Uncovering stereochemical relations in a compound with a stereogenic N—O axis: methyl 2-(4-methyl-2-thio­xo-2,3-di­hydro­thia­zol-3-yl­oxy)­propanoate

The geometry of racemic methyl 2-(4-methyl-2-thio­xo-2,3-di­hydro­thia­zol-3-yl­oxy)­propanoate, C₈H₁₁NO₃S₂, (I), is characterized by a distorted heterocyclic five-membered ring and an enantiomorphic N-alkoxy substituent, which is inclined at an angle of −68.8° to the thia­zole­thione plane in (M)-(I). The unit cell consists of a 1:1 ratio of R,P- and S,M-configured mol­ecules of (I). The combination of a P configuration at the N—O axis and an R configuration at the asymmetric propanoate C_β atom on one side, and an S,M configuration on the other side, is considered to originate from steric interactions. The largest substituent at the asymmetric propanoate C_β atom, i.e. the methoxycarbonyl group, resides above the methyl substituent; the medium-sized propanoate γ-methyl substituent points in the opposite direction with respect to the N—O bond, whereas the H atom is located above the C=S double bond of the thiazolethione subunit.

S1. Comment

The N,O-functionality in N-(alkoxy)thiazole-2(3H)-thiones constitutes an element of chirality (Fig. 1). The barrier to rotation about this axis is, however, small, thus leading to an almost unhindered topomerization of N-alkoxy-substituents at room temperature (Hartung et al., 2001a). Since N-(alkoxy)thiazolethiones have become compounds of significant contemporary interest for investigations of mechanistic and biological aspects of oxyl radical chemistry, for instance, in an early stage of ageing processes or clinical phenomena induced by oxidative stress (Hartung et al., 2002), it was considered essential to uncover the principles of stereocontrol at this axis in the solid state with the aid of a homomorphic ligand. Thus, lactic acid derivatives of N-hydroxy-4-methylthiazole-2(3H)-thione have been prepared (Hartung et al., 2001b); both enantiomers of lactic acid occur naturally. Since the synthesis of the title compound, (I), starting from methyl (S)-lactate provided material that failed to crystallize, racemic N-(1-methoxycarbonylethyl-1-oxy)-4-methylthiazole-2(3H)thione, (I), was synthesized and investigated by X-ray diffraction.

Compound (I) crystallizes in the triclinic space group P1. The unit cell contains one molecule each of (R,P)-(I) and (S,M)-(2) (Figs. 2 and 3). Ring atoms S2, C6 and O1 are slightly removed from the thiazolethione plane [S2—C2—N3—O1 = 4.0 (2)°, C6—C4—C5—S1 = 176.9 (2)° and O1—N3—C4—C5 = 173.2 (1)°]. The heterocyclic core is characterized by a distorted five-membered ring since the connectivities between atoms C2 and C5 towards atom S2 [S1—C2 = 1.724 (2) Å and S1—C5 = 1.724 (2) Å] are longer than those between the other endocyclic atoms [N3—C2 = 1.352 (2), N3—C4 = 1.399 (2) and C4—C5 = 1.332 (3) Å]. Furthermore, the C2—S1—C5 = 92.5 (1)° bond angle is smaller than 108° (required for a regular five-membered ring). The C2—S2 [1.658 (2) Å] and N3—O8 [1.385 (2) Å] bond lengths are interpreted as C=S and N—O bonds and are in agreement with literature values for related N-(alkyl)thiazole-2(3H)-thiones (C2—S2; Rochester et al., 1987; Ugozzoli & Andreetti, 1987; Shin & Lim, 1995) and N-hydroxy-4-methylthiazole-2(3H)-thione (C2—S2 and N3—O8; Bond & Jones, 2000). Three intramolecular contacts were observed for (I) in the solid state [O2···H6A = 2.34 (3) Å, S2···H7 = 2.598 (17) Å and C2···H7 = 2.685 (19) Å]. Furthermore, the S2A···H6CB distance [2.85 (3) Å] between two adjacent molecules in combination with the associated S2A—C6B—H6CB angle [157 (2)°] may be interpreted as a C—H acceptor interaction between a C=S and a CH₃ group functionality (Steiner, 1996).

The substituent at O1 is bent from the heterocyclic plane of (I) [C2—N3—O8—C7 = −68.6 (2)° in (M)-(I)] for steric and electronic reasons (Hartung et al., 2001a). The location of the substituents on atom C7 in (I) may be rationalized by subdividing the heterocyclic plane, as seen in a projection along the N—O axis, into a lower hemisphere (S) and two upper parts (NW/NE) [for (S,M)-(I) see Fig. 4]. Substituents on atom C7 exhibit the smallest steric repulsion from the 4-methylthiazole-2(3H)-thione subunit in (S,M)-(I), if located in the NE part, which positions the largest substituent (L, i.e. the ester functionality) in a synclinal (-sc) arrangement [N3—O1—C7—C8 = −70.9 (2)°] and thus in the opposite direction of the heterocyclic plane. If rotated towards the NW area (+sc arrangement of L), steric repulsion should arise between (i) the L and C=S groups and (ii) the two CH₃-groups bound to atoms C5 and C7. An increase of conformational energy is also expected if L is located in the southern hemisphere in (S,M)-(I) [antiperiplanar (ap) arrangement of L], since this geometry would incline the 7-CH₃ group into closer proximity with the thiocarbonyl substituent. According to this interpretation, energetically favorable configurations of (I) are restricted to the combinations (S,M) and (P,R).

It is noteworthy that the stereochemical model, which is outlined in Fig. 4, is also applicable for interpreting the observed configuration at the N—O axes in related structures, i.e. secondary N-(alkoxy)pyridine-2(1H)-thiones, N-(alkoxy)-2(1H)-pyridones and N-(alkoxy)-4-(p-chlorophenyl)thiazole-2(3H)-thiones (Hartung et al., 1996; Hartung et al., 1999). As all of these compounds selectively afford oxygen-centered radicals upon photochemical excitation (Hartung et al., 2002), the mnemonic device outlined in Fig. 4 is considered to be useful in order to predict preferred geometries in the vicinity of the reactive N–O bond, thus contibuting to a rationalization of selectivities in future solid-state photochemical experiments.

S2. Experimental

A solution of N-hydroxy-4-methylthiazole-2(3H)thione (Barton et al., 1986) (783 mg, 5.32 mmol) in anhydrous CH₃CN (11 ml) was treated with K₂CO₃ (2.01 g, 14.5 mmol), NBu₄HSO₄ (180 mg, 532 mmol] and racemic methyl [2-(p-toluenesulfonyloxy)]propionate (1.25 g, 4.84 mmol) (Hartung et al., 1997). The reaction mixture was stirred for 2 h at 293 K and worked up according to the procedure described by Hartung et al. (1999) to furnish (I) (813 mg, 72%). Crystals suitable for X-ray analysis were obtained from a saturated solution of (I) in diethyl ether, which was stored in an atmosphere saturated with n-pentane vapor. M.p. 342–344 K. Analysis calculated: C 41.18, H 4.75, N 6.00, S 27.49%; found: C 41.33, H 4.58, N 6.02, S 27.30%. ¹H NMR (200 MHz, CDCl₃): δ_H 1.61 (d, J = 7 Hz, 3H), 2.33 (q, J = 1 Hz, 3H), 3.72 (s, 3H), 6.08 (q, 7 Hz, 1H), 6.14 (q, J = 1 Hz, 1H); ¹³C NMR (50 MHz,CDCl₃): δ_C 13.8, 16.3, 52.3, 77.9, 102.5, 139.4, 180.2.

S3. Refinement

The H atoms of the two methyl groups (C9 and C10) were placed in idealized positions, with C—H distances of 0.96 Å. All other H atoms were located from a difference Fourier map and their positions were refined freely, with isotropic displacement parameters.

Computing details

Data collection: CAD-4 EXPRESS Software (Enraf–Nonius, 1993); cell refinement: CAD-4 EXPRESS Software; data reduction: CAD-4 EXPRESS Software; program(s) used to solve structure: SHELXS97 (Sheldrick, 1990); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997); molecular graphics: ORTEP-3 (Farugia, 1997) and PLATON2002 (Spek, 2002); software used to prepare material for publication: SHELXL97 (Sheldrick, 1997).

Figures

	Fig. 1. Stereochemical descriptors for an assignment of configurations at the N—O axis in N-(alkoxy)-4-methylthiazole-2(3H)-thiones. The descriptor P (plus) denotes a clockwise arrangement of substituents of highest priority, whereas M (minus) is used for an anticlockwise configuration. (R = H or alkyl.)
	Fig. 2. The molecular structure of (I), with the atomic numbering scheme. Displacement ellipsoids are shown at the 50% probability level.
	Fig. 3. The packing of (S,M)-(I) and (R,P)-(I) in the unit cell, viewed along 100.
	Fig. 4. A guideline for predicting a preferred N,O-configuration in secondary chiral N-(alkoxy)thiazole-2(3H)-thiones. The stereochemical descriptors are valid for the following priority of substituents: O1 > L (CO2CH3) > M (CH3) > S (H). (+sc denotes +synclinal, -sc denotes -synclinal and ap denotes antiperiplanar.)

methyl 2-(4-methyl-2-thioxo-2,3-dihydrothiazol-3-yloxy)propanoate

Crystal data

C8H11NO3S2	Z = 2
Mr = 233.30	F(000) = 244
Triclinic, P1	Dx = 1.433 Mg m^−3
Hall symbol: -P 1	Melting point: 342-344 K K
a = 7.802 (1) Å	Mo Kα radiation, λ = 0.71073 Å
b = 8.622 (1) Å	Cell parameters from 25 reflections
c = 9.441 (1) Å	θ = 2.4–11.7°
α = 113.84 (1)°	µ = 0.47 mm^−1
β = 91.18 (1)°	T = 300 K
γ = 109.04 (1)°	Prism, colourless
V = 540.52 (13) Å^3	0.75 × 0.40 × 0.20 mm

Data collection

Enraf–Nonius CAD-4 diffractometer	1915 reflections with I > 2˘I)
Radiation source: fine-focus sealed tube	Rint = 0.020
Graphite monochromator	θmax = 26.0°, θmin = 2.4°
ω/2θ scans	h = −9→3
Absorption correction: ψ scan (North et al., 1968)	k = −10→10
Tmin = 0.632, Tmax = 0.855	l = −11→11
3209 measured reflections	3 standard reflections every 120 min
2122 independent reflections	intensity decay: 19.4%

Refinement

Refinement on F^2	Primary atom site location: structure-invariant direct methods
Least-squares matrix: full	Secondary atom site location: difference Fourier map
R[F^2 > 2σ(F^2)] = 0.037	Hydrogen site location: inferred from neighbouring sites
wR(F^2) = 0.103	H atoms treated by a mixture of independent and constrained refinement
S = 1.10	w = 1/[σ^2(Fo^2) + (0.0632P)^2 + 0.1124P] where P = (Fo^2 + 2Fc^2)/3
2122 reflections	(Δ/σ)max = 0.004
147 parameters	Δρmax = 0.30 e Å^−3
0 restraints	Δρmin = −0.39 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.

Refinement. Refinement of F² against ALL reflections. The weighted R-factor wR and goodness of fit S are based on F², conventional R-factors R are based on F, with F set to zero for negative F². The threshold expression of F² > σ(F²) is used only for calculating R-factors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F² are statistically about twice as large as those based on F, and R- factors based on ALL data will be even larger.

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

	x	y	z	Uiso*/Ueq
S1	0.23226 (6)	0.02289 (6)	0.23304 (5)	0.05018 (17)
S2	0.51210 (6)	−0.14822 (7)	0.12017 (5)	0.05137 (17)
O1	0.16201 (15)	−0.41822 (15)	−0.13339 (13)	0.0396 (3)
O2	0.06735 (17)	−0.28979 (19)	−0.33914 (15)	0.0533 (3)
O3	0.32221 (18)	−0.29529 (19)	−0.44193 (15)	0.0539 (3)
N3	0.15731 (17)	−0.26005 (17)	−0.01458 (15)	0.0357 (3)
C2	0.3036 (2)	−0.1407 (2)	0.10107 (18)	0.0384 (3)
C4	−0.0124 (2)	−0.2393 (2)	0.0044 (2)	0.0406 (4)
C5	0.0078 (3)	−0.0892 (3)	0.1339 (2)	0.0495 (4)
H5	−0.088 (3)	−0.048 (3)	0.163 (3)	0.069 (7)*
C6	−0.1829 (2)	−0.3765 (3)	−0.1080 (2)	0.0511 (4)
H6A	−0.172 (3)	−0.395 (3)	−0.217 (3)	0.067 (6)*
H6B	−0.212 (4)	−0.500 (4)	−0.112 (3)	0.080 (8)*
H6C	−0.288 (4)	−0.346 (4)	−0.077 (3)	0.080 (8)*
C7	0.2831 (2)	−0.3867 (2)	−0.24121 (19)	0.0419 (4)
H7	0.397 (3)	−0.291 (3)	−0.181 (2)	0.049 (5)*
C8	0.2066 (2)	−0.3204 (2)	−0.34456 (18)	0.0417 (4)
C9	0.3051 (3)	−0.5671 (3)	−0.3312 (3)	0.0631 (5)
H9A	0.3540	−0.6010	−0.2589	0.076*
H9B	0.3879	−0.5561	−0.4034	0.076*
H9C	0.1873	−0.6587	−0.3886	0.076*
C10	0.2784 (3)	−0.2125 (3)	−0.5349 (2)	0.0637 (5)
H10A	0.3688	−0.1999	−0.6010	0.076*
H10B	0.2782	−0.0944	−0.4668	0.076*
H10C	0.1589	−0.2875	−0.5991	0.076*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
S1	0.0543 (3)	0.0453 (3)	0.0424 (3)	0.0200 (2)	0.0114 (2)	0.0095 (2)
S2	0.0370 (2)	0.0662 (3)	0.0442 (3)	0.0194 (2)	0.00319 (18)	0.0173 (2)
O1	0.0405 (6)	0.0372 (5)	0.0389 (6)	0.0161 (5)	0.0120 (5)	0.0127 (5)
O2	0.0486 (7)	0.0688 (8)	0.0510 (7)	0.0268 (6)	0.0125 (6)	0.0297 (7)
O3	0.0516 (7)	0.0641 (8)	0.0422 (7)	0.0173 (6)	0.0160 (6)	0.0223 (6)
N3	0.0349 (6)	0.0382 (6)	0.0341 (6)	0.0155 (5)	0.0089 (5)	0.0141 (5)
C2	0.0394 (8)	0.0419 (8)	0.0344 (7)	0.0151 (6)	0.0091 (6)	0.0170 (6)
C4	0.0359 (8)	0.0460 (8)	0.0473 (9)	0.0190 (7)	0.0141 (7)	0.0239 (7)
C5	0.0463 (9)	0.0520 (10)	0.0555 (10)	0.0262 (8)	0.0180 (8)	0.0217 (8)
C6	0.0342 (8)	0.0576 (11)	0.0590 (12)	0.0150 (8)	0.0100 (8)	0.0243 (9)
C7	0.0355 (8)	0.0505 (9)	0.0352 (8)	0.0166 (7)	0.0103 (6)	0.0134 (7)
C8	0.0402 (8)	0.0407 (8)	0.0327 (7)	0.0103 (6)	0.0071 (6)	0.0086 (6)
C9	0.0732 (13)	0.0710 (13)	0.0565 (11)	0.0476 (11)	0.0224 (10)	0.0214 (10)
C10	0.0743 (14)	0.0684 (13)	0.0411 (9)	0.0143 (11)	0.0113 (9)	0.0260 (9)

Geometric parameters (Å, º)

S1—C2	1.724 (2)	O3—C10	1.432 (3)
S1—C5	1.724 (2)	C5—H5	0.93 (2)
S2—C2	1.658 (2)	C6—H6A	0.99 (3)
O1—N3	1.385 (2)	C6—H6B	0.99 (3)
N3—C2	1.352 (2)	C6—H6C	0.95 (3)
N3—C4	1.399 (2)	C7—H7	0.96 (2)
C4—C5	1.332 (3)	C9—H9A	0.9600
C4—C6	1.481 (2)	C9—H9B	0.9600
O1—C7	1.4484 (18)	C9—H9C	0.9600
O2—C8	1.197 (2)	C10—H10A	0.9600
O3—C8	1.332 (2)	C10—H10B	0.9600
C7—C9	1.510 (3)	C10—H10C	0.9600
C7—C8	1.511 (2)
C2—S1—C5	92.50 (8)	O1—C7—C8	111.73 (13)
N3—O1—C7	113.8 (1)	C9—C7—C8	113.78 (15)
O1—N3—C2	122.2 (1)	O1—C7—H7	108.2 (12)
O1—N3—C4	118.9 (1)	C9—C7—H7	112.8 (12)
C2—N3—C4	117.8 (1)	C8—C7—H7	105.9 (12)
S1—C2—S2	125.1 (1)	O2—C8—O3	124.31 (16)
S1—C2—N3	107.0 (1)	O2—C8—C7	126.46 (15)
S2—C2—N3	127.9 (1)	O3—C8—C7	109.20 (14)
N3—C4—C5	110.2 (2)	C7—C9—H9A	109.5
N3—C4—C6	120.9 (2)	C7—C9—H9B	109.5
C5—C4—C6	128.9 (2)	H9A—C9—H9B	109.5
S1—C5—C4	112.2 (1)	C7—C9—H9C	109.5
C4—C5—H5	123.0 (14)	H9A—C9—H9C	109.5
S1—C5—H5	124.8 (14)	H9B—C9—H9C	109.5
C4—C6—H6A	111.7 (14)	O3—C10—H10A	109.5
C4—C6—H6B	113.0 (15)	O3—C10—H10B	109.5
H6A—C6—H6B	104 (2)	H10A—C10—H10B	109.5
C4—C6—H6C	111.0 (16)	O3—C10—H10C	109.5
H6A—C6—H6C	112 (2)	H10A—C10—H10C	109.5
H6B—C6—H6C	104 (2)	H10B—C10—H10C	109.5
O1—C7—C9	104.36 (15)	C8—O3—C10	115.46 (15)
N3—C4—C5—S1	−1.0 (2)	C5—C4—N3—O1	173.2 (1)
C6—C4—C5—S1	176.9 (2)	C6—C4—N3—O1	−4.9 (2)
O1—C7—C8—O2	2.4 (2)	C2—N3—O1—C7	−68.6 (2)
C9—C7—C8—O2	120.2 (2)	C4—N3—O1—C7	123.89 (14)
O1—C7—C8—O3	−179.47 (13)	C9—C7—O1—N3	165.75 (14)
C9—C7—C8—O3	−61.61 (19)	C8—C7—O1—N3	−70.88 (16)
S2—C2—N3—O1	4.0 (2)	O2—C8—O3—C10	5.1 (2)
S1—C2—N3—O1	−174.2 (1)	C7—C8—O3—C10	−173.09 (15)
S2—C2—N3—C4	171.7 (1)	N3—C2—S1—C5	4.7 (1)
S1—C2—N3—C4	−6.5 (2)	S2—C2—S1—C5	−173.6 (1)
C5—C4—N3—C2	5.1 (2)	C4—C5—S1—C2	−2.2 (1)
C6—C4—N3—C2	−173.0 (2)