Copper-Catalyzed Decarboxylative Difluoromethylation

Article abstract of DOI:10.1021/jacs.9b05363

We report herein a highly efficient Cu-catalyzed protocol for the conversion of aliphatic carboxylic acids to the corresponding difluoromethylated analogues. This robust, operationally simple and scalable protocol tolerates a variety of functional groups and can convert a diverse array of acid-containing complex molecules to the alkyl-CF₂H products. Mechanistic studies support the involvement of alkyl radicals.

Full text of DOI:10.1021/jacs.9b05363

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Communication
Copper-Catalyzed Decarboxylative Difluoromethylation
Xiaojun Zeng, Wenhao Yan, Samson B. Zacate, Tzu-Hsuan Chao, Xiaodong Sun, Zhi Cao, Kate G. E.
Bradford, Matthew Paeth, Sam B. Tyndall, Kundi Yang, Tung-Chun Kuo, Mu-Jeng Cheng, and Wei Liu
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b05363 • Publication Date (Web): 08 Jul 2019
Downloaded from http://pubs.acs.org on July 8, 2019
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Copper-Catalyzed Decarboxylative Difluoromethylation
†
†
†
‡
§
*,§
Xiaojun Zeng, Wenhao Yan, Samson B. Zacate, Tzu-Hsuan Chao, Xiaodong Sun, Zhi Cao , Kate
†
†
†
†
‡
‡
G. E. Bradford, Matthew Paeth, Sam B. Tyndall, Kundi Yang, Tung-Chun Kuo, Mu-Jeng Cheng,
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*
,†
Wei Liu
†Department of Chemistry and Biochemistry, Miami University, Oxford, OH, 45056, United States
‡Department of Chemistry, National Cheng Kung University, Tainan, 701, Taiwan
§State Key Laboratory of Coal Conversion, Institute of Coal Chemistry, Chinese Academy of Sciences, Taiyuan, Shanxi
0
30001, P. R. China; National Energy Center for Coal to Liquids, Synfuels China Technology Co., Ltd, Beijing, 101400, P.
R. China
Supporting Information Placeholder
metal catalyzed/promoted cross-coupling reactions have
been widely applied to the formation of aryl-CF H
bonds using pre-functionalized arenes.
ABSTRACT: We report herein a highly efficient Cu-
catalyzed protocol for the conversion of aliphatic
2
7
carboxylic
acids
to
the
corresponding
difluoromethylated analogues. This robust, operationally
simple and scalable protocol tolerates a variety of
functional groups and can convert a diverse array of
acid-containing complex molecules to the alkyl-CF H
2
products. Mechanistic studies support the involvement
of alkyl radicals.
Organic molecules containing fluorine atoms have
emerged as important pharmaceuticals, agrochemicals,
materials, and radiopharmaceuticals because of the
effect fluorine has on the permeability, lipophilicity and
1
metabolic stability of organic molecules. In recent
years, there has been a growing interest in organic
molecules bearing difluoromethyl (CF H) groups due to
2
their unique chemical and physical properties. In
medicinal chemistry, CF H groups have been harnessed
2
as lipophilic hydrogen bond donors and metabolically
2
stable bioisosteres of hydroxyl, thiol or amine groups,
to modify the pharmacological and biological activity of
the lead compounds. However, the widespread
Figure 1. Alkyl difluoromethylation: previous methods and
current work.
incorporation of CF H groups has been hampered by the
2
challenges associated with their synthesis and therefore
it is imperative that chemists develop novel methods for
efficient difluoromethylation reactions.
Despite the progress on the aryl difluoromethylation,
methods for the construction of Csp -CF H bonds
remain rather limited. With few exceptions,
3
2
8
Significant amounts of work have been conducted on
conventional approaches toward alkyl-CF H installation
2
the construction of aryl-CF H bonds. Traditional
fall into two main categories: i) difunctionalization of
2
9
approaches to difluoromethylated arenes include gem-
alkenes with in-situ generated difluoromethyl radicals
deoxydifluorination of aldehydes using sulfur
and ii) difluoromethylation of pre-functionalized
3
tetrafluoride or its derivative as well as oxidative
substrates with nucleophilic or electrophilic CF H
2
4
10
desulfurization-difluorination. Difluoromethylation of
reagents. However, these methods usually suffer from
arenes and heteroarenes via C-H bond activation has
limited substrate scope or require the pre-
functionalization of the parent molecules, and are not
suitable for late-stage modification of complicated
5
been reported. Aryl-CF bonds can also be constructed
2
6
by direct difluorination of benzylic C-H bonds. Finally,
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Table 1. Reaction Optimization
Page 2 of 7
molecules. Thus, a new mode of CF H transfer allowing
2
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
for the transformation of native, abundant functional
3
groups into Csp -CF H bonds will be of high value to
2
the synthetic organic and medicinal chemistry fields
(Figure 1).
entry
variation from the standard conditions
yield (%)a
1
2
3
None
98%
23%
76%
use the NHPI ester
acetonitrile as the solvent
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
4
5
DMF as the solvent
THF as the solvent
46%
65%
6
7
8
9
CuI instead of CuCl
94%
N.D.
23%
59%
97%
NiCl
2
glyme as the catalyst
no bipyridine
reaction was run at r.t
1
0
in-situ generation of RAE
Figure 2. Proposed mechanism for the copper-catalyzed
decarboxylative difluoromethylation of alkyl carboxylic
acids
1
1
1
2
reaction was set up in air
no CuCl
89%
N.D.
13
0.5 equiv. of 11
52%
Given our group’s long-term interest in the
development of new fluoroalkylation reactions, we
a0.1mmol scale, 1.3 equiv. of 11. Yields were determined by 19
NMR using 1-fluoro-3-nitrobenzene as the internal standard.
F
reason that
a
technique allowing for the
To test this hypothesis, we exposed the RAE of 3-
phenylpropanoic acid (10) to a variety of difluoromethyl
sources in the presence of Cu(I) catalysts. Upon
investigating a range of reaction parameters, we
discovered that in the presence of catalytic amounts of
CuCl (20 mol%), bipyridine (20 mol%) as the ligand,
and 1.3 equiv. of (DMPU) Zn(CF H) (11)
difluoromethyl source, 10 can be selectively converted
to the corresponding difluoromethylated product 12 in a
difluoromethylation of alkyl radicals can nicely
3
complement current methods for Csp -CF H bond-
2
formation. Selective functionalization of alkyl radicals
has emerged as a powerful way to construct C-C
1
1
bonds. Yet, difluoromethylation of carbon-centered
alkyl radicals remains elusive. We recently questioned
1
4b, 17
as the
2
2
2
whether copper could mediate the transfer of CF H
2
groups to alkyl radicals, thus allowing for a catalytic
difluoromethylation reaction. An ideal source of the
alkyl radicals would derive from alkyl carboxylic acids,
as they are readily available, highly stable, inexpensive
and abundant in bioactive molecules. The direct
9
8% yield at 60 ºC in DMSO (Table 1, entry 1). Using
the analogous N-hydroxyphthalimide (NHPI) ester
afforded a much lower yield (entry 2). Solvents play an
important role in this difluoromethylation reaction;
replacing DMSO with other solvents led to diminished
yields (entries 3-5). Other copper (I) salts can also be
used (entry 6), while the use of other transition-metal
catalysts, including Ni, did not afford the desired
product (entry 7). Lower yields were observed when the
reactions were run in the absence of bipyridine (entry 8)
or at a lower temperature (entry 9). In addition, the RAE
can be synthesized in-situ without purification,
providing the difluoromethylated product in a similar
yield (entry 10). Interestingly, only a slight drop of yield
was observed when the reaction was set up in air (entry
3
3
conversion of Csp -COOH groups into Csp -CF H
2
bonds could enable widespread incorporation of
difluoromethyl groups. We hypothesized that the merger
1
2
of redox-active esters (RAEs) with copper catalysis
1
3
could realize this transformation (Figure 2).
Specifically, we reasoned that the transmetallation of a
nucleophilic difluoromethyl source with a copper(I)
I
catalyst 1 should afford a reactive [Cu -CF H] species 2
(
2
0
14
cal’d E = –1.2 V vs Ag/AgCl, see SI). We anticipated
that 2 undergoes a single electron transfer with the RAE
1
5
5
(E = –1.2 V vs Ag/AgCl) , readily synthesized from
the starting carboxylic acid 4, to generate, followed by
1
1). Control experiments revealed that no
difluoromethylated products were formed in the absence
of copper catalysts (entry 12). The reaction proceeded
with a workable yield with equal amounts of the CF H
source (entry 13). Finally, replacing 11 with its CF or
the extrusion of CO , the substrate-derived alkyl radical
2
II
6
and a [Cu -CF H] species 7. The alkyl radical was
2
expected to rapidly recombine with 7, affording a
III
2
reactive [alkyl-Cu -CF H] intermediate. The high-
2
18
3
3
valent copper(III) complex could undergo Csp -CF H
bond-forming reductive elimination , affording the
2
C F analogues under the same conditions did not lead
1
6
2 5
to the formation of the corresponding trifluoromethyl or
pentafluoroethyl products.
alkyl-CF H product and regenerating the copper(I)
2
catalyst.
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Table 2. Substrate Scope of the Copper-Catalyzed Decarboxylative Difluoromethylationa
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
a
Unless otherwise noted, reactions were run with 0.20 mmol isolated RAEs, 0.26 mmol 11 (1.3 equiv.), CuCl (20 mol%) and bpy (20 mol%) in 1 mL DMSO
b
19
at 60 ºC. Isolated yields based on RAEs. Determined by F NMR due to the volatility of the products; isolated yields based on RAEs shown in parentheses
c
Reactions were run with 0.20 mmol carboxylic acids. Isolated yields based on carboxylic acids.
With the optimized conditions in hand, we evaluated
the scope of this decarboxylative difluoromethylation
reaction. As shown in Table 2, the reaction tolerates a
variety of functional groups and is amenable to a wide
range of primary, secondary and tertiary acids.
Remarkably, substrates containing alkyl and aryl halides
oxygen-containing heterocycles (35, 36, 42, 54), which
are ubiquitous in drug-like molecules, all afforded the
desired products in good yields. Notably, the
unprotected indole ring (36) was not affected in the
transformation. Likewise, acidic phenolic hydroxyl and
terminal alkyne groups (27, 37) were tolerated.
Carboxylic acids at activated positions, including phenyl
acetic acids and oxyacetic acids (32-34, 40-43), were all
converted to their corresponding difluoromethylated
analogues. Substrates containing two carboxylic acid
groups were doubly difluoromethylated (38, 39).
(
15, 29, 44) can be successfully difluoromethylated
without affecting the halogen atoms. The aldehyde
group (40), which could be problematic under typical
oxidative, reductive or nucleophilic conditions, was
undisturbed under this condition. Several nitrogen- and
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Table 3. Copper-Catalyzed Late-Stage Difluoromethylation of Complex Carboxylic Acidsa
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
O
NHBoc
CF2H
Cl
Cl
O
2
CF H
NHBoc
H
N
H
N
CF2H
CF2H
Cl
Cl
Cl
58
59
60
61
from Boc-Gabapentin
4%
from Boc-Baclofen
89%
from Diclofenac
41%
from Aceclofenac
92%
9
Cl
O
O
O
O
2
CF H
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
N
N
CF2H
CF2H
N
O
CF2H
O
6
2
63
from Isoxepac
94%
64
from Tolmetin
44%
65
from Indomethacin
1% (85% in situ )
from Oxaprozin
79%
c
9
CF2H
CF2H
O
H
R
H
CF2H
Cl
N
CF2H
H
H
O
H
H
R
Cl
O
R
H
H
6
6
67
from Oleic acid
93%
68
69 R=OH 82%
70 R=OAc 85%
from Chlorambucil
2% (79% in situ )
from Dehydrocholic acid
88%
c
9
from Cholic acid
O
O
O
O
O
2
CF H
NH H
O
H
N
N
CF2H
O
S
S
CF2H
HN
NH
CF2H
O
S
H
O
OH
F
71
72
73
74
from Erdosteine
9%
from D(+)Biotin
56%
from Mycophenolic acid
80% (75% in situ )
from Lipitor Acetonide
66%
c
8
a
Unless otherwise noted, reactions were run with 0.20 mmol RAEs, 0.26 mmol 11 (1.3 equiv.), CuCl (20 mol%) and bpy (20 mol%) in 1 mL DMSO at 60
b
ºC. Isolated yields based on RAEs. Reactions were run with 0.20 mmol carboxylic acids. Isolated yields based on carboxylic acids
Furthermore, a range of secondary carboxylic acids
appended to a variety of rings (cycloheptyl, cyclohexyl,
cyclopentyl, pyranyl, piperidine, pyrrolidine and
azetidine) and paired with different functional groups
could be successfully difluoromethylated in good to
excellent yields (45 - 55). Two tertiary carboxylic acids
Difluoromethyl products derived from Boc-gabapentin,
Boc-baclofen, diclofenac and aceclofenac were
synthesized in moderate to excellent yields (58 – 61).
Notably, the secondary amine groups in diclofenac and
aceclofenac
did
not
interfere
with
the
difluoromethylation reactions. Several heterocycle-
bearing drug molecules, including indomethacin,
isoxepac, oxaprozin and tolmetin, some of which
contain basic nitrogens, were also successfully
difluoromethylated (62 - 65). Cholic acid, which
contains three unprotected alcohol groups, along with
two other steroidal carboxylic acids, were also
difluoromethylated (68 - 70). Moreover, the successful
(56 and 57) in which three carbon atoms were tied into a
ring structure were also difluoromethylated in good
yields. To evaluate the generality of the protocol using
in-situ formed RAEs for the difluoromethylation
reactions, five different carboxylic acids, including
primary (24), secondary (53), tertiary (57), benzylic
(32), oxyacetic (41) and heterocycle-containing (54)
acids, were subjected to this one-pot protocol.
Gratifying, all of these acids afforded the corresponding
difluoromethylated products in comparable yields.
Finally, the scalability of this reaction has been
demonstrated through the gram scale synthesis of
compound 49.
difluoromethylation
of
erdosteine
and
biotin
demonstrates that the transformation is also tolerant of
thioethers (71 and 72). Finally, an immunosuppressant
drug, mycophenolic acid, and the acetonide of a
cholesterol-lowering drug, Lipitor, both of which
contain multiple functional groups, were converted to
their difluoromethyl analogues in good yields. (73 and
To further showcase the utility of this decarboxylative
difluoromethylation protocol, we subjected a large
variety of carboxylic acid-containing bioactive
molecules to the optimized conditions (Table 3).
7
4) The in-situ protocol has also been evaluated on three
of these complex molecules (62, 66, 73), all of which
afforded the difluoromethylated products in good yields.
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These examples further highlight the versatility of this
WL thanks Miami University for the start-up funding.
T.H.C. and M.J.C. acknowledge financial support from the
Ministry of Science and Technology of the Republic of
China under grant no. MOST 107-2113-M-006-008-MY2.
1
2
3
4
5
6
7
8
9
copper-catalyzed difluoromethylation reaction and its
real-world utility for late-stage functionalization of
medicinal agents.
REFERENCES:
1
.(a) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V., Fluorine in
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011). Chem. Rev. 2014, 114 (4), 2432-2506; (d) Gouverneur, V.,
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Figure 3. Radical trapping and radical clock experiments.
2
.(a) Sessler, C. D.; Rahm, M.; Becker, S.; Goldberg, J. M.; Wang, F.;
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Finally, we sought to establish the involvement of alkyl
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2
1
Bond Donor Properties of the Difluoromethyl Group. J. Org. Chem. 1995,
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radical-trapping
reagent,
TEMPO,
to
the
difluoromethylation of 10 led to a decreased yield of 11
with the concurrent formation of TEMPO-trapped
product 75. In addition, difluoromethylation of a radical
clock substrate 76 afforded the ring-opened product 77
in an 89% yield, while the unrearranged product 78 was
not detected. Both experiments support the intermediacy
of the alkyl radicals, consistent with the proposed
mechanism.
3
. For a review, see: (a) Singh, R. P.; Shreeve, J’ne. M., Recent Advances
in Nucleophilic Fluorination Reactions of Organic Compounds- Using
Deoxofluor and DAST. Synthesis 2002, (17), 2561-2578; For a recent
example, see: (b) Melvin, P. R.; Ferguson, D. M.; Schimler, S. D.; Bland,
D. C.; Sanford, M. S., Room Temperature Deoxyfluorination of
Benzaldehydes and α-Ketoesters with Sulfuryl Fluoride and
To conclude, we have developed the first alkyl
decarboxylative difluoromethylation reaction, allowing
for a general approach to the installation of the Csp -
Tetramethylammonium Fluoride. Org. Lett. 2019, 21 (5), 1350-1353.
4
.(a) Rozen, S., Attaching the Fluorine Atom to Organic Molecules Using
BrF and Other Reagents Directly Derived from F . Acc. Chem. Res. 2005,
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3
3
2
3
CF H moiety. This copper-catalyzed protocol exhibits
Rearrangement and Analogous Reactions. J. Fluorine. Chem. 2012, 143,
238-262.
5
2
high efficiency and an excellent substrate scope,
enabling late-stage difluoromethylation of complex
molecules. Furthermore, this transformation represents
the first example of redox-active esters being used for C-
C bond formation via non-photo-mediated copper
catalysis. More importantly, the unprecedented transfer
. For selected examples, see: (a) Fujiwara, Y.; Dixon, J. A.; Rodriguez,
R. A.; Baxter, R. D.; Dixon, D. D.; Collins, M. R.; Blackmond, D. G.;
Baran, P. S., A New Reagent for Direct Difluoromethylation. J. Am.
Chem. Soc. 2012, 134 (3), 1494-1497; (b) Sakamoto, R.; Kashiwagi, H.;
Maruoka, K., The Direct C–H Difluoromethylation of Heteroarenes Based
on the Photolysis of Hypervalent Iodine(III) Reagents That Contain
Difluoroacetoxy Ligands. Org. Lett. 2017, 19 (19), 5126-5129; (c) Tung,
T. T.; Christensen, S. B.; Nielsen, J., Difluoroacetic Acid as a New
Reagent for Direct C−H Difluoromethylation of Heteroaromatic
Compounds. Chem. Eur. J. 2017, 23 (72), 18125-18128; (d) Zhu, S.-Q.;
Liu, Y.-L.; Li, H.; Xu, X.-H.; Qing, F.-L., Direct and Regioselective C–H
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of CF H to alkyl radicals could open a new avenue for
2
the development of novel difluoromethylation reactions.
These studies are currently ongoing in our research lab.
6
.(a) Xu, P.; Guo, S.; Wang, L.; Tang, P., Silver-Catalyzed Oxidative
ASSOCIATED CONTENT
Activation of Benzylic C-H Bonds for the Synthesis of
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Supporting Information. The Supporting Information is
available free of charge on the ACS Publications website.
7
. For reviews, see: (a) Chen, B.; Vicic, D. A., Transition-Metal-Catalyzed
General information, experimental details, computational
details, characterizations of new compounds and NMR
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13-141; (b) Belhomme, M.-C.; Besset, T.; Poisson, T.; Pannecoucke, X.,
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Y., Recent Advances in Difluoromethylation Reaction. Curr. Org. Chem.
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Difluoromethylation Reactions of Organic Compounds. Chem. Eur. J.
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Transition-Metal (Cu, Pd, Ni)-Catalyzed Difluoroalkylation via Cross-
Coupling with Difluoroalkyl Halides. Acc. Chem. Res. 2018, 51 (9), 2264-
AUTHOR INFORMATION
Corresponding Author
caozhi@sxicc.ac.cn
wei.liu@miamioh.edu
017, 23 (59), 14676-14701; (f) Feng, Z.; Xiao, Y.-L.; Zhang, X.,
ACKNOWLEDGMENT
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278.
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Me3SiCF2H. Angew. Chem. Int. Ed. 2016, 55 (41), 12632-12636; (d)
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2433; (d) Kautzky, J. A.; Wang, T.; Evans, R. W.; MacMillan, D. W. C.,
18. When excess (DMPU) Zn(CF H) was used, tetrafluoroethane
2
2
2
Decarboxylative Trifluoromethylation of Aliphatic Carboxylic Acids. J.
Am. Chem. Soc. 2018, 140 (21), 6522-6526; (e) Xiao, H.; Liu, Z.; Shen,
H.; Zhang, B.; Zhu, L.; Li, C., Copper-Catalyzed Late-Stage Benzylic
C(sp3)–H Trifluoromethylation. Chem 2019, 5 (4), 940-949; (f) Kornfilt,
2 2 2 2
(HCF CF H) and difluoromethane (CF H ) were detected in the crude
reaction mixtures.
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