Evaluation of sodium acetate trihydrate-urea des as a benign reaction media for the Biginelli reaction. Unexpected synthesis of methylenebis(3-hydroxy-5,5-dimethylcyclohex-2-enones), hexahydroxanthene-1,8-diones and hexahydroacridine-1,8-diones

Article abstract of DOI:10.1039/c6ra13848a

In this work, the low melting mixture sodium acetate trihydrate-urea was synthesized and the eutectic composition was determined and characterized using differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA). The physical properties

Full text of DOI:10.1039/c6ra13848a

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Evaluation of sodium acetate trihydrate‐urea DES as a benign
reaction media for the Biginelli reaction. Unexpected synthesis of
methylenebis(3‐hydroxy‐5,5‐dimethylcyclohex‐2‐enones),
hexahydroxanthene‐1,8‐diones and hexahydroacridine‐1,8‐diones
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
Camilo A. Navarro,a Cesar A. Sierraa and Cristian Ochoa‐Puentesa*
www.rsc.org/
In this work, the low melting mixture sodium acetate trihydrate‐urea was synthesized and the eutectic composition was
determined and characterized using differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA). The
physical properties of the deep eutectic solvent (DES) such as viscosity, electrical conductivity, density, pH and refractive
index were mesured and analyzed as function of temperature. To explore the use of this DES as a reaction media, the
Biginelli one‐pot reaction for the obtention of polyhydroquinoxaline derivatives was studyied and unexpectedly
methylenebis(3‐hydroxy‐5,5‐dimethylcyclohex‐2‐enones) and hexahydroxanthene‐1,8‐diones were obtained when the
reaction was performed at 60 oC and hexahydroacridine‐1,8‐diones when the reaction was conducted at 100 oC. Our
results showed that the nature of the obtained products can be tuned by increasing the temperature of the reaction.
field, the low melting mixtures have been introduced as reaction
media for a variety of organic C–C‐coupling reactions. Diels‐Alder,
Perkin, aldol, Biginelli and Pictet–Spengler reaction, Knoevenagel
condensation, addition of organolithium and Grignard reagents to
Introduction
ketones, metal‐catalysed reactions like Suzuki, Heck, and
Sonogashira reactions, and the Huisgen 1,3‐dipolar cycloaddition
are some examples of successfully conducted reactions.9, 10
Organic solvents are widely used in chemical laboratories and the
chemical industry as liquid media in which different processes like
synthesis, extraction, separation, purification and drying of
chemical products take place. They also serve as medium to
perform some analytical, spectroscopic and spectrometric methods
and for the determination of physicochemical properties. Due to
their extensive use, hazardous and toxic properties, many organic
solvents are considered as dangerous waste by‐products. As
alternative for common organic solvents, a new class of “green
reaction media” which include ionic liquids, water, perfluorinated
biphasic solvents, supercritical liquids, carbonic esters and deep
eutectic solvents (DESs) have emerged.1
The Biginelli reaction is one of the most important multicomponent
reactions based on acid‐catalyzed three‐component condensation
of a β‐dicarbonyl compound, an aldehyde and urea or thiourea.11
This remarkable reaction offers straightforward access to
biologically active dihydropyrimidones12 and therefore in the last
decades many improved procedures with new catalysts, building
blocks and solvents have been reported.13
Recently König et al. introduced the use of tartaric acid‐N,N‐
dimethyl urea DES for the synthesis of several nitrogenated
hereocycles,14 including dihydropyrimidones.15 Interestingly, these
reports show that this DES acts as solvent, catalyst and reactant
allowing the efficient construction of highly functionalized
nitrogenated heterocycles in good to excellent yields.
A DES would be defined as a mixture of two or more components
(hydrogen bond donors and hydrogen‐bond acceptors) which may
be solid or liquid with
a particular composition (eutectic
composition) that present a high melting point depression.2 DESs
can be formed by mixing the starting components under moderate
temperatures and many of them can be obtained from cheap,
readily available, and toxicologically well characterized starting
materials.3 Recent advances in the use of DES include processes of
extraction,4, 5 dissolution and separation,6 catalysis,7 preparation of
Based on the aforementioned results and the recent reports about
the base‐catalyzed Biginelli reaction,16, 17 we hypothesized that the
sodium acetate trihydrate‐urea DES may promote the reaction
between dimedone, aldehydes and urea to obtain
polyhydroquinoxaline derivatives of biological significance via
Biginelli reaction,18 and herein we report the unexpected results
obtained during this multicomponent reaction.
materials,8 electrochemistry and organic synthesis.3, In this last
9
a. Grupo de Investigación en Macromoléculas, Departamento de Química,
Universidad Nacional de Colombia–Sede Bogotá, Carrera 45 # 26‐85, A.A. 5997,
Bogotá, Colombia, E‐mail: cochoapu@unal.edu.co; Tel.: +57‐1‐3165000
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
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Results and discussion
100
80
91.97% (‐8.03%) ‐H2O
84.06% (‐15.94%) ‐H2O
77.37% (‐22.63%) ‐H2O
Thermal analysis (DSC/TGA)
60
38.26% (‐61.74%)
‐ Urea
The sodium acetate trihydrate‐urea DES was first reported as a
eutectic mixture composed by CH3COONa∙3H2O and CO(NH2)2 in the
mass ratio 0.4:0.6, with a melting point of 30 °C.19 Based on this, we
decided to prepare this low melting system to be used as DES in
40
20
0
organic synthesis, but during several experiments
a non‐
homogenous mixture with dispersed solids was obtained. Then, we
focused on study the mixture by differential scanning calorimetry
(DSC) and thermogravimetric analysis (TGA) in order to determine
the eutectic point and the thermal stability of the mixture. Figure 1
shows the phase diagram constructed with 11 samples of
CH3COONa∙3H2O/CO(NH2)2 of different molar composition (1:0;
0.8:0.2; 0.6:0.4; 0.5:0.5; 0.4:0.6; 0.3:0.7; 0.2:0.8; 0.15:0.85; 0.1:0.9;
0.05:0.95 and 0:1).
0
25 50 75 100 125 150 175 200 225 250
t(°C)
Figure 2. TGA profile in N2 atmosphere for the sodium acetate
trihydrate‐urea DES.
Once the thermal stability of the DES was established, and to better
understand the role of this solvent in the model reaction and other
future applications, some physicochemical properties such as
density, refractive index, pH, viscosity and electrical conductivity as
function of temperature were studied.
150
120
90
60
30
0
Density
It is well known that the composition and the temperature of a
liquid notoriously affect density.
0
0.2
0.4
0.6
0.8
1
1.310
1.305
1.300
1.295
1.290
1.285
1.280
1.275
1.270
1.265
X urea
Figure 1. Phase diagram for sodium acetate trihydrate‐urea
mixtures.
The eutectic point found for the mixture was 33 °C with a molar
composition of 0.4:0.6 CH3COONa∙3H2O/CO(NH2)2, which is
different from the reported by Li and co‐workers.19 This depression
of the melting point might arise from the interaction between urea
molecules and acetate ions as shown by the crystallographic data
for the adduct [(CH3)3N+CH2CH2OH‐]2C2O42‐∙2(NH2)2CS, where a
hydrogen bonding between the oxalate anion and the thiourea has
been described.20 The thermogravimetric analysis (Figure 2) shows
that the DES loses 61.7 wt% in four consecutive steps. The first
three steps correspond to mass loss of 8.03 % (71 °C), 7.91 % (108
°C) and 6.69 % (131 °C), which is consistent with the release of the
three crystallization water molecules present in the acetate.
Decomposition of urea starts at 133 °C and ends at 214 °C, where
only sodium acetate anhydride remains. DSC and TGA analysis
allows concluding that the DES can be used as reaction media at
temperatures between 33 and 130 °C, where no decomposition of
its components is present.
30
40
50
60
70
80
90
t(°C)
Figure 3. Density (ρ) of sodium acetate trihydrate‐urea DES as a
function of temperature.
Density measurements for the CH3COONa∙3H2O/CO(NH2)2 DES
(Figure 3) were performed at temperatures ranging from 35 to 80
°C, and it was observed that this property decreases linearly with
temperature. The increase in molecules‐ions mobility in the DES by
changes in temperature has been attributed to molecular
rearrangements caused by the vibrations when the components
absorbed the energy given to the system.21 This increases the
solution molar volume which reduces density. In addition, the loose
of some water content during heating decreases the mass and also
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contribute to have lower density values. The variation of density
with temperature was modeled according to equation 1.
11
10
9
ρ(g/cm3) = a(t/oC) + b
(1)
where ρ is the density, t is the temperature, a and b are constants
(Table 1).
Refractive index
8
30
40
50
60
t(°C)
70
80
90
Refractive index (nD) of the DES was measured as a function of
temperature and is shown in Figure 4.
Figure 5. pH for sodium acetate trihydrate‐urea DES as a function of
temperature.
1.448
1.446
1.444
1.442
1.44
As shown in Figure 5, the increase of temperatures decreases the
pH in the DES showing values for the pH in the range of 10.07 to
8.45. The variation of pH with temperature was fitted by the
general second‐order polynomial equation
1.438
1.436
1.434
1.432
pH = a(t/oC)2 + b(t/oC) + c
(3)
30
40
50
60
70
80
90
t(°C)
where t is the temperature, a, b and c are unitless parameters
shown in Table 1.
Figure 4. Refractive index (nD) of sodium acetate trihydrate‐urea
DES as a function of temperature.
Table 1. Values of parameters a, b, c and correlation coefficient for
equations 1‐3.
The refractive index (nD) of the DES lies within the range of 1.446‐
1.430 for the temperature range of 35‐80 C and decreases with
o
increasing temperature. This behavior was the expected due to its
proportionality with the square root of electrical permittivity and
magnetic permeability which change nonlinearly.22 The relationship
between refractive index and temperature was fitted linearly
according with the general equation
Physical
properties
a
b
c
R2
ρ
‐7x10‐4
‐3x10‐4
‐5x10‐3
1.3293
1.4565
0.0147
0.9993
0.9963
0.9919
nD = a(t/oC) + b
(2)
nD
where nD is the refractive index, t is the temperature, a and b are
unitless parameters shown in Table 1.
pH
10.126
pH
Viscosity
pH is a physical property that may influence the selection of a
solvent for potential biochemical and industrial applications. The
relationship of the measured pH values for the DES at different
temperatures (35‐80 oC) is presented in Figure 5.
The viscosity (η) is defined as the internal friction measurement of a
moving fluid which describes the resistance of a substance to flow.
The viscosity strongly influences the ability of a liquid to transport
compounds within it, and therefore is directly related with the
conversion of reagents into products in a chemical reaction. The
viscosity of the DES was studied in the same range of temperatures
as the other physicochemical properties (Figure 6).
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As shown in Figure 7, the ionic conductivity of the DES increases
with temperature. This behavior may be explained by two factors:
first, the increased kinetic energy rise the frequency of collisions
between molecules which weakens the intermolecular forces,24 and
second, the high movement of the small charge carriers due to the
decreases in viscosity increase the ionic conductivity as described
by the Walden Rule.25 The temperature dependence of the
experimental conductivity was correlated using
4.0
3.5
3.0
2.5
2.0
1.5
0.0028 0.00285 0.0029 0.00295 0.003 0.00305 0.0031 0.00315 0.0032 0.00325 0.0033
t‐1/K‐1
Ln k = ln k0 ‐ (Ek/RT)
(5)
Where k0 is a constant and Ek is the activation energy of
conductivity. Values of k0 and Ek/R are shown in Table 2.
Figure 6. Viscosity change for sodium acetate trihydrate‐urea DES
as a function of temperature.
Table 2. Values found for η0, Eη/R, k0, Ek/R and correlation
coefficients for equations 4 and 5.
The viscosity of the DES is higher in comparison to other common
organic solvents, but has lower values compared to other DES
based on choline chloride and tetrabutylammonium bromide.5, 22, 23
DES viscosity reduces with an increase in temperature, and
although its graph is non‐linear (see supporting information), this
result is consistent with the reports for other DES. Heating will
increase the kinetic energy and as a result the attractive forces
between molecules and ions in the DES may weaken. In addition,
the water content and the size of the molecules might benefit the
fluidity due to smaller size species moves with diminished
resistance. The viscosity of the DES was modeled according with the
expression
Physical
η0
Eη/R
k0
Ek/R
R2
properties
η
3.58x10‐5
4229.8
0.9969
0.9938
k
1741.1
1569
Ln η = ln η0 + (Eη/RT)
(4)
Once the physicochemical properties of the sodium acetate
trihydrate‐urea DES were studied as function of temperature, the
DES was evaluated in the Biginelli reaction for the synthesis of
polyhydroquinoxaline derivatives. TGA analysis and the variation of
density and viscosity as function of temperature showed that the
sodium acetate trihydrate‐urea DES may be used at high
temperatures (under 130 oC) were the mobility of substrates is
favored and no decomposition of the components is present.
Therefore, dimedone (1) (1 mmol), 4‐chlorobenzaldehyde (2) (1
mmol) and urea (3) (1 mmol) were added to 2 g of the DES and the
reaction mixture was heated at 90 oC during 6 h. After reaction
completion (monitoring by thin layer chromatography) water was
added and the solid product was filtered and recrystallized from
ethanol. The structure of the obtained compound which was
where η0 is a constant, Eη is the activation energy of a viscous flow,
R is the gas constant, and T is the temperature in Kelvin. Values of
η0 and Eη/R are shown in Table 2.
Electrical conductivity
Electrical conductivity (k) is defined as the ability to conduct an
electric current. Conductivity of the DES was studied at different
temperatures (35‐80 oC) and it is illustrated in Figure 7.
1
elucidated by FT‐IR, H‐NMR, 13C‐NMR and elemental analysis (see
3.2
3.0
2.8
2.6
2.4
2.2
2.0
supporting information) indicates that the polyhydroquinoxaline
expected (4) was not synthesized, and instead, under the reaction
conditions the hexahydroxacridine‐1,8‐dione (5a) was obtained
(Scheme 1).
0.0028
0.0029
0.003
0.0031
t‐1/k‐1
0.0032
0.0033
Figure 7. Conductivity as a function of temperature for sodium
acetate trihydrate‐urea DES.
4 | J. Name., 2012, 00, 1‐3
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hydroxy intermediate,29 which could not be isolated from the
reaction mixture.
Cl
O
NH
R
O
O
OH
N
O
H
O
4
(
)
O
R
H
O
Sodium acetate trihydrate-urea
90 oC, 6h
O
O
H
O
1 mmol
or
+
H2N
NH2
1
(
)
Sodium acetate trihydrate-urea
60 oC, 2h
3
(
)
Cl
+
O
or
R
O
H
O
O
O
O
n
O
Cl
2 mmol
2
(
)
1 mmol, n=1, 2
O
N
H
5a
(
) 68%
Cl
OCH3
OCH3
Scheme 1. Unexpected one‐pot multicomponent synthesis of the
hexahydroxacridine‐1,8‐dione (5a).
H3CO
O
OCH3
O
OH
O
OH
OH
The unexpected synthesis of the hexahydroxacridine‐1,8‐dione (5a)
led us to hypothesize that the high temperature and the time of the
reaction promoted the decomposition of urea, yielding the
ammonia needed for the formation of (5a). Therefore the same
reaction was performed at 60 oC and after 2h a white solid labeled
O
H
O
O
H
O
O O
H
(6a), 84%
(6b), 80%
(6c), 86%
Br
N
O
O
1
as (6a) was obtained (Scheme 2). FT‐IR, H‐NMR, 13C‐NMR spectra
O
OH
O
OH
O
OH
and elemental analysis showed that the structure of (6a)
corresponds to
a
bis‐hydroxy compound26 (see supporting
information) which may be formed by the Michael addition of one
equivalent of dimedone to the Knoevenagel aduct of 4‐
chlorobenzaldehyde and a second equivalent of dimedone.27 This
result shows that the urea does not react under these conditions
and although heating was extended for 12h the formation of (5a)
did not take place.
O
H
O
O
H
O
O
H
O
(6f), 87%
(6d), 75%
(6e), 89%
S
O
OH
O
OH
O
OH
O
H
O
O
H
O
O
H
O
(6g), 78%
(6h), 72%
(6i), 83%
OH
OH
N
O
O
O
O
O
O
O
O
O
(6k), 75%
(6l), 72%
(6j), 69%
Scheme 3. Synthesis of bis‐hydroxy derivatives (6a‐6i) and
hexahydroxanthene‐1,8‐diones (6j‐6l).
In order to confirm that compound (6a) is an intermediate for the
obtention of (5a), this bis‐hydroxy derivative was added to the DES
and the mixture was heated to 100 oC during 6h obtaining the
hexahydroxacridine‐1,8‐dione (5a) in good yield (Scheme 2).
Scheme 2. Synthesis of the bis‐hydroxy derivative (6a) and the
hexahydroxacridine‐1,8‐dione (5a) in sodium acetate trihydrate‐
urea DES under different conditions.
The obtention of the bishydroxy derivative (6a) and its conversion
to the hexahydroxacridine‐1,8‐dione (5a) under the reaction
conditions here explored, indicates that the reaction may proceed
following one of the three possible mechanisms proposed for the
Biginelli reaction17, 30 (Scheme 4).
The same type of bis‐hydroxy derivatives were obtained in
moderate to good yields when the reactivity of different aldehydes
was studied under the same reaction conditions using 2 mmol of
dimedone (Scheme 3). Similar results were found by Azizi and co‐
workers using a choline chloride‐urea DES.28 Interestingly, the
hexahydroxanthene‐1,8‐diones (6j‐6l) were obtained when 2‐
pyridinecarboxaldehyde, 2,3‐dihydrofuran and 3,4‐dihydro‐2H‐
pyran were used. These compounds may be obtained by an
intramolecular cyclization‐dehydration of the corresponding bis‐
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Cl
the reaction and the hexahydroxacridine‐1,8‐dione (5a) would be
obtained from both (6a) and (10) (Scheme 5). Other possible
intermediates like (8) and (9) were not detected from the crude
reaction mixture by H‐NMR and after completion of reaction the
intermediates (6a) and (10) were not detected (TLC) when
Cl
O
O
O
O
O
OH
O
O
1
DES
-H2O
H
+
DES
Cl
O
O
H
O
compared with authentic samples.
(1)
(2)
(7)
(6a)
Knoevenagel route
-H2O
DES
O
O
Cl
O
DES
-H2O
NH2
O
+
H2N
NH2
Cl
O
N
H
O
OH
DES
(8)
(1)
(3)
O
O
O
H
O
Enamine route
Cl
O
N
(6a)
O
N
H
NH2
DES
-H2O
O
H
O
O
DES
+
(5a)
H2N
NH2
Cl
Cl
Cl
N
H
(9)
(2)
(3)
Imine route
(5a)
O
O
Scheme 4. Possible synthetic routes to obtain (5a) by the Biginelli
DES
reaction.
O
(10)
As shown in Scheme 4, only the Knoevenagel route will promote
the formation of the bis‐hydroxy derivative (6a). The obtention of
(6a) may be attributed to the high reactivity of the 2‐
Scheme 5. Bis‐hydroxy derivative (6a) and hexahydroxanthene‐1,8‐
dione (10) as intermediates for the synthesis of the
arylidenedimedone intermediate (7) which preferably reacts with hexahydroacridine‐1,8‐dione (5a).
dimedone affording (6a)31 and its further reaction with ammonia
may yield (5a) (Scheme 4). This is consistent with one of the
proposed mechanisms for the Hantzsch dihydropyridine synthesis.32
All these results show that although the TGA indicates that the DES
is stable below 130 C, the eutectic mixture decomposes at lower
o
temperature yielding ammonia under the reaction conditions here
employed, and affording the hexahydroxacridine‐1,8‐dione (5a).
This finding is in agreement with the recent report of Simeonov and
Afonso34 which shows the obtention of dihydropyridines via
Hantzsch reaction in sorbitol‐urea DES. In this study the
decomposition of urea (source of ammonia for the reaction) occur
Intrigued by the results, the reaction was studied by 1H‐NMR in
DMSO‐6d (Figure 8).
o
below 100 C and is enhanced in diols based DES by the formation
of carbonates.
Hexahydroxacridine‐1,8‐diones
are
extensively
studied
nitrogenated heterocycles with biological activity as SITR1
inhibitors,35 DNA intercalator,36 calcium,37 and potassium38 channel
modulators, antimicrobial39 and antifungal agents,40 and carbonic
anhydrase inhibitors.41 In addition, the interesting photophysical
and photochemical properties of several acridinediones have
promoted their use as laser dyes,42 initiators in
photopolymerization,43 chemosensors,44 fluorescent probes for
monitoring of polymerization processes,45 in the preparation of
blue light‐emitting devises,46 and dye‐sensitized solar cells.47
In spite of the different synthetic methodologies reported for the
synthesis of hexahydroxacridine‐1,8‐diones,48 their known
biological activity and photophysical properties have inspired the
design of new synthetic strategies to obtain this versatile
heterocyclic compound. Motivated for the few reports concerning
the synthesis of dihydropyridine derivatives and related compounds
under Biginelli conditions,49 the unexpected formation of (5a) led us
to synthesize a series of hexahydroxacridine‐1,8‐diones starting
from dimedone and different aromatic aldehydes (Scheme 6).
Figure 8. Crude 1H NMR spectra for the reaction forming 5a.
After 4h the spectrum showed characteristic signals for the
methinic protons belonging to both the bis‐hydroxy intermediate
(6a) at 5.97 ppm (singlet), and the hexahydroacridine‐1,8‐dione (5a)
at 4.79 ppm (singlet). Interestingly, a signal (singlet) at 4.50 ppm
was detectable and assigned to the methinic proton of the
hexahydroxanthene‐1,8‐dione (10)33 which suggests that this
compound is formed from the bis‐hydroxy derivative (6a) during
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General information
All the chemicals and solvents were purchased from commercial
suppliers and used without further purification. Melting points,
reported without correction, were measured using a Stuart SMP10
apparatus. The FT‐IR spectra were obtained with a Shimadzu IR
prestige 21 spectrophotometer (Columbia, MD, USA). 1H 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. The peak patterns are indicated as follows: s,
singlet; d, doublet; t, triplet; m, multiplet; q, quartet. The coupling
constants, J, are reported in Hertz (Hz). Elemental analyses were
performed on a Thermo Scientific Flash 2000 CHNS/O analyser and
their results were found to be in agreement with the calculated
values. For the DSC analysis, 11 samples of CH3COONa.
3H2O/CO(NH2)2 of different molar composition (1/0; 0.8/0.2;
0.6/0.4; 0.5/0.5; 0.4/0.6; 0.3/0.7; 0.2/0.8; 0.15/0.85; 0.1/0.9;
0.05/0.95 and 0/1) were formed by heating and stirring between 35
and 120oC until a liquid was formed. A portion of each warm
mixture liquid was loaded into a hermetically sealed aluminum pan.
The sample was then cooled to ‐60oC and then heated to 145oC at
1oC/min under a nitrogen atmosphere on a differential scanning
calorimeter DSC 1 STARe System (Mettler Toledo). TGA analysis for
the DES was run in nitrogen (40 mL/min) atmosphere using a TGA 1
STARe System (Mettler Toledo). Programmed heating rate was
2oC/min starting from 25oC until 240oC. The density of the DES was
measured using a liquid densitometer (Anton Paar DMA4500M). An
Abbe type refractometer (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 viscosity was determined
using a Oswalt (Cannon‐Fenske Routine Type) viscometer. 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.
Scheme 6. Synthesis of hexahydroxacridine‐1,8‐diones (5a‐5l).
All hexahydroxacridine‐1,8‐diones (5a‐5l) were obtained in
General procedure for the synthesis of bis‐hydroxy derivatives (6a‐
moderate to good yields after purification by recrystallization from 6i) and hexahydroxanthene‐1,8‐diones (6j‐6l).
ethanol. The masked aldehydes dihydrofuran and dihydropyran also
1.5g of sodium acetate trihydrate‐urea DES (0.4 : 0.6) was heated to
35 C to obtain a clear melt. To this melt a mixture of dimedone
reacted under the reaction conditions employed here to give the
corresponding hexahydroxacridine‐1,8‐diones (5k) and (5l) which to
the best of our knowledge have not been reported before. As
mention previously, when these masked aldehydes and 2‐
pyridinecarboxaldehyde were used in the reaction at 60oC the bis‐
hydroxy derivatives were not obtained and instead of this, the
xanthenes (6j‐6l) were formed. Therefore the synthesis of
compounds (5j‐5l) also supports the fact that these
hexahydroxacridine‐1,8‐diones are formed from the reaction of (6j‐
6l) with ammonia, which was further confirmed when these
xanthenes were heated in the DES for 6h. Similar results have been
reported recently.50
o
(2.00 mmol) and aromatic aldehydes (1.00 mmol) was added and
o
the reaction was stirred at 60 C for 2h. After completion of the
reaction (monitored by TLC), the reaction mixture was quenched by
adding water while still hot, cooled to room temperature and the
crude solid was filtered, washed with water (3 x 5 mL) and
recrystallized from ethanol to afford the pure product.
2,2'‐((4‐Chlorophenyl)methylene)bis(3‐hydroxy‐5,5‐
dimethylcyclohex‐2‐enone) (6a). White solid, mp: 145 ‐ 147 °C, IR
ν
max/cm‐1: 2957 (CH), 1581 (C=O), 1491 (C=C), 1374 (HCH). 1H‐NMR
(400 MHz, CDCl3): δ (ppm) 11.87 (s, 1H, OH), 7.23 (d, J = 8.5 Hz, 2H,
H‐Ar), 7.01 (d, J = 8.0 Hz, 2H, H‐Ar), 5.47 (s, 1H,CH), 2.49 ‐ 2.28 (m,
Experimental
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Journal Name
8H, 4CH2), 1.22 (s, 6H, 2CH3), 1.10 (s, 6H, 2CH3). 13C‐NMR (100 MHz,
CDCl3): δ (ppm) 190.7, 189.5, 136.9, 131.7, 128.5, 128.4, 115.5,
47.2, 46.6, 32.58, 31.6, 29.7, 27.6. Anal. calcd for C23H27ClO4 : C,
68.56; H, 6.75; found: C, 68.84; H, 6.76.
Ar), 7.11 (d, J = 8.3 Hz, 2H, H‐Ar), 5.56 (s, 1H, CH), 2.51 ‐ 2.29 (m, 8H,
4CH2), 1.25 (s, 6H, 2CH3), 1.11 (s, 6H, 2CH3). 13C NMR (100 MHz,
CDCl3) δ 190.5, 189.5, 138.2, 128.3, 126.9, 125.9, 115.7, 47.2, 46.6,
32.8, 31.5, 29.7, 27.5. Anal. calcd for C23H28O4 : C, 74.97; H, 7.66;
found: C, 74.63; H, 7.55.
2,2'‐((4‐Methoxyphenyl)methylene)bis(3‐hydroxy‐5,5‐
dimethylcyclohex‐2‐enone) (6b). White solid, mp: 143 ‐ 145 °C, IR 2,2'‐(Thiophen‐2‐ylmethylene)bis(3‐hydroxy‐5,5‐
ν
max/cm‐1: 2960 (CH), 1599 (C=O), 1509 (C=C), 1377 (HCH). 1H‐NMR dimethylcyclohex‐2‐enone) (6h). White solid, mp: 155 ‐ 157 °C, IR
1
(400 MHz, CDCl3): δ (ppm) 11.91 (s, 1H, OH), 6.99 (d, J = 8.1 Hz, 2H,
ν
max/cm‐1: 2967 (CH), 1581 (C=O), 1447 (C=C), 1376 (HCH). H NMR
H‐Ar), 6.81 (d, J = 8.8 Hz, 2H, H‐Ar), 5.48 (s, 1H, CH), 3.77 (s, 3H, (400 MHz, CDCl3) δ 12.32 (s, 1H, OH), 7.10 (s, 1H, H‐Ar), 6.92 ‐ 6.80
OCH3), 2.39 (m, 8H, 4CH2), 1.22 (s, 6H, 2CH3), 1.10 (s, 6H, 2CH3). 13C‐ (m, 1H, H‐Ar), 6.67 ‐ 6.57 (m, 1H, H‐Ar), 5.63 (s, 1H, CH), 2.44 – 2.28
NMR (100 MHz, CDCl3): δ (ppm) 190.5, 189.5, 157.8, 130.0, 127.9, (m, 8H, 4CH2), 1.22 (s, 6H, 2CH3), 1.10 (s, 6H, 2CH3). 13C NMR (100
115.9, 113.8, 55.3, 47.2, 46.6, 32.2, 31.54, 29.8, 27.5. Anal. calcd for MHz, CDCl3) δ 190.0, 189.6, 143.8, 126.5, 124.7, 123.6, 116.1, 47.1,
C24H30O5 : C, 72.34; H, 7.59; found: C, 72.03; H, 7.41.
2,2'‐((3,4,5‐Trimethoxyphenyl)methylene)bis(3‐hydroxy‐5,5‐
46.3, 31.3, 30.5, 30.1, 26.9. Anal. calcd for C21H26O4S : C, 67.35; H,
7.00; S, 8.56; found: C, 67.21; H, 7.08; S, 8.54.
dimethylcyclohex‐2‐enone) (6c). White solid, mp: 190 ‐ 191 °C, IR 2,2'‐Methylenebis(3‐hydroxy‐5,5‐dimethylcyclohex‐2‐enone) (6i).
max/cm‐1: 2954 (CH), 1582 (C=O), 1508 (C=C), 1374 (HCH). 1H‐NMR White solid, mp: 192 ‐ 194 °C, IR νmax/cm‐1: 2968 (CH), 1608 (C=O),
ν
(400 MHz, CDCl3): δ (ppm) 12.02 (s, 1H, OH), 6.34 (s, 2H, H‐Ar), 5.49 1579 (C=C), 1379 (HCH). 1H NMR (400 MHz, CDCl3) δ 11.53 (s, 1H,
(s, 1H, CH), 3.81 (s, 3H, OCH3), 3.75 (s, 6H, 2OCH3), 2.46 – 2.32 (m, OH), 3.15 (s, 2H, CH2), 2.29 (s, 4H, 2CH2), 2.28 (s, 4H, 2CH2), 1.05 (s,
8H, 4CH2), 1.24 (s, 6H, 2CH3), 1.12 (s, 6H, 2CH3). 13C‐NMR (100 MHz, 12H, 4CH3). 13C NMR (100 MHz, CDCl3) δ 189.6, 113.6, 46.1, 31.9,
CDCl3): δ (ppm) 190.5, 189.4, 153.0, 133.9, 115.7, 104.3, 61.0, 56.0, 29.6, 27.2, 16.0. Anal. calcd for C17H24O4 : C, 69.84; H, 8.27; found:
47.2, 46.5, 32.9, 31.3, 30.2, 27.0. Anal. calcd for C26H34O7 : C, 68.10; C, 69.61; H, 8.21.
H, 7.47; found: C, 67.94; H, 7.41.
3,3,6,6‐Tetramethyl‐9‐(pyridin‐2‐yl)‐3,4,5,6,7,9‐hexahydro‐1H‐
xanthene‐1,8(2H)‐dione (6j). Yellow solid, mp: 175 ‐ 178 °C, IR
ν
2,2'‐((4‐(Dimethylamino)phenyl)methylene)bis(3‐hydroxy‐5,5‐
dimethylcyclohex‐2‐enone) (6d). Yellow solid, mp: 198 ‐ 200 °C, IR
max/cm‐1: 2932(CH), 1657(C=O), 1625(C=C). 1H NMR (400 MHz,
ν
max/cm‐1: 2961 (CH), 1599 (C=O), 1522 (C=C), 1370 (HCH). 1H‐NMR CDCl3) δ 8.38 (d, J = 4.1, 1H, H‐Ar), 7.62 – 7.57 (m, 2H, H‐Ar), 7.01
(400 MHz, CDCl3): δ (ppm) 11.92 (s, 1H, OH), 6.97 (d, J = 8.2 Hz, 2H, (m, 1H, H‐Ar), 4.86 (s, 1H, CH), 2.54 (d, J = 17.9 Hz, 2H, CH2), 2.45 (d,
H‐Ar), 6.74 (s, 2H, H‐Ar), 5.47 (s, 1H, CH), 2.92 (s, 6H, N(CH3)2), 2.47 J = 17.5 Hz, 2H, CH2), 2.23 (d, J = 16.2 Hz, 2H, CH2), 2.16 (d, J = 16.2
– 2.26 (m, 8H, 4CH2), 1.22 (s, 6H, 2CH3), 1.10 (s, 6H, 2CH3). 13C NMR Hz, 2H, CH2), 1.09 (s, 6H, 2CH3), 1.00 (s, 6H, 2CH3). 13C‐NMR (100
(100 MHz, CDCl3) δ 190.4, 189.4, 127.7, 116.0, 113.2, 46.9, 41.3, MHz, CDCl3): δ(ppm) 197.1, 163.6, 161.7, 148.9, 135.9, 125.3, 121.6,
32.0, 31.5, 29.8, 27.4. Anal. calcd for C25H33NO4 : C, 72.96; H, 8.08; 114.3, 50.8, 41.0, 34.5, 32.4, 29.4, 27.3. Anal. calcd for C22H25NO3: C,
N, 3.40; found: C, 72.85; H, 8.03; N, 3.34.
75.19; H, 7.17; N, 3.99; found: C, 74.71; H, 6.90; N, 3.61.
2,2'‐(Benzo[d][1,3]dioxol‐5‐ylmethylene)bis(3‐hydroxy‐5,5‐
9‐(3‐Hydroxypropyl)‐3,3,6,6‐tetramethyl‐3,4,5,6,7,9‐hexahydro‐
dimethylcyclohex‐2‐enone) (6e). White solid, mp: 177 ‐ 180 °C, IR 1H‐xanthene‐1,8(2H)‐dione (6k). White solid, mp: 129 ‐ 130 °C; IR
1
ν
max/cm‐1: 2960 (CH), 1584 (C=O), 1520 (C=C), 1373 (HCH). H NMR
ν
max/cm‐1: 3428 (OH), 1651 (C=O), 1616 (C=C). 1H‐NMR (400 MHz,
(400 MHz, CDCl3) δ 11.94 (s, 1H, OH), 6.70 (d, J = 8.1 Hz, 1H, H‐Ar), CDCl3): δ(ppm) 3.80 (t, J = 4.5, 1H, CH), 3.60 (t, J = 6.6, 2H, CH2), 2.38
6.57 (s, 1H, H‐Ar), 6.54 (dd, J = 8.2, 1.2 Hz, 1H, H‐Ar), 5.91 (s, 2H, (s, 4H, 2CH2), 2.30 (d, J = 16.2, 2H, CH2), 2.25 (d, J = 16.2, 2H, CH2),
OCH2O), 5.45 (s, 1H, CH), 2.48 ‐ 2.27 (m, 8H, 4CH2), 1.21 (s, 6H, 1.90 (s, 1H, OH), 1.58 – 1.53 (m, 2H, CH2), 1.41 – 1.34 (m, 2H, CH2),
2CH3), 1.09 (s, 6H, 2CH3). 13C NMR (100 MHz, CDCl3) δ 190.4, 189.5 , 1.10 (s, 12H, 4CH3). 13C‐NMR (100 MHz, CDCl3): δ(ppm) 197.4,
147.8, 145.7, 132.0, 119.8, 115.8, 108.0, 107.7, 101.0, 47.2, 46.5, 164.1, 115.0, 62.8, 51.0, 41.0, 32.1, 30.6, 29.5, 28.9, 27.5, 24.7.
32.6, 31.5, 29.7, 27.6. Anal. calcd for C24H28O6 : C, 69.88; H, 6.84; Anal. calcd for C20H28O4: C, 72.26; H, 8.49; found: C, 72.61; H, 8.50.
found: C, 69.44; H, 6.64.
2,2'‐((4‐Bromophenyl)methylene)bis(3‐hydroxy‐5,5‐
9‐(4‐Hydroxybutyl)‐3,3,6,6‐tetramethyl‐3,4,5,6,7,9‐hexahydro‐1H‐
xanthene‐1,8(2H)‐dione (6l). White solid, mp: 125 ‐ 127 °C; IR
dimethylcyclohex‐2‐enone) (6f). White solid, mp: 174 ‐ 176 °C, IR
ν
max/cm‐1: 3390 (OH), 1664 (C=O),. 1643 (C=O), 1616 (C=C). 1H‐NMR
1
ν
max/cm‐1: 2957 (CH), 1583 (C=O), 1486 (C=C), 1371 (HCH). H NMR (400 MHz, CDCl3): δ(ppm) 3.78 (t, J = 4.5, 1H, CH), 3.55 (t, J = 6.5,
(400 MHz, CDCl3) δ 11.87 (s, 1H, OH), 7.38 (d, J = 8.5 Hz, 2H, H‐Ar), 2H, CH2), 2.37 (s, 4H, 2CH2), 2.30 (d, J = 16.2, 2H, CH2), 2.24 (d, J =
6.96 (d, J = 7.8 Hz, 2H, H‐Ar), 5.45 (s, 1H, CH), 2.49 ‐ 2.28 (m, 8H, 16.2, 2H, CH2), 1.60 (bs, 1H, OH), 1.55 (m, 2H, CH2), 1.57 ‐ 1.46 (m,
4CH2), 1.21 (s, 6H, 2CH3), 1.10 (s, 6H, 2CH3). 13C NMR (100 MHz, 2H, CH2), 1.18 ‐ 1.12 (m, 2H, CH2), 1.10 (s, 12H, 4CH3). 13C‐NMR (100
CDCl3) δ 190.7, 189.5, 137.4, 131.4, 128.7, 119.7, 115.4, 47.1, 46.5, MHz, CDCl3): δ(ppm) 197.2, 164.0, 114.9, 62.7, 50.9, 40.9, 33.6,
32.6, 31.5, 29.7, 27.5. Anal. calcd for C23H27BrO4 : C, 61.75; H, 6.08; 32.6, 32.0, 29.4, 27.3, 25.2, 21.5. Anal. calcd for C21H30O4: C, 72.80;
found: C, 61.33; H, 6.08.
H, 8.73; found: C, 72.53; H, 8.68.
2,2'‐(Phenylmethylene)bis(3‐hydroxy‐5,5‐dimethylcyclohex‐2‐
enone) (6g). White solid, mp: 192 ‐ 194 °C, IR νmax/cm‐1: 2961 (CH), General procedure for the synthesis of hexahydroxacridine‐1,8‐
1
1591 (C=O), 1491 (C=C), 1372 (HCH). H NMR (400 MHz, CDCl3) δ diones (5a‐5l).
11.92 (s, 1H, OH), 7.32 ‐ 7.26 (m, 2H, H‐Ar), 7.18 (t, J = 7.3 Hz, 1H, H‐
8 | J. Name., 2012, 00, 1‐3
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1.5g of sodium acetate trihydrate‐urea DES (0.4 : 0.6) was heated to 4.99 (s, 1H, CH), 2.39 ‐ 2.15 (m, 8H, 4CH2), 1.08 (s, 6H, 2CH3), 0.99 (s,
o
35 C to obtain a clear melt. To this melt a mixture of dimedone 6H, 2CH3). 13C‐NMR (100 MHz, CDCl3): δ(ppm) 195.8, 148.1, 147.4,
(2.00 mmol) and aromatic aldehydes (1.00 mmol) was added and 145.7, 141.0, 121.3, 113.9, 109.1, 107.9, 100.8, 50.9, 41.5, 33.5,
o
the reaction was stirred at 100 C for 8h. After completion of the 32.8, 29.6, 27.4. Anal. calcd for C24H27NO4: C, 73.26; H, 6.92; N, 3.56,
reaction (monitored by TLC), the reaction mixture was quenched by found: C, 73.24; H, 6.92; N, 3.58.
adding water while still hot, cooled to room temperature and the 9‐(4‐Bromophenyl)‐3,3,6,6‐tetramethyl‐3,4,6,7,9,10‐
crude solid was filtered, washed with water (3 x 5 mL) and hexahydroacridine‐1,8(2H,5H)‐dione (5f). Yellow solid, mp 299 ‐
1
recrystallized from ethanol to afford the pure product.
300 °C, IR νmax/cm‐1: 3277 (NH), 1645 (C=O), 1608 (C=C). H‐NMR
(400 MHz, CDCl3): δ(ppm) 7.31 (d, J = 8.4 Hz, 2H, H‐Ar), 7.21 (d, J =
8.5 Hz, 2H, H‐Ar), 7.00 (s, 1H, NH), 5.03 (s, 1H, CH), 2.34 (d, J = 16.7
9‐(4‐Chlorophenyl)‐3,3,6,6‐tetramethyl‐3,4,6,7,9,10‐
hexahydroacridine‐1,8(2H,5H)‐dione (5a). Yellow solid, mp: 298 ‐ Hz, 2H, CH2), 2.27 – 2.20 (m, 4H, 2CH2), 2.15 (d, J = 16.3 Hz, 2H,
1
300 °C, IR νmax/cm‐1: 3278 (NH), 1649 (C=O), 1608 (C=C). H‐NMR CH2), 1.08 (s, 6H, 2CH3), 0.96 (s, 6H, 2CH3). 13C‐NMR (100 MHz,
(400 MHz, CDCl3): δ(ppm) 7.35 (s, 1H, NH), 7.28 (d, J = 7.9 Hz, 2H, H‐ CDCl3): δ(ppm) 195.7, 148.6, 145.7, 131.2, 130.0, 120.0, 113.3, 50.8,
Ar), 7.15 (d, J = 7.9 Hz, 2H, H‐Ar), 5.05 (s, 1H, CH), 2.33 (d, J = 16.3 41.2, 33.6, 32.8, 29.6, 27.3. Anal. calcd for C23H26BrNO2: C, 64.49; H,
Hz, 2H, CH2), 2.27 – 2.21 (m, 4H, 2CH2), 2.15 (d, J = 16.3 Hz, 2H, 6.12; N, 3.27, found: C, 64.12; H, 6.11; N, 3.24.
CH2), 1.07 (s, 6H, 2CH3), 0.95 (s, 6H, 2CH3). 13C‐NMR (100 MHz, 3,3,6,6‐Tetramethyl‐9‐phenyl‐3,4,6,7,9,10‐hexahydroacridine‐
CDCl3): δ(ppm) 195.8, 148.8, 145.2, 131.7, 129.6, 128.2, 113.3, 50.8, 1,8(2H,5H)‐dione (5g). Yellow solid, mp: 191 ‐ 193 °C, IR νmax/cm‐1:
41.1, 33.5, 32.8, 29.7, 27.2 Anal. calcd for C23H26ClNO2: C, 71.96; H, 3281 (NH), 1638 (C=O), 1605 (C=C). 1H‐NMR (400 MHz, CDCl3):
6.83; N, 3.65; found: C, 71.99; H, 6.81; N, 3.63.
9‐(4‐Methoxyphenyl)‐3,3,6,6‐tetramethyl‐3,4,6,7,9,10‐
δ(ppm) 7.59 (s, 1H, NH), 7.33 (d, J = 7.5 Hz, 2H, H‐Ar), 7.18 (t, J = 7.3
Hz, 2H, H‐Ar), 7.06 (t, J = 7.1 Hz, 1H, H‐Ar), 5.09 (s, 1H, CH), 2.32 (d, J
hexahydroacridine‐1,8(2H,5H)‐dione (5b). Yellow solid, mp: 270 ‐ = 16.9 Hz, 2H, CH2), 2.24 (d, J = 16.8 Hz, 4H, 2CH2), 2.15 (d, J = 16.3
1
273 °C, IR νmax/cm‐1: 3275 (NH), 1673 (C=O), 1604 (C=C). H‐NMR Hz, 2H, CH2), 1.07 (s, 6H, 2CH3), 0.95 (s, 6H, 2CH3). 13C‐NMR (100
(400 MHz, CDCl3): δ(ppm) 7.93 (s, 1H, NH), 7.26 (s, 2H, H‐Ar), 6.74 MHz, CDCl3): δ(ppm) 196.0, 149.2, 146.7, 128.2, 128.1, 126.1, 113.5,
(s, 2H, H‐Ar), 5.06 (s, 1H, CH), 3.69 (s, 3H, OCH3), 2.26 ‐ 2.14 (m, 8H, 51.0, 40.9, 33.8, 32.7, 29.7, 27.2. Anal. calcd for C23H27NO2: C, 79.05;
4CH2), 1.08 (s, 6H, 2CH3), 0.97 (s, 6H, 2CH3). 13C‐NMR (100 MHz, H, 7.79; N, 4.01, found: C, 78.85; H, 7.73; N, 3.84.
CDCl3): δ(ppm) 196.2, 157.8, 149.1, 139.3, 129.1, 113.5, 113.4, 55.1, 3,3,6,6‐Tetramethyl‐9‐(thiophen‐2‐yl)‐3,4,6,7,9,10‐
51.0, 40.8, 32.9, 32.7, 29.7, 27.2. Anal. calcd for C24H29NO3: C, 75.96; hexahydroacridine‐1,8(2H,5H)‐dione (5h). White solid, mp: >300
1
H, 7.70; N, 3.69; found: C, 75.97; H, 7.63; N, 3.87.
°C, IR νmax/cm‐1: 3277 (NH), 1638 (C=O), 1605 (C=C). H‐NMR (400
3,3,6,6‐Tetramethyl‐9‐(3,4,5‐trimethoxyphenyl)‐3,4,6,7,9,10‐
MHz, DMSO‐d6): δ(ppm) 9.43 (s, 1H, NH), 7.13 (d, J = 4.9 Hz, 1H, H‐
hexahydroacridine‐1,8(2H,5H)‐dione (5c). Yellow solid, mp: 258 ‐ Ar), 6.79 (t, J = 4.10 Hz 1H, H‐Ar), 6.65 (d, J = 2.6 Hz, 1H, H‐Ar), 5.14
1
261 °C, IR νmax/cm‐1: 3225 (NH), 1591 (C=O), 1604 (C=C). H‐NMR (s, 1H, CH), 2.44 (d, J = 17.2 Hz, 2H, CH2), 2.32 (d, J = 17.2 Hz, 2H,
(400 MHz, DMSO‐d6): δ(ppm) 9.29 (s, 1H, NH), 6.42 (s, 2H, H‐Ar), CH2), 2.21 (d, J = 16.1 Hz, 2H, CH2), 2.07 (d, J = 16.1 Hz, 2H, CH2),
4.79 (s, 1H, CH), 3.65 (s, 6H, 2OCH3), 3.57 (s, 3H, OCH3), 2.45 (d, J = 1.02 (s, 6H, 2CH3), 0.94 (s, 6H, 2CH3). 13C‐NMR (100 MHz, DMSO‐d6):
17.0 Hz, 2H, CH2), 2.33 (d, J = 17.1 Hz, 2H, CH2), 2.19 (d, J = 16.1 Hz, δ(ppm) 194.3, 151.0, 149.6, 126.2, 123.0, 122.8, 110.9, 50.2, 39.5,
2H, CH2), 2.03 (d, J = 16.1 Hz, 2H, CH2), 1.02 (s, 6H, 2CH3), 0.91 (s, 32.1, 29.2, 27.3, 26.5. Anal. calcd for C21H25NO2S: C, 70.95; H, 7.09;
6H, 2CH3). 13C‐NMR (100 MHz, DMSO‐d6): δ(ppm) 194.5, 152.2, N, 3.94; S, 9.02, found: C, 70.72; H, 7.10; N, 4.22; S, 9.11.
149.4, 142.8, 135.5, 111.2, 104.9, 59.9, 55.6, 50.3, 32.6, 32.1, 29.1, 3,3,6,6‐Tetramethyl‐3,4,6,7,9,10‐hexahydroacridine‐1,8(2H,5H)‐
26.4. Anal. calcd for C26H33NO5: C, 71.05; H, 7.57; N, 3.19, found: C, dione (5i). Light green solid, mp: 150 ‐ 152 °C, IR νmax/cm‐1: cm‐1:
1
70.81; H, 7.64; N, 3.06.
9‐(4‐(Dimethylamino)phenyl)‐3,3,6,6‐tetramethyl‐3,4,6,7,9,10‐
3220 (NH), 1691 (C=O), 1587 (C=C). H‐NMR (400 MHz, DMSO‐d6):
δ(ppm) 8.86 (s, 1H, NH), 2.82 (s, 2H, CH2), 2.24 (s, 4H, 2CH2), 2.13 (s,
hexahydroacridine‐1,8(2H,5H)‐dione (5d). Yellow solid, mp: 264 ‐ 4H, 2CH2), 0.99 (s, 12H, 4CH3). ). 13C‐NMR (100 MHz, DMSO‐d6):
266 °C, IR νmax/cm‐1: 3277 (NH), 1647 (C=O), 1603 (C=C). H‐NMR δ(ppm) 194.9, 150.2, 107.2, 50.0, 39.6, 32.0, 27.9, 18.4. Anal. calcd
1
(400 MHz, CDCl3): δ(ppm) 7.67 (s, 1H, NH), 7.18 (d, J = 8.4 Hz, 2H, H‐ for C17H23NO2: C, 74.69; H, 8.48; N, 5.12, found: C, 74.60; H, 8.34; N,
Ar), 6.57 (d, J = 8.1 Hz, 2H, H‐Ar), 4.99 (s, 1H, CH), 2.81 (s, 6H, 5.39.
N(CH3)2), 2.28 ‐ 2.09 (m, 8H, 4CH2), 1.05 (s, 6H, 2CH3), 0.95 (s, 6H, 3,3,6,6‐Tetramethyl‐9‐(pyridin‐2‐yl)‐3,4,6,7,9,10‐
2CH3). 13C‐NMR (100 MHz, CDCl3): δ(ppm) 196.2, 149.0, 148.7, hexahydroacridine‐1,8(2H,5H)‐dione (5j). Red solid, mp >300 °C, IR
1
128.8, 113.8, 113.7, 112.5, 51.1, 40.8, 40.8, 32.7, 32.6, 29.7, 27.4.
ν
max/cm‐1: 3281 (NH), 1624 (C=O), 1605 (C=C). H‐NMR (400 MHz,
Anal. calcd for C25H32N2O2: C, 76.49; H, 8.22; N, 7.14, found: C, CDCl3): δ(ppm) 8.39 (d, J = 4.1 Hz, 1H, H‐Ar), 7.59 (d, J = 7.6 Hz, 1H,
76.07; H, 8.24; N, 7.12.
9‐(Benzo[d][1,3]dioxol‐5‐yl)‐3,3,6,6‐tetramethyl‐3,4,6,7,9,10‐
H‐Ar), 7.53 (t, J = 7.3 Hz, 1H, H‐Ar), 7.01 ‐ 6.95 (m, 1H, H‐Ar), 6.91 (s,
1H, NH), 5.21 (s, 1H, CH), 2.38 ‐ 2.11 (m, 8H, 2CH2), 1.07 (s, 6H,
hexahydroacridine‐1,8(2H,5H)‐dione (5e). Yellow solid, mp >300 2CH3), 0.98 (s, 6H, 2CH3). 13C‐NMR (100 MHz, CDCl3): δ(ppm) 195.8,
°C, IR νmax/cm‐1: 3271 (NH), 1643 (C=O), 1605 (C=C). 1H‐NMR (400 163.8, 149.0, 148.7, 135.9, 124.5, 121.3, 112.5, 50.9, 41.3, 36.7,
MHz, CDCl3): δ(ppm) 6.84 (s, 1H, H‐Ar), 6.78 (d, J = 7.9 Hz, 1H, H‐Ar), 32.9, 29.6, 27.2. Anal. calcd for C22H26N2O2: C, 75.40; H, 7.48; N,
6.73 (s, 1H, NH), 6.63 (d, J = 7.9 Hz, 1H, H‐Ar), 5.83 (s, 2H, OCH2O), 7.99, found: C, 75.17; H, 7.44; N, 8.09.
This journal is © The Royal Society of Chemistry 20xx
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9‐(3‐Hydroxypropyl)‐3,3,6,6‐tetramethyl‐3,4,6,7,9,10‐
Acknowledgements
hexahydroacridine‐1,8(2H,5H)‐dione (5k). Yellow solid, mp: 282 ‐
Authors wish to thank professor Coralia Osorio and Oscar
Rodriguez for providing research facilities and valuable
discussion and suggestions. We would also like to thank the
Universidad Nacional de Colombia for financial support.
285 °C, IR νmax/cm‐1: 3261 (NH), 1616 (C=O), 1599 (C=C). H‐NMR
1
(400 MHz, DMSO‐d6): δ(ppm) 9.03 (s, 1H, NH), 4.25 (m, 1H, CH),
3.80 (s, 1H, OH), 3.22 (m, 2H, OCH2), 2.36 (d, J = 17.1 Hz, 2H, CH2),
2.23 (d, J = 17.2 Hz, 2H, CH2), 2.17 (d, J = 16.0 Hz, 2H, CH2), 2.07 (d, J
= 16.0 Hz, 2H, CH2), 1.21 (s, 4H, 2CH2), 1.01 (s, 12H, 4CH3). 13C‐NMR
(100 MHz, DMSO‐d6): δ(ppm) 194.7, 150.4, 111.5, 61.3, 50.4, 31.9,
31.3 29.3, 28.7, 26.5, 26.0. Anal. calcd for C20H29NO3: C, 72.47; H,
8.82; N, 4,23, found: C, 72.60; H, 8.84; N, 4.14.
Notes and references
‡ Footnotes relating to the main text should appear here. These
might include comments relevant to but not central to the
matter under discussion, limited experimental and spectral data,
9‐(4‐Hydroxybutyl)‐3,3,6,6‐tetramethyl‐3,4,6,7,9,10‐
and crystallographic data.
§
§§
etc.
hexahydroacridine‐1,8(2H,5H)‐dione (5l). Yellow solid, mp: 246 ‐
248 °C, IR νmax/cm‐1: 3283 (NH), 1618 (C=O), 1608 (C=C). H‐NMR
1
(400 MHz, DMSO‐d6): δ(ppm) 9.01 (s, 1H, NH), 4.22 (t, J = 4.5 Hz,
1H, CH), 3.79 (s, 1H, OH), 3.29 ‐ 3.22 (m, 2H, OCH2), 2.35 (d, J = 17.0
Hz, 2H), 2.23 (d, J = 17.2 Hz, 2H), 2.17 (d, J = 16.0 Hz, 2H), 2,07 (d, J =
16.0 Hz, 2H), 1.29 – 1.20 (m, 4H, 2CH2), 1.08 – 1.01 (m, 14H, 4CH3,
CH2). 13C‐NMR (100 MHz, DMSO‐d6): δ(ppm) 194.7, 150.3, 111.6,
60.8, 50.4, 34.9, 33.0, 32.0, 29.3, 26.4, 26.2, 21.2. Anal. calcd for
C21H31NO3: C, 73.01; H, 9.04; N, 4.05, found: C, 73.31; H, 9.10; N,
3.97.
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In conclusion, we have synthesized, determined the eutectic
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melting mixture sodium acetate trihydrate‐urea as function of
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concluding that under the conditions here employed the bis‐
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formed during the reaction and the hexahydroacridine‐1,8‐
diones might be obtained from the reaction of these
intermediates with ammonia which is generated from the in
situ decomposition of urea. To the best of our knowledge,
there are few reports about the obtention of
hexahydroacridine‐1,8‐diones under Biginelli contitions and
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