4-Amino-5-(4-bromobenzoyl)-3-(benzo[d]thiazol-2-yl)-2-[(2′,3′,4′,6′-tetra-O-acetyl-β-d-galactopyranosyl)sulfanyl]thiophene

The benzothiazole and thiophene rings are almost coplanar. The NH2 group forms intramolecular hydrogen bonds. The Sgalactose—Cthiophene bond is short. The molecules are connected by two ‘weak’ hydrogen bonds and a short N⋯S contact.


Structure description
Benzothiazoles are the most widely applied class of heterocyclic compounds in medicinal chemistry, and benzothiazole derivatives have been employed in many pharmaceutical preparations (Bonde et al., 2015), because they offer a variety of pharmacological properties useful in treating many diseases . As clinical drugs, they often act with high therapeutic efficacy (Huang et al., 2009). The broad pharmacological activities of benzothiazoles suggest that they are also important for developing future drugs (Rana et al., 2008). Recently we have explored various novel synthetic methods to obtain benzothiazole derivatives (Azzam et al. 2017a(Azzam et al. ,b, 2020a(Azzam et al. ,b,c, 2021Elgemeie et al., 2000a,b;. As a part of our current plan directed toward discovering synthetic methodologies for the preparation of S-glycosylated derivatives of heterocyclic nitrogen bases (Elgemeie et al., 2017a,b,c), we have lately described the synthesis and biological activity of a series of heterocyclic S-glycosides that have promising cytotoxic activity (Abu-Zaied et al., 2011, 2019a,b, 2020, 2021Elgemeie et al., 2009Elgemeie et al., , 2018. We found that our reported dihydropyridine S-glycosides have a strong anti-P-glycoprotein effect against human tumor cells data reports (Scala et al., 1997). Consistent with these outcomes and our past research (Elgemeie et al., 2015(Elgemeie et al., , 2016(Elgemeie et al., , 2019, the purpose of the current study was to design and synthesize benzothiazole-based thiophene thioglycosides. The synthesis of our target benzothiazole-2-thiophene thioglycoside was carried out by the reaction of benzothiazole 2-thiophenethiol derivative 1 with 2,3,4,6-tetra-O-acetyl--d-galactopyranosyl bromide 2 in the presence of potassium hydroxide to give the corresponding benzothiazole-2-thiophene S-glycoside 3 in good yield (Fig. 1). It has been suggested that the cis-() sugars react via a simple S N 2 reaction to give the -glycoside products such as 3 (Masoud et al., 2017;Hammad et al., 2018). The structure of 3 was confirmed based on the spectroscopic data ( 13 C NMR, 1 H NMR, and IR). The 1 H NMR spectrum of compound 3 showed the anomeric proton as a doublet at = 5.39 p.p.m. with a spin-spin coupling constant (J 1 0 ,2 0 = 8.8 Hz) confirming the -configuration. The other six protons of galactose resonated at 4.00-5.30 p.p.m. In order to establish the structure of the product unambiguously, its crystal structure was determined and is reported here. To the best of our knowledge, this is the first reported X-ray structure of the new compound type benzothiazole-2-thiophene thioglycoside.
The structure of 3 is shown in Fig. 2. The dimensions of the benzothiazole moiety are as expected (a selection of molecular dimensions is presented in Table 1). The benzothiazole and thiophene ring systems are approximately coplanar [interplanar angle 7.43 (12) ], a geometry that is reinforced by the two intramolecular hydrogen bonds from the NH 2 group to the thiazole nitrogen atom and the C O group (Table 2), whereas the bromophenyl and thiophene rings subtend an angle of 58.23 (6) . The intramolecular S2Á Á ÁS3 contact is 3.1416 (8) Å .
The configuration (equatorial position of the sulfur atom) at the anomeric carbon of the sugar (here C31) is confirmed, as is the axial configuration of the substituent at C34, characteristic of galactose. The galactose ring displays a slightly The molecule of 3 in the crystal. Ellipsoids represent 50% probability levels. The dashed lines indicate intramolecular hydrogen bonds.  Symmetry codes: (i) x; y þ 1; z; (ii) Àx þ 2; y À 1 2 ; Àz þ 1.

Figure 1
Reaction scheme. flattened chair conformation, with absolute torsion angles < 50 about C32-C33 and C33-C34. The configurations at C31-C35 are S, R, S, R, R, respectively. The S3-C31 bond is as expected longer than S3-C2, with values of 1.819 (2) and 1.759 (2) Å , respectively; the latter is significantly shorter than the values found for similar compounds in search of the Cambridge Structural Database (Groom et al., 2016; performed using CONQUEST Version 2021.3.0) for purely organic galactose derivatives substituted with a sulfur atom at the anomeric carbon. There were 22 hits, of which two were axially substituted (NODQEC, Khiar et al., 1997;YINFUY, Smith et al., 2013) and the remainder equatorially substituted. The 29 C-S bond lengths for the latter lay in the range 1.788-1.856, average 1.808 (13) Å . Restricting the analysis to the ten hits with an sp 2 carbon atom altered these values only marginally.
The N-H donor groups do not participate in intermolecular hydrogen bonding, but two short and acceptably linear C-HÁ Á ÁO contacts between the galactose moieties may be classed as 'weak' hydrogen bonds (Table 2). Additionally, a short contact N2Á Á ÁS3 of 3.249 (2) Å is observed (operator x, 1 + y, z). The net effect is to form ribbons of molecules parallel to the b axis (Fig. 3).

Synthesis and crystallization
Thiophene thiol derivative 1 (2.23 g, 5 mmol) was dissolved in acetone (10 ml) containing 0.5 ml of aq. KOH (0.25 g, 5 mmol). The mixture was warmed to 50 C for 15 min. After cooling, a solution of 2,3,4,6-tetra-O-acetyl--d-galacto-pyranosyl bromide 2 (2.05 g, 5 mmol) in acetone (10 ml) was added dropwise over 30 min. The reaction mixture was stirred at room temperature and monitored by TLC until the reaction was complete (8 h). The residue was washed with distilled water to remove KBr, then dried and crystallized from ethanol to produce compound 3 (