AS A NOVEL AND EFFICIENT CATALYST FOR THE SYNTHESIS OF PYRIDINE DICARBONITRILES

Pyridine dicarbonitriles have been synthesized in good yields via a one-pot multi–component reaction of aldehyde, malononitrile, and thiol in the presence of nano-TiO2 as a catalyst in ethanol.


INTRODUCTION
In recent years, multicomponent reactions (MCRs) have become important tools in modern preparative synthetic chemistry because these reactions increase the efficiency by combining several operational steps without any isolation of intermediates or change of the conditions [1,2] and MCRs have recently emerged as valuable tools in the preparation of structurally diverse chemical libraries of drug-like heterocyclic compounds [3][4][5].
The pyridine nucleus is of considerable interest as this ring is the key constituent in a range of bioactive compounds, both naturally occurring and synthetic, and often of considerable complexity [6].The pyridine dicarbonitrile substructure was therefore chosen as a basic structural scaffold for the design of a reaction-based library [7].Thus, the synthesis of highly substituted pyridines has attracted much attention, and a number of procedures have been developed using a variety of protocols, such as hetero-Diels-Alder reaction of 3-siloxy-1-aza-1,3-butadienes with electron-deficient acetylenes [8], three-component condensation of aldehyde, malononitrile, and thiol [9], ruthenium-catalyzed cycloisomerization of 3-azadienynes [10], Mannich reaction of aldehydes and iminium salts [11] and Vilsmeier-Haack reaction of Rhydroxyketenedithioacetals [12].Among these, one of the very convenient approaches which attracted our attention is the three-component condensation of aldehyde, malononitrile, and thiol to the highly substituted pyridines developed by Evdokimov et al. [9].Herein, we report a mild, practical and highly efficient procedure for the preparation of the title compounds using nano-TiO 2 catalyst at room temperature (Scheme 1).
To the best of our knowledge there are no reports on the synthesis of these compounds with 4-methyl thiophenol using nano-TiO 2 as the catalyst.A plausible mechanism for this reaction is suggested in Scheme 2. Scheme 2. Mechanism for the synthesis of pyridine dicarbonitriles.
The investigation on nano-TiO 2 catalytic activity for the synthesis of many organic molecules is current work in our laboratory.The dimensions of applied TiO 2 nanoparticles were determined with SEM and are 38 nm (Figure 1).In connection with our recent interested aimed at the development of efficient protocols for the preparation of biologically active heterocycles [26][27][28][29], herein, we selected nano-TiO 2 as a new catalyst to synthesise of pyridine dicarbonitriles.The reaction of various aldehydes, 4methyl thiophenol, malononitrile in the presence of nano-TiO 2 in ethanol afforded pyridine dicarbonitriles at room temperature in good yields (Table 1).We performed the effect of various solvents on the synthesis of 4a.This reaction was carried out in various solvents and the best results in terms of yield and time obtained in ethanol (Table 2).In each reaction, the yield is a function of the reaction time and the best time for all reactions was completed after 1 h.The reactions proceeded well with 5 mol% of catalyst and use of an increased amount of catalyst does not make much difference.In order to show the merit of the present work, we compared the result of the synthesis of these compounds in the presence of various catalysts but the best results obtained with nano-TiO 2 (Table 3).

CONCLUSION
In conclusion, we have described a highly efficient procedure for the preparation of pyridine dicarbonitriles via a condensation reaction of various aldehydes, malononitrile, and thiol using nano-TiO 2 as a catalyst.The procedure offers several advantages including high yields, operational simplicity, cleaner reaction, minimal environmental impact and low cost, which make it a useful and attractive process for the synthesis of these compounds.

EXPERIMENTAL
All products were characterized by m.p., IR, 1 H NMR and GC/MS.Melting points were measured by using the capillary tube method with an electrothermal 9200 apparatus. 1H and 13 C NMR spectra were recorded on a Bruker DRX Avance spectrometer at 500 and 125 MHz, respectively, with CDCl 3 as solvent.IR spectra were recorded from KBr disk on the FT-IR Bruker Tensor 27.GC/MS spectra were recorded on an Agilent Technologies 6890 network GC system and an Agilent 5973 network Mass selective detector.Thin layer chromatography (TLC) on commercial aluminum-backed plates of silica gel, 60 F254 was used to monitor the progress of reactions.All products were characterized by spectra and physical data.
Synthesis of nano-TiO 2 .A 500 mL three-necked flask containing 5 mL of titanium tetrachloride was equipped with a condenser, a gas trap and a water steam producer.The titanium tetrachloride was heated to 130 o C. By adding water steam to hot titanium tetrachloride for 15 min, a milky solution was formed.After washing the condenser, the milky solution was filtered to obtain a white solid.By heating of the white solid in oven at 400 o C for 7 h, the TiO 2 nanoparticle as a white crystalline powder was formed.
Typical procedure for preparation of pyridine dicarbonitriles.To a magnetically stirred solution of aldehyde (1 mmol), 4-methyl thiophenol (1 mmol) and nano-TiO 2 (5 mol%) in ethanol (5 mL) was added malononitrile (2 mmol) and stirring was continued for 1 h.The precipitate was filtered and washed with ethanol to give product.

Table 1 .
Synthesis of pyridine dicarbonitriles with deifferent aldehydes a Yields were analyzed by GC.

Table 2 .
Synthesis of 4a in the presence of different solvents using Nano-TiO2 as a catalyst.
a Yields were analyzed by GC.

Table 3 .
Synthesis of 4a using various catalysts.
a Yields were analyzed by GC.