Palladium-Catalyzed Benzodifluoroalkylation of Alkynes: A Route to Fluorine-Containing 1,1-Diarylethylenes

Article abstract of DOI:10.1002/adsc.201701569

A palladium(0)-catalyzed three-component reaction of 2-iodo-2,2-difluoroacetophenones, alkynes and arylboronic acids is introduced for the synthesis of 1-benzoyldifluoromethyl-2,2-diphenylethylenes in good yields and with excellent stereoselectivity. The

Full text of DOI:10.1002/adsc.201701569

Title: Palladium-Catalyzed Benzodifluoroalkylation of Alkynes: A Route
to Fluorine-Containing 1,1-Diarylethylenes
Authors: Junqing Liang, Guozhi Huang, Peng Peng, Tianyu Zhang,
Jingjing Wu, and Fanhong Wu
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10.1002/adsc.201701569
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Palladium-Catalyzed Benzodifluoroalkylation of Alkynes: A
Route to Fluorine-Containing 1,1-Diarylethylenes
Junqing Liang,a Guozhi Huang,a Peng Peng,a Tianyu Zhang,a Jingjing Wu,a,b,* and
Fanhong Wua, *
a School of Chemical and Environmental Engineering, Shanghai Institute of Technology, Shanghai 201418, People’s
Republic of China
E-mail: wujj@sit.edu.cn; wfh@sit.edu.cn
b Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
Shanghai 200032, China
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
boronic acids, and perfluoroalkyl iodides for quickly
Abstract.
A
palladium(0)-catalyzed three-component
reaction of 2-iodo-2,2-difluoroacetophenones, alkynes and access to trisubstituted or tetrasubstituted alkenes
arylboronic acids is introduced for the synthesis of 1-
benzoyldifluoromethyl-2,2-diphenylethylenes in good
yields and with excellent stereoselectivity. The 1-
containing perfluoroalkyl groups have been reported
by Nevado[9a, 9b] and Chaładaj[9c] groups, respectively.
Liang used ethyl difluoroiodoacetate as
a
benzoyldifluoromethyl-2,2-diphenylethylene
products
difluoroalkylation agent in multicomponent reaction
to construct a variety of gem-difluoroalkylated
alkenes in the present of transition-metal catalysts.[9d-
synthesized through a radical reaction process are versatile
synthons for the construction of various fluorine-containing
compounds, which have antiproliferative activity on human
tumor cells.
f]
However, direct introduction of more complicated
CF2-containing
moieties
into
alkynes
via
multicomponent reaction is still a challenge task.
Spontaneous carbonylation
Keywords: multicomponent reactions; 2-iodo-2,2-
difluoroacetophenones; 1-benzoyldifluoromethyl-2,2-
diphenylethylenes; palladium; antiproliferative activity
and
perfluoroalkylation/difluoroalkylation reactions have
been achieved via the Pd-catalyzed four-component
reactions with iodopolyfluoroalkanes, alkynes,
boronic acids and carbon monoxide.[10] We recently
focused on the introduction of benzoyldifluoroalkyl
The introduction of gem-difluoroalkyl motifs into
molecules can improve their physicochemical and
biological properties.[1] Consequently, the efficient
synthesis of gem-difluoroalkylated compounds has
attracted increasing attention.[2] However, most
research has focused on the gem-difluoroalkylation of
aromatic compounds,[3] with methods to afford gem-
difluoroalkylated alkenes much less explored.
Traditionally, the synthesis of gem-difluoroalkylated
alkenes was achieved by the difluoroalkylation of
alkenyl halides,[4] ethyl bromodifluoroacetate through
groups
to
different
scaffolds
by
using
iododifluoromethyl ketones as difluoroalkylation
agents.[7, 11] We have accomplished the synthesis of 1-
benzoyldifluoromethyl-2,2-diphenylethylenes
through
multistep
reactions
involving
iododifluoromethylation of alkyne using 2-iodo-2,2-
difluoroacetophenone followed by cross-coupling
reaction with phenylboronic acid.[7] On the basis of
previous work, we proposed that spontaneous
introduction of the benzoyldifluoroalkyl group and an
aryl group into alkynes could be achieved in a one-
pot operation. Herein, we report a Pd(0)-catalyzed
cross-coupling reactions with alkenes or radical
[5]
addition reaction of alkynes,
Copper or iron
three-component
difluoroacetophenones, alkynes and arylboronic acids
producing 1-benzoyldifluoromethyl-2,2-
reaction
of
2-iodo-2,2-
catalyzed decarboxylative difluoromethylations of
alkenes.[6] Our group has reported iododifluoromethyl
ketones as alternative difluoroalkylation agents to
generate gem-difluoroalkylated alkenes via radical
reactions with terminal and internal alkynes.[7]
diphenylethylenes in a highly stereoselective manner
(Scheme 1).
Multicomponent reactions have proven to be an
efficient and powerful tool in organic synthesis [8] and
have been applied to synthesize series of
fluoroalkylated unsaturated compounds successfully
in recent years.[9] Pd-catalyzed three-component
reactions of terminal alkynes or internal alkynes,
1
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10.1002/adsc.201701569
Advanced Synthesis & Catalysis
Scheme 1. The synthesis of benzoyldifluoro-1,1-
diarylethylene
donating groups in the aromatic ring were well
tolerated and gave the expected trisubstituted
benzoyldifluoro alkenes 2a−2c in high yield as well
as halogen atoms (2d and 2e). Whereas, the presence
We began the optimization of reaction conditions
by selecting the addition of 2,2-difluoro-2-iodo-1-
phenylethanone 1a and phenylboronic acid to
ethynylbenzene as a model reaction. Gratifyingly, the
reaction proceeded smoothly in toluene with K2CO3
as a base catalyzed by either Pd(0) or Pd(II) at 60°C
under nitrogen, leading to the desired product 2,2-
of
electron-withdrawing
group,
such
as
trifluoromethyl, brought negative influence in the
reaction efficiency, resulting in no corresponding
product but the recovery of starting materials. When
2,2-difluoro-2-iodo-1-(thiophen-2-yl)ethan-1-one 1f
was employed in the three-component reaction, the
expected product 2f was obtained in moderate yield.
difluoro-1,4,4-triphenylbut-3-en-1-one
2a
in
moderate yields (Table 1, entries 1 and 2). Since
Pd(PPh3)4 is cheaper and more available than
PdCl2(PPh3)2, we chose Pd(PPh3)4 as optimized
catalyst. Control reaction demonstrated that no
reaction occurred in the absence of base (Table 1,
entries 3). Screening of base and solvents (Table 1,
entries 4-8) indicated that K3PO4 and toluene were
the most suitable base and solvent (Table 1, entry 5).
Increasing or decreasing the temperature failed to
improve the yield of product 2a (Table 1, entries 9-
10). When the catalyst loading was reduced to 4
mol%, desired product 4a was observed in a
decreased yield (Table 1, entry 11). Consequently,
the optimized reaction conditions were confirmed by
using Pd(PPh3)4 as catalyst in the presence of K3PO4
in toluene at 60°C under nitrogen (Table 1, entry 5).
Scheme 2. Scope of 2-iodo-2,2-difluoroacetophenones.
Table 1. Optimization of the reaction conditions for
difluoroalkylation of alkynes.[a]
The scope of alkynes and arylboronic acids were
explored next (Scheme 3). Aryl alkynes bearing both
electron-donating as well as electron-withdrawing
groups were tested in combination with 1a and
phenylboronic acid providing the corresponding 1-
benzoyldifluoromethyl-2,2-diphenylethylenes (3a−3i)
in good yields with perfect stereocontrol as single
isomers. X-ray diffraction analysis of compound 3f
confirmed the structural assignment of the reaction
Entry
Catalyst
(mol%)
base
solvent
Yield
(%)[b]
1
Pd(PPh3)4 (5)
K2CO3
toluene
toluene
toluene
toluene
toluene
63
50
0
60
89
25
14
0
products
(Figure
1).[12]
2-Ethynyl-6-
2
PdCl2(PPh3)2 (5) K2CO3
methoxynaphthalene was found to undergo the
reaction smoothly to give the corresponding product
3i in 64% yield. However, alkyl-substituted alkynes
were not suitable substrates. To our delight, the
internal alkyne prop-1-yn-1-ylbenzene is also a
competent substrate, providing the corresponding
product 3j in low yield. A number of arylboronic
acids were investigated next. In general, electronic
properties of substituents on the phenyl group of
boronic acids did not have significant effect on the
reaction efficiency. The corresponding products
3k−3t were obtained in moderate to good yields with
excellent stereoselectivity. Also, the naphthyl and
thienyl substrates worked well and gave the
corresponding products 3s and 3t in moderate yields.
It is worth mentioning that the alkyne with a 3,4,5-
trimethoxy substituent on the aryl group participated
efficiently in the reaction to give the corresponding
product 3u in 69% yield.
3
4
5
6
7
8
Pd(PPh3)4 (5)
Pd(PPh3)4 (5)
Pd(PPh3)4 (5)
Pd(PPh3)4 (5)
Pd(PPh3)4 (5)
Pd(PPh3)4 (5)
Pd(PPh3)4 (5)
Pd(PPh3)4 (5)
Pd(PPh3)4 (4)
-
CsCO3
K3PO4
K3PO4 1,4-dioxane
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
THF
CH3CN
toluene
toluene
toluene
9[c]
10[d]
11
57
70
60
[a] Reaction conditions: 1a (1.0 mmol), ethynylbenzene (1.2
mmol), phenylboronic acid (1.0 mmol), toluene (2.0 ml),
12h, under N2.
[b] GC yield.
[c] Performed at 40 ºC.
[d] Performed at 80 ºC.
With the optimized reaction conditions in hand, we
set out to explore the scope and generality of the
three-component reaction. First, idifferent 2-iodo-
2,2-difluoroacetophenones were investigated in
combination
with
ethynylbenzene
and
Electron-
phenylboroaaaanic acid (Scheme 2).
2
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10.1002/adsc.201701569
Advanced Synthesis & Catalysis
Scheme 4. Gram-scale reaction.
The benzoyl group in the products from the three-
component reaction is a versatile functional group,
which could be readily transformed to a variety of
interesting fluorinated moiety. New methods to
introduce difluoromethyl (-CF2H) group or
tetrafluoroethylene (-CF2CF2-) group are high
demand due to their wide application in
pharmaceutical and materials.[13] Hartwig had
reported the synthesis of (difluoromethyl)benzene via
Haller-Bauer
difluoroacetophenone.[14]
transformations several
reaction
of
α-phenyl-α,α-
in the
Hence,
2-difluoromethyl-1,1-
diarylethylenes 4 have been readily synthesized from
debenzoylation of compounds 2a, 3a and 3c
respectively by using Hartwig’s procedure (Scheme 5,
eq. 1). Moreover, much attention has been paid to the
development of new synthetic method for the
synthesis of compounds contain -CF2CF2- fragment.
[15]
In this work, we efficiently obtained the -CF2CF2-
eoxofluorination of carbonyl group in compound 2a
(Scheme 5, eq. 2). These two reactions demonstrate
the wide and valuable application of the three-
component reaction in synthetic organofluorine
chemistry. More transformation was achieved
through the conversion of carbonyl group into
hydroxyl group (Scheme 5, eq. 3), providing
additional evidence for the flexibility of this
methodology.
Scheme 3. Scope of alkynes and arylboronic acids.
Figure 1. Crystal structure of compound 3f.
Scheme 5. Further transformation reactions.
We also carried out a gram-scale reaction which
gave product 2a in high yield of 80%. This result
could be achieved by reducing the amount of Pd
catalyst to 3 mol% of substrate 1a (Scheme 4).
Considering that the trisubstituted alkene scaffold
is a key structure found in numerous nature products
as well as pharmaceuticals,[16] we speculated that the
fluorinated trisubstituted alkenes 2 and 3 obtained
from this three-component reaction might have
potential antitumor activity. The antiproliferative
3
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10.1002/adsc.201701569
Advanced Synthesis & Catalysis
activity of the selected compounds was evaluated on
six human tumor cells, namely, HeLa, A549, HTC-
116, HepG2, MKN45 and MGC-803 by using
Combretastatin A-4 (CA-4) as the positive control.
The results are summarized in Table 2 and indicated
diarylethylene
scaffold
present
certain
antiproliferative activity on the human tumor cells
and could be used for developing potential new
antitumor drugs via further structure-activity
relationship study.
that
compounds
with
benzoyldifluoro-1,1-
Table 2 Inhibitory activities of selected compounds on cell proliferation.
Compound
Cellular IC50 (μmol/mL)
HeLa
76.23
143.10
14.32
77.42
91.63
17.56
11.33
A549
452.30
14.57
28.60
396.10
115.40
36.90
5.99
HTC-116
79.54
22.99
23.64
73.36
126.60
18.58
9.00
HepG2
29.99
13.49
49.49
63.06
83.75
16.68
16.04
MKN45
57.31
49.74
35.30
73.98
95.09
78.32
3.42
MGC-803
84.81
39.36
34.61
79.63
86.62
19.89
1.76
2b
2c
3f
3j
3n
3t
CA-4
Three control experiments were designed to
rationalize the reaction pathway. First, we added the
radical
scavenger
2,2,6,6-tetramethyl-1-
piperidinyloxy (TEMPO) to the three-component
reaction under standard conditions. No desired
product 2a was obtained; instead, compound 7 and 8
was detected in 56% and 27% yield respectively (19F
NMR δ -55.70 for compound 1a, δ -71.76 for
compound 7, δ -121.79 for compound 8, see the
Supporting Information) (Scheme 6, eq. 1). The result
seems to support that a gem-difluoroalkyl radical
addition pathway might be involved in this process.
Then, the reaction of compound 1a with
ethynylbenzene in the absence of phenylboronic acid
Scheme 6. Control experiments.
were
carried
out
to
check
whether
iododifluoroalkylation product 9 could be afforded
under our standard condition (Scheme 6, eq. 2). We
observed the formation of vinyl iodide 9 in low yield.
However, the addition of a catalytic amount of
phenylboronic acid (10 mol%) led to the formation of
three-component reaction product 2a with trace
amount of vinyl iodide 9 (Scheme 6, eq. 3). Moreover,
the vinyl iodide 9 was independently obtained
and used to react with phenylboronic acid under
standard conditions. The expect Suzuki coupling
product 2a was obtained in high yield (Scheme 6,
eq. 4). Additionally, small amount (ca. 19%) of vinyl
iodide intermediate 9 was observed at the beginning
of the reaction gradually decreases with time. These
results indicated that the vinyl iodide 9 might be
formed in the one-pot process.
On the basis of the control experiments and
literature data,[9] we proposed a reaction mechanism
shown in Scheme 7. As depicted, Pd(0) species reacts
with benzoyldifluoroalkylation agent 1 to form
benzoyldifluoroalkyl radical and Pd(I) species A
through an iodine atom transfer process. The
benzoyldifluoroalkyl radical adds to the alkyne
moiety to generate the vinyl radical B, which could
be transferred to the corresponding vinyl iodide C
via atom transfer of iodine from the Pd(I) species
A accompanied by regenerative Pd(0) species. Then,
the vinyl iodide intermediate C is capable of
coupling with boronic acid through the typical
oxidative addition, transmetalation and reductive
elimination pathway to form the Suzuki coupling
product 1-benzoyldifluoromethyl-2,2-diphenylethyl
enes while regenerating Pd(0).
In conclusion, we have successfully developed a
Pd(0)-catalyzed three-component difluoroalkylation
of alkynes with 2-iodo-2,2-difluoroacetophenones
and (hetero)arylboronic acids, generating 1-
benzoyldifluoromethyl-2,2-diphenylethyl enes with
complete stereocontrol. The reaction provides a
general method for the construction of various gem-
difluoroalkylated
compounds
in
excellent
stereoselectivities. Bioactivity test showed that the
compounds with benzoyldifluoro-1,1-diarylethylene
scaffold could be developed as potential antitumor
drug. Preliminary mechanistic investigation indicated
that the formation of the vinyl iodide intermediate
was involved in this radical-mediate transformation.
4
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10.1002/adsc.201701569
Advanced Synthesis & Catalysis
Further synthetic application of the three-component
reaction and structure-activity relationship study of
the target compounds are currently underway in our
laboratory.
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Scheme 7. Plausible mechanism.
Experimental Section
General procedure for one-pot Synthesis of
Benzoyldifluoro-1,1-Diarylethylenes 2: An oven-dried
tube was charged with Phenylboronic acid (1.0 mmol, 1.0
equiv), K3PO4 (2.0 mmol, 2.0 equiv), and Pd(PPh3)4 (0.05
mmol, 5 mol %). The tube was evacuated and backfilled
with nitrogen (repeated three times). Then, 2-iodo-2,2-
difluoroacetophenones 1 (1.0 mmol, 1.0 equiv) dissolved
in toluene (2.0 mL), and Phenylacetylene (1.2 mmol,
1.2equiv) were added into the tube. The reaction mixture
was stirring at 60 °C for 6-12 h. After completion of the
reaction (as indicated by TLC), the reaction was quenched
with water, and the reaction mixture was extracted with
ethyl acetate (3*10 mL). The combined organic layers
were washed with saturated brine, dried over Na2SO4,
concentrated in vacuum and the crude residue was purified
by silica-gel column chromatography (petroleum
ether/EtOAc = 100/1) to afford the desired product 2.
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10.1002/adsc.201701569
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