Synthesis of cyclic ethers by cyclodehydration of 1,n-diols using heteropoly acids as catalysts

Heteropoly acids were used as catalysts for cyclodehydration of various 1,n-diols. Cyclodehydration of butane-1,4-diol, pentane-1,5-diol and hexane-1,6-diol catalysed by H3PW12O40 gave tetrahydrofuran, tetrahydropyran and oxepane, respectively. Cyclodehydration of diethylene glycol, triethylene glycol, diethylene glycol monomethyl ether and polyethylene glycol 200 catalysed by H3PW12O40 gave 1,4-dioxane. In particular, cyclodehydration of hexane-1,6-diol gave an excellent yield of oxepane (80%). The selectivity exhibited by the H3PW12O40 catalyst was even better than that exhibited by other reported catalyst systems for similar cyclodehydration reactions.


Introduction
Many natural compounds, such as inostamycins, isosorbide and polyether antibiotics, incorporate cyclic ethers as structural subunits and have significant biological activity [1][2][3]. Additionally, some cyclic ethers have distinctive aromas and are used as flavours [4]; (2)-ambrox is a typical representative of this type of cyclic ether [5]. Many of the commonly used synthetic approaches for the formation of cyclic ethers, including cycloaddition and cyclization, involve chlorine chemistry or heavy metals at different levels [6,7]. Additionally, cyclization reactions are often conducted under acidic conditions [8,9]. Cyclodehydration of 1,n-diols to cyclic ethers is an industrially important reaction [4]. These reactions are usually carried out using inorganic and organic acids, solid acid catalysts (such as clays), group (IV) metal halides, metallocenes, sulfated zirconia, zeolite or calcium phosphate. There is a strong interest in the use of solid acid catalysts to replace conventional homogeneous catalysts, such as inorganic and organic acids [10]. Although conventional catalysts are very effective, they produce highly corrosive media and chemically reactive waste streams [11]. However, using heteropoly acids (HPAs) for the general operation of large chemical processes is ecofriendly and safe [12][13][14].
HPA catalysts provide several advantages that make them economically and environmentally attractive [15]. HPAs can be viewed as versatile catalysts because they contain multiple active sites, including metals, protons and oxygen atoms. Protons can act as Brønsted acids to promote acidcatalysed reactions [16]. HPA catalysts can contain one or two types of acidic sites, acidic protons and/or Lewis-acidic metals [17]. Both types of acidic sites can work as active sites in acid catalysis. HPA catalysts can improve many classical acid catalysis reactions, such as cracking, condensation, isomerization, Friedel-Crafts and amination reactions [18][19][20][21]. Therefore, there has been considerable interest in the use of HPAs as catalysts.

Materials
All the chemicals were purchased commercially. All reagents were of analytical grade and were used directly.

The synthetic method of catalyst 2a-2d
All the catalysts (2a -2d) were synthesized using the same approach. The following method is provided for catalyst 2a as an example. Concentrated H 3 PO 4 was added to a boiling aqueous solution of Na 2 WO 4 . 2H 2 O in a 4 : 1 acid/salt ratio and boiling was maintained in a reflux system for 8 h. The salt was precipitated by the addition of KCl, then purified by recrystallization and cooled overnight to 58C. The product was filtered, washed and then vacuum-dried for 8 h. The product was treated with ether and a concentrated HCl (37%) solution. The released Dawson acid formed an additional compound with the ether, which allowed it to be separated from the solution. After obtaining the ether solution with the acid, the ether was eliminated and the remaining solution was placed in a vacuum-desiccator until crystallization.

Upscaling with 2a as a catalyst
A mixture of butane-1,4-diol (900.12 g, 10 mol) and catalyst 2a (49.04 g, 0.01 mol) was placed in a roundbottom flask fitted with a distillation unit. The mixture was stirred and heated in an oil bath. When the temperature reached 1008C, THF and water began to distil from the mixture. Stirring and heating at this temperature were continued until the distillation stopped (8 h). THF (664.60 g, 9.23 mol; 92.3% yield) was obtained after drying over molecular sieves and filtering.

Synthesis of compounds 3a -3g
Compounds 3a-3g were all synthesized using the same approach. The following method is provided for the synthesis of THF (3a) as an example.
A mixture of butane-1,4-diol (200 mmol) and an HPA (H 3 PW 12 O 40 ) catalyst (0.2 mmol) was added to a round-bottom flask fitted with a distillation unit. The mixture was stirred magnetically and heated in an oil bath. When the temperature reached 1008C, THF and water began to distil from the mixture. The mixture was continuously stirred and heated at this temperature until the distillation was complete. THF was obtained by drying the distillate over CaCl 2 and filtering. Reactions were performed with various 1,n-diols and the products were identified using 1 H NMR, 13 C NMR and mass spectrometry.

Results and discussion
The cyclodehydration reaction conditions were optimized under solvent-free conditions using butane-1,4-diol (1a) as the reagent.
As with all catalysis, the first step in using HPAs for selective catalytic dehydration of butane-1,4-diol to THF was to choose an appropriate HPA catalyst. The metals of the HPA catalysts were the selected focus because they are the active sites in the acid-catalysed reactions [18,19]. Accordingly, a series of . Catalysts 2a and 2c provided higher yields than the other catalysts. Moreover, although Mo and W belong to the same group, they displayed different catalytic activities in this reaction; the order of the catalytic activities was in accordance with that of the Brønsted acidity of the HPAs [16]. Tungsten HPA 2a was the catalyst of choice because of its stronger acidity, higher thermal stability and lower oxidation potential than 2b, 2c and 2d. Overall, catalyst 2a (H 3 PW 12 O 40 ) gave the best yield (98%).
The effect of the amount of catalyst 2a (H 3 PW 12 O 40 ) on the reaction yield was thoroughly investigated. The yield of THF (3a, structure shown in table 3) progressively increased from 70 to 99% with increased catalyst loading (table 2). Notably, a catalyst loading of 0.1 mol% was highly effective for the model reaction. The effect of the temperature and reaction time was subsequently investigated, both of which significantly affected the reaction. The yield of THF progressively increased from 62 to 98% with increased reaction time. A yield of 98% was obtained under optimum conditions of 0.1 mol% catalyst loading at 1008C for 3 h reaction. THF was obtained as the only product.
Based upon the above optimum reaction conditions, amplification experiments were performed. The upscaling experiment with 2a as a catalyst was described in 'Material and methods'. The generally good yields (664.60 g, 9.23 mol; 92.3% yield) enabled the production of THF in the order of 100 g. Therefore, this method has prospective applications in the production of THF.
Compounds 3a -3g (table 3) were all synthesized using the same approach according to the synthetic method described for 3a in 'Material and methods'. Products 3a -3g were identified using 1 H NMR, 13 C NMR and mass spectrometry.

Conclusion
Cyclic ethers were obtained by the reaction of 1,n-diols using HPA catalyst H 3 PW 12 O 40 (2a), an inexpensive and simply prepared catalyst. The selectivity exhibited by catalyst H 3 PW 12 O 40 was better than that of several reported catalyst systems for similar cyclodehydration reactions. Similar catalysts also catalysed the conversion of polyethylene glycols and triethylene glycol to 1,4-dioxane. Cyclodehydration of hexane-1,6-diol gave oxepane in excellent yield. With H 3 PW 12 O 40 as a catalyst, the upscaling experiment provided generally good yields, enabling THF production in the order of 100 g; this method has prospective applications in the production of THF. Therefore, the HPA catalyst H 3 PW 12 O 40 is a promising solid acid catalyst on which further research will be undertaken.