10-(Prop-2-yn-1-yl)-2,7-diaza­phenothia­zine

Beata Morak-Młodawska; Kinga Suwińska; Krystian Pluta; Małgorzata Jeleń

doi:10.1107/S1600536812018879

. 2012 May 2;68(Pt 6):o1590–o1591. doi: 10.1107/S1600536812018879

10-(Prop-2-yn-1-yl)-2,7-diazaphenothiazine¹

Beata Morak-Młodawska ^a, Kinga Suwińska ^b,^c, Krystian Pluta ^a,^*, Małgorzata Jeleń ^a

PMCID: PMC3379202 PMID: 22719400

Abstract

In the title molecule [systematic name: 10-(prop-2-yn-1-yl)dipyrido[3,4-b:3′,4′-e][1,4]thiazine], C₁₃H₉N₃S, the dihedral angle between the two pyridine rings is 146.33 (7)° and the angle between two halves of the thiazine ring is 138.84 (8)°, resulting in a butterfly shape for the tricyclic system. The central thiazine ring adopts a boat conformation, with the 2-propynyl substituent at the thiazine N atom located in a pseudo-equatorial position and oriented to the concave side of the diazaphenothiazine system. In the crystal, molecules are arranged via π–π interactions between the pyridine rings [centroid–centroid distances = 3.838 (1) and 3.845 (1) Å] into stacks extending along [001]. There are C—H⋯C and C—H⋯N interactions between molecules of neighbouring stacks.

Related literature

For recent literature on the biological activity of phenothiazines, see: Aaron et al. (2009 ▶); Pluta et al. (2011 ▶). For the structure of 10-(2-propynyl)phenothiazine and its transformations into anticancer derivatives, see: Bisi et al. (2008 ▶). For the synthesis and the anticancer and immunosuppressive activity of 2,7-diazaphenothiazines, see: Morak-Młodawska & Pluta (2009 ▶); Zimecki et al. (2009 ▶); Pluta et al. (2010 ▶). For planar and folded structures of the 2,7-diazaphenothiazine system, see: Morak et al. (2002 ▶); Morak-Młodawska et al. (2010 ▶). For alkylation of azaphenothiazines, see: Pluta et al. (2009 ▶).

Experimental

Crystal data

C₁₃H₉N₃S
M _r = 239.29
Monoclinic,
a = 14.1150 (9) Å
b = 10.1909 (6) Å
c = 7.6749 (5) Å
β = 104.212 (3)°
V = 1070.20 (12) Å³
Z = 4
Mo Kα radiation
μ = 0.28 mm⁻¹
T = 100 K
0.60 × 0.50 × 0.35 mm

Data collection

Nonius KappaCCD diffractometer upgraded with APEXII detector
7015 measured reflections
2407 independent reflections
2011 reflections with I > 2σ(I)
R _int = 0.041

Refinement

R[F ² > 2σ(F ²)] = 0.049
wR(F ²) = 0.114
S = 1.11
2407 reflections
154 parameters
H-atom parameters constrained
Δρ_max = 0.45 e Å⁻³
Δρ_min = −0.35 e Å⁻³

Data collection: COLLECT (Nonius, 1998 ▶); cell refinement: DENZO and SCALEPACK (Otwinowski & Minor, 1997 ▶); data reduction: DENZO and SCALEPACK; 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 ▶).

Supplementary Material

Crystal structure: contains datablock(s) I, global. DOI: 10.1107/S1600536812018879/gk2475sup1.cif

e-68-o1590-sup1.cif^{(21.1KB, cif)}

Structure factors: contains datablock(s) I. DOI: 10.1107/S1600536812018879/gk2475Isup2.hkl

e-68-o1590-Isup2.hkl^{(118.3KB, hkl)}

Supplementary material file. DOI: 10.1107/S1600536812018879/gk2475Isup3.cml

Additional supplementary materials: crystallographic information; 3D view; checkCIF report

Table 1. Hydrogen-bond geometry (Å, °).

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
C4—H4⋯N2ⁱ	0.95	2.62	3.457 (3)	147
C13—H13⋯C11ⁱⁱ	0.95	2.78	3.677 (3)	159
C13—H13⋯C12ⁱⁱ	0.95	2.78	3.686 (3)	161
C3—H3⋯C13ⁱ	0.95	2.78	3.662 (3)	155
C8—H8⋯C13ⁱⁱⁱ	0.95	2.69	3.407 (3)	133

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Symmetry codes: (i) Inline graphic ; (ii) ; (iii) .

Acknowledgments

The work was supported by the Medical University of Silesia (grant KNW-1–073/P/1/0).

supplementary crystallographic information

Comment

Phenothiazines exhibit not only recognized neuroleptic, antihistaminic and antitussive activities but recently also anticancer, antibacterial and reversal multidrug resistance [Aaron et al., (2009); Pluta et al., (2011)]. The modifications of the phenothiazine structures are mainly directed into 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). Synthesis of substituted 10-(2-propynyl)phenothiazines and their transformations into various aminobutynyl derivatives of anticancer and multidrug resistance reverting activities was reported by Bisi et al. (2008). We modified the phenothiazine structure via the substitution of the benzene ring with the pyridine ring to form 2,7-diazaphenothiazines (Morak-Młodawska & Pluta, 2009) possessing anticancer and immunosuppressive activities (Zimecki et al., 2009; Pluta et al. 2010). Alkylation of azaphenothiazines proceeds at the thiazine and/or the azine nitrogen atoms, depending on the reaction conditions (Pluta et al., 2009). N-Alkylation of 10H-2,7-diazaphenothiazine led to both types of the products showing planar and folded 2,7-diazaphenothiazine ring system (Morak-Młodawska et al., 2010). 10H-2,7-Diazaphenothiazine was transformed into the title compound, C₁₃H₉N₃S, a convenient substrate to other 2,7-diazaphenothiazine derivatives using aminomethylation or 1,3-dipolar cycloaddition. The X-ray study showed the propynyl group to be attached to the thiazine nitrogen atom. In the molecule, the butterfly angle between the two pyridine rings is 146.33 (7)° and the angle between two halves of the thiazine ring is 138.84 (8)°. The 2-propynyl substituent is in a pseudo-equatorial position with the angle S5···N10–C11 of 163.8 (2)° and directed to the concave side of the diazaphenothiazine system with the angle between the N10/C11/C12/C13 and C4a/C5a/C9a/C10a planes of 86.3 (1)°. The thiazine nitrogen atom shows pyramidality as the sum of the C–N10–C bond angles is 356.1 (1)°. Hydrogen bond C4–H4···N2 (Table 1) results in one-dimensional polymeric chain parallel to the b axis. Acidic hydrogen atom H13 is in close contact to C11 and C12 atoms of the propynyl substituent (both H···C distances equal to 2.78 Å). This suggests, that H13 is involved in C–H···C interactions to these two carbon atoms rather than in the C–H···π interaction to the π system of the triple C12≡C13 bond (H13···center_C12_≡_C13 distance of 2.96 Å ). Additionally, the C12≡ C13 bond π electrons interact with two aromatic H atoms (H3 and H8) of two other adjacent molecules with short C–H···C intermolecular contacts (less than the sum of van der Waals radii) between H3 and H8, and C13 (see Table 1). On the basis of these interactions a three-dimensional network is formed. Molecules π-stack along the c axis. Aromatic rings N2/C1/C10a/C4a/C4/C3 π-stack with centroid-to-centroid distance of 3.845 (1) Å, similarly, for rings N7/C6/C5A/C9A/C9/C8 the centroid-to-centroid distance is 3.838 (1) Å (see Figure 2).

Experimental

To a suspension of 10H-2,7-diazaphenothiazine (100 mg, 0.5 mmol) in 5 ml DMF potassium tert-butoxide (80 mg, 0.72 mmol) was added. The mixture was stirred at room temperature for 1 h. Then a solution of propargyl bromide (80 mg, 0.64 mmol) in toluene was added dropwise. The solution was stirred at room temperature for 24 h and poured into water (15 ml), extracted with methylene chloride (15 ml), dried with Na₂SO₄ and evaporated to the brown oil. The residue was purified by column chromatography (silica gel, CHCl₃) to yield 10-(2-propynyl)-2,7-diazaphenothiazine (72 mg, 60%), mp. 149–150°C. ¹H NMR in CDCl₃: δ 2.57 (t, J = 2.5 Hz, 1H), 4.54(d, J = 2.5 Hz, 2H), 7.14 (m, 2H, H-9, H-4), 8.12 (s, 1H, H-1), 8.22 (d, J = 5.5 Hz, H-3), 8.35 (d, J = 5.5 Hz, H-8), 8.40 (s, 1H, H-6). FAB MS: 240 (M+H, 100), 201 (M—CH₂CCH+1, 45).