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Acta Crystallogr Sect E Struct Rep Online. 2009 October 1; 65(Pt 10): o2353.
Published online 2009 September 5. doi:  10.1107/S1600536809034667
PMCID: PMC2970210

Methyl 5,6-dimeth­oxy-1H-indole-2-carboxyl­ate

Abstract

The title compound, C12H13NO4, was prepared as a precursor to an indole derivative with possible anti­mitotic properties. The mol­ecule is very nearly planar; the maximum deviation of any non-H atom from the mean plane of the indole ring is 0.120 (3) Å for each of two meth­oxy C atoms. The pairs of mol­ecules related by the inversion centre at (0,0,An external file that holds a picture, illustration, etc.
Object name is e-65-o2353-efi1.jpg) are connected by two symmetry-equivalent N—H(...)O hydrogen bonds, while the pairs of mol­ecules related by the inversion centre at (0,0,0) exhibit a π-stacking inter­action of the indole rings, with an inter­planar separation of 3.39 (3) Å.

Related literature

For related structures see: Shoja (1988a [triangle],b [triangle]). For pharmaceutical applications see: Fuwa & Sasaki (2009 [triangle]); Li & Martins (2003 [triangle]). For a study of π–π packing inter­actions see: Janiak (2000 [triangle]).

An external file that holds a picture, illustration, etc.
Object name is e-65-o2353-scheme1.jpg

Experimental

Crystal data

  • C12H13NO4
  • M r = 235.23
  • Orthorhombic, An external file that holds a picture, illustration, etc.
Object name is e-65-o2353-efi2.jpg
  • a = 17.0768 (19) Å
  • b = 7.7232 (11) Å
  • c = 17.678 (2) Å
  • V = 2331.5 (5) Å3
  • Z = 8
  • Cu Kα radiation
  • μ = 0.85 mm−1
  • T = 295 K
  • 0.36 × 0.22 × 0.21 mm

Data collection

  • Enraf–Nonius CAD-4 diffractometer
  • Absorption correction: none
  • 9909 measured reflections
  • 2098 independent reflections
  • 1522 reflections with I > 2σ(I)
  • R int = 0.030
  • 3 standard reflections every 171 reflections intensity decay: 1%

Refinement

  • R[F 2 > 2σ(F 2)] = 0.035
  • wR(F 2) = 0.102
  • S = 1.02
  • 2098 reflections
  • 162 parameters
  • H atoms treated by a mixture of independent and constrained refinement
  • Δρmax = 0.14 e Å−3
  • Δρmin = −0.12 e Å−3

Data collection: CAD-4 EXPRESS (Enraf–Nonius, 1994 [triangle]); cell refinement: CAD-4 EXPRESS; data reduction: XCAD4 (Harms & Wocadlo, 1995 [triangle]); program(s) used to solve structure: SHELXS97 (Sheldrick, 2008 [triangle]); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008 [triangle]); molecular graphics: ORTEP-3 for Windows (Farrugia, 1997 [triangle]) and Mercury (Macrae et al., 2006 [triangle]); software used to prepare material for publication: WinGX (Farrugia, 1999 [triangle]).

Table 1
Hydrogen-bond geometry (Å, °)

Supplementary Material

Crystal structure: contains datablocks global, I. DOI: 10.1107/S1600536809034667/fj2241sup1.cif

Structure factors: contains datablocks I. DOI: 10.1107/S1600536809034667/fj2241Isup2.hkl

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

Acknowledgments

This work was supported in part by funds provided by the University of North Carolina at Charlotte. Support for REU participant TBM was provided by the National Science Foundation, award number CHE-0851797.

supplementary crystallographic information

Comment

The indole core is a common structure observed in a wide variety of biologically active compounds and pharmaceutical products (Li & Martins, 2003). Indole structures are considered as privileged structure motifs, due to their ability to bind many receptors within the body (Fuwa & Sasaki, 2009). As a result, a great deal of research has been dedicated to incorporating the indole functionality in the design and synthesis of anti-mitotic compounds for the treatment of cancer. The title compound was prepared as a precursor to an indole derivative with possible anti-mitotic properties.

The title molecule is nearly planar; the deviations of the methoxy carbons from the indole mean plane are 0.058 (3) Å, 0.119 (3) Å, and -0.120 (3) Å for C13, C12, and C11, respectively. These values can be compared with those for two similar structures. In 5,6-Dimethoxyindole (Shoja, 1988a) one of the methoxy carbon atoms was out of the plane by 0.257 (4) Å, while in 5,6-Dimethoxy-1-indanone (Shoja, 1988b) one of the methoxy carbon atoms was out of the plane of the aromatic ring by 0.270 Å.

The members of each pair of molecules related by inversions at (0,0,1/2) are joined by two symmetry-equivalent N—H···O hydrogen bonds, as shown in Figure 2 and described in Table 1. The indole ring system of each pair of molecules related by inversions at (0,0,0) exhibit π-π interactions, as shown in Figure 3. An exhaustive study has been made of structures in the Cambridge Structural Database which show π-π interactions between nitrogen-containing aromatic ring systems (Janiak, 2000). This study showed that parallel ring systems which interact are offset by an amount related to the distance between ring centroids. The planes of the indole rings of the present structure are 3.39 (3) Å apart, and the centroid-centroid line makes an angle of 23.8° with the normal to the plane of the indole rings. These values are in agreement with those found for similar systems in the Janiak study. The π-π interactions may account for the near-planarity of the molecule.

Experimental

Preparation of title compound (IV): In a two-necked round-bottomed flask containing 2 ml of methanol, 244 mg (1.47 mmol) of 3,4-dimethoxybenzaldehyde (I) (commercially available) and 575 mg (5.0 mmol) of methyl 2-azidoacetate (II) were dissolved under N2. This solution was cooled to 0 °C in an ice bath. Freshly prepared NaOMe in methanol was added to the mixture of the aldehyde and the azide compounds drop-wise over 15 minutes. The mixture gradually formed a slurry upon reacting with the NaOMe. The reaction was further stirred for 2.5 h and then poured into 50 ml of water. This resulted in the formation of a solid yellow precipitate (III) which was separated from the liquid by suction filtration. The solid (III) was then dissolved in 3 ml of toluene and transferred to a clean, dry microwave reactor vessel equipped with a stir bar. The vessel was sealed with a septum and heated in the microwave reactor at 130 °C for 30 minutes. At the end of heating the vessel was purged with a needle to release the gas pressure. The final product (IV) crystallized from the toluene and was separated by suction filtration in 70% yield.

Refinement

H1, the hydrogen atom bonded to N, was located in a difference map and refined. All other H atoms were constrained using a riding model. The aromatic C—H bond lengths were fixed at 0.93 Å and the methyl C—H bond lengths at 0.96 Å, with Uiso(H) = 1.5 Ueq. (C). An idealized tetrahedral geometry was used for the methyl groups, and the torsion angles around the O—C bonds were refined.

Figures

Fig. 1.
View of the title compound (50% probability displacement ellipsoids).
Fig. 2.
Packing diagram showing the hydrogen bonding between molecules related by inversions at (0,0,1/2).
Fig. 3.
Packing diagram showing the π–π interactions between molecules related by inversions at (0,0,0).
Fig. 4.
Synthesis scheme

Crystal data

C12H13NO4F(000) = 992
Mr = 235.23Dx = 1.34 Mg m3
Orthorhombic, PbcaCu Kα radiation, λ = 1.54184 Å
Hall symbol: -P 2ac 2abCell parameters from 25 reflections
a = 17.0768 (19) Åθ = 10.0–43.0°
b = 7.7232 (11) ŵ = 0.85 mm1
c = 17.678 (2) ÅT = 295 K
V = 2331.5 (5) Å3Prism, colourless
Z = 80.36 × 0.22 × 0.21 mm

Data collection

Enraf–Nonius CAD-4 diffractometerθmax = 67.4°, θmin = 5°
Non–profiled ω/2θ scansh = −20→20
9909 measured reflectionsk = 0→9
2098 independent reflectionsl = −21→21
1522 reflections with I > 2σ(I)3 standard reflections every 171 reflections
Rint = 0.030 intensity decay: 1%

Refinement

Refinement on F2H atoms treated by a mixture of independent and constrained refinement
Least-squares matrix: fullw = 1/[σ2(Fo2) + (0.0613P)2 + 0.2248P] where P = (Fo2 + 2Fc2)/3
R[F2 > 2σ(F2)] = 0.035(Δ/σ)max < 0.001
wR(F2) = 0.102Δρmax = 0.14 e Å3
S = 1.02Δρmin = −0.12 e Å3
2098 reflectionsExtinction correction: SHELXL97 (Sheldrick, 2008), Fc*=kFc[1+0.001xFc2λ3/sin(2θ)]-1/4
162 parametersExtinction coefficient: 0.0047 (4)
0 restraints

Special details

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

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

xyzUiso*/Ueq
N0.05760 (8)0.76815 (19)0.51504 (7)0.0509 (3)
O10.07015 (8)1.05091 (17)0.41553 (7)0.0727 (4)
O20.17099 (7)0.92154 (18)0.35786 (7)0.0722 (4)
O30.00702 (6)0.30330 (14)0.69682 (6)0.0564 (3)
O40.12332 (7)0.14080 (15)0.64271 (7)0.0656 (4)
C20.11320 (9)0.7786 (2)0.45863 (8)0.0516 (4)
C30.15832 (9)0.6316 (2)0.46040 (8)0.0530 (4)
H30.20010.60620.42850.064*
C40.15041 (8)0.3618 (2)0.54858 (8)0.0495 (4)
H40.19180.29970.52770.059*
C50.10882 (9)0.2958 (2)0.60783 (8)0.0476 (4)
C60.04402 (8)0.3882 (2)0.63953 (8)0.0453 (4)
C70.02331 (8)0.5479 (2)0.61286 (8)0.0459 (4)
H7−0.0180.60960.6340.055*
C80.06679 (8)0.6150 (2)0.55251 (8)0.0448 (4)
C90.12971 (8)0.5256 (2)0.51953 (8)0.0466 (4)
C100.11447 (10)0.9300 (2)0.41017 (9)0.0556 (4)
C110.17434 (13)1.0657 (4)0.30566 (12)0.0936 (8)
H11A0.12711.06930.27630.14*
H11B0.21841.05170.27250.14*
H11C0.17971.17180.33350.14*
C120.18869 (10)0.0457 (2)0.61719 (11)0.0661 (5)
H12A0.18260.02010.56440.099*
H12B0.1925−0.06040.64520.099*
H12C0.23540.11280.62460.099*
C13−0.05334 (10)0.3942 (2)0.73565 (10)0.0622 (5)
H13A−0.03240.49890.75680.093*
H13B−0.07370.32280.77550.093*
H13C−0.09460.42210.70090.093*
H10.0202 (10)0.852 (2)0.5251 (10)0.064 (5)*

Atomic displacement parameters (Å2)

U11U22U33U12U13U23
N0.0517 (7)0.0518 (8)0.0492 (7)−0.0002 (6)0.0024 (6)0.0013 (6)
O10.0850 (9)0.0656 (9)0.0676 (8)0.0067 (7)0.0120 (7)0.0111 (6)
O20.0623 (7)0.0919 (10)0.0624 (7)0.0005 (7)0.0096 (6)0.0236 (7)
O30.0601 (6)0.0515 (7)0.0576 (6)0.0056 (5)0.0185 (5)0.0030 (5)
O40.0607 (7)0.0554 (7)0.0806 (8)0.0140 (6)0.0226 (6)0.0125 (6)
C20.0472 (8)0.0623 (10)0.0454 (8)−0.0074 (8)−0.0004 (7)0.0008 (7)
C30.0422 (8)0.0693 (11)0.0475 (8)−0.0042 (8)0.0021 (6)0.0007 (8)
C40.0390 (7)0.0577 (10)0.0517 (8)0.0014 (7)0.0033 (6)−0.0050 (8)
C50.0442 (8)0.0465 (9)0.0520 (8)0.0006 (6)0.0013 (6)−0.0026 (7)
C60.0437 (7)0.0482 (9)0.0438 (7)−0.0035 (7)0.0026 (6)−0.0036 (7)
C70.0435 (8)0.0486 (9)0.0457 (8)0.0003 (7)0.0029 (6)−0.0069 (7)
C80.0431 (7)0.0474 (8)0.0438 (7)−0.0037 (6)−0.0037 (6)−0.0030 (7)
C90.0375 (7)0.0583 (10)0.0441 (7)−0.0041 (7)−0.0016 (6)−0.0028 (7)
C100.0522 (9)0.0675 (11)0.0470 (8)−0.0070 (9)−0.0033 (7)0.0026 (8)
C110.0829 (14)0.124 (2)0.0739 (12)−0.0071 (13)0.0069 (11)0.0451 (13)
C120.0582 (10)0.0595 (11)0.0806 (12)0.0141 (9)0.0098 (9)0.0036 (9)
C130.0647 (10)0.0622 (10)0.0598 (10)0.0076 (9)0.0219 (8)0.0008 (9)

Geometric parameters (Å, °)

N—C81.365 (2)C4—H40.93
N—C21.3792 (19)C5—C61.431 (2)
N—H10.926 (19)C6—C71.367 (2)
O1—C101.206 (2)C7—C81.399 (2)
O2—C101.338 (2)C7—H70.93
O2—C111.447 (2)C8—C91.404 (2)
O3—C61.3619 (18)C11—H11A0.96
O3—C131.4235 (19)C11—H11B0.96
O4—C51.3695 (19)C11—H11C0.96
O4—C121.410 (2)C12—H12A0.96
C2—C31.373 (2)C12—H12B0.96
C2—C101.449 (2)C12—H12C0.96
C3—C91.415 (2)C13—H13A0.96
C3—H30.93C13—H13B0.96
C4—C51.364 (2)C13—H13C0.96
C4—C91.410 (2)
C8—N—C2108.82 (14)C7—C8—C9122.74 (14)
C8—N—H1126.2 (11)C8—C9—C4118.80 (14)
C2—N—H1125.0 (11)C8—C9—C3106.66 (14)
C10—O2—C11115.57 (16)C4—C9—C3134.55 (14)
C6—O3—C13117.19 (12)O1—C10—O2123.01 (16)
C5—O4—C12117.03 (13)O1—C10—C2124.67 (15)
C3—C2—N108.74 (14)O2—C10—C2112.32 (16)
C3—C2—C10132.24 (14)O2—C11—H11A109.5
N—C2—C10119.01 (15)O2—C11—H11B109.5
C2—C3—C9107.56 (14)H11A—C11—H11B109.5
C2—C3—H3126.2O2—C11—H11C109.5
C9—C3—H3126.2H11A—C11—H11C109.5
C5—C4—C9118.94 (14)H11B—C11—H11C109.5
C5—C4—H4120.5O4—C12—H12A109.5
C9—C4—H4120.5O4—C12—H12B109.5
C4—C5—O4125.31 (14)H12A—C12—H12B109.5
C4—C5—C6121.15 (15)O4—C12—H12C109.5
O4—C5—C6113.54 (13)H12A—C12—H12C109.5
O3—C6—C7124.82 (13)H12B—C12—H12C109.5
O3—C6—C5114.20 (13)O3—C13—H13A109.5
C7—C6—C5120.98 (14)O3—C13—H13B109.5
C6—C7—C8117.36 (13)H13A—C13—H13B109.5
C6—C7—H7121.3O3—C13—H13C109.5
C8—C7—H7121.3H13A—C13—H13C109.5
N—C8—C7129.03 (14)H13B—C13—H13C109.5
N—C8—C9108.22 (13)

Hydrogen-bond geometry (Å, °)

D—H···AD—HH···AD···AD—H···A
N—H1···O1i0.926 (19)2.011 (19)2.867 (2)152.9 (16)

Symmetry codes: (i) −x, −y+2, −z+1.

Footnotes

Supplementary data and figures for this paper are available from the IUCr electronic archives (Reference: FJ2241).

References

  • Enraf–Nonius (1994). CAD-4 EXPRESS Enraf–Nonius, Delft, The Netherlands.
  • Farrugia, L. J. (1997). J. Appl. Cryst.30, 565.
  • Farrugia, L. J. (1999). J. Appl. Cryst.32, 837–838.
  • Fuwa, H. & Sasaki, M. (2009). J. Org. Chem.74, 212–221. [PubMed]
  • Harms, K. & Wocadlo, S. (1995). XCAD4 University of Marburg, Germany.
  • Janiak, C. (2000). J. Chem. Soc. Dalton Trans. pp. 3885–3896.
  • Li, L. & Martins, A. (2003). Tetrahedron Lett 44, 5987–5990.
  • Macrae, C. F., Edgington, P. R., McCabe, P., Pidcock, E., Shields, G. P., Taylor, R., Towler, M. & van de Streek, J. (2006). J. Appl. Cryst.39, 453–457.
  • Sheldrick, G. M. (2008). Acta Cryst. A64, 112–122. [PubMed]
  • Shoja, M. (1988a). Acta Cryst. C44, 2238–2239.
  • Shoja, M. (1988b). Acta Cryst. C44, 1496–1497.

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