Synthesis of Fluoroalkyl Sulfides via Additive-Free Hydrothiolation and Sequential Functionalization Reactions

Article abstract of DOI:10.1021/acs.joc.1c00361

A modular synthetic method, involving a hydrothiolation, silylation, and fluoroalkylation, for the construction of highly functionalized fluoroalkyl sulfides has been developed. The use of aprotic polar solvents enables the additive-free chemoselective hydrothiolation of tetrafluoroethylene, trifluorochloroethylene, and hexafluoropropene with various thiols. The stepwise functionalization reactions convert the hydrothiolated intermediates into the tetrafluoroethyl sulfides in high efficiency. The method avoids the use of the environmental pollutant Halon-2402, which was employed as a building block in a reported synthetic route.

Full text of DOI:10.1021/acs.joc.1c00361

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Synthesis of Fluoroalkyl Sulfides via Additive-Free Hydrothiolation
and Sequential Functionalization Reactions
Denise E. Sunagawa, Naoyoshi Ishida, Hiroaki Iwamoto, Masato Ohashi, Corinne Fruit,
and Sensuke Ogoshi*
Cite This: J. Org. Chem. 2021, 86, 6015−6024
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ABSTRACT: A modular synthetic method, involving a hydrothiolation,
silylation, and fluoroalkylation, for the construction of highly function-
alized fluoroalkyl sulfides has been developed. The use of aprotic polar
solvents enables the additive-free chemoselective hydrothiolation of
tetrafluoroethylene, trifluorochloroethylene, and hexafluoropropene with
various thiols. The stepwise functionalization reactions convert the
hydrothiolated intermediates into the tetrafluoroethyl sulfides in high
efficiency. The method avoids the use of the environmental pollutant
Halon-2402, which was employed as a building block in a reported
synthetic route.
Scheme 1. Synthesis of Highly Functionalized
erfluoroalkyl groups have been established as effective
Pmolecular motifs, given that organofluorine compounds
show unique conformational and electrostatic effects due to
the electronic properties of the fluorine atom.1 In particular,
fluoroalkanes that contain heteroatoms such as oxygen,
nitrogen, and sulfur have garnered great attention in the
context of modifying bioactive and functional materials.
Various synthetic methods for the generation of fluoroalkyl
ethers, amines, and sulfides have been developed.2 Further-
more, fluoroalkyl compounds that bear a tetrafluoroethyl
moiety have been synthesized via nucleophilic substitutions
using 1,2-dibromo-1,1,2,2-tetrafluoroethane (Halon-2402) as a
building block (Scheme 1a).3,4 However, Halon-2402 is an
ozone-layer-depleting fluorocarbon, and its production has
been forbidden in countries that have ratified the “Montreal
Protocol”.5
Tetrafluoroethyl Sulfides from TFE via (a) the Sequential
Substitution of Halon-2402 or (b) a Hydrothiolation/
Silylation (This Work); (c) the Hydrosilylation Proceeds
Chemoselectively in the Absence of Additives
Tetrafluoroethylene (TFE) and chlorotrifluoroethylene
(CTFE) have been widely employed as fluorinated feedstock
chemicals for the production of various organofluorine
compounds such as fluorinated polymers.6 Importantly, the
potential of TFE and CTFE to deplete the ozone layer is
negligible.7 In the 1950s and 1960s, several examples of base-
promoted hydrothiolation reactions of TFE and CTFE have
been reported.8 Moreover, various organic transformations of
highly functionalized organofluorine compounds have recently
been realized by exploiting the unique reactivity of these
fluorinated feedstock chemicals.9,10 Previously, our group has
reported the carbo-, oxy-, fluoro-, and azacupration of TFE,
followed by additional functionalization reactions to synthesize
tetrafluoroethyl-bridged organic compounds.11 In the present
Received: February 13, 2021
Published: March 29, 2021
https://doi.org/10.1021/acs.joc.1c00361
© 2021 American Chemical Society
J. Org. Chem. 2021, 86, 6015−6024
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study, we have developed a modular synthetic method that
involves a hydrothiolation, followed by a silylation and various
functionalization reactions, to obtain highly functionalized
tetrafluoroethyl sulfides (Scheme 1b). We discovered that the
use of polar aprotic solvents enables the hydrothiolation of
various fluoroalkenes in the absence of additives to give the
corresponding sulfides within 1 h.12 Furthermore, under the
applied reaction conditions, the addition reaction occurs
chemoselectively at the thiol moieties even in substrates that
contain hydroxyl or amine groups that could not be used under
the previous conditions involving basic additives (Scheme
1c).8 The subsequent silylation and copper(I)-mediated
fluoroalkylation of aryl iodides also proceeds with high
efficiency and substrate compatibility.
stoichiometric amount of KOH (entry 4: 2a, 66%, 3a, 8%).
The use of sodium hydride furnished 2a in low yield and 3a as
the major product (entry 5: 2a, 5%; 3a, 76%). Although the
reactions in DMF or DMSO also provided 2a quantitatively
(entry 6: DMF, >99%; entry 7: DMSO, >99%), no reaction
occurred in THF and C6D6 (entry 8, THF: 0%; entry 9, C6D6:
0%).
To investigate the impact of the solvent on the reactivity, 1H
NMR measurements of thiol 1a in mixtures of the
corresponding solvent and C6D6 (4:1) were conducted (Figure
1a). The chemical shifts of the thiol proton (SH) of 1a in the
In a preliminary study, we attempted the thiocupration of
TFE using its sodium thiolate and a copper(I) salt under
previously reported conditions.11 Although the reaction
furnished the desired tetrafluoroethyl sulfide copper(I) species
in low yield, the product was obtained as part of a complex
mixture including the corresponding β-fluorine-elimination
product. In contrast, the hydrothiolation of tetrafluoroethylene
(TFE) with 2-naphthyl thiol (1a) in an aprotic polar solvent
such as DMA proceeded quantitatively at room temperature in
the absence of additives (Table 1, entry 1; >99%).
Table 1. Optimization of the Hydrothiolation of 1a under a
a
TFE Atmosphere
yield of 2a
yield of 3a
b c
b
,
entry additive
solvent
(%)
(%)
d
1
2
3
4
5
6
7
8
9
none
DMA/C6D6 (4:1)
>99 (89)
0
5
6
8
76
0
0
0
0
NaOtBu DMA/C6D6 (4:1)
78
67
66
5
>99
>99
0
KOH
KOH
NaH
none
none
none
none
DMA/C6D6 (4:1)
DMF/C6D6 (4:1)
DMA/C6D6 (4:1)
DMF/C6D6 (4:1)
DMSO/C6D6 (4:1)
THF/C6D6 (4:1)
C6D6
e
Figure 1. Mechanistic study and proposed reaction pathway of the
hydrothiolation of TFE with thiol 1.
0
mixed solvents indicated that thiol 1a is more acidic in the
aprotic polar solvents DMA, DMF, and DMSO than in THF
and benzene [DMSO: δH(SH) = 5.41 ppm; DMA: δH(SH) =
5.28 ppm; DMF: δH(SH) = 4.97 ppm; THF: δH(SH) = 3.90
ppm; benzene: δH(SH) = 3.15 ppm]. Therefore, we expected
that the hydrogen bonding between the SH proton of thiol 1a
and the solvent molecules would enhance the nucleophilicity
of 1a, thus increasing its reactivity in the hydrothiolation
(Figure 1b; for details, see the SI).13,14
Next, we carried out an investigation of the substrate scope
of the hydrothiolation of TFE (Table 2). The hydrothiolation
products that bear a naphthalene or alkyl-substituted phenyl
rings were obtained in excellent yield (2a: 89%; 2b: 96%; 2c:
89%). The reactions of electron-deficient benzene thiol
derivatives that bear a trifluoromethyl or bromo group also
provided the corresponding tetrafluoroethyl sulfides in good
yield (2d: 82%; 2e: 83%). A thiol with a nitro group at the
para-position of the phenyl ring 1f required a slightly higher
temperature (40 °C) but furnished sulfide 2f in excellent yield
(92%). An aryl thiol with electron-donating groups 1g could
also be used under these hydrothiolation conditions (2g:
a
Standard conditions: 1a (0.5 mmol) and the additive (0.5 mmol) in
the specified solvent (1.0 mL) under a TFE atmosphere (2.0 atm).
b
Yields of 2a and 3a were determined by 19F NMR analysis of the
crude reaction product using an internal standard. Yield after
purification is shown in parentheses. Combined yield of isomers of
3a. The reaction time was 15 min. A catalytic amount of KOH (0.2
equiv) was used.
c
d
e
Furthermore, thiol 1a was fully converted to 2a within 15
min. Considering previously reported base-promoted hydro-
thiolation reactions,8,10e we also tested the reaction using
various base additives (entries 2−5). The hydrothiolation
yields of 2a using alkoxide and hydroxide bases were inferior to
that obtained without the additive (entry 2: 2a, 78%; entry 3:
2a, 67%). The double-addition products 3a, which would be
formed through β-fluorine elimination, followed by a second
addition reaction, were also detected as side products by 19F
NMR spectroscopy when these additives were used (entry 2:
3a, 5%; entry 3: 3a, 6%). The reaction using a catalytic amount
of KOH (0.2 equiv) resulted in the similar result to that with a
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Table 2. Substrate Scope of the Additive-Free
Hydrothiolation of TFE
Scheme 2. Hydrothiolation of TFE Using Thiols That
Contain Unprotected Hydroxyl and Amine Moieties
a
the additive-free conditions represent a complementary
method to the base-promoted hydrothiolation.
Then, the polar-aprotic-solvent-assisted hydrothiolation was
applied to other fluoroalkene feedstocks (Scheme 3). The
a
Scheme 3. Hydrothiolation of CTFE and HFP
a
Standard conditions: 1 (0.5 mmol) in DMA (1.0 mL) under a TFE
b
atmosphere (2.0 atm). Gram-scale reactions: 1a (15 mmol), 1h (7.0
mmol), and 1l (4.0 mmol) were used. Pressure of TFE was 5.0 atm.
c
a
CTFE (5.0 atm) was used.
92%). Benzyl thiol 1h was successfully converted into the
corresponding sulfide 2h under the optimized conditions (40
°C, 87%). Although a high reaction temperature (150 °C) was
required for the reaction of aliphatic thiols 1i and 1j, both
products were obtained in good yield (2i: 86%; 2j: 74%).
Furthermore, the double hydrothiolation of dithiols 1k and 1l
also proceeded at ambient temperature to give the bis-
(tetrafluoroethylsulfide)arenes in high yield (2k: 97%; 2l:
89%). The hydrothiolation of a dithiol with a para-terphenyl
moiety 1m required an elevated reaction temperature (60 °C)
due to its low solubility, but the corresponding product 2m
was obtained in good yield (78%).
To investigate the advantages of this additive-free hydro-
thiolation, reactions using substrates with two reactive sites,
i.e., a thiol group and another group at which the reactivity was
not desired, were conducted (Scheme 2). Under the
aforementioned conditions, 3-hydroxy-benzene thiol (1n)
was selectively converted to the tetrafluoroethyl sulfide 2n in
85% yield. The corresponding tetrafluoroethyl ether 2n′ was
not detected. In contrast, the reaction of 1n with a catalytic
amount of the base KOH under previously reported conditions
furnished 2n′ (>99%).10e Furthermore, the additive-free
conditions were also effective for the hydrothiolation of a
thiol bearing an amine (NH2) moiety 1o [additive-free
conditions: sulfide 2o, 93%; previous conditions:10e complex
product mixture].15 The hydrothiolation in an aprotic polar
solvent thus proceeds in a highly thiol-selective manner, while
reactions of thiols 1a, 1f, and 1l using CTFE (3.5 atm)
afforded the corresponding 1-chloro-1,2,2-trifluoroethyl sul-
fides in high yield (Scheme 3a; 4a: 83%; 4f: 93%; 4l: 81%),
although a slightly longer reaction time or harsher conditions
were needed compared to those used with TFE (Scheme 3a).
Hexafluoropropene (HFP) was also reactive in the additive-
free hydrothiolation (Scheme 3b). Thiol 1a was fully converted
at ambient temperature within a short reaction time. However,
a mixture of hydrothiolation product 5a and β-fluoro-
elimination products (E/Z)-6a [5a: 25%; (E/Z)-6a: 65% (E/
Z = 26:74)] was obtained.
We then investigated the silylation of the obtained
fluoroalkyl sulfides 2 or 4 (Scheme 4). On the basis of
reported silylation conditions,16 we added the fluoroalkyl
sulfides to a mixture of lithium diisopropylamide (LDA) and
trimethylsilyl chloride (TMSCl) in THF at −78 °C and
allowed the mixture to warm to room temperature. Mixing the
sulfide and LDA prior to the addition of TMSCl resulted in the
β-fluorine elimination to give the fluoroalkene even at low
temperature. The optimized silylation conditions converted
sulfides 2 or 4 into the corresponding fluoroalkyl silane
products 7 or 8 in high yield (7a: 82%; 7h: 87%; 8a: 88%).
Subsequently, we investigated the coupling reactions of the
silylated tetrafluoroethyl sulfides 7 with aryl iodides and other
electrophiles using transmetalation with a copper(I) complex
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products in good yield (9af: 84%; 9ag: 78%; 9ah: 65%; 9ai:
73%). We also tested other types of carbon electrophiles,
namely, an alkenyl iodide and an acid chloride. The coupling
reaction between benzyl sulfide 7h and the (Z)-alkenyl iodide
furnished a tetrafluoroethyl sulfide bearing an (Z)-alkene
moiety [(Z)-9hj] in high yield and stereospecificity (77%, Z/E
= >99:1). An esterification using the corresponding chlor-
oformate afforded ester 9hk in high yield (83%). Furthermore,
the reaction of 7h using a carbamoyl chloride furnished the
corresponding amide 9hl in good yield (92%).
Scheme 4. Base-Mediated Silylation of Hydrothiolation
Products 2 or 4
a
Then, we examined the modular synthesis of tetrafluoroethyl
sulfide for the development of functional molecules, as
tetrafluoroethyl groups attached to sulfur atoms are known
as a useful motif for functional organic materials.2c,4c 1,5-
Bis(tetrafluoroethylthio)naphthalene (2l) was subjected to the
stepwise functionalization process (Scheme 5). The double
a
The yields of gram-scale reactions are shown in parentheses.
(Table 3). The optimization of the reaction conditions
demonstrated that treatment of 7a with copper(I) alkoxide
Scheme 5. Diarylation Sequence for
Bis(tetrafluoroethylthio)arene 2l. ORTEP Drawing of 7l
with Thermal Ellipsoids at 50% Probability
Table 3. Scope of the Copper(I)-Mediated Carbon−Carbon
a
Bond Formation of 7
silylation and subsequent copper(I)-mediated arylation of
sulfide 2l via the fluoroalkylated silane derivative 7l gave the
corresponding diarylation product 9lm in good yield (62%
over 3 steps).
a
Standard conditions: 7 (0.5 mmol), CuOtBu (0.6 mmol), and phen
In summary, we have developed a stepwise procedure for the
synthesis of highly functionalized tetrafluoroethyl sulfides using
fluoroalkene feedstocks. Our results constitute the first
examples of the chemoselective additive-free hydrothiolation
of TFE (tetrafluoroethylene), CTFE (chlorotrifluoroethylene),
and HFP (hexafluoropropene) in aprotic polar solvents. This
hydrothiolation allows using substrates that bear unprotected
hydroxy and amine moieties and is thus complementary to the
previously reported corresponding base-mediated reactions. A
sequential functionalization protocol, which includes silylations
and copper(I)-mediated fluoroalkylations of aryl iodides,
exhibited high functional-group tolerance, which allowed the
modular synthesis of highly functionalized tetrafluoroethyl
sulfides for the development of novel functional materials and
bioactive compounds.
(0.6 mmol) in THF (1.0 mL) at 40 °C, followed by addition of the
corresponding electrophiles (0.5 mmol) at room temperature.
and the ligand 1,10-phenanthroline (phen) can generate the
corresponding alkylcopper(I) species (for details, see Tables
S2−S4).17−19 The resulting alkylcopper(I) species reacts with
the electrophile phenyl iodide to give the corresponding
coupling product 9aa in good yield (80%). With the optimized
coupling conditions in hand, we screened a variety of aryl
iodide coupling partners. Aryl iodides with an electron-
withdrawing or electron-donating group, namely, a trifluor-
omethyl or a methoxy group, at the para-position gave 9ab and
9ac in high yield (9ab: 86%; 9ac: 88%). A heteroaryl iodide
with a chloride moiety furnished 9ad (75%), whereby the
chloride moiety remained intact to be used for subsequent
transformations. The reaction of a pyridine bearing a bromide
group furnished 9ae in moderate yield (48%). Furthermore,
various heteroaryl-based iodides (e.g., quinoline, pyrazine,
quinazoline, and dibenzofuran) could be employed in the
copper(I)-mediated arylation of 7 to furnish the corresponding
EXPERIMENTAL SECTION
■
General Information. All manipulations were conducted under a
nitrogen atmosphere using standard Schlenk or drybox techniques.
1H, 13C, 19F nuclear magnetic resonance spectra were recorded on
Bruker Avance III 400 and 600 spectrometers. The chemical shifts in
1H NMR spectra were recorded relative to residual protonated solvent
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[C6D5H (δ 7.16) or CHCl3 (δ7.26)]. The chemical shifts in 19F NMR
spectra were recorded relative to α,α,α-trifluorotoluene (δ −65.4).
The chemical shifts in 13C NMR spectra were recorded relative to
CDCl3 (δ 77.16). Analytical gas chromatography (GC) was carried
out on a Shimadzu GC-2025 gas chromatography, equipped with a
flame ionization detector. High resolution mass spectra (HRMS) were
obtained using a JEOL JMS-700 spectrometer with a TOF mass at the
Instrumental Analysis Center, Faculty of Engineering, Osaka
University. Gel permeation chromatography (GPC) was performed
on a Japan Analytical Industry LC9225NEXT HPLC system equipped
with JAIGEL1H and JAIGEL-2H.
Materials. All commercially available reagents, solvents, and thiols
1a−1o were supplied from TCI, Sigma-Aldrich, and FUJIFILM Wako
Pure Chemical Corporation. Tetrahydrofuran (THF) was degassed
and distilled from sodium benzophenone ketyl. Caution! Tetrafluoro-
ethylene (TFE) is suspected to be carcinogen. The reaction mixture must
be handled in a well-ventilated fume hood.
(1,1,2,2-Tetrafluoroethyl)[4-(trifluoromethyl)phenyl]sulfane (2d).
The crude material was purified by the silica-gel column
chromatography (eluent, hexane). Colorless oil, 114.1 mg (0.41
1
mmol), 82% yield. H NMR (400 MHz, CDCl3): δ 7.79 (d, J = 8.1
Hz, 2H), 7.67 (d, J = 8.2 Hz, 2H), 5.83 (tt, JHF = 53.7, 3.0 Hz, 1H).
19F NMR (376 MHz, CDCl3): δ −66.3 (s, 3F), −93.6 (td, JFF = 8.2,
J
HF = 2.0 Hz, 2F), −135.0 (dt, JHF = 53.7, JFF = 8.6 Hz, 2F). 13C{1H}
NMR (100 MHz, CDCl3): δ 137.2, 132.9 (q, JCF = 33.0 Hz), 128.3,
126.3 (q, JCF = 3.6 Hz), 125.1, 124.6 (t, JCF = 26.8 Hz), 109.7 (tt, JCF
= 252.4, 37.6 Hz). HRMS-EI (m/z): [M]+ calcd for C9H5F7S,
278.0000; found, 277.9995.
(4-Bromophenyl)(1,1,2,2-tetrafluoroethyl)sulfane (2e).4a Color-
1
less oil, 119.8 mg (0.41 mmol), 83% yield. H NMR (400 MHz,
CDCl3): δ 7.55 (d, J = 8.6 Hz, 2H), 7.51 (d, J = 8.6 Hz, 2H), 5.80 (tt,
JHF = 53.8, 3.1 Hz, 1H). 19F NMR (376 MHz, CDCl3): δ −94.5 (td,
J
FF = 8.6, JHF = 3.1 Hz, 2F), −135.3 (dt, JHF = 53.8, JFF = 8.8 Hz, 2F).
13C{1H} NMR (100 MHz, CDCl3): δ 138.5, 132.8, 126.0, 122.6 (t,
General Procedure for the Hydrothiolation of TFE, CTFE,
and HFP. A dimethylformamide (DMA) solution (1.0 mL) of thiol
1a (80.1 mg, 0.50 mmol) was transferred to a pressure-tight reaction
vessel (total volume is 12 mL) under a nitrogen atmosphere.
Tetrafluoroethylene (TFE) was charged to the resulting solution (2.0
atm). The reaction mixture is placed still without stirring. After 15
min, the reaction mixture was poured into deionized water (3.0 mL),
and the resultant mixture was extracted with hexane (3.0 mL) three
times. The combined organic phase was washed with brine (5.0 mL)
and then dried over anhydrous MgSO4. After filtration, the solvents
were removed by evaporation under reduced pressure. The
corresponding sulfide product 2a was obtained in a pure form. The
crude material was purified by the gel permeation chromatography or
silica-gel chromatography when the resulting materials include
impurities such as a trace amount of the starting material.
J
CF = 2.6 Hz), 122.4 (tt, JCF = 282.9, 29.6 Hz), 109.6 (tt, JCF = 251.6,
37.9 Hz). HRMS-EI (m/z): [M]+ calcd for C8H5BrF4S, 287.9232;
found, 287.9229.
(4-Nitrophenyl)(1,1,2,2-tetrafluoroethyl)sulfane (2f).20 The crude
material was purified by the silica-gel column chromatography
(eluent, hexane). Light yellow oil, 117.4 mg (0.46 mmol), 92%
yield. 1H NMR (400 MHz, CDCl3): δ 8.24 (d, J = 8.8 Hz, 2H), 7.83
(d, J = 8.7 Hz, 2H), 5.87 (tt, JHF = 53.7, 2.7 Hz, 1H). 19F NMR (376
MHz, CDCl3): δ −92.8 (td, JFF = 8.2, JHF = 2.2 Hz, 2F), −134.6 (dt,
JHF = 53.3, JFF = 8.2 Hz, 2F). 13C{1H} NMR (100 MHz, CDCl3): δ
149.3, 137.2, 131.9, 124.2, 122.6 (tt, JCF = 284.2, 30.4 Hz), 109.6 (tt,
J
CF = 251.9, 37.9 Hz). HRMS-EI (m/z): [M]+ calcd for C8H5F4NO2S,
254.9977; found, 254.9977.
(2,4-Dimethoxyphenyl)(1,1,2,2-tetrafluoroethyl)sulfane (2g).
1
Light yellow oil, 124.3 mg (0.46 mmol), 92% yield. H NMR (400
General Procedure for the Hydrothiolation of TFE in Large
Reaction Scale. Based on the above general procedure, the reaction
of thiol 1a (1.44 g, 9.00 mmol) in DMA solution (5.0 mL) with TFE
(5.0 atm) was conducted for 1 h in an autoclave reactor with stirring
(total volume: 50.0 mL). After the extraction of the mixture, the
desired compound was obtained as a white solid (2201.8 mg, 94%). In
this case, the reaction outcomes of the hydrothiolation were almost
not affected by whether the mixture was stirred or not.
MHz, CDCl3): δ 7.17 (d, J = 3.1 Hz, 1H), 7.00 (dd, J = 9.0, 3.1 Hz,
1H), 6.90 (d, J = 9.0 Hz, 1H), 5.82 (tt, JHF = 53.7, 4.1 Hz, 1H), 3.84
(s, 3H), 3.77 (s, 3H). 19F NMR (376 MHz, CDCl3): δ −96.4 (td, JFF
= 10.1, JHF = 3.8 Hz, 2F), −136.4 (dt, JHF = 53.5, JFF = 10.0 Hz, 2F).
13C{1H} NMR (100 MHz, CDCl3): δ 155.4, 153.5, 124.1, 122.3 (tt,
J
J
CF = 284.3 28.2 Hz), 118.5, 112.9, 112.1 (q, JCF = 2.9 Hz), 109.7 (tt,
CF = 252.0, 36.1 Hz). HRMS-EI (m/z): [M]+ calcd for C10H10F4O2S,
270.0338; found, 270.0335.
Naphthalen-2-yl(1,1,2,2-tetrafluoroethyl)sulfane (2a).10e Color-
[4-(tert-Butyl)benzyl](1,1,2,2-tetrafluoroethyl)sulfane (2h). The
crude material was purified by the gel permeation chromatography
(eluent, CHCl3). Colorless oil, 121.9 mg (0.43 mmol), 87% yield. 1H
NMR (400 MHz, CDCl3): δ 7.41 (d, J = 8.3 Hz, 2H), 7.33 (d, J = 8.3
Hz, 2H), 5.79 (tt, JHF = 54.0, 3.3 Hz, 1H), 4.15 (s, 2H), 1.36 (s, 9H).
19F NMR (376 MHz, CDCl3): δ −95.2 (td, JFF = 9.0, JHF = 3.0 Hz,
2F), −135.1 (dt, JHF = 54.2, JFF = 8.8 Hz, 2F). 13C{1H} NMR (100
MHz, CDCl3): δ 151.2, 132.3, 128.9, 126.0, 123.9 (tt, JCF = 281.5,
29.8 Hz), 110.0 (tt, JCF = 250.3, 37.9 Hz), 34.7, 32.0, 31.4. HRMS-EI
(m/z): [M]+ calcd for C13H16F4S, 280.0909; found, 280.0912.
Decyl(1,1,2,2-tetrafluoroethyl)sulfane (2i). The crude material
was purified by the gel permeation chromatography (eluent, CHCl3).
Colorless oil, 117.9 mg (0.43 mmol), 86% yield. 1H NMR (400 MHz,
CDCl3): δ 5.78 (tt, JHF = 54.1, 3.2 Hz, 1H), 2.89 (t, J = 7.4 Hz, 2H),
1.68 (quin, J = 7.4 Hz, 2H), 1.46−1.21 (m, 14H), 0.89 (t, J = 6.8 Hz,
3H). 19F NMR (376 MHz, CDCl3): δ −95.0 (td, JFF = 9.1, JHF = 2.7
Hz, 2F), −135.2 (dt, JHF = 54.0, JFF = 8.9 Hz, 2F). 13C{1H} NMR
1
less oil, 115.7 mg (0.44 mmol), 89% yield. H NMR (400 MHz,
CDCl3): δ 7.83 (s, 1H), 7.35 (d, J = 8.6 Hz, 1H), 7.32 (d, J = 8.0 Hz,
1H), 7.29−7.22 (m, 2H), 7.12−7.01 (m, 2H), 5.10 (tt, JHF = 53.6, 3.4
Hz, 1H). 19F NMR (376 MHz, CDCl3): δ −94.6 (td, JFF = 9.3, JHF
=
3.0 Hz, 2F), −135.3 (dt, JHF = 53.6, JFF = 9.3 Hz, 2F). 13C{1H} NMR
(150 MHz, CDCl3): δ 137.7, 133.9, 133.5, 132.5, 129.2, 128.2, 128.0,
127.8, 127.1, 122.9 (tt, JCF = 282.7, 29.2 Hz), 120.6, 109.7 (tt, JCF
=
251.4, 37. 1 Hz). HRMS-EI (m/z): [M]+ calcd for C12H8F4S,
260.0283; found, 260.0279.
[4-(tert-Butyl)phenyl](1,1,2,2-tetrafluoroethyl)sulfane (2b). Col-
1
orless oil, 127.8 mg (0.48 mmol), 96% yield. H NMR (400 MHz,
CDCl3): δ 7.58 (d, J = 8.4 Hz, 2H), 7.44 (d, J = 8.4 Hz, 2H), 5.77 (tt,
J
HF = 53.7, 3.6 Hz, 1H), 1.34 (s, 9H). 19F NMR (376 MHz, CDCl3):
δ −95.6 (td, JFF = 9.6, JHF = 3.1 Hz, 2F), −136.1 (dt, JHF = 53.5, JFF
=
9.7 Hz, 2F). 13C{1H} NMR (100 MHz, CDCl3): δ 154.4, 136.9,
126.7, 122.6 (tt, JCF = 282.2, 28.9 Hz), 120.0 (t, JCF = 2.9 Hz), 109.5
(tt, JCF = 251.8, 37.1 Hz), 35.0, 31.3; HRMS-EI (m/z): [M]+ calcd for
C12H14F4S, 266.0752; found: 266.0755.
(100 MHz, CDCl3): δ 124.3 (tt, JCF = 280.4, 29.7 Hz), 110.0 (tt, JCF
=
249.9, 38.3 Hz), 32.1, 29.9, 29.7, 29.6, 29.5, 29.2, 28.8, 28.0, 22.8,
14.2. HRMS-EI (m/z): [M − H]+ calcd for C12H21F4S, 273.1300;
found, 273.1302.
[4-(tert-Butyl)-2-methylphenyl](1,1,2,2-tetrafluoroethyl)sulfane
(2c). Colorless oil, 124.7 mg (0.44 mmol), 89% yield. 1H NMR (400
MHz, CDCl3): δ 7.69 (d, J = 1.8 Hz, 1H), 7.43 (dd, J = 8.0, 2.1 Hz,
1H), 7.28 (d, J = 8.0 Hz, 1H), 5.79 (tt, JHF = 53.8, 3.4 Hz, 1H), 2.53
(s, 3H), 1.35 (s, 9H). 19F NMR (376 MHz, CDCl3): δ −94.8 (td, JFF
= 9.4, JHF = 3.3 Hz, 2F), −135.8 (dt, JHF = 53.5, JFF = 9.5 Hz, 2F).
13C{1H} NMR (100 MHz, CDCl3): δ 150.1, 141.5, 136.1, 130.8,
128.4, 123.1 (tt, JCF = 282.5, 29.0 Hz), 122.5, 109.7 (tt, JCF = 251.5,
37.4 Hz), 34.5, 31.3, 20.9. HRMS-EI (m/z): [M]+ calcd for
C13H16F4S, 280.0909; Found, 280.0906.
3-Methoxybutyl 2-[(1,1,2,2-Tetrafluoroethyl)thio]acetate (2j).
The crude material was purified by the gel permeation chromatog-
raphy (eluent, CHCl3). Colorless oil, 102.9 mg (0.37 mmol), 74%
1
yield. H NMR (400 MHz, CDCl3): δ 5.85 (tt, JHF = 53.7, 3.2 Hz,
1H), 4.20 (t, J = 6.2 Hz, 2H), 3.60 (s, 2H), 3.35 (sextet, 6.2 Hz, H),
3.24 (d, J = 1.7 Hz, 3H), 1.80−1.65 (m, 2H), 1.10 (dd, J = 6.2, 1.6
Hz, 3H). 19F NMR (376 MHz, CDCl3): δ −96.7 (q, J = 8.0 Hz, 2F),
−136.2 (q, J = 8.5 Hz, 2F). 13C{1H} NMR (100 MHz, CDCl3): δ
6019
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Note
168.1, 123.1 (tt, JCF = 283.2, 29.7), 109.7 (tt, JCF = 250.3 37.7 Hz),
73.4, 63.3, 56.0, 35.3, 30.0 (t, JCF = 4.0 Hz), 18.9. HRMS-EI (m/z):
[M]+ calcd for C9H14F4O3S, 278.0600; found, 278.0596.
NMR (400 MHz, CDCl3): δ 8.80 (d, J = 8.5 Hz, 2H), 8.07 (d, J = 7.3
Hz, 2H), 7.68 (t, J = 7.9 Hz, 2H), 6.16 (ddd, JHF = 48.3, 7.8, 4.0 Hz,
1H). 19F NMR (376 MHz, CDCl3): δ −86.7 (ddd, JFF = 223.2, JFF
=
Bis{4-[(1,1,2,2-tetrafluoroethyl)thio]phenyl}sulfane (2k). Color-
19.2, JHF = 3.5 Hz, 2F), −91.3 (ddd, JFF = 223.4, JFF = 18.1, JHF = 7.2
1
Hz, 2F), −150.2 (dt, JHF = 48.3, JFF = 18.5 Hz, 2F). 13C{1H} NMR
less viscous oil, 218.5 mg (0.49 mmol), 97% yield. H NMR (400
MHz, CDCl3): δ 7.46 (d, J = 8.3 Hz, 4H), 7.23 (d, J = 8.3 Hz, 4H),
(100 MHz, CDCl3): δ 139.2, 137.0, 130.5, 127.3, 124.3 (td, JCF
=
5.67 (tt, JHF = 53.8, 3.2 Hz, 2H). 19F NMR (376 MHz, CDCl3): δ
286.1, 28.6 Hz), 122.3, 97.1 (ddd, JCF = 251.3, 34.1, 31.3 Hz).
HRMS-EI (m/z): [M]+ calcd for C14H8Cl2F6S2: 423.9349; Found:
423.9346.
−94.1 (td, JFF = 8.6, JHF = 3.1 Hz, 4F), −135.0 (dt, JHF = 53.7, JFF
=
9.0 Hz, 4F). 13C{1H} NMR (100 MHz, CDCl3): δ 138.7, 137.8,
131.6, 122.7 (t, JCF = 2.7 Hz), 122.5 (tt, JCF = 282.9, 29.6 Hz), 109.6
(tt, JCF = 252.2, 37.5 Hz). HRMS-EI (m/z): [M]+ calcd for
C16H10F8S3, 449.9817; found, 449.9811.
(1,1,2,3,3,3-Hexafluoropropyl)(naphthalen-2-yl)sulfane (5a).
The crude material was purified by the silica-gel column
chromatography (eluent, hexane:AcOEt = 99:1). Colorless oil, 76.7
mg (0.25 mmol), 25% yield. 1H NMR (400 MHz, CDCl3): δ 8.22 (s,
1H), 7.95−7.83 (m, 3H), 7.70−7.64 (m, 1H), 7.64−7.55 (m, 2H),
4.78 (ddq, J = 43.6, 18.2, 5.5 Hz, 1H). 19F NMR (376 MHz, CDCl3):
δ −73.6 (s, 3F), −81.7 (ddq, JFF = 231.6, 20.4 Hz, JHF = 10.2 Hz 1F),
−88.7 (ddq, JFF = 231.6, 18.3 Hz, JHF = 9.2 Hz 1F), −203.8 to −204.0
(m, 1F). 13C{1H} NMR (100 MHz, CDCl3): δ 137.8, 134.1, 133.6,
132.5, 129.4, 128.3, 128.2, 128., 127.2, 121.9 (td, JCF = 258.5, 26.0
Hz), 121.1, 87.2−83.9 (m). HRMS-EI (m/z): [M]+ calcd for
C13H8F6S, 310.0251; found, 310.0244.
1,5-Bis[(1,1,2,2-tetrafluoroethyl)thio]naphthalene (2l). White
1
solid, 1.40 g (3.57 mmol), 89% yield, mp 69 °C. H NMR (400
MHz, CDCl3): δ 8.79 (d, J = 8.6 Hz, 2H), 8.06 (d, J = 7.1 Hz, 2H),
7.67 (t, J = 7.9 Hz, 2H), 5.80 (tt, JHF = 53.7, 3.0 Hz, 2H). 19F NMR
(376 MHz, CDCl3): δ −93.8 (td, JFF = 8.7, JHF = 2.6 Hz, 4F), −135.3
(dt, JHF = 53.8, JFF = 8.8 Hz, 4F). 13C{1H} NMR (100 MHz, CDCl3):
δ 139.2, 137.1, 130.5, 127.2, 122.8 (tt, JCF = 283.9, 29.8 Hz), 121.7 (t,
JCF = 2.4 Hz), 109.6 (tt, JCF = 251.7, 37.9 Hz). HRMS-EI (m/z):
[M]+ calcd for C14H8F8S2, 391.9940; found, 391.9936.
4,4′′-Bis[(1,1,2,2-tetrafluoroethyl)thio]-1,1′:4′,1′′-terphenyl (2m).
White solid, 192.8 mg (0.39 mmol), 78% yield, mp 138 °C. 1H NMR
(400 MHz, CDCl3): δ 7.78−7.72 (m, 4H), 7.71−7.65 (m, 8H), 5.83
(tt, JHF = 53.8, 3.3 Hz, 2H). 19F NMR (376 MHz, CDCl3): δ −91.6
(t, JFF = 9.2 Hz, 4F), −132.4 (t, JFF = 9.2 Hz, 4F). 13C{1H} NMR
(100 MHz, CDCl3): δ 143.0, 139.5, 137.6, 128.1, 127.9, 127.7, 122.6,
109.6 (tt, JCF = 253.1, 37.5 Hz). HRMS-EI (m/z): [M]+ calcd for
C22H14F8S2, 494.0409; found, 494.0408.
(E and Z)-Naphthalen-2-yl(perfluoroprop-1-en-1-yl)sulfane [(E
or Z)-6a]. Colorless oil, 189.1 mg (0.65 mmol), 65% yield. (E)-6a: 1H
NMR (400 MHz, CDCl3): δ 8.06 (s, 1H), 7.92−7.80 (m, 3H), 7.62−
7.50 (m, 3H). 19F NMR (376 MHz, CDCl3): δ −70.6 (dd, J = 21.1,
11.7 Hz, 3F), −122.8 (dq, J = 146.5, 21.1 Hz, 1F), −158.3 (dq, J =
146.4, 11.7 Hz, 1F). (Z)-6a: 1H NMR (400 MHz, CDCl3): δ 8.02 (s,
1H), 7.92−7.80 (m, 3H), 7.62−7.50 (m, 3H). 19F NMR (376 MHz,
CDCl3): δ −67.5 (dd, J = 10.7 Hz, 3F), −102.4 (qd, J = 10.4, 3.1 Hz,
1F), −138.7 (qd, J = 10.6, 3.2 Hz, 1F).
3-[(1,1,2,2-Tetrafluoroethyl)thio]phenol (2n). Colorless oil, 96.1
1
mg (0.42 mmol), 85% yield. H NMR (400 MHz, CDCl3): δ 7.33−
General Procedure for the Silylation of 2 and 4. A solution
i
7.21 (m, 2H), 7.15 (s, 1H), 7.01−6.93 (m, 1H), 5.78 (tt, JHF = 53.7,
3.4 Hz, 1H), 5.22 (br-s, 1H). 19F NMR (376 MHz, CDCl3): δ −95.0
(td, JFF = 9.3, JHF = 2.9 Hz, 2F), −135.8 (dt, JHF = 53.8, JFF = 9.3 Hz,
2F). 13C{1H} NMR (100 MHz, CDCl3): δ 155.8, 130.6, 129.6, 124.6
(t, JCF = 4.0 Hz), 123.6, 122.6 (tt, JCF = 282.7, 29.3 Hz), 118.1, 109.5
(tt, JCF = 251.7, 37.0 Hz). HRMS-EI (m/z): [M]+ calcd for
C8H6F4OS, 226.0075; found, 226.0078.
(20.0 mL) of Pr2NH (555 mg, 773 μL, 5.50 mmol) in THF was
added to a solution of nBuLi in hexane (1.6 M, 3.40 mL, 5.50 mmol)
at −78 °C under a nitrogen atmosphere. After stirring for 1 h, the
reaction mixture was slowly added to a solution of the tetrafluoroethyl
sulfide 2a (1.30 g, 5.00 mmol) and chlorotrimethylsilane (598 mg,
695 μL, 5.50 mmol) in THF (30.0 mL) at −78 °C by a syringe pump
(0.15 mmol/min). After stirring at −78 °C for 1 h, the reaction
mixture was allowed to warm to room temperature gradually. After
additional stirring for 5 h, this mixture was poured into deionized
water. The mixture was extracted with hexane three times. The
combined organic layer was washed with brine and then dried over
anhydrous MgSO4. After filtration, the solvents were removed by
evaporation. The crude product was purified by silica-gel column
chromatography (typically, hexane:AcOEt = 99:1) to afford the
silylation product 7a as a white solid.
4-[(1,1,2,2-Tetrafluoroethyl)thio]aniline (2o).15 The crude materi-
al was purified by the silica-gel column chromatography (eluent,
1
hexane). Colorless oil, 104.7 mg (0.46 mmol), 93% yield. H NMR
(400 MHz, CDCl3): δ 7.40 (d, J = 8.3 Hz, 2H), 6.66 (d, J = 8.4 Hz,
2H), 5.74 (t, JHF = 53.8, 1H), 3.93 (br-s, 2H). 19F NMR (376 MHz,
CDCl3): δ −97.1 (td, JFF = 9.4, JHF = 2.1 Hz, 2F), −136.5 (dt, JHF
=
53.5, JFF = 9.7 Hz, 2F). 13C{1H} NMR (100 MHz, CDCl3): δ 149.1,
138.9, 122.4 (tt, JCF = 281.7, 28.8 Hz), 115.5, 110.2, 109.5 (tt, JCF
=
251.1, 36.8 Hz). HRMS-EI (m/z): [M]+ calcd for C8H7F4NS,
225.0235; found, 225.0239.
Trimethyl[1,1,2,2-tetrafluoro-2-(naphthalen-2-ylthio)ethyl]silane
(7a). The crude material was purified by the silica-gel column
chromatography (eluent, hexane:AcOEt = 99:1). White solid, 1.36 g
(2-Chloro-1,1,2-trifluoroethyl)(naphthalen-2-yl)sulfane (4a).
Colorless oil, 114.8 mg (0.41 mmol), 83% yield. 1H NMR (400
MHz, CDCl3): δ 8.22 (s, 1H), 7.91−7.86 (m, 3H), 7.71−7.66 (m,
1
(4.09 mmol), 82% yield, mp 43 °C. H NMR (400 MHz, CDCl3): δ
8.20 (s, 1H), 7.90−7.83 (m, 3H), 7.68 (d, J = 8.5 Hz, 1H), 7.59−7.51
(m, 2H), 0.28 (s, 9H). 19F NMR (376 MHz, CDCl3): δ −82.2 (t, JFF
= 5.2, 2F), −122.0 (t, JFF = 5.0, 2F). 13C{1H} NMR (100 MHz,
CDCl3): δ 137.7, 133.8, 133.6, 133.1, 128.8, 128.2, 127.9, 127.65,
127.59 (tt, JCF = 280.4, 32.4 Hz), 126.9, 123.0 (tt, JCF = 270.7, 45.0
Hz), 121.9, −3.9. HRMS-EI (m/z): [M]+ calcd for C15H16F4SSi,
332.0678; found, 332.0679.
1H), 7.63−7.54 (m, 2H), 6.15 (ddd, JHF = 48.3, 7.8, 4.1 Hz, 1H). 19
NMR (376 MHz, CDCl3): δ −87.8 (ddd, JFF = 226.0, JFF = 19.7, JHF
F
=
3.9 Hz, 1F), −92.6 (ddd, JFF = 226.1, JFF = 18.1, JHF = 7.9 Hz, 1F),
−150.5 (dt, JHF = 48.2, JFF = 18.7 Hz, 1F). 13C{1H} NMR (100 MHz,
CDCl3): δ 137.7, 134.0, 133.5, 132.5, 129.3, 128.3, 128.0, 127.9,
127.1, 124.3 (td, JCF = 283.9 Hz, 27.1 Hz), 121.4 (t, JCF = 2.6 Hz),
97.1 (ddd, JCF = 252.6, 38. 2, 33.7 Hz). HRMS-EI (m/z): [M]+ calcd
for C12H8ClF3S, 275.9987; found, 275.9989.
{2-{[4-(tert-Butyl)benzyl]thio}-1,1,2,2-tetrafluoroethyl}trimeth-
ylsilane (7h). The crude material was purified by the silica-gel column
chromatography (eluent, hexane:AcOEt = 99:1). Yellowish oil, 1.53 g
(4.34 mmol), 87% yield. 1H NMR (400 MHz, CDCl3): δ 7.37 (d, J =
8.2 Hz, 2H), 7.29 (d, J = 8.2 Hz, 2H), 4.14 (s, 2H), 1.56 (s, 9H), 1.32
(s, 9H). 19F NMR (376 MHz, CDCl3): δ −92.1 (t, JFF = 6.7, 2F),
−119.9 (t, JFF = 6.7, 2F). 13C{1H} NMR (100 MHz, CDCl3): δ 150.8,
(2-Chloro-1,1,2-trifluoroethyl)(4-nitrophenyl)sulfane (4f). Color-
1
less oil, 126.4 mg (0.47 mmol), 93% yield. H NMR (400 MHz,
CDCl3): δ 8.24 (d, J = 8.9 Hz, 2H), 7.83 (d, J = 8.7 Hz, 2H), 6.22
(ddd, JHF = 48.4, 6.49, 4.2 Hz, 1H). 19F NMR (376 MHz, CDCl3): δ
−82.9 (dd, JFF = 217.5, JFF = 18.6 Hz, 1F), −86.2 (dd, JFF = 217.3, JFF
= 17.9 Hz, 1F), −116.9 (t, JFF = 18.1 Hz, 1F). 13C{1H} NMR (100
MHz, CDCl3): δ 149.2, 137.0, 132.5, 124.2, 124.1(td, JCF = 287.6 Hz,
27.2 Hz), 97.2 (dt, JCF = 253.2, 35.9 Hz). HRMS-EI (m/z): [M]+
calcd for C8H5ClF3NO2S: 270.9682; Found: 270.9677.
132.8, 129.0, 128.2 (tt, JCF = 281.3, 32.3 Hz), 125.8, 122.6 (tt, JCF
=
271.4, 44.2 Hz), 34.7, 31.8 (t, JCF = 4.4 Hz), 31.4, −3.9. HRMS-EI
(m/z): [M]+ calcd for C16H24F4SSi, 352.1304; found, 352.1300.
[1-Chloro-1,2,2-trifluoro-2-(naphthalen-2-ylthio)ethyl]trimeth-
ylsilane (8a). The crude material was purified by the silica-gel column
chromatography (eluent, hexane:AcOEt = 99:1). White solid, 1.54 g
1,5-Bis[(2-chloro-1,1,2-trifluoroethyl)thio]naphthalene (4l).
White solid, 172.1 mg (0.40 mmol), 81% yield, mp 86 °C. 1H
6020
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Note
1
(4.41 mmol), 88% yield, mp 63 °C. H NMR (400 MHz, CDCl3): δ
289.4, 37.7 Hz), 122.4 (t, JCF = 6.1 Hz), 120.6, 120.0 (t, JCF = 5.4 Hz),
115.0 (tt, JCF = 255.8, 34.0 Hz). HRMS-EI (m/z): [M]+ calcd for
C17H10ClF4NS, 371.0159; found, 371.0152.
8.21 (s, 1H), 7.90−7.84 (m, 3H), 7.69 (dd, J = 8.5, 1.0 Hz, 1H),
7.59−7.51 (m, 2H), 0.33 (s, 9H). 19F NMR (376 MHz, CDCl3): δ
−75.3 (ddd, JFF = 217.2, JFF = 16.1, JHF = 3.1 Hz, 1F), −77.4 (ddd, JFF
= 212.7, JFF = 16.8, JHF = 3.6 Hz, 1F), −141.9 (td, JHF = 16.3, JFF = 3.7
Hz, 1F). 13C{1H} NMR (100 MHz, CDCl3): δ 137.7, 133.8, 133.5,
133.1, 129.6 (td, JCF = 283.3, 30.8 Hz), 128.8, 128.2, 127.9, 127.7,
126.9, 122.6, 110.1 (ddd, JCF = 265.8, 44.0, 41.1 Hz), −3.0. HRMS-EI
(m/z): [M]+ calcd for C15H16ClF3SSi, 348.0383; found, 348.0384.
General Procedure for the Copper(I)-Mediated Fluoroalky-
lation of Electrophiles with 7. CuOtBu (82.0 mg, 0.60 mmol) and
1,10-phenanthroline (108 mg, 0.60 mmol) were added to a 20 mL
reaction vial equipped with a stir bar. THF (2.0 mL) was then added
to the reaction vial under a nitrogen atmosphere. The resulting dark
red mixture was stirred at room temperature for 1 min. Subsequently,
the silylation product 7a (166 mg, 0.50 mmol) was added dropwise to
the mixture at room temperature. After stirring at 40 °C on the oil
bath for 5 h, phenyl iodide (102 mg, 0.50 mmol) was added. After
additional stirring at room temperature for 1 h, the reaction mixture
was poured into deionized water. The mixture was extracted with
hexane three times. The combined organic layer was washed with
brine and then dried over anhydrous MgSO4. After filtration, the
solvents were removed by evaporation. The crude product was
purified by gel permeation chromatography to afford the correspond-
ing product 9aa as a white solid.
Naphthalen-2-yl(1,1,2,2-tetrafluoro-2-phenylethyl)sulfane
(9aa). The crude material was purified by the gel permeation
chromatography (eluent, CHCl3). White solid, 134.1 mg (0.40
mmol), 80% yield, mp 45 °C. 1H NMR (400 MHz, CDCl3): δ 8.14 (s,
1H), 7.89−7.80 (m, 3H), 7.62 (d, J = 8.1 Hz, 3H), 7.59−7.500 (m,
3H), 7.497−7.43 (m, 2H). 19F NMR (376 MHz, CDCl3): δ −90.3 (t,
JFF = 5.5 Hz, 2F), −111.7 (t, JFF = 5.4 Hz, 2F). 13C{1H} NMR (100
MHz, CDCl3): δ 137.6, 133.8, 133.5, 132.8, 131.4, 130.4 (t, JCF = 24.8
Hz), 128.9, 128.5, 128.2, 127.8, 127.8, 127.0 (t, JCF = 5.8 Hz), 126.9,
124.5 (tt, JCF = 289.5, 39.5 Hz), 121,7, 116.7 (tt, JCF = 253.7, 32.3
Hz). HRMS-EI (m/z): [M]+ calcd for C18H12F4S, 336.0596; found,
336.0592.
Naphthalen-2-yl{1,1,2,2-tetrafluoro-2-[4-(trifluoromethyl)-
phenyl]ethyl}sulfane (9ab). The crude material was purified by the
gel permeation chromatography (eluent, CHCl3). White solid, 173.9
mg (0.43 mmol), 86% yield, mp 69 °C. 1H NMR (400 MHz, CDCl3):
δ 8.18 (s, 1H), 7.93−7.82 (m, 3H), 7.82−7.71 (m, 4H), 7.70−7.63
(m, 1H), 7.62−7.51 (m, 2H). 19F NMR (376 MHz, CDCl3): δ −66.2
(s, 3F), −90.4 (t, JFF = 5.0 Hz, 2F), −112.0 (t, JFF = 4.3 Hz, 2F).
13C{1H} NMR (100 MHz, CDCl3): δ 137.7, 133.91, 133.88 (q, J =
41.7 Hz), 133.5, 132.7, 129.0, 128.2, 127.9, 127.9, 127.7 (t, JCF = 6.0
Hz), 127.0, 125.5 (q, JCF = 3.4 Hz), 124.6, 124.2 (tt, JCF = 289.4, 38.7
Hz), 122.8, 121.2, 116.2 (tt, JCF = 254.9, 33.1 Hz). HRMS-EI (m/z):
[M]+ calcd for C19H11F7S, 404.0470; found, 404.0473.
Naphthalen-2-yl[1,1,2,2-tetrafluoro-2-(4-methoxyphenyl)ethyl]-
sulfane (9ac). The crude material was purified by the gel permeation
chromatography (eluent, CHCl3). White solid, 161.2 mg (0.44
mmol), 88% yield, mp 62 °C. 1H NMR (400 MHz, CDCl3): δ 8.15 (s,
1H),7.91−7.80 (m, 3H), 7.70−7.62 (m, 1H), 7.61−7.51 (m, 4H),
6.97 (d, J = 8.7 Hz, 2H), 3.83 (s, 3H). 19F NMR (376 MHz, CDCl3):
δ −90.6 (br, 2F), −110.9 (br, 2F). 13C{1H} NMR (150 MHz,
CDCl3): δ 162.0, 137.5, 133.8, 133.5, 132.8, 128.8, 128.6 (t, JCF = 6.0
Hz), 128.2, 127.8, 127.7, 126.9, 124.6 (tt, JCF = 289.3, 40.1 Hz), 122.4
(t, JCF = 25.4 Hz), 121.8, 116.8 (tt, JCF = 254.1, 32.0 Hz), 113.9, 55.4.
HRMS-EI (m/z): [M]+ calcd for C19H14F4OS, 366.0701; found,
366.0694.
2-Bromo-5-[1,1,2,2-tetrafluoro-2-(naphthalen-2-ylthio)ethyl]-
pyridine (9ae). The crude material was purified by the gel permeation
chromatography (eluent, CHCl3). White solid, 99.8 mg (0.24 mmol),
1
48% yield, mp 129 °C. H NMR (400 MHz, CDCl3): δ 8.60 (d, J =
1.9 Hz, 1H), 8.14 (s, 1H), 7.91−7.81 (m, 3H), 7.72 (dd, J = 8.4, 2.3
Hz, 1H), 7.60−7.52 (m, 4H). 19F NMR (376 MHz, CDCl3): δ −90.7
(t, JFF = 5.4 Hz, 2F), −112.4 (t, JFF = 5.6 Hz, 2F). 13C{1H} NMR
(100 MHz, CDCl3): δ 148.7, 145.7, 137.8, 137.0, 133.9, 133.5, 132.6,
129.1, 128.2, 128.05, 128.01, 127.9, 127.1, 126.1 (t, JCF = 26.1 Hz),
123.8 (tt, JCF = 290.4, 37. Three Hz), 120.8, 115.8 (tt, JCF = 256.8,
34.5 Hz). HRMS-EI (m/z): [M]+ calcd for C17H10BrF4NS, 414.9653;
found, 414.9652.
6-[1,1,2,2-Tetrafluoro-2-(naphthalen-2-ylthio)ethyl]quinoline
(9af). The crude material was purified by the gel permeation
chromatography (eluent, CHCl3). Yellowish solid, 163.3 mg (0.42
mmol), 84% yield, mp 81 °C. 1H NMR (400 MHz, CDCl3): δ 9.08−
8.99 (m, 1H), 8.23 (d, J = 8.2 Hz, 1H), 8.19 (d, J = 8.92 Hz, 1H),
8.12 (s, 2H), 7.90 (d, J = 8.8 Hz, 1H), 7.87−7.76 (m, 3H), 7.61 (d, J
= 8.6 Hz, 1H), 7.58−7.44 (m, 3H). 19F NMR (376 MHz, CDCl3): δ
−90.3 (t, JFF = 5.9 Hz, 2F), −111.3 (t, JFF = 5.9 Hz, 2F). 13C{1H}
NMR (100 MHz, CDCl3): δ 152.5, 149.2, 137.7, 137.0, 133.8, 133.4,
132.8, 130.2, 128.9, 128.6 (t, JCF = 24.9 Hz), 128.2, 127.9, 127.8,
127.8, 127.4, 126.94, 126.90, 124.4 (tt, JCF = 289.6, 38.9 Hz), 122.2,
121.4, 116.6 (tt, JCF = 254.9, 32.6 Hz). HRMS-EI (m/z): [M]+ calcd
for C21H13F4NS, 387.0705; found, 387.0708.
2-[1,1,2,2-Tetrafluoro-2-(naphthalen-2-ylthio)ethyl]pyrazine
(9ag). The crude material was purified by the gel permeation
chromatography (eluent, CHCl3). White solid, 131.9 mg (0.39
mmol), 78% yield, mp 41 °C. 1H NMR (400 MHz, CDCl3): δ 8.96 (s,
1H), 8.78 (s, 1H), 8.68 (s, 1H), 8.16 (s, 1H), 7.90−7.81 (m, 3H),
7.63 (d, J = 8.6 Hz, 1H), 7.60−7.51 (m, 2H). 19F NMR (376 MHz,
CDCl3): δ −90.6 (t, JFF = 6.2 Hz, 2F), −115.8 (t, JFF = 6.2 Hz, 2F).
13C{1H} NMR (100 MHz, CDCl3): δ 147.1, 145.3 (t, JCF = 29.0 Hz),
144.2, 143.9, 137.8, 133.9, 133.5, 132.7, 129.0, 128.2, 127.9, 127.9,
127.0, 123.9 (tt, JCF = 289.9, 36.7 Hz), 121.0, 114.0 (tt, JCF = 256.1,
33.4 Hz). HRMS-EI (m/z): [M]+ calcd for C16H10F4N2S,: 338.0501;
found, 338.0497.
4-Chloro-6-[1,1,2,2-tetrafluoro-2-(naphthalen-2-ylthio)ethyl]-
quinazoline (9ah). The crude material was purified by the gel
permeation chromatography (eluent, CHCl3). White solid, 137.4 mg
1
(0.32 mmol), 65% yield, mp 81 °C. H NMR (400 MHz, CDCl3): δ
9.11 (s, 1H), 8.53 (s, 1H), 8.23−8.07 (m, 3H), 7.92−7.75 (m, 3H),
7.61 (d, J = 8.5 Hz, 1H), 7.59−7.48 (m, 2H). 19F NMR (376 MHz,
CDCl3): δ −90.2 (t, JFF = 5.0 Hz, 2F), −111.4 (t, JFF = 5.0 Hz, 2F).
13C{1H} NMR (150 MHz, CDCl3): δ 163.5, 155.3, 152.1, 137.7,
133.8, 133.4, 132.6, 132.3 (t, JCF = 5.2 Hz), 131.3 (t, JCF = 25.4 Hz),
129.7, 129.0, 128.1, 127.9, 127.8, 127.0, 125.9 (t, JCF = 6.9 Hz), 124.1
(tt, JCF = 289.6, 38.7 Hz), 123.5, 121.1, 116.0 (tt, JCF = 255.4, 33.3
Hz). HRMS-EI (m/z): [M]+ calcd for C20H11ClF4N2S, 422.0268;
found, 422.0265.
2-[1,1,2,2-Tetrafluoro-2-(naphthalen-2-ylthio)ethyl]dibenzo-
[b,d]furan (9ai). The crude material was purified by the gel
permeation chromatography (eluent, CHCl3). Yellowish solid, 156.6
mg (0.37 mmol), 73% yield, mp 110 °C. 1H NMR (400 MHz,
CDCl3): δ 8.20 (s, 1H), 8.13 (s, 1H), 7.98 (d, J = 7.6 Hz, 1H), 7.87−
7.76 (m, 3H), 7.71 (d, J = 8.6 Hz, 1H), 7.67−7.57 (m, 3H), 7.57−
7.47 (m, 3H), 7.39 (t, J = 7.4 Hz, 1H). 19F NMR (376 MHz, CDCl3):
δ −90.3 (t, JFF = 5.6 Hz, 2F), −109.9 (t, JFF = 5.8 Hz, 2F). 13C{1H}
NMR (100 MHz, CDCl3): δ 157.7, 156.9, 137.6, 133.8, 133.5, 132.8,
128.9, 128.2, 128.2, 127.8, 127.8, 126.9, 126.0 (t, JCF = 6.1 Hz), 125.1
(t, JCF = 25.1 Hz), 124.6, 124.5 (tt, JCF = 289.6, 39.8 Hz), 123.6,
123.4, 121.8, 121.1, 120.1 (t, J = 6.5 Hz), 117.0 (tt, JCF = 254.9, 32.4
Hz), 112.1, 111.8. HRMS-EI (m/z): [M]+ calcd for C24H14F4OS,
426.0701; found, 426.0695.
2-Chloro-4-[1,1,2,2-tetrafluoro-2-(naphthalen-2-ylthio)ethyl]-
pyridine (9ad). The crude material was purified by the gel permeation
chromatography (eluent, CHCl3). Yellowish solid, 139.4 mg (0.37
1
mmol), 75% yield, mp 61 °C. H NMR (400 MHz, CDCl3): δ 8.53
(d, J = 5.1 Hz, 1H), 8.15 (s, 1H), 7.91−7.81 (m, 3H), 7.66−7.51 (m,
4H), 7.42 (d, J = 5.1 Hz, 1H). 19F NMR (376 MHz, CDCl3): δ −90.4
(t, JFF = 5.1 Hz, 2F), −113.5 (t, JFF = 5.2 Hz, 2F). 13C{1H} NMR
(150 MHz, CDCl3): δ 152.3, 150.3, 141.7 (t, J = 26.5 Hz), 137.9,
Ethyl (Z)-5-{[4-(tert-Butyl)benzyl]thio}-4,4,5,5-tetrafluoropent-2-
enoate [(Z)-9hj]. The crude material was purified by the gel
permeation chromatography (eluent, CHCl3). Colorless oil, 146.0
133.9, 133.5, 132.6, 129.1, 128.2, 128.0, 127.9, 127.1, 123.7 (tt, JCF
=
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pubs.acs.org/joc
Note
mg (0.39 mmol), 77% yield. 1H NMR (400 MHz, CDCl3): δ 7.36 (d,
J = 8.3 Hz, 2H), 7.29 (d, J = 8.3 Hz, 2H), 6.36 (dt, J = 12.7, 2.4 Hz,
1H), 5.98 (q, J = 13.6 Hz, 1H), 4.27 (q, J = 7.1 Hz, 2H), 4.14 (s, 2H),
1.32 (s, 9H), 1.31 (t, J = 7.1 Hz, 3H). 19F NMR (376 MHz, CDCl3):
= 25.3 Hz), 116.8 (tt, JCF = 253.8, 32.2 Hz), 114.3, 68.3, 32.1, 29.79,
29.77, 29.73, 29.70, 29.50, 29.49, 29.3, 26.1, 22.8, 14.3. HRMS-EI (m/
z): [M]+ calcd for C50H64F8O2S2, 912.4220; found, 912.4223.
Procedure for the Synthesis of 1-(Dodecyloxy)-4-iodoben-
zene.21 To a DMF solution (15.0 mL) of 4-iodophenol (1.50 g, 6.8
mmol) and K2CO3 (1.88 g, 13.6 mmol) was added 1-bromododecane
(2.03 g, 8.16 mmol). After stirring at 60 °C on the oil bath for 24 h,
the reaction mixture was poured into deionized water (10 mL) and
then extracted with Et2O (10 mL) three times. The combined organic
phase was further washed with brine (10 mL), and dried over
anhydrous MgSO4. All volatiles were removed under reduced
pressure, and the crude product was further purified by silica-gel
column chromatography (eluate: hexane), affording aryl iodide (2.48
g, 94%) as colorless oil. 1H NMR (400 MHz, CDCl3): δ 7.54 (d, J =
8.9 Hz, 2H), 6.67 (d, J = 8.8 Hz, 2H), 3.91 (t, J = 6.6 Hz, 2H), 1.76
(dt, J = 7.0 Hz, 2H), 1.50−1.38 (m, 2H), 1.38−1.19 (m, 16H), 0.88
(t, J = 6.7 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 159.2,
138.3, 117.1, 82.5, 86.2, 32.1, 29.8, 29.8, 29.7, 29.7, 29.5, 29.5, 29.3,
26.1, 22.8, 14.3. HRMS-EI (m/z): [M]+ calcd for C18H9IO, 388.1263;
found, 388.1259.
δ −92.9 (t, JFF = 7.0 Hz, 2F), −111.4 (ddt, JHF = 14.1, 2.7 Hz, JFF
=
7.2 Hz, 2F). 13C{1H} NMR (100 MHz, CDCl3): δ 164.7, 151.0,
132.1, 130.7 (t, JCF = 5.4 Hz), 129.0, 125.9, 125.0 (tt, JCF = 288.1,
31.8 Hz), 124.5 (t, JCF = 24.8 Hz), 114.4 (tt, JCF = 253.3, 33.6 Hz),
61.7, 34.7, 32.3, 31.4, 14.0. HRMS-EI (m/z): [M]+ calcd for
C18H22F4O2S, 378.1277; found, 378.1281.
Ethyl 3-{[4-(tert-Butyl)benzyl]thio}-2,2,3,3-tetrafluoropropa-
noate (9hk). The crude material was purified by the gel permeation
chromatography (eluent, CHCl3). Colorless oil, 146.2 mg (0.46
1
mmol), 83% yield. H NMR (400 MHz, CDCl3): δ 7.43 (d, J = 7.4
Hz, 2H), 7.34 (d, J = 7.8 Hz, 2H), 4.45 (q, J = 7.1 Hz, 2H), 4.19 (s,
2H), 1.41 (t, J = 7.2 Hz, 3H) 1.37 (s, 9H). 19F NMR (376 MHz,
CDCl3): δ −92.2 (t, JFF = 6.7 Hz, 2F), −119.8 (t, JFF = 6.6 Hz, 2F).
13C{1H} NMR (100 MHz, CDCl3): δ 159.9 (t, JCF = 30.4 Hz), 151.1,
131.8, 129.0, 125.9, 123.9 (tt, JCF = 289.0, 33.5 Hz), 109.3 (tt, JCF
=
264.0, 34.8 Hz), 64.2, 34.6, 32.5, 31.3, 13.8. HRMS-EI (m/z): [M]+
calcd for C16H20F4O2S, 352.1120; found, 352.1119.
3-{[4-(tert-Butyl)benzyl]thio}-2,2,3,3-tetrafluoro-N,N-diphenyl-
propanamide (9hl). The crude material was purified by the gel
permeation chromatography (eluent, CHCl3). White solid, 218.8 mg
(0.42 mmol), 92% yield, mp 119 °C. 1H NMR (400 MHz, CDCl3): δ
7.34−7.16 (m, 14H), 4.00 (s, 2H), 1.20 (s, 9H). 19F NMR (376
MHz, CDCl3): δ −91.3 (t, JFF = 7.5 Hz, 2F), −111.0 (t, JFF = 7.5 Hz,
2F). 13C{1H} NMR (100 MHz, CDCl3): δ 159.5 (t, J = 26.4 Hz),
150.8, 132.2, 129.4, 129.0, 127.6, 125.8, 124.3 (tt, JCF = 290.8, 32.2
Hz), 111.2 (tt, JCF = 272.1, 31.8 Hz), 34.7, 32.9 (t, J = 4.8 Hz), 31.4.
HRMS-EI (m/z): [M]+ calcd for C26H25F4NOS, 475.1593; found,
475.1598.
Procedure for the Synthesis of 9lm from 2l. A solution (20.0
mL) of iPr2NH (75.9 mg, 105.7 μL, 0.75 mmol) in THF was added to
a solution of nBuLi in hexane (1.6 M, 0.47 mL, 0.75 mmol) at −78 °C
under a nitrogen atmosphere. After stirring for 1 h, the reaction
mixture was slowly added to a solution of the tetrafluoroethyl sulfide
2l (117.7 mg, 0.30 mmol) and chlorotrimethylsilane (81.5 mg, 94.8
μL, 0.75 mmol) in THF (1.0 mL) at −78 °C by a syringe pump (0.15
mmol/min). After stirring at −78 °C for 1 h, the reaction mixture was
allowed to warm to room temperature gradually. After additional
stirring for 6 h, this mixture was poured into deionized water. The
mixture was extracted with hexane three times. The combined organic
layer was washed with brine and then dried over anhydrous MgSO4.
After filtration, the solvents were removed by evaporation. The crude
product 7l was subjected to the next step without further purification.
For the X-ray diffraction analysis, 7l was recrystallized from a mixed
solvent system of Et2O/MeOH (1:5).
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.1c00361.
Experimental procedures, compound characterization
data, NMR spectra, and computational data (PDF)
Accession Codes
CCDC 2062399 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
Sensuke Ogoshi − Department of Applied Chemistry, Faculty
of Engineering, Osaka University, Suita, Osaka 565-0871,
Japan; orcid.org/0000-0003-4188-8555;
Email: ogoshi@chem.eng.osaka-u.ac.jp
Authors
Denise E. Sunagawa − Department of Applied Chemistry,
Faculty of Engineering, Osaka University, Suita, Osaka 565-
0871, Japan
Naoyoshi Ishida − Department of Applied Chemistry, Faculty
of Engineering, Osaka University, Suita, Osaka 565-0871,
Japan
Hiroaki Iwamoto − Department of Applied Chemistry,
Faculty of Engineering, Osaka University, Suita, Osaka 565-
0871, Japan; orcid.org/0000-0002-4771-1956
Masato Ohashi − Department of Applied Chemistry, Faculty
of Engineering, Osaka University, Suita, Osaka 565-0871,
Japan; orcid.org/0000-0001-8718-2799
Corinne Fruit − Normandie University, UNIROUEN, INSA
Rouen, CNRS, COBRA, F-76000 Rouen, France;
orcid.org/0000-0002-2878-4885
CuOtBu (102.5 mg, 0.75 mmol) and 1,10-phenanthroline (135.2
mg, 0.75 mmol) were added to a 6.0 mL reaction vial equipped with a
stir bar. THF (1.0 mL) was then added to the reaction vial under a
nitrogen atmosphere. The resulting dark red mixture was stirred at
room temperature for 1 min. Subsequently, the silylation product was
added dropwise to the mixture at room temperature. After stirring at
room temperature for 1 h, 4-dodecyloxy-1-iodobenzene (485.4 mg,
0.75 mmol) was added. After additional stirring at 60 °C on the oil
bath for 16 h, the reaction mixture was poured into deionized water.
The mixture was extracted with hexane three times. The combined
organic layer was washed with brine and then dried over anhydrous
MgSO4. After filtration, the solvents were removed by evaporation.
The crude product was purified by gel permeation chromatography to
afford the corresponding product 9lm (169.8 mg, 0.19 mmol, 62%) as
a white solid (mp 103 °C). 1H NMR (400 MHz, CDCl3): δ 8.67 (d, J
= 8.5 Hz, 2H), 7.96 (d, J = 7.1 Hz, 2H), 7.58 (dd, J = 8.4, 7.3 Hz,
2H), 7.51 (d, J = 8.7 Hz, 4H), 6.93 (d, J = 8.7 Hz, 4H), 3.98 (t, J = 6.5
Hz, 4H), 1.79 (quin, J = 7.0 Hz, 4H), 1.50−1.40 (m, 4H), 1.40−1.19
(m, 32H), 0.88 (t, J = 6.8 Hz, 6H). 19F NMR (376 MHz, CDCl3): δ
−86.8 (t, JFF = 6.1 Hz, 4F), −107.6 (t, JFF = 6.1 Hz, 4F). 13C{1H}
NMR (100 MHz, CDCl3): δ 161.6, 138.9, 137.1, 130.3, 128.5, (t, JCF
= 6.0 Hz), 126.8, 124.6 (tt, JCF = 290.2, 40.4 Hz), 122.5, 121.9 (t, JCF
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.1c00361
Notes
The authors declare no competing financial interest.
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J. Org. Chem. 2021, 86, 6015−6024

The Journal of Organic Chemistry
pubs.acs.org/joc
Note
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ACKNOWLEDGMENTS
■
This work was supported by JSPS KAKENHI grants
JP17H03057 and 20K15278 as well as by a Grant-in-Aid for
Scientific Research on Innovative Areas (“Precisely Designed
Catalysts with Customized Scaffolding” JSPS KAKENHI grant
JP15H05803). N.I. would like to thank the JSPS for a
scholarship (19J10485).
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