α-trifluoromethyl-substituted β-ethoxyvinyl zinc reagent: Preparation and palladium-catalyzed cross-coupling as a novel route to functionalized CF3-containing compounds

Full text of DOI:10.1021/jo952215a

3200
J . Org. Chem. 1996, 61, 3200-3204
from the readily available 2-bromo-3,3,3-trifluoropropene
r-Tr iflu or om eth yl-Su bstitu ted
(1).6 As a part of our effort to explore the synthetic utility
of these CF3-containing vinyl ethers, we have conceived
the possibility to make the organometallic derivatives of
these vinyl ethers (Scheme 1). While our attempt at the
preparation of R-metalated vinyl ether 3 by direct meta-
lation with a strong base turned out to be problematic,7
we have been able to obtain the â-metalated reagent 4
via direct zinc insertion into the carbon-bromine bond
of the corresponding vinyl bromide. Such a zinc reagent
can be regarded as a synthetic equivalent of R-CF3-
substituted acetaldehyde enolate 5 and is valuable for
the incorporation of a functionalized CF3-substituted C2-
unit into organic molecules. In this paper, we report the
preparation and synthetic application of the vinyl zinc
reagent 4.
â-Eth oxyvin yl Zin c Rea gen t: P r ep a r a tion
a n d P a lla d iu m -Ca ta lyzed Cr oss-Cou p lin g
a s a Novel Rou te to F u n ction a lized
CF 3-Con ta in in g Com p ou n d s
Guo-qiang Shi,* Xian-Hai Huang, and Feng Hong
Laboratory of Organometallic Chemistry,
Shanghai Institute of Organic Chemistry,
354 Fenglin Lu, 200032 Shanghai, P.R. China
Received December 15, 1995
For the past few decades, great efforts have been made
in the search for practical and efficient methods for the
synthesis of selectively fluorinated organic compounds.1
Fluorinated organometallic reagents provide a useful
method for the introduction of fluorine into organic
molecules.2 However, due to the lack of suitable precur-
sors as well as the limited thermal stability of many of
these fluorinated organometallic reagents, their chem-
istry is much less developed than that of their hydrocar-
bon analogs. A particular example is various R-trifluo-
romethyl-substituted organolithium and magnesium
reagents. These reagents are known to be rather ther-
mally unstable due to their proclivity toward â-elimina-
tion, thus making carbon-carbon bond formation at a
CF3-substituted carbanionic center a challenging prob-
lem.3 Fortunately, the stability of fluorinated organo-
metallic reagents is very much dependent on the nature
of the metal employed. Thus, by changing from lithium
or magnesium to a less electropositive metal such as zinc,
two R-CF3-substituted vinyl zinc reagents, namely CF3-
(ZnX)CdCH2 and CF3(ZnX)CdCF2, have been recently
prepared.4,5 The exceptional thermal stability of these two
“internal” vinyl zinc reagents, in contrast to their lithium
and magnesium counterparts, ensured several synthetic
applications with these two carbanion equivalents. How-
ever, the general lack of functionality in the products
derived from these reagents set a severe limit to their
practical utility in the synthesis of functionalized CF3-
containing compounds.
P r ep a r a tion of th e Vin yl Br om id e 7. The bromi-
nation of the trifluoromethylated vinyl ether 2 was
simply achieved by a bromination-dehydrobromination
sequence. Thus, when treated consecutively with 1 equiv
of bromine and 2 equiv of triethylamine in CH2Cl2 at 0
°C, vinyl ether 2 was readily converted to vinyl bromide
7 as a 60:40 Z/E mixture in 80% yield (Scheme 2). The
assignment of the Z/E configuration was based on the
large difference of 19F chemical shifts of the two isomers
(∆δ ) 3.5 ppm), the downfield signal being assigned to
the one E isomer that has a CF3 group experiencing a
greater steric interaction with the vincinal substitutent8
(OC2H5 vs H).
Since the stereochemistry of the vinyl bromide 7 was
considered to be important for the subsequent prepara-
tion of the zinc reagent, efforts have been made to control
the Z/E selectivity during the formation of 7. At 0 °C,
the addition of bromine to vinyl ether 2 was already
found not to be stereoselective, affording syn/anti adducts
6 in a ratio of 3:2. When this step was conducted at -78
°C, the stereochemistry of the initial adduct and, conse-
quently, the final Z/E ratio of the elimination product
remained essentially unchanged. The use of a solvent
other than CH2Cl2 could not significantly improve the Z/E
ratio either. Finally, we accidentally found that the use
of 2 equiv of bromine at the first addition step followed
by the same treatment with triethylamine led to forma-
tion of vinyl bromide 7 exclusively as Z-form. This led
us to assume that isomerization of 7 had occurred in the
presence of excess bromine and triethylamine. Indeed,
in a control experiment, addition of bromine (1.0 equiv)
to a 60:40 Z/E mixture of 7 rapidly afforded the adduct
8 which, when treated with triethylamine, lost a molecule
of bromine to give back compound 7 with a 98:2 Z/E ratio.
In this reaction, triethylamine has acted as a nucleophile
for halophilic debromination.9 The high stereoselectivity
of the latter step can be rationalized by assuming that
the debromination had taken place in an anti manner
and that conformation A is much more preferred than B
due to minimization of the electrostatic repulsion be-
tween the CF3 and ethoxy groups.10 Thus, by controlling
We have recently established a very convenient method
for the synthesis of (Z)-3,3,3-trifluoropropenyl ethers 2
(1) (a) Welch, J . T. Selective Fluorination in Organic and Bioorganic
Chemistry; American Chemical Society: Washington DC, 1991. (b)
Welch, J . T.; Eswarakrishnan, S. Fluorine in Bioorganic Chemistry;
J ohn Wiley & Sons: New York, 1991. (c) McClinton, M. A.; McClinton,
D. A. Tetrahedron 1992, 48, 6555. (d) Hudlicky, M. Chemistry of
Organic Fluorine Compounds; Ellis Horwood: Chichester, 1992.
(2) For recent reviews see (a) Burton, D. J .; Yang, Z.-Y.; Morken,
D. A. Tetrahedron 1994, 50, 2993. (b) Burton, D. J .; Yang, Z.-Y.
Tetrahedron 1992, 48, 189.
(3) For synthetic studies on R-CF3-substituted organometallic re-
agents, see (a) Nemoto, H.; Satoh, A.; Fukumoto, K. Synlett 1995, 199.
(b) Yamazaki, T.; Hiraoka, S.; Kitazame, T. J . Org. Chem. 1994, 59,
5100. (c) Watanabe, H.; Yan, F.; Sakai, T.; Uneyama, K. J . Org. Chem.
1994, 59, 758. (d) Watanabe, H.; Yamashita, F.; Uneyama, K. Tetra-
hedron Lett. 1993, 34, 1941. (e) Qian C.-P.; Nakai, T. Tetrahedron Lett.
1990, 31, 7043. (f) Kitagawa, O.; Hashimoto, A.; Kobayashi, Y.;
Taguchi, T. Chem. Lett. 1990, 1307. (g) Ishihara T.; Kuroboshi, M.;
Yamaguchi, K. Chem. Lett. 1990, 211. (h) Uneyama, K.; Momota, M.
Bull. Chem. Soc. J pn. 1989, 62, 3378. (i) Fujita, M.; Hiyama, T. Bull.
Chem. Soc. J pn. 1988, 61, 3321. (j) Yokozawa, T.; Ishikawa, N.; Nakai,
T. Chem. Lett. 1987, 1971. (k) Hemer, I.; Posta, A.; Dedek, V. J .
Fluorine Chem. 1984, 61, 3321. (l) Fuchigami, T.; Nakagawa, Y. J .
Org. Chem. 1987, 52, 5276 and references cited therein. (m) Gassman,
P. G.; O’Reilly, N. J . J . Org. Chem. 1987, 52, 2481. (n) Arakesmith, F.
G.; Steward, O. J .; Tarrant, P. J . Org. Chem. 1968, 33, 280.
(4) J iang, B.; Xu, Y.-Y. J . Org. Chem. 1991, 56, 7336.
(6) Fong, H.; Hu, C.-M. Chem. Commun. 1996, 57.
(7) After the reaction of vinyl ether 2 (R ) OC2H5) with n-BuLi or
t-BuLi at -78 °C was quenched with water, the reaction mixture was
very complicated as revealed by 19F NMR analysis.
(8) Gunther, H. NMR Spectroscopy, An Introduction; J ohn Wiley &
Sons: New York, 1980; p 342.
(5) (a) Morken, P. A.; Lu, H.-Y.; Nakamara, A.; Burton, D. J .
Tetrahedron Lett. 1991, 32, 4271. (b) Morken, P. A.; Burton, D. J . J .
Org. Chem. 1993, 58, 1167.
(9) A similar reaction has been recently studied. Cho, B.-R.; Lee,
S.-H.; Kim, Y.-K. J . Org. Chem. 1995, 60, 2072.
S0022-3263(95)02215-8 CCC: $12.00 © 1996 American Chemical Society

Notes
J . Org. Chem., Vol. 61, No. 9, 1996 3201
Sch em e 1
Sch em e 3
Sch em e 4
Sch em e 2
mixture of 7 for the same reaction gave rise to two new
peak at -25.4 and -28.8 ppm, respectively, with a 60:
40 intensity ratio, indicating that the corresponding
E-isomer of 7 was also able to undergo metal insertion
reaction with the retention of the stereochemistry of the
double bond. The geometry of the double bond in 7 has
thus appeared to be not crucial to the reactivity of the
carbon-bromine bond toward insertion reaction. Since
TMEDA was found to be indispensable to the formation
of the zinc reagent, the latter was assumed to have a
chelate structure with TMEDA as a bidentate ligand
(Scheme 3). Remarkably, both isomers of the zinc
reagent 4 have been found to be stable indefinitely at
room temperature or for a prolonged time in refluxing
THF.
Cr oss-Cou p lin g Rea ction s of th e Zin c Rea gen t 4.
With a convenient route to the CF3-containing vinyl zinc
reagent 4, we decided to establish the feasibility of using
4 in cross-coupling reactions. In the case of nonfluori-
nated materials, the transition metal-catalyzed coupling
reaction of organic zinc reagents has already been
established as an efficient method for the construction
of a new carbon-carbon bond.12 The palladium-catalyzed
coupling reactions of some perfluorinated alkenyl zinc
reagents have also found their use in organofluorine
synthesis.2 When the zinc reagent Z-4 was reacted with
a variety of aryl and alkenyl substrates in THF using 2
mol% of Pd(PPh3)4 as the catalyst, the expected cross-
coupling reaction occurred smoothly affording the the
expected coupling product 10 as a single stereoisomer in
high yield (Scheme 4). The results were summarized in
Table 1.
As shown in the table, both bromides and iodides can
be effectively used for the coupling reaction. With the
bromides, however, the reaction required a higher tem-
perature (70 °C) in order to have a reaction rate compa-
rable to that observed with the iodides at 50 °C. This
difference of reactivity has made the chemoselective
coupling possible with p-bromoiodobenzene (entry 2,
Table 1). It is worth noting that the zinc reagent was
inert toward an aldehyde group so that the coupling
reaction with o-bromobenzaldehyde was able to proceed
normally (entry 7, table 1). Also noteworthy is the
coupling reaction with vinyl halides and triflates (entry
9-12), which opened a convenient route to 2-trifluoro-
methylated 1-alkoxy-1,3-dienes. These dienes should be
valuable for the synthesis of CF3-containing cyclic com-
pounds by virtue of their ability to undergo cycloaddition
reactions.
the experimental conditions, we were able to obtain vinyl
bromide 7 with high Z-selectivity.
P r ep a r a tion of th e Zin c Rea gen t 4. With the vinyl
bromide 7 in hand, we attempted to prepare the vinyl
zinc reagent 4 by way of oxidative addition of zinc to 7.
Although the presence of a CF3 group R to the carbon-
halogen bond in vinyl halide was known to facilitate the
metal insertion into the carbon-halogen bond,4,5 the
feasibility to perform such a reaction with compound 7
was not obvious because of the presence of the syntheti-
cally desirable ethoxy group â to the reaction center. The
electron-donating effect of this ethoxy group may have
increased the electron density on the brominated carbon,
thereby making the metal insertion into the carbon-
halogen bond difficult. Furthermore, vinyl zinc com-
pounds bearing an alkoxy group â to the anionic center
might be prone to undergo demetalloalkoxylation. In
fact, simple (â-alkoxyvinyl)lithium was found to be stable
only at a temperature below -70 °C,11 and no corre-
sponding zinc derivative has been prepared before.
Fortunately, when vinyl bromide (Z)-7 was treated with
silver-activated zinc in THF in the presence of 1 equiv
of TMEDA, an exothermic reaction occurred. 19F NMR
analysis of the reaction mixture revealed that the start-
ing material disappeared and a single new peak at -25.4
ppm appeared which corresponded to the zinc reagent
Z-4 (Scheme 3). On the other hand, use of a 60:40 Z/E
(10) CHARMm 22 force field calculation indicated that conformation
A is 3.88 kcal/mol lower in energy compared to conformation B.
(11) Kreisler, S. Y.; Schlosser, M. J . Org. Chem. 1978, 43, 1595.
(12) For recent reviews, see (a) Knochel, P.; Singer, R. D. Chem.
Rev. 1993, 93, 2117. (b) Erdik, E. Tetrahedron 1992, 48, 9577.

3202 J . Org. Chem., Vol. 61, No. 9, 1996
Notes
Ta ble 1. P a lla d iu m -Ca ta lyzed Cr oss-Cou p lin g Rea ction s
of th e Zin c Rea gen t (Z)-4 w ith Or ga n ic Ha lid es a n d
Tr ifla tesa
Sch em e 5
with proved biological activities,13,14 i.e. the fluoro analog
of Naproxen 12 and the fluorinated pyrethroid 15 (Scheme
5). Thus, simple acid hydrolysis of the coupling product
11 followed by oxidation of the resulting aldehyde directly
afforded 12 in 85% overall yield. On the other hand,
reduction of the aldehyde obtained from the hydrolysis
of the coupling product 13 with NaBH4 gave the alcohol
14, which was used as the key intermediate for the novel
synthetic pyrethroid 15. The previous methods for the
preparation of such CF3-substituted compounds appeared
to be much less efficient.13,14
In conclusion, we have developed a convenient prepa-
ration of a novel R-trifluoromethyl-substituted â-ethoxy-
vinyl zinc reagent 4 and used it successfully in the
palladium-catalyzed cross-coupling reactions with a va-
riety of aryl and vinyl halides or triflates. The ease of
preparation, the presence of a latent carbonyl group and
the feasibility of palladium-catalyzed cross-coupling reac-
tion should make the zinc reagent 4 find further synthetic
utilities as a valuable CF3-containing synthon in the
construction of various trifluoromethylated target mol-
ecules.
Exp er im en ta l Section
1H NMR spectra were recorded on 300 or 400 MHz spectrom-
eters with Me4Si as an internal standard. 19F NMR spectra were
obtained on a 60 MHz spectrometer using trifluoroacetic acid
as an external standard, downfield shifts being designated as
negative. Mass spectra were obtained using EI ionization at
70 eV. All reactions were routinely monitored with the aid of
TLC or 19F NMR spectroscopy. THF was distilled from sodium
benzophenone ketyl, and TMEDA was freshly distilled from
calcium hydride. Silver-activated zinc powder was prepared by
a published method using commercial zinc dust.15
a
All reactions were performed in THF on a 2.0 mmol scale for
1.5 equiv of the zinc reagent using 2 mol % of Pd(PPh3)4 as the
catalyst. Yield of isolated product. c For these entries, a 60:40
b
mixture of the zinc reagent (Z)-4 and (E)-4 was used instead of
pure (Z)-4. Total yield of two separable isomers.
d
In order to find out whether the other isomer (E)-4
could also be used for the coupling reaction, a 60:40 Z/E
mixture of 4 was used to react with halide substrate 9c,
9i, and 9l under the same reaction conditions. The
results showed that both isomers exhibited comparable
reactivity in the coupling reaction affording easily sepa-
rable Z/E isomers of the coupling product 10c, 10g, and
10h , each in approximately 50:50 Z/E ratio (entry 3, 9,
12; Table 1).
(Z)-1-Eth oxy-3,3,3-tr iflu or op r op en e (2, R ) C2H5).6
A
reaction flask equipped with a dry-ice condenser and an addition
funnel was charged with a solution of potassium hydroxide (33.3
(13) Middleton, W. J .; Binghan, E. M. J . Fluorine Chem. 1983, 22,
561.
(14) (a) Bushell, M. J . In Recent Advances in the Chemistry of Insect
Control II; Crombie, L., Ed.; The Royal Society of Chemistry: Cam-
bridge, 1990; p 125. (b) Matsuo, N.; Tsushima, K.; Takagaki, T.; Hirano,
M.; Ohno, N. Recent Advances in the Chemistry of Insect Control III;
The Royal Society of Chemistry: Cambridge, 1994; p 208.
(15) Rousseau, G.; Conia, J . M. Tetrahedron Lett. 1981, 22, 649.
The reaction described above has allowed us to have a
simple route to two important CF3-containing compounds

Notes
J . Org. Chem., Vol. 61, No. 9, 1996 3203
g, 0.59 mol) in ethanol. 2-Bromo-3,3,3-trifluoropropene (34.9 g,
0.20 mol) was added over 5 min, during which the reaction
mixture started to reflux. After being stirred for 60 min, the
reaction mixture was poured into water (150 mL). The organic
layer was separated, dried over Na2SO4, and distilled to afford
27.4 g (96%) of 2; bp 102-104 °C (lit.16 102-103 °C). 1H NMR
(CDCl3) δ 6.32 (d, J ) 6.8 Hz, 1 H), 4.56-4.74 (m, 1 H), 4.0 (q,
J ) 7.0 Hz, 2 H), 1.32 (t, J ) 7.0 Hz, 3 H); 19F NMR (CDCl3) δ
-20.0 (d, 6.7 Hz).
(Z/E)-2-Br om o-1-eth oxy-3,3,3-tr iflu or op r op en e (7). To a
solution of (Z)-1-ethoxy-3,3,3-trifluoropropene (5.6 g, 40 mmol)
in CH2Cl2 (40 mL) cooled to -20 °C was added dropwise a
solution of bromine (6.4 g, 40 mmol) in CH2Cl2 (10 mL). After
the reaction mixture was kept at 0 °C for 30 min and then
recooled to -20 °C, triethylamine (8.1 g, 80 mmol) was added
over 10 min. The reaction mixture was stirred at room tem-
perature for 1 h and then poured into water (100 mL). The
organic layer was separated and the aqueous phase was
extracted with CH2Cl2 (3 × 20 mL). The combined organic phase
was washed with 2 N HCl to pH neutral and dried over MgSO4.
Distillation under reduced pressure gave 7.0 g (80%) of 7 as a
60:40 Z/E mixture; bp 60-62 °C/37 mmHg. (Z)-7: 1H NMR
(CDCl3) δ 7.23 (q, J ) 1.6 Hz, 1 H), 4.13 (q, J ) 7.1 Hz, 2 H),
1.39 (t, J ) 7.1 Hz, 3 H); 19F NMR (CDCl3) δ -13.5 (d, J ) 1.6
Hz); MS (EI, m/ z) 220 (M+ + 1, 6), 218 (M+ - 1, 6), 149 (78),
140 (34), 69 (100). Anal. Calcd for C5H6BrF3O: C, 27.42; H,
2.76. Found: C, 27.44; H, 2.75. (E)-7: 1H NMR (CDCl3) δ 6.72
(s, 1 H); 4.05 (q, J ) 7.1 Hz, 2 H); 1.32 (t, J ) 7.1 Hz, 3 H); 19F
NMR(CDCl3) δ -17.0 (s). When the above reaction was per-
formed with 2 equiv of bromine (12.8 g, 80 mmol), compound 7
was obtained in 77% yield with a Z/E ratio of g98:2.
-16.8 (d, J ) 1.7 Hz); MS (EI, m/ z) 217 (M+ + 1, 19), 216 (M+,
100), 188 (5), 168 (14), 140 (33), 109 (12). Anal. Calcd for
C
11H11F3O: C, 61.11; H, 5.13. Found: C, 60.65; H, 5.30.
(E )-2-(4-B r o m o p h e n y l)-1-e t h o x y -3,3,3-t r iflu o r o p r o -
p en e (10b). Organozinc reagent (Z)-4 (3.0 mmol) and p-
bromoiodobenzene (0.57 g, 2.0 mmol) for 7 h at 50 °C yielded
0.55 g (94%) of 10b as an oil after chromatography using a 9:1
mixture of petroleum ether and ethyl acetate as the eluent: 1H
NMR (CD3COCD3) δ 7.60 (d, J ) 8.7 Hz, 2 H), 7.40 (d, J ) 8.7
Hz, 2 H), 7.30 (q, J ) 1.7 Hz, 1 H), 4.20 (q, J ) 7.1 Hz, 2 H),
1.31 (t, J ) 7.1 Hz, 3 H); 19F NMR (CD3COCD3) δ -16.7 (d, J )
1.7 Hz); MS (EI, m/ z) 296 (M+ + 1, 45), 295 (M+, 7), 294 (M+
-
1, 47), 262 (100), 157 (13), 139 (44). Anal. Calcd for C11H10
BrF3O: C, 44.77; H, 3.42. Found: C, 44.56; H, 3.26.
-
(Z/E)-1-Eth oxy-3,3,3-tr iflu or o2-(4-n itr op h en yl)p r op en e
(10c). A 60:40 mixture of the zinc reagent (Z)- and (E)-4 (3.0
mmol) and p-nitroiodobenzene (0.50 g, 2.0 mmol) for 7 h at 50
°C yielded first 0.24 g (46%) of (E)-10c and then 0.25 g (48%) of
(Z)-10c after chromatography using a 9:1 mixture of petroleum
ether and ethyl acetate as the eluent. (E)-10c: 1H NMR (CD3-
COCD3) δ 8.26 (d, J ) 7.0 Hz, 2 H), 7.79 (d, J ) 7.0 Hz, 2 H),
7.47 (q, J ) 1.8 Hz, 1 H), 4.29 (q, J ) 7.1 Hz, 2 H), 1.35 (t. J )
7.1 Hz, 3 H); 19F NMR (CD3COCD3) δ -17.0 (d, J ) 1.8 Hz); MS
(EI, m/ z) 261 (M+, 22), 249 (100), 203 (30), 233 (23), 139 (6).
Anal. Calcd for C11H10F3NO3: C, 50.58; H, 3.86; N, 5.36.
Found: C, 50.52; H, 3.94; N, 5.28. (Z)-10c: 1H NMR (CD3COCD3)
δ 8.25 (d, J ) 8.2 Hz, 2 H), 7.62 (d, J ) 8.2 Hz, 2 H), 7.21 (s, 1
H), 4.26 (q, J ) 7.1 Hz, 2 H), 1.35 (t. J ) 7.1 Hz, 3 H); 19F NMR
(CD3COCD3) δ -20.0 (s); MS (EI, m/ z) 262 (M+ + 1, 74), 261
(M+, 100), 245 (24), 233 (23), 139 (17).
Use of organozinc reagent (Z)-4 (3.0 mmol) and 1-bromo-4-
nitrobenzene (9f, 0.40 g, 2.0 mmol) for 8 h at 70 °C yielded only
the E isomer of 10c in 92% yield.
1,2-Dibr om o-1-eth oxy-3,3,3-tr iflu or op r op a n e (6). When
the above reaction was worked up before addition of triethyl-
amine, a 3:2 syn/ anti mixture of 6 was obtained quantitatively.
The assignment of the relative stereochemistry was based on
the coupling constant between 1-H and 2-H (J H-H 2.1 Hz for
the syn vs 4.1 Hz for the anti isomer). 1H NMR (CDCl3) δ 6.18
(d, J ) 2.1 Hz, 1 × 0.6 H), 6.05 (d, J ) 4.1 Hz, 1 × 0.4 H), 4.60
(dq, J ) 4.1, 6.5 Hz, 1 × 0.4 H), 4.53 (dq, J ) 2.1, 6.5 Hz, 1 ×
0.6 H), 3.07 (m, 2 × 0.4 H), 3.63 (m, 2 × 0.6 H), 1.32 (t, J ) 7.2
Hz, 3 H); 19F NMR (CDCl3) δ -32.0 (d, J ) 6.5 Hz, 3 × 0.4 F),
-30.0 (d, J ) 6.5, 3 × 0.6 F).
(E)-1-Eth oxy-3,3,3-tr iflu or o-2-(3-p yr id yl)p r op en e (10d ).
Organozinc reagent (Z)-4 (3.0 mmol) and 3-iodopyridine (0.41
g, 2.0 mmol) for 6 h at 50 °C yielded 0.39 g (91%) of 10d as an
oil after chromatography using a 9:1 mixture of petroleum ether
and ethyl acetate as the eluent: 1H NMR (CD3COCD3) δ 8.68
(s, 1 H), 8.53 (dd, J ) 4.8, 1.5 Hz, 1 H), 7.82 (d, J ) 8.1 Hz, 1 H),
7.40 (m, 2 H), 4.22 (q, J ) 7.1 Hz, 2 H), 1.30 (t, J ) 7.1 Hz, 3 H);
19F NMR (CD3COCD3) δ -16.7 (d, J ) 1.8 Hz); MS (EI, m/ z):
218 (M+ + 1, 85), 217 (M+, 100), 189 (17), 169 (25), 141 (28), 63
(10). Anal. Calcd for C10H10F3NO: C, 55.30; H, 4.64; N, 6.45.
Found: C, 54.91; H, 4.84; N, 6.31.
2-[(E )-2-E t h o x y -1-(t r iflu o r o m e t h y l)e t h e n y l]b e n za l-
d eh yd e (10e). Organozinc reagent (Z)-4 (3.0 mmol) and 2-bro-
mobenzaldehyde (0.38 g, 2.0 mmol) for 12 h at 70 °C yielded
0.35 g (72%) of 10e as an oil after chromatography using a 9:1
mixture of petroleum ether and ethyl acetate as the eluent: 1H
NMR (CD3COCD3) δ 10.08 (s, 1 H), 7.95 (d, J ) 7.0 Hz, 1 H),
7.75 (t, J ) 7.0 Hz, 1 H), 7.60 (t, J ) 7.0 Hz, 1 H), 7.47 (q, J )
1.8 Hz, 1 H), 7.45 (d, J ) 7.0 Hz, 1 H), 4.12 (q, J ) 7.1 Hz, 2 H),
1.18 (t, J ) 7.1 Hz, 3 H); 19F NMR (CD3COCD3) δ -15.3 (d, J )
1.8 Hz); MS (EI, m/ z) 245 (M+ + 1, 7), 244 (M+, 2), 217 (19),
200 (100), 167 (28), 131 (51), 89 (9). Anal. Calcd for
P r ep a r a tion of th e Zin c Rea gen t 4. A small quantity of
trimethylchlorosilane (ca. 0.5 mL) was added to a stirred
suspension of silver-activated zinc powder (4.0 g, 60 mmol) in
dry THF (30 mL). After 10 min, TMEDA (5.8 mL, 40 mmol)
and vinyl bromide (Z)-7 (8.8 g, 40 mmol) were successively added
in one portion. The reaction commenced in less than 1 min when
the solution became warm and turned deep-brown. After the
heat evolution ceased, 19F NMR analysis of the reaction mixture
indicated the appearance of a new peak at -25.4 ppm corre-
sponding to the zinc reagent (Z)-4 and a small peak at -18 ppm
attributable to (E)-1-ethoxy-3,3,3-trifluoropropene formed from
the protonation of the zinc reagent. The yield of the zinc reagent
determined by 19F NMR integration vs internal PhCF3 standard
ranged 80-85%.
C
12H11F3O2: C, 59.02; H, 4.54. Found: C, 58.86; H, 4.80.
(E)-1-E t h oxy-3,3,3-t r iflu or o-2-(2-t h iop h en e-yl)p r op en e
When the same reaction was performed using a 60:40 Z/E
mixture of the vinyl bromide 7, a 60/40 mixture of zinc reagent
(Z)-4 and (E)-4 was formed as revealed by two new 19F NMR
peaks at -25.4 and -28.8 ppm.
(10f). Organozinc reagent (Z)-4 (3.0 mmol) and 2-bromothiophene
(0.33 g, 2.0 mmol) for 6 h at 70 °C yielded 0.38 g (85%) of 10f as
an oil after chromatography using a 9:1 mixture of petroleum
1
ether and ethyl acetate as the eluent: H NMR (CD3COCD3) δ
Gen er a l P r oced u r e for th e Cr oss-Cou p lin g Rea ction s
Exem p lified by th e Rea ction of th e Zin c Rea gen t (Z)-4
w ith Iod oben zen e. To a solution of iodobenzene (0.41 g, 2.0
mmol) and Pd(PPh3)4 (0.046 g, 0.040 mmol) in THF (10 mL) was
added a solution of the zinc reagent (Z)-4 in THF (5.0 mL, ca.
3.0 mmol). The reaction mixture was heated at 50 °C and
monitored by TLC for the disappearance of the starting iodo-
benzene. Diethyl ether (20 mL) was added, and the organic
phase was washed with water (10 mL). Evaporation of the
solvents gave a residue which was subjected to chromatography
eluting with a 9:1 mixture of petroleum ether and ethyl acetate
to afford 0.41 g (95%) of the coupling product (E)-1-eth oxy-3,3,3-
tr iflu or o-2-p h en ylp r op en e (10a ) as an oil: 1H NMR (CD3-
COCD3) δ 7.40 (m, 5 H), 7.25 (q, J ) 1.7 Hz, 1 H), 4.18 (q, J )
7.1 Hz, 2 H), 1.28 (t, J ) 7.1 Hz, 3 H); 19F NMR (CD3COCD3) δ
7.30 (d, J ) 5.4 Hz, 1 H), 7.11 (q, J ) 1.5 Hz, 1 H), 7.03 (m, 1
H), 6.91 (dd, J ) 5.3, 3.8 Hz, 1 H), 4.17 (q, J ) 7.1 Hz, 2 H), 1.28
(t, J ) 7.1 Hz, 3 H); 19F NMR (CD3COCD3) δ -15.4 (d, J ) 1.5
Hz); MS (EI, m/ z) 223 (M+ + 1, 18), 222 (M+, 100), 174 (23),
165 (23), 146 (21), 115 (21). Anal. Calcd for C9H9F3OS: C,
48.64; H, 4.08. Found: C, 48.55; H, 4.14.
(Z/E )-2-(1-Cycloh e xe n yl)-1-e t h oxy-3,3,3-t r iflu or op r o-
p en e (10g). A 60:40 mixture of the zinc reagent (Z)- and (E)-4
and (3.0 mmol) and 1-iodocyclohexene (0.42 g, 2.0 mmol) for 6 h
at 50 °C yielded first 0.21 g (47%) of (E)-10g and then 0.22 g
(49%) of (Z)-10g after chromatography using a 9:1 mixture of
petroleum ether and ethyl acetate as the eluent. (E)-10g: 1H
NMR (CD3COCD3) δ 6.90 (q, J ) 2.0 Hz, 1 H), 5.75 (m, 1 H),
4.05 (q, J ) 7.1 Hz, 2 H), 2.12 (m, 4 H), 1.65 (m, 4 H), 1.28 (t, J
) 7.1 Hz, 3 H); 19F NMR (CD3COCD3) δ -15.7 (d, J ) 2.0 Hz);
MS (EI, m/ z) 221 (M+ + 1, 12), 220 (M+, 100), 191 (70), 163
(52), 123 (41). Anal. Calcd for C11H15F3O: C, 59.99; H, 6.86.
(16) Henne, A. L.; Nager, M. J . Am. Chem. Soc. 1952, 74, 650.

3204 J . Org. Chem., Vol. 61, No. 9, 1996
Notes
Found: C, 59.78; H, 7.06. (Z)-10g: 1H NMR (CD3COCD3) δ 6.60
(s, 1 H), 5.69 (m, 1 H), 4.05 (q, J ) 7.1 Hz, 2 H), 2.10 (m, 4 H),
1.63 (m, 4 H), 1.30 (t, J ) 7.1 Hz, 3 H); 19F NMR (CD3COCD3)
δ -19.8 (s); MS (EI, m/ z) 221 (M+ + 1, 12) 220 (M+, 100) 191
(59), 163 (38), 123 (27).
7.22 (dd, J ) 8.7, 2.5 Hz, 1 H), 4.82 (q, J ) 9.0 Hz, 1 H), 3.95 (s,
3 H); 19F NMR (CD3COCD3) δ -9.0 (d, J ) 9.0 Hz).
(E )-1-E t h oxy-2-(4-e t h oxyp h e n yl)-3,3,3-t r iflu or op r o-
p en e (13). Organozinc reagent (Z)-4 (3.0 mmol) and 1-bromo-
4-ethoxybenzene (0.42 g, 2.0 mmol) for 8 h at 70 °C yielded 0.47
Use of organozinc reagent (Z)-4 (3.0 mmol) and 1-bromocy-
clohexene ( 0.32 g, 2.0 mmol) for 7 h at 70 °C or cyclohexenyl
triflate for 6 h at 50 °C yielded only the (E)-10g in 90% and
86% yield, respectively.
g (90%) of 13 as an oil after chromatography using a 20:
1
mixture of petroleum ether and ethyl acetate as the eluent: 1H
NMR (CD3COCD3) δ 7.33 (d, J ) 8.6 Hz, 2 H), 7.17 (q, J ) 1.5
Hz, 1 H), 6.92 (d, J ) 8.7 Hz, 2 H), 4.13 (q, J ) 7.1 Hz, 2 H),
4.05 (q, J ) 7.0 Hz, 2 H), 1.34 (t, J ) 7.0 Hz, 3 H), 1.27 (t, J )
7.1 Hz, 3 H); 19F NMR (CD3COCD3) δ -16.5 (d, 1.5 Hz); MS
(EI, m/ z) 261 (M+ + 1, 18), 260 (M+, 100), 203 (50), 184 (43),
175 (30), 156 (16), 94 (91) Anal. Calcd for C13H15F3O2: C, 60.00;
H, 5.81. Found: C, 59.77; H, 5.75.
(1Z,2E)- a n d (1E, 2E)-1-Eth oxy-2-(tr iflu or om eth yl)-4-
p h en yl-1,3-bu ta d ien e (10h ). A 60:40 mixture of the zinc
reagent (Z)- and (E)-4 and (3.0 mmol) and (E)-1-bromo-2-
phenylethene (0.37 g, 2.0 mmol) for 7 h at 70 °C yielded first
0.21g (44%) of (E)-10h and then 0.23g (47%) of (Z)-10h after
chromatography using a 20:1 mixture of petroleum ether and
ethyl acetate as the eluent. (E)-10h : 1H NMR (CD3COCD3) δ
7.50 (m, 2 H), 7.39 (m, 2 H), 7.28 (m, 1H), 7.15 (s, 1 H), 6.95 (d,
J ) 17.0 Hz, 1 H), 6.82 (d, J ) 17.0 Hz, 1 H), 4.24 (q, J ) 7.1
Hz, 2 H), 1.38 (t, J ) 7.1 Hz, 3 H); 19F NMR (CD3COCD3) δ -15.0
(s); MS (EI, m/ z) 243 (M+ + 1, 17), 242 (M+, 100), 165 (34), 145
(47), 115 (30). Anal. Calcd for C13H13F3O: C, 64.46; H, 5.41.
Found: C, 64.58; H, 5.42. (Z)-10h : 1H NMR (CD3COCD3) δ 7.45
(m, 2 H), 7.31 (m, 2 H), 7.23 (m, 1 H), 7.12 (s, 1 H), 6.69 (d, J )
16.5 Hz, 1 H), 6.61 (d, J ) 16.5 Hz, 1 H), 4.13 (q, J ) 7.1 Hz, 2
H), 1.32 (t, J ) 7.1 Hz, 3 H);19F NMR (CD3COCD3) δ -18.0 (s);
MS (EI, m/ z) 243 (M+ + 1, 15), 242 (M+, 100), 196 (34), 165
(43), 145 (58), 115 (37)
(E)-1-E t h oxy-3,3,3-t r iflu or o-2-(6-m et h oxy-2-n a p h t h yl)-
pr open e (11). Organozinc reagent (Z)-4 (3.0 mmol) and 2-bromo-
6-methoxynaphthalene (0.47 g, 2.0 mmol) for 8 h at 70 °C yielded
0.53 g (90%) of 11 as a white solid after chromatography using
a 20:1 mixture of petroleum ether and ethyl acetate as the
eluent: mp 90-92 °C; 1H NMR (CD3COCD3) δ 7.70 (m, 3H),
7.37 (d, J ) 8.7 Hz, 1 H), 7.20 (s, 1 H), 7.13 (q, J ) 1.9 Hz, 1 H),
7.01 (dd, J ) 8.7, 2.6 Hz, 1 H), 4.02 (q, J ) 7.1 Hz, 2 H), 3.78(s,
3 H), 1.17(t, J ) 7.1 Hz, 3 H); 19F NMR (CD3COCD3) δ -16.5 (d,
1.9 Hz); MS (EI, m/ z) 297 (M+ + 1, 21), 296 (M+, 100), 267 (42),
252 (46), 155 (6), 139 (7). Anal. Calcd for C16H15F3O2: C, 64.86;
H, 5.10. Found: C, 64.55; H, 4.98.
3,3,3-Tr iflu or o-2-(6-m eth oxy-2-n a p h th yl)p r op a n oic a cid
(12). A mixture containing compound 11 (0.30 g, 1.0 mmol),
dioxane (2.5 mL), and concentrated hydrochloric acid (1.0 mL)
was heated at 60 °C for 1 h. After usual workup, the crude
aldehyde was dissolved in acetone (2.5 mL) and treated with a
solution of K2Cr2O7 (0.44 g, 1.5 mmol) in 2 N sulfuric acid (2.0
mL). After 30 min, the reaction was quenched with 2-propanol
(1.0 mL) and the mixture extracted with diethyl ether (3 × 10
mL). The ethereal phase was extracted with 2 M aqueous NaOH
(2 × 10 mL). The combined aqueous layers were acidified with
2 N sulfuric acid and extracted with diethyl ether (3 × 10 mL).
The organic phase was dried and concentrated. The solid was
crystallized from hexane-diethyl ether to give 0.24 g (85% based
on 11) of 12; mp 141-142 °C (lit.13 140-142 °C). 1H NMR (CD3-
COCD3) δ 8.01 (s, 1 H), 7.90 (d, J ) 3.0 Hz, 1 H), 7.87 (d, J )
3.0 Hz, 1 H), 7.60 (d, J ) 8.7 Hz, 1 H), 7.38 (d, J ) 2.5 Hz, 1 H),
2-(4-E t h oxyp h en yl)-3,3,3-t r iflu or o-1-p r op a n ol (14).
A
mixture containing compound 13 (0.52 g, 2.0 mmol), dioxane (5.0
mL), and concentrated hydrochloric acid (2.0 mL) was heated
at 60 °C for 1 h. After usual workup, the crude aldehyde was
dissolved in diethyl ether (5.0 mL), and NaBH4 (0. 19 g, 5.0
mmol) was added. After being stirred at 25 °C, the reaction
mixture was poured into water and extracted with diethyl ether
(3 × 5 mL). The organic phase was concentrated, and the crude
product was purified by column chromatography on silica gel
eluting with a 2:1 mixture of petroleum ether and ethyl acetate
to give 0.43 g (92%) of 14 as an oil. 1H NMR (CDCl3) δ 7.16 (d,
J ) 6.7 Hz, 2 H), 6.85 (d, J ) 6.7 Hz, 2 H), 4.10 (dd, J ) 11.4,
5.7 Hz, 1 H), 3.98 (q, J ) 7.0 Hz, 2H), 3.94 (dd, J ) 11.4, 8.0 Hz,
1 H), 3.43 (m, 1H), 3.14 (broad s, 1 H), 1.38 (t, J ) 7.0 Hz, 3 H);
19F NMR (CDCl3) δ -9.5 (d, J ) 8.5 Hz); MS (EI, m/ z) 234 (M+,
34), 203 (57), 175 (90), 125 (37), 73 (100). Anal. Calcd for
C
11H13F3O2: C, 56.41; H, 5.59. Found: C, 56.78; H, 6.01.
2-(4-Eth oxyp h en yl)-3,3,3-tr iflu or o-1-(3-p h en oxyben zyl)-
oxyp r op a n e (15). A mixture of compound 14 (0.23 g, 1.0 mmol),
m-phenoxybenzyl bromide (0.53 g, 2.0 mmol) and tetrabutyl-
amonium bromide (0.064 g, 0.20 mmol), in 10 M aqueous NaOH
(2.0 mL) was stirred at 25 °C for 3 h. The reaction mixture was
diluted with water (10 mL) and extracted with diethyl ether (3
× 10 mL). The organic phase was washed with brine, dried,
and concentrated. The residue was subjected to chromatography
on silica gel eluting with a 20:1 mixture of petroleum ether and
ethyl acetate to afford 0.39 g (94%) of 15. 1H NMR (CDCl3) δ
7.28 (m, 7 H), 6.90 (m, 6 H), 4.50 (AB system, J ) 12.4 Hz, 2 H),
4.02 (q, J ) 7.0 Hz, 2 H), 3.97 (dd, J ) 9.9, 5.8 Hz, 1 H), 3.80
(dd, J ) 9.9, 7.3 Hz, 1 H), 3.57 (m, 1 H), 1.43 (t, J ) 7.0 Hz, 3
H); 19F NMR (CDCl3) δ -10.0 (d, J ) 10.0 Hz); MS (EI, m/ z)
417 (M+ + 1, 7), 416 (M+, 25), 386 (14), 203 (100), 183 (67), 125
(15). Anal. Calcd for C24H23F3O3: C, 69.22; H, 5.57. Found:
C, 69.38; H, 5.47.
Ack n ow led gm en t. This work was supported by
grants from the National Natural Science Foundation
of China and Shanghai Municipal Scientific Committee.
J O952215A