Ag-Mediated Trifluoromethylthiolation of Inert Csp3-H Bond

Article abstract of DOI:10.1021/acs.joc.8b02207

Ag-mediated trifluoromethylthiolation of inert Csp³-H bond with CF₃SOCl is described. Widely available reagents and operational simplicity make this protocol attractive.

Full text of DOI:10.1021/acs.joc.8b02207

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Note
Ag-mediated trifluoromethylthiolation of inert Csp3-H bond
Yue Zhao, Jin-Hong Lin, Xiao-Chun Hang, and Ji-Chang Xiao
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02207 • Publication Date (Web): 31 Oct 2018
Downloaded from http://pubs.acs.org on October 31, 2018
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Ag-mediated trifluoromethylthiolation of inert
3
Csp -H bond
ab
b
a
b
Yue Zhao, Jin-Hong Lin, * Xiao-Chun Hang * and Ji-Chang Xiao *
1
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aKey Laboratory of Flexible Electronics (KLOFE) and Institute of Advanced Materials
IAM), Nanjing Tech University (NanjingTech), 30 South Puzhu Road, Nanjing 211800,
China
(
bKey Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry,
University of Chinese Academy of Sciences, Chinese Academy of Sciences, 345 Lingling
Road, Shanghai 200032, China
Abstract
Ag CO , K S O , Ph P
2
3
2
2
8
3
R H + CF SOCl
R SCF3
3
3
Ag-Mediated trifluoromethylthiolation of inert Csp -H bond with CF SOCl is
3
described. Widely available reagents and operational simplicity make this protocol
attractive.
Due to its strong electron-withdrawing nature (Hammett constants σ = 0.50, σ =
p
m
1
0
.40) and high lipophilicity (Hansch parameter π = 1.44), trifluoromethylthio group
(CF S) has received increasing attention in medicinal chemistry, agrochemistry and
3
material science.2 Consequently, determined efforts have been devoted to the
development of efficient methods for the installation of a CF S moiety to organic
3
molecules.2d,3 As C-H functionalization is an attractive concept because of its step
economy, C-H trifluoromethylthiolation has become a straightforward strategy for CF3S
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installation. Compared with trifluoromethylthiolation of Csp -H bond and Csp-H bond ,
3
trifluoromethylthiolation of insert Csp -H bond remains a challenging task.
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In 2014, Qing reported a Cu-catalyzed Csp -H trifluoromethylthiolation, in which the
3
6
Csp -H bond has to be an activated benzylic C-H bond (Scheme 1, eq 1). Shortly
3
afterwards, Besset disclosed a Pd-catalyzed trifluoromethylthiolation of inert Csp -H
bond. The desired products could be obtained in moderate yields, but a bulky directing
7
group is required to be incorporated into the substrates (eq 2). Almost at the same time,
8
9
Chen and Tang independently described a radical trifluoromethylthiolation of alkanes
with AgSCF under oxidative conditions (eqs 3-4). A wide substrate scope and good
3
functional group compatibility were observed in both approaches. Recently,
photocatalytic radical trifluoromethylthiolation was achieved by the group of Glorius (eq
5
).10 Although good site selectivity and high yields were obtained, an expensive
photocatalyst is needed. Apparently, the trifluoromethylthiolation reagents used in the
above methods are expensive or have to be prepared via tedious synthetic procedures. We
have been interested in the development of effective protocols for the incorporation of
fluorine-containing functionalities into organic molecules.11 We found that
trifluoromethanesulfinic chloride (CF SOCl) could act as a trifluoromethylthio source to
3
3
realize Ag-mediated radical trifluoromethylthiolation of inert Csp -H bond (eq 6). All
reagents in this protocol are widely available and easy to handle.
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Previous work:
R
H
SCF3
CuTc, KCl
oxidant
(1)
(2)
+ AgSCF3
R
O
O
O
R2
R2
R1
[Pd]
+
N SCF3
N
R1
N
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
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
H
H
N
N
H
SCF3
O
K S O
8
2
2
R-H + AgSCF3
R SCF3
o
(3)
(4)
CH CN, 60 C, 12 h
3
Na S O
8
2
2
R H + AgSCF3
R SCF3
o
MeCN/H O/DCE, 35 C
2
O
[
Ir], PhCO Na
2
R H
+
N SCF3
(5)
(6)
R SCF3
blue LEDs
O
This work:
Ag CO , K S O , Ph P
2
3
2
2
8
3
R H + CF SOCl
R SCF3
3
o
MeCN, 60 C, 12 h
3
Scheme 1. Csp -H trifluoromethylthiolation
As it has been previously reported that phosphorus species could reduce CF SO Cl to
3
2
provide active trifluoromethylthiolation intermediates,12 Ph P was used as a reducing
3
agent in our initial attempts at the trifluoromethylthiolation of octane with CF SOCl
3
(Table 1). A brief survey of the metal complex (entries 1-5) revealed that Ag CO was
2
3
quite effective (entry 2). Interestingly, no desired product was observed in other solvents
entries 6-8) except CH CN. An oxidant is necessary in the reaction, and replacing
(
3
K S O with other oxidants dramatically decreased the yield (entries 9-10). A reaction
2
2
8
o
temperature of 60 C proved superior to a lower or higher temperature (entry 2 vs entries
11-12). Increasing the loading of oxidant from 1.0 equiv to 1.5 equiv increased the yield
to 77% (entry 13). However, the results were not reproducible (yields varied between
4
7% and 77%) if substrate 1a was used in the same equivalent with reagent 2 (entry 13).
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To our delight, the reaction could be well reproduced by using slight excess of substrate
1
a (entry 14). A lower yield was obtained within a shorter reaction time (entry 15). 1
equiv of Ag CO was necessary, and decreasing the loading of Ag CO led to the
2
3
2
3
0
1
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dramatic decrease in the yield (entries 16-19). No desired product was observed by
replacing Ag CO with K CO (entry 20), suggesting that Ag CO played a crucial role in
2
3
2
3
2
3
the reaction.
Table 1. Optimization of the reaction conditions
MX
SCF3
Ph3P, K2S2O8
+
CF3SOCl
solvent, 60 oC, 12 h
1a
2
3a
entry
MX
solvent
ratiob
yield (%)c
1
2
AgNO3 CH CN
1:1:1:1.5:1
1:1:1:1.5:1
1:1:1:1.5:1
1:1:1:1.5:1
1:1:1:1.5:1
1:1:1:1.5:1
1:1:1:1.5:1
1:1:1:1.5:1
1:1:1:1.5:1
1:1:1:1.5:1
1:1:1:1.5:1
1:1:1:1.5:1
1:1:1:1.5:1.5
1.5:1:1:1.5:1.5
1.5:1:1:1.5:1.5
0
55
21
0
3
Ag CO
CH CN
2
3
3
3
AgF
CH CN
3
4
CuSCN CH CN
3
5
CuCl
CH CN
0
3
6
Ag CO
DMF
DCM
0
2
3
3
3
3
3
3
3
3
3
3
3
3
3
7
Ag CO
0
2
8
Ag CO
PhCH3
0
2
9d
10e
Ag CO
CH CN
trace
trace
46
57
77
80
65
57
35
0
2
3
Ag CO
CH CN
2
3
1
1f
2g
13
Ag CO
CH CN
2
3
1
Ag CO
CH CN
2
3
Ag CO
CH CN
2
3
1
4
Ag CO
CH CN
2
3
1
5h
Ag CO
CH CN
2
3
1
6
Ag CO
CH CN 1.5:1:0.8:1.5:1.5
2
3
17
Ag CO
CH CN 1.5:1:0.6:1.5:1.5
2
3
1
1
8
9
Ag CO
CH CN 1.5:1:0.5:1.5:1.5
2
3
-
CH CN
1.5:1:0:1.5:1.5
1.5:1:1:1.5:1.5
0
3
20
K CO
CH CN
0
2
3
3
a
Reaction conditions:1a, 2 (0.4 mmol), MX (1 equiv), Ph P (1.5 equiv), and K S O in CH CN (3 mL)
3
2
2
8
3
at 60 C for 12 h ; Molar ratio of 1a:2:MX:Ph P:K S O ; The yields were determined by 19F NMR
o
b
c
3
2
2
8
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d
e
f
spectroscopy; NaIO was used instead of K S O ; PhI(OAc) was used instead of K S O ; The
4
2
2
8
2
2
2
8
o
g
o
h
reaction temperature was 50 C; The reaction temperature was 70 C; The reaction time was 6 h.
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
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5
5
5
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0
1
2
3
4
5
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0
1
2
3
4
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0
1
2
3
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1
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9
0
With the optimized reaction conditions in hand (Table 1, entry 14), we then
investigated the substrate scope of the Ag-mediated trifluoromethylthiolation of inert
3
Csp -H bond. As shown in Scheme 2, a variety of alkanes could be converted smoothly
into the desired products in moderate to high yields. A large-scale reaction (10 mmol of
1
9
CF SOCl) could also give the desired product in a good yield (3a, 75% F NMR yield),
3
demonstrating the potential application of this reaction. Some trifluoromethylthiolation
1
9
products are volatile and therefore lower isolated yields compared to F NMR yields
were obtained. Although C-H bond dissociation energies decrease in the order of
secondary > tertiary, both secondary and tertiary carbons were found to be quite reactive,
and tertiary carbon showed a higher reactivity. If two tertiary carbons were present in the
substrates, trifluoromethylthiolation would prefer to take place at the position which is
remote from electron-withdrawing groups (3q-3t). A wide range of functional group
could be tolerated, such as ketones, esters, amides, ethers, halides, and nitriles,
demonstrating the synthetic utility of this protocol. To our surprise, the benzylic C-H
bond is inert under these conditions. For instance, no desired product was observed for
the conversion of toluene or 1-ethylnaphthalene.
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Ag CO , Ph P, K S O
8
2
3
3
2
2
R
H
+ CF SOCl
R
SCF3
3
3
o
CH CN, 60 C, 12h
3
1
2
SCF3
SCF3
SCF3
SCF3
a
b
3
a, 64% (80% , 75% ) 3b, 37% (59%)a
3c, 58%
3d, 55%
H3C CH3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
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7
8
9
0
1
2
3
4
5
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7
8
9
0
1
2
3
4
5
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
O
O H C CH
SCF3
3
3
SCF3
H C
3
Br
SCF3
H C
3
SCF3
H C
3
CN
H C CH3
3
e, 67% (83%)a
3f, 23% (44%)a
3g, 37% (45%)a
3h, 38% (56%)a
3
O
O
O H C CH
CH3
SCF3
3
3
SCF3
SCF
3 O
H C
O
H CO
3
3
C H O
SCF3
2
5
CH3
H C CH3
H3C CH3
3
i, 44% (63%)a
3j, 55% (71%)a
3k, 64% (75%)a
3l, 19% (43%)a
3
O
O
O
N O
O
SCF3
N
CH3
SCF3
CH3
H C
3
CH3
CH3
H C SCF3
m, 54%
tBu
O
3
3
3n, 81%
3o, 47%
O
CH3
O
CH3
O
H C
3
CH3
SCF3
SCF3
H C CH3
O
O
O
SCF3
H C CH3
3
3
NC
F3C
3
p, 83%
3q, 86%
3r, 76%
O
CH3
O
CH3
SCF3
CH3
SCF3
H C CH3
O
O
H C
3
3
H CO
3
F
3
s, 67%
3t, 83%
3
Scheme 2. Ag-mediated trifluoromethylthiolation of inert Csp -H bond. Isolated yields;
Reaction conditions: substrate 1 (1.5 equiv), CF SOCl (0.4 mmol, 1 equiv), Ag CO (1
3
2
3
o
equiv), Ph P (1.5 equiv), and K S O (1.5 equiv) in CH CN (3 mL) at 60 C for 12 h.
3
2
2
8
3
a
19
b
19
The yields were determined by F NMR spectroscopy; A 75% F NMR yield was
obtained by increasing the reaction scale to 10 mmol (CF SOCl).
3
Some preliminary experimental results were collected to gain more mechanistic
insights into the C-H trifluoromethylthiolation process. The reaction gave the desired
product in low yields in the presence of a radical scavenger, such as TEMPO
(
2,2,6,6-tetramethylpiperidin-1-oxyl), hydroquinone or 1,4-dinitrobenzene, suggesting
that a radical pathway may be involved (Scheme 3, eq 1). For the conversion of substrate
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1o, a cyclization product (3o’) was produced in 45% yield (eq 2), further supporting the
radical mechanism. Without the presence of the CF SOCl/Ph P system, substrate 1o
3
3
could also be converted into cyclization product 3o’, indicating that the Ag CO /K S O
8
2
3
2
2
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
system would lead to the generation of a radical intermediate from the substrate (eq 3).
SCF3
optimal conditions
+ CF SOCl
(1)
3
with or without
an additive (1 equiv)
1a
2
3a
yield (%)a
additive
none
TEMPO
80%
19%
trace
5%
hydroquinone
1,4-dinitrobenzene
O
O
CH3
optimal conditions
3
o
+
(2)
(3)
tBu
CH3
tBu
H C CH3
3o', 45%b
3
47%b
1o
O
O
Ag CO (0.4 mmol)
2
3
CH3
K S O (0.6 mmol)
2
2
8
o
CH CN, 60 C, 12 h
tBu
3
CH3
tBu
H C CH3
3
3o', 47%b
1o (0.6 mmol)
Scheme 3. Mechanistic evidence. The yield was determined by 19F NMR
a
b
spectroscopy; Isolated yield.
Although Ph P is a reducing agent and K S O is an oxidizing agent, the reaction
3
2
2
8
between them is quite slow, whereas the reaction of Ph P with CF SOCl occurred
3
3
rapidly. Almost no Ph P was converted by heating the mixture of Ph P and K S O at 60
3
3
2
2
8
o
C for 10 min. But after stirring the mixture of Ph P and CF SOCl for 10 min, CF SOCl
3
3
3
was completely consumed to produce a major product, CF SSCF , which was confirmed
3
3
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5
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1
9
13
+
31
by F NMR spectroscopy (δ: -46.2 ppm) and GC-MS (M : 201.9) (Scheme 4, eq 1). P
NMR analysis of the reaction mixture revealed that Ph P was completely converted into
3
+
-
14
two species, Ph P=O and (Ph P Cl Cl ) (δ: +65 ppm) (eq 1). The molar ratio of these
3
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
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0
1
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0
1
2
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9
0
1
2
3
4
5
6
7
8
9
0
3
1
+
-
two species determined by P NMR spectroscopy was 3.4:1 [Ph P=O : (Ph P Cl Cl )].
3
3
After the complete conversion of CF SOCl into CF SSCF , substrate 1a and the
3
3
3
o
Ag CO /K S O reagent system were added and the resultant mixture was stirred at 60 C
2
3
2
2
8
1
9
for 12 h (eq 2). A 60% F NMR yield of the desired product was obtained, suggesting
that CF SSCF is a key intermediate for this trifluoromethylthiolation process.
3
3
1
0 min
CF SOCl
Ph P
+
-
3
3
CF SSCF
Ph P=O
Ph P Cl Cl
(1)
(2)
o
3
3
3
3
CH CN, 60 C
3
a
b
(
0.4 mmol) (1.5 equiv)
70%
(
3.4
:
1
)
1a (1.5 equiv)
Ag CO (1 equiv)
K2S2O8 (1.5 equiv)
2
3
SCF3
10 min
CF SOCl
Ph P
3
3
CF SSCF
o
3
3
o
CH CN, 60 C
CH CN, 60 C, 12 h
3
3
(
0.4 mmol) (1.5 equiv)
3a, 60%a
7
0%a
Scheme 4. Mechanistic investigations. The yield was determined by 19F NMR
a
b
31
spectroscopy; Molar ratio determined by P NMR spectroscopy;
On the basis of the above results, the plausible mechanism is proposed as shown in
Scheme 5. CF SOCl could be reduced by Ph P to form CF SCl (trifluoromethanesulfenyl
3
3
3
+
chloride) via a halogen bonding process to form chlorophosphonium salt (ClP Ph ) and
3
1
2
an Arbuzov conversion to release Ph P=O. A further halogen bonding process between
3
+
Ph P and CF SCl generates chlorophosphonium salt (ClP Ph ) and trifluoromethylthio
3
3
3
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-
anion (CF S ), which attacks CF SCl to produce CF SSCF and a chloride anion. The
3
3
3
3
+
disproportionation of peroxydisulfate anion in the presence of a Ag salt gives sulfate
15
radical anion. The abstraction of a hydrogen atom from the substrates by the sulfate
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
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radical anion would readily occur to generate an alkyl radical. The reaction of the alkyl
radical with CF SSCF provides the final trifluoromethylthiolation product and a
3
3
trifluoromethylthio radical (CF S˙), the combination of which with the alkyl radical also
3
furnishes the trifluoromethylthiolation product.
O
PPh3
- Ph P=O
3
CF S-O-
+
O
S
+
3
+ Cl P Ph3
F3CS
P Ph
CF3SCl
3
F3C
Cl
Cl-
PPh
CF SCl
3
3
CF S-
F3CS Cl
CF SSCF
3
+
3
-
3
ClP Ph
Cl
3
Ag+ Ag2+ SO42- R-H HSO4-
+
CF SSCF CF S
R
3
3
3
2-
S O
2
R
8
SO4
R SCF3
Scheme 5. The proposed reaction mechanism
In summary, we have described the Ag-mediate trifluoromethylthiolation of
3
inert Csp -H bond with CF SOCl. All reagents used in this process were widely
3
available, and the reactions occurred smoothly under mild conditions. A broad
substrate scope and good functional group compatibility were observed,
demonstrating the synthetic utility of this trifluoromethylthiolation protocol. Due
to its operational convenience and step economy, the protocol may find application
in the synthesis of CF S-containing pharmaceuticals and agrochemicals.
3
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EXPERIMENTAL SECTION
0
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General information. H, C and F NMR spectra were detected on a 500 MHz, 400
1
13
19
MHz or 300 MHz NMR spectrometer. Data for H NMR, C NMR and F NMR were
recorded as follows: chemical shift (δ, ppm), multiplicity(s = singlet, d = doublet, t =
triplet, m = multiplet, q = quartet, coupling constant (s) in Hz). Mass spectra were
obtained on GC-MS or LC-MS (ESI). High resolution mass data were recorded on a high
resolution mass spectrometer in the ESI mode. The mass analyzer type for HRMS-ESI is
Fourier transform mass spectrometer. Unless otherwise noted, all reagents including
CF SOCl (95% purity) were obtained commercially and used without further
3
purification.
General procedure for trifluoromethylthiolation. Under a N atmosphere, into a 15
2
mL sealed tube was added triphenylphosphine (0.6 mmol, 1.5 equiv), K S O (0.6 mmol,
2
2
8
1.5 equiv), Ag CO (0.4 mmol, 1.0 equiv), CH CN (3 mL), alkane substrate (0.6 mmol,
2
3
3
1
.5 equiv), and trifluoromethanesulfinic chloride (0.4 mmol, 1.0 equiv). The tube was
o
sealed and the mixture was stirred at 60 C for 12 h. After being cooled to room
temperature, the mixture was filtered to remove the solid. The solid was washed with
dichloromethane, and the combined organic phase was concentrated to remove the
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solvent. The residue was subjected to flash column chromatography to give the pure
product.
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1
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cyclooctyl(trifluoromethyl)sulfane (3a) : 64% yield; 54mg; ; H NMR (400 MHz, CDCl )
3
1
3
δ 3.53-3.46 (m, 1H), 2.11 – 2.04 (m, 2H), 1.83 – 1.69 (m, 4H), 1.63 – 1.49 (m, 8H). C
19
NMR (101 MHz, CDCl ) δ 131.7 (q, J = 306.1 Hz), 45.9, 32.9, 27.5, 25.9, 25.0. F NMR
3
+
(376 MHz, CDCl ) δ -39.70 (s, 3F). GC-MS (EI): m/z = 212.2 (M ).
3
8
1H NMR (400 MHz,
cycloheptyl(trifluoromethyl)sulfane (3b) : 37% yield; 29mg;
CDCl ) δ 3.49-3.42 (m, 1H), 2.13-2.06 (m, 2H), 1.78-1.66 (m, 4H), 1.63 – 1.49 (m, 6H).
3
1
3
19
C NMR (101 MHz, CDCl ) δ 131.6 (q, J = 306.2 Hz), 46.3, 35.8, 28.4, 25.7. F NMR
3
+
(
376 MHz, CDCl ) δ -39.68 (s, 3F). GC-MS (EI): m/z = 198.1 (M ).
3
8
1
cyclodecyl(trifluoromethyl)sulfane (3c) : 58% yield; 56mg; H NMR (400 MHz, CDCl )
3
1
3
δ 3.59 – 3.53 (m, 1H), 1.97-1.79 (m, 4H), 1.71-1.61 (m, 4H), 1.57-1.52 (m, 10H). C
1
9
NMR (101 MHz, CDCl ) δ 131.7 (q, J = 306.1 Hz), 44.0, 32.2, 25.6, 25.1, 24.9, 23.7. F
3
+
NMR (376 MHz, CDCl ) δ -39.61 (s, 3F). GC-MS (EI): m/z = 240.2 (M ).
3
8
1H NMR (400 MHz,
cyclododecyl(trifluoromethyl)sulfane (3d) : 55% yield; 59mg;
CDCl ) δ 3.35-3.29 (m, 1H), 1.86-1.77 (m, 2H), 1.69-1.61 (m, 2H), 1.57-1.50 (m, 2H),
3
1
3
1
2
.42 – 1.31 (m, 16H). C NMR (101 MHz, CDCl ) δ 131.8 (q, J = 306.1 Hz), 42.9, 31.3,
3
1
9
4.2, 24.0, 23.8, 23.7, 22.3. F NMR (376 MHz, CDCl ) δ -39.59 (s, 3F). GC-MS (EI):
3
m/z = 268.1 (M+).
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5-methyl-5-((trifluoromethyl)thio)hexan-2-one (3e) : 67% yield; 57mg; 1H NMR (400
8
MHz, CDCl ) δ 2.60 (t, J = 8.1 Hz, 2H), 2.15 (s, 3H), 1.92 (t, J = 7.6 Hz, 2H), 1.41 (s,
3
13
6
H) . C NMR (101 MHz, CDCl ) δ 207.6, 131.1 (q, J = 308.1 Hz), 51.7, 39.4, 36.4,
3
0
1
2
3
4
5
6
7
8
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1
2
3
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9
0
1
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0
1
2
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6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
9
+
30.2, 29.7. F NMR (376 MHz, CDCl ) δ -35.97(s, 3F). GC-MS (EI): m/z = 214.0 (M ).
3
8
1
4
-methyl-4-((trifluoromethyl)thio)pentan-2-one (3f) : 23% yield; 18mg; H NMR (400
1
3
MHz, CDCl ) δ 2.90 (s, 2H), 2.16 (s, 3H),1.58 (s, 6H). C NMR (101 MHz, CDCl ) δ
3
3
1
9
2
05.5, 131.2 (q, J = 307.7 Hz), 54.8, 49.4, 32.1, 29.2. F NMR (376 MHz, CDCl ) δ
3
35.68 (s, 3F). GC-MS (EI): m/z = 200.0 (M+).
-
8
1
4-((trifluoromethyl)thio)pentanenitrile (3g) : 37% yield; 27mg; H NMR (400 MHz,
CDCl ) δ 3.42-3.34 (m, 1H), 2.54 (t, J = 7.3 Hz, 2H), 2.07-1.91 (m, 2H), 1.49 (d, J = 7.0
3
1
3
Hz, 3H). C NMR (101 MHz, CDCl ) δ 130.9 (q, J = 308.1 Hz), 118.8, 40.2, 32.7, 22.4,
3
1
9
+
1
5.1. F NMR (376 MHz, CDCl ) δ -38.94 (s, 3F). GC-MS (EI): m/z = 183.0 (M ).
3
8
1H
(
4-bromo-2-methylbutan-2-yl)(trifluoromethyl)sulfane (3h) : 38% yield; 38mg;
NMR (400 MHz, CDCl ) δ 3.48 (t, J = 8.3 Hz, 2H), 2.28 (t, J = 8.0 Hz, 2H),1.48 (s, 6H).
3
1
3
19
C NMR (101 MHz, CDCl ) δ 130.9 (q, J = 307.9 Hz), 52.0, 46.4, 29.7, 27.5. F NMR
3
+
(376 MHz, CDCl ) δ -35.95 (s, 3F). GC-MS (EI): m/z = 251.9 (M ).
3
2
-methyl-2-((trifluoromethyl)thio)propyl acetate (3i): 44% yield; 38mg; Colorless liquid;
1
13
H NMR(400 MHz, CDCl ) δ 4.14 (s, 2H), 2.10 (s, 3H), 1.46 (s, 6H). C NMR (101
3
1
9
MHz, CDCl ) δ170.8, 130.9 (q, J = 309.1 Hz), 71.1, 50.1, 26.5, 21.0. F NMR (376 MHz,
3
+
CDCl ) δ -35.45 (s, 3F). HRMS-ESI (m/z): Calcd for C H F O SN [M + NH ] ,
3
7
15
3
2
4
-1
234.0770. Found, 234.0770. IR(KBr): 2962, 1261, 1096, 1027, 799, 704 cm .
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ethyl 3-methyl-3-((trifluoromethyl)thio)butanoate (3j): 55% yield; 51mg;
Colorless
1
liquid; H NMR (400 MHz, CDCl ) δ 4.15 (q, J = 7.1 Hz, 2H), 2.75 (s, 2H), 1.59 (s, 6H),
3
13
1
.26 (t, J = 7.1 Hz, 3H). C NMR (101 MHz, CDCl ) δ 169.9, 131.1 (q, J = 307.9 Hz),
3
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
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3
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3
3
3
3
3
4
4
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1
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1
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9
0
1
2
3
4
5
6
7
8
9
0
1
9
61.0, 49.2, 47.8, 29.4, 14.5. F NMR (376 MHz, CDCl ) δ -35.91 (s, 3F). HRMS-ESI
3
+
(
m/z): Calcd for C H F O SN [M + NH ] , 248.0927. Found, 248.0926. IR(KBr): 2962,
8
17
3
2
4
-1
2929, 1734, 1466, 1371, 1119, 1035, 869, 805, 756, 721 cm .
9
1H
methyl 4-methyl-4-((trifluoromethyl)thio)pentanoate (3k) : 64% yield; 59mg;
NMR (400 MHz, CDCl ) δ 3.66 (s, 3H), 2.47 (t, J = 8.3 Hz, 2H), 2.01 (t, J = 8.1 Hz, 2H),
3
1
3
1.43 (s, 6H). C NMR (101 MHz, CDCl ) δ 173.7, 131.1 (q, J = 307.6 Hz), 52.1, 51.5,
3
1
9
3
7.9, 30.1, 29.5. F NMR (376 MHz, CDCl ) δ -35.97 (s, 3F). GC-MS (EI): m/z = 129.1
3
+
([M-SCF ] ).
3
10
4
-(2-((trifluoromethyl)thio)propan-2-yl)cyclohexan-1-one (3l) : 19% yield; 18mg; 1H
NMR (400 MHz, CDCl ) δ 2.45 – 2.21 (m, 6H), 2.05-1.99 (m, 1H), 1.62-1.51 (m, 2H),
3
1
3
1.46 (s, 6H). C NMR (101 MHz, CDCl ) δ 210.9, 131.3 (q, J = 309.1 Hz), 55.5, 46.4,
3
1
9
4
0.9, 27.7, 27.2. F NMR (376 MHz, CDCl ) δ -35.01 (s, 3F). GC-MS (EI): m/z = 240.1
3
(M+).
-(3-methyl-3-((trifluoromethyl)thio)butoxy)isoindoline-1,3-dione (3m) : 54% yield; 72
8
2
1
mg; H NMR (400 MHz, CDCl ) δ 7.83-7.79 (m, 2H), 7.76-7.73 (m, 2H), 4.38 (t, J = 6.4
3
1
3
Hz, 2H), 2.22 (t, J = 6.4 Hz, 2H), 1.56 (s, 6H). C NMR (101 MHz, CDCl ) δ 163.7,
3
1
9
1
34.9, 131.0 (q, J = 307.6 Hz), 129.2, 123.9, 75.5, 50.8, 40.9, 30.0. F NMR (376 MHz,
+
CDCl ) δ -35.89 (s, 3F). MS (EI): m/z =232.1 ([M-SCF ] ).
3
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2-(3-methyl-3-((trifluoromethyl)thio)butyl)isoindoline-1,3-dione (3n) : 81% yield; 103
1
mg; H NMR (400 MHz, CDCl ) δ 7.82-7.80 (m, 2H), 7.70-7.68 (m, 2H), 3.82 (t, J = 7.9
3
13
Hz, 2H), 2.04 (t, J = 7.9 Hz, 2H), 1.52 (s, 6H). C NMR (101 MHz, CDCl ) δ 168.3,
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
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0
1
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6
7
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0
1
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134.3, 132.4, 131.0 (q, J = 307.9 Hz), 123.5, 50.4, 41.1, 34.5, 29.6. F NMR (376 MHz,
+
CDCl ) δ -35.76 (s, 3F). GC-MS (EI): m/z = 317.1 (M ).
3
1-(4-(tert-butyl)phenyl)-4-methyl-4-((trifluoromethyl)thio)pentan-1-one (3o): 47% yield;
1
6
2 mg; Colorless liquid; H NMR (400 MHz, CDCl ) δ 7.92 (d, J = 8.5 Hz, 2H), 7.49 (d,
3
J = 8.5 Hz, 2H), 3.14 (t, J = 7.8 Hz, 2H), 2.14 (t, J = 7.7 Hz, 2H), 1.51 (s, 6H), 1.35 (s,
1
3
9H). C NMR (101 MHz, CDCl ) δ 199.1 , 157.3 , 134.5 , 131.3 (q, J = 309.1 Hz), 128.4 ,
3
1
9
1
25.9 , 52.1 , 37.1 , 35.5 , 34.4 , 31.4 , 30.0 . F NMR (376 MHz, CDCl ) δ -35.77(s, 3F) .
3
+
HRMS-ESI (m/z): Calcd for C H F OS [M + H] , 333.1494. Found, 333.1494.
17
24 3
IR(KBr): 2967, 2907,2870, 1683, 1606, 1568, 1470, 1392, 1318, 1225, 1098, 999, 842,
55, 583 cm-1.
7
9
1
3-methyl-3-((trifluoromethyl)thio)butyl benzoate (3p) : 83% yield; 97 mg; H NMR (400
MHz, CDCl ) δ 8.03 (d, J = 8.0 Hz, 1H), 7.56 (t, J = 7.6 Hz, 1H), 7.44 (t, J = 7.7 Hz, 2H),
3
1
3
4.52 (t, J = 6.7 Hz, 2H), 2.21 (t, J = 6.7 Hz, 2H), 1.56 (s, 6H). C NMR (101 MHz,
CDCl ) δ 166.7, 133.4, 131.1 (q, J = 307.6 Hz), 130.4, 129.9, 128.7, 61.9, 50.6, 41.6,
3
19
+
3
0.1. F NMR (376 MHz, CDCl ) δ -35.76 (s, 3F). GC-MS (EI): m/z = 292.1 (M ).
3
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5-methyl-5-((trifluoromethyl)thio)hexan-2-yl 4-cyanobenzoate (3q) : 86% yield; 119 mg;
1
H NMR (400 MHz, CDCl ) δ 8.11 (d, J = 8.2 Hz, 2H), 7.73 (d, J = 8.2 Hz, 2H),
3
1
3
5.18-5.13 (m, 1H), 1.95 – 1.68 (m, 4H), 1.44 (s, 6H), 1.37 (d, J = 6.3 Hz, 3H). C NMR
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(101 MHz, CDCl ) δ 164.7 , 134.7 , 132.5 , 131.2 (q, J = 307.6 Hz), 130.3 , 118.3 , 116.6 ,
3
1
9
7
2.8 , 51.8 , 38.9 , 31.4 , 29.7 , 20.2 . F NMR (376 MHz, CDCl ) δ -35.80 (s, 3F).
3
+
GC-MS (EI): m/z = 244.1 ([M-SCF ] ).
3
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5-methyl-5-((trifluoromethyl)thio)hexan-2-yl 4-(trifluoromethyl)benzoate (3r) : 76%
1
yield; 118 mg; H NMR (400 MHz, CDCl ) δ 8.14 (d, J = 8.1 Hz, 2H), 7.71 (d, J = 8.1
3
Hz, 2H), 5.30 – 4.93 (m, 1H), 1.98 – 1.66 (m, 4H), 1.46 (s, 6H), 1.39 (d, J = 6.3 Hz,
1
3
3
H). C NMR (101 MHz, CDCl ) δ 165.3, 134.7 (q, J = 32.7 Hz), 134.2, 131.3 (q, J
3
=
309.1), 130.3, 125.7 (q, J = 3.7 Hz), 124.0 (q, J = 272.6 Hz),72.5, 51.9, 39.0, 31.5, 29.8,
1
9
20.4. F NMR (376 MHz, CDCl ) δ -35.83 (s, 3F), -63.18 (s, 3F). ESI (m/z):
3
+
C H F O SNa [M + Na] , 411.1.
1
6
18
6
2
9
5-methyl-5-((trifluoromethyl)thio)hexan-2-yl 4-methoxybenzoate (3s) : 67% yield; 93
1
mg; H NMR (400 MHz, CDCl ) δ 7.98 (d, J = 8.6 Hz, 2H), 6.91 (d, J = 8.8 Hz, 2H),
3
5
3
1
.13-5.09 (m, 1H), 3.85 (s, 3H), 1.93 – 1.67 (m, 4H), 1.45 (s, 6H), 1.35 (d, J = 6.2 Hz,
1
3
H). C NMR (101 MHz, CDCl ) δ 166.2, 163.6, 131.8, 131.3 (q, J = 307.6 Hz), 123.3,
3
19
13.9, 71.2, 55.7, 52.0, 39.1, 31.6, 29.8, 20.4. F NMR (376 MHz, CDCl ) δ -35.76 (s,
3
3F). GC-MS (EI): m/z = 350.2 (M+).
9
5
-methyl-5-((trifluoromethyl)thio)hexan-2-yl 4-fluorobenzoate (3t) : 83% yield; 112 mg;
1
H NMR (400 MHz, CDCl ) δ 8.06-8.02 (m, 2H), 7.10 (t, J = 8.5 Hz, 2H), 5.15-5.11 (m,
3
1
3
1
H), 1.92– 1.68 (m, 4H), 1.45 (s, 6H), 1.36 (d, J = 6.2 Hz, 3H). C NMR (101 MHz,
CDCl ) δ 166.1 (d, J = 253.5 Hz), 165.5, 132.4 (d, J = 9.8 Hz), 131.3 (q, J = 307.6 Hz),
3
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127.2 (d, J = 3.4 Hz), 115.8 (d, J = 21.9 Hz), 71.9, 51.9, 39.0, 31.6, 29.8, 20.4. F NMR
(
376 MHz, CDCl ) δ -35.80 (s, 3F) , -105.96 ~ -106.05 (m, 1F). GC-MS (EI): m/z =
3
+
2
37.1 ([M-SCF ] ).
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0
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6-(tert-butyl)-4,4-dimethyl-3,4-dihydronaphthalen-1(2H)-one (3o)’: 45% yield; 41 mg;
1
Colorless liquid; H NMR (400 MHz, CDCl ) δ 7.95 (d, J = 8.3 Hz, 1H), 7.42 (d, J = 1.9
3
Hz, 1H), 7.33 (dd, J = 8.3, 19 Hz, 1H), 2.70 (t, J = 6.8 Hz, 2H), 2.01 (t, J = 6.8 Hz, 2H),
1
3
1
1
.39 (s, 6H), 1.34 (s, 9H). C NMR (101 MHz, CDCl ) δ 198.5 ,157.7, 152.3, 129.1,
3
27.5, 123.9, 122.6, 37.6, 35.6, 35.4, 34.4, 31.4, 30.1. HRMS-ESI (m/z): Calcd for
+
C H O [M + H] , 231.1743. Found, 231.1743. IR(KBr): 3351, 2961, 2868, 1685, 1604,
1
6
23
-1
1
465, 1387, 1285, 1198, 1092, 1021, 880, 837, 810, 696, 655, 569, 485 cm .
ASSOCIATED CONTENT
1
19 13
Supporting Information Available. Copies of H/ F/ C NMR spectra of compounds.
This material is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding author
* Dr. Jin-Hong Lin
Email: jlin@sioc.ac.cn.
*
Prof. Xiao-Chun Hang
Email: iamxchhang@njtech.edu.cn.
Prof. Ji-Chang Xiao
*
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Email: jchxiao@sioc.ac.cn
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
The authors thank National Basic Research Program of China
(2015CB931903), the National Natural Science Foundation (21421002, 21472222,
21502214, 21672242), the Chinese Academy of Sciences (XDA02020105,
XDA02020106), and Key Research Program of Frontier Sciences (CAS)
(QYZDJ-SSW-SLH049) for financial support.
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