Domino Knoevenagel/Michael synthesis of 2,2’-arylmethylenebis(3-hydroxy-5,5-dimethyl-2-cyclohexen-1-one) derivatives catalyzed by silica-diphenic acid and their single crystal X-ray analysis

Article abstract of DOI:10.1007/s12039-016-1088-y

An efficient and eco-friendly procedure has been developed for the synthesis of various 2,2’-arylmethylenebis(3-hydroxy-5,5-dimethyl-2-cyclohexene-1-one) derivatives which were isolated and characterized by melting point, IR, ¹H-NMR, ¹³

Full text of DOI:10.1007/s12039-016-1088-y

c
J. Chem. Sci. ꢀ Indian Academy of Sciences.
DOI 10.1007/s12039-016-1088-y
Domino Knoevenagel/Michael synthesis of 2,2’-arylmethylenebis(3-
hydroxy-5,5-dimethyl-2-cyclohexen-1-one) derivatives catalyzed by
silica-diphenic acid and their single crystal X-ray analysis
RUPALI VAIDa, MONIKA GUPTAa,∗, RAJNI KANTb and VIVEK K GUPTAb
aDepartment of Chemistry, University of Jammu, Jammu 180 006, India
bPost-Graduate Department of Physics & Electronics, University of Jammu, Jammu Tawi 180 006, India
e-mail: monika.gupta77@rediffmail.com
MS received 20 August 2015; revised 14 October 2015; accepted 30 March 2016
Abstract. An efficient and eco-friendly procedure has been developed for the synthesis of various 2,2’-
arylmethylenebis(3-hydroxy-5,5-dimethyl-2-cyclohexene-1-one) derivatives which were isolated and charac-
1
terized by melting point, IR, H-NMR, 13C-NMR and mass spectrometric techniques. Out of the fourteen
compounds synthesized, four compounds yielded crystals suitable for single crystal X-ray analysis which
showed that 2,2’-phenylmethylenebis(3-hydroxy-5,5-dimethyl-2-cyclohexene-1-one) crystallizes in the tetrago-
nal system with space group I41/a, 2,2’-(3-nitrophenyl)methylenebis(3-hydroxy-5,5-dimethyl-2-cyclohexene-
1-one) crystallizes in the monoclinic system with space group P21/n, 2,2’-(4-nitrophenyl)methylenebis(3-
hydroxy-5,5-dimethyl-2-cyclohexene-1-one) crystallizes in the orthorhombic system with space group Pca21
and 2,2’-(4-chlorophenyl)methylenebis(3-hydroxy-5,5-dimethyl-2-cyclohexene-1-one) crystallizes in the mon-
oclinic space group P21/c.
Keywords. Crystal structure; single crystal X-ray analysis; 5,5-dimethyl-1,3-cyclohexanedione; hetero-
geneous catalyst.
1. Introduction
including long reaction times, poor yield of products,
harsh reaction conditions and use of expensive and/or
toxic solvents. Due to the biological importance of 2,2’-
arylmethylenebis(3-hydroxy-5,5-dimethyl-2-cyclohex-
ene-1-one) compounds, there is a strong demand for
the development of mild and highly efficient procedure
for their synthesis. In this regard, we have synthesized
2,2’-arylmethylenebis(3-hydroxy-5,5-dimethyl-2-cyclo-
hexene-1-one) derivatives via one-pot Knoevenagel/
Michael reaction between various aromatic aldehydes
and 5,5-dimethyl-1,3-cyclohexanedione (dimedone) by
using silica supported diphenic acid as a recyclable het-
erogeneous catalyst (scheme 1). The mild and selective
action of silica-diphenic acid in the formation of the
above mentioned products has been clearly depicted
in scheme 1 which shows that the reaction stops after
the formation of product 1 and does not undergo
cyclization step to form product 2.
2,2’-Arylmethylenebis(3-hydroxy-5,5-dimethyl-2-cyclo-
hexene-1-one) compounds and their derivatives are
biologically important key synthons for the synthesis of
various xanthenes and acridinedione derivatives.1 These
compounds also show significant biological and thera-
peutic activities such as antiviral, antibacterial,2 anti-
oxidant,3 lipoxygenase inhibitor, tyrosinase inhibitors
against dermatological disorders including hyperpig-
mentation and skin melanoma4 and also action against
disorders like asthma and inflammatory processes.5
For the synthesis of 2,2’-arylmethylenebis(3-hydroxy-
5,5-dimethyl-2 cyclohexene-1-one) compounds, various
synthetic methods have been reported in the literature
which involve the usage of different types of cata-
lysts such as KF/Al2O3,6 SmCl3,7 L-lysine,8 CaCl2,9
HClO4–SiO2,10 zirconium oxychloride/sodium amide
(ZrOCl2/NaNH2),11 I2,12 FeCl3.6H2O/TMSCl/[bmim]
[BF4]13 and cetyltrimethyl ammonium bromide
(CTMAB).14 Some of the above mentioned protocols
are valuable but suffer from one or more drawbacks
2. Experimental
2.1 Materials and methods
All the chemicals and solvents were purchased from
Sigma-Aldrich and Merck and were used without
∗For correspondence

Rupali Vaid et al.
CH3
CH3
O
R
R
CHO
O
O
O
O
O
O
Silica-Diphenic acid
+
EtOH:H2O
Stirring, 80oC
CH3
CH3
CH3
CH3
H3C
H3C
H3C
H3C
R
O
2
CH3
Aldehyde
OH
OH
1
O
CH3
5,5'-Dimethyl-1,3-cyclohexanedione
Scheme 1. Reaction scheme terminating after formation of product 1.
O
-O C
OH
OH
OH
HO
O
HO
C
C
Ethanol
O
O
SiO2
+
HO
HO
Reflux, 12 h
OH
HO
C
-O
C O
OH
C
O
OH
SiO2
O
O C
-O
O
O
OH
O
C
Activated Silica
Diphenic Acid
OH
HO
O
O
C
C
O
O-
Silica- Diphenic Acid
Scheme 2. Preparation of silica-diphenic acid.
further purification. Silica gel was purchased from 2.2 Preparation and characterization of silica
ACROSS Organics. All melting points of the products supported diphenic acid
were taken on Perfit melting point apparatus and com-
The detailed preparation scheme and characterization
(FTIR, TGA, SEM and TEM) of silica-diphenic acid
has already been reported.15 Scheme 2 shows the pre-
paration of silica-diphenic acid
pared with those reported in the literature. FTIR spectra
of the products were recorded on SHIMADZU prestige
1
spectrophotometer. H-NMR and 13C-NMR spectra of
the products were recorded in DMSO-d6 on Bruker
Avance III 400 MHz spectrometer using TMS as an
internal standard (Department of Chemistry, University
of Jammu, Jammu). The mass spectra were recorded
on Esquire 3000 Bruker Daltonics spectrometer (ESI)
(IIIM, Jammu). Suitable crystals of 2,2’-arylmethylene
bis(3-hydroxy-5,5-dimethyl-2-cyclohexene-1-one) com-
pounds were selected and their single-crystal X-ray data
were recorded on a CCD area-detector diffractometer
(X’calibur system – Oxford diffraction make, U.K.)
(Department of Physics and Electronics, University of
Jammu, Jammu).
2.3 Determination of Acidity of silica-diphenic acid
In the reported characterization of silica-diphenic
acid,15 the nature of bonding of diphenic acid with acti-
vated silica was well explained by FTIR spectroscopy
which concluded that out of the two carboxylic groups
of diphenic acid, one carboxylic group remains free and
becomes responsible for catalyzing the reactions. Fur-
ther, to explain the nature of bonding of diphenic acid
over activated silica, we have performed the acid-base

Application of silica-diphenic acid catalyst
titrations which gave a quantitative knowledge of avail- diluted with EtOAc (20 mL). After dilution, the reac-
ability of free carboxylic groups for catalysis per sil- tion mixture was filtered to separate the catalyst fol-
ica support. The detailed procedure and conclusions lowed by washing of filtrate with distilled water and
related to the acid-base titration are reported in the dried over anhydrous Na2SO4. Finally, the solvent was
Supplementary Information.
allowed to evaporate over water bath and crude product
was obtained. The crude product was further recrystal-
lized from ethanol at room temperature to isolate pure
product.
The pure products were characterized by melting
point, IR, 1H-NMR, 13C-NMR and mass spectrometry.
Table 1 shows the calculated and experimental mass
(ESI) values (g/mol) for all compounds along with
their molecular formula. Some compounds were also
characterized by single-crystal X-ray analysis.
2.4 General procedure for the synthesis of 2,2’-aryl-
methylenebis(3-hydroxy-5,5-dimethyl-2-cyclohexene-
1-one)
2.4a Grinding method: In a pre-weighed agate mor-
tar, an aldehyde (1 mmol), 5,5-dimethyl-1,3-cyclohex-
anedione (2 mmol) and silica supported diphenic acid
(0.05 g) as a heterogeneous catalyst were subjected to
mechanical grinding with the help of pestle for appro-
priate time at room temperature. On completion of the
reaction (monitored by TLC), ethyl acetate was added
to the reaction mixture and the mixture filtered to sep-
arate the catalyst, followed by washing of the filtrate
with distilled water and dried over anhydrous Na2SO4.
Finally, the solvent was allowed to evaporate over
water-bath and the crude product obtained was finally
recrystallized from ethanol to isolate pure products.
2.5 X-ray data collection and structure refinement
Several attempts have been made to grow crystals of all
the compounds 1-16, but only four compounds formed
crystals suitable for single crystal X-ray analysis. These
crystals were obtained by very slow evaporation of their
ethanol solution at room temperature. The structures of
the four compounds were determined by single-crystal
X-ray diffraction analysis. X-ray intensity data of these
2.4b Thermal heating method: To a solution of etha- compounds were collected on a CCD area-detector
nol (2 mL) and water (0.4 mL) in a round bottom diffractometer (X’calibur system – Oxford diffraction
flask (50 mL), aldehyde (1 mmol), 5,5-dimethyl-1,3- make, U.K.) equipped with graphite monochromated
cyclohexanedione (2 mmol) and the heterogeneous cat- MoKα radiation (λ = 0.71073 Å) at room temperature.
alyst silica supported diphenic acid (0.05 g) were added The crystal used for data collection was of dimensions
and the reaction mixture was allowed to be refluxed 0.30 x 0.20 x 0.20 mm. The data were corrected for
at 80◦C in an oil-bath for an appropriate duration. On Lorentz and polarisation factors. The structures were
completion of the reaction (monitored by TLC), the solved by direct methods using SHELXS97.16 All non-
reaction mixture was cooled to room temperature and hydrogen atoms of the molecule were located in the
Table 1. Calculated and experimental mass (ESI) values for all compounds along
with their molecular formula.
S.No.
Molecular Formula
Calculated Mass
Experimental Mass (+ESI)
1
2
3
4
5
6
7
8
C23H28O4
C23H27NO6
C23H27NO6
C23H27NO6
C23H27O4Cl
C23H27O4Cl
C23H27O4Br
C23H27O4Br
C24H30O4
C24H30O5
C25H32O6
C25H31NO4
C24H30O6
C27H30O4
368
413
413
413
402
402
449
449
382
398
428
411
414
419
358
394
368.96
414.02
414.16
414.19
403.11
403.16
450.11
450.09
383.03
382.97
429.22
412.05
415.09
420.13
359.11
395.02
9
10
11
12
13
14
15
16
C21H26O5
C25H30O4

Rupali Vaid et al.

Application of silica-diphenic acid catalyst

Rupali Vaid et al.

Application of silica-diphenic acid catalyst
best E-map. Full-matrix least-squares refinement was their mixture has less volume than the sum of their indi-
carried out using SHELXL97. Atomic scattering factors vidual components at the given fractions. Their mixing
were taken from International Tables for X-ray Crys- is an exothermic reaction by which sufficient amount of
tallography (1992, Vol. C, tables 4.2.6.8 and 6.1.1.4). energy was released which helps the reactant molecules
Molecular drawings were obtained using DIAMOND, to condense and form the desired product. Finally, the
Version 2.1 (table 1).17
reaction of test substrates was also carried out at differ-
ent temperatures in case of thermal method and it has
been observed that 80◦C was the optimum temperature
for the reaction to give products in excellent yield.
The biological importance of 2,2’-arylmethylene-
bis(3- hydroxy-5,5-dimethyl-2-cyclohexene-1-one) com-
pounds and their use as starting materials for the design
and synthesis of new biologically active agents, has
inspired us to extend the scope of the newly developed
protocols. Hence, to evaluate the generality of the
present protocols, different aromatic aldehydes substi-
tuted with electron-donating and electron-withdrawing
substituents were selected and reacted with 5,5-dimeth-
yl-1,3-cyclohexanedione under optimized reaction con-
ditions as shown in scheme 1 and the experimental
details are summarized in table 2.
3. Results and Discussions
The domino synthesis of 2,2’-arylmethylene bis(3-
hydroxy-5,5-dimethyl-2- cyclohexene-1-one) derivatives
via Knoevenagel/Michael reaction is an important syn-
thesis as they are key synthons for the preparation of
various biologically important organic molecules. In
this regard, we have synthesized these derivatives in
the presence of silica supported diphenic acid as a
heterogeneous catalyst.
3.1 Optimization of reaction conditions
The structure-activity relationship has been infer-
red from the above table which explains that aro-
matic aldehydes substituted with electron-withdrawing
groups undergo faster reactions than aromatic alde-
hydes substituted with electron-donating groups and
heteroaromatic aldehydes. Among sixteen different
2,2’-arylmethylene bis(3-hydroxy-5,5-dimethyl-2-cyclo-
hexene-1-one) compounds which were synthesized by
above mentioned protocols, four compounds were
grown as good crystals and their structures were con-
To optimize the reaction conditions, benzaldehyde
(1 mmol) and 5,5-dimethyl-1,3-cyclohexanedione (2
mmol) were selected as test substrates. Initially, the
reaction of benzaldehyde with 5,5-dimethyl-1,3-cyclo-
hexanedione was carried out by mechanochemical grin-
ding method, in which reactants and catalyst were taken
in a pre-weighed mortar and mixed thoroughly with
pestle for few minutes in the absence of solvent. The
reaction of test substrates was also carried out under
thermal conditions, using a conventional pre-heated oil
bath.
1
firmed by single-crystal X-ray data analysis, IR, H-
NMR, 13C-NMR and mass spectroscopy.
Firstly, the reaction between test substrates has been
carried out without as well as with different types of cat-
alysts such as silica, diphenic acid and silica-diphenic
acid and it has been found that of the various catalysts,
silica-diphenic acid gave the best yield of products. The
reaction of test substrates was also carried out using dif-
ferent amounts of silica-diphenic acid and it has been
observed that in mechanochemical activation as well as
in thermal activation of reaction, 0.05 g of the catalyst
was sufficient to catalyze the reaction and provide excel-
lent yield of the resulting product. In case of mecha-
nochemical grinding method, initially, there was no need
of solvent for the reaction to take place but on comple-
tion of the reaction, ethyl acetate was added in the reac-
tion mixture to isolate the product. Whereas, in the case
of thermal method, solvent was essential and for this
different types of solvent mixtures were tried and it has
been found that ethanol (2 mL): water (0.4 mL) solution
was best for the reaction to take place efficiently. The
reasons for the positive effects of ethanol: water sol-
Grinding conditions
Thermal conditions
100
80
60
40
20
0
1
2
3
4
5
Number of runs
Figure 1. Recyclability graph of silica-diphenic acid in
vent mixture was that ethanol is miscible with water and case of (Entry 3, table 2).

Rupali Vaid et al.
were carried out in case of 3-nitrobenzaldehyde and
3.2 Recyclability of Silica-diphenic acid
5,5-dimethyl-1,3-cyclohexanedione (entry 3, table 2)
by both mechanochemical grinding and thermal heating
method. After examining the five runs in both cases, a
slight drop in the activity of the catalyst was observed.
In order to classify silica-diphenic acid as a hetero-
geneous catalyst, recyclability of the catalyst needs to
be examined. Hence a series of five consecutive runs
Table 3. Recyclability of silica-diphenic acid in case of 3-nitrobenzaldehyde and 5,5-dimethyl-
1,3-cyclohexanedione (entry 3, table 2).
Grinding conditiona
Thermal conditionb
Entry Yield (%)c
TON
TOF (TON/min) Yield (%)c
TON
TOF (TON/min)
1
2
3
4
5
98
98
97
95
94
2.57×104
2.57×104
2.52×104
2.50×104
2.47×104
5.14×103
5.14×103
5.04×103
5.00×103
4.94×103
98
96
95
94
92
2.57×104
2.52×104
2.50×104
2.47×104
2.42×104
5.14×103
5.04×103
5.00×103
4.94×103
4.84×103
a3-Nitrobenzaldehyde (1 mmol), 5,5-dimethyl-1,3-cyclohexanedione (2 mmol), silica-diphenic
acid (0.05 g) were grind in motar and pestle for required time in solvent free conditions. 3-
b
Nitrobenzaldehyde (1 mmol), 5,5-dimethyl-1,3-cyclohexanedione (2 mmol), silica-diphenic acid
(0.05 g) were taken in round bottom flask and refluxed for required time in ethanol: water solvent
mixture. cYield of pure products.
silica-diphenic
acid
H+
H+
H+
O
O
2
O
Ar
O
+
H3C
H3C
H
Ar
H
O
H
OH
H3C
H3C
O
1
3
H3C
H3C
-H2O
O
O
4
Ar
O
5
H3C
H3C
CH3
CH3
O
Ar
0
+
O
H
O
CH3
H3C
H3C
+H
H+ H+
CH3
OH
OH
silica-diphenic
acid
6
O
Ar
0
CH3
CH3
H3C
H3C
OH
O
Scheme 3. Plausible mechanism for the silica-diphenic acid-catalyzed synthesis of 2,2’-arylmethylenebis(3-hydroxy-5,5-
dimethyl-2-cyclohexene-1-one).

Application of silica-diphenic acid catalyst
Further, to explain the lifetime and stability of the are important starting materials for the synthesis of
catalyst, turnover number (TON) must be calculated various biologically active compounds.
as the total moles of product synthesized per mole of
the catalyst. The cumulative turnover number (TON) is Supplementary Information (SI)
also calculated as the total moles of product synthesized
The supplementary information includes the following:
over repeated reaction cycles per mole of active catalyst
Procedure of acid-base titration with conclusion, spec-
initially added in the first run.21 The calculations were
tral data of synthesized products, mass spectra of three
carried out in case of silica-diphenic acid and results are
products as figures S1, S2 and S3, ORTEPs of com-
shown in table 2 and graphically represented in figure 1.
pounds 1, 3, 4 and 6 (table 2) with figures showing
The efficiency of recyclable catalyst and the absence
packing arrangements as figures S4, S5, S6, S7, S8, S9,
of significant catalyst decomposition during the exper-
S10 and S11, figures S12 to S15 showing intramolecu-
iment are convincingly explained by determining the
lar hydrogen bondings in compounds 3 and 6, optimiza-
turnover frequencies (TOF) of the catalyst over the con-
tion tables as table S1, S2, S3 and S4, crystal discussion,
secutive five runs. This has been calculated in case of
table S5 explaining the summary of the crystal struc-
silica-diphenic acid as shown in the above table which
ture, data collection and structure refinement parame-
concluded that TON and TOF values were almost con-
ters for compounds 1, 3, 4 and 6, tables S6 and S7
stant, indicating the excellent recyclability of the silica-
showing geometry of intramolecular interactions for
diphenic acid in both grinding as well as under thermal
compounds 3 and 6 (table 2) and tables S8, S9, S10
conditions (table 3).
and S11 showing bond lengths and bond angles of com-
pounds 1, 3, 4 and 6. Supplementary Information is
available at www.ias.ac.in/chemsci.
3.3 Mechanism
A plausible mechanism for the reaction between alde-
hydes (1 mmol) and 5,5-dimethyl-1,3-cyclohexaned-
ione (2 mmol) in presence of silica-diphenic acid as
a mild, efficient and heterogeneous catalyst has been
proposed (scheme 3). In the first step of the proposed
mechanism, aldehyde molecule (2) was protonated and
activated by the catalyst and undergoes Knoevenagel
condensation with 5,5-dimethyl-1,3-cyclohexanedione
(1) to form intermediate product (4) which was fur-
ther activated by catalyst, so that it undergoes Michael
reaction with another molecule of 5,5-dimethyl-1,3-
cyclohexanedione (5) to form final desired product (6).
Acknowledgements
Authors are grateful to Head, Department of Physics
and Electronics, University of Jammu for recording
single crystal X-ray data of products and also thankful
to Department of Chemistry, University of Jammu for
providing necessary facilities for accomplishing this
work.
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4. Conclusion
Domino synthesis of 2,2’-arylmethylene bis(3-hydroxy-
5,5-dimethyl-2-cyclohexene-1-one) compounds has been
carried out successfully in presence of silica supported
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