£-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)-addition
R'MgBrCuBr, SMe2

CF2
R
1,1-Difluoroallenes

THF, –60 °C

R"Xcat. Pd

Cu
CF2

R"
CF2
R'

R'
R

R

2,2-Disubstituted
1,1-difluoroalkenes

REPRINTED FROM

Vol.41 No.12

2012 p.1619–1621
CMLTAG
December 5, 2012

The Chemical Society of Japan
Published on the web December 1, 2012; doi:10.1246/cl.2012.1619

doi:10.1246/cl.2012.1619
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)
1,1-Diﬂuoroallenes underwent £-selective addition withalkylcopper reagents. The resulting 2,2-diﬂuorovinylcopper
intermediates were captured by electrophiles or subjected topalladium-catalyzed coupling to give 2,2-disubstituted 1,1diﬂuoroalkenes in good yield.
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 themto 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 ofpotential mechanism-based enzyme inhibitors4 and as a bioisostere for the carbonyl group, which leads to enhancement of
the biological activities of the original molecules.5 In spite of theimportance of diﬂuoroalkenes, methods for their synthesis,
especially routes to 2,2-disubstituted 1,1-diﬂuoroalkenes, arestill limited.6,7
Recently, we reported synthetic methods for the preparationof 1,1-diﬂuoroallenes, in which diﬂuorovinylidenation of carbonyl groups were readily eﬀected to provide easy access tothese allene derivatives arrayed with a variety of substituents.8
On the basis of these results, we planned a new route for thesynthesis of disubstituted 1,1-diﬂuoroalkenes (Scheme 1). Nucleophilic addition of an organometallic species (Nu­M) at the£-position of 1,1-diﬂuoroallenes would give 2,2-diﬂuorovinylmetal intermediates. Capture of these intermediates by electrophiles (E­X) would provide the desired 2,2-disubstituted 1,1diﬂuoroalkenes 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 1,1diﬂuoroallene has a higher LUMO coeﬃcient at the £-carbon(0.693) than at the ¡-carbon (0.275), whereas a positiveelectrostatic charge is localized at the ¡-carbon (+0.272), anda negative charge is indicated at the £-carbon (¹0.341).11 The
desired £-attack, therefore, might be accessible under orbitalcontrolled conditions.
Consequently, organometallic species were examined to
study their potential for inducing £-addition (Table 1). Whendiﬂuoroallene 1 was treated with methyllithium or ethylmagnesium bromide, complex mixtures were obtained (Entries 1 and
2). Diethylzinc caused an undesired ¡-attack to form monoﬂuoroallene 3a in 12% yield (SNV reaction, Entry 3). On theChem. Lett. 2012, 41, 1619­1621

M

Nu–M

CF2

E

2

CF2

3

Nu

-addition

R

E–X

CF2
R

Nu

R

Scheme 1. Three-component coupling leading to 1,1-diﬂuoroalkenes.
CF2
α

Cα

C
β

CH2
γ

Cβ

Cγ

Coefficient of LUMO:

0.275

0.581

0.693

Electrostatic Charge:+0.272–0.067–0.341Figure 1. LUMO coeﬃcients and electrostatic charges of 1,1diﬂuoroallene (B3LYP/6-31G*).
Table 1. £-Selective addition to 1,1-diﬂuoroallenes
Nu–M

CF2
R

THF
–60 °C
1–3 h

M

H3O+

CF2

H

F

CF2
Nu

Nu

+

R

R

Nu

R

1
R = (CH2)2(1-Naph)

2

Entry
1
2a
3a
4
5a
6

2/%
®
®
®
67, 2a®
95, 2a3/%®
®
12, 3a1, 3a34, 3a1, 3a93, 2btrace

7

Nu­M (equiv)
MeLi (2.8)
EtMgBr (2.8)
Et2Zn (1.7)
EtMgBr (1.7), CuBr¢SMe2 (2.0)
EtMgBr (1.0), CuBr¢SMe2 (0.1)
EtMgBr (1.7)
CuBr (1.7), SMe2 (1.7)
n-BuMgBr (1.7)
CuBr (1.7), SMe2 (1.7)

3

Diﬂuoroallene 1 was recovered in 45% (Entry 2), 70%(Entry 3), and 53% yields (Entry 5), respectively.
aother 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 thecorresponding 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 following 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© 2012 The Chemical Society of Japanwww.csj.jp/journals/chem-lett/1620
Table 2. Introduction of a halogen or stannyl group to diﬂuoroallenes
EtMgBrCuBr, SMe 2

CF2

E

Cu
E–X

CF2

THF, –60 °C
1hR

THF, –60 °C

Et

1) EtMgBr (1.7 equiv)
CuBr (1.7 equiv)
SMe2 (1.7 equiv)
THF, –60 °C, 1–2 h

CF2
Et
R

R

CF2

2

1
R = (CH2)2(1-Naph)

Entry
1
2
3
4
5

Table 3. Three-component synthesis of disubstituted 1,1-diﬂuoroalkenes

E­X (equiv)
NISa (5.1)
NBSa (1.7)
NCSa (5.1)
n-Bu3SnCl (1.7)
Me3SnCl (1.7)

E
I
Br
Cl
Sn(n-Bu)3
SnMe3

t/h
2
2
2
3
9

2/%
84, 2c75, 2d76, 2e66,b 2f
68,b 2gR
1
R = (CH2)2(1-Naph)

PhI

20

R
2

2

t/h

Yield/%
Ph90, 2h

CF2
Et
R

a

NIS: N-iodosuccinimide, NBS: N-bromosuccinimide, NCS:
N-chlorosuccinimide. b 19F NMR yield (PhCF3).

Et2) 5 mol% [Pd2(dba)3]·CHCl3
20 mol% PPh3
R'X (1.0 equiv)
THF–HMPA (5:1), RT

Entry R′X
1

R'
CF2

2

PhCH2Br

1253,a 2i

Ph
CF2
Et
R

Sn(n -Bu)3

10 mol% [Pd(PPh3)4]
10 mol% CuI
PhI (3 equiv)

Et

DMF, 80 °C, 6 h

CF2
R
2f
R = (CH2)2(1-Naph)3

Ph(E )-PhCH2=CHCH2Br

Ph

4

CF2

CF2

Et

Et

R
2h 66%

66,b 2jR4(E )-MeCH2=CHCH2Br 20(19 F NMR yield, PhCF3 )85,b 2k
CF2Et
R

Scheme 2. Stille coupling of 2,2-diﬂuorovinylstannane 2f.
a 19

intermediate with NIS, NBS, or NCS, the corresponding 2halogenated 1,1-diﬂuoroalkenes 2c­2e were obtained in 75%­
84% yield (Entries 1­3). These 2-halo-1,1-diﬂuoroalkenes act aseﬃcient Suzuki coupling partners.7g Stannylation of the diﬂuorovinylcopper species proceeded to give 2-tributylstannyl- and2-trimethylstannyl-1,1-diﬂuoroalkenes 2f and 2g in 66% and
68% yield, respectively (Entries 4 and 5). The obtained
diﬂuorovinylstannanes were then subjected to the Stille coupling
reaction (Scheme 2).7c,7e Treatment of the isolated stannane 2f
with iodobenzene in the presence of [Pd(PPh3)4] (10 mol %) andCuI (10 mol %) aﬀorded the corresponding ¢,¢-diﬂuorostyrene
2h in 66% yield.
The above-mentioned £-selective addition was combinedwith subsequent cross coupling in a one-pot operation to aﬀord athree-component coupling (Table 3).6,13­15 1,1-Diﬂuoroallene 1
was ﬁrst subjected to the £-selective addition of an ethylcopper
reagent. When the resulting vinylcopper intermediates reactedwith iodobenzene in the presence of [Pd2(dba)3]¢CHCl3(10 mol % Pd) and PPh3 (20 mol %), the desired diﬂuorostyrene
2h was obtained in 90% yield (Entry 1). A benzyl group was
introduced by the one-pot coupling sequence to aﬀord 2i(Entry 2). Cinnamyl bromide and crotyl bromide were also
advantageous, aﬀording the corresponding 1,1-diﬂuoroalka-1,4dienes 2j and 2k in 66% and 85% yield, respectively, whereallylation took place selectively at the ¡-carbon to the bromine
substituent (Entries 3 and 4).
In summary, we developed a method for £-selective
addition to 1,1-diﬂuoroallenes using organocopper reagents.
The resulting diﬂuorovinylcopper intermediates were captured
by a wide range of electrophiles to give functionalized 1,1diﬂuoroalkenes that act as coupling partners. The £-addition
reaction was successfully followed by palladium-catalyzed crossChem. Lett. 2012, 41, 1619­1621

F NMR yield (PhCF3). bSingle regioisomer.

coupling to provide a three-component coupling sequence forthe synthesis of 2,2-disubstituted 1,1-diﬂuoroalkenes.
This research is partly supported by MEXT KAKENHI
Grant Number 24106705 (Grants-in-Aid for Scientiﬁc Researchon Innovative Areas, No. 2105) and JSPS KAKENHI Grant
Number 23655028.
References and Notes
1 a) G. Chelucci, Chem. Rev. 2012, 112, 1344. b) H. Amii, K.
Uneyama, Chem. Rev. 2009, 109, 2119.
2 a) G. Landelle, P. A. Champagne, X. Barbeau, J.-F. Paquin,Org. Lett. 2009, 11, 681. b) Y. Gimbert, A. Moradpour, G.
Dive, D. Dehareng, K. Lahlil, J. Org. Chem. 1993, 58, 4685.
c) K. Okuhara, J. Org. Chem. 1976, 41, 1487.
3 a) J. Ichikawa, Chim. Oggi 2007, 25 (4), 54. b) J. Ichikawa,in Fluorine-Containing Synthons in ACS Symposium Series,
ed. by V. A. Soloshonok, Oxford University Press andAmerican Chemical Society, Washington, D.C., 2005,
Vol. 911, p. 262. doi:10.1021/bk-2005-0911.ch014. c) J.
Ichikawa, Org. Synth. 2011, 88, 162. d) J. Ichikawa, Y.
Wada, H. Kuroki, J. Mihara, R. Nadano, Org. Biomol. Chem.
2007, 5, 3956. e) J. Ichikawa, Y. Wada, M. Fujiwara, K.
Sakoda, Synthesis 2002, 1917.
4 a) J.-P. Bégué, D. Bonnet-Delpon, Bioorganic and Medicinal
Chemistry of Fluorine, John Wiley & Sons, Hoboken, 2008.
doi:10.1002/9780470281895. b) P. Kirsh, Modern Fluoroorganic Chemistry, Wiley-VCH, Weinheim, 2004. c) D. B.
Berkowitz, K. R. Karukurichi, R. de la Salud-Bea, D. L.
Nelson, C. D. McCune, J. Fluorine Chem. 2008, 129, 731.
5 a) J. Ichikawa, J. Synth. Org. Chem., Jpn. 2010, 68, 1175,© 2012 The Chemical Society of Japanwww.csj.jp/journals/chem-lett/1621
and references cited therein. See also: b) G. Magueur, B.
Crousse, M. Ourévitch, D. Bonnet-Delpon, J.-P. Bégué,J. Fluorine Chem. 2006, 127, 637.
6 a) K. Fuchibe, H. Jyono, M. Fujiwara, T. Kudo, M. Yokota,
J. Ichikawa, Chem.®Eur. J. 2011, 17, 12175. b) J. Ichikawa,
J. Fluorine Chem. 2000, 105, 257, and references citedtherein.
7 For recent reports on the diﬂuoroalkene synthesis, see:
[Wittig-type diﬂuoromethylenation]: a) I. Nowak, M. J.
Robins, Org. Lett. 2005, 7, 721. b) P. S. Bhadury, M. Palit,
M. Sharma, S. K. Raza, D. K. Jaiswal, J. Fluorine Chem.
2002, 116, 75. [Cross coupling reaction]: c) S. Y. Han, H. Y.
Lee, J. H. Jeon, I. H. Jeong, Tetrahedron Lett. 2012, 53,
1833. d) T. Fujita, T. Ichitsuka, K. Fuchibe, J. Ichikawa,Chem. Lett. 2011, 40, 986. e) S. Y. Han, I. H. Jeong, Org.
Lett. 2010, 12, 5518. f) T. M. Gøgsig, L. S. Søbjerg, A. T.
Lindhardt, K. L. Jensen, T. Skrydstrup, J. Org. Chem. 2008,
73, 3404. g) A. Raghavanpillai, D. J. Burton, J. Org. Chem.
2006, 71, 194. [SN2¤-type reaction of triﬂuoromethylalkenes]: h) J. Ichikawa, H. Fukui, Y. Ishibashi, J. Org.
Chem. 2003, 68, 7800. i) T. Miura, Y. Ito, M. Murakami,
Chem. Lett. 2008, 37, 1006. j) J. Ichikawa, R. Nadano, N.
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10 For the £-selective addition of thiolate ion to 1,1-diﬂuoroallenes, see: Y.-y. Xu, F.-q. Jin, W.-y. Huang, J. Fluorine
Chem. 1995, 70, 5.

Chem. Lett. 2012, 41, 1619­1621

11 For the graphical presentation of LUMO of 1,1-diﬂuoroallene, see Supporting Information.15
12 Steric hindrance also plays an important role in theregioselectivity. Hammond and his co-workers reported that
3,3-disubstituted 1,1-diﬂuoroallenes undergo ¡-attack underconditions identical to those used in this work to give 3. See
ref. 9b.
13 Typical procedure: To a THF (2 mL) suspension ofcopper(I) bromide (49 mg, 0.35 mmol) was added dimethyl
sulﬁde (0.025 mL, 0.34 mmol) at room temperature, and thesuspension was stirred for 2 h. A THF solution of ethylmagnesium bromide (0.90 mol L¹1, 0.38 mL, 0.34 mmol)
was added to the suspension at ¹60 °C and stirred for 30 min
at the same temperature. A hexane solution of 1,1-diﬂuoroallene 1 (0.46 mol L¹1, 0.43 mL, 0.20 mmol) was added to
the yellow suspension of ethylcopper reagent at ¹60 °C, andthe mixture was stirred for 1 h. Hexamethylphosphoric
triamide (0.50 mL), [Pd2(dba)3]¢CHCl3 (10 mg, 0.0097
mmol), and triphenylphosphine (11 mg, 0.042 mmol) wereadded, and the resulting solution was stirred for 15 min.
After iodobenzene (0.022 mL, 0.20 mmol) was added, thereaction mixture was warmed to room temperature andstirred for 8 h. Phosphate buﬀer (pH 7) was added to quench
the reaction. Organic materials were extracted with ethyl
acetate. The combined extracts were washed with brine anddried over anhydrous sodium sulfate. After removal of thesolvent under reduced pressure, the residue was puriﬁed bycolumn chromatography (SiO2, hexane) to give 2h (60 mg,90%) as a colorless liquid.15
14 For the concept of reaction integration, including one-pot
reactions, see: a) J. Yoshida, K. Saito, T. Nokami, A. Nagaki,
Synlett 2011, 1189. b) S. Suga, D. Yamada, J. Yoshida,
Chem. Lett. 2010, 39, 404.
15 Supporting Information is available electronically on the
CSJ-Journal Web site, http://www.csj.jp/journals/chem-lett/index.html.

© 2012 The Chemical Society of Japanwww.csj.jp/journals/chem-lett/