The room temperature preparation of the 1-chloro-2,2-difluorovinylzinc reagent from HCFC-133a (CF3CH2Cl). The first ambient, high yield, one-flask preparation of α-chloro-β,β-difluorostyrenes

Article abstract of DOI:10.1016/S0040-4039(02)01591-5

The reaction of LDA (2.0 equiv.) with a THF solution of ZnCl₂ (1.0 equiv.) and HCFC-133a (CF₃CH₂Cl) (1.0 equiv.) at 15-20°C gives a 91% yield of [F₂C=CClZnCl]. Addition of ArI and Pd(PPh₃)₄ at rt to 65°C gives 65-85% isolated yields of ArCCl=CF₂. This one-flask procedure provides the first room temperature generation of the 1-chloro-2,2-difluorovinylzinc reagent and the first high yield preparation of α-chloro-β,β-difluorostyrenes from a cheap, readily available industrial precursor.

Full text of DOI:10.1016/S0040-4039(02)01591-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 6979–6982
The room temperature preparation of the
1
-chloro-2,2-difluorovinylzinc reagent from HCFC-133a
(
CF CH Cl). The first ambient, high yield, one-flask preparation
3
2
of a-chloro-b,b-difluorostyrenes
R. Anilkumar and Donald J. Burton*
Department of Chemistry, University of Iowa, Iowa City, IA 52242, USA
Received 12 June 2002; accepted 31 July 2002
Abstract—The reaction of LDA (2.0 equiv.) with a THF solution of ZnCl (1.0 equiv.) and HCFC-133a (CF CH Cl) (1.0 equiv.)
2
3
2
at 15–20°C gives a 91% yield of [F CꢀCClZnCl]. Addition of ArI and Pd(PPh ) at rt to 65°C gives 65–85% isolated yields of
2
3 4
ArCClꢀCF . This one-flask procedure provides the first room temperature generation of the 1-chloro-2,2-difluorovinylzinc reagent
2
and the first high yield preparation of a-chloro-b,b-difluorostyrenes from a cheap, readily available industrial precursor. © 2002
Elsevier Science Ltd. All rights reserved.
Tarrant and co-workers reported the first preparation
of 1-chloro-2,2-difluorovinyllithium 1 via metallation of
in ether. The intermediate lithium reagent 1 is pre-
sumably trapped in situ by the zinc chloride to form the
1-chloro-2,2-difluorovinylzinc reagent 5 (Scheme 3).
The in situ formed 5 was subsequently reacted with
3,8-diiododeuteroporphyrin derivatives with Pd(0)
catalysis to give a 99% yield of 3,8-bis(1-chloro-2,2-
difluorovinyl)deuteroporphyrin derivatives. The yield of
1
-chloro-2,2-difluoroethylene 2 with n-BuLi at low tem-
1
peratures. Two decades later, Normant et al. utilized
halogen–metal exchange with 1,1-dichloro-2,2-
difluoroethylene 3 and n-BuLi to prepare 1. Subse-
quently, Normant reported an improved yield of 1 from
2
3
via addition of a molar equivalent of tetrahydrofuran
3
pentane/ether
(
THF) as a co-solvent. Similar results were obtained
F2C=CHCl
+
n-BuLi
[F C=CClLi]
2
4
o
by Okuhara. Scheme 1 summarizes these initial
preparations.
-100 C
2
1
ether
F2C=CCl2
+
n-BuLi
[F2C=CClLi]
5–8
o
-
100 C
Recently, based on the work of Coe with CF CFH ,
1
3
2
3
Percy and co-workers developed an excellent, high yield
preparation of 1 from 1-chloro-2,2,2-trifluoroethane
ether/THF
3
+
n-BuLi
1
9
o
(
HCFC-133a) 4 at low temperatures (Scheme 2). This
-120 C
(>85%)
dehydrofluorination–metallation approach was success-
Scheme 1.
9
THF/hexane
CF3CH2Cl
+
2 n-BuLi
1
o
The most recent preparation of 1 was reported by
-78 C
4
1
1,12
Kumadaki and co-workers.
These workers reacted 2
with sec-BuLi in the presence of zinc chloride at −60°C
Scheme 2.
sec-BuLi
ZnCl2
2
[1]
[CF2=CClZnCl]
o
ether/cyclohexane
-60 C
Keywords: HCFC-133a; chlorodifluorovinylzinc; Pd(0) coupling;
chlorodifluorovinyllithium; a-chloro-b,b-difluorostyrene.
5
o
-
60 C
*
Corresponding author. Fax: 319-335-1270; e-mail: donald-
burton@uiowa.edu
Scheme 3.
0
040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01591-5

6
980
R. Anilkumar, D. J. Burton / Tetrahedron Letters 43 (2002) 6979–6982
ZnCl2
5
is not reported in this work; however, calculation of
4
2 LDA
[CF2=CClZnCl]
+
o
THF/15-20 C
the yield from data reported in the experimental section
91% (19F NMR)
5
1
1
of this paper indicates that the yield of 5 is ꢀ28–29%.
Consequently, the in situ preparation of 5 is achieved at
−
Scheme 5.
60°C; however, the efficiency of the in situ preparation
is modest, at best. In the Pd(0) coupling reaction, 13
equivalents of 5 (per vinyl iodide) is utilized to achieve
the cross-coupled product, and the yield of the coupled
product was reportedly based on the vinyl iodide.
2
LDA/ ZnCl2
ArI
4
+
[5]
ArCCl=CF2
o
THF/15-20 C
Pd(PPh3)4
RT-65 C
o
7
Scheme 6.
Recently, we reported the in situ preparation of
[
F CꢀCFZnCl] at room temperature via the reaction of
2
powder in THF, a 86.5% yield of [F CꢀCClZnI] was
13
2
CF CFH with LDA and zinc chloride (Scheme 4).
Subsequent Pd(0) cross-coupling of this zinc reagent
15
3
2
produced.
with an aryl iodide is a cost-effective route to a,b,b-
In order to test the viability of 5 in Pd(0)-catalyzed
cross-coupling processes, addition of an aryl iodide and
Pd(PPh ) to the solution of 5 and warming (rt to 65°C)
13
trifluorostyrenes.
3
4
The success of this previous work prompted us to
determine: (a) if this in situ preparative route could be
utilized to prepare 5 in good yield (at room tempera-
ture), in contrast to the poor yield attained by the
provided the a-chloro-b,b-difluorostyrenes 7 in excel-
‡
lent isolated yields (Scheme 6). In this Stille type
cross-coupling reactions a ratio of 1:0.85 (5/aryl iodide)
was employed to ensure that all the aryl iodide was
consumed (to facilitate the isolation of 7); no large
excess of 5 was necessary. Table 1 summarizes the
preparation of several derivatives of 7 prepared by this
methodology. As noted in Table 1, the reaction is
tolerant of a wide variety of functional groups and
gives good yields of 7 even with a hindered ortho
substituent (entry 4). It should also be noted that the
reaction is readily scaled up, and a stock solution of 5
can be prepared and subsequently employed in func-
tionalization reactions.
1
1,12
previous procedure;
(b) if the cisoid and transoid
12
structures of 5 proposed by these workers had any
validity, and (c) if the in situ generation of 5 (by our
methodology) could be utilized in Pd(0) cross-coupling
11
reactions without the necessity of a large excess of 5.
We now wish to report that when a THF solution of 4
and anhydrous zinc chloride is treated with LDA at
1
9
1
5–20°C, a 91% yield of 5 is formed (as detected by
F
†
NMR analysis of the reaction mixture) (Scheme 5).
Zinc iodide reacted similarly in this reaction. When the
reaction mixture was quenched with iodine,
F CꢀCClI, 6 was isolated, consistent with the forma-
tion of 5. When 6 was reacted with activated zinc
When 4 is reacted in situ with LDA and zinc chloride
(as described above), a clear, pale yellow solution of 5
1
4
2
1
9
19
is produced in 91% F NMR yield. The F NMR
i
spectrum of the zinc reagent 5 in THF/ Pr NH shows
2
two major doublets at −78.9 and −92.9 ppm, respec-
ZnCl2
iPr NH
tively, with J =59.0 Hz, assigned to the mono zinc
FF
2 LDA
[CF2=CFZnCl]
3%
.
CF3CFH2
+
2
o
16
1
5-20 C/THF
reagent complexed to THF and/or diisopropylamine.
7
This data is similar to the data reported by Kumadaki
for 5 generated from 2 and sec-BuLi/Et O/cyclohexane
2
Scheme 4.
11
(
Normant’s procedure).
†
‡
General procedure for the preparation of stock solution of 5: a
two-neck 500 mL round bottom flask fitted with a nitrogen tee and
a septum was charged with diisopropylamine (42.0 mL, 300.0
mmol) and dry THF (120.0 mL). The solution was cooled to 0°C
and 2.5 M n-BuLi (120.0 mL, 300.0 mmol) was slowly added to the
amine/THF solution over 40 min; then the solution was stirred for
an additional 10 min. A 1 L three-neck round bottom flask fitted
with a dry ice/isopropanol condenser, septum, and a low tempera-
ture thermometer was assembled while hot and flushed with N2 as
it cooled. The flask was charged with ZnCl2 (20.4 g, 150.0 mmol)
and THF (110.0 mL). This saturated solution was cooled to 15°C
with a cold water bath, then CF CH Cl (14.0 mL, 165.0 mmol) was
Typical procedure for the cross-coupling reaction of 5 with aryl
iodides: 25.0 mmol of the zinc reagent 5 was added (via syringe) to
a three-neck 250 mL flask equipped with a condenser, stopper and
septum under a nitrogen atmosphere. 4-Iodotoluene (21.3 mmol)
and tetrakistriphenylphosphine palladium (ꢀ1.5 mol%) were added
to the above zinc reagent 5 and the reaction mixture was stirred at
1
9
rt for 12 h. The reaction progress was monitored by F NMR by
sampling small aliquots of the reaction mixture. After the reaction
was completed, the reaction mixture was triturated several times
with pentane or hexane (6×20 mL) and the combined extracts
concentrated by rotary evaporation. The crude liquid obtained was
distilled under reduced pressure (bp 51°C @ 9 mm) or purified by
column chromatography (silica gel) to obtain p-methyl-a-chloro-
b,b-styrene as a clear liquid in 83% (3.33 g, 17.7 mmol) yield.
3
2
condensed into the THF/ZnCl2 solution. Then, the pre-generated
LDA was slowly added to the THF/ZnCl /CF CH Cl solution (1.5
2
3
2
1
9
h) through a cannula, maintaining the temperature between 15 and
0°C (the tip of the cannula was dipped into the THF to avoid
Spectral characteristics: F NMR (CDCl ): l −84.6 (d, J=35.2 Hz,
3
1
2
1F), −89.9 (d, J=35.4 Hz, 1F); H NMR (CDCl ): l 7.39 (dd,
3
decomposition of the vinyllithium 1 at the tip of the cannula). After
J=1.2, 8.2 Hz, 2H), 7.18 (d, J=8.1 Hz, 2H), 2.34 (s, 3H); 13
C
the addition of the LDA solution was completed, the reaction
NMR (CDCl ): l 153.9 (dd, J=287.3, 292.0 Hz), 138.9 (s), 129.3
3
mixture was stirred at 20°C for 2 h, then allowed to settle. The 19
F
(s), 127.8 (d, J=5.5 Hz), 127.6 (dd, J=2.9, 5.4 Hz), 93.4 (dd,
+
+
NMR spectrum of the zinc reagent was recorded (using C H CF as
J=22.9, 37.5 Hz), 21.9 (s). GC–MS: 190 (M +2, 32), 188 (M , 100),
6
5
3
1
9
35
an internal standard), and the F NMR yield of 5 was determined
153 (48), 133 (85). HRMS: calcd for C H ClF2 188.0204, obsd.
9
7
3
7
to be 91%.
188.0204; calcd for C H ClF2 190.0175, obsd. 190.0180.
9 7

R. Anilkumar, D. J. Burton / Tetrahedron Letters 43 (2002) 6979–6982
6981
1
7
Thus, the chemical shift and coupling constants show
minor variation due to complexation of 5 with different
solvents, but are consistent with the formation of 5.
spectrum and HRMS spectrum of the volatile mate-
rial confirmed it to be 2. Thus, we propose that the
spectrum observed for the zinc reagent by Kumadaki is
the spectrum of 2. Slight modification of the peak
heights and coupling constants can occur due to com-
plexation with different solvents or phasing of the
instrument. It is not necessary to invoke isomeric zinc
reagents to account for the spectral data.
However, when 2 is reacted with sec-BuLi/Et O/cyclo-
2
1
1
hexane in the presence of zinc chloride, Kumadaki
reports the formation of a ‘new’ zinc reagent with the
1
9
following F NMR data: −86.96 ppm (1F, d, J=42
Hz), −87.16 ppm (1F, d, J=42 Hz), and −91.47 ppm
11,12
(
2F, d, J=42 Hz).
He ascribes this data to a
mixture of cisoid and transoid-bis (1-chloro-2,2-
In conclusion, we have described a general, high yield
preparation of the 1-chloro-2,2-difluorovinylzinc
reagent via the in situ reaction of CF CH Cl(HCFC-
12
difluorovinyl)-zinc. We question the assignment of
this data to the cisoid and transoid-bis-zinc reagent. As
noted by Kumadaki, ‘‘the chemical shifts of his zinc
reagent are very similar to those of 2, but coupling
patterns of both spectra are different and a different
distance between mid peaks at lower field is
2
2
133a) with LDA/ZnCl2 at room temperature. The
HCFC-133a is a readily available industrial material
and the reaction can be easily scaled up to provide a
stable stock solution of the zinc reagent for functional-
ization reactions. The zinc reagent readily couples with
aryl iodides with Pd(0) catalysis to provide the first,
general high yield synthesis of a-chloro-b,b-
1
1,12
observed’’.
We have generated 5 from 4 as described
above. When the solution of 5 is partially hydrolyzed
1
9
with glacial acetic acid, the following F NMR spec-
trum was observed (cf. Fig. 1). Note that both the zinc
reagent 5 and 2 can be readily distinguished. Fig. 2
shows only 2 after complete hydrolysis with glacial
acetic acid. 2 was subsequently removed from this
18–20
difluorostyrenes.
Thus, the styrenes can be readily
prepared from the cheap industrial precursor,
CF CH Cl, via a one-flask procedure. Work is in pro-
3
2
gress with other CF CH X (X=Br, I, CF ) derivatives,
3
2
3
19
reaction mixture under reduced pressure. The F NMR
with additional functionalization reactions, as well as
Table 1. Preparation of a-chloro-b,b-difluorostyrenes (7) from HCFC-133a
o
1
) 15-20 C, THF
CF CH Cl
+
ZnCl2
+
2 LDA
ArCCl=CF2
7a-h)
3
2
2
) ArI, Pd(PPh ) ∆
3
4,
(
Entry
Ar
Temp/Time
Styrene
NMR Yield (%)
Yielda,b
−
1
2
3
4
5
6
7
8
C H
65°C/1 h
rt/12 h
rt/15 h
65°C/12 h
65°C/3 h
rt/18 h
7a
7b
7c
7d
7e
7f
94
99
90
95
91
96
94
87
77
83
77
75
70
85
79
65
6
5
−
p-MeC H
6
4
−
m-NO C H
2
6
4
−
i
o- PrC H
6
4
−
p-EtO CC H
2
6
4
c
m-BrC H −
6
4
−
m-MeOC H
2-Thienyl
60°C/3 h
rt/4 h; 60°C/3 h
7g
7h
6
4
a
Isolated yields of pure products were obtained either by column chromatography or distillation under reduced pressure.
b
c
19
1
13
All products give satisfactory F, H, C NMR and HRMS data consistent with the assigned structure.
% of the bis styrene was formed.
1
Figure 1. Partial hydrolysis of [CF ꢀCClZnCl] with acetic acid.
2

6
982
R. Anilkumar, D. J. Burton / Tetrahedron Letters 43 (2002) 6979–6982
Figure 2. Complete hydrolysis of [CF ꢀCClZnCl] with acetic acid.
2
other metal halides trapping agents, to elucidate the
generality of this new, in situ approach.
10. Brown, S. J.; Corr, S.; Percy, J. M. Tetrahedron Lett.
2000, 41, 5269–5273.
1
1. Shigeoka, T.; Kuwahara, Y.; Watanabe, K.; Sato, K.;
Omote, M.; Ando, A.; Kumadaki, I. J. Fluorine Chem.
2000, 103, 99–103.
Acknowledgements
12. Ando, A.; Kumadaki, I. J. Fluorine Chem. 1999, 100,
135–146.
We thank the National Science Foundation for support
of this research.
13. Anilkumar, R.; Burton, D. J. Tetrahedron Lett. 2002, 43,
2731–2733.
19
i
1
4. F CꢀCClI: F NMR: (THF/ Pr NH): −77.3 ppm (d,
2
2
JFF=28.1 Hz) and −81.4 ppm (d, JFF=29.2 Hz). HRMS:
3
5
References
calcd for C
F
2
2
ClI 223.8701, obsd. 223.8701; calcd for
37
C F ClI 225.8672, obsd. 225.8665.
2
9
2
1
1
2
3
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2
1
1
9
9
J
FF=51.3 Hz) and −91.1 ppm (d, JFF=51.5 Hz);
F
F
NMR data for [F
CꢀCClZnI] (THF/TMEDA);
2
NMR: −76.6 (d, J=54.5 Hz) and −90.9 (d, J=55.0 Hz).
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19
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35
2
6. Burdon, J.; Coe, P. L.; Haslock, I. B.; Powell, R. L. J.
17. HRMS: 2 calcd for C
2
HF
calcd for C HF Cl: 99.9705, obsd. 99.9709.
2 2
Cl: 97.9735, obsd. 97.9733;
37
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