INTERACTION OF NINHYDRIN WITH N-HYDROXYUREA AND N-ALKOXYUREAS IN ACETIC ACID

We have established that ninhydrin reacted with N -hydroxyurea and N -alkoxyureas in acetic acid with the predominant formation of the diastereomers of the 1,3a,8a-trihydroxy-1,3,3a,8a-tetrahydroindeno[1,2- d ]imidazole-2,8-dione and, respectively, 1-alkoxy-3a,8a-dihydroxy-1,3,3a,8a-tetrahydroindeno[1,2- d ]imidazole-2,8-diones with sic -orientation of 3a,8a-HO-groups. The X-ray structural analysis of 1,3a S ,8a R -trihydroxy-1,3,3a,8a-tetrahydroindeno[1,2- d ]imidazole-2,8-dione and 1- n -butyloxy-3a S ,8a R -dihydroxy-1,3,3a,8a-tetrahydroindeno[1,2- d ]imidazole-2,8-dione has demonstrated their specific structural features.


Scheme 1. Ninhydrin's interaction with the ureas.
Compounds 1a,b were used as the essential intermediates in the diastereoselective synthesis of some dihydrofuran derivatives 3 and pharmaceuticals. 3,5 The study of the vicinal polycarbonyl compounds interaction with N-hydroxyurea and it derivatives 6-10 has recently been started by our research group and needs to be continued. Derivatives of N-hydroxyurea are common in pharmaceuticals. But the ninhydrin's interaction with Nhydroxyurea and N-alkoxyureas has not been investigated in contrast to the arylglyoxal reactions with N-hydroxyurea and N-alkoxyureas. [6][7][8][9][10] Earlier we have found 8 that most of arylglyoxals reacted with N-hydroxyurea and N-alkoxyureas in acetic acid producing 3-hydroxyhydantoins 2 and 3-alkoxyhydantoins 3 (Scheme 2).

Scheme 2.
Interaction of the most of arylglyoxals with Nhydroxyurea and N-alkoxyureas in the acetic acid.
Thus the goal of our present research is to investigate the interaction of ninhydrin with N-hydroxyurea and Nalkoxyureas in acetic acid medium.

1-
The structure was solved by the direct methods with the SHELX-2016 12 software. The positions of the hydrogen atoms were located from electron density difference maps and refined by the "riding" model with Uiso = nUeq of the carrier atoms (n = 1.5 for methyl and hydroxyl groups and n = 1.2 for other hydrogen atoms). Full-matrix least-squares refinement of the structures against F 2 in anisotropic approximation for non-hydrogen atoms was converged to wR2 = 0.194 using 1846 reflections (R1 = 0.078 for 699 reflections with F>4σ(F), S = 0.903) for compound 7, wR2 = 0.201 using 2688 reflections (R1 = 0.0695 for 1645 reflections with F>4σ(F), S = 1.038) for compound 10a. The atomic coordinates, molecular geometry parameters, and crystallographic data of compound 7 and 10a were deposited to the Cambridge Crystallographic Data Center, 12 Union Road, CB2, 1EZ UK [fax:+44-1223-336033, email: deposit@ccdc.cam.ac.uk and is available on request quoting the deposit number CCDC 1976149 (7), 1971812 (10a).
In the 1 H NMR spectra of compounds 7, 8a-11a the singlets of protons of cis 3a-HO and 8a-HO groups are situated in the different fields (6.64-6.85 ppm and 7.26-7.56 ppm) whereas the singlets of trans 3a-HO and 8a-HO moieties of diastereomers 8b-11b are situated closely in the 6.99-7.17 ppm region ( Table 1). The singlets of NH-protons of cis-3a,8a-dihydroxy diastereomers 8a-11a are situated in the lower field than the same singlets of NH-protons of trans-3a,8a-dihydroxy diastereomers 8b-11b. In the 13 C NMR spectra of compounds 7, 8a-11a the chemical shifts of carbon atoms connected with HO-groups, NOCH2 (NOMe for compound 8a) carbon atoms, and the carbon atoms of carbonyl groups are typical ( Table 2). Finally, the structure of compound 7 and 10a have been proved by XRD study (Figures 1-3, Tables 3 and 4). The molecular structure of compound 7 is similar to the molecular structure of compound 10a. The molecular structures of compounds 7 and 10a contains cis-fused indane and imidazolidine moiety (Fig. 1, 2) with the angle between the indane and imidazolidine planes is 64º (7), 60º (10a). At that two hydroxyl groups are cis-oriented to each other (the O(2)-C(2)-C(3)-O(3) torsion angle in Table 3). However, some difference is revealed in the compensation of steric repulsion appeared due to cis-fusing. The C(3) atom deviates on 0.42 Å from the mean plain of remaining atoms of the heterocycle and on 0.24 Ǻ from the mean plane of five-membered carbocycle in molecule 7. In molecule 10a, the N(2) atom deviates on 0.20 Å from the mean plain of remaining heterocyclic atoms while the carbocycle is planar. The endocyclic C(2)-C(3) bond which is joint for cis-fused cycles is elongated (Table 3) Table 3. Some molecular characteristics in the 7 and 10a crystals. The C(3)-C(4) bond in molecules 7, 10a is elongated (Table 3) compare to average length of C(sp 3 )-C(sp 2 ) ordinary bond (1.510 Å). 13 In the molecule 7, the endocyclic C(2)-C(6) bond is elongated compare to the same C(2)-C(6) bond in the molecule 10a (Table 3)  The N(1) atom has a planar configuration while the N(2) atom has a pyramidal configuration (Table 3) in the both molecules. At that the N(1)-C(1) amide bond is shorter than N(2)-C(1) amide bond (Table 3) indicating stronger conjugation between N(1) lone pair and C(1)=O(1) carbonyl bond as compared to conjugation between N(2) lone pair and C(1)=O(1) carbonyl bond in both molecules. The similar phenomenon is typical for 3-hydroxy-and 3-alkoxy-5-arylimidazolidine-2,4-diones, 6,8 N-methoxyurea 11 (Table 4).  (3) x, y, -1+z 2.07 The formation of tricyclic compounds 7-11 may be realized in the following way (Scheme 7). At the first stage the ninhydrin's interaction with N-hydroxyurea or Nalkoxyureas on N-hydroxyamino group or N-alkoxyamino group takes place, forming ureas 12. In the same manner the arylglyoxals react with N-hydroxyurea, 6-8 N-alkoxyureas, 9 N-alkoxy-N'-arylureas 10 and N-alkoxy-N'-alkylureas. 10 On the second stage compounds 7 and 8a-11a are formed due to the intramolecular cyclization. In these heterocycles the vicinal HO-groups of hemiaminal moieties have cis mutual orientation.
In the ureas 12 the rotation around N-C bond with further cyclization gives diastereomers 8b-11b having trans mutual orientation of the vicinal HO-groups. Probably, this rotation is retarded and proceeds more slowly than the cyclization yielding cis-3a,8a-dihydroxydiastereomers 7 and 8a-11a.