TfNHNHBoc as a SCF3 source for the sulfenylation of indoles

Article abstract of DOI:10.1039/c8cc04600j

An unprecedented use of trifluoromethanesulfonyl hydrazides as effective SCF₃ sources has been established in the sulfenylation of indoles. A range of substituted indoles participated in CuCl-catalyzed oxidative sulfenylation reaction with TfNHNHBoc in the presence of dimethyl sulfoxide to furnish structurally diverse 3-indolyl trifluoromethyl thioethers in moderate to good yields with very high regioselectivity.

Full text of DOI:10.1039/c8cc04600j

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TfNHNHBoc as a SCF3 source for the sulfenylation of indoles
Jing-Yu Guo,† Rui-Han Dai,† Wen-Cong Xu, Ruo-Xin Wu and Shi-Kai Tian*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
An unprecedented use of trifluoromethanesulfonyl hydrazides as include requiring multiple steps and expensive fluorinated
effective SCF3 sources has been established in the sulfenylation of starting materials for the preparation of SCF3-containg
indoles. A range of substituted indoles participated in CuCl- reagents, using highly corrosive liquids, and generating
catalyzed oxidative sulfenylation reaction with TfNHNHBoc in the excessive phosphorus compounds as wastes. In this context,
presence of dimethyl sulfoxide to furnish structurally diverse 3- we
investigated
the
possibility
of
using
indolyl trifluoromethyl thioethers in moderate to good yields with trifluoromethanesulfonyl hydrazides as SCF3 sources to
very high regioselectivity.
functionalize indoles.
We have recently reported a copper-catalyzed oxidative
chlorotrifluoromethylation of arylalkenes with NaCl and
trifluoromethanesulfonyl hydrazides.10 On this basis, we
envisioned that changing reaction conditions might deliver the
SCF3 moiety of trifluoromethanesulfonyl hydrazides to target
In recent years, the use of arene- and alkanesulfonyl
hydrazides as sulfenylating agents in the formation of C-S
bonds have been recognized as a powerful approach for the
preparation of various thioethers.1,2 In general, sulfonyl
hydrazides are readily accessible and stable solids, free of
unpleasant odor, and compatible with water and air, and
consequently, they are much more amenable to manipulation
when compared to traditional sulfenylating agents such as
thiols, disulfides, sulfenyl halides, and sulfonamides. To extend
the scope of sulfonyl hydrazides in the sulfenylation reactions,
we have successively established that TfNHNHBoc is able to
serve as an effective SCF3 source for the sulfenylation of
indoles.
compounds.
Initially,
we
surveyed
a
few
trifluoromethanesulfonyl hydrazides in the model reaction of
indole (1a) in the presence of 10 mol% of CuCl and one
equivalent of dimethyl sulfoxide in acetonitrile at 80 °C (Table
1, entries 1-6). The N′-substituent was found to affect
significantly the ability of a trifluoromethanesulfonyl hydrazide
to serve as a SCF3 source and the best results were obtained
from the reaction with TfNHNHBoc (2a), delivering thioether
3a in 78% yield (determined by 19F NMR spectroscopic
analysis) with very high regioselectivity (Table 1, entry 1).
Replacing CuCl with some other copper salts, dimethyl
sulfoxide with some other oxidants, or acetonitrile with some
other solvents led to much lower yields or even no desired
product at all (Table 1, entries 7-22). Interestingly, both
increasing and decreasing the amount of dimethyl sulfoxide
led to much lower yields, and furthermore, the use of dimethyl
sulfoxide as the solvent decreased the yield to 2% (Table 1,
The SCF3 group is present in some pharmaceuticals such as
Tiflorex, Toltrazuril, and Cefazaflur.3 Recently, much attention
has been paid to the introduction of the SCF3 group into target
compounds using a variety of nucleophilic and electrophilic
reagents.4 In this regard, indolyl trifluoromethyl thioethers
have been reported to be accessed through functionalization
of indoles with SCF3-containg reagents via cleavage of S-N5 and
S-O6 bonds under various conditions.7 Combination of
CF3SO2Cl8 or CF3SO2Na9 with a reducing agent has also
emerged as an important approach for the introduction of the
SCF3 group into indoles. Some drawbacks of these methods
entries 23-25). Finally, elevating the temperature to 100
slightly decreased the yield to 72% (Table 1, entry 26).
°C
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Table 1 Optimization of the reaction conditionsa
aromatic compounds such as N,N-dimethylaniline and
naphthalen-2-ol.
SCF3
CuCl (10 mol%)
DMSO (1 equiv)
MeCN, 80 o
R
+
TfNHNHBoc
R
N
C
N
2a
H
H
3
1
Entry 2, R
[Cu]
CuCl
[O]
Solvent
Yieldb (%)
1
2a, Boc
DMSO CH3CN
DMSO CH3CN
DMSO CH3CN
DMSO CH3CN
DMSO CH3CN
DMSO CH3CN
DMSO CH3CN
DMSO CH3CN
DMSO CH3CN
DMSO CH3CN
DMSO CH3CN
DMSO CH3CN
78
13
trace
0
2
2b, CO2Et CuCl
3
2c, Cbz
2d, COPh
2e, Ts
2f, Ph
2a
CuCl
4
CuCl
5
CuCl
3
6
CuCl
0
7
CuBr
20
21
41
0
8
2a
CuI
9
2a
Cu(MeCN)4BF4
Cu(MeCN)4PF6
10
11
12
13
14
15
16
17
18
19
20
21
22
23c
24d
25
26e
a
2a
.
2a
CuCl2 2H2O
0
.
2a
CuSO4 5H2O
0
2a
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
H2O2
CH3CN
CH3CN
0
2a
TBHP
0
2a
K2S2O8 CH3CN
25
48
53
2
2a
air
O2
CH3CN
CH3CN
2a
2a
DMSO Dioxane
DMSO DMF
2a
0
2a
DMSO EtOH
DMSO DCE
0
2a
8
a
Scheme
conditions:
equiv), acetonitrile (2.0 mL), 80
1
Sulfenylation of indoles with TfNHNHBoc.
(0.40 mmol), 2a (0.80 mmol), CuCl (10 mol%), DMSO (1.0
C, 10 h. b Isolated yields were given.
Reaction
2a
DMSO Toluene
DMSO CH3CN
DMSO CH3CN
DMSO DMSO
DMSO CH3CN
0
1
2a
38
32
2
°
2a
2a
2a
72
Reaction conditions: 1a (0.20 mmol),
2 (0.40 mmol), [Cu] (10 mol%),
[O] (1.0 equiv), solvent (1.0 mL), 80 °
C, 10 h. b Determined by 19F NMR
spectroscopic analysis using PhCF3 as an internal standard. c 0.50 equiv
of DMSO was used. 2.0 equiv of DMSO was used. e The reaction was
d
To gain insights into the reaction mechanism, we
performed the following reactions. Simply heating TfNHNHBoc
performed at 100 °C.
Under the optimized reaction conditions, a range of
(2a) in acetonitrile at 80 °C for 4 h gave CF3SSCF3, which was
substituted indoles smoothly participated in the copper- detected by 19F NMR spectroscopic analysis (eqn (2)). Addition
catalyzed oxidative sulfenylation reaction with TfNHNHBoc of one equivalent of CuCl to the above mixture led to the
(
2a) to furnish structurally diverse 3-indolyl trifluoromethyl formation of CuSCF3 (eqn (3)). Heating TfNHNHBoc (2a) in
thioethers in moderate to good yields with very high acetonitrile at 80
C for 4 h followed by addition of indole (1a
°
)
regioselectivity (Scheme 1). It is noteworthy that the reaction and CuCl furnished thioether 3a in 25% yield (determined by
tolerated a variety of functional groups such as alkoxy, 19F NMR spectroscopic analysis) (eqn (4)). The yield is much
hydroxyl, fluoro, chloro, bromo, and ester. When the C-3 lower than that performed under the standard conditions as
position of the indole ring was occupied by a substituent (e.g. shown in Scheme 1 (80% yield) due to the low boiling point
in 3-methyl-1H-indole), the C-2 sulfenylation product was not (34-35
obtained. The sulfenylation reaction with TfNHNHBoc (2a) was experiment without CuCl only gave a trace amount of
further extended to pyrrole delivering 2-pyrrolyl thioether 3a (eqn (5)). Finally, replacing dimethyl sulfoxide
trifluoromethyl thioether in 30% yield but with very high with dibenzyl sulfoxide permitted us to isolate BnSBn in 41%
°C) of CF3SSCF3 generated in the first step. A control
4,
5
regioselectivity (eqn (1)). Increasing the amount of CuCl to one yield, demonstrating the role of dimethyl sulfoxide as an
equivalent improved the yield to 37%, and in contrast, oxidant in the above sulfenylation reaction (eqn (6)).
elevating the temperature to 100 °C decreased the yield to
11%. Finally, the reaction was not applicable to less reactive
2 | J. Name., 2012, 00, 1-3
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3-indolyl trifluoromethyl thioethers in moderate to good yields
with very high regioselectivity. All the starting materials and
reagents are readily accessible and/or inexpensive. Preliminary
mechanistic studies showed that at an early stage TfNHNHBoc
decomposed to CF3SSCF3 and at a late stage CuCl catalyzed the
oxidative sulfenylation of indoles with CF3SSCF3.
We are grateful for the financial support from the National
Natural Science Foundation of China (21772182 and
21472178), the National Key Basic Research Program of China
(2014CB931800), and the Strategic Priority Research Program
of the Chinese Academy of Sciences (XDB20000000).
Conflicts of interest
There are no conflicts to declare.
Notes and references
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