Synthesis and crystal structures of 3-hydroxy-2,4-dimethyl-2H-thiophen-5-one and 3-hydroxy-4-methyl-2H-thiophen-5-one

The structures of two hydroxy-thiophenone derivatives related to the antibiotic thiolactomycin are presented. The main structural feature of both compounds is C(6) hydrogen-bonded chains formed between the OH and C=O groups.

The structures of two hydroxy-thiophenone derivatives related to the antibiotic thiolactomycin are presented. These are the racemic 3-hydroxy-2,4-dimethyl-2H-thiophen-5-one, C 6 H 8 O 2 S, and 3-hydroxy-4-methyl-2H-thiophen-5-one, C 5 H 6 O 2 S. The main structural feature of both compounds is C(6) hydrogenbonded chains formed between the OH and C O groups. In achiral C 5 H 6 O 2 S, these chains propagate only by translation, corresponding to x + 1, y, z + 1. However, in contrast, for racemic C 6 H 8 O 2 S the hydrogen-bonded chains propagate through a Àx + 3 2 , y + 1 2 , z operation, giving chains lying parallel to the crystallographic b-axis direction that are composed of alternate R and S enantiomers. The crystals of 3-hydroxy-4-methyl-2H-thiophen-5-one were found to be twinned by a 180 rotation about the reciprocal 001 direction. In the final refinement the twin ratio refined to 0.568 (2):0.432 (2).

Structural commentary
The molecular structures of compounds 4 and 5 are shown in Figs. 1 and 2, respectively. As can be seen from Tables 1 and 2, equivalent geometric parameters in the two structures are similar, with the largest difference in bond length being found for the S1-C4 values [1.816 (3) and 1.799 (3) Å ]. A notable structural difference is the orientation of the hydroxy groups containing the O2 atoms. In both structures, this O atom is coplanar with the SC 4 ring, but in structure 4 the H atom points towards C5 and is eclipsed by the C2 C3 double bond whilst in structure 5 the H atom points towards the CH 2 group and is eclipsed by the C3-C4 single bond. This change in orientation is associated with a change in the bond angles involving O2 [compare C4-C3-O2 angles of 113.4 (2) and 119.7 (3) ]. A search of the Cambridge Structural Database (version 5.40;Groom et al., 2016) found only three other structures with similar 4-hydroxy-thiophen-2-one cores. These are TLM itself (BIHKIM, Nawata et al., 1989) and two other derivatives (FIVKEA, Chambers et al., 1987;POXZOS, Kikionis et al., 2009). These have generally similar geometric parameters to those of 4 and 5. Two of the database structures have the same hydroxy group orientation as 5. Only POXZOS has the same hydroxy orientation as 4, and here this orientation is predetermined by the OH group participating in an intramolecular six-membered hydrogen-bonded ring. As with structures 4 and 5, in the database structures the orientation of the OH group is associated with systematic changes to the C-C-O bond angles involving OH.

Supramolecular features
The main supramolecular feature of both structures 4 and 5 is a one-dimensional C(6) hydrogen-bonded chain utilizing OH as the donor group and O1 as the acceptor group, see Tables 3  and 4. Behind these basic similarities there lies a great deal of difference in detail. In 5 the chains propagate by translations corresponding to x + 1, y, z + 1. This propagation by translation alone gives the repeating pattern shown in Fig. 3 where all of the SC 4 rings of the hydrogen-bonded unit are coplanar and all of the S atoms lie on the same side of the chain. When travelling along the b-axis direction, neighbouring chains bear their S atoms on different sides, giving the layered structure shown in Fig. 4. In contrast, for structure 4 the chain propagates through a Àx + 3 2 , y + 1 2 , z operation giving a chain lying

Figure 1
The molecular structure of 4 with non-H atoms shown as 50% probability ellipsoids. H atoms are drawn as small spheres of arbitrary size.

Figure 2
The molecular structure of 5 with non-H atoms shown as 50% probability ellipsoids. H atoms are drawn as small spheres of arbitrary size.
parallel to the crystallographic b-axis direction. As shown in Fig. 5, this results in the neighbouring R and S enantiomers of the racemic chain having perpendicular relationships between the planes of their SC 4 rings. This different chain geometry gives a very different packing arrangement from that of structure 5, see Fig. 6. The only interchain contact significantly shorter than the sum of van der Waals radii in either structure occurs in structure 5. This is a C-HÁ Á ÁO contact between the CH 2 group and the ketone O atom. Of the 4-hydroxy-thiophen-2-one structures described in the literature, both those of FIVKEA and BIHKIM (TLM) display the same C(6) hydrogen-bonded chain motif as 4 and 5. In both cases, the geometrical detail of the chain is similar to that found in 4, with the difference that both literature examples are enantiopure. The final structure, POXZOS, contains additional carboxylic acid and carbonyl groups and these strong hydrogen-bonding groups dominate the intermolecular contacts formed and so stop the formation of the otherwise common C(6) motif.

Synthesis and crystallization
General synthesis of thiolactone analogues 4 and 5: Bromine (1.1 eq) was added to a stirring solution of the corresponding oxoester (1 eq.) dissolved in chloroform (50 ml) at 273 K. The mixtures were allowed to warm to ambient temperature and stirred for 20 h before removing the solvent under vacuum. The resulting crude mixtures were dissolved in THF (50 ml) before adding trimethylamine (1.1 eq.) and thioacetic acid (1.1 eq.) and stirring at ambient temperature for a further 18 h. The resulting mixtures were reduced under vacuum to give dark-orange oils that were vacuum filtered over silica using petrol (40/60) and diethyl ether (5:2) as eluent before removing the solvent. The mixtures were dissolved in ethanol (50 ml) before adding a solution of sodium hydroxide (2 eq.) dissolved in water (20 ml) and stirring for 24 h at 333 K. After cooling, HCl (0.1M) was added until the solutions reached pH 5 before washing with ethyl acetate (3 Â 50 ml) and drying over anhydrous magnesium sulfate. The mixtures were reduced under vacuum and precipitated using petrol (40/60) and 1160 Nashawi et al. Part of the hydrogen-bonded chain motif present in the structure of 5. The chain extends parallel to the [101] direction.

Figure 4
Packing diagram for compound 5 in a view down the a axis. Note the alternating MeÁ Á ÁMe and SÁ Á ÁS layers.

Figure 5
Part of the hydrogen-bonded chain motif present in the structure of 4. The chain extends parallel to the cystallographic b axis.

Figure 6
Packing diagram for compound 4 with a view down the a axis. diethyl ether to give the products as a solid. For 4, crystals suitable for crystallographic analysis were grown from a THF solution. For 5, crystals were grown from a toluene solution.

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 5. For both structures, C-bound H atoms were placed in the expected geometric positions and treated in riding modes with C-H = 0.98, 0.99 and 1.00 Å for methyl, CH 2 and CH groups, respectively. U iso (H) = 1.5U eq (C) for methyl groups and 1.2U eq (C) for the other CH groups. The H atoms of the hydroxy groups were refined isotropically. Data collection on 5 was carried out by the National Crystallography Service (Cole & Gale, 2012). The crystals of 5 were found to be twinned by a 180 rotation about the reciprocal 001 direction. This feature was accounted for by producing a hklf 5 formatted datafile during data processing.

3-Hydroxy-2,4-dimethyl-2H-thiophen-5-one (4)
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.

3-Hydroxy-4-methyl-2H-thiophen-5-one (5)
Crystal data where P = (F o 2 + 2F c 2 )/3 (Δ/σ) max < 0.001 Δρ max = 0.43 e Å −3 Δρ min = −0.33 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. Refinement. Refined as a 2-component twin against a hklf 5 formatted datafile. This datafile was created by CrysalisPro for twinning by a 180 degree rotation about rec 001. Matrix used -0.9970 -0.0004 0.0038 0.0195 -0.9997 0.0133 0.7232 0.0009 0.9991 BASF refined to 0.432 (2).