Role of surfactant and micelle promoted mild, green, highly efficient and sustainable approach for construction of novel fused pyrimidines at room temperature in water

Abstract

A facile, efficient and green protocol for surfactant catalyzed synthesis of fused pyrimidines in water at room temperature was developed for the first time. The influence of the sodium lauryl sulphate (SLS) micelles and their different concentrations on reactivity was studied. It was found that best yield was obtained with 10 mol% catalyst loading with minimum time as compare to other surfactants and catalysts were used. This procedure resulted in a general and environmentally benign protocol has advantage of better efficiency of catalyst, excellent yield, short reaction time and easy to work up.

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Introduction

Scaffold decoration of bioactive molecules represents one of the most vibrant research areas in organic chemistry and has a rich history within the realm of fragment-based drug design. Designing the new drugs is based on the development of hybrid molecules by combining different pharmacophore fragments in a single structure, which may lead to compounds with interesting biological profile. As pathogenic bacteria continuously evolve the mechanism of resistance to currently used antibacterial, so the discovery of novel and potent antibacterial drugs is the best way to overcome bacterial resistance and to develop effective therapies.¹ Multicomponent reactions (MCRs) are of increasing significance in organic and medicinal chemistry. Multicomponent reactions have been refined in recent years into a powerful and useful tool in synthetic chemistry. Such processes enable the rapid elaboration of complex structures in a highly efficient, higher yield than almost any sequential synthesis of the same target, a single purification step, time and energy saving, low expenditures, easy adaptation to combinatorial synthesis and modular manner. In addition, the implementation of several transformations in a single manipulation is highly compatible with the goals of sustainable and “green” chemistry.^2–8

Pyrimidine and its derivatives have been studied for several years because of their chemical and biological significance. They have been reported as anti-viral, anti-tumor, anti-inflammatory, antihypertensive activities,^9–11 calcium channel modulators¹² and antimicrobial agents.^13–15 Numerous heterocyclic systems fused with pyrimidines are known for their important biological activities.¹⁶ Some chromeno pyrimidine derivatives show antiplatelet and antithrombotic activities.¹⁷

The ‘greening’ of global chemical processes has became a major issue in the chemical industry.¹⁸ As a consequence, in recent year much effort has been directed toward the use of water as solvent for organic reactions.^19–26 The development of simple and efficient chemical processes or methodologies for the synthesis of biologically active compounds in water is one of the major challenges for chemists, although water is a safe, very cheap, readily available, and environmentally benign solvent.²⁷ Recently, many researchers have been synthesized different fused pyrimidines in water.²⁸ Unfortunately, many of these reported methods suffer from one or the other limitations such as drastic reaction conditions, long reaction time with poor yield, side products formation, strong oxidizing agents, use of toxic reagents, use of expensive catalyst, more catalyst loading, and tedious workup procedure. Although today's environmental consciousness imposes the use of water as a solvent on both industrial and academic chemists, organic solvents are still used instead of water for mainly two reasons. First, most organic substances are insoluble in water, and as a result, water does not function as a reaction medium. Second, many reactive substrates, reagents, and catalysts are decomposed or deactivated by water. Some of these problems were solved with the discovery of surfactant combined catalysts by Kobayashi et al.²⁹ Therefore, three-component reaction which exploits different surfactants as catalyst in water could reveal an ideal methodology, provided that the catalyst shows high catalytic activity in water and remove all drawbacks of reported methods.

As part of our continuing efforts on the development of new routes for the synthesis of heterocyclic³⁰ herein, we wish to report surfactant miceller catalyzed synthesis of fused pyrimidine by one-pot three component reaction of 4-hydroxy coumarin, aldehydes and urea/thiourea, 3-amino-1,2,4-traizole, or 2-amino benzothiazole in water at room temperature (Scheme 1).

Scheme 1 Synthesis of chromeno[4,3-d]benzothiazolo[3,2-a]pyrimidin-6(7H)-one.

Results and discussion

Three component reaction starting from benzaldehyde, 4-hydroxy coumarin and 2-amino benzothiazole has proved to be a facile method for preparation of chromeno[4,3-d]benzothiazolo[3,2-a]pyrimidin-6(7H)-one (4). To optimize the reaction conditions, first of all we studied the effect of different solvents using SLS (Table 1). Table 1 showed that among all solvents, reaction was well tolerated in water with significant yield isolated in comparable with short reaction time (Table 1, entry 1). That's why water was chosen as solvent for further studies and all other catalysts have used in aqueous medium.

Table 1 Effect of different solvents using SLS on synthesis of chromeno[4,3-d]benzothiazolo[3,2-a]pyrimidin-6(7H)-one

Entry	Solvents (10 mL)	Time (h)	Yield^a (%)
a Isolated yield.
1	Water	5.0	91
2	Dichloromethane	12	0
3	Methanol	12	0
4	Ethanol	12	0
5	Acetonitrile	12	0
6	Chloroform	12	0
7	Toluene	12	0
8	Hexane	12	0

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From the viewpoint of today's environmental consciousness, however, it is desirable to avoid the use of harmful organic solvents. Therefore, we next initiated investigations to develop a new system for surfactant catalyzed reactions in water without using organic solvents. The main drawback in the use of water (low solubility of most organic substances in water) could be overcome by using surfactants, which solubilize organic materials or form emulsions with them in water. To address this solubility issue, therefore, we planned to use surfactants hopefully small amounts of them for the surfactant catalyzed reactions in water.

To optimize the effect of reaction time on the yield of target product, a model reaction was carried out at different time using 4-hydroxy coumarin (2 mmol), benzaldehyde (2 mmol) and 2-amino benzothiazole (2 mmol) in water using surfactant at room temperature. The reaction time 5 h was found to be optimum time (Fig. 1). Further increasing the reaction time did not increase yield. Highest yield (from 30–91%) of product was obtained at 5 h of reaction time.

Fig. 1 Optimization of reaction time and yield.

Yield of product was dependent on the reaction time in the presence of surfactant as catalyst in water. When the loading of catalyst was not enough, the maximum yield could not be reached. To avoid this kind of problem, an optimum amount of catalyst loading had to be investigated. For this study, synthesis of chromeno[4,3-d]benzothiazolo[3,2-a]pyrimidin-6(7H)-one (4) carried out using 4-hydroxy coumarin (2 mmol), benzaldehyde (2 mmol) and 2-amino benzothiazole (2 mmol) in the presence of different amount of catalyst (2, 5, 8, 10 and 15 mol%) respectively (Table 2). Highest yield was obtained with 10 mol% of SLS as catalyst. The catalyst loading 10 mol% was found to be the optimal quantity. Other surfactants such as SDS and TBAB have also been used as catalyst with same mol% but give lower yield as compared to SLS (Table 2, entries 6 and 7). That's why we have used other catalysts which were also give poor yield as compared to SLS (entries 8–12). So, further we have extended our work with SLS (10 mol%) as catalyst.

Table 2 Effect of different catalysts at room temperature in water

Entry	Catalysts	Time (h)	Yield^a (%)
a Isolated yield.
1	Sodium lauryl sulphate (2 mol%)	7.0	52
2	Sodium lauryl sulphate (5 mol%)	6.0	78
3	Sodium lauryl sulphate (8 mol%)	5.5	86
4	Sodium lauryl sulphate (10 mol%)	5.0	91
5	Sodium lauryl sulphate (15 mol%)	5.0	91
6	Sodium dodesyl sulphate (10 mol%)	5.0	81
7	TBAB (10 mol%)	5.0	76
8	KCl (10 mol%)	8.0	55
9	Mg(NO3)2 (10 mol%)	9.0	51
10	p-Toluene sulphonic acid (10 mol%)	8.0	49
11	CaCl2 (10 mol%)	8.5	41
12	LiBr (10 mol%)	7.5	59

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After optimization of reaction conditions the reaction was carried out with various aromatic aldehydes, 4-hydroxy coumarin and 2-aminobenzothiazole or urea/thiourea or 3-amino-1,2,4-triazole to afford chromeno[4,3-d]benzothiazolo[3,2-a]pyrimidin-6(7H)-one (4), 3,4-dihydro-1H-chromeno[4,3-d]pyrimidine-2,5-dione (6) and dihydro-6H-chromeno[4,3-d][1,2,4]triazolo[1,5-a]pyrimidin-6-one (8) derivatives respectively. Catalytic activity of SLS has been explored for the synthesis of these derivatives at room temperature in aqueous medium, results are incorporated in Table 3. Table 3 revealed that reaction proceeded efficiently with para substituted aldehydes with good yield whereas ortho and meta substituted aldehydes gave the slightly lower yield comparatively to para substituted aldehydes.

Table 3 Synthesis of fused pyrimidine derivatives

R	R1	R2	Product	Yield^a (%)	Time (h)
a Isolated yield.
–C6H5	H	H		95	5.0
–C6H5–CH=CH	H	H		85	4.5
4-Cl–C6H5	H	H		86	4.0
4 N(CH3)2–C6H5	H	H		94	4.0
3-OH–C6H5	H	H		93	4.0
4-OCH3–C6H5	H	H		91	4.0
4-CH3–C6H5	H	H		94	4.5
4-NO2–C6H5	H	H		86	5.0
2-CH3–C6H5	H	H		91	5.0
2-OCH3–C5H6	H	H		90	5.0
4-OH–C6H5	H	H		91	5.0
4-Cl–C6H5	Me	H		85	4.5
–C6H5	NO2	H		81	3.5
4-CH3–C6H5	H	Cl		87	4.0
4-Br–C6H5	Me	Cl		88	4.0
C6H5	—	—		95	5.0
4-Cl–C6H5	—	—		93	5.0
C6H5	—	—		91	5.0
4-N(CH3)2–C6H5	—	—		93	5.0
2-OH–C6H5	—	—		81	5.0

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Role of surfactant

The catalytic effect of the micellar solution of may be attributed to the hydrophobic nature of organic substrates. Formation of emulsion droplets takes place in water in the presence of surfactant and substrate molecules. It is suggested that most of the organic substrates are concentrated in these spherical droplets, which act as a hydrophobic reaction sites and results in an increase in the effective concentration of the organic reactants. In micellar solution, organic substrates are pushed away from water molecules towards the hydrophobic core of micelle droplets thus inducing efficient collisions between organic substrates which eventually enhance the reaction rate and result in rapid reactions in water.^29,31

Mechanism and role of aqueous medium

We speculate that in the presence of organic substrates, SLS molecules form stable colloidal particles in which the surfactant moiety of the SLS surrounds the organic substrates and the counter cations are attracted to the surface of the particles through electrostatic interactions between the anionic surfactant molecules. Although each sodium cation is hydrated by several water molecules, they can be readily replaced by a substrate because of the high exchange rate of sodium for substitution of inner sphere water ligands.³² The substrates to be activated move to the interface from the organic phase, coordinate to the cations, and then react with nucleophilic substances there. The hydrophobic interior of the micelles swiftly excludes the water molecules generated during the reaction, thus shifting the equilibrium towards the desired product that ultimately leads to an increase in the reaction yield.^33,34

According to results found above, SLS worked well only in water. A comparable study of different solvents in the three component reaction revealed that the reaction in water was faster. In the SLS-catalyzed reactions stated in this article, most of the reaction mixtures became turbid, and formation of these colloidal dispersions is a characteristic feature for the present reaction system. Thus, we have tried to observe the SLS-induced colloidal particles. This observation implies the formation of micelle or micelle like colloidal aggregates, analyzing an aliquot of the reaction mixture, we observed that the spherical particles were clearly formed which is supported by literature (Fig. 2).^35–39

Fig. 2 Micelle formation detected by light microscopy.

A plausible mechanism for the synthesis of chromeno[4,3-d]benzothiazolo[3,2-a]pyrimidin-6(7H)-one derivatives (4) is depicted in Scheme 2. In the beginning, Knoevenagel condensation of the 4-hydroxycoumarin (1) and aldehyde (2) in the presence of SLS produces intermediate. This is followed by Michael addition of 2-aminobenzothiazole (3) to the C=C bond of intermediate (A) and form intermediate (B) through tautomerization. Then, an intramolecular cyclic condensation between the amino and the carbonyl groups of the Michael adduct B occurs to afford intermediate (C), which afford the desired compounds (4) on dehydration.

Scheme 2 A plausible mechanism for the synthesis of derivatives (4).

Thus, the micelle intervention consists probably of the concentration and disposition of the chemical species where the exterior coat of the SDS micelle structure would strongly bind to all the reactants (precursors and intermediaries) as well as the final product according to its structural features and electrostatic interactions. Therefore, our proposed scheme is explained in terms of the anionic SDS micelle nature and the concentration effect (hydrophobic interaction between reactants and aqueous medium).^40,41

Materials and methods

Experimental

The ¹H NMR spectra were measured using BRUKER AVANCE II 400 NMR spectrometer with tetramethylsilane as an internal standard at 20–25 °C; data for ¹H NMR are reported as follows: chemical shift (ppm), integration, multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet, and br, broad), coupling constant (Hz). IR spectra were recorded by SHIMADZU; IR spectrometer of sample dispersed in KBr pellet or Nujol is reported in terms of frequency of absorption (cm⁻¹). E-Merck pre-coated TLC plates and RANKEM silica gel G were used for preparative thin-layer chromatography. Melting points were determined in open capillaries and are uncorrected. AR grade of 4-hydroxy coumarin, aldehydes, urea, thiourea, 3-amino-1,2,4-triazole, SLS and other catalysts were purchased from Himedia Laboratory Ltd., Mumbai, India. 2-Amino benzothiazole was purchased from Sigma Aldrich and used without further purification.

One-pot three-component reaction

Typical procedure. A mixture of substituted aromatic aldehydes (2 mmol), 4-hydroxy coumarin (2 mmol), and 2-amino benzothiazole or urea/thiourea or 3-amino-1,2,4-triazole (2 mmol) were stirrer at room temperature in water (10 mL) using SLS as catalyst (10 mol%). The reaction was monitored by TLC. After completion of the reaction, solid mass was filtered then washed with water. Collect the solid material as target compounds and recrystallized from ethanol (5 mL) to afford the pure product.

Characterization data

7-Phenylchromeno[4,3-d]benzothiazolo[3,2-a]pyrimidin-6(7H)-one (4a). White powder, mp 200–202 °C; IR (v_max) cm⁻¹ 2930, 2850, 1720, 1600, 1402, 1202, 1160, 1050; ¹H NMR (500 MHz, DMSO d₆): δ_H 6.23 (s, 1H, –CH), 7.05–7.12 (m, 3H, Ar-H), 7.17 (t, 2H, J = 8.0 Hz, Ar-H), 7.22–7.29 (m, 4H, Ar-H), 7.30–7.52 (m, 4H); ¹³C NMR (125 MHz, DMSO d₆): 68, 103, 114, 115, 115, 119, 122, 122, 123, 123, 124, 126, 126, 127, 127, 131, 141, 152, 164, 167, 168; ESI-MS: m/z calculated for C₂₃H₁₄N₂O₂S 382.43 found [M + H]⁺ 382.

7-Styrylchromeno[4,3-d]benzothiazolo[3,2-a]pyrimidin-6(7H)-one (4b). Light brown crystal, mp 180–182; IR (v_max) cm⁻¹ 2950, 2830, 1716, 1609, 1412, 1206, 1103, 1044; ¹H NMR (500 MHz, DMSO d₆): δ_H 5.73 (s, 1H, –CH), 6.38 (d, 1H, =CH), 6.78 (d, 1H, =CH), 7.10–7.45 (m, 8H, Ar-H), 7.56 (t, 2H, J = 7.5 Hz, Ar-H), 7.63 (m, 3H, Ar-H); ¹³C NMR (125 MHz, DMSO d₆): 65, 101, 102, 104, 111, 115, 116, 117, 123, 124, 126, 127, 128, 129, 131, 132, 137, 143, 152, 153, 160, 161, 163, 164, 165; ESI-MS: m/z calculated for C₂₅H₁₆N₂O₂S 408.47 found [M + H]⁺ 409.

7-(4-Chlorophenyl)chromeno[4,3-d]benzothiazolo[3,2-a]pyrimidin-6(7H)-one (4c). Light yellow powder, mp 188–189; IR (v_max) cm⁻¹ 2953, 2810, 1718, 1622, 1432, 1232, 1110, 1005; ¹H NMR (500 MHz, DMSO d₆): δ_H 6.39 (s, 1H, –CH), 6.94–7.09 (m, 2H, Ar-H), 7.16 (d, 1H, J = 8.0 Hz, Ar-H), 7.21 (t, 1H, J = 7.5 Hz, Ar-H), 7.39–7.59 (m, 4H, J = 8.0 Hz), 7.82 (d, 2H, J = 8.5 Hz, Ar-H), 7.90 (d, 2H, J = 7.0 Hz, Ar-H); ¹³C NMR (125 MHz, DMSO d₆): 68, 106, 113, 118, 118, 121, 125, 125, 125, 126, 129, 130, 134, 146, 155, 163, 167, 170; ESI-MS: m/z calculated for C₂₃H₁₃ClN₂O₂S 416.88 found [M + H]⁺ 418.

7-(4-Dimethylaminophenyl)chromeno[4,3-d]benzothiazolo[3,2-a]pyrimidin-6(7H)-one (4d). Reddish brown powder, mp 160–162; IR (v_max) cm⁻¹ 2943, 2809, 1718, 1604, 1415, 1202, 1106, 1022; ¹H NMR (500 MHz, DMSO d₆): δ_H 3.08 (s, 6H, –N(CH₃)₂), 6.26 (s, 1H, –CH), 7.15–7.41 (m, 8H, Ar-H), 7.51 (t, 2H, J = 7.5 Hz, Ar-H), 7.79 (d, 2H, J = 7.5 Hz, Ar-H); ¹³C NMR (125 MHz, DMSO d₆): 44, 65, 103, 111, 115, 115, 118, 119, 122, 122, 122, 124, 126, 128, 128, 128, 131, 141, 152, 164, 167; ESI-MS: m/z calculated for C₂₅H₁₉N₃O₂S 425.50 found [M + H]⁺ 426.

7-(3-Hydroxyphenyl)chromeno[4,3-d]benzothiazolo[3,2-a]pyrimidin-6(7H)-one (4e). Off white powder, mp 200–202 °C; IR (v_max) cm⁻¹ 2933, 2819, 1720, 1600, 1402, 1206, 1115, 1005; ¹H NMR (500 MHz, DMSO d₆): δ_H 6.20 (s, 1H, –CH), 6.45–6.56 (m, 3H, Ar-H), 6.94 (t, 1H, J = 7.5 Hz, Ar-H), 7.22–7.31 (m, 4H, Ar-H), 7.38–7.51 (m, 4H, Ar-H), 9.26 (br, 1H, OH); ¹³C NMR (125 MHz, DMSO d₆): 65, 103, 112, 113, 114, 115, 117, 119, 122, 122, 123, 123, 124, 127, 128, 131, 141, 143, 152, 157, 164, 167, 168; ESI-MS: m/z calculated for C₂₃H₁₄N₂O₃S 398.43 found [M + H]⁺ 399.

7-(4-Methoxyphenyl)chromeno[4,3-d]benzothiazolo[3,2-a]pyrimidin-6(7H)-one (4f). Off white powder, mp 234–236 °C; IR (v_max) cm⁻¹ 2963, 2849, 1713, 1612, 1402, 1212, 1121, 1034; ¹H NMR (500 MHz, DMSO d₆): δ_H 3.73 (s, 3H, OCH₃), 6.24 (s, 1H, –CH), 6.80 (d, 2H, J = 7.0 Hz, Ar-H), 7.16–7.29 (m, 4H, Ar-H), 7.51 (t, 2H, J = 7.5 Hz, Ar-H), 7.68 (d, 2H, J = 7.0 Hz, Ar-H), 7.79 (d, 2H, J = 7.5 Hz, Ar-H); ¹³C NMR (125 MHz, DMSO d₆): 56, 66, 103, 118, 121, 125, 128, 133, 133, 133, 134, 138, 141, 142, 145, 150, 152, 164, 166; ESI-MS: m/z calculated for C₂₄H₁₆N₂O₃S 412.46 found [M + H]⁺ 413.

7-(4-Methylphenyl)chromeno[4,3-d]benzothiazolo[3,2-a]pyrimidin-6(7H)-one (4g). Yellow powder, mp > 250 °C; IR (v_max) cm⁻¹ 2963, 2844, 1712, 1612, 1442, 1202, 1105, 1035; ¹H NMR (500 MHz, DMSO d₆): δ_H 2.80 (s, 3H, CH₃), 6.24 (s, 1H, –CH), 7.19–7.40 (m, 8H, Ar-H), 7.51 (t, 2H, J = 7.5 Hz, Ar-H), 7.80 (d, 2H, J = 7.0 Hz, Ar-H); ¹³C NMR (125 MHz, DMSO d₆): 27, 65, 102, 111,116, 119, 119, 123, 123, 124, 124, 128, 131, 140, 145, 152, 154, 164, 167; ESI-MS: m/z calculated for C₂₄H₁₆N₂O₂S 396.46 found [M]⁺ 397.

7-(4-Nitrophenyl)chromeno[4,3-d]benzothiazolo[3,2-a]pyrimidin-6(7H)-one (4h). Off white powder, mp 200–202 °C; IR (v_max) cm⁻¹ 2952, 2822, 1715, 1602, 1412, 1217, 1125, 1021; ¹H NMR (500 MHz, DMSO d₆): δ_H 6.34 (s, 1H, –CH), 7.22–7.31 (m, 5H, Ar-H), 7.36 (d, 2H, J = 7.0 Hz, Ar-H), 7.53 (t, 2H, J = 7.5 Hz, Ar-H), 7.81 (d, 2H, J = 7.5 Hz, Ar-H), 8.08 (d, 2H, J = 7.5 Hz, Ar-H); ¹³C NMR (125 MHz, DMSO d₆): 67, 103, 111, 115, 118, 122, 123, 123, 124, 124, 126, 128, 128, 131, 144, 152, 161, 164, 167; ESI-MS: m/z calculated for C₂₃H₁₃N₃O₄S 427.43 found [M + H]⁺ 427.48.

7-(2-Methylphenyl)chromeno[4,3-d]benzothiazolo[3,2-a]pyrimidin-6(7H)-one (4i). Off white powder, mp > 250 °C; IR (v_max) cm⁻¹ 2954, 2839, 1709, 1618, 1422, 1232, 1115, 1022; ¹H NMR (500 MHz, DMSO d₆): δ_H 2.61 (s, 3H, CH₃), 6.37 (s, 1H, –CH), 7.27 (t, 2H, J = 7.0 Hz, Ar-H), 7.32 (d, 2H, J = &.5 Hz, Ar-H), 7.39 (d, 2H, J = 7.0 Hz, Ar-H), 7.56 (t, 2H, J = 7.5 Hz, Ar-H), 7.86 (d, 2H, J = 7.5 Hz, Ar-H), 8.08 (d, 2H, J = 7.5 Hz, Ar-H); ¹³C NMR (125 MHz, DMSO d₆): 38, 67, 103, 115, 118, 123, 123, 124, 124, 128, 128, 130, 131, 140, 144, 150, 152, 164, 166; ESI-MS: m/z calculated for C₂₄H₁₆N₂O₂S 396.46 found [M + H]⁺ 397.

7-(2-Methoxyphenyl)chromeno[4,3-d]benzothiazolo[3,2-a]pyrimidin-6(7H)-one (4j). Off white powder, mp 234–236 °C; IR (v_max) cm⁻¹ 2953, 2824, 1716, 1615, 1415, 1209, 1119, 1018; ¹H NMR (500 MHz, DMSO d₆): δ_H 3.73 (s, 3H, OCH₃), 6.26 (s, 1H, –CH), 6.78 (d, 2H, J = 7.0 Hz, Ar-H), 7.14–7.30 (m, 4H, Ar-H), 7.52 (t, 2H, J = 7.5 Hz, Ar-H), 7.68 (d, 2H, J = 7.0 Hz, Ar-H), 7.79 (d, 2H, J = 7.5 Hz, Ar-H); ¹³C NMR (125 MHz, DMSO d₆): 55, 66, 106, 115, 119, 122, 122, 123, 123, 126, 131, 134, 135, 143, 149, 152, 156, 167, 169; ESI-MS: m/z calculated for C₂₄H₁₆N₂O₃S 412.46 found [M + H]⁺ 413.

7-(4-Hydroxyphenyl)chromeno[4,3-d]benzothiazolo[3,2-a]pyrimidin-6(7H)-one (4k). Off white powder, mp 200–202 °C; IR (v_max) cm⁻¹ 2931, 2837, 1718, 1630, 1441, 1214, 1127, 1015; ¹H NMR (500 MHz, DMSO d₆): δ_H 6.18 (s, 1H, –CH), 6.54 (d, 1H, J = 7.5 Hz, Ar-H), 6.86 (t, 1H, J = 7.5 Hz, Ar-H), 7.19–7.26 (m, 4H, Ar-H), 7.42–7.51 (m, 4H, Ar-H), 7.60 (d, 2H, J = 7.5 Hz, Ar-H), 8.91 (br, 1H, OH); ¹³C NMR (125 MHz, DMSO d₆): 65, 101, 109, 111, 112, 113, 115, 117, 120, 120, 120, 121, 124, 125, 128, 138, 141, 149, 159, 154, 162, 164, 166, 167; ESI-MS: m/z calculated for C₂₃H₁₄N₂O₃S 398.43 found [M + H]⁺ 399.

7-(4-Chloroyphenyl)-11-methylbenzo[4,5]thiazolo[3,2-a]chromeno[4,3-d]pyrimidin-6(7H)-one (4l). Off white powder, mp 184–186 °C; IR (v_max) cm⁻¹ 2921, 2830, 1708, 1609, 1410, 1208, 1106, 1019; ¹H NMR (500 MHz, DMSO d₆): δ_H 2.29 (s, 3H, CH₃), 6.29 (s, 1H, –CH), 7.14 (d, 2H, J = 7.5 Hz, Ar-H), 7.22–7.40 (m, 4H, Ar-H), 7.40–7.629 (m, 2H, Ar-H), 7.88 (d, 2H, J = 7.5 Hz, Ar-H), 7.93 (d, 1H, J = 8.5 Hz, Ar-H); ¹³C NMR (125 MHz, DMSO d₆): 23, 67, 104, 116, 116, 117, 117, 123, 128, 129, 129, 129, 130, 131, 132, 138, 139, 152, 164, 166; ESI-MS: m/z calculated for C₂₄H₁₅ClN₂O₂S 430.91 found [M]⁺ 430.

11-Nitro-7-phenyl-11-methylbenzo[4,5]thiazolo[3,2-a]chromeno[4,3-d]pyrimidin-6(7H)-one (4m). Off white powder, mp 215–217 °C; IR (v_max) cm⁻¹ 2970, 2834, 1720, 1615, 1411, 1201, 1104, 1019; ¹H NMR (500 MHz, DMSO d₆): δ_H 6.42 (s, 1H, –CH), 7.21 (t, 2H, J = 8.0 Hz, Ar-H), 7.28 (d, 2H, J = 8.5 Hz, Ar-H), 7.36 (d, 2H, J = 8.5 Hz, Ar-H), 7.53 (t, 2H, J = 8.0 Hz, Ar-H), 7.81 (d, 2H, J = 8.0 Hz, Ar-H), 8.04 (d, 2H, J = 9.0 Hz, Ar-H); ¹³C NMR (125 MHz, DMSO d₆): 69, 103, 111, 115, 118, 122, 122, 123, 127, 130, 131, 139, 145, 149, 151, 157, 164, 166; ESI-MS: m/z calculated for C₂₃H₁₃N₃O₄S 427.43 found [M]⁺ 427.08.

2-Chloro-7-(p-tolyl)benzo[4,5]thiazolo[3,2-a]chromeno[4,3-d]pyrimidin-6(7H)-one (4n). Off white powder, mp 225–227 °C; IR (v_max) cm⁻¹ 2962, 2844, 1709, 1618, 1419, 1222, 1118, 1022; ¹H NMR (500 MHz, DMSO d₆): δ_H 2.39 (s, 3H, CH₃), 6.30 (s, 1H, –CH), 6.89–6.94 (dd, 2H, J = 8.0, 8.5 Hz, Ar-H), 7.06 (t, 2H, J = 8.0 Hz), 7.40 (t, 1H, J = 7.0 Hz, Ar-H), 7.32 (d, 2H, J = 7.5 Hz, Ar-H), 7.36 (d, 1H, J = 7.5 Hz, Ar-H), 7.70 (d, 1H, J = 7.5 Hz, Ar-H), 8.10 (d, 2H, J = 8.5 Hz, Ar-H); ¹³C NMR (125 MHz, DMSO d₆): 21, 69, 102, 117, 118, 121, 121, 121, 126, 127, 128, 129, 129, 129, 130, 1132, 134, 143, 150, 151, 161, 163, 167; ESI-MS: m/z calculated for C₂₄H₁₅ClN₂O₂S 430.90 found [M]⁺ 430.9.

7-(4-Bromophenyl)-2-chloro-11-methylbenzo[4,5]thiazolo[3,2-a]chromeno[4,3-d]pyrimidin-6(7H)-one (4o). Off white powder, mp > 250 °C; IR (v_max) cm⁻¹ 2956, 2833, 1710, 1602, 1412, 1202, 1105, 1015; ¹H NMR (500 MHz, DMSO d₆): δ_H 2.23 (s, 3H, CH₃), 6.31 (s, 1H, –CH), 6.82–7.05 (m, 1H, Ar-H), 7.09–7.23 (m, 4H, Ar–H), 7.32 (d, 2H, J = 7.5 Hz, Ar–H), 7.52 (d, 1H, J = 7.0 Hz, Ar–H), 7.80–7.92 (m, 2H, Ar–H); ¹³C NMR (125 MHz, DMSO d₆): 22, 70, 104, 109, 113, 125, 126, 126, 127, 128, 129, 129, 129, 130, 130, 138, 143, 151, 153, 165, 170; ESI-MS: m/z calculated for C₂₄H₁₄BrClN₂O₂S 509.80 found [M]⁺ 509.8.

4-Pheny l-3,4-dihydro-2H-chromeno[4,3-d]pyrimidine-2,5(1H)-dione (6a). Off white powder, mp 160–162 °C (reported 160–162 °C);^{42 1}H NMR (500 MHz, DMSO d₆): δ_H 6.36 (s, 3H, –CH), 7.09–7.39 (m, 9H, Ar-H), 7.60 (s, 1H, NH), 7.90 (s, 1H, NH); ¹³C NMR (125 MHz, DMSO d₆): 36, 104, 116, 118, 123, 123, 125, 125, 126, 126, 127, 131, 140, 152, 164, 165; ESI-MS: m/z calculated for C₁₇H₁₂N₂O₃ 292.29 found [M]⁺ 292.3.

4-(4-Chlorophenyl)-3,4-dihydro-2H-chromeno[4,3-d]pyrimidine-2,5(1H)-dione (6b). 4-Pheny off white powder, mp 195–197 °C (reported 197–198 °C);^{43 1}H NMR (500 MHz, DMSO d₆): δ_H 6.28 (s, 1H), 7.13 (d, 2H, J = 8.5 Hz, Ar-H), 7.54–7.34 (m, 6H, Ar-H), 7.56 (s, 1H, NH), 7.87 (s, 1H, Ar-H); ¹³C NMR (125 MHz, DMSO d₆): 35, 104, 116, 118, 123, 128, 128, 129, 130, 131, 132, 137, 139, 152, 164, 165; ESI-MS: m/z calculated for C₁₇H₁₁ClN₂O₃ 326.73 found [M]⁺ 326.73.

4-Phenyl-2-thioxo-1,2,3,4-tetrahydro-5H-chromeno[4,3-d]pyrimidine-5-one (6c). Off white powder, mp 185–187 °C (reported 188–190 °C);^{42 1}H NMR (500 MHz, DMSO d₆): δ_H 6.34 (s, 1H, –CH), 7.24–7.39 (m, 9H, Ar-H), 7.82 (s, 1H, Ar-H), 8.09 (s, 1H, Ar-H); ¹³C NMR (125 MHz, DMSO d₆): 36, 103, 115, 119, 123, 123, 124, 127, 131, 132, 145, 150, 152, 164, 166; ESI-MS: m/z calculated for C₁₇H₁₂N₂O₂S 308.35 found [M]⁺ 308.35.

4-(4-Dimethyaminophenyl)-2-thioxo-1,2,3,4-tetrahydro-5H-chromeno[4,3-d]pyrimidine-5-one (6d). Off white powder, mp 232–234 °C (reported 232–234 °C);^{42 1}H NMR (500 MHz, DMSO d₆): δ_H 3.11 (s, 6H, N(CH₃)₂), 6.26 (s, 1H, –CH), 7.17–7.28 (m, 4H, Ar-H), 7.49–7.56 (m, 4H, Ar-H), 7.69 (s, 1H, NH), 7.80 (s, 1H, NH); ¹³C NMR (125 MHz, DMSO d₆): 36, 45, 103, 111, 115, 119, 123, 123, 124, 124, 128, 131, 153, 164, 167; ESI-MS: m/z calculated for C₁₉H₁₇N₃O₂S 351.42 found [M]⁺ 351.42.

7-(2-Hydroxyphenyl)-7,12-dihydro-6H-chromeno[4,3-d][1,2,4]triazolo[1,5-a]pyrimidin-6-one (8). Off white powder, mp 210–212 °C; ¹H NMR (500 MHz, DMSO d₆): δ_H 6.26 (s, 1H, –CH), 6.89–6.69 (m, 2H, Ar-H), 7.40–7.51 (m, 4H, Ar-H), 7.69–7.75 (m, 2H, Ar-H), 7.88 (d, 1H, J = 7.5 Hz, Ar-H), 8.35 (s, 1H, =CH), 10.38 (s, 1H, OH); ¹³C NMR (125 MHz, DMSO d₆): 36, 102, 116, 116, 118, 119, 123, 125, 128, 129, 130, 133, 135, 143, 153, 158, 158; ESI-MS: m/z calculated for C₁₈H₁₂N₄O₃ 332.3 found [M]⁺ 332.3.

Acknowledgements

We are grateful thanks to SAIF Punjab University Chandigarh, India spectral analytical data.

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c6ra10801f

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