1,4-dihydropyridine scaffolds represents heterocyclic unit of remarkable biological and pharmacological efficiency
[1]
. More than a hundred years ago, 1,4-dihydropyridine derivatives was reported by Arthur Hantzsch
[2]
. These are important precursors due to their pharmacological and biological activities such as antihypertensive
[3]
, anti-anginal and as calcium channel blockers
[4]
[5]
[6]
[7]
[8]
for the treatment of cardiovascular diseases
[9]
. A number of DHP derivatives are employed as potential drug candidates for the treatment of congestive heart failure, and also acts as NADH mimics for the reduction of carbonyl compounds and their derivatives. Apart from these 1,4-DHP also possess many more pharmacological activities such as anti-bacterial, anti-cancer, anti-microbial, anti-tubercular, antioxidant agents, antiulcer, CFTR, antimalarial and HIV-I protease inhibitory and many more (
Scheme 1
)
[10]
[11]
[12]
.
The biological activity of 1,4-dihydropyridine derivatives in numerous sectors has recently gained significant attention, which have persuaded scientists to develop novel new processes for synthesizing them. 1,4-dihydropyridine generally synthesized by condensation of aldehydes, β-ketoester and ammonia or ammonium acetate. The number of attempts has been taken to improve the yield and selectivity of the product under milder condition of this Hantzsch reaction using different alternate process in the literature. All of these aforesaid reaction required one of the following conditions like microwave
[13]
[14]
[15]
, ionic liquids
[16]
and higher temperature
[17]
[18]
[19]
, ultrasound irradiation, catalyst or reagents like TMSl
[20]
, Molecular Iodine
[21]
, Yb(OTf)3
[22]
, FeCl3
[23]
, Ceric Ammonium Nitrate
[24]
, Silica gel supported sodium bisulfate
[25]
and Scandium (III) triflate
[26]
. However, all of these methods have some drawbacks, such as the use of hazardous solvents, extended heating, tiresome work-up, by-products, and limited yield.
In a recent year, Nano catalytic approach for the synthesis of 1,4-dihydropyridine is more advantageous over conventional method due to its enormous activity and selectivity. This methodology becomes green, non-toxic and eco-friendly process. To this content, Safari et al. in 2011, introduce Cobalt nanoparticles catalysed synthesis of 1,4-dihydropyridine
[27]
. In 2012, Tajbakhsh et al. and co-workers reported that TiO2 has been used as a catalyst in the production of Dihydropyridine
[28]
. In the same year Yang et al. synthesiszed the 1,4-dihydropyridine using magnetic nanocrystalline Fe3O4 as catalyst
[29]
. Further, synthesis of 1,4-dihydropyridine derivatives via one pot condensation of dimedone or
Scheme 1. Some commercial drugs containing the 1,4-dihydropyridine core moieties.4-hydroxycumarine, aldehydes and ammonium acetate using Fe<sub>3</sub>O<sub>4</sub>@SiO<sub>2</sub> nano-particles as a heterogeneous catalyst in 2014 by Dam et al. <xref ref-type="bibr" rid="scirp.133816-30">
[30]
</xref>. Alinezhad et al. reported synthesis of 1,4-dihydropyridine using Cu-doped ZnO nanocrystalline powder as a heterogeneous catalyst <xref ref-type="bibr" rid="scirp.133816-31">
[31]
</xref>. Bajajand and co-workers report CuO nanoflakes for the synthesis of 1,4-dihydropyridine <xref ref-type="bibr" rid="scirp.133816-32">
[32]
</xref>. Dehghanizadeh et al. used zinc oxide nanoparticles as heterogeneous nanocatalyst for the synthesis of 1,4-dihydropyridine <xref ref-type="bibr" rid="scirp.133816-33">
[33]
</xref>. A Nickel oxide loaded on Zirconia (NiO/ZrO<sub>2</sub>) as a nano catalyst for synthesis of 1,4-dihydropyridine reported by Bhaskaruni et al. in 2019 <xref ref-type="bibr" rid="scirp.133816-34">
[34]
</xref>. Later, Cahyana et al. introduce copper iodide nanoparticles for synthesis of 1,4-dihydropyridine <xref ref-type="bibr" rid="scirp.133816-35">
[35]
</xref>. However, all above methods has significant drawbacks, such as a longer reaction duration, low yield, lack of recyclability, and a challenging isolation process of the desired products. These challenges encourage researcher to developed new and green synthetic approach to overcome the disadvantages associated to Hantzsch condensation. In this context, polymer supported titanium dioxide (Polyindole TiO<sub>2</sub>) nanocatalytic systems have been developed as green, eco-friendly and reusable nanocatalyst to synthesized 1,4-dihydropyridine.The current study describes the synthesis of polyindole-TiO<sub>2</sub> nanocomposites and their use as a recyclable and possible catalyst for the single-pot, multicomponent synthesis of dihydropyridine without the need of solvents. The synthesis of 1,4-dihydropyridines derivatives derived from raw materials including aldehyde, methyl acetoacetate and ammonia solution under solvent free mild green condition.2. Results and DiscussionTiO<sub>2</sub> nanoparticle FTIR spectra are shown in <xref ref-type="fig" rid="fig1(a)">
Figure 1(a)
</xref>. The O-H bond’s stretching vibration shows band at ~3400 cm<sup>−1</sup>, and the bending vibration of O-H group shows peak at 1700 cm<sup>−1</sup>. The peaks identified at 461 and 501.5 cm<sup>−1</sup> is due to the stretching and bending vibrations of Ti-O-Ti group. Broad band in the polyindole-TiO<sub>2</sub> FTIR spectrum at about 3600 cm<sup>−1</sup> suggests the presence of -NH bonds (<xref ref-type="fig" rid="fig1(b)">
Figure 1(b)
</xref>). The nitrogen of the indole is not the polymerization site, as indicated by the band at 1570 cm<sup>−1</sup>, which is caused by stretching and deformation vibrations of the -NH bond. The benzene ring is not impacted during the polymerization of indole, according to the sharp band at 740 cm<sup>−1</sup>. The stretching mode of the benzene ring, which is represented by the peaks at 1454 cm<sup>−1</sup> and 1610 cm<sup>−1</sup>, indicates that the benzene ring was not the site of polymerization. This indicates that polymerization occurred.TiO<sub>2</sub> and polyindole-TiO<sub>2</sub> nanocomposites’ surface morphologies were examined using scanning electron microscopy (SEM), and they are depicted in <xref ref-type="fig" rid="fig2(a)">
Figure 2(a)
</xref> and <xref ref-type="fig" rid="fig2(b)">
Figure 2(b)
</xref>, respectively. As shown in the SEM image, the TiO<sub>2</sub> nanoparticles are heavily aggregated and have a spherical morphology. <xref ref-type="fig" rid="fig2(a)">
Figure 2(a)
</xref>. While the TiO<sub>2</sub> nanoparticles, which range in size from 40 to 60 nm, are dispersed in clusters formed by the accumulation of Polyindole particles. By<xref ref-type="bibr" rid="scirp.133816-"></xref><p class="imgGroupCss_v"><img class=" imgMarkCss lazy" data-original="https://html.scirp.org/file/1810423-rId13.jpeg?20240814120511" /></p>Figure 1. FT-IR spectra of (a) TiO<sub>2</sub> & (b) Polyindole TiO<sub>2</sub> (Pin-TiO<sub>2</sub>) nanoparticles.
Figure 2. SEM images of (a) TiO<sub>2</sub> & (b) Polyindole TiO<sub>2</sub> (Pin-TiO<sub>2</sub>) nanoparticles.
generating spheres, this functions as a soft template. According to SEM findings, the Polyindole matrix contains nanostructured TiO2 particles that are evenly dispersed.
The crystal structure of Polyindole (PIn), TiO2 and Polyindole-TiO2 (PIn-TiO2) are characterized by XRD. The X-ray diffraction pattern for the synthesized nano TiO2 is shown in
Figure 3(a)
. The diffraction peak appears at 2θ values with 27.19˚, 35.89˚, 39.56˚, 40.99˚, 44.45˚ and 54.18˚ correlates the crystal planes of (110), (101), (200), (111), (210) and (211) which is matched and confirmed with the standard reference XRD pattern of TiO2 (JCPDS Card No.21-1276). The high intense peak of the XRD pattern at 2θ value of 27.19 confirmed the prepared TiO2 nanoparticle correlates the rutile phase and the preferred orientation plane was (110). The X-ray diffraction pattern of synthesized polyindole (PIn) as presented in
Figure 3(b)
shows broad peaks at 19.54 and 25.58˚. The presence of
these broad peaks confirms the polymerization of indole, and diffraction peak at 25.58˚ validates the partial crystalline nature of PIn. Strong diffraction peak at 27.19˚ in the XRD pattern of the polyindole-TiO2 nanocomposites shown in
Figure 3(c)
indicate that TiO2 is present in the nanocomposite in rutile phase.
In these efforts to develop an efficient & environmentally benign methodology for the synthesis of dihydropyridine, we initiated our studies by subjecting catalytic amount of polyindole TiO2 to the mixture of benzaldehyde, methyl acetoacetate and ammonia solution (25%) in solvent free condition at room temperature. Unfortunately, the resulted yield was very poor even after 24 h of stirring. To increase the yield of the reaction, various solvent systems were screened at 50˚C temperature. We pleased to see that the synthesis of DHP was effective catalyzed by polyindole TiO2 in solvent free condition at elevated temperature leading to high yield of product. The results are summarized in
Table 1
. It is evident that the best result was obtained by the application of 5 mol% of Polyindole TiO2 in solvent free condition at 50˚C. Higher and lower amount of catalyst subsequently reduce the yield of the product (
Table 1
, entry 5). In typical procedure 1 mmole of aldehyde, 2 mmole of methyl acetoacetate and 2 mmole of ammonia solution were mixed in solvent free condition in presence of 5 mole % of polyindole TiO2 and reaction mixture was stirred for 1 to 2 h at 50. After workup it produced the corresponding DHP’s with good yield.
After having optimization condition in our hand, we further explore the substrate scope in
Figure 4
. Electron rich and electron deficient aromatic aldehyde as well as heterocyclic aldehyde work well with our protocol. First of all, aromatic aldehyde possessing an array of either electron donating or withdrawing substituents at both the p and m-position delivered the desired 1, 4-dihydropyridines products (2B, 2D-E, 2G, 2H) in excellent yields. Further, the sterically congested o-substituted aldehyde substrate is also suitable to produce the desired 1,4-dihydropyridines products (2C) in good yield. Interestingly, polyaromatic substrates like, [1,1’-biphenyl]-4-carbaldehyde were equally competent in furnishing the product 2J in excellent yield. Pleasingly, the efficiency of this reaction was not suppressed when heteroaromatic substrates such as thiophene-2-carbaldehyde and 1H-pyrrole-2-carbaldehyde was employed. Notably, the Polyindole TiO2 offers much easier recyclability than the homogeneous one (
Table 2
).
Figure 4. Substrate scope for the synthesis of 1,4-dihydropyridines derivatives<sup>a</sup>. <sup>a</sup>Reaction conditions: Aromatic aldehyde (1 mmol), methyl acetoacetate (2 mmol) and aq. ammonia solution (2 mmol), 50˚C, 1 - 2 h.
Figure 4. Substrate scope for the synthesis of 1,4-dihydropyridines derivatives<sup>a</sup>. <sup>a</sup>Reaction conditions: Aromatic aldehyde (1 mmol), methyl acetoacetate (2 mmol) and aq. ammonia solution (2 mmol), 50˚C, 1 - 2 h.
Figure 4. Substrate scope for the synthesis of 1,4-dihydropyridines derivatives<sup>a</sup>. <sup>a</sup>Reaction conditions: Aromatic aldehyde (1 mmol), methyl acetoacetate (2 mmol) and aq. ammonia solution (2 mmol), 50˚C, 1 - 2 h.
Plausible General Mechanism:
As reported in the literature,
[36]
the plausible mechanism for nanocatalyzed synthesis of 1,4-dihydropyridine contains the activation of aldehydes and diketones
<xref ref-type="bibr" rid="scirp.133816-"></xref>Table 1. Optimization of reaction conditions for the synthesis of 1,4-dihydropyridines.
Entry
Catalyst (wt.%)
Solvent
Temp ˚C
Time (h)
Yield (%)a
1
5
Neat
RT
24
35
2
5
MeOH
RT
24
25
3
5
EtOH
RT
24
30
4
5
THF
RT
4
10
5
5
Neat
50
1.5
95
6
0
Neat
50
6.5
70
7
10
Neat
50
1.5
83
8
15
Neat
50
1.5
70
9
5
MeOH
50
4.0
75
10
5
EtOH
50
4.5
69
11
5
IPA
50
6
70
aIsolated yield.
<xref ref-type="bibr" rid="scirp.133816-"></xref>Table 2. Catalyst recovery study data under optimized condition.
Entry
Time (h)
Yield (%)a
1st cycle
1.5
98
2nd cycle
1.5
96
3rd cycle
2.0
93
4th cycle
2.5
90
5th cycle
3.5
89
6th cycle
5.0
85
aIsolated yield.
by nanoparticles followed by nucleophilic attack to form intermediate A. Intermediate A was further activated by the nanoparticle and facilitated the nucleophilic attack by intermediate B to form intermediate C. After following the intra-molecular cyclization to generate intermediate D, which was further deprotonated to form intermediate E, and finally the resulting 1,4-dihydropyridine (F) is formed after dehydration of intermediate E (
Scheme 2
).
3. Experimental Method
General experimental description:
Chemicals, reagents and solvents were obtained from Sigma Aldrich Company. All compounds were identified by their physical and spectroscopic data. The nanomaterial has been characterized by Fourier transform infrared analysis galaxy series FT-IR 5000 spectrometer, scanning electron microscopy (SEM) by MIRA III from TESCAN Company and Philips XL30, X-ray diffraction by JEOL JDX-8030 (30 kV, 20 mA), On a Brucker spectrophotometer (400 MHz) in
Scheme 2. Plausible mechanism for synthesis of 1, 4-dihydropyridine.DMSO-d<sub>6</sub> or CDCl<sub>3</sub>. All the <sup>1</sup>H and <sup>13</sup>C{<sup>1</sup>H} NMR spectra were referenced internally to the residual solvent signals. On an Agilent model, the mass spectra were captured. Melting points were determined uncorrected utilizing capillary tubes on an electrothermal digital instrument.Preparation of TiO<sub>2</sub> Nanoparticles:Under a nitrogen atmosphere, titanium tetrachloride (TiCl<sub>4</sub>) was added drop by drop to ethanol and water (1:1) to create TiO<sub>2</sub> nanoparticles. At room temperature, the reaction mixture was agitated for 12 hours to produce a yellow-colored solution of TiO<sub>2</sub> nanoparticles. After being obtained, the nanoparticles were filtered, dried at 80˚C in an oven, and then calcined for an hour at 350˚C in a furnace.Preparation of Polyindole-TiO<sub>2</sub> Nanoparticles:The monomer indole (1 mmol) and a 5% aq hydrochloric acid solution were added to a round-bottom flask and warmed to 40˚C to form a clear solution. To this clear solution, TiO<sub>2</sub> nanoparticles were added, polymerization reaction was allowed to proceed for two hours. Under constant stirring, ammonium persulfate (1 mmol) solution in 10 ml de-ionised water was added dropwise to the monomer solution containing TiO<sub>2</sub> at 0˚C - 5˚C. The reaction mixture was allowed to stand for 12 hours at room temperature to form greenish-black precipitation of polymerized material, which was filtered and washed with cold water. The isolated polyindole-TiO<sub>2</sub> nanoparticles were dried under vacuum at 70˚C and characterized by FTIR, XRD, and SEM.General procedure for the synthesis of 1,4-dihydropyridine:A mixture of aromatic aldehyde (1 mmol), methyl acetoacetate (2 mmol), and aq. ammonia solution (2 mmol) was mixed at room temperature. The mixture was stirred for 5 minutes. Polyindole-TiO<sub>2</sub> Nano-PiN.TiO<sub>2</sub> (5%W) as a catalyst was then added, and the reaction mixture was stirred magnetically at 50˚C. The progress and completion of the reaction were monitored by TLC (n-hexane/ethyl acetate: 3:1 v/v) during appropriate time periods. After completion of the reaction, 5 ml of methanol was added, and the catalyst was separated by simple filtration. Filtrate was added to 15 ml of cold water, and precipitates were filtered off and washed with the cold methanol-water mixture. Further purification is done by crystallization using methanol to obtain a pure product as a solid material.4. Spectroscopic Data for the New CompoundsDimethyl 1,4-dihydro-2,6-dimethyl-4-phenylpyridine-3,5-dicarboxylate (2A):
Appearance: white solid, Melting Point: 191˚C - 193˚C.
We present a solvent-free catalytic method for synthesizing biologically relevant dihydropyridine derivatives from aromatic aldehydes, methyl acetoacetate, and aqueous ammonium. Key aspects of this protocol include 1) The use of a recyclable catalyst; 2) Short reaction times; 3) Broad substrate compatibility with excellent functional group tolerance, yielding compounds with potential medicinal activity. Additionally, recyclability studies demonstrate that the catalyst maintains nearly unchanged catalytic activity over multiple cycles without loss of efficacy. In order to synthesis 1,4-dihydropyridine under environmentally friendly conditions, we have created stable and novel polyindole-TiO2 nanoparticles. This approach emphasizes the beneficial features such shorter reaction times, the removal of hazardous solvents and byproducts, quick work-up, and straightforward product separation. The nano-catalyst also demonstrated good reactivity and effective catalytic recyclability.
Appendix
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