Stereospecific synthesis of unsymmetrical (E)- and (Z)-1,2-difluorostilbenes

Article abstract of DOI:10.1016/j.jfluchem.2016.01.018

The synthesis of 1,2-difluorostilbenes via a Susuki reaction using a benzene/ethanol/water solvent mixture required long reaction times and generated significant quantities of a homo-coupled boronic acid product, which was difficult to separate. Therefore, we attempted 1,4-dioxane as a solvent for these reactions, which showed remarkable increased reaction rates and minimized the amount of homo-coupled products to aid in purification. Both (E)- and (Z)-1-chloro-1,2-difluorostyrenes stereospecifically gave the 1,2-difluorostilbenes in moderate to excellent yields. We investigated 4 protocols for the reaction. Protocols 2 and 3 were recommended for scale up, since the chlorostyrene starting material can be obtained in large quantities stereospecifically as described in previous reports. This work represents the first practical synthesis of unsymmetrical (E)- and (Z)-1,2-difluorostilbenes from readily available starting materials.

Full text of DOI:10.1016/j.jfluchem.2016.01.018

Journal of Fluorine Chemistry 185 (2016) 206–212
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Stereospecific synthesis of unsymmetrical (E)- and (Z)-1,2-
difluorostilbenes$
*
Chongsoo Lim, Yi Wang, 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:
The synthesis of 1,2-difluorostilbenes via a Susuki reaction using a benzene/ethanol/water solvent
mixture required long reaction times and generated significant quantities of a homo-coupled boronic
acid product, which was difficult to separate. Therefore, we attempted 1,4-dioxane as a solvent for these
reactions, which showed remarkable increased reaction rates and minimized the amount of homo-
coupled products to aid in purification. Both (E)- and (Z)-1-chloro-1,2-difluorostyrenes stereospecifically
gave the 1,2-difluorostilbenes in moderate to excellent yields. We investigated 4 protocols for the
reaction. Protocols 2 and 3 were recommended for scale up, since the chlorostyrene starting material can
be obtained in large quantities stereospecifically as described in previous reports. This work represents
the first practical synthesis of unsymmetrical (E)- and (Z)-1,2-difluorostilbenes from readily available
starting materials.
Received 6 November 2015
Received in revised form 25 January 2016
Accepted 28 January 2016
Available online 5 March 2016
Keywords:
Unsymmetrical (E)-1,2-difluorostilbenes
Unsymmetrical (Z)-1,2-difluorostilbenes
1,4-Dioxane was a superior solvent to the
normal Suzuki reaction systems
Protocol for scaled up synthesis of
unsymmetrical 1,2-difluorostilbenes
ã 2016 Published by Elsevier B.V.
1. Introduction
these methods remains tedious and difficult. Symmetrical (E)-1,2-
diflurostilbenes can be prepared in good yield through Stille-type
Receiving little attention, unsymmetrical (Z)-1,2-difluorostil-
benes were previously synthesized via photochemical isomeriza-
tion of (E)-1,2-difluorostilbenes and separated by GLPC [1].
Additional attempts to improve separation via HPLC have been
reported [2]. Nevertheless, obtaining significant quantities with
coupling of (E)-(1,2-difluoro-1,2- ethenediyl) bis[tributylstannane]
(Eq. 1) [3]. (Z)-1,2-difluorostilbenes can be prepared in several
steps (Eq. 2) [2]. However, the reaction is tedious due to the
number of steps, and does not contain a common intermediate
similar to the preparation of (E)-1,2-difluorostilbene [3].
$
Abstracted in part from Chongsoo Lim Ph.D. thesis, University of Iowa, 2004.
* Corresponding author. Fax: +1 319 335 1270.
E-mail address: mburton105@gmail.com (D.J. Burton).
http://dx.doi.org/10.1016/j.jfluchem.2016.01.018
0022-1139/ã 2016 Published by Elsevier B.V.

C. Lim et al. / Journal of Fluorine Chemistry 185 (2016) 206–212
207
The synthesis for some unsymmetrical (E)-1,2-difluorostilbenes
has been reported through the reaction of an alkyl lithium or
Grignard reagent with trifluorostyrenes [4]. However, this route
does not provide access to the (Z)-1,2-difluorostilbenes and
contains no common intermediate for further derivatization.
(5)). Two synthetic procedures were attempted: first, the zinc
reagent from (Z)-2-chloro-1,2-difluoro-1-iodoethene was generat-
ed in situ followed by a Negishi coupling [6] and then a boronic acid
and Pd catalyst were added to affect the formation of the final
unsymmetrical 1,2-difluorostilbene (Eq. (4)). Second, a Suzuki
reaction with (Z)-2-chloro-1,2-difluoro-1-iodoethene and an aryl
boronic acid was carried out in 1,4-dioxane to generate the (Z)-1-
chloro-1,2-difluorostyrenes in situ. Sequentially, a second boronic
acid was added to achieve the formation of the final unsym-
metrical (Z)-1,2-difluorostilbene (Eq. (5)).
2. Results and discussion
Our objective for the synthesis of unsymmetrical (E)- and (Z)-
1,2-difluorostilbenes was to start from an easily obtained and
stereospecific stating material: such as (E)- or (Z)-2-chloro-1,2-
difluoro-1-iodoethene [5], (E)- or (Z)-1-chloro-1,2-difluorostyr-
enes [6]. Initially, we carried out these reactions on a small scale to
establish the stereospecificity of the final product and to assist in
purification. We investigated several protocols to accomplish this
objective and these protocols are discussed in detail below.
3. Further butadienyl derivatives
To illustrate that the reaction can be extended further, we
developed a method for the preparation of a butadienyl silane
(Eq. (6)). By conventional methods, elaboration of the silane to a
stannane followed by Stille-type coupling with an aromatic iodide
would lead to an extended derivative [10]. Further coupling with
methods described in this account could yield 1,4-bis(aryl)-1,2,3,4-
tetrafluorobutadiene derivatives.
2.1. Protocol 1: Preparation of (E)- or (Z)-1,2-difluorostilbenes in
benzene/ethanol/water
Initially, sequential Suzuki couplings were attempted with
varied boronic acids and (E)- or (Z)-2-chloro-1,2-difluoro-1-
iodoethene. When a benzene/ethanol/water solvent mixture was
used, the 2nd step of the reaction required a significant amount of
time and heat while resulting in substantial amounts of a homo-
coupled boronic acid byproduct [7]. Electron-withdrawing groups
exacerbated the issue, requiring additional heat and time. Also,
when the compound contained a methoxy group on the aryl ring,
the product could not be effectively purified. In only one case were
we able to obtain reasonable yield and purity of the final product
(Eq. (3)).
4. Comparisons and conclusion
(E)- and (Z)-1,2-difluorostilbenes can be readily prepared by the
protocols 2, 3, or 4, since the 1,4-dioxane solvent system showed an
enhanced rate as compared to the benzene/ethanol/water solvent
mixture described in protocol 1. However, protocols 2 and 3 are
recommended for scale up as the 1-chloro-1,2-difluorostyrenes are
readily prepared in good yields [6] and further derivatization from
a common styrene could lead to a library of unsymmetrical (E)- and
(Z)-1,2-difluorostilbenes. We feel this methodology provided the
best stereospecific route to unsymmetrical (E)- or (Z)-1,2-
difluorostilbenes. Both NMR and Mass spectra data support the
assigned structures.
2.2. Protocol 2: Preparation of (E)-1,2-difluorostilbenes in 1,4-dioxane
Since the benzene/ethanol/water solvent mixture did not meet
our objective, we looked for a better solvent system to accomplish
the preparation of unsymmetrical 1,2-difluorostilbenes more
rapidly and to affect the purification of the final stilbene. Molander
and Yun have described coupling reactions of primary alkylboronic
acids in 1,4-dioxane [8]. Richards and coworkers have also
described Suzuki reactions aided by the use of 1,4-dioxane as a
solvent system [9]. To test the effectiveness of 1,4-dioxane as a
reaction solvent, the reactions were monitored by 19F-NMR
spectroscopy. 1,4-Dioxane showed a remarkable rate increase, as
compared to the benzene/ethanol/water mixture, for the Suzuki
coupling of (E)-1-chloro-1,2-difluorostyrenes. The reaction was
completed in less time and the amount of homocoupled product
was decreased [7]. Protocol 2 was successfully carried out for a
series of unsymmetrical (E)-1,2-difluorostilbenes with both
electron-withdrawing and electron-donating groups (Table 1).
5. Experimental
Routine 19F NMR spectra were recorded on a JEOL FX90Q
Spectrometer (83.81 MHz) and high-resolution data was obtained
on a Bruker AC-300 Spectrometer (282.41 MHz). Chemical shifts
have been reported in ppm relative to internal CFCl3. Spectra of
reaction mixtures were obtained in the 7Li external lock mode.
Quantitative determinations were carried out by integration
relative to internal benzotrifluoride. Routine 1H NMR
(300.17 MHz) spectra and high-resolution data were generally
obtained on a Bruker AC-300 Spectrometer. Unless noted other-
wise, CDCl3 was used as the NMR lock solvent. Chemical shifts have
been reported in ppm relative to internal TMS. High resolution {1H}
13C NMR spectra were recorded on a Bruker AC-300 Spectrometer
(75.48 MHz). Chemical shifts have been reported in ppm relative to
internal TMS. High-resolution mass spectra were obtained by the
University of Iowa, High Resolution Mass Spectrometry Facility.
Silica gel was purchased from EM Science (Silica Gel 60, particle
2.3. Protocol 3: Preparation of (Z)-1,2-difluorostilbenes in 1,4-dioxane
As expected, coupling of the (Z)-1-chloro-1,2-difluorostyrenes
was slightly slower, but gave reasonable yields and purity.
Occasionally, the reaction was terminated early to minimize
self-coupling of the boronic acid. A series of unsymmetrical (Z)-1,2-
difluorostilbenes with both electron-withdrawing and electron-
donating groups were successfully synthesized in moderate yields
and high purity (Table 2).
sized 0.063–0.200 mm, 70–230 Mesh, ASTM). The aryl boronic
acids were obtained commercially and used without further
purification. The 1-chloro-1,2-difluorostyrenes [6] and 2-chloro-
1,2-difluoro-1-iodoethene [5] were synthesized according to
literature. Pd(PPh3)4 was prepared by Coulson’s procedure [11].
Dry 1,4-dioxane was achieved by the addition of NaBH4. The
solution was filtered and distilled under argon until about 60–70%
of the 1,4-dioxane was distilled; the rest was destroyed with ice. It
was used immediately. As with all protocols, the reaction was
carried by bubbling Argon through the reaction mixture (Fig. 1).
2.4. Protocol 4: One-pot preparation of unsymmetrical (Z)-1,2-
difluorostilbenes
To expedite the synthetic procedure, we attempted sequential
couplings to (Z)-2-chloro-1,2-difluoro-1-iodoethene (Eqs. (4) and

208
C. Lim et al. / Journal of Fluorine Chemistry 185 (2016) 206–212
Table 1
Preparation of unsymmetrical (E)-1,2-difluorostilbenes in 1,4-dioxane.
Entry
X
Y
Yielda
(%)
t
(h)
ꢀC
2
3
3
4
5
m-CH3
p-OMe
p-F
2-thienyl
p-NO2
p-F
p-F
p-OMe
p-F
p-F
54
67
73
53
65
1.5
4
2
1.5
1.5
100
100
100
100
100
aIsolated yield.

C. Lim et al. / Journal of Fluorine Chemistry 185 (2016) 206–212
209
Table 2
Preparation of unsymmetrical (Z)-1,2-difluorostilbenes in 1,4-dioxane.
Entry
X
Y
Yielda
(%)
t (h)
ꢀC
6
7
8
9
p-Me
p-OMe
o-CF3
p-F
p-F
p-F
m-CF3
60
72
48
65
6
6
9
5
100
100
100
100
p-OMe
a
Isolated yield.
5.1. Protocol 1: Preparation of (E)-1-(4-fluorophenyl)-2-(4-
methylphenyl)-1,2-difluoroethene (1) in benzene/ethanol/water
reaction was stopped (1.5–4 h, Table 2) by the addition of 10 mL of
water. Organic materials were extracted by hexane (3 ꢁ15 mL) was
washed with water (10 mL). The combined organic layers were
dried over MgSO4 and concentrated by rotary evaporation. Silica
gel column chromatography gave the corresponding unsym-
metrical (E)-1,2-difluorostilbene.
A 100 mL 3-necked round bottom, as described above, was
charged with palladium tetrakis(triphenylphosphine) (0.09 g,
0.08 mmol) and 15 mL of benzene. Argon was bubbled through
the above solution via a steel needle for 30 min. Then, (E)-1-chloro-
2-iodo-1,2-difluoroethene (0.4 g, 1.8 mmol), 4-fluorophenylbor-
onic acid (0.21 g, 1.5 mmol), Na2CO3 (0.48 g, 4.5 mmol), and
20 mL of ethanol/water (1:1) were added to the Pd(0) solution.
The temperature of the reaction mixture was increased to the
reflux temperature (65 ꢀC) while Argon was bubbled through. After
12 h, 19F-NMR analysis showed competition of the Suzuki coupling
reaction of 4-fluorophenylboronic acid and (E)-1-chloro-2-iodo-
1,2-difluoroethene. Then, 4-tolylboronic acid (0.2 g, 1.5 mmol) was
added and the reaction mixture was returned to reflux. After 48 h,
19F NMR analysis showed 84% conversion. Volatiles were removed
by rotary evaporation. Organic materials were extracted by diethyl
ether (3 ꢁ 30 mL) and washed with water (20 mL). The combined
organic layers were dried over MgSO4 and concentrated by rotary
evaporation. Silica gel column chromatography (Rf = 0.4 in hexane)
gave 1 as white crystals (0.23 g, 0.93 mmol, 62% isolated yield,
mp = 82–83 ꢀC, purity = 99% by 1H NMR). 1H NMR (CDCl3): 7.74 (ddt,
5.3. (E)-1-(4-fluorophenyl)-2-(3-methylphenyl)-1,2-difluoroethene
(2)
Palladium tetrakis(triphenylphosphine) (0.06 g, 0.05 mmol),
8 mL dry 1,4-dioxane, (E)-1-chloro-2-(3-tolyl)-1,2-difluoroethene
(0.2 g, 1.06 mmol), 4-fluorophenylboronic acid (0.2 g, 1.2 mmol),
and K3PO4 (0.68 g, 3.2 mmol) gave 2 as white crystals (0.14 g,
0.57 mmol, 54% isolated yield, mp = 52–53 ꢀC, purity = 95% by 1H
4
NMR, Rf = 0.3 in hexane). 1H NMR (CDCl3): 7.74 (dd, JHF = 5.3 Hz,
0
JHF = 3.6 Hz, 2H), 7.56 (bs, 2H), 7.34 (t, 3,3 JHF = 7.9 Hz, 1H), 7.25–7.11
(m, 3H), 2.41 (s, 3H). 19F NMR (CDCl3): ꢂ151.8 (d, 3JFF = 121.4 Hz,1F),
3
ꢂ152.4 (d, JFF = 121.6 Hz, 1F), ꢂ111.8 (m, 1F). 13C NMR (CDCl3):
1
5
1
162.7 (dd, JCF = 249.9 Hz, JCF = 2.7 Hz), 148.3 (dd, JCF = 206.1 Hz,
2JCF = 18.4 Hz), 147.6 (dd, JCF = 193.7 Hz, JCF = 9.1 Hz), 138.2 (d,
1
2
4JCF = 1.9 Hz), 130.1 (dd, JCF = 21.6 Hz, JCF = 3.5 Hz), 129.9 (d,
2
3
5JCF = 1.9 Hz), 128.4 (d, JCF = 1.9 Hz), 127.9 (dt, JCF = 9.4 Hz,
4
3
3
4,5
3
3,4
2
3,4
4JHF = 5.3 Hz, JHH = 9.2 Hz,
J
= 2.3 Hz, 2H), 7.64 (d, JHH = 8.4 Hz,
J
= 8.1 Hz), 126.6 (dt, JCF = 22.4 Hz,
J = 3.4 Hz), 126.3 (dd,
HF
CF
CF
2H), 7.26 (d, 3JHH = 8.3 Hz, 2H), 7.14 (t, 3JHF = 3JHH = 8.8 Hz, 2H), 2.4 (s,
3JCF = 8.6 Hz, 4JCF = 7.9 Hz),123.0 (dd, 3JCF = 9.4 Hz, 4JCF = 8.0 Hz),115.6
3H). 19F NMR (CDCl3): ꢂ152.9 (d, JFF = 120.8 Hz, 1F), ꢂ152.4 (d,
(dd, JCF = 21.9 Hz, JCF = 1.8 Hz), 21.6 (s). HRMS (C15H11F3, calculat-
ed: 248.0813, observed: 248.0813). GC–MS 248 (M+, 93), 233 (49),
232 (39), 228 (49), 227 (46), 225 (21), 229 (23), 214 (E5), 207 (32),
206 (18), 201 (41),197 (20),196 (18),193 (17),188 (17),183 (93),181
(24), 175 (24), 170 (15), 169 (52), 162 (22), 151 (60), 137 (17), 132
(33),125 (40),120 (15),107 (13),107 (21),105 (19),101 (19), 99 (18),
98 (22), 96 (19), 95 (20), 91 (18), 90 (20), 89 (19), 87 (24), 86 (16), 81
(43), 77 (45), 75 (56), 74 (44), 69 (21), 68 (17), 66 (31), 65 (30), 63
(42), 62 (89), 57 (23), 56 (44), 52 (99), 51 (74), 50 (100), 41 (30).
3
2
4
3JFF = 120.8 Hz, 1F), ꢂ112 (m, 1F). 13C NMR (CDCl3): 162.6 (dd,
1JCF = 250.0 Hz, 5JCF = 1.5 Hz), 148.4 (dd, 1JCF = 186.9 Hz, 2JCF = 2.1 Hz),
147.3 (dd, 1JCF = 171.8 Hz, 2JCF = 13.9 Hz), 139.2 (d, 5JCF = 1.6 Hz), 129.2
4
3,30,4
3
2
(d, JCF = 1.4 Hz), 127.8 (q,
J
= 8.8 Hz), 127.2 (d, JCF = 18.5 Hz),
CF
2
3
126.6 (dd, JCF = 19.2 Hz, JCF = 3.9 Hz), 125.7 (dd, JCF = 8.6 Hz,
4JCF = 8.1 Hz), 115.6 (dd, JCF = 22.0 Hz, JCF = 1.6 Hz), 21.4 (s). HRMS
(C15H11F3, calculated: 248.0813, observed: 248.0813). GC–MS 248
(M+, 100), 233 (29), 232 (26), 183 (18).
2
4
5.2. Protocol 2: General preparation of (E)-1-(aryl)-2-(aryl0)-1,2-
difluoroethene (2–5) from (E)-1-chloro-1,2-difluorostyrenes.
5.4. (E)-1-(4-fluorophenyl)-2-(4-methoxyphenyl)-1,2-difluoroethene
(3)
A 50 mL 3-necked round bottom, as described above, was
charged with palladium tetrakis(triphenylphosphine), dry 1,4-
dioxane, (E)-1-chloro-2-aryl-1,2-difluoroethene, aryl-boronic acid,
and K3PO4. The temperature of the reaction mixture was increased
to the reflux temperature (100 ꢀC) while Argon was bubbled
through. After 19F NMR analysis indicated 100% conversion, the
Palladium tetrakis(triphenylphosphine) (0.03 g, 0.026 mmol),
4 mL dry 1,4-dioxane, (E)-1-chloro-2-(4-methoxyphenyl)-1,2-
difluoroethene (0.14 g, 0.68 mmol), 4-fluorophenylboronic acid
(0.12 g, 0.86 mmol), and K3PO4 (0.43 g 2.03 mmol) gave 3 as white
crystals (0.12 g, 0.46 mmol, 67% isolated yield, mp = 87–88 ꢀC,
purity = 95% by 1H-NMR, eluent 30:1 hexane/ethyl acetate). 1H-

210
C. Lim et al. / Journal of Fluorine Chemistry 185 (2016) 206–212
3
3JFF = 119.8 Hz, 1F), ꢂ145.2 (d, JFF = 119.9 Hz, 1F), ꢂ109.4 (m, 1F).
6
13C NMR (CDCl3): 163.4(dd, 1JCF = 250.6 Hz, JCF = 3.1 Hz), 150.1(dd,
2
5
1JCF = 241.5 Hz, JCF = 46.4 Hz), 147.4 (d, JCF = 3.0 Hz), 146.3 (ddd,
2
6
2
1JCF = 233.7 Hz, JCF = 47.0 Hz, JCF = 2.1 Hz), 136.1 (dd, JCF = 24.2 Hz,
3JCF = 6.7 Hz), 128.52 (dd, JCF = 16.5 Hz, JCF = 9.6 Hz), 128.51 (d,
2
3
3JCF = 9.6 Hz), 126.3 (dd, JCF = 10.8 Hz, JCF = 8.1 Hz), 123.9 (d, JCF
=
3
3
4
2
4
2.4 Hz), 116.0 (dd, JCF = 21.9 Hz, JCF = 2.0 Hz). HRMS (C14H8F3NO2,
calculated: 279.0507, observed: 279.0503).
5.8. Protocol 3: General preparation of (Z)-1-(aryl)-2-(aryl0)-1,2-
difluoroethene (6–9) from (Z)-1-chloro-1,2-difluorostyrenes
A 50 mL 3-necked round bottom, as described above, was
charged with palladium tetrakis(triphenylphosphine), dry 1,4-
dioxane, (Z)-1-chloro-2-aryl-1,2-difluoroethene, aryl-boronic acid,
and K3PO4. The temperature of the reaction mixture was increased
to the reflux temperature (100 ꢀC) while Argon was bubbled
through. After 19F NMR analysis indicated 100% conversion, the
reaction was stopped (5–9 h, Table 2) by the addition of 10 mL of
water. Organic materials were extracted by hexane (3 ꢁ15 mL) was
washed with water (10 mL). The combined organic layers were
dried over MgSO4 and concentrated by rotary evaporation. Silica
gel column chromatography gave the corresponding unsym-
metrical (Z)-1,2-difluorostilbene.
Fig. 1. Reaction apparatus.
3
NMR (CDCl3): 7.74–7.67 (m, 4H), 7.13 (t, JHH = 3JHF = 8.6 Hz, 2H),
6.97 (d, 4JHH = 8.6 Hz, 2H), 3.86 (s, 3H). 19F NMR (CDCl3): ꢂ154.2 (d,
3JFF = 120.6 Hz, 1F), ꢂ151.8 (d, 3JFF = 120.6 Hz, 1F), ꢂ112.1 (m, 1F). 13
C
1
5
NMR (CDCl3): 162.5 (dd, JCF = 248.0 Hz, JCF = 3.0 Hz), 160.1 (d,
5JCF = 2.5 Hz), 148.3 (ddd, 1JCF = 232.3 Hz, 2JCF = 47.1 Hz, 6JCF = 2.3 Hz),
1
2
2
146.7(dd, JCF = 229.8 Hz, JCF = 48.0 Hz), 127.6 (dd, JCF = 15.8 Hz,
3
3
3JCF = 9.5 Hz), 127.59 (d, JCF = 9.5 Hz), 127.4 (dd, JCF = 9.1 Hz,
2
3
3JCF = 7.8 Hz), 122.6 (dd, JCF = 24.6 Hz, JCF = 6.0 Hz), 115.6 (dd,
2JCF = 21.7 Hz, JCF = 2.0 Hz), 114.0 (d, JCF = 2.0 Hz), 55.3 (s). HRMS
4
4
5.9. (Z)-1-(4-fluorophenyl)-2-(4-methylphenyl)-1,2-difluoroethene
(6)
(C15H11F3O, calculated: 264.0762, observed: 264.0763).
5.5. (E)-1-(4-fluorophenyl)-2-(4-methoxyphenyl)-1,2-difluoroethene
(3)
Palladium tetrakis(triphenylphosphine) (0.03 g, 0.03 mmol),
6 mL dry 1,4-dioxane, (Z)-1-chloro-2-(4-tolyl)-1,2-difluoroethene
(0.1 g, 0.53 mmol), 4-fluorophenylboronic acid (0.08 g, 0.6 mmol),
and K3PO4 (0.34 g, 1.59 mmol) gave 6 as colorless liquid (0.08 g,
0.32 mmol, 60% isolated yield, purity = 99% by 1H NMR, Rf = 0.3 in
Palladium tetrakis(triphenylphosphine) (0.02 g, 0.017 mmol),
4 mL dry 1,4-dioxane, (E)-1-chloro-2-(4-fluorophenyl)-1,2-difluor-
oethene (0.12 g, 0.62 mmol), 4-methoxyphenylboronic acid (0.11 g,
0.72 mmol), and K3PO4 (0.39 g 1.84 mmol) gave 3 as white crystals
(0.12 g, 0.46 mmol, 73% isolated yield, mp = 87–88 ꢀC, eluent 30:1
hexane/ethyl acetate).
4
3
hexane). 1H NMR (CDCl3): 7.37 (ddm, JHF = 5.4 Hz, JHH = 8.2 Hz,
3
3
2H), 7.27 (d, JHH = 8.1 Hz, 2H), 7.17 (d, JHH = 8.2 Hz, 2H), 7.04 (t,
3JHF = 3JHH = 8.5 Hz, 2H), 2.40 (s, 3H). 19F NMR (CDCl3): ꢂ129.4 (d,
3JFF = 13.6 Hz, 1F), ꢂ127.4 (d, JFF = 13.7 Hz, 1F), ꢂ111.2 (m, 1F). 13C-
3
1
1
NMR (CDCl3): 163.1(d, JCF = 250.0 Hz), 145.5 (dd, JCF = 247.1 Hz,
5.6. (E)-1-(4-fluorophenyl)-2-(2-thienyl)-1,2-difluoroethene (4)
2JCF = 21.6 Hz), 144.3 (dd, JCF = 245.2 Hz, JCF = 21.6 Hz), 140.0 (s),
1
2
3
3,4
3,4
130.0 (dt, JCF = 8.0 Hz,
J
= 4.1 Hz), 129.3 (s), 128.0 (t,
J = 3.6
CF
CF
Palladium tetrakis(triphenylphosphine) (0.03 g, 0.026 mmol),
3 mL dry 1,4-dioxane, (E)-1-chloro-2-(4-fluoro)-1,2-difluoroe-
thene (0.10 g, 0.55 mmol), 2-thienylboronic acid (0.09 g,
0.64 mmol), and K3PO4 (0.35 g 1.65 mmol) gave 4 as white solid
(0.07 g, 0.29 mmol, 53% isolated yield, mp = 71–72 ꢀC, eluent
hexane). 1H NMR (CDCl3): 7.74–7.69 (m, 2H), 7.46–7.41 (m, 2H),
Hz), 126.9 (d, 2JCF = 24.5 Hz), 126.4 (dd, 2JCF = 24.8 Hz, 3JCF = 2.5 Hz),
2
115.7 (d, JCF = 21.9 Hz), 21.4 (s). HRMS (C15H11F3, calculated:
248.0813, observed: 248.0814). GC–MS 249 (18), 248 (M+, 97),
233 (100), 228 (20), 227 (38), 225 (16), 201 (19), 196 (19), 183 (59),
151 (17), 109 (16), 98 (21).
3
7.16–7.11 (m, 3H). 19F NMR (CDCl3): ꢂ149.3 (d, JFF = 117.9 Hz, 1F),
5.10. (Z)-1-(4-fluorophenyl)-2-(4-methoxyphenyl)-1,2-
difluoroethene (7)
3
ꢂ148.8 (d, JFF = 118.0 Hz, 1F), ꢂ111.7 (m, 1F). 13C NMR (CDCl3):
1
5
1
162.7 (dd, JCF = 248.7 Hz, JCF = 2.8 Hz), 145.9 (ddd, JCF = 189.0 Hz,
2JCF = 12.9 Hz, 6JCF = 1.7 Hz), 145.8 (dd, 1JCF = 192.9 Hz, JCF = 11.9 Hz),
2
Palladium tetrakis(triphenylphosphine) (0.06 g, 0.06 mmol),
12 mL dry 1,4-dioxane, (Z)-1-chloro-2-(4-methoxyphenyl)-1,2-
difluoroethene (0.2 g, 1.0 mmol), 4-fluorophenylboronic acid
(0.16 g,1.2 mmol), and K3PO4 (0.68 g, 3.18 mmol) gave 7 as colorless
liquid (0.19 g, 0.72 mmol, 72% isolated yield, purity = 99% by 1H-
NMR, Rf = 0.05 in hexane). 1H-NMR (CDCl3): 7.29 (dd, 3JHH = 8.9 Hz,
2
3
2
131.6 (dd, JCF = 24.1 Hz, JCF = 3.7 Hz), 128.7 (dd, JCF = 29.6 Hz,
3JCF = 2.2 Hz), 127.4 (t, JCF = 4JCF = 12.7 Hz), 127.37 (d, JCF = 9.0 Hz),
3
4
127.3 (s), 125.6 (t, JCF = 4JCF = 5.4 Hz), 115.8 (dd, JCF = 21.8 Hz,
4JCF = 1.9 Hz). HRMS (C12H7F3S, calculated: 240.0221, observed:
240.0226).
3
2
3
3
4JHF = 5.3 Hz, 2H), 7.25 (d, JHH = 9.0 Hz, 2H), 6.96 (t, JHH =3JHF = 8.7
5.7. (E)-1-(4-fluorophenyl)-2-(4-nitrophenyl)-1,2-difluoroethene (5)
Hz, 2H), 6.82 (d, JHH = 8.9 Hz, 2H), 3.79 (s, 3H). 19F-NMR (CDCl3):
3
ꢂ130.8 (d, 3JFF = 14.9 Hz,1F), ꢂ126.2 (d, 3JFF = 14.9 Hz,1F), ꢂ111.3 (bs,
Palladium tetrakis(triphenylphosphine) (0.03 g, 0.026 mmol),
4 mL dry 1,4-dioxane, (E)-1-chloro-2-(4-nitrophenyl)-1,2-difluor-
oethene (0.12 g, 0.55 mmol), 2-thienylboronic acid (0.09 g,
0.64 mmol), and K3PO4 (0.35 g 1.65 mmol) gave 5 as white solid
(0.10 g, 0.36 mmol, 65% isolated yield, mp = 117–118 ꢀC, eluent 20:1
hexane/ethyl acetate). 1H NMR (CDCl3): 8.31 (d, 3JHH = 8.6 Hz, 2H),
1F). 13C-NMR (CDCl3): 163.0 (d, 1JCF = 250.1 Hz), 160.6(s), 145.4 (dd,
1JCF = 247.4 Hz, JCF = 20.8 Hz), 143.9 (dd, JCF = 244.8 Hz, JCF = 22.0
Hz), 129.9 (dt, 3JCF = 13.4 Hz, 3,4JCF = 3.9 Hz), 129.8 (t, 3,4JCF = 3.5 Hz),
126.5 (dd, 2JCF = 25.0 Hz, 3JCF = 3.5), 122.1 (d, 2JCF = 24.8 Hz), 115.6 (d,
2JCF = 22.0 Hz), 114.1 (s), 55.3 (s). HRMS (C15H11OF3, calculated:
264.0762, observed: 248.0758). GC–MS 264- (M+, 55), 249 (32),
201 (100), 57 (19), 51 (18), 50 (20).
2
1
2
3
4
3
7.80 (dd, JHH = 9.1 Hz, JHF = 5.3 Hz, 2H), 7.92 (d, JHH = 9.2 Hz, 2H),
3
7.19 (t, JHH =3JHF = 8.5 Hz, 2H). 19F NMR (CDCl3): ꢂ154.1 (d,

C. Lim et al. / Journal of Fluorine Chemistry 185 (2016) 206–212
211
5.11. (Z)-1-(4-fluorophenyl)-2-(2-trifluoromethylphenyl)-1,2-
difluoroethene (8)
with water (15 mL). The combined organic layers were dried over
MgSO4, and concentrated by rotary evaporation. Silica gel column
chromatography (Rf = 0.45 in hexane) gave 10 as white crystals
(0.60 g, 2.6 mmol, 68% isoiated yield, mp = 51–53 ꢀC, purity = 99% by
1H-NMR). 1H NMR (CDCl3): 7.34–7.28 (m, 7H), 6.98 (t, 3JHF = 8.5 Hz,
Palladium tetrakis(triphenylphosphine) (0.03 g, 0.026 mmol),
3 mL dry 1,4-dioxane, (Z)-1-chloro-2-(2-trifluoromethylphenyl)-
1,2-difluoroethene (0.1 g, 0.41 mmol), 4-fluorophenylboronic acid
(0.07 g, 0.50 mmol), and K3PO4 (0.26 g, 1.23 mmol) gave 8 as
colorless oil (0.06 g, 0.2 mmol, 48% isolated yield, eluent hexane).
3
2H). 19F-NMR (CDCl3): ꢂ128.0 (d, JFF = 13.8 Hz, 1F), ꢂ128.6 (d,
3JFF = 13.9 Hz, 1F), ꢂ110.8 (m, 1F). 13C NMR (CDCl3): 163.2 (d,
2
1JCF = 250.9 Hz), 145.4 (dd, 1JCF = 247.3 Hz, JCF = 21.1 Hz), 144.7 (dd,
3
3
1H NMR (CDCl3): 7.81 (d, JHH = 7.6 Hz, 1H), 7.59 (td, JHH =3JHH
=
1JCF = 246.2 Hz, 2JCF = 20.8 Hz), 130.2 (dt, 3JCF = 8.2 Hz, 3,4JCF = 3.7 Hz),
130.0 (d, 2JCF = 24.1 Hz), 129.6 (s), 128.6 (s), 128.0 (t, 3,4JCF = 4.2 Hz),
126.2 (dd, 2JCF = 24.6 Hz, 3JCF = 3.3 Hz),115.7 (d, 2JCF = 22.1 Hz). HRMS
(C14H9F3, calculated: 234.0656, observed: 234.0658). GC–MS 234
(M+, 75), 233 (28), 232 (17), 219 (17), 214 (100),183 (66), 81 (28), 75
(20), 74 (25), 63 (22), 62 (25), 57 (43), 51 (79), 50 (73).
7.6 Hz, JHH = 0.6 Hz, 1H), 7.51 (t, JHH =3JHH = 7.5 Hz, 1H), 7.37 (d,
4
3
3
4
3JHH = 7.6 Hz, 1H), 7.10 (dd, JHH = 8.9 Hz, JHF = 5.3 Hz, 2H), 6.90 (t,
3JHH,=3JHF = 8.5 Hz, 2H). 19F-NMR (CDCl3): ꢂ130.7 (d, JFF = 15.5 Hz,
3
1F), ꢂ117.6 (m, 1F), ꢂ111.1 (m, 1F), ꢂ61.3 (d, 4JFF = 10.4 Hz, 3F). 13C-
1
1
NMR (CDCl3): 162.9 (d, JCF = 249.0 Hz), 145.5 (dd, JCF = 246.5 Hz,
1
2
2JCF = 20.6 Hz), 142.6 (dd, JCF = 250.2 Hz, JCF = 22.9 Hz), 133.4 (t,
3JCF = 4JCF = 2.3 Hz), 132.4 (s), 130.9 (d, JCF = 2.6 Hz), 130.8 (qd,
5.14. Protocol 4b: Preparation of (Z)-1-(3-nitrophenyl)-2-(phenyl)-
1,2-difluoroethene (11)
4
2JCF = 25.2 Hz, JCF = 2.5 Hz), 129.1 (ddd, JCF = 8.4 Hz, JCF = 5.0 Hz,
3
3
3
4JCF = 3.4 Hz), 127.9 (dt, JCF = 23.1 Hz, JCF = 4JCF = 2.0 Hz), 127.3 (qd,
2
3
3JCF = 4 .9 Hz, JCF = 2.1 Hz), 125.5 (dd, JCF = 24.6 Hz, JCF = 3.5 Hz),
A 50 mL 3-necked round bottom, as described above, was
charged with palladium tetrakis(triphenylphosphine) (0.03 g,
4
2
3
1
2
123.4 (q, JCF = 272.3 Hz), 115.6 (d, JCF = 21.9 Hz). HRMS (C15H8F6,
calculated: 302.0530, observed: 302.0531).
0.03 mmol),
(Z)-1-chloro-2-iodo-1,2-difluoroethene
(0.22 g,
1 mmol) and 12 mL of dry dioxane. Argon was bubbled through
above Pd(0) solution by a syringe needle for 30 min. Then,
phenylboronic acid (0.13 g, 1.1 mmol) and K3PO4 (0.64 g, 3 mmol)
were added to the above solution. The temperature of the reaction
mixture was increased to the reflux (100 ꢀC) while argon was
bubbled through the reaction mixture. 19F-NMR analysis indicated
100% conversion after reflux for 2 hours. To the above reaction
mixture, (3-nitrophenyl) boronic acid (0.17 g, 1.1 mmol), palladium
tetrakis(triphenylphosphine) (0.01 g, 0.01 mmol), and K3PO4
(0.42 g, 2 mmol) were added. The temperature of the reaction
mixture was increased again to the reflux (100 ꢀC). After 19F NMR
analysis indicated 100% conversion, the reaction was stopped (6 h).
Water (10 mL) was added to the reaction mixture. Organic
materials were extracted by hexane (3 ꢁ 20 mL) and washed with
water (20 mL). The organic layer was dried over anhydrous MgSO4,
and concentrated by rotary evaporation. Silica gel column
chromatography (Rf = 0.05 in hexane) gave 11 as yellow crystals
(0.18 g, 0.69 mmol, 69% isolated yield, mp = 38–39 ꢀC, purity = 98%
by 1H NMR). 1H NMR (CDCl3): 8.19 (bt, 4,5JHF = 1.9 Hz, 1H), 8.16 (bd,
5.12. (Z)-1-(4-methoxyphenyl)-2-(3-trifluoromethylphenyl)-1,2-
difluoroethene (9)
Palladium tetrakis(triphenylphosphine) (0.03 g, 0.026 mmol),
4 mL dry 1,4-dioxane, (Z)-1-chloro-2-(4-methoxyphenyl)-1,2-
difluoroethene (0.14 g, 0.68 mmol), 3-trifluoromethylphenylbor-
onic acid (0.16 g, 0.84 mmol), and K3PO4 (0.43 g, 2.00 mmol) gave 9
as yellow oil (0.14 g, 0.45 mmol, 65% isolated yield, eluent 40:1
hexane/ethyl acetate). 1H NMR (CDCl3): 7.60 (s, 1H), 7.54 (d,
3
3
3JHH = 7.6 Hz, 1H), 7.44 (d, JHH = 7.6 Hz, 1H), 7.37 (t, JHH =3JHH = 7.9
3
4
3
Hz, 1H), 7.29 (dd, JHH = 9.0 Hz, JHH = 1.0 Hz, 2H), 6.86 (d, JHH
=
8.3 Hz, 2H). 19F-NMR (CDCl3): ꢂ121.8 (d, 3JFF = 14.2 Hz, 1F), ꢂ134.2
(d, JFF = 14.2 Hz, 1F), ꢂ63.4 (s, 3F). 13C NMR (CDCl3): 161.6 (d,
3
5JCF = 1.2 Hz), 146.6 (dd, JCF = 249.3 Hz, JCF = 20.1.Hz), 143.4 (dd,
1JCF = 242.8 Hz, 2 JCF = 22.3 Hz), 131.4 (dd, 2JCF = 24.7 Hz, 3JCF = 1.4 Hz),
131.0 (q, 2JCF = 32.5 Hz), 130.6 (m), 130.1 (t, 3JCF = 4JCF = 3.3 Hz), 128.9
1
2
3
3
4
(s), 125.6 (q, JCF = 3.7 Hz), 124.3 (dd, JCF = 8.7 Hz, JCF = 3.9 Hz),
123.7 (q, 1JCF = 270.8 Hz), 121.6 (d, 2JCF = 24.5 Hz), 114.3 (s), 55.4 (s).
HRMS (C16H11OF5, calculated: 314.0730, observed: 314.0728).
3JHH = 8.2 Hz, 1H), 7.58 (bd, 3JHH = 8.2 Hz, 1H), 7.45–7.36 (m, 6H). 19
F
NMR (CDCl3): ꢂ133.0 (d, 3JFF = 12.5 Hz, 1F), ꢂ121.3 (d, 3JFF = 12.4 Hz,
1
2
5.13. Protocol 4a: Preparation of (Z)-1-(4-fluorophenyl)-2-(phenyl)-
1,2-difluoroethene (10)
1F). 13C NMR (CDCl3): 148.3 (s), 147.1 (dd, JCF = 252.5 Hz, JCF
=
1
2
20.2 Hz), 143.3 (dd, JCF = 246.2 Hz, JCF = 22.4 Hz), 133.2 (dd,
3JCF = 4.4 Hz, JCF = 2.9 Hz), 132.0 (dd, JCF = 25.2 Hz, JCF = 1.5 Hz),
4
2
3
A 50 mL 3-necked round bottom, as described above, was
charged with acid washed zinc powder (0.39 g, 6.0 mmol) and 7 mL
of THF. Then, (Z)-1-chloro-2-iodo-1,2-difluoroethene (1.12 g,
5.0 mmol) was transferred to the above solution via syringe. The
130.6 (d, 4JCF = 1.8 Hz), 129.5 (s), 129.2 (bd, 2JCF = 23.4 Hz), 129.0 (s),
3,4
3
4
128.5 (t,
J = 3.0 Hz), 123.9 (s), 122.5 (dd, JCF = 5.1 Hz, JCF = 3.8
CF
Hz). HRMS (C14H9F2O2N, calculated: 261.0601, observed:
261.0597). GC ꢃ MS 261 (M+, 100), 215 (18), 214 (90), 194 (16),
165 (26), 164 (15), 50 (17).
reaction mixture was stirred for 1 hour at reflux temperature. 19
F
NMR confirmed the generation of the corresponding zinc reagent
(99% NMR yield). Another 50 mL 3-necked round bottom, as
described above, was charged with 1-fluoro-4-iodobenzene
(0.85 g, 3.85 mmol), and palladium tetrakis(triphenylphosphine)
(0.22 g, 0.19 mmol). The pregenerated zinc reagent was added
dropwised to the Pd(0) soiution via a syringe. The reaction mixture
was stirred for 2 h at the reflux temperature, and 19F NMR analysis
showed the formation of (Z)-1-chloro-2-(4-fluorophenyl)-1,2-
difluoroethene (98% NMR yield). Without isolation of the product,
the reaction mixture was mixed with phenylboronic acid (0.56 g,
4.6 mmol), KOH (0.85 g, 15.2 mmol), palladium tetrakis(triphenyl-
phosphine) (0.22 g, 0.19 mmol), and 15 mL of water. The reaction
mixture was stirred for 24 hours at reflux temperature, and the
completion of the reaction was confirmed by 19F NMR analysis.
After removal of volatiles by rotary evaporation, the organic
material was extracted by diethyl ether (3 ꢁ10 mL) and washed
5.15. Preparation of (1E,3Z)-1-chloro-1,2,3,4-difluoro-4-
trimethylsilylbutadiene (12)
A 50 mL 3-necked round bottom, as described above, was
charged with acid washed zinc powder (0.39 g, 6.0 mmol) and 7 mL
of THF. Then, (Z)-1-chloro-2-iodo-1,2-difluoroethene (1.12 g,
5.0 mmol) was transferred to the above solution via syringe. The
reaction mixture was stirred for 1 hour at reflux temperature, and
19F NMR analysis confirmed generation of the corresponding zinc
reagent (98% NMR yield). The stirring of the reaction mixture was
stopped to settle down unreacted zinc metal for over 1 h. The
concentration of the THF solution of the zinc reagent was
estimated to be 0.88 M by 19F NMR analysis using an internal
standard (trifluorotoluene). Another 50 mL 3-necked round
bottom, as described above, was charged with (E)-1-iodo-2-

212
C. Lim et al. / Journal of Fluorine Chemistry 185 (2016) 206–212
trimethylsilyl-1,2-difluoroethene (3.0 g, 11.3 mmol) and palladium
tetrakis(triphenylphosphine) (0.69 g, 0.7 mmol). The pregenerated
zinc reagent was added dropwised to the Pd(0) solution via
Acknowledgements
We wish to thank the National Science Foundation and the Air
Force Office of Scientific Research for support of this work. D.J.
wishes to thank Michael Sinnwell for help with manuscript
preparation.
syringe. The reaction mixture was stirred for 8 h at the reflux. 19
F
NMR analysis showed the formation of (1E,3Z)-1-chloro-1,2,3,4-
tetrafluoro-4-trimethylsilylbutadiene (96% NMR yield). Volatiles
including the product were flash distilled and collected by a liquid
nitrogen trap. Simple distillation (bp = 122–124 ꢀC) of the distillates
under atmospheric pressure gave 12 (1.96 g, 8.44 mmol, 75%
isolated yield, purity = 93% by 1H NMR). 1H NMR (CDCl3): 0.29 (dd,
References
[1] For a typical example:, J. Guo-Zhen, C. Guo-Fei, W. Zong-Mei, J. Xi-Kui, Acta
Chim. Sin. 5 (1987) 273–279.
[2] D.J. Burton, C.A. Wesolowski, Q. Liu, C.R. Davis, J. Fluorine Chem. 131 (2010)
989–995.
5
4JHF = 1.3 Hz, JHF = 0.8 Hz, 9H). 19F NMR (CDCl3): ꢂ157.6 (bdd,
3
3
4
3JFF = 137.3 Hz, JFF = 34.4 Hz, 1F), ꢂ148.2 (ddd, JFF = 139.1 Hz, JFF
=
5
3
4
[3] (a) Q. Liu, D.J. Burton, J. Fluorine Chem. 131 (2010) 1082–1085;
11.1 Hz, JFF = 11.1 Hz, 1F), ꢂ141.0 (ddd, JFF = 35.1 Hz, JFF = 12.0 Hz,
(b) Q. Liu, D.J. Burton, Org. Lett. 4 (2002) 1483–1485.
3JFF = 8.7 Hz, 1F), ꢂ96.2 (ddd, JFF = 10.1 Hz, JFF = 10.1 Hz, JFF = 4.5
3
5
3
[4] J., Irisawa, O., Yokokoji, T., Shimizu, Y., Ishida, H., Ko, K., Oike, K., Machida, Asahi
Glass Co., Ltd., Japan, Seimi Chem Kk. Difluorostilbene compounds, liquid-
crystal compositions thereof, and liquid-crystal display devices, Patent, 1994.
[5] C. Lim, C.A. Wesolowski, D.J. Burton, J. Fluorine Chem. 159 (2014) 21–28.
[6] C. Lim, D.J. Burton, J. Fluorine Chem. 167 (2014) 61–73.
[7] Unpublished results:, C. Lim, Ph.D. Thesis, University of Iowa, 2004 pp. 181.
[8] G.A. Molander, C. Yun, Tetrahedron 58 (2002) 1465–1470.
[9] T.E. Pickett, F.X. Roca, C.J. Richards, J. Org. Chem. 68 (2003) 2592–2599.
[10] S. Lukaszewski-Rose, D.J. Burton, J. Fluorine Chem. 179 (2015) 23–32.
[11] D.R. Coulson, Inorg. Synth. 13 (1972) 121–124.
Hz, 1F). 13CNMR (CDCl3): 163.1 (ddt, JCF = 284.1 Hz, JCF = 71.7 Hz,
1
2
3,4
J
= 2.5 Hz), 149.7 (dddd, 1JCF = 226.9 Hz, 2JCF = 38.5 Hz, 2JCF = 23.7
CF
3
1
2
3
Hz, JCF = 2.1 Hz), 141.2 (dddd, JCF = 307.0 Hz, JCF = 32.2 Hz, JCF
=
4
1
2
7.4 Hz, JCF = 4.2 Hz), 133.1 (dddd, JCF = 250.1 Hz, JCF = 32.2 Hz,
2JCF = 23.1 Hz, 3JCF = 2.3 Hz), ꢂ2.9 (bt,
J = 2.0 Hz). HRMS
CF
4,5
(C7H9F435Cl28Si, calculated: 232.0098, observed: 232.0096). GC–
MS 234 (M+ + 2, 0.04), 232 (M+, 0.08), 142 (17), 140 (50), 109 (24),
101 (30), 93 (15), 90 (31), 81.4 (34), 80.5 (40), 77.4 (87), 76.6 (100),
73(30), 63 (18), 62 (24), 49.3 (35), 48.6 (51), 47 (35), 46 (52), 45 (16),
43 (89).