Preparation and reactivity of some new keto- and styrene-based trifluoromethoxylated synthons

Article abstract of DOI:10.1055/s-0028-1088155

We describe the preparation, by the means of an initial fluorodesulfurization reaction, of 2-trifluoromethoxy acetophenone as well as β-trifluoromethoxystyrenes derivatives. The synthesis and reactivity of these compounds are discussed in relation to the

Full text of DOI:10.1055/s-0028-1088155

LETTER
1131
Preparation and Reactivity of some New Keto- and Styrene-Based
Trifluoromethoxylated Synthons
T
rifluoromethoxy
i
lated S
a
ynthons dh Zriba, Emmanuel Magnier,* Jean-Claude Blazejewski
Institut Lavoisier de Versailles (ILV), UMR CNRS 8180, Université de Versailles, St Quentin en Yvelines,
45 Avenue des Etats-Unis, 78035 Versailles Cedex, France
Fax +33(1)39254452; E-mail: magnier@chimie.uvsq.fr
Received 19 January 2009
trifluoromethoxy entity on organic molecules including
those which are functionalized, either via direct trifluo-
romethylation of alcohols with trifluoromethyloxonium
salts,12 stabilization and use of the formerly elusive
CF3OH,13 and a new method for the generation of the tri-
fluoromethoxide anion.14
Abstract: We describe the preparation, by the means of an initial
fluorodesulfurization reaction, of 2-trifluoromethoxy acetophenone
as well as b-trifluoromethoxystyrenes derivatives. The synthesis
and reactivity of these compounds are discussed in relation to the
perturbation induced by the aliphatic trifluoromethoxy group.
Key words: ethers, fluorine, halogenation, Heck reaction, ketones
Despite all these recent advances, no laboratory-scale
convenient methods for the preparation of simple mole-
cules such as a-trifluoromethoxyketones or b-trifluo-
romethoxystyrenes appear in the literature. We thought
that the synthesis and the study of the reactivity of these
molecules will bring some new knowledge about the very
poorly known influence of a trifluoromethoxy group on
aliphatic structures.
The preparation and study of trifluoromethyl ethers is cur-
rently the subject of intense research owing to the peculiar
properties of this substituent, close to those of fluorine or
chlorine, but with increased lipophilicity and a moderate
steric bulk, accompanied by interesting conformational
plasticity.1,2 Moreover trifluoromethyl ethers are usually
stable under strongly acidic or basic conditions.3 Howev-
er, these observations can only be strictly applied to the
aromatic series as very little is known concerning the be-
havior of, and the properties induced by a trifluo-
romethoxy substituent in the aliphatic series. This is easily
explained by the few available methods for the introduc-
tion of this group on aliphatic positions and explains
therefore the poor number of compounds previously de-
scribed in the literature.
We selected the fluorodesulfurization reaction of a xan-
thate for the introduction of the trifluoromethoxy
group.7,15 Based on our earlier experience,10 the possible
participation of adjacent functionalities during the fluo-
rodesulfurization process led us to believe that the pres-
ence of a carbonyl group should be avoided during this
reaction. Moreover, the known propensity of ketones to
furnish ketene dithioacetals under basic conditions used
for the formation of xanthates reinforced this opinion.16
The keto functionality should thus be preferably intro-
duced after the fluorination step. We guessed that the
presence of a phenyl group, providing a benzylic position
susceptible to further oxidation, could constitute an entry
point for the introduction of the requisite carbonyl group
while not interfering with the fluorination reaction. Based
on these considerations phenethyl alcohol (1a) was select-
ed as the starting material for our study (Scheme 1).
The story of aliphatic trifluoromethyl ethers began during
the sixties with Aldrich and Sheppard disclosure of the
reaction of alkyl fluoroformates with SF4.4 Meanwhile,
the addition reactions of CF3OF or CF3OCl to double
bonds or diazoketones gave access to unique trifluo-
romethoxylated structures.5 Much more recently, exten-
sion of the fluorodesulfurization reaction6 to the specific
case of xanthates enabled the introduction of a trifluo-
romethoxy group on an aliphatic substrate, under relative-
ly mild conditions, accessible to the common chemist.7,8
This gave a new impetus to the preparation of functional-
ized trifluoromethyl ethers as exemplified by a series of
recent patents from a Merck group describing a novel gen-
eration of ‘green’ and highly efficient fluorinated surfac-
tants,9 and our own work concerning the preparation of 2-
trifluoromethoxyethyl triflate and its derivatives,10 as well
as an easy entry to a-trifluoromethoxylated esters and
their Knoevelagel-like adducts.11 Very recently, some
progress has been made for the direct introduction of the
Formation of the xanthate 2a from phenethyl alcohol
readily occurred (75% yield) under phase-transfer condi-
tions.17 Further fluorodesulfurization of xanthate 2a af-
OC(S)SMe
OH
CS2, MeI, NaOH
H2O, n-Bu4NBr
R1
R1
1a R1 = H
2a R1 = H 75%
1b R1 = OMe
2b R1 = OMe 75%
DBH, HF, Py, CH2CI2
–78 °C to r.t.
R2
OCF3
3a R1 = R2 = H
n-BuLi, THF
–78 °C
3b R1 = Br, R2 = H
3c R1 = OMe, R2 = Br
R1
SYNLETT 2009, No. 7, pp 1131–1135
Advanced online publication: 20.03.2009
DOI: 10.1055/s-0028-1088155; Art ID: G00909ST
x
x.
x
x.
2
0
0
9
R2
Scheme 1 Fluorodesulfurization reaction
© Georg Thieme Verlag Stuttgart · New York

1132
R. Zriba et al.
LETTER
forded a mixture of trifluoromethyl ether 3a12 and its Transformation of monobrominated ether 4a to the corre-
para-brominated derivative 3b8 in various relative sponding alcohol 5 (not isolated) was readily accom-
amounts (1:1 to 3:1) depending on the exact reaction con- plished with calcium carbonate in a mixed solvent system
ditions (time and temperature). These two compounds in 88% crude yield.27 Ensuing oxidation of the crude
could be partially separated either by column chromatog- benzylic alcohol 5 to ketone 6 occurred uneventfully us-
raphy or by tedious distillation. Nevertheless, more con- ing classical PCC conditions (85% yield).19
veniently, the debromination can occur cleanly by direct
In a more straightforward way, dibrominated ether 4b
treatment of the mixture with butyllithium. The overall
could be directly converted to acetophenone derivative 6
yield for 3a from 2a was 58% in the latter case.18
(94% yield) upon hydrolysis in an acidic medium.28,29
As explained above, we thought that the benzylic position
in 3a could be easily amenable to keto functionality. How-
The a-functionalization of the carbonyl group of ace-
tophenone 6 and its derivatives was further studied
ever, all attempts to oxidize this position with powerful
(Table 1).
reagents (PCC, CrO3/H2SO4, KMnO4, RuO2/NaIO4,
Mn2O7)19,20 failed, showing the strong deactivating effect
Table 1 Further Functionalization of Acetophenone Derivatives
of the trifluoromethoxy group. Contrary to the aromatic
O
O
OTBS
reagent
series where the inductive deactivating power of OCF3
may be counter balanced by its resonance electron-donat-
ing effect, no such compensation seems possible in the
aliphatic series.21,22
OCF3
OCF3
OCF3
Ph
Ph
Ph
R1
7a–d, 8
R2
R
9
In an effort to enhance the reactivity of the benzylic posi-
tion towards oxidation, we also investigated the fluo-
rodesulfurization of para-methoxyphenethyl alcohol (1b,
Scheme 1). Using the same reaction sequence as before:
formation of a xanthate 2b (75%), followed by fluorode-
sulfurization, the dibromo compound 3c was obtained in
84% yield. Unfortunately, this compound could not be de-
brominated cleanly with BuLi.
Entry
R
Reagent
TBSClb
MeIc
Product
Yield (%)a
1
2
3
4
5
6
6 H
9
99
78
76
95
81
37
6 H
8 R1 = Me, R2 = H
7a R1 = Cl, R2 = H
7b R1 = Br, R2 = H
7c R1 = R2 = Cl
6 H
NCSd
NBSd
NCSe
6 H
7a Cl
7b Br
However, we were pleased to find that the benzylic posi-
tions in 3a or 3c while deactivated for oxidation were still
susceptible to radical reactions (Scheme 2).
NBSe
7d R1 = R2 = Br
a Isolated yield.
b Conditions: KHMDS, THF, –78 °C.
c Conditions: LiHMDS, THF, 0 °C.
R1 R2
NBS (1.1 or 3 equiv)
d Conditions: PTSA (1 equiv), CCl4, reflux.
e Conditions: LiHMDS, HMPA, –78 °C.
OCF3
3a or 3c
Ar
AIBN (cat.), CCl4, reflux
4
4a Ar = Ph, R1 = H, R2 = Br 96%
4b Ar = Ph, R1 = R2 = Br 99%
Attempted direct conversion of 6 to its silyl enol ether de-
rivative 9 using Et3N failed,30 showing the poor acidity of
the a-protons in the presence of a trifluoromethoxy group.
However, the potassium enolate derived from ketone 6
was converted in high yield (99%) to 9 as the single Z-iso-
mer (entry 1).31 This stereochemistry was based on a pos-
itive NOE observed between the vinylic hydrogen nucleus
and the ortho protons of the aromatic ring. The reactivity
of this compound was relatively poor under classical silyl
enol ether activations (Lewis acid treatment or fluorode-
silylation). We did not succeed in alkylation or halogena-
tion reactions with good and/or reproducible yields by this
method.
4c Ar = 3,5-Br2-4-MeOC6H2, R1 = H, R2 = Br 91%
4d Ar = 3,5-Br2-4-MeOC6H2, R1 = R2 = Br 80%
Scheme 2 Benzylic bromination
Ethers 3a or 3c could thus selectively be mono (96% and
91% yield, respectively) or dibrominated (99% and 80%
yield), by radical bromination with one or three equiva-
lents of NBS ensuring a potential entry point to the wanted
ketone.23,24 Effective access to the trifluoromethoxylated
acetophenone 625 was further secured either from mono-
brominated ether 4a26 or the dibrominated derivative 4b
(Scheme 3).
By contrast, alkylation of 6 with iodomethane to pro-
piophenone 8 proceeded with a good yield in a basic me-
dium (entry 2). Under acidic conditions, halogenation of
acetophenone 6 stopped cleanly at the monosubstitution
stage even with an excess of halogenating agent (entries 3
and 4).32 Further dichlorination to 7c from 6 or dibromi-
nation to 7d from 7b could be effected under basic condi-
tions (entries 5 and 6).
OH
OCF3
CaCO3, MeCN–H2O
4a
PCC
88%
5
6
O
85%
OCF3
10% HCl, reflux
94%
4b
Scheme 3 Preparation of a-trifluoromethoxy acetophenone
Synlett 2009, No. 7, 1131–1135 © Thieme Stuttgart · New York

LETTER
Trifluoromethoxylated Synthons
1133
The benzylic brominated derivatives 4a–c, readily made renes with promising potential for further functionaliza-
available by this work, led us also to consider a facile ac- tion by coupling reactions.
cess to the series of trifluoromethoxystyrenes (Scheme 4).
Acknowledgment
R
DBU, Et2O, reflux
4a–c
OCF3
10a–c
One of us (R.Z.) thanks the CNRS for a postdoctoral grant. Julien
Solles is acknowledged for technical assistance and Sophie Clift for
improvement of the English manuscript.
Ar
10a Ar = Ph, R = H Z/E = 2.5:1
10b Ar = Ph, R = Br Z/E = 1:9
10c Ar = 3,5-Br2-4-MeOC6H2, R = H Z/E = 10:1
References and Notes
Scheme 4 Access to trifluoromethoxylated styrenes
(1) Olah, G. A.; Yamato, T.; Hashimoto, T.; Shih, J. G.; Trivedi,
N.; Singh, B. P.; Piteau, M.; Olah, J. A. J. Am. Chem. Soc.
1987, 109, 3708.
(2) Leroux, F.; Jeschke, P.; Schlosser, M. Chem. Rev. 2005, 105,
827.
Under the action of the non-nucleophilic base DBU, in re-
fluxing diethyl ether, we observed a clean dehydrobromi-
nation reaction of 4a–c leading to the corresponding b-
trifluoromethoxystyrene derivatives 10a–c in good yield
(73–92%) as isomeric mixtures.33 Like in the case of silyl
enol ether 9, the stereochemistry of these compounds was
(3) However, see: Iijima, A.; Amii, H. Tetrahedron Lett. 2008,
49, 6013.
(4) (a) Aldrich, P. E.; Sheppard, W. A. J. Org. Chem. 1964, 29,
11. (b) Yagupol’skii, L. M.; Alekseenko, A. N.; Il’chenko,
A. Y. Sov. Prog. Chem. (Engl. Transl.) 1978, 44, 52.
(5) (a) Barton, D. H. R.; Danks, L. J.; Ganguly, A. K.; Hesse,
R. H.; Tarzia, G.; Pechet, M. M. J. Chem. Soc., Perkin Trans.
1 1976, 101. (b) Barton, D. H. R.; Hesse, R. H.; Jackman,
G. P.; Pechet, M. M. J. Chem. Soc., Perkin Trans. 1 1977,
2604. (c) Kamil, W. A.; Haspel-Hentrich, F.; Shreeve, J. M.
Inorg. Chem. 1986, 25, 376; and references cited therein.
(d) Leroy, J.; Wakselman, C. J. Chem. Soc., Perkin Trans. 1
1978, 1224.
1
ascertained by H NMR NOE experiments. These mole-
cules proved to be quite stable and did not polymerize
when kept at room temperature in the laboratory. This sta-
bility was reflected upon our failure to obtain any adducts
during attempted Diels–Alder reactions with common
dienes like dimethyl-2-butene or cyclopentadiene. This
behavior is in line with our recent observation that the tri-
fluoromethoxy group acts as a fluorine twin in Diels–
Alder reactions,34 and the known very poor reactivity of
fluorinated styrenes under such conditions.35
(6) (a) Kollonitsch, J.; Marburg, S.; Perkins, L. M. J. Org.
Chem. 1976, 41, 3107. (b) Sondej, S. C.; Katzenellenbogen,
J. A. J. Org. Chem. 1986, 51, 3508.
The b-brominated styrene 10b seemed an attractive sub-
strate for further functionalization of the double bond by
coupling reactions. We were thus pleased to find that
Suzuki coupling36 of the E-isomer of 10b with 3,5-dime-
thylbenzene boronic acid, as an example, occurred readily
to give the styrene 11 (85% yield), opening the way
to more elaborate trifluoromethoxy-bearing substrates
(Scheme 5).37
(7) (a) Kuroboshi, M.; Kanie, K.; Hiyama, T. Adv. Synth. Catal.
2001, 343, 235. (b) Shimizu, M.; Hiyama, T. Angew. Chem.
Int. Ed. 2005, 44, 214.
(8) Kanie, K.; Tanaka, Y.; Suzuki, K.; Kuroboshi, M.; Hiyama,
T. Bull. Chem. Soc. Jpn. 2000, 73, 471.
(9) (a) Kirsch, P.; Franz, K.-D.; Ruhl, A. WO 2006072401,
2006. (b) Kirsch, P.; Franz, K.-D.; Ruhl, A. US 2008149878,
2008. (c) Wolfgang, H.; Ignatyev, N. M.; Seidel, M.;
Montenegro, E.; Kirsch, P.; Bathe, A. WO 2008003444,
2008. (d) Wolfgang, H.; Ignatyev, N. M.; Seidel, M.;
Montenegro, E.; Kirsch, P.; Bathe, A. WO 2008003446,
2008. (e) We thank one of the referees for bringing these
works to our attention.
(10) Blazejewski, J.-C.; Anselmi, E.; Wakselman, C. J. Org.
Chem. 2001, 66, 1061.
(11) Blazejewski, J.-C.; Anselmi, E.; Wernicke, A.; Wakselman,
C. J. Fluorine Chem. 2002, 117, 161.
(12) Umemoto, T.; Adachi, K.; Ishihara, S. J. Org. Chem. 2007,
72, 6905.
(13) Christe, K. O.; Hegge, J.; Hoge, B.; Haiges, R. Angew.
Pd(PPh3)4, Cs2CO3
(E)-10b
+
B(OH)2
H2O, toluene, reflux
OCF3
11
Scheme 5 Suzuki coupling
Chem. Int. Ed. 2007, 46, 6155.
(14) Kolomeitsev, A. A.; Vorobyev, M.; Gillandt, H.
Tetrahedron Lett. 2008, 49, 449.
In conclusion, on aliphatic chains the long range inductive
deactivating power of the trifluoromethoxy group seems
to be the main factor influencing the reactivity of neigh-
boring positions. This is in contrast to the case of aromatic
substrates where this effect may be compensated by the
resonance electron-donating effect. Nevertheless, the use
of radical reactions, which are still operative, enabled us to
prepare a representative example of a-trifluoromethoxy-
ketones and study its reactivity. Some intermediates were
also easily transformed to new b-trifluoromethoxysty-
(15) The preparation of some a-trifluoromethoxylated esters was
recently described using the direct nucleophilic substitution
of a-triflyl esters with the trifluoromethoxide anion, see ref.
14. However, the possibility to extend this reaction to the
case of a-keto triflates remains to be established.
(16) Anselmi, E.; Blazejewski, J.-C.; Wakselman, C.
Tetrahedron Lett. 1998, 39, 9651.
(17) Lee, A. W. M.; Chan, W. H.; Wong, H. C.; Wong, M. S.
Synth. Commun. 1989, 19, 547.
(18) Preparation of Phenethyl Trifluoromethyl Ether (3a)
HF–pyridine complex (50 mL) was added dropwise to a
Synlett 2009, No. 7, 1131–1135 © Thieme Stuttgart · New York

1134
R. Zriba et al.
LETTER
cooled (–78 °C) suspension of 1,3-dibromo-5,5-dimethyl-
hydantoin (DBH, 55 g, 1.92 mol) in CH2Cl2 (250 mL),
followed by a solution of the xanthate (15 g, 70.7 mmol) in
CH2Cl2 (40 mL). The mixture was stirred at –78 °C for 1 h,
then for 2 h at r.t., and poured in cold H2O (200 mL). The
organic layer was separated. The aqueous phase was sat.
with NaCl and extracted with CH2Cl2 (2 × 100 mL). The
combined organic layers were washed with a 37% NaHSO3
solution, brine (2 × 250 mL), dried over MgSO4, and
concentrated under vacuum. The residue was purified by
flash chromatography (SiO2, pentane) to give 9.5 g of a
mixture of brominated and nonbrominated products. This
mixture was dissolved in dry THF (56 mL), cooled at –78 °C
under argon, and a solution of n-BuLi in hexanes (2.5 M,
11.3 mL) was added dropwise. The solution was stirred for
an additional 30 min, H2O (10 mL) was added, and the
mixture was warmed to r.t. A sat. soln of NH4Cl (50 mL) and
Et2O (50 mL) were added and the two phases separated. The
aqueous layer was extracted twice with Et2O (50 mL). The
organic layers were combined, washed with brine (100 mL),
dried (MgSO4), and concentrated under vacuum to give 7.6
g (58%) of pure 3a as a colorless oil. The spectroscopic data
were in full accord with previous publication.12 1H NMR
(200 MHz, CDCl3): d = 3.01 (t, J = 7.3 Hz, 2 H, CH2), 4.16
(28) Gelling, J. O.; Feringa, B. L. J. Am. Chem. Soc. 1990, 12,
7599.
(29) 2-Trifluoromethoxy Acetophenone (6)
Compound 4b (9.1 g) was refluxed for 8 h in a solution of
10% HCl (150 mL) and MeCN (60 mL). After extraction
with Et2O (4 × 50 mL), the organic layers were dried
(MgSO4) and concentrated under reduced pressure. Flash
chromatography (SiO2, pentane–Et2O, 9:1) afforded 4.48 g
(84%) of 6 as a colorless oil. 1H NMR (200 MHz, CDCl3):
d = 5.17 (s, 2 H, CH2), 7.48 (m, 2 H, CHAr), 7.62 (m, 1 H,
CHAr), 7.88 (m, 2 H, CHAr). 13C NMR (50 MHz, CDCl3):
d = 68.3 (q, JCF = 2.7 Hz, CH2), 121.7 (q, JCF = 254 Hz,
CF3), 126.8 (2 CHAr), 129.0 (2 CHAr), 133.7 (CAr), 134.3
(CHAr), 190.2 (C). 19F NMR (188 MHz, CFCl3): d = –61.5.
Anal. Calcd (%) for C9H7F3O2: C, 52.95; H, 3.46. Found: C,
52.71; H, 3.29. MS: m/z (%) = 205 (100) [M + H+].
(30) Poirier, J.-M.; Hennequin, L.; Fomani, M. Bull. Soc. Chim.
Fr. 1986, 436.
(31) 1-tert-Butyldimethylsilyloxy-2-trifluoromethoxystyrene
(9)
To a solution of ketone 6 (0.31 g, 1.52 mmol) in THF (10
mL) was added, at –78 °C under argon, KHMDS (3.8 mL,
2.43 mmol, 1.0 M solution in toluene) and HMPA (0.3 mL,
1.52 mmol). After 5 min, a solution of TBSCl (340 mg, 2.28
mmol) in THF (2 mL) was added dropwise and stirring was
continued at the same temperature for 8 h. The reaction
mixture was allowed to reach r.t. and a sat. soln of NH4Cl
was added. The organic layer was collected, washed with
brine, dried (MgSO4), and concentrated. The product was
purified by flash chromatography (SiO2, pentane–Et2O, 9:1)
to give 0.53 g (99%) of 9 as a colorless oil. 1H NMR (200
MHz, CDCl3): d = 0.12 (s, 6 H, 2 CH3), 0.98 (s, 9 H, 3 CH3),
6.48 (s, 1 H, CH), 7.35–7.45 (m, 3 H, 3CHAr), 7.46–7.52 (m,
2 H, 2 CHAr). 13C NMR (50 MHz, CDCl3): d = –4.34 (s, 2
CH3), 18.57 (C), 25.79 (3 CH3), 119.40 (q, JC–F = 13.0 Hz,
CH), 120.9 (q, JC–F = 257 Hz, CF3), 125.6 (2 CHAr), 128.5 (2
CHAr), 128.8 (CHAr), 135.2 (CAr), 142.5 (C). 19F NMR (188
MHz, CFCl3): d = –60.9. Anal. Calcd (%) for C15H21F3O2Si:
C, 56.58; H, 6.65. Found: C, 56.65; H, 6.96.
(t, J = 7.3 Hz, 2 H, CH2), 7.18–7.41 (m, 5 H, 5CHAr). 13
C
NMR (50 MHz, CDCl3): d = 35.3 (CH2), 67.8 (q, JCF = 3 Hz,
CH2), 121.4 (q, JCF = 254 Hz, C), 127.0 (CHAr), 128.7 (2
CHAr), 129.0 (2 CHAr), 136.6 (CAr). 19F NMR (188 MHz,
CFCl3): d = –61.2 (OCF3). MS: m/z (%) = 191 [M + H+], 105
+
(100) [C8H9 ].
(19) Hudlicky, M. Oxidations in Organic Chemistry, ACS
Monograph 186; American Chemical Society: Washington
DC, 1990.
(20) Trömel, M.; Russ, M. Angew. Chem., Int. Ed. Engl. 1987,
26, 1007.
(21) Leroux, F. R.; Manteau, B.; Vors, J.-P.; Pazenok, S. Beilstein
J. Org. Chem. 2008, 4, doi:10.3762/bjoc.4.13.
(22) Agouridas, V.; Laïos, I.; Cleeren, A.; Kizilian, E.; Magnier,
E.; Blazejewski, J.-C.; Leclercq, G. Bioorg. Med. Chem.
2006, 14, 7531.
(32) Pravst, I.; Zupan, M.; Stavber, S. Tetrahedron 2008, 64,
5191.
(23) March, J. In Advanced Organic Chemistry: Reactions,
Mechanisms, and Structure, 4th ed.; John Wiley and Sons:
New York, 1992, 694–697.
(33) a-Bromo-b-trifluoromethoxystyrene (10b)
DBU (1.66 mL, 11.1 mmol) was added to a solution of
dibromide 4b (2.95 g, 8.52 mmol) in dry Et2O (60 mL). The
mixture was refluxed for 8 h. After evaporation of the
solvent, the crude product was purified by flash
chromatography (SiO2, pentane) giving 2.1 g (92%) of a
mixture of Z/E isomers of 10b as a colorless oil. Anal. Calcd
(%) for C9H6BrF3O: C, 40.48; H, 2.26. Found: C, 40.49; H,
2.41. Further purification allowed the separation of the two
isomers.
(24) Preparation of (2,2-Dibromo-2-phenyl)ethyl
Trifluoromethyl Ether (4b)
A solution of trifluoromethyl ether 3a (5 g, 26.3 mmol), NBS
(14.04 g, 78.9 mmol), and AIBN (0.21 g, 1.3 mmol) in CCl4
(100 mL) was refluxed until completion (TLC). The mixture
was concentrated, and the residue was filtered through a
short silica gel column, rinsed with pentane. After
concentration of the filtrate, the resulting oil was purified by
flash chromatography (SiO2, pentane) to give 9 g (99%) of
4b as a yellow oil. 1H NMR (200 MHz, CDCl3): d = 4.70 (s,
2 H, CH2), 7.31 (3 H, CHAr), 7.69 (m, 2 H, CHAr). 13C NMR
(50 MHz, CDCl3): d = 61.9 (C), 75.3 (q, JCF = 3 Hz, CH2),
121.1 (q, JCF = 257 Hz, C), 127.3 (2 CHAr), 128.6 (2 CHAr),
129.9 (CHAr), 140.5 (C). 19F NMR (188 MHz, CFCl3): d =
–60.8 (OCF3). Anal. Calcd (%) for C9H7Br2F3O: C, 31.07;
H, 2.02. Found: C, 31.12; H, 1.76.
E-Isomer: 1H NMR (200 MHz, CDCl3): d = 7.10 (s, 1 H,
CH), 7.35 (m, 3 H, CHAr), 7.46 (m, 2 H, CHAr). 13C NMR (50
MHz, CDCl3): d = 112.9 (C), 121.1 (q, JCF = 258 Hz, CF3),
127.9 (2 CHar), 128.8 (2 CHAr), 129.6 (CHAr), 132.9 (q,
JCF = 3 Hz, CH), 134.9 (CAr). 19F NMR (188 MHz, CFCl3):
d = –60.4 (OCF3).
Z-Isomer: 1H NMR (200 MHz, CDCl3): d = 6.95 (s, 1 H,
CH), 7.37 (m, 3 H, CHAr), 7.55 (m, 2 H, CHAr). 19F NMR
(188 MHz, CFCl3): d = –60.9 (OCF3).
(25) Farnham, W. B.; Middleton, W. J. EP 164124 A2 19851211,
1985; Chem. Abstr. 1985, 105, 114600.
(26) This compound was also obtained albeit in poor yield (10%)
upon oxidation with NaBrO3/NaHSO3 system. See: Kikuchi,
D.; Sakaguchi, S.; Ishii, Y. J. Org. Chem. 1998, 63, 6023.
(27) Smith, J. G.; Dribble, P. W.; Sandborn, R. E. J. Org. Chem.
1986, 51, 3762.
(34) Magnier, E.; Diter, P.; Blazejewski, J.-C. Tetrahedron Lett.
2008, 49, 4575.
(35) (a) Ernet, T.; Haufe, G. Tetrahedron Lett. 1996, 37, 7251.
(b) Bogachev, A. A.; Kobrina, L. S.; Meyer, O. G. J.; Haufe,
G. J. Fluorine Chem. 1999, 97, 135.
(36) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.
Synlett 2009, No. 7, 1131–1135 © Thieme Stuttgart · New York

LETTER
Trifluoromethoxylated Synthons
1135
(37) Preparation of a-(3,5-Dimethylphenyl)-b-
trifluoromethoxystyrene (11)
(200 MHz, CDCl3): d = 2.20 (s, 6 H, 2 CH3), 6.66 (s, 1 H,
CH), 6.82 (s, 2 H, 2 CHar), 6.87 (s, 1 H, CHAr), 7.15 (m, 2
H, CHAr), 7.21 (m, 3 H, CHAr). 13C NMR (50 MHz, CDCl3):
d = 21.3 (2 CH3), 121.6 (q, JCF = 256 Hz, C), 127.7 (2 CHar),
128.1 (CHAr), 128.3 (2 CHAr), 128.6 (2 CHAr), 129.8 (CHAr),
130.7 (C), 130.8 (q, JCF = 3.8 Hz, CH), 135.3 (C), 137.8 (C),
138.3 (C). 19F NMR (188 MHz, CFCl3): d = –60.63. Anal.
Calcd (%) for C17H15F3O: C, 69.85; H, 5.17. Found: C,
70.09; H, 5.27.
A mixture of bromostyrene 10b (212 mg, 0.8 mmol),
Pd(PPh3)4 (44 mg, 0.5 mol%), 3,5-dimethylbenzene boronic
acid (144 mg, 0.96 mmol), Cs2CO3 (520 mg, 1.6 mmol),
distilled H2O (0.32 mL), and toluene (8 mL) was stirred for
2 h at reflux. The solution was extracted with Et2O (4 × 10
mL). Drying of the organic layers (MgSO4), followed by
concentration and flash chromatography (SiO2, pentane)
gave 199 mg (85%) of pure 11 as a colorless oil. 1H NMR
Synlett 2009, No. 7, 1131–1135 © Thieme Stuttgart · New York

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