Synthesis of 6-Amino-2,4-dihydropyrano[2,3-c]pyrazol-5-carbonitriles Catalyzed by Silica-Supported Tetramethylguanidine Under Solvent-Free Conditions

Abstract An efficient, high-yielding, and rapid protocol has been developed for the synthesis of diversity-oriented 6-amino-2,4-dihydropyrano[2,3-c]pyrazol-5-carbonitriles derivatives via a four-component, one-pot cyclocondensation reaction of ethyl acetoacetate, hydrazine hydrate, aldehydes, and malononitrile using silica-supported tetramethylguanidine as a heterogeneous catalyst for the first time. The protocol proves to be efficient and environmentally benign in terms of very easy workup, good yields, and ease of recovery of catalyst. In addition, the present method is superior in terms of green media, the amount of catalyst, and reaction time. GRAPHICAL ABSTRACT

Recently, heterogeneous catalysts have been highly acknowledged for the sustainable development of any catalytic process because of their easy recovery, recyclability, minimization of undesired toxic wastes, and E factor. [23] The usage of heterogeneous metal Lewis acid catalyst instead of traditional homogeneous metal Lewis and Brønsted acid catalysts could be a more environmentally friendly alternative. The problems usually connected with the homogeneous catalysts can be easily overcome by heterogenization of a homogeneous counterpart onto insoluble inorganic or organic solid support in which active components are strongly immobilized. [24] Solid catalysts provide numerous opportunities for recovering and recycling catalysts from reaction environments. Among the various heterogeneous catalysts, particularly, silica-supported tetramethylguanidine has the advantages of low cost, ease of preparation, environmental friendliness, high efficiency, and catalyst recyclability (Fig. 1).
It is evident from the previous literature that silica-supported tetramethylguanidine has generated enormous interest as a green and a potential solid catalyst to construct carbon-carbon and carbon-heteroatom bonds in various organic transformations. [25,26] Considering these subjects and based on our previous endeavors in exploring novel and practical multicomponent reactions to synthesize useful  heterocyclic compounds, [27][28][29][30] we decided to investigate efficiency of silica-supported tetramethylguanidine catalyst for the synthesis of 6-amino-2,4-dihydropyrano[2,3c]pyrazol-5-carbonitriles. Herein we report a tandem synthesis of 6-amino-2,4dihydropyrano[2,3-c]pyrazol-5-carbonitriles derivatives from ethyl acetoacetate, hydrazine hydrate, aldehydes, and malononitrile using silica-supported tetramethylguanidine as expeditious reusable catalyst in an excellent yield (Scheme 1).
To see the effect of solvent, we screened different solvents such as EtOH, acetonitrile, methanol, and water at reflux. It was observed that under solvent conditions the reactions required longer times (2-4 h) to afford comparable yields (Table 1, entries 7 and 10-12). When the reaction was performed under solvent-free conditions, good yield of target product was obtained (Table 1, entry 9). Moreover, we found that the yields were obviously affected by the amount of SiO 2 TMG loaded. When 5, 10, 15, and 20 mol% of SiO 2 TMG were used, the yields were 81%, 96%, 95%, and 92%, respectively (Table 1, entries 9 and 13-15). Therefore, 10 mol% of SiO 2 TMG was sufficient and optimal quantity for the completion of the reaction.

SILICA-SUPPORTED TETRAMETHYLGUANIDINE
Encouraged by the general interest of this convergent and experimentally simple transformation, we then evaluated its scope and efficiency in the generation of 6-amino-2,4-dihydropyrano[2,3-c]pyrazol-5-carbonitriles arrays by recourse to a diverse range of several substituted aryl=aliphatic aldehydes. It was gratifying to observe that most of the tested substrates exhibited satisfactory reactivity profiles, in all cases leading to a smooth heterocyclization sequence that readily afforded the target structures (Table 2). Compared with aromatic aldehydes, aliphatic aldehyde afforded relatively lower yields of the corresponding 6-Amino-2,4dihydropyrano[2,3-c]pyrazol-5-carbonitriles. A possible mechanism of this one-pot reaction is expected on the basis of reported literature [15] (Scheme 2).
The reusability of the SiO 2 TMG catalyst is one of its most important benefits and makes it useful for commercial applications as well. Thus the recovery and reusability of the catalyst were investigated. The recyclability of the catalyst was checked with model reaction (Table 4, entries 1-4). The catalyst was recovered after completion of the first fresh run, the reaction mixture was cooled to room temperature, and then the residue was treated with boiling ethanol, filtered through a sintered funnel, and washed thoroughly with the same solvent. The catalyst was separated from the reaction mixture. The recovered SiO 2 TMG was dried at 90-100 C for 12 h and tested in up to three more reaction cycles. The same catalyst was reused for subsequent reactions (three runs) with fresh substrates under the same conditions. The catalyst showed excellent recyclability in all these reactions (Table 4), as the reaction times and yield remained almost the same without loss of catalytic activity.

EXPERIMENTAL
Chemicals were purchased from Aldrich, Merck, and Alfa Aesar chemical companies. The NMR spectra were recorded in dimethylsulfoxide (DMSO-d 6 ) on a Jeol JNM ECP 400 NMR instrument using Tetramethylsilane (TMS) as an  internal standard. High-resolution mass spectra (HRMS) were recorded on a Jeol JMS-700 mass spectrometer. Melting points were taken in open capillaries on an Electrothermal-9100 instrument (Japan).

Preparation of Silica-Supported Tetramethylguanidine (SiO 2 TMG) Catalyst
Silica-supported tetramethylguanidine was prepared by adopting the literature precedent. [31] 1,1,3,3-Tetramethylguanidine (TMG, 0.2 mol) and mixed xylenes were mixed together and heated to 120 C. Chloropropyl trimethoxysilane (0.081 mol) was added dropwise over 2 h, and the solution allowed to react for 2 h. It treated with activated silica in presence of triethyl amine, and the solution was allowed to react for 1 h. On cooling, a solid precipitate was filtered and dried at 85-90 C to yield the desired product.
General Procedure for the Synthesis of 6-Amino-2,4dihydropyrano[2,3-c]pyrazol-5-carbonitriles To a prestirred mixture of ethyl acetoacetate (1 mmol), hydrazine hydrate (1 mmol), aldehydes (1 mmol), and malononitrile (1 mmol) were added, followed by SiO 2 TMG (10 mol%). The reaction mixture was then heated at 100 C. The reaction was monitored by thin-layer chromatography (TLC). After completion of the reaction, the reaction mixture was cooled to room temperature. The residue was treated with boiling ethanol, filtered through a sintered funnel, and washed thoroughly with the same solvent. The combined filtrate was evaporated in vacuo to afford the crude product, which was recrystallized from ethanol to afford pure compound 5. The spectral and analytical data of the model representative compound are given here.

CONCLUSION
In summary, we have described an efficient and environmentally benign protocol for the synthesis of fully substituted 6-amino-2,4-dihydropyrano[2,3-c]pyrazol-5carbonitriles via reaction of ethyl acetoacetate, hydrazine hydrate, and malononitrile with diverse aldehydes using silica-supported tetramethylguanidine as expeditious reusable catalyst in excellent yields. The main advantages of this present methodology are the simple workup, easy recovery of catalyst, and lack of need for anhydrous conditions, base, or any additional activators.

FUNDING
This work was supported by a research grant from Pukyong National University (2014).

SUPPORTING INFORMATION
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