N-{3-[Bis(2-hydroxy­ethyl)amino­meth­yl]-5-nitro­phen­yl}benzamide

Anna Mai; Gul S Khan; George R Clark; David Barker

doi:10.1107/S1600536808009410

. 2008 May 3;64(Pt 6):o978–o979. doi: 10.1107/S1600536808009410

N-{3-[Bis(2-hydroxyethyl)aminomethyl]-5-nitrophenyl}benzamide

Anna Mai ^a, Gul S Khan ^a, George R Clark ^a, David Barker ^a,^*

PMCID: PMC2961623 PMID: 21202707

Abstract

The title compound, C₁₈H₂₁N₃O₅, was prepared by the reaction of 3-benzamido-5-nitrobenzyl methanesulfonate with diethanolamine and is an intermediate in the synthesis of DNA minor-groove-binding polybenzamide agents capable of being conjugated to additional biologically active species. The asymmetric unit contains two independent molecules, which differ only in the orientations of the hydroxyethyl groups. In the crystal structure, intermolecular N—H⋯O and O—H⋯O hydrogen bonds link molecules into one-dimensional chains.

Related literature

For related literature on the biological activity of polybenzamide DNA binding agents, see: Storl et al. (1993 ▶). For related literature on natural and synthetic minor-groove binding agents, including agents containing conjugates, see: Arcamone et al. (1964 ▶); Atwell et al. (1995 ▶); Baraldi et al. (1999 ▶, 2004 ▶, 2007 ▶); Kumar et al. (2004 ▶); Sengupta et al. (1996 ▶); Stafford et al. (2007 ▶); Turner et al. (1999 ▶); Wemmer (2000 ▶); Yan et al. (1997 ▶). For related literature, see: Barker et al. (2008 ▶).

Experimental

Crystal data

C₁₈H₂₁N₃O₅
M _r = 359.38
Monoclinic,
a = 22.7867 (3) Å
b = 11.0879 (1) Å
c = 13.5106 (1) Å
β = 90.114 (1)°
V = 3413.54 (6) Å³
Z = 8
Mo Kα radiation
μ = 0.10 mm⁻¹
T = 90 (2) K
0.34 × 0.22 × 0.20 mm

Data collection

Bruker SMART CCD diffractometer
Absorption correction: multi-scan (SADABS; Sheldrick, 1997 ▶) T _min = 0.858, T _max = 0.978
20279 measured reflections
6944 independent reflections
5142 reflections with I > 2σ(I)
R _int = 0.039

Refinement

R[F ² > 2σ(F ²)] = 0.058
wR(F ²) = 0.134
S = 1.04
6944 reflections
485 parameters
H atoms treated by a mixture of independent and constrained refinement
Δρ_max = 0.25 e Å⁻³
Δρ_min = −0.29 e Å⁻³

Data collection: SMART (Bruker, 1995 ▶); cell refinement: SAINT (Bruker, 1995 ▶); data reduction: SAINT; program(s) used to solve structure: SHELXS97 (Sheldrick, 2008 ▶); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008 ▶); molecular graphics: ORTEPIII (Burnett & Johnson, 1996 ▶); software used to prepare material for publication: SHELXTL (Sheldrick, 2008 ▶).

Supplementary Material

Crystal structure: contains datablocks I, global. DOI: 10.1107/S1600536808009410/lh2602sup1.cif

e-64-0o978-sup1.cif^{(27.2KB, cif)}

Structure factors: contains datablocks I. DOI: 10.1107/S1600536808009410/lh2602Isup2.hkl

e-64-0o978-Isup2.hkl^{(333KB, 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
O4A—HO4A⋯O1Aⁱ	0.93 (4)	1.82 (4)	2.736 (2)	168 (3)
O5A—HO5A⋯O4B	0.89 (3)	1.85 (3)	2.738 (2)	178 (3)
N1A—H1A⋯O5B	0.86	2.27	3.089 (2)	159
O5B—HO5B⋯O4B	0.90 (4)	2.30 (4)	3.130 (3)	153 (3)
O4B—HO4B⋯O4A	1.03 (4)	1.75 (4)	2.762 (3)	169 (3)
N1B—H1B⋯O5A	0.86	2.49	3.332 (2)	167

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Symmetry code: (i) Inline graphic .

Acknowledgments

The authors acknowledge financial support from the Higher Education Commission of Pakistan and the University of Auckland, New Zealand.

supplementary crystallographic information

Comment

The naturally occurring antibiotic oligopeptides distamycin A, isolated from Streptomyces Distallicus, and netropsin, from Streptomyces netropsis, are powerful DNA minor groove-binding agents but their cytotoxity precludes their use as medicines (Arcamone et al., 1964, Baraldi et al., 2004, Wemmer et al., 2000, Storl et al., 1993). In order to increase the DNA binding affinity and sequence specificity along with minimizing the unwanted physiological activities associated with these natural DNA binders, many synthetic oligopeptides have been prepared (Baraldi et al., 2007). In addition, numerous biologically active species have been conjugated to natural and synthetic DNA binding oligopeptides with the purpose of increasing the concentration of these species near DNA (Kumar et al., 2004, Stafford et al., 2007). The title compound is a key intermediate required in the synthesis of a novel polybenzamide DNA minor groove-binding agent.

Experimental

N,N-Bis(2-hydroxyethyl)-3-benzamido-5-nitrobenzylamine was prepared using the method of Barker et al.(2008). To a solution of 3-benzamido-5-nitrobenzyl methanesulfonate (0.129 g, 0.368 mmol) in dry THF (1 ml) was added dropwise to a stirred suspension of diethanolamine (0.387 g, 3.68 mmol) in dry THF (2 ml) at 273 K. The mixture was then stirred under an atmosphere of nitrogen overnight before being concentrated in vacuo to give a crude residue. This residue was diluted with ethyl acetate (10 ml) and extracted with 2M HCl (2 x 10 ml). The combined acidic extracts were neutralized with 4M NaOH and then extracted with ethyl acetate (2 x 15 ml). The combined organic extracts were dried (MgSO₄), filtered and the solvent removed in vacuo, to afford the title compound (0.128 g, 97%), as a yellow solid, which was recrystallized from ethyl acetate to give yellow crystals (m.p. 385–387 K) suitable for X-ray crystallography. Spectroscopic analysis: IR (ν_max, thin film, cm^-1) 2906, 1680, 1527, 1377. ¹H NMR (300 MHz, CDCl₃, δ, p.p.m.) 2.60 (4H, m, N(CH₂CH₂OH)₂, 3.61 (2H, s, Ar—CH₂N), 3.68 (4H, m, N(CH₂CH₂OH)₂), 7.32 (3H, m, Ar—H), 7.46 (1H, m, Ar—H), 7.59 (1H, s, Ar—H), 7.67 (1H, m, Ar—H), 8.10 (1H, br s, Ar—H), 8.35 (1H, m, Ar—H) and 9.03 (NH). ¹³C NMR (75 MHz, CDCl₃, δ, p.p.m.) 55.9 (CH₂, N(CH₂CH₂OH)₂), 58.4 (CH₂, Ar—CH₂N), 59.2 (CH₂, N(CH₂CH₂OH)₂), 114.5 (CH, Ar—C), 118.6 (CH, Ar—C), 125.9 (CH, Ar—C), 127.2 (CH, Ar—C), 128.4 (CH, Ar—C), 132.3 (CH, Ar—C), 133.2 (quat. Ar—C), 139.2 (quat. Ar—C), 142.3 (quat. Ar—C), 148.1 (quat. Ar—C) and 166.4 (C=O) MS m/z (FAB) 360 (M⁺, 9%), 219 (4), 154 (100), and 120 (NHCOC₆H₅, 8). HRMS (FAB), found: MH⁺ 360.15572. C₁₈H₂₂N₃O₅ requires: 360.15595.