Supporting information
Crystallographic Information File (CIF) https://doi.org/10.1107/S0108270107031071/tr3017sup1.cif | |
Structure factor file (CIF format) https://doi.org/10.1107/S0108270107031071/tr3017IIsup2.hkl | |
Structure factor file (CIF format) https://doi.org/10.1107/S0108270107031071/tr3017IIIsup3.hkl |
CCDC references: 659138; 659139
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.
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 Uiso(H) values of 1.5Ueq(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 Uiso(H) = 1.5Ueq(C)].
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).
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) Å3 | Prism, colourless |
Z = 8 | 0.55 × 0.42 × 0.20 mm |
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 on F2 | Primary atom site location: structure-invariant direct methods |
Least-squares matrix: full | Secondary atom site location: difference Fourier map |
R[F2 > 2σ(F2)] = 0.046 | Hydrogen site location: difference Fourier map |
wR(F2) = 0.207 | H atoms treated by a mixture of independent and constrained refinement |
S = 1.00 | w = 1/[σ2(Fo2) + (0.2P)2] where P = (Fo2 + 2Fc2)/3 |
3471 reflections | (Δ/σ)max < 0.001 |
229 parameters | Δρmax = 0.21 e Å−3 |
0 restraints | Δρmin = −0.29 e Å−3 |
C20H23N3OS | V = 3676.4 (18) Å3 |
Mr = 353.47 | Z = 8 |
Monoclinic, C2/c | Cu Kα radiation |
a = 29.384 (6) Å | µ = 1.66 mm−1 |
b = 7.146 (1) Å | T = 293 K |
c = 21.750 (4) Å | 0.55 × 0.42 × 0.20 mm |
β = 126.39 (3)° |
Bruker SMART APEX CCD diffractometer | 3471 independent reflections |
Absorption correction: multi-scan (SADABS; Sheldrick, 2002) | 3267 reflections with I > 2σ(I) |
Tmin = 0.498, Tmax = 0.733 | Rint = 0.020 |
19486 measured reflections |
R[F2 > 2σ(F2)] = 0.046 | 0 restraints |
wR(F2) = 0.207 | H atoms treated by a mixture of independent and constrained refinement |
S = 1.00 | Δρmax = 0.21 e Å−3 |
3471 reflections | Δρmin = −0.29 e Å−3 |
229 parameters |
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. |
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* |
U11 | U22 | U33 | U12 | U13 | U23 | |
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) |
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) |
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) Å3 | Prism, colourless |
Z = 4 | 0.35 × 0.13 × 0.10 mm |
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 on F2 | Primary atom site location: structure-invariant direct methods |
Least-squares matrix: full | Secondary atom site location: difference Fourier map |
R[F2 > 2σ(F2)] = 0.039 | Hydrogen site location: difference Fourier map |
wR(F2) = 0.114 | Only H-atom coordinates refined |
S = 1.05 | w = 1/[σ2(Fo2) + (0.0786P)2 + 0.2252P] where P = (Fo2 + 2Fc2)/3 |
3279 reflections | (Δ/σ)max = 0.001 |
289 parameters | Δρmax = 0.24 e Å−3 |
0 restraints | Δρmin = −0.21 e Å−3 |
C20H21N3OS | V = 1740.8 (6) Å3 |
Mr = 351.46 | Z = 4 |
Monoclinic, P21/c | Cu Kα radiation |
a = 17.548 (3) Å | µ = 1.75 mm−1 |
b = 11.007 (2) Å | T = 293 K |
c = 9.033 (2) Å | 0.35 × 0.13 × 0.10 mm |
β = 93.83 (3)° |
Bruker SMART APEX CCD diffractometer | 3279 independent reflections |
Absorption correction: multi-scan (SADABS; Sheldrick, 2002). | 3192 reflections with I > 2σ(I) |
Tmin = 0.635, Tmax = 0.845 | Rint = 0.017 |
19164 measured reflections |
R[F2 > 2σ(F2)] = 0.039 | 0 restraints |
wR(F2) = 0.114 | Only H-atom coordinates refined |
S = 1.05 | Δρmax = 0.24 e Å−3 |
3279 reflections | Δρmin = −0.21 e Å−3 |
289 parameters |
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. |
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* |
U11 | U22 | U33 | U12 | U13 | U23 | |
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) |
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) |
D—H···A | D—H | H···A | D···A | D—H···A |
C10—H103···O3i | 0.89 (2) | 2.59 (2) | 3.450 (2) | 160.9 (18) |
C10—H102···CgAii | 1.01 (2) | 2.783 (19) | 3.4919 (19) | 127.7 (15) |
C22—H222···CgBiii | 1.01 (2) | 2.88 (2) | 3.831 (2) | 155.4 (16) |
C26—H261···CgCiv | 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. |
Experimental details
(II) | (III) | |
Crystal data | ||
Chemical formula | C20H23N3OS | C20H21N3OS |
Mr | 353.47 | 351.46 |
Crystal system, space group | Monoclinic, C2/c | Monoclinic, P21/c |
Temperature (K) | 293 | 293 |
a, b, c (Å) | 29.384 (6), 7.146 (1), 21.750 (4) | 17.548 (3), 11.007 (2), 9.033 (2) |
β (°) | 126.39 (3) | 93.83 (3) |
V (Å3) | 3676.4 (18) | 1740.8 (6) |
Z | 8 | 4 |
Radiation type | Cu Kα | Cu Kα |
µ (mm−1) | 1.66 | 1.75 |
Crystal size (mm) | 0.55 × 0.42 × 0.20 | 0.35 × 0.13 × 0.10 |
Data collection | ||
Diffractometer | Bruker SMART APEX CCD diffractometer | Bruker SMART APEX CCD diffractometer |
Absorption correction | Multi-scan (SADABS; Sheldrick, 2002) | Multi-scan (SADABS; Sheldrick, 2002). |
Tmin, Tmax | 0.498, 0.733 | 0.635, 0.845 |
No. of measured, independent and observed [I > 2σ(I)] reflections | 19486, 3471, 3267 | 19164, 3279, 3192 |
Rint | 0.020 | 0.017 |
(sin θ/λ)max (Å−1) | 0.610 | 0.610 |
Refinement | ||
R[F2 > 2σ(F2)], wR(F2), S | 0.046, 0.207, 1.00 | 0.039, 0.114, 1.05 |
No. of reflections | 3471 | 3279 |
No. of parameters | 229 | 289 |
H-atom treatment | H atoms treated by a mixture of independent and constrained refinement | Only H-atom coordinates refined |
Δρmax, Δρmin (e Å−3) | 0.21, −0.29 | 0.24, −0.21 |
Computer programs: SMART (Bruker, 2003), SAINT (Bruker, 2003), SAINT, SIR92 (Altomare et al., 1993), SHELXL97 (Sheldrick, 1997), ORTEP-3 for Windows (Farrugia, 1997) and XP in SHELXTL-Plus (Sheldrick, 1989), SHELXL97 and WinGX (Farrugia, 1999).
D—H···A | D—H | H···A | D···A | D—H···A |
C10—H103···O3i | 0.89 (2) | 2.59 (2) | 3.450 (2) | 160.9 (18) |
C10—H102···CgAii | 1.01 (2) | 2.783 (19) | 3.4919 (19) | 127.7 (15) |
C22—H222···CgBiii | 1.01 (2) | 2.88 (2) | 3.831 (2) | 155.4 (16) |
C26—H261···CgCiv | 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. |
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—Car (C═C—Car; 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).