Efficient and Ecofriendly Route for the Solvent-Free Synthesis of 4-Alkoxy-5H-chromen[2,3-d]pyrimidines Using Phosphonic Acid Functionalized KIT-6 Confined Ionic Liquid as Recoverable Catalyst

Abstract Phosphonic acid functionalized KIT-6 confined ionic liquid (IL, 1-butyl-3-methylimidazolium tetrafluoroborate [BMIm][BF4]) catalyzed the one-pot condensation reaction of iminochromenes and salicylaldehydes with different primary alcohols to achieve the corresponding 4-alkoxy-5H-chromen[2,3-d]pyrimidines under solvent-free conditions and in good yields. This efficient nanocatalyst can be recovered for at least five reaction runs without significant loss of either activity or confined IL. GRAPHICAL ABSTRACT


INTRODUCTION
Multicomponent reactions (MCRs) have emerged as invaluable tools in the drug discovery process in a one-pot synthetic operation. MCRs include two or more steps without any isolation of intermediates, which reduce time and save both energy and raw materials. [1] These techniques permit fast, automated, economical, and highthroughput synthesis of the libraries of pharmaceutical and organic compounds.
Because of the diverse applications of the fluorescent compounds in biochemical and medical research, [2] new multicomponent synthetic approaches to obtain these compounds have received much attention. There are various synthetic strategies for the synthesis of pyrimidine derivatives, [3] some of which report the reaction of iminocoumarines in alcoholic solvents. In most of these reports, amines applied as nucleophiles and ultimately amino-5H-chromeno [2,3-d]pyrimidine-2-yl-phenols were obtained as major products. First, Costa and coworkers reported the synthesis of dimeric chromene derivatives via the condensation of salicylaldehyde and malononitrile in the CH 3 OH and H 2 O media. [4] They realized that during the dimerization process, CH 3 OH as well as malononitrile attacked the intermediate as a nucleophile. According to our interest for the synthesis of pyrimidine derivatives, we tried to use alcohols as reactant for the synthesis of new pyrimidine derivatives. Therefore, due to the low nucleophylic property of alcohols, it was observed a suitable opportunity for solid acid catalysts. Recently ZnCl 2 was reported as a Lewis acid catalyst for the synthesis of 4-methoxy-5H-chromeno [2,3-d]pyrimidine derivatives. [5] three-dimensional cubic Ia3d MSNs, having two interpenetrating continuous networks of chiral channels, provide highly opened nanoporous hosts with simple access for the guests and facilitating mass transfer through the channels. [12] KIT-6, composed of two interwoven nanochannels similar to that found in MCM-48, [13] was introduced as a promising candidate for the potential applications in hybrid catalyst generation and enzyme immobilization. [14,15] On the other hand, the relatively mild acidic behavior of phosphonic acid compared to stronger Brønsted acids such as H 2 SO 4 may make it less prone to promotion of side reactions. Moreover, during recent years, phosphonic acid functionalized materials have been applied in the various fields such as bioelectrochemistry, electroanalysis, and biomimetic membranes. [16] Following our previous research on multicomponent reactions and nanocatalysts, [17] it was of interest to investigate novel approaches for the synthesis of fluorescent chromenopyrimidine derivatives. Therefore, we report phosphonic acid functionalized KIT-6 confined ionic liquid [BMIm] [BF 4 ], IL@[phosphonic acid@KIT-6], as a recoverable nanocatalyst and promoter for the green synthesis of 4-methoxy-5H-chromen [2,3-d] pyrimidine derivatives.

RESULTS AND DISCUSSION
In the present study, we designed and prepared KIT-6-functionalized phosphonic acid confined IL, IL@[phosphonicacid@KIT-6], as a promising candidate to catalyze different organic conversions. To this purpose, the silica framework KIT-6 has been synthesized via co-condensation of TEOS in the presence of the structure-directing agents under acidic conditions, and its surface was furnished by the covalent linkage of aminopropyl using 3-aminopropyl trimethoxysilane (APTMS). [18] Then phosphonic acid was incorporated into amine ends using Scheme 1. Synthesis of [phosphonicacid@KIT-6] and IL@ .
a straightforward Mannich-type reaction [19] between phosphorous acid and imine (from reaction between primary amine in aminopropyl functionalized KIT-6 and formaldehyde) in the presence of excess amount of concentrated HCl. Then the IL@[phosphonicacid@KIT-6] was prepared by filling the 3D mesochannels of phosphonic acid functionalized KIT-6 with [BMIm][BF 4 ] (Scheme 1). The catalyst was comprehensively characterized by x-ray powder diffraction (XRD), N 2 adsorption-desorption analysis, Fourier transform-infrared (FT-IR), thermal gravimetric analysis (TGA), transmission electron microscopy (TEM), and scanning electron microscopy (SEM) (see the supplementary data). SEM and TEM recognize the ordered cubically honeycomb-like network with uniform mesochannels and morphology of the mesoporous solid KIT-6 ( Fig. 1). The average pore diameter, which estimated from the TEM images, was about 7.5 nm, which agreed well with that from the N 2 sorption and XRD analysis. [19,20] Figure 1. TEM image KIT-6 and N 2 sorption isotherm experiment of nanocatalyst in the subsequent modification process.
To illustrate the efficiency of this catalytic system, its ability was compared with different Lewis and Brønsted acids ( Table 2). This clearly indicated that [BMIm] [BF 4 ]@[phosphonicacid@KIT-6] could be introduced as the best catalyst for the aforementioned purpose. In a separate experiment, the use of [phosphonicacid@KIT-6] as a catalyst has worse results. This demonstrates the beneficial role of the ionic liquid in obtaining acceptable conversions.
Based on the best of our knowledge, this investigation presents the first report of an ecosafe and efficient synthesis of 4-alkoxy-5H-chromene [2,3-d]pyrimidines. On the other hand, our method not only provides better yields in mild condition and reduced reaction times but also introduces recyclable Brønsted acid functionalized three-dimensional cubic Ia3d MSNs. Although the exact mechanism for the later reaction has not been established, it is reasonable to propose that product 5 results by nucleophilic attack of alcohol 4 to the obtained product 3 from the tandem Knoevenagel and Pinner reactions (Scheme 2) to produce intermediate 6. Finally, the intermediate 6 reacted with salicylic aldehyde, followed by proton transfer to obtain the product 5 (Scheme 3).
Finally, to determine the applicability of catalyst recovery, the reaction mixture was filtered off and the remaining catalyst was washed to remove the probable residual product, dried under vacuum, and reused in subsequent runs. In five consecutive runs, the conversion stayed with no detectable loss (1st run: 90%, 1st reuse 89%, 2nd reuse: 90%, 3rd reuse: 88%, 4th reuse: 86%, Fig. 2), and the recovery yield of IL@[phosphonicacid@KIT-6] was more than 92%.
To explore the high potent and efficiency of this catalyst, we evaluated [BMIm] [BF 4 ]@[phosphonicacid@KIT-6] as catalyst in the one-pot condensation    4 ] as a green, robust, and convenient reusable nanocatalyst for the synthesis of 4-alkoxy-5H-chromen [2,3-d]pyrimidine derivates under solvent-free conditions. Herein, 4-alkoxy-5H-chromen [2,3-d]pyrimidines was prepared via one-pot, three-component condensation of iminochromenes and salicylaldehyde with different primary alcohols under mild conditions and in excellent yields. Based on our observations, it could be concluded that good yields, a Yields refer to isolated pure products based on the reaction of 3(a-c) (1 mmol), salicylaldehydes 1(a-c) (1 mmol), alcohol 4(a-e) (1.5 mmol), cat. (2 mol %), at rt and solvent-free conditions. The reaction mixture was stirred for 40 min. All known products have been reported in the literature, and they were characterized by comparing their melting points and NMR spectra with authentic samples. [5]  operational simplicity, practicability, and economical and environmental benefits are the worthy advantages of this protocol.

EXPERIMENTAL Preparation of the Catalyst, IL@[Phosphonicacid@KIT-6]
The amine functionalized mesoporous silica KIT-6 ([n-PrNH 2 -KIT-6]) was prepared according to the procedure reported in our previous article. [18] Then, as-synthesized [n-PrNH 2 -KIT-6] (0.2 mol amine group), crystalline phosphorous acid (0.4 mol), and concentrated HCl (0.6 mol) were dissolved in 200 mL water, and the mixture was refluxed in a three-necked flask fitted with thermometer, condenser, and dropping funnel. During 1 h, 60 mL of a 40% (w=v) aqueous formaldehyde solution was added dropwise, and the reaction was refluxed for 1 h. The solvent was evaporated, and the concentrated residue was neutralized with concentrated ammonia solution. Finally, the obtained solid was filtered off, washed with hot dry MeOH for 12 h in a continuous extraction apparatus (Soxhelet), and then dried at 100 C overnight to furnish the corresponding surface-bound phosphonic acid . In the next step to achieve IL@[KIT-6-phosphonicacid], Scheme 3. Proposed mechanism for the synthesis of 4-alkoxy-5H-chromen[2,3-d]pyrimidines 5. 1 g of [phosphonicacid@KIT-6] was added to a solution of 1-butyl-3-methylimidazolium tetrafluoroborate (3 mL) in dry acetone (50 mL). The reaction mixture was stirred at room temperature overnight. After stirring, acetone was removed under reduced pressure. The resulting solid was then dried at 70 C under vacuum for 24 h, to obtain the designed catalyst IL@[KIT-6-phosphonicacid].
General Procedure for the Synthesis of 4-Methoxy-5Hchromen [2,3-d]pyrimidine IL@[Phosphonicacid@KIT-6] catalyst (2 mol%) was added gently to a magnetically stirred mixture of iminocoumarine 3(a-c) (1 mmol), salicylaldehyde 1a (1 mmol), and alcohol 4(a-e) (1.5 mmol). The reaction mixture was stirred for 40 min at room temperature. The progress of the reaction was monitored by thin-layer chromatography (TLC). When the spot for the product (Rf 0.8 in silica gel, EtOAc=n-hexane (1:5) was visible, the catalyst was separated by filtration or centrifuging, and the final product was purified by column chromatography using EtOAc=n-hexane 1:6 as an eluent and recrystallized from EtOH.