Heterogeneous recyclable nano-CeO₂ catalyst: efficient and eco-friendly synthesis of novel fused triazolo and tetrazolo pyrimidine derivatives in aqueous medium

Abstract

A ceria nano catalyst was used for the one-pot, multi-component condensation reaction of benzoylacetonitrile, aromatic aldehydes and 5-aminotriazole/5-aminotetrazole, and proceeds via C–C and C–N bond formation to deliver the desired triazolo/tetrazolo[1,5-a]pyrimidine derivatives. This protocol provides cleaner conversion with high selectivity and shorter reaction times. The CeO₂ nanoparticles were prepared by a simple coprecipitation method and characterized using XRD, TEM, and XPS techniques.

---

1. Introduction

Nowadays, concerns about the environmental impact of renewable sources and replacement of highly volatile, environmentally harmful and biologically incompatible conventional organic solvents is a subject of great interest.¹ In view of environmental concern, water has been used as a green solvent for a variety of organic reactions due to its easy availability and because of possessing, non-flammable, non-carcinogenic and environmentally benign properties.² In addition, its unique reactivity and selectivity make water a green solvent.³ Nano metal oxides have been emerging as sustainable alternatives to conventional materials, as they are robust, having high surface area and their production is economical.⁴ Among the various nano metal oxides, cerium oxide (CeO₂) has become the subject of increasing interest mainly because of its high redox ability and also due to the presence of oxygen defects.⁵ In addition to this, CeO₂-NPs has also attracted tremendous interest due to its unique catalytic activities, low toxicity, stability, and easy handling.⁶

Multicomponent reactions (MCRs) are fast and effective methods for the sustainable and diversity oriented synthesis of heterocyclic scaffold, which provide, one of the most sustainable platform.⁷ The approach of conducting the reaction in water will be one of the most suitable directions, which not only meets the necessities of green chemistry but for developing libraries of medicinal scaffolds.⁸ Over the past decades, there has been great interest in the synthesis of pyrimidine compounds due to their wide range of applications.⁹ Pyrimidine with fused triazole or tetrazole derivatives are also known for their medicinal applications.¹⁰ They exhibit antimicrobial,¹¹ anticancer,¹² antiviral,¹³ anticonvulsant and antidepressant activities.¹⁴ Some of these compounds are showing remarkable activity in the inhibition of tyrosine-kinases¹⁵ and phosphodiesterases,¹⁶ along with having antihypertensive¹⁷ and antiviral activities.¹⁸

In view of the demands of organic synthesis, there is still need to develop new catalytic, environmentally benign and efficient protocols for the preparation of pyrimidines. In continuation of our efforts toward the development of novel heterocyclic compounds using green protocols,¹⁹ herein, we report a synthesis of triazolo and tetrazolo[1,5-a]pyrimidines catalyzed by CeO₂-nanoparticles. To the best of our knowledge, for the first time, an ecofriendly process was developed for the synthesis of novel triazolo/tetrazolo[1,5-a]pyrimidine scaffold from benzoylacetonitrile, aromatic aldehydes and 5-aminotriazole/5-aminotetrazole in the presence of ceria nanoparticles using aqueous medium. The catalyst material was prepared and was characterized by XRD, TEM, and XPS techniques.

2. Results and discussion

The CeO₂ nanoparticles were synthesized by a modified coprecipitation method using appropriate amounts of the corresponding Ce(NO₃)₃·6H₂O (Aldrich, AR grade) precursor. The desired amount of the precursor was dissolved in double-distilled water under mild stirring conditions. Dilute aqueous ammonia solution was added dropwise over a period until the pH of the solution reached ∼8.5. The resulting pale yellow colored slurry was decanted, filtered, and washed several times with double distilled water. The obtained precipitate was oven-dried at 393 K for 12 h and calcined at 773 K for 5 h at a heating rate of 5 K min⁻¹ in an air atmosphere.

The XRD patterns of the synthesized ceria material which was calcined at 773 K are shown in Fig. 1(a). The main peaks (111), (200), (220) and (311) observed in this figure correspond to the fluorite structure of ceria and confirmed its formation. The average crystallite size was calculated using the intense peaks such as (111), (220), and (311) with the help of Scherrer equation, and the obtained value is around 8.9 nm. Fig. 1(b) shows the TEM image of ceria, from the figure it is clear that the average particle size of ceria is 7–9 nm, which is in good agreement with the XRD results.

Fig. 1 (a) Powder X-ray diffraction patterns of ceria nanoparticles (b) transmission electron microscopy image of ceria nanoparticles.

The oxidation state of a cerium on the surface of the cerium oxide can readily be determined by XPS, and in this context, the XPS analyses were performed on ceria sample the results corresponding to Ce 3d, O 1s is shown in Fig. 2. Fig. 2(a) shows the Ce 3d XPS spectrum. The peaks designated as u, u′′, u′′′ and v, v′′, v′′′ can be assigned to Ce⁴⁺, while the peaks u′ and v′ belong to Ce³⁺. The O 1s core level XPS profile (Fig. 2(b)) of the ceria sample is noted by a broad peak centered at 530.5 eV, which is attributed to the lattice oxygen (O_I). The peak centered at 532.5 eV, could be associated to adsorbed water and/or carbonates (O_II) from the XPS figure, it is clear that on the surface of the ceria material cerium exist in both 3+ and 4 + oxidation states along with the presence of two types of oxygen (lattice oxygen and adsorbed oxygen).²⁰

Fig. 2 XP spectra of ceria 3d and O 1s of ceria nanoparticles.

In perspective of a sustainable chemistry program for the synthesis of the triazolo and tetrazolo[1,5-a]pyrimidine derivatives using CeO₂ as catalyst, initially we explored the reaction of benzoylacetonitrile 1 (1 mmol), benzaldehyde 2a (1 mmol) and 5-aminotriazole 3 (1 mmol) as a model substrate to investigate the feasibility of the strategy and to optimize the reaction conditions (Table 1). Initially, the above reaction was performed in neat condition which failed to yield the desired product even after 8 h (Table 1, entry 1) and later the above reaction was conducted with various solvents such as ethanol, water, acetonitrile, toluene and dioxane (Table 1, entries 2–6). Among them, water was found to be the best solvent of choice. Further, we carried out the same reaction in the presence of different acids and bases such as p-TSA, AcOH, pyridine, triethylamine and piperidine, using water as a solvent and these catalysts did not promote the reaction efficiently (Table 1, entries 7–11). The reaction was also done in the presence of different nano metal oxides, such as Fe₃O_4, CuO, ZnO, TiO₂ and CeO₂ (Table 1, entries 12–16). Among these, the CeO₂ nanoparticles were identified as the suitable catalyst for 5a which was isolated is maximum amounts (90%). The yield of the desired product was also checked using different mol ratios of 20% and 30 mol% (Table 1, entries 17–18). The maximum yield was obtained when the 20 mol% catalyst was used (Table 1, entry 17). Besides, we also studied the effect of temperature on the above by conducting the reaction at different temperatures like room temperature, 40, 60, 80 and 100 °C (Table 1, entries 18–22). It was established that 80 °C was the optimum temperature to get the maximum yield of the title compounds.

Table 1 Optimization of reaction conditions for the synthesis of 5a

Entry^a	Catalyst (mol%)	Solvent	Temp (°C)	Time (h)	Yield^b (%)
a Reaction conditions: benzoylacetonitrile 1 (1 mmol), benzaldehyde 2a (1 mmol), 5-aminotriazole 3 (1 mmol), solvent (5 mL) and catalyst.b Isolated yield.
1	—	Neat	80	12	None
2	—	Ethanol	80	16	20
3	—	Water	80	12	44
4	—	Acetonitrile	80	14	18
5	—	Toluene	80	24	12
6	—	Dioxane	80	24	10
7	p-TSA (10%)	Water	80	6	54
8	Acetic acid (10%)	Water	80	6	46
9	Pyridine (10%)	Water	80	8	40
10	Triethylamine (10%)	Water	80	6	43
11	Piperidine (10%)	Water	80	6	49
12	Fe3O4 (10%)	Water	80	6	56
13	CuO (10%)	Water	80	6	45
14	ZnO (10%)	Water	80	6	62
15	TiO2 (10%)	Water	80	6	58
16	CeO2 (10%)	Water	80	3	82
17	CeO2 (20%)	Water	80	2	90
18	CeO2 (30%)	Water	80	2	86
19	CeO2 (20%)	Water	rt	2	60
20	CeO2 (20%)	Water	40	2	72
21	CeO2 (20%)	Water	60	2	84
22	CeO2 (20%)	Water	100	2	90

---

In all the studied examples, the aromatic aldehydes reacted smoothly and obtained the corresponding triazolo and tetrazolo[1,5-a]pyrimidines in decent yields (Table 2, entries 1–30). Having optimized the reaction conditions, we then explored its applicability for a library of products employing various aromatic aldehydes. The reaction proceeded smoothly whether the aromatic aldehydes contains either electron donating or electron withdrawing groups, producing the corresponding title compounds in excellent yields. Moreover, with comparing the available variations we noted an interesting in the reaction with respect to the 5-aminotriazole 3 provided in excellent yields (Table 2, entries 1–15), in the presence of 5-aminotetrazole 4 under similar reaction conditions desired product in moderate yields (Table 2, entries 16–30). After that, we examined the reaction with a diversity of substituted aromatic aldehydes and couldn't observe any remarkable differences in their reactivity and product yields even though the aromatic aldehydes contains different types of substituents on aromatic ring.

Table 2 Synthesis of triazolo, tetrazolo[1,5-a]pyrimidine derivatives (5a–o and 6a–o)^a

a Reaction conditions: benzoylacetonitrile 1 (1 mmol), aromatic aldehydes 2a–o (1 mmol), 5-aminotriazole/5-aminotetrazole 3/4 (1 mmol), nano-CeO₂ (20 mol%) and water (5 mL).b Yields of the isolated products.

---

A plausible mechanism for the formation of triazolo and tetrazolo[1,5-a]pyrimidines using CeO₂ NPs is shown in Scheme 1. Initially, the reaction may occur via a Knoevenagel condensation between aromatic aldehyde 2 and benzoylacetonitrile 1 to form the intermediate (A) with the eliminations of water in the presence of the ceria material, which makes the aldehydes more electrophilic. Consequently, the Michael addition reaction of the intermediate (A) attacks with 5-aminotriazole 3 formation of intermediate (B), which undergoes intermolecular cyclization to give intermediate (C). Finally, intermediate C undergoes intermolecular dehydrogenation to afford the title product. In view of green and sustainable protocols, the nanosized CeO₂ catalyst was employed for reusable studies for the synthesis of compound 5a with benzoylacetonitrile 1, benzaldehyde 2a and 5-aminotriazole 3. The results showed that the CeO₂ catalyst can be reused several times without a noticeable loss of catalytic activity. After each cycle, the reaction was followed by extraction of products. The collected catalyst was washed with acetone for several times to remove organic substances and used for the next run. A chart of the catalytic activity of recycled CeO₂ material is provided in Fig. 3. All the synthesized compounds were confirmed by their spectral data (IR, ESI-MS, ¹H NMR, and ¹³C NMR). Spectral data for all the compounds were in full agreement with the proposed structures. The structure of compound 5a was further confirmed by single crystal X-ray diffraction analysis (Fig. 4, CCDC-1440718). The compound 5a crystallizes in the centrosymmetric monoclinic C2/c space group with one molecule in the asymmetric unit (Table 3) gives the pertinent crystallographic data.

Scheme 1 Proposed mechanism for the formation of compound 5a.

Fig. 3 Reusability studies of the nano-sized CeO₂ for the synthesis of compound 5a.

Fig. 4 ORTEP representation of compound 5a (CCDC 1440718).

Table 3 Salient crystallographic data and structure refinement parameters of compound 5a

	5a
Identification code	shelxl
Formula weight	298.33
Temperature	296(2) K
Wavelength	0.71073 Å
Crystal system, space group	Monoclinic, C2/c
Unit cell dimension	a = 14.200(8) Å alpha α = 90°b = 19.440(3) Å beta = 121.10°(4)c = 13.057(6) Å gamma = 90°
Volume	3086(3) Å^3
Z, density (calculated)	8, 1.284 Mg m^−3
Adsorption coefficient	0.084 mm^−1
F(000)	1240
Crystal size	0.40 mm
Limiting indices	−19 ≤ h ≤ 18, −25 ≤ k ≤ 19, −17 ≤ l ≤ 17
Theta range for data collection	1.98–28.70°
R indices [I > 2 Sigma(I)]	R = 0.0721, wR2 = 0.1932
R indices (all data)	R = 0.1185, wR2 = 0.2388
Reflections collected	12 450/3835 [R(int) = 0.0493]
Independent reflections	856
Completeness to theta max	028.70, 96.1%
Absorption correction	Semi-empirical from equivalents
Refinement method	Full-matrix least-squares on F^2
Max. and min. transmission	0.9796 and 0.9646
Goodness of fit	1.026
Data/restraints/parameters	3835/0/209
Largest diff. peak and hole	0.512 and −0.447 Å^−3
CCDC	1440718

---

3. Experimental results

3.1. Materials and method

All reagents were procured from commercial sources and used without further purification. A Bruker WM-4 (X) spectrophotometer (577 model) was used for recording IR spectra (KBr). NMR spectra were recorded on a Bruker WM-500 spectrophotometer at 500 MHz (¹H), Bruker WM-400 spectrophotometer at 400 MHz (¹H) and 100 MHz (¹³C) respectively, in DMSO-d₆ with TMS as an internal standard. Elemental analysis was performed on a Carlo Erba EA 1108 automatic elemental analyzer. Mass spectra (ESI) were carried out on a jeo1 JMSD-300 spectrometer. The compound 5a was crystallized from chloroform to yield prismatic crystals. XRD data was acquired in the 2θ range of 12–80° on a Rigaku Multiflex instrument using Cu Kα (λ = 1.5418 Å) radiation and a scintillation counter detector. Crystalline phases present in the samples were identified with the help of Powder Diffraction File-International Centre for Diffraction Data (PDF-ICDD). The average size of the crystalline domains (D) of the prepared materials were estimated with the help of the Scherrer eqn (1) using the XRD data of all prominent lines.

D = Kλ/β cos θ (1)

where D denotes the crystallite size, λ is the X-ray wavelength (1.541 Å), K indicates the particle shape factor taken as 1, β represents the peak width (FWHM, full width at half maximum) in radians and θ is the Bragg diffraction angle. TEM studies were made on a JEM-2010 (JEOL) instrument equipped with a slow-scan CCD camera at an accelerating voltage of 200 kV. The XPS measurements were performed on a Shimadzu (ESCA 3400) spectrometer by using Al Kα (1486.7 eV) radiation as the excitation source. Charging effects of catalyst samples were corrected by using the binding energy of the adventitious carbon (C 1s) at 284.6 eV as internal reference. The XPS analysis was done at ambient temperature and pressures usually in the order of less than 10⁻⁸ Pa.

3.2. General procedure for the synthesis of triazolo and tetrazolo[1,5-a]pyrimidine derivatives (5a–o and 6a–o)

A dry 50 mL flask was charged with 3-oxo-3-phenylpropanenitrile (1 mmol), aromatic aldehydes (1 mmol), 5-aminotriazole/5-aminotetrazole (1 mmol) in water (5 mL) and nano-CeO₂ was added. The reaction mixture was stirred at 60 °C for 2–3 h the progress of the reaction was monitored by TLC. After completion of the reaction the product was extracted with ethyl acetate and purified by column chromatography using silica gel (ethyl acetate : n-hexane 4 : 6) to afford pure compounds 5a–o and 6a–o in good yields.

5,7-Diphenyl-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidine-6-carbonitrile (5a). White powder; mp: 330–332 °C; IR (KBr) υ_max (cm⁻¹): 3128, 2922, 2346, 1552; ¹H NMR (400 MHz, DMSO-d₆): δ 6.42 (s, 1H), 7.38–7.45 (m, 5H), 7.55 (d, J = 8 Hz, 3H), 7.66 (d, J = 8 Hz, 2H), 7.78 (s, 1H), 11.44 (s, 1H); ¹³C NMR (100 MHz, DMSO-d₆): δ 150.94, 149.91, 147.53, 140.09, 132.30, 131.47, 129.39, 129.12, 129.02, 127.83, 118.80, 81.01, 60.44; ESI-MS: m/z 300 (M + 1)⁺; anal. calcd for C₁₈H₁₃N₅; C, 72.23; H, 4.38; N, 23.40; found: C, 72.16; H, 4.33; N, 23.61.

5-Phenyl-7-(p-tolyl)-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidine-6-carbonitrile (5b). White powder; mp: 343–345 °C; IR (KBr) υ_max (cm⁻¹): 3158, 2992, 2327, 1558; ¹H NMR (400 MHz, DMSO-d₆): δ 2.32 (s, 3H), 6.37 (s, 1H), 7.23–7.29 (m, 4H), 7.53–7.58 (m, 3H), 7.66 (d, J = 8 Hz, 2H), 7.76 (s, 1H), 11.40 (s, 1H); ¹³C NMR (100 MHz, DMSO-d₆): δ 150.83, 149.77, 147.46, 138.82, 137.25, 132.36, 131.41, 129.90, 129.10, 129.00, 118.78, 81.15, 60.23, 21.21; ESI-MS: m/z 314 (M + 1)⁺; anal. calcd for C₁₉H₁₅N₅; C, 72.83; H, 4.82; N, 22.35; found: C, 72.83; H, 4.87; N, 22.49.

7-(4-Methoxyphenyl)-5-phenyl-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidine-6-carbonitrile (5c). White powder; mp: 332–334 °C; IR (KBr) υ_max (cm⁻¹): 3134, 2984, 2356, 1558; ¹H NMR (400 MHz, DMSO-d₆): δ 3.78 (s, 3H), 6.38 (s, 1H), 6.99 (d, J = 8 Hz, 1H), 7.27 (d, J = 8 Hz, 1H), 7.33 (d, J = 8 Hz, 1H), 7.56 (d, J = 8 Hz, 2H), 7.66 (d, J = 8 Hz, 2H), 7.75 (d, J = 8 Hz, 1H), 8.02 (t, J = 8 Hz, 1H), 8.85 (s, 1H), 11.37 (s, 1H); ¹³C NMR (100 MHz, DMSO-d₆): δ 160.09, 158.40, 150.78, 149.73, 147.36, 133.09, 132.39, 132.22, 131.40, 129.65, 129.23, 129.09, 129.00, 118.84, 114.49, 80.74, 59.93, 55.67; ESI-MS: m/z 330 (M + 1)⁺; anal. calcd for C₁₉H₁₅N₅O; C, 69.29; H, 4.59; N, 21.26; found: C, 69.43; H, 4.64; N, 21.09.

5-Phenyl-7-(4-(trifluoromethyl)phenyl)-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidine-6-carbonitrile (5d). White powder; mp: 326–328 °C; IR (KBr) υ_max (cm⁻¹): 3168, 2928, 2398, 1568; ¹H NMR (400 MHz, DMSO-d₆): δ 6.60 (s, 1H), 7.57 (d, J = 8 Hz, 2H), 7.66 (t, J = 8 Hz, 4H), 7.83 (d, J = 8 Hz, 3H), 8.55 (s, 1H), 11.54 (s, 1H); ¹³C NMR (100 MHz, DMSO-d₆): δ 151.20, 150.41, 147.64, 144.26, 132.16, 131.55, 129.11, 129.04, 128.85, 126.43, 118.58, 80.25, 59.85; ESI-MS: m/z 368 (M + 1)⁺; anal. calcd for C₁₉H₁₂F₃N₅; C, 62.13; H, 3.29; N, 19.07; found: C, 62.27; H, 3.34; N, 19.32.

7-(4-Nitrophenyl)-5-phenyl-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidine-6-carbonitrile(5e). White powder; mp: 312–314 °C; IR (KBr) υ_max (cm⁻¹): 3169, 2955, 2386, 1556; ¹H NMR (400 MHz, DMSO-d₆): δ 6.49 (s, 1H), 7.46 (d, J = 8 Hz, 2H), 7.51–7.57 (m, 5H), 7.68 (d, J = 8 Hz, 2H), 7.81 (s, 1H), 11.52 (s, 1H); ¹³C NMR (100 MHz, DMSO-d₆): δ 152.69, 144.58, 138.36, 133.86, 130.58, 130.68, 129.63, 129.06, 126.58, 126.39, 118.25, 90.58, 57.58; ESI-MS: m/z 345 (M + 1)⁺; anal. calcd for C₁₈H₁₂N₆O₂; C, 62.79; H, 3.51; N, 24.41; found: C, 62.61; H, 3.56; N, 24.62.

7-(4-Fluorophenyl)-5-phenyl-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidine-6-carbonitrile (5f). White powder; mp: 346–348 °C; IR (KBr) υ_max (cm⁻¹): 3196, 2983, 2338, 1568; ¹H NMR (400 MHz, DMSO-d₆): δ 6.45 (s, 1H), 7.62 (t, J = 8 Hz, 3H), 7.74 (d, J = 8 Hz, 2H), 7.95–8.00 (m, 3H), 8.24 (t, J = 8 Hz, 1H), 8.27 (s, 1H), 9.26 (s, 1H); ¹³C NMR (100 MHz, DMSO-d₆): δ 154.27, 143.34, 135.69, 134.14, 131.58, 130.07, 129.41, 129.31, 129.02, 126.52, 125.91, 116.59, 93.35, 59.14; ESI-MS: m/z 318 (M + 1)⁺; anal. calcd for C₁₈H₁₂FN₅; C, 68.13; H, 3.81; N, 22.07; found: C, 68.24; H, 3.86; N, 22.27.

7-(4-Chlorophenyl)-5-phenyl-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidine-6-carbonitrile (5g). White powder; mp: 372–374 °C; IR (KBr) υ_max (cm⁻¹): 3128, 2998, 2384, 1523; ¹H NMR (400 MHz, DMSO-d₆): δ 6.48 (s, 1H), 7.45 (d, J = 8 Hz, 2H), 7.51–7.57 (m, 4H), 7.67 (d, J = 8 Hz, 2H), 7.73–7.75 (m, 1H), 7.80 (s, 1H), 11.48 (s, 1H); ¹³C NMR (100 MHz, DMSO-d₆): δ 155.58, 147.58, 137.58, 135.55, 130.82, 129.25, 129.25, 127.39, 125.58, 118.58, 86.96, 55.58; ESI-MS: m/z 334 (M + 1)⁺; anal. calcd for C₁₈H₁₂ClN₅; C, 64.77; H, 3.62; N, 20.98; found: C, 64.56; H, 3.57; N, 20.81.

7-(Naphthalen-1-yl)-5-phenyl-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidine-6-carbonitrile (5h). White powder; mp: 384–386 °C; IR (KBr) υ_max (cm⁻¹): 3158, 2925, 2328, 1572; ¹H NMR (400 MHz, DMSO-d₆): δ 6.53 (s, 1H), 7.29 (d, J = 8 Hz, 1H), 7.46 (s, 1H), 7.61 (t, J = 8 Hz, 2H), 7.72 (d, J = 8 Hz, 2H) 7.89 (d, J = 8 Hz, 2H), 7.95–8.00 (m, 2H), 8.26 (t, J = 8 Hz, 2H), 8.56 (s, 1H), 11.46 (s, 1H); ¹³C NMR (100 MHz, DMSO-d₆): δ 160.54, 156.38, 137.40, 136.44, 135.30, 133.60, 131.61, 129.72, 129.23, 128.24, 127.48, 125.68, 120.49, 117.63, 109.07, 106.94, 56.05; ESI-MS: m/z 350 (M + 1)⁺; anal. calcd for C₂₂H₁₅N₅; C, 75.63; H, 4.33; N, 20.04; found: C, 75.79; H, 4.38; N, 20.26.

7-(4-Hydroxyphenyl)-5-phenyl-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidine-6-carbonitrile (5i). White powder; mp: 330–332 °C; IR (KBr) υ_max (cm⁻¹): 3184, 2949, 2358, 1527; ¹H NMR (400 MHz, DMSO-d₆): δ 6.38 (s, 1H), 6.89 (d, J = 8 Hz, 1H), 7.26 (d, J = 8 Hz, 1H), 7.38 (d, J = 8 Hz, 1H), 7.52 (d, J = 8 Hz, 2H), 7.64 (d, J = 8 Hz, 2H), 7.78 (d, J = 8 Hz, 1H), 8.14 (t, J = 8 Hz, 1H), 8.82 (s, 1H), 10.32 (s, 1H), 11.48 (s, 1H); ¹³C NMR (100 MHz, DMSO-d₆): δ 156.55, 142.96, 138.35, 133.25, 132.94, 130.59, 129.59, 128.06, 127.58, 125.89, 117.28, 85.58, 54.82; ESI-MS: m/z 316 (M + 1)⁺; anal. calcd for C₁₈H₁₃N₅O; C, 68.56; H, 4.16; N, 22.21; found: C, 68.71; H, 4.21; N, 22.45.

Methyl 4-(6-cyano-5-phenyl-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl)benzoate (5j). White powder; mp: 346–348 °C; IR (KBr) υ_max (cm⁻¹): 3126, 2978, 2394, 1581; ¹H NMR (400 MHz, DMSO-d₆): δ 3.68 (s, 3H), 6.46 (s, 1H), 6.76 (d, J = 8 Hz, 2H), 7.18 (d, J = 8 Hz, 1H), 7.42 (d, J = 8 Hz, 1H), 7.56 (d, J = 8 Hz, 2H), 7.71 (d, J = 8 Hz, 2H), 7.84 (d, J = 8 Hz, 1H), 8.78 (s, 1H), 11.42 (s, 1H); ¹³C NMR (100 MHz, DMSO-d₆): δ 152.85, 147.58, 136.22, 135.58, 132.28, 130.58, 128.25, 127.25, 126.25, 119.25, 82.58, 63.45, 56.28; ESI-MS: m/z 358 (M + 1)⁺; anal. calcd for C₂₀H₁₅N₅O₂; C, 67.22; H, 4.23; N, 19.60; found: C, 67.39; H, 4.28; N, 19.48.

7-(4-Hydroxy-3-methoxyphenyl)-5-phenyl-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidine-6-carbonitrile (5k). White powder; mp: 345–347 °C; IR (KBr) υ_max (cm⁻¹): 3159, 2915, 2314, 1586; ¹H NMR (400 MHz, DMSO-d₆): δ 3.77 (s, 3H), 6.28 (s, 1H), 6.81 (t, J = 8 Hz, 2H), 6.96 (s, 1H), 7.57 (t, J = 8 Hz, 2H), 7.67 (d, J = 8 Hz, 2H), 7.76 (s, 1H), 8.01 (s, 1H), 8.86 (s, 1H), 9.23 (s, 1H); ¹³C NMR (100 MHz, DMSO-d₆): δ 150.70, 149.63, 148.14, 147.66, 147.30, 132.46, 131.38, 131.11, 129.68, 129.02, 120.53, 116.17, 112.15, 81.27, 60.28, 56.18; ESI-MS: m/z 346 (M + 1)⁺; anal. calcd for C₁₉H₁₅N₅O₂; C, 66.08; H, 4.38; N, 20.28; found: C, 66.23; H, 4.43; N, 20.03.

7-(3,4-Dimethoxyphenyl)-5-phenyl-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidine-6-carbonitrile (5l). White powder; mp: 362–364 °C; IR (KBr) υ_max (cm⁻¹): 3158, 2958, 2388, 1529; ¹H NMR (400 MHz, DMSO-d₆): δ 3.64 (s, 3H), 3.76 (s, 3H), 6.48 (s, 1H), 6.68 (t, J = 8 Hz, 2H), 6.89 (s, 1H), 7.48 (t, J = 8 Hz, 1H), 7.85 (d, J = 8 Hz, 2H), 7.96 (d, J = 8 Hz, 1H), 8.18 (s, 1H), 8.44 (s, 1H), 11.23 (s, 1H); ¹³C NMR (100 MHz, DMSO-d₆): δ 150.93, 142.58, 137.58, 132.86, 130.58, 129.25, 128.28, 126.25, 124.56, 116.28, 82.25, 62.45, 59.86, 52.58; ESI-MS: m/z 360 (M + 1)⁺; anal. calcd for C₂₀H₁₇N₅O₂; C, 66.84; H, 4.77; N, 19.49 Found: C, 66.68; H, 4.72; N, 19.67.

7-(2-Nitrophenyl)-5-phenyl-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidine-6-carbonitrile (5m). White powder; mp: 355–357 °C; IR (KBr) υ_max (cm⁻¹): 3199, 2958, 2353, 1559; ¹H NMR (400 MHz, DMSO-d₆): δ 6.98 (s, 1H), 7.57 (d, J = 8 Hz, 1H), 7.66 (s, 1H), 7.70 (t, J = 8 Hz, 2H), 7.77 (t, J = 8 Hz, 1H), 7.86 (d, J = 8 Hz, 1H), 8.09 (t, J = 8 Hz, 2H), 8.11 (d, J = 8 Hz, 1H), 9.26 (s, 1H), 11.57 (s, 1H); ¹³C NMR (100 MHz, DMSO-d₆): δ 155.14, 151.13, 149.32, 147.52, 134.38, 133.19, 132.41, 131.65, 130.18, 129.14, 128.94, 126.04, 125.32, 118.35, 78.93, 56.76; ESI-MS: m/z 345 (M + 1)⁺; anal. calcd for C₁₈H₁₂N₆O₂; C, 62.79; H, 3.51; N, 24.41 found: C, 62.58; H, 3.56; N, 24.63.

7-(3-Nitrophenyl)-5-phenyl-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidine-6-carbonitrile (5n). White powder; mp: 364–366 °C; IR (KBr) υ_max (cm⁻¹): 3169, 2929, 2358, 1548; ¹H NMR (400 MHz, DMSO-d₆): δ 6.73 (s, 1H), 7.57 (d, J = 8 Hz, 3H), 7.69 (d, J = 8 Hz, 3H), 7.79 (t, J = 8 Hz, 2H), 7.91 (s, 1H), 8.29 (s, 1H), 11.58 (s, 1H); ¹³C NMR (100 MHz, DMSO-d₆): δ 151.30, 150.73, 148.49, 141.84, 134.57, 132.14, 131.58, 131.29, 129.11, 124.47, 122.74, 118.55, 79.89, 59.44; ESI-MS: m/z 345 (M + 1)⁺; anal. calcd for C₁₈H₁₂N₆O₂; C, 62.79; H, 3.51; N, 24.41 found: C, 62.56; H, 3.55; N, 24.67.

7-(2-Chlorophenyl)-5-phenyl-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidine-6-carbonitrile (5o). White powder; mp: 312–314 °C; IR (KBr) υ_max (cm⁻¹): 3168, 2916, 2328, 1552; ¹H NMR (400 MHz, DMSO-d₆): δ 6.64 (s, 1H), 7.68 (d, J = 8 Hz, 3H), 7.82 (d, J = 8 Hz, 3H), 7.85 (t, J = 8 Hz, 2H), 7.86 (t, J = 8 Hz, 1H), 8.38 (s, 1H), 11.38 (s, 1H); ¹³C NMR (100 MHz, DMSO-d₆): δ 156.58, 153.58, 144.35, 140.58, 132.58, 131.25, 130.92, 130.25, 129.18, 128.88, 127.63, 126.36, 117.26, 81.82, 53.35; ESI-MS: m/z 334 (M + 1)⁺; anal. calcd for C₁₈H₁₂ClN₅; C, 64.77; H, 3.62; N, 20.98 found: C, 64.88; H, 3.67; N, 20.83.

5,7-Diphenyl-4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-carbonitrile (6a). White powder; mp: 386–388 °C; IR (KBr) υ_max (cm⁻¹): 3138, 2937, 2325, 1582; ¹H NMR (400 MHz, DMSO-d₆): δ 5.76 (s, 1H), 7.63–7.69 (m, 4H), 7.87 (d, J = 8 Hz, 2H), 8.01 (d, J = 8 Hz, 2H), 8.16 (d, J = 8 Hz, 2H), 9.25 (s, 1H); ¹³C NMR (100 MHz, DMSO-d₆): δ 155.88, 154.45, 137.63, 134.69, 132.74, 129.14, 128.99, 119.37, 119.05, 112.32, 101.01, 57.71; ESI-MS: m/z 301 (M + 1)⁺; anal. calcd for C₁₇H₁₂N₆; C, 67.99; H, 4.03; N, 27.98; found: C, 67.84; H, 4.08; N, 27.78.

5-Phenyl-7-(p-tolyl)-4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-carbonitrile (6b). White powder; mp: 379–381 °C; IR (KBr) υ_max (cm⁻¹): 3166, 2958, 2354, 1547; ¹H NMR (400 MHz, DMSO-d₆): δ 2.09 (s, 3H), 6.48 (s, 1H), 7.64–7.81 (m, 2H), 7.85 (t, J = 8 Hz, 2H), 7.86 (d, J = 8 Hz, 2H), 8.10 (d, J = 8 Hz, 2H), 8.22 (d, J = 8 Hz, 1H), 9.26 (s, 1H); ¹³C NMR (100 MHz, DMSO-d₆): δ 158.15, 142.98, 138.45, 133.74, 131.74, 131.32, 130.19, 129.90, 129.77, 129.46, 129.04, 119.40, 83.60, 56.08, 21.35; ESI-MS: m/z 315 (M + 1)⁺; anal. calcd for C₁₈H₁₄N₆; C, 68.78; H, 4.49; N, 26.74; found: C, 68.94; H, 4.44; N, 26.87.

7-(4-Methoxyphenyl)-5-phenyl-4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-carbonitrile (6c). White powder; mp: 396–398 °C; IR (KBr) υ_max (cm⁻¹): 3166, 2958, 2354, 1547; ¹H NMR (400 MHz, DMSO-d₆): δ 3.89 (s, 3H), 6.47 (s, 1H), 7.18 (d, J = 8 Hz, 2H), 7.59 (t, J = 8 Hz, 2H), 7.71 (t, J = 8 Hz, 1H), 7.84 (d, J = 8 Hz, 2H), 8.12 (d, J = 8 Hz, 2H), 9.02 (s, 1H); ¹³C NMR (100 MHz, DMSO-d₆): δ 155.85, 136.55, 134.10, 133.50, 129.62, 129.17, 124.78, 117.85, 115.46, 107.21, 58.40, 56.27; ESI-MS: m/z 331 (M + 1)⁺; anal. calcd for C₁₈H₁₄N₆O; C, 65.44; H, 4.27; N, 25.44; found: C, 65.61; H, 4.22; N, 25.27.

5-Phenyl-7-(4-(trifluoromethyl)phenyl)-4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-carbonitrile (6d). White powder; mp: 364–366 °C; IR (KBr) υ_max (cm⁻¹): 3168, 2938, 2318, 1527; ¹H NMR (400 MHz, DMSO-d₆): δ 6.59 (s, 1H), 7.26–7.45 (m, 3H), 7.78 (t, J = 8 Hz, 2H), 7.92 (d, J = 8 Hz, 2H), 8.06 (d, J = 8 Hz, 2H), 9.44 (s, 1H); ¹³C NMR (100 MHz, DMSO-d₆): δ 149.55, 132.71, 131.69, 131.23, 130.19, 130.11, 129.96, 129.19, 128.94, 119.85, 116.55, 83.77, 57.69; ESI-MS: m/z 369 (M + 1)⁺; anal. calcd for C₁₈H₁₁F₃N₆; C, 58.70; H, 3.01; N, 22.82 found: C, 58.52; H, 3.06; N, 22.98.

7-(4-Nitrophenyl)-5-phenyl-4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-carbonitrile (6e). White powder; mp: 347–349 °C; IR (KBr) υ_max (cm⁻¹): 3169, 2966, 2383, 1556; ¹H NMR (400 MHz, DMSO-d₆): δ 6.27 (s, 1H), 7.38 (t, J = 8 Hz, 4H), 7.61–7.67 (m, 2H), 7.74 (d, J = 8 Hz, 1H), 7.86 (d, J = 8 Hz, 1H), 8.13 (d, J = 8 Hz, 1H), 9.03 (s, 1H); ¹³C NMR (100 MHz, DMSO-d₆): δ 150.25, 146.25, 138.28, 135.23, 132.82, 130.82, 130.25, 129.25, 127.54, 116.42, 115.71, 82.25, 54.58; ESI-MS: m/z 346 (M + 1)⁺; anal. calcd for C₁₇H₁₁N₇O₂; C, 59.13; H, 3.21; N, 28.39 found: C, 59.26; H, 3.26; N, 28.57.

7-(4-Fluorophenyl)-5-phenyl-4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-carbonitrile (6f). White powder; mp: 372–374 °C; IR (KBr) υ_max (cm⁻¹): 3158, 2958, 2358, 1582; ¹H NMR (400 MHz, DMSO-d₆): δ 6.78 (s, 1H), 7.33 (t, J = 8 Hz, 2H), 7.53 (t, J = 8 Hz, 4H), 7.64 (d, J = 8 Hz, 3H), 10.16 (s, 1H); ¹³C NMR (100 MHz, DMSO-d₆): δ 149.55, 140.78, 136.90, 132.71, 131.69, 131.23, 130.19, 130.11, 129.96, 129.19, 128.94, 119.85, 116.55, 83.77, 56.86; ESI-MS: m/z 319 (M + 1)⁺; anal. calcd for C₁₇H₁₁FN₆; C, 64.15; H, 3.48; N, 26.40 found: C, 64.23; H, 3.43; N, 26.64.

7-(4-Chlorophenyl)-5-phenyl-4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-carbonitrile (6g). White powder; mp: 338–340 °C; IR (KBr) υ_max (cm⁻¹): 3159, 2968, 2338, 1528; ¹H NMR (400 MHz, DMSO-d₆): δ 6.64 (s, 1H), 7.48 (t, J = 8 Hz, 2H), 7.64 (t, J = 8 Hz, 2H), 7.82 (t, J = 8 Hz, 2H), 7.92 (d, J = 8 Hz, 3H), 10.54 (s, 1H); ¹³C NMR (100 MHz, DMSO-d₆): δ 156.56, 147.42, 134.28, 133.25, 132.58, 131.85, 130.57, 129.74, 128.17, 117.24, 114.17, 79.11, 55.77; ESI-MS: m/z 335 (M + 1)⁺; anal. calcd for C₁₇H₁₁ClN₆; C, 60.99; H, 3.31; N, 25.10 found: C, 60.84; H, 3.36; N, 25.29.

7-(Naphthalen-1-yl)-5-phenyl-4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-carbonitrile (6h). White powder; mp: 369–371 °C; IR (KBr) υ_max (cm⁻¹): 3198, 2929, 2373, 1547; ¹H NMR (400 MHz, DMSO-d₆): δ 6.64 (s, 1H), 7.34 (d, J = 8 Hz, 1H), 7.64 (t, J = 8 Hz, 2H), 7.84 (d, J = 8 Hz, 2H) 7.89 (d, J = 8 Hz, 2H), 7.91–8.12 (m, 3H), 8.32 (t, J = 8 Hz, 2H), 11.18 (s, 1H) ¹³C NMR (100 MHz, DMSO-d₆): δ 156.56, 147.42, 134.28, 133.25, 132.58, 131.85, 130.57, 129.74, 128.17, 117.24, 114.17, 79.11, 55.77; ESI-MS: m/z 351 (M + 1)⁺; anal. calcd for C₂₁H₁₄N₆; C, 71.99; H, 4.03; N, 23.99 found: C, 71.82; H, 4.09; N, 23.24.19.

7-(4-Hydroxyphenyl)-5-phenyl-4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-carbonitrile (6i). White powder; mp: 356–358 °C; IR (KBr) υ_max (cm⁻¹): 3166, 2958, 2354, 1547; ¹H NMR (400 MHz, DMSO-d₆): δ 6.24 (s, 1H), 7.47 (d, J = 8 Hz, 2H), 7.82 (t, J = 8 Hz, 2H), 7.91 (d, J = 8 Hz, 2H), 8.07 (t, J = 8 Hz, 2H), 8.14 (d, J = 8 Hz, 1H), 9.26 (s, 1H), 12.38 (s, 1H); ¹³C NMR (100 MHz, DMSO-d₆): δ 156.57, 137.47, 135.72, 134.17, 130.12, 129.47, 125.82, 119.57, 116.57, 92.68, 56.25; ESI-MS: m/z 317 (M + 1)⁺; anal. calcd for C₁₇H₁₂N₆O; C, 64.55; H, 3.82; N, 26.57; found: C, 64.73; H, 3.77; N, 26.79.

Methyl 4-(6-cyano-5-phenyl-4,7-dihydrotetrazolo[1,5-a]pyrimidin-7-yl)benzoate (6j). White powder; mp: 362–364 °C; IR (KBr) υ_max (cm⁻¹): 3149, 2935, 2327, 1582; ¹H NMR (400 MHz, DMSO-d₆): δ 3.61 (s, 3H), 6.51 (s, 1H), 7.28 (d, J = 8 Hz, 2H), 7.67 (t, J = 8 Hz, 2H), 7.84 (d, J = 8 Hz, 2H), 8.02 (t, J = 8 Hz, 2H), 8.21 (d, J = 8 Hz, 1H), 11.21 (s, 1H); ¹³C NMR (100 MHz, DMSO-d₆): δ 155.65, 136.88, 134.58, 133.25, 129.62, 129.14, 124.24, 117.87, 115.14, 107.25, 62.58, 61.38, 56.25; ESI-MS: m/z 359 (M + 1)⁺; anal. calcd for C₁₉H₁₄N₆O₂; C, 63.68; H, 3.94; N, 23.45; found: C, 63.92; H, 3.88; N, 23.21.

7-(3-Hydroxy-4-methoxyphenyl)-5-phenyl-4,7-dihydro-[1,2,4]tetrazolo[1,5-a]pyrimidine-6-carbonitrile (6k). White powder; mp: 354–358 °C; IR (KBr) υ_max (cm⁻¹): 3158, 2954, 2324, 1522; ¹H NMR (400 MHz, DMSO-d₆): δ 3.77 (s, 3H), 6.28 (s, 1H), 6.81 (d, J = 8 Hz, 2H), 6.95 (s, 1H), 7.56–7.76 (m, 4H), 8.00 (d, J = 8 Hz, 2H), 8.86 (s, 1H), 9.25 (s, 1H); ¹³C NMR (100 MHz, DMSO-d₆): δ 156.58, 134.56, 133.85, 132.28, 130.48, 128.58, 126.75, 118.28, 117.28, 89.27, 60.58, 55.58; ESI-MS: m/z 347 (M + 1)⁺; anal. calcd for C₁₉H₁₅N₅O₂; C, 62.42; H, 4.07; N, 24.27; found: C, 62.60; H, 4.12; N, 24.02.

7-(3,4-Dimethoxyphenyl)-5-phenyl-4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-carbonitrile (6l). White powder; mp: 354–358 °C; IR (KBr) υ_max (cm⁻¹): 3158, 2954, 2324, 1522; ¹H NMR (400 MHz, DMSO-d₆): δ 3.62 (s, 3H), 3.81 (s, 3H), 6.37 (s, 1H), 6.79 (d, J = 8 Hz, 2H), 7.49–7.74 (m, 4H), 8.02 (d, J = 8 Hz, 1H), 8.18 (s, 1H), 11.34 (s, 1H); ¹³C NMR (100 MHz, DMSO-d₆): δ 154.55, 144.58, 136.22, 133.85, 131.28, 129.58, 127.18, 115.57, 117.48, 86.77, 60.58, 58.48, 54.58; ESI-MS: m/z 361 (M + 1)⁺; anal. calcd for C₁₉H₁₆N₆O₂; C, 63.32; H, 4.48; N, 23.32; found: C, 63.17; H, 4.53; N, 23.15.

7-(2-Nitrophenyl)-5-phenyl-4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-carbonitrile (6m). White powder; mp: 346–348 °C; IR (KBr) υ_max (cm⁻¹): 3187, 2981, 2328, 1589; ¹H NMR (400 MHz, DMSO-d₆): δ 6.48 (s, 1H), 7.47 (d, J = 8 Hz, 1H), 7.58 (s, 1H), 7.72 (t, J = 8 Hz, 2H), 7.81 (t, J = 8 Hz, 1H), 7.90 (d, J = 8 Hz, 1H), 8.21 (t, J = 8 Hz, 2H), 8.32 (d, J = 8 Hz, 1H), 11.48 (s, 1H); ¹³C NMR (100 MHz, DMSO-d₆): δ 154.52, 150.85, 145.58, 144.55, 136.58, 132.58, 131.83, 130.28, 127.28, 124.58, 119.26, 84.82, 56.58; ESI-MS: m/z 346 (M + 1)⁺; anal. calcd for C₁₇H₁₁N₇O₂; C, 59.13; H, 3.21; N, 28.39 found: C, 59.31; H, 3.26; N, 28.53.

7-(3-Nitrophenyl)-5-phenyl-4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-carbonitrile (6n). White powder; mp: 322–324 °C; IR (KBr) υ_max (cm⁻¹): 3158, 2965, 2318, 1573; ¹H NMR (400 MHz, DMSO-d₆): δ 6.26 (s, 1H), 7.28 (d, J = 8 Hz, 3H), 7.42 (d, J = 8 Hz, 3H), 7.71 (t, J = 8 Hz, 2H), 8.26 (s, 1H), 11.58 (s, 1H); ¹³C NMR (100 MHz, DMSO-d₆): δ 152.29, 149.58, 145.51, 136.56, 134.58, 132.58, 130.58, 129.28, 128.58, 127.95, 125.28, 125.01, 118.58, 81.83, 53.55; ESI-MS: m/z 346 (M + 1)⁺; anal. calcd for C₁₇H₁₁N₇O₂; C, 59.13; H, 3.21; N, 28.39 found: C, 59.29; H, 3.26; N, 28.60.

7-(2-Chlorophenyl)-5-phenyl-4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-carbonitrile (6o). White powder; mp: 346–348 °C; IR (KBr) υ_max (cm⁻¹): 3159, 2928, 2385, 1512; ¹H NMR (400 MHz, DMSO-d₆): δ 6.37 (s, 1H), 7.58 (d, J = 8 Hz, 1H), 7.74 (s, 1H), 7.82 (t, J = 8 Hz, 2H), 7.96 (t, J = 8 Hz, 1H), 8.04 (d, J = 8 Hz, 1H), 8.32 (t, J = 8 Hz, 2H), 8.48 (d, J = 8 Hz, 1H), 11.10 (s, 1H); ¹³C NMR (100 MHz, DMSO-d₆): δ 149.77, 148.13, 145.27, 134.85, 132.75, 130.58, 130.58, 129.34, 128.58, 126.83, 125.28, 118.28, 87.47, 52.48; ESI-MS: m/z 335 (M + 1)⁺; anal. calcd for C₁₇H₁₁ClN₆; C, 60.99; H, 3.31; N, 25.10 found: C, 60.82; H, 3.37; N, 25.34.

3.3. Crystal structure determination

The single-crystal X-ray diffraction data of the crystals 5a were collected on a Bruker Kappa APEX-II CCD DUO diffractometer at 293(2) K using graphite-monochromated Mo Kα radiation (λ = 0.71073 Å). No absorption correction was applied. The lattice parameters were determined from least-squares analysis, and reflection data were integrated using the program SHELXTL.²¹ The crystal structures were solved by direct methods using SHELXS-97 and refined by full-matrix least-squares refinement on F² with anisotropic displacement parameters for non-H atoms using SHELXL-97.²² All the aromatic and aliphatic C–H hydrogens were generated by the riding model in idealized geometries. The software used to prepare material for publication was Mercury 2.3 (Build RC4), ORTEP-3 and X-Seed.²³

4. Conclusion

We have achieved a simple and highly efficient method for the multicomponent synthesis of a medicinally relevant family of triazolo and tetrazolo[1,5-a]pyrimidine derivatives using CeO₂ catalyst. This synthetic protocol offers several advantages including substantial improvements in the reaction rates and yields and also avoids the use of hazardous catalysts and solvents. The promising points for the presented methodology are its efficiency, generality, high yield, short reaction time, ease of handling of the catalyst, cleaner reaction profile, ease of product isolation, simplicity, potential for recycling of the catalyst, and finally agreement with the green chemistry protocols.

Acknowledgements

The authors are thankful to the Director, National Institute of Technology, Warangal, for providing facilities. L.S. thanks The Ministry of Human Resource Development and PSVK are grateful to CSIR, New Delhi, India [File 09/922 (0005) 2012/EMR-I] for financial support. The authors also wish to thank the STIC, Cochin for the single crystal X-ray analysis.

References

1. (a) F. X. Zhu, W. Wang and H. X. Li, J. Am. Chem. Soc., 2011, 133, 11632; (b) C. J. Li and L. Chen, Chem. Soc. Rev., 2006, 35, 68; (c) J. iwari, M. Saquib, S. Singh, F. Tufail, M. Singh, J. Singh and J. Singh, Green Chem., 2016, 18, 3221; (d) D. Chandrasekhar, S. Borra, J. S. Kapure, G. S. Shivaji, G. Srinivasulu and R. A. Maurya, Org. Chem. Front., 2015, 2, 1308.
2. (a) R. N. Butler and A. G. Coyne, Chem. Rev., 2010, 110, 6302; (b) T. N. Poudel, Y. R. Lee and S. H. Kim, Green Chem., 2015, 17, 4579; (c) A. Koike and M. Akita, Org. Chem. Front., 2016 10.1039/c6qo00139d.
3. (a) U. M. Lindström, Chem. Rev., 2002, 102, 2751; (b) J. Huang, W. Wang and H. Li, ACS Catal., 2013, 3, 1526; (c) N. Poomathi, S. Mayakrishnan, D. Muralidharan, R. Srinivasan and P. T. Perumal, Green Chem., 2015, 17, 3362; (d) R. K. Saunthwal, M. Patel, R. K. Tiwari, K. Parang and A. K. Verma, Green Chem., 2015, 17, 1434; (e) J. Liu, M. Lei and L. Hu, Green Chem., 2012, 14, 2534.
4. (a) F. Atsushi and P. L. Dhepe, Chem. Rec., 2009, 9, 224; (b) G. Oskam, J. Sol-Gel Sci. Technol., 2006, 37, 161; (c) F. Chahdoura, S. M. Ladeira and M. Gomez, Org. Chem. Front., 2015, 2, 312; (d) L. Tang, Y. Yang, L. Wen, S. Zhang, Z. Zha and Z. Wang, Org. Chem. Front., 2015, 2, 114.
5. (a) E. Kockrick, C. Schrage, A. Grigas, D. Geiger and S. Kaskel, J. Solid State Chem., 2008, 181, 1614; (b) M. Baalousha, Y. Ju. Nam, P. A. Cole, J. A. Hriljac, I. P. Jones, C. R. Tyler, V. Stone, T. F. Fernandes, M. A. Jepson and J. R. Lead, Environ. Toxicol. Chem., 2012, 31, 994; (c) S. Santoro, S. I. Kozhushkov, L. Ackermann and L. Vaccaro, Green Chem., 2016, 18, 3471; (d) T. Vinodkumar, B. Govinda Rao and B. M. Reddy, Catal. Today, 2015, 253, 57.
6. (a) A. Asati, S. Santra, C. Kaittanis, S. Nath and J. M. Perez, Angew. Chem., Int. Ed., 2009, 48, 2308; (b) H. Jin, N. Wang, L. Xu and S. Hou, Mater. Lett., 2010, 64, 1254; (c) M. B. Gawande, V. D. Bonifácio, R. S. Varma, I. D. Nogueira, N. Bundaleski, C. A. A. Ghumman, O. M. Teodoro and P. S. Branco, Green Chem., 2013, 15, 1226; (d) T. Vinodkumar, D. Naga Durgasri, S. Maloth and B. M. Reddy, J. Chem. Sci., 2015, 127, 1145.
7. (a) C. De Graaff, E. Ruijter and R. V. a. Orru, Chem. Soc. Rev., 2012, 41, 3969; (b) R. C. Cioc, E. Ruijter and R. V. A. Orru, Green Chem., 2014, 16, 2958; (c) N. Isambert and R. Lavilla, Chem.–Eur. J., 2008, 14, 8444; (d) P. Slobbe, E. Ruijter and R. V. A. Orru, MedChemComm, 2012, 3, 1189; (e) G. Sapuppo, Q. Wang, D. Swinnen and J. Zhu, Org. Chem. Front., 2014, 1, 240.
8. (a) M. C. Pirrung and K. Das Sarma, J. Am. Chem. Soc., 2004, 126, 444; (b) M. Abbas, J. Bethke and L. a. Wessjohann, Chem. Commun., 2006, 8, 541; (c) T. Z. Tzitzikas and A. Domling, Org. Chem. Front., 2014, 1, 834; (d) P. Sagar Vijay Kumar, L. Suresh and G. V. P. Chandramouli, J. Saudi Chem. Soc., 2015 DOI:10.1016/j.jscs.2015.08.001.
9. (a) L. Suresh, Y. Poornachandra, S. Kanakaraju, C. Ganesh Kumar and G. V. P. Chandramouli, Org. Biomol. Chem., 2015, 13, 7294; (b) F. Xie, H. Zhao, L. Zhao, L. Lou and Y. Hu, Bioorg. Med. Chem. Lett., 2009, 19, 275; (c) V. Yerragunta, P. Patil, V. Anusha, T. Kumaraswamy, D. Suman and T. Samhitha, PharmaTutor Mag., 2013, 1, 39; (d) R. Wang and Z. Q. Liu, Org. Chem. Front., 2014, 1, 792.
10. (a) V. A. Chebanov, E. A. Muravyova, S. M. Desenko, V. I. Musatov, I. V Knyazeva, S. V Shishkina, O. V. Shishkin and C. O. Kappe, J. Comb. Chem., 2006, 8, 427; (b) T. Okamura, Y. Kurogi, K. Hashimoto, H. Nishikawa and Y. Nagao, Bioorg. Med. Chem. Lett., 2004, 14, 2443; (c) N. D. Desai, Synth. Commun., 2006, 36, 2169; (d) L. Suresh, P. Sagar Vijay Kumar, Y. Poornachandra, C. Ganesh Kumar and G. V. P. Chandramouli, Bioorg. Med. Chem., 2016 DOI:10.1016/j.bmc.2016.06.025; (e) L. Suresh, P. Onkarab, P. Sagar Vijay Kumara, Y. Pydisetty and G. V. P. Chandramouli, Bioorg. Med. Chem. Lett., 2016 DOI:10.1016/j.bmcl.2016.06.086.
11. (a) Q. Chen, X. L. Zhu, L. L. Jiang, Z. M. Liu and G. F. Yang, Eur. J. Med. Chem., 2008, 43, 595; (b) Y. A. H. Mostafa, M. A. Hussein, A. A. Radwan and A. E. H. N. Kfafy, Arch. Pharm. Sci. Res., 2008, 31, 279.
12. H. N. Hafez and A. R. B. A. El-Gazzar, Bioorg. Med. Chem. Lett., 2009, 19, 4143.
13. (a) N. Liu, F. Zhao, P. Zhan and X. Liu, MedChemComm, 2015, 117, 10; (b) H. Jia, D. Rai, P. Zhan, X. Chen, X. Jiang and X. Liu, Med. Chem., 2015, 7, 587.
14. H. Wang, C. Wei, X. Deng, F. Li and Z. Quan, Arch. Pharm., 2009, 342, 671.
15. A. Hirabayashi, H. Mukaiyama, H. Kobayashi, H. Shiohara, S. Nakayama, M. Ozawa, K. Miyazawa, K. Misawa, H. Ohnota and M. Isaji, Bioorg. Med. Chem., 2008, 16, 7347.
16. K. M. Abu-Zied, A. B. A. El-Gazzar and N. A. Hassan, J. Chin. Chem. Soc., 2008, 55, 209.
17. K. A. Ali, E. A. Ragab, T. A. Farghaly and M. M. Abdalla, Acta Pol. Pharm., 2011, 68, 237.
18. W. Yu, C. Goddard, E. Clearfield, C. Mills, T. Xiao, H. Guo, J. D. Morrey, N. E. Motter, K. Zhao, T. M. Block, A. Cuconati and X. Xu, J. Med. Chem., 2011, 54, 5660.
19. (a) P. Sagar Vijay Kumar, L. Suresh, T. Vinodkumar, B. M. Reddy and G. V. P. Chandramouli, ACS Sustainable Chem. Eng., 2016, 4, 2376; (b) P. S. V. Kumar, L. Suresh, G. Bhargavi, S. Basavoju and G. V. P. Chandramouli, ACS Sustainable Chem. Eng., 2015, 3, 2944.
20. T. Vinodkumar, D. Naga Durgasri, B. M. Reddy and I. Alxneit, Catal. Lett., 2014, 144, 2033.
21. SHELXTL, Program for the Solution and Refinement of Crystal Structures, version 6.14, Bruker AXS, Wisconsin, USA, 2000.
22. G. M. Sheldrick, SHELX-2013: Program for the Solution and refinement of Crystal Structures, University of Göttingen, Germany, 1997.
23. (a) C. F. Macrae, I. J. Bruno, J. A. Chisholm, P. R. Edgington, P. McCabe, E. Pidcock, L. Rodriguez-Monge, R. Taylor, J. van de Streek and P. A. Wood, J. Appl. Crystallogr., 2008, 41, 466; (b) M. N. Burnett, C. K. Johnson and L. J. J. Farrugia, J. Appl. Crystallogr., 1997, 30, 565.

---

Footnote

† Electronic supplementary information (ESI) available. CCDC 1440718. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c6ra16307f

---