Methyl (Z)-2-chloro-3-(2-methoxy­carbonyl­phen­yl)prop-2-enoate

Casey J Fadgen; Thomas L Groy; Seth D Rose

doi:10.1107/S160053681000084X

. 2010 Jan 16;66(Pt 2):o376. doi: 10.1107/S160053681000084X

Methyl (Z)-2-chloro-3-(2-methoxycarbonylphenyl)prop-2-enoate

Casey J Fadgen ^a, Thomas L Groy ^a,^*, Seth D Rose ^a

PMCID: PMC2979665 PMID: 21579798

Abstract

In the title compound, C₁₂H₁₁ClO₄, the propenoate C=C bond is in the Z configuration. The propenoate C=O and C=C groups are essentially coplanar [C=C—C=O torsion angle = 172.4 (3)°] with the O atom synperiplanar to the Cl atom. However, the π systems of the aromatic ring and chloropropenoate substituent are not coplanar; the corresponding dihedral angle is 51.5 (1)°. The noncoplanarity is likely due to steric interactions between the propenoate H atom and the ortho-methoxycarbonyl group on the aromatic ring. Even in the observed noncoplanar conformation, the ortho C=O to H distance (2.40 Å) is less than the sum of the van der Waals radii of O and H (2.65 Å).

Related literature

For the structure of 2-nitrocinnamic acid, in which the alkene group is noncoplanar with the aromatic ring, as in the title compound, see: Smith et al. (2006 ▶). For numerous structures of cinnamic acid derivatives, with coplanar aromatic and alkene groups, see: ethyl p-methoxycinnamate (Luger et al., 1996 ▶), p-cresyl cinnamate (Kaitner & Stilinović, 2007 ▶), 4-methylcoumarin ester of trans-cinnamic acid (Yang et al., 2006 ▶), methyl esters of m- and p-bromocinnamic acids (Leiserowitz & Schmidt, 1965 ▶), methyl 3,5-dinitro-trans-cinnamate (Sharma et al., 1995 ▶), N-cinnamoylsaccharin (Ersanlı et al., 2005 ▶), and 2-ethoxycinnamic acid (Fernandes et al., 2001 ▶). For the chlorination step of the synthesis, see: Markó et al. (1997 ▶). For van der Waals radii, see: Rowland & Taylor (1996 ▶).

Experimental

Crystal data

C₁₂H₁₁ClO₄
M _r = 254.66
Monoclinic,
a = 10.722 (5) Å
b = 15.331 (7) Å
c = 7.676 (4) Å
β = 110.395 (10)°
V = 1182.7 (10) Å³
Z = 4
Mo Kα radiation
μ = 0.32 mm⁻¹
T = 299 K
0.40 × 0.10 × 0.04 mm

Data collection

Bruker SMART APEX CCD diffractometer
Absorption correction: multi-scan (SADABS; Bruker, 2008 ▶) T _min = 0.882, T _max = 0.988
9313 measured reflections
2110 independent reflections
1559 reflections with I > 2σ(I)
R _int = 0.036

Refinement

R[F ² > 2σ(F ²)] = 0.038
wR(F ²) = 0.096
S = 1.01
2110 reflections
156 parameters
H-atom parameters constrained
Δρ_max = 0.21 e Å⁻³
Δρ_min = −0.18 e Å⁻³

Data collection: APEX2 and BIS (Bruker, 2008 ▶); cell refinement: SAINT (Bruker, 2008 ▶); data reduction: SAINT; program(s) used to solve structure: SHELXS97 (Sheldrick, 2008 ▶); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008 ▶); molecular graphics: XSHELL (Bruker, 2004 ▶); software used to prepare material for publication: SHELXL97.

Supplementary Material

Crystal structure: contains datablocks global, I. DOI: 10.1107/S160053681000084X/ya2113sup1.cif

e-66-0o376-sup1.cif^{(14.7KB, cif)}

Structure factors: contains datablocks I. DOI: 10.1107/S160053681000084X/ya2113Isup2.hkl

e-66-0o376-Isup2.hkl^{(103.8KB, hkl)}

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

Acknowledgments

The authors thank the Arizona Biomedical Research Commission for financial support.

supplementary crystallographic information

Comment

The title compound (1) is of interest in the development of anticancer enzyme inhibitors. Determination of the E/Z stereochemistry and the preferred conformation were needed for in silico docking of 1 and its derivatives to target enzymes.

Synthesis of 1 was carried out as shown in Fig. 1. Esterification of o-carboxycinnamic acid was accomplished by treatment with CH₃OH/HCl. The subsequent formation of the Z-isomer during synthesis can be rationalized on the basis of the known lack of stereospecificity of the dichlorination reaction when applied to aromatic-substituted alkenes, carried out essentially by the method of Markó et al. (1997).

Subsequent elimination of HCl from the dichloro derivative by treatment with triethylamine in dichloromethane produced 1 in ~10:1 ratio (by NMR) with its E isomer. Regioselectivity (i.e., preferential formation of the 2-chloropropenoate over 3-chloropropenoate) results from the more facile deprotonation of the more acidic H atom in the α-position to the ester carbonyl group, with loss of the 3-chlorine atom.

Fig. 2 shows that 1 has Z configuration at the alkene double bond and that the π systems of the aromatic ring and the chloropropenoate substituent are not coplanar. The C2—C1—C7—C8 torsion angle is 133.5 (3)° and the C6—C1—C7—C8 torsion angle is -49.4 (4)°; the dihedral angle formed by the plane of the aromatic ring and the plane of the chloropropenoate substituent (C7, C8, C9, Cl1, O1, O2) is equal to 51.5 (1)°. The ortho-methoxycarbonyl substituent is slightly non-coplanar with the aromatic ring, as shown by the O3—C11—C2—C1 torsion angle of -10.7 (4)°. Loss of resonance stabilization by twisting of the ortho-methoxycarbonyl and propenoate groups relative to the aromatic ring is presumably balanced by relief of steric strain due to proximity of the ortho-carbonyl oxygen and the propenoate hydrogen.

Experimental

2-Carboxycinnamic acid (2-CCA) dimethyl ester.

Acetyl chloride (1 ml) was slowly added to 25 ml of cold methanol in a 100-ml round-bottom flask. The reaction mixture was warmed slowly then refluxed for 10 minutes prior to addition of 381 mg (2 mmol) of 2-CCA. The reaction mixture was refluxed and monitored by thin-layer chromatography (TLC). Typically, the reaction was complete in less than 2 h. The reaction mixture was concentrated by rotary evaporation and passed through a short silica gel column with dichloromethane elution to yield 420 mg (~95%) of a viscous, clear oil.

Dichlorination of 2-CCA dimethyl ester.

KMnO₄ (730 mg, 4.62 mmol) and benzyltriethylammonium chloride (1.040 g, 4.57 mmol) were stirred in 20 ml of dry dichloromethane. The resulting dark purple solution was cooled on ice for 20 min. Chlorotrimethylsilane (~2 g, 18.4 mmol) was slowly added to the stirred solution, which gradually took on a dark green color. The reaction mixture was allowed to warm to room temperature, and 2-CCA dimethyl ester (1 g, 4.55 mmol) was added. The reaction mixture was monitored by TLC, but the reaction was terminated prior to completion because of reagent degradation (green color vanishing and dark or brown color appearing, along with multiple spots appearing upon TLC). The organic solution was successively washed with 0.1 M sodium thiosulfate and brine, followed by drying over anhydrous sodium sulfate. A silica gel column was used to separate the mixture (elution with 1:1 hexanes–chloroform). Recrystallization from dichloromethane/hexanes yielded 640 mg of white solid. M.p. 70.5–72 °C. ¹H NMR (400 MHz in CDCl₃) δ, 7.97 (d, 1H, J = 8.0 Hz), 7.69 (d, 1H, J = 7.6 Hz), 7.60 (t, 1H, J = 7.6 Hz), 7.44 (app t, 1H, J = 7.6, 8.0 Hz), 6.62 (d, 1H, J = 10.4 Hz), 4.75 (d, 1H, 10.4 Hz), 3.95 (s, 3H), 3.88 (s, 3H); ¹³C NMR (100 MHz in CDCl₃) δ, 167.5, 167.0, 137.7, 132.6, 130.6, 130.0, 128.9, 128.6, 59.2, 55.8, 53.4, 52.6. Anal. Calcd (%) for C₁₂H₁₁ClO₄: C, 49.51; H, 4.15. Found: C, 49.30; H, 4.11.

Elimination of HCl to form 1.

In 2 ml of dichloromethane was dissolved 300 mg (1.03 mmol) of the above dichloro ester. Triethylamine (110 mg, 1.10 mmol) was then added, and the reaction was monitored by TLC. The reaction mixture was washed successively with ~5 ml of 1.0 M HCl and brine, followed by drying over anhydrous sodium sulfate. Formation of an approximately 10:1 ratio of 1 to its E isomer was indicated by ¹H NMR spectroscopy of the crude product. Subsequent crystallizations from dichloromethane/hexanes yielded ~90 mg of white solid, 1 (0.35 mmol, 34%). ¹H NMR (500 MHz in CDCl₃) δ, 8.45 (s, 1H), 8.05 (d, 1H, J = 12.5 Hz), 7.66 (d, 1H, J = 8 Hz), 7.57 (app t, 1H, J = 12.5, 8 Hz), 7.44 (app t, 1H, J = 8, 7.5 Hz), 3.90 (s, 3H), 3.88 (s, 3H).