A highly efficient room temperature non-organometallic route for the synthesis of α,β,β-trifluorostyrenes by dehydrohalogenation

Article abstract of DOI:10.1016/S0040-4039(03)01628-9

Various 1-aryl-1,2,2,2-tetrafluoroethanes (ArCHFCF₃, Ar=phenyl, substituted phenyl, naphthyl, heteroaryl) were synthesized by the fluorination of the corresponding alcohols with DAST. Dehydrofluorination of ArCHFCF₃ using lithium hexamethyldisilazide (LHMDS) base in THF at room temperature produced 1,2,2-trifluorostyrenes (ArCF=CF₂) in 61-91% isolated yields. This procedure provides an excellent non-organometallic alternative to the generally used metallation-Pd(0) coupling methods.

Full text of DOI:10.1016/S0040-4039(03)01628-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 6661–6664
A highly efficient room temperature non-organometallic route for
the synthesis of a,b,b-trifluorostyrenes by dehydrohalogenation
R. Anilkumar and Donald J. Burton*
Department of Chemistry, The University of Iowa, Iowa City, IA 52242, USA
Received 11 June 2003; revised 1 July 2003; accepted 2 July 2003
Abstract—Various 1-aryl-1,2,2,2-tetrafluoroethanes (ArCHFCF3, Ar=phenyl, substituted phenyl, naphthyl, heteroaryl) were
synthesized by the fluorination of the corresponding alcohols with DAST. Dehydrofluorination of ArCHFCF3 using lithium
hexamethyldisilazide (LHMDS) base in THF at room temperature produced 1,2,2-trifluorostyrenes (ArCF=CF2) in 61–91%
isolated yields. This procedure provides an excellent non-organometallic alternative to the generally used metallation-Pd(0)
coupling methods.
© 2003 Elsevier Ltd. All rights reserved.
Among the fluorinated olefins 1,2,2-trifluorostyrene
(TFS) has received increased attention as a monomer in
recent years.1 In particular, co-polymers have received
interest as ion exchange membranes for fuel cell separa-
tors, dialysis membranes, and packing material for
liquid chromatography columns.2 The challenge in any
applications of TFS has been its preparation; synthesiz-
ing TFS in good yield and purity has been a major
task.3 Formation of the styrene via organometallic
reagents has received recent attention. One of the ear-
lier methods was developed by Dixon,4 wherein reac-
tion of an aryl lithium reagent with tetrafluoroethylene
generated the styrene in low isolated yields. Stilbene
formation was the major side reaction in this process.5
Synthesis of TFS via trifluovinylzinc and trifl-
uorovinyltin was developed in the past two decades.6
An excellent method for TFS and substituted TFS was
developed in this laboratory where the trifluorovinyl-
zinc reagent was generated by Zn(0) insertion into
CF2=CFX (X=Br, I).7 Subsequent Pd(0)-catalyzed
cross coupling of the zinc reagent with aryl iodides
generated TFS and substituted TFS in very good iso-
lated yields. Although this method provided the first
room temperature entry to TFS in high yield, it
required CF2=CFX, (X=Br, I), which although com-
mercially available, are not cheap precursors—particu-
larly for large scale or commercial preparation of TFS.
Also, these gases are not environmentally friendly thus
causing an important drawback in this preparation.
Recently, Coe and co-workers8 developed an excellent
method for the generation of trifluovinyl lithium from a
cheap, commercially available large volume precursor,
1,1,1,2-tetrafluoroethane (HFC-134a) at low tempera-
ture. With this background, we have very recently
developed a remarkable room temperature preparation
of 1,2,2-trifluorostyrene based on metallation—in situ
transmetallation—coupling strategy starting from read-
ily available HFC-134a (Scheme 1).9
As part of our ongoing efforts to develop synthetic
methodologies for fluorinated styrenes we have
explored non-organometallic routes for
a highly
efficient synthesis of 1,2,2-trifluorostyrenes. One such
strategy was a dehydrofluorination method, where
dehydrofluorination of the corresponding fluorinated
precursor (C6H5CHFCF3) was expected to produce
TFS. Elimination of HF is a difficult process due to the
high bond dissociation energy of the CꢀF bond espe-
cially from a CF3 group.10 But dehydrofluorination has
been attempted with several derivatives of fluorinated
compounds to produce the corresponding fluorinated
olefins.11 Unfortunately, the reaction conditions have
involved high temperatures and afforded only modest
Keywords: HFC-134a; DAST; DBU; LHMDS; 1,2,2-trifluorostyrene;
trifluoromethylketone; dehydrofluorination; dehydrochlorination;
trifluoroethenylzinc; Pd(0) coupling.
* Corresponding author. Fax: 319-335-1270; e-mail: donald-burton@
uiowa.edu
Scheme 1.
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01628-9

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R. Anilkumar, D. J. Burton / Tetrahedron Letters 44 (2003) 6661–6664
yields of dehydrofluorinated products. Mild bases did
not effect the elimination; use of strong bases caused
nucleophilic attack on the product olefin, thus leading
to addition or addition–elimination products.12 Insight
into the mechanism of this base promoted dehydro-
halogenation reaction was studied by various groups
and it was proposed that the elimination proceeds
through an intermediate carbanion mechanism rather
than the normal E2 process.10,13
tion process and produced TFS with traces of side
products. Reaction with lithium hexamethyldisilazide
(LHMDS) was then attempted; dehydrofluorination
with almost complete conversion of C6H5CHFCF3 to
TFS was observed. No addition–elimination product
was formed in this reaction. Simple acidic work-up
followed by careful distillation under vacuum afforded
the TFS in 74% isolated yield.
After standardizing the reaction conditions for the
dehydrofluorination using the LHMDS, we have
applied the same strategy for the synthesis of several
aryl substituted 1,2,2-trifluorostyrenes. The correspond-
ing starting materials, substituted trifluoromethylace-
tophenones [ArC(O)CF3, Ar=p-ClC6H4-, p-MeC6H4-,
p-MeOC6H4-, m-BrC6H4-, m-CF3C6H4-, m-NO2C6H4-,
1-naphthyl and 2-thienyl] were synthesized by the reac-
tion of the corresponding Grignard reagent with either
trifluoroacetic acid or its ethylester.15 The ketones thus
obtained were reduced in high yield (>90%) to the
corresponding alcohol [ArCH(OH)CF3] with sodium
borohydride.16 The direct synthesis of alcohols can also
be achieved by the reaction of trifluoromethyltrimethyl-
silane and the corresponding aldehyde in the presence
of a fluoride ion source.17 The alcohols were then
treated with DAST at −70°C, followed by warming to
rt in CH2Cl2 medium (5–8 h), to obtain the correspond-
ing aryl substituted tetrafluoroethanes (ArCHFCF3) in
good isolated yields (Table 2). Dehydrofluorination of
the aryl substituted tetrafluoroethanes was then carried
out using 1.1–1.2 equiv. of lithium hexamethyldisilazide
in THF at 15°C.† The results of the dehyrofluorination
Despite the information concerning the difficulty in
dehydrofluorination and formation of addition or addi-
tion–elimination side products, we felt that the prepara-
tion of the precursor, 1-phenyl-1,2,2,2-tetrafluoroethane
(C6H5CHFCF3), is trivial and an alternate base could
be developed to effect the dehydrofluorination under
mild reaction conditions without the consumption of
the product olefin. The precursor 1-phenyl-1,2,2,2-tetra-
fluoroethane (C6H5CHFCF3) was synthesized in 72%
isolated yield from commercially available trifl-
uoromethylphenylethanol by reaction with DAST in
CH2Cl2.14 Dehydrofluorination of 1-phenyl-1,2,2,2-tet-
rafluoroethane was attempted using various bases
under different conditions and the results are summa-
rized in Table 1.
Bases like DBU, NaOH and NaOMe did not effect the
dehydrofluorination even under refluxing conditions;
whereas lithium bases such as n-BuLi, t-BuLi, LDA,
produced traces of TFS with significant amount of the
addition–elimination product. A sterically hindered
base lithium-2,2,6,6-tetramethyl-4-methoxy piperidine
(4-methoxy LTMP), suppressed the addition–elimina-
Table 1. Dehydrofluorination of C6H5CHFCF3 using various bases
Entry
Base
Reaction conditions
Styrenea
Unreacted starting materiala
Addition–elimination producta
1
2
3
4
5
6
7
8
DBU
NaOH
NaOMe
n-BuLi
LDA
t-BuLi
4-Methoxy LTMP
LHMDS
DMF, 75°C, 12 h
MeOH, heat, 12 h
MeOH, rt, then heat
THF, 0°C, 1 h
THF, 0°C, 1 h
THF, rt, 1 h
0
0
0
2
10
5
100
100
100
35
50
40
3
0
0
0
33
10
50
10
0
THF, 0°C, 12 h
82
91
THF, 0oC, 3 h
2
a 19F NMR yield based on PhCF3 as internal standard.
† Typical procedure for the dehydrofluorination using LHMDS: A 250 mL three-necked RB fitted with a nitrogen tee, septum and a thermometer
was charged with THF (15.0 mL) and p-MeC6H4CHFCF3 (5.0 g, 26.0 mmol). The solution was cooled to 15°C by an ice-water bath. A solution
of LHMDS [pre-generated from hexamethyldisilazane (6.6 mL 31.3 mmol), and n-BuLi (12.6 mL, 2.5 M, 31.3 mmol) in THF (15.0 mL) at 0°C]
was slowly added to the RB (ꢀ20 min) through a cannula. The mixture was stirred at that temperature for 1 h and then warmed to rt. The
reaction progress was monitored via 19F NMR, and after 3 h above 90% conversion to the styrene was observed. After complete conversion (8
h) the reaction mixture was quenched with water (35.0 mL) and pentane (40.0 mL) was added. The aqueous and organic layer was separated
(emulsion formation could be broken with dil. HCl) and the aqueous layer extracted with pentane (2×25 mL). The combined organic extracts
were washed with dil. HCl (4×40 mL) and then with water. The pentane extracts were dried over anhydrous Na2SO4 and evaporated under mild
vacuum without the loss of the volatile styrene. The resulting solution on distillation through a 10 mm vigreux column under vacuum produced
3.64 g (21.6 mmol, 81%) of pure p-MeC6H4CFꢁCF2. Bp: 45°C/8 mm 19F NMR (CDCl3): l −101.5 (dd, J=73.3, 31.0 Hz, 1F), −116.2 (dd,
1
J=110.5, 77.3 Hz, 1F), −177.0 (dd, J=109.5, 31.8 Hz, 1F); H NMR (CDCl3): l 7.33 (d, J=8.2 Hz, 2H), 7.21 (d, J=8.2 Hz, 2H), 2.35 (s, 3H);
13C NMR (CDCl3): l 155.6 (ddd, J=291.5, 281.9, 50.6 Hz), 138.9 (s), 129.4 (s), 128.9 (ddd, J=227.1, 46.6, 19.5 Hz), 124.4 (m), 21.2 (s);
GC–MS: 172 (M+) (100), 151 (68), 121 (55), 101 (38), 75 (28). HR-MS: calcd for C9H7F3 172.0500, found 172.0500.

R. Anilkumar, D. J. Burton / Tetrahedron Letters 44 (2003) 6661–6664
Table 2. Preparation of 1,2,2-trifluorostyrenes by dehydrofluorination
6663
Entry
Ar
Isolated yield of
ArCHFCF3
Reaction time
(h)
NMR yield of styrene
(ArCFꢁCF2)
Isolated yield of styrenea,b
(ArCFꢁCF2)
1c
2d
3
C6H5-
72
84
83
69
76
63
78
72
69
3
1.5
8
8
0.5
1
1
1
1
91
84
93
90
79
90
88
95
89
74
72
81
82
69
61
83
91
69
p-ClC6H4-
p-MeC6H4-
p-MeOC6H4-
m-BrC6H4-
m-F3CC6H4-
m-O2NC6H4-
1-Naphthyl-
2-Thienyl-
4
5d,e
6
7
8
9c
a Isolated yield of pure styrene after distillation under reduced pressure or column chromatography.
b All products gave satisfactory 19F, 1H, 13C NMR and HRMS consistent with assigned structure and are in agreement with samples prepared
in our laboratory by other methods.7,9
c The distilled styrene contaminated with 1–2% hexamethyldisilazane.
d 1.1 equiv. LHMDS used.
e Some cyclodimerization of the styrene observed when the reaction mixture kept for longer time.
of various 1-aryl-1,2,2,2-tetrafluoethanes are summa-
rized in Table 2. The reaction proceeded very smoothly
and rapidly to produce 1,2,2-trifluorostyrenes in excel-
lent yield (even for the p-methyl and p-methoxy deriva-
tives the reaction was more than 90% complete in 3 h,
entries 3 and 4). Longer reaction time (24 h) resulted in
traces (ꢀ2%) of the addition–elimination product (19F
NMR). The product olefins were extracted with pen-
tane and purified either by column chromatography or
by careful vacuum distillation through a 10 cm vigreux
column. 4-Methoxy substituted 1,2,2-trifluorostyrene
partially dimerized during distillation and was purified
by column chromatography.
the precursor, C6H5CHFCF2Cl in 71% isolated yield.
Dehydrochlorination of C6H5CHFCF2Cl was
attempted at rt with LHMDS in THF solvent, and the
reaction proceeded smoothly in 2 h to produce the TFS
in 94% (by 19F NMR) yield. Dehydrochlorination of
C6H5CHFCF2Cl was also attempted in CH2Cl2 using
DBU as a base at room temperature, and by 24 h most
of the starting material has been transformed to
product in 86% (by 19F NMR) yield (Scheme 2). The
pKa of the benzilic hydrogen in C6H5CHFCF3 is esti-
mated to be ꢀ30.0,12a and a mild base like DBU
(pKa=23.9)21 did not effect the dehydrofluorination (cf.
also Table 1). Stronger bases, like LHMDS (pKa=
29.5),22 were required to effect the dehydrofluorination.
The fact that DBU was efficient to perform the dehy-
drochlorination of C6H5CHFCF2Cl, even though its
pKa is not significantly different from C6H5CHFCF3
confirm the above argument about the leaving group
ability of the chloride ion.
After successfully synthesizing 1,2,2-trifluorostyrenes by
dehydrofluorination, we attempted to generate TFS by
dehydrochlorination of the chlorinated precursor 2-
chloro-1-phenyl-1,2,2-trifluoroethane (C6H5CHFCF2Cl).
Dehydrohalogenation of fluorinated phenylethanes to
the corresponding fluorinated olefins using mild bases is
well known in the literature.18 Dehydrochlorination is
expected to proceed easier than dehydrofluorination
due to the better leaving group ability of Cl− compared
to F−. Substitution of CF3 group of C6H5CHFCF3 by
CF2Cl does not significantly change the acidity of the
benzilic hydrogen or stabilize the intermediate carban-
ion,10,12a,19 but studies have shown that the better leav-
ing group at the 2-position significantly alters the
reaction progress.13b,c Consequently, we prepared the
analogous chloro derivative to determine if a weaker
base could be utilized in this reaction.
In conclusion, a highly efficient synthesis of various
1,2,2-trifluorostyrenes was achieved by a room temper-
ature dehydrohalogenation methodology where the
reactive olefinic species survived under the reaction
conditions without undergoing an addition–elimination
reaction with the base. Various bases were scanned to
The precursor ketone [C6H5C(O)CF2Cl] was obtained
by the reaction of chlorodifluoroacetic acid with excess
phenylmagnesium bromide.15a An alternative facile
method of preparation of a-halodifluoromethylketones
from trifluoromethylketones has recently been
reported.20 NaBH4 reduction of the ketone, followed by
reaction of the alcohol with DAST in CH2Cl2 produced
Scheme 2.

6664
R. Anilkumar, D. J. Burton / Tetrahedron Letters 44 (2003) 6661–6664
effect this conversion and lithium hexamethyldisilazide
was found to be the best choice. Overall, this methodol-
ogy provides an excellent non-organometallic alterna-
tive route for the synthesis of 1,2,2-trifluorostyrenes in
high yield and purity. We are currently extending this
methodology to the synthesis of other a-halo-b,b-
difluorostyrenes, as well as investigating the selectivity
in this elimination to achieve the stereospecific prepara-
tion of C6H5CFꢁCFRF type olefins starting from
C6H5CHFCF2RF precursors.
8. (a) Burdon, J.; Coe, P. L.; Haslock, I. B.; Powell, R. L.
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L. J. Am. Chem. Soc. 1973, 95, 2029–2030.
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N.; Neckers, D. C. J. Org. Chem. 1980, 45, 2903–2907; (c)
Modarai, B. J. Org. Chem. 1976, 41, 1980–1983; (d)
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Acknowledgements
We thank Dr. Charles Stone for stimulating discussions
and insight into this project. We thank National Sci-
ence Foundation for support of this research.
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