A solid solution of ethyl and d 3-methyl 2-[(4-methylpyridin-2-yl)amino]-4-(pyridin-2-yl)thiazole-5-carboxylate

The crystal structure of a solid solution of ethyl and d 3-methyl 2-[(4-methylpyridin-2-yl)amino]-4-(pyridin-2-yl)thiazole-5-carboxylate is reported.


Structural commentary
Inspection of the difference electron-density map after initial refinement of the structure representing the anticipated compound 3 against the data clearly revealed unexpected negative residual electron density around C19, the methyl C atom of the ethyl ester group (Fig. 2, top), indicating that too much electron density was assigned to this site in the model. Taking the crystallization conditions (see section 5) into account, we concluded that partial in situ transesterification, as depicted in Fig. 3, had occurred. Methanol is known to have the strongest replacing power in transesterification reactions (Otera, 1993). After modelling the structure as a solid solution of 3 and the corresponding d 3 -methyl ester 4, the negative residual electron density around C19 disappeared (Fig. 2,bottom)  Chemical synthesis of 2-aminothiazole 3 from -bromoketone 1 and 1-(4methylpyridin-2-yl)thiourea (2).

Figure 2
F obs -F calc electron-density maps (isosurface level 0.18 e Å À3 ). Positive and negative residual electron density shown respectively as green and red mesh. Top: after initial structure refinement as ethyl ester 3. Bottom: after refinement as solid solution of ethyl (3) and d 3 -methyl ester (4). The pictures were generated with ShelXle (Hü bschle et al., 2011).

Figure 3
In situ transesterification reaction of 3 to 4 in the crystallization solvent methanol-d 4 . 0.880 (6):0.120 (6) for 3 and 4 in the crystal. The presence of both 3 and 4 in the sample was subsequently confirmed by high-resolution mass spectrometry (see supporting information). Fig. 4 shows the individual molecular structures of 3 and 4 that make up the solid solution. Selected geometric parameters are listed in Table 1. Bond lengths and angles of the central 1,3-thiazole five-membered heterocyclic ring are as expected (Eicher et al., 2013). The thiazole S atom and the pivot C6 atom of the picoline moiety as well as the pivot C2 atom of the thiazole ring and the picoline nitrogen atom N1 exhibit a synperiplanar conformation, as revealed by the respective torsion angles in Table 1. The thiazole ring and picoline six-membered ring are nearly coplanar to one another with a dihedral angle between the respective mean planes of 3.2 (6) . The intramolecular S1Á Á ÁN1 distance is 2.646 (1) Å and corresponding C5-S1Á Á ÁN1 angle is 162.70 (4) . The arrangement can structurally be regarded as a chalcogen bond between the lone pair of the picoline N atom and the hole at the S atom opposite to the C5-S1 bond (Scilabra et al., 2019;Vogel et al., 2019). The plane of the carboxylate unit is tilted out of the thiazole mean plane by 4.9 (2) , whereas the mean plane of the pyridine ring appended to C4 is tilted out of the latter plane by 68.06 (4) . This significant twist between the thiazole and pyridine rings should weaken the conjugation of electrons in the molecule. Indeed, the related N-(4-(pyridin-3-yl)-1,3-thiazol-2-yl)pyridin-2-amine, for example, exhibits a virtually planar molecular structure in the crystal (CSD refcode: XOVJAV; Makam & Kannan, 2014). The twist between the pyridine ring and the thiazole ring in 3 and 4 can be ascribed to involvement of the pyridine N atom in intermolecular hydrogen bonding (see Section 3) and steric clashes with the neighbouring carboxylate substituent, which appears to be preferentially conjugated to the thiazole ring.

Supramolecular features
The supramolecular structure of the solid solution of 3 and 4 is dominated by hydrogen bonds of the N-HÁ Á ÁN type between the secondary amino group and the pyridine N atom. As shown for the major component 3 in Fig. 5, this results in polymeric hydrogen-bonded zigzag tapes extending in the [001] direction through glide symmetry. The geometric parameters (Table 2) are within the ranges expected for strong hydrogen bonds (Thakuria et al., 2017). Molecules in adjacent tapes are linked through two short C-HÁ Á ÁO contacts between the -CH groups of the picoline ring and the formal C O groups of the carboxylate moieties, forming approximately planar dimeric picoline thiazole ester units (Fig. 6). The corresponding geometric parameters (Table 2) support the interpretation that these are weak hydrogen bonds (Thakuria et al., 2017 Hydrogen-bonded zigzag tape of the molecules in the solid solution of 3 and 4, shown only for the major component 3 for clarity, viewed approximately along the b-axis direction towards the origin. Carbonbound H atoms are omitted for clarity. Symmetry code: (i) x, Ày + 1 2 , z À 1 2 .

Synthesis and crystallization
Syntheses of the starting materials can be found in the literature, as indicated. Solvents were of reagent grade and distilled before use. The melting point (uncorrected) was determined on a Boetius melting-point apparatus (VEB Kombinat NAGEMA, Dresden, GDR). 1 H and 13 C NMR spectra were recorded at room temperature on an Agilent Technologies VNMRS 400 NMR spectrometer. The residual solvent signals of DMSO-d6 ( 1H = 2.50 ppm, 13C = 39.51 ppm) were used to reference the spectra (abbreviations: s = singlet, d = doublet, t = triplet, q = quartet, td = triplet of doublets, m = multiplet). The mass spectrum was recorded on a Q Exactive TM Plus Orbitrap mass spectrometer (Thermo Scientific, Bremen, Germany), using methanol as solvent.
Crystals of the title solid solution of 3 and 4 suitable for X-ray analysis were obtained from a solution of 3 in methanold 4 upon standing at room temperature for a couple of weeks.

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 3. The ratio of the occupancies of the ethyl group belonging to 3 and the d 3 -methyl ester group belonging to 4 was refined by means of a free variable, resulting in 0.880 (6):0.120 (6). Carbon-bound H and D atoms were placed at geometrically calculated positions with C aromatic -H = 0.95 Å , C methylene -H = 0.99 Å and C methyl -H/ D = 0.98 Å and refined with U iso (H) = 1.2 U eq (C) (1.5 for methyl groups). The methylene H atoms (belonging to 3) attached to C18 were included in the split model refined for the solid solution, but the parent C18 was not. The torsion angle of the methyl group of C19 was initially determined through a circular difference-Fourier synthesis and subsequently refined while maintaining the tetrahedral angles. The methyl group of C11 was treated as idealized disordered C-HÁ Á ÁO hydrogen-bonded association of two adjacent molecules in the solid solution of 3 and 4, shown only for the major component 3 for clarity. For the sake of clarity, rotational disorder of the methyl groups is also not shown. Symmetry code: (ii) Àx + 2, Ày + 1, Àz + 1. methyl group. Refinement of the ratio of occupancies by means of a free variable yielded 0.21 (4):0.79 (4). The amino H atom was located in a difference-Fourier map and refined semi-freely with the N-H distance restrained to a target value of 0.88 (2) Å and U iso (H) = 1.2U eq (N). The amino group was treated as non-deuterated only in agreement with the mass spectrum in methanol, although partial H/D exchange during the crystallization from methanol-d 4 cannot be ruled out. Computer programs: APEX3 (Bruker, 2017) and SAINT (Bruker, 2004), SHELXT2014/ 4 (Sheldrick, 2015a), SHELXL2018/3 (Sheldrick, 2015b), DIAMOND (Brandenburg, 2018), enCIFer (Allen et al., 2004) and publCIF (Westrip, 2010

Computing details
Data collection: APEX3 (Bruker, 2017); cell refinement: SAINT (Bruker, 2004); data reduction: SAINT (Bruker, 2004); program(s) used to solve structure: SHELXT2014/4 (Sheldrick, 2015a); program(s) used to refine structure: SHELXL2018/3 (Sheldrick, 2015b); molecular graphics: DIAMOND (Brandenburg, 2018); software used to prepare material for publication: enCIFer (Allen et al., 2004) and publCIF (Westrip, 2010). 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.