Crystal structure of 4-bromo-5,7-dimethoxy-2,3-dihydro-1H-inden-1-one

In the title molecule, C11H11BrO3, the dihydroindene moiety is essentially planar but with a slight twist in the saturated portion of the five-membered ring. The methoxy groups lie close to the above plane. In the crystal, π-stacking interactions between six-membered rings form stacks of molecules extending along the a-axis directions, which are linked by weak C—H⋯O and C—H⋯Br hydrogen bonds.


Chemical context
Aberrant expression of protein kinases is a hallmark of several cancers, and small molecules targeting specific kinases are in clinical use as cancer therapeutics (Du & Lovly, 2018;Kannaiyan & Mahadevan, 2018;Roskoski, 2023).Development of resistance to the kinase inhibitors is a frequent occurrence, which motivates a continuing search for new kinase inhibitors (Yang et al., 2022).One of the key characteristics of the kinase inhibitors is the capacity to form two hydrogen bonds, one as donor and one as acceptor, with the hinge region of the kinase (Arter et al., 2022;Attwood et al., 2021).Planarity with two functional groups capable of making the two essential hydrogen bonds, along with other substituents to target the unique residues of the ATP binding pocket for potency and specificity, are the fundamental structural features of kinase inhibitors.
We have developed 5-hydroxy-1,4-naphthoquinones as HER2 and PIM1 kinase inhibitors (Schroeder et al., 2014(Schroeder et al., , 2016;;Sridhar et al., 2014).To circumvent the issue of oxidation-reduction reactions of the quinone moiety, 5,7-dihydroxy-2,3-dihydro-1H-inden-1-one is currently under development as a new core structure.The new series based upon this platform is capable of making the requisite hydrogen bonds to the kinase hinge region and has potential for functionalization at the 2, 3, 4, 5 and 6 positions to enable specific and potent inhibition of the kinase of interest.Bromination serves as an initial step for functionalizing the core structure of 5,7dimethoxy-2,3-dihydro-1H-inden-1-one.
Bromination by free radical or electrophilic aromatic substitution mechanisms using N-bromosuccinimide (NBS) is known to introduce a bromine atom on an allylic or benzylic carbon atom or on an aromatic ring (Djerassi, 1948;Li et al., 2014).When subjected to bromination with NBS in benzene in the presence of azobisisobutyronitrile (AIBN) for 15 h at ambient temperature, 5,7-dimethoxy-2,3-dihydro-1H-inden-1-one yielded a single product.From among the product outcomes depicted as 1A, 1B and 1C in Fig. 1, NMR spectroscopy indicated that electrophilic aromatic substitution had occurred to form a single species -either 1A or 1B.X-ray crystallography has identified the product as 1B (Fig. 2), the detailed structural characterization and crystal packing arrangement of which we describe herein.

Structural commentary
The dihydroindene moiety is planar to within 0.045 (3) A (r.m.s.deviation of the contributing atoms = 0.003 A ˚) with C9 that distance from one side of the mean plane and C8 0.018 (4) A ˚from the opposite side.This twist in the fivemembered ring is towards the upper end of the range seen in related structures (see Database survey).Both methoxy groups are nearly coplanar with the C1-C6 ring as indicated by the C10-O1-C3-C4 and C11-O2-C5-C4 torsion angles which are, respectively, 2.7 (4) and 6.6 (5) � .All bond distances and interbond angles are as expected for the formulation given.

Figure 2
The title molecule with labeling scheme and 50% probability displacement ellipsoids.   1 and Figs. 4 and 5).Johnson et al., 2002).In AWOBOF and LAQCAJ, the C-Br distances are virtually the same as in the title molecule [1.892 (3) A ˚] and the twist in the five-membered ring is slightly less.Among the other disubstituted molecules, the greatest deviation of the saturated carbon atoms of the five-membered ring from the mean plane of the bicyclic moiety is in CAPHIN [0.091 (2) and À 0.122 (2) A ˚] while the least is in MUQCEG [0.016 (3) and À 0.012 (3) A ˚].As in the title molecule, the methyl carbon atoms of the methoxy groups in CAPHEJ, CETCAG and MXINDO10 lie in or very close to the mean plane of the ninemembered ring system.Where �-stacking of the sixmembered aromatic rings occurs in the disubstituted examples, this involves only pairs of molecules (LAQCAJ and MXINDO10) rather than extended stacks.

Hirshfeld surface analysis
The Hirshfeld surface was constructed with CrystalExplorer 21.5 (Spackman et al., 2021)   The fragment used in the database survey.

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 2. Hydrogen atoms were included as riding contributions in idealized positions with isotropic displacement parameters tied to those of the attached atoms.One reflection affected by the beamstop was omitted from the final refinement.

Special details
Experimental.The diffraction data were obtained from 3 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.H-atoms attached to carbon were placed in calculated positions (C-H = 0.95 -0.99 Å).All were included as riding contributions with isotropic displacement parameters 1.2 -1.5 times those of the attached atoms.One reflection affected by the beamstop was omitted from the final refinement.Refined as a 2-component inversion twin.
Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å

Figure 3 A
Figure 3A portion of one stack viewed along the c-axis direction with the �-stacking interactions depicted by dashed lines.Non-interacting hydrogen atoms are omitted for clarity.

Figure 4
Figure 4Packing viewed along the c-axis direction with the C-H� � �O and C-H� � �Br hydrogen bonds depicted, respectively, by black and green dashed lines.The �-stacking interactions are depicted by orange dashed lines and non-interacting hydrogen atoms are omitted for clarity.

Figure 5
Figure 5Packing viewed along the a-axis direction with the C-H� � �O and C-H� � �Br hydrogen bonds depicted, respectively, by black and green dashed lines.The �-stacking interactions are depicted by orange dashed lines and non-interacting hydrogen atoms are omitted for clarity.

Figure 7
Figure 7The Hirshfeld surface plotted over (a) d norm and (b) over the shape index including two additional molecules in the stack plus two more in an adjacent stack with the C-H� � �O and C-H� � �Br hydrogen bonds shown by green dashed lines.
Fig. 7a shows the surface plotted over d norm in the range À 0.1265 to 1.2968 in arbitrary units with four neighboring molecules.The two above and below the surface constitute part of the column formed by the �-stacking interactions, while the two at the right are part of an adjacent column showing the C-H� � �O and C-H� � �Br hydrogen bonds that link columns.Fig. 7b shows the surface plotted over the shape function and the flat area in the center containing red and blue triangles clearly shows the �-stacking interactions.The 2-D fingerprint plots are shown in Fig.

Table 2
Experimental details.