Room temperature preparation of α-chloro-β,β- difluoroethenylzinc reagent (CF2CClZnCl) by the metallation of HCFC-133a (CF3CH2Cl) and a high yield one-pot synthesis of α-chloro-β,β-difluorostyrenes

Article abstract of DOI:10.1016/j.jfluchem.2005.03.021

α-Chloro-β,β-difluorovinylzinc reagent [CF ₂CClZnCl] was generated in 91% yield by the metallation of a THF solution of commercially available HCFC-133a (CF₃CH₂Cl) and zinc chloride at 15-20 °C using LDA as base. The corresponding reaction with Halothane (CF₃CHClBr) produced a poor yield of CF ₂CClZnCl. The palladium catalyzed coupling reaction of the CF ₂CClZnCl with aryl iodides under mild reaction conditions produced α-chloro-β,β-difluorostyrenes in 64-90% isolated yields. The stability of the intermediate CF₂CClLi and the nature of the zinc reagents are discussed.

Full text of DOI:10.1016/j.jfluchem.2005.03.021

Journal of Fluorine Chemistry 126 (2005) 835–843
www.elsevier.com/locate/fluor
Room temperature preparation of a-chloro-b,b-difluoroethenylzinc
reagent (CF CClZnCl) by the metallation of HCFC-133a
2
(
CF CH Cl) and a high yield one-pot synthesis
3
2
of a-chloro-b,b-difluorostyrenes
*
R. Anilkumar, Donald J. Burton
Department of Chemistry, The University of Iowa,
4
05 CB, Iowa City, IA 52242, USA
Received 19 February 2005; received in revised form 24 March 2005; accepted 29 March 2005
Abstract
a-Chloro-b,b-difluorovinylzinc reagent [CF
commercially available HCFC-133a (CF CH Cl) and zinc chloride at 15–20 8C using LDA as base. The corresponding reaction with
2
CClZnCl] was generated in 91% yield by the metallation of a THF solution of
3
2
TM
Halothane (CF
aryl iodides under mild reaction conditions produced a-chloro-b,b-difluorostyrenes in 64–90% isolated yields. The stability of the
intermediate CF CClLi and the nature of the zinc reagents are discussed.
2005 Elsevier B.V. All rights reserved.
3 2 2
CHClBr) produced a poor yield of CF CClZnCl. The palladium catalyzed coupling reaction of the CF CClZnCl with
2
#
Keywords: HCFC-133a; Chlorodifluorovinylzinc; Pd(0) coupling; Chlorodifluorovinyllithium; a-Chloro-b,b-difluorostyrene; Metallation; Transmetallation;
TM
Halothane
1
. Introduction
oacetate in HMPA followed by the trapping of the carbene
with chlorodifluoroacetophenone produced an accidental
formation of a-chloro-b,b-difluorostyrene along with the
desired alcohol [2]. A more traditional route for a-halo-b,b-
difluorostyrene was by a two-step process: addition of
The a-halo-b,b-difluorostyrenes are building blocks in
organofluorine chemistry not only due to the reactivity of the
gem-difluoromethylene unit towards nucleophilic reagents
but also by the possible functionalization at the halogen site.
There are not many convenient methods available for the
general synthesis of a-halo-b,b-difluorostyrenes. The few
methods reported for the synthesis of a-chloro-b,b-
difluorostyrenes were not general or involved multi step
procedure with low overall yields. Cohen developed a multi-
step procedure, where zinc mediated dehalogenation of an
appropriate precursor produced a-chloro-b,b-difluorostyr-
ene in low overall yield [1]. In another method, lithium
chloride mediated decarboxylation of methylchlorodifluor-
halogen to RCH CF [3,4] followed by dehydrohalogena-
2
tion using a selective base [5]. Though this method is not
t
general, the use of bases like Li CO or KO Bu improved the
2
3
yield of the a-halo-b,b-difluorostyrene significantly. Treat-
ment of benzotrichlorides in presence of chlorodifluoro-
methane at 575 8C has been reported to produce a-chloro-
b,b-difluorostyrene in poor yield along with (a,b,b-
trichloro-b,b-difluoroethyl)benzene as a by product [6].
Recent advancement in the synthesis of a,b,b-trifluor-
ostyrenes via trifluorovinylzinc synthon, broadened the
scope for the synthesis a-halo-b,b-difluorostyrene through
the corresponding zinc reagent [7–10]. One such method
was recently reported from this laboratory where a-bromo-
*
Corresponding author. Tel.: +1 319 335 1368; fax: +1 319 335 1270.
E-mail address: donald-burton@uiowa.edu (D.J. Burton).
0022-1139/$ – see front matter # 2005 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2005.03.021

836
R. Anilkumar, D.J. Burton / Journal of Fluorine Chemistry 126 (2005) 835–843
b,b-difluorostyrenes were synthesized by the Pd(0) cata-
lyzed coupling of CF2 CBrZnBr with aryl iodides [11].
Normant and co-workers generated various fluorovinylzinc
reagents including a-chloro-b-fluorovinylzinc reagent by
the metallation of halo or hydro fluoroalkenes via the
corresponding vinyllithium species [12–16]. But fluorinated
vinyllithiums are thermally unstable and need to be
generated at very low temperature in order to have
reasonable yield of the zinc reagent [17–19].
Scheme 1. Synthesis of a-chloro-b,b-difluorovinylzinc reagent by the
metallation of CF CH Cl.
3
2
2. Results and discussion
Kumudaki and co-workers reported the generation of the
a-chloro-b,b-difluorovinylzinc reagent under relatively
2.1. Metallation of 1-chloro-2,2,2-trifluoroethane
(HCFC-133a)
highertemperature(ꢀ60 8C)bythemetallationofCF CHCl
2
[
20,21] and 1-bromo-1-chloro-2,2,2-trifluoroethane (Haloth-
Following the reaction conditions standardized for the
metallation of 1,1,1,2-tetrafluoroethane (HFC-134a), reac-
tion of 1-chloro-2,2,2-trifluoroethane (HCFC-133a) with
TM
ane )[22].Buttheinterpretationofthiszincreagentasanew
zinc reagent compared to the zinc reagent generated by the
Normant procedure was questionable, and the spectral data
described were different from each other. The assigned bis
cioid/transoid interpretation of the zinc reagent is highly
unlikely and we have proposed the observed spectra could be
of the starting material (CF2 CHCl) [23].
LDA in presence of ZnCl at 15 8C, produced a 91% yield of
2
1
the a-chloro-b,b-difluorovinylzinc reagent ( F NMR vs.
9
PhCF ) (Scheme 1). When ZnCl was replaced with ZnI in
2
3
2
this metallation reaction the resultant CF2 CClZnI was
formed in 89% yield (Scheme 1).
Recently, Coe and co-workers identified fluorocarbon
HFC-134a and HCFC-133a as excellent precursors for the
generation of trifluorovinyllithium and a-chloro-b,b-
difluorovinyllithium at low temperature [24,25]. Based
on this method, we have recently developed an excellent
room temperature preparation of the trifluorovinylzinc
reagent by the metallation of HFC-134a, and this reagent
was utilized for Pd(0) catalyzed coupling reactions with
aryl iodides to obtain a,b,b-trifluorostyrenes under mild
reaction conditions [26, 27]. We have then applied similar
strategy for the synthesis of a-halo-b,b-difluorovinylzinc
reagents [CF2 CXZnX, where X = Cl, Br, I] and the
corresponding a-halo-b,b-difluorostyreness by the metal-
lation of the corresponding commercially available
precursors [23,28,29]. This methodology serves as the
first general methodology for the synthesis of a-halo-b,b-
difluorovinylzinc reagents and corresponding a-halo-b,b-
difluorostyrenes. In our previous communication we have
described the synthesis of a-chloro-b,b-difluorovinylzinc
reagent by the metallation of HCFC-133a [23]. In that
Treatment of this zinc reagent with acetic acid or iodine
produced the corresponding hydrolysis product (CF2 CFH)
or iodinolysis product (CF2 CClI) in quantitative yields,
1
9
thus confirming the formation of the zinc reagent. The
F
NMR analysis of the zinc reagent mixture showed peaks for
the mono and bis zinc reagents complexed to both THF and
diisopropylamine. The major doublets at ꢀ78.9 and ꢀ92.7
with J = 59 Hz were assigned to the mono zinc reagent
FF
complexed to THF and/or diisopropylamine. Addition of
stiochiometric amount of TMEDA to the medium produced
one set of peaks resulting from the preferential complexation
of the mono and bis zinc reagent (mono/bis 70:30)
complexed to TMEDA over diisopropylamine or THF.
The major doublets appeared at ꢀ76.7 and ꢀ91.0 with a
coupling constant of 56 Hz corresponding to the mono zinc
reagent complexed to TMEDA and shoulder doublets at
ꢀ76.3 (behind the major doublet) and ꢀ92.1 (front of major
doublet) with a coupling constant of 58 Hz corresponding to
1
9
the bis zinc reagent complexed to TMEDA. The F NMR
chemical shifts of the TMEDA complexes of mono and bis
zinc reagents are summarized in Fig. 1.
1
9
report, we have unequivocally assigned the F NMR
chemical shifts for the a-chloro-b,b-difluorovinylzinc
reagent and confirmed that the spectral data for this zinc
reagent was similar to that generated by the Normant
method. Herein we describe the full account of this study
concerning the development of a general synthetic method
for a-chloro-b,b-difluorostyrenes via a-chloro-b,b-
difluorovinylzinc reagent.
In order to demonstrate unequivocally that the above
chemical shifts assignments for the mono and bis zinc
1
9
reagents were correct, we have performed a series of
F
NMR experiments (Scheme 2). At first we have attempted to
generate only the bis zinc reagent by using half equivalent of
zinc chloride rather than the usual one equivalent. This
experiment produced exclusively the bis zinc reagent and the
19
Fig. 1. The F NMR chemical shifts of TMEDA complexes of mono and bis zinc reagents.

R. Anilkumar, D.J. Burton / Journal of Fluorine Chemistry 126 (2005) 835–843
837
2
Scheme 2. Schlenk Equilibrium between the mono and bis zinc reagents via ZnCl .
The increase in the yield of the chlorodifluorovinylzinc
reagent (91% by the metallation of HCFC-133a) compared to
that of trifluorovinylzinc reagent (73% by the metallation of
HFC-134a) [26,27] under similar reaction conditions is most
likely due to the increased stability of the intermediate chloro-
difluorovinyllithium compared to trifluorovinyllithium. In
order to gain a better understanding of the stability of the
chlorodifluorovinyllithium we have performed a series of
experiments where the [CF2 CClLi] was generated at
ꢀ
80 8C using LDA in THF-TMEDA medium and the
1
9
Fig. 2. The F NMR of the bis-a-chloro-b,b-difluorovinylzinc reagent in
THF-TMEDA.
resulting solution was warmed to ꢀ10 8C (at ꢀ15 to ꢀ10 8C
the solution turned completely dark) and quenched with zinc
chloride to produce a 69% yield of the zinc reagent. The
reaction under similar conditions without TMEDA produced
a 60% yield of the zinc reagent. Though the solution of
CF2 CClLi turned dark during the warming process, most of
the [CF2 CClLi] was still intact at ꢀ10 8C in both the
experiments as detected by the significant formation of the
zinc reagent upon transmetallation. But similar thermal
stability experiments for trifluorovinyllithium (CF2 CFLi
was generated with or without TMEDA at ꢀ80 8C and
warmed to 0 8C) produced only less than 5% yield of the zinc
reagent [27]. These observations clearly show that CF2 CFLi
chemical shifts and splitting pattern of this zinc reagent
matched exactly for the minor component of the usual
reaction, thus proving that the major zinc reagent in the usual
reaction is the mono reagent (Fig. 2). We then added another
one equiv. of ZnCl to this reaction mixture to shift the
2
equilibrium (Scheme 2) to the mono side and obtained an
85:15 mixture of the mono and bis zinc reagents proving that
our assignments of the mono and bis zinc reagents were
correct (Fig. 3). In another experiment we increased the
concentration of ZnCl from 0.5 to 0.75 equivalents, and this
2
reaction produced a 35:65 mixture of the mono and bis zinc
reagents and the ratio changed to 85:15 when excess (1
decomposed almost completely at a much lower temperature
i
(ꢀ25 8C in TMEDA/THF and ꢀ45 8C in presence of Pr NH/
2
equiv.) ZnCl was added to this reaction mixture. These
2
THF [27]) and these experiments confirmed the increased
stability of [CF2 CClLi] compared to [CF2 CFLi] at higher
temperature.
experiments confirm the presence of a Schlenk equilibrium
between the mono and bis zinc reagents through zinc
chloride (Scheme 2).
2.2. Derivatization of a-chloro-b,b-difluorovinylzinc
reagent to a-chloro-b,b-difluorostyrenes
A coupling reaction, performed with this zinc reagent and
iodobenzene using tetrakis(triphenylphosphine)palladium
catalyst at 65 8C, produced the a-chloro-b,b-difluorostyrene
in 94% NMR yield. The isolated yield of the styrene was
77% (Scheme 3).
After the successful synthesis of the parent a-chloro-b,b-
difluorostyrene, this methodology was utilized for the
synthesis of a series of substituted a-chloro-b,b-difluor-
ostyrene styrenes. Thus the zinc reagent was coupled with
1
9
Fig. 3. The F NMR of the mono and bis-a-chloro-b,b-difluorovinylzinc
reagent mixture in THF-TMEDA (mono/bis: 85:15) obtained by the addi-
variety of substituted aryl iodides (1:0.85) using Pd(PPh3)4
tion of ZnCl
2
to the bis-a-chloro-b,b-difluorovinylzinc reagent.
catalyst (1.5 mol%) at room temperature or 65 8C to obtain

838
R. Anilkumar, D.J. Burton / Journal of Fluorine Chemistry 126 (2005) 835–843
reduced product. 3-Iodonitrobenzene also coupled with zinc
reagent at rt for 15 h to produce the corresponding styrene in
7% isolated yield (entry 6). 3-Iodoanisole reacted with the
7
Scheme 3. Synthesis of a-chloro-b,b-difluorostyrene.
zinc reagent at 60 8C for 4 h to produce the styrene in 79%
isolated yield (entry 7). m-Iodobenzotrifluoride coupled
smoothly under the normal coupling reaction conditions to
produce the trifluoromethyl-substituted styrene in 67%
isolated yield (entry 8). The coupling reaction of o-
iodobenzotrifluoride with chlorodifluorovinylzinc reagent
required prolonged heating (48 h at 65 8C) to effect
complete conversion, and the isolated yield of corresponding
styrene was 69% (entry 9). Reaction with 2-iodoisopro-
pylbenzene produced the corresponding styrene in 75%
isolated yield when heated with the zinc reagent at 65 8C for
12 h (entry 10). Reaction of 2-iodo-3-nitrotoluene with the
zinc reagent proceeded smoothly under heating conditions
to produce the 2-methyl-6-nitro-a-chloro-b,b-difluorostyr-
ene in 90% isolated yield (entry 11). These results indicate
(entry 10, 11) that the coupling reaction was smooth even
when the aryl iodide is substituted at the ortho positions with
bulky isopropyl, trifluoromethyl or nitro groups. 4-Iodo-2-
nitroanisole coupled with the zinc reagent at 65 8C for 3 h to
produce the corresponding styrene in 80% isolated yield
(entry 12). 1-Chloro-4-iodobenzene coupled with the zinc
reagent and palladium under normal coupling reaction
conditions to produce the corresponding chloro substituted
styrene in 76% isolated yield (entry 13). Coupling reaction
of bromobenzene with zinc reagent was also attempted, but a
sluggish reaction was the result even at heating conditions
for a prolonged reaction time. When 1-bromo-4-iodoben-
zene was used for the coupling reaction the corresponding
the substituted a-chloro-b,b-difluorostyrenes in 65–90%
isolated yield. Generally the reaction was feasible at 65 8C
for 3 h or at room temperature for a prolonged time. The
results of these coupling experiments to produce the
corresponding substituted styrenes are summarized in
Table 1. odides with electron donating and withdrawing
groups in the benzene ring coupled smoothly under the
general coupling reaction conditions to produce the
corresponding a-chloro-b,b-difluorostyrenes in good
yields. 1-Fluoro-4-iodobenzene was transformed to the
corresponding styrene in 81% isolated yield when it was
stirred with the zinc reagent and Pd(0) at rt for 14 h (entry 2).
4-Iodotoluene coupled with the zinc reagent smoothly when
treated with the palladium catalyst at rt for 12 h to produce
4
3
-methyl-a-chloro-b,b-difluorostyrene in 83% yield (entry
). The ester group tolerated the reaction conditions
resulting in the corresponding 4-carbethoxy-a-chloro-b,b-
difluorostyrene in 70% isolated yield (entry 4). The coupling
reaction of 4-iodoacetophenone with zinc reagent did not
1
9
result in a good conversion (40% by F NMR) to the styrene
entry 5). The major product in this reaction was the reduced
(
product CF2 CHCl, presumably resulting form protonation
of the zinc reagent with the enol. This was confirmed by
carrying out a blank experiment where the zinc reagent
generated in THF was heated with acetophenone in presence
of palladium catalyst, producing a major amount of the
Table 1
Synthesis of a-chloro-b,b-difluorostyrenes
ꢁ
1:
15ꢀ20 C=THF
CF3CH2Cl1:1 equiv: þ ZnCl21:0 equiv: þ LDA2:0 equiv:
ꢀ!
ArCCl¼CF2
ꢁ
2:
Arl;PdðPPh3Þ ;rt: 65
C
4
a
No.
Iodide (ArI)
Temp./time
a-Chloro-b,b-difluorostyrenes
CCl CF
CCl CF
CCl CF
CCl CF
CCl CF
CCl CF
CCl CF
CCl CF
CCl CF
CHC CCl CF
o-Me-o’-O NC
p-MeO-m-O NC
p-ClC
m-BrC
p-CF
NMR yield
Yield (%)
1
C
6
H
5
I
65 8C, 4 h
rt, 14 h
C
6
H
5
2
94
97
99
91
40
90
94
89
88
95
96
87
95
96
86
87
77
81
83
70
–
2
3
p-FC
p-MeC
p-EtO CC
p-(MeCO)C
m-NO
m-MeOC
m-CF
o-F CC
o-(CH
o-Me-o’-O
p-MeO-m-O
p-ClC
m-BrC
p-IC
6
H
4
I
p-FC
p-MeC
p-EtO CC
p-(MeCO)C
m-O NC
m-MeOC
m-CF
o-F CC
o-(CH
6
H
4
2
6
H
4
I
rt, 12 h
6
H
4
2
4
2
6
H
4
I
65 8C, 3 h
65 8C, 3 h
rt, 15 h
2
6
H
4
2
b
5
6
H
4
I
6
H
4
2
6
2
C
6
H
4
I
2
6
H
4
2
77
79
67
69
75
90
80
76
85
64
65
c
7
6
H
4
I
60 8C, 4 h
rt, 12 h
6
H
4
2
8
9
0
1
3
C
6
H
4
I
3
C
6
H
4
2
3
6
H
4
I
65 8C, 48 h
65 8C, 12 h
65 8C, 3 h
65 8C, 3;h
rt, 15 h
3
6
H
4
2
1
1
3
)
2
CHC
NC
NC
6
H
4
I
3
)
2
6
H
4
2
2
6
H
4
I
2
6
H
4
CCl CF
2
c,d
12
2
6
H
4
I
2
6
H
4
CCl CF
2
13
6
H
4
I
6
H
4
CCl CF
CCl CF
CFC CCl CF
2
e
14
6
H
4
I
rt, 18 h
6
H
4
2
15
6
H
4
I
rt, 24 h
2
6
H
4
2
16
rt 4 h then 60 8C, 3 h
a
Isolated yields of pure products.
b
c
d
e
The major product was the reduced product CF
Purified by column chromatography.
2
CHCl.
The product styrene was only 95% pure.
1
% of the bis styrene was formed.

R. Anilkumar, D.J. Burton / Journal of Fluorine Chemistry 126 (2005) 835–843
839
bromo substituted styrene was formed in 85% along with 1%
bis styrene resulting from the coupling at both the bromine
and iodine site (entry 14).
reaction towards the metal halogen exchange but the major
reaction was the trans metallation to the corresponding
butylzinc chloride as indicated by the poor yield of the desired
t
The bis styrene was produced in 64% isolated yield from
,4-diiodobenzene by treatment with zinc reagent and
zinc reagent. Even the more sterically hindered, BuLi,
1
produced only 27% yield of the chlorodifluorovinylzinc
reagent at ꢀ78 8C. The best yield of the zinc reagent (43%)
was observed when 3 equiv. of LDA was used as a base at
ꢀ78 8C in this metallation reaction. Our observations differ
with the results reported by Kumudaki during the metallation
palladium catalyst at rt for 24 h (entry 15). The heterocyclic
iodide, 2-iodothiophene reacted with zinc reagent within 4 h
under normal coupling reaction conditions to produce the
styrene in 65% isolated yield.
TM
of Halothane in the presence of zinc chloride [20–22]. We
2
2
.3. Metallation of 1-bromo-1-chloro-2,2,
TM
have not observed any species corresponding to his reported
new zinc reagent and the small amount of zinc reagent formed
was spectroscopically similar to the chlorodifluorovinylzinc
-trifluoroethane (Halothane
)
Simultaneously with our metallation reactions of HCFC-
33a, we have also considered other commercially available
reagent generated by the metallation of CF CH Cl [23]. The
3 2
1
yield of the zinc reagent formed during the metallation of
TM
Halothane was not mentioned in his report [22]. It is also
precursors for the synthesis of the chlorodifluorovinylzinc
reagent. 1-Bromo-1-chloro-2,2,2-trifluoroethane (Halotha-
TM
ne ) was chosen as an alternative precursor (being a liquid)
not clear why a large excess of zinc reagent (4 equiv.) is used
for the coupling reactions with aryl iodides (1 equiv.) though
half equiv of zinc reagent is enough based on the assigned bis
and its availability as a commercial anesthetic. It was
TM
19
anticipated that the metallation of Halothane
using a
structure. In most cases the F NMR yields of the styrene are
moderate to good at best (no isolated yields reported). The
argument that the new zinc reagent is formed by a different
lithium base in the presence of a zinc salt could generate the
corresponding chlorodifluorovinylzinc reagent, which can
easily couple with aryl iodides to produce the corresponding
a-chloro-b,b-difluorostyrenes. Thus, as per the conditions
standardized for the metallation of HFC-134a, the metallation
s
mechanism during the BuLi mediated matallation at ꢀ60 8C
in comparison to our metallation reaction conditions and the
temporarily assigned bis structure for the new zinc reagent
based on their observed chemical shifts is unexplainable [22].
TM
of Halothane was carried out using LDA at 15 8C in the
presence of zinc chloride. This reaction produced a black
1
9
We have unequivocally assigned the F NMR chemical shifts
for the bis zinc reagent (which appeared as shoulders along
with the mono zinc reagent) by performing the Schlenk
equilibrium experiments described in Section 2.1 (Scheme 2,
Figs. 2 and 3) and structural assignment of their zinc reagent
1
9
reaction mixture and the F NMR spectrum showed a set of
peaks, which indicated the formation of many products along
TM
with a large amount of unreacted Halothane . The products
formed in this reaction were identified as CF2 CClZnCl
(
Halothane was recovered in 40% yield (Scheme 4).
25%), CF2 CClBr (9%), CF2 CClH (4%). The unreacted
TM
as the bis zinc reagent [(CF CCl) Zn] does not agree with
2 2
our data.
1
The F NMR chemical shift values for the zinc reagent
9
In conclusion, a room temperature preparation of
[CF CClZnCl] has been achieved from commercially
available HCFC-133a via the in situ capture of [CF CClLi]
with zinc halide utilizing LDA as a base. Corresponding
TM
obtained by the metallation of Halothane (CF2 CClZnCl)
2
matched exactly for the zinc reagent generated by the
metallation of HCFC-133a. In order to improve the yield of
2
TM
the zinc reagent, metallation of Halothane was performed
TM
reaction with Halothane
[CF CClZnCl]. Subsequent Pd(0) coupling of the zinc
produced a poor yield of
t
with various bases (n-BuLi, BuLi, 4-methoxy-2,2,6,6-
2
tetramethylpiperidine, LHMDS), varying the zinc salt
(
reagent with aryl iodides gives the resultant a-chloro-b,b-
difluorostyrenes derivatives in excellent yields. The metal-
lation–coupling process could be performed either as a‘one-
pot’ reaction or a stock solution of the zinc reagent prepared
could be used for separate coupling reactions. The
ZnI , ZnCl ,TMEDA) and by performing the reaction at
2 2
low temperature. But none of these trials yielded a very good
yield of the zinc reagent, but instead produced a mixture with
varying amount of zinc reagent. With 2 equiv. of LHMDS as
base, 1-bromo-1-chloro-2,2-difluoroethylene was produced
intermediate [CF
stable than [CF
mono and bis zinc reagents were unequivocally assigned by
CClLi] was found to be thermally more
2
1
9
19
in 95%yield(by F NMR) and nozinc reagentformation was
detected. Butyl lithium bases were expected to give a better
2
CFLi]. F NMR chemical shifts of the
TM
2
Scheme 4. Metallation of Halothane using various bases in presence of ZnCl .

840
R. Anilkumar, D.J. Burton / Journal of Fluorine Chemistry 126 (2005) 835–843
performing Schlenk equilibrium experiments on the
corresponding TMEDA complexes.
aromatic iodide (typically 0.80–0.85 equiv.) and the
tetrakistriphenylphosphinepalladium (1.5 mol%). The mix-
ture was stirred at rt or heated at 60 8C. The reaction progress
1
9
was monitored using F NMR by sampling small aliquots of
the reaction mixture. After complete conversion, the
reaction mixture was triturated several times with pentane
or hexane and the combined extracts evaporated on a rotary
evaporator. The crude product was purified by distillation
under reduced pressure or by column chromatography over
silica gel.
3
. Experimental
1
1
13
H, { H} C and F NMR spectra were recorded on a
19
Brucker AC-300 or a WM 360 Spectrometer. Chemical
shifts have been reported in ppm relative to an internal
reference (CDCl , CFCl or TMS). Unless noted otherwise,
3
3
CDCl was used as the NMR lock solvent. Low Resolution
3
Mass spectra were obtained using a Voyeger GC-MS
instrument operated at 70 eV in the electron impact mode,
using a 15 m CB-5 column. The reported fragment peaks
correspond to the most abundant ions, in addition to the
parent ion(s). High-resolution mass spectra (HRMS) were
obtained by the University of Iowa High Resolution Mass
Spectrometry Facility. Column chromatography was carried
out using silica gel purchased from Em Science (Silica Gel
3
.3. Synthesis of C H CCl CF
6 5 2
Iodobenzene (4.33 g, 21.25 mmol) and Pd(PPh3)4
0.423 g, 1.5 mol%) were added to the zinc reagent
(
(
25.0 mmol). The reaction mixture was heated at 65 8C
1
9
for 4 h. F NMR of the reaction mixture showed complete
conversion of the zinc reagent to the corresponding styrene
1
94% based on F NMR). The reaction mixture was then
9
(
6
0, particle size 63–200 microns). Tetrahydrofuran (THF)
triturated with pentane (7 ꢂ 20 mL). The combined pentane
extracts were subjected to rotary evaporated under vacuum.
The crude mixture was then carefully distilled under reduced
pressure through a 8 cm vigreux column to obtain the pure
a-chloro-b,b-styrene as a clear liquid in 77% (2.86 g,
was dried by distillation from sodium benzophenone/ketyl at
atmospheric pressure immediately prior to use. Pd(PPh3)4
was prepared by Coulson’s procedure [30]. N was used
2
without further purification. All other reagents and
chemicals were obtained from commercial sources and
used directly. All boiling points were measured during
distillation and are uncorrected.
1
6.4 mmol) yield.
bp: 44–46 8C at 9 mm Hg (reported 100 8C at 100 mm
Hg) [5].
1
9
F NMR (CDCl ): d ꢀ83.8 (d, J = 33 Hz, 1F), ꢀ89.4 (d,
3
3.1. General procedure for the synthesis of
a-chloro-b,b-difluorovinylzinc reagent
from HCFC-133a
1
J = 33 Hz, 1F); H NMR (CDCl ): d 7.50 (m, 2H), 7.33 (m,
3
1
H); C NMR (CDCl ): d 154.0 (dd, J = 292, 290 Hz),
3
3
1
9
3
30.7 (d, J = 5 Hz), 128.8 (s), 128.5 (s), 127.7 (t, J = 4 Hz),
2. 9 (dd, J = 36, 23, Hz); GC/MS: 176 (M + 2) (54), 174
A 250 mL three-necked RB fitted with a dry-ice/
isopropanol condenser, septum and a thermometer were
charged with ZnCl2 (20.4 g, 150.0 mmol) and THF
+
(M ) (100), 139 (88), 119 (75), 99 (32), 89 (45).
(
110.0 mL) under N2 atmosphere. The suspension was
3.4. Synthesis of p-FC H CCl CF
6 4 2
cooled to 15 8C and HCFC-133a (14.0 mL, 165.0 mmol)
was condensed into the slurry. Then an LDA solution
Following the general procedure for the coupling
reaction, 1-fluoro-4-iodobenzene (4.72 g, 21.25 mmol), zinc
reagent (25.0 mmol) and Pd(PPh ) (0.423 g, 1.5 mol%)
[
generated from diisopropylamine (42.0 mL, 300.0 mmol)
and n-BuLi (120.0 mL, 2.5 M, 300.0 mmol) in THF
120 mL) at 0 8C] solution was slowly added (1.5 h) through
3
4
(
were stirred at rt for 14 h to give the corresponding styrene in
1
9
a cannula to the HCFC-133a/ZnCl slurry while keeping the
97% yield (by F NMR). The reaction mixture was
triturated several times with pentane. Evaporation of the
solvent followed by careful distillation under reduced
pressure afforded the p-fluoro-a-chloro-b,b-difluorostyrene
as a clear liquid in 81% (3.30 g, 17.2 mmol) yield.
2
temperature at 15–20 8C (the tip of the cannula was dipped
into the THF to avoid decomposition of the chlorodifluor-
ovinyllithium, formed by the reaction of gaseous HCFC-
1
33a with LDA, at the tip). The pale yellow reaction mixture
was stirred for 2 h at 20 8C and then allowed to settle. The
F NMR analysis of the reaction mixture showed 91% yield
of the chlorodifluorovinylzinc reagent.
bp: 51–52 8C at 9 mm Hg.
1
9
19
F NMR (CDCl ): d ꢀ84.1 (dd, J = 35, 2 Hz 1F), ꢀ89.6
3
1
(d, J = 35 Hz, 1F), ꢀ112.2 (m, 1F); H NMR (CDCl ): d
3
1
.45 (m, 2H), 7.05 (m, 2H); C NMR (CDCl ): d 162.7 (d,
3
7
3
3.2. General procedure for the coupling reaction of
the a-chloro-b,b-difluorovinylzinc reagent with
aromatic iodides
J = 250 Hz), 153.9 (dd, J = 292, 289 Hz), 129.7 (m), 126.7
(t, J = 4 Hz), 115.7 (d, J = 22 Hz), 92.0 (dd, J = 37, 24 Hz);
+
GC/MS: 194 (M + 2) (42), 192 (M ) (100), 157 (98), 137
3
64), 107 (51); HRMS: calcd. for C H F Cl 191.9954,
5
(
8 4 3
3
7
An amount of 25.0 mmol of the zinc reagent generated in
the previous experiment [CF2 CIZnCl] was added the
found 191.9956 calcd. for C H F Cl 193.9924, found
8 4 3
193.9926.

R. Anilkumar, D.J. Burton / Journal of Fluorine Chemistry 126 (2005) 835–843
841
1
9
3
.5. Synthesis of p-MeC H CCl CF
6
F NMR (CDCl ): d ꢀ80.3 (d, J = 27 Hz, 1F), ꢀ86.0 (d,
4
2
3
1
J = 27 Hz, 1F); H NMR (CDCl ): d 8.40 (t, J = 2 Hz, 1H),
8.21 (dm, J = 8, 1 Hz, 1H), 7.89 (dm, J = 8, 1 Hz, 1H), 7.63
1
(t, J = 8 Hz, 1H); C NMR (CDCl ): d 154.7 (dd, J = 294,
293 Hz), 148.5 (s), 133.3 (dd, J = 6, 4 Hz). 132.6 (d,
J = 5 Hz), 129.8 (s), 123.6 (s), 122.7 (t, J = 5 Hz), 91.6 (dd,
35
J = 38, 25 Hz); HRMS: calcd. for C H ClF NO
3
Following the general procedure for the coupling
reaction, 4-iodotoluene (4.64 g, 21.25 mmol), zinc reagent
25.0 mmol) and Pd(PPh ) (0.423 g, 1.5 mol%) were stirred
3
3
(
3
4
at rt for 12 h to give the corresponding styrene in 99% yield
(
1
by F NMR). The reaction mixture was triturated several
9
8
4
2
2
2
3
7
times with pentane. Evaporation of the solvent followed by
careful distillation under reduced pressure yielded the p-
methyl-a-chloro-b,b-styrene as a clear liquid in 83%
218.9899, found 218.9899, calcd. for C H Cl F NO
8 4 2
220.9869, found 220.9860.
(
3.33 g, 17.7 mmol) yield.
bp: 51 8C at 9 mm Hg.
3.8. Synthesis of m-MeOC H CCl CF
2
6
4
1
9
F NMR (CDCl ): d ꢀ84.6 (d, J = 35 Hz, 1F), ꢀ89.9 (d,
Following the general procedure for the coupling
reaction, 3-iodoanisol (4.07 g, 17.4 mmol), zinc reagent
3
1
J = 35 Hz, 1F); H NMR (CDCl ): d 7.39 (d, J = 8 Hz, 2H),
7
3
1
.18 (dd, J = 8.1 Hz, 2H), 2.34 (s, 3H); C NMR (CDCl ): d
3
(20.5 mmol) and Pd(PPh ) (0.348 g, 1.5 mol%) at 60 8C
3
3 4
1
J = 6 Hz), 127.6 (dd, J = 5, 3 Hz), 93.4 (dd, J = 38, 23 Hz),
53.9 (dd, J = 292, 287 Hz), 138.9 (s), 129.3 (s), 127.8 (d,
for 4 h to give the corresponding styrene in 94% yield (by
1
F NMR). The mixture was triturated many times with
9
+
1.9 (s); GC/MS: 190 (M + 2) (32), 188 (M ) (100), 153
2
hexanes. Evaporation of the solvent followed by purifica-
tion by silica gel column chromatography (eluent: 2%
ethyl acetate-hexanes) afforded the m-methoxy-a-chloro-
b,b-styrene as a clear liquid in 79% (2.8 g, 13.7 mmol)
yield.
3
5
(48), 133 (85); HRMS: calcd. for C H ClF 188.0204
9 7 2
found 188.0204, calcd. for C H Cl F 190.0175, found
3
7
9
7
2
1
90.0180.
1
9
3
.6. Synthesis of p-EtO CC H CCl CF
2
F NMR (CDCl ): d ꢀ83.4 (d, J = 32 Hz, 1F), ꢀ88.5
6
4
2
3
1
d, J = 32 Hz, 1F); H NMR (CDCl ): d 7.29 (t, J = 8 Hz,
(
1H), 7.10 (dm, J = 8, 2 Hz, 1H), 7.05 (bs, 1H), 6.87 (dd,
3
Following the general procedure for the coupling
reaction, ethyl-4-iodobenzoate (3.2 g, 11.59 mmol), zinc
reagent (14.0 mmol) and Pd(PPh ) (0.230 g, 1.5 mol%)
1
J = 8, 2 Hz, 2H), 3.80 (s, 3H); C NMR (CDCl ): d
3
3
159.7 (s), 154.1 (dd, J = 292, 289 Hz), 132.0 (d, J = 4 Hz),
129.6 (s), 120.2 (dd, J = 4, 3 Hz), 114.5 (s), 113.6 (t,
J = 5 Hz), 92.9 (dd, J = 22, 35 Hz), 55.4 (s). GC/MS: 206
3
4
were stirred at 65 8C for 3 h to give the corresponding
1
9
styrene in 91% yield (by F NMR). The reaction mixture
was triturated several times with hexanes. Evaporation of the
solvent followed by distillation under reduced pressure
afforded the p-ethoxycarbonyl-a-chloro-b,b-styrene as a
pale yellow liquid in 70% (2.0 g, 8.1 mmol) yield.
bp: 109–110 8C at 10 mm Hg.
+
(M + 2) (38), 204 (M ) (100), 174 (17), 161 (44), 139
3
(44); HRMS: calcd. for C H ClF O 204.0153, found
5
9
7
7
2
3
204.0155, calcd. for C H ClF O 206.0124 found
9
7
2
206.0120.
3.9. Synthesis of m-CF C H CCl CF
2
1
9
F NMR (CDCl ): d ꢀ81.1 (d, J = 28 Hz, 1F), ꢀ86.6 (d,
3
3
6
4
1
J = 28 Hz, 1F); H NMR (CDCl ): d 8.05 (dm, J = 8, 2 Hz,
3
2
H), 7.58 (dm, J = 8, 2 Hz, 2H), 4.39 (q, J = 7 Hz, 2H), 1.39
1
Following the general procedure for the coupling
reaction, 3-iodobenzotrifluoride (5.78 g, 21.25 mmol),
zinc reagent (25.0 mmol) and Pd(PPh3)4 (0.423 g,
1.5 mol%) were stirred at rt for 12 h to give the
3
(
t, J = 7 Hz, 3H); C NMR (CDCl ): d 165.8 (s), 154.4 (dd,
3
J = 295, 291, Hz), 134.9 (d, J = 5 Hz), 130.6 (s), 129.7 (s),
27.5 (q, J = 4 Hz), 92.6 (dd, J = 36, 24 Hz), 61.2 (s), 14.3
1
3
9
5
s); HRMS: calcd. for C H ClF O 246.0259, found
19
(
corresponding styrene in 89% yield (by F NMR). The
1
1
2 2
3
46.0260, calcd. for C H Cl F O 248.0220, found
7
2
2
reaction mixture was triturated several times with hexanes.
Evaporation of the solvent followed by careful distillation
under reduced pressure afforded the m-trifluoromethyl-a-
chloro-b,b-styrene as a pale yellow liquid in 67% (3.46 g,
1
1
9
2 2
48.0223.
.7. Synthesis of m-O NC H CCl CF
2
3
2
6
4
1
4.3 mmol) yield.
bp: 44–45 8C at 9 mm Hg.
Following the general procedure for the coupling
1
9
reaction, 1-iodo-3-nitrobenzene (5.29 g, 21.25 mmol), zinc
reagent (25.0 mmol) and Pd(PPh ) (0.423 g, 1.5 mol%)
were stirred at rt for 15 h to give the corresponding styrene in
F NMR (CDCl ): d ꢀ63.3 (s, 3F), ꢀ81.8 (d, J = 29 Hz,
3
1
1F), ꢀ87.5 (d, J = 30 Hz, 1F); H NMR (CDCl ): d 7.78 (d,
3
4
3
J = 1 Hz, 1H), 7.70 (dm, J = 8, 1 Hz, 1H), 7.60 (d, J = 8 Hz,
1
9
13
1H), 7.51 (t, J = 8 Hz, 1H); C NMR (CDCl ): d 154.5 (dd,
9
0% yield (by F NMR). The reaction mixture was
3
triturated several times with hexanes. Evaporation of the
solvent followed by distillation under reduced pressure
afforded the m-nitro-a-chloro-b,b-styrene as a pale yellow
liquid in 77% (3.6 g, 16.4 mmol) yield.
J = 294, 291 Hz), 131.8 (d, J = 6 Hz), 131.3 (q, J = 32 Hz),
130.9 (bs), 129.4 (s), 125.6 (d, J = 3 Hz), 124.7 (m), 123.8
(q, J = 272 Hz), 92.1 (dd, J = 37, 26 Hz); GC/MS:
+
244 (M + 2) (32), 242 (M ) (100), 207 (40), 187 (48),
138 (45).
bp: 95–96 8C at 9 mm Hg.

842
R. Anilkumar, D.J. Burton / Journal of Fluorine Chemistry 126 (2005) 835–843
3
.10. Synthesis of o-CF C H CCl CF
2
afforded the corresponding styrene as a pale yellow solid in
3
6
4
9
0% (3.58 g, 15.36 mmol) yield.
bp: 111 8C at 9 mm Hg.
mp: 67.5–69 8C.
Following the general procedure for the coupling
reaction, 2-iodobenzotrifluoride (5.78 g, 21.25 mmol), zinc
1
9
reagent (25.0 mmol) and Pd(PPh ) (0.423 g, 1.5 mol%)
3
F NMR (CDCl ): d ꢀ85.5 (d, J = 32 Hz, 1F), ꢀ86.7 (d,
4
3
1
J = 32 Hz, 1F); H NMR (CDCl ): d 8.13 (s, 1H), 8.08 (d,
were stirred at 65 8C for 48 h to give the corresponding
3
1
9
13
J = 8 Hz, 1H), 7.51 (d, J = 8 Hz, 1H), 2.44 (s, 3H); C NMR
styrene in 88% yield (by F NMR). The reaction mixture
was triturated several times with hexanes. Evaporation of the
solvent followed by distillation under reduced pressure
afforded the o-trifluoromethyl-a-chloro-b,b-styrene as a
colorless liquid in 69% (3.54 g, 14.6 mmol) yield.
bp: 65–67 8C at 9 mm Hg.
(CDCl ): d 153.8 (dd, J = 294, 289 Hz), 148.6 (s), 140.2 (s),
3
136.4 (d, J = 3 Hz), 131.6 (s), 125.4 (s), 121.2 (s), 88.9 (dd,
3
5
J = 44, 25 Hz), 19.5 (s); HRMS: calcd. for C H ClF NO
9
6
2
2
2
37
233.0055, found 233.0052, calcd. for C H ClF NO
9
6
2
235.0026, found 235.0024.
3.13. Synthesis of m-NO -p-OMeC H CCl CF
2
19
F NMR (CDCl ): d ꢀ61.3 (d, J = 5 Hz, 3F), ꢀ86.3 (d,
3
1
J = 33 Hz, 1F), ꢀ86.6 (dq, J = 33, 5 Hz, 1F); H NMR
2
6
4
(
CDCl ): d 7.73 (dd, J = 8, 1 Hz, 1H), 7.55 (m, 2H), 7.46
3
1
dd, J = 8, 1 Hz, 1H); C NMR (CDCl ): d 153.7 (dd,
3
(
J = 291, 289 Hz), 132.8 (s), 132.4 (s), 130.4 (s), 129.2 (s),
Following the general procedure for the coupling
reaction, 2-nitro-4-iodoanisol (3.34 g, 12.0 mmol), zinc
reagent (15.0 mmol) and Pd(PPh ) (0.238 g, 1.5 mol%)
3
1
2
26.7 (q, J = 5 Hz), 123.6 (q, J = 273 Hz), 87.8 (dd, J = 44,
3
4
+
7 Hz); GC/MS; 244 (M + 2) (32), 242 (M ) (88), 207
+
were stirred at 65 8C for 3 h to give the corresponding
19
(
C H ClF5 241.9922, found 241.9921, calcd. for
100), 187 (44), 157 (37), 138 (46); HRMS: calcd. for
3
styrene in 87% yield (by F NMR). The mixture was
triturated several times with hexanes. Evaporation of the
solvent followed by purification by column chromatography
5
9
4
3
7
C H ClF 243.9892 found 243.9890.
9
4
5
(silica gel, using 5% ethyl acetate-hexane as eluent) afforded
the p-methoxy-m-nitro-a-chloro-b,b-styrene as pale yellow
3
.11. Synthesis of o-(CH ) CHC H CCl CF
2
3
2
6
4
oil in 80% (2.4 g, 9.6 mmol) yield.
1
9
Following the general procedure for the coupling
reaction, 2-isopropyliodobenzene (5.23 g, 21.25 mmol),
zinc reagent (25.0 mmol) and Pd(PPh3)4 (0.423 g,
F NMR (CDCl ): d ꢀ86.0 (d, J = 34 Hz, 1F), ꢀ88.5 (d,
3
1
J = 34 Hz, 1F); H NMR (CDCl ): d 7.56 (d, J = 3 Hz, 1H),
7.43 (d, J = 9 Hz, 1H), 7.20 (dd, J = 9, 3 Hz, 1H), 3.91 (s,
3
1
3
3H); C NMR (CDCl ): d 161.2 (s), 153.8 (dd, J = 292,
1
.5 mol%) were stirred at 65 8C for 12 h to give the
3
1
9
corresponding styrene in 95% yield (by F NMR). The
reaction mixture was triturated several times with hexanes.
Evaporation of the solvent followed by distillation under
reduced pressure afforded the o-isopropyl-a-chloro-b,b-
styrene as a colorless liquid in 75% (3.45 g, 15.9 mmol)
yield.
288 Hz), 148.9 (s), 133.6 (d, J = 3 Hz), 122.2 (s), 119.4(s),
110.5 (s), 88.1 (dd, J = 42, 26 Hz), 56.1 (s); HRMS: calcd.
3
for C H ClF NO 249.0004, found 248.9995, calcd. for
5
9
7
6
2
3
3
C H ClF NO 250.9975 found 250.9980.
9
6
2
3
3.14. Synthesis of p-ClC H CCl CF
2
6
4
bp: 68–70 8C at 9 mm Hg.
1
9
F NMR (CDCl ): d ꢀ87.0 (d, J = 38 Hz, 1F), ꢀ89.4 (d,
Following the general procedure for the coupling
reaction, 1-chloro-4-iodobenzene (5.06 g, 21.25 mmol),
zinc reagent (25.0 mmol) and Pd(PPh3)4 (0.423 g,
1.5 mol%) were stirred at rt for 15 h generated the styrene
3
1
J = 38 Hz, 1F); H NMR (CDCl ): d 7.37 (m, 2H), 7.21 (m,
2H), 3.14 (septet, J = 7 Hz, 1H), 1.23 (d, J = 7 Hz, 6H);
NMR (CDCl ): d 153.7 (dd, J = 291, 284 Hz), 148.9 (d,
J = 3 Hz), 130.6 (s), 130.5 (s), 128.9 (s), 126.1 (s), 90.3 (dd,
J = 45, 21 Hz), 30.3 (s), 23.9 (s); GC/MS: 218 (M + 2) (34),
+
16 (M ) (100), 167 (52), 165 (78), 146 (55), 129 (68), 115
3
1
3
C
3
1
9
in 95% yield (by F NMR). The reaction mixture was
triturated several times with hexanes. Evaporation of the
solvent followed by distillation under reduced pressure
afforded the p-methyl-a-chloro-b,b-styrene as a clear liquid
in 76% (3.34 g, 16.0 mmol) yield.
2
3
5
(
51); HRMS: calcd. for C H
1
ClF2 216.0517, found
1
11
3
7
2
16.0516, calcd. for C H
1
ClF2 218.0488, found
11
1
2
18.0483.
bp: 67–68 8C at 9 mm Hg.
1
9
F NMR (CDCl ): d ꢀ82.9 (d, J = 32 Hz, 1F), ꢀ88.3 (d,
3
1
J = 32 Hz, 1F); H NMR (CDCl ): d 7.44 (dm, J = 8, 0.6 Hz,
3
.12. Synthesis of 2-Me-6-NO C H CCl CF
2
6
4
2
3
1
H), 7.36 (dm, J = 9, 2 Hz, 2H); C NMR (CDCl ): d 154.0
3
2
3
Following the general procedure for the coupling
reaction, 2-iodo-3-nitrotoluene (4.47 g, 17.0 mmol), zinc
reagent (20.0 mmol) and Pd(PPh ) (0.338 g, 1.5 mol%)
(dd, J = 295, 290 Hz), 134.8 (s), 129.2 (d, J = 6 Hz), 128.9
(dd, J = 6, 4 Hz), 128.8 (s), 92.2 (dd, J = 36, 23 Hz); GC/
+
MS: 212 (M + 4) (16), 210 (M + 2) (76), 208 (M ) (100),
175 (32), 173 (85), 138 (95), 128 (28); HRMS: calcd. for
3
4
were stirred at 65 8C for 3 h to give the corresponding
1
9
35
C H Cl F 207.9658, found 207.9658, calcd. for
styrene in 96% yield (by F NMR). The reaction mixture
was triturated several times with hexanes. Evaporation of the
solvent followed by distillation under reduced pressure
8
4
2 2
37
3
C H Cl ClF 209.9629, found 209.9633, calcd. for
5
8
4
2
3
7
C H Cl F 211.9599, found 211.9596.
8
4
2 2

R. Anilkumar, D.J. Burton / Journal of Fluorine Chemistry 126 (2005) 835–843
843
3
.15. Synthesis of m-BrC H CCl CF
2
1,1-difluoroethenyl)thiophene as a clear liquid in 65%
(2.48 g, 13.77 mmol) yield.
6
4
Following the general procedure for the coupling reaction
-bromo-3-iodobenzene (6.0 g, 21.25 mmol), zinc reagent
25.0 mmol) and Pd(PPh ) (0.423 g, 1.5 mol%) were stirred
bp: 39–40 8C at 9 mm Hg.
1
9
1
F NMR (CDCl ): d ꢀ85.0 (d, J = 29 Hz, 1F), ꢀ86.3 (d,
3
1
J = 29 Hz, 1F); H NMR (CDCl ): d 7.33 (dd, J = 5, 1 Hz,
(
3
4
3
1
9
at rt for 18 h to give the styrene in 96% yield (by F NMR).
The reaction mixture was triturated several times with
hexanes. Evaporation of the solvent followed by distillation
under reduced pressure afforded the m-bromo-a-chloro-b,b-
styrene as a clear liquid in 85% (4.56 g, 18.0 mmol) yield.
bp: 62–63 8C at 9 mm Hg.
1H), 7.22 (dd, J = 4, 1 Hz, 1H), 7.0 (ddd, J = 5, 4, 1 Hz, 1H);
1
C NMR (CDCl ): d 153.6 (dd, J = 293, 291 Hz), 132.9 (d,
3
3
J = 6 Hz), 127.3 (s), 127.1 (t, J = 5 Hz), 126.9 (dd, J = 5,
3 Hz), 89.5 (dd, J = 39, 28 Hz); GC/MS: 182 (M + 2) (41),
+
180 (M ) (82), 145 (100), 101 (54); HRMS: calcd. for
3
5
C H ClF2S 179.9612, found 179.9615, calcd. for
6
3
1
9
37
C H ClF S 181.9583 found 181.9581.
6 3 2
F NMR (CDCl ): d ꢀ82.1 (d, J = 30 Hz, 1F), ꢀ87.5 (d,
3
1
J = 30 Hz, 1F); H NMR (CDCl ): d 7.66 (m, 1H), 7.44 (m,
3
1
3
2
H), 7.24 (t, J = 8 Hz, 1H); C NMR (CDCl ): d 154.3 (dd,
3
J = 294, 291 Hz), 132.7 (d, J = 5 Hz), 131.9 (s), 130.7 (dd,
J = 5, 4 Hz), 130.0 (s), 126.3 (dd, J = 6, 2 Hz), 122.7 (s),
Acknowledgement
9
2.2 (dd, J = 36, 23 Hz); GC/MS: 256 (M + 4) (32), 254
We are grateful to the National Science Foundation for
support to this research work.
+
M + 2) (85), 252 (M ) (69), 173 (54), 138 (100); HRMS:
(
calcd. for C H Br ClF 251.9153, found 251.9158, calcd.
7
4
35
9
35
8
2
8
1
for C H Br ClF 253.9132, found 253.9150, calcd. for
8
9
4
2
7
C H Br ClF 253.9123 found 253.9150, calcd. for
37
References
8
4
2
8
1
37
C H Br ClF 255.9103, found 255.9116.
8
4
2
[
1] S.G. Cohen, H.T. Wolosinski, P.J. Scheuer, J. Am. Chem. Soc. 71
1949) 3439–3440.
(
3
.16. Synthesis of p-F C ClCC H CCl CF
2 6 4 2
[
2] D.J. Burton, G.A. Wheaton, J. Org. Chem. 43 (1978) 2643–2651.
3] D.J. Burton, J. Fluorine Chem. 23 (1983) 339–357.
[
Following the general procedure for the coupling
[4] I. Tellier, R. Sauvetre, J.F. Normant, J. Organomet. Chem. 303 (1986)
09–315.
3
reaction, 1,4-diiodobenzene (3.5 g, 10.6 mmol), zinc
reagent (25.0 mmol) and Pd(PPh ) (0.423 g, 1.5 mol%)
were stirred at rt for 24 h generated the styrene in 86% yield
[
5] D.J. Burton, A.L. Anderson, R. Takei, H.F. Koch, T.L. Shih, J. Fluorine
Chem. 16 (1980) 229–235.
3
4
[
6] K.V. Dvornikova, V.E. Platonov, G.G. Yakbson, J. Fluorine Chem. 28
1
9
(
by F NMR). The reaction mixture was triturated several
(
1985) 99–113.
times with hexanes. Evaporation of the solvent followed by
distillation under reduced pressure yielded the bis-a-chloro-
b,b-styrene as a low melting solid 64% (1.84 g, 6.8 mmol).
bp: 76–78 8C at 9 mm Hg.
[7] P.L. Heinze, D.J. Burton, J. Fluorine. Chem. 31 (1986) 115–119.
[
[
8] P.L. Heinze, D.J. Burton, J. Org. Chem. 53 (1988) 2714–2720.
9] T.D. Spawn, D.J. Burton, Bull. Soc. Chim. Fr. (1986) 876–880.
[
10] S.W. Hansen, T.D. Spawn, D.J. Burton, J. Fluorine. Chem. 35 (1987)
15–420.
4
1
9
F NMR (CDCl ): d ꢀ82.1 (d, J = 31 Hz, 2F), ꢀ87.6 (d,
3
[11] B.V. Nguyen, D.J. Burton, J. Org. Chem. 63 (1998) 1714–1715.
[12] J.P. Gillet, R. Sauvetre, J.F. Normant, Synthesis (1986) 538–543.
1
J = 31 Hz, 2F); H NMR (CDCl ): d 7.56 (s, 4H); C NMR
13
3
[
[
[
13] J.F. Normant, J. Organomet. Chem. 400 (1990) 19–34.
(
CDCl ): d 154.3 (dd, J = 295, 294 Hz), 131.0 (d, J = 5 Hz),
3
14] J.P. Gillet, R. Sauvetre, J.F. Normant, Synthesis (1986) 355–360.
15] J.P. Gillet, R. Sauvetre, J.F. Normant, Tetrahedron. Lett. 26 (1985)
1
27.7 (t, distorted), 92.4 (dd, J = 23, 37 Hz); GC/MS: 274
+
(
M + 4) (12), 272 (M + 2) (70), 270 (M ) (100), 237 (18),
35 (48), 200 (91), 185 (28); HRMS: calcd. for
3
999–4002.
2
C H Cl F 269.9626, found 269.9623, calcd. for
[
16] D. Masure, C. Chuit, R. Sauvetre, J.F. Normant, Synthesis (1978) 458–
460.
3
5
1
0
4
2 4
37
3
C H Cl ClF 271.9597, found 271.9584, calcd. for
5
[
17] P. Tarrant, P. Johncock, J. Savory, J. Org. Chem. 28 (1963) 839–843.
1
0
4
4
3
C H Cl F 273.9567, found 273.9567.
7
[18] D.J. Burton, Z. Yang, P.A. Morken, Tetrahedron (1994) 2993–3063.
1
0
4
2 4
[
19] A.K. Brisdon, K.K. Banger, J. Fluorine. Chem. 100 (1999) 35–43.
20] T. Shigeoka, Y. Kuwahara, K. Watanabe, K. Sato, M. Omote, A. Ando,
I. Kumadaki, J. Fluorine. Chem. 103 (2000) 99–103.
[
3
1
.17. Synthesis of 2-(2-chloro-1,
-difluoroethenyl)thiophene
[21] A. Ando, I. Kumadaki, J. Fluorine. Chem. 100 (1999) 135–146.
[
22] M. Nishihara, Y. Nakuamura, N. Maruyama, K. Sato, M. Omote, A.
Ando, I. Kumadaki, J. Fluorine. Chem. 122 (2003) 247–249.
23] R. Anilkumar, D.J. Burton, Tetrahedron Lett. 43 (2002) 6979–6982.
24] J. Burdon, P.L. Coe, I.B. Haslock, R.L. Powell, Chem. Commun.
(1996) 49–50.
Following the general procedure for the coupling
reaction, 2-iodothiophene (4.46 g, 21.25 mmol), zinc
reagent (25.0 mmol) and Pd(PPh ) (0.423 g, 1.5 mol%)
[
[
3
4
1
were stirred at rt for 4 h ( F NMR showed only 45%
9
[25] J. Burdon, P.L. Coe, I.B. Haslock, R.L. Powell, J. Fluorine. Chem. 99
1999) 127–131.
[26] R. Anilkumar, D.J. Burton, Tetrahedron Lett. 43 (2002) 2731–2733.
(
conversion). The mixture was then heated at 65 8C for 3 h to
1
9
obtain the corresponding styrene in 87% yield (by
F
[
[
[
27] A. Raghavanpillai, D.J. Burton, J. Org. Chem. 69 (2004) 7083–7091.
28] R. Anilkumar, D.J. Burton, J. Fluorine. Chem. 125 (2004) 561–566.
29] R. Anilkumar, D.J. Burton, J. Fluorine. Chem. 125 (2005).
NMR). The reaction mixture was triturated many times with
hexanes. Evaporation of the solvent followed by careful
distillation under reduced pressure yielded the 2-(2-chloro-
[30] D.R. Coulson, Inorg. Synth. 13 (1972) 121–124.