Synthesis and characterization of novel N-acyl cyclic urea derivatives

A series of novel N-acyl cyclic urea derivatives (3a-3l) have been synthesized by the reactions of 1-((6-chloropyridin-3-yl)methyl)imidazolidin-2-one (1) with various acyl chlorides in the yields of 35-95%. Subsequently, N-acyl cyclic urea derivatives containing α-tertiary amine (5a-5k) have been synthesized by the nucleophilic substitution reaction of 1-(2-haloacetyl)-3-((6chloropyridin-3-yl)methyl)imidazolidin-2-one (3e or 3f) with various secondary amines in the yields of 49-86%. The synthesized compounds were characterized by 1 H NMR spectroscopy, 13 C NMR spectroscopy, high-resolution mass spectroscopy, IR and elemental analysis.


Introduction
The cyclic urea derivatives have been reported to display a wide range of biological activities, such as the HIV protease inhibitors, 1 selective NK1 antagonists, 2 Chk1 inhibitors, 3 calciumselective fluoroionophore, 4 anti-Alzheimer's disease 5 and herbicide. 6Furthermore, cyclic urea derivatives are also used as novel building blocks for bent-core liquid crystals. 7][10][11][12][13][14] The modification of cyclic urea would have the potential to generate new functional molecules, which may result in interesting biological activities.

Acylation of 1-((6-chloropyridin-3-yl)methyl)imidazolidin-2-one (1)
In order to optimize the reaction conditions of N-acylation, we investigated the effects of solvents, times and bases on the reaction of 1 with benzoyl chloride (2g) (Table 1).Initially, the acylation reactions were carried out at different temperature in toluene without any base (entries 1-3).Increasing the temperature from 70 o C to 110 o C could dramatically increase the yield of 1benzoyl-3-((6-chloropyridin-3-yl)methyl)imidazolidin-2-one (3g) in shorter reaction time.In the presence of pyridine (C5H5N), the yield of 3g increased significantly to 80% in 4 h (entry 4).In contrast, in the presence of triethylamine (Et3N), the yield of 3g reached to 89% in 1 h (entry 5).Therefore, Et3N is more effective for the reaction.Moreover, the effects of solvents such as toluene, THF and CH2Cl2 were also studied (entries 5-7).The yields of 3g were 89%, 83% and 78%, respectively.Although 3g had the highest yield when the reaction was conducted in toluene at higher temperature, considering the level of the solvent toxicity, energy-saving, the simplicity of experiment procedure, THF was chosen as solvent for the reaction.In a further step, reactions of 1 with various acyl chlorides were carried out in the presence of Et3N.The results were listed in table 2. The reactions of 1 with various aliphatic acyl chlorides gave N-acyl cyclic urea derivatives 3a-f in excellent yields of 84-95% (entries 1-6).Haloacetyl chlorides reacted with 1 to afford desired products 3e and 3f without any base in the yields of 95% and 89%, respectively (entries 5,6).Analogously, the reactions of 1 and aromatic substituted acyl chlorides also attained 3g-i in 53-94% yields (entries 7-9).As 4-nitrobenzoyl chloride had poorly solubility in THF, toluene was used as solvent to give 3i in moderate yield of 53% (entry 9).Other acyl chlorides (2j-2l) obtained from the reactions of corresponding carboxylic acid and thionyl chloride in-situ also reacted with 1 in CH2Cl2 to give 3j-3l in modest yields of 53%, 35% and 58%, respectively (entries 10-12).

Conclusions
We have developed simple and efficient protocols for synthesis of novel N-acyl cyclic urea derivatives.Notably, these compounds have polyfunctional biological active groups and maybe exhibit multidirectional activity in pharmaceutical and agricultural chemistry.

Experiment Section
General.All starting materials were obtained commercially and all solvents were dried using standard laboratory procedures.NMR spectra were recorded on a Bruker DRX-500 and DRX-400 NMR spectrometer with CDCl3 as solvent and TMS as internal standard.Mass spectra were recorded on a Waters GCT Premier spectrometer.Elemental analyses were obtained on a Vario EL β.The melting points were determined on an X-4 binocular microscope melting point apparatus and were uncorrected.All reactions were carried out under nitrogen atmosphere.

General procedure for the synthesis of compounds (3a-l)
In a 100 mL two necked round bottom flask equipped with a dropping funnel, a condenser and a magnetic stirrer, 1-((6-chloropyridin-3-yl)methyl)imidazolidin-2-one (1) (1.06 g, 5 mmol) and Et3N (0.51 g, 5 mmol) in dry THF (10 mL) were stirred under an atmosphere of nitrogen.Then acyl chloride (7.5 mmol) was added dropwise and the reaction mixture was left to stir for 1 h (monitored by TLC) at reflux temperature.The reaction mixture was cooled to room temperature and concentrated under vacuum.The residue was taken up in CH2Cl2 (30 mL) and washed with saturated NaHCO3 (3×20 mL) and brine (20 mL).The organic layer was dried over anhydrous MgSO4.The solvent was evaporated in a rotary evaporator.The residue was washed with anhydrous ether to give the corresponding pure compound.

General procedure for the synthesis of compounds (5a-l)
In a double-necked round bottomed flask (100 mL) equipped with a condenser, a mixture of an appropriate 4 (2-2.4mmol) and NaHCO3 (0.17 g, 2 mmol) or K2CO3 (0.14 g, 1 mmol) were dissolved in dry acetonitrile (CH3CN) (10 mL) and stirred for 1 h at 82 o C under nitrogen atmosphere.Subsequently, 3e (2 mmol, 0.58 g) (3f as substrate was used in the synthesis of 5g and 5j) was added to the mixture and heated at 82 o C for 1-8 h (monitored by TLC).The solvent was evaporated at reduced pressure, then the residue was dissolved in CH2Cl2 (40 mL) and washed with H2O and brine.The organic layer was dried over MgSO4 and concentrated to afford the crude product, which was purified by column chromatography on SiO2 eluting with appropriate solvents.

Table 1 .
Optimization of N-acylation reaction

Table 2 .
Synthesis of N-acyl cyclic urea derivatives 3a-l