Asymmetric silver-catalysed intermolecular bromotrifluoromethoxylation of alkenes with a new trifluoromethoxylation reagent

Article abstract of DOI:10.1038/nchem.2711

Fluorinated organic compounds are becoming increasingly important in pharmaceuticals, agrochemicals and materials science. The introduction of trifluoromethoxy groups into new drugs and agrochemicals has attracted much attention due to their strongly electron-withdrawing nature and high lipophilicity. However, synthesis of trifluoromethoxylated organic molecules is difficult owing to the decomposition of trifluoromethoxide anion and β-fluoride elimination from transition-metal-trifluoromethoxide complexes, and no catalytic enantioselective trifluoromethoxylation reaction has been reported until now. Here, we present an example of an asymmetric silver-catalysed intermolecular bromotrifluoromethoxylation of alkenes with trifluoromethyl arylsulfonate (TFMS) as a new trifluoromethoxylation reagent. Compared to other trifluoromethoxylation reagents, TFMS is easily prepared and thermally stable with good reactivity. In addition, this reaction is operationally simple, scalable and proceeds under mild reaction conditions. Furthermore, broad scope and good functional group compatibility has been demonstrated by application of the method to the bromotrifluoromethoxylation of double bonds in natural products and natural product derivatives.

Full text of DOI:10.1038/nchem.2711

ARTICLES
PUBLISHED ONLINE: 23 JANUARY 2017 | DOI: 10.1038/NCHEM.2711
Asymmetric silver-catalysed intermolecular
bromotrifluoromethoxylation of alkenes with a
new trifluoromethoxylation reagent
1
1
1
1
1,2
*
Shuo Guo , Fei Cong , Rui Guo , Liang Wang and Pingping Tang
Fluorinated organic compounds are becoming increasingly important in pharmaceuticals, agrochemicals and materials
science. The introduction of trifluoromethoxy groups into new drugs and agrochemicals has attracted much attention due
to their strongly electron-withdrawing nature and high lipophilicity. However, synthesis of trifluoromethoxylated organic
molecules is difficult owing to the decomposition of trifluoromethoxide anion and β-fluoride elimination from transition-
metal–trifluoromethoxide complexes, and no catalytic enantioselective trifluoromethoxylation reaction has been reported
until now. Here, we present an example of an asymmetric silver-catalysed intermolecular bromotrifluoromethoxylation of
alkenes with trifluoromethyl arylsulfonate (TFMS) as a new trifluoromethoxylation reagent. Compared to other
trifluoromethoxylation reagents, TFMS is easily prepared and thermally stable with good reactivity. In addition, this
reaction is operationally simple, scalable and proceeds under mild reaction conditions. Furthermore, broad scope and good
functional group compatibility has been demonstrated by application of the method to the bromotrifluoromethoxylation of
double bonds in natural products and natural product derivatives.
he development of new methods for the introduction of values (π = 1.04) compared to that of the CF (π = 0.88), CH
3
x
3
x
fluorine into small molecules has recently received significant (π = 0.52), OCH (π = –0.02), which is important in permeability
x
3
x
T
attention due to the growing importance of fluorinated and absorption of the compounds bearing this functional group in
organic compounds in pharmaceuticals, agrochemicals and biological systems. However, due to the reversible decomposition of
1
–5
materials . In particular, the trifluoromethoxy group (OCF ) is trifluoromethoxide anion to afford fluoride and fluorophosgene, as
3
of great interest in new drug and agrochemical design because of well as β-fluoride elimination from transition-metal–trifluorometh-
6
–10
its electron-withdrawing effects and high lipophilicity . For oxide complexes, methods for the introduction of this functional
1
1–13
example, the OCF3 group has one of the highest lipophilicity group remain a significant challenge
. Furthermore, to the best
a
O
O
OCF3
S
O
O
OCF3
CF3OF
S
R
F3C
OCF3
O2N
NO2
FMT (1948)
Gas, toxic
TFMT (1965)
Volatile liquid, expensive
DNTFB (2010)
Low reactivity
TFMS (2016)
Easily prepared, thermally stable
this work)
(
b
O
O
O
S
O
R1
S
+
OCF3
OCF3
Ag (cat.)
CsF
F
R4
Br
Chiral ligand
R1
R
R
+
AgOCF3
+
R2
Br
R2
R4
R3
R3
AgOCF3 generated in situ
c
AgF (30 mol%)
(DHQD)2PHAL
DBDMH, CsF
Br
N
R1
O
O
O
OCF3
R4
S
R1
Br
R2
OCF3
N
+
R2
Br
R4
R3
MeCN/DCM, 25 to –20 °C
R3
O
F
1
2a
3
DBDMH
Figure 1 | Trifluoromethyl aryl sulfonate (TFMS) as a new trifluoromethoxylation reagent. a, Compared to traditional trifluoromethoxylation reagents,
TFMS is easily prepared and thermally stable with good reactivity. b, In the presence of silver salts and fluoride, TFMS could be used as a new
trifluoromethoxylation reagent to generate AgOCF in situ, which was used for bromotrifluoromethoxylation of alkenes. c, The first example of an asymmetric
3
silver-catalysed intermolecular bromotrifluoromethoxylation of alkenes with TFMS as a new trifluoromethoxylation reagent was described. This reaction is
operationally simple, scalable and proceeds under mild reaction conditions with excellent functional group tolerance.
1
2
State Key Laboratory and Institute of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, China. Collaborative Innovation Center of Chemical
Science and Engineering, Tianjin 300071, China. *e-mail: ptang@nankai.edu.cn
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.2711
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Table 1 | Optimization of reaction conditions for asymmetric silver-catalysed intermolecular bromotrifluoromethoxylation of alkenes.
OCF3
Br
Br
N
Conditions
DBDMH
O
+
[OCF3]
MeCN/DCM, 25 to –20 °C
N
F
Br
F
O
1a
2
3a
DBDMH
†
e.r.
Entry
3
[OCF ]
[Ag]
Fluoride
Chiral ligand
Yield (%)*
1
2a
2a
2a
2b
2c
2d
2e
2f
2a
2a
2a
2a
2a
2a
2a
2a
AgF
AgF
AgF
AgF
AgF
AgF
AgF
AgF
AgF
AgF
AgF
AgF
AgF
None
None
None
NaF
KF
L1
L1
L1
L1
L1
L1
L1
L1
L2
L3
L4
L5
L6
L1
93
98
98
75
82
97
89
94
70
54
89
92
0
90:10
91:9
2
3
4
5
6
7
8
9
CsF
CsF
CsF
CsF
CsF
CsF
CsF
CsF
CsF
CsF
CsF
None
CsF
None
91.5:8.5
91.5:8.5
89.5:10.5
90:10
90:10
90:10
22.5:77.5
52:48
62.5:37.5
50:50
–
1
1
1
1
1
1
1
0
1
2
3
4
5
6
40
50
0
62:38
57.5:42.5
–
L1
None
O
O
O
O
O
O
O
O
O
iPr O
O
O
S
S
S
S
S
S
OCF3
OCF3
OCF3
OCF3
OCF3
OCF3
iPr
F
F3C
O2N
H
MeO
Et
iPr
2a
2b
2c
2d
2e
2f
Et
Et
Et
Et
N
N
N
N N
N
N N
OMe
N
O
O
O
O
N
MeO
OMe
MeO
OMe
OH
N
N
N
N
(DHQD)2PHAL
(DHQ)2PHAL
L1
L2
L3
Et
Et
Et
Et
Ph
N
N
N
N
O
O
O
O
O
OH
O
O
P
N
N
MeO
OMe
MeO
OMe
O
O
Ph
N
N
N
N
(DHQD)2AQN
(DHQD)2PYR
L4
L5
L6
2
atmosphere, 25 to −20 °C. *Yields
Reaction conditions: styrene 1a (1.0 equiv.), 2 (3.0 equiv.), AgF (30 mol%), chiral ligand (10 mol%), DBDMH (1.0 equiv.), fluoride ion (2.0 equiv.), 2:1 (v:v) MeCN/DCM, N
were determined by F NMR with benzotrifluoride as a standard. The enantiomeric ratios (e.r.) were determined by chiral GC analysis.
1
9
†
of our knowledge, no catalytic enantioselective trifluoromethoxyla- The Liu group has reported a palladium-catalysed intramolecular
tion reaction has been reported to date. aminotrifluoromethoxylation of alkenes with AgOCF as the tri-
Traditional methods for the synthesis of trifluoromethyl ethers fluoromethoxylation reagent . The Zhang group has reported a
3
3
0
1
4
31
through chlorine/fluorine exchange on chlorinated precursors , silver-mediated trifluoromethoxylation of α-diazo esters . The
15
deoxyfluorination of fluoroformates , oxidative fluorodesulfuriza- Hartwig group have reported a silver-mediated fluorodecarboxyla-
tion , and electrophilic trifluoromethylation of hydroxyl tion for the synthesis of trifluoromethyl aryl ethers from
16
groups1
7–23
suffer from poor substrate scope, harsh reaction con- α-phenoxy-α,α-difluoro acetic acid . Also the structures of Cu(I),
32
ditions and use of highly toxic reagents. Recently, Ngai and co- Ag(I) and Au(I) trifluoromethoxide complexes and their appli-
3
3
34
workers explored a two-step sequence to prepare trifluoromethoxy- cations have been reported by Vicic and Weng , respectively.
2
4–26
lated compounds through intramolecular OCF migration
. In Despite the advances of these methods, new trifluoromethoxylation
3
addition, methods for the formation of trifluoromethyl ethers reagents were scarce (Fig. 1a). For instance, fluoroxytrifluoro-
were also developed with transition metals. For example, Ritter’s methane (FTM) was employed for direct trifluoromethoxylation
3
5
group has reported a silver-mediated cross coupling of aryl stan- of alkenes and aromatics through a radical mechanism , but
nanes and aryl boronic acids with tris(dimethylamino)sulfonium this reagent is a toxic gas and so is not easy to handle.
27
trifluoromethoxide (TASOCF ) . Qing and co-workers have Trifluoromethyl triflate (TFMT) which has been known since its
3
3
6
reported
a silver-mediated oxidative trifluoromethylation of preparation by Noftle and Cady , was used as a source of the tri-
2
8,29
37,38
phenols and alcohols to prepare the trifluoromethyl ethers
.
fluoromethoxide anion in nucleophilic substitution reactions
.
2
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.2711
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Table 2 | Substrates scope for asymmetric silver-catalysed intermolecular bromotrifluoromethoxylation of simple alkenes.
AgF (30 mol%)
Br
R1
O
O
(DHQD)2PHAL
DBDMH, CsF
O
OCF3
N
R1
R2
R4
S
Br
+
N
OCF3
R2
MeCN/DCM, 25 to –20 °C
R4
Br
R3
R3
F
O
DBDMH
1
2a
3
OCF3
OCF3
OCF3
Br
OCF3
Br
OCF3
Br
*
OCF3
Br
Br
Br
*
*
*
*
*
F
3
Cl
Br
I
O2N
3e, 59% yield
F3CO
a, 92% yield
3b, 94% yield
3c, 79% yield
3d, 83% yield
3f, 83% yield
91.5:8.5 e.r.
92:8 e.r.
91:9 e.r.
90:10 e.r.
83.5:16.5 e.r.
89:11 e.r.
OCF3
Br
OCF3
OCF3
OCF3
OCF3
OCF3
Br
Br
Br
Br
Br
*
*
*
*
*
*
tBu
NC
F3C
MeO2C
Ph
3
g, 88% yield
3h, 60% yield
72:28 e.r.
3i, 79% yield
85:15 e.r. (S)
3j, 75% yield
83.5:16.5 e.r.
3k, 73% yield
78:22 e.r.
3l, 77% yield
68.5:31.5 e.r.
88:12 e.r.
OCF3
Br
OCF3
Br
OCF3
OCF3
OCF3
OCF3
Br
Br
Br
Br
Br
O
O
*
*
*
*
*
*
N
N
Me
3
Br
N
m, 61% yield
2:18 e.r.
3n, 75% yield
83:17 e.r.
3o, 74% yield
82.5:17.5 e.r.
3p, 83% yield
77.5:22.5 e.r.
3q, 94% yield
83:17 e.r.
3r, 89% yield
91.5:8.5 e.r.
8
O
OCF3
Br
OCF3
OCF3
OCF3
*
OCF3
Br
OMe
NHBoc
3
*
*
*
Br
*
*
Br
*
*
OAc
*
OAc
2
*
N
Br
Br
OCF3
3t, 77% yield
N
3
s, 90% yield
3u, 87% yield
3v, 90% yield
3w, 85% yield
3x, 82% yield
6
2:38 e.r.
d.r. = 1.7:1 (S)
d.r. > 20:1, 58.5:41.5 e.r.
d.r. > 20:1, 68.5:31.5 e.r.
d.r. > 20:1, 87:13 e.r.
Br
d.r. > 20:1,85:15 e.r.
2R, 3S)
OCF3
(
Br
Br
*
Br
Br
*
OBn
*
OBn
*
*
BnO
*
BnO
*
*
8
OCF3
*
OCF3
OCF3
OCF3
OCF3
Br
‡
‡
†
3y, 82% yield
3z, 52% yield
3aa , 76% yield
3bb, 72% yield
3cc , 84% yield
3dd, 80% yield
r.r. = 5.8:1, 68:32 e.r.
r.r. = 4.3:1, 55:45 e.r.
d.r. > 20:1
d.r. > 20:1, 73:27 e.r.
r.r. = 19:1, d.r. > 20:1
O
OCF3
Br
Br
Br
*
Br
Br
OCF3
*
OCF3
* *
*
O
*
OCF3
*
*
OCF3
Br
OCF3
‡
†
‡
†
‡
3
ee, 80% yield
3ff, 80% yield
r.r. > 20:1, d.r. = 1:1
†
3hh , 95% yield
3ii , 88% yield
3jj , 90% yield
d.r. > 20:1
3
gg, 39% yield
r.r. = 14:1, d.r. = 3:1
d.r. > 20:1
d.r. > 20:1
Reaction conditions: alkenes 1 (1.0 equiv), 2a (3.0 equiv), AgF (30 mol%), (DHQD)
2
PHAL (10 mol%), DBDMH (1.0 equiv.), CsF (2.0 equiv.), 2:1 (v:v) MeCN/DCM, N
2
atmosphere, 25 to −20 °C. Yields of
isolated products are given unless otherwise noted. The enantiomeric ratios (e.r.) were determined by chiral GC or HPLC analysis on commercial columns. The regioisomeric ratios (r.r.) and diastereomeric ratios
1
19
†
19
‡
(
d.r.) were determined by H NMR or F NMR. Asterisks designate stereogenic centres. Yields were determined by F NMR with benzotrifluoride as a standard. No enantioselectivities were observed.
However, this reagent is a volatile liquid (bp = 19 °C) and expensive, applied to direct bromotrifluoromethoxylation of double bonds in
which limits its synthetic utility. Recently, Langlois and co-workers complex small molecules (Fig. 1c).
reported a new and direct trifluoromethoxylation reaction with 2,4-
39
dinitro(trifluoromethoxy)benzene (DNTFB) . However, this Results and discussion
reagent showed lower reactivity and suffered from poor substrate The initial investigation was focused on the reaction of 4-fluorostyr-
scope. Therefore, the development of a catalytic asymmetric tri- ene 1a with various TFMSs (2) using 1,3-dibromo-5,5-dimethylhy-
fluoromethoxylation method with a new trifluoromethoxylation dantoin (DBDMH) as a bromine source. As briefly illustrated in
reagent is highly desirable.
Table 1 (see Supplementary Tables 1–6 for more details), after
We were inspired by Togni’s finding that trifluoromethyl aryl extensive screening with AgF as the catalyst, fluoride salts were
sulfonate (TFMS), which is easily prepared from aryl sulfonic acid found to be suitable nucleophiles for the activation of TFMS.
4
0
with Togni’s reagent, was largely unreactive toward nucleophiles . Different fluoride salts were evaluated and CsF gave the highest
Due to the favourable stability and ease of preparation, we hypoth- yield and enantioselectivity (entries 1–3). Next, a thorough evalu-
esized that TFMS could be used as a new trifluoromethoxylation ation of different TFMSs revealed that substituents on the aromatic
reagent if a suitable nucleophile was found to activate the reagent rings influenced the reaction yields (entries 3–7), and sulfonate 2a
to generate the trifluoromethoxide anion in situ, which would was found to be particularly effective and was chosen as the trifluor-
bromotrifluoromethoxylate alkenes (Fig. 1b). Here, we present an omethoxylation reagent for further optimization. It is worth
example of an asymmetric silver-catalysed intermolecular bromotri- mention that substituents on the aromatic rings slightly influenced
fluoromethoxylation of alkenes with TFMS as a new trifluoro- enantioselectivity. Enantioselectivities varied dramatically with the
methoxylation reagent. This protocol is operationally simple, chiral ligands and the dimeric cinchona alkaloid (DHQD) PHAL
2
scalable, proceeds under mild reaction conditions and can be (L1) was found to give the highest (entries 8–13). Control
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Supplementary Fig. 2). After thoroughly optimizing the reaction
conditions, reactions with AgF (30 mol%), L1 (10 mol%), 2.0
equiv of CsF, 3.0 equiv of TFMS 2a, 1.0 equiv of DBDMH in 2:1
Table 3 | Substrate scope for asymmetric silver-catalysed
bromotrifluoromethoxylation of complex small molecules.
R1
AgF (30 mol%)
O
O
OCF3
(v:v) MeCN/DCM under N atmosphere were found to produce
2
(DHQD)2PHAL
R4
S
R1
DBDMH, CsF
Br
high yields and enanotioselectivities of the desired product.
R2
OCF3
+
F
R2
3 R4
Having established the optimum conditions, we explored the
substrate scope of the transformation (Table 2). First, a variety of
styrenes bearing electron-donating to electron-withdrawing substi-
tuents were successfully converted to the desired products with
good isolated yields (59–94%) and enantioselectivities (58.5:41.5
to 92:8 e.r.) (1a–1x). A good range of functional groups including
ester, amide, nitrile, nitro, chloride, bromide and iodide were well
tolerated under mild reaction conditions. Notably, heteroaromatic
substrates and an amino acid derivative (1r, 1s, 1t) were also suc-
cessfully employed to provide the corresponding products (3r, 3s,
R3
MeCN/DCM, 25 to –20 °C
R
4
2a
5
Complex olefin
O
F3CO
O
Br
H
*
H
O
H
O
O
H
H
F3CO
H
AcO
N
Br
F3CO
OBz
Br
3
t). The enantioselectivity was affected by the electronic properties
H
of the aromatic substituents. Generally, electron-withdrawing
groups provided higher enantioselectivities (up to 92:8 e.r.), while
electron-donating groups gave lower enantioselectivities. Next, we
turned our attention to expanding the substrate scope to unacti-
vated alkenes (1y–1jj). To our great delight, the bromotrifluoro-
methoxylation reaction with mono-, di-, tri-, and even tetra-
substituted alkenes proceeded smoothly with good yields, but
lower enantioselectivities. Compared to tri-substituted alkenes
5a, 72% yield
5b, 80% yield
r.r. = 4.6:1, d.r. > 20:1
r.r. = 2.3:1, d.r. > 20:1
N
†
5c, 42% yield
r.r. = 3.9:1, d.r. = 1.8:1
(
1cc, 1dd, 1ee, 1ff), lower regioisomeric ratios (r.r.) were observed
AcO
O
OAc
OAc
X-ray of 5a
X-ray of 5b
with mono-substituted alkenes (1y, 1z). It is worth mentioning that
exclusive chemoselectivity for bromotrifluoromethoxylation of
electron-rich olefins was observed in the presence of unsaturated
olefins (3q, 3ee). Cyclic alkenes (1hh, 1ii, 1jj) were also suitable
for this bromotrifluoromethoxylation reaction. The reaction exhib-
ited excellent diastereoselectivities to give the desired trans-products
Me
O
O
O
O
H
H
Br
HO
O
O
Br
*
H
H
(
3hh, 3ii, 3jj) in good yields, but no enantioselectivities were
observed. Furthermore, the reaction of acyclic (E)-olefins (1v, 1x,
bb) proceeded to give the opposite diastereoisomers (3v, 3x,
3bb) as compared with the reaction of acyclic (Z)-olefins (1u,
w, 1aa). The absolute configurations of products 3i, 3t, 3x were
*
OCF3
OCF3
1
5d, 70% yield
5e, 70% yield
d.r. = 3:1
d.r. = 3.2:1
1
determined by single-crystal X-ray diffraction analysis, and the
major enantiomers (3i, 3t) were found to have (S)-configurations,
the major enantiomer 3x was found to have the (2R, 3S)-configur-
ation. We currently have not established the absolute configurations
of other products. In addition, we prepared 3r on a gram scale
under standard reaction conditions in 90% isolated yield with
Reaction conditions: alkenes 4 (1.0 equiv.), 2a (3.0 equiv.), AgF (30 mol%), (DHQD)
DBDMH (1.0 equiv.), CsF (2.0 equiv.), 2:1 (v:v) MeCN/DCM, N atmosphere, 25 to −20 °C. Yields
of isolated products are given. The regioisomeric ratios (r.r.) and diastereomeric ratios (d.r.) were
determined by H NMR or F NMR. Asterisks designate stereogenic centres. 2.0 equiv. of DBDMH
were used.
2
PHAL (10 mol%),
2
1
19
†
experiments were performed and lower yields and enantioselectiv- 92.5:7.5 e.r., which demonstrates both scalability and practicality
ities were observed in the absence of AgF (entry 14–16). of this method.
Interestingly, without AgF and CsF, lower yield and enantioselectiv-
Encouraged by our success with simple alkenes, more complex
19
ity were also found (entry 14). F NMR experiments showed that substrates were then investigated (Table 3). Gratifyingly, the sub-
L1 can activate TFMS and trifluoromethoxide anion could be gen- strates 4a and 4b, bearing a cyclic alkenyl group, were compatible
erated in the absence of DBDMH and fluoride sources (see under the standard reaction conditions and provided the desired
a
O
b
O
O
O
1
2
) CsF (1.0 equiv)
CD3CN, 30 min
S
S
OCF3
F
+
AgOCF3
) AgF (1.0 equiv)
F
MeO
H
F
CF3
O
Ag
OMe
2a
6
7
N
N
19F-NMR
H
Br
+
N
N
O
O
N
N
Et
Et
6
unknown
7
6
90 80 70 60 50 40 30 20 10 0 –20 –40 –60 –80 –100 –120 –140
19
Figure 2 | Insights into the reaction mechanism of asymmetric silver-catalysed intermolecular bromotrifluoromethoxylation of alkenes. a, F NMR
spectroscopy of reaction revealed that AgOCF
outcome observed was proposed.
3
was generated in the reaction. b, One possible transition-state model that predicts the stereochemical
4
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trans-products 5a and 5b in good yields and diastereoselectivities, References
but with low regioselectivities. The structure of major isomers of 5a 1. Müller, K., Faeh, C. & Diederich, F. Fluorine in pharmaceuticals: looking beyond
intuition. Science 317, 1881–1886 (2007).
and 5b were confirmed by single-crystal X-ray diffraction analysis.
In addition, the cinchonine derivative 4c was also a good candidate
for this transformation, thus giving 5c in 42% yield with 3.9:1
2.
Berger, R., Resnati, G., Metrangolo, P., Weber, E. & Hulliger, J. Organic fluorine
compounds: a great opportunity for enhanced materials properties. Chem. Soc.
Rev. 40, 3496–3508 (2011).
regioselectivity and 1.8:1 diastereoselectivity. Finally, the bromotri- 3. Isanbor, C. & O’Hagan, D. Fluorine in medicinal chemistry: a review of anti-
fluoromethoxylation reaction with the estrone derivative (4d) and
taxol derivative (4e) proceeded smoothly to provide the corresponding
product 5d, 5e in good isolated yields with low diastereoselectivities.
Detailed configurations for 5c, 5d, 5e have not yet been determined.
Although we do not yet have a precise understanding of the reaction
mechanism and the origin of the enantioselectivity, some preliminary
cancer agents. J. Fluorine Chem. 127, 303–319 (2006).
Purser, S., Moore, P. R., Swallow, S. & Gouverneur, V. Fluorine in medicinal
chemistry. Chem. Soc. Rev. 37, 320–330 (2008).
Jeschke, P. The unique role of fluorine in the design of active ingredients for
modern crop protection. ChemBioChem. 5, 570–589 (2004).
Shimizu, M. & Hiyama, T. Modern synthetic methods for fluorine-substituted
target molecules. Angew. Chem. Int. Ed. 44, 214–231 (2005).
4
5
6
.
.
.
studies were conducted. Monitoring of the reaction between TFMS 2a 7. Leroux, F., Jeschke, P. & Schlosser, M. α-Fluorinated ethers, thioethers, and
19
amines: anomerically biased species. Chem. Rev. 105, 827–856 (2005).
Jeschke, P., Baston, E. & Leroux, F. R. α-Fluorinated ethers as “exotic” entity in
medicinal chemistry. Mini-Rev. Med. Chem. 7, 1027–1034 (2007).
Manteau, B., Pazenok, S., Vors, J. P. & Leroux, F. R. New trends in the chemistry
of α-fluorinated ethers, thioethers, amines and phosphines. J. Fluorine Chem.
131, 140–158 (2010).
and CsF by F NMR spectroscopy showed that CsOCF (–21 ppm)
3
8
.
.
and aryl sulfonyl fluoride (6) were generated in the reaction.
Addition of 1.0 equiv. AgF to this solution led to immediate formation
9
38,41
of AgOCF (7, –25 ppm) (Fig. 2a) . Furthermore, control exper-
3
iments were performed to demonstrate that AgOCF3 (7) was
formed when AgF react directly with TFMS 2a, which demonstrates
1
1
0. Landelle, G., Panossian, A. & Leroux, F. R. Trifluoromethyl ethers and
thioethers as tools for medicinal chemistry and drug discovery. Curr. Top. Med.
-
that AgOCF can be generated in situ during the reaction. Based on
3
Chem. 14, 941–951 (2014).
these observations and the absolute configuration determined, one
possible transition state arrangement that predicts the stereochemi-
cal outcome observed is proposed (Fig. 2b). The styrene substrate is
located in the chiral pocket via π,π-stacking with the quinoline of
the catalyst. The tertiary amine of the catalyst activates DBDMH
and directs the bromine toward the double bond of the substrate.
The nitrogen on one of the quinolines likely coordinates the
1. Leroux, F., Manteau, B., Vors, J. & Pazenok, S. Trifluoromethyl ethers –
synthesis and properties of an unusual substituent. Beilstein J. Org. Chem. 4,
13 (2008).
2. Liang, T., Neumann, C. N. & Ritter, T. Introduction of fluorine and fluorine-
containing functional groups. Angew. Chem. Int. Ed. 52, 8214–8264 (2013).
3. Tlili, A., Toulgoat, F. & Billard, T. Synthetic approaches to trifluoromethoxy-
substituted compounds. Angew. Chem. Int. Ed. 55, 11726–11735 (2016).
4. Yagupol’skii, L. M. Synthesis of derivatives of phenyl trifluoromethyl ether. Dokl.
Akad. Nauk SSSR 105, 100–102 (1955).
1
1
1
AgOCF and steers it to the reacting site. Further experiments are
3
needed to investigate the reaction mechanism.
15. Sheppard, W. A. α-Fluorinated ethers. I. aryl fluoroalkyl ethers. J. Org. Chem. 29,
–11 (1964).
1
1
6. Kuroboshi, M., Suzuki, K. & Hiyama, T. Oxidative desulfurization-fluorination
of xanthates. A convenient synthesis of trifluoromethyl ethers and difluoro
Conclusion
We have developed an asymmetric silver-catalysed intermolecular
(
methylthio) methyl ethers. Tetrahedron Lett. 33, 4173–4176 (1992).
bromotrifluoromethoxylation of alkenes with TFMS as a new tri- 17. Umemoto, T. Electrophilic perfluoroalkylating agents. Chem. Rev. 96,
fluoromethoxylation reagent. This new method offers direct access
to a variety of trifluoromethoxylated compounds from olefin sub-
strates including natural products and their derivatives. Compared
to other trifluoromethoxylation reagents, TFMS is easily prepared
and thermally stable with good reactivity. Additionally, the reaction
1757–1778 (1996).
1
3
8. Umemoto, T., Adachi, K. & Ishihara, S. CF oxonium salts, O-(trifluoromethyl)
dibenzofuranium salts: in situ synthesis, properties, and application as a real
+
CF
3
species reagent. J. Org. Chem. 72, 6905–6917 (2007).
1
9. Stanek, K., Koller, R. & Togni, A. Reactivity of a 10-I-3 hypervalent iodine
trifluoromethylation reagent with phenols. J. Org. Chem. 73, 7678–7685 (2008).
tolerates a wide range of functional groups and is amenable to gram- 20. Fantasia, S., Welch, J. M. & Togni, A. Reactivity of a hypervalent iodine
trifluoromethylating reagent toward THF: ring opening and formation of
trifluoromethyl ethers. J. Org. Chem. 75, 1779–1782 (2010).
1. Koller, R. et al. Zinc-mediated formation of trifluoromethyl ethers from alcohols
and hypervalent iodine trifluoromethylation reagents. Angew. Chem. Int. Ed. 48,
scale synthesis. With its operational simplicity and mild conditions,
this method could enable wide applications in pharmaceutical and
agrochemical research and development for the synthesis of
trifluoromethoxylated compounds.
2
4332–4336 (2009).
22. Liang, A. et al. Regioselective synthesis of N-heteroaromatic trifluoromethoxy
Methods
compounds by direct O−CF
5102–5106 (2016).
23. Brantley, J. N., Samant, A. V. & Toste, F. D. Isolation and reactivity of
3
bond formation. Chem. Eur. J. 22,
1
19
13
General. For H, F and C NMR spectra of compounds in this manuscript see
Supplementary Information. For details of the synthetic procedures and tables
including detail experimental, see Supplementary Information.
trifluoromethyl iodonium salts. ACS Cent. Sci. 2, 341–350 (2016).
24. Hojczyk, K. N., Feng, P., Zhan, C. & Ngai, M. Y. Trifluoromethoxylation of
General procedure. In a glove box, to silver fluoride (9.51 mg, 0.0750 mmol,
arenes: synthesis of ortho-trifluoromethoxylated aniline derivatives by OCF
migration. Angew. Chem. Int. Ed. 53, 14559–14563 (2014).
3
3
0.0 mol%), (DHQD)
2
PHAL (hydroquinidine 1,4-phthalazinediyldiether; 19.5 mg,
0
.0250 mmol, 10.0 mol%) and CsF (76.0 mg, 0.500 mmol, 2.00 equiv.) in a 20.0 ml
25. Feng, P., Lee, K. N., Lee, J. W., Zhan, C. & Ngai, M. Y. Access to a new class
of synthetic building blocks via trifluoromethoxylation of pyridines and
pyrimidines. Chem. Sci. 7, 424–429 (2016).
26. Lee, K. N., Lei, Z., Morales-Rivera, C. A., Liu, P. & Ngai, M. Y. Mechanistic
studies on intramolecular C–H trifluoromethoxylation of (hetero) arenes via
dried Schlenk tube, were added DBDMH (71.5 mg, 0.250 mmol, 1.00 equiv.),
CH CN (2.00 ml) and DCM (1.00 ml). Trifluoromethyl 4-fluorobenzenesulfonate
130 µl, 0.750 mmol, 3.00 equiv.) was added to the reaction and the resulting
mixture was stirred for 30 min at 25 °C, then cooled to −20 °C. Styrene (1)
0.250 mmol, 1.00 equiv.) in DCM (0.200 ml) was added dropwise and the reaction
mixture was stirred at −20 °C for a further 24 h. The reaction was quenched with a
saturated aqueous solution of Na SO (1.0 ml), then NH Cl (2.0 ml) at −20 °C. The
aqueous layer was extracted with CH Cl (8.0 ml × 3). The combined organic layers
were dried over anhydrous MgSO . The filtrate was concentrated in vacuo and the
3
(
(
OCF -migration. Org. Biomol. Chem. 14, 5599–5605 (2016).
3
27. Huang, C., Liang, T., Harada, S., Lee, E. & Ritter, T. Silver-mediated
2
3
4
trifluoromethoxylation of aryl stannanes and arylboronic acids. J. Am. Chem.
Soc. 133, 13308–13310 (2011).
28. Liu, J. et al. Silver-mediated oxidative trifluoromethylation of phenols:
direct synthesis of aryl trifluoromethyl ethers. Angew. Chem. Int. Ed. 54,
2
2
4
residue was purified by preparative TLC or column chromatography on silica gel.
1
1839–11842 (2015).
Data availability. The crystallographic data have been deposited at the Cambridge
Crystallographic Data Centre (CCDC) as CCDC 1503812 (3i), 1491566 (3t),
29. Liu, J., Xu, X. & Qing, F. Silver-mediated oxidative trifluoromethylation of
alcohols to alkyl trifluoromethyl ethers. Org. Lett. 17, 5048–5051 (2015).
30. Chen, C., Chen, P. & Liu, G. Palladium-catalyzed intramolecular
aminotrifluoromethoxylation of alkenes. J. Am. Chem. Soc. 137,
1
503813 (3x), 1491568 (5a) and 1491567 (5b) and can be obtained free of charge
from www.ccdc.cam.ac.uk/getstructures.
1
5648–15651 (2015).
Received 8 July 2016; accepted 30 November 2016;
published online 23 January 2017
3
1. Zha, G. et al. Silver-mediated direct trifluoromethoxylation of α-diazo esters via
the OCF anion. Chem. Commun. 52, 7458–7461 (2016).
3
–
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.2711
ARTICLES
3
3
3
3
3
2. Zhang, Q. et al. Fluorodecarboxylation for the synthesis of trifluoromethyl aryl
ethers. Angew. Chem. Int. Ed. 55, 9758–9762 (2016).
3. Zhang, C. & Vicic, D. A. Oxygen-bound trifluoromethoxide complexes of
copper and gold. Organometallics 31, 7812–7815 (2012).
4. Chen, S. et al. Aryl-BIAN-ligated silver (I) trifluoromethoxide complex. Dalton
Trans. 44, 19682–19686 (2015).
5. Rozen, S. Selective fluorinations by reagents containing the OF group.
Chem. Rev. 96, 1717–1736 (1996).
6. Noftle, R. E. & Cady, G. H. Preparationandpropertiesofbis(trifluoromethylsulfuryl)
peroxide and trifluoromethyl trifluoromethanesulfonate. Inorg. Chem. 4,
41. Sokolenko, T. M., Davydova, Y. A. & Yagupolskii, Y. L. Efficient synthesis of 5′-
fluoroalkoxythiazoles via α-bromo-α-fluoroalkoxyacetophenones Hantzsch type
cyclization with thioureas or thioamides. J. Fluorine Chem. 136, 20–25 (2012).
Acknowledgements
The authors dedicate this manuscript to Qi-lin Zhou on the occasion of his sixtieth
birthday. We are grateful for financial support from the State Key Laboratory of Elemento-
Organic Chemistry, the National Key Research and Development Program of China
(
2016YFA0602900) and NFSC (21402098, 21421062, 21522205).
Author contributions
1
010–1012 (1965).
S.G., F.C., R.G. and L.W. performed the experiments and analysed the data. P.T. designed
and directed the project. P.T. wrote the manuscript. All of the authors discussed the
results and commented on the manuscript.
3
3
3
7. Taylor, S. L. & Martin, J. C. Trifluoromethyl triflate: synthesis and reactions.
J. Org. Chem. 52, 4147–4156 (1987).
8. Kolomeitsev, A. A., Vorobyev, M. & Gillandt, H. Versatile application of
trifluoromethyl triflate. Tetrahedron Lett. 49, 449–454 (2008).
9. Marrec, O., Billard, T., Vors, J., Pazenok, S. & Langlois, B. R. A new and
direct trifluoromethoxylation of aliphatic substrates with 2, 4-dinitro
Additional information
Supplementary information and chemical compound information are available in the
online version of the paper. Reprints and permissions information is available online at
www.nature.com/reprints. CorrespondenceandrequestsformaterialsshouldbeaddressedtoP.T.
(trifluoromethoxy) benzene. Adv. Synth. Catal. 352, 2831–2837 (2010).
4
0. Koller, R., Huchet, Q., Battaglia, P., Welch, J. M. & Togni, A. Acid-mediated
formation of trifluoromethyl sulfonates from sulfonic acids and a hypervalent
iodine trifluoromethylating agent. Chem. Commun. 2009, 5993–5995 (2009).
Competing financial interests
The authors declare no competing financial interests.
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