Synthesis of N-(2-SF5-ethyl)amines and impact of the SF5 substituent on their basicity and lipophilicity

Article abstract of DOI:10.1016/j.tet.2021.132424

The synthesis of N-(2-SF₅-ethyl)amines is reported via the S_N2 reaction between various amines and 2-(pentafluoro-λ⁶-sulfanyl)ethyl trifluoromethanesulfonate as the SF₅-containing electrophile. A total of 14 exa

Full text of DOI:10.1016/j.tet.2021.132424

Tetrahedron xxx (xxxx) xxx
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of N-(2-SF5-ethyl)amines and impact of the SF5 substituent
on their basicity and lipophilicity
Audrey Gilbert, Pauline Langowski, Jean-François Paquin*
ꢀ
ꢀ
ꢀ
PROTEO, CCVC, Departement de Chimie, Universite Laval, Quebec, QC, G1V 0A6, Canada
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of N-(2-SF5-ethyl)amines is reported via the SN2 reaction between various amines and 2-
(pentafluoro-l
6-sulfanyl)ethyl trifluoromethanesulfonate as the SF5-containing electrophile. A total of 14
Received 8 July 2021
Received in revised form
20 August 2021
Accepted 23 August 2021
Available online xxx
examples of SF5-containing aliphatic amines were synthesized, with yields going from 19 to 92%.
Moreover, the effect of the SF5 substituent on the basicity and the lipophilicity of the amine was eval-
uated, and the SF5 group showed to decrease both the pKaH and the log D (pH ¼ 7.0) values.
© 2021 Elsevier Ltd. All rights reserved.
Keywords:
Amines
Pentafluorosulfanyl
Nucleophilic substitution
Basicity
Lipophilicity
1. Introduction
its extreme properties, which make it attractive in many fields of
chemistry such as medicinal chemistry [7], agrochemistry [8] and
Amines occupy a place of choice in medicinal chemistry, and as
such, their synthesis, as well as the evaluation of their physico-
chemical properties, is of great importance for drug-development
purposes [1]. In particular, the log D (measure of lipophilicity)
and pKa (measure of basicity) values of amines are important pa-
rameters that are closely monitored since they can have a great
impact on the biological properties [2].
material sciences (Scheme 1) [9]. Indeed, the SF5 group, in addition
to being significantly bulky and stable [10], has a strong electro-
negativity (Xr ¼ 3.65) as well as a high electron-withdrawing ca-
pacity, with a Hammet constant of sp ¼ 0.68, compared to sp ¼ 0.53
for the CF3 substituent [11]. The SF5-group also presents a great
hydrophobicity, with a Hansch value (
p
(SF5)) of 1.50, compared to
(CF3)) of 1.09 [12]. Overall,
the trifluoromethyl substituent value (
p
The addition of a fluorinated substituent to an amine is a
powerful tool to modulate its physicochemical properties, in
particular the lipophilicity and the basicity [3]. The fluorine atom, in
addition to being poorly polarizable, presents the highest electro-
negativity of the periodic table (Xr ¼ 3.98) [4]. These properties
generally translate into the increase of the lipophilicity of a com-
pound upon fluorination [3,5], albeit decreased lipophilicities have
also been reported upon fluorination on aliphatic positions [3,5],
while a decreased pKa value for neighboring substituents is typi-
cally observed when replacing a CeH bond by a CeF bond on a
molecule [3,6].
the SF5-substituent shows similar properties to the trifluoromethyl
(CF3), but always enhanced compared to the latter, which accounts
for the SF5 group often referred to as a "super CF3" [13].
While some pentafluorosulfanylated anilines are commercially
available, the synthesis of SF5-containing aliphatic amines has, to
the best of our knowledge, never been reported. However,
considering the interesting properties of the SF5-moiety, the pen-
tafluorosulfanylation of amines is envisaged to strongly affect their
physicochemical properties, which could represent a useful tool in
drug-development processes. In that context, we report herein the
first synthesis of N-(2-SF5-ethyl)amines as well as the evaluation of
the effect of pentafluorosulfanylation on the basicity and the lip-
ophilicity of the amine (Scheme 1).
Among the fluorinated functional groups, the penta-
fluorosulfanyl (SF5) substituent is of particular interest, considering
* Corresponding author.
E-mail address: jean-francois.paquin@chm.ulaval.ca (J.-F. Paquin).
https://doi.org/10.1016/j.tet.2021.132424
0040-4020/© 2021 Elsevier Ltd. All rights reserved.
Please cite this article as: A. Gilbert, P. Langowski and J.-F. Paquin, Synthesis of N-(2-SF5-ethyl)amines and impact of the SF5 substituent on their
basicity and lipophilicity, Tetrahedron, https://doi.org/10.1016/j.tet.2021.132424

A. Gilbert, P. Langowski and J.-F. Paquin
Tetrahedron xxx (xxxx) xxx
Scheme 1. Context and target.
2. Results and discussion
(entry 8) proved to be superior, with yields of the desired com-
pound 4a of 57 and 56% respectively.
2.1. Synthesis of the N-(2-SF5-ethyl)amines
Next, the reaction time and the amount of each reagent was
optimized in the reaction (Table 2). In all cases, full conversions
were observed with a reaction time reduced to 1 h, and for that
reaction time, dichloromethane afforded the desired compound 4a
with a 74% NMR yield (entry 1). Dichloromethane proved slightly
superior to toluene (result not shown) and was therefore kept for
the rest of the optimization. The equivalents of the SF5-triflate 3
were increased (entries 2e3), as well as the equivalents of N-
benzylmethylamine 1a (entries 4e5), and using 1.5 equivalents of
the SF5-triflate 3 proved optimal with an isolated yield of the
desired compound 4a of 91% (entry 5). Finally, increasing the
equivalents of K2CO3 did not further improve the yield (entries
6e7), and the conditions depicted in entry 5 were therefore chosen
as optimal.
With the optimized reaction conditions in hand, the scope of the
reaction was evaluated (Scheme 4). While the model substrate 4a
was obtained with a 91% yield after a 1-h reaction, performing the
reaction with other amines showed incomplete conversions with
this reaction time. The latter was therefore re-optimized, and 3 h
proved optimal and was kept for the evaluation of the scope.
Moreover, some of the amines proved unstable on silica gel (4b-4d,
4f) and were therefore isolated as oxalate salts [17]. First, a series of
5 and 6-membered ring cyclic amines were submitted to the re-
action conditions (4b-4f). In all cases, moderate to excellent yields
were obtained, with the exception of the ketone-substituted amine
4e, for which a low 19% yield was obtained. This was attributed to a
decreased nucleophilicity of the amine due to the presence of the
electron-withdrawing ketone. Heterocycles 4g and 4h were ob-
tained with good yields of 57% and 78% respectively. Next, several
anilines were submitted to the reaction conditions. While N-
methylaniline led to a moderate yield of 53% of the desired com-
pound 4i, the use of the primary aniline as the nucleophile led to a
low yield of 39% of the desired compound 4j, along with 13% of the
double-alkylated side product 4k. The formation of this side reac-
Our synthetic strategy towards the desired SF5-containing
amines is based on the use of a SN2 reaction between the amine and
an appropriate SF5-containing electrophile (Scheme 2) [14]. Two
SF5-containing electrophiles, i.e., the tosylate 2 and the triflate 3,
were evaluated in the SN2 reaction with amines.
The synthesis of the SF5-containing electrophiles was performed
via the three-step protocols depicted in Scheme 3. First, the SF5Cl
radical addition on vinyl acetate was performed using Et3B as the
radical initiator [15], followed by the reduction of the acetate and
the CeCl bond using LiAlH4, leading to SF5-ethanol 5 [16]. The
alcohol group was next activated with either TsCl under basic
conditions, yielding the desired SF5-containing tosylate 2 with an
overall yield of 63%, or with the use of Tf2O, to afford the desired
SF5-containing triflate 3 with an 83% overall yield.
The SN2 reaction of the SF5-tosylate 2 with N-benzylmethyl-
amine (1a) as the model substrate was next attempted under
various reaction conditions (results not shown), but the desired
product 4a could never be observed in the reaction mixture. The
optimization of the reaction was therefore conducted with the SF5-
containing triflate 3 (Tables 1 and 2). First, the reaction was con-
ducted in various solvents at room temperature for 20 h, using 1
equivalent of triflate 3, the nucleophile, N-benzylmethylamine (1a),
and the base K2CO3 (Table 1). To our delight, in all solvents with the
exception of DMF (entry 3) and DMSO (entry 4), the final com-
pound 4a could be detected in the reaction mixture. In all cases, full
conversions were observed, and NMR yields going from 32 to 57%
were obtained, the remaining of the conversion attributed to
degradation, since no other compounds could be identified in the
crude mixtures. No sign of the elimination product was detected in
the reaction mixtures. Toluene (entry 7) and dichloromethane
tion was overcome by the presence of a methyl group at the a-
position from the nitrogen atom, since no sign of the double-
alkylated compound and a good 84% yield of compound 4l was
obtained when using (S)-1-phenylethylamine as the nucleophile.
Two proline derivatives were also tested in the reaction and led to
good yields of 67% for compound 4m and 62% for compound 4n.
Scheme 2. Synthetic strategy towards the SF5-containing aliphatic amines.
2

A. Gilbert, P. Langowski and J.-F. Paquin
Tetrahedron xxx (xxxx) xxx
Scheme 3. Synthesis of the SF5-containing electrophiles.
Table 1
Solvent optimization of the SN2 reaction of the SF5-triflate 3 and N-benzylmethylamine (1a).
Entry
Solvent
Yield (%)a
1
2
3
MeCN
THF
DMF
32
40
0
4
5
6
7
8
9
10
DMSO
EtOH
EtOAc
toluene
CH2Cl2
Et2O
0
39
41
57
56
36
48
1,4-dioxane
a
Estimated by 19F NMR analysis of the crude mixture using 2-fluoro-4-nitrotoluene as the internal standard.
Table 2
Optimization of the reaction time and the amounts of reagent for the SN2 reaction of the SF5-triflate 3 and N-benzylmethylamine (1a).
Entry
1a (x equiv.)
3 (y equiv.)
K2CO3 (z equiv.)
Yield (%)a
1
2
3
4
5
6
7
1
1
1
1
1.1
1.5
1.5
1.5
1
1
1
1
1
1.1
1.5
74
82
77
82
1.1
1.5
1
1
1
87 (91)b
86
1
86
a
Estimated by 19F NMR analysis of the crude mixture using 2-fluoro-4-nitrotoluene as the internal standard.
Isolated yield.
b
Finally, the functionalized piperidine derivative 4o could be ob-
tained with an excellent yield of 92%.
containing amine 4o was chosen as the model substrate for the
evaluation of these physicochemical properties. For comparison
reasons, the basicity and the lipophilicity of analogous compounds
bearing either an ethyl alkyl chain 6 or the CF3 substituent at the
alpha 7 or beta positions 8 of the nitrogen atoms were evaluated.
The synthesis of these compounds is depicted in Scheme 5. First,
compound 6, bearing the ethyl alkyl chain, was synthesized via the
alkylation of amine 1o with iodoethane with a good yield of 66%.
2.2. Evaluation of the modulation of the physicochemical properties
Having established a synthetic route towards the desired SF5-
containing aliphatic amines, the effect of the SF5 substituent on the
basicity and the lipophilicity of the amine was evaluated. The SF5-
3

A. Gilbert, P. Langowski and J.-F. Paquin
Tetrahedron xxx (xxxx) xxx
Scheme 4. Scope of the reaction for the synthesis of SF5-containing aliphatic amines aReaction time of 1 h bIsolated as the oxalate salt.
Next, the CF3-containing analogues 7 and 8 were obtained via the
alkylation of amine 1o with the corresponding CF3-containing tri-
flates. In the case of compound 7, considering the low boiling point
of 2,2,2-trifluoroethyl trifluoromethanesulfonate [18], the triflate
was generated in situ and the desired amine 7 was obtained with a
low 42% yield. Amine 8 was afforded with a good 83% yield upon
alkylation with 3,3,3-trifluoropropyl trifluoromethanesulfonate.
measured value was acceptable for the purposes of this study,
considering that the objective is to compare the pKaH values of the
compounds at study rather than assessing their absolute pKaH
values.
The results obtained for the pKaH values of compounds 4o, 6, 7
and 8 are summarized in Table 3. First, the pKaH value of the ethyl
derivative 6 was evaluated to 9.2. Upon trifluoromethylation, as in
substrate 7, the pKaH value considerably lowered to 4.9. This was
expected, considering the strong electron-withdrawing capacity of
the CF3 group. Next, the pKaH value of derivative 8, bearing the CF3
group one carbon further to the nitrogen atom led to an interme-
diate value of 7.2. This shows that the effect of fluorination on the
basicity of the amine is highly dependent on the distance between
the nitrogen atom and the fluorinated group, since a difference of
2.3 pKaH units was observed between the alpha-CF3 and the beta-
CF3-substituted amines. Finally, the SF5 group showed to further
decrease the basicity of the amine, since a value of 6.5 was obtained
for the pKaH value of compound 4o. Indeed, when comparing the
obtained pKaH values for compounds 4o and 8, bearing the fluori-
nated substituent at the same carbon length from the nitrogen
2.2.1. Evaluation of the basicity of compounds 4o, 6, 7 and 8
The effect of pentafluorosulfanylation on the basicity of the
amine was next evaluated through the measurement of the pKaH
values of compounds 4o, 6, 7 and 8 via an NMR-based titration
[19,20]. This method has previously shown to be reliable and lead
to similar results compared to other titration methods such as UV
spectroscopy, potentiometric and capillary electrophoretic tech-
niques [21]. In order to validate the method and estimate the error
of the obtained pKaH values, the titration of N-methylmorpholine
(via 1H NMR in D2O), with a known pKaH value of 7.41, was per-
formed, and the pKaH value that was calculated is 7.5. [22] It was
considered that the difference between the literature and the
4

A. Gilbert, P. Langowski and J.-F. Paquin
Tetrahedron xxx (xxxx) xxx
Scheme 5. Synthesis of the analogous amines for the evaluation of the physicochemical properties.
Table 3
pKaH values of compounds 4o, 6, 7 and 8.
Amine
pKaH
9.2
Fig. 1. Comparison of the log P value of alcohols 9 and 10.
atom, it is possible to see that the SF5 group induced a decrease of
the pKaH value of 0.7 unit stronger than the CF3 group. This was
expected, since the SF5 substituent has a stronger electron-
withdrawing capacity than the CF3 [11]. This result shows that
the SF5 group can indeed strongly affect the basicity of an amine,
which could be of great interest in medicinal chemistry.
4.9
2.2.2. Evaluation of the lipophilicity of compounds 4o, 6, 7 and 8
The effect of pentafluorosulfanylation on the lipophilicity of
amines 4o, 6, 7 and 8 was next evaluated. Considering the Hansch
7.2
value for the SF5 group (
p
¼ 1.50) compared to the CF3 group
(p
¼ 1.09), its introduction into a compound is expected to increase
the lipophilicity, resulting in a higher log P value [12]. For example,
using a protocol based on a 19F NMR method recently published by
Linclau and coworkers, the log P value of the SF5-containing ethanol
9 was evaluated to be 0.92, while the CF3 analogue 10 has a log P
value of 0.41, as determined in the original paper from Linclau
(Fig. 1) [5c,20]. Hence, as anticipated, the more lipophilic SF5 sub-
stituent increased the log P value.
6.5
In case of amines 4o, 6, 7 and 8, the lipophilicity was evaluated
through the measurement of their log D (pH ¼ 7.0) values (calcu-
lated from the distribution coefficient in a water/1-octoanol
biphasic system with a pH 7.0 buffer), using an adaptation to Lin-
clau's protocol [5c,20]. Considering that amines are basic com-
pounds, this approach was used instead of the log P values, in order
5

A. Gilbert, P. Langowski and J.-F. Paquin
Tetrahedron xxx (xxxx) xxx
Table 4
evaluated to approximatively 3, which also reaches the upper limit
value for the log D determination method of 3. In this case, a low
signal was obtained in the aqueous phase, which allowed to
calculate a value of 3.03, but considering the limit of the method,
this value was considered unprecise and therefore approximated to
3. Nonetheless, this result shows that amine 8, bearing the CF3-
group at one carbon further from the nitrogen atom, is less lipo-
philic than its alpha-trifluoromethylated analogue 7. This can again
be explained by the pKaH value of 7.2 obtained for this compound,
which indicates that at pH ¼ 7.0, both ammonium and free-amine
species are present in almost equimolar quantities. This translates
into a decreased log D (pH ¼ 7.0) value, when compared to the more
acidic amine 7. Finally, the lipophilicity of the SF5-containing amine
4o was evaluated to a log D (pH ¼ 7.0) value of 1.90. A higher log D
(pH ¼ 7.0) value could be expected for the SF5 derivative, consid-
ering its high Hansch hydrophobic constant as well as its pKaH value
of 6.5, but the presence of the SF5 substituent showed to decrease
the lipophilicity of the amine 4o when compared to its tri-
fluoromethylated analogue 8. The contribution of the free-amine
species at pH ¼ 7.0 should be slightly higher with compound 4o
than in the case of compound 8, resulting in a higher log D
(pH ¼ 7.0) value. However, this was not observed, and the log D
(pH ¼ 7.0) value of the pentafluorosulfanylated derivative 4o is
considerably lower than the log D (pH ¼ 7.0) value for the beta-CF3
analogue 8. This suggests that in this specific case, another effect is
at play. We hypothesized that the reduction of the lipophilicity
from the dipolar moment induced by the presence of the SF5 group
causes a stronger effect over the potential increase of lipophilicity
from the fluorinated surface. This could possibly be explained by
the octahedral geometry of the SF5 moiety. Indeed, considering the
bond-vector analysis published by Müller in 2014, each polarized
SeF bond increases the polarity of a compound and therefore,
lowers its lipophilicity [5b]. Müller showed that the orientation of
these polarized bonds can have a great effect on the resulting
dipolar moment, since several polarized bonds can compensate
each other and result in a lower global dipolar moment. When
comparing the CF3 substituent, which has an inverted cone ge-
ometry, with the octahedral SF5 group, it is possible to imagine that
the dipolar moment induced by each of the CeF bonds is partially
compensated with the other CeF bonds, while for the SF5 moiety,
the axial SeF bond is not cancelled by the equatorial SeF bonds. In
the case of compound 4o, this resulting dipolar moment is believed
to affect the log D (pH ¼ 7.0) value of the compound to a greater
extent than the fluorinated surface's hydrophobicity, leading to a
lower log D (pH ¼ 7.0) value than expected.
Log D (pH ¼ 7.0) values of compounds 4o, 6, 7 and 8.
Amine
log D (pH ¼ 7.0)a
0.64
>3b
~3
1.90
a
Average value of a triplicate result. 2,2,2-trifluoroethanol was used as the in-
ternal standard.
b
The compound was not detected in the aqueous phase.
to take into account all forms of the compounds (ionized and
neutral). The results are summarized in Table 4. First, the ethyl
derivative 6 led to a log D (pH ¼ 7.0) value of 0.64, while the log D
(pH ¼ 7.0) value of its trifluomethylated analogue 7 could not be
evaluated, due to its high lipophilicity. Indeed, no signal could be
detected in the 19F NMR spectra of the buffer phase. The log D
(pH ¼ 7.0) value of compound 7 therefore exceeds the limit of the
log D (pH ¼ 7.0) determination method (considered to be around 3
in Linclau's original paper [(5c)]) and could not be evaluated. This
difference in the log D (pH ¼ 7.0) values between compounds 6 and
7 can be explained by their respective pKaH values. With a pKaH
value of 9.2, compound 6 is more ionized to the ammonium species
at pH ¼ 7.0 than compound 7, that has a pKaH value of 4.9. This leads
for amine 6 to a higher solubility in water, since the ammonium
species is more hydrophilic than the free-amine species, and
therefore a decreased log D (pH ¼ 7.0) value. In the case of the
trifluoromethylated analogue 7, the major species at pH ¼ 7.0 is the
free-amine species, which is neutral and therefore, more soluble in
the organic phase. This translates into an increased log D (pH ¼ 7.0)
value for compound 7. Combining this effect with the fact that
fluorination tends to increase the lipophilicity of compounds leads
to a lipophilicity value for compound 7 that exceeds the limit of the
log D (pH ¼ 7.0) determination method. This shows how strongly
fluorination of a compound can modulate physicochemical prop-
erties such as the basicity and the lipophilicity of a molecule. The
log D (pH ¼ 7.0) value of the beta-CF3-substituted amine 8 was next
3. Conclusion
In conclusion, we have reported the first synthesis of N-(2-SF5-
ethyl)amines via the alkylation of amines, using 2-(pentafluoro-l6
-
sulfanyl)ethyl trifluoromethanesulfonate as the electrophile. A total
of 14 examples with yields going from 19 to 92% are reported,
providing the first synthetic access to these potentially valuable
pentafluorosulfanylated building-blocks. Moreover, the effect of
the SF5-substituent on the lipophilicity and the basicity of the
amine was evaluated. The SF5-group showed to lower the basicity
of the amine in a greater manner compared to the CF3 group,
highlighting the enhanced properties of the SF5 moiety compared
to its trifluoromethylated analogue. The latter also showed to lower
the lipophilicity of the amine, a result that was attributed to the
strong dipolar moment induced by the presence of the highly
electronegative SF5 moiety. These results show that the unique
properties of the SF5 group can translate into modulation of
important physicochemical properties of a compound, which could
be of great interest in medicinal chemistry. To the best of our
6

A. Gilbert, P. Langowski and J.-F. Paquin
Tetrahedron xxx (xxxx) xxx
knowledge, this represents the first example of the direct assess-
ment of the SF5 substituent on such properties.
the reaction was stirred at room temperature for 2 h. The crude was
next diluted with CH2Cl2 and the solvent was removed under
reduced pressure. The crude mixture was purified by flash chro-
matography on silica gel using hexane/EtOAc (9:1) as the eluent to
afford the title compound 2 as a white solid (2.15 g, 6.59 mmol, 63%
4. Experimental
4.1. General information
over three steps). 1H NMR (500 MHz, CDCl3):
d
(ppm) ¼ 7.80 (d,
J ¼ 8.3 Hz, 2H), 7.42e7.31 (m, 2H), 4.40 (t, J ¼ 6.2 Hz, 2H), 4.01e3.79
All reactions were carried out under an argon atmosphere with
dry solvents. All commercially available compounds were used as
received. SF5Cl was purchased at SynQuest Labs inc. and was
condensed at a known concentration in hexane. This solution was
then used for the SF5Cl additions and could be stored for several
months in a ꢀ35 ꢁC freezer. Thin-layer chromatography (TLC)
analysis of reaction mixtures was performed using Silicycle silica
gel 60 Å F254 TLC plates, and visualized under UV or by staining
with potassium permanganate. Flash column chromatography was
carried out on Silicycle silica gel 60 Å, 230e400 mesh. 1H, 13C and
19F NMR spectra were recorded in CDCl3 at room temperature using
an Agilent DD2 500 MHz or a Varian Inova 400 MHz spectrometer.
1H and 13C NMR chemical shifts are reported in ppm downfield of
tetramethylsilane and are respectively referenced to tetrame-
(m, 2H), 2.47 (s, 3H); 19F NMR (470 MHz, CDCl3):
d
(ppm) ¼ 82.9e79.4 (m, 1F), 66.6 (dt, J ¼ 146.8, 7.8 Hz, 4F).
Analytical data were identical to those previously reported [14a].
4.3. Synthesis of 2-(pentafluoro-
trifluoromethanesulfonate 3
l
6-sulfanyl)ethyl
Following the procedure described by Carreira and coworkers
[16], to a solution of vinyl acetate (2 mL, 20.91 mmol, 1 equiv.) in
CH2Cl2 (84 mL, 0.25 M) at ꢀ40 ꢁC were successively added SF5Cl
(32.0 mL, 0.98 M in hexane, 31.36 mmol, 1.5 equiv.) and Et3B
(2.1 mL, 1 M in THF, 2.09 mmol, 0.1 equiv.). The reaction was stirred
at ꢀ40 ꢁC for 3 hours before it was quenched by the addition of a
saturated solution of NaHCO3. The phases were separated, and the
organic phase was dried over MgSO4, filtered and carefully
concentrated under reduced pressure (to avoid evaporation of the
product, the pressure was kept at 400 mmHg in a 40 ꢁC water bath).
The crude SF5Cl addition product was next dissolved in Et2O
(139 mL, 0.15 M) and put in an ice bath at 0 ꢁC. LiAlH4 (20.9 mL, 1 M
in Et2O, 20.91 mmol, 1 equiv.) was then added dropwise to the
mixture, and the reaction was stirred at 0 ꢁC for 15 min. The reac-
tion was next quenched with a saturated solution of Rochelle's salt,
and the mixture was stirred at room temperature for 1 h. The
mixture was then extracted 3 times with Et2O, and the organic
phases were combined, washed with brine, dried over Na2SO4,
filtered and concentrated under reduced pressure (to avoid evap-
oration of the product, the pressure was kept at 400 mmHg in a
40 ꢁC water bath). Next, following the procedure described by
Seppelt and co-worker [14b], to a solution of the crude SF5-alcohol
in CH2Cl2 (6 mL) was added pyridine (1.7 mL, 20.91 mmol, 1 equiv.).
This mixture was added dropwise to a solution of Tf2O (5.3 mL,
31.37 mmol, 1 equiv.) in CH2Cl2 (24 mL) at 0 ꢁC. The reaction was
stirred at 0 ꢁC for 2 h before it was quenched by the addition of ice-
cold water. The phases were separated, and the organic phase was
dried over Na2SO4, filtered and concentrated under reduced pres-
sure. The crude product was purified by flash chromatography on
silica gel using hexane/EtOAc (90:10) as the eluent to afford the title
compound 3 as a brown oil (5.30 g, 17.42 mmol, 83% over three
thylsilane (
d
¼ 0.00 ppm) and residual solvent ( ¼ 77.16 ppm). For
d
19F NMR, calibration was performed using a unified scale [23].
Multiplicities are reported using the following abbreviations:
s ¼ singlet, d ¼ doublet, t ¼ triplet, q ¼ quartet, p ¼ pentet,
sext ¼ sextet, m ¼ multiplet, bs ¼ broad signal. High-resolution
mass spectra were obtained on a LC/MSeTOF Agilent 6210 using
electrospray ionization (ESI) or atmospheric pressure photoioni-
zation (APPI). When in all conditions tested for HRMS analysis (ESI
(þ), ESI (ꢀ), APPI), we could not detect any significant ions, low-
resolution mass spectra were obtained on a Thermo Trace ULTRA
GCMS equipped with an Agilent J&W HP-1 capillary column, an ITQ
900 mass selective detector (EI) or (CI) using the following method:
40 ꢁC for 1 min then 10 ꢁC/min until 330 ꢁC. Infrared spectra were
recorded using an ABB MB3000 FT-IR spectrometer. The melting
points (m.p.) were recorded on a MPA100 apparatus using the
following method: 40 ꢁCe200 ꢁC at 2 ꢁC/min.
4.2. Synthesis of 2-(pentafluoro-
methylbenzenesulfonate 2
l
6-sulfanyl)ethyl 4-
Following the procedure described by Carreira and coworkers
[16], to a solution of vinyl acetate (1 mL, 10.45 mmol, 1 equiv.) in
CH2Cl2 (42 mL, 0.25 M) at ꢀ40 ꢁC were successively added SF5Cl
(8.52 mL, 1.84 M in hexane, 15.68 mmol, 1.5 equiv.) and Et3B (1 mL,
1 M in THF, 1.05 mmol, 0.1 equiv.). The reaction was stirred
at ꢀ40 ꢁC for 3 hours before it was quenched by the addition of a
saturated solution of NaHCO3. The phases were separated, and the
organic phase was dried over MgSO4, filtered and carefully
concentrated under reduced pressure (to avoid evaporation of the
product, the pressure was kept at 400 mmHg in a 40 ꢁC water bath).
The crude SF5Cl addition product was next dissolved in dry Et2O
(70 mL, 0.15 M) and put in an ice bath at 0 ꢁC. LiAlH4 (10.5 mL,1 M in
Et2O, 10.45 mmol, 1 equiv.) was then added dropwise to the
mixture, and the reaction was stirred at 0 ꢁC for 15 min. The reac-
tion was next quenched with a saturated solution of Rochelle's salt,
and the mixture was stirred at room temperature for 1 h. The
mixture was then extracted 3 times with Et2O, and the organic
phases were combined, washed with brine, dried over Na2SO4,
filtered and concentrated under reduced pressure (to avoid evap-
oration of the product, the pressure was kept at 400 mmHg in a
40 ꢁC water bath). The crude SF5-alcohol was next dissolved in dry
CH2Cl2 (10.5 mL, 1 M) and this solution was added in a round-
bottom flask containing TsCl (2 g, 10.45 mmol, 1 equiv.). Et3N
(2.9 mL, 20.90 mmol, 3 equiv.) was next added to the mixture, and
steps). 1H NMR (500 MHz, CDCl3):
4.10e3.91 (m, 2H); 19F NMR (470 MHz, CDCl3):
d
(ppm) ¼ 4.86 (t, J ¼ 5.8 Hz, 2H),
d
(ppm) ¼ 81.2e79.6
(m, 1F), 66.6 (dt, J ¼ 146.7, 7.3 Hz, 4F), ꢀ74.5 (s, 3F). Analytical data
were identical to those previously reported [14b].
4.4. Synthesis of the amines
4.4.1. 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid 11
Following the procedure described by Gobec and coworkers
[24], to a solution of isonipecotic acid (1,00 g, 7.74 mmol, 1 equiv) in
1,4-dioxane (5 mL) at 0 ꢁC was added a freshly prepared solution of
NaOH in H2O (1 M, 7.74 mL, 7.74 mmol,1 equiv.). A solution of Boc2O
(2.03 g, 9.29 mmol,1.2 equiv.) in 1,4-dioxane (7 mL) was then added
to the reaction mixture over 30 min. The reaction mixture was next
allowed to warm to room temperature and stirred for 1 h. The crude
mixture was next concentrated under reduced pressure (ca.
10e15 mL), and the crude mixture was acidified to pH z 3e4 with
a 10% HCl solution in water. The crude mixture was next extracted 3
times with EtOAc, and the organic phases were combined, washed
with brine, dried over MgSO4, filtered and concentrated under
7

A. Gilbert, P. Langowski and J.-F. Paquin
Tetrahedron xxx (xxxx) xxx
reduced pressure to afford the title compound 11 as a white solid
(1.60 g, 6.98 mmol, 91%). The crude product was used in the next
step without further purification. 1H NMR (500 MHz, CDCl3):
dried over MgSO4, filtered and concentrated under reduced pres-
sure. The crude mixtures were purified by flash chromatography on
silica gel or by the formation of an oxalate salt with oxalic acid (1.1
equiv.), using the protocol described by Trudell and coworkers
[17b].
d
(ppm) ¼ 4.04 (br s, 2H), 2.87 (t, J ¼ 10.8 Hz, 2H), 2.58 (tt, J ¼ 10.8,
3.9 Hz, 1H), 1.93 (br d, J ¼ 13.0 Hz, 2H), 1.75e1.59 (m, 2H), 1.46 (s,
9H). Analytical data were identical to those previously reported
[25].
4.5.2. N-benzyl-N-methyl-2-(pentafluoro-
amine 4a
l
6-sulfanyl)ethan-1-
4.4.2. 1-(tert-butyl) 4-(4-fluorobenzyl) piperidine-1,4-
dicarboxylate 12
N-Benzylmethylamine 1a (40.0 mg, 0.33 mmol), K2CO3
(45.6 mg, 0.33 mmol), 2-(pentafluoro-
l
6-sulfanyl)ethyl tri-
Following the procedure described by Aida and coworkers [26],
1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (500 mg,
2.18 mmol, 1 equiv.) was dissolved in CH2Cl2 (8.7 mL) and put in an
ice bath at 0 ꢁC. 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide
(EDC) (439 mg, 2.29 mmol, 1.05 equiv.) and 4-
dimethylaminopyridine (DMAP) (13.3 mg, 0.11 mmol, 0.05 equiv.)
were added to the mixture at 0 ꢁC, before (4-fluorophenyl)meth-
anol (0.24 mL, 2.18 mmol, 1 equiv.) was added to the mixture. The
mixture was allowed to warm to room temperature and was stirred
overnight. The mixture was next washed twice with a 10% HCl
solution and once with brine. The organic phase was dried over
Na2SO4, filtered and the solvent was removed under reduced
pressure. The crude mixture was purified by flash chromatography
on silica gel using hexane/EtOAc (80:20) as the eluent to afford the
title compound 12 as a colorless oil (666.9 mg, 1.98 mmol, 91%). 1H
fluoromethanesulfonate 3 (150.6 mg, 0.50 mmol) and CH2Cl2
(1.3 mL) were engaged in the general procedure for 1 h to afford the
title compound 4a as a colorless oil (83.5 mg, 0.30 mmol, 91%) after
purification by flash chromatography on silica gel using hexane/
EtOAc (95:5) as the eluent. 1H NMR (500 MHz, CDCl3):
d
(ppm) ¼ 7.35e7.26 (m, 5H), 3.86e3.70 (m, 2H), 3.56 (s, 2H),
3.02e2.88 (m, 2H), 2.25 (s, 3H); 13C NMR (126 MHz, CDCl3):
(ppm) ¼ 138.2, 128.8, 128.4, 127.4, 69.0 (p, J ¼ 10.6 Hz), 62.1, 52.3
(p,
4.9 Hz), 42.0; 19F NMR (470 MHz, CDCl3):
d
J
¼
d
(ppm) ¼ 86.1e84.2 (m, 1F), 66.3 (dt, J ¼ 145.9, 8.2 Hz, 4F); HRMS-
ESI (þ) m/z calcd for C10H15F5NS [MþH]þ 276.0840 found 276.0854;
IR (ATR, Diamond):
1026, 816.
n
(cmꢀ1) ¼ 2982, 2797, 1497, 1454, 1327, 1132,
4.5.3. 1-(2-(pentafluoro-
Piperidine (40.0 mg, 0.47 mmol), K2CO3 (64.9 mg, 0.47 mmol), 2-
6-sulfanyl)ethyl
(pentafluoro- trifluoromethanesulfonate 3
l
6-sulfanyl)ethyl)piperidine oxalate 4b
NMR (500 MHz, CDCl3):
d
(ppm) ¼ 7.36e7.28 (m, 2H), 7.07e6.96 (m,
2H), 5.08 (s, 2H), 4.01 (s, 2H), 2.81 (s, 2H), 2.48 (tt, J ¼ 11.1, 3.9 Hz,
l
1H), 1.87 (d, J ¼ 13.0 Hz, 2H), 1.73e1.53 (m, 2H), 1.44 (s, 9H); 13C
(214.3 mg, 0.70 mmol) and CH2Cl2 (1.9 mL) were engaged in the
general procedure to afford the title compound 4b as a white solid
(102.1 mg, 0.31 mmol, 66%) after precipitation as an oxalate salt
with oxalic acid (46.5 mg, 0.52 mmol). m.p. ¼ 118.7e119.1 ꢁC; 1H
NMR (126 MHz, CDCl3):
d
(ppm) ¼ 174.3, 163.6,161.6, 154.7, 131.8 (d,
J ¼ 3.4 Hz), 130.1 (d, J ¼ 8.3 Hz), 115.5 (d, J ¼ 21.7 Hz), 79.6, 65.6, 41.1,
28.4, 27.9; 19F NMR (470 MHz, CDCl3):
d
(ppm) ¼ ꢀ113.6 (ddd,
J ¼ 14.1, 8.9, 5.6 Hz, 1F); GC-MS (CI) calcd for C18H23FNO4 [M ꢀ H]þ
NMR (500 MHz, CD3OD):
d
(ppm) ¼ 4.39e4.17 (m, 2H), 3.75e3.57
336.16 found 336.40; IR (ATR, Diamond):
1732, 1688, 1512, 1366, 1225, 1153.
n
(cmꢀ1) ¼ 2976, 2858,
(m, 2H), 3.26 (br s, 4H), 1.85 (br t, J ¼ 5.9 Hz, 4H), 1.66 (br s, 2H).; 13
C
NMR (126 MHz, CD3OD):
d
(ppm) ¼ 164.7, 64.9e61.7 (m), 53.5,
51.6e50.2 (m), 23.0, 21.2; 19F NMR (470 MHz, CD3OD):
4.4.3. 4-fluorobenzyl piperidine-4-carboxylate 1o
d
(ppm) ¼ 82.8e78.4 (m, 1F), 65.7 (dt, J ¼ 144.6, 7.3 Hz, 4F); HRMS-
Following the procedure described by Kiyoshi and coworkers
[27], 1-(tert-butyl) 4-(4-fluorobenzyl)piperidine-1,4-dicarboxylate
(300 mg, 0.89 mmol, 1 equiv.) was dissolved in CH2Cl2 (3.3 mL,
0.27 M) at room temperature. Trifluoroacetic acid (1.0 mL, 0.8 M)
was added, and the mixture was stirred for 1 h. The reaction was
then quenched with a 1 M NaOH solution and extracted 3 times
with CH2Cl2. The organic phases were combined, washed with
brine and dried over Na2SO4. The crude mixture was filtered and
evaporated under reduced pressure to afford the title compound 1o
as a colorless oil (192.5 mg, 0.81 mmol, 91%). 1H NMR (500 MHz,
ESI (þ) m/z calcd for C7H15F5NS [MþH]þ 240.0840 found 240.0866;
IR (ATR, Diamond):
1200, 827.
n
(cmꢀ1) ¼ 3043, 2945, 2528, 1709, 1452, 1396,
4.5.4. 4-methyl-1-(2-(pentafluoro-
oxalate 4c
l
6-sulfanyl)ethyl)piperidine
4-Methylpiperidine (40.0 mg, 0.40 mmol), K2CO3 (55.7 mg,
0.40 mmol), 2-(pentafluoro- tri-
l
6-sulfanyl)ethyl
fluoromethanesulfonate 3 (184.0 mg, 0.61 mmol) and CH2Cl2
(1.6 mL) were engaged in the general procedure to afford the title
compound 4c as a white solid (123.5 mg, 0.36 mmol, 89%) after
precipitation as an oxalate salt with oxalic acid (39.9 mg,
0.44 mmol). m.p. ¼ 135.1e135.4 ꢁC; 1H NMR (500 MHz, CD3OD):
CDCl3):
d
(ppm) ¼ 7.38e7.27 (m, 2H), 7.10e6.98 (m, 2H), 5.08 (s,
2H), 3.09 (dt, J ¼ 12.6, 3.6 Hz, 2H), 2.63 (td, J ¼ 12.3, 2.7 Hz, 2H), 2.46
(tt, J ¼ 11.4, 3.9 Hz, 1H), 1.94e1.80 (m, 2H), 1.67e1.56 (m, 2H), 1.52
(br s, NH); 13C NMR (126 MHz, CDCl3):
d
(ppm) ¼ 174.9, 163.6, 132.0,
d
(ppm) ¼ 4.38e4.24 (m, 2H), 3.72e3.65 (m, 2H), 3.56 (d,
130.0 (d, J ¼ 8.2 Hz), 115.5 (d, J ¼ 21.5 Hz), 65.4, 45.9, 41.6, 29.3; 19
F
J ¼ 12.3 Hz, 2H), 3.09e2.92 (m, 2H), 1.91 (d, J ¼ 14.4 Hz, 2H),
NMR (470 MHz, CDCl3):
d
(ppm) ¼ ꢀ113.8 (ddd, J ¼ 14.0, 8.9, 5.5 Hz,
1.78e1.59 (m, 1H), 1.58e1.36 (m, 2H), 1.01 (d, J ¼ 6.6 Hz, 3H); 13C
1F); HRMS-ESI (þ) m/z calcd for C13H17FNO2 [MþH]þ 238.1238
NMR (126 MHz, CD3OD):
d
(ppm) ¼ 164.8, 63.9 (p, J ¼ 16.0 Hz), 52.9,
found 238.1255; IR (ATR, Diamond):
1512, 1448, 1223, 1142, 824.
n
(cmꢀ1) ¼ 2945, 2810, 1726,
50.9e50.5 (m), 30.8, 28.1, 19.7; 19F NMR (470 MHz, CD3OD):
d
(ppm) ¼ 82.4e77.9 (m, 1F), 65.7 (dt, J ¼ 144.7, 7.6 Hz, 4F); HRMS-
ESI (þ) m/z calcd for C8H17F5NS [MþH]þ 254.0996 found 254.1005;
4.5. Alkylation of amines
IR (ATR, Diamond):
1209, 825.
n
(cmꢀ1) ¼ 3042, 2935, 2858, 1715, 1439, 1391,
4.5.1. General procedure
To a solution of the amine (1 equiv.) in dry CH2Cl2 (0.25 M)
under argon were successively added K2CO3 (1 equiv.) and 2-
4.5.5. 4-(2-(pentafluoro-
Morpholine (40.0 mg, 0.46 mmol), K2CO3 (63.4 mg,
0.46 mmol),2-(pentafluoro- tri-
6-sulfanyl)ethyl
l
6-sulfanyl)ethyl)morpholine oxalate 4d
(pentafluoro-
l
6-sulfanyl)ethyl trifluoromethanesulfonate
3
(1.5
l
equiv.). The reaction was stirred at room temperature for 3 h. The
mixture was then diluted with water and extracted 3 times with
CH2Cl2. The organic phases were combined, washed with brine,
fluoromethanesulfonate 3 (209.5 mg, 0.69 mmol) and CH2Cl2
(1.8 mL) were engaged in the general procedure to afford the title
compound 4d as a white solid (103.3 mg, 0.31 mmol, 68%) after
8

A. Gilbert, P. Langowski and J.-F. Paquin
Tetrahedron xxx (xxxx) xxx
precipitation as an oxalate salt with oxalic acid (45.5 mg,
(153.2 mg, 0.50 mmol) and CH2Cl2 (1.3 mL) were engaged in the
general procedure to afford the title compound 4h as a colorless oil
(72.8 mg, 0.27 mmol, 78%) after purification by flash chromatog-
raphy on silica gel using hexane/EtOAc (95:5) as the eluent. 1H NMR
0.51 mmol). m.p. ¼ 127.5e127.7 ꢁC; 1H NMR (500 MHz, CD3OD):
d
(ppm) ¼ 4.22e4.02 (m, 2H), 3.80 (t, J ¼ 4.6 Hz, 4H), 3.37e3.31 (m,
2H), 2.95 (br s, 4H); 13C NMR (126 MHz, CD3OD):
d
(ppm) ¼ 162.8,
65.9e65.2 (m), 65.0, 52.6, 52.4e51.8 (m); 19F NMR (470 MHz,
(500 MHz, CDCl3):
d
(ppm) ¼ 7.12e7.04 (m, 2H), 6.70 (td, J ¼ 7.4,
CD3OD):
d
(ppm) ¼ 83.2e79.8 (m,1F), 65.2 (dt, J ¼ 144.3, 7.7 Hz, 4F);
0.9 Hz, 1H), 6.46 (d, J ¼ 8.0 Hz, 1H), 3.91e3.77 (m, 2H), 3.70e3.62
HRMS-ESI (þ) m/z calcd for C6H13F5NOS [MþH]þ 242.0633 found
(m, 2H), 3.39 (t, J ¼ 8.4 Hz, 2H), 2.98 (t, J ¼ 8.3 Hz, 2H); 13C NMR
242.0655; IR (ATR, Diamond):
1456, 1311, 1084, 829.
n
(cmꢀ1) ¼ 3040, 2783, 2648, 1718,
(126 MHz, CDCl3):
d
(ppm) ¼ 150.5, 129.7, 127.6, 124.8, 118.5, 106.4,
67.7 (p, J ¼ 10.2 Hz), 52.8, 44.7 (p, J ¼ 5.6 Hz), 28.6; 19F NMR
(470 MHz, CDCl3):
d
(ppm) ¼ 90.7e72.9 (m, 1F), 66.6 (dt, J ¼ 146.2,
4.5.6. 1-(2-(pentafluoro-
Piperidin-4-one hydrochloride hydrate (40.0 mg, 0.26 mmol),
K2CO3 (71.9 mg, 0.52 mmol, 2 equiv.), 2-(pentafluoro-
6-sulfanyl)
l
6-sulfanyl)ethyl)piperidin-4-one 4e
8.1 Hz, 4F); HRMS-ESI (þ) m/z calcd for C10H13F5NS [MþH]þ
274.0683 found 274.0653; IR (ATR, Diamond):
2849, 1607, 1489, 1267, 1148, 878, 810.
n
(cmꢀ1) ¼ 2955,
l
ethyl trifluoromethane sulfonate 3 (118.8 mg, 0.39 mmol) and
CH2Cl2 (1.0 mL) were engaged in the general procedure to afford
the title compound 4e as a colorless oil (12.7 mg, 0.05 mmol, 19%)
after purification by flash chromatography on silica gel using hex-
ane/EtOAc (70:30) as the eluent. 1H NMR (500 MHz, CDCl3):
4.5.10. N-methyl-N-(2-(pentafluoro-
N-Methylaniline (20.0 mg, 0.19 mmol), K2CO3 (25.8 mg,
0.19 mmol), 2-(pentafluoro- tri-
6-sulfanyl)ethyl
l
6-sulfanyl)ethyl)aniline 4i
l
d
(ppm) ¼ 3.92e3.74 (m, 2H), 3.10e2.94 (m, 2H), 2.83 (t, J ¼ 6.2 Hz,
fluoromethanesulfonate 3 (85.2 mg, 0.28 mmol) and CH2Cl2
(0.75 mL) were engaged in the general procedure to afford the title
compound 4i as a colorless oil (26.6 mg, 0.10 mmol, 53%) after
purification by flash chromatography on silica gel using hexane/
EtOAc (95:5) as the eluent. 1H NMR (500 MHz, CDCl3):
4H), 2.46 (t, J ¼ 6.2 Hz, 4H); 13C NMR (126 MHz, CDCl3):
d
(ppm) ¼ 207.9, 68.9 (t, J ¼ 11.5 Hz), 53.0, 52.3 (p, J ¼ 5.0 Hz), 41.1,
29.7; 19F NMR (470 MHz, CDCl3):
d
(ppm) ¼ 87.0e77.4 (m, 1F), 66.3
(dt, J ¼ 146.0, 8.1 Hz, 4F); HRMS-ESI (þ) m/z calcd for C7H13F5NOS
[MþH]þ 254.0633 found 254.0609; IR (ATR, Diamond):
(cmꢀ1) ¼ 2922, 2853, 1720, 1475, 1420, 1194, 1049, 816.
n
d
(ppm) ¼ 7.30e7.26 (m, 2H), 6.82e6.75 (m, 1H), 6.73e6.70 (m, 2H),
3.95e3.88 (m, 2H), 3.87e3.75 (m, 2H), 2.98 (s, 3H); 13C NMR
(126 MHz, CDCl3):
d
(ppm) ¼ 147.4, 129.6, 117.6, 112.1, 66.7 (p,
4.5.7. 1-(2-(pentafluoro-
Pyrrolidine (20.0 mg, 0.28 mmol), K2CO3 (38.8 mg,
0.28 mmol),2-(pentafluoro- tri-
6-sulfanyl)ethyl
l
6-sulfanyl)ethyl)pyrrolidine oxalate 4f
J ¼ 8.9 Hz), 48.3 (p, J ¼ 5.8 Hz), 38.3; 19F NMR (470 MHz, CDCl3):
d
(ppm) ¼ 86.1e81.9 (m, 1F), 66.7 (dt, J ¼ 145.7, 8.1 Hz, 4F); HRMS-
l
ESI (þ) m/z calcd for C9H13F5NS [MþH]þ 262.0683 found 262.0656;
fluoromethanesulfonate 3 (128.3 mg, 0.42 mmol) and CH2Cl2
(1.1 mL) were engaged in the general procedure to afford the title
compound 4f as a white solid (45.9 mg, 0.15 mmol, 52%) after
precipitation as an oxalate salt with oxalic acid (27.9 mg,
0.31 mmol). m.p. ¼ 119.7e121.2 ꢁC; 1H NMR (500 MHz, CD3OD):
IR (ATR, Diamond):
1119, 812.
n
(cmꢀ1) ¼ 3097, 2829, 1601, 1506, 1366, 1196,
4.5.11. N-(2-(pentafluoro-
Aniline (20.0 mg, 0.21 mmol), K2CO3 (29.7 mg, 0.21 mmol), 2-
(pentafluoro- trifluoromethanesulfonate
6-sulfanyl)ethyl
l
6-sulfanyl)ethyl)aniline 4j
d
(ppm) ¼ 4.37e4.13 (m, 2H), 3.85e3.68 (m, 2H), 3.41 (br s, 4H),
2.09 (br s, 4H); 13C NMR (126 MHz, CD3OD):
d
(ppm) ¼ 165.0, 65.0
l
3
(p, J ¼ 16.1 Hz), 54.3, 49.4 (t, J ¼ 6.5 Hz), 22.60; 19F NMR (470 MHz,
(98.0 mg, 0.32 mmol) and CH2Cl2 (0.9 mL) were engaged in the
general procedure to afford the title compound 4j as a colorless oil
(20.4 mg, 0.08 mmol, 39%) after purification by flash chromatog-
raphy on silica gel using hexane/EtOAc (95:5) as the eluent. 1H NMR
CD3OD):
d
(ppm) ¼ 83.0e78.4 (m,1F), 65.3 (dt, J ¼ 144.5, 7.4 Hz, 4F);
HRMS-ESI (þ) m/z calcd for C6H13F5NS [MþH]þ 226.0683 found
226.0669; IR (ATR, Diamond):
1173, 1070, 833, 704.
n
(cmꢀ1) ¼ 3032, 1717, 1657, 1466,
(500 MHz, CDCl3):
d
(ppm) ¼ 7.24e7.19 (m, 2H), 6.78 (tt, J ¼ 7.4,
1.1 Hz, 1H), 6.64e6.61 (m, 2H), 3.90e3.72 (m, 5H); 13C NMR
4.5.8. 2-(2-(pentafluoro-
tetrahydroisoquinoline 4g
1-Phenyl-1,2,3,4-tetrahydroisoquinoline (40.0 mg, 0.19 mmol),
K2CO3 (26.4 mg, 0.19 mmol), 2-(pentafluoro-
6-sulfanyl)ethyl tri-
l
6-sulfanyl)ethyl)-1-phenyl-1,2,3,4-
(126 MHz, CDCl3):
d
(ppm) ¼ 145.9, 129.7, 118.7, 112.9, 69.9 (p,
J ¼ 10.1 Hz), 39.9 (p, J ¼ 5.3 Hz); 19F NMR (470 MHz, CDCl3):
d
(ppm) ¼ 85.3e84.0 (m, 1F), 66.2 (dt, J ¼ 145.8, 8.2 Hz, 4F); HRMS-
l
ESI (þ) m/z calcd for C8H11F5NS [MþH]þ 248.0527 found 248.0556;
fluoromethanesulfonate 3 (87.2 mg, 0.29 mmol) and CH2Cl2
(0.8 mL) were engaged in the general procedure to afford the title
compound 4g as a white solid (50.1 mg, 0.11 mmol, 57%) after pu-
rification by flash chromatography on silica gel using hexane/EtOAc
(95:5) as the eluent. m.p. ¼ 78.6e81.0; 1H NMR (500 MHz, CDCl3):
IR (ATR, Diamond):
1117, 812.
n
(cmꢀ1) ¼ 3416, 3057, 2918, 1603, 1508, 1256,
4.5.12. N,N-bis(2-(pentafluoro-
Aniline (20.0 mg, 0.21 mmol), K2CO3 (29.7 mg, 0.21 mmol), 2-
(pentafluoro- trifluoromethanesulfonate
6-sulfanyl)ethyl
l
6-sulfanyl)ethyl)aniline 4k
d
(ppm) ¼ 7.38e7.19 (m, 5H), 7.14e7.07 (m, 2H), 7.03e6.95 (m, 1H),
6.76e6.55 (m, 1H), 4.64 (s, 1H), 3.89e3.68 (m, 1H), 3.65e3.46 (m,
1H), 3.24e3.00 (m, 3H), 3.01e2.90 (m, 1H), 2.90e2.59 (m, 2H); 13
NMR (126 MHz, CDCl3):
(ppm) ¼ 143.2, 137.8, 134.1, 129.4, 128.8,
l
3
C
(98.0 mg, 0.32 mmol) and CH2Cl2 (0.9 mL) were engaged in the
general procedure to afford the title compound 4k as a white solid
(11.0 mg, 0.03 mmol, 13%) after purification by flash chromatog-
raphy on silica gel using hexane/EtOAc (95:5) as the eluent.
d
128.48, 128.46, 127.7, 126.2, 125.9, 68.8 (p, J ¼ 10.0 Hz), 68.3, 49.9 (p,
J
d
¼
5.3 Hz), 48.3, 29.2; 19F NMR (470 MHz, CDCl3):
(ppm) ¼ 86.0e84.5 (m, 1F), 66.2 (dt, J ¼ 145.8, 8.3 Hz, 4F); HRMS-
m.p.
(ppm) ¼ 7.34e7.30 (m, 2H), 6.87 (tt, J ¼ 7.4, 0.9 Hz, 1H), 6.72e6.69
(m, 2H), 3.89e3.76 (m, 8H); 13C NMR (126 MHz, CDCl3):
¼
68.4e71.6 ꢁC; 1H NMR (500 MHz, CDCl3):
ESI (þ) m/z calcd for C17H19F5NS [MþH]þ 364.1153 found 364.1167;
d
IR (ATR, Diamond):
1126, 816.
n
(cmꢀ1) ¼ 2934, 2822, 1491, 1454, 1313, 1135,
d
(ppm) ¼ 144.5, 130.2, 119.1, 112.4, 67.0 (p, J ¼ 9.8 Hz), 47.0 (p,
J ¼ 6.1 Hz); 19F NMR (470 MHz, CDCl3):
(ppm) ¼ 84.6e83.3 (m,1F),
d
4.5.9. 1-(2-(pentafluoro-
Indoline (40.0 mg, 0.34 mmol), K2CO3 (46.3 mg, 0.34 mmol), 2-
(pentafluoro- trifluoromethanesulfonate
6-sulfanyl)ethyl
l
6-sulfanyl)ethyl)indoline 4h
66.7 (dt, J ¼ 145.7, 7.7 Hz, 4F); GC-MS (CI) calcd for C10H13F10NOS2
[M]þ 401.03 found 401.27; IR (ATR, Diamond):
2922, 1603, 1506, 1375, 1296, 1203, 804.
n
(cmꢀ1) ¼ 3072,
l
3
9

A. Gilbert, P. Langowski and J.-F. Paquin
Tetrahedron xxx (xxxx) xxx
4.5.13. (S)-2-(pentafluoro-
l
6-sulfanyl)-N-(1-phenylethyl)ethan-1-
hexane/EtOAc (80:20) as the eluent. 1H NMR (500 MHz, CDCl3):
amine 4l
d
(ppm) ¼ 7.36e7.28 (m, 2H), 7.09e7.00 (m, 2H), 5.08 (s, 2H),
(S)-1-Phenylethan-1-amine (40.0 mg, 0.33 mmol), K2CO3
(45.6 mg, 0.33 mmol), 2-(pentafluoro-
6-sulfanyl)ethyl tri-
3.82e3.73 (m, 2H), 3.00e2.66 (m, 4H), 2.33 (tt, J ¼ 11.1, 4.0 Hz, 1H),
2.16 (td, J ¼ 11.4, 2.3 Hz, 2H), 1.95e1.86 (m, 2H), 1.74 (qd, J ¼ 11.2,
l
fluoromethanesulfonate 3 (150.6 mg, 0.50 mmol) and CH2Cl2
(1.3 mL) were engaged in the general procedure to afford the title
compound 4l as a colorless oil (76.7 mg, 0.28 mmol, 84%) after
purification by flash chromatography on silica gel using hexane/
3.7 Hz, 2H); 13C NMR (126 MHz, CDCl3):
d
(ppm) ¼ 174.5, 162.6 (d,
J ¼ 247.0 Hz), 131.9 (d, J ¼ 3.2 Hz), 130.1 (d, J ¼ 8.3 Hz), 115.5 (d,
J ¼ 21.6 Hz), 68.7 (p, J ¼ 11.0 Hz), 65.5, 53.3 (p, J ¼ 5.1 Hz), 52.8, 40.7,
28.1; 19F NMR (470 MHz, CDCl3):
d
(ppm) ¼ 86.1e84.1 (m, 1F), 66.3
EtOAc (80:20) as the eluent. ½a D20
ꢂ
¼ ꢀ44.5 (c 1.0, MeOH); 1H NMR
(dt, J ¼ 145.9, 8.1 Hz, 4F), ꢀ113.6 (ddd, J ¼ 14.0, 8.7, 5.3 Hz, 1F);
HRMS-ESI (þ) m/z calcd for C15H20F6NO2S [MþH]þ 392.1113 found
(500 MHz, CDCl3):
d
(ppm) ¼ 7.46e7.13 (m, 5H), 3.87e3.59 (m, 3H),
392.1131; IR (ATR, Diamond):
1512, 1225, 1142, 816.
n
(cmꢀ1) ¼ 2951, 2860, 2808, 1730,
3.12e2.80 (m, 2H), 1.50 (br s, NH), 1.35 (d, J ¼ 6.6 Hz, 3H); 13C NMR
(126 MHz, CDCl3):
d
(ppm) ¼ 144.8, 128.7, 127.3, 126.6, 71.8 (p,
J ¼ 11.1 Hz), 58.0, 43.5 (p, J ¼ 4.5 Hz), 24.4; 19F NMR (470 MHz,
4.6. Synthesis of the amines for the lipophilicity and basicity studies
CDCl3):
d
(ppm) ¼ 85.9e84.6 (m, 1F), 65.7 (dt, J ¼ 145.3, 8.4 Hz, 4F);
HRMS-ESI (þ) m/z calcd for C10H15F5NS [MþH]þ 276.0840 found
4.6.1. 4-fluorobenzyl 1-ethylpiperidine-4-carboxylate 6
276.0852; IR (ATR, Diamond):
1454, 1373, 1126, 812.
n
(cmꢀ1) ¼ 3061, 2964, 2820, 1491,
To a solution of 4-fluorobenzyl piperidine-4-carboxylate 1o
(61.0 mg, 0.26 mmol, 1 equiv.) in CH2Cl2 (1.0 mL, 0.25 M) at room
temperature were successively added K2CO3 (35.5 mg, 0.26 mmol,1
4.5.14. Methyl (2-(pentafluoro-l
6-sulfanyl)ethyl)-L-prolinate 4m
equiv.) and iodoethane (31 mL, 0.39 mmol, 1.5 equiv.). The reaction
Methyl
L
-prolinate hydrochloride (40.0 mg, 0.24 mmol), K2CO3
mixture was stirred for 18 h at room temperature, before the re-
action was quenched by the addition of water. The reaction mixture
was extracted 3 times with CH2Cl2, and the organic phases were
combined, washed with brine, dried over MgSO4, filtered and
concentrated under reduced pressure to afford the title compound
6 as a colorless oil (44.8 mg, 0.17 mmol, 66%) after purification by
flash chromatography on silica gel using CH2Cl2/MeOH (90:10) as
(66.7 mg, 0.48 mmol), 2-(pentafluoro-
l
6-sulfanyl)ethyl trifluoro-
methane sulfonate 3 (110.2 mg, 0.36 mmol) and CH2Cl2 (1.0 mL)
were engaged in the general procedure to afford the title com-
pound 4m as a colorless oil (45 mg, 0.16 mmol, 67%) after purifi-
cation by flash chromatography on silica gel using hexane/EtOAc
(80:20) as the eluent. ½a D20
ꢂ
¼ ꢀ44.2 (c 1.0, CHCl3); 1H NMR
(500 MHz, CDCl3):
d
(ppm) ¼ 3.90e3.78 (m, 2H), 3.74 (s, 3H), 3.33
the eluent. 1H NMR (500 MHz, CDCl3):
d
(ppm) ¼ 7.34e7.30 (m, 2H),
(dd, J ¼ 8.8, 5.4 Hz, 1H), 3.26 (ddd, J ¼ 12.5, 10.6, 6.0 Hz, 1H),
3.18e3.10 (m, 1H), 3.01 (ddd, J ¼ 12.6, 10.5, 5.7 Hz, 1H), 2.57e2.46
(m, 1H), 2.17e2.09 (m, 1H), 2.01e1.80 (m, 3H); 13C NMR (126 MHz,
7.07e7.02 (m, 2H), 5.09 (s, 2H), 2.98e2.92 (m, 2H), 2.51 (q,
J ¼ 7.2 Hz, 2H), 2.45e2.37 (m, 1H), 2.17 (br s, 1H), 2.04e1.98 (m, 2H),
1.93e1.83 (m, 2H), 1.14 (t, J ¼ 7.2 Hz, 3H); 13C NMR (126 MHz,
CDCl3):
d
(ppm) ¼ 174.1, 69.6 (p, J ¼ 11.3 Hz), 65.6, 53.4, 52.0, 49.7 (p,
CDCl3):
d
(ppm) ¼ 174.4, 162.6 (d, J ¼ 247.0 Hz), 131.8 (d, J ¼ 3.3 Hz),
J
d
¼
5.5 Hz), 29.3, 23.4; 19F NMR (470 MHz, CDCl3):
130.1 (d, J ¼ 8.2 Hz), 115.5 (d, J ¼ 21.6 Hz), 65.5, 52.5, 52.1, 40.5, 27.5,
(ppm) ¼ 89.0e82.2 (m, 1F), 65.9 (dt, J ¼ 145.9, 8.2 Hz, 4F); HRMS-
11.5; 19F NMR (470 MHz, CDCl3):
d
(ppm) ¼ ꢀ113.7 (s, 1F); HRMS-
ESI (þ) m/z calcd for C8H15F5NO2S [MþH]þ 284.0738 found
ESI (þ) m/z calcd for
C
15H21FNO2 [MþH]þ 266.1551 found
284.0712; IR (ATR, Diamond):
1200, 1136, 1045, 814.
n
(cmꢀ1) ¼ 2957, 2849, 1736, 1437,
266.1562; IR (ATR, Diamond):
1730, 1512, 1223, 1155.
n
(cmꢀ1) ¼ 2951, 2934, 2804, 2762,
4.5.15. (S)-(1-(2-(pentafluoro-
methanol 4n
l
6-sulfanyl)ethyl)pyrrolidin-2-yl)
4.6.2. 4-fluorobenzyl 1-(2,2,2-trifluoroethyl)piperidine-4-
carboxylate 7
L-prolinol (40.0 mg, 0.40 mmol), K2CO3 (54.6 mg, 0.40 mmol),2-
To a solution of Tf2O (0.41 mL, 2.42 mmol, 5.7 equiv.) in CH2Cl2
(1.85 mL) at 0 ꢁC was added dropwise a solution of trifluoroethanol
(0.1 mL, 1.61 mmol, 3.8 equiv.), pyridine (0.13 mL, 1.61 mmol, 3.8
equiv.) and CH2Cl2 (0.45 mL). The mixture was stirred for 2 h at 0 ꢁC.
Water was next added, and the phases were separated. The organic
phase was directly transferred in another reaction vial, rinsing with
1.4 mL of CH2Cl2 for the transfer. A solution of 4-fluorobenzyl
piperidine-4-carboxylate 1o (100 mg, 0.42 mmol, 1 equiv.) in
CH2Cl2 (0.5 mL) and K2CO3 (58.2 mg, 0.42 mmol, 1 equiv.) were
successively added to the reaction mixture, and the reaction was
stirred for 20 h at room temperature. Water was next added to
quench the reaction, and the reaction mixture was extracted 3
times with CH2Cl2. The organic phases were combined, washed
with brine, dried over MgSO4, filtered and concentrated under
reduced pressure to afford the title compound 7 as a colorless oil
(56.7 mg, 0.18 mmol, 42%) after purification by flash chromatog-
raphy on silica gel using hexane/EtOAc (90:10) as the eluent. 1H
(pentafluoro-
l
6-sulfanyl)ethyl trifluoromethane sulfonate
3
(180.4 mg, 0.59 mmol) and CH2Cl2 (1.6 mL) were engaged in the
general procedure to afford the title compound 4n as a yellowish oil
(63.2 mg, 0.25 mmol, 62%) after purification by flash chromatog-
raphy on silica gel using hexane/EtOAc (50:50) as the eluent.
½
a 2D0
ꢂ
¼
ꢀ22.6 (c 1.2, CHCl3); 1H NMR (500 MHz, CDCl3):
d
(ppm) ¼ 3.85e3.78 (m, 2H), 3.63 (dd, J ¼ 11.1, 3.5 Hz,1H), 3.42 (dd,
J ¼ 11.1, 3.0 Hz,1H), 3.35e3.28 (m,1H), 3.18e3.13 (m,1H), 2.87e2.68
(m, 3H), 2.38e2.31 (m, 1H), 1.94e1.87 (m, 1H), 1.82e1.73 (m, 3H);
13C NMR (126 MHz, CDCl3):
d
(ppm) ¼ 70.0 (p, J ¼ 11.7 Hz), 65.1,
62.2, 54.4, 50.1 (p, J ¼ 5.2 Hz), 27.3, 23.8; 19F NMR (470 MHz, CDCl3):
d
(ppm) ¼ 85.6e84.3 (m, 1F), 66.1 (dt, J ¼ 146.0, 8.2 Hz, 4F); HRMS-
ESI (þ) m/z calcd for C7H15F5NOS [MþH]þ 256.0789 found
256.0808; IR (ATR, Diamond):
1364, 1155, 1038 825.
n
(cmꢀ1) ¼ 3437, 2961, 2818, 1464,
4.5.16. 4-fluorobenzyl 1-(2-(pentafluoro-
piperidine-4-carboxylate 4o
l
6-sulfanyl)ethyl)
NMR (500 MHz, CDCl3):
d
(ppm) ¼ 7.34e7.30 (m, 2H), 7.07e7.02 (m,
2H), 5.08 (s, 2H), 2.99e2.92 (m, 4H), 2.40 (td, J ¼ 11.4, 2.6 Hz, 2H),
2.33 (tt, J ¼ 11.1, 4.1 Hz, 1H), 1.92e1.88 (m, 2H), 1.83e1.75 (m, 2H);
4-Fluorobenzyl
piperidine-4-carboxylate
(100.0
mg,
0.42 mmol), K2CO3 (58.2 mg, 0.42 mmol), 2-(pentafluoro-
l
6-sul-
13C NMR (126 MHz, CDCl3):
d
(ppm) ¼ 174.5, 162.6 (d, J ¼ 246.9 Hz),
fanyl)ethyl trifluoromethane sulfonate 3 (192.3 mg, 0.63 mmol) and
CH2Cl2 (1.7 mL) were engaged in the general procedure to afford
the title compound 4o as a colorless oil (151.0 mg, 0.39 mmol, 92%)
after purification by flash chromatography on silica gel using
131.9 (d, J ¼ 3.3 Hz), 130.1 (d, J ¼ 8.3 Hz), 125.5 (q, J ¼ 280.7 Hz),
115.5 (d, J ¼ 21.6 Hz), 65.5, 58.5 (q, J ¼ 30.3 Hz), 53.3, 40.5, 28.2; 19
F
NMR (470 MHz, CDCl3):
d
(ppm) ¼ ꢀ69.0 (t, J ¼ 9.6 Hz, 3F), ꢀ113.6
to ꢀ113.7 (m, 1F); HRMS-ESI (þ) m/z calcd for C15H18F4NO2 [MþH]þ
10

A. Gilbert, P. Langowski and J.-F. Paquin
Tetrahedron xxx (xxxx) xxx
(cmꢀ1) ¼ 2955,
M.E. Fraley, M.M. Zrada, C.A. Buser, E.S. Walsh, K. Hamilton, L.B. Lobell, W. Tao,
M.T. Abrams, V.J. South, H.E. Huber, N.E. Kohl, G.D. Hartman, Bioorg. Med.
Chem. Lett 17 (2007) 2697e2702;
320.1268 found 320.1285; IR (ATR, Diamond):
2932, 2799, 1732, 1514, 1271, 1140, 1095.
n
d) E.J. Hicken, F.P. Marmsater, M.C. Munson, S.T. Schlachter, J.E. Robinson,
S. Allen, L.E. Burgess, R.K. DeLisle, J.P. Rizzi, G.T. Topalov, Q. Zhao, J.M. Hicks,
N.C. Kallan, E. Tarlton, A. Allen, M. Callejo, A. Cox, S. Rana, N. Klopfenstein,
R. Woessner, J.P. Lyssikatos, ACS Med. Chem. Lett. 5 (2014) 78e83;
e) I.M. McDonald, R.A. Mate, F.C. Zusi, H. Huang, D.J. Post-Munson,
M.A. Ferrante, L. Gallagher, R.L. Bertekap Jr., R.J. Knox, B.J. Robertson,
D.G. Harden, D.G. Morgan, N.J. Lodge, S.I. Dworetzky, R.E. Olson, J.E. Macor,
Bioorg. Med. Chem. Lett 23 (2013) 1684e1688;
4.6.3. 4-fluorobenzyl 1-(3,3,3-trifluoropropyl)piperidine-4-
carboxylate 8
To a solution of 3,3,3-trifluoropropan-1-ol (150 mL, 1.70 mmol, 1
equiv.) in CH2Cl2 (0.6 mL) was added pyridine (0.14 mL, 1.70 mmol,
1 equiv.). This mixture was added dropwise to a solution of Tf2O
(0.43 mL, 2.55 mmol, 1.5 equiv.) in CH2Cl2 (1.8 mL) at 0 ꢁC. The
reaction was stirred at 0 ꢁC for 2 h before it was quenched by the
addition of ice-cold water. The phases were separated, and the
organic phase was dried over Na2SO4, filtered and concentrated
under reduced pressure. The crude product was used in the next
step without further purification. The crude product (155.6 mg,
f) F. Reck, R.A. Alm, P. Brassil, J.V. Newman, P. Ciaccio, J. McNulty, H. Barthlow,
K. Goteti, J. Breen, J. Comita-Prevoir, M. Cronin, D.E. Ehmann, B. Geng,
A.A. Godfrey, S.L. Fisher, J. Med. Chem. 55 (2012) 6916e6933.
[3] a) B.E. Smart, J. Fluor. Chem. 109 (2001) 3e11;
€
b) H.-J. Bohm, D. Banner, S. Bendels, M. Kansy, B. Kuhn, K. Müller, U. Obst-
Sander, M. Stahl, Chembiochem 5 (2004) 637e643;
c) K. Müller, C. Faeh, F. Diederich, Science 317 (2007) 1881e1887;
d) S. Purser, P.R. Moore, S. Swallow, V. Gouverneur, Chem. Soc. Rev. 37 (2008)
320e330;
0.63 mmol, 1.5 equiv.) was transferred to
a solution of 4-
fluorobenzyl piperidine-4-carboxylate 1o (100 mg, 0.42 mmol, 1
equiv.) and K2CO3 (58.2 mg, 0.42 mmol, 1 equiv.) in CH2Cl2 (1.7 mL,
0.25 M) at room temperature and under argon. The mixture was
stirred at room temperature for 18 h before the addition of water.
The mixture was extracted 3 times with CH2Cl2, and the organic
phases were combined, washed with brine, dried over MgSO4,
filtered and concentrated under reduced pressure. The crude
product was purified by flash chromatography on silica gel using
hexanes/EtOAc (70:30) as the eluent to afford the title compound 8
as a colorless oil (116.5 mg, 0.35 mmol, 83%). 1H NMR (500 MHz,
e) E.P. Gillis, K.J. Eastman, M.D. Hill, D.J. Donnelly, N. Meanwell, J. Med. Chem.
58 (2015) 8315e8359;
f) Y. Zhou, J. Wang, Z. Gu, S. Wang, W. Zhu, J.L. Acena, V.A. Soloshonok,
K. Izawa, H. Liu, Chem. Rev. 116 (2016) 422e518;
g) N. Meanwell, J. Med. Chem. 61 (2018) 5822e5880;
~
h) H. Mei, J. Han, S. Fustero, M. Medio-Simon, D.M. Sedgwick, C. Santi,
R. Ruzziconi, V.A. Soloshonok, Chem. Eur J. 25 (2019) 11797e11819.
[4] a) P. Kirsch, Introduction, in: Modern Fluoroorganic Chemistry, second ed.,
Wiley-VCH, Weinheim, Germany, 2013, pp. 1e24;
b) D. O'Hagan, Chem. Soc. Rev. 37 (2008) 308e319;
c) R.J. Ouellette, J.D. Rawn, Structure and bonding in organic compounds, in:
Organic Chemistry. Structure, Mechanism, Synthesis, second ed., Elsevier Inc,
Amsterdam, 2018, pp. 1e30.
CDCl3):
d
(ppm) ¼ 7.34e7.29 (m, 2H), 7.08e6.98 (m, 2H), 5.08 (s,
[5] a) Q.A. Huchet, B. Kuhn, B. Wagner, H. Fischer, M. Kansy, D. Zimmerli,
E.M. Carreira, K. Müller, J. Fluor. Chem. 152 (2013) 119e128;
b) K. Müller, Chimia 68 (2014) 356e362;
2H), 2.87e2.81 (m, 2H), 2.60e2.55 (m, 2H), 2.38e2.25 (m, 3H), 2.06
(td, J ¼ 11.4, 2.4 Hz, 2H), 1.96e1.90 (m, 2H), 1.82e1.71 (m, 2H); 13C
c) B. Linclau, Z. Wang, G. Compain, V. Paumelle, C.Q. Fontenelle, N. Wells,
A. Weymouth-Wilson, Angew. Chem. Int. Ed. 55 (2016) 674e678.
NMR (126 MHz, CDCl3):
d
(ppm) ¼ 174.6, 162.6 (d, J ¼ 246.8 Hz),
€
[6] a) M. Morgenthaler, E. Schweizer, A. Hoffmann-Roder, F. Benini, R.E. Martin,
131.9 (d, J ¼ 3.3 Hz), 130.1 (d, J ¼ 8.2 Hz), 126.6 (q, J ¼ 276.3 Hz),
G. Jaeschke, B. Wagner, H. Fischer, S. Bendels, D. Zimmerli, J. Schneider,
F. Diederich, M. Kansy, K. Müller, ChemMedChem 2 (2007) 1100e1115;
b) C.D. Cox, P.J. Coleman, M.J. Breslin, D.B. Whitman, R.M. Garbaccio,
M.E. Fraley, C.A. Buser, E.S. Walsh, K. Hamilton, M.D. Schaber, R.B. Lobell,
W. Tao, J.P. Davide, R.E. Diehl, M.T. Abrams, V.J. South, H.E. Huber, M. Torrent,
T. Prueksaritanont, C. Li, D.E. Slaughter, E. Mahan, C. Fernandez-Metzler,
Y. Yan, L.C. Kuo, N.E. Kohl, G.D. Hartman, J. Med. Chem. 51 (2008) 4239e4252;
c) N. Meanwell, Chem. Res. Toxicol. 24 (2011) 1420e1456;
d) P.S. Charifson, W.P. Walters, J. Med. Chem. 57 (2014) 9701e9717.
[7] (For selected examples, see:). a) J.T. Welch, D.S. Lim, Bioorg. Med. Chem. 15
(2007) 6659e6666;
115.5 (d, J ¼ 21.6 Hz), 65.5, 52.8, 51.0 (q, J ¼ 3.3 Hz), 40.9, 31.9 (q,
J ¼ 27.6 Hz), 28.2; 19F NMR (470 MHz, CDCl3):
d
(ppm) ¼ ꢀ65.4 (t,
J ¼ 10.8 Hz), ꢀ113.7 (ddd, J ¼ 14.0, 8.9, 5.5 Hz); HRMS-ESI (þ) m/z
calcd for C16H20F4NO2 [MþH]þ 334.1425 found 334.1407; IR (ATR,
Diamond):
n
(cmꢀ1) ¼ 2955, 2793, 1728, 1512, 1257, 1149, 1003, 825.
Declaration of competing interest
b) P. Wipf, T. Mo, S.J. Geib, D. Caridha, G.S. Dow, L. Gerena, N. Roncal,
E.E. Milner, Org. Biomol. Chem. 7 (2009) 4163e4165;
c) T. Mo, X. Mi, E.E. Milner, G.S. Dow, P. Wipf, Tetrahedron Lett. 51 (2010)
5137e5140;
The authors declare that they have no known competing
financial interests or personal relationships that could have
appeared to influence the work reported in this paper.
d) P.W. Chia, S.C. Brennan, A.M.Z. Slawin, D. Riccardi, Org. Biomol. Chem. 10
(2012) 7922e7927;
e) S. Altomonte, G.L. Baillie, R.A. Ross, J. Riley, M. Zanda, RSC Adv. 4 (2014)
20164e20176;
Acknowledgments
We acknowledge the financial support of the Natural Sciences
and Engineering Research Council of Canada (NSERC) and Uni-
f) C.M.M. Hendriks, T.M. Penning, T. Zang, D. Wiemuth, S. Gründer,
I.A. Sanhueza, F. Schoenebeck, C. Bolm, Bioorg. Med. Chem. Lett 25 (2015)
4437e4440;
g) Y. Zhang, Y. Wang, C. He, X. Liu, Y. Lu, T. Chen, Q. Pan, J. Xiong, M. She, Z. Tu,
X. Qin, M. Li, M.D. Tortorella, J.J. Talley, J. Med. Chem. 60 (2017) 4135e4146;
h) S. Sansook, C.A. Ocasio, I.J. Day, G.J. Tizzard, S.J. Coles, O. Fedorov,
J.M. Bennett, J.M. Elkins, J. Spencer, Org. Biomol. Chem. 15 (2017) 8655e8660;
i) G.C. Moraski, R. Bristol, N. Seeger, H.I. Boshoff, P.S.-Y. Tsang, M. Miller,
J. ChemMedChem 12 (2017) 1108e1115;
ꢀ
versite Laval.
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tet.2021.132424.
ꢀ
ꢀ
j) E. Pujol, N. Blanco-Cabra, E. Julian, R. Leiva, E. Torrents, S. Vazquez, Mole-
cules 23 (2018) 2853e2870;
k) S. Kandil, C. Pannecouque, F.M. Chapman, A. Westwell, C. McGuigan, Bioorg.
Med. Chem. Lett 29 (2019) 126721e126726;
l) F. Pertusati, S. Ferla, M. Bassetto, A. Brancale, S. Khandil, A.D. Westwell,
C. McGuigan, Eur. J. Med. Chem. 180 (2019) 1e14;
m) S. Mori, N. Tsuemoto, T. Kasagawa, E. Nakano, S. Fujii, H. Kagechika, Chem.
Pharm. Bull. 67 (2019) 1278e1283;
n) G.A. Naclerio, N.S. Abutaleb, K.I. Onyedibe, M.N. Seleem, H.O. Sintim, RSC
Med. Chem. 11 (2020) 101e110;
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