Solid-phase synthesis of arylidene and alkylidene malonates, as versatile intermediates, catalyzed using mesoporous poly-melamine–formaldehyde as a nitrogen-rich porous organic polymer (POP)

Article abstract of DOI:10.1007/s11164-021-04476-w

An efficient solid/slurry-state synthesis of arylidene and alkylidene malonates as versatile intermediates is developed in the presence of mesoporous poly-melamine–formaldehyde. The condensation reaction was conducted through a ball milling process as a non-conventional procedure and a greener methodology at room temperature under solvent-free conditions. The mesoporous heterogeneous catalyst could be recovered and reused ten times, and the results showed a negligible loss of catalytic activity. Various aryl- and heteroarylidene malonates, as well as dimethyl (cyclohexylidene)malonate, were isolated in good to high yields under optimal conditions. The use of hazardous reagents and solvents were minimized in the current method, and separation of catalyst and products, as well as the recovery and reusing of catalyst, were performed by cost-effective procedures. This work revealed that the synergistic effect of numerous Lewis base sites together with acceptor-donner hydrogen bonding functional groups in porous organic polymer (POP), and its high porosity plays a vital role to promote the carbon–carbon coupling reaction in the solid phase synthesis.

Full text of DOI:10.1007/s11164-021-04476-w

Research on Chemical Intermediates
https://doi.org/10.1007/s11164-021-04476-w
Solid‑phase synthesis of arylidene and alkylidene
malonates, as versatile intermediates, catalyzed
using mesoporous poly‑melamine–formaldehyde
as a nitrogen‑rich porous organic polymer (POP)
Nader Ghafari Khaligh1 · Hayedeh Gorjian2 · Hoda Fahim2 ·
Salam J. J. Titinchi3
Received: 13 January 2021 / Accepted: 19 April 2021
© The Author(s), under exclusive licence to Springer Nature B.V. 2021
Abstract
An efcient solid/slurry-state synthesis of arylidene and alkylidene malonates as
versatile intermediates is developed in the presence of mesoporous poly-melamine–
formaldehyde. The condensation reaction was conducted through a ball milling pro-
cess as a non-conventional procedure and a greener methodology at room tempera-
ture under solvent-free conditions. The mesoporous heterogeneous catalyst could be
recovered and reused ten times, and the results showed a negligible loss of catalytic
activity. Various aryl- and heteroarylidene malonates, as well as dimethyl (cyclohex-
ylidene)malonate, were isolated in good to high yields under optimal conditions.
The use of hazardous reagents and solvents were minimized in the current method,
and separation of catalyst and products, as well as the recovery and reusing of cata-
lyst, were performed by cost-efective procedures. This work revealed that the syn-
ergistic efect of numerous Lewis base sites together with acceptor-donner hydrogen
bonding functional groups in porous organic polymer (POP), and its high porosity
plays a vital role to promote the carbon–carbon coupling reaction in the solid phase
synthesis.
Keywords Porous materials · Solid-Slurry synthesis · Heterogeneous catalysis ·
Carbon–carbon coupling · Sustainable process
*
Nader Ghafari Khaligh
ngkhaligh@um.edu.my
1
2
3
Nanotechnology and Catalysis Research Center, Institute of Advanced Studies (IAS), University
of Malaya, 50603 Kuala Lumpur, Malaysia
Department of Food Science and Technology, Sari Agricultural Sciences and Natural Resources
University, 578 Sari, Iran
Department of Chemistry, University of the Western Cape, Cape Town 7535, South Africa
Vol.:(0123456789)
1 3

N. G. Khaligh et al.
Introduction
Microwave and ultrasound irradiation along with the milling process has been
mentioned as non-conventional processes in organic synthesis. In particular, ball
milling as a mechanochemistry process has been extensively employed in organic
synthesis as an eco-friendly, and greener approach to perform the organic syn-
thesis, which can lead to minimize and reduce environmental concerns [1, 2].
The solid-phase synthesis using milling can be easily scaled up to gram/kilogram
amount of reactants, which in turn is interested in industrial processes. Many
previous reports have been indicated that ball milling leads to the use of small
amount catalysts, shorter reaction times, and higher yield of desired products [2].
Design and introduce more efcient and greener methods for the preparing of
intermediates and fne chemicals is one of the most important areas of chemistry
research; for example, (a) the avoid or minimize the use of toxic reagents and vol-
atile solvents, or conducting a reaction under solvent-free conditions, which leads
to reduce the toxic and hazard waste generation, (b) the use of a small amount of
catalyst, or the use of high recyclable catalysts, (c) conducting a reaction at room
temperature to enhance the energy efciency [3, 4].
The Knoevenagel condensation products bearing a carbon–carbon double
bond have been widely employed as versatile and valuable organic intermediates
in academic or industry felds [5, 6]. The Knoevenagel condensation reaction is
often performed by a homogeneous system viz. into a solvent using organic bases
such as aliphatic or cyclic amines and their salts, amino acids. The conventional
catalyst of the Knoevenagel condensation reactions is piperidine which is used
with or without acetic acid in an organic solvent. Homogeneous catalysts are not
environmentally benign and sustainable since their separation from the reaction
mixtures, and their recovery or recycling is difcult. The conventional procedure
and some reported methods have limitations such as the use of fammable, vola-
tile, and toxic solvents for the reaction or preparation of the catalyst, preparation
of the catalysts using tedious and multi-step processes, utilization of expensive
metal-based catalyst and generation of metal waste, etc.
Recently, our group fabricated and characterized mesoporous poly-mela-
mine–formaldehyde (mPMF) as a nitrogen-rich porous organic polymer, which was
applied successfully in several organic syntheses [7, 8]. Owing to the presence of
numerous aminal functional groups and triazine rings, mPMF contains the hydrogen
bond donating-accepting agent and abundant Lewis base sites. In continuation of
our interest in the synthesis of versatile intermediates through the Knoevenagel con-
densation reaction [9], herein, the catalytic performance of mPMF is successfully
demonstrated for the preparation of aryl/heteroarylidene malonates and dimethyl
(cyclohexylidene)malonate, as versatile intermediates in organic chemistry, under
practical and environmental-friendly conditions using a Retsch PM100 planetary
ball mill in a slurry-state. The mPMF is easy to handling and storage, and it can be
easily separated from the Knoevenagels’ products and recycled for at least ten runs.
Based on the results of this work, mPMF can be an appropriate alternative to piperi-
dine, a toxic liquid with high fammability in liquid and vapor states.
1 3

Solid-phase synthesis of arylidene and alkylidene malonates,…
Results and discussion
The catalytic efciency of mPMF in carbon–carbon coupling
The mPMF was fabricated according to the previous report in the literature [8]. The
Brunauer–Emmett–Teller (BET) surface area and pore volume were determined to
be 972.9 and 2.34 cm3 g−1 (See supplementary information, Figure S1). As seen in
Figure S2, mPFM contains the micropores and mesopores based on its pore size dis-
tribution curve (See supplementary information).
The catalytic performance of mPMF was investigated for the synthesis of
arylidene malonates via the Knoevenagel condensation of dimethyl malonate with
aryl/ heteroaryl aldehydes and cyclohexane carboxaldehyde. We selected dimethyl
malonate (pKa =15.87) [10] because it is a much weaker acid than malononitrile
(pKa =11.1) [11], acetylacetone (pKa =8.99) [12], 5,5–dimethyl–1,3––cyclohexane-
dione (dimedone) (pKa =5.23) [13], Meldrum acid (pKa =4.83) [14], and barbituric
acid (pKa =4.01) [15]. The Knoevenagel condensation of the 4–chlorobenzaldehyde
and dimethyl malonate was studied under diferent conditions to fnd the optimized
reaction conditions (Table 1).
Initially, the milling of model reactants was carried out using four balls (diameter
45 mm) at 600 revolutions per minute (rpm) by a planetary ball mill at room temper-
ature in the absence of catalyst and solvent. The dimethyl 2-(4-chlorobenzylidene)
malonate 2a was detected in 35% conversion after six hours (Table 1, entry 1). In the
presence of the porous organic polymers mPMF (50 mg, 7.6 wt. % based on dime-
thyl malonate) at room temperature after six hours, the conversion was improved
to 75% (Table 1, entry 2). A conversion of 100% was obtained by increasing the
amount of mPMF to 100 mg (Table 1, entry 3).
By shortening the milling time to three hours, there was no drop in the con-
version (Table 1, entry 4), however, a sudden drop was observed in the conver-
sion of 2a within two hours (Table 1, entry 5). As shown in Table 1 entries 6–8,
Table 1 The results of Knoevenagel condensation of model reactants at diferent conditions.a
Entry
(wt. % based on
Number of Revolutions per Ball diam- Milling
Conversion (%)
methyl malonate) ball mill
minute (rpm)
eter (mm)
time (h)
1
2
3
4b
5
6
7
8
0
7.6
4
4
4
4
4
4
2
2
600
600
600
600
600
400
600
600
5
5
5
5
5
5
5
7
6
6
6
3
2
3
3
3
35
75
100
100
72
78
56
62
15.1
15.1
15.1
15.1
15.1
15.1
a
Reaction conditions: 4–chlorobenzaldehyde 1a (5.0 mmol), dimethyl malonate (5.0 mmol), room tem-
perature
b Selected optimal condition
1 3

N. G. Khaligh et al.
the technical parameters also infuence the conversion. Decreasing the speed and
number of balls to 400 revolutions per minute (rpm) and two balls, respectively,
led to a signifcant drop in conversion (Table 1, entries 6 and 7). The increase of
the diameter of balls up to 7 mm also resulted in a 62% conversion (Table 1, entry
8). Entry 4 was chosen as the optimized reaction conditions (Table 1).
The substrate scope of the current method for the preparation of versatile inter-
mediates 2(a–n) was evaluated through the solid/slurry condensation of various
aldehydes 1(a–n) with dimethyl malonate in optimal conditions using a non-
conventional process (Scheme 1). The reaction mixture often formed a disper-
sion of the catalyst in the liquid phase of reactants (slurry phase) rather than a
solid phase because dimethyl malonate is a liquid and most of the aldehydes are
liquid or have low melting points such as benzaldehyde, 4–methylbenzaldehyde,
4–methoxybenzaldehyde, 4–fuorobenzaldehyde, 4– (trifuoromethyl)benzalde-
hyde, cinnamaldehyde, cyclohexanecarboxaldehyde, and 4–chlorobenzaldehyde.
Various substituted aromatic aldehydes, as well as heteroaromatic aldehydes
and cyclohexane carboxaldehyde, aforded high to excellent yields of the corre-
sponding dimethyl malonates under optimized reaction conditions (Table 2). The
heteroaromatic aldehydes such as pyridine–4–carboxaldehyde and 2,6–dichloro-
pyridine–3–carboxaldehyde gave the desired arylidene malonates in 82 and 78%
yield, respectively (Table 2, entries 6 and 12). The conjugated aldehyde such
as cinnamaldehyde gave 84% yield with no isomerization (Table 2, entry 11).
4–Methoxybenzaldehyde, 4-dimethyl amino benzaldehyde, and 3,4,5–trimeth-
oxybenzaldehyde were converted to the corresponding arylidene malonates in a
somewhat lower yield due to their electron-rich rings (Table 2, entries 4, 9, and
13). A lower yield for 3,4,5–trimethoxybenzaldehyde can be also attributed to the
steric hindrance of three methoxy groups. Dimethyl (cyclohexylidene)malonate
was successfully isolated in 72% yield (Table 2, entry 14).
Based on a survey of the literature [18, 19], a possible catalytic mechanism
is illustrated as shown in Scheme 2. The mMPF can act as a nucleophile and
base toward the aldehyde and the dimethyl malonate through H-bonding, which
resulted in the stability of the corresponding intermediate (I) (Scheme 2). In the
second step, the water is eliminated from intermediate (II) which gives the cor-
responding arylidene or alkylidene malonates.
O
O
R
O
O
O
O
O
H
mPMF (15.1 wt. % based on dimethyl malonate)
rpm (600), 4 ball (5 mm), r.t., 3 h
R
+
O
O
H
1(a-n)
2(a-n)
Isolated yield 70-92%
Scheme 1 Reaction conditions and isolated yield of desired products through the current protocol
1 3

Solid-phase synthesis of arylidene and alkylidene malonates,…
Table 2 Substrate-scope of the Knoevenagel condensation of various aldehydes with methyl malonate
using porous organic polymer mMPF.a
Entry Aldehydes 1(a-n)
Product 2(a-n) Yield (%)b Melting point (°C)
MS (ESI)
Found
Reported [16, 17] m/z [M+H]+
1
2
3
4
5
6
4–Cl–C6H4–
C6H5–
4–CH3–C6H4-
4–CH3O–C6H4-
4–NO2–C6H4-
a
b
c
d
e
f
92
88
87
76
92
82
36–38
39–40
Oil
36–37
40–41
Oil
255.0 and 257.0
221.1
235.1
251.1
266.1
Oil
Oil
134–136 135–136
71–73
4–Pyridinecarbox-
72–73
222.1
aldehyde
7
8
9
10
11
12
4–NC–C6H4-
g
h
i
j
k
l
86
91
74
88
84
78
95–96
41–42
85–87
36–38
80–82
75–77
97–98
43–44
86–87
38–39
81–82
–
246.1
289.1
264.1
239.1
247.1
290.1
4–CF3–C6H4-
4– (CH3)2 N–C6H4-
4–F–C6H4-
C6H5–CH=CH-
2,6–Dichloropyri-
dine–3–carboxal-
dehyde
13
3,4,5–(CH3O)3–
m
n
70
72
36–37
Oil
–
311.3
227.1
C6H2-
14
(CH2)5CH–
Oil
a
Chemicals including aldehyde 1(a-n) (5.0 mmol), dimethyl malonate (5.0 mmol), and mMPF (100 mg)
were ground at room temperature for 3 h by the use of four balls (5 mm) with revolution rate (600 rpm)
b Isolated yield
Scheme 2 A possible catalytic mechanism for the Knoevenagel condensation reaction using mPMF
1 3

N. G. Khaligh et al.
Easy separable and recyclability of mPMF
The mPMF could be separated by vacuum fltration using a Büchner funnel after
adding hot ethanol to the milling jar. The separated mPMF was washed with hot
ethanol several times and dried at 50 °C overnight. The recovered mPMF was
reused for ten successive runs. Dimethyl 2– (4–chlorobenzylidene)malonate 2a
was isolated in 88% yield after the 10th run which demonstrated high recyclabil-
ity of mPMF.
Scale‑up model Knoevenagel condensation reaction
Furthermore, a scale-up of the model reaction was investigated by the condensa-
tion of 4-chlorobenzaldehyde (7.03 g, 50 mmol) and dimethyl malonate (6.60 g,
50 mmol) in the presence of the mMPF (1.0 g) at room temperature under opti-
mized mechanical parameters. The corresponding product 2a was aforded in
78% yield (9.93 g) after three hours.
The superiority of the current protocol
In order to verify any advantage of using the mPMF, a comparison of the cata-
lytic activity of mPMF and a few catalytic protocols was performed for some sub-
strates in Table 2. Nanteuil and Waser reported a 76% yield of 2n using a stoichi-
ometry ratio of ammonium acetate/acetic acid at 60 °C after 20 h [17], whereas
our protocol gave the same product in 72% yield at room temperature after 3 h
using only 15 wt. % of mMPF. Sakai et al. obtained 2d and 2 g in 66 and 69%
yield, respectively, using metal-containing catalyst viz. Indium(III) chloride/ace-
tic anhydride in a toxic and fammable solvent (toluene) at 60 °C after 6 h [16].
The present protocol gave the same product of 2d and 2 g in 76 and 74% yields,
respectively, at room temperature within 3 h under solvent-free conditions.
Experimental
Synthesis of dimethyl 2–(4–chlorobenzylidene)malonate (2a) by the current
protocol
A mixture of 4-chlorobenzaldehyde (0.703 g, 5.0 mmol) (1a), dimethyl malonate
(0.660 g, 5.0 mmol), and mPMF (100 mg) was added into a milling jar, and the
slurry mixture was ground at 600 rpm in the presence of four balls (5 mm). The
mPMF was separated by vacuum fltration using a Büchner funnel after add-
ing 5 mL of hot ethanol to the milling jar. After washing of catalyst by ethanol
(5 × 2 mL), mPMF was dried at 50 °C overnight under vacuum and reused in the
subsequent runs. The crude products were purifed by column chromatography
(90:10 hexane/EtOAc) which gave the corresponding arylidene and alkylidene
1 3

Solid-phase synthesis of arylidene and alkylidene malonates,…
malonates. All known products were approved by comparison of their melting
point and 1H NMR with the ones reported in the literature (Table 2, entries 1–11
and 14) [16, 17].
The spectra data of the new products
2[2–(2,6–Dichloro-pyridine-3-yl)-vinyl]-dimethyl malonate (Table 2, entry 12): IR
(KBr): νmax 3095, 3052, 3016, 2961, 2854, 1730, 1710, 1637, 1574, 1544, 1454,
1
1440, 1426, 1368, 1347, 1274, 1228, 1195, 1140, 1077, 1069, 967 cm−1; H NMR
(600 MHz, CDCl3) δ 7.90 (s, 1H), 7.73 (d, J=8.2 Hz, 1H), 7.28 (dd, J=8.0, 0.7 Hz,
1H), 3.85 (s, 3H), 3.75 (s, 3H) ppm; 13C NMR (150 MHz, CDCl3) δ 165.2, 163.2,
151.5, 150.4, 139.5, 136.7, 130.8, 127.3, 123.2, 52.2, 52.0 ppm; MS (ESI): m/z
[M+H]+ 290.1.
2-(3,4,5-Trimethoxy-benzylidene)-dimethyl malonate (Table 2, entry 13): IR
(KBr): νmax 3090, 3056, 3010, 2965, 2859, 1735, 1718, 1634, 1571, 1538, 1451,
1
1437, 1417, 1363, 1342, 1271, 1222, 1198, 1141, 1081, 1072, 965 cm−1; H NMR
(600 MHz, CDCl3) δ 7.61 (s, 1H), 6.64 (s, 2H), 3.81 (s, 3H), 3.79 (s, 3H), 3.78 (s,
9H) ppm; 13C NMR (150 MHz, CDCl3) δ 167.37, 164.54, 153.31, 142.75, 140.44,
128.05, 124.61, 106.87, 60.96, 56.12, 52.71, 52.68 ppm; MS (ESI): m/z [M+H]+:
311.3.
1H NMR of some known products
2–(4–chlorobenzylidene)-dimethyl malonate (Table 2, entry 1): 1H NMR (600 MHz,
CDCl3) δ=7.71 (s, 1H), 7.35 (s, 4H), 3.85 (s, 6H) ppm.
2–(4–methyl-benzylidene)-dimethyl malonate (Table 2, entry 3): 1H NMR
(600 MHz, CDCl3) δ 7.75 (s, 1H), 7.33 (d, J=8.0 Hz, 2H), 7.20 (d, J=8.0, 0.7 Hz,
2H), 3.86 (s, 3H), 3.84 (s, 3H), 2.38 (s, 3H) ppm.
2–(4–methoxy-benzylidene)-dimethyl malonate (Table 2, entry 4): 1H NMR
(600 MHz, CDCl3) δ 7.73 (s, 1H), 7.41 (d, J=8.0 Hz, 2H), 6.91 (d, J=8.0, 0.7 Hz,
2H), 3.88 (s, 3H), 3.84 (s, 3H), 3.83 (s, 3H) ppm.
2–(4–cyanobenzylidene)-dimethyl malonate (Table 2, entry 7): 1H NMR
(600 MHz, CDCl3) δ=7.77 (s, 1H), 7.70 (d, J=8.0 Hz, 2H), 7.55 (d, J=8.1 Hz,
2H), 3.89 (s, 3H), 3.85 (s, 3H) ppm.
2–[4–(trifuoromethyl)benzylidene]-dimethyl malonate (Table 2, entry 8):
1H NMR (600 MHz, CDCl3) δ=7.78 (s, 1H), 7.66 (d, J=8.0 Hz, 2H), 7.54 (d,
J=8.0 Hz, 2H), 3.88 (s, 3H), 3.85 (s, 3H) ppm.
(E)–2–(3-phenylallylidene)–dimethyl malonate (Table 2, entry 11): 1H NMR
(600 MHz, CDCl3) δ=7.54 (d, J=11.4 Hz, 1H), 7.48 (d, J=6.0 Hz, 2H), 7.36–7.33
(m, 3H), 7.25 (dd, J=15.6, 15.0 Hz, 1H), 7.03 (d, J=16.0 Hz, 1H), 3.89 (s, 3H),
3.80 (s, 3H) ppm.
1
Cyclohexylidene-dimethyl malonate (Table 2, entry 14): H NMR (600 MHz,
CDCl3) δ=6.86 (t, J=10.2 Hz, 1H), 3.84 (s, 3H), 3.78 (s, 3H), 2.41–2.37 (m, 1H),
1.80–1.62 (m, 5H), 1.36–1.09 (m, 5H) ppm.
1 3

N. G. Khaligh et al.
Conclusion
In conclusion, a new catalytic application of mesoporous poly-melamine–formalde-
hyde (mPMF) was demonstrated for the Knoevenagel condensation reaction at room
temperature by a solid/slurry phase process. Avoid toxic, fammable, and corrosive
reagents and solvents, a catalytic amount of the catalyst, easy separation of porous
polymer catalyst, good to high yields of the desired products, wide scope of the sub-
strate, metal-free, acid-free and solvent-free conditions are among most-valuable
merits of the current methodology. Moreover, the cost-efectiveness and high recy-
clability of mPMF make it an interesting heterogeneous base catalyst for solid-phase
organic synthesis. The conversion, selectivity, and catalytic efciency of the current
protocol were superior to some previous reports in the literature.
Supplementary Information The online version contains supplementary material available at https://doi.
org/10.1007/s11164-021-04476-w.
Acknowledgements This work was partially supported by a research grant (RU001-2020) from the Uni-
versity of Malaya (Malaysia), and the authors are thankful to the Analytical and Testing staf member of
Nanotechnology & Catalysis Research Center from the University of Malaya (Malaysia).
Declarations
Confict of interest There are no conficts of interest to declare.
References
1. J.L. Do, T Frisčič. ACS Cent. Sci. 3, 13 (2017)
2. M.A.P. Martins, C.P. Frizzo, D.N. Moreira, L. Buriol, P. Machado, Chem. Rev. 109, 4140 (2009)
3. K. Tanaka, F. Toka, Chem. Rev. 100, 1025 (2000)
4. S. Wenda, S. Illner, A. Mell, U. Kragl, Green Chem. 13, 3007 (2011)
5. T. Laue, A. Plagens, Named Organic Reactions (Wiley, NewYork, 2005), pp. 176–186
6. L.G. Voskressensky, A.A. Festa, A.V. Varlamov, Tetrahedron 70, 551 (2014)
7. L. Zaharani, N.G. Khaligh, T. Mihankhah, M.R. Johan, Mol. Divers. (2020).
8. N.G. Khaligh, T. Mihankhah, Polycycl. Arom. Comp. (2020).
9. N.G. Khaligh, T. Mihankhah, M.R. Johan, Res. Chem. Intermed. 45, 3291 (2019)
10. E.M. Arnett, J.A. Harrelson Jr., J. Am. Chem. Soc. 109, 809 (1987)
11. D. Wang, Z. Li, Catal. Sci. Technol. 5, 1623 (2015)
12. J. Stary, J.O. Liljenzin, Pure Appl. Chem. 54, 2557 (1982)
13. F.M. Wong, J.R. Keefe, W.M. Wu, Tetrahedron Lett. 43, 3561 (2002)
14. H. McNab, Chem. Soc. Rev. 7, 345 (1978)
15. W.M. Haynes, ed. CRC Handbook of Chemistry and Physics (97th ed.). CRC Press. pp. 5–89 (2016)
16. Y. Ogiwara, K. Takahashi, T. Kitazawa, N. Sakai, J. Org. Chem. 80, 3101 (2015)
17. F. de Nanteuil, J. Waser, Angew. Chem. Int. Ed. 52, 9009 (2013)
18. N.G. Khaigh, M.R. Johan, Mini-Rev. Org. Chem. 17, 828 (2020)
19. L. Zaharani, N.G. Khaligh, H. Gorjian, M.R. Johan, Turk. J. Chem. 45, 261 (2021)
Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in published
maps and institutional afliations.
1 3