New utility of electrophilic trifluoromethylthiolation reagents for the synthesis of a variety of triflones

Article abstract of DOI:10.1016/j.jfluchem.2016.12.012

The synthesis of various triflones has been achieved using electrophilic trifluoromethylthiolation reagents as building blocks, and not as reagents. Trifluoromethanesulfonyl hypervalent iodonium ylide 1a and its diazo-analogue 1b are well-known reagents for electrophilic trifluoromethylthiolation of nucleophiles under copper catalysis. In this paper, we disclose another facet of these reagents as synthetic building blocks of triflones via intramolecular rearrangements. The diazo-compound 1b was converted into amide-, ester- and enol-triflones via the Wolff rearrangement followed by a nucleophilic reaction with aryl- and alkylamines, amino acids, alcohols, and silyl enol ether in heated conditions. On the other hand, the ylide reagent 1a was converted into vinyl triflone via an intramolecular I-O-rearrangement under heat. More interestingly, both 1a and 1b reacted with acetonitrile to give an oxazole-triflone under copper catalysis.

Full text of DOI:10.1016/j.jfluchem.2016.12.012

G Model
FLUOR 8920 No. of Pages 6
Journal of Fluorine Chemistry xxx (2016) xxx–xxx
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Full Paper
New utility of electrophilic trifluoromethylthiolation reagents for the
synthesis of a variety of triflones
Zhongyan Huang, Shichong Jia, Chen Wang, Etsuko Tokunaga, Yuji Sumii, Norio Shibata*
Department of Nanopharmaceutical Sciences, Nagoya Institute of Technology, Gokiso, Showa-ku, Nagoya 466-8555, Japan
A R T I C L E I N F O
A B S T R A C T
Article history:
Received 1 November 2016
Received in revised form 6 December 2016
Accepted 7 December 2016
Available online xxx
The synthesis of various triflones has been achieved using electrophilic trifluoromethylthiolation
reagents as building blocks, and not as reagents. Trifluoromethanesulfonyl hypervalent iodonium ylide
1a and its diazo-analogue 1b are well-known reagents for electrophilic trifluoromethylthiolation of
nucleophiles under copper catalysis. In this paper, we disclose another facet of these reagents as synthetic
building blocks of triflones via intramolecular rearrangements. The diazo-compound 1b was converted
into amide-, ester- and enol-triflones via the Wolff rearrangement followed by a nucleophilic reaction
with aryl- and alkylamines, amino acids, alcohols, and silyl enol ether in heated conditions. On the other
hand, the ylide reagent 1a was converted into vinyl triflone via an intramolecular I-O-rearrangement
under heat. More interestingly, both 1a and 1b reacted with acetonitrile to give an oxazole-triflone under
copper catalysis.
Keywords:
Fluorine
Trifluoromethanesulfonyl
Triflone
Trifluoromethylthiolation
Rearrangement
©
2016 Elsevier B.V. All rights reserved.
1
. Introduction
trifluoromethylthiolation of aromatics by 1 has also been achieved
in the presence of copper catalysts. During our study of the
trifluoromethylthiolation reactions using 1, we noticed that
reagent 1 has potential not only for electrophilic transfer
trifluoromethylthiolation under copper catalysis, but also as
attractive building blocks of triflones under catalyst-free con-
Organofluorine compounds have commanded a central posi-
tion in agrochemical and pharmaceutical research [1–3]. A variety
of fluorine-containing drugs have been registered in data-bases,
and they can be categorized according to the functional groups in
their molecular structures such as fluorine (F), trifluormethyl (CF
and difluoromethyl (CF H) groups, among others. In recent
decades, the trifluoromethylthio (SCF ) group has gained increas-
ing significance due to its impressive lipophilicity but similar
electron-withdrawing property to the CF group, which is highly
advantageous as this alternation improves the cell-permeability of
the original CF -containing drugs [4–19]. Shelf-stable electrophilic
3
)
ditions. Namely, pharmaceutically attractive b-lactam-triflones
2
were directly synthesized by the reaction of 1b with imines in
catalyst-free thermal conditions [34]. In situ generation of ketene-
triflone from 1b via the Wolff-rearrangement followed by
Staudinger [2 + 2] cycloaddition with imines is proposed for this
reaction mechanism, resulting in the formation of multi-substi-
3
3
3
tuted b-lactam-triflones in good to high yields with high
reagents for trifluoromethylthiolation have become widely devel-
oped as reagents for the preparation of trifluoromethylthio
compounds, and should be useful for the late stage functionaliza-
tion of target compounds [20–27]. Our group has also contributed
to this area by disclosing two novel reagents, trifluoromethane-
sulfonyl hypervalent iodonium ylide 1a and its diazo-analogue 1b
diastereoselectivity (Fig. 1a).
Triflones are compounds that contain a trifluoromethanesul-
fonyl (triflyl, SO
electron-withdrawing effect of the SO
stronger than that of the nitro (NO ) group. While NO
hydrophilic, SO CF is lipophilic [39,40]. The uniqueness of the
SO CF group also caught our attention for several years as a
2
CF
3
) group in their structures [35–38]. The
CF group is slightly
is slightly
2
3
2
2
2
3
[28–33]. Both reagents have been revealed as being effective for
2
3
electrophilic trifluoromethylthiolation reactions of enamines,
potential functional group to produce drug candidates, resulting in
the development of the efficient synthesis of heteroaryl triflones
containing isoxazoles, pyrazoles, pyrazolo[5,1-a]isoquinolines,
indoles, pyridines, and quinolines [41–44]. The synthesis of vinyl
triflones was also reported [45]. As part of our ongoing studies on
the synthesis of triflones and electrophilic trifluoromethylthiola-
tion reagents, we disclose herein the synthesis of amide-, ester-
indoles,
b-keto esters, pyrroles, silyl enol ethers, allylsilanes and
allyl
alcohols under copper catalysis. Coupling-type
*
Corresponding author.
E-mail address: nozshiba@nitech.ac.jp (N. Shibata).
http://dx.doi.org/10.1016/j.jfluchem.2016.12.012
022-1139/© 2016 Elsevier B.V. All rights reserved.
0
Please cite this article in press as: Z. Huang, et al., New utility of electrophilic trifluoromethylthiolation reagents for the synthesis of a variety of
triflones, J. Fluorine Chem. (2016), http://dx.doi.org/10.1016/j.jfluchem.2016.12.012

G Model
FLUOR 8920 No. of Pages 6
2
Z. Huang et al. / Journal of Fluorine Chemistry xxx (2016) xxx–xxx
Fig. 2. 19F NMR charts of diazo-triflone 1b and ketene B in CDCl
using C
. b) Neat 1b
3
6 6
F
(
d
= 162.2 ppm) as the internal standard. a) diazo-triflone 1b in CDCl
3
ꢀ
was heated at 120 C for 30 min under N
2
atmosphere, after cooled to room
was added, then NMR analysis. c) Neat 1b was heated at
atmosphere, after cooled to room temperature CDCl
temperature 1b and CDCl
3
ꢀ
120 C for 30 min under N
2
3
was added, then NMR analysis.
Fig. 1. Electrophilic trifluoromethylthiolation reagents 1 and their alternative
utility for the synthesis of triflones.
ꢀ
of the reaction. Namely, 1b was first heated in toluene at 100 C for
1
h, then 2a was added. This two-step, one-pot procedure
ꢀ
significantly improved the yield of 3a to 75% at 100 C. The yield
triflones 3, enol-triflone 5, vinyl triflone 7 and oxazole triflone 8
from electrophilic trifluoromethylthiolation reagents 1 as triflone-
containing building blocks (Fig. 1b).
of 2a decreased sharply to 25% when the reaction was conducted at
ꢀ
8
0 C. Increasing the ratio of 2a with 1b to 1:2 and in toluene
(
0.03 M) under this two-step, one-pot reaction procedure gave a
good yield of 3a, 86%. The formation of ketene was ascertained by
an F NMR experiment (Fig. 2) and IR spectra [34].
2. Results and discussion
19
With the optimal reaction conditions in hand, a series of
nucleophiles 2 were next examined for transformation to the
corresponding triflones 3 (Scheme 1). Substituted anilines with
halogen such as chloro 2b, bromo 2c, iodo 2d, electron-donating
We first examined the reaction of diazo-reagent 1b with aniline
2a) (Table 1). The treatment of 2a with 1b in toluene at 100 C
ꢀ
(
afforded
N,2-diphenyl-2-((trifluoromethyl)sulfonyl)acetamide
(
3a) in 48% yield (entry 1). This expected the production of this
2
OMe 2e and electron-withdrawing NO 2f were well-tolerated to
compound because of the nucleophilic reaction of 2a with in-situ
generated ketene triflone B via the Wolff rearrangement of a
carbene intermediate A, while a considerable amount of
(
2 2 3
((trifluoromethyl)sulfonyl)methyl)benzene, PhCH SO CF ) was
accompanied. Encouraged by initial result, we attempted to
optimize the reaction conditions. An excess amount of 2a in
different solvent conditions, including solvent-free, did not
improve the results (entries 1–9). We next changed the procedure
Table 1
Optimization of reaction conditions of 1b with 2a.
Entry
Molar ratio
a:1b
Solvent
Yield (%)a
2
1
2
3
4
5
6
7
8
9
1:1
1.5:1
3:1
10:1
1:2
1:1
1:1
1:1
1:1
1:1.5
1:1.5
1:2.0
1:2.0
Toluene
Toluene
Toluene
Solvent-free
Toluene
DCE
Dioxane
p-Xylene
Benzene
Toluene
Toluene
Toluene
Toluene
48
48
48
4
33
46
b
47
48
b
40
75
25
82
c
1
0
c,d
1
1
c
1
2
c,e
13
86
a
Reaction conditions: aniline 2a (0.1 mmol for entries 10–13), 1b (0.1 mmol for
ꢀ
19
entries 1–9), solvent (1.0 mL), 100 C for 1 h. Yields were determined by F NMR
spectroscopy with trifluoromethyl benzene as the internal standard.
b
8
1
h.
c
ꢀ
b in toluene (0.1 M) at 100 C for 1 h, then aniline 2a was added, and the
mixture solution was heated for another 2 h.
Scheme 1. Reaction of diazo-triflone 1b with nucleophiles 2. Reaction conditions:
d
e
ꢀ
ꢀ
8
0 C.
diazo-triflone 1b (0.4 mmol), toluene (6.0 mL), 100 C for 1 h, then nucleophiles 2
ꢀ
Toluene (0.03 M).
(0.2 mmol) in 1.0 mL toluene was added, stirred at 100 C for another 2 h.
Please cite this article in press as: Z. Huang, et al., New utility of electrophilic trifluoromethylthiolation reagents for the synthesis of a variety of
triflones, J. Fluorine Chem. (2016), http://dx.doi.org/10.1016/j.jfluchem.2016.12.012

G Model
FLUOR 8920 No. of Pages 6
Z. Huang et al. / Journal of Fluorine Chemistry xxx (2016) xxx–xxx
3
and its derivative. None of the intermolecular products were
detected and corresponding intramolecular products 7 and its
derivative were isolated, respectively (see Scheme S1 in Support-
ing information).
More interestingly, both ylide reagent 1a and diazo-reagent 1b
reacted with acetonitrile in the presence of a catalytic amount of
CuCl to afford 2-methyl-5-phenyl-4-((trifluoromethyl)sulfonyl)
oxazole 8 in 40% and 48% yield, respectively (Scheme 5).
3
. Conclusion
A new utility of two electrophilic trifluoromethylthiolation
Scheme 2. Reaction of diazo-triflone 1b with 4.
reagents 1a and 1b was described. In our previous study, reagents 1
are a powerful source for transfer-trifluoromethylthiolation under
copper catalysis. On the other hand, these two reagents were found
to be useful triflone-containing building blocks, depending on
reaction conditions. The diazo reagent 1b was nicely converted into
a variety of triflones including vinyl-triflone, amide-, ester- and
enol-triflones, and oxazole-triflone are synthesized in one step
from 1 with moderate to excellent yields. The intramolecular
I-O-rearrangement and the Wolff rearrangement triggered by
thermolysis are keys for this transformation.
provide the corresponding amido-triflones 3b–f in high yields.
Secondary aniline, alkylamine, heteroarylamine and amino acids of
glycine and leucine also reacted nicely with 1b to furnish
corresponding acyclic amide-triflones 3g–k in high yields.
Phenethyl alcohol (2l) also reacted with 1b under the same
conditions to furnish ester-triflone 3l in 94% yield.
It should be noted that this reaction was extended to the
reaction with silyl enol ether 4 under the same reaction conditions
to provide enol-triflone 5 in 47% yield (Scheme 2). The enol
structure of 5 was ascertained by the comparison of chemical shift
of vinyl proton with the reported enol compounds [46].
4
. Experimental
All the triflones obtained here have an
a-carbonyl a-phenyl
4
.1. General
triflyl structure. Therefore, the -hydrogen atom is exceptionally
a
acidic and a variety of additional functionalizations at this position
should be possible. Indeed, the chemistry of triflones in alkylation
and conjugated addition are well summarized by Hendrickson
et al. [47]. Manthorpe and co-workers recently investigated the
All reagents were used as received from commercial sources,
unless specified otherwise, or prepared as described in the
literature. Reactions requiring anhydrous conditions were per-
formed in flame-dried glassware under the positive pressure of
nitrogen. Thin-layer chromatography (TLC) was carried out on
reactivity of
a-triflyl esters, amides and ketones in methylation
and allylation reactions [48]. We next examined the fluorination of
triflones 3 to construct a quarter carbon center. Fluorination of
amide-triflone 3a with N-fluorobis(phenylsulfonyl)amine (NFSI) in
1
19
13
0
.25 mm Merck silica-gel (60-F254). H NMR, F NMR and C NMR
1
19
were recorded on either a Varian Mercury 300 ( H at 300 MHz,
at 282 MHz) or on a Bruker-500 ( H at 500 MHz, C at 125 MHz)
spectrometer. Chemical shifts ( ) are reported in parts per million
F
1
13
t
the presence of BuONa provided the corresponding product 7 in
d
92% yield (Scheme 3).
and coupling constants (J) are in hertz. Mass spectra were recorded
on a SHIMAZU LCMS-2020 (ESI–MS). Infrared spectra were
recorded on a JASCO FT/IR-200 spectrometer.
In contrast, the reaction of trifluoromethanesulfonyl hyper-
ꢀ
valent iodonium ylide reagent 1a with 2a in toluene at 100 C did
not give the desired 3a, but tetra-substituted vinyl triflone 7 was
obtained in 9% yield as a mixture of E/Z isomers via an
intramolecular I-O-rearrangement [49]. The yield of 7 was
improved to 35% in the absence of aniline and 52% yield of 7
was finally obtained in dichloroethane (Scheme 4). The intramo-
lecular reaction was confirmed by a crossover experiment using 1a
4
.2. Reaction procedures
4
.2.1. Synthesis of triflones 3 and 5
Diazo-triflone 1b (0.4 mmol, 2.0 equiv) was heated in 6.0 mL
ꢀ
toluene at 100 C for 1 h, nucleophiles 2 or 4 (0.2 mmol,1.0 equiv) in
ꢀ
1
.0 mL toluene was added dropwise, then heated at 100 C for
another 2 h. Solvent was removed under reduced pressure, and the
residue was purified by column chromatography with ethyl
acetate/hexane as the eluent to afford triflones 3 or 5.
Scheme 3. Fluorination of amide-triflone 3a with NFSI.
Scheme 4. Reaction of 1a (0.2 mmol) with or without 2a (0.2 mmol) in toluene or
ꢀ
dichloroethane (6.0 mL) at 100 C for 1 h.
Scheme 5. Reaction of 1a or 1b in MeCN under CuCl catalysis.
Please cite this article in press as: Z. Huang, et al., New utility of electrophilic trifluoromethylthiolation reagents for the synthesis of a variety of
triflones, J. Fluorine Chem. (2016), http://dx.doi.org/10.1016/j.jfluchem.2016.12.012

G Model
FLUOR 8920 No. of Pages 6
4
Z. Huang et al. / Journal of Fluorine Chemistry xxx (2016) xxx–xxx
4
.2.2. Fluorination of amide-triflone 3a
(282 MHz, (CD
3
)
2
CO)
d
ꢁ75.1; IR (KBr) 3384, 3186, 3101, 3071, 2962,
ꢁ1
To a mixture of 3a (0.1 mmol) in 1.5 mL THF under a nitrogen
1698, 1595, 1531, 1363, 1210, 1124 cm ; HRMS (ESI) calcd. for
C H F INNaO S [M + Na] : 491.9354, Found: 491.9369.
15 11 3 3
t
+
atmosphere, BuONa (0.12 mmol) was added, and after the reaction
was stirred at room temperature for 30 min, NFSI (0.11 mmol) was
added in one pot. The reaction was stirred for another 30 min,
quenched with 1 M HCl, and extracted with ether. The organic
solvent was removed under reduced pressure, and the residue was
purified by column chromatography with ethyl acetate/hexane as
the eluent to afford fluorinated product 6.
4.3.5. N-(4-Methoxyphenyl)-2-phenyl-2-((trifluoro-methyl)sulfonyl)
acetamide (3e)
White solids. M.p.: 178–180 C; H NMR (500 MHz, (CD
9.80 (brs, 1H), 7.81 (dd, J = 8.0, 2.0 Hz, 2H), 7.55-7.50 (m, 5H), 6.90
ꢀ
1
3 2
) CO) d
13
(ddd, J = 9.0, 3.0, 2.0 Hz, 2H), 5.97 (s, 1H), 3.77 (s, 3H); C NMR
125 MHz, (CD CO) 159.8, 157.8,131.6, 131.5, 131.3, 129.8, 127.9,
122.3, 120.7 (q, J = 327.4 Hz), 114.9, 71.8, 55.6; F NMR (282 MHz,
(
3
)
2
d
19
4.2.3. Synthesis of vinyl triflone 7
Trifluoromethanesulfonyl hypervalent iodonium ylide 1a
0.2 mmol, 1.0 equiv) was heated in 6.0 mL DCE at 100 C for 1 h.
Solvent was removed under reduced pressure, and the residue was
purified by column chromatography with ethyl acetate/hexane as
the eluent to afford triflone 7.
(CD
3
)
2
CO)
d
ꢁ75.3; IR (KBr) 3329, 3125, 3078, 3012, 2950, 2838,
ꢀ
ꢁ1
(
1671, 1530, 1370, 1216, 1120, 1032 cm ; HRMS (ESI) calcd. for
C H F NNaO S [M + Na] : 396.0493, Found: 396.0492.
16 14 3 4
+
4.3.6. N-(4-Nitrophenyl)-2-phenyl-2-((trifluoromethyl)-sulfonyl)
acetamide (3f)
Colorless crystals. M.p.: 167–168 C; 1H NMR (500 MHz,
ꢀ
4
.2.4. Synthesis of oxazole- triflone 8
To a mixture of 1a (or 1b) (0.2 mmol) in 1.5 mL MeCN under a
(CD
3 2
) CO) d 10.46 (brs, 1H), 8.26 (ddd, J = 9.0, 3.0, 2.0 Hz, 2H),
nitrogen atmosphere, CuCl (0.04 mmol) was added, then the
reaction was performed at room temperature or heated at 90 C for
7.89 (ddd, J = 9.0, 3.0, 2.0 Hz, 2H), 7.81 (dd, J = 8.0, 2.0 Hz, 2H), 7.58-
ꢀ
13
7.53 (m, 3H), 6.09 (s, 1H); C NMR (125 MHz, (CD
3 2
) CO) d 161.2,
1
5 h. Solvent was removed under reduced pressure, and the residue
145.0, 144.3, 131.7, 131.6, 130.0, 126.5, 125.7, 120.7 (q, J = 327.2 Hz),
19
was purified by column chromatography with ethyl acetate/
hexane as the eluent to afford oxzole-triflones 8.
120.6, 72.0; F NMR (282 MHz, (CD
3
)
2
CO)
d
ꢁ75.0; IR (KBr) 3378,
3167, 3098, 3074, 2963, 1706, 1617, 1598, 1557, 1515, 1342, 1208,
ꢁ1
+
1
110 cm ; HRMS (ESI) calcd. for C15
11 3 2 5
H F N NaO S [M + Na] :
4
4
9
(
(
1
.3. Characterization of products
411.0238, Found: 411.0234.
.3.1. N,2-Diphenyl-2-((trifluoromethyl)sulfonyl)acet-amide (3a)
4.3.7. N-Methyl-N,2-diphenyl-2-((trifluoromethyl)-sulfonyl)
ꢀ
1
White solids. M.p.: 145–146 C; H NMR (500 MHz, (CD
3
)
2
CO)
d
acetamide (3g)
1
.96 (brs, 1H), 7.83-7.81 (m, 2H), 7.61-7.60 (m, 2H), 7.55-7.50
Brown oil; H NMR (500 MHz, CDCl
3
)
d
7.38-7.34 (m, 4H), 7.29-
m, 3H), 7.36-7.33 (m, 2H), 7.16-7.13 (m, 1H), 6.03 (s, 1H); 1 C NMR
125 MHz, (CD CO) 160.3, 138.7, 131.6, 131.4, 129.8, 129.8, 127.1,
25.8, 120.8 (q, J = 327.2 Hz), 120.6, 71.9; F NMR (282 MHz,
CD CO)
ꢁ75.2; IR (KBr) 3325, 3132, 3062, 3044, 2965, 1674,
599, 1528, 1443, 1371, 1218, 1120 cm ; HRMS (ESI) calcd. for
3
7.28 (m, 4H), 7.00 (s, 2H), 5.22 (s, 1H), 3.25 (s, 3H); C NMR
(125 MHz, CDCl 161.6, 142.0, 130.6, 130.5, 130.4, 129.5, 129.2,
127.6, 125.8, 119.8 (q, J = 328.5 Hz), 68.3, 38.0; F NMR (282 MHz,
13
3
)
2
d
3
) d
19
19
(
1
C
3
)
2
d
CDCl
3
)
d
ꢁ73.9; IR (KBr) 3065, 3036, 2965, 2943, 1673, 1595, 1495,
ꢁ
1
ꢁ1
1372, 1208, 1118 cm ; HRMS (ESI) calcd. for C16
[M + Na] : 380.0544, Found: 380.0546.
H
14
F
3
NNaO
3
S
+
+
15
H F
12 3
NNaO
3
S [M + Na] : 366.0388, Found: 366.0386.
4
.3.2. N-(4-Chlorophenyl)-2-phenyl-2-((trifluoromethyl)-sulfonyl)
acetamide (3b)
Colorless crystals. M.p.: 168–169 C; 1H NMR (500 MHz,
CD CO) 10.05 (brs, 1H), 7.81-7.79 (m, 2H), 7.64 (ddd, J = 9.0,
.0, 2.0 Hz, 2H), 7.55-7.50 (m, 3H), 7.38 (ddd, J = 9.0, 3.0, 2.0 Hz, 2H),
4.3.8. 2-Phenyl-N-(3-phenylpropyl)-2-((trifluoromethyl)-sulfonyl)
acetamide (3h)
ꢀ
White solids. M.p.: 145–146 C; 1H NMR (500 MHz, CDCl
ꢀ
3
)
d
(
3
6
3
)
2
d
7.49-7.47 (m, 2H), 7.43-7.35 (m, 3H), 7.21-7.17 (m, 2H), 7.13-7.10 (m,
1H), 7.06-7.04 (m, 2H), 6.41 (brs,1H), 5.13 (s,1H), 3.31-3.22 (m, 2H),
13
13
.01 (s, 1H); C NMR (125 MHz, (CD
3
)
2
CO)
d
160.5, 137.5, 131.6,
2.54 (t, J = 8.0 Hz, 2H), 1.77 (dddd, J = 8.0, 8.0, 7.0, 7.0 Hz, 2H);
NMR (125 MHz, CDCl
128.5, 126.3, 125.2, 119.9 (q, J = 327.8 Hz), 71.4, 40.3, 33.2, 30.7;
C
1
31.4, 130.2, 129.9, 129.8, 126.9, 122.2, 120.7 (q, J = 327.4 Hz), 71.9;
3
) d 160.9, 141.0, 130.9, 130.6, 129.5, 128.7,
1
9
19
F NMR (282 MHz, (CD
044, 2977, 1690, 1527, 1493, 1365, 1211, 1108 cm ; HRMS (ESI)
3
)
2
CO)
d
ꢁ75.1; IR (KBr) 3375, 3109, 3067,
F
ꢁ
1
3
NMR (282 MHz, CDCl
2977, 2951, 2923, 2865, 1680, 1520, 1363, 1209, 1117 cm ; HRMS
3
)
d
ꢁ73.4; IR (KBr) 3376, 3086, 3063, 3029,
+
ꢁ1
calcd. for C15
H11ClF
3
NNaO
3
S [M + Na] : 399.9998, Found: 399.9995.
+
(
18 3 3
ESI) calcd. for C18H F NNaO S [M + Na] : 408.0857, Found:
4.3.3. N-(4-Bromophenyl)-2-phenyl-2-((trifluoromethyl)-sulfonyl)
408.0858.
acetamide (3c)
Colorless crystals. M.p.: 192–193 C; 1H NMR (500 MHz,
ꢀ
4.3.9. 2-Phenyl-N-(4-phenylthiazol-2-yl)-2-((trifluoro-methyl)
sulfonyl)acetamide (3i)
(
3
CD
3
)
2
CO)
d
10.06 (brs, 1H), 7.81-7.79 (m, 2H), 7.59 (ddd, J = 9.0,
13
White solids. M.p.: 165–166 C; 1H NMR (500 MHz, CDCl
ꢀ
.0, 2.0 Hz, 2H), 7.55-7.50 (m, 5H), 6.01 (s, 1H); C NMR (125 MHz,
3
) d
(
1
CD
3
)
2
CO)
d
160.5, 137.9, 132.8, 131.5, 131.4, 129.8, 126.9, 122.5,
12.26 (brs, 1H), 7.81-7.79 (m, 2H), 7.44-7.41 (m, 2H), 7.36 (tt, J = 7.5,
2.0 Hz, 1H), 7.29-7.26 (m, 2H), 7.14 (t, J = 7.5 Hz, 2H), 7.14
19
20.7 (q, J = 327.6 Hz), 117.9, 71.9; F NMR (282 MHz, (CD
75.1; IR (KBr) 3377, 3098, 3065, 3042, 2975, 1695, 1597, 1526,
490, 1364, 1210, 1108 cm
3
)
2
CO)
d
13
ꢁ
(d, J = 7.5 Hz, 2H), 4.70 (s, 1H); C NMR (125 MHz, CDCl
3
) d
ꢁ1
1
;
HRMS (ESI) calcd. for
159.8, 159.4, 149.4, 133.4, 130.9, 130.5, 129.8, 129.3, 129.2, 126.0,
+
19
C
15
H
11BrF
3
NNaO
3
S [M + Na] : 443.9493, Found: 443.9499.
3
123.9, 119.5 (q, J = 328.5 Hz), 109.4, 70.9; F NMR (282 MHz, CDCl )
d
ꢁ73.0; IR (KBr) 317.0, 3065, 2942, 2915, 2861, 1697, 1562, 1372,
ꢁ1
4
.3.4. N-(4-Iodophenyl)-2-phenyl-2-((trifluoromethyl)-sulfonyl)
acetamide (3d)
White solids. M.p.: 208–209 C; H NMR (500 MHz, (CD
0.02 (brs, 1H), 7.80 (dd, J = 8.0, 2.0 Hz, 2H), 7.01 (ddd, J = 9.0, 3.0,
.0 Hz, 2H), 7.55-7.50 (m, 3H), 7.46 (ddd, J = 9.0, 3.0, 2.0 Hz, 2H), 6.01
1213, 1113 cm
[M + Na] : 449.0217, Found: 449.0227.
18 13 3 2 3 2
; HRMS (ESI) calcd. for C H F N NaO S
+
ꢀ
1
3 2
) CO) d
1
2
4.3.10. Ethyl 2-(2-phenyl-2-((trifluoromethyl)sulfonyl)-acetamido)
acetate (3j)
13
ꢀ
(
s, 1H); C NMR (125 MHz, (CD
3
)
2
CO)
d
160.4, 138.8, 138.5, 131.5,
White solids. M.p.: 103–104 C; The compound was observed
two mixture rotamers (3j’ and 3j”) in H NMR with a ratio of 2: 1.
19
1
131.4, 129.8, 126.9, 122.7, 120.7 (q, J = 327.6 Hz), 88.7, 71.9; F NMR
Please cite this article in press as: Z. Huang, et al., New utility of electrophilic trifluoromethylthiolation reagents for the synthesis of a variety of
triflones, J. Fluorine Chem. (2016), http://dx.doi.org/10.1016/j.jfluchem.2016.12.012

G Model
FLUOR 8920 No. of Pages 6
Z. Huang et al. / Journal of Fluorine Chemistry xxx (2016) xxx–xxx
5
1
125.8, 121.3, 120.0 (q, J = 325.7 Hz), 68.2; 19F NMR (282 MHz, CDCl
)
3
3
j’: H NMR (500 MHz, CDCl
3
)
d
7.55-7.53 (m, 2H), 7.44-7.36 (m,
3
H), 6.98 (brs,1H), 5.32 (s,1H), 4.17-4.11 (m, 2H), 4.09-3.95 (m, 2H),
d
ꢁ74.1; IR (KBr) 3090, 3063, 3028, 1599, 1579, 1539, 1485, 1356,
13
ꢁ1
1.22-1.18 (m, 3H); C NMR (125 MHz, CDCl
3
)
d
169.1, 161.3, 131.0,
1260, 1213, 1194, 1117 cm ; HRMS (ESI) calcd. for C15
[M + Na] : 476.9245, Found: 476.9241; 7’’ (mix with 7 ): H NMR
(500 MHz, CDCl
(m, 2H), 7.01-6.98 (m, 1H), 6.89-6.87 (m, 2H); C NMR (125 MHz,
CDCl 171.3, 155.1, 132.7, 132.0, 130.5, 129.7, 128.7, 124.9, 119.5,
119.2 (q, J = 326.7 Hz), 72.3; F NMR (282 MHz, CDCl
(KBr) 3086, 3063, 1600, 1581, 1541, 1353, 1278, 1206, 1188, 1118,
1096 cm ; HRMS (ESI) calcd. for C15
476.9245, Found: 476.9249.
H F
10 3
INaO
3
S
+
0
1
1
30.8, 129.5, 124.9, 119.9 (q, J = 328.0 Hz), 71.1, 62.2, 42.1, 14.2; 3j”:
1
H NMR (500 MHz, CDCl
3
)
d
7.55-7.53 (m, 2H), 7.44-7.36 (m, 3H),
3
) d 7.53-7.51 (m, 2H), 7.36-7.32 (m, 3H), 7.18-7.15
13
6.87 (brs, 1H), 5.25 (s, 1H), 4.17-4.11 (m, 2H), 4.09-3.95 (m, 2H),
13
1
.22-1.18 (m, 3H); C NMR (125 MHz, CDCl
30.8, 129.6, 124.8, 119.9 (q, J = 328.0 Hz), 71.2, 62.1, 42.1, 14.2;
NMR (282 MHz, CDCl
ꢁ73.3; IR (KBr) 3293, 3090, 2990, 2947,
747, 1660, 1561, 1370, 1212, 1119 cm ; HRMS (ESI) calcd. for
3
)
d
169.0, 161.1, 131.1,
3
) d
19
19
1
F
3
)
d
ꢁ73.7; IR
3
)
d
ꢁ
1
ꢁ1
+
1
C
H F
10 3
INaO
3
S [M + Na] :
+
13 14
H F
3
NNaO
5
S [M + Na] : 376.0442, Found: 376.0449.
4
.3.11. Ethyl 3-methyl-2-(2-phenyl-2-((trifluoromethyl)-sulfonyl)
4.3.16. 2-Methyl-5-phenyl-4-((trifluoromethyl)sulfonyl)-oxazole (8)
ꢀ
1
acetamido)butanoate (3k)
White solids. M.p.: 61–62 C; H NMR (300 MHz, CDCl
3
)
d
7.87
(dd, J = 8.1, 1.5 Hz, 2H), 7.56-7.48 (m, 3H), 2.62 (s, 3H); C NMR
(125 MHz, CDCl 161.4, 159.6, 131.9, 129.0, 128.7, 126.2, 123.6,
119.7 (q, J = 323.7 Hz), 13.8; F NMR (282 MHz, CDCl
(KBr) 3111, 3068, 3006, 2923, 2853, 1599, 1551, 1485, 1372, 1225,
ꢀ
13
White solids. M.p.: 75–76 C; The compound was observed
1
mixture of rotamers and isomers in H NMR with the ratio couldn’t
calculated. H NMR (500 MHz, CDCl
3
) d
1
19
3
)
d
7.55-7.50 (m, 2H), 7.42-7.32
3
)
d
ꢁ77.6; IR
(
m, 3H), 7.04 (brs, 1H), 5.30-5.27 (m, 1H), 4.54-4.50 (m, 1H), 4.18-
ꢁ
1
+
4
.08 (m, 2H), 2.21-2.14 (m, 1H), 1.21-1.18 (m, 3H), 0.90-0.79
1128, 1097 cm ; HRMS (ESI) calcd. for C11
8 3 3
H F NNaO S [M + Na] :
13
(
m, 6H); C NMR (125 MHz, CDCl
3
) d 171.3, 160.5, 130.8, 130.6,
314.0075, Found: 314.0078.
1
29.3, 125.1, 119.8 (q, J = 328.2 Hz), 71.2, 61.9, 58.2, 31.7, 18.9, 17.7,
19
14.2; F NMR (282 MHz, CDCl
3
)
d
ꢁ73.3, ꢁ73.4; IR (KBr) 3340,
Acknowledgements
ꢁ1
3
067, 3036, 2972, 2881, 1742, 1668, 1529, 1368, 1203, 1115 cm
;
+
HRMS (ESI) calcd. for C16
H
20
F
3
NNaO
5
S [M + Na] : 418.0912, Found:
This work was financially supported in part by the Platform for
Drug Discovery, Informatics, and Structural Life Science from the
Ministry of Education, Culture, Sports, Science and Technology
(MEXT) Japan, the Japan Agency for Medical Research and
Development (AMED), the Advanced Catalytic Transformation
(ACT-C) from the Japan Science and Technology (JST) Agency, the
Hoansha Foundation, and the Kobayashi International Scholarship
Foundation. Mr. Zhongyan Huang thanks the Hori Sciences & Arts
Foundation (Japan) for support. Ms. Chen Wang thanks Shaanxi
University of Science & Technology for scholarship to study abroad.
4
18.0914.
4.3.12. Phenethyl 2-phenyl-2-((trifluoromethyl)sulfonyl)-acetate (3l)
ꢀ
1
Colorless crystals. M.p.: 57–58 C; H NMR (500 MHz, CDCl
.57-7.55 (m, 2H), 7.54-7.50 (m, 1H), 7.47-7.44 (m, 2H), 7.32-7.25
m, 3H), 7.19 (d, J = 7.5 Hz, 2H), 5.32 (s, 1H), 4.51 (t, J = 7.0 Hz, 2H),
.02 (t, J = 7.0 Hz, 2H); 13C NMR (125 MHz, CDCl
162.4, 136.7,
30.9, 130.8, 129.4, 129.0, 128.8, 127.0, 124.4, 119.9 (q, J = 328.0 Hz),
3
) d
7
(
3
1
7
3
3
) d
1
9
0.4, 68.0, 34.7; F NMR (282 MHz, CDCl
3
)
d
ꢁ73.6; IR (KBr) 3085,
ꢁ1
030, 3005, 2953, 2877, 1739, 1373, 1213, 1121 cm ; HRMS (ESI)
+
calcd. for C17
H
15
F
3
NaO
4
S [M + Na] : 395.0541, Found: 395.0537.
Appendix A. Supplementary data
4
.3.13. (Z)-4-Hydroxy-1,4-diphenyl-1-((trifluoromethyl)-sulfonyl)
but-3-en-2-one (5)
White solids. M.p.: 112–113 C; H NMR (300 MHz, CDCl
d, J = 7.5 Hz, 2H), 7.66 (d, J = 7.5 Hz, 2H), 7.57 (t, J = 7.5 Hz, 1H), 7.50-
.43 (m, 5H), 6.38 (s, 1H), 5.38 (s, 1H); 13C NMR (125 MHz, CDCl
85.8, 182.0, 133.4, 132.6, 130.7, 130.6, 129.3, 128.8, 127.2, 125.5,
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.jfluchem.
2016.12.012.
ꢀ
1
3
) d 7.86
(
7
3
)
d
References
1
1
19.8 (q, J = 327.2 Hz), 96.9, 73.9; 1 F NMR (282 MHz, CDCl
9
[1] T. Hiyama, Organofluorine Compounds: Chemistry and Properties, Springer,
3
)
d
;
ꢁ
1
Berlin, 2000.
ꢁ
73.4; IR (KBr) 3424, 3066, 2965,1601, 1570,1365,1211, 1117 cm
[2] P. Kirsch, Modern Fluoroorganic Chemistry: Synthesis, Reactivity,
+
13 3 4
HRMS (ESI) calcd. for C17H F NaO S [M + Na] : 393.0384, Found:
Applications, Wiley-VCH Weinheim, Germany, 2004.
[
[
[
3] K. Uneyama, Organofluorine Chemistry, Blackwell Oxford, U.K, 2006.
4] D. O’Hagan, Chem. Soc. Rev. 37 (2008) 308–319.
5] T. Liang, C.N. Neumann, T. Ritter, Angew. Chem. Int. Ed. 52 (2013) 8214–8264.
3
93.0384.
4
.3.14. 2-Fluoro-N,2-diphenyl-2-((trifluoromethyl)-sulfonyl)
[6] W. Zhu, J. Wang, S. Wang, Z. Gu, J.L. Acena, K. Izawa, H. Liu, V.A. Soloshonok, J.
Fluorine Chem. 167 (2014) 37–54.
[7] J. Wang, M. Sánchez-Roselló, J.L. Aceña, C. Pozo, A.E. Sorochinsky, S. Fustero, V.
A. Soloshonok, H. Liu, Chem. Rev. 114 (2014) 2432–2506.
[8] E.P. Gillis, K.J. Eastman, M.D. Hill, D.J. Donnelly, N.A. Meanwell, J. Med. Chem. 58
(2015) 8315–8359.
acetamide (6)
White solids. M.p.: 105–106 C; H NMR (300 MHz, (CD
ꢀ
1
3
)
2
CO)
d
10.23 (brs, 1H), 7.95 (d, J = 7.5 Hz, 2H), 7.72-7.60 (m, 5H), 7.37
13
(
(
1
t, J = 7.5 Hz, 2H), 7.22 (t, J = 7.5 Hz, 1H); C NMR (125 MHz,
CD CO) 159.1 (d, J = 18.7 Hz), 136.6, 132.0, 129.0 (d, J = 2.5 Hz),
26.8 (d, J = 8.7 Hz), 125.9 (d, J = 7.5 Hz), 125.7, 120.9, 120.8, 120.3
[
9] A.J. Cresswell, S.G. Davies, P.M. Roberts, J.E. Thomson, Chem. Rev. 115 (2015)
66–611.
10] D. O’Hagan, H. Deng, Chem. Rev. 115 (2015) 634–649.
[11] J. Charpentier, N. Früh, A. Togni, Chem. Rev. 115 (2015) 650–682.
3
)
2
d
5
[
19
(
(
2
q, J = 330.0 Hz), 107.0 (d, J = 121.2 Hz);
CD CO)
923, 1686, 1598, 1532, 1449, 1386, 1211, 1118 cm ; HRMS (ESI)
F NMR (282 MHz,
[
[
[
12] X. Liu, C. Xu, M. Wang, Q. Liu, Chem. Rev. 115 (2015) 683–730.
13] C. Ni, M. Hu, J. Hu, Chem. Rev. 115 (2015) 765–825.
14] X. Yang, T. Wu, R.J. Phipps, F.D. Toste, Chem. Rev. 115 (2015) 826–870.
3
)
2
d
ꢁ70.7 (s, 3F), ꢁ152.1 (m, 1F); IR (KBr) 3312, 3067,
ꢁ1
+
calcd. for C15
H
11
F
4
NNaO
3
S [M + Na] : 384.0293, Found: 384.0301.
[15] S. Fustero, A. Simón-Fuentes, P. Barrio, G. Haufe, Chem. Rev. 115 (2015) 871–
30.
16] T. Ahrens, J. Kohlmann, M. Ahrens, T. Braun, Chem. Rev. 115 (2015) 931–972.
9
[
4
.3.15. (2-Iodo-1-phenoxy-2-((trifluoromethyl)sulfonyl)-vinyl)
benzene (7)
Pale yellow oil. The compound was observed two mixture E/Z
[17] V.G. Nenajdenko, V.M. Muzalevskiy, A.V. Shastin, Chem. Rev. 115 (2015) 973–
1050.
[18] P.R. Savoie, J.T. Welch, Chem. Rev. 115 (2015) 1130–1190.
isomers (7’ and 7’’) in crude 1 F NMR with a ratio of 2.5: 1. 7 : H
NMR (500 MHz, CDCl 7.30-7.27 (m, 1H), 7.24-7.19 (m, 4H), 7.17-
.14 (m, 2H), 7.02 (t, J = 7.5 Hz, 1H), 6.85-6.83 (m, 2H); C NMR
125 MHz, CDCl 176.4, 153.3, 131.0, 130.2, 129.6, 129.3, 127.7,
9
0
1
[19] X.-H. Xu, K. Matsuzaki, N. Shibata, Chem. Rev. 115 (2015) 731–764.
[20] V.N. Boiko, Beilstein J. Org. Chem. 6 (2010) 880–921.
3
)
d
[21] A. Thili, T. Billard, Angew. Chem. Int. Ed. 52 (2013) 6818–6819.
[22] F. Toulgoat, S. Alazet, T. Billard, Eur. J. Org. Chem. (2014) 2415–2428.
13
7
(
[23] S. Alazet, L. Zimmer, T. Billard, Chem. Eur. J. 20 (2014) 8589–8593.
3
) d
Please cite this article in press as: Z. Huang, et al., New utility of electrophilic trifluoromethylthiolation reagents for the synthesis of a variety of
triflones, J. Fluorine Chem. (2016), http://dx.doi.org/10.1016/j.jfluchem.2016.12.012

G Model
FLUOR 8920 No. of Pages 6
6
Z. Huang et al. / Journal of Fluorine Chemistry xxx (2016) xxx–xxx
[38] F. Terrier, E. Magnier, E. Kizilian, C. Wakselman, E. Buncel, J. Am. Chem. Soc.127
[
[
[
24] M. Maeno, N. Shibata, D. Cahard, Org. Lett. 17 (2015) 1990–1993.
25] X. Shao, C. Xu, L. Lu, Q. Shen, Acc. Chem. Res 48 (2015) 1227–1236.
26] P. Zhang, M. Li, X.-S. Xue, C. Xu, Q. Zhao, Y. Liu, H. Wang, Y. Guo, L. Lu, Q. Shen, J.
Org. Chem. 81 (2016) 7486–7509.
(2005) 5563–5571.
[39] C. Hansch, R.M. Muir, T. Fujita, P.P. Maloney, F. Geiger, M. Streich, J. Am. Chem.
Soc. 85 (1963) 2817–2824.
[
27] S. Barata-Vallejo, S. Bonesi, A. Postigo, Org. Biomol. Chem. 14 (2016) 7150–
[40] T. Papp, L. Kollár, T. Kégl, Chem. Phys. Lett. 588 (2013) 51–56.
[41] X.-H. Xu, G.-K. Liu, A. Azuma, E. Tokunaga, N. Shibata, Org. Lett.13 (2011) 4854–
4857.
[42] H. Kawai, Z. Yuan, E. Tokunaga, N. Shibata, Org. Lett. 14 (2012) 5330–5333.
[43] X.-H. Xu, X. Wang, G.-K. Liu, E. Tokunaga, N. Shibata, Org. Lett. 14 (2012) 2544–
2547.
7182.
[
28] Y.-D. Yang, A. Azuma, E. Tokunaga, M. Yamasaki, M. Shiro, N. Shibata, J. Am.
Chem. Soc. 135 (2013) 8782–8785.
[
[
29] Z. Huang, Y.-D. Yang, E. Tokunaga, N. Shibata, Org. Lett. 17 (2015) 1094–1097.
30] S. Arimori, M. Takada, N. Shibata, Org. Lett. 17 (2015) 1063–1065.
[
31] A. Arimori, M. Takada, N. Shibata, Dalton Trans. 44 (2015) 19456–19459.
32] Z. Huang, Y.-D. Yang, E. Tokunaga, N. Shibata, Asian J. Org. Chem. 4 (2015) 525–
27.
33] Z. Huang, K. Okuyama, C. Wang, E. Tokunaga, X. Li, N. Shibata, ChemistryOpen 3
2016) 188–191.
34] Z. Huang, C. Wang, E. Tokunaga, Y. Sumii, N. Shibata, Org. Lett. 17 (2015) 5610–
613.
[44] X.-H. Xu, M. Taniguchi, A. Azuma, G.-K. Liu, E. Tokunaga, N. Shibata, Org. Lett.15
(2013) 686–689.
[45] X.-H. Xu, M. Taniguchi, X. Wang, E. Tokunaga, T. Ozawa, H. Masuda, N. Shibata,
Angew. Chem. Int. Ed. 52 (2013) 12628–12631.
[46] H.-C. Lin, R.-T. Tsai, H.-P. Wu, H.-Y. Lee, G.-A. Lee, Tetrahedron 72 (2016) 184–
191.
[47] J.B. Hendrickson, D.D. Sternbach, K.W. Bair, Acc. Chem. Res 10 (1977) 306–312.
[48] H.I. Kong, M.A. Gill, A.H. Hrdina, J.E. Crichton, J.M. Manthorpe, J. Fluorine Chem.
153 (2013) 151–161.
[
[
[
5
(
5
[
35] W. Sheppard, J. Am. Chem. Soc. 85 (1963) 1314–1318.
[
36] C. Hansch, A. Leo, R.W. Taft, Chem. Rev. 91 (1991) 165–195.
[
37] R. Goumont, E. Kizilian, E. Buncel, F. Terrier, Org. Biomol. Chem. 1 (2003) 1741–
[49] R.M. Moriarty, B.R. Bailey III, O. Prakash, I. Prakash, J. Am. Chem. Soc.107 (1985)
1748.
1375–1378.
Please cite this article in press as: Z. Huang, et al., New utility of electrophilic trifluoromethylthiolation reagents for the synthesis of a variety of
triflones, J. Fluorine Chem. (2016), http://dx.doi.org/10.1016/j.jfluchem.2016.12.012