organic compounds\(\def\hfill{\hskip 5em}\def\hfil{\hskip 3em}\def\eqno#1{\hfil {#1}}\)

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ISSN: 2056-9890

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

aDepartment of Chemistry, The University of North Carolina at Charlotte, 9201 University City Blvd, Charlotte, NC 28223, USA
*Correspondence e-mail: djones@uncc.edu, cogle@uncc.edu

(Received 21 July 2009; accepted 28 August 2009; online 5 September 2009)

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,[1\over2]) 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[Shoja, M. (1988a). Acta Cryst. C44, 2238-2239.],b[Shoja, M. (1988b). Acta Cryst. C44, 1496-1497.]). For pharmaceutical applications see: Fuwa & Sasaki (2009[Fuwa, H. & Sasaki, M. (2009). J. Org. Chem. 74, 212-221.]); Li & Martins (2003[Li, L. & Martins, A. (2003). Tetrahedron Lett. 44, 5987-5990.]). For a study of ππ packing inter­actions see: Janiak (2000[Janiak, C. (2000). J. Chem. Soc. Dalton Trans. pp. 3885-3896.]).

[Scheme 1]

Experimental

Crystal data
  • C12H13NO4

  • Mr = 235.23

  • Orthorhombic, P b c a

  • 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)

  • Rint = 0.030

  • 3 standard reflections every 171 reflections intensity decay: 1%

Refinement
  • R[F2 > 2σ(F2)] = 0.035

  • wR(F2) = 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

Table 1
Hydrogen-bond geometry (Å, °)

D—H⋯A D—H H⋯A DA D—H⋯A
N—H1⋯O1i 0.926 (19) 2.011 (19) 2.867 (2) 152.9 (16)
Symmetry code: (i) -x, -y+2, -z+1.

Data collection: CAD-4 EXPRESS (Enraf–Nonius, 1994[Enraf-Nonius (1994). CAD-4 EXPRESS. Enraf-Nonius, Delft, The Netherlands.]); cell refinement: CAD-4 EXPRESS; data reduction: XCAD4 (Harms & Wocadlo, 1995[Harms, K. & Wocadlo, S. (1995). XCAD4. University of Marburg, Germany.]); program(s) used to solve structure: SHELXS97 (Sheldrick, 2008[Sheldrick, G. M. (2008). Acta Cryst. A64, 112-122.]); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008[Sheldrick, G. M. (2008). Acta Cryst. A64, 112-122.]); molecular graphics: ORTEP-3 for Windows (Farrugia, 1997[Farrugia, L. J. (1997). J. Appl. Cryst. 30, 565.]) and Mercury (Macrae et al., 2006[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.]); software used to prepare material for publication: WinGX (Farrugia, 1999[Farrugia, L. J. (1999). J. Appl. Cryst. 32, 837-838.]).

Supporting information


Comment top

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.

Related literature top

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

Experimental top

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 top

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.

Computing details top

Data collection: CAD-4 EXPRESS (Enraf–Nonius, 1994); cell refinement: CAD-4 EXPRESS (Enraf–Nonius, 1994); data reduction: XCAD4 (Harms & Wocadlo, 1995); 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) and Mercury (Macrae et al., 2006); software used to prepare material for publication: WinGX (Farrugia, 1999).

Figures top
[Figure 1] Fig. 1. View of the title compound (50% probability displacement ellipsoids).
[Figure 2] Fig. 2. Packing diagram showing the hydrogen bonding between molecules related by inversions at (0,0,1/2).
[Figure 3] Fig. 3. Packing diagram showing the ππ interactions between molecules related by inversions at (0,0,0).
[Figure 4] Fig. 4. Synthesis scheme
Methyl 5,6-dimethoxy-1H-indole-2-carboxylate top
Crystal data top
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 top
Enraf–Nonius CAD-4
diffractometer
θmax = 67.4°, θmin = 5°
Non–profiled ω/2θ scansh = 2020
9909 measured reflectionsk = 09
2098 independent reflectionsl = 2121
1522 reflections with I > 2σ(I)3 standard reflections every 171 reflections
Rint = 0.030 intensity decay: 1%
Refinement top
Refinement on F2H atoms treated by a mixture of independent and constrained refinement
Least-squares matrix: full w = 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
Crystal data top
C12H13NO4V = 2331.5 (5) Å3
Mr = 235.23Z = 8
Orthorhombic, PbcaCu Kα radiation
a = 17.0768 (19) ŵ = 0.85 mm1
b = 7.7232 (11) ÅT = 295 K
c = 17.678 (2) Å0.36 × 0.22 × 0.21 mm
Data collection top
Enraf–Nonius CAD-4
diffractometer
Rint = 0.030
9909 measured reflections3 standard reflections every 171 reflections
2098 independent reflections intensity decay: 1%
1522 reflections with I > 2σ(I)
Refinement top
R[F2 > 2σ(F2)] = 0.0350 restraints
wR(F2) = 0.102H atoms treated by a mixture of independent and constrained refinement
S = 1.02Δρmax = 0.14 e Å3
2098 reflectionsΔρmin = 0.12 e Å3
162 parameters
Special details top

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) top
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)
H70.0180.60960.6340.055*
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*
H12B0.19250.06040.64520.099*
H12C0.23540.11280.62460.099*
C130.05334 (10)0.3942 (2)0.73565 (10)0.0622 (5)
H13A0.03240.49890.75680.093*
H13B0.07370.32280.77550.093*
H13C0.09460.42210.70090.093*
H10.0202 (10)0.852 (2)0.5251 (10)0.064 (5)*
Atomic displacement parameters (Å2) top
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, º) top
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, º) top
D—H···AD—HH···AD···AD—H···A
N—H1···O1i0.926 (19)2.011 (19)2.867 (2)152.9 (16)
Symmetry code: (i) x, y+2, z+1.

Experimental details

Crystal data
Chemical formulaC12H13NO4
Mr235.23
Crystal system, space groupOrthorhombic, Pbca
Temperature (K)295
a, b, c (Å)17.0768 (19), 7.7232 (11), 17.678 (2)
V3)2331.5 (5)
Z8
Radiation typeCu Kα
µ (mm1)0.85
Crystal size (mm)0.36 × 0.22 × 0.21
Data collection
DiffractometerEnraf–Nonius CAD-4
diffractometer
Absorption correction
No. of measured, independent and
observed [I > 2σ(I)] reflections
9909, 2098, 1522
Rint0.030
(sin θ/λ)max1)0.599
Refinement
R[F2 > 2σ(F2)], wR(F2), S 0.035, 0.102, 1.02
No. of reflections2098
No. of parameters162
H-atom treatmentH atoms treated by a mixture of independent and constrained refinement
Δρmax, Δρmin (e Å3)0.14, 0.12

Computer programs: CAD-4 EXPRESS (Enraf–Nonius, 1994), XCAD4 (Harms & Wocadlo, 1995), SHELXS97 (Sheldrick, 2008), SHELXL97 (Sheldrick, 2008), ORTEP-3 for Windows (Farrugia, 1997) and Mercury (Macrae et al., 2006), WinGX (Farrugia, 1999).

Hydrogen-bond geometry (Å, º) top
D—H···AD—HH···AD···AD—H···A
N—H1···O1i0.926 (19)2.011 (19)2.867 (2)152.9 (16)
Symmetry code: (i) x, y+2, z+1.
 

Acknowledgements

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.

References

First citationEnraf–Nonius (1994). CAD-4 EXPRESS. Enraf–Nonius, Delft, The Netherlands.  Google Scholar
First citationFarrugia, L. J. (1997). J. Appl. Cryst. 30, 565.  CrossRef IUCr Journals Google Scholar
First citationFarrugia, L. J. (1999). J. Appl. Cryst. 32, 837–838.  CrossRef CAS IUCr Journals Google Scholar
First citationFuwa, H. & Sasaki, M. (2009). J. Org. Chem. 74, 212–221.  Web of Science CrossRef PubMed CAS Google Scholar
First citationHarms, K. & Wocadlo, S. (1995). XCAD4. University of Marburg, Germany.  Google Scholar
First citationJaniak, C. (2000). J. Chem. Soc. Dalton Trans. pp. 3885–3896.  Web of Science CrossRef Google Scholar
First citationLi, L. & Martins, A. (2003). Tetrahedron Lett. 44, 5987–5990.  Web of Science CrossRef CAS Google Scholar
First citationMacrae, 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.  Web of Science CrossRef CAS IUCr Journals Google Scholar
First citationSheldrick, G. M. (2008). Acta Cryst. A64, 112–122.  Web of Science CrossRef CAS IUCr Journals Google Scholar
First citationShoja, M. (1988a). Acta Cryst. C44, 2238–2239.  CSD CrossRef CAS Web of Science IUCr Journals Google Scholar
First citationShoja, M. (1988b). Acta Cryst. C44, 1496–1497.  CSD CrossRef CAS Web of Science IUCr Journals Google Scholar

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