Crystal structure and anti­mycobacterial evaluation of 2-(cyclo­hexyl­meth­yl)-7-nitro-5-(tri­fluoro­meth­yl)benzo[d]iso­thia­zol-3(2H)-one

Richter, A.; Goddard, R.; Imming, P.; Seidel, R.W.

doi:10.1107/S2056989023010137

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ISSN: 2056-9890

Volume 79| Part 12| December 2023| Pages 1194-1198

https://doi.org/10.1107/S2056989023010137

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Crystal structure and antimycobacterial evaluation of 2-(cyclohexylmethyl)-7-nitro-5-(trifluoromethyl)benzo[d]isothiazol-3(2H)-one¹

Adrian Richter,^a Richard Goddard,^b Peter Imming ^a and Rüdiger W. Seidel ^a ^*

^aInstitut für Pharmazie, Martin-Luther-Universität Halle-Wittenberg, Wolfgang-Langenbeck-Str. 4, 06120 Halle (Saale), Germany, and ^bMax-Planck-Institut für Kohlenforschung, Kaiser-Wilhelm-Platz 1, 45470 Mülheim an der Ruhr, Germany
^*Correspondence e-mail: ruediger.seidel@pharmazie.uni-halle.de

Edited by L. Van Meervelt, Katholieke Universiteit Leuven, Belgium (Received 22 November 2023; accepted 22 November 2023; online 30 November 2023)

The title compound, C₁₅H₁₅F₃N₂O₃S, crystallizes in the monoclinic system, space group I2/a, with Z = 8. As expected, the nine-membered heterobicyclic system is virtually planar and the cyclohexyl group adopts a chair conformation. There is structural evidence for intramolecular N—S⋯O chalcogen bonding between the benzisothiazolinone S atom and one O atom of the nitro group, approximately aligned along the extension of the covalent N—S bond [N—S⋯O = 162.7 (1)°]. In the crystal, the molecules form centrosymmetric dimers through C—H⋯O weak hydrogen bonding between a C—H group of the electron-deficient benzene ring and the benzothiazolinone carbonyl O atom with an R²₂(10) motif. In contrast to the previously described N-acyl 7-nitro-5-(trifluoromethyl)benzo[d]isothiazol-3(2H)-ones, the title N-cyclohexylmethyl analogue does not inhibit growth of Mycobacterium aurum and Mycobacterium smegmatis in vitro.

Keywords: benzisothiazolinone; benzothiazinone; mycobacteria; hydrogen bonding; crystal structure.

CCDC reference: 2309724

1. Chemical context

Benzisothiazolinones (BITs) are known to exhibit broad-spectrum antimicrobial effects (Gopinath et al., 2017 ). The unsubstituted BIT and other isothiazolinones are widely used as biocides (Silva et al., 2020 ). In the course of our quest for new antimycobacterial agents, we recently reported the N-acyl BITs 1a and 1b (Fig. 1). They displayed in vitro activity against mycobacteria including Mycobacterium tuberculosis (Richter et al., 2022 ), the major etiological agent of tuberculosis. Together with the corresponding S-oxides, they were originally discovered by chance in an attempt to oxidize benzothiazinones at the S atom (BTZs; Eckhardt et al., 2020 ). BTZs, in particular 8-NO₂-BTZs, are a promising class of antituberculosis drug candidates (Seidel et al., 2023 ), two of which have progressed to clinical studies, viz. BTZ-043 and PBTZ-169 (Fig. 1; Makarov & Mikušová, 2020 ). The pyridine-1-carbonyl spiro ketal side chain appended to the N atom in 2-position of the BIT scaffold in 1b is inspired by that of BTZ-043. In an attempt to synthesize the analogous BIT 3 bearing the PBTZ-169-inspired piperazin-1-carbonyl side chain from the precursor 2 and cyclohexylmethyl bromide, we unintentionally obtained 4, the title compound (Fig. 2).

Figure 1
Chemical diagrams of previously reported BITs 1a and 1b exhibiting in vitro antimycobacterial activity (Richter et al., 2022

) and antitubercular BTZs that have advanced to clinical studies (Makarov & Mikušová, 2020

Figure 2
Unintentional formation of 4, the title compound, from the 2-(piperazine-1-carbonyl)-BIT 2 and cyclohexylmethyl bromide.

2. Structural commentary

Fig. 3 shows the molecular structure of 4 in the crystal, and Table 1 lists selected bond lengths and angles. The nine-membered heterobicyclic system is virtually planar with a r.m.s. deviation of 0.0294 Å. The C—C—C bond angles within the benzene ring alternate in magnitude by ca ±2°, with the larger angles being associated with the C atoms bonded to electron-withdrawing groups, viz. C(=O)N, NO₂ and CF₃. The somewhat long C3—O1 distance of 1.226 (3) Å is consistent with the relatively low wavenumber of the carbonyl band at 1630 cm⁻¹ in the IR spectrum (see supporting information), which is typical of amides. The dihedral angle between the BIT mean plane and the plane defined by the three atoms of the nitro group is 11.4 (3)°. The intramolecular S1⋯O2 distance of 2.603 (2) Å and the N2—S1⋯O2 angle of 162.74 (8)° suggest the existence of an intramolecular chalcogen bond on the extension of the covalent N—S bond (Scilabra et al., 2019 ; Vogel et al., 2019 ; Pizzi et al., 2023 ). The orientation of the BIT moiety and the cyclohexylmethyl group to one another renders the molecule axially chiral, although the centrosymmetric crystal structure contains both enantiomeric conformers. The cyclohexyl group adopts a low-energy chair conformation with the C—C—C bond angles being close to the ideal tetrahedral angle (Table 1).

Table 1
Selected geometric parameters (Å, °)

C3—O1	1.226 (3)	C5—C6	1.395 (3)
C3—N2	1.366 (3)	C5—C8	1.488 (3)
C3—C3A	1.463 (3)	C6—C7	1.374 (3)
C3A—C4	1.384 (3)	C7—C7A	1.391 (3)
C3A—C7A	1.402 (3)	C7—N1	1.448 (3)
C4—C5	1.388 (3)	C7A—S1	1.706 (2)

N2—C3—C3A	108.44 (19)	C12—C11—C10	111.2 (2)
C4—C3A—C7A	121.2 (2)	C13—C12—C11	111.3 (2)
C4—C3A—C3	126.9 (2)	C12—C13—C14	110.9 (2)
C7A—C3A—C3	112.0 (2)	C15—C14—C13	111.2 (2)
C6—C7—C7A	121.8 (2)	C14—C15—C10	111.6 (2)
C7—C7A—C3A	118.1 (2)	C3—N2—S1	116.46 (16)
C3A—C7A—S1	112.84 (18)	C9—N2—S1	121.45 (16)
C15—C10—C11	110.53 (19)	C7A—S1—N2	90.24 (10)

Figure 3
Molecular structure of 4. Displacement ellipsoids are drawn at the 50% probability level. H atoms are represented by small spheres of arbitrary radius.

3. Supramolecular features

The most prominent supramolecular feature of the crystal structure of 4 is weak intermolecular C—H⋯O hydrogen bonding. As shown in Fig. 4, the molecules form centrosymmetric dimers through C—H⋯O hydrogen bonds between the C4—H4 moiety of the benzene ring and the carbonyl O atom of an adjacent symmetry-related molecule. The C4—H4 group is likely activated for weak hydrogen bonding through the electron-withdrawing effect exerted by the C(=O)N and CF₃ groups in ortho positions and the NO₂ group in the para position. The graph-set descriptor for the hydrogen-bond motif is $[R_{2}^{2}]$ (10) (Bernstein et al., 1995 ). Table 2 lists the corresponding geometric parameters, which are typical of weak hydrogen bonds (Thakuria et al., 2017 ). The dominance of the short O⋯H contacts is also revealed by a Hirshfeld surface analysis (Spackman & Jayatilaka, 2009 ), as shown in Fig. 5. In addition, H⋯H contacts, mostly resulting from close packing of the cyclohexyl groups, as shown in Fig. 6, are evident. The packing index (Kitaigorodskii, 1973 ) of the crystal structure, as calculated with PLATON (Spek, 2020 ), is 71.6%. Notably, the crystal structure also features a short intermolecular O⋯N contact (2.87 Å) between adjacent molecules related by 2₁ screw symmetry. Intermolecular F⋯F contacts between CF₃ groups are not encountered.

Table 2
Hydrogen-bond geometry (Å, °)

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
C4—H4⋯O1ⁱ	0.95	2.25	3.193 (3)	175
Symmetry code: (i) $[-x+{\script{1\over 2}}, -y-{\script{1\over 2}}, -z+{\script{1\over 2}}]$ .

Figure 4
Centrosymmetric C—H⋯O hydrogen-bonded dimer of 4 in the crystal, viewed along the b-axis direction towards the origin. Dashed lines represent hydrogen bonds. Colour scheme: C, grey; H, white; F, green; N, blue; O, red; S, yellow. Symmetry code: (i) −x + $[{1\over 2}]$ , −y − $[{1\over 2}]$ , −z + $[{1\over 2}]$ .

Figure 5
(a) Hirshfeld surface mapped with d_norm (white areas indicate van der Waals contacts, red areas shorter-than and blue areas longer-than van der Waals contacts) and (b) the corresponding two-dimensional fingerprint plot; d_i and d_e are the respective interior and exterior distances of the nearest atom to the Hirshfeld surface over the range 0.4–2.6 Å (blue, few points; green, moderate fraction; red, many points). The figure was generated with CrystalExplorer (Spackman et al., 2021

Figure 6
Packing diagram of 4, viewed along the b-axis direction. H atoms have been omitted for clarity. Colour scheme: C, grey; F, green; N, blue; O, red; S, yellow.

4. Database survey

As of November 2023, a search of the Cambridge Structural Database (CSD; Groom et al., 2016 ) reveals more than 50 crystal structures containing a BIT scaffold. Specifically, two 7-NO₂-5-CF₃-BITs with 2-(piperidine-1-carbonyl) side chains and their benzisothiazol-3-ol constitutional isomers (Richter et al., 2022) as well as the corresponding BIT 1-oxides (Eckhardt et al., 2020) have previously been structurally characterized by us. Of note, the centrosymmetric C—H⋯O weak hydrogen-bond-dimer motif encountered in the crystal structure of 4 is not found in the BIT structures contained in the CSD. For a data-mining survey of the CSD for a statistical assessment of the chalcogen bond ability of the sulfur atom in BITs and related compounds, we direct the interested reader to the recent publication by Pizzi et al. (2023).

5. Antimycobacterial evaluation

Compound 4 was subjected to in vitro testing against Mycobacterium aurum and Mycobacterium smegmatis using the broth microdilution method, as described previously (Richter et al., 2022). The generally considered non-pathogenic mycobacterial species M. aurum (Gupta et al., 2009 ; Namouchi et al., 2017 ; Phelan et al., 2015 ) and M. smegmatis (Sundarsingh et al., 2020 ) have been used as surrogate bacteria in early-stage antituberculosis drug discovery. Using Middlebrook 7H9 liquid growth medium supplemented with 10% ADS [5% (m/v) bovine serum albumin fraction V, 0.81% (m/v) sodium chloride and 2% (m/v) dextrose in purified water] and 0.05% polysorbate 80, we found no in vitro activity of 4 against M. aurum DSM 43999 and M. smegmatis mc² 155 up to 100 μM. The findings essentially confirm that, similar to antitubercular BTZs (Seidel et al., 2023), the nature of the side chain appended to the N atom in position 2 of the BIT scaffold has a crucial bearing on the antimycobacterial activity (Richter et al., 2022).

6. Synthesis and crystallization

General: Chemicals were of reagent-grade quality and used as received. 7-Nitro-5-(trifluoromethyl)benzo[d]isothiazol-3(2H)-one was prepared as described previously (Richter et al., 2022). Solvents were distilled prior to use and stored over 4 Å molecular sieves. Flash chromatography was performed on an Interchim puriFlash 430 instrument. NMR spectra were recorded on an Agilent Technologies VNMRS 400 MHz or a Varian INOVA 500 MHz NMR spectrometer. ¹H and ¹³C chemical shifts are reported relative to the residual solvent signal of CDCl₃ (δ_H = 7.26 ppm; δ_C = 77.10 ppm) or CD₃OD (δ_H = 4.78 ppm). The ¹⁹F chemical shifts are reported relative to the signal of CFCl₃ (δ_F = 0 ppm) as an external standard. HPLC analysis was conducted with a Shimadzu instrument with a CBM-40 control unit, two LC-40D pumps and an SPD-M40 PDA UV detector, using an Agilent Poroshell 120, EC-C18, 3.0 × 50 mm, 2.7 µm column at a flow rate of 1.2 mL min⁻¹, eluting with water/acetonitrile. APCI mass spectrometry was carried out on an Advion Expression compact mass spectrometer using the direct analysis probe method. The ESI mass spectrum was measured on a Thermo Scientific Q Exactive^TM Plus Orbitrap mass spectrometer and the EI mass spectrum on a Finnigan MAT 95 mass spectrometer. The IR spectrum was recorded on a Bruker Tensor II Platinum ATR spectrometer at a resolution of 4 cm⁻¹, accumulating 16 scans.

Synthesis of 2-(4-Boc-piperazine-1-carbonyl)-7-nitro-5-(trifluoromethyl)benzo[d]isothiazol-3(2H)-one: 7-Nitro-5-(trifluoromethyl)benzo[d]isothiazol-3(2H)-one (600 mg, 2.27 mmol) and 4-Boc-1-piperazinecarbonyl chloride were dissolved in 35 mL of dichloromethane. Pyridine (1.83 mL, 22.7 mmol, 10.0 eq.) was added and the reaction mixture was stirred for 24 h at room temperature. After removal of the solvent in vacuo, the product was isolated as a yellow solid by flash chromatography on silica gel (ethyl acetate/heptane gradient), eluting after the O-acylated constitutional isomer major product (vide infra). Yield: 152 mg (0.32 mmol, 14%). ¹H NMR (500 MHz, CDCl₃): δ 8.79 (m, J = 0.9 Hz, 1H), 8.57 (m, J = 1.0 Hz, 1H), 3.61 (s, 8H), 1.49 (s, 9H) ppm. ¹³C NMR (101 MHz, CDCl₃): δ 161.1, 154.6, 150.0, 142.3, 140.5, 130.5 (q, ³J = 3.7 Hz), 129.9 (q, ²J = 35 Hz), 128.3, 125.8 (q, ³J = 4 Hz), 122.5 (q, ¹J = 273 Hz), 80.7, 46.8, 43.5, 28.5. ¹⁹F NMR (376 MHz, CDCl₃): δ −62.18 ppm. MS(APCI⁺): m/z calculated for C₁₈H₂₀F₃N₄O₆S⁺: 477.1; found: 476.9 [M+H⁺]. The constitutional isomer 7-nitro-5-(trifluoromethyl)benzo[d]isothiazol-3-yl 4-Boc-piperazine-1-carboxylate was isolated as major product in 76% yield (823 mg, 1.72 mmol). ¹H NMR (500 MHz, CDCl₃): δ 8.73 (m, 1H), 8.42 (m, 1H), 3.76 (m, 2H), 3.67–3.52 (m, 6H), 1.50 (s, 9H) ppm. ¹³C NMR (126 MHz, CDCl₃): δ 156.9, 154.6, 151.0, 149.5, 141.4, 129.9, 129.4 (q, ²J = 35 Hz), 126.9 (q, ³J = 4 Hz), 122.8 (q, ¹J = 273 Hz), 121.9 (q, ³J = 3 Hz), 80.8, 45.2, 44.5, 43.4, 28.5 ppm. ¹⁹F NMR (470 MHz, CDCl₃): δ −61.59 ppm. MS(APCI⁺): m/z calculated for C₁₈H₂₀F₃N₄O₆S⁺: 477.1; found: 476.9 [M+H⁺].

Synthesis of 4-(7-nitro-3-oxo-5-(trifluoromethyl)-2,3-dihydrobenzo[d]isothiazole-2-carbonyl)piperazin-1-ium chloride (2): 2-(4-Boc-piperazine-1-carbonyl)-7-nitro-5-(trifluoromethyl)benzo[d]isothiazol-3(2H)-one was dissolved in 1 mL of 4 M HCl in 1,4-dioxane. After stirring overnight at room temperature, compound 2 was collected by filtration to yield 86 mg (0.21 mmol, 65%). ¹H NMR (400 MHz, CD₃OD): δ 8.93 (m, 1H), 8.62 (m, 1H), 3.90–3.85 (m, 4H), 3.46–3.40 (m, 4H). MS(APCI⁺): m/z calculated for C₁₃H₁₂F₃N₄O₄S⁺: 377.1; found: 376.9 [M+H⁺].

Synthesis of 2-(cyclohexylmethyl)-7-nitro-5-(trifluoromethyl)benzo[d]isothiazol-3(2H)-one (4): Compound 2 (50 mg, 0.12 mmol), cyclohexylmethyl bromide (18 µL, 0.13 mmol, 1.1 eq.), potassium iodide (∼1 mg) and potassium carbonate (20 mg, 0.14 mmol, 1.2 eq.) were suspended in 5 mL of acetonitrile. The reaction mixture was stirred at room temperature and the progress of the reaction was monitored by TLC. After the starting material had been consumed, the solvent was removed in vacuo. The residue was subjected to flash chromatography on silica gel (chloroform/heptane gradient) to yield 4 as a yellow powder (14 mg, 0.04 mmol, 33%, HPLC purity >97%). ¹H NMR (400 MHz, CDCl₃): δ 8.70 (m, 1H), 8.48 (m, 1H), 4.39 (d, J = 6.4 Hz, 2H), 2.00–1.88 (m, 3H), 1.84–1.71 (m, 3H), 1.38–1.24 (m, 3H), 1.18–1.08 (m, 2H). ¹³C NMR (101 MHz, CDCl₃) δ 163.3, 149.4, 141.2, 129.1, 128.6 (q, ²J_C,F = 35 Hz), 126.7 (q, ³J_C,F = 4 Hz), 124.4 (q, ¹J_C,F = 273 Hz), 122.0 (q, ³J_C,F = 4 Hz), 75.3, 37.5, 29.8, 26.5, 25.8. HRMS(ESI⁺): m/z calculated for C₁₅H₁₆F₃N₂O₃S⁺: 361.08282; found: 361.08264 [M+H]⁺. MS(EI⁺): m/z calculated for C₁₅H₁₅F₃N₂O₃S⁺: 360; found: 360 [M⁺]. IR(ATR): ν^~ 1630 (C=O). Yellow needles of 4 suitable for single-crystal X-ray diffraction analysis were obtained when a chloroform/heptane solution of the compound slowly evaporated to dryness at room temperature.

7. Refinement

Crystal data, data collection and structure refinement details are given in Table 3. H atoms were placed in geometrically calculated positions and refined using the appropriate riding model, with C_aromatic—H = 0.95 Å, C_methylene—H = 0.99 Å, C_methine—H = 1.00 Å and U_iso(H) = 1.2U_eq(C).

Table 3
Experimental details

Crystal data
Chemical formula	C₁₅H₁₅F₃N₂O₃S
M_r	360.35
Crystal system, space group	Monoclinic, I2/a
Temperature (K)	100
a, b, c (Å)	21.9709 (15), 5.1271 (4), 27.022 (2)
β (°)	93.633 (4)
V (Å³)	3037.8 (4)
Z	8
Radiation type	Mo Kα
μ (mm⁻¹)	0.27
Crystal size (mm)	0.20 × 0.06 × 0.06

Data collection
Diffractometer	Bruker Kappa Mach3 APEXII
Absorption correction	Gaussian (SADABS; Krause et al., 2015 )
T_min, T_max	0.967, 0.992
No. of measured, independent and observed [I > 2σ(I)] reflections	61976, 2836, 2243
R_int	0.100
(sin θ/λ)_max (Å⁻¹)	0.606

Refinement
R[F² > 2σ(F²)], wR(F²), S	0.042, 0.116, 1.04
No. of reflections	2836
No. of parameters	217
H-atom treatment	H-atom parameters constrained
Δρ_max, Δρ_min (e Å⁻³)	0.34, −0.33
Computer programs: APEX3 (Bruker, 2017 ), SAINT (Bruker, 2004 ), SHELXT2014/5 (Sheldrick, 2015a ), SHELXL2019/3 (Sheldrick, 2015b ), DIAMOND (Brandenburg, 2018 ), enCIFer (Allen et al., 2004 ) and publCIF (Westrip, 2010 ).

Supporting information

CCDC reference: 2309724

Crystal structure: contains datablocks global, I. DOI: https://doi.org/10.1107/S2056989023010137/vm2292sup1.cif

Structure factors: contains datablock I. DOI: https://doi.org/10.1107/S2056989023010137/vm2292Isup2.hkl

Supporting information file. DOI: https://doi.org/10.1107/S2056989023010137/vm2292Isup3.cdx

NMR, MS, IR and HPLC data associated with the article. DOI: https://doi.org/10.1107/S2056989023010137/vm2292sup4.pdf

Supporting information file. DOI: https://doi.org/10.1107/S2056989023010137/vm2292Isup5.cml

checkCIF report

Computing details top

2-(Cyclohexylmethyl)-7-nitro-5-(trifluoromethyl)benzo[d]isothiazol-3(2H)-one top

Crystal data top

C₁₅H₁₅F₃N₂O₃S	F(000) = 1488
M_r = 360.35	D_x = 1.576 Mg m⁻³
Monoclinic, I2/a	Mo Kα radiation, λ = 0.71073 Å
a = 21.9709 (15) Å	Cell parameters from 9947 reflections
b = 5.1271 (4) Å	θ = 2.5–28.4°
c = 27.022 (2) Å	µ = 0.27 mm⁻¹
β = 93.633 (4)°	T = 100 K
V = 3037.8 (4) Å³	Needle, yellow
Z = 8	0.20 × 0.06 × 0.06 mm

Data collection top

Bruker Kappa Mach3 APEXII diffractometer	2836 independent reflections
Radiation source: microfocus X-ray source	2243 reflections with I > 2σ(I)
Incoatec Helios mirrors monochromator	R_int = 0.100
Detector resolution: 66.67 pixels mm^-1	θ_max = 25.5°, θ_min = 1.5°
φ and ω scans	h = −26→26
Absorption correction: gaussian (SADABS; Krause et al., 2015)	k = −6→6
T_min = 0.967, T_max = 0.992	l = −32→32
61976 measured reflections

Refinement top

Refinement on F²	Primary atom site location: dual
Least-squares matrix: full	Secondary atom site location: difference Fourier map
R[F² > 2σ(F²)] = 0.042	Hydrogen site location: inferred from neighbouring sites
wR(F²) = 0.116	H-atom parameters constrained
S = 1.04	w = 1/[σ²(F_o²) + (0.0554P)² + 5.9357P] where P = (F_o² + 2F_c²)/3
2836 reflections	(Δ/σ)_max < 0.001
217 parameters	Δρ_max = 0.34 e Å⁻³
0 restraints	Δρ_min = −0.33 e Å⁻³

Special details top

Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s. planes.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å²) top

	x	y	z	U_iso*/U_eq
C3	0.18859 (9)	0.1371 (5)	0.21632 (9)	0.0197 (5)
C3A	0.15790 (10)	0.1247 (5)	0.26275 (8)	0.0183 (5)
C4	0.16991 (10)	−0.0481 (5)	0.30149 (9)	0.0197 (5)
H4	0.201655	−0.173215	0.300101	0.024*
C5	0.13485 (10)	−0.0359 (5)	0.34241 (9)	0.0198 (5)
C6	0.08669 (10)	0.1406 (5)	0.34402 (9)	0.0202 (5)
H6	0.061716	0.142709	0.371460	0.024*
C7	0.07599 (10)	0.3113 (5)	0.30523 (9)	0.0196 (5)
C7A	0.11180 (9)	0.3127 (5)	0.26458 (8)	0.0186 (5)
C8	0.14904 (10)	−0.2056 (5)	0.38629 (9)	0.0217 (5)
C9	0.18439 (10)	0.4007 (5)	0.13941 (8)	0.0207 (5)
H9A	0.227784	0.350627	0.138129	0.025*
H9B	0.181497	0.591480	0.134170	0.025*
C10	0.14732 (10)	0.2631 (5)	0.09739 (8)	0.0209 (5)
H10	0.141760	0.077299	0.107440	0.025*
C11	0.08388 (10)	0.3832 (5)	0.08715 (9)	0.0234 (5)
H11A	0.060785	0.370255	0.117343	0.028*
H11B	0.088125	0.570227	0.078966	0.028*
C12	0.04881 (10)	0.2450 (6)	0.04447 (9)	0.0278 (6)
H12A	0.041006	0.062157	0.053996	0.033*
H12B	0.008923	0.331937	0.037643	0.033*
C13	0.08402 (11)	0.2483 (6)	−0.00212 (9)	0.0283 (6)
H13A	0.088292	0.430440	−0.013581	0.034*
H13B	0.061107	0.149498	−0.028697	0.034*
C14	0.14704 (11)	0.1280 (6)	0.00764 (9)	0.0278 (6)
H14A	0.142728	−0.059395	0.015561	0.033*
H14B	0.169975	0.141924	−0.022619	0.033*
C15	0.18246 (10)	0.2642 (5)	0.05047 (9)	0.0245 (6)
H15A	0.190777	0.446672	0.040981	0.029*
H15B	0.222109	0.175301	0.057240	0.029*
N1	0.02611 (9)	0.4958 (4)	0.30532 (8)	0.0226 (5)
N2	0.16422 (8)	0.3389 (4)	0.18865 (7)	0.0207 (5)
O1	0.22911 (7)	−0.0059 (4)	0.20281 (6)	0.0246 (4)
O2	0.02475 (7)	0.6650 (3)	0.27241 (6)	0.0258 (4)
O3	−0.01168 (8)	0.4766 (4)	0.33673 (7)	0.0300 (4)
F1	0.18323 (6)	−0.4115 (3)	0.37631 (5)	0.0285 (4)
F2	0.17958 (7)	−0.0767 (3)	0.42334 (5)	0.0310 (4)
F3	0.09820 (6)	−0.2979 (3)	0.40528 (5)	0.0289 (4)
S1	0.10703 (2)	0.51050 (12)	0.21373 (2)	0.02003 (18)

Atomic displacement parameters (Å²) top

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
C3	0.0068 (10)	0.0277 (13)	0.0242 (13)	−0.0001 (10)	−0.0013 (9)	−0.0037 (10)
C3A	0.0076 (10)	0.0246 (13)	0.0222 (12)	−0.0019 (9)	−0.0016 (9)	−0.0043 (10)
C4	0.0064 (10)	0.0272 (14)	0.0252 (12)	−0.0005 (9)	−0.0017 (9)	−0.0032 (10)
C5	0.0092 (11)	0.0281 (14)	0.0216 (12)	−0.0024 (9)	−0.0023 (9)	−0.0037 (10)
C6	0.0071 (10)	0.0309 (14)	0.0225 (12)	−0.0028 (10)	0.0006 (9)	−0.0050 (10)
C7	0.0069 (10)	0.0263 (13)	0.0254 (12)	−0.0007 (9)	−0.0005 (9)	−0.0052 (10)
C7A	0.0079 (10)	0.0250 (13)	0.0223 (12)	−0.0004 (9)	−0.0043 (9)	−0.0048 (10)
C8	0.0114 (11)	0.0308 (14)	0.0231 (12)	−0.0011 (10)	0.0029 (9)	−0.0044 (11)
C9	0.0098 (11)	0.0313 (14)	0.0211 (12)	−0.0002 (10)	0.0018 (9)	0.0016 (10)
C10	0.0089 (10)	0.0295 (14)	0.0240 (12)	−0.0012 (10)	−0.0011 (9)	0.0017 (10)
C11	0.0081 (11)	0.0362 (14)	0.0258 (13)	0.0000 (10)	0.0005 (9)	0.0032 (11)
C12	0.0101 (11)	0.0443 (17)	0.0287 (13)	−0.0033 (11)	−0.0020 (10)	0.0013 (12)
C13	0.0143 (12)	0.0441 (17)	0.0259 (13)	−0.0040 (11)	−0.0035 (10)	−0.0006 (12)
C14	0.0178 (12)	0.0401 (16)	0.0253 (13)	0.0008 (11)	0.0008 (10)	−0.0029 (12)
C15	0.0112 (11)	0.0374 (15)	0.0249 (13)	0.0014 (10)	0.0009 (9)	−0.0005 (11)
N1	0.0092 (10)	0.0306 (12)	0.0275 (11)	0.0023 (8)	−0.0015 (8)	−0.0055 (10)
N2	0.0100 (9)	0.0278 (11)	0.0243 (11)	0.0004 (8)	0.0002 (8)	0.0002 (9)
O1	0.0121 (8)	0.0344 (10)	0.0277 (9)	0.0061 (7)	0.0051 (7)	0.0018 (8)
O2	0.0152 (8)	0.0298 (10)	0.0319 (10)	0.0052 (7)	−0.0024 (7)	−0.0004 (8)
O3	0.0132 (9)	0.0445 (12)	0.0331 (10)	0.0060 (8)	0.0074 (8)	−0.0038 (9)
F1	0.0221 (7)	0.0346 (9)	0.0291 (8)	0.0088 (6)	0.0047 (6)	0.0042 (7)
F2	0.0263 (8)	0.0426 (9)	0.0229 (7)	−0.0050 (7)	−0.0073 (6)	−0.0018 (7)
F3	0.0131 (7)	0.0415 (9)	0.0326 (8)	−0.0026 (6)	0.0060 (6)	0.0070 (7)
S1	0.0096 (3)	0.0265 (3)	0.0238 (3)	0.0017 (2)	−0.0003 (2)	−0.0008 (3)

Geometric parameters (Å, º) top

C3—O1	1.226 (3)	C10—C15	1.526 (3)
C3—N2	1.366 (3)	C10—C11	1.533 (3)
C3—C3A	1.463 (3)	C10—H10	1.0000
C3A—C4	1.384 (3)	C11—C12	1.521 (3)
C3A—C7A	1.402 (3)	C11—H11A	0.9900
C4—C5	1.388 (3)	C11—H11B	0.9900
C4—H4	0.9500	C12—C13	1.519 (3)
C5—C6	1.395 (3)	C12—H12A	0.9900
C5—C8	1.488 (3)	C12—H12B	0.9900
C6—C7	1.374 (3)	C13—C14	1.523 (3)
C6—H6	0.9500	C13—H13A	0.9900
C7—C7A	1.391 (3)	C13—H13B	0.9900
C7—N1	1.448 (3)	C14—C15	1.523 (3)
C7A—S1	1.706 (2)	C14—H14A	0.9900
C8—F1	1.333 (3)	C14—H14B	0.9900
C8—F2	1.343 (3)	C15—H15A	0.9900
C8—F3	1.345 (3)	C15—H15B	0.9900
C9—N2	1.464 (3)	N1—O3	1.228 (3)
C9—C10	1.528 (3)	N1—O2	1.241 (3)
C9—H9A	0.9900	N2—S1	1.709 (2)
C9—H9B	0.9900

O1—C3—N2	123.8 (2)	C11—C10—H10	107.8
O1—C3—C3A	127.7 (2)	C12—C11—C10	111.2 (2)
N2—C3—C3A	108.44 (19)	C12—C11—H11A	109.4
C4—C3A—C7A	121.2 (2)	C10—C11—H11A	109.4
C4—C3A—C3	126.9 (2)	C12—C11—H11B	109.4
C7A—C3A—C3	112.0 (2)	C10—C11—H11B	109.4
C3A—C4—C5	119.0 (2)	H11A—C11—H11B	108.0
C3A—C4—H4	120.5	C13—C12—C11	111.3 (2)
C5—C4—H4	120.5	C13—C12—H12A	109.4
C4—C5—C6	121.0 (2)	C11—C12—H12A	109.4
C4—C5—C8	120.6 (2)	C13—C12—H12B	109.4
C6—C5—C8	118.4 (2)	C11—C12—H12B	109.4
C7—C6—C5	118.9 (2)	H12A—C12—H12B	108.0
C7—C6—H6	120.6	C12—C13—C14	110.9 (2)
C5—C6—H6	120.6	C12—C13—H13A	109.5
C6—C7—C7A	121.8 (2)	C14—C13—H13A	109.5
C6—C7—N1	120.5 (2)	C12—C13—H13B	109.5
C7A—C7—N1	117.6 (2)	C14—C13—H13B	109.5
C7—C7A—C3A	118.1 (2)	H13A—C13—H13B	108.0
C7—C7A—S1	129.07 (18)	C15—C14—C13	111.2 (2)
C3A—C7A—S1	112.84 (18)	C15—C14—H14A	109.4
F1—C8—F2	106.21 (18)	C13—C14—H14A	109.4
F1—C8—F3	106.9 (2)	C15—C14—H14B	109.4
F2—C8—F3	106.07 (18)	C13—C14—H14B	109.4
F1—C8—C5	113.21 (19)	H14A—C14—H14B	108.0
F2—C8—C5	112.1 (2)	C14—C15—C10	111.6 (2)
F3—C8—C5	111.90 (18)	C14—C15—H15A	109.3
N2—C9—C10	113.45 (19)	C10—C15—H15A	109.3
N2—C9—H9A	108.9	C14—C15—H15B	109.3
C10—C9—H9A	108.9	C10—C15—H15B	109.3
N2—C9—H9B	108.9	H15A—C15—H15B	108.0
C10—C9—H9B	108.9	O3—N1—O2	124.3 (2)
H9A—C9—H9B	107.7	O3—N1—C7	119.6 (2)
C15—C10—C9	109.99 (19)	O2—N1—C7	116.06 (19)
C15—C10—C11	110.53 (19)	C3—N2—C9	122.1 (2)
C9—C10—C11	112.6 (2)	C3—N2—S1	116.46 (16)
C15—C10—H10	107.8	C9—N2—S1	121.45 (16)
C9—C10—H10	107.8	C7A—S1—N2	90.24 (10)

O1—C3—C3A—C4	2.0 (4)	C6—C5—C8—F3	41.5 (3)
N2—C3—C3A—C4	−178.5 (2)	N2—C9—C10—C15	−161.7 (2)
O1—C3—C3A—C7A	−177.3 (2)	N2—C9—C10—C11	74.5 (3)
N2—C3—C3A—C7A	2.3 (3)	C15—C10—C11—C12	55.4 (3)
C7A—C3A—C4—C5	0.9 (3)	C9—C10—C11—C12	178.9 (2)
C3—C3A—C4—C5	−178.2 (2)	C10—C11—C12—C13	−56.3 (3)
C3A—C4—C5—C6	2.4 (3)	C11—C12—C13—C14	56.3 (3)
C3A—C4—C5—C8	−175.7 (2)	C12—C13—C14—C15	−55.7 (3)
C4—C5—C6—C7	−2.8 (3)	C13—C14—C15—C10	55.6 (3)
C8—C5—C6—C7	175.3 (2)	C9—C10—C15—C14	179.9 (2)
C5—C6—C7—C7A	0.0 (3)	C11—C10—C15—C14	−55.2 (3)
C5—C6—C7—N1	179.4 (2)	C6—C7—N1—O3	−9.8 (3)
C6—C7—C7A—C3A	3.2 (3)	C7A—C7—N1—O3	169.7 (2)
N1—C7—C7A—C3A	−176.3 (2)	C6—C7—N1—O2	170.6 (2)
C6—C7—C7A—S1	−178.69 (19)	C7A—C7—N1—O2	−9.9 (3)
N1—C7—C7A—S1	1.9 (3)	O1—C3—N2—C9	0.7 (3)
C4—C3A—C7A—C7	−3.6 (3)	C3A—C3—N2—C9	−178.87 (19)
C3—C3A—C7A—C7	175.6 (2)	O1—C3—N2—S1	178.73 (18)
C4—C3A—C7A—S1	177.93 (18)	C3A—C3—N2—S1	−0.8 (2)
C3—C3A—C7A—S1	−2.8 (2)	C10—C9—N2—C3	91.3 (3)
C4—C5—C8—F1	−19.4 (3)	C10—C9—N2—S1	−86.6 (2)
C6—C5—C8—F1	162.4 (2)	C7—C7A—S1—N2	−176.2 (2)
C4—C5—C8—F2	100.7 (3)	C3A—C7A—S1—N2	1.96 (17)
C6—C5—C8—F2	−77.5 (3)	C3—N2—S1—C7A	−0.63 (18)
C4—C5—C8—F3	−140.3 (2)	C9—N2—S1—C7A	177.45 (19)

Hydrogen-bond geometry (Å, º) top

D—H···A	D—H	H···A	D···A	D—H···A
C4—H4···O1ⁱ	0.95	2.25	3.193 (3)	175

Symmetry code: (i) −x+1/2, −y−1/2, −z+1/2.

Footnotes

¹Dedicated to Professor Martin Feigel on the occasion of his 75th birthday.

Acknowledgements

We thank Professor Christian W. Lehmann for providing access to the X-ray diffraction facility, Heike Schucht for technical assistance with the X-ray intensity data collection, Dirk Kampen and Simone Marcus for measuring the ESI and EI mass spectra and Dr Christian Heiser for recording the IR spectrum. Thanks are also due to Dr Jens-Ulrich Rahfeld, Dr Nadine Taudte and Nadine Jänckel for providing and maintaining the biosafety level 2 laboratory. We acknowledge the financial support of the Open Access Publication Fund of the Martin-Luther-Universität Halle-Wittenberg.

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