Oxidative trifluoromethylation and fluoroolefination of unactivated olefins

Article abstract of DOI:10.1039/c6cc08178a

Fluorine-containing organic compounds are gaining increasing importance in medicinal chemistry. Described herein is a mild and efficient method for the radical addition of olefins with TMSCF₃ and TMSCF₂R (R = COOEt or CF₃) to deliver various α-trifluoromethylated ketones and α-fluoroolefinated ketones.

Full text of DOI:10.1039/c6cc08178a

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Marilyn M. Olmstead, Alan L. Balch, Josep M. Poblet, Luis Echegoyenet al.
Reactivity differences of Sc3N@C2n (2n 68 and 80). Synthesis of the
first methanofullerene derivatives of Sc N@D5h-C80
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Oxidative trifluoromethylation and fluoroolefination of
unactivated olefins
Ye-bin Wu a, Guo-ping Lu a, Tao Yuan a, Zhu-bing Xu a, Li Wan c, and Chun Cai* a,b
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
The fluorine-containing organic compounds are becoming S-(trifluoromethyl)diphenylsulfonium salt in the presence of an
privileged in medicinal chemistry. Described herein is a mild and excess amount of Na2S2O4 or HOCH2SO2Na, but the yields of α-
efficient method for the radical addition of olefins with TMSCF3 trifluoromethylated ketones are only 20-40%.6 In 2013, some
and TMSCF2R (R=COOEt or CF3) to deliver various α- progress has been made by Maiti’s group, accomplishing the
trifluoromethylated ketones and α-fuoroolefinated ketones.
reaction with inexpensive CF3SO2Na as the CF3 source in
excellent yields.7 Akita et al. developed photoredox-catalyzed
Fluorine, emerged as a magic element in pharmaceuticals, trifluoromethylation and oxidation mediated by an
agrochemicals and functional materials, has become more and alkoxysulfonium ion.8 These radical processes implied that the
more significant for a large range of applications.1 Unique outcome of the reaction is significantly affected by the means
physical and chemical advantages conferred by the C-F bond for the generation of the trifluoromethyl radical. AgCF3 has
usually result in enhanced membrane permeability, elevated been utilized effectively as the source of the trifluoromethyl
electronegativity and oxidation resistance.2 Among them, the radical, starting from commercially available TMSCF3 and AgF.9
CF3 unit is of extensive interest owing to its strong electron- Besides, TMSCF3 has been used extensively in organic
withdrawing power and high lipophilicity. Hence, the synthesis due to the advantages such as low cost, easy
development of new synthetic methods for the direct handling and storage. Inspired by these results, we wonder if
installation of CF3 containing small molecules has already AgCF3, generated in situ from TMSCF3 and AgF, could react
become one of the hottest fields in modern organic chemistry. with olefins and O2 to offer a direct entry towards the α-
α-trifluoromethylated carbonyl compounds as versatile trifluoromethylated carbonyl compounds.
building blocks have been well-developed in construction of
On the other hand, fluoroalkenes as building blocks and
diverse fluorinated compounds.3 The traditional synthetic targets are important in organic synthesis.11 The fluoroalkene
methods for preparing α-trifluoromethylated ketones rely on group is considered isopolar and isosteric with amide and
electrophilic or radical trifluoromethylation of enolates possesses distinct biophysical properties, including decreasing
prepared from the corresponding aldehydes, ketones, esters, H-bond donating and accepting abilities.12 Synthetic methods
and amides.4 In 2012, Grushin and co-workers developed a for constructing fluoroalkenes have not been thoroughly
nucleophilic trifluoromethylation of α-haloketones with the investigated to date and only few strategies were published. In
fluoroform-derived CuCF3 reagent.5 Despite this significant 2012, Jiang et. al reported a new route to bromofluoroalkenes
progress to deliver α-trifluoromethylated ketones, methods via the silver-assisteded difunctionalization of terminal alkynes
for the direct oxidative trifluoromethlation of widely available with NBS and AgF.13 More recently, Poisson and co-workers
alkenes remain sluggish. In 2011, Xiao and co-workers developed a copper salt-controlled divergent reactivity toward
reported the oxidative trifluoromethylation of styrenes with an α-diazocarbonyl compounds. The reported method allowed an
easy access to α-fluorovinylphosphonate in good yields.14 Base
on our initial investigations, here we also described a new
method to access α-fluoroolefinated carbonyl compounds.
Initially, we commenced our investigation by treating
styrene (1a) with TMSCF3 (2a) in the presence of AgF. To our
delight, the reaction provided a 75% yield of the desired
product 3a. When other silver (I) salts and CsF were used in
placing of AgF, less product was obtained (Table 1, entries 2-4).
After screening different solvents, DMF gave the best result
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(entries 5-7). Further screening of the reaction conditions commercially available BrCF2COOEt. Surprisingly, the
revealed that the adding method of 2a is crucial to obtaining undesired fluoroolefinated product 4a was generated in a 85%
higher yields of 3a. With the optimized reaction conditions yield under the previously optimized reaction conditions.
established, the substrate scope of the protocol was surveyed Exploring other substrates, the results were consistent with 4a
(Table 2).
(table 3). Generally, a range of substrates which bear electron-
donating and neutral groups could react with 2b to give the
corresponding adducts in moderate to good yields (4a-4g).
However, styrene bearing electron-withdrewing substituent
demonstrated lower yield (4i).
Table 1. Optimization of reaction conditions a
Table 2. Synthesis of α-CF3 substituted ketones from styrenes a, b
Entry
1c
catalyst
AgF
Solvent
DMF
DMF
DMF
DMF
DMF
MeCN
THF
Yield b(%)
75
2c,d
3c,d
4c,d
5
AgNO3
AgOAc
Ag2CO3
AgF
trace
17
trace
85
6
AgF
30
7
AgF
trace
60
8
AgF
DMSO
DMF
DMF
9
None
AgF
nr
10e
93 (89)f
a
Reaction conditions: 1a (0. 25 mmol), 2a (2 equiv.), Ag(I) salt (1.5 equiv.),
solvent (1 mL), vigorous stirring under O2 atmosphere at room temperterature, 2
b
h. Yield based on 19F NMR spectroscopy using trifluoroacetophenone as an
e
internal standard. c 2a (1.5 equiv.). d CsF (1.5 equiv.) was added. 2a was added
f
in two portions, one at the beginning and another one after 1h. Value in
parentheses refers to the isolated yield.
The reaction condition has shown excellent tolerance to
both
electron-withdrawing
and
electron-donating
substituents, including many common functional groups such
as ester, ether, aldehyde, cyano, nitro, trifluoromethyl,
methoxy, and halogen, owing to the mild reaction conditions.
Also, 2-substituted and 3-substituted styrenes reacted
a Reaction conditions: 1a (0. 25 mmol), 2a (2 equiv.), AgF (1.5 equiv.), DMF (1 mL),
b
vigorous stirring under O2 atmosphere at room temperterature, 2 h. isolated
efficiently to generate α-trifluoromethylated ketones (3k-3p
,
yield.
3w). Note that olefins bearing carbonyl groups were selectively
trifluoromethylated at the double bond without nucleophilic
addition to the carbonyl group. Heteroaromatic olefin
including 2-vinylthiophene also underwent the oxidative
trifluoromethylation successfully (3u). Fortunately, aliphatic
olefin reacted as efficiently as aromatic olefins (3v). Besides,
this oxidative trifluoromethylation method was suitable for
styrenes with a methyl group or aryl group at the β position
Inspired by these results, we tried to expand this kind of
reaction to other fluorinated TMS-sources, such as TMSCF2CF3.
To our delight, the oxidative fluoroolefinated products were
generated in good yield (5a-5c). Lately, TMSCF2H was also
tested. This difluoromethylation reagent is easily prepared by
reducing TMSCF3 with NaBH4.15 However, only trace of the
desired product could be observed via GC-MS analysis, owing
to the substantially less reactive of TMSCF2H. Either an
increase of the temperature or an extansion of the reaction
time did not lead to higher conversion.
(3s, 3t).
Because of the easy setup of “AgCF2R” species, we
investigated whether it was possible to expand this
transformation to other fluorinated substrates. Meanwhile,
difluoroalkylation compared with perfluoroalkylation can not
only introduce fluorine atoms into a molecule, but also install a
nonfluorinated moiety simultaneously which can be further
modified into various CF2 containing functional groups.10
Hence, we explore the difluoroalkylation using TMSCF2COOEt
instead of TMSCF3. This regent could be obtained from
A preliminary investigation of the reaction mechanism
suggested that the reaction is likely to involve CF3 or CF2R
(R=COOEt or CF3) radical.16 Under the optimized reaction
conditions, styrene did not produce α-CF3-substituted or α-
fuoroolefinated ketone in the presence of TEMPO. Consistent
with this observation, TEMPO-CF3 and TEMPO-CF2R was
2 | J. Name., 2012, 00, 1-3
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detected in the reaction mixture by GC-MS. Then to gain the process are its wide functional-group tolerance, mild
insight
reaction conditions. TMSCF2COOEt and TMSCF2CF3 were also
successfully applied in the reaction to deliver fluoroolefinated
products. Its simple settings underline the great potential for
the application in synthetic, medicinal, and agrochemical
research.
Table 3. Synthesis of fluoroolefinated carbonyl compounds from styrenes a, b
Acknowledgements
We gratefully acknowledge Nature Science Foundation of
Jiangsu Province (BK 20131346, BK 20140776) for financial
support. This work was also supported by National Natural
Science Foundation of China (21476116, 21402093) and
Chinese Postdoctoral Science Foundation (2015M571761) for
financial support.
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