N-Trifluoromethylthio-dibenzenesulfonimide: A Shelf-Stable, Broadly Applicable Electrophilic Trifluoromethylthiolating Reagent

Article abstract of DOI:10.1021/acs.joc.6b01178

The super electrophilicity of a shelf-stable, easily prepared trifluoromethylthiolating reagent N-trifluoromethylthio-dibenzenesulfonimide 7 was demonstrated. Consistent with the theoretical prediction, 7 exhibits reactivity remarkably higher than that of other known electrophilic trifluoromethylthiolating reagents. In the absence of any additive, 7 reacted with a wide range of electron-rich arenes and activated heteroarenes under mild conditions. Likewise, reactions of 7 with styrene derivatives can be fine-tuned by simply changing the reaction solvents to generate trifluoromethylthiolated styrenes or oxo-trifluoromethylthio or amino-trifluoromethylthio difunctionalized compounds in high yields.

Full text of DOI:10.1021/acs.joc.6b01178

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Article
N-Trifluoromethylthiodibenzenesulfonimide: A Shelf-Stable,
Broadly Applicable Electrophilic Trifluoromethylthiolating Reagent
Panpan Zhang, Man Li, Xiao-Song Xue, Chunfa Xu, Qunchao Zhao,
Yafei Liu, HaoYang Wang, Yinlong Guo, Long Lu, and Qilong Shen
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b01178 • Publication Date (Web): 21 Jul 2016
Downloaded from http://pubs.acs.org on July 25, 2016
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Page 1 of 89
The Journal of Organic Chemistry
N-Trifluoromethylthiodibenzenesulfonimide: A Shelf-Stable, Broadly Applicable Elec-
trophilic Trifluoromethylthiolating Reagent
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Panpan Zhang, Man Li, XiaoꢀSong Xue, * Chunfa Xu, Qunchao Zhao, Yafei Liu, Haoyang
†
†
†,
†,
Wang, Yinlong Guo, Long Lu, * and Qilong Shen *
†
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Acadꢀ
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emy of Sciences, 345 Lingling Road, Shanghai 200032
‡
State Key Laboratory of ElementoꢀOrganic Chemistry, Collaborative Innovation Center of Chemical
Science and Engineer, Nankai University, Tianjin 300071
ABSTRACT: The super electrophilicity of a shelfꢀstable, easily prepared trifluoromethylthiolatꢀ
ing reagent Nꢀtrifluoromethylthioꢀdibenzenesulfonimide 7 was demonstrated. Consistent with
the theoretical prediction, Nꢀtrifluoromethylthioꢀdibenzenesulfonimide 7 exhibits remarkably
higher reactivity than other known electrophilic trifluoromethylthiolating reagents. In the abꢀ
sence of any additive, Nꢀtrifluoromethylthioꢀdibenzenesulfonimide 7 reacted with a wide range
of electronꢀrich arenes and activated heteroarenes under mild conditions. Likewise, reactions
of Nꢀtrifluoromethylthioꢀdibenzenesulfonimide 7 with styrene derivatives can be fineꢀtuned by
simply changing the reaction solvents to generate trifluoromethylthiolated styrenes or oxoꢀ
trifluoromethylthio or aminoꢀtrifluoromethylthio difunctionalized compounds in high yields.
INTRODUCTION
1
With a significantly high Hansch’s hydrophobicity parameter (π = 1.44), electronꢀwithdrawing
trifluoromethylthio group (CF Sꢀ) has been considered as one of privileged fragments that are
3
able to improve drug molecules’ pharmacokinetic and physicochemical properties such as lipꢀ
2
ophilicity and metabolic stability. Drugs and agrochemicals bearing a trifluoromethylthio group
3
4
5
such as coccidiostat medicine Toltrazuril, pesticide Fipronil and anorectic drug Tiflorex (Fig.
1
) have already been on the market. Consequently, in the past several years, great effort has
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been intensively devoted to explore new efficient methods for the incorporation of the trifluoꢀ
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romethylthio group into small molecules.
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Figure 1. Drugs and agrochemicals containing a trifluoromethylthio group.
7ꢀ8
Among many strategies developed for introduction of the trifluoromethylthio group, diꢀ
rect trifluoromethylthiolation using an electrophilic trifluoromethylthiolating reagent represents
one of the most straightforward and promising approaches for the incorporation of the trifluoꢀ
9
romethylthio group into small molecules. In the early 1960s, the first two electrophilic trifluoꢀ
10
romethylthiolating reagents CF SCl and CF SSCF were reported. Yet, the highly toxic nature
3
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11
of both reagents limited their practical applications. Since then, a series of readily prepared,
easy to handle and stable electrophilic trifluoromethylthiolating reagents have been designed
12ꢀ17
and synthesized,
which allowing the efficient incorporation of the trifluoromethylthio group
into small molecules under mild conditions (Fig. 2).
Figure 2. Electrophilic trifluoromethylthiolating reagents.
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In 2013, our group discovered a general method for the preparation of a family of amideꢀ
1
2
based electrophilic trifluoromethylthiolating reagents by treating halogenated amide with Agꢀ
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SCF in CH CN at room temperature.
By using this method, we were able to efficiently
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15b
16b
synthesize Nꢀtrifluoromethylthiosuccinimide 4,
Nꢀtrifluoromethylthiophthalimide 5 and Nꢀ
17a
trifluoromethylthiosaccharin 6. We were thrilled to find that Nꢀtrifluoromethylthiosaccharin 6
is much more electrophilic than Nꢀtrifluoromethylthiophthalimide 5, albeit the only structural difꢀ
ference is that one of the carbonyl group in reagent 5 is replaced by a stronger electronꢀ
withdrawing sulfonyl group in reagent 6. As a logical extension, we envisaged that if a comꢀ
pound with two sulfonyl groups such as (PhSO ) NSCF 7 could be developed, a new trifluoꢀ
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romethylthiolating reagent with much higher reactivity would be created.
On the other hand, to quantitatively compare the electrophilicity of various trifluoromethylꢀ
thiolating reagents, one of us has established a new parameterꢀtrifluoromethylthio cation doꢀ
+
nating ability (Tt DA) through density functional theory calculations. The lower the value of
+
Tt DA, the higher the electrophilicity of the reagent, which fits well with the experimentally obꢀ
18
served electrophilic reactivities of the reagents. An excellent correlation has been observed
+
between the Tt DAs of the reagents and the pK values of the corresponding amides. More
a
+
specifically, the lower the pK of the corresponding amide,the lower Tt DA of the reagent and
a
the higher electrophilicity of the reagent. For example, as the amides vary from succinimide to
19
20
phthalimide and to saccharin, their pK values show a decreasing trend (10.52, 10.06, and
a
21
+
1
.8 ), as well as the Tt DA values of the corresponding reagents 4ꢀ6 (34.9, 33.0 and 17.9 kcal
ꢀ1
22
mol , respectively). Following this trend, considering the pK of (PhSO ) NH (1.45), we preꢀ
a
2 2
+
dicted that (PhSO ) NSCF 7 would exhibit an even lower Tt DA value. Indeed, applying the
2
2
3
+
ꢀ1
same theoretical model to (PhSO ) NSCF 7 gave a Tt DA of 9.8 kcal mol , indicating that
2
2
3
(
PhSO ) NSCF should be much more electrophilic than Nꢀtrifluoromethylthiosaccharin 6
2 2 3
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+
ꢀ1
+
(
Tt DA: 17.9 kcal mol ), and surprisingly even slightly more electrophilic than CF SCl (Tt DA:
3
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ꢀ
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1.1 kcal mol ).
To prove the validity of the theoretical prediction and our instinct rationale about the elecꢀ
trophilicity of (PhSO ) NSCF , in the past two years, we have successfully synthesized
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(
PhSO ) NSCF and systematically studied its reactivity. As described in this paper, our studies
2 2 3
disclosed that, consistent with the theoretical prediction, Nꢀtrifluoromethylthioꢀ
dibenzenesulfonimide 7 exhibits unprecedentedly remarkably higher electrophilicity than other
known electrophilic trifluoromethylthiolating reagents. In the absence of any additive, Nꢀ
trifluoromethylthioꢀdibenzenesulfonimide 7 reacted with a wide range of electronꢀrich arenes
and activated heteroarenes under mild conditions to give the corresponding trifluoromethylthioꢀ
lated compounds in high yields. Likewise, in the absence of any additive, reactions of Nꢀ
o
trifluoromethylthioꢀdibenzenesulfonimide 7 with styrene derivatives at 80 C occurred smoothly
to give trifluoromethylthioalkenes in high yields. In addition, when the same reaction was conꢀ
ducted at room temperature, a formoxyꢀtrifluoromethylthio difunctionalized product was formed
in high yields. Furthermore, the reactions can be fineꢀtuned to generate acetoxyꢀ, hydroxyꢀ or
aminoꢀtrifluoromethylthio difunctionalized compounds in high yields when different solvents
were used. Finally, a dearomative trifluoromethylthiolation reaction took place for reactions of
2
ꢀnaphthol derivatives with reagent 7 in the presence of a Lewis acid catalyst. Initial mechanisꢀ
tic studies for the reaction of formoxyꢀtrifluoromethylthio difunctionalzation of styrene indicated
that the reaction proceeded through a cation intermediate, thus supporting that reagent 7 is a
super electrophilic trifluoromethylthiolating reagent.
RESULTS AND DISCUSSION
+
+
Tt DA Value of N-trifluoromethylthio-dibenzene-sulfonimide 7. The Tt DA parameter was
recently proposed as a quantitative descriptor for the electrophilic trifluoromethylthiolating abilꢀ
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18
+
ity of various reagents. Accordingly, we computed the Tt DA value of Nꢀtrifluoromethylthioꢀ
dibenzenesulfonimide 7 using the same method described in the previous study, and the result
is summarized in Table 1. Notably, Nꢀtrifluoromethylthioꢀdibenzenesulfonimide 7 shows the
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smallest Tt DA value (9.8 kcal mol ) among those reported NꢀSCF reagents. Unexpectedly,
3
+
the Tt DA value of Nꢀtrifluoromethylthioꢀdibenzenesulfonimide 7 is even slightly smaller than
0
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that of CF SCl. These results suggest that, if Nꢀtrifluoromethylthioꢀdibenzenesulfonimide 7
3
could be developed, it would be a powerful electrophilic trifluoromethylthiolating reagent.
+
Table 1. Calculated relative Tt DA values of electrophilic trifluoromethylthiolating reagents.
a
b
Taken from ref. 18, Calculated in this study.
23,24
Preparation of N-Trifluoromethylthio-dibenzene sulfonimide 7.
To verify the theoretical
prediction, we set to synthesize Nꢀtrifluoromethylthioꢀdibenzenesulfonimide 7 and test its
reactivity. It turned out that the preparation of Nꢀtrifluoromethylthioꢀdibenzenesulfonimide 7
was relatively easy and can be accomplished in two steps starting from commercially available
materials. However, the purification of this compound is rather a tedious task. Treatment of
bis(phenylsulfonyl)imide with tertꢀbutyl hypochlorite in methanol at room temperature for 5 min
25
generated Nꢀchloroꢀdibenzenesulfonimide in 73% yield, which was further reacted with 1.2
equivalents of AgSCF in CH Cl for 2 h to form Nꢀtrifluoromethylthioꢀdibenzenesulfonimide 7
3
2
2
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19
in 89% yield, as determined by F NMR spectroscopy (Fig. 3). The main side product in the
reaction mixture (typically 10ꢀ20% impurity) is bis(phenylsulfonyl)imide which is difficult to be
removed. Initial efforts using column chromatography, recrysallization or extraction with
aqueous dilute sodium bicarbonate solution remained fruitless. After many tries, we
discovered that 99% pure Nꢀtrifluoromethylthioꢀdibenzenesulfonimide 7 can be obtained by
multiple extraction of the oily crude mixture with petroleum ether, followed by the removing
petroleum ether under vacuum. The reaction can be easily scaled up to 4.0 g quantities and
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compound 7 was isolated as a white solid in 74% yield. Compound 7 was characterized by H,
13
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C, and F NMR spectroscopies and elemental analysis. The structure of compound 7 was
unambiguously confirmed by Xꢀray analysis of its single crystals (See Supporting Information
for details).
Figure 3. Preparation of Nꢀtrifluoromethylthioꢀdibenzenesulfonimide 7.
NꢀTrifluoromethylthioꢀdibenzenesulfonimide 7, a white crystalline solid, is slightly moisture
sensitive but not air and light sensitive. No detectable decomposition was observed after more
than threeꢀmonth storage in a desiccator on shelf at ambient temperature. Compound 7 is staꢀ
o
ble in solvents such as ClCH CH Cl, toluene, CHCl and CH CN at 80 C for at least 24 h as
2
2
3
3
19
determined by F NMR spectroscopy. Compound 7 is less stable in solvents such as DMF or
DMSO. It was completely decomposed after 24 h in DMF, DMSO or acetone at room temperaꢀ
o
19
ture or 12 h at 80 C as determined by F NMR spectroscopy.
Optimization of Reaction Conditions for Direct Trifluoromethylthiolation of Electron-rich
heteroarene. One of the most straightforward methods for the preparation of trifluoromethylꢀ
thiolated arenes or heteroarenes is the FriedelꢀCraftsꢀtype trifluoromethylthiolation of arenes
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with an electrophilic trifluoromethylthiolating reagent. Typically, a Lewis acid or Br
Ø
nsted acid
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is required to activate the trifluoromethylthiolating reagent.
For example, reactions of a
variety of arenes or heteroarenes such as phenols, indoles, pyrroles with Nꢀ
trifluoromethylthiosaccharin 6 occurred successfully in the presence of 1.0 equivalent of
17a
TMSCl or triflic acid to give the corresponding trifluoromethylthiolated arenes in high yields.
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A problematic substrate of the FriedelꢀCraftsꢀtype trifluoromethylthiolation reaction is benꢀ
zofuran. Under the generally optimized conditions using 1.0 equivalent of triflic acid as the acꢀ
tivator, reaction of 5ꢀbromobenzofuran with Nꢀtrifluoromethylthiosaccharin 6 occurred in less
than 12% yield (Scheme 1, entries 1ꢀ2). With the new reagent inꢀhand, we set to test if it is
electrophilic enough to react with 5ꢀbromobenzofuran. Initially, reaction of 5ꢀbromobenzofuran
with Nꢀtrifluoromethylthioꢀdibenzenesulfonimide 7 was conducted in the presence of 1.0
equivalent of triflic acid in acetonitrile. It was found that the reaction occurred in less than 2%
o
after 6 h at 80 C. To our delight, the same reaction in DMF occurred smoothly to give 3ꢀ
19
trifluoromethylthioꢀ5ꢀbromobenzofuran in 74% yield, as determined by F NMR spectroscopy
Scheme 1, entries 3ꢀ4). Switching the additive from triflic acid to TMSCl led to completely shut
(
down the reaction (Scheme 1, entry 5). Most strikingly, control experiment disclosed that
the triflic acid is not required for the reaction. Reaction of 5ꢀbromobenzofuran with Nꢀ
trifluoromethylthioꢀdibenzenesulfonimide 7 in DMF in the absence of triflic acid occurred in
o
8
3% yield after 6 h at 80 C. The choice of the solvents is crucial for the conversion of the
reaction. Reactions in other common solvents such as DMSO, THF, dioxane, toluene or
ClCH CH Cl occurred in less than 25% yields (Scheme 1, entries 7ꢀ11). Further optimization
2
2
showed that the yield increased to 90% when 2.0 equivalents of reagent 7 were used (Scheme
, entry 12). Finally, the reaction time can be shortened to 1 h without erosion of the yield
1
(
Scheme 1, entry 14). We also attempted to decrease the reaction temperature, however,
o
reaction conducted at 40 C was much slower and occurred in only 62% yield after 6 h
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(
Scheme 1, entry 13). As a comparison, no trifluoromethylthiolated product 3ꢀ
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trifluoromethylthioꢀ5ꢀbromobenzofuran was detected for the reaction of 5ꢀbromobenzofuran
with Nꢀtrifluoromethylthiosaccharin 6 in DMF for 1 h (Scheme 1, entry 15). These results clearꢀ
ly support the theoretical prediction that the electrophilicity of Nꢀtrifluoromethylthioꢀ
dibenzenesulfonimide 7 is much higher than that of Nꢀtrifluoromethylthiosaccharin 6.
0
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Scheme 1. Optimization of conditions for reaction of 5-bromobenzofuran with reagent
7
a,b
.
SCF3
O O O O
Br
Br
conditions
S
S
+
Ph
N
Ph
O
O
SCF3
7
8b
yield
entry
reagent
solvent
additive
%)b
(
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CH CN
TfOH
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3
DMF
TfOH
CH CN
TfOH
ꢀ
3
DMF
DMF
TfOH
74
ꢀ
TMSCl
DMF
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ꢀ
ꢀ
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ꢀ
ꢀ
83
ꢀ
DMSO
THF
25
ꢀ
dioxane
toluene
10
11
12
ꢀ
ClCH CH Cl
ꢀ
2
2
2
c
DMF
90
13
DMF
DMF
DMF
62e
88d
1
4
5
1
ꢀ
a
Reaction conditions: 5ꢀbromobenzofuran (0.1 mmol), reagent 7 (0.15 mmol), additive (0.1 mmol) in 0.5
o
b
19
mL of solvent 80 C for 6 h; Yields were determined by F NMR spectroscopy using trifluoroꢀ
methylbenzene as the internal standard; 2.0 Equivalents of reagent 7 were used; Reaction was conꢀ
ducted for 1 h; Reaction was conducted at 40 C for 6 h.
c
d
e
o
Reaction of N-trifluoromethylthio-dibenzenesulfonimide 7 with electron-rich het-
eroarenes, activated electron-poor heteroarenes and arenes. As summary in Scheme 2,
the reaction conditions optimized for trifluoromethylthiolation of 5ꢀbromobenzofuran turned out
to be quite efficient for trifluoromethylthiolation of a wide range of electronꢀrich heteroarenes
and arenes. Reactions of a variety of heteroarene such as benzofuran, benzothiophene,
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26
benzo[d]thiazole, imidazol(1,2ꢀα)pyridines bearing electron withdrawing groups (bromide,
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
26
cyano, nitro, ester group) and pyrroles all underwent trifluoromethylthiolation in the absence
of any additive in high yields (Scheme 2, 8aꢀg, 8kꢀu, 8vꢀz). Reactions of indoles were even
faster than these heteroarenes. These reactions typically occurred in full conversion after 24 h
at room temperature in CH Cl to give the corresponding trifluoromethylthioindoles in high
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
2
yields (Scheme 2, 8aaꢀ8ae).
Strikingly, activated electronꢀpoor pyridine or pyrimidine with electronꢀdonating substituent
such as a methoxy group reacted with reagent 7 to give the corresponding trifluoromethylthioꢀ
lated compounds in good yields under the current conditions (Scheme 2, 8hꢀj). The same reꢀ
actions with previously reported electrophilic trifluoromethylthiolating reagents 2ꢀ6, however,
occurred in less than 5% yields even in the presence of 1.0 equivalent of Lewis acid or
BrØnsted acid. Reaction of 2,6ꢀdimethoxypyridine with reagent 7 proceeded smoothly to give a
mixture of monoꢀ and diꢀtrifluoromethylthiolated products in roughly 1:1 ratio (Scheme 2, 8h
and 8h’). Likewise, reaction of 5ꢀhydroquinoline with reagent 7 also generated the bisꢀ
trifluoromethylthiolated compound in 55% yield (Scheme 2, 8i). Nevertheless, no trifluoromeꢀ
thylthiolated products were observed when we tried to trifluoromethylthiolate a few other hetꢀ
eroarenes such as 4,6ꢀdimethylpyrimidinꢀ2ꢀol, quinoxalinꢀ2ꢀol, quinolinꢀ2ꢀol. Previously, trifluoꢀ
romethylthiolated pyridine was accessed through reaction of in situ formed pyridyl Grignard
12c
reagent with Billard’s 2nd generation reagent 1ꢀTs.
Encouraged by the excellent reactivity of reagent 7, we next shifted our efforts to trifluoꢀ
romethylthiolate common unactivated arenes, another family of problematic substrates for
FriedelꢀCraftsꢀtype electrophilic trifluoromethylthiolation. Interestingly, under the optimized
conditions, reactions of these arenes with reagent 7 worked but these reactions were slower
Scheme 2. Direct Trifluoromethylthiolation of Electron-Rich Heteroarenes, Activated
a,b
Electron-poor Heteroarenes and Arenes.
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1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
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a
o
Reaction conditions: heteroarene or arene (0.5 mmol), reagent 7 (1.0 mmol), in DMF(2.0 mL) at 80 C
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
b
c
d
for 1 h; Isolated yields; 1.5 Equivalents of reagent 7 (0.75 mmol) were used; Indole (0.3 mmol), reaꢀ
gent 7 (0.36 mmol) in CH Cl (1.5 mL) at room temperature for 24 h; Arene (1.0 mmol), reagent 7 (0.5
mmol) in CH Cl (2.0 mL) at 40 C for 36 h in the presence of 1.2 equivalent triflic acid; Arene (0.5
mmol), reagent 7 (0.6 mmol), in CH Cl (2.0 mL) at 40 C for 36 h in the presence of 0.4 equivalent boꢀ
e
2
2
o
f
2
2
o
2
2
g
o
ron trifluoride etherate. Arene (0.1 mmol), reagent 7 (0.2 mmol), in DMF(0.5 mL) at 80 C for 6 h, the
19
yield was determined by F NMR spectroscopy using trifluoromethylbenzene as the internal standard.
h
o
Arene (0.8 mmol), reagent 7 (0.4 mmol) in CH Cl (2.0 mL) at 40 C for 36 h in the presence of 1.2
2
2
equivalent triflic acid, then the crude product was oxidized by 4.0 equivalent H O in HOAc (2.0 mL) at
2
2
o
i
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
90 C for 9 h; The reaction was conducted on 0.3 mmol scale.
and required longer reaction time. For example, reactions of naphthalene and 1,3,5ꢀ
o
trimethylbenzene in DMF occurred in 42% and 92%, respectively after 6 h at 80 C, as deterꢀ
19
mined by F NMR spectroscopy (Scheme 2, 8ag, 8ai). Reaction of more sterically hindered
triꢀisopropylbenzene, however, occurred to less than 5% conversion. Yet, in the presence 1.2
equivalent of triflic acid, triꢀisopropylbenzene reacted with reagent 7 to give the corresponding
trifluoromethylthiolated product in 87% yield (Scheme 2, 8ah). Similarly, a number of other
common arenes were successfully trifluoromethylthiolated in good yields (Scheme 2, 8afꢀ8ak).
Because the trifluoromethylthiolated arenes derived from 1,3ꢀdimethylbenzene and naphathꢀ
lene were difficult to be purified, these compounds were oxidized to the corresponding sulfoxꢀ
ides 8af and 8ai (Scheme 2, 8af,8ai).
Dearomative Trifluoromethylthiolation of Naphthol Derivatives. The reactions of naphthol
derivatives with regent 7 were different from those of other electron rich arenes. For example,
the formation of a new dearomative trifluoromethylthiolated product 9c instead of the direct
FriedelꢀCraftsꢀtype electrophilic trifluoromethylthiolating product was observed when 1,3ꢀ
o
dimethylnaphthol was reacted with reagent 7 in DMF at 80 C for 1 h. The yield could not be
improved by either elongating the reaction time or increasing reaction temperature. Yet, the
yield of the same reaction could be significantly improved to 95% when a combination of 10
mol% Sc(OTf) and 10 mol% of benzyl version of BOX ligand was used as catalyst (Eq. 1)
3
(See the supporting information for details of the optimization process). Nevertheless, comꢀ
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pound 9a is racemic as determined by chiral HPLC, although an optically pure Lewis acid was
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
used as the catalyst.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Scheme 3. Scope for Dearomative Trifluoromethylthiolation of Naphthol Derivatives
a,b
with Reagent 7.
R1
R SCF
1
3
10 mol% Sc(OTf)3
10 mol% BOXꢀBn
OH
R2
O
R
+ 7
R
o
CH Cl , 40 C, 36 h
2
2
R2
9
Me SCF3
Me SCF3
O
Me SCF3
O
O
Me
Me
9b, 90% (57%c)
9c, 95% (42%c)
9
a, 82%
Me SCF3
O
Me SCF3
O
Me SCF3
O
Me
Ph
Me
Me
Et
9f, 98% (27%c)
9d, 88%
9e, 86%d
OMe
Me SCF3
Me SCF3
Me SCF3
O
O
tBu
O
Bn
g, 99% (30%c)
9h, 75%e
9i, 76%e
9
a
Reaction conditions: naphthol derivative (0.5 mmol), reagent 7 (1.0 mmol), Sc(OTf) (10 mol%), BOXꢀ
3
o
b
c
Bn (10 mol%) in CH Cl (2 mL) at 40 C for 36 h; Isolated yields; Reaction of naphthol derivative (0.1
mmol) and reagent 7 (0.2 mmol) was conducted in DMF (0.5 mL) at 50 C for 12 h and the yield was
determined by F NMR spectroscopy using trifluoromethylbenzene as the internal standard; The reacꢀ
tion was conducted on 0.2 mmol scale; The reactions were conducted on 0.3 mmol scale
2
2
o
19
d
e
.
As summarized in Scheme 3, a few derivatives of naphthol bearing different substituents
could be successfully trifluoromethylthiolated to give the dearomative compounds in excellent
yields. For example, reaction of 1ꢀmethylnaphthalenꢀ2ꢀol or 1,7ꢀdimethylnaphthalenꢀ2ꢀol unꢀ
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derwent dearomative trifluoromethylthiolation to give compound 9a and 9b in 82% and 90%
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
yield, respectively. To the best of our knowledge, the current reaction represents the first
27
dearomative trifluoromethylthiolation reaction, although much more efforts are still needed to
realize the asymmetric version of the reaction.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Direct Trifluoromethylthiolation of Styrene Derivatives. The high reactivity of reagent 7
promotes us to study its reactions with other nucleophiles such as alkenes. We quickly discovꢀ
ered that reaction of styrene derivatives with reagent 7 in DMF generated trifluoromethylthioꢀ
o
lated alkenes after 1 h at 80 C in high yields. The discovery of such a simple and mild condiꢀ
tion for direct trifluoromethylthiolation of alkenes is attractive. Previously, direct trifluoromethylꢀ
thiolation of alkenes with an electrophilic trifluoromethylthiolating reagent has been achieved
28
by a dual photoredox/halide catalysis. Other methods for the preparation of the trifluoromeꢀ
29
thylthiolated alkenes include the trifluoromethylthiolation of alkenyl iodides with CuSCF3 or
copperꢀcatalyzed trifluoromethylthiolation of alkenyl boronic acids with an electrophilic trifluoꢀ
14a,16b,e
romethylthiolating reagent.
As summarized in Scheme 4, a variety of styrene derivatives with different substituted
group can be efficiently trifluoromethylthiolated under the mild reaction conditions. In general,
reaction of styrene derivatives with electronꢀdonating groups reacted much faster than those
with electronꢀwithdrawing groups. For example, reaction of 1ꢀmethylꢀ4ꢀvinylbenzene with reaꢀ
gent 7 afforded (E)ꢀ(4ꢀmethylstyryl)(trifluoromethyl)thioether 10b in 88% yield, while reaction of
19
methyl 4ꢀvinylbenzoate with reagent 7 occurred in less than 10% yield, as determined by
F
NMR spectroscopy. Not only the styrene derivatives reacted highly efficiently, other arylꢀ
substituted alkenes such as 9ꢀvinylanthracene, vinylferrocene, 1ꢀvinylnaphthalene, 1Hꢀindene
or acenaphthylene also reacted with reagent 7 effectively to give the corresponding trifluoroꢀ
methylthiolated alkenes (10mꢀq) in high yields. Likewise, reaction of 1,2ꢀdisubstituted
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Scheme 4. Scope for Direct Trifluoromethylthiolation of Styrene Derivatives with Rea-
gent 7.
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
a
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
a
Reaction conditions: styrene derivative (0.5 mmol), reagent 7 (1.0 mmol) in DMF (2.0 mL) at
0 C for 1 h, isolated yields.
o
8
styrene derivative (E)ꢀ1ꢀmethoxyꢀ4ꢀ(propꢀ1ꢀenꢀ1ꢀyl)benzene with reagent 7 also occurred
o
smoothly after 1 h at 80 C to give the trifluoromethylthiolated alkene as a mixture of two isoꢀ
mers in 2.4 : 1 ratio (Scheme 4, 10t/10t’). Because of the mild conditions of the reactions, varꢀ
ious functional groups such as chloride, fluoride, enolizable ketone, ester, amide, alkyl chloride
or azide are compatible (Scheme 4, 10f, 10hꢀi, 10rꢀs, 10uꢀv). We also tried to extend this diꢀ
rect trifluoromethylthiolation of styrene derivatives to alkyl substituted alkenes. However, the
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19
reactions were messy under the current reaction conditions, as determined by F NMR specꢀ
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
troscopy.
Preliminary Mechanistic Study of The Direct Trifluoromethylthiolating Reaction of
Styrene Derivatives with Reagent 7. Experimentally, we observed that styrene derivatives
with electronꢀdonating groups reacted much faster than those with electronꢀwithdrawing
groups. In addition, the reaction occurred highly regioselectively to give βꢀtrifluoromethylthioꢀ
substituted styrene derivatives. Furthermore, we also observed that reactions of alkylꢀ
substituted alkenes with reagent 7 did occur in full conversion. Yet, a mixture that was difficult
to be separated and identified was generated.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Base on these observations, we tentatively proposed a working mechanism to explain the
different rate and regioselectivity for the direct trifluoromethylthiolation of styrene derivatives,
as shown in Fig. 4. Initially, the electrophilic reagent 7 is attacked by styrene to form benzylic
cation intermediate A or thiiranium intermediate A’, followed by αꢀprotonꢀelimination to
generate compound 10. Since the intermediate A or A’ is stabilized by the electronꢀdonating
group but destabilized by the electronꢀwithdrawing group in the para position of the arenes, a
faster reaction of substrate with an electronꢀdonating group is expected. On the other hand,
the cation formed after the nucleophilic attack of an alkylꢀsubstituted alkene undergoes
elimination from two different αꢀprotons and the cation intermediate may also undergo cationic
rearrangement, thus resulting in a mixture of different products for the reactions of alkylꢀ
substituted alkenes.
To gain some experimental evidences about the proposed mechanism, at the beginning,
we tried to monitor the reaction of 1ꢀmethylꢀ4ꢀvinylbenze with reagent 7 in DMF in a NMR tube
19
by F NMR spectroscopy to find if the cation intermediate can be observed. However, the
o
main peak observed in the reaction mixture after 15 min at 80 C was the
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1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Figure 4. Proposed mechanism for direct trifluoromethylthiolation of styrene derivatives.
trifluoromethylthiolated alkene product. We then monitored the reaction mixture at room temꢀ
perature with the hope that the proton elimination process will be slower at this temperature.
19
To our delight, a new peak at ꢀ41.6 ppm in F NMR spectroscopy appeared in 75% yield.
o
Heating the mixture at 80 C for 1 h formed the trifluoromethylthiolated alkene in roughly 78%
yield. This experiment suggests that the species with a chemical shift at ꢀ41.6 ppm is an interꢀ
mediate toward the final product. To shed light on the structure of this species, we conducted
an electrospray ionization tandem mass spectrometry (ESIꢀMS/MS) experiment. Two major
peaks were detected in the ESIꢀMS spectrum after 1ꢀmethylꢀ4ꢀvinylbenzene with reagent 7 in
DMF was quickly mixed at room temperature. One signal at m/z 147 was assigned to be
+
2DMF—H and the other signal at m/z 292 was assigned to be intermediate Bꢀthe addition of
intermediate A or A’ with a molecule DMF (Fig. 4). ESIꢀMS/MS experiments showed that DMF
can be easily dissociated from intermediate B to form intermediate A or A’(m/z 219). Interestꢀ
ingly, addition of water to the reaction mixture generated 1ꢀ(pꢀtolyl)ꢀ2ꢀ(trifluoromethylthio)ethyl
formate 11c in 78% yield that was formed through hydrolysis of dimethylated carbamate ion B.
These experiments clearly suggest intermediate B is derived from the attack of DMF toward
intermediate A or A’. Overall, these experiments support our mechanistic assumption that the
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reaction is proceeded through a nucleophilic attack of styrene to electrophilic trifluoromethylꢀ
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
thiolating reagent 7.
Scheme 5. Scope for Direct Formoxyꢀ, Acetoxyꢀ, or HydroxyꢀTrifluoromethylthiolation of
a,b
Styrene Derivatives in Different Solvents.
O O O O
OR
S
S
conditions
SCF3
Ar
+
Ph
N
Ph
Ar
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
SCF3
7
11-13
DMF as the solvent, rt, 1 h
O
O
O
O
H
O
H
O
H
SCF3
SCF3
SCF3
R
N
R
R = H, 11a, 91%
F, 11b, 73%
R = Cl, 11e, 67%
OAc, 11f, 86%
S
11i, 64%
Me, 11c, 85%
tBu, 11d, 74%
O
N , 11g, 59%
3
O
H
H
O
H
H
O
N
SCF3
F3CS
O
H
11j, 51%e
O
11h, 74%
O
o
c
HOAc as the solvent, 40 C, 36 h
OAc
OMe OAc
OAc
SCF3
SCF3
MeO
SCF3
SCF3
R
1
2f, 74%
12g, 85%
R = H, 12a, 53%
OAc
Me OAc
Me, 12b, 79%
tBu, 12c, 78%
Ph, 12d, 68%
OMe, 12e, 80%
Me
Me
SCF3
Me
Me
12h, 83%
OAc
12i, 78%
OAc
OAc
SCF3
SCF3
SCF3
S
12l, 63%
12j, 78%
12k, 76%
O
OAc
H
H
H
SCF3
F3CS
OH
1
2m, 87%
OAc
12n, 80%
OH
DMSO as the solvent, rt, 2 hd
OH
SCF3
SCF3 MeO
SCF3
R
R
R = H, 13a, 63%
Me, 13b, 87%
tBu, 13c, 74%
F, 13d, 67%
R = Cl, 13e, 60%
OAc, 13f, 74%
13h, 71%
N , 13g, 73%
3
OH
OH
O
SCF3
N
O
SCF3
1
3i, 84%
13j, 68%
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a
Reaction conditions: alkene (0.5 mmol), reagent 7 (1.0 mmol), in DMF (2.0 mL) at room temperature
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
b
c
o
d
for 1 h; Isolated yields; The reactions were conducted in HOAc (2.0 mL) at 40 C for 36 h; The reacꢀ
tions were conducted in DMSO (2.0 mL) at room temperature for 2 h; Alkene (0.4 mmol) was used
e
.
Direct Formoxy-, Actoxy- or Hydroxy-Trifluoromethylthiolation of Styrene Derivatives in
the Absence of Activator. Compound 11c, the hydrolysis product of intermediate B can be
generally regarded as a product derived from formoxyꢀtrifluoromethylthio difunctionalization of
styrene. Since 1,2ꢀdifunctionalization of alkenes represents one of the most direct, atomꢀ
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
30
economical and synthetically important transformations, we studied this reaction in detail. In
general, styrene derivatives with electronꢀdonating groups reacted smoothly at room temperaꢀ
ture after 1 h to give the corresponding formoxyꢀtrifluoromethylthiolated compounds 11aꢀj in
high yields, as summarized in Scheme 5. Interestingly, other polar solvent such as acetic acid
or DMSO could also react with intermediate A or A’ to generate the corresponding actoxyꢀ, or
hydroxylꢀtrifluoromethylthiolated products 12aꢀn and 13aꢀj in high yields. In these cases, cyclic
alkenes also reacted with reagent 7 to give the corresponding products in high yields (Scheme
5
, 12m, 13i). The hydroxylꢀtrifluoromethylthiolated products are likely derived from hydrolysis
31
of the intermediates formed from the reaction of DMSO with intermediate A or A’. Previously
reported acetoxyꢀtrifluoromethylthio difunctionalization of styrene derivatives typically required
a combination of a catalytic amount of diarylselenide and stoichiometric amount of triflic acid to
17e,23
activate Nꢀtrifluoromethylthiosaccharin 6
or stoichiometric Lewis acid or BrØnsted acid to
12b
activate Billard’s reagent 1.
32
Direct Amino-Trifluoromethylthiolation of Alkenes in the Absence of Activator. Interestꢀ
ingly, when a less polar solvent CH Cl was used as the solvent, reaction of styrene derivaꢀ
2
2
tives with reagent 7 also occurred smoothly to give the corresponding aminoꢀ
trifluoromethylthio difunctionalized products 14aꢀq in synthetically useful yields, although the
reactions were slow and generally required to react in refluxed dichloromethane for 36 h. As
summarized in Scheme 6, styrene derivatives with electronꢀdonating groups reacted in high
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yields (Scheme 6, 14bꢀd, 14gꢀi), while reactions of styrene derivatives with electronꢀ
withdrawing groups occurred much slower and in much lower yields (Scheme 6, 14eꢀf). Furꢀ
thermore, cyclic alkenes or symmetric internal alkene reacted with reagent 7 to generate the
corresponding products as a pair of inseparable diastereomers in high yields (Scheme 6, 14nꢀ
q).
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Scheme 6. Scope for Direct Amino-Trifluoromethylthiolation of Alkenes with Reagent
a,b
7.
O O O O
N(SO Ph)
2 2
CH Cl
2
S
S
2
SCF3
+
Ph
N
Ph
R
R
reflux
36 h
SCF3
7
14
N(SO Ph)2
N(SO2Ph)2
N(SO Ph)
2 2
2
SCF3 Me
SCF3 Me
SCF3
R
Me
14g, 60%
14h, 78%
N(SO Ph)
R = H, 14a, 46%
Me, 14b, 76%
tBu, 14c, 76%
Ph, 14d, 62%
F, 14e, 43%
Br, 14f, 24%
N(SO2Ph)2
SCF3
2
2
SCF3
Cl
O
1
4i, 61%
14j, 31% Me
H
N(SO Ph)
2
2
O
H
H
SCF3
F3CS
N
O
N(SO Ph)
2
2
14k, 46%
14l, 75% (dr = 1: 1)
N(SO Ph)2
(PhO S) N
SCF3
N(SO Ph)
2
2
2
2
2
SCF3
n
SCF3
n = 1, 14n, 93%c
14m, 70%
, 14o, 83%d
, 14p, 62%d
14q, 52%
2
8
a
b
o
Reaction conditions: alkene (0.5 mmol), reagent 7 (1.0 mmol), in CH Cl (2.0 mL) at 50 C for 36 h;
2
2
c
o
d
Isolated yields; 40 C; 1.5 Equivalents of reagent 7 (0.75 mmol) were used
.
Reaction of Other Nucleophiles with N-trifluoromethylthio-dibenzenesulfonimide 7. We
also tried to extend the difunctionlization method of styrenes to other nucleophiles. However,
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the direct nucleophilic substitution products from the reactions of the nucleophiles such as 1Hꢀ
indazoles, amines, thiols or sodium benzenesulfinates with reagent 7 instead of the difunctionꢀ
alization products were obtained, as summarized in Scheme 7. Furthermore, Reactions of stryꢀ
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
rene, reagent 7 with other nucleophiles such as TMSCN or TMSN in different solvents were
3
also studied. In these cases, the reactions were messy.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Scheme 7. Scope for Trifluoromethylthiolation of Different Nucleophiles with Reagent
a,b
7.
O O O O
S
S
conditions
Cl
Nu
Nu SCF3
+
Ph
N
Ph
SCF3
15ꢀ18
7
F
Me
N
N
N
N
N
N
N
N
SCF3
SCF3
SCF3
SCF3
1
1
5a, 69%
15b, 67%
15c, 80%
15d, 51%
Me
N
NHSCF3
SCF3
N
N
NHSCF3
O N
2
SCF3
6a, 94%c
16b, 91%c
SSCF3
16c, 71%
16d, 85%
SSCF3
N
SSCF3
SSCF3 Ph
O
F
F
Br
17a, 85%d
17b, 88%d
17c, 97%d
17d, 85%d
SO SCF3
SO SCF
SO SCF
SO SCF
2
2
3
2
3
2
3
Me
18c, 92%e
Br
NC
1
8a, 80%e
18b, 87%e
O
18d, 92%e
a
o
Reaction conditions: Indazole or amine (0.5 mmol), reagent 7 (0.75 mmol) in DMF (2.0 mL) at 80 C
b
c
for 1 h; Isolated yields. Amine (0.3 mmol), reagent 7 (0.36 mmol) in CH Cl (1.5 mL) at room temperaꢀ
2
2
d
ture for 24 h; Thiol (0.3 mmol), reagent 7 (0.33 mmol) in CH Cl (1.5 mL) at room temperature for 12 h;
2
2
e
Sodium benzenesulfinate (0.6 mmol), reagent 7 (0.30 mmol) in AcOH (1.5 mL) at room temperature
for 12 h
.
Comparison of the Reactivities of N-trifluoromethylthio-dibenzenesulfonimide 7 with
other Electrophilic trifluoromethylthiolating Reagents. From the reactions of reagent 7
with heteroarenes, arenes, styrene derivatives in different solvents, we can clearly see the
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Scheme
8.
Comparison
of
the
Reactivities
of
N-trifluoromethylthio-
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
a
dibenzenesulfonimide 7 with other Electrophilic Trifluoromethylthiolating Reagents.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
a
19
Yields were determined by F NMR spectroscopy using trifluoromethbenzene as the internal standꢀ
ard
.
power of reagent 7 as highly electrophilic trifluoromethylthiolating reagent. To gain more unꢀ
derstanding about the electrophilicity of different electrophilic trifluoromethylthiolating reagents,
we conducted a study to compare the electrophilicities of the known trifluoromethylthiolating
reagents such as reagent 1, and its more powerful analog 1ꢀTs, reagent 3, 5 and 6. The reꢀ
sults for the reactions of these reagents with 5ꢀbromobenzofuran, 4ꢀmethylstyrene or 4ꢀ
methoxystyrene under the optimization conditions developed in this paper were summarized in
Scheme 8. In general, reagents 1, 1ꢀTs, and 5 showed significantly lower reactivities than reaꢀ
gent 7 since no desired trifluoromethylthiolating products were observed for reactions of these
substrates with reagents 1, 1ꢀTs, and 5. Reagent 3 or 6 did react with 4ꢀmethylstyrene but both
reactions were much slower than those with reagent 7. Interestingly, Reagent 3 has a much
+
ꢀ1
worse electrophilicity parameter (Tt DA: 53.7 kcal mol ) than any of the other reagents (9.8ꢀ
ꢀ1
4
3.0 kcal mol ). Yet, more reactive 4ꢀmethoxystyrene reacted with reagent 3 gave correspondꢀ
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+
ing trifluoromethylthiolated alkenes in 83% yield. These results suggest that Tt DAs are more
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
reliable when comparing electrophilicity of the analog electrophilic NꢀSCF reagents. Overall,
3
these experiments clearly suggest the super electrophilicity of reagent Nꢀtrifluoromethylthioꢀ
dibenzenesulfonimide 7 than other NꢀSCF electrophilic trifluoromethylthiolating reagents.
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
CONCLUSION
In summary, we have successfully demonstrated that a new electrophilic reagent Nꢀ
trifluoromethylthioꢀdibenzenesulfonimide 7 is a super electrophilic trifluoromethylthiolating reaꢀ
gent, in consistent with our theoretical prediction. In the absence of any additive, reactions of
Nꢀtrifluoromethylthioꢀdibenzenesulfonimide 7 with a wide range of electronꢀrich arenes and acꢀ
tivated heteroarenes underwent FriedelꢀCraftsꢀtype electrophilic trifluoromethylthiolation under
mild conditions. In the presence of a Lewis acid, reactions of 1ꢀsubstitutedꢀ2ꢀnaphthol derivaꢀ
tives with reagent 7 occurred to give dearomative trifluoromethylthiolation products in high
yields. In addition, in the absence of any additive, reactions of Nꢀtrifluoromethylthioꢀ
o
dibenzenesulfonimide 7 with styrene derivatives in DMF occurred smoothly at 80 C for 1 h to
give the trifluoromethylthiolated alkenes in high yields. Interestingly, the same reaction conꢀ
ducted at room temperature gave formoxyꢀtrifluoromethylthio difunctionalized compounds in
high yields. Furthermore, the reactions can be fineꢀtuned by the changing of the solvents to
generate acetoxyꢀ or hydroxyꢀtrifluoromethylthio difunctionalized compounds in high yields.
Likewise, when the reaction was conducted in less polar solvent dichloromethane, an aminoꢀ
trifluoromethylthio difunctionalization was successfully realized. Overall, as shown in this paꢀ
per, the super electrophilicity of the reagent 7 and the simple, mild reaction conditions of the
reactions involving reagent 7 make it the choice of the reagent for the incorporation of the triꢀ
fluoromethylthio group into small molecules. Improving the purification process of the reagent
and expanding the scopes of this reagent is underway and will be reported in the near future.
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EXPERIMENTAL SECTION
General information
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
All solvents were purified by standard methods. H NMR spectra were recorded on a 500
19
MHz, 400 MHz or 300 MHz spectrometer. F NMR spectra were recorded on a 376 MHz or
13
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
282 MHz spectrometer. C NMR spectra were recorded on a 400 MHz or 500 MHz spectromꢀ
1
13
eter. H NMR and C NMR chemical shifts were determined relative to internal standard TMS
19
at δ 0.0 and F NMR chemical shifts were determined relative to CFCl as inter standard.
3
Chemical shifts (δ) are reported in ppm, and coupling constants (J) are in Hertz (Hz). The folꢀ
lowing abbreviations were used to explain the multiplicities: s = singlet, d = doublet, t = triplet,
19
q = quartet, m = multiplet, br = broad. All reactions were monitored by TLC or F NMR. Flash
column chromatograph was carried out using 300ꢀ400 mesh silica gel at medium pressure. All
reagents were received from commercial sources. Solvents were freshly dried and degassed
according to the purification handbook Purification of Laboratory Chemicals before using.
Preparation of N-trifluoromethylthio-dibenzenesulfonimide 7. To a suspension of Nꢀ
(phenylsulfonyl)benzenesulfonamide (9.0 g, 30 mmol) in MeOH (10 mL) was added tBuOCl
(5.0 mL) quickly. The suspension turned to clear solution and a large amount of white precipiꢀ
tate was formed after a few min. The precipitate was filtered and dried under high vacuum to
1
give NꢀchloroꢀNꢀ(phenylsulfonyl)benzenesulfonamide as a white powder (7.3 g, 73% yield). H
NMR (400 MHz, CDCl , 293 K, TMS) δ 8.09ꢀ8.02 (m, 4 H), 7.77ꢀ7.70 (m, 2 H), 7.63ꢀ7.56 (m,
3
13
1
4 H); C NMR (126 MHz, CDCl , 293 K, TMS) δ 136.6, 135.2, 129.4, 129.3 ppm.
3
A 100 mL roundꢀbottomed flask charged with NꢀchloroꢀNꢀ(phenylsulfonyl) benzenesulfonaꢀ
mide (4.0 g, 12 mmol) and AgSCF (3.0 g, 14 mmol) was added dichloromethane (50 mL).
3
The mixture was stirred vigorously at room temperature for 120 min, then filtered through a
pad of Celite and was washed with dichloromethane (50 mL). The filtrate was concentrated in
vacuo to give a colorless oil. The residue was extracted with petroleum ether (50 mL × 10).
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The solution was combined and the solvent was evaporated under vacuum. The colorless oil
was transferred into a 50 mL roundꢀbottomed flask using 20 mL dichloromethane. The solvent
was evaporated under vacuum. The residue was further dried under high vacuum to give Nꢀ
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
trifluoromethylthioꢀdibenzenesulfonimide 7 as a white solid (> 99% purity, 3.5 g, 74%). H
NMR (400 MHz, CDCl , 293 K, TMS) δ 8.05 (d, J = 8.1 Hz, 4 H), 7.71 (t, J = 7.4 Hz, 2 H), 7.58
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
19
13
(
t, J = 7.7 Hz, 4 H); F NMR (376 MHz, CDCl ) δ ꢀ48.20 (s, 3 F); C NMR (126 MHz, CDCl ,
3
3
2
93 K, TMS) δ 138.0, 135.1, 129.3, 129.2, 127.6 (q, J = 318.8 Hz) ppm. Elemental Analysis for
C H F NO S Calcd: C, 39.29; H, 2.54; N, 3.52; Found: C, 39.30; H, 2.56; N, 3.62.
13
10
3
4 3
General Procedure for Trifluoromethylthiolation of Electron-rich Arenes and Het-
eroarenes (8a-8z)
NꢀTrifluoromethylthioꢀdibenzenesulfonimide 7 (398 mg, 1.0 mmol) was placed into an ovenꢀ
dried Schlenk tube that was equipped with a stirring bar under argon. Benzofuran (59 mg, 0.5
o
mmol) and freshly distilled DMF (2.0 mL) were added. The reaction was stirred at 80 C for 1
h. Distilled water (10.0 mL) and ether (50.0 mL) was added and the organic phase was sepaꢀ
rated. The organic phase was washed with distilled water (10.0 mL × 3). The organic extracts
were dried over anhydrous Na SO and concentrated in vacuo. The residue was purified by
2
4
flash chromatography on silica gel to give 3ꢀtrifluoromethylthioꢀbenzofuran 8a (70 mg, 65%,
eluent: petroleum ether, R = 0.7) as a colorless liquid.
f
General Procedure for Trifluoromethylthiolation of Indoles (8aa-8ae)
A 25 mL ovenꢀdried schlenk tube charged with 5ꢀbromoꢀ3ꢀtrifluoromethylthioꢀ1Hꢀindole (59
mg,
0.3 mmol), Nꢀtrifluoromethylthioꢀdibenzenesulfonimide 7 (144 mg, 0.36 mmol) was added
CH Cl (1.5 mL). The mixture was stirred at room temperature for 24 h. The solvent was reꢀ
2
2
moved under vacuum and the residue was purified by flask column chromatography to give 5ꢀ
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bromoꢀ3ꢀtrifluoromethylthioꢀ1Hꢀindole 8aa (80 mg, 86%, eluent: petroleum ether/ethyl acetate
10:1, R = 0.2) as a white solid.
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
=
f
General Procedure for Trifluoromethylthiolation of Common Arenes (8ag, 8ah, 8aj)
NꢀTrifluoromethylthioꢀdibenzenesulfonimide 7 (199 mg, 0.5 mmol) was placed into an ovenꢀ
dried Schlenk tube that was equipped with a stirring bar under argon. Mesitylene (121 mg, 1.0
mmol), triflic acid (90 mg, 0.6 mmol) and freshly distilled CH Cl (2.0 mL) were added. The reꢀ
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
2
o
action was stirred at 40 C for 36 h. The solvent was removed under vacuum and the residue
was purified by flask column chromatography to give mesityltrifluoromethylthioether 8ag (80
mg, 73%, eluent: petroleum ether, R = 0.8) as a colorless liquid.
f
General procedure for oxidation of compound 8af and 8ai
30% (w/w) Aqueous solution of H O (1.6 mmol, 4.0 equiv) was dropped at room temperature
2
2
onto a solution of the above crude sulfide in acetic acid (2.5 mL). The reaction was stirred at
o
9
0 C for 9 h. The mixture was poured into water (10.0 mL) and extracted with diethyl ether
(
20 mL × 3). The gathered organic phases were washed with water (15 mL), saturated aqueꢀ
ous NaHCO (15 mL × 2) and brine (15 mL), then dried over Na SO The solvent was reꢀ
3
2
4.
moved under vacuum and the residue was purified by flask column chromatography to give
2
,4ꢀdimethylꢀ1ꢀ(trifluoromethylsulfinyl)benzene 8af (32 mg, 35%, eluent: petroleum ether/ether
=
10:1, R = 0.3) as a colorless oil
f
Procedure for Trifluoromethylthiolation of (R)-2,5,7,8-tetramethyl-2-((4R,8R)-4,8,12-
trimethyltridecyl)chroman (8ak)
NꢀTrifluoromethylthioꢀdibenzenesulfonimide 7 (239 mg, 0.6 mmol) was placed into an ovenꢀ
dried Schlenk tube that was equipped with a stirring bar under argon. (R)ꢀ2,5,7,8ꢀTetramethylꢀ
2
ꢀ((4R,8R)ꢀ4,8,12ꢀtrimethyltridecyl)chroman (207 mg, 0.5 mmol), boron trifluoride etherate (29
mg, , 0.2 mmol) and freshly distilled CH Cl (2.0 mL) were added. The reaction was stirred at
2
2
o
4
0 C for 36 h. The solvent was removed under vacuum and the residue was purified by flask
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Page 26 of 89
column chromatography to give (R)ꢀ2,5,7,8ꢀTetramethylꢀ6ꢀ(trifluoromethylthio)ꢀ2ꢀ((4R,8R)ꢀ
,8,12ꢀtrimethyltridecyl)chroman 8ak (233 mg, 91%, eluent: petroleum ether, R = 0.8) as a
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
4
f
light yellow oil.
-(Trifluoromethylthio)benzofuran 8a.
7a
3
The general procedure conducted with
Nꢀ
trifluoromethylthioꢀdibenzenesulfonimide 7 (398 mg, 1.0 mmol), benzofuran (59 mg, 0.5 mmol)
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
and DMF (2 mL) gave 8a (70 mg, 65%) as a colorless liquid. Eluent: petroleum ether, R = 0.7.
f
1
H NMR (400 MHz, CDCl ) δ 7.94 (s, 1 H), 7.76 (dd, J = 5.9, 2.7 Hz, 1 H), 7.61ꢀ7.53 (m, 1 H),
3
19
13
7.45ꢀ7.36 (m, 2 H); F NMR (376 MHz, CDCl ) δ ꢀ43.14 (s, 3 F) ppm. C NMR (101 MHz,
3
CDCl ) δ 155.6, 151.7 (d, J = 1.1 Hz), 129.1 (q, J = 309.8 Hz), 128.2, 125.8, 124.3, 120.2,
3
1
12.2, 103.3 (q, J = 2.8 Hz) ppm.
5-Bromo-3-(trifluoromethylthio)benzofuran 8b. The general procedure conducted with Nꢀ
trifluoromethylthioꢀdibenzenesulfonimide 7 (398 mg, 1.0 mmol), 5ꢀbromobenzofuran (99 mg,
0
.5 mmol) and DMF (2 mL) gave 8b (104 mg, 70%) as a colorless liquid. Eluent: petroleum
1
ether, R = 0.7. H NMR (400 MHz, CDCl ) δ 7.93 (s, 1 H), 7.86 (s, 1 H), 7.50 (d, J = 8.8 Hz, 1
f
3
19
13
H), 7.43 (d, J = 8.7 Hz, 1 H); F NMR (376 MHz, CDCl ) δ ꢀ43.02 (s, 3 F); C NMR (101 MHz,
3
CDCl ) δ 154.4, 152.8, 130.2, 129.0, 128.9 (q, J = 311.1 Hz), 123.0, 117.7, 113.7, 103.1 (q, J
3
=
2
3.1 Hz) ppm. MS (EI): 296, 298. HRMS (EI) for C H OF SBr Calcd: 295.9118; Found:
9 4 3
ꢀ1
95.9115. IR (KBr): ν = 1530, 1438, 1281, 1258, 1167, 1102, 1053, 1014, 802, 694, 619 cm .
Methyl 3-(trifluoromethylthio)benzofuran-5-carboxylate 8c. The general procedure conꢀ
ducted with Nꢀtrifluoromethylthioꢀdibenzenesulfonimide 7 (398 mg, 1.0 mmol), methyl benzoꢀ
furanꢀ5ꢀcarboxylate (88 mg, 0.5 mmol) and DMF (2 mL) gave 8c (120 mg, 87%) as a white
1
solid. Eluent: petroleum ether/diethyl ether = 100:1, R = 0.4. H NMR (400 MHz, CDCl ) δ
f
3
8
.45 (s, 1 H), 8.13 (d, J = 8.7 Hz, 1 H), 8.00 (s, 1 H), 7.59 (d, J = 8.7 Hz, 1 H), 3.93 (s, 3 H);
19
13
F NMR (376 MHz, CDCl ) δ ꢀ42.97 (s, 3 F); C NMR (101 MHz, CDCl ) δ 166.8, 158.0,
3
3
1
52.9, 128.9 (q, J = 311.1 Hz), 128.3, 127.6, 126.9, 122.6, 112.2, 104.3 (q, J = 3.1 Hz), 52.5
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The Journal of Organic Chemistry
ppm. MS (EI): 245 (100), 276 (61.79). HRMS (EI) for C H O F S Calcd: 276.0068; Found:
11
7
3 3
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
2
76.0072. IR (KBr): ν = 1711, 1612, 1592, 1533, 1434, 1315, 1277, 1236, 1192, 1166, 1098,
ꢀ1
o
974, 771, 746, 700, 620, 424 cm . Mp: 81.1ꢀ82.0 C.
3
-(Trifluoromethylthio)benzo[b]thiophene 8d. The general procedure conducted with Nꢀ
trifluoromethylthioꢀdibenzenesulfonimide 7 (398 mg, 1.0 mmol), benzo[b]thiophene (67 mg, 0.5
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
mmol) and DMF (2 mL) gave 8d (91 mg, 78%) as a colorless liquid. Eluent: petroleum ether, Rf
1
=
0.8. H NMR (400 MHz, CDCl ) δ 8.04 (d, J = 8.0 Hz, 1 H), 7.96 (s, 1 H), 7.91ꢀ7.86 (m, 1 H),
3
19
7.51 (ddd, J = 8.1, 7.2, 1.1 Hz, 1 H), 7.47ꢀ7.41 (m, 1 H); F NMR (376 MHz, CDCl ) δ ꢀ42.62
3
13
(
s, 3 F); C NMR (101 MHz, CDCl ) δ 139.6, 139.5, 138.1, 129.2 (q, J = 311.1 Hz), 125.5,
3
1
25.5, 123.0, 123.0, 115.4 (q, J = 2.1 Hz) ppm. MS (EI): 165 (100), 234 (67.60). HRMS (EI) for
C H F S Calcd: 233.9785; Found: 233.9779. IR (KBr): ν = 1455, 1421, 1255, 1107, 838, 754,
9
5 3 2
ꢀ1
7
30, 460, 444 cm .
5
-Chloro-3-(trifluoromethylthio)benzo[b]thiophene 8e. The general procedure conducted
with
Nꢀtrifluoromethylthioꢀdibenzenesulfonimide
7
(398
mg,
1.0
mmol),
5ꢀ
chlorobenzo[b]thiophene (85 mg, 0.5 mmol) and DMF (2 mL) gave 8e (106 mg, 79%) as a
1
white solid. Eluent: petroleum ether, R = 0.7. H NMR (400 MHz, CDCl ) δ 8.06ꢀ7.96 (m, 2 H),
f
3
19
7
.80 (d, J = 8.6 Hz, 1 H), 7.41 (dd, J = 8.6, 1.8 Hz, 1 H); F NMR (376 MHz, CDCl ) δ ꢀ42.58
3
13
(
s, 3 F); C NMR (101 MHz, CDCl ) δ 140.9, 139.8, 137.7, 132.3, 129.0 (q, J = 312.1 Hz),
3
126.2, 124.0, 122.7, 114.9 (q, J = 2.1 Hz) ppm. MS (EI):199 (100), 268. HRMS (EI) for
C H F S Cl Calcd: 267.9395. Found: 267.9397. IR (KBr): ν = 1425, 1410, 1248, 1162, 1126,
9
4 3 2
ꢀ1
o
1
104, 1076, 876, 843, 794, 619, 459 cm . Mp: 85.6ꢀ87.1 C.
5-Bromo-3-(trifluoromethylthio)benzo[b]thiophene 8f. The general procedure conducted
with Nꢀtrifluoromethylthioꢀdibenzenesulfonimide (398 mg, 1.0 mmol), 5ꢀ
7
bromobenzo[b]thiophene (107 mg, 0.5 mmol) and DMF (2 mL) gave 8f (133 mg, 85%) as a
1
white solid. Eluent: petroleum ether, R = 0.7. H NMR (400 MHz, CDCl ) δ 8.17 (s, 1 H), 8.00
f
3
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19
(
s, 1 H), 7.74 (d, J = 8.5 Hz, 1 H), 7.54 (dd, J = 8.5, 1.4 Hz, 1 H); F NMR (376 MHz, CDCl ) δ
3
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
3
ꢀ
42.56 (s, 3 F); C NMR (101 MHz, CDCl ) δ 141.3, 139.6, 138.2, 128.9 (q, J = 311.1 Hz),
3
128.8, 125.8, 124.3, 120.0, 114.9 (q, J = 2.1 Hz) ppm. MS (EI): 314(100). HRMS (EI) for
C H F S Br Calcd: 311.8890; Found: 311.8893. IR (KBr): ν = 1582, 1423, 1404, 1161, 1129,
9
4 3 2
ꢀ1
o
1
103, 1067, 876, 842, 794, 615, 460 cm . Mp: 85.9ꢀ87.3 C.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
5
-(Trifluoromethylthio)-2,3-dihydrothieno[3,4-b][1,4]dioxine 8g. The general procedure
conducted with Nꢀtrifluoromethylthioꢀdibenzenesulfonimide 7 (398 mg, 1.0 mmol), 2,3ꢀ
dihydrothieno[3,4ꢀb][1,4]dioxine (71 mg, 0.5 mmol) and DMF (2 mL) gave 8g (104 mg, 86%)
1
as a white solid. Eluent: petroleum ether/ethyl acetate = 80:1, R = 0.4. H NMR (400 MHz,
f
19
CDCl ) δ 6.65 (s, 1 H), 4.32ꢀ4.29 (m, 2 H), 4.23ꢀ4.19 (m, 2 H); F NMR (376 MHz, CDCl ) δ ꢀ
3
3
1
3
45.11 (s, 3 F); C NMR (101 MHz, CDCl ) δ 147.6, 141.5, 128.6 (q, J = 313.1 Hz), 108.0, 94.3
3
(
d, J = 2.0 Hz), 65.3, 64.3 ppm. MS (EI): 173 (100), 242 (76.32). HRMS (EI) for C H O F S
7 5 2 3 2
Calcd: 241.9683; Found: 241.9686. IR (KBr): ν = 1573, 1491, 1450, 1418, 1371, 1248, 1196,
ꢀ1
o
1
142, 1108, 1068, 977, 907, 758, 750, 693, 451 cm . Mp: 68.5ꢀ69.3 C.
2
,6-Dimethoxy-3-(trifluoromethylthio)pyridine 8h. The general procedure conducted with
Nꢀtrifluoromethylthioꢀdibenzenesulfonimide 7 (398 mg, 1.0 mmol), 2,6ꢀdimethoxypyridine (70
mg, 0.5 mmol) and DMF (2 mL) gave 8h (38 mg, 32%) as a white solid and 8h’ (65 mg, 39%)
1
as a white solid. Eluent: petroleum ether, R = 0.3. H NMR (400 MHz, CDCl ) δ 7.74 (d, J =
f
3
19
8.2 Hz, 1 H), 6.36 (d, J = 8.2 Hz, 1 H), 4.01 (s, 3 H), 3.96 (s, 3 H); F NMR (376 MHz, CDCl )
3
1
3
δ ꢀ43.78 (s, 3 F); C NMR (101 MHz, CDCl ) δ 165.6, 164.3, 150.2, 129.6 (q, J = 311.1 Hz),
3
1
03.1, 96.1 (d, J = 2.0 Hz), 54.4, 54.1 ppm. MS (EI): 239 (100). HRMS (EI) for C H NO F S
8 8 2 3
Calcd: 239.0228; Found: 239.0219. IR (KBr): ν = 1585, 1573, 1475, 1467, 1415, 1379, 1328,
ꢀ1
o
1
268, 1240, 1107, 1070, 1030, 1013, 812, 767, 753 cm . Mp: 38.5ꢀ39.5 C.
2
,6-Dimethoxy-3,5-bis(trifluoromethylthio)pyridine 8h’. Eluent: petroleum ether, R = 0.4,
f
1
19
pale yellow solid (65 mg, 39%). H NMR (400 MHz, CDCl ) δ 8.08 (s, 1 H), 4.07 (s, 6 H); F
3
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The Journal of Organic Chemistry
13
NMR (376 MHz, CDCl ) δ ꢀ42.76 (s, 3 F); C NMR (101 MHz, CDCl ) δ 166.3, 159.0, 129.3
3
3
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
(
q, J = 311.1 Hz), 98.2 (d, J = 2.1 Hz), 55.2 ppm. MS (EI): 339 (100). HRMS (EI) for
C H NO F S Calcd: 338.9822; Found: 338.9806. IR (KBr): ν = 1574, 1546, 1482, 1467, 1389,
9
7
2 6 2
ꢀ1
o
1
304, 1273, 1243, 1121, 1084, 770, 754, 434 cm . Mp: 63.2ꢀ64.2 C.
6
,8-Bis(trifluoromethylthio)quinolin-5-ol 8i. The general procedure conducted with Nꢀ
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
trifluoromethylthioꢀdibenzenesulfonimide 7 (398 mg, 1.0 mmol), quinolinꢀ5ꢀol (73 mg, 0.5
mmol) and DMF (2 mL) gave 8i (94 mg, 55%) as a yellow orange solid. Eluent: petroleum
1
ether/ethyl acetate = 2:1, R = 0.3. H NMR (400 MHz, CDCl ) δ 9.16 (dd, J = 4.2, 1.6 Hz, 1 H),
f
3
19
8
.71 (dd, J = 8.4, 1.6 Hz, 1 H), 8.27 (br, 1 H), 7.58 (dd, J = 8.4, 4.3 Hz, 1 H), 7.42 (s, 1 H); F
13
NMR (376 MHz, CDCl ) δ ꢀ42.30 (s, 3 F), ꢀ42.50 (s, 3 F); C NMR (101 MHz, CDCl ) δ 158.5,
3
3
153.6, 150.4, 144.4, 132.9, 129.7 (q, J = 311.1 Hz), 128.6 (q, J = 313.1 Hz), 122.1, 120.3,
1
3
17.5, 102.7 ppm. MS (EI): 345 (100). HRMS (EI) for C H NOF S Calcd: 344.9717; Found:
11 5 6 2
44.9727. IR (KBr): ν = 2924, 1570, 1489, 1265, 1201, 1165, 1124, 1100, 1080, 870, 785, 498
ꢀ1
o
cm . Mp: 144.5ꢀ145.5 C.
,4,6-Trimethoxy-5-(trifluoromethylthio)pyrimidine 8j. The general procedure conducted
with Nꢀtrifluoromethylthioꢀdibenzenesulfonimide (398 mg, 1.0 mmol), 2,4,6ꢀ
2
7
trimethoxypyrimidine (85 mg, 0.5 mmol) and DMF (2 mL) gave 8j (119 mg, 89%) as a white
1
solid. Eluent: petroleum ether/ethyl acetate = 70:1, R = 0.4. H NMR (400 MHz, CDCl ) δ 4.03
f
3
19
13
(s, 6 H), 4.01 (s, 3 H); F NMR (376 MHz, CDCl ) δ ꢀ43.63 (s, 3 F); C NMR (101 MHz,
3
CDCl ) δ 173.3, 166.0, 129.3 (q, J = 310.9 Hz), 80.9 (q, J = 1.8 Hz), 55.38, 55.35. MS (EI): 77
3
(100), 141 (95.23), 201 (81.81), 270 (53.94). HRMS (EI) for C H N O F S Calcd: 270.0286;
8 9 2 3 3
Found: 270.0278. IR (KBr): ν = 1569, 1500, 1469, 1454, 1366, 1196, 1122, 1048, 1002, 911,
ꢀ1
o
7
97, 432 cm . Mp: 126.5ꢀ127.5 C.
2
-(Trifluoromethylthio)benzo[d]thiazole 8k. The general procedure conducted with Nꢀ
trifluoromethylthioꢀdibenzenesulfonimide 7 (398 mg, 1.0 mmol), benzo[d]thiazole (68 mg, 0.5
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