Organocatalytic clean synthesis of densely functionalized 4H-pyrans by bifunctional tetraethylammonium 2-(carbamoyl)benzoate using ball milling technique under mild conditions

ABSTRACT A green and simple method has been developed for efficient preparation of diverse annulated 2-amino-3-cyano-4H-pyran derivatives in the presence of a low loading of tetraethylammonium 2-(carbamoyl)benzoate (TEACB), as a bifunctional organocatalyst, under solvent-free conditions using the ball milling technique. This procedure is a clean, transition-metal-free, and environmentally friendly approach that offers many advantages including short reaction times, high to quantitative yields, low cost, and straightforward work-up. GRAPHICAL ABSTRACT


Introduction
Designing and conducting chemical reactions through "green" experimental protocols is an enormous challenge that chemists have to confront to improve the quality of the environment for present and future generations. An ultimate goal in green chemistry is to eliminate or minimize the use of volatile organic solvents in modern organic synthesis. Hence, development of new synthetic methodologies under solvent-free conditions is an important area of research with growing popularity. The interest for solvent-free reactions arises from advantages such as reducing or eliminating solvent usage and consequently low pollution and costs, simplicity in relevant processes, and handling (1)(2)(3)(4). These factors are especially important in industry. On the other hand, multicomponent reactions (MCRs), defined as any process in which three or more reactants combine in one pot to generate a product containing all or most atoms of the starting materials, are highly atom efficient (5)(6)(7)(8). Thus, an ideal MCR involves the simultaneous addition of reactants, catalyst, or reagents at the beginning of the reaction and requires that all reactants couple in an exclusive ordered mode under the same reaction conditions (5)(6)(7)(8). Their superior atom economy, resulting in substantial minimization of waste, labour, time, and cost as well as high efficiency, mild conditions, high convergence, and their general compatibility with green solvents, would justify a central place in the toolbox of green synthetic methodologies (5)(6)(7)(8). Therefore, academic and industrial research groups have increasingly focused on the use of MCRs for synthesizing a broad range of products especially important heterocyclic compounds such as 4H-pyran derivatives nowadays (9,(10)(11)(12). Recently, several techniques for efficient application of solvent-free conditions or MCRs have been developed  TEACB (2) Ball milling, ambient temperature 5 98 g a Reaction conditions: 2-hydroxynaphthalene-1,4-dione (6, 1 mmol), 4-chlorobenzaldehyde (7a, 1 mmol), and malononitrile (8, 1.0 mmol). b The yields refer to the isolated product 9a. c The Knoevenagel condensation product V was formed in almost quantitative yield. d Lithium phthalimide-N-oxyl. e Sodium phthalimide-N-oxyl. f Potassium phthalimide-N-oxyl. g Quantitative conversion of the substrates to the desired product 9a was observed. Simple trituration of the reaction mixture in water and its subsequent filtering afforded essentially pure solid 9a.
individually. However, when these two wings of green chemistry can be combined, an excellent green chemistry protocol is expected (13)(14)(15)(16).
One of the most important processes to combine solvent-free reactions and MCRs is the use of ball milling solid-state mechanochemical techniques (17)(18)(19). The ball milling technique has also received increasing attention in organic synthesis in recent years. Subsequently, some specific books and review papers have been published on the topic. Some typical examples include the carbon-carbon or carbon-heteroatom bond formation, oxidation by solid oxidants, asymmetric organocatalytic reactions, dehydrogenative coupling, and peptide or polymeric material synthesis (9,(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31). Furthermore, organocatalysis, namely the use of small organic molecules to catalyze organic transformations, is a relatively new and popular field within the domain of organic synthesis. Once the field of organocatalysis had been publicly defined, it grew quickly (32)(33)(34)(35)(36)(37). Although the impact of transition-metal-based catalysts on chemical synthesis cannot be completely understated, some metal-based systems can be expensive, toxic, and sensitive to air or moisture (38)(39)(40). Hence, the advent of organocatalysis brought the prospect of a complementary mode of catalysis, with the potential for savings in cost, time and energy, an easier experimental procedure, and reductions in chemical waste (41)(42)(43)(44)(45).
hand, compound 3 serves as a precursor for the blood anticoagulant warfarin while compound 4 shows an antibacterial activity ( Figure 1) (46,47).
In continuation of our interest to develop the catalytic scope of TEACB (5), as an effective, bifunctional organocatalyst, easy to handle and readily available catalyst, for the synthesis of cyanohydrin trimethylsilylethers (69), cyclotrimerization of isocyanates (70), and fabrication of cross-linked poly(urethane-isocyanurate) networks (71), we decided to investigate a transition-metal-free method for the synthesis of 2amino-4H-pyran scaffold with diverse substituents using a ball mill under a solvent-free condition (Scheme 1).
conditions. POPINO afforded higher yield compared to other salts including Li + and Na + (Entries 2-4, Table 1). Then, the effect of TEACB (5), as a bifunctional organocatalyst, on the completion of the reaction was studied in the next step (Entries 5 and 6, Table 1).
The obtained results demonstrated that higher yields in shorter reaction times can be obtained in the presence of 2 mol% catalyst loading of TEACB (5) using the ball milling technique at ambient temperature (Entry 6, Table 1). Therefore, TEACB (5) loading of 2 mol% under solvent-free ball milling conditions was developed to other derivatives of aromatic aldehydes (7a-j) for the synthesis of the desired 2-amino-4H-chromene derivatives 9a-j (Scheme 2).
The mechanism suggested in Scheme 7 seems to be reasonable for the one-pot three-component reaction of phenolic compounds 6, 10, 12 or 14, aldehydes 7, and malononitrile (8) catalyzed by TEACB (5) under solvent-free conditions using the ball milling technique. The first step includes the formation of cyanocinnamonitrile intermediate V from the reaction between aldehyde 7 and malononitrile (8). Then, Michael addition of the phenolic compounds 6, 10, 12, or 14 (intermediate VI) on this intermediate and subsequent cyclization and tautomerization of the next intermediates VII and VIII, respectively, in the presence of TEACB (5), afford the desired product (9, 11, 13, or 15). It is noteworthy that all the above steps can also be competitively catalyzed through weaker hydrogen bonding interactions of the carbamoyl moiety of TEACB (5) with the substrates and reaction intermediates rather than proton transfer from the carboxylic acid functional group of intermediate II.
Finally, to demonstrate the efficiency and capability of the present protocol in the synthesis of different 2amino-4H-pyran derivatives, it has been compared with some of the previously reported and published procedures. Summarized results in Table 6 clearly show that the present protocol is indeed superior to several of the others in terms of the product yield, reaction time, elimination of solvent, and the required reaction temperature.

Conclusions
In conclusion, the use of TEACB, as a bifunctional organocatalyst, was demonstrated for the clean and rapid synthesis of a wide range of 2-amino-3-cyano-4H-pyran derivatives under solvent-free conditions at ambient temperature using the ball milling technique. This new method offers the following competitive advantages: (i) avoiding the use of any transition-metal, corrosive catalyst, and toxic or volatile solvent, (ii) the use of ambient Scheme 6. A plausible mechanism for the one-pot three-component reaction of enolic components 6, 10, 12 or 14, aldehydes 7 and malononitrile (8) catalyzed by TEACB (5) under solvent-free conditions using the ball milling technique. temperature, (iii) ease of product and catalyst purification/isolation by aqueous work-up, (iv) no side reaction, and (v) low costs and simplicity in process and handling.

Experimental Section
General All commercially available chemicals were obtained from Merck and Aldrich, and used without further purifications, except for benzaldehyde, which was used as a freshly distilled sample. The ball mill was a Retsch MM 400 swing mill with its 3D-driving of the balls. Two stainless steel balls with 12 mm diameter were used, and the milling frequency was at 28 Hz and the ambient temperatures. Analytical thin layer chromatography (TLC) was performed using Merck 0.2 mm silica gel 60 F-254 Al-plates. Melting points, which are uncorrected, were determined using an Electrothermal 9100 apparatus. 1 H NMR (500 MHz) and 13 C NMR (125 MHz) spectra were recorded on a Bruker DRX-500 Avance spectrometer in CDCl 3 , as a solvent, at ambient temperature. All chemical shifts are given relative to tetramethylsilane. Infrared (IR) spectra were acquired on a Shimadzu FT-IR8400S spectrometer. All yields refer to the isolated products.

Preparation of TEACB (5)
To a 25 mL round-bottomed flask equipped with a magnetic stirrer and a condenser, phthalimide (6.80 mmol, 1.00 g) and tetraethylammonium hydroxide were added (6.80 mmol, 20% w/w in water, d = 1.01 g/mL, 5.0 mL). The mixture was stirred at room temperature for 5 min. To this was added 5 mL of distilled water and the mixture was refluxed for 4 h and then allowed to cool. The solvent was evaporated and the residue was kept at 0-4°C for 1 h to afford pure TEACB (5)  General procedure for the preparation of 2amino-4H-pyran derivatives (9, 11, 13, or 15) A clean and dry 10 mL ball mill vessel with two stainless steel balls was charged with malononitrile (8, 1.0 mmol), aromatic aldehydes 7 (1 mmol), enolic or phenolic components 6, 10, 13, or 16 (1 mmol), and TEACB 5 (2 mol%). The vessel was closed, and the milling was started at ambient temperatures and a speed of 28 Hz for the specific times indicated in Tables 2-5 until products 9, 11, 13, or 15 were formed completely. The reaction progress was monitored by TLC. After completion of the reaction, the product was triturated in a 10 mL beaker containing 5 mL of water for 5 min. The obtained solid was filtered on a Buchner funnel and dried in an oven at 60°C to afford the pure products. The filtrate was evaporated to dryness under reduced pressure, and then EtOH (1 mL) was added. TEACB (5) was filtered off and dried in an oven at 75°C for the subsequent experiments.

Disclosure statement
No potential conflict of interest was reported by the authors.