An alternative, practical, and ecological protocol for synthesis of arylidene analogues of Meldrum’s acid as useful intermediates

Article abstract of DOI:10.1007/s11164-019-03796-2

This paper presents an ecological protocol for Knoevenagel condensation using a catalytic amount of 4,4′-trimethylenedipiperidine as a versatile, efficient, safe, commercially available, inexpensive, and recyclable organocatalyst by a ball-milling process

Full text of DOI:10.1007/s11164-019-03796-2

Research on Chemical Intermediates
https://doi.org/10.1007/s11164-019-03796-2
An alternative, practical, and ecological protocol
for synthesis of arylidene analogues of Meldrum’s acid
as useful intermediates
Nader Ghafari Khaligh1 · Taraneh Mihankhah · Mohd Raꢀe Johan
2
1
Received: 23 January 2019 / Accepted: 2 March 2019
©
Springer Nature B.V. 2019
Abstract
This paper presents an ecological protocol for Knoevenagel condensation using a
catalytic amount of 4,4′-trimethylenedipiperidine as a versatile, eꢀcient, safe, com-
mercially available, inexpensive, and recyclable organocatalyst by a ball-milling
process at room temperature. The scope of the present protocol was explored and
demonstrated for Knoevenagel condensation of the active methylene, such as Mel-
drum’s acid with various aryl and heteroaryl aldehydes. The developed protocol pro-
vides a good to excellent conversion of various aldehydes to respective Knoevenagel
products in an environmentally friendly process. Furthermore, this eꢀcient process
displays a combination of the synthetic virtues of conventional Knoevenagel con-
densation with ecological beneꢁts and the convenience of a facile mechanochemis-
try procedure.
Keywords Versatile intermediate · C–C coupling · Heterogeneous catalysis · Solid-
state reactions · Waste prevention
Introduction
Mechanochemistry and the ball milling process have been developed as clean
and solvent-free approaches to chemical transformations and organic synthesis
which can minimize usage of toxic, ꢂammable, and volatile organic solvents and
reduce environmental pollution [1]. In addition, the ball milling process ꢁts well
with the principles of green chemistry and the industrial processes. It often leads
*
Nader Ghaꢃari Khaligh
ngkhaligh@gmail.com; ngkhaligh@um.edu.my
1
2
Nanotechnology and Catalysis Research Center, Institute of Postgraduate Studies, University
of Malaya, 3rd Floor, Block A, 50603 Kuala Lumpur, Malaysia
Environmental Research Laboratory, Department of Water and Environmental Engineering,
School of Civil Engineering, Iran University of Science and Technology, 16765-163 Tehran,
Iran
Vol.:(012
1
3456789)
3

N. G. Khaligh et al.
to improvements in the chemical reactions, including a reduced amount of catalyst
loading, shorter reaction time, and higher yield [2].
Knoevenagel condensation is a well-known reaction for the formation of a car-
bon–carbon double bond that is widely used both in academic organizations and in
the agrochemical, pharmaceutical, and perfume industries [3–5]. The Knoevenagel
products are important reagents and versatile building blocks in organic synthesis
both as intermediates and ꢁnal products [6].
Arylidene analogues of Meldrum’s acid are versatile substrates for various kinds
of reactions [7, 8] and well-known intermediates for the synthesis of heterocyclic
compounds of biological importance such as cardiotonics [9], anti-proliferative and
HIV integrase inhibitory activities [10, 11], and in vitro antimalarial and antioxi-
dant properties [12]. They are used to generate 3-arylpropanoic acids from the cor-
responding benzaldehydes [13].
As a consequence of this popularity, a number of protocols are being continuously
developed for this useful conversion [14]. In general, the Knoevenagel condensa-
tion reaction is carried out in organic solvents using organic bases as catalysts, such
as aliphatic amines or their corresponding ammonium salts, urea, ethylenediamine,
dimethylamine, pyrrolidine, 2-methylpiperidine, and piperidine, and the amino acids
glycine, β-alanine, or DL-proline [5, 15, 16]. Most of these catalysts have disad-
vantages, including being extremely or highly ꢂammable liquids, gases, or vapors,
harmful to aquatic life with long-lasting eꢃects, toxic or explosive if heated, and
may cause an allergic skin reaction or asthma symptoms. Hence, the development of
an environmentally friendly, metal-free solid base, and sustainable catalytic protocol
for Knoevenagel condensation which can tolerate a wide variety of functionality is
still highly demanded. Also, the design and development of new reagents and cata-
lysts for conducting organic reactions play important roles in organic synthesis and
provide a useful and broad area for selectivity.
In pursuit of our interest in the solvent-free organic transformations using safe and
green catalysts [17–19], we recently used planetary ball milling for the synthesis of
Schiꢃ bases [20, 21]. To circumvent the problems associated with using toxic, highly
ꢂammable, and volatile base catalysts such as piperidine, dimethylamine, pyrroli-
dine, and 2-methylpiperidine, herein, a simple and eꢀcient Knoevenagel mechano-
condensation protocol is developed. The structure of 4,4′-trimethylenedipiperidine
(
TMDP) bearing two piperidine rings linked by a 3-carbon spacer encouraged us
to believe that TMDP can catalyze Knoevenagel condensation. TMDP is non-toxic,
inꢂammable, highly thermally stable, inexpensive, commercially available, easy to
handle and store, and recyclable. The aforementioned properties of TMDP as a solid
organocatalyst along with the easy separation and puriꢁcation of the Knoevenagel
products in good to excellent yields are attractive features for this current protocol.
To the best of our knowledge, no report has been presented on Knoevenagel reac-
tion using TMDP as an organocatalyst through the ball milling process; moreover,
TMDP has never been applied as an organocatalyst in organic chemistry. The results
promise wide applicability of TMDP as an ecological and economical organocata-
lyst for typical C–C bond-formation processes through solid- or melt-state milling
processes instead of piperidine which is toxic and a highly ꢂammable liquid and
vapor.
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An alternative, practical, and ecological protocol for…
Results and Discussion
Thermal stability of TMDP
Herein, thermal analysis of TMDP is studied for the ꢁrst time. Diꢃerential scan-
ning calorimetry (DSC) was performed on TMDP to determine its melting and boil-
ing points or decomposition onset temperatures. The thermal behavior of TMDP is
displayed as a DSC plot in a temperature range from 30 to 500 °C in Fig. 1. In
nitrogen atmosphere, two sharp and one broad endothermic peak centered around
5
8, 332, and 110 °C on the DSC curves of TMDP were recorded, and no exother-
mic peak was observed. The ꢁrst peak is likely due to the melting of TMDP which
−
1
began at 52.3 °C and ended at 66.6 °C with a latent heat of fusion of 196.88 J g
−1
(
41.42 kJ mol ). According to the melting point deꢁnition of pure non-polymeric
compounds based on DSC as the onset temperature of the ꢁrst endotherm, the melt-
ing point of TMDP is 52.3 °C which is very diꢃerent from that was reported in
the literature (65–68.5 °C; Sigma Aldrich). Then, an endothermic broad peak is
observed in the range 76–157 °C, which can be attributed to desorption of inher-
ent moisture and physically adsorbed water in TMDP with a latent heat of desorp-
−
1
−1
tion of 70.01 J g (14.72 kJ mol ). The onset of the third endothermic peak was
seen at 313.8 °C, and its end-set was at 335.9 °C with a latent heat of evaporation
−1
−1
of 427.84 J g (90.00 kJ mol ). The boiling point of a pure compound is essential
information necessary before any industrial implementation. The maximum temper-
ature of the second sharp endothermic peak at 332.5 °C was assigned as the boiling
point of TMDP which, apart from the appreciable loss of weight, shows a common
feature due to the decreasing heat capacity of the sample, namely that the baseline
Fig. 1 DSC analysis of TMDP
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3

N. G. Khaligh et al.
shifts in the exothermic direction. The TMDP showed a relatively wide liquid range
(
>280 °C), which melted at 52.3 °C, but did not begin to boil until it reached a tem-
perature of 332.5 °C.
A thermogravimetric analysis/diꢃerential thermal analysis (TGA/DTA) curve of
TMDP is presented in a temperature range from 30 to 800 °C in Fig. 2. Two peaks
are visible on the DTA curve, and TMDP decomposition proceeds in one stage
according to the TGA/DTG curve. The DTA curve of TMDP obtained by analysis
in nitrogen atmosphere shows a broad peak below 126 °C with a maximum mass
loss of 11.2%; this is attributed to the content of inherent moisture and physically
adsorbed water in TMDP. The onset of temperature decomposition of TMDP was
observed at 200.16 °C, and its thermal decomposition ended at 233.81 °C. The
maximum mass loss of 88.6% was related to the total decomposition of TMDP. At
2
00–246 °C, completed. The thermal stability of organocatalysts plays an important
role when their reactions need to be performed at high temperature. All the preced-
ing results show that TMDP is thermally stable even at relatively high temperatures,
and its thermal stability could be a consequence of the presence of hydrogen bonds
in the structure of TMDP.
Knoevenagel condensation and catalytic eꢀciency of TMDP
In order to verify the catalytic performance of TMDP, it was used in the Knoev-
enagel condensation of aryl and heteroaryl aldehydes with Meldrum’s acid as an
active methylene. Initially, the condensation reaction between 4-chlorobenzaldehyde
and Meldrum’s acid was chosen as the model reaction to obtain the information on
the optimal conditions (Table 1).
The model reactants were ground using the planetary ball mill at room tempera-
ture under catalyst- and solvent-free conditions. The 5-(4-chlorobenzylidene)-2,2-di-
methyl-1,3-dioxane-4,6-dione (2a) was formed with 37% conversion after 60 min,
indicating the requirement of a promoter for the reaction (Table 1, entry 1). Next,
Fig. 2 TGA/DTA analysis of TMDP
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3

An alternative, practical, and ecological protocol for…
Table 1 Condensation reaction of 4-chlorobenzaldehyde with Meldrum’s acid at diꢃerent conditions
Entry
Loading
TMDP
Number of
Speed (rpm)
Ball mill
diameter
(mm)
Milling
Conversion (%)
milling balls
time (min)
(
mol%)
1
2
3
4
5
6
7
8
9
0
5
4
4
4
4
4
4
4
2
2
600
600
600
600
600
600
400
600
600
5
5
5
5
5
5
5
5
7
60
60
60
10
5
37
78
100
100
72
75
78
56
76
10
10
10
15
10
10
10
5
10
10
10
Reaction conditions: 4-chlorobenzaldehyde 1a (5.0 mmol), Meldrum’s acid (5.0 mmol), room tempera-
ture.
Bold data indicate optimized reaction conditions
the model reactants were milled in the presence of TMDP (5 mol%) at room tem-
perature for 60 min under identical conditions to aꢃord the (2a) with 78% conver-
sion (Table 1, entry 2). A signiꢁcant improvement was observed in conversion by
increasing of TMDP loading (Table 1, entry 3).
The conversion remained constant when the reaction time was curtailed to 10 min
(
Table 1, entry 4), while further decreasing of the reaction time to 5 min led to a
severe drop in conversion of 2a (Table 1, entry 5). Also, the increasing of TMDP
loading up to 15% led to 75% conversion after 5 min (Table 1, entry 6). The results
exhibited that the technical parameters such as revolution per minute (rpm), size,
and number of ball millings play important roles in performing Knoevenagel con-
densation (Table 1, entries 7–9). We selected entry 4 in Table 1 as the optimized
reaction conditions.
The scope and generality of the current protocol for the Knoevenagel condensa-
tion was evaluated through the reaction of various aldehydes 1(a–j) and Meldrum’s
acid using planetary ball milling under optimized reaction conditions (Scheme 1).
A broad range of the arylidene analogues of Meldrum’s acid was isolated in
good to excellent yield under optimal reaction conditions (Table 2). The reaction
was found to be compatible with diverse functional groups such as halogen, ether,
nitro, and hydroxyl (Table 2, entries 1, 4, 5, and 10). Furfural gave the desired
H C
3
O
CH3
O
O
R
H C
O
CH3
O
3
O
H
TMDP (10 mol%)
R
+
O
rpm (600), r.t., 10 min
H
O
O
1(a-j)
2(a-j)
Scheme 1 Knoevenagel condensation of various aldehydes 1(a–j) and Meldrum’s acid
1
3

N. G. Khaligh et al.
Table 2 Knoevenagel condensation of various aryl aldehydes with Meldrum’s acid in the presence of
TMDP under optimized reaction conditions
Entry
Aldehydes 1(a–j)
Knoevenagel
Yield (%)a
Melting point (°C)
product 2(a–j)
Found
Reported [refs.]
1
2
3
4
5
6
7
8
9
4-Cl–C H –
2a
2b
2c
2d
2e
2f
2g
2h
2i
90
87
85
82
95
78
86
81
82
88
159–161
84–85
157–158
122–123
213–214
92–93
193–194
105–106
165–166
193–194
156–158 [22]
84 [22]
150 [22]
120–122 [22]
217–218 [23]
92 [22]
196–197 [24]
109 [22]
6
4
C H –
6
5
4-CH –C H –
3
6
4
4-CH O–C H –
3
6
4
4-NO –C H –
2
6
4
Furan–2–yl
Thiohen–2–yl
C H –CH=CH–
6
5
4-(CH ) N–C H –
170 [22]
192–193 [25]
3
2
6
4
1
0
4-OH–C H –
2j
6
4
Reaction conditions: aldehydes 1(a–j) (5.0 mmol), Meldrum’s acid (5.0 mmol), TMDP (0.5 mmol), six
balls with diameter 7 mm, revolution rate (600 rpm), room temperature, milling time (30 min)
a
Isolated yield
Knoevenagel product in 78% yield without the formation of side products, which are
normally observed under strongly acidic or basic conditions (Table 2, entry 6). No
isomerization for conjugated aldehydes such as cinnamaldehyde was observed in the
presence of TMDP under optimized conditions (Table 2, entry 8). Aldehydes bear-
ing electron-withdrawing substituents aꢃorded a slightly higher yield of the Kno-
evenagel products than electron-donating substituents at the same position due to
increasing the electrophilicity of the carbonyl group (Table 2, entries 1 and 5 vs. 3,
4
, 9, and 10).
On completion of the reaction, the TMDP could be separated and recovered by
washing with deionized water followed by evaporation of water from an aqueous
solution containing TMDP. The recovered organocatalyst was successfully used for
three subsequent runs with an average 88% yield of 2a which approved the recycla-
bility of TMDP in this current protocol.
Based on the theoretical and experimental reports in the literature [26], a possible
mechanism is postulated and illustrated in Scheme 2. In this mechanism, TMDP acts
both as a nucleophile toward the aldehyde and as a base toward the active methylene,
involving the corresponding iminium intermediate (II) as the acceptor (Scheme 2).
The ꢁrst step includes the formation of the carbinolamine intermediate (I) through the
attack of piperidine to the carbonyl group and participation of the second piperidine
moiety as base to activate methylene compound, leading to a lower free-energy barrier
for the formation of the carbinolamine intermediate (I). The second reaction step is
the elimination of water from carbinolamine intermediate (I) which lead to the forma-
tion of two charged species, including iminium ion (II) and the deprotonated active
methylene. It is speculated that the piperidine moieties of TMDP act both as a nucleo-
phile toward the aldehyde and as a base toward the active methylene. The nucleophilic
attack of deprotonated active methylene to iminium ion (II) led to the formation of the
1
3

An alternative, practical, and ecological protocol for…
H
O
N
H N
N
H
N
H
N
R
H
R
N
H
H
(
I)
H
H
O
O
O
O
O
H
H
H
O
H
O
O
O
O
O
O
H
O
H O
2
N
H
N
H
N
H
(III)
N
H
N
O
O
N
H
(II)
O
O
H
H
R
O
O
O
H
R
R
O
O
O
O
O
H
Scheme 2 A possible mechanism of the Knoevenagel condensation of various aldehydes 1(a–j) and
Meldrum’s acid in the presence of TMDP
intermediate (III) followed by proton exchange with the TMDP which aꢃord the Kno-
evenagel product.
The feasibility of the present method on a gram-scaled experiment was performed
with 4-chlorobenzaldehyde (7.03 g, 50 mmol) and Meldrum’s acid (7.21 g, 50 mmol)
using TMDP (2.10 g, 10 mol%) under optimized reaction conditions which aꢃorded
1
1.2 g of 2a (84% isolated yield) within 10 min, almost similar in all respects with the
mmol-scale entry.
Then, the catalytic eꢀciencies of TMDP, triethylamine, and piperidine were com-
pared under the aforementioned optimized conditions which gave the desired product
2
a in 90, 41, and 52% yields, respectively. Lesser yield obtained with the use of trieth-
ylamine and piperidine signiꢁed the role of the number of hydrogen bond donor (HBD)
and hydrogen bond acceptor (HBA) sites in promoting the Knoevenagel condensation.
A beneꢁt of utilizing TMDP over piperidine is its safety and non-toxicity. The lower
volatility of TMDP, as compared to piperidine or pyridine, allows it to be safely han-
dled by less experienced chemists. Also, a cleaner reaction and multiple rounds of recy-
cling justify its higher cost compared to piperidine.
Experimental
General
Unless speciꢁed, all chemicals were analytical grade and purchased from Merck,
Aldrich, and Fluka Chemical Companies and used without further puriꢁcation.
1
13
The known products were characterized by their melting point, H NMR, and
C
1
3

N. G. Khaligh et al.
NMR. The purity determination of the substrates and reaction monitoring were
accompanied by TLC using silica gel SIL G/UV 254 plates. In all the cases, the
1
13
H and C NMR spectra were recorded with Bruker Avance 400 MHz instru-
ment. All chemical shifts are quoted in parts per million (ppm) relative to TMS
using deuterated solvent. Melting points were recorded on a Büchi B-545 appara-
tus in open capillary tubes. Ball milling was performed in a Retsch PM100 plan-
etary ball mill using a stainless-steel chamber and four or six stainless steel balls
(
diameter: 5 or 7 mm) with 300–600 revolutions per minute (rpm). Diꢃerential
scanning calorimetry (DSC) curves were obtained with the use of a DSC-Mettler
Toledo DSC 822e calorimeter. The measurements were taken in the aluminum
pans with a pierced lid with the sample mass 17.01 mg under a dry nitrogen gas
−
1
atmosphere (30 mL min ). Dynamic scans were performed at a heating rate
−
1
of 10 °C min in the temperature range 30–500 °C. TGA/DTA curves were
obtained with the use of a Mettler Toledo TGA/SDTA 851e. All measurements
were taken in the Al O crucible with the sample mass 6.81 mg under nitrogen
2
3
−
1
atmosphere (30 mL min ). Dynamic scans were performed at the heating rate of
0 °C min− in the temperature range 30–800 °C.
1
1
Typical procedure for the synthesis of arylidene analogues of Meldrum’s acid
in the presence of TMDP
The aldehyde (5.0 mmol), Meldrum’s acid (5.0 mmol), and TMDP (10 mol%)
were ground vigorously using four milling balls with a diameter of 5 mm at
6
00 rpm for 10 min at room temperature. Then, 10 mL of water was added to the
grinding jar, TMDP was separated by ꢁltration, and after evaporation, solvent was
reused in the subsequent runs. The crude material was puriꢁed by column chro-
matography (95:5 hexane/EtOAc) to give the corresponding Knoevenagel prod-
1
ucts. The physical (melting point) and spectroscopic data ( H NMR) of all the
known Knoevenagel products [2(a–j)] were in good agreement with that reported
in the literature [22–25].
1H NMR of the known products
1
5
-(4-Chloro-benzylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (2a):
H NMR
(
400 MHz, CDCl ) δ = 8.37 (s, 1H), 8.02 (d, J = 8.2 Hz, 2H), 7.45 (d, J = 8.2 Hz,
3
2
H), 1.80 (s, 6H) ppm.
1
5
-Benzylidene-2,2-dimethyl-1,3-dioxane-4,6-diones (2b): H NMR (400 MHz,
CDCl ) δ = 8.34 (s, 1H), 7.14 (d, J = 8.0 Hz, 2H), 7.04 (t, J = 8.0 Hz, 2H), 6.89 (t,
3
J = 8.0 Hz, 1H), 1.69 (s, 6H) ppm.
1
2
,2-Dimethyl-5-(4-methylbenzylidene)-1,3-dioxane-4,6-diones (2c): H NMR
(
400 MHz, CDCl ) δ=8.36 (s, 1H), 8.01 (d, J=8.4 Hz, 2H), 7.27 (d, J=8.4 Hz,
3
2
H), 2.42 (s, 3H), 1.78 (s, 6) ppm.
1
3

An alternative, practical, and ecological protocol for…
1
5
-(4-Methoxybenzylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (2d):
HNMR
(
400 MHz, CDCl ) δ=8.38 (s, 1H), 8.24 (d, J=8.0 Hz, 2H), 7.00 (d, J=8.0 Hz,
3
2
H), 3.91 (s, 3H), 1.79 (s, 6H) ppm.
,2-Dimethyl-5-(4-Nitro-benzylidene)-1,3-dioxane -4, 6-dione (2e): H NMR
400 MHz, CDCl ) δ=8.45 (s, 1H), 8.31 (d, J=8.6 Hz, 2H), 8.05 (d, J=8.6 Hz,
1
2
(
3
2
H), 1.85 (s, 6H) ppm.
-Furan-2-ylmethylene-2,2-dimethyl-1,3-dioxane-4,6-dione (2f):
400 MHz, CDCl ) δ=8.45 (d, J=3.6 Hz, 1H), 8.34 (s, 1H), 7.83 (s, 1H), 6.73 (d,
1
5
H
NMR
(
3
J=3.5 Hz, 1H), 1.76 (s, 6H) ppm.
,2-Dimethyl-5-(thiophen-2-ylmethylene)-1,3-dioxane-4,6-dione (2g): HNMR
400 MH, CDCl ) δ=8.65 (s, 1H), 8.01 (d, J=4.0 Hz, 1H), 7.89 (d, J=4.0 Hz, 1H),
1
2
(
3
7
.27-7.24 (m, 1H), 1.77 (s, 6H) ppm.
,2-Dimethyl-5-(3-phenyl-allylidene)-1,3-dioxane-4,6-dione (2h):
400 MHz, CDCl ) δ=8.33-8.31 (m, 1H), 8.18 (d, J=12.0 Hz, 1H), 7.66 (m, 2H),
1
2
H
NMR
(
3
7
.43-7.41 (m, 4H), 1.76 (s, 6H) ppm.
-(4-Dimethylamino-benzylidene)-2,2-dimethyl-1,3-dioxane-4,6-diones (2i):
NMR (400 MHz, CDCl ) δ=8.29-8.21 (m, 3H), 6.69 (d, J=9.5 Hz, 2H), 2.48 (s,
1
5
H
3
6
H), 1.76 (s, 6H) ppm.
-(4-Hydroxy-benzylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (2j): H NMR
1
5
(
400 MHz, CDCl ) δ=10.92 (s, 1H), 8.28 (s, 1H), 8.12 (d, J=8.4 Hz, 2H), 6.92 (d,
3
J=8.4 Hz, 2H), 1.75 (s, 6H) ppm.
Conclusion
In summary, an eꢀcient protocol has been developed for Knoevenagel condensation
using TMDP as a new organocatalyst under mild and solvent-free conditions which
is considered a clean and ecological procedure. The aldehydes 1a–j were reacted
with Meldrum’s acid in the presence of catalytic amounts of TMDP using planetary
ball milling at room temperature. The Knoevenagel products were obtained in high
to excellent yields under the optimized conditions. This work represents, to the best
of our knowledge, the ꢁrst study of the catalytic eꢀciency of TMDP in Knoevenagel
condensation through the milling process at room temperature in a short reaction
time under solvent-free conditions. This current protocol can be considered as an
ecological and economical method because TMDP is solid, non-toxic, inexpensive,
commercially available, recyclable, with easy handling and storage. The achieved
experimental data showed that TMDP can be used as a green and safe alterna-
tive reagent instead of piperidine in organic synthesis under mild conditions, and
we hope that our work will encourage further research in this area with promising
results for future applications of TMDP in both academic and industrial processes.
Further studies are currently in progress to broaden the potential catalytic activity of
TMDP in other organic reactions and will be reported as appropriate.
Acknowledgements The authors are grateful to staꢃ members at the Analytical and Testing Center of
Research House of Professor Reza, and express thanks to the University of Malaya for partial support of
this work.
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N. G. Khaligh et al.
Compliance with ethical standards
Conꢀicts of interest There are no conꢂicts of interest to declare.
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