Crystal structure of potassium [4-amino-5-(benzo[d]thiazol-2-yl)-6-(methylsulfanyl)pyrimidin-2-yl](phenylsulfonyl)azanide dimethylformamide monosolvate hemihydrate

The title compound, the potassium salt of a benzothiazol(methylsulfanyl)pyriminidine, was obtained in a reaction designed to deliver a neutral 2-pyrimidylbenzothiazole. It crystallized with two independent molecular units in the asymmetric unit.


Chemical context
Benzothiazoles are versatile heterocyclic biologically active compounds that are common in a variety of pharmaceutical preparations (Azzam et al., 2017a,b). These compounds are of great importance in the field of medicinal chemistry because of their remarkable pharmacological potential (Keri et al., 2015). Benzothiazole derivatives show a high degree of structural diversity that has proved beneficial in the search for new therapeutic agents (Gill et al., 2015). Research in benzothiazole-based medicinal chemistry has rapidly become an active topic, since numerous benzothiazole-based compounds have been widely used as clinical drugs to treat various types of diseases with high therapeutic potency (Sharma et al., 2013). The medicinal properties associated with benzothiazolerelated drugs have encouraged medicinal chemists to synthesize a large number of new therapeutics (Elgemeie & Elghandour, 1990;Elgemeie et al., 2000a,b). In recent years, 2-pyrimidylbenzothiazoles have appeared as an important pharmacological class in the development of anti-tumor agents (Das et al., 2003); their promising biological profile and synthetic accessibility have been attractive in their design and development as potential chemotherapeutics. In order to access this class of compounds in high yield and to introduce diversity, a variety of new synthetic methods has been invented (Seenaiah et al., 2014). Recently, we have described the syntheses of various antimetabolites starting from heterocyclic and acyclic cyanoketene dithioacetals (Elgemeie et al., 2015(Elgemeie et al., , 2016(Elgemeie et al., , 2017. As part of this program the reaction of ISSN 2056-9890 2-(benzo[d]thiazol-2-yl)-3,3-bis(methylthio)acrylonitrile (2) with N-(diaminomethylene)benzenesulfonamide (3) was studied (Fig. 1). The reaction between 2 and 3 in KOH/ dioxane gave a product that was crystallized from DMF and identified by X-ray crystallography as the title compound, 5, rather than the expected neutral 2-pyrimidylbenzothiazole derivative, 4. Compound 4 appears to be formed, at least in part, on dissolving 5 in deuterated DMSO; 1 H NMR measurements showed the free NH proton at 11.50 ppm. However, we have still been unable to isolate and crystallize derivative 4.
The formation of 5 from the reaction of 2 and 3 is assumed to proceed via initial addition of the amino group of 3 to the double bond of 2, followed by elimination of CH 3 SH and cyclization via addition of the amino group to the cyano group of benzothiazole to give the product 4, which separated as its potassium salt 5 in the presence of KOH in the reaction medium. The 1 H NMR spectra of the product 4, formed in part in solution in deuterated DMSO, revealed the presence of a pyrimidine methylthio group at = 2.19 ppm and an amino group at = 8.49 ppm in solution. Compound 5 and its derivatives showed interesting preclinical antiviral biological results compared to current antiviral drugs and are currently being patented (Elgemeie et al., 2018).

Structural commentary
The X-ray crystal structure indicated the exclusive presence of structure 5 in the solid state. The molecular structure of compound 5 is illustrated in Fig. 2. The asymmetric unit contains two potassium cations, two anions of 4 deprotonated at the sulfonamide nitrogen, two molecules of DMF and one of water; it was chosen arbitrarily in an attempt to maximize the number of weak interactions (bonds to potassium, hydrogen bonds) within this unit.
The potassium ions both display a highly irregular sixcoordination; all K-N and K-O contacts (Table 1) are < 2.92 Å , and the next longest are > 3.33 Å . The atom K1 is coordinated by the pyrimidine nitrogen atom N2 and the deprotonated sulfonamide nitrogen N5, the sulfonamide oxygen atom O1 0 and the water oxygen O1W within the asymmetric unit, and by the sulfonamide oxygen atom O2 0 and the DMF oxygen O92 at (Àx + 1, Ày + 1, Àz + 1). The atom K2 is coordinated by N2 0 , N5 0 and both DMF oxygen atoms within the asymmetric unit, plus O2 at (Àx + 1, Ày + 1, Àz + 1) and O1 at (x, y À 1, z). The angles subtended by the chelating The molecular structure of compound 5, with the atom labelling (anion 1 has unprimed atom labels, anion 2 has primed atom labels). Displacement ellipsoids are drawn at the 50% probability level. Dashed lines indicate contacts to the potassium ions (thick) or classical hydrogen bonds (thin). For clarity, the sulfonamide phenyl group is not labelled.

Figure 1
The attempted synthesis of compound 4.
anions via N2/N5 are particularly narrow. The bridging nature of O92 is shown in Fig. 3.
Each anion displays an intramolecular hydrogen bond (N4-H01Á Á ÁN3 and N4 0 -H01 0 Á Á ÁN3 0 ; Table 2), forming an S(6) ring motif. The anions display some differences in conformation; the angle between the benzothiazole ring (seven atoms) and the pyrimidine ring plus immediate substituents (ten atoms) is 20.56 (5) for anion 1 (unprimed atoms) but 42.20 (2) for anion 2 (primed atoms). Comparing the torsion angles in Table 1, it may be seen that the signs of the torsion angles C9-C8-C2-S1 are different for the two anions [22.06 (18) and À42.51 (16) ]. A molecular fit of the ten atoms of the pyrimidine ring, inverting one anion, gives an r.m.s. deviation of 0.03 Å (Fig. 4); the benzothiazole rings are then a better fit, but the phenyl rings of the sulfonamide groups then point to opposite sides in the two anions, cf. torsion angle C10-N5-S3-C13 is 62.49 (11) , and 65.28 (11) in the non-inverted system.

Supramolecular features
Classical hydrogen bonds are shown in Table 2. These four hydrogen bonds combined with the contacts at the potassium ions give a highly complex packing pattern. If the potassium ions are omitted, a much more simple pattern emerges; the residues are linked via the water molecules to form chains parallel to the b-axis direction, two of which are shown in Fig. 5.

Figure 4
A view of the molecular fit of the two independent anions of compound 5. Fitted atoms are labelled; anion 1 (inverted from the refined coordinates) is green, anion 2 (primed atoms) is purple.

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 3. The NH and OH hydrogen atoms were identified in difference-Fourier maps and refined freely.
Methyl groups were identified from difference-Fourier maps, idealized and refined as rigid groups [C-H = 0.98 Å , H-C-H = 109.5 with U iso (H) = 1.5U eq (C-methyl)], and allowed to rotate but not to tip (AFIX 137). Other hydrogen atoms were included using a riding model starting from calculated positions: C-H aromatic = 0.95 Å with U iso (H) = 1.2U eq (C).

Figure 5
A view normal to plane (101) of the crystal packing of compound 5. Hydrogen bonds (  (Rigaku OD, 2015); cell refinement: CrysAlis PRO (Rigaku OD, 2015); data reduction: CrysAlis PRO (Rigaku OD, 2015); program(s) used to solve structure: SHELXS97 (Sheldrick, 2008); program(s) used to refine structure: SHELXL2017 (Sheldrick, 2015); molecular graphics: XP (Siemens, 1994); software used to prepare material for publication: SHELXL2017 (Sheldrick, 2015). 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) 7.5026 (