THE PECULIARITIES OF THE 4-CARBOXYPHENYLGLYOXAL AND N-ALKOXY-N’-ARYLUREAS INTERACTION

It was found that 3-alkoxy-4,5-dihydroxyimidazolidin-2-ones are the only products of interaction of N-alkoxyureas with arylglyoxals which have strong electronegative substituent in the forth position of the aryl moiety. The possibility of obtaining such products as 3-alkoxy-1aryl-5-(4-carboxyphenyl)-4,5-dihydroxyimidazolidin-2-ones, 3-alkoxy-1-alkyl-5-(4-carboxyphenyl)-4,5-dihydroxyimidazolidin-2-ones and 3-alkoxy-1-phenyl-4,5-dihydroxy-5-(4-nitrophenyl)-imidazolidin-2-ones has been verified in the experimental way. In most the cases 3alkoxy-4,5-dihydroxyimidazolidin-2-ones were produced as a mixture of diastereomers.


INTRODUCTION
As it was shown in our previous publications 1-6 the arylglyoxals' interaction with N-hydroxyurea and Nalkoxyureas is a very promising way to get valuable pharmaceutical materials. Three types of products can be produced by this reaction. As we have shown some of the products transform into others.
The mechanism of this interaction could not be completely established because of lack of experimental evidence. In any case the formation pattern of each product type is valuable. It is important to know this pattern not only in order to determine the reaction mechanism, but also to get further perspective synthones and materials in pharmacy, organic synthesis and bioorganic chemistry.
The relevance of the products which can be obtained by the interaction of arylglyoxals with N-hydroxyurea or Nalkoxyureas is significant because of the importance of imidazolidin-2-ones and imidazolidin-2,4-diones among pharmaceutical materials. [7][8][9][10] Arylglyoxals are widely used in synthesis of these biologically active nitrogen-containing heterocycles. 11 Despite the differences between the products of the arylglyoxals interaction with N-hydroxyurea or Nalkoxyureas we have observed several patterns in their formation. In fact, the type of the product strongly depends on the glyoxal reagent. However, when we use arylglyoxals with electron-donating groups in aryl moiety, the substituted ureas 1 might be not the only products of this reaction. 1 As usual the first type products, substituted ureas 1, forms imidazolidin-2-ones 2 and 3, which further turns into hydantoins 4. Nevertheless, it is possible to obtain only the substituted ureas 5 in this interaction. 2,6 For this result the strong intramolecular effects should take place in the compounds 5 (Scheme 2).
The mixture of the second type products, 4,5dihydroxyimidazolidin-2-ones 2 and 3, and the third type of products, hydantoins 4, are obtained in all the other cases. This fact serves as clear evidence that the cyclization of substituted ureas into 5-arylimidazolidin-2-ones is an easy process. This process could be retarded by intramolecular effect or steric factor. 1,2,[4][5][6] Very often the second type products, 4,5dihydroxyimidazolidin-2-ones 2 and 3, turn into third type products, hydantoins 4, 1,6 but not always.  For now the most convenient method of getting only the third type product is using acetic acid as a solvent for the reaction of arylglyoxals with N-hydroxyurea or Nalkoxyureas. 3 The products are only 3-hydroxyhydantoines 6 or 3-alkoxyhydantoines 7 respectively (Scheme 3).

Scheme 3.
The products of interaction of arylglyoxals with Nhydroxyurea or N-alkoxyureas in acetic acid.
To sum up all the information about arylglyoxals interaction with N-hydroxyurea derivatives we should note that the experimental investigation of the second type product formation overall pattern needed to be continued. For this reason we have chosen to explore the reaction of 4carboxyphenylglyoxal with different N-alkoxy-N'-arylureas in acetic acid medium and for at least one case to change this alkoxyurea's reagent to the one of the N-alkoxy-N'alkylureas.

EXPERIMENTAL
1 H NMR spectra were recorded on a Varian VXP-300 spectrometer (300 MHz) and VARIAN VNMRS 400 spectrometer (400 MHz). 13 C NMR spectra were recorded on a Varian VXP-300 spectrometer (75 MHz). The solvents DMSO-d6 and CDCl3 were used. 1 H NMR chemical shifts relative to the residual solvent protons as an internal standard [(CD3)2SO: 2.500 ppm, CDCl3: 7.260 ppm] were reported. Solvent carbon atoms served as an internal standard for 13 C NMR spectra [(CD3)2SO: 39.52 ppm]. Mass spectra were recorded on a VG 70-70EQ mass spectrometer in fast atom bombardment mode (FAB). The solvents were purified and dried according to the standard procedures.

N-n-Octyloxy-N'-phenylurea
A solution of phenylisocyanate (0.714 g, 5.994 mmol) in benzene (5 mL) was added to a solution of n-octyloxyamine (0.959 g, 6.600 mmol) in benzene (5 mL). The reaction solution was maintained at 20 °С for 72 h, then benzene was evaporated under vacuum (20 mmHg), hexane (11 mL) was added to the residue and the obtained mixture was kept at -5°С for 20 h. The formed precipitate was filtered off, washed by hexane (6 mL
We assume, in the interaction of 4-nitrophenylgyoxals with N-alkoxy-N'-arylureas, 5 that the main product in both cases is similar. In the last case it is the diastereomer 12a or 13a with 4-hydroxyl-and 5-hydroxyl groups in the cisconformation to each other. Their percentage in the products' mixtures is approximately 91-98 %. Thus, the formation pattern of the second type products, 3alkoxy-4,5-dihydroxyimidazolidin-2-ones, in the arylglyoxals reaction with N-alkoxyureas has been clarified. It is necessary to use arylglyoxals with a strong electronwithdrawing substituent in 4-position of the aryl moiety to obtain these products. Additionally we have studied the interaction of 4-nitrophenylglyoxal with N-n-alkoxy-N'phenylureas which have a long carbon chain in order to obtain 3-alkoxy-4,5-dihydroxy-5-(aryl)-1-phenylimidazolidin-2-ones with lipophilic N-alkoxy moiety. The main reason for this was to find out whether the alkoxyl substituent in urea reagent influences the reaction or not.
The mixture of these diastereomers contains more than 90 % of cis-4,5-dihydroxy diastereomers 15a,16a. The trace amounts of trans-4,5-dihydroxy diastereomers 15b,16b can be easily removed by crystallization. The products of the 4nitrophenylglyoxal interaction's with N-n-octyloxy-N'phenylurea and N-n-dodecyloxy-N'-phenylurea demonstrate, that the nature of the N-alkoxy substituent in urea does not influence the reaction.
We propose the next scheme of the arylglyoxals interaction with N-hydroxyurea or N-alkoxyureas (Scheme 9) to explain the fact that diastereomers with cis orientation of 4-HO-and 5-HO-groups dominate over the trans 4,5dihydroxy diastereomers in all the reactions which are reported in this study. Scheme 9. The proposed mechanism of the interaction of Nalkoxy-N'-arylureas and N-alkoxy-N'-alkylureas with 4carboxyphenylglyoxal and 4-nitrophenylglyoxal.
According to this scheme in the beginning of the interaction the open-chain N-substituted urea 17 is formed. Compounds 17 may be stabilized by the intramolecular hydrogen bond. The acyclic urea 17 form further the compounds 12-16. Thus, the diastereomers 12a-16a with 4-HO-and 5-HO-groups in the cis-conformation to each other have been produced. It is probable that the diastereomers 12a-16a are also stabilized by the intramolecular hydrogen bond. N-Alkoxyurea 17A slowly transforms into a conformation 17B by the rotation of carbamoyl moiety around N-C bond or the N-alkoxy nitrogen inversion. The conformation 17B eventually forms trans-4,5-dihydroxy diastereomers 12b-16b.
Probably the low process temperature (approximately 20°C) preserves the further isomerization of the formed cis-4,5-dihydroxy diastereomers 12a-16a into trans-4,5dihydroxy diastereomers 12b-16b. CH  It is evident that the presence of a strong electronegative substituent in the forth position of 5-aryl moiety, such as carboxyl group or nitro group, destabilizes "benzylic" cation A and makes the further transformation of the compounds 12-16 into hydantoins 18 impossible.