3-(2-Amino-1-methyl-4-oxo-4,5-dihydro-1H-imidazol-5-yl)-5-fluoro-3-hydr­oxy-1-methyl­indolin-2-one methanol hemisolvate

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

doi:10.1107/S1600536809043797

. 2009 Oct 31;65(Pt 11):o2909–o2910. doi: 10.1107/S1600536809043797

3-(2-Amino-1-methyl-4-oxo-4,5-dihydro-1H-imidazol-5-yl)-5-fluoro-3-hydroxy-1-methylindolin-2-one methanol hemisolvate

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

PMCID: PMC2971372 PMID: 21578489

Abstract

In the title compound, C₁₃H₁₃FN₄O₃·0.5CH₃OH, molecules are packed in the crystal structure by a series of O—H⋯N, N—H⋯O, N—H⋯F and O—H⋯O intermolecular hydrogen bonds. The indole and creatinine units make a dihedral angle of 60.80 (4)°.

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 the in vitro cytotoxicity evaluation of some substituted isatin derivatives, see: Vine et al. (2007 ▶). For 2-indol-3-yl-methylenequinuclidin-3-ols and NADPH oxidase activity, see: Sekhar et al. (2003 ▶) and for 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, see: Sonar et al. (2007 ▶). For the crystal and molecular structure of isatin, see: Frolova et al. (1988 ▶), for 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 for 1,1′-diacetyl-3-hydroxy-2,2′,3,3′-tetrahydro-3,3′-bi(1H-indole)-2,2′-dione, see: Usman et al. (2002 ▶). For the aldol condensation enolate mechanism via a six-membered transition state, see: Zimmerman & Traxler (1957 ▶).

Experimental

Crystal data

C₁₃H₁₃FN₄O₃·0.5CH₄O
M _r = 308.30
Monoclinic,
a = 14.3088 (3) Å
b = 10.7900 (2) Å
c = 18.1286 (5) Å
β = 107.676 (1)°
V = 2666.77 (10) Å³
Z = 8
Cu Kα radiation
μ = 1.04 mm⁻¹
T = 90 K
0.15 × 0.03 × 0.02 mm

Data collection

Bruker X8 Proteum diffractometer
Absorption correction: multi-scan (SADABS in APEX2; Bruker, 2006 ▶) T _min = 0.805, T _max = 0.979
19606 measured reflections
2448 independent reflections
2196 reflections with I > 2σ(I)
R _int = 0.041

Refinement

R[F ² > 2σ(F ²)] = 0.035
wR(F ²) = 0.092
S = 1.04
2448 reflections
211 parameters
H-atom parameters constrained
Δρ_max = 0.25 e Å⁻³
Δρ_min = −0.27 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/S1600536809043797/hg2556sup1.cif

e-65-o2909-sup1.cif^{(20.1KB, cif)}

Structure factors: contains datablocks I. DOI: 10.1107/S1600536809043797/hg2556Isup2.hkl

e-65-o2909-Isup2.hkl^{(120.4KB, 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⋯N2ⁱ	0.84	1.97	2.8074 (16)	171
N3—H3A⋯O3ⁱⁱ	0.88	2.25	3.1265 (16)	177
N3—H3B⋯O1ⁱⁱⁱ	0.88	2.12	2.8490 (17)	140
N3—H3B⋯F1^iv	0.88	2.45	2.8743 (14)	110
O1S—H1S4⋯O3	0.84	2.01	2.846 (3)	171

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

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

Isatin analogs display diverse biological activities, (Pandeya et al., 2005; Cane et al., 2000 and Vine et al., 2007). In continuation of our work on radiosensitizers (Sekhar et al., 2003; Sonar et al., 2007), we focused on 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. The main aim of X-ray analysis of the title compound was to confirm the stereochemistry of the molecule and to obtain detailed information on the structural conformation, which may be useful in structure-activity relationship (SAR) analysis. The title compound was prepared by the aldol condensation of 5-fluoro-N-methyl indol-2,3-dione 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 methyl alcohol. This aldol condensation reaction proceeds by the formation of the E-enolate, as per the Zimmerman-Traxler model (Zimmerman & Traxler, 1957). The molecular structure and the atom-numbering scheme are shown in Fig.1. The isatin ring is planar with r.m.s. deviation of 0.0232 (11) Å and the creatinine ring has r.m.s. deviation of 0.0307 (8) 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 60.80 (4) °. Intermolecular O—H···N, N—H···O, N—H···F and O—H···O hydrogen bonds stabilize the crystal structure and form a supramolecular aggregation.

Experimental

A mixture of 5-fluoro-N-methyl 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 methyl alcohol gave a white crystalline product of 3-(2-amino-1-methyl-4-oxo-4,5-dihydro-1H-imidazol-5-yl)- 5-fluoro-3-hydroxy-1-methylindolin-2-one methanolate, which was suitable for X-ray analysis. ¹H NMR (DMSO-d₆): δ 3.05 (s, 3H), 3.18 (s, 3H), 4.11 (s, 1H), 6.58 (s, 1H, OH), 6.85–6.89 (dd, J=2.7 Hz, J=5.4 Hz, 1H), 6.93–6.97 (dd, J=2.7 Hz, J=4.2 Hz, 1H), 7.11–7.18 (m, 1H), 7.42 (bs, 1H, NH), 7.72 (bs, 1H, NH), p.p.m.; ¹³C NMR (DMSO-d₆): δ 26.08, 32.76, 48.62, 69.87, 76.29, 109.14, 109.25, 111.16, 111.50, 115.42, 115.72, 128.84, 128.95, 140.23, 156.35, 159.49, 171.98, 173.97, 181.85 p.p.m..