S-Nanoparticle/SDS: an efficient and recyclable catalytic system for synthesis of substituted 4H-pyrido[1,2-a]pyrimidines in aqueous admicellar medium

Abstract

A novel and green methodology has been described for the synthesis of substituted 4H-pyrido[1,2-a]pyrimidines under admicellar catalysis by sulfur nano-particles that can be efficiently recycled up to the fifth run. The greenness of the procedure was well established, as organic solvent was avoided in the reaction media as well as in the preparation of catalyst.

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Due to increasing concerns on toxic organic solvents and their deleterious effects on human health and the environment, the use of water as a green solvent has grabbed considerable interest in recent years.¹ Water, being inexpensive, readily available, non-toxic and non-flammable, is close to being an ideal solvent from both an environmental and economical point of view. Moreover its unique properties like high dielectric constant, extensive hydrogen bonding and cohesive energy density exhibit enhancements of rate and selectivity of numerous organic reactions.² As a result, many efforts have been devoted toward the development of catalytic processes using water as a reaction medium to accomplish greener synthesis. Though, water has various advantages but its use in reactions has remained limited because of the low solubility of organic substrate and instability of the most of catalysts in it. To overcome these drawbacks various surfactants have been used which promotes the organic reactions efficiently through the formation of micelles.³

Recently in aqueous medium a new reaction template, termed admicelles have been proposed by the adsorption of surfactant on solid–liquid interfaces of nano particles.⁴ Again, the utilization of nanoparticles in organic transformations is of considerable current interest because of their high surface area and their highly active surface atoms compared to the bulk materials.⁵ Furthermore, due to numerous advantages like high catalytic activity, economical feasibility, eco friendliness, operational simplicity and easy recoverability their use as heterogeneous catalysts is quite encouraging.⁶ However, in the case of nano catalysts a major drawback is their self-aggregation especially in aqueous media which leads to the formation of larger particles having low catalytic activity. Addition of a small quantity of surfactant can resolve this problem by producing admicelles along with increasing solubility of organic compounds. Presence of hydrophobic core inside admicelles provides a region which has ability to solubilize water-insoluble organic substrates. This phenomenon is referred as ‘adsolubilization’ or ‘surface solubilization’.⁷ Thus on the surface of the nano particles a reaction template is formed where nano catalyst accelerates the reactions under admicellar environment. Formation of admicelles have been widely utilized in many practical applications, including flotation, petroleum recovery, food science, agriculture etc.⁸ and can provide a notable improvement in outcome of many reactions via conventional admicellar catalysis.⁹

Among a wide choice of nanoparticles in admicellar catalysis, sulfur-based nanoparticles are cheaper, ubiquitous and eco-friendly. Since, these nanoparticles are non-metallic in nature and are often recovered easily from the reaction mixture, thus they may be considered as safe, cost effective as well as greener compared to traditional metal based nano catalysts. Some examples are available in the literature about the preparations and properties of sulfur nanoparticles (S₈-NPs).¹⁰

Recently, there has been considerable increase of interest in the synthesis of pyridopyrimidine derivatives because of the interesting biological activities associated with them such as antibacterial,¹¹ insecticidal,¹² anti-inflammatory,¹³ antifolate, antiviral, and antitumor activities. Moreover, pyrido[1,2-a]pyrimidine derivatives are also an important structural component in some marketed drugs including pemirolast (antiasthmatic agent),¹⁴ pirenperone (tranquilizer)¹⁵ and barmastine¹⁶ (antiallergic agent). As a consequence several strategies have been developed for the synthesis of 4H-pyrido[1,2-a]pyrimidines.¹⁷ However these protocols suffer from many drawbacks such as utilization of highly toxic and corrosive reagents, volatile organic solvents, metallic catalysts, harsh reaction conditions or generation of environmentally hazardous wastes. Moreover the most concerning drawback of almost all existing methods is that the catalysts are consumed during the reaction and cannot be recovered or reused thereby reduces the turn over frequency (TOF) which is an important parameter from an industrial point of view. Thus to overcome these shortcomings and our interest in the development of expeditious synthesis of heterocyclic scaffolds¹⁸ we have envisioned a practical and greener route to synthesise pyrido[1,2-a]pyrimidine derivatives under admicellar environment formed by the adsorption of sodium dodecyl sulphate (SDS) on the surface of sulfur-nanoparticles at a lower surfactant concentration (below critical micellar concentration, CMC) (Scheme 1).

Scheme 1

The formation of S₈-NPs was achieved by annealing elemental sulfur which was obtained in turn by catalytic conversion of H₂S.¹⁹ To characterize the structure and morphology of the synthesized S₈-NPs, XRD and transmission electron microscopic (TEM) study was performed which confirmed the successful preparation of the desired nanoparticles. Fig. 1 displays the XRD pattern for (a) fresh nano-sulfur and (b) recovered nano-sulfur. XRD spectra shows broad peaks at the positions of 22.86°, 25.56°, 27.45°, 28.39°, 31.23°, 39.92°, 42.42°, 47.41, 50.92° and 65.22°, which are in good agreement with the standard JCPDS file for S₈-NP (JCPDS PDF #78-1889) and can be indexed as cubic orthorhombic face-centred S₈ (i.e., α-form) with face-centred lattice sites. The crystallite sizes were calculated by applying the full width at half-maximum (fwhm) of characteristic peaks (222) and (117) to the Scherrer equation and found between 13.8 and 25.6 nm. These sizes are consistent with those estimated through the TEM images, revealing the single crystal structure of nanoparticles.

Fig. 1 XRD patterns of (a) fresh nano-sulfur (red line) (b) after the fifth cycle of the nano-sulfur (black line).

Fig. 2 shows the representative TEM micrograph of synthesised S₈-NPs. The typical TEM image shows abundance of betel shape and very few of spherical particles with size between 14.5 and 26.7 nm. Furthermore to find the elemental composition EDX analysis was performed. EDX confirmed the presence of sulphur element, carbon and oxygen only (Fig. 3).

Fig. 2 TEM micrograph of S₈-NPs.

Fig. 3 EDX patterns of the S₈-NPs.

In the EDX spectrum, the peak due to carbon originates from the carbon present on gride.

After the successful preparation and characterization of S₈-NPs we examined their catalytic activity under admicellar environment for the environmentally benign synthesis of 4H-pyrido[1,2-a]pyrimidines. Uses of S₈-NPs in admicellar catalysis is very significant and are extremely advantageous over other nano catalysts because it utilizes only elemental sulphur as a source material therefore no impurities were recognized in the synthesized S₈-NPs sample. Moreover its utilization in industries will lead almost zero waste generation along with easy recovery and reusability of the catalyst. Additionally procedure for preparation of S₈-NPs is also very cheap because needs of special equipment, high pressure, temperature and toxic chemicals are avoided during catalyst preparation which make their implementation simple, cost effective and scalable in reactions.

The aim of our work was to accomplish the environmentally favourable reaction conditions for the simple synthesis of substituted 4H-pyrido[1,2-a]pyrimidines 4, for this purpose, 2-aminopyridine 1, cyclohexanecarbaldehyde 2 and 2-phenylacetaldehyde 3 were selected as model reactant in a stoichiometry optimized by Kai Yang et al.^17c In our initial experiment we have scrutinized the reaction condition regarding solvent and catalyst for obtaining good yield of product. Considering the fact, cyclization reactions occur more frequently in polar solvents and also from green chemistry point of view we initially performed the reaction in aqueous medium using S₈-NPs as a heterogeneous catalyst. Reaction took place but only trace product was detected probably due to the limited solubility of some reactants in water (Table 1, entry 1). To overcome this problem, we turn our interest towards the use of an admicellar system produced by the S₈ NPs in aqueous solution of sodium dodecyl sulphate (SDS: cmc value 8.2 mM)^20a as a reaction template. It seemed a promising way to utilize SDS in combination with S₈-NPs because under aqueous condition adsorption of anionic amphiphile sodium dodecyl sulphate (below CMC) on surface of S₈-NPs leads to the formation of hemimicelles, where the hydrophobic tail groups are oriented toward the polar aqueous medium, then chain–chain interactions of surfactant give an another layer where the head groups are positioned toward the water. Thus a bilayer structures was formed on the surface of S₈-NPs, these aggregates have been termed as admicelle (Fig. 1). Hydrophobic area of admicelles brings the organic reagents into close proximity and S₈-NPs catalyze the reaction between them.

Table 1 Effect of surfactant for the synthesis of compound 4^a

Entry	Surfactant	Temp (°C)	Concentration (mM)	Yield^b (%)
a Reaction condition: 2-aminopyridine (1.0 mmol), cyclohexanecarbaldehyde (2.0 mmol), 2-phenyl acetaldehyde (1.1 mmol) in 10 ml, 7 mM aqueous surfactant solution with 10 mol% S-NP for 12 h.b Isolated yield.
1	—	85	—	Trace
2	SDS	85	2.0	41
3	SDS	85	5.0	53
4	SDS	85	7.0	74
5	SDS	85	8.0	70
6	SDS	85	12.0	34
7	SDS	80	7.0	67
8	SDS	r.t.	7.0	23
9	SDS	Reflux	7.0	74
10	CTAB	85	0.8	54
11	TTAB	85	3.1	47

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Firstly we performed the reaction with 2.0 mM concentration of SDS in water but again yield was not satisfactory although it increased in comparison to previous result (Table 1, entry 2). Encouraged by this success, we run this experiment with 5.0 mM of SDS in 10 ml water. This produced 53% yield of the mentioned scaffold (Table 1, entry 3). Pleasingly the most striking yield (74%) was obtained when we raise the concentration of SDS from 5.0 to 7.0 mM (Table 1, entry 4). However no significant improvement in the yield was noticed on further increase of concentration (Table 1, entry 5). It is important to note that at very high concentration of SDS (above CMC) yield of the product was very low because of the formation of micelles which solubilizes the organic substrates within its hydrophobic core (Table 1, entry 6). Therefore inhibiting the admicellar catalysis during the reaction. Besides SDS, action of other surfactant like cetyltrimethyl ammonium bromide (CTAB: cmc value 0.92 mM)^20b and tetradecyl trimethyl ammonium bromide (TTAB: cmc value 3.8 mM)^20c were also investigated (Table 1, entries 10 and 11) but the yields that obtained were not as good as it was in SDS–H₂O system.

Thus the survey of surfactants revealed that 7.0 mM SDS in combination with S₈-NPs is sufficient for completion of reaction. With the hope to enhance the yield of the product, a series of experiments were also performed by varying amount of catalyst i.e. S₈-NPs, ranging from 5 mol% to 20 mol%. Results shows that 10 mol% of catalyst is sufficient to produce the desired product 4 with excellent yield (Table 2, entry 5). On the other hand no substantial improvement in the yield was observed on further increasing the catalyst loading beyond 10 mol% (Table 2, entries 7 and 8).

Table 2 Optimization of catalyst and its amount for the synthesis of compound 4^a

Entry	Catalyst	Amount (mol%)	Time (h)	Yield^b (%)
a Reaction condition: 2-aminopyridine (1.0 mmol), cyclohexanecarbaldehyde (2.0 mmol), 2-phenyl acetaldehyde (1.1 mmol) in 10 ml, 7 mM aqueous SDS solution at 85 °C.b Isolated yield.
1	—	—	20	12
2	PTSA	10	20	39
3	TFA	10	20	32
4	SiO2	10	20	28
5	S8-NP	10	12	74
6	S8-NPs	5	20	69
7	S8-NPs	15	12	72
8	S8-NPs	20	12	74

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In order to prove that S₈-NPs are crucial for this transformation in admicellar system we performed the model reaction in the presence of several other catalysts such as PTSA (p-toluenesulfonic acid), TFA (trifluoroacetic acid) and SiO₂ (Table 2, entry 2–4). The results clearly reveals that among various catalysts tested S₈-NPs is best, both in cost and yield considerations (Table 2, entry 5). Also it is abundant, cheap, non toxic, easily handled and recyclable catalysts which is one of the most important criteria from industrial point of view. Moreover its small amount (10 mol%) gave the product with highest conversion. Thus the condition was pre-set but the pursuit to improve the yield of desired product continued. In a quest to improve the yield further we reconsidered the model reaction under the diverse range of temperature (Table 1). We observed that the yield of product 4 was improved and the time taken by reaction was shortened as the temperature was increased to 85 °C. However yield remained unaffected when temperature was increased further to reflux (Table 1, entry 9). Lastly, effect of solvent was evaluated and it was found that water has shown its superiority to other organic solvents tested [DMF, CH₃CN and EtOH] (Table 3).

Table 3 Optimization of solvent for the synthesis of compound 4^a

Entry	Solvent	Time (h)	Yield^b (%)
a Reaction condition: 2-aminopyridine (1.0 mmol), cyclohexanecarbaldehyde (2.0 mmol), 2-phenyl acetaldehyde (1.1 mmol) in 10 ml, 7 mM aqueous SDS solution with S8-NPs (10 mol%) at 85 °C.b Isolated yield.
1	DMF	18	57
2	CH3CN	18	41
3	EtOH	14	65
4	H2O	12	74

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After optimization of reaction condition we sought to investigate the scope of this methodology by using variety of reactants. The results are summarized in Table 4. Results attest that present protocol is compatible with a broad range of substituents in the aldehydes or 2-aminopyridines. Both electron-donating and electron-withdrawing groups were tolerated and did not show any considerable effect. Particularly benzaldehyde was effective providing an excellent yield of the desired product, although 2-methylbenzaldehyde gave a slightly lower yield probably due to the steric hindrance effects. After investigation of the aldehydes and 2-aminopyridines, we improved the reaction scope by using various carbonyl compounds 3{a–g} (Fig. 4). As seen in Table 3, they were also found to be compatible in terms of these conversions yielding the expected products 4 in 41 to 92%. However in the case of the cyclohexanone a side product was found which presumably indicates the participation of two molecules of aldehydes 2 in the reaction (Fig. 5).

Table 4 Scope of substrate for the synthesis of compound 4^a

Entry	2-Amino pyridine (R1)	Aldehydes (R2)	Ketones/aldehydes 3	Time (h)	Product	Yield^b (%)
a Reaction condition (except where designated): 2-aminopyridine {1} (1.0 mmol), aldehyde {2} (1.1 mmol), ketones/aldehydes {3} (3.0 mmol) and S8 NP (10 mol%) in 10 ml, 7 mM aqueous SDS solution at 85 °C.b Isolated yield.c {1} (1.0 mmol), {2} (2.0 mmol), {3} (1.1 mmol) and S8 NP (10 mol%) in 10 ml, 7 mM aqueous SDS solution at 85 °C.d {1} (1.0 mmol), {2}, {3} (4.1 mmol) and S8 NP (10 mol%) in 10 ml, 7 mM aqueous SDS solution at 85 °C.
1	H	4-ClC6H4	3a	12	4a	54
2	H	4-ClC6H4	3b	18	4b	52
3	H	4-ClC6H4	3c	12	4c	68^c
4	H	4-ClC6H4	3d	11	4d	49^c
5	H	C6H10	3c	12	4e	74^c
6	H	CH2–C6H5	3c	8	4f	70^d
7	H	4-ClC6H4	3f	84	4g	41
8	H	C6H5	3g	10	4h	80
9	Cl	4-ClC6H4	3g	11	4i	82
10	H	C6H10	3g	12	4j	92
11	H	4-CH3C6H4	3g	7	4k	78
12	C5H10N	4-ClC6H4	3g	10	4l	72
13	COOEt	4-ClC6H4	3g	17	4m	67
14	H	4-NO2C6H4	3g	22	4n	62
15	H	4-OMeC6H4	3g	7	4o	84

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Fig. 4 Structure of bilayer admicelles on the surface of S₈-NPs.

Fig. 5 Various carbonyl compounds 3 (ketones/aldehydes) employed during library synthesis.

On the basis of above described experimental results and literature survey a conceivable mechanism for this conversion is shown in Scheme 2. In aqueous medium at low concentration of SDS (below CMC) S₈-NPs promotes the formation of admicelles. The presence of hydrophobic environments within admicelles provides a region which is capable of solubilizing water-insoluble components. We speculated that the first step of the current reaction is the formation of intermediate 6 through S₈-NPs-promoted Knoevenagel condensation of aldehyde²¹ 2 with ketone/aldehyde 3 under admicellar environment. Presumably, 4H-pyrido[1,2-a]pyrimidines 4 could arise in two ways: (a) via condensation of intermediate 6 with 2-aminopyridine 1 catalyzed by S₈-NPs to afford imine 7 followed by an intramolecular cyclization reaction. (b) Michael addition of intermediate 6 (nucleophilic pyridine ring N atom) to 1 presumably affording ketone intermediate 8, which subsequently undergoes intramolecular cyclization onto the keto moiety to give 9 and finally generates the desired product 4 via elimination of water catalyzed by S₈-NPs–SDS system. Structures of compounds 4(a–o) were fully characterized by ¹HNMR, ¹³CNMR, IR, and mass spectroscopy.

Scheme 2 Plausible mechanistic pathways for synthesis of compound 4.

After completion of the reaction catalyst could be recycled easily and the data (Table 5) clearly revealed that the S₈-NPs was almost equally effective in the synthesis of compound 4 from fresh up to the fifth cycle. The EDX analysis of the catalyst taken after the fifth cycle of the reaction did not show any change as it is clear by Fig. 6. A comparative study of the XRD patterns of the fresh catalyst and the recovered catalyst (S₈-NPs) after five cycles (Fig. 1a and b) also confirmed that the catalyst remained unchanged and does not undergo substantial leaching during the reaction process. However a slight decrease in the yield was observed with a bit longer reaction time after the fifth run probably due to change in morphology (Fig. 7). The TEM micrograph (Fig. 7) during the 5 consecutive cycles shows the aggregation of the nanoparticles that might be the cause of reduced activity of catalyst.

Table 5 Recyclability test of nano-sulfur catalyst in the synthesis of compound 4^a

a Reaction condition: 2-aminopyridine {1} (1.0 mmol), aldehyde {2} (1.1 mmol), ketones/aldehydes {3} (3.0 mmol) and S8-NP (10 mol%) in 10 ml, 7 mM aqueous SDS solution at 85 °C.b Isolated yield.
Catalytic runs	1^st run	2^nd run	3^rd run	4^th run	5^th run
Yield^b (%)	74	74	72	69	66

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Fig. 6 EDX patterns of the recycled S₈-NPs.

Fig. 7 TEM micrograph of recycled S₈-NPs.

In conclusion, we have disclosed the first time use of inexpensive, ubiquitous and environmentally benign nano-sulfur to prepare an efficient and highly active admicellar reaction template (S₈-NPs/SDS) in aqueous medium to accelerate green synthesis of 4H-pyrido[1,2-a]pyrimidines. Developed protocol shares much important green chemistry attributes as it is performed without organic solvents and any acid, base or metal catalysts thus contributing to health-hazard minimization, operational simplicity and improved atom- and cost efficiency. To the best of our knowledge ability of S₈-NPs in admicellar catalysis is not explored yet in synthetic chemistry, therefore we believe that present protocol is going to be a breakthrough for its application in organic synthesis.

Experimental material and methods

All chemical were reagent grade purchased from Aldrich and Alfa Aesar and were used without purification. NMR spectra were recorded on a BRUKER AVANCE II-400FT Spectrometer (400 for ¹H NMR, 100 MHz for ¹³C) using DMSO as solvent and TMS as an internal reference. ESI-MS were recorded on a JEOL SX-102 (FAB) mass spectrometer at 70 eV. Elemental analyses were carried out in a Coleman automatic carbon, hydrogen and nitrogen analyzer.

Typical procedure for the synthesis of nano-sulfur

For a typical synthesis of S₈-NPs, elemental sulfur (1 g) was heated at 120 °C in an oven for 25 min. After that, the melted substance was cooled to room temperature naturally and placed over an ice bath. Lastly, it was grinded with mortar and pestle. This entire process was repeated three times and then washed with double distilled water (3 × 15 ml) and dried at 100 °C in an oven.

Representative procedure for the synthesis of 4e

To a homogeneous solution of SDS (7.0 mM) in water (10 ml), 2-aminopyridine 1 (1.0 mmol), cyclohexanecarbaldehyde 2 (2 mmol), 2-phenylacetaldehyde 3 (1.1 mmol) and S₈-NP (10 mol%) were added and stirred for 12 h at 85 °C. Progress of the reaction was checked by TLC. After completion of the reaction, the resulting mixture was diluted with 10 ml CH₂Cl₂ and washed with concentrated ammonia solution (20 ml). After that it was ultra-centrifuged (3500 rpm) to pellet out the S₈-NPs. Recovered catalyst was washed with hot ethanol (3 × 10 ml) and decanted to remove any adhering organic compound. It was next dried in an oven at 100 °C and reused upto five cycles. The aqueous layer was separated out with CH₂Cl₂ (3 × 10 ml). The organic layer was washed with brine solution (30 ml), dried over Na₂SO₄ and concentrated under vacuum to result in a crude product. The crude product was purified by flash column chromatography (CH₂Cl₂/EtOAc/MeOH/concentrated ammonia solution 100 : 50 : 1.5 : 1.5, v/v) afforded the desired product 4d.

4-(4-Chlorophenyl)-2-ethyl-3-methyl-4H-pyrido[1,2-a]pyrimidine (4a)

58%; yellow solid, mp (°C): found-101, reported 103–104;^{17c 1}H NMR (400 MHz, DMSO) δ (ppm): 7.34–7.20 (m, 4H), 6.91–6.85 (m, 1H), 6.79–6.72 (m, 2H), 6.03 (t, 1H, J = 6.3), 5.38 (s, 1H), 2.33 (dt, 2H, J = 13.5, 6.6), 1.50 (s, 3H), 1.19 (t, 3H, J = 7.5); ¹³C NMR (100 MHz, CDCl₃) δ (ppm): 148.7, 140.5, 140.9, 134.9, 134.1, 133.5, 129.8, 128.7, 123.1, 109.5, 103.2, 68.5, 26.3, 15.4, 13.4; MS (ESI): m/z 285.3 [M + H⁺].

4-(4-Chlorophenyl)-3-methyl-2-phenyl-4H-pyrido[1,2-a]pyrimidine (4b)

52%; yellow solid, mp (°C): found-162, reported-165–166;^{17c 1}H NMR (400 MHz, DMSO) δ (ppm): 7.48–7.23 (m, 9H), 6.94–6.82 (m, 3H), 6.10 (t, 1H, J = 6.6), 5.52 (s, 1H), 1.56 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ (ppm): 148.5, 140.9, 140.4, 139.4, 134.7, 134.3, 133.9, 129.8, 129.2, 128.6, 128.0, 127.6, 123.4, 109.0, 105.6, 68.1, 17.7; MS (ESI): m/z 333.2 [M + H⁺].

4-(4-Chlorophenyl)-3-phenyl-4H-pyrido[1,2-a]pyrimidine (4c)

68%; yellow solid, mp (°C): found-150, reported-148–150;^{17c 1}H NMR (400 MHz, DMSO) δ (ppm): 7.41 (s, 1H), 7.42–7.38 (m, 2H), 7.30–7.26 (m, 6H), 7.13–6.99 (m, 3H), 6.71 (d, 1H, J = 9.0), 6.23 (td, 1H, J = 6.6, J = 1.5), 6.02 (s, 1H); ¹³C NMR (100 MHz, CDCl₃) δ (ppm): 149.4, 139.3, 136.8, 135.2, 134.4, 134.1, 133.7, 129.9, 128.0, 128.2, 126.0, 124.3, 123.9, 111.2, 110.4, 65.5; MS (ESI): m/z 319.3 [M + H⁺].

4-(4-Chlorophenyl)-3-propyl-4H-pyrido[1,2-a]pyrimidine (4d)

49%; yellow solid, mp (°C): found-72 °C, reported-75–76;^{17c 1}H NMR (400 MHz, DMSO) δ (ppm): 7.32–7.27 (m, 4H), 6.90–6.82 (m, 1H), 6.75–6.69 (m, 2H), 6.50 (s, 1H), 6.03–6.04 (m, 1H), 5.53 (s, 1H), 1.86–1.78 (m, 2H), 1.55–1.29 (m, 2H), 0.89 (t, 3H, J = 7.2); ¹³C NMR (100 MHz, CDCl₃) δ (ppm): 149.5, 140.8, 135.2, 134.1, 133.8, 129.9, 129.4, 128.7, 123.4, 113.5, 109.5, 66.7, 33.6, 19.6, 13.4; MS (ESI): m/z 285.3 [M + H⁺].

4-Cyclohexyl-3-phenyl-4H-pyrido[1,2-a]pyrimidine (4e)

74%; yellow solid, mp (°C): found: 147, reported-146–148;^{17c 1}H NMR (400 MHz, DMSO) δ (ppm): 7.46–7.40 (m, 2H), 7.32–7.27 (m, 2H), 7.22 (s, 1H), 7.14 (t, 1H, J = 7.2), 7.09–7.03 (m, 1H), 6.94 (d, 1H, J = 6.6), 6.75 (d, 1H, J = 9.0), 6.22 (t, 1H, J = 6.6), 4.83 (d, 1H, J = 4.2), 1.71–1.59 (m, 6H), 1.05–0.73 (m, 5H); ¹³C NMR (100 MHz, CDCl₃) δ (ppm): 151.8, 138.3, 136.6, 134.0, 134.2, 128.4, 125.9, 123.4, 122.7, 111.2, 108.6, 66.4, 45.0, 30.4, 28.2, 26.6, 26.4; MS (ESI): m/z 291.4 [M + H⁺].

4-Benzyl-3-phenyl-4H-pyrido[1,2-a]pyrimidine (4f)

70%; yellow solid, mp (°C): found-122 °C, reported-122–123;^{17c 1}H NMR (400 MHz, DMSO) δ (ppm): 7.52–7.43 (m, 2H), 7.43–7.39 (m, 2H), 7.22–7.10 (m, 5H), 7.01–6.96 (m, 3H), 6.75 (d, 1H, J = 8.7), 6.34 (d, 1H, J = 6.9), 5.85 (d, 1H, J = 6.6), 5.11 (dd, 1H, J = 9.4, J = 3.2), 3.06–2.84 (m, 2H); ¹³C NMR (100 MHz, CDCl₃) δ (ppm): 150.4, 137.3, 136.5, 136.6, 134.8, 133.4, 129.2, 129.0, 128.5, 127.0, 125.7, 123.8, 122.6, 111.3, 108.8, 64.8, 40.2; MS (ESI): m/z 298.7 [M + H⁺].

4-(4-Chlorophenyl)-2,3-diphenyl-4H-pyrido[1,2-a]pyrimidine (4g)

41%; yellow solid, mp (°C): found-177, reported-179–180;^{17c 1}H NMR (400 MHz, DMSO) δ (ppm): 7.44–7.37 (m, 4H), 7.30–7.33 (m, 2H), 7.23–7.18 (m, 3H), 7.04–7.03 (m, 5H), 6.93–6.85 (m, 3H), 6.24 (t, 1H, J = 6.6), 5.83 (s, 1H); ¹³C NMR (100 MHz, CDCl₃) δ (ppm): 149.4, 143.6, 140.2, 140.0, 139.6, 135.2, 134.6, 134.7, 130.4, 129.3, 129.2, 128.7, 128.5, 127.7, 127.3, 126.4, 123.5, 110.2, 107.4, 67.4; MS (ESI): m/z 394.6 [M + H⁺].

11-Phenyl-2,3,4,11-tetrahydro-1H-pyrido[2,1-b]quinazoline (4h)

80%; yellow solid, mp (°C): found-152, reported-154–156;^{17c 1}H NMR (400 MHz, DMSO) δ (ppm): 7.32–7.26 (m, 5H), 6.87 (t, 1H, J = 7.8), 6.71–6.65 (m, 2H), 5.94 (t, 1H, J = 6.6), 5.35 (s, 1H), 2.36–2.28 (m, 2H), 1.72–1.57 (m, 6H); ¹³C NMR (100 MHz, CDCl₃) δ (ppm): 148.3, 142.4, 136.4, 135.5, 133.3, 128.9, 128.4, 126.4, 123.2, 108.3, 106.4, 68.1, 30.5, 26.4, 23.3, 22.4; MS (ESI): m/z 263.2 [M + H⁺].

8-Chloro-11-(4-chlorophenyl)-2,3,4,11-tetrahydro-1H-pyrido [2,1-b]quinazoline (4i)

82%; yellow solid, mp (°C): found-132 °C, reported-130–132;^{17c 1}H NMR (400 MHz, DMSO) δ (ppm): 7.31–7.36 (m, 2H), 7.25–7.20 (m, 2H), 6.87–6.81 (m, 1H), 6.74 (s, 1H), 6.71 (d, 1H, J = 2.1), 5.36 (s, 1H), 2.32–2.25 (m, 2H), 1.75–1.57 (m, 6H); ¹³C NMR (100 MHz, CDCl₃) δ (ppm): 146.4, 140.0, 136.2, 134.5, 134.6, 132.7, 129.4, 128.1, 124.8, 115.1, 107.0, 68.0, 29.5, 26.4, 22.7, 22.3; MS (ESI): m/z 330.4 [M + H⁺].

11-Cyclohexyl-2,3,4,11-tetrahydro-1H-pyrido[2,1-b]quinazoline (4j)

92%; yellow solid, mp (°C): found-139, reported-138–140;^{17c 1}H NMR (400 MHz, DMSO) δ (ppm): 6.95 (t, 1H, J = 7.2), 6.72 (d, 1H, J = 6.6), 6.67 (d, 1H, J = 9.0), 6.02 (t, 1H, J = 6.6), 3.96 (d, 1H, J = 3.9), 2.35–2.21 (m, 3H), 2.07–1.56 (m, 11H), 1.23–0.6 (m, 5H); ¹³C NMR (100 MHz, CDCl₃) δ (ppm): 150.3, 138.6, 136.5, 132.7, 122.5, 106.7, 105.5, 69.2, 44.6, 30.9, 30.3, 28.5, 28.1, 26.8, 26.5, 26.4, 23.2, 23.0; MS (ESI): m/z 269.2 [M + H⁺].

(p-Tolyl)-2,3,4,11-tetrahydro-1H-pyrido[2,1-b]quinazoline (4k)

78%; yellow solid, mp (°C): found-126, reported-126–127;^{17c 1}H NMR (400 MHz, DMSO) δ (ppm): 7.26–7.13 (m, 4H), 6.89 (t, 1H, J = 7.8), 6.75–6.67 (m, 2H), 5.98 (t, 1H, J = 6.6), 5.34 (s, 1H), 2.36–2.32 (m, 5H), 1.75–1.56 (m, 6H); ¹³C NMR (100 MHz, CDCl₃) δ (ppm): 148.7, 139.6, 138.4, 136.7, 135.0, 133.2, 129.4, 126.7, 123.3, 108.5, 106.7, 66.4, 30.4, 26.5, 23.4, 22.7, 21.4; MS (ESI): m/z 276.5 [M + H⁺].

11-(4-Chlorophenyl)-8-(piperidin-1-yl)-2,3,4,11-tetrahydro-1H-pyrido[2,1-b]quinazoline 4(l)

72%; yellow solid, mp (°C): found-166, reported-165–167;^{17c 1}H NMR (400 MHz, DMSO) δ (ppm): 7.34–7.23 (m, 4H), 7.02 (s, 2H), 6.05 (s, 1H), 5.36 (s, 1H), 2.83–2.69 (m, 4H), 2.44–2.24 (m, 2H), 1.76–1.47 (m, 12H); ¹³C NMR (100 MHz, CDCl₃) δ (ppm): 145.7, 140.5, 139.5, 134.8, 132.9, 129.4, 128.5, 122.0, 119.3, 105.7, 68.7, 51.0, 28.3, 26.1, 25.2, 23.5, 22.9, 22.7; MS (ESI): m/z 380.1 [M + H⁺].

11-(4-Nitrophenyl)-2,3,4,11-tetrahydro-1H-pyrido[2,1-b]quinazoline 4(n)

62%; yellow solid, mp (°C): found-149, reported-150–152;^{17c 1}H NMR (400 MHz, DMSO) δ (ppm): 8.24–8.20 (m, 2H), 7.52–7.43 (m, 3H), 7.30–7.27 (m, 1H), 7.03 (d, 1H, J = 6.3), 6.44 (t, 1H, J = 6.3), 5.74 (s, 1H), 2.51–2.35 (m, 2H), 1.93–1.63 (m, 6H); MS (ESI): m/z 308.0 [M + H⁺].

11-(4-Methoxyphenyl)-2,3,4,11-tetrahydro-1H-pyrido[2,1-b]quinazoline 4(o)

84%; yellow solid, mp (°C): found-89, reported-88–90;^{17c 1}H NMR (400 MHz, DMSO) δ (ppm): 7.29–7.23 (m, 2H), 6.86–6.80 (m, 3H), 6.74–6.66 (m, 2H), 5.97 (t, 1H, J = 6.6), 5.34 (s, 1H), 3.75 (s, 3H), 2.37–2.25 (m, 2H), 1.73–1.59 (m, 6H); ¹³C NMR (100 MHz, CDCl₃) δ (ppm): 159.9, 148.5, 136.8, 135.2, 135.3, 133.6, 128.6, 123.9, 114.4, 108.8, 107.0, 67.5, 55.1, 30.4, 26.9, 23.0, 22.6; MS (ESI): m/z 295.0 [M + H⁺].

Acknowledgements

P. Rai and Rahila thanks to CSIR for their Senior Research Fellowship. H. Sagir thanks to UGC for her Junior Research Fellowship. Authors gratefully acknowledge the SAIF, Punjab University, Chandigarh, for providing all the spectroscopic data and Nanotechnology Application Centre, University of Allahabad for powder XRD and EDX.

Notes and references

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