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

Monroe, T.B.; Moazami, Y.; Jones, D.S.; Ogle, C.A.

doi:10.1107/S1600536809034667

organic compounds

CRYSTALLOGRAPHIC
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ISSN: 2056-9890

Volume 65| Part 10| October 2009| Page o2353

doi:10.1107/S1600536809034667

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

Thomas Blake Monroe,^a Yasamin Moazami,^a Daniel S. Jones ^a ^* and Craig A. Ogle ^a ^*

^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 ,b ). For pharmaceutical applications see: Fuwa & Sasaki (2009 ); Li & Martins (2003 ). For a study of π–π packing interactions see: Janiak (2000 ).

Experimental

Crystal data

C₁₂H₁₃NO₄
M_r = 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)
R_int = 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
Δρ_max = 0.14 e Å⁻³
Δρ_min = −0.12 e Å⁻³

Table 1
Hydrogen-bond geometry (Å, °)

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 code: (i) -x, -y+2, -z+1.

Data collection: CAD-4 EXPRESS (Enraf–Nonius, 1994 ); cell refinement: CAD-4 EXPRESS; 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 ).

Supporting information

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

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

checkCIF report

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 π–π 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.

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

	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

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

Crystal data top

C₁₂H₁₃NO₄	F(000) = 992
M_r = 235.23	D_x = 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	θ_max = 67.4°, θ_min = 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
R_int = 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(F_o²) + (0.0613P)² + 0.2248P] where P = (F_o² + 2F_c²)/3
R[F² > 2σ(F²)] = 0.035	(Δ/σ)_max < 0.001
wR(F²) = 0.102	Δρ_max = 0.14 e Å⁻³
S = 1.02	Δρ_min = −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
M_r = 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	R_int = 0.030
9909 measured reflections	3 standard reflections every 171 reflections
2098 independent reflections	intensity decay: 1%
1522 reflections with I > 2σ(I)

Refinement top

R[F² > 2σ(F²)] = 0.035	0 restraints
wR(F²) = 0.102	H atoms treated by a mixture of independent and constrained refinement
S = 1.02	Δρ_max = 0.14 e Å⁻³
2098 reflections	Δρ_min = −0.12 e Å⁻³
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

	x	y	z	U_iso*/U_eq
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, º) 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, º) 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 code: (i) −x, −y+2, −z+1.

Experimental details

Crystal data
Chemical formula	C₁₂H₁₃NO₄
M_r	235.23
Crystal system, space group	Orthorhombic, Pbca
Temperature (K)	295
a, b, c (Å)	17.0768 (19), 7.7232 (11), 17.678 (2)
V (Å³)	2331.5 (5)
Z	8
Radiation type	Cu Kα
µ (mm⁻¹)	0.85
Crystal size (mm)	0.36 × 0.22 × 0.21

Data collection
Diffractometer	Enraf–Nonius CAD-4 diffractometer
Absorption correction	–
No. of measured, independent and observed [I > 2σ(I)] reflections	9909, 2098, 1522
R_int	0.030
(sin θ/λ)_max (Å⁻¹)	0.599

Refinement
R[F² > 2σ(F²)], wR(F²), S	0.035, 0.102, 1.02
No. of reflections	2098
No. of parameters	162
H-atom treatment	H atoms treated by a mixture of independent and constrained refinement
Δρ_max, Δρ_min (e Å⁻³)	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···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 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.

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