Trifluoromethanesulfonic Anhydride as a Low-Cost and Versatile Trifluoromethylation Reagent

Article abstract of DOI:10.1002/anie.201803566

A large number of reagents have been developed for the synthesis of trifluoromethylated compounds. However, an ongoing challenge in trifluoromethylation reaction is the use of less expensive and practical trifluoromethyl sources. We report herein the unprecedented direct trifluoromethylation of (hetero)arenes using trifluoromethanesulfonic anhydride as a radical trifluoromethylation reagent by merging photoredox catalysis and pyridine activation. Furthermore, introduction of both the CF₃ and OTf groups of the trifluoromethanesulfonic anhydride into internal alkynes to access tetrasubstituted trifluoromethylated alkenes was achieved. Since trifluoromethanesulfonic anhydride is a low-cost and abundant chemical, this method provides a cost-efficient and practical route to trifluoromethylated compounds.

Full text of DOI:10.1002/anie.201803566

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Accepted Article
Title: Trifluoromethanesulfonic Anhydride as a Low-Cost and Versatile
Trifluoromethylation Reagent
Authors: Feng-Ling Qing, Yao Ouyang, and Xiu-Hua Xu
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201803566
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10.1002/anie.201803566
Angewandte Chemie International Edition
COMMUNICATION
Trifluoromethanesulfonic Anhydride as a Low-Cost and Versatile
Trifluoromethylation Reagent
Yao Ouyang, Xiu-Hua Xu, and Feng-Ling Qing*
Abstract: A large number of reagents have been developed for the
synthesis of trifluoromethylated compounds. However, an ongoing
challenge in trifluoromethylation reaction is the use of less expensive
and practical trifluoromethyl sources. We report herein the
unprecedented direct trifluoromethylation of (hetero)arenes using
trifluoromethanesulfonic anhydride as a radical trifluoromethylation
reagent by merging photoredox catalysis and pyridine activation.
Furthermore, the introduction of both of the CF3 and OTf groups of
trifluoromethanesulfonic anhydride into internal alkynes to access
tetrasubstituted trifluoromethylated alkenes is developed. As
Trifluoromethanesulfonic anhydride ((CF3SO2)2O, Tf2O) is an
inexpensive and abundant chemical,[15] and thus represents an
attractive and practical trifluoromethylation reagent. However,
the use of Tf2O as trifluoromethyl source has not been reported.
Due to its significant electrophilic characteristic,[16] Tf2O normally
reacts with O-nucleophiles to produce the triflates, a class of
widely used coupling partners for cross-coupling reactions
(Scheme 1a). In this way, the O-S bond of Tf2O is cleaved via a
two-electron addition-elimination process. We envisioned that if
Tf2O could serve as a CF3 radical precursor by cleavage of the
CF3-S bond via a single-electron-transfer (SET) pathway, it
would provide a new and easily available trifluoromethylation
reagent for cost-efficient synthesis of trifluoromethylated
compounds.
trifluoromethanesulfonic anhydride is
a low-cost and abundant
chemical, this protocol provides a cost-efficient and practical route to
trifluoromethylated compounds.
The
prominent
applications
of
trifluoromethylated
compounds in pharmaceuticals, agrochemicals and advanced
functional materials have triggered extensive efforts on
introduction of trifluoromethyl group (CF3) into organic
molecules.[1] Over the past decade, impressive achievements
have been made in the field[2-4] and radical trifluoromethylation
has emerged as an attractive and straightforward strategy for
the preparation of trifluoromethylated compounds.[2] Compared
to the nucleophilic and electrophilic trifluoromethylations, radical
trifluoromethylation can directly introduce CF3 into organic
molecules without requirement of additional step(s) to prepare
functionalized substrates (e.g. organohalides and organometallic
reagents), thus providing a more efficient route to access
trifluoromethylated compounds. Among the developed radical
trifluoromethylation methods, the photoredox- or transition-
metal-catalyzed radical trifluoromethylation has received great
Scheme 1. The reaction of Tf2O.
attention recently. In this context,
a
large number of
trifluoromethylation reagents have been recognized as the
trifluoromethyl radical precursors, such as CF3X (X = I, Br),[5]
CF3CO2H and its derivatives,[6] CF3SO2-containing compounds
(CF3SO2Na,[7] Zn(SO2CF3)2,[8] [CF3SO2Ag],[9] CF3SO2Cl,[10]
triflones[11]), TMSCF3,[12] Umemoto reagent,[13] and Togni
reagent.[14] However, most of them are either expensive
(Zn(SO2CF3)2, Umemoto and Togni reagents), commercially
unavailable ([CF3SO2Ag], triflones), gaseous (CF3I, CF3Br) or
volatile (CF3SO2Cl, TMSCF3), which significantly restricts their
widespread applications. Therefore, the searching for low-cost
and practical radical CF3 sources remains appealing.
In view of the weakness of S-O bond of Tf2O, which is prone
to acceptance of a nucleophile, we hypothesized that if a
nucleophile can serve as a Tf2O activating reagent (AR) for the
formation of a triflated complex A (AR+-SO2CF3TfO-), in which
complex A could readily facilitate the cleavage of CF3-S bond via
a SET pathway by photoredox catalysis, and thus it would be
feasible to use Tf2O for the radical trifluoromethylation (Scheme
1b). It was noteworthy that this activation mode was similar to
Stephenson’s the activation of (CF3CO)2O with pyridine N-
oxide.[6b] In continuation of our research interest in visible-light-
induced fluoroalkylation reactions,[17] we herein disclose the
unprecedented application of Tf2O as radical CF3 source for the
direct trifluoromethylation of (hetero)arenes by a combination of
the pyridine activation with photoredox catalysis. The reaction
system is also extended to a simultaneous trifluoromethylation
and trifluoromethanesulfonyloxylation (triflation) of alkynes.
[*]
Y. Ouyang, Dr. X.-H. Xu, Prof. Dr. F.-L. Qing
Key Laboratory of Organofluorine Chemistry, Center for Excellence
in Molecules Synthesis, Shanghai Institute of Organic Chemistry,
Chinese Academy of Science, 345 Lingling Lu, Shanghai 200032
(China)
On the basis of our hypothesis, firstly, several activating
reagents including NEt3, pyridine and PhSPh that Tf2O was
activated for the formation of complex A were identified.[18] Then,
the direct trifluoromethylation of mesitylene (1a) with Tf2O in the
presence of activating agent and catalytic Ru(bpy)3Cl2 under
visible-light irradiation was investigated (Table 1, entries 1-3). To
E-mail: flq@mail.sioc.ac.cn
Prof. Dr. F.-L. Qing
College of Chemistry, Chemical Engineering and Biotechnology,
Donghua University, 2999 North Renmin Lu, Shanghai, 201620
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/anie.201803566
Angewandte Chemie International Edition
COMMUNICATION
our delight, the trifluoromethylation reaction proceeded smoothly
to give the trifluoromethylated product 2a in high yield when
pyridine was used as the activating agent (entry 1). In contrast,
NEt3 and PhSPh were ineffective (entries 2-3). Further
optimization of reaction conditions by examining a series of
pyridine derivatives, photocatalysts and solvents diminished the
reaction efficiency (see the supporting information). Decreasing
the catalyst loading from 3 mol% to 2 mol% resulted in a
comparable yield and better mono/bis-selectivity (entry 4), but a
lower catalyst loading (1 mol%) reduced the yield of 2a to 60%
(entry 5). Additionally, only a trace of 2a was formed in the
presence of a catalytic amount of pyridine (entry 6). Finally, the
control experiments demonstrated that both the photocatalyst
and visible light were essential for the trifluoromethylation
(entries 7 and 8).
complex compound pentoxifylline (1w), thus demonstrating the
potential utility of this reaction for late-stage trifluoromethylation.
CF3
Ru(bpy)3Cl2 (2 mol%)
pyridine, LEDs
R
R
+ (CF3SO2)2O
DCE, rt, 6 h
X
1
X
2
OMe
CF3
CF3
MeO
CF3
2a, 86%
2b, 65%[a]
2c, 56%[a]
(mono:bis = 4:1)[a]
(mono:bis = 2.5:1)[a]
OMe
(mono:bis = 3:1)[a,b]
CO2Me
OMe
TfO
CF3
2e, 51%
MeO2C
CF3
CF3
2d, 61%
2f, 55%
Table 1. Optimization of reaction conditions[a]
Cl
O
O
O
CF3
Cl
B
B
O
CF3
[a] (mono:bis = 5:1)[a] 2h, 66%
Cl
(mono:bis = 4:1)[a]
2g, 75%
O
B
O
O
MeO2C
CF3
HO2C
CF3
O
CF3
Entry
1
Activating reagent
pyridine
NEt3
x
Yield (2a-mono/2a-bis, %)[b]
O
3.0
3.0
3.0
2.0
1.0
2.0
2.0
2.0
56/32
0
[a] (mono:bis = 3.7:1)[a]
2j, 74%
2k, 72%
2i, 66%
2
3
PhSPh
0
S
S
MeO2C
CF3
CF3
O
4
pyridine
pyridine
pyridine
pyridine
pyridine
67/20
54/6
trace
0
S
B
CF3
5
O
NC
CN
Br
6[c]
7[d]
8[e]
[a] (mono:bis = 2.4:1)[a]
2n, 46%[d]
2l, 65%
2m, 57%
Ts
Ts
N
0
CF3
N
CF3
CF3
CF3
[a] Reaction conditions: 1a (0.2 mmol), (CF3SO2)2O (0.6 mmol), activating
reagent (0.6 mmol), Ru(bpy)3Cl2 (x mol%), DCE (2.0 mL), LEDs, N2, rt, 6 h. [b]
Yields determined by 19F NMR spectroscopy using trifluoromethoxybenzene
as an internal standard. [c] Pyridine (0.04 mmol). [d] Without Ru(bpy)3Cl2. [e]
No light.
O
S
MeO2C
2o, 55%
Ac
2p, 59%
2q, 65%
2r, 51%
CF3
N
N
MeO
MeO
N
N
Cl
Cl
N
S
MeO
OMe
With the optimized reaction conditions in hand (Table 1, entry
4), the substrate scope of the C─H trifluoromethylation of
(hetero)arenes with Tf2O was investigated (Scheme 2).
Benzenes bearing either electron-donating or electron-
withdrawing substituents (1a-h) underwent the current reaction
smoothly with good regioselectivities to afford the corresponding
trifluoromethylated products in moderate to excellent yields.
However, phenols and anilines were not compatible with the
reaction conditions. A variety of heteroarenes including furan (1i-
k), thiophene (1l-n), pyrrole (1o,p), benzofuran (1q),
benzo[b]thiophene (1r), thiazole (1s), pyrimidine (1t),
quinoxaline (1u), and thieno[2,3-d]pyrimidine (1v) were all viable
substrates under the reaction conditions, furnishing the
corresponding CF3-heteroaromatics with moderate efficiency. In
most cases, good regioselectivities were observed. Electron-
poor substrates (1n, 1s, 1t) afforded the products in slightly
lower yields along with the recovery of some of the starting
materials. Highly electron-deficient heteroarenes such as
pyridines and pyrazines displayed minimal reactivity. Importantly,
the synthetically useful triflate (1e), boronate (1g, 1i, 1l), and
bromide (1m) were all tolerated under the reaction conditions.
Remarkably, this protocol could be successfully applied to
CF3
CF3
2t, 43%[c,d]
2s, 50%[c,d]
2u, 51%[a,b](mono/bis = 3.2/1)[a]
O
O
Cl
N
N
N
CF3
CF3
N
2w, 50%[b]
S
O
N
Cl
N
2v, 57%[b]
Scheme 2. Substrate scope of C─H trifluoromethylation of (hetero)arenes.
Reaction conditions: 1 (0.4 mmol), (CF3SO2)2O (1.2 mmol), pyridine (1.2
mmol), Ru(bpy)3Cl2 (0.008 mol), DCE (4.0 mL), LEDs, N2, rt, 6 h, isolated
yields.
[a]
Determined
by
19F
NMR
spectroscopy
using
trifluoromethoxybenzene as an internal standard. [b] 12 h. [c] 72 h. [d] Some of
the starting material was recovered.
As the reaction design shown in Scheme 1b, Tf2O was
transformed to the CF3 radical and OTf anion. In the light of the
atom economy, we wondered whether both of the CF3 and OTf
groups could be simultaneously introduced into organic
molecules. Inspired by the recent advances of the
trifluoromethylation functionalization reaction of alkenes and
alkynes,[19] the internal alkynes were subjected to the
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10.1002/anie.201803566
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COMMUNICATION
photoredox trifluoromethylation protocol (Scheme 3). Gratifyingly, intermediate C by [Ru(bpy)3]3+ would give the cation D and
the simultaneous trifluoromethylation and triflation of alkynes 3
regenerate [Ru(bpy)3]2+ to close the catalytic cycle. Finally, the
deprotonation of intermediate D affords the desired products 2.
In the cases of alkynes 3, the similar CF3-radical addition and
then SET oxidation by [Ru(bpy)3]3+ gave vinylic cation D'. The
reaction of intermediate D' with OTf anion provided products 4.
proceeded
trifluoromethylated
smoothly
to
afford
in
the
high
tetrasubstituted
regio- and
alkenes
4
stereoselectivities. In some cases, the competing C─H
trifluoromethylation of the benzene ring could be detected.
Furthermore, neither terminal alkynes nor alkenes were suitable
substrates for this transformation. To date, however, only Koike
and Akita recently have reported the photoredox-catalyzed
trifluoromethylation and triflation of alkynes,[20] but the more
TfO
SO2CF3
Tf2O
+
Py
*[Ru(bpy)3]2+
visible light
N
A
expensive
S-(trifluoromethyl)diphenylsulfonium
[Ru(bpy)3]2+
SET
trifluoromethanesulfonate (Yagupol’skii-Umemoto reagent) was
used as CF3 source. Thus, this reaction provides a low-cost,
atom-economy, and practical method for preparation of the
tetrasubstituted trifluoromethylated alkenes.
Py
TfO
N
SO2CF3
SO2
[Ru(bpy)3]3+
CF3
B
SET
- H
CF3
CF3
CF3
R
R
R
R
X
X
X
X
1
C
D
2
Ru3+
TfO
CF3
R
CF3
CF3
Ar
TfO
CF3
R
Ar
Ar
Ru2+
Ar
R
R
3
C'
D'
4
Scheme 4. Proposed reaction mechanism.
In conclusion, we have developed an unprecedented
photoredox-catalyzed trifluoromethylation of (hetero)arenes
using the low-cost and abundant Tf2O as a trifluoromethyl radical
source in the presence of pyridine. This reaction is compatible
with a range of arenes and heteroarenes. Furthermore, internal
alkynes underwent the simultaneous trifluoromethylation and
trifluoromethanesulfonyloxylation in this protocol to access
tetrasubstituted trifluoromethylated alkenes. The relative cost
and versatile reactivities of Tf2O render this protocol highly
attractive for the synthesis of trifluoromethylated compounds.
Acknowledgements
National Natural Science Foundation of China (21332010,
21421002), the Strategic Priority Research Program of the
Chinese Academy of Sciences (XDB20000000), and Youth
Innovation Promotion Association CAS (No. 2016234) are
greatly acknowledged for funding this work. We are grateful to
Professors Xingang Zhang and Lingling Chu for helpful
discussion.
Scheme 3. Trifluoromethyltriflation of alkynes. Reaction conditions: 3 (0.4
mmol), (CF3SO2)2O (1.2 mmol), pyridine (1.2 mmol), Ru(bpy)3Cl2 (0.008 mol),
DCE (4.0 mL), LEDs, N2, rt, 12 h, isolated yields. [a] Determined by 19F NMR
spectroscopy using trifluoromethoxybenzene as an internal standard.
On the basis of the above results and literature
reports,[10a,14,18] a proposed reaction mechanism was depicted in
Scheme 4. Irradiation of the photoredox catalyst [Ru(bpy)3]2+
with blue LEDs could generate the excited state *[Ru(bpy)3]2+,
Keywords: trifluoromethylation • trifluoromethanesulfonic
anhydride • photoredox catalysis • pyridine • radical
which is
a strong reductant. Single-electron reduction of
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COMMUNICATION
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10.1002/anie.201803566
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
Yao Ouyang, Xiu-Hua Xu, Feng-Ling
Qing*
Page No. – Page No.
Trifluoromethanesulfonic Anhydride
as a Low-Cost and Versatile
Trifluoromethylation Reagent
An unprecedented application of trifluoromethanesulfonic anhydride as a radical
trifluoromethylation reagent was developed by merging photoredox catalysis and
pyridine activation. The synthetic utility of this protocol was exemplified by C─H
trifluoromethylation of (hetero)arenes and trifluoromethyltriflation of alkynes.
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