Multicomponent reactions (MCRs) are an important class of convergent organic reactions, where three or more starting materials react to form a product that contains atoms derived from all of the participating reagents, and these processes are often referred to as high atom economy. MCRs have been widely used for the convergent synthesis of complex and important organic molecules from simple and readily available starting materials and have emerged as a powerful tool for drug discovery. This approach offers the possibility of producing large numbers of compounds with the same scaffold and a diverse range of side chains, and therefore allows for fast and efficient structural optimization with respect to the activity and selectivity properties of a pharmaceutically interesting compound series, as well as enabling the evaluation of several other pharmacologically important features of an active molecule ^{[1, 2, 3]}.

In recent years, the synthesis of naphthopyran-based compounds and their derivatives has received an increasing amount of attention because of their biological activity, such as their antiviral ^[4], mutagenic ^[5], antimicrobial ^[6], antiproliferative ^[7], and anticancer activity ^[8], as well as their activity toward the central nervous system ^[9]. Indenopyrans are ‘privileged medicinal scaffolds’ that have been used for the development of pharmaceutical agents in a variety of different disease areas. Compounds with this particular motif show a wide range of pharmacological activity, such as antiulcer ^[10], antiallergenic ^[11], and antidepressant activity ^[12]. Indenopyrans have received increasing levels of attention in recent years because of their pharmacological and medicinal importance.

A survey of the literature revealed that only few methods are available for the synthesis of indenonaphthapyrans. Wu et al. ^[13] developed a simple and facile procedure for the synthesis of 13-aryl-indeno[1,2-b]naphtha[1,2-e]pyran-12(13H)-ones by the one-pot condensation of β-naphthol with an aldehyde and 2H-indene-1,3-dione under solvent-free conditions in the presence of silica chloride as a heterogeneous catalyst. Wu et al. ^[14] also reported the synthesis of 13-aryl-indeno[1,2-b]-  naphtha[1,2-e]pyran- 12(13H)-ones under solvent-free conditions using sulfamic acid as a catalyst. However, there are several limitations to these methods, such as the requirement for forcing reaction conditions, unsatisfactory yields, and long reaction time. Furthermore, some of these catalysts are either expensive or difficult to prepare. Given the importance of indenonaphthopyrans and the urgent need for the development of environmentally benign chemical production processes, the development of suitable green synthetic methods for these compounds has attracted considerable interest.

Solid acids have many advantages over liquid acids in terms of their application in organic catalysis. For example, solids acids do less harm to the environment and do not cause any significant issues in terms of their corrosion or the disposal of effluent containing these materials. Furthermore, they are reusable and readily separated from liquid products. As economically and ecologically benign catalysts, research toward their application has attracted considerable interest from academia and industry, and the replacement of traditional homogeneous catalysts with solid acids appears to be becoming an inevitable trend ^[15].

Poly(4-vinylpyridinium) hydrogen sulfate (P(4-VPH)HSO₄) has recently received considerable attention as an efficient catalyst for the construction of carbon-carbon and carbon- hetero atom bonds ^{[15, 16, 17, 18]} because of its eco-friendly nature, ease of handling, high reactivity, and easy work-up procedures. P(4-VPH)HSO₄ has been reported as a novel solid acid catalyst for the chemoselective 1,1-diacetate protection and deprotection of aldehydes ^[15], as well as the synthesis of 14-aryl-14H- dibenzo[a,j]xanthenes ^[16], xanthene derivatives ^[17], and 12- aryl - 12H - indeno[1,2 - b]naphtho[3,2 - e]pyran - 5,11,13- triones ^[18].

Scheme 1. Synthesis of of 13-aryl-indeno[1,2-b]naphtha[1,2-e]pyran-12(13H)-ones.

Scheme 1. Synthesis of of 13-aryl-indeno[1,2-b]naphtha[1,2-e]pyran-12(13H)-ones.

In continuation to our on-going studies toward the development of new routes for the synthesis of heterocyclic compounds ^{[19, 20, 21, 22]}, we herein report a simple, convenient, and environmentally benign method for the synthesis of 13-aryl- indeno[1,2-b]naphtha[1,2-e]pyran-12(13H)-one derivatives via the one step three-component coupling of an aromatic aldehyde with β-naphthol and 2H-indene-1,3-dione in the presence of a P(4-VPH)HSO₄ catalyst under solvent-free conditions at 80 °C (Scheme 1).

Table 1 Synthesis of 13-aryl-indeno[1,2-b]naphtha[1,2-e]pyran-12(13H)-one in the presence of the P(4-VPH)HSO4 catalyst under different reaction conditions. Entry Solvent Catalyst (mg) Temperature (°C) Time (min) Yield a (%) 1 CH3CN 15 reflux 120 36 2 1,4-dioxane 15 reflux 120 44 3 EtOH 15 reflux 120 69 4 DMF 15 reflux 120 43 5 CHCl3 15 reflux 120 42 6 solvent-free 15 80 40 92 7 solvent-free 15 RT 120 41 8 solvent-free 15 50 120 56 9 solvent-free 15 60 90 68 10 solvent-free 15 70 60 81 11 solvent-free 15 90 40 92 12 solvent-free 0 80 90 — 13 solvent-free 5 80 40 44 14 solvent-free 10 80 40 72 15 solvent-free 20 80 40 92 16 solvent-free 25 80 40 93 Reaction conditions: benzaldehyde (1 mmol), β-naphthol (1 mmol), 2H-indene-1,3-dione (1 mmol). a Isolated yield.

Table 1 Synthesis of 13-aryl-indeno[1,2-b]naphtha[1,2-e]pyran-12(13H)-one in the presence of the P(4-VPH)HSO4 catalyst under different reaction conditions.

As part of our initial study to determine the optimum reaction conditions for this transformation, the reaction of benzaldehyde (1 mmol) with β-naphthol (1 mmol) and 2H-indene- 1,3- dione (1 mmol) was examined as a model reaction in the presence of 15 mg of P(4-VPH)HSO₄ as a catalyst under refluxing conditions in a variety of different solvents, including CH₃CN, 1,4-dioxane, EtOH, DMF, and CHCl₃ (Table 1, entries 1-5). The reaction was also conducted under solvent-free conditions at 80 °C, where it proceeded to completion within 30 min (Table 1, entry 6). The reaction was also investigated at a variety of different temperatures, including room temperature, as well as 50, 60, 70, 80, and 90 °C (Table 1, entries 6-11). The greatest yield with the shortest reaction time was obtained under the solvent-free conditions at 80 °C.

The optimal amount of the catalyst was determined by conducting a series of reactions involving a 0-, 5-, 10-, 15-, 20-, or 25-mg charge of the P(4-VPH)HSO₄ catalyst under solvent-free conditions at 80 °C (Table 1, entries 6 and 12-16). The results of these experiments demonstrated that a 15-mg charge of the P(4-VPH)HSO₄ catalyst provided the highest yield of the product at 80 °C (Table 1, entry 6). The use of a smaller amount of catalyst resulted in a lower yield, whereas the use of a larger amount did not have any impact on the reaction time or the yield (Table 1, entries 6 and 12-16). A blank reaction was carried out involving benzaldehyde, β-naphthol, and 2H-indene-1,3-dione in the absence of the catalyst under the optimized conditions to determine the role of the catalyst. This reaction did not provide any of the desired product and confirmed the importance of the catalyst to the reaction (Table 1, entry 12).

To evaluate the scope of this catalytic transformation, the optimized reaction conditions were subsequently applied to the reaction of 2H-indene-1,3-dione with a variety of different aromatic aldehydes and β-naphthol (Table 2, entries 1-12). A wide range of aromatic aldehydes bearing either electron- donating or electron-withdrawing substituents reacted successfully with 2H-indene-1,3-dione and β-naphthol under the optimized conditions to give the corresponding 13-aryl- indeno[1,2- b]naphtha[1,2- e]pyran-12(13H)-one derivatives in high yields over short reaction time.

Based on these results, it was clear that the electronic and steric effects of the substituents on the aldehydes had a significant impact on the yields of the products. In comparison with electron-donating groups, such as the methyl and methoxy groups (Table 2, entries 3 and 4), electron-withdrawing groups, as well as aromatic aldehydes substituted with halogen atoms, gave shorter reaction time (Table 2, entries 5, 6, 8, and 9). When ortho substituted aldehydes were used, they gave the corresponding products in good yields but required a longer reaction time (Table 2, entry 7). In contrast to aromatic aldehydes, aliphatic aldehydes could not be used under the optimized conditions and failed to provide any of the desired products.

In the interests of green chemistry and developing an environmentally benign process, we decided to study the catalytic activity of recycled solid acid P(4-VPH)HSO₄ for the synthesis of 13-aryl-indeno[1,2-b]naphtha[1,2-e]pyran-12(13H)-one using the model reaction system under the optimized conditions (Fig. 1). After the separation of product, the catalyst was washed with CH₂Cl₂ and vacuum dried to remove any residual CH₂Cl₂, and the resulting catalyst was reused directly in the next run. As shown in Fig. 1, the solid acid P(4-VPH)HSO₄ could be recycled at least four times without any significant reduction in its catalytic activity, with yields in the range of 87% to 92%.

Table 2 Synthesis of various 13-aryl-indeno[1,2-b]naphtha[1,2-e]pyran-12(13H)-ones. Entry     Aldehyde              Product Time (min) Yield a (%) Melting point (°C) Entry Aldehyde Product Time (min) Yield a (%) Melting point (°C) 1 40 92 202-204 (202-203 [13]) 7 60 86 240-241 (240-241 [13]) 2 30 93 206-208 (208-209 [13]) 8 30 93 208-210 3 60 89 193-195 (192-193 [13]) 9 30 92 220-222 4 60 90 224-226 (225-226 [13]) 10 60 87 228-230 5 40 90 242-243 (240-241 [13]) 11 30 92 250-252 (252-253 [13]) 6 30 92 224-226 (225-226 [13]) 12 30 91 244-245 (245-246 [13])

Table 2 Synthesis of various 13-aryl-indeno[1,2-b]naphtha[1,2-e]pyran-12(13H)-ones.

Fig. 1. Reusability of P(4-VPH)HSO₄.

Fig. 1. Reusability of P(4-VPH)HSO4.

A probable mechanism for the formation of the 13-aryl-indeno[1,2-b]naphtha[1,2-e]pyran-12(13H)-ones using P(4-VPH)HSO₄ as a catalyst is shown in Scheme 2. The protonated form of the aldehyde would be formed under the acidic conditions, as well as the enol form of the diketone (intermediate c), which would exist in equilibrium. Intermediate a would then be formed from the nucleophilic attack of 2-naththol on the protonated aldehyde. Subsequent protonation of intermediate a followed by the removal of water would result in the formation of intermediate b, which has been well documented in the literature of ortho-quinone methides (o-QMs) ^[23]. The nucleophilic attach of intermediate c on the protonated form of intermediate b would give the acyclic adduct intermediate, which would undergo intramolecular cyclization, followed by the loss of water to form the targeted molecules.

Scheme 2. Proposed mechanism for the formation of 13-aryl- indeno[1,2-b]naphtha[1,2-e]pyran-12(13H)-ones.

Scheme 2. Proposed mechanism for the formation of 13-aryl- indeno[1,2-b]naphtha[1,2-e]pyran-12(13H)-ones.

A simple and highly efficient method for the synthesis of 13-aryl-indeno[1,2-b]naphtha[1,2-e]pyran-12(13H)-ones has been developed via the P(4-VPH)HSO₄ catalyzed condensation of an aromatic aldehyde with β-naphthol and 2H-indene-1,3- dione under solvent-free conditions at 80 °C. The current approach offers the advantages of simple methodology, clean and mild reaction conditions, high atom-economy, short reaction time, low environmental impact, wide substrate scope, high yields, and excellent product purity.

Acknowledgments

The author Mansoor would like to express his gratitude to the management of C. Abdul Hakeem College, Melvisharam, India, for the use of their facilities and their general support.