Efficient Rapid Access to Biginelli for the Multicomponent Synthesis of 1,2,3,4-Tetrahydropyrimidines in Room-Temperature Diisopropyl Ethyl Ammonium Acetate

Chetan K Jadhav; Amol S Nipate; Asha V Chate; Vishal D Songire; Anil P Patil; Charansingh H Gill

doi:10.1021/acsomega.9b02286

. 2019 Dec 17;4(27):22313–22324. doi: 10.1021/acsomega.9b02286

Efficient Rapid Access to Biginelli for the Multicomponent Synthesis of 1,2,3,4-Tetrahydropyrimidines in Room-Temperature Diisopropyl Ethyl Ammonium Acetate

Chetan K Jadhav ^†, Amol S Nipate ^†, Asha V Chate ^†, Vishal D Songire ^†, Anil P Patil ^‡, Charansingh H Gill ^†,^*

PMCID: PMC6941212 PMID: 31909314

Abstract

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The diisopropyl ethyl ammonium acetate (DIPEAc)-promoted Biginelli protocol has been developed for the first time by a successive one-pot three-component reaction of aldehydes, ethylcyanoacetate/ethyl acetoacetate, and thiourea/urea to afford pharmacologically promising 1,2,3,4-tetrahydropyrimidines in high yields at room temperature. The key benefits of the present scheme are the capability to allow a variability of functional groups, short reaction times, easy workup, high yields, recyclability of the catalyst, and solvent-free conditions, thus providing economic and environmental advantages. In addition, a series of 4-oxo-6-aryl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitriles analogues were synthesized and selected for their in vitro antifungal and antibacterial activities.

Introduction

Room-temperature ionic liquids (RTILs) have taken the attention of the chemical community all over the globe as a green alternative option to traditional ecofriendly media for catalysis, synthesis, separation, and other several chemical tasks.¹⁻⁷ RTILs include numerous exclusive properties, such as extensive liquid range, nonvolatility, low toxicity, high thermal stability, noncombustible, excellent solubility, and recyclability.⁸ RTILs act as “neoteric solvents” for a wide range of industrial and chemical processes. In recent times, RTILs have been originating to be valuable as environmental friendly media for multitudinous organic revolutions.^9,10 On the other hand, multicomponent reactions (MCRs) are one of the more dominant and practical tackles in organic synthesis for the creation of pharmacologically relevant frameworks from the point of view of green chemistry. MCRs give benefits of atom economy, high yields, flexibility, target specificity, and especially one-pot operation;¹¹⁻¹³ the discrimination and returns of the MCRs are significantly affected by the choice of an appropriate catalyst. Thus, the introduction of a dynamic, inexpensive, mild, and environmental friendly catalyst for significant MCRs superior to analogues of pharmaceutical and biological prominence is in demand. In this paper, we have validated DIPEAc as ionic liquid catalyzed the efficient synthesis of 4-oxo-6-aryl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile analogues via one-pot multicomponent reactions under ecofriendly reaction conditions (Schemes 1 and 2).

The pyrimidine moiety is an essential part of RNA and DNA, providing various biological properties such as potent fungicide and bactericide.¹⁴ Some pyrimidine analogues are also known to acquire anticancer,¹⁵ antimalarial,¹⁶ antiviral,¹⁷ antibacterial,^18,19 antifungal,^20,21 anticonvulsant,²² and antihistamine²³ activities. Certain 3,4-dihydropyrimidines have developed as essential props of numerous calcium antihypertensive agents, adrenergic, channel blockers, and neuropeptide antagonists.²⁴ A number of natural marine products accommodate the 3,4-dihydropyrimidine nucleus, described in the literature for remarkable anti-HIV alkaloid batzelladine B activities (Figure 1).^25,26

Pyrimidine-incorporated bioactive molecules.

Thus, the enlargement of synthetic strategies for the creation of this molecule using an inexpensive, reusable, mild, and nontoxic catalyst is of enormous significance from the industrial and academic points of view. Even though various modes have been reported in the literature, the Biginelli MCR is moderately versatile because it can be implemented with numerous chemical takes in all three key components (i.e., aldehyde, β-ketoester, and thiourea or urea) paramount to a manifold of thiones/dihydropyrimidinones.²⁷ These reactions can be accomplished under a variability of tentative conditions, and several improvements have been reported in recent years, such as p-TsOH·H₂O,²⁸ H₃BO₃,²⁹ [Al(H₂O)₆](BF₄)₃,³⁰ thiamine hydrochloride,³¹ imidazole-1-yl-acetic acid,³² l-(+)-tartaric acid-dimethylurea,³² HClO₄–SiO₂,^33,34 SnCl₂·2H₂O,³⁵ polymer-supported benzimidazolium-based ionic liquid,³⁶ basic IL,³⁷ Al-plante MCM-41,³⁸ (NH₄)₂CO₃,³⁹ CeCl₃·7H₂O,⁴⁰ CaCl₂,³⁹ Ce(NH₄)₂(NO₃)₆polyvinylsulfonic acid,³⁴ and Fe(OTs)₃·6H₂O.⁴¹ However, numerous of these testified methods become infected with several disadvantages such as strong acidic conditions, use of hazardous or costly reagents, long reaction times, low yields of products, and sophisticated treatment. Moreover, many of these schemes utilize organic solvents as the reaction medium. Hence, innovative, competent, and ecofriendly procedures are still powerfully needed to generate pharmacologically active molecules.

As per our investigation, the existential of this work is to begin a rapid and efficient Biginelli multicomponent synthetic protocol for obtaining 1,2,3,4-tetrahydropyrimidines under ecofriendly conditions. As an extension of emerging economic and efficient MCR strategy to develop pharmaceutically and biologically significant molecules,⁴² herein, we reported a first-time three-component method in DIPEAc at room temperature to access a library of 1,2,3,4-tetrahydropyrimidine in good to excellent yields.

Results and Discussion

Chemistry

To achieve optimized conditions for the Biginelli protocol based on the reaction of benzaldehyde (1a) (3 mmol), ethylcyanoacetate (2) (3 mmol), and thiourea (3) (3.2 mmol) as model substrates, we checked altered catalysts, temperatures, and solvents, and the results of this study are summarized in Table 1. It was found that when the reaction was carried out in the nonappearance of the catalyst in ethanol, no product was perceived, even after 9 h (Table 1, entry 1). To obtain the preferred product (4a), we tested the reaction using different catalysts such as Cs₂CO₃, p-TSA, β-CD, CTAB, SDS, ChCl:2urea, ChCl:2ZnCl₂, PEG-400, DIPEAc, and dicationic ionic liquid (Table 1, entries 2–11). Thus, room-temperature DIPEAc as the pre-eminent catalyst was tested for this reaction. In the presence of DIPEAc, compound 4a was isolated in 93% yield after only 45 min at room temperature. The model reaction in water using phase transfer catalysts is found to be sluggish and formed the desired 4a in less yields. Therefore, it can be thought that DIPEAc is green and a superior solvent and catalyst compared to the others shown in Table 1.

Table 1. Efficiency Comparison of Various Catalysts for the Synthesis of 4-Oxo-6-aryl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (4a)^a.

entry	catalyst	medium	time	yield^b (%)/time (h)
1		EtOH	9 h	trace
2	Cs₂CO₃	EtOH	7 h	61
3	p-TSA	H₂O	7 h	68
4	β-CD	H₂O	6 h	65
5	CTAB	H₂O	6 h	59
6	SDS	H₂O	6 h	52
7	ChCl:2urea	ChCl:2urea	2 h	80
8	ChCl:2ZnCl₂	ChCl:2ZnCl₂	3 h	76
9	PEG-400	PEG-400	6 h	74
10	DIPEAc	DIPEAc	45 min	94
11	dicationic ionic liquid	dicationic ionic liquid	7 h	73

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Reaction conditions: aldehyde (3 mmol), ethylcyanoacetate (3 mmol), thiourea (3.2 mmol) in medium (5 mL), stirred at room temperature.

Isolated yields b: no condensation. Bold values are for highlighting the good result.

The amount of the catalyst is another critical parameter in terms of reaction efficiency. To confirm the amount of the DIPEAc, the model reaction was examined by a set of experiments by the varying amounts from 1 to 5 mL; as the amount of DIPEAc increases gradually, a steady increase was observed in the product yield. DIPEAc (4 mL) furnishes 4a in 96% yield at room temperature (Table 2, entries 1). Further increase in the amount of DIPEAc does not increase in the yield of the product. The model reaction was carried out without any catalyst and solvent; the trace amount of the product was achieved after a long period (Table 2, entry 1). Further, the efficiency of DIPEAc was checked by using 20 mol % DIPEAc in various solvents (Table 2, entries 7–12). In ethanol, the reaction takes place smoothly with high yield. While in water, MeOH, acetonitrile, DCM, CH₂Cl₂, and DMF reaction proceeds with lower yields at reflux temperature. None of the solvents exist the advantage of time and yield over the solvent-free condition. Hence, the solvent-free condition was regarded as the finest for the cost and environmental suitability.

Table 2. Solvent Effects on the Reaction of Aldehyde, Ethylcyanoacetate, and Thiourea for the Synthesis of 4-Oxo-6-phenyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (4a)^a.

entry	DIPEAc	temp. (°C)	solvent	time (min)	yield (%)^b
1	0	RT		24h	trace
2	1 mL	RT		45	60
3	2 mL	RT		45	75
4	3 mL	RT		45	80
5	4 mL	RT		45	96
6	5 mL	RT		45	95
7	20 mol %	reflux	H₂O	320	75
8	20 mol %	reflux	EtOH	320	80
9	20 mol %	reflux	MeOH	320	75
10	20 mol %	reflux	CH₃CN	320	55
11	20 mol %	reflux	CH₂Cl₂	320	52
12	20 mol %	reflux	DMF	320	50

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Reaction conditions: aldehyde (3 mmol), ethylcyanoacetate (3 mmol),thiourea (3.2 mmol) in solvent (5 mL), stirred at room temp.

Isolated yields. Bold values are for highlighting the good result.

In summary, the highest efficiency and fastest reaction time for the model Biginelli reaction was observed at room temperature by using 4 mL of DIPEAc. Having ideal conditions in hand, the adaptability of the protocol was examined for the construction of 4-oxo-6-aryl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitriles (4a–v). Various substituents on aldehyde including methyl, methoxy, cyano, nitro, halogen (−Cl, −F, −Br), and hydroxyl moieties were used. The results of all reactions performed under these conditions are shown in Table 3. Aldehyde containing electron-donating groups such as −Me, −OMe, and electron-withdrawing group such as −NO₂ on the aromatic ring was compatible with this transformation, and corresponding 4-oxo-6-aryl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitriles (4a–v) were obtained in good to high yields. To our enchantment, halogen-substituted 2-benzylidene malononitrile gave the products with high yields (4g, 4h, and 4l). Moreover, sterically crowded di- and trisubstituted benzaldehyde provided the desired products in high yields (4i, 4j, and 4r). The heteroaryl aldehydes and aliphatic aldehydes also keep well under the present reaction conditions without any difficulties (4m, 4t, and 4w–4zz).

Table 3. Recycling of DIPEAc (IL) for The Synthesis of Compounds 4a and 4aa^a.

run	catalyst recovery	product yield (%)
1	96	96
2	92	93
3	91	90
4	90	89
5	80	78

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Reaction conditions: aldehyde (3 mmol), ethylcyanoacetate (3 mmol),thiourea/urea(3.2 mmol) in solvent (4 mL), stirred at room temp. Bold values are for highlighting the good result.

For assessing the generality of optimized reaction conditions, we considered the scope of the reaction by the cyclocondensation of aldehydes, ethyl acetoacetate, and urea/thiourea in DIPEAc at room temperature. DIPEAc also acts as an efficient promoter to catalyze the synthesis of ethyl 6-methyl-4-(4-substitutedphenyl)-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate in high yields (Table 3, entries 21–30).

The Biginelli formation of 1,2,3,4-tetrahydropyrimidine derivatives has been confirmed by spectroscopic techniques and physical data such as IR, ¹H NMR, ¹³C NMR, and liquid chromatography–mass spectrometry (LCMS). According to the ¹H NMR spectrum of representative compound 4a, the characteristic two singlet’s at 11.71 and 8.96 for two protons of −NH group present in pyrimidine ring, 7.52–7.56 ppm and a doublet at 7.78–7.81 four protons present in phenyl ring confirmed the 4a. ¹³C NMR spectral data, in which the carbon signals of −SCH₂ and −NCH₂ groups, were resonated at 183.29 and 183.53 ppm, respectively. The signals at 166.22 point out the presence of the carbonyl carbon atom, while all further carbons gave peaks at expected values. Again, the construction of compound 4a was confirmed by LCMS: m/z [M + Na]⁺. The calculated m/z for compound 4a C₁₁H₇N₃OSNa⁺ is 252.2 and observed at 252.2 [M + Na]⁺.

Recycling of the Catalyst

Effectual reusability and recovery of the ionic liquid are other significant features of our proposed protocol. We check the reusability of the catalyst. The reaction was performed between aldehyde, ethylcyanoacetate, and thiourea under the optimized reaction conditions. DIPEAc was disconnected from the reaction mixture by the following procedure. After completion of the reaction, the reaction mixture was cooled to room temperature, and then, water and ethyl acetate were added. The product (4a) was extracted with ethyl acetate. As the DIPEAc is highly water-soluble, it goes into the aqueous layer. Evaporation of the aqueous layer under reduced pressure provided the catalyst (DIPEAc). Recyclability graph of catalytic efficiency of DIPEAc was tested for four consecutive cycles; the isolated yields were almost alike until the fourth recycling (Figure 2), but a reduction in the catalytic activity of DIPEAc was observed after the fifth cycle; the outcomes are summarized in Table 3. Furthermore, in order to explore the stability of DIPEAc during four consecutive runs, the IR spectra of the recovered DIPEAc (after four cycles) were matched with those of the fresh sample. As documented in Figure 3, the IR spectra displayed by the recovered catalyst were found to be almost similar to the fresh one.

Reuse and recovery of DIPEAc and its effect on yield.

IR spectrum of reuse and recovery of DIPEAc (pink spectrum: fresh; green spectrum: after IV recycles).

Plausible Reaction Mechanism

To explain the mechanism of this one-pot three-component cyclocondensation leading to 1,2,3,4-tetrahydropyrimidine is accredited to the exclusive role of DIPEAc as a medium. It has the capacity to dissolve a number of inorganic/organic solutes readily. This might sensibly maintain the high concentrations of the reactants while initiating the reaction and even the progress of the reaction. Hence high to saturate the solutions of the reactants in the reaction mass would be responsible for degree acceleration of Biginelli reaction.

The stronger hydrogen bonding capability of DIPEAc and the motives for this could be elucidated as follows: (1) The use of DIPEAc elevated the solubility of reactants, which leads to superior interfacial area and lower mass transfer resistance.⁴³ (2) The stimulating effects of DIPEAc to the reaction could be endorsed to its polarity, hydrobonding, and hydrophobic effects.⁴⁴ Hydrophobic effect: The hydrophobic effect leads to extraordinary negative volume of initiation which means better stabilization of activated complexes than hydrophobic reactants in the reaction. Polarity effect: The high polarity of DIPEAc outcomes in the extra polar interpreted states than primary states, so the reaction promptness can be improved. Hydrogen-bonding effect: DIPEAc could initiate the reactants and intermediate products by forming the hydrogen bonds with the hydroxyl oxygen and carbonyl oxygen, respectively (Schemes 3and 4), constructing them easy to form consistent products. It was assumed that only polar protic solvents could give the preferred product, and the hydrogen-bonding effect is the core difference between polar protic solvents and other solvents, so the hydrogen-bonding effect may be the important factor to promote the reaction. Then, it might improve the electrophilic character of carbonyl carbon of the reactants, namely, aldehyde and intermediate. It also increases the rate of in situ formation of catenation from ethylcyanoacetate/ethyl acetoacetate. They may be causing the rate of acceleration resulting in high yields of the 1,2,3,4-tetrahydropyrimidine, subsidiary the role of DIPEAc in a rate enhancement. The proposed mechanism has gone through the Knoevenagel condensation followed by Michael addition and then intermolecular cyclization that is presented in Scheme 5.

Scheme 3 — Reaction conditions: Aldehydes (**1a–z**) (3 mmol), ethylcyanoacetate/ethyl acetoacetate (3 mmol), and thiourea/urea (3.2 mmol) in DIPEAc (4 mL) stirred at room temp;

isolated yields,

melting points are in good contact with those reported in the literature.^36,50,51

Scheme 4 — Reaction conditions: aldehyde (**1aa–nn**) (3 mmol), ethylcyanoacetate/ethyl acetoacetate (3 mmol), thiourea/urea (3.2 mmol) in DIPEAc (4 mL), stirred at room temp;

isolated yields,

melting points are in good contact with those reported in the literature.^36,50,51

Antimicrobial Screening

Twenty analogues of 4-oxo-6-aryl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitriles (4a–t) were evaluated against four bacterial Streptococcus pyogenes, Escherichia coli,S. aureus, and Pseudomonas aeruginosa, and two fungal C. Albicans and Aspergillus niger strains. Ampicillin, rifampicin, and rifapentine were described to have enormously highly antibacterial activities⁴⁵ in the middle of these three antibacterial standard drugs; ampicillin was used as an antibacterial standard to match with the synthesized compounds (4a–t). The results of antifungal and antibacterial screening were summarized in Table 4. The results exposed that maximum of the compounds have shown adequate to superb inhibitory activity against the three tested bacteria. The electronic property of the compounds has an adjacent correlation with their biological activity.⁴⁶ Compounds 4e, 4f, and 4i showed decent antibacterial activity against all four bacterial pathogens because of the presence of withdrawing groups (−NO₂ and −CF₃) and electron-donating groups (−OH and −OCH₃) in the molecule (Figure 4). Compound 4f showed good antibacterial activity against the Gram-positive strains, P. aeruginosa, E. coli, Staphylococcus aureus, and S. pyogenes. We imagine that the presence of −OH and −OCH₃ moieties in the molecule could contribute significantly to the antibacterial activities. Compound 4e and 4i showed decent antibacterial activity against P. aeruginosa and E. coli and less activity against S. aureus. Compounds 4e, 4f, 4i, and 4n showed decent antibacterial activity against all bacterial strains (Schemes 4 and 5).

Table 4. Antimicrobial Screening of 4-Oxo-6-aryl-2-thioxo-1,2,3,4-Tetrahydropyrimidine-5-carbonitriles (4a–t)^a.

	minimum inhibitory concentration (MIC) in μg/mL
compound	E. c. MTCC (443)	P. a. MTCC (1688)	S. a. MTCC (96)	S. p. MTCC (442)	C. a. MTCC (227)	A. n. MTCC (282)
4a	500	100	250	250	100	500
4b	250	500	500	100	500	100
4c	100	100	100	100	500	250
4d	100	200	250	250	500	100
4e	50	25	500	50	500	250
4f	50	12.5	25	250	100	250
4g	500	100	500	250	250	500
4h	100	100	200	250	100	100
4i	12.5	25	100	50	500	250
4j	100	500	100	100	100	25
4k	500	500	500	250	12.5	50
4l	500	250	500	250	50	100
4m	100	100	250	50	50	100
4n	25	100	250	100	500	250
4o	50	100	100	100	500	250
4p	100	200	100	250	500	200
4q	200	100	250	200	100	100
4r	500	200	200	250	100	250
4s	250	500	100	500	250	100
4t	50	50	200	200	250	100
ampicillin	100	100	250	100
griseofulvin					500	100

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E. c., Escherichia coli; P. a., Pseudomonas aeruginosa; S. a.,Staphylococcus aureus; S. p., Streptococcus pyogenes; C.a., Candida albicans; A. n., Aspergillus niger.

Structure–activity relationship of hybrid compounds.

Compounds 4-oxo-6-aryl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitriles (4a–t) were also screened for their in vitro antifungal activity against two fungal strains such as A. niger and Candida albicans by using the microdilution method.⁴⁷ The results of antifungal screening were summarized in Table 4. Antifungal screening results revealed that several compounds showed excellent inhibition against the tested fungal strains compared to standard drug griseofulvin. Compounds 4j, 4k, and 4m showed potent activities against all of the tested fungal strains. It may be because of the presence of the active pyrimidine ring and electron-donating and electron-withdrawing groups on the phenyl ring and presence of thiophene.

Conclusions

In conclusion, an environmentally and highly efficient green methodology has been established for the synthesis of functionalized 1,2,3,4-tetrahydropyrimidine derivatives using an inexpensive and recoverable room-temperature DIPEAc catalytic solvent-free system. This, to the best of our knowledge, has no examples. This reaction scheme exposes a number of advantages, such as uniqueness, high atom efficiency, mild reaction conditions, clean reaction profiles, easy workup procedure, and ecofriendliness. Furthermore, the prevention of hazardous organic solvents during the entire procedure (synthesis, ionic liquid preparation, and workup procedure) makes it a convenient and attractive method for the synthesis of these important compounds. In addition, a series of 4-oxo-6-aryl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitriles analogs were screened for their in vitro antifungal and antibacterial activities. The consequences exposed that compounds 4e, 4f, and 4i presented better antibacterial potency which is equal to the reference drug ampicillin. Compounds 4j, 4k, and 4m were originated to be decent antifungal activity matched to the standard drug griseofulvin.

Experimental Section

Materials and Methods

All of the reagents used were of laboratory grade. Melting points of all of the synthesized analogues were resolute in an open capillary tube and are uncorrected. The progress of the reaction was monitored by thin-layer chromatography on Merck’s silica plates, and imagining was accomplished by iodine/ultraviolet light. IR spectra were acquired on a Bruker ALPHA (Eco-ATR) spectrometer. ¹H NMR spectra were recorded with a Bruker AvIII HD-400 MHz spectrometer operating at 400 MHz using DMSO solvent and tetramethylsilane (TMS) as the internal standard and chemical shift in δ ppm. Mass spectra were recorded on a Waters UPLCTQD (ESI-MS and APCI-MS) instrument, and elemental analysis was recorded on the CHNS auto-analyzer (Thermo Fischer EA1112 SERIES). Chemical shifts (δ) are reported in parts per million using TMS as an internal standard. The splitting pattern abbreviations are designed as singlet (s); doublet (d); double doublet (dd); bs (broad singlet), triplet (t); quartet (q); and multiplets (m).

Preparation of DIPEAc

General Procedure for the Synthesis of Diisopropylethylammonium Acetate (DIPEAc)

A mixture of N,N-diisopropylethylamine (3 mmol) and acetic acid (3 mmol) was stirred at 0–10 °C for 20 min. The viscous liquid, diisopropylethylammonium acetate, was achieved.^48,49

General Procedure for Synthesis of 4-Oxo-6-phenyl-2-thioxo-1,2,3,4-(tetrahydropyrimidine-5-carbonitrile)

A mixture of aldehyde (1a) (1 mmol), ethylcyanoacetate/ethyl acetoacetate (2) (1 mmol), and thiourea/urea (3) (1.2 mmol) in DIPEAc (4 mL) was stirred at room temperature; the evolution of reaction was supervised by thin-layer chromatography [ethyl acetate/N-hexane (3:7)] as a solvent after a stirring reaction mixture was cooled for 45 min and a poured on crushed ice. Thus, acquired solid was filtered, dried, and purified by crystallization using ethanol as a solvent. The result is summarized in Table 4. The synthesis compound is confirmed by mp, IR, NMR, and mass spectra.

Spectral Analysis of Compounds

4-Oxo-6-phenyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (4a)

IR (ATR, υ cm^–1) characteristic absorptions: 2221.12 (CN stretching), 1722.36 (C=O stretching), 3244.37 (N–H stretching), 1448.54 (C=C aromatic stretching), 2902.28 (C–H stretching). ¹H NMR (400 MHz, DMSO-d₆, ppm): 11.71 (s, 1H, NH), 8.96 (s, 1H, NH), 7.78–7.81 (d, 2H, Ar–H), 7.11–7.15 (d, 2H, Ar–H), 7.54–7.56 (d, 2H, Ar–H), ¹³C NMR (100 MHz, DMSO-d₆, ppm): 85.12, 118.62, 123.66, 128.62, 130.59, 131.52, 136.68, 138.64, 139.10, 162.22, 166.22, 183.29, 183.53 mass (LCMS): m/z [M + Na]⁺ calcd for C₁₁H₇N₃OSNa⁺, 252.2; found, 252.2. Anal. Calcd for C₁₁H₇N₃OS: N, 18.33; C, 57.63; S, 13.98; H, 3.08. Found: N, 18.33; C, 57.63; S, 13.98; H, 3.09.

4-(4-Chlorophenyl)-2-mercapto-6-oxo-1,6-dihydropyrimidine-5-carbonitrile (4b)

IR (ATR, υ cm^–1) characteristic absorptions: 2205.85 (CN stretching), 1629.96 (C=O stretching), 3115.80 (N–H stretching), 1461.01 (C=C aromatic stretching), 2893.47 (C–H stretching) 896.64 (C–Cl stretching). ¹H NMR (400 MHz, DMSO-d₆, ppm): 11.72 (s, 1H, NH), 8.97 (s, 1H, NH), 7.48–7.52 (d, 2H, Ar–H), 7.21–7.26 (d, 2H, Ar–H), ¹³C NMR (100 MHz, DMSO-d₆, ppm): 85.12, 119.53, 128.26, 130.22, 134.73, 135.19, 136.92, 162.66, 166.35, 184.23 mass (LCMS): m/z [M + Na]⁺ calcd for C₁₁H₆ClN₃OSNa⁺, 286.7; found, 286.7. Anal. Calcd for C₁₁H₆ClN₃OS: N, 15.94; C, 50.10; S, 12.16; H, 2.29. Found: N, 15.94; C, 50.10; S, 12.16; H, 2.29.

6-(4-Nitrophenyl)-4-oxo-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (4c)

IR (ATR, υ cm^–1) characteristic absorptions: 2220.80 (CN stretching), 1630.96 (C=O stretching), 3145.80 (N–H stretching), 1460.01 (C=C aromatic stretching), 2800.47 C–H stretching) 890.64 (C–NO₂ stretching). ¹H NMR (400 MHz, DMSO-d₆, ppm): 8.1 (s, 1H, NH), 8.97 (s, 1H, NH), 7.48–7.52 (d, 2H, Ar–H), 7.21–7.26 (d, 2H, Ar–H), ¹³C NMR (100 MHz, DMSO-d₆, ppm): 74.7, 115.8, 123.3, 123.3, 134.73, 126.6, 126.6, 137.7, 147.1, 169.1; 166.9, 175.2 mass (LCMS): m/z [M + Na]⁺ calcd for C₁₁H₆N₄O₃SNa⁺, 297.2; found, 297.2. Anal. Calcd for C₁₁H₆N₄O₃S: N, 20.43; C, 48.17; S, 11.69; H, 2.21. Found: N, 20.50; C, 48.23; S, 20.45; H, 2.28.

6-(4-Bromophenyl)-4-oxo-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (4d)

IR (ATR, υ cm^–1) characteristic absorptions: 2200.80 (CN stretching), 1640.69 (C=O stretching), 3145.80 (N–H stretching), 1464.02 (C=C aromatic stretching), 2820.47 (C–H stretching) 900.64 (C–Br stretching). ¹H NMR (400 MHz, DMSO-d₆, ppm): 12.66 (s, 1H, NH), 12.29 (s, 1H, NH), 7.68–7.70 (d, 2H, Ar–H), 7.33–7.38 (d, 2H, Ar–H), ¹³C NMR (100 MHz, DMSO-d₆, ppm): 75.4, 116.8, 122.3, 123.3, 128.6, 128.8, 126.6, 130.7, 131.6, 166.9; 169.7, 175.5 mass (LCMS): m/z [M + Na]⁺ calcd for C₁₁H₆BrN₃OSNa⁺, 331.1; found, 331.2. Anal. Calcd for C₁₁H₆BrN₃OS: N, 13.64; C, 42.88; S, 10.40; H, 1.96. Found: N, 13.60; C, 42.60; S, 10.20; H, 2.0.

6-(4-Methoxyphenyl)-4-oxo-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (4e)

IR (ATR, υ cm^–1) characteristic absorptions: 2260.00 (CN stretching), 1620.69 (C=O stretching), 3245.80 (N–H stretching), 1520.02 (C=C aromatic stretching), 2850.26 (C–H stretching) 2830.12 (O–CH₃ stretching). ¹H NMR (400 MHz, DMSO-d₆, ppm): 11.66 (s, 1H, NH), 11.29 (s, 1H, NH), 7.52–7.54 (d, 2H, Ar–H), 6.94–6.98 (d, 2H, Ar–H), ¹³C NMR (100 MHz, DMSO-d₆, ppm): 55.08, 75.2, 115.8, 121.1, 123.7, 124.2, 129.8, 130.1, 159.8, 166.9, 169.1, 175.2 mass (LCMS): m/z [M + Na]⁺ calcd for C₁₂H₉N₃O₂SNa⁺, 282.3; found, 282.3. Anal. Calcd for C₁₂H₉N₃O₂S: N, 16.21; C, 55.59; S, 12.36; H, 3.50. Found: N, 16.24; C, 55.60; S, 12.35; H, 3.50.

6-(3-Hydroxy-4-methoxyphenyl)-4-oxo-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (4f)

IR (ATR, υ cm^–1) characteristic absorptions: 2200.80 (CN stretching), 1640.69 (C=O stretching), 3145.80 (N–H stretching), 1564.02 (C=C aromatic stretching), 2800.38 (C–H stretching) 2815.15 (O–CH₃ stretching), 3305.10 (O–H stretching). ¹H NMR (400 MHz, DMSO-d₆, ppm): 12.32 (s, 1H, NH), 11.99 (s, 1H, NH), 9.12 (s, 1H, OH), 7.12 (d, 1H, Ar–H), 6.69–6.76 (s, 2H, Ar–H), 3.80 (s, 3H, OCH₃), ¹³C NMR (100 MHz, DMSO-d₆, ppm): 56.3, 74.7, 112.1, 113.2, 115.9, 122.3, 127.9, 147.3, 149.4, 166.9, 169.1, 175.2 mass (LCMS): m/z [M + Na]⁺ calcd for C₁₂H₉N₃O₃SNa⁺, 398.3; found, 398.3. Anal. Calcd for C₁₂H₉N₃O₃S: N, 15.26; C, 52.36; S, 11.65; H, 3.30. Found: N, 15.25; C, 52.35; S, 11.66; H, 3.52.

6-(4-Fluorophenyl)-4-oxo-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (4g)

IR (ATR, υ cm^–1) characteristic absorptions: 2211.10 (CN stretching), 1640.69 (C=O stretching), 3250.80 (N–H stretching), 1540.02 (C=C aromatic stretching), 2790.26 (C–H stretching) 1250.11 (C–F stretching). ¹H NMR (400 MHz, DMSO-d₆, ppm): 12.33 (s, 1H, NH), 12.39 (s, 1H, NH), 7.36–7.40 (d, 2H, Ar–H), 7.24–7.28 (d, 2H, Ar–H), ¹³C NMR (100 MHz, DMSO-d₆, ppm): 75.7, 115.4, 115.8, 128.2, 127.9, 127.2, 162.3, 167.1, 169.5, 166.9, 175.2 mass (LCMS): m/z [M + Na]⁺ calcd for C₁₁H₆FN₃OSNa⁺, 270.2; found, 270.2. Anal. Calcd for C₁₁H₆FN₃OS: N, 15.55; C, 48.89; S, 12.97; H, 2.45. Found: N, 15.54; C, 48.85; S, 12.98; H, 2.44.

6-(2-Chlorophenyl)-4-oxo-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (4h)

IR (ATR, υ cm^–1) characteristic absorptions: 2205.85 (CN stretching), 1629.96 (C=O stretching), 3115.80 (N–H stretching), 1461.01 (C=C aromatic stretching), 2893.47 (C–H stretching) 906.64 (C–Cl stretching). ¹H NMR (400 MHz, DMSO-d₆, ppm): 11.66 (s, 1H, NH), 11.43 (s, 1H, NH), 7.48–7.52 (d, 2H, Ar–H), 7.21–7.26 (d, 2H, Ar–H), ¹³C NMR (100 MHz, DMSO-d₆, ppm): 85.12, 115.8, 126.7, 127.8, 129.3, 129.9, 131.1, 135.3, 166.9, 169.1; 175.2 mass (LCMS): m/z [M + Na]⁺ calcd for C₁₁H₆ClN₃OSNa⁺, 286.7; found, 286.7. Anal. Calcd for C₁₁H₆ClN₃OS: N, 15.02; C, 51.52; S, 11.46; H, 3.60. Found: N, 15.10; C, 51.45; S, 11.40; H, 3.65.

6-(2-Nitrophenyl)-4-oxo-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (4i)

IR (ATR, υ cm^–1) characteristic absorptions: 2220.80 (CN stretching), 1630.96 (C=O stretching), 3145.80 (N–H stretching), 1460.01 (C=C aromatic stretching), 2800.47 (C–H stretching) 890.64 (C–NO₂ stretching). ¹H NMR (400 MHz, DMSO-d₆, ppm): 11.99 (s, 1H, NH), 12.39 (s, 1H, NH), 7.60–7.76 (d, 2H, Ar–H), 7.89–8.26 (d, 2H, Ar–H), ¹³C NMR (100 MHz, DMSO-d₆, ppm): 76.7, 116.8, 123.8, 127.3, 128.8, 130.0, 134.2, 145.6, 147.1, 166.2; 169.2, 178.2 mass (LCMS): m/z [M + Na]⁺ calcd for C₁₁H₆N₄O₃SNa⁺, 297.2; found, 297.2. Anal. Calcd for C₁₁H₆N₄O₃S: N, 20.43; C, 48.17; S, 11.69; H, 2.21. Found: N, 20.50; C, 48.23; S, 20.45; H, 2.28.

6-(2-Bromophenyl)-4-oxo-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (4j)

IR (ATR, υ cm^–1) characteristic absorptions: 2250.80 (CN stretching), 1610.69 (C=O stretching), 3120.80 (N–H stretching), 1464.02 (C=C aromatic stretching), 2820.47 (C–H stretching) 960.64 (C–Br stretching). ¹H NMR (400 MHz, DMSO-d₆, ppm): 12.53 (s, 1H, NH), 11.29 (s, 1H, NH), 7.49–7.53 (d, 2H, Ar–H), 7.33–7.38 (d, 2H, Ar–H), ¹³C NMR (100 MHz, DMSO-d₆, ppm): 76.3, 115.2, 118.6, 127.5, 128.6, 132.6, 138.2, 166.9, 169.1, 166.9; 169.7, 176.5 mass (LCMS): m/z [M + Na]⁺ calcd for C₁₁H₆BrN₃OSNa⁺, 331.1; found, 331.2. Anal. Calcd for C₁₁H₆BrN₃OS: N, 13.64; C, 42.88; S, 10.40; H, 1.96. Found: N, 13.10; C, 42.20; S, 10.30; H, 2.01.

4-Oxo-2-thioxo-6-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (4k)

IR (ATR, υ cm^–1) characteristic absorptions: 2190.80 (CN stretching), 1710.69 (C=O stretching), 3220.80 (N–H stretching), 1464.02 (C=C aromatic stretching), 2820.47 (C–H stretching) 1000.64 (C–CF₃ stretching). ¹H NMR (400 MHz, DMSO-d₆, ppm): 12.26 (s, 1H, NH), 12.43 (s, 1H, NH), 7.42–7.46 (d, 2H, Ar–H), 7.27–7.30 (d, 2H, Ar–H), ¹³C NMR (100 MHz, DMSO-d₆, ppm): 76.8, 115.8, 124.1, 125.0, 125.1, 129.4, 130.2, 134.9, 166.8, 169.2; 178.3 mass (LCMS): m/z [M + Na]⁺ calcd for C₁₂H₆F₃N₃OSNa⁺, 320.2; found, 320.2. Anal. Calcd for C₁₂H₆F₃N₃OS: N, 14.14; C, 48.49; S, 10.79; H, 2.03. Found: N, 14.15; C, 48.48; S, 10.78; H, 2.08.

6-(3,4-Dimethoxy-5-methylphenyl)-4-oxo-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (4l)

IR (ATR, υ cm^–1) characteristic absorptions: 2220.80 (CN stretching), 1650.69 (C=O stretching), 3045.80 (N–H stretching), 1564.02 (C=C aromatic stretching), 2800.38 (C–H stretching) 2875.15 (O–CH₃ stretching), 2875.15 (O–CH₃ stretching), 3305.10. ¹H NMR (400 MHz, DMSO-d₆, ppm): 12.66 (s, 1H, NH), 12.39 (s, 1H, NH), 7.14 (s, 1H, Ar–H), 6.84 (s, 1H, Ar–H), 3.83 (s, 3H, OCH₃), 3.68 (s, 3H, OCH₃), ¹³C NMR (100 MHz, DMSO-d₆, ppm): 16.1, 56.1, 60.3, 108.5, 115.7, 119.9, 125.4, 127.4, 145.2, 151.2, 166.9, 169.1, 175.2 mass (LCMS): m/z [M + Na]⁺ calcd for C₁₄H₁₃N₃O₃SNa⁺, 326.3; found, 326.3. Anal. Calcd for C₁₄H₁₃N₃O₃S: N, 13.85; C, 55.43; S, 10.57; H, 4.32. Found: N, 13.85; C, 55.43; S, 10.57; H, 4.32.

4-Oxo-6-(thiophen-2-yl)-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (4m)

IR (ATR, υ cm^–1) characteristic absorptions: 2200.60 (CN stretching), 170.59 (C=O stretching), 3145.90 (N–H stretching), 1570.02 (C=C aromatic stretching), 2814.38 (C–H stretching) (thiophene ring stretching), 3305.10. ¹H NMR (400 MHz, DMSO-d₆, ppm): 11.23 (s, 1H, NH), 11.00 (s, 1H, NH), 7.95 (s, 1H, Ar–H), 7.36 (t, 1H, Ar–H), 7.85 (s, 1H, Ar–H), ¹³C NMR (100 MHz, DMSO-d₆, ppm): 80.7, 115.8, 127.1, 128.3, 130.5, 136.6, 166.9, 176.8, 177.1 mass (LCMS): m/z [M + Na]⁺ calcd for C₉H₅N₃OS₂Na⁺, 258.3; found, 258.3. Anal. Calcd for C₉H₅N₃OS₂: N, 17.86; C, 45.95; S, 27.25; H, 2.14. Found: N, 17.85; C, 45.96; S, 27.24; H, 2.15.

6-(3-Hydroxyphenyl)-4-oxo-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (4n)

IR (ATR, υ cm^–1) characteristic absorptions: 2200.80 (CN stretching), 1640.69 (C=O stretching), 3145.80 (N–H stretching), 1564.02 (C=C aromatic stretching), 2800.38 (C–H stretching) 3305.10 (O–H stretching). ¹H NMR (400 MHz, DMSO-d₆, ppm): 12.32 (s, 1H, NH), 11.99 (s, 1H, NH), 9.45 (s, 1H, OH), 7.24–7.28 (d, 1H, Ar–H), 6.69–6.83 (d, 2H, Ar–H), ¹³C NMR (100 MHz, DMSO-d₆, ppm): 75.7, 112.1, 115.1, 115.8, 120.9, 130.0, 135.6, 158.4, 149.4, 166.9, 169.1, 175.2 mass (LCMS): m/z [M + Na]⁺ calcd for C₁₁H₇N₃O₂SNa⁺, 268.2; found, 268.2. Anal. Calcd for C₁₁H₇N₃O₂S: N, 17.13; C, 53.87; S, 13.07; H, 2.88. Found: N, 17.14; C, 53.88; S, 13.06; H, 2.87.

6-(4-Hydroxyphenyl)-4-oxo-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (4o)

IR (ATR, υ cm^–1) characteristic absorptions: 2212.80 (CN stretching), 1660.69 (C=O stretching), 3100.80 (N–H stretching), 1564.02 (C=C aromatic stretching), 2800.38 (C–H stretching) 3300.10 (O–H stretching). ¹H NMR (400 MHz, DMSO-d₆, ppm): 12.32 (s, 1H, NH), 11.99 (s, 1H, NH), 9.45 (s, 1H, OH), 7.31–7.35 (d, 1H, Ar–H), 6.35–6.39 (d, 2H, Ar–H), ¹³C NMR (100 MHz, DMSO-d₆, ppm): 75.7, 112.1, 115.1, 115.8, 120.9, 130.0, 135.6, 158.4, 149.4, 166.9, 169.1, 175.2 mass (LCMS): m/z [M + Na]⁺ calcd for C₁₁H₇N₃O₂SNa⁺, 268.2; found, 268.2. Anal. Calcd for C₁₁H₇N₃O₂S: N, 17.13; C, 53.87; S, 13.07; H, 2.88. Found: N, 17.14; C, 53.88; S, 13.06; H, 2.89.

6-(3-Cyanophenyl)-4-oxo-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (4p)

IR (ATR, υ cm^–1) characteristic absorptions: 2212.80 (CN stretching), 2160.80, (CN stretching), 1660.69 (C=O stretching), 3100.80 (N–H stretching), 1600.02 (C=C aromatic stretching), 2800.38 (C–H stretching). ¹H NMR (400 MHz, DMSO-d₆, ppm): 12.66 (s, 1H, NH), 12.39 (s, 1H, NH), 9.45 (s, 1H, OH), 7.80–7.83 (d, 1H, Ar–H), 7.61 (t, 1H, Ar–H), 7.89 (s, 1H, Ar–H), ¹³C NMR (100 MHz, DMSO-d₆, ppm): 75.2, 112.5, 115.8, 118.8, 129.3, 129.6, 131.4, 132.6, 134.9, 166.9, 169.1, 175.4 mass (LCMS): m/z [M + Na]⁺ calcd for C₁₂H₆N₄OSNa⁺, 277.3; found, 277.3. Anal. Calcd for C₁₂H₆N₄OS: N, 22.04; C, 56.59; S, 12.61; H, 2.38. Found: N, 22.05; C, 56.58; S, 12.62; H, 2.37.

6-(2-Hydroxyphenyl)-4-oxo-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (4q)

IR (ATR, υ cm^–1) characteristic absorptions: 2220.10 (CN stretching), 1645.69 (C=O stretching), 3105.60 (N–H stretching), 1530.02 (C=C aromatic stretching), 2812.38 (C–H stretching) 3301.00 (O–H stretching). ¹H NMR (400 MHz, DMSO-d₆, ppm): 12.32 (s, 1H, NH), 11.99 (s, 1H, NH), 9.45 (s, 1H, OH), 7.31–7.35 (d, 1H, Ar–H), 6.35–6.39 (d, 2H, Ar–H), ¹³C NMR (100 MHz, DMSO-d₆, ppm): 75.7, 112.1, 115.1, 115.8, 120.9, 130.0, 135.6, 158.4, 149.4, 166.9, 169.1, 175.2 mass (LCMS): m/z [M + Na]⁺ calcd for C₁₁H₇N₃O₂SNa⁺, 268.2; found, 268.2. Anal. Calcd for C₁₁H₇N₃O₂S: N, 17.13; C, 53.87; S, 13.07; H, 2.88. Found: N, 17.14; C, 53.88; S, 13.06; H, 2.89.

6-(4-Hydroxy-3-methoxyphenyl)-4-oxo-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (4r)

IR (ATR, υ cm^–1) characteristic absorptions: 2214.80 (CN stretching), 1630.69 (C=O stretching), 3142.80 (N–H stretching), 1564.02 (C=C aromatic stretching), 2800.38 (C–H stretching) 2820.25 (O–CH₃ stretching), 3310.10 (O–H stretching). ¹H NMR (400 MHz, DMSO-d₆, ppm): 12.32 (s, 1H, NH), 11.99 (s, 1H, NH), 9.12 (s, 1H, OH), 7.12 (d, 1H, Ar–H), 6.69–6.76 (s, 2H, Ar–H), 3.80 (s, 3H, OCH₃), ¹³C NMR (100 MHz, DMSO-d₆, ppm): 56.3, 74.7, 112.1, 113.2, 115.9, 122.3, 127.9, 147.3, 149.4, 166.9, 169.1, 175.2 mass (LCMS): m/z [M + Na]⁺ calcd for C₁₂H₉N₃O₃SNa⁺, 398.3; found, 398.3. Anal. Calcd for C₁₂H₉N₃O₃S: N, 15.26; C, 52.36; S, 11.65; H, 3.30. Found: N, 15.27; C, 52.35; S, 11.66; H, 3.51.

4-Oxo-2-thioxo-6-(p-tolyl)-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (4s)

IR (ATR, υ cm^–1) characteristic absorptions: 2200.80 (CN stretching), 1640.69 (C=O stretching), 3145.80 (N–H stretching), 1464.02 (C=C aromatic stretching), 2820.47 (C–H stretching). ¹H NMR (400 MHz, DMSO-d₆, ppm): 12.12 (s, 1H, NH), 12.31 (s, 1H, NH), 7.68–7.70 (d, 2H, Ar–H), 7.33–7.38 (d, 2H, Ar–H), 2.41 (s, 3H, CH₃), ¹³C NMR (100 MHz, DMSO-d₆, ppm): 21.3, 75.4, 116.8, 122.3, 123.3, 128.6, 128.8, 126.6, 130.7, 131.6, 166.9; 169.7, 175.5 mass (LCMS): m/z [M + Na]⁺ calcd for C₁₂H₉N₃OSNa⁺, 266.3; found, 266.3. Anal. Calcd for C₁₂H₉N₃OS: N, 17.27; C, 59.24; S, 13.18; H, 3.73. Found: N, 17.28; C, 59.25; S, 13.17; H, 3.74.

4-Oxo-6-(pyridin-3-yl)-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (4t)

IR (ATR, υ cm^–1) characteristic absorptions: 2221.10 (CN stretching), 1620.69 (C=O stretching), 3256.80 (N–H stretching), 1486.02 (C=C aromatic stretching), 3450.47 (pyridine ring stretching). ¹H NMR (400 MHz, DMSO-d₆, ppm): 12.66 (s, 1H, NH), 12.39 (s, 1H, NH), 7.68–7.70 (d, 2H, Ar–H), 8.37 (s, 1H, Ar–H), 8.70 (s, 1H, Ar–H), ¹³C NMR (100 MHz, DMSO-d₆, ppm): 80.7, 115.8, 123.8, 131.6, 133.7, 149.5, 150.00, 166.9, 169.1, 175.2 mass (LCMS): m/z [M + Na]⁺ calcd for C₁₀H₆N₄OSNa⁺, 253.2; found, 253.2. Anal. Calcd for C₁₀H₆N₄OS: N, 24.33; C, 52.17; S, 13.92; H, 2.63. Found: N, 24.34; C, 52.18; S, 13.93; H, 2.64.

2,4-Dioxo-6-phenyl-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (4u)

IR (ATR, υ cm^–1) characteristic absorptions: 2218.10 (CN stretching), 1732.69 (C=O stretching), 3256.80 (N–H stretching), 1486.02 (C=C aromatic stretching). ¹H NMR (400 MHz, DMSO-d₆, ppm): 11.35 (s, 1H, NH), 10.98 (s, 1H, NH), 7.71–7.73 (d, 2H, Ar–H), 7.52–7.54 (d, 2H, Ar–H), ¹³C NMR (100 MHz, DMSO-d₆, ppm): 72.2, 115.8, 127.9, 128.3, 128.4, 128.6, 128.7, 131.6, 150.7, 161.6, 168.9 mass (LCMS): m/z [M + Na]⁺ calcd for C₁₁H₇N₃O₂Na⁺, 236.2; found, 236.2. Anal. Calcd for C₁₁H₇N₃O₂: N, 19.71; C, 61.97; H, 3.31. Found: N, 19.72; C, 61.98; H, 3.32.

6-(4-Chlorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (4v)

IR (ATR, υ cm^–1) characteristic absorptions: 2212.36 (CN stretching), 1640.69 (C=O stretching), 3301.80 (N–H stretching), 1510.02 (C=C aromatic stretching). ¹H NMR (400 MHz, DMSO-d₆, ppm): 11.10 (s, 1H, NH), 10.30 (s, 1H, NH), 7.44–7.48 (d, 2H, Ar–H), 7.28–7.32 (d, 2H, Ar–H), ¹³C NMR (100 MHz, DMSO-d₆, ppm): 73.4, 115.8, 120.2, 120.6, 128.8, 128.9, 129.7, 133.5, 150.7, 161.6, 168.9 mass (LCMS): m/z [M + Na]⁺ calcd for C₁₁H₆ClN₃O₂Na⁺, 270.6; found, 270.6. Anal. Calcd for C₁₁H₆ClN₃O₂: N, 16.97; C, 53.35; H, 2.44. Found: N, 16.96; C, 53.54; H, 2.45.

6-Butyl-4-oxo-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (4w)

IR (ATR, υ cm^–1) characteristic absorptions: 2200.26 (CN stretching), 1650.69 (C=O stretching), 3320.10 (N–H stretching), 1512.12 (C=C aromatic stretching). ¹H NMR (400 MHz, DMSO-d₆, ppm): 12.66 (s, 1H, NH), 8.14 (s, 1H, NH), 1.94 (t, 2H), 1.38 (d, 2H, Ar–H), ¹³C NMR (100 MHz, DMSO-d₆, ppm): 20.9, 22.8, 28.2, 64.8, 115.8, 116.2, 175.2, 182.4 mass (LCMS): m/z [M + Na]⁺ calcd for C₉H₁₁N₃OSNa⁺, 232.3; found, 232.3. Anal. Calcd for C₉H₁₁N₃OS: N, 20.08; C, 51.66; H, 5.30; S, 15.32. Found: N, 20.02; C, 51.67; H, 5.31; S, 15.31.

6-Butyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (4x)

IR (ATR, υ cm^–1) characteristic absorptions: 2203.22 (CN stretching), 1660.60 (C=O stretching), 1760.10 (C=O stretching), 3300.10 (N–H stretching), 1552.12 (C=C aromatic stretching). ¹H NMR (400 MHz, DMSO-d₆, ppm): 10.80 (s, 1H, NH), 10.10 (s, 1H, NH), 1.84 (t, 2H), 1.48 (d, 2H, Ar–H), ¹³C NMR (100 MHz, DMSO-d₆, ppm): 14.6, 21.2, 22.7, 28.9, 85.4, 116.5, 150.2, 161.3, 173.5 mass (LCMS): m/z [M + Na]⁺ calcd for C₉H₁₁N₃O₂Na⁺, 216.2; found, 216.2. Anal. Calcd for C₉H₁₁N₃O₂: N, 21.75; C, 55.95; H, 5.74. Found: N, 21.71; C, 55.96; H, 5.73.

6-Butyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (4y)

IR (ATR, υ cm^–1) characteristic absorptions: 2203.22 (CN stretching), 1660.60 (C=O stretching), 3300.10 (N–H stretching), 1552.12 (C=C aromatic stretching). ¹H NMR (400 MHz, DMSO-d₆, ppm): 10.50 (s, 1H, NH), 10.10 (s, 1H, NH), 1.98 (t, 2H), 1.30 (q, 1H), 1.38 (t, 2H), 0.93 (s, 3H), ¹³C NMR (100 MHz, DMSO-d₆, ppm): 14.2, 21.1, 29.7, 64.9, 166.2, 175.2, 179.8 mass (LCMS): m/z [M + Na]⁺ calcd for C₈H₉N₃OSNa⁺, 218.2; found, 218.2. Anal. Calcd for C₈H₉N₃OS: N, 21.52; C, 49.22; H, 4.65; S, 16.42. Found: N, 21.51; C, 49.23; H, 4.64; S, 16.41.

2,4-Dioxo-6-propyl-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (4z)

IR (ATR, υ cm^–1) characteristic absorptions: 2203.22 (CN stretching), 1660.60 (C=O stretching), 1760.10 (C=O stretching), 3300.10 (N–H stretching), 1552.12 (C=C aromatic stretching). ¹H NMR (400 MHz, DMSO-d₆, ppm): 9.50 (s, 1H, NH), 9.10 (s, 1H, NH), 1.88 (t, 2H), 1.40 (q, 1H), 1.38 (t, 2H), 0.98 (s, 3H), ¹³C NMR (100 MHz, DMSO-d₆, ppm): 16.2, 23.1, 28.7, 65.9, 167.2, 176.2, 180.8 mass (LCMS): m/z [M + Na]⁺ calcd for C₈H₉N₃OSNa⁺, 202.2; found, 202.2. Anal. Calcd for C₈H₉N₃OS: N, 23.45; C, 53.63; H, 5.06. Found: N, 23.46; C, 53.63; H, 5.07.

Ethyl 6-Methyl-2-oxo-4-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxylate (4aa)

IR (ATR, υ cm^–1) characteristic absorptions: 3230.22 (NH stretching), 1697.60 (C=O stretching), 1760.10 (C=O stretching), 1552.12 (C=C aromatic stretching). ¹H NMR (400 MHz, DMSO-d₆, ppm): 9.18 (s, 1H, NH), 7.73 (s, 1H, NH), 7.33–7.22 (m, 5H, Ar–H), 5.14 (d, 1H), 4.00–3.95 (q, 2H), 2.24 (s, 3H), 1.10–1.07 (t, 3H), ¹³C NMR (100 MHz, DMSO-d₆, ppm): 14.09, 17.79, 53.98, 59.21, 99.29, 126.26, 127.28, 128.41, 144.88, 148.37, 152.15, 165.36 mass (LCMS): m/z [M + Na]⁺ calcd for C₁₄H₁₆N₂O₃Na⁺, 283.3; found, 283.3. Anal. Calcd for C₁₄H₁₆N₂O₃: N, 10.76; C, 64.60; H, 6.20. Found: N, 10.77; C, 64.61; H, 6.21.

Ethyl 4-(2-Chlorophenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (4bb)

IR (ATR, υ cm^–1) characteristic absorptions: 3228.22 (NH stretching), 1677.00 (C=O stretching), 1645.10 (C=O stretching), 1552.12 (C=C aromatic stretching). ¹H NMR (400 MHz, DMSO-d₆, ppm): 9.21 (s, 1H, NH), 7.74 (s, 1H, NH), 7.45–7.44 (d, 1H, Ar–H), 7.25–7.23 (t, 2H, Ar–H), 7.31–7.30 (d, 1H, Ar–H), 7.20–7.21 (t, 1H, Ar–H), 5.61 (d, 1H), 3.91–3.86 (q, 2H), 2.30 (s, 2H), 1.00–0.97 (t, 3H), ¹³C NMR (100 MHz, DMSO-d₆, ppm): 13.95, 17.77, 53.40, 59.21, 90.83, 128.36, 131.75, 143.78, 148.68, 151.79, 165.36 mass (LCMS): m/z [M + Na]⁺ calcd for C₁₄H₁₅ClN₂O₃Na⁺, 317.7; found, 317.7. Anal. Calcd for C₁₄H₁₅ClN₂O₃: N, 9.50; C, 57.05; H, 5.13. Found: N, 9.51; C, 57.04; H, 5.13.

Ethyl 4-(4-Chlorophenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (4cc)

IR (ATR, υ cm^–1) characteristic absorptions: 3228.22 (NH stretching), 1677.00 (C=O stretching), 1645.10 (C=O stretching), 1552.12 (C=C aromatic stretching). ¹H NMR (400 MHz, DMSO-d₆, ppm): 9.21 (s, 1H, NH), 7.74 (s, 1H, NH), 7.40–7.38 (d, 2H, Ar–H), 7.25–7.23 (d, 2H, Ar–H), 5.14 (d, 1H), 4.01–3.95 (q, 2H), 2.24 (s, 3H), 1.11–1.07 (t, 3H), ¹³C NMR (100 MHz, DMSO-d₆, ppm): 14.5, 17.77, 53.40, 59.21, 90.83, 128.36, 131.75, 143.78, 148.68, 151.79, 165.36 mass (LCMS): m/z [M + Na]⁺ calcd for C₁₄H₁₅ClN₂O₃Na⁺, 317.7; found, 317.7. Anal. Calcd for C₁₄H₁₅ClN₂O₃: N, 9.50; C, 57.05; H, 5.13. Found: N, 9.51; C, 57.04; H, 5.13.

Ethyl 6-Methyl-4-(3-nitrophenyl)-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (4dd)

IR (ATR, υ cm^–1) characteristic absorptions: 3323.12 (NH stretching), 1677.00 (C=O stretching), 1685.10 (C=O stretching), 1562.12 (C=C aromatic stretching). ¹H NMR (400 MHz, DMSO-d₆, ppm): 9.33 (s, 1H, NH), 8.08 (s, 1H, NH), 8.16 (s, 1H, NH) 8.14–8.12 (d, 1H, Ar–H), 7.70–7.69 (d, 1H, Ar–H), 7.67–7.63 (t, 1H, Ar–H), 5.30 (s, 1H), 4.01–3.94 (q, 2H), 2.27 (s, 3H), 1.11–1.08 (t, 3H), ¹³C NMR (100 MHz, DMSO-d₆, ppm): 13.97, 17.81, 53.53, 59.34, 98.32, 120.96, 122.30, 130.19, 132.94, 146.96, 147.63, 149.63, 151.63, 166.03 mass (LCMS): m/z [M + Na]⁺ calcd for C₁₄H₁₅N₃O₅Na⁺, 328.3; found, 328.3. Anal. Calcd for C₁₄H₁₅N₃O₅: N, 13.76; C, 55.08; H, 4.95. Found: N, 13.77; C, 55.09; H, 4.96.

Ethyl 6-Methyl-4-(4-nitrophenyl)-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (4ee)

IR (ATR, υ cm^–1) characteristic absorptions: 3224.12 (NH stretching), 1697.00 (C=O stretching), 1641.10 (C=O stretching), 1562.12 (C=C aromatic stretching). ¹H NMR (400 MHz, DMSO-d₆, ppm): 9.35 (s, 1H, NH), 8.22–8.20 (d, 2H), 7.88 (s, 1H) 7.51–7.49 (d, 2H, Ar–H), 5.27 (d, 1H, Ar–H), 4.01–3.95 (q, 2H, Ar–H), 2.26 (s, 3H), 1.11–1.07 (t, 3H), ¹³C NMR (100 MHz, DMSO-d₆, ppm): 14.02, 17.81, 53.67, 59.34, 98.32, 123.80, 127.64, 146.71, 149.36, 151.72, 151.98, 165.04 mass (LCMS): m/z [M + Na]⁺ calcd for C₁₄H₁₅N₃O₅Na⁺, 328.3; found, 328.3. Anal. Calcd for C₁₄H₁₅N₃O₅: N, 13.76; C, 55.08; H, 4.95. Found: N, 13.77; C, 55.09; H, 4.96.

Ethyl 4-(4-Methoxyphenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (4ff)

IR (ATR, υ cm^–1) characteristic absorptions: 3230.12 (NH stretching), 1701.00 (C=O stretching), 1645.10 (C=O stretching), 1562.12 (C=C aromatic stretching). ¹H NMR (400 MHz, DMSO-d₆, ppm): 9.15 (s, 1H, NH), 7.66 (s, 1H) 7.15–7.13 (d, 2H, Ar–H), 6.88–6.85 (d, 2H, Ar–H), 5.09 (d, 1H), 4.00–3.94 (q, 2H), 3.71 (s, 3H), 2.23 (s, 3H), 1.11–1.08 (t, 3H), ¹³C NMR (100 MHz, DMSO-d₆, ppm): 14.10, 17.75, 53.33, 55.05, 59.15, 99.58, 113.17, 127.39, 137.05, 148.01, 152.16, 158.44, 165.38 mass (LCMS): m/z [M + Na]⁺ calcd for C₁₅H₁₈N₂O₄Na⁺, 313.3; found, 313.3. Anal. Calcd for C₁₅H₁₈N₂O₄: N, 9.65; C, 62.06; H, 6.25. Found: N, 9.66; C, 62.06; H, 6.25.

Ethyl 6-Methyl-2-oxo-4-(thiophen-2-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxylate (4gg)

IR (ATR, υ cm^–1) characteristic absorptions: 3230.12 (NH stretching), 1701.00 (C=O stretching), 1646.10 (C=O stretching), 1562.12 (C=C aromatic stretching). ¹H NMR (400 MHz, DMSO-d₆, ppm): 9.31 (s, 1H, NH), 7.90 (s, 1H) 7.35–7.34 (d, 1H, Ar–H), 6.93–6.88 (dd, 2H, Ar–H), 5.41 (d, 1H), 4.08–4.03 (q, 2H), 2.21 (s, 3H), 1.18–1.14 (t, 3H), ¹³C NMR (100 MHz, DMSO-d₆, ppm): 14.15, 17.68, 49.35, 59.35, 99.78, 123.50, 124.63, 126.66, 148.65, 148.79, 152.23, 165.03 mass (LCMS): m/z [M + Na]⁺ calcd for C₁₂H₁₄N₂O₃SNa⁺, 289.3; found, 289.3. Anal. Calcd for C₁₂H₁₄N₂O₃S: N, 10.52; C, 54.12; H, 5.30. Found: N, 10.52; C, 54.12; H, 5.30.

Ethyl 6-Methyl-4-phenyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (4hh)

IR (ATR, υ cm^–1) characteristic absorptions: 3230.12 (NH stretching), 3107.02 (NH stretching), 1697.00 (C=O stretching), 1697.43.10 (C=O stretching), 1562.12 (C=C aromatic stretching), ¹H NMR (400 MHz, DMSO-d₆, ppm): 9.18 (s, 1H, NH), 7.73 (s, 1H) 7.33–7.22 (d, 1H, Ar–H), 5.14 (d, 1H), 4.08–3.95 (q, 2H), 2.24 (s, 3H), 1.10–1.07 (t, 3H), ¹³C NMR (100 MHz, DMSO-d₆, ppm): 14.09, 17.79, 53.98, 59.21, 99.29, 126.26, 127.28, 128.41, 144.88, 148.37, 152.15, 165.36 mass (LCMS): m/z [M + Na]⁺ calcd for C₁₄H₁₆N₂O₂SNa⁺, 299.3; found, 299.3. Anal. Calcd for C₁₄H₁₆N₂O₂S: N, 10.14; C, 60.85; H, 5.84; S, 11.60. Found: N, 1; C, 54.12; H, 5.84, S, 11.60.

Ethyl 4-(4-Chlorophenyl)-6-methyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (4ii)

IR (ATR, υ cm^–1) characteristic absorptions: 3228.22 (NH stretching), 1677.00 (C=O stretching), 1645.10 (C=O stretching), 1552.12 (C=C aromatic stretching). ¹H NMR (400 MHz, DMSO-d₆, ppm): 9.21 (s, 1H, NH), 7.74 (s, 1H, NH), 7.40–7.38 (d, 2H, Ar–H), 7.25–7.23 (d, 2H, Ar–H), 5.14 (d, 1H), 4.01–3.95 (q, 2H), 2.24 (s, 3H), 1.11–1.07 (t, 3H) ¹³C NMR (100 MHz, DMSO-d₆, ppm): 14.5, 17.77, 53.40, 59.21, 90.83, 128.36, 131.75, 143.78, 148.68, 151.79, 165.36 mass (LCMS): m/z [M + Na]⁺ calcd for C₁₄H₁₅ClN₂O₂SNa⁺, 333.8; found, 333.8. Anal. Calcd for C₁₄H₁₅ClN₂O₂S: N, 9.01; C, 54.10; H, 4.86; S, 10.32. Found: N, 9.51; C, 57.04; H, 5.13; S, 10.32.

Ethyl 4-(4-Methoxyphenyl)-6-methyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (4jj)

IR (ATR, υ cm^–1) characteristic absorptions: 3232.12 (NH stretching), 1721.00 (C=O stretching), 1646.10 (C=O stretching), 1562.12 (C=C aromatic stretching). ¹H NMR (400 MHz, DMSO-d₆, ppm): 9.16 (s, 1H, NH), 7.64 (s, 1H) 7.14–7.13 (d, 2H, Ar–H), 6.88–6.85 (d, 2H, Ar–H), 5.09 (d, 1H), 4.00–3.94 (q, 2H), 3.71 (s, 3H), 2.23 (s, 3H), 1.11–1.08 (t, 3H), ¹³C NMR (100 MHz, DMSO-d₆, ppm): 14.10, 17.75, 53.33, 55.05, 59.15, 99.58, 113.17, 127.39, 137.05, 148.01, 152.16, 158.44, 165.38 mass (LCMS): m/z [M + Na]⁺ calcd for C₁₅H₁₈N₂O₃SNa⁺, 329.4; found, 329.4. Anal. Calcd for C₁₅H₁₈N₂O₃S: N, 9.14; C, 58.80; H, 5.92; S, 10.46. Found: N, 9.15; C, 58.80; H, 5.15; S, 10.46.

Ethyl 6-Methyl-4-propyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (4kk)

IR (ATR, υ cm^–1) characteristic absorptions: 3232.12 (NH stretching), 1721.00 (C=O stretching), 1562.12 (C=C aromatic stretching). ¹H NMR (400 MHz, DMSO-d₆, ppm): 9.65 (s, 1H, NH), 8.10 (s, 1H) 4.51–3.72 (m, 3H), 2.16 (s, 3H), 1.46–1.23 (m, 4H), 1.19 (t, 3H), 0.85 (t, 3H), ¹³C NMR (100 MHz, DMSO-d₆, ppm): 14.23, 14.69, 17.47, 18.17, 50.25, 59.52, 99.86, 136.28, 162.66, 174.35 mass (LCMS): m/z [M + Na]⁺ calcd for C₁₁H₁₈N₂O₂SNa⁺, 265.3; found, 265.3. Anal. Calcd for C₁₁H₁₈N₂O₂S: N, 11.56; C, 54.52; H, 7.49; S, 13.23. Found: N, 11.56; C, 54.52; H, 7.49; S, 13.23.

Ethyl 4-Hexyl-6-methyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (4ll)

IR (ATR, υ cm^–1) characteristic absorptions: 3332.12 (NH stretching), 1691.00 (C=O stretching), 1552.12 (C=C aromatic stretching). ¹H NMR (400 MHz, DMSO-d₆, ppm): 9.75 (s, 1H, NH), 8.23 (s, 1H) 4.11–3.88 (m, 3H), 2.16 (s, 3H), 1.46–1.23 (m, 4H),1.18 (t, 3H),0.85 (t, 3H), ¹³C NMR (100 MHz, DMSO-d₆, ppm): 14.01, 14.26, 17.82, 21.95, 36.52, 49.99, 59.07, 99.39, 136.40, 160.83, 177.38 mass (LCMS): m/z [M + Na]⁺ calcd for C₁₄H₂₄N₂O₂SNa⁺, 307.4; found, 307.4. Anal. Calcd for C₁₄H₂₄N₂O₂S: N, 9.85; C, 59.12; H, 8.51; S, 11.27. Found: N, 9.85; C, 59.12; H, 8.51; S, 11.27.

Ethyl 6-Methyl-2-oxo-4-propyl-1,2,3,4-tetrahydropyrimidine-5-carboxylate (4mm)

IR (ATR, υ cm^–1) characteristic absorptions: 3240.10 (N–H stretching), 1628.75 (C=O stretching), 3140.15, 1393.29 (C=C aromatic stretching), 2955.56 (C–H stretching) 1508.94 (CH₃ bending). ¹H NMR (400 MHz, DMSO-d₆, ppm): 8.95 (s, 1H, NH), 7.35 (s, 1H) 4.52–3.71 (m, 3H), 2.16 (s, 3H), 1.44–1.25 (m, 4H), 1.19 (t, 3H), 0.85 (t, 3H), ¹³C NMR (100 MHz, DMSO-d₆, ppm): 14.23, 14.69, 17.47, 18.17, 50.25, 59.52, 99.86, 148.77, 153.27, 165.83 mass (LCMS): m/z [M + Na]⁺ calcd for C₁₁H₁₈N₂O₃Na⁺, 249.3; found, 249.3. Anal. Calcd for C₁₁H₁₈N₂O₃: N, 12.38; C, 58.39; H, 8.02. Found: N, 12.38; C, 58.39; H, 8.01.

Ethyl 4-Butyl-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (4nn)

IR (ATR, υ cm^–1) characteristic absorptions: 3230.21 (N–H stretching), 1640.75 (C=O stretching), 3146.15, 1343.29 (C=C aromatic stretching), 2945.56 (C–H stretching) 1518.94 (CH₃ bending). ¹H NMR (400 MHz, DMSO-d₆, ppm): 8.95 (s, 1H, NH), 7.35 (s, 1H) 4.52–3.71 (m, 3H), 2.16 (s, 3H), 1.44–1.25 (m, 4H), 1.19 (t, 3H), 0.85 (t, 3H), ¹³C NMR (100 MHz, DMSO-d₆, ppm): 14.23, 14.69, 17.47, 18.17, 50.25, 59.52, 99.86, 148.77, 153.27, 165.83 mass (LCMS): m/z [M + Na]⁺ calcd for C₁₂H₂₀N₂O₃Na⁺, 263.03; found, 263.03. Anal. Calcd for C₁₂H₂₀N₂O₃: N, 11.66; C, 59.98; H, 8.39. Found: N, 11.66; C, 59.98; H, 8.39.

Acknowledgments

The authors C.K.J. and A.S.N. are very much grateful to the Council for Scientific and Industrial Research (CSIR), New Delhi, for the award research fellowship. Authors are also thankful to the Authority of Department of Chemistry, Dr. Babasaheb Ambedkar Marathwada University, Aurangabad-431004, India, for providing laboratory facility. We are also thankful to SAIF, CSIR-CDRI, Lucknow, India, for providing spectral analysis data.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsomega.9b02286.

Spectral data for synthesized compounds and copy of ¹H NMR, ¹³C NMR, LCMS, and FT-IR of products (PDF)

Author Contributions

The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript.

The authors declare no competing financial interest.

Supplementary Material

ao9b02286_si_001.pdf^{(938.3KB, pdf)}

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PERMALINK

Efficient Rapid Access to Biginelli for the Multicomponent Synthesis of 1,2,3,4-Tetrahydropyrimidines in Room-Temperature Diisopropyl Ethyl Ammonium Acetate

Chetan K Jadhav

Amol S Nipate

Asha V Chate

Vishal D Songire

Anil P Patil

Charansingh H Gill

Abstract

Introduction

Scheme 1. Synthesis of 4-Oxo-6-phenyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (4a) by Using DIPEAc as RTIL.

Scheme 2. Synthesis of Diisopropylethylammonium Acetate (DIPEAc).

Figure 1.

Results and Discussion

Chemistry

Table 1. Efficiency Comparison of Various Catalysts for the Synthesis of 4-Oxo-6-aryl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (4a)a.

Table 2. Solvent Effects on the Reaction of Aldehyde, Ethylcyanoacetate, and Thiourea for the Synthesis of 4-Oxo-6-phenyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (4a)a.

Table 3. Recycling of DIPEAc (IL) for The Synthesis of Compounds 4a and 4aaa.

Recycling of the Catalyst

Figure 2.

Figure 3.

Plausible Reaction Mechanism

Scheme 3. Synthesis of 4-Oxo-6-aryl-2-thioxo-1,2,3,4-Tetrahydropyrimidine-5-carbonitriles (4a–z) by Using DIPEAc as RTIL.

Scheme 4. Synthesis of Ethyl 6-Methyl-2-oxo-4-aryl-1,2,3,4-tetrahydropyrimidine-5-carboxylates (4aa–nn) by Using DIPEAc as RTIL.

Scheme 5. 4-Oxo-6-phenyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile.

Antimicrobial Screening

Table 4. Antimicrobial Screening of 4-Oxo-6-aryl-2-thioxo-1,2,3,4-Tetrahydropyrimidine-5-carbonitriles (4a–t)a.

Figure 4.

Conclusions

Experimental Section

Materials and Methods

Preparation of DIPEAc

General Procedure for the Synthesis of Diisopropylethylammonium Acetate (DIPEAc)

General Procedure for Synthesis of 4-Oxo-6-phenyl-2-thioxo-1,2,3,4-(tetrahydropyrimidine-5-carbonitrile)

Spectral Analysis of Compounds

4-Oxo-6-phenyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (4a)

4-(4-Chlorophenyl)-2-mercapto-6-oxo-1,6-dihydropyrimidine-5-carbonitrile (4b)

6-(4-Nitrophenyl)-4-oxo-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (4c)

6-(4-Bromophenyl)-4-oxo-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (4d)

6-(4-Methoxyphenyl)-4-oxo-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (4e)

6-(3-Hydroxy-4-methoxyphenyl)-4-oxo-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (4f)

6-(4-Fluorophenyl)-4-oxo-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (4g)

6-(2-Chlorophenyl)-4-oxo-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (4h)

6-(2-Nitrophenyl)-4-oxo-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (4i)

6-(2-Bromophenyl)-4-oxo-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (4j)

4-Oxo-2-thioxo-6-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (4k)

6-(3,4-Dimethoxy-5-methylphenyl)-4-oxo-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (4l)

4-Oxo-6-(thiophen-2-yl)-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (4m)

6-(3-Hydroxyphenyl)-4-oxo-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (4n)

6-(4-Hydroxyphenyl)-4-oxo-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (4o)

6-(3-Cyanophenyl)-4-oxo-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (4p)

6-(2-Hydroxyphenyl)-4-oxo-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (4q)

6-(4-Hydroxy-3-methoxyphenyl)-4-oxo-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (4r)

4-Oxo-2-thioxo-6-(p-tolyl)-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (4s)

4-Oxo-6-(pyridin-3-yl)-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (4t)

2,4-Dioxo-6-phenyl-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (4u)

6-(4-Chlorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (4v)

6-Butyl-4-oxo-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (4w)

6-Butyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (4x)

6-Butyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (4y)

2,4-Dioxo-6-propyl-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (4z)

Ethyl 6-Methyl-2-oxo-4-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxylate (4aa)

Ethyl 4-(2-Chlorophenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (4bb)

Ethyl 4-(4-Chlorophenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (4cc)

Ethyl 6-Methyl-4-(3-nitrophenyl)-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (4dd)

Ethyl 6-Methyl-4-(4-nitrophenyl)-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (4ee)

Ethyl 4-(4-Methoxyphenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (4ff)

Ethyl 6-Methyl-2-oxo-4-(thiophen-2-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxylate (4gg)

Ethyl 6-Methyl-4-phenyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (4hh)

Ethyl 4-(4-Chlorophenyl)-6-methyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (4ii)

Ethyl 4-(4-Methoxyphenyl)-6-methyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (4jj)

Ethyl 6-Methyl-4-propyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (4kk)

Ethyl 4-Hexyl-6-methyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (4ll)

Ethyl 6-Methyl-2-oxo-4-propyl-1,2,3,4-tetrahydropyrimidine-5-carboxylate (4mm)

Ethyl 4-Butyl-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (4nn)

Acknowledgments

Supporting Information Available

Author Contributions

Supplementary Material

References

Table 1. Efficiency Comparison of Various Catalysts for the Synthesis of 4-Oxo-6-aryl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (4a)^a.

Table 2. Solvent Effects on the Reaction of Aldehyde, Ethylcyanoacetate, and Thiourea for the Synthesis of 4-Oxo-6-phenyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (4a)^a.

Table 3. Recycling of DIPEAc (IL) for The Synthesis of Compounds 4a and 4aa^a.

Table 4. Antimicrobial Screening of 4-Oxo-6-aryl-2-thioxo-1,2,3,4-Tetrahydropyrimidine-5-carbonitriles (4a–t)^a.