(Trifluoromethylselenyl)methylchalcogenyl as Emerging Fluorinated Groups: Synthesis under Photoredox Catalysis and Determination of the Lipophilicity

Article abstract of DOI:10.1002/chem.202100053

The synthesis of molecules bearing (trifluoromethylselenyl)methylchalcogenyl groups is described via an efficient two-step strategy based on a metal-free photoredox catalyzed decarboxylative trifluoromethylselenolation with good yields up to 88 %, which raised to 98 % in flow chemistry conditions. The flow methods allowed also to scale up the reaction. The mechanism of this key reaction was studied. The physicochemical characterization of these emerging groups was performed by determining their Hansch–Leo lipophilicity parameters with high values up to 2.24. This reaction was also extended to perfluoroalkylselenolation with yields up to 95 %. Finally, this method was successfully applied to the functionalization of relevant bioactive molecules such as tocopherol or estrone derivatives.

Full text of DOI:10.1002/chem.202100053

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&
Synthetic Methods
(Trifluoromethylselenyl)methylchalcogenyl as Emerging
Fluorinated Groups: Synthesis under Photoredox Catalysis and
Determination of the Lipophilicity
Kevin Grollier+,[a] Arnaud De Zordo-Banliat+,[b] Flavien Bourdreux,[b] Bruce Pegot,[b]
Guillaume Dagousset,[b] Emmanuel Magnier,*[b] and Thierry Billard*[a, c]
Abstract: The synthesis of molecules bearing (trifluorometh-
ylselenyl)methylchalcogenyl groups is described via an effi-
cient two-step strategy based on a metal-free photoredox
catalyzed decarboxylative trifluoromethylselenolation with
good yields up to 88%, which raised to 98% in flow chemis-
try conditions. The flow methods allowed also to scale up
the reaction. The mechanism of this key reaction was stud-
ied. The physicochemical characterization of these emerging
groups was performed by determining their Hansch–Leo li-
pophilicity parameters with high values up to 2.24. This reac-
tion was also extended to perfluoroalkylselenolation with
yields up to 95%. Finally, this method was successfully ap-
plied to the functionalization of relevant bioactive molecules
such as tocopherol or estrone derivatives.
years, in particular by introducing heteroatoms.[5] In this field,
chalcogens are the most considered. Indeed, trifluoromethyl-
chalcogenyl groups possess, inter alia, high Hansch–Leo lipo-
philicity parameters.[6]
Introduction
Since the fluorine discovery by Henri Moissan one century
ago,[1] fluorinated compounds have known a growing inter-
est.[2] Throughout these years, such substrates have demon-
strated their successful usage in a large panel of applications,
with a wide diversity from materials to life sciences.[3]
If fragments with oxygen and sulfur were well studied,[5,7] se-
lenium derivatives were less developed until recently,[8] maybe
due to the toxicity associated to selenium.[9] However, seleni-
um is an essential trace element for human biochemistry[10]
and seleno-proteins play a crucial role in physiology for live
species.[11] In recent years, selenylated molecules have found
promising applications in various fields such as, for instance,
materials or drug design.[12] Thus, recently, nonsteroidal anti-in-
flammatory derivatives bearing a CF3Se group have been
tested as potential anticancer agents with promising results.[13]
In our ongoing efforts to design new fluorinated moieties
with expected unknown properties, in particular concerning
lipophilicity, we considered more sophisticated groups by
merging another chalcogen with CF3Se group. In order to
avoid weak chalcogen–chalcogen bonds and to introduce
some structural modularity, a methylene bridge between
both heteroatoms was envisaged. Therefore, we focused our
interest onto (trifluoromethylselenyl)methylchalcogenyl groups
(CF3SeCH2E; E=O, S, Se).
Nowadays, introduction of fluorinated substituents onto
molecules is quite a staple in the design of new compounds
for targeted applications. This is mainly due to the exclusive
characteristics of fluorinated groups which confer to molecules
specific properties in particular concerning physicochemical
and electronic aspects.[4]
In the objective to continue to propose new fluorinated
moieties with modulative properties, the concept and develop-
ment of “emerging fluorinated groups” appeared these last
[a] K. Grollier,+ Dr. T. Billard
Institute of Chemistry and Biochemistry (ICBMS, UMR CNRS 5246)
Univ Lyon, UniversitØ Lyon 1, CNRS, CPE, INSA
43 Bd du 11 novembre 1918, 69622 Villeurbanne (France)
E-mail: Thierry.billard@univ-lyon1.fr
[b] A. De Zordo-Banliat,+ F. Bourdreux, Dr. B. Pegot, Dr. G. Dagousset,
Dr. E. Magnier
Institut Lavoisier de Versailles (UMR CNRS 8180)
UniversitØ Paris-Saclay, UVSQ, CNRS
78035 Versailles (France)
Results and Discussion
E-mail: Emmanuel.magnier@uvsq.fr
The synthesis of molecules bearing these substituents was first
considered. Visible light photocatalysis has emerged over the
last decade as a powerful tool for the synthesis of various sub-
strates in eco-friendly conditions.[14] More specifically, photore-
dox-catalyzed decarboxylation is an approach which was
widely described and, in particular, the use of R-ECH2CO2H sub-
strates as starting materials was considered.[15] Indeed, such
[c] Dr. T. Billard
CERMEP-In vivo imaging
59 Bd Pinel, 69677 Lyon (France)
[+] These authors contributed equally to this work.
Supporting information and the ORCID identification number(s) for the
author(s) of this article can be found under:
https://doi.org/10.1002/chem.202100053.
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substrates are easy to obtain by carboxymethylation of corre-
sponding chalcogenols with haloacetate reagents. This strat-
egy was perfectly adapted to our objective. The interest for
such approach was confirmed during our study by the work of
Zhang et al. which described the photoredox-catalyzed decar-
boxylative trifluoromethylselenolation of aliphatic carboxylic
acids.[16] Two examples of naphthyl-ECH2SeCF3 (E=O, S) com-
pounds were described with medium yields. Nevertheless, this
method is based on the use of [CF3Se][NMe4] as anionic tri-
fluoromethylselenolating reagent. This reagent suffers from
some stability issues and its synthesis requires tedious condi-
tions.[8b,17] Furthermore, this decarboxylation required the use
of one equivalent of NFSI as oxidant.
decreased the observed yield (Table 1, entry 6). Interestingly, a
dilution by half of the reacting medium gave rise to a better
result of 82% (Table 1, entry 7), as previously observed in the
literature.[20] This may be due to the high molar absorption co-
efficient of RFTA. Even in these diluted conditions, the use of
more polar solvents clearly did not favor the reaction (Table 1,
entries 8, 9). No significant modifications were observed with
an increase of reaction time (Table 1, entry 10). Finally, the
compulsory uses of photocatalyst and blue LED irradiation
were confirmed (Table 1, entries 11, 12).
With these optimal conditions in hand (Table 1, entry 7), sev-
eral compounds were synthesized in batch and in flow condi-
tions (Scheme 1).
Trifluoromethylselenotoluenesulfonate (CF3SeTs, 1a) was re-
cently described as an electrophilic trifluoromethylselenolative
reagent.[18] Visible-light activation of this substrate to perform
radical trifluoromethylselenolations was also performed.[19]
Consequently, the use of this reagent in the photoredox decar-
boxylation was postulated as a valuable alternative, which
would avoid the addition of an oxidant. Such hypothesis was
confirmed by the recently published decarboxylative cyanation
of carboxylic acids based on the use of TsCN as reagent[20] and
an inexpensive and non-toxic derivative of vitamin B2 as organ-
ic photocatalyst.[21]
Globally, good results were obtained. If a slight steric hin-
drance did not have significant influence (3c), a more impor-
tant one precluded the formation of the expected compound
(3d). The presence of electron-donating group on the aromatic
ring seems to favor the reaction (3b, 3e-g, 3i). In contrast,
strong electron-withdrawing group as CF3 did not provide the
expected product (3h). The reaction appears to be compatible
with the presence of chlorine atom onto the aryl moiety (3g).
Similar result was observed in naphthyl series (3k). Very origi-
nal bis-adduct was also obtained, starting from the corre-
sponding bis-carboxylic acid, albeit with moderate yield (3j).
This reaction proved not limited to the oxygen atom and other
chalcogens were also considered. Similar results were obtained
with sulfur (5a-b) or selenium (7a). Everything else being
equal, the yields are similar to those of oxygen.
Therefore, photoredox-catalyzed decarboxylative trifluoro-
methylselenolation was optimized with compound 2b as
model substrate and riboflavin tetraacetate (RFTA) as photocat-
alyst.
Reaction led to the expected product 3b with 45% yield in
acetonitrile (Table 1, entry 1). Doubling the photocatalyst
amount did not bring any improvements (Table 1, entry 2). A
more polar solvent as DMSO decreased considerably the yield
(Table 1, entry 3) and protic solvents were deleterious for the
reaction (Table 1, entries 4, 5). The addition of Cs2CO3 as base
In addition, this transformation was also performed with the
use of continuous-flow reactor (Scheme 2). This technic is per-
fectly well adapted to photochemical transformations and
Table 1. Reaction between 1a and 2b under photoredox conditions.
Entry
Solvent
[2b] [m]
3b [%][a]
1
2
3
4
5
6
7
8
CH3CN
CH3CN[b]
DMSO
MeOH
H2O
CH3CN[c]
CH3CN
DMF
0.1
0.1
0.1
0.1
0.1
0.1
0.05
0.05
0.05
0.05
0.05
0.05
45
46
12
–
–
38
82
17
–
78
–
–
9
DMAc
10
11
12
CH3CN[d]
CH3CN[e]
CH3CN[f]
Scheme 1. Synthesis of CF3SeCH2E-molecules (E=O, S, Se). Yields deter-
mined by 19F NMR with PhOCF3 as the internal standard; in parentheses, iso-
lated yields. [a] Flow rate of 167 mLminÀ1 (residence time of 1 h) at 258C.
[b] with 2.4 equiv of 1a.
[a] Yield determined by 19F NMR with PhOCF3 as internal standard.
[b] With 10 mol% of RFTA. [c] With 1 equiv of Cs2CO3. [d] 24 h. [e] Without
RFTA. [f] Without irradiation.
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Scheme 2. Synthesis of ((p-tolyloxy)methyl)(trifluromethyl)selane (3b) using
continuous flow.
scale-up experiments are facilitated under safer reaction condi-
tions.[22] After slight modifications of the reaction conditions,
with a flow rate of 167 mLminÀ1, the irradiation could be de-
creased to only 1 h of residence time, and the expected CF3Se-
product 3b was obtained in 98% yield. Furthermore, flow pho-
toredox reactions are easier to scale-up than in batch condi-
tions. Thus, the same experiment was performed on a larger
scale (half a gram of starting carboxylic acid À3 mmol) without
any significant loss of the yield. In general, continuous flow
provided a better yield (Scheme 1), in particular in the case of
the more sterically hindered adduct 3c (87% yield in flow, vs.
45% in batch).
Scheme 4. Functionalization of some bioactive compounds. Yields deter-
mined by 19F NMR with PhOCF3 as the internal standard; in parentheses, iso-
lated yields.
Other fluoroalkylselenotoluenesulfonates reagents were also
developed by one of our group with higher homolog of the
fluorinated part.[18a] Consequently, the reaction was extended
to others fluorinated reagents 1b,c (Scheme 3).
Similar results to CF3 series were obtained with C3F7 and
C6F13 moieties. These examples constitute the first examples of
photoredox-catalyzed decarboxylative perfluoroalkylselenola-
tion.
nolation of double bond, as previously described.[19b] Derivati-
zation of tocopherol led also to a moderate result (3m) which
could be explained by steric hindrance as demonstrated in
Scheme 1. Nevertheless, the result remains interesting in view
of the complexity of molecule. Finally, with estrone good yield
was observed in both trifluoromethyl (3n) and tridecafluoro-
hexyl series (9n). This result demonstrates that not hindered
aromatic ring favors the reaction and confirms the hypothesis
put forward with tocopherol.
Finally, this method was applied to some relevant bioactive
compounds. Thus, eugenol, major component of clove bud oil
used as local antiseptic and anesthetic, a-tocopherol, compo-
nent of vitamin E used as antioxidant, and estrone, a steroid
estrogen hormone, were functionalized with RFSeCH2O groups
(Scheme 4).
To better understand this decarboxylative trifluoromethylse-
lenolation, a mechanistic study has been performed. As both
light and photocatalyst were required for the reaction (Table 1,
entries 11, 12, and Scheme 5), a radical-based mechanism was
hypothesized. This hypothesis was confirmed by a reaction
quenched in presence of TEMPO (Scheme 5).
Eugenol derivative (3l) was obtained in only moderate yield.
A complex mixture was observed at the end of the reaction
with some by-products arising from radical trifluoromethylsele-
Due to the high oxidation potential of the excited state of
RTFA (E= +1,67 V vs. SCE),[23] we envisioned an oxidative
quenching cycle with carboxylic acids 2–4–6 (E= +1.16 V vs.
Scheme 3. Synthesis of RFSeCH2O-molecules. Yields determined by 19F NMR
with PhOCF3 as the internal standard; in parentheses, isolated yields.
Scheme 5. Control reactions.
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SCE).[24] To confirm this hypothesis, fluorescence quenching ex-
periments were performed with p-methylphenoxyacetic acid
2b and trifluoromethylselenotoluenesulfonate 1a (Figure 1).
The quenching constant of 1a was calculated to be almost ten
times less important (kq(1a) = 4.7”108 mÀ1 sÀ1) than the quench-
ing constant with 2b (kq(2b) = 3.5”109 mÀ1 sÀ1). This result indi-
cated that RFTA* is mostly quenched by the carboxylic acid
substrate. Finally, the quantum yield of the reaction was mea-
sured (see Supporting Information for more details). The maxi-
mum value F=0.23 indicated that a photocatalytic pathway is
favored over a radical chain mechanism.
Based on these studies, a plausible mechanism was pro-
posed (Scheme 6). First, the excited photocatalyst (RFTA*) per-
forms a PCET (proton coupled electron transfer) with carboxylic
acid 2, 4, or 6, leading to [RFTA-H] and O-centered radical in-
termediate I, which evolves into carbon-centered radical II
after a fast decarboxylation step. Intermediate II then reacts
C
with reagent 1a to form the desired product. The resulting Ts
C
radical is then reduced into TsH by [RFTA-H] , which regener-
ates the photocatalyst.
In order to further study the properties of the (trifluorometh-
ylselenyl)methylchalcogenyl groups, their Hansch-Leo lipophi-
licity parameters were determined. As previously described,[6b]
octanol-water partition coefficient (logP) of substituted ben-
zene 3a, 5a and 7a were measured and compared to benzene
(Figure 2). The measures were replicated several times and the
mean values were obtained with a good standard deviation.
Figure 2. Hansch–Leo lipophilicity parameters (pR) of CF3SeCH2E groups.
Scatter dot plot with means and standard deviations.
Compared to CF3E groups, lipophilicity of CF3SeCH2E groups
is systematically increased (Table 2). Furthermore, the values
grow with atomic number of chalcogen (E). The evolution of
the Hansch–Leo parameters demonstrates an additive effect of
both chalcogen atom and CH2 moiety leading to a continuous
increase of pR parameters (Figure 3). Compared to CH2SeCF3,
the addition of a second chalcogen generally increases pR
apart for oxygen because of the hydrophilic character of OCH2
moiety. Nevertheless, ECH2SeCF3 groups are more lipophilic
than corresponding ECF3. Thus, the SeCH2SeCF3 moiety ap-
pears to be very lipophilic with a pR =2.24 which constitutes
one of the highest determined values for fluorinated groups.
Table 2. Hansch–Leo lipophilicity parameters (pR) observed by merging
chalcogen(s) and CF3 group.
[6]
[6]
[a]
ECH3
pR
ECF3
pR
ECH2SeCF3
pR
Figure 1. Fluorescence quenching experiments.
CH3
0.56
À0.02
0.61
CF3
0.88
1.04
1.44
1.61
CH2SeCF3
1.63
1.39
2.04
2.24
OCH3
SCH3
SeCH3
OCF3
SCF3
SeCF3
OCH2SeCF3
SCH2SeCF3
SeCH2SeCF3
[b]
[c]
0.74
[a] Determined in this paper, see supporting information. [b] logP calcu-
lated using Advanced Chemistry Development (ACD/Labs) Software
V11.02 (ꢀ 1994–2020 ACD/Labs). [c] Re-evaluated value, see Supporting
Information.
Conclusions
(Trifluoromethylselenyl)methylchalcogenyl groups are innova-
tive fluorinated substituents with high Hansch–Leo lipophilicity
parameters. Their introduction onto organic molecules is easy
Scheme 6. Proposed mechanism.
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The crude residue is then purified by flash chromatography to
afford the desired product.
Luminescence quenching experiments
A stock solution of photocatalyst was prepared by dissolving RFTA
(3 mg, 5 mmol) in 10 mL of MeCN. Of this solution, 1 mL were fur-
ther diluted with MeCN to give a total volume of 10 mL ([RFTA]=
5”10À5 m). A stock solution of carboxylic acid 2b was prepared by
dissolving 2b (100 mg, 600 mmol) in 20 mL of MeCN ([2b]=3”
10À2 m). A stock solution of TsSeCF3 1a was prepared by dissolving
1a (181 mg, 600 mmol) in 20 mL of MeCN ([1a]=3”10À2 m). For
each experiment, 6 samples were prepared in the dark. Quartz cuv-
ettes (3.5 mL) were filled with photocatalyst stock solution
(0.3 mL), quencher stock solution (0 mL, 0.2 mL, 0.4 mL, 0.6 mL,
0.8 mL, 1.0 mL) and MeCN (2.7 mL, 2.5 mL, 2.3 mL, 2.1 mL, 1.9 mL,
1.7 mL) to obtain a total volume of 3 mL. The final concentrations
were [RFTA]=5 10À6 m and [Quencher]=2”10À3 m, 4”10À3 m, 6”
10À3 m, 8”10À3 m, 1”10À2 m. For each sample, emission spectra
were acquired between 400 nm and 600 nm (excitation at
450 nm). Rates of quenching (kq) were determined using Stern–
Volmer kinetics: I0/I=kqt0[quencher]+1, where I0 is the lumines-
cence intensity without the quencher, I is the intensity with the
quencher, and t0 is the excited state lifetime of the photocatalyst.
Figure 3. Hansch–Leo lipophilicity parameters (pR) evolution.
to perform in two steps starting from corresponding chalcoge-
nols via an efficient metal-free photoredox decarboxylative tri-
fluoromethylselenolation as key step. This synthesis was opti-
mized in flow conditions allowing rapid process easy to scale-
up. These results demonstrate that not only the association of
chalcogens and trifluoromethyl moiety remains a pertinent
strategy to develop new fluorinated emerging groups with
specific properties but also confirm, as already widely de-
scribed in the literature, that photoredox catalysis and flow
chemistry constitute very efficient and well-adapted ap-
proaches in modern fluorine chemistry.
Determination of Hansch–Leo parameters (pR)
To a 10 mL pear-shaped flask was added octanol (ca. 2 mL), water
(ca. 2 mL) and the molecule to study (ca. 2 mL). The resulting bi-
phasic mixture was hand-shacked for 5 min and then the flask was
centrifuged for 5 min to enable complete phase separation. Using
two syringes with needles, a sample was carefully taken from each
layer. In particular for taking a water sample aliquot, a long needle
with trocar was used. Upon reaching the water phase, the trocar
was removed, the aliquot was taken with syringe and the needle
quickly removed from the solution. Then a small amount of water
phase was discarded (to ensure all traces of octanol were out of
the needle). The needles were carefully wiped with dry tissue
before the sample was transferred into the HPLC vial. Samples
were injected in HPLC (eluent MeOH/H2O) with an UV detector.
LogP was determined as the logarithm of the ratio between the
peak areas of molecules in octanol and water. The Hansch–Leo pa-
rameter was calculated as pR =logP(molecule)ÀlogP(benzene).
Experimental Section
Decarboxylative perfluoroalkylselenolation in batch condi-
tions
To a tube equipped with a magnetic stir bar are added TsSeRF (1;
0.18 mmol, 1.2 equiv), carboxylic acid (2, 4, 6; 0.15 mmol, 1 equiv)
and RFTA (0.008 mmol, 0.05 equiv) in 3 mL of dry CH3CN (previous-
ly sparged with N2). The tube is sealed with an adapted septum
and the mixture is sparged for 5 min with a N2 balloon. The reac-
tion mixture is then stirred for 15 h at 308C under blue light irradi-
ation. Conversion is checked by 19F NMR with PhOCF3 as internal
standard. The reaction mixture is partitioned between Et2O or pen-
tane and water, the combined organic layers are washed with
brine, dried over MgSO4, filtered, and concentrated under moder-
ate vacuum. The crude residue is then purified by flash chromatog-
raphy to afford the desired product (3, 5, 7, 8, 9).
Acknowledgements
This work was supported by a grant from the French National
Research Agency (ANR 18-CE07-0039-01). The NMR Centre of
the university of Lyon is thanked for their contribution. The au-
thors are grateful to the CNRS and the French Ministry of Re-
search for financial support. The French Fluorine Network (GIS-
FLUOR) is also acknowledged for its support.
Decarboxylative trifluoromethylselenolation in flow condi-
tions
To a tube under argon were added the carboxylic acid (2, 4, 6;
0.1 mmol, 1 equiv), TsSeCF3 (1a; 0.12 mmol, 1.2 equiv) and RFTA
(5.0 mmol, 0.05 equiv). CH3CN (2 mL) was added and the solution is
degassed with argon for 10 min and stirred at room temperature
until full dissolution of reagents. Then, using an easy-Photochem
E-series system from Vapourtec with a 10 mL reactor irradiated
with a 450 nm LED system, 1 mL of the solution (0.05 mmol) was
pumped at a flow rate of 167 mLminÀ1 at 258C. The reaction mix-
ture is collected and partitioned between Et2O or pentane and
water, the combined organic layers are washed with brine, dried
over MgSO4, filtered and concentrated under moderate vacuum.
Conflict of interest
The authors declare no conflict of interest.
Keywords: decarboxylation · fluorine · lipophilicity
photoredox · selenium
·
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Manuscript received: January 6, 2021
Accepted manuscript online: February 4, 2021
Version of record online: March 3, 2021
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