Reaction of Halothane with sec-butyllithium in the presence of zinc halides - One-pot preparation of chlorodifluorovinylzinc reagent and its derivatization to α-chloro-β,β-difluorostyrene

Article abstract of DOI:10.1016/S0022-1139(03)00053-8

Halothane, 2-bromo-2-chloro-1,1,1-trifluoroethane, reacts with sec -butyllithium in the presence of zinc halides to afford a chlorodifluorovinylzinc reagent. This zinc reagent reacts with aryl halides in the presence of a palladium catalyst to give chlorodifluorostyrene derivatives in moderate to good yields.

Full text of DOI:10.1016/S0022-1139(03)00053-8

Journal of Fluorine Chemistry 122 (2003) 247–249
Short communication
Reaction of Halothane with sec-butyllithium in the presence of
zinc halides—one-pot preparation of chlorodifluorovinylzinc
reagent and its derivatization to a-chloro-b,b-difluorostyrene
Masakazu Nishihara, Yuki Nakamura, Naoki Maruyama, Kazuyuki Sato,
1
*
Masaaki Omote, Akira Ando , Itsumaro Kumadaki
Faculty of Pharmaceutical Sciences, Setsunan University, 45-1 Nagaotoge-cho, Hirakata, Osaka 573-0101, Japan
Received 9 January 2003; received in revised form 17 February 2003; accepted 20 February 2003
Abstract
Halothane, 2-bromo-2-chloro-1,1,1-trifluoroethane, reacts with sec-butyllithium in the presence of zinc halides to afford a chlorodi-
fluorovinylzinc reagent. This zinc reagent reacts with aryl halides in the presence of a palladium catalyst to give chlorodifluorostyrene
derivatives in moderate to good yields.
#
2003 Elsevier Science B.V. All rights reserved.
Keywords: Halothane; sec-Butyllithium; Aryl iodide; Chlorodifluorostyrene; Cross-coupling reaction
1
. Introduction
-Chloro-2,2-difluorovinylzinc chloride (3) has been used
Using a similar method, Burton and co-workers reported
recently that treatment of 4 by lithium diisopropylamide
(LDA) in the presence of zinc chloride gave 3 [4]. While 1
and 4 are gas at room temperature and difficult to do with,
Halothane (2-bromo-2-chloro-1,1,1-trifluoroethane, 6) is a
liquid at room temperature and much easier to work with.
We would like to describe herein a simple preparation of 5 by
thereactionof6withsec-BuLiinthepresenceofzincchloride
and its application for the synthesis of a-chloro-b,b-difluor-
ostyrenes (Scheme 1).
1
for the cross-coupling reaction with aryl iodides in the
presence of palladium catalyst to give a-chloro-b,b-difluor-
ostyrenes. Normant and co-workers [1] reported pre-
paration of the vinylzinc reagent from 1-chloro-2,2-
difluoroethene (1) through hydrogen abstraction and metal-
lation. On the other hand, Percy and co-workers [2] reported
that 2 was formed from 1-chloro-2,2,2-trifluoroethane (4)
by the reaction with BuLi, in situ. In these reactions, 1-
chloro-2,2-difluorovinyllithium (2), a common intermedi-
ate, is very unstable even at a low temperature. We have
reported the modification of synthesis of a fluorovinylzinc
reagent. Thus, lithiation of 1 was carried out in the presence
of zinc chloride so as to make 2 react promptly with zinc
chloride. By this modification, a new vinylzinc reagent was
obtained invariably as a colorless clear solution. This
vinylzinc reagent was quite stable and showed a different
19F NMR from that of 3. We temporarily assigned its
structure as bis(1-chloro-2,2-difluoroethenyl)zinc (5) [3].
2. Results and discussion
We have reported the reaction of Halothane (6) with
carbonyl compounds that gave abnormal products (13) that
was not expected from the normal Grignard reaction [5]. Our
previous study was focused on elucidating the mechanism
of this abnormal Grignard reaction. Halothane (6) has an
acidic hydrogen atom on the same carbon that has bromine
and chlorine atoms. So, deprotonation of 6 with LDA
gave 1-bromo-1-chloro-2,2,2-trifluoroethyllithium (14),
which reacted with a carbonyl compound to afford 13
*
Corresponding author. Tel.: þ81-72-866-3141; fax: þ81-72-850-7020.
(Scheme 2) [6].
If 14 loses lithium fluoride, it may provide the ethene (7).
E-mail addresses: aando@pharm.setsunan.ac.jp (A. Ando),
kumadaki@pharm.setsunan.ac.jp (I. Kumadaki).
1
If another mole of sec-BuLi is present in addition to zinc
chloride, 7 will be lithiated and then converted to a zinc
Co-corresponding author. Tel.: þ81-72-866-3140;
fax: þ81-72-850-7020.
0022-1139/$ – see front matter # 2003 Elsevier Science B.V. All rights reserved.
doi:10.1016/S0022-1139(03)00053-8

248
M. Nishihara et al. / Journal of Fluorine Chemistry 122 (2003) 247–249
Scheme 3.
Scheme 4.
Table 1
Reaction of bis(1-chloro-2,2-difluorovinyl)zinc with aryl iodides
a
þ
MS (M )
Entry
Ar–I
Yields
1
2
3
4
5
6
7
C
6
H
5
–
57
61
13
66
83
66
96
C
C
–
8
H
H
5
ClF
ClF
2
: 174.005
: 188.020
3 6 4
4-CH C H –
9
7
2
2-NO
4-NO
2
C
C
6
H
H
4
–
–
2
6
4
C
C
C
C
8
H
4
ClF
2
NO
2
: 218.990
: 246.026
O: 204.015
: 207.966
4-C
4-CH
4-ClC
2
H
5
O
OC
2
CC
6
H
4
–
11
9
H
9
ClF
ClF
Cl
2 2
O
3
6
H
4
–
H
7
4
2
6
H
4
–
8
H
2
F
2
a
Yields were estimated by 19F NMR.
Next, the cross-coupling reaction of our vinylzinc reagent
with aryl iodides in the presence of palladium catalyst is
described. A solution of the vinylzinc reagent (0.8 mmol)
was added to a mixture of 4-iodoanisole (0.2 mmol) and
tetrakis(triphenylphosphine)palladium (0.012 mmol) in
THF (3 ml) at room temperature, and the mixture was stirred
Scheme 1.
3
at the same temperature for 1 h. By a usual workup, 4-(1-
chloro-2,2-difluorovinyl)anisole was obtained at 66% yield.
The yield was estimated by 19F NMR (entry 6 in Table 1).
The structure of the product was determined by spectral data
of a sample purified by a column chromatography. This
reaction proceeded with most of aryl iodides at room
temperature in a short reaction time in moderate to good
yields. The results are shown in Scheme 4 and Table 1.
Scheme 2.
2-Nitroiodobenzene was less reactive and gave the pro-
duct at 13% yield (entry 3). In this case, the cross-coupling
reaction might be disturbed with the bulky o-nitro group.
Burton suggested that our zinc reagent was same one
as theirs and that our 19F NMR spectrum must be that of
reagent. Therefore, we tried the reaction of Halothane with
sec-BuLi in the presence of zinc halides.
When a solution of sec-BuLi (9.1 mmol) was added to a
mixture of Halothane (4.4 mmol) and zinc chloride
2
-chloro-1,1-difluoroethene (1). In our experiment, any peaks
(
colorless solution of a zinc reagent was obtained, which
4.0 mmol) in THF (10 ml) at À60 8C for 1 h, a clear and
of Burton’s 1-chloro-2,2-difluorovinylzinc chloride (3) were
not observed. The zinc reagent, which we temporarily assig-
ned as bis(1-chloro-2,2-difluorovinyl)zinc (5), can be stored
showed the same 19F NMR spectrum as that of 5
2
Scheme 3). This solution is stable enough to be kept in
(
a freezer for several months. When zinc bromide was used in
THF, the reaction mixture colored dark brown. Thus, we
usually used zinc chloride. By using Et O as a solvent for the
3
Typical procedure of the cross-coupling reaction is as follows. To a
mixture of 4-iodoanisole (47 mg, 0.2 mmol) and Pd(PPh
3 4
) (14 mg,
2
0
.012 mmol) in THF (3 ml), the zinc reagent (4 ml, 0.8 mmol) was added
reaction of zinc bromide, a clear solution could be obtained.
at room temperature, and the mixture was stirred for 1 h at same
temperature. The reaction mixture was poured into ice and 10% HCl. The
2
Typical procedure for the preparation of chlorodifluorovinylzinc (5)
reagent is as follows. To a solution of Halothane (0.423 ml, 4.4 mmol)
and zinc chloride (0.547 g, 4.0 mmol) in THF (10 ml), sec-BuLi
whole mixture was extracted with Et
2 2
O. The Et O layer was washed with
saturated NaCl, and dried over MgSO . After evaporation of the solvent,
4
the yield was determined by 19F NMR. Purification of the residue gave a
þ
(
0.978 M in hexane/cyclohexane, 9.3 ml/9.1mmol) was added at
colorless oil (8, Ar ¼ 4-CH
calculated for C ClF
(CDCl
3
OC
6
H
5
–). MS m/z: 204 (M ). HRMS
À60 8C for 1h. This shows the same 19F NMR spectrum as that
obtained from 2-chloro-1,1-difluoroethene [3]. The solution was
transferred to a sealed bottle and stored in a freezer under Ar
atomosphere.
O (M ): 204.015. Found: 204.015. 1H NMR
þ
9
H
7
2
3
) d: 7.44 (2H, d, J ¼ 9 Hz), 6.92 (2H, d, J ¼ 9 Hz), 3.83 (3H, s).
F NMR (CDCl
) d: À21.09 (1F, d, J ¼ 38:1 Hz), –26.03 (1F, d,
J ¼ 38:1 Hz). All the other products showed reasonable spectral data.
1
9
3

M. Nishihara et al. / Journal of Fluorine Chemistry 122 (2003) 247–249
249
for several months and reactive enough for the cross-coupling
References
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Inourmethod,equimolaramountofsec-BuLiwasusedforthe
deprotonation of Halothane, and then another mole of sec-
BuLi was used for halogen–lithium exchange reaction. Bur-
ton’s group used LDA as a base at a much higher temperature.
So, the structure and reactivity of zinc reagent obtained by our
method are different from Burton’s reagent.
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