A simple and efficient method for the facile access of highly functionalized pyridines and their fluorescence property studies

Abstract

In this paper, we have described a simple and convenient method for the one-pot multicomponent reaction of aldehydes, malononitrile and thiols in the presence of a catalytic amount of Bronsted base potassium hydroxide for the efficient synthesis of highly functionalized pyridines. The notable features of this protocol are the simple experimental procedure, short reaction time, broad substrate scope and good yields using a catalytic amount of readily available and cheap base. The photophysical behaviours of the synthesized pyridines have been investigated by UV-Vis and fluorescence spectroscopy and some of the synthesized substituted pyridines exhibit promising fluorescence quantum yields.

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Introduction

Multicomponent reactions (MCRs) have gained significant attention in recent times due to advantages such as atom, step and pot economy.¹ MCRs are considered a vital tool for both combinatorial chemistry and diversity-oriented synthesis.² Synthesis of functionalized heterocyles by MCRs has become an attractive approach in modern organic synthesis.³ Among the heterocyclic systems, the pyridine nucleus is of considerable significance owing to its presence in biologically active compounds, active pharmaceuticals, broad range of natural products and functional materials.⁴ For example, diploclidine⁵ is a recently isolated natural product containing the pyridine core (Fig. 1). Similarly, streptonigrin and lavendamycin are bio-active natural products having a highly substituted pyridine moiety.⁶ In addition to these, substituted pyridines are prominent building blocks in supramolecular chemistry due to their π-stacking and directed H-bond forming ability.⁷

Fig. 1 Natural products with a substituted pyridine moiety.

Considering the wide applications of functionalized pyridines, the design and development of a new methodology for the synthesis of pyridines have attracted huge attention from both synthetic and medicinal chemists.⁸ Recently, a plethora of methods for the synthesis of substituted pyridines have been reported in the literature. Among them, regiospecific metallacycle-mediated synthesis,⁹ nickel-catalyzed dehydrogenative [4 + 2] cycloaddition of 1,3-dienes with nitriles,¹⁰ tandem Blaise reaction intermediate and 1,3-enynes,¹¹ coupling of oxime acetates with aldehydes¹²etc. are notable. Very recently Deiters et al.,¹³ have synthesized the pyridine core of cyclothiazomycin in a regioselective manner via [2 + 2 + 2] cyclotrimerization as a key step. Substituted 2-amino pyridines tethered with nitrile and amino functionalities as shown in Fig. 2 are considered as privileged medicinal scaffolds.¹⁴

Fig. 2 Highly substituted pyridines having potent biological activity.

Literature studies revealed that these penta-substituted pyridines exhibit significant and diverse medicinal properties, such as antibacterial,¹⁵ anticancer,¹⁶ potassium channel opener for treatment of urinary incontinence,¹⁷ anti hepatitis B virus (HBV) infection,¹⁸ Parkinson's disease, hypoxia, asthma, cancer and kidney disease¹⁹etc. Evdokimov et al.²⁰ reported a multi component reaction of aldehydes, two equivalents of malononitrile and thiophenols for the one-pot synthesis of 2-amino-3,5-dicarbonitrile-6-sulfanylpyridines using Et₃N or DABCO as a catalyst. However, this method suffers from some limitations such as low yields (20 to 48%) and occurrence of by products “enaminonitriles”. The broad pharmacological applications of this moiety inspired the development of a few improved methods using various catalysts such as basic ionic liquid [bmIm]OH,²¹ piperidine/microwave,²² ZnCl₂,²³ silica nanoparticle,²⁴ KF/alumina,²⁵ DBU,²⁶ boric acid,²⁷ ZrOCl₂·8H₂O/NaNH₂ in [bmim]BF₄ under ultrasound irradiation,²⁸ nanocrystalline magnesium oxide²⁹ and very recently by Zn(II) and Cd(II) metal-organic frameworks (MOFs) etc.³⁰ Most of the literature methods suffer from one or another draw back such as low yields, toxic or expensive catalyst or a longer reaction time. Therefore, development of an improved and generalized method for the synthesis of these privileged molecules using a readily available and inexpensive catalyst has remained important. In continuation of our work on the development of new synthetic methodologies for the synthesis of diverse heterocycles,³¹ we have observed that the one-pot multicomponent reaction of aldehyde with malononitrile and thiophenol in the presence of a catalytic amount of KOH provides 2-amino-3,5-dicarbonitrile-6-thio-pyridines in good yields (Scheme 1).

Scheme 1 Synthesis of highly substituted 4-aryl pyridines.

It is significant to mention that Xin et al.³² had reported a multicomponent reaction for the synthesis of substituted pyridines tethered with 2-alkoxy group using stoichiometric amount of NaOH (Scheme 2). Whereas herein, we report a four component reaction catalyzed by catalytic amount of either NaOH or KOH for the efficient synthesis of 2-amino, 4-aryl/alkyl pyridine dicarbonitriles by replacing 1,3-dicarbonyl by another equivalent of malononitrile and adding one equivalent of thiol.

Scheme 2 Substrate directed base catalyzed multicomponent reactions for the diversity oriented synthesis of highly functionalized pyridines.

It is noteworthy to mention that previous studies by other groups^25,33 reported that this multicomponent reaction was unsuccessful in the presence of sodium hydroxide. It's our surprise that a catalytic amount of NaOH or KOH is useful for the efficient synthesis of functionalized 2-amino pyridine derivatives.

Results and discussion

Initially, the reaction of 4-methoxybenzaldehyde (1.0 equiv.), malononitrile (2.0 equiv.) and thiophenol (1.0 equiv.) was chosen as a model reaction in the presence of 10 mol% base catalyst in ethanol at reflux temperature. Among the readily available bases, we screened this reaction with Na₂CO₃, KOH, NaOH, NaHCO₃ and LiOH (Table 1, entries 2–7). KOH was found to be the most efficient catalyst of choice for this transformation in terms of reaction time and yields obtained. Trace amounts of product were obtained in the absence of catalyst after 20 h reaction time (Table 1, entry 1). Similarly, various solvents like ethanol, acetonitrile, THF, dichloromethane and water were also screened for the same reaction keeping the substrate ratio intact (Table 1, entries 7–11). Among all these solvents, EtOH was found to be the best solvent for this transformation.

Table 1 Optimization of reaction conditions^a

Entry	Catalyst	Solvent	Time (h)	Yield^b (%)
a Reaction conditions: 4-methoxybenzaldehyde (3.0 mmol), malononitrile (6.0 mmol), thiophenol (3.0 mmol), catalyst (10 mol%) in ethanol (10 ml) at reflux temperature. b Isolated yields. c Reaction performed at room temperature.
1	—	EtOH	20	Trace
2	Na2CO3	EtOH	1.0	62
3	NaHCO3	EtOH	1.0	55
4	NaOH	EtOH	1.0	74
5	LiOH	EtOH	1.0	62
6	KOH	EtOH	4.5	35^c
7	KOH	EtOH	0.5	86
8	KOH	CH3CN	1.5	79
9	KOH	THF	1.5	35
10	KOH	CH2Cl2	12	30
11	KOH	H2O	2.5	35

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To find the optimum reaction condition, the same model reaction was carried out in the presence of different amounts of KOH (Table 2). The variation of the quantity of KOH from 5 mol% to 30 mol% gave different yields of 1a in 57, 86, 81 and 79% respectively. Higher loading of the catalyst lowered the reaction time but did not improve the reaction yield. Among them the best amount of KOH was 10 mol%.

Table 2 Optimization of catalyst amount^a

Entry	KOH (mol%)	Time (min)	Yield ^b (%)
a Reaction conditions: 4-methoxybenzaldehyde (3.0 mmol), malononitrile (6.0 mmol), thiophenol (3.0 mmol), catalyst (10 mol%) in ethanol (10 ml) at reflux temperature. b Isolated yield.
1	5	90	57
2	10	30	86
3	20	25	81
4	30	20	79

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With the optimized conditions in hand, we turned our attention to investigate the scope and general applicability of this methodology by carrying out the synthesis of pyridines using different aldehydes and thiols (Table 3). We have found that a series of substituted aromatic aldehydes tethered with either electron-withdrawing or electron-donating groups produced 2-amino-3,5-dicarbonitrile-6-sulfanylpyridines in good to excellent yields (Table 3, entries 1, 3–10, 12 and 14–16). Aliphatic aldehydes such as cyclohexanecarbaldehyde also underwent this multicomponent reaction smoothly to provide the corresponding pyridine derivative (1k) in good yield. Similarly, a bulky aldehyde such as 2-naphthaldehyde was also found to be suitable to obtain the corresponding pyridine derivative (1m). Next, the variability of thiols was tested under the given reaction conditions. Benzyl thiol and cyclohexyl thiol were also found to be suitable for this multicomponent reaction to provide corresponding pyridine derivatives (1h, 1i, 1m and 1l respectively) in good to excellent yields. Interestingly, in case of 2-amino thiophenol, the corresponding expected pyridine derivative (1n) was found in very good yield and we did not observe any 2,6-diamino pyridine derivatives. Similarly, 2-methyl thiophenol also provided pyridine derivatives (1o and 1p) in good yields.

Table 3 Synthesis of 2-amino-3,5-dicarbonitrile-6-thio-pyridines

Entry	R^1	R^2	Product^a	Time min/hour	Yield^b (%)
a All products were fully characterized by IR, ^1H NMR, ^13C NMR and elemental analysis. b Isolated yield.
1	4-OMeC6H4	C6H5	1a	30 min	86
2	C6H5	C6H5	1b	1.0 h	80
3	4-Cl-C6H4	C6H5	1c	1.0 h	81
4	4-Me-C6H4	C6H5	1d	1.0 h	85
5	3-Cl-C6H4	C6H5	1e	45 min	73
6	4-Br-C6H4	C6H5	1f	1.0 h	71
7	4-SMe-C6H4	C6H5	1g	50 min	83
8	4-Cl-C6H4	C6H5CH2	1h	30 min	83
9	4-Me-C6H4	C6H5CH2	1i	30 min	89
10	3-NO2-C6H4	C6H5	1j	1.0 h	75
11	C6H11	C6H5	1k	1.5 h	76
12	4-Cl-C6H4	C6H11	1l	30 min	82
13	β-C10H7	C6H5CH2	1m	30 min	85
14	4-Br-C6H4	2-NH2-C6H4	1n	30 min	90
15	4-Br-C6H4	2-Me-C6H4	1o	1.0 h	90
16	4-CN-C6H4	2-Me-C6H4	1p	30 min	88

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Interestingly, in case of sterically hindered aldehydes such as 2,6-dichlorobenzaldehyde, 2-chloro-6-fluorobenzaldehyde and 2,6-dimethoxybenzaldehyde, the corresponding expected pyridines were not observed using this methodology. Similar to other literature reported methods,^14,20 we also observed the corresponding dihydropyridines (Table 4, entries 1–3). Although, Kantam et al.²⁹ observed the corresponding pyridine derivative in the case of 2,6-dimethoxybenzaldehyde, however in this method, even after a prolonged reaction time we observed only the corresponding dihydropyridine 2c.

Table 4 Synthesis of dihydropyridines using o,o′-disubstituted aldehydes

Entry	R^1	R^2	Product^a	Time (hour)	Yield ^b (%)
a All products were fully characterized by IR, ^1H NMR, ^13C NMR and elemental analysis. b Isolated yield.
1	–Cl	–Cl	2a	1.5	93
2	–Cl	–F	2b	1.0	91
3	–OMe	–OMe	2c	1.0	96

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All the synthesized molecules were fully characterized using the usual spectroscopic techniques. Among them, for compound 1e, single crystal X-ray crystallographic analysis was done, which further supported our spectroscopic data (Fig. 3).

Fig. 3 ORTEP plot of compound 1e (CCDC 875077).

After having these successful results, we were interested to see whether this protocol could be extended to other active methylene compounds bearing only one –CN, such as ethyl cyanoacetate as shown in Scheme 3. Unfortunately, the reaction did not afford the desired substituted 2-amino pyridine (1q). Instead, we found the corresponding Knovenegel product (3a) and disulphide (4), which may be due to the lower reactivity of 3a and lower nucleophilicity of the ethyl cyanoacetate.

Scheme 3 Reaction with ethyl cyanoacetate instead of malononitrile.

Taking cue from the work of Alvarez-Insua et al.,³⁴ we also investigated the possibility of replacing thiols by other nucleophiles such as alcohols and amines using the same catalyst. Interestingly, we found that in the absence of thiol, i.e., the reaction of 4-methoxybenzaldehyde, malononitrile in ethanol and a catalytic amount of KOH, the corresponding expected product 5a was not formed. However, by changing the reaction procedure and increasing the amount of KOH (1 mol. equiv.) we were able to synthesize the corresponding oxo-pyridine derivatives (Table 5, entries 1 and 2). In this reaction, the sequence of the addition of reagents is very crucial, e.g. when all the reactants were mixed at once in the presence of KOH (1.0 equiv.) it provided the corresponding Knoevenagel alkene (3b) along with an unwanted side product (6) (Scheme 4).

Scheme 4 Dependency on the addition sequence of starting materials.

Table 5 Synthesis of amino and oxo pyridines

Entry	R^1	R^2XH	Product^a	Time (hour)	Yield^b (%)
a All products were fully characterized by IR, ^1H NMR, ^13C NMR and elemental analysis. b Isolated yield.
1	4-OMe-C6H4	CH3CH2OH	5a	2.0	88
2	4-OMe-C6H4	CH3OH	5b	1.0	91
3	4-OMe-C6H4	Pyrrolidine	5c	2.0	77
4	4-OMe-C6H4	Piperazine	5d	1.5	83

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Similar to ethanol and methanol, aliphatic cyclic amines such as pyrrolidine and piperazine provided the corresponding substituted pyridines (Table 5, entries 3 and 4) in good yields. In the case of aromatic amines the reaction was not successful.

A mechanism portraying the probable sequence of events for the synthesis of thiopyridine derivatives is shown in Scheme 5. Condensation of an aldehyde with malononitrile leads to the corresponding Knoevenagel product. Next, the second molecule of malononitrile undergoes Michael addition followed by simultaneous thiolate addition to C≡N of the adduct and cyclization leads to dihydropyridine, which undergoes oxidative aromatization to provide highly substituted pyridine.

Scheme 5 Proposed mechanism for the KOH mediated synthesis of thio-pyridine derivatives.

Photophysical properties

Synthesis of organic compounds with high quantum yield has been the subject of intense study because of their demand as dyes,³⁵ biological markers,³⁶ functional organic devices and sensors,³⁷ as well as in organic light emitting devices (OLEDs). An organic molecular system of a donor-π-electron bridge acts as a molecular rectifier.³⁸ Considering the biaryl structure and extended conjugation with the CN moiety, we were interested to see the optical behaviour of the synthesized highly substituted pyridines containing D-π-A (donor-π system-acceptor) push pull system. Initially, UV-Vis and fluorescence behaviour of compound 1a was investigated at room temperature in different polar protic and aprotic solvents such as chloroform, methanol, acetonitrile and DMSO (Table 6, Fig. 4). Because of solubility problems we could not study the UV-Vis and fluorescent properties of 1a in non-polar solvents. Similar to 1a, we have also screened the UV-Vis and fluorescence properties of the other thiopyridines (1b–1p, see ESI†), however their results were not encouraging compared to 1a.

Fig. 4 (Top) UV-Vis spectra of compound 1a in different solvents (10⁻⁵ M; 25 °C). (Bottom) Fluorescence spectra of compound 1a in different solvents [10⁻⁵ M; 25 °C; λ^ex = (a) 343 nm, (b) 351 nm, (c) 344 nm, (d) 343 nm; slit = 2/2].

Table 6 UV-Vis and fluorescent data of 1a in different solvents

Compound	Solvent	λ ^abs max (nm)	λ ^em max (nm)	Δ[small upsilon, Greek, macron] (cm^−1)	Ø^af
a Quantum yield was calculated with respect to quinine sulphate dihydrate in water. Øf = quantum yield, λ^absmax = absorbance maxima, λ^emmax = fluorescence maxima, Δ[small upsilon, Greek, macron] = Stoke's shift.
1a	DMSO	351	406	3860	0.09
	CH3CN	343	421	5402	0.06
	MeOH	344	388	3297	0.10
	CHCl3	343	426	5681	0.18

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Next, we were interested to study the UV-Vis and fluorescence properties of compounds (5a–d) and among them compounds 5a and 5d showed prominent quantum yields (see ESI† for 5b and 5c) in CHCl₃. The UV-Vis and fluorescence data for compound 5a and 5d are summarized in Table 7 and Fig. 5 and 6 respectively.

Fig. 5 (Top) UV-Vis spectra of compound 5a in different solvents (10⁻⁵ M; 25 °C). (Bottom) Fluorescence spectra of compound 5a in different solvents [10⁻⁵ M; 25 °C; λ^ex = (a) 329 nm, (b) 320 nm, (c) 306 nm, (d) 322 nm; slit = 2/2].

Fig. 6 (Top) UV-Vis spectra of compound 5d in different solvents (10⁻⁵ M; 25 °C). (Bottom) Fluorescence spectra of compound 5d in different solvents [10⁻⁵M; 25 °C; λ^ex = (a) 335 nm, (b) 342 nm, (c) 342 nm, (d) 341 nm; slit = 2/2].

Table 7 UV-Vis and fluorescent data of 5a and 5d in different solvents

Compound	Solvent	λ ^abs max (nm)	λ ^em max (nm)	Δ[small upsilon, Greek, macron] (cm^−1)	Ø^af
a Quantum yield was calculated with respect to quinine sulphate dihydrate in water. Øf = Quantum yield, λ^absmax = absorbance maxima, λ^emmax = fluorescence maxima, Δ[small upsilon, Greek, macron] = Stoke's shift.
5a	DMSO	329	394	5015	0.06
	CH3CN	320	394	5870	0.08
	MeOH	322	367	3808	0.12
	CHCl3	306	424	9095	0.14
5d	DMSO	342	504	9399	0.35
	CH3CN	342	507	9516	0.23
	MeOH	335	377	3326	0.08
	CHCl3	341	488	8834	0.57

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From these graphs we have found that in UV-Vis spectra, peaks appeared around 343–351 nm for 1a, 306–329 nm for 5a and 335–342 nm for 5d. In the case of compound 5a, a prominent blue-shift was observed in the chloroform solvent at 306 nm. The emission spectra appeared around 388–426 nm for 1a, 367–424 nm for 5a and 377–507 nm for 5d. Interestingly, for 5d a large red-shifted, low energy band was observed in both acetonitrile and dipolar aprotic DMSO solvent at 507 nm and 504 nm respectively. Also, for 5d in acetonitrile a high stoke shift Δ[small upsilon, Greek, macron] (9516 cm⁻¹) was observed. The absorption maxima, emission maxima and fluorescence quantum yield depends on various factors such as the structure of the molecule, nature of the solvent, probe–probe interaction, probe–solvent interaction, temperature, pH and concentration etc.^36c In this investigation we have observed that fluorescence quantum yield of these compounds is dependent on the type of the substituent group. Among all the compounds of Table 3, 1a showed a maximum quantum yield of 0.18 in CHCl₃. The quantum yields of other compounds (1b–1p) were in the range Ø_f = 0.00–0.05. Substitution effects have been greatly observed in the case of 1a, which may be due to the presence of 4-OMe, a strong electron donating group in the C4-aryl of the pyridine ring as compared to the other derivatives. We believe that this –OMe enables the effective charge transfer in the excited state and reduces the non-radiative decay which causes intense fluorescence. Similarly, 5d shows a maximum quantum yield of Ø_f = 0.57 in CHCl₃ among all the synthesized pyridine derivatives. This may be due to the presence of a secondary nitrogen atom in the 4-position of the piperazine moiety that has an influence on the tertiary nitrogen atom at the C6 position of the pyridine ring, likely via a through-space interaction. From these studies we have concluded that for these types of highly substituted pyridines, the photophysical behaviour is dependent on the substitution pattern as well as the types of solvents used i.e. the surrounding environment of the molecule. Considering the above behaviours, we believe that these substituted pyridines may find potential application as new fluorescent probes or luminescence material.

Conclusion

In summary, the present work describes an efficient one-pot multicomponent strategy for the synthesis of 2-amino-3,5-dicarbonitrile-6-sulfanylpyridines from the reaction of aldehydes, malononitrile and thiols using a cost effective, environmentally benign KOH as the catalyst. This protocol has the advantages of a wide scope of substrates, operational simplicity, no need of column chromatographic separation, shorter reaction times, high yields, ready availability and low cost of the catalyst. To the best of our knowledge we have for the first time studied the photophysical properties of 2-amino-3,5-dicarbonyl-6-sulfanylpyridines and have compared with the analogues of substituted amino and oxo-pyridines.

Experimental

General Information

All reagents and chemicals required for the reaction were procured from commercial sources and used without further purification. IR spectra were recorded in a Shimadzu FTIR spectrophotometer. ¹H NMR spectra and ¹³C NMR spectra were recorded on a Jeol 500, Varian 400 and Bruker 300/400/500 MHz spectrometer in CDCl₃ and DMSO-d₆ using TMS as the internal reference. Elemental analyses were carried out in a Perkin Elmer 2400 automatic CHN analyzer or Elementer Vario EL III. All new compounds were characterized by recording melting point without correction, ¹H NMR, ¹³C NMR and elemental analysis. The UV-Vis absorption spectra were recorded on Shimadzu UV-Vis spectrophotometer (UV-2550) and fluorescence spectra was recorded on a Horiba Jobin Yuon fluoromax-4 spectrofluorometer. Quantum yields were determined with respect to quinine sulphate as a standard.³⁹

General procedure for the synthesis of 2-amino-4-(aryl/alkyl)-6-(aryl/alkylsulfanyl)-pyridine-3,5-dicarbonitrile (1a–1p). A mixture of aldehyde (3.0 mmol), malononitrile (6.0 mmol), KOH (10 mol%), thiol (3.0 mmol) and ethanol (10 ml) at room temperature was taken in a 25 mL round bottom flask fitted with reflux condenser. The reaction mixture was stirred at reflux conditions in open air. After some time the reaction converted to a clear solution. The progress of the reaction was monitored with TLC (hexane–ethyl acetate, 8 : 2). After completion of the reaction, the reaction mixture was gradually cooled to room temperature. The solid product was collected by simple filtration and washed with ethanol and dried. The solid was dissolved in ethyl acetate and washed with water. The collected ethyl acetate layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to get the crude solid which was then purified by recrystalization from ethanol (for the product: 1b–1e, 1g, 1j,1k and 1n,1o; Table 1) and acetonitrile (for the product: 1a, 1f, 1h–1i, 1l,1m and 1p; Table 1) to obtain pure products.

2-Amino-4-(4-methoxyphenyl)-6-(phenylsulfanyl)pyridine-3,5-dicarbonitrile (1a)²¹. White solid. 86% yield. M.P.: 235–237 °C; IR ν_max (KBr): 3441, 3332, 3227, 3056, 2983, 2846, 2227, 2215, 1641, 1606, 1512, 1463, 1290, 1259, 1190, 1019, 837, 756; ¹H NMR (CDCl₃, 500 MHz): δ = 7.55 (dd, J = 7.4, 2.3 Hz, 2H, Ar–H), 7.51 (d, J = 8.4 Hz, 2H, Ar–H), 7.48–7.45 (m, 3H, Ar–H), 7.05 (d, J = 8.6 Hz, 2H, Ar–H), 5.43 (bs, 2H, NH₂), 3.87 (s, 3H, OCH₃); ¹³C NMR (DMSO-d₆, 125 MHz): δ = 166.6, 161.3, 160.2, 158.8, 135.3, 130.7, 130.1, 129.9, 127.7, 126.3, 116.0, 115.8, 114.6, 93.9, 87.5, 55.8; Anal. Calcd. for C₂₀H₁₄N₄OS (358.42): C, 67.02; H, 3.94; N, 15.63. Found: C, 67.26; H, 3.71; N, 15.84.

2-Amino-4-(phenyl)-6-(phenylsulfanyl)pyridine-3,5-dicarbonitrile (1b)²¹. White solid, 80% yield. M.P.: 214–216 °C; IR ν_max (KBr): 3485, 3361, 3211, 3053, 2218, 1618, 1546, 1263, 753; ¹H NMR (CDCl₃, 400 MHz): δ = 7.57–7.50 (m, 7H, Ar–H), 7.49–7.48 (m, 3H, Ar–H), 5.53 (bs, 2H, NH₂); ¹³C NMR (CDCl₃,125 MHz): δ = 169.1, 159.3, 158.4, 135.8, 133.2, 131.0, 130.0, 129.3, 129.0, 128.5, 127.2, 115.2, 114.8, 95.9, 87.4; Anal. Calcd. for C₁₉H₁₂N₄S (328.39): C, 69.49; H, 3.68; N, 17.06. Found: C, 69.58; H, 3.75; N, 17.29.

2-Amino-4-(4-chlorophenyl)-6-(phenylsulfanyl) pyridine-3,5-dicarbonitrile (1c)²¹. White solid, 81% yield. M.P.: 227–229 °C; IR ν_max (KBr): 3451, 3370, 3214, 3090, 2219, 1624, 1549, 1261, 754; ¹H NMR (CDCl₃, 500 MHz): δ = 7.56–7.51 (m, 4H, Ar–H), 7.49–7.44 (m, 5H, Ar–H), 5.48 (bs, 2H, NH₂); ¹³C NMR (DMSO-d₆, 125 MHz): δ = 166.6, 160.1, 158.0, 135.8, 135.3, 133.2, 130.9, 130.2, 129.9, 129.4, 127.5, 115.7, 115.4, 93.8, 87.6; Anal. Calcd. for C₁₉H₁₁ClN₄S (362.84): C, 62.89; H, 3.06; N, 15.44. Found: C, 62.72; H, 3.14; N, 15.87.

2-Amino-4-(4-methylphenyl)-6-(phenylsulfanyl) pyridine-3,5-dicarbonitrile (1d)²¹. White solid, 85% yield. M.P.: 208–210 °C; IR ν_max (KBr): 3473, 3368, 3216, 3074, 2927, 1623, 1547, 1267, 758; ¹H NMR (CDCl₃, 500 MHz): δ = 7.55 (dd, J = 7.4, 1.7 Hz, 2H, Ar–H), 7.48–7.45 (m, 3H, Ar–H), 7.43 (d, J = 8.0 Hz, 2H, Ar–H), 7.34 (d, J = 8.0 Hz, 2H, Ar–H), 5.44 (bs, 2H, NH₂), 2.43 (s, 3H, CH₃); ¹³C NMR (125 MHz, DMSO-d₆): δ = 166.6, 160.2, 159.1, 140.7, 135.3, 131.5, 130.1, 129.9, 129.7, 128.8, 127.6, 115.9, 115.6, 93.8, 87.5, 19.0; Anal. Calcd. for C₂₀H₁₄N₄S (342.42): C, 70.15; H, 4.12; N, 16.36. Found: C, 69.81; H, 3.95; N, 16.83.

2-Amino-4-(3-chlorophenyl)-6-(phenylsulfanyl) pyridine-3,5-dicarbonitrile (1e)²⁵. White solid, 73% yield. M.P.: 248–250 °C; IR ν_max (KBr): 3454, 3344, 3224, 3070, 2218, 1629, 1556, 1529, 1479, 1313, 1257, 1024, 788, 756, 717; ¹H NMR (CDCl₃, 500 MHz): δ = 7.56–7.52 (m, 3H, Ar–H), 7.51–7.49 (m, 2H, Ar–H), 7.48–7.44 (m, 3H, Ar–H), 7.40–7.38 (td, J = 8.0, 1.15 Hz, 1H, Ar–H), 5.49 (bs, 2H, NH₂); ¹³C NMR (DMSO-d₆, 125 MHz): δ = 166.6, 160.0, 157.6, 136.4, 135.3, 133.8, 131.2, 130.8, 130.2, 130.0, 128.7, 127.7, 127.5, 115.5, 115.3, 93.8, 87.7; Anal. Calcd. for C₁₉H₁₁ClN₄S (362.84): C, 62.89; H, 3.06; N, 15.44. Found: C, 62.96; H, 3.14; N, 15.83.

2-Amino-4-(4-bromophenyl)-6-(phenylsulfanyl) pyridine-3,5-dicarbonitrile (1f)²⁵. White solid, 71% yield. M.P.: 233–235 °C; IR ν_max (KBr): 3449, 3375, 3219, 3087, 2221, 1629, 1547, 1259, 759; ¹H NMR (CDCl₃, 400 MHz): δ = 7.69 (d, J = 8.4 Hz, 2H, Ar–H), 7.56–7.54 (m, 2H, Ar–H), 7.49–7.44 (m, 3H, Ar–H), 7.41 (d, J = 8.8 Hz, 2H, Ar–H), 5.54 (bs, 2H, NH₂); ¹³CNMR (DMSO-d₆,125 MHz): δ = 166.6, 160.1, 158.0, 135.3, 133.6, 132.3, 131.1, 130.2, 130.0, 127.5, 124.6, 115.7, 115.4, 93.7, 87.5; Anal. Calcd. for C₁₉H₁₁BrN₄S (407.29): C, 56.03; H, 2.72; N, 13.76. Found: C, 56.15; H, 2.79; N, 12.88.

2-Amino-4-[4-(methylsulfanyl)phenyl]-6-(phenylsulfanyl) pyridine-3,5-dicarbonitrile (1g)²¹. White solid, 83% yield. M.P.: 253–255 °C; IR ν_max (KBr): 3451, 3341, 3221, 3059, 2974, 2839, 2219, 1648, 1619, 1518, 1459, 1291, 1260, 1189, 1017, 839, 758; ¹H NMR (CDCl₃, 400 MHz): δ = 7.55 (d, J = 7.6 Hz, 2H, Ar–H), 7.47–7.41 (m, 5H, Ar–H), 7.37 (d, J = 8.4 Hz, 2H, Ar–H), 5.49 (bs, 2H, NH₂), 2.53 (s, 3H, CH₃); ¹³C NMR (DMSO-d₆, 125 MHz): δ = 166.7, 160.2, 158.6, 142.3, 135.3, 130.2, 130.1, 129.9, 129.5, 127.6, 125.6, 115.9, 115.6, 93.8, 87.4, 14.4; Anal. Calcd. for C₂₀H₁₄N₄S₂ (374.48): C, 64.15; H, 3.77; N, 14.96. Found: C, 64.21; H, 3.83; N, 15.27.

2-Amino-6-(benzylsulfanyl)-4-(4-chlorophenyl) pyridine-3,5-dicarbonitrile (1h)²². White solid, 83% yield. M.P.: 201–203 °C; IR ν_max (KBr): 3451, 3352, 3216, 2225, 2212, 1618, 1543, 1261, 758; ¹H NMR (CDCl₃, 400 MHz): δ = 7.51 (d, J = 8.4 Hz, 2H, Ar–H), 7.44 (d, J = 8.4 Hz, 2H, Ar–H), 7.38 (d, J = 6.8 Hz, 2H, Ar–H), 7.35–7.28 (m, 3H, Ar–H), 5.74 (bs, 2H, NH₂), 4.44 (s, 2H, CH₂); ¹³C NMR (CDCl₃, 100 MHz): δ = 169.0, 168.1, 159.3, 157.0, 141.2, 136.1, 131.6, 130.0, 129.6, 129.2, 128.9, 127.9, 115.3, 114.7, 112.3, 35.1; Anal. Calcd. for C₂₀H₁₃ClN₄S (376.86): C, 63.74; H, 3.48; N, 14.87. Found: C, 63.82; H, 3.51; N, 15.17.

2-Amino-6-(benzylsulfanyl)-4-(4-methylphenyl) pyridine-3,5-dicarbonitrile (1i)²⁹. Yellow crystal, 89% yield. M.P.: 209–211 °C; IR ν_max (KBr): 3471, 3327, 3211, 3030, 2924, 2226, 2218, 1620, 1573, 1271, 777; ¹H NMR (CDCl₃, 400 MHz,): δ = 7.41–7.38 (m, 4H, Ar–H), 7.34–7.31 (m, 5H, Ar–H), 5.69 (bs, 2H, NH₂), 4.44 (s, 2H, CH₂), 2.41 (s, 3H, CH₃); ¹³C NMR (CDCl₃, 100 MHz,): δ = 170.0, 168.7, 159.4, 158.4, 141.5, 136.3, 130.4, 129.9, 129.2, 128.8, 128.5, 127.8, 115.7, 115.1, 112.6, 35.0, 21.6; Anal. Calcd. for C₂₁H₁₆N₄S (356.44): C, 70.76; H, 4.52; N, 15.72. Found: C, 70.69; H, 4.47; N, 15.83.

2-Amino-4-(3-nitrophenyl)-6-(phenylsulfanyl) pyridine-3,5-dicarbonitrile (1j)²⁶. Yellow solid, 75% yield. M.P.: 218–220 °C; IR ν_max (KBr): 3441, 3323, 3227, 3041, 2218, 2211, 1644, 1609, 1551, 1522, 1515, 1468, 1418, 1349, 1346, 1311, 1264, 1238, 1172, 1111, 1028, 1009, 890, 862, 851, 811, 790, 754, 713, 554; ¹H NMR (CDCl₃ + DMSO-d₆, 400 MHz): δ = 8.43 (s, 1H, Ar–H), 8.40 (m, 1H, Ar–H), 7.89 (d, J = 7.6 Hz, 1H, Ar–H), 7.81 (t, J = 7.6 Hz, 1H, Ar–H), 7.58–7.55 (m, 2H, Ar–H), 7.49–7.47 (m, 3H, Ar–H), 6.92 (bs, 2H, NH₂); ¹³C NMR (DMSO-d₆, 125 MHz): δ =166.7, 162.0, 156.8, 148.1, 135.9, 135.7, 135.3, 131.2, 130.2, 130.0, 127.5, 125.7, 124.1, 116.9, 115.6, 115.3, 87.8; Anal. Calcd. for C₁₉H₁₁N₅O₂S (373.39): C, 61.12; H, 2.97; N, 18.76. Found: C, 61.19; H, 3.02; N, 18.89.

2-Amino-4-cyclohexyl-6-(phenylsulfanyl)pyridine-3,5-dicarbonitrile (1k)²³. White solid, 76% yield. M.P.: 202–204 °C; IR ν_max (KBr): 3478, 3348, 3216, 3064, 2934, 2855, 2219, 1625, 1555, 1524, 1442, 1255, 1108, 936, 754, 706; ¹H NMR (CDCl₃, 300 MHz): δ = 7.53–7.50 (m, 2H, Ar–H), 7.45–7.39 (m, 3H, Ar–H), 5.41 (bs, 2H, NH₂), 3.10–3.01 (m, 1H, CH)), 2.18–2.02 (m, 2H, CH₂), 1.97–1.85 (m, 2H, CH₂), 1.82–1.72 (m, 3H, CH + CH₂), 1.49–1.33 (m, 3H, CH + CH₂); ¹³C NMR (CDCl₃, 100 MHz): δ = 169.4, 164.7, 160.1, 135.9, 123.0, 129.43, 127.5, 115.7, 115.2, 95.5, 86.6, 44.8, 30.1, 26.5, 25.4; Anal. Calcd. for C₁₉H₁₈N₄S (334.44): C, 68.23; H, 5.42; N, 16.75. Found: C, 68.31; H, 5.47; N, 16.86.

2-Amino-4-(4-chlorophenyl)-6-(cyclohexylsulfanyl)pyridine-3,5-dicarbonitrile (1l)²⁰. White solid, 82% yield. M.P.: 222–224 °C; IR ν_max (KBr): 3497, 3392, 3063, 2933, 2853, 2217, 1605, 1544, 1494, 1449, 1267, 1093, 835, 803, 779; ¹H NMR (CDCl₃, 300 MHz): δ = 7.52 (d, J = 8.4 Hz, 2H, Ar–H), 7.45 (d, J = 8.6 Hz, 2H, Ar–H), 5.67 (bs, 2H, NH₂), 3.97–3.89 (m, 1H, CH), 2.08–2.04 (m, 2H, CH₂), 1.82–1.78 (m, 2H, CH₂), 1.66–1.25 (m, 6H, 3CH₂); ¹³C NMR (CDCl₃, 100 MHz): δ = 169.9, 159.4, 156.9, 137.4, 131.9, 130.0, 129.6, 115.5, 115.0, 96.7, 86.2, 44.2, 32.8, 26.0, 25.7; Anal. Calcd. for C₁₉H₁₇ClN₄S (368.88): C, 61.86; H, 4.65; N, 15.19. Found: C, 61.77; H, 4.71; N, 15.28.

2-Amino-6-(benzylsulfanyl)-4-(naphthalen-2-yl)pyridine-3,5-dicarbonitrile (1m). White solid, 85% yield. M.P.: 214–216 °C. IR ν_max (KBr): 3473, 3332, 3219, 3053, 3028, 2976, 2927, 2214, 1627, 1546, 1269, 759, 700; ¹H NMR (CDCl₃, 400 MHz): δ = 8.02–7.84 (m, 4H, Ar–H), 7.63–7.48 (m, 3H, Ar–H), 7.42–7.22 (m, 5H, Ar–H), 5.72 (bs, 2H, NH₂), 4.48 (s, 2H, CH₂); ¹³C NMR (CDCl₃, 100 MHz): δ = 168.9, 159.5, 158.4, 136.3, 134.3, 133.0, 130.7, 129.3, 129.1, 129.0, 128.9, 128.1, 128.0, 127.9, 127.3, 125.2, 115.6, 115.0, 97.0, 87.3, 35.2; Anal. Calcd. for C₂₄H₁₆N₄S (392.48): C, 73.45; H, 4.11; N, 14.28. Found: C, 73.53; H, 4.19; N, 15.37.

2-Amino-6-[(2-aminophenyl)sulfanyl]-4-(4-bromophenyl) pyridine-3,5-dicarbonitrile (1n). Yellow solid. 90% yield. M.P.: 198–200 °C. IR ν_max (KBr): 3334, 3219, 3079, 2213, 1629, 1544, 1492, 1423, 1316, 1263, 1160, 1071, 1011, 832, 802, 777, 751, 681; ¹H NMR (DMSO-d₆, 500 MHz): δ = 9.28 (s, 2H, NH₂), 7.79 (d, J = 8.5 Hz, 2H, Ar–H), 7.62 (d, J = 8.0 Hz, 1H, Ar–H), 7.59 (d, J = 8.0 Hz, 1H, Ar–H), 7.53 (d, J = 8.5 Hz, 2H, Ar–H), 7.32 (t, J = 7.5 Hz, 1H, Ar–H), 7.24 (t, J = 8.0 Hz, 1H, Ar–H), 2.09 (s, 2H, NH₂); ¹³C NMR (DMSO-d₆, 125 MHz): δ = 161.0, 159.4, 158.4, 137.3, 134.5, 132.7, 132.2, 131.0, 130.9, 130.1, 128.8, 127.2, 126.9, 124.2, 116.3, 81.8, 81.7; Anal. Calcd. for C₁₉H₁₂BrN₅S (422.30): C, 54.04; H, 2.86; N, 16.58. Found: C, 54.11; H, 2.92; N, 17.05.

2-Amino-4-(4-bromophenyl)-6-[(2-methylphenyl) sulfanyl] pyridine-3,5-dicarbonitrile (1o). Light yellow solid, 90% yield. M.P.: 234–236 °C. IR ν_max (KBr): 3477, 3348, 3220, 3065, 2956, 2921, 2214, 1632, 1543, 1521, 1491, 1259, 1035, 1010, 833, 774; ¹H NMR (DMSO-d₆, 500 MHz): δ = 7.80–7.79 (t, J = 4.5, 2.5 Hz, 2H, Ar–H), 7.78–7.77 (t, J = 4.5, 2.0 Hz, 2H, Ar–H), 7.55 (bs, 2H, NH₂), 7.54–7.51 (m, 1H, Ar–H), 7.44–7.41 (m, 2H, Ar–H), 7.29–7.26 (m, 1H, Ar–H), 2.34 (s, 3H, CH₃); ¹³C NMR (DMSO-d₆, 125 MHz): δ = 166.6, 160.1, 158.0, 143.3, 136.7, 133.7, 132.3, 131.4, 131.1, 131.0, 127.3, 126.8, 124.6, 115.8, 115.4, 93.5, 87.2, 21.0; Anal. Calcd. for C₂₀H₁₃BrN₄S (421.31): C, 57.02; H, 3.11; N, 13.30. Found: C, 56.98; H, 2.97; N, 13.01.

2-Amino-4-(4-cyanophenyl)-6-[(2-methylphenyl) sulfanyl] pyridine-3,5-dicarbonitrile (1p). White solid, 88% yield. M.P.: 268–270 °C. IR ν_max (KBr): 3432, 3323, 3227, 3091, 3057, 2985, 2930, 2236, 2212, 1637, 1542, 1464, 1263, 1028, 846, 814, 755, 708; ¹H NMR (DMSO-d₆, 500 MHz): δ = 8.04–8.02 (d, J = 8.3 Hz, 2H, Ar–H), 7.76–7.74 (d, J = 8.3 Hz, 2H, Ar–H), 7.76 (bs, 2H merged, NH₂), 7.55–7.53 (d, J = 7.56 Hz, 1H, Ar–H), 7.42–7.40 (m, 2H, Ar–H), 7.30–7.25 (m, 1H, Ar–H), 2.38 (s, 3H, CH₃); ¹³C NMR (DMSO-d₆, 125 MHz): δ = 166.5, 159.5, 156.6, 142.8, 138.3, 136.1, 132.5, 130.8, 130.4, 129.5, 126.7, 126.2, 117.9, 114.6, 113.3, 92.8, 86.4, 20.5; Anal. Calcd. for C₂₁H₁₃N₅S (367.43): C, 68.65; H, 3.57; N, 19.06. Found: C, 68.57; H, 3.49; N, 18.93.

2-Amino-4-(2,6-dichlorophenyl)-6-(phenylsulfanyl)-1,4-dihydropyridine-3,5-dicarbonitrile (2a)¹⁴. Light-yellow solid, 93% yield. M.P.: 314–316 °C. IR ν_max (KBr): 3463, 3366, 3252, 3081, 2976, 2878, 2211, 2179, 1649, 1616, 1502, 1444, 1257, 1028, 783, 743, 694, 555; ¹H NMR (DMSO-d₆, 500 MHz): δ = 9.14 (bs, 1H, NH), 7.50–7.43 (m, 6H, Ar–H), 7.39–7.33 (m, 2H, Ar–H), 5.94 (bs, 2H, NH₂), 5.59 (s, 1H, CH); ¹³C NMR (DMSO-d₆, 125 MHz): δ = 152.0, 143.2, 135.7, 131.1, 130.8, 130.4, 130.3, 129.2, 120.4, 118.0, 116.4, 115.7, 88.6, 52.7, 39.4; Anal. Calcd. for C₁₉H₁₂N₄Cl₂S (399.30): C, 57.15; H, 3.03; N, 14.03. Found: C, 57.18; H, 3.06; N, 14.08.

2-Amino-4-(2-chloro-6-fluorophenyl)-6-(phenylsulfanyl)-1,4-dihydropyridine-3,5-dicarbonitrile (2b)¹⁴. White solid, 91% yield. M.P.: 297–298 °C; IR ν_max (KBr): 3463, 3358, 3228, 3081, 2976, 2870, 2211, 2179, 1657, 1608, 1494, 1461, 1249, 1029, 898, 784, 751, 694, 678, 555; ¹H NMR (DMSO-d₆, 500 MHz): δ = 9.21(bs, 1H, NH), 7.44–7.33 (m, 7H, Ar–H), 7.26 (m, 1H, Ar–H), 5.94 (bs, 2H, NH₂), 5.20 (s, 1H, CH); ¹³C NMR (DMSO-d₆, 125 MHz): δ = 151.7, 142.8, 131.1, 131.0, 130.7, 130.5, 130.4, 128.9, 126.7, 120.6, 118.2, 116.1, 115.9, 89.1, 53.0, 36.2; Anal. Calcd. for C₁₉H₁₂N₄FSCl (382.84): C, 59.61; H, 3.16; N, 14.63. Found: C, 59.67; H, 3.12; N, 14.69.

2-Amino-4-(2,6-dimethoxyphenyl)-6-(phenylsulfanyl)-1,4-dihydropyridine-3,5-dicarbonitrile (2c). Yellow solid, 96% yield. M.P.: 203–205 °C. IR ν_max (KBr): 3431, 3341, 3236, 3081, 3057, 3000, 2976, 2943, 2894, 2737, 2201, 2195, 1673, 1657, 1600, 1494, 1347, 1249, 1110, 1045, 783, 751, 677, 571; ¹H NMR (DMSO-d₆, 500 MHz): δ = 8.98 (bs, 1H, NH), 7.43–7.33 (m, 5H, Ar–H), 7.23–7.19(m, 1H, Ar–H), 6.67(d, J = 8.2 Hz, 2H, Ar–H), 5.62 (bs, 2H, NH₂), 5.04 (s, 1H, CH), 3.70 (s, 6H, 2OCH₃); ¹³C NMR (DMSO-d₆, 125 MHz): δ = 151.9, 150.3, 143.1, 135.7, 131.6, 129.4, 121.6, 119.3, 117.5, 115.8, 109.7, 105.2, 87.9, 56.6, 54.2, 31.6; Anal. Calcd. for C₂₁H₁₈N₄O₂S (390.46): C, 64.60; H, 4.65; N, 14.35. Found: C, 64.65; H, 4.61; N, 14.38.

General procedure for the synthesis of 2-amino-6-(alkoxy)-4-(4-methoxyphenyl)pyridine -3,5-dicarbonitrile (5a,5b). To a 25 ml round bottom flask potassium hydroxide (3.0 mmol) was added to 10 ml ethanol and stirred till it get dissolves. To this solution 4-methoxybenzaldehyde (3.0 mmol) and malononitrile (6.0 mmol) were subsequently added and stirred at room temperature. The progress of the reaction was monitored by TLC (hexane–ethyl acetate, 8 : 2). After the completion of the reaction the solid precipitated out at the stipulated time mentioned in Table 4. The solid precipitate was filtered off to obtain the desired product. The crude product was then recrystalized from acetonitrile.

2-Amino-6-ethoxy-4-(4-methoxyphenyl) pyridine-3,5-dicarbonitrile (5a)³⁴. White solid, 88% yield. M.P.: 180–182 °C; IR ν_max (KBr): 3416, 3338, 3242, 3112, 3090, 2968, 2937, 2906, 2842, 2226, 2214, 1655, 1607, 1548, 1436, 1381, 1339, 1299, 1243, 1180, 1019, 924, 841, 786, 663, 611, 553; ¹H NMR (DMSO-d₆, 500 MHz): δ = 7.91 (broad, 2H, NH₂), 7.49 (d, J = 7.5 Hz, 2H, Ar–H), 7.11 (d, J = 8.0 Hz, 2H, Ar–H), 4.44 (q, J = 7.0 Hz, 2H, OCH₂), 3.85 (s, 3H, CH₃), 1.36 (t, J = 7.0 Hz, 3H, CH₃); ¹³C NMR (DMSO-d₆, 125 MHz): δ = 165.9, 161.7, 161.2, 160.9, 130.6, 126.6, 116.2, 115.7, 114.5, 83.9, 83.5, 63.8, 55.8, 14.7; Anal. Calcd. for C₁₆H₁₄N₄O₂ (294.31): C, 65.30; H, 4.79; N, 19.04. Found: C, 65.38; H, 4.83; N, 18.91.

2-Amino-6-methoxy-4-(4-methoxyphenyl) pyridine-3,5-dicarbonitrile (5b). White solid, 91% yield. M.P.: 154–156 °C; IR ν_max (KBr): 3425, 3324, 3234, 3123, 3032, 2956, 2942, 2865, 2842, 2223, 2210, 1643, 1608, 1557, 1514, 1458, 1367, 1290, 1258, 1183, 1022, 995, 828, 785, 602, 575; ¹H NMR (DMSO-d₆, 500 MHz): δ = 7.93 (bs, 2H, NH₂), 7.49 (d, J = 8.5 Hz, 2H, Ar–H), 7.11 (d, J = 9.0 Hz, 2H, Ar–H), 3.97 (s, 3H, OCH₃), 3.84 (s, 3H, OCH₃); ¹³C NMR (DMSO-d₆, 125 MHz): δ = 166.3, 161.7, 161.2, 160.9, 130.6, 126.5, 116.2, 115.7, 114.5, 83.8, 83.6, 55.8, 55.1; Anal. Calcd. for C₁₅H₁₂N₄O₂ (280.28): C, 64.28; H, 4.32; N, 19.99. Found: C, 64.32; H, 4.36; N, 20.08.

General procedure for the synthesis of 2-amino-6-(alkylamino)-4-(4-methoxyphenyl) pyridine-3,5-dicarbonitrile (5c,5d). A mixture of 4-methoxybenzaldehyde (3.0 mmol), amine (3.0 mmol), malononitrile (6.0 mmol) and potassium hydroxide (10 mol%) were added in 10 ml ethanol in to a 25 ml round bottom flask. The resultant mixture was stirred at room temperature. The progress of the reaction was monitored with TLC (hexane–ethyl acetate, 5 : 5). After the completion of the reaction the solid precipitate came out at the stipulated time mentioned in Table 4. The solid precipitate was filtered off to obtain the desired product. The crude product was purified by recrystalization from acetonitrile.

2-Amino-4-(4-methoxyphenyl)-6-(pyrrolidin-1-yl)pyridine-3,5-dicarbonitrile (5c)^37d. Yellow solid, 77% yield. M.P.: 224–226 °C ; IR ν_max (KBr): 3447, 3340, 3239, 3087, 2976, 2950, 2933, 2918, 2876, 2841, 2213, 2206, 1646, 1611, 1556, 1520, 1497, 1444, 1350, 1292, 1247, 1227, 1174, 1020, 833, 692, 567, 504; ¹H NMR (DMSO-d₆, 500 MHz): δ = 7.42 (d, J = 8.5 Hz, 2H, Ar–H), 7.24 (bs, 2H, NH₂), 7.08 (d, J = 8.5 Hz, 2H, Ar–H), 3.84 (s, 3H, OCH₃), 3.69 (bs, 4H, CH₂–N–CH₂), 1.90 (bs, 4H, 2CH₂); ¹³C NMR (DMSO-d₆,125 MHz): δ = 161.7, 160.8, 160.2, 157.9, 130.7, 127.9, 118.9, 117.2, 114.3, 80.6, 80.5, 55.7, 49.6, 25.3; Anal. Calcd. for C₁₈H₁₇N₅O (319.36): C, 67.70; H, 5.37; N, 21.93. Found: C, 66.78; H, 5.42; N, 22.07.

2-Amino-4-(4-methoxyphenyl)-6-(piperazin-1-yl)pyridine-3,5-dicarbonitrile (5d). Yellow solid, 83% yield. M.P.: 200–201 °C. IR ν_max (KBr): 3402, 3329, 3304, 3229, 2971, 2944, 2913, 2858, 2822, 2705, 2186, 2158, 1668, 1607, 1544, 1501, 1425, 1397, 1313, 1247, 1183, 1122, 1021, 891, 836, 805, 598, 530, 461; ¹H NMR (DMSO-d₆, 300 MHz): δ = 8.30 (bs, 1H, NH), 7.35 (d, J = 8.7 Hz, 2H, Ar–H), 7.04 (d, J = 8.7 Hz, 2H, Ar–H), 6.79 (bs, 2H, NH₂), 3.82 (s, 3H, OCH₃), 3.69 (bs, 4H, CH₂–N–CH₂), 2.75 (bs, 4H, CH₂–NH–CH₂); ¹³C NMR (DMSO-d₆, 75 MHz): δ = 162.8, 160.1, 159.3, 158.8, 130.0, 127.8, 117.1, 116.7, 113.7, 85.2, 80.3, 55.2, 44.9, 43.2; Anal. Calcd. for C₁₈H₁₈N₆O (334.38): C, 64.66; H, 5.43; N, 25.13. Found: C, 64.72; H, 5.48; N, 25.24.

Ethyl 3-(4-chlorophenyl)-2-cyanoacrylate (3a). Yellow solid, 72% yield. M.P.: 87 °C. IR ν_max (KBr): 2242, 1760, 1581; ¹H NMR (CDCl₃, 400 MHz): δ = 8.18 (s, 1H, CH), 7.91 (d, J = 8.4 Hz, 2H, Ar–H), 7.44 (d, J = 8.4 Hz, 2H, Ar–H), 4.38 (q, J = 7.2 Hz, 2H, OCH₂), 1.38 (t, J = 6.8 Hz, 3H, CH₃); ¹³C NMR (CDCl₃, 75 MHz): δ = 162.3, 153.4, 139.6, 132.3, 130.0, 129.7, 115.3, 103.6, 62.9, 14.2; Anal. Calcd. for C₁₂H₁₀ClNO₂ (235.66): C, 61.16; H, 4.28; N, 5.94. Found: C, 61.22; H, 4.32; N, 5.83.

(4-Methoxybenzylidine)propanedinitrile (3b). Pale yellow solid, 79% yield. M.P.: 112–114 °C. IR ν_max (KBr): 2225, 1562; ¹H NMR (CDCl₃, 500 MHz): δ = 7.91 (d, J = 8.5 Hz, 2H, Ar–H), 7.65 (s, 1H, CH), 7.01 (d, J = 8.5 Hz, 2H, Ar–H), 3.91 (s, 3H, OCH₃); ¹³C NMR (CDCl₃, 125 MHz): δ = 164.9, 159.1, 133.6, 124.1, 115.3, 114.6, 113.5, 78.5, 56.0; Anal. Calcd. for C₁₁H₈N₂O (184.20): C, 71.73; H, 4.38; N, 15.21. Found: C, 71.78; H, 4.33; N, 15.28.

Diphenyl disulfide (4). Colorless crystal, 71% yield. M.P.: 58–60 °C. IR ν_max (KBr): 3070, 3056, 3030, 3012, 1574, 1474, 1437, 1073, 1022, 740, 687; ¹H NMR (DMSO-d₆, 500 MHz): δ = 7.53 (d, J = 7.5 Hz, 4H, Ar–H), 7.39 (t, J = 7.5 Hz, 4H, Ar–H), 7.30 (t, J = 7.5 Hz, 2H, Ar–H); ¹³C NMR (DMSO-d₆, 125 MHz,): δ = 136.3, 129.9, 128.0, 127.7; Anal. Calcd. for C₁₂H₁₀S₂ (218.34): C, 66.01; H, 4.62. Found: C, 66.08; H, 4.67.

2-Aminoprop-1-ene-1,1,3-tricarbonitrile (6). Light brown solid, 57% yield. M.P.:165–167 °C. IR ν_max (KBr): 3345, 3235, 3204, 2973, 2920, 2265, 2222, 2205, 1655, 1557, 1383, 1310, 908, 625; ¹H NMR (DMSO-d₆, 500 MHz): δ = 9.00 (d, J = 24.5 Hz, 2H, NH₂), 3.84 (s, 2H, CH₂); ¹³C NMR (DMSO-d₆, 125 MHz): δ = 165.2, 115.8, 115.1, 114.7, 50.2, 22.6; Anal. Calcd. for C₆H₄N₄ (132.12): C, 54.54; H, 3.05; N, 42.41. Found: C, 54.58; H, 3.11; N, 42.52.

Acknowledgements

We gratefully acknowledge financial support from the Department of Science and Technology India, with Sanction No. SR/FT/CS-042/2009 for carrying out this work. M.N.K and S.P are thankful to CSIR and UGC respectively for their research fellowships. The authors are grateful to SAIF CDRI Lucknow, SAIF IIT Madras and IIT Guwahati for providing analytical facilities. Authors are also thankful to IIT Patna for providing basic facilities to carry out this work. We thankfully acknowledge Dr. Debabrata Seth for his valuable discussion on photophysical properties.

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Footnote

† Electronic supplementary information (ESI) available: ¹H, ¹³C-NMR spectra of all synthesized compounds. CCDC reference numbers 875077. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c2ra21385k

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