Crystal structure of N-[(2S,5R)-4-oxo-2,3-diphenyl-1,3-thiazinan-5-yl]acetamide 0.375-hydrate

The crystal structure of the title compound displays boat and half-chair configurations of the thiazine ring.


Chemical context
In a recent paper, we reported the 2,4,6-tripropyl-1,3,5,2,4,6trioxatriphosphorinane-2,4,6-trioxide (T3P)-promoted cyclization of N-[phenylmethylidene]aniline with 3-sulfanylpropanoic acid to produce 2,3-diphenyl-2,3,5,6-tetrahydro-4H-1,3-thiazin-4-one . As noted before , prior to this, the N-aryl compounds had not easily been prepared by condensation of imines with thioacids. With respect to the thioacid, the use of a homochiral cysteine derivative is desirable because, along with putting a functional group on the ring, it creates a second chiral center at the 5-position of the thiazinone, potentially allowing the separation of two diastereomers into cis and trans homochiral heterocycles. A condensation of N-acetylcysteine with two very active (CX 3 ) 2 C NH imines has been reported (Raasch, 1974), giving a thiazinone with one chiral center. Although a search of 2,3,5,6-tetrahydro-4H-1,3-thiazin-4-ones with a nitrogen atom at the 5-position and carbon atoms at positions 2 and 3 found 156 compounds, there were only two compounds with an aryl group at the 3-position and both involved a more complex bridged structure synthesized by a cycloaddition route (Potts, et al., 1974). Herein we report the T3P-promoted cyclization of N- [phenylmethylidene]aniline with N-acetyl-l-cysteine. One major product arose along with at least three minor products, as determined by NMR spectroscopy. The major product was isolated by column chromatography followed by recrystallization. The structure is reported as the title compound here. The minor products have not yet been satisfactorily isolated. As reported here, the major product is the cis diastereomer. ISSN 2056-9890

Structural commentary
The two independent organic molecules in the asymmetric unit exhibit different geometries for the thiazine ring (Fig. 1). In molecule A, the ring takes a boat configuration with the groups at the 2-and 5-positions pseudo-equatorial and the hydrogens at these positions within 1.993 Å of each other. The stability gained by having both groups pseudo-equatorial must offset the higher energy expected in a boat conformation. The dihedral angle between the C1-and C8-benzene rings is 51.7 (2) . An intramolecular N2-H2NÁ Á ÁO1 hydrogen bond is observed, which closes an S(5) ring.
In molecule B, the thiazine ring adopts a half-chair conformation. The groups at the 2-and 5-positions cannot readily be defined as pseudo-axial or pseudo-equatorial, but the phenyl ring at the 2-position is closer to axial, while the amide group at the 5-position is closer to equatorial. The dihedral angle between the phenyl rings (C20-C25 and C26-C31) is 84.4 (2) . This conformation is similar to that observed for 2,3-diphenyl-2,3,5,6-tetrahydro-4H-1,3-thiazin-4one . Molecule B features an intramolecular C21-H21Á Á ÁO4 link, which generates an S(10) loop.
The residual electron density suggested several solvent molecule sites but only with partial occupancies. The best model fixed the occupancy for each of the three water-molecule sites at 0.25.

Supramolecular features
In the crystal, the N-H grouping of molecule B (corresponding to the one involved in the intramolecular N2-H2NÁ Á ÁO1 hydrogen bond in molecule A) participates in an intermolecular N4-H4NÁ Á ÁO2 hydrogen bond to molecule A (Table 1). Molecule A participates in a C7-H7Á Á ÁO3 interaction back to molecule B. The crystal packing is shown in Fig. 2.

Synthesis and crystallization
A two-necked 25 ml round-bottom flask was oven-dried, cooled under N 2 , and charged with a stir bar and N-benzylideneaniline (1.087 g, 6 mmol). Tetrahydrofuran (2.3 ml) was added, the solid dissolved, and the solution was stirred. Pyridine (1.95 ml, 24 mmol) was added and then N-acetyl-lcysteine (6 mmol, 0.9824 g) was added. Finally, 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (T3P) in 2-methyltetrahydrofuran (50 weight%; 7.1 ml, 12 mmol) was added. The reaction was stirred at room temperature. TLC (EtOAc) after one day showed the reaction was complete, with two product spots, but the reaction was allowed to stir another 13 days. The mixture was poured into a separatory funnel with dichloromethane and distilled water. The layers were separated and the aqueous was then extracted twice with dichloromethane. The organics were combined and washed with saturated sodium bicarbonate and then saturated sodium chloride. The organic was dried over sodium sulfate, and concentrated under vacuum to a solid. The crude was chromatographed on 30 g flash silica gel, eluting with 50% ethyl acetate/hexanes and 100% ethyl acetate. Fractions containing the larger, more polar spot on TLC were combined, ORTEP view of the title compound. Displacement ellipsoids are drawn at the 50% probability level.

Figure 2
The crystal packing of the title compound. Table 1 Hydrogen-bond geometry (Å , ).

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 2. The hydrogen atoms bound to the nitrogen atom was located in the difference Fourier map and refined isotropically. The C-bound H atoms were geometrically placed with C-H = 0.93-0.97 Å , and refined as riding with U iso (H) = 1.2U eq (C). The three solvent molecule sites were given occupancy of 0.25 each, as that proved to be the best way to account for the residual electron density.

Special details
Experimental. Absorption correction: SADABS was used for absorption correction. R(int) was 0.0331 before and 0.0128 after correction. The Ratio of minimum to maximum transmission is 0.8482. The λ/2 correction factor is 0.0015. The data collection nominally covered a full sphere of reciprocal space by a combination of 4 sets of ω scans each set at different φ and/or 2θ angles and each scan (10 s exposure) covering -0.300° degrees in ω. The crystal to detector distance was 5.82 cm. 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 F 2 against ALL reflections. The weighted R-factor wR and goodness of fit S are based on F 2 , conventional R-factors R are based on F, with F set to zero for negative F 2 . The threshold expression of F 2 > σ(F 2 ) is used only for calculating R-factors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F 2 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 (Å 2 )
x y z U iso */U eq Occ. (