Crystal structure of 5-(β-d-glucopyranosylthio)-N-(4-methylphenyl)-1,3,4-thiadiazol-2-amine

In the title compound, the angle between the tolyl and thiadiazole rings is 9.2 (1)°. The hydrogen bonding is a combination of a ribbon involving hydrogen bonds of the sugar residues, and a layer based on N—H⋯O and O—H⋯N hydrogen bonds.


Chemical context
There has been considerable recent interest in the chemistry of compounds involving both heterocyclic and carbohydrate moieties (Lopes et al., 2021). Heterocyclic thioglycosides are promising candidates in synthetic carbohydrate research, and some of these compounds have displayed various antagonistic activities (Abu-Zaied et al., 2011, 2019. 1,3,4-Thiadiazoles are an important class of heterocycles that have found diverse applications in organic synthesis, biological applications, and pharmaceuticals (Sun et al., 2011), thus motivating researchers to prepare many derivatives of these compounds (Matysiak, 2015). Our interest in synthesizing novel active heterocycles Hebishy et al., 2022;Abdallah et al., 2022) and their glycosylic derivatives (Azzam et al., 2022a,b) led us to expect that 1,3,4-thiazole compounds and their sugar-linked products could be valuable systems for designing novel cytotoxic agents (Yang et al., 2012). In our previous work, many antiviral heterocyclic thioglycosides, such as azole and azine thioglycosides, were synthesized and found to display effective cytotoxicities (Elgemeie et al., 2016(Elgemeie et al., , 2017a(Elgemeie et al., ,b, 2018Elgemeie & Mohamed-Ezzat, 2022a,b). We have also reported that dihydropyridine thioglycosides can be used as inhibitors of the glycosylation of proteins (Scala et al., 1997).
In the current study, we have designed a facile synthesis of 1,3,4-thiadiazole thioglucosides by coupling of potassium 1,3,4-thiadiazolates and protected -d-glucopyranosyl bromide. Our target derivative was synthesized by the reaction of the thiosemicarbazide derivative 1 with carbon disulfide in boiling KOH/EtOH to afford the corresponding potassium 1,3,4-thiadiazole thiolate 2 in good yield (Fig. 1). Compound 2 was then coupled with acetylated -d-glucopyranose bromide 3 in DMF at room temperature to give a product that could in principle be either the 1,3,4-thiadiazole S-glucoside 4 or the isomeric N-glucoside 5, corresponding to two different modes of glycosylation. Deprotection then provided a final product that should be either the 1,3,4-thiadiazole S-glucoside 6 or the isomeric N-glucoside 7. Spectroscopic data cannot distinguish these two structures with absolute certainty, although it had already been proposed that a simple S N 2 reaction between 2 and 3 would give the -glucoside product 4 (Masoud et al., 2017;Hammad et al., 2018), which would imply the final formation of 6. This is consistent with the spectroscopic data; thus the 1 H NMR spectrum of 6 showed the signal of the anomeric proton as a doublet at 4.72 (J 1',2' = 10.8 Hz), strongly implying a -d-configuration. The 13 C NMR spectrum exhib-ited a signal at 86.89 corresponding to C-1 0 , whereas the signals at 61. 34, 70.00, 73.07 and 78.32, 81.42 were allocated to C-6 0 , C-4', C-2 0 , C-3 0 and C-5 0 . The X-ray structure determination, presented here, unambiguously shows the isolated product to be the 1,3,4-thiadiazole-5-thioglucoside 6 ( Fig. 1).

Structural commentary
The molecular structure of compound 6 is shown in Fig. 2. Note that the standard sugar numbering has been slightly modified (to C11-16) for the crystallographic numbering. Molecular dimensions (Table 1) may be regarded as normal; e.g. the bond lengths at S2 are significantly different, consistent with the different hybridization of the carbon atoms [C2-S2 = 1.7473 (17), C11-S2 = 1.811 (2) Å ], and the angle C5-N1-C21 is wide at 128.45 (18) . The interplanar angle between the tolyl and thiadiazole rings is 9.2 (1) . The (equatorial) position of the substituent at the glucose ring is confirmed by the torsion angle C15-O1-C11-S2 of 177.11 (10) . The absolute configuration was confirmed by the Flack parameter, with chiralities S,R,S,S,R at C11-15 respectively consistent with the presence of d-glucose.

Figure 2
The molecule of compound 6 in the crystal. Ellipsoids represent 50% probability levels.
complex, and this is indeed the case. However, the packing may be analysed in terms of more easily assimilable substructures. One, formally one-dimensional, substructure involving the sugar residues can readily be identified (Fig. 3), the hydrogen bonds O2-H02Á Á ÁO3 and O3-H03Á Á ÁO4(Àx + 3, y + 1 2 , Àz + 1 for both) combine via the 2 1 screw axis to form ribbons of molecules parallel to the b axis. The ribbons lie in layers roughly parallel to (105). The OH group at C16 is directed away from its layer to form contacts to the neighbouring layer.
A second, two-dimensional, substructure ( Fig. 4) is based on the remaining three hydrogen bonds (of the types O-HÁ Á ÁN and N-HÁ Á ÁO), and connects the molecules first by translation (both O-HÁ Á ÁN hydrogen bonds; x + 1, y À 1, z) to form chains parallel to (110) (horizontal in the Figure), and secondly by a-axis translation (the N-HÁ Á ÁO hydrogen bond; x À 1, y, z). The overall effect is to create layers parallel to the ab plane.
The contact O5-H05Á Á ÁN3(x + 1, y À 1, z) may be regarded as the second, weaker, branch of a three-centre interaction, but this contact is omitted from the packing diagrams for clarity. Similarly, the two C-HÁ Á ÁS interactions are probably interpretable as 'weak' hydrogen bonds, but we do not discuss their structural role in detail.

Synthesis and crystallization
Preparation of intermediate 4: A solution of 2,3,4,6-tetra-Oacetyl--d-glucopyranosyl bromide (3) (10 mmol) in dry DMF (15 mL) was added dropwise over 30 min to a solution of the potassium thiolate 2 (10 mmol) in 20 mL of DMF. The reaction mixture was stirred at room temperature until completion (monitored by TLC), then the mixture was poured into icewater, and the resulting precipitate was collected by filtration, dried, and crystallized from ethanol to give the acetylated glucoside 4. Packing diagram of compound 6: the layer substructure involving the O-HÁ Á ÁN and N-HÁ Á ÁO hydrogen bonds (indicated by thick dashed lines). The view direction is perpendicular to the ab plane. The labelled atom (O1) indicates the asymmetric unit. Table 2 Hydrogen-bond geometry (Å , ).

Figure 3
Packing diagram of compound 6: the glucose-based substructure involving two O-HÁ Á ÁO hydrogen bonds (indicated by thick dashed lines). The view direction is perpendicular to the plane (105). The labelled atom (O1) indicates the asymmetric unit.
NÁB.: The NMR data, as given here and in Section 1, refer to sugar numbering C1 0 -C6 0 , which is different from the crystallographic numbering of the glucose moiety in 6 (C11-C16).
White powder ( H 4.92,N 7.59,S 11.58. Found: C 49.82,H 4.81,N 7.52,S 11.46%. Preparation of title compound 6: In a 50 mL flask, the tetraacetylated glucoside derivative 4 (0.01 mol) was dissolved in 20 mL of dry methanol, and then ammonia gas was passed through the solution at 273 K for 10 min. The mixture was then stirred until the reaction was complete (monitored by TLC using chloroform/methanol 9:1). The solution was concentrated under reduced pressure to afford a solid residue, which was washed several times with boiling chloroform. The residue was dried, purified and recrystallized from ethanol to give the corresponding free glucoside 6.

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 3. Hydrogen atoms of the NH and OH groups were refined freely, the latter however with O-H distances restrained to be approximately equal (command SADI). The methyl group was included as an idealized rigid group allowed to rotate but not tip (C-H = 0.98 Å , H-C-H = 109.5 ). Other hydrogen atoms were included using a riding model starting from calculated positions (C-H aromatic 0.95 Å , C-H methine 1.00 Å , C-H methylene 0.99 Å ). The U(H) values were fixed at 1.5 Â U eq of the parent carbon atoms for the methyl group and 1.2 Â U eq for other hydrogens. An extinc-tion correction was performed; the extinction parameter as defined by Sheldrick (2015a) refined to 0.0009 (3). The absolute configuration (corresponding to d-glucose) was confirmed by the Flack parameter of À0.006 (5). Computer programs: CrysAlis PRO (Rigaku OD, 2021), SHELXT (Sheldrick, 2015b), SHELXL2018/3 (Sheldrick, 2015a) and XP (Siemens, 1994).  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. Least-squares planes (x,y,z in crystal coordinates) and deviations from them (* indicates atom used to define plane