4,6-Dimethyl-2-[(4-phenyl­piperidin-1-yl)meth­yl]isothia­zolo[5,4-b]pyridin-3(2H)-one and 4,6-dimethyl-2-[(4-phenyl-1,2,3,6-tetra­hydro­pyridin-1-yl)meth­yl]isothia­zolo[5,4-b]pyridin-3(2H)-one

In the crystal structures of the title compounds, C₂₀H₂₃N₃OS, (II), and C₂₀H₂₁N₃OS, (III), significant differences occur in the conformation of, respectively, the phenyl­piperidine and phenyl­tetra­hydro­pyridine substituents at the 2-position of the iso­thiazolo­pyridine system. The piperidine ring adopts a chair conformation, while the tetra­hydro­pyridine ring assumes a half-chair form. The phenyl­piperidine and phenyl­tetra­hydro­pyridine fragments exhibit different conformations resulting from the steric and conjugation effects in the phenyl ring, respectively. Theoretical calculations show that both conformations are energetically stable and correspond to a minimum of energy for the analyzed systems. The mol­ecular packing in (II) is influenced by [pi]-[pi] inter­actions of the iso­thiazolo­pyridine systems, with a shortest centroid-to-centroid separation of 3.5843 (11) Å between pyridine rings. In the crystal structure of (III), the mol­ecules are linked by C-H...O hydrogen bonds and C-H...[pi] inter­actions.

S1. Comment

The 4-arylpiperazinyl group is known to constitute part of the pharmacophore for many pharmacologically active heterocycles (Barlocco et al., 2001; Viaud et al., 1995). In previous papers, we have described the synthesis of 2-[(4-arylpiperazin-1-yl)methyl]isothiazolo[5,4-b]pyridin-3(2H)-one compounds and detailed the evolution of their analgesic properties (Malinka et al., 2001, 2005). The results of the bioanalyses showed that the unsubstituted parent compound (Ia) was inactive in analgesic tests. A systematic modification of (Ia) by a substitution (R) on the aromatic ring of the 4-phenylpiperazinyl system showed that the presence of electron-withdrawing substituents [2-Cl in (Ib), 2-F in (Ic), 3-CF₃ in (Id) and 4-NO₂ in (Ie)] led to isothiazolopyridines active in this assay. In contrast, the use of electron-donating groups [2-OCH₃ in (If) and 2-CH₃ in (Ig)] reduced analgesic action.

The X-ray crystallographic data of isothiazolopyridines (I) (Karczmarzyk & Malinka, 2005) showed that for the unsubstituted compound (Ia) and its derivatives with electron-withdrawing substituents 3-CF₃, (Id) and 4-NO₂, (Ie), a lone pair on the 4-N piperazine atom forms part of a 4-N–aromatic ring π system. The near coplanarity of the piperazine and phenyl rings observed in (Ia), (Id) and (Ie) is constrained by the occurrence of this effect. In ortho-substituted compounds [2-Cl in (Ib), 2-OCH₃ in (If), 5-Cl-2-CH₃ in (Ih), 2-OC₂H₅ in (Ii) and 2-CH₃ in (Ig)], the 4-N–Ar conjugation is very weak or not present. The nearly perpendicular orientation of the piperazine and aromatic rings within these compounds is the result of an ortho steric hindrance effect. X-ray data also indicated that a chair conformation of the piperazine ring might be considered as a pharmacophoric conformation for analgesic isothiazolopyridines of type (I).

To find out whether replacement of the 4-N atom of the piperazine ring by a methylene or a vinyl C atom in the inactive compound (Ia) induces analgesic action, we prepared the analogues (II) and (III) and determined the conformation of the piperidine rings and the effect of the Ar–piperidine conjugation for these compounds. In pharmacological investigation, compound (III), to our surprise, exhibited significant analgesic action (Malinka et al., 2005). Evaluation of the analgesic activity of (II) is in progress.

The geometry (bond lengths, angles and planarity) of the isothiazolopyridine rings is very similar in (II) and (III) and the related structures (Ia), (Ib) and (Id)–(Ii). The conformation of the phenylpiperidine and phenyltetrahydropyridine substituents is described by the torsion angles S1—N2—C12—N21 of 56.69 (18) and 25.74 (16)°, N2—C12—N21—C22 of 69.03 (19) and 78.47 (16)°, and N2—C12—N21—C26 of -168.97 (16) and -157.01 (13)° for (II) and (III), respectively. Comparison of these torsion angles with those found in (Ia) [24.5 (2), 77.9 (2) and -159.4 (2)°, respectively] shows nearly the same trans–gauche–trans conformation of the substituent in (Ia) and (III) and a somewhat different gauche–gauche–trans conformation in (II) (Fig. 3).

The piperidine ring in (II) adopts a chair conformation, while the occurrence of the double bond in the tetrahydropyridinyl ring of (III) favours a half-chair conformation. The puckering parameters (Cremer & Pople, 1975) are Q = 0.581 (2) Å and θ = 179.5 (2)° for the piperidine ring, and Q = 0.515 (1) Å, θ = 128.2 (2)° and ϕ = -157.1 (2)° for the tetrahydropyridinyl ring. The bond lengths and angles in the phenylpiperidine system of (II) are normal, and the conjugation effect between the electron systems of the piperidine and phenyl rings characteristic for (Ia) does not occur. The mutual, nearly perpendicular, orientation of the piperidine and phenyl rings, described by the C23—C24—C31—C32 torsion angle of -71.9 (2)°, is constrained by steric interaction of the H atoms of the methylene and methine groups. In (III), a weak conjugation of the vinyl bond C24═C25 in the tetrahydropyridinyl ring with the π-electron system of the phenyl ring is observed. The double bond of 1.344 (2) Å is longer than expected for a Csp²═Csp² bond in cyclohexene [1.326 (12) Å; Allen et al., 1987], and the C25—C24—C31—C32 torsion angle of 175.07 (16)° confirms the occurrence of this conjugation, while the C24—C31 bond length of 1.489 (2) Å, comparable to an average Csp²—C_ar (C═C—C_ar; unconjugated) single bond of 1.488 (12) Å (Allen et al., 1987), is more characteristic for an unconjugated system.

Because the orientation of the piperidine ring in (II), the tetrahydropyridine ring in (III) and the piperazine ring in (Ia) with respect to the phenyl ring is strictly connected with the steric and conjugation effects, the energy for the free-rotation on the N24—C31 or C24—C31 bond, taking account of the one degree of freedom described by the C23—N(C)24—C31—C32 torsion angle (ψ), was calculated for isolated molecules of (Ia), (II) and (III) using the AM1 semiempirical SCF-MO method (Dewar et al., 1985) implemented in the program package WINMOPAC (Shchepin & Litvinov, 1998). The differences in heat of formation, ΔH, of the conformations were calculated after energy minimization and optimization of all geometrical parameters for each rotation, with a 10° increment from -180 to +180° of ψ (Fig. 4). The calculation showed that the energy differences between rotamers, of about 1.0, 2.0 and 1.5 kcal mol^-1 for (Ia), (II) and (III), respectively, are relatively low, but certain tendencies in the energy minima distributions are visible. The conjugation of the vinyl bond in the tetrahydropyridine ring and the lone pair at the N atom of the piperazine ring with the π-electron system of the phenyl ring gives the minimum of energy for ψ close to 0° in (Ia) and -30° in (III). The lack of the mentioned conjugation in the phenylpiperidine system in (II) moves the minimum of energy to a ψ value of about 60°. The calculated conformations with minima of energy are in good agreement with those observed in the crystalline state of the investigated molecules.

There are no classical hydrogen bonds present in the crystal structure of (II). The molecular packing in the crystal is influenced by the presence of the weak π–π interactions (Spek, 2003). The pyridine rings of the isotriazolopyridine systems belonging to the inversion- and translation-related molecules overlap each other, forming molecular stacks in the [010] direction, with centroid-to-centroid separations of 3.5843 (11) Å [3.5850 in abstract] between the pyridine rings at (x, y, z) and (-x, -y + 1, -z + 1) and 3.6498 (11) Å for the pyridine rings at (x, y, z) and (-x, -y + 2, -z + 1) (Fig. 5). The π–π distances are 3.405 and 3.555 Å, respectively, and they are comparable to a van der Waals distance of about 3.4 Å for the overlapping π aromatic ring systems. The packing of the molecules in the crystal structure of (III) is governed by C—H···O hydrogen bonds, linking the molecules into molecular chains parallel to the [010] direction, and C—H···π interactions (Table 1). In conclusion, (i) the small difference in rotation energy within the arylpiperazine(piperidine) systems of isothiazolopyridines (Ia), (II) and (III) allows the side chain to adopt any spatial shape under physiological conditions, and (ii) the analgesic activity of piperidine derivative (III) suggests that the 4-N piperazine atom of analgesic isothiazolopyridines (I) is not protonated in the bioactive form of these compounds. Therefore, an electrostatic potential on the piperazine N atoms cannot be ruled out when analysing the biological properties of the compounds of series (I).

Related literature

For related literature, see: Allen et al. (1987); Barlocco et al. (2001); Cremer & Pople (1975); Dewar et al. (1985); Karczmarzyk & Malinka (2005); Malinka et al. (2001, 2005); Shchepin & Litvinov (1998); Spek (2003); Viaud et al. (1995).

S2. Experimental

Compound (III) was prepared from 2-hydroxymethyl-4,6-dimethylisothiazolo[5,4-b]pyridin-3(2H)-one and commercially available 4-phenyl-1,2,3,6-tetrahydropyridine according to the method described by Malinka et al. (2005). Compound (II) was obtained similarly. The chemical experimental data for the preparation of (II), along with its physicochemical and spectral data (¹H NMR), are given in supporting material, available on request. [Do you wish to include any of this in the _exptl_special_details section of the CIF, so that it is available online?] Crystals suitable for X-ray diffraction analysis were grown by slow evaporation from a hexane solution.

S3. Refinement

All H atoms in (II) were treated as riding on their parent C atoms, with C—H distances of 0.93 Å (aromatic), 0.96 Å (CH₃), 0.97 Å (CH₂) and 0.98 Å (CH) and U_iso(H) values of 1.5U_eq(C). In (III), the H atoms were located in a difference Fourier map and their coordinates refined isotropically [C—H = 0.88 (3)–1.02 (3) Å and U_iso(H) = 1.5U_eq(C)].

Computing details

For both compounds, data collection: SMART (Bruker, 2003); cell refinement: SAINT (Bruker, 2003); data reduction: SAINT; program(s) used to solve structure: SIR92 (Altomare et al., 1993); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997); molecular graphics: ORTEP-3 for Windows (Farrugia, 1997) and XP in SHELXTL-Plus (Sheldrick, 1989); software used to prepare material for publication: SHELXL97 and WinGX (Farrugia, 1999).

Figures

	Fig. 1. A view of (II), showing the atomic numbering scheme. Displacement ellipsoids are drawn at the 50% probability level. H atoms are represented as small spheres of arbitrary radii.
	Fig. 2. A view of (III), showing the atomic numbering scheme. Displacement ellipsoids are drawn at the 50% probability level. H atoms are represented as small spheres of arbitrary radii.
	Fig. 3. Overlay of molecules (a) (Ia) and (II) and (b) (Ia) and (III) by least-squares fitting of the isothiazolopyridine ring systems [the average deviation of atoms is 0.029 and 0.004 Å for (a) and (b), respectively].
	Fig. 4. The energy effect upon C(N)24—C31 rotation as calculated with the AM1 semi-empirical method.
	Fig. 5. A view of part of the crystal structure of (II) along (a) [100] and (b) [010], showing the formation of a column of stacked pyridine rings.

(II) 4,6-Dimethyl-2-[(4-phenylpiperidin-1-yl)methyl]isothiazolo[5,4-b]pyridin-3(2H)-one

Crystal data

C20H23N3OS	F(000) = 1504
Mr = 353.47	Dx = 1.277 Mg m^−3
Monoclinic, C2/c	Melting point = 409–411 K
Hall symbol: -C 2yc	Cu Kα radiation, λ = 1.54178 Å
a = 29.384 (6) Å	Cell parameters from 197 reflections
b = 7.146 (1) Å	θ = 12.2–78.1°
c = 21.750 (4) Å	µ = 1.66 mm^−1
β = 126.39 (3)°	T = 293 K
V = 3676.4 (18) Å^3	Prism, colourless
Z = 8	0.55 × 0.42 × 0.20 mm

Data collection

Bruker SMART APEX CCD diffractometer	3471 independent reflections
Radiation source: fine-focus sealed tube	3267 reflections with I > 2σ(I)
Graphite monochromator	Rint = 0.020
ω scans	θmax = 70.1°, θmin = 3.7°
Absorption correction: multi-scan (SADABS; Sheldrick, 2002)	h = −35→35
Tmin = 0.498, Tmax = 0.733	k = −7→8
19486 measured reflections	l = −26→26

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)] = 0.046	Hydrogen site location: difference Fourier map
wR(F^2) = 0.207	H atoms treated by a mixture of independent and constrained refinement
S = 1.00	w = 1/[σ^2(Fo^2) + (0.2P)^2] where P = (Fo^2 + 2Fc^2)/3
3471 reflections	(Δ/σ)max < 0.001
229 parameters	Δρmax = 0.21 e Å^−3
0 restraints	Δρmin = −0.29 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	0.615694 (18)	0.82018 (6)	0.02092 (3)	0.0738 (3)
O3	0.47843 (6)	0.8666 (2)	−0.17815 (7)	0.0779 (4)
N2	0.57161 (6)	0.8642 (2)	−0.07479 (8)	0.0670 (4)
N7	0.56421 (6)	0.73655 (19)	0.08589 (8)	0.0651 (4)
N21	0.63434 (6)	0.76397 (18)	−0.10415 (8)	0.0618 (4)
C3	0.51432 (7)	0.8450 (2)	−0.10962 (9)	0.0603 (4)
C4	0.45661 (7)	0.76738 (19)	−0.05809 (9)	0.0591 (4)
C5	0.46279 (8)	0.7242 (2)	0.00865 (10)	0.0646 (4)
H51	0.4307	0.7030	0.0067	0.097*
C6	0.51601 (8)	0.71173 (19)	0.07879 (9)	0.0629 (4)
C8	0.55749 (7)	0.77848 (18)	0.02127 (9)	0.0580 (4)
C9	0.50663 (6)	0.79560 (17)	−0.05054 (8)	0.0553 (4)
C10	0.39929 (8)	0.7828 (3)	−0.13291 (11)	0.0796 (5)
H101	0.3710	0.7855	−0.1240	0.119*
H102	0.3929	0.6769	−0.1643	0.119*
H103	0.3972	0.8957	−0.1583	0.119*
C11	0.52233 (10)	0.6679 (3)	0.15074 (12)	0.0803 (5)
H111	0.5484	0.7543	0.1900	0.121*
H112	0.5364	0.5427	0.1667	0.121*
H113	0.4863	0.6786	0.1417	0.121*
C12	0.59612 (8)	0.9110 (2)	−0.11472 (11)	0.0712 (4)
H121	0.5662	0.9266	−0.1688	0.107*
H122	0.6166	1.0283	−0.0952	0.107*
C22	0.60240 (7)	0.5935 (2)	−0.14499 (10)	0.0662 (4)
H221	0.5754	0.6212	−0.1989	0.099*
H222	0.5815	0.5524	−0.1259	0.099*
C23	0.64138 (7)	0.4387 (2)	−0.13468 (10)	0.0631 (4)
H231	0.6192	0.3293	−0.1632	0.095*
H232	0.6665	0.4046	−0.0811	0.095*
C24	0.67629 (6)	0.5000 (2)	−0.16220 (8)	0.0593 (4)
H241	0.6494	0.5323	−0.2164	0.089*
C25	0.70756 (8)	0.6791 (2)	−0.12048 (14)	0.0768 (5)
H251	0.7281	0.7241	−0.1396	0.115*
H252	0.7347	0.6530	−0.0664	0.115*
C26	0.66676 (9)	0.8292 (2)	−0.13154 (13)	0.0743 (5)
H261	0.6877	0.9410	−0.1038	0.111*
H262	0.6410	0.8609	−0.1853	0.111*
C31	0.71325 (7)	0.3446 (2)	−0.15737 (9)	0.0586 (4)
C32	0.76106 (8)	0.2820 (3)	−0.08768 (10)	0.0719 (4)
H321	0.7713	0.3381	−0.0425	0.108*
C33	0.79364 (8)	0.1364 (3)	−0.08508 (11)	0.0782 (5)
H331	0.8254	0.0962	−0.0381	0.117*
C34	0.77960 (8)	0.0514 (3)	−0.15060 (11)	0.0729 (5)
H341	0.8030 (12)	−0.041 (4)	−0.1533 (16)	0.109*
C35	0.73202 (8)	0.1109 (3)	−0.21990 (10)	0.0747 (5)
H351	0.7218	0.0538	−0.2649	0.112*
C36	0.69957 (7)	0.2557 (2)	−0.22252 (9)	0.0677 (4)
H361	0.6676	0.2940	−0.2696	0.102*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
S1	0.0575 (4)	0.0857 (4)	0.0738 (4)	0.01057 (16)	0.0366 (3)	0.01170 (17)
O3	0.0757 (8)	0.0934 (8)	0.0581 (7)	−0.0018 (6)	0.0361 (6)	−0.0034 (5)
N2	0.0666 (8)	0.0703 (8)	0.0715 (8)	0.0079 (6)	0.0450 (7)	0.0027 (6)
N7	0.0680 (8)	0.0573 (7)	0.0628 (7)	0.0042 (5)	0.0348 (6)	0.0064 (5)
N21	0.0655 (8)	0.0558 (7)	0.0746 (8)	−0.0012 (5)	0.0473 (7)	0.0018 (5)
C3	0.0677 (9)	0.0509 (7)	0.0635 (9)	0.0028 (6)	0.0396 (8)	−0.0058 (5)
C4	0.0619 (8)	0.0473 (7)	0.0632 (8)	−0.0054 (5)	0.0345 (7)	−0.0105 (5)
C5	0.0708 (9)	0.0513 (7)	0.0752 (10)	−0.0091 (6)	0.0452 (8)	−0.0069 (6)
C6	0.0763 (10)	0.0441 (7)	0.0685 (9)	−0.0026 (6)	0.0432 (8)	0.0009 (5)
C8	0.0634 (8)	0.0449 (6)	0.0634 (8)	0.0036 (5)	0.0363 (7)	0.0007 (5)
C9	0.0612 (8)	0.0413 (6)	0.0603 (8)	0.0001 (5)	0.0343 (7)	−0.0064 (5)
C10	0.0592 (10)	0.0981 (13)	0.0679 (10)	−0.0126 (8)	0.0304 (8)	−0.0152 (8)
C11	0.0980 (14)	0.0702 (10)	0.0811 (12)	−0.0016 (8)	0.0576 (11)	0.0100 (8)
C12	0.0819 (11)	0.0607 (8)	0.0865 (11)	0.0072 (7)	0.0584 (10)	0.0063 (7)
C22	0.0628 (9)	0.0603 (8)	0.0844 (10)	−0.0057 (6)	0.0485 (8)	0.0009 (7)
C23	0.0677 (9)	0.0571 (8)	0.0758 (9)	−0.0041 (6)	0.0487 (8)	0.0029 (6)
C24	0.0623 (8)	0.0616 (8)	0.0599 (7)	0.0020 (6)	0.0396 (7)	0.0079 (6)
C25	0.0746 (11)	0.0661 (10)	0.1100 (15)	−0.0112 (7)	0.0658 (11)	−0.0039 (8)
C26	0.0817 (12)	0.0577 (9)	0.1052 (14)	−0.0090 (7)	0.0673 (11)	0.0000 (7)
C31	0.0598 (8)	0.0635 (8)	0.0603 (8)	0.0004 (6)	0.0398 (7)	0.0065 (6)
C32	0.0672 (10)	0.0878 (11)	0.0590 (9)	0.0085 (8)	0.0365 (8)	0.0030 (7)
C33	0.0684 (11)	0.0924 (12)	0.0713 (10)	0.0159 (8)	0.0401 (9)	0.0126 (8)
C34	0.0728 (10)	0.0734 (10)	0.0868 (11)	0.0071 (7)	0.0551 (9)	0.0081 (8)
C35	0.0815 (11)	0.0772 (10)	0.0764 (10)	0.0001 (8)	0.0528 (9)	−0.0058 (8)
C36	0.0678 (9)	0.0764 (10)	0.0602 (9)	0.0033 (7)	0.0386 (8)	0.0053 (7)

Geometric parameters (Å, º)

S1—N2	1.7061 (17)	C22—C23	1.510 (2)
S1—C8	1.7403 (16)	C22—H221	0.9700
O3—C3	1.222 (2)	C22—H222	0.9700
N2—C3	1.383 (2)	C23—C24	1.527 (2)
N2—C12	1.458 (2)	C23—H231	0.9700
N7—C8	1.332 (2)	C23—H232	0.9700
N7—C6	1.342 (2)	C24—C31	1.513 (2)
N21—C12	1.453 (2)	C24—C25	1.522 (2)
N21—C26	1.467 (2)	C24—H241	0.9800
N21—C22	1.471 (2)	C25—C26	1.518 (2)
C3—C9	1.473 (2)	C25—H251	0.9700
C4—C9	1.394 (2)	C25—H252	0.9700
C4—C5	1.387 (2)	C26—H261	0.9700
C4—C10	1.498 (3)	C26—H262	0.9700
C5—C6	1.396 (3)	C31—C32	1.394 (2)
C5—H51	0.9300	C31—C36	1.377 (2)
C6—C11	1.495 (3)	C32—C33	1.393 (3)
C8—C9	1.385 (2)	C32—H321	0.9300
C10—H101	0.9600	C33—C34	1.368 (3)
C10—H102	0.9600	C33—H331	0.9300
C10—H103	0.9600	C34—C35	1.381 (3)
C11—H111	0.9600	C34—H341	0.98 (3)
C11—H112	0.9600	C35—C36	1.385 (3)
C11—H113	0.9600	C35—H351	0.9300
C12—H121	0.9700	C36—H361	0.9300
C12—H122	0.9700
N2—S1—C8	90.01 (8)	C23—C22—H221	109.4
C3—N2—C12	124.55 (15)	N21—C22—H222	109.4
C3—N2—S1	116.50 (12)	C23—C22—H222	109.4
C12—N2—S1	118.90 (13)	H221—C22—H222	108.0
C8—N7—C6	115.00 (14)	C22—C23—C24	111.01 (12)
C12—N21—C26	109.47 (13)	C22—C23—H231	109.4
C12—N21—C22	110.29 (13)	C24—C23—H231	109.4
C26—N21—C22	110.67 (13)	C22—C23—H232	109.4
O3—C3—N2	123.01 (16)	C24—C23—H232	109.4
O3—C3—C9	128.78 (16)	H231—C23—H232	108.0
N2—C3—C9	108.22 (14)	C31—C24—C23	112.58 (12)
C9—C4—C5	115.79 (15)	C31—C24—C25	114.92 (13)
C9—C4—C10	123.02 (15)	C23—C24—C25	108.40 (13)
C5—C4—C10	121.19 (16)	C31—C24—H241	106.8
C4—C5—C6	121.60 (16)	C23—C24—H241	106.8
C4—C5—H51	119.2	C25—C24—H241	106.8
C6—C5—H51	119.2	C24—C25—C26	111.05 (15)
N7—C6—C5	122.59 (15)	C24—C25—H251	109.4
N7—C6—C11	116.08 (17)	C26—C25—H251	109.4
C5—C6—C11	121.33 (18)	C24—C25—H252	109.4
N7—C8—C9	126.50 (15)	C26—C25—H252	109.4
N7—C8—S1	120.81 (12)	H251—C25—H252	108.0
C9—C8—S1	112.69 (12)	N21—C26—C25	110.70 (13)
C4—C9—C8	118.50 (14)	N21—C26—H261	109.5
C4—C9—C3	128.95 (14)	C25—C26—H261	109.5
C8—C9—C3	112.54 (14)	N21—C26—H262	109.5
C4—C10—H101	109.5	C25—C26—H262	109.5
C4—C10—H102	109.5	H261—C26—H262	108.1
H101—C10—H102	109.5	C32—C31—C36	117.48 (16)
C4—C10—H103	109.5	C32—C31—C24	121.98 (14)
H101—C10—H103	109.5	C36—C31—C24	120.52 (14)
H102—C10—H103	109.5	C31—C32—C33	120.58 (16)
C6—C11—H111	109.5	C31—C32—H321	119.7
C6—C11—H112	109.5	C33—C32—H321	119.7
H111—C11—H112	109.5	C34—C33—C32	120.95 (17)
C6—C11—H113	109.5	C34—C33—H331	119.5
H111—C11—H113	109.5	C32—C33—H331	119.5
H112—C11—H113	109.5	C33—C34—C35	118.98 (17)
N21—C12—N2	110.39 (13)	C33—C34—H341	125.0 (16)
N21—C12—H121	109.6	C35—C34—H341	115.7 (16)
N2—C12—H121	109.6	C36—C35—C34	120.10 (16)
N21—C12—H122	109.6	C36—C35—H351	120.0
N2—C12—H122	109.6	C34—C35—H351	120.0
H121—C12—H122	108.1	C35—C36—C31	121.91 (16)
N21—C22—C23	111.15 (13)	C35—C36—H361	119.0
N21—C22—H221	109.4	C31—C36—H361	119.0
C8—S1—N2—C3	−1.86 (12)	N2—C3—C9—C8	−1.27 (16)
C8—S1—N2—C12	−179.35 (13)	C26—N21—C12—N2	−168.97 (16)
C12—N2—C3—O3	−0.3 (2)	C22—N21—C12—N2	69.03 (18)
S1—N2—C3—O3	−177.61 (12)	C3—N2—C12—N21	−120.58 (17)
C12—N2—C3—C9	179.45 (13)	S1—N2—C12—N21	56.69 (18)
S1—N2—C3—C9	2.11 (16)	C12—N21—C22—C23	−179.94 (12)
C9—C4—C5—C6	0.5 (2)	C26—N21—C22—C23	58.77 (18)
C10—C4—C5—C6	−179.24 (14)	N21—C22—C23—C24	−57.61 (18)
C8—N7—C6—C5	1.5 (2)	C22—C23—C24—C31	−176.43 (13)
C8—N7—C6—C11	−178.94 (13)	C22—C23—C24—C25	55.30 (18)
C4—C5—C6—N7	−1.4 (2)	C31—C24—C25—C26	177.45 (14)
C4—C5—C6—C11	179.08 (15)	C23—C24—C25—C26	−55.62 (19)
C6—N7—C8—C9	−0.9 (2)	C12—N21—C26—C25	179.42 (16)
C6—N7—C8—S1	178.57 (10)	C22—N21—C26—C25	−58.8 (2)
N2—S1—C8—N7	−178.55 (12)	C24—C25—C26—N21	58.2 (2)
N2—S1—C8—C9	1.00 (11)	C23—C24—C31—C32	−71.9 (2)
C5—C4—C9—C8	0.12 (19)	C25—C24—C31—C32	52.9 (2)
C10—C4—C9—C8	179.86 (14)	C23—C24—C31—C36	106.23 (16)
C5—C4—C9—C3	−179.18 (13)	C25—C24—C31—C36	−129.00 (17)
C10—C4—C9—C3	0.6 (2)	C36—C31—C32—C33	0.7 (3)
N7—C8—C9—C4	0.1 (2)	C24—C31—C32—C33	178.84 (17)
S1—C8—C9—C4	−179.42 (10)	C31—C32—C33—C34	0.0 (3)
N7—C8—C9—C3	179.51 (13)	C32—C33—C34—C35	−0.7 (3)
S1—C8—C9—C3	−0.01 (14)	C33—C34—C35—C36	0.6 (3)
O3—C3—C9—C4	−2.2 (2)	C34—C35—C36—C31	0.1 (3)
N2—C3—C9—C4	178.06 (13)	C32—C31—C36—C35	−0.7 (3)
O3—C3—C9—C8	178.43 (15)	C24—C31—C36—C35	−178.93 (16)

(III) 4,6-dimethyl-2-[(4-phenyl-1,2,3,6-tetrahydropyridin-1- yl)methyl]isothiazolo[5,4-b]-3(2H)-one

Crystal data

C20H21N3OS	F(000) = 744
Mr = 351.46	Dx = 1.341 Mg m^−3
Monoclinic, P21/c	Melting point = 427–429 K
Hall symbol: -P 2ybc	Cu Kα radiation, λ = 1.54178 Å
a = 17.548 (3) Å	Cell parameters from 110 reflections
b = 11.007 (2) Å	θ = 12.6–79.5°
c = 9.033 (2) Å	µ = 1.75 mm^−1
β = 93.83 (3)°	T = 293 K
V = 1740.8 (6) Å^3	Prism, colourless
Z = 4	0.35 × 0.13 × 0.10 mm

Data collection

Bruker SMART APEX CCD diffractometer	3279 independent reflections
Radiation source: fine-focus sealed tube	3192 reflections with I > 2σ(I)
Graphite monochromator	Rint = 0.017
ω scans	θmax = 70.1°, θmin = 2.5°
Absorption correction: multi-scan (SADABS; Sheldrick, 2002).	h = −21→21
Tmin = 0.635, Tmax = 0.845	k = −13→13
19164 measured reflections	l = −10→10

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)] = 0.039	Hydrogen site location: difference Fourier map
wR(F^2) = 0.114	Only H-atom coordinates refined
S = 1.05	w = 1/[σ^2(Fo^2) + (0.0786P)^2 + 0.2252P] where P = (Fo^2 + 2Fc^2)/3
3279 reflections	(Δ/σ)max = 0.001
289 parameters	Δρmax = 0.24 e Å^−3
0 restraints	Δρmin = −0.21 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	0.223073 (19)	0.88960 (3)	0.41064 (4)	0.05327 (15)
O3	0.07750 (6)	0.73055 (10)	0.63600 (14)	0.0645 (3)
N2	0.17753 (7)	0.77445 (11)	0.49554 (14)	0.0520 (3)
N7	0.17484 (7)	1.11331 (11)	0.47690 (14)	0.0522 (3)
N21	0.27824 (6)	0.65014 (10)	0.42501 (12)	0.0479 (3)
C3	0.11699 (7)	0.80549 (13)	0.57721 (15)	0.0482 (3)
C4	0.06261 (7)	1.01377 (13)	0.65557 (14)	0.0477 (3)
C5	0.07163 (8)	1.13713 (14)	0.63717 (17)	0.0529 (3)
H51	0.0400 (12)	1.189 (2)	0.683 (2)	0.079*
C6	0.12766 (8)	1.18421 (13)	0.54919 (16)	0.0520 (3)
C8	0.16477 (7)	0.99394 (13)	0.49440 (14)	0.0468 (3)
C9	0.11156 (7)	0.93859 (12)	0.57973 (14)	0.0456 (3)
C10	0.00421 (9)	0.96340 (16)	0.75291 (19)	0.0566 (3)
H101	0.0294 (13)	0.924 (2)	0.837 (3)	0.085*
H102	−0.0322 (13)	0.904 (2)	0.701 (2)	0.085*
H103	−0.0272 (12)	1.021 (2)	0.783 (2)	0.085*
C11	0.13811 (12)	1.31869 (16)	0.5341 (2)	0.0692 (4)
H111	0.0925 (16)	1.353 (2)	0.506 (3)	0.104*
H112	0.1540 (14)	1.354 (2)	0.632 (3)	0.104*
H113	0.1716 (16)	1.330 (3)	0.468 (3)	0.104*
C12	0.20008 (8)	0.64929 (14)	0.46635 (19)	0.0530 (3)
H121	0.1698 (12)	0.6181 (19)	0.384 (2)	0.079*
H122	0.1905 (12)	0.6023 (19)	0.553 (2)	0.079*
C22	0.33429 (8)	0.66203 (16)	0.55178 (16)	0.0552 (3)
H221	0.3176 (12)	0.727 (2)	0.616 (2)	0.083*
H222	0.3385 (12)	0.583 (2)	0.610 (2)	0.083*
C23	0.41175 (9)	0.69089 (16)	0.49752 (18)	0.0584 (4)
H231	0.4507 (13)	0.694 (2)	0.575 (2)	0.088*
H232	0.4088 (13)	0.779 (2)	0.467 (2)	0.088*
C24	0.43179 (8)	0.61487 (11)	0.36950 (15)	0.0474 (3)
C25	0.37742 (9)	0.54603 (14)	0.29922 (17)	0.0579 (4)
H251	0.3900 (12)	0.488 (2)	0.229 (2)	0.087*
C26	0.29633 (9)	0.54355 (15)	0.3389 (2)	0.0595 (4)
H261	0.2664 (13)	0.541 (2)	0.250 (3)	0.089*
H262	0.2882 (13)	0.468 (2)	0.389 (2)	0.089*
C31	0.51106 (8)	0.62121 (12)	0.32073 (16)	0.0503 (3)
C32	0.56435 (10)	0.69992 (16)	0.3883 (2)	0.0664 (4)
H321	0.5496 (14)	0.751 (2)	0.463 (3)	0.100*
C33	0.63761 (10)	0.71086 (18)	0.3396 (2)	0.0743 (5)
H331	0.6733 (15)	0.774 (3)	0.388 (3)	0.112*
C34	0.65891 (10)	0.64276 (19)	0.2214 (2)	0.0718 (5)
H341	0.7093 (15)	0.654 (3)	0.188 (3)	0.108*
C35	0.60747 (10)	0.56346 (19)	0.1544 (2)	0.0717 (5)
H351	0.6249 (14)	0.511 (3)	0.071 (3)	0.108*
C36	0.53452 (9)	0.55159 (17)	0.20241 (17)	0.0619 (4)
H361	0.5013 (13)	0.492 (2)	0.154 (2)	0.093*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
S1	0.0479 (2)	0.0533 (2)	0.0609 (2)	−0.00166 (13)	0.02087 (16)	0.00107 (13)
O3	0.0534 (6)	0.0548 (6)	0.0885 (7)	−0.0040 (4)	0.0273 (5)	0.0092 (5)
N2	0.0455 (6)	0.0483 (6)	0.0638 (7)	−0.0009 (5)	0.0168 (5)	0.0014 (5)
N7	0.0463 (6)	0.0522 (7)	0.0592 (7)	−0.0032 (5)	0.0130 (5)	0.0049 (5)
N21	0.0439 (6)	0.0496 (6)	0.0507 (6)	0.0006 (5)	0.0069 (5)	−0.0056 (5)
C3	0.0384 (6)	0.0530 (7)	0.0538 (7)	−0.0012 (5)	0.0080 (5)	0.0029 (6)
C4	0.0367 (6)	0.0560 (7)	0.0507 (7)	0.0001 (5)	0.0062 (5)	0.0020 (5)
C5	0.0460 (7)	0.0548 (8)	0.0592 (8)	0.0036 (6)	0.0121 (6)	−0.0002 (6)
C6	0.0466 (7)	0.0518 (7)	0.0582 (7)	−0.0004 (6)	0.0079 (6)	0.0026 (6)
C8	0.0390 (6)	0.0531 (7)	0.0488 (6)	−0.0010 (5)	0.0069 (5)	0.0027 (5)
C9	0.0356 (6)	0.0522 (7)	0.0493 (7)	−0.0013 (5)	0.0053 (5)	0.0030 (5)
C10	0.0453 (7)	0.0599 (8)	0.0666 (8)	0.0011 (6)	0.0190 (6)	0.0033 (7)
C11	0.0712 (11)	0.0531 (9)	0.0859 (12)	−0.0009 (7)	0.0244 (9)	0.0044 (8)
C12	0.0471 (7)	0.0499 (7)	0.0627 (8)	−0.0028 (6)	0.0106 (6)	−0.0039 (6)
C22	0.0508 (7)	0.0674 (9)	0.0478 (7)	0.0011 (6)	0.0067 (6)	−0.0075 (6)
C23	0.0475 (7)	0.0718 (9)	0.0562 (8)	−0.0007 (7)	0.0051 (6)	−0.0151 (7)
C24	0.0480 (7)	0.0456 (7)	0.0492 (7)	0.0061 (5)	0.0066 (5)	0.0009 (5)
C25	0.0570 (8)	0.0557 (8)	0.0624 (8)	0.0015 (6)	0.0132 (7)	−0.0144 (6)
C26	0.0528 (8)	0.0584 (8)	0.0675 (9)	−0.0043 (7)	0.0073 (7)	−0.0170 (7)
C31	0.0483 (7)	0.0500 (7)	0.0531 (7)	0.0095 (5)	0.0070 (6)	0.0050 (5)
C32	0.0547 (8)	0.0628 (9)	0.0833 (11)	−0.0007 (7)	0.0176 (8)	−0.0109 (8)
C33	0.0543 (9)	0.0705 (10)	0.0999 (13)	−0.0012 (8)	0.0174 (9)	0.0000 (9)
C34	0.0530 (9)	0.0842 (11)	0.0804 (11)	0.0164 (8)	0.0208 (8)	0.0206 (9)
C35	0.0614 (10)	0.0936 (13)	0.0616 (9)	0.0245 (9)	0.0144 (7)	0.0024 (8)
C36	0.0550 (8)	0.0740 (10)	0.0570 (8)	0.0141 (7)	0.0061 (6)	−0.0040 (7)

Geometric parameters (Å, º)

S1—N2	1.7074 (12)	C12—H122	0.96 (2)
S1—C8	1.7440 (14)	C22—C23	1.509 (2)
O3—C3	1.2213 (17)	C22—H221	0.98 (2)
N2—C3	1.3764 (17)	C22—H222	1.01 (2)
N2—C12	1.4622 (19)	C23—C24	1.4884 (19)
N7—C8	1.3366 (19)	C23—H231	0.94 (2)
N7—C6	1.3389 (19)	C23—H232	1.01 (2)
N21—C12	1.4454 (18)	C24—C25	1.344 (2)
N21—C26	1.4544 (18)	C24—C31	1.489 (2)
N21—C22	1.4647 (18)	C25—C26	1.491 (2)
C3—C9	1.468 (2)	C25—H251	0.93 (2)
C4—C5	1.378 (2)	C26—H261	0.93 (2)
C4—C9	1.4038 (19)	C26—H262	0.96 (2)
C4—C10	1.5004 (19)	C31—C32	1.386 (2)
C5—C6	1.404 (2)	C31—C36	1.399 (2)
C5—H51	0.92 (2)	C32—C33	1.391 (2)
C6—C11	1.499 (2)	C32—H321	0.92 (2)
C8—C9	1.3905 (18)	C33—C34	1.377 (3)
C10—H101	0.96 (2)	C33—H331	1.02 (3)
C10—H102	1.01 (2)	C34—C35	1.368 (3)
C10—H103	0.89 (2)	C34—H341	0.96 (3)
C11—H111	0.90 (3)	C35—C36	1.385 (2)
C11—H112	0.99 (3)	C35—H351	1.02 (3)
C11—H113	0.88 (3)	C36—H361	0.96 (3)
C12—H121	0.95 (2)
N2—S1—C8	89.33 (6)	H121—C12—H122	109.0 (17)
C3—N2—C12	123.95 (11)	N21—C22—C23	109.71 (12)
C3—N2—S1	117.24 (10)	N21—C22—H221	108.6 (13)
C12—N2—S1	118.55 (9)	C23—C22—H221	110.7 (13)
C8—N7—C6	115.11 (12)	N21—C22—H222	110.4 (12)
C12—N21—C26	112.19 (11)	C23—C22—H222	108.2 (12)
C12—N21—C22	113.44 (11)	H221—C22—H222	109.2 (17)
C26—N21—C22	109.34 (12)	C24—C23—C22	113.49 (13)
O3—C3—N2	123.10 (13)	C24—C23—H231	113.6 (14)
O3—C3—C9	128.89 (12)	C22—C23—H231	112.9 (13)
N2—C3—C9	108.01 (11)	C24—C23—H232	110.0 (12)
C5—C4—C9	116.29 (12)	C22—C23—H232	105.0 (13)
C5—C4—C10	121.54 (13)	H231—C23—H232	100.6 (18)
C9—C4—C10	122.16 (13)	C25—C24—C31	122.31 (13)
C4—C5—C6	121.48 (13)	C25—C24—C23	119.14 (13)
C4—C5—H51	119.1 (13)	C31—C24—C23	118.52 (12)
C6—C5—H51	119.5 (13)	C24—C25—C26	123.76 (13)
N7—C6—C5	122.69 (14)	C24—C25—H251	120.7 (14)
N7—C6—C11	116.62 (13)	C26—C25—H251	115.1 (14)
C5—C6—C11	120.69 (14)	N21—C26—C25	111.08 (12)
N7—C8—C9	126.53 (13)	N21—C26—H261	110.6 (14)
N7—C8—S1	120.67 (10)	C25—C26—H261	106.7 (14)
C9—C8—S1	112.77 (11)	N21—C26—H262	113.7 (13)
C8—C9—C4	117.88 (13)	C25—C26—H262	107.6 (14)
C8—C9—C3	112.45 (11)	H261—C26—H262	106.8 (18)
C4—C9—C3	129.66 (11)	C32—C31—C36	117.02 (15)
C4—C10—H101	109.7 (14)	C32—C31—C24	121.02 (13)
C4—C10—H102	113.7 (13)	C36—C31—C24	121.93 (14)
H101—C10—H102	108.8 (18)	C31—C32—C33	121.70 (16)
C4—C10—H103	112.2 (14)	C31—C32—H321	119.1 (16)
H101—C10—H103	109.9 (18)	C33—C32—H321	119.0 (16)
H102—C10—H103	102.3 (18)	C34—C33—C32	120.15 (19)
C6—C11—H111	108.8 (17)	C34—C33—H331	120.9 (15)
C6—C11—H112	109.5 (15)	C32—C33—H331	118.8 (15)
H111—C11—H112	106 (2)	C35—C34—C33	119.04 (17)
C6—C11—H113	107.4 (18)	C35—C34—H341	122.6 (16)
H111—C11—H113	112 (2)	C33—C34—H341	118.3 (16)
H112—C11—H113	113 (2)	C34—C35—C36	121.21 (17)
N21—C12—N2	108.27 (11)	C34—C35—H351	118.0 (14)
N21—C12—H121	106.9 (13)	C36—C35—H351	120.7 (14)
N2—C12—H121	109.8 (13)	C35—C36—C31	120.86 (17)
N21—C12—H122	115.7 (13)	C35—C36—H361	117.8 (13)
N2—C12—H122	107.1 (13)	C31—C36—H361	121.3 (13)
C8—S1—N2—C3	4.07 (11)	N2—C3—C9—C4	−175.58 (13)
C8—S1—N2—C12	178.45 (11)	C26—N21—C12—N2	−157.01 (13)
C12—N2—C3—O3	1.8 (2)	C22—N21—C12—N2	78.47 (16)
S1—N2—C3—O3	175.85 (11)	C3—N2—C12—N21	−160.29 (13)
C12—N2—C3—C9	−179.00 (13)	S1—N2—C12—N21	25.74 (16)
S1—N2—C3—C9	−4.96 (15)	C12—N21—C22—C23	−167.08 (13)
C9—C4—C5—C6	−1.0 (2)	C26—N21—C22—C23	66.87 (16)
C10—C4—C5—C6	178.28 (14)	N21—C22—C23—C24	−44.96 (19)
C8—N7—C6—C5	0.0 (2)	C22—C23—C24—C25	11.3 (2)
C8—N7—C6—C11	179.05 (15)	C22—C23—C24—C31	−170.76 (13)
C4—C5—C6—N7	0.8 (2)	C31—C24—C25—C26	−175.94 (14)
C4—C5—C6—C11	−178.20 (15)	C23—C24—C25—C26	1.9 (2)
C6—N7—C8—C9	−0.6 (2)	C12—N21—C26—C25	−179.36 (13)
C6—N7—C8—S1	−178.62 (10)	C22—N21—C26—C25	−52.60 (17)
N2—S1—C8—N7	176.47 (12)	C24—C25—C26—N21	18.9 (2)
N2—S1—C8—C9	−1.81 (10)	C25—C24—C31—C32	175.07 (16)
N7—C8—C9—C4	0.3 (2)	C23—C24—C31—C32	−2.8 (2)
S1—C8—C9—C4	178.49 (9)	C25—C24—C31—C36	−2.8 (2)
N7—C8—C9—C3	−178.73 (13)	C23—C24—C31—C36	179.29 (14)
S1—C8—C9—C3	−0.57 (14)	C36—C31—C32—C33	0.9 (3)
C5—C4—C9—C8	0.48 (18)	C24—C31—C32—C33	−177.07 (16)
C10—C4—C9—C8	−178.80 (13)	C31—C32—C33—C34	0.1 (3)
C5—C4—C9—C3	179.36 (13)	C32—C33—C34—C35	−0.9 (3)
C10—C4—C9—C3	0.1 (2)	C33—C34—C35—C36	0.6 (3)
O3—C3—C9—C8	−177.52 (14)	C34—C35—C36—C31	0.4 (3)
N2—C3—C9—C8	3.35 (15)	C32—C31—C36—C35	−1.2 (2)
O3—C3—C9—C4	3.5 (2)	C24—C31—C36—C35	176.79 (14)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
C10—H103···O3^i	0.89 (2)	2.59 (2)	3.450 (2)	160.9 (18)
C10—H102···CgA^ii	1.01 (2)	2.783 (19)	3.4919 (19)	127.7 (15)
C22—H222···CgB^iii	1.01 (2)	2.88 (2)	3.831 (2)	155.4 (16)
C26—H261···CgC^iv	0.93 (2)	2.90 (3)	3.784 (2)	159.1 (18)

Symmetry codes: (i) −x, y+1/2, −z+3/2; (ii) −x, −y+2, −z+1; (iii) −x+1, −y+1, −z+1; (iv) x, −y+1/2, z−3/2.