Efficient Rapid Access to Biginelli for the Multicomponent Synthesis of 1,2,3,4-Tetrahydropyrimidines in Room-Temperature Diisopropyl Ethyl Ammonium Acetate

Abstract

The diisopropyl ethyl ammonium acetate (DIPEAc)-promoted Biginelli protocol has been developed for the first time by a successive one-pot three-component reaction of aldehydes, ethylcyanoacetate/ethyl acetoacetate, and thiourea/urea to afford pharmacologically promising 1,2,3,4-tetrahydropyrimidines in high yields at room temperature. The key benefits of the present scheme are the capability to allow a variability of functional groups, short reaction times, easy workup, high yields, recyclability of the catalyst, and solvent-free conditions, thus providing economic and environmental advantages. In addition, a series of 4-oxo-6-aryl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitriles analogues were synthesized and selected for their in vitro antifungal and antibacterial activities.

Scheme 1. Synthesis of 4-Oxo-6-phenyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (4a) by Using DIPEAc as RTIL

Scheme 2. Synthesis of Diisopropylethylammonium Acetate (DIPEAc)

Figure 1

Pyrimidine-incorporated bioactive molecules.

Figure 2

Reuse and recovery of DIPEAc and its effect on yield.

Figure 3

IR spectrum of reuse and recovery of DIPEAc (pink spectrum: fresh; green spectrum: after IV recycles).

Figure 4

Structure–activity relationship of hybrid compounds.

Scheme 3. Synthesis of 4-Oxo-6-aryl-2-thioxo-1,2,3,4-Tetrahydropyrimidine-5-carbonitriles (4a–z) by Using DIPEAc as RTIL

Reaction conditions: Aldehydes (1a–z) (3 mmol), ethylcyanoacetate/ethyl acetoacetate (3 mmol), and thiourea/urea (3.2 mmol) in DIPEAc (4 mL) stirred at room temp; isolated yields, melting points are in good contact with those reported in the literature.^,,

Scheme 4. Synthesis of Ethyl 6-Methyl-2-oxo-4-aryl-1,2,3,4-tetrahydropyrimidine-5-carboxylates (4aa–nn) by Using DIPEAc as RTIL

Reaction conditions: aldehyde (1aa–nn) (3 mmol), ethylcyanoacetate/ethyl acetoacetate (3 mmol), thiourea/urea (3.2 mmol) in DIPEAc (4 mL), stirred at room temp; isolated yields, melting points are in good contact with those reported in the literature.^,,

Scheme 5. 4-Oxo-6-phenyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile