trans-(3R,2aS)-(-)-3-Phenyl-2,3,5,6,7,8-hexa­hydro-oxazolo­[3,2-a]­pyridine-5-thione

The crystal structure of the title compound, C₁₃H₁₅NOS, is very similar to that of the corresponding oxazolo­pyridin-5-one. However, a significant participation of a tautomeric thio-enolic form is observed, as reflected by the short N-C(=S) bond length of 1.328 (4) Å.

Key indicators

• Single-crystal X-ray study
• T = 296 K
• Mean [sigma](C-C) = 0.006 Å
• R factor = 0.058
• wR factor = 0.167
• Data-to-parameter ratio = 22.2

checkCIF results

No syntax errors found

ADDSYM reports no extra symmetry


 Alert Level C:



PLAT_360  Alert C Short  C(sp3)-C(sp3) Bond  C(6)   -   C(7)   =       1.41 Ang.

General Notes



REFLT_03
         From the CIF: _diffrn_reflns_theta_max           28.74
         From the CIF: _reflns_number_total               3247
         Count of symmetry unique reflns         1873
         Completeness (_total/calc)            173.36%
         TEST3: Check Friedels for noncentro structure
         Estimate of Friedel pairs measured      1374
         Fraction of Friedel pairs measured     0.734
         Are heavy atom types Z>Si present          yes
          Please check that the estimate of the number of Friedel pairs is
          correct. If it is not, please give the correct count in the
          _publ_section_exptl_refinement section of the submitted CIF.


 0 Alert Level A = Potentially serious problem

 0 Alert Level B = Potential problem

 1 Alert Level C = Please check

---

S1. Comment

Chiral non-racemic hexahydrooxazolo[3,2-a]pyridin-5-ones are strategic starting materials for the asymmetric synthesis of alkaloids and piperidine derivatives, via the stereoselective C—C bond formation at the α position of the N atom (Micouin et al., 1994; Husson & Royer, 1999; Amat et al., 2003, and references therein). The stereoselectivity of this key step is mainly driven by the geometry of the fused rings of the oxazolopyridine moiety and by the functionalization of atom C5. The synthesis and X-ray structure of trans-(3R,2aS)-(-)-3-phenyl-2,3,5,6,7,8-hexahydro-oxazolo[3,2-a]pyridin-5-one have been recently reported (Amat et al., 2003; Roa et al., 2003). The carbonyl group at C5 can be easily substituted by a thiocarbonyl group (see Experimental), providing (I), for which we report here the X-ray characterization.

The core of (I) consists of trans-fused cycles (Fig. 1). As expected, the synthesis does not modify the absolute configuration of the chiral centers, which are retained as 2aS and 3R. The five-membered oxazole ring (O1/C2/C3/N4/C2a) approximates an envelope conformation on O1, as described by the puckering descriptor ϕ = 173.7 (6)° (Cremer & Pople, 1975; Spek, 2003). A similar puckering analysis describes the six-membered N4/C2a/C8/C7/C6/C5 ring as an envelope on C8, with angles θ = 59.9 (5) and ϕ = 123.6 (6)° (Boeyens, 1978; Spek, 2003). For the six-membered ring, the mean deviation from the N4/C2a/C7/C6/C5 least-squares plane is 0.038 Å and atom C8 deviates from this plane by −0.675 Å; in the case of the oxazole ring, the mean deviation from the C2/C3/N4/C2a plane is 0.023 Å and atom O1 deviates by −0.527 Å. The resulting trans-fused bicycle is almost planar, with a dihedral angle between the rings of 14.7 (3)°. The phenyl ring at C3 makes a dihedral angle of 78.86 (9)° with the mean plane of the bicycle (excluding H atoms), minimizing steric hindrance for the overall molecule.

The geometry of (I) is very similar (Table 1) to that of the starting material; a fit between both structures, excluding S1 and H atoms, gives an r.m.s. deviation of 0.083 Å (Fig. 2). Hence, the substitution of the carbonyl group at C5 by a thiocarbonyl group does not significantly affect the geometry of the oxazolopyridine core. However, a structural feature observed in (I) points out its potential utility as a synthon for alkaloid synthesis; the short bond length N4—C5 of 1.328 (4) Å indicates a significant participation of a tautomeric thio–enolic form in the solid state and, probably, in solution. This distance is even shorter than that observed for the starting material, 1.3513 (1) Å (Roa et al., 2003). This behaviour should facilitate the functionalization at C5. On the other hand, due to the large radii of the S atom, a good stereoselectivity can be expected for this synthetic step.

S2. Experimental

0.300 g of trans-(3R,2aS)-(-)-3-phenyl-2,3,5,6,7,8-hexahydrooxazolo[3,2-a]pyridine-5-one was dissolved in anhydrous benzene (30 ml) and 0.335 g of Lawesson's reagent [2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane 2,4-disulfide] was added to the solution. The reaction was refluxed until all starting material had been consumed, ca 1 h [TLC monitoring, SiO₂, hexane-AcOEt (7:3)]. Solvent is then removed under vacuum and the crude is purified by column chromatography [SiO₂, petroleum ether–AcOEt (9:1)] yielding (I) as a pale yellow solid (yield: 81%; m.p. 372 K). Single crystals are obtained by slow evaporation of an AcOEt solution at 298 K. The successful substitution of the carbonyl group by a thiocarbonyl fragment was confirmed by IR data [starting material: ν(C═O) = 1649 cm⁻¹; (I): ν(C═S) = 1594 cm⁻¹], as well as ¹³C NMR data [CDCl₃, displacement for C5; starting material: δ = 168 p.p.m.; (I): δ = 203 p.p.m.].

S3. Refinement

All H atoms were placed at idealized positions and treated as riding atoms, with C—H distances constrained to 0.93 (aromatic CH), 0.97 (CH₂) or 0.98 Å (CH), and U_iso(H) = 1.2 U_eq(parent).

Computing details

Data collection: XSCANS (Siemens, 1996); cell refinement: XSCANS; data reduction: XSCANS; program(s) used to solve structure: SHELXTL (Sheldrick, 1998); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997); molecular graphics: SHELXTL; software used to prepare material for publication: SHELXL97.

Figures

	Fig. 1. The structure of (I), with displacement ellipsoids at the 20% probability level for non-H atoms. H atoms are shown as small spheres of arbitrary radii.
	Fig. 2. The superimposed fit for the molecules of (I) (solid lines) and the starting material (open lines). The atom-numbering scheme is given for (I). For clarity, H atoms have been omitted for both molecules.

trans-(3R,2aS)-(-)-3-Phenyl-2,3,5,6,7,8-hexahydro-oxazolo[3,2-a]pyridine- 5-thione

Crystal data

C13H15NOS	F(000) = 496
Mr = 233.32	Dx = 1.243 Mg m^−3
Orthorhombic, P212121	Mo Kα radiation, λ = 0.71073 Å
Hall symbol: P 2ac 2ab	Cell parameters from 68 reflections
a = 7.7811 (7) Å	θ = 4.7–13.7°
b = 10.4190 (9) Å	µ = 0.24 mm^−1
c = 15.3834 (12) Å	T = 296 K
V = 1247.15 (18) Å^3	Plate, pale yellow
Z = 4	0.65 × 0.60 × 0.18 mm

Data collection

Bruker P4 diffractometer	1958 reflections with I > 2σ(I)
Radiation source: fine-focus sealed tube	Rint = 0.019
Graphite monochromator	θmax = 28.7°, θmin = 2.4°
ω scans	h = −10→10
Absorption correction: ψ scan (XSCANS; Siemens, 1996)	k = −14→14
Tmin = 0.858, Tmax = 0.960	l = −20→20
4962 measured reflections	3 standard reflections every 97 reflections
3247 independent reflections	intensity decay: 0.5%

Refinement

Refinement on F^2	Hydrogen site location: inferred from neighbouring sites
Least-squares matrix: full	H-atom parameters constrained
R[F^2 > 2σ(F^2)] = 0.058	w = 1/[σ^2(Fo^2) + (0.0716P)^2 + 0.236P] where P = (Fo^2 + 2Fc^2)/3
wR(F^2) = 0.167	(Δ/σ)max = 0.001
S = 1.03	Δρmax = 0.29 e Å^−3
3247 reflections	Δρmin = −0.14 e Å^−3
146 parameters	Extinction correction: SHELXL97, Fc^*=kFc[1+0.001xFc^2λ^3/sin(2θ)]^-1/4
0 restraints	Extinction coefficient: 0.023 (4)
Primary atom site location: structure-invariant direct methods	Absolute structure: Flack (1983), 1374 Friedel pairs
Secondary atom site location: difference Fourier map	Absolute structure parameter: −0.03 (15)

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	0.50403 (11)	0.60387 (9)	0.09581 (6)	0.0923 (3)
O1	0.9222 (4)	0.3680 (3)	0.25475 (19)	0.1244 (12)
C2	0.7732 (6)	0.3776 (5)	0.3068 (3)	0.1271 (18)
H2C	0.8006	0.4174	0.3620	0.152*
H2D	0.7258	0.2931	0.3178	0.152*
C2a	0.9398 (4)	0.4891 (4)	0.2150 (2)	0.0827 (9)
H211	0.9890	0.5506	0.2562	0.099*
C3	0.6431 (4)	0.4604 (3)	0.2563 (2)	0.0745 (8)
H3A	0.5645	0.4042	0.2242	0.089*
N4	0.7598 (3)	0.5248 (2)	0.19439 (15)	0.0665 (6)
C5	0.7078 (4)	0.5829 (3)	0.1222 (2)	0.0723 (8)
C6	0.8501 (5)	0.6279 (5)	0.0618 (3)	0.1202 (16)
H6C	0.8271	0.5922	0.0047	0.144*
H6D	0.8407	0.7204	0.0566	0.144*
C7	1.0227 (5)	0.5990 (4)	0.0829 (3)	0.1038 (12)
H7A	1.0711	0.6714	0.1140	0.125*
H7B	1.0870	0.5894	0.0292	0.125*
C8	1.0480 (4)	0.4813 (4)	0.1363 (2)	0.0890 (10)
H8C	1.0168	0.4060	0.1028	0.107*
H8D	1.1678	0.4736	0.1528	0.107*
C9	0.5415 (4)	0.5470 (3)	0.31357 (18)	0.0706 (8)
C10	0.6084 (6)	0.6624 (4)	0.3449 (2)	0.0922 (11)
H10B	0.7173	0.6879	0.3271	0.111*
C10'	0.3797 (5)	0.5083 (4)	0.3399 (2)	0.0970 (11)
H10C	0.3331	0.4311	0.3208	0.116*
C11	0.5190 (9)	0.7388 (5)	0.4009 (3)	0.1190 (16)
H11B	0.5682	0.8141	0.4219	0.143*
C11'	0.2860 (6)	0.5908 (7)	0.3976 (3)	0.1251 (18)
H11C	0.1764	0.5682	0.4162	0.150*
C12	0.3611 (9)	0.7054 (7)	0.4255 (3)	0.1262 (19)
H12B	0.2994	0.7596	0.4620	0.151*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
S1	0.0688 (4)	0.1071 (6)	0.1010 (6)	0.0064 (5)	−0.0152 (5)	0.0274 (5)
O1	0.101 (2)	0.148 (2)	0.124 (2)	0.0502 (18)	0.0233 (18)	0.061 (2)
C2	0.122 (3)	0.138 (4)	0.121 (3)	0.047 (3)	0.039 (3)	0.065 (3)
C2a	0.0647 (17)	0.112 (3)	0.0712 (18)	0.0029 (18)	−0.0079 (15)	0.0162 (18)
C3	0.0732 (19)	0.0727 (17)	0.0775 (19)	−0.0025 (15)	0.0099 (15)	0.0155 (15)
N4	0.0615 (13)	0.0759 (14)	0.0620 (12)	−0.0035 (12)	−0.0002 (11)	0.0133 (11)
C5	0.0673 (16)	0.0808 (18)	0.0686 (16)	−0.0026 (15)	−0.0037 (14)	0.0201 (15)
C6	0.082 (2)	0.169 (4)	0.109 (3)	−0.011 (3)	0.007 (2)	0.068 (3)
C7	0.094 (3)	0.123 (3)	0.095 (2)	−0.002 (2)	0.028 (2)	0.010 (2)
C8	0.0674 (19)	0.111 (2)	0.089 (2)	0.0047 (18)	0.0042 (16)	−0.001 (2)
C9	0.0696 (19)	0.0871 (19)	0.0552 (14)	0.0017 (15)	−0.0023 (13)	0.0191 (14)
C10	0.114 (3)	0.093 (2)	0.0692 (18)	0.000 (2)	−0.006 (2)	0.0136 (19)
C10'	0.076 (2)	0.145 (3)	0.0703 (19)	0.006 (2)	0.0075 (17)	0.014 (2)
C11	0.169 (5)	0.110 (3)	0.078 (2)	0.030 (3)	−0.004 (3)	0.005 (2)
C11'	0.088 (2)	0.211 (6)	0.076 (2)	0.027 (4)	0.013 (2)	0.033 (3)
C12	0.150 (5)	0.155 (5)	0.074 (3)	0.059 (4)	−0.004 (3)	0.007 (3)

Geometric parameters (Å, º)

S1—C5	1.652 (3)	C7—C8	1.490 (5)
O1—C2a	1.409 (5)	C7—H7A	0.9700
O1—C2	1.412 (5)	C7—H7B	0.9700
C2—C3	1.540 (5)	C8—H8C	0.9700
C2—H2C	0.9700	C8—H8D	0.9700
C2—H2D	0.9700	C9—C10'	1.382 (5)
C2a—C8	1.476 (5)	C9—C10	1.396 (5)
C2a—N4	1.483 (4)	C10—C11	1.364 (6)
C2a—H211	0.9800	C10—H10B	0.9300
C3—N4	1.477 (4)	C10'—C11'	1.435 (6)
C3—C9	1.489 (5)	C10'—H10C	0.9300
C3—H3A	0.9800	C11—C12	1.332 (7)
N4—C5	1.328 (4)	C11—H11B	0.9300
C5—C6	1.520 (5)	C11'—C12	1.397 (7)
C6—C7	1.415 (5)	C11'—H11C	0.9300
C6—H6C	0.9700	C12—H12B	0.9300
C6—H6D	0.9700
C2a—O1—C2	105.2 (3)	C6—C7—C8	115.3 (3)
O1—C2—C3	107.1 (3)	C6—C7—H7A	108.5
O1—C2—H2C	110.3	C8—C7—H7A	108.5
C3—C2—H2C	110.3	C6—C7—H7B	108.5
O1—C2—H2D	110.3	C8—C7—H7B	108.5
C3—C2—H2D	110.3	H7A—C7—H7B	107.5
H2C—C2—H2D	108.5	C2a—C8—C7	109.4 (3)
O1—C2a—C8	111.2 (3)	C2a—C8—H8C	109.8
O1—C2a—N4	103.0 (3)	C7—C8—H8C	109.8
C8—C2a—N4	112.1 (3)	C2a—C8—H8D	109.8
O1—C2a—H211	110.1	C7—C8—H8D	109.8
C8—C2a—H211	110.1	H8C—C8—H8D	108.2
N4—C2a—H211	110.1	C10'—C9—C10	119.3 (3)
N4—C3—C9	115.6 (3)	C10'—C9—C3	118.7 (3)
N4—C3—C2	100.1 (3)	C10—C9—C3	121.9 (3)
C9—C3—C2	113.0 (3)	C11—C10—C9	122.1 (4)
N4—C3—H3A	109.2	C11—C10—H10B	119.0
C9—C3—H3A	109.2	C9—C10—H10B	119.0
C2—C3—H3A	109.2	C9—C10'—C11'	118.0 (4)
C5—N4—C3	124.0 (3)	C9—C10'—H10C	121.0
C5—N4—C2a	125.5 (2)	C11'—C10'—H10C	121.0
C3—N4—C2a	109.2 (2)	C12—C11—C10	119.8 (5)
N4—C5—C6	115.5 (3)	C12—C11—H11B	120.1
N4—C5—S1	123.9 (2)	C10—C11—H11B	120.1
C6—C5—S1	120.5 (2)	C12—C11'—C10'	119.3 (4)
C7—C6—C5	119.0 (3)	C12—C11'—H11C	120.3
C7—C6—H6C	107.6	C10'—C11'—H11C	120.3
C5—C6—H6C	107.6	C11—C12—C11'	121.5 (5)
C7—C6—H6D	107.6	C11—C12—H12B	119.3
C5—C6—H6D	107.6	C11'—C12—H12B	119.3
H6C—C6—H6D	107.0
C2a—O1—C2—C3	37.4 (5)	S1—C5—C6—C7	−174.8 (4)
C2—O1—C2a—C8	−159.3 (3)	C5—C6—C7—C8	27.2 (7)
C2—O1—C2a—N4	−39.0 (4)	O1—C2a—C8—C7	163.7 (3)
O1—C2—C3—N4	−19.1 (5)	N4—C2a—C8—C7	48.9 (4)
O1—C2—C3—C9	−142.7 (4)	C6—C7—C8—C2a	−53.5 (5)
C9—C3—N4—C5	−75.7 (4)	N4—C3—C9—C10'	148.4 (3)
C2—C3—N4—C5	162.7 (4)	C2—C3—C9—C10'	−97.1 (4)
C9—C3—N4—C2a	116.8 (3)	N4—C3—C9—C10	−35.1 (4)
C2—C3—N4—C2a	−4.8 (4)	C2—C3—C9—C10	79.4 (4)
O1—C2a—N4—C5	−140.4 (3)	C10'—C9—C10—C11	−0.1 (5)
C8—C2a—N4—C5	−20.7 (5)	C3—C9—C10—C11	−176.6 (3)
O1—C2a—N4—C3	26.9 (3)	C10—C9—C10'—C11'	1.2 (4)
C8—C2a—N4—C3	146.6 (3)	C3—C9—C10'—C11'	177.8 (3)
C3—N4—C5—C6	−172.4 (3)	C9—C10—C11—C12	−1.7 (6)
C2a—N4—C5—C6	−6.9 (5)	C9—C10'—C11'—C12	−0.6 (5)
C3—N4—C5—S1	6.1 (5)	C10—C11—C12—C11'	2.3 (7)
C2a—N4—C5—S1	171.6 (3)	C10'—C11'—C12—C11	−1.2 (6)
N4—C5—C6—C7	3.7 (7)