Crystal structures and Hirshfeld surface analyses of 6,8-dimethoxy-3-methyl-1H-isochromen-1-one and 5-bromo-6,8-dimethoxy-3-methyl-1H-isochromen-1-one chloroform monosolvate

Bromination of 6,8-dimethoxy-3-methyl-1H-isochromen-1-one resulted in the formation of the 5-bromo derivative, 5-bromo-6,8-dimethoxy-3-methyl-1H-isochromen-1-one. The two molecules differ essentially in the orientation of the methoxy group on position 6 of the isocoumarin ring system.


Chemical context
Compound I is the protected form of the isocoumarin 6,8dihydroxy-3-methyl-1H-isochromen-1-one (L), which is a phytotoxin produced by the Ceratocystis fimbriata species coffea and platani (Gremaud & Tabacchi, 1994;Bü rki et al., 2003). These fungi are pathogenic agents responsible for infections of coffee, plane and elm trees (Michel, 2001). Compound L has also been isolated from the organic extracts of the fungus Ceratocystis minor (Hemingway et al., 1977). The crystal structure of L has been reported for a sample obtained from the fermented culture of the endophytic marine fungus Cephalosporium sp. (Shao et al., 2009). Herein, we report on the crystal structures and Hirshfeld surface analyses of the 6,8dimethoxy derivative of L, viz. 6,8-dimethoxy-3-methyl-1Hisochromen-1-one (I) and compound II, 5-bromo-6,8-dimethoxy-3-methyl-1H-isochromen-1-one, the brominated derivative of I. The syntheses of compounds I and II were undertaken during the syntheses of derivatives of natural isocoumarins, metabolites of the pathogenic fungus Ceratocystis fimbriata sp. (Tiouabi, 2005).

Structural commentary
The molecular structures of compounds I and II are illustrated in Figs. 1 and 2, respectively. Compound II crystallized as a chloroform monosolvate. Both isocoumarin molecules are essentially planar with an r.m.s. deviation of 0.02 Å for I and 0.016 Å for II (H atoms not included). The maximum deviation from their mean planes is 0.047 (1) Å for atom O2 in I, and 0.035 (8) Å for atom C10 in II. The two molecules differ essentially in the orientation of the methoxy group on atom C2. In I it is anti with respect to that on atom C4, while in II, owing to the steric hindrance of the Br atom, it has been rotated by 180 about the C2-O3 bond and is positioned syn with respect to the methoxy group on atom C4 (Fig. 3).

Supramolecular features
The crystal packing of compound I is illustrated in Fig. 4. Molecules are linked by bifurcated C-HÁ Á ÁO hydrogen bonds, C1-H1Á Á ÁO1 i and C7-H7Á Á ÁO1 i , forming chains propagating along the c-axis direction ( Table 1). The chains are linked by C-HÁ Á Á interactions (C12-H12AÁ Á ÁCg ii and C12-H12BÁ Á ÁCg iii , where Cg is the centroid of the C1-C4/C8/ C9 benzene ring), forming a supramolecular framework (Table 1 and  The molecular structure of compound I, with atom labelling. Displacement ellipsoids are drawn at the 50% probability level.

Figure 2
The molecular structure of compound II, with atom labelling. Displacement ellipsoids are drawn at the 50% probability level. For clarity, the chloroform solvate molecule has been omitted.

Hirshfeld surfaces and fingerprint plots for I and IIÁCHCl 3
The Hirshfeld surface analysis (Spackman & Jayatilaka, 2009) and the calculation of the associated two-dimensional fingerprint plots (McKinnon et al., 2007) were performed with CrystalExplorer17.5 (Turner et al., 2017), following the protocol of Tiekink and collaborators (Tan et al., 2019). The Hirshfeld surface is colour-mapped with the normalized contact distance, d norm , from red (distances shorter than the sum of the van der Waals radii) through white to blue (distances longer than the sum of the van der Waals radii).

Figure 5
A view along the c axis of the crystal packing of compound IIÁCHCl 3 . The hydrogen bonds (Table 2) are shown as dashed lines.  Hydrogen-bond geometry (Å , ) for I.

Figure 4
A view along the a axis of the crystal packing of compound I. The hydrogen bonds (Table 1) are shown as dashed lines and the C-HÁ Á Á interactions as blue arrows. For clarity, only the H atoms (grey sticks and blue balls) involved in these interactions have been included. mapped over d norm , are shown in Fig. 6a and b, respectively. The faint red spots indicate that short contacts are significant in the crystal packing of both compounds. The full two-dimensional fingerprint plot for I and fingerprint plots delineated into HÁ Á ÁH (40.3%), OÁ Á ÁH/HÁ Á ÁO (28.2%), CÁ Á ÁH/HÁ Á ÁC (24.6%), CÁ Á ÁO (3.0%) and OÁ Á ÁO (2.9%) contacts, are shown in Fig. 7. The CÁ Á ÁC contacts contribute only 1.0%.

Figure 9
Reaction schemes for the syntheses of compounds I and II, with atomlabelling schemes in relation to the NMR spectra (see x6. Synthesis and crystallization).   Table 2).
Preparation of Reagent A (1 M Ac 2 O; 10 À3 M HClO 4 ), was carried out according to the protocol of Edwards & Rao (Edwards & Rao, 1966). 0.0501 ml of HClO 4 at 70% (0.575 mmol) were dissolved in 50 ml of AcOEt. 30 ml of this solution were added to a solution of 14.4 ml of Ac 2 O (0.153 mol) in 105.6 ml of AcOEt to give 150 ml of Reagent A.
Synthesis of 6,8-dimethoxy-3-methyl-1H-isochromen-1-one (I): In a 250 ml flask equipped with a magnetic stirrer and under an atmosphere of argon, the keto-acid (1) was dissolved in 150 ml of Reagent A. The mixture was stirred vigorously for 10-15 min, then washed with an aqueous solution of saturated NaHCO 3 . The organic phase was dried over anhydrous Na 2 SO 4 , then filtered and the filtrate concentrated using rotary evaporation. The brown solid obtained was purified by chromatography on a silica column using as eluent CH 2 Cl 2 / AcOEt (15/1, v/v). On evaporation of the eluent 1.20 g of compound I (yield 95%) were obtained as colourless blocklike crystals.
Analytical data for I: Synthesis of 5-bromo-6,8-dimethoxy-3-methyl-1H-isochromen-1-one (II): In a 25 ml flask equipped with a magnetic stirrer and under an atmosphere of argon, NBS (N-bromosuccinimide) (28 mg, 0.158 mmol) was added under stirring to a solution of compound I (0.136 mmol) dissolved in CH 3 CN (1.5 ml). The reaction mixture was stirred for 2 h at room temperature. On completion of the reaction, followed by thinlayer chromatography using CH 2 Cl 2 /AcOEt (15/2, v/v) as eluent, NaBH 4 (5.2 mg, 0.136 mmol) was added, resulting in the transformation of the yellow solution into a white suspension. After 1 h the reaction mixture was diluted using water and then extracted five times using AcOEt. The organic phases were combined, dried over anhydrous Na 2 SO 4 , then filtered and the filtrate concentrated using rotary evaporation. The white solid obtained was purified by chromatography on a silica column using CH 2 Cl 2 /AcOEt (20/1, v/v) as eluent. On evaporation of the eluent, 30 mg of compound II (yield 74%) were obtained as colourless rod-like crystals.

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 4. For both I and II the C-bound H atoms were included in calculated positions and treated as riding on their parent C atom: C-H = 0.95-1.00 Å with U iso (H) = 1.5U eq (C-methyl) and 1.2U eq (C) for other H atoms.
Compound IIÁCHCl 3 was refined as a two-component twin with a 180 rotation about axis c*. Details are given in the archived CIF. The final refined BASF factor is 0.2590 (19). Two of the chloroform solvate chlorine atoms (Cl2 and Cl3) are disordered over two positions and were refined with a fixed occupancy ratio (Cl2A:Cl2B and Cl3A:Cl3B) of 0.5:0.5. SHELXS97 (Sheldrick, 2008); program(s) used to refine structure: SHELXL2018/3 (Sheldrick, 2015). Molecular graphics: PLATON (Spek, 2020) and Mercury (Macrae et al., 2020) for (I); Mercury (Macrae et al., 2020) for (II). For both structures, software used to prepare material for publication: SHELXL2018/3 (Sheldrick, 2015), PLATON (Spek, 2020) and publCIF (Westrip, 2010). where P = (F o 2 + 2F c 2 )/3 (Δ/σ) max < 0.001 Δρ max = 0.22 e Å −3 Δρ min = −0.18 e Å −3 Special details 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.