An Environmentally Benign Protocol for Aqueous Synthesis of Tetrahydrobenzo[b]Pyrans Catalyzed by Cost-Effective Ionic Liquid

A mild, efficient, and environmentally benign protocol for the synthesis of tetrahydrobenzo[b]pyran derivatives in the presence of readily accessible, biodegradable, and choline hydroxide based ionic liquid as catalyst has been established. The key features of the reported methodology include good to excellent yields of desired products, simple work-up procedure and good recyclability of catalysts, which may be a practical alternative to the existing conventional processes for the preparation of 4-H pyrans to cater to the requirements of academia as well as industry.


Introduction
As an important class of oxygen-containing heterocycles, tetrahydrobenzo [b]pyrans are widely employed as potential biodegradable agrochemicals [1], photoactive materials [2], cosmetics and pigments [3]. Because of the inherent reactivity of the pyran ring, 4-H pyrans are versatile synthons, which can be easily converted into pyridine compounds as pharmacologically important calcium

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antagonists [4,5]. Tetrahedronhydro [b]pyran compounds themselves have a broad spectrum of biological properties [6,7], such as spasmolytic, anticancer, diuretic, anticoagulant, and antiancaphylactia activities [8,9]. They can also be used as cognitive enhancers not only for the treatment of neurodegenerative disease, for example, Parkinson's disease, Huntington's disease, Alzheimer's disease, amyotrophic lateral sclerosis, AIDS associated dementia and Down syndrome but also for the treatment of schizophrenia and myoclonus [10]. Due to the versatile utilization of the pyran derivatives in the field of organic synthesis as well as in medicinal chemistry, many researchers have been encouraged to develop highly efficient procedures for the preparation of these kinds of compounds.
Ionic quids (ILs) with the unique properties of low volatility, good and tunable solubility, non-flammability, and excellent recyclability are receiving considerable global attention and used extensively in organic synthesis as green reaction media or designable catalysts [33][34][35][36][37][38][39][40]. Thus, some task-specific ionic liquids were successfully introduced as catalysts for the preparation of the desired tetrahydrobenzo[b]pyran derivates [41][42][43][44]. However, disadvantages associated with high price, a little toxicity and difficulty of biodegradability, to some extent, limit these methodologies at the industrial scale. Choline chloride (ChCl), a member of the vitamin B family, is a very cheap, commercially available, biodegradable and non-toxic quarternary ammonium salt, which can be simply produced by gas phase reaction or directly extracted from biomass [45,46]. Compared to the intensive studies of ChCl-derived deep eutectic solvents as catalysts for organic transformations [45,46] the research with regard to the application of ChCl-based ionic liquids to organic synthesis is very rare [47]. As part of our ongoing pursuit for the establishment of "green organic synthesis" [48][49][50][51][52][53][54][55][56], we herein prepared a type of non-toxic, cheap and biodegradable ChCl-derived ionic liquids and present their usage as catalysts for the synthesis of 4H-benzo[b]pyrans via MCRs of aldehydes, methylene active compounds and 5,5-dimethyl-1,3-cyclohexanedione in aqueous medium. These type of ionic liquids can be readily prepared through anion exchange reactions (Scheme 1) and they are all liquids at room temperature (25 °C

Results and Discussion
Initially, the reaction of p-anisaldehyde, malononitrile and dimedone was selected as model for the optimization of reaction conditions. As shown in Table 1, [bmim]BF 4 and [bmim]PF 6 , two traditional ionic liquids frequently used as reaction media for organic transformations, gave significantly lower yields of products (Table 1, entries 1-2). Moreover, new DBU derived ILs were found to be less suitable as catalysts for the preparation of the pyran product while they exhibited excellent catalytic activities for aza-Michael addition [48][49][50] and Knoevenagel condensation [48][49][50][51][52][53][54][55][56] [12][13][14][15]. Moreover, a brief screening of solvents showed that the much better results in terms of both reaction rate and yield were observed with water as reaction medium than those performed in organic solvents (Table 1, entries 13 and [16][17][18][19]. To extend the scope and demonstrate the generality of the present method, we explored the reaction of various aromatic aldehydes with malononitrile and dimedone under the optimized reaction conditions to furnish respective substituted pyrans and the results are demonstrated at Table 2. To our pleasure, the reactions proceeded smoothly and good to excellent yields of desired products were obtained within several hours. The electronic nature of substituents on the aromatic ring has some effects on the transformation. The aromatic aldehydes bearing electron-donating groups such as MeO, OH, 3,4-2(Me) reacted much slower with malononitrile and dimedone than other aromatic aldehydes substituted with NO 2 , CN, F, Cl, Br ( Table 2, entries 1-10). The heterocyclic aldehydes such as 2-thienyl and furyl aldedydes were also demonstrated to be efficient reagents for this reaction ( Table 2, entries 12 and 14). However, when pyridine and 2-naphthyl aldehydes were subjected to the procedures, only intermediates-Knoevenagel condensation products were detected (Table 2, entries 11 and 13). In addition, the reaction of trans-cinnamaldehyde with malononitrile and dimedone was performed under the same conditions and some lower yield (69%) was observed (Table 2, entry 14). It is noteworthy to mention that aliphatic aldehydes were suitable for the condensation achieving good product yields ( Table 2, entries 16 and 17).  2, 4a-i).
In order to demonstrate the industrial applicability of this methodology, the aqueous one-pot synthesis of 4H-benzo[b]pyrans via the reaction of p-anisaldehyde, malononitrile, dimedone catalyzed by [Ch]][OH] was carried out on a larger scale (100 mmol). The reaction was completed in 2 h. The excellent yield of 98% for the conjugate product was obtained. On the same scale, the recyclability of the catalytic system was investigated using the same reaction as model reaction. Upon the completion of the reaction, the product was isolated by filtration while the filtrate was dried to remove water at 80 °C under vacuum. The recovered ionic liquid was reused in subsequent reactions. As shown in Figure 1  Yields/% A plausible mechanism for the reactions is illustrated in Scheme 3. Due to the strong basicity of hydroxyl anion of the IL (see Table S1) and hydrogen bond formed between hydroxyl group of side chain of Ch and carboxyl moiety of aldehydes, the dual activation of methylene ingredients and aldehydes facilitate the formation of a Knoevenagel condensation product 5. Dimedone can be easily converted to its enolic form in the presence of [Ch][OH] that could readily react with acrylonitrile 5, affording the Michael addition product 6, followed by tautomerism, intramolecular O-cyclization and proton transfer reactions under dual activities of the IL to give the desired product 4. 13 C NMR data of benzaldehyde and the mixture of IL [Ch][OH] and benzaldehyde also provided the catalytic role of the hydrogen bond (see Figures S1 and S2).

Materials and General Methods
NMR spectra were recorded Bruker Advance DPX 400 MHz spectrometer (Bruker BioSpin Corporation, Fällanden, Switzerland) with chemical shift values (δ) in parts per million, relative to the internal standard of tetramethylsilane (TMS). Melting points were determined using YRT-3 apparatus (Reliant Instument, Tianjin, China) and were not corrected. All chemical were purchased from Aladdin, Aldrich or Fluka (Buches SG, Switzerland). All reactions were monitored by thin layer chromatography (TLC).

General Procedure for the Synthesis of the ChCl-Based Ionic Liquids
A mixture of ChCl (20 mmol), MX (20 mmol) and methanol (25 mL) was stirred at reflux for 12 h. Then methanol was evaporated at 60 °C in high vacuum until the weight of the residue remained constant. The resulting liquids were the [Ch]X. The ionic liquids were characterized by 1 H NMR, 13

Typical Procedure for One-Pot Synthesis of Tetrahydrobenzo[b]Pyrans
To a mixture of aromatic aldehyde (5 mmol), methyl active compound (5 mmol), and dimedone (5 mmol) in water (10 mL), [Ch][OH] was added. Upon addition, the reaction was stirred at reflux until the disappearance of starting material by TLC. After the completion of the reaction, the reaction mixture was filtrated to obtain a solid, which was recrystallized in 95% ethanol to give pure product. The ionic liquid was recovered from the remaining filtrate, subsequently remove water in vacuum at 80 °C and reused several times without further purification. The product was characterized by melting point measurement and NMR.

Conclusions
In summary, a simple, efficient and environmentally benign protocol for preparation of tetrahydrobenzo[b]pyrans was developed using novel basic, biodegradable, and cost-effective ionic liquid [Ch][OH] as catalyst in aqueous solution. Compared with the traditional imidazole derived ionic liquids, [Ch][OH] not only produced comparative or better results in terms of reaction rate and product yield but also is biodegradable, cheap and can be reused six times without significant loss of its catalytic efficiency. The applications of the novel ChCl-derived ionic liquids for other organic transformations are currently being investigated in our lab.