An improved, efficient route to 2,2-difluoroethenylbenzenes

Article abstract of DOI:10.1016/j.jfluchem.2011.06.005

Treatment of vinylidene fluoride with tert-BuLi at -115 °C gave a solution of [F₂CCHLi]. Addition of Bu₃SnCl to this lithium reagent at -110 °C gave an 88% isolated yield of F₂CCHSnBu ₃. Reaction of F₂

Full text of DOI:10.1016/j.jfluchem.2011.06.005

Journal of Fluorine Chemistry 133 (2012) 16–19
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
An improved, efficient route to 2,2-difluoroethenylbenzenes
*
Long Lu, Donald J. Burton
Department of Chemistry, The University of Iowa, Iowa City, IA 52242, USA
A R T I C L E I N F O
A B S T R A C T
Article history:
Treatment of vinylidene fluoride with tert-BuLi at ꢀ115 8C gave a solution of [F2C55CHLi]. Addition of
Bu3SnCl to this lithium reagent at ꢀ110 8C gave an 88% isolated yield of F2C55CHSnBu3. Reaction of
F2C55CHSnBu3 with substituted aryl iodides under Stille-Liebeskind conditions [Pd(PPh3)4/Cu(I)I] at
room temperature afforded the 2,2-difluoroethenylbenzines in good yield. In the absence of the Cu(I)I
co-catalyst, no reaction occurred. This work provides the most efficient route for the conversion of aryl
halides to 2,2-difluorostyrenes.
Received 23 May 2011
Received in revised form 2 June 2011
Accepted 7 June 2011
Available online 13 July 2011
Dedicated to Professor
ß 2011 Elsevier B.V. All rights reserved.
Wei-Yuan Huang on the occasion
of his 90th birthday.
Keywords:
2,2-Difluoroethenyltributylstannane
Pd(PPh3)4
Cu(I)I
Co-catalysis
2,2-Difluoroethenyllithium
Vinylidene fluoride
Coupling reactions
2,2-Difluorostyrenes
1. Introduction
Although this unstable lithium reagent was employed in the
preparation of the 2,2-difluorovinylzinc reagent and added to
Recently, the introduction of the 2,2-difluorovinyl and the
1,1,2-trifluorovinyl groups into organic compounds has been of
interest for organic synthesis and biological studies. Munroe and
co-workers have investigated coupling of unsaturated stannanes
with 1-carbacephem-3-enol triflates. The vinyl stannanes consis-
tently gave the highest yield of the coupled product and proceeded
at the lowest temperature [1]. The 2,2-difluorovinylstannane gave
a 78% yield of the coupled products at 25 8C. The experimental
preparation of F2C55CHSnBu3 was not described. Subsequently,
Farina et al. described general methodology for the synthesis of
cephem side chains in cephalosporin chemistry [2]. The tables in
this manuscript describe the use of F2C55CFSnBu3 (with Pd(0)
catalysis) as an efficient route to coupling of vinyl triflates and 3-
(halomethyl)cephems. Sauvetre and Normant reported the metal-
lation of vinylidene fluoride with sec-butyllithium at low
temperatures, as illustrated in Eq. (1) [3].
aldehydes and ketones to provide allylic alcohols, the vinylstan-
nane was not described [4,5]. The F2C55CHSnBu3 was prepared in
our laboratory via the conversion of F2C55CHSiEt3 with KF and
Bu3SnCl, as illustrated in Eq. (2) [6]. Subsequently, Lentz and co-
workers reported the preparation of [F2C55CHLi] from
THF/Et2O
F2C=CH2 + Et3SiCl
F2C=CHSiEt3
60%
tBuLi
-110 °C
KF/DMF
Bu3SnCl
RT overnight
(2)
F2C=CHSnBu3
92%
sec
-
BuLi
either 1,1-difluoroethene or 2-chloro-1,1-difluoroethane via Nor-
mant’s method. Reaction of this vinyllithium with Bu3SnCl
provided the 2,2-difluoroethenylstannane, as shown in Eq. (3) [7].
F2C¼CH2
ꢀ!
½F2C¼CHLiꢂ
(1)
THF=Et2Oꢀ115
ꢁ
C
2O
F2C¼CH2 þ sec-BuLiTHꢀF=!Et ½F2C¼CHLiꢂ ꢀ! F2C¼CHSnBu3
(3)
Bu3SnCl
* Corresponding author. Tel.: +1 319 335 1363; fax: +1 319 335 1270.
ꢀ110 ꢁC
78%
E-mail address: donald-burton@uiowa.edu (D.J. Burton).
0022-1139/$ – see front matter ß 2011 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2011.06.005

L. Lu, D.J. Burton / Journal of Fluorine Chemistry 133 (2012) 16–19
17
Later, Nenajdenko et al. reported the direct preparation of 2,2-
difluorovinylbenzenes from aromatic aldehydes, as shown in
Eq. (10) [11]. This type of
2. Results and discussion
Recently, we reported a useful, convenient preparation of the
2,2-difluorovinylzinc reagent in good yield via treatment of
F2C55CHI with acid-washed zinc in dry DMF, as shown in Eq. (4)
[8]. The zinc reagent reacted smoothly with aryl iodides
NH2NH2 H2O
Ar
H
CF2Br2 Ar
ArCHO
NNH2
CF2
Cu(I)Cl
(10)
a
H
F2C¼CHI þ Zn ꢀDM!F ½F2C¼CHZnXꢂ
(4)
60 ꢁC
20-36%
60ꢀ80%
X¼I or F2C¼CH
conversion, aldehydes to 2,2-difluorovinylbenzenes, is
or bromides in DMF in the presence of 5 mol.% Pd(PPh3)4 at 60 8C to
give 2,2-difluorostyrenes, Eq. (5) [8]. The one drawback to this
approach is the use of F2C55CHI
variant of the Wittig approach to this class of compounds
[12]. The approaches by Heitz and Nenajdenko simplify the
approach to 2,2-difluorostyrenes and utilize readily available
precursors, but they do not offer any advantage over the use of
F2C55CHI. The preparation of F2C55CHI utilizes vinylidene
fluoride as the initial precursor. Thus, like the work of Heitz,
if vinylidene fluoride could be utilized directly or in a one-step
approach to a useful precursor, then perhaps a more efficient
route to the 2,2-difluorostyrenes could be developed. Our choice
of precursors was F2C55CHSnBu3. McCarthy and co-workers have
Pd(PPh3)4
[F2C=CHZnX] +
CH=CF2
X
DMF, 60 °C
(5)
R
R
1-4 h
X = I, Br
69-92%
as the 2,2-difluorovinyl precursor. This vinyl iodide is not
commercially available. It has been prepared by the addition of
ICl to vinylidene fluoride followed by elimination of HCl with base,
as illustrated in Eq. (6). In his initial report, Park employed KOH/
mineral oil
demonstrated that 1-fluorovinylstannanes provides
a mild,
stereospecific entry to monofluoroolefins [13]. Also, recent
work in our laboratory has demonstrated the utility of
vinylstannanes in the preparation of functionalized vinyl
fluoride derivatives [14–20].
The F2C55CHSnBu3 can be prepared via the previously described
route shown in Eq. (2). This route looks attractive, since all the
starting materials are commercially available. However, the 60%
yield of the vinylsilane has the same modest yield limitation of
F2C55CHI. Also, two steps and two isolations are required before
conversion to the 2,2-difluorostyrenes. Thus, we decided to
attempt a more direct route to F2C55CHSnBu3, and the direct
conversion of this vinylstannane to the styrenes.
As noted in Eq. (1), Normant prepared the vinyllithium reagent
directly from vinylidene fluoride via metallation with sec-BuLi. To
accomplish the same conversion, we utilized tert-BuLi as the base
for better handling at low temperatures (ꢀ115 8C). Initially, we
attempted to accomplish this transformation in a manner similar
to the preparation of F2C55CHSiEt3 [21]. As demonstrated by others,
Et3SiCl reacts slower in a metallation process than a vinyl hydrogen
or halogen in a fluoroolefin. Thus, the olefin and Et3SiCl can be
treated at low temperature with an alkyllithium and only
metallation of the olefin occurs, which then captures the Et3SiCl
to give the vinylsilane. Thus, the unstable vinyllithium does not
need to be pregenerated. However, when we treated a mixture of
vinylidene fluoride and Bu3SnCl at ꢀ115 8C with tert-BuLi, a 1:1
mixture of F2C55CHSnBu3 and tert-BuSnBu3 was observed. Bu3SnCl
is known to be a better electrophile than R3SiCl and competes for
the tert-BuLi. Consequently, we pregenerated the vinyllithium at
low temperature. Addition of Bu3SnCl to the vinyllithium provided
an excellent isolated yield of F2C55CHSnBu3, as illustrated in
Eq. (11) [22]. Subsequent Pd(0)
ICI
base
F2C¼CH2ꢀ! CF2ClCH2I ꢀ!F2C¼CHI
(6)
80ꢀ90%
as the base and obtained 65% of the vinyl iodide [9]. Later, Lentz
utilized potassium tert-butylate as the base and obtained 62% of
the vinyl iodide [7]. Thus, a two step preparation of the key
precursor is employed and the overall yield of the vinyl iodide is
modest at best. An alternative precursor is F2C55CHBr. However,
when this vinyl bromide was reacted with zinc to prepare the
requisite vinylzinc reagent, less satisfactory results were obtained,
and a novel acid–base reaction was observed and produced a
mixture of vinylzinc reagents, as illustrated in Eq. (7) [8]. Thus, the
vinyl iodide was the
DMF
F2C¼CHBr þ Zn ꢀ! ½F2C¼CHZnXꢂ þ ½F2C¼CBrZnXꢂ
(7)
90ꢁC=1 h
only 2,2-difluorovinyl halide precursor that gave satisfactory
results.
The 2,2-difluorostyrenes also provide a useful entry to the 2,2,2-
trifluoroethylbenzenes, as shown in Eq. (8) [8]. Thus, an efficient
preparation of 2,2-
KF
F2C=CH
CF3CH2
83-95%
(8)
H2O
R
R
DMSO or DMF
difluorostyrenes provides an entry to two classes of compounds.
Heitz and Knebelkamp have reported a possible simple one step
approach to 2,2-difluorostyrenes via a Heck reaction. They reacted
aryl iodides or bromides with vinylidene fluoride, utilizing
palladium (II) acetate as the catalyst, as illustrated in Eq. (9)
[10]. Unfortunately, the 2,2-difluorostyrenes were found only as a
minor product; the
Bu3SnCl
t-BuLi
F2C¼CH2
ꢀ!
½F2C¼CHLiꢂꢀ1ꢀ0!5 ꢁC F2C¼CHSnBu3 (11)
THF=Et2Oꢀ115 to ꢀ110
ꢁ
88%
C
catalyzed coupling of F2C55CHSnBu3 with aromatic iodides, under
Liebeskind conditions (Cu(I)I as a co-catalyst) [23,24], gave good
yields of the substituted 2,2-difluorostyrenes (Table 1). Electron-
withdrawing substituents on the ring promote a rapid RT reaction
(entries 1–5). An electron-releasing substituent reacts at RT but at
slower rate (entry 6). Note: when the co-catalyst, Cu(I)I is not
utilized, the reaction does not proceed (entry 7), consistent with
H
Pd(OAc)2
H
I(Br) + F2C=CH2
solvent
(9)
R
R
F
Et3N
115 °C
32-72%
the formation of
a vinylcopper intermediate in the Stille-
major product was 1-fluorostyrenes.
Liebeskind reaction process [17].

18
L. Lu, D.J. Burton / Journal of Fluorine Chemistry 133 (2012) 16–19
Table 1
BuLi (35 ml, 1.7 M in pentane, 59 mmol) was slowly added over 1 h
(via syringe) with stirring. The internal temperature was main-
tained between ꢀ105 and ꢀ115 8C during the addition. After the
addition of the tert-BuLi was completed, the solution was stirred at
ꢀ100 8C for 1 h, then n-tributyltin chloride (16.28 g, 50 mmol) was
added slowly over 2 h while the solution was controlled below
ꢀ95 8C, Then, the reaction mixture was stirred at ꢀ95 8C for 1 h and
then allowed to warm to RT over 3 h and stirred overnight at RT.
The reaction mixture was treated with 0.1 N aqueous HCl (30 ml)
and extracted with ether (2 ꢄ 100 ml). The combined organic layer
was washed with brine and dried over anhydrous MgSO4. After
filtration, the ether was removed via rotary evaporation, and the
residue was purified on a silica gel chromatography column using
hexane as eluent to give 2,2-difluoroethenyltri-n-burtystannane
(15.5 g, 88% yield) as a colorless liquid. The 19F NMR, 1H NMR, and
13C NMR were in good agreement with the literature data [6].
Pd(PPh3)4/Cu(I)I catalyzed coupling reactions of F2C5CHSnBu3 with aryl iodides.
CH=CF2
I
Pd(PPh3)4
Cu(I)I
DMF, RT
F2C=CHSnBu3
+
R
R
Entry
R
Rx. conditions
Yield (%)a
1
2
3
4
5
6
7
3-NO2
2-NO2
4-NO2
4-C(O)Me
4-CN
RT/2 h
RT/2 h
RT/2 h
RT/2 h
RT/2 h
RT/48 h
RT/24 h
78
70
81
66
85
3-OMe
4-CN
53
No Rxb
a
Isolated yields based on ArI.
In the absence of Cu(I)I.
b
4.2.2. Preparation of 3-(2,2-difluoroethenyl)nitrobenzene
General procedure: A 250 ml flask, equipped with a magnetic stir
bar and septum, was charged with Pd(PPh3)4 (0.09 g, 0.078 mmol),
Cu(I)I (0.19 g, 1.0 mmol), 3-iodonitrobenzene (0.50 g, 2.0 mmol),
and dry DMF (10 ml). Then, F2C55CHSnBu3 (0.88 g, 2.5 mmol) was
added at RT with stirring. The reaction was completed within 2 h at
RT, as determined by 19F NMR analysis for the disapperance of the
vinylstannane. The reaction mixture was then diluted with Et2O
(100 ml) and washed with aqueous KF solution (15%, 50 ml). The
ether layer was separated, dried over anhydrous MgSO4 and
concentrated. The residue was chromatographed on a silica gel
column using a 1:20 mixture of ethylacetate and hexane as eluent
to afford 0.29 g (78%) of 3-(2,2-difluoroethenyl) nitrobenzene as a
white solid, mp 31–33 8C (lit. 32–33 8C [8]). The 19F NMR, 1H NMR,
13C NMR were in good agreement with the literature data [8].
3. Conclusion
Vinylidene fluoride can be readily converted to F2C55CHSnBu3
in good yield via reaction of [F2C55CHLi] and Bu3SnCl at low
temperature. The vinylstannane can be efficiently coupled with
aromatic iodides using Stille-Liebeskind conditions, Pd(PPh3)4/
Cu(I)I. This route provides a shorter, more efficient route to 2,2-
difluorostyrenes.
4. Experimental
4.1. General
All boiling points are uncorrected. 19F NMR (282.44 MHz), 1H
NMR (200.17 MHz) and 13C NMR (75.48 MHz) spectra were
recorded in CDCl3 solvent. All chemical shifts are reported in
parts per million downfield of the standards. 19F NMR spectra are
referenced against internal CFCl3, and 1H NMR and 13C NMR
spectra against TMS. FTIR spectra were recorded as CCl4 solutions
using a solution cell with a 0.1 cm path length and absorbance
frequencies reported in cmꢀ1. GCMS spectra were obtained at
70 eV in the electron-impact mode. High resolution mass spectra
determinations were made at the University of Iowa High
Resolution Mass Spectrometry Facility.
4.2.3. Preparation of 2-(2,2-difluoroethenyl)nitrobenzene
Similar to Section 4.2.2, reaction of F2C55CHSnBu3 (0.88 g,
2.5 mmol), 2-iodonitrobenzene (0.50 g, 200 mmol), Pd(PPh3)4
(0.09 g, 0.078 mmol), Cu(I)I (0.19 g, 1.0 mmol) and dry DMF
(10 ml) at RT for 2 h yielded 2-(2,2-difluoroethenyl)nitrobenzene
(0.26 g, 70%) as a yellow oil after chromatography using a mixture
of ethyl acetate and hexane (1:20) as eluent. 19F NMR:
d
ꢀ80.56
2
3
3
(dd, JFF = 22.2 Hz, JHF = 3.5 Hz, 1F), ꢀ82.58 (dd, JHF = 24.5 Hz,
2JFF = 22.2 Hz, 1F); 1H NMR:
d 7.98 (d, JHH = 8.0 Hz, 1H), 7.61 (d,
3
3JHH = 4.8 Hz, 2H), 7.42 (m, 1H), 5.93 (dd, JHF = 24.5 Hz,
3
3JHF = 3.5 Hz); 13C NMR:
d
156.8 (dd, 1JCF = 299.0 Hz,
1JCF = 289.9 Hz), 147.8 (m), 133.1 (s), 130.4 (dd, JCF = 8.2 Hz,
4JCF = 1.2 Hz), 128.0 (s), 125.1 (3JCF = 8.9 Hz, 3JCF = 5.5 Hz), 124.9 (s),
4
4.2. Materials
2
2
77.97 (dd, JCF = 34.7 Hz, JCF = 12.5 Hz). GC–MS, m/z (relative
intensity): 185 (M+, 25). FTIR (CCl4, cmꢀ1): 1661.59 (C55C) cmꢀ1
.
Tert-BuLi (1.7 M in pentane) was obtained from the Aldrich
Chemical Company. Vinylidene fluoride was obtained from PCR.
Most aromatic iodides and n-tributyltin chloride were obtained
from Aldrich and used directly. Tetrakis (triphenylphosphine)
palladium was prepared by the literature procedure [25]. Cu(I)I
was prepared via the reported procedure [26]. THF was distilled
from sodium benzophenone at atmospheric pressure. DMF was
dried by stirring overnight over CaH2, then distilled at reduced
pressure (bp ꢃ65 8C/5 mm Hg) prior to use and stored under
nitrogen. 4-iodobenzonitrile was obtained from Kodak and used
directly. Silica gel was obtained from EM Scientific (silica gel 60,
4.2.4. Preparation of 4-(2,2-difluoroethenyl)nitrobenzene
Similar to Section 4.2.2, reaction of F2C55CHSnBu3 (0.88 g,
2.5 mmol), 4-iodonitrobenzene (0.50 g, 2.0 mmol), Pd(PPh3)4
(0.19 g, 0.078 mmol), Cu(I)I (0.19 g, 1.0 mmol) in dry DMF
(10 ml) at RT for 2 h afforded 4-(2,2-difluoroethenyl)nitrobenzene
(0.30 g, 81%) as a white solid after chromatography using a mixture
of ethylacetate and hexane (1:20) as eluent, mp 35–37 8C (lit. 35–
37 8C [8]). The 19F NMR, 1H NMR, 13C NMR were in good agreement
with the literature data [8].
particle size 0.063–0200
mm, 70–30 Mesh, ASTM).
4.2.5. Preparation of 4-(2,2-difluoroethenyl)benzonitrile
4.2.1. Preparation of 2,2-difluoroethenyltri-n-butylstannane
Similar to Section 4.2.2, reaction of F2C55CHSnBu3 (0.88 g,
2.5 mmol), 4-iodobenzonitrile (0.46 g, 2.0 mmol), Pd(PPh3)4
(0.09 g, 0.078 mmol), Cu(I)I (0.19 g, 1.0 mmol) in dry DMF
(10 ml) at RT for 2 h gave 0.28 g (85%) of 4-(2,2-difluoroethenyl)
benzonitrile as colorless crystals after chromatography using a
mixture of ethylacetate and hexane (1:20) as eluent, mp 64–65 8C.
A 250 ml three-necked flask, equipped with a low temperature
thermometer, a magnetic stir bar, a N2 tee and a dry ice/acetone
condenser, was charged with anhydrous ether (20 ml), anhydrous
THF (40 ml), and vinylidene fluoride (5.0 g, 78 mmol) and then
cooled to ꢀ115 8C with a pentane/liquid nitrogen bath. Then tert-

L. Lu, D.J. Burton / Journal of Fluorine Chemistry 133 (2012) 16–19
19
3
2
The 19F NMR:
d
ꢀ78.36 (dd, JHF = 25.7 Hz, JFF = 20.4 Hz, 1F),
Acknowledgement
We thank the National Science Foundation for financial support.
ꢀ80.00 (d, 2JFF = 20.4 Hz, 1F); 1H NMR:
d
7.62 (d, 3JHH = 8.3 Hz, 2H),
3
3
3
7.43 (d, JHH = 8.3 Hz, 2H), 5.35 (dd, JHF = 25.7 Hz, JHF = 3.2 Hz,
1H); 13C NMR:
d 156.9 (dd, JCF = 301.2 Hz, JCF = 292.1 Hz), 135.2
1
1
4
4
5
(dd, JCF = 7.7 Hz, JCF = 6.2 Hz), 132.3 (s), 127.9 (dd, JCF = 7.0 Hz,
5JCF = 3.7 Hz), 118.5 (s), 110.4 (t, JCF = 2.3 Hz), 81.71 (dd,
6
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2JCF = 30.5 Hz, JCF = 12.8 Hz). GC–MS, m/z (relative intensity):
2
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4.2.6. Preparation of 4-(2,2-difluoroethenyl)acetophenone
Similar to Section 4.2.2, reaction of F2C55CHSnBu3 (0.88 g,
2.5 mmol), 4-iodoacetophenone (0.49 g, 2.0 mmol), Pd(PPh3)4
(0.09 g, 0.078 mmol), Cu(I)I (0.19 g, 1.0 mmol) in dry DMF
(10 ml) for 2 h yielded 0.24 g (66%) of 4-(2,2-difluoroethenyl)ace-
tophenone as colorless crystals after chromatography using a
mixture of ethylacetate and hexane (1:20) as eluent, mp 38–40 8C
(lit. 38–39 8C [8]). The 19F NMR, 1H NMR, 13C NMR and FTIR were
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Cu(I)I (0.19 g, 1.0 mmol) in dry DMF (10 ml) at RT for 48 h afforded
3-(2,2-difluoroethenyl)anisole (0.18 g, 53%) as an oil after chro-
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eluent. The 19F NMR, 1H NMR, 13C NMR were in good agreement
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