1,3-Thia­zolidine derivatives from regioselective [2+3]-cyclo­additions of azomethine yl­ides with thio­ketones

1,3-Thiazolidines may be used in the synthesis of pharmaceuticals such as immunomodulating drugs or antibiotics (Hwu et al., 1999; Pellegrini et al., 1999). Thioketones are recognized as `superdipolarophilic' compounds and combine smoothly with 1,3-dipoles to yield sulfur-containing five-membered heterocycles (Huisgen et al., 1995). However, there are few papers dealing with the reactions of azomethine ylides with thioketones. Heating 1,2,3-triazoline, (I), with adamantane-2-thione, (IV), or 9H-fluorene-9-thione, (V), in boiling toluene, resulted in the formation of 1,3-thiazolidines (VI) or (VII), respectively (Mlostoń & Skrzypek, 1990) (see Scheme). The molecular formulae of C₂₈H₃₁NO₄S for (VI) and C₃₁H₂₅NO₄S for (VII) were established from elemental analyses and mass spectra. Desulfurization of (VII) with Raney nickel resulted unexpectedly in ring contraction and formation of the corresponding azetidine derivative (Mlostoń et al., 2000, 2002). On the other hand, the same procedure with (VI) led to recovery of the starting material, which suggested that the formation of (VI) and (VII) had occurred with different regioselectivity. The X-ray crystallographic analyses of (VI) and (VII) were undertaken to elucidate their structures and thereby determine the influence of the location of the ester groups on the course of the subsequent desulfurization reaction. The two structures (Figs. 1 and 2) confirm that the regioselectivity of the addition step leading to the formation of the heterocyclic ring from thioketones and azomethine ylides is dependent on the type of thioketone used (see Scheme).

The asymmetric unit of compound (VI) contains two independent molecules of the thiazolidine derivative plus a site for a methanol molecule which is approximately 55% occupied. Although the unit cell is metrically very close to orthorhombic, tests with PLATON (Spek, 2003) indicated the absence of any additional crystallographic symmetry. The two symmetry-independent thiazolidine molecules have the same configuration and almost identical conformations. The weighted r.m.s. fit (Mackay, 1984) of the atoms from the two molecules is 0.18 Å and the two molecules are related by a rotation of approximately 175°. Compound (VII) crystallizes with just one independent molecule in the asymmetric unit. The bond lengths and angles in the two structures are generally in good agreement with expected values (Allen et al., 1987), although in (VI), the C4A—C5A and C4B—C5B bonds are quite long at about 1.61 Å and the S—C bond lengths are asymmetric (Table 1). As a consequence of the long C—C bonds, the C2A—N3A—C4A and C2B—N3B—C4B bond angles are larger than the corresponding angles in compound (VII), where the C4—C5 bond is not unduly long and the S—C bonds are more symmetrical (Table 2). Elongation of C—C bonds in the range 1.56–1.61 Å has been observed frequently in spirocyclic thiazolidine, thiazole, oxathiolane and dithiolane ring systems (Linden et al., 1998). Steric crowding is probably responsible for the observed geometry of the thiazolidine ring in compound (VI). There are several very short intramolecular contacts between the H atoms of the adamantanyl group and the ester C and O atoms, as well as with the thiazolidine S atom. The shortest contacts of this type are 2.29 and 2.31 Å for H591···C45A and H593···C45B, respectively, which are approximately 0.6 Å shorter than the sum of the van der Waals radii of these atoms, and three other H···C or H···S contacts in each of the independent molecules are between 0.37–0.51 Å shorter than the sum of the van der Waals radii. The steric constraints introduced by the adamantanyl group also severely restrict the orientations that can be adopted by the ester substituents, which results in additional short intramolecular contacts, namely O44A···O48A [2.7221 (16) Å], O44B···O48B [2.7415 (18) Å], O42A···N3A [2.6230 (17) Å], O46A···N3A [2.6094 (16) Å], O42B···N3B [2.6001 (18) Å] and O46B···N3B [2.5896 (16) Å]. By contrast, the less bulky planar fluorenyl substituent in compound (VII) is not involved in any unduly short intramolecular contacts and the bond lengths and angles within the thiazolidine ring are consequently less distorted than in compound (VI).

The 1,3-thiazolidine rings of both compounds have envelope conformations. For compound (VI), the puckering parameters (Cremer & Pople, 1975) are q₂ = 0.3953 (14) and 0.4549 (14) Å, and ϕ₂ = 146.7 (2) and 150.87 (19)° for the rings defined by the atom sequences S1A—C2A—N3A—C4A—C5A and S1B—C2B—N3B—C4B—C5B, respectively, and the envelope flaps are formed by the spiro-C atoms C5A and C5B, respectively. For compound (VII), the puckering parameters are q₂ = 0.4592 (9) Å and ϕ₂ = 110.25 (10)° for the atom sequence S1—C2—N3—C4—C5, with atom C4 forming the envelope flap.

The phenyl substituents at atoms C2A and C2B of compound (VI) occupy pseudo-axial positions, while those at atoms N3A and N3B, as well as all the phenyl substituents in compound (VII), occupy pseudo-equatorial positions. In compound (VII), the planes of both phenyl substituents lie almost perpendicular to the mean plane of the 1,3-thiazolidine ring, with interplanar angles of 61.06 (4) and 65.14 (3)° for the phenyl substituents at N3 and C4, respectively. The planes of the phenyl substituents at atoms C2A and C2B of compound (VI) are aligned similarly, with the corresponding interplanar angles being 75.39 (5) and 72.04 (5)°, respectively. In contrast, the planes of the phenyl substituents at atoms N3A and N3B of compound (VI) lie almost parallel to the planes of the respective 1,3-thiazolidine rings, with interplanar angles of 21.30 (8) and 21.67 (8)°, respectively.

The fluorene substituent in compound (VII) is almost planar, although slight envelope puckering of the central five-membered ring pushes the spiro-C atom, C5, out of the plane and gives the entire fluorene moiety a flat-dish shape. Excluding atom C5, the r.m.s. deviation of atoms C51 to C62 from their mean plane is 0.040 Å, with a maximum deviation of 0.0638 (9) Å for atom C51. Atom C5 lies 0.1896 (11) Å from this plane. The flatness of the dish is shown by the angle of intersection between the two phenyl rings of the fluorene moiety, which is 4.50 (7)°.

In compound (VI), the hydroxy group of the methanol molecule forms bifurcated intermolecular hydrogen bonds with both of the ester carbonyl O atoms of a neighbouring thiazolidine molecule, although one interaction is significantly weaker then the other (Table 2). These interactions form a six-membered loop with a graph-set motif of R²₁(6) (Bernstein et al., 1995). Two intermolecular C—H···O interactions link the independent thiazolidine molecules to each other and a third interaction links one of these molecules to a neighbouring methanol molecule. The combination of O—H···O and C—H···O interactions links two of each of the independent thiazolidine molecules and two methanol molecules into a closed centrosymmetric hexameric unit (Fig. 3). Compound (VII) does not display any significant intermolecular C—H···O interactions.