Tandem Aldol-Michael reactions in aqueous diethylamine medium: a greener and efficient approach to dimedone-barbituric acid derivatives

Background Green chemistry is a rapidly developing new field that provides us with a proactive avenue for the sustainable development of future science and technologies. Green chemistry uses highly efficient and environmentally benign synthetic protocols to deliver lifesaving medicines, accelerating lead optimization processes in drug discovery, with reduced unnecessary environmental impact. From this view point, it is desirable to use water instead of organic solvents as a reaction medium, since water is safe, abundant and an environmentally benign solvent. Results A convenient one-pot method for the efficient synthesis of the novel Zwitterion derivatives 4a-pvia a three-component condensation reaction of barbituric acid derivatives 1a,b, dimedone 2, and various aldehydes 3 in the presence of aqueous diethylamine media is described. This new approach is environmentally benign, with clean synthetic procedure, short reaction times and easy work-up procedure which proceeded smoothly to provide excellent yield (88-98%). The synthesized products were characterized by elemental analysis, IR, MS, NMR and CHN analysis. The structure of 4a was further confirmed by single crystal X-ray diffraction. The compound crystallizes in the orthorhombic space group Pbca with α = 14.6669 (5) Å, b = 18.3084 (6) Å, c = 19.0294 (6) Å, α = 90°, β = 90°, = 90°, V = 5109.9 (3) Å3, and Z = 8. The molecules are packed in crystal structure by weak intermolecular C–H⋅ ⋅ ⋅O hydrogen bonding interactions. Conclusions An environmentally benign Aldol-Michael protocol for the synthesis of dimedone-barbituric derivatives using aqueous diethylamine medium is achieved.

number of compounds having these systems have been synthesized with diverse pharmacological activities [16,17].
As a part of our work on one-pot multicomponent reactions (MCRs) for the synthesis of various heterocyclic compounds, we report here a highly efficient procedure for the preparation of dimedone-barbituric derivatives based on tandem Aldol-Michael reactions using aqueous diethylamine medium.

Results and discussion
In a typical experimental procedure, a mixture of barbituric acid 1a,b, dimedone 2 and aromatic aldehyde 3 in water was stirred in the presence of a stoichiometric amount of diethylamine (1.0 equiv.) to afford the 'Zwitterion adduct salts' of dimedone-barbituric acid derivative 4a in high yields (Scheme 1).
A possible mechanism for the tandem Aldol-Michael reaction is shown in Figure 2. In the first step of the reaction, olefin is produced by a Aldol condensation between aryl aldehyde 3 and 1a,b promoted by DEA. Dimedone in the presence of DEA is then converted to its corresponding diethylammonium dimedonate that easily reacts with olefin to give product 4a-p [22][23][24][25][26][27][28][29][30][31].
In the absence of DEA, the reaction does not proceed efficiently and only a poor yield of products was obtained after 10 h. The structures of products were confirmed by physical and spectroscopic (IR, MS, NMR) data, and by elemental analysis. The workup procedure is very simple and the products do not require further purification.
The X-ray zwitterion structure of 4a ( Figure 3) was obtained using X-ray structure determination from a single crystal grown from CHCl 3 /Et 2 O as solvents. The structure shows interesting characteristics (Table 1). We were unable to determine the location of the C6 and C14 hydrogens by 1 HNMR analysis. This is because the hydrogen from C6 dimedone, rather than hydrogen from C14 of the barbituric acid moiety, is removed by the basicity of diethylamine. This was confirmed by the X-ray structure because one hydrogen is on the diethylamine and the other is involved in hydrogen bonding interactions between both barbituric acid and dimedone moiety. The hydrogen-bonding interactions are listed in Table 2. Figure 4 depicts the packing of the molecules in the crystal structure. The crystal structure is stabilized by C-H⋅ ⋅ ⋅O hydrogen bonds into a three-dimensional framework structure. It is noteworthy to mention that 1 HNMR have also shown a singlet signal at δ 15.28 ppm which can be assigned to the OH group which makes a hydrogen bond.
With the optimal reaction conditions established, the generality of the Aldol-Michael reactions was next investigated by using a series of aryl aldehyde 3 (Table 3). Various aldehydes derivatives with either electron-withdrawing or electron-donating groups at the para-, meta-, or even sterically hindered ortho-position on the aromatic ring were tolerated and gave the corresponding condensed products 4a-p in excellent chemical yield up to 98% (Scheme 2).

Conclusions
In summary, a mild, efficient, and expeditious method has been developed for the synthesis of zwitterion-condensed products 4a-p via a three component; one-pot cyclocondensation reaction of aromatic aldehyde, barbituric acid, and dimedone using aqueous diethylamine medium. The main advantage of the present methodology is a simple work-up procedure with milder reaction conditions. This method provides excellent yields of the products with high selectivity. Further studies on expanding the application of this method and the biological evaluation of these dimedone-barbituric derivatives are in progress.

Experimental section General
All chemicals were purchased from Aldrich, Sigma-Aldrich, Fluka etc., and were used without further purification, unless otherwise stated. All melting points were measured on a Gallenkamp melting point apparatus in open glass capillaries and are uncorrected. IR Spectra were measured as KBr pellets on a Nicolet 6700 FT-IR spectrophotometer. The NMR spectra were recorded on a Jeol-400 NMR spectrometer. 1 H NMR (400 MHz), and 13 C NMR (100 MHz) were run in either deuterated dimethylsulphoxide (DMSO-d 6 ) or deuterated chloroform (CDCl 3 ). Chemical shifts (δ) are referred in terms of ppm and J -coupling constants are given in Hz. Mass spectra were recorded on a Jeol of JMS-600H. Elemental analysis was carried out on an Elmer 2400 Elemental Analyzer; CHN mode.
General procedure for aldol condensation Michael addition for the synthesis of 4a-p (GP1) A mixture of aldehyde 3 (1.5 mmol), dimedone 2 (1.5 mmol), barbituric acid derivatives 1a,b (1.5 mmol) and Et 2 NH (1.5 mmol, 155 μL) in 1.5 mL of degassed H 2 O was stirred at room temperature for 1-2 hours until TLC showed complete disappearance of the reactants. The product precipitated and the mixture was filtered and washed with ether (3 × 20 mL). The solid was recrystallized from a mixture of CH 2 Cl 2 /Et 2 O to afford pure product 4a-p.

5-((2-Hydroxy
4a was prepared from 1,3-dimethylbarbituric acid 1a, dimedone 2 and benzaldehyde according to the general procedure (GP1) yielding colorless crystalline material (671 mg, 1  The structure of 4a was confirmed by X-ray crystal structure analysis. CCDC-933624 contains the supplementary crystallographic data for this compound. This data can be obtained free of charge from the Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif. A colorless crystal suitable for X-ray analysis was obtained from recrystallization of the compound from CHCl 3 /Et 2 O at room temperature after 2 days.