An efficient one-pot multicomponent synthesis and characterization of 5-cyano-1,2,3,4-tetrahydropyrimidine derivatives

A series of pyrimidine-5-carbonitrile derivatives was efficiently synthesized via one-pot, multi component reaction (MCRs) of 1,3-bifunctional synthon (ethylcyano acetate), substituted pyrazole-4-carbaldehyde, and thiourea/urea in the presence of basic catalyst. The key advantages of this process are high yields, shorter reaction times, easy work-up, and purification of products by non-chromatographic method.


INTRODUCTION
Multi component reactions (MCRs) have more importance, great interest enjoying an outstanding status in modern organic synthesis and medicinal chemistry because they are onepot processes bringing together three or more components and show high atom economy and high selectivity. 1,2MCRs comply with the principles of green chemistry in terms of economy of steps as well as many of the rigid criteria of an ideal organic synthesis.These reactions are effective in construction highly functionalized small organic molecules from readily available starting materials in a single step with natural flexibility for creating molecular complexity and diversity coupled with minimization of time, labor, cost and waste production. 3The literature survey indicated that a wide range of pharmacological activities are exhibited by the compounds encompassing pyrimidines nucleus.In addition to this, various analogs of pyrimidines have been found to posses antibacterial, 4 antifungal, 5 antileishmanial, 6 antiinflammatory, 7 analgesic, 8 antihypertensive, 9 antipyretic, 10 antiviral, 11 antidiabetic, 12 antiallerggic, 13 anticonvulsant, 14 antioxidant, 15 antihistaminic, 16 herbicidal, 17 and anticancer activities 18 and many of pyrimidines derivatives are reported to possess potential central nervous system (CNS) depressant properties 19 and also act as calcium channel blockers. 20n a view of great importance of pyrimidines derivatives, various methods for synthesis of pyrimidines derivatives have been reported.During the last few years, some methods were introduced for the synthesis of these compounds.Many methods for synthesis of 5-cyano-1,2,3,4-tetrahydropyrimidine derivatives have been reported using various catalyst such as Magnesium methoxide (Mg(OMe) 2 ), 21 piperidine, 22 sodium ethoxide, 23 and also under microwave irradiation. 24

RGV-231 to 250
R= various substituted phenyl group X = S, O  Several methods are used in the synthesis of these 5-cyano-1,2,3,4tetrahydropyrimidines.The synthesis of these heterocycles has been usually carried out in polar protic organic solvents such as water, methanol and polar aprotic organic solvents such as acetonitrile, DMF and DMSO.The choice of a solvent is a crucial factor for International Letters of Chemistry, Physics and Astronomy Vol.40 multicomponent reactions.So at the first step we looked into the solvent selection for this reaction.We had selected protic solvent ethanol for this reaction.A part from the solvent, the efficiency of the multicomponent reactions is mainly affected by the catalyst and the reaction time.To evaluate the catalytic effect of various catalysts we started with the model reaction of ethylcyanoacetate (0.03 mole) with 3-(4-chlorophenyl)-1-phenyl-1H-pyrazole-4-carbaldehyde (0.03 mole) and thiourea (0.03 mole) in ethanol with use of various catalysts to afford pyrimidine derivatives in various yields (Table 2).It can be seen from Table 2 that potassium carbonate (K 2 CO 3 ) is the most efficient (Table 2, entry 3) among the all catalysts studied.
In order to evaluate the generality of this model reaction we then prepared a range of 5cyano-1,2,3,4-tetrahydropyrimidine derivatives under the optimized reaction conditions.In all cases, aryl aldehydes with substituents carrying either electron-donating or electronwithdrawing groups reacted successfully and gave the expected products in good to excellent yields in relatively short reaction times.The kind of aldehyde has no significant effect on the reaction.The results are shown in Table 1.
Plausible mechanism for the formation of substituted pyrano[2,3-b]indoles using base as catalyst.
Possible mechanism for the base catalyzed synthesis of substituted pyrano[2,3-b]indoles has been proposed in Scheme 2. In summary, this paper describes a convenient and efficient process for the synthesis of 5-cyano-1,2,3,4-tetrahydropyrimidine derivatives through the three components coupling of substituted pyrazole-4-carbaldehyde, ethylcyano acetate and thiourea/urea in the presence of K 2 CO 3 in ethanol at reflux temperature.Reaction profile is very clean and no side products are formed.All the synthesized 5-cyano-1,2,3,4tetrahydropyrimidines have been characterized on the basis of elemental and spectral studies.

EXPERIMENTAL SECTION
All research chemicals were purchased from Sigma-Aldrich and used as such for the reactions.Reactions were monitored by thin-layer chromatography (TLC) on pre-coated silica gel GF254 plates from E-Merck Co and compounds visualized either by exposure to UV light or staining with reagents.Melting points were determined in open capillaries and are uncorrected.The IR spectra were recorded on SHIMADZU-FTIR-8400 spectrophotometer using KBr pellet method. 1 H NMR spectra were recorded on Bruker 400 MHz NMR spectrometer in DMSO-d6 with TMS as internal standard.Mass spectrum was recorded on JOEL SX 102/DA-600-Mass spectrometer and elemental analysis was carried out using Heraus C, H, and N rapid analyzer

CONCLUSION
In conclusion, we have developed a highly efficient base catalyzed, one pot, three component protocol for the synthesis of 5-cyano-1,2,3,4-tetrahydropyrimidine derivatives via condensation of substituted pyrazole-4-carbaldehyde, ethylcyano acetate and thiourea/urea in the presence of base catalyst.The advantages of this method are clean reaction, short reaction time, high yield, easy purification and economic availability of the catalyst.

Table 2 .
Effects of different catalysts on the reaction productivity.