Remote trifluoromethylthiolation of alcohols under visible light

Article abstract of DOI:10.1016/j.tet.2020.131153

An unprecedented remote and regioselective trifluoromethylthiolation reaction of alcohols was developed. Under mild conditions, a panel of free-alcohols was selectively functionalized with TolSO₂SCF₃ reagent as the SCF₃ source in the presence of hypervalent iodide (PIDA) under blue light irradiation. This approach offered an operationally simple tool for the construction of a challenging C(sp³)-SCF₃ bond at the δ-position of an alcohol by C(sp³)-H bond functionalization. Initial mechanistic studies suggested a radical pathway.

Full text of DOI:10.1016/j.tet.2020.131153

Journal Pre-proof
Remote trifluoromethylthiolation of alcohols under visible light
Manuel Barday, Remi Blieck, Louise Ruyet, Tatiana Besset
PII:
S0040-4020(20)30284-2
https://doi.org/10.1016/j.tet.2020.131153
TET 131153
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 16 February 2020
Revised Date: 23 March 2020
Accepted Date: 24 March 2020
Please cite this article as: Barday M, Blieck R, Ruyet L, Besset T, Remote trifluoromethylthiolation of
alcohols under visible light, Tetrahedron (2020), doi: https://doi.org/10.1016/j.tet.2020.131153.
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Remote trifluoromethylthiolation of alcohols
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Manuel Barday, § Remi Blieck, § Louise Ruyet and Tatiana Besset
Normandie Univ, INSA Rouen, UNIROUEN, CNRS, COBRA (UMR 6014), 76000 Rouen, France.

1
Tetrahedron
journal homepage: www.elsevier.com
Remote trifluoromethylthiolation of alcohols under visible light.
Manuel Bardaya,§ , Remi Blieck a,§, Louise Ruyeta, and Tatiana Besset
a Normandie Univ, INSA Rouen, UNIROUEN, CNRS, COBRA (UMR 6014), 76000 Rouen, France.
§ Both authors contributed equally.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An unprecedented remote and regioselective trifluoromethylthiolation reaction of alcohols was
developed. Under mild conditions, a panel of free-alcohols was selectively functionalized with
TolSO2SCF3 reagent as the SCF3 source in the presence of hypervalent iodide (PIDA) under
blue light irradiation. This approach offered an operationally simple tool for the construction of
Available online
a
challenging C(sp3)-SCF3 bond at the δ-position of an alcohol by C(sp3)-H bond
functionalization. Initial mechanistic studies suggested a radical pathway.
Keywords:
Trifluoromethylthiolation;
Fluorine chemistry;
Visible light;
2009 Elsevier Ltd. All rights reserved
.
Remote position;
C(sp3)-H bond functionalization
the trifluoromethylthiolation of a C(sp3)-H bond at a remote
position of a functional group remains a challenge, restricted to
few examples. Recently, major contributions from the groups of
Leonori11 and Cook12 described a visible-light-mediated radical
cascade process for the synthesis of SCF3-containing nitrogen
1. Introduction
Organofluorine chemistry is a fascinating research field.
Beyond the strong interest that represents fluorinated molecules
in several fields such as pharmaceuticals and agrochemicals
industries,1 the quest for new tools to overcome difficult-to-
achieve synthetic challenges is of prime importance in organic
chemistry to extend the portfolio of fluorinated molecules.2
Indeed, the incorporation of a fluorine atom or a fluorinated
group onto a molecule constitutes an efficient way to modulate
their physical and chemical properties thanks to the unique
properties of the fluorine atom.3 Any advances will therefore
have a strong impact, offering new synthetic pathways to this
highly important class of compounds.
heterocycles
as
well
as
a
copper-catalyzed
trifluoromethylthiolation of sulfonamides and amides,
respectively. In that context, our purpose was to develop a
synthetic
tool,
which
would
allow
the
distal
trifluoromethylthiolation of simple and inexpensive alcohols, a
ubiquitous functional group. Among others, 1,5-HAT process is
one of the strategies used for the remote functionalization of
alcohols via the in situ generation of alkoxy radicals, usually
generated from alcohol surrogates or peroxides.13 In contrast,
only few reports depicted the in situ generation of an alkoxy
radical directly from a free-alcohol.14
To reach that challenging goal and inspired by the recent work
of Zhu, who demonstrated the possibility to employ hypervalent
iodine as a radical promotor with alcohols,14c we envisioned the
introduction of a SCF3 group at a remote position of an alcohol.
Among the fluorinated groups, the SCF3 residue appeared as a
promising motif due to its unique features such as its high
electron-withdrawing character and its Hansch parameter.4
Taking into account these considerations, several research groups
dedicated a lot of efforts to offer straightforward and efficient
methodologies to introduce such moiety on aromatic, vinylic and
aliphatic derivatives.5,6 Besides, the direct functionalization of a
simple C-H bond proved to be very attractive as it affords more
step- and atom-economic processes. Although key advances were
made for the functionalization of C(sp3)-H bond with a fluorine
atom via transition metal catalysis and photocatalysis, the
number of reports regarding the introduction of other fluorinated
groups is still limited.7,8,9 Only a handful of methods allowed the
Scheme 1. Working hypothesis for the remote trifluorome-
thylthiolation reaction of alcohol derivatives.
formation of a C(sp3)-SCF3 by C(sp3)-H functionalization10 and
———
Corresponding author. Tel.: +33-2-35-52-24-03; e-mail: tatiana.besset@insa-rouen.fr

2
Tetrahedron
Indeed, we hypothesized that in the presence of a proper
reaction, the corresponding trifluoromethylthiolated compounds
oxidant and under light irradiation, an alkoxy radical would be
generated and would undergo a 1,5-HAT event to afford the
corresponding alkyl radical. This latter would react with a SCF3
reagent to furnish the corresponding δ-trifluoromethylthiolated
alcohol (Scheme 1). With this goal in mind, we selected a new
class of SCF3 sources, namely ArSO2SCF3.15 Herein we report
3m-p were obtained in lower yields.
Table 1. Optimization of the remote trifluoromethylthiolation of
the alcohol 1a.a
our
recent
study
regarding
the
first
remote
trifluoromethylthiolation reaction of free-alcohols under visible
light irradiation.
Entry
Oxidant
Light source
Solvent
Yield
2a+3a (%)b
2. Results and Discussions
1c, d
2c,d
3c, d
4c, d
5c, d
6c, d
7
PIDA
PIFA
Blue LEDs 34W
Blue LEDs 34W
Blue LEDs 34W
Blue LEDs 34W
Blue LEDs 34W
Blue LEDs 34W
Blue LEDs 34W
Blue LEDs 34W
Blue LEDs 34W
Blue LEDs 34W
Blue LEDs 34W
Blue LEDs 34W
Blue LEDs 34W
Blue LEDs 34W
White bulb 14 W
CH2Cl2
CH2Cl2
55
33
At the outset of the project, a reaction was performed using 5-
phenyl-1-pentanol 1a as model substrate in the presence of
TolSO2SCF3 (reagent I) and PIDA under blue light irradiation.
Pleasingly, the expected trifluoromethylthiolated product was
observed in a 55% NMR yield as a mixture of the corresponding
alcohol 2a and the acetylated one 3a (Table 1, entry 1). When
PIFA was used, a lower yield of the trifluoromethylthiolated
products was obtained (Table 1, entry 2). Therefore, we pursue
PIDA
PIDA
PIDA
PIDA
PIDA
PhI(OPiv)2
PhIO
ClCH2CH2Cl 54
DMF
31
CH3CN
acetone
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
39
the
optimization
by
a
two-steps
process
28
(trifluoromethylthiolation/acetylation) to get selectively 3a. Other
solvents such as 1,2-dichloroethane, DMF, acetonitrile and
acetone were tested leading in all cases to lower yields (Table 1;
entries 3-6). When PIDA was used as the oxidant under more
concentrated conditions (Table 1, entry 7), 3a was isolated in an
encouraging 49% yield. The reaction is highly selective to the
δ position as no other regioisomer was observed.16 Then, the
nature of the oxidant, the reaction concentration as well as the
stoichiometry of the oxidant and 1a were further investigated but
no significant improvement was observed (Table 1, entries 8-14).
Therefore, PIDA was selected as the oxidant. Indeed, even if the
NMR yield obtained with PhI(OPiv)2 was similar to the one
obtained with PIDA, the pivaloylation step has been less efficient
than the acylation one. Switching from blue LEDs to white bulb
(14 W or 15.5 W, Table 1, entries 15 and 16) led to no
conversion. A control experiment carried out in the dark
showcased the importance of light in this process (Table 1, entry
17). When the reaction was conducted under air, no significant
change was obtained (Table1, entry 18). Finally, by tuning the
irradiation wavelength of the lamp and the reaction time (Table 1,
entries 19-22), the best reaction conditions were obtained
affording 3a in 51% yield (Table 1, entry 22).
72 (49)e
73f (38)e
52
8
9
10g
11h
12i
13j
14k
15
PIDA
PIDA
PIDA
PIDA
PIDA
PIDA
PIDA
47
67
53
55
43
NR
NR
16
White bulb 15.5 CH2Cl2
W
17
18l
19
20
21
PIDA
PIDA
PIDA
PIDA
PIDA
PIDA
darkness
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
NR
Blue LEDs 34W
405 nm
63
69
With the best reaction conditions in hand, we explored the
scope of the reaction (Scheme 2). Trifluoromethylthiolation of
primary alcohols was first investigated and decent yields were
obtained taking into consideration the volatility and the tedious
purification of the products. The corresponding acetylated
products 3 were obtained with a complete regioselectivity. A
panel of alcohols were functionalized with the SCF3 group such
as those having electron rich and electron poor aryl as
substituents (3b and 3c) and an alcohol bearing a naphthyl group
(3d) was isolated in 39% yield. Even alcohols with a simple
aliphatic chain (1-pentanol 1e and 1-octanol 1f) were
trifluoromethylthiolated in moderate yields. Various functional
groups such as an ester, an azide and a protected primary amine
were tolerated (3g-i). In addition, the reaction of alcohols 1j and
1k substituted with a cyclohexyl or an adamantanyl group at the
C3 position smoothly led to 3j in 44% yield as a mixture of
diastereoisomers (dr = 1.2/1) and 3k in 42% yield. The reaction
was not restricted to the functionalization of secondary C(sp3)
centers as the introduction of the SCF3 group was also possible
on the more sterically hindered methine (3l). Finally, when
secondary (1m and 1n) and tertiary (1o) acyclic alcohols and
even the cyclic secondary alcohol 1p were engaged in the
450-455 nm
475-480 nm
450-455 nm
73 (50)e
27
22m
76 (51)e
a
Reaction conditions: 1a (5 equiv.), I (0.2 mmol, 1 equiv.), oxidant (2.3
equiv.), solvent (1.5 mL), 20 °C, 15 h, argon.
b
Yields determined by 19F NMR of the crude reaction mixture after the
trifluoromethylthiolation step using α,α,α-trifluoroacetophenone as an
internal standard.
c 1 mL of CH2Cl2 was used.
d No acetylation reaction.
e
Isolated yield of 3a after acetylation reaction; for detailed reaction
conditions, see Supporting Information.
f PivCl was used instead of AcCl for the second step.
g 0.5 mL of CH2Cl2 was used.
h 2.5 mL of CH2Cl2 was used.
i 5 equiv. of PIDA.
j 1.5 equiv. of PIDA.
k 3 equiv. of 1a.
l Reaction conducted under an air atmosphere.

3
m 16 h.
NR
[Bis(trifluoroacetoxy)iodo]benzene.
=
no reaction. PIDA
=
(Diacetoxyiodo)benzene. PIFA
=
Scheme 3. Control experiment and proposed mechanism.
3. Conclusion
In conclusion, we developed a straightforward access to δ-
trifluoromethylthiolated alcohols under mild and simple reaction
conditions. Under blue light irradiation (450-455 nm), this
process allows the challenging C(sp3)-SCF3 bond formation of a
large variety of alcohols with PIDA as a promoter with a
complete regioselectivity. Indeed, simple primary, secondary and
tertiary unprotected alcohols were functionalized on secondary
and tertiary carbon centers and the transformation turned out to
be tolerant to various functional groups. Preliminary mechanistic
studies suggested a radical pathway for this transformation.
4. Experimental section
4.1. Material and instrumentation
All reactions were carried out using oven-dried glassware and
magnetic stirring under argon unless otherwise stated. Analytical
thin layer chromatography was performed on silica gel aluminum
plates with F-254 indicator and visualized by UV light (254 nm)
and/or chemical staining with a KMnO4 solution, p-anisaldehyde
Scheme 2. Remote trifluoromethylthiolation of alcohol
derivatives 1: scope of the reaction. Reaction conditions: 1) 1a (5
equiv.), I (0.4 mmol, 1 equiv.), PIDA (2.3 equiv.), CH2Cl2 (3
mL), 20 °C, 16 h, argon then 2) MeCOCl, 20 °C, 10 min under
argon. The reaction was carried out using 1.2 mmol of I. The
product was obtained with an inseparable impurity.
or
a
phosphomolybdic acid solution. Flash column
chromatography was performed using 0.040-0.063 nm silica gel.
Reverse-phase chromatography was performed with a Puriflash®
interchim 4250 using a Thermoscientific® hypersil gold 5 µm. 1H
NMR spectra were recorded on a Bruker DXP 300 MHz
spectrometer at 300.1 MHz, 13C NMR spectra at 75.5 MHz and
19F NMR spectra at 282.4 MHz. Chemical shifts (δ) are quoted in
ppm relative to CDCl3 (1H, 13C) and CFCl3 (19F). Coupling
constants (J) are reported in Hz. The following abbreviations
were used to show the multiplicities: s: singlet, d: doublet, t:
triplet, q: quadruplet, dd: doublet of doublet, m: multiplet. The
a
b
In order to suggest a plausible mechanism involved in our
reaction, the reaction was performed in the presence of a radical
inhibitor.17 The reaction carried out in the presence of BHT did
not afford traces of the trifluoromethylthiolated alcohol by 19F
NMR, which strongly supported a radical pathway (Scheme 3, a).
Based on this result and the literature data,14c the following
mechanism was suggested (Scheme 3, b). The first step might be
the formation of the dialkoxyiodo benzene intermediate A in the
presence of the alcohol 1. Under irradiation, the homolysis of the
intermediate A might lead to the formation of the alkoxy radical
B, which might provide an alkyl radical C after a 1,5-HAT event.
This alkyl radical could then directly react with the TolSO2SCF3
(reagent I) or alternatively, with an in situ generated CF3SSCF3
dimer, to afford the expected trifluoromethylthiolated product.
residual solvent signals were used as references (CDCl3: δH
=
7.26 ppm, δC = 77.00 ppm) or relative to internal standard
(CFCl3: δF = 0 ppm). High-resolution mass spectrometry
(HRMS) was recorded with a Waters LCT Premier mass
spectrometer with a micro-TOF analyzer. IR spectra were
recorded on a PerkinElmer Spectrum 100, the wave numbers (ν)
of recorded IR-signals (ATR) are quoted in cm-1. Melting points
were reported for new compounds, recorded on a Heizbank
system Kofler WME and were uncorrected.
Tetrahydrofuran (THF) and toluene were distilled over
sodium/benzophenone and dichloromethane (CH2Cl2) was
distilled over CaH2 prior use. HPLC grade methanol (MeOH)
was used for hydrogenation. Dry N,N-dimethylformamide (DMF)
over molecular sieve from Acros Organic was used. n-
Butylamine purchased from Merck was used without
purification. Unless otherwise stated, the reaction optimization
was performed using
a PhotoRedOx Box supplied by
HepatoChem using a 34W blue kessil LED. An Evoluchem®
P201-18-2 450-455 nm 18W was used for the photochemical

4
Tetrahedron
reactions. All commercially available alcohols were used
Cyclohexane/EtOAc=70/30) to afford 1h as a colorless oil (2.1 g,
12.2 mmol, 75 %).
without prior purification. Alcohols 1b, 1c, 1d, 1h, 1i and 1n
were prepared as described below.
4.2.4. Procedure for the synthesis of 5-Phthalimido-1-
4.2. General Procedures
pentanol 1i:
5-Phthalimido-1-pentanol 1i was synthesized following the
literature.21 A round- bottom flask, equipped with a condenser,
under argon, was charged with 5-aminopentanol (1 mL, 9 mmol,
1 equiv.), phthalimide (2.2 g, 15.3 mmol, 1.7 equiv.) and toluene
(9 mL). Iron-(III) nitrate nonahydrate (181.8 mg, 0.45 mmol,
0.05 equiv.) was added and the reaction mixture was stirred at
110 °C for 24 h. The reaction mixture was filtered over celite®
and the solvent was evaporated under vacuum. The crude mixture
4.2.1. Procedure for the synthesis of S-(Trifluoromethyl)-4-
methylbenzenesulfonothioate I:
The procedure was adapted from a previously reported
procedure.18 Sodium 4-methylbenzenesulfinate (4.0 g, 23 mmol,
1.5 equiv.) and N-trifluoromethylthiophthalimide19 (3.7 g,
15 mmol, 1 equiv.) were placed into an over-dried flask equipped
with a stirring bar under Ar, then glacial acetic acid (75 mL) was
added. The reaction was stirred 2 hours at 25 °C, protected from
light. After full conversion observed by 19F NMR, 60 mL of brine
and 300 mL of Et2O were added, and the organic layer was
separated. The aqueous layer was extracted with Et2O
(3 × 100 mL) and the combined organic layers were washed with
a saturated aqueous solution of NaHCO3 (3 × 200 mL). The
combined organic layers were dried over Na2SO4 and
concentrated under vacuum. The residue was purified by flash
column chromatography on silica gel (height: 17 cm, width: 4
cm, Petroleum ether/EtOAc=90/10) to afford I as a pale-yellow
oil (3.3 g, 12.9 mmol, 86%).
was
purified
by
flash
column
chromatography (height: 20 cm, width: 4 cm, CH2Cl2/EtOAc=90/
10) to afford 1i as a colorless oil (1.3 g, 5.4 mmol, 60 %).
4.2.5.
Procedure
for
the
synthesis
of
1-[(4-
trifluoromethyl)phenyl]-1-heptanol 1o:
1-[(4-Trifluoromethyl)phenyl]-1-heptanol 1o was synthesized
following the literature.22 An oven-dried round-bottom flask,
under argon, was charged with 4-(trifluoromethyl)benzaldehyde
(780 µL, 5.7 mmol, 1 equiv.), then evacuated under high vacuum
and backfilled with argon three times. Freshly distilled THF (10
mL) was added. A solution of hexyllithium in hexanes (2.2 M,
5.2 mL, 11.5 mmol, 2 equiv.) was diluted in freshly distilled THF
(10 mL) and added dropwise at −78 °C to the reaction mixture.
The reaction mixture was then allowed to warm up to room
temperature and stirred for 2 hours at 25 °C. Then, water (10 mL)
was added, and the aqueous layer was extracted with Et2O (3 ×
15 mL). The combined organic layers were dried over Na2SO4
and concentrated under vacuum. The crude mixture was purified
by flash column chromatography (height: 20 cm, width: 3 cm,
Cyclohexane/EtOAc=90/10) to afford 1o as a yellow oil (1.11 g,
4.05 mmol, 71 %).
4.2.2. General procedure for the synthesis of the alcohols 1b-d
with a representative example for the synthesis of 5-(naphthalen-
2-yl)pentan-1-ol 1d. 5-(Naphthalen-2-yl)pentan-1-ol 1d was
synthesized following the literature.20 An oven-dried Schlenk
tube equipped with a Rotaflo® tap, under nitrogen, was charged
with PdCl2(PPh3)2 (168 mg, 0.24 mmol, 0.05 equiv.) and
degassed n-BuNH2 (10 mL). Then, CuI (91 mg, 0.48 mmol, 0.1
equiv.) was added along with 2-bromonaphthalene (1.0 g, 4.8
mmol, 1 equiv.) and 4-pentyn-1-ol (493 µL, 5.3 mmol, 1.1
equiv.). The tube was sealed and the mixture stirred at 80 °C for
17 h. After cooling down, the reaction was quenched with a
saturated aqueous solution of NH4Cl (30 mL) and the aqueous
layer was extracted with ethyl acetate (3 × 30 mL). The
combined organic layers were washed with water (3 × 100 mL),
brine (100 mL), dried over Na2SO4 and concentrated under
vacuum. The crude material was purified by flash
chromatography (height: 17 cm, width: 4 cm, Petroleum
ether/EtOAc=70/30) to afford 1d-int as a beige solid (0.930 g,
87%). An oven-dried 100 mL round-bottomed flask, under
nitrogen, was charged with Pd/C (93 mg, 10% w/w) followed by
1d-int (0.9 g, 4.4 mmol, 1 equiv.) dissolved in MeOH (44 mL).
The flask was evacuated then backfilled with hydrogen three
times. The mixture was stirred at 25 °C for 17 h. Then, the crude
mixture was filtered over celite, concentrated under vacuum and
purified by flash chromatography (height: 17 cm, width: 4 cm;
Petroleum ether/EtOAc=70/30) to afford 1d as a colorless oil
(0.834 g, 3.9 mmol, 89%).
4.2.3. General procedure for the synthesis of the derivatives 3:
An oven-dried microwave tube equipped with a stirring bar
under argon was charged with PIDA (296 mg, 0.9 mmol, 2.3
equiv.), freshly distilled degassed CH2Cl2 (3 mL), I (102 mg, 0.4
mmol, 1 equiv.) followed by 1 (2 mmol, 5 equiv.). The mixture
was stirred at 20 °C for 16 h under irradiation with a blue LED
(450-455 nm) placed 5 cm away. α,α,α-Trifluoroacetophenone
(56 µL, 0.4 mmol, 1 equiv.) was added as an internal standard.
The reaction volume was halved via argon bubbling and acetyl
chloride (3.9 mL, 56 mmol, 135 equiv.) was added. The mixture
was stirred at 20 °C for 10 min. Upon full conversion by TLC,
the crude mixture was poured onto an ice-cold saturated solution
of NaHCO3 (100 mL). The aqueous layer was extracted with
CH2Cl2 (3 × 30 mL). The combined organic layers were washed
with brine (70 mL), dried over Na2SO4, concentrated under
vacuum and purified by flash column chromatography to afford
the desired product 3.
4.2.3. Procedure for the synthesis of 8-azidooctan-1-ol 1h:
An oven dried 3-neck round bottom flask equipped with a
reflux condenser was charged with sodium azide (2.4 g, 32.4
mmol, 2 equiv.). The flask was evacuated under high vacuum
and backfilled with argon three times. Dry DMF (26 mL) was
added followed by 8-chlorooctanol (2.8 mL, 16.2 mmol, 1
equiv.). The reaction mixture was stirred at 60 °C for 16 h. The
reaction mixture was diluted with diethyl ether (100 mL) and the
organic layer was washed with water (5 × 150 mL). The
combined organic layers were dried over Na2SO4 and
concentrated under vacuum. The crude mixture was purified by
flash column chromatography (height: 15 cm, width: 4 cm,
4.3. Physical and spectral data
4.3.1. S-(Trifluoromethyl)-4-methylbenzenesulfonothioate I.
Rf (Petroleum ether/EtOAc=90/10): 0.3. H NMR (300.1 MHz,
CDCl3) δ 7.88 (d, J = 7.8 Hz, 2H), 7.40 (d, J = 7.9 Hz, 2H), 2.49
(s, 3H). 19F NMR (282.4 MHz, CDCl3) δ -39.0 (s, 3F), NMR data
are in accordance with the literature data.23
1
4.3.2. 5-(4-Methoxyphenyl)pentan-1-ol 1b. Purification by
flash column chromatography (height: 15 cm, width: 3 cm,
Petroleum ether/EtOAc=80/20 to 70/30) afforded 1b as a
colorless oil (0.797 g, 0.21 mmol, 52%) from 4-bromoanisole
(1.0 mL, 8 mmol), according to the procedure described above.

5
1
Rf (petroleum ether/EtOAc=80/20): 0.3. H NMR (300.1 MHz,
555, 480, 451. HRMS (CI+) calcd for C12H14F3S m/z 247.0768
[M−OAc]+, found 247.0779 (ꢀ = 4.40 ppm).
CDCl3) δ 7.09 (d, J = 8.6 Hz, 2H), 6.82 (d, J = 8.6 Hz, 2H), 3.79
(s, 3H), 3.70-3.56 (m, 2H), 2.64-2.49 (m, 2H), 1.72-1.51 (m, 4H),
1.46-1.32 (m, 2H). The –OH proton was not observed in 1H
NMR. NMR data are in accordance with the literature data.24
4.3.9.
5-(4-Methoxyphenyl)-4-((trifluoromethyl)thio)pentyl
acetate 3b. Purification by flash column chromatography (height:
15 cm, width: 3 cm, Petroleum ether/EtOAc=95/5) afforded 3b as
4.3.3.
5-(4-(Trifluoromethyl)phenyl)pentan-1-ol
1c.
a colorless oil (52 mg, 0.16 mmol, 39%) from 5-(4-
Purification by flash column chromatography (height: 15 cm,
width: 3 cm, Petroleum ether/EtOAc=80/20) afforded 1c as a
colorless oil (0.66 g, 0.13 mmol, 33%) from 1-bromo-4-
(trifluoromethyl)benzene (1.61 mL, 8 mmol) according to the
procedure described above. Rf (petroleum ether/EtOAc=80/20):
methoxyphenyl)pentan-1-ol (388 mg, 2 mmol, 5 equiv.). Rf
(Petroleum ether/EtOAc=95/5): 0.29. 1H NMR (300.1 MHz,
CDCl3) δ 7.10 (d, J = 8.5 Hz, 2H), 6.85 (d, J = 8.5 Hz, 2H), 4.03
(t, J = 6.0 Hz, 2H), 3.80 (s, 3H), 3.44-3.30 (m, 1H), 3.05 (dd, J =
14.3, 5.7 Hz, 1H), 2.84 (dd, J = 14.3, 8.3 Hz, 1H), 2.01 (s, 3H),
1.93- 1.55 (m, 4H). 19F NMR (282.4 MHz, CDCl3) δ -39.5 (s,
3F). 13C NMR (75.5 MHz, CDCl3) δ 171.0, 158.5, 131.1 (q, J =
305.7 Hz), 130.3, 129.6, 113.9, 63.6, 55.2, 47.3, 41.2, 29.8, 25.4,
20.8. IR (neat, cm-1) ν: 2956, 2839, 1737, 1612, 1584, 1512,
1465, 1365, 1301, 1243, 1178, 1145, 1104, 1035, 910, 832, 811,
755, 732, 648, 605, 522, 490. HRMS (API+) calcd for
C15H20F3O3S m/z 337.1085 [M+H]+, found 337.1087 (ꢀ = −0.90
ppm).
1
0.3. H NMR (300.1 MHz, CDCl3) δ 7.52 (d, J = 8.1 Hz, 2H),
7.28 (d, J = 8.1 Hz, 2H), 3.76-3.56 (m, 2H), 2.75-2.60 (m, 2H),
1.73-1.54 (m, 4H), 1.49-1.33 (m, 2H). 19F NMR (282.4 MHz,
1
CDCl3) δ -62.8 (s, 3F). The –OH proton was not observed in H
NMR. NMR data are in accordance with the literature data.25
4.3.4. 5-(Naphthalen-2-yl)pentan-1-ol 1d. Rf (Petroleum
1
ether/EtOAc=70/30): 0.5. H NMR (300.1 MHz, CDCl3) δ 7.84-
7.73 (m, 3H), 7.61 (s, 1H), 7.49-7.37 (m, 2H), 7.34 (dd, J = 8.2,
0.8 Hz, 1H), 3.71-3.59 (m, 2H), 2.80 (dd, J = 7.8, 7.8 Hz, 2H),
1.83-1.70 (m, 2H), 1.69-1.56 (m, 2H), 1.52-1.39 (m, 2H). The –
OH proton was not observed in 1H NMR. NMR data are in
accordance with the literature data.26
4.3.10.
5-(4-(Trifluoromethyl)phenyl)-4-((trifluorome-
thyl)thio)pentyl acetate 3c. Purification by flash column
chromatography (height: 15 cm, width: 3 cm, Petroleum
ether/EtOAc=98/2) afforded 3c as a colorless oil (79 mg, 0.22
mmol, 18%, with an inseparable impurity) from I (307 mg, 1.2
mmol, 1 equiv.) and 5-(4-(trifluoromethyl)phenyl)pentan-1-ol
(1.39 g, 6 mmol, 5 equiv.). Rf (Petroleum ether/EtOAc=98/2):
4.3.5. 8-Azidooctan-1-ol 1h. Rf (Cyclohexane/EtOAc=70/30):
1
0.5. H NMR (300.1 MHz, CDCl3) δ 3.60 (t, J = 6.6 Hz, 2H),
3.23 (t, J = 6.9 Hz, 2H), 1.96-1.88 (m, 1H), 1.61-1.24 (m, 12H).
13C NMR (75.5 MHz, CDCl3) δ 62.7, 51.3, 32.6, 29.1, 29.0, 28.7,
26.5, 25.5. IR (neat, cm-1) ν: 3336, 2929, 2857, 2090, 1463,
1349, 1251, 1055, 892, 724, 636, 556. HRMS (EI+) calcd for
C8H17NO m/z 143.1310 [M−N2]+, found 143.1304 (∆ = −4.55
ppm).
1
0.29. H NMR (300.1 MHz, CDCl3) δ 7.58 (d, J = 8.0 Hz, 2H),
7.31 (d, J = 8.0 Hz, 2H), 4.05 (t, J = 5.9 Hz, 2H), 3.48-3.33 (m,
1H), 3.15 (dd, J = 14.2, 6.4 Hz, 1H), 2.99 (dd, J = 14.2, 8.3 Hz,
1H), 1.99 (s, 3H), 1.92-1.57 (m, 4H). 19F NMR (282.4 MHz,
CDCl3) δ -39.6 (s, 3F), -63.0 (s, 3F). 13C NMR (75.5 MHz,
CDCl3) δ 171.0, 141.7, 131.0 (q, J = 305.8 Hz), 129.7, 129.3 (q, J
= 32.3 Hz), 125.5 (q, J = 3.7 Hz), 124.0 (q, J = 272.6 Hz), 63.4,
46.7, 41.9, 30.2, 25.5, 20.8. IR (neat, cm-1) ν: 2940, 2866, 1735,
1620, 1420, 1366, 1323, 1241, 1161, 1107, 1066, 1018, 952, 909,
843, 817, 756, 732, 664, 634, 596, 507, 489. HRMS (CI+) calcd
for C13H13F6S m/z 315.0642 [M−OAc]+, found 315.0643 (ꢀ =
0.28 ppm).
4.3.6.
5-Phthalimido-1-pentanol
1i.
Rf
1
(CH2Cl2/EtOAc=90/10): 0.51. H NMR (300.1 MHz, CDCl3) δ
7.85-7.73 (m, 2H), 7.73-7.60 (m, 2H), 3.74-3.52 (m, 4H), 2.09 (s,
1H), 1.75-1.51 (m, 4H), 1.45-1.30 (m, 2H). 13C NMR (75.5
MHz, CDCl3) δ 168.4, 133.8, 131.9, 123.0, 62.3, 37.7, 32.0, 28.2,
22.9. NMR data are in accordance with the literature data.27
4.3.11.
5-(Naphthalen-2-yl)-4-((trifluoromethyl)thio)pentyl
4.3.7.
1-[(4-Trifluoromethyl)phenyl]-1-heptanol 1n.
Rf
(Cyclohexane/EtOAc=90/10): 0.1. 1H NMR (300.1 MHz,
CDCl3) δ 7.58 (d, J = 7.8 Hz, 2H), 7.42 (d, J = 7.8 Hz, 2H),
4.77-4.63 (m, 1H), 2.45 (br s, 1H), 1.82-1.60 (m, 2H), 1.46-1.15
(m, 8H), 0.96-0.81 (m, 3H). 19F NMR (282.4 MHz, CDCl3) δ -
62.5 (s). 13C NMR (75.5 MHz, CDCl3) δ 148.8, 129.6 (q, J =
32.4 Hz), 126.1, 125.3 (q, J = 3.8 Hz), 124.2 (q, J = 271.8 Hz),
74.0, 39.2, 31.7, 29.1, 25.6, 22.5, 14.0. IR (neat, cm-1) ν: 3344,
2931, 2859, 1621, 1467, 1418, 1323, 1163, 1122, 1067, 1017,
842, 763, 732, 658, 543. HRMS (EI+) calcd for C14H19F3O m/z
acetate 3d. Purification by flash column chromatography (height:
15 cm, width: 3 cm, Pentane/EtOAc=98/2 to 96/4) afforded 3d as
a colorless oil (56 mg, 0.16 mmol, 39%) from 5-(naphthalen-2-
yl)pentan-1-ol (373 mg, 2 mmol, 5 equiv.). Rf (Petroleum
1
ether/EtOAc=98/2): 0.2. H NMR (300.1 MHz, CDCl3) δ 7.89-
7.78 (m, 3H), 7.65 (s, 1H), 7.55-7.43 (m, 2H), 7.33 (dd, J = 8.2,
1.1 Hz, 1H), 4.03 (t, J = 6.0 Hz, 2H), 3.62-3.46 (m, 1H), 3.30
(dd, J = 14.0, 5.9 Hz, 1H), 3.07 (dd, J = 13.9, 8.7 Hz, 1H), 2.01-
1.54 (m, 7H). 19F NMR (282.4 MHz, CDCl3) δ -39.5 (s, 3F). 13
C
260.1388 [M]+ found 260.1379 (∆ = −3.32 ppm).
NMR (75.5 MHz, CDCl3) δ 170.9, 135.1, 133.4, 132.4, 131.1 (q,
J = 305.5 Hz), 128.2, 128.0, 127.6, 127.6, 127.3, 126.2, 125.7,
63.5, 46.9, 42.3, 29.9, 25.4, 20.7. IR (neat, cm-1) ν: 3053, 2953,
2860, 1735, 1606, 1508, 1448, 1365, 1236, 1105, 1040, 957, 908,
856, 816, 748, 731, 634, 620, 605, 584, 557, 475. HRMS (API+)
calcd for C16H16F3S m/z 297.0925 [M−OAc]+, found 297.0916 (ꢀ
= −3.00 ppm).
,
4.3.8. 5-Phenyl-4-((trifluoromethyl)thio)pentyl acetate 3a.
Purification by flash column chromatography (height: 15 cm,
width: 3 cm, Petroleum ether/EtOAc=98/2) afforded 3a as a
colorless oil (62 mg, 0.20 mmol, 51%) from 5-phenyl-1-pentanol
(336 µL, 2 mmol, 5 equiv.). A scale-up with I (307 mg, 1.2
mmol, 1 equiv.) and 5-phenyl-1-pentanol (1.0 mL, 6 mmol, 5
equiv.) led to 3a (168 mg, 0.55 mmol 46%). Rf (Petroleum
4.3.12. 4-((Trifluoromethyl)thio)pentyl acetate 3e. Purification
by flash column chromatography (height: 15 cm, width: 3 cm,
Pentane/EtOAc=98/2) afforded 3e as a colorless oil (34 mg, 0.15
mmol, 37%, with an inseparable impurity) from pentanol (217
µL, 2 mmol, 5 equiv.). Rf (Petroleum ether/EtOAc=98/2): 0.3. 1H
NMR (300.1 MHz, CDCl3) δ 4.15-4.02 (m, 2H), 3.40-3.26 (m,
1H), 2.05 (s, 3H), 1.85-1.59 (m, 4H), 1.43 (d, J = 6.8 Hz, 3H).
19F NMR (282.4 MHz, CDCl3) δ -39.7 (s, 3F). 13C NMR (75.5
MHz, CDCl3) δ 171.1, 131.0 (q, J = 305.6 Hz), 63.8, 40.8, 33.3,
1
ether/EtOAc=98/2): 0.29. H NMR (300.1 MHz, CDCl3) δ 7.38-
7.14 (m, 5H), 4.03 (t, J = 6.0 Hz, 2H), 3.49-3.35 (m, 1H), 3.12
(dd, J = 13.9, 5.6 Hz, 1H), 2.90 (dd, J = 13.9, 8.5 Hz, 1H), 2.00
(s, 3H), 1.96-1.47 (m, 4H). 19F NMR (282.4 MHz, CDCl3) δ -
39.6 (s, 3F). 13C NMR (75.5 MHz, CDCl3) δ 171.0, 137.6, 130.9
(q, J = 306.8 Hz), 129.3, 128.5, 126.9, 63.5, 47.0, 42.1, 29.9,
25.4, 20.8. IR (neat, cm-1) ν: 3030, 2932, 2853, 1737, 1603,
1496, 1454, 1365, 1237, 1144, 1103, 1041, 743, 699, 634, 605,

6
Tetrahedron
25.8, 22.3, 20.9. IR (neat, cm-1) ν: 2966, 1739, 1454, 1385,
Pentane/EtOAc=98/2) afforded 3j as a colorless oil (47 mg, 0.18
mmol, 44%, d.r. 1.2/1) from 2-cyclohexylethanol (279 µL, 2
mmol, 5 equiv.). Rf (Petroleum ether/EtOAc=98/2): 0.3. 1H
NMR (300.1 MHz, CDCl3) δ 4.20-4.39 (m, 4H, maj+min), 3.59-
3.50 (m, 1H, min), 2.89 (td, J = 10.1, 4.1 Hz, 1H, maj), 2.32-2.16
(m, 2H, maj+min), 2.08-1.90 (m, 8H, maj+min), 1.88-1.44 (m,
14H, maj+min), 1.38-1.23 (m, 3H, maj+min), 1.19-1.00 (m, 2H,
maj+min). 19F NMR (282.4 MHz, CDCl3) δ -39.3 (s, 3F, min), -
40.1 (s, 3F, maj). 13C NMR (75.5 MHz, CDCl3) δ 171.1
(maj+min), 131.5 (q, J = 305.6 Hz, min), 131.3 (q, J = 305.6 Hz,
maj), 62.1 (maj), 62.0 (min), 49.8 (maj), 48.6 (min), 38.6 (maj),
37.6 (min), 35.3 (maj), 33.0 (maj), 32.6 (min), 32.1 (min), 31.6
(min), 28.6 (maj), 25.9 (min), 24.6 (maj), 24.5 (maj), 21.7 (min),
20.9 (maj+min). IR (neat, cm-1) ν: 2933, 2859, 1738, 1449, 1388,
1367, 1233, 1144, 1100, 1043, 968, 757, 733, 697, 635, 606.
HRMS (CI+) calcd for C9H14F3S m/z 211.0768 [M−OAc]+, found
211.0760 (ꢀ = −4.05 ppm).
1365, 1234, 1189, 1178, 1149, 1101, 1051, 962, 913, 815, 755,
663, 634, 606, 555. HRMS (CI+) calcd for C6H10F3S m/z
171.0455 [M−OAc]+, found 171.0454 (ꢀ = −0.88 ppm).
4.3.13. 4-((Trifluoromethyl)thio)octyl acetate 3f. Purification
by flash column chromatography (height: 15 cm, width: 3 cm,
Pentane/EtOAc=98/2) afforded 3f as a colorless oil (39 mg, 0.14
mmol, 36%) from octanol (314 µL, 2 mmol, 5 equiv.). Rf
(Petroleum ether/EtOAc=98/2): 0.3. 1H NMR (300.1 MHz,
CDCl3) δ 4.16-4.01 (m, 2H), 3.24-3.07 (m, 1H), 2.05 (s, 3H),
1.90-1.55 (m, 6H), 1.54-1.23 (m, 4H), 0.91 (t, J = 6.9 Hz, 3H).
19F NMR (282.4 MHz, CDCl3) δ -39.6 (s, 3F). 13C NMR (75.5
MHz, CDCl3) δ 171.0, 131.0 (q, J = 306.0 Hz), 63.8, 46.2, 34.8,
31.5, 28.5, 25.5, 22.3, 20.8, 13.8. IR (neat, cm-1) ν: 2935, 2862,
1739, 1458, 1365, 1234, 1177, 1148, 1108, 1038, 953, 878, 807,
755, 733, 663, 634, 606, 555. HRMS (CI+) calcd for C9H16F3S
m/z 213.0925 [M−OAc]+, found 213.0925 (ꢀ = 0.17 ppm).
4.3.18. 2-((1r,3s,5R,7S)-2-((Trifluoromethyl)thio)adamantan-
1-yl)ethyl acetate 3k. Purification by flash column
4.3.14. Ethyl 6-acetoxy-3-((trifluoromethyl)thio)hexanoate 3g.
Purification by flash column chromatography (height: 15 cm,
chromatography
(height:
15
cm,
width:
3
cm,
width:
3
cm, Pentane/CH2Cl2=60/40 to 50/50 then
Pentane/CH2Cl2=30/70 to 50/50 then Pentane/EtOAc=95/5)
afforded 3k as a colorless oil (54 mg, 0.17 mmol, 42%) from 2-
(adamantan-1-yl)ethan-1-ol (360 mg, 2 mmol, 5 equiv.). Rf
(Petroleum ether/EtOAc=98/2): 0.3. 1H NMR (300.1 MHz,
CDCl3) δ 4.24-4.05 (m, 2H), 3.37 (s, 1H), 2.27-2.16 (m, 1H),
2.09-1.57 (m, 15H), 1.54-1.37 (m, 2H). 19F NMR (282.4 MHz,
CDCl3) δ -40.0 (s, 3F). 13C NMR (75.5 MHz, CDCl3) δ 171.1,
131.4 (q, J = 305.6 Hz), 60.0, 56.9, 42.3, 39.1, 38.6, 37.7, 36.4,
35.7, 35.4, 31.5, 27.6, 27.4, 21.0. IR (neat, cm-1) ν: 2910, 2850,
1723, 1451, 1367, 1253, 1139, 1097, 1037, 979, 967, 951, 896,
826, 768, 754, 644, 609, 480. HRMS (CI+) calcd for C13H18F3S
m/z 263.1081 [M−OAc]+, found 263.1091 (ꢀ = 3.63 ppm).
Pentane/EtOAc=95/5) afforded 3g as a colorless oil (33 mg, 0.11
mmol, 27%) from ethyl 6-hydroxyhexanoate (320 µL, 2 mmol, 5
equiv.). Rf (Petroleum ether/EtOAc=98/2): 0.2. H NMR (300.1
1
MHz, CDCl3) δ 4.18 (q, J = 7.2 Hz, 2H), 4.13-4.02 (m, 2H),
3.62-3.45 (m, 1H), 2.86-2.63 (m, 2H), 2.05 (s, 3H), 1.95-1.66 (m,
4H), 1.28 (t, J = 7.2 Hz, 3H). 19F NMR (282.4 MHz, CDCl3) δ -
39.9 (s, 3F). 13C NMR (75.5 MHz, CDCl3) δ 171.0, 170.2, 130.7
(q, J = 306.7 Hz), 63.5, 61.0, 41.6, 40.8, 31.4, 25.9, 20.8, 14.1.
IR (neat, cm-1) ν: 2984, 2879, 1730, 1375, 1351, 1234, 1149,
1099, 1031, 945, 756, 634, 606, 474. HRMS (CI+) calcd for
C11H18F3O4S m/z 303.0878 [M+H]+, found 303.0882 (ꢀ = 1.33
ppm).
4.3.19. 4-Methyl-4-((trifluoromethyl)thio)pentyl acetate 3l.
Purification by flash column chromatography (height: 15 cm,
4.3.15. 8-Azide-4-((trifluoromethyl)thio)octyl acetate 3h.
Purification by flash column chromatography (height: 15 cm,
width: 3 cm, Pentane/EtOAc=80/20) afforded 3h as a colorless
oil (56 mg, 0.18 mmol, 45%, with an inseparable impurity),
from 8-azidooctan-1-ol (0.34 g, 2 mmol, 5 equiv.). Rf (Petroleum
width:
3
cm, Pentane/CH2Cl2=70/30 to 50/50 then
Pentane/EtOAc=98/2) afforded 3l as a colorless oil (49 mg, 0.20
mmol, 50%) from 4-methyl-1-pentanol (248 µL, 2 mmol, 5
1
equiv.). Rf (Petroleum ether/EtOAc=98/2): 0.3. H NMR (300.1
1
ether/EtOAc=80/20): 0.4. H NMR (300.1 MHz, CDCl3) δ 4.14-
MHz, CDCl3) δ 4.06 (t, J = 5.5 Hz, 2H), 2.04 (s, 3H), 1.85-1.65
(m, 4H), 1.44 (s, 6H). 19F NMR (282.4 MHz, CDCl3) δ -36.3 (s,
3F). 13C NMR (75.5 MHz, CDCl3) δ 171.1, 130.7 (q, J = 308.0
Hz), 64.1, 51.5, 39.3 (d, J = 1.1 Hz), 29.4 (d, J = 1.8 Hz), 24.1,
20.9. IR (neat, cm-1) ν: 2966, 1740, 1599, 1505, 1469, 1389,
1370, 1238, 1098, 1041, 877, 839, 755, 699, 635, 606, 556, 419.
HRMS (CI+) calcd for C7H12F3S m/z 185.0612 [M−OAc]+, found
185.0603 (ꢀ = −4.83 ppm).
4.02 (m, 2H), 3.36-3.24 (m, 2H), 3.19-3.09 (m, 1H), 2.04 (s, 3H),
1.87-1.48 (m, 10H). 19F NMR (282.4 MHz, CDCl3) δ -39.5 (s,
3F). 13C NMR (75.5 MHz, CDCl3) δ 171.0, 131.0 (q, J = 306.5
Hz), 63.7, 51.1, 46.0, 34.7, 31.6, 28.5, 25.5, 23.6, 20.8. IR (neat,
cm-1) ν: 2959, 2932, 2862, 1741, 1457, 1365, 1236, 1106, 755.
HRMS (AP+) calcd for C11H19F3N3O2S m/z 314.1150 [M+H]+,
found 314.1145 (∆ = −1.6 ppm).
4.3.16. 5-Phthalimido-4-((trifluoromethyl)thio)pentyl acetate
3i. Purification by reverse phase chromatography (height: 25 cm,
width: 2 cm, H2O/acetonitrile=100/0 to 10/90) afforded 3i as a
white solid (30 mg, 0.08 mmol, 20%) from 5-phthalimido-1-
pentanol (0.47 g, 2 mmol, 5 equiv.). mp = 59-60 °C. Rf
(Petroleum ether/EtOAc=80/20): 0.1. 1H NMR (300.1 MHz,
CDCl3) δ 7.92-7.83 (m, 2H), 7.80-7.69 (m, 2H), 4.08 (t, J = 6.0
Hz, 2H), 4.00-3.81 (m, 2H), 3.70-3.56 (m, 1H), 2.01 (s, 3H) 1.91-
4.3.20. 5-((Trifluoromethyl)thio)hexan-2-yl acetate 3m.
Purification by flash column chromatography (height: 15 cm,
width:
3
cm, Pentane/CH2Cl2=70/30 to 50/50 then
Pentane/EtOAc=98/2) afforded 3m as a colorless oil (84 mg,
0.12 mmol, 29%, d.r. 2.4/1) from I (307 mg, 1.2 mmol, 1 equiv.)
and 2-hexanol (756 µL, 6 mmol, 5 equiv.). Rf (Petroleum
1
ether/EtOAc=98/2): 0.3. H NMR (300.1 MHz, CDCl3) δ 4.99-
4.81 (m, 1H, maj+min), 3.39-3.21 (m, 1H, maj+min), 2.03 (s,
3H, maj+min), 1.79-1.54 (m, 4H, maj+min), 1.41 (d, J = 6.9 Hz,
3H, maj+min), 1.22 (d, J = 6.4 Hz, 3H, maj+min). 19F NMR
(282.4 MHz, CDCl3) δ -39.7 (s, 3F). 13C NMR (75.5 MHz,
CDCl3) δ 170.7 (maj+min), 131.3 (q, J = 307.3 Hz, maj+min),
70.3 (min), 70.2 (maj), 41.0 (min), 40.9 (maj), 32.9 (min), 32.7
(maj), 32.6 (min), 32.5 (maj), 22.3 (maj), 22.2 (min), 21.2
(maj+min), 19.9 (maj+min). IR (neat, cm-1) ν: 2979, 2938, 1873,
1736, 1454, 1373, 1239, 1101, 1049, 1020, 952, 837, 756, 631,
609, 492. HRMS (CI+) calcd for C7H12F3S m/z 185.0612
[M−OAc]+, found 185.0606 (ꢀ = −3.14 ppm).
1.60 (m, 4H). 19F NMR (282.4 MHz, CDCl3) δ -39.7 (s, 3F). 13
C
NMR (75.5 MHz, CDCl3) δ 170.9, 168.0, 134.2, 131.7, 130.6 (q,
J = 307.3 Hz), 123.5, 63.5, 44.2, 42.1, 29.3, 25.5, 20.8. IR (neat,
cm-1) ν: 2924, 2854, 1773, 1740, 1713, 1469, 1429, 1397, 1366,
1247, 1149, 1028, 1108, 722. HRMS (CI+) calcd for
C16H17F3NO4S m/z 376.0830 [M+H]+, found 376.0838 (∆ = 1.97
ppm).
4.3.17. 2-(2-((Trifluoromethyl)thio)cyclohexyl)ethyl acetate 3j.
Purification by flash column chromatography (height: 15 cm,
width:
3
cm, Pentane/CH2Cl2=30/70 to 50/50 then

7
Leroux, F. Curr. Top. Med. Chem. 2014, 14, 941–951; (e)
4.3.21.
1-[(4-Trifluoromethyl)phenyl]-4-((trifluoromethyl)-
Besset, T.; Jubault, P.; Pannecoucke, X.; Poisson, T. Org. Chem.
Front. 2016, 3, 1004–1010; (f) Landelle, G.; Panossian, A.;
Pazenok, S.; Vors, J.-P.; Leroux, F. R. Beilstein J. Org. Chem.
2013, 9, 2476–2536; (g) Champagne, P. A.; Desroches, J.; Hamel,
J.-D.; Vandamme, M.; Paquin, J.-F. Chem. Rev. 2015, 115, 9073–
9174; (h) Merino, E.; Nevado, C. Chem. Soc. Rev. 2014, 43,
6598–6608; (i) Egami, H.; Sodeoka, M. Angew. Chem. Int. Ed.
2014, 53, 8294–8308; (j) Belhomme, M.-C.; Besset, T.; Poisson,
T.; Pannecoucke, X. Chem. Eur. J. 2015, 21, 12836–12865; (k)
Song, H.-X.; Han, Q.-Y.; Zhao, C.-L.; Zhang, C.-P. Green Chem.
2018, 20, 1662–1731.
thio)-heptyl acetate 3n. Purification by flash column
chromatography (height 15 cm, width 3 cm, Pentane/Et2O=95/5)
afforded 3n as a colorless oil (46 mg, 0.12 mmol, 29%, d.r. 1/1)
from 1-[(4-trifluoromethyl)phenyl]-1-heptanol (0.52 g, 2 mmol, 5
1
equiv.). Rf (Petroleum ether/EtOAc=95/5): 0.4. H NMR (300.1
MHz, CDCl3) δ 7.62 (d, J = 8.1 Hz, 2H), 7.44 (d, J = 8.1 Hz,
2H), 5.85-5.71 (m 1H), 3.23-3.08 (m, 1H), 2.14-2.06 (m, 3H),
2.06-1.86 (m, 2H), 1.79-1.53 (m, 4H), 1.51-1.34 (m, 2H), 0.91 (t,
J = 7.2 Hz, 3H). 19F NMR (282.4 MHz, CDCl3) δ -39.6 (s, 3F), -
39.6 (s, 3F), -63.2 (s, 6F). 13C NMR (75.5 MHz, CDCl3) δ 170.1
(maj+min), 144.2 (maj+min), 131.1 (q, J = 306 Hz, maj+min),
130.3 (q, J = 32.3 Hz, maj+min), 126.7 (min), 126.6 (maj), 125.6
(q, J = 3.6 Hz, maj+min), 123.9 (q, J = 272.7 Hz, maj+min), 74.9
(maj), 74.6 (min), 46.0 (min), 45.8 (maj), 37.2 (min), 37.1 (maj),
32.9 (maj+min), 31.0 (min), 30.8 (maj), 21.0 (maj+min), 19.7
(maj+min), 13.6 (maj+min). IR (neat, cm-1) ν: 2963, 2877, 1739,
1623, 1421, 1374, 1325, 1231, 1104, 1067, 1017, 954, 898, 840,
756, 665, 633, 605. HRMS (API−) calcd for C17H20F6O2S m/z
402.1088 [M]−, found 402.1095 (∆ = 1.70 ppm).
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4.3.22. 2-Methyl-5-((trifluoromethyl)thio)hexan-2-yl acetate
3o. Purification by flash column chromatography (height: 15 cm,
width:
3
cm, Pentane/CH2Cl2=70/30 to 50/50 then
Pentane/EtOAc=98/2) afforded 3o as a colorless oil (60 mg, 0.08
mmol, 19%) from I (307 mg, 1.2 mmol, 1 equiv.) and 2-methyl-
2-hexanol (857 µL,
6 mmol, 5 equiv.). Rf (Petroleum
1
ether/EtOAc=98/2): 0.3. H NMR (300.1 MHz, CDCl3) δ 3.38-
3.21 (m, 1H), 1.96 (s, 3H), 1.92-1.80 (m, 2H), 1.72-1.57 (m, 2H),
1.43 (s, 6H), 1.40 (s, 3H). 19F NMR (282.4 MHz, CDCl3) δ -39.7
(s, 3F). 13C NMR (75.5 MHz, CDCl3) δ 170.4, 130.9 (q, J =
305.9 Hz), 81.5, 41.3, 37.6, 31.1, 26.0, 25.9, 22.3, 22.1. IR (neat,
cm-1) ν: 2979, 2936, 1732, 1454, 1385, 1367, 1252, 1212, 1100,
1047, 1017, 943, 856, 756, 635, 610, 491. HRMS (CI+) calcd for
C8H14F3S m/z 199.0768 [M−OAc]+, found 199.0762 (ꢀ = −3.3
ppm).
4.3.23. 4-((Trifluoromethyl)thio)cyclooctyl acetate 3p.
Purification by flash column chromatography (height: 15 cm,
width:
3
cm, Pentane/CH2Cl2=80/20 to 50/50 then
Pentane/EtOAc=98/2) afforded 3p as a colorless oil (24 mg, 0.09
mmol, 22%, d.r. 1.7/1, with an inseparable impurity) from
cyclooctanol (264 µL, 2 mmol, 5 equiv.). Rf (Petroleum
1
ether/EtOAc=98/2): 0.32. H NMR (300.1 MHz, CDCl3) δ 5.02-
4.81 (m, 1H, maj+min), 3.60-3.34 (m, 1H, maj+min), 2.33-1.37
(m, 15H, maj+min). 19F NMR (282.4 MHz, CDCl3) δ -39.4 (s,
3F, min), -39.6 (s, 3F, maj). 13C NMR (75.5 MHz, CDCl3) δ
170.3 (maj+min), 130.9 (q, J = 306.2 Hz, maj+min), 73.8 (maj),
73.4 (min), 45.4 (min), 45.1 (maj), 32.7 (min), 31.4 (maj), 31.1
(min), 30.8 (maj), 30.2 (min), 29.1 (maj), 29.0 (maj), 28.6 (min),
24.5 (maj), 24.4 (min), 23.1 (maj), 22.1 (min), 21.4 (min), 21.4
(maj). IR (neat, cm-1) ν: 2939, 2862, 1731, 1470, 1448, 1367,
1239, 1100, 1037, 1018, 960, 871, 786, 756, 649, 609, 542.
HRMS (CI+) calcd for C9H14F3S m/z 211.0768 [M−OAc]+, found
211.0766 (ꢀ = −1.16 ppm).
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6. Acknowledgments
This work was partially supported by Normandie Université
(NU), the Région Normandie, the Centre National de la
Recherche Scientifique (CNRS), Université de Rouen Normandie
(URN), INSA Rouen Normandie, Labex SynOrg (ANR-11-
LABX-0029) and Innovation Chimie Carnot (I2C). M.B. R.B.,
L.R. and T.B. thank the European Research Council (ERC) under
the European Union’s Horizon 2020 research and innovation
programme (grant agreement no. 758710).
Supplementary Material

Declaration of interests
☒ 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.
☐The authors declare the following financial interests/personal relationships which may be considered
as potential competing interests: