Silica Triflate Promoted Highly Efficient and Solvent-Free One-Pot Multicomponent Protocol for Synthesis of 2-Amino-4H-Chromenes

Abstract The synthesis of 2-amino-2-chromenes under solvent-free conditions is disclosed here using a silica triflate catalyzed one-pot three component condensation. The 2-amino-2-chromenes product was obtained in outstanding yield under the optimal reaction conditions of a range of functionalized aromatic aldehydes, malononitrile, and α/β-naphthol. This procedure stands out for its wide substrate scope, reduced reaction time, great yield, functional group compatibility, operational simplicity, and outstanding catalyst recyclability.


Introduction
Multicomponent reactions are now one of the most promising and efficient ways for synthesizing a wide range of compounds from three or more available starting materials in a single synthetic operation. MCRs are frequently utilized to generate carbon-carbon and carbon-nitrogen bonds. 1 The high atom economy, operational simplicity, cost and time effective, high selectivity and reduction of number of steps, energy consumption, reduction of waste production are the notable features of multicomponent reactions. 2 Therefore, it finds the unique position in organic synthesis and researchers have made considerable efforts to develop novel MCRs.
The 2-amino-4H-chromene and their derivatives have received great attention in both pharmaceutical and medicinal chemistry due to broad spectrum of biological activities such as antibacterial, anti-inflammatory, antioxidant, anti-HIV, anti-cancer, anticoagulant, antitumor, antimicrobial, and cytotoxic properties. 3 They are being examined in neurodegenerative disorders such as Alzheimer's disease, Parkinson disease and Huntington's disease. 4 Remarkably, number of drug molecules possessing 4H-chromene scaffold is currently in use for the treatment of diseases suchas asthma, hypertension, ischemia and urinary incontinence. 5 Moreover, they have also been used as laser dyes, pigments, fluorescence markers and cosmetics. 6 Therefore, the synthesis of 2amino-4H-chromenes has been received tremendous attention and many methods have been established for their synthesis. The most common method reported for the synthesis of chromenes derivatives was one-pot three components reactions between malononitrile, aldehydes and phenols using various catalytic systems. 7 The number ofcatalytic system using homogenous and heterogeneous reagents such as Fe(HSO 4 ) 3 , 8 MeSO 3 H, 9 PTSA, 10 heteropolyacid, 11 sulfonic acid melting points in comparison with the literature values, FTIR and 1 H NMR and 13 C NMR spectroscopy were used for structural identification.
Procedure for the preparation of silica triflate A 500 mL suction flask, charged with 18.0 g silica gel (type 60, 15-40 mm), was equipped with constant pressure dropping funnel containing trifluoromethanesulfonyl chloride (8.4 g, 0.05 mol) and gas inlet tube for conducting HCl gas over water as an adsorbing liquid. Trifluoromethanesulfonyl chloride was added drop wise over a period of 30 min and stirred slowly at room temperature for 30 min. The mixture was then heated to 60 C while it was stirring for 1 h to remove all HCl and the excess amounts of trifluoromethanesulfonyl chloride. The reaction mixture was washed with 50 mL of dry CH 2 Cl 2 and dried under vacuum. Silica triflate was obtained as a white solid (20.38-20.62 g) which was stored in a capped bottle. It is characterized by IR spectrum; IR (KBr): 1255, 1230, 1130, 1010, 95, 820, 650, 530, 500 cm À1 .
General procedure for preparation of 2-amino-4H-chromenes A mixture of a/b-naphthol (1 mmol), aldehyde (1 mmol), malononitrile (1 mmol), and silica triflate (10 mol%) was heated in an oil bath at 60 C with constant stirring till the reaction was completed. After completion of the reaction (monitored by TLC), the reaction mixture was cooled at room temperature. Then ethyl acetate was (5 mL) added, the catalyst was separated by filtration and solvent evaporated under the reduced pressure to get crude product. The crude product was purified by recrystallization from hot ethanol to give the pure product in good to excellent yields.

Result and discussion
Initially, to examine the catalytic efficiency of the silica triflate and for the optimization of the reaction conditions, we select the reaction between b-naphthol (1a), benzaldehyde (2a), and malononitrile (3a) as model reaction (Scheme 2). In order to optimize the reaction condition, the model reaction carried at different temperature and using different mol% of catalyst in the presence of different solvents and also under solvent-free conditions. The result summarized in product (4a) was not formed (Table 1, entries 1-4).For further study, we performed the model reaction in the presence of 10 mol% catalyst at room temperature. Surprisingly, a sensible amount of the desired product (4a) noticed (Table 1, entry 5). Excited by thisoutcome, further we performed the model reaction at different temperature using the 10 mol% catalyst (Table 1, entry 6-8). To our satisfaction, by increasing the temperature, the reaction proceeds smoothly, and at 60 C desired product(4a) was obtained in 96% yield (Table 1, entry 6). It is observed that an optimum yield of product (4a) was obtained at 60 C (Table 1, entry 6). There is no significant improvement in reaction time and yield of product was observed above that temperature (Table  1, entry 7-9), so 60 C was chosen as the reaction temperature.To test the efficiency of the catalyst in the presence of different solvents, we have to performed the model reaction using the various solvent such water, ethanol, methanol, acetonitrile, dimethyl formamide and dimethyl sulfoxide. The attempted reactions were carried out in reflux conditions, and the corresponding results are summarized in Table 1(entry [10][11][12][13][14]. Compared to all applied solvents, the solventfree system offers the best result in term of yield % and reaction time. After the optimization of the reaction temperature, we optimize the amount of catalyst required for the title reaction. With increasing catalyst amount from 5 mol% to 20 mol%, simultaneous increase in the yield of the desired product (4a) was observed from 67% to 96% respectively (Table 1, entries [16][17][18]. The increase in the catalyst amount above 10 mol% showed no significant effect on the yield of the desired product( Table 1, entry [17][18]. Therefore, for further investigationof the scope of this novel approch, the 10 mol% of the catalyst was chosen as optimized amount. Furthermore, we have explored the recyclability of silica triflate from post reaction mixture and reused for subsequent trial runs. The catalyst recyclability experiments showed that the recycle catalyst was very effective without noticeable loss of catalytic activity even after being reused for three times (Table 1, entry 19). We have found that catalytic activity of catalyst was almost the same as that of the freshly used catalyst. The same IR spectra are used for the demonstration of the stability of the composition of the catalyst before and after the reactions.
With these results in hand, we then investigated the substrate scope and limitations of synthesis of 2-amino-4H-chromenes derivatives in the presence of 10 mol% silica triflate as catalyst under the solvent-free condition. The generality of the current protocol was investigated in the reaction of differently substituted aldehydes, containing either electron-donating or electron-withdrawing groups in the ortho, meta, and para positions with malononitrile and either a or b-naphthol under secured optimal conditions. The scope of this novel approch is illustrated in Table 2 and 3.The corresponding 2-amino-4H-chromenes derivatives were obtained in good to excellent yields in relatively short times without formation of any by-products. It was found that the aryl aldehydes with electron-withdrawing groups reacted faster than those with electron-donating groups as was expected. The results show that the reactivity of a and b-naphthol are comparatively same and both of them could be converted to the target products with excellent yield. In general, benzaldehyde and benzaldehyde-bearing electron-withdrawing groups gave the corresponding 2-amino-4H-chromenes derivatives in excellent yield within 5-10 min( Table 2, entries  4a-4d & Table 3, entries 6a-6d).The chloro-and bromo-benzaldehyde also reacts under the optimized reaction condition and afforded the desired product in good yield in short reaction time (Table 2, entries 4e-4g & Table 3, entries 6e-6g).
Under the optimized conditions, benzaldehyde containing electron-donating groups such as 4-CH 3 , 4-OCH 3 reacted in slow rate and provided the desired products in in good yields (Table 2,  entries 4i-4j & Table 3, entries 6i-6j). Notably, there is significant effect of steric hindrance on yields desired products. The ortho-substituted aryl aldehydes provided the desired product in moderate yields (Table 3, entry 6d).
Finally, a comparison was made between the present work and already reported methods for the synthesis of compound 4a. The result presented in the Table 4. The comparative study showed that reported methods has its own advantages, but some they suffer from disadvantages such as poor yield, long reaction time, and use of organic solvents and employment of expensive catalyst. So present method furnishes green reaction medium, takes shorter reaction time and a small quantity of this inexpensive and readily available catalyst is sufficient to get excellent yield of 2-amino-4H-chromenes derivatives.
On the basis of literature, 49(a) the plausible mechanism for the synthesis of 2-amino-4H-chromenes using silica triflate shown in scheme 2.

Conclusion
In conclusion, we have described here ecofriendly and efficient synthesis of 2-amino-4H-chromenes by the one-pot three-component condensation of aldehydes, a or b-naphthol and malononitrileusing silica triflatecatalyst under solvent-free condition. This strategy not only offers   substantial improvements in the reaction rates and yields, but also avoids the use of hazardous catalysts or solvents. The inexpensive catalyst, faster reaction, clean reaction profiles, excellent yield, easy product isolation, no column purification, high catalytic activity, catalyst recyclability, easy handling, low corrosiveness and environmental compatibility are advantages of this method. We believed that the demonstrated method is vital in organic, material, medicinal and industrial chemistry.