Eco-friendly grinding synthesis of a double-layered nanomaterial and the correlation between its basicity, calcination and catalytic activity in the green synthesis of novel fused pyrimidines

Abstract

The synthesis of hydrotalcite using Al : Mg molar ratios of 1.0 : 3.0 by a grinding method at room temperature is reported. The prepared hydrotalcite was characterized by TG, FT-IR, SEM, XRD and Hammett titration method. The calcined hydrotalcite with a Mg : Al molar ratio of 3 : 1 derived from calcinations at 750 K was found to be a suitable catalyst that can give the highest basicity and the best catalytic activity for this synthesis. The effect of the molar ratio, catalyst loading, reaction time and basicity was investigated in the facile, efficient and green synthesis of novel fused pyrimidines by a three-component reaction of 4-hydroxy coumarin, aldehydes and 2-amino benzothiazole under solvent-free conditions for the first time. The influence of the hydrotalcite and the different amounts of it on reactivity was studied. It was found that the best yield was obtained with 80 mg of catalyst loading in the least time as compared to the other catalysts used. This protocol reported herein represents a rapid and cost-effective route for the synthesis of hydrotalcites and reports on their versatile applications for the synthesis of densely functionalized novel fused pyrimidines.

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Introduction

Pyrimidine and its derivatives have been studied for several years because of their chemical and biological significance. They have been reported as antiviral, antitumour, anti-inflammatory, antihypertensive activities,^1–3 calcium channel modulators,⁴ and antimicrobial agents.^5–7 Numerous heterocyclic systems fused with pyrimidines are known for their important biological activities.⁸ Some chromenopyrimidine derivatives show antiplatelet and antithrombotic activities.⁹ They also exhibit various types of biological activity, including analgesic,¹⁰ antibiotic,¹¹ cytotoxic¹² and antitumour properties.¹³ The thiazole moiety is a prevalent scaffold in a number of naturally occurring and synthetic molecules with attractive biological activities, such as antiviral, anticancer, antibacterial, antifungal, anticonvulsant, antiparkinsonian and anti-inflammatory, that are well illustrated by the large number of drugs in the market containing this heterocyclic moiety.^14–21 Coumarin derivatives, which are widely distributed in plants,²² have been extensively investigated as anticoagulation, antiviral,²³ anti-inflammatory,²⁴ antibacterial²⁵ and anticancer agents.²⁶

Layered double hydroxides (LDHs), which are referred to as anionic clays in comparison with cationic clays and also as hydrotalcite-like compounds (HT), are an important class of ionic lamellar solid. LDHs have the general formula [M(_1−x)²⁺M_x³⁺(OH)₂]^y+[Aⁿ⁻]_y/n]·mH₂O, where M²⁺ and M³⁺ are divalent (Mg²⁺, Zn²⁺, Ni²⁺, etc.) and trivalent cations (Al³⁺, Cr³⁺, etc.), and x is normally between 0.17 and 0.33.²⁷ The main property of hydrotalcites is their anion exchange capacity, which makes them unique inorganic materials to intercalate organic or inorganic anions.²⁸ Hydrotalcites are increasingly regarded as a good alternative to the traditional homogenous base catalysts, such as NaOH and KOH, for several base-catalyzed reactions that are important for the pharmaceutical and fragrance industries,²⁹ as electrode modifiers and catalyst supports.³⁰ A well-documented example is the isomerization of eugenol and safrole.³¹ Their structure consists of positively charged brucite (magnesium hydroxide)-like layers with an interlayer space containing charge compensating anions and water molecules.³² As far as green chemistry is concerned, hydrotalcites offer several advantages over the traditional corrosive, dissolved catalysts, such as easy separation from the reaction mixture, recycling possibilities and decreased corrosion of the reactor.³³

The variety of applications of hydrotalcite-based materials is virtually unlimited. Hydrotalcites can be implicated in the preparation of catalysts dedicated to the production of H₂,³⁴ a wide range of organic compounds³⁵ and the production of biodiesel by the trans-esterification of triglycerides with methanol.³⁶ In addition to the above, numerous experimental investigations have been published on the use of hydrotalcites for catalytic applications.³⁷ A study on the synthesis of hydrotalcites has received considerable attention, and to date, various methods have been reported, including the salt-oxide method,³⁸ co-precipitation method,³⁹ induced hydrolysis,⁴⁰ reconstruction,⁴¹ anion-exchange⁴² sol–gel⁴³ and hydrothermal treatment.⁴⁴ Various authors^43,45,46 reported a synthetic hydrotalcite preparation at high temperature (325–350 °C) and in a long duration synthesis (18 h). However, co-precipitation at a fixed pH is the most commonly used method. The purpose of the present work was to develop a new green method that is simple, more economical, free of impurities and industrially feasible. Thus, the present method fulfils the requirements of rapid synthesis and good quality.

Therefore, as a part of our ongoing research aimed at the development of new catalysts and their application in the synthesis of heterocycles,⁴⁷ we report herein a rapid and cost-effective method (grinding method) for the synthesis of hydrotalcite, and furthermore, we demonstrate it in the synthesis of novel fused pyrimidines via a three-component reaction under solvent-free conditions.

Results and discussion

Characterization of the hydrotalcite

The IR spectra (Fig. 1) show absorption bands at higher wavenumbers of 3695 and 3471 cm⁻¹, which are assigned to the O–H stretching vibrations of water bonded to M₃OH units. The shorter O–H bonds existing in the hydrotalcite causes an increase in electrostatic attraction within the hydrotalcite layers.⁴⁸ The weak bands at 2930 cm⁻¹ and 2880 cm⁻¹ suggest strongly hydrogen bonded water molecules to interlayer anions such as carbonates.⁴⁹ Hydrotalcites containing physically adsorbed water give strong water deformation modes at 1631 cm⁻¹. This is attributed to adjacent water molecules in the hydrotalcite interlayers.⁴⁸ The band at 1364 cm⁻¹ was assigned to a carbonate bonded to the hydroxyl surface of the hydrotalcite.⁴⁹ The band at 1024 cm⁻¹ was assigned to the symmetric stretch of the free carbonate canions.⁴⁸ The band at 777 cm⁻¹ was assigned to the bending vibration of free carbonate anions. The IR absorption band at 443 cm⁻¹ was assigned to Al–O bonds.⁵⁰

Fig. 1 FT-IR spectra of the hydrotalcite (Mg–Al–CO₃).

Fig. 2 presents the XRD pattern of the hydrotalcites as well as the product of their thermal decomposition. The obtained results reveal that the prepared sample had a hexagonal structure with peaks characteristic of hydrotalcite. The Mg : Al atomic ratio was measured using X-ray microanalysis and was found to be 3.16, which is in good agreement with the metallic ratio (3.0) taken in solution. The value of x [x = M^III/M^II + M^III] was found to be 0.24, which suggest the purity of the hydrotalcite.⁵¹ Thermal treatment of the sample resulted in the change of the chemical composition and phase content. It should be noticed that both the interlayer and weakly absorbed water were removed from the hydrotalcite sample at these temperatures (Fig. 2). The presence of a CO₃²⁻ anion in the interlayer gallery of the hydrotalcite was confirmed by the characteristic basal spacing d₀₀₃ = 7.76 Å and indicates a gallery height of 2.96 Å with the crystalline material.⁵² The ordering is achieved also in the stacking direction, as the (003), (006) and (009) diffraction lines become sharper and more intense. The crystallite size of this sample was found to be 24.87 nm as calculated using Scherrer's formula.⁵³ More intensive and sharper reflections of the (003) and (006) planes was found at low 2θ values (11–23°). Fig. 2 shows a typical SEM image of the Mg–Al–CO₃ hydrotalcite. As seen in this figure, the lamellar particles have a rounded hexagonal shape and are typical of a hydrotalcite-like material, which confirms the structure of the hydrotalcite; furthermore, the material was found to be mesoporous, with a surface area of 90 m² g⁻¹. Electron microscopy was chosen as a convenient tool to investigate the morphology of hydrotalcite-based materials and to investigate the effect of the preparation parameters on their morphology.

Fig. 2 XRD pattern and SEM image of hydrotalcite (Mg–Al, 3 : 1).

The TG graph (Fig. 3) of the hydrotalcite (Al : Mg : CO₃) exhibits a total mass of 38.26% at 330–570 °C, and other mass losses at 60–230 °C, 230–330 °C and 570–670 °C, respectively. The TG results indicate that the hydrotalcite (Al : Mg : CO₃) is thermally stable up to 230 °C.⁵⁴ The second mass loss between 223 and 330 °C was ascribed to the dehydroxylation of the brucite-like layers along with anion decomposition, leaving a Mg, Al oxo-hydroxide up to 330 °C. Finally, the third mass loss was assigned to progressive elimination of hydroxyl ions and the production of metal oxides and a spinel structure.

Fig. 3 DTG curve of hydrotalcite (Mg–Al, 3 : 1).

The powder X-ray diffractogram of the Ca–Al–CO₃ LDH sample given in Fig. 4 shows the structure of the hydrotalcite, displaying the characteristic reflection of (i) sharp and intense basal reflections of the 003 and 006 planes in the low angle, and (ii) intense reflections of the 009, 110 and 113 planes from the middle to the end angle. The LDH samples synthesized under different synthetic parameter have a similar structure; however, variations in the interlayer d-spacing of the characteristic 003 planes (d₀₀₃), the crystallinity, and other structural features were observed to be affected by the synthesis parameters. The metallic ratios for Ca–Al–CO₃ were observed by powder X-ray diffractometer and found to be 3 : 2 : 1. According to X-ray diffraction patterns, as shown in Fig. 4, the LDHs Ca–Al–CO₃ sample have good systematic, narrow, sharp strong lines at low 2θ values (peaks close to 2θ = 11°, 24°, and 35°; ascribed to diffraction by the basal planes (003), (006) and (009), respectively) on the one hand, but broad and asymmetric ones at high 2θ values (peaks close to 2θ = 38°, 46°, and 60°; ascribed to diffraction by the (105), (108) and (110) planes,⁵⁵ which are characteristic of clay minerals with a layered structure). Generally, the sharpness and intensity of the XRD peak is considered to be proportional to the crystallinity. A characteristic basal spacing d₀₀₃ of 3.38 Å was confirmed in the interlayer gallery of the hydrotalcite. By XRD, the crystallite size of this sample was observed to be 47.025 nm. Fig. 4 shows the typical SEM image of Ca : Al LDH (3 : 1 molar ratio). As seen in this figure, the existing lamellar comprises almost homogeneous spherical aggregates with a hexagonal shape, which is the typical structure of hydrotalcite-like materials. However, big needle shaped particles are also shown. The LDH material shows high crystallinity, which shows a uniform distribution in the support.

Fig. 4 P-XRD pattern and SEM image of hydrotalcite (Ca–Al, 3 : 1).

Chemistry

To optimize the reaction conditions, a model reaction of 4-hydroxy coumarin, benzaldehyde and 2-aminobenzothiazole was carried under solvent-free conditions. Under neat conditions, the reaction yield of the target product was too low, even when the reaction was performed at 90 and 120 °C for 10 h (Table 1, entries 2 and 3). Furthermore, to identify the best catalyst, different model reactions were performed with many catalysts, including hydrotalcites (Mg–Al–CO₃ and Ca–Al–CO₃) and different metal oxides, hydroxides and chlorides. The best result was obtained with Mg–Al hydrotalcite (Table 1, entry 4), while a slightly lower yield was obtained with Ca–Al hydrotalcite (Table 1, entry 5), and the other catalysts gave moderate yields of desired product (Table 1, entries 6–11). Mg–Al hydrotalcite catalyzes the reaction efficiently in a short reaction time and with a good yield. In order to evaluate the appropriate catalyst loading, a model reaction of benzaldehyde, 4-hydroxy coumarin and 2-aminobenzothiazole was carried out using 10 mg, 20 mg, 50 mg, 80 mg and 100 mg of hydrotalcite at 70 °C under solvent-free conditions (Table 1, entries 12–16). It was found that the reaction times and yields varied. On changing the amount of catalyst from 10–50 mg, the reaction time decreased and the yield increased. On the other hand, there was no significant improvement in reaction time and yield using a higher quantity of catalyst (100 mg). So, 80 mg of hydrotalcite as the catalyst was found to be the optimal quantity and was sufficient to catalyze the reaction at 70 °C under solvent-free conditions for the synthesis of chromeno[4,3-d]benzothiazolo[3,2-a]pyrimidin-6(7H)-one.

Table 1 Optimization of the reaction conditions^a

Entry	Catalyst (in gram)	Time (h)	Temperature (°C)	Yield^b% of 4a
a Reaction conditions: benzaldehyde (0.0025 mol), 4-hydroxy coumarin (0.0025 mol) and 2-amino benzothiazole (0.0025 mol), solvent-free conditions.b Isolated yield.
1	Neat	10	70	15
2	Neat	10	90	17
3	Neat	10	120	16
4	Mg–Al–CO3, HT (0.08)	2.0	70	95
5	Ca–Al–CO3, HT (0.08)	2.0	70	86
6	AlCl3 (0.133)	5.0	70	55
7	MgCl2 (0.095)	4.0	70	62
8	Mg(OH)2 (0.058)	4.0	70	41
9	Al(OH)3 (0.078)	4.5	70	53
10	Ca(OH)2 (0.074)	4.0	70	55
11	Al2O3 (0.101)	4.5	70	60
12	Mg–Al–CO3, HT (0.01)	6.0	70	78
13	Mg–Al–CO3, HT (0.02)	4.0	70	85
14	Mg–Al–CO3, HT (0.05)	3.0	70	89
15	Mg–Al–CO3, HT (0.08)	2.0	70	95
16	Mg–Al–CO3, HT (0.10)	2.0	70	95

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The methodology involves the multi-component reaction of benzaldehyde (0.0025 mol), 4-hydroxy coumarine and 2-amino benzothiazole (0.0025 mol) using hydrotalcite (Mg–Al–CO₃) as a catalyst and resulted in product formation within 2–3 h (Scheme 1). The structure of chromeno[4,3-d]benzothiazolo[3,2-a]pyrimidin-6(7H)-one was confirmed by ¹H NMR, ¹³C NMR, mass spectra and elemental analyses. The NMR spectra of the product 4a was characterized by a singlet at 6.39 δ due to the C–H hydrogen and a multiplet at 7.05–7.17 δ, a triplet at 7.17 δ and a multiplet at 7.22–7.30 δ for three, two and four aromatic hydrogens, The hydrogen of the aromatic ring of benzothiazole exhibits a multiplet at 7.38–7.51 δ. The mass spectra of product 4a show a molecular ion peak at 383, supported by the good agreement with CHN elemental analysis. This supports the probable structure of product 4a. Other derivatives show the corresponding pattern, and the only difference is an additional peak that arises due to substitution at the aromatic ring of the aldehyde moiety in compounds such as, which demonstrated two additional peaks at 6.38 and 6.75 δ due to the two =CH and compound 4d, which showed a singlet at 3.08 δ for six hydrogens of the –N(CH₃)₂ group. A variety of electron-donating and electron-withdrawing groups on the aromatic aldehydes and benzothiazole have been studied (4a–4o) Table 2.

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

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

R	R1	R2	Product	Yield^a (%)	Time (h)	M.P. (°C)
a Isolated yield.
–C6H5	H	H		95	2.0	200–202
–C6H5–CH=CH	H	H		78	2.0	180–182
4-Cl–C6H5	H	H		86	2.5	188–190
4-N(CH3)2–C6H5	H	H		83	1.5	160–162
3-OH–C6H5	H	H		89	2.0	210–212
4-OMe–C6H5	H	H		94	1.5	234–236
4-Me–C6H5	H	H		95	1.5	>250
4-NO2–C6H5	H	H		90	2.0	>250
2-Me–C6H5	H	H		91	1.5	>250
2-OCH3–C5H6	H	H		90	2.0	210–212
4-OH–C6H5	H	H		95	1.5	>250
4-Cl–C6H5	Me	H		90	2.0	184–186
–C6H5	NO2	H		88	1.5	215–217
4-Me–C6H5	H	Cl		81	1.5	225–227
4-Br–C6H5	Me	Cl		79	1.5	>250

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Recyclability and reusability of hydrotalcite

For studying the recyclability and reusability, a model reaction was carried out using benzaldehyde, 4-hydroxy coumarin and 2-aminobenzothiazole by incorporating 80 mg of hydrotalcite as a catalyst (Fig. 5). After completion of the reaction, the contents were filtered to recycle the hydrotalcite catalyst. To remove any organic impurities, recycled hydrotalcite was washed with methanol. Mg^II hydrotalcite catalyst could be readily recovered and reused for at least five runs without any significant loss of activity (Table 3).

Fig. 5 Recyclability and reusability of hydrotalcite catalyst.

Table 3 Reusability of hydrotalcite (Mg–Al–CO₃, HT)

Entry	Number of runs	Time (h)	Yield^a (%)
a Isolated yield.
1	Fresh HT	2.0	95
2	HT (recycle I)	2.0	94
3	HT (recycle II)	2.5	94
4	HT (recycle III)	2.5	93
5	HT (recycle IV)	2.5	92

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Leaching test

The filtrate was analyzed for leached metal content by ICP emission spectroscopy. No metal was detected. These results confirmed that metal leaching did not occur. Furthermore, the Mg–Al mixed oxide was found to be thermally and mechanically stable and no significant difference was observed in particle size and morphology of the used catalyst, as evidenced by SEM.⁵⁶ To ensue the sustainability of the structure of the recovered hydrotalcite (Fig. 6), XRD analysis was carried out and showed its similar profile to the fresh catalyst, which confirmed that the layered structure of hydrotalcite was maintained after the reaction.

Fig. 6 XRD pattern of recovered hydrotalcite.

SEM analysis and effect of ageing time

To test if the ageing time could influence the crystal growth kinetically or thermodynamically, we considered ageing time as a parameter to control the particle size. To visualize the influence of ageing time on the crystallinity of the material, SEM images of the hydrotalcite samples at a Mg/Al molar ratio of 3.0 were recorded. The SEM images at different ageing times are shown in Fig. 7. A well-developed layered and platelet structure of the hydrotalcite is shown in the SEM image. The crystallinity of the hydrotalcite was observed to increase slowly up to 3 h at a temperature of 110 °C (the hydrothermal treatment temperature), followed by a sharp increase in the time range 6–9 h. On the other hand, poor crystallinity was observed at 0 h ageing time. The observations from the SEM images were in good agreement with the P-XRD pattern. These results confirmed an increase in the crystallinity of hydrotalcite sample at a Mg/Al ratio of 3.0 under hydrothermal treatment. From the results, it is clear that the crystallinity of the hydrotalcite sample depends on the ageing time and temperature conditions. The crystalline size of the hydrotalcite sample increased on increasing the ageing time. It seems that the ageing time has an effect on particle size, and it is thought that the particles may go through further crystal growth or intergrowth into larger particles (secondary particles) by the aggregation of primary particles upon ageing. High crystallinity prevented the formation of a poorly lamellar structure, and loss of the lamellar structure was the main cause of the catalyst deactivation.

Fig. 7 SEM image of hydrotalcite with Mg/Al (3 : 1) at different ageing times at 110 °C.

Surface area measurement and XPS analysis

The surface area of the hydrotalcite samples was determined from the N₂ adsorption data measured at 77 K. The samples were activated at 80 °C for 4 h under vacuum prior to the N₂ adsorption measurements. The specific surface areas of the samples were calculated from the N₂ adsorption isotherms according to the BET method, and are shown in Table 4. As seen in Table 4 and Fig. 9, as the metallic ratio of Mg/Al increases from 1 : 1 to 3 : 1, the surface area (Table 1) and basicity (Fig. 9) also increase.

Table 4 Specific surface area of synthesized hydrotalcite (Mg/Al)

S. N.	Mg/Al ratios	SBET (m^2 g^−1)
1	1 : 1	78
2	2 : 1	84
3	3 : 1	92

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XPS measurements were performed using a Kratos AXIS HSi instrument equipped with a charge neutralizer and a Mg Kα X-ray source. Spectra were recorded at normal emission using an analyser pass energy of 20 eV and X-ray power of 144 W, and were energy referenced to the valence band and adventitious carbon. The surface composition of Mg–HT (before and after use) was studied by X-ray photoelectron spectroscopy (XPS) analysis (Fig. 8). The corresponding Mg 2p and Al 2s spectra are shown in Fig. 8(a) and (b). Both Fig. 8(a) and (b) exhibit a single broad feature indicative of a unique chemical environment. As the Mg²⁺ content rose across the series from Mg/Al (1 : 1) to Mg/Al (3 : 1), the binding energies of both features decreased. The Al 2 s BE (binding energy) for Mg/Al (3 : 1) was 119.1 eV, close to that of pure Al₂O₃ at 119.4 eV, and progressively shifted downwards to 118.5 eV for the Mg/Al (3 : 1) sample. The Mg 2p binding energy (BE) of the hydrotalcites likewise fell from 49.9 eV to 49.5 eV, approaching that of pure MgO at 49.0 eV. These changes reflect the change in intra-layer electron density in the ‘brucite-like’ layer as Mg²⁺ is replaced by Al³⁺. The O 1s for Al₂O₃ exhibited a single state at 530.9 eV binding energy (BE), characteristic of the hydroxyl environment.⁵⁷ The O 1s binding energy changes with chemical composition, suggesting that the chemical form of the surface oxygen species depends on the chemical composition. Peak deconvolution and fitting revealed these comprise two well-defined components: the parent state at 530.9 eV, together with a new lower binding energy feature at ∼529.3 eV, characteristic of O²⁻.⁵⁸ The increase in O²⁻ character is consistent with the incorporation of Mg²⁺ centres into the hydrotalcite framework, and also in line with the Hammett basicity measurements shown in Fig. 9 and 10, which show that the strength of the strongest base sites of these materials increases with the Mg content.

Fig. 8 (a) Mg 2p XP spectra, (b) Al 2s XP spectra for hydrotalcite materials and O 1s XP spectra.

Fig. 9 Basicity of hydrotalcite with different metal ratios.

Fig. 10 Basicity of 3.0 hydrotalcite at different temperatures.

The surface composition of the MgO, Al₂O₃ and Mg(1 − x)Al_xO samples was measured by XPS. The XPS quantitative analysis results have been incorporated in Table 5. The binding energy (Table 5, column 2) changes with chemical composition, suggesting that the chemical form of the surface oxygen species depends on the chemical composition. The measured O 1s binding energy increases as the Al content increases. The amount of surface oxygen also depends on the chemical composition. As expected, the Al_s and Mg_s values follow qualitative trends that parallel the bulk sample composition. As x increases, Al_s increased and Mg_s decreased (Table 5). As the Al content in HT samples increased; however, the Al_s/Al_b ratios decreased and Mg_s/Mg_b ratios increased. In HT samples with a low Al content, Mg_s/O_s ratios were very similar to those in MgO, but these ratios decreased as the Al content increased. The Al_s/O_s ratios were between 0.3 and 0.6 in all the samples; these values are much lower than in pure Al₂O₃ (0.81).

Table 5 Surface composition of hydrotalcite by XPS analysis

Samples	Surface composition
	O 1s B. E.^a (eV)	Mgs/Mgb	Als/Alb	Als/Os	Mgs/Os
a Binding energy.
MgO	529.3	1.04	—	—	1.10
Mg/Al (1 : 1)	530.6	1.38	1.44	0.35	0.91
Mg/Al (2 : 1)	530.8	1.65	1.38	0.40	0.50
Mg/Al (3 : 1)	531.2	2.50	1.20	0.63	0.70
Al2O3	530.9	—	1.12	0.81	—

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Basicity of hydrotalcite

The basicity of the catalyst was determined using the Hammett indicator and benzoic acid titration method.⁵⁹ From the results of Fig. 9, the basic strength of all the samples was found to be in the range of 9.3–15.0. The basicity results also revealed that calcined hydrotalcite possesses different types of surface basic sites, with the main basic sites H_ in the range of 7.2–9.8 and the other sites with H_ in the range of 9.8–15.0. Results were also reported by Di Cosimo et al.⁶⁰ that suggested that calcined hydrotalcite contains outer surface basic sites of Mg/Al metal, while pure MgO possesses strong basic sites consisting predominantly of surface oxygen. The Hammett titration method was proven in the above study by our present experimental. Our results also revealed that the basic site responsible for the basicity of the hydrotalcite plays a vital role.

Furthermore, we found out from our study that basicity is related with the loading of the molar ratios of the Mg/Al metal contents. The results clearly demonstrate that the total basicity of the hydrotalcite (sample) increases gradually up to the optimum limit of the molar ratios of Mg/Al. Because the total basicity increases as the Mg/Al molar ratios reach up to the maximum value of 3.0, but the molar ratios increase from 3.0, it decreases further, with a resultant loss in the catalytic activity of the hydrotalcite. Our experimental studies were also proven quantitatively by other research, which have found similar trends as in the present study.⁶¹ Nakatsuka et al.'s^61a and Fishel and Davis'^61b groups also measured the number of basic sites or the basicity by titration with benzoic acid and by the TPD of CO₂, respectively, and found similar results in that a maximum basic site density was observed at a Mg/Al ratio of 2.6 and 3.0, respectively. So, a molar ratio of Mg/Al of 3.0 was found to be optimum for the best results and, therefore, we measured the basicity of 3.0 HT calcined at different temperatures. From our study or data (Fig. 10), it was clearly proven that a 750 K calcinations temperature was optimum because of the maximum basicity (reaching 3.6 mmol g⁻¹) being reached at this temperature. Below 573 K and above 750 K temperature, the basicity level was too low. In terms of the catalytic activity of hydrotalcite, basicity plays a major role and it could be expected that the catalytic activity increases with an increase in the basicity.

A plausible mechanism for the synthesis of chromeno[4,3-d]benzothiazolo[3,2-a]pyrimidin-6(7H)-one derivatives (4) is given in Scheme 2. In the beginning, the mechanism involves Knoevenagel condensation of the 4-hydroxycoumarin (1) and aldehyde (2) in the presence of hydrotalcite, producing an intermediate, whereby the basic sites of the catalyst abstract an acidic proton of malononitrile and then a subsequent attack on the carbonyl group furnishes the condensed product I.⁶² This is followed by the Michael addition of 2-aminobenzothiazole (3) to the C=C bond of intermediate (A) to 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 then affords the desired compounds (4) on dehydration.

Scheme 2 A plausible reaction mechanism.

Materials and methods

Experimental

The ¹H NMR spectra were measured using a 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 a SHIMADZU IR spectrometer for a sample dispersed in a KBr pellet or Nujol, reported in terms of the frequency of absorption (cm⁻¹). E-Merck pre-coated TLC plates and RANKEM silica gel G were used for the preparative thin-layer chromatography. All melting points were determined in open capillaries and are uncorrected. AR grade 4-hydroxy coumarin, aldehydes and other catalysts were purchased from Himedia Laboratory Ltd., Mumbai, India. 2-Amino benzothiazole was purchased from Sigma Aldrich and used without further purification.

Preparation of hydrotalcite (HT)

Typical procedure. Al₂O₃ (1.02 g) was suspended in distilled water (2 ml) and magnesium hydroxide (3.5 g) was added to the mixture, and the contents were stirred giving a pH of 8. Then, sodium bicarbonate (2.4 g) was added to bring the pH of the mixture to 10. The mixture was ground with a mortar and pestle for 5 min at room temperature, and the resulting white product was filtered and repeatedly washed with distilled water and dried at 100 °C.

Typical procedure for the synthesis of fused pyrimidines (4a–4o). A mixture of aldehydes (0.0025 mol), 4-hydroxycoumarin (0.0025 mol) and 2-amino benzothiazole (0.0025 mol) were heated at 70 °C under solvent-free conditions using hydrotalcite as a catalyst. After completion of the reaction (by TLC analysis), the reaction mixture was cooled to room temperature and poured into cold water. Then, the solid mass obtained was dissolved in ethanol and filtered. The solid hydrotalcite was separated out as a solid. The product was recrystallized in ethanol. Hydrotalcite was washed with ethanol to remove organic impurities.

Reusability of the hydrotalcite

Recycled hydrotalcite was reused for five times as such with a mixture of aldehydes (0.0025 mol), 4-hydroxycoumarin (0.0025 mol) and 2-amino benzothiazole (0.0025 mol) at 70 °C. The yield and time taken in each of the five runs are given in Table 3.

Characterization data

7-Phenylchromeno[4,3-d]benzothiazolo[3,2-a]pyrimidin-6(7H)-one (4a). White powder, mp 200–202 °C; ¹H NMR (500 MHz, DMSO d₆): δ_H 6.23 (s, 1H, –CH), 7.05–7.17 (m, 3H, Ar-H), 7.17 (t, 2H, J = 8.0 Hz, Ar-H), 7.22–7.30 (m, 4H, Ar-H), 7.38–7.51 (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]⁺ 383.

7-Styrylchromeno[4,3-d]benzothiazolo[3,2-a]pyrimidin-6(7H)-one (4b). Light brown crystal, mp 180–182; ¹H NMR (500 MHz, DMSO d₆): δ_H 5.63 (s, 1H, –CH), 6.26 (d, 1H, =CH), 6.70 (d, 1H, =CH), 7.19–7.38 (m, 8H, Ar-H), 7.58 (t, 2H, J = 7.5 Hz, Ar-H), 7.84 (t, 3H, J = 8.0 Hz, Ar-H); ¹³C NMR (125 MHz, DMSO d₆): 65, 101, 102, 103, 112, 114, 116, 117, 120, 122, 124, 128, 129, 131, 133, 137, 144, 151, 152, 157, 161, 163, 164, 167; 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; 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), 7.39–7.62 (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; 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), 7.59 (t, 2H, J = 7.5 Hz, Ar-H), 7.86 (d, 2H, J = 7.5 Hz, Ar-H); ¹³C NMR (125 MHz, DMSO d₆): 45, 65, 103, 111, 114, 115, 118, 118, 119, 121, 123, 124, 125, 126, 128, 131, 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; 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), 7.22–7.28 (m, 4H, Ar-H), 7.41–7.51 (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; 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), 7.16–7.43 (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; 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; ¹H NMR (500 MHz, DMSO d₆): δ_H 6.17 (s, 1H, –CH), 7.20–7.25 (m, 5H, Ar-H), 7.29 (d, 2H, J = 7.0 Hz, Ar-H), 7.50 (t, 2H, J = 7.5 Hz, Ar-H), 7.81 (d, 2H, J = 7.5 Hz, Ar-H), 8.13 (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]⁺ 429.

7-(2-Methylphenyl)chromeno[4,3-d]benzothiazolo[3,2-a]pyrimidin-6(7H)-one (4i). Off white powder, mp > 250 °C; ¹H NMR (500 MHz, DMSO d₆): δ_H 2.61 (s, 3H, CH₃), 6.37 (s, 1H, –CH), 7.21–7.25 (m, 4H, Ar–H), 7.29 (t, 2H, J = 7.0 Hz, Ar-H), 7.46 (t, 2H, J = 7.5 Hz, Ar-H), 7.86 (d, 2H, J = 7.5 Hz, Ar-H), 8.13 (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; ¹H NMR (500 MHz, DMSO d₆): δ_H 3.73 (s, 3H, OCH₃), 6.24 (s, 1H, –CH), 6.78 (d, 2H, J = 7.0 Hz, Ar-H), 7.19–7.31 (m, 4H, Ar-H), 7.53 (t, 2H, J = 7.5 Hz, Ar-H), 7.71 (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; ¹H NMR (500 MHz, DMSO d₆): δ_H 6.16 (s, 1H, –CH), 6.54 (d, 1H, J = 7.5 Hz, Ar-H), 6.86 (d, 1H, J = 7.5 Hz, Ar-H), 7.19–7.26 (m, 4H, Ar-H), 7.35–7.51 (m, 4H, Ar-H), 7.80 (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; 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), 7.24–7.35 (m, 4H, Ar-H), 7.55–7.59 (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 + H]⁺ 431.

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; ¹H NMR (500 MHz, DMSO d₆): δ_H 6.37 (s, 1H, –CH), 7.27 (t, 2H, J = 8.0 Hz, Ar-H), 7.33 (d, 2H, J = 8.5 Hz, Ar-H), 7.40 (d, 2H, J = 8.5 Hz, Ar-H), 7.56 (t, 2H, J = 8.0 Hz, Ar-H), 7.84 (d, 2H, J = 8.0 Hz, Ar-H), 8.09 (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]⁺ 427.5.

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; 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), 7.25–7.36 (m, 4H, 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; ¹H NMR (500 MHz, DMSO d₆): δ_H 2.23 (s, 3H, CH₃), 6.29 (s, 1H, –CH), 7.09–7.23 (m, 8H, Ar-H), 7.32 (t, 2H, J = 7.5 Hz, Ar-H); ¹³C NMR (125 MHz, DMSO d₆): 22, 66, 104, 107, 113, 117, 125, 126, 128, 129, 130, 130, 134, 143, 151, 155, 162, 164; ESI-MS: m/z calculated for C₂₄H₁₄BrClN₂O₂S 509.80 found [M]⁺ 509.8.

Acknowledgements

We are grateful thanks to Chandigarh and Punjab University, Chandigarh for spectral analytical data.

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c6ra08111h

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