Running title
Chin. J. Chem.
chemical transformation, the isolated yields of corresponding
products were also good, and most importantly, the product E/Z
ratio was always high (Scheme 3, 4a-4g). Enamide substrates with
thiophene as a substituent also showed good adaptability. They
were all smoothly transformed into the desired product. Although
the separation yield was not very high, the E/Z ratio of the prod-
uct was still very good (Scheme 3, 4h-4i). We can see that the
Heck reaction involving palladium-catalyzed fluoroolefins exhibits
good substrate adaptability, whether it is a heterocyclic or aro-
matic amine substrate.
mediately afterwards, we performed a double bromination reac-
tion on this 1,3-butadiene fragment. The surprising result of the
experiment was that 2 bromines were also introduced into the
benzene ring (Scheme 5, path b). Structural analysis indicated that
the addition of this butadiene was a 1, 4 addition. In the third
step, we reduced the double bond with the neutral reducing agent
sodium borohydride, and the results showed that the double bond
at the 1, 2 position was reduced to a saturated bond (Scheme 5,
path C). The isolated yield was also relatively good, and this result
is very helpful for the selective reduction of dienes in the future.
Scheme 3 Substrate scope of heterocyclic amides. a
Scheme 5 Functional groups modifications.
H
N
mol%)
O
Pd(acac)2 (3
H
wt%)
Pd/C
(10
H2 10 atm)
Cl
N
CF3
mol%)
P(2-furanyl)3 (3
R
Het
(
A
path
path
path
R
Het
O
O
NH
CF3
KHCO
eq)
O
3 (2.0
MeOH, 70 o 4 h
DMF, 100 o 12 h
C,
C,
CF3
7
O
isolated
97%
Br
H
yield:
H
H
N
CF3
N
CF3
N
CF3
Br
O
O
Br
O
O
O
N
N
4b
N
CF3
Br2
HN
O
B
O
NH
4c
4a
CCl4
58% 99:1)
(>
64% 99:1) b
70% 99:1)
(>
(>
Br
isolated
8
H
N
H
N
CF3
H
N
57%
CF3
yield:
CF3
F
CF3
O
O
O
Cl
N
F
N
O
3a
N
NaBH4
THF
C
O
4e
4d
NH
4f
>
46%
99:1)
57%
99:1)
(
(>
38% 99:1)
(>
9
F3C
H
H
N
H
N
isolated
55%
yield:
N
CF3
CF3
CF3
O
O
N
O
S
S
COOMe
COOMe
4h
4i
4g
52% 99:1)
(>
>
43% 94:6)
(
68%
99:1)
(
Conclusions
a Reaction conditions:heterocyclic amide
2.0 mmol), DMF
mmol), 2
mmol),
3 mol%),
P(2-furanyl)3
ratio in bracket).
(1.0
(2.0
Pd(acac)2
(
100 o 12 h.b Isolated
C,
(3 mol%),KHCO3
(
(2.0 mL),
yield (E/Z
In summary, we have developed a new strategy to easily syn-
thesize 4-trifluoromethylated 1,3-butadiene through the
Pd(0)-catalyzed fluorination Heck reaction. More importantly, the
conversion process has the advantages of good regioselectivity
and chemical selectivity, and good tolerance of the functional
group of the substrate. It is a simple and effective synthesis
method. We also conducted a series of derivatization experiments
on the synthesized compounds and obtained some useful prod-
ucts. We believe that the discovery of this reaction will play an
important role in the synthesis of 4-trifluoromethylated
1,3-butadienes in the future.
Apart from the preparation of novel 4-trifluoromethylation
of 1,3-butadienes, we envisioned that this methodology would
be amenable to more biologically relevant substrates. To demon-
strate this potential, one case study was performed:
3-aminoestrone, a versatile precursor of various biologically active
compounds to treat hormone-sensitive diseases such as prostate
and breast cancers, [36] led to 4-trifluoromethylation of
1,3-butadienes 6 in an isolated yield of 75% (Scheme 4).
Scheme 4. Application example.
Experimental
O
O
mol%)
Pd(acac)2 (3
The reaction was carried out in an autoclave containing a 25.0
mL glass reaction tube. Pd(acac)2 (0.03 mmol), ligand (0.03 mmol),
acrylamide (1.0 mmol), (E)-1-chloro-3,3,3-trifluoroprop-1-ene (2.0
mmol), KHCO3 (2.0 mmol), DMF (2.0 mL) were added to the tube.
The tube was placed in the autoclave. Once sealed, the autoclave
was purged three times with nitrogen, and then heated in an oil
bath at 100 °C for 12 h. After the reaction, the autoclave was then
cooled to room temperature and the crude product was purified
by column chromatography on silica gel using a mixture of ethyl
acetate and petroleum ether as eluent to give the following com-
pounds.
3 mol%)
(
P(2-furanyl)3
H
H
HN
H
H
KHCO
3 (2.0
eq)
HN
DMF
mL)
(2.0
100 o 12 h
O
C,
F
3C
O
5
6
isolated
yield:75%
Finally, we also carried out Functional groups modifications
on the obtained 4-trifluoromethylated-1,3-allene. We took 3a as
the research object (Scheme 5) and first used it to perform a sim-
ple hydrogenation reaction. Under the action of a palladi-
Information
um-carbon catalyst, it can be simply hydrogenated and reduced to
terminal trifluoromethylated valeramide (Scheme 5, path A). Im-
Chin. J. Chem. 2021, 39, XXX-XXX
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