Trifluoromethyl- and Fluoroalkylselenolations of Alkynyl Copper(I) Compounds

Article abstract of DOI:10.1002/chem.201702028

The successful perfluoroalkylselenolation of alkynyl copper(I) compounds is described herein. The reaction occurs under oxidant free conditions at room temperature. This convenient one-pot procedure is based on the in situ generation of trifluoromethylsel

Full text of DOI:10.1002/chem.201702028

A Journal of
Accepted Article
Title: Direct Trifluoromethyl- and Fluoroalkylselenolations of Alkynyl
Copper (I) compounds.
Authors: Anis Tlili, Clément Ghiazza, and Thierry Billard
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10.1002/chem.201702028
COMMUNICATION
Trifluoromethyl- and Fluoroalkylselenolations of Alkynyl Copper
I) compounds.
(
[
a]
[a,b]
[a]
Clément Ghiazza , Thierry Billard , Anis Tlili*
Abstract: The successful perfluoroalkylselenolation of alkynyl
copper (I) compounds is described herein. The reaction occurs
under oxidant free conditions at room temperature. This convenient
one-pot procedure is based on the in-situ generation of
trifluoromethylselenyl chlorides. The developed system shows high
functional group tolerance and also promotes the employment of
fluoroalkyl derivatives.
trifluoromethylselenolation of terminal alkynes, few reports have
[
9]
been disclosed recently. The group of Rueping reported an
oxidative coupling in the presence of stoichiometric amounts of
copper/ligand (copper(II)triflate/2,2’-bipyridine) in conjunction
with tetramethylammonium trifluoromethylselenate. Interestingly,
molecular oxygen was used as oxidant (Scheme 1, a). Moreover,
the group of You and Weng reported
trifluoromethylselenyl complexe ([(bpy)Cu(SeCF
promote the trifluoromethylselenolation of terminal alkynes.
a
discrete copper
3
)] able to
2
)
[
10]
The introduction of fluorine or fluorine-containing groups into
organic molecules has gained considerable importance over the
last years. Especially the newly gained properties of such
Herein the presence of potassium fluoride as base (5 equiv.) as
well as DMP (Dess-Martin periodinane, more than 3 equiv.) are
primordial (Scheme 1, a). Furthermore, our group demonstrated
[
1]
molecules have fostered developments in their synthesis.
that
lithiated
terminal
alkynes
undergo
Consequently, it is not surprising today that fluorinated
molecules are finding a plethora of applications in all areas of life
trifluoromethylselenolation at -78°C. Even though high yields
have been obtained, a limitation in the reaction scope has been
observed (Scheme 1, b). It should be mentioned also that
alkynyl trifluoromethyl selenide can be obtained via the direct
trifluoromethylselenolation of alkynyl(phenyl) iodoniums using
tetramethylammonium trifluoromethylselenate. However, the
pre-synthesis of the iodonium starting material is major
[
2]
science. Especially in drug discovery fluorination has become
an essential tool as it can be associated with a variety of
dramatic effects on a molecule’s properties such as better
lipophilicity, higher selectivity, increased efficacy or easier
[
1d]
administration.
trifluoromethylthiolating reagents has attracted much attention in
order to access large panel of trifluoromethylthiolated
compounds (Hansch-Leo parameter, π
their advantageous, the introduction of other trifluoromethyl
In this context, the development of
[11]
drawback (Scheme 1, c).
a
[
3]
R
= 1.44). Motivated by
Oxidative coupling
Me4NSeCF3
[
4]
chalcogen groups has gained interest recently. This includes
the trifluoromethylselenyl group which possesses
high Hansch-Leo parameter (π = 1.29).
2
Cu(OTf) /bpy
a
(stoichio.)
O2
[
5]
R
R
R
R
SeCF3 (a)
From a retrosynthetic perspective, the direct introduction of
SeCF group is the more elegant approach. From this point of
view, several methodologies have been developed using σ-
[(bpy)Cu(SeCF
KF, DMP
3 2
)]
3
Organolithium
[
6]
bonded
copper trifluoromethylselenyl
or
ammonium
nucleophilic
R
Li
+
[Cl-SeCF3]
SeCF3
(
b)
[
7]
trifluoromethylselenyl
salts
as
a
+
δ
trifluoromethylselenyl source. In complementarity, we recently
revisited the use of trifluoromethylselenyl chlorides as an
electrophilic source. It is noteworthy that the key of success here
is the in-situ generation of this volatile electrophilic reagent. After
observing general activity with this reagent in aromatic
Iodonium
OTs
I
+
Me4NSeCF3
R
SeCF3 (c)
[
8]
R
electrophilic substitution
organomagnesium or organolithium coumpouds, we attempted
to evaluate its reactivity towards the formation of C(sp)-SeCF
bonds. Regarding the state of the art for the direct
as well as in the presence of
[
5]
This work
R
3
Cu
+
[Cl-SeRf]
R
SeRf
+
δ
Rf = CF3, CF
CF SO
2
CF3, CF
2
Ph, CF H
2
CF
2
CF
2
CF
2
CF
2
CF
3
[a]
C. Ghiazza, Dr. T. Billard, Dr. A. Tlili
2
2
Institute of Chemistry and Biochemistry (ICBMS-UMR CNRS 5246)
Univ Lyon, Université Lyon 1, CNRS
43 Bd du 11 Novembre 1918, 69622 Villeurbanne, France
E-mail: anis.tlili@univ-lyon1.fr
www.FMI-Lyon.fr
Scheme 1. State of the art of the trifluoromethylselenolation of alkynes
[b]
Dr. T. Billard
CERMEP – in vivo imaging, Groupement Hospitalier Est
5
9 Bd Pinel, 69003 Lyon, France
With our continuous interest to develop and discover new
[
12]
methodologies,
we report herein a new approach for the
Supporting information for this article is given via a link at the end of the
document.((Please delete this text if not appropriate))
C(sp)-SeCF bond formation based on the employment of
3
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Chemistry - A European Journal
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COMMUNICATION
[
13]
alkynyl copper compounds.
reveal large substrate
selenyldifluoromethyl moieties (SeCF
The developed methodology
conversions and yields have been observed. The use of DMSO
was deleterious to the reaction outcome since only 3% of the
product was observed. DMF furnished the product in slightly
better yield of 64 % (Entry 8). The product could be formed in
80 % with a slight excess of the trifluoromethylselenolating
reagent (Entry 10). Finally, once again the background reaction
in absence of any additional ligand demonstrated lower product
formation (Entry 11).
a
scope
and encompass
2
SO Ph) as well
2
H, SeCF
2
as higher fluorinated homologues. The key point is the in-situ
generation of perfluoroalkylselenyl chloride.
Initial investigation focused on the identification of the best
catalyst system. By employing (phenylethynyl) copper without
any additional ligand the desired product was obtained in 47%
yield. In order to improve the reaction we decided to test
ancillary ligands that are commonly used in copper catalyzed
With the best condition in hand (Entry 10), we turned our
attention to study the scope and limitation of the reaction with a
particular focuses of studying different functional groups as
demonstrated in Scheme 3. In general, when aryl acetylene
derivatives were evaluated, the reaction was tolerant to both
electrons withdrawing or donating substituents and the desired
products were obtained in moderate to excellent yields.
Moreover, the reaction turns out to be tolerant also to aliphatic
alkynyl derivatives with basically similar reactivity. In more detail,
when ((3-hydroxyphenyl)ethynyl) copper was evaluated, we
[
13]
cross-coupling reactions.
In this context we investigated 4
different known families of ligand. (Scheme 2) Starting with
amines, by adding 1 equivalent of bipyridine (bpy, L1) the
desired product was formed in higher yield of 60%. No further
improvement was observed when 4,4′-Dimethyl-2,2′-dipyridyl
was used (L2) since only 58% was achieved. 1,10-
phenanthroline derivatives (L3 and L4) were not suitable since
less than 34% of the desired product was formed. TMEDA also
was less efficient than L1 and only 53% was observed. The use
of L-proline, dibenzoylmethane as well as triphenylphosphine
demonstrated obviously the presence of new species in fluorine
NMR. We confirmed the α-trifluoromethylselenolation of L7 with
3
were glad to observe only the C-SeCF bond formation (product
2a) and no trifluoromethylselenolation of the free oxygen was
detectable.
[
14]
less than 10% yield.
Table
1.
Optimization
of
the
reaction
conditions
for
the
trifluoromethylselenolation of (phenylethynyl)copper
Scheme 2. Ligand optimisation for the trifluoromethylselenolation of
(
phenylethynyl) copper
Cu
SeCF
3
L1
+
[Cl-SeCF3]
Cu
SeCF
3
THF, RT, 16h
L
+
[Cl-SeCF3]
1b
2b
THF, RT, 16h
SO
2
Cl
2
[
a]
1
b
2
b
Entry
Deviation from standard conditions
Yield %
Ph
SeCF
3
1
2
None
60
81
Reaction time 64h
-
N
N
3
4
50 °C
65
29
45
32
3
N
N
DCM instead of THF
4
7%
L1, 60%
L2, 58%
5
3
CH CN instead of THF
6
1,4-dioxane instead of THF
DMSO instead of THF
DMF instead of THF
N
N
N
N
7
N
N
8
64
71
80
65
L3, 32%
L4, 34%
L5, 53%
9
1.1 equiv. of [Cl-SeCF
1.2 equiv. of [Cl-SeCF
No L1 in DMF with 1. 2 equiv. of [Cl-SeCF
Reactions were performed with BnSeCF (0.3 mmol, 1 equiv.), SO
3
] in DMF
O
O
10
3
] in DMF
O
1
1
3
]
N
H
P
[a]
OH
3
2
Cl
2
(0.3
mmol, 1 equiv.) and dry DMF (1 mL) unless otherwise noted. The reaction
mixture was stirred for 5 hours at room temperature. The mixture was added
to another schlenck tube containg alkynyl copper (I) (0.3 mmol), L1 (0.3 mmol)
and the reaction media was stirred for 16h at room temperature. Yields
L6, 51%
L7, 44%
L8, 37%
[
a]
Reactions were performed with BnSeCF
mmol, 1 equiv.) and dry DMF (1 mL). The reaction mixture was stirred for 5
hours at room temperature. The mixture was added to another schlenck tube
containg alkynyl copper (I) (0.3 mmol), L (0.3 mmol). Yields determined by
NMR spectroscopy with PhOCF as an internal standard.
3
(0.3 mmol, 1 equiv.), SO
2
Cl
2
(0.3
1
9
determined by F NMR spectroscopy with PhOCF as an internal standard.
3
1
9
F
In similar way, when the (phenylethynyl) copper substituted
3
in para position with an acetyl group was evaluated, the desired
1
9
Attempts to improve the reaction outcome we turned our
attention to study further the different parameters (Table 1).
While the desired product was obtained in 60% yield in the
presence of L1 after 16h (Entry 1). The yield could be further
increased to 81% by extending the reaction time (Entry 2).
Afterwards, several solvents have been examined including
product 2c was obtained with an excellent yield of 82% ( F
NMR) with full selectivity. Furthermore, bromo as well as cyano
containing starting materials were also tolerated under our
reaction conditions, the desired product could be obtained in
excellent yield (products 2d, 2e). Interestingly, the
trifluoromethylselenolation of (triisopropylsilyl)acetylene copper
occur with an excellent yield of 88% (product 2f). Noteworthy,
3
DCM (Entry 4), CH CN (Entry 5), 1,4-dioxane (Entry 6). Only low
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Chemistry - A European Journal
10.1002/chem.201702028
COMMUNICATION
the products 2d and 2f could be used in follow up reactions
under transition metal catalysis. Finally, aliphatic alkynyl copper
underwent trifluoromethylselenolation in moderate to excellent
yields (2g, 2h, 2i, 2j). More specifically, the ester derivatives 2h
N
L1
R
Cu
+
[Cl-SeRf]
R
SeRf
DMF, RT, 16h
N
is
also
tolerated
and
undergo
selective
L1
SeCF
trifluoromethylselenolation with good yield. Finally, this process
is highly selective toward alkenes. Indeed, no addition of
chlorotrifluoroselenyl to the double bound of product 2i is
detectable under this condition.
2
H
SeCF
3
SeCF
2
2
SO Ph
2
b, 73% (76%)
SeCF
3b, 17% (52%)
4b, 53% (57%)[b]
[
a]
Scheme 3. Tifluoromethylselenolation of alkynyl copper compounds.
2
CF
3
SeCF CF CF CF CF CF
2
2
2
2
2
3
N
N
L1
5
b, 56% (70%)
6b, 38%
R
Cu
+
[Cl-SeCF3]
R
SeCF3
DMF, RT, 16h
1
2
O
O
O
L1
O
SeCF
3
SeCF
2
H
SeCF3
3h, 37% (34%)[b]
SeCF3
SeCF3
2h, 41% (57%)
HO
O
O
O
O
O
2
a, 32% (50%)
SeCF3
2b, 73% (76%)
2c, 63% (82%)
SeCF
2
CF
3
2 2 2 2 2 3
SeCF CF CF CF CF CF
4h, 39% (50%)
5h, 24% (36%)
SeCF3
Si
SeCF3
[
a]
Reactions were performed with BnSeCF
0.24 mmol, 1.2 equiv.) and dry DMF (1 mL). The reaction mixture was stirred
3 2 2
(0.24 mmol, 1.2 equiv.), SO Cl
NC
Br
(
for 5 hours at room temperature. The mixture was added to another schlenck
tube containg alkynyl copper (I) (0.2 mmol), L1 (0.2 mmol) and the reaction
2
d, 71% (83%)
2e, 74% (87%)
2f, (88%)
media was stirred for 16h at room temperature. Yields shown are those of
O
O
SeCF3
19
isolated products; yields determined by F NMR spectroscopy with PhOCF
3
[
b]
as an internal standard are shown in parentheses. Reactions performed in
dry THF (1 mL).
SeCF3
SeCF3
2
g, 50% (76%)
2h, 41% (57%)
2i, 44% (48%)
In conclusion, we demonstrated herein that the direct
trifluoromethylselenolation of alkynes could be successfully
promoted by making use of alkynyl copper (I) compounds. The
system shows high functional group tolerance in comparison
with the reported systems and the desired product were
obtained in good yields. Moreover, aliphatic as well as aromatic
alkynes were effective under our reaction conditions.
Furthermore, we demonstrated that the procedure could be
extended to fluoroalkyl derivatives. The evaluation of other
nucleophile as well as catalytic version of such transformation is
under way and will be reported in due course.
SeCF3
2
j, 75 % (88 %)
[
a]
Reactions were performed with BnSeCF (0.4 mmol, 1.2 equiv.), SO Cl (0.4
3
2 2
mmol, 1.2 equiv.) and dry DMF (1 mL). The reaction mixture was stirred for 5
hours at room temperature. The mixture was added to another schlenck tube
containg alkynyl copper (I) (0.33 mmol), L1 (0.33 mmol). The reaction media
was stirred for 16h at room temperature. Yields shown are those of isolated
products; yields determined by F NMR spectroscopy with PhOCF
internal standard are shown in parentheses.
1
9
3
as an
After observing general reactivity with aliphatic as well as
aromatic alkynyl copper (I) derivatives, we turned our attention
to evaluate for the first time the fluoroalkylselenolations of
alkynyl copper derivatives (Scheme 4). We were glad to observe
Experimental Section
the incorporation of SeCF
2 2
SO Ph in satisfactory yield (52%,
product 3b). Noteworthy, easily follow up reactions could be
[
12e]
easily be designed.
2
The challenging SeCF H alkyne product
was also obtained in good yield (57%, product 4b). Moreover,
the system turned to be tolerant to higher homologues and
products 5b and 6b were obtained in moderate to good yield.
Furthermore, the alkyne benzoate derivatives were also
successfully employed and the corresponding desired product
were obtained in low to good yields.
Typical
[(trifluoromethyl)selanyl]ethynyl}benzene 2b: to
equipped with a magnetic stirrer are added BnSeCF
2
equiv.), SO Cl (0.4 mmol, 1.2 equiv.) and dry DMF (1 mL). The reaction
procedure:
Synthesis
of
{2-
a
flame-dried-flask
(0.4 mmol, 1.2
3
2
mixture was stirred for 5 hours at room temperature under nitrogen. The
mixture was added to another flame-dried-flask containg phenylacetylene
copper (I) (0.33 mmol, 1 equiv.), L1 (0.33 mmol, 1 equiv.) and the
reaction media was stirred for 16h at room temperature under nitrogen.
[
a]
Scheme 4. Fluoroalkylselenolations of alkynyl copper compounds.
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Chemistry - A European Journal
10.1002/chem.201702028
COMMUNICATION
1
9
[
4]
A. Tlili, F. Toulgoat, T. Billard, Angew. Chem. Int. Ed. 2016, 55, 11726-
3
Conversion is checked by F NMR with PhOCF as internal standard.
1
1735.
The reaction mixture is partitioned between DCM and water. The
aqueous layer is extracted with DCM and the combined organic layers
[
[
5]
6]
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4
are washed with brine, dried over MgSO , filtered and concentrated to
dryness. The crude residue is purified by flash chromatography to afford
1
the desired product H NMR (300 MHz, CDCl
3
) d = 7.49 (m, 2H), 7.39-
1
9
7
.33 (m, 3H). F NMR (282 MHz, CDCl
3
) δ = -36.14 (s, 3F).
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Chemistry - A European Journal
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COMMUNICATION
COMMUNICATION
C. Ghiazza, T. Billard, Anis Tlili*
Page No. – Page No.
Trifluoromethyl- and
Fluoroalkylselenolations of
Alkynylcopper (I) compounds .
The successful fluoroalkylselenolation of alkynyl copper (I) is described herein. The
system shows high functional group tolerance and the applicability of the procedure
is extended to various fluoroalkyl derivatives. This convenient one-pot procedure
occurs under oxidant free conditions at room temperature.
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