1-Isopropyl-4-nitro-6-meth­oxy-1H-benzimidazole

Moore, M.D.; Jain, P.; Flaherty, P.T.; Wildfong, P.L.D.

doi:10.1107/S160053680801859X

organic compounds

CRYSTALLOGRAPHIC
COMMUNICATIONS

ISSN: 2056-9890

Volume 64| Part 7| July 2008| Pages o1336-o1337

doi:10.1107/S160053680801859X

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1-Isopropyl-4-nitro-6-methoxy-1H-benzimidazole

Michael D. Moore,^a Prashi Jain,^a Patrick T. Flaherty ^a and Peter L. D. Wildfong ^a ^*

^aMylan School of Pharmacy, Duquesne University, 600 Forbes Avenue, Pittsburgh, PA 15282, USA
^*Correspondence e-mail: wildfongp@duq.edu

(Received 10 June 2008; accepted 19 June 2008; online 25 June 2008)

There are two independent molecules in the asymmetric unit of the title compound, C₁₁H₁₃N₃O₃. The interplanar angles for the two rings of the benzimidazole ring system is 2.21 (12)° in one molecule and 0.72 (12)° in the other. The nitro group is twisted in the same direction relative to the least-squares plane through its attached benzene ring in both molecules, with interplanar angles of 15.22 (9) and 18.02 (8)°. In the crystal structure, molecules are stacked along the a axis through π–π interactions (centroid–centroid distance 4.1954 Å). C—H⋯O hydrogen bonds are also present.

Related literature

For background to the biological applications of benzimidazole cores, see: Townsend & Revankar (1970 ); Kamal et al. (2006 ); Bentancor et al. (2004 ); Somsak et al. (2003 ); Scholz et al. (2003 ); Sachs et al. (1995 ); Shin et al. (1997 ); Chackalamannil et al. (2003 ); Nicolaou et al. (1998 ); Lanusse & Prichard (1993 ); Wang (1984 ); Banks (1984 ); Sharma & Abuzar (1983 ); Lopez-Rodriguez et al. (2002 ). For other related literature on benzimidazole cores, see: Elderfield et al. (1946 ); Grimmett (2002 ); Kumar et al. (1982 ); Mizzoni & Spoerri (1945 ); Reddy & Reddy (1979 ). For related literature, see: Flaherty et al. (2008 ).

Experimental

Crystal data

C₁₁H₁₃N₃O₃
M_r = 235.24
Orthorhombic, P 2₁ 2₁ 2₁
a = 7.63920 (10) Å
b = 16.0029 (3) Å
c = 17.9496 (3) Å
V = 2194.33 (6) Å³
Z = 8
Mo Kα radiation
μ = 0.11 mm⁻¹
T = 150 (2) K
0.43 × 0.33 × 0.28 mm

Data collection

Bruker SMART APEXII diffractometer
Absorption correction: multi-scan (SADABS; Sheldrick, 2002 ) T_min = 0.959, T_max = 0.971
39389 measured reflections
3989 independent reflections
3649 reflections with I > 2σ(I)
R_int = 0.026

Refinement

R[F² > 2σ(F²)] = 0.034
wR(F²) = 0.099
S = 1.09
3989 reflections
313 parameters
H-atom parameters constrained
Δρ_max = 0.47 e Å⁻³
Δρ_min = −0.20 e Å⁻³

Table 1
Hydrogen-bond geometry (Å, °)

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
C15—H1⋯O6ⁱ	0.93	2.46	3.3670 (8)	164
C4—H15⋯O3ⁱⁱ	0.93	2.49	3.3723 (8)	159
Symmetry codes: (i) $[-x+{\script{1\over 2}}, -y+1, z+{\script{1\over 2}}]$ ; (ii) $[-x+{\script{3\over 2}}, -y+1, z-{\script{1\over 2}}]$ .

Data collection: APEX2 and SMART (Bruker, 1998 ); cell refinement: SAINT (Bruker, 1998); data reduction: SAINT; program(s) used to solve structure: SHELXS97 (Sheldrick, 2008 ); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008); molecular graphics: ORTEP-3 for Windows (Farrugia, 1997 ); software used to prepare material for publication: SHELXTL (Sheldrick, 2008) and PLATON (Spek, 2003 ).

Supporting information

Crystal structure: contains datablocks I, global. DOI: 10.1107/S160053680801859X/zl2123sup1.cif

Structure factors: contains datablock I. DOI: 10.1107/S160053680801859X/zl2123Isup2.hkl

checkCIF report

Comment top

The benzimidazole core has found application in multiple biologically active compounds including ATP mimics (Townsend & Revankar, 1970, Kamal et al., 2006, Bentancor et al., 2004, Somsak et al., 2003, Scholz et al., 2003), ATPase inhibitors (Sachs et al., 1995, Shin et al., 1997), peptide mimics (Chackalamannil et al., 2003, Nicolaou et al., 1998, antihelmentics (Lanusse & Prichard, 1993, Wang, 1984, Banks, 1984, Sharma & Abuzar, 1983), and serotonergic compounds (Lopez-Rodriguez et al., 2002). Although multiple strategies exist to synthesize the imidazole ring onto the parent phenyl ring, the most prevalent strategy utilizes an ortho-phenyldiamine precursor, for example, compound 2 (Grimmett, 2002). Subsequent N-alkylation on the benzimidazole core presents an ambident nucleophile (Kumar et al., 1982, Reddy & Reddy, 1979). Alkylation on the preformed benzimidazole has been shown to occur on the most nucleophilic nitrogen. However, this strategy often presents a mixture of products and fails completely with bulky, less-reactive electrophiles. A strategy of one-pot N-alkylation on the precursor phenyldiamine has been developed, followed by cyclization to afford 1-N-alkyl-4-nitro-6-methoxybenzimidazole (Flaherty et al., In preparation). Unequivocal characterization of the alkylation site was essential to determine the utility of this method.

There are two molecules in the asymmetric unit of the title compound (Fig. 1). The nitro groups are twisted away from the least squares plane of the attached benzene rings, with the O2—N1—C6—C5 torsion angles being 17.24 (2)° and 14.72 (2)° for each molecule in the asymmetric unit, respectively, and the O1—N1—C6—C7 torsion angles being 18.51 (2)° and 15.10 (2)° for each molecule, respectively. Molecules in the crystal structure (Fig. 2) are stacked in parallel pairs along the a axis through π-π interactions, where the distance between C1 to C6 (centroid Cg2) and C12 to C18 (centroid Cg5) is 4.1954 Å [symmetry operation: x, y, z]. The crystal structure is further stabilized by weak C—H···O hydrogen bonds (Table 1). Additional stabilization arises from C—H···π interactions involving C22—H10A with C3—C4—C5—N2—N3 (centroid Cg1) and C10—H14C with C14—C15—C16—N5—N6 (centroid Cg4) imidazole rings having X—Cg···H distances of 3.6317 (17) Å and 3.6818 (17) Å, respectively.

Related literature top

For background to the biological applications of benzimidazole cores, see: Townsend & Revankar (1970); Kamal et al. (2006); Bentancor et al. (2004); Somsak et al. (2003); Scholz et al. (2003); Sachs et al. (1995); Shin et al. (1997); Chackalamannil et al. (2003); Nicolaou et al. (1998); Lanusse & Prichard (1993); Wang (1984); Banks (1984); Sharma & Abuzar (1983); Lopez-Rodriguez et al. (2002). For other related literature on benzimidazole cores, see: Elderfield et al. (1946); Grimmett (2002); Kumar et al. (1982); Mizzoni & Spoerri (1945); Reddy & Reddy (1979). For related literature, see: Flaherty et al. (2008).

Experimental top

Known compound 1 (Fig. 3) could be prepared in one step from commercially available starting material according to the procedure of Elderfield (Elderfield et al., 1946). Desymmetrization by Zinin mono reduction (Mizzoni & Spoerri, 1945) to 5-methoxy-3-nitrobenzene-1,2-diamine, 2 (Fig. 3), proceeded well. Reductive alkylation between 2 (Fig.3) and acetone generated the 2-isopropyl intermediate which was directly cyclized to 3 (Fig. 3) in formic acid and concentrated hydrochloric acid.

All compounds were obtained from Aldrich or Acros and used as supplied unless otherwise indicated. All reactions were conducted under an atmosphere of N₂ unless otherwise indicated. Melting points were determined on a MelTemp apparatus and are uncorrected. ¹H NMR analyses were determined on a 400 MHz Brucker NMR, and elemental analyses were preformed by Atlantic Microlabs.

CAUTION: Although the nitration to generate 1 (Fig. 3) proceeded in a controlled manner consistent with the literature (Elderfield et al., 1946) and the differential scanning calorimetry of solid 1 (Fig. 3) did not indicate an exothermic event upon melting, these compounds should be handled with great care and proper precaution.

5-Methoxy-3-nitrobenzene-1,2-diamine (2, Fig. 3): A solution of 4-methoxy-2,6-dinitroaniline (Elderfield et al., 1946) (1, Fig.3) (1.07 g, 5.0 mmole) in 50 ml of 100% EtOH was added to a 10% aqueous solution of (NH₄)₂S. This mixture was warmed to 333 K (60 °C). and stirred at 333 K (60 °C) for 1.5 h. This mixture was cooled to 273 K (0 °C) and the solid was collected on a #1 Whatman filter paper. The collected solids were washed with 5 ml of ice-cold CS₂ then 5.0 ml of ice cold water to afford 0.65 g red needles after drying (70%). MP: 456–457.9 K (183–184.9 °C). ¹H NMR (CDCl₃) δ 3.53 (br s, 2H), 3.78 (s, 3H), 5.70 (s, 3H), 6.63 (s, 1H), 7.17 (s, 1H). Anal. Calcd for C₇H₉N₃O₃: C, 45.90; H, 4.95; N, 22.94. Found: C, 45.97; H, 4.99; N, 22.82.

1-Isopropyl-6-methoxy-4-nitro-1H-benzo[d]imidazole (3, Fig. 3): A solution of NaHB(O₂CH)₃ was prepared by slowly adding 99% formic acid (10.0 ml, 290 mmole) to a suspension of NaBH₄ (1.83 g, 48.4 mmole) in THF (50 ml) at 273 K (0 °C) followed by stirring for an additional 5 min at 273 K (0 °C). To this solution was added a solution of 5-methoxy-3-nitrobenzene-1,2-diamine (2, Fig. 3) (2.1609 g, 11.8 mmole) in ACS grade acetone (20 ml) and THF (50.0 ml). The ice bath was removed and the mixture was permitted to stir for an additional 2 h at 296 K (23 °C). The solvent was removed under reduced pressure and the residue was dissolved into ice-cold 200 ml formic acid and then 60.0 ml concentrated HCl was added at 273 K (0 °C). This was brought directly to reflux for 15 min. The reaction was cooled to ambient temperature and the solvent was removed under reduced pressure. The residue was taken up into 15 ml ice-cold water and with cooling with an ice bath was made basic with a slight excess of 6 N NaOH. The precipitated dark solid was collected on #1 Whatman filter paper to 2.8 g. This solid was separated on SiO₂ with 1:1 hexanes/ethyl acetate to afford 1.7 g of a bright yellow solid (74%). This material was recrystallized from CHCl₃ to produce the material for crystallographic analysis. MP: 399–400 K (126–127 °C). ¹H (CDCl₃): δ 1.67 (2 t, 30 Hz, 6H), 3.96 (s, 1H), 4.69 (m, 1H), 7.24 (s, 1H), 7.82 (s, 1H), 8.26 (s, 1H). Anal. Calcd for C₁₁H₁₃N₃O₃: C, 56.16; H, 5.57; N, 17.86. C, 56.45; H,5.62; N, 17.55.

Computing details top

Data collection: SMART (Bruker, 1998); cell refinement: SAINT (Bruker, 1998); data reduction: SAINT (Bruker, 1998); program(s) used to solve structure: SHELXS97 (Sheldrick, 2008); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008); molecular graphics: SHELXTL (Sheldrick, 2008) and PLATON (Spek, 2003); software used to prepare material for publication: ORTEP-3 for Windows (Farrugia, 1997).

Figures top

	Fig. 1. The molecular structure of the title compound, shown with 30% probability displacement ellipsoids (arbitrary spheres for H atoms).
	Fig. 2. A packing diagram of (I) showing the π-π stacking interactions along the a axis between the benzimidazole rings (dashed line).
	Fig. 3. The molecular synthesis scheme used to produce the title compound (3). The following were also used: a: (NH₄)₂S,EtOH; b: formic acid, acetone, THF; c: conc. HCl, formic acid.

1-Isopropyl-4-nitro-6-methoxy-1H-benzimidazole top

Crystal data top

C₁₁H₁₃N₃O₃	F(000) = 992.0
M_r = 235.24	D_x = 1.424 Mg m⁻³
Orthorhombic, P2₁2₁2₁	Mo Kα radiation, λ = 0.71073 Å
Hall symbol: P 2ac 2ab	Cell parameters from 12882 reflections
a = 7.6392 (1) Å	θ = 2.3–30.9°
b = 16.0029 (3) Å	µ = 0.11 mm⁻¹
c = 17.9496 (3) Å	T = 150 K
V = 2194.33 (6) Å³	Rhomboid, yellow
Z = 8	0.43 × 0.33 × 0.28 mm

Data collection top

Bruker SMART APEXII diffractometer	3989 independent reflections
Radiation source: fine-focus sealed tube	3649 reflections with I > 2σ(I)
Graphite monochromator	R_int = 0.026
ϕ and ω scans	θ_max = 31.2°, θ_min = 1.7°
Absorption correction: multi-scan (SADABS; Sheldrick, 2002)	h = −11→11
T_min = 0.959, T_max = 0.971	k = −23→23
39389 measured reflections	l = −25→26

Refinement top

Refinement on F²	Primary atom site location: structure-invariant direct methods
Least-squares matrix: full	Secondary atom site location: difference Fourier map
R[F² > 2σ(F²)] = 0.034	Hydrogen site location: inferred from neighbouring sites
wR(F²) = 0.099	H-atom parameters constrained
S = 1.09	w = 1/[σ²(F_o²) + (0.0626P)² + 0.1952P] where P = (F_o² + 2F_c²)/3
3989 reflections	(Δ/σ)_max = 0.006
313 parameters	Δρ_max = 0.47 e Å⁻³
0 restraints	Δρ_min = −0.20 e Å⁻³

Crystal data top

C₁₁H₁₃N₃O₃	V = 2194.33 (6) Å³
M_r = 235.24	Z = 8
Orthorhombic, P2₁2₁2₁	Mo Kα radiation
a = 7.6392 (1) Å	µ = 0.11 mm⁻¹
b = 16.0029 (3) Å	T = 150 K
c = 17.9496 (3) Å	0.43 × 0.33 × 0.28 mm

Data collection top

Bruker SMART APEXII diffractometer	3989 independent reflections
Absorption correction: multi-scan (SADABS; Sheldrick, 2002)	3649 reflections with I > 2σ(I)
T_min = 0.959, T_max = 0.971	R_int = 0.026
39389 measured reflections

Refinement top

R[F² > 2σ(F²)] = 0.034	0 restraints
wR(F²) = 0.099	H-atom parameters constrained
S = 1.09	Δρ_max = 0.47 e Å⁻³
3989 reflections	Δρ_min = −0.20 e Å⁻³
313 parameters

Special details top

Geometry. All e.s.d.'s (except the e.s.d. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell e.s.d.'s are taken into account individually in the estimation of e.s.d.'s in distances, angles and torsion angles; correlations between e.s.d.'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell e.s.d.'s is used for estimating e.s.d.'s involving l.s. planes.

Refinement. Refinement of F² against ALL reflections. The weighted R-factor wR and goodness of fit S are based on F², conventional R-factors R are based on F, with F set to zero for negative F². The threshold expression of F² > σ(F²) is used only for calculating R-factors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F² are statistically about twice as large as those based on F, and R- factors based on ALL data will be even larger.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å²) top

	x	y	z	U_iso*/U_eq
O6	0.21889 (17)	0.44035 (7)	0.15295 (6)	0.0298 (2)
N4	0.04946 (18)	0.68089 (7)	0.29007 (7)	0.0257 (2)
C14	0.24765 (18)	0.47797 (8)	0.35375 (7)	0.0192 (2)
N6	0.28545 (16)	0.45465 (7)	0.42604 (6)	0.0205 (2)
C16	0.17746 (18)	0.55944 (8)	0.35923 (7)	0.0201 (2)
C18	0.13756 (19)	0.55466 (9)	0.22533 (8)	0.0233 (3)
H5	0.0985	0.5799	0.1817	0.028*
C13	0.26894 (18)	0.43410 (8)	0.28697 (7)	0.0209 (2)
H7	0.3191	0.3812	0.2856	0.025*
O5	−0.0279 (2)	0.70366 (8)	0.23365 (7)	0.0401 (3)
C17	0.12331 (19)	0.59655 (8)	0.29232 (8)	0.0213 (2)
C12	0.2109 (2)	0.47402 (9)	0.22273 (7)	0.0222 (3)
N5	0.17167 (17)	0.58463 (7)	0.43318 (7)	0.0236 (2)
O4	0.0687 (2)	0.72566 (7)	0.34467 (7)	0.0436 (3)
C21	0.2167 (2)	0.30465 (8)	0.43829 (8)	0.0258 (3)
H9A	0.1150	0.3176	0.4675	0.039*
H9B	0.2632	0.2517	0.4537	0.039*
H9C	0.1850	0.3020	0.3866	0.039*
C19	0.2891 (2)	0.35769 (9)	0.14715 (8)	0.0290 (3)
H11A	0.4060	0.3569	0.1668	0.043*
H11B	0.2913	0.3410	0.0958	0.043*
H11C	0.2172	0.3197	0.1750	0.043*
C20	0.35454 (19)	0.37233 (8)	0.44953 (8)	0.0222 (2)
H8	0.4568	0.3588	0.4189	0.027*
C15	0.2357 (2)	0.52027 (8)	0.46970 (8)	0.0235 (3)
H1	0.2463	0.5195	0.5213	0.028*
C22	0.4111 (2)	0.37599 (10)	0.53068 (8)	0.0300 (3)
H10A	0.4943	0.4204	0.5372	0.045*
H10B	0.4640	0.3238	0.5445	0.045*
H10C	0.3108	0.3861	0.5616	0.045*
C5	0.63745 (18)	0.55518 (8)	0.10934 (7)	0.0200 (2)
N1	0.51798 (17)	0.67741 (7)	0.17962 (7)	0.0257 (2)
O3	0.74288 (17)	0.44725 (7)	0.31636 (5)	0.0290 (2)
C6	0.60053 (18)	0.59506 (8)	0.17718 (8)	0.0209 (2)
N3	0.74022 (16)	0.45062 (7)	0.04131 (6)	0.0197 (2)
C3	0.71541 (17)	0.47535 (8)	0.11420 (7)	0.0185 (2)
C1	0.71502 (19)	0.47734 (9)	0.24614 (7)	0.0215 (2)
C2	0.75604 (18)	0.43486 (8)	0.18085 (7)	0.0205 (2)
H18	0.8078	0.3823	0.1816	0.025*
N2	0.61682 (17)	0.57845 (7)	0.03556 (6)	0.0233 (2)
C7	0.63817 (19)	0.55723 (9)	0.24427 (8)	0.0229 (3)
H20	0.6126	0.5847	0.2886	0.027*
O1	0.5265 (2)	0.71814 (9)	0.23746 (8)	0.0493 (4)
O2	0.44371 (17)	0.70267 (7)	0.12361 (7)	0.0342 (3)
C11	0.6778 (2)	0.29985 (8)	0.03307 (8)	0.0252 (3)
H13A	0.6454	0.3014	0.0847	0.038*
H13B	0.7288	0.2465	0.0217	0.038*
H13C	0.5757	0.3082	0.0028	0.038*
C4	0.67924 (19)	0.51421 (8)	−0.00193 (8)	0.0231 (3)
H15	0.6815	0.5125	−0.0537	0.028*
C9	0.80998 (18)	0.36854 (8)	0.01721 (7)	0.0207 (2)
H12	0.9166	0.3568	0.0457	0.025*
C10	0.8569 (2)	0.37134 (10)	−0.06505 (8)	0.0268 (3)
H14A	0.7523	0.3781	−0.0940	0.040*
H14B	0.9138	0.3202	−0.0789	0.040*
H14C	0.9343	0.4175	−0.0742	0.040*
C8	0.8120 (2)	0.36434 (9)	0.32175 (8)	0.0270 (3)
H22A	0.7336	0.3259	0.2978	0.041*
H22B	0.8245	0.3494	0.3733	0.041*
H22C	0.9242	0.3621	0.2978	0.041*

Atomic displacement parameters (Å²) top

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
O6	0.0465 (6)	0.0262 (5)	0.0168 (4)	0.0047 (5)	0.0021 (4)	−0.0026 (4)
N4	0.0284 (6)	0.0188 (5)	0.0301 (6)	−0.0002 (5)	−0.0001 (5)	0.0018 (4)
C14	0.0220 (6)	0.0178 (5)	0.0179 (5)	−0.0014 (5)	0.0023 (4)	−0.0004 (4)
N6	0.0256 (5)	0.0189 (5)	0.0169 (5)	0.0000 (4)	0.0010 (4)	−0.0004 (4)
C16	0.0227 (5)	0.0177 (5)	0.0201 (5)	−0.0023 (5)	0.0020 (5)	−0.0006 (4)
C18	0.0282 (6)	0.0230 (6)	0.0187 (6)	−0.0020 (5)	0.0006 (5)	0.0012 (5)
C13	0.0250 (6)	0.0192 (5)	0.0185 (5)	−0.0004 (5)	0.0031 (5)	−0.0010 (4)
O5	0.0549 (8)	0.0277 (6)	0.0377 (7)	0.0083 (6)	−0.0124 (6)	0.0042 (5)
C17	0.0233 (6)	0.0171 (5)	0.0236 (6)	−0.0016 (5)	0.0014 (5)	0.0007 (5)
C12	0.0277 (6)	0.0225 (6)	0.0165 (5)	−0.0024 (5)	0.0026 (5)	−0.0004 (5)
N5	0.0296 (6)	0.0204 (5)	0.0207 (5)	−0.0006 (4)	0.0031 (4)	−0.0032 (4)
O4	0.0650 (9)	0.0257 (5)	0.0402 (7)	0.0130 (6)	−0.0125 (7)	−0.0092 (5)
C21	0.0304 (7)	0.0203 (6)	0.0266 (6)	−0.0002 (5)	0.0000 (5)	−0.0001 (5)
C19	0.0358 (8)	0.0259 (7)	0.0252 (6)	−0.0001 (6)	0.0027 (6)	−0.0064 (5)
C20	0.0237 (6)	0.0210 (6)	0.0218 (6)	0.0029 (5)	0.0009 (5)	0.0013 (5)
C15	0.0294 (7)	0.0218 (6)	0.0194 (6)	−0.0021 (5)	0.0019 (5)	−0.0031 (5)
C22	0.0319 (7)	0.0327 (7)	0.0254 (7)	0.0010 (6)	−0.0068 (6)	0.0043 (6)
C5	0.0221 (5)	0.0175 (5)	0.0204 (6)	−0.0012 (5)	−0.0016 (5)	−0.0002 (4)
N1	0.0285 (6)	0.0191 (5)	0.0296 (6)	0.0024 (4)	−0.0017 (5)	−0.0039 (5)
O3	0.0439 (6)	0.0263 (5)	0.0167 (4)	0.0065 (5)	−0.0040 (4)	0.0010 (4)
C6	0.0228 (6)	0.0167 (5)	0.0230 (6)	0.0002 (5)	−0.0020 (5)	−0.0028 (5)
N3	0.0256 (5)	0.0179 (5)	0.0157 (4)	0.0001 (4)	−0.0005 (4)	−0.0007 (4)
C3	0.0215 (5)	0.0170 (5)	0.0170 (5)	−0.0018 (5)	−0.0001 (4)	−0.0016 (4)
C1	0.0257 (6)	0.0225 (6)	0.0162 (5)	−0.0012 (5)	−0.0023 (5)	−0.0003 (5)
C2	0.0247 (6)	0.0187 (5)	0.0181 (5)	0.0000 (5)	−0.0021 (5)	0.0001 (4)
N2	0.0291 (6)	0.0197 (5)	0.0210 (5)	0.0005 (4)	−0.0031 (4)	0.0008 (4)
C7	0.0275 (6)	0.0226 (6)	0.0185 (5)	0.0001 (5)	−0.0022 (5)	−0.0032 (5)
O1	0.0723 (10)	0.0350 (7)	0.0405 (8)	0.0216 (7)	−0.0183 (7)	−0.0192 (6)
O2	0.0425 (7)	0.0281 (5)	0.0320 (6)	0.0112 (5)	−0.0047 (5)	0.0008 (4)
C11	0.0312 (7)	0.0197 (6)	0.0247 (6)	−0.0003 (5)	0.0022 (5)	−0.0016 (5)
C4	0.0292 (6)	0.0214 (6)	0.0187 (6)	−0.0005 (5)	−0.0022 (5)	0.0017 (5)
C9	0.0237 (6)	0.0195 (5)	0.0189 (5)	0.0024 (5)	0.0000 (5)	−0.0020 (4)
C10	0.0306 (7)	0.0297 (7)	0.0201 (6)	0.0021 (6)	0.0036 (5)	−0.0017 (5)
C8	0.0335 (7)	0.0232 (6)	0.0243 (6)	−0.0003 (6)	−0.0019 (6)	0.0051 (5)

Geometric parameters (Å, º) top

O6—C12	1.3649 (16)	C5—N2	1.3846 (17)
O6—C19	1.4312 (18)	C5—C6	1.4035 (18)
N4—O4	1.2229 (17)	C5—C3	1.4122 (18)
N4—O5	1.2279 (18)	N1—O2	1.2231 (17)
N4—C17	1.4635 (17)	N1—O1	1.2277 (17)
C14—N6	1.3807 (16)	N1—C6	1.4615 (17)
C14—C13	1.3986 (17)	O3—C1	1.3659 (16)
C14—C16	1.4131 (18)	O3—C8	1.4314 (17)
N6—C15	1.3643 (17)	C6—C7	1.3781 (19)
N6—C20	1.4805 (16)	N3—C4	1.3620 (17)
C16—N5	1.3879 (17)	N3—C3	1.3800 (16)
C16—C17	1.4022 (18)	N3—C9	1.4820 (16)
C18—C17	1.3810 (19)	C3—C2	1.3955 (17)
C18—C12	1.408 (2)	C1—C2	1.3907 (18)
C18—H5	0.9300	C1—C7	1.4073 (19)
C13—C12	1.3908 (18)	C2—H18	0.9300
C13—H7	0.9300	N2—C4	1.3179 (18)
N5—C15	1.3153 (18)	C7—H20	0.9300
C21—C20	1.524 (2)	C11—C9	1.5195 (19)
C21—H9A	0.9600	C11—H13A	0.9600
C21—H9B	0.9600	C11—H13B	0.9600
C21—H9C	0.9600	C11—H13C	0.9600
C19—H11A	0.9600	C4—H15	0.9300
C19—H11B	0.9600	C9—C10	1.5202 (19)
C19—H11C	0.9600	C9—H12	0.9800
C20—C22	1.520 (2)	C10—H14A	0.9600
C20—H8	0.9800	C10—H14B	0.9600
C15—H1	0.9300	C10—H14C	0.9600
C22—H10A	0.9600	C8—H22A	0.9600
C22—H10B	0.9600	C8—H22B	0.9600
C22—H10C	0.9600	C8—H22C	0.9600

C12—O6—C19	116.63 (11)	N2—C5—C6	133.21 (12)
O4—N4—O5	123.03 (13)	N2—C5—C3	110.51 (11)
O4—N4—C17	118.16 (12)	C6—C5—C3	116.26 (11)
O5—N4—C17	118.82 (13)	O2—N1—O1	122.99 (13)
N6—C14—C13	130.20 (12)	O2—N1—C6	118.27 (12)
N6—C14—C16	105.27 (11)	O1—N1—C6	118.75 (13)
C13—C14—C16	124.53 (12)	C1—O3—C8	116.52 (11)
C15—N6—C14	105.88 (11)	C7—C6—C5	121.09 (12)
C15—N6—C20	128.35 (11)	C7—C6—N1	117.39 (12)
C14—N6—C20	125.65 (11)	C5—C6—N1	121.51 (12)
N5—C16—C17	133.37 (12)	C4—N3—C3	106.19 (11)
N5—C16—C14	110.28 (11)	C4—N3—C9	128.25 (11)
C17—C16—C14	116.30 (11)	C3—N3—C9	125.47 (11)
C17—C18—C12	120.35 (12)	N3—C3—C2	130.47 (12)
C17—C18—H5	119.8	N3—C3—C5	105.00 (11)
C12—C18—H5	119.8	C2—C3—C5	124.53 (12)
C12—C13—C14	116.29 (12)	O3—C1—C2	124.77 (12)
C12—C13—H7	121.9	O3—C1—C7	114.03 (11)
C14—C13—H7	121.9	C2—C1—C7	121.20 (12)
C18—C17—C16	121.13 (12)	C1—C2—C3	116.45 (12)
C18—C17—N4	117.00 (12)	C1—C2—H18	121.8
C16—C17—N4	121.87 (12)	C3—C2—H18	121.8
O6—C12—C13	124.43 (13)	C4—N2—C5	103.73 (11)
O6—C12—C18	114.21 (12)	C6—C7—C1	120.47 (12)
C13—C12—C18	121.36 (12)	C6—C7—H20	119.8
C15—N5—C16	103.74 (11)	C1—C7—H20	119.8
C20—C21—H9A	109.5	C9—C11—H13A	109.5
C20—C21—H9B	109.5	C9—C11—H13B	109.5
H9A—C21—H9B	109.5	H13A—C11—H13B	109.5
C20—C21—H9C	109.5	C9—C11—H13C	109.5
H9A—C21—H9C	109.5	H13A—C11—H13C	109.5
H9B—C21—H9C	109.5	H13B—C11—H13C	109.5
O6—C19—H11A	109.5	N2—C4—N3	114.57 (12)
O6—C19—H11B	109.5	N2—C4—H15	122.7
H11A—C19—H11B	109.5	N3—C4—H15	122.7
O6—C19—H11C	109.5	N3—C9—C10	110.01 (11)
H11A—C19—H11C	109.5	N3—C9—C11	110.34 (11)
H11B—C19—H11C	109.5	C10—C9—C11	111.10 (12)
N6—C20—C22	109.87 (11)	N3—C9—H12	108.4
N6—C20—C21	110.38 (11)	C10—C9—H12	108.4
C22—C20—C21	110.53 (12)	C11—C9—H12	108.4
N6—C20—H8	108.7	C9—C10—H14A	109.5
C22—C20—H8	108.7	C9—C10—H14B	109.5
C21—C20—H8	108.7	H14A—C10—H14B	109.5
N5—C15—N6	114.83 (12)	C9—C10—H14C	109.5
N5—C15—H1	122.6	H14A—C10—H14C	109.5
N6—C15—H1	122.6	H14B—C10—H14C	109.5
C20—C22—H10A	109.5	O3—C8—H22A	109.5
C20—C22—H10B	109.5	O3—C8—H22B	109.5
H10A—C22—H10B	109.5	H22A—C8—H22B	109.5
C20—C22—H10C	109.5	O3—C8—H22C	109.5
H10A—C22—H10C	109.5	H22A—C8—H22C	109.5
H10B—C22—H10C	109.5	H22B—C8—H22C	109.5

Hydrogen-bond geometry (Å, º) top

D—H···A	D—H	H···A	D···A	D—H···A
C15—H1···O6ⁱ	0.93	2.46	3.3670 (8)	164
C4—H15···O3ⁱⁱ	0.93	2.49	3.3723 (8)	159

Symmetry codes: (i) −x+1/2, −y+1, z+1/2; (ii) −x+3/2, −y+1, z−1/2.

Experimental details

Crystal data
Chemical formula	C₁₁H₁₃N₃O₃
M_r	235.24
Crystal system, space group	Orthorhombic, P2₁2₁2₁
Temperature (K)	150
a, b, c (Å)	7.6392 (1), 16.0029 (3), 17.9496 (3)
V (Å³)	2194.33 (6)
Z	8
Radiation type	Mo Kα
µ (mm⁻¹)	0.11
Crystal size (mm)	0.43 × 0.33 × 0.28

Data collection
Diffractometer	Bruker SMART APEXII diffractometer
Absorption correction	Multi-scan (SADABS; Sheldrick, 2002)
T_min, T_max	0.959, 0.971
No. of measured, independent and observed [I > 2σ(I)] reflections	39389, 3989, 3649
R_int	0.026
(sin θ/λ)_max (Å⁻¹)	0.728

Refinement
R[F² > 2σ(F²)], wR(F²), S	0.034, 0.099, 1.09
No. of reflections	3989
No. of parameters	313
H-atom treatment	H-atom parameters constrained
Δρ_max, Δρ_min (e Å⁻³)	0.47, −0.20

Computer programs: SMART (Bruker, 1998), SAINT (Bruker, 1998), SHELXS97 (Sheldrick, 2008), SHELXL97 (Sheldrick, 2008), SHELXTL (Sheldrick, 2008) and PLATON (Spek, 2003), ORTEP-3 for Windows (Farrugia, 1997).

Hydrogen-bond geometry (Å, º) top

D—H···A	D—H	H···A	D···A	D—H···A
C15—H1···O6ⁱ	0.93	2.46	3.3670 (8)	164
C4—H15···O3ⁱⁱ	0.93	2.49	3.3723 (8)	159

Symmetry codes: (i) −x+1/2, −y+1, z+1/2; (ii) −x+3/2, −y+1, z−1/2.

Acknowledgements

Financial support from Duquesne University (Mylan School of Pharmacy), an equipment grant from the National Science Foundation (NMR: CHE 0614785), and an NSF X-ray facility grant (CRIF 0234872) are gratefully acknowledged.

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