Published on the web December 1, 2012
1619
£-Selective Addition to 1,1-Difluoroallenes: Three-component Coupling
Leading to 2,2-Disubstituted 1,1-Difluoroalkenes
Kohei Fuchibe, Mikiko Ueda, Misaki Yokota, and Junji Ichikawa*
Division of Chemistry, Faculty of Pure and Applied Sciences, University of Tsukuba,
Tsukuba, Ibaraki 305-8571
(Received September 14, 2012; CL-120951; E-mail: junji@chem.tsukuba.ac.jp)
M
E
1,1-Difluoroallenes underwent £-selective addition with
2
Nu–M
E–X
CF2
CF2
CF2
3
alkylcopper reagents. The resulting 2,2-difluorovinylcopper
intermediates were captured by electrophiles or subjected to
palladium-catalyzed coupling to give 2,2-disubstituted 1,1-
difluoroalkenes in good yield.
Nu
Nu
-addition
R
R
R
Scheme 1. Three-component coupling leading to 1,1-difluoro-
alkenes.
CF2
C
CH2
1,1-Difluoroalkenes are useful as synthetic intermediates
and components of pharmaceuticals and agrochemicals. They
incorporate an electrophilic and polarized double bond as well as
vinylic fluorines with leaving group ability,1 which leads them
to react with nucleophiles rather than electrophiles at the vinylic
CF2 carbon to give monofluorinated alkenes (SNV reaction).2,3
The difluoroalkene moiety is also used for the development of
potential mechanism-based enzyme inhibitors4 and as a bio-
isostere for the carbonyl group, which leads to enhancement of
the biological activities of the original molecules.5 In spite of the
importance of difluoroalkenes, methods for their synthesis,
especially routes to 2,2-disubstituted 1,1-difluoroalkenes, are
still limited.6,7
Recently, we reported synthetic methods for the preparation
of 1,1-difluoroallenes, in which difluorovinylidenation of car-
bonyl groups were readily effected to provide easy access to
these allene derivatives arrayed with a variety of substituents.8
On the basis of these results, we planned a new route for the
synthesis of disubstituted 1,1-difluoroalkenes (Scheme 1). Nu-
cleophilic addition of an organometallic species (Nu-M) at the
£-position of 1,1-difluoroallenes would give 2,2-difluorovinyl-
metal intermediates. Capture of these intermediates by electro-
philes (E-X) would provide the desired 2,2-disubstituted 1,1-
difluoroalkenes bearing newly introduced substituents on the C2
(E) and C3 (Nu) positions. However, organometallic species
normally attack the ¡-position of difluoroallenes to give the SNV
products, monofluoroallenes,9 and no £-selective addition of a
carbanion equivalent to a 1,1-difluoroallene has been reported.10
In order to examine the possibility of the nucleophilic
addition at the £-position, a DFT calculation was performed on
1,1-difluoroallene (Figure 1). The results suggested that 1,1-
difluoroallene has a higher LUMO coefficient at the £-carbon
(0.693) than at the ¡-carbon (0.275), whereas a positive
electrostatic charge is localized at the ¡-carbon (+0.272), and
a negative charge is indicated at the £-carbon (¹0.341).11 The
desired £-attack, therefore, might be accessible under orbital-
controlled conditions.
α
β
γ
C
C
β
C
γ
α
Coefficient of LUMO:
Electrostatic Charge:
0.275
0.581
0.693
+0.272 –0.067 –0.341
Figure 1. LUMO coefficients and electrostatic charges of 1,1-
difluoroallene (B3LYP/6-31G*).
Table 1. £-Selective addition to 1,1-difluoroallenes
M
H
F
Nu–M
H3O+
CF2
CF2
CF2
+
R
Nu
Nu
THF
–60 °C
1–3 h
Nu
R
R
R
1
2
3
R = (CH2)2(1-Naph)
Entry Nu-M (equiv)
2/%
3/%
1
MeLi (2.8)
EtMgBr (2.8)
Et2Zn (1.7)
®
®
®
®
®
2a
3a
4
12, 3a
1, 3a
34, 3a
1, 3a
EtMgBr (1.7), CuBr¢SMe2 (2.0) 67, 2a
EtMgBr (1.0), CuBr¢SMe2 (0.1)
EtMgBr (1.7)
5a
6
®
95, 2a
CuBr (1.7), SMe2 (1.7)
n-BuMgBr (1.7)
CuBr (1.7), SMe2 (1.7)
7
93, 2b
trace
aDifluoroallene 1 was recovered in 45% (Entry 2), 70%
(Entry 3), and 53% yields (Entry 5), respectively.
other hand, ethylcopper, generated in situ from ethylmagnesium
bromide and the CuBr¢SMe2 complex, promoted the desired
£-addition to give difluoroalkene 2a in 67% yield (Entry 4).
However, a catalytic amount of CuBr¢SMe2 was not effective
(Entry 5). Further optimization revealed that the use of CuBr
and SMe2 with ethyl- or butylmagnesium bromide gave the
corresponding 3-alkyl-1,1-difluoroalkenes 2a and 2b in 95% and
93% yield, respectively (Entries 6 and 7). The £-addition step
probably generated difluorovinylcopper intermediates, and fol-
lowing a methanol quench, protonolysis gave the products 2.12
Next, the 2,2-difluorovinylcopper intermediate was captured
with electrophiles, which led to the corresponding functionalized
1,1-difluoroalkenes (Table 2). On treatment of the copper
Consequently, organometallic species were examined to
study their potential for inducing £-addition (Table 1). When
difluoroallene 1 was treated with methyllithium or ethylmagne-
sium bromide, complex mixtures were obtained (Entries 1 and
2). Diethylzinc caused an undesired ¡-attack to form mono-
fluoroallene 3a in 12% yield (SNV reaction, Entry 3). On the
Chem. Lett. 2012, 41, 1619-1621
© 2012 The Chemical Society of Japan
Fuchibe, Kohei
