Macozinone: Revised synthesis and crystal structure of a promising new drug for treating drug-sensitive and drug-resistant tuberculosis

Article abstract of DOI:10.1107/S2053229619009185

Mycobacterium tuberculosis (Mtb), the principal etiological agent of tuberculosis (TB), infects over one-quarter of humanity and is now the leading cause of infectious disease mortality by a single pathogen. Macozinone {2-[4-(cyclohexylmethyl)piperazin-1-

Full text of DOI:10.1107/S2053229619009185

research papers
Macozinone: revised synthesis and crystal structure
of a promising new drug for treating drug-sensitive
and drug-resistant tuberculosis
ISSN 2053-2296
a
a,b
Gang Zhang * and Courtney C. Aldrich
*
a
State Key Laboratory of Bioactive Substances and Function of Natural Medicine, Institute of Materia Medica, Peking
Received 10 March 2019
Accepted 26 June 2019
Union Medical College and Chinese Academy of Medical Sciences, Beijing 100050, People’s Republic of China, and
b
Department of Medicinal Chemistry, University of Minnesota, Minneapolis, Minnesota 55455, USA. *Correspondence
e-mail: gzhang@imm.ac.cn, aldri015@umn.edu
Edited by Y. Ohgo, Teikyo University, Japan
Mycobacterium tuberculosis (Mtb), the principal etiological agent of tubercu-
losis (TB), infects over one-quarter of humanity and is now the leading cause of
infectious disease mortality by a single pathogen. Macozinone {2-[4-(cyclo-
hexylmethyl)piperazin-1-yl]-8-nitro-6-(trifluoromethyl)-4H-1,3-benzothiazin-4-
one, C H F N O S} is a promising new drug for treating drug-sensitive and
Keywords: macozinone; crystal structure;
synthesis; drug sensitive; drug resistant; tuber-
culosis.
CCDC reference: 1572644
20
23
3
4
3
drug-resistant TB that has successfully completed phase I clinical trials. We
1
report the complete spectroscopic and structural characterization by H NMR,
Supporting information: this article has
supporting information at journals.iucr.org/c
13
C NMR, HRMS, IR, and X-ray crystallography. The cyclohexyl moiety is
observed to be nearly perpendicular to the core formed by the 1,3-benzothia-
zin-4-one and piperazine groups. The central piperazine ring adopts a slightly
2
distorted chair conformation caused by sp -hybridization of the nitro N atom,
which donates into the electron-deficient 1,3-benzothiazin-4-one group.
1
. Introduction
Tuberculosis (TB) caused by Mycobacterium tuberculosis
Mtb) is the leading source of infectious disease mortality by a
(
single pathogen (WHO, 2018). The emergence of drug-resis-
tant (DR) TB, HIV co-infection, and comorbidity with type II
diabetes mellitus further complicates treatment options and
demands a new generation of TB drugs effective against DR-
TB, compatible with HIV antiretrovirals, and strongly bacter-
icidal to overcome the impaired host immune system in
diabetic and HIV patients.
1,3-Benzothiazin-4-ones (BTZs) are a novel class of TB
drug candidates that possess potent activity against both drug-
susceptible and drug-resistant Mtb strains (Makarov et al.,
2009). Biochemical and genetic studies revealed that BTZs
0
inhibit decaprenylphosphoryl-ꢀ-d-ribose 2 -epimerase (DprE1,
Rv3790), which is a critical flavoenzyme involved in the
biosynthesis of the mycobacterial cell wall (Makarov et al.,
2009). BTZs are bioactivated by the dihydroflavin cofactor
FADH of DprE1 through reduction of the C-8 nitro group to
2
a nitroso intermediate, which covalently reacts with Cys387 in
the enzyme active site to form a semi-mercaptal enzyme-
inhibitor adduct (Trefzer et al., 2010). Macozinone (PBTZ169)
is the most potent BTZ derivative yet described with subna-
nomolar whole-cell activity and has successfully completed
phase I clinical trials. The extraordinary potency of macozi-
none is derived from its covalent mode of inhibition, as well as
the cellular location of the target DprE1 (Trefzer et al., 2010,
2012; Neres et al., 2012; Brecik et al., 2015).
Herein we report the synthesis of macozinone using the
classic Makarov route to the BTZs (Makarov et al., 2007), but
#
2019 International Union of Crystallography
Acta Cryst. (2019). C75, 1031–1035
https://doi.org/10.1107/S2053229619009185 1031

research papers
with slight modification to prepare the requisite 2-chloro-3-
nitro-5-(trifluoromethyl)benzamide building block that avoids
generation of the reactive acid chloride. Macozinone (see
Scheme) was fully characterized by single-crystal X-ray
diffraction (XRD) analysis.
Table 1
Experimental details.
Crystal data
Chemical formula
20 23 3 4 3
C H F N O S
456.48
Monoclinic, P2 /c
1
205
15.051 (7), 5.295 (2), 26.548 (11)
M
r
Crystal system, space group
Temperature (K)
˚
a, b, c (A)
ꢀ
ꢀ
V (A )
( )
˚
97.372 (7)
2098.3 (15)
4
Mo Kꢂ
0.21
3
Z
Radiation type
ꢂ1
ꢃ (mm
Crystal size (mm)
)
0.16 ꢃ 0.15 ꢃ 0.12
Data collection
Diffractometer
Absorption correction
Bruker D8 Venture
Multi-scan (SADABS; Bruker,
2
. Experimental
2013)
2
.1. Chemical synthesis
Tmin, Tmax
No. of measured, independent and
observed [I > 2ꢄ(I)] reflections
0.641, 0.746
11854, 4794, 3412
All chemicals were obtained from commercial sources and
used without further preparation. 2-Chloro-3-nitro-5-(trifluoro-
methyl)benzoic acid was prepared as described (Makarov et
al., 2014). Proton and carbon NMR spectra were recorded in
deuterated solvents on a Varian Mercury 400 MHz spectro-
meter. The chemical shifts are reported in parts per million (ꢁ)
relative to an internal tetramethylsilane (TMS) standard.
Coupling constants are reported in Hertz. IR spectra were
recorded on a Bruker TENSOR FT–IR spectrometer. Melting
points were determined using a Yanaco melting-point appa-
ratus and are uncorrected. Mass spectra were determined on
an Exactive Plus LC/MSD Orbitrap from Thermo Fisher
Scientific.
R
int
0.025
0.654
˚
ꢂ1
)
(sin ꢅ/ꢆ)max (A
Refinement
2
R[F > 2ꢄ(F )], wR(F ), S
No. of reflections
No. of parameters
No. of restraints
H-atom treatment
2
2
0.047, 0.122, 1.05
4794
326
36
H-atom parameters constrained
0.29, ꢂ0.21
˚
ꢂ3
)
Áꢇmax, Áꢇmin (e A
Computer programs: APEX2 (Bruker, 2013), SAINT (Bruker, 2013), SHELXT
Sheldrick, 2015a), SHELXL2018 (Sheldrick, 2015b) and OLEX2 (Dolomanov et al.,
009).
(
2
2.1.1. 2-Chloro-3-nitro-5-(trifluoromethyl)benzamide (2).
(50 ml) and 0.6 N aqueous HCl (50 ml), dried (Mg SO ), and
2 4
To a strirred solution of 2-chloro-3-nitro-5-(trifluoromethyl)-
benzoic acid (2.7 g, 10 mmol, 1.0 equiv.), pyridine (0.50 ml,
filtered. The filtrate was concentrated under reduced pressure
to provide 2 as a white solid [yield 2.42 g, 90%; m.p. 190–
193 C; literature (Welch et al., 1969) 195–197 C]. H NMR
and MS data are consistent with previously reported spectra
(Cooper et al., 2013).
ꢀ
ꢀ
1
6.2 mmol, 0.62 equiv.), and Boc O (2.8 g, 13.0 mmol, 1.3 equiv.)
2
in 1,4-dioxane (10 ml) at room temperature was added
ammonium bicarbonate (1.00 g, 12.6 mmol, 1.26 equiv.). The
reaction was stirred overnight at room temperature and then
2.1.2. 2-[4-(Cyclohexylmethyl)piperazin-1-yl]-8-nitro-6-(tri-
fluoromethyl)-4H-1,3-benzothiazin-4-one (macozinone). Potas-
sium carbonate (0.62 g, 4.5 mmol, 1.2 equiv.) was added to a
partitioned between EtOAc (50 ml) and H O (50 ml). The
2
organic layer was separated, washed consecutively with water
Figure 1
The synthesis of macozinone beginning from 2-chloro-3-nitro-5-(trifluoromethyl)benzoic acid (1), which was directly converted to the benzamide
derivative (2). Condensation of 2 with sodium 4-(cyclohexylmethyl)piperazine-1-carbodithioate (3) afforded macozinone. The synthesis of macozinone
reported by Makarov et al. (2014) is highlighted in blue.
ꢁ
1
032 Zhang and Aldrich
Revised synthesis of macozinone
Acta Cryst. (2019). C75, 1031–1035

research papers
solution of 2-chloro-3-nitro-5-(trifluoromethyl)benzamide (2;
.0 g, 3.7 mmol, 1.0 equiv.), and sodium 4-(cyclohexylmeth-
yl)piperazine-1-carbodithioate (3; 1.25 g, 4.5 mmol, 1.2 equiv.),
1
in dimethylformamide (DMF, 20 ml). The mixture was heated
ꢀ
at 60 C for 2 h and then cooled to room temperature. The
mixture was filtered and the filtrate was concentrated under
reduced pressure. The crude product was purified by flash
chromatography (petroleum ether/ethyl acetate 10:1!5:1!
2
:1!1:1!1:2!1:10!100% ethyl acetate) on silica gel to
afford the title compound (yield 1.36 g, 80%) as a yellow solid
ꢀ
[
m.p. 185–187 C; literature (Makarov et al., 2014) 184–
1
ꢀ
1
1
4
1
86 C]; H NMR (400 MHz, CDCl ): ꢁ 9.10 (d, J = 2.1 Hz,
3
H), 8.75 (d, J = 2.1 Hz, 1H), 3.87–4.15 (m, 4H), 2.47–2.60 (m,
H), 2.17–2.20 (m, 2H), 1.68–1.80 (m, 4H), 1.50–1.58 (m, 1H),
13
.19–1.25 (m, 4H), 0.84–0.93 (m, 2 H); C NMR (100 MHz,
4
CDCl ): ꢁ 166.5, 162.0, 143.9, 134.1, 133.4 (q, J
1
(
(
= 4.0 Hz),
C–F
3
2
29.7 (q, J = 35.0 Hz), 126.8, 126.0 (q, J = 4.0 Hz), 122.4
1
q, J
3
Figure 2
(a) The molecular structure of macozinone and (b) a structural side view
of macozinone.
C–F C–F
= 271 Hz), 65.1, 53.1, 46.6, 35.0, 31.7, 26.7, 26.0; IR
ꢂ1
C–F
KBr) ꢈ (cm ) 2923, 1649, 1298, 1141, 1000, 916, 863, 781;
+
+
HRMS (ESI–TOF ) m/z [M + H] calculated for
+
C H F N O S 457.1516; found 457.1521 (error 1.1 ppm).
4-(cyclohexylmethyl)piperazine-1-carbodithioate (Makarov et
al., 2007) (3) in DMF using the conditions developed by
Makarov et al. (2007) for the synthesis of earlier BTZ deriva-
tives, through nucleophilic aromatic substitution followed by
intramolecular cyclization and concomitant expulsion of
hydrogen sulfide, afforded macozinone in 80% yield. Macozi-
2
0
24
3
4
3
2
.2. Crystal growth of macozinone
Macozinone (5.0 mg) was suspended in ethyl acetate
(
1
EtOAc, 1 ml) and stirred vigorously at room temperature for
6 h. The remaining solid was removed by gravity filtration
and the filtrate was transferred to a 5 ml glass tube. Hexane
3.0 ml) was added slowly on top of the saturated EtOAc
1
13
none was fully characterized by H NMR, C NMR, HRMS
and IR spectroscopy, and single-crystal X-ray diffraction
1
analysis. Previously, only H NMR and HRMS data has been
(
solution of macozinone. The tube was capped and placed in a
cool cabinet in the dark to promote crystallization. After 7 d,
crystals suitable for X-ray diffraction analysis had formed.
provided for macozinone (Makarov et al., 2014). For compar-
ison, we have illustrated the synthesis of macozinone reported
by Makarov (Fig. 1, highlighted in blue), which also began from
1, but used refluxing conditions with thionyl chloride in CHCl3
2.3. Crystal data of macozinone
to obtain the acid chloride that was reacted with ice-cold
ammonium hydroxide under Schotten–Baumann conditions to
yield 2 (Cooper et al., 2013). Reaction of 2 with carbonyl di-
sulfide afforded 2-(methylsulfanyl)-8-nitro-6-(trifluoromethyl)-
A search of the Cambridge Structural Database (CSD,
Version 5.37; Groom et al., 2016) and Scifinder (Version of
018, https://www.cas.org/products/scifinder) revealed no hits.
Crystal data, data collection and structure refinement details
are summarized in Table 1. H atoms were placed in calculated
positions and included as riding contributions with isotropic
displacement parameters. H atoms belonging to aryl groups
were located in difference density maps and were refined
2
4
H-thiochromen-4-one, 4, which was subsequently condensed
with 5-(cyclohexylmethy)piperazine to afford macozinone in
1% yield (Makarov et al., 2014).
7
˚
freely. The aryl H atoms were constrained with C—H = 0.95 A,
˚
the methylene groups with C—H = 0.99 A [U (H) =
iso
˚
.2U (C)] and the methyl groups with C—H = 0.98 A
1
eq
[
U (H) = 1.5U (C)].
iso eq
3
. Results and discussion
3.1. Chemical synthesis
The synthesis of macozinone is shown in Fig. 1, beginning
from 2-chloro-3-nitro-5-(trifluoromethyl)benzoic acid (Maka-
rov et al., 2014) (1), which was directly converted to the benz-
amide derivative (2) in 90% yield under mild room-tempera-
ture conditions by activation with di-tert-butyl dicarbonate
Figure 3
Outline of the unit cell with axes, showing all the molecular entities in the
crystal. Partial crystal disorder exists at the nitro and trifluoromethyl
positions of the target compound.
(Boc O) and subsequent in situ reaction with ammonia derived
from ammonium bicarbonate. Condensation of 2 with sodium
2
ꢁ
Acta Cryst. (2019). C75, 1031–1035
Zhang and Aldrich
Revised synthesis of macozinone 1033

research papers
3
.2. Crystal data
Table 2
Hydrogen-bond geometry (A, ).
˚
ꢀ
A search of the Cambridge Structural Database (CSD,
D—Hꢄ ꢄ ꢄA
D—H
Hꢄ ꢄ ꢄA
Dꢄ ꢄ ꢄA
D—Hꢄ ꢄ ꢄA
Version 5.37; Groom et al., 2016) for the thiopyran-4-one
fragment resulted in 42 hits, of which 10 possessing the most
similar structures were compared with those of the title
compound (Table S5 in the supporting information) (Nara-
simhamurthy et al., 2003; Duvvuru et al., 2012; Gendron et al.,
N2—O2ꢄ ꢄ ꢄH12B
N2—O3ꢄ ꢄ ꢄH13B
0.98 (1)
0.98 (1)
2.68 (1)
2.94 (1)
3.311 (3)
3.844 (15)
123 (1)
153 (1)
Table 2 and Fig. S2 in the supporting information), as well as
the N1 atoms of the 1,3-benzothiazin-4-one group and atom
H10A of 1,4-piperazine (C10—H10Aꢄ ꢄ ꢄN1; Fig. S1 in the
supporting information). The supermolecular aggregate was
formed via the stronger intermolecular hydrogen bond in
three dimensions, which promoted crystallization along the bc-
axis direction in the crystal lattice and crystallization of
2
015; Rosiak et al., 2006; Schmidt et al., 2005; Ramalingam et
al., 1979; Xu et al., 2015; Wang et al., 2011; Mojtahedi et al.,
011; Karisalmi et al., 2003). This is the first small-molecule
2
crystal structure reported for macozinone or any BTZ
analogue.
Macozinone crystallized in the monoclinic system space
group P2 /c (Fig. 2). The key feature of macozinone is the
1
macozinone in the space group P2 /c.
1
planar 1,3-benzothiazin-4-one heterocycle. The dihedral angle
between 1,3-benzothiazin-4-one and the least-squares plane of
the appended piperazine ring is 38.56 (5) . The cyclohexyl ring
is almost perpendicular to the 1,3-benzothiazin-4-one and
piperazine core. In the 1,3-benzothiazin-4-one fragment, the
The crystal structure of the reduced nitroso derivative of
macozinone covalently bound to DprE1 (PDB code: 4ncr) was
determined by Cole and co-workers (Makarov et al., 2014).
Comparison of our single-molecule crystal and the reduced
nitroso macozinone structure of the complex with DprE1
revealed significant differences in the conformations of the
piperazine and cyclohexyl rings. The small-molecule crystal
structure (Fig. 4, I) displays a lower energy classic chair
conformation for the cyclohexyl ring, but a twist-boat
conformation is observed in the adduct structure (Fig. 4, II),
which is presumably caused by the sterically congested
environment in the enzyme active site. Similarly, the piper-
azine adopts the lowest-energy chair conformation in the
single-molecule structure, but a higher-energy distorted chair
conformation in the adduct structure. The implications of this
work directly impinge on future drug-discovery efforts and
suggest the introduction of conformational constraints onto
the piperazine ring of macozinone that enforce the higher-
energy twist-boat conformation (Fig. 4, II) may further
enhance potency. Modifications of drugs that reduce mol-
ecular symmetry and planarity have been shown to improve
aqueous solubility which can in turn enhance membrane
permeability, oral bioavailability, and drug distribution in the
body (Ishikawa et al., 2011; Degorce et al., 2018; Zhang et al.,
ꢀ
˚
C1—S1 bond length is 1.776 (2) A, which is very close to the
reported literature values (Narasimhamurthy et al., 2003;
Duvvuru et al., 2012; Gendron et al., 2015; Rosiak et al., 2006;
Schmidt et al., 2005; Ramalingam et al., 1979; Xu et al., 2015;
Wang et al., 2011; Mojtahedi et al., 2011; Karisalmi et al., 2003).
˚
Similarly, the C4—S1 bond length of 1.739 (2) A and the C1—
ꢀ
S1—C4 bond angle of 100.61 (10) are comparable to the
control crystal structures (Table S4 in the supporting infor-
˚
mation). Interestingly, the C1—N3 bond length of 1.330 (2) A
is much shorter than the calculated C—N bond of N-methyl-
˚
piperazine (1.455 A). The C1—N3—C13, C1—N3—C10, and
C10—N3—C13 angles are 125.62 (17), 120.85 (19), and
1
ꢀ
2
13.11 (17) , respectively, which indicates that atom N3 is sp -
hybridized, driven by resonance stabilization of the nitrogen
lone-pair into the electron-deficient 1,3-benzothiazin-4-one
moiety. The piperazine ring in the structure adopts a slightly
2
distorted chair conformation due to the sp -hybridization of
atom N3, with atoms N3 and N4 deviating by 0.689 and
˚
0.591 A, respectively, from the least-squares plane defined by
atoms C10/C11/C12/C13.
2019).
In the crystal lattice of macozinone, there are four mol-
ecules in each cell unit (Fig. 3). Strong intermolecular
hydrogen-bond interactions were observed between the O
4. Conclusion
atoms of the NO group and atoms H12B and H13B of the 1,4-
2
Macozinone is a promising new drug for treating drug-sensi-
tive and drug-resistant TB that has successfully completed
phase I clinical trials. We report the complete spectroscopic
piperazine moiety (N2—O2ꢄ ꢄ ꢄH13B and N2—O3ꢄ ꢄ ꢄH12B;
1
and structural characterization of macozinone by H NMR,
13
C NMR, HRMS, IR, and X-ray crystallography. The cyclo-
hexyl group is nearly perpendicular to the core formed by the
,3-benzothiazin-4-one and piperazine groups. The central
1
piperazine ring adopts a slightly distorted chair conformation
2
caused by the sp hybridization of the N2 atom, which donates
into the electron-deficient 1,3-benzothiazin-4-one group.
Figure 4
Overlay of small-molecule crystal of macozinone and its fragment from
the cocrystal with DprE1 (PDB code: 4ncr). The small-molecule crystal
structure of macozinone is shown as a cyan stick structure (denoted I) and
the fragment of macozinone from the cocrystal with DprE1 is shown as a
yellow stick structure (denoted II).
Acknowledgements
We are grateful to the Center of Pharmaceutical Polymorphs,
Institute of Materia Medica, Chinese Academy of Medical
ꢁ
1
034 Zhang and Aldrich
Revised synthesis of macozinone
Acta Cryst. (2019). C75, 1031–1035

research papers
Sciences, and Peking Union Medical College for providing
instrument facilities. GZ thanks Dr Hualong Chen for assis-
tance with the crystal data collection and processing.
Makarov, V., Lechartier, B., Zhang, M., Neres, J., van der Sar, A. M.,
Raadsen, S. A., Hartkoorn, R. C., Ryabova, O. B., Vocat, A.,
Decosterd, L. A., Widmer, N., Buclin, T., Bitter, W., Andries, K.,
Pojer, F., Dyson, P. J. & Cole, S. T. (2014). EMBO Mol. Med. 6, 372–
383.
Makarov, V., et al. (2009). Science, 324, 801–804.
Funding information
Mojtahedi, M., Abaee, M., Khakbaz, M., Alishiri, T., Samianifard, M.,
Mesbah, A. & Harms, K. (2011). Synthesis, 2011, 3821–3826.
Narasimhamurthy, T., Benny, J. C. N., Pandiarajan, K. & Rathore, R. S.
Funding for this research was provided by: the CAMS Inno-
vation Fund for Medical Sciences (grant No. CAMS-2017-
I2M-1-011).
(2003). Acta Cryst. C59, o620–o621.
Neres, J., Pojer, F., Molteni, E., Chiarelli, L. R., Dhar, N., Boy-
Rottger, S., Buroni, S., Fullam, E., Degiacomi, G., Lucarelli, A. P.,
Read, R. J., Zanoni, G., Edmondson, D. E., De Rossi, E., Pasca,
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Acta Cryst. (2019). C75, 1031–1035
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supporting information
supporting information
Acta Cryst. (2019). C75, 1031-1035 [https://doi.org/10.1107/S2053229619009185]
Macozinone: revised synthesis and crystal structure of a promising new drug for
treating drug-sensitive and drug-resistant tuberculosis
Gang Zhang and Courtney C. Aldrich
Computing details
Data collection: APEX2 (Bruker, 2013); cell refinement: SAINT (Bruker, 2013); data reduction: SAINT (Bruker, 2013);
program(s) used to solve structure: SHELXT (Sheldrick, 2015a); program(s) used to refine structure: SHELXL2018
(Sheldrick, 2015b); molecular graphics: OLEX2 (Dolomanov et al., 2009); software used to prepare material for
publication: OLEX2 (Dolomanov et al., 2009).
{2-[4-(Cyclohexylmethyl)piperazin-1-yl]-8-nitro-6-(trifluoromethyl)-4H-1,3-benzothiazin-4-one
Crystal data
C
M
20
H
23
F
3
N
4
O
3
S
F(000) = 952
= 1.445 Mg m
−3
r
= 456.48
D
x
Monoclinic, P2
1
/c
Mo Kα radiation, λ = 0.71073 Å
Cell parameters from 4036 reflections
θ = 2.7–27.7°
µ = 0.21 mm
T = 205 K
a = 15.051 (7) Å
b = 5.295 (2) Å
c = 26.548 (11) Å
β = 97.372 (7)°
V = 2098.3 (15) Å
Z = 4
−1
3
Block, colourless
0.16 × 0.15 × 0.12 mm
Data collection
Bruker D8 Venture
diffractometer
4794 independent reflections
3412 reflections with I > 2σ(I)
phi and ω scans
R
int = 0.025
Absorption correction: multi-scan
θmax = 27.7°, θmin = 1.9°
(
SADABS; Bruker, 2014/3)
h = −19→18
k = −6→6
T
min = 0.641, Tmax = 0.746
11854 measured reflections
l = −26→34
Refinement
2
Refinement on F
Hydrogen site location: inferred from
neighbouring sites
Least-squares matrix: full
R[F > 2σ(F )] = 0.047
2
2
H-atom parameters constrained
2
2
2
2
wR(F ) = 0.122
w = 1/[σ (F
o
) + (0.0422P) + 1.0593P]
2
2
S = 1.05
where P = (F
o
+ 2F )/3
c
4
3
3
794 reflections
26 parameters
6 restraints
(Δ/σ)max = 0.001
Δρmax = 0.28 e Å
Δρmin = −0.21 e Å
−
3
−
3
Primary atom site location: dual
Acta Cryst. (2019). C75, 1031-1035
sup-1

supporting information
Special details
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.
Refinement. Single-crystal X-ray diffraction measurements were carried out on a Bruker SMART APEXII CCD
diffractometer at 205.0 K using graphite-monochromated Mo Kα radiation (λ = 0.71070 Å). Absorption correction was
performed with Multi-scan BRUKER SADABS. All structures were solved by direct methods and refined by full-matrix
2
least squares on F using the OLEX 2-1.2 computer program package.
2
Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å )
x
y
z
Uiso*/Ueq
Occ. (<1)
S1
F1
F1A
F2
F2A
F3
F3A
O1
O2
O3
N1
N2
N3
N4
C1
C2
C3
C4
C5
C6
H6
C7
C8
C9
H9
C10
H10A
H10B
C11
H11A
H11B
C12
H12A
H12B
C13
0.52703 (3)
0.8552 (9)
0.8725 (9)
0.9241 (6)
0.9244 (7)
0.65072 (11)
−0.1746 (17)
−0.143 (3)
0.170 (3)
0.184 (2)
0.076 (3)
−0.052 (4)
0.0187 (4)
0.832 (3)
0.42522 (2)
0.4930 (6)
0.4794 (5)
0.4874 (6)
0.5097 (9)
0.5547 (4)
0.5517 (5)
0.34831 (6)
0.5164 (5)
0.5709 (6)
0.34317 (6)
0.53079 (7)
0.33536 (6)
0.28300 (6)
0.36293 (7)
0.36797 (7)
0.42019 (7)
0.44857 (7)
0.49754 (7)
0.51622 (8)
0.548954
0.48713 (8)
0.50615 (10)
0.43980 (8)
0.420233
0.28127 (8)
0.273247
0.260462
0.26915 (7)
0.232706
0.04694 (16)
0.108 (3)
0.111 (4)
0.128 (4)
0.125 (5)
0.102 (3)
0.129 (5)
0.0694 (5)
0.070 (4)
0.081 (4)
0.0487 (4)
0.0526 (5)
0.0515 (5)
0.0434 (4)
0.0425 (5)
0.0464 (5)
0.0413 (5)
0.0372 (4)
0.0410 (5)
0.0468 (5)
0.056*
0.0479 (5)
0.0662 (7)
0.0486 (5)
0.058*
0.0603 (7)
0.072*
0.072*
0.0493 (5)
0.059*
0.54 (2)
0.46 (2)
0.54 (2)
0.46 (2)
0.54 (2)
0.46 (2)
0.8780 (7)
0.8502 (11)
0.63947 (12)
0.5728 (11)
0.6875 (10)
0.54185 (11)
0.63712 (12)
0.43493 (11)
0.26569 (10)
0.50279 (12)
0.61018 (13)
0.65155 (12)
0.61939 (12)
0.66502 (12)
0.73970 (13)
0.769070
0.77130 (13)
0.85604 (17)
0.72686 (13)
0.747755
0.41082 (14)
0.439959
0.431976
0.31140 (14)
0.296009
0.5
0.5
0.755 (3)
0.3384 (4)
0.7050 (4)
0.6421 (4)
0.7797 (3)
0.5254 (4)
0.2030 (5)
0.2764 (4)
0.4688 (4)
0.5100 (4)
0.3740 (4)
0.407636
0.1896 (4)
0.0546 (6)
0.1392 (5)
0.009301
0.5820 (6)
0.424089
0.716647
0.5553 (5)
0.523696
0.409934
0.8181 (5)
0.671138
0.966621
0.8555 (5)
0.291271
0.28611 (15)
0.266122
0.253750
0.38519 (16)
0.287546
0.33727 (7)
0.355248
0.347326
0.35200 (9)
0.059*
0.0543 (6)
0.065*
0.065*
0.0615 (7)
Acta Cryst. (2019). C75, 1031-1035
sup-2

supporting information
H13A
H13B
C14
H14A
H14B
C15
0.404235
0.398081
0.16929 (13)
0.139390
0.148037
0.14244 (13)
0.174017
0.16959 (17)
0.235041
0.144881
0.1376 (2)
0.152016
0.169625
0.0386 (2)
0.006208
0.022299
0.01126 (18)
0.036229
−0.054178
0.04285 (15)
0.028111
0.010587
0.6660 (9)
0.5785 (13)
1.010959
0.873235
0.7631 (5)
0.893787
0.598650
0.7943 (4)
0.663337
1.0481 (5)
1.062146
1.180598
1.0897 (6)
1.262774
0.974292
1.0477 (6)
1.179663
1.060636
0.7948 (6)
0.662908
0.780856
0.7530 (6)
0.580029
0.868432
0.690 (3)
0.850 (4)
0.336436
0.388956
0.26748 (8)
0.285327
0.277928
0.21079 (7)
0.193265
0.19249 (9)
0.198156
0.212410
0.13692 (10)
0.127726
0.116704
0.12409 (11)
0.140110
0.087238
0.14168 (10)
0.121730
0.135811
0.074*
0.074*
0.0508 (5)
0.061*
0.061*
0.0431 (5)
0.052*
0.0625 (6)
0.075*
0.075*
0.0831 (9)
0.100*
0.100*
0.0823 (9)
0.099*
0.099*
0.0745 (8)
0.089*
0.089*
0.0645 (7)
0.077*
0.077*
0.063 (2)
0.080 (4)
H15
C16
H16A
H16B
C17
H17A
H17B
C18
H18A
H18B
C19
H19A
H19B
C20
0.19717 (9)
0.206253
0.217269
0.5751 (5)
0.5140 (6)
H20A
H20B
O3A
O2A
0.5
0.5
2
Atomic displacement parameters (Å )
11
22
33
12
13
23
U
U
U
U
U
U
S1
F1
F1A
F2
0.0422 (3)
0.092 (5)
0.079 (5)
0.0577 (4)
0.053 (3)
0.132 (8)
0.0374 (3)
0.168 (8)
0.107 (5)
0.0079 (2)
0.019 (3)
0.066 (5)
−0.00828 (19)
−0.029 (5)
−0.043 (4)
0.020 (4)
−0.0052 (2)
−0.001 (3)
−0.058 (6)
0.080 (6)
0.040 (3)
0.164 (8)
0.183 (8)
0.031 (3)
F2A
F3
0.048 (4)
0.090 (4)
0.124 (7)
0.0746 (11)
0.072 (6)
0.091 (5)
0.129 (7)
0.174 (11)
0.0853 (13)
0.100 (10)
0.091 (9)
0.0666 (13)
0.0619 (13)
0.0688 (13)
0.0533 (11)
0.0573 (14)
0.0625 (15)
0.0532 (13)
0.0463 (12)
0.0489 (13)
0.0585 (14)
0.221 (12)
0.074 (3)
0.085 (5)
0.0458 (9)
0.035 (4)
0.070 (6)
0.0354 (8)
0.0419 (10)
0.0390 (9)
0.0337 (8)
0.0354 (9)
0.0353 (10)
0.0362 (10)
0.0337 (9)
0.0357 (10)
0.0405 (10)
0.001 (3)
0.048 (4)
0.080 (7)
0.0258 (10)
0.050 (6)
−0.047 (6)
−0.042 (3)
−0.001 (5)
−0.0022 (8)
−0.008 (4)
−0.031 (5)
−0.0031 (7)
−0.0067 (8)
−0.0094 (7)
−0.0065 (6)
−0.0033 (7)
0.0037 (8)
0.0014 (7)
−0.0002 (7)
−0.0018 (7)
−0.0066 (8)
−0.023 (7)
−0.010 (4)
0.042 (6)
F3A
O1
O2
O3
N1
N2
N3
N4
C1
C2
C3
C4
C5
C6
−0.0171 (9)
−0.016 (4)
−0.043 (5)
−0.0064 (9)
−0.0093 (9)
−0.0053 (9)
−0.0019 (8)
0.0010 (9)
−0.0052 (10)
0.0007 (9)
0.0025 (8)
−0.0031 (9)
−0.0007 (10)
0.073 (7)
0.017 (5)
0.0419 (9)
0.0508 (10)
0.0428 (9)
0.0404 (9)
0.0327 (9)
0.0411 (10)
0.0338 (9)
0.0305 (9)
0.0369 (10)
0.0384 (10)
0.0050 (9)
0.0087 (10)
0.0082 (9)
0.0026 (8)
−0.0037 (9)
0.0037 (10)
−0.0008 (9)
−0.0029 (8)
−0.0004 (9)
−0.0007 (10)
Acta Cryst. (2019). C75, 1031-1035
sup-3

supporting information
C7
C8
C9
0.0365 (10)
0.0518 (14)
0.0382 (10)
0.0479 (12)
0.0487 (11)
0.0557 (12)
0.0616 (14)
0.0394 (10)
0.0428 (10)
0.0654 (15)
0.098 (2)
0.0575 (14)
0.0741 (19)
0.0606 (15)
0.098 (2)
0.0646 (15)
0.0663 (16)
0.0593 (15)
0.0706 (16)
0.0447 (12)
0.0550 (15)
0.081 (2)
0.0474 (11)
0.0668 (16)
0.0463 (11)
0.0328 (10)
0.0319 (10)
0.0369 (10)
0.0552 (13)
0.0403 (11)
0.0386 (10)
0.0618 (14)
0.0654 (17)
0.0639 (16)
0.0659 (16)
0.0602 (14)
0.039 (2)
0.0065 (10)
0.0172 (13)
0.0061 (10)
0.0152 (13)
0.0043 (11)
0.0179 (11)
0.0123 (12)
0.0025 (10)
0.0037 (9)
−0.0078 (12)
−0.0008 (17)
0.0223 (17)
0.0025 (14)
−0.0067 (13)
0.011 (4)
−0.0032 (8)
−0.0144 (12)
0.0029 (8)
0.0002 (11)
−0.0065 (14)
−0.0055 (11)
−0.0019 (12)
−0.0067 (10)
−0.0117 (10)
−0.0148 (12)
0.0004 (10)
−0.0023 (9)
0.0056 (12)
0.0278 (16)
0.0081 (15)
−0.0043 (14)
0.0029 (13)
−0.016 (3)
C10
C11
C12
C13
C14
C15
C16
C17
C18
C19
C20
O3A
O2A
−0.0042 (9)
−0.0056 (8)
−0.0095 (9)
−0.0248 (11)
−0.0025 (8)
−0.0070 (8)
−0.0122 (11)
−0.0073 (15)
−0.0313 (15)
−0.0305 (13)
−0.0136 (10)
−0.018 (3)
0.100 (2)
0.0721 (19)
0.078 (2)
0.0796 (18)
0.082 (7)
0.0699 (16)
0.0483 (12)
0.062 (5)
0.090 (8)
0.060 (6)
0.080 (8)
0.026 (5)
−0.027 (6)
−0.020 (5)
Geometric parameters (Å, º)
S1—C1
S1—C4
F1—C8
F1A—C8
F2—C8
1.776 (2)
1.739 (2)
C9—H9
0.9400
0.9800
0.9800
1.496 (3)
0.9800
0.9800
0.9800
0.9800
1.506 (3)
0.9800
0.9800
0.9800
0.9800
1.516 (3)
0.9900
1.504 (3)
1.512 (3)
0.9800
0.9800
1.508 (3)
0.9800
C10—H10A
C10—H10B
C10—C11
C11—H11A
C11—H11B
C12—H12A
C12—H12B
C12—C13
C13—H13A
C13—H13B
C14—H14A
C14—H14B
C14—C15
C15—H15
C15—C16
C15—C20
C16—H16A
C16—H16B
C16—C17
C17—H17A
C17—H17B
C17—C18
1.262 (10)
1.305 (11)
1.342 (9)
1.229 (11)
1.293 (9)
1.347 (10)
1.216 (3)
1.200 (16)
1.253 (14)
1.296 (3)
1.353 (3)
1.455 (3)
1.203 (14)
1.211 (18)
1.330 (2)
1.470 (3)
1.455 (3)
1.444 (3)
1.449 (2)
1.459 (2)
1.496 (3)
1.390 (3)
1.390 (3)
1.407 (3)
1.373 (3)
0.9400
F2A—C8
F3—C8
F3A—C8
O1—C2
O2—N2
O3—N2
N1—C1
N1—C2
N2—C5
N2—O3A
N2—O2A
N3—C1
N3—C10
N3—C13
N4—C11
N4—C12
N4—C14
C2—C3
C3—C4
C3—C9
C4—C5
C5—C6
C6—H6
C6—C7
0.9800
1.501 (4)
0.9800
0.9800
1.494 (4)
0.9800
C18—H18A
C18—H18B
C18—C19
C19—H19A
C19—H19B
C19—C20
0.9800
1.505 (3)
1.368 (3)
Acta Cryst. (2019). C75, 1031-1035
sup-4

supporting information
C7—C8
C7—C9
1.492 (3)
1.372 (3)
C20—H20A
C20—H20B
0.9800
0.9800
C4—S1—C1
C1—N1—C2
O2—N2—O3
O2—N2—C5
O3—N2—C5
O3A—N2—C5
O3A—N2—O2A
O2A—N2—C5
C1—N3—C10
C1—N3—C13
C13—N3—C10
C11—N4—C12
C11—N4—C14
C12—N4—C14
N1—C1—S1
N1—C1—N3
N3—C1—S1
O1—C2—N1
O1—C2—C3
N1—C2—C3
C4—C3—C2
C9—C3—C2
C9—C3—C4
C3—C4—S1
C3—C4—C5
C5—C4—S1
C4—C5—N2
C6—C5—N2
C6—C5—C4
C5—C6—H6
C7—C6—C5
C7—C6—H6
C6—C7—C8
C6—C7—C9
C9—C7—C8
F1—C8—F2
F1—C8—F3
F1—C8—C7
F1A—C8—F3A
F1A—C8—C7
F2—C8—C7
F2A—C8—F1A
F2A—C8—F3A
F2A—C8—C7
F3—C8—F2
100.61 (10)
124.30 (17)
121.8 (11)
119.3 (6)
118.3 (9)
116.8 (9)
N4—C11—H11B
C10—C11—H11A
C10—C11—H11B
H11A—C11—H11B
N4—C12—H12A
N4—C12—H12B
N4—C12—C13
H12A—C12—H12B
C13—C12—H12A
C13—C12—H12B
N3—C13—C12
N3—C13—H13A
N3—C13—H13B
C12—C13—H13A
C12—C13—H13B
H13A—C13—H13B
N4—C14—H14A
N4—C14—H14B
N4—C14—C15
H14A—C14—H14B
C15—C14—H14A
C15—C14—H14B
C14—C15—H15
C16—C15—C14
C16—C15—H15
C16—C15—C20
C20—C15—C14
C20—C15—H15
C15—C16—H16A
C15—C16—H16B
C15—C16—C17
H16A—C16—H16B
C17—C16—H16A
C17—C16—H16B
C16—C17—H17A
C16—C17—H17B
H17A—C17—H17B
C18—C17—C16
C18—C17—H17A
C18—C17—H17B
C17—C18—H18A
C17—C18—H18B
H18A—C18—H18B
C19—C18—C17
C19—C18—H18A
109.4
109.4
109.4
108.0
109.5
109.5
110.69 (18)
108.1
109.5
109.5
110.48 (19)
109.6
109.6
109.6
109.6
108.1
108.8
108.8
113.72 (17)
107.7
108.8
108.8
107.9
111.66 (18)
107.9
110.74 (19)
110.58 (18)
107.9
109.1
109.1
112.4 (2)
107.9
109.1
109.1
109.1
109.1
107.8
123.7 (11)
118.8 (7)
120.85 (19)
125.62 (17)
113.11 (17)
108.74 (16)
111.55 (17)
111.45 (16)
127.78 (15)
119.23 (18)
112.98 (16)
120.73 (19)
118.38 (19)
120.89 (19)
124.04 (17)
115.71 (19)
120.25 (18)
122.06 (14)
116.85 (17)
121.09 (16)
121.74 (18)
116.08 (17)
122.16 (19)
120.1
119.89 (18)
120.1
119.7 (2)
119.47 (19)
120.8 (2)
108.5 (8)
110.5 (7)
112.9 (6)
101.1 (8)
114.4 (5)
112.6 (2)
109.1
109.1
109.3
109.3
108.0
111.5 (2)
109.3
108.4 (5)
105.8 (9)
108.2 (7)
115.5 (7)
102.6 (5)
Acta Cryst. (2019). C75, 1031-1035
sup-5

supporting information
F3—C8—C7
F3A—C8—C7
C3—C9—H9
C7—C9—C3
C7—C9—H9
N3—C10—H10A
N3—C10—H10B
N3—C10—C11
H10A—C10—H10B
C11—C10—H10A
C11—C10—H10B
N4—C11—C10
N4—C11—H11A
113.2 (4)
110.6 (5)
119.3
121.3 (2)
119.3
109.6
109.6
110.19 (17)
108.1
109.6
C19—C18—H18B
C18—C19—H19A
C18—C19—H19B
C18—C19—C20
H19A—C19—H19B
C20—C19—H19A
C20—C19—H19B
C15—C20—H20A
C15—C20—H20B
C19—C20—C15
109.3
109.2
109.2
111.9 (2)
107.9
109.2
109.2
109.0
109.0
113.1 (2)
109.0
109.0
107.8
109.6
111.31 (19)
109.4
C19—C20—H20A
C19—C20—H20B
H20A—C20—H20B
S1—C4—C5—N2
S1—C4—C5—C6
O1—C2—C3—C4
O1—C2—C3—C9
O2—N2—C5—C4
O2—N2—C5—C6
O3—N2—C5—C4
O3—N2—C5—C6
N1—C2—C3—C4
N1—C2—C3—C9
N2—C5—C6—C7
N3—C10—C11—N4
N4—C12—C13—N3
N4—C14—C15—C16
N4—C14—C15—C20
C1—S1—C4—C3
C1—S1—C4—C5
C1—N1—C2—O1
C1—N1—C2—C3
C1—N3—C10—C11
C1—N3—C13—C12
C2—N1—C1—S1
C2—N1—C1—N3
C2—C3—C4—S1
C2—C3—C4—C5
C2—C3—C9—C7
C3—C4—C5—N2
C3—C4—C5—C6
C4—S1—C1—N1
C4—S1—C1—N3
C4—C3—C9—C7
C4—C5—C6—C7
C5—C6—C7—C8
C5—C6—C7—C9
0.2 (3)
C6—C7—C8—F2A
C6—C7—C8—F3
C6—C7—C8—F3A
C6—C7—C9—C3
C8—C7—C9—C3
C9—C3—C4—S1
C9—C3—C4—C5
C9—C7—C8—F1
C9—C7—C8—F1A
C9—C7—C8—F2
C9—C7—C8—F2A
C9—C7—C8—F3
C9—C7—C8—F3A
C10—N3—C1—S1
C10—N3—C1—N1
−67.1 (12)
18.7 (9)
56.3 (13)
1.7 (3)
−175.3 (2)
178.49 (16)
−1.7 (3)
−37.8 (9)
−13.4 (11)
82.5 (9)
109.9 (12)
−164.3 (8)
−126.7 (13)
173.83 (17)
−7.3 (3)
−177.98 (16)
−174.1 (2)
6.2 (3)
1.0 (11)
179.3 (11)
−170.4 (7)
7.9 (8)
5.9 (3)
−173.8 (2)
−179.0 (2)
56.2 (3)
−56.6 (3)
−61.0 (3)
175.2 (2)
−2.88 (19)
177.31 (17)
174.7 (2)
−5.3 (3)
135.4 (2)
−135.5 (2)
0.1 (3)
−178.6 (2)
−1.2 (3)
178.66 (19)
179.5 (2)
−179.62 (18)
2.2 (3)
3.8 (2)
−177.46 (16)
−0.2 (3)
C10—N3—C13—C12
C11—N4—C12—C13
C11—N4—C14—C15
C12—N4—C11—C10
C12—N4—C14—C15
C13—N3—C1—S1
51.9 (3)
61.2 (2)
−73.9 (2)
−61.4 (2)
164.3 (2)
1.8 (3)
−179.3 (2)
−51.6 (3)
175.31 (17)
−175.5 (2)
−175.9 (2)
177.0 (2)
53.5 (3)
52.7 (3)
−53.5 (4)
53.2 (3)
−53.7 (3)
−52.2 (3)
163.6 (6)
C13—N3—C1—N1
C13—N3—C10—C11
C14—N4—C11—C10
C14—N4—C12—C13
C14—C15—C16—C17
C14—C15—C20—C19
C15—C16—C17—C18
C16—C15—C20—C19
C16—C17—C18—C19
C17—C18—C19—C20
C18—C19—C20—C15
C20—C15—C16—C17
O3A—N2—C5—C4
−0.8 (3)
175.8 (2)
−1.2 (3)
Acta Cryst. (2019). C75, 1031-1035
sup-6

supporting information
C6—C7—C8—F1
C6—C7—C8—F1A
C6—C7—C8—F2
145.3 (9)
169.7 (10)
−94.5 (8)
O3A—N2—C5—C6
O2A—N2—C5—C4
O2A—N2—C5—C6
−18.1 (7)
−7.0 (11)
171.2 (11)
Hydrogen-bond geometry (Å, º)
D—H···A
D—H
H···A
D···A
D—H···A
N2—O2···H12B
N2—O3···H13B
0.98 (1)
0.98 (1)
2.68 (1)
2.94 (1)
3.311 (3)
3.844 (15)
123 (1)
153 (1)
Acta Cryst. (2019). C75, 1031-1035
sup-7