supplementary materials
Methyl 5,6-dimethoxy-1H-indole-2-carboxylate
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.
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.
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).
Methyl 5,6-dimethoxy-1
H-indole-2-carboxylate
top
Crystal data top
| C12H13NO4 | F(000) = 992 |
| Mr = 235.23 | Dx = 1.34 Mg m−3 |
| Orthorhombic, Pbca | Cu Kα radiation, λ = 1.54184 Å |
| Hall symbol: -P 2ac 2ab | Cell parameters from 25 reflections |
| a = 17.0768 (19) Å | θ = 10.0–43.0° |
| b = 7.7232 (11) Å | µ = 0.85 mm−1 |
| c = 17.678 (2) Å | T = 295 K |
| V = 2331.5 (5) Å3 | Prism, colourless |
| Z = 8 | 0.36 × 0.22 × 0.21 mm |
Data collection top
Enraf–Nonius CAD-4
diffractometer | θmax = 67.4°, θmin = 5° |
| Non–profiled ω/2θ scans | h = −20→20 |
| 9909 measured reflections | k = 0→9 |
| 2098 independent reflections | l = −21→21 |
| 1522 reflections with I > 2σ(I) | 3 standard reflections every 171 reflections |
| Rint = 0.030 | intensity decay: 1% |
Refinement top
| Refinement on F2 | H 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) = 0.102 | Δρmax = 0.14 e Å−3 |
| S = 1.02 | Δρmin = −0.12 e Å−3 |
| 2098 reflections | Extinction correction: SHELXL97 (Sheldrick, 2008), Fc*=kFc[1+0.001xFc2λ3/sin(2θ)]-1/4 |
| 162 parameters | Extinction coefficient: 0.0047 (4) |
| 0 restraints | |
Crystal data top
| C12H13NO4 | V = 2331.5 (5) Å3 |
| Mr = 235.23 | Z = 8 |
| Orthorhombic, Pbca | Cu Kα radiation |
| a = 17.0768 (19) Å | µ = 0.85 mm−1 |
| b = 7.7232 (11) Å | T = 295 K |
| c = 17.678 (2) Å | 0.36 × 0.22 × 0.21 mm |
Data collection top
Enraf–Nonius CAD-4
diffractometer | Rint = 0.030 |
| 9909 measured reflections | θmax = 67.4° |
| 2098 independent reflections | 3 standard reflections every 171 reflections |
| 1522 reflections with I > 2σ(I) | intensity decay: 1% |
Refinement top
| R[F2 > 2σ(F2)] = 0.035 | H atoms treated by a mixture of independent and constrained refinement |
| wR(F2) = 0.102 | Δρmax = 0.14 e Å−3 |
| S = 1.02 | Δρmin = −0.12 e Å−3 |
| 2098 reflections | Absolute structure: ? |
| 162 parameters | Flack parameter: ? |
| 0 restraints | Rogers parameter: ? |
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| | x | y | z | Uiso*/Ueq | |
| N | 0.05760 (8) | 0.76815 (19) | 0.51504 (7) | 0.0509 (3) | |
| O1 | 0.07015 (8) | 1.05091 (17) | 0.41553 (7) | 0.0727 (4) | |
| O2 | 0.17099 (7) | 0.92154 (18) | 0.35786 (7) | 0.0722 (4) | |
| O3 | 0.00702 (6) | 0.30330 (14) | 0.69682 (6) | 0.0564 (3) | |
| O4 | 0.12332 (7) | 0.14080 (15) | 0.64271 (7) | 0.0656 (4) | |
| C2 | 0.11320 (9) | 0.7786 (2) | 0.45863 (8) | 0.0516 (4) | |
| C3 | 0.15832 (9) | 0.6316 (2) | 0.46040 (8) | 0.0530 (4) | |
| H3 | 0.2001 | 0.6062 | 0.4285 | 0.064* | |
| C4 | 0.15041 (8) | 0.3618 (2) | 0.54858 (8) | 0.0495 (4) | |
| H4 | 0.1918 | 0.2997 | 0.5277 | 0.059* | |
| C5 | 0.10882 (9) | 0.2958 (2) | 0.60783 (8) | 0.0476 (4) | |
| C6 | 0.04402 (8) | 0.3882 (2) | 0.63953 (8) | 0.0453 (4) | |
| C7 | 0.02331 (8) | 0.5479 (2) | 0.61286 (8) | 0.0459 (4) | |
| H7 | −0.018 | 0.6096 | 0.634 | 0.055* | |
| C8 | 0.06679 (8) | 0.6150 (2) | 0.55251 (8) | 0.0448 (4) | |
| C9 | 0.12971 (8) | 0.5256 (2) | 0.51953 (8) | 0.0466 (4) | |
| C10 | 0.11447 (10) | 0.9300 (2) | 0.41017 (9) | 0.0556 (4) | |
| C11 | 0.17434 (13) | 1.0657 (4) | 0.30566 (12) | 0.0936 (8) | |
| H11A | 0.1271 | 1.0693 | 0.2763 | 0.14* | |
| H11B | 0.2184 | 1.0517 | 0.2725 | 0.14* | |
| H11C | 0.1797 | 1.1718 | 0.3335 | 0.14* | |
| C12 | 0.18869 (10) | 0.0457 (2) | 0.61719 (11) | 0.0661 (5) | |
| H12A | 0.1826 | 0.0201 | 0.5644 | 0.099* | |
| H12B | 0.1925 | −0.0604 | 0.6452 | 0.099* | |
| H12C | 0.2354 | 0.1128 | 0.6246 | 0.099* | |
| C13 | −0.05334 (10) | 0.3942 (2) | 0.73565 (10) | 0.0622 (5) | |
| H13A | −0.0324 | 0.4989 | 0.7568 | 0.093* | |
| H13B | −0.0737 | 0.3228 | 0.7755 | 0.093* | |
| H13C | −0.0946 | 0.4221 | 0.7009 | 0.093* | |
| H1 | 0.0202 (10) | 0.852 (2) | 0.5251 (10) | 0.064 (5)* | |
Atomic displacement parameters (Å2) top| | U11 | U22 | U33 | U12 | U13 | U23 |
| N | 0.0517 (7) | 0.0518 (8) | 0.0492 (7) | −0.0002 (6) | 0.0024 (6) | 0.0013 (6) |
| O1 | 0.0850 (9) | 0.0656 (9) | 0.0676 (8) | 0.0067 (7) | 0.0120 (7) | 0.0111 (6) |
| O2 | 0.0623 (7) | 0.0919 (10) | 0.0624 (7) | 0.0005 (7) | 0.0096 (6) | 0.0236 (7) |
| O3 | 0.0601 (6) | 0.0515 (7) | 0.0576 (6) | 0.0056 (5) | 0.0185 (5) | 0.0030 (5) |
| O4 | 0.0607 (7) | 0.0554 (7) | 0.0806 (8) | 0.0140 (6) | 0.0226 (6) | 0.0125 (6) |
| C2 | 0.0472 (8) | 0.0623 (10) | 0.0454 (8) | −0.0074 (8) | −0.0004 (7) | 0.0008 (7) |
| C3 | 0.0422 (8) | 0.0693 (11) | 0.0475 (8) | −0.0042 (8) | 0.0021 (6) | 0.0007 (8) |
| C4 | 0.0390 (7) | 0.0577 (10) | 0.0517 (8) | 0.0014 (7) | 0.0033 (6) | −0.0050 (8) |
| C5 | 0.0442 (8) | 0.0465 (9) | 0.0520 (8) | 0.0006 (6) | 0.0013 (6) | −0.0026 (7) |
| C6 | 0.0437 (7) | 0.0482 (9) | 0.0438 (7) | −0.0035 (7) | 0.0026 (6) | −0.0036 (7) |
| C7 | 0.0435 (8) | 0.0486 (9) | 0.0457 (8) | 0.0003 (7) | 0.0029 (6) | −0.0069 (7) |
| C8 | 0.0431 (7) | 0.0474 (8) | 0.0438 (7) | −0.0037 (6) | −0.0037 (6) | −0.0030 (7) |
| C9 | 0.0375 (7) | 0.0583 (10) | 0.0441 (7) | −0.0041 (7) | −0.0016 (6) | −0.0028 (7) |
| C10 | 0.0522 (9) | 0.0675 (11) | 0.0470 (8) | −0.0070 (9) | −0.0033 (7) | 0.0026 (8) |
| C11 | 0.0829 (14) | 0.124 (2) | 0.0739 (12) | −0.0071 (13) | 0.0069 (11) | 0.0451 (13) |
| C12 | 0.0582 (10) | 0.0595 (11) | 0.0806 (12) | 0.0141 (9) | 0.0098 (9) | 0.0036 (9) |
| C13 | 0.0647 (10) | 0.0622 (10) | 0.0598 (10) | 0.0076 (9) | 0.0219 (8) | 0.0008 (9) |
Geometric parameters (Å, °) top
| N—C8 | 1.365 (2) | C4—H4 | 0.93 |
| N—C2 | 1.3792 (19) | C5—C6 | 1.431 (2) |
| N—H1 | 0.926 (19) | C6—C7 | 1.367 (2) |
| O1—C10 | 1.206 (2) | C7—C8 | 1.399 (2) |
| O2—C10 | 1.338 (2) | C7—H7 | 0.93 |
| O2—C11 | 1.447 (2) | C8—C9 | 1.404 (2) |
| O3—C6 | 1.3619 (18) | C11—H11A | 0.96 |
| O3—C13 | 1.4235 (19) | C11—H11B | 0.96 |
| O4—C5 | 1.3695 (19) | C11—H11C | 0.96 |
| O4—C12 | 1.410 (2) | C12—H12A | 0.96 |
| C2—C3 | 1.373 (2) | C12—H12B | 0.96 |
| C2—C10 | 1.449 (2) | C12—H12C | 0.96 |
| C3—C9 | 1.415 (2) | C13—H13A | 0.96 |
| C3—H3 | 0.93 | C13—H13B | 0.96 |
| C4—C5 | 1.364 (2) | C13—H13C | 0.96 |
| C4—C9 | 1.410 (2) | | |
| | | |
| C8—N—C2 | 108.82 (14) | C7—C8—C9 | 122.74 (14) |
| C8—N—H1 | 126.2 (11) | C8—C9—C4 | 118.80 (14) |
| C2—N—H1 | 125.0 (11) | C8—C9—C3 | 106.66 (14) |
| C10—O2—C11 | 115.57 (16) | C4—C9—C3 | 134.55 (14) |
| C6—O3—C13 | 117.19 (12) | O1—C10—O2 | 123.01 (16) |
| C5—O4—C12 | 117.03 (13) | O1—C10—C2 | 124.67 (15) |
| C3—C2—N | 108.74 (14) | O2—C10—C2 | 112.32 (16) |
| C3—C2—C10 | 132.24 (14) | O2—C11—H11A | 109.5 |
| N—C2—C10 | 119.01 (15) | O2—C11—H11B | 109.5 |
| C2—C3—C9 | 107.56 (14) | H11A—C11—H11B | 109.5 |
| C2—C3—H3 | 126.2 | O2—C11—H11C | 109.5 |
| C9—C3—H3 | 126.2 | H11A—C11—H11C | 109.5 |
| C5—C4—C9 | 118.94 (14) | H11B—C11—H11C | 109.5 |
| C5—C4—H4 | 120.5 | O4—C12—H12A | 109.5 |
| C9—C4—H4 | 120.5 | O4—C12—H12B | 109.5 |
| C4—C5—O4 | 125.31 (14) | H12A—C12—H12B | 109.5 |
| C4—C5—C6 | 121.15 (15) | O4—C12—H12C | 109.5 |
| O4—C5—C6 | 113.54 (13) | H12A—C12—H12C | 109.5 |
| O3—C6—C7 | 124.82 (13) | H12B—C12—H12C | 109.5 |
| O3—C6—C5 | 114.20 (13) | O3—C13—H13A | 109.5 |
| C7—C6—C5 | 120.98 (14) | O3—C13—H13B | 109.5 |
| C6—C7—C8 | 117.36 (13) | H13A—C13—H13B | 109.5 |
| C6—C7—H7 | 121.3 | O3—C13—H13C | 109.5 |
| C8—C7—H7 | 121.3 | H13A—C13—H13C | 109.5 |
| N—C8—C7 | 129.03 (14) | H13B—C13—H13C | 109.5 |
| N—C8—C9 | 108.22 (13) | | |
Hydrogen-bond geometry (Å, °) top
| D—H···A | D—H | H···A | D···A | D—H···A |
| N—H1···O1i | 0.926 (19) | 2.011 (19) | 2.867 (2) | 152.9 (16) |
| Symmetry codes: (i) −x, −y+2, −z+1. |
Table 1
Hydrogen-bond geometry (Å, °) top
| D—H···A | D—H | H···A | D···A | D—H···A |
| N—H1···O1i | 0.926 (19) | 2.011 (19) | 2.867 (2) | 152.9 (16) |
| Symmetry codes: (i) −x, −y+2, −z+1. |
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.
Enraf–Nonius (1994). CAD-4 EXPRESS. Enraf–Nonius, Delft, The Netherlands.
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Harms, K. & Wocadlo, S. (1995). XCAD4. University of Marburg, Germany.
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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.
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) 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 ![[pi]](/logos/entities/pi_rmgif.gif)
-stacking interaction of the indole rings, with an interplanar separation of 3.39 (3) Å.![[Figure 1]](./fj2241fig1thm.gif)
![[Figure 2]](./fj2241fig2thm.gif)
![[Figure 3]](./fj2241fig3thm.gif)
![[Figure 4]](./fj2241fig4thm.gif)
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.