Ethyl 2-[(2-oxo-2H-chromen-6-yl)oxy]acetate

Ethyl 2-[(2-oxo-2H-chromen-6-yl)oxy]acetate, a coumarin derivative, crystallizes in sheets, within which molecules are held by weak C—H⋯O hydrogen-bonding interactions and between which molecules interact by π–π stacking and additional C—H⋯O weak hydrogen bonds between ethyl acetoxy groups.


Chemical context
Chromen-2-one, also known as coumarin, and its derivatives hold considerable significance in both natural product and synthetic organic chemistry.Coumarin's structure is characterized by a benzene ring fused to an �-pyrone ring, which makes it valuable in pharmaceutical research (Murray et al., 1982).Coumarin derivatives have shown biological activity as anticancer (Emami & Dadashpour, 2015), antioxidant (Matos et al., 2017), anticoagulant (Satish, 2016) and antineurodegenerative agents (Jameel et al., 2016).We have previously reported a number of synthetically derived molecules based on coumarin, chromene and flavone as substrates/inhibitors of several important cytochrome P450 enzymes, including P450s 1A1, 1A2, and 2A6 (Goyal et al., 2023;Foroozesh et al., 1997).As part of an ongoing program of research into the pharmacological properties of coumarin derivatives, we have undertaken the synthesis of ethyl 2-[(2-oxo-2H-chromen-6-yl)oxy] acetate, the structural characterization of which we report herein.

Structural commentary
Ethyl 2-[(2-oxo-2H-chromen-6-yl)oxy]acetate deposits in the form of colorless blocks by slow cooling of a 2:1 ethyl acetate: hexanes solution.The molecule crystallizes in completely ordered fashion with the appended ethyl oxyacetate group at the 6-position arranged in a fully extended, linear arrange-ment (Fig. 1).Thus, all non-hydrogen atoms of the molecule reside within the same plane with an average deviation of 0.0457 A ˚. Coplanar pairs of ethyl 2-[(2-oxo-2H-chromen-6-yl)oxy] acetate molecules are organized in a head-to-tail fashion by apparent C5-H5� � �O4 and C6-H6� � �O3 weak hydrogenbonding interactions around an inversion center (Table 1, Fig. 2).The adjoining rows of molecules above and below those shown in Fig. 2 are related by 2 1 screw axes to those in these centrosymmetric dyads, with which they form C8-H8� � �O1 and C1-H1� � �O1 hydrogen bonds (Fig. 3).The replication of these rows of molecules, which are alternately related by inversion centers and 2 1 axes, creates sheets whose planes lie approximately in the direction of the ac face diagonal of the unit cell (Fig. 4).Molecules between sheets are also related by inversion centers (Fig. 5) and enjoy pairs of C12-H12A� � �O3 hydrogen-bond contacts.The layered packing arrangement is guided by �-� stacking between the coumarin ring systems, with a separation of 3.4460 (6) A between the centroids of the �-pyrone rings (C1-C3/O2/C4/ C9) of adjacent molecules, as assessed by PLATON (Spek, 2020).This distance is only modestly greater than the 3.35 A separation between the sheets of carbon atoms in graphite (Chung, 2002) and is reinforced by the hydrogen bonding between extended ethyl oxyacetate chains in adjacent layers (Fig. 5).

Figure 3
Rows of ethyl 2-[(2-oxo-2H-chromen-6-yl)oxy]acetate molecules to both sides of, and in the same plane as, the centrosymmetric diads in Fig. 2.These molecules are related to those in the centrosymmetric dyads by a 2 1 operation, the position for one such axis being shown.This patterned arrangement is assisted by C8-H8� � �O1 and by C1-H1� � �O1 close contacts, in which the corresponding H8� � �O1 and H1� � �O1 distances are 2.27 and 2.61 A ˚.The symmetry transformation whereby one molecule is converted to the other across these hydrogen bonds is Ellipsoids are shown at the 50% probability level.

Database survey
A variety of chromen-2-ones that are substituted in the 6-position of the ring system have been characterized structurally by X-ray diffraction.Examples include 6-methoxycoumarin (Baures et al., 2002), 6-benzyloxycoumarin (Adfa et al., 2010), 6-acetoxycoumarin (Murthy et al., 1988) (Wang et al., 2022).Of these, only 6-methoxycoumarin has a planar molecular structure and therefore a sheetlike packing arrangement in the crystalline state that is analogous to that observed for ethyl 2-[(2-oxo-2Hchromen-6-yl)oxy]acetate.Because aryloxy substituents in the 6-position of the coumarin ring system are typically not oriented to be in the same plane as the coumarin core, a pattern that such derivatives display is packing as centrosymmetric dyads with with parallel coplanar arrangement of the coumarin cores.

Synthesis and crystallization
Potassium carbonate (0.512 g, 3.70 mmol) was added to a stirred solution of 6-hydroxy-2H-chromen-2-one (0.200 g, 1.233 mmol) in 10 mL of acetone, and stirring was continued for 30 minutes at 298 K. Bromoethyl acetate (0.309 g, 1.850 mmol) was added slowly to the reaction mixture, and upon completion, the temperature was elevated to 313 K with stirring for 12 h.The reaction mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure.The resulting crude solid was purified via flash chromatography on silica gel with 20:80 ethyl acetate:hexanes as the eluting solvent to yield ethyl 2-[(2-oxo-2H-chrome-6-yl)oxy] acetate as a white solid, m.p. 377-380 K.The H12A� � �O3 distance is 2.57 A ˚, and the symmetry transformation relating these molecules is À x + 1, À y + 1, À z + 1. Displacement ellipsoids are presented at the 50% probability level.

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 2.All hydrogen atoms were refined isotropically with displacement parameters 1.2-1.5 times those of the carbon atoms to which they are attached.

Special details
Experimental.The diffraction data were obtained from 6 sets of frames, each of width 0.50 ° in ω or φ, collected with scan parameters determined by the "strategy" routine in APEX4.The scan time was 10.00 sec/frame.Geometry.All esds (except the esd in the dihedral angle between two l.s.planes) are estimated using the full covariance matrix.The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry.An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s.planes.Refinement.Refinement of F 2 against ALL reflections.The weighted R-factor wR and goodness of fit S are based on F 2 , conventional R-factors R are based on F, with F set to zero for negative F 2 .The threshold expression of F 2 > 2sigma(F 2 ) is used only for calculating R-factors(gt) etc. and is not relevant to the choice of reflections for refinement.R-factors based on F 2 are statistically about twice as large as those based on F, and R-factors based on ALL data will be even larger.

Figure 4
Figure 4Packing diagram for ethyl 2-[(2-oxo-2H-chromen-6-yl)oxy]acetate illustrating the arrangement of molecules into sheets in the approximate direction of the ac face diagonal of the unit cell.All H atoms are omitted for clarity, and displacement ellipsoids are drawn at 50% probability.

Table 2
Experimental details.