Crystal structure of methyl (Z)-2-[(Z)-3-methyl-2-({(E)-1-[(R*)-4-methyl-cyclo-hex-3-en-1-yl]ethyl-idene}hydrazinyl-idene)-4-oxo-thia-zolidin-5-yl-idene]acetate.

The new title 4-thia-zolidinone derivative, C16H21N3O3S, was obtained from the cyclization reaction of 4-methyl-3-thio-semicarbazone and dimethyl acetyl-enedi-carboxyl-ate (DMAD). The cyclo-hexyl-idene ring has an envelope conformation with the stereogenic centre C atom as the flap. Its mean plane makes a dihedral angle of 56.23 (9)° with the thia-zolidine ring mean plane. In the crystal, mol-ecules are linked by C-H⋯O hydrogen bonds forming chains propagating in the [001] direction. Within the chains there are offset π-π inter-actions between the thia-zolidine rings of inversion-related mol-ecules [centroid-centroid distance = 3.703 (1) Å]. The chains are linked by further C-H⋯O hydrogen bonds, forming slabs parallel to the ac plane.

Chemical context

It has been reported that thia­zolidinones exhibit anti­bacterial (Mayekar & Mulwad, 2008 ▸), anti­fungal (Omar et al. 2010 ▸), anti­convulsant (Bhat et al., 2008 ▸), anti­tubercular (Babaoglu et al., 2003 ▸), anti-inflammatory (Vigorita et al. 2003 ▸), anti­histaminic (Agrawal et al., 2000 ▸), cardiovascular (Suzuki et al., 1999 ▸) and anti-HIV (Rawal et al., 2005 ▸) activities.

With the aim of preparing new thia­zolidinone derivatives, we report herein on the synthesis (Fig. 1 ▸) and crystal structure of the title compound 3, from 4-methyl-3-thio­semicarbazone 1. Treatment of 1 with dimethyl acetyl­enedi­carboxyl­ate 2 in boiling ethanol for 1 h, afforded the thia­zolidin-4-one 3 in 90% yield. Its structure has also been fully characterized by NMR spectroscopy while its relative stereochemistry was determined based mainly on the synthetic pathway and implied by the X-ray diffraction analysis.

Figure 1

Reaction scheme for the synthesis of title compound 3.

Structural commentary

The title compound 3, is built up from an thia­zolidinone ring linked to cyclo­hexyl­idene-hydrazone and meth­oxy-oxo­ethyl­idene units (Fig. 2 ▸). The compound crystallizes in the centrosymmetric space group P , and the stereogenic centre at C8 was assigned as having an R configuration. As expected, the thia­zolidine ring and all the atoms attached to it (plane A = S1/C4/C5/N1/C6/N2/N3/O1/C3/C14) are roughly coplanar with an r.m.s. deviation of 0.036 Å. Its mean plane makes a dihedral angle of 56.0 (1)° with the mean plane of the cyclo­hexyl­idene ring (C8-C13). The meth­oxy­carbonyl group (C1/O2/O3/C2) is also twisted slightly with respect to plane A, their mean planes being inclined to one another by 11.2 (2)°. The six-membered cyclo­hexyl­idene ring has an envelope conformation with atom C8 as the flap: puckering parameters are Q = 0.494 (2) Å, θ = 129.8 (2)° and φ = 180.8 (3)°. The C7=N3 and N2=C6 bond lengths are 1.282 (2) and 1.278 (2) Å, respectively, consistent with C=N double bonding. The C6—N2—N3—C7, C4—C3—C2—O3 and C3—C2—O3—C1 torsion angles are 175.5 (2), −172.4 (2) and 172.5 (2)°, respectively.

Figure 2

The mol­ecular structure of the title compound 3, with the atom labelling. Displacement ellipsoids are drawn at the 30% probability level.

Supra­molecular features

In the crystal, mol­ecules are linked C3—H3⋯O3i hydrogen bonds, forming chains propagating along [001]; see Table 1 ▸ and Fig. 3 ▸. Within the chains there are weak offset π–π stacking inter­actions between inversion-related thia­zole rings [see Fig. 3 ▸; Cg1⋯Cg1(−x + 1, −y + 1, −z) = 3.703 (1) Å,where Cg1 is the centroid of the S1/N1/C4–C6 ring, inter­planar distance = 3.468 (1) Å, slippage = 1.298 Å]. The chains are linked by further C—H⋯O hydrogen bonds, forming slabs lying parallel to the ac plane (Table 1 ▸, Figs. 4 ▸ and 5 ▸).

Table 1

Hydrogen-bond geometry (Å, °)

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
C3—H3⋯O3i	0.95	2.59	3.4133 (19)	146
C1—H1C⋯O1ii	0.98	2.51	3.208 (2)	128
C14—H14A⋯O2iii	0.98	2.45	3.252 (2)	139
C14—H14B⋯O2iv	0.98	2.48	3.409 (2)	159
C15—H15A⋯O3iv	0.98	2.55	3.351 (2)	139

Symmetry codes: (i) ; (ii) ; (iii) ; (iv) .

Figure 3

Partial crystal packing for title compound 3, showing the C3—H3⋯O3i hydrogen bonds and the offset π–π inter­actions between inversion-related mol­ecules, forming chains in the [001] direction (dashed lines; only atom H3 has been included).

Figure 4

Packing and hydrogen-bonding inter­actions of the title compound viewed along the b axis. For clarity, only the H atoms involved in the hydrogen bonds (dashed lines) inter­actions have been included.

Figure 5

Packing and hydrogen-bonding inter­actions of the title compound, viewed along the a axis. For clarity, only the H atoms involved in hydrogen bonding (dashed lines) have been included.

Database survey

A search of the Cambridge Structural Database (CSD, Version 5.38, last update May 2017; Groom et al., 2016 ▸) using a thia­zolidone substituted by meth­oxy-oxo­ethyll­idene and methyl­hydrazone as the main skeleton gave eight hits. The most relevant structures are methyl (2-{[1-(4-hy­droxy­phen­yl)ethyl­idene]hydrazono}-4-oxo-3-phenyl-1,3-thia­zolidin-5-yl­idene)acetate (AGOMUG; Mohamed, Mague et al., 2013 ▸), methyl (2-{[1-(4-methyl­phen­yl)ethyl­idene]hydrazono}-4-oxo-3-phenyl-1,3-thia­zolidin-5-yl­idene)acetate (NIPPAF; Mague et al., 2013 ▸) and dimethyl 2-[(4-{N-[5-(2-meth­oxy-2-oxo­ethyl­idene)-4-oxo-3-phenyl-1,3-thia­zolidin-2-yl­idene]ethane­hydrazono­yl}phen­yl)amino]­but-2-enedioate (RIMDIC; Mohamed, Akkurt et al., 2013 ▸).

A comparison of the main C—N, N—N, C—S bond lengths in the title compound and the structures extracted from the CSD shows a good correlation. The C=N—N=C torsion angles indicate that in each case the four atoms are nearly planar, viz. 175.5 (2)° in the title compound, 172.1 (2)° in AGOMUG, −178.9 (2) and −165.5 (2)° in NIPPAF and −167.4 (5)° in RIMDIC.

Synthesis and crystallization

To a solution of 4-methyl-3-thio­semicarbazone (200 mg, 1.33 mmol) in ethanol (15 ml) was added dimethyl acetyl­enedi­carboxyl­ate (DMAD) (0.24 ml, 1.66 mmol). The mixture was stirred under reflux for 1 h, leading to the corresponding thia­zolidinone. After cooling, the mixture was extracted with ethyl acetate (3 × 20 ml). The organic layer was washed with water, dried on anhydrous Na2SO4 and then evaporated under reduced pressure. The obtained residue was chromatographed on a silica gel column using hexane as eluent, to give compound 3 (yield 404 mg, 90%). Yellow prismatic crystals were obtained from a petroleum ether solution, by slow evaporation of the solvent at room temperature.

Refinement

Crystal data, data collection and structure refinement details are summarized in Table 2 ▸. The C-bound H atoms were placed in calculated positions with C—H = 0.95–1.00 Å, and refined in the riding-model approximation with U iso(H) = 1.5U eq(C-meth­yl) and 1.2U eq(C) for other H atoms.

Table 2

Experimental details

Crystal data
Chemical formula	C16H21N3O3S
M r	335.42
Crystal system, space group	Triclinic, P
Temperature (K)	100
a, b, c (Å)	9.0982 (2), 9.9556 (3), 10.5071 (3)
α, β, γ (°)	66.772 (1), 74.572 (1), 77.706 (1)
V (Å3)	836.76 (4)
Z	2
Radiation type	Cu Kα
μ (mm−1)	1.88
Crystal size (mm)	0.39 × 0.28 × 0.20
Data collection
Diffractometer	D8 Venture CMOS area detector
Absorption correction	Numerical (SADABS; Bruker, 2012 ▸)
T min, T max	0.733, 0.919
No. of measured, independent and observed [I > 2σ(I)] reflections	30681, 3405, 3195
R int	0.035
(sin θ/λ)max (Å−1)	0.625
Refinement
R[F 2 > 2σ(F 2)], wR(F 2), S	0.038, 0.102, 1.06
No. of reflections	3405
No. of parameters	212
H-atom treatment	H-atom parameters constrained
Δρmax, Δρmin (e Å−3)	0.42, −0.46

Computer programs: APEX2 and SAINT (Bruker, 2012 ▸), SHELXS2014 (Sheldrick, 2008 ▸), SHELXL2014 (Sheldrick, 2015 ▸), ORTEP-3 for Windows (Farrugia, 2012 ▸), DIAMOND (Brandenburg & Putz, 2012 ▸), PLATON (Spek, 2009 ▸) and publCIF (Westrip, 2010 ▸).

Crystal structure: contains datablock(s) I, Global. DOI: 10.1107/S2056989017014311/su5396sup1.cif

Structure factors: contains datablock(s) I. DOI: 10.1107/S2056989017014311/su5396Isup2.hkl

Click here for additional data file.

Supporting information file. DOI: 10.1107/S2056989017014311/su5396Isup3.cml

CCDC reference: 1577993

Additional supporting information: crystallographic information; 3D view; checkCIF report

C16H21N3O3S	Z = 2
Mr = 335.42	F(000) = 356
Triclinic, P1	Dx = 1.331 Mg m−3
a = 9.0982 (2) Å	Cu Kα radiation, λ = 1.54178 Å
b = 9.9556 (3) Å	Cell parameters from 9903 reflections
c = 10.5071 (3) Å	θ = 4.9–74.5°
α = 66.772 (1)°	µ = 1.88 mm−1
β = 74.572 (1)°	T = 100 K
γ = 77.706 (1)°	Prismatic, yellow
V = 836.76 (4) Å3	0.39 × 0.28 × 0.20 mm

D8 Venture CMOS area detector diffractometer	3195 reflections with I > 2σ(I)
Radiation source: microsource	Rint = 0.035
φ and ω scans	θmax = 74.5°, θmin = 4.7°
Absorption correction: numerical (SADABS; Bruker, 2012)	h = −11→11
Tmin = 0.733, Tmax = 0.919	k = −12→12
30681 measured reflections	l = −12→13
3405 independent reflections

Refinement on F2	Primary atom site location: structure-invariant direct methods
Least-squares matrix: full	Secondary atom site location: difference Fourier map
R[F2 > 2σ(F2)] = 0.038	Hydrogen site location: inferred from neighbouring sites
wR(F2) = 0.102	H-atom parameters constrained
S = 1.06	w = 1/[σ2(Fo2) + (0.048P)2 + 0.6482P] where P = (Fo2 + 2Fc2)/3
3405 reflections	(Δ/σ)max = 0.016
212 parameters	Δρmax = 0.42 e Å−3
0 restraints	Δρmin = −0.46 e Å−3

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.

	x	y	z	Uiso*/Ueq
S1	0.40715 (4)	0.68958 (4)	−0.11410 (4)	0.01854 (12)
O1	0.80122 (13)	0.54559 (13)	−0.29654 (13)	0.0255 (3)
O2	0.21903 (13)	0.59108 (14)	−0.22869 (13)	0.0262 (3)
O3	0.31331 (13)	0.45665 (12)	−0.36926 (12)	0.0219 (3)
N1	0.70665 (15)	0.66298 (14)	−0.13721 (14)	0.0192 (3)
N2	0.56362 (16)	0.77397 (15)	0.02334 (15)	0.0222 (3)
N3	0.40773 (15)	0.81672 (15)	0.07586 (15)	0.0215 (3)
C1	0.15960 (19)	0.4245 (2)	−0.3520 (2)	0.0267 (4)
H1A	0.1267	0.3563	−0.2554	0.040*
H1B	0.1594	0.3793	−0.4196	0.040*
H1C	0.0887	0.5160	−0.3692	0.040*
C2	0.32641 (18)	0.53614 (17)	−0.29626 (17)	0.0194 (3)
C3	0.48814 (18)	0.54559 (17)	−0.30630 (17)	0.0205 (3)
H3	0.5657	0.5084	−0.3690	0.025*
C4	0.52821 (17)	0.60574 (17)	−0.22856 (17)	0.0184 (3)
C5	0.69402 (18)	0.59946 (17)	−0.22780 (17)	0.0193 (3)
C6	0.56930 (18)	0.71493 (17)	−0.06627 (17)	0.0189 (3)
C7	0.38679 (18)	0.86854 (17)	0.17420 (17)	0.0201 (3)
C8	0.22330 (18)	0.90988 (17)	0.23980 (17)	0.0200 (3)
H8	0.2202	1.0019	0.2579	0.024*
C9	0.1056 (2)	0.9394 (2)	0.14898 (19)	0.0281 (4)
H9A	0.1337	1.0203	0.0579	0.034*
H9B	0.1069	0.8502	0.1285	0.034*
C10	−0.0542 (2)	0.9808 (2)	0.22322 (18)	0.0263 (4)
H10	−0.1269	1.0467	0.1702	0.032*
C11	−0.0941 (2)	0.92015 (19)	0.3727 (2)	0.0259 (4)
C12	0.01418 (19)	0.83015 (18)	0.45599 (18)	0.0235 (3)
H12A	−0.0295	0.7375	0.5188	0.028*
H12B	0.0236	0.8805	0.5175	0.028*
C13	0.1742 (2)	0.7892 (2)	0.38279 (19)	0.0289 (4)
H13A	0.1778	0.6962	0.3681	0.035*
H13B	0.2474	0.7725	0.4440	0.035*
C14	0.85481 (18)	0.66081 (19)	−0.10627 (19)	0.0243 (4)
H14A	0.9379	0.6357	−0.1775	0.036*
H14B	0.8625	0.5871	−0.0124	0.036*
H14C	0.8633	0.7581	−0.1082	0.036*
C15	0.51144 (19)	0.88538 (19)	0.23429 (18)	0.0239 (3)
H15A	0.5290	0.7966	0.3162	0.036*
H15B	0.4803	0.9709	0.2638	0.036*
H15C	0.6064	0.8996	0.1621	0.036*
C16	−0.2564 (2)	0.9523 (2)	0.4458 (2)	0.0317 (4)
H16A	−0.3170	0.8763	0.4573	0.048*
H16B	−0.3016	1.0488	0.3888	0.048*
H16C	−0.2564	0.9526	0.5390	0.048*

	U11	U22	U33	U12	U13	U23
S1	0.01467 (19)	0.0227 (2)	0.0196 (2)	−0.00267 (14)	−0.00178 (14)	−0.00991 (15)
O1	0.0160 (5)	0.0333 (6)	0.0293 (7)	−0.0041 (5)	0.0009 (5)	−0.0163 (5)
O2	0.0173 (6)	0.0360 (7)	0.0308 (7)	−0.0030 (5)	−0.0017 (5)	−0.0198 (5)
O3	0.0184 (5)	0.0264 (6)	0.0251 (6)	−0.0044 (4)	−0.0042 (4)	−0.0130 (5)
N1	0.0152 (6)	0.0218 (6)	0.0207 (7)	−0.0042 (5)	−0.0028 (5)	−0.0073 (5)
N2	0.0195 (7)	0.0258 (7)	0.0221 (7)	−0.0038 (5)	−0.0033 (5)	−0.0097 (6)
N3	0.0195 (7)	0.0250 (7)	0.0217 (7)	−0.0035 (5)	−0.0025 (5)	−0.0110 (6)
C1	0.0207 (8)	0.0324 (9)	0.0324 (10)	−0.0078 (7)	−0.0060 (7)	−0.0144 (8)
C2	0.0196 (8)	0.0206 (7)	0.0179 (8)	−0.0039 (6)	−0.0031 (6)	−0.0063 (6)
C3	0.0170 (7)	0.0240 (8)	0.0206 (8)	−0.0040 (6)	−0.0001 (6)	−0.0097 (6)
C4	0.0149 (7)	0.0197 (7)	0.0185 (8)	−0.0035 (6)	−0.0002 (6)	−0.0060 (6)
C5	0.0167 (7)	0.0206 (7)	0.0191 (8)	−0.0048 (6)	−0.0011 (6)	−0.0057 (6)
C6	0.0172 (7)	0.0190 (7)	0.0187 (8)	−0.0036 (6)	−0.0030 (6)	−0.0045 (6)
C7	0.0228 (8)	0.0196 (7)	0.0182 (8)	−0.0043 (6)	−0.0052 (6)	−0.0055 (6)
C8	0.0224 (8)	0.0216 (7)	0.0184 (8)	−0.0029 (6)	−0.0050 (6)	−0.0092 (6)
C9	0.0258 (9)	0.0407 (10)	0.0236 (9)	0.0015 (7)	−0.0088 (7)	−0.0180 (8)
C10	0.0229 (8)	0.0360 (9)	0.0225 (9)	−0.0026 (7)	−0.0083 (7)	−0.0111 (7)
C11	0.0227 (8)	0.0282 (8)	0.0349 (10)	−0.0060 (7)	−0.0035 (7)	−0.0197 (8)
C12	0.0267 (8)	0.0240 (8)	0.0210 (8)	−0.0058 (6)	−0.0024 (6)	−0.0096 (7)
C13	0.0260 (9)	0.0283 (9)	0.0239 (9)	0.0004 (7)	−0.0038 (7)	−0.0032 (7)
C14	0.0165 (8)	0.0305 (9)	0.0277 (9)	−0.0028 (6)	−0.0062 (6)	−0.0114 (7)
C15	0.0232 (8)	0.0284 (8)	0.0247 (8)	−0.0027 (6)	−0.0074 (7)	−0.0130 (7)
C16	0.0241 (9)	0.0427 (10)	0.0343 (10)	−0.0031 (7)	−0.0046 (7)	−0.0215 (9)

S1—C4	1.7469 (16)	C8—H8	1.0000
S1—C6	1.7736 (16)	C9—C10	1.512 (2)
O1—C5	1.212 (2)	C9—H9A	0.9900
O2—C2	1.211 (2)	C9—H9B	0.9900
O3—C2	1.3403 (19)	C10—C11	1.416 (3)
O3—C1	1.4495 (19)	C10—H10	0.9500
N1—C5	1.372 (2)	C11—C12	1.415 (2)
N1—C6	1.385 (2)	C11—C16	1.504 (2)
N1—C14	1.462 (2)	C12—C13	1.509 (2)
N2—C6	1.278 (2)	C12—H12A	0.9900
N2—N3	1.4174 (19)	C12—H12B	0.9900
N3—C7	1.282 (2)	C13—H13A	0.9900
C1—H1A	0.9800	C13—H13B	0.9900
C1—H1B	0.9800	C14—H14A	0.9800
C1—H1C	0.9800	C14—H14B	0.9800
C2—C3	1.467 (2)	C14—H14C	0.9800
C3—C4	1.340 (2)	C15—H15A	0.9800
C3—H3	0.9500	C15—H15B	0.9800
C4—C5	1.499 (2)	C15—H15C	0.9800
C7—C15	1.503 (2)	C16—H16A	0.9800
C7—C8	1.508 (2)	C16—H16B	0.9800
C8—C9	1.527 (2)	C16—H16C	0.9800
C8—C13	1.532 (2)
C4—S1—C6	90.05 (7)	C10—C9—H9B	109.4
C2—O3—C1	115.77 (13)	C8—C9—H9B	109.4
C5—N1—C6	115.69 (13)	H9A—C9—H9B	108.0
C5—N1—C14	121.75 (13)	C11—C10—C9	119.25 (15)
C6—N1—C14	122.23 (13)	C11—C10—H10	120.4
C6—N2—N3	108.81 (13)	C9—C10—H10	120.4
C7—N3—N2	114.54 (13)	C12—C11—C10	122.07 (16)
O3—C1—H1A	109.5	C12—C11—C16	118.75 (16)
O3—C1—H1B	109.5	C10—C11—C16	119.18 (16)
H1A—C1—H1B	109.5	C11—C12—C13	118.89 (15)
O3—C1—H1C	109.5	C11—C12—H12A	107.6
H1A—C1—H1C	109.5	C13—C12—H12A	107.6
H1B—C1—H1C	109.5	C11—C12—H12B	107.6
O2—C2—O3	124.53 (14)	C13—C12—H12B	107.6
O2—C2—C3	124.24 (15)	H12A—C12—H12B	107.0
O3—C2—C3	111.22 (13)	C12—C13—C8	111.68 (14)
C4—C3—C2	121.12 (14)	C12—C13—H13A	109.3
C4—C3—H3	119.4	C8—C13—H13A	109.3
C2—C3—H3	119.4	C12—C13—H13B	109.3
C3—C4—C5	120.42 (14)	C8—C13—H13B	109.3
C3—C4—S1	127.81 (12)	H13A—C13—H13B	107.9
C5—C4—S1	111.70 (11)	N1—C14—H14A	109.5
O1—C5—N1	124.96 (14)	N1—C14—H14B	109.5
O1—C5—C4	125.02 (15)	H14A—C14—H14B	109.5
N1—C5—C4	110.01 (13)	N1—C14—H14C	109.5
N2—C6—N1	122.47 (14)	H14A—C14—H14C	109.5
N2—C6—S1	125.00 (12)	H14B—C14—H14C	109.5
N1—C6—S1	112.53 (11)	C7—C15—H15A	109.5
N3—C7—C15	125.43 (15)	C7—C15—H15B	109.5
N3—C7—C8	117.47 (14)	H15A—C15—H15B	109.5
C15—C7—C8	117.04 (14)	C7—C15—H15C	109.5
C7—C8—C9	115.06 (13)	H15A—C15—H15C	109.5
C7—C8—C13	109.94 (13)	H15B—C15—H15C	109.5
C9—C8—C13	108.72 (14)	C11—C16—H16A	109.5
C7—C8—H8	107.6	C11—C16—H16B	109.5
C9—C8—H8	107.6	H16A—C16—H16B	109.5
C13—C8—H8	107.6	C11—C16—H16C	109.5
C10—C9—C8	111.08 (14)	H16A—C16—H16C	109.5
C10—C9—H9A	109.4	H16B—C16—H16C	109.5
C8—C9—H9A	109.4

D—H···A	D—H	H···A	D···A	D—H···A
C3—H3···O3i	0.95	2.59	3.4133 (19)	146
C1—H1C···O1ii	0.98	2.51	3.208 (2)	128
C14—H14A···O2iii	0.98	2.45	3.252 (2)	139
C14—H14B···O2iv	0.98	2.48	3.409 (2)	159
C15—H15A···O3iv	0.98	2.55	3.351 (2)	139