Organic Letters
Letter
step- and atom-economic means to access various fascinating
With the optimized reaction conditions established, we first
investigated the scope of various arylboronic acids (Scheme 2).
9
CF -containing compounds. Fluoroalkylation−borylation of
2
alkynes has also been reported by Zhang’s group, and the
mechanistic studies suggested that trans-fluoroalkylated alkenyl
a
Scheme 2. Substrate Scope of Arylboronic Acids
10
iodide is a key intermediate. Meanwhile, radical cascade of
phenol-linked 1,6-enynes has been one of the most efficient
routes for the construction of functionalized benzofuran
1
1
derivatives. Inspired by these advances and our previous
1
2
work, we envisaged that difluoroalkylated benzofuran
derivative would be constructed via palladium-catalyzed
cascade difluoroalkylation-arylation of 1,6-enyne and difluor-
oalkylated benzofuran could be further afforded through an
13
isomerization process catalyzed by Fe(OTf) (Scheme 1c).
3
Furthermore, we expected this methodology could be extended
to the synthesis of difluoroalkylated benzothiophene and
indole derivatives.
To test the hypothesis, our study was carried out by
employing phenol-linked 1,6-enyne 1a as the model substrate,
ethyl difluoroiodoacetate (1.5 equiv) as the fluoroalkylating
reagent, and phenyl boronic acid 2a (2.0 equiv) as the coupling
partner in the presence of Cs CO3 (2.0 equiv) and
2
PdCl (PPh ) (10 mol %) in 1,4-dioxane at 80 °C for 22 h.
2
3 2
Gratifyingly, the desired product 3a was obtained in 55% yield
(Table 1, entry 1). In order to improve the yield, a series of
a
Table 1. Optimization of Reaction Conditions
a
Yields of the isolated products. The Z/E values were determined by
F NMR and H NMR analysis. DCE as the solvent. The yield was
1
9
1
b
c
entry
catalyst
ligand
PCy3
base
solvent
yield (%)
obtained on a 3.5 mmol scale.
1
2
3
4
5
6
7
8
9
PdCl (PPh )
Cs CO
2
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
DCE
55
47
65
82
0
2
3
2
2
2
3
3
3
PdCl (PPh )
Cs CO
2
2
3
PdCl (PPh )
PPh3
Cs CO
2
2
3
PdCl (PPh )
DPE-phos
DPE-phos
DPE-phos
DPE-phos
DPE-phos
DPE-phos
DPE-phos
Cs CO
2
2
3
2
3
To our delight, substrates with both electron-donating and
electron-withdrawing substituents at the para-position of the
phenyl ring were successfully aryldifluoroalkylated. For
example, methyl, methoxy, tert-butyl, nitrile, formyl, trifluor-
omethyl, trifluoromethoxy, and halide (F, Cl and Br) groups
were well tolerated, affording the corresponding products 3b−
3k in moderate to high yields. The structure and the Z/E
conformation of 3k was implied by X-ray crystal structure
analysis. m-Methyl-, -bromo-, and -chloro-substituted arylbor-
onic acids could also generate the desired products 3l−3n in
Cs CO
2
3
PdCl (PPh )
3 2
0
2
PdCl (PPh )
K CO
46
trace
82
78
2
3
2
2
3
PdCl (PPh )
Na CO
2
2
3
2
3
PdCl (PPh )
Cs CO
2
2
3
2
3
1
0
PdCl (PPh )
Cs CO
2
MeCN
2
3
2
3
a
Reaction conditions: 1a (0.2 mmol), 2a (0.4 mmol), ethyl
difluoroiodoacetate (0.3 mmol), catalyst (10 mol %), ligand (20
mol %), base (0.4 mmol) in solvent (2.0 mL), stirring at 80 °C under
Ar for 22 h. Isolated yields.
70−79% yields. In addition, 2-naphthylboronic acid and 3-
thiopheneboronic acid were also capable and produced the
target products 3o and 3p in 46% and 45% yields, respectively.
Notablely, the reaction of arylboronic acids with thiophenolic
1,6-enyne and ethyl difluoroiodoacetate proceeded smoothly
to deliver the desired benzo[b]thiophene derivatives 3q and 3r
in good yields, respectively.
Next, the scope of different phenolic 1,6-enyne derivatives
was evaluated, and the results are summarized in Scheme 3.
Various substituent groups on the benzene ring attached at the
terminal alkyne were first examined under the optimized
conditions, and most of them were compatible with the
protocol. For the para-position of the phenyl ring, substrates
substituted with electron-donating groups including methyl,
ethyl, phenyl, tert-butyl, and methoxy smoothly converted into
products 3ba−3fa in 51−88% yields. Gratifyingly, compounds
with electron-withdrawing groups such as acetyl, ether, nitrile,
and trifluoromethyl also afforded the corresponding products
ligands were screened, and the results indicated that the
product 3a could be isolated in a high yield of 82% by using
DPE-phos as the ligand (Table 1, entries 2−4). Better results
were not observed when other Pd catalysts such as Pd(TFA) ,
2
2
2
(
occurred in the absence of a catalyst or a base, illustrating their
necessity in this transformation (Table 1, entries 5 and 6, see
the SI for details). Switching Cs CO to other bases resulted in
2
3
a lower yield (Table 1, entries 7 and 8, see the SI for details). A
brief survey of the solvents revealed that DCE was also suitable
solvent for the reaction as the same yield of 3a was observed
(Table 1, entries 9 and 10, see the SI for details). Reducing the
lower yield (see the SI for details).
B
Org. Lett. XXXX, XXX, XXX−XXX
Zhang, Pengbo
