Synthesis and crystal structures of 5'-phenylspiro[indoline-3, 2'-pyrrolidin]-2-one derivatives

Background The spiro- indole-pyrrolidine ring system is a frequently encountered structural motif in many biologically important and pharmacologically relevant alkaloids. The derivatives of spirooxindole ring systems are used as antimicrobial, antitumour agents and as inhibitors of the human NKI receptor besides being found in a number of alkaloids like horsifiline, spirotryprostatin and (+) elacomine. The recently discovered small-molecule MDM2 inhibitor MI-219 and its analogues are in advanced preclinical development as cancer therapeutics. Results In the crystal structures of the two organic compounds, 4'-Nitro-3',5'-diphenylspiro[indoline-3,2'-pyrrolidin]-2-one and 3'-(4-Methoxyphenyl)- 4'-nitro -5'-phenylspiro[indoline-3,2'-pyrrolidin]-2-one, N-H···O hydrogen bonds make the R22 (8) ring motif. Further, the structures are stabilized by intermolecular hydrogen bonds. Conclusion The crystal structures of 4'-Nitro-3',5'-diphenylspiro[indoline-3,2'-pyrrolidin]-2-one and 3'-(4-Methoxyphenyl)- 4'-nitro -5'-phenylspiro[indoline-3,2'-pyrrolidin]-2-one have been investigated in detail. In both the compounds, the R22(8) motif is present. Due to the substitution of methoxyphenyl instead of phenyl ring, the entire configuration is inverted with respect to the 2-oxyindole ring.


Background
1,3-Dipolar cycloaddition of azomethineylides to exocyclic olefins constitutes a versatile protocol for the construction of poly functionalized spiro-heterocycles viz. pyrrolidines [1] and pyrrolizines [2], which widely occur in natural products and biologically active compounds. The spiro-indole-pyrrolidine ring system is a frequently encountered structural motif in many biologically important and pharmacologically relevant alkaloids. Compounds with an indole/oxindole framework are promising pharmacophore which exhibit interesting applications in the biological and pharmacological arena [3]. The derivatives of spirooxindole ring systems are used as antimicrobial, antitumour agents and as inhibitors of the human NKI receptor besides being found in a number of alkaloids like horsifiline, spirotryprostatin and (+) elacomine [4]. The recently discovered small-molecule MDM2 inhibitor MI-219 and its analogues are in advanced preclinical development as cancer therapeutics [5]. Our interest in preparing pharmacologically active pyrrolidines led us to the compounds, 4'-Nitro-3',5'diphenylspiro[indoline-3,2'-pyrrolidin]-2-one (I) and 3'-(4-Methoxyphenyl)-4'-nitro -5'-phenylspiro[indoline-3, 2'-pyrrolidin]-2-one (II), and we have undertaken the Xray crystal structure determination of these compounds in order to establish their conformations.

Results and Discussion
In both the molecules, the 2-oxyindole ring is planar (r. m.s deviation: 0.031 Å and 0.018 Å for I and II, respectively), which is common in spiro complexes [9,10]

X-ray Crystallography
Single crystal X-ray intensity data for the compounds (Scheme 2) and (Scheme 3) were collected using a Nonius CAD-4 MACH 3 diffractometer with MoK α (0.71073 Å) radiation at room temperature (293 K). The data reduction was carried out using XCAD4 [12]. The absorption corrections were applied using the ψ-scan method [13]. The structures of both the compounds were solved by direct methods using SHELXS97 [14] and all the non-hydrogen atoms were refined anisotropically by full-matrix least-squares on F 2 taking all the unique reflections using SHELXL97 [14]. The hydrogen atoms attached with carbon atoms were placed in their calculated positions and included in the isotropic refinement using the riding model with C-H = 0.93Å (-CH) or 0.97Å (-CH 2 ) Å or 0.96Å (-CH 3 ) Å with Uiso(H) = 1.2 Ueq (parent C atom) and amino bound hydrogen atoms were located from the difference Fourier map and include in the refinement isotropically. The crystal data, experimental conditions and structure refinement parameters for the compounds (I) and (II) are presented in Table 1. The re-crystallization of the compound (I) and repeated data collection with different crystal samples did not improve the R value and other statistical parameters. Crystals of better quality could not be obtained for the compound (I). Table 2 gives the geometry of the hydrogen bonds present in I and II. The molecular structures of compounds (I) and   (II) showing the atom numbering scheme using ORTEP-3 [15] are given in Figures 4 and 5, respectively.

Conclusions
The title compounds were synthesized and the corresponding molecular crystal structures have been determined by single-crystal X-ray diffraction. In both the compounds, the R 2 2 (8) motif is present. Even though most of the conformational features are similar when seen separately, by super positioning the two structures it is found that the entire configuration is inverted with respect to the 2-oxyindole ring. This is due to the substitution of methoxyphenyl instead of phenyl ring in compound (I).

Additional material
Crystallographic data (excluding structure factors) for the structures of compounds (I) and (II) reported in this paper have been deposited with the Cambridge