A tandem nucleophilic addition, defluorination and destannylation. Stereospecific synthesis of trifluoromethylated alkyl and aryl vinyl ethers

Article abstract of DOI:10.1055/s-2004-831231

A novel tandem reaction, including nucleophilic addition, defluorination and destannylation reactions, has been found and its application to the stereospecific synthesis of trifluoromethylated alkyl- and aryl vinyl ethers with exclusive formation of E-isomers in 73-96% yields is reported. An Ad _N-E mechanism for the tandem reaction leading to alkyl- and aryl vinyl ethers is proposed.

Full text of DOI:10.1055/s-2004-831231

PAPER
2637
A Tandem Nucleophilic Addition, Defluorination and Destannylation.
Stereospecific Synthesis of Trifluoromethylated Alkyl and Aryl Vinyl Ethers
S
tereospecific Syn
a
thesis of
T
r
n
ifluoromethy
c
latedAlky
h
l
and
A
ryl
V
a
inyl
E
thersng Shen,* Guoping Wang
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin
Lu, Shanghai 200032, P. R. China
Fax +86(21)64166128; E-mail: shenyc@mail.sioc.ac.cn
Received 7 June 2004; revised 21 July 2004
stannane, while the fluorinated species gave the
Abstract: A novel tandem reaction, including nucleophilic addi-
destannylated product (Scheme 1).
tion, defluorination and destannylation reactions, has been found
and its application to the stereospecific synthesis of trifluorometh-
C6H5
C6H5
C6H5
SnBu3
F
H
ylated alkyl- and aryl vinyl ethers with exclusive formation of E-
isomers in 73–96% yields is reported. An AdN -E mechanism for the
tandem reaction leading to alkyl- and aryl vinyl ethers is proposed.
NaOCH3/CH3OH
reflux, 16 h
F
C6H5
Key words: trifluoromethylated alkyl- and aryl vinyl ethers, nu-
cleophilic addition, defluorination, destannylation
Scheme 1
Fortunately, we tried to employ this method in the destan-
nylation reaction of polyfluorovinylstannane and found a
novel tandem reaction including nucleophilic addition,
defluorination and destannylation reaction. It was applied
to the stereospecific synthesis of substituted trifluoro-
methyl vinyl ethers in good to excellent yields and they
would be useful fluorine-containing intermediates in or-
ganic synthesis (Scheme 2).
In recent years much attention has been paid to the synthe-
sis of vinyl ethers since they have emerged as highly valu-
able intermediates in a variety of synthetic applications,1
especially in the synthesis of biologically active com-
pounds.2 Moreover, vinyl ethers are valuable precursors
of acyl anion equivalents which are employed in the for-
mation of C–C bonds as a powerful strategy in the devel-
opment of new synthetic methodologies.3 They readily
add to a wide variety of electrophiles, forming adducts
which are converted to the acetyl derivatives.4 It is well
known that Reppe vinylation is the usual method for the
preparation of vinyl ethers from the alcohol and acetylene
in the presence of potassium hydroxide as catalyst at high-
er temperature and pressure.5 Recently, several other
methods also have been reported including Julia olefina-
tion, catalytic metathesis and Horner–Wadsworth–Em-
mons (HWE) reaction.6 However, to the best of our
knowledge the synthesis of fluorine-containing species is
still limited,7 including palladium-catalyzed cross-cou-
pling reaction of the zinc reagent with organic halides and
triflates, but the starting materials are not easily accessi-
ble.7d Therefore the development of an efficient method
for the synthesis of the title compounds would be valu-
able. As part of our continuing investigation to explore the
new synthetic utility of (Z)-a-fluoro-b-trifluoromethylvi-
nylstannane in organic synthesis,8 herein we report a nov-
el tandem nucleophilic addition, defluorination and
destannylation reaction.
F3C
F3C
Ar
H
SnBu3
F
RONa/ROH
reflux, 4–5 h
OR
Ar
1
2
Scheme 2
Treatment of (Z)-a-fluoro-b-trifluoromethylvinylstan-
nanes 1 with sodium methoxide (or ethoxide) in refluxing
methanol (or ethanol) for four to five hours gave trifluo-
romethylated alkyl vinyl ethers 2 in 73–95% yields. The
results are summarized in Table 1. The reaction was ste-
reospecific and the E-isomer was obtained exclusively.
No Z-isomer was isolated or detected.
On the basis of literature reported10 H,CF3 coupling con-
stants across the double bond, if trifluoromethyl group is
trans with respect to the H, the 4JF,Htrans = 0.5 Hz, while for
4
those cis with respect to the H, the JF,Hcis = 1.85 Hz. In
4
our case, the JF,H ranged from 1.70–1.90 Hz, hence the
configuration of the products 2 could be ascertained as the
It has been reported in the literature9 that the stereospecif-
ic destannylation reaction of vinylstannane by using re-
fluxing methanolic sodium methoxide depends upon the
functionalities present in the molecule. The tributylstan-
nyl group was not removed from nonfluorinated vinyl-
E-configuration.
An AdN -E mechanism shown in Scheme 3 is proposed for
the formation of the products 2.
In general, vinylic substrates react with nucleophiles very
poorly, but nucleophilic substitution is greatly enhanced
in substrates 1 carrying the strong electron-withdrawing
CF3 and F groups, since they can stabilize the carbanion
and make the carbon of the C–F bond more positive. Thus,
SYNTHESIS 2004, No. 16, pp 2637–2640
x
x.
x
x
.
2
0
0
4
Advanced online publication: 22.09.2004
DOI: 10.1055/s-2004-831231; Art ID: F08204SS
© Georg Thieme Verlag Stuttgart · New York

2638
Y. Shen, G. Wang
PAPER
Table 1 Trifluoromethylated Alkyl Vinyl Ethers 2 Prepared
F3C
Ar
F3C
Ar
H
SnBu3
F
R'OH/K2CO3
DMF
Com-
pound
Ar
R
Reaction Yield
Time (h) (%)a
OR'
6
1
2a
2b
2c
2d
2e
2f
3-CH3C6H4
4-ClC6H4
CH3
4
4
4
5
5
5
5
95
91
82
73
81
95
89
Scheme 4
Table 2 Trifluoromethylated Aryl Vinyl Ethers 3 Prepared
CH3
4-CH3OC6H4
4-CH3C6H4
4-ClC6H4
CH3
Com- Ar
pound
R¢
Reaction Yield (%)a
time (h)
CH3CH2
CH3CH2
CH3CH2
CH3CH2
6a
6b
6c
6d
4-CH3OC6H4
C6H5
6
6
6
6
96
90
82
88
3-CH3C6H4
4-CH3OC6H4
3-CH3C6H4
4-CH3OC6H4
3-CH3C6H4
C6H5
2g
2-C6H5CH2C6H4
2-C6H5CH2C6H4
a Isolated yields.
a Isolated yields.
the vinyl fluorides 1 are more susceptible to nucleophilic
attack.
In conclusion, a novel tandem reaction, including nucleo-
philic addition, defluorination and destannylation reac-
tions, has been found and its application to the
stereospecific synthesis of trifluoromethylated alkyl- and
aryl vinyl ethers in good to excellent yields has been de-
scribed. This methodology provides a simple and conve-
nient synthesis of the title compounds from easily
accessible starting materials. They are not easily available
with existing synthetic methods and would be useful in
preparing fluorine-containing intermediates in organic
synthesis.
The reaction is initiated by the nucleophilic attack of so-
dium alkoxide ion forming imtermediate 3. After simulta-
neous movement of two pairs of electrons, defluorination
occurred and the intermediate 4 and fluoride ion were
formed. Finally, destannylation takes place when the fluo-
ride ion attacks tributylstannyl group to afford 5, followed
by abstraction of a proton giving 2. In our studies, the re-
tention of configuration was observed for the tandem nu-
cleophilic addition, defluorination and destannylation
reaction in polyfluorovinylstannane.
Similarly, the (Z)-a-fluoro-b-trifluoromethylvinylstan-
nanes 1 reacted with phenol in the presence of potassium
carbonate in DMF to give exclusively the E-isomers of the
trifluoromethylated aryl vinyl ethers 6 in 82–96% yields.
The results are summarized in Table 2.
(Z)-2-Aryl-1-tributylstannyl-1,3,3,3-tetrafluoroprop-1-enes 1 were
prepared according to the known method.8a Petroleum ether (PE)
used had a bp 60–90 °C. The IR spectra of liquid products were ob-
tained as films on a Digilab FTS-20E spectrometer. 1H NMR spec-
tra were recorded on a Bruker AM-300 (300 MHz) spectrometer (d
values in ppm from tetramethylsilane, in CDCl3, J values are given
in Hz). 19F NMR spectra were taken on a Varian EM-360 (60 MHz)
spectrometer (d values in ppm from external trifluoroacetic acid, in
CDCl3, positive for upfield shifts). Mass spectra were measured on
a Finnigan GC-MS-4021 mass spectrometer. High-resolution mass
spectrometry data were obtained on a Finnigan-Mat 8430 high-res-
olution mass spectrometer. All reactions were performed in oven-
dried glassware under dry N2. Solvents were evaporated under re-
duced pressure with a rotary evaporator and the residue was purified
by column chromatography on a silica gel column (100–200 mesh).
CF3
SnBu3
F3C
Ar
SnBu3
F
Nucleophilic
addition
Ar
F
+ OR
OR
3
1
defluorination
–F
F3C
Ar
destannylation
–SnBu3F
F3C
Ar
SnBu3
Trifluoromethylated Alkyl Vinyl Ethers 2; General Procedure
To anhyd MeOH or EtOH (4 mL) was added clean Na (0.23 mg, 1
mmol) under N2. After the reaction was complete, the appropriate
vinyl fluoride 1 (0.8 mmol) was added. The reaction mixture was re-
fluxed for 4–5 h under N2 until the starting material had disappeared
(monitored by TLC analysis). Evaporation of the solvent gave a res-
idue, which was purified by column chromatography eluting with
PE–EtOAc (98:2) to give the product 2.
+ F
OR
OR
5
4
H+
H
F3C
Ar
OR
(E)-2-(3-Methylphenyl)-3,3,3-trifluoropropen-1-yl Methyl
Ether [(E)-2a]
2
Yield: 95%; oil.
IR (neat): 1670, 1330, 1270, 1150, 1110 cm–1.
Scheme 3
Synthesis 2004, No. 16, 2637–2640 © Thieme Stuttgart · New York

PAPER
Stereospecific Synthesis of Trifluoromethylated Alkyl and Aryl Vinyl Ethers
2639
1H NMR (CDCl3/TMS): d = 7.27–7.11 (m, 4 H), 6.89 (q, J = 1.9
Hz, 1 H), 3.79 (s, 3 H), 2.36 (s, 3 H).
(E)-2-(3-Methylphenyl)-3,3,3-trifluoropropen-1-yl Ethyl Ether
[(E)-2f]
Yield: 95%; oil.
IR (neat): 1660, 1320, 1310, 1150, 1110 cm–1.
1H NMR (CDCl3/TMS): d = 7.27–7.24 (m, 3 H), 7.13–7.10 (m, 1
H), 6.95 (q, J = 1.8 Hz, 1 H), 4.02 (q, J = 7.1 Hz, 2 H), 2.36 (s, 3
H), 1.31 (t, J = 7.1 Hz, 3 H).
19F NMR (CDCl3/TFA): d = –16.8 (s, 3 F).
19F NMR (CDCl3/TFA): d = –17.3 (s, 3 F).
MS: m/z (%) = 216 (M+, 100), 201 (21), 186 (4), 173 (22), 168 (3),
153 (14).
HRMS: m/z calcd for C11H11F3O (216.20): 216.0762; found:
216.0787.
(E)-2-(4-Chlorophenyl)-3,3,3-trifluoropropen-1-yl Methyl
Ether [(E)-2b]
Yield: 91%; oil.
IR (neat): 1670, 1500, 1330, 1270, 1160, 1110 cm–1.
1H NMR (CDCl3/TMS): d = 7.40–7.32 (m, 4 H), 6.91 (q, J = 1.8
Hz, 1 H), 3.81 (s, 3 H).
MS: m/z (%) = 230 (M+, 100), 211 (4), 182 (20), 173 (9), 161 (1),
154 (57).
HRMS: m/z calcd for C12H13F3O (230.22): 230.0919; found:
230.0929.
(E)-2-(4-Methoxyphenyl)-3,3,3-trifluoropropen-1-yl Ethyl
Ether [(E)-2g]
Yield: 89%; oil.
IR (neat): 1660, 1520, 1290, 1250, 1160, 1100 cm–1.
1H NMR (CDCl3/TMS): d = 7.43–7.35 (m, 2 H), 6.92 (q, J = 1.8
Hz, 1 H), 6.90–6.86 (m, 2 H), 4.02 (q, J = 7.1 Hz, 2 H), 3.81 (s, 3
H), 1.31 (t, J = 7.1 Hz, 3 H).
19F NMR (CDCl3/TFA): d = –17.2 (s, 3 F).
MS: m/z (%) = 238 (M+ + 2, 33), 236 (M+, 100), 221 (29), 217 (9),
193 (36), 186 (14), 143 (48).
HRMS: m/z calcd for C10H8ClF3O (236.62): 236.0216; found:
236.0193.
(E)-2-(4-Methoxyphenyl)-3,3,3-trifluoropropen-1-yl Methyl
Ether [(E)-2c]
Yield: 82%; oil.
IR (neat): 1670, 1610,1520, 1330, 1290, 1250, 1160, 1110 cm–1.
1H NMR (CDCl3/TMS): d = 7.38–7.34 (m, 2 H), 6.93–6.88 (m, 2
H), 6.86 (q, J = 1.9 Hz, 1 H), 3.80 (s, 3 H), 3.77 (s, 3 H).
19F NMR (CDCl3/TFA): d = –16.9 (s, 3 F).
MS: m/z (%) = 246 (M+, 100), 227 (31), 198 (52), 189 (35), 170
(14).
HRMS: m/z calcd for C12H13F3O2 (246.22): 246.0868; found:
246.0862.
Trifluoromethylated Aryl Vinyl Ethers 6; General Procedure
To anhyd DMF (4 mL) were added K2CO3 (0.20 g, 1.5 mmol), phe-
nol (1 mmol) and the appropriate vinyl fluoride 1 (0.8 mmol). The
reaction mixture was refluxed for 6 h until the starting material had
disappeared (monitored by TLC analysis). Then Et2O (40 mL) was
added. The organic layer was washed with H2O (2 × 20 mL) and
dried (Na2SO4). Evaporation of the solvent gave a residue, which
was purified by column chromatography eluting with PE–EtOAc
(98:2) to afford the product 6.
19F NMR (CDCl3/TFA): d = –17.2 (s, 3 F).
MS: m/z (%) = 232 (M+, 100), 217 (64), 202 (6), 189 (30), 148 (33).
HRMS: m/z calcd for C11H11F3O2 (232.22): 232.0711; found:
232.0709.
(E)-2-(4-Methylphenyl)-3,3,3-trifluoropropen-1-yl Ethyl Ether
[(E)-2d]
Yield: 73%; oil.
IR (neat): 1660, 1520, 1330, 1310, 1160, 1100 cm–1.
(E)-2-(4-Methoxyphenyl)-3,3,3-trifluoropropen-1-yl Phenyl
Ether [(E)-6a]
Yield: 96%; oil.
1H NMR (CDCl3/TMS): d = 7.35 (d, J = 8.1 Hz, 2 H), 7.16 (d,
J = 8.0 Hz, 2 H), 6.94 (q, J = 1.9 Hz, 1 H), 4.02 (q, J = 7.1 Hz, 2
H), 2.35 (s, 3 H), 1.31 (t, J = 7.1 Hz, 3 H).
19F NMR (CDCl3/TFA): d = –17.3 (s, 3 F).
IR (neat): 1670, 1610, 1520, 1490, 1290, 1240, 1200, 1170, 1110
cm–1.
MS: m/z (%) = 230 (M+, 100), 211 (3), 201 (5), 182 (21), 173 (8),
154 (31).
1H NMR (CDCl3/TMS): d = 7.48–7.35 (m, 4 H), 7.32 (q, J = 1.7
Hz, 1 H), 7.18–6.91 (m, 5 H), 3.82 (s, 3 H).
19F NMR (CDCl3/TFA): d = –17.2 (s, 3 F).
MS: m/z (%) = 294 (M+, 100), 279 (4), 265 (8), 245 (3), 217 (5), 201
HRMS: m/z calcd for C12H13F3O (230.22): 230.0919; found:
230.0905.
(8).
(E)-2-(4-Chlorolphenyl)-3,3,3-trifluoropropen-1-yl Ethyl Ether
HRMS: m/z calcd for C16H13F3O2 (294.27): 294.0868; found:
294.0827.
[(E)-2e]
Yield: 81%; oil.
IR (neat): 1660, 1500, 1330, 1160, 1100 cm–1.
1H NMR (CDCl3/TMS): d = 7.42–7.31 (m, 4 H), 6.98 (q, J = 1.8
Hz, 1 H), 4.05 (q, J = 7.1 Hz, 2 H), 1.31 (t, J = 7.1 Hz, 3 H).
(E)-2-(3-Methylphenyl)-3,3,3-trifluoropropen-1-yl Phenyl
Ether [(E)-6b]
Yield: 90%; oil.
19F NMR (CDCl3/TFA): d = –16.9 (s, 3 F).
MS: m/z (%) = 252 (M+ + 2, 33), 250 (M+, 100), 231 (5), 222 (10),
IR (neat): 1670, 1600, 1490, 1320, 1260, 1220, 1190, 1160, 1110
cm–1.
1H NMR (CDCl3/TMS): d = 7.41–7.22 (m, 6 H), 7.19–7.03 (m, 4
H), 2.38 (s, 3 H).
202 (37), 174 (22), 167 (34).
HRMS: m/z calcd for C11H10ClF3O (250.64): 250.0372; found:
250.0368.
19F NMR (CDCl3/TFA): d = –17.0 (s, 3 F).
MS: m/z (%) = 278 (M+, 100), 260 (24), 241 (17), 229 (13), 209
(19), 191 (10), 181 (22), 165 (24).
Synthesis 2004, No. 16, 2637–2640 © Thieme Stuttgart · New York

2640
Y. Shen, G. Wang
PAPER
Anal. Calcd for C16H13F3O (278.27): C, 69.06; H, 4.71. Found: C,
69.42; H, 4.95.
(2) (a) Nakamura, Y.; Matsubara, R.; Kiyohara, H.; Kabayashi,
S. Org. Lett. 2003, 5, 2481. (b) Savinov, S. N.; Austin, D. J.
Org. Lett. 2002, 4, 1415. (c) Kulkarni, M. G.; Rasne, R. M.;
Davawala, S. I.; Doke, A. K. Tetrahedron Lett. 2002, 43,
2297. (d) Harrowven, D. C.; Tyte, M. J. Tetrahedron Lett.
2002, 43, 5971. (e) Jensen, K. B.; Roberson, M.; Jorgensen,
K. A. J. Org. Chem. 2000, 65, 9080. (f) Zhuang, W.;
Thorhauge, J.; Jorgensen, K. A. Chem. Commun. 2000, 459.
(3) Yu, W.; Jin, Z. J. Am. Chem. Soc. 2000, 122, 9840; and
references cited therein.
(4) Friesen, R. W. J. Chem. Soc., Perkin Trans. 1 2001, 1969;
and references cited therein.
(5) (a) Reppe, W. Liebigs Ann. Chem. 1956, 601, 81.
(b) Trofimov, B. A.; Vasil’tsov, A. M.; Schmidt, E. Y.;
Zaitsev, A. B.; Mikhaleva, A. I.; Afonin, A. V. Synthesis
2000, 1521.
(6) (a) Surprenant, S.; Chan, W. Y.; Berthelette, C. Org. Lett.
2003, 5, 4851. (b) Okimoto, Y.; Sakaguchi, S.; Ishii, Y. J.
Am. Chem. Soc. 2002, 124, 1590; and references cited
therein. (c) Bosch, M.; Schlaf, M. J. Org. Chem. 2003, 68,
5225. (d) Blouin, M.; Frenette, R. J. Org. Chem. 2001, 66,
9043. (e) Chakravarty, M.; Srinivas, B.; Muthiah, C.;
Swamy, K. C. K. Synthesis 2003, 2368. (f) Roeschlaub, C.
A.; Sammes, P. G. J. Chem. Soc., Perkin Trans. 1 2000,
2243.
(7) (a) Begue, J.-P.; Bonnet-Delpon, D.; Mesureur, D.; Nee, G.;
Wu, S. W. J. Org. Chem. 1992, 57, 3807. (b) Hong, F.; Hu,
C.-M. Chem. Commun. 1996, 57. (c) Shi, G.-Q.; Huang, X.-
H.; Hong, F. J. Chem. Soc., Perkin Trans. 1 1996, 763.
(d) Shi, G.-Q.; Huang, X.-H.; Hong, F. J. Org. Chem. 1996,
61, 3200. (e) Purrington, S. T.; Thomas, H. N. J. Fluorine
Chem. 1998, 90, 47. (f) Zhu, S. Z.; Jin, G. F.; Peng, W. M.;
Huang, Q. C. Tetrahedron 2003, 59, 2899; and references
cited therein.
(E)-2-(4-Methoxyphenyl)-3,3,3-trifluoropropen-1-yl (2-Benzyl-
phenyl) Ether [(E)-6c]
Yield: 82%; oil.
IR (neat): 1670, 1610, 1520, 1490, 1450, 1290, 1240, 1170, 1120
cm–1.
1H NMR (CDCl3/TMS): d = 7.40 (d, J = 8.8 Hz, 2 H), 7.22 (q,
J = 1.7 Hz, 1 H), 7.25–7.12 (m, 5 H), 7.05–6.96 (m, 4 H), 6.88 (d,
J = 8.5 Hz, 2 H), 3.91 (s, 2 H), 3.82 (s, 3 H).
19F NMR (CDCl3/TFA): d = –16.7 (s, 3 F).
MS: m/z (%) = 384 (M+, 50), 353 (2), 332 (1), 202 (18), 181 (100).
Anal. Calcd for C23H19F3O2 (384.40): C, 71.87; H, 4.98. Found: C,
71.72; H, 5.10.
(E)-2-(3-Methylphenyl)-3,3,3-trifluoropropen-1-yl (2-Benzyl-
phenyl) Ether [(E)-6d]
Yield: 88%; oil.
IR (neat): 1670, 1590, 1490, 1450, 1320, 1260, 1220, 1150, 1120
cm–1.
1H NMR (CDCl3/TMS): d = 7.32–7.23 (m, 5 H), 7.21 (q, J = 1.9
Hz, 1 H), 7.19–6.98 (m, 8 H), 3.89 (s, 2 H), 2.36 (s, 3 H).
19F NMR (CDCl3/TFA): d = –17.1 (s, 3 F).
MS: m/z (%) = 368 (M+, 24), 353 (2), 328 (2), 275 (5), 181 (100),
165 (27).
HRMS: m/z calcd for C23H19F3O (368.39): 368.1388; found:
368.1392.
Acknowledgment
(8) (a) Shen, Y.; Wang, G. Org. Lett. 2002, 4, 2083. (b) Shen,
Y.; Wang, G. Synthesis 2002, 209.
(9) McCarthy, J. R.; Matthews, D. P.; Stemerick, D. M.; Huber,
E. W.; Bey, P.; Lippert, B. J.; Snyder, R. D.; Sunkara, P. S.
J. Am. Chem. Soc. 1991, 113, 7439.
We thank the National Natural Science Foundation of China and the
Chinese Academy of Sciences for financial support.
(10) Cullen, W. R.; Waldman, M. C. Can. J. Chem. 1969, 47,
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Synthesis 2004, No. 16, 2637–2640 © Thieme Stuttgart · New York