Pd-Catalyzed Transfer of Difluorocarbene for Three Component Cross-Coupling?

Article abstract of DOI:10.1002/cjoc.202000297

Outstanding accomplishments have been achieved in the chemistry of difluorocarbene, but transition- metal-catalyzed transfer of difluorocarbene for coupling remains a challenging task. Herein, we describe a Pd-catalyzed coupling of difluorocarbene with two aryl carbon centers to give difluoromethylenation products, which cannot be obtained by any previous difluorocarbene-transformation method.

Full text of DOI:10.1002/cjoc.202000297

Chinese Journal
of Chemistry
CJC
中 国 化 学 - An International Journal
Accepted Article
Title: Pd-catalyzed transfer of difluorocarbene for three component cross-coupling
Authors: Zhi-Wei Xu, Wei Zhang, Jin-Hong Lin,* Chuan-Ming Jin,* Ji-Chang Xiao*
This manuscript has been accepted and appears as an Accepted Article online.
This work may now be cited as: Chin. J. Chem. 2020, 38, 10.1002/cjoc.202000297.
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published online in Early View: http://dx.doi.org/10.1002/cjoc.202000297.
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Chinese Journal
of Chemistry
Palladium, Catalysis, Difluorocarbene, Cross-Coupling, Three Component
Report
CJC
中
国 化 学 - An International Journal
Pd-catalyzed transfer of difluorocarbene for three component
cross-coupling
Zhi-Wei Xu,ab# Wei Zhang,b# Jin-Hong Lin,b* Chuan-Ming Jin,a* Ji-Chang Xiaob*
aHubei Key Laboratory of Pollutant Analysis and Reuse Technology, College of Chemistry and Chemical Engineering, Hubei Normal University, Huangshi,
435002, PR China.
bKey Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of
Sciences, 345 Lingling Road, Shanghai, 200032, PR China.
#These authors contributed equally to this work.
Dedicated to the 70th anniversary of Shanghai Institute of Organic Chemistry
Cite this paper: Chin. J. Chem. 2019, 37, XXX—XXX. DOI: 10.1002/cjoc.201900XXX
Outstanding accomplishments have been achieved in the chemistry of difluorocarbene, but transition-metal-catalyzed transfer of difluorocarbene for
coupling remains a challenging task. Herein we describe a Pd-catalyzed coupling of difluorocarbene with two aryl carbon centers to give
difluoromethylenation products, which cannot be obtained by any previous difluorocarbene-transformation method.
As the incorporation of fluorine atoms into organic molecules
may lead to profound changes of their physicochemical properties,
fluorine element has been recognized as a magic atom in various
difluorocarbene source.13b Interestingly, they found that the
nucleophilicity and electrophilicity of Pd=CF2 species is
controllable by switching the oxidation state of Pd: Pd0=CF2 is a
nucleophile and PdII=CF2 is an electrophile. The successive
coordination of :CF2/:CF2 or :CF2/CO to Pd complexes was achieved
to enable access to various products containing a CF2CF2, COCF2 or
COCF2CF2 unit.13c We have also developed a difluoromethylation of
boronic acids with Ph3P+CF2CO2- via a difluorocarbene coupling (eq
1).14 The above catalytic methods involve the coupling of
difluorocarbene with a carbon center and a proton to afford
products with HCF2 as a terminal group. In continuation of our
interest in the chemistry of difluorocarbene,15 we have now
investigated a Pd-catalyzed three-component coupling between
difluorocarbene and two different aryl carbon centers to provide
difluoromethylenation products (eq 2).
research
areas,
such
as
pharmaceutical/agrochemical
developments and material sciences.1 Difluorocarbene has proved
to be a valuable intermediate for fluorine incorporation.2 Typical
difluorocarbene reactions includes [2+1] cyclization of
alkenes/alkynes3 and difluoromethylation of X-H bonds (X =
heteroatom)4. Hu disclosed an efficient C-H difluoromethylation by
using TMSCF2Br, a reagent developed by them recently,5 as a
difluorocarbene source.6 Difluorocarbene can also act as a dipolar
CF2 unit for consecutive bond-forming reactions,7 which were
described by Dilman.8 Outstanding accomplishments have been
achieved in the chemistry of difluorocarbene. However, the
transition-metal-catalyzed transfer of difluorocarbene remains a
challenging research area, despite the fact that metal carbenes
have found widespread applications in organic synthesis.9
Scheme 1. Pd-catalyzed coupling of difluorocarbene with other partners
Traditional
methods
for
the
formation
of
work:
Previous
metal-difluorocarbene complexes require a two-step procedure,
the synthesis of M-CF3 complexes and the subsequent
defluorination.10 In the previous studies of metal difluorocarbene
species, stoichiometric amount of metal sources was usually used
and metal complexes were obtained as desired products.10-11
Transition-metal-catalyzed coupling of difluorocarbene with other
partners is quite challenging due to the high reactivity of
difluorocarbene and side reactions of M=CF2 intermediates.12
Recently, Zhang reported highly effective catalytic methods to
obtain various HCF2-containing products (Scheme 1, eq 1).13 On
the basis of their work on Pd-catalyzed difluoromethylation of aryl
boronic acids with BrCF2CO2Et,13a they further developed a more
efficient method by using inexpensive and abundant industrial raw
material ClCF2H, which is also an ozone-depletion chemical, as a
H+
or
R-CF2H
R-CF2CF2H
[Pd] (cat.),
R
+
[:CF2]
terminal
HCF
2
(1)
B(OH)2
group:
or
R-COCF2H R-COCF2CF2H
source:
[:CF2]
BrCF2CO2Et, ClCF2H
-
+
or
BrCF
Ph3P CF2CO2
2PO(OEt)2
work:
This
(2)
F
F
-
:CF
with
2 coupling
carbon centers
[Ph]+
[Pd]
Ph3P+CF2CO2
(cat.)
Ar
+
+
B(OH)2
two
aryl
Ar
Ph
Results and Discussion
Since
a
proton source is needed in Pd-catalyzed
difluoromethylation with difluorocarbene,13-14 an electrophilic
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First author et al.
Report
carbon source would be necessary for the three-component
coupling. We have previously shown that a trimer of Pd=CF2 can
F
F
-
P)
mol%)
60 o
Ph3P+CF2CO2
Pd(Ph3 4 (20
+
Ph
Ph
B(OH)2
[Ph]+
+
- 14
be easily obtained by a reaction of Pd(PPh3)4 with Ph3P+CF2CO2 .
Cs CO ,
C
p-xylene,
3
2
Ph
-
2a
3
4a
[Ph]+
It was found that the coupling between boronic ester 1a, the
Pd=CF2 trimer and a phenyl cation equivalent, Ph2IOTf, could give
the desired difluoromethylenation product in a 40% yield (Scheme
2, eq 1). Apparently, the stoichiometric use of Pd source would
limit the practicability of this protocol. However, the use of
Pd(PPh3)4 as a catalyst did not afford the desired product at all
:
Ph
O
Ph
N2+ BF4
I
I
Ph4P+ X-
I
OTf
O
=
Cl,
Br, NTf
I,
(X
)
2
O
3a 5%a
3d N.D.
3e trace
,
,
3b tracea
3c N.D.
,
3f N.D.
,
,
,
NMe3
TfO-
-
when Ph3P+CF2CO2 was used as a difluorocarbene source. To our
- S
- S
S
S
TfO-
TfO-
TfO
TfO
Ph
delight, a 14% yield was obtained by using boronic acid 2a instead
of boronic ester 1a in the presence of another ligand and a silver
salt (eq 2).
CF3
3k N.D.
3j N.D.
,
3g N.D.
,
3h N.D.
,
3i N.D.
,
,
-S
TfO-
S
- S
- S
- S
TfO
TfO
TfO
TfO
CF2Br
CF3
CF2CF3
CF3
3p 12%
(70%)
(CF2)3
CF2H
Scheme 2. Preliminary investigation of the three-component coupling.
,
b
3m N.D.
,
3n trace
,
3l N.D.
,
3o 2%
,
F
F
Cs2CO3, JohnPhos
Reaction conditions: 2a (0.1 mmol), Ph3P+CF2CO2 (3 equiv), [Ph]+ (1.5
equiv), Pd(PPh3)4 (20 mol %), Cs2CO3 (2 equiv) and p-xylene (1.5 mL) at 60
oC under a N2 atmosphere for 8-12 h. N.D. = Not Detected. The yields were
determined by 19F NMR spectroscopy. a1 equiv of [Ph]+ was used and the
Ph
-
+
+
Ph2IOTf
Ph
(1)
Bpin
[(Ph3P)PdCF2]3
:
p
60 o 8 h
C,
-xylene,,
Ph
19F NMR
F2
C
1a
[(Ph3P)PdCF2]3
40%
yield:
Ph3P Pd
F2C
Pd PPh3
CF2
Pd
reaction time was 4 h. The molar ratio of 2a : Ph3P+CF2CO2- : [Ph]+ = 1:3:3,
bathocuproine (25 mol %) was used as a ligand, 1 mL of p-xylene was used,
b
PPh3
F
F
, Cs2CO3
AgNO3
-
Ph
mol%)
Ph P+CF2CO2
Ph2IOTf
Pd(PPh3)4 (20
+
+
Ph
(2)
B(OH)2
3
and the reaction time was 6 h.
p
60 o 8 h
C,
-xylene,
Ph
19F NMR
2a
14%
yield:
With the optimal reaction conditions in hand, we then
investigated the substrate scope of the Pd-catalyzed coupling
between aryl boronic acids, difluorocarbene and the sulfonium
salt. As shown in Scheme 4, the coupling process was extended to
a wide range of boronic acids. Electron-rich, -neutral and -deficient
aryl boronic acids could all undergo coupling reactions to afford
the desired products in moderate to good yields. But a strong
electron donating group would destabilize the product and thus it
is hard to isolate the product by flash column chromatography (4e).
The compatibility of TMS (4f) and halide groups (4l-4m) under
these conditions may allow for further transformations of these
products. The direct coupling between substrate 2 and sulfonium
salt 3p cannot be completely suppressed and thus Ar-Ph was
produced as a side product in each coupling reaction. The removal
of the side products led to lower isolated yields compared with
the 19F NMR yields because of the similar polarity between the
expected products and side products. The yield was dramatically
decreased by using other sulfonium salt (4s).
Although a low yield was obtained in the catalytic version, the
successful coupling by using the trimer prompted us to further
screen catalytic reaction conditions. Significant effort was made in
order to increase the yield for the coupling between boronic acid
-
2a, Ph3P+CF2CO2 and Ph2IOTf, but all attempts failed. We believed
that the phenyl cation equivalent played an important role, and
thus a variety of equivalents were examined (Scheme 3). No
desired product was detected in most cases. Fortunately, using
trifluoromethyl sulfonium salt (3p) as a phenyl cation equivalent
delivered 4a in 12% yield. The sulfonium salt has served as an
effective trifluoromethylation reagent,16 and Zhang found that it
can also act as a phenylation reagent for coupling reactions.17 The
12% yield indicated the possibility of the catalytic reactions, and
thus a large number of reaction conditions were further screened
(Please see supporting information). After a detailed survey, the
yield was increased to 70% by using bathocuproine as a ligand.
The incorporation of a CF2 unit into organic molecules has
received increasing attention.18 Since some pharmaceuticals such
as Ledipasvir contain a Ar-CF2-Ar motif, it would be desirable to
develop efficient methods for the installation of this moiety.
Traditional deoxyfluorination of carbonyls suffers from the use of
hazardous reagents, DAST or deoxofluor.19 Recently, Szymczak
found that ArCF2- anion can be captured by a Lewis acid to give an
Scheme 3. Screening coupling reaction conditions.
-
isolable ArCF2 anion equivalent, which can be used to synthesize
ArCF2Ar molecules by using
a stoichiometric amount of a
transition metal.20 Our straightforward approach is also quite
attractive due to the safe operations and the use of
substoichiometric amount of a Pd source.
a
Scheme 4. Substrate scope of the coupling reaction.
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© 2019 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2019, 37, XXX－XXX
This article is protected by copyright. All rights reserved.

Running title
Chin. J. Chem.
P)
mol%)
Pd(Ph3 4 (20
Ar'
Ar'
Ar-B(OH)2
F
F
LnPdII-Ar
-
F F
-OTf
Ph3P+CF2CO2
Bathocuproine
mol%)
S
(25
+
+
Ar
B(OH)2
LnPdII-Ar
Cs CO , p
, 65 o 6 h
CF3
Ar
Ar'
C,
-xylene
F
CF2
Ph
2
3
Ar
Ph
CF2Ph
2
4
B
Ar-B(OH)2
LnPdII-OTf
CF2Ph
B
A
F
F
F
F
F
F
F
F
F
Ph
Ph
Ph
Ph
Ph
Ph
nBu
MeO
Ph
4a
LnPdII-OTf
CF2Ph
A
LnPd0
Catalytic
1
Catalytic
2
Cycle
Cycle
4b
4c
4d
30%
,
4e
,
47%
32%
43%
,
,
,
(66%)
(51%)
(58%)
(46%)
Ph
(61%)
F
Ph2S+CF3 TfO-
F
F
F
F
F
F
F
F
Ph
F
OTf
LnPdII=CF2
Ph
Ph
Ph
PhSCF3
Ph2S+CF3 TfO-
LnPdII OTf
:CF2
Ph
D
TMS
Ph
LnPd0=CF2
Ph
C-
4f
4g
4h
4i
4j
40%
F
38%
38%
40%
44%
,
,
,
,
,
(60%)
(50%)
(60%)
(60%)
F
(54%)
(52%)
Ph3P+CF2CO2
:CF2
F
F
F
F
F
Ph
Ph
Br
F
F
Ph
F
F
Ph
Ph
NC
Cl
F
O
,
4k
4l
4m
4n
4o
41%
N
45%
35%
Ph
42%
F
,
,
,
,
(43%)
(60%)
(24%)
F
(45%)
F
Conclusions
F
F
Ph
Ph
In summary, we have described the Pd-catalyzed transfer of
difluorocarbene for three-component coupling reactions between
F
aryl boronic acids, Ph3P+CF2CO2 and Ph2S+CF3 TfO-. This work
-
S
O
Ph
represents the first example of coupling between difluorocarbene
with two other aryl centers, and may provide more possibilities for
the difluorocarbene chemistry.
4p
4q
4r
4s
(16%)
26%
44%
46%
,
,
,
(48%)
(57%)
(52%)
Isolate yields are shown. The numbers in parentheses are yields
determined by 19F NMR spectroscopy. Reaction conditions: 1 (0.2 mmol),
-
Ph3P+CF2CO2 (0.6 mmol), [Ar’2SCF3]+[OTf]- (0.6 mmol), Pd(Ph3P)4 (0.04
Supporting Information
The supporting information for this article is available on the
WWW under https://doi.org/10.1002/cjoc.2018xxxxx.
mmol), bathocuproine (0.05 mmol), Cs2CO3 (0.4 mmol) and p-xylene (1 mL)
at 65 oC for 6 h under a N2 atmosphere.
The coupling process may proceed via the coordination of
difluorocarbene to Pd0 to produce Pd0=CF2 complex, which further
reacts with the sulfonium salt to generate PdII species
(intermediate A) (Scheme 5, catalytic cycle 1). The subsequent
transmetallation and a reductive elimination gives the final
product 4. Three possibilities exist for the formation of
intermediate A. It may be formed via an oxidative addition of
sulfonium salt to Pd0=CF2 to give PhPdII=CF2 complex followed by a
migratory insertion. Owing to the electron donation from a d
orbital on Pd to the vacant p orbital on CF2 carbon, the CF2 carbon
in Pd0=CF2 species may exhibit nucleophilicity.13c Therefore, the
carbon may also attack the phenyl ring in the sulfonium salt via a
nucleophilic aromatic substitution process (SNAr) to directly
deliver intermediate A. The third possibility is a radical process. A
single-electron-transfer process may occur between Pd0=CF2 and
the sulfonium salt to generate Ph radical and Pd+=CF2 species.21
The combination of these two intermediates could also deliver
intermediate A. Catalytic cycle 2 involves the first oxidative
addition and the subsequent coordination of difluorocarbene. If
the first step is the oxidation of Pd0 to provide PhPdII (intermediate
C), many other phenyl cation equivalents may be reactive for this
coupling reaction. However, as shown in Scheme 3, most [Ph]+
reagents failed. Therefore, catalytic cycle 2 is excluded. The
coupling reaction can work only when an active [Ph]+ reagent,
Ph2S+CF3 TfO-, is used, probably because the Pd0=CF2 complex is a
quite inert intermediate.
Acknowledgement
We thank the National Natural Science Foundation (21421002,
21672242, 21971252, 21991122), Key Research Program of
Frontier Sciences, Chinese Academy of Sciences (CAS)
(QYZDJSSW-SLH049), Youth Innovation Promotion Association CAS
(2019256) for financial support.
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© 2019 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
This article is protected by copyright. All rights reserved.

First author et al.
Report
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Manuscript revised: XXXX, 2019
Manuscript accepted: XXXX, 2019
Accepted manuscript online: XXXX, 2019
Version of record online: XXXX, 2019
Chin. J. Chem. 2019, 37, XXX－XXX
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Page No.
Pd-catalyzed transfer of difluorocarbene for
three component cross-coupling
F
F
-
Ph3P+
Ph +
]
[Pd]
(cat.)
Ar
+
+
[
CF2CO2
B(OH)2
Ar
:CF
Ph
with
2 coupling
carbon centers
two
aryl
Described herein is the Pd-catalyzed transfer of difluorocarbene for three-component coupling
process. This work represents the first example of coupling between difluorocarbene with two
other aryl carbon centers.
Zhi-Wei Xu,a,b,# Wei Zhang,b,# Jin-Hong Lin,b,*
Chuan-Ming Jin,a,* Ji-Chang Xiaob,*
www.cjc.wiley-vch.de
© 2019 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2019, 37, XXX－XXX
This article is protected by copyright. All rights reserved.