Synthesis of 3-((trifluoromethyl)thio)indoles via a reaction of 2-alkynylaniline with trifluoromethanesulfanylamide

Article abstract of DOI:10.1039/c3cc45958f

3-((Trifluoromethyl)thio)indoles can be synthesized by a palladium(ii)-catalyzed reaction of 2-alkynylaniline with trifluoromethanesulfanylamide in the presence of bismuth(iii) chloride. The presence of bismuth(iii) chloride is crucial for the success of this transformation, which activates the trifluoromethanesulfanylamide during the reaction. The Royal Society of Chemistry 2014.

Full text of DOI:10.1039/c3cc45958f

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Synthesis of 3-((trifluoromethyl)thio)indoles
via a reaction of 2-alkynylaniline with
trifluoromethanesulfanylamide†
Jie Sheng,a Shaoyu Lia and Jie Wu*ab
Cite this: Chem. Commun., 2014,
50, 578
Received 5th August 2013,
Accepted 18th October 2013
DOI: 10.1039/c3cc45958f
www.rsc.org/chemcomm
3-((Trifluoromethyl)thio)indoles can be synthesized by a palladium(II)-
catalyzed reaction of 2-alkynylaniline with trifluoromethanesulfanyl-
amide in the presence of bismuth(III) chloride. The presence of
bismuth(III) chloride is crucial for the success of this transformation,
which activates the trifluoromethanesulfanylamide during the reaction.
Scheme 1 Incorporation of the (trifluoromethyl)thio moiety into an indole
scaffold.
Currently, much attention has been paid to the introduction
of fluorine atoms into drugs or leading compounds, with the
aim of improving their medicinal properties.1,2 Due to its high formation of indoles are based on the palladium(II)-catalyzed
hydrophobicity, the (trifluoromethyl)thio (SCF3) moiety has reactions of 2-alkynylanilines.7 Recently, Liu and co-workers
been used as the fluorine source recently.3 As a result, several reported a silver-catalyzed intramolecular oxidative aminofluori-
efforts have been made to incorporate the (trifluoromethyl)thio nation of alkynes to produce 4-fluoroisoquinolines and 4-fluoro-
moiety into small molecules.4,5 For instance, Qing and co-workers pyrrolo[a]isoquinolines.2h During the investigation, they found
reported a transition-metal-free oxidative trifluoromethylthiol- that the presence of free N–H inhibited the fluorination process.
ation of alkynes using elemental sulfur with the Ruppert– Inspired by these intriguing studies and in continuation of our
Prakash reagent (CF3SiMe3).4a Buchwald and co-workers work on the synthesis of fluorinated heterocycles,8 we envisioned
described the trifluoromethylthiolation of aryl halides utilizing that N,N-dimethyl-2-alkynylaniline9 could be employed in the
AgSCF3 as a reagent.4c The reaction of alkenes or alkynes with reaction of trifluoromethanesulfanylamide for the generation of
trifluoromethanesulfanylamide as an equivalent of the trifluoro- (trifluoromethyl)thio-substituted indoles (Scheme 1). Thus, we
methanesulfanyl cation (CF3S+) was explored by Billard and started to explore this proposed transformation.
co-workers.5e Recently, the progress of the formation of C–SCF3
bond through direct trifluoromethylthiolation was summarized our initial efforts focused on the model reaction of N,N-dimethyl-
by Billard and co-workers.5a
2-alkynylaniline 1a with trifluoromethanesulfanylamide 2. The
In order to achieve this proposed trifluoromethylthiolation,
Indole and its derivatives have attracted continuous interest optimization of conditions for the reaction is summarized in
due to their presence in natural products and pharmaceuticals Table 1. Initially, the reaction was carried out in dichloroethane
with remarkable biological activities.6 It is highly desirable to (DCE), in the presence of Pd(OAc)2 (10 mol%) at 80 1C (Table 1,
incorporate the (trifluoromethyl)thio moiety into an indole entry 1). However, no reaction occurred. It was reported that the
scaffold (Scheme 1). The most established methods for the electrophilic addition of arenesulfinamide could be activated in
the presence of a Lewis acid.5b–f Thus, reactions using different
metal salts were examined. However, no reaction took place when
BF3ÁOEt2, FeCl3, InCl3, CuF2, CuBr, AgOTf, AgTFA, or AgNTf2 were
added (Table 1, entries 2–9). Interestingly, the desired product
3a was obtained in 49% yield when BiCl3 was used (Table 1,
entry 10). A control experiment without the addition of the
palladium(II) catalyst gave a lower yield (28%, Table 1, entry 11).
The presence of a quantitative amount of bismuth(III) chloride
is essential for the successful transformation. The reaction
a Department of Chemistry, Fudan University, 220 Handan Road, Shanghai 200433,
China. E-mail: jie_wu@fudan.edu.cn; Fax: +86 21 6564 1740;
Tel: +86 21 6510 2412
b State Key Laboratory of Organometallic Chemistry, Shanghai Institute of
Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Road,
Shanghai 200032, China
† Electronic supplementary information (ESI) available: Experimental procedure,
characterization data, 19F, 1H and 13C NMR spectra of compounds 3. See DOI:
10.1039/c3cc45958f
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Table 1 Initial studies of the reaction of N,N-dimethyl-2-alkynylaniline 1a
with trifluoromethanesulfanylamide 2
Table 2 Synthesis of 3-((trifluoromethyl)thio)indoles via a palladium(II)-
catalyzed reaction of N,N-dimethyl-2-alkynylaniline with trifluoromethane-
sulfanylamide in the presence of bismuth(III) chloridea
Entry
[Pd]
Lewis acid
T (1C)
Solvent
Yielda (%)
1
2
3
4
5
6
7
8
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
—
—
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
70
60
100
80
80
80
80
80
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DMF
MeCN
Toluene
THF
0
0
0
0
0
0
0
0
0
BF3ÁOEt2
FeCl3
InCl3
CuF2
CuBr
AgOTf
AgTFA
AgNTf2
BiCl3
BiCl3
BiCl3
BiCl3
BiCl3
BiCl3
BiI3
Bi(OAc)3
Bi(OTf)3
BiCl3
BiCl3
BiCl3
BiCl3
BiCl3
BiCl3
BiCl3
BiCl3
BiCl3
BiCl3
BiCl3
BiCl3
BiCl3
9
10
11
12b
13b
14c
15d
16
17
18
19
20
21
22e
23f
24f
25f
26f
27f
28f
29f
30f
31f
49
28
Trace
Trace
47
39
0
—
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2
0
Trace
25
36
39
59
80
47
36
67
0
65
0
40
33
PdBr2
Pd(TFA)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
a
Isolated yield based on 2-alkynylaniline 1.
Various N,N-dimethyl-2-alkynylanilines with electron-withdrawing
or electron-donating groups on the aromatic ring worked well
under standard conditions. Different functional groups including
fluoro, chloro, methyl, and ester were all compatible during the
reaction process. Additionally, the substituents attached to the
triple bond of N,N-dimethyl-2-alkynylanilines were tolerated
as well. For instance, compound 3j with an ester group was
1,4-Dioxane
a
Isolated yield based on N,N-dimethyl-2-(2-phenylethynyl)aniline 1a.
b
c
In the presence of 0.5 equivalents of BiCl3. In the presence of
d
1.5 equivalents of BiCl3. In the presence of 5 mol% of Pd(OAc)2.
e
f
In the presence of 2.0 equivalents of PhNHSCF3. In the presence of
3.0 equivalents of PhNHSCF3.
failed when 0.5 equivalents of BiCl3 were used in the trans- obtained in 72% yield. The alkyl substituted (cyclopropyl and
formation (Table 1, entries 12 and 13). The results were not be n-butyl) N,N-dimethyl-2-alkynylanilines were all good substrates
improved when the amount of BiCl3 was increased (Table 1, in the transformation. However, reaction of N,N-dimethyl-2-
entry 14), or when the amount of the palladium(II) catalyst was ethynylaniline with trifluoromethanesulfanylamide failed to
reduced (Table 1, entry 15). It seemed that the chloride anion produce the expected product.
was important in the reaction. No reaction occurred when other
A possible mechanism was proposed, which is shown in
bismuth(III) salts were employed (Table 1, entries 16–18). The Scheme 2. We envisioned that an intramolecular cyclization of
results were poor when Pd(OAc)2 was switched to PdCl2, PdBr2, N,N-dimethyl-2-alkynylaniline would happen to produce inter-
or Pd(TFA)2 (Table 1, entries 19–21). The corresponding 3-((tri- mediate A. Subsequently, the methyl group of intermediate A
fluoromethyl)thio)indole 3a could be obtained in 80% yield would be removed by attack of the chloride from bismuth(III)
when 3.0 equivalents of trifluoromethanesulfanylamide 2 were chloride. In the meantime, the trifluoromethanesulfanyl cation
used in the reaction (Table 1, entry 23). Changing the tempera- (CF3S+) would be formed via an activation of trifluoromethane-
ture did not improve the final outcome (Table 1, entries 24–26). sulfanylamide 2 by bismuth(III) chloride, which would react
Further screening of the solvents indicated that DCE was the with the in situ generated indole to produce the 3-((trifluoro-
best choice (Table 1, entries 27–31).
methyl)thio)indole 3.
With the optimal conditions established for this palladium(II)-
Reactions of other 2-alkynylanilines with trifluoromethane-
catalyzed fluorination process, we turned our attention to sulfanylamide were then explored (Scheme 3). The reactions
exploring the substrate scope of this reaction, by using different also proceeded smoothly when 2-alkynylanilines 1o–1r were
2-alkynylanilines. The results are summarized in Table 2. employed. During the reaction process, the ethyl or benzyl
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Financial support from the National Natural Science Founda-
tion of China (No. 21032007, 21172038) is gratefully acknowledged.
Notes and references
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Scheme 2 A possible mechanism for the reaction of N,N-dimethyl-2-
alkynylaniline with trifluoromethanesulfanylamide.
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Scheme 3 Reactions of other 2-alkynylanilines with trifluoromethane-
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group was selectively removed. This is reasonable based on the
above mechanism, since the benzyl cation or ethyl cation is
more electrophilic during the transformation. Interestingly,
substrate 1s was a good substrate under the conditions, which
reacted with trifluoromethanesulfanylamide to give the desired
product 3q in 60% yield (Scheme 3, eqn (3)). These results
indicated that the reaction underwent an intramolecular cycli-
zation, first catalyzed by Pd(II) to produce the indole ring, which
then went through electrophilic addition with trifluoromethane-
sulfanylamide in the presence of bismuth(III) chloride to generate
the 3-((trifluoromethyl)thio)indole.
In summary, we have described a facile route to 3-((trifluoro-
methyl)thio)indoles via a palladium(II)-catalyzed reaction of
2-alkynylaniline with trifluoromethanesulfanylamide in the pre-
sence of bismuth(III) chloride. Different functional groups could
be compatible in this transformation. Exploration of the use of
trifluoromethanesulfanylamide for the trifluoromethylthiolation
of other heterocycles is ongoing in our laboratory.
580 | Chem. Commun., 2014, 50, 578--580
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