.69 (dd, J = 8.1 and 0.9 Hz, 1H, CHAr), 7.60
(ddd, J = 8.4, 6.9 and 1.4 Hz, 1H, CHAr), 7.46-7.39 (m, 1H, CHAr), 3.13 (t,
J = 6.6 Hz, 2H, CCH2), 2.96 (t, J = 6.2 Hz, 2H, CCH2), 2.06-1.80 (m, 4H,
CH2CH2CH2CH2) ppm; 13C NMR (75 MHz, CDCl3): δC = 159.4, 146.5,
135.2, 131.1, 128.6, 128.2, 127.3, 127.0, 125.7, 33.6, 29.3, 23.3, 23.0
ppm; MS (EI): m/z 184 (12%), 183 (M+, 100), 182 (100), 180 (18), 168
(23), 167 (26), 155 (13), 154 (17).
Synthesis of catalysts.
2,3-Dihydro-1H-cyclopenta[b]quinoline (3bb).[53] Yellow oil; purification
by preparative TLC (hexane/ethyl acetate 5.0/5.0), 56% yield; IR (ATR): ν
= 2955, 2889, 2839, 1620, 1570, 1496, 1404, 1214, 901, 860, 781, 750
cm-1; 1H NMR (300 MHz, CDCl3): δH = 8.02 (d, J = 8.4 Hz, 1H, CHAr),
7.88 (s, 1H, CHAr), 7.72 (dd, J = 8.1 and 1.2 Hz, 1H, CHAr), 7.61 (ddd, J =
8.4, 6.9 and 1.5 Hz, 1H, CHAr), 7.49-7.40 (m, 1H, CHAr), 3.16 (t, J = 7.6
Hz, 2H, CH2), 3.08 (td, J = 7.5 and 1.4 Hz, 2H, CH2), 2.20 (p, J = 7.6 Hz,
2H, CH2CH2CH2) ppm; 13C NMR (75 MHz, CDCl3): δC = 168.0, 147.4,
135.8, 130.5, 128.6, 128.5, 127.5, 127.5, 125.6, 34.7, 30.6, 23.7 ppm;
MS (EI): m/z 169 (M+, 71%), 168 (100), 167 (30).
1,3-Bis(carboxymethyl)imidazole (bcmim).[37b] A mixture of glycine
(15.0 g, 200 mmol), gly (solution in water, 40% w/w, 11.4 mL, 100 mmol)
and formaldehyde (solution in water, 36%, 7.7 mL, 100 mmol) was stirred
at 95 °C for 2 hours. After cooling down, the resultant brown precipitate
was filtered and washed with cold water to obtain a colorless solid. The
remaining water was co-evaporated with methanol under reduced
pressure to afford bcmim as a colorless solid in 70% yield.
1,3-bis(carboxymethyl)imidazolium chloride (bcmim-Cl).[50] A mixture
of 1,3-bis(carboxymethyl)imidazole (5.52 g, 30 mmol) and concentrated
HCl (5.4 mL, 66 mmol) was stirred and refluxed for 30 minutes. Then,
hydrogen chloride was removed under reduced pressure and the
resultant solid was filtered and washed with acetone and diethyl ether to
afford (bcmim-Cl) as a colorless solid in 93% yield.
Methyl 2-methylquinoline-3-carboxylate (3bc).[54] Pale yellow solid;
purification by column chromatography (hexane/ethyl acetate 8.0/2.0),
75% yield; m.p.: 57-59 °C (AcOEt) [Lit.:[55] 48-49 °C (ligroine)]; IR (ATR):
ν = 3263, 2955, 1718, 1620, 1568, 1492, 1438, 1421, 1281, 1253, 1204,
1133, 1066, 788, 749 cm-1; 1H NMR (300 MHz, CDCl3): δH = 8.75 (s, 1H,
CHAr), 8.05 (dd, J = 8.5 and 0.5 Hz, 1H, CHAr), 7.86 (dd, J = 8.1 and 1.1
Hz, 1H, CHAr), 7.79 (ddd, J = 8.5, 6.9 and 1.5 Hz, 1H, CHAr), 7.54 (ddd, J
= 8.1, 7.0 and 1.1 Hz, 1H, CHAr), 3.98 (s, 3H, OCH3), 3.00 (s, 3H, CCH3)
ppm; 13C NMR (101 MHz, CDCl3): δC = 167.0, 158.6, 148.8, 140.2, 131.9,
128.7, 128.6, 126.7, 125.9, 123.7, 52.5, 25.8 ppm; MS (EI): m/z 202
(14%), 201 (M+, 100), 170 (75), 169 (74), 142 (70), 141 (26), 140 (22),
116 (13), 115 (24), 101 (16), 75 (11).
General procedure for the synthesis of 2-aminobenzaldehydes.[41]
To a solution of the corresponding 2-nitrobenzaldehyde (1 mmol) in
ethanol (7 mL) iron powder was added (559 mg, 10 mmol), followed by
water (1 mL) and concentrated HCl (14 µL). The mixture was stirred and
refluxed for 90 minutes. After cooling down, the solvent was evaporated
under vacuum, ethyl acetate was added, and the organic phase was
washed with water and dried over MgSO4. After evaporation of the
solvent, an oil was obtained, which was purified by column
chromatography using mixtures of hexane and ethyl acetate to afford the
corresponding 2-aminobenzaldehydes.
9-Methyl-8,9,10,11-tetrahydrobenzo[c]acridine (3cd). Pale yellow
solid; purification by column chromatography (hexane/ethyl acetate
9.5/0.5), 75% yield; m.p.: 90-92 °C (AcOEt); IR (ATR): ν = 3051, 2953,
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900880
European Journal of Organic Chemistry
FULL PAPER
2942, 2918, 2861, 1597, 1491, 1445, 1404, 1373, 1257, 1215, 1026, 923,
852, 819, 808, 800, 748, 722 cm-1; 1H NMR (400 MHz, CDCl3): δH = 9.27
(d, J = 8.1 Hz, 1H, CHAr), 7.87-7.81 (m, 1H, CHAr), 7.73 (s, 1H, CHAr),
7.70-7.59 (m, 3H, 3×CHAr), 7.54 (d, J = 8.8 Hz, 1H, CHAr), 3.32 (ddd, J =
17.8, 5.5 and 3.4 Hz, 1H, CCCH), 3.17 (ddd, J = 17.7, 11.4 and 6.0 Hz,
1H, CCCH), 3.00 (dd, J = 16.3 and 3.8 Hz, 1H, NCCH), 2.58 (dd, J =
16.4 and 10.7 Hz, 1H, NCCH), 2.13-1.91 (m, 2H, CHCH3 and NCCH2CH),
1.61 (dtd, J = 12.8, 11.2 and 5.7 Hz, 1H, NCCH2CH), 1.12 (d, J = 6.6 Hz,
3H, CH3) ppm; 13C NMR (101 MHz, CDCl3): δC = 157.4, 144.4, 135.4,
133.4, 131.3, 131.0, 127.8, 127.7, 126.8, 126.7, 125.1, 124.9, 124.3,
37.7, 33.3, 31.7, 29.2, 21.8 ppm; MS (EI): m/z 248 (16%), 247 (M+, 100),
246 (20), 232 (25), 230 (12), 218 (12), 217 (11), 205 (21), 204 (16);
HRMS (GC/MS-EI/Q-TOF): m/z calcd. for C18H17N 247.1361, found
247.1357.
126.2, 124.4, 29.3, 25.8 ppm; MS (EI): m/z 265 (M++2, 47%), 263 (M+,
48), 251 (10), 250 (100), 249 (11), 248 (89), 222 (45), 220 (39), 141 (37),
140 (19), 114 (18), 99 (11); HRMS (GC/MS-EI/Q-TOF): m/z calcd. for
C12H10BrNO 262.9946, found 262.9949.
7,8-Dihydro-6H-cyclopenta[b]-1,3-dioxolo[4,5-g]quinoline (3fb). Off-
white solid; purification by column chromatography (hexane/ethyl acetate
8.0/2.0), 68% yield; m.p.: 182-184 °C (AcOEt); IR (ATR): ν = 2948, 2917,
2852, 2788, 1625, 1496, 1456, 1389, 1232, 1200, 1033, 940, 928, 870,
1
849, 788 cm-1; H NMR (400 MHz, CDCl3): δH = 7.70 (s, 1H, CHAr), 7.33
(s, 1H, CHAr), 6.97 (s, 1H, CHAr), 6.06 (s, 2H, 2×CHAr), 3.09 (t, J = 7.6 Hz,
2H, CCH2), 3.06-2.97 (m, 2H, CCH2), 2.17 (p, J = 7.5 Hz, 2H,
CH2CH2CH2) ppm; 13C NMR (101 MHz, CDCl3): δC = 165.4, 149.9, 147.1,
145.4, 133.9, 130.0, 124.1, 105.4, 102.9, 101.6, 34.4, 30.5, 23.8 ppm;
MS (EI): m/z 214 (13%), 213 (M+, 100), 212 (73), 155 (21), 154 (22);
HRMS (GC/MS-EI/Q-TOF): m/z calcd. for C13H11NO2 213.0790, found
213.0796.
8,9,10,11-Tetrahydrobenzo[c]acridin-8-one (3ce). Pale yellow solid;
purification by column chromatography (hexane/ethyl acetate 8.0/2.0),
78% yield; m.p.: 152-154 °C (AcOEt); IR (ATR): ν = 3043, 3025, 2957,
2888, 2869, 2818, 1674, 1584, 1489, 1398, 1349, 1335, 1266, 1202,
1173, 1128, 931, 903, 817, 795, 756 cm-1; 1H NMR (400 MHz, CDCl3): δH
= 9.43-9.20 (m, 1H, CHAr), 8.75 (s, 1H, CHAr), 7.96-7.82 (m, 1H, CHAr),
7.82-7.61 (m, 4H, 4×CHAr), 3.48-3.27 (m, 2H, COCH2), 2.90-2.68 (m, 2H,
CCH2), 2.45-2.18 (m, 2H, CH2CH2CH2) ppm; 13C NMR (101 MHz,
CDCl3): δC = 198.3, 161.5, 148.8, 135.8, 134.9, 130.8, 129.5, 128.0,
127.9, 127.3, 126.6, 126.0, 125.5, 125.0, 39.1, 33.5, 22.2 ppm; MS (EI):
m/z 248 (20%), 247 (M+, 100), 219 (52), 191 (41), 190 (31); HRMS
(GC/MS-EI/Q-TOF): m/z calcd. for C17H13NO 247.0997, found 247.1002.
Methyl 2-methyl-1,3-dioxolo[4,5-g]quinoline-3-carboxylate (3fc).[57]
Yellow solid; purification by column chromatography (hexane/ethyl
acetate 7.0/3.0), 46% yield; m.p.: 210-212 °C (CH2Cl2); IR (ATR): ν =
3061, 2956, 2921, 2851, 1716, 1616, 1599, 1459, 1398, 1241, 1201, 104,
935 cm-1; 1H NMR (400 MHz, CDCl3): δH = 8.56 (s, 1H, CHAr), 7.37 (s, 1H,
CHAr), 7.07 (s, 1H, CHAr), 6.13 (s, 2H, 2×CHAr), 3.96 (s, 3H, OCH3), 2.94
(s, 3H, CCH3) ppm; 13C NMR (101 MHz, CDCl3): δC = 167.1, 156.8,
152.9, 148.1, 147.4, 138.9, 122.8, 121.7, 105.1, 103.3, 102.2 52.4, 25.2
ppm; MS (EI): m/z 246 (14%), 245 (M+, 100), 214 (53), 213 (26), 187 (11),
186 (28), 185 (19), 128 (22).
7-Chloro-1,2,3,4-tetrahydroacridin-1-one (3de).[56] Yellow solid;
purification by column chromatography (hexane/ethyl acetate 7.0/3.0),
74% yield; m.p.: 160-162 °C (AcOEt) (Lit.:[56] 160-162 °C): IR (ATR): ν =
2956, 2888, 1682, 1587, 1484, 1399, 1371, 1207, 1169, 1135, 1073,
6,7,8,9-Tetrahydro-1,3-Dioxolo[4,5-b]acridin-9-one (3fe).[56] White
solid; purification by column chromatography (hexane/ethyl acetate
4.0/6.0), 93% yield; m.p.: 213-214 °C (AcOEt) (Lit.:[56] 210-212 °C); IR
(ATR): ν = 3029, 2959, 2906, 2892, 2788, 1666, 1588, 1469, 1460, 1446,
1398, 1357, 1243, 1211, 1180, 1135, 1036, 1004, 946, 938, 907, 898,
849, 837, 785, 778, 687 cm-1; 1H NMR (400 MHz, CDCl3): δH = 8.59 (s,
1H, CHAr), 7.33 (s, 1H, CHAr), 7.10 (s, 1H, CHAr), 6.14 (s, 2H, 2×CHAr),
3.31-3.14 (m, 2H, COCH2), 2.82-2.67 (m, 2H, CCH2), 2.35-2.09 (m, 2H,
CH2CH2CH2) ppm; 13C NMR (101 MHz, CDCl3): δC = 198.0, 160.2, 153.4,
148.6, 148.2, 135.4, 124.8, 123.9, 104.9, 104.0, 102.3, 39.0, 32.8, 22.0
ppm; MS (EI): m/z 242 (13%), 241 (M+, 100), 240 (31), 214 (15), 213 (69),
212 (15), 207 (25), 185 (30), 128 (11), 127 (19), 100 (11), 77 (11).
1061, 1003, 935, 913, 841, 677 cm-1; 1H NMR (400 MHz, CDCl3): δH
=
8.76 (s, 1H, CHAr), 8.02 (d, J = 9.0 Hz, 1H, CHAr), 7.90 (d, J = 2.3 Hz, 1H,
CHAr), 7.74 (dd, J = 9.0 and 2.3 Hz, 1H, CHAr), 3.37-3.28 (m, 2H, COCH2),
2.85-2.77 (m, 2H, CCH2), 2.34-2.23 (m, 2H, COCH2CH2) ppm; 13C NMR
(101 MHz, CDCl3): δC = 197.5, 162.3, 147.8, 136.4, 133.4, 132.7, 130.1,
128.1, 127.5, 127.0, 39.1, 33.3, 21.7 ppm; MS (EI): m/z 233 (M++2, 31%),
232 (27), 231 (M+, 96), 230 (23), 207 (11), 205 (32), 204 (20), 203 (100),
202 (23), 175 (22), 167 (19), 140 (44), 84 (12).
6-Bromo-1,2,3,4-tetrahydroacridine (3ea). Off-white solid; purification
by preparative TLC (hexane/ethyl acetate 9.5/0.5), 82% yield; m.p.: 80-
82 °C (AcOEt); IR (ATR): ν = 2940, 2866, 1605, 1590, 1556, 1476, 1409,
1225, 1057, 946, 906, 872, 803, 701 cm-1; 1H NMR (400 MHz, CDCl3): δH
= 8.18 (d, J = 1.8 Hz, 1H, CHAr), 7.76 (s, 1H, CHAr), 7.54 (d, J = 8.7 Hz,
1H, CHAr), 7.50 (dd, J = 8.7 and 1.8 Hz, 1H, CHAr), 3.12 (t, J = 6.6 Hz, 2H,
6-Methyl-6,7,8,9-tetrahydro-1,3-dioxolo[4,5-b]acridine (3fg). Off-white
solid; purification by column chromatography (hexane/ethyl acetate
8.0/2.0), 65% yield; m.p.: 118-120 °C (AcOEt); IR (ATR): ν = 2938, 2921,
2862, 1618, 1489, 1458, 1394, 1245, 1210, 1173, 1033, 938, 925, 876,
1
855, 779, 727 cm-1; H NMR (400 MHz, CDCl3): δH = 7.63 (s, 1H, CHAr),
CCH2), 2.94 (t,
J = 6.1 Hz, 2H, CCH2), 2.05-1.80 (m, 4H,
7.36 (s, 1H, CHAr), 6.94 (s, 1H, CHAr), 6.06 (s, 2H, 2×CHAr), 3.27-3.10 (m,
1H, CH), 2.98-2.81 (m, 2H, CCH2), 2.15-2.03, 2.00-1.88 (2 m, 2H,
CCH2CH2), 1.85-1.65 (m, 2H, CHCH2), 1.45 (d, J = 7.1 Hz, 3H, CH3)
ppm; 13C NMR (101 MHz, CDCl3): δC = 160.4, 150.2, 147.4, 134.8, 134.7,
128.7, 123.9, 104.9, 102.0, 101.6, 36.0, 31.5, 29.6, 21.9, 20.2 ppm; MS
(EI): m/z 242 (15%), 241 (M+, 100), 240 (70), 227 (11), 226 (76), 224 (13),
213 (24), 212 (70), 211 (15); HRMS (GC/MS-EI/Q-TOF): m/z calcd. for
C15H15NO2 241.1103, found 241.1096.
CH2CH2CH2CH2) ppm; 13C NMR (101 MHz, CDCl3): δC = 160.5, 146.8,
135.2, 131.6, 130.5, 129.3, 128.3, 125.8, 122.6, 33.4, 29.3, 23.1, 22.8
ppm; MS (EI): m/z 264 (14%), 263 (M++2, 99), 262 (57), 261 (M+, 100),
260 (48), 182 (59), 181 (13), 180 (26), 167 (23), 154 (18), 127 (12), 90
(13); HRMS (GC/MS-EI/Q-TOF): m/z calcd. for C13H12BrN 261.0153,
found 261.0163.
1-(7-Bromo-2-methylquinol-3-yl)ethanone (3ef). Off-white solid;
purification by column chromatography (hexane/ethyl acetate 8.0/2.0),
94% yield; m.p.: 152-154 °C (AcOEt); IR (ATR): ν = 3066, 2998, 2966,
2925, 1680, 1615, 1557, 1474, 1422, 1405, 1378, 1362, 1353, 1268,
1230, 1211, 1181, 1056, 1044, 1029, 945, 916, 888, 798, 769, 685 cm-1;
1H NMR (400 MHz, CDCl3): δH = 8.43 (s, 1H, CHAr), 8.22 (d, J = 1.8 Hz,
1H, CHAr), 7.71 (d, J = 8.6 Hz, 1H, CHAr), 7.63 (dd, J = 8.6 and 1.9 Hz,
1H, CHAr), 2.90 (s, 3H, COCH3), 2.71 (s, 3H, CCH3) ppm; 13C NMR (101
MHz, CDCl3): δC = 199.7, 159.0, 148.8, 137.9, 131.5, 131.2, 130.4, 129.6,
6,7-Dimethoxy-1,2,3,4-tetrahydroacridine
(3ga).[58] White solid;
purification by column chromatography (hexane/ethyl acetate 4.0/6.0),
64% yield; m.p.: 107-109 °C (AcOEt) (Lit.:[58] 107-109 °C); IR (ATR): ν =
2934, 2860, 2832, 1625, 1604, 1497, 1458, 1437, 1392, 1319, 1246,
1220, 1207, 1153, 1011, 893, 849, 727 cm-1; 1H NMR (400 MHz, CDCl3):
δH = 7.63 (s, 1H, CHAr), 7.32 (s, 1H, CHAr), 6.92 (s, 1H, CHAr), 4.00 (s, 3H,
CH3), 3.97 (s, 3H, CH3), 3.06 (t, J = 6.5 Hz, 2H, CCH2), 2.91 (t, J = 6.3
Hz, 2H, CCH2), 2.01-1.92, 1.92-1.81 (2 m, 4H, CH2CH2CH2CH2) ppm;
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900880
European Journal of Organic Chemistry
FULL PAPER
13C NMR (101 MHz, CDCl3): δC = 156.6, 151.8, 149.2, 143.4, 133.7,
129.0, 122.6, 107.1, 104.5, 56.1, 56.0, 33.2, 29.1, 23.4, 23.1 ppm; MS
(EI): m/z 244 (16%), 243 (M+, 100), 242 (17), 228 (16), 200 (12).
OCH3), 2.82 (s, 3H, CH3) ppm; 13C NMR (101 MHz, CDCl3): δC = 168.9,
154.6, 147.3, 147.0, 135.6, 130.7, 129.3, 128.7, 128.6, 128.4, 127.5,
126.8, 126.7, 125.3, 52.4, 23.7 ppm; MS (EI): m/z 278 (M++1, 25%), 277
(M+, 100), 247 (20), 246 (98), 216 (36), 218 (51), 217 (46), 216 (14), 176
(26).
6,7-Dimethoxy-2-methyl-1,2,3,4-tetrahydroacridine (3gd). White solid;
purification by column chromatography (hexane/ethyl acetate 5.0/5.0),
67% yield; m.p.: 151-153 °C (AcOEt); IR (ATR): ν = 3019, 3000, 2951,
2930, 2917, 2863, 2836, 1624, 1605, 1500, 1457, 1427, 1389, 1245,
1223, 1205, 1152, 1021, 1008, 884, 866, 853, 806, 748, 731 cm-1; 1H
NMR (400 MHz, CDCl3): δH = 7.63 (s, 1H, CHAr), 7.33 (s, 1H, CHAr), 6.93
(s, 1H, CHAr), 4.00 (s, 3H, OCH3), 3.98 (s, 3H, OCH3), 3.16 (ddd, J = 17.7,
5.8 and 3.4 Hz, 1H, CCCH), 3.05 (ddd, J = 17.6, 11.3 and 6.1 Hz, 1H,
CCCH), 2.96 (ddd, J = 16.4, 4.5 and 1.1 Hz, 1H, NCCH), 2.55 (dd, J =
16.2 and 10.7 Hz, 1H, NCCH), 2.09-1.89 (m, 2H, CH, CHCH3 and
NCCH2CH), 1.58 (dtd, J = 12.9, 11.1 and 5.9 Hz, 1H, NCCH2CH), 1.11 (d,
J = 6.5 Hz, 3H, CH3) ppm; 13C NMR (101 MHz, CDCl3): δC = 156.4, 151.9,
149.2, 143.6, 133.7, 128.7, 122.6, 107.2, 104.5, 56.1, 56.0, 37.7, 32.8,
31.6, 29.3, 21.8 ppm; MS (EI): m/z 258 (16%), 257 (M+, 100), 256 (11),
242 (29); HRMS (GC/MS-EI/Q-TOF): m/z calcd. for C16H19NO2 257.1416,
found 257.1429.
2-Methyl-9-phenyl-1,2,3,4-tetrahydroacridine (5ad).[11] Yellow solid;
purification by distillation and preparative TLC (hexane/ethyl acetate
8.0/2.0), 84% yield; m.p.: 113-114 °C (AcOEt) (Lit.:[60] 107-108 °C); IR
(ATR): ν = 2959, 2928, 1572, 1484, 1398, 1355, 1263, 1154, 1072, 1030,
966, 928, 759, 703 cm-1; 1H NMR (300 MHz, CDCl3): δH = 8.06 (d, J = 8.4
Hz, 1H, CHAr), 7.61 (dt, J = 8.4 Hz, 1H, CHAr), 7.56-7.45 (m, 3H, 3×CHAr),
7.35-7.30 (m, 2H, 2×CHAr), 7.26-7.20 (m, 2H, 2×CHAr), 3.34 (ddd, J =
17.9, 5.6 and 3.3 Hz, 1H, NCCH), 3.20 (ddd, J = 17.8, 11.6 and 6.1 Hz,
1H, NCCH), 2.67 (ddd, J = 17.0, 4.8 and 2.0 Hz, 1H, CCH), 2.24 (dd, J =
17.0 and 10.8 Hz, 1H, CCH), 2.05 (dtd, J = 10.6, 5.7 and 3.0 Hz, 1H,
CCH2CH), 1.97-1.81 (m, 1H, NCCH2CH), 1.68-1.51 (m, 1H, NCCH2CH),
1.01 (d, J = 6.6 Hz, 3H, CH3) ppm; 13C NMR (101 MHz, CDCl3): δC
=
158.8, 146.9, 146.1, 137.1, 129.3, 129.1, 128.8, 128.7, 128.6, 128.2,
128.1, 127.9, 126.7, 126.0, 125.6, 36.6, 33.81, 31.2, 29.4, 21.9 ppm; MS
(EI): m/z 274 (M++1, 20%), 273 (M+, 100), 272 (M+-1, 62), 231 (11), 230
(15).
1-(6,7-Dimethoxy-2-methylquinol-3-yl)ethanone (3gf).[57] White solid;
purification by column chromatography (hexane/ethyl acetate 4.0/6.0),
75% yield; m.p.: 147-149 °C (AcOEt); IR (ATR): ν = 2934, 2860, 2832,
1625, 1604, 1497, 1458, 1437, 1392, 1320, 1207, 1153, 1011, 893, 849
cm-1; 1H NMR (400 MHz, CDCl3): δH = 8.34 (s, 1H, CHAr), 7.35 (s, 1H,
CHAr), 7.06 (s, 1H, CHAr), 4.04 (s, 3H, OCH3), 4.01, (s, 3H, OCH3), 2.87
(s, 3H, COCH3), 2.68 (s, 3H, CCH3) ppm; 13C NMR (101 MHz, CDCl3): δC
= 199.6, 155.7, 154.3, 149.8, 145.7, 136.7, 129.0, 120.9, 107.4, 105.5,
56.3, 56.1, 29.0, 25.5 ppm; MS (EI): m/z 246 (12%), 245 (M+, 73), 231
(13), 230 (100), 202 (32), 171 (9).
9-Phenyl-1,2,3,4-tetrahydroacridin-1-one (5ae).[59] Yellow solid;
purification by preparative TLC (hexane/ethyl acetate 7.0/3.0), 81% yield;
m.p.: 161-162 °C (AcOEt) (Lit.:[59] 154-156 °C); IR (ATR): ν = 2952, 1687,
1
1551, 1486, 1220, 769, 757, 704 cm-1; H NMR (300 MHz, CDCl3): δH
=
8.07 (d, J = 8.4 Hz, 1H, CHAr), 7.75 (ddd, J = 8.4, 6.7 and 1.6 Hz, 1H,
CHAr), 7.58-7.44 (m, 4H, 4×CHAr), 7.39 (ddd, J = 8.4, 6.7 and 1.2 Hz, 1H,
CHAr), 7.28-7.05 (m, 2H, 2×CHAr), 7.40-7.32 (m, 2H, 2×CHAr), 3.49-3.34
(m, 2H, NCCH2), 278-2.66 (m, 2H, COCH2) 2.24 (p, J = 6.5 Hz, 2H,
CH2CH2CH2) ppm; 13C NMR (101 MHz, CDCl3): δC = 198.0, 162.3, 151.7,
148.6, 137.7, 131.9, 128.5, 128.3, 128.2, 128.1, 127.7, 127.6, 126.6,
124.0, 40.7, 34.6, 21.5 ppm; MS (EI): m/z 274 (M++1, 100%), 273 (M+,
100), 272 (M+-1, 92), 245 (47), 244 (93), 217 (31), 216 (31), 189 (15).
9-Phenyl-1,2,3,4-tetrahydroacridine (5aa).[11] Orange solid; purification
by distillation and preparative TLC (hexane/ethyl acetate 8.0/2.0), 90%
yield; m.p.: 152-155 °C (AcOEt) (Lit.:[59] 139-142 °C); IR (ATR): ν = 2934,
1571, 1485, 1432, 1398, 1354, 1065, 756, 705 cm-1; 1H NMR (300 MHz,
CDCl3): δH = 8.08 (d, J = 8.4 Hz, 1H, CHAr), 7.69-7.50 (m, 1H, CHAr),
7.57-7.45 (m, 3H, 3×CHAr), 7.39-7.31 (m, 2H, 2×CHAr), 7.29-7.19 (m, 2H,
2×CHAr), 3.24 (t, J = 6.6 Hz, 2H, NCCH2), 2.62 (t, J = 6.5 Hz, 2H,
CCCH2), 2.13-1.89 (m, 2H, NCCH2CH2), 1.87-1.74 (m, 2H, CCCH2CH2)
ppm; 13C NMR (101 MHz, CDCl3): δC = 159.0, 147.6, 145.4, 136.9, 129.1,
128.9, 128.8, 128.7, 128.0, 127.6, 126.8, 125.9, 125.8, 33.6, 28.1, 23.0,
22.8 ppm; MS (EI): m/z 260 (M++1, 20%), 259 (M+, 100), 258 (67), 230
(15).
1-(2-Methyl-4-phenylquinol-3-yl)ethanone (5af).[11] Orange solid;
without further purification, 94% yield; m.p.: 117-119 °C (AcOEt) (Lit.:[59]
114-116 °C); IR (ATR): ν = 1689, 1561, 1484, 1392, 1360, 1213, 1027,
762, 751, 710, 702 cm-1; 1H NMR (300 MHz, CDCl3): δH = 8.14 (d, J = 8.4
Hz, CHAr), 7.74 (ddd, J = 8.4, 6.8 and 1.5 Hz, 1H, CHAr), 7.66-7.58 (m,
1H, CHAr), 7.57-7.40 (m, 4H, 4×CHAr), 7.40-7.32 (m, 2H, 2×CHAr), 2.73 (s,
3H, COCH3), 2.00 (s, 3H, CCH3) ppm; 13C NMR (101 MHz, CDCl3): δC
=
205.6, 153.6, 147.1, 144.5, 135.1, 134.9, 130.5, 130.1, 129.1, 128.9,
128.6, 126.8, 126.3, 125.2, 32.0, 23.8 ppm; MS (EI): m/z 262 (M++1,
10%), 261 (M+, 52), 247 (19), 246 (100), 128 (43), 217 (29), 176 (22).
9-Phenyl-2,3-dihydro-1H-cyclopenta[b]quinoline (5ab).[11] Orange
solid; purification by distillation and preparative TLC (hexane/ethyl
acetate 8.0/2.0), 87% yield; m.p.: 138-139 °C (AcOEt) (Lit.:[59] 138-
141 °C); IR (ATR): ν = 2923, 1572, 1488, 1387, 764, 722, 705, 668 cm-1;
1H NMR (300 MHz, CDCl3): δH = 8.12 (d, J = 8.0 Hz, 1H, CHAr), 7.78-7.58
(m, 1H, CHAr), 7.59-7.44 (m, 1H, CHAr), 7.54-7.42 (m, 4H, 4×CHAr), 7.44-
7.32 (m, 2H, 2×CHAr), 3.27 (t, J = 7.7 Hz, 2H, NCCH2), 2.91 (t, J = 7.4 Hz,
2H, CCCH2), 2.18 (p, J = 7.6 Hz, 2H, CH2CH2CH2) ppm; 13C NMR (101
MHz, CDCl3): δC = 167.3, 147.5, 143.3, 136.7, 133.9, 129.3, 128.7, 128.6,
128.5, 128.2, 126.3, 125.8, 125.7, 35.1, 30.4, 23.7 ppm; MS (EI): m/z
246 (M++1, 19%), 245 (M+, 100), 244 (M+-1, 76), 243 (11), 168 (14).
2,4-Diphenylquinoline (5aj).[61] Yellow oil; purification by preparative
TLC (hexane/ethyl acetate 8.0/2.0), 60% yield; IR (ATR): ν = 1264, 771,
1
734, 701 cm-1; H NMR (300 MHz, CDCl3): δH = 8.30 (d, J = 8.3 Hz, 1H,
CHAr), 8.21 (d, J = 6.8 Hz, 2H, 2×CHAr), 7.92 (dd, J = 6.8 and 1.0 Hz, 1H,
CHAr), 7.83 (s, 1H, CHAr), 7.75 (ddd, J = 8.4, 6.9 and 1.4 Hz, 1H, CHAr),
7.64-7.38 (m, 9H, 9×CHAr) ppm; 13C NMR (75 MHz, CDCl3): δC = 156.9,
149.5, 148.7, 139.5, 138.4, 129.7, 129.0, 128.7, 128.6, 127.8, 119.5
ppm; MS (EI): m/z 282 (M++1, 16%), 281 (M+, 79), 280 (M+-1, 100), 202
(15).
Methyl 2-methyl-4-phenylquinoline-3-carboxylate (5ac).[59] Yellow
solid; purification by preparative TLC (hexane/ethyl acetate 8.0/2.0), 96%
yield; m.p.: 110-112 °C (AcOEt) (Lit.:[59] 99-100 °C); IR (ATR): ν = 1726,
1583, 1488, 1424, 1393, 1295, 1227, 1170, 1126, 1066, 968, 759 cm-1;
1H NMR (300 MHz, CDCl3): δH = 8.15 (d, J = 8.4 Hz, 1H, CHAr), 7.75 (ddd,
J = 8.3, 6.9 and 1.4 Hz, 1H, CHAr), 7.61 (dd, J = 8.5 and 1.4 Hz, 1H,
CHAr), 7.54-7.42 (m, 4H, 4×CHAr), 7.42-7.34 (m, 2H, 2×CHAr), 3.59 (s, 3H,
3-Methyl-2,4-diphenylquinoline (5ak). Yellow solid; purification by
preparative TLC (hexane/ethyl acetate 8.0/2.0), 86% yield; m.p.: 156-
157 °C (AcOEt); IR (ATR): ν = 1571, 1483, 1440, 1348, 1006, 793, 773,
763, 754, 714, 698, 670 cm-1; 1H NMR (300 MHz, CDCl3): δH = 8.22 (d, J
= 8.4 Hz, 1H, CHAr), 7.80-7.60 (m, 3H, 3×CHAr), 7.58-7.43 (m, 9H,
9×CHAr), 7.35-7.27 (m, 2H, 2×CHAr), 2.16 (s, 3H, CH3) ppm; 13C NMR
(101 MHz, CDCl3): δC = 160.8, 148.2, 146.1, 141.2, 137.8, 129.4, 129.3,
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10.1002/ejoc.201900880
European Journal of Organic Chemistry
FULL PAPER
129.1, 128.8, 128.4, 128.3, 128.0, 127.2, 126.9, 126.5, 126.1, 18.7 ppm;
MS (EI): m/z 296 (M++1, 16%), 295 (M+, 90), 294 (M+-1, 100), 293 (21),
292 (18), 291 (12), 217 (14), 145 (10); HRMS (GC/MS-EI/Q-TOF): m/z
calcd. for C22H17N 295.1361, found 295.1342.
CCOCH2), 2.17 (p, J = 6.5 Hz, 2H, CH2CH2CH2) ppm; 13C NMR (101
MHz, CDCl3): δC = 197.7, 162.6, 150.8, 147.0, 136.9, 132.8, 132.6, 130.2,
128.4, 128.1, 128.0, 126.8, 124.6, 40.7, 34.6, 21.4 ppm; MS (EI): m/z
309 (M++2, 56%), 308 (M++1, 56), 307 (M+, 98), 306 (M+-1, 100), 281
(11), 280 (27), 279 (38), 278 (77), 217 (43), 214 (20), 189 (14), 120 (15);
HRMS (GC/MS-EI/Q-TOF): m/z calcd. for C19H14ClNO 307.0764, found
307.0755.
3-Ethyl-4-phenyl-2-propylquinoline (5ai). Yellow oil; purification by
preparative TLC (hexane/ethyl acetate 8.0/2.0), 46% yield; m.p.: 119-
121 °C (AcOEt); IR (ATR): ν = 2965, 2932, 2871, 1576, 1487, 1398,
1378, 1264, 1072, 1023, 761, 737, 702 cm-1; 1H NMR (300 MHz, CDCl3):
δH = 8.10 (d, J = 8.4 Hz, 1H, CHAr), 7.60 (ddd, J = 8.3, 6.8 and 1.5 Hz, 1H,
CHAr), 7.56-7.43 (m, 3H, 3×CHAr), 7.40-7.16 (m, 4H, 4×CHAr), 3.24-2.94
(m, 2H, CH2CH2CH3), 2.62 (q, J = 7.5 Hz, 2H, CH2CH3), 2.02-1.81 (m,
2H, CH2CH2CH3), 1.11 (t, J = 7.4 Hz, 3H, CH2CH3), 1.05 (t, J = 7.5 Hz,
3H, CH2CH2CH3) ppm; 13C NMR (101 MHz, CDCl3): δC = 162.0, 137.6,
133.3, 129.4, 128.5, 128.3, 127.8, 127.2, 126.3, 125.7, 38.1, 12.6, 23.1,
15.5, 14.6 ppm; MS (EI): m/z 275 (M+, 32%), 274 (M+-1, 62), 260 (14),
247 (39), 246 (100), 232 (16), 231 (17), 217 (11); HRMS (GC/MS-EI/Q-
TOF): m/z calcd. for C20H21N 275.1674, found 275.1655.
6-Chloro-3-ethyl-4-phenyl-2-propylquinoline (5bi). White solid;
purification by preparative TLC (hexane/ethyl acetate 7.0/3.0), 35% yield;
m.p.: 97-99 °C (AcOEt); IR (ATR): ν = 3056, 2967, 2931, 2899, 2871,
1577, 1480, 1375, 1169, 1076, 969, 826, 765, 707 cm-1; 1H NMR (400
MHz, CDCl3): δH = 7.97 (d, J = 8.9 Hz, 1H, CHAr), 7.57-7.45 (m, 4H,
4×CHAr), 7.25-7.21 (m, 2H, 2×CHAr), 7.17 (d, J = 2.2 Hz, 1H, CHAr), 3.07-
2.94 (m, 2H, NCCH2), 2.60 (q, J = 7.5 Hz, 2H, CCH2CH3), 1.99-1.82 (m,
2H, CCH2CH2), 1.10 (t, J = 7.4 Hz, 3H, CH2CH2CH3), 1.04 (t, J = 7.5 Hz,
3H, CCH2CH3) ppm; 13C NMR (101 MHz, CDCl3): δC = 162.4, 145.9,
144.7, 137.0, 134.2, 131.3, 130.4, 129.4, 129.1, 128.7, 128.1, 127.9,
125.0, 77.2, 38.2, 23.3, 23.1, 15.4, 14.6 ppm; MS (EI): m/z 311 (M++2,
10%), 310 (23), 309 (M+, 29), 308 (57), 294 (14), 283 (13), 282 (37), 281
(39), 280 (100), 278 (11), 266 (16), 265 (13); HRMS (GC/MS-EI/Q-TOF):
m/z calcd. for C20H20ClN 309.1284, found 309.1264.
2-Methyl-4-phenyl-3-propylquinoline (5ah). Yellow oil; purification by
preparative TLC (hexane/ethyl acetate 8.0/2.0), 58% yield; IR (ATR): ν =
2915, 1412, 1357, 1308, 1226, 1084, 987, 943, 777, 725 cm-1; 1H NMR
(300 MHz, CDCl3): δH = 8.07 (d, J = 8.4 Hz, 1H, CHAr), 7.67-7.56 (m, 1H,
CHAr), 7.54-7.45 (m, 3H, 3×CHAr), 7.40-7.26 (m, 1H, CHAr), 7.34-7.11 (m,
3H, 3×CHAr), 2.83 (s, 3H, CCH3), 2.68-2.43 (m, 2H, CCH2), 2.68-2.43 (m,
2H, CCH2CH2CH3), 1.05 (t, J = 7.5 Hz, 3H, CH2CH3), 0.83 (t, J = 7.3 Hz,
3H, CH3) ppm; 13C NMR (75 MHz, CDCl3): δC = 158.6, 147.1, 145.7,
137.5, 132.4, 129.4, 128.6, 128.5, 128.2, 127.8, 127.3, 126.4, 125.8,
32.6, 23.8, 23.7, 14.7 ppm; MS (EI): m/z 261 (M+, 0.6%), 232 (17), 220
(17), 219 (100); HRMS (GC/MS-EI/Q-TOF): m/z calcd. for C19H19N
261.1517, found 261.1519.
6-Chloro-3-methyl-2,4-diphenylquinoline
(5bk).[63] White
solid;
purification by distillation and preparative TLC (hexane/ethyl acetate
9.0/1.0), 53% yield; m.p. 159-161 °C (AcOEt) (Lit.[63] 154-155 °C); IR
(ATR): ν = 3064, 3032, 1572, 1475, 1442, 1371, 1346, 1278, 1076, 1009,
944, 842, 835, 793, 755, 719, 697 cm-1; 1H NMR (300 MHz, CDCl3): δH
=
8.09 (d, J = 8.9 Hz, 1H, CHAr), 7.63-7.39 (m, 9H, 9×CHAr), 7.35 (d, J = 2.2
Hz, 1H, CHAr), 7.32-7.22 (m, 2H, 2×CHAr), 2.14 (s, 3H, CH3) ppm; 13C
NMR (101 MHz, CDCl3): δC = 161.2, 147.2, 144.7, 141.2, 137.1, 132.2,
131.2, 129.6, 129.3, 129.0, 128.5, 128.4, 128.3, 127.9, 127.9, 124.8,
18.8 ppm; MS (EI): m/z 331 (15%), 330 (M++2, 40), 329 (48), 328 (M+,
40), 146 (10).
2-Butyl-4-phenylquinoline (5ah’).[62] Yellow oil; purification by
preparative TLC (hexane/ethyl acetate 8.0/2.0), 15% yield; IR (ATR): ν =
2875, 1512, 1387, 1356, 1242, 1059, 1018, 950, 769, 754 cm-1; 1H NMR
(300 MHz, CDCl3): δH = 8.16 (d, J = 8.4 Hz, 1H, CHAr), 7.97-7.83 (m, 1H,
CHAr), 7.70 (ddd, J = 8.4, 6.9 and 1.4 Hz, 1H, CHAr), 7.62-7.38 (m, 6H,
6×CHAr), 3.25-2.91 (m, 2H, CCH2), 2.16-1.70 (m, 2H, CCH2CH2), 1.47 (q,
2H, CH2CH3), 0.97 (t, J = 7.3 Hz, 3H, CH3) ppm; 13C NMR (75 MHz,
CDCl3): δC = 162.6, 138.3, 129.7, 129.6, 129.0, 128.7, 128.5, 126.0,
125.8, 125.4, 121.7, 39.0, 32.4, 22.9, 14.1 ppm; MS (EI): m/z 262 (M++1,
11%), 261 (M+, 48), 233 (18), 232 (100), 231 (30), 230 (12), 189 (17).
6-Chloro-3-methyl-2,4-diphenylquinoline
(5bk).[63] White
solid;
purification by distillation and preparative TLC (hexane/ethyl acetate
9.0/1.0), 53% yield; m.p. 159-161 °C (AcOEt) (Lit.[63] 154-155 °C); IR
(ATR): ν = 3064, 3032, 1572, 1475, 1442, 1371, 1346, 1278, 1076, 1009,
944, 842, 835, 793, 755, 719, 697 cm-1; 1H NMR (300 MHz, CDCl3): δH
=
8.09 (d, J = 8.9 Hz, 1H, CHAr), 7.63-7.39 (m, 9H, 9×CHAr), 7.35 (d, J = 2.2
Hz, 1H, CHAr), 7.32-7.22 (m, 2H, 2×CHAr), 2.14 (s, 3H, CH3) ppm; 13C
NMR (101 MHz, CDCl3): δC = 161.2, 147.2, 144.7, 141.2, 137.1, 132.2,
131.2, 129.6, 129.3, 129.0, 128.5, 128.4, 128.3, 127.9, 127.9, 124.8,
18.8 ppm; MS (EI): m/z 331 (15%), 330 (M++2, 40), 329 (48), 328 (M+,
40), 146 (10).
5-Chloro-9-phenyl-2,3-dihydro-1H-cyclopenta[b]quinoline
(5bb).
Brownish solid; purification by distillation and preparative TLC
(hexane/ethyl acetate 7.0/3.0), 84% yield; m.p.: 107-109 °C (AcOEt); IR
(ATR): ν = 2954, 1604, 1565, 1486, 1385, 1342, 1163, 1076, 949, 881,
829, 780, 757 cm-1; 1H NMR (300 MHz, CDCl3): δH = 8.02 (d, J = 8.8 Hz,
1H, CHAr), 7.74-7.44 (m, 5H, 5×CHAr), 7.43-7.29 (m, 2H, 2×CHAr), 3.24 (t,
J = 7.7 Hz, 2H, NCCH2), 2.90 (t, J = 7.4 Hz, 2H, CCCH2), 2.17 (p, J = 7.6
Hz, 2H, CH2CH2CH2) ppm; 13C NMR (75 MHz, CDCl3): δC = 167.8, 146.1,
142.4, 136.0, 134.9, 131.6, 130.2, 129.3, 129.2, 128.9, 128.5, 127.2,
124.7, 35.1, 30.5, 23.6 ppm; MS (EI): m/z 281 (M++2, 34%), 280 (M++1,
26), 279 (M+, 100), 278 (M+-1, 24), 245 (19), 244 (95), 243 (21), 242 (20),
241 (14), 120 (14); HRMS (GC/MS-EI/Q-TOF): m/z calcd. for C18H14ClN
279.0815, found 279.0811.
9-Chloro-7-phenyl-5,6-dihydrobenzo[c]acridine (5bm). Yellow solid;
purification by preparative TLC (hexane/ethyl acetate 9.0/1.0), 47% yield;
m.p.: 141-142 °C (AcOEt); IR (ATR): ν = 2928, 1488, 1477, 1354, 1077,
940, 829, 796, 768, 737, 723, 705 cm-1; 1H NMR (300 MHz, CDCl3): δH
=
8.59 (dd, J = 7.6 and 1.4 Hz, 1H, CHAr), 8.12 (d, J = 8.9 Hz, 1H, CHAr),
7.73-7.13 (m, 11H, 11×CHAr), 2.95-2.76 (m, 4H, 2×CH2) ppm; 13C NMR
(101 MHz, CDCl3): δC = 153.5, 145.5, 144.9, 139.4, 136.3, 134.7, 131.9,
131.2, 130.1, 129.6, 129.5, 129.2, 128.9, 128.4, 128.1, 127.9, 127.5,
126.5, 125.0, 29.8, 28.2, 26.7 ppm; MS (EI): m/z 344 (M++2, 7%), 343
(M++1, 32), 342 (M+, 43), 343 (M+-1, 100), 340 (70), 339 (15), 305 (23),
303 (11), 153 (24), 152 (24), 151 (18); HRMS (GC/MS-EI/Q-TOF): m/z
calcd. for C23H16ClN 341.0971, found 341.0946.
9-Phenyl-1,2,3,4-tetrahydroacridin-1-one
(5be).
Yellow
solid;
purification by column cromatography (hexane/ethyl acetate 7.0/3.0),
68% yield; m.p.: 199-200 °C (AcOEt); IR (ATR): ν = 1687, 1550, 1476,
1389, 1215, 1155, 1078, 1015, 947, 839, 698 cm-1; 1H NMR (300 MHz,
CDCl3): δH = 8.02 (d, J = 9.0 Hz, 1H, CHAr), 7.70 (dd, J = 9.0 and 2.3 Hz,
1H, CHAr), 7.58-7.47 (m, 3H, 3×CHAr), 7.43 (d, J = 9.0 Hz, 1H, CHAr),
7.21-7.13 (m, 2H, 2×CHAr), 3.62-3.27 (m, 2H, NCCH2), 2.81-2.64 (m, 2H,
Methyl 2-methyl-4-(2-chlorophenyl)quinoline-3-carboxylate (5cc).
Yellow solid; purification by preparative TLC (hexane/ethyl acetate
8.0/2.0), 90% yield; m.p.: 136-137 °C (AcOEt); IR (ATR): ν = 1722, 1577,
1471, 1431, 1285, 1227, 1168, 1052, 835, 793, 758, 731, 711 cm-1; 1H
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10.1002/ejoc.201900880
European Journal of Organic Chemistry
FULL PAPER
NMR (300 MHz, CDCl3): δH = 8.06 (d, J = 9.0 Hz, 1H, CHAr), 7.68 (dd, J =
9.0 and 2.3 Hz, 1H, CHAr), 7.57 (dd, J = 7.9 and 1.3 Hz, 1H, CHAr), 7.46
(td, J = 7.7 and 1.9 Hz, 1H, CHAr), 7.40 (td, J = 7.4 and 1.5 Hz, 1H, CHAr),
7.32-7.20 (m, 2H, CHAr), 3.59 (2, 3H, CCH3), 2.81 (s, 3H, OCH3) ppm;
13C NMR (75 MHz, CDCl3): δC = 167.8, 155.6, 145.6, 144.0, 134.0, 133.6,
133.1, 131.9, 130.9, 130.6, 130.4, 129.9, 128.1, 126.9, 125.7, 125.1,
52.5, 23.9 ppm; MS (EI): m/z 250 (M++4, 0.04%), 248 (M++2, 0.01), 246
(M+, 0.03), 312 (34), 311 (20), 310 (100); HRMS (GC/MS-EI/Q-TOF): m/z
calcd. for C18H13Cl2NO2 345.0323, found 345.0331.
4×CH2) ppm; 13C NMR (75 MHz, CDCl3): δC = 165.2, 144.2, 142.1, 135.8,
135.4, 133.7, 131.9, 131.1, 130.3, 130.0, 129.9, 129.5, 127.2, 124.6,
44.0, 40.2, 32.0, 31.1, 30.6, 27.9, 27.0, 24.5 ppm; MS (EI): m/z 346
(M++4, 3%), 344 (M++2, 13), 343 (M++1, 70), 342 (M+, 33), 341 (M+-1,
100), 340 (25), 326 (12), 314 (22), 312 (29), 308 (23), 307 (15), 306 (77),
242 (12), 241 (16), 127 (15), 120 (13); HRMS (GC/MS-EI/Q-TOF): m/z
calcd. for C20H17Cl2N 341.0738, found 341.0722.
9-Chloro-7-(2-chlorophenyl)-5,6-dihydrobenzo[c]acridine
(5cm).
Yellow oil; purification by preparative TLC (hexane/ethyl acetate 9.0/1.0),
46% yield; m.p.: 130-131 °C (AcOEt); IR (ATR): ν = 2931, 1577, 1472,
1432, 1357, 1260, 1080, 1032, 938, 869, 823, 794, 764, 735 cm-1; 1H
NMR (300 MHz, CDCl3): δH = 8.61 (dd, J = 7.8 and 1.4 Hz, 1H, CHAr),
8.61 (d, J = 8.9 Hz, 1H, CHAr), 7.69-7.55 (m, 2H, 2×CHAr), 7.52-7.34 (m,
4H, 4×CHAr), 7.31-7.14 (m, 3H, 3×CHAr), 3.10-2.60 (m, 4H, 2×CH2) ppm;
13C NMR (101 MHz, CDCl3): δC = 153.5, 145.6, 142.0, 139.5, 135.1,
134.5, 133.8, 132.2, 131.3, 131.2, 130.2, 130.1, 129.9, 129.8, 127.9,
127.6, 127.5, 127.4, 126.5, 124.3, 28.0, 26.3 ppm; MS (EI): m/z 380
(M++4, 2%), 378 (M++2, 21), 377 (M++1, 66), 376 (M+, 45), 375 (M+-1, 42),
342 (14), 341 (12), 340 (42), 338 (20), 303 (28), 302 (19), 301 (19), 300
(13), 264 (11), 152 (46), 151 (45); HRMS (GC/MS-EI/Q-TOF): m/z calcd.
for C23H15Cl2N 375.0582, found 375.0590.
9-(2-Chlorophenyl)-2-methyl-1,2,3,4-tetrahydroacridine (5cd). Orange
solid; purification by preparative TLC (hexane/ethyl acetate 8.0/2.0), 92%
yield; m.p.: 135-138 °C (AcOEt); IR (ATR): ν = 2957, 2923, 1573, 1468,
1426, 1173, 1050, 975, 375, 828, 764, 734, 707 cm-1; 1H NMR (300 MHz,
CDCl3): δH = 8.02 (d, J = 9.0 Hz, 1H, CHAr), 7.70-7.52 (m, 2H, 2×CHAr),
7.52-7.38 (m, 2H, 2×CHAr), 7.19-7.10 (m, 2H, 2×CHAr), 3.55-2.95 (m, 2H,
NCCH2), 2.66-2.47 (m, 1H, CCH), 2.34-2.17 (m, 1H, CCH), 2.13-1.98 (m,
1H, CCH), 1.98-1.84 (m, 1H, CCH2CH), 1.74-1.51 (m, 1H, NCCH2CH),
1.02 (d, J = 6.5 Hz, 3H, CH3) ppm; 13C NMR (101 MHz, CDCl3): δC
=159.4, 159.2, 144.4, 143.5, 135.2, 133.5, 133.1, 131.8, 130.8, 130.6,
130.3, 130.2, 130.0, 129.9, 129.8, 127.5, 127.4, 126.9, 124.0, 36.3, 35.6,
33.6, 31.0, 30.9, 29.1, 28.9, 21.9, 21.7 ppm; MS (EI): m/z 346 (M++4,
3%), 344 (M++2, 11), 342 (M+, 35), 341 (M+-1, 100), 340 (18), 328 (15),
326 (28), 312 (13), 308 (30), 307 (18), 306 (89), 290 (12), 264 (20), 254
(14), 241 (15), 229 (12), 228 (20), 202 (11), 127 (17), 120 (12); HRMS
(GC/MS-EI/Q-TOF): m/z calcd. for C20H17Cl2N 341.0738, found 341.0733.
General procedure for the derivatization of quinolines. To a solution
of 1-(2-methyl-4-phenylquinol-3-yl)ethanone (0.5 mmol) in ethanol (0.5
mL), the corresponding aldehyde 6 was added (0.5 mmol), stirring the
reaction mixture for 4 hours at room temperature. After the reaction time,
the mixture was filtered through celite to remove the catalyst, eluting with
ethyl acetate. Then, the solvent was evaporated under reduced pressure,
affording the corresponding product 7, which was purified by
recrystallization in CH2Cl2 or CH2Cl2/n-pentane.
9-(2-Chlorophenyl)-1,2,3,4-tetrahydroacridin-1-one (5ce). Orange
solid; purification by preparative TLC (hexane/ethyl acetate 7.0/3.0), 89%
yield; m.p.: 139-140 °C (AcOEt); IR (ATR): ν = 3072, 2953, 1694, 1553,
1469, 1165, 1082, 1015, 948, 842, 749, 707 cm-1; 1H NMR (300 MHz,
CDCl3): δH = 8.04 (d, J = 9.0 Hz, 1H, CHAr), 7.70 (ddd, J = 9.0, 2.4 and
0.8 Hz, 1H, CHAr), 7.60-7.52 (m, 1H, CHAr), 7.50-7.36 (m, 1H, CHAr), 7.31
(d, J = 2.3 Hz, 1H, CHAr), 7.17-7.06 (m, 1H, CHAr), 3.38 (td, J = 5.9 and
1.4 Hz, 2H, NCCH2), 2.98-2.60 (m, 2H, COCH2), 2.36-2.17 (m, 2H,
CH2CH2CH2) ppm; 13C NMR (101 MHz, CDCl3): δC = 197.3, 162.5, 147.3,
147.2, 136.0, 132.9, 132.1, 130.4, 129.6, 129.5, 129.4, 127.5, 126.9,
125.9, 124.6, 40.2, 34.4, 21.3 ppm; MS (EI): m/z 346 (M++4, 0.0008%),
344 (M++2, 0.003), 342 (M+, 1), 308 (32), 308 (20), 306 (100); HRMS
(GC/MS-EI/Q-TOF): m/z calcd. for C19H13ClNO [M-Cl]+ 306.0686, found
306.0688.
General procedure for the tandem reaction.
A mixture of the
corresponding 2-aminobenzaldehyde or 2-aminoarylketone (0.5 mmol),
the corresponding ketone 2 (5 equivalents) and bcmim-Cl (10 mol%)
were stirred at 80 during 6 hours. After cooling down, the corresponding
aldehyde 6 was added (0.5 mmol), stirring the reaction mixture for 4
hours at room temperature. The mixture was filtered through celite to
remove the catalyst, eluting with ethyl acetate. Then, the solvent was
evaporated under reduced pressure, affording the corresponding product
7, which was purified by recrystallization in CH2Cl2 or CH2Cl2/n-pentane.
1-[6-Chloro-4-(2-chlorophenyl)-2-methylquinol-3-yl]ethanone (5cf).
Orange solid; purification by preparative TLC (hexane/ethyl acetate
8.0/2.0), 91% yield; m.p.: 144-146 °C (AcOEt); IR (ATR): ν = 1699, 1468,
1376, 1355, 1201, 1079, 1058, 962, 837, 764, 736, 711, 687 cm-1; 1H
NMR (300 MHz, CDCl3): δH = 8.04 (d, J = 9.0 Hz, 1H, CHAr), 7.66 (dd, J =
9.0 and 2.3 Hz, 1H, CHAr), 7.59 (dd, J = 8.0 and 1.3 Hz, 1H, CHAr), 7.51
(dd, J = 7.4 and 1.7 Hz, 1H, CHAr), 7.49-7.36 (m, 1H, CHAr), 7.31-7.19 (m,
2H, 2×CHAr), 2.71 (s, 3H, CCH3), 2.15 (s, 3H, COCH3) ppm; 13C NMR
(101 MHz, CDCl3): δC = 204.3, 154.2, 145.4, 140.9, 135.8, 133.4, 133.1,
132.1, 131.5, 131.1, 130.5, 130.2, 127.6, 125.6, 124.7, 31.4, 23.8 ppm;
MS (EI): m/z 320 (M++4, 0.008%), 318 (M+, 0.05), 316 (M+, 5), 296 (34),
295 (20), 294 (100); HRMS (GC/MS-EI/Q-TOF): m/z calcd. for
C18H13ClNO [M-Cl]+ 294.0686, found 294.0688.
(E)-3-(3
Hydroxy-4-methoxyphenyl)-1-(2-methyl-4-phenylquinol-3-
yl)prop-2-en-1-one (7a).[49] Yellow solid; purification by recrystallization
in CH2Cl2, 66% yield; m.p.: 220-222 °C (CH2Cl2) (Lit.:[49] 213 °C); IR
(ATR): ν = 1624, 1601, 1507, 1440, 1284, 1232, 1168, 1133, 1051, 1024,
778, 754, 725 cm-1; 1H NMR (300 MHz, CDCl3): δH = 8.22 (d, J = 8.5 Hz,
1H, CHAr), 7.77 (ddd, J = 8.4, 6.8 and 1.5 Hz, 1H, CHAr), 7.64 (dd, J = 8.5
and 1.4 Hz, 1H, CHAr), 7.55-7.43 (m, 1H, CHAr), 7.38 (dd, J = 5.1 and 2.0
Hz, 3H, 3×CHAr), 7.35-7.26 (m, 2H, 2×CHAr), 7.01 (d, J = 16.2 Hz, 1H,
ArCH), 6.93 (d, J = 2.0 Hz, 1H, CHAr), 6.87-6.75 (m, 2H, 2×CHAr), 6.45 (d,
J = 16.1 Hz, 1H, COCH), 3.89 (s, 3H, OCH3), 2.74 (s, 3H, CCH3) ppm;
13C NMR (101 MHz, CDCl3): δC = 197.3, 155.1, 149.6, 147.2, 146.2,
145.9, 130.4, 130.0, 128.7, 128.5, 126.8, 126.5, 126.2, 122.6, 113.4,
110.8, 105.4, 56.1, 23.7 ppm; MS (DIP, EI): m/z 396 (M++1, 27%), 395
(M+, 100), 394 (47), 380 (14), 367 (12), 366 (35), 258 (24), 218 (25), 217
(25), 177 (23), 176 (25), 151 (12), 137 (14), 89 (12); HRMS (GC/MS-
EI/Q-TOF): m/z calcd. for C26H21NO3 395.1521, found 395.1526.
2-Chloro-11-(2-chlorophenyl)-7,8,9,10-tetrahydro-6H-
cyclohepta[b]quinoline (5cl). Yellow oil; purification by preparative TLC
(hexane/ethyl acetate 9.0/1.0), 65% yield; m.p.: 151-152 °C (AcOEt); IR
(ATR): ν = 2925, 2849, 1469, 1449, 1171, 1078, 1051, 958, 827, 776,
760, 735, 705 cm-1; 1H NMR (300 MHz, CDCl3): δH = 7.99 (d, J = 8.9 Hz,
1H, CHAr), 7.61-7.49 (m, 2H, 2×CHAr), 7.48-7.36 (m, 2H, 2×CHAr), 7.18-
7.13 (m, 1H, CHAr), 7.07 (m, J = 2.3 Hz, 1H, CHAr), 3.38-3.16 (m, 2H,
NCCH2), 2.62 (ddd, J = 7.7, 4.6 and 2.7 Hz, 1H, CCH), 2.16-1.46 (m, 8H,
(E)-3-(4-Chlorophenyl)-1-(2-methyl-4-phenylquinol-3-yl)prop-2-en-1-
one (7b).[64] Yellow solid; purification by recrystallization with CH2Cl2/n-
pentane, 52% yield; m.p.: 200-203 °C (CH2Cl2); IR (ATR): ν = 1639, 1487,
1397, 1302, 1227, 1170, 1086, 1048, 986, 812, 774, 755, 701 cm-1; 1H
NMR (300 MHz, CDCl3): δH = 8.21 (d, J = 8.4 Hz, 1H, CHAr), 7.79 (ddd, J
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900880
European Journal of Organic Chemistry
FULL PAPER
= 8.4, 6.8 and 1.4 Hz, 1H, CHAr), 7.71-7.61 (m, 1H, CHAr), 7.55-7.49 (m,
1H, CHAr), 7.47-7.36 (m, 3H, 3×CHAr), 7.37-7.20 (m, 6H, 6×CHAr), 7.08 (d,
J = 16.2 Hz, 1H, ArCH), 6.55 (d, J = 16.2 Hz, 1H, COCH), 2.76 (s, 3H,
CH3) ppm; 13C NMR (101 MHz, CDCl3): δC = 197.1, 168.4, 155.0, 147.3,
146.2, 145.1, 137.1, 135.2, 132.7, 132.6, 131.5, 130.7, 130.1, 129.6,
129.4, 128.9, 128.6, 128.2, 126.9, 126.5, 125.4, 23.8 ppm; MS (DIP, EI):
m/z 385 (M++2, 7%), 383 (M+, 21), 259 (20), 258 (100), 218 (11), 217
(13), 176 (14), 165 (12); HRMS (GC/MS-EI/Q-TOF): m/z calcd. for
C25H18ClNO 383.1077, found 383.1078.
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196.3, 154.9, 143.1, 132.7, 130.7, 130.4, 130.2, 129.0, 128.7, 128.6,
127.0, 126.4, 118.3, 113.9, 24.0 ppm; MS (EI): m/z 374 (M+, 28%), 259
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22.5 ppm; MS (EI): m/z 417 (M+, 27%), 272 (11), 259 (19), 258 (100),
218 (14), 217 (16), 176 (15), 151 (20); HRMS (GC/MS-EI/Q-TOF): m/z
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Acknowledgments
This work was financially supported by the University of Alicante
(VIGROB-173, VIGROB-285 and VIGROB-316), the Spanish
Ministerio de Economía y Competitividad (CTQ2015-66624-P,
CTQ2017-88171-P), the Spanish Ministerio de Ciencia,
Innovación y Universidades (PGC2018-096616-B-I00) and the
Generalitat Valenciana (AICO/2017/007). M.A.-S. thanks the
Spanish Ministerio de Educación, Cultura y Deporte for a
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