Trifluoromethylation and Monofluoroalkenylation of Alkenes through Radical–Radical Cross-Coupling

Article abstract of DOI:10.1002/chem.201901349

The first visible-light-induced trifluoromethylation and monofluoroalkenylation of simple alkenes via a challenging radical–radical cross-coupling step was achieved. This method provided a mild, step-economical and redox-neutral route to privileged two different fluorinated difunctionalized allyl compounds. The utility of this method is illustrated by late-stage modification of medically important molecules.

Full text of DOI:10.1002/chem.201901349

A Journal of
Accepted Article
Title: Trifluoromethylation and Monofluoroalkenylation of Alkenes
Through Radical-Radical Cross-Coupling
Authors: Qingmin Wang, Qiang Wang, Yi Qu, Hao Tian, Yuxiu Liu, and
Hongjian Song
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To be cited as: Chem. Eur. J. 10.1002/chem.201901349
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Trifluoromethylation and Monofluoroalkenylation of Alkenes
Through Radical–Radical Cross-Coupling
Qiang Wang, Yi Qu, Hao Tian, Yuxiu Liu, Hongjian Song, and Qingmin Wang*
Abstract: The first visible-light-induced trifluoromethylation and
Scheme 1. The radical trifluoromethylative difunctionalization of alkenes.
monofluoroalkenylation of simple alkenes via a challenging radical–
radical cross-coupling step was achieved. This method provided a
mild, step-economical and redox-neutral route to privileged two
The radical trifluoromethylative difunctionalization of alkenes
is one of the most efficient methods for enriching the library of
fluorine-containing compounds. Basically, all these reactions
different fluorinated difunctionalized allyl compounds. The utility of
this method is illustrated by late-stage modification of medically
important molecules.
experience
a
common trifluoromethylated alkyl radical
intermediate I (Scheme 1), which can undergo several different
pathways to afford diverse trifluoromethylated products. These
pathways include single electron transfer (SET) oxidation,[5]
reduction,[6] atom transfer reaction[4d,7], recombination with metal
species,[8] radical addition[9] and dimerization.[10] However, the
radical-radical cross-coupling of intermediate I with another
radical species has not been explored. We hypothesized that
combining intermediate I with another fluorine-containing radical
would provide an efficient, step-economical route to two different
fluorinated difunctionalized molecules.
Owing to the small size and high electronegativity of fluorine
and the unique chemical and physical properties of fluorine-
containing structural motifs, fluorinated organic compounds have
widely application in pharmaceutical and agrochemical fields.[1]
Nowadays, about 20–25% of pharmaceuticals and 30–40% of
agrochemicals in the market are estimated to be molecules
containing fluorine.[2] Therefore, great efforts have been made to
develop highly efficient and selective methods for constructing
diverse fluorine-containing compounds.[3] However, these
methods are often limited to introduce only one fluorine atom or
one fluorine-containing group into organic molecules, and this is
obviously not enough for the research and development of
modern medicine and pesticides. So, it’s an urgent task for
chemists to exploit an efficient and step-economical route to
introduce two different fluorine-containing groups into one
organic molecule at the same time.[4]
Scheme 2. The radical trifluoromethylation and monofluoroalkenylation of
alkenes.
Monofluoroalkenes are important structural motifs in
materials and medicinal chemistry,[11] and they can be
synthesized from readily available gem-difluoroalkenes by
defluorinative nucleophilic addition.[12] But these transformations
always require strong nucleophiles and harsh reaction
conditions which limit the scope of the reaction. Recently,
chemists have realized photoinduced defluorinative cross-
coupling reactions to afford monofluoroalkenes by using
difluoroalkenes as substrates.[13] For example, the group of
[*]
Q. Wang, Y. Qu, H. Tian, Y. Liu, H. Song, Prof. Q. Wang
State Key Laboratory of Elemento-Organic Chemistry, Research
Institute of Elemento-Organic Chemistry, College of Chemistry,
Collaborative Innovation Center of Chemical Science and
Engineering (Tianjin), Nankai University, Tianjin 300071 (China)
Fax: (+86) 22-23503952
E-mail: wangqm@nankai.edu.cn
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Hashmi reported the monofluoroalkenylation of dimethylamino
compounds through radical–radical cross-coupling of α-
aminoalkyl radicals with monofluoroalkenyl radicals derived from
gem-difluoroalkenes (Scheme 2a). Based on this, we wondered
if the cross-coupling of trifluoromethylated α-aminoalkyl radicals
with monofluoroalkenyl radicals was also possible. If so, it would
consume 3a, we increased the ratios of easily available 1a and 2
to 3a, and the yield was improved to 71% (entry 3). A further
screening of the equivalents of these substrates revealed that 3
equivalents of 1a and 6 equivalents of 2 was the optimal choice
(74% yield, entry 5). Then changing the solvent to DMSO, DMA,
or MeCN did not further improve the results (entries 6–8). But
when the reaction time extended to 48 hours, we obtained the
best yield (82%, entry 9). Finally, in the absence of a
photocatalyst or light (entries 10 and 11), no reaction occurred,
which indicated that both the photocatalyst and irradiation were
essential.
give us
a
chance to recombine intermediate
I
and
monofluoroalkenyl radicals to afford both trifluoromethylated and
monofluoroalkenylated molecules (Scheme 2a). In this
assumption, the trifluoromethylated α-aminoalkyl radicals could
be obtained through addition of trifluoromethyl radical to
enamine compounds (Scheme 2a). Nevertheless, this
hypothesis still faces some difficulties. For example, the
trifluoromethylated α-aminoalkyl radicals may also undergo other
competitive reactions as described above (Scheme 2b) without
obtaining the target cross-coupling products or reducing the
yields. With these questions in mind, we studied this reaction.
Table 2. Substrate scope with regard to the radical receptors. [a,b]
Table 1. Optimization of conditions for radical trifluoromethylation and
monofluoroalkenylation.
Entry
1a[a]
2[a]
3a[a]
Solvent
DMF
Yield [%][b]
1
1
1
2
2
3
3
3
3
3
3
3
2
3
4
6
6
6
6
6
6
6
6
1.2
1.5
1
30
39
71
72
74
65
66
trace
82
0
2
DMF
3
4
DMF
[a] Reaction conditions: 1 (0.6 mmol), 2 (1.2 mmol), 3a (0.2 mmol),
Ir[dF(CF3)ppy]2(dtbbpy)PF6 (0.002 mmol) in DMF (2 mL) irradiated with a 3
W blue LED bulb at rt under Ar for 48 h after being degassed. [b] Yields of
isolated product are given.
1
DMF
5
1
DMF
6
1
DMSO
DMA
MeCN
DMF
7
1
With the optimal conditions established, we first explored the
substrate scope with respect to different radical receptors (Table
2). The results revealed that the substituents on the alkenes
have a large effect on the reaction efficiency. Substrate bearing
a free N–H bond went smoothly to afford the final product 4b. In
addition, the reaction of different types of vinyl ethers and vinyl
esters 1c–1g all furnished the desired products with moderate to
good yields (43–85%), whereas the OTMS and SPh substituted
ethylene, 1h and 1i, respectively, failed to give the desired
product. Additionally, this reaction did not tolerate non-
heteroatom substituted alkenes as a complex mixture of
products were obtained in the cases of 1j–1l, even though the
starting materials were consumed. These experimental results
indicated that the nitrogen or oxygen substituted vinyl structural
motif is crucial for this transformation. We speculated that
replacement of the α-aminoalkyl radicals or α-oxyalkyl radicals
by simple alkyl radicals is unfavorable for the radical
recombination process because of their different lifetimes and
reactive tendency.[13a, 16]
8
1
9[c]
10[c,d]
11[c,e]
1
1
DMF
1
DMF
0
[a] Chemical equivalent. [b] Determined by 19F NMR spectroscopy with
(trifluoromethyl)benzene as an internal standard. [c] 48 h. [d] Without
photocatalyst. [e] Without irradiation.
To optimize the reaction conditions, we chose commercially
available N-vinyl-2-pyrrolidone (1a) as radical receptor,
CF3SO2Na (2) as trifluoromethyl radical source and gem-
difluoroalkene 3a as monofluoroalkenyl radical source. As
shown in Table 1, the proposed trifluoromethylation and
monofluoroalkenylation was indeed feasible during an initial test
with Ir[dF(CF3)ppy]2(dtbbpy)PF6 as photosensitizer and a 3 W
blue LED as the light source (entry 1). This can be rationalized
by the strong oxidation potential of photosensitizer’s long-lived
(2.3 s) excited state (E1/2[*IrIII/IrII] = +1.21 V vs. SCE) and the
strong reducing ability of the corresponding IrII complex
(E1/2[IrIII/IrII] = -1.37 V vs. SCE).[14] Regarding these values, both
We then examined various tetrasubstituted gem-
difluoroalkenes with 1e as radical receptor (Table 3). A range of
substrates (3b–3j), including those with two phenyl rings
containing electron-donating or electron-withdrawing groups, as
well as a fluorene ring, afforded 5b–5j in 50–85% yields.
Furthermore, substrate bearing a methyl substituent on the
alkene also gave out the final product in moderate yield (5k).
ox
SET oxidation of 2 (E1/2 = 1.05 V vs. SCE)[15] and SET
red
reduction of 3a (E1/2
=
-1.04
V
vs. SCE)[13a] are
thermodynamically feasible. Next, when the chemical equivalent
of 2 and 3a were both increased, the yield was not significantly
improved (entry 2). Moreover, we found that substrate 1a was
fully consumed but substrate 3a had a large surplus under these
conditions. The main side products were trifluoromethylated
derivatives of 1a as we mentioned above in Scheme 2b. These
results strongly supported the existence of trifluoromethylated α-
aminoalkyl radical I in this system. In order to completely
Table 3. Substrate scope with regard to the tetrasubstituted gem-
difluoroalkenes.[a,b]
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help to improve their bioactivities and other properties. These
examples demonstrate that this step-economical method
represent a powerful late-stage strategy to introduce two
different fluorine-containing groups into bioactive molecules.
[a] Reaction conditions: 1e (0.6 mmol), 2 (1.2 mmol), 3 (0.2 mmol),
Ir[dF(CF3)ppy]2(dtbbpy)PF6 (0.002 mmol) in DMF (2 mL) irradiated with a 3
W blue LED bulb at rt under Ar for 48 h after being degassed. [b] Yields of
isolated product are given. [c] Z/E or E/Z ratios were determined by 1H NMR
spectroscopy. [d] Only Z configuration of the product was isolated.
Next, we turned our attention to the trisubstituted gem-
difluoroalkenes (Table 4). We found substrates bearing an
electron-donating or electron-withdrawing substituent at different
positions (meta or para) on the phenyl rings, all smoothly
afforded the corresponding products in good yields with different
Z/E selectivity (5l–5u). Moreover, we also evaluated some
heterocyclic substituted substrates, the reactions could also be
carried out smoothly despite in lower yields (5v–5y). Notably, for
indole derived gem-difluoroalkene 3y, the reaction gave access
to a by-product 5y which containing carbazole structure. This
result indicated that monofluoroalkenyl radical intermediate
might be formed in this reaction.
Scheme 3. Late-stage trifluoromethylation and monofluoroalkenylation of
bioactive molecules.
To gain more insight into the mechanism of this
transformation, we carried out a series of control experiments
(Scheme 4). When the reaction was carried out in the presence
of a radical scavenger (2,2,6,6-tetramethyl-1-piperidinyl-oxy,
TEMPO), none of the desired product formed (Scheme 4a).
Moreover, the detection of TEMPO-CF3 adduct indicated that
this reaction might proceed through a radical pathway. There
were two possible pathways for the reaction, involving either
radical–radical cross-coupling or radical addition/elimination (see
the Supporting Information). In the substrate expansion section
in table 4, indole derived substrate 3y obtained its own
defluorinative cyclization by-product at a 16% yield under
standard reaction conditions. Here, when the radical-radical
cross-coupling was blocked by removing the radical receptor 1e,
the yield of this by-product was increased to 45% (Scheme 4b).
We thought that the by-product 5y was most likely to be
Table 4. Substrate scope with regard to the trisubstituted gem-
difluoroalkenes.[a,b]
obtained
by
intramolecular
radical
cyclization
of
monofluoroalkenyl radical which formed via photoinduced
defluorination process. These results strongly imply the
involvement of monofluoroalkenyl radical in this reaction. What’s
more, the trifluoromethylated by-products generated in above
conditional optimization proved the existence of α-aminoalkyl
radical I in this reaction. Therefore, an addition/elimination
process is less likely, and the subsequent generation of carbon-
carbon bond is more likely formed by free radical coupling.
[a] Reaction conditions: 1e (0.6 mmol), 2 (1.2 mmol), 3 (0.2 mmol),
Ir[dF(CF3)ppy]2(dtbbpy)PF6 (0.002 mmol) in DMF (2 mL) irradiated with a 3
W blue LED bulb at rt under Ar for 48 h after being degassed. [b] Yields of
isolated product are given and Z/E ratios were determined by 1H NMR
spectroscopy. [c] Only Z configuration of the product was isolated.
The challenging late-stage modification of medically
important molecules is indispensable for the development of
innovative methods. As depicted in Scheme 3, the vinyl
derivatives of some bioactive molecules, such as cholestanol,
vitamin E and benzbromarone were tolerated to this reaction
(4m–4o). The successful incorporation of the trifluoromethyl and
monofluoroalkenyl motif into such bioactive compounds could
Scheme 4. Mechanistic studies.
On the basis of the above-described mechanistic
experiments and previous work,[13a] we propose the mechanism
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shown in Scheme 5 by taking substrates 1e and 3a as examples.
Science Foundation of China (21732002, 21672117) for
generous financial support for our research programs.
Under
visible-light
irradiation,
the
photocatalyst
Ir[dF(CF3)ppy]2(dtbbpy)PF6 is photoexcited to the strongly
oxidizing complex *Ir[dF(CF3)ppy]2(dtbbpy)+. Then this species
undergoes SET by accepting one electron from CF3SO2Na to
generate CF3 radical and IrII complex. The CF3 radical selectively
combines with the electron-rich olefin 1e to obtain the α-oxyalkyl
radical intermediate A. On the other hand, subsequent SET
reduction of gem-difluoroalkene 3a by IrII complex would
complete the photoredox catalytic cycle and generate radical
anion B, which might be prone to undergo C–F bond
fragmentation to generate monofluoroalkenyl radical C. Finally,
according to the “persistent-radical effect”,[17] the selective cross-
recombination of the less reactive α-oxyalkyl radical A with the
more reactive monofluoroalkenyl radical C could afford product
4e.
Keywords: trifluoromethylation • monofluoroalkenylation •
photoredox • radical coupling • late-stage functionalization
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Scheme 5. Proposed reaction mechanism.
In summary, we have developed an unprecedented
trifluoromethylation and monofluoroalkenylation reaction of
simple alkenes through an efficient, step-economical, and redox-
neutral route to privileged allyl compounds by photoredox
catalysis. Mechanistic investigations indicate a radical–radical
cross-coupling reaction of α-aminoalkyl radicals or α-oxyalkyl
radicals with monofluoroalkenyl radicals. The mild reaction
conditions, broad substrate scope, excellent functional-group
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Acknowledgements
We are grateful to the National Key Research and Development
Program of China (2018YFD0200100) and the National Natural
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Qiang Wang, Yi Qu, Hao Tian, Yuxiu
Liu, Hongjian Song, and Qingmin
Wang*
Page No. – Page No.
Trifluoromethylation and
Monofluoroalkenylation of Alkenes
Through Radical–Radical Cross-
Coupling
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