New Method for the Synthesis of 1-Methylimidazolium Trifluoroacetate and Its Application in Biginelli Reaction

A new method for the synthesis of 1-methylimidazolium trifluoroacetate ([Hmi]Tfa), a protic ionic liquid (PIL), under ultrasonic irradiation has been developed. In addition, the product [Hmi]Tfa was successfully employed as solvent and catalyst in Biginelli reaction to prepare 3,4-dihydropyrimidinones (DHPMs) in high yield under mild reaction conditions.


Introduction
In recent years, ionic liquids (ILs) have attracted increasing interest and been successfully employed in variety of catalytic reactions as environmentally benign solvents and catalysts due to their relatively low viscosities, low vapor pressure, and high thermal and chemical stability, etc. [1,2].Many organic processes can be significantly improved in ILs [1,3].Particularly, protic ionic liquids (PILs) can play dual roles, solvent and catalyst, in some reactions.PILs are usually formed through the transfer of a proton from a Brönsted acid, AH, to a Brönsted base, B, to yield [BH + ][A − ] species [4]: 3,4-Dihydropyrimidin-2-(1H)-ones (DHPMs) and their derivatives have recently attracted considerable interest because of their pharmacological properties and biological activities, such as potent calcium channel blockers, antihypertensive, antiviral, antiproliferative effect, standing against cancer cell lines, and potent HIV gp-120-CD4 inhibitors [5][6][7][8].For example, DHPMs 1a, 1b were shown to have antiviral and anticancer activity.In addition, DHPMs monastrol and oxo-monastrol possess excellent anticancer activity [9][10][11].
Herein, we would like to report the synthesis of 1-methylimidazolium trifluoroacetate ([Hmi]Tfa) from trifluoroacetic acid and 1-methylimidazole under mild conditions using ultrasonic irradiation.[Hmi]Tfa was then applied as solvent and catalyst for Biginelli reaction to afford DHPMs in high yield and excellent purity.Additionally, the catalyst can be easily recycled without noticeable lost of reactivity.

Synthesis of [Hmi]Tfa (Scheme 1)
Optimal conditions for the synthesis of ionic liquid [Hmi]Tfa: the molar ratio of trifluoroacetic acid and 1methylimidazole was chosen 1:1.The results are shown in Table 1.
Because the reaction between 1-methylimidazole and trifluoroacetic acid is exothermic, it was performed at ambient temperature (30˚C).The control reaction without sonication resulted in slightly lower yield while required longer time.The benefit of ultrasonic irradiation has been shown by higher yield of product.The most important effect of ultrasonic is by passing its waves through a liquid medium in the generation of energy.The driving energy is provided by cavitation, the formation and collapse of bubble, which liberates considerable energy in very short time.

Synthesis of DHPMs
We report here the application of different activation methods on Biginelli condensation to produce 3,4-dihydropyrimidinones using [Hmi]Tfa catalyst under solventfree conditions (Scheme 2).The one-pot synthesis of DHPMs under different conditions involving the condensation of aromatic aldehydes, 1,3-dicarbonyl, urea has been extensively studied.However, many of these methods employ expensive catalysts which are difficult to recycle and reuse, long reaction time, strongly acidic conditions, and difficult to handle especially on large scale.Therefore, the discovery of an inexpensive catalyst for the preparation of DHPMs under neutral and mild conditions is of prime importance.
Due to the increasing environmental and economical concerns in recent years, it is now essential for chemists to search for environmentally benign catalytic processes.In this report, [Hmi]Tfa was employed in Biginelli reaction under mild and solvent-free conditions.In addition, we hope that [Hmi]Tfa will be applicable as a ecofriendly solvent-catalyst for other organic reactions.
The scope of aromatic aldehydes are summarized in Table 2.In most cases, products were obtained in good yields under mild conditions.Microwave irradiation offered the best yield in comparison with other methods.To our best knowledge, this is the first high yielding Biginelli systhesis of DHPMs [18,20].
Consequently, the possibility to recycle catalyst was examined.As shown in Table 3, [Hmi]Tfa could be reused without significant loss of activity.

Conclusion
The first applicatio thesis of [Hmi]Tfa has been studied.[Hmi]Tfa could be obtained in high yield and short reaction time.[Hmi]Tfa has been successfully applied as solvent and catalyst for Biginelli reaction.The reaction is easy to be handled enabling large scale applications of this eco-friendly process.[Hmi]Tfa can be considered as "green" solvent and catalyst in organic synthesis because it can be easily recycled and reused.

Acknowledgem
We are grateful to Nafosted Science and Technology Development, Vietnam) for financial support through contract No. 104.01-2010.34.

Table 1 . Synthesis of [Hmi]Tfa by ultrasonic irradiation.
a Isolated yield.b Without ultrasonic irradiation.