Facile Synthesis of ¢,¢-Difluorostyrenes via the Negishi Couplingof Thermally Stable 2,2-Difluorovinyl Zinc­TMEDA Complex
Takeshi Fujita, Tomohiro Ichitsuka, Kohei Fuchibe, and Junji Ichikawa*
Department of Chemistry, Graduate School of Pure and Applied Sciences,
University of Tsukuba, Tsukuba, Ibaraki 305-8571(Received June 13, 2011; CL-110493; E-mail: junji@chem.tsukuba.ac.jp)

1. s -BuLi
TMEDA

H
CF2

H

2. ZnCl2

H

H
CF2

cat. Pd(0)ZnCl•TMEDA

CF2

X

R

R

stable, storable

X = I, Br, Cl, OTf

REPRINTED FROM

Vol.40 No.9 2011 p.986–988
CMLTAG
September 5, 2011

The Chemical Society of Japan
Published on the web September 5, 2011; doi:10.1246/cl.2011.986

doi:10.1246/cl.2011.986
Published on the web September 5, 2011

986

Facile Synthesis of ¢,¢-Difluorostyrenes via the Negishi Couplingof Thermally Stable 2,2-Difluorovinyl Zinc­TMEDA Complex
Takeshi Fujita, Tomohiro Ichitsuka, Kohei Fuchibe, and Junji Ichikawa*
Department of Chemistry, Graduate School of Pure and Applied Sciences,
University of Tsukuba, Tsukuba, Ibaraki 305-8571(Received June 13, 2011; CL-110493; E-mail: junji@chem.tsukuba.ac.jp)
2,2-Diﬂuorovinylzinc chloride­TMEDA complex, readily
prepared from 1,1-diﬂuoroethylene, undergoes the palladiumcatalyzed coupling reaction with aryl halides to aﬀord ¢,¢diﬂuorostyrenes in high yield. This reaction not only proceedssmoothly with sterically hindered triﬂates and halides including
chlorides, but also exhibits excellent chemoselectivities for multihalogenated substrates. The intermediary TMEDA complex was
found to be thermally stable and storable.
¢,¢-Diﬂuorostyrenes constitute a major class of compounds
in 1,1-diﬂuoro-1-alkenes and have attracted considerable attention,
especially as building blocks for ﬂuorine-containing organic
molecules1 and as monomers for functional polymers.2 To date
several methodologies have been established for the synthesis of¢,¢-diﬂuorostyrenes. Typically phosphane ylide-based reactions3and metal-mediated coupling reactions4,5 have been used.6 While
the synthetic methods via phosphane ylide intermediates require
arylaldehydes and an excess amount of expensive phosphanes,
metal-mediated reactions are more straightforward. Two types ofmetal-mediated coupling reactions have been developed: coupling
reactions between 2,2-diﬂuorovinylmetal reagents and aryl halides(eq 1)4 and between arylmetal reagents and diﬂuorovinyl halides.5
In both cases, the use of diﬂuorovinyl halides, which are rarelycommercially available, is required.
In 1985, Sauvêtre and Normant achieved the preparation of adiﬂuorovinylzinc reagent directly from commercially available
1,1-diﬂuoroethylene, the smallest compound in the 1,1-diﬂuoro1-alkene family, by sequential lithiation and zincation.7 They
applied this reagent to the palladium-catalyzed coupling reaction
with heteroaryl halides, albeit in low yield (eq 2).7b The low yieldobtained was probably due to the poor stability of the intermediarydiﬂuorovinylzinc chloride in the presence of a lithium salt.8,9Herein we report the preparation of a thermally stable diﬂuorovinylzinc reagent by complexation with N,N,N¤,N¤-tetramethylethylenediamine (TMEDA), which allows the eﬃcient synthesis of¢,¢-diﬂuorostyrenes via the palladium-catalyzed Negishi coupling
reaction (eq 3).10
H
X

CF2

ZnX

CF2

H

cat.
Pd(0)

H

zincation

(1)

CF2

ArI

R

X = I, OTs
H
H

CF2

2. ZnCl2

CF2

H

cat.
Pd(0)

H

1. s -BuLi

ZnCl

2-IC5H4N

N

CF2

(2)

50%
H
CF2

1. s -BuLi
TMEDA
H 2. ZnCl2

H
CF2

H

cat.
Pd(0)
ZnCl•TMEDA

ArX

CF2

R

(3)

X = I, Br, Cl, OTf

Typically, organozinc reagents are known to be often
stabilized by coordination of two amine molecules.11 This

Chem. Lett. 2011, 40, 986­988

Table 1. Screening of amine ligands for preparation of the zincreagentH
CF2

s -BuLi (1.0 equiv)H1(1.2 equiv)

Entry
1
2
3
4
5
6
7b
8b
9

THF–Et2O (4:1),–110 °C, 20 min

ZnX2 (x equiv)
Amine (y equiv)–100 °C, 30 min

ZnX2(x equiv)
ZnCl2 (1.0)
ZnCl2 (1.0)
ZnCl2 (1.0)
ZnCl2 (1.0)
ZnCl2 (1.0)
ZnCl2 (1.0)
ZnCl2 (1.0)
Znl2 (1.0)
ZnCl2¢TMEDA (1.0)

H
CF2

ZnX•Amine
2

Amine ligand(y equiv)

Yield/%aNMP (2.6)
Pyridine (2.6)
NEt3 (2.6)
DABCO (1.3)
TMEDA (1.3)
TMEDA (1.3)
TMEDA (1.3)

50
9
36
70
0
90
95
70
62

Yields are determined by 19F NMR using PhCF3 as an internal
standard. bLithiation was carried out in the presence of
TMEDA.
amotivated us to seek an appropriate choice of amines to construct
a thermally stable 2,2-diﬂuorovinylzinc complex as a manageable
reaction intermediate. We ﬁrst reviewed the previously reported
conditions in which no ligands were employed.7b The conditions
furnished 2,2-diﬂuorovinylzinc chloride in 50% yield (Table 1,
Entry 1). The main reason for the low yield might be due to thedecomposition of 2,2-diﬂuorovinylzinc chloride to ﬂuoroacetylene.8,9 Next we screened monodentate amine ligands (2.6 equiv)
as additives. Use of NMP and pyridine decreased the yield of
the corresponding complexes 2 (Entries 2 and 3), whereas
NEt3 marginally enhanced the formation of 2 (Entry 4). While
1,4-diazabicyclo[2.2.2]octane (DABCO), which can act as an exobidentate ligand, prevented the process (Entry 5), addition of
TMEDA turned out to be highly eﬀective for the formation of 2
(Entries 6­9).12,13 The best result (95% yield) was obtained whens-BuLi was added to the mixture of 1 and TMEDA, followed byaddition of ZnCl2 (Entry 7).14 The obtained zinc­TMEDA complex 2a is thermally stable and thus storable.
Having prepared thermally stable diﬂuorovinylzinc­TMEDA
complex 2a, its palladium-catalyzed Negishi coupling was
examined using a wide variety of aryl halides and pseudohalides(Table 2). Aryl iodides 3a­3d, aryl bromide 3e, and aryl triﬂate 3f
participated in the coupling reaction to produce diﬂuorostyrenes
4a­4f, respectively, in high yield (Entries 1­6).15,16 In the reactionof 3g­3j, PEPPSI-IPr was used as an electron-rich palladiumcatalyst or Cy-JohnPhos as an electron-rich ligand (Entries
7­10).17,18 Sterically hindered ortho-monosubstituted substrate
3g (Entry 7) and ortho-disubstituted substrates 3h and 3i (Entries 8© 2011 The Chemical Society of Japanwww.csj.jp/journals/chem-lett/987
Table 3. Chemoselectivity in the coupling reaction of 2aTable 2. Diﬂuorostyrene synthesis with diﬂuorovinylzinc­
TMEDA 2a
H
CF2

Ar–X

ZnCl•TMEDA
2a(1.2 equiv)

Entry

2

R

3
4b

Time/h Yield/%a

Pd catalyst (mol %)3a[Pd(PPh3)4] (2)6

59 (86), 4a(p -OMe) 3b[Pd(PPh3)4] (2)687, 4b(o -NH2) 3c[Pd(PPh3)4] (2)1

87, 4c(p -NO2) 3d[Pd2(dba)3] (2)/PPh3 (8)1284, 4d(p -Me)
I

Ar

CF2

2a
(1.3 equiv)X'

THF–Et2O

H

OTf
3k

CF2

3l

CF2

OTf

3e

[Pd(PPh3)4] (2)1087, 4eBrPh96, 4l
Br

Cl

TfO
6

3f

[Pd(PPh3)4] (2)63m

73, 4m3g

PEPPSI-IPr (5)1082, 4g

H

TfO

Ph

Cl

4e

OMe

Ph

Cl

TfO
7

Cl

CF2

Ph

Cl

Ph

H

TfO

3d

90, 4f92, 4k

H

2c

5

X'

Yield/%a

Ar−X

I

Ar
4k–n

I
Br

CF2

3k–n

Entry

1b

H

Pd catalyst
Ar

ZnCl •TMEDA

4a–j

3a–j

Ar–X

1

CF2

THF–Et 2O, reflux

X

H

H

Pd catalyst

CF2

3n

87, 4n

Cl

I
3h

8

PEPPSI-IPr (4)1279, 4h

MeO
Me
I
9

3i
Me

TfO

5f
Me

[Pd2(dba)3] (2.5)/
Cy-JohnPhos (10)

24

H

Br
3o

Br

CF2

69 (71),g 4o(59), 4i
a

Cl
10

3j

8

(71), 4g

Pha
Isolated yield. In parentheses are shown yields determinedby 19F NMR using PhCF3 as an internal standard. bRoom
temperature.

NN

Cl Pd ClNClPEPPSI-IPr

P

Cy-JohnPhos

and 9)16 successfully underwent the coupling reaction. Even thereaction of aryl chloride 3j eﬃciently proceeded to give 4g in goodyield (Entry 10).
It is noteworthy that the reaction exhibited complete chemoselectivity (Table 3). Both 3-iodophenyl triﬂate (3k) and 3-bromo4-iodobiphenyl (3l) showed thorough selective substitution of theiodo group (Entries 1 and 2). Likewise, the triﬂyloxy groups of 3mand 3n were exclusively substituted over the chlorine atoms(Entries 3 and 4). In the case of 3-bromophenyl triﬂate (3o), thetriﬂyloxy group reacted preferentially (>85% selectivity), although triﬂates and bromides generally show similar reactivity
toward transition-metal-catalyzed coupling reactions (Entry 5). As
a result, the relative reactivity of aryl halides and pseudohalides
was found to be in the order of I > OTf > Br > Cl.19
Intriguingly, even a boronate ester moiety was tolerated in thiscoupling reaction. Boronate ester 5 bearing a chlorine atom wasreacted with the diﬂuorovinylzinc­TMEDA complex 2a to givethe corresponding diﬂuorostyrene 6 in high yield without theChem. Lett. 2011, 40, 986­988

Isolated yield. In parentheses are shown yields determined by
F NMR using PhCF3 as an internal standard. bReaction
conditions: [Pd2(dba)3] (2.5 mol %), P(2-furyl)3 (10 mol %), rt,
4 h. c[Pd2(dba)3] (2.5 mol %), P(2-furyl)3 (10 mol %), 55 °C,
4 h. d[PdCl2(dppp)] (5 mol %), LiCl (375 mol %), reﬂux, 23 h.
e[PdCl2(dppf)] (4 mol %), reﬂux, 12 h. f[Pd2(dba)3] (2.5
mol %), dppb (5 mol %), 45 °C, 24 h. gBy-products formed by
the reaction of the bromo group were observed by 19F NMR(10% in total).
19

PEPPSI-IPr (5)formation of any self-Suzuki­Miyaura coupling products (eq 4).
The subsequent transformation of boronate 6 into triﬂuoroborate
7 followed by the subsequent Suzuki­Miyaura coupling with
3-iodophenol aﬀorded the desired coupling product 8. The direct
Negishi coupling of 2a and 2¤-halobiphenyl-3-ol cannot produce
8, because the zinc reagent undergoes protonolysis with aphenolic hydroxy group. However, the outstanding chemoselectivity of the zinc-mediated diﬂuorovinylation compensates thislimitation.
OBO

2a (1.25 equiv)H

PEPPSI-IPr (5.0 mol%)Cl
THF–Et 2O, reflux, 6 h
5

O

B

O

CF2
6 73%
OH

I

H

KHF2 (6 equiv)
MeOH–H2O
60 °C, 2 h

BF3K

CF2

© 2011 The Chemical Society of Japan(1.2 equiv)HO

K2CO3 (3.0 equiv)

H(4)

Pd(OAc)2 (10 mol%)
CF2
MeOH–H2O, 65 °C, 5 h
7 80%

8 70%

www.csj.jp/journals/chem-lett/988
In conclusion, we have disclosed a facile approach to ¢,¢diﬂuorostyrenes from 1,1-diﬂuoroethylene via the palladiumcatalyzed coupling of the thermally stable 2,2-diﬂuorovinylzinc
chloride­TMEDA complex 2a. The high functional group tolerance and the elegant chemoselectivity of the reaction would
facilitate the construction of a library of various ¢,¢-diﬂuorostyrenes. The zinc­TMEDA complex 2a has proven to be storable,
and thus is an excellent reagent for introducing the diﬂuorovinylgroup.
This research was supported in part by Grant-in-Aid for
Scientiﬁc Research from MEXT, Japan. We acknowledge Central
Glass Co., Ltd. for the generous gift of 1,1-diﬂuoroethylene.
This paper is in celebration of the 2010 Nobel Prize awarded
to Professors Richard F. Heck, Akira Suzuki, and Ei-ichi Negishi.
References and Notes
1 K. Uneyama, Organofluorine Chemistry, Blackwell Publishing, Oxford, UK, 2006, Chap. 1, pp. 60­67; K. Uneyama,
Organofluorine Chemistry, Blackwell Publishing, Oxford, UK,2006, Chap. 2, pp. 112­121.
2 R. Souzy, B. Ameduri, B. Boutevin, Prog. Polym. Sci. 2004,
29, 75.
3 a) S. A. Fuqua, W. G. Duncan, R. M. Silverstein, J. Org.
Chem. 1965, 30, 1027. b) S. A. Fuqua, W. G. Duncan, R. M.
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Hayashi, T. Nakai, N. Ishikawa, D. J. Burton, D. G. Naae, H.
S. Kesling, Chem. Lett. 1979, 983. d) M. Obayashi, E. Ito, K.
Matsui, K. Kondo, Tetrahedron Lett. 1982, 23, 2323. e) P. S.
Bhadury, M. Palit, M. Sharma, S. K. Raza, D. K. Jaiswal, J.
Fluorine Chem. 2002, 116, 75. f) I. Nowak, M. J. Robins, Org.
Lett. 2005, 7, 721.
4 a) J. Ichikawa, M. Fujiwara, H. Nawata, T. Okauchi, T.
Minami, Tetrahedron Lett. 1996, 37, 8799. b) B. V. Nguyen,
D. J. Burton, J. Org. Chem. 1997, 62, 7758. c) J. Ichikawa,
J. Fluorine Chem. 2000, 105, 257. d) A. Raghavanpillai, D. J.
Burton, J. Org. Chem. 2006, 71, 194.
5 T. M. Gøgsig, L. S. Søbjerg, A. T. Lindhardt, K. L. Jensen,
T. Skrydstrup, J. Org. Chem. 2008, 73, 3404.
6 For other approaches to ¢,¢-diﬂuorostyrene, see: a) V. G.
Nenajdenko, G. N. Varseev, V. N. Korotchenko, A. V. Shastin,
E. S. Balenkova, J. Fluorine Chem. 2003, 124, 115. b) G. K. S.
Prakash, Y. Wang, J. Hu, G. A. Olah, J. Fluorine Chem. 2005,
126, 1361. c) M. Pohmakotr, K. Boonkitpattarakul, W.
Ieawsuwan, S. Jarussophon, N. Duangdee, P. Tuchinda, V.
Reutrakul, Tetrahedron 2006, 62, 5973. d) Y. Zhao, W. Huang,
L. Zhu, J. Hu, Org. Lett. 2010, 12, 1444.
7 a) J.-P. Gillet, R. Sauvetre, J.-F. Normant, Tetrahedron Lett.
1985, 26, 3999. b) J. P. Gillet, R. Sauvêtre, J. F. Normant,
Synthesis 1986, 538.
8 Fluoroacetylenes have been prepared by lithiation of 1,1diﬂuoroethylene. See: T. Hanamoto, Y. Koga, T. Kawanami, H.
Furuno, J. Inanaga, Angew. Chem., Int. Ed. 2004, 43, 3582.
9 Without any lithium salts, ﬂuoroacetylenes are hardly produced from 2,2-diﬂuorovinylzinc species. See ref. 4.

Chem. Lett. 2011, 40, 986­988

10 For a recent review on the Negishi coupling, see: E.-i. Negishi,
Q. Hu, Z. Huang, M. Qian, G. Wang, Aldrichimica Acta 2005,
38, 71.
11 H. Schumann, S. Freitag, F. Girgsdies, H. Hemling, G.
Kociok-Köhn, Eur. J. Inorg. Chem. 1998, 245, and references
cited therein.
12 An equimolar amount of TMEDA could not complete thecomplexation.
13 The formation of 2a was supported by the 19F NMR (470
MHz) spectra of the reaction mixture. The data are shown
below (¤: parts per million from hexaﬂuorobenzene). 2a: ¤87.9 (1F, dd, JFF = 58 Hz, JFH = 58 Hz), 98.7 (1F, dd, JFF =58 Hz, JFH = 15 Hz). cf. 2,2-Diﬂuorovinylzinc chloride: ¤ 86.2
(1F, dd, JFF = 55 Hz, JFH = 55 Hz), 98.5 (1F, dd, JFF = 55 Hz,
JFH = 14 Hz). 1,1-Diﬂuoroethylene: ¤ 80.0­80.2 (m).
14 To a solution of TMEDA (98 ¯L, 0.65 mmol) in THF (2.0 mL)
and diethyl ether (0.50 mL) at ¹110 °C was slowly added
gaseous 1,1-diﬂuoroethylene (14.5 mL, 0.60 mmol) via syringe, and the mixture was stirred at the same temperature for5 min. To the solution at ¹110 °C was slowly added s-BuLi(0.96 M in hexane, 0.52 mL, 0.50 mmol) and the mixture wasstirred at the same temperature for 20 min. To the reaction
mixture at ¹110 °C was added a THF solution of anhydrous
ZnCl2 (1.00 M, 0.50 mL, 0.50 mmol). After the reaction
mixture was stirred at ¹100 °C for 30 min, a THF­ether
solution of 2a was obtained as a colorless solution (0.48 mmol,
95%: The yield and the concentration were determined by
19
F NMR using PhCF3 as an internal standard).
15 In a two-necked ﬂask was placed the prepared THF­ether
solution of 2a (0.125 M, 7.6 mL, 0.95 mmol). To the solution
were added a solution of 4-iodoanisole (3b, 189 mg, 0.81mmol) in THF (1.5 mL) and [Pd(PPh3)4] (17 mg, 15 ¯mol).
After reﬂuxing for 6 h, the reaction mixture was ﬁlteredthrough a pad of silica gel (diethyl ether). The ﬁltrate wasconcentrated under reduced pressure and puriﬁed by preparative thin layer chromatography (silica gel, pentane:diethyl
ether = 20:1) to give 4b (119 mg, 87%) as a colorless liquid.
16 Diﬂuorostyrene 4a was diﬃcult to isolate in high yield becauseof its volatility. Diﬂuorostyrene 4i and unreacted iodide 3i
were inseparable by distillation and column chromatography.
17 PEPPSI-IPr is known as an eﬃcient catalyst for the Negishi
coupling. For reviews, see: a) M. G. Organ, S. Avola, I.
Dubovyk, N. Hadei, E. A. B. Kantchev, C. J. O’Brien, C.
Valente, Chem.®Eur. J. 2006, 12, 4749. b) E. A. B. Kantchev,
C. J. O’Brien, M. G. Organ, Angew. Chem., Int. Ed. 2007, 46,2768. c) C. Valente, M. E. Belowich, N. Hadei, M. G. Organ,
Eur. J. Org. Chem. 2010, 4343.
18 Cy-JohnPhos is a Buchwald ligand, which is used for various
coupling reactions of sterically hindered substrates. For areview, see: R. Martin, S. L. Buchwald, Acc. Chem. Res. 2008,
41, 1461.
19 For several examples on chemoselective coupling reactions,see: a) M. Rottländer, N. Palmer, P. Knochel, Synlett 1996,
573. b) T. Kamikawa, T. Hayashi, Tetrahedron Lett. 1997, 38,
7087. c) A. F. Littke, C. Dai, G. C. Fu, J. Am. Chem. Soc.
2000, 122, 4020.

© 2011 The Chemical Society of Japanwww.csj.jp/journals/chem-lett/