Synthesis of fluoroalkylated alkynes: Via visible-light photocatalysis

Article abstract of DOI:10.1039/c8ob02486c

Fluoroalkylated alkynes, which are versatile building blocks for the synthesis of various biologically active organofluorine compounds, were synthesized from easily available alkynyl halides and fluoroalkyl halides by visible-light photocatalysis. Addition of fluoroalkyl radicals to alkynes and subsequent dehalogenation selectively yielded fluoroalkylated alkynes.

Full text of DOI:10.1039/c8ob02486c

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Synthesis of fluoroalkylated alkynes via
visible-light photocatalysis†
Cite this: DOI: 10.1039/c8ob02486c
Naila Iqbal, Naeem Iqbal, Sung Su Han and Eun Jin Cho
*
Received 6th October 2018,
Accepted 6th November 2018
DOI: 10.1039/c8ob02486c
rsc.li/obc
Fluoroalkylated alkynes, which are versatile building blocks for the of methods for selective synthesis of fluoroalkylated alkynes is
synthesis of various biologically active organofluorine compounds, in high demand.
were synthesized from easily available alkynyl halides and fluoro-
Recently, Noël and co-workers have reported the synthesis
alkyl halides by visible-light photocatalysis. Addition of fluoroalkyl of difluoroalkylated alkynes from phenyl propionic acid deriva-
radicals to alkynes and subsequent dehalogenation selectively tives by visible-light photocatalysis (Scheme 1b).10 We have pre-
yielded fluoroalkylated alkynes.
viously reported that trifluoromethylated alkynes could be
obtained from terminal alkynes via alkynyl iodide intermedi-
ates (Scheme 1c).11 We have tried to extend these results for
the preparation of a diverse range of synthetically important
alkynyl fluoroalkylated compounds. However, replacing CF3I
with other fluoroalkyl halides such as ethyl bromodifluoro-
acetate (BrCF2CO2Et) did not yield the expected difluoroalkylated
Incorporation of fluorinated moieties into organic molecules
has gained tremendous importance among synthetic/medic-
inal chemists mainly because of the unique properties that
fluorine imparts to the organic molecules.1 Fluoroalkylation
can change the properties of organic molecules, such as meta-
bolic stability, lipophilicity, and bioavailability, with minimum
structural alterations.2 The significant medicinal importance
and natural scarcity of fluorinated organic molecules have
urged synthetic chemists to develop new methods for the
incorporation of fluoroalkyl moieties into organic
compounds.3
Radical fluoroalkylation has long been employed for the
installation of fluoroalkyl groups and the recent research inter-
est in visible-light photocatalysis has provided this protocol
significant augmentation.4,5 However, most of the previous
research efforts were dedicated towards aryl and alkenyl fluoro-
alkylation (Scheme 1a), while alkynyl fluoroalkylation has
been less explored.6 Terminal alkynes have not been suitable
substrates for the selective synthesis of fluoroalkylated alkynes
in photocatalysis,7 because most reactions with terminal
alkynes yielded di- or tri-substituted fluoroalkylated alkene
products instead (Scheme 1a).8 Considering that fluoroalkyl-
ated alkynes are important organofluorine compounds, in
that they are versatile building-blocks for the synthesis of
complex biologically active organofluorine target molecules
through further reactions of the alkyne moiety,9 development
Department of Chemistry, Chung-Ang University, 84 Heukseok-ro, Dongjak-gu, Seoul
06974, Republic of Korea. E-mail: ejcho@cau.ac.kr
†Electronic supplementary information (ESI) available: Characterization data
and 1H and 13C NMR spectra of the synthesized compounds. See DOI: 10.1039/
c8ob02486c
Scheme 1 Visible light-mediated radical fluoroalkylations.
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Table 2 Substrate scope of alkynyl difluoroalkylationa,b
alkyne because the necessary bromide intermediate could not
be formed under the photocatalytic conditions (Scheme 1c).
Probably, in situ generation of the required halide intermediate
is limited to CF3I. The inability of terminal alkynes to undergo
selective alkynyl fluoroalkylations forced us to use prefunctio-
nalized alkynyl halides with various fluoroalkyl halides under
mild photocatalytic conditions (Scheme 1d).
The investigation was initiated by reacting an alkynyl
bromide 1a with BrCF2CO2Et (3a) as the fluoroalkylating
source (Table 1). The reaction with fac-Ir(ppy)3 and TMEDA at
0.1 M concentration in MeCN (entry 1) produced the desired
product 4a in 48% yield under visible light irradiation. As
expected, the use of terminal alkynes did not yield any difluor-
oalkylated product under the same conditions (entry 2). The
different cyclometalated Ru catalysts showed slightly better
reactivities (entries 3 and 4). Replacement of bromide with
iodide (2a) in the alkynyl substrate gave improved results
(entries 5 and 6), and fac-Ir(ppy)3 emerged as the better photo-
catalyst. Solvent screening did not improve the reaction yield
(entries 7 and 8). Surprisingly, no reaction occurred when DBU
was used as a base (entry 9). Fluctuation in the stoichiometric
ratio of the reactants showed that the use of 3a as the limiting
reactant with 1.5 equivalents of the alkynyl substrate provided
a better reaction yield (Table 1, entries 10–12). The absence of
the photocatalyst, light source, or base almost completely sup-
pressed the reaction (Table 1, entries 13–15).
a Reaction scale: 2 (1.5 mmol), 3 (1 mmol). b Isolated yields.
tion conditions. Heteroaryl-substituted compounds were also
found to be suitable substrates to obtain the corresponding
difluoroalkylated products 4j and 4k. α,α-Difluoropropargyl-
phosphonates 4l and 4m were synthesized under the given
conditions, where the phosphonate moiety can be utilized as a
versatile intermediate in the synthesis of biologically impor-
tant molecules. It is also notable that aromatic and hetero-
aromatic rings remained unreactive under the reaction con-
ditions. However, aliphatic alkynylhalides did not undergo
selective fluoroalkylation, producing multiple unidentified
side products. The optimized conditions were also amenable
for gram-scale reaction, proving the practicality of the process
Next, to investigate the generality of this alkynyl-difluoroalk-
ylation, various substrates were examined under the optimal
catalytic conditions (Table 2). Reactions of phenylacetylene
derivatives, containing both electron-donating (4b, 4c, 4d, 4e,
4f) and electron-withdrawing substituents (4g, 4h, 4i), gave
good results. Various functional groups including phenolic
ether (4e, 4f) and ketone 4i were tolerated under the mild reac-
Table 1 Optimization of alkynyl difluoroalkylationa
Entry
X
Photocatalyst
Base
Solvent
Variation
Yieldb (%)
1
2
3
4
5
6
7
8
Br
H
Br
Br
I
I
I
I
I
I
I
fac-Ir(ppy)3
fac-Ir(ppy)3
[Ru(phen)3]Cl2
[Ru(bpy)3]Cl2
fac-Ir(ppy)3
[Ru(phen)3]Cl2
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
—
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
DBU
TMEDA
TMEDA
TMEDA
TMEDA
—
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
DMF
DMSO
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
—
—
—
—
—
—
—
—
48
0
52
51
60
56
58
49
0
38
70
66
0
9
—
10
11c
12
13
14
15
3a (1.2 eq.)
3a (1 eq.)
3a (3 eq.)
—
—
No light
I
I
I
I
fac-Ir(ppy)3
fac-Ir(ppy)3
6
4
TMEDA
a All reactions were carried out at the 0.1 mmol scale. b GC yields are reported by using 2,2,2-trifluoroacetophenone as the internal standard.
c (Iodoethynyl)benzene 2a (1.5 eq.).
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Replacement of the solvents has a detrimental effect on the
reaction yields (Table 3, entries 7–9), and increasing the reac-
tion concentration to 0.2 M resulted in slightly better reactivity
(Table 3, entries 10 and 11). These conditions were not very
effective on a larger scale, which forced us to increase the
amounts of catalyst and base to obtain full conversion and
higher yield in large-scale reactions (Table 3, entry 12).
Controlled reactions showed that the light source, catalyst, and
base were compulsory components for the reaction (Table 3,
entries 13–15).
The optimized reaction conditions were applied for the per-
fluoroalkylation of different alkynyl bromides 1 (Table 4).
Substrates having electron-donating groups on the aromatic
rings (6a, 6b and 6d) gave a slightly higher yield than those
Scheme 2 Gram-scale reaction and synthetic applications.
having
an
electron-withdrawing
substituent
(6e).
(Scheme 2a). Furthermore, the synthetic utility of fluoroalky-
lated alkynes was investigated. Product 4b was borylated to
give 4ba despite the formation of a mixture of isomers. In
addition, 4b was selectively reduced to give difluoroalkylated
Z-alkene 4bb (Scheme 2b).12,13
To extend the scope of fluoroalkylation, we next tried
alkynyl perfluoroalkylations using other perfluoroalkyl iodides
as the fluoroalkylating reagents. The use of iodide 2a with
nanofluoro-1-iodo butane 5a provided the alkynyl-perfluoro-
alkylated product 6a in 48% yield (Table 3, entry 1). The use of
the bromide substrate 1a instead of 2a as the model substrate
resulted in an improved yield (60%) of 6a (Table 3, entry 2).
Ru catalysts were found to be better photocatalysts for this per-
fluoroalkylation reaction (Table 3, entries 2–4). Unlike the
aforementioned difluoroalkylation reaction, DBU proved to be
the best base for perfluoroalkylation (Table 3, entries 5–7).
Perfluoroalkylating sources with longer and shorter carbon
chain lengths (C8F17 (6f), C3F7 (6g), and CF3 (6h)) were also
suitable for obtaining the corresponding fluoroalkylated
alkynyl products. Unfortunately, alkynyl fluoroalkylation was
not successful with an aliphatic side chain.
Subjecting terminal alkynes to the optimized conditions
with C4F9I resulted in the formation of the desired product in
only 31% yield, along with the generation of alkenyl fluoroalky-
lated products. This also supports the fact that the use of pre-
functionalized alkynyl halides is required for selective alkynyl
fluoroalkylation (Scheme 3).
Controlled experiments were conducted to gain insight into
the reaction mechanism. Complete suppression of the reaction
in the presence of radical scavengers like 1,4-dinitrobenzene
supports the hypothesis that the reaction proceeds via a
radical mechanism (Scheme 4a).14 Furthermore, coupling of
the CF2CO2Et radical with TEMPO resulted in the formation of
compound 8, which confirms that the reaction follows a
radical pathway (Scheme 4b).
Table 3 Optimization of alkynyl-fluoroalkylation conditionsa
Based on these observations we proposed a reaction mecha-
nism for the synthesis of alkynyl fluoroalkylations (Scheme 5).
Yieldb
(%)
Table 4 Substrate scope of alkynyl-perfluoroalkylationsa,b
Entry
1
Photocatalyst
Base
Solvent
MeCN
Variation
fac-Ir(ppy)3
TMEDA
2a instead
48
of 1a
—
—
—
—
—
—
—
2
3
4
5
6
7
8
9
fac-Ir(ppy)3
TMEDA
TMEDA
TMEDA
TEA
DIPEA
DBU
DBU
DBU
DBU
DBU
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
DMF
DMSO
MeCN
MeCN
MeCN
60
65
65
13
7
80
66
56
82
64
89
[Ru(bpy)3]Cl2
[Ru(phen)3]Cl2
[Ru(phen)3]Cl2
[Ru(phen)3]Cl2
[Ru(phen)3]Cl2
[Ru(phen)3]Cl2
[Ru(phen)3]Cl2
[Ru(phen)3]Cl2
[Ru(phen)3]Cl2
[Ru(phen)3]Cl2
—
10
11
12c
0.2 M
0.5 M
DBU (3 eq.),
(0.2 M)
—
—
No light
DBU
13
14
15
—
TMEDA
—
TMEDA
MeCN
MeCN
MeCN
0
12
0
[Ru(phen)3]Cl2
[Ru(phen)3]Cl2
a All reactions were carried out at the 0.1 mmol scale. b GC yields by
using 2,2,2-trifluoroacetophenone as the internal standard. a Reaction scale: 1 (1.0 mmol). b GC yields by using 2,2,2-trifluoroaceto-
c [Ru(phen)3]Cl2 (3 mol%).
phenone as the internal standard. c Isolated yield.
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range of functional groups. The synthesized molecules can be
used as versatile building blocks for the synthesis of fluori-
nated target molecules because alkynes can undergo a diverse
range of organic transformations.9
Scheme 3 Alkynyl perfluoroalkylation of terminal alkynes.
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
We gratefully acknowledge the National Research Foundation
of
Korea
[NRF-2012M3A7B4049657,
NRF-2014-011165,
NRF-2016K1A3A1A19945930, and NRF-2017R1A2B2004082].
Scheme 4 Reactions with radical scavengers.
Notes and references
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Scheme 5 Proposed mechanism.
Photoexcitation of cyclometalated Ru or Ir complexes [MnLx]
under visible-light irradiation by using blue LEDs will produce
[Mn+1Lx•−]* via metal-to-ligand charge-transfer (MLCT). Single-
electron donation to fluoroalkylhalide 2 will generate the oxi-
dized photocatalyst [Mn+1Lx]+ and the fluoroalkyl radical Rf.
•
The [MnLx] complex is then regenerated by electron transfer
•
from the sacrificial electron donor (TMEDA or DBU), and Rf
adds to the alkynyl halide in a regioselective manner to
produce a fluoroalkylated alkenyl radical A. This intermediate
can undergo dehalogenation to yield the alkynyl fluoroalkyl-
ated product 3. Based on our previous observations,11 we pro-
posed that the fluoroalkenyl radical intermediate may also
abstract a halogen from the fluorinating source to produce the
fluoroalkylated dihalogenated tetrasubstituted alkene B.
However, this dihalogenated alkene B was not observed during
the reaction.
Conclusions
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and alkynyl-perfluoroalkylation reactions of alkynyl halides by
visible-light photocatalysis to access a diverse range of fluoro-
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