Convenient stereoselective synthesis of β-perfluoroalkyl α,β-unsaturated esters via H?rner-Wadsworth-Emmons reactions

Article abstract of DOI:10.1016/j.tet.2015.08.048

Condensation of H?rner-Wadsworth-Emmons reagents 3 and ketones 2 with a perfluoroalkyl (Rf) moiety prepared in situ was proved to be significantly efficient and powerful methods for the construction of a wide variety of α,β-unsaturated esters with Rf and R¹ groups both at the β-position due to convenient avoidance of usually tedious as well as troublesome isolation steps of these ketones 2.

Full text of DOI:10.1016/j.tet.2015.08.048

Tetrahedron 71 (2015) 8059e8066
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Convenient stereoselective synthesis of
b
-perfluoroalkyl
€
a,
b-unsaturated esters via HornereWadswortheEmmons reactions
*
Takashi Yamazaki , Noriko Mano, Reo Hikage, Tsutomu Kaneko,
Tomoko Kawasaki-Takasuka, Shigeyuki Yamada
Division of Applied Chemistry, Institute of Engineering, Tokyo University of Agriculture and Technology, 2-24-16 Nakamachi, Koganei, 184-8588, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 29 July 2015
Received in revised form 18 August 2015
Accepted 20 August 2015
Available online 22 August 2015
€
Condensation of HornereWadswortheEmmons reagents 3 and ketones 2 with a perfluoroalkyl (Rf)
moiety prepared in situ was proved to be significantly efficient and powerful methods for the con-
struction of a wide variety of a,b b-position due to
-unsaturated esters with Rf and R1 groups both at the
convenient avoidance of usually tedious as well as troublesome isolation steps of these ketones 2.
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
€
HornereWadswortheEmmons reactions
a,b-Unsaturated esters
Perfluoroalkyl groups
Perfluoroalkylated hemiacetals
Perfluoroalkylated ketones
1. Introduction
points. For solving these problems, we have envisioned convenient
synthetic route as shown in Scheme 1.7 Thus, reaction of readily
Versatility of
fluoroalkyl (Rf) group at the
a
,
b
-unsaturated carbonyl compounds with a per-
position has been demonstrated thus
available perfluorinated esters 1 and appropriate Grignard reagents
R1MgX should furnish intermediary magnesium acetals Int-1. In
spite of greater stability of Int-1, the corresponding ketones 2
present in their equilibrating relationship8 are considered to be
b
far as, for example, acceptors for Michael addition reactions,1
DielseAlder cycloaddition,2 and 1,3-dipolar addition,3 and sub-
strates for asymmetric dihydroxylation.4 The high potency
appeared in these instances is mainly attributable to their lower-
lying LUMO energy levels,1a which are apparently affected by the
strongly electron-withdrawing Rf moieties directly connected to
€
trapped in situ by the HornereWadswortheEmmons (HWE) re-
agents 3 activated by LiBr and Et3N to produce the desired 4 and 5
with avoiding tedious isolation steps of ketones 2.9,10 Moreover,
a similar type of intermediates to Int-1 could be constructed by
such opposite combination as RfLi and appropriate non-fluorinated
esters, which would open an alternative route to get access to the
identical target molecules.
the
p-systems. Since most of these synthetic applications are
known to proceed in a stereospecific manner, stereoselective con-
struction of such molecules at the olefinic site is regarded as one of
the most important subjects.
Among this type of compounds, preparation of
saturated esters with a variety of an additional substituent at the
position was required for our purpose, and literature search
suggested that Wittig type processes were one of the most plau-
sible routes for their syntheses.5,6 However, it should be pointed
out that only a few fluorinated ketones were commercially avail-
able and their preparations are not always easy especially for ‘small
molecules’ among this category due to their possibly low boiling
b-Rf-a,b-un-
OMgX
OR
O
b
ROMgX
ROMgX
R1MgX
RfCO2R
Rf
Rf
R1
R1
1
2
Int-1
R1
Rf
CO2R2
H
(EtO)2P(O)CH2CO2R2 (3)
4 (R2=Bn)
5 (R2=Et)
LiBr, Et3N
Scheme 1. Basic concept of the present method.
* Corresponding author. Tel./fax: þ81 42 388 7038; e-mail address: tyamazak
@cc.tuat.ac.jp (T. Yamazaki).
http://dx.doi.org/10.1016/j.tet.2015.08.048
0040-4020/Ó 2015 Elsevier Ltd. All rights reserved.

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T. Yamazaki et al. / Tetrahedron 71 (2015) 8059e8066
In this article are described our recent results based on this concept
which actually enabled the particularly convenient as well as effi-
attached carbon atom was selected as the adequate proton source
to nicely improve the yield of the target 4aa to 75% (69% isolated
yield) with the excellent 95% E isomer preference.
cient preparation of the requisite a,b-unsaturated esters 4 and 5 in
moderate to excellent chemical yields even when Rf and R1 are, for
example, CF3 and Et, respectively in smaller lab scale reactions.11
By employment of the optimized conditions thus determined,
we have further investigated the scope and limitation of the pres-
ent procedure whose results were compared with the ones ob-
tained by the condensation with isolated fluorinated ketones 2
(‘conventional method’). Our procedure allowed to isolate the de-
sired 4aa and 4ak in 69% and 72% total yields for two steps (entries
1 and 12, Table 2, respectively), which were well compared with the
yields obtained by the ‘conventional method’ only in a single
condensation step (82% and 87%, entries 2 and 13). In the case of 4-
MeOC6H4 as R1, 25% lower yield with respect to the ‘conventional
method’ was, at least in part, due to formation of the byproduct,
2,2,2-trifluoro-1,1-diphenyl-ethanol 8aa in 27% yield. Possible de-
stabilization of Int-1 by the electron-donating MeO group would
shift the equilibrium to 2 at the Grignard reaction step, which was
considered as the major reason of this undesired result. Such sit-
uation was compensated by employment of the corresponding
lithium species instead of the Grignard reagent, attaining 79%
chemical yield with 95% E selectivity (entries 5e7). One important
issue to be mentioned at this point is the unfortunate contamina-
tion of the corresponding ethyl (entries 3 and 7) and methyl (entry
16) esters as byproducts when organolithium was used as nucleo-
philes, and these byproducts should stem from transesterification
by the alcohols originally included in the substrate esters 1. This
drawback was readily overcome by use of the substrate ester 1a and
2. Results and discussion
Determination of suitable reaction conditions was set as the
starting point of our investigation using ethyl trifluoroacetate 1a
(Rf: CF3, R: Et), phenylmagnesium bromide (R1: Ph, X: Br), and
benzyl diethyl phosphonoacetate 3a12 (R2: Bn) as the representa-
tive combination whose results were collected in Table 1. To a so-
lution of Int-1aa (Rf: CF3, R1: Ph, R: Et) formed by treatment of 1a
with PhMgBr in THF at ꢀ80 ꢁC for 1 h, followed by 0 ꢁC for an ad-
ditional 1 h was introduced a mixture containing the HWE reagent
3a, LiBr, and Et3N in THF, and the whole solution was refluxed for
the indicated period. In addition to approximately 30% detection of
the desired 4aa by 19F NMR, formation of the major byproduct,
trifluoroacetophenone ethyl hemiacetal 7aa, was noticed to some
extent in entries 2 to 5. This phenomena would be interpreted as
a consequence of significant energetic preference of Int-1aa to 2aa
even at the THF reflux temperature, leaving a larger amount of the
former seemingly intact. Then, for alteration of their equilibrium
composition, 5 equiv of a proton source was added before in-
troduction of the enolate derived from 3a. H2O actually affected the
reaction (entries 6 vs 7), and a catalytic amount of quaternary
ammonium salt was also effective (entries 8e10). EtOH (entry 9)
was proved to record slightly better yield of 4aa but, at the same
moment, 2,2,2-trifluoro-1-phenylethanol 9aa was detected in 34%
yield possibly due to existence of the competing Meer-
weinePonndorfeVerley type pathway which has been already
demonstrated13 to be smoothly promoted by the in situ-formed
EtOMgBr under THF reflux conditions. For suppression of this un-
desired conversion, t-BuOH without no hydrogen at the oxygen-
Table 2
Reactions with a variety of combination of esters and Grignard reagents
1) R1MgX, THF,
C, 1 h
CF3CO2Et (1a) or
2) t-BuOH,
R1
Rf
CO2Bn
H
C2F5CO2Me (1b)
time
n-Bu4NBr
O
P
O
LiBr, Et3N
EtO
EtO
4
OBn
Table 1
Investigation of reaction conditions
3a
Rf
O
Entry
R1
Timea (h)
Product
Isolated yield (%)
1) PhMgBr
1
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
C2F5
C2F5
C2F5
C2F5
C2F5
C2F5
Ph
Ph
Ph
Ph
2
2
2
2
2
6
2
2
2
2
6
1
6
2
6
2
2
2
2
4aa
4aa
4aa
4aa
4ab
4ab
4ab
4af
69 (95:5)
82 (90:10)
70d (92:8)
86 (91:9)
Ph
CF3
2aa
CF3CO2Et
2b
2) ROH
1a
3c
Ph
CO2Bn
H
time
4c,e
5
46f (99:1)
71 (92:8)
F3C
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
C2H5
n-C4H9
c-C6H11
c-C6H11
n-C8H17
n-C8H17
Ph
HO R
Ph
CF3
O
P
O
6b
LiBr,
4aa
EtO
EtO
7c
79d (95:5)
54 (89:11)
67 (90:10)
27g (89:11)
77 (71:29)
72 (98:2)
Et3N
OBn
8
7aa (R=OEt)
8aa (R=Ph)
9aa (R=H)
9c
4ah
4ai
4ai
3a
10
11b
12
13b
14
15b
16c
17c
18
19c
Solv.a
Time (h)
4ak
4ak
4ba
4ba
4ba
4bb
4be
4be
Entry
ROH
19F NMR yieldb (%)
87 (90:10)
26g (>99:1)
83 (>99:1)
81d (>99:1)
52h (>99:1)
32 (>99:1)
30 (>99:1)
4aa
Byproducts
1
2
3
Et2O
THF
THF
THF
THF
2
2
6
6
6
5
2
2
2
2
d
1
33 (8aa)
Ph
Ph
d
36 [89]
27 [78]
31 [87]
33 [85]
2
35 [97]
47 [>99]
50 [94]
75 [95]
27 (7aa), 5 (8aa)
27 (7aa), 6 (8aa)
42 (7aa), 3 (8aa)
44 (7aa), 4 (8aa)
95 (7aa)
7 (2aa), 36 (8aa)
3 (2aa), 40 (8aa)
9 (2aa), 34 (9aa)
3 (2aa), 7 (8aa)
d
4-MeOC6H4
CH3
CH3
4c
5c
6
d
d
THFd
THFd
THFd
THFd
THFd
d
a
Reaction time under reflux after mixing the enolate from 3a and ketone pre-
cursors Int-1.
7
H2O
H2O
EtOH
t-BuOH
8e
9e
10e
b
c
Results obtained under the ‘conventional method’.
RLi was used instead of RMgX without addition of a proton source.
The corresponding ethyl esters (12% (5aa) in entry 3, 13% (5ab) in entry 7) or
d
a
Solvent both for the reaction with 3a and the preparation of PhMgBr.
methyl ester (7% (6ba) in entry 16) were contained in the isolated products.
b
e
In the bracket was shown the percentage of the E isomer determined by 19F
3b was used instead of 3a, giving 5aa as the product.
f
NMR.
27% of 2,2,2-trifluoro-1,1-diphenylethanol 8aa was obtained.
c
g
2 (entry 4) and 3 (entry 5) equiv of 3a were used (1.3 equiv for other cases).
PhMgBr in Et2O was employed.
4 mol % of n-Bu4NBr was added right after addition of ROH.
Determined by 19F NMR.
d
e
h
This lower isolated yield (88% by 19F NMR) was due to the presence of some
unidentified byproducts with the close Rf values to 4bb.

T. Yamazaki et al. / Tetrahedron 71 (2015) 8059e8066
8061
the HWE reagent 3b both with the same alcohol part, affording
the synthesis of
b
-Rf-acrylates from the 3b-derived enolate and
pure 5aa (the ethyl ester of 4aa) in 86% yield basically in an iden-
tical E/Z ratio (entry 4). A major gap in the yield between our route
and the ‘conventional method’ was noticed in the case of c-
C6H11MgBr (entries 10 and 11), which was clearly explained by
a separate experiment to be as a consequence of the sluggish re-
action of ethyl trifluoroacetate 1a with c-C6H11MgBr only attaining
15% isolated yield (33% by 19F NMR) of the desired cyclohexyl tri-
fluoromethyl ketone 2ai.14 Linear alkyl substituents as shown in
entries 8 and 9 were found to work in a similar manner, producing
the desired enoates 4af and 4ah in good yields. Methyl penta-
fluoropropionate 1b was also applicable to the present process as
the substrate ester, leading to successful construction of the cor-
RfCO2Et by way of the in situ DIBAL reduction of the latter, the
lithium hemiacetal in our hands was transmetallated to the cor-
responding aluminium acetal by the addition of Et2AlCl, which
nicely solved this serious problem. Because of the possible fluorous
characteristics of 5ca by its higher fluorine content of 50.0% than
the other a,b-unsaturated esters 4 and 5 with shorter Rf chains,
VertrelÒ (1,1,1,2,2,3,4,5,5,5-decafluoropentane) was employed as
the extraction solvent instead of diethyl ether to effectively im-
prove its isolated yield to 94% (entry 2). Avoidance of extractive
workup procedures was found to be similarly valid, and chro-
matographic purification of crude materials after addition of NaF to
a reaction mixture and filtration through a pad of silica gel led to
semiquantitative isolation of (E)-5ca in 98% yield (entry 3). In-
stability of n-C6F13Li even at low temperature and its weak nucle-
ophilicity rendered the expediency of the present process lower
especially for the benzoate with the electron-donating MeO group
as R1 (entry 4). On the other hands, the opposite trend was also
noticed and the quantitative yield was attained by the one with the
electron-withdrawing CF3 substituent (entry 5). Applicability of
acetate, propanoate, and octanoate was clarified to this modified
route without any significant problem, while the corresponding
isobutyrate was proved not to be a good substrate possibly because
of steric hindrance around the carbonyl moiety. The already re-
ported data for the compound 5ce (entry 6)17 in connection to the
cases of Rf]CF3 or C2F5 allowed us to speculate the same E ste-
reochemistry constructed at the olefinic part for other products.
As shown above, Tables 2 and 3 unambiguously demonstrated
the utility of the present protocol for stereoselective construction of
responding
a,b-unsaturated esters 4. The low yield in entry 14
would be the direct reflection of the higher stability of the mag-
nesium hemiacetal obtained from pentafluorinated propiophenone
Int-1ba than the corresponding intermediates with a CF3 group,
affording the desired product 4ba only in 26% yield along with 29%
(both determined by 19F NMR) of the unreacted ketone 2ba as the
byproduct. The corresponding lithium reagents improved the re-
action with realizing a similar level of the chemical yield to the one
of the ‘conventional method’ (entries 15 and 16), in spite of a small
amount of the possible contamination as described above. E ster-
eoselectivity for all the products was confirmed by comparison of
the reported data (4aa and 4ab15) as well as by our independent
NOE experiment for 4ai, showing the distinct NOE cross peak be-
tween vinylic H at the
a position and the allylic H at the g position
only for the minor isomer. Major isomers of other new products
were estimated as E on the basis of these instances.
Different from the strategy starting from perfluorinated esters 1,
a,b-unsaturated esters 4 and 5 with Rf and R groups both at the b-
an alternative incorporation pathway of a n-C6F13 moiety to the
a
,
b
-
position. Especially important feature was exemplified by the in-
stances of entries 8e10, 18, and 19 in Table 2 and entries 6e8 in
Table 3: in spite of presence of such ‘small’ R1 substituents as Me, Et,
n-Bu, and c-Hex, syntheses of the product enoates 4 and 5 were
attained in moderate to high yields even in a small scale process. As
pointed out in the introductory part, the ‘conventional method’
requires the preparation of the requisite ketones 2 at first, while it is
quite apparent that their syntheses are not always easy task by
considering their low boiling points and high volatility.18 Successful
elimination of this possibly troublesome steps unveiled the con-
siderable advantage of the present protocol over the previously
reported methods.
unsaturated ester framework was envisioned by using n-C6F13Li
generated from the readily available iodide. Thus, smooth lith-
iumehalogen exchange of n-C6F13I was performed by subjection of
MeLi complexed with LiBr to a mixture of this iodide and PhCO2Et
in Et2O.16 Spontaneous nucleophilic attack of thus prepared n-
C6F13Li was occurred to the benzoate, and the following in-
troduction of the 3b-based enolate stereospecifically furnished the
product enoate (E)-5ca in 77% isolated yield (entry 1 in Table 3). At
this point, we have encountered reproducibility problems of this
reaction. With reference to the previous report by Pastor et al.9b on
The reaction mechanism was elucidated as shown in Scheme 2.
In the first ketone formation step, appropriate Grignard reagents
R1MgBr were reacted with perfluoroalkylated esters RfCO2R 1 to
furnish magnesium acetals Int-1 (X: MgBr), which were sub-
stantially stabilized by the strongly electron-withdrawing Rf moi-
eties. The higher nucleophilicity of magnesium alkoxides was
considered to play an important role in increase of the preference of
Int-1 to 2, leading to final production of hemiacetals 7 and/or ke-
tones 2 after THF refluxing even in the presence of the activated
HWE reagents 3. Thus, in this circumstance, it was assumed that
only an extraordinarily small amount of 2 was present, which
reacted quickly with ROMgBr rather than the 3-based reagents.
However, addition of a proton source converted Int-1 to the cor-
responding hemiacetals 7 whose transformation to 2 would be
more feasible on the basis of lower nucleophilicity of the resultant
ROH than the one of ROMgBr. An electron-donating R1 group
should destabilize Int-1 at the ketone formation stage to increase
the amount of 2 which would follow the further reaction with other
R1MgBr molecules to afford 8.
Table 3
Synthesis of a,b-Unsaturated esters with a n-C6F13 group by way of n-C6F13Li
1) n-C6F13
Et2O,
LiBr,
C, 0.5 h
R1CO2Et
R1
CO2Et
H
2) Et2
15 min
C,
rt, 3 h
O
P
O
n-C6F13
LiBr, Et3N
EtO
EtO
5c
OEt
E:Z >99:1
3b
Entry
R1
Product
Isolated yield (%)
1
2
3
4
5
6
7
8
9
Ph
Ph
Ph
5ca
5ca
5ca
5cb
5cc
5ce
5cf
5cg
5cj
77a,b
94a,c
98
49
>99
71
42
22
56
4-MeOC6H4
4-F3CC6H4
CH3
C2H5
i-C3H7
n-C7H15
An equilibrium mixture containing ketones 2 and hemiacetals 7
was subjected to a solution of the reactive enolates Int-2 conve-
niently derived from HWE reagents 3, LiBr, and Et3N in a separate
flask. This operation led to facile carbonecarbon bond formation to
construct diastereomeric Int-3 and Int-4, which were further
a
b
c
Et2AlCl was not used.
Et2O was used for extraction.
VertrelÒ (1,1,1,2,2,3,4,5,5,5-decafluoropentane) was used as the extraction
solvent.

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T. Yamazaki et al. / Tetrahedron 71 (2015) 8059e8066
treatment of the same trifluorinated hydrates with 3c,20 and longer
ketone formation
period and higher temperature were found to be required for at-
tainment of a good level of conversion. In the latter case, as shown
below, the steric repulsion between Bn and Rf groups in Int-8
seemed to surpass the electronic interaction between Rf and CO2Et
in Int-7, giving rise to formation of the corresponding (Z)-isomers
in a preferential manner. These two types of destabilizing factors in
the intermediary oxaphosphetanes should be the definitive reason
for requirement of more forcing conditions to prepare the desired
RfLi
R1CO2R
X=Li
OX
R1MgBr
X=MgBr
R3OH
RfCO2R
Rf
OR
R1
Int-1
1
ROMgBr
ROMgBr
a-substituted
a
,b
-unsaturated esters 12 rather than the instances of
OH
R1MgBr
11.
R1 Rf
R1
OH
OR
O
ROH
ROH
Li Li
R1 Rf
Rf
8
O
P
O
O
P
O
R1
H
Rf
2
EtO
EtO
7
OH
OEt
OEt
ROMgBr
EtO O
EtO O
Rf
H
Bn
Bn
Int-7
R1 Rf
Int-8
9
Li
HWE Reactions
O
O
O
P
O
1) LiBr, THF, rt
Li
EtO
EtO
P
EtO
EtO
OBn
OBn
2) Et3
C, 10 min
O
O
O
P
O
O
LiBr, Et3N
Et3 Br
EtO
EtO
EtO
EtO
P
3a
OR2
OR2
R1 Rf
CO2Bn
1) RfCH(OH)2
2) rt, 1 h
C
3
Int-2
2
Rf
11ad (Rf: CF3),
79% yield, E:Z=>99:1
11bd (Rf: C2F5),
Li
Li
71% yield, E:Z=>99:1
O
O
O
O
O
O
EtO
EtO
P
EtO
EtO
P
Rf
OR2
OR2
R1
1
Rf
R
Li
H
Int-3
H
Int-4
O
P
O
O
P
O
1) LiBr, THF, rt
EtO
EtO
EtO
EtO
OEt
OEt
2) Et3
C, 10 min
Li
Li
Bn
Bn
3c
O
O
O
O
R1
Rf
R1
CO2Et
Bn
EtO
EtO
P
O
EtO
EtO
P
O
1) RfCH(OH)2
C, 12 h
C
CO2R2
OR2
OR2
R1
Rf
Rf
H
H
Rf
H
Int-6
Int-5
12al (Rf: CF3),
(E)-4,5
81% yield, E:Z=15:85
12bl (Rf: C2F5),
50% yield, E:Z=18:82
Scheme 2. Possible reaction mechanism.
Scheme 3. Preparation of other types of a,b-unsaturated esters.
converted to the corresponding oxaphosphetanes Int-5 and Int-6,
respectively. Judging from the experimental results, determinant of
stereoselectivity would be the electronically repulsive interaction
between Rf and CO2R2 moieties, and thus, the reaction might pro-
3. Conclusion
ceed via the more preferable Int-6 to furnish the desired a,b-un-
saturated esters 4 and 5 with high (E)-stereochemistry.19 This
mechanistic consideration consistently explained the (E)-stereo-
specificity for the cases of C2F5 or n-C6F13 as Rf which apparently
caused severer electronic as well as steric repulsion than the case of
intermediates with a CF3 group, the latter of which were, different
from the former, suffered from a small amount of the corre-
sponding (Z)-isomers (1e15%).
As depicted above, we have successfully demonstrated the
convenient syntheses of
-unsaturated esters 4e6 with Rf and R1
groups both at the position in good to excellent isolated yields
with a high level of (E)-stereoselectivity by way of the conden-
sation reactions of the in situ-produced Rf-possessing ketones 2
a,b
b
and HWE reagents 3. Moreover, construction of other types of b-
Rf-containing acrylates 11 and 12 has also been succeeded by
simple extension of this method. The most important feature of
this procedure is that no isolation was required for ketones 2 with
an Rf group, which realized the incorporation of ‘smaller’ Rf and R1
moieties in good to high chemical yields even in a small scale
process. We believe this method opens an avenue to synthesize
Extension of the present method was also carried out for the
synthesis of
which possessed an additional substituent
b
-Rf-
a
,
b
-unsaturated esters 11 and 12, the latter of
to the ester moiety
a
(Scheme 3). As our expectation, the enolate from 3a smoothly
condensed with perfluorinated aldehyde hydrates to furnish the
desired compounds 11 in a stereospecific fashion. On the other
hand, construction of 12 with a benzyl group was realized by
a wide variety of
-position.
a,b-unsaturated esters with an Rf moiety at the
b

T. Yamazaki et al. / Tetrahedron 71 (2015) 8059e8066
8063
4. Experimental section
4.1. General
128.18, 128.20, 128.3, 130.0, 134.8, 142.1 (q, J¼30.4 Hz), 160.4, 164.7.
19F NMR
ꢀ68.73 (s; E isomer) and ꢀ61.32 (s; Z isomer).
d
4.2.3. Benzyl 3-(trifluoromethyl)pent-2-enoate (4af). 54% yield,
Unless otherwise noted, materials were obtained from com-
mercial suppliers and were used without further purification. All
manipulations involving air-sensitive materials were performed
under argon. Anhydrous Et2O, THF and CH2Cl2 were purchased and
were used without further purification.
E:Z¼89:11. Rf¼0.41 (n-hexane: AcOEt¼20:1). 1H NMR
d 1.14 (3H, t,
J¼7.2 Hz; Z isomer) and 1.17 (3H, t, J¼7.5 Hz; E isomer), 2.33 (2H, dq,
J¼1.5, 7.2 Hz; Z isomer) and 2.70 (2H, q, J¼7.5 Hz; E isomer), 5.20
(2H, s; Z isomer) and 5.21 (2H, s; E isomer), 6.06 (1H, s; Z isomer)
and 6.34 (1H, s; E isomer), 7.38e7.39 (5H, m). 13C NMR
d 11.5 (Z
1H, 13C, and 19F NMR spectra were recorded with a JEOL JNM-
LA300 (1H: 300.40 MHz, 13C: 75.45 MHz, and 19F: 282.65 MHz), in
CDCl3. Chemical shifts were recorded in parts per million (ppm),
downfield from internal tetramethylsilane (for 1H and 13C NMR,
isomer) and 13.2 (E isomer), 20.2 (q, J¼1.2 Hz), 66.7 (E isomer) and
67.2 (Z isomer), 121.3 (q, J¼6.2 Hz), 123.5 (q, J¼274.6 Hz), 128.4,
128.5, 128.6, 135.3, 148.2 (q, J¼28.5 Hz), 164.3. 19F NMR
ꢀ70.32 (s;
d
E isomer) and ꢀ64.48 (s; Z isomer). IR (neat)
n 2982, 2944, 1730,
1456, 1311, 1255, 1190, 1132, 1040, 971, 746, 698. Anal. Calcd for
C13H13F3O2: C, 60.46; H, 5.07. Found: C, 60.59; H, 5.22.
Me4Si:
d
0.00 ppm, and for 19F NMR, C6F6:
d
ꢀ163 ppm). 13C NMR
spectra of minor isomers may not be fully reported because of
difficult visualization of peaks with small intensities even after
a long data acquisition time. Infrared (IR) spectra were obtained on
a JASCO FT/IR-4100 spectrometer, and all spectra were reported in
wave numbers (cmꢀ1). Analytical thin-layer chromatography (TLC)
on silica gel 60 F254 (Merck) was routinely used for monitoring
reactions. Column chromatography was conducted with silica gel
60 N (spherical, neutral, 63e210 nm, Kanto). Elemental analyses
were performed by PerkineElmer SeriesII CHNS/O analyzer. High
resolution mass spectra in a FAB mode were acquired on a JEOL
JMS-700.
4.2.4. Benzyl 3-(trifluoromethyl)hept-2-enoate (4ah). 67% yield,
E:Z¼90:10. Rf¼0.48 (n-hexane: AcOEt¼4:1). 1H NMR
d 0.93 (3H, t,
J¼7.2 Hz; Z isomer) and 1.17 (3H, t, J¼7.5 Hz; E isomer),1.35 (2H, sex,
J¼7.5 Hz), 1.46e1.56 (2H, m), 2.62e2.67 (2H, m), 5.20 (2H, s), 6.35
(1H, s), 7.38e7.39 (5H, m). 13C NMR
d 13.57 (E isomer) and 13.61 (Z
isomer), 22.0 (Z isomer) and 22.8 (E isomer), 26.6, 29.5 (Z isomer)
and 31.0 (E isomer), 66.6 (E isomer) and 67.1 (Z isomer), 121.5 (q,
J¼6.2 Hz), 123.4 (q, J¼274.6 Hz), 128.4, 128.5, 128.6, 135.3, 148.3 (q,
J¼28.5 Hz), 164.3. 19F NMR
d
ꢀ70.32 (s; E isomer) and ꢀ64.48 (s; Z
isomer). IR (neat)
n 2962, 2875, 1731, 1457, 1364, 1314, 1188, 1127,
973, 894, 747, 697. Anal. Calcd for C15H17F3O2: C, 62.93; H, 5.99.
Found: C, 63.07; H, 6.08.
4.2. General procedure for preparation of
-unsaturated esters (4 and 5)
b-Rf-b-substituted
a,b
4.2.5. Benzyl 3-cyclohexyl-4,4,4-trifluorobut-2-enoate (4ai). 19F
NMR yield: 27%, E:Z¼89:11 (77% isolated yield, E:Z¼79:21 by the
conventional method. The following physical properties were
recorded by the material obtained from the conventional method).
(E)-isomer Rf¼0.61 (n-hexane:AcOEt¼10:1). 1H NMR
To a solution of ethyl trifluoroacetate 1a 0.10 mL (1.00 mmol) in
THF (2.0 mL) was slowly added at ꢀ80 ꢁC 0.92 mL of PhMgBr (1.3 M
in Et2O, 1.20 mmol) and the mixture was stirred for 1 h at that
temperature, followed by 1 h at 0 ꢁC where t-BuOH 0.48 mL
(5.00 mmol) and Bu4NBr 0.012 g (0.04 mmol) were further added.
The enolate solution from a crude HWE reagent 3a12 (0.37 g,
1.30 mmol), LiBr (0.14 g, 1.60 mmol), Et3N 0.19 mL (1.40 mmol) in
THF (1.0 mL) prepared above was, after cooling to 0 ꢁC again, slowly
introduced to the Grignard mixture with the aid of cannula (0.5 mL
of THF was added for rinsing inside after transfer the solution), and
the resultant materials were stirred at 50 ꢁC for 2 h. The mixture
was quenched by the addition of 1 M HCl aq so as to control the pH
of the solution from 6 to 7, and the usual workup and purification
by column chromatography (n-hexane:AcOEt¼4:1) afforded
d
1.46e1.79 (10H, m), 3.30e3.41 (1H, m), 5.21 (2H, s), 6.32 (1H, m),
7.34e7.40 (5H, m). 13C NMR
d 14.1, 25.6, 26.5, 30.5, 38.1, 66.7, 121.6
(q, J¼6.8 Hz), 123.5 (q, J¼276.9 Hz), 128.4, 128.5, 128.6, 135.2, 149.8
(q, J¼26.6 Hz), 164.6. 19F NMR
d
ꢀ63.51 (s). IR (neat)
n 2932, 1730,
1656, 1498, 1452, 1328, 1276, 1189, 1134, 1093, 1003, 897, 747, 696.
HRMS m/z calcd for C17H19F3O2 [M]þ: 312.1337; found: 312.1357.
(Z)-isomer Rf¼0.46 (n-hexane:AcOEt¼10:1). 1H NMR
d
1.55e1.90 (10H, m), 2.22e2.30 (1H, m), 5.19 (2H, s), 6.04 (1H, m),
7.35e7.39 (5H, m). 13C NMR
d 13.9, 25.7, 26.3, 32.3, 39.2, 67.2, 122.8
(q, J¼276.9 Hz), 123.1 (q, J¼3.8 Hz), 128.5, 128.6, 135.1, 144.3 (q,
0.211
g
of benzyl 4,4,4-trifluoro-3-phenylbut-2-enoate 4aa
J¼28.6 Hz), 165.2. 19F NMR
d
ꢀ65.34 (s). IR (neat)
n 2934, 1739, 1660,
(0.689 mmol, 69% yield, E:Z¼95:5) as a colourless oil.
1497, 1453, 1351, 1271, 1166, 1132, 981, 839, 751, 698. HRMS m/z
calcd for C17H19F3O2 [M]þ: 312.1337; found: 312.1344.
4.2.1. Preparation of benzyl 4,4,4-trifluoro-3-phenylbut-2-enoate
(4aa).14 Rf¼0.81 (n-hexane:AcOEt¼1:1). 1H NMR
d
5.02 (2H, s; E
4.2.6. Benzyl 3-(trifluoromethyl)undec-2-enoate (4ak). Yield: 72%,
isomer) and 5.27 (2H, s; Z isomer), 6.64 (1H, s; E isomer) and 6.36
E:Z¼98:2. Rf¼0.58 (n-hexane: AcOEt¼10:1). 1H NMR
d 0.89 (3H, br t,
(1H, s; Z isomer), 7.25e7.41 (10H, m). 13C NMR
d
66.8 (E isomer) and
J¼6.9 Hz), 1.26e1.34 (10H, m), 1.52e1.55 (2H, m), 2.61e2.66 (2H,
67.4 (Z isomer), 122.4 (q, J¼273.9 Hz), 124.2 (q, J¼5.6 Hz), 128.22,
128.26, 128.3, 128.4, 128.5, 130.8, 134.7 (E isomer) and 134.9 (Z
isomer), 142.5 (q, J¼31.0 Hz), 163.8 (E isomer) and 164.2 (Z isomer).
m), 5.20 (2H, s), 6.34 (1H, s; E isomer) and 6.06 (1H, s; Z isomer),
7.36e7.39 (5H, m). 13C NMR
d 14.00 (Z isomer) and 14.04 (E isomer),
22.60 (Z isomer) and 22.64 (E isomer), 26.9, 27.4, 28.9, 29.2, 29.7,
31.77 (Z isomer) and 31.82 (E isomer), 66.7 (E isomer) and 67.1 (Z
isomer), 121.5 (q, J¼6.2 Hz), 123.5 (q, J¼274.6 Hz), 128.4, 128.5,
19F NMR
d
ꢀ68.81 (s; E isomer) and ꢀ61.30 (s; Z isomer).
4.2.2. Benzyl 4,4,4-trifluoro-3-(4-methoxyphenyl)but-2-enoate
(4ab).14 Yield: 46%, E:Z¼99:1 (Yield: 79%, E:Z¼95:5 with 13% of
the corresponding ethyl ester 5ab by way of 4-MeOC6H4Li instead
of the corresponding Grignard reagent). Rf¼0.40 (n-
128.5,128.6,135.3,147.1 (q, J¼29.2 Hz),164.3. 19F NMR
ꢀ70.27 (s; E
d
isomer) and ꢀ64.46 (s; Z isomer). IR (neat)
n 2926, 2855, 1732, 1669,
1457, 1313, 1193, 1131, 894, 747, 696. Anal. Calcd for C19H25F3O2: C,
66.65; H, 7.36. Found: C, 66.24; H, 7.52.
hexane:AcOEt¼4:1). 1H NMR
d 3.82 (3H, s; E isomer) and 3.84 (3H,
s; Z isomer), 5.05 (2H, s; E isomer) and 5.26 (2H, s; Z isomer), 6.56
(1H, q, J¼1.2 Hz; Z isomer) and 6.60 (1H, q, J¼1.2 Hz; E isomer),
6.85e6.93 (2H, m), 7.12e7.21 (4H, m), 7.29e7.39 (3H, m). 13C NMR
4.2.7. Benzyl 4,4,5,5,5-pentafluoro-3-phenylpent-2-enoate (4ba). 19F
NMR yield: 22%, E:Z¼>99:1 (Yield: 81%, E:Z¼>99:1 with 7% of the
corresponding ethyl ester 8a by using PhLi instead of PhMgBr).
d
54.9 (E isomer) and 55.0 (Z isomer), 66.7 (E isomer) and 67.2 (Z
Rf¼0.54 (n-hexane:AcOEt¼4:1). 1H NMR
d 5.00 (2H, s), 6.67 (1H, s),
isomer), 113.6, 120.7, 122.5 (q, J¼274.6 Hz), 123.6 (q, J¼5.0 Hz),
7.07e7.11 (2H, m), 7.21e7.26 (2H, m), 7.29e7.40 (6H, m). 13C NMR

8064
T. Yamazaki et al. / Tetrahedron 71 (2015) 8059e8066
d
66.9, 127.2 (t, J¼8.1 Hz), 112.1 (qt, J¼37.8, 252.0 Hz), 118.7 (tq,
J¼39.1, 282.9 Hz), 128.1e129.2, 131.0, 134.7, 142.1 (t, J¼21.7 Hz),
163.7. 19F NMR
3066,
8.7 Hz), 7.19 (3H, d, J¼8.7 Hz). 13C NMR
d 13.7, 55.1, 61.1, 105.0e119.5
(m), 113.5, 123.4, 127.8 (t, J¼8.7 Hz), 130.6, 141.8 (t, J¼21.7 Hz), 160.4,
d
ꢀ83.24 (3F, s), ꢀ116.36 (2F, s). IR (neat)
n
164.2. 19F NMR
d
ꢀ127.42 (2F, m), ꢀ124.08 (2F, m), ꢀ122.88 (2F, m),
3036, 1738, 1457, 1446, 1332, 1210, 1161, 1056, 751, 697, 653. Calcd
for C18H13F5O2: C, 60.68; H, 3.68. Found: C, 60.83; H, 3.70.
ꢀ120.98 (2F, m), ꢀ112.51 (2F, t, J¼14.8 Hz), ꢀ82.05 (m). IR (neat)
n
2986, 2941, 2910, 2843, 1737, 1610, 1515, 1364, 1294, 1243, 1203,
1146, 1121, 1070, 1035, 834, 736, 713. Anal. Calcd for C18H13F13O3: C,
41.24; H, 2.50. Found: C, 41.54; H, 2.44.
4.2.8. Benzyl 4,4,5,5,5-pentafluoro-3-(4-methoxyphenyl)pent-2-
enoate
(4bb). 52%
yield,
E:Z¼>99:1.
Rf¼0.38
(n-
hexane:AcOEt¼4:1). 1H NMR
d
3.75 (3H, s), 5.02 (2H, s), 6.62 (1H, t,
4.3.3. Ethyl
4,4,5,5,6,6,7,7,8,8,9,9,9-tridecafluoro-3-[p-(tri-fluo-
J¼1.2 Hz), 6.83e6.86 (2H, m), 7.13e7.16 (4H, m), 7.31e7.32 (3H, m).
romethyl)phenyl]non-2-enoate
(5cc). Quantitative
yield,
1.05 (3H, t,
13C NMR
d
55.1, 66.9, 112.2 (qt, J¼39.1, 255.8 Hz), 113.6, 118.7 (tq,
E:Z¼>99:1. Rf¼0.15 (n-hexane:CH2Cl2¼4:1). 1H NMR
d
J¼37.8, 286.7 Hz), 123.0, 126.9 (t, J¼8.1 Hz), 128.36, 128.39, 128.41,
J¼7.1 Hz), 4.04 (2H, q, J¼7.1 Hz), 6.68 (1H, t, J¼1.4 Hz), 7.39 (2H, d,
130.3, 134.8, 141.8 (q, J¼21.1 Hz), 160.3, 164.0. 19F NMR
d
ꢀ83.33 (s),
J¼8.1 Hz), 7.7 (2H, d, J¼8.1 Hz). 13C NMR
d 13.5, 61.4, 104.6e119.5
ꢀ116.55 (s). IR (neat)
n
3067, 3036, 2960, 2841, 1737, 1610, 1514,
(m), 123.8 (q, J¼271.7 Hz), 125.0 (q, J¼3.7 Hz), 129.2 (t, J¼8.7 Hz),
1458, 1252, 1211, 1162, 1055, 834, 745, 698. HRMS (FAB) m/z calcd
129.7, 131.5 (q, J¼32.9 Hz), 135.1, 141.1 (t, J¼22.3 Hz), 163.4. 19F NMR
for C19H15F5O3 [M]þ: 386.0941; found: 386.0971.
d
ꢀ127.42 (2F, m), ꢀ124.05 (2F, m), ꢀ122.87 (2F, m), ꢀ120.83 (2F, m),
ꢀ112.27 (2F, t, J¼16.0 Hz), ꢀ82.06 (3F, m), ꢀ64.19 (3F, s). IR (neat)
n
4.2.9. Benzyl 4,4,5,5,5-pentafluoro-3-methylpent-2-enoate
(4be). 32% yield, E:Z¼>99:1. Rf¼0.68 (n-hexane:AcOEt¼4:1). 1H
2990, 1738, 1620, 1410, 1328, 1244, 1203, 1137, 1069, 1022, 994, 910,
842, 806, 766, 745, 714, 666, 633. Anal. Calcd for C18H13F13O3: C,
41.24; H, 2.50. Found: C, 41.54; H, 2.44.
NMR
d
2.28 (3H, s), 5.21 (2H, s), 6.36 (1H, q, J¼1.3 Hz), 7.38e7.40
(5H, m). 13C NMR
d
13.0 (m), 66.8, 116.6 (qt, J¼38.5, 290.9 Hz), 118.7
(tq, J¼37.8, 286.6 Hz), 124.1 (t, J¼8.7 Hz), 128.4, 128.5, 128.5, 128.7,
4.3.4. Ethyl 4,4,5,5,6,6,7,7,8,8,9,9,9-tridecafluoro-3-methylnon-2-
enoate (5ce).16 Yield: 71%, E:Z¼>99:1. Rf¼0.46 (n-hexane:
135.2, 142.6 (t, J¼21.1 Hz), 164.3. 19F NMR
d
ꢀ84.52 (3F, s), ꢀ119.69
(2F, s). IR (neat)
n
3037, 2960, 1732, 1666, 1498, 1456, 1330, 1263,
CH2Cl2¼4:1). 1H NMR
d
1.32 (3H, t, J¼7.2 Hz), 2.28 (3H, q,
1209,1109,1014, 886, 751, 697. HRMS m/z calcd for C13H11F5O3 [M]+:
J¼1.3 Hz), 4.24 (2H, q, J¼7.1 Hz), 6.30 (1H, q, J¼1.3 Hz). 13C NMR
294.0679; found: 294.0688.
d
13.2 (m), 14.0, 61.0, 106.7e123.4 (m), 124.9 (t, J¼9.3 Hz), 142.4 (t,
J¼21.1 Hz), 164.6. 19F NMR
d
ꢀ127.39 (2F, m), ꢀ124.04 (2F, m),
4.3. General procedure for preparation of
substituted -unsaturated esters (5)
b-n-C6F13
-b
-
ꢀ123.06 (2F, m), ꢀ122.73 (2F, m), ꢀ115.50 (2F, t, J¼14.8 Hz),
a
,
b
ꢀ82.03 (3F, m). IR (neat)
n 2989, 2965, 2914, 1733, 1666, 1449,
1354, 1243, 1120, 1147, 1122, 1106, 1041, 905, 886, 837, 808, 779,
745, 722, 702, 648. Anal. Calcd for C12H9F13O2: C, 33.35; H, 2.10.
Found: C, 33.38; H, 2.02.
To a solution of 1,1,2,2,3,3,4,4,5,5,6,6,6-tridecafluorohexyl iodide
(0.22 mL, 1.0 mmol), ethyl benzoate (0.16 mL, 1.1 mmol) in Et2O
(3 mL) was added at ꢀ80 ꢁC methyllithium (1.5 M in Et2O with
lithium bromide; 0.73 mL, 1.1 mmol) and stirring was continued for
30 min at the same temperature where diethyl-aluminium chloride
(1 M in n-hexane; 1.1 mL, 1.1 mmol) was gradually added and fur-
ther stirring for 15 min at ꢀ80 ꢁC.
4.3.5. Ethyl 3-ethyl-4,4,5,5,6,6,7,7,8,8,9,9,9-tridecafluoronon-2-
enoate (5cf). 42% yield, E:Z¼>99:1 by Method 4. Rf¼0.41 (n-
hexane:CH2Cl2¼4:1). 1H NMR
d
1.81 (3H, t, J¼7.5 Hz), 1.33 (3H, t,
J¼7.2 Hz), 2.69 (2H, q, J¼7.4 Hz), 4.24 (2H, q, J¼7.1 Hz), 6.26 (1H, t,
In a separate flask, lithium bromide (0.12 g, 1.4 mmol), triethyl
phosphonoacetate (0.26 mL, 1.3 mmol), and THF (1 mL) was mixed
at 0 ꢁC where triethylamine (0.19 mL, 1.4 mmol) was added and the
solution was stirred for 10 min at room temperature. This mixture
was slowly introduced to an aluminium acetal solution prepared
above with the aid of cannula and the whole mixture was further
stirred for 1 h at room temperature. To this solution were succes-
sively added Et2O (3 mL), NaF (0.185 g, 4.4 mmol) and H2O (59 mg,
3.3 mmol), which was stirred for 0.5 h at room temperature. Fil-
tration with a pad of silica gel and concentration furnished a crude
mixture which was purified by silica gel column chromatography
(n-hexane:CH2Cl2¼6:1) to afford 0.484 g (0.979 mmol, 98% yield,
E:Z¼>99:1) of the title compound 5ca as a colourless oil.
J¼1.5 Hz). 13C NMR
d 13.8, 14.0, 21.0, 61.0, 104.7e119.7 (m), 125.1 (t,
J¼9.3 Hz), 148.5 (t, J¼20.5 Hz), 164.2. 19F NMR
d
ꢀ127.39 (2F, m),
ꢀ124.05 (2F, m), ꢀ122.91 (2F, m), ꢀ122.58 (2F, m), ꢀ114.49 (2F, t,
J¼13.7 Hz), ꢀ82.05 (3F, m). IR (neat)
n 2987, 2948, 2888, 1733, 1658,
1468, 1383, 1364, 1295, 1245, 1202, 1147, 1121, 1070, 1041, 1019, 899,
806, 769, 744, 710, 660. Anal. Calcd for C13H11F13O2: C, 34.99; H,
2.48. Found: C, 34.92; H, 2.35.
4.3.6. Ethyl 4,4,5,5,6,6,7,7,8,8,9,9,9-tridecafluoro-3-isopropyl-non-2-
enoate (5cg). 22% yield, E:Z¼>99:1. Rf¼0.51 (n-hexane:
CH2Cl2¼4:1). 1H NMR
1.27 (6H, d, J¼6.9 Hz), 1.33 (3H, t, J¼7.1 Hz),
d
3.23 (1H, sept, J¼7.1 Hz), 4.25 (2H, q, J¼7.1 Hz), 6.25 (1H, m). 13C
NMR
d
14.0, 20.4, 28.5, 61.2, 104.7e123.0 (m), 126.0 (t, J¼9.9 Hz),
149.5 (t, J¼19.8 Hz), 164.7. 19F NMR
d
ꢀ127.41 (2F, m), ꢀ124.05 (2F,
4.3.1. Ethyl 4,4,5,5,6,6,7,7,8,8,9,9,9-tridecafluoro-3-phenylnon-2-
m), ꢀ122.90 (2F, m), ꢀ121.71 (2F, m), ꢀ111.40 (2F, t, J¼16.0 Hz),
enoate (5ca). Rf¼0.30 (n-hexane:CH2Cl2¼4:1). 1H NMR
d
1.03 (3H,
ꢀ82.05 (3F, m). IR (neat)
n 2987, 2948, 2888, 1733, 1658, 1468, 1383,
t, J¼7.1 Hz), 4.02 (2H, q, J¼7.1 Hz), 6.62 (1H, t, J¼1.4 Hz), 7.24e7.26
1364, 1295, 1245, 1202, 1147, 1121, 1070, 1041, 1019, 900, 806, 769,
744, 711, 660. Anal. Calcd for C14H13F13O2: C, 36.54; H, 2.85. Found:
C, 36.67; H, 2.74.
(2H, m), 7.35e7.43 (3H, m). 13C NMR
d 13.6, 61.1, 106.3e122.9 (m),
128.0, 128.3 (t, J¼8.7 Hz), 129.1, 129.2, 142.1 (t, J¼21.7 Hz), 164.0. 19
F
NMR
d
ꢀ127.39 (2F, m), ꢀ124.08 (2F, m), ꢀ122.86 (2F, m), ꢀ120.90
(2F, m), ꢀ112.36 (2F, t, J¼14.9 Hz), ꢀ82.05 (3F, m). IR (neat):
n
2988,
4.3.7. Ethyl 3-(1,1,2,2,3,3,4,4,5,5,6,6,6-tridecafluorohexyl)dec-2-
1739, 1446, 1365, 1242, 1200, 1146, 1122, 1071, 1028, 714, 698, 664,
621. Anal. Calcd for C17H11F13O2: C, 41.31; H, 2.24. Found: C, 41.47; H,
2.22.
enoate
(5cj). 56%
yield,
E:Z¼>99:1.
Rf¼0.53
(n-
hexane:CH2Cl2¼4:1). 1H NMR
d
0.88 (3H, t, J¼6.8 Hz), 1.24e1.42
(11H, m), 1.48e1.58 (2H, m), 2.62 (2H, m), 4.24 (2H, q, J¼7.2 Hz),
6.25 (1H, m). 13C NMR
60.9, 104.2e123.4 (m), 125.0 (t, J¼9.3 Hz), 147.4 (t, J¼20.8 Hz), 164.3.
19F NMR
ꢀ127.47 (2F, m), ꢀ124.11 (2F, m), ꢀ122.96 (2F, m),
ꢀ122.63 (2F, m), ꢀ111.47 (2F, t, J¼15.8 Hz), ꢀ82.07 (3F, m). IR (neat)
2960, 2933, 2860, 1732, 1657, 1468, 1377, 1363, 1242, 1198, 1147,
d 13.97, 13.99, 22.6, 27.8, 28.9, 29.8, 30.0, 31.8,
4.3.2. Ethyl 4,4,5,5,6,6,7,7,8,8,9,9,9-tridecafluoro-3-(p-methoxy-phe-
nyl)non-2-enoate (5cb). 49% yield, E:Z¼>99:1. Rf¼0.15 (n-
d
hexane:CH2Cl2¼4:1). 1H NMR
d
1.09 (3H, t, J¼7.1 Hz), 3.83 (3H, s),
4.05 (2H, q, J¼7.2 Hz), 6.57 (1H, t, J¼1.4 Hz), 6.85 (2H, td, J¼2.4,
n

T. Yamazaki et al. / Tetrahedron 71 (2015) 8059e8066
8065
1122, 1077, 1039, 889, 839, 809, 778, 738, 722, 710, 659. Anal. Calcd
for C18H9F13O2: C, 41.87; H, 4.10. Found: C, 42.00; H, 3.93.
4.5.2. Ethyl 2-benzyl-4,4,5,5,5-pentafluoropent-2-enoate (12bl). (E)-
isomer: Rf¼0.55 (n-hexane:AcOEt¼10:1). 1H NMR
d 1.20 (3H, t,
J¼7.2 Hz), 3.92 (2H, br s), 4.17 (2H, q, J¼7.0 Hz), 6.70 (1H, t,
4.4. General procedure for preparation of
saturated esters (11)
b-CF3-
a,
b-un-
J¼14.7 Hz), 7.18e7.37 (5H, m). 13C NMR
d
13.8, 33.5 (t, J¼2.5 Hz),
62.0, 108.5e120.7 (m), 123.7 (t, J¼22.9 Hz), 126.7, 128.49, 128.54,
129.3, 136.8 (t, J¼1.2 Hz), 144.3 (t, J¼3.7 Hz), 165.3 (t, J¼1.3 Hz). 19
F
To an enolate solution from the HWE reagent 3a (2.86 g,
10.0 mmol), LiBr (1.08 g, 12.3 mmol), Et3N 1.53 mL (11.3 mmol) in
THF (10 mL) prepared above, was slowly introduced at 0 ꢁC 1.27 g
(10.9 mmol) of trifluoroacetaldehyde hydrate, CF3CH(OH)2, and the
resultant materials were stirred at rt for 1 h. The mixture was
quenched by the addition of 1 M HCl aq so as to control the pH of
the solution from 6 to 7, and the usual workup and purification by
column chromatography (n-hexane: AcOEt¼5:1) afforded 1.82 g of
benzyl 4,4,4-trifluoro-3-phenyl-but-2-enoate 11ad (7.9 mmol, 79%
yield, E:Z¼>99:1) as a colourless oil.
NMR
d
ꢀ86.37 (s), ꢀ112.09 (d, J¼13.6 Hz). IR (neat)
n 3200, 2950,
2550, 2400, 2150, 1950, 1920, 1890, 1870, 1850, 1830, 1800, 1780,
1750, 1735, 1720, 1340, 1320, 1250, 1190, 1110, 1030, 810, 730, 700,
600, 530, 480. HRMS (FAB) m/z calcd for C14H14F5O2 [MþH]þ:
309.0914; found: 309.0941.
(Z)-isomer: Rf¼0.48 (n-hexane:AcOEt¼10:1). 1H NMR
d 1.20
(3H, t, J¼7.2 Hz), 3.69 (2H, m), 4.19 (2H, q, J¼7.2 Hz), 5.35 (1H, t,
J¼14.1 Hz), 7.17e7.41 (5H, m). 13C NMR
13.6, 41.0 (t, J¼1.2 Hz), 61.7,
d
107.5e121.0 (m), 115.4 (t, J¼20.4 Hz) 127.4, 128.8, 129.3, 134.8, 147.1
(t, J¼5.6 Hz), 166.9 (t, J¼1.9 Hz). 19F NMR
d
ꢀ86.33 (s), ꢀ113.88 (d,
J¼13.9 Hz). IR (neat)
n 3250, 2950, 2600, 2400, 2200, 1950, 1930,
4.4.1. Preparation of benzyl 4,4,4-trifluorobut-2-enoate
1900, 1880, 1850, 1840, 1810, 1780, 1755, 1740, 1725, 1380, 1320,
1280, 1200, 1130, 1040, 820, 730, 700, 600, 540, 480. HRMS (FAB) m/
z calcd for C14H14F5O2 [MþH]þ: 309.0914; found: 309.0931.
(11ad).1a Rf¼0.59 (n-hexane:AcOEt¼5:1). 1H NMR
d 5.24 (2H, s),
6.53 (1H, qd, J¼1.9, 15.7 Hz), 6.81 (1H, qd, J¼6.5, 15.8 Hz), 7.25e7.29
(5H, m). 13C NMR
d
67.2, 121.9 (q, J¼269.9 Hz), 128.3, 128.5, 128.6 (q,
J¼6.2 Hz), 131.5, 131.9, 167.2. 19F NMR
d
e66.93 (d, J¼7.1 Hz). IR
Acknowledgements
(neat) n 3000,1730,1665,1375,1310,1260,1190,1130, 965, 740, 700.
Generous gift of VertrelÒ (1,1,1,2,2,3,4,5,5,5-decafluoro-pentane)
by Dupont-Mitsui Fluorochemicals Co., Ltd. is gratefully
acknowledged.
4.4.2. Benzyl 4,4,5,5,5-pentafluoropent-2-enoate (11bd). Rf¼0.55 (n-
hexane/AcOEt¼10:1). 1H NMR
d
5.24 (2H, s), 6.59 (1H, td, J¼2.0,
15.8 Hz), 6.84 (1H, td, J¼11.4, 15.8 Hz), 7.31e7.46 (5H, m). 13C NMR
d
67.5, 111.5 (qt, J¼39.1, 251.4 Hz), 118.5 (tq, J¼36.7, 284.8 Hz), 128.5,
128.7, 130.7 (t, J¼8.7 Hz), 130.8 (t, J¼24.0 Hz), 163.4. 19F NMR
References and notes
d
ꢀ118.50 (2F, d, J¼11.6 Hz), ꢀ85.86 (3F, s). IR (neat)
n 3250, 2950,
1. (a) Shinohara, N.; Haga, J.; Yamazaki, T.; Kitazume, T.; Nakamura, S. J. Org. Chem.
1995, 60, 4363e4374; (b) Soloshonok, V. A.; Cai, C.; Hruby, V. J.; Van Meervelt, L.
Tetrahedron 1999, 55, 12045e12058; (c) Molteni, M.; Volonterio, A.; Zanda, M.
Org. Lett. 2003, 5, 3887e3890; (d) Christophe, C.; Billard, T.; Langlois, B. R. Eur. J.
Org. Chem. 2005, 3745e3748; (e) Powell, A.; Al Nakeeb, M.; Wilkinson, B.;
Micklefield, J. J. Chem. Soc., Chem. Commun. 2007, 2683e2685; (f) Zhang, F.; Liu,
Z.-J.; Liu, J.-T. Tetrahedron 2010, 66, 6864e6868; (g) Dong, X.-Q.; Fang, X.; Wang,
C.-J. Org. Lett. 2011, 13, 4426e4429.
2550, 2400, 2150, 1950, 1930, 1900, 1880, 1850, 1835, 1810, 1780,
1755,1740,1725,1580,1565,1440,1340,1280,1200,1120,1040, 970,
730, 700, 540, 480. HRMS (FAB) m/z calcd for C12H9F5O2 [MþH]þ:
281.0601; found: 281.0586.
4.5. General procedure for preparation of
-unsaturated esters (12)
b-CF3-a-substituted
a,b
2. (a) Okano, T.; Nagai, T.; Eguchi, S.; Kimoto, H. Heterocycles 1999, 50, 53e56; (b)
€
uger, J.; Blond, G.; Frohlich, R.; Billard, T.; Haufe, G.; Langlois, B. R. J. Org. Chem.
2006, 71, 2735e2739; (c) Shibatomi, K.; Kobayashi, F.; Narayama, A.; Fujisawa,
I.; Iwasa, S. Chem. Commun. 2012, 413e415.
To an enolate solution from the a
-benzylated HWE reagent 3c19
(0.94 g, 3.0 mmol), LiBr (0.313 g, 3.60 mmol), Et3N 0.46 mL
(3.3 mmol) in THF (5.0 mL) prepared above was slowly introduced
at 0 ꢁC 0.38 g (3.3 mmol) of CF3CH(OH)2, and the resultant materials
were stirred at 50 ꢁC for overnight. The mixture was quenched by
the addition of 1 M HCl aq so as to control the pH of the solution
from 6 to 7, and the usual workup and purification by column
chromatography (n-hexane:AcOEt¼10:1) afforded 0.625 g of ethyl
2-benzyl-4,4,4-trifluorobut-2-enoate 12al (2.42 mmol, 81% yield,
E:Z¼15:85) as a colourless oil.
3. (a) Li, Q.-H.; Tong, M.-C.; Li, J.; Tao, H.-Y.; Wang, C.-J. Chem. Commun. 2011,
11110e11112; (b) Li, Q.-H.; Xue, Z.-Y.; Tao, H.-Y.; Wang, C.-J. Tetrahedron Lett.
2012, 53, 3650e3653; (c) Schmidt, M. A.; Katipally, K.; Ramirez, A.; Soltani, O.;
Hou, X.-P.; Zhang, H.-P.; Chen, B.-C.; Qian, X.-H.; Deshpande, R. P. Tetrahedron
Lett. 2012, 53, 3994e3997.
4. Wang, H.; Zhao, X.-M.; Li, Y.-H.; Lu, L. J. Org. Chem. 2006, 71, 3278e3281.
5. (a) Dong, K.-W.; Li, Y.; Wang, Z.; Ding, K.-L. Angew. Chem., Int. Ed. 2013, 52,
14191e14195; (b) Xiao, Y.-L.; Chang, W.-C.; Liu, H.-W.; Liu, P.-H. Org. Lett. 2011,
13, 5912e5915; (c) Wang, P.; Tang, Y.; Tirrell, D. A. J. Am. Chem. Soc. 2003, 125,
6900e6906; (d) Konno, T.; Takehana, T.; Mishima, M.; Ishihara, T. J. Org. Chem.
2006, 71, 3545e3550; (e) Pinna, G. A.; Cignarella, G.; Ruiu, S.; Loriga, G.;
Murineddu, G.; Villa, S.; Grella, G. E.; Cossu, G.; Fratta, W. Bioorg. Med. Chem.
2003, 11, 4015e4026.
4.5.1. Ethyl 2-benzyl-4,4,4-trifluorobut-2-enoate (12al). (E)-isomer:
6. Preparation methods other than Wittig protocols. Michael addition to b-CF3-
propynoate, see (a) Zine, K.; Petrignet, J.; Thibonnet, J.; Abarbri, M. Synlett 2012,
755e759; (b) Wang, P.-A.; Deng, M.-Z.; Pan, R.-Q.; Zhang, S.-Y. J. Fluorine Chem.
Rf¼0.63 (n-hexane:AcOEt¼10:1). 1H NMR
d
1.21 (3H, t, J¼7.1 Hz),
3.89 (2H, br s), 4.17 (2H, q, J¼7.0 Hz), 6.76 (1H, q, J¼8.4 Hz),
2003, 124, 93e97 Coupling with b-CF3-b-I-acrylates, see; (c) Hafner, A.; Brase, S.
7.17e7.41 (5H, m). 13C NMR
126.0 (q, J¼34.8 Hz), 126.6, 128.5, 128.6, 136.8, 142.3 (q, J¼5.0 Hz),
165.4. 19F NMR
2930, 1725, 1705,
d
13.7, 33.6, 61.8, 122.8 (q, J¼271.3 Hz),
Adv. Synth. Catal. 2011, 353, 3044e3048; (d) Thibonnet, J.; Duchene, A.; Parrain,
J.-L.; Abarbri, M. J. Org. Chem. 2004, 69, 4262e4264 Perkin reaction, see; (e)
Cserenyi, S.; Felfoeldi, K.; Forgo, P.; Palinko, I. J. Fluorine Chem. 2006, 127,
850e853 Diazoacetate; (f) Chen, Y.; Huang, L.-Y.; Zhang, X. P. J. Org. Chem. 2003,
68, 5925e5929 Coupling with b-CF3-acrylates, see; (g) Gong, Y.; Kato, K.; Ki-
moto, H. J. Fluorine Chem. 2000, 105, 169e173.
7. The following article includes an important method which enables the con-
struction of b-substituted b-Rf-a,b-unsaturated esters in excellent yields. See
Shen, Y.-C.; Gao, S. J. Org. Chem. 1993, 58, 4564e4566.
8. (a) Smart, B. E. J. Fluorine Chem. 2001, 109, 3e11; (b) Kirsch, P. Modern Fluo-
roorganic Chemistry: Synthesis, Reactivity, Applications; Wiley-VCH: Weinheim,
2004; (c) Uneyama, K. Organofluorine Chemistry; Blackwell: Oxford, UK, 2006;
(d) Yamazaki, T.; Taguchi, T.; Ojima, I. In Fluorine in Medicinal Chemistry and
Chemical Biology; Ojima, I., Ed.; Wiley: West Sussex, UK, 2009; pp 3e46.
9. In situ formation of aldehydes by DIBAL reduction of esters, followed by suc-
cessive HWE type condensation, see (a) Thenappan, A.; Burton, D. J. J. Org.
Chem. 1990, 55, 4639e4642; (b) Lanier, M.; Haddach, M.; Pastor, R.; Riess, J. G.
Tetrahedron Lett. 1993, 34, 2469e2472.
d
ꢀ58.94 (d, J¼6.78 Hz). IR (neat)
n
1665, 1605, 1440, 1360, 1260, 1205, 1140, 1075, 1020, 940, 750, 700.
Anal. Calcd for C13H13F3O2: C, 60.46; H, 5.07. Found: C, 60.57; H,
5.05.
(Z)-isomer: Rf¼0.51 (n-hexane:AcOEt¼10:1). 1H NMR
d 1.24
(3H, t, J¼7.1 Hz), 3.67 (2H, dq, J¼4.2, 2.1 Hz), 4.20 (2H, q, J¼7.0 Hz),
5.47 (1H, qt, J¼7.8, 1.8 Hz), 7.17e7.41 (5H, m). 13C NMR
d 13.7, 40.1,
61.7, 119.4 (q, J¼35.7 Hz), 122.1 (q, J¼270.3 Hz), 127.3, 128.8, 129.3,
135.0, 144.7 (q, J¼5.2 Hz), 166.5. 19F NMR
d
ꢀ60.82 (d, J¼6.8 Hz). IR
(neat)
n 2930, 1730, 1705, 1680, 1380, 1285, 1250, 1190, 1140, 1020,
860, 740, 700. Anal. Calcd for C13H13F3O2: C, 60.46; H, 5.07. Found:
C, 60.41; H, 5.05.

8066
T. Yamazaki et al. / Tetrahedron 71 (2015) 8059e8066
10. For the two-step procedures of 1) transformation of RfCO2R to RfCH(OH)OR,
followed by 2) condensation with HWE reagents, see (a) Tsukamoto, T.; Kita-
zume, T. Synlett 1992, 977e979; (b) Nakamura, Y.; Okada, M.; Koura, M.; Tojo,
M.; Saito, A.; Sato, A.; Taguchi, T. J. Fluorine Chem. 2006, 127, 627e636.
11. We have found out one example, which, on the synthesis of ethyl 3-(tri-
fluoromethyl)pent-2-enoate, used a crude mixture of 1,1,1-tifluorobutan-2-one
obtained from CF3CO2Et and EtMgBr. After quenching of this Grignard reaction
and extraction, the resultant ethereal layer was added to the HWE reagent 3b
after treatment with NaH. The obtained product was further hydrogenated and
reduced to the saturated alcohol, which was eventually tosylated to isolate the
corresponding tosylate in a total yield of 42%. See Miyazaki, H. WO 2008143332.
12. Brendan, M.; O’Leary, B. M.; Szabo, T.; Sventrup, N.; Schalley, C. A.; Lutzen, A.;
Schafer, M.; Rebek, J., Jr. J. Am. Chem. Soc. 2001, 123, 11519e11533.
15. (a) Yamada, S.; Takahashi, T.; Konno, T.; Ishihara, T. Chem. Commun. 2007,
3679e3681; (b) Yamada, S.; Takahashi, T.; Konno, T.; Ishihara, T. J. Fluorine
Chem. 2013, 149, 95e103.
16. (a) Chen, L. S.; Chen, G. J.; Tamborski, C. J. Fluorine Chem. 1984, 26, 341e358; (b)
Uno, H.; Shiraishi, Y.; Shimokawa, K.; Suzuki, H. Chem. Lett. 1987, 1153e1156; (c)
Gassman, P. G.; O’Reilly, N. J. J. Org. Chem. 1987, 52, 2481e2490.
17. Yajima, T.; Jahan, I.; Tonoi, T.; Shinmen, M.; Nishikawa, A.; Yamaguchi, K.; Se-
kine, I.; Nagano, H. Tetrahedron 2012, 68, 6856e6861.
18. For example, boiling points of representative fluorinated ketones are as follows.
Trifluoroacetone 2ae (CF3C(O)CH3): 22 ꢁC, 1,1,1-trifluorobutan-2-one 2af
(CF3C(O)C2H5): 44e45 ꢁC, 1,1,1,2,2-pentafluorobutan-3-one 2be (C2F5C(O)CH3):
41.9 ꢁC (data from the catalog of SynQuest Laboratory); 1,1,1-trifluorohexan-2-
one 2ah (CF3C(O)C4H9): 89 ꢁC Trabelsi, H.; Bertaina, B.; Cambon, A. Can. J. Chem.
1985, 63, 426e431.
13. Yamazaki, T.; Terajima, T.; Kawasaki-Takasuka, T. Tetrahedron 2008, 64,
2419e2424.
19. For the mechanistic study of HWE reactions, see Ando, K. J. Org. Chem. 1999, 64,
14. In this case, c-C6H11MgBr was prepared in a 30 mmol scale, and only one report
was found for the construction of the same ketone 2ai in 66% yield by c-
C6H11MgCl. See Creary, X. J. Org. Chem. 1987, 52, 5026e5030.
6815e6821.
€
20. Hackeloer, K.; Schnakenburg, G.; Waldvogel, S. R. Eur. J. Org. Chem. 2011,
6314e6319.