Ortho-lithiation reaction of aryl triflones

Article abstract of DOI:10.1016/j.tet.2018.07.055

The ortho-lithiation of substituted arenes is a powerful methodology to synthesize ortho-substituted arenes. While a wide variety of directed metalation groups (DMGs) have been reported, trifluoromethyl sulfone has never been used. We disclose the first example of ortho-lithiation of aryl triflones. We found that the trifluoromethyl sulfonyl group is not only an important structural motif in biologically active molecules and specialty materials, but also an excellent DMG moiety for ortho-metalation reactions. The use of a base that causes steric hindrance, LTMP, is the key for successful transformation to furnish a variety of ortho-substituted aryl triflones in good yields. Further functionalization of resulting ortho-substituted aryl triflones was demonstrated by metal-catalyzed coupling reactions.

Full text of DOI:10.1016/j.tet.2018.07.055

Accepted Manuscript
Ortho-lithiation reaction of aryl-triflones
Yuji Sumii, Misaki Taniguchi, Xiu-Hua Xu, Etsuko Tokunaga, Norio Shibata
PII:
S0040-4020(18)30921-9
10.1016/j.tet.2018.07.055
TET 29715
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 27 June 2018
Revised Date: 27 July 2018
Accepted Date: 28 July 2018
Please cite this article as: Sumii Y, Taniguchi M, Xu X-H, Tokunaga E, Shibata N, Ortho-lithiation
reaction of aryl-triflones, Tetrahedron (2018), doi: 10.1016/j.tet.2018.07.055.
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Ortho-Lithiation Reaction of Aryl-triflones
Leave this area blank for abstract info.
Yuji Sumii a , Misaki Taniguchi a , Xiu-Hua Xu a ,
Etsuko Tokunaga a , and Norio Shibata a,b,
*
a Department of Life Science and Applied Chemistry, Department of Nanopharmaceutical Sciences, Nagoya
Institute of Technology, Gokiso, Showa-ku, Nagoya 466-5888, Japan.
b Institute of Advanced Fluorine-Containing Materials, Zhejiang Normal University,688 Yingbin Avenue,
321004 Jinhua, China.

1
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Tetrahedron
journal homepage: www.elsevier.com
Ortho-Lithiation Reaction of Aryl-triflones
Yuji Sumii a , Misaki Taniguchi a , Xiu-Hua Xu a , Etsuko Tokunaga a , and Norio Shibata a,b,
a Department of Life Science and Applied Chemistry, Department of Nanopharmaceutical Sciences, Nagoya Institute of Technology, Gokiso, Showa-ku, Nagoya
466-5888, Japan.
b Institute of Advanced Fluorine-Containing Materials, Zhejiang Normal University,688 Yingbin Avenue, 321004 Jinhua, China.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
The ortho-lithiation of substituted arenes is a powerful methodology to synthesize ortho-
substituted arenes. While a wide variety of directed metalation groups (DMGs) have been
reported, trifluoromethyl sulfone has never been used. We disclose the first example of ortho-
lithiation of aryl triflones. We found that the trifluoromethyl sulfonyl group is not only an
important structural motif in biologically active molecules and specialty materials, but also an
excellent DMG moiety for ortho-metalation reactions. The use of a base that causes steric
hindrance, LTMP, is the key for successful transformation to furnish a variety of ortho-
substituted aryl triflones in good yields. Further functionalization of resulting ortho-substituted
aryl triflones was demonstrated by metal-catalyzed coupling reactions.
Available online
Keywords:
Aryl triflone
Ortho-lithiation
Directed Metalation Group
Trifluoromethanesulfonyl
Fluorine
2009 Elsevier Ltd. All rights reserved
.
———
Corresponding author. Tel.: +81-52-735-7543; fax: +81-52-735-7543; e-mail: nozshiba@nitech.ac.jp

2
Tetrahedron
1. Introduction
reported the first use of S-trifluoromethyl sulfoximine (-
ACCEPTED MANUSCRIPT
S(O)=NH-CF3) as an ortho-directing group for the ortho-
functionalization of arenes bonded to trifluoromethyl
Fluorinated and fluoro-functionalized aromatic compounds are
a
conjugated sulfur atom.23 We disclose herein the ortho-lithiation
of aryl triflones. The SO2CF3 group was useful as a DMG when
combined with lithium tetramethylpiperidide (LTMP). A wide
variety of electrophiles were smoothly reacted with ortho-
lithiated aryl triflones to provide corresponding ortho-substituted
triflones in good yields. Since simple aryl triflones are
commercially or readily available, our method is simple and
straightforward for the preparation of ortho-substituted aryl
triflones. Besides, to our knowledge, this is the first example of
ortho-lithiation of aryl triflones.
increasingly valuable motifs in applications for specialty
materials, pharmaceuticals, herbicides, and fungicides.1a Two of
the most popular fluorinated aromatic compounds that have
succeeded on the market thus far are aryl fluorides (Ar–F) and
benzotrifluorides (Ar–CF3), thus considerable attention has been
devoted to the synthesis of Ar–F and Ar–CF3 in both academia
and industry in the past few decades.1b In this context, the
attention of medicinal chemists has shifted spontaneously to a
wide variety of arenes with heteroatom-linked trifluoromethyl
modifications, such as trifluoromethoxy arenes (Ar–OCF3),2
trifluoromethylthio
arenes
(Ar–SCF3)3
and
trifluoromethanesulfonyl arenes (aryl triflones, Ar–SO2CF3).3d,4-10
Aryl triflones have functional group,
a
trifluoromethanesulfonyl (-SO2CF3), which is strong electron-
withdrawing group in organic chemistry while the lipophilicity of
the SO2CF3 group is moderate (σm = 0.79, σp = 0.93, π =
0.55).3d,11 Thus, the replacement of a CF3 moiety in bioactive
CF3-compounds by a SO2CF3 group is a potential strategy for the
design of new drug candidates. Indeed, aryl triflones are
becoming popular as central structural motifs not only in
biologically active molecules,8 but also in functional materials9
and chiral catalysts (Fig. 1).10 Although there are many methods
for the synthesis of aryl triflones, only a few reports are available
for functionalization at the ortho-position of aryl triflones, such
as
nitration,12
bromination,13
chlorination,14
and
Scheme 1. Directed ortho-lithiation of substituted aromatics.
trifluoroethoxylation.15
Starting with the optimization of reaction conditions, bases
were screened in the ortho-methylation of phenyl triflone 1. The
use of 1.0 equivalent of n-BuLi, a general reaction condition of
ortho-lithiation, gave no desired product with incomplete
conversion (Table 1, entry 1). NMR analysis of the obtained
byproduct suggests that the CF3 group was eliminated by the
nucleophilic attack of n-BuLi to provide n-butyl phenyl sulfone.
Thus, sterically demanding lithium amides were selected as the
base. Even, the use of lithium bis(trimethylsilyl)amide (LHMDS)
resulted in no reaction (entry 2), while the use of lithium
diisopropylamide (LDA) gave the ortho-methylated phenyl
triflone (2a) in 15% yield (entry 3). The more sterically hindered
base LTMP improved yield to 55% (entry 4). The equivalent of
LTMP and methyl iodide (MeI) affected yield, and the
combination of 1.5 equivalents of LTMP and 2.0 equivalents of
MeI successfully provided 2a in 73% yield (entries 5–8).
Table 1
Optimization of base and equivalent electrophile for ortho-lithiation of 1.a
Fig. 1. Examples of aryl triflone-containing biologically attractive
Entry
Base
X (equiv)
1.0
Yield (%)
molecules and catalysts.
1
n-BuLi
LiHMDS
LDA
0
One of the most powerful strategies for the synthesis of ortho-
substituted arenes is the direct ortho-metalation of arenes16
bearing a "directed metalation group" (DMG) such as thiol
(SH),17 sulfonic acid (-SO3H),18 alkyl thiol ether (-SR),19 alkyl
sulfone (-SO2R),20 sulfone amide (-S(O)NR2),21 sulfoximine (-
S(O)=NH-R),22 or S-trifluoromethyl sulfoximine (-S(O)=NH-
CF3).23 Despite the prestigious position of ortho-metalation of
arenes with DMG in synthetic organic chemistry since the
discovery of the ortho-metalation by Wittig24 and Gilman,25 it is
rather surprising that the ortho-metalation of aryl triflones has
rarely been reported. In recent years, Magnier and co-workers
2
1.0
NR
15
55
65
73
44
62
3
1.0
4
LTMP
LTMP
LTMP
LTMP
LTMP
1.0
5
1.5
6 b
1.5
7
2.0
8 b
2.0
a Reactions were performed with 1 (1.0 mmol), Base (X equiv) and MeI (1.0
equiv) in THF (5.0 mL) at –78 °C.

3
b MeI (2.0 equiv) was used.
Table 3
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Substrate scopes of ortho-lithiation of 1.
We next tested the affection between reaction temperature and
solvent. When the reaction was performed at 0 °C, no desired
product was obtained (Table 2, entry 1). After testing lower
temperatures, an ortho-methylated product 2a was obtained only
when the reaction was performed at –78 °C (entries 2–5). After
solvent screening, we found that the use of THF as a solvent is
essential for this ortho-lithiation reaction while the use of other
solvents (hexane, toluene, Et2O) produced almost no desired
product (entries 6–8). Addition of TMEDA (N,N,N',N'-
tetramethylethylenediamine) deceased the yield which suggested
the importance of chelation between ortho-lithium and oxygen of
triflone for this transformation (entry 9). These results suggest
that the ortho-lithiated intermediate I is unstable but is stabilized
by valance coordination of the triflyl group and THF.
Table 2
Optimization of solvent and reaction temperature for ortho-lithiation of 1. a
Entry
Solvent
THF
Temp. (°C)
0
Yield (%)b
Finally, we attempted the transformation of halogen groups at
the ortho-position of phenyl triflones. Suzuki-Miyaura cross
coupling with ortho-iodo phenyl triflone 2b and phenyl boronic
acid proceeded to afford biphenyl triflone 2m in 46% yield.
Introduction of an azide group by sodium azide under copper
catalysis from ortho-bromo phenyl triflone 2b provided ortho-
azide phenyl triflone 2n in 53% yield.
1
2
3
4
5
6
7
8
9 c
0
THF
–20
0
THF
–40
0
THF
–60
0
THF
–78
73
0
Hexane
Toluene
Et2O
–78
–78
0
–78
2
THF
–78
59
a Reactions were performed with 1 (1.0 mmol), LTMP (1.5 equiv) and MeI
(2.0 equiv) in solvent (5.0 mL) at the given temperature.
b Yields were determined by 19F NMR with trifluoromethylbenzene as the
internal standard.
Scheme 2. Coupling reaction of ortho-iodo and ortho-bromo phenyl triflones.
c TMEDA (1.5 equiv) was added to the reaction mixture.
In summary, we disclosed the ortho-lithiation of aryl triflones.
The trifluoromethyl sulfonyl group is not only an important
structural motif in biologically active molecules and specialty
materials, but also an excellent moiety of DMG for ortho-
metalation reactions. Various types of electrophiles have shown
to be compatible with this transformation resulting in a wide
variety of ortho-substituted aryl triflones in good yields in a
regioselective manner. The use of a base such as LTMP that
causes steric hindrance is key for the success of this
transformation as it suppresses the nucleophilic attack of lithiated
bases on the sulfur atom at the sulfonyl center. Extension of this
methodology to obtain structurally more complex ortho-
substituted aryl triflones by combining our previous method for
the synthesis of aryl triflones via benzynes is currently under
investigation.
With the optimized reaction conditions in hand, we
investigated the use of several electrophiles in the ortho-
substitution reaction of phenyl triflone 1 (Table 3). Methyl-, I-,
and Br-substituted phenyl triflones 2a–c were obtained in good
yields. Fluorination by using N-fluoro-bis(phenylsulfonyl)imide
(NFSI) produced ortho-fluoro phenyl triflone 2d in low yield.
Silylation and hydroxylation provided the corresponding ortho-
trimethylsilyl phenyl triflone 2e and ortho-hydroxy phenyl
triflone 2f, respectively in moderate yields. Phenyl triflone with
boronic acid at the ortho-position 2g was obtained in 56% yield
by using B(OMe)3 as an electrophile with an acidic work up. The
use of allyl bromide or benzyl bromide provided the
corresponding ortho-alkylated phenyl triflone 2h and 2i with
acceptable yields. It should be interesting to note that the addition
of a carbonyl group provided phenyl triflones having an ester
(2j), aldehyde (2k) or ketone group (2l) at the ortho-position in
good yields, in spite of the products containing a reactive
carbonyl group.
2. Experimental section
2.1. General methods
All reactions were performed in oven-dried glassware under a
positive pressure of nitrogen. Solvents were transferred via
syringe and were introduced into the reaction vessels though a
rubber septum. Column chromatography was carried out on a
column packed with silica-gel 60N spherical neutral size 63-210.
1
The H NMR (300 and 500 MHz), 19F NMR (282 MHz), 13C
NMR (150.9 MHz) spectra for solution in CDCl3 were recorded
on a Bruker Avance 500 spectrometers. Chemical shifts (δ) are

4
Tetrahedron
ACCEPTED MANUSCRIPT
expressed in ppm downfield from internal TMS (δ = 0.00),
1H), 7.68 (t, J = 7.2 Hz, 1H), 7.49–7.42 (m, 2H), 2.72 (s, 3F)
CHCl3 (δ = 77.0), C6F6 (δ = –162.2). High resolution mass
spectrometries were recorded on a SHIMADZU GCMS-
QP5050A (EI-MS). Infrared spectra were recorded on a JASCO
FT/IR-4100 spectrometer.
ppm; 19F NMR (282 MHz, CDCl3) δ: −78.8 (s, 3H) ppm; 13C
NMR (150.9 MHz, CDCl3) δ: 20.6, 120.1 (q, J = 326.7 Hz),
127.2, 129.7, 133.3, 133.6, 136.4, 142.2 ppm; IR (KBr): 1363,
1203, 1145, 1122, 1057, 1043, 758, 690, 607 cm-1; HRMS (EI)
m/z: calcd for C8H7O2F3S [M]+ 224.0119, Found: 224.0143.
2.2. Phenyl(trifluoromethyl)sulfide (3)26
2.6. 1-Iodo-2-((trifluoromethyl)sulfonyl)benzene (2b) 4v
CF3I
NaH
SH
SCF3
SO2CF3
RuCl3•xH2O
According
to
the
general
procedure,
2,2,6,6-
H2O-MeCN-CCl4, rt
DMF, 0 °C
1
tetramethylpiperidine (255 µL, 1.50 mmol) in dry THF (5.0 mL),
n-BuLi (1.30 M solution in hexane, 1.15 mL, 1.50 mmol),
phenyltriflone 1 (210 mg, 1.00 mmol) and I2 (508 mg, 2.00
mmol) in dry THF (2.0 mL) gave the title compound (227 mg,
68%) as a yellow solid. 1H NMR (300 MHz, CDCl3) δ: 8.28–8.24
(m, 2H), 7.70–7.64 (m, 1H), 7.45–7.39 (m, 1H) ppm; 19F NMR
(282 MHz, CDCl3) δ: −75.9 (s, 3F) ppm; 13C NMR (150.9 MHz,
CDCl3) δ: 119.5 (q, J = 327.7 Hz), 129.2, 134.1, 134.8, 136.8,
144.3, 145.8 ppm; IR (KBr): 1714, 1369, 1213, 1139, 760, 725
cm-1; HRMS (EI) m/z: calcd for C7H4O2F3SI [M]+ 335.8929,
Found: 335.8911.
3
To a stirring mixture of NaH (60% w/w in oil, 1.04 g, 26.0
mmol) in dry DMF (20.0 mL) was added thiophenol (2.04 mL,
20.0 mmol) at 0 °C, and the mixture was stirred at 0 °C for 20
min. CF3I (3.10 g, 26.0 mmol) was added to the mixture via
balloon, and the mixture was stirred at 0 °C for 12 h. H2O was
added to the mixture and the mixture was extracted with Et2O.
The combined organic layer was washed with brine, dried with
Na2SO4, and concentrated under reduced pressure. The residue
was purified by silica gel column chromatography to give Ph-
1
SCF3 3 (2.33 g, 65%) as yellowish oil. H NMR (300 MHz,
CDCl3) δ: 7.66 (d, J = 7.5 Hz, 2H), 7.52–7.40 (m, 3H) ppm; 19F
NMR (282 MHz, CDCl3) δ: −43.2 (s, 3H) ppm.
2.7. 1-Bromo-2-((trifluoromethyl)sulfonyl)benzene (2c)4v
According
to
the
general
procedure,
2,2,6,6-
2.3. ((Trifluoromethyl)sulfonyl)benzene (1)27
tetramethylpiperidine (255 µL, 1.50 mmol) in dry THF (5.0 mL),
n-BuLi (1.30 M solution in hexane, 1.15 mL, 1.50 mmol),
phenyltriflone 1 (210 mg, 1.00 mmol) and Br2 (102 µL, 2.00
To a stirring mixture of Ph-SCF3 3 (2.32 g, 13.0 mmol) in
H2O-MeCN-CCl4 (16.0 mL, 2:1:1) was added RuCl3•xH2O (135
mg, 0.65 mmol) at rt, and the mixture was stirred for 5 min.
NaIO4 (8.34 g, 39.0 mmol) was added to the mixture, and the
mixture was stirred at rt for 1 h. The reaction mixture was diluted
with Et2O and filtered through the Celite®. The organic layer was
separated and the aqueous layer was extracted with Et2O. The
combined organic layer was washed with brine, dried with
Na2SO4, and concentrated under reduced pressure. The residue
was purified by silica gel column chromatography to give phenyl
1
mmol) gave the title compound (210 mg, 73%) as yellow oil. H
NMR (300 MHz, CDCl3) δ: 8.23 (d, J = 4.8 Hz, 1H), 7.89 (d, J =
4.8 Hz, 1H), 7.64–7.61 (m, 2H) ppm; 19F NMR (282 MHz,
CDCl3) δ: −76.2 (s, 3F) ppm; 13C NMR (150.9 MHz, CDCl3) δ:
119.7 (q, J = 327.4 Hz), 123.5, 128.5, 131.4, 135.1, 137.1, 137.2
ppm; IR (KBr): 1373, 1215, 1142, 1090, 7026, 756, 604 cm-1;
HRMS (EI) m/z: calcd for C7H4O2F3SBr [M]+ 287.9067, Found:
287.9088, calcd for C6H4Br [M–SO2CF3]+ 154.9496, Found:
154.9510.
1
triflone 1 (1.80 g, 65%) as yellowish oil. H NMR (300 MHz,
27,28
CDCl3) δ: 8.06 (d, J = 8.1 Hz, 2H), 7.86 (t, J = 8.3 Hz, 1H),
7.72–7.67 (m, 2H) ppm; 19F NMR (282 MHz, CDCl3) δ: −78.9 (s,
3H) ppm; 13C NMR (150.9 MHz, CDCl3) δ: 119.7 (q, J = 325.8
Hz), 129.9, 130.7, 131.3, 136.6 ppm; IR (KBr): 1369, 1219,
1142, 1074, 771, 721, 685, 603 cm-1; HRMS (EI) m/z: calcd for
C7H5O2F3S [M]+ 209.9962, Found: 209.9991.
2.8. 1-Fluoro-2-((trifluoromethyl)sulfonyl)benzene (2d)
According
to
the
general
procedure,
2,2,6,6-
tetramethylpiperidine (255 µL, 1.50 mmol) in dry THF (5.0 mL),
n-BuLi (1.30 M solution in hexane, 1.15 mL, 1.50 mmol),
phenyltriflone
1
(210 mg, 1.00 mmol) and N-
fluorobenzenesulfoimide (631 mg, 2.00 mmol) in THF (2.0 mL)
gave the title compound (71.7 mg, 31%) as yellow oil. H NMR
2.4. General procedure of ortho-lithiation and addition
1
(300 MHz, CDCl3) δ: 8.05–8.00 (m, 1H), 7.85–7.81 (m, 1H),
7.48–7.43 (m, 1H), 7.39–7.33 (m, 1H) ppm; 19F NMR (282 MHz,
CDCl3) δ: −78.8 (d, J = 9.0 Hz, 3F), –104.2 (s, 1F) ppm; 13C
NMR (150.9 MHz, CDCl3) δ: 118.2 (d, J = 19.6 Hz), 125.3,
133.4, 139.4 (d, J = 9.0 Hz), 161.2 (d, J = 265.0 Hz) ppm.
To a stirring mixture of 2,2,6,6-tetramethylpiperidine (255 µL,
1.50 mmol) in dry THF (5.0 mL) was added n-BuLi (1.30 M
solution in hexane, 1.15 mL, 1.50 mmol) at –78 °C, and the
mixture was stirred at 0 °C for 30 min. The mixture was cooled
to –78 °C, phenyltriflone 1 (210 mg, 1.00 mmol) was slowly
added to the mixture, and the mixture was stirred at –78 °C for 2
h. Electrophile (2.00 mmol) was added to the mixture and the
mixture was stirred at –78 °C for overnight. H2O was added at rt
and the mixture was diluted with Et2O. The organic layer was
separated and the aqueous layer was extracted with Et2O. The
combined organic layer was washed with brine, dried with
Na2SO4, and concentrated under reduced pressure. The residue
was purified by silica gel column chromatography to give ortho-
substituted phenyl triflone 2.
2.9. Trimethyl(2-((trifluoromethyl)sulfonyl)phenyl)silane (2e)
According
to
the
general
procedure,
2,2,6,6-
tetramethylpiperidine (255 µL, 1.50 mmol) in dry THF (5.0 mL),
n-BuLi (1.30 M solution in hexane, 1.15 mL, 1.50 mmol),
phenyltriflone 1 (210 mg, 1.00 mmol) and TMSCl (253 µL, 2.00
mmol) in THF (2.0 mL) gave the title compound (71.7 mg, 31%)
as yellow oil. 1H NMR (300 MHz, CDCl3) δ: 8.12 (d, J = 7.8 Hz,
1H), 7.92 (d, J = 7.5 Hz, 1H), 7.78–7.73 (m, 1H), 7.68–7.62 (m,
1H), 0.43 (s, 9H) ppm; 19F NMR (282 MHz, CDCl3) δ: −77.8 (s,
3F) ppm; 13C NMR (150.9 MHz, CDCl3) δ: 0.93, 119.9 (q, J =
327.5 Hz), 130.1, 132.9, 135.1, 136.3, 137.4, 145.0 ppm; IR
(KBr): 1365, 1255, 1211, 1140, 849, 756, 663, 607 cm-1; HRMS
(EI) m/z: calcd for C9H10O2F3SiS [M–Me]+ 267.0123, Found:
267.0120.
2.5. 1-Methyl-2-((trifluoromethyl)sulfonyl)benzene (2a) 27
According
to
the
general
procedure,
2,2,6,6-
tetramethylpiperidine (255 µL, 1.50 mmol) in dry THF (5.0 mL),
n-BuLi (1.30 M solution in hexane, 1.15 mL, 1.50 mmol),
phenyltriflone 1 (210 mg, 1.00 mmol) and methyl iodide (124
µL, 2.00 mmol) gave the title compound (165 mg, 73%) as
colorless oil. 1H NMR (300 MHz, CDCl3) δ: 8.08 (d, J = 8.1 Hz,
2.10. 2-((Trifluoromethyl)sulfonyl)phenol (2f) 29

5
To a stirring mixture of 2,2,6,6-tetramethylpiperidine (255 µL,
1.50 mmol) in dry THF (5.0 mL) was added n-BuLi (1.30 M
solution in hexane, 1.15 mL, 1.50 mmol) at –78 °C, and the
mixture was stirred at 0 °C for 30 min. The mixture was cooled
to –78 °C, phenyltriflone 1 (210 mg, 1.00 mmol) was slowly
added to the mixture, and the mixture was stirred at –78 °C for 2
h. (MeO)3B (223 µL, 2.00 mmol) was added to the mixture and
the mixture was stirred at –78 °C for overnight. 3.0 M NaOH and
30% H2O2 were added to the mixture. The reaction mixture was
neutralized with 1M HCl and extracted with Et2O. The combined
organic layer was washed with brine, dried with Na2SO4, and
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography to give the title compound 3f
6H), 4.49 (s, 2H) ppm; 19F NMR (282 MHz, CDCl3) δ: −78.7
ACCEPTED MANUSCRIPT
(s, 3F) ppm; 13C NMR (150.9 MHz, CDCl3) δ: 38.0, 120.0 (q, J =
326.7 Hz), 126.7, 127.5, 128.7, 129.3, 129.7, 133.2, 133.3, 136.4,
138.9, 145.1 ppm; IR (KBr): 1363, 1217, 1140, 1111, 1059, 758,
698, 606 cm-1; HRMS (EI) m/z: calcd for C14H11O2F3S [M]+
300.0432, Found: 300.0424.
2.14. Ethyl 2-((trifluoromethyl)sulfonyl)benzoate (2j)
According
to
the
general
procedure,
2,2,6,6-
tetramethylpiperidine (255 µL, 1.50 mmol) in dry THF (5.0 mL),
n-BuLi (1.30 M solution in hexane, 1.15 mL, 1.50 mmol),
phenyltriflone 1 (210 mg, 1.00 mmol) and ethyl cyanoformate
(198 µL, 2.00 mmol) gave the title compound (151 mg, 54%) as
1
1
(117 mg, 52%) as a yellow solid. H NMR (300 MHz, CDCl3) δ:
yellow oil. H NMR (300 MHz, CDCl3) δ: 8.11 (d, J = 7.8 Hz,
7.76–7.70 (m, 2H), 7.16–7.11 (m, 2H) ppm; 19F NMR (282 MHz,
CDCl3) δ: −79.8 (s, 3F) ppm; 13C NMR (150.9 MHz, CDCl3) δ:
112.9, 119.7, 119.8 (q, J = 325.6 Hz), 121.3, 131.5, 139.8, 158.9
ppm.
1H), 7.88–7.85 (m, 1H), 7.77–7.71 (m, 2H), 4.47–4.40 (m, 2H),
1.40–1.36 (m, 3H) ppm; 19F NMR (282 MHz, CDCl3) δ: −75.8 (s,
3F) ppm; 13C NMR (150.9 MHz, CDCl3) δ: 13.6, 62.8, 119.7 (q,
J = 327.6 Hz), 129.3, 129.8, 131.0, 132.5, 136.3, 136.6, 165.9
ppm; IR (KBr): 1739, 1371, 1294, 1259, 1211, 1144, 1105, 1055,
773, 725, 606 cm-1; HRMS (EI) m/z: calcd for C10H9O4F3S [M]+
282.0174, Found: 282.0192.
2.11. (2-((Trifluoromethyl)sulfonyl)phenyl)boronic acid (2g)
To a stirring mixture of 2,2,6,6-tetramethylpiperidine (1.28
mL, 7.50 mmol) in dry THF (15.0 mL) was added n-BuLi (1.30
M solution in hexane, 5.77 mL, 7.50 mmol) at –78 °C, and the
mixture was stirred at 0 °C for 30 min. The mixture was cooled
to –78 °C, phenyltriflone 1 (1.05 g, 5.00 mmol) was slowly
added to the mixture, and the mixture was stirred at –78 °C for 2
h. (MeO)3B (1.12 mL, 10.0 mmol) was added to the mixture and
the mixture was stirred at –78 °C for overnight. The reaction
mixture was acidified with 10% HCl and extracted with Et2O.
The combined organic layer was washed with brine, dried with
Na2SO4, and concentrated under reduced pressure. The residue
was purified by silica gel column chromatography to give the
2.15. 2-((Trifluoromethyl)sulfonyl)benzaldehyde (2k)
According
to
the
general
procedure,
2,2,6,6-
tetramethylpiperidine (255 µL, 1.50 mmol) in dry THF (5.0 mL),
n-BuLi (1.30 M solution in hexane, 1.15 mL, 1.50 mmol),
phenyltriflone 1 (210 mg, 1.00 mmol) and DMF (155 µL, 2.00
1
mmol) gave the title compound (150 mg, 63%) as yellow oil. H
NMR (300 MHz, CDCl3) δ: 10.8 (s, 1H), 8.27–8.21 (m, 2H), 8.00
(dd, J = 11.1, 0.9 Hz, 1H), 7.93 (dd, J = 7.8, 1.5 Hz, 1H) ppm;
19F NMR (282 MHz, CDCl3) δ: −78.8 (s, 3F) ppm; 13C NMR
(150.9 MHz, CDCl3) δ: 119.5 (q, J = 326.0 Hz), 130.4, 131.9,
133.3, 134.0, 136.9, 137.0, 188.2 ppm; IR (KBr): 1705, 1367,
1219, 1142, 1107, 775, 606 cm-1; HRMS (EI) m/z: calcd for
C8H5O3F3S [M]+ 237.9912, Found: 237.9904.
1
title compound 3g (712 mg, 56%) as a yellow solid. H NMR
(300 MHz, CDCl3) δ: 8.14 (d, J = 8.1 Hz, 1H), 8.02 (d, J = 6.9
Hz, 1H), 7.87–7.82 (m, 1H), 7.75–7.70 (m, 1H), 5.45 (s, 2H)
ppm; 19F NMR (282 MHz, CDCl3) δ: −77.9 (s, 3F) ppm; 13C
NMR (150.9 MHz, acetone-d6) δ: 120.2 (q, J = 326.3 Hz), 129.7,
130.9, 132.5, 133.4, 136.0 ppm, one carbon could not observed;
IR (KBr): 3645, 1360, 1215, 1144, 764, 687, 607 cm-1; HRMS
(EI) m/z: calcd for C7H6BO4F3S [M]+ 254.0032, Found:
254.0036.
2.16. Phenyl(2-((trifluoromethyl)sulfonyl)phenyl)methanone (2l)
According
to
the
general
procedure,
2,2,6,6-
tetramethylpiperidine (255 µL, 1.50 mmol) in dry THF (5.0 mL),
n-BuLi (1.30 M solution in hexane, 1.15 mL, 1.50 mmol),
phenyltriflone 1 (210 mg, 1.00 mmol) and PhCOCl (232 µL, 2.00
mmol) gave the title compound (220 mg, 70%) as a yellow solid.
1H NMR (300 MHz, CDCl3) δ: 8.17 (d, J = 7.8 Hz, 1H), 7.92–
7.87 (m, 1H), 7.81–7.73 (m, 3H), 7.63–7.58 (m, 1H), 7.51–7.46
(m, 3H) ppm; 19F NMR (282 MHz, CDCl3) δ: −77.4 (s, 3F) ppm;
13C NMR (150.9 MHz, CDCl3) δ: 119.5 (q, J = 326.9 Hz), 128.6,
128.9, 129.7, 130.0, 130.4, 132.8, 134.0, 136.0, 136.2, 143.3,
193.4 ppm; IR (KBr): 1680, 1369, 1273, 1213, 1146, 1113, 930,
773, 708, 606 cm-1; HRMS (EI) m/z: calcd for C14H9O3F3S [M]+
314.0225, Found: 314.0211.
2.12. 1-Allyl-2-((trifluoromethyl)sulfonyl)benzene (2h)
According
to
the
general
procedure,
2,2,6,6-
tetramethylpiperidine (255 µL, 1.50 mmol) in dry THF (5.0 mL),
n-BuLi (1.30 M solution in hexane, 1.15 mL, 1.50 mmol),
phenyltriflone 1 (210 mg, 1.00 mmol) and allyl bromide (173 µL,
2.00 mmol) gave the title compound (86.6 mg, 35%) as yellow
1
oil. H NMR (300 MHz, CDCl3) δ: 8.03 (d, J = 7.8 Hz, 1H),
7.69–7.64 (m, 1H), 7.46–7.40 (m, 2H), 5.94–5.85 (m, 1H), 5.09–
5.01 (m, 2H), 3.79 (d, J = 6.0 Hz, 2H) ppm; 19F NMR (282 MHz,
CDCl3) δ: −78.8 (s, 3F) ppm; 13C NMR (150.9 MHz, CDCl3) δ:
37.0, 117.5, 119.6 (q, J = 326.8 Hz), 127.5, 129.5, 132.8, 133.3,
135.7, 136.4, 144.2 ppm; IR (KBr): 1365, 1213, 1144, 920, 762,
698, 606 cm-1; HRMS (EI) m/z: calcd for C10H9O2F3S [M]+
250.0275, Found: 250.0277.
2.17. 2-((Trifluoromethyl)sulfonyl)-1,1'-biphenyl (2m)
The mixture of 2b (370 mg, 1.10 mmol), phenyl boronic acid
(122 mg, 1.00 mmol), Pd(PPh3)4 (35.0 mg, 0.03 mmol) in EtOH
(5.0 mL) was refluxed for 6h. Saturated NH4Cl aq was added to
the mixture and the mixture was extracted with EtOAc. The
organic layer was separated and the aqueous layer was extracted
with Et2O. The combined organic layer was washed with brine,
dried with Na2SO4, and concentrated under reduced pressure. The
residue was purified by silica gel column chromatography to give
2.13. 1-Benzyl-2-((trifluoromethyl)sulfonyl)benzene (2i)
According
to
the
general
procedure,
2,2,6,6-
tetramethylpiperidine (255 µL, 1.50 mmol) in dry THF (5.0 mL),
n-BuLi (1.30 M solution in hexane, 1.15 mL, 1.50 mmol),
phenyltriflone 1 (210 mg, 1.00 mmol) and BnBr (237 µL, 2.00
1
the title compound (131 mg, 46%) as a white solid. H NMR
(300 MHz, CDCl3) δ: 8.22 (d, J = 8.1 Hz, 1H), 7.83–7.77 (m,
1H), 7.69–7.63 (m, 1H), 7.47–7.26 (m, 6H) ppm; 19F NMR (282
MHz, CDCl3) δ: −78.0 (s, 3F) ppm; 13C NMR (150.9 MHz,
CDCl3) δ: 119.6 (q, J = 327.0 Hz), 127.3, 128.3, 128.6, 129.4,
1
mmol) gave the title compound (168 mg, 56%) as yellow oil. H
NMR (300 MHz, CDCl3) δ: 8.15 (d, J = 7.8 Hz, 1H), 7.66 (dd, J
= 7.2, 6.9 Hz, 1H), 7.49 (dd, J = 7.8, 7.5 Hz, 1H), 7.35–7.17 (m,

6
Tetrahedron
ACCEPTED MANUSCRIPT
(d) Werner, G.; Butenschön, H. Eur. J. Org. Chem. 2012, 3132–
3141;
(e) Kawai, H.; Yuan, Z.; Tokunaga, E.; Shibata, N. Org. Lett.
2012, 14, 5330–5333;
129.7, 133.0, 133.9, 135.7, 137.5, 145.9 ppm; IR (KBr): 1684,
1369, 1215, 1144, 1119, 1074, 764, 604 cm-1; HRMS (EI) m/z:
calcd for C13H9O2F3S [M]+ 286.0275, Found: 286.0290.
(f) Xu, X.-H.; Taniguchi, M.; Azuma, A.; Liu, G. K.; Tokunaga,
E.; Shibata, N. Org. Lett. 2013, 15, 686–689;
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5809;
(i) Kawai, H.; Sugita, Y.; Tokunaga, E.; Sato, H.; Shiro, M.;
Shibata, N. ChemistryOpen 2014, 3, 14–18;
(j) Aithagani, S. K.; Yempalla, K. R.; Munagala, G.;
Vishwakarma, R. A.; Singh, P. P. RSC Adv. 2014, 4, 50208–
50211;
(k) Okusu, S.; Hirano, K.; Tokunaga, E.; Shibata, N.
ChemistryOpen 2015, 4, 581–585;
(l) Matsuzaki, K.; Okuyama, K.; Tokunaga, E.; Saito, N.; Shiro,
M.; Shibata, N. Org. Lett. 2015, 17, 3038–3041;
(m) Huang, Z.; Wang, C.; Tokunaga, E.; Sumii, Y.; Shibata, N.
Org. Lett. 2015, 17, 5610–5613;
(n) Xie, F.; Zhang, Z.; Yu, X.; Tang, G.; Li, X. Angew. Chem., Int.
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7658–7665;
2.18. 1-Azido-2-((trifluoromethyl)sulfonyl)benzene (2n)
The mixture of 2c (145 mg, 0.5 mmol), NaN3 (98.0 mg, 3.0
mmol), CuI (10.0 mg, 0.05 mmol) in acetone-H2O (4.0 mL, 3:1)
was stirred at 60 °C for 12h. CuI (10.0 mg, 0.05 mmol) was
added to the mixture and the mixture was stirred at 80 °C for 2h.
Removal of the solvent in vacue and the residue was dissolved in
H2O and Et2O. The organic layer was separated and the aqueous
layer was extracted with Et2O. The combined organic layer was
washed with brine, dried with Na2SO4, and concentrated under
reduced pressure. The residue was purified by silica gel column
chromatography to give the title compound (66.7 mg, 53%) as
1
brown oil. H NMR (300 MHz, CDCl3) δ: 8.09 (d, J = 7.8 Hz,
1H), 7.86–7.81 (m, 1H), 7.44–7.37 (m, 2H) ppm; 19F NMR (282
MHz, CDCl3) δ: −77.1 (s, 3F) ppm; 13C NMR (150.9 MHz,
CDCl3) δ: 119.8 (q, J = 326.7 Hz), 120.5, 121.8, 125.2, 134.2,
137.8, 142.5 ppm; IR (KBr): 2129, 1587, 1473, 1369, 1290,
1213, 1136, 1109, 1055, 731, 650, 603 cm-1; HRMS (EI) m/z:
calcd for C7H4N3O2F3S [M]+ 250.9976, Found: 250.9988.
(p) Huang, Z.; Okuyama, K.; Wang, C.; Tokunaga, E.; Li, X.;
Shibata, N. ChemistryOpen 2016, 5, 188–191;
(q) Wang, F.; Yu, X.; Qi, Z.; Li, X. Chem. Eur. J. 2016, 22, 511–
516;
Acknowledgments
(r) Smyth, L. A.; Phillips, E. M.; Chan, V. S.; Napolitano, J. G.;
Henry, R.; Shekhar, S. J. Org. Chem. 2016, 81, 1285–1294;
(s) Qiu, D.; He, J.; Yue, X.; Shi, J.; Li, Y. Org. Lett. 2016, 18,
3130–3133;
(t) Huang, Z.; Jia, S.; Wang, C.; Tokunaga, E.; Sumii, Y.; Shibata,
N. J. Fluorine Chem. 2017, 198, 61–66;
This research is partially supported by JSPS KAKENHI Grant
Number JP 18H02553 as a Grant-in-Aid for Scientific Research
(B).
(u) Wei, W.; Cui, H.; Yang, D.; Yue, H.; He, C.; Zhang, Y.; Wang,
H. Green Chem. 2017, 19, 5608–5613;
Supplementary data
(v) Das, P.; Shibata, N. J. Org. Chem. 2017, 82, 11915–11924;
(w) Zhao, X.; Huang, Y.; Qing, F.-L.; Xu, X.-H, RSC Adv. 2017, 7,
47–50;
(x) Das, P.; Gondo, S.; Tokunaga, E.; Sumii, Y.; Shibata, N. Org.
Lett. 2018, 20, 558–561;
Supplementary data related to this article can be found at
https://doi.org/10.1016/j.tet.xxxxxxx
(y) Sumii, Y.; Sugita, Y.; Tokunaga E.; Shibata, N.
ChemistryOpen 2018, 7, 204–211;
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