A one-pot synthesis of (E)-α-bromo-α,β-unsaturated esters and their trifluoromethylation: A general and stereoselective route to (E)-α-trifluoromethyl-α,β-unsaturated esters

Article abstract of DOI:10.1016/S0040-4039(01)01153-4

Bromination of a phosphonate anion derived in situ from ethyl bis(2,2,2-trifluoroethyl)phosphonoacetate 3 followed by the addition of aldehydes produced (E)-α-bromo-α,β-unsaturated esters 5 stereoselectively. The treatment of 5 with FSO₂CF₂CO₂Me and CuI in DMF/HMPA provided (E)-α-trifluoromethyl-α,β-unsaturated esters 6.

Full text of DOI:10.1016/S0040-4039(01)01153-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 5929–5931
A one-pot synthesis of (E)-a-bromo-a,b-unsaturated esters and
their trifluoromethylation: a general and stereoselective route to
(E)-a-trifluoromethyl-a,b-unsaturated esters
Feng-Ling Qinga,b,* and Xingang Zhanga
aLaboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin Lu, Shanghai 200032, China
bCollege of Chemistry and Chemical Engineering, Donghua University, 1882 West Yanan Lu, Shanghai 200051, China
Received 6 April 2001; revised 30 May 2001; accepted 28 June 2001
Abstract—Bromination of a phosphonate anion derived in situ from ethyl bis(2,2,2-trifluoroethyl)phosphonoacetate 3 followed by
the addition of aldehydes produced (E)-a-bromo-a,b-unsaturated esters
5 stereoselectively. The treatment of 5 with
FSO2CF2CO2Me and CuI in DMF/HMPA provided (E)-a-trifluoromethyl-a,b-unsaturated esters 6. © 2001 Elsevier Science Ltd.
All rights reserved.
Considerable attention has been given to trifluoro-
methyl-containing organic compounds as agrochemical
and pharmaceutical agents due to their unique proper-
ties arising from their electron density, acidity, and
lipophilicity.1 Accordingly, the development of newer
methods for the synthesis of trifluoromethyl-containing
organic compounds continues to be an important area
of research in agricultural, medicinal, and organic
chemistry.2 In continuation of our ongoing projects
involving the synthesis of trifluoromethyl-containing
nucleosides,3 we required (E)-a-trifluoromethyl-a,b-
unsaturated esters. We envisaged the preparation of
such trifluoromethyl-containing building blocks via the
trifluoromethylation of (E)-a-bromo-a,b-unsaturated
esters. Herein, we wish to report a one-pot synthesis of
(E)-a-bromo-a,b-unsaturated esters and their tri-
fluoromethylation for the preparation of (E)-a-tri-
fluoromethyl-a,b-unsaturated esters.
Although there are some limitations with respect to the
stereoselective construction of alkenes, Wittig and
Horner–Wadsworth–Emmons (HWE) reactions are
powerful and attractive methods for the synthesis of
various alkenes.4 Kogen et al.5 recently reported a novel
reagent, methyl bis(2,2,2-trifluoroethoxy)bromophos-
phonoacetate, and the HWE reaction of aldehydes with
Scheme 1.
Keywords: a-bromo-a,b-unsaturated esters; trifluoromethylation.
* Corresponding author. Fax: 86-21-64166128; e-mail: flq@pub.sioc.ac.cn
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01153-4

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F.-L. Qing, X. Zhang / Tetrahedron Letters 42 (2001) 5929–5931
yield (10%), along with unreacted 4a. We were
delighted, however, to obtain 5a in 57% yield and with
high E-selectivity (E:Z=24:1) using 2 equiv. of 3. For
further evaluation of this one-pot procedure, we exam-
ined the HWE reactions of 3 with various aldehydes.
As shown in Scheme 3 and Table 1,7 the reactions with
aromatic aldehydes gave (E)-a-bromo-a,b-unsaturated
esters stereoselectively with high yields (87–57%)
(entries 1–3), branched aliphatic aldehydes were slightly
less reactive (59–44%), but high stereoselectivity still
remained (entries 4–6). It is worth noting that the yield
of 5 obtained by this one-pot procedure was higher
than that prepared from 3 in three steps as Kogen et
al.5 reported.
this novel reagent in the presence of t-BuOK which
gave (E)-a-bromo-a,b-unsaturated esters with high
stereoselectivity. However, when we attempted to make
ethyl bis(2,2,2-trifluoroethyl)bromophonoacetate
1
using Kogen’s methodology (Scheme 1), we found that
the yield of 1 was low (35% overall yield from 3), and
that during treatment of ethyl bis(2,2,2-tri-
fluoroethyl)-dibromophosphonoacetate 2 with 1 equiv.
of SnCl2, some of the over-reduced product 3 appeared
and unreacted dibromide 2 remained. The polarity of 1
was very close to that of 2 and 3, and therefore it was
very difficult to separate from them by flash chro-
matography.
Forty years ago, Emmons et al.6 reported that halo-
genation of a phosphonate anion in situ followed by the
addition of an aldehyde or ketone gave a vinylic halide
(Scheme 2). This was a simple procedure (one-pot) for
the synthesis of vinylic halides. However, a mixture of
Z- and E-isomers was obtained.
We recently described a novel route to (Z)-a-tri-
fluoromethyl-a,b-unsaturated esters by coupling (Z)-a-
bromo-a,b-unsaturated esters with CF3Cu generated in
situ.3 Having the (E)-a-bromo-a,b-unsaturated esters 5
in hand, we were interested in exploring the feasibility
of using 5 in trifluoromethylation reactions for the
synthesis
of
(E)-a-trifluoromethyl-a,b-unsaturated
In view of this, we decided to use a one-pot procedure
for the preparation of (E)-a-bromo-a,b-unsaturated
esters 5. First, the synthesis of 5a was carried out using
Emmons’s procedure. Reaction of the aldehyde 4a with
the phosphonate anion prepared in situ from 1 equiv.
of 3 in the presence of NaH gave 5a in only a poor
esters. The coupling of 5 with CF3Cu generated in situ
from FSO2CF2CO2Me and CuI proceeded readily giv-
ing (E)-a-trifluoromethyl-a,b-unsaturated esters
(Scheme 4).
6
As shown in Table 2, 5c and 5a with an electron-with-
drawing nitro group at the para position gave 6c and
6a, respectively, in high yield (entries 1 and 3). How-
ever, 5b with an electron-donating para methoxy group
gave 6b in only a 65% yield, along with unreacted 5b
(entry 2). In addition, branched aliphatic (E)-a-bromo-
a,b-unsaturated esters were slightly less reactive,
although they reacted high stereoselectivity. The follow-
ing observations are noteworthy: (1) an excess of
FSO2CF2CO2CH3 (2.5 equiv.) and CuI (0.8 equiv.) are
necessary for the complete conversion of 5; (2) limited
E/Z isomerization occurred (entries 2–4), but the major
products were the E-isomers; (3) in the case of com-
pound 5f (entry 6), the yield was low (46%) because
fluoro-containing by-products were produced (detected
Scheme 2.
Scheme 3.
Table 1. A one-pot synthesis of (E)-a-bromo-a,b-unsaturated esters 5

F.-L. Qing, X. Zhang / Tetrahedron Letters 42 (2001) 5929–5931
5931
Yamazaki, T. Experimental Methods in Organic Fluorine
Chemistry; Gordon and Breach Science: Amsterdam, 1998;
(c) Burton, D. J.; Yang, Z. Y.; Qiu, W. Chem. Rev. 1996,
96, 1641.
3. Zhang, X.; Qing, F. L.; Yu, Y. J. Org. Chem. 2000, 65,
7075.
Scheme 4.
4. (a) Wadsworth, W. S. Org. React. 1977, 25, 73; (b)
Maryanoff, B. E.; Reitz, A. B. Chem. Rev. 1989, 89, 863;
(c) Vedejs, E.; Peterson, M. J. Top. Stereochem. 1994, 21,
1.
5. (a) Tago, K.; Kogen, H. Org. Lett. 2000, 2, 1975; (b)
Tago, K.; Kogen, H. Tetrahedron 2000, 56, 8825.
6. Wadsworth, Jr., W. S.; Emmons, W. D. J. Am. Chem. Soc.
1961, 83, 1733.
Table 2. Synthesis of (E)-a-trifluoromethyl-a,b-unsaturated
esters 6
Entry
5 (E:Z)
Product
Yield (%)a
E:Zb
1
2
3
4
5
6
5a (24:1)
5b (25:1)
5c (E only)
5d (E only)
5e (E only)
5f (E only)
6a
6b
6c
6d
6e
6f
91
65
92
61
56
46
24:1
11:1
28:1
24:1
E only
E only
7. Representative procedure for the synthesis of (E)-a-
bromo-a,b-unsaturated esters 5. Ethyl bis(trifluoro-
ethyl)phosphonoacetate9 (664 mg, 2 mmol) in anhydrous
THF (2 ml) was added dropwise at −30°C to a slurry of
60% sodium hydride (80 mg, 2 mmol) in anhydrous THF
(4 ml). The solution was stirred for 30 min at −30°C until
the solution turned clear. Bromine (0.1 ml, 2 mmol) in
anhydrous THF (1.5 ml) was added dropwise to the
reaction mixture at −30°C. During the addition, the reac-
tion gradually became cloudy. After the addition of
bromine, the reaction mixture was warmed briefly at 10–
15°C, then cooled to −78°C and 60% sodium hydride (80
mg, 2 mmol) was added all at once. The reaction mixture
was stirred for 30 min at −78°C. Then 3-methoxybenzalde-
hyde 4b (136 mg, 1 mmol) in anhydrous THF (1.5 ml) was
added dropwise to the mixture at such a rate as to
maintain the temperature at −78°C. The solution was
stirred for about 4–5 h at −78°C. Then the reaction
mixture was stirred overnight at 5–10°C. Saturated
aqueous NH4Cl solution was added to the reaction mix-
ture and the aqueous mixture was extracted with ethyl
acetate. The combined organic layer was washed with
water and brine, dried over Na2SO4 and concentrated. The
residue was purified by silica gel column chromatography
(petroleum ether:ethyl acetate=20:1) to give 224 mg (79%
yield) of 5b as a light yellow oil: 1H NMR (300 MHz,
CDCl3) l 7.27 (m, 3H), 6.84 (d, J=7.7 Hz, 2H), 4.24 (q,
J=7.1 Hz, 2H), 3.81 (s, 3H), 1.24 (t, J=7.1 Hz, 3H); IR
(thin film) 1720, 1602, 1512, 1255, 1176 cm−1; MS m/z 286
(M+, 43), 284 (M+, 44), 177 (100). Anal. calcd for
C12H13O3Br: C, 50.55; H, 4.59. Found: C, 50.36; H, 4.59.
8. Allmendinger, T.; Lang, R. W. Tetrahedron Lett. 1991, 32,
339.
a Isolated yield based on 5.
b Determined by 19F NMR.
by 19F NMR of the reaction mixture). The configura-
tion of the double bond in 6 was determined by the
chemical shifts of the alkenyl proton. The alkenyl pro-
ton in the E isomer appeared at higher field than in the
Z isomer.8
In conclusion, we describe a one-pot methodology for
the stereoselective and efficient preparation of (E)-a-
bromo-a,b-unsaturated esters 5. Using 5 as the key
intermediate, we succeeded in developing a general
procedure for the highly stereoselective synthesis of
(E)-a-trifluoromethyl-a,b-unsaturated esters 6.
References
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Synthesis and Chemistry of Agrochemical III; Baker, D. R.;
Fenyes, J. G.; Steffens, J. J., Eds. ACS Symposium Series
504; American Chemical Society: Washington, DC, 1992.
2. (a) Asymmetric Fluoroorganic Chemistry; Ramachandran,
P. V., Ed. ACS Symposium Series 746; American Chemi-
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9. Still, W. C.; Gennari, C. Tetrahedron Lett. 1983, 24, 4405.
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