An Efficient Protocol for the One Pot Synthesis of Pyranopyrazoles in Aqueous Medium using Triethanolamine as a Catalyst

Triethanolamine is an efficient and green catalyst for the synthesis of 6-amino-1, 4-dihydro-4-substituted-3-methylpyrano-[2, 3-c] pyrazole-5-carbonitrile in aqueous medium reflux conditions. The procedure is easier, eco friendly, simple with easy workup affording good yield of the corresponding products.


Introduction
The present scenario for organic synthesis indicates the crave for green and economical synthesis of organic compounds. One of it is multi component synthesis. Strecker's synthesis for amino acids was the first report on multi component reaction [1]. Last few decades show large development in it. The main aim of such reactions is to fasten the reaction rate by reducing number of steps involved and eventually increase the yield of reaction. In this context to achieve great efficiency catalysts are employed. Catalysts such as Nano α-Al 2 O 3 supported ammonium dihydrogenphosphate [2], tungstate sulfuric acid [3], Fe 3 -xTixO 4 @SO 3 H nanoparticles [4], nano-titania sulfuric acid (15-nm TSA) [5], nanostructured MgO [6], H 14 [NAP 5 W 30 O 110 ] [7] and Zno Nanoparticles [8] were used. Organic catalysts such as Triethylamine [9], DABCO [10], Trishydroxymethyl aminomethane [11] are also reported in various organic transformations. Triethanolamine contains basic tertiary amine and primary alcoholic part ( Figure 1).
It is used for activation of both CO 2 and epoxides to convert them in to cyclic carbonates [12]. It is also reported as a ligand for copper catalyzed hydroxylation of aryl halides in aqueous medium [13]. It is used as aqueous solvent for controllable preparation of ZnO nano flowers in sol gel technique [14]. Its aqueous solution is reported as electrolyte in CO 2 Photo electro-conversion catalyzed by Cu-Doped Graphene-Titania Catalyst [15]. Also it is found to increase the rate of oxidation of mesitylene catalyzed by cobalt bromide [16]. It is used as sacrificial electron donor in photocatalytic system [17]. Furthermore; it improved the catalytic performance of CuBr/ PMDETA in the atom transfer radical polymerization [18]. It is also used as phase transfer catalyst for synthesis of 1-(arylsulfonyl) aryl/heterylmethanes [19]. It is used as medium for synthesis of 3-substituted coumarins using L-proline as a catalyst [20]. It is reported as catalyst in 10 mol% for synthesis of 2-amino-3-cyano-4H-pyran derivatives under ultrasound irradiation at 60 0 C [21].

Result and Discussion
To explore the synthetic application of triethanolamine, in the present work we report the catalytic facet of it for the synthesis of heterocyclic compounds bearing pyrazole skeleton. To optimize the reaction conditions, we choosed anisaldehyde as the prototype. Initially, 10mol% of triethanolamine was taken for solvent free reaction at room temperature. But the reaction afforded a low yield of the product after 2 hour stirring. Then we used 10ml of water for room temperature stirring [24]. After 2 hours stirring it gave 62% of yield. The yield of reaction gets drastically changed on increasing temperature. At 90 0 C we got 85% of yield of the product. When 20mol% of triethanolamine was used then we got 92% of yield at 90 0 C in 10 ml water. Other solvents were also studied expecting better yield but other than ethanol and water we got poor yields (Table 1). Further increase of temperature and amount of triethanolamine did not improve yield significantly (Table 1). After optimizing the reaction conditions, differently substituted aldehydes with electron donating as well as electron withdrawing groups were reacted to examine the feasibility of this catalytic reaction (Scheme 1). Almost all aldehydes bearing various substituents such as -Cl, F, -NO 2 , -OMe etc afforded good yield of the corresponding products. All the synthesized compounds showed sharp peaks at 3410, 3356cm-1(-NH 2 ) and 2190cm -1 (-CN) in IR spectra which supports for the formation of pyranopyrazole. The formed products being insoluble in water were easy to separate from the aqueous medium by simple filtration. The reason for catalytic activity of triethanolamine is it's solubility in aqueous medium and basic nature. Products are simply purified by re crystallization with ethanol. Thus the protocol described herein is efficient for the synthesis of pyrazopyrazoles which do not need purification by column chromatography.

Experimental
Melting points were recorded in open capillaries and were uncorrected. Progress of reaction was monitored by TLC (30% of ethyl acetate: n-hexane). IR spectra were taken by KBr disc on Shimadzu IR Affinity 1 spectrophometer. 1 HNMR spectra were recorded on a Varian 400MHz spectrophotometer in the specified solvents. Chemical shifts were expressed in ppm relative to TMS. Mass spectra were recorded on a Macro mass spectrometer (Waters) by electro spray method (ES).
To a stirred mixture of aromatic aldehyde (2mmol), malononitrile (2mmol) and triethanolamine (20mol %) in 10ml of water, 3-methyl-1H-pyrazol-5(4H)-one (2mmol) was added. The resulting mixture was stirred and heated at 90 0 C for appropriate Arc Org Inorg Chem Sci   (Table 2). After completion of reaction, the reaction mixture was cooled, filtered off the residue as the crude product which was further purified by re crystallization form ethanol (Scheme 2). Representative Spectral Data

Conclusion
In summary, we have developed an efficient protocol for the synthesis of pyranopyrazoles by a simple method using a catalytic amount of triethanol amine. Herein; not only the yield of reaction is improved but also the reaction time is reduced. The workup of the reaction is very simple which make it easier to isolate the product.