[18-C-6H3O+]: an in-situ generated macrocyclic complex and an efficient, novel catalyst for synthesis of pyrano[2,3-c]pyrazole derivatives

Synthesis of small aromatic heterocycles is of greater importance in the organic chemistry due to their vibrant applications in pharmaceuticals, agrochemicals and veterinary products. Pyranopyrazoles are one such class of heterocycles associated with numerous applications. Hence herein we report a multicomponent crown ether catalyzed, ultrasound irradiated methodology to make different functionalized pyranopyrazoles in a single step. This technique involves the in-situ generation of [18-C-6H3O+][OH−] complex, which in turn activates the aromatic aldehyde and aids in the facile nucleophilic addition.


Results and discussion
We began our investigation by performing a model reaction using benzaldehyde (1a), 2a, 3 and 4a as substrates, and 2 mol% of 18-crown- [6]-ether/H 2 O in methanol under ultrasound irradiation for 10 min. We were encouraged by the formation of 5a in 52% yield. Further sonication did not show any changes in the product yield. In order to confirm the influence of the catalytic system few control experiments were carried out. First, the reaction was conducted without crown ether/H 2 O, trace amount of product was formed after 25 min. About 35% of the product was obtained when the reaction was carried out only with water, and 20% yield was obtained when only crown ether was used (
A series of reactions were carried out in order to find a suitable solvent for this reaction and concluded that water itself is the best medium, which made our methodology more eco-friendly and greener (Table 1, entries 5-10). After choosing the catalyst and solvent the reaction progress was checked with different quantities of 18-crown-[6]-ether and found that the reaction profile improved considerably from 2 to 10 mol%, but further increase did not make any effect on the yield (Table 1, entries 10-16). Finally, it was concluded that 10 mol% of the catalyst is required on 2 mmol scale reaction. To confirm the effect of ultrasound waves on the reaction kinetics one reaction under reflux condition was conducted, desired product formation was observed after 40 min by checking TLC (Table 1, entry 17).
Intrigued by the formation of desired product 5a, we examined the generality of the reaction with various substrates using the optimized conditions. Aldehydes bearing electron-donating groups and electron-withdrawing groups (1b-1j) were examined and gratifyingly all were well tolerated to furnish good yield of products (5b-5j) (Fig. 4). Moreover, heteroaryl aldehyde (1k) and cinnamaldehyde (1l) also provided the corresponding pypys (5k and 5l respectively) in good yield.
Furthermore, employing ketones (1m, 1n) in place of aldehyde resulted in the formation of a quaternary carbon center at the pyran ring in the product (5m, 5n), which made our method much more interesting. After the successful demonstration of the feasibility of aromatic aldehydes and ketones for this strategy. We employed phenyl hydrazine (4b) and ethyl cyanoacetate (2b) in the reaction (Fig. 1). The results were satisfying giving good yield of the products (5o-5q). The formation of products (5o-5q) were confirmed by comparing their melting points with reported melting points [5][6][7] . Next, we were interested in the synthesis of bis-pypys with the established conditions by using bis-aldehyde functionalities (Fig. 2). For that terephthaldehyde (1o) and phthalaldehyde (1p) were chosen and furnished the respective bis-pypys (5r, 5s) in moderate yield. The study was further extended to synthesize N-arylated pypys using phenyl hydrazine (4b) instead of hydrazine hydrate (4a) under the same conditions and to our delight, the formation of 5t was observed in 73% and 5u in 64% yield.
Based on the observations and literature reports, we propose a pathway, that first involves the C-H activation of malononitrile by lewis basic water molecule and activation of aromatic aldehyde by the [18-C-6H 3 O + ][OH − ] complex, which resulted in the formation of Knoevenagel adduct (I). Further [18-C-6H 3 O + ][OH − ] activates the ethyl acetoacetate and speeds up the formation of pyrazolone (II). Michael addition of pyrazolone (II) with Knoevenagel adduct (I) and finally cyclization and tautomerization gives the final product (Fig. 5).
In order to elaborate the synthetic application of our strategy, a 10g-scale synthesis of 5a was demonstrated and delightfully the yield was reproduced which clearly indicates that there is a substantial potential for industrial application. All the products were confirmed by comparing their physical and spectroscopic data with reported data.

Conclusion
We have successfully developed a simple, expeditious and green method for the synthesis of various pyrano [2,3-c] pyrazoles and bis-pyrano [2,3-c]pyrazoles by using 18-Crown- [6]-ether under ultrasonication condition in the aqueous medium. The catalyst generated within the reaction medium boosted up the reaction rate and yield. The crown ether hydronium ion complex are known but the catalytic activity of these complex for the synthesis of pyranopyrazoles was found to be new and understudied in current literature.  www.nature.com/scientificreports/ General procedure for the synthesis of pyrano[2,3-c]pyrazoles using crown ether as a catalyst. To a mixture of aromatic aldehyde 1a-p (2 mmol), 2 (2 mmol), 3 (2 mmol), 4a/4b (2 mmol) in water (10 mL) taken in a 50 mL RB flask, crown ether 10 mol% was added. The reaction mixture was subjected to sonication for 10 min at room temperature. The completion of reaction was confirmed using TLC. The solid product was filtered and recrystallized from aqueous ethanol to get the pure products.