Heterocyclic tautomerism: reassignment of two crystal structures of 2-amino-1,3-thia­zolidin-4-one derivatives

The structures of 5-(2-hy­droxy­ethyl)-2-[(pyridin-2-yl)amino]-1,3-thia­zolidin-4-one, C₁₀H₁₁N₃O₂S, (I), and ethyl 4-[(4-oxo-1,3-thia­zolidin-2-yl)amino]­benzoate, C₁₂H₁₂N₂O₃S, (II), which are identical to the entries with refcodes GACXOZ [Váňa et al. (2009). J. Heterocycl. Chem. 46, 635–639] and HEGLUC [Behbehani & Ibrahim (2012). Mol­ecules, 17, 6362–6385], respectively, in the Cambridge Structural Database [Allen (2002). Acta Cryst. B58, 380–388], have been redetermined at 130 K. This structural study shows that both investigated compounds exist in their crystal structures as the tautomer with the carbonyl–imine group in the five-membered heterocyclic ring and an exocyclic amine N atom, rather than the previously reported tautomer with a secondary amide group and an exocyclic imine N atom. The physico­chemical and spectroscopic data of the two investigated compounds are the same as those of GACXOZ and HEGLUC, respectively. In the thia­zolidin-4-one system of (I), the S and chiral C atoms, along with the hy­droxy­ethyl group, are disordered. The thia­zolidin-4-one fragment takes up two alternative locations in the crystal structure, which allows the mol­ecule to adopt R and S configurations. The occupancy factors of the disordered atoms are 0.883 (2) (for the R configuration) and 0.117 (2) (for the S configuration). In (I), the main factor that determines the crystal packing is a system of hydrogen bonds, involving both strong N—H...N and O—H...O and weak C—H...O hydrogen bonds, linking the mol­ecules into a three-dimensional hydrogen-bond network. On the other hand, in (II), the mol­ecules are linked via N—H...O hydrogen bonds into chains.

S1. Introduction

1,3-Thia­zolidin-4-one derivatives are a well known class of patented drugs, among which are, for example, hypoglycaemic thia­zolidinediones (pioglitazone and its analogues), aldose redu­ctase inhibitors (epalrestat), anti-inflammatory agents (darbufelone) and new-generation diuretics (etozoline). In modern medicinal chemistry, the thia­zolidinone core is a powerful biophore for the rational design of `drug-like' molecules. Modern research into the pharmacological potential of 1,3-thia­zolidin-4-ones has allowed the establishment of a wide spectrum of pharmacological activities, including anti­cancer, anti-inflammatory, anti­viral, anti­parasitic, anti­microbial and anti­oxidant (Lesyk & Zimenkovsky, 2004; Lesyk et al., 2011).

It is worth noting that studies regarding amino–imino tautomerism in 2-amino­(imino)-1,3-thia­zolidin-4-one derivatives have been carried out continually for almost 50 years. The investigations have been performed on crystalline and liquid phases using different spectroscopic techniques, e.g. IR, UV, ¹H and ¹³C NMR, or sometimes with calculations in quantum chemistry. X-ray crystallography is not commonly used among the analytical methods applied to structural studies concerning tautomerism. In the Cambridge Structural Database (CSD, Version 5.35; Allen, 2002), we found only 21 structures with the amine form (refcodes EKELEL FIVPIJ, FOWQOY, IHUFAS, IMPTHA01, IMPTHA12, IMTAZO01, INMTZO, JOBGOW, KUKZUM, PACPIU, PATAZO, PTHAZO10, SALYOT, SINQOW, SINQUC, TEBDAH, ULACAM, VELBEU, WOSMAS and YUQCAP) and 16 with the imino form (refcodes EHITZO, GACXOZ, HEGLUC, HEGMAJ, HEGMEN, HEGMIR, HEGMOX, IMTAZO, IOTAGP, IXTAZD10, RIPMOT, ROMXUN, SOHHIH, ULACEQ, VAMPUW and YARLIN), the latter set including two structures with an incorrectly specified tautomeric form.

As part of a programme aimed at the development of new biologically active compounds, we have prepared 5-(2-hy­droxy­ethyl)-2-[(pyridin-2-yl)amino]-1,3-thia­zolidin-4-one, (I) [CSD refcode GACXOZ; Váňa et al., 2009], and ethyl 4-[(4-oxo-1,3-thia­zolidin-2-yl)amino]­benzoate, (II) [CSD refcode HEGLUC; Behbehani & Ibrahim, 2012] (Scheme 1), and have made corrections to the inter­pretations of their previously published structures. According to the previous reports, the investigated compounds exist in tautomeric form A2, with a secondary amide group in the five-membered heterocyclic ring and an exocyclic imine N atom (see Scheme 2).

S2. Experimental

S2.1. Synthesis and crystallization

The title compounds were synthesized by methods used for obtaining 2-amino­(imino)-1,3-thia­zolidin-4-one derivatives (Subtel'na et al., 2010; Geronikaki et al., 2008; Ostapiuk et al., 2012). Compound (I) was prepared by the [2+3]-cyclo­condensation reaction of 3-bromo­tetra­hydro­furan-2-one (α-bromo-γ-butyrolactone) with 1-(pyridin-2-yl)thio­urea in the presence of fused sodium acetate in refluxing ethanol. Compound (II) was synthesized through cyclo­condensation of ethyl 4-(2-chloro­acetyl­amino)­benzoate and ammonium thio­cyanate in ethanol (Behbehani & Ibrahim, 2012). It is known that the above-mentioned reactions do not stop at the nucleophilic substitution stage (Geronikaki et al., 2008; Ostapiuk et al., 2012). The inter­mediate α-thio­cyanato­amide undergoes spontaneous cyclization/rearrangement to give the thia­zolidin-4-one derivative, (II).

The physicochemical and spectroscopic data of (I) and (II) are the same as for GACXOZ and HEGLUC, respectively. Crystals suitable for single-crystal X-ray diffraction analysis were grown by slow evaporation of solutions in methanol [for (I)] and di­methyl­formamide [for (II)].

S2.2. Refinement

For both (I) and (II), N-bound H atoms were obtained from difference Fourier maps and refined freely. The remaining H atoms were positioned geometrically and refined within the riding-model approximation, with methyl C—H = 0.98, methyl­ene C—H = 0.99, methine C—H = 1.00, Csp² C—H = 0.95 and O—H = 0.88 Å, and with U_iso(H) = 1.2U_eq(C), or 1.5U_eq(C,O) for methyl and hy­droxy H atoms. The methyl groups were refined as rigid groups, which were allowed to rotate. Non-H atoms of the disordered part of the molecule of (I) were obtained from difference Fourier maps. During refinement, the EADP instruction (SHELXL2014; Sheldrick, 2008) was used to constrain the displacement ellipsoids of the atoms in the alternative positions a and b. Bond distances between corresponding atoms were restrained with a SADI instruction. The H atoms of the OH groups of the hy­droxy­ethyl residues in positions a and b were separated in an arbitrary manner (DFIX instruction) with a distance of 0.61 Å. [Please rephrase without using software-specific terms.]

S3. Results and discussion

S3.1. Tautomeric forms

Our revision of the X-ray studies has shown that, in their crystal structures, compounds (I) and (II) adopt tautomeric form A1 rather than the previously suggested form A2 (Scheme 2 and Figs. 1 and 2). In both structures, the H atom was located at the exocyclic N atom (N6). This observation for (II) is supported by the presence of N6—H6···O18ⁱ hydrogen bonds (Table 2 and Fig. 3), in which atom N6 acts as a proton donor and carbonyl atom O18 as a proton acceptor. The formation of this N—H···O hydrogen bond is promoted by the anti­periplanar conformation of the C2—N3 and N6—H6 bonds [torsion angle N3—C2—N6—H6 = 180 (2)°].

In (I), the presence of N6—H6···N3ⁱ hydrogen bonds between the amidine groups (Table 3 and Fig. 4a) may lead to ambiguity about the amine/imine character of atoms N3 and N6. It is known that the presence of N—H···N hydrogen-bond contacts enhances the resonance effect, which is significant even for unassociated molecules. Therefore, one may be inclined to think that, for structure (I) forming hydrogen-bonded dimers, both tautomeric forms are possible, and the C2—N3 and C2—N6 bond lengths do not provide much useful information for solving this problem because of resonance inter­actions which render their lengths similar regardless of the tautomeric form. However, atom H6 was located and refined at this position and, in addition, analysis of the C2—N3 and C2—N6 bond lengths performed for tautomeric forms A1 and A2 did not confirm these suppositions.

The average C2—N3 and C2—N6 bond lengths in 20 2-amino-1,3-thia­zolidin-4-one derivatives deposited in the CSD and exhibiting the A1 tautomeric form are similar and adopt values of 1.325 (1) and 1.315 (2) Å, respectively (refcodes EKELEL, FIVPIJ, FOBQOY, IHUFAS, IMPTHA12, IMTAZO01, INMTZO, JOBGOW, KUKZUM, PACPIU, PTHAZO10, SALYOT, SINQOW, SINQUC, TEBDAH, ULACAM, VELBEU, VEQFAA, WOSMAS and YUQCAP; R < 0.07). These mean C2—N3 and C2—N6 bond lengths are inter­mediate between the lengths of single and double C—N bonds. In comparison with the usual literature C═N double-bond value of 1.279 (1) Å (Allen et al., 1987), they are lengthened by about 33 and 16σ, respectively. On the other hand, they are shortened by about 26 and 24σ, respectively, compared with the mean value for a Csp²—N single-bond length [1.383 (2) Å]. This latter value was obtained from 117 structures of 2-imine-1,3-thia­zolidin-4-one derivatives substituted at N3 (R <0.07). Based on six records revealing the A2 tautomeric form, the average C2—N3 and C2—N6 bond lengths were calculated as 1.374 (3) and 1.280 (2) Å, respectively (refcodes EHITZO, HEGMAJ, HEGMEN, HEGMIR, HEGMOX and VAMPUV; R < 0.07), which are clearly different from one another. The former is similar to the normal Csp²—N single-bond length in heterocyclic rings, while the latter is close to a normal C═N double-bond length.

Our observations thus indicate an unequal resonance effect in tautomeric forms A1 and A2, which allows the use of the C—N bond values to distinguish the forms. Crystal structure analysis of (I) and (II) shows that the inter­atomic lengths C2—N3 and C2—N6 [1.3256 (17) and 1.3385 (19) Å in (I), and 1.3182 (15) and 1.3282 (15) Å in (II)] have comparable values, which is a typical feature of tautomeric form A1.

We thus submit that the original tautomeric assignments of GACXOZ and HEGLUC were incorrect, and propose they both be reassigned to the A1 form, supported by the evidence presented here. From the comparison of (I)/GACXOZ and (II)/HEGLUC it is clear that the molecules in pairs have the same geometry and, what is particularly important, very similar C2—N3 and C2—N6 bond lengths. In the first pair, the bond lengths are 1.326/1.322 and 1.338/1.337 Å, while in the second pair they have values of 1.318/1.308 and 1.328/1.333 Å, respectively. The structural differences relate to the position of the mobile N—H hydrogen only. We think that incorrect localization of the H atom at the endocyclic and not at the exocyclic N atom in GACXOZ and HEGLUC is most likely a result of the fact that the H atoms bonded to N atoms were positioned geometrically and were treated using a riding model, with the U_iso(H) parameter calculated and not refined. If U_iso(H) had been refined by the authors of the earlier papers, the mistake would have been noticed and corrected.

S3.2. Further details of the structural analysis

Some atoms in the crystal structure of (I) are disordered. This observation concerns the part of the molecule that includes atoms S1, C5, C14, C15 and O16 of the 2-hy­droxy­ethyl-1,3-thia­zolidin-4-one fragment. Each of these atoms takes up two alternative locations in the crystal structure, labelled a and b. This arrangement results in two different enanti­omers of the molecule, with atoms S1, C5, C14, C15 and O16 in position a having an R configuration and the atoms in position b have an S configuration (for the molecule shown in Fig. 1), and vice versa for a symmetry-related site. The occupancy factor for atoms S1, C5, C14, C15 and O16 in orientation a is 0.883 (2), while in orientation b the occupancy factor is 0.117 (2).

The thia­zolidine ring with atoms S1 and C5 in arrangement a is approximately planar (r.m.s. deviation = 0.0213 Å), while the ring with these atoms in arrangement b is folded (r.m.s. deviation = 0.1130 Å) and adopts a half-chair conformation [Cremer & Pople (1975) puckering parameters Q = 0.253 (8) Å and ϕ = 130.0 (16)°].

The pairs of bonds S1—C2/N6—C7 and C2—N6/C7—N8 are in a synperiplanar conformation. The torsion angles S1a/(S1b)—C2—N6—C7 and C2—N6—C7—N8 are 4.2 (2)/-14.7 (3) and -10.6 (2)°, respectively. The arrangements of the two alternative hy­droxy­ethyl residues are determined by torsion angles C5a—14a—C15a—O16a = 55.8 (2)° and C5b—C14b—C15b—O16b = 178.1 (14)°, from which the pairs of bonds C5a—C14a/C15a—O16a and C5b—C14b/C15b—O16b are synclinal and synperiplanar, respectively.

The heterocyclic and phenyl rings in (II) are both flat and approximately coplanar. The dihedral angle between their mean planes is 6.59 (6)°. Atoms C13, O14, O15 and C16 form a flat system (r.m.s. deviation = 0.0015 Å) that is twisted out of the mean plane of the phenyl ring by 2.23 (8)°. The remaining atom C17 is tlted from the flat system formed by atoms C13, O14, O15 and C16 by 0.201 (3) Å. Atoms C13 and C17 are in an anti­periplanar conformation [torsion angle C13—O15—C16—C17 = 172.17 (12)°]. On the other hand, the C13═O14 carbonyl group is in a synperiplanar conformation in relation to the S1—C2 bond of the heterocyclic ring [torsion angle S1—C2···C13—O14 = -1.83 (18)°].

The partial double-bond character of the C2—N6 bond in (I) and (II) accounts for the hindered rotation of the 2-pyridyl­amino [in (I)] or phenyl­amino [in (II)] residues in the analysed structures. The dihedral angles between the cyclic systems are 11.67 (11)/27.4 (4)° for (I) and 6.59 (6)° for (II). The two values given for (I) result from the previously described disorder concerning the arrangement of atoms S1 and C5 in the crystal structure.

The main factor that determines the crystal packing and the formation of the supra­molecular structure of (I) is the system of hydrogen bonds, involving both strong N—H···N and O—H···O and weak C—H···O hydrogen bonds. The N6—H6···N3ⁱ and C12—H12···O13ⁱ hydrogen bonds link the molecules into centrosymmetric dimers and generate centrosymmetric R₂²(8) (Bernstein et al., 1995) ring motifs. Neighbouring dimers are linked through O16a—H16A···O13ⁱⁱ and O16b—H16B···O13ⁱⁱ hydrogen bonds to form the next centrosymmetric ring motif of R₂²(14) type (Fig. 4a). These contacts link the molecules of (I) into tapes extending along the [110] direction (Table 3, and Figs. 4a and 4b). Neighbouring molecular tapes are linked through nonclassical C10—H10···O16ⁱⁱⁱ hydrogen bonds into layers parallel to the (111) plane, and these layers are connected by C14a—H14B···O16a^iv hydrogen bonds, forming a three-dimensional hydrogen-bond network.

The molecules of (II) are linked in the crystal structure through N6—H6···O18ⁱ hydrogen bonds into chains extending along the [110] direction (Table 2 and Fig. 3).

Related literature

For related literature, see: Allen (2002); Allen et al. (1987); Behbehani & Ibrahim (2012); Bernstein et al. (1995); Cremer & Pople (1975); Geronikaki et al. (2008); Lesyk & Zimenkovsky (2004); Lesyk et al. (2011); Ostapiuk et al. (2012); Sheldrick (2008); Subtel'na, Atamanyuk, Szymanska, Kieć-Kononowicz, Zimenkovsky, Vasylenko, Gzella & Lesyk (2010); Váňa et al. (2009).

Computing details

For both compounds, data collection: CrysAlis PRO (Agilent, 2012); cell refinement: CrysAlis PRO (Agilent, 2012); data reduction: CrysAlis PRO (Agilent, 2012); program(s) used to solve structure: SHELXS97 (Sheldrick, 2008); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008); molecular graphics: ORTEP-3 for Windows (Farrugia, 2012); software used to prepare material for publication: WinGX (Farrugia, 2012), OLEX2 (Dolomanov et al., 2009) and PLATON (Spek, 2009).

Figures

	Fig. 1. The molecular structure of (I), showing the atomic labelling scheme. Displacement ellipsoids are drawn at the 30% probability level. The disordered part b of the molecule is coloured grey, as distinct from the major component in black.
	Fig. 2. A view of the molecule of (II), showing the atomic labelling scheme. Displacement ellipsoids are drawn at the 30% probability level.
	Fig. 3. Part of the crystal structure of (II), showing the formation of the hydrogen-bonded chain along [110]. See Table 2 for symmetry code. H atoms not involved in hydrogen bonding have been omitted for clarity. Hydrogen bonds are shown as dashed lines.
	Fig. 4. (a) The molecular tape in (I), generated by the centrosymmetric dimers. For symmetry codes, see Table 3. H atoms not involved in hydrogen bonding have been omitted for clarity. (b) The molecular tape in (I), expanded along the [110] direction. Hydrogen bonds are shown as dashed lines. Grey shading denotes the disordered part of the molecule.

(I) 5-(2-Hydroxyethyl)-2-[(pyridin-2-yl)amino]-1,3-thiazolidin-4-one

Crystal data

C10H11N3O2S	F(000) = 248
Mr = 237.28	Dx = 1.491 Mg m^−3
Triclinic, P1	Melting point = 459–461 K
a = 5.78910 (15) Å	Mo Kα radiation, λ = 0.71073 Å
b = 8.8045 (2) Å	Cell parameters from 3632 reflections
c = 10.9688 (3) Å	θ = 3.0–29.1°
α = 90.638 (2)°	µ = 0.29 mm^−1
β = 95.794 (2)°	T = 130 K
γ = 107.990 (2)°	Lath, colourless
V = 528.50 (3) Å^3	0.42 × 0.22 × 0.10 mm
Z = 2

Data collection

Agilent Xcalibur Atlas diffractometer	2501 independent reflections
Radiation source: Enhance (Mo) X-ray Source	2338 reflections with I > 2σ(I)
Detector resolution: 10.3088 pixels mm^-1	Rint = 0.016
ω scans	θmax = 29.1°, θmin = 2.4°
Absorption correction: multi-scan (CrysAlis PRO; Agilent, 2012)	h = −6→7
Tmin = 0.939, Tmax = 1.000	k = −11→11
5332 measured reflections	l = −14→14

Refinement

Refinement on F^2	4 restraints
Least-squares matrix: full	Hydrogen site location: mixed
R[F^2 > 2σ(F^2)] = 0.036	H atoms treated by a mixture of independent and constrained refinement
wR(F^2) = 0.088	w = 1/[σ^2(Fo^2) + (0.0328P)^2 + 0.2306P] where P = (Fo^2 + 2Fc^2)/3
S = 1.13	(Δ/σ)max < 0.001
2501 reflections	Δρmax = 0.34 e Å^−3
167 parameters	Δρmin = −0.21 e Å^−3

Special details

Geometry. All e.s.d.'s (except the e.s.d. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell e.s.d.'s are taken into account individually in the estimation of e.s.d.'s in distances, angles and torsion angles; correlations between e.s.d.'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell e.s.d.'s is used for estimating e.s.d.'s involving l.s. planes.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Ų)

	x	y	z	Uiso*/Ueq	Occ. (<1)
S1A	0.40161 (15)	0.38579 (7)	0.27170 (4)	0.01982 (15)	0.883 (2)
C2	0.2062 (3)	0.44461 (16)	0.36246 (12)	0.0199 (3)
N3	0.1772 (2)	0.38288 (14)	0.47166 (10)	0.0214 (3)
C4	0.2935 (3)	0.26908 (18)	0.48923 (13)	0.0267 (3)
N6	0.0916 (2)	0.55040 (14)	0.32764 (11)	0.0206 (3)
H6	0.004 (4)	0.572 (2)	0.3822 (18)	0.034 (5)*
C7	0.0942 (3)	0.62302 (16)	0.21345 (12)	0.0202 (3)
N8	0.2530 (2)	0.60269 (15)	0.14094 (11)	0.0230 (3)
C9	0.2538 (3)	0.66848 (18)	0.03061 (13)	0.0259 (3)
H9	0.3640	0.6533	−0.0234	0.031*
C10	0.1021 (3)	0.75713 (19)	−0.00803 (13)	0.0274 (3)
H10	0.1087	0.8026	−0.0862	0.033*
C11	−0.0599 (3)	0.77766 (19)	0.07079 (14)	0.0274 (3)
H11	−0.1652	0.8388	0.0472	0.033*
C12	−0.0682 (3)	0.70917 (18)	0.18365 (13)	0.0233 (3)
H12	−0.1794	0.7202	0.2386	0.028*
O13	0.2882 (3)	0.19347 (15)	0.58229 (10)	0.0383 (3)
C15A	0.5049 (3)	0.0412 (2)	0.2396 (2)	0.0218 (4)	0.883 (2)
H15A	0.4441	−0.0734	0.2128	0.026*	0.883 (2)
H15B	0.4880	0.1044	0.1670	0.026*	0.883 (2)
C5A	0.4400 (3)	0.2454 (2)	0.38628 (14)	0.0206 (3)	0.883 (2)
H5A	0.6166	0.2736	0.4186	0.025*	0.883 (2)
C14A	0.3496 (3)	0.07226 (19)	0.33477 (15)	0.0219 (3)	0.883 (2)
H14A	0.3511	−0.0003	0.4030	0.026*	0.883 (2)
H14B	0.1786	0.0475	0.2970	0.026*	0.883 (2)
O16A	0.7567 (2)	0.08204 (17)	0.28591 (13)	0.0269 (3)	0.883 (2)
H16A	0.7756	0.0159	0.3375	0.040*	0.883 (2)
S1B	0.3118 (10)	0.3571 (5)	0.2556 (4)	0.01982 (15)	0.117 (2)
C5B	0.312 (3)	0.2013 (16)	0.3623 (11)	0.0206 (3)	0.117 (2)
H5B	0.1685	0.1039	0.3387	0.025*	0.117 (2)
C14B	0.547 (2)	0.1577 (14)	0.3752 (11)	0.0219 (3)	0.117 (2)
H14C	0.5457	0.0840	0.4428	0.026*	0.117 (2)
H14D	0.6892	0.2551	0.3939	0.026*	0.117 (2)
C15B	0.564 (3)	0.077 (2)	0.2534 (17)	0.0218 (4)	0.117 (2)
H15C	0.4218	−0.0207	0.2370	0.026*	0.117 (2)
H15D	0.5559	0.1502	0.1864	0.026*	0.117 (2)
O16B	0.778 (2)	0.0357 (15)	0.2525 (11)	0.0269 (3)	0.117 (2)
H16B	0.7745	−0.0389	0.3001	0.040*	0.117 (2)

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
S1A	0.0243 (3)	0.0197 (2)	0.0173 (2)	0.0081 (2)	0.0067 (2)	0.00383 (16)
C2	0.0251 (7)	0.0173 (6)	0.0162 (6)	0.0040 (5)	0.0048 (5)	0.0009 (5)
N3	0.0285 (7)	0.0208 (6)	0.0167 (5)	0.0093 (5)	0.0056 (5)	0.0035 (4)
C4	0.0405 (9)	0.0245 (7)	0.0194 (7)	0.0151 (7)	0.0078 (6)	0.0030 (6)
N6	0.0242 (6)	0.0225 (6)	0.0167 (5)	0.0082 (5)	0.0065 (5)	0.0046 (5)
C7	0.0233 (7)	0.0186 (6)	0.0163 (6)	0.0028 (5)	0.0025 (5)	0.0034 (5)
N8	0.0280 (7)	0.0226 (6)	0.0186 (6)	0.0067 (5)	0.0065 (5)	0.0041 (5)
C9	0.0286 (8)	0.0287 (8)	0.0189 (7)	0.0052 (6)	0.0073 (6)	0.0045 (6)
C10	0.0291 (8)	0.0307 (8)	0.0190 (7)	0.0039 (6)	0.0032 (6)	0.0095 (6)
C11	0.0259 (8)	0.0294 (8)	0.0256 (7)	0.0072 (6)	0.0011 (6)	0.0089 (6)
C12	0.0228 (7)	0.0247 (7)	0.0221 (7)	0.0061 (6)	0.0045 (5)	0.0045 (6)
O13	0.0691 (9)	0.0381 (7)	0.0218 (5)	0.0333 (6)	0.0163 (5)	0.0136 (5)
C15A	0.0223 (11)	0.0206 (11)	0.0222 (8)	0.0058 (8)	0.0040 (8)	0.0014 (7)
C5A	0.0244 (9)	0.0209 (8)	0.0184 (7)	0.0095 (7)	0.0032 (6)	0.0034 (6)
C14A	0.0216 (8)	0.0198 (8)	0.0248 (8)	0.0064 (6)	0.0052 (6)	0.0025 (6)
O16A	0.0254 (7)	0.0284 (8)	0.0295 (8)	0.0108 (5)	0.0069 (5)	0.0088 (6)
S1B	0.0243 (3)	0.0197 (2)	0.0173 (2)	0.0081 (2)	0.0067 (2)	0.00383 (16)
C5B	0.0244 (9)	0.0209 (8)	0.0184 (7)	0.0095 (7)	0.0032 (6)	0.0034 (6)
C14B	0.0216 (8)	0.0198 (8)	0.0248 (8)	0.0064 (6)	0.0052 (6)	0.0025 (6)
C15B	0.0223 (11)	0.0206 (11)	0.0222 (8)	0.0058 (8)	0.0040 (8)	0.0014 (7)
O16B	0.0254 (7)	0.0284 (8)	0.0295 (8)	0.0108 (5)	0.0069 (5)	0.0088 (6)

Geometric parameters (Å, º)

S1A—C2	1.7655 (15)	C12—H12	0.9500
S1A—C5A	1.8178 (16)	C15A—O16A	1.427 (2)
C2—N3	1.3256 (17)	C15A—C14A	1.520 (3)
C2—N6	1.3385 (19)	C15A—H15A	0.9900
C2—S1B	1.660 (5)	C15A—H15B	0.9900
N3—C4	1.3744 (19)	C5A—C14A	1.532 (2)
C4—O13	1.2227 (18)	C5A—H5A	1.0000
C4—C5A	1.528 (2)	C14A—H14A	0.9900
C4—C5B	1.535 (13)	C14A—H14B	0.9900
N6—C7	1.4119 (17)	O16A—H16A	0.8400
N6—H6	0.88 (2)	S1B—C5B	1.813 (13)
C7—N8	1.3251 (19)	C5B—C14B	1.520 (14)
C7—C12	1.396 (2)	C5B—H5B	1.0000
N8—C9	1.3473 (18)	C14B—C15B	1.533 (15)
C9—C10	1.384 (2)	C14B—H14C	0.9900
C9—H9	0.9500	C14B—H14D	0.9900
C10—C11	1.387 (2)	C15B—O16B	1.397 (16)
C10—H10	0.9500	C15B—H15C	0.9900
C11—C12	1.382 (2)	C15B—H15D	0.9900
C11—H11	0.9500	O16B—H16B	0.8400
C2—S1A—C5A	89.64 (7)	C14A—C15A—H15B	109.2
N3—C2—N6	118.87 (13)	H15A—C15A—H15B	107.9
N3—C2—S1B	120.45 (18)	C4—C5A—C14A	111.18 (14)
N6—C2—S1B	118.35 (18)	C4—C5A—S1A	105.24 (11)
N3—C2—S1A	117.77 (11)	C14A—C5A—S1A	112.27 (11)
N6—C2—S1A	123.35 (10)	C4—C5A—H5A	109.3
C2—N3—C4	111.24 (12)	C14A—C5A—H5A	109.3
O13—C4—N3	123.02 (14)	S1A—C5A—H5A	109.3
O13—C4—C5A	121.08 (14)	C15A—C14A—C5A	112.54 (14)
N3—C4—C5A	115.86 (12)	C15A—C14A—H14A	109.1
O13—C4—C5B	123.3 (5)	C5A—C14A—H14A	109.1
N3—C4—C5B	107.5 (4)	C15A—C14A—H14B	109.1
C2—N6—C7	126.46 (13)	C5A—C14A—H14B	109.1
C2—N6—H6	114.2 (13)	H14A—C14A—H14B	107.8
C7—N6—H6	119.3 (13)	C15A—O16A—H16A	109.5
N8—C7—C12	124.43 (13)	C2—S1B—C5B	87.4 (4)
N8—C7—N6	116.53 (12)	C14B—C5B—C4	105.5 (9)
C12—C7—N6	119.04 (13)	C14B—C5B—S1B	113.8 (9)
C7—N8—C9	117.15 (13)	C4—C5B—S1B	106.5 (7)
N8—C9—C10	123.26 (14)	C14B—C5B—H5B	110.3
N8—C9—H9	118.4	C4—C5B—H5B	110.3
C10—C9—H9	118.4	S1B—C5B—H5B	110.3
C9—C10—C11	118.06 (13)	C5B—C14B—C15B	107.7 (11)
C9—C10—H10	121.0	C5B—C14B—H14C	110.2
C11—C10—H10	121.0	C15B—C14B—H14C	110.2
C12—C11—C10	120.01 (14)	C5B—C14B—H14D	110.2
C12—C11—H11	120.0	C15B—C14B—H14D	110.2
C10—C11—H11	120.0	H14C—C14B—H14D	108.5
C11—C12—C7	117.06 (14)	O16B—C15B—C14B	113.1 (13)
C11—C12—H12	121.5	O16B—C15B—H15C	109.0
C7—C12—H12	121.5	C14B—C15B—H15C	109.0
O16A—C15A—C14A	112.19 (16)	O16B—C15B—H15D	109.0
O16A—C15A—H15A	109.2	C14B—C15B—H15D	109.0
C14A—C15A—H15A	109.2	H15C—C15B—H15D	107.8
O16A—C15A—H15B	109.2	C15B—O16B—H16B	109.5
C5A_a—S1A_a—C2—N3	4.74 (12)	C5B—C4—C5A—C14A	−43.3 (9)
C5A—S1A—C2—N6	−176.87 (13)	O13—C4—C5A—S1A	−178.17 (14)
C5A—S1A—C2—S1B	−99.0 (5)	N3—C4—C5A—S1A	−0.17 (18)
N6—C2—N3—C4	175.93 (13)	C5B—C4—C5A—S1A	78.4 (10)
S1B—C2—N3—C4	13.5 (3)	C2—S1A—C5A—C4	−2.25 (12)
S1A—C2—N3—C4	−5.60 (17)	C2—S1A—C5A—C14A	118.83 (13)
C2—N3—C4—O13	−178.53 (15)	O16A—C15A—C14A—C5A	55.8 (2)
C2—N3—C4—C5A	3.5 (2)	C4—C5A—C14A—C15A	−175.19 (15)
C2—N3—C4—C5B	−25.5 (6)	S1A—C5A—C14A—C15A	67.21 (17)
N3—C2—N6—C7	−177.41 (13)	N3—C2—S1B—C5B	3.1 (5)
S1B—C2—N6—C7	−14.7 (3)	N6—C2—S1B—C5B	−159.4 (5)
S1A—C2—N6—C7	4.2 (2)	S1A—C2—S1B—C5B	88.8 (7)
C2—N6—C7—N8	−10.6 (2)	O13—C4—C5B—C14B	−59.0 (11)
C2—N6—C7—C12	168.97 (14)	N3—C4—C5B—C14B	148.0 (7)
C12—C7—N8—C9	−0.9 (2)	C5A—C4—C5B—C14B	35.7 (7)
N6—C7—N8—C9	178.62 (12)	O13—C4—C5B—S1B	179.7 (3)
C7—N8—C9—C10	1.3 (2)	N3—C4—C5B—S1B	26.7 (8)
N8—C9—C10—C11	−0.6 (2)	C5A—C4—C5B—S1B	−85.6 (11)
C9—C10—C11—C12	−0.6 (2)	C2—S1B—C5B—C14B	−132.4 (10)
C10—C11—C12—C7	1.0 (2)	C2—S1B—C5B—C4	−16.6 (7)
N8—C7—C12—C11	−0.3 (2)	C4—C5B—C14B—C15B	175.6 (11)
N6—C7—C12—C11	−179.74 (13)	S1B—C5B—C14B—C15B	−67.9 (14)
O13—C4—C5A—C14A	60.0 (2)	C5B—C14B—C15B—O16B	178.1 (14)
N3—C4—C5A—C14A	−121.96 (15)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
N6—H6···N3^i	0.88 (2)	2.10 (2)	2.9733 (17)	173 (2)
O16a—H16A···O13^ii	0.84	2.00	2.7940 (19)	158
O16b—H16B···O13^ii	0.84	1.86	2.692 (12)	168
C10—H10···O16a^iii	0.95	2.52	3.442 (2)	164
C12—H12···O13^i	0.95	2.31	3.199 (2)	155
C14a—H14B···O16a^iv	0.99	2.54	3.448 (2)	152

Symmetry codes: (i) −x, −y+1, −z+1; (ii) −x+1, −y, −z+1; (iii) −x+1, −y+1, −z; (iv) x−1, y, z.

(II) Ethyl 4-[(4-oxothiazolidin-2-yl)amino]benzoate

Crystal data

C12H12N2O3S	F(000) = 276
Mr = 264.30	Dx = 1.496 Mg m^−3
Triclinic, P1	Melting point = 461–462 K
a = 3.9850 (2) Å	Mo Kα radiation, λ = 0.71073 Å
b = 5.5113 (3) Å	Cell parameters from 5612 reflections
c = 26.8877 (14) Å	θ = 2.3–29.0°
α = 84.483 (5)°	µ = 0.28 mm^−1
β = 89.670 (5)°	T = 130 K
γ = 86.338 (5)°	Lath, colourless
V = 586.58 (6) Å^3	0.40 × 0.34 × 0.05 mm
Z = 2

Data collection

Agilent Xcalibur Atlas diffractometer	2804 independent reflections
Radiation source: Enhance (Mo) X-ray Source	2604 reflections with I > 2σ(I)
Detector resolution: 10.3088 pixels mm^-1	Rint = 0.017
ω scans	θmax = 29.1°, θmin = 2.3°
Absorption correction: multi-scan (CrysAlis PRO; Agilent, 2010)	h = −5→5
Tmin = 0.908, Tmax = 1.000	k = −7→7
7855 measured reflections	l = −35→35

Refinement

Refinement on F^2	0 restraints
Least-squares matrix: full	Hydrogen site location: mixed
R[F^2 > 2σ(F^2)] = 0.030	H atoms treated by a mixture of independent and constrained refinement
wR(F^2) = 0.078	w = 1/[σ^2(Fo^2) + (0.0367P)^2 + 0.3017P] where P = (Fo^2 + 2Fc^2)/3
S = 1.05	(Δ/σ)max < 0.001
2804 reflections	Δρmax = 0.54 e Å^−3
168 parameters	Δρmin = −0.23 e Å^−3

Special details

Geometry. All e.s.d.'s (except the e.s.d. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell e.s.d.'s are taken into account individually in the estimation of e.s.d.'s in distances, angles and torsion angles; correlations between e.s.d.'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell e.s.d.'s is used for estimating e.s.d.'s involving l.s. planes.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Ų)

	x	y	z	Uiso*/Ueq
S1	0.90166 (7)	0.46485 (5)	0.05976 (2)	0.01454 (9)
C2	0.7690 (3)	0.4621 (2)	0.12301 (4)	0.0130 (2)
N3	0.5653 (3)	0.64554 (18)	0.13492 (4)	0.0152 (2)
C4	0.4898 (3)	0.8077 (2)	0.09439 (4)	0.0145 (2)
C5	0.6724 (3)	0.7546 (2)	0.04612 (4)	0.0151 (2)
H5A	0.8277	0.8836	0.0360	0.018*
H5B	0.5092	0.7468	0.0188	0.018*
N6	0.8822 (3)	0.27244 (18)	0.15391 (4)	0.0148 (2)
H6	1.014 (4)	0.167 (3)	0.1409 (7)	0.028 (4)*
C7	0.8121 (3)	0.2168 (2)	0.20533 (4)	0.0142 (2)
C8	0.6325 (3)	0.3760 (2)	0.23453 (5)	0.0177 (2)
H8	0.5475	0.5321	0.2203	0.021*
C9	0.5797 (3)	0.3034 (2)	0.28469 (5)	0.0188 (3)
H9	0.4585	0.4111	0.3049	0.023*
C10	0.7019 (3)	0.0748 (2)	0.30575 (4)	0.0168 (2)
C11	0.8843 (3)	−0.0814 (2)	0.27639 (5)	0.0185 (2)
H11	0.9711	−0.2368	0.2908	0.022*
C12	0.9398 (3)	−0.0119 (2)	0.22645 (5)	0.0174 (2)
H12	1.0643	−0.1191	0.2065	0.021*
C13	0.6394 (3)	−0.0095 (2)	0.35919 (5)	0.0198 (3)
O14	0.7419 (3)	−0.20429 (19)	0.37957 (4)	0.0322 (3)
O15	0.4537 (3)	0.15882 (17)	0.38186 (3)	0.0237 (2)
C16	0.3732 (4)	0.0971 (3)	0.43390 (5)	0.0244 (3)
H16A	0.5800	0.0440	0.4532	0.029*
H16B	0.2180	−0.0367	0.4374	0.029*
C17	0.2087 (4)	0.3256 (3)	0.45242 (5)	0.0288 (3)
H17A	0.0085	0.3785	0.4323	0.043*
H17B	0.3674	0.4549	0.4496	0.043*
H17C	0.1435	0.2917	0.4875	0.043*
O18	0.2933 (2)	0.98859 (16)	0.09484 (3)	0.01938 (19)

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
S1	0.01742 (16)	0.01331 (14)	0.01236 (14)	0.00285 (11)	0.00282 (10)	−0.00122 (10)
C2	0.0132 (5)	0.0136 (5)	0.0126 (5)	−0.0021 (4)	0.0011 (4)	−0.0021 (4)
N3	0.0167 (5)	0.0141 (5)	0.0145 (5)	0.0019 (4)	0.0017 (4)	−0.0020 (4)
C4	0.0147 (5)	0.0137 (5)	0.0153 (5)	−0.0005 (4)	0.0011 (4)	−0.0033 (4)
C5	0.0167 (6)	0.0129 (5)	0.0149 (5)	0.0025 (4)	0.0020 (4)	0.0000 (4)
N6	0.0170 (5)	0.0129 (5)	0.0141 (5)	0.0028 (4)	0.0021 (4)	−0.0023 (4)
C7	0.0155 (5)	0.0136 (5)	0.0136 (5)	−0.0012 (4)	−0.0004 (4)	−0.0015 (4)
C8	0.0233 (6)	0.0133 (5)	0.0161 (6)	0.0023 (5)	0.0015 (5)	−0.0007 (4)
C9	0.0238 (6)	0.0157 (6)	0.0166 (6)	0.0020 (5)	0.0023 (5)	−0.0020 (4)
C10	0.0190 (6)	0.0162 (6)	0.0150 (6)	−0.0019 (5)	−0.0004 (4)	−0.0002 (4)
C11	0.0224 (6)	0.0136 (5)	0.0187 (6)	0.0015 (5)	−0.0010 (5)	0.0002 (4)
C12	0.0205 (6)	0.0133 (5)	0.0182 (6)	0.0025 (5)	0.0005 (5)	−0.0019 (4)
C13	0.0238 (6)	0.0185 (6)	0.0166 (6)	−0.0004 (5)	0.0008 (5)	0.0003 (5)
O14	0.0480 (7)	0.0236 (5)	0.0217 (5)	0.0104 (5)	0.0064 (4)	0.0063 (4)
O15	0.0336 (5)	0.0215 (5)	0.0143 (4)	0.0049 (4)	0.0051 (4)	0.0020 (3)
C16	0.0315 (7)	0.0260 (7)	0.0142 (6)	0.0027 (6)	0.0048 (5)	0.0024 (5)
C17	0.0338 (8)	0.0298 (7)	0.0214 (7)	0.0054 (6)	0.0058 (6)	−0.0011 (5)
O18	0.0223 (5)	0.0150 (4)	0.0201 (4)	0.0060 (3)	0.0021 (3)	−0.0024 (3)

Geometric parameters (Å, º)

S1—C2	1.7770 (12)	C9—H9	0.9500
S1—C5	1.7957 (12)	C10—C11	1.3918 (18)
C2—N3	1.3182 (15)	C10—C13	1.4915 (17)
C2—N6	1.3282 (15)	C11—C12	1.3811 (17)
N3—C4	1.3634 (15)	C11—H11	0.9500
C4—O18	1.2287 (15)	C12—H12	0.9500
C4—C5	1.5279 (16)	C13—O14	1.2054 (16)
C5—H5A	0.9900	C13—O15	1.3400 (16)
C5—H5B	0.9900	O15—C16	1.4470 (15)
N6—C7	1.4171 (15)	C16—C17	1.5081 (19)
N6—H6	0.859 (19)	C16—H16A	0.9900
C7—C8	1.3946 (17)	C16—H16B	0.9900
C7—C12	1.3977 (16)	C17—H17A	0.9800
C8—C9	1.3881 (17)	C17—H17B	0.9800
C8—H8	0.9500	C17—H17C	0.9800
C9—C10	1.3902 (17)
C2—S1—C5	89.35 (5)	C9—C10—C11	119.57 (11)
N3—C2—N6	125.95 (11)	C9—C10—C13	121.63 (12)
N3—C2—S1	117.49 (9)	C11—C10—C13	118.79 (11)
N6—C2—S1	116.55 (9)	C12—C11—C10	120.38 (11)
C2—N3—C4	111.51 (10)	C12—C11—H11	119.8
O18—C4—N3	124.59 (11)	C10—C11—H11	119.8
O18—C4—C5	119.87 (10)	C11—C12—C7	119.75 (11)
N3—C4—C5	115.53 (10)	C11—C12—H12	120.1
C4—C5—S1	105.83 (8)	C7—C12—H12	120.1
C4—C5—H5A	110.6	O14—C13—O15	124.04 (12)
S1—C5—H5A	110.6	O14—C13—C10	124.54 (12)
C4—C5—H5B	110.6	O15—C13—C10	111.42 (11)
S1—C5—H5B	110.6	C13—O15—C16	116.64 (10)
H5A—C5—H5B	108.7	O15—C16—C17	106.36 (11)
C2—N6—C7	129.30 (10)	O15—C16—H16A	110.5
C2—N6—H6	115.7 (12)	C17—C16—H16A	110.5
C7—N6—H6	115.0 (12)	O15—C16—H16B	110.5
C8—C7—C12	120.37 (11)	C17—C16—H16B	110.5
C8—C7—N6	123.86 (11)	H16A—C16—H16B	108.6
C12—C7—N6	115.76 (11)	C16—C17—H17A	109.5
C9—C8—C7	119.11 (11)	C16—C17—H17B	109.5
C9—C8—H8	120.4	H17A—C17—H17B	109.5
C7—C8—H8	120.4	C16—C17—H17C	109.5
C8—C9—C10	120.81 (12)	H17A—C17—H17C	109.5
C8—C9—H9	119.6	H17B—C17—H17C	109.5
C10—C9—H9	119.6
C5—S1—C2—N3	2.42 (10)	C7—C8—C9—C10	−0.3 (2)
C5—S1—C2—N6	−178.37 (10)	C8—C9—C10—C11	1.1 (2)
N6—C2—N3—C4	−178.45 (11)	C8—C9—C10—C13	−178.21 (12)
S1—C2—N3—C4	0.67 (14)	C9—C10—C11—C12	−0.94 (19)
C2—N3—C4—O18	176.49 (11)	C13—C10—C11—C12	178.37 (12)
C2—N3—C4—C5	−4.32 (15)	C10—C11—C12—C7	0.04 (19)
O18—C4—C5—S1	−174.96 (9)	C8—C7—C12—C11	0.75 (19)
N3—C4—C5—S1	5.82 (13)	N6—C7—C12—C11	179.87 (11)
C2—S1—C5—C4	−4.21 (8)	C9—C10—C13—O14	−179.18 (13)
N3—C2—N6—C7	1.3 (2)	C11—C10—C13—O14	1.5 (2)
S1—C2—N6—C7	−177.79 (10)	C9—C10—C13—O15	0.89 (18)
C2—N6—C7—C8	−8.0 (2)	C11—C10—C13—O15	−178.41 (11)
C2—N6—C7—C12	172.90 (12)	O14—C13—O15—C16	−0.5 (2)
C12—C7—C8—C9	−0.62 (19)	C10—C13—O15—C16	179.45 (11)
N6—C7—C8—C9	−179.66 (11)	C13—O15—C16—C17	172.17 (12)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
N6—H6···O18^i	0.857 (17)	1.954 (17)	2.7882 (14)	164.3 (17)

Symmetry code: (i) x+1, y−1, z.