Methyl 5-fluoro-1H-indole-2-carboxyl­ate

Harrison, W.T.A.; Yathirajan, H.S.; Ashalatha, B.V.; Vijaya Raj, K.K.; Narayana, B.

doi:10.1107/S1600536806031448

organic compounds

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ISSN: 2056-9890

Volume 62| Part 9| September 2006| Pages o4050-o4051

https://doi.org/10.1107/S1600536806031448

Methyl 5-fluoro-1H-indole-2-carboxylate

William T. A. Harrison,^a ^* H. S. Yathirajan,^b B. V. Ashalatha,^c K. K. Vijaya Raj ^c and B. Narayana ^c

^aDepartment of Chemistry, University of Aberdeen, Meston Walk, Aberdeen AB24 3UE, Scotland, ^bDepartment of Studies in Chemistry, University of Mysore, Manasagangotri, Mysore 570 006, India, and ^cDepartment of Chemistry, Mangalore University, Mangalagangotri 574 199, India
^*Correspondence e-mail: w.harrison@abdn.ac.uk

(Received 8 August 2006; accepted 9 August 2006; online 23 August 2006)

The geometrical parameters for the title compound, C₁₀H₈FNO₂, are normal. In the crystal structure, the molecules form inversion-symmetry-generated dimeric pairs by way of two N—H⋯O hydrogen bonds.

Comment

Several indolecarboxylic acid derivatives show biological activity: methyl indole-3-carboxylate, extracted from a marine microorganism (Hu et al., 2005 ), is cytotoxic against the K562 human leukaemia strain. Methyl indole-2-carboxylic acid may serve as a glycine site antagonist and hence aid in the treatment of human brain injuries (Morzyk-Ociepa et al., 2004 ). 5-Fluoroindole-3-acetic acid (Antolic et al., 1996 ) has plant-growth regulating activity. The crystal structure of methyl indole-2-carboxylate has been deposited [Parsons, S., McNab, H. & Wood, P. (2004). refcode OCAQEP] with the Cambridge Structural Database (CSD; Version 5.27; Allen, 2002 ). As part of our ongoing research in this area, the structure of the related title compound, (I) (Fig. 1), prepared by the Fischer indole synthesis reaction (Narayana et al., 2005 ), is now presented.

The geometrical parameters for (I) are consistent with those of the compounds noted above. In particular, methyl indole-2-carboxylic acid, (II) (Morzyk-Ociepa et al., 2004), has almost identical geometry to (I). For example, the benzene-ring bond lengths (Å) in (I) are C1—C2 = 1.396 (2) [equivalent value in (II) = 1.390 (2) Å], C2—C3 = 1.375 (2) [1.372 (2)], C3—C4 = 1.399 (2) [1.404 (2)], C4—C5 = 1.356 (2) [1.357 (2)], C5—C6 = 1.408 (2) [1.409 (2)] and C6—C1 = 1.416 (2) [1.403 (2)]. Apart from the methyl H atoms, the molecule in (I) is essentially planar [r.m.s. deviation of the non-H atoms from the mean plane = 0.031 Å, max. = 0.0327 (11) Å for N1]. The bond angle sum about N1 is 359.7°. The crystal packing in (I) exhibits inversion-symmetry-generated dimeric pairs of molecules linked by two N—H⋯O hydrogen bonds (Table 1 and Fig. 2). A similar pairing arrangement was seen in the structure of methyl indole-2-carboxylate (CSD refcode OCAQEP) although the overall structure is different to (I). Conversely, in methyl indole-2-carboxylic acid (Morzyk-Ociepa et al., 2004) a completely different arrangement of N—H⋯O and O—H⋯O hydrogen bonds leads to chains of molecules. There are no π–π stacking interactions in (I), the shortest intermolecular ring-centroid separation being 4.35 Å.

Figure 1
View of (I), showing 50% probability displacement ellipsoids and arbitrary spheres for the H atoms.

Figure 2
Unit cell packing in (I) with all H atoms except H1 omitted for clarity and hydrogen bonds indicated by dashed lines. See Table 1

for symmetry code.

Experimental

Methyl pyruvate-4-fluorophenylhydrazone (2 g, 0.0095 mol) was added to 10 g polyphosphoric acid and continuously stirred for proper mixing. The reaction mass was slowly heated to 353–363 K and maintained for 4 h. The progress of the reaction was monitored by TLC. The reaction mass was cooled and water (100 ml) was added to break up the lumps until it became a slurry. The separated solid was filtered off and washed with water. The dried crude product was charcoalized in ethyl acetate, filtered over hyflo/silica gel, slowly cooled to room temperature and kept overnight with stirring. After recrystallization from ethyl acetate, colourless crystals of (I) were obtained in 60% yield (m.p. 474 K). Analysis found (calculated) for C₁₀H₈FNO₂: C 62.11 (62.18), H 4.09 (4.17), N 7.13 (7.25)%.

Crystal data

C₁₀H₈FNO₂
M_r = 193.17
Monoclinic, P 2₁ /n
a = 12.4420 (7) Å
b = 3.8185 (1) Å
c = 18.269 (1) Å
β = 100.125 (2)°
V = 854.43 (7) Å³
Z = 4
D_x = 1.502 Mg m⁻³
Mo Kα radiation
μ = 0.12 mm⁻¹
T = 120 (2) K
Needle, colourless
0.41 × 0.07 × 0.05 mm

Data collection

Nonius KappaCCD diffractometer
φ and ω scans
Absorption correction: multi-scan (SADABS; Bruker, 2003 ) T_min = 0.952, T_max = 0.994
10458 measured reflections
1937 independent reflections
1311 reflections with I > 2σ(I)
R_int = 0.052
θ_max = 27.6°

Refinement

Refinement on F²
R[F² > 2σ(F²)] = 0.042
wR(F²) = 0.110
S = 1.03
1937 reflections
132 parameters
H atoms treated by a mixture of independent and constrained refinement
w = 1/[σ²(F_o²) + (0.0568P)² + 0.104P] where P = (F_o² + 2F_c²)/3
(Δ/σ)_max < 0.001
Δρ_max = 0.23 e Å⁻³
Δρ_min = −0.26 e Å⁻³
Extinction correction: SHELXL97
Extinction coefficient: 0.014 (3)

Table 1
Hydrogen-bond geometry (Å, °)

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
N1—H1⋯O2ⁱ	0.883 (18)	2.019 (18)	2.8555 (18)	157.7 (15)
Symmetry code: (i) -x+1, -y, -z.

The N-bound H atom was located in a difference map and its position was freely refined with U_iso(H) = 1.2U_eq(N). The C-bound H atoms were placed in idealized locations (C—H = 0.95–0.99 Å) and refined as riding with U_iso(H) = 1.2U_eq(C) or 1.5U_eq(methyl C). The methyl group was rotated about its C—N bond to best fit the electron density.

Data collection: COLLECT (Nonius, 1998 ); cell refinement: SCALEPACK (Otwinowski & Minor, 1997 ); data reduction: SCALEPACK, DENZO (Otwinowski & Minor, 1997) and SORTAV (Blessing, 1995 ); program(s) used to solve structure: SHELXS97 (Sheldrick, 1997 ); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997); molecular graphics: ORTEP-3 (Farrugia, 1997 ); software used to prepare material for publication: SHELXL97.

Supporting information

Crystal structure: contains datablocks I, global. DOI: https://doi.org/10.1107/S1600536806031448/sj2100sup1.cif

Structure factors: contains datablock I. DOI: https://doi.org/10.1107/S1600536806031448/sj2100Isup2.hkl

Computing details top

Data collection: COLLECT (Nonius, 1998); cell refinement: SCALEPACK (Otwinowski & Minor, 1997); data reduction: SCALEPACK, DENZO (Otwinowski & Minor, 1997) and SORTAV (Blessing, 1995); program(s) used to solve structure: SHELXS97 (Sheldrick, 1997); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997); molecular graphics: ORTEP-3 (Farrugia, 1997); software used to prepare material for publication: SHELXL97.

Methyl 5-fluoro-1H-indole-2-carboxylate top

Crystal data top

C₁₀H₈FNO₂	F(000) = 400
M_r = 193.17	D_x = 1.502 Mg m⁻³
Monoclinic, P2₁/n	Mo Kα radiation, λ = 0.71073 Å
Hall symbol: -P 2yn	Cell parameters from 2189 reflections
a = 12.4420 (7) Å	θ = 1.0–27.5°
b = 3.8185 (1) Å	µ = 0.12 mm⁻¹
c = 18.269 (1) Å	T = 120 K
β = 100.125 (2)°	Needle, colourless
V = 854.43 (7) Å³	0.41 × 0.07 × 0.05 mm
Z = 4

Data collection top

Nonius KappaCCD diffractometer	1937 independent reflections
Radiation source: fine-focus sealed tube	1311 reflections with I > 2σ(I)
Graphite monochromator	R_int = 0.052
φ and ω scans	θ_max = 27.6°, θ_min = 4.0°
Absorption correction: multi-scan (SADABS; Bruker, 2003)	h = −16→16
T_min = 0.952, T_max = 0.994	k = −4→4
10458 measured reflections	l = −22→23

Refinement top

Refinement on F²	Secondary atom site location: difference Fourier map
Least-squares matrix: full	Hydrogen site location: difmap and geom
R[F² > 2σ(F²)] = 0.042	H atoms treated by a mixture of independent and constrained refinement
wR(F²) = 0.110	w = 1/[σ²(F_o²) + (0.0568P)² + 0.104P] where P = (F_o² + 2F_c²)/3
S = 1.03	(Δ/σ)_max < 0.001
1937 reflections	Δρ_max = 0.23 e Å⁻³
132 parameters	Δρ_min = −0.26 e Å⁻³
0 restraints	Extinction correction: SHELXL97, Fc^*=kFc[1+0.001xFc²λ³/sin(2θ)]^-1/4
Primary atom site location: structure-invariant direct methods	Extinction coefficient: 0.014 (3)

Special details top

Experimental. 1H NMR (CDCl3, 300?MHz): δ 3.92 (s, 3H, –CH3), 7.01 (dt, 1H, Ar—H), 7.10 (s, 1H, Ar—H), 7.25 (dd, J =2.4 and 9.3 Hz, 1H, Ar—H), 7.44 (dd, J = 4.2 and 8.7 Hz, 1H, Ar—H), 11.38 (br s, 1H, –NH–, exchangeable with D2O).

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
C1	0.48721 (12)	0.2695 (4)	0.17446 (9)	0.0207 (4)
C2	0.39008 (13)	0.1753 (4)	0.19763 (9)	0.0241 (4)
H2	0.3330	0.0610	0.1649	0.029*
C3	0.38010 (13)	0.2540 (4)	0.26959 (9)	0.0255 (4)
H3	0.3156	0.1922	0.2877	0.031*
C4	0.46546 (14)	0.4259 (4)	0.31588 (9)	0.0252 (4)
C5	0.56073 (13)	0.5227 (4)	0.29536 (9)	0.0232 (4)
H5	0.6165	0.6391	0.3288	0.028*
C6	0.57298 (13)	0.4421 (4)	0.22209 (9)	0.0204 (4)
C7	0.65781 (12)	0.4953 (4)	0.18042 (9)	0.0210 (4)
H7	0.7259	0.6068	0.1972	0.025*
C8	0.62237 (12)	0.3543 (4)	0.11111 (9)	0.0200 (4)
C9	0.67713 (12)	0.3284 (4)	0.04739 (9)	0.0216 (4)
C10	0.83499 (14)	0.4799 (5)	−0.00077 (10)	0.0318 (4)
H10A	0.9051	0.5999	0.0142	0.048*
H10B	0.7929	0.5979	−0.0442	0.048*
H10C	0.8481	0.2360	−0.0134	0.048*
N1	0.51896 (10)	0.2191 (3)	0.10736 (8)	0.0213 (3)
H1	0.4827 (14)	0.101 (4)	0.0694 (10)	0.026*
O1	0.77453 (9)	0.4888 (3)	0.05982 (6)	0.0247 (3)
O2	0.64084 (9)	0.1788 (3)	−0.01054 (6)	0.0286 (3)
F1	0.44961 (8)	0.5000 (3)	0.38680 (5)	0.0356 (3)

Atomic displacement parameters (Å²) top

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
C1	0.0213 (8)	0.0185 (8)	0.0214 (9)	0.0024 (6)	0.0017 (7)	0.0013 (6)
C2	0.0209 (8)	0.0225 (9)	0.0277 (10)	−0.0002 (7)	0.0013 (7)	0.0015 (7)
C3	0.0231 (9)	0.0231 (9)	0.0313 (10)	0.0032 (7)	0.0076 (7)	0.0044 (7)
C4	0.0299 (9)	0.0267 (9)	0.0199 (9)	0.0059 (7)	0.0071 (7)	0.0002 (7)
C5	0.0240 (9)	0.0229 (9)	0.0216 (9)	0.0012 (6)	0.0007 (7)	0.0004 (7)
C6	0.0212 (8)	0.0168 (8)	0.0229 (9)	0.0027 (6)	0.0030 (6)	0.0023 (6)
C7	0.0200 (8)	0.0189 (8)	0.0230 (9)	−0.0008 (6)	0.0002 (7)	0.0007 (7)
C8	0.0207 (8)	0.0176 (8)	0.0210 (9)	0.0025 (6)	0.0015 (6)	0.0031 (6)
C9	0.0223 (8)	0.0196 (8)	0.0216 (9)	0.0029 (7)	0.0001 (7)	0.0037 (7)
C10	0.0327 (10)	0.0346 (10)	0.0310 (11)	−0.0048 (8)	0.0137 (8)	−0.0018 (8)
N1	0.0191 (7)	0.0225 (7)	0.0208 (8)	0.0001 (5)	−0.0004 (5)	−0.0027 (6)
O1	0.0231 (6)	0.0287 (7)	0.0231 (7)	−0.0044 (5)	0.0064 (5)	−0.0024 (5)
O2	0.0289 (7)	0.0352 (7)	0.0210 (7)	−0.0044 (5)	0.0022 (5)	−0.0051 (5)
F1	0.0394 (6)	0.0447 (7)	0.0254 (6)	−0.0011 (5)	0.0127 (5)	−0.0044 (5)

Geometric parameters (Å, º) top

C1—N1	1.366 (2)	C7—C8	1.375 (2)
C1—C2	1.396 (2)	C7—H7	0.9500
C1—C6	1.416 (2)	C8—N1	1.377 (2)
C2—C3	1.375 (2)	C8—C9	1.452 (2)
C2—H2	0.9500	C9—O2	1.2173 (18)
C3—C4	1.399 (2)	C9—O1	1.3412 (19)
C3—H3	0.9500	C10—O1	1.444 (2)
C4—C5	1.356 (2)	C10—H10A	0.9800
C4—F1	1.3739 (19)	C10—H10B	0.9800
C5—C6	1.408 (2)	C10—H10C	0.9800
C5—H5	0.9500	N1—H1	0.883 (18)
C6—C7	1.420 (2)

N1—C1—C2	129.66 (14)	C8—C7—H7	126.6
N1—C1—C6	108.14 (14)	C6—C7—H7	126.6
C2—C1—C6	122.19 (15)	C7—C8—N1	109.76 (14)
C3—C2—C1	117.52 (15)	C7—C8—C9	130.19 (15)
C3—C2—H2	121.2	N1—C8—C9	120.04 (14)
C1—C2—H2	121.2	O2—C9—O1	123.19 (15)
C2—C3—C4	119.59 (15)	O2—C9—C8	125.07 (15)
C2—C3—H3	120.2	O1—C9—C8	111.74 (13)
C4—C3—H3	120.2	O1—C10—H10A	109.5
C5—C4—F1	118.81 (14)	O1—C10—H10B	109.5
C5—C4—C3	124.63 (16)	H10A—C10—H10B	109.5
F1—C4—C3	116.56 (14)	O1—C10—H10C	109.5
C4—C5—C6	116.71 (15)	H10A—C10—H10C	109.5
C4—C5—H5	121.6	H10B—C10—H10C	109.5
C6—C5—H5	121.6	C1—N1—C8	108.52 (13)
C5—C6—C1	119.36 (15)	C1—N1—H1	126.1 (11)
C5—C6—C7	133.90 (15)	C8—N1—H1	125.1 (11)
C1—C6—C7	106.74 (14)	C9—O1—C10	115.88 (12)
C8—C7—C6	106.83 (14)

N1—C1—C2—C3	178.99 (15)	C1—C6—C7—C8	−0.57 (16)
C6—C1—C2—C3	−0.5 (2)	C6—C7—C8—N1	0.64 (17)
C1—C2—C3—C4	0.7 (2)	C6—C7—C8—C9	−178.29 (15)
C2—C3—C4—C5	−0.5 (3)	C7—C8—C9—O2	175.35 (15)
C2—C3—C4—F1	179.30 (13)	N1—C8—C9—O2	−3.5 (2)
F1—C4—C5—C6	−179.78 (12)	C7—C8—C9—O1	−4.2 (2)
C3—C4—C5—C6	0.0 (2)	N1—C8—C9—O1	176.93 (12)
C4—C5—C6—C1	0.2 (2)	C2—C1—N1—C8	−179.43 (15)
C4—C5—C6—C7	−179.57 (16)	C6—C1—N1—C8	0.09 (17)
N1—C1—C6—C5	−179.56 (13)	C7—C8—N1—C1	−0.46 (17)
C2—C1—C6—C5	0.0 (2)	C9—C8—N1—C1	178.59 (13)
N1—C1—C6—C7	0.30 (16)	O2—C9—O1—C10	1.0 (2)
C2—C1—C6—C7	179.86 (14)	C8—C9—O1—C10	−179.46 (13)
C5—C6—C7—C8	179.26 (16)

Hydrogen-bond geometry (Å, º) top

D—H···A	D—H	H···A	D···A	D—H···A
N1—H1···O2ⁱ	0.883 (18)	2.019 (18)	2.8555 (18)	157.7 (15)

Symmetry code: (i) −x+1, −y, −z.

Acknowledgements

We thank the EPSRC National Crystallography Service (University of Southampton, England) for data collection. ABV thanks Mangalore University for provision of research facilities.

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