3-(2-Amino-1-methyl-4-oxo-4,5-dihydro-1H-imidazol-5-yl)-3-hydr­oxy-1-phenyl­indolin-2-one ethanol solvate

Narsimha Reddy Penthala; Thirupathi Reddy Yerram Reddy; Sean Parkin; Peter A Crooks

doi:10.1107/S1600536809033881

. 2009 Sep 12;65(Pt 10):o2439–o2440. doi: 10.1107/S1600536809033881

3-(2-Amino-1-methyl-4-oxo-4,5-dihydro-1H-imidazol-5-yl)-3-hydroxy-1-phenylindolin-2-one ethanol solvate

Narsimha Reddy Penthala ^a, Thirupathi Reddy Yerram Reddy ^a, Sean Parkin ^b, Peter A Crooks ^a,^*

PMCID: PMC2970360 PMID: 21577895

Abstract

In the title compound, C₁₈H₁₆N₄O₃·C₂H₅OH, molecules are linked into chains by a series of intermolecular N—H⋯O, N—H⋯N and O—H⋯O hydrogen bonds which stabilize the crystal structure. The indole and creatinine units make a dihedral angle of 56.45 (4)°. The title compound has two chiral centres. The crystal structure indicates the compound is racemic (RR and SS).

Related literature

For the biological activity of isatin and its derivatives, see: Pandeya et al. (2005 ▶). The endogenous oxindoles 5-hydroxyoxindole and isatin are antiproliferative and proapoptotic, see: Cane et al. (2000 ▶). For in vitro cytotoxicity evaluation of some substituted isatin derivatives, see: Vine et al. (2007 ▶). 2-Indol-3-yl-methylenequinuclidin-3-ols and NADPH oxidase activity has been reported by Sekhar et al. (2003 ▶), and novel substituted (Z)-2-(N-benzylindol-3-ylmethylene)quinuclidin-3-one and (Z)-(±)-2-(N-benzylindol-3-yl methylene)quinuclidin-3-ol derivatives as potent thermal sensitizing agents by Sonar et al. (2007 ▶). For the crystal and molecular structure of isatin, see: Frolova et al. (1988 ▶). For the structure of 3-(2-amino-1-methyl-4-oxo-4,5-dihydro-1H-imidazol-5-yl)-3-hydroxyindolin-2-one monohydrate, see: Penthala et al. (2009 ▶) and of 1,1′-diacetyl-3-hydroxy-2,2′,3,3′-tetrahydro-3,3′-bi(1H-indole)-2,2′-dione, see: Usman et al. (2002 ▶). The aldol condensation enolate mechanism via a six-membered transition state has been described by Zimmerman & Traxler (1957 ▶).

Experimental

Crystal data

C₁₈H₁₆N₄O₃·C₂H₆O
M _r = 382.42
Triclinic,
a = 7.4912 (1) Å
b = 11.0018 (2) Å
c = 12.0835 (2) Å
α = 78.152 (1)°
β = 74.413 (1)°
γ = 74.090 (1)°
V = 913.15 (3) Å³
Z = 2
Cu Kα radiation
μ = 0.82 mm⁻¹
T = 90 K
0.11 × 0.11 × 0.08 mm

Data collection

Bruker X8 Proteum diffractometer
Absorption correction: multi-scan (SADABS in APEX2; Bruker, 2006 ▶) T _min = 0.828, T _max = 0.938
13576 measured reflections
3294 independent reflections
3126 reflections with I > 2σ(I)
R _int = 0.035

Refinement

R[F ² > 2σ(F ²)] = 0.037
wR(F ²) = 0.098
S = 1.07
3294 reflections
258 parameters
H-atom parameters constrained
Δρ_max = 0.37 e Å⁻³
Δρ_min = −0.41 e Å⁻³

Data collection: APEX2 (Bruker, 2006 ▶); cell refinement: SAINT (Bruker, 2006 ▶); data reduction: SAINT; program(s) used to solve structure: SHELXS97 (Sheldrick, 2008 ▶); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008 ▶); molecular graphics: XP in SHELXTL (Sheldrick, 2008 ▶); software used to prepare material for publication: SHELXL97 and local procedures.

Supplementary Material

Crystal structure: contains datablocks global, I. DOI: 10.1107/S1600536809033881/hg2557sup1.cif

e-65-o2439-sup1.cif^{(22.2KB, cif)}

Structure factors: contains datablocks I. DOI: 10.1107/S1600536809033881/hg2557Isup2.hkl

e-65-o2439-Isup2.hkl^{(161.6KB, hkl)}

Additional supplementary materials: crystallographic information; 3D view; checkCIF report

Table 1. Hydrogen-bond geometry (Å, °).

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
O2—H2⋯O1S	0.84	2.19	2.9579 (14)	152
O2—H2⋯O3ⁱ	0.84	2.58	3.2440 (12)	137
N3—H3A⋯O1ⁱⁱ	0.88	2.02	2.8898 (13)	169
N3—H3B⋯N2ⁱⁱⁱ	0.88	2.06	2.9391 (15)	174
O1S—H1S⋯O3ⁱ	0.84	1.89	2.7048 (13)	162

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Symmetry codes: (i) Inline graphic ; (ii) ; (iii) .

Acknowledgments

This investigation was supported by NIH/National Cancer Institute grant PO1 CA104457 (PAC) and by NSF MRI grant CHE 0319176 (SP).

supplementary crystallographic information

Comment

1H-Indole-2,3-diones (isatins) are versatile molecules that display diverse biological activities, (Pandeya et al., 2005), including anticancer activity. (Cane et al., 2000 and Vine et al., 2007). Based on the results of earlier work on radiosensitizers such as (Z)-2-(N-benzylindol-3-ylmethylene)quinuclidin-3-one and (Z)-(±)-2-(N-benzylindol-3-ylmethylene) quinuclidin-3-ol derivatives (Sekhar et al., 2003; Sonar et al., 2007), we have carried out the design, synthesis and structural analysis of a series of 3-(2-amino-1-methyl-4-oxo-4,5-dihydro-1H-imidazol-5-yl)-3- hydroxyindolin-2-one analogs with different substituents on the indole moiety. This X-ray analysis of the title compound was performed to confirm the stereochemistry of the molecule and to obtain detailed information on the conformation of the molecule, which may be useful in structure-activity relationship (SAR) analysis. The title compound was prepared by the aldol condensation of N-phenylindol-2,3-dione (N -phenyl isatin) with 2-amino- 1-methyl-1H-imidazol-4(5H)-one (creatinine) in the presence of sodium acetate in acetic acid under microwave irradiation. The compound was crystallized from ethyl alcohol. This aldol condensation reaction proceeds by the formation of the E-enolate, as per the Zimmerman-Traxler model (Zimmerman & Traxler, 1957), which favores anti products, and leads to the formation of a racemic compound (equimolar RR and SS enantiomers). The molecular structure and the atom-numbering scheme are shown in Fig.1. The isatin ring is planar (r.m.s. deviation = 0.00342 (10) Å) with bond distances and angles comparable with those previously reported for other isatin derivatives (Frolova et al., 1988; Usman, et al., 2002 and Penthala et al. 2009). The indole and creatinine moieties make a dihedral angle of 56.45 (4)°. Intermolecular N—H···O and O—H···N hydrogen bonds stabilize the crystal structure and form a supramolecular aggregation.

Experimental

A mixture of N-phenyl isatin (1 mmol), creatinine (1.1 mmol) and sodium acetate (1.2 mmol) in acetic acid (1 ml) was irradiated in a domestic microwave oven for 30 sec with intermittent cooling every 5 sec. The reaction mixture was allowed to cool to room temperature, 10 ml of saturated sodium bicarbonate solution was added and the mixture was stirred for 10 minutes. The precipitate thus obtained was collected by filtration, washed with cold water and dried to afford the crude product. Crystallization from ethyl alcohol gave a white crystalline product of 3-(2-amino-1-methyl-4-oxo-4,5-dihydro-1H- imidazol-5-yl)-3-hydroxy-1-phenylindolin-2-one ethanolate which was suitable for X-ray analysis. ¹H NMR (DMSO-d₆): δ 3.25 (s, 3H), 4.22 (s, 1H), 6.62 (s, 1H, OH), 6.64–6.65 (d, J=2.4 Hz, 1H), 7.00–7.03 (t, J=7.5 Hz, 1H), 7.17–7.23 (m, 2H), 7.44–7.47 (m, 4H), 7.55–7.57 (d, J=7.5 Hz, 1H), 7.60 (bs, 2H, NH₂) p.p.m.; ¹³C NMR (DMSO-d₆): δ 33.02, 70.60, 76.26, 108.92, 122.74, 124.38, 126.95, 127.10, 128.13, 129.60, 129.86, 134.40, 143.93, 171.90, 174.09, 182.53 p.p.m..