[2-Chloro-3-nitro-5-(tri­fluoro­meth­yl)phen­yl](piperidin-1-yl)methanone: structural characterization of a side product in benzo­thia­zinone synthesis

Eckhardt, T.; Goddard, R.; Rudolph, I.; Richter, A.; Lehmann, C.; Imming, P.; Seidel, R.W.

doi:10.1107/S2056989020010658

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ISSN: 2056-9890

Volume 76| Part 9| September 2020| Pages 1442-1446

https://doi.org/10.1107/S2056989020010658

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[2-Chloro-3-nitro-5-(trifluoromethyl)phenyl](piperidin-1-yl)methanone: structural characterization of a side product in benzothiazinone synthesis

Tamira Eckhardt,^a Richard Goddard,^b Ines Rudolph,^a Adrian Richter,^a Christoph Lehmann,^a Peter Imming ^a and Rüdiger W. Seidel ^a ^*

^aInstitut für Pharmazie, 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 14 July 2020; accepted 3 August 2020; online 11 August 2020)

1,3-Benzothiazin-4-ones (BTZs) are a promising new class of anti-tuberculosis drug candidates, some of which have reached clinical trials. The title compound, the benzamide derivative [2-chloro-3-nitro-5-(trifluoromethyl)phenyl](piperidin-1-yl)methanone, C₁₃H₁₂ClF₃N₂O₃, occurs as a side product as a result of competitive reaction pathways in the nucleophilic attack during the synthesis of the BTZ 8-nitro-2-(piperidin-1-yl)-6-(trifluoromethyl)-1,3-benzothiazin-4-one, following the original synthetic route, whereby the corresponding benzoyl isothiocyanate is reacted with piperidine as secondary amine. In the title compound, the nitro group and the nearly planar amide group are significantly twisted out of the plane of the benzene ring. The piperidine ring adopts a chair conformation. The trifluoromethyl group exhibits slight rotational disorder with a refined ratio of occupancies of 0.972 (2):0.028 (2). There is structural evidence for intermolecular weak C—H⋯O hydrogen bonds.

Keywords: benzothiazinones; nitrobenzamides; anti-tuberculosis drugs; reaction mechanism; crystal structure.

CCDC reference: 2021003

1. Chemical context

1,3-Benzothiazin-4-ones (BTZs) are promising anti-tuberculosis drug candidates, some of which have already reached clinical trials (Mikušová et al., 2014 ; Makarov & Mikušová, 2020 ). Various methods for the synthesis of BTZs have been reported (Makarov et al., 2007 ; Moellmann et al., 2009 ; Makarov, 2011 ; Rudolph, 2014 ; Rudolph et al., 2016 ; Zhang & Aldrich, 2019 ). In the original synthesis, 2-chlorobenzoyl chloride derivatives are reacted with ammonium or alkali metal thiocyanates to form the corresponding 2-chlorobenzoyl isothiocyanates (Makarov et al., 2007; Moellmann et al., 2009). These are reactive species and are treated in situ with secondary amines to afford the corresponding thiourea derivatives, which undergo ring closure to give 1,3-thiazin-4-ones via an intramolecular nucleophilic substitution reaction. The latter step is favoured when electron-withdrawing substituents are present on the benzene ring.

Fig. 1 depicts the synthesis following the original procedure for a BTZ previously reported by us (Rudolph, 2014; Rudolph et al., 2016; Richter, Rudolph et al., 2018 ). After treatment of 2-chloro-3-nitro-5-(trifluoromethyl)benzoic acid (1) with thionyl chloride and subsequently ammonium thiocyanate, the corresponding 2-chloro-3-nitro-5-(trifluoromethyl)benzoyl isothiocyanate (2) was reacted with piperidine. As illustrated, nucleophilic attack of the piperidine nitrogen atom at the isothiocyanate carbon atom leads to the anticipated 8-nitro-2-(piperidin-1-yl)-6-(trifluoromethyl)-1,3-benzothiazin-4-one (3). The alternative nucleophilic attack at the carbonyl carbon atom affords the side product (2-chloro-3-nitro-5-(trifluoromethyl)phenyl)(piperidin-1-yl)methanone (4), which was structurally characterized by X-ray crystallography in the present work. The ratio of 3 to 4 was found to vary depending on the reaction conditions. Temperatures at or below 283 K favour the formation of the anticipated 3, whereas substantial amounts of 4 form at elevated temperatures (Rudolph, 2014). Since BTZs are in clinical development [see, for example, Makarov & Mikušová (2020) or Mariandyshev et al. (2020 )], this observation is not only important for the improvement of synthetic yields but also for the compilation of known synthetic side products for drug quality control.

Figure 1
Synthetic pathway from 2-chloro-3-nitro-5-(trifluoromethyl)benzoic acid (1) to BTZ 3 and side product 4, illustrating the two different points of nucleophilic attack of piperidine at the intermediate 2-chloro-3-nitro-5-(trifluoromethyl)benzoyl isothiocyanate (2), resulting in 3 and 4 (Rudolph, 2014

It is interesting to note that dinitrobenzamide derivatives related to 4 have been found to have some anti-mycobacterial activity (Christophe et al., 2009 ; Trefzer et al., 2010 ; Tiwari et al., 2013 ), and the non-chlorinated analogue of 4 was reported to have anticoccidial activity (Welch et al., 1969 ).

2. Structural commentary

Fig. 2 shows the molecular structure of 4 in the solid state. Selected geometric parameters are listed in Table 1. The dihedral angle between the plane of the nitro group and the mean plane of the benzene ring is 38.1 (2)°, which can be attributed to the steric demand of the neighbouring chloro substituent at the benzene ring. The trifluoromethyl group exhibits rotational disorder over two sites with 97.2 (2)% occupancy for the major site. The plane of the amide group, as defined by C8, O3 and N2, is tilted out of the mean plane of the benzene ring by 79.6 (1)°. The Winkler–Dunitz parameters for the amide linkage τ (twist angle) = 1.2° and χ_N (pyramidalization at nitrogen) = 4.0° indicate an almost planar amide group (Winkler & Dunitz, 1971 ). In the IR spectrum (see supporting information), the band at 1639 cm⁻¹ can be assigned to the C=O stretching vibration of the amide group. The molecule is axially chiral, although the centrosymmetric crystal structure contains both enantiomers. The ¹³C NMR spectrum of 4 in methanol-d₄ as well as chloroform-d at room temperature (see supporting information) displays five distinct signals in the aliphatic region, which are assigned to the piperidine carbon atoms, indicating that the rotation about the amide C—N bond is slow in solution under these conditions. The ¹³C NMR chemical shift of the α-carbon atom C13 syn to the carbonyl oxygen atom of the amide group is shielded compared with that of the anti α-carbon atom C9. In chloroform-d, the observed shielding magnitude of Δδ_C = 5.0 ppm is within the range expected for a benzoylpiperidine (Rubiralta et al., 1991 ). In the corresponding ¹H NMR spectrum, the syn protons with respect to the amide carbonyl oxygen atom are deshielded compared with those in the anti position (Δδ_H = 0.58 ppm). Complete assignments of ¹H and ¹³C NMR data in chloroform-d by ¹³C,¹H-HSQC and -HMBC NMR spectra can be found in the supporting information. Notably, the two separated methylene ¹H NMR signals assigned to C10 in chloroform-d appear as one signal in methanol-d₄.

Table 1
Selected geometric parameters (Å, °)

C1—C8	1.510 (3)	C7—F3	1.328 (3)
C2—Cl1	1.725 (2)	C7—F2	1.336 (3)
C3—N1	1.468 (3)	C8—O3	1.234 (2)
C5—C7	1.497 (3)	C8—N2	1.342 (3)
C7—F1	1.325 (3)

C4—C3—N1	116.41 (17)	N2—C9—C10	110.59 (18)
C2—C3—N1	122.35 (18)	C9—C10—C11	110.61 (19)
F1—C7—F3	107.69 (19)	C12—C11—C10	109.74 (18)
F1—C7—F2	105.98 (19)	C13—C12—C11	111.01 (18)
F3—C7—F2	105.59 (17)	N2—C13—C12	111.35 (17)
F1—C7—C5	112.43 (17)	O2—N1—O1	124.48 (17)
F3—C7—C5	112.80 (18)	O2—N1—C3	117.04 (17)
F2—C7—C5	111.86 (17)	O1—N1—C3	118.44 (16)
O3—C8—N2	124.72 (18)	C8—N2—C13	120.26 (16)
O3—C8—C1	118.43 (18)	C8—N2—C9	124.74 (16)
N2—C8—C1	116.85 (17)	C13—N2—C9	114.89 (16)

C4—C3—N1—O2	36.6 (2)	O3—C8—N2—C13	3.0 (3)
C2—C3—N1—O2	−143.29 (19)	C1—C8—N2—C13	−176.62 (17)
C4—C3—N1—O1	−141.34 (18)	O3—C8—N2—C9	179.0 (2)
C2—C3—N1—O1	38.8 (3)	C1—C8—N2—C9	−0.6 (3)

Figure 2
Molecular structure of 4. Displacement ellipsoids are drawn at the 50% probability level. H atoms are represented by small spheres of arbitrary radii. The minor occupancy component of the disordered trifluoromethyl group is depicted by empty ellipsoids.

In the solid state, the piperidine ring in 4 adopts a low-energy chair conformation with some minor angular deviations from ideal tetrahedral values, resulting from planarity at N2 due to involvement in the amide linkage. The puckering parameters of the piperidine six-membered ring, as calculated with PLATON (Spek, 2020 ), are Q = 0.555 (2) Å, θ = 4.1 (2)° and φ = 161 (3)°. By way of comparison, the total puckering amplitude Q is 0.63 Å and the magnitude of distortion θ is 0° for an ideal cyclohexane chair (Cremer & Pople, 1975 ).

3. Supramolecular features

In general, the crystal structure of 4 appears to be dominated by close packing. According to Kitaigorodskii (1973 ), the space group Pbca is among those available for the densest packing of molecules of arbitrary shape. Nevertheless, the solid-state supramolecular structure features C—H⋯O contacts between an aromatic CH moiety and the amide oxygen atom of an adjacent molecule (Fig. 3a). The corresponding geometric parameters (Table 2) support the interpretation as a weak hydrogen bond (Thakuria et al., 2017 ). These interactions link the molecules into strands extending by 2₁ screw symmetry in the [010] direction. The α-methylene groups of the piperidine ring, on which the amide group should exert an electron-withdrawing effect, also form intermolecular C—H⋯O and C—H⋯π contacts, respectively, to the nitro group and the benzene ring of adjacent molecules (Fig. 3b–d). The corresponding geometric parameters (Table 2), however, reveal that these contacts may not have the same significance here as the aforementioned C_aromatic—H⋯O_amide short contact (Wood et al., 2009 ). It is also worth noting that π–π stacking of the aromatic rings is not observed.

Table 2
Hydrogen-bond geometry (Å, °)

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
C6—H6⋯O3ⁱ	0.95	2.59	3.526 (3)	169
C9—H9A⋯O1ⁱⁱ	0.99	2.45	3.361 (3)	154
C9—H9B⋯O1ⁱⁱⁱ	0.99	2.58	3.369 (3)	137
C13—H13A⋯Cg(C1–C6)^iv	0.99	2.92	3.447 (2)	114
Symmetry codes: (i) $[-x+1, y+{\script{1\over 2}}, -z+{\script{1\over 2}}]$ ; (ii) $[-x+{\script{1\over 2}}, y+{\script{1\over 2}}, z]$ ; (iii) x, y+1, z; (iv) $[x+{\script{3\over 2}}, -y+{\script{1\over 2}}, -z]$ .

Figure 3
Short contacts (dashed lines) between adjacent molecules in the crystal structure of 4. The minor component of the disordered trifluoromethyl group is omitted for clarity. Symmetry codes: (i) −x + 1, y + $[{1\over 2}]$ , −z + $[{1\over 2}]$ ; (ii) −x + $[{1\over 2}]$ , y + $[{1\over 2}]$ , z; (iii) x, y + 1, z; (iv) x + $[{3\over 2}]$ , −y + $[{1\over 2}]$ , −z.

4. Database survey

A search of the Cambridge Structural Database (CSD; version 5.41 with March 2020 updates; Groom et al., 2016 ) for related substituted N-benzoyl-piperidine compounds revealed about 30 structures, of which (2-chloro-3,5-dinitrophenyl)(piperidin-1-yl)methanone (CSD refcode: URALIJ; Luo et al., 2011 ) is structurally most related to 4. Similar to 4, the 3-nitro group with the neighbouring chloro substituent is tilted out of the mean plane of the benzene ring by 36.2°. At 75.8°, the dihedral angle between the amide plane and the mean plane of the benzene ring is comparable with that in 4. Likewise, the piperidine ring exhibits a chair conformation with a planar structure at the nitrogen atom. In contrast to 4, the solid-state supramolecular structure of URALIJ exhibits π–π stacking of the aromatic rings. Interestingly, a CSD search for the 2-chloro-3-nitro-5-(trifluoromethyl)phenyl moiety present in 4 led to only one structure, viz. 2-chloro-1,3-dinitro-5-(trifluoromethyl)benzene (JIHNUM; del Casino et al., 2018 ), also known as chloralin, which is active against Plasmodium, but which also shows toxicity in mice.

5. Anti-mycobacterial evaluation

The anti-mycobacterial activity of 4 was evaluated against Mycobacterium smegmatis mc² 155 and Mycobacterium abscessus ATCC19977, using broth microdilution assays [for the assay protocols, see the supporting information and Richter, Strauch et al. (2018 )]. For both mycobacterial species, no growth inhibition was detectable up to a concentration of 100 µM. For M. smegmatis, the findings are consistent with the activity data for a related nitrobenzamide derivative reported by Tiwari et al. (2013). CT319, a 3-nitro-5-(trifluoromethyl)benzamide derivative, however, showed activity against M. smegmatis mc² 155 and other mycobacterial strains (Trefzer et al., 2010).

6. Synthesis and crystallization

Chemicals were purchased and used as received. The synthesis of 1 is described elsewhere (Welch et al., 1969). Solvents were of reagent grade and were distilled before use. The IR spectrum was measured on a Bruker TENSOR II FT–IR spectrometer at a resolution of 4 cm⁻¹. NMR spectra were recorded at room temperature on an Agilent Technologies VNMRS 400 MHz NMR spectrometer (abbreviations: d = doublet, q = quartet, m = multiplet). Chemical shifts are referenced to the residual signals of methanol-d₄ (δ_H = 3.35 ppm, δ_C = 49.3 ppm) or chloroform-d (δ_H = 7.26 ppm, δ_C = 77.2 ppm).

2.7 mL (37.0 mmol) of SOCl₂ were added to a stirred solution of 1 (5.00 g,18.5 mmol) in toluene, and the mixture was heated to reflux for two h. The solvent was subsequently removed under reduced pressure, and the acid chloride thus obtained was used without purification. The residue was taken up in 6.5 mL of acetonitrile and a solution of 1.41 g (18.5 mmol) NH₄SCN in 55 mL of acetonitrile was added dropwise with stirring to obtain 2 in situ. After stirring for 5 min at 313 K, the resulting NH₄Cl precipitate was filtered off, and 3.7 mL (37.0 mmol) of piperidine were added. The mixture was refluxed overnight, and then the solvent was removed under reduced pressure. Water was added to the residue and, after extraction with dichloromethane, the organic phase was washed with 10% aqueous NaHCO₃ and dried over MgSO₄. After removal of the solvent, the crude product was subjected to flash chromatography on silica gel, eluting with ethyl acetate/n-heptane (gradient 10–50% v/v), to isolate 1.09 g (3.0 mmol, 16%) of 3 and a minor amount of the side product 4. ¹H and ¹³C NMR spectroscopic and mass spectrometric data of 3 were in agreement with those in the literature (Rudolph, 2014; Rudolph et al., 2016). Crystals of 4 suitable for X-ray crystallography were obtained from a solution in ethyl acetate/heptane (1:1) by slow evaporation of the solvents at room temperature. NMR spectroscopic data for 4:

¹H NMR (400 MHz, CD₃OD) δ 8.42 (d, ⁴J_meta = 2.2 Hz, 1H, Ar—H), 8.09 (d, ⁴J_meta = 2.2 Hz, 1H, Ar—H), 3.88–3.71 (m, 2H, N—CH₂), 3.33–3.21 (m, 2H, N—CH₂), 1.76 (m, 4H, CH₂), 1.64 (m, 2H, CH₂) ppm; ¹³C NMR (101 MHz, CD₃OD) δ 165.5, 150.7, 141.8, 132.3 (q, ²J_C,F = 35 Hz), 129.2 (q, ³J_C,F = 4 Hz), 128.1, 124.4 (q, ³J_C,F = 4 Hz), 124.1 (q, ¹J_C,F = 273 Hz), 49.5, 44.3, 27.6, 26.7, 25.5 ppm.

¹H NMR (400 MHz, CDCl₃ δ) 8.07 (d, ⁴J_meta = 2.0 Hz, 1H, C4—H), 7.73 (d, ⁴J_meta = 2.0 Hz, 1H, C6—H), 3.83–3.68 (m, 2H, C13—CH₂), 3.22 (ddd, ²J_gem = 13.2 Hz, ³J_vic = 7.1, 4.0 Hz, 1H, C9—CH₂), 3.15 (ddd, ²J_gem = 13.2 Hz, ³J_vic = 7.1, 4.0 Hz, 1H, C9—CH₂), 1.70 (m, 4H, C11, C12—CH₂), 1.65–1.57 (m, 1H, C10—CH₂), 1.56–1.47 (m, 1H, C10—CH₂) ppm; ¹³C NMR (101 MHz, CDCl₃ δ) 163.5 (C8, C=O), 148.9 (C3), 141.1 (C1), 131.2 (q, ²J_C,F = 35 Hz, C5), 127.8 (q, ³J_C,F = 4 Hz, C6), 127.6 (C2), 122.7 (q, ³J_C,F = 4 Hz, C4), 122.4 (q, ¹J_C,F = 273 Hz, C7), 48.3 (C9), 43.3 (C13), 26.7 (C10), 25.7 (C12), 24.6 (C11) ppm.

7. Refinement

Crystal data, data collection and structure refinement details are summarized in Table 3. The rotational disorder of the trifluoromethyl group was refined using a split model with similar distance restraints on the 1,2- and 1,3-distances and equal atomic displacement parameters for opposite fluorine atoms belonging to different disorder sites. Refinement of the ratio of occupancies by means of a free variable resulted in 0.972 (2):0.028 (2). Hydrogen-atom positions were calculated geometrically with C_a—H = 0.95 Å and C_m—H = 0.99 Å (a = aromatic and m = methylene), and refined with the appropriate riding model and U_iso(H) = 1.2 U_eq(C).

Table 3
Experimental details

Crystal data
Chemical formula	C₁₃H₁₂ClF₃N₂O₃
M_r	336.70
Crystal system, space group	Orthorhombic, Pbca
Temperature (K)	100
a, b, c (Å)	18.0904 (7), 7.8971 (3), 19.8043 (8)
V (Å³)	2829.28 (19)
Z	8
Radiation type	Cu Kα
μ (mm⁻¹)	2.88
Crystal size (mm)	0.59 × 0.50 × 0.44

Data collection
Diffractometer	Bruker Kappa Mach3 APEXII
Absorption correction	Gaussian (SADABS; Krause et al., 2015 )
T_min, T_max	0.297, 0.586
No. of measured, independent and observed [I > 2σ(I)] reflections	49954, 2784, 2699
R_int	0.041
(sin θ/λ)_max (Å⁻¹)	0.617

Refinement
R[F² > 2σ(F²)], wR(F²), S	0.043, 0.115, 1.15
No. of reflections	2784
No. of parameters	209
No. of restraints	45
H-atom treatment	H-atom parameters constrained
Δρ_max, Δρ_min (e Å⁻³)	0.32, −0.32
Computer programs: APEX3 (Bruker, 2017 ), SAINT (Bruker, 2004 ), SHELXT2014/4 (Sheldrick, 2015a ), SHELXL2018/3 (Sheldrick, 2015b ), DIAMOND (Brandenburg, 2018 ), enCIFer (Allen et al., 2004 ) and publCIF (Westrip, 2010 ).

Supporting information

CCDC reference: 2021003

Crystal structure: contains datablocks global, I. DOI: https://doi.org/10.1107/S2056989020010658/vm2238sup1.cif

Structure factors: contains datablock I. DOI: https://doi.org/10.1107/S2056989020010658/vm2238Isup2.hkl

Supporting information file. DOI: https://doi.org/10.1107/S2056989020010658/vm2238Isup3.cdx

IR and NMR spectra, assay protocol for anti-mycobacterial activity. DOI: https://doi.org/10.1107/S2056989020010658/vm2238sup4.pdf

Supporting information file. DOI: https://doi.org/10.1107/S2056989020010658/vm2238Isup5.cml

checkCIF report

Computing details top

Data collection: APEX3 (Bruker, 2017); cell refinement: SAINT (Bruker, 2004); data reduction: SAINT (Bruker, 2004); program(s) used to solve structure: SHELXT2014/4 (Sheldrick, 2015a); program(s) used to refine structure: SHELXL2018/3 (Sheldrick, 2015b); molecular graphics: DIAMOND (Brandenburg, 2018); software used to prepare material for publication: enCIFer (Allen et al., 2004) and publCIF (Westrip, 2010).

[2-Chloro-3-nitro-5-(trifluoromethyl)phenyl](piperidin-1-yl)methanone top

Crystal data top

C₁₃H₁₂ClF₃N₂O₃	D_x = 1.581 Mg m⁻³
M_r = 336.70	Cu Kα radiation, λ = 1.54178 Å
Orthorhombic, Pbca	Cell parameters from 9968 reflections
a = 18.0904 (7) Å	θ = 4.9–71.6°
b = 7.8971 (3) Å	µ = 2.88 mm⁻¹
c = 19.8043 (8) Å	T = 100 K
V = 2829.28 (19) Å³	Block, colourless
Z = 8	0.59 × 0.50 × 0.44 mm
F(000) = 1376

Data collection top

Bruker Kappa Mach3 APEXII diffractometer	2784 independent reflections
Radiation source: 0.2 × 2 mm² focus rotating anode	2699 reflections with I > 2σ(I)
MONTEL graded multilayer optics monochromator	R_int = 0.041
Detector resolution: 66.67 pixels mm^-1	θ_max = 72.2°, θ_min = 4.9°
φ– and ω–scans	h = −21→22
Absorption correction: gaussian (SADABS; Krause et al., 2015)	k = −9→9
T_min = 0.297, T_max = 0.586	l = −24→24
49954 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)] = 0.043	Hydrogen site location: inferred from neighbouring sites
wR(F²) = 0.115	H-atom parameters constrained
S = 1.15	w = 1/[σ²(F_o²) + (0.0508P)² + 2.7994P] where P = (F_o² + 2F_c²)/3
2784 reflections	(Δ/σ)_max < 0.001
209 parameters	Δρ_max = 0.32 e Å⁻³
45 restraints	Δρ_min = −0.32 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	Occ. (<1)
C1	0.41556 (10)	0.3250 (3)	0.23581 (10)	0.0230 (4)
C2	0.38370 (10)	0.1651 (3)	0.23833 (10)	0.0224 (4)
C3	0.35007 (10)	0.1004 (3)	0.18023 (10)	0.0227 (4)
C4	0.34763 (10)	0.1927 (3)	0.12111 (10)	0.0243 (4)
H4	0.325215	0.146458	0.081847	0.029*
C5	0.37831 (10)	0.3541 (3)	0.11961 (10)	0.0242 (4)
C6	0.41190 (11)	0.4206 (3)	0.17666 (10)	0.0250 (4)
H6	0.432417	0.531321	0.175487	0.030*
C7	0.37425 (12)	0.4549 (3)	0.05572 (11)	0.0298 (5)
C8	0.45848 (10)	0.3906 (2)	0.29575 (10)	0.0232 (4)
C9	0.34929 (13)	0.5683 (3)	0.32422 (11)	0.0327 (5)
H9A	0.325497	0.503425	0.287381	0.039*
H9B	0.351745	0.688568	0.310277	0.039*
C10	0.30335 (12)	0.5528 (3)	0.38813 (13)	0.0404 (6)
H10A	0.296350	0.431647	0.399304	0.048*
H10B	0.254021	0.603627	0.380559	0.048*
C11	0.34134 (13)	0.6421 (3)	0.44689 (11)	0.0373 (5)
H11A	0.344826	0.764952	0.437412	0.045*
H11B	0.311898	0.626777	0.488581	0.045*
C12	0.41843 (12)	0.5691 (3)	0.45695 (10)	0.0294 (5)
H12A	0.443955	0.632047	0.493365	0.035*
H12B	0.414464	0.449164	0.470978	0.035*
C13	0.46343 (11)	0.5807 (3)	0.39245 (10)	0.0277 (4)
H13A	0.473754	0.701122	0.382205	0.033*
H13B	0.511333	0.522352	0.398982	0.033*
N1	0.31581 (9)	−0.0681 (2)	0.17845 (9)	0.0253 (4)
N2	0.42423 (9)	0.5038 (2)	0.33544 (8)	0.0249 (4)
O1	0.28104 (8)	−0.1161 (2)	0.22819 (8)	0.0324 (4)
O2	0.32229 (8)	−0.1493 (2)	0.12611 (8)	0.0341 (4)
O3	0.52198 (7)	0.33806 (19)	0.30471 (7)	0.0288 (3)
F1	0.38438 (14)	0.3603 (2)	0.00122 (7)	0.0711 (7)	0.972 (2)
F2	0.30831 (8)	0.52847 (19)	0.04797 (8)	0.0418 (4)	0.972 (2)
F3	0.42321 (8)	0.5801 (2)	0.05379 (8)	0.0470 (4)	0.972 (2)
F1'	0.352 (3)	0.612 (3)	0.0688 (18)	0.0711 (7)	0.028 (2)
F2'	0.4387 (11)	0.472 (6)	0.0269 (18)	0.0418 (4)	0.028 (2)
F3'	0.325 (2)	0.397 (5)	0.0129 (15)	0.0470 (4)	0.028 (2)
Cl1	0.38924 (3)	0.05417 (6)	0.31320 (2)	0.02635 (16)

Atomic displacement parameters (Å²) top

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
C1	0.0194 (9)	0.0250 (9)	0.0246 (9)	0.0021 (7)	0.0012 (7)	−0.0019 (8)
C2	0.0186 (8)	0.0246 (9)	0.0239 (9)	0.0021 (7)	0.0011 (7)	0.0002 (8)
C3	0.0166 (8)	0.0219 (9)	0.0296 (10)	0.0011 (7)	0.0009 (7)	−0.0021 (8)
C4	0.0202 (9)	0.0288 (10)	0.0239 (9)	0.0050 (8)	−0.0004 (7)	−0.0031 (8)
C5	0.0219 (9)	0.0261 (10)	0.0247 (10)	0.0056 (8)	0.0021 (7)	0.0011 (8)
C6	0.0248 (10)	0.0226 (9)	0.0277 (10)	0.0006 (8)	0.0004 (8)	0.0002 (8)
C7	0.0350 (11)	0.0292 (11)	0.0251 (10)	0.0056 (9)	0.0005 (8)	−0.0002 (8)
C8	0.0225 (9)	0.0226 (9)	0.0245 (9)	−0.0035 (8)	−0.0003 (7)	0.0033 (8)
C9	0.0335 (11)	0.0298 (11)	0.0347 (11)	0.0094 (9)	−0.0117 (9)	−0.0088 (9)
C10	0.0200 (10)	0.0517 (15)	0.0495 (14)	0.0058 (9)	−0.0038 (9)	−0.0188 (11)
C11	0.0324 (11)	0.0474 (14)	0.0322 (11)	0.0039 (10)	−0.0011 (9)	−0.0114 (10)
C12	0.0308 (11)	0.0327 (11)	0.0247 (10)	−0.0010 (9)	−0.0013 (8)	0.0002 (8)
C13	0.0267 (10)	0.0306 (10)	0.0257 (10)	−0.0070 (8)	−0.0028 (8)	−0.0018 (8)
N1	0.0190 (8)	0.0260 (9)	0.0310 (9)	−0.0009 (6)	−0.0037 (7)	−0.0016 (7)
N2	0.0213 (8)	0.0277 (9)	0.0257 (8)	−0.0010 (7)	−0.0042 (7)	−0.0030 (7)
O1	0.0267 (7)	0.0334 (8)	0.0371 (8)	−0.0062 (6)	0.0010 (6)	0.0028 (7)
O2	0.0348 (8)	0.0320 (8)	0.0356 (8)	−0.0010 (6)	−0.0045 (6)	−0.0098 (7)
O3	0.0204 (7)	0.0324 (8)	0.0337 (8)	0.0005 (6)	−0.0017 (6)	−0.0003 (6)
F1	0.151 (2)	0.0382 (9)	0.0239 (7)	0.0278 (10)	0.0154 (9)	−0.0002 (6)
F2	0.0336 (7)	0.0457 (8)	0.0460 (8)	0.0053 (6)	−0.0056 (6)	0.0175 (7)
F3	0.0389 (8)	0.0567 (10)	0.0453 (8)	−0.0142 (7)	−0.0052 (6)	0.0251 (7)
F1'	0.151 (2)	0.0382 (9)	0.0239 (7)	0.0278 (10)	0.0154 (9)	−0.0002 (6)
F2'	0.0336 (7)	0.0457 (8)	0.0460 (8)	0.0053 (6)	−0.0056 (6)	0.0175 (7)
F3'	0.0389 (8)	0.0567 (10)	0.0453 (8)	−0.0142 (7)	−0.0052 (6)	0.0251 (7)
Cl1	0.0267 (3)	0.0273 (3)	0.0250 (3)	−0.00271 (18)	0.00002 (17)	0.00364 (17)

Geometric parameters (Å, º) top

C1—C2	1.389 (3)	C8—N2	1.342 (3)
C1—C6	1.395 (3)	C9—N2	1.465 (3)
C1—C8	1.510 (3)	C9—C10	1.519 (3)
C2—C3	1.398 (3)	C9—H9A	0.9900
C2—Cl1	1.725 (2)	C9—H9B	0.9900
C3—C4	1.380 (3)	C10—C11	1.525 (3)
C3—N1	1.468 (3)	C10—H10A	0.9900
C4—C5	1.390 (3)	C10—H10B	0.9900
C4—H4	0.9500	C11—C12	1.522 (3)
C5—C6	1.386 (3)	C11—H11A	0.9900
C5—C7	1.497 (3)	C11—H11B	0.9900
C6—H6	0.9500	C12—C13	1.518 (3)
C7—F2'	1.304 (14)	C12—H12A	0.9900
C7—F3'	1.314 (14)	C12—H12B	0.9900
C7—F1	1.325 (3)	C13—N2	1.465 (2)
C7—F3	1.328 (3)	C13—H13A	0.9900
C7—F1'	1.332 (14)	C13—H13B	0.9900
C7—F2	1.336 (3)	N1—O2	1.225 (2)
C8—O3	1.234 (2)	N1—O1	1.229 (2)

C2—C1—C6	120.16 (18)	C10—C9—H9A	109.5
C2—C1—C8	119.82 (17)	N2—C9—H9B	109.5
C6—C1—C8	119.90 (17)	C10—C9—H9B	109.5
C1—C2—C3	118.92 (18)	H9A—C9—H9B	108.1
C1—C2—Cl1	117.93 (15)	C9—C10—C11	110.61 (19)
C3—C2—Cl1	123.13 (16)	C9—C10—H10A	109.5
C4—C3—C2	121.24 (18)	C11—C10—H10A	109.5
C4—C3—N1	116.41 (17)	C9—C10—H10B	109.5
C2—C3—N1	122.35 (18)	C11—C10—H10B	109.5
C3—C4—C5	119.32 (18)	H10A—C10—H10B	108.1
C3—C4—H4	120.3	C12—C11—C10	109.74 (18)
C5—C4—H4	120.3	C12—C11—H11A	109.7
C6—C5—C4	120.33 (18)	C10—C11—H11A	109.7
C6—C5—C7	120.58 (19)	C12—C11—H11B	109.7
C4—C5—C7	119.09 (18)	C10—C11—H11B	109.7
C5—C6—C1	119.98 (19)	H11A—C11—H11B	108.2
C5—C6—H6	120.0	C13—C12—C11	111.01 (18)
C1—C6—H6	120.0	C13—C12—H12A	109.4
F2'—C7—F3'	111.1 (19)	C11—C12—H12A	109.4
F1—C7—F3	107.69 (19)	C13—C12—H12B	109.4
F2'—C7—F1'	105.2 (19)	C11—C12—H12B	109.4
F3'—C7—F1'	104.0 (19)	H12A—C12—H12B	108.0
F1—C7—F2	105.98 (19)	N2—C13—C12	111.35 (17)
F3—C7—F2	105.59 (17)	N2—C13—H13A	109.4
F2'—C7—C5	112.3 (15)	C12—C13—H13A	109.4
F3'—C7—C5	113.2 (15)	N2—C13—H13B	109.4
F1—C7—C5	112.43 (17)	C12—C13—H13B	109.4
F3—C7—C5	112.80 (18)	H13A—C13—H13B	108.0
F1'—C7—C5	110.3 (15)	O2—N1—O1	124.48 (17)
F2—C7—C5	111.86 (17)	O2—N1—C3	117.04 (17)
O3—C8—N2	124.72 (18)	O1—N1—C3	118.44 (16)
O3—C8—C1	118.43 (18)	C8—N2—C13	120.26 (16)
N2—C8—C1	116.85 (17)	C8—N2—C9	124.74 (16)
N2—C9—C10	110.59 (18)	C13—N2—C9	114.89 (16)
N2—C9—H9A	109.5

C6—C1—C2—C3	1.9 (3)	C6—C5—C7—F1'	−47 (3)
C8—C1—C2—C3	−174.16 (17)	C4—C5—C7—F1'	133 (3)
C6—C1—C2—Cl1	−179.32 (15)	C6—C5—C7—F2	−99.4 (2)
C8—C1—C2—Cl1	4.6 (2)	C4—C5—C7—F2	80.3 (2)
C1—C2—C3—C4	−0.5 (3)	C2—C1—C8—O3	77.8 (2)
Cl1—C2—C3—C4	−179.22 (14)	C6—C1—C8—O3	−98.3 (2)
C1—C2—C3—N1	179.37 (16)	C2—C1—C8—N2	−102.6 (2)
Cl1—C2—C3—N1	0.6 (3)	C6—C1—C8—N2	81.4 (2)
C2—C3—C4—C5	−0.9 (3)	N2—C9—C10—C11	55.5 (3)
N1—C3—C4—C5	179.25 (16)	C9—C10—C11—C12	−56.9 (3)
C3—C4—C5—C6	0.9 (3)	C10—C11—C12—C13	55.8 (3)
C3—C4—C5—C7	−178.87 (18)	C11—C12—C13—N2	−53.4 (2)
C4—C5—C6—C1	0.5 (3)	C4—C3—N1—O2	36.6 (2)
C7—C5—C6—C1	−179.75 (18)	C2—C3—N1—O2	−143.29 (19)
C2—C1—C6—C5	−1.9 (3)	C4—C3—N1—O1	−141.34 (18)
C8—C1—C6—C5	174.13 (18)	C2—C3—N1—O1	38.8 (3)
C6—C5—C7—F2'	70 (2)	O3—C8—N2—C13	3.0 (3)
C4—C5—C7—F2'	−110 (2)	C1—C8—N2—C13	−176.62 (17)
C6—C5—C7—F3'	−163 (2)	O3—C8—N2—C9	179.0 (2)
C4—C5—C7—F3'	17 (2)	C1—C8—N2—C9	−0.6 (3)
C6—C5—C7—F1	141.5 (2)	C12—C13—N2—C8	−130.0 (2)
C4—C5—C7—F1	−38.8 (3)	C12—C13—N2—C9	53.6 (2)
C6—C5—C7—F3	19.5 (3)	C10—C9—N2—C8	129.2 (2)
C4—C5—C7—F3	−160.82 (18)	C10—C9—N2—C13	−54.6 (2)

Hydrogen-bond geometry (Å, º) top

D—H···A	D—H	H···A	D···A	D—H···A
C6—H6···O3ⁱ	0.95	2.59	3.526 (3)	169
C9—H9A···O1ⁱⁱ	0.99	2.45	3.361 (3)	154
C9—H9B···O1ⁱⁱⁱ	0.99	2.58	3.369 (3)	137
C13—H13A···Cg(C1–C6)^iv	0.99	2.92	3.447 (2)	114

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

Acknowledgements

We thank Professor Christian W. Lehmann for providing access to the X-ray diffraction facility and Heike Schucht for technical assistance.

Funding information

We acknowledge the financial support within the funding programme Open Access Publishing by the German Research Foundation (DFG).

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