ent protocol for synthesis ofpyrido[1,2-a]pyrimidin-4-one derivatives over solidheteropolyacid catalysts†
Sulaiman N. Basahel,ab Nesreen S. Ahmed,*ac Katabathini Narasimharao*ab
and Mohamed Mokhtarab
Aluminium exchanged tungstophosphoric acid salts with Keggin structure (AlxH3�xPW12O40) were prepared
by simple ion exchange method. The prepared heteropolyacid salts were characterized by various
techniques such as elemental analysis, XRD, FTIR, UV-vis, N2-physisorption, NH3-TPD and FTIR-pyridine
adsorption. All the prepared catalysts possess both Brønsted and Lewis acid sites, however increase of
surface area and Lewis acid sites was observed with increase of Al content. The catalysts have been
applied as heterogeneous catalysts to synthesize pyrido[1,2-a]pyrimidines under mild reaction conditions.
A variety of biologically active pyrido[1,2-a]pyrimidines were obtained in best yields ever (above 90%) by
using a simple, eco-friendly and efficient protocol catalyzed by AlxH3�xPW12O40 catalysts. Al3PW12O40
catalyst showed highest activity due to introduction of more number of Lewis acid sites to parent
H3PW12O40 by complete exchange of H+ ions by Al3+ ions.
1. Introduction
The pyrimidine core has always attracted much attention ascompounds containing this structural motif are known toexhibit diverse pharmaceutical potency. The purine bases ofDNA and RNA as well as the building blocks of numerousnatural products are known to have the pyrimidine unit.1 It wasreported that pyrido[1,2-a]pyrimidine derivatives are usefulbuilding blocks for the synthesis of well-known drugs [Fig. 1]such as antipsychotic agents2 antiasthmatic agent,3 tranquil-izer,4 anti-allergic and antiulcerative agents.5
A vast number of methods have been developed for thesynthesis of pyridopyrimidine derivatives.6 The pyrido[1,2-a]-pyrimidin-4-ones (Scheme 1) forms the best-known class ofpyrido[1,2-a]pyrimidines, to which numerous synthetic routesare available,7 however, the reported methods usually requireslonger reaction time, complex synthetic methodologies,expensive homogeneous catalyst and oen used harmfulorganic solvents.
Reported literature methods to synthesize pyrido[1,2-a]-pyrimidin-2-ones involved different methodologies. Roma
et al.8 obtained a mixture of pyrido[1,2-a]pyrimidin-2-ones andpyrido[1,2-a]pyrimidin-4-ones by performing the cyclization of2-aminopyridine with the Vilsmeier–Haack reagent whichprepared in situ from N-alkyl-N-arylethoxycarbonylacetamideand phosphorus oxychloride was used as catalyst. Doad et al.synthesized of derivatives of pyrido[1,2-a]pyrimidin-2-ones bythe reaction of 2-aminopyridines with allene-1,3-dicarboxylicesters.9 Dorokhov et al.10 reported the cyclization of 2-amino-pyridine with ethyl cyanoacetate at 80–100 �C under 14 kbarpressure. Suri et al.11 used acid catalyzed cyclization of N-acetoacetylated-2-amino pyridines/picolines/quinolines undermicrowave irradiation. Formation of signicant amount ofundesired products was observed when the reaction was carriedout between 2-aminopyridine and phenylpropiolic ester.12 Thusexploration of more simple and convenient synthetic methodfor the synthesis of pyrido[1,2-a]pyrimidin-2-ones still remainsan active research area.
Keggin structured heteropoly compounds are known topossess high acidity and oxidizing properties. These materialscan be used to replace classical mineral acids with someadvantages, such as a lower corrosion and a lower production ofwastes, thus leading to eco-efficient processes.13 The bulk het-eropolyacids, such as tungstophosphoric and tungstosilicicacids, lead to low catalytic yield in some acid reactions, mainlydue to their low specic surface area. This disadvantage can beovercome by using their salts with different cations or sup-porting the heteropolyacid on adequate porous supports.14 Theacidic properties of the salts of the heteropolyacids depend onthe cation type, the constituent elements of the polyanion andtheir tertiary structure.15 The partial hydrolysis and the presence
Fig. 1 Few examples of biologically active agents consisted of pyrido[1,2-a]pyrimidine derivatives.
Scheme 1 Synthesis of pyrido[1,2-a]pyrimidin-4-one derivatives IIIa–h.
RSC Advances Paper
of in homogeneities resulting from the synthesis also exerta marked inuence. The salts of the Keggin heteropolyacids canbe classied into two groups.16 The salts of small cations
11922 | RSC Adv., 2016, 6, 11921–11932
(classied as type A) are very soluble in water or organicsolvents, possess a low specic surface area, and in generalbehave in many respects in a similar way to the parent acid. The
a AAS analysis by dissolving the salts in standard NaOH solution. b XPSanalysis.
Paper RSC Advances
salts of large cations (classied as type B) are insoluble in water,have high specic surface area and relatively high thermalstability. The salts of large cations gave excellent catalyticactivity in diverse acid reactions.17 However, the salts of the Atype have been less utilized. The salts of the Al3+ cation of thetungstophosphoric acid (AlPW) have interesting characteristicsfor their use as catalysts because they can present Lewis and/orBrønsted acid sites. Baba et al.18 studied the generation of acidicsites in the Al3+ and Cu2+ neutral salts of tungstophosphoricacid. Firouzabadi et al.19 have studied the effect of the non-hygroscopic AlPW12O40 salt in the acylation of aromaticcompounds.
Previous reports have also suggested that synthesis of pyrido-[1,2-a]pyrimidines process can be successfully carried out byvarious Lewis acidic catalysts. In view of these considerations, itis interesting to study the exchange of Al with HPW as itgenerates the Lewis acidic sites over the catalyst surface,whereby the rate of the reaction would be increased signi-cantly as compared to that of parent H3PW catalyst. Therefore, itis our aim to test the scope for synthesis of pyrido[1,2-a]-pyrimidine derivatives using AlPW catalyst (Scheme 1). In ourcontinued interest in the development of highly expedientmethods for the synthesis of important organic derivatives20 wereport in this paper a simple and convenient synthesis protocolfor synthesis of pyrido[1,2-a]pyrimidine derivatives catalyzed bysolid Keggin structured AlPW catalysts. The objective of thiswork is to prepare and characterize the AlPW salts and applythem as catalysts to obtain pyrido[1,2-a]pyrimidine derivativesin higher yields and correlate the characteristic properties ofAlPW catalysts with their catalytic activity.
2. Experimental2.1 Preparation of Al salts of tungstophosphoric acid
First, tungstophosphoric acid (H3PW) was dried at 100 �C toremove the physically adsorbed water before use. AlxH3�x-PW12O40 samples (x ¼ 1, 2 and 3) were prepared by dropwiseaddition of predetermined amounts of a 0.02 mol dm�3
aluminum nitrate aqueous–ethanol (50 : 50 volume ratio)solution to a 0.08 mol dm�3 ethanol solution of tungstophos-phoric acid at room temperature. The obtained white precipi-tate was le to dry overnight at room temperature in a vacuumoven to remove the ethanol and water. Fine white powders wereobtained by oven-drying the materials in air at 100 �C. Nofurther pretreatments were applied to the materials, which werestored in air before analysis and reaction testing. Catalysts areabbreviated with reference to their Al content (e.g., Al2 ¼ Al2-HPW12O40). The extent of proton exchange by Al and nalcomposition of the salts were determined by elemental analysis(Table 1).
2.2 Characterization of catalysts
X-ray powder diffraction (XRD) studies were performed for all ofthe prepared solid samples using a Bruker diffractometer(Bruker D8 advance target). The patterns were run with copperKa and a monochromator (l ¼ 1.5405 A) at 40 kV and 40 mA.
The crystallite size of the MgSil phase was calculated usingScherrer's equation:
D ¼ Bl/b1/2 cos q (1)
where D is the average crystallite size of the phase underinvestigation, B is the Scherrer constant (0.89), ‘l’ is wavelengthof the X-ray beam used (1.54056 A), ‘b1/2’ is the full width at halfmaximum (FWHM) of the diffraction peak and ‘q’ is thediffraction angle. The identication of different crystallinephases in the samples was performed by comparing the datawith the Joint Committee for Powder Diffraction Standards(JCPDS) les.
FTIR spectra of catalysts obtained at room temperature usingPerkin-Elmer Spectrum 100 FTIR spectrometer. Then, thesamples were subjected to pyridine adsorption analysis. Theanalysis was carried out over a catalyst coated on a silicone diskwhich was treated under vacuum for 5 h. Later, the sampleswere treated with pyridine vapor and nally heated at 100 �Cunder vacuum for 30 min. The amount of Brønsted and Lewisacid sites was calculated via integration of the area of theabsorption bands showing the maximum values of intensity at1446 cm�1 and 1536 cm�1, respectively. Integrated absorbanceof each band was obtained using the appropriate soware byapplying the corresponding extinction coefficient and normal-ized by the weight of the samples.
DR UV-vis absorption spectra of the samples were collectedusing a Thermo-Scientic evolution spectrophotometer equip-ped with an integrating sphere in the wavelength range 200–800nm to measure the reectance spectra of each sample. A smallamount (10 mg) of the sample in powder form was dispersedand pressed rmly between two microscope glass plates tocreate a thin absorbing lm.
The textural properties of the synthesized samples weredetermined from nitrogen adsorption/desorption isothermmeasurements at �196 �C using a model NOVA 3200e auto-mated gas sorption system (Quantachrome, USA). Prior tomeasurement, each sample was degassed for 6 h at 150 �C. Thespecic surface area, SBET, was calculated by applying the Bru-nauer–Emmett–Teller (BET) equation. The average pore radiuswas estimated from the relation 2Vp/SBET, where Vp is the totalpore volume (at P/P0 ¼ 0.975). Pore size distribution over themesopore range was generated by the Barrett–Joyner–Halenda
RSC Adv., 2016, 6, 11921–11932 | 11923
RSC Advances Paper
(BJH) analysis of the desorption branches, and the values for theaverage pore size in radius were calculated.
The acidity of the samples were further characterized bytemperature programmed desorption (TPD) using 99.9% NH3/He. TPDs were performed in a Quantachrome CHEMBET 3000apparatus coupled to a thermal conductivity detector. Sample(0.1 g) was pretreated under the ow of helium gas [25 mlmin�1, 99.99%] at 200 �C for 1 hour. Sample was then cooled to30 �C and saturated the sample with of NH3 (50 ml min�1) for 1hour. The loosely bound NH3 to the sample surface wasremoved by owing helium gas (50 ml min�1) for 1 hour. TheNH3-TPD patterns were recorded by increasing the temperatureof the sample at 10 �C min�1 up to 800 �C.
2.3 Typical procedure for the synthesis of pyrido[1,2-a]-pyrimidin-4-ones
Solid catalyst (0.1 g), was added to a mixture of 2-amino-6-methylpyridine I (1.08 g, 10 mmol) and 1,3-diketone deriva-tives IIa–c (10 mmol) in absolute ethanol (10 ml), and then thereaction was started at reuxing temperature. The progress ofthe reaction was monitored by TLC. Upon completion of thereaction, the mixture was ltered on hot to extract the solidcatalyst. Dissolution of the products in hot alcohol aer evap-orating the volatile materials by vacuum, compounds IIIa–hwere re-crystallized. The used catalyst was collected by washingwith hot ethyl alcohol.
2.4 Analyses of the reaction products
All melting points were measured on a Gallenkamp meltingpoint apparatus and are uncorrected. The infrared spectra wererecorded for the compounds in Perkin-Elmer SP 100 infraredspectrophotometer. The 1H NMR and 13C NMR spectra wererecorded on a Bruker WM-600 and WM 350 MHz spectrometer,receptively using TMS (0.00 ppm). The signal of the deuteratedsolvents was used as internal standard. Chemical shis (d) aregiven in ppm relative to the signal for TMS as a standard, andcoupling constant in Hz. Mass spectra were recorded on a Shi-madzu GCMS-QP 1000 EX mass spectrometer at 70 eV.Elemental analyses (C, H, N and S) were carried out at theMicroanalytical Center of Cairo University, Giza, Egypt, theresults were found to be in good agreement (�0.3%) with thecalculated values.
2-Methyl-4H-pyrido[1,2-a]pyrimidin-4-one (IIIa). Yellowcrystals from ethanol and n-hexane (3 : 1), m.p. 120–122 �C [ref.21 m.p. 118–119 �C], FTIR vmax/cm
The bulk and surface composition of the parent H3PW andAlPW samples were performed by elemental and XPS analysisrespectively. Good agreement between nominal and observedbulk Al content was observed for all the samples (Table 1). Theresults show that the surface composition varies withincreasing bulk Al content from 3.9 to 12.5 wt%. The almostlinear increase in surface Al and concomitant decrease insurface W conrms the incorporation of Al into the H3PWclusters rather than simple encapsulation of H3PW particles
with Al over layer. The surface Al content is slightly lower thanthe bulk, suggesting that the surface is Al-depleted. The bulkand theoretical values are in excellent agreement; however,there is a signicant deviation between the surface and bulk Al/W ratios at low Al content. This kind of deviation was previ-ously observed by other authors and consistent with the reportsfor the metal (M) salts of H3PW. The observed deviation wasaccounted for by structural models proposed for intermediateMxH3�xPW12O40 compositions, in which M3PW12O40 coreparticles purportedly are coated with a surface layer ofH3PW12O40 clusters.27
3.2 X-ray diffraction
X-ray powder diffraction is commonly used to study the struc-ture of heteropoly compounds. The powder XRD patterns of allthe samples are shown in Fig. 2. Pure H3PW sample exhibits allof the reections corresponding to a cubic Pn3m crystallinestructure.28 Aer initial ion-exchange to form AlH2PW12O40,a new set of peaks evolved; the diffraction peaks correspondingto the free acid disappeared as the Al content increased to 2 and3. The shi in H3PW peaks toward higher angles in the AlPWsamples is consistent with the body-centered cubic (bcc)structure of Al3PW12O40 salts reported in the literature29 and theobserved XRD results indicate the presence of a unique crys-talline Al3PW12O40 phase in all AlPW samples. From X-ray peakbroadening, it is possible to calculate the average particle size ofthe phases using Scherrer's equation. The crystallite size (D indiameter) of the AlPW samples, summarized in Table 1, wascalculated from this eqn (1). Analysis of the line widths of theXRD peaks of the AlxPW salts (x ¼ 0–3) show that the size of theprimary crystallites decrease from 80 to 30 nm as Al loadingincreases to Al2, and particle size increases to 40 nm for the Al3sample, indicating the formation of aggregates of the Al3PWcore at high Al loading.
FTIR spectra have proved to be a powerful technique to studythe changes in the primary, secondary and tertiary structures ofthe heteropoly compounds. The FTIR spectrum of H3PWsample showed bands at 1080, 981, 886, 791, 593, and 525 cm�1,which corresponds to the P–Oa, W]Od, W–Ob–W, W–Oc–Wstretching vibrations, and to Oa–P–Oa deformation, respectivelyand they are in accordance with those reported in the literaturefor the H3PW.30 The subscripts correspond to oxygen atomsbinding W and P (a), or bridging different WO6 octahedra thatshare corners (b) or edges (c), and terminal oxygen atoms and(d) bonded to only oneW atom; similar FTIR spectra were foundfor all the AlPW samples (Fig. 3).
It can observed that the band assigned to the W]Od
stretching for AlPW samples is broadened as a result of the
Fig. 3 FTIR spectra of all the samples.
Fig. 4 DR UV-vis spectra of all the samples.
RSC Adv., 2016, 6, 11921–11932 | 11925
Table 2 Textural and acidity measurements of the catalysts
interaction between the [PW12O40]3� anion and Al3+ cations.
However, transformation of the Keggin species; [PW12O40]3�
into the lacunary Keggin phase; [PW11O39]7� during the prepa-
ration was not detected for all the AlPW salts. These results
Fig. 5 Pore size distribution of all the samples.
Fig. 6 NH3-TPD patterns of all the samples.
11926 | RSC Adv., 2016, 6, 11921–11932
indicating that the primary Keggin structure of all the preparedsamples still remained intact aer the partial or full substitu-tion of Al ions, even though XRD patterns of the AlPW samplesshowed some differences.
Fig. 7 FTIR analysis for pyridine adsorbed samples.
Table 3 Reaction of Ia with IIa in presence of different catalysts underreflux conditions
CatalystReactiontimea (min) Yield (%)
H3PW 30 40AlH2PW 30 67Al2HPW 30 81Al3PW 18 93
a Reaction conditions: ethanol solvent (10 ml), 10 mmol of 6-methyl-2-aminopyridine and 10 mmol of 1,3-dicarbonyl derivatives, 0.1 g(3.35 � 10�5 mol) of catalyst under reux.
Compound number Reaction timea (min) Yield (%) Literature yield (%)
18 93 60 (ref. 24)
18 91 66 (ref. 25)
15 96 22 (ref. 26)
a Reaction conditions: ethanol solvent (10 ml), 10 mmol of 6-methyl-2-aminopyridine and 10 mmol of 1,3-dicarbonyl derivatives, 0.1 g (3.35 � 10�5
mol) of Al3PW catalyst under reux.
RSC Advances Paper
3.4 Diffuse reectance UV-vis spectroscopy
Fig. 4 shows the diffuse reectance UV-vis spectra for all thesamples. Two main absorptions are present in the spectrum ofparent H3PW sample; the rst is centered at 260 nm. In thediffuse reectance spectra of pure heteropoly acids the mainabsorption band in the UV-vis range is due to the ligand-metalcharge transfer (LMCT): O2 / W6+. This type of transitionusually observed between 200 and 400 nm,31 thus the transitionat 260 nm could be attributed to the oxygen–tungsten charge-transfer absorption band for Keggin anions. Another LMCTbroad band centered at 360 nm was observed for the H3PWsample. For the AlPW samples, these bands are clearly shied tolower wavelengths and the bands were observed at 230 and 310nm, respectively.
11928 | RSC Adv., 2016, 6, 11921–11932
Fournier et al.32 reported that the LMCT band shis towardshigher wavelength and it broadens when the size of the counter-ion decreases (H+), i.e. when their polarization power increasesand the relative distance between heteropolyanions decreases(this is the case for parent H3PW). The AlPW salts containingcounter-ion (Al3+), the polarization action is lower and asa consequence, the heteropoly anions are isolated one fromanother.
3.5 N2-physisorption
The textural properties of the samples were measured by N2-physisorption studies. The surface area of AlPW samplesincreased with Al3+ content; rising from 7m2 g�1 for Al1PW to 27m2 g�1 for Al3PW sample was observed (Table 2). This isconsistent with the results observed by Moffat et al.,33 they
Fig. 8 Reusability of Al3PW catalyst for synthesis of 4H-pyrido[1,2-a]-pyrimidin-4-one.
Paper RSC Advances
reported that metal salts of H3PW have dense porous networksand corresponding higher surface areas than the parent H3PW.Our results are in accordance with those ndings, revealinga signicant increase in the average pore radius from 20 to 40 Afor AlPW samples (Fig. 5).
Okuhara et al.34 showed that large voids exist between theprimary particles (micro crystallites) in these materials. If thesize of the primary AlPW clusters is about 12 nm, then the mostclosely packed aggregates could form voids of around 2–3 nm.Inter particle voids between larger crystallites would increasethe overall apparent average pore diameter, consistent with thepresent study.
3.6 NH3-TPD measurements
Ammonia TPD technique usually enables the determination ofthe amount of acidic sites and the strength of acid sites presenton the catalyst surface together with the total acidity. The NH3-TPD patterns in the temperature range of 100–800 �C werecollected for all the samples are shown in Fig. 6.
The strength of acid sites is related to the correspondingdesorption temperature. Generally, the acid sites are classiedinto the weak (150–300 �C), medium (300–450 �C) and strong(450–700 �C) acid sites.35 For parent H3PW sample, a smallbroad hump for medium strength acid sites and two desorptionpeaks at high temperature (650 �C and 720 �C) that wereascribed to strong acidic sites were observed. The NH3 desorp-tion of AlH2PW has the rst desorption maximum at 260 �C(weak acidic sites) and the second peak with the desorptionmaximum at 385 �C (strong acidic sites). Ion exchange with oneAl atom resulted in shi of the high temperature desorptionpeaks to lower temperature (620 �C and 700 �C). Al2HPW andAl3PW samples showed a major broad peak ranging from 150 to675 �C with a small shoulder at 720 �C.
The TPD prole of dried parent HPW sample was sharp andthe desorption takes place in the high temperature regionindicating that this sample is energetically homogeneous.Complex desorption proles were observed for AlPW samples ina broad temperature region (150–750 �C), composed of at leastthree overlapped peaks indicate energetic heterogeneity ofAlPW salts. This observation is in accordance with the reportedresults for alkaline metal salts of H3PW.36
The total acidity of calculated from TPD analysis was pre-sented in Table 2. The acidity of pure H3PW is 1.415 mmol pergram of catalyst. Also the total acidity of the strong acidic siteswas decreased with increase of Al content. The density of acidicsites on the surface, the highest value, 0.471 mmol per m2 per gper cat, was obtained for H3PW, which was related to its lowspecic surface area (3.0 m2 g�1). Therefore, as expected, theamount and the distribution of the acid strengths on the activephase were signicantly inuenced by the proton exchangewith Al.
3.7 FTIR analysis for pyridine adsorbed samples
The nature of acidic sites such as Brønsted and Lewis acid sitescan be distinguished by using pyridine as probe molecule byFTIR studies. It is known that pyridine adsorbed samples
exhibit peaks at 1446, 1486 and 1536 cm�1. The peak 1446 cm�1
is characteristic of Lewis-coordinated pyridine (L), whereas theband at 1536 cm�1 was due to Brønsted-coordinated pyridine(B), and the band at 1486 cm�1 is due to Lewis- and Brønsted-coordinated pyridine (L + B).37
The FTIR spectra of adsorbed pyridine on parent H3PWshowed typically intense bands at 1485, 1530 and 1541 cm�1
that are mainly characteristic of Brønsted type acidity (Fig. 7). Inthe FTIR spectra of adsorbed pyridine on AlPW samples, newband at 1448 cm�1 which is attributed to Lewis acid sites wasappeared. The intensity of this peak is higher for the Al3PWsample. It can be concluded that compared with parent H3PWsample the Lewis acid sites were introduced by partialexchanging of H with Al ions.
Thus AlPW samples maintained its Brønsted acidity andincreased in Lewis acidity, which might be considered as beingadvantageous for catalyzing the reaction involved in synthesisof pyrido[1,2-a]pyrimidine-4-one derivatives. From the aboveresults it can be concluded that partial exchanging of protonswith Al ions can introduce Lewis acid sites into pure H3PWmolecules and thereby modify the acid strength of parent H3PWvia Lewis acid sites assisting Brønsted acid sites.
The intensity ratio of B and L acidic sites were calculatedfrom the transmittance intensities at 1536 and 1446 cm�1. Withincrease in Al3+ content, the increase in the Lewis acidity ismuch more than the Brønsted acidity and it was observed thatLewis acidity (L/B ¼ 0.71) maximum for Al3PW sample.
3.8 Synthesis of pyrido[1,2-a]pyrimidin-4-one derivatives
The title compounds were synthesized by a simple and conve-nient route as outlined in the Scheme 1.
The calculated amounts of substituted 2-aminopyridine and1,3-di-ketone derivative were stirred in ethyl alcohol and thenthe reaction mixture was heated to 80 �C to begin the reux ofethyl alcohol and nally calculated amount of solid
RSC Adv., 2016, 6, 11921–11932 | 11929
RSC Advances Paper
heteropolyacid catalyst was added to the reaction mixture toinitiate the reaction. The mixture was kept at ethanol reuxtemperature (80 �C) until TLC showed no more starting mate-rial. The catalyst was ltered, washed with ethyl alcohol andthen the ltrate was taken in a round bottom ask to remove thealcohol under reduced pressure and the product was recrystal-lized to afford the pyrido[1,2-a]pyrimidin-4-one derivative.
In the formation of the pyrido[1,2-a]pyrimidine-4-one deriv-ative, the reaction was completed in 30 minutes when H3PW,AlH2PW, Al2HPW were used as catalysts and the reaction timewas drastically reduced to 18 minutes in case of Al3PW catalyst(Table 3). The yield of the product was also depended on thetype of the catalyst used. It was found that higher yields wereobserved in case of Al3PW catalyst compared to parent H3PWand other AlPW salts. Recrystallization of the 2,6-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one yielded yellow crystals with 93%
Scheme 2 Plausible mechanism of the reaction between 2-aminopyrid
11930 | RSC Adv., 2016, 6, 11921–11932
yield. The products with greater purity were obtained in case ofall the catalysts.
The scope and generality of the methodology is illustratedwith respect to eight different substituted 1,3-diketone deriva-tives and the results are presented in Table 2. Interestingly,substituted 1,3-diketone derivatives participated well in thereaction system. The reaction underwent smoothly withdifferent 1,3-diketone derivatives to afford the correspondingsubstituted-4H-pyrido[1,2-a]pyrimidin-4-one derivatives in goodyields (entries IIIa–h, Table 4). The yields of 4H-pyrido[1,2-a]-pyrimidin-4-one derivatives reported in the literature reportsare poor (maximum 69%), in comparison the present protocolinvolved solid Al3PW catalyst offered very high yields (91 to98%). The yield of 4H-pyrido[1,2-a]pyrimidin-4-one derivativewith chlorine moiety is relatively lower than the other
derivatives without chlorine group. This could be explained theeffect of electron withdrawing ability of chlorine atom.
The synthesized compounds were characterized by IR, 1Hand 13C NMR spectral methods. The 1H-NMR spectral data ofsynthesized compounds displayed characteristic protons of thepyridine nucleus of pyridopyrimidine (C6–C9) and the protonsof the two methylene groups at 6.71 (ESI†). All the derivativesdisplayed the characteristic peaks at C6–C9 of the pyridine ringappeared at 7.8, 7.1 and 6.85 respectively. The imine protonspresent in the derivatives were appeared as singlet at d 8.4–8.7.The 1H NMR also showed the peaks at d 3.01 and 3.92 with J¼ 7Hz for –CH2 and –OCH2 protons. The data from mass analysisand melting points determined for the synthesized derivativesare in accordance with the values reported in the literature. Theelemental microanalyses of the starting materials compoundsthe derivatives conrmed their chemical structures and werewithin the acceptable range.
The reusability of the highly active Al3PW catalyst waschecked for several reaction cycles (Fig. 8), the catalyst removedaer the completion of the reaction by ltration, washed withhot ethanol and dried under vacuum. The recovered catalystwas reused for ve times using the same reaction conditions.The results showed that the regenerated catalyst performs thereactions efficiently under the same reaction conditions evenaer being used for ve times. The slight decrease in yieldobserved in the catalytic activity of the Al3PW catalyst on thefourth and h time and the decrease of activity could beattributed to the weight loss of the catalyst during the workingup in each time. These results are indicating the robust natureof the Al3PW catalyst to synthesize 4H-pyrido[1,2-a]pyrimidin-4-one derivatives.
The plausible mechanism of the reaction between 2-amino-pyridine and 1,3-dicarbonyl derivative is presented in Scheme 2.The interaction between these two molecules is known toproceed through the intermediacy of enamines, which arecyclized to the desired pyridopyrimidines. The nitrogen ring of2-aminopyridine combined to the double bond of the 1,3-dicarbonyl to give a carbanion intermediate. This carbanionabstracts a proton from the amino group to give the interme-diate enamine product. The intermediate product gives the nalproduct aer the catalytic dehydration.
To study the stability of the Keggin structure of the catalystsaer the regeneration in each cycle, FTIR spectra of fresh andused Al3PW catalyst were compared (ESI, Fig. S1†). The FTIRspectra of the samples have not showed any major differencesin bands at 1080, 981, 886, 791, 593, and 525 cm�1, whichcorresponds to the characteristic P–Oa, W–Od, W–Ob–W, W–Oc–
W stretching vibrations. The results are indicating that Kegginion was intact in Al3PW catalyst aer use of several reactioncycles.
Authors also tested homogeneous acid catalysts such asconc. HCl and conc. H2SO4, which offered mixture of productsas these acids known to protonate the multiple carbonyl groups.However, the Al3PW catalyst is selective for protonate singlecarbonyl carbon to make NH2 attack more favorable. Theobserved catalytic performance of the catalysts indicates theacidity of the catalyst play a key role in obtaining the highest 4H-
pyrido[1,2-a]pyrimidin-4-one derivative yield. A through char-acterization of the catalysts was performed to understand therole of physico-chemical properties of heteropoly acid salts inthe catalytic activity.
4. Conclusions
A simple and efficient synthesis of some substituted pyrido[1,2-a]pyrimidin-4-ones derivatives was carried out using Kegginstructured AlPW salts as heterogeneous catalysts. The synthesisof pyrido[1,2-a]pyrimidin-4-ones derivatives by one-pot twocomponent cyclization of 2-aminopyridine and 1,3-dicarbonylderivatives using a catalytic amount of AlPW catalyst at lowreaction temperature. This method not only preserves thesimplicity, low temperature need, short time, but also consis-tently gives the corresponding products in excellent yields (90–93%). Among the prepared catalysts, Al3PW offered high yieldsof pyrido[1,2-a]pyrimidin-4-ones derivatives due to its highsurface area and more number of Lewis acid sites.
Acknowledgements
This project was funded by Saudi Basic Industries Corporation(SABIC) and the Deanship of Scientic Research (DSR), KingAbdulaziz University, Jeddah, under grant no. 11-130-1436-S.The authors therefore acknowledge with thanks SABIC and DSRtechnical and nancial support.
References
1 R. N. Castle and S. D. Phillips, in Comprehensive HeterocyclicChemistry, ed. A. R. Katritzky and C. W. Rees, Pergamonpress, Oxford, 1984, vol. 3, pp. 329–368; J. M. Blaney,C. Hansch, C. Silipo and A. Vittoria, Chem. Rev., 1984, 84,333–407.
2 J. E. Leysen, P. M. Janssen, A. A. Megens and A. Schotte, J.Clin. Psychiatry, 1994, 55, 5–12.
3 Y. Yanagihara, H. Kasai, T. Kawashima and T. Shida, Jpn. J.Pharmacol., 1988, 48, 91–101.
4 F. Awouters, J. Vermeire, F. Smeyers, P. Vermote, R. Van Beekand C. J. E. Niemegeers, Drug Dev. Res., 1986, 8, 95–102.
5 R. L. Smith, R. J. Barrett and E. Sanders-Bush, J. Pharmacol.Exp. Ther., 1995, 275, 1050–1057.
6 I. Devi, J. L. Borah and P. L. Bhuyan, Tetrahedron Lett., 2003,44, 8307–8310; Y. Gao, S. J. Tu, T. J. Li, X. J. Zhang, S. L. Zhu,F. Fang and D. Q. Shi, Synth. Commun., 2004, 34, 1295–1299;Y. L. Li, B. X. Du, X. S. Wang, D. Q. Shi and S. J. Tu, J. Chem.Res., 2006, 2006, 157–159.
7 I. Hermecz, J. Kokosi, B. Podanyi and Z. Liko, Tetrahedron,1996, 52, 7789–7796; P. L. Ferrarini, C. Mori, F. Mori,G. Saccomanni, S. Barontini, M. Macchia, P. Barili andM. Hamdan, J. Heterocycl. Chem., 1999, 36, 1065–1072;L. Selic, S. Strah, R. Toplak and B. Stanovnik, Heterocycles,1998, 47, 1017–1022; L. Selic and B. Stanovnik, J.Heterocycl. Chem., 1997, 34, 813–816; A. Bowler,A. Dinsmore, P. Doyle and D. Young, J. Chem. Soc., PerkinTrans. 1, 1997, 1297–1306.
RSC Adv., 2016, 6, 11921–11932 | 11931
RSC Advances Paper
8 G. Roma, M. B. DiBraccio, A. Albi, M. Mazzei and A. Ermili, J.Heterocycl. Chem., 1987, 24, 329–335.
9 G. J. S. Doad, D. I. Okor, F. Scheinmann, P. A. Bates andM. B. Hursthouse, J. Chem. Soc., Perkin Trans. 1, 1988,2993–3003.
10 V. A. Dorokhov, S. V. Baranin, A. Dib, V. S. Bogdanov,I. P. Yakovlev, G. A. Stashina and V. M. Zhulin, Chem.Abstr., 1991, 114, 101911.
11 O. P. Suri, K. A. Suri, B. D. Gupta and N. K. Satti, Synth.Commun., 2002, 32, 741–746.
12 G. C. B. Harriman, S. Chi, M. Zhang, A. Crowe, R. A. Bennettand I. Parsons, Tetrahedron Lett., 2003, 44, 3659–3661.
13 J. H. Clark, Acc. Chem. Res., 2002, 35, 791–797.14 I. V. Kozhevnikov, Catal. Rev.: Sci. Eng., 1995, 37, 311–352.15 M. Misono, Catal. Rev.: Sci. Eng., 1988, 30, 339–392.16 T. Okuhara, N. Mizuno and M. Misono, Adv. Catal., 1996, 41,
113–252.17 M. Misono, J. Chem. Soc., Chem. Commun., 2001, 1141–1152.18 T. Baba, H. Watanabe and Y. Ono, J. Phys. Chem., 1983, 87,
2406–2411.19 H. Firouzabadi, N. Iranpoor, F. Nowrouzi and K. Amani,
Chem. Commun., 2003, 764–765.20 K. Narasimharao, E. Al-Sabban, T. S. Saleh, A. G. Gallastegui,
A. C. Sanz, S. Basahel, S. Al-Thabaiti, A. Alyoubi, A. Obaidand M. Mokhtar, J. Mol. Catal. A: Chem., 2013, 379, 152–162; T. S. Saleh, K. Narasimharao, N. S. Ahmed,S. N. Basahel, S. A. Al-Thabaiti and M. Mokhtar, J. Mol.Catal. A: Chem., 2013, 367, 12–22; M. Mokhtar, T. S. Salehand S. N. Basahel, J. Mol. Catal. A: Chem., 2012, 353–354,122–131.
21 H. G. Bonacorso, F. J. Righi, I. R. Rodrigues, C. A. Cechinel,M. B. Costa, A. D. Watsowski, M. P. Martins and N. Zanatta, J.Heterocycl. Chem., 2006, 43, 229–233.
22 M. Shur and S. S. Israelstem, J. Org. Chem., 1968, 33, 3015–3020.
11932 | RSC Adv., 2016, 6, 11921–11932
23 P. L. Ferrarini, C. Mori, O. Livi, G. Biagi and A. M. Marini, J.Heterocycl. Chem., 1983, 20, 1053–1057.
24 J. C. Christopher, W. D. Leslie, A. R. James and T. Vasilios, J.Heterocycl. Chem., 1982, 19, 1017–1019.
25 L. F. Pier, C. Mori, O. Livi, G. Biagi and A. M. Marini, J.Heterocycl. Chem., 1983, 20, 1053–1057.
26 N. Sin, A. C. Good, B. L. Venables, P. M. Scola andN. A. Meanwell, US pat., 183694 2006.
27 K. Narasimharao, D. R. Brown, A. F. Lee, A. D. Newman,P. F. Siril, S. J. Tavener and K. Wilson, J. Catal., 2007, 248,226–234.
28 J. A. Dias, E. Caliman and S. C. L. Dias, MicroporousMesoporous Mater., 2004, 76, 221–232.
29 P. M. Rao, P. Goldberg-Oppenheimer, S. Kababya, S. Vegaand M. V. Landau, J. Mol. Catal. A: Chem., 2007, 275, 214–227.
30 M. T. Pope, Heteropoly and Isopoly Oxometalates, Springer-Verlag, Berlin, 1983.
31 Y. Miao, G. Lu, X. Liu, Y. Guo, Y. Wang and Y. Guo,Microporous Mesoporous Mater., 2009, 122, 55–60.
32 M. Fournier, C. Louis, M. Che, P. Chaquin and D. Masure, J.Catal., 1989, 119, 400–414.
33 J. B. Higheld, B. K. Hodnett, J. B. McMonagle andJ. B. Moffat, Proc. 8th Int. Congr. Catalysis, IUPAC, VerlagChemie, Frankfurt AM Main, 1984, vol. 5, p. 611.
34 T. Okuhara, T. Nishimura, H. Watanabe and M. Misono, J.Mol. Catal., 1992, 74, 247–256.
35 F. Jing, B. Katryniok, E. Bordes-Richard and S. Paul, Catal.Today, 2013, 203, 32–39.
36 L. Damjanovica, V. Rakic, U. B. Mioc and A. Auroux,Thermochim. Acta, 2005, 434, 81–87.
37 T. T. Ali, K. Narasimharao, N. S. Ahmed, S. Basahel, S. Al-Thabaiti and M. Mokhtar, Appl. Catal., A, 2014, 486, 19–31.
![Page 1: Simple and efficient protocol for synthesis of pyrido[1,2 ...mmoustafa.kau.edu.sa/Files/0052879/Files/152133_authorreprints.pdfSimple and efficient protocol for synthesis of pyrido[1,2-a]pyrimidin-4-one](https://reader031.documents.pub/reader031/viewer/2022011823/5ed126d99a19383f1d0b18c4/html5/thumbnails/1.jpg)
![Page 2: Simple and efficient protocol for synthesis of pyrido[1,2 ...mmoustafa.kau.edu.sa/Files/0052879/Files/152133_authorreprints.pdfSimple and efficient protocol for synthesis of pyrido[1,2-a]pyrimidin-4-one](https://reader031.documents.pub/reader031/viewer/2022011823/5ed126d99a19383f1d0b18c4/html5/thumbnails/2.jpg)
![Page 3: Simple and efficient protocol for synthesis of pyrido[1,2 ...mmoustafa.kau.edu.sa/Files/0052879/Files/152133_authorreprints.pdfSimple and efficient protocol for synthesis of pyrido[1,2-a]pyrimidin-4-one](https://reader031.documents.pub/reader031/viewer/2022011823/5ed126d99a19383f1d0b18c4/html5/thumbnails/3.jpg)
![Page 4: Simple and efficient protocol for synthesis of pyrido[1,2 ...mmoustafa.kau.edu.sa/Files/0052879/Files/152133_authorreprints.pdfSimple and efficient protocol for synthesis of pyrido[1,2-a]pyrimidin-4-one](https://reader031.documents.pub/reader031/viewer/2022011823/5ed126d99a19383f1d0b18c4/html5/thumbnails/4.jpg)
![Page 5: Simple and efficient protocol for synthesis of pyrido[1,2 ...mmoustafa.kau.edu.sa/Files/0052879/Files/152133_authorreprints.pdfSimple and efficient protocol for synthesis of pyrido[1,2-a]pyrimidin-4-one](https://reader031.documents.pub/reader031/viewer/2022011823/5ed126d99a19383f1d0b18c4/html5/thumbnails/5.jpg)
![Page 6: Simple and efficient protocol for synthesis of pyrido[1,2 ...mmoustafa.kau.edu.sa/Files/0052879/Files/152133_authorreprints.pdfSimple and efficient protocol for synthesis of pyrido[1,2-a]pyrimidin-4-one](https://reader031.documents.pub/reader031/viewer/2022011823/5ed126d99a19383f1d0b18c4/html5/thumbnails/6.jpg)
![Page 7: Simple and efficient protocol for synthesis of pyrido[1,2 ...mmoustafa.kau.edu.sa/Files/0052879/Files/152133_authorreprints.pdfSimple and efficient protocol for synthesis of pyrido[1,2-a]pyrimidin-4-one](https://reader031.documents.pub/reader031/viewer/2022011823/5ed126d99a19383f1d0b18c4/html5/thumbnails/7.jpg)
![Page 8: Simple and efficient protocol for synthesis of pyrido[1,2 ...mmoustafa.kau.edu.sa/Files/0052879/Files/152133_authorreprints.pdfSimple and efficient protocol for synthesis of pyrido[1,2-a]pyrimidin-4-one](https://reader031.documents.pub/reader031/viewer/2022011823/5ed126d99a19383f1d0b18c4/html5/thumbnails/8.jpg)
![Page 9: Simple and efficient protocol for synthesis of pyrido[1,2 ...mmoustafa.kau.edu.sa/Files/0052879/Files/152133_authorreprints.pdfSimple and efficient protocol for synthesis of pyrido[1,2-a]pyrimidin-4-one](https://reader031.documents.pub/reader031/viewer/2022011823/5ed126d99a19383f1d0b18c4/html5/thumbnails/9.jpg)
![Page 10: Simple and efficient protocol for synthesis of pyrido[1,2 ...mmoustafa.kau.edu.sa/Files/0052879/Files/152133_authorreprints.pdfSimple and efficient protocol for synthesis of pyrido[1,2-a]pyrimidin-4-one](https://reader031.documents.pub/reader031/viewer/2022011823/5ed126d99a19383f1d0b18c4/html5/thumbnails/10.jpg)
![Page 11: Simple and efficient protocol for synthesis of pyrido[1,2 ...mmoustafa.kau.edu.sa/Files/0052879/Files/152133_authorreprints.pdfSimple and efficient protocol for synthesis of pyrido[1,2-a]pyrimidin-4-one](https://reader031.documents.pub/reader031/viewer/2022011823/5ed126d99a19383f1d0b18c4/html5/thumbnails/11.jpg)
![Page 12: Simple and efficient protocol for synthesis of pyrido[1,2 ...mmoustafa.kau.edu.sa/Files/0052879/Files/152133_authorreprints.pdfSimple and efficient protocol for synthesis of pyrido[1,2-a]pyrimidin-4-one](https://reader031.documents.pub/reader031/viewer/2022011823/5ed126d99a19383f1d0b18c4/html5/thumbnails/12.jpg)
![Tetrahydro-1H-pyrido[4,3-b]- Benzofuran and Indole ...](https://static.documents.pub/doc/80x56/620e13d4efc8605bf6374a3c/tetrahydro-1h-pyrido43-b-benzofuran-and-indole-.jpg)
![Synthesis of Some Spiro Indeno[1,2-b]pyrido[2,3-d]Pyrimidine-5,3 ...](https://static.documents.pub/doc/80x56/5868d38d1a28ab01578bca38/synthesis-of-some-spiro-indeno12-bpyrido23-dpyrimidine-53-.jpg)
![Nitriles in heterocyclic synthesis: synthesis of pyrido[3 ...Pyrido[3’,2’:4,5]Thieno[2,3-d] Pyrimidines Derivative. Open Access Library ... It has been found that the prepared](https://static.documents.pub/doc/80x56/5f6cd35cd578922a78464875/nitriles-in-heterocyclic-synthesis-synthesis-of-pyrido3-pyrido3a2a45thieno23-d.jpg)
