Copper-Catalyzed Carboxylation of C-F Bonds with CO2

Article abstract of DOI:10.1021/acscatal.9b02351

An effective Cu-catalyzed selective formal carboxylation of C-F bonds with an atmospheric pressure of CO₂ is reported. A variety of gem-difluoroalkenes, gem-difluorodienes, and α-trifluoro-methyl alkenes show high reactivity and selectivity for

Full text of DOI:10.1021/acscatal.9b02351

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Letter
Copper-Catalyzed Carboxylation of C-F Bonds with CO2
Si-Shun Yan, Dong-Shan Wu, Jian-Heng Ye, Li Gong, Xin Zeng,
Chuan-Kun Ran, Yong-Yuan Gui, Jing Li, and Da-Gang Yu
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ACS Catalysis
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Copper-Catalyzed Carboxylation of C−F Bonds with CO2
Si-Shun Yan,† Dong-Shan Wu,† Jian-Heng Ye,† Li Gong,† Xin Zeng,† Chuan-Kun Ran,†,‡ Yong-Yuan
Gui,†,‡ Jing Li,† and Da-Gang Yu*,†¶
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† Key Laboratory of Green Chemistry & Technology of Ministry of Education, College of Chemistry, Sichuan University,
Chengdu 610064, P. R. China.
‡ College of Chemistry and Materials Science, Sichuan Normal University, Chengdu 610068, P. R. China.
¶ State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, P. R. China.
ABSTRACT: An effective Cu-catalyzed selective formal carboxylation of C−F bonds with an atmospheric pressure of CO2 is
reported. A variety of gem-difluoroalkenes, gem-difluorodienes and -trifluoro-methyl alkenes show high reactivity and selectivity
for this ipso mono-carboxylation. Under mild conditions, diverse important -fluoroacrylic acids and ,-difluorocarboxylates are
obtained in good-to-high yields. Moreover, this operationally-simple protocol features good functional group tolerance, is readily
scalable, and the resulting products are readily converted into bioactive -fluorinated carbonyl compounds, indicating potential
application in biochemistry and drug discovery. Mechanistic studies reveal that fluorinated boronate esters might be vital
intermediates in this transformation.
KEYWORDS: carbon dioxide, carboxylation, C−F bond cleavage, selectivity, copper catalysis
As an inexpensive and renewable carbon source, CO2 has
been widely used in organic synthesis to make value-added
chemicals.1 Among these transformations, catalytic
carboxylation with CO2 is well demonstrated to construct
valuable carboxylic acids,2 which is a functional group that
exists widely in natural products, agrochemicals and
pharmaceuticals.3 Recently, the reductive carboxylation of
organic (pseudo)halides with CO2 has been extensively
studied,4,5 presenting powerful and efficient alternatives to
existing carboxylation methods with organometallic
reagents.2,6 Notably, the catalytic carboxylation of diverse
C−X bonds (X = Cl, Br, I, O, N) in the presence of reductants
is well documented using different transition metal catalysts
(Figure 1A).4,5 However, the transition metal-catalyzed formal
carboxylation of C−F bonds with CO2 is considered
challenging and has been rarely investigated.7 This is
reasonable due to the low reactivity of CO2 and exceptional
inertness of C−F bonds, which show much higher bond
dissociation energy and are less reactive toward oxidative
addition to low-valent transition metal catalyst than other C−X
bonds.8 Therefore, a novel strategy should be considered to
address such a challenge. Herein, we report the first copper-
catalyzed selective formal carboxylation of C−F bonds with
CO2 (Figure 1B). A variety of valuable -fluoroacrylic acids
and ,-difluorocarboxylates are obtained in high selectivities
and efficiency using inexpensive catalyst and non-metallic
reductants.
alternative access to complex partially fluorinated
molecules,11-14 we wondered whether selective carboxylation
of C−F bonds in gem-difluoroalkenes13 with CO2 could
constitute a direct and efficient entry to -fluoroacrylic acids.
Realizing this hypothesis, however, suffers several challenges.
Besides the above-mentioned inertness of both C–F bonds and
CO2, it is also challenging to realize selective mono- instead of
di-carboxylation of C–F bonds in gem-difluoroalkenes due to
their similar bond energies.
(A) Previous carboxylation of C-X bonds with CO2
cat. Ni or Pd or Cu
ligand
+
CO2
R CO2H
R
X
reductant
X = Cl, Br, I, OR1, NMe3X
(Mn, Zn, Et2Zn,...)
(1-10 atm)
(B) Copper-catalyzed selective carboxylation of C-F bonds with CO2 (This work)
cat. Cu/L
Rf
F
CO2
Rf CO2H
+
(B(OR)2)2
(1 atm)
+ High selectivity + Good FG tolerance
+ Important and diverse
+ Mild conditions + Broad substrate scope + Easy derivation
Challenges: low reactivity (C-F cleavage and CO2 activation)
selectivity (mono-, regio- and stereo-selectivities)
Figure 1. Catalytic carboxylation of C−X bonds with CO2.
O
O
O
O
O
Ph
N
H
F
O
F
Analgesic
Anticonvulsant
O
H
N
N
N
OEt
-Fluoroacrylic acids are important motifs widely present in
medicines and bioactive molecules (Figure 2).9 Previous
methods for their synthesis suffer, however, from tedious
procedures, limited substrate scope, poor functional group
tolerance, and low selectivity or yield.9b,10 Moreover, some
expensive reagents are usually required, thus limiting
applicability. Since selective functionalization of C−F bonds
in easily available multifluorinated compounds provides an
N
O
AcHN
F
N
O
S
OEt
F
O
Anti-infectious
Respiratory drug
Figure 2. Selected bioactive -fluoroacrylates and derivatives.
As direct carboxylation of C−F bonds with CO2 is difficult
via oxidative addition, we wondered whether we could realize
the C−F bond cleavage via β-F elimination13,14 and generate
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reactive organometallic reagents, which might react with CO2
Page 2 of 7
heterocycles, such as pyridine (2q), benzothiophene (2ab), and
quinoline (2ac), were also compatible with this reaction.
Interestingly, the reaction of substrate 1ad bearing both an
aliphatic and an aryl gem-difluoroalkene provided the single
product 2ad in a satisfactory yield, demonstrating the high
selectivity of this reaction and acceptable toleration of
aliphatic gem-difluoroalkenes. Importantly, the more
challenging gem-difluorodienes were also applicable (Scheme
2), affording the desired products 2ae-2ah with high chemo-
and stereoselectivity, thus significantly extending the scope of
the reaction.
1
2
3
4
5
6
7
8
under mild reaction conditions. We began our investigations
by evaluating the reaction of 4-(2,2-difluorovinyl)-1,1'-
biphenyl (1a) with CO2 and a copper(I)/diboron catalytic
system (Table 1). When we conducted the reaction using
KOAc or CsF as base, no or only trace amounts of the desired
product 2a was detected (entries 1-2). We suspected that a
stronger base may be essential to activate the diboron reagents
and promote this transformation. Further screening of several
strong bases revealed that LiOtBu afforded 2a in the highest
yield (entries 3-5). We also tested other cuprous catalysts and
found that CuTc gave the best result (entries 3, 6 and 7). Other
solvents, such as DMAc and o-xylene, all resulted in lower
yields (entries 8-9). The Xantphos was found to be the best
ligand and the B2pin2 was the diboron sources of choice
(Please see SI for details). Control experiments showed that
both the copper catalyst and base were vital to this
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Scheme 1. Substrate Scope of gem-Difluoroalkenesa
CuTc (5 mol%)
Xantphos (5 mol%)
LiOtBu (3.5 equiv)
B2pin2 (1.5 equiv)
F
CO2R
+
CO2
Ar
Ar
F
DMF, 80 °C, 24 h
then HCl (aq.) or MeI
F
1
(1 atm, closed)
CO2H
2
, R = H or Me
CO2Me
transformation (entries 10-11). Notably, this
formal
F
F
R
R
carboxylation proceeded with high efficiency (entry 12. Please
see SI for details) and high (Z)-selectivity; no (E)-isomer was
detected by 19F NMR.
Table 1. Optimization of the Reaction Conditionsa
2a, R = Ph, 85%
2g, R = OPh, 82%
2m, R = CF3, 69%d
, R = CO2Me, 75%
, R = CN, 70%
, R = SO2Me, 66%
b
d
2b
2c
2d
2e
2h
2n
2o
2p
2q
, R = H, 70%
, R = OCF3, 64%
b,c
b
d
2i
2j
, R = Me, 60%
, R = F, 68%
, R = Cl, 65%
, R = iPr, 60%b
d
, R = tBu, 76%b,c
, R = Br, 70%
, R = Py, 73%
d
2k
b,c
2f
2l
, R = OMe, 55%
, R = NPh2, 85%
R
R
CO2H
NC
CO2Me
CO2H
[Cu] (5 mol%)
Xantphos (5 mol%)
base (3.5 equiv)
F
F
F
b
2r
, R = Me, 74%
2v
, R = F, 84%
2w
CO2H
F
d
b,c
B2pin2 (1.5 equiv)
2u
, 68%
, R = Me, 52%
b,c
2s
, R = OMe, 71%
+
CO2
2x
, R = OMe, 66%
solvent, 80 °C, 24 h
then HCl (aq.)
2t
F
, R = Cl, 68%
F
Ph
Ph
MeO
CO2H
CO2H
CO2H
1a
(1 atm, closed)
base
2a
F
F
F
F
b
entry
[Cu]
solvent
2a
Yield of
(%)
2y
2z, 66%b
2aa, 67%b
, 82%
1
2
CuTc
CuTc
CuTc
CuTc
CuTc
CuI
KOAc
CsF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMAc
N.D.
trace
88 (85)
59
CO2Me
CO2H
F
CO2H
3
LiOtBu
NaOtBu
KOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
-
F
F
N
F
F
S
4
d
2ac
2ad
, 68%
2ab
, 52%
, 70%
5
44
aReaction conditions are shown in Table 1, entry 3. 36 h. CuTc
(10 mol%) and Xantphos (10 mol%) were used. dIsolated yields of
methyl ester using MeI as esterification reagent.
b
c
6
73
7
CuOAc
CuTc
CuTc
-
83
8
70
9
o-xylene
DMF
65
10
11
12c
N.D.
N.D.
85
CuTc
CuTc
DMF
Scheme 2. Substrate Scope of gem-Difluorodienesa
LiOtBu
DMF
CuTc (5 mol%)
aReaction conditions: 1a (0.4 mmol), 1 atm of CO2, [Cu] (0.02
mmol), Xantphos (0.02 mmol), base (1.4 mmol), B2pin2 (0.6
mmol), solvent (2 mL), 80 ºC, 24 h. Yields were determined by
Xantphos (5 mol%)
LiOtBu (3.5 equiv)
B2pin2 (1.5 equiv)
R1
R1
CO2R
F
+
CO2
R2
R2
b
DMF, 80 °C, 24 h
then HCl (aq.) or MeI
R3
F
R3
F
UPLC using anisole as an internal standard, and the isolated
yields are given in parentheses. 2 h instead of 24 h. CuTc =
copper(I) thiophene-2-carboxylate. N.D. = not detected. DMF =
N,N-dimethylformamide. DMAc = N,N-dimethylacetamide.
1
(1 atm, closed)
2
, R = H or Me
c
Ph
CO2Me
CO2Me
CO2H
Ph
CO2Me Ph
Ph
F
, 76%
F
F
F
b
c
b
2ae
2af
2ag
, 61%
, 72% (Z/E = 15:1)
2ah
, 45% (Z/E > 20:1)
The best reaction conditions were used for further
evaluation of the scope of gem-difluoroalkenes (Scheme 1).
Substrates bearing either an electron-donating group (EDG)
(2e-2h, 2l, 2s and 2x) or an electron-withdrawing group
(EWG) (2m-2q and 2u) on the phenyl ring showed good
reactivity and gave the carboxylated products 2 in moderate-
to-high yields. Substituents at different positions on the arenes,
such as the para-, meta- and ortho-positions, did not inhibit
the reaction. It is worth noting that a variety of synthetically
valuable functional groups, including ether (2f, 2g, 2h, 2s and
2x), fluoro (2i, 2v and 2aa), chloro (2j and 2t), bromo (2k),
amino (2l), and sulfone (2p), were all tolerated, providing
opportunities for subsequent useful transformations.
Moreover, some base-sensitive functional groups, such as
methyl ester (2n) and nitrile (2o and 2u), could remain intact
under our reaction conditions. Naphthalenes (2y and 2z) and
aReaction conditions are shown in Table 1, entry 3. bThe Z/E ratio
c
was determined by 19F NMR analysis of reaction mixture. CuTc
(10 mol%) and Xantphos (10 mol%) were used, 36 h.
After realizing the selective carboxylation of C(sp2)−F
bonds in gem-difluoroalkenes, we wondered whether we could
apply this catalytic system to realize a selective defluorinative
carboxylation of C(sp3)−F bonds in -trifluoromethyl
alkenes14 with CO2. The aliphatic C–F bond is well-known to
be highly unreactive due to the high BDE of a C(sp3)–F bond.
Moreover, it is rather difficult to avoid multiple
defluorinations and thus realize
a
selective mono-
carboxylation, since the C–F bonds in the initial products
might be activated by the carboxyl group.
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With these challenges in mind, we investigated the
carboxylation of trifluoromethyl alkene 3a with CO2. To our
delight, we found that 3a underwent a highly selective ipso-
carboxylation of one C−F bond to give the ,-
difluorocarboxylate 4a in 70% yield under slightly modified
pyrrolidine 6 in one step.18 Notably, the facile condensation of
2b with amines gave direct access to bioactive compounds,
including anticonvulsant agent 7 (Figure 2) and quinuclidine
acrylamide 8, which can be used for the treatment or
prophylaxis of psychotic disorders and intellectual impairment
disorders.9a,d
1
2
3
4
5
6
7
8
reaction
conditions
(Scheme
3).
Bis(hexylene
glycolato)diboron turned out to be a better choice for this case
with better yields than B2pin2 (Please see SI for details).
To shed light on the mechanism of this transformation,
several experiments were conducted (Figure 4). As we
detected the Z-fluorinated vinylboronate ester 9a in the
reaction of 1a under the N2 atmosphere, we speculated that 9a
might be the intermediate of the reaction. So we synthesized
9a according to the literature via Cu-catalyzed stereoselective
borylation of gem-difluoroalkenes with B2pin2.13f,13h When it
was subjected to the carboxylation reaction, the desired
product 2a was obtained in 79% yield in 0.5 hour (Figure 4A).
Surprisingly, the carboxylation of 9a also proceeded in the
absence of a Cu-catalyst (Figure 4B), albeit with a lower
efficiency than with Cu-catalysis (Figure 4A). Moreover,
preliminary kinetic studies indicated that the Cu-catalysis
should dominate the carboxylation of fluorinated
vinylboronate ester with CO2 (See SI for details). In order to
explain the unusual results in Figure 4B, we further studied the
carboxylations of 9b and 9c in the same conditions (Figure
4C). The results indicated that the electron-withdrawing effect
of -substitutions could activate the vinylboronate ester.
Notably, this represents
a
rare example for an ipso-
functionalization of
a
C−F bond in -trifluoromethyl
9
alkenes.15 Although gem-difluoroalkenes typically are
obtained via SN2’-type reactions in most cases,14 the formation
of isomer 4a’ was not observed in our reaction. Importantly,
the generated difluoromethylene group (CF2) at benzylic
position has good metabolic stability, which is often regarded
as the bioisosteres of oxygen atom, carbonyl group and
methylene group,16 thus providing a possibility for the
application of the product 4 in medicine and bioactive
molecules. Furthermore, the substrate scope of 3 was
investigated (Scheme 3). For example, the substrates with
different substituents on the arenes, including methoxy (4b,
4g), chloro (4c, 4h, 4o), bromo (4d), and trifluoromethyl (4f)
were tested and they afforded the desired ,-
difluorocarboxylates in moderate-to-good yields. Besides the
substrates bearing monosubstituted benzenes, those with
disubstitutions (4j, 4k, and 4m) could also react well to
furnish the products effectively. The substrates bearing
naphthalene (4l and 4n) or fluorene (4p) also showed good
reactivity in this transformation. Notably, multiple
defluorinations were not observed in all cases.17
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(A) Gram-scale reaction
CuTc (5 mol%)
Xantphos (5 mol%)
LiOtBu (3.5 equiv)
B2pin2 (1.5 equiv)
CO2H
F
+
CO2
F
DMF, 80 °C, 24 h
then HCl (aq.)
F
Ph2
N
Ph2
N
1l
(1 atm, closed)
2l
, 1.04 g, 78%
, 1.23 g, 4 mmol
(B) Synthetic applications of products
NBn
TFA (10 mol%)
DCM, 0 - 25 °C, 3 h
CO2Me
OH
LiAlH4 (1.0 equiv)
Scheme 3. Substrate Scope of -Trifluoromethyl Alkenesa
F
Et2O, -10 °C, 6 min
F
CO2Me
F
Ph
MeO
N
SiMe3
Ph
CuCl (10 mol%)
Ph
Bn
(4.0 equiv)
5
2a''
6
, 84%
, 87%
Xantphos (10 mol%)
KOMe (3.0 equiv)
(B(OR1
) )2 (1.5 equiv)
2
CO2C6H13
NH2
CF3
R
+
CO2
R
F
sec-butylamine (1.5 equiv)
HATU (2.0 equiv)
NMP, 80 °C, 24 h
then nC6H13
F
O
•2HCl
F
I
H
N
CO2H
N
(1.0 equiv)
NEt3 (3.0 equiv)
N
3
(1 atm, closed)
4
H
HATU (2.0 equiv)
NEt3 (4.0 equiv)
DMF, 25 °C, 6 h
F
DMF, 25 °C, 5 h
F
O
N
7
2b
8
, 90%
, 82%
anticonvulsant activity
CO2C6H13
F
R
CO2C6H13
F
CO2C6H13
F
F
F
F
R
4a
, R = Ph, 70%
, R = OMe, 56%
, R = Cl, 64%
, R = Br, 62%
, R = tBu, 56%
, R = CF3, 51%
Figure 3. Gram-scale synthesis and synthetic applications of
4g
4h
4i
, R = OMe, 52%
, R = Cl, 62%
, R = Ph, 68%
4b
4c
4d
4e
4j
, 42%
products.
4f
CuTc (5 mol%)
Xantphos (5 mol%)
F
CO2C6H13
F
CO2C6H13
CO2C6H13
CO2H
O
(A)
(B)
LiOtBu (2.5 equiv)
Bpin
F
F
+
+
CO2
F
F
F
F
DMF, 80 °C, t
then HCl (aq.)
O
Ph
F
F
Ph
Ph
4k
, 65%
4l
4m
Ph
Ph
, 58%
, 66%
9a
9a
2a
t = 0.5 h, 79%
(1 atm, closed)
CO2C6H13
F
CO2C6H13
F
without [Cu/L]
CO2C6H13
F
CO2H
Bpin
LiOtBu (2.5 equiv)
F
F
CO2
F
F
DMF, 80 °C, t
then HCl (aq.)
2a
(1 atm, closed)
Cl
4n
4o
4p
, 58%
, 55%
, 59%
t = 0.5 h, 10%
t = 24 h, 71%
aReaction conditions: 3 (0.2 mmol), 1 atm of CO2, CuCl (0.02
mmol), Xantphos (0.02 mmol), KOMe (0.6 mmol), (B(OR1)2)2
(0.3 mmol), NMP (2 mL), 80 ºC, 24 h; isolated yields. (B(OR1)2)2
= Bis(hexylene glycolato)diboron.
without [Cu/L]
LiOtBu (2.5 equiv)
Bpin
CO2H
R
(C)
+
CO2
DMF, 80 °C, 24 h
then HCl (aq.)
R
9b
(1 atm, closed)
, R = H
10
, R = H, N.D.
9c
, R = CO2Et, Z/E = 10 :1
11
, R = CO2Et, 61%, Z/E = 2.76 :1
To further demonstrate the utility of this transformation, we
conducted a gram-scale reaction of 1l to synthesize 2l in 78%
yield (Figure 3A. See SI for details). Moreover, products could
be readily converted into valuable compounds (Figure 3B. See
SI for details). For example, the methyl ester 2a’’ readily
underwent either reduction to generate fluoroallyl alcohol 5 or
[3+2] cycloaddition with an azomethine ylide to give fluoro-
Figure 4. Control experiments.
Based on the experimental results and previous reports,19 we
proposed the following possible mechanism for the
carboxylation of 1 (Figure 5). Copper(I) alkoxide A would
easily undergo transmetalation with the diboron reagent to
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afford the boryl-copper(I) species B. Subsequently, insertion
1
2
3
4
5
6
7
8
of a difluoroalkene 1 into the Cu−B bond of B would result in
the formation of intermediate C. Among different
configurations (C, C’ and C’’), the steric repulsion between
the bulky boryl group and the R group in C’’ makes it
unstable. Thus, syn β-F elimination via C’ selectively affords
the (Z)-fluorinated pinacol alkenylboronate D and a Cu(I)-F
ACKNOWLEDGMENT
We thank Prof. Ruben Martin (ICIQ) for valuable discussion and
Prof. Jason J. Chruma (SCU) for helpful manuscript revisions. We
thank the National Natural Science Foundation of China
(21822108, 21772129), the “973” Project from the MOST of
China (2015CB856600), the “1000-Youth Talents Program”, and
the Fundamental Research Funds for the Central Universities for
financial support. This work is dedicated to Prof. Qing-Yun Chen
on the occasion of his 90th birthday.
species. In path A,
transmetallation/carboxylation process would give the desired
product and regenerate the active catalyst A. As
a
subsequent Cu(I)-catalyzed
2
9
demonstrated, the direct carboxylation of D with CO2 (path B)
might also happen in the presence of LiOtBu, even though this
is less efficient than path A and less favored in the reaction
mixture. Another possible pathway to directly generate E from
1 and B via a sigma bond metathesis can not be excluded at
this stage.
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F
R
1
F
LCu
F
F
tBuO Bpin
B2pin2
Bpin
F
F
LCu
H
R
LCu Bpin
H
R
Bpin
C'
B
C
LCu
F
H
R
F
Bpin
LiOtBu
C''
LCu OtBu
LCuTc
A
F-CuL
Bpin
CO2Li
CO2H
CO2
R
R
LiOtBu
LiOtBu
F
D
F
CO2Li
R
path A
LiOtBu
path B
H
F
F
CuL
R
H
R
F
2
CO2
F
tBuO Bpin
CO2H
E
R
2
Figure 5. Proposed mechanism.
In conclusion, we have realized the first Cu-catalyzed
highly selective formal ipso-carboxylation of C−F bonds in
fluorinated alkenes with CO2. A variety of valuable -
fluoroacrylic acids and ,-difluorocarboxylates, which exist
among many drugs but are otherwise difficult to access, were
obtained in good yields under mild conditions. Diverse
functional groups were well tolerated in the presence of
nonmetallic reductants. This method displays inexpensive
catalyst, broad substrate scope, high mono-, chemo- and
stereo-selectivities, scalability, and rapid access to bioactive
molecules, providing great potential for application in organic
synthesis, biochemistry and drug discovery.
AUTHOR INFORMATION
Corresponding Author
Da-Gang Yu: dgyu@scu.edu.cn
ORCID
Da-Gang Yu: 0000-0001-5888-1494
Conflict
of
Interest
A Chinese Patent on this work has been applied with the number
(201910261590.6) on 2nd April, 2019.
ASSOCIATED CONTENT
Supporting Information
Experimental details, spectroscopic data and copies of NMR
spectra for all products are available free of charge via the Internet
Liu,
Y.;
Martin,
R.
Ni-Catalyzed
Divergent
ACS Paragon Plus Environment

Page 5 of 7
ACS Catalysis
Cyclization/Carboxylation of Unactivated Primary and Secondary
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Carboxylation
of
gem-Difluoroalkenes
with
CO2
by
ACS Paragon Plus Environment

ACS Catalysis
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(15) The only example for ipso-functionalization of a C−F bond in -
trifluoromethyl alkenes, see: Zeng, H.; Zhu, C.; Jiang, H. Single
C(sp3) −F Bond Activation in a CF3 Group: Ipso-Defluorooxylation of
(Trifluoromethyl)alkenes with Oximes. Org. Lett. 2019, 21, 1130–
1133.
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Table of Contents
CO2H
F
R
R
+ High selectivity
+ Mild conditions
+ Good FG tolerance
F
F
4
5
CO2
cat. [Cu]
+ Broad substrate scope
+ Important and diverse
+ Easy derivation
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F
F
F F
F
CO2H
Ar
Ar
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