Nickel-Catalyzed Direct Trifluoroethylation of Aryl Iodides with 1,1,1-Trifluoro-2-Iodoethane via Reductive Coupling

Article abstract of DOI:10.1002/adsc.202000985

A nickel-catalyzed direct trifluoroethylation of aryl iodides with an industrial raw material CF₃CH₂I has been developed, demonstrating high efficiency, excellent functional-group compatibility, especially with large sterically hindered groups. The key to success is the combination of nickel with readily available nitrogen and phosphine ligands. The powerful potential of this strategy is further demonstrated by the late-stage modification of several derived bioactive molecules. (Figure presented.).

Full text of DOI:10.1002/adsc.202000985

Title: Combinatorial Nickel-Catalyzed Direct Trifluoroethylation of Aryl
Iodides with 1,1,1-Trifluoro-2-Iodoethane via Reductive Coupling
Authors: Han Li, Jie Sheng, Guang-Xu Liao, Bing-Bing Wu, Hui-Qi Ni,
Yan Li, and Xi-Sheng Wang
This manuscript has been accepted after peer review and appears as an
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of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
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content of this Accepted Article.
To be cited as: Adv. Synth. Catal. 10.1002/adsc.202000985
Link to VoR: https://doi.org/10.1002/adsc.202000985

10.1002/adsc.202000985
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.202((will be filled in by the editorial staff))
Nickel-Catalyzed Direct Trifluoroethylation of Aryl Iodides
with 1,1,1-Trifluoro-2-Iodoethane via Reductive Coupling
Han Li,a Jie Sheng, a Guang-Xu Liao, a Bing-Bing Wu, a Hui-Qi Ni, a Yan Li a and Xi-
Sheng Wanga,*
a
Hefei National Laboratory for Physical Sciences at the Microscale and Department of Chemistry, Center for
Excellence in Molecular Synthesis of CAS, University of Science and Technology of China, 96 Jinzhai Road, Hefei,
Anhui 230026, P. R. China. E-mail: xswang77@ustc.edu.cn
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
compounds with trifluoroethyl (pseudo)halides
Abstract: A nickel-catalyzed direct trifluoroethylation of
aryl iodides with an industrial raw material CF3CH2I has (Scheme 1a), and palladium-catalyzed direct
trifluoroethylation of C(sp2)-H bonds has then been
been developed, demonstrating high efficiency, excellent
functional-group compatibility, especially with large
sterically hindered groups. The key to success is the
combination of nickel with readily available nitrogen and
phosphine ligands. The powerful potential of this strategy
is further demonstrated by the late-stage modification of
several derived bioactive molecules.
achieved
with
mesityl(2,2,2-trifluoroethyl)-
iodoniumsalts[10] as a trifluoroethlating agent (Scheme
1b). Meanwhile, to avoid the prepreparation of
arylboronic
compounds
or
trifluoroethyl
iodoniumsalts, aryl iodides have also been directly
used for trifluoroethylation with 1,1,1-trifluoro-2-
iodoethane via a classical Ullmann reaction, but
requiring the promotion of excess copper powder[11]
(Scheme 1c).
Keywords: aryl halides; nickel; reductive coupling;
radical reactions; C-C coupling
Considering all these known methods still suffer
from unsatisfactory atom-economy, low reaction
activity or poor functional-group compatibility, thus, it
is of great significance to develop a new catalytic
system for efficient trifluorethylation conversion of
partners, which is emerging as a powerful strategy to
forge C-C bonds in a high atom- and step-economic
Organic compounds bearing fluorine atom(s) play
critical roles in many areas of modern scientific
research,
especially
for
pharmaceuticals,
agrochemicals and special materials.[1] Hence, the
selective incorporation of fluorine atom or fluorinated
moieties into non-fluorinated parent molecules has
triggered constant extensive efforts on the rational and
efficient synthesis of such target compounds.[2]
Among all the fluorine-containing motifs, (2,2,2-
trifluoroethyl)arenes have received considerable
attention due to their favourable properties over the
non-fluorinated analogues, such as lipophilicity,
metabolic stability and bioavailability.[3] The
traditional synthesis methods towards trifluoroethyl
arenes have been developed by the late-stage
construction of trifluoroethyl groups on the functional
arenes, including trifluorination from aldehydes,[4]
hydrofluorination from difluorostyrenes[5] and
nucleophilic substitution on benzylic compounds with
“CuCF3”.[6] While multistep prefunctionalization was
normally required for the synthesis of such starting
materials, the direct introduction of trifluoroethyl
group into arenes have been established as an efficient
and convenient alternative approach to make
trifluoroethyl arenes.[7] As results, the classical
palladium[8]- or nickel[9]-catalyzed cross-coupling
reactions have been developed to couple arylboronic
Scheme 1. Previous arts and current work on
trifluoroethylation
1
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10.1002/adsc.202000985
Advanced Synthesis & Catalysis
path.[12] As one part of our efforts to develop novel
methods for facile incorporation of fluoroalkyl
moieties into organic molecules, we envisioned that
this nickel--catalyzed reductive cross-coupling
strategy could be used for trifluoroethlation of aryl
halide with readily available trifluoroethyl iodide.
During the preparation of our manuscript, a similar
tactic to access trifluoroethyl arenes via coupling of
aryl halides and trifluoroethyl chloride with zinc used
as the reductant has been reported by Zhang and co-
workers.[13] However, the catalytic reactivity of this
system is not good enough with only low to moderate
yields, and large sterically hindered substituents on the
aryl halides are not tolerated which still remains as a
big challenge.
Herein, we report a combinatorial nickel-catalyzed
direct trifluoroethylation of aryl iodides with readily
available 1,1,1-trifluoro-2-iodoethane. Using the in-
situ-generated catalysts by combination of nickel with
various nitrogen and phosphine ligands, this method
demonstrates high efficiency, excellent functional-
group compatibility, especially with large sterically
hindered groups. The powerful potential of this
strategy is further elaborated by the late-stage
modification of several derived bioactive molecules.
We commenced our study by using 4-iodo-biphenyl
(1a) and 1,1,1-trifluoro-2-iodoethane (2) as coupling
partners in the presence of a catalytic loading of NiI2
(10 mol%) and stoichiometric reductant Mn in DMA
at 80 °C. After a systematic study of reaction
parameters (For details, see the SI), we found that the
employing of ligand combination with nickel was
crucial for the effective conversion of 1a in this
Table 1. Optimization of the reaction conditions.a)
catalytic reductive coupling system. For example,
nitrogen ligand dtbpy gave only 49% yield and
phosphine ligand dppf showed no reactivity for this
transformation (Table 1 ， entries 1-2), while a
combination of dtbpy and dppf as ligands promoted
the yield remarkably to 88% (entry 3). Along with
dppf as one of the ligands, other nitrogen ligands could
also catalyze this reaction but with lower yields
(entries 4-5). Moreover, the combination of dtbpy with
other nitrogen or phosphine ligands could afford
slightly lower yields as well (entries 6-8, for details,
see the SI), which provided further evidence that the
key for this catalytic transformation is the combination
of both ligands to nickel species. Various nickel(II)
sources were next investigated in this catalytic system
(entries 9-12, for details, see the SI), among which NiI2,
perform the best reactivity. It is worth mentioning that
Ni(cod)2 could give a higher yield with 94% (entry 13),
but we still used NiI2 as the catalyst for the reaction,
because of the convenience of operation and the
robustness of this transformation,. Finally, several
control experiments indicated that the nickel catalyst,
ligands and reductant were indispensable for the
success of this coupling (entries 14-16).
With the optimized conditions established, we then
investigated the scope of this trifluoroethylation
protocol. First, a series of p-substituted derivatives
were tested, and the results are listed in Scheme 2
according to their Hammett substituent constants of
the substituents.[14] Indeed, aryl iodides installed with
strongly electron-withdrawing functional groups, such
as cyano (1b), CF3 (1c), acetyl (1d), CO2Me (1e) and
CHO (1f), were found to couple smoothly to give the
desired trifluoroethylated arenes in good to excellent
yield. Meanwhile, substrates possessing inductively
electron-withdrawing substituents were also feasible,
with the mesyl (3g), tosylate (3h) and chloro (3i)
products being obtained in 72-90% yield. Additionally,
aryl iodide 1j bearing boronic acid ester was coupled
smoothly with boronic acid ester group completely
retained, furnishing 3j in moderate yield. Likewise,
electron-donating functional groups (1k-1o) on the
aryl rings were also compatible well, giving the
corresponding products in moderate to excellent yields.
Furthermore, meta-substituents on aryl iodides (1p-1s)
were also compatible with this reaction with slightly
lower yields. Moreover, it should be noted that ortho-
substituents were also well tolerated in this reaction,
affording the trifluoroethylated arenes (3u-3w) with
large sterically hindered groups in moderate to
excellent yields. To our delight, when the reaction with
3w was run on a gram scale, the desired product was
obtained in 90% yield, demonstrating the great
powerful potential application prospect of this strategy
in drug synthesis. Also, disubstituted aryl iodides (1x)
could furnish the corresponding product in 87% yield.
Finally, naphthalene (3y-3aa) and dibenzothiophene
(3ab) derived iodides were also trifluoroethylated
successfully under the optimized conditions.
Entry
Ni
Ligand
Yield (%)b)
1
2
NiI2
NiI2
NiI2
dtbpy
dppf
dtbpy /dppf
bpy /dppf
49
0
88 (94)
25
3c)
4
NiI2
NiI2
NiI2
NiI2
NiI2
dmbpy/dppf
dtbpy /4-CN-Py
dtbpy /DMAP
dtbpy /BINAP
dtbpy /dppf
dtbpy /dppf
dtbpy /dppf
dtbpy /dppf
dtbpy /dppf
dtbpy /dppf
-
5
6
7
8
9c)
10c)
11
12
13
14
15
16d)
27
84
65
72
82
80
54
NiBr2
NiCl2
Ni(OAc)2
Ni(NO3)2·6H2O
Ni(cod)2
-
63
94 (97)
0
16
NiI2
NiI2
dtbpy /dppf
0
a)
Reaction conditions: 1a (0.2 mmol, 1.0 equiv), 2 (3.0
equiv), Nil2 (10 mol%), ligand (10-20 mol%), Mn (3.5
b)
equiv), DMA (1.0 mL), 80 °C, 24 h. GC yields with
dodecane used as internal standard, numbers in parentheses
c)
was isolated yields. The yields were average of two
independent experiments. d) Lack of Mn.
2
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10.1002/adsc.202000985
Advanced Synthesis & Catalysis
to 5a and 5b in 86 and 63% yield, respectively. Delightfully,
both biologically active molecules, fenofibrate and
ezetimibe -derived iodides, furnished the corresponding
trifluoroethylation products (5c, 5d) in excellent yields.
Moreover, the iodide of loratadine (5e) was also compatible
with this transformation with a moderate yield. All these
results clearly demonstrate the significant potential of the
present method for late- stage functionalization of complex
aryl iodides derived from bioactive molecules.
Scheme 2. Scope of the aryl iodides. a) Reaction conditions:
1a (0.2 mmol, 1.0 equiv), 2 (3.0 equiv), Nil2 (10 mol%),
dppf (10 mol%), Mn (3.5 equiv), DMA (1.0 mL), 80 °C, 24
h. b) Isolated yield. c) Yields were determined by 19F NMR
with benzotrifluoride as internal standard due to the
volatility of product. d) 3.6 mmol scale.
Scheme 4. Control experiments.
In order to gain insight into the mechanism of the
reaction, various control experiments were carried out.
First of all, to probe whether the trifluoroethylation
species was free radical or nucleophilic organometallic
intermediate, radical inhibition experiment was
initially conducted. The coupling reaction was
completely quenched by the addition of stoichiometric
amount of TEMPO (2,2,6,6-tetramethylpiperidine-
Noxyl radical) under the standard reaction conditions
(Scheme 4a), in addition, the expect product TEMPO-
CH2CF3 was detected by GC-MS with a yield 60%
based on 19F NMR data, indicating this transformation
may proceed through a radical process.[15] Then,
several verification experiments were further
implemented to rule out the possible generation of
trifluoroethyl manganese species. Whether treating
1,1,1-trifluoro-2-iodoethane with manganese power in
DMA (Scheme 4b) or with standard condition in the
absence of aryl iodide (Scheme 4c), we could not
detect the trifluoroethyl manganese species, nor the
hydrogenated product 7. Finally, we prepared the aryl
nickel complex A according to the literature[12n,16] and
a 45% yield of 3e was obtained when complex A was
treated with 2 (Scheme 4d). Also, the subjection of
complex A into the standard conditions afforded 3e in
Scheme 3. Late-stage trifluoroethylation of bioactive
molecules derivatives. a) Reaction conditions: 1a (0.2 mmol,
1.0 equiv), 2 (3.0 equiv), Nil2 (10 mol%), dppf (10 mol%),
Mn (3.5 equiv), DMA (1.0 mL), 80 °C, 24 h. b) Isolated yield.
The broad substrate scope and wide functional-group
compatibility make late-stage trifluoroethylation of
bioactive molecules possible. To demonstrate this potential,
several aryl iodides were prepared from bioactive molecules
and tested in the optimized conditions, the results are
summarized in Scheme 3. The aryl iodides derived from
tyrosine and estrone could be trifluoroethylated successfully
3
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10.1002/adsc.202000985
Advanced Synthesis & Catalysis
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yield observed with the NiI2/dtbpy/dppf catalytic
system (82%, Scheme 2). Although there is lack of
direct evidence, this result showed that the complex A
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Experimental Section
General procedure
Aryl iodide 1 (1.0 equiv, 0.2 mmol, if solid), NiI2 (10 mol %,
0.02 mmol, 6.3 mg), dtbpy (10 mol%, 0.02 mmol, 5.4 mg),
dppf (10 mol%, 0.02 mmol, 11.1 mg) and Mn (3.5 equiv,
0.7 mmol, 38.5 mg) were combined in a 5 mL oven-dried
sealing tube. The vessel was evacuated and backfilled with
N2 (repeated for 3 times), and aryl iodide 1 (1.0 equiv, 0.2
mmol, if liquid), 2 (3 equiv, 0.6 mmol) and DMA (1.0 mL)
were then added into the reaction system subsequently via
syringe. The tube was sealed with a Teflon lined cap and
heated in a preheated oil bath at 80 ˚C. After stirring for 24
h, the reaction mixture was cooled to room temperature,
diluted with EtOAc and filtered through a pad of celite. The
filtrate was added into brine and extracted with EtOAc, the
combined organic phase was dried over Na2SO4, filtrated
and concentrated under vacuum and purified by flash
column chromatography to give the corresponding product.
Acknowledgements
We gratefully acknowledge the National Science Foundation of
China (21971228, 21772187) and China Postdoctoral Science
Foundation (2019M653580) for financial support.
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10.1002/adsc.202000985
Advanced Synthesis & Catalysis
COMMUNICATION
Combinatorial Nickel-Catalyzed Direct
Trifluoroethylation of Aryl Iodides with 1,1,1-
Trifluoro-2-Iodoethane Via Reductive
Coupling
Adv. Synth. Catal. Year, Volume, Page – Page
Han Li, Jie Sheng, Guang-Xu Liao, Bing-Bing
Wu, Hui-Qi Ni, Yan Li, and Xi-Sheng Wang*
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