Metal-Free Visible-Light-Mediated Hydrotrifluoromethylation of Unactivated Alkenes and Alkynes in Continuous Flow

Article abstract of DOI:10.1002/ejoc.201901252

We report herein a novel photoredox-catalyzed hydrotrifluoromethylation of unsaturated systems under continuous flow. This metal-free method is easily broadened to other perfluoroalkyl groups (R_F = CF₃, CFCl₂, CF₂

Full text of DOI:10.1002/ejoc.201901252

DOI: 10.1002/ejoc.201901252
Communication
Photoredox in Flow | Very Important Paper |
Metal-Free Visible-Light-Mediated Hydrotrifluoromethylation of
Unactivated Alkenes and Alkynes in Continuous Flow
Anne-Laure Barthelemy,[a] Guillaume Dagousset,*[a] and Emmanuel Magnier*[a]
Abstract: We report herein a novel photoredox-catalyzed hy- the use of sulfilimino iminiums as sources of ·RF radicals. The
drotrifluoromethylation of unsaturated systems under continu- mild reaction conditions are compatible with unactivated alk-
ous flow. This metal-free method is easily broadened to other enes bearing a wide range of functionalities, as well as with
perfluoroalkyl groups (RF = CF3, CFCl2, CF2Br, C4F9) thanks to alkynes for the first time.
in this report and an expensive Ir-based photocatalyst was
used. Therefore, the development of a general metal-free con-
tinuous-flow method that would be compatible with unacti-
vated alkenes is highly desirable.[11] In addition, if alkynes are
substrates of choice for photoredox-catalyzed trifluoromethyl-
ation in batch,[11a,11c,12] analogous reactions in flow have not
been reported yet, to the best of our knowledge. We wish to
report herein a new and efficient hydrotrifluoromethylation of
unactivated alkenes in flow. This metal-free process has been
successfully extended to other perfluoroalkyl groups, and for
the first time to alkynes as substrates.
Owing to the specificities of the fluorine atom, the introduc-
tion of a trifluoromethyl group into organic compounds has a
dramatic impact on the physicochemical and biological proper-
ties of these molecules. It has undoubtedly triggered the devel-
opment of a wide range of efficient methods to synthesize tri-
fluoromethylated compounds, notably via nucleophilic or elec-
trophilic trifluoromethylations.[1] Concerning radical ap-
proaches, visible-light photoredox catalysis has recently estab-
lished itself as one of the most efficient methodology to per-
form trifluoromethylation reactions.[2,3] However, in classical
batch conditions using standard glassware, one potential draw-
back of such procedures is that visible light is rapidly absorbed
on a millimeter scale, according to Beer–Lambert–Bouguer's
law. Therefore, the desired reaction can only occur near the
surface of the flask, in a very small volume compared to the
total reaction mixture. As a consequence, prolonged irradiation
time is needed to go until complete conversion. This may lead
to the formation of undesired side-products, and this limitation
is clearly amplified in the case of large-scale experiments.
To circumvent this issue, continuous flow has recently ap-
peared as the technique of choice to perform photochemical
reactions.[4] Indeed, the narrow tubing of flow reactors allows
for a homogeneous and optimal irradiation of the reaction mix-
ture, thanks to a very high surface-to-volume ratio. Regarding
the trifluoromethyl group, pioneer studies were successfully re-
ported by the groups of Noël[5] and Stephenson.[6] Efforts were
mainly focused on the C–H trifluoromethylation of (hetero)-
arenes[5a,5b,5f,5g,6] or thiols (Scheme 1a).[5c–5e,7] Surprisingly, to
the best of our knowledge, only one example of trifluorometh-
ylation of alkenes was recently reported by Noël and co-workers
(Scheme 1b).[8–10] Although good yields and high E selectivity
were achieved, aliphatic olefinic substrates were not described
Scheme 1. Main developments in continuous-flow photoredox-catalyzed tri-
fluoromethylation reactions.
[a] Institut Lavoisier de Versailles, UMR 8180,
Université de Versailles-Saint-Quentin
We recently disclosed the use of fluorinated sulfilimino
iminiums 1 as new sources of perfluoroalkyl radicals under
photoredox catalysis.[13] Based on this experience and on our
recent work on continuous-flow photocatalyzed reactions,[14]
we envisioned that these reagents, easily prepared in one step
78035 Versailles Cedex, France
E-mail: guillaume.dagousset@uvsq.fr
emmanuel.magnier@uvsq.fr
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under https://doi.org/10.1002/ejoc.201901252.
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from the corresponding sulfoxide at a multi-gram scale, would the corresponding adduct 5a was obtained in 50 % yield (Table
be suitable partners to perform hydroperfluoroalkyation of alk- 1, entry 1). Encouraged by this result, the reaction parameters
enes. Indeed, when alkene 2a was treated with 1 equiv. of
CF3-sulfilimino iminium 1a, 2 equiv. of Hantzsch ester 3 (HE) as
H atom source, and Rhodamine 4 as photocatalyst (5 mol-%)
with a flow rate of 0.5 mL min–1 under green LEDs irradiation,
were then optimized, including the flow rate (entries 3–4), the
solvent (entry 5), the stoichiometry of reagents and catalyst (en-
tries 6–7,10), and the concentration of the reaction mixture (en-
tries 8–9). Finally, the best conditions were found by dissolving
alkene 2a with 1.5 equiv. of 1a, 2.7 equiv. of 3 and 5 mol-% of
photocatalyst 4 in CH2Cl2 (0.025
M), with a flow rate of
Table 1. Survey of reaction conditions for the photoredox-catalyzed hydrotri-
fluoromethylation of alkene 1a.
1 mL min–1 (entry 7).[15]
With these mild reaction conditions in hand, the scope of
this hydrotrifluoromethylation was next investigated, and the
results are summarized in Scheme 2. First, sulfilimino iminiums
1b–1d with other perfluoroalkyl groups (RF = CF2Br, CFCl2 and
C4F9, respectively) were also suitable partners for this reaction,
giving access to the expected monofluoromethyl, difluoro-
methyl and perfluoroalkyl adducts 5ab–5ad in up to 60 % yield.
Pleasingly, a wide number of mono-substituted or 1,1-disubsti-
tuted alkenes 2b–2g bearing a variety of functional groups
(ether, carbamate, ester, halogen, sulfonic ester, phthalimide,
ketone) were smoothly trifluoromethylated by this continuous-
flow process, affording the corresponding CF3-adducts 5b–5g
in good yields. Importantly, this photocatalyzed reaction was
also readily performed with steroid derivatives 2h–2i and with
natural compound (+)-Nootkatone 2j, showing that it is easily
applicable to the late-stage functionalization of small complex
molecules.
Entry
x; y
Solvent
Flow rate
Residence
time (tR)
Yield [%][a,b,c]
[mL min–1
]
1
2
3
4
5
6
7
1; 2
1.5; 3
1.5; 3
1.5; 3
DCE
DCE
DCE
DCE
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
0.5
0.5
1.0
2.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
20 min
20 min
10 min
5 min
10 min
10 min
10 min
10 min
10 min
10 min
10 min
10 min
50
60
66
62
75
71
1.5; 3
1.5; 2.5
1.5; 2.7
1.5; 2.7
1.5; 2.7
1.5; 2.7
1.5; 2.7
1.5; 2.7
87 (76)[d]
8[e]
9[f]
10[g]
11[h]
12[i]
47
63
72
0
Encouraged by these results, we next thought to extend the
scope of this reaction to alkynes. While aliphatic alkynes such
as 1-octyne (6a) gave only poor yield of the corresponding tri-
fluoromethylated alkene (22 % NMR yield for 7a), we were
pleased to see that aromatic alkynes 6b–6f bearing electron-
donating (OMe, OPh, NHCbz) or -withdrawing groups (CO2Me)
were efficiently trifluoromethylated under the same reaction
conditions (flow rate of 1 mL min–1, tR = 10 min). This difference
0
[a] General conditions: 2a (0.20 mmol), 1a (x equiv.), 3 (y equiv.), and 4
(5 mol-%) in 8 mL of solvent irradiated with green LEDs (525 nm) at 25 °C
inside a 10 mL reactor of a E-series Vapourtec flow system. See ESI for more
details. [b] Yields determined by 19F NMR spectroscopy using PhOCF3 as an
internal standard. [c] d.r. = 1.1:1 in all cases. [d] Yield into brackets referred
to chromatographically pure product. [e] With 20 mL of CH2Cl2. [f] With 4 mL
of CH2Cl2. [g] With 2.5 mol-% of 4. [h] Without 4. [i] In the dark.
Scheme 2. Scope of hydroperfluoroalkylation of alkenes and alkynes in flow. General conditions: alkene 2 or alkyne 6 (0.2 mmol), 1 (0.3 mmol), Hantzsch
ester 3 (HE, 0.54 mmol), 4 (5 mol-%) in 8 mL of CH2Cl2 at 25 °C. Flow rate of 1 mL min–1 (tR = 10 min) under green LED irradiation. Yields refer to
chromatographically pure product. [a] d.r. = 1.1:1. [b] d.r. = 1:1. [c] d.r. = 1:1. [d] d.r. = 2:1. [e] With 3 equiv. of 1a and 3 equiv. of 3. [f] Yields into brackets
determined by 19F NMR spectroscopy using PhOCF3 as an internal standard. [g] Reaction performed on a 2 mmol scale. d.r. = diastereomeric ratio.
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of reactivity between aliphatic and aromatic alkynes could not
In conclusion, we have successfully developed a novel
be rationalized. However, it is worth to note that similar reac- photoredox-catalyzed hydroperfluoroalkylation protocol under
tions in batch are carried out with aliphatic alkynes, while aro- continuous-flow conditions, which uses sulfilimino iminiums as
matic alkynes are usually unreactive substrates.[11a,11c,12b–12d]
Importantly, the reaction with alkyne 7e could be carried out
on a ten-fold higher scale (2 mmol) without any decrease in
yield. This demonstrated the practicality and efficiency of con-
tinuous-flow photocatalysis to perform large-scale experiments
with a significant throughput (1.5 mmol h–1).
In order to gain some insight into the mechanism of this
hydroperfluoroalkylation process, some control experiments
were performed. Both the light and the photocatalyst 4 were
essential parameters for the reaction to proceed (Table 1, en-
tries 11–12), which suggested that a radical pathway was in-
volved. Moreover, some luminescene quenching experiments
were carried out (Scheme 3a). The rate of quenching deter-
mined using Stern-Volmer plots showed that a reductive
quenching cycle involving the oxidation of Hantzsch ester 3 by
the excited state 4* of Rhodamine B was favoured over an oxid-
ative quenching cycle (i.e. direct reduction of 1 by 4*).
versatile sources of perfluoroalkyl radicals. This process is quite
efficient (residence time of 10 min) and tolerates a large array of
functional groups. Importantly, both alkenes and alkynes were
smoothly perfluoroalkylated under these mild and metal-free
reaction conditions. Extension of this work to other perfluoro-
alkylation reactions is currently underway in our laboratory and
will be reported in due course.
Experimental Section
General Procedure: In a dry tube under argon were added the
sulfilimino iminium 1 (0.3 mmol, 1.5 equiv.), Hantzsch Ester 3
(0.54 mmol, 2.7 equiv.), Rhodamine B 4 (0.01 mmol, 5 mol-%) and
the alkene 2 (0.2 mmol, 1 equiv.). CH2Cl2 (8 mL) was added and the
solution is degazed with argon and stirred at room temperature
until complete dissolution of Hantzsch ester 3. Then, using an easy-
Photochem E-series system from Vapourtec with a 10 mL reactor
irradiated with a green 525 nm LED system, 8 mL of the solution
(0.2 mmol) was pumped at a flow rate of 1 mL min–1 at 25 °C. After
Based on this analysis and on previous Electron Para-
magnetic Resonance experiments with sulfilimino iminiums
1,[13] a plausible mechanism is depicted in Scheme 3b. After
irradiation with visible light, the formed excited state 4*
oxidizes HE 3. The highly reductive species 4·– generated reacts
collecting the reaction mixture, a solution of HCl 1
M (10 mL) was
added and the solution was extracted with CH2Cl2 (2 × 20 mL).
The combined organic layers were dried with MgSO4, filtered and
evaporated under reduced pressure. The crude was then purified
by prepartive TLC on silica gel to afford the corresponding pure
product 5.
·
with 1 to form the corresponding RF radical A, which subse-
quently adds onto alkene 2 (or alkyne 6). Final HAT (Hydrogen
atom transfer) of the formed radical intermediate B with HE 3 or
radical cation 10 would lead to the desired perfluoroalkylated
adduct 5 (or 7).[16]
Acknowledgments
ALB thanks the French Ministry of Research for a doctoral fel-
lowship. LabEx Charmmmat is gratefully acknowledged for the
funding of the continuous flow device.
Keywords: Flow chemistry · Sulfilimino iminium ·
Trifluoromethylation · Photoredox catalysis · Radicals
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Received: August 23, 2019
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Communication
Photoredox in Flow
A new versatile protocol for the hydro-
perfluoroalkylation of alkenes and alk-
ynes using suliflimino iminiums as
sources of perfluoroalkyl radicals was
developed. This visible-light-mediated
process is performed in continuous
flow with high efficiency (10 min of
residence time), and under mild metal-
free conditions.
A.-L. Barthelemy, G. Dagousset,*
E. Magnier* .......................................... 1–5
Metal-Free Visible-Light-Mediated
Hydrotrifluoromethylation of Unac-
tivated Alkenes and Alkynes in Con-
tinuous Flow
DOI: 10.1002/ejoc.201901252
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