The first spontaneous resolution of a sulfoxide: Dianin’s compound analogue, (R)-4-(4-hydroxyphenyl)-2,2,4-trimethylthiachroman-1-oxide

The single epimer of Dianin’s compound analogue, (R)-4-(4-hydroxyphenyl)-2,2,4-trimethylthiachroman-1-oxide, was prepared by multiple recrystallization and studied by X-ray diffraction.

The title sulfoxide, C 18 H 20 O 2 S, was prepared by controlled oxidation of thia-Dianin's compound using hydrogen peroxide in glacial acetic acid. On recrystallization from glacial acetic acid, it was found to form unsolvated, spontaneously resolved crystals, the initial crystal structure analysis revealing the presence of both sulfoxide epimers in the crystal. On multiple recrystallization a single epimer was observed, with crystallization occurring in the unchanged orthorhombic space group P2 1 2 1 2 1 , with Z 0 = 1. The molecule possesses a distal conformation, referring to the juxtaposition of the p-hydoxyphenyl substituent with respect to its syn-related methyl group, with the sulfoxide oxygen atom anti to the aromatic substituent. The molecular packing features O-HÁ Á ÁO hydrogen bond chains running parallel to the b axis of the unit cell.

Chemical context
A significant body of work in the literature relates to specifically targeted structural modification of Dianin's compound, 4-(4-hydroxyphenyl)-2,2,4-trimethylchroman 2, (MacNicol, 1984;Finocchiaro & Failla, 1996;Collet & Jacques, 1976;Frampton et al., 2017a,b,c). Crystallization of the new compounds has normally resulted in one of two outcomes: formation of clathrates in the space group R3 (or R3) or spontaneous resolution, also a subject of much current interest (Pé rez-García & Amabilino, 2007), to form an unsolvated conglomerate in space group P2 1 2 1 2 1 , with Z 0 = 1, in which the individual crystals are formed by supramolecular assembly of a single enantiomer. A notable departure from the above crystallization modes has, however, been found in the case of Dianin's sulfone 4, (Frampton et al., 1992), which crystallizes unsolvated in the polar monoclinic space group Cc, with Z 0 = 1, and these crystals exhibited a significant SHG effect. The present work was undertaken to establish if the corresponding sulfoxide 1 would retain the clathrating ability of its immediate progenitor thia-Dianin's compound 3, or would undergo spontaneous resolution, alternative possibilities being the formation of a polar monoclinic crystal or crystallization in a more frequently encountered space group. Interestingly, the achiral bis-sulfoxide trans-(R,S)-, 0 -di-tert-butylsulfinyl-paraxylene undergoes conformational spontaneous resolution in the space group P2 1 2 1 2 1 : on dissolution, rapid conformational racemization occurs at room temperature; however, the authors make the point that at 173 K, from calculations, it could be possible to obtain one chiral conformation from a single crystal (Xu et al., 2014). Accordingly, the sulfoxide 1 was prepared by controlled oxidation of 3 as described in Section 5, and its crystal structure determined.

Structural commentary
Initial attempts to determine the crystal structure of 1 revealed the presence of both sulfoxide epimers in the crystal in a ratio of approximately 90:10. It was found that multiple recrystallization of 1 from glacial acetic acid yielded a single epimer, the structure of which is presented here. The crystal structure of 1 is orthorhombic, space group P2 1 2 1 2 1 with a single independent molecule in the asymmetric unit, (Z 0 = 1), Fig. 1. The molecule possesses a distal conformation, this referring to the juxtaposition of the p-hydroxyphenyl substituent with respect to the syn-related methyl group. The C2-C3-C4-C11 torsion angle is 154.0 (2) , the corresponding torsion angle for racemic Dianin's compound 2 has a magnitude of 80.67 (Lee et al., 2014) and for 4-(4-hydroxyphenyl)-2,2,4-trimethylchroman-1,1-dioxide 4, it is 76.8 (Frampton et al., 1992). The expected torsional angle value for a distal conformation is 160 whereas that for a proximal conformation is 80 . The torsion angle S1-C2-C3-C4, defining the heterocyclic ring chirality, has a value of À67.3 (2) . Fig. 2 shows an overlay of 1 (brown) with sulfone 4 (cyan). In this figure, the six aromatic atoms of the chroman unit for each structure have been overlaid using the standard molecule overlay routine in Mercury (Macrae et al., 2008), resulting in an r.m.s. displacement of 0.0147 Å , and this clearly demonstrates the difference between the distal and proximal conformations of 1 and 4, respectively. The absolute configuration of 1, was determined as being R at the chiral centre C4 by anomalous dispersion methods, (Parsons et al. 2013), the Flack x parameter was determined as À0.002 (7) using 1246 quotients [(I + ) À (I À )]/[(I + ) + (I À )].

Supramolecular features
The structure of 1 is isostructural with the enantiomerically pure amine counterparts of Dianin's and thia-Dianin View of the structure overlay of 1 (brown) and 4 (cyan).

Synthesis and crystallization
Preparation of 1: 4-(4-hydroxyphenyl)-2,2,4-trimethylthiachroman 3 (MacNicol, 1969) (0.25 g, 0.88 mmol) was dissolved in glacial acetic acid (10 mL) and a 50% excess of 30% hydrogen peroxide (0.15 mL, 1.32 mmol) added. After the reaction was left overnight at ca 278 K, the precipitated white solid was filtered off, washed several times with ether, and initially recrystallized from aqueous dimethyl sulfoxide yielding 0.168 g, (63%) of product. A further recrystallization from glacial acetic acid gave colourless crystals which were analysed by X-ray diffraction as described in the text. The crystals were obtained by spontaneous resolution on crystallization, yielding a 50:50 mixture of the pure enantiomers. These crystals also incorporated both spontaneously resolved sulfoxide epimers, four further recrystallizations were performed giving a single epimer of purity greater than 99% [500 MHz 1 H NMR, DMSO-d 6 solution analysis gave 99.5 (2)% purity] and the very minor residual second epimer was undetectable in the subsequent X-ray analysis. These crystals melted over a wide range, ca 513-536 K, possibly arising from sulfoxide epimerization, along with decomposition, at high temperature. MS  A partial view of the crystal packing down the a axis showing the hydrogen-bonded chain. The intermolecular O-HÁ Á ÁO hydrogen bond is shown as a dotted line. Table 1 Hydrogen-bond geometry (Å , ).  (3) 169 (3) Symmetry code: (i) x; y À 1; z.

Figure 4
View of the crystal packing of 1 down the b axis.

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 2. The hydrogen atom of the OH group was localized in the difference-Fourier map and refined isotropically. The other hydrogen atoms were placed in calculated positions and refined within the riding model with C-H = 0.95-0.99 Å and fixed isotropic displacement parameters [U iso (H) = 1.5U eq (C) for the methyl groups and 1.

(R)-4-(4-Hydroxyphenyl)-2,2,4-trimethyl-3H-1λ 4 -benzothiopyran-1-one
Crystal data 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.