Synthesis of aryl propionamide scaffold containing a pentafluorosulfanyl moiety as SARMs

Article abstract of DOI:10.3390/molecules24234227

The pentafluorosulfane (SF₅) group, as a more electronegative bioisostere than the trifluoromethyl (CF₃) group, has been gaining greater attention and increasingly reported usage in medicinal chemistry. Ostarine is the selective androgen receptor modulators (SARMs) containing a CF₃ group in clinical trial III. In this study, 21 ostarine derivatives for replacing the CF₃ group with SF₅ substituents were synthesized. Some SF₅-derivatives showed androgen receptor (AR) agonistic activities in vitro. The results pointed to the potential of using this scaffold to develop new AR agonists.

Full text of DOI:10.3390/molecules24234227

Article
Synthesis of Aryl Propionamide Scaffold Containing
a Pentafluorosulfanyl Moiety as SARMs
1,†
2,†
2
2,
1
1,
Pingxuan Shao , Yan Zhou , Dehua Yang , Ming-Wei Wang *, Wei Lu and Jiyu Jin *
1
Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development,
School of Chemistry and Molecular Engineering, East China Normal University, 3663 North Zhongshan
Road, Shanghai 200062, China
The National Center for Drug Screening and the CAS Key Laboratory of Receptor Research, S
2
hanghai Institute of Materia Medica, Chinese Academy of Sciences (CAS),
189 Guo Shou Jing Road, Shanghai, China
* Correspondence: mwwang@simm.ac.cn (M.-W.W.); jyjin@chem.ecnu.edu.cn (J.J.)
†
These two authors contributed equally to this work.
Received: 18 October 2019; Accepted: 18 November 2019; Published: 20 November 2019
Abstract: The pentafluorosulfane (SF
trifluoromethyl (CF ) group, has been gaining greater attention and increasingly reported usage in
medicinal chemistry. Ostarine is the selective androgen receptor modulators (SARMs) containing a
CF group in clinical trial III. In this study, 21 ostarine derivatives for replacing the CF group with
SF substituents were synthesized. Some SF -derivatives showed androgen receptor (AR) agonistic
5) group, as a more electronegative bioisostere than the
3
3
3
5
5
activities in vitro. The results pointed to the potential of using this scaffold to develop new AR
agonists.
Keywords: pentafluorosulfanyl; aryl propionamide; androgen receptor; agonist; SARMs
1. Introduction
Fluorine has been used widely in drug design and development, and 20–25% of pharmaceuticals
contain a fluorine atom at present [1]. It is known that the existence of fluorine can influence
electrostatic interactions and hydrogen bonding of a ligand [2]. Besides, the introduction of fluorine
into a compound can change its lipophilicity, pKa, and metabolic stability [1]. Direct fluorination and
addition of fluorinated functional groups are common methods to incorporate fluorine. The most
common example of functional groups is trifluoromethyl (CF
The pentafluorosulfanyl (SF ) group, not only a bioisostere of the CF
greater attention and increasingly reported usage in medicinal chemistry according to the literature
[3–5]. Some of the special properties of SF have been described, such as chemical and hydrolytically
stability [5], steric demand and symmetry (volume of SF is slightly less than t-butyl and greater than
CF ), electron-withdrawing effect [6,7], electronegativity (SF = 3.65, CF = 3.36), and nontoxicity of its
degradation products [3]. However, the synthetic accessibility of the SF group has limited its use.
Access to SF -substituted benzenes is primarily accomplished through two methods, namely,
treatment of thiophenols with fluorine gas and chlorofluorination of dibenzyl disulfides to give
3
).
5
3
group, has been gaining
5
5
3
5
3
5
5
chlorotetrafluorosulfanyl benzenes (ArSF
shortcomings of these methods may include low yield and reaction safety. SF
blocks are attractive due to their reported bioactivities [9].
4
Cl), which are, in turn, fluorinated to SF
5
analogs [7,8]. The
-bearing building
5
Androgen exerts its action via the androgen receptor (AR). Upon activation, AR translocates to
the nucleus to mediate both androgenic and anabolic effects. Selective androgen receptor modulators
(SARMs) bind AR and display tissue-selective activation of androgenic signaling [10–12]. Several
nonsteroidal SARMs, such as ostarine [13,14], GSK2881078 [15], and LGD4033 [16], were developed
Molecules 2019, 24, 4227; doi:10.3390/molecules24234227
www.mdpi.com/journal/molecules

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for clinical trials (Figure 1). Among them, ostarine was shown to improve muscle functions in patients
with cancer cachexia [17].
It appears that the strong electron-withdrawing effect of trifluoromethyl in SARMs plays a key
role in AR binding [18–20]. Since none of the reported SARMs bears SF5 moiety, we decided to study
the possibility and effect of replacing the CF3 group with SF5 substituents.
Figure 1. Structures of testosterone and selected SARMs (selective androgen receptor modulators).
2. Results and Discussion
2.1. Chemistry
Meta-SF5 derivatives 12a–g and 13a–g were prepared, as illustrated in Scheme 1. 3-
(pentafluorosulfanyl)aniline (1) was brominated with 1,3-Dibromo-5,5-dimethylhydantoin in DMAc
(N,N-dimethylacetamide) in order to form compound 4-Bromo-3-(pentafluorosulfanyl)aniline (2).
The second step consisted of the aromatic nucleophilic displacement of bromide from compound 2
using copper cyanide, leading to the formation of 4-amino-2-(pentafluorosulfanyl)benzonitrile (3).
(R)-N-methacryloylproline 6, prepared using D-proline (5) and methacryloyl chloride (4), was
reacted with N-bromosuccinimide in DMF (N,N-dimethylformamide) to afford bromolactone 7 as a
single enantiomer. Acidic hydrolysis with aqueous HBr then produced the key intermediate (R)-3-
Bromo-2-hydroxy-2-methylpropanoic acid (8) [21]. Amide coupling with anilines 1,3 using thionyl
chloride produced chiral anilides 9–10. Amide derivatives 9–10 were reacted with different
commercial phenols (11a–g) using potassium carbonate in 2-propanol to give the desired (S)-meta-SF5
derivatives (12a–g, 13a–g).
Para-SF5 derivatives 16a–g were prepared, as illustrated in Scheme 2. Amide coupling with 4-
(pentafluorosulfanyl)aniline (14) using thionyl chloride produced chiral anilide 15. Amide derivative
15 was reacted with different commercial phenols (11a–g) using potassium carbonate in 2-propanol
to give the desired (S)-para-SF5 derivatives (16a–g).

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Scheme 1. Synthesis of (S)-meta-SF5 derivatives 12a–g, 13a–g. Reagents and conditions: (a) DBDMH
(1,3-Dibromo-5,5-dimethylhydantoin), DMAc, 10 °C 30 min; (b) CuCN, NMP (1-Methyl-2-
pyrrolidinone）, 180 °C, 2 h; (c) 2N NaOH, Acetone, 0 °C to rt, 3 h; (d) NBS (N-Bromosuccinimide),
DMF, rt, 16 h; (e) 20% HBr(aq), reflux, 16 h; (f) 8, SOCl2, DMAc, –10 °C, 3 h followed by 21, DMAc, rt,
16 h; (g) K2CO3, 2-Propanol, reflux, 4 h.
Scheme 2. Synthesis of (S)-para-SF5 derivatives 16a–g. Reagents and conditions: (a) 8, SOCl2, DMAc, -
10 oC, 3 h followed by 14, DMAc, rt, 16 h; (b) K2CO3, 2-Propanol, reflux, 4 h.
2.2. AR Activity In Vitro
All compounds listed in Tables 1 and 2 were evaluated in vitro for their agonist activities using
a luciferase reporter gene assay with CV-1 (Cercopithecus aethiops kidney cell line) and C2C12 cells

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(mouse myoblast cell line) expressing AR. The results of the reference compound (ostarine) are also
shown for comparison in Table 1.
Accordingly, with cyano and SF5 moieties, a series of para-substituted O-linked analogs were
synthesized. All of these compounds displayed different degrees of AR agonist activity in CV-1 cells
(Table 1). The introduction of the methoxy and N-amide groups as an electron-donating group on the
para-phenyl ring (13e,g) resulted in significantly decreased AR agonist activity. When electron-
withdrawing groups were introduced, compounds 13b, 13c, 13d, and 13f exhibited weak agonist
activity (Table 1). The remaining compounds exhibited less than 66% efficacy of 1 μM
dihydrotestosterone (DHT) at the concentrations tested. When the para-position of the phenyl ring
was cyano moiety as an electron-withdrawing group, compound 13a showed potent agonist activity:
30 μM elicited 89.5% of the efficacy observed with 1 μM DHT, similar to that of ostarine (85.8%
efficacy). The agonistic activity of the compounds in C2C12 cells was comparable.
To investigate the importance of the cyano moiety, compound series 12a–g and 16a–g in which
the cyano is absent, were synthesized. Unfortunately, 16a–g in which the SF5 group as a bioisostere
of the SF3 group is in the para position were completely inactive, and analogs 12a–g bearing only SF5
group at meta position lost AR agonist activity (Table 2). Thus, cyano moiety is required for AR
agonism.
Table 1. AR (androgen receptor) agonist activity of ostarine derivatives.
Agonist activity in CV-1
Agonist activity in C2C12
Compounds
EC50 (nM)
3.1 ± 0.9
Efficacy (%)
100
EC50 (nM)
0.1 ± 0.03
Efficacy (%)
100
DHT
Ostarine
13a
13b
13c
13d
13e
13f
13g
1.7 ± 0.1
80.3 ± 74.5
28.1 ± 3.3
180.0 ± 116.0
1449.5 ± 99.7
426.8 ± 387.8
15.1 ± 7.2
85.8 ± 7.4
89.5 ± 15.4
46.1 ± 11.3
66.3 ± 2.8*
51.2 ± 10.3
65.1 ± 10.0
46.0 ± 5.2*
26.6 ± 15.2
3.9 ± 1.3
119.7 ± 109.9
42.1 ± 21.7
196.6 ± 110.0
1035.8 ± 643.1
305.3 ± 161.7
66.9 ± 19.7
81.9 ± 11.6
80.8 ± 8.1
45.8 ± 21.9
69.9 ± 5.9*
53.2 ± 7.9*
68.4 ± 16.9
57.3 ± 16.3
42.1 ± 6.9
1135.0 ± 357.8
921.4 ± 112.5
Data presented are means ± SD of three independent experiments. EC50, half maximal effective concentration.
Table 2. AR agonist activity of aryl propionamide derivatives.
Agonist activity in CV-1
Agonist activity in CV-1
Compounds
Compounds
EC50 (nM)
Efficacy (%)
EC50 (nM)
1.7 ± 0.1
NA
Efficacy (%)
85.8 ± 7.4
NA
DHT
12a
3.1 ± 0.9
100
Ostarine
16a
1508 ± 429.9
9.1 ± 6.5

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12b
12c
12d
12e
12f
12g
51213.5 ± 5806.1
1282 ± 79.2
NA
5.2 ± 3.6
6.7 ± 4.9
NA
1.6 ± 1.4
5.7 ± 9.5
0.3 ± 1.6
16b
16c
16d
16e
16f
16g
NA
NA
NA
NA
NA
NA
NA
NA
NA
0.7 ± 2.2
1.5 ± 0.5
NA
12733.5 ± 2144.7
NA
2144.0 ± 694.4
Data presented are the means ± SD of three independent experiments. NA, not active.
3. Materials and Methods
All reagents were commercially available and were used without further purification. The
solvents used were of analytical grade. Melting points were taken on a Fisher Johns melting point
1
13
apparatus, uncorrected, and reported in degrees centigrade. H NMR and C NMR spectra were
scanned on a Bruker DRX-400 (400 MHz) using tetramethylsilane (TMS) as internal standard and one
or two of the following solvents: DMSO-d6 and CDCl3. Chemical shifts were given in δ, ppm. Splitting
patterns were designated as follows: s: singlet; d: doublet; t: triplet; q: quartet; m: multiplet. The mass
spectra (MS) were recorded on a Finnigan MAT-95 mass spectrometer. The purity of all testing
compounds was established by HPLC to be >95%. HPLC analysis was performed at room
temperature using an Agilent Eclipse XDBC18 (250 mm × 4.6 mm) and as a mobile phase gradient
from 5% MeCN/H2O (1‰ TFA (trifluoroethanoic acid)) for 1 min, 5% MeCN/H2O (1‰ TFA) to 95%
MeCN/H2O (1‰ TFA) for 9 min, and 95% MeCN/H2O (1‰ TFA) for 5 min more, a flow rate of 1
mL/min, and plotted at 254 nm (Supplementary Materials).
3.1. General Synthesis
4-Bromo-3-(pentafluorosulfanyl)aniline (2)
In a 100 mL round-bottomed flask, 3-(pentafluorosulfanyl)aniline (1) (2 g, 9.13 mmol, 1 eq) in 15
mL DMAc was added to give a yellow solution. The reaction mixture was cooled to −20 °C with
stirring on. Then, 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione (1.435 g, 5.02 mmol, 0.55 eq) was
added in 10 mL DMAc. The reaction mixture was held at –20 °C with stirring on for 16 h. The 100 mL
water was added. The aq layer was backextracted with EA. The organic layers were combined and
washed with water and brine. The organic was dried with Na2SO4, filtered, and concentrated to give
crude product 3.3 g. The crude product was purified by column chromatography to give 4-Bromo-3-
1
(pentafluorosulfanyl)aniline (2) (1.7 g, 62.5% yield) as an orange oil. H NMR (400 MHz, CDCl3) δ
19
7.47 (d, J = 8.8 Hz, 1H), 7.12 (s, 1H), 6.97 (d, J = 8.8 Hz, 1H), 4.30 (s, 2H). F NMR (376 MHz, CDCl3) δ
13
84.81–82.68 (m, 1F), 65.22 (d, J = 152 Hz, 4F). C NMR (101 MHz, CDCl3) δ 154.32, 154.15, 153.98,
145.52, 136.59, 118.89, 116.06, 116.01, 115.96, 115.90, 104.15. ESI-MS m/z: 297.97, 300.14 [M + H, M +
+
2H] .
4-amino-2-(pentafluorosulfanyl)benzonitrile (3)
In a 100 mL round-bottomed flask, 4-Bromo-3-(pentafluorosulfanyl)aniline (2) (1.7 g, 5.70 mmol,
1 eq) and cyanocopper (0.613 g, 6.84 mmol, 1.2 eq) were added in 30 mL NMP (1-Methyl-2-
pyrrolidinone） to give a brown solution. The reaction vessel was purged with nitrogen. The reaction
was heated to 180 °C with stirring on for 4 h. Then, 100 mL 25% EDA (ethylenediamine) (aq) was
added. The aq layer was backextracted with EA. The organic layers were combined and washed with
25% EDA (aq) and brine. The organic was dried with Na2SO4, filtered, and concentrated to give crude
product 1.5 g. The crude product was purified by column chromatography to give 4-amino-2-
1
(pentafluorosulfanyl)benzonitrile (3) (1.05 g, 75% yield) as orange solid. m.p. 149–151 °C; H NMR
19
(400 MHz, CDCl3) δ 7.54 (d, J = 8.4 Hz, 1H), 7.09 (s, 1H), 6.76 (d, J = 8.4 Hz, 1H), 4.46 (s, 2H). F NMR
13
(376 MHz, CDCl3) δ 82.40–80.21 (m, 1F), 65.27 (d, J = 151.1 Hz, 4F). C NMR (101 MHz, CDCl3) δ
+
156.35, 150.29, 136.39, 117.38, 116.09, 113.80, 97.05. ESI-MS m/z: 245.25 [M + H] .
methacryloyl-D-proline (6)

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A solution of methacryloyl chloride (4) (17.49 mL, 181 mmol, 1.04 eq) in 100 mL acetone was
added to a solution of D-proline (5) (20 g, 174 mmol, 1 eq) in 2M NaOH (100 mL, 200 mmol, 1.15 eq)
and 100 mL acetone dropwise at 0 °C for 30 min. The pH of the reaction mixture was maintained
within 10~11 range via simultaneous dropwise addition of 5 mL 2M NaOH (aq) during the addition
of methacryloyl chloride. The reaction mixture was warmed up to room temperature with stirring on
for 16 h. The mixture was concentrated by rotovap. The reaction mixture was washed with Et2O.
Then, 150 mL 2M HCl was added to adjust pH to 2. The aq layer was backextracted with EA. The
organic layers were combined and washed with sat.NaCl (aq). The organic was dried with Na2SO4,
filtered, and concentrated to give methacryloyl-D-proline (6) (31.5 g, 99% yield) as white solid. The
1
crude product was used until the next step without further purification. m.p. 102–104 °C; H NMR
(400 MHz, CDCl3) δ: 9.78 (s, 1H), 5.32 (d, J = 9 Hz, 1H), 5.25–5.03 (m, 1H), 4.57 (s, 1H), 3.63 (s, 2H), 2.22
(dd, J = 14.7, 7.7 Hz, 2H), 2.07–1.84 (m, 5H).
(3R,8aR)-3-(bromomethyl)-3-methyltetrahydro-1H-pyrrolo[2,1-c][1,4]oxazine-1,4(3H)-dione (7)
In a 500 mL round-bottomed flask, methacryloyl-D-proline (6) (31.5 g, 172 mmol, 1 eq) in 150
mL anhydrous DMF was added to give a colorless solution. The reaction vessel was purged with
nitrogen. The reaction mixture was cooled to 0 °C with stirring on for 30 min. 1-bromopyrrolidine-
2,5-dione (61.2 g, 344 mmol, 2 eq) in 150 mL anhydrous DMF was added dropwise at 0 °C for 120
min. The reaction mixture was warmed up to room temperature with stirring on for overnight. The
mixture was concentrated by rotovap. Then, 1000 mL EA (ethyl acetate) was added. The organic was
washed with sat.NaHCO3, water, and brine. The organic was dried with Na2SO4, filtered, and
concentrated to give the crude product. Then, 30 mL EA and 150 mL Et2O were added. The product
was filtered through sintered glass funnel with 30 mL Et2O to give (3R,8aR)-3-(bromomethyl)-3-
methyltetrahydro-1H-pyrrolo[2,1-c][1,4]oxazine-1,4(3H)-dione (7) (40 g, 89% yield) as white solid.
1
m.p. 158–160 °C; H NMR (400 MHz, DMSO) δ 4.77–4.66 (m, 1H), 4.03 (d, J = 11.5 Hz, 1H), 3.87 (d, J =
11.3 Hz, 1H), 3.52 (dd, J = 18.7, 9.2 Hz, 1H), 3.40 (t, J = 10.3 Hz, 1H), 2.27 (dd, J = 17.3, 6.7 Hz, 1H), 1.95
13
(dt, J = 17.5, 8 Hz, 2H), 1.82 (dd, J = 19, 10.4 Hz, 1H), 1.58 (s, 3H). C NMR (101 MHz, DMSO) δ 167.26,
163.07, 83.88, 57.22, 45.41, 37.82, 29.02, 22.92, 21.58.
(R)-3-Bromo-2-hydroxy-2-methylpropanoic acid (8)
In
a 250 mL round-bottomed flask, (3R,8aR)-3-(bromomethyl)-3-methyltetrahydro-1H-
pyrrolo[2,1-c][1,4]oxazine-1,4(3H)-dione (7) (25 g, 95 mmol, 1 eq) in HBr (250 mL, 921 mmol, 9.7 eq)
was added to give an orange solution. The reaction was heated to 100°C with stirring on for 16 h.
Then, 250 mL sat.NaCl was added. The aq layer was backextracted with EA. The organic layers were
combined and washed with sat.NaCl (aq). The organic was washed with sat.NaHCO3. Later, 45 mL
12M HCl was added to adjust pH to 1. The aq layer was backextracted with EA. The organic layers
were combined and washed with water and sat.NaCl (aq). The organic was dried with Na2SO4,
filtered, and concentrated to give (R)-3-Bromo-2-hydroxy-2-methylpropanoic acid (8) (12.2 g, 69.9 %
1
yield) as white solid. m.p. 111–113 °C; H NMR (400 MHz, DMSO) δ 12.84 (s, 1H), 5.43 (s, 1H), 3.65
13
(d, J = 10.2 Hz, 1H), 3.54 (d, J = 10 Hz, 1H), 1.37 (s, 3H). C NMR (101 MHz, DMSO) δ 174.51, 73.11,
20
40.94, 24.45. [α]D = +9.9 (c = 1.1, MeOH).
3.2. General Procedure for the Synthesis of 9, 10, and 15
In a 100 mL round-bottomed flask, (R)-3-Bromo-2-hydroxy-2-methylpropanoic acid (1.7 eq) in
anhydrous 25 mL DMAc was added to give a yellow solution. The reaction vessel was purged with
nitrogen. The reaction mixture was cooled to −10 °C with stirring on. Thionyl chloride (1.85 eq) was
added slowly. The reaction mixture was held at −5 °C with stirring on for 3 h. 1, 3, or 14 (1 eq) in 15
mL anhydous DMAc was added. The reaction mixture was warmed up to room temperaure with
stirring on for 16 h. Then, 60 mL water was added. The aq layer was backextracted with EA. The
organic layers were combined and washed with sat.NaHCO3 (aq), sat.NH4Cl (aq), and sat.NaCl (aq).
The organic was dried with Na2SO4, filtered, and concentrated to give crude product. The crude
product was purified by column chromatography to give 9, 10, and 15.

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(R)-3-Bromo-2-hydroxy-2-methyl-N-(3-(pentafluorosulfanyl)phenyl)propanamide (9)
1
Yellow solid (1.7 g, 96% yield). m.p. 105–107 °C; H NMR (400 MHz, CDCl3) δ 8.77 (s, 1H), 8.03
(s, 1H), 7.74 (d, J = 7.7 Hz, 1H), 7.51 (d, J = 8 Hz, 1H), 7.42 (t, J = 7.9 Hz, 1H), 4.01 (d, J = 10.4 Hz, 1H),
19
3.59 (d, J = 10.4 Hz, 1H), 3.01 (s, 1H), 1.61 (s, 3H). F NMR (376 MHz, CDCl3) δ 84.94–82.68 (m, 1F),
13
62.66 (d, J = 150.2 Hz, 4F). C NMR (101 MHz, CDCl3) δ 171.12, 154.28, 137.42, 129.28, 122.63, 122.04,
+
20
117.46, 75.39, 41.50, 24.79. ESI-MS m/z: 409.14, 411.22 [M + H, M + 2H] . [α]D = −28.1 (c = 1.1, MeOH).
(R)-3-Bromo-N-(4-cyano-3-(pentafluorosulfanyl)phenyl)-2-hydroxy-2-methylpropanamide (10)
1
Light-yellow solid (450 mg, 49% yield). m.p. 125–127 °C; H NMR (400 MHz, CDCl3) δ 9.03 (s,
1H), 8.22 (s, 1H), 7.97 (d, J = 8.3 Hz, 1H), 7.81 (d, J = 7.9 Hz, 1H), 4.02 (d, J = 10.5 Hz, 1H), 3.60 (d, J =
19
10.5 Hz, 1H), 3.01 (s, 1H), 1.65 (s, 3H). F NMR (376 MHz, CDCl3) δ 81.81–78.79 (m, 1F), 65.52 (d, J =
13
151.5 Hz, 4F). C NMR (101 MHz, CDCl3) δ 171.63, 155.37, 141.15, 136.09, 121.67, 119.13, 116.10, 104.70,
+
20
75.59, 40.98, 24.83. ESI-MS m/z: 384.24, 386.19 [M + H, M + 2H] . [α]D = –23.3 (c = 0.1, MeOH).
(R)-3-Bromo-2-hydroxy-2-methyl-N-(4-(pentafluorosulfanyl)phenyl)propanamide (15)
1
Light-yellow solid (1.1 g, 88% yield). m.p. 117–119 °C; H NMR (400 MHz, CDCl3) δ 8.85 (s, 1H),
7.73 (d, J = 9.4 Hz, 2H), 7.69 (d, J = 9.3 Hz, 2H), 4.02 (d, J = 10.4 Hz, 1H), 3.60 (d, J = 10.5 Hz, 1H), 3.21
19
13
(s, 1H), 1.63 (s, 3H). F NMR (376 MHz, CDCl3) δ 85.87–83.96 (m, 1F), 63.38 (d, J = 150.3 Hz, 4F).
C
NMR (101 MHz, CDCl3) δ 171.30, 149.60, 139.66, 127.13, 127.09, 127.04, 119.10, 75.42, 41.38, 24.80. ESI-
+
20
MS m/z: 384.24, 386.26 [M + H, M + 2H] . [α]D = −28 (c = 1, MeOH).
3.3. General Procedure for the Synthesis of 12a–g, 13a–g, and 16a–g
In a 50 mL round-bottomed flask, 9, 10, or 15 (1 eq), different commercial phenols 11a–g (1.5 eq),
and potassium carbonate (3 eq) were added in 20 mL 2-propanol to give a white suspension. The
reaction vessel was purged with nitrogen. The reaction was heated to 85 °C with stirring on for 16 h.
The reaction mixture was filtered through sintered glass funnel. The mixture was concentrated by
rotovap. The crude product was purified by column chromatography to give 12a–g, 13a–g, and 16a–
g.
(S)-3-(4-cyanophenoxy)-2-hydroxy-2-methyl-N-(3-(pentafluoro-l6-sulfanyl)phenyl)propanamide (12a)
1
White solid (50 mg, 46% yield). m.p. 70–72 °C; H NMR (400 MHz, CDCl3) δ 8.92 (s, 1H), 8.09 (t,
J = 2 Hz, 1H), 7.76 (d, J = 8 Hz, 1H), 7.57 (d, J = 8.8 Hz, 2H), 7.53 (dd, J = 8.4, 1.3 Hz, 1H), 7.44 (t, J = 8.2
Hz, 1H), 6.98 (d, J = 8.9 Hz, 2H), 4.50 (d, J = 9.2 Hz, 1H), 4.06 (d, J = 9.2 Hz, 1H), 3.43 (s, 1H), 1.62 (s,
19
13
3H). F NMR (376 MHz, CDCl3) δ 84.99–82.98 (m, 1F), 62.66 (d, J = 150.2 Hz, 4F). C NMR (101 MHz,
CDCl3) δ 171.80, 161.13, 154.29, 137.55, 134.12, 129.30, 122.52, 122, 118.80, 117.40, 116.33, 115.48, 105.10,
+
20
75.58, 72.74, 23.03. HRMS(ESI)m/z calcd for C17H15F5N2O3S [M + H] : 423.0802, Found: 423.0818. [α]D
= +3 (c = 0.1, MeOH).
(S)-3-(4-fluorophenoxy)-2-hydroxy-2-methyl-N-(3-(pentafluoro-l6-sulfanyl)phenyl)propanamide (12b)
1
White solid (95 mg, 88% yield). m.p. 91–93 °C; H NMR (400 MHz, CDCl3) δ 8.94 (s, 1H), 8.08 (t,
J = 1.9 Hz, 1H), 7.74 (d, J = 8.2 Hz, 1H), 7.50 (dd, J = 8.3, 1.2 Hz, 1H), 7.40 (t, J = 8.2 Hz, 1H), 6.94 (dt, J
= 11.9, 3 Hz, 2H), 6.87–6.78 (m, 2H), 4.40 (d, J = 9 Hz, 1H), 3.94 (d, J = 9 Hz, 1H), 3.58 (s, 1H), 1.57 (s,
19
13
3H). F NMR (376 MHz, CDCl3) δ 85.25–82.86 (m, 1F), 62.63 (d, J = 150.1 Hz, 4F), –122.19 (s, 1F).
C
NMR (101 MHz, CDCl3) δ 172.39, 159.06, 156.67, 153.98, 137.67, 129.23, 122.54, 121.85, 117.38, 116.14,
+
116.06, 115.98, 115.90, 75.62, 73.32, 22.94. HRMS(ESI)m/z calcd for C16H15F6NO3S [M + H] : 416.0755,
20
Found: 416.0744. [α]D = –3.3 (c = 0.3, MeOH).
(S)-3-(4-chlorophenoxy)-2-hydroxy-2-methyl-N-(3-(pentafluoro-l6-sulfanyl)phenyl)propanamide (12c)
1
White solid (110 mg, 98% yield). m.p. 82–84 °C; H NMR (400 MHz, CDCl3) δ 8.93 (s, 1H), 8.08
(t, J = 2 Hz, 1H), 7.72 (d, J = 8 Hz, 1H), 7.50 (dd, J = 8.3, 1.4 Hz, 1H), 7.40 (t, J = 8.2 Hz, 1H), 7.23 – 7.17

Molecules 2019, 24, 4227
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19
(m, 2H), 6.86–6.78 (m, 2H), 4.39 (d, J = 9 Hz, 1H), 3.94 (d, J = 9.2 Hz, 1H), 3.58 (s, 1H), 1.57 (s, 3H). F
13
NMR (376 MHz, CDCl3) δ 84.97–82.86 (m, 1F), 62.65 (d, J = 150.2 Hz, 4F). C NMR (101 MHz, CDCl3)
δ 172.30, 156.50, 154.25, 137.63, 129.50, 129.24, 126.84, 122.56, 121.90, 117.39, 116.11, 75.59, 72.91, 22.95.
+
20
HRMS(ESI)m/z calcd for C16H15ClF5NO3S [M + H] : 432.0460, Found: 432.0455. [α]D = +1.2 (c = 0.2,
MeOH).
(S)-2-hydroxy-2-methyl-N-(3-(pentafluoro-l6-sulfanyl)phenyl)-3-(4-(trifluoromethyl)phenoxy)propanamide
(12d)
1
White solid (70 mg, 58% yield). m.p. 96–98 °C; H NMR (400 MHz, CDCl3) δ 8.93 (s, 1H), 8.09 (s,
1H), 7.74 (d, J = 8 Hz, 1H), 7.53 (t, J = 6.8 Hz, 3H), 7.42 (t, J = 8.2 Hz, 1H), 6.97 (d, J = 8.4 Hz, 2H), 4.49
19
(d, J = 9 Hz, 1H), 4.03 (d, J = 9 Hz, 1H), 3.44 (s, 1H), 1.60 (s, 3H). F NMR (376 MHz, CDCl3) δ 84.86 –
13
82.96 (m, 1F), 62.64 (d, J = 150.1 Hz, 4F), –61.69 (s, 3F). C NMR (101 MHz, CDCl3) δ 172.03, 160.21,
154.26, 137.55, 129.28, 127.10, 127.06, 125.54, 124.23, 123.90, 122.85, 122.51, 121.96, 117.37, 114.72, 75.59,
+
20
72.57, 23. HRMS(ESI)m/z calcd for C17H15F8NO3S [M + Na] : 488.0543, Found: 488.0521. [α]D = –2.5 (c
= 0.2, MeOH).
(S)-3-(4-acetamidophenoxy)-2-hydroxy-2-methyl-N-(3-(pentafluoro-l6-sulfanyl)phenyl)propanamide (12e)
1
White solid (100 mg, 85% yield). m.p. 79–81 °C; H NMR (400 MHz, DMSO) δ 10.19 (s, 1H), 9.76
(s, 1H), 8.53 (s, 1H), 8.06 (d, J = 7.5 Hz, 1H), 7.57 (p, J = 8.3 Hz, 2H), 7.45 (d, J = 8.9 Hz, 2H), 6.86 (d, J =
19
8.9 Hz, 2H), 6.13 (s, 1H), 4.17 (d, J = 9.5 Hz, 1H), 3.93 (d, J = 9.5 Hz, 1H), 2 (s, 3H), 1.43 (s, 3H). F NMR
13
(376 MHz, DMSO) δ 88.61–86.49 (m, 1F), 63.66 (d, J = 150.6 Hz, 4F). C NMR (101 MHz, DMSO) δ
173.81, 167.68, 154.23, 152.87, 139.30, 132.74, 129.49, 123.32, 120.33, 116.73, 114.55, 74.67, 73.73, 23.76,
+
20
23.04. HRMS(ESI)m/z calcd for C18H19F5N2O4S [M + H] : 455.1064, Found: 455.1046. [α]D = –2.5 (c =
1.2, MeOH).
(S)-2-hydroxy-2-methyl-N-(3-(pentafluoro-l6-sulfanyl)phenyl)-3-(4-propionylphenoxy)propanamide (12f)
1
White solid (95 mg, 80% yield). m.p. 76–78 °C; H NMR (400 MHz, CDCl3) δ 9.11 (s, 1H), 8.12 (s,
1H), 7.85 (d, J = 8.7 Hz, 2H), 7.74 (d, J = 8 Hz, 1H), 7.49 (d, J = 8.3 Hz, 1H), 7.39 (t, J = 8.2 Hz, 1H), 6.86
(d, J = 8.5 Hz, 2H), 4.47 (d, J = 9.3 Hz, 1H), 4.26 (s, 1H), 4.05 (d, J = 9.2 Hz, 1H), 2.91 (q, J = 7.2 Hz, 2H),
19
1.60 (s, 3H), 1.17 (t, J = 7.3 Hz, 3H). F NMR (376 MHz, CDCl3) δ 84.90–82.96 (m, 1F), 62.65 (d, J = 150.2
13
Hz, 4F). C NMR (101 MHz, CDCl3) δ 200.16, 172.43, 161.78, 154.17, 137.71, 130.52, 130.24, 129.21,
122.60, 121.82, 117.38, 114.38, 75.55, 72.78, 31.48, 22.94, 8.36. HRMS(ESI)m/z calcd for C19H20F5NO4S [M
+
20
+ Na] : 476.0931, Found: 476.0923. [α]D = +1 (c = 0.2, MeOH).
(S)-3-(2-fluoro-4-methoxyphenoxy)-2-hydroxy-2-methyl-N-(3-(pentafluoro-l6-sulfanyl)phenyl)propanamide
(12g)
1
White solid (100 mg, 86% yield). m.p. 92–94 °C; H NMR (400 MHz, CDCl3) δ 8.98 (s, 1H), 8.09
(t, J = 2 Hz, 1H), 7.71 (d, J = 8.2 Hz, 1H), 7.49 (dd, J = 8.3, 1.4 Hz, 1H), 7.39 (t, J = 8.2 Hz, 1H), 6.93 (t, J =
9.2 Hz, 1H), 6.64 (dd, J = 12.6, 2.9 Hz, 1H), 6.56 (ddd, J = 9, 2.9, 1.5 Hz, 1H), 4.43 (d, J = 9.3 Hz, 1H), 3.97
19
(d, J = 9.2 Hz, 1H), 3.90 (s, 1H), 3.72 (s, 3H), 1.56 (s, 3H). F NMR (376 MHz, CDCl3) δ 85.16 – 82.99
13
(m, 1F), 62.64 (d, J = 150.1 Hz, 4F), –131.31 (s, 1F). C NMR (101 MHz, CDCl3) δ 172.62, 155.42, 155.33,
154.62, 154.20, 152.18, 139.77, 139.65, 137.74, 129.15, 122.63, 121.77, 118, 117.98, 117.46, 109.15, 109.12,
+
103.35, 103.13, 75.61, 75.38, 55.74, 22.94. HRMS(ESI)m/z calcd for C17H17F6NO4S [M + Na] : 468.0680,
20
Found: 468.0692. [α]D = –7 (c = 0.1, MeOH).
(S)-N-(4-cyano-3-(pentafluoro-l6-sulfanyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2-methylpropanamide
(13a)
1
White solid (260 mg, 60% yield). m.p. 77–79 °C; H NMR (400 MHz, CDCl3) δ 9.20 (s, 1H), 8.27
(s, 1H), 7.96 (d, J = 8.4 Hz, 1H), 7.78 (d, J = 8.5 Hz, 1H), 7.57 (d, J = 8 Hz, 2H), 6.98 (d, J = 8.2 Hz, 2H),
19
4.50 (d, J = 9.2 Hz, 1H), 4.07 (d, J = 9 Hz, 1H), 3.53 (s, 1H), 1.63 (s, 3H). F NMR (376 MHz, CDCl3) δ
13
81.19–79.05 (m, 1F), 65.53 (d, J = 151.3 Hz, 4F). C NMR (101 MHz, CDCl3) δ 172.36, 161.02, 155.55,

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141.42, 136.05, 134.13, 121.61, 119.10, 118.76, 116.13, 115.46, 105.18, 104.46, 75.79, 72.60, 22.99.
+
20
HRMS(ESI)m/z calcd for C18H14F5N3O3S [M + Na] : 470.0574, Found: 470.0566. [α]D = –5.8 (c = 1,
MeOH).
(S)-N-(4-cyano-3-(pentafluoro-l6-sulfanyl)phenyl)-3-(4-fluorophenoxy)-2-hydroxy-2-methylpropanamide
(13b)
1
White solid (40 mg, 62% yield). m.p. 85–87 °C; H NMR (400 MHz, CDCl3) δ 9.16 (s, 1H), 8.25 (s,
1H), 7.96 (d, J = 8.5 Hz, 1H), 7.79 (d, J = 8.4 Hz, 1H), 6.98 (t, J = 8.4 Hz, 2H), 6.86 (dd, J = 8.8, 4.1 Hz,
19
2H), 4.43 (d, J = 9 Hz, 1H), 3.95 (d, J = 9 Hz, 1H), 3.46 (s, 1H), 1.59 (s, 3H). F NMR (376 MHz, CDCl3)
13
δ 81.37–79.25 (m, 1F), 65.53 (d, J = 151.2 Hz, 4F), –121.89 (s, 1F). C NMR (101 MHz, CDCl3) δ 172.76,
159.14, 156.76, 155.58, 153.75, 141.41, 136.07, 121.55, 119.04, 116.25, 116.15, 116.04, 116.02, 115.96,
+
104.48, 75.89, 73.05, 22.92. HRMS(ESI)m/z calcd for C17H14F6N2O3S [M + H] : 441.0708, Found: 441.0723.
20
[α]D = −0.7 (c = 0.2, MeOH).
(S)-3-(4-chlorophenoxy)-N-(4-cyano-3-(pentafluoro-l6-sulfanyl)phenyl)-2-hydroxy-2-methylpropanamide
(13c)
1
White solid (51 mg, 76% yield). m.p. 65–67 °C; H NMR (400 MHz, CDCl3) δ 9.14 (s, 1H), 8.24 (s,
1H), 7.95 (d, J = 8.5 Hz, 1H), 7.79 (d, J = 8.5 Hz, 1H), 7.25 (d, J = 9 Hz, 2H), 6.84 (d, J = 8.8 Hz, 2H), 4.44
19
(d, J = 9 Hz, 1H), 3.97 (d, J = 9 Hz, 1H), 3.40 (s, 1H), 1.59 (s, 3H). F NMR (376 MHz, CDCl3) δ 81.55 –
13
78.71 (m, 1F), 65.49 (d, J = 151.3 Hz, 4F). C NMR (101 MHz, CDCl3) δ 172.61, 156.23, 155.58, 141.36,
136.07, 129.60, 127.10, 121.55, 119.04, 116.14, 116.07, 104.53, 75.85, 72.60, 22.96. HRMS(ESI)m/z calcd
+
20
for C17H14ClF5N2O3S [M + H] : 457.0412, Found: 457.0408. [α]D = −3 (c = 0.1, MeOH).
(S)-N-(4-cyano-3-(pentafluoro-l6-sulfanyl)phenyl)-2-hydroxy-2-methyl-3-(4
(trifluoromethyl)phenoxy)propanamide (13d)
1
White solid (30 mg, 42% yield). m.p. 69–71 °C; H NMR (400 MHz, CDCl3) δ 9.19 (s, 1H), 8.27 (s,
1H), 7.95 (d, J = 8.3 Hz, 1H), 7.77 (d, J = 8.5 Hz, 1H), 7.55 (d, J = 8.4 Hz, 2H), 6.98 (d, J = 8.5 Hz, 2H),
19
4.51 (d, J = 9.2 Hz, 1H), 4.05 (d, J = 9 Hz, 1H), 3.49 (s, 1H), 1.62 (s, 3H). F NMR (376 MHz, CDCl3) δ
13
80.94 – 79.24 (m, 1F), 65.52 (d, J = 151.2 Hz, 4F), –61.72 (s, 3F). C NMR (101 MHz, CDCl3) δ 172.54,
160.05, 155.73, 155.55, 155.36, 141.42, 136.05, 131.62, 127.13, 127.10, 127.06, 125.50, 124.69, 124.36,
124.03, 123.71, 122.80, 121.58, 119.07, 116.17, 114.72, 104.41, 75.84, 72.43, 22.96. HRMS(ESI)m/z calcd
+
20
for C18H14F8N2O3S [M + Na] : 513.0495, Found: 513.0483. [α]D = −3 (c = 0.1, MeOH).
(S)-3-(4-acetamidophenoxy)-N-(4-cyano-3-(pentafluoro-l6-sulfanyl)phenyl)-2-hydroxy-2-methylpropanamide
(13e)
1
White solid (40 mg, 57% yield). m.p. 112–114 °C; H NMR (400 MHz, DMSO) δ 10.69 (s, 1H), 9.78
(s, 1H), 8.80 (s, 1H), 8.35 (d, J = 8.7 Hz, 1H), 8.12 (d, J = 8.7 Hz, 1H), 7.45 (d, J = 9 Hz, 2H), 6.85 (d, J = 9
19
Hz, 2H), 6.29 (s, 1H), 4.18 (d, J = 9.7 Hz, 1H), 3.95 (d, J = 9.6 Hz, 1H), 1.99 (s, 3H), 1.44 (s, 3H). F NMR
13
(376 MHz, DMSO) δ 83.68 (m, 1F), 66.17 (d, J = 152 Hz, 4F). C NMR (101 MHz, DMSO) δ 174.78,
167.68, 154.14, 143.36, 136.56, 132.80, 122.40, 120.33, 118.99, 116.37, 114.59, 101.46, 74.86, 73.74, 23.76,
+
20
22.97. HRMS(ESI)m/z calcd for C19H18F5N3O4S [M + Na] : 502.0836, Found: 502.0829. [α]D = −5.2 (c =
0.3, MeOH).
(S)-N-(4-cyano-3-(pentafluoro-l6-sulfanyl)phenyl)-2-hydroxy-2-methyl-3-(4-propionylphenoxy)propanamide
(13f)
1
White solid (37 mg, 53% yield). m.p. 66–68 °C; H NMR (400 MHz, DMSO) δ 10.71 (s, 1H), 8.79
(d, J = 1.9 Hz, 1H), 8.35 (d, J = 8.7 Hz, 1H), 8.12 (d, J = 8.7 Hz, 1H), 7.91 (d, J = 8.9 Hz, 2H), 7.03 (d, J =
8.8 Hz, 2H), 6.36 (s, 1H), 4.33 (d, J = 9.9 Hz, 1H), 4.09 (d, J = 9.8 Hz, 1H), 2.96 (q, J = 7.2 Hz, 2H), 1.46
19
(s, 3H), 1.06 (t, J = 7.2 Hz, 3H). F NMR (376 MHz, DMSO) δ 83.81 (p, J = 153.6 Hz, 1F), 66.16 (d, J =
13
151.9 Hz, 4F). C NMR (101 MHz, DMSO) δ 198.75, 174.59, 162.06, 143.31, 136.56, 129.99, 129.71,

Molecules 2019, 24, 4227
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122.45, 119.04, 116.34, 114.41, 101.52, 74.75, 73.59, 30.75, 22.92, 8.23. HRMS(ESI)m/z calcd for
+
20
C20H19F5N2O4S [M + Na] : 501.0883, Found: 501.0883. [α]D = −1 (c = 0.1, MeOH).
(S)-N-(4-cyano-3-(pentafluoro-l6-sulfanyl)phenyl)-3-(2-fluoro-4-methoxyphenoxy)-2-hydroxy-2-
methylpropanamide (13g)
1
White solid (55 mg, 80% yield). m.p. 58–60 °C; H NMR (400 MHz, CDCl3) δ 9.24 (s, 1H), 8.26 (s,
1H), 7.93 (d, J = 8.5 Hz, 1H), 7.76 (d, J = 8.4 Hz, 1H), 6.93 (t, J = 9.1 Hz, 1H), 6.64 (d, J = 12.7 Hz, 1H),
6.59 (d, J = 8.9 Hz, 1H), 4.45 (d, J = 9.2 Hz, 1H), 3.97 (d, J = 9.2 Hz, 1H), 3.84 (s, 1H), 3.74 (s, 3H), 1.57
19
(s, 3H). F NMR (376 MHz, CDCl3) δ 81.73–79.26 (m, 1F), 65.50 (d, J = 151.3 Hz, 4F), –131.34 (s, 1F).
13
C NMR (101 MHz, CDCl3) δ 173.15, 155.56, 155.47, 155.28, 154.60, 152.16, 141.55, 139.54, 139.43,
135.97, 121.66, 119.13, 118.08, 118.06, 116.22, 109.20, 109.16, 104.26, 103.35, 103.14, 75.68, 75.54, 55.79,
+
20
22.85. HRMS(ESI)m/z calcd for C18H16F6N2O4S [M + Na] : 493.0633, Found: 493.0601. [α]D = −2.5 (c =
0.1, MeOH).
(S)-3-(4-cyanophenoxy)-2-hydroxy-2-methyl-N-(4-(pentafluoro-l6-sulfanyl)phenyl)propanamide (16a)
1
White solid (140 mg, 71% yield). m.p. 73–75 °C; H NMR (400 MHz, CDCl3) δ 8.87 (s, 1H), 7.68 –
7.59 (m, 4H), 7.49 (d, J = 8.5 Hz, 2H), 6.90 (d, J = 8.5 Hz, 2H), 4.42 (d, J = 9.2 Hz, 1H), 3.99 (d, J = 9.2 Hz,
19
1H), 3.34 (s, 1H), 1.54 (s, 3H). F NMR (376 MHz, CDCl3) δ 84.93 (p, J = 150.4 Hz, 1F), 63.41 (d, J =
13
150.1 Hz, 4F). C NMR (101 MHz, CDCl3) δ 170.80, 160.11, 138.79, 133.11, 126.10, 117.97, 117.76, 114.47,
+
104.13, 74.61, 71.75, 22.02. HRMS(ESI)m/z calcd for C17H15F5N2O3S [M + H] : 423.0802, Found: 423.0818.
20
[α]D = +0.2 (c = 0.9, MeOH).
(S)-3-(4-fluorophenoxy)-2-hydroxy-2-methyl-N-(4-(pentafluoro-l6-sulfanyl)phenyl)propanamide (16b)
1
White solid (90 mg, 83% yield). m.p. 87–89 °C; H NMR (400 MHz, CDCl3) δ 8.93 (s, 1H), 7.73 (d,
J = 9.5 Hz, 2H), 7.70 (d, J = 9.8 Hz, 2H), 6.98 (t, J = 8.5 Hz, 2H), 6.86 (dd, J = 9.1, 4.1 Hz, 2H), 4.42 (d, J =
19
9 Hz, 1H), 3.95 (d, J = 8.9 Hz, 1H), 3.40 (s, 1H), 1.58 (s, 3H). F NMR (376 MHz, CDCl3) δ 86.09 – 84.13
13
(m, 1F), 63.41 (d, J = 150.1 Hz, 4F), –122.12 (s, 1F). C NMR (101 MHz, CDCl3) δ 172.27, 159.09, 156.71,
153.90, 153.88, 139.90, 127.14, 127.10, 127.05, 118.92, 116.20, 116.05, 115.97, 75.65, 73.21, 23.
+
20
HRMS(ESI)m/z calcd for C16H15F6NO3S [M + H] : 416.0755, Found: 416.0744. [α]D = −6.2 (c = 0.2,
MeOH).
(S)-3-(4-chlorophenoxy)-2-hydroxy-2-methyl-N-(4-(pentafluoro-l6-sulfanyl)phenyl)propanamide (16c)
1
White solid (88 mg, 78% yield). m.p. 65–68 °C; H NMR (400 MHz, CDCl3) δ 8.94 (s, 1H), 7.70 (q,
J = 9.5 Hz, 4H), 7.22 (d, J = 8.5 Hz, 2H), 6.83 (d, J = 8.5 Hz, 2H), 4.41 (d, J = 8.9 Hz, 1H), 3.95 (d, J = 9 Hz,
19
1H), 3.48 (s, 1H), 1.58 (s, 3H). F NMR (376 MHz, CDCl3) δ 84.98 (d, J = 150.4 Hz,, 1F), 63.42 (d, J =
13
150.3 Hz, 4F). C NMR (101 MHz, CDCl3) δ 172.25, 156.41, 149.45, 139.85, 129.54, 127.08, 126.91, 118.95,
+
116.08, 75.63, 72.81, 23. HRMS(ESI)m/z calcd for C16H15ClF5NO3S [M + H] : 432.0460, Found: 432.0455.
20
[α]D = −1.7 (c = 0.5, MeOH).
(S)-2-hydroxy-2-methyl-N-(4-(pentafluorosulfanyl)phenyl)-3-(4-(trifluoromethyl)phenoxy)propanamide
(16d)
1
White solid (20 mg, 17% yield). m.p. 78–80 °C; H NMR (400 MHz, CDCl3) δ 8.93 (s, 1H), 7.73 (d,
J = 9.5 Hz, 2H), 7.69 (d, J = 9.5 Hz, 2H), 7.55 (d, J = 8.8 Hz, 2H), 6.98 (d, J = 8.7 Hz, 2H), 4.49 (d, J = 9 Hz,
19
1H), 4.04 (d, J = 9 Hz, 1H), 3.37 (s, 1H), 1.61 (s, 3H). F NMR (376 MHz, CDCl3) δ 84.90 (p, J = 150.4
13
Hz, 1F), 63.39 (d, J = 150.2 Hz, 4F), –61.70 (s, 3F). C NMR (101 MHz, CDCl3) δ 171.98, 160.17, 149.53,
139.81, 127.15, 127.12, 127.08, 127.06, 125.52, 124.33, 124, 122.83, 118.96, 114.75, 75.63, 72.59, 23.03.
+
20
HRMS(ESI)m/z calcd for C17H15F8NO3S [M + Na] : 488.0543, Found: 488.0521. [α]D = −3.7 (c = 0.3,
MeOH).
(S)-3-(4-acetamidophenoxy)-2-hydroxy-2-methyl-N-(4-(pentafluorosulfanyl)phenyl)propanamide (16e)

Molecules 2019, 24, 4227
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1
White solid (98 mg, 83% yield). m.p. 156–157 °C; H NMR (400 MHz, DMSO) δ 10.17 (s, 1H), 9.77
(s, 1H), 8.02 (d, J = 8.9 Hz, 2H), 7.85 (d, J = 9.2 Hz, 2H), 7.45 (d, J = 8.9 Hz, 2H), 6.85 (d, J = 8.9 Hz, 2H),
19
6.17 (s, 1H), 4.17 (d, J = 9.5 Hz, 1H), 3.94 (d, J = 9.5 Hz, 1H), 2 (s, 3H), 1.43 (s, 3H). F NMR (376 MHz,
13
DMSO) δ 89.74–87.61 (m, 1F), 64.86 (d, J = 150.7 Hz, 5F). C NMR (101 MHz, DMSO) δ 173.79, 167.68,
154.24, 141.77, 132.74, 126.47, 120.36, 119.57, 114.57, 74.73, 73.78, 23.75, 22.99. HRMS(ESI)m/z calcd for
+
20
C18H19F5N2O4S [M + Na] : 477.0883, Found: 477.0859. [α]D = −0.6 (c = 0.5, MeOH).
(S)-2-hydroxy-2-methyl-N-(4-(pentafluorosulfanyl)phenyl)-3-(4-propionylphenoxy)propanamide (16f)
1
White solid (100 mg, 85% yield). m.p. 100–102 °C; H NMR (400 MHz, CDCl3) δ 8.99 (s, 1H), 7.91
(d, J = 8.8 Hz, 2H), 7.71 (s, 4H), 6.91 (d, J = 8.8 Hz, 2H), 4.49 (d, J = 9.2 Hz, 1H), 4.06 (d, J = 9.2 Hz, 1H),
19
3.66 (s, 1H), 2.94 (q, J = 7.2 Hz, 2H), 1.61 (s, 3H), 1.20 (t, J = 7.2 Hz, 3H). F NMR (376 MHz, CDCl3) δ
13
86.14–83.94 (m, 1F), 63.41 (d, J = 150.2 Hz, 4F). C NMR (101 MHz, CDCl3) δ 199.69, 172.11, 161.50,
149.46, 139.89, 130.88, 130.28, 127.07, 118.96, 114.40, 75.60, 72.59, 31.51, 23.04, 8.35. HRMS(ESI)m/z
+
20
calcd for C19H20F5NO4S [M + Na] : 476.0931, Found: 476.0923. [α]D = +0.2 (c = 0.7, MeOH).
(S)-3-(2-fluoro-4-methoxyphenoxy)-2-hydroxy-2-methyl-N-(4-(pentafluorosulfanyl)phenyl)propanamide
(16g)
1
White solid (100 mg, 86% yield). m.p. 91–93 °C; H NMR (400 MHz, CDCl3) δ 9 (s, 1H), 7.76 –
7.62 (m, 4H), 6.92 (t, J = 9.2 Hz, 1H), 6.64 (dd, J = 12.7, 2.9 Hz, 1H), 6.57 (ddd, J = 9, 2.9, 1.4 Hz, 1H),
19
4.42 (d, J = 9.3 Hz, 1H), 3.97 (d, J = 9.2 Hz, 1H), 3.90 (s, 1H), 3.72 (s, 3H), 1.56 (s, 3H). F NMR (376
13
MHz, CDCl3) δ 86.57–84.10 (m, 1F), 63.39 (d, J = 150.3 Hz, 3F), –131.31 (s, 1F). C NMR (101 MHz,
CDCl3) δ 172.68, 155.45, 155.36, 154.62, 152.18, 149.38, 139.98, 139.73, 139.62, 127.02, 126.97, 126.93,
119.04, 117.99, 117.97, 109.17, 109.15, 103.36, 103.14, 75.59, 75.39, 55.74, 22.97. HRMS(ESI)m/z calcd for
+
20
C17H17F6NO4S [M + H] : 446.0861, Found: 446.0818. [α]D = –3.9 (c = 0.8, MeOH).
3.4. Cell Preparation
CV-1 cells and C2C12 cells were both provided and certified by the Cell Bank at Shanghai
Institutes for Biological Sciences, the Chinese Academy of Sciences, and confirmed as negative for
mycoplasma contamination. CV-1 cells were cultured in phenol red-free LG-DMEM medium (Life
Technologies, Carlsbad, CA, USA) supplemented with 10% (v/v) fetal bovine serum, 50 IU/mL
penicillin, and 50 μg/mL streptomycin. C2C12 were cultured in phenol red-free HG-DMEM medium
(Life Technologies, Carlsbad, CA, USA) supplemented with 10% (v/v) fetal bovine serum, 50 IU/mL
penicillin, 50 μg/mL streptomycin, and 1% sodium pyruvate. Cells were maintained at 37 °C in a 5%
CO2 incubator and seeded onto a 10 cm cell culture dish before transfection. After overnight culture,
the cells were transiently co-transfected with AR expressing plasmid (pSVAR0) and luciferase
reporter gene vector (MMTV-Luc) using FuGENE® HD Transfection Reagent (Promega, Madison,
WI, USA) with cells reaching 80–90% confluence. After 18 h, the transfected cells were distributed to
384-well plates at a density of 15,000 cells per well and incubated for further 6 h at 37 °C before
compound treatment.
3.5. Agonist Assay
DHT (Sigma, St. Louis，MO，USA) and ostarine were used as positive controls. The agonist
activity of compounds was measured by Steadylite plus Reporter Gene Assay System (PerkinElmer,
Boston, MA, USA) according to the manufacturer’s instructions. In brief, after incubation for 6 h, as
mentioned above, 10 μL testing compounds diluted in culture medium with eight different working
concentrations (384 pM to 30 μM; DHT (1 fM–1 μM); ostarine (32 pM–2.5 μM)) were added to the cell
well (40 μL). After 24 h incubation, Steadylite reagent (50 μL, equal volume) was introduced, gently
shook for 2 min, and kept at room temperature for 15 min before luminescence 384 measurement on
an EnSpire multilabel plate reader (PerkinElmer, Boston, MA, USA).
3.6. Cytotoxicity

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CellTiter-Glo® 2.0 assay (Promega, Madison, WI, USA) was applied to assess cytotoxicity. In
brief, cells were seeded onto 384-well plates at a density of 1500 cells per well and incubated for 24 h.
A total of 10 μL testing compounds diluted in culture medium were added and reacted for 24 h.
CellTiter-Glo reagent was then introduced, and luminescence 384 was measured as above.
3. Conclusions
In summary, a small library of SF5-containing ostarine analogs instead of the CF3 group was
synthesized, and their biological activity and SAR (structure-activity relationship), as SARMs, were
studied. A series of para-SF5, meta-CN derivatives (13a–g) displayed different degrees of AR agonist
activity. It appears that mono-SF5 substitution in the phenyl ring (12a–g, 16a–g) resulted in a total loss
of AR agonist activity. The derivatives containing the SF5 group maintained fewer AR agonist
activities than the derivatives containing the CF3 group. The results pointed to the potential of using
this derivative containing the SF5 group scaffold to develop new AR agonists.
Supplementary Materials: The following are available online at www.mdpi.com/xxx/s1, 1H, 13C, 19F
NMR spectra, HPLC and HRMS of the synthesized compounds can be found in the Supporting Information.
Author Contributions: P.S. and J.J. collaborated in the synthesis and purification of compounds; P.S., W.L. and
J.J. collaborated in the discussion of structure-activity relationship, and writing of the manuscript; Y.Z., D.Y. and
M.-W.W. supervised the biological work and wrote the biological component of this manuscript; Y.Z., D.Y. and
M.-W.W. revised the manuscript; All the authors discussed, edited, and approved the final version.
Funding: We thank Yang Feng for technical assistance. This work was partially supported by the “Personalized
Medicines‒Molecular Signature-based Drug Discovery and Development Strategic Priority Research Program”
of Chinese Academy of Sciences grants (XDA12020347 to M.-W.W.; XDA12040308 to D.Y.), the Thousand Talents
Program in China (to M.-W.W.), and the financial support for Shanghai Science and Technology Council
(16DZ2280100).
Conflicts of interest: There are no conflicts to declare.
Abbreviations
SF5
Pentafluorosulfane
CF3
Trifluoromethyl
SARMs
AR
Selective androgen receptor modulators
Androgen receptor
DMAc
DMF
DHT
SAR
TMS
N,N-dimethylacetamide
N,N-dimethylformamide
Dihydrotestosterone
Structure-activity relationship
Tetramethylsilane
References
1.
2.
3.
4.
Purser, S.; Moore, P.R.; Swallow, S.; Gouverneur, V. Fluorine in medicinal chemistry. Chem. Soc. Rev. 2008,
37, 320–330.
Sowaileh, M.F.; Hazlitt, R.A.; Colby, D.A. Application of the Pentafluorosulfanyl Group as a Bioisosteric
Replacement. ChemMedChem 2017, 12, 1481–1490.
Savoie, P.R.; Welch, J.T. Preparation and utility of organic pentafluorosulfanyl-containing compounds.
Chem. Rev. 2015, 115, 1130–1190.
Bassetto, M.; Ferla, S.; Pertusati, F. Polyfluorinated groups in medicinal chemistry. Future Med. Chem. 2015,
7, 527–546.

Molecules 2019, 24, 4227
13 of 14
5.
6.
Altomonte, S.; Zanda, M. Synthetic chemistry and biological activity of pentafluorosulphanyl (SF5) organic
molecules. J. Fluor. Chem. 2012, 143, 57–93.
Saethre, L.J.; Berrah, N.; Bozek, J.D.; Borve, K.J.; Carroll, T.X.; Kukk, E.; Gard, G.L.; Winter, R.; Thomas, T.D.
Chemical insights from high-resolution X-ray photoelectron spectroscopy and ab initio theory: Propyne,
trifluoropropyne, and ethynylsulfur pentafluoride. J. Am. Chem. Soc. 2001, 123, 10729–10737.
Bowden, R.D.; Comina, P.J.; Greenhall, M.P.; Kariuki, B.M.; Loveday, A.; Philp, D. A new method for the
synthesis of aromatic sulfurpentafluorides and studies of the stability of the sulfurpentafluoride group in
common synthetic transformations. Tetrahedron 2000, 56, 3399–3408.
Umemoto, T.; Garrick, L.M.; Saito, N. Discovery of practical production processes for arylsulfur
pentafluorides and their higher homologues, bis- and tris(sulfur pentafluorides): Beginning of a new era of
“super-trifluoromethyl” arene chemistry and its industry. Beilstein J. Org. Chem. 2012, 8, 461–471.
Gujjar, R.; El Mazouni, F.; White, K.L.; White, J.; Creason, S.; Shackleford, D.M.; Deng, X.Y.; Charman, W.N.;
Bathurst, I.; Burrows, J.; et al. Lead Optimization of Aryl and Aralkyl Amine-Based Triazolopyrimidine
Inhibitors of Plasmodium falciparum Dihydroorotate Dehydrogenase with Antimalarial Activity in Mice.
J. Med. Chem. 2011, 54, 3935–3949.
7.
8.
9.
10. Bhasin, S.; Jasuja, R. Selective androgen receptor modulators as function promoting therapies. Curr. Opin.
Clin. Nutr. Metab. Care 2009, 12, 232–240.
11. Narayanan, R.; Mohler, M.L.; Bohl, C.E.; Miller, D.D.; Dalton, J.T. Selective androgen receptor modulators
in preclinical and clinical development. Nucl. Recept. Signal. 2008, 6, e010.
12. Bhasin, S.; Calof, O.M.; Storer, T.W.; Lee, M.L.; Mazer, N.A.; Jasuja, R.; Montori, V.M.; Gao, W.Q.; Dalton,
J.T. Drug Insight: Testosterone and selective androgen receptor modulators as anabolic therapies for
chronic illness and aging. Nat. Clin. Pract. Endoc. 2006, 2, 146–159.
13. Marhefka, C.A.; Gao, W.; Chung, K.; Kim, J.; He, Y.; Yin, D.; Bohl, C.; Dalton, J.T.; Miller, D.D. Design,
synthesis, and biological characterization of metabolically stable selective androgen receptor modulators.
J. Med. Chem. 2004, 47, 993–998.
14. Yin, D.; Gao, W.; Kearbey, J.D.; Xu, H.; Chung, K.; He, Y.; Marhefka, C.A.; Veverka, K.A.; Miller, D.D.;
Dalton, J.T. Pharmacodynamics of selective androgen receptor modulators. J. Pharmacol. Exp. Ther. 2003,
304, 1334–1340.
15. Clark, R.V.; Walker, A.C.; Andrews, S.; Turnbull, P.; Wald, J.A.; Magee, M.H. Safety, pharmacokinetics and
pharmacological effects of the selective androgen receptor modulator, GSK2881078, in healthy men and
postmenopausal women. Br. J. Clin. Pharmacol. 2017, 83, 2179–2194.
16. Basaria, S.; Collins, L.; Dillon, E.L.; Orwoll, K.; Storer, T.W.; Miciek, R.; Ulloor, J.; Zhang, A.Q.; Eder, R.;
Zientek, H.; et al. The Safety, Pharmacokinetics, and Effects of LGD-4033, a Novel Nonsteroidal Oral,
Selective Androgen Receptor Modulator, in Healthy Young Men. J. Gerontol. Ser. a-Biol. Sci. Med. Sci. 2013,
68, 87–95.
17. Zilbermint, M.F.; Dobs, A.S. Nonsteroidal selective androgen receptor modulator Ostarine (TM) in cancer
cachexia. Future Oncol. 2009, 5, 1211–1220.
18. Ferla, S.; Bassetto, M.; Pertusati, F.; Kandil, S.; Westwell, A.D.; Brancale, A.; McGuigan, C. Rational design
and synthesis of novel anti-prostate cancer agents bearing a 3,5-bis-trifluoromethylphenyl moiety. Bioorg.
Med. Chem. Lett. 2016, 26, 3636–3640.
19. Guo, C.X.; Linton, A.; Kephart, S.; Ornelas, M.; Pairish, M.; Gonzalez, J.; Greasley, S.; Nagata, A.; Burke,
B.J.; Edwards, M.; et al. Discovery of Aryloxy Tetramethylcyclobutanes as Novel Androgen Receptor
Antagonists. J. Med. Chem. 2011, 54, 7693–7704.
20. Jung, M.E.; Ouk, S.; Yoo, D.; Sawyers, C.L.; Chen, C.; Tran, C.; Wongvipat, J. Structure-Activity Relationship
for Thiohydantoin Androgen Receptor Antagonists for Castration-Resistant Prostate Cancer (CRPC). J.
Med. Chem. 2010, 53, 2779–2796.

Molecules 2019, 24, 4227
14 of 14
21. Piatnitski Chekler, E.L.; Unwalla, R.; Khan, T.A.; Tangirala, R.S.; Johnson, M.; St Andre, M.; Anderson, J.T.;
Kenney, T.; Chiparri, S.; McNally, C.; et al. 1-(2-Hydroxy-2-methyl-3-phenoxypropanoyl)indoline-4-
carbonitrile derivatives as potent and tissue selective androgen receptor modulators. J. Med. Chem. 2014,
57, 2462–2471.
Sample Availability: Samples of the compounds 3–16g are available from the authors.
© 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access
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