The Pd-catalyzed synthesis of difluoroethyl and difluorovinyl compounds with a chlorodifluoroethyl iodonium salt (CDFI)

Article abstract of DOI:10.1016/j.cclet.2021.09.004

Herein, we report a simple and efficient method for the direct installation of chlorodifluoroethyl group onto aromatic molecules of various aromatic amides with a new 2-chloro,2,2-difluoroethyl(mesityl)iodonium salt (CDFI). Moreover, the chlorodifluoroeth

Full text of DOI:10.1016/j.cclet.2021.09.004

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The Pd-catalyzed synthesis of difluoroethyl and difluorovinyl
compounds with a chlorodifluoroethyl iodonium salt (CDFI)
Yaru Niu , Chengyao Kimmy Cao , Chenxin Ge , Hongmei Qu ,
Chao Chen
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DOI:
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https://doi.org/10.1016/j.cclet.2021.09.004
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Please cite this article as: Yaru Niu , Chengyao Kimmy Cao , Chenxin Ge , Hongmei Qu ,
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a chlorodifluoroethyl iodonium salt (CDFI), Chinese Chemical Letters (2021), doi:
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Communication
The Pd-catalyzed synthesis of difluoroethyl and difluorovinyl compounds with a
chlorodifluoroethyl iodonium salt (CDFI)
Yaru Niua,b, Chengyao Kimmy Caob, Chenxin Geb, Hongmei Quaququhongmei@126.com, Chao
Chenb,c,*chenchao01@mails.tsinghua.edu.cn
aKey Laboratory of Systems Bioengineering, Ministry of Education, Department of Pharmaceutical
Engineering, School of Chemical Engineering and Technology, Tianjin University, Tianjin 300350, China
bKey Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology (Ministry of Education, MOE), Department of Chemistry, Tsinghua University,
Beijing 100084, China
cState Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, China
*Corresponding authors: Professor Chao Chen
Tsinghua University
tsinghua university
beijing, china BAS TYPE ADDRESS F...
Beijing 100084
China
Phone: 0086-13661384696
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Herein, we report a simple and efficient method for the direct installation of chlorodifluoroethyl
group onto aromatic molecules of various aromatic amides with a new 2-chloro,2,2-
difluoroethyl(mesityl)iodonium salt (CDFI). Moreover, the chlorodifluoroethyl compounds
could be smoothly converted into difluorovinyl compounds in a one-pot or discrete procedure
and regarded as a steady source of difluorovinyl compounds with “HCl-mask”.
Available online
Keywords:
Iodonium salts
C-H activation
Pd-catalyzed
Difluoroethylation
Difluorovinylation
Graphical Abstract
Due to the high electronegativity and small size of fluorine,
fluorine and fluorine-containing substituents often provide
advantageous properties to the molecules, such as modification
of the electronic properties, improvement of the metabolic
stability, and enhancement of the lypophilicity [1,2]. By
estimation, approximately 30% of all agrochemicals and 20% of
all pharmaceuticals contain fluoro atom(s) [3,4]. Among various
fluorinated compounds, difluoroethylated (-CH2CF2-) and
difluorovinylated (-CH=CF2) groups are both crucial
pharmaceutical moieties and precursors of drugs, and the
difluorovinylated moiety is regarded as an important carbonyl
bioisostere (Fig. 1) [5-11]. Hence, the development of a
convenient and efficient reaction to introduce difluoroethyl or
difluorovinyl groups has been attractive from the chemistry
community. The difluoroethyl moieties are usually built from
difluorination of carbonyl group with active fluodides (e.g.
Herein, we report a simple and efficient method for the direct
installation of chlorodifluoroethyl group onto aromatic
molecules of various aromatic amides with a new 2-
chloro,2,2-difluoroethyl(mesityl)iodonium
salt
(CDFI).
Moreover, the chlorodifluoroethyl compounds could be
smoothly converted into difluorovinyl compounds in a one-
pot or discrete procedure and regarded as a steady source of
difluorovinyl compounds with “HCl-mask”.

DAST-diethylaminosulfur trifluoride) or reduction of difluoro-
actetate derivatives with boranes [12-18], which are not so
efficient and straightforward. There some difluorovinyl reactions
emerged, especially aided by transition-metal catalysis besides
the traditional Wittig type reaction of carbonyl compounds with
Ph3P=CF2 ylid (Scheme 1) [19-24]. But still now, the
development of effective introduction of difluoroethylated (-
CH2CF2-) and difluorovinylated (-CH=CF2) moieties in organic
compounds is highly desirable. Herein, we would like to present
a new method to synthesize difluoroethyl compounds with a
novel iodonium salt. Moreover, the newly formed difluoroethyl
compounds could be directly eliminated to deliverd
difluorovinylated (-CH=CF2) compounds (Scheme 1) in situ or in
a discrete procedure.
Scheme 2. The synthesis and structure of chlorodifluoroethyl
iodonium salts and the application in the synthesis of difluoroethyl
and difluorovinyl compounds.
The iodonium salt 1 was readily synthesized from 1-chloro-
1,1-difluoro-2-iodoethane (ICH2CF2Cl), which could be prepared
from iodine chloride (ICl) with 1,1-difluoroethene (CH2=CF2)
[43,44]. Subsequently, ICH2CF2Cl was oxidized by trifluoroper-
acetic acid prepared in situ to gained the key intermediate (2-
chloro-2,2-difluoroethyl)-λ3-iodanediyl bistrifluoroacetate 3.
Then, the intermediate 3 was changed the ligand with mesitylene
in the presence of triflic acid (TfOH) to generate 2-chloro-2,2-
difluoroethyl(mesityl)iodonium triflate ([MesICH2CF2Cl]+ [OTf]-)
1 in excellent yield.
As is shown in Scheme 2, the structure of the iodonium salt is
established by X-ray crystallography. The single crystal could be
obtained by slow evaporation of its diethyl ether-
dichloromethane solution. The crystal data shows that the
C(CH2)-I bond is 2.317 Å and the C(CF2)-Cl bond 1.778 Å. Due
to the presence of the sterically hindered mesityl group, the bond
length of the other C(Ar)-I bond is 2.129 Å, which seems more
difficult to react. Therefore, this reagent could be used as a
general -CH2CF2- source, which had the possibility for the further
functionalization.
Fig. 1. Some pharmaceutical molecules containing difluoroethylated
(-CH2CF2-) and difluorovinylated (-CH=CF2) moieties.
With the iodonium salt 1 in hand, we turn to investigate the
chlorodifluoroethylation of 4-(tert-butyl)-N-methylbenzamide 2a
as the model substrate in the presence of palladium catalyst. To
test the reaction feasibility, we screened different solvents,
palladium catalysts and acid additives to find the optimal reaction
conditions for this transformation (Table 1). The reaction of 2a
with the iodonium salts in dry dichloroethane (DCE) without
catalyst gave no product (entry 1). Hence, various palladium
catalysts, such as PdCl2, Pd2(dba)3, Pd(TFA)2 and Pd(OAc)2 were
examined. As is shown in Table 1, the result with Pd(OAc)2 as
catalyst provided the o-substituted product 4a in 93% yield
(entries 2-5). However, in the presence of palladium acetate, the
chlorodifluoroethylation reaction could not occur without acid
additives (entry 6). This indicated that the choice of acid
additives was also critical, and then the acetic acid (AcOH) as an
additive was tested, which afforded only trace product 4a (entry
7). When p-toluenesulfonic acid monohydrate (TsOH·H2O) and
boron trifluoride ethyl ether (BF3·Et2O) were employed, the
product can be delivered in a moderate yield (entries 8 and 9).
Pleasingly, trifluoroacetic acid (TFA) was found to be an ideal
additive to afford the expected product in 93% yield (entry 5).
Other solvents, such as methanol (MeOH), tetrahydrofuran
(THF), toluene (Tol), dichloromethane (DCM), and
dichloroethane (DCE) were also screened for optimized
Scheme 1. Traditional synthetic routes to gem-difuorinated
compounds.
Nowadays, hypervalent iodonium reagents have experienced a
rapid development and received considerable attention as mild,
non-toxic and selective reagents in organic synthesis [25-27].
And recently they have been effectively used in C-H
functionalization reactions to introduce F-containing moieties,
including CF3 [28-31] or CH2CF3 [32-35]. During the research of
the organic synthesis with hypervalent iodonium reagents in our
group [36-42], we designed a new type of iodonium salt 1, which
is apparently a useful source of -CH2CF2- group and provides a
possibility for the further functionalization of the fluorinated
products (Scheme 2).

conditions, and it was observed that DCE afforded better yield
than the other solvents (entries 10-13). After extensive evaluation,
we established that a combination of Pd(OAc)2 (10 mol%),
trifluoroacetic acid (TFA) (1.2 equiv.), and iodonium salt (1.2
equiv.) in DCE at ambient temperature was optimal and produced
the desired chlorodifluoroethylation product (4a) in 93% yield.
Table 1
Optimization of the reaction conditions.
Entry
1
2
3
4
5
6
7
8
Catalyst
-
PdCl2
Solvent
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
MeOH
THF
Toluene
CH2Cl2
Acid
TFA
TFA
TFA
TFA
TFA
-
AcOH
TsOH·H2O
BF3·Et2O
TFA
NMR yield (%)
n.d.
n.d.
65
75
93
n.d.
6
57
75
n.d.
31
Pd2(dba)3
Pd(TFA)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
9
10
11
12
13
TFA
TFA
TFA
76
70
a Reactions were performed on a 0.1 mmol scale: Iodonium salts, Pd
catalyst and acid in a solvent (0.5 mL), 25 °C, 24 h under a N2
atmosphere. n.d. = not detected.
b NMR yield.
Scheme 3. The scope of chlorodifluoroethylation reaction of various
benzamides 2 with CDFI 1. Reactions were performed on a 1.0
mmol scale; isolated yield. a Reactions were performed on a 6 mmol
scale.
With the optimal conditions in hand, the generality of this
transformation was then examined with different aryl-substituted
benzamides (Scheme 3). It was found that electron-donating
methyl and methoxy groups in o-, m- and p-positions were well
tolerated and the corresponding products formed in good to
excellent yields (4b-4f). Moreover, benzamides with either a tert-
butyl or phenyl group all worked well to afford products 4a or 4t
in 87%, 75% yields, respectively. Chloromethyl substituent at the
p-position was also tolerable, rendering the corresponding
products 4g in 66% yield. Remarkably, the N-methylbenzamides
bearing halogen substitutions such as fluoro (4h, 4o), chloro (4i,
4l, 4p), bromo (4j, 4m) and iodo (4k) groups could be well
introduced to the 4-, 5-, 6-positions of the aryl ring in the present
system, and all afforded the target products in satisfied yields.
More appealingly, electron-withdrawing groups including ester,
trifluoromethyl, and trifluoromethoxy groups were remarkably
suitable for the reaction, which led to the o-
chlorodifluoroethylated products in moderate to good yields (4n,
4q, 4r). Further, multi-substituted N-methylbenzamide also
reacted well and resulted in 80% yield (4s). Notably,
naphthamide were also effectively converted into their
corresponding products, and the yields of 4u and 4v were 57%
and 85%, respectively. Moreover, chlorodifluoroethylation of
heterocyclic thiophene structure (4w, 4x), including no
Next, we investigated a variety of diverse N-substituted
handles under optimal conditions to further broaden the substrate
scope (Scheme 4). First, we explored the application of N-
substituted amide equipped with isopropyl, tert-butyl, phenethyl
and cyclohexyl substituents on the nitrogen atom. To our delight,
electron-donating and electron-withdrawing groups on the aryl
ring were well-tolerated in moderate to good yields (6a-6e, 62%-
86%). Notably, N,N-disubstituted substrates including 6f and 6g
also reacted well in 43% and 66% yield, respectively. Moreover,
quinazolinone derivatives with 2-position substituted with phenyl
group could also be applied in this system to gave the Pd-N
coordinated cyclopalladium complex catalyzed product 6h and
the structure was confirmed by the X-ray diffraction analysis
(CCDC: 2094743, see Supporting information).
substituent and
a chloro-substituted thiophene, were also
converted smoothly into the desired products. Finally, the
structure of 4u was confirmed by X-ray diffraction analysis
(CCDC: 2064869, see Supporting information for more details).

chlorodifluoroethyl iodonium salts and sequentially the
difluorovinyl compounds were isolated in comparable yields.
Having established the substrate generality of the reaction, we
conducted related experiments to understand the mechanism of
this transformation. At first, we tried to monitor the
cyclopalladated species by 19F NMR under the reaction
conditions, which is a critical intermediate in the reaction [48,49].
The formation of the intermediate
I was isolated and
characterized by 19F NMR spectroscopy (δ −73.5). Then we
detected the stoichiometric reaction of the cyclopalladated
species
I
with the treatment of 2-chloro,2,2-difluoro-
ethyl(mesityl)iodonium salt. To our delight, the expected
chlorodifluoroethylated products were obtained rapidly at room
temperature. Based on these results, we proposed the following
mechanism (Scheme 6). First, in the presence of trifluoroacetic
acid (TFA), the reaction was initiated through the palladium
acetate activation process. Then, the palladium species were able
to construct a cyclometalated intermediate I with the guidance of
directing group. Subsequently, the complex I was chlorodifluoro-
ethylated by CDFI 1 to form the intermediate II. Finally, the
CH2CF2Cl on the Pd(IV) center was transferred to the aromatic
ring to produce intermediate III, which experienced the
elimination reaction to afford the product and regenerated the
active Pd(II) species for the next catalytic cycle.
Scheme 4. The scope of chlorodifluoroethylation reaction of various
benzamides 5 with CDFI 1. Reactions were performed on a 1.0
mmol scale; isolated yield.
Scheme 5. The scope of elimination reaction of various benzamides
4 and 2. Reactions were performed on a 1.0 mmol scale. Isolated
yield (in bracket were that performed on a 0.5 mmol scale).
Scheme 6. A plausible mechanism.
The broad functional group tolerance of this palladium
catalyzed chlorodifluoroethylation reaction gave facilely access
to difluorovinyl derivatives via elimination reaction (Scheme 5).
When 2 equiv. of DBU was added to the DCE solution of the
chlorodifluoroethylated substrates, the dehydrochlorination
products 7 were formed in high yields at room temperature. Most
of the substrates were able to undergo dehydrochlorination to
provide the corresponding products in outstanding yields, such as
methyl (7c, 82%), chloromethyl (7g, 67%), methoxy (7d, 7f,
75%, 71%), tert-butyl (7a, 83%) and phenyl (7t, 77%). In
particular, product 7u could be readily dehydrochlorinated to
give 8-(2,2-difluorovinyl)-N-methyl-1-naphthamide in 91% yield.
It is worthy to note that product 7j was obtained in 74% yield and
the molecular structure of 7j was unambiguously established by
X-ray crystallography (CCDC: 2064872, see Supporting
information for details).
In conclusion, we have developed a novel CDFI reagent 1 and
used it for chlorodifluoroethylation of C−H bond in N-
methylbenzamides by the Pd-catalyst. Remarkably, the highly
efficient iodonium salt, the broad scope of amides, and the mild
reaction conditions make our methodology extraordinarily
significant in drug discovery and organic synthesis. Furthermore,
the value of this methodology is further demonstrated by the
facile removal the HCl mask and efficient transformation to
difluorovinyl products. And the further application of this 2-
chloro,2,2-difluoroethyl(mesityl)iodonium salt is currently
ongoing in our laboratory.
mmc1.pdf
mmc2.rar
Declaration of competing interest
This procedure enables us to regard the chlorodifluoro-
ethylated products as “HCl-masked” difluorovinyl derivatives,
since most of the difluorovinyl compounds are relatively reactive
and can not be stored for long time due to its high activity to
undergo polymerization [45-47]. In addition, the difluorovinyl
compounds could be made in a one-pot procedure. Thus, DBU (4
equiv.) was added to the reaction mixture of benzamides with
The authors declare that they have no known
competing financial interests or personal
relationships that could have appeared to influence
the work reported in this paper.

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