Green chemistry approach to synthesis of some new trifluoromethyl containing tetrahydropyrimidines under solvent free conditions

A simple, efficient and modified Biginelli procedure was carried out for the synthesis of tetrahydropyrimidines 4a-o by a solvent-free and catalyst-free condition, by the condensation of 1,3-dicarbonyl compound 1 , arylaldehydes 2 and urea/thiourea 3 . Neat reactants subjected to microwave irradiation gave the required products more quickly and in better yield in comparison to traditional methodologies. The observed yields and improvement in reaction rates are due to the solvent free conditions coupled with the use of microwave radiation.


Introduction
Environmental concerns in research and industry are increasing 1 with the increasing pressure to reduce the amount of pollutants produced, including organic solvents whose recovery is mandated by ever more strict laws.Hence the challenge for a sustainable environment calls for the use of clean procedures to avoid the use of harmful solvents.The emergence of microwave assisted solid phase synthesis 2 is a step forward in this direction.In this expeditious and solventfree approach 3 the adsorbed reactants over solid supports are exposed to microwave irradiation.The salient features of these high yield protocols with enhanced reaction rates are greater selectivity and experimental ease of manipulation, 4 but this technique does not exactly meet the definition of 'no solvent'. 5The usage of solvent is only eliminated at the primary reaction stage whereas an appreciable amount of solvent is still required for the adsorption of reactants and elution of the product at the pre-and post-reaction stages, respectively.A "neat reaction" is an alternative solvent-free approach that eliminates the use of a solid support as well as solvent from the reaction.There has not been much advancement in this area as direct heating of the reactants in the absence of solvent with a solid support often leads to charring.But these

Results and Discussions
The present procedure for the synthesis of tetrahydropyrimidines by a solvent-free and catalystfree condensation of 1,3-dicarbonyl compound, aldehyde, and urea/thiourea provides a simple, efficient, cost-effective with 100% green modification of the Biginelli's reaction.Most significantly, this solvent-free and catalyst-free process of three-component condensation throws a challenge to the existing procedures, 11,14 which use volatile and hazardous solvents and toxic catalysts, and in general lead to a new direction in organic synthesis.
The 1,3-dicarbonyl i.e. 4,4,4-trifluoro-1-(4-methoxypheny)butane-1,3-dione 1 was cyclized with arylaldehydes 2 and urea/thiourea 3 to give the tetrahydropyrimidines 15 4a-o (Scheme 1), which was considered to be a final product in Biginelli reaction.The structure of the final products was confirmed by the earlier report by Saloutin, V. I et al., 16 Kappe et al. 17 and D. Subhas Bose et al. 18 In the 1 H NMR spectrum of 4b, the most characteristic signals are two doublets at 4.14-4.16and 4.96-4.99δppm which are corresponding to the trans-axial methane protons.The observed coupling constant J = 10.96Hz and 11.0 Hz assigned to the H 4 and H 5 protons respectively, agree very well with the values found in the references. 16,18It is therefore reasonable to assume that the same relative stereochemistry appears in 4a-o.It may be presumed that the -OH group at C-6 may be cis to H 5 , thereby the elimination of water requires drastic conditions.In MS the molecular ion peak appears at 424 m/z which was further supports that the elimination of water does not take place.Mass spectra were determined using direct inlet probe on a GCMS-QP2010 mass spectrometer.Analytical thin layer chromatography (TLC) was performed on Silica Gel 60 F254 precoated plates.

General procedure for the preparation of tetrahydropyrimidines
A mixture of 4,4,4-trifluoro-1-(4-methoxypheny)butane-1,3-dione 1 (5 mmol), different aromatic aldehydes 2 (5 mmol) and thio/urea 3 (5 mmol) was placed in a flask and irradiated under microwave at the power of 600W and 110-120 o C for different time which is described in Table 1.After cooling, the resulting solid was crushed, washed with cold water, filtered and dried under vacuum to give the crude product which is reasonably pure (>90%, purity by 1 H NMR).However, recrystallization from hot ethanol provides the analytically pure product.

Scheme 1 Table 1 .
Synthesis 1 Yields refer to those of recrystallized pure products characterized by mp and spectral data (IR,1H NMR and mass spectra).General Procedures.Melting points were measured in open capillaries and are uncorrected.The syntheses were carried out in a Questron Technologies Corp. QPro-M microwave synthesizer.Eemental analyses were performed on a Carlo Erba EA 1108 elemental analyzer at SAIF, CDRI Lucknow.IR spectra were recorded on KBr discs, using FTIR-8400 spectrophotometer.1H-NMRspectra were taken on a Bruker AVANCE II 400 ( 1 H: 400 Mz, [d 6 ] DMSO) spectrometer.