The crystal structure of (E)-2-ethoxy-1-methoxy-4-(2-(methylsulfonyl)vinyl)benzene, C₁₂H₁₆O₄S

1 Source of materials

Purification of the crude title compound, (E)-2-ethoxy-1-methoxy-4-(2-(methylsulfonyl)vinyl)benzene (6 g), was achieved by washing with petroleum ether. The material was suspended in petroleum ether (200 mL), and the solid was isolated by vacuum filtration. After washing the filter cake with additional petroleum ether (10 mL), the product was dried in vacuo at 40 °C, yielding (E)-1-ethoxy-2-methoxy-4-(2-(methylsulfonyl)vinyl)benzene as a white, crystalline powder. Single crystals of X-ray diffraction quality were obtained from the purified material: a solution of the compound (256 mg, 1.0 mmol) in tetrahydrofuran (20 mL) was prepared at room temperature and filtered into a small vial. The vial was covered with a perforated film, and slow evaporation of the solvent at ambient temperature afforded colorless plates over a period of several days.

2 Experimental details

All hydrogen atoms were placed in geometrically idealized positions and refined using a riding model. Methyl groups were treated as idealized rotating groups. The isotropic displacement parameters (U_iso) of the hydrogen atoms were constrained to 1.2 times the U_eq of their parent atom for the aromatic and methylene groups, and 1.5 times the U_eq for the methyl groups.

3 Comment

Apremilast, marketed under the trade name Otezla, is a first-in-class, orally administered small-molecule inhibitor of phosphodiesterase 4 (PDE4). Its development represents a significant advancement in the treatment of chronic inflammatory diseases. Apremilast is primarily indicated for the treatment of moderate-to-severe plaque psoriasis, active psoriatic arthritis, and oral ulcers associated disease. ^{7 , 8} As the management of these conditions has historically been dominated by injectable biologic agents, the oral route of administration for apremilast provides a critical therapeutic alternative, offering patients greater convenience and a distinct mechanism of action. ⁹

The title compound, (E)-2-ethoxy-1-methoxy-4-(2-(methylsulfonyl)vinyl)benzene, is a key intermediate in the convergent synthetic route to apremilast. The core framework of apremilast is assembled via a conjugate addition reaction, wherein the vinyl sulfone moiety of the title compound reacts with a nucleophilic phthalimide precursor. The (E)-geometry of this vinyl group is crucial for achieving high reactivity and diastereoselectivity in this transformation.

As part of our ongoing research interest on the structure-activity relationship about the antimicrobial agent, and understanding of hydrogen bonding schemes of related compounds, ^{10 , 11 , 12} this study presents the crystal structure of the title compound and provides a determination of its structure.

The asymmetric unit of the title compound, contains one discrete molecule (cf. left part of the figure). The molecular structure of the title compound features a vinyl bridge (C2=C3) that connects the methylsulfonyl group to the substituted phenyl ring. The crystal diffraction data unambiguously establishes the configuration of this moiety. The geometry about the C2=C3 double bond is unequivocally assigned as E. This assignment is principally based on the C2–C3 bond distance of 1.328(2) Å, which is characteristic of a double bond, and the observed torsion angle of S1–C2–C3–C4, which is 178.44(11)°. A value proximal to ±180° indicates an anti-periplanar conformation of the connected S1 and C4 atoms across the vinyl group. This arrangement is likely the thermodynamically more stable isomer, as it minimizes the steric hindrance between the bulky sulfonyl and aryl groups.

A distinctive feature in the molecular conformation of the title compound is the high degree of planarity exhibited by its core structure. This extensive planar region comprises the phenyl ring, methoxy and ethoxy groups, vinyl bridge (C2=C3), and the S atom of the sulfonyl group (C4–C5–C6–C7–C8–C9–O3–C10–C11–O4–C12–C3–C2–S1). The RMS deviation of the plane is 0.0396 Å. Among these atoms, the greatest deviation from the calculated plane is observed for the C10 atom of the methoxy group, with a perpendicular distance of 0.1018 Å from the plane. To our best search, this conjugated planar structure moiety has not been previously reported in crystallographic literature. This spatial arrangement appears to achieve a favorable balance between maximizing electronic conjugation effects and minimizing steric hindrance between substituents.

In detail, the phenyl ring itself is planar. The vinyl group is observed to be nearly coplanar with the aromatic ring. This is quantitatively supported by the torsion angle C2–C3–C4–C9 (174.05(14)°). Additionally, the orientations of the methoxy and ethoxy substituents position their oxygen atoms and the first carbon atoms of their alkyl chains almost in the plane of the phenyl ring (e.g., C10–O3–C7–C6 = 5.3(2)°; C11–O4–C8–C9 = 3.8(2)°).

Smaller planar molecular fragments consisting of the phenyl ring, methoxy and ethoxy groups, and vinyl bridge, (C4–C5–C6–C7–C8–C9–O3–C10–C11–O4–C12–C3–C2), have been previously reported in the literature. ^{13 , 14 , 15}

The crystal structure is stabilized by a network of weak C–H⋯O hydrogen bonding interactions (cf. right part of the figure. Some hydrogen atoms are omitted for clarity). These include: C1–H1C⋯O3^I with D⋯A = 3.373(2) Å, where ^I = 1−x, 1−y, 1−z; C2–H2⋯O1^II with D⋯A = 3.3093(18) Å, where ^II = x, 3/2−y, 1/2+z; C5–H5⋯O1^III with D⋯A = 3.3997(18) Å, where ^III = x, 3/2−y, 1/2+z; and C9–H9⋯O2^IV with D⋯A = 3.1999(17) Å, where ^IV = 1−x, 1−y, −z. Additionally, there is an intramolecular hydrogen bond (medium strong): C3–H3⋯O2, with D⋯A distance of 2.8974(17) Å. These interactions connect the molecules into a two-dimensional network structure along the bc direction.

In addition to hydrogen bonds, the crystal packing is further stabilized by π–π stacking interactions. The phenyl rings of adjacent molecules are related through an inversion center and arranged in a parallel-displaced manner. The distance between ring centroids is 3.905 Å, with a perpendicular distance of 3.499 Å and a slippage distance of 1.733 Å.

The structure also exhibits a weak C–H⋯π interaction between a methyl hydrogen atom (H10A) and the phenyl ring of an adjacent molecule, with an H⋯Cg (centroid) distance of 2.95 Å. This intermolecular interaction occurs along the crystallographic direction (x, 3/2 −y, 1/2+z).