Visible-Light-Promoted Synthesis of α-CF2H-Substituted Ketones by Radical Difluoromethylation of Enol Acetates

Article abstract of DOI:10.1021/acs.orglett.0c04021

An efficient and novel visible-light-promoted radical difluoromethylation of enol acetates for the synthesis of α-CF2H-substituted ketones has been described. Upon irradiation under blue LED with catalytic amounts of fac-Ir(ppy)3, this photocatalytic procedure employs difluoromethyltriphenylphosphonium bromide as a radical precursor. Various α-CF2H-substituted ketones are successfully created via designed systems based on the SET process. The methodology has also provided an operationally simple process with broad functional group compatibility.

Full text of DOI:10.1021/acs.orglett.0c04021

pubs.acs.org/OrgLett
Letter
Visible-Light-Promoted Synthesis of α‑CF2H‑Substituted Ketones by
Radical Difluoromethylation of Enol Acetates
Zengqiang Feng,∥ Baoxiang Zhu,∥ Bingbing Dong, Li Cheng, Yunpu Li, Zechao Wang,*
and Junliang Wu*
Cite This: Org. Lett. 2021, 23, 508−513
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ABSTRACT: An efficient and novel visible-light-promoted radical
difluoromethylation of enol acetates for the synthesis of α-CF2H-
substituted ketones has been described. Upon irradiation under blue
LED with catalytic amounts of fac-Ir(ppy)3, this photocatalytic
procedure employs difluoromethyltriphenylphosphonium bromide as
a radical precursor. Various α-CF2H-substituted ketones are
successfully created via designed systems based on the SET process.
The methodology has also provided an operationally simple process with broad functional group compatibility.
rganofluorine compounds have been extensively utilized
in agrochemicals, pharmaceuticals, and organic func-
Scheme 1. Difluoromethylating Reagents
O
tional materials because of their special biological, physical, and
chemical properties.1 In particular, the CF2H group has
garnered substantial attention since it serves as a more
lipophilic isostere of the hydroxamic acid, thiol, carbinol, or
amide group.2 As a result, the CF2H group regularly replaces
the thio, amino, and hydroxyl groups of lead moieties in drug
discovery.3 As the CF2H group is weakly acidic, it is able to
form hydrogen-bonding interactions to enhance biologically
active compounds’ binding selectivity. Consequently, the
CF2H group is commonly applied to the pharmaceuticals
and agrochemicals.4
The preparation of difluoromethyl compounds has drawn
significant attention. Therefore, many reports have demon-
strated the difluoroalkylation of organic compounds.5 Tradi-
tionally, difluoromethyl compounds have been synthesized by
using numerous fluorine reagents, such as SF4, HF, DAST
(N,N-diethylaminosulfur trifluoride), and BAST (bis(2-
methoxyethyl)aminosulfur trifluoride).6 However, not only
are the reaction conditions strict, but the CF2R sources are also
volatile, unstable, and hazardous. Organic scientists make use
of electrophilic,7 nucleophilic,8 and radical9 approaches to
form CF2H-substituted compounds by using difluoromethylat-
ing reagents (Scheme 1). In1994, Chen first disclosed the
direct radical transfer of a CF2H unit using HCF2I as the
difluoromethylating reagent.9g In 2012, Baran’s group
presented Zn(SO2CF2H)2 as an efficient difluoromethylating
reagent for the radical difluoromethylation of heteroarenes.9b It
is known that difluoromethylenation with difluorocarbene is a
widely used straightforward approach to synthesis of
difluoromethyl compounds. Haszeldine and co-workers
reported the first difluorocarbene reagent ClCF2CO2Na in
fluorochemistry.10 From then on, many difluorocarbene
sources were utilized for organic chemistry.11 However,
many of the earlier reagents were hazardous. Recently, various
new difluorocarbene reagents have been demonstrated with
highly efficiency.12 Zhang’s group first established palladium/
nickel-catalyzed cross-coupling reactions with ClCF2H, which
was low cost and commonly applied to the industrial
material.5r,s Zhang’s group also used BrCF2CO2Et to form
diversified fluoroalkylated arenes.5u Both ClCF2H and
BrCF2CO2Et were used as difluorocarbene precursors and
catalytic transition-metal-difluorocarbene species were in-
volved, which had a great application value.
Recently, a variety of methodologies for synthesis of α-
CF2R-substituted ketones attracted great interest because of
the use of CF2R as a useful structural motif (Scheme 2).13
Received: December 4, 2020
Published: December 29, 2020
https://dx.doi.org/10.1021/acs.orglett.0c04021
© 2020 American Chemical Society
Org. Lett. 2021, 23, 508−513
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a
Scheme 2. Strategies for Synthesis of α-CF2R-Substituted
Table 1. Optimization of the Reaction Conditions
Ketones
b
entry
photocatalyst
fac-Ir(ppy)3
2a (equiv)
solvent
yield (%)
1
2
3
4
5
6
7
8
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
2
3
2
2
2
2
2
2
MeCN
DCM
DCE
toluene
DMF
DMAC
THF
DMSO
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
trace
trace
trace
trace
46
64
74
86
88
89
85
trace
trace
0
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
eosin Y disodium salt
4CzIPN
9
10
11
12
13
14
15
16
Ru(bpy)3Cl2
solvent Red 43
0
0
0
Previous reports presented various methods to synthesize α-
CF2R-substituted ketones (R = CO2Et),13f,g which need
multistep processes to form α-CF2H-substituted ketones.
Therefore, we visualized that photoredox catalysts can promote
radical difluoromethylation under mild conditions. Herein, we
report a new and highly efficient synthesis of α-CF2H-
substituted ketones using [Ph3PCF2H]+Br− (difluoromethyl-
triphenylphosphonium bromide) as a radical difluoromethylat-
ing reagent under visible-light photoredox catalysis. Qing’s
group first used fluoroalkylphosphonium salts as the
fluoroalkylating sources.9l−n The fluoroalkylating reagents
could be synthesized simply on a multigram scale from readily
available BrCF2CO2Et.14
We selected enol acetate (1a) as the model substrate and
phosphonium salt (2a) as the difluoromethylating source with
fac-Ir(ppy)3 under blue LED. As shown in Table 1, the solvent
presented a profound effect on the result of the procedure.
Only trace of α-CF2H-substituted ketone 3a was identified
after screening of acetonitrile, DCM (dichloromethane), DCE
(1,2-dichloroethane), and toluene (Table 1, entries 1−4).
Reactions in DMF (N,N-dimethylformamide), DMAC (N,N-
dimethylacetamide), and THF (tetrahydrofuran) provided 3a
in 46%, 64%, and 74% yields, respectively (Table 1, entries 5−
7). To our surprise, the yield of α-CF2H-substituted ketone 3a
was significantly increased upon switching to DMSO (dimethyl
sulfoxide) and NMP (N-methylpyrrolidone) (Table 1, entries
8 and 9). Then we investigated the effect of the amount of 2a.
It was found that 2 equiv of 2a showed the best result, giving
3a in 89% yield (Table 1, entry 10). Subsequently, we
examined four other photocatalysts (entries 12−15); photo-
catalyst eosin Y disodium salt was less effective since only trace
amount of α-CF2H-substituted ketone could be detected and
other photocatalysts could not provide the desired compound.
This reaction could not work either without fac-Ir(ppy)3 or in
the dark (entries 16 and 17). More detailed data refer to the
Supporting Information.
c
17
fac-Ir(ppy)3
a
Reaction conditions: 1a (0.2 mmol, 1 equiv), 2a, photocatalyst
(0.006 mmol, 3 mol %), solvent (2.0 mL), room temperature, 36 h,
b
c
argon atmosphere, 15 W blue LED. Isolated yield. In the dark.
Reactions of electron-donating groups (OMe, OBn, OAc,
OPh) were compatible with the present reaction system, which
gave the α-CF2H-substituted ketones without significant
decreased yields (3e: 71%, 3g: 76%, 3h: 65%, 3l: 64%). In
contrast, aliphatic enol acetates (e.g., cyclohept-1-en-1-yl
acetate) failed in this reaction conditions (3y). We found
that the substrate cyclohept-1-en-1-yl acetate was still left in
the reaction. Notably, o-phenyl-substituted product could not
be isolated because of self-dehydrofluorination in silica gel
column chromatography.15 Furthermore, dual-substituted
phenyl enol acetates (3m−3p) were all smoothly difluor-
omethylated to afford the desired products in 51−76% yields.
Weaker electron-withdrawing groups (3q−3s), such as F, Cl,
and Br, were all suitable substrates for this process and
generated α-CF2H-substituted ketones in 47%, 55%, and 43%
yields, respectively. However, a strongly electron-withdrawing
NO2 group at the para-position was not tolerated under the
reaction conditions (3t). These results indicated that electron-
withdrawing groups made the efficiency of the reaction
decreased. In addition, cyclic and branched enol acetates
were explored under the reaction conditions. Cyclic enol
acetate could work well, achieving 3u in 61% yield. α-Branched
enol acetate generated the corresponding product 3v in 62%
yield. The scope of this difluoromethylation method was then
tested on heteroaromatic substrates. We found that these
reactions were sensitive to the heteroaryl enol acetates (3w and
3x), giving 50% and 35% yields, respectively.
To examine the utility of difluoromethylation, we performed
a gram-scale reaction and some synthetic transformations of α-
CF2H-substituted ketones (Scheme 4). As shown in Scheme
4a, the gram-scale reaction of 1z and [Ph3PCF2H]+Br−
successfully afforded 1.045 g of 3z in 66% yield. Subsequently,
synthetic applications of 3b were carried out. Scheme 4b shows
the reduction of 3b with NaBH4 in ethanol to give the
corresponding CF2H-containing alcohol 4 in 95% yield. As
With the optimized conditions in hand (Table 1, entry 10),
we then investigated the generality of this radical difluor-
omethylation with numerous aromatic enol acetates (Scheme
3). Initially, various para- and meta-substituted phenyl enol
acetates were subjected to this new catalytic protocol and
furnished α-CF2H-substituted ketones in good yields (3b−3l).
509
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a
Scheme 3. Scope of Substrates
Scheme 4. Gram-Scale Reaction and Synthetic
Transformations
Scheme 5. Radical-Trapping Experiments
a
Reaction conditions: 1a (0.2 mmol, 1 equiv), 2a (0.4 mmol, 2
equiv), fac-Ir(ppy)3 (0.006 mmol, 3 mol %), NMP (2.0 mL), room
temperature, 36 h, argon atmosphere, 15 W blue LED, isolated yield.
shown in Scheme 4c, cyanohydrin derivative 5 was formed in
90% yield via silylcyanation.16 Amidation of 5 led to the CF2H-
containing amide product 6 in 68% yield. It is known that α-
CF2H-substituted ketones are unstable under basic reaction
conditions,9o,15 and easily go through defluorination via F
elimination. Therefore, when aniline reacted with 3d,
dehydrofluorination product 7 was obtained in 79% yield
(Scheme 4d). 1-Phenylvinyl trifluoromethanesulfonate 8 was
selected as a substrate. Product 3a was formed in 27% isolated
yield under standard conditions (Scheme 4e). Then the
reaction time was extended to 72 h, which only made product
3a increase slightly in Scheme 4f (31% isolated yield). Most of
the 1-phenylvinyl trifluoromethanesulfonate was left in the
reaction. Trimethyl((1-phenylvinyl)oxy)silane was also used as
substrate, and product 3a was obtained in 13% 19F NMR yield
(Scheme 4g). Most of trimethyl((1-phenylvinyl)oxy)silane was
converted to phenylacetophenone under our reaction con-
ditions.
radical scavenger BHT (butylated hydroxytoluene) was added
under the standard conditions as well. α-CF2H-substituted
ketone 3a was reduced to 45% 19F NMR yield, which showed a
radical route was included (Scheme 5b).
Based on previous mechanistic studies and our experiment
results,17 we propose a possible reaction mechanism in Scheme
6. First, photocatalyst fac-IrIII(ppy)3 gives reducing excited-
state fac-IrIII(ppy)3* under visible light irradiation. fac-
IrIII(ppy)3* is able to reduce[Ph3PCF2H]+Br− to a CF2H
radical. Meanwhile, fac-IrIII(ppy)3* is oxidized to fac-IrIV(ppy)3
via a SET process.18 Next the radical intermediate A is formed
via the addition of CF2H radical to substrate 1. While fac-
IrIV(ppy)3 and intermediate A meet together, fac-IrIII(ppy)3 is
regenerated through a second SET procedure in next catalytic
cycle. Finally, nucleophilic species (e.g., bromide ion) attack
the intermediate B, and target product 3 is generated in the
reaction system. Mechanistic experiments and Stern−Volmer
fluorescence quenching experiments were conducted as shown
in the Supporting Information.
We conducted mechanistic experiments involving radical
species to make sure difluoromethylation proceeded through a
radical-type process. We added a radical scavenger TEMPO to
the reaction to perceive a pathway involving radical species
(Scheme 5a). α-CF2H-substituted ketone 3a was decreased to
12% 19F NMR yield (Scheme 5a). TEMPO−CF2H was
detected via 19F NMR. To validate the radical process, another
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Letter
Baoxiang Zhu − College of Chemistry and Institute of Green
Catalysis, Zhengzhou University, Zhengzhou 450001, P.R.
China
Scheme 6. Proposed Reaction Mechanism
Bingbing Dong − College of Chemistry and Institute of Green
Catalysis, Zhengzhou University, Zhengzhou 450001, P.R.
China
Li Cheng − College of Chemistry and Institute of Green
Catalysis, Zhengzhou University, Zhengzhou 450001, P.R.
China
Yunpu Li − College of Chemistry and Institute of Green
Catalysis, Zhengzhou University, Zhengzhou 450001, P.R.
China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c04021
In summary, we have successfully developed a photoredox-
catalyzed radical-type process of aromatic enol acetates with
difluoromethyl triphenylphosphonium bromide to prepare α-
CF2H-substituted ketones. The reaction can tolerate numerous
functional groups in higher yields than previous reports.
Moreover, this methodology provides a high-efficient process
with moderate to good yields, mild conditions, and easily
prepared substrates. The present photocatalytic difluorome-
thylation is scaled up to gram scale simply. Additionally, the
radical pathway is suggested by radical-trapping experiments.
Compared with previous reports of the synthesis of α-CF2H-
substituted ketones, our approach not only does not rely on
external oxidants but also employs difluoromethyltriphenyl-
phosphonium bromide as the difluoromethylation reagent,
which is easily synthesized and commercially available. As
CF2H is an essential functional group, this reaction has broad
applications in organic synthesis and pharmaceuticals.
Author Contributions
∥Z.F. and B.Z. contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by grants from the Top Youth Talent
Fund of Zhengzhou University and The State Key Laboratory
of Bio-organic and Natural Products Chemistry, CAS
(SKLBNPC18440).
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ASSOCIATED CONTENT
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The Supporting Information is available free of charge at
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CCDC 2052322 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
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Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Authors
■
Junliang Wu − College of Chemistry and Institute of Green
Catalysis, Zhengzhou University, Zhengzhou 450001, P.R.
China; orcid.org/0000-0001-5123-5051; Email: wujl@
zzu.edu.cn
Zechao Wang − Division of Molecular Catalysis & Synthesis,
Henan Institute of Advanced Technology, Zhengzhou
University, Zhengzhou 450001, P.R. China; orcid.org/
0000-0001-6472-5324; Email: zechaowang@zzu.edu.cn
Authors
Zengqiang Feng − College of Chemistry and Institute of Green
Catalysis, Zhengzhou University, Zhengzhou 450001, P.R.
China
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