Ultrasound mediated, green innovation for the synthesis of polysubstituted 1,4-dihydropyridines

Abstract

An elegant, atom efficient protocol via a one-pot four-component cyclocondensation reaction of aromatic aldehydes, malononitrile, acetylenedicarboxylates and arylamines catalyzed by copper(I) iodide in aqueous medium under ultrasound irradiation has been developed for the synthesis of a series of novel pharmacologically interesting polysubstituted 1,4-dihydropyridines. In comparison with the reported methods, our approach is expedient and offers several advantages such as: a shorter reaction time, excellent yields, milder conditions, convenience and environmental benignity. We have herein successfully demonstrated the utility of sonication in a multicomponent reaction (MCR), which exhibits a better functional group tolerance, and straightforward product isolation and purification by precipitation.

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Introduction

In the last two decades, enormous drive and exploration towards promoting green chemistry practices has been taking place steadily. Multi-component reactions (MCRs) are one of the major contributions to the field of green chemistry, and have time and again served as the best tools to gain access to biologically active heterocyclic molecules with interesting properties¹ by a one-pot, single-step process. This approach offers several potential advantages over conventional synthesis. Assembling N-heterocycles via multi-component strategies is one of the vital areas in synthetic organic chemistry.

These heterocycles are a remarkable scaffold of prime importance to mankind. These heterocyclic skeletons are often an enticing framework for synthetic organic chemists and pharmaceutical and agricultural industries in designing compounds of immense chemical and biological interest.² Accordingly, molecules containing the 1,4-dihydropyridine scaffold are an important class of privileged heterocycles that have been enjoying a renaissance of interest owing to the abundance of these components in various natural products, new materials and pharmaceuticals. These ubiquitous motifs have a wide range of biological applications.³ They are often used in the treatment of cardiovascular diseases, angina pectoris, Alzheimer’s disease and hypertension.⁴ They are prominent in commercially available drug molecules such as felodipine, amlodipine, nifedipine and nicardipine (Fig. 1).⁵ The classical methods for the synthesis of 1,4-dihydropyridines usually involve the Hantzsch reaction,⁶ cycloaddition reactions,⁷ Michael condensation,⁸ Huisgen dipolar additions⁹ and others.¹⁰

Fig. 1 Some biologically potent 1,4-DHPs.

A rigorous literature survey reveals that a few synthetic methodologies have been reported recently which employ varied catalysts, solvents and conditions such as: nanoparticles,¹¹ meglumine,¹² KF/Al₂O₃,¹³ triethylamine,¹⁴ NaOH,¹⁵ polyethylene glycol (PEG), ethanol,¹⁶ grinding conditions,¹⁷ trifluoroacetic acid,¹⁸ (NH₄)₂HPO₄,¹⁹ Cu(OTf)₂ (ref. 20) and Sc(OTf)₃.²¹ Although a variety of approaches have been documented and are found to have unique advantages, they suffer from one or other drawbacks such as the preparation of the catalyst, the use of expensive catalysts, organic bases and organic solvents, prolonged reaction times, exposure to chemicals leading to environmental concerns during grinding using the grindstone method, the requirement for expensive starting materials, unsatisfactory yields and a lack of generality.

Owing to the aforementioned prominent medicinal profile of 1,4-dihydropyridines, the development of better eco-sustainable, economical and energy efficient methods remains a challenging task and therefore has attracted the keen attention of synthetic and medicinal chemists in designing them.

Another noteworthy recent finding includes the identification of benzofuran and Huisgen’s dipole chemistry because of their relevance as building blocks in drug design. Benzofuran is a very prevalent basic core unit of pharmaceutical interest which is found in many natural products (such as moracin, egonol and homoegonol), bioactive molecules and other compounds.²² Due to its excellent chemotherapeutic and physiological properties,²³ this scaffold constitutes an integral part of chemical, medicinal and life sciences that has led to a considerable amount of modern research on benzofurans being pursued in many parts of the world. This heterocycle can also serve as a versatile biodynamic motif that can be used to construct novel active therapeutic agents.²⁴ The increasing enthusiasm for this nucleus is due to its ability to display an array of valuable pharmacological activities such as immunomodulatory, anticancer, antihyperglycemic, antiparasitic and kinase inhibitor activities, and with applications as brightening agents, fluorescent sensors, drugs, antioxidants and oxidants etc.,²⁵ benzofurans are regarded as potential medicinal leads in developing therapeutic agents.

Furthermore, the highly active nature of Huisgen’s dipoles plays a crucial role in organic synthesis as they are very receptive to participating as key substrates in many kinds of multi-component reactions and have led to a library of structurally diverse heterocyclic and carbocyclic molecules.²⁶ They can be conveniently generated by the addition of amines to electron-deficient alkynes which, upon further treatment with various electrophiles and other reagents, would furnish a number of C–C and C–N bond formation reactions.²⁷

As part of the green chemistry concept, catalysis in aqueous systems under sonochemical conditions has become an attractive method after more than two decades of extensive studies in this domain.²⁸ This approach has proven to be fast, efficient, clean and reliable in chemical laboratories when compared to traditional methods. Sonochemistry, a frontier area in chemical research has been used increasingly in organic synthesis as it facilitates an unusual mechanism for generating high-energy chemical reactions. The phenomenon of acoustic cavitation, indeed, the backbone of sonochemistry, offers immense potential for increasing reaction rates that can be attributed to the mechanical effects of the sound waves (heterogeneous processes) and chemical induction (homogeneous processes) in an energy-efficient manner. It is during the cavitation bubble collapse that immense pressures, temperatures and the extraordinary heating and cooling rates set in to drive the reactions towards completion in very short times.²⁹ The rapid reaction rate, simplicity, controllable reaction conditions, high purity of the product, enhanced catalyst efficiency and safety of the technique are the essence of sonochemical reactions. These characteristics place sonochemistry amongst the elite of green chemical methods.³⁰ Since water is non-toxic, an abundant natural resource, inexpensive, non-flammable, eco-compatible and is known to facilitate excellent cavitation up to 50–60 °C, it is emerging as the solvent of choice for sonochemistry.³¹ As a result of inter- and intra-molecular non-covalent interactions, it causes special effects in reactions leading to assembly processes occurring. Copper(I) iodide, a versatile Lewis acid catalyst has found applications in numerous organic transformations.³² It holds great promise for future research as it offers advantages such as remarkable catalytic activity, operational simplicity, commercial availability, inexpensiveness, non-corrosiveness and a less toxic nature.

To the best of our knowledge, there are no reports in the literature on the use of copper iodide in water under sonic conditions for the synthesis of these nitrogen heterocycles. Encouraged by all these findings, substantial efforts have been made by us to meticulously design a library of diversified potent 1,4-dihydropyridines via a one-pot four-component cyclocondensation reaction of aromatic aldehydes, malononitrile, acetylenedicarboxylates and arylamines catalyzed by copper(I) iodide in aqueous medium under ultrasound irradiation as shown in Scheme 1.

Scheme 1 Preparation of polysubstituted 1,4-dihydropyridines 5(a–r).

Results and discussion

To explore the feasibility and generality of the copper(I) iodide catalyzed sonicated domino MCR, the reaction variables including the catalyst, reaction solvent, feed ratio of catalyst and energy efficiency were optimized to observe their roles in enhancing the rate and yields of the products. Benzofuran-2-carboxaldehyde, malononitrile, aniline and DMAD were chosen as model substrates.

A variety of catalysts were explored under different reaction conditions (room temperature, reflux temperature of the solvent, microwave and ultrasonic irradiation) and the results are presented in Table 1. To rationalize the influence of the catalyst, the four component reaction was first carried out in the absence of catalyst wherein a maximum yield of only 40% was obtained and most of the starting materials were recovered (Table 1, entry 1). It was further observed that the yield of the reaction hardly improved in the presence of other catalysts which included an amino acid (L-proline), organic nitrogen bases (DBU, piperidine, Et₃N), Lewis acids (InCl₃, Cu(OTf)₂, CuO, CuSO₄·5H₂O, CuCN, CuCl, CuBr, CuNO₃), an amino sugar (meglumine) and inorganic bases (K₂CO₃, NaOH) (Table 1, entries 2–12, 14–17) whereas the use of CuI proved to be superior, as it gave the best yield of 5a in 30 min (Table 1, entry 13). Hence, CuI and ultrasonic irradiation were chosen for our further studies.

Table 1 Optimization of the catalyst for the synthesis of 5a^a

Entry	Catalyst	Reaction conditions
		RT (25 °C)		Reflux (80 °C)		MW		US
		Time (min)	Yield^b (%)	Time (min)	Yield^b (%)	Time (min)	Yield^b (%)	Time (min)	Yield^b (%)
a Reaction conditions: benzofuran-2-carboxaldehyde (1 mmol), malononitrile (1 mmol), aniline (1 mmol), DMAD (1 mmol), catalyst (0.20 mmol) and H2O (3 mL).b Isolated yields.
1	No catalyst	600	10	600	15	30	40	30	40
2	L-Proline	600	10	600	35	30	50	30	50
3	DBU	600	10	600	25	30	50	30	55
4	Piperidine	600	10	600	30	30	50	30	60
5	Et3N	600	15	600	30	30	50	30	60
6	InCl3	600	25	600	35	30	50	30	65
7	K2CO3	600	60	600	62	30	65	30	67
8	Meglumine	600	85	600	80	30	75	30	60
9	NaOH	600	85	600	86	30	80	30	78
10	Cu(OTf)2	600	70	600	75	30	70	30	78
11	CuO	600	75	600	80	30	70	30	70
12	CuSO4·5H2O	600	65	600	70	30	50	30	55
13	CuI	600	60	600	67	30	84	30	96
14	CuCN	600	40	600	40	30	45	30	47
15	CuCl	600	45	600	50	30	53	30	55
16	CuBr	600	50	600	60	30	63	30	67
17	CuNO3	600	62	600	65	30	68	30	72

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Various solvents (non-polar, polar aprotic and polar protic solvents) were assessed in order to identify the best choice and the results of the findings are tabulated in Table 2. We, initially probed this experiment under solvent-free conditions and observed that sonication gave the maximum yield (45%) for 5a whereas unsatisfactory yields were obtained under other conditions even after prolonged times (Table 2, entry 1).

Table 2 Optimization of the solvent for the synthesis of 5a^a

Entry	Solvent	Reaction condition
		RT (25 °C)		Reflux		MW		US
		Time (min)	Yield^b (%)	Time (min)	Yield^b (%)	Time (min)	Yield^b (%)	Time (min)	Yield^b (%)
a Reaction conditions: benzofuran-2-carboxaldehyde (1 mmol), malononitrile (1 mmol), aniline (1 mmol), DMAD (1 mmol), CuI (0.20 mmol) and solvent (3 mL).b Isolated yields.
1	No solvent	600	15	600	20	30	25	30	45
2	Toluene	600	16	600	25	30	35	30	45
3	n-Hexane	600	15	600	25	30	40	30	50
4	DCM	600	18	600	30	30	45	30	55
5	THF	600	12	600	35	30	40	30	50
6	DMSO	600	12	600	25	30	30	30	58
7	CH3CN	600	10	600	20	30	35	30	60
8	DMF	600	05	600	15	30	30	30	55
9	Ethanol	600	10	600	20	30	80	30	87
10	H2O	600	25	600	50	30	82	30	96

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Furthermore, the studies revealed that the use of nonpolar solvents made the reactions very slow and low yields were obtained (Table 2, entries 2 and 3), whereas in the case of polar aprotic solvents, moderate yields were obtained (Table 2, entries 4–8) and to our delight, polar protic solvents gave very high yields (Table 2, entries 9 and 10).

With the intention to maximize the product yield in short reaction times, the amount of catalyst required to promote this successful transformation was ascertained and the results are summarized in Table 3. When the reaction was carried out using 0.05 mmol, 0.10 mmol, 0.15 mmol and 0.20 mmol of the catalyst, the rate of the reaction progressed steadily with low to good yields. To our pleasure, an excellent chemical yield of 96% was obtained when 0.20 mmol of the catalyst was employed (Table 3, entry 4). Further addition of the catalyst did not show any significant enhancement in the yield of the desired product. Consequently, the best results were achieved by using 0.20 mmol of CuI as the catalyst and water as a green solvent in the presence of ultrasonic waves for the synthesis of 5a.

Table 3 Optimization of the amount of CuI for the synthesis of 5a^a

Entry	Amount of CuI (mmol)	Time (min)	Yield^b (%)
a Reaction conditions: benzofuran-2-carboxaldehyde (1 mmol), malononitrile (1 mmol), aniline (1 mmol), DMAD (1 mmol), catalyst and H2O (3 mL).b Isolated yields.
1	0.05	30	50
2	0.10	30	70
3	0.15	30	82
4	0.20	30	96

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The possibility of recycling the catalyst was then examined. After completion of the reaction (30 min), the reaction mixture was treated with EtOAc (5 mL) to dissolve the product formed, and filtered through a pre-weighed sintered glass crucible. The solid (CuI) present in the sintered glass crucible was repeatedly washed with water and dried in a hot air oven, the crucible was weighed, and the solid (19 mg) was collected and kept aside for reuse. In the present reaction, it was found that 20 mol% of CuI was reusable without an appreciable loss of activity for four runs. From Fig. 2, it can be seen that in the first four runs the activity was more or less maintained but after the fourth run the yields were low, which may be due to loss of the catalyst during recovery.

Fig. 2 Reusability of CuI for the synthesis of 5(a–r).

To broaden the scope of the designed protocol, we used benzofuran-2-carboxaldehyde and other aromatic aldehydes, malononitrile, diversely substituted aromatic amines (bearing electron donating and electron withdrawing groups) and non-aromatic amines, and dialkyl acetylenedicarboxylates (DMAD, DEAD) with CuI as the catalyst in water for the tandem one-pot multicomponent synthesis of fifteen novel polysubstituted 1,4-dihydropyridines assisted by ultrasound. Gratifyingly, in all cases these four components congregated successfully into the corresponding 5-cyano-1,4-dihydropyridine-2,3-dicarboxylate analogs in good to excellent yields (Table 4, entries 1–14). Furthermore, the protocol was successfully extended to a series of substituted aromatic aldehydes and excellent yields were obtained (Table 4, entries 15–19). To our disappointment, complex mixtures of products were observed when non-aromatic amines such as n-hexylamine, cyclohexyl amine, ethyl amine and iso-propylamine were used (Table 4, entries 19–22). It was also noted that the electronic effects of the substituents tethered to the aromatic ring showed a marginal effect on the reactivity and did not have much impact on the product yields.

Table 4 Synthesis of 5(a–r) using ultrasound^a

Entry	Aldehyde R	R^1	R^2	Product	Time (min)	Yield^b (%)	Melting point (°C)
a Reaction conditions: aromatic aldehyde (1 mmol), malononitrile (1 mmol), aniline/amine (1 mmol), DMAD/DEAD (1 mmol), CuI (0.20 mmol) and H2O (3 mL) at 25 °C (35 kHz constant frequency, 80 W).b Isolated yields.
1		CH3	H	5a	30	96	193–194
2		C2H5	H	5b	30	93	182–183
3		CH3	4-Cl	5c	30	91	163–164
4		C2H5	4-Cl	5d	30	92	151–152
5		CH3	4-CH3	5e	30	93	133–134
6		C2H5	4-CH3	5f	30	93	218–219
7		CH3	4-NO2	5g	30	89	159–160
8		C2H5	4-NO2	5h	30	90	148–149
9		CH3	2-Cl	5i	30	90	203–204
10		C2H5	2-Cl	5j	30	94	172–173
11		CH3	4-OCH3	5k	30	92	160–161
12		C2H5	4-OCH3	5l	30	87	144–145
13		CH3	3-Cl	5m	30	90	177–178
14		C2H5	3-Cl	5n	30	85	161–162
15	3,4,5-(OCH3)3C6H2	CH3	4-Cl	5o	30	90	217–218
16	4-ClC6H4	CH3	4-CH3	5p	30	87	187–188 (ref. 16a)
17	4-ClC6H4	CH3	4-Cl	5q	30	87	128–129 (ref. 14b)
18	3-NO2C6H4	CH3	4-CH3	5r	30	96	213–214 (ref. 14b)
19	4-ClC6H4	CH3	n-Hexylamine	Inseparable mixture	30	—	—
20	3-NO2C6H4	CH3	Cyclohexylamine	Inseparable mixture	30	—	—
21	3,4,5-(OCH3)3C6H2	CH3	Ethylamine	Inseparable mixture	30	—	—
22	3,4,5-(OCH3)3C6H2	CH3	Iso-propylamine	Inseparable mixture	30	—	—

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All the products were fully characterized by IR, ¹H NMR, ¹³C NMR, ESI-MS and by elemental analysis. In the IR spectrum of compound 5a, a stretching band at 2187 cm⁻¹ appeared which confirms the presence of a nitrile group in the product. In the ¹H NMR spectrum, three singlets appeared at 3.45, 3.69 and 4.23 ppm indicating the presence of the –CH₃ protons of the two –COOMe groups and the –NH₂ protons of the amino group at the C-2 carbon, respectively. The proton at the fourth position of the dihydropyridine appeared as a singlet at 4.92 ppm confirming the fusion of malononitrile and DMAD. The ¹³C NMR spectrum further confirmed the formation of dihydropyridine as it exhibited a signal at 165.3 ppm corresponding to the C-2 carbon of 5a. The mass spectrometry data showed a peak at m/z 430.1 [M + H]⁺ which corresponds to the expected formula of the isolated 1,4-dihydropyridine. All this evidence corroborates the structure of 5a.

Further, the chemical structure of the representative compounds 5b and 5f were unequivocally confirmed by single-crystal X-ray diffraction studies as shown in Fig. 3 and 4. Compounds 5b and 5f were recrystallized in ethanol.

Fig. 3 ORTEP plot of compound 5b.

Fig. 4 ORTEP plot of compound 5f.

Generally, when ultrasound is passed through a liquid–solid system, a bubble cavitation ascends due to variation in the bulk pressure and causes a series of unique physical phenomena that can affect the solid. Asymmetric bubble collapse occurs at the interface generating high-pressure/high-velocity microjets and high energy shockwaves leading to intermolecular reactions in short times. These jets trigger the activity of the solid catalyst, cause disruption of the interfacial boundary and intensify contact through efficient mixing. As a result localized erosion, particle fragmentation by overall particle size reduction, and disengagement of the heterogeneous reactants, intermediates and product take place, enhancing the overall heat and mass transfer.^28b,33 In addition, the implosive bubble collapse induces extremely high temperatures (as much as 4700 °C) and pressures (10 Pa) in a microscopic region of the sonicated liquid.^28c As a result the rate of the chemical reaction increases by many folds, which is termed “false sonochemistry”. Therefore, it is feasible to assume that these effects are responsible for the chemical enhancement of the reactions.

In conclusion, the present study deals with the development of an efficient synthetic strategy to construct complex 1,4-dihydropyridines that could further streamline their syntheses with the aid of the green and harmless sound energy technique.

The attractive features of this procedure are the use of inexpensive starting materials, high atom efficiency, clean reaction profiles, the use of an ecofriendly solvent, mild reaction conditions, its generality, the very high yields that are obtained and the use of an energy efficient technique which meets the essential criteria of a green chemical approaches. These pharmacophoric frameworks will hopefully provide insights for medicinal chemists to explore their virtue in developing novel pharmaceutical agents to tackle the varied pathological aspects and modify the disease processes. These analogs are of particular interest, as they contain reactive handles and as such, could be used as a foundation for the synthesis of more complex biologically important molecules.

Experimental section

Material and methods

Reagents and solvents were purchased from Sigma Aldrich. All materials were of commercial reagent grade. Melting points were determined using Thiele’s apparatus (conc. H₂SO₄) with a calibrated thermometer. The progress of the reaction and the purity of the compounds were monitored by TLC [analytical silica gel plates (Merck 60 F₂₅₄)]. Infrared (IR) spectra were recorded using an Agilent Cary 630 FT-IR Spectrophotometer. ¹H NMR spectra were recorded on an Advance Bruker instrument operating at 400 or 500 MHz and ¹³C NMR spectra were recorded at 100 MHz in CDCl₃. Chemical shifts were reported in ppm. ESI-MS analysis was carried out using an ESI-Q TOF instrument. CHN analysis was performed using an Elementar vario MICRO cube analyzer. Sonication was performed using a SIDILU Indian sonic bath operating at 35 kHz (constant frequency, 80 W) and maintained at 25 °C by circulating water.

General procedure for the synthesis of polysubstituted 1,4-dihydropyridines 5(a–r)

A 50 mL flask was charged with benzofuran-2-carboxaldehyde/aromatic aldehyde (1 mmol), malononitrile (1 mmol), copper iodide (0.20 mmol) and water (3 mL) and sonicated (35 kHz) at 25 °C for 10 min. Then a solution of acetylenedicarboxylates (1 mmol) and aniline or non-aromatic amine (1 mmol) in water (3 mL) was added to the above flask and the resulting mixture was further sonicated (35 kHz) at 25 °C for an additional 20 min. After completion of the reaction [monitored by TLC using hexane : ethyl acetate (9 : 1) as eluent], the reaction mixture was treated with EtOAc (5 mL) to dissolve the product, and filtered through a pre-weighed sintered glass crucible. The solid (CuI) present in the sintered glass crucible was repeatedly washed with water and dried in a hot air oven, the crucible was weighed, and the solid (19 mg) was collected and kept aside for reuse. The filtrate was then taken into a separating funnel, the organic layer was separated, and dried over anhydrous Na₂SO₄ to get the crude compound which was then recrystallized from ethanol to get the pure product. The structures of all the products were confirmed by IR, ¹H NMR, ¹³C NMR, ESI-MS and CHN analyses.

Spectral data

Dimethyl-6-amino-4-(benzofuran-2-yl)-5-cyano-1-phenyl-1,4-dihydropyridine-2,3-dicarboxylate (5a). Yellow crystal; mp 193–194 °C; IR (ν cm⁻¹): 3336, 2975, 2187, 1740, 1653, 1217; ¹H NMR (500 MHz, CDCl₃): δ 3.45 (s, 3H, –CH₃), 3.69 (s, 3H, –CH₃), 4.23 (s, 2H, –NH₂), 4.92 (s, 1H, –CH), 6.57 (s, 1H, Ar–H), 7.19–7.55 (m, 9H, Ar–H) ppm; ¹³C NMR (100 MHz, CDCl₃): δ 32.4, 51.5, 52.1, 59.9, 103.6, 112.6, 118.9, 120.5, 122.5, 125.0, 127.7, 129.7, 131.2, 132.2, 135.1, 137.1, 141.3, 150.1, 154.3, 157.5, 163.0, 165.3 ppm; ESI-MS, m/z: 430.1 [M + H]⁺; anal. calc. for C₂₄H₁₉N₃O₅ (%): C, 67.13, H, 4.46, N, 9.79; found: C, 67.18, H, 4.41, N, 9.74.

Diethyl-6-amino-4-(benzofuran-2-yl)-5-cyano-1-phenyl-1,4-dihydropyridine-2,3-dicarboxylate (5b). Yellow crystal; mp 182–183 °C; IR (ν cm⁻¹): 3325, 2952, 2190, 1752, 1651, 1221; ¹H NMR (500 MHz, CDCl₃): δ 1.19–1.22 (t, J = 7.0 Hz, 3H, –CH₃), 1.39–1.42 (t, J = 7.0 Hz, 3H, –CH₃), 4.20–4.25 (q, J = 7.0 Hz, 4H, –CH₂), 4.85 (s, 2H, –NH₂), 5.19 (s, 1H, –CH), 6.56 (s, 1H, Ar–H), 7.13–7.55 (m, 9H, Ar–H) ppm; ¹³C NMR (100 MHz, CDCl₃): δ 14.6, 15.3, 30.7, 56.9, 60.3, 61.7, 99.4, 107.0, 110.6, 113.5, 114.1, 118.5, 121.0, 123.2, 126.0, 127.6, 129.6, 131.2, 142.9, 149.8, 156.1, 163.6, 166.9, 169.2 ppm; ESI-MS, m/z: 458.1 [M + H]⁺; anal. calc. for C₂₆H₂₃N₃O₅ (%): C, 68.26, H, 5.07, N, 9.19; found: C, 68.34, H, 5.02, N, 9.11.

Dimethyl-6-amino-4-(benzofuran-2-yl)-1-(4′-chlorophenyl)-5-cyano-1,4-dihydropyridine-2,3-dicarboxylate (5c). Brown powder; mp 118–119 °C; IR (ν cm⁻¹): 3380, 2945, 2181, 1743, 1621, 1205; ¹H NMR (400 MHz, CDCl₃): δ 3.51 (s, 3H, –CH₃), 3.69 (s, 3H, –CH₃), 4.46 (s, 2H, –NH₂), 5.29 (s, 1H, –CH), 6.57 (s, 1H, Ar–H), 7.19–7.54 (m, 8H, Ar–H) ppm; ¹³C NMR (100 MHz, CDCl₃): δ 32.9, 52.4, 52.9, 59.9, 102.4, 111.3, 119.8, 121.1, 122.8, 124.0, 128.5, 130.4, 131.5, 133.1, 133.8, 137.0, 142.4, 151.0, 155.2, 158.2, 163.2, 165.2 ppm; ESI-MS, m/z: 464.0 [M + H]⁺; anal. calc. for C₂₄H₁₈ClN₃O₅ (%): C, 62.14, H, 3.91, N, 9.06; found: C, 62.19, H, 3.98, N, 9.03.

Diethyl-6-amino-4-(benzofuran-2-yl)-1-(4′-chlorophenyl)-5-cyano-1,4-dihydropyridine-2,3-dicarboxylate (5d). Yellow crystal; mp 151–152 °C; IR (ν cm⁻¹): 3390, 2983, 2105, 1745, 1668, 1217; ¹H NMR (400 MHz, CDCl₃): δ 1.21–1.25 (t, J = 6.8 Hz, 3H, –CH₃), 1.37–1.40 (t, J = 6.8 Hz, 3H, –CH₃), 4.07–4.12 (q, J = 6.8 Hz, 4H, –CH₂), 4.85 (s, 2H, –NH₂), 5.19 (s, 1H, –CH), 7.25–7.65 (m, 9H, Ar–H) ppm; ¹³C NMR (100 MHz, CDCl₃): δ 13.7, 14.3, 29.0, 57.1, 60.1, 62.2, 94.9, 106.3, 112.4, 112.5, 113.7, 119.4, 122.3, 123.3, 124.8, 127.3, 129.1, 130.2, 143.7, 148.6, 156.9, 163.3, 167.0, 168.5 ppm; ESI-MS, m/z: 492.1 [M + H]⁺; anal. calc. for C₂₆H₂₂ClN₃O₅ (%): C, 63.48, H, 4.51, N, 8.54; found: C, 63.55, H, 4.59, N, 8.59.

Dimethyl-6-amino-4-(benzofuran-2-yl)-5-cyano-1-p-tolyl-1,4-dihydropyridine-2,3-dicarboxylate (5e). Yellow powder; mp 133–134 °C; IR (ν cm⁻¹): 3325, 2978, 2105, 1755, 1632, 1219; ¹H NMR (400 MHz, CDCl₃): δ 2.36 (s, 3H, –CH₃), 3.10 (s, 3H, –CH₃), 3.47 (s, 3H, –CH₃), 4.54 (s, 2H, –NH₂), 4.80 (s, 1H, –CH), 6.82 (s, 1H, Ar–H), 7.20–7.62 (m, 8H, Ar–H) ppm; ¹³C NMR (100 MHz, CDCl₃): δ 24.5, 31.1, 51.5, 52.1, 58.8, 103.1, 112.4, 120.0, 122.8, 124.2, 126.4, 128.7, 130.6, 131.4, 132.6, 133.7, 137.3, 143.6, 149.5, 153.7, 156.9, 161.8, 163.9 ppm; ESI-MS, m/z: 444.1 [M + H]⁺; anal. calc. for C₂₅H₂₁N₃O₅ (%): C, 67.71, H, 4.77, N, 9.48; found: C, 67.79, H, 4.85, N, 9.42.

Diethyl-6-amino-4-(benzofuran-2-yl)-5-cyano-1-p-tolyl-1,4-dihydropyridine-2,3-dicarboxylate (5f). Yellow crystal; mp 218–219 °C; IR (ν cm⁻¹): 3397, 2938, 2143, 1751, 1653, 1981; ¹H NMR (400 MHz, CDCl₃): δ 0.92–0.95 (t, J = 6.8 Hz, 3H, –CH₃), 1.26–1.29 (t, J = 6.8 Hz, 3H, –CH₃), 2.39 (s, 3H, –CH₃), 4.19–4.24 (q, J = 6.8 Hz, 4H, –CH₂), 4.59 (s, 2H, –NH₂), 4.79 (s, 1H, –CH), 6.84 (s, 1H, Ar–H), 7.21–7.59 (m, 8H, Ar–H) ppm; ¹³C NMR (100 MHz, CDCl₃): δ 14.9, 15.6, 30.5, 55.5, 61.3, 62.5, 101.7, 108.0, 110.7, 113.7, 115.5, 118.0, 120.6, 123.2, 125.0, 128.6, 131.8, 135.1, 142.9, 150.5, 155.5, 162.7, 166.7, 169.2 ppm; ESI-MS, m/z: 472.1 [M + H]⁺; anal. calc. for C₂₇H₂₅N₃O₅ (%): C, 68.78, H, 5.34, N, 8.91; found: C, 68.69, H, 5.38, N, 8.98.

Dimethyl-6-amino-4-(benzofuran-2-yl)-5-cyano-1-(4′-nitrophenyl)-1,4-dihydropyridine-2,3-dicarboxylate (5g). Yellow powder; mp 159–160 °C; IR (ν cm⁻¹): 3341, 2930, 2176, 1752, 1634, 1203; ¹H NMR (400 MHz, CDCl₃): δ 3.45 (s, 3H, –CH₃), 3.70 (s, 3H, –CH₃), 4.37 (s, 2H, –NH₂), 5.29 (s, 1H, –CH), 6.62 (s, 1H, Ar–H), 7.24–7.72 (m, 8H, Ar–H) ppm; ¹³C NMR (100 MHz, CDCl₃): δ 32.9, 52.3, 52.8, 58.5, 104.1, 112.4, 121.4, 122.7, 123.8, 124.6, 125.5, 127.1, 128.2, 130.1, 131.9, 137.1, 143.6, 151.0, 155.0, 158.7, 162.2, 164.2 ppm; ESI-MS, m/z: 475.1 [M + H]⁺; anal. calc. for C₂₄H₁₈N₄O₇ (%): C, 60.76, H, 3.82, N, 11.81; found: C, 60.84, H, 3.89, N, 11.88.

Diethyl-6-amino-4-(benzofuran-2-yl)-5-cyano-1-(4′-nitrophenyl)-1,4-dihydropyridine-2,3-dicarboxylate (5h). Yellow powder; mp 148–149 °C; IR (ν cm⁻¹): 3322, 2943, 2195, 1748, 1670, 1233; ¹H NMR (400 MHz, CDCl₃): δ 1.12–1.15 (t, J = 6.8 Hz, 3H, –CH₃), 1.28–1.31 (t, J = 6.8 Hz, 3H, –CH₃), 4.16–4.21 (q, J = 6.8 Hz, 4H, –CH₂), 5.43 (s, 1H, –CH), 6.85 (s, 2H, –NH₂), 7.22–7.72 (m, 9H, Ar–H) ppm; ¹³C NMR (100 MHz, CDCl₃): δ 15.0, 15.1, 29.4, 57.4, 60.3, 61.5, 101.0, 106.5, 112.0, 112.6, 116.1, 119.6, 123.5, 125.1, 126.9, 129.1, 130.2, 135.4, 144.0, 148.3, 156.6, 163.8, 166.6, 167.5 ppm; ESI-MS, m/z: 503.1 [M + H]⁺; anal. calc. for C₂₆H₂₂N₄O₇ (%): C, 62.15, H, 4.41, N, 11.15; found: C, 62.21, H, 4.47, N, 11.17.

Dimethyl-6-amino-4-(benzofuran-2-yl)-1-(2′-chlorophenyl)-5-cyano-1,4-dihydropyridine-2,3-dicarboxylate (5i). Golden yellow powder; mp 203–204 °C; IR (ν cm⁻¹): 3327, 2938, 2185, 1747, 1631, 1246; ¹H NMR (500 MHz, CDCl₃): δ 3.47 (s, 3H, –CH₃), 3.68 (s, 3H, –CH₃), 4.19 (s, 2H, –NH₂), 4.88 (s, 1H, –CH), 6.61 (s, 1H, Ar–H), 7.19–7.62 (m, 8H, Ar–H) ppm; ¹³C NMR (100 MHz, CDCl₃): δ 33.5, 52.6, 53.2, 60.1, 103.6, 110.5, 118.7, 120.8, 122.5, 124.7, 128.5, 130.0, 132.6, 135.5, 137.1, 142.3, 146.9, 150.6, 155.5, 157.5, 162.5, 165.4 ppm; ESI-MS, m/z: 464.0 [M + H]⁺; anal. calc. for C₂₄H₁₈ClN₃O₅ (%): C, 62.14, H, 3.91, N, 9.06; found: C, 62.19, H, 3.98, N, 9.02.

Diethyl-6-amino-4-(benzofuran-2-yl)-1-(2′-chlorophenyl)-5-cyano-1,4-dihydropyridine-2,3-dicarboxylate (5j). Golden yellow powder; mp 172–173 °C; IR (ν cm⁻¹): 3321, 2943, 2156, 1739, 1669, 1287; ¹H NMR (500 MHz, CDCl₃): δ 1.18–1.21 (t, J = 7.0 Hz, 3H, –CH₃), 1.36–1.39 (t, J = 7.0 Hz, 3H, –CH₃), 4.07–4.12 (q, J = 7.0 Hz, 4H, –CH₂), 4.42 (s, 2H, –NH₂), 4.78 (s, 1H, –CH), 6.46 (s, 1H, Ar–H), 7.09–7.73 (m, 8H, Ar–H) ppm; ¹³C NMR (100 MHz, CDCl₃): δ 13.9, 14.5, 30.0, 56.8, 60.2, 61.4, 99.5, 107.3, 111.6, 112.5, 115.0, 119.7, 121.3, 123.0, 119.7, 121.3, 123.0, 125.1, 125.7, 129.6, 131.6, 143.0, 148.6, 157.1, 163.7, 166.6, 168.4 ppm; ESI-MS, m/z: 492.1 [M + H]⁺; anal. calc. for C₂₆H₂₂ClN₃O₅ (%): C, 63.48, H, 4.51, N, 8.54; found: C, 63.42, H, 4.50, N, 8.59.

Dimethyl-6-amino-4-(benzofuran-2-yl)-5-cyano-1-(4-methoxyphenyl)-1,4-dihydropyridine-2,3-dicarboxylate (5k). Yellow powder; mp 160–161 °C; IR (ν cm⁻¹): 3314, 2955, 2163, 1745, 1638, 1209; ¹H NMR (400 MHz, CDCl₃): δ 3.50 (s, 3H, –OCH₃), 3.68 (s, 3H, –CH₃), 3.85 (s, 3H, –CH₃), 4.20 (s, 2H, –NH₂), 4.91 (s, 1H, –CH), 6.56 (s, 1H, Ar–H), 7.18–7.54 (m, 8H, Ar–H) ppm; ¹³C NMR (100 MHz, CDCl₃): δ 33.4, 51.6, 52.3, 56.3, 60.0, 103.9, 112.0, 120.6, 121.8, 123.0, 124.5, 128.7, 130.9, 131.6, 133.2, 134.0, 138.0, 140.9, 149.9, 156.4, 159.5, 162.2, 164.6 ppm; ESI-MS, m/z: 460.1 [M + H]⁺; anal. calc. for C₂₅H₂₁N₃O₆ (%): C, 65.35, H, 4.61, N, 9.15; found: C, 65.21, H, 4.66, N, 9.17.

Diethyl-6-amino-4-(benzofuran-2-yl)-5-cyano-1-(4′-methoxyphenyl)-1,4-dihydropyridine-2,3-dicarboxylate (5l). Yellow powder; mp 144–145 °C; IR (ν cm⁻¹): 3357, 2917, 2182, 1746, 1616, 1211; ¹H NMR (400 MHz, CDCl₃): δ 0.90–0.94 (t, J = 6.8 Hz, 3H, –CH₃), 1.26–1.29 (t, J = 6.8 Hz, 3H, –CH₃), 2.29 (s, 3H, –OCH₃), 4.12–4.16 (q, J = 6.8 Hz, 4H, –CH₂), 4.53 (s, 2H, –NH₂), 4.82 (s, 1H, –CH), 6.84 (s, 1H, Ar–H), 7.21–7.59 (m, 8H, Ar–H) ppm; ¹³C NMR (100 MHz, CDCl₃): δ 13.0, 13.7, 28.4, 52.7, 55.5, 61.6, 62.5, 99.2, 106.6, 112.5, 114.0, 115.1, 118.4, 121.5, 123.4, 125.0, 128.0, 130.4, 134.2, 143.6, 151.7, 157.1, 163.8, 166.1, 167.8 ppm; ESI-MS, m/z: 488.1 [M + H]⁺; anal. calc. for C₂₇H₂₅N₃O₆ (%): C, C, 66.52, H, 5.17, N, 8.62; found: C, 66.59, H, 5.12, N, 8.60.

Dimethyl-6-amino-4-(benzofuran-2-yl)-1-(3′-chlorophenyl)-5-cyano-1,4-dihydropyridine-2,3-dicarboxylate (5m). Yellow powder; mp 177–178 °C; IR (ν cm⁻¹): 3356, 2957, 2128, 1751, 1676, 1219; ¹H NMR (400 MHz, CDCl₃): δ 3.51 (s, 3H, –CH₃), 3.68 (s, 3H, –CH₃), 4.96 (s, 2H, –NH₂), 5.29 (s, 1H, –CH), 6.73 (s, 1H, Ar–H), 7.20–7.49 (m, 8H, Ar–H) ppm; ¹³C NMR (100 MHz, CDCl₃): δ 33.8, 53.4, 54.1, 62.3, 103.6, 112.5, 119.4, 121.1, 124.2, 125.8, 128.5, 130.1, 132.0, 133.1, 134.5, 137.00, 141.5, 151.5, 154.7, 159.3, 162.1, 166.5 ppm; ESI-MS, m/z: 464.0 [M + H]⁺; anal. calc. for C₂₄H₁₈ClN₃O₅ (%): C, 2.14, H, 3.91, N, 9.06; found: C, 62.11, H, 3.97, N, 9.01.

Diethyl-6-amino-4-(benzofuran-2-yl)-1-(3′-chlorophenyl)-5-cyano-1,4-dihydropyridine-2,3-dicarboxylate (5n). Yellow powder; mp 161–162 °C; IR (ν cm⁻¹): 3319, 2979, 2167, 1742, 1636, 1269; ¹H NMR (400 MHz, CDCl₃): δ 1.17–1.21 (t, J = 6.8 Hz, 3H, –CH₃), 1.33–1.36 (t, J = 6.8 Hz, 3H, –CH₃), 4.10–4.15 (q, J = 6.8 Hz, 4H, –CH₂), 4.79 (s, 2H, –NH₂), 5.05 (s, 1H, –CH), 6.62 (s, 1H, Ar–H), 7.20–7.45 (m, 8H, Ar–H) ppm; ¹³C NMR (100 MHz, CDCl₃): δ 15.3, 16.1, 30.6, 56.4, 60.3, 61.5, 99.7, 107.9, 111.5, 113.8, 115.6, 119.5, 120.7, 123.6, 127.6, 131.7, 133.4, 136.4, 142.7, 148.9, 157.3, 163.8, 165.6, 170.2 ppm; ESI-MS, m/z: 492.1 [M + H]⁺; anal. calc. for C₂₆H₂₂ClN₃O₅ (%): C, 63.48, H, 4.51, N, 8.54; found: C, 63.43, H, 4.48, N, 8.59.

Dimethyl-6-amino-1-(4′-chlorophenyl)-5-cyano-4-(3′′,4′′,5′′-trimethoxyphenyl)-1,4-dihydropyridine-2,3-dicarboxylate (5o). Yellow powder; mp 217–218 °C; IR (ν cm⁻¹): 3319, 2979, 2167, 1742, 1636, 1269; ¹H NMR (400 MHz, CDCl₃): δ 3.53 (s, 3H, –CH₃), 3.65 (s, 3H, –CH₃), 3.86 (s, 3H, –OCH₃), 3.90 (s, 6H, –OCH₃), 4.63 (s, 2H, –NH₂), 5.31 (s, 1H, –CH), 6.59 (s, 2H, Ar–H), 7.25–7.49 (m, 4H, Ar–H) ppm; ¹³C NMR (100 MHz, CDCl₃): δ 38.0, 55.1, 55.2, 62.0, 62.6, 63.0, 103.4, 105.3, 115.1, 120.1, 127.7, 130.9, 138.0, 140.6, 141.9, 150.1, 153.0, 160.9, 163.8, 165.5 ppm; ESI-MS, m/z: 514.1 [M + H]⁺; anal. calc. for C₂₅H₂₄ClN₃O₇ (%): C, 58.43, H, 4.71, N, 8.18; found: C, 58.31, H, 4.80, N, 8.29.

Dimethyl-6-amino-4-(4′-chlorophenyl)-5-cyano-1-p-tolyl-1,4-dihydropyridine-2,3-dicarboxylate (5p). Yellow powder; mp 187–188 °C; IR (ν cm⁻¹): 3363, 2921, 2110, 1735, 1659, 1227; ¹H NMR (400 MHz, CDCl₃): δ 2.4 (s, 3H, –CH₃), 3.45 (s, 3H, –OCH₃), 3.59 (s, 3H, –OCH₃), 4.11 (s, 2H, –NH₂), 4.68 (s, 1H, –CH), 7.18–7.29 (m, 8H, Ar–H) ppm; ¹³C NMR (100 MHz, CDCl₃): δ 22.0, 38.5, 52.6, 62.6, 105.6, 112.6, 121.1, 128.5, 129.3, 130.3, 131.1, 132.5, 133.1, 141.0, 142.0, 142.8, 149.1, 162.1, 165.6 ppm; ESI-MS, m/z: 438.1 [M + H]⁺; anal. calc. for C₂₃H₂₀ClN₃O₄ (%): C, 63.09, H, 4.60, N, 9.60; found: C, 63.18, H, 4.67, N, 9.72.

Dimethyl-6-amino-1,4-bis(4′-chlorophenyl)-5-cyano-1,4-dihydropyridine-2,3-dicarboxylate (5q). Yellow powder; mp 128–129 °C; IR (ν cm⁻¹): 3360, 2989, 2119, 1746, 1643, 1210; ¹H NMR (400 MHz, CDCl₃): δ 3.41 (s, 3H, –CH₃), 3.69 (s, 3H, –CH₃), 4.13 (s, 2H, –NH₂), 4.63 (s, 1H, –CH), 7.22–7.47 (m, 8H, Ar–H) ppm; ¹³C NMR (100 MHz, CDCl₃): δ 18.8, 36.7, 50.5, 51.1, 56.4, 61.8, 104.6, 120.5, 127.7, 128.4, 129.9, 130.0, 130.7, 131.4, 132.1, 132.6, 134.0, 135.8, 140.8, 141.2, 143.5, 149.7, 157.2, 159.2, 163.9, 164.7 ppm; ESI-MS, m/z: 458.1 [M + H]⁺; anal. calc. for C₂₂H₁₇Cl₂N₃O₄ (%): C, 57.66, H, 3.74, N, 9.17; found: C, 57.50, H, 4.03, N, 8.95.

Dimethyl-6-amino-5-cyano-4-(3′-nitrophenyl)-1-p-tolyl-1,4-dihydropyridine-2,3-dicarboxylate (5r). Yellow powder; mp 213–214 °C; IR (ν cm⁻¹): 3382, 2942, 2120, 1749, 1610, 1237; ¹H NMR (400 MHz, CDCl₃): δ 2.49 (s, 3H, –CH₃), 3.46 (s, 3H, –OCH₃), 3.59 (s, 3H, –OCH₃), 4.18 (s, 2H, –NH₂), 4.82 (s, 1H, –CH), 7.26–8.28 (m, 8H, Ar–H) ppm; ¹³C NMR (100 MHz, CDCl₃): δ 18.1, 20.2, 37.3, 50.8, 51.3, 58.2, 60.3, 103.9, 120.5, 121.6, 122.5, 129.3, 130.1, 130.7, 131.5, 132.6, 134.1, 141.1, 142.5, 146.7, 148.1, 151.9, 162.4163.9 ppm; ESI-MS, m/z: 449.1 [M + H]⁺; anal. calc. for C₂₃H₂₀N₄O₆ (%): C, 61.60, H, 4.50, N, 12.49; found: C, 61.49, H, 4.85, N, 12.11.

Acknowledgements

The authors gratefully acknowledge the financial assistance by the VGST, Dept. of IT, BT and Science & Technology, Government of Karnataka for the CESEM Award Grant No. 24 (2010–2011). We also acknowledge the NMR centers, IISc, Bangalore for providing ¹H and ¹³C NMR spectra.

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Footnote

† Electronic supplementary information (ESI) available: detailed spectroscopic data of all new compounds; single crystal data for compounds 5b (CCDC 1423053) and 5f (CCDC 1423055). For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c6ra05441b

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