A Trifluoromethylcarbene Source

Article abstract of DOI:10.1021/acs.orglett.6b01042

The trifluoromethylcarbene (:CHCF₃) was found to be conveniently generated from (2,2,2-trifluoroethyl)diphenyl-sulfonium triflate (Ph₂S⁺CH₂CF₃ ^-OTf), which was successfully applied in Fe-catalyzed cyclopropanation of olefins, giving the corresponding trifluoromethylated cyclopropanes in high yields.

Full text of DOI:10.1021/acs.orglett.6b01042

Letter
pubs.acs.org/OrgLett
A Trifluoromethylcarbene Source
Yaya Duan,† Jin-Hong Lin,*,† Ji-Chang Xiao,*,† and Yu-Cheng Gu‡
†Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling
Road, Shanghai 200032, China
‡Syngenta, Jealott’s Hill International Research Centre, Bracknell, Berkshire RG42 6EY, U.K.
S
* Supporting Information
ABSTRACT: The trifluoromethylcarbene (:CHCF3) was found to be
conveniently generated from (2,2,2-trifluoroethyl)diphenyl-sulfonium triflate
(Ph2S+CH2CF3 −OTf), which was successfully applied in Fe-catalyzed
cyclopropanation of olefins, giving the corresponding trifluoromethylated
cyclopropanes in high yields.
rifluoromethylcarbene has proven to be a versatile
intermediate for the synthesis of CF3-containing com-
prompting us to search for other suitable catalysts. As
porphyrin-coordinated transition-metal complexes can effi-
ciently catalyze many transformations,12 various porphyrin
complexes (TPP)M (TPP = 5,10,15,20-tetraphenyl-21H,23H-
porphine) were then screened (Table 1, entries 4−7). To our
delight, a 40% yield was obtained with the use of (TPP)FeCl as
the catalyst (Table 1, entry 5). A brief survey of the reaction
solvents (Table 1, entries 8−11) revealed that DMA was a
suitable solvent, in which the conversion gave the desired
product in 88% yield (Table 1, entry 11). Lowering the loading
of the catalyst led to a dramatic decrease of the yield (Table 1,
entry 12). The examination of the molar ratio of the starting
materials (Table 1, entries 13−15) showed that a slight excess
of 2 and base could afford the product in high yield (Table 1,
entry 14). Other bases were also effective for this reaction
(Table 1, entries 15−18). Compared to TBAT, CsF was a
better choice due to the cost and the atom-economy issues
(Table 1, entry 16). Elevating the temperature did not increase
the yield (Table 1, entry 19). Increasing the concentration of
starting materials and shortening the reaction time gave
comparable yields (Table 1, entries 20−22). The reaction
proceeded very fast and could give the product in 85% yield
within 0.5 h (Table 1, entry 22).
T
pounds, which have found widespread application in medicinal
and agricultural chemistry due to the unique properties of CF3-
functionality.1 As a triplet carbene, trifluoromethylcarbene has
been applied to a variety of organic transformations,2 such as
trifluoroethylation,3 cyclopropanation,4 cyclopropenation,4f and
aziridination.5 In spite of these important accomplishments, the
safe generation of trifluoromethylcarbene remains a significant
challenge. There has been only one known source to produce
trifluoromethylcarbene, 2,2,2-trifluorodiazoethane (CF3CHN2),
which is generated from 2,2,2-trifluoroethyl amine.2−5 A severe
limitation of CF3CHN2 is that it is a gas, which is potentially
explosive and toxic. As is well-known, carbene could be readily
generated from ylides including phosphonium ylides6 and sulfur
ylides.7 Based on our previous observation that difluorocarbene
can be produced from phosphonium ylide8 and that (2,2,2-
trifluoroethyl)diphenylsulfonium triflate (Ph2S+CH2CF3 −OTf,
2) is a mild and general trifluoroethylidenesulfur ylide reagent,9
we speculated that this sulfur ylide reagent may serve as a
trifluoromethylcarbene precursor and have now investigated its
application in Fe-catalyzed cyclopropanation of olefins.
We have shown that trifluoroethylidenesulfur ylide is a
valuable tool for the cyclopropanation of olefins.9 However, as
is the case for most sulfur ylides, this ylide can only be applied
to the conversion of electron-deficient olefins by this approach,
not to electron-neutral or -rich olefins. Interestingly, the use of
the sulfur ylide as the trifluoromethylcarbene precursor allows
for the cyclopropanation of electron-rich, -neutral, and
-deficient aryl olefins. The preliminary results are described
herein.
We then explored the scope of the trifluoromethylcarbene’s
cyclopropanation under the optimized reaction conditions
(Table 1, entry 22). As shown in Scheme 1, the scale was
increased by 5-fold to show the practicality and generality of
this transformation. Interestingly, 3a was obtained in a slightly
higher yield on the increased scale (19F NMR yield: 91% vs
85%). High diastereoselectivity was observed in all reactions,
and the diastereoselectivity determined by 19F NMR was above
98/2 in all cases with the exception of 3p and 3q. The trans-
Since copper complexes such as cupric sulfate (CuSO4)10
and cupric acetylacetonate [Cu(acac)2]11 and a rhodium
complex7a have been found to be able to promote the
cyclopropanation with sulfur ylide, we first employed these
metal sources as catalysts to examine the conversion of 4-
methoxystyrene (1a) with 2 in the presence of TBAT, a known
nice base for deprotonation of 2 to generate trifluoro-
ethylidenesulfur ylide9 (Table 1, entries 1−3). Disappointingly,
none of them were effective enough for this reaction,
1
configuration was assigned by H−1H NOESY analysis of 3a
(see Supporting Information). All of the electron-rich, -neutral,
and -deficient aryl olefins could be converted smoothly to the
expected products in good to excellent yields (3a−3o). The
conversion of terminal olefins might not be particularly
Received: April 11, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b01042
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Letter
a
a
Table 1. Optimization of Reaction Conditions
Scheme 1. Substrate Scope for Cyclopropanation
b
c
entry
solvent
cat.
base
ratio
yield (%)
1
Cy
CuSO4
TBAT
TBAT
TBAT
TBAT
TBAT
TBAT
TBAT
TBAT
TBAT
TBAT
TBAT
TBAT
TBAT
TBAT
TBAT
CsF
1:2:2
1:2:2
1:2:2
1:2:2
1:2:2
1:2:2
1:2:2
1:2:2
1:2:2
1:2:2
1:2:2
1:2:2
2:1:1
0
2
Cy
Cu(acac)2
Rh2(OAc)4
(TPP)Cu
16
0
3
Cy
4
Cy
0
5
Cy
(TPP)FeCl
(TPP)Co
40
3
6
Cy
7
Cy
(TPP)Ni
0
8
DCM
THF
DMF
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
(TPP)FeCl
(TPP)FeCl
(TPP)FeCl
(TPP)FeCl
(TPP)FeCl
(TPP)FeCl
(TPP)FeCl
(TPP)FeCl
(TPP)FeCl
(TPP)FeCl
(TPP)FeCl
(TPP)FeCl
(TPP)FeCl
(TPP)FeCl
(TPP)FeCl
10
59
74
88
68
83
86
81
88
82
62
85
85
82
85
9
10
11
d
12
13
14
15
16
17
18
1:1.1:1.2
1.1:1:1.1
1:1.1:1.2
1:1.1:1.2
1:1.1:1.2
1:1.1:1.2
1:1.1:1.2
1:1.1:1.2
1:1.1:1.2
Cs2CO3
TBAF
CsF
e
19
fg
20 ,
CsF
a
b
Isolated yields. Yields were determined by 19F NMR.
fg
21 ,
CsF
fh
22 ,
CsF
Scheme 2. Large-Scale Reaction
a
Reaction conditions: 1a (0.1 mmol), 2 and base in solvent (2 mL);
Cy = cyclohexane; TPP = 5,10,15,20-tetraphenyl-21H,23H-porphine.
b
c
Molar ratio of 1a:2:base. Determined by 19F NMR with the use of
d
trifluoromethylbenzene as an internal standard. 2.5 mol % of the
catalyst was used. The reaction was performed at 50 °C. 1 mL of
DMA was used. The reaction time was shortened to 1 h. The
reaction time was shortened to 0.5 h.
e
f
g
h
intramolecular cyclization of CF3-substrates suffer from tedious
procedures to prepare the starting materials.4a,15 Recently,
Baran found that trifluoromethylcyclopropyl sulfinate salt is a
good reagent for a radical reaction to afford CF3-cyclo-
propanes.16 But only one position of the cyclopropyl ring is
substituted. Obviously, one of the most straightforward and
convenient protocols is the cyclopropanation of olefins with
CF3-containing reagents. As the most commonly used reagent,
2,2,2-trifluorodiazoethane (CF3CHN2) has been widely used in
the transition-metal-catalyzed cyclopropanation reactions.4b,d−f
However, CF3CHN2 is a gas which is potentially explosive and
toxic, thus limiting its application. We have previously reported
that 2 is an efficient sulfur ylide reagent for cyclopropanation of
olefins, but is only limited to electron-deficient olefins under
metal-free conditions.9 Apparently, the protocol described
above is attractive and promising due to the ready availability
of salt 2, a wide substrate scope, and mild reaction conditions.
Trifluoromethylcarbene cannot be directly observed in the
reaction system by 19F NMR. Fortunately, we found that salt 2
can react with (TPP)FeCl under the optimal reaction
conditions in the absence of olefin substrate to give CF3-
olefins 4, which was determined by 19F NMR and HRMS
(High Resolution Mass Spectroscopy) (Scheme 3, eq 1). The
formation of CF3-olefins suggests that a trifluoromethylcarbene
species is formed. If this is the case, 2 should be finally
converted to diphenylsulfide (Ph2S) in the catalytic cyclo-
propanation reaction. Indeed, Ph2S was isolated in high yield
for cyclopropanation of olefin 3a (Scheme 3, eq 2). Based on
the previous reports that carbene can react with aldehydes in
sensitive to steric effects, as evidenced by the high yields
obtained for products 3p−3r. But the steric effects obviously
affect the diastereoselectivity (3p−3q). In the case of the
internal olefin, no desired product was detected by 19F NMR
(3s). The conversion could be applied well to conjugated aryl
1,3-diene (3t). For the reaction of conjugated aliphatic 1,3-
diene, a very low yield (<20%) was obtained. Aliphatic olefin
cannot be converted at all under these optimal conditions due
to its lower reactivity (3u). Since Ferrocene derivatives have
been widely used as ligands or catalysts,13 the incorporation of a
CF3-cyclopropyl motif into this scaffold may find new
applications in catalytic chemistry (3v). The utility of this
cyclopropanation reaction was further demonstrated by the
development of a convenient route to a CF3-cyclopropyl
estrone derivative (3w).
For the small-scale reaction, a 5 mol % of the catalyst loading
was required, and the decrease in the catalyst loading would
dramatically decrease the yield (Table 1, entry 12 vs 11).
However, the use of 0.5 mol % catalyst could afford the desired
product in 90% yield (1.95 g) with increase of the scale of the
reaction by 100-fold (Scheme 2), demonstrating the synthetic
utility of this protocol from a practical point of view.
As the incorporation of the CF3 group into cyclopropanes
represents important structural modifications which can
improve the bioactivity of the target molecules,14 the synthesis
of CF3-cyclopropanes has received a great deal of attention
from the synthetic community. Traditional approaches such as
B
DOI: 10.1021/acs.orglett.6b01042
Org. Lett. XXXX, XXX, XXX−XXX

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expected to become an efficient and versatile trifluoromethyl-
carbene reagent.
Scheme 3. Experimental Evidence
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b01042.
Experimental procedures and characterization for new
compounds are provided (PDF)
AUTHOR INFORMATION
a
b
Determined by 19F NMR. Isolated yield based on salt 2.
■
Corresponding Authors
the presence of the Ph3P/Fe-catalyst to give olefins,17 we
examined the conversion of aldehyde 4-BrC6H4CHO with the
Ph3P/Fe-catalyst/2 system to find out if olefin could be
produced (Scheme 3, eq 3). Gratifyingly, the aldehyde was
successfully transformed into the desired olefin 5, further
supporting the trifluoromethylcarbene hypothesis.
*E-mail: jlin@sioc.ac.cn (J.-H.L.).
*E-mail: jchxiao@sioc.ac.cn (J.-C.X.).
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
On the basis of the above results, we proposed a reaction
mechanism shown in Scheme 4. Sulfur ylides have been
■
We thank National Basic Research Program of China
(2015CB931900, 2012CBA01200), the National Natural
Science Foundation (21421002, 21472222, 21502214), the
Chinese Academy of Sciences (XDA02020105,
XDA02020106), and the Syngenta Ph.D. Fellowship Awarded
to Y. Duan for financial support.
Scheme 4. A Plausible Reaction Mechanism Was Proposed
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