Using Chlorotrifluoroethane for Trifluoroethylation of (Hetero)aryl Bromides and Chlorides via Nickel Catalysis

Article abstract of DOI:10.1021/acs.orglett.1c00058

A nickel-catalyzed reductive cross-coupling between industrial chemical CF3CH2Cl and (hetero)aryl bromides and chlorides has been reported. The reaction is synthetically simple without the preparation of arylmetals and exhibits high functional group tolerance. The utility of this protocol has been demonstrated by the late-stage modification of pharmaceuticals, providing a facile route for medicinal chemistry.

Full text of DOI:10.1021/acs.orglett.1c00058

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Letter
Using Chlorotrifluoroethane for Trifluoroethylation of (Hetero)aryl
Bromides and Chlorides via Nickel Catalysis
Xuefei Li, Xing Gao, Chun-Yang He, and Xingang Zhang*
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ABSTRACT: A nickel-catalyzed reductive cross-coupling between
industrial chemical CF3CH2Cl and (hetero)aryl bromides and chlorides
has been reported. The reaction is synthetically simple without the
preparation of arylmetals and exhibits high functional group tolerance. The
utility of this protocol has been demonstrated by the late-stage
modification of pharmaceuticals, providing a facile route for medicinal
chemistry.
Scheme 1. Transformations of CF3CH2Cl and Its
Applications
he site-selective introduction of fluorinated groups into
organic molecules has become a synthetic topic of great
T
interest, because of the important applications of organo-
fluorinated compounds in life and materials sciences.1
Although impressive achievements have been made over the
past decade,2 for practical applications, the use of abundant
and inexpensive industrial chemicals, such as inactive
fluoroalkyl chlorides, as fluorine sources has been scarcely
reported.3 For instance, chlorotrifluoroethane (CF3CH2Cl) is
an inexpensive raw industrial chemical used as a trifluor-
oethylating reagent for the production of refrigerant 1,1,1,2-
tetrafluoroethane (R134a)4 and some important pharmaceut-
ical intermediates, such as 2,2,2-trifluoroethanol
(CF3CH2OH),5 2,2,2-trifluoroethanamine (CF3CH2NH2),6
and 1,1,1-trifluoro-2-iodoethane (CF3CH2I)7 (Scheme 1a).
These transformations of CF3CH2Cl are limited in SN2 type
reactions with simple nucleophiles.3c,4−7 The use of a
transition metal-catalyzed strategy would be promising for
overcoming the limitations and pave a new way to access much
more structurally diversified compounds of interest in life and
materials sciences. To the best of our knowledge, such a
strategy remains challenging due to the strong bond
dissociation energy of the C−Cl bond and easy β-fluoride
elimination of the intermediate trifluoroethylmetal species.3c,d,8
In this context, we demonstrate the feasibility of transition
metal-catalyzed trifluoroethylation with CF3CH2Cl to access
trifluoroethylated (hetero)arenes that are of interest in
medicinal chemistry.
Trifluoroethylated arenes are usually prepared from the
stoichiometric reaction of benzyl bromides with trifluorometh-
yl copper (CuCF3) species.9 However, it is difficult to apply
this method to the late-stage modification of bioactive
molecules because of the availability of benzyl halides.
Accordingly, the trifluoroethylation of aromatic compounds
by a transition metal-mediated or -catalyzed strategy has been
developed.10 These methods either require an expensive
catalyst, such as palladium,10b−d or are limited to the use of
Received: January 7, 2021
Published: February 5, 2021
https://dx.doi.org/10.1021/acs.orglett.1c00058
Org. Lett. 2021, 23, 1400−1405
© 2021 American Chemical Society
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arylmetals, including moisture and functional group sensitive
Grignard reagents3d (Scheme 1b). The direct C−H bond
trifluoroethylation of (hetero)arenes has also been reported,
but a directing group or expensive trifluoroethylating reagent is
needed (Scheme 1c).11 Notably, the trifluoroethylating
reagents used in these methods, such as CF3CH2I and
CF3CH2OTs, are derived from CF3CH2Cl.10,11 Inspired by
our nickel-catalyzed cross-coupling between industrial chem-
ical ClCF2H and aryl chlorides,3e we report herein the first
example of nickel-catalyzed cross-coupling of inexpensive and
widely available (hetero)aryl bromides and chlorides with
CF3CH2Cl (Scheme 1d). This protocol has the advantages of
being inexpensive and synthetically convenient without the
preparation of arylmetal reagents and having a broad substrate
scope, including pharmaceuticals, thus providing cost-efficient
access for applications in medicinal chemistry.
7), but the use of MgCl2 as the additive could provide 3 in 71%
yield without observation of 4 and 5 (entry 8). Other additives
were also tested but were inferior to MgCl2 (for details, see the
Supporting Information). The role of MgCl2 is probably to
facilitate the reduction of the [NiII] complex by Zn to generate
an active nickel species.3e,12b Finally, the optimal reaction
conditions were identified by decreasing the loading amount of
Zn to 2.2 equiv with 1.0 equiv of MgCl2 as the additive,
providing 3 in 73% yield (entry 10). Essentially, the absence of
nickel, ligand, and reductant led to no product (entries 11−13,
respectively), thus demonstrating the essential role of [Ni/L]
and Zn in promoting the reaction.
With the viable reaction conditions in hand, a wide range of
aryl bromides were examined to ascertain the substrate scope
of this protocol (Scheme 2). Generally, moderate to good
yields were obtained. Aryl bromides bearing electron-donating
or electron-withdrawing substituents underwent the current
nickel-catalyzed trifluoroethylation smoothly (10−17). The
reaction exhibited good functional group tolerance. Versatile
synthetic handles, such as formyl, enolizable ketone, ester,
nitrile, and trimethylsilyl moieties, were compatible with the
reaction conditions (13−18, 20, and 21). Notably, hydroxyl
group and boronate-containing substrates (19, 22, and 23) did
not affect the reaction efficiency and provided the correspond-
ing products efficiently. In particular, the organoboron
compatibility of this protocol provides a good platform for
subsequent derivatization, which is in sharp contrast to the
previous palladium-catalyzed trifluoroethylation reactions
using arylborons as the coupling partner,10b−d,f,g thus
demonstrating the advantage of this protocol. In addition to
the aryl bromides, aryl chlorides could also be applied to the
reaction (3, 7, 9, 10, 15−19, 22, and 24) and even higher
yields were obtained in some cases (16 and 17), while previous
reports of trifluoroethylation of aromatic compounds demon-
strate that aryl chlorides make up a class of unreactive
substrates.10b Although aryl chlorides are the inexpensive and
widely available feedstock, the reductive cross-coupling
reactions with aryl chlorides are limited and only rare examples
of nickel-catalyzed cross-coupling of aryl chlorides with alkyl
chlorides have been reported thus far.3e,14 Thereby, the current
nickel-catalyzed process provides a cost-efficient route for
application of aryl chlorides in organic synthesis.
The reaction was not restricted to aryl halides, as heteroaryl
halides were also suitable substrates. A series of quinoline-,
isoquinoline-, indole-, and benzoxazole-derived heteroaryl
bromides and chlorides furnished the corresponding trifluor-
oethylated products efficiently (26−33). However, simple
pyridine derivatives led to poor yields.
The high functional group compatibility and broad substrate
scope of this method encourage us to examine the
trifluoroethylation of a series of aryl chloride-containing
pharmaceuticals. Clofibrate 34a and fenofibrate 34b used to
treat hyperlipidemia were competent coupling partners,
providing the trifluoroethylated compounds 35a and 35b,
respectively, in high yields. Importantly, N-heterocycle-
containing substrates did not interfere with the reaction
efficiency. For instance, chlormezanone 34c and indomethacin-
derived ester 34d efficiently furnished products 35c and 35d,
respectively; even pyridine-containing H1 receptor antagonist
loratadine 34e was a competent coupling partner. Because aryl
chlorides are quite common in pharmaceuticals and natural
products, this method also provides a facile route for drug
discovery and development.
We began our studies by choosing bromobenzene 2a as the
model substrate to test the nickel-catalyzed reductive cross-
coupling with ClCH2CF3 1 (Table 1). After extensive efforts
Table 1. Representative Results for Optimization of Ni-
a
Catalyzed Reductive Cross-Coupling between 1 and 2a
b
entry
[Ni]
additive (x)
none
TMSCl (0.5)
MgCl2 (0.5)
NaI (0.5)
KI (0.5)
TMEDA (0.5)
TMEDA
MgCl2 (0.5)
MgCl2 (1.0)
MgCl2 (1.0)
MgCl2 (1.0)
MgCl2 (1.0)
MgCl2 (1.0)
M (y)
yield (%) (3/4/5)
1
2
3
4
5
6
7
8
NiBr2
NiBr2
NiBr2
NiBr2
NiBr2
NiBr2
NiBr2
NiBr2
NiBr2
NiBr2
none
Mn (3)
Mn (3)
Mn (3)
Mn (3)
Mn (3)
Mn (3)
Zn (3)
Zn (3)
Zn (3)
Zn (2.2)
Zn (2.2)
Zn (2.2)
none
32/4/0
10/4/3
2/5/0
34/4/1
46/4/0
50/10/3
14/3/0
23/4/1
71/0/0
73/0/0
0/0/0
9
10
11
12
c
NiBr2
NiBr2
3/15/0
0/0/0
13
a
Reaction conditions (unless otherwise specified): 1 (0.2 mmol, 1.0
b
equiv), 2a (1.5 equiv), DMA (2 mL), 80 °C, 12 h. Determined by
c
19F NMR using fluorobenzene as an internal standard. Reaction
conducted without ligand.
(for details, see the Supporting Information), we found that
the combination of NiBr2 (10 mol %) with 4,4′-ditBu-bpy (10
mol %) in the presence of Mn (3.0 equiv) in DMA at 80 °C
could afford the desired product 3 in 32% yield (entry 1).
Under these reaction conditions, an only 4% yield of
hydrodechlorinated byproduct 4 was formed and no gem-
difluoroethylene 5 was observed. Encouraged by these results,
we examined a series of additives previously demonstrated to
have a beneficial effect on the reaction efficiency (entries 2−5).
12
TMSCl and MgCl2 was less reactive (entries 2 and 3,
respectively), and the addition of NaI13 to the reaction mixture
led to 3 in a comparable yield (entry 4). The use of KI as the
additive could improve the yield of 3 to 46% (entry 5). In
addition to KI, TMEDA also improved the reaction efficiency,
providing 3 in 50% yield, but severe formation of byproducts 4
and 5 was observed (entry 6). Switching the reductant from
Mn to Zn (3.0 equiv) dramatically diminished the yield (entry
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a
Scheme 2. Ni-Catalyzed Reductive Cross-Coupling between 1 and (Hetero)aryl Bromides and Chlorides
a
Reaction conditions (unless otherwise specified): 1 (0.2−0.4 mmol), DMA (4 mL), 80 °C, 12 h. X = Br, 2 (1.5 equiv), MgCl2 (1.0 equiv), Zn (2.2
b
equiv); X = Cl, 6 (2.0 equiv), MgCl2 (1.5 equiv), Zn (3.0 equiv). All yields are isolated yields. Yield determined by 19F NMR using fluorobenzene
as an internal standard. Reaction performed for 15 h. Reaction performed for 20 h.
c
d
The importance and utility of this protocol have also been
demonstrated by gram-scale synthesis. As shown in Scheme 3a,
gram-scale synthesis of compound 22 proceeded smoothly, in
87% yield. Arylboronate 22 can serve as a versatile building
block for the rapid synthesis of complex molecules of medicinal
interest. For instance, Suzuki reaction of 22 with 2-
bromopyrimidine 36 provided heteroarene-containing product
37 in 80% yield (Scheme 3b). Compound 22 could be easily
converted into aryl boronic acid 38 (Scheme 3c), which
subsequently reacted with imidazole via a Chan−Lam
reaction15 to provide compound 40 in 70% yield (Scheme 3d).
To identify whether a trifluoroethyl radical is involved in the
reaction, several radical trapping experiments were conducted
(Scheme 4). No trifluoroethylated product 18 was obtained
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CF3CH2Cl to give the trifluoroethyl radical and [NiII], in
which [NiI] is supposed to be generated through compro-
portionation of [Ni0] with [NiII].20 Subsequently, reduction of
[NiII] with Zn produces [Ni0], which undergoes oxidative
addition with aryl halide to give [Ar-NiII(Ln)X] (A).
Recombination of A with the trifluoroethyl radical provides
key intermediate [Ar-NiIII(Ln)CH2CF3(X)] (B). B undergoes
reductive elimination to deliver the trifluoroethylated product
and release the [NiI] simultaneously. For path II, the reaction
starts with the oxidative addition of aryl halide to [Ni0]. The
resulting nickel complex A is then reduced by Zn to give
arylnickel(I) [Ar-NiI(Ln)X] (C). C undergoes the second
oxidative addition with CF3CH2Cl to give key intermediate B
through a cage rebound process. Finally, reductive elimination
of B provides the trifluoroethylated product and [NiI]. [NiI] is
then reduced by Zn to give [Ni0].
Scheme 3. Gram-Scale Synthesis and Transformations of 22
In conclusion, we have developed the first example of nickel-
catalyzed trifluoroethylation of (hetero)aryl bromides and
chlorides with industry raw material ClCH2CF3 using Zn as a
reductant. The reaction proceeds under mild reaction
conditions with high efficiency, broad substrate scope, and
high functional group tolerance. The approach can also be
used for direct modification of aryl chloride-containing
pharmaceuticals, thus demonstrating its utility in medicinal
chemistry. The reaction features the advantages of synthetic
simplicity without pre-formation of arylmetals and use of
abundant and inexpensive chemicals, including NiBr2,
CF3CH2Cl, and aryl chlorides, providing a cost-efficient
route for organic synthesis and related chemistry.
Scheme 4. Mechanistic Studies
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c00058.
when a reaction mixture of ClCH2CF3 1 and aryl bromide 2m
was treated with an electron transfer (ET) scavenger 1,4-
dinitrobenzene3b,16 under standard reaction conditions
(Scheme 4a). The addition of hydroquinone to the reaction
mixture also dramatically diminished the yield (Scheme 4b). A
radical clock experiment by using α-cyclopropyl styrene17 41
as a probe indeed provided ring-expanded product 42 (Scheme
4c). These results suggest that a trifluoroethyl radical is likely
involved in the reaction. We also found that the use of
nonfluorinated alkyl chlorides failed to provide the correspond-
ing products under standard reaction conditions, thus
demonstrating the important role of CF3 in activating the
C−Cl bond.
Experimental procedures and spectra data for all new
compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Xingang Zhang − Key Laboratory of Organofluorine
Chemistry, Center for Excellence in Molecular Synthesis,
Shanghai Institute of Organic Chemistry, University of
Chinese Academy of Sciences, Chinese Academy of Sciences,
Shanghai 200032, China; orcid.org/0000-0002-4406-
6533; Email: xgzhang@mail.sioc.ac.cn
On the basis of results presented above and previous
reports,3e,18,19 two possible pathways were proposed (Scheme
5). One is based on the radical chain mechanism (path I),18
and the other is a radical cage rebound pathway (path II).19
For path I, the reaction begins with the reaction of [NiI] with
Authors
Xuefei Li − Key Laboratory of Organofluorine Chemistry,
Center for Excellence in Molecular Synthesis, Shanghai
Institute of Organic Chemistry, University of Chinese
Academy of Sciences, Chinese Academy of Sciences, Shanghai
200032, China
Xing Gao − Key Laboratory of Organofluorine Chemistry,
Center for Excellence in Molecular Synthesis, Shanghai
Institute of Organic Chemistry, University of Chinese
Academy of Sciences, Chinese Academy of Sciences, Shanghai
200032, China
Scheme 5. Proposed Reaction Mechanisms
Chun-Yang He − Key Laboratory of Biocatalysis & Chiral
Drug Synthesis of Guizhou Province, Generic Drug Research
Center of Guizhou Province, Zunyi Medical University,
Zunyi, Guizhou 563003, P. R. China; orcid.org/0000-
0002-0599-7335
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Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c00058
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
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This work was financially supported by the National Natural
Science Foundation of China (21931013 and 21991122) and
the Strategic Priority Research Program of the Chinese
Academy of Sciences (XDB20000000).
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