Pd-Catalyzed Transfer of Difluorocarbene

Article abstract of DOI:10.1021/acs.orglett.6b02141

The study of transition-metal difluorocarbene complex has long been a subject of active investigation, but the transition-metal-catalyzed transfer of difluorocarbene remains a significant challenge. The Pd-catalyzed transfer of difluorocarbene is described to realize the coupling reaction of boronic acids with difluorocarbene to give (difluoromethyl)arenes and -olefins. Mechanistic investigations reveal that the Pd? -CF₂ complex is an important intermediate for this transformation. This complex is prone to trimerization without the presence of starting materials.

Full text of DOI:10.1021/acs.orglett.6b02141

Letter
pubs.acs.org/OrgLett
Pd-Catalyzed Transfer of Difluorocarbene
Xiao-Yun Deng, Jin-Hong Lin, and Ji-Chang Xiao*
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences,
Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China
S
* Supporting Information
ABSTRACT: The study of transition-metal difluorocarbene complex has long been a subject of active investigation, but the
transition-metal-catalyzed transfer of difluorocarbene remains a significant challenge. The Pd-catalyzed transfer of
difluorocarbene is described to realize the coupling reaction of boronic acids with difluorocarbene to give (difluoromethyl)arenes
and -olefins. Mechanistic investigations reveal that the PdCF2 complex is an important intermediate for this transformation.
This complex is prone to trimerization without the presence of starting materials.
he past decades have witnessed outstanding advances in
product. Zhang et al. described the Pd-catalyzed difluorome-
thylation of arylboronic acids with bromodifluoroacetate to
afford the difluoromethylated arenes.7 They proposed that the
PdCF2 complex was formed and the CF2 moiety was
transferred to give the difluoromethylation products, whereas
no strong and direct evidence was found to support the
palladium−difluorocarbene process. We have been interested in
the chemistry of difluorocarbene and have developed an
T
the chemistry of difluorocarbene,1 but research on the
transformation of difluorocarbene is now bottlenecked by the
limited reaction classes. Unlike the nonfluorinated carbene
complex, metal difluorocarbene complex has seldom been used
in organic reactions.2 Although a number of approaches have
been developed to produce the difluorocarbene complex,2−4
the transfer of difluorocarbene catalyzed by metal has been
found to be a very difficult task. The metalCF2 complex, an
important intermediate for the transfer reaction, may be quite
sensitive to moisture, and the difluorocarbene would be easily
converted into carbon monoxide (CO) by hydrolysis.2,3 Some
complexes are stable against moisture, but the M = CF2 bond
(M = transition metal) is so strong that the CF2 moiety cannot
be smoothly transferred.4 Intramolecular migratory insertion of
difluorocarbene would produce a new complex that cannot
readily undergo demetalation, thus prohibiting further transfer
of the difluorocarbene.5 In addition, even if the transfer of
difluorocarbene from a stoichiometric M = CF2 complex to a
reaction partner can occur, it is still not easy to realize the
catalytic versions. Apparently, both the facile formation of the
difluorocarbene complex and the efficient cleavage of the M =
CF2 bond are vital factors for the catalytic transfer of
difluorocarbene.
efficient difluorocarbene reagent, Ph3P+CF2CO2 (PDFA).8
−
Our previous observation implies that Cu might be able to
transfer difluorocarbene,8k but stoichiometric copper must be
used and the CuCF2 complex could not be identified.
Herein, we report the Pd-catalyzed transfer of difluorocarbene
to realize the coupling reaction of boronic acids with
difluorocarbene in situ produced from PDFA to afford
(difluoromethyl)arenes and -olefins.9 The Pd source could
react with PDFA to furnish a Pd−CF2 complex, which was
confirmed by X-ray crystallography.
We have shown that p-xylene is an appropriate solvent for
the dissociation of PDFA into difluorocarbene.8j Our initial
attempts at the Pd-catalyzed difluorocarbene transfer in p-
xylene at 70 °C showed that both a weak acid and a base were
necessary (Table 1, entries 1−5). The weak acid was the proton
source for the installation of difluoromethyl group, while the
base may promote the transmetalation of boronic acid with the
Pd complex.10 The presence of water increased the yield
Recently, Takahira and Morizawa reported Ru-catalyzed mild
olefin cross-metathesis with tetrafluoroethylene to give gem-
difluoroolefins.6 The RuCF2 complex was believed to be
generated and difluorocarbene in the complex was transferred,
but this CF2 moiety was unwanted and released to form a side
Received: July 20, 2016
© XXXX American Chemical Society
A
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Table 1. Screening Reaction Conditions
Scheme 1. Pd-Catalyzed Transfer of Difluorocarbene for
a
Difluoromethylation
a
H2O
(equiv)
temp
(°C)
yield
entry
[H+]
base (equiv)
(%)
1
2
3
4
5
6
7
8
9
K2CO3 (2.5)
K2CO3 (2.5)
K2CO3 (2.5)
K2CO3 (2.5)
K2CO3 (2.5)
K2CO3 (2.5)
KOH (2.5)
CsF (2.5)
70
70
70
70
70
70
70
70
70
trace
trace
5
H2O
HCO2H
CH3COCO2H
13
b
dione
27
dione
dione
dione
dione
2.5
2.5
2.5
2.5
42
33
14
Ca(OH)2
(2.5)
48
10
11
12
13
14
dione
dione
dione
dione
dione
dione
dione
2.5
2.5
2.5
2.5
2.5
2.5
2.5
Ca(OH)2
(4.0)
70
60
61
45
67
74
62
82
90
Ca(OH)2
(4.0)
Ca(OH)2
(4.0)
80
Ca(OH)2
(4.0)
90
Ca(OH)2
(4.0)
100
90
c
15
Ca(OH)2
(4.0)
a
d
Reaction conditions: mixture of 1 (0.2 mmol), 2 (1.0 mmol), 1,3-
cyclopendione (0.2 mmol), Ca(OH)2 (0.8 mmol), Pd(PPh3)4 (0.04
mmol) and H2O (0.5 mmol) in p-xylene (2 mL) was stirred at 90 °C
16
Ca(OH)2
(4.0)
90
a
Determined by 19F NMR using PhCF3 as an internal standard.
Dione =1,3-cyclopentadione. 4 equiv of PDFA was used. 5 equiv of
b
b
c
d
for 3 h under N2 atmosphere. The yield was determined by 19F NMR
using PhCF3 as an internal standard.
PDFA was used.
the conversion of electron-rich, -neutral, and -deficient
vinylboronic acids (3o−t). It is noteworthy that only one
single stereoisomer of the desired products was observed for
the conversion of vinylboronic acids.
slightly (Table 1, entry 6 vs entry 5) because it is favorable for
the transmetalation process by dissolving the base. A brief
survey of the base (Table 1, entries 6−9) revealed that a higher
yield could be obtained by using Ca(OH)2 (Table 1, entry 9).
Increasing the loading of Ca(OH)2 further increased the yield
(Table 1, entry 10 vs entry 9). The reaction temperature was
also an important factor for the transfer process (Table 1,
entries 10−14), where lowering the temperature led to a
decrease in the yield (Table 1, entry 11 vs entry 10). Elevating
the temperature to 90 °C gave a good yield of the product
(Table 1, entry 13), but the yield was decreased with further
temperature elevation (Table 1, entry 14). The loading of
PDFA apparently affected the yield (Table 1, entries 15−16),
and a 90% yield was obtained with the use of 5 equiv of PDFA
(Table 1, entry 16) (For more reaction conditions, see the
Supporting Information). Under these optimal conditions, O-
difluoromethylation of dione to produce 3-(difluoromethoxy)-
cyclopent-2-en-1-one was observed as a side reaction.
With the optimal reaction conditions obtained (Table 1,
entry 16), we then investigated the scope of substrates for the
Pd-catalyzed difluorocarbene transfer reaction. As shown in
Scheme 1, the transformation can be applied not only to
arylboronic acids (3a−n) but also to vinylboronic acids (3o−t).
Electron-rich and -neutral arylboronic acids were adequately
converted into the desired products in moderate to good yields
(3a−i and 3k−m). A significantly higher yield of the p-MeO-
substituted product (3b) was obtained compared with that of
the o-MeO-substituted product (3c), which may be owing to
steric effects. In the case of an electron-deficient aryl substrate,
the desired product was produced in low yields (3j). In
contrast, the difluorocarbene transfer protocol was suitable for
[Ph3P+CF2H X−] was observed as a side product detected by
19F NMR spectroscopy in the difluorocarbene transfer process.
However, no desired product was obtained using [Ph3P+CF2H
−
Br−] instead of [Ph3P+CF2CO2 ] (PDFA), indicating that the
conversion of PDFA into [Ph3P+CF2H X−] is not a necessary
path for this transformation. We therefore reason that PDFA
may readily undergo decarboxylation and subsequent dissoci-
ation to generate difluorocarbene, which then coordinates with
the Pd source. Indeed, it was found that Pd(Ph3P)4 can react
with PDFA to give a Pd−CF2 complex A, [Pd(CF2) (PPh3)]3,
which may be produced from the PdCF2 monomer through
trimerization (Scheme 2). The structure of this complex was
confirmed by X-ray crystallography.11 Interestingly, the bond
lengths [2.051(3)−2.090(3) Å] of the six Pd−CF2 bonds are
slightly different, as are the lengths of the three Pd−Pd bonds
[2.5891(3)−2.5916(3) Å] (see the Supporting Information).
The length of any Pd−CF2 bond is shorter than the sum (2.15
Å) of the covalent radii between the Pd (1.39 Å) and C (0.76
Å) atom, implying that a strong interaction between Pd and
CF2 exists.
The Pd−CF2 complex A was detected by 19F NMR
spectroscopy (<5%) in the difluorocarbene transfer reaction,
and the use of complex A instead of the Pd/PDFA system
could also produce the expected coupling product albeit at a
low yield (6%) (Scheme 3). It is reasonable to speculate that
the real active intermediate for the transfer reaction is not the
trimer A but a palladium−difluorocarbene monomer. The
B
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complex, suggesting that the dione is necessary for the
formation of complex B. Indeed, under the optimal reaction
conditions, except that the additional 1 equiv of water was used
instead of dione (1 equiv)/Ca(OH)2 (1 equiv), only trace
amounts of the desired product (2%) was observed (Scheme 5,
Scheme 2. Formation of the Pd−CF2 Complex
Scheme 5. Effects of Dione
a
Determined by 19F NMR using PhCF3 as an internal standard.
Scheme 3. Difluoromethylation with Pd−CF2 Trimer
eq 3). However, although the presence of the basic form of 1,3-
cyclopentadione (compound I) can significantly increase the
yield (40% vs 2%), the yield was still quite low (Scheme 5, eq
4). Apparently, 1,3-cyclopentadione played two important roles
in this difluorocarbene transfer reaction. First, after its
neutralization with Ca(OH)2, the basic form can act as a
ligand to coordinate with the Pd complex, which aids the
formation of the Pd−CF2H complex. Second, compared with
water, 1,3-cyclopentadione is also a superior hydrogen source
to directly protonate the PdCF2 monomer. Though a strong
base can easily neutralize 1,3-cyclopentadione, the low
solubility of Ca(OH)2 may lead to a rather slow neutralization
process. Therefore, both water and 1,3-cyclopentadione are
proton sources for the conversion of PdCF2 to Pd−CF2H.
On the basis of the above results, we propose the reaction
mechanism shown in Scheme 6. Decarboxylation and further
a
Determined by 19F NMR using PhCF3 as an internal standard.
monomer would readily undergo trimerization to produce A
without the presence of starting materials. The low yield
obtained by using trimer (Scheme 3) might be because the
detrimerization of A to generate the monomer was not easy or
the trimer may undergo decomposition to give other unknown
species instead of monomer.
Because the PdCF2 monomer may be the active species,
we then collected more experimental data to determine how
this species is converted. Stirring the Pd/PDFA system with the
mixture of dione/Ca(OH)2 (dione = 1,3-cyclopentadione)
produced a Pd−CF2H complex B, which was confirmed by 19
F
Scheme 6. Proposed Reaction Mechanism
NMR and HR ESI-MS (Scheme 4, eq 1) (see the Supporting
Scheme 4. Conversion of PdCF2 monomer to Pd−CF2H
a
Determined by 19F NMR using PhCF3 as an internal standard.
Information). After complex B was generated and the PDFA
was completely consumed, the addition of substrate 1a and
water into the reaction mixture furnished the expected product
(Scheme 4, eq 2). It seems that the PdCF2 monomer can be
easily protonated by the dione/Ca(OH)2 system to give Pd−
CF2H B, which should be an important intermediate for this
difluorocarbene transfer reaction. How the protonation process
proceeds remains elusive. The proton may directly attack at the
CF2 moiety, but it may also first attack at Pd to afford HPd+
CF2, which was followed by intramolecular proton migration to
produce B.
The 1,3-cyclopentadione is a weak acid and Ca(OH)2 is a
strong base, meaning that the dione/Ca(OH)2 system might
undergo full neutralization to produce 1 equiv of water
(Scheme 4, eq 1). However, the addition of 1 equiv of water
instead of dione/Ca(OH)2 to the Pd/PDFA system did not
result in the desired protonation to afford the Pd−CF2H
dissociation of PDFA generate difluorocarbene.8a,j Difluorocar-
bene then coordinates with the Pd source to produce the Pd
CF2 complex, whose protonation gives the intermediate B. In
the protonation process, both dione and water may be the
possible proton sources, but dione should be the superior one.
The proton may attack at two different sites in the monomer,
Pd or CF2.4c If it attacks at Pd, the intramolecular proton
migration would then occur to produce the complex B. The
coordination of the basic form of dione with Pd is very
important for the formation of complex B. Transmetalation of
boronic acid with B affords the intermediate C, whose reductive
elimination affords the final product and regenerates the
catalyst.
C
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In summary, we have developed an efficient Pd-catalyzed
difluorocarbene transfer reaction for the coupling reaction of
boronic acids with difluorocarbene to furnish (difluoromethyl)-
arenes and -olefins. This work represents the first example
providing valuable experimental evidence to elucidate the
mechanism for the palladium-catalyzed difluorocarbene transfer
reaction. The mechanism investigations revealed the formation
of the palladium−difluorocarbene complex, which was prone to
trimerization. This convenient strategy may find widespread
applications in other transition-metal-catalyzed difluorocarbene
transfer reactions.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b02141.
Experimental procedures, analytical data for products, X-
ray data, and NMR spectra of products (PDF)
X-ray data for the Pd−CF2 complex (CIF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: jchxiao@sioc.ac.cn.
Notes
The authors declare no competing financial interest.
(9) For recent reviews for the difluoromethylation reaction, see:
(a) Hu, J.; Zhang, W.; Wang, F. Chem. Commun. 2009, 7465.
(b) Landelle, G.; Panossian, A.; Pazenok, S.; Vors, J.-P.; Leroux, F. R.
Beilstein J. Org. Chem. 2013, 9, 2476. (c) Liang, T.; Neumann, C. N.;
Ritter, T. Angew. Chem., Int. Ed. 2013, 52, 8214. (d) Lu, Y.; Liu, C.;
Chen, Q.-Y. Curr. Org. Chem. 2015, 19, 1638. For recent examples for
the difluoromethylation reaction, see: (e) Fier, P. S.; Hartwig, J. F. J.
Am. Chem. Soc. 2012, 134, 5524. (f) Prakash, G. K. S.; Ganesh, S. K.;
Jones, J. P.; Kulkarni, A.; Masood, K.; Swabeck, J. K.; Olah, G. A.
Angew. Chem., Int. Ed. 2012, 51, 12090. (g) Fujiwara, Y.; Dixon, J. A.;
Rodriguez, R. A.; Baxter, R. D.; Dixon, D. D.; Collins, M. R.;
Blackmond, D. G.; Baran, P. S. J. Am. Chem. Soc. 2012, 134, 1494.
(h) Gu, Y.; Leng, X.; Shen, Q. Nat. Commun. 2014, 5, 5405. (i) Lin,
Q.-Y.; Xu, X.-H.; Zhang, K.; Qing, F.-L. Angew. Chem., Int. Ed. 2016,
55, 1479. (j) Xu, L.; Vicic, D. A. J. Am. Chem. Soc. 2016, 138, 2536.
(10) Suzuki, A. Pure Appl. Chem. 1985, 57, 1749.
ACKNOWLEDGMENTS
■
We thank National Basic Research Program of China
(2015CB931900, 2012CBA01200), the National Natural
Science Foundation (21421002, 21472222, 21502214), the
Chinese Academy of Sciences (XDA02020105,
XDA02020106), and the Science and Technology Commission
of Shanghai Municipality (15DZ1200102) for financial support.
We also thank Prof. Yinlong Guo (Shanghai Institute of
Organic Chemistry) and Dr. Haoyang Wang (Shanghai
Institute of Organic Chemistry) for helpful discussion on the
determination of intermediates by mass spectrometry.
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