Silver-Mediated Trifluoromethylthiolation-Iodination of Arynes

Article abstract of DOI:10.1021/acs.orglett.6b00142

(Chemical Equation Presented). A one-pot trifluoromethylthiolation-iodination of arynes with trifluoromethylthiosilver (AgSCF₃) and 1-iodophenylacetylene is described. This protocol allows rapid construction of o-trifluoromethylthiolated arene building blocks in moderate yields. These products were found to be excellent precursors for Yagupolskii-Umemoto-type electrophilic trifluoromethylation reagents.

Full text of DOI:10.1021/acs.orglett.6b00142

Letter
pubs.acs.org/OrgLett
Silver-Mediated Trifluoromethylthiolation−Iodination of Arynes
Yuwen Zeng and Jinbo Hu*
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling
Road, Shanghai 200032, China
S
* Supporting Information
ABSTRACT: A one-pot trifluoromethylthiolation−iodination of arynes with trifluoromethylthiosilver (AgSCF3) and 1-
iodophenylacetylene is described. This protocol allows rapid construction of o-trifluoromethylthiolated arene building blocks in
moderate yields. These products were found to be excellent precursors for Yagupolskii−Umemoto-type electrophilic
trifluoromethylation reagents.
he incorporation of fluorine-containing functional groups
Tinto organic molecules often leads to an improvement of
their physical and biochemical properties.1 Among fluorinated
molecules, aryl trifluoromethylthioethers (ArSCF3) have
attracted considerable attention in life sciences owing to the
intrinsic properties of the SCF3 group,2,3 including strong
electronegativity (Hammett constant: σm = 0.40 and σp = 0.50;
larger than F and similar to CF3) and high lipophilicity (Hansch
constant πR = 1.44; much higher than F and CF3). Thus, the
development of straightforward and efficient approaches for the
introduction of the SCF3 group onto aromatic rings is highly
desirable.
Although numerous methods are now available for synthesiz-
ing ArSCF3 (Scheme 1),4 prominent limitations still remain.
For example, while traditional nucleophilic/electrophilic
trifluoromethylthiolation reactions (Scheme 1, a−c) are less
efficient and limited to specific substrates,5 recent transition-
metal-mediated cross-coupling reactions (Scheme 1, d−g)
usually require the use of toxic and/or expensive trifluor-
omethylthiolating reagent under rather harsh conditions.6
Moreover, existing protocols feature monofunctionalization.
Herein, we report a vicinal difunctionalization protocol for
aryne trifluoromethylthiolation under mild conditions (Scheme
1, h), which offers another functional group (iodine) for further
transformation.7
In our previous studies on perfluoroalkylation of arynes,8 we
demonstrated that silver is a promising metal for aryne
insertion reactions. In this scenario, we initially screened the
stable and readily prepared AgSCF3 as a nucleophilic SCF3
source.9 We reasoned that the in situ generated aryne could
undergo Ag−S bond insertion to provide an o-SCF3 arylsilver
intermediate I, which may further undergo protonation to
afford a trifluoromethylthiolated product (Scheme 2, path a).
However, this reaction turned out to be messy, and only a trace
Scheme 1. Strategies for the Introduction of
Trifluoromethylthio Group(s) onto Aromatic Rings
Scheme 2. Trifluoromethylthiolation of Aryne
Received: January 15, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b00142
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
amount of PhSCF3 was observed (Table 1, entry 1). We then
analyzed the reaction mixture and found a large quantity of
iodination product. These results are in line with our previous
work,8,12 in which iodination reagents are found to be superb in
trapping arylsilver intermediates. Among those I+ reagents, 1-
iodophenylacetylene provides the best result (Table 1, entry
12). The effect of ligand was also investigated.14 However, no
higher yields were obtained, probably due to the interference of
intramolecular coordination of the S atom. Finally, after further
tuning of the reaction parameters, the reaction yield increased
to 69% (Table 1, entry 13).
Having established optimized reaction conditions, we then
explored the scope of this silver-mediated trifluoromethylth-
iolation−iodination reaction (Table 2). For electron-neutral
and electron-rich arynes (entries 1−10), moderate yields were
Table 1. Reactions of Aryne, Trifluoromethylthiosilver, and
Electrophiles
a
entry
electrophile
none
R
yield (%)
1
H
1
0
2
2-naphthaldehyde
phenyloxirane
CH(OH)Nap
3
CH2CH(OH)Ph
0
−
4
TEMPO+ BF4
TEMPO
0
+
−
5
NO2 BF4
NO2
0
Table 2. Scope of Silver-Mediated
Trifluoromethylthiolation−Iodination of Arynes
−
6
NO+ BF4
NO
0
−
7
Col2Br+ PF6
Br
I
0
−
8
Py2I+ BF4
0
9
NIS
I
0
10
11
12
iC3F7I
I
53
28
61
69
nC4F9I
I
PhCC−I
I
b
13
PhCC−I
I
a
Reaction condition: 1a (0.1 mmol, 1 equiv), CsF (4 equiv), AgSCF3
(1.5 equiv) and electrophile (2 equiv) in MeCN (4 mL). Yields were
b
determined by 19F NMR. AgSCF3 (3 equiv).
aryne multiple-insertion compounds as major byproducts
(Scheme 2, path b). These byproducts indicate that, unlike
the unstable arylsilver intermediate10 and moderately stable o-
trifluoromethyl-substituted arylsilver intermediate,8a intermedi-
ate I is a much more stable species that possesses a much
longer lifetime and can undergo uncontrollable insertion with
the short-lived aryne to afford a series of congeners.11 Although
not conclusive, we believe that these differences in stability and
activity may stem from the intramolecular coordination
between the silver center and ortho heteroatoms (Scheme 3).
Scheme 3. Comparison of Different Arylsilvers
To diminish these undesired aryne multiple-insertion
reactions and achieve the desired vicinal difunctionalization
product, we envisioned that introducing a quenching step12 to
terminate this reaction after the initial trifluoromethylthiolation
step may solve this problem (Scheme 2, path c). Here, an
interesting dichotomy exists in choosing a suitable trapping
reagent, which is that the incoming reagent should not only be
stable (compatible with excess fluoride anions and the highly
active aryne intermediate)13 but also possess a sufficient
reactivity to capture the stable arylsilver intermediate I. In
this context, we screened a series of electrophiles with either
good stability (Table 1, entries 2 and 3) or high reactivity
(Table 1, entries 4−9). However, these reagents could not
meet the aforementioned requirements simultaneously.
a
We then continued trying some electrophilic iodination
reagents with moderate reactivity (Table 1, entries 10−12).
These reactions afford the corresponding trifluorothiolation−
Reaction conditions: aryne precursor (0.5 mmol, 1 equiv), CsF (4
equiv), AgSCF3 (3 equiv), 1-iodophenylacetylene (2 equiv), MeCN
b
c
(20 mL). Isolated yields. CsF (6 equiv).
B
DOI: 10.1021/acs.orglett.6b00142
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
obtained (46−74%), while an aryne with an electron-with-
drawing group (entry 11) gives a reduced yield (32%), probably
owing to more preferred, unproductive pathways. Functional
groups such as acetal, allyl, and bromide are compatible in this
transformation (entries 6, 9, and 11). Additionally, sterically
hindered 3,6-dimethylbenzyne (entry 3) is also amenable to
this reaction (64%). However, for dialkyl-substituted substrates
(1b−d), more CsF (6 equiv) and longer reaction times (24 h)
are needed to achieve full conversions. Although good
regioselectivities were observed in 3-substituted benzynes (1g,
1i, and 1l), the regioselectivity of 4-substituted benzyne 1j is
distinctly low (1.3:1).
used as key precursors for synthesizing Yagupolskii−Umemoto-
type electrophilic trifluoromethylation reagent.15
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b00142.
Experimental procedures and characterization data for
products (PDF)
To gain more insights into the trifluoromethylthiolation
process, we carried out a competing experiment in which the
same amount of AgCF3 and AgSCF3 was employed as different
perfluoroalkyl sources (eq 1). After the reaction reached
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: jinbohu@sioc.ac.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the National Basic Research
Program of China (2015CB931900, 2012CB215500), the
National Natural Science Foundation of China (21372246,
21421002), Shanghai City (15XD1504400), and the Chinese
Academy of Sciences.
completion, we found that the yield of trifluoromethylthiolated
products (ArSCF3, 41%) is close to that of trifluoromethylated
products (ArCF3, 42%), indicating that the rate of benzyne
thioargentation is comparable with that of benzyne carboar-
gentation. This result further demonstrates that the different
outcome of trifluoromethylthiolation of benzyne (Table 1,
entry 1) (compared to the trifluoromethylation of benzyne as
previously reported in ref 8a) comes not from the silver-
mediated insertion (the first step), but from the exceptional
stability of the arylsilver intermediate I (affecting the second
step) (Scheme 2).
To illustrate further the synthetic value of these o-
trifluoromethylthiolated aryl iodides, we performed the
Sonogashira coupling reaction between compound 2a and the
phenylacetylene. After simple evaporation and filtration, the
coupling product could readily undergo triflic acid mediated
intramolecular cyclization reaction to afford a Yagupolskii−
Umemoto-type reagent 3 in high yield (Scheme 4).15 It is
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Electrophilic Trifluoromethylation Reagent
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C
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Letter
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