Synthesis of New Unsymmetrical 4 , 5-Dihydroxy-2-imidazolidinones . Dynamic NMR Spectroscopic Study of the Prototropic Tautomerism in 1-( 2-Benzimidazolyl )-3-phenyl-4 , 5-dihydroxy-2-imidazolidinone

The acid-catalyzed cyclocondensation in refluxing acetonitrile of aqueous glyoxal with N-heteroaryl-N'-phenylureas 4a-f (heteroaryl = 2-thiazolyl, 2-pyrimidinyl, 2-pyrazinyl, 2-pyridinyl, 3-pyridinyl and 2-benzimidazolyl) led to the formation of the corresponding 1-heteroaryl-3-phenyl-4,5-dihydroxy-2-imidazolidinones 5a-f. All the products were characterized by elemental and spectroscopic analyses. The free-energy barrier (∆GP P) for prototropic tautomerism in 1-(2-benzimidazolyl)-3-phenyl-4,5dihydroxy-2-imidazolidinone (5f) was determined by dynamic NMR studies to be 81 ± 2 KJ mol P P.


Introduction
Synthesis of imidazolidines through the cyclocondensation of diamines, bisamides and urea derivatives with aqueous glyoxal and other appropriate carbonyl compounds has been the subject of numerous investigations [1][2][3][4][5][6][7][8][9][10].In 1962, Slezak et al. reported the acid-catalyzed reaction of urea derivatives with aqueous glyoxal leading to the formation of the corresponding glycolurils 1 (Figure 1) [11].The formation of hydantoin derivatives 2 (Figure 1) had been found previously to take place under similar reaction conditions [12].The additions of N,N'-dimethylurea and urea to aqueous glyoxal under both acidic and basic conditions to form 4,5-dihydroxy-2-imidazolidinones derivatives 3 (Figure 1) have been studied by Vail et al. [13].On the basis of NMR spectroscopy, they showed that initially equimolar amounts of the cis and trans isomers were formed by a non-stereospecific addition, but the resulting equilibrium product mixture contained predominantly the trans isomer.In acidic solution, the products would be subject to protonation and subsequent formation of other products.2-Imidazolidinones are important building blocks in Medicinal Chemistry as central nervous system depressants and enzyme inhibitors [14][15][16].They are also used as textile finishing agents [17].
The mass spectra of compounds 5a-f exhibited medium intensity parent ions, while the radical cations of N-heteroaryl-N'-phenylureas 4a-f and heteroarylisocyanate cations appeared with high intensity.The P 1 PH-NMR spectra of compounds 5a-f showed two well-resolved AB quartet spin systems corresponding to two chemically different CH-OH moieties.Based on the lack of coupling between two unequivalent methine protons, it seems likely that the hydroxyl groups are trans to each other.The other peaks of the spectra were those arising from the protons of two aromatic moieties.Upon addition of DB 2 B O to the NMR samples, the hydroxyl signals disappeared and the signals of the methine moieties quickly collapsed to two singlets.Physicochemical data show that the NH proton in benzimidazoles, as in imidazoles, migrates rapidly between the two nitrogen atoms (degenerate tautomerism) (Scheme 2).The imidazole ring with a nonsymmetrical substitution exhibits an HNB 1 B …HNB 3 B tautomerism that has been studied both experimentally and theoretically [22].
The P 1 PH-NMR spectrum of 5f in DMSO-dB 6 B at room temperature (25 °C) exhibited two rather sharp doublets at δ 7.48 and 7.50 ppm (J = 7.07 and 6.5 Hz), arising from CH-4P ' P and CH-7P ' P protons, each of them exhibiting a further doublet splitting due to the long range coupling with one of the benzimidazolyl hydrogens.Increasing the temperature results in coalescence of the two doublets (TB C B = 384 ± 1 K), as shown in Figure 2.Although no extensive line-shape analysis for 5f was undertaken, the variable temperature spectra allowed us to calculate the free energy barriers ∆GP ≠ P for the dynamic 364 NMR process in 5f from coalescence of the CH-4P ' P and CH-7P ' P protons.By using the expression, k = π∆υ/ 2 , the first-order rate constant (k) for dynamic NMR effect in 5f was calculated as 31 sP -1 P.
2 '   3 ' 4 '   5 '   6 '  7 '  PC-NMR spectra of 5f also show 14 and 11 peaks at 298 and 384 K, respectively.This clearly indicates that the tautomers are interconverting fast at 384 K on the NMR time scale.No conversion occurred when we examined reaction of 4a-f with glyoxal in the presence of sodium hydroxide in different solvents.On the other hand, reaction of compounds 5a-f with sodium hydroxide regenerated the starting materials 4a-f.Imidazolidinones 5a-f are stable materials and can be stored at room temperature for extended periods.

General
All commercially available chemicals and reagents were used without further purification.Melting points were determined with an Electrothermal model 9100 apparatus and are uncorrected.IR spectra were recorded on a Shimadzu 4300 spectrophotometer.The P 1 PH-and P 13 PC-NMR spectra were recorded in DMSO-dB 6 B on a DRX-500 AVANCE spectrometer at 298 K.Chemical shifts (δ) are reported in ppm and are referenced to the NMR solvent peak.Mass spectra of the products were obtained with a HP (Agilent Technologies) 5937 Mass Selective Detector.Elemental analyses were carried out with a Thermo Finnigan (FLASH 1112 SERIES EA) CHNS-O analyzer.Flash chromatography (FC) was carried out using silica gel 60 (63-200 mesh).Progress of the reactions was monitored by TLC using precoated sheets of silica gel Merck 60 FB 254 B on aluminium.

General procedure for the synthesis of 1-heteroaryl-3-phenyl-4,5-dihydroxy-2-imidazolidinones 5a-f.
A stirring solution of N-heteroaryl-N'-phenylurea 4a-f (1 mmol), glyoxal (0.14 g of 40% aqueous solution, 1 mmol) and formic acid (0.005 g of 98% aqueous solution, 0.1 mmol) in acetonitrile (30 mL) was refluxed for the time given in Table 1.The solvent was then removed under reduced pressure and the crude material was purified by flash chromatography on silica gel, eluting with a 4:1 THF/hexane mixture to give a white crystalline product.
Application of the absolute rate theory with a transmission coefficient of 1 gives the free energy of activation (∆GP ≠ P) as 81 ± 2 KJ molP -1 P for compound 5f, where all known sources of errors are estimated and included[23].The experimental data available are not suitable for obtaining meaningful values of ∆H P ≠ P and ∆S P ≠ P even though the errors in ∆GP ≠ Pare not large[24].

Figure 2 .
Figure 2. Variable-temperature 500 MHz P 1 PH-NMR spectra of the aromatic region of 5f in DMSO-dB 6 B .

Table 1 .
Yields, melting points and elemental analyses of compounds 5a-f.