Perlite-SO3H nanoparticles as an efficient and reusable catalyst for one-pot three-component synthesis of 1,2-dihydro-1-aryl-naphtho[1,2-e][1,3]oxazine-3-one derivatives under both microwave-assisted and thermal solvent-free conditions: Single crystal X-ray structure analysis and theoretical study

Document Type : Research Paper


1 Department of Chemistry, University of Zanjan, P.O. Box: 45195-313, Zanjan, Iran

2 Young Researchers and Elite Club, Gorgan Branch, Islamic Azad University, Gorgan, Iran

3 Faculty of Chemistry, University of Wrocław, 14 Joliot-Curie St., 50-383 Wrocław, Poland


A general synthetic route for the synthesis of 1,2-dihydro-1-aryl-naphtho[1,2-e][1,3]oxazine-3-one derivatives has been developed using perlite-SO3H nanoparticles as efficient catalyst under both microwave-assisted and thermal solvent-free conditions. The combination of 2-naphthol, aldehyde and urea enabled the synthesis of 1,2-dihydro-1-aryl-naphtho[1,2-e][1,3]oxazine-3-one derivatives in the presence of perlite-SO3H nanoparticles in good to excellent yields. This method provides several advantages like simple work-up, environmentally benign, and shorter reaction times along with high yields. In order to explore the recyclability of the catalyst, the perlite-SO3H nanoparticles in solvent-free conditions were used as catalyst for the same reaction repeatedly and the change in their catalytic activity was studied. It was found that perlite-SO3H nanoparticles could be reused for four cycles with negligible loss of their activity. Single crystal X-ray structure analysis and theoretical studies also were investigated for 4i product. The electronic properties of the compound have been analyzed using DFT calculations (B3LYP/6-311+G*). The FMO analysis suggests that charge transfer takes place within the molecule and the HOMO is localized mainly on naphthalene and oxazinone rings whereas the LUMO resides on the naphthalene ring.



       The use of heterogeneous catalysts [1-3]has received considerable importance in organic synthesis because of their ease of handling, enhanced reaction rates, greater selectivity, simple work-up, and recoverability of catalysts. Among the various heterogeneous catalysts, particularly, perlite nanoparticles has advantages of eco-friendly, low cost, ease of preparation and catalyst recycling [4]. Perlite is an amorphous volcanic glass that has relatively high water content, typically formed by the hydration of obsidian. Because of its low density and relatively low price, many commercial applications for perlite have developed In the construction and manufacturing fields, it is used in lightweight plasters and mortars, insulation and ceiling tiles, however there are few reports about using perlite as suitable support for catalytic applications [5-8].

      Multicomponent reactions (MCRs) [9-13] can be defined as convergent chemical processes where three or more reagents are combined in such a way that the final product retains significant portions of all starting materials. Therefore, they lead to the connection of three or more starting materials in a single synthetic operation with high atom economy and bond-forming efficiency, thereby increasing molecular diversity and complexity in a fast and often experimentally simple fashion [14,15]. For this reason, multicomponent reactions are particularly well suited for diversity-oriented synthesis [16-18] and the exploratory   power  arising  from  their  conciseness  makes them also very powerful for library synthesis aimed at carrying out structure-activity relationship (SAR) studies of drug-like compounds, which are an essential part of the research performed in pharmaceutical and agrochemical companies [19,20]. For all these reasons, the development of new multicomponent reactions is rapidly becoming one of the frontiers of organic synthesis.

      Aromatic condensed oxazinone derivatives have received considerable attention due to the attractive pharmacological properties associated with their heterocyclic scaffold [21]. Since many of these heterocyclic systems exhibit biological activities such as anti-inflammatory, antiulcer, antipyretic, antihypertensive and antifungal, these derivatives have become an integral part of pharmacologically important heterocyclic compounds [22-26]. Some of them also act as 5-HT ligands [27], DP receptor antagonists [28], integrin antagonists [29], platelet fibrinogen receptor antagonists [30], calmodulin antagonists [31], inhibitors of the transforming growth factor b (TGF-b) signaling pathway [32], soybean lipoxygenase [33], Janus kinase (JAK) and other protein kinases [34]. Moreover, benzo[1,4]oxazin-3-one analogs act as effective potassium channel openers, immunomodulating reagents, and etc. [35,36]. This class of heterocyclic compounds has been also used as precursors in the synthesis of phosphinic ligands for asymmetric catalysis [37]. Therefore, aromatic condensed oxazinone derivatives scaffold can be viewed as a ‘privileged structure’ among pharmaceutical compounds [38,39]. Inspite of their high potential, there are only few reports which describe the synthesis of naphthalene-condensed oxazinone derivatives [40-43]. In general, all these methods require elevated temperature non recyclable catalyst except those reported by Chaskar et al. [40]. Besides, a multi-step and cumbersome reaction involving the use of harsh conditions is required for the synthesis of starting materials such as amino alkylnaphthol. Therefore, development of simple, robust and safer methodologies for the synthesis of naphthoxazinone derivatives is of the prime interest for obtaining these products under conditions tolerated by sensitive functional groups from both synthetic and environmental points of view [44].

      Microwave chemistry and microwave-assisted organic synthesis (MAOs) are nowadays undeniably effective tools in medicinal chemistry [45]. The availability of safe, single-mode dedicated microwave units has allowed the incorporation of this new technology into accelerating drug-discovery, hit-to-lead, and lead optimization programs. The development of more economical synthetic routes can ameliorate the overall process since drug discovery is a costly exercise with a high attrition rate [45]. The use of MAOs has been shown to dramatically reduce processing times, increase product yields, and enhance the purity of the product when compared to the conventionally processed experiments [45]. Since there are several manufacturers of professional-grade equipment and a plethora of adapted methods, one can conclude that this interest continues to grow [46].

      Motivated by the afore-mentioned findings, and in a continuation of our interest in synthesis of a wide range of heterocyclic systems in our laboratory [47-54], we describe here a facile one-pot three-component synthesis of 1,2-dihydro-1-aryl-naphtho[1,2-e][1,3]oxazine-3-one derivatives (4) from 2-naphthol (1), aldehyde (2) and urea (3) in the presence of perlite-SO3H nanoparticles as efficient catalyst under both microwave and thermal solvent-free conditions (Scheme 1).

      In recent years, computational chemistry has become an important tool for chemists and a well-accepted partner for experimental chemistry [55-58].Density functional theory (DFT) method has become a major tool in the methodological arsenal of computational organic chemists. In the present work, we investigate the energetic and structural properties of crystal structures of 4i using DFT calculations. The optimized geometry, frontier molecular orbitals (FMO), detail of quantum molecular descriptors, molecular electrostatic potential (MEP), chemical tensors, natural charge and NBO analysis were calculated.



      Recently, it has been reported that multi-component reactions of 2-naphthol (1) with benzaldehyde (2a) and urea (3) in the presence of a number of catalysts and reagents such as H2NSO3H [59], HClO4/SiO2 [60], 2,4,6-trichloro-1,3,5-triazine [61], InCl3 [62] and CH3SO3H [63] afforded uncyclized product (5a) in good yields, without any formation of cycloadduct (4a) (Scheme 2).

      To optimize the reaction conditions to give cycloadduct 4a, the reaction of 2-naphthol (1) with benzaldehyde (2a) and urea (3) in the presence of various types of perlite as catalyst was used as a model reaction to oxazinone derivatives synthesis. According to the obtained data, using the perlite-SO3H nanoparticles (0.01 g) under solvent-free conditions for the oxazinone formation represents the best reaction conditions (Table 1).


Scheme 1. Synthesis of 1,2-dihydro-1-aryl-naphtho[1,2-e][1,3]oxazine-3-one derivatives (4a-j)


Scheme 2. Possible cyclized and uncyclized products of the reaction


      Table 1 clearly demonstrates that perlite-SO3H nanoparticles are an effective catalyst in terms of yield of the obtained product. To find out the optimum quantity of perlite-SO3H nanoparticles, the model reaction was carried out at 110 °C using different quantities of perlite-SO3H nanoparticles (Table 2). According to the obtained data, 0.01 g of perlite-SO3H nanoparticles gave the best yield in 45 min (Table 2, entry 3).


 Table 1. Reaction between 2-Naphthol (1), Benzaldehyde (2a) and Urea (3) in the  Presence  of  Various  Types of  Perlite as Catalyst under Thermal and Solvent-Free Conditionsa


Table 2. Optimization Amount of perlite-SO3H nanoparticles on the Reaction of  2-Naphthol (1), Benzaldehyde (2a) and Urea (3) under Thermal and Solvent-Free Conditions



      The above reaction was also examined in various solvents (Table 3). The results indicated that different solvents affect the efficiency of the reaction. These solvents required a longer time and gave low to moderate yields, and the best results were obtained when solvent-free conditions were used (Table 3, entry 5).

      Encouraged by this success, we attempted the reaction of 2-naphthol (1) with a range of  other  aromatic  aldehydes (2) and urea under similar conditions (using perlite-SO3H nanoparticles), furnishing the respective 1,2-dihydro-1-aryl-naphtho[1,2-e][1,3]oxazine-3-one derivatives in good yields. The optimized results are summarized in Table 4. The termal solvent-free conditions are well suited  for either electron-donating or electron-withdrawing substituents on the aromatic aldehydes.


Table 3. Solvent Effect on the Reaction Between 2-Naphthol (1), Benzaldehyde (2a) and Urea (3) under Thermal and Solvent-Free Conditions (0.01 g)


        Table 4. Selected Interatomic Distances and Torsion Angles of 4i


 Crystal Structure of 4i

      Centrosymmetric crystals of 4i (space group P21/n) contain racemic 4i compound. The molecular structure of (S)-enantiomer is shown in Fig. 1. A summary of the conditions for the data collection and the structure refinement parameters are given in Experimental Part. The selected geometrical parameters are given in Table 4.

      In 4i molecule, the bond lengths and angles are within normal ranges [64], and the overall conformation of 4i is very similar to those observed in previously reported 1-phenyl, 1-(4-fluorophenyl) and 1-(4-chlorophenyl) derivatives [65-67]. The six-membered ring O(1)/C(1)/N(1)/C(2)/C(3)/C(4) is slightly puckered (Cremer & Pople [68] amplitude Q = 0.280(2) Å). The mutual orientation of the planar regions, i.e. phenyl and naphthalene moieties, is defined by the dihedral angle between them, which is 77.6(1)°,  and by  the  torsion  angle C(13)-C(2)-C(3)-C(12) amounting to -77.21(17)°.



Fig. 1. (a) X-Ray crystal structure of (S)-enantiomer of 4i compound (displacement ellipsoids at 50%  probability  level), (b) Geometrical  structure  of  the  4i compound (optimized at B3LYP/6-311+G* level).


      In the crystal lattice of 4i, the adjacent molecules of the same chirality, related by the action of the 21 screw axis, are joined to each other viaN(1)-H(1N)···O(2)ihydrogen bondsand weak C(17)-H(17)···O(1)ii interactions to form homochiralchains running down the b-axis (Fig. 5; geometry and symmetry codes therein). The inter-chain contacts are provided by the weak π···π interactions involving C(3)/C(4)/C(5)/C(6)/C(7)/C(12) rings of the adjacent molecules related by the inversion [centroid···centroidiiidistance of 3.652(2) Å, centroid···plane perpendicular distance of 3.567(1)Å; symmetry code (iii) -x,-y+1,-z+1)].

      Also in order to decrease the reaction time, microwave irradiation under solvent-free conditions was used. The reaction time decreased from almost 1 h to a few minutes. Moreover, the yields of products increased in all cases examined (Table 5).  


Fig. 2. Molecules of 4i joined to each other via N/C-H···O contacts (dashed lines) to form homochiralchains  running down  the b-axis. [H···A, D···A, and D–H···A for  N(1)-H(1N)···O(2)i: 2.08(2), 2.807(2) Å and  143(2)°; for C(17)–H(17)···O(1)ii: 2.58, 3.187(2) Å and 122°. Symmetrycodes (i) -x+1/2, y+1/2, -z+3/2; (ii) x, y+1, z].


Table 5. Reaction Between 2-Naphthol (1),  Aromatic  Aldehydes (2)  and   Urea (3)   under  Solvent-Free (I) and Microwave-Assisteda (II) Conditions Using 0.01 g Perlite-SO3H NPs as Catalyst


A plausible mechanism for the formation of 2-dihydro-1-aryl-naphtho[1,2-e][1,3]oxazine-3-one  derivatives in  the presence of perlite-SO3H nanoparticles is shown in Scheme 3. It may be proposed that similar to several classical multi-component condensations, the initial event in this reaction is the condensation of aldehyde and urea to give reactive acylimine intermediate. Subsequently, the resulting acylimine intermediate undergoes a cyclization with 2-naphthol affording the corresponding products and ammonia [69,70].


Scheme 3.Aproposed mechanism for the synthesis of 2-dihydro-1-aryl-naphtho[1,2-e][1,3]oxazine-3- one derivatives in the presence of perlite-SO3H nanoparticles.



 Fig. 3. Development of the yield after several recycling cycles of the catalyst.


       In order to explore the recyclability of the catalyst, the perlite-SO3H nanoparticles in solvent-free conditions were used as a catalyst for the same reaction repeatedly and the change in their catalytic activity was studied. The relation between the number of cycles of the reaction and the catalytic activity in terms of yield of the products is presented in Fig. 3. It was found that perlite-SO3H nanoparticles could be reused for four cycles with negligible loss of their activity.


Electronic Properties and MEP Analysis

      Quantum chemical methods are important to obtaininformation about molecular structure and electrochemical behavior. The Frontier Molecular Orbitals (FMO) analysis was carried out for 4i compound at B3LYP/6-311+G* level [71].The results of FMO such as EHOMO, EHOMO-1, ELUMO, ELUMO+1 and HOMO-LUMO energy gap (Eg) of the molecule 4i are summarized in Table 6.


Table 6. Calculated   (B3LYP/6-311+G*) HOMO,  LUMO,  Energy Gaps (HOMO-LUMO) and Related Molecular Properties of 4i Molecule


Fig. 4. Calculated frontier molecular orbitals HOMO (a) and LUMO (b) of structure 4i.


      The energy values  of the highest occupied molecular orbital (EHOMO) can act as an electron donor and  the  lowest unoccupied molecular orbital (ELUMO) can act as the electron acceptor and their energy gaps reflect the chemical activity of the molecule [72].As shown in Fig. 4 and Table 6, EHOMO and ELUMO of the title compound is -6.3 eV and -1.68 eV, respectively. As seen in Fig. 4, charge transfer takes place within the molecule. The graphic pictures of HOMO and LUMO orbitals show that the HOMO of 4i molecule is localized   mainly  on  naphthalene and  oxazinone  rings, whereas the LUMO is focused mainly on naphthalene ring. The HOMO → LUMO transition implies an electron density transfer from oxazinone to naphthalene ring.

      Also in this work, electronic structure of the 4i compound was studied using total densities of states (DOSs) [73].DOS plot shows population analysis per orbital and demonstrates a simple view of the character of the molecular orbitals in a certain energy range [74]. According to Fig. 5, DOS analysis indicates that the calculated HOMO-LUMO energy gap (Eg) of the 4i molecule is4.62 eV.

      A detail of quantum molecular descriptors of 4i structure such as the ionization potential (I), electron affinity (A), chemical hardness (η), electronic chemical potential (µ) and electrophilicity (ω) are summarized in Table 6. Dipole moment (µD) is a good measure for the asymmetric nature of a structure [71]. The size of the dipole moment depends on the composition and dimensionality of the 3D structures. As shown in Table 6, dipole moment of the title structure is 5.567 Debye that the high value of dipole momentis due to its asymmetric character that the atoms are irregularly arranged which gives rise to the increased dipole moment. In addition, the point group of structure is C1 (see Table 6).