Sulfonic Acid and Ionic Liquid Functionalized Covalent Organic Framework for Efficient Catalysis of the Biginelli Reaction

Article abstract of DOI:10.1021/acs.joc.0c02423

A quinoline-linked and ionic liquid-decorated covalent organic framework was prepared by incorporation of a multicomponent Povarov reaction and postsynthetic modification. The imidazolium and sulfonic acid-decorated COF-IM-SO3H can be a highly efficient B

Full text of DOI:10.1021/acs.joc.0c02423

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Sulfonic Acid and Ionic Liquid Functionalized Covalent Organic
Framework for Efficient Catalysis of the Biginelli Reaction
Bing-Jian Yao,‡ Wen-Xiu Wu,‡ Luo-Gang Ding, and Yu-Bin Dong*
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ABSTRACT: A quinoline-linked and ionic liquid-decorated covalent
organic framework was prepared by incorporation of a multicomponent
Povarov reaction and postsynthetic modification. The imidazolium and
sulfonic acid-decorated COF-IM-SO3H can be a highly efficient Brønsted
acid catalyst to promote the Biginelli reaction under solvent-free
conditions in a heterogeneous way. In addition, a scaled-up Biginelli
reaction has been readily realized over a COF-IM-SO3H@chitosan
aerogel-based cup reactor.
multicomponent one-pot in situ polymerization methodology,
wing to the high degree of atom economy, multi-
Ocomponent reactions (MCRs) have attracted intense which can be an alternative way to synthesize the robust
linkage connected COFs.10
attention in organic and medicinal chemistry.1 Among various
MCRs, the Biginelli reaction,2 which is derived from aldehyde,
β-keto ester, and urea or thiourea with a catalytic amount of
acid, is one of the most important one-pot multicomponent
reactions due to the important pharmacological functionality of
the generated dihydropyrimidine derivatives (DHPMs).3 For
pursuing a “greener synthesis” of DHPMs in a facial, clean, and
atomic economic manner, metal-free organocatalysis has been
recognized as one of the feasible synthetic methodologies.4
However, the homogeneous organocatalysts faced some
problems such as catalyst separation and recycling, involved
hazardous organic solvents, and sometimes a long reaction
time.5 To address these issues, heterogeneous organocatalysis
should be an effective way to realize the green synthesis of
DHPMs.6 To meet the multifaceted requirements of good
stability, high activity, simplified product separation, facile
catalyst recycling, and so on, the design and synthesis of new
types of heterogeneous organocatalysts for the Biginelli
reaction are highly imperative.
As a result of their permanent porosity, highly ordered and
extended structure, good chemical stability, and tunable
functionality, covalent organic frameworks (COFs)7 have
emerged as a new type of organic material that can be
excellent candidates for the construction of heterogeneous
organocatalysts.8 In this context, the most reported COFs,
however, are connected via imine linkage, which suffers from
poor chemical stability against strong acidic or reducing
reagents.9 In order to expand linkage type and improve the
chemical stability of COFs, we and others recently developed a
In this contribution, we report herein a new quinoline-linked
COF-IM with an imidazole group via a three-component one-
pot in situ Povarov reaction. After postsynthetic modification
(PSM) with 1,3-propane sultone, both sulfonic acid and ionic
liquid (IL)-decorated COF-IM-SO3H, which can be a highly
active heterogeneous Brønsted acid type catalyst for the
Biginelli reaction, were generated. In addition, a scaled-up
Biginelli reaction was realized via a COF-IM-SO3H@chitosan
aerogel based fixed-bed model reactor.
Based on the model multicomponent Povarov reaction,11
among aniline, benzaldehyde (Ba), and 1-vinylimidazole
(VIM) (Scheme S1, Figures S1−S3), the three-component
one-pot in situ polymerization of 1,3,5-tri(4-aminophenyl)-
benzene (TAPB), 2,5-dimethoxybenzene-1,4-dicarboxaldehyde
(DMTPA), and VIM in the presence of Yb(OTf)3 and 2,3-
dicyano-5,6-dichloroben-quinone (DDQ) under solvothermal
conditions (MeCN, 80 °C, 3 days) afforded COF-IM as the
brick red crystalline solids in 87% yield (Scheme 1). Formation
of the quinoline linkage was verified by FTIR and solid-state
NMR spectroscopy (Figure S4), and the assignments were
made based on the molecular model compounds.
Received: October 13, 2020
Published: January 8, 2021
https://dx.doi.org/10.1021/acs.joc.0c02423
© 2021 American Chemical Society
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Scheme 1. Synthesis of COF-IM and COF-IM-SO3H
As revealed by the measured powder X-ray diffraction
(PXRD) patterns, the obtained COF-IM exhibited good
crystallinity (Figure 1a). The simulation of its PXRD patterns
The porosity of COF-IM was examined by N2 adsorption−
desorption measurements at 77 K. As shown in Figure 1c, the
N2 adsorption capacity and Brunauer−Emmett−Teller (BET)
surface area of COF-IM was 598 cm3 g−1 and 1203 m2 g−1,
respectively, and the total pore volume was calculated to be
0.615 cm3 g−1. The average pore size distribution is centered at
ca. 2.7 nm based on Barrett−Joyner−Halenda analysis, which
is in good agreement with that calculated from its crystal
structure (Figure S5). As expected, COF-IM is chemically
stable, and it can tolerate various conditions such as HCl,
NaOH, and NaBH4 aqueous solutions (Figure S6).
The excellent chemical stability allowed COF-IM to be
further modified. As shown in Scheme 1, sulfonic acid could be
easily decorated on the framework via PSM. Upon reaction of
COF-IM with 1,3-propane sultone in acetone for 24 h,
together with subsequent protonation, sulfonic acid-function-
alized COF-IM-SO3H was obtained as a brick red crystalline
powder in 48% yield. As indicated in Figure 1a, the crystallinity
and structural integrality of COF-IM was well maintained after
PSM. Besides IR and solid-state NMR spectra character-
izations (Figure S4), the N2 adsorption isotherm of COF-IM-
SO3H indicated that its N2 adsorption capacity and BET
surface area, respectively, decreased to 351.5 cm3 g−1 and 504.6
m2 g−1 (Figure 1c), which is undoubtedly caused by the partial
channel occupation after PSM. Accordingly, the pore volume
and size of COF-IM-SO3H decreased to 0.319 cm3 g−1 and 2.5
nm (Figure S5), respectively.
Thermogravimetric analysis (TGA, Figure 1d) revealed that
both COF-IM and COF-IM-SO3H were thermally stable at
250 °C, indicating their sufficient stability for catalytic
applications. The SEM and TEM images showed COF-IM
and COF-IM-SO3H, which were highly crystalline, and
nanoscale spherical particles with good phase purity (Figure
S7). In addition, the energy-dispersive X-ray spectra (EDX-
mapping) of COF-IM and COF-IM-SO3H clearly indicated
the required elemental composition (Figure S8).
Figure 1. (a) Simulated and measured PXRD patterns of COF-IM
and COF-IM-SO3H: comparison between the experimental (red and
green lines) and Pawley refined profile (black dots), the simulated
pattern for eclipsed (AA) stacking mode (purple line), and the
refinement difference (blue line). (b) Crystal structure viewed down
the crystallographic c axis. (c) N2 adsorption isotherms of COF-IM
and COF-IM-SO3H at 77 K. (d) TGA traces of COF-IM and COF-
IM-SO3H.
with Materials Studio (version 2018)12 suggested that COF-
IM possesses preferably the 2D eclipsed AA-type stacking
arrangement using the space group P3 with the lattice
parameters a = b = 36.9554 Å, c = 3.9068 Å, α = β = 90°, γ
= 120°, residuals Rwp = 4.33% and Rp = 3.36% (Table S1).
Pawley refinement showed a negligible difference between the
simulated and experimental PXRD pattern, and COF-IM
displayed prominent peaks at 2.77, 4.80, 5.56, and 7.37
corresponding to (100), (110), (200), and (210) facets,
respectively. Figure 1b showed that the eclipsed 2D structure
contains hexagonal pores with a diameter of ∼2.7 nm based on
crystal structural analysis.
In addition, COF-IM-SO3H is stable against organic
(DMSO, DMF, toluene, MeCN, CH2Cl2, THF, acetone)
and aqueous media (Figure S6), which would ensure the safety
in the catalysis with different media. More importantly, the
coexistence of SO3H and ILs would allow COF-IM-SO3H to
promote MCRs efficiently.13
As shown in Figure 2a, the reaction of benzaldehyde, ethyl
acetoacetate, and urea was chosen as the model Biginelli
reaction to examine the catalytic activity of COF-IM-SO3H.
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conditions, the reactions gave excellent yields (90−98%) for
different aromatic aldehydes with a wide range of functional
groups, such as −OH, −NO2, −CH3, −Cl, and −OCH3, at
different substituted positions on substituted benzaldehydes
(Table 1, entries 1−8). For heterocyclic aldehydes, such as 3-
Table 1. Scope of the Biginelli Reaction Catalyzed by COF-
a
IM-SO3H
b
EN
R1
R2
X
yield (%)
1
2
3
4
5
6
7
8
Ph
2-ClPh
4-ClPh
4-NO2Ph
4-MePh
2-MeOPh
4-MeOPh
4-OHPh
3-pyridine
2-fural
cyclohexyl
hexyl
(1,1′-biphenyl)-4-yl
2-naphtyl
Ph
4-ClPh
4-MePh
Ph
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Me
Me
Me
Et
Et
Et
Me
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
S
98 (4a)
90 (4b)
92 (4c)
94 (4d)
93 (4e)
90 (4f)
96 (4g)
92 (4h)
75 (4i)
89 (4j)
90 (4k)
92 (4l)
60 (4m)
60 (4n)
96 (4o)
94 (4p)
93 (4q)
93 (4r)
89 (4s)
91 (4t)
86 (4u)
Figure 2. (a) Model Biginelli reaction. (b) Effect of temperature,
reaction time, and catalyst amount on the catalytic Biginelli reaction
over COF-IM-SO3H. Reaction conditions: solvent-free, benzaldehyde
(1.0 mmol), ethyl acetoacetate (1.0 mmol), urea (1.0 mmol), COF-
IM-SO3H (0.3−1.0 mol %, 2.59−8.64 mg), 25−90 °C. (c) Catalytic
cycles.
9
Compared with organic and aqueous media such as EtOH,
MeOH, toluene, and water (Figure S9), the solvent-free was
confirmed to be the best condition for the reaction (Figure
2b). In addition, the reaction temperature was screened, and
Figure 2b showed that the best reaction temperature was 90
°C, and the maximum isolated yield of 98% was achieved
within ∼2.5 h. When the catalyst loading was switched to 0.3
and 0.6 mol % at 90 °C, it gave reasonable isolated yields (80−
84%), and higher yields of 93 and 95% can be reached by
extending the reaction time to 5.0 h. When the reaction was
conducted at 25 and 60 °C over 1.0 mol % of the catalyst, it
turned into the Biginelli adducts in the yield of 4 and 23%
within 2.5 h, respectively, indicating the positive correlation
between catalytic efficiency and temperature. Thus, the best
reaction conditions herein were determined as 1.0 mol %
COF-IM-SO3H, 90 °C, solvent-free, and 2.5 h. Based on each
sulfonic acid unit present in COF-IM-SO3H, the correspond-
ing turnover number (TON) and turnover frequency (TOF)
were 98 and 39 h−1, respectively. By comparison, sulfonic acid-
10
11
12
13
14
15
16
17
18
19
20
21
4-ClPh
4-MeOPh
Ph
S
S
S
a
Reaction conditions: solvent-free, aromatic aldehyde (1.0 mmol),
ethyl acetoacetate (1.0 mmol), urea or thiourea (1.0 mmol), COF-
b
IM-SO3H (8.64 mg, 1.0 mol %), 90 °C, 2.5 h. Isolated yields.
Compounds 4a−u were characterized by H NMR, 13C NMR, and
1
MS spectra (Figures S12−S32).
pyridine carboxaldehyde and furfural, the corresponding
product was obtained in 75 and 89% yields, respectively
(Table 1, entries 9 and 10). The reaction worked well for
aliphatic aldehydes: cyclohexanealdehyde and hexaldehyde
gave 90 and 92% yields, respectively (Table 1, entries 11 and
12). The large substrates of 2-naphthaldehyde and 4-
phenylbenzaldehyde gave a moderate 60% yield (Table 1,
entries 13 and 14), and the decrease in yield might result from
their limited diffusion within the COF framework. In the case
of using methyl acetoacetate instead of ethyl acetoacetate, the
target products of benzaldehyde, 4-chlorobenzaldehyde, and 4-
methylbenzaldehyde were isolated in excellent yields of 96, 94,
and 93%, respectively (Table 1, entries 15−17).
Additionally, the reactions of thiourea with different
benzaldehydes and ethyl acetoacetate were also examined,
and they could afford corresponding products in 89−93%
yields (Table 1, entries 18−20). Moreover, the reaction
between benzaldehyde, methyl acetoacetate, and thiourea gives
the corresponding product in 86% yield (Table 1, entry 21).
The mechanism of this COF-IM-SO3H-catalyzed Biginelli
reaction was proposed under solvent-free conditions, which is
believed to be the same as suggested by Kappe (Figure S33).38
−
functionalized ionic liquids containing the HSO4 counter-
anion would enhance the Brønsted acidity of the catalyst
(Table S2), which is well consistent with the previous work.14
Of note, COF-IM-SO3H herein is one of the best catalysts for
the Biginelli reaction among the reported heterogeneous
catalysts (Table S3),15−37 which may be attributed to its high
density of sulfonic acid moiety and high surface area.
The hot leaching test demonstrated that COF-IM-SO3H is a
typical heterogeneous catalyst (Figure S10), and the isolated
yield of the desired Biginelli adducts was still up to 94% even
after five catalytic cycles (Figure 2c). The crystallinity and
structural integrity of COF-IM-SO3H, however, were intact
after multiple catalytic runs (Figures S10 and S11), indicating
the robust nature of the quinoline linkage. In addition, the
SEM-EDX mapping (Figure S10) and elemental analysis
(Table S4) revealed that no changes in morphology or
chemical composition occurred. Thus, COF-IM-SO3H herein
is an ideal platform for loading of Brønsted acid and task-
specific ILs for the catalysis of the Biginelli reaction.
The Biginelli reaction can be readily extended to various
other substrates with 100% selectivity. Under the optimized
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For practical application, we designed and fabricated a COF-
IM-SO3H@chitosan aerogel-based cup-like reactor39 (Figure
3a,b), which was used as a fixed-bed model to realize the
and its cup-like reactor can act as a highly efficient and reusable
fixed-bed model to realize the scaled-up Biginelli reaction. The
potential utility of this strategy is highlighted by the
preparation of many more new COF-based multifunctional
heterogeneous organocatalysts to promote various organic
transformations in a green and facile way.
EXPERIMENTAL SECTION
■
All chemicals were obtained from commercial sources and used
without further purification. Proton nuclear magnetic resonance (1H
NMR) data were obtained on a Bruker Avance 400 HD spectrometer
with tetramethylsilane (TMS) as the internal standard. Fourier
transform infrared (FT-IR) spectroscopy was performed on a Bruker
ALPHA spectrometer in the range of 400−4000 cm−1. High-
resolution mass spectrometry (HRMS) analysis was carried out on
a Bruker maXis ultrahigh-resolution-TOF mass spectrometer.
Elemental analysis was performed on an Elemental UNICUBE
elemental analyzer. The solid-state 13C cross-polarization magic angle
spinning (CP-MAS) NMR spectra were obtained on a Bruker
AVANCE II 400 spectrometer. Scanning electron microscopy (SEM)
was conducted on a Gemini Zeiss SUPRA scanning electron
microscope equipped with an energy-dispersive X-ray detector. The
Powder X-ray diffraction patterns were measured on a D8 Advance X-
ray powder diffractometer (Cu Kα radiation λ = 1.5405 Å). N2
adsorption−desorption isotherms were obtained on an ASAP 2020/
TriStar 3000 (Micromeritics). Thermogravimetric analyses (TGA)
were performed on a TA Instrument Q5 simultaneous TGA at a
heating rate of 10 °C min−1 from 25 to 800 °C under 60 mL min−1
with flowing nitrogen. Melting points were measured on a X-4 Digital
display microscopic melting point tester. Differential thermal scanning
(DSC) was performed on a METTLER TOLEDO DSC3+ instrument.
Synthesis Model Compounds A and B. Synthesis of A. A
mixture of aniline (149 mg, 1.6 mmol), benzaldehyde (170 mg, 1.6
mmol), 1-vinylimidazole (151 mg, 1.6 mmol), Yb(OTf)3 (50 mg, 5
mol %), and DDQ (25.6 mg, 0.096 mmol) in 30 mL of MeCN was
sealed in a Pyrex tube. The tube was flash frozen in a liquid nitrogen
bath and evacuated to an internal pressure of 0.5 mbar and flame-
sealed. After the mixture was heated at 80 °C (oil bath) in N2 for 72
h, the crude product was purified via column chromatography (eluent:
dichloromethane/petroleum ether = 4:1) to afford A as a yellow
Figure 3. (a) Side and (b) top views and (c) SEM images of the
COF-IM-SO3H@chitosan cup reactor. (d) Reaction monitoring.
Reaction conditions: solvent-free, benzaldehyde (305.6 mmol), ethyl
acetoacetate (305.6 mmol), urea (305.6 mmol), COF-IM-SO3H@
chitosan (1.65 g, 0.5 mol % COF-IM-SO3H equiv), 90 °C.
scaled-up Biginelli reaction. The COF-IM-SO3H content in
porous aerogel is up to 80 wt %. SEM images indicated that the
COF-IM-SO3H nanoparticles are homogeneously blended in
the macropores aerogel with no detectable interface boundary
(Figure 3c). PXRD patterns indicated that the structural
integrity and crystallinity of COF-IM-SO3H were well retained
(Figure S34). As the ice-template-generated macropore aerogel
did not significantly contribute to the surface area, the COF-
IM-SO3H@chitosan showed a decreased N2 adsorption
capacity (221.5 cm3 g−1) and a lower BET specific surface
area (160.6 m2 g−1) (Figure S34).
As shown in Figure 3d, when 31.2 mL of (305.6 mmol)
benzaldehyde, 38.7 mL of ethyl acetoacetate (305.6 mmol),
and 18.35 g of urea (305.6 mmol) were used to perform the
reaction in a cup-like reactor (1.65 g of COF-IM-SO3H@
chitosan, 0.5 mol % COF-IM-SO3H equiv), a 93% isolated
yield (73.9 g) of the desired product was obtained within 6 h.
After the reaction, the product−catalyst separation was easily
achieved by simply washing with hot ethanol, and the cup-like
reactor was directly used for the next catalytic cycle after
vacuum drying. The COF-IM-SO3H@chitosan reactor was
very stable under the given conditions, and it could be reused
at least five times without loss of its catalytic activity (yield ≥
92%) (Figure S34). Thus, the aerogel monolith used herein is
highly efficient, versatile, maneuverable toward organic
catalytic conversion, and it could effectively overcome the
issues of catalyst regeneration and product separation.
1
powder in 94% yield (407.8 mg): mp 125−126 °C; H NMR (400
MHz, DMSO-d6) δ 8.41 (d, 1H), 8.33 (q, J = 6.3 Hz, 2H), 8.21 (d, J
= 8.4 Hz, 1H), 8.16 (t, J = 7.0 Hz, 1H), 7.91 (t, J = 7.0 Hz, 1H), 7.77
(t, J = 7.3 Hz, 1H), 7.65 (m, J = 6.7 Hz, 3H), 7.55 (m, J = 7.2 Hz,
3H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 156.8, 148.8, 142.8,
137.9, 135.5 (2C), 131.7, 131.1, 130.2 (2C), 129.4, 128.5 (2C),
127.9, 125.0, 124.0, 120.8, 119.4; IR (KBr, cm−1) 3106 (s), 1589 (m),
1488 (m), 1405 (w), 1325 (m), 1210 (m), 1210 (w), 1054 (m), 937
(s), 841 (w), 758 (m), 693 (w), 658 (m); HRMS (ESI) m/z [M +
H]+ calcd for C18H13N3 272.1182, found 272.1186.
Synthesis of B. A mixture of A (271 mg, 1 mmol) and 1,3-propane
sultone (134 mg, 1.1 mmol) in 10 mL of acetone was stirred at room
temperature for 24 h. Then, the precipitated solid product was
collected by filtration, washed with acetone, and then dried under a
vacuum at room temperature. The solids were mixed with 10 mL of
H2SO4 aqueous solution (0.05 mM, pH = 4) and stirred for 1 h at
room temperature. After rotary evaporation, washing with ethyl
acetate (3 × 5 mL), and vacuum drying, B was generated in 78% yield
(307.7 mg): Tg −58.3 °C; 1H NMR (400 MHz, DMSO-d6) δ 8.43 (d,
1H), 8.33 (q, J = 6.3 Hz, 2H), 8.22 (d, J = 8.4 Hz, 1H), 8.17 (t, J = 7.0
Hz, 1H), 7.92 (t, J = 7.0 Hz, 1H), 7.81 (q, J = 7.3 Hz, 2H), 7.69 (m, J
In conclusion, we report a robust quinoline-linked COF with
SO3H and ILs moieties. Due to its strong acidity and high
porosity, the obtained COF-IM-SO3H can be an efficient
Brønsted acid type catalyst to promote the Biginelli reaction
under solvent-free conditions in a heterogeneous way. Besides,
an ice-templated COF-IM-SO3H@chitosan aerogel with
remarkably high COF loading (up to 80 wt %) was prepared,
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= 6.7 Hz, 2H), 7.56 (m, J = 7.2 Hz, 3H), 4.33 (t, J = 6.9 Hz, 2H), 2.40
(t, J = 6.9 Hz, 2H), 2.10 (m, J = 6.9 Hz, 2H); 13C{1H} NMR (100
MHz, DMSO-d6) δ 156.8, 148.6, 143.0, 137.8, 135.9, 131.7, 130.7,
130.0, 129.4 (2C), 128.5, 128.0 (2C), 125.1, 124.1, 122.5, 120.3,
119.4, 48.0, 47.8, 26.7; IR (KBr, cm−1) 3113 (m), 1590 (m), 1497
(w), 1358 (w), 1210 (m), 1108 (w), 1027 (s), 977 (m),775 (w), 522
(m); HRMS (ESI) m/z [M]+ calcd for C21H20N3O3S+ 394.1220,
found 394.1294; [M]− calcd for HSO4− 96.9601, found 96.9649; [M
− H]− calcd for C21H21N3O7S2 490.0748, found 490.0877.
the general procedure: white powder (265 mg, 90%); mp 223−224
°C;40a 1H NMR (400 MHz, DMSO-d6) δ 9.28 (s, 1H), 7.71 (s, 1H),
7.41−7.24 (m, 4H), 5.63 (d, J = 2.7 Hz, 1H), 3.86 (q, J = 7.1 Hz,
2H), 2.30 (s, 3H), 0.97 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100
MHz, DMSO-d6) δ 165.4, 151.7, 149.8, 142.2, 132.1, 129.8, 129.5,
129.2, 128.2, 98.4, 59.5, 51.9, 18.1, 14.4; HRMS (ESI) m/z [M + H]+
calcd for C14H15ClN2O3 295.0844, found 295.0842.
5-(Ethoxycarbonyl)-6-methyl-4-(4-chlorophenyl)-3,4-dihydro-
pyrimidin-2(1H)-one (4c). The compound was prepared according to
the general procedure: white powder (271 mg, 92%); mp 217−218
°C;40a 1H NMR (400 MHz, DMSO-d6) δ 9.26 (s, 1H), 7.78 (s, 1H),
7.39 (d, J = 8.5 Hz, 2H), 7.24 (d, J = 8.5 Hz, 2H), 5.15 (d, J = 3.2 Hz,
1H), 3.98 (q, J = 7.1 Hz, 2H), 2.26 (s, 3H), 1.09 (t, J = 7.1 Hz, 3H);
13C{1H} NMR (100 MHz, DMSO-d6) δ 165.7, 152.4, 149.2, 144.3,
132.2, 128.9, 128.6, 99.3, 59.7, 53.9, 18.3, 14.5; HRMS (ESI) m/z [M
+ H]+ calcd for C14H15ClN2O3 295.0844, found 295.0848.
5-(Ethoxycarbonyl)-6-methyl-4-(4-nitrophenyl)-3,4-dihydr-opyri-
midin-2(1H)-one (4d). The compound was prepared according to the
general procedure: yellow powder (287 mg, 94%); mp 201−202
°C;40a 1H NMR (400 MHz, DMSO-d6) δ 9.38 (s, 1H), 8.22 (d, J =
8.7 Hz, 2H), 7.91 (s, 1H), 7.51 (d, J = 8.7 Hz, 2H), 5.29 (d, J = 3.3
Hz, 1H), 3.99 (q, J = 7.1 Hz, 2H), 2.28 (s, 3H), 1.10 (t, J = 7.1 Hz,
3H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 165.5, 152.5, 152.2,
149.9, 147.2, 128.1, 124.3, 98.6, 59.9, 54.1, 18.3, 14.5; HRMS (ESI)
m/z [M + H]+ calcd for C14H15N3O5 306.1084, found 306.1082.
5-(Ethoxycarbonyl)-6-methyl-4-(4-methylphenyl)-3,4-dihydro-
pyrimidin-2(1H)-one (4e). The compound was prepared according to
the general procedure: white powder (255 mg, 93%); mp 216−217
°C;40a 1H NMR (400 MHz, DMSO-d6) δ 9.15 (s, 1H), 7.68 (s, 1H),
7.11 (s, 4H), 5.10 (d, J = 3.2 Hz, 1H), 3.98 (q, J = 7.1 Hz, 2H), 2.26
(s, 3H), 2.23 (s, 3H), 1.10 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100
MHz, DMSO-d6) δ 165.8, 152.6, 148.6, 142.4, 136.8, 129.3, 126.6,
99.9, 59.6, 54.5, 21.1, 18.2, 14.6; HRMS (ESI) m/z [M + H]+ calcd
for C15H18N2O3 275.1390, found 275.1391.
5-(Ethoxycarbonyl)-6-methyl-4-(2-methoxyphenyl)-3,4-dihydro-
pyrimidin-2(1H)-one (4f). The compound was prepared according to
the general procedure: white powder (262 mg, 90%); mp 264−268
°C;40b 1H NMR (400 MHz, DMSO-d6) δ 9.11 (s, 1H), 7.27 (s, 1H),
6.85−7.25 (m, 4H,), 5.49 (d, J = 3.1 Hz, 1H), 3.91 (q, J = 7.1 Hz,
2H), 3.79 (s, 3H), 2.28 (s, 3H), 1.00 (t, J = 7.1 Hz, 3H); 13C{1H}
NMR (100 MHz, DMSO-d6) δ 165.8, 157.0, 152.6, 149.3, 132.1,
129.6, 127.6, 120.6, 111.6, 59.4, 55.8, 49.7, 18.2, 14.5; HRMS (ESI)
m/z [M + H]+ calcd for C15H18N2O4 291.1339, found 291.1336.
5-(Ethoxycarbonyl)-6-methyl-4-(4-methoxyphenyl)-3,4-dihydro-
pyrimidin-2(1H)-one (4g). The compound was prepared according to
the general procedure: white powder (279 mg, 96%); mp 204−206
°C;40a 1H NMR (400 MHz, DMSO-d6) δ 9.15 (s, 1H), 7.70 (s, 1H),
7.13 (d, J = 8.7 Hz, 2H), 6.86 (d, J = 8.7 Hz, 2H), 5.09 (d, J = 3.1 Hz,
1H), 3.97 (q, J = 7.1 Hz, 2H), 3.72 (s, 3H), 2.24 (s, 3H),1.10 (t, J =
7.1 Hz, 3H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 165.8, 158.9,
152.6, 148.5, 137.5, 127.9, 114.2, 100.0, 59.6, 55.5, 53.8, 18.2, 14.6;
HRMS (ESI) m/z [M + H]+ calcd for C15H18N2O4 291.1339, found
291.1335.
5-(Ethoxycarbonyl)-6-methyl-4-(4-hydroxyphenyl)-3,4-dihydro-
pyrimidin-2(1H)-one (4h). The compound was prepared according to
the general procedure: white powder (255 mg, 92%); mp 225−226
°C;40c 1H NMR (400 MHz, DMSO-d6) δ 9.32 (s, 1H), 9.10 (s, 1H),
7.57 (s, 1H), 7.01(d, J = 8.1 Hz, 2H), 6.67 (d, J = 8.1 Hz, 2H), 5.03
(d, J = 3.0 Hz, 1H), 3.98 (q, J = 7.1 Hz, 2H), 2.23 (s, 3H), 1.10 (t, J =
7.1 Hz, 3H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 166.3, 157.0,
152.6, 148.6, 136.3, 128.4, 115.4, 100.7, 59.6, 53.4, 18.9, 15.1; HRMS
(ESI) m/z [M + H]+ calcd for C14H16N2O4 277.1183, found
277.1187.
5-(Ethoxycarbonyl)-6-methyl-4-(3-pyridine)-3,4-dihydropy-rimi-
din-2(1H)-one (4i). The compound was prepared according to the
general procedure: white powder (196 mg, 75%); mp 205−206
°C;40d 1H NMR (400 MHz, DMSO-d6) δ 9.31 (s, 1H), 8.45 (d, J =
8.7 Hz, 2H), 7.80 (d, J = 8.7 Hz, 1H), 7.60 (s, 1H), 7.36 (t, J = 8.7
Hz, 1H), 5.20 (d, J = 3.1 Hz, 1H), 3.97 (q, J = 7.1 Hz, 2H), 2.27 (s,
3H), 1.10 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, DMSO-d6)
Synthesis COF-IM and COF-IM-SO3H. Synthesis of COF-IM.
The synthetic procedure refers to our reported work with
modification.10b In brief, a mixture of 1,3,5-tri(4-aminophenyl)-
benzene (TAPB) (56.2 mg, 0.16 mmol), 2,5-dimethoxy terephtha-
laldehyde (DMTPA) (46.5 mg, 0.24 mmol), 1-vinylimidazole (VIM)
(226.4 μL, 2.50 mmol), Yb(OTf)3 (15.0 mg, 0.024 mmol), and DDQ
(8 mg, 0.03 mmol) in 3 mL of MeCN was sealed in a Pyrex tube. The
tube was flash frozen in a liquid nitrogen bath, evacuated to an
internal pressure of 0.5 mbar, and flame-sealed. Upon warming to
room temperature, it was heated under N2 at 80 °C (oil bath) for 3
days. The obtained solids were completely washed with THF (15 mL
× 6) and dried in a vacuum at 120 °C for 24 h to produce COF-IM as
brick red solids in 87% yield (120.3 mg). Elemental Analysis (%)
calcd for (C18H13N3O)n (desolvated) (%): C, 75.22; H, 4.56; N,
14.63; O, 5.57. Found (%): C, 75.45; H, 4.52; N, 14.59; O, 5.35. FT-
IR (KBr, cm−1): 3359 (w), 1592 (m), 1500 (s), 1408 (m), 1288 (w),
1210 (m), 1035 (w), 828 (m). Solid-state 13C {1H} MAS NMR (δ,
ppm): 157, 150, 144, 137, 132, 124, 120, 116, 110, 56.
Synthesis of COF-IM-SO3H. COF-IM (287 mg, 1 mmol) was
dispersed in 20 mL of acetone solution of 1,3-propane sultone (1.1
mmol, 134 mg). After the mixture was stirred at room temperature for
24 h, the precipitate was collected by centrifugation and completely
washed with acetone (5 mL). After drying under a vacuum, the solids
were mixed with 10 mL of H2SO4 aqueous solution (0.05 mM, pH =
4), and the mixture was stirred for 1 h at room temperature to afford
COF-IM-SO3H as brick red solids. According to the elemental
analysis of sulfur content (3.75 wt %), the postsynthetic modification
yield was ca. 48% (197.2 mg). FT-IR (KBr, cm−1): 3359 (w), 1592
(m), 1500 (s), 1408 (w), 1288 (w), 1210 (m), 1108 (w), 1035 (m),
824 (m). Solid-state 13C {1H} MAS NMR (δ, ppm): 157, 150, 142,
137, 134, 124, 120, 117, 112, 56, 50, 23.
Catalytic Biginelli Reaction over COF-IM-SO3H. General
Procedure. In a typical procedure, a mixture of aromatic aldehyde
(1.0 mmol), ethyl acetoacetate (1.0 mmol), and urea (1.0 mmol) was
stirred at 90 °C (oil bath), utilizing COF-IM-SO3H (8.64 mg, 1.0 mol
%) under solvent-free conditions for the appropriate time until the
reaction was complete (monitored by TLC). After the addition of hot
ethanol (5 mL, 60 °C) and after the mixture was centrifuged and
filtrated, the formed precipitate was collected. The crude product was
purified by recrystallization in ethanol, and the structure of the desired
Biginelli adduct (3,4-dihydopyrimidin-2(1H)-ones) was confirmed by
1H NMR, 13C NMR, and MS spectra.
5-Ethoxycarbonyl-6-methyl-4-phenyl-3,4-dihydropyrimidin-
(1H)-one (4a). The compound was prepared according to the general
procedure: white powder (255 mg, 98%); mp 202−204 °C;40a 1H
NMR (400 MHz, DMSO-d6) δ 9.19 (s, 1H), 7.74 (s, 1H), 7.32 (t,
2H), 7.25 (d, 3H), 5.15 (d, J = 3.2 Hz, 1H), 3.97 (q, J = 7.1 Hz, 2H),
2.25 (s, 3H), 1.09 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100 MHz,
DMSO-d6) δ 165.8, 152.6, 148.8, 145.3, 129.2, 127.7, 126.7, 99.7,
59.6, 54.4, 18.2, 14.5; HRMS (ESI) m/z [M + H]+ calcd for
C14H16N2O3 261.1234, found 261.1234.
5-(Ethoxycarbonyl)-6-methyl-4-(2-chlorophenyl)-3,4-dihy-dro-
pyrimidin-2(1H)-one (4b). The compound was prepared according to
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Note
δ 166.0, 152.3, 149.6, 141.0, 134.4, 124.3, 98.8, 59.8, 53.8, 18.2, 14.5;
HRMS (ESI) m/z [M + H]+ calcd for C13H15N3O3 262.1186, found
262.1185.
13C{1H} NMR (100 MHz, DMSO-d6) δ 166.3, 152.6, 149.0, 142.2,
136.9, 129.4, 126.6, 99.6, 53.6, 21.1, 18.3; HRMS (ESI) m/z [M +
H]+ calcd for C14H16N2O3 261.1234, found 261.1237.
5-(Ethoxycarbonyl)-6-methyl-4-(2-furaldehyde)-3,4-dihydropyri-
midin-2(1H)-one (4j). The compound was prepared according to the
general procedure: white powder (223 mg, 89%); mp 203−205 °C;40c
1H NMR (400 MHz, DMSO-d6) δ 9.24 (s, 1H), 7.75 (s, 1H), 7.55 (d,
1H), 6.35 (t, 1H), 6.09 (d, 1H), 5.20 (s, 1H), 4.03 (q, J = 7.1 Hz,
2H), 2.23 (s, 3H), 1.14 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100
MHz, DMSO-d6) δ 165.5, 156.8, 152.5, 150.2, 142.6, 110.8, 106.2,
97.6, 59.7, 49.1, 18.2, 14.6; HRMS (ESI) m/z [M + H]+ calcd for
C12H14N2O4 251.1026, found 251.1022.
5-(Ethoxycarbonyl)-6-methyl-4-phenyl-3,4-dihydropyrimidin-
2(1H)-thione (4r). The compound was prepared according to the
general procedure: white powder (257 mg, 93%); mp 209−210
°C;40b 1H NMR (400 MHz, DMSO-d6) δ 10.34 (s, 1H), 9.65 (s, 1H),
7.37−7.21 (m, 5H), 5.17 (d, J = 3.4 Hz, 1H), 4.00 (q, J = 7.1 Hz,
2H), 2.29 (s, 3H), 1.10 (s, 3H); 13C{1H} NMR (100 MHz, DMSO-
d6) δ 174.7, 166.0, 145.5, 144.0, 129.0, 128.2, 126.9, 101.2, 60.6, 54.5,
18.1, 14.5; HRMS (ESI) m/z [M + H]+ calcd for C14H16N2O2S
277.1005, found 277.1004.
5-(Ethoxycarbonyl)-6-methyl-4-(4-chlorophenyl)-3,4-dihydro-
pyrimidin-2(1H)-thione (4s). The compound was prepared according
to the general procedure: white powder (276 mg, 89%); mp 192−193
°C;40f 1H NMR (400 MHz, DMSO-d6) δ 10.39 (s, 1H), 9.67 (s, 1H),
7.44 (d, J = 8.5 Hz, 2H), 7.22 (d, J = 8.5 Hz, 2H), 5.17 (d, J = 3.4 Hz,
1H), 4.00 (q, J = 7.1 Hz, 2H),2.29 (s, 3H), 1.10 (t, J = 6.6 Hz, 3H);
13C{1H} NMR (100 MHz, DMSO-d6) δ 174.7, 165.5, 145.9, 142.9,
132.7, 129.1, 128.8, 100.8, 60.1, 53.9, 17.7, 14.0; HRMS (ESI) m/z
[M + H]+ calcd for C14H15ClN2O2S 311.0616, found 311.0612.
5-(Ethoxycarbonyl)-6-methyl-4-(4-methoxyphenyl)-3,4-dihydro-
pyrimidin-2(1H)-thione (4t). The compound was prepared according
to the general procedure: white powder (279 mg, 91%); mp 155−157
°C;40g 1H NMR (400 MHz, DMSO-d6) δ 10.29 (s, 1H), 9.60 (s, 1H),
7.13 (d, J = 8.7 Hz, 2H), 6.89 (d, J = 8.7 Hz, 2H), 5.11 (d, J = 3.4 Hz,
1H), 4.01 (q, J = 7.1 Hz, 2H), 3.72 (s, 3H), 2.28 (s, 3H), 1.11 (t, J =
7.0 Hz, 3H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 174.5, 166.1,
159.8, 145.2, 136.7, 127.7, 114.4, 101.4, 60.0, 55.0, 53.9, 17.6, 14.0;
HRMS (ESI) m/z [M + H]+ calcd for C15H18N2O3S 307.1111, found
307.1114.
5-(Ethoxycarbonyl)-6-methyl-4-cyclohexyl-3,4-dihydropyrimi-
din-2(1H)-one (4k). The compound was prepared according to the
general procedure: white powder (240 mg, 90%); mp 233−234 °C;40a
1H NMR (400 MHz, DMSO-d6) δ 8.93 (s, 1H), 7.34 (s, 1H), 4.08−
3.89 (m, 3H), 2.16 (s, 3H), 1.07−1.14 (t, J = 7.1 Hz, 3H), 0.84−0.9,
1.16−1.73 (m, 11H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 166.3,
153.7, 149.0, 98.4, 59.5, 55.4, 45.3, 29.0, 26.7, 26.5, 26.4, 26.1, 18.2,
14.6; HRMS (ESI) m/z [M + H]+ calcd for C14H22N2O3 267.1703,
found 267.1727.
5-(Ethoxycarbonyl)-6-methyl-4-hexyl-3,4-dihydropyrimidin-
2(1H)-one (4l). The compound was prepared according to the general
procedure: white powder (234 mg, 92%); mp 227−228 °C;40a 1H
NMR (400 MHz, DMSO-d6) δ 9.01 (s, 1H), 7.34 (s, 1H), 4.00−4.08
(q, J = 7.1 Hz, 3H), 2.14 (s, 3H), 1.19−1.37(m, 11H), 0.81−0.88 (t, J
= 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 165.9, 153.3,
148.8, 99.8, 59.5, 50.5, 37.1, 31.5, 23.8, 22.5, 18.2, 14.7, 14.3; HRMS
(ESI) m/z [M + H]+ calcd for C13H22N2O3 255.1703, found
255.1706.
5-(Ethoxycarbonyl)-6-methyl-4-(4-biphenylyl)-3,4-dihydro-pyri-
midin-2(1H)-one (4m). The compound was prepared according to
the general procedure: white powder (202 mg, 60%); mp 216−217
°C;40e 1H NMR (400 MHz, DMSO-d6) δ 9.25 (s, 1H), 7.80 (s, 1H),
7.65−7.33 (m, 9H), 5.21 (s, 1H), 4.02 (q, J = 7.1 Hz, 2H), 2.28 (s,
3H), 1.13 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, DMSO-d6)
δ 165.8, 152.5, 149.2, 140.9, 133.9, 130.5, 128.9, 128.4, 126.5, 126.2,
126.1, 124.7, 124.1, 119.5, 100.2, 60.1, 50.2, 18.2, 14.3; HRMS (ESI)
m/z [M + H]+ calcd for C20H20N2O3 337.1547, found 337.1542.
5-(Ethoxycarbonyl)-6-methyl-4-(2-Naphthyl)-3,4-dihydropy ri-
midin-2(1H)-one (4n). The compound was prepared according to
the general procedure: white powder (186 mg, 60%); mp 253−254
°C;40a 1H NMR (400 MHz, DMSO-d6) δ 9.25 (s, 1H), 8.31−7.83
(m, 3H), 7.74 (d, J = 8.2 Hz, 1H), 7.60−7.40 (m, 3H), 6.05 (d, J =
3.0 Hz,1H), 3.79 (q, J = 7.1 Hz, 2H), 2.35 (s, 3H), 0.81 (t, J = 7.1 Hz,
3H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 165.7, 152.1, 149.6,
140.9, 130.7, 128.9, 128.4, 126.5, 126.2, 124.7, 124.1, 123.0, 99.6,
59.5, 49.8, 18.2, 14.3; HRMS (ESI) m/z [M + H]+ calcd for
C18H18N2O3 311.1390, found 311.1394.
5-(Methoxycarbonyl)-6-methyl-4-phenyl-3,4-dihydropyrim-idin-
2(1H)-thione (4u). The compound was prepared according to the
general procedure: white powder (226 mg, 86%); mp 233−235
°C;40h 1H NMR (400 MHz, DMSO-d6) δ 10.36 (s, 1H), 9.67 (s, 1H),
7.37−7.21 (m, 5H), 5.17 (d, J = 3.4 Hz, 1H), 3.56 (s, 2H), 2.30 (s,
3H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 174.7, 166.1, 145.8,
143.2, 129.1, 127.8, 126.8, 100.9, 54.4, 51.6, 17.0; HRMS (ESI) m/z
[M + H]+ calcd for C13H14N2O2S 285.0668, found 285.0665.
Leaching Test. The solvent-free reaction system is relatively
viscous, and it is difficult to directly separate the catalyst and the
reactants without adding a solvent. For easy handling, the alternative
leaching test was conducted and assessed in an ethanol system. The
solid catalyst of COF-IM-SO3H was separated from the hot reaction
solution right after the reaction for 3.0 h. The reaction was continued
with the residual filtrate in the absence of COF-IM-SO3H for an
additional 5.0 h.
Catalyst Regeneration. After each catalytic cycle, a certain amount
of hot ethanol was added to the reaction system to dissolve the
reaction product, and the COF-IM-SO3H was recovered by
centrifugation. After the product was completely washed with THF
and dried overnight under a vacuum at 60 °C, the regenerated catalyst
was used for the next catalytic run under the same reaction
conditions.
Scaled-up Synthesis. Preparation of COF-IM-SO3H@chitosan.
Chitosan powder (0.33 g) of was dissolved in 10 mL of deionized
water added with 120 μL of acetic acid. Once the transparent solution
formed, 1.32 g of COF-IM-SO3H powder was added inside. Then,
500 μL of 1,4-butanediol diglycidyl ether was added as the cross-
linker with strong stirring and ultrasonic shaking. The obtained
solution was immediately transferred into the “split-flask” mold and
allowed to stand for ca. 12 h until a stable hydrogel was formed. Then,
the obtained hydrogel was transferred into a cooler for 12 h to
generate the ice crystals. Finally, the frozen sample was freeze-dried at
−50 °C for 24 h in a freeze-dryer to form the dry COF-chitosan
aerogel monolith with 80 wt % of COF-IM-SO3H loading. After
thorough washing with ethanol to remove residual acetic acid, the
obtained COF-IM-SO3H@chitosan aerogel was applied to catalysis.
Scaled-up Model Biginelli Reaction. A mixture of benzaldehyde
(31.2 mL, 305.6 mmol), ethyl acetoacetate (38.7 mL, 305.6 mmol),
5-(Methoxycarbonyl)-6-methyl-4-phenyl-3,4-dihydropyrim-idin-
2(1H)-one (4o). The compound was prepared according to the
general procedure: pink powder (237 mg, 96%); mp 238−239 °C;40b
1H NMR (400 MHz, DMSO-d6) δ 9.23 (s, 1H), 7.76 (s, 1H), 7.34−
7.22 (m, 5H), 5.14 (d, J = 3.4 Hz, 1H), 3.53 (s, 3H), 2.25 (s, 3H);
13C{1H} NMR (100 MHz, DMSO-d6) δ 166.3, 152.6, 149.1, 145.1,
129.4, 127.8, 127.2, 100.0, 54.3, 51.3, 18.3; HRMS (ESI) m/z [M +
Na]+ calcd for C13H14N2O3 269.0897, found 269.0894.
5-(Methoxycarbonyl)-6-methyl-4-(4-chlorophenyl)-3,4-dihydro-
pyrimidin-2(1H)-one (4p). The compound was prepared according to
the general procedure: pink powder (264 mg, 94%); mp 202−204
°C;40b 1H NMR (400 MHz, DMSO-d6) δ 9.28 (s, 1H), 7.80 (s, 1H),
7.40−7.24 (m, 4H), 5.14 (d, J = 3.4 Hz, 1H), 3.53 (s, 3H), 2.25 (s,
3H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 166.2, 152.4, 149.5,
144.5, 132.3, 129.4, 99.05, 53.7, 50.9, 18.3; HRMS (ESI) m/z [M +
H]+ calcd for C13H13ClN2O3 281.0687, found 281.0685.
5-(Methoxycarbonyl)-6-methyl-4-(4-methylphenyl)-3,4-dihydro-
pyrimidin-2(1H)-one (4q). The compound was prepared according to
the general procedure: pink powder (242 mg, 93%); mp 207−211
°C;40b 1H NMR (400 MHz, DMSO-d6) δ 9.18 (s, 1H), 7.70 (s, 1H),
7.11 (s, 4H), 5.10 (d, J = 3.4 Hz, 1H), 3.52 (s, 3H), 2.25 (s, 6H);
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Note
and urea (18.35 g, 305.6 mmol) was heated at 90 °C (oil bath) for 6 h
in a split-flask (250 mL) equipped with a COF-IM-SO3H@chitosan
aerogel (1.65 g, 0.5 mol % COF-IM-SO3H equiv) (monitored by
TLC). After the reaction, the system was diluted with hot ethanol (1
L, 60 °C), and the crude product was purified by recrystallization in
ethanol. The amount of the product obtained was 73.9 g (93%). After
the product was thoroughly washed with THF and dried overnight in
a vacuum at 80 °C, the COF-IM-SO3H@chitosan aerogel was used
for the next catalytic cycle under the same reaction conditions.
REFERENCES
■
̈
(1) (a) Neochoritis, C. G.; Zhao, T.; Domling, A. Tetrazoles via
Multicomponent Reactions. Chem. Rev. 2019, 119, 1970−2042.
(b) Rotstein, B. H.; Zaretsky, S.; Rai, V.; Yudin, A. K. Chemistry and
Biology of Multicomponent Reactions. Chem. Rev. 2012, 112, 3083−
3135. (c) Reguera, L.; Rivera, D. G. Multicomponent Reaction
Toolbox for Peptide Macrocyclization and Stapling. Chem. Rev. 2019,
́
119, 9836−9860. (d) Toure, B. B.; Hall, D. G. Natural Product
Synthesis Using Multicomponent Reaction Strategies. Chem. Rev.
2009, 109, 4439−4486.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.0c02423.
■
(2) Biginelli, P. Aldehyde-Urea Derivatives of Aceto- and Oxalo-
acetic Acids. Gazz. Chim. Ital. 1893, 23, 360−413.
sı
(3) (a) Lima, C. G. S.; Silva, S.; Goncalves, R. H.; Leite, E. R.;
Schwab, R. S.; Correa, A. G.; Paixao, M. W. Highly Efficient and
Magnetically Recoverable Niobium Nanocatalyst for the Multi-
component Biginelli Reaction. ChemCatChem 2014, 6, 3455−3463.
(b) Atwal, K. S.; Swanson, B. N.; Unger, S. E.; Floyd, D. M.;
Moreland, S.; Hedberg, A.; O'Reilly, B. C. Dihydropyrimidine
Calcium Channel Blockers. 3,3−Carbamoyl−4−Aryl−1,2,3,4-Tetra-
hydro−6−Methyl− 5−PyrimidinecarBoxylic Acid Esters as Orally
Effective Antihypertensive Agents. J. Med. Chem. 1991, 34, 806−811.
(c) Barrow, J. C.; Nantermet, P. G.; Selnick, H. G.; Glass, K. L.; Rittle,
K. E.; Gilbert, K. F.; Steele, T. G.; Homnick, C. F.; Freidinger, R. M.;
Ransom, R. W.; Kling, P.; Reiss, D.; Broten, T. P.; Schorn, T. W.;
Chang, R. S.; O’Malley, S. S.; Olah, T. V.; Ellis, J. D.; Barrish, A.;
Kassahun, K.; Leppert, P.; Nagarathnam, D.; Forray, C. In Vitro and
in Vivo Evaluation of Dihydropyrimidinone C-5 Amides as Potent
and Selective α1A Receptor Antagonists for the Treatment of Benign
Prostatic Hyperplasia. J. Med. Chem. 2000, 43, 2703−2718. (d) Kaan,
H. Y. K.; Ulaganathan, V.; Rath, O.; Prokopcova, H.; Dallinger, D.;
Kappe, C. O.; Kozielski, F. Structural Basis for Inhibition of Eg5 by
Dihydropyrimidines: Stereoselectivity of Antimitotic Inhibitors
Enastron, Dimethylenastron and Fluorastrol. J. Med. Chem. 2010,
53, 5676−5683. (e) Blasco, M. A.; Thumann, S.; Wittmann, J.;
Characterization of model compounds, COF-IM, COF-
IM-SO3H, and COF-IM-SO3H@chitosan; general cata-
lytic products characterization; catalyst hot leaching,
catalytic cycles, and proposed mechanism; crystallo-
graphic information for COF-IM; abbreviations (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Yu-Bin Dong − College of Chemistry, Chemical Engineering
and Materials Science, Collaborative Innovation Center of
Functionalized Probes for Chemical Imaging in Universities of
Shandong, Key Laboratory of Molecular and Nano Probes,
Ministry of Education, Shandong Normal University, Jinan
250014, People’s Rupublic of China; orcid.org/0000-
0002-9698-8863; Email: yubindong@sdnu.edu.cn
Authors
Bing-Jian Yao − College of Chemistry, Chemical Engineering
and Materials Science, Collaborative Innovation Center of
Functionalized Probes for Chemical Imaging in Universities of
Shandong, Key Laboratory of Molecular and Nano Probes,
Ministry of Education, Shandong Normal University, Jinan
250014, People’s Rupublic of China
Wen-Xiu Wu − College of Chemistry, Chemical Engineering
and Materials Science, Collaborative Innovation Center of
Functionalized Probes for Chemical Imaging in Universities of
Shandong, Key Laboratory of Molecular and Nano Probes,
Ministry of Education, Shandong Normal University, Jinan
250014, People’s Rupublic of China
Luo-Gang Ding − College of Chemistry, Chemical Engineering
and Materials Science, Collaborative Innovation Center of
Functionalized Probes for Chemical Imaging in Universities
of Shandong, Key Laboratory of Molecular and Nano
Probes, Ministry of Education, Shandong Normal University,
Jinan 250014, People’s Rupublic of China
̈
Giannis, A.; Groger, H. Enantioselective Biocatalytic Synthesis of (S)-
Monastrol. Bioorg. Bioorg. Med. Chem. Lett. 2010, 20, 4679−4682.
(4) (a) Ranu, B. C.; Hajra, A.; Jana, U. Indium (III) Chloride-
Catalyzed One-Pot Synthesis of Dihydropyrimidinones by a Three-
Component Coupling of 1,3-Dicarbonyl Compounds, Aldehydes, and
Urea: An Improved Procedure for the Biginelli Reaction. J. Org. Chem.
2000, 65, 6270−6272. (b) Dennis, R.; Lopes, F. A.; Da, S. V. S. S.;
Canto, K. F. S.; D’Oca, M. G. M.; Godoi, M. N. Multicomponent
Biginelli’s Synthesis of 3,4-Dihydropyrimidin-2(1H)-Ones Promoted
by SnCl2·2H2O. J. Braz. Chem. Soc. 2004, 15, 165−169.
(5) (a) Nagarajaiah, H.; Mukhopadhyay, A.; Moorthy, J. N. Biginelli
Reaction: An Overview. Tetrahedron Lett. 2016, 57, 5135−5149.
(b) Martınez, S.; Meseguer, M.; Casas, L.ıs; Rodrıguez, E.; Molins, E.;
Moreno-Manas, M.; Roig, A.; Sebastian, R. M; Vallribera, A. Silica
Aerogel-Iron Oxide Nanocomposites: Recoverable Catalysts in
Conjugate Additions and in the Biginelli Reaction. Tetrahedron
2003, 59, 1553−1556. (c) Rani, V. R.; Srinivas, N.; Kishan, M. R.;
et al. Zeolite-Catalyzed Cyclocondensation Reaction for the Selective
Synthesis of 3,4-Dihydropyrimidin-2(1H)-Ones. Green Chem. 2001, 3,
305−306.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.0c02423
(6) Pramanik, M.; Bhaumik, A. Phosphonic Acid Functionalized
Ordered Mesoporous Material: A New and Ecofriendly Catalyst for
One-Pot Multicomponent Biginelli Reaction under Solvent-Free
Conditions. ACS Appl. Mater. Interfaces 2014, 6, 933−941.
Author Contributions
‡B.-J.Y. and W.X.W. contributed equally.
̂
́
(7) (a) Cote, A. P.; Benin, A. I.; Ockwig, N. W.; O’Keeffe, M.;
Matzger, A. J.; Yaghi, O. M. Porous, Crystalline, Covalent Organic
Frameworks. Science 2005, 310, 1166−1170. (b) Diercks, C.; Yaghi,
O. M. The atom, the molecule, and the covalent organic framework.
Science 2017, 355, 923−931.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
(8) (a) Ma, H. C.; Zou, J.; Li, X. T.; Chen, G. J.; Dong, Y. B.
Homochiral Covalent Organic Frameworks for Asymmetric Catalysis.
Chem. - Eur. J. 2020, 26, 1−18. (b) Guo, J.; Jiang, D.-L. Covalent
Organic Frameworks for Heterogeneous Catalysis: Principle, Current
Status, and Challenges. ACS Cent. Sci. 2020, 6, 869−879.
We are grateful for financial support from the NSFC
(21971153, 21671122, 22072077, and 21604049), Chang-
Jiang Scholars Program of China, The Taishan Scholars
Climbing Program of Shandong Province.
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Note
(9) Chen, G. J.; Li, X. B.; Zhao, C. C.; Ma, H. C.; Kan, J. L.; Xin, Y.
B.; Chen, C. X.; Dong, Y. B. Ru Nanoparticles-Loaded Covalent
Organic Framework for Solvent Free One-Pot Tandem Reactions in
Air. Inorg. Chem. 2018, 57, 2678−2685.
(10) (a) Wang, P. L.; Ding, S. Y.; Zhang, Z. C.; Wang, Z. P.; Wang,
W. Constructing Robust Covalent Organic Frameworks via Multi-
component Reactions. J. Am. Chem. Soc. 2019, 141, 18004−18008.
(b) Li, X. T.; Zou, J.; Wang, T. H.; Ma, H. C.; Chen, G. J.; Dong, Y.-
B. Construction of Covalent Organic Frameworks via Three
Component One-Pot Strecker and Povarov Reactions. J. Am. Chem.
Soc. 2020, 142, 6521−6526.
(11) Shindoh, N.; Tokuyama, H.; Takemoto, Y.; Takasu, K.
AutoTandem Catalysis in the Synthesis of Substituted Quinolines
from Aldimines and Electron-Rich Olefins: Cascade Povarov-
Hydrogen Transfer Reaction. J. Org. Chem. 2008, 73, 7451−7456.
(12) Materials Studio, Release Notes; Accelrys Software, 2018.
(13) (a) Isambert, N.; del Mar Sanchez Duque, M.; Plaquevent, J.-
(23) Palaniappan, S.; John, A. A Novel Polyaniline-Fluoroboric Acid-
Dodecylhydrogensulfate Salt: Versatile Reusable Polymer Based Solid
Acid Catalyst for Organic Transformations. J. Mol. Catal. A: Chem.
2005, 233, 9−15.
(24) Quan, Z. J.; Da, Y. X.; Zhang, Z.; Wang, X. C. PS-PEG-SO3H as
an Efficient Catalyst for 3, 4-Dihydropyrimidones via Biginelli
Reaction. Catal. Commun. 2009, 10, 1146−1148.
(25) Zhou, H.; He, M.; Liu, C.; Luo, G. One-Pot Synthesis of 3, 4-
Dihydropyrimidin-2 (1H)-Ones using Hydrochloric Acid-β-cyclo-
dextrinCombined Catalysts. Lett. Org. Chem. 2006, 3, 225−227.
(26) Asghari, S.; Tajbakhsh, M.; Kenari, B. J.; Khaksar, S.
Supramolecular Synthesis of 3, 4-Dihydropyrimidine-2 (1H)-One/
Thiones under Neat Conditions. Chin. Chem. Lett. 2011, 22, 127−
130.
(27) Mahdavinia, G. H.; Sepehrian, H. MCM-41 Anchored Sulfonic
Acid (MCM-41-R-SO3H): A Mild, Reusable and Highly Efficient
Heterogeneous Catalyst for the Biginelli Reaction. Chin. Chem. Lett.
2008, 19, 1435−1439.
́
C.; Genisson, Y.; Rodriguez, J.; Constantieux, T. Multicomponent
Reactions and Ionic Liquids: A Perfect synergy for Eco-Compatible
Heterocyclic Synthesis. Chem. Soc. Rev. 2011, 40, 1347−1357.
(b) Alvim, H. G. O.; de Lima, T. B.; de Oliveira, H. C. B.; Gozzo,
F. C.; de Macedo, J. L.; Abdelnur, P. V.; Silva, W. A.; Neto, B. A. D.
Ionic Liquid Effect over the Biginelli Reaction under Homogeneous
and Heterogeneous Catalysis. ACS Catal. 2013, 3, 1420−1430.
(14) (a) Gui, J. Z.; Liu, D.; Wang, C.; Lu, F.; Lian, J. Z.; Jiang, H.;
Sun, Z. L. One-Pot Synthesis of 3,4-Dihydropyrimidin-2(1H)-Ones
Catalyzed by Acidic Ionic Liquids Under Solvent-Free Conditions.
Synth. Commun. 2009, 39, 3436−3443. (b) Mohammad, A. K. Z.;
Zeinab, H. Synthesis of [P4-VP]-Fe3O4 Supported Brønsted Acid
Ionic Liquid and Its Application as a Highly Efficient Heterogeneous
and Reusable Nanocatalyst in the Biginelli Reaction under Solvent-
Free Conditions. React. Kinet., Mech. Catal. 2018, 125, 1023−1037.
(c) Bhagat, P. R.; Khiratkar, A. G.; Muskawar, P. N. Polymer-
Supported Benzimidazolium Based Ionic Liquid: An Efficient and
Reusable Brnsted Acid Catalyst for Biginelli Reaction. RSC Adv. 2016,
6, 105087−105093.
(15) Wang, Z. T.; Wang, S. C.; Xu, L. W. Polymer Supported Ionic
Liquid Catalyzed Synthesis of 1,2,3,4-Tetrahydro-2-Oxo-Pyrimidine-5
Carboxylates via Biginelli Reaction. Helv. Chim. Acta 2005, 88, 986−
989.
(16) Chari, M. A.; Syamasundar, K. Silicagel Supported Sodium
Hydrogensulfate as a Heterogenous Catalyst for High Yield Synthesis
of 3,4-Dihydropyrimidin-2 (1H)-Ones. J. Mol. Catal. A: Chem. 2004,
221, 137−139.
(28) Dilmaghani, K. A.; Zeynizadeh, B.; Yari, M. One-Pot Synthesis
of 3, 4-Dihydropyrimidin-2 (1H)-Ones and Their Sulfur Derivatives
with H2SO4 Supported on Silica Gel or Alumina. Phosphorus, Sulfur
Silicon Relat. Elem. 2009, 184, 1722−1728.
(29) Heravi, M. M.; Derikvand, F.; Bamoharram, F. F. A Catalytic
Method for Synthesis of Biginelli-type 3, 4-Dihydropyrimidin-2 (1H)-
One using 12-Tungstophosphoric Acid. J. Mol. Catal. A: Chem. 2005,
242, 173−175.
(30) Romanelli, G. P.; Sathicq, A. G.; Autino, J. C.; Baronetti, G.;
Thomas, H. J. Solvent-Free Approach to 3, 4-Dihydropyrimidin-2
(1H)-(thio) Ones: Biginelli Reaction Catalyzed by A Wells-Dawson
Reusable Heteropolyacid. Synth. Commun. 2007, 37, 3907−3916.
(31) Fazaeli, R.; Tangestaninejad, S.; Aliyan, H.; Moghadam, M.
One-Pot Synthesis of Dihydropyrimidinones using Facile and
Reusable Polyoxometalate Catalysts for the Biginelli Reaction. Appl.
Catal., A 2006, 309, 44−51.
(32) Fazaeli, R.; Tangestaninejad, S.; Aliyan, H. Heterogeneous
Polyoxometalates: Efficient, Facile and Reusable Catalysts for One-
Pot Synthesis of Dihydropyrimidinones. Asian J. Chem. 2010, 22,
877−887.
(33) Javidi, J.; Esmaeilpour, M.; Dodeji, F. N. Immobilization of
Phosphomolybdic Acid Nanoparticles on Imidazole Functionalized
Fe3O4@SiO2: A Novel and Reusable Nanocatalyst for One-Pot
Synthesis of Biginelli-Type 3,4-Dihydro-Pyrimidine-2-(1H)-Ones/
Thiones under Solvent-Free Conditions. RSC Adv. 2015, 5, 308−315.
(34) Afradi, M.; Foroughifar, N.; Pasdar, H.; Moghanian, H. l-
Proline N-Sulfonic Acid-Functionalized Magnetic Nanoparticles: A
Novel and Magnetically Reusable Catalyst for One-Pot Synthesis of
3,4-Dihydropyrimidine-2-(1H)-Thiones under Solvent-Free Condi-
tions. RSC Adv. 2016, 6, 59343−59351.
(17) Sharghi, H.; Jokar, M. Al2O3/MeSO3H: a Novel and Recyclable
Catalyst for One-Pot Synthesis of 3, 4-Dihydropyrimidinones or Their
Sulfur Derivatives in Biginelli Condensation. Synth. Commun. 2009,
39, 958−979.
(18) Arjun, M.; Sridhar, D.; Chari, M. A.; Sarangapani, M. An
Efficient Biginelli One-Pot Synthesis of New Benzoxazole-Substituted
Dihydropyrimidinones and Thiones Catalysed by Alumina-Supported
Trifluoromethane Sulfonic Acid under Solvent Free Conditions. J.
Heterocycl. Chem. 2009, 46, 119−123.
(19) Zhang, G. P.; Tian, D. Y.; Shi, W. M. Efficient Catalytic
Synthesis of 3,4-Dihydropyrimidin-2-Ones/Thiones via Little Acidic
Ionic Liquid Combined with Rapid Heating Ways. J. Heterocycl. Chem.
2018, 55, 2522−2531.
(20) Da Silva, D. L.; Fernandes, S. A.; Sabino, A. A.; Fatima, A.
Sulfonic Acid Calixarenes as Efficient and Reusable Organocatalysts
for the Synthesis of 3, 4-Dihydropyrimidin-2 (1H)-Ones/-Thiones.
Tetrahedron Lett. 2011, 52, 6328−6330.
(21) Salehi, P.; Dabiri, M.; Zolfigol, M. A.; Bodaghi Fard, M. A.
Efficient Synthesis of 3,4-Dihydropyrimidin-2(1H)-Ones over Silica
Sulfuric Acid as a Reusable Catalyst under Solvent-Free Conditions.
Heterocycles 2003, 60, 2435−2440.
(35) Leila, M.; Najafib, G. R.; Saeidiroshan, H. New Method for
Preparation of MWCNT-SO3H as An Efficient and Reusable Catalyst
for the Solvent-Free Synthesis of 3,4-Dihydropyrimidin-2(1H)-Ones/
Thiones. Iranian. J. Catal. 2015, 5, 357−364.
(36) Kalbasi, R. J.; Massah, A. R.; Daneshvarnejad, B. Preparation
and Characterization of Bentonite/PS-SO3H Nanocomposites as An
Efficient Acid Catalyst for the Biginelli Reaction. Appl. Clay Sci. 2012,
55, 1−9.
(37) Verma, A.; De, D.; Tomar, K.; Bharadwaj, P. K. An Amine
Functionalized Metal−Organic Framework as An Effective Catalyst
for Conversion of CO2 and Biginelli Reactions. Inorg. Chem. 2017, 56,
9765−9771.
(38) Kappe, C. O. A Reexamination of the Mechanism of the
Biginelli Dihydropyrimidine Synthesis. Support for an N-Acyliminium
Ion Intermediate. J. Org. Chem. 1997, 62, 7201−7204.
(39) (a) Li, F.; Ding, L.-G.; Yao, B.-J.; Huang, N.; Li, J.-T.; Fu, Q.-J.;
Dong, Y.-B. Pd Loaded and Covalent-Organic Framework Involved
Chitosan Aerogels and Their Application for Continuous Flow-
Through Aqueous CB Decontamination. J. Mater. Chem. A 2018, 6,
11140−11146. (b) Ding, L.-G.; Yao, B.-J.; Li, F.; Shi, S.-C.; Huang,
N.; Yin, H.-B.; Guan, Q.; Dong, Y.-B. Ionic Liquid-Decorated COF
(22) Shi, X. L.; Yang, H.; Tao, M.; Zhang, W. Sulfonic Acid
Functionalized Polypropylene Fiber: Highly Efficient and Rrecyclable
Heterogeneous Brønsted Acid Catalyst. RSC Adv. 2013, 3, 3939−
3945.
3031
https://dx.doi.org/10.1021/acs.joc.0c02423
J. Org. Chem. 2021, 86, 3024−3032

The Journal of Organic Chemistry
pubs.acs.org/joc
Note
and Its Covalent Composite Aerogel for Selective CO2 Adsorption
and Catalytic Conversion. J. Mater. Chem. A 2019, 7, 4689−469.
(c) Wang, J.-C.; Liu, C.-X.; Kan, X.; Wu, X.-W.; Kan, J.-L.; Dong, Y.-
B. Pd@COF-QA: a Phase Transfer Composite Catalyst for Aqueous
Suzuki−Miyaura Coupling Reaction. Green Chem. 2020, 22, 1150−
1155.
(40) (a) Pasunooti, K. K.; Chai, H.; Jensen, C. N.; Gorityala, B. K.;
Wang, S.; Liu, X.-W. A Microwave-Assisted, Copper-Catalyzed Three-
Component Synthesis of Dihydropyrimidinones under Mild Con-
ditions. Tetrahedron Lett. 2011, 52, 80−84. (b) Davood, A.;
Omolbanin, Younes A.; B. Sulfonic Acid-Functionalized Titanomag-
netite Nanoparticles as Recyclable Heterogeneous Acid Catalyst for
One-Pot Solvent−Free Synthesis of 3,4−Dihydropyrimidin−2(1H)-
Ones/Thiones. J. Iran. Chem. Soc. 2016, 13, 2029−2038.
(c) Dezfoolinezhad, E.; Ghodrati, K.; Badri, R. Polyionene/Br3
Grafted on Magnetic Nanoparticles as an Efficient and Eco−Friendly
Catalyst for the Metal Free Synthesis of 3,4−Dihydropyrimidin−
2(1H)-−Ones/Thiones. Silicon 2019, 11, 1593−1609. (d) Yao, N.;
Lu, M.; Liu, X. B.; Tan, J.; Hu, Y. L. Copper−Doped Mesoporous
Silica Supported Dual Acidic Ionic Liquid as an Efficient and
Cooperative Reusability Catalyst for Biginelli Reaction. J. Mol. Liq.
2018, 262, 328−335. (e) Rashmi, S. V.; Sandhya, N. C.; Raghava, B.;
Kumara, M. N.; Mantelingu, K.; Rangappa, K. S. Trifluoroethanol as a
Metal-Free, Homogeneous, and Recyclable Medium for the Efficient
One−pot Synthesis of Dihydropyrimidones. Synth. Commun. 2012,
42, 424−433. (f) Bahrami, K.; Mehdi Khodaei, M.; Farrokhi, A.
Highly Efficient Solvent−Free Synthesis of Dihydropyrimidinones
Catalyzed by Zinc Oxide. Synth. Commun. 2009, 39, 1801−1808.
(g) Carvalho, R. B.; Joshi, S. V. Solvent and Catalyst Free Synthesis of
3,4−Dihydropyrimidin−2(1H)-−Ones/Thiones by Twin Screw
Extrusion. Green Chem. 2019, 21, 1921−1924. (h) Safari, J.;
Gandomi, R. S. Titanium Dioxide Supported on MWCNTs as an
Eco−Friendly Catalyst in the Synthesis of 3,4−Dihydropyrimidin−2−
(1H)-−Ones Accelerated under Microwave Irradiation. New J. Chem.
2014, 38, 3514−3521.
3032
https://dx.doi.org/10.1021/acs.joc.0c02423
J. Org. Chem. 2021, 86, 3024−3032