supplementary materials


gk2524 scheme

Acta Cryst. (2012). E68, o3324-o3325    [ doi:10.1107/S1600536812045680 ]

N-[4-(9-Chloroquino[3,2-b]benzo[1,4]thiazin-6-yl)butyl]acetamide

M. Jelen, K. Suwinska, K. Pluta and B. Morak-Mlodawska

Abstract top

In the title molecule, C21H20ClN3OS, the tetracyclic system is close to planar [r.m.s. deviation = 0.110 (4) Å]. The dihedral angle between the quinoline ring system and the benzene ring is 178.3 (1)° and the angle between two (S-C=C-N) halves of the thiazine ring is 173.4 (1)°. In the crystal, molecules are arranged via [pi]-[pi] interactions [centroid-centroid distances = 3.603 (2)-3.739 (2) Å] into slipped stacks extending along [010]. Intermolecular N-H...O hydrogen bonds link the amide groups of neighbouring molecules along the stack, generating a C(4) motif. The title compound shows promising antiproliferative and anticancer activity.

Comment top

Classical phenothiazines are widely recognized as neuroleptic, antihistaminic and antitissive drugs. New phenothiazines are obtained by the introduction of new pharmacophoric substituents at the thiazine nitrogen atom and the substitution of the benzene ring with an azine ring (Pluta et al., 2009, 2011). Both classical and newly synthesized phenothiazines exhibit valuable anticancer, antibacterial and reversal multidrug resistance (Aaron et al., 2009; Pluta et al., 2011). We modified the phenothiazine structure via the substitution of the benzene ring with the quinoline ring to form linear fused quinobenzothiazines. The title compound (Fig. 1) was obtained in a few step synthesis starting from the reaction of diquinodithiin or 2,2'-dichloro-3,3'-diquinolinyl disulfide with p-chloroaniline. The obtained 6H-9-chloroquinobenzothiazine via thiazine ring formation (Pluta et al., 2009) was next alkylated with phthalimidobutyl bromide, hydrolyzed with hydrazine and acetylated with acetic anhydride (Pluta et al., 2012). The structure elucidation was based on the 1H NMR spectrum which did not take all the doubts away. These reactions may lead to alternative products (II-V) (Fig. 1) as the results of other ring closure reaction, the Smiles rearrangement, tautomeric forms and competitive N-alkylation. The X-ray analysis fully confirmed the proposed structure as [3,2-b], the chlorine atom in position 9 and the acetylaminobutyl substituent at the thiazine nitrogen atom N6. The tetracyclic ring system (the plane from C1 atom up to C12A atom) in title molecule is unexpectedly almost planar [r.m.s. deviation 0.110 (4) Å]) with the dihedral angle between the quinoline and the benzene ring of 178.3 (1)° and the angle between two halves of the thiazine ring of 173.4 (1)°. All the classical neuroleptic phenothiazines are folded along theN–S axis with the angle of 134.0–153.6 ° (Chu, 1988) and the title molecule is the first example of planar azaphenothiazine with the aminoalkyl group at the thiazine nitrogen atom. Other similar tetracyclic compounds with the thiazine ring, 6-benzyl-10-trifluoromethylquinobenzothiazine (Pluta et al., 2012), 6-methyldihydroquinobenzothiazine (Luck et al., 2003) and 5H-naphthobenzothiazine (Yoshida et al., 1994) were also folded. Close to planar structure was 6H-8-trifluoromethylquinobenzothiazine (Pluta et al., 2012). The C10A–S11–C11A and C5A–N6–C6A bond angles are quite large, 102.2 (2)° and 123.8 (3)° and enable the thiazine ring to adopt the flat conformation. Both the thiazine N6 and the amide N18 nitrogen atoms do not show pyramidality as the sum of C–N–X bond angles (X = C or H) is 360.1 (5)° and 360°, repectively. The side chain is not coplanar with the tetracyclic system. The torsion angles involving the butyl group (C14–C17) show the antiperiplanar arrangement of the carbon chain. The torsion angle C16–C17–N18–C19 [135.2 (4)°] describes the anticlinal arrangement of these atoms. In the crystal, molecules are arranged into stacks via ππ interactions with centroid-to-centroid distances in the range of 3.603 (2)–3.739 (2) Å and extending along the b crystallographic axis ( Fig. 3). N–H···O hydrogen bond (Table 1) connects adjacent molecules along the stacks via catemeric C(4) motif (Fig. 4). The significant antiproliferative and anticancer activities of the title molecule most probabably result from intercalation of specific DNA by the planar azaphenothiazine system.

Related literature top

For recent literature on biological activity of phenothiazines, see: Aaron et al. (2009); Pluta et al. (2011). For the synthesis and biological activity of 6-substituted quinobenzothiazines, see: Jeleń & Pluta (2009); Pluta et al. (2012). For the folded structures of similar tetracyclic systems, see: Jeleń et al. (2012); Luck et al. (2003); Yoshida et al. (1994). For crystal structures of phenothiazines, see: Chu (1988). For information on azaphenothiazines, and their nomenclature and synthesis, see: Pluta et al. (2009).

Experimental top

The title compound was obtained in a few step synthesis starting from the reaction of diquinodithiin or 2,2'-dichloro-3,3'-diquinolinyl disulfide with p-chloroaniline (Jeleń et al., 2009). The obtained 6H-9-chloroquinobenzothiazine was alkylated with phthalimidobutyl bromide in dry toluene in the presence of sodium hydride, hydrolyzed with hydrazine in ethanol and acetylated with acetican hydride in pyridine. The title compound has melting point 417-418 K (Pluta et al., 2012). X-ray quality crystals were grown from chloroform-ethanol mixture by slow evaporation.

Refinement top

All H atoms were treated as riding atoms in geometrically calculated positions, with d(C–H) = 0.95, 0.99 and 0.98 Å for aromatic, methylene and methyl hydrogens, respectively, d(N–H) = 0.88 Å , and Uiso(H) = kUeq(C,N), where k = 1.5 for the methyl group and k = 1.2 otherwise.

Computing details top

Data collection: COLLECT (Nonius, 1998); cell refinement: DENZO and SCALEPACK (Otwinowski & Minor, 1997); data reduction: DENZO and SCALEPACK (Otwinowski & Minor, 1997); program(s) used to solve structure: SHELXS97 (Sheldrick, 2008); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008); molecular graphics: ORTEPIII (Burnett & Johnson, 1996) and Mercury (Macrae et al., 2008); software used to prepare material for publication: publCIF (Westrip, 2010).

Figures top
[Figure 1]
[Figure 2]
[Figure 3]
[Figure 4]
Alternative structures of the title compound.

ORTEP drawing with displacement ellipsoids shown at the 50% probability level. SmilesCrystal packing shown along the b crystallographic axis.

ππ stacking of the aromatic rings and one dimensional hydrogen-bond network.
N-[4-(9-Chloroquino[3,2-b]benzo[1,4]thiazin-6-yl)butyl]acetamide top
Crystal data top
C21H20ClN3OSF(000) = 832
Mr = 397.92Dx = 1.464 Mg m3
Monoclinic, P21/cMo Kα radiation, λ = 0.71073 Å
Hall symbol: -P 2ybcCell parameters from 5229 reflections
a = 12.7800 (4) Åθ = 2.9–24.7°
b = 4.9530 (11) ŵ = 0.35 mm1
c = 28.781 (2) ÅT = 100 K
β = 97.726 (5)°Needle, yellow
V = 1805.3 (4) Å30.60 × 0.10 × 0.05 mm
Z = 4
Data collection top
Nonius KappaCCD
diffractometer upgraded with an APEXII detector
1987 reflections with I > 2σ(I)
Radiation source: fine-focus sealed tubeRint = 0.121
Graphite monochromatorθmax = 24.7°, θmin = 3.1°
Detector resolution: 8.3 pixels mm-1h = 1515
ω scank = 55
17434 measured reflectionsl = 3233
3032 independent reflections
Refinement top
Refinement on F2Primary atom site location: structure-invariant direct methods
Least-squares matrix: fullSecondary atom site location: difference Fourier map
R[F2 > 2σ(F2)] = 0.067Hydrogen site location: inferred from neighbouring sites
wR(F2) = 0.127H-atom parameters constrained
S = 1.10 w = 1/[σ2(Fo2) + (0.016P)2 + 1.5516P]
where P = (Fo2 + 2Fc2)/3
3032 reflections(Δ/σ)max < 0.001
245 parametersΔρmax = 0.32 e Å3
0 restraintsΔρmin = 0.29 e Å3
Crystal data top
C21H20ClN3OSV = 1805.3 (4) Å3
Mr = 397.92Z = 4
Monoclinic, P21/cMo Kα radiation
a = 12.7800 (4) ŵ = 0.35 mm1
b = 4.9530 (11) ÅT = 100 K
c = 28.781 (2) Å0.60 × 0.10 × 0.05 mm
β = 97.726 (5)°
Data collection top
Nonius KappaCCD
diffractometer upgraded with an APEXII detector
1987 reflections with I > 2σ(I)
17434 measured reflectionsRint = 0.121
3032 independent reflectionsθmax = 24.7°
Refinement top
R[F2 > 2σ(F2)] = 0.067H-atom parameters constrained
wR(F2) = 0.127Δρmax = 0.32 e Å3
S = 1.10Δρmin = 0.29 e Å3
3032 reflectionsAbsolute structure: ?
245 parametersFlack parameter: ?
0 restraintsRogers parameter: ?
Special details top

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 > 2σ(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 (Å2) top
xyzUiso*/Ueq
C11.1591 (3)0.0335 (8)0.38503 (15)0.0286 (11)
H11.19690.00220.41530.034*
C21.1827 (3)0.1165 (8)0.34779 (14)0.0298 (11)
H21.23600.25130.35200.036*
C31.1264 (3)0.0669 (8)0.30318 (15)0.0285 (11)
H31.14260.16890.27710.034*
C41.0484 (3)0.1260 (8)0.29646 (14)0.0252 (10)
H41.01160.15570.26600.030*
C4A1.0226 (3)0.2802 (8)0.33455 (14)0.0240 (10)
C5A0.9204 (3)0.6158 (8)0.36259 (14)0.0249 (10)
C6A0.8031 (3)0.9780 (8)0.38605 (14)0.0249 (10)
C70.7205 (3)1.1593 (8)0.37258 (14)0.0251 (10)
H70.68951.16300.34070.030*
C80.6820 (3)1.3348 (8)0.40429 (14)0.0281 (11)
H80.62891.46360.39390.034*
C90.7229 (3)1.3170 (8)0.45101 (14)0.0278 (11)
C100.8017 (3)1.1362 (8)0.46564 (14)0.0283 (11)
H100.82801.12390.49800.034*
C10A0.8439 (3)0.9705 (8)0.43379 (14)0.0258 (10)
C11A0.9741 (3)0.5778 (8)0.40921 (14)0.0244 (10)
C121.0516 (3)0.3889 (8)0.41680 (14)0.0246 (10)
H121.08710.36160.44760.030*
C12A1.0802 (3)0.2326 (8)0.37939 (14)0.0243 (10)
C140.8053 (3)0.8667 (8)0.30219 (13)0.0257 (10)
H14A0.86110.81310.28330.031*
H14B0.79361.06320.29780.031*
C150.7036 (3)0.7195 (8)0.28324 (13)0.0252 (10)
H15A0.64820.76130.30310.030*
H15B0.71600.52220.28430.030*
C160.6666 (3)0.8062 (8)0.23276 (13)0.0272 (11)
H16A0.64220.99600.23270.033*
H16B0.72710.79820.21470.033*
C170.5779 (3)0.6321 (9)0.20864 (14)0.0316 (11)
H17A0.59480.43980.21540.038*
H17B0.51190.67500.22150.038*
C190.5476 (3)0.4691 (9)0.12731 (15)0.0290 (11)
C200.5415 (3)0.5422 (9)0.07638 (14)0.0362 (12)
H20A0.59990.45650.06310.054*
H20B0.54630.73870.07330.054*
H20C0.47420.47910.05950.054*
N50.9431 (2)0.4684 (6)0.32683 (11)0.0227 (8)
N60.8438 (3)0.8161 (6)0.35178 (11)0.0237 (8)
N180.5615 (3)0.6734 (7)0.15804 (11)0.0279 (9)
H180.56070.83960.14720.033*
O210.5405 (2)0.2316 (6)0.14005 (10)0.0400 (8)
S110.94961 (9)0.7684 (2)0.45749 (4)0.0304 (3)
Cl130.67276 (9)1.5212 (2)0.49241 (4)0.0364 (3)
Atomic displacement parameters (Å2) top
U11U22U33U12U13U23
C10.025 (3)0.028 (3)0.032 (3)0.002 (2)0.003 (2)0.005 (2)
C20.025 (3)0.026 (3)0.040 (3)0.000 (2)0.008 (2)0.002 (2)
C30.030 (3)0.022 (3)0.035 (3)0.006 (2)0.007 (2)0.000 (2)
C40.027 (3)0.023 (2)0.026 (2)0.009 (2)0.002 (2)0.001 (2)
C4A0.025 (2)0.016 (2)0.032 (2)0.004 (2)0.007 (2)0.003 (2)
C5A0.026 (3)0.019 (2)0.030 (2)0.002 (2)0.005 (2)0.002 (2)
C6A0.023 (2)0.023 (2)0.029 (2)0.004 (2)0.003 (2)0.003 (2)
C70.027 (3)0.024 (3)0.025 (2)0.009 (2)0.005 (2)0.001 (2)
C80.026 (3)0.022 (3)0.037 (3)0.003 (2)0.006 (2)0.005 (2)
C90.030 (3)0.021 (3)0.034 (3)0.002 (2)0.008 (2)0.003 (2)
C100.031 (3)0.027 (3)0.027 (2)0.005 (2)0.001 (2)0.001 (2)
C10A0.024 (2)0.024 (2)0.029 (2)0.002 (2)0.004 (2)0.002 (2)
C11A0.027 (3)0.019 (2)0.028 (2)0.004 (2)0.007 (2)0.0015 (19)
C120.024 (2)0.021 (2)0.029 (2)0.006 (2)0.004 (2)0.005 (2)
C12A0.021 (2)0.021 (2)0.031 (2)0.003 (2)0.005 (2)0.003 (2)
C140.033 (3)0.021 (2)0.023 (2)0.002 (2)0.003 (2)0.0061 (19)
C150.028 (3)0.021 (2)0.026 (2)0.003 (2)0.001 (2)0.0018 (19)
C160.032 (3)0.020 (2)0.032 (2)0.000 (2)0.009 (2)0.0005 (19)
C170.037 (3)0.028 (3)0.029 (2)0.002 (2)0.001 (2)0.008 (2)
C190.022 (2)0.029 (3)0.034 (3)0.002 (2)0.003 (2)0.000 (2)
C200.037 (3)0.033 (3)0.040 (3)0.002 (2)0.009 (2)0.011 (2)
N50.0211 (19)0.018 (2)0.029 (2)0.0004 (17)0.0033 (16)0.0048 (16)
N60.027 (2)0.021 (2)0.0228 (19)0.0017 (17)0.0043 (16)0.0008 (16)
N180.035 (2)0.018 (2)0.029 (2)0.0034 (17)0.0004 (17)0.0051 (16)
O210.050 (2)0.0159 (18)0.050 (2)0.0015 (16)0.0054 (16)0.0007 (15)
S110.0343 (7)0.0290 (7)0.0271 (6)0.0036 (6)0.0006 (5)0.0018 (5)
Cl130.0404 (7)0.0309 (7)0.0391 (7)0.0040 (6)0.0105 (6)0.0054 (5)
Geometric parameters (Å, º) top
C1—C21.371 (5)C10A—S111.745 (4)
C1—C12A1.405 (5)C11A—C121.359 (5)
C1—H10.9500C11A—S111.743 (4)
C2—C31.406 (5)C12—C12A1.413 (5)
C2—H20.9500C12—H120.9500
C3—C41.376 (5)C14—N61.468 (4)
C3—H30.9500C14—C151.526 (5)
C4—C4A1.411 (5)C14—H14A0.9900
C4—H40.9500C14—H14B0.9900
C4A—N51.374 (5)C15—C161.528 (5)
C4A—C12A1.417 (5)C15—H15A0.9900
C5A—N51.325 (5)C15—H15B0.9900
C5A—N61.399 (5)C16—C171.515 (5)
C5A—C11A1.435 (5)C16—H16A0.9900
C6A—C71.400 (5)C16—H16B0.9900
C6A—C10A1.403 (5)C17—N181.458 (5)
C6A—N61.423 (5)C17—H17A0.9900
C7—C81.397 (5)C17—H17B0.9900
C7—H70.9500C19—O211.239 (5)
C8—C91.378 (5)C19—N181.340 (5)
C8—H80.9500C19—C201.502 (5)
C9—C101.371 (5)C20—H20A0.9800
C9—Cl131.749 (4)C20—H20B0.9800
C10—C10A1.392 (5)C20—H20C0.9800
C10—H100.9500N18—H180.8800
C2—C1—C12A121.4 (4)C1—C12A—C4A119.9 (4)
C2—C1—H1119.3C12—C12A—C4A116.6 (4)
C12A—C1—H1119.3N6—C14—C15115.1 (3)
C1—C2—C3118.7 (4)N6—C14—H14A108.5
C1—C2—H2120.7C15—C14—H14A108.5
C3—C2—H2120.7N6—C14—H14B108.5
C4—C3—C2121.4 (4)C15—C14—H14B108.5
C4—C3—H3119.3H14A—C14—H14B107.5
C2—C3—H3119.3C14—C15—C16110.2 (3)
C3—C4—C4A120.5 (4)C14—C15—H15A109.6
C3—C4—H4119.8C16—C15—H15A109.6
C4A—C4—H4119.8C14—C15—H15B109.6
N5—C4A—C4119.1 (4)C16—C15—H15B109.6
N5—C4A—C12A122.8 (4)H15A—C15—H15B108.1
C4—C4A—C12A118.1 (4)C17—C16—C15113.1 (3)
N5—C5A—N6115.9 (4)C17—C16—H16A109.0
N5—C5A—C11A121.8 (4)C15—C16—H16A109.0
N6—C5A—C11A122.2 (4)C17—C16—H16B109.0
C7—C6A—C10A117.1 (4)C15—C16—H16B109.0
C7—C6A—N6120.1 (4)H16A—C16—H16B107.8
C10A—C6A—N6122.8 (4)N18—C17—C16112.1 (3)
C8—C7—C6A122.5 (4)N18—C17—H17A109.2
C8—C7—H7118.8C16—C17—H17A109.2
C6A—C7—H7118.8N18—C17—H17B109.2
C9—C8—C7118.5 (4)C16—C17—H17B109.2
C9—C8—H8120.8H17A—C17—H17B107.9
C7—C8—H8120.8O21—C19—N18122.0 (4)
C10—C9—C8120.5 (4)O21—C19—C20121.4 (4)
C10—C9—Cl13119.3 (3)N18—C19—C20116.5 (4)
C8—C9—Cl13120.1 (3)C19—C20—H20A109.5
C9—C10—C10A121.1 (4)C19—C20—H20B109.5
C9—C10—H10119.5H20A—C20—H20B109.5
C10A—C10—H10119.5C19—C20—H20C109.5
C10—C10A—C6A120.3 (4)H20A—C20—H20C109.5
C10—C10A—S11115.4 (3)H20B—C20—H20C109.5
C6A—C10A—S11124.3 (3)C5A—N5—C4A118.8 (3)
C12—C11A—C5A119.2 (4)C5A—N6—C6A123.8 (3)
C12—C11A—S11116.7 (3)C5A—N6—C14118.1 (3)
C5A—C11A—S11124.1 (3)C6A—N6—C14118.2 (3)
C11A—C12—C12A120.8 (4)C19—N18—C17122.8 (3)
C11A—C12—H12119.6C19—N18—H18118.6
C12A—C12—H12119.6C17—N18—H18118.6
C1—C12A—C12123.5 (4)C11A—S11—C10A102.2 (2)
Hydrogen-bond geometry (Å, º) top
D—H···AD—HH···AD···AD—H···A
N18—H18···O21i0.881.972.819 (4)163
Symmetry code: (i) x, y+1, z.
Hydrogen-bond geometry (Å, º) top
D—H···AD—HH···AD···AD—H···A
N18—H18···O21i0.881.972.819 (4)163
Symmetry code: (i) x, y+1, z.
Acknowledgements top

The work was supported by the National Centre of Science (grant No. N405 101739).

references
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