Formal [3+3] cyclocondensations of 1,3-bis(silyloxy)-1,3-butadienes with 1-chloro-1,1-difluoro-4,4-dimethoxybut-3-en-2-one and 1,1-difluoro-4,4- dimethoxybut-3-en-2-one. Regioselective synthesis of fluorinated salicylates and pyran-4-ones

Article abstract of DOI:10.1016/j.jfluchem.2012.03.019

The TiCl₄-mediated [3+3] cyclocondensation of 1,3-bis(silyloxy)-1,3-butadienes with 1-chloro-1,1-difluoro-4,4-dimethoxybut-3- en-2-one or 1,1-difluoro-4,4-dimethoxybut-3-en-2-one afforded CF₂Cl- and CF₂H-substituted salicy

Full text of DOI:10.1016/j.jfluchem.2012.03.019

Journal of Fluorine Chemistry 139 (2012) 28–45
Contents lists available at SciVerse ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Formal [3+3] cyclocondensations of 1,3-bis(silyloxy)-1,3-butadienes with
1-chloro-1,1-difluoro-4,4-dimethoxybut-3-en-2-one and 1,1-difluoro-4,4-
dimethoxybut-3-en-2-one. Regioselective synthesis of fluorinated salicylates
and pyran-4-ones
Sebastian Reimanna,b, Alina Bunescu a,b, Robert Litschko a, Silke Erfle a,b, Lutz Domke a,
Franziska Bendrath a, Zharylkasyn A. Abilov c, Anke Spannenberg b, Alexander Villinger a, Peter Langer a,b,
*
a Department of Chemistry, The University of Rostock, Albert Einstein Str. 3a, 18059 Rostock, Germany
b Leibniz Institute for Catalysis at the University of Rostock e.V. (LIKAT), Albert Einstein Str. 29a, 18059 Rostock, Germany
c Al-Farabi Kazakh National University, Al-Farabi Ave. 71, 050040 Almaty, Kazakhstan
A R T I C L E I N F O
A B S T R A C T
Article history:
The TiCl4-mediated [3+3] cyclocondensation of 1,3-bis(silyloxy)-1,3-butadienes with 1-chloro-1,1-
difluoro-4,4-dimethoxybut-3-en-2-one or 1,1-difluoro-4,4-dimethoxybut-3-en-2-one afforded CF2Cl-
and CF2H-substituted salicylates, respectively. The Me3SiOTf-mediated [3+3] cyclocondensation of the
same building blocks provided CF2Cl- and CF2H-substituted pyran-4-ones and CF2Cl-substituted
cyclohexenones. The formation of CF2H-substituted cyclohexenones was not observed. Besides the type
of Lewis acid, the product distribution is also influenced by the substitution pattern of the 1,3-
bis(silyloxy)-1,3-butadiene: The Me3SiOTf mediated cyclization of C4-unsubstituted dienes resulted in
the formation of CF2Cl-substituted pyran-4-ones, while the cyclization of C4-substituted dienes afforded
CF2Cl-substituted cyclohexenones. The TiCl4-mediated cyclization of C4-substituted dienes with 1,1-
difluoro-4,4-dimethoxybut-3-en-2-one failed. Therefore, 3-substituted CF2H-salicylates were prepared
by transformation of the respective CF2Cl-salicylates with tributyltin hydride.
Received 23 November 2011
Received in revised form 23 March 2012
Accepted 28 March 2012
Available online 4 April 2012
Keywords:
Cyclizations
Lewis acids
Silyl enol ethers
Organofluorine compounds
Regioselectivity
ß 2012 Elsevier B.V. All rights reserved.
The unique properties of fluorine-containing carba- and
heterocycles are of considerable importance in organic and
medicinal chemistry. The replacement of hydrogen by fluorine
in organic molecules has often led to dramatic changes in their
physicochemical and biological properties.[1,2] This has a drastic
effect on the overall electronic distribution within the molecule
thereby affecting dipole moments and the acidity, basicity or
activity of neighboring groups; any of which can affect molecular
interactions with receptors or other interacting molecules [3].
Therefore, the synthesis of fluorinated molecules plays an
important role in drug discovery and many pharmaceuticals, such
as well known ciprofloxacin, ofloxacin, or norfloxacin which all
contain fluorine atoms [4,5]. In this context, fluorinated natural
product analogues have been developed which often show a better
biological activity than the natural products themselves. Last but
not the least, highly fluorinated arenes show a very good solubility
in fluorophilic solvents. These properties make them excellent
ligands for catalytic reactions in fluorous biphase systems [6] and
useful organocatalysts [7].
A large number of methods have been developed for the
introduction of fluorine into different organic compounds [8]. In
particular, transition-metal-catalyzed and organo-catalyzed C–F
and C–CF3 bond-forming reactions, on both aromatic rings and
aliphatic chains, were explored in recent years [9,10]. However,
molecules containing a CF2Cl- or CF2H group have been studied
much more rarely. These molecules can be interesting for
pharmacological studies, like antibacterial and cytotoxicity screen-
ings, and investigations of AChE inhibitions. In fact, CF2H-
substituted arenes have been reported to be of considerable
pharmacological relevance, for example, as tyrosine kinase
inhibitors [11].
CF2Cl-substituted arenes have been prepared by reaction of
arenes with bis(chlorodifluoroacetyl)peroxide [12], by UV-medi-
ated reaction of difluoromethylarenes with chlorine [13], reaction
of (ethylthio)difluoromethyl-arenes with BrF3 [14] and fluorina-
tion of trichloromethyl-arenes (using Olah’s reagent or KF in ionic
liquids) [15]. CF2H-substituted arenes can be prepared by direct
introduction of fluorine into the desired positions of organic
compounds (e.g. benzaldehyde) using fluorinating agents, such as
* Corresponding author at: Department of Chemistry, The University of Rostock,
Albert Einstein Str. 3a, 18059 Rostock, Germany. Fax: +49 0381 498 6412.
E-mail address: peter.langer@uni-rostock.de (P. Langer).
0022-1139/$ – see front matter ß 2012 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.jfluchem.2012.03.019

S. Reimann et al. / Journal of Fluorine Chemistry 139 (2012) 28–45
29
O
O
OMe
O
CH3C(OMe)3
R1
i
sulfur tetrafluoride [16], 4-tert-butyl-2,6-dimethylsulfur-trifluor-
ide [17] and dimethylaminosulfur-trifluoride (DAST) [18]. All these
methods rely on the fluorination or chlorination of suitable
benzene derivatives. Despite their utility, they have severe
drawbacks with regard to the preparative scope. Moreover, some
halogenation reagents are toxic and the starting materials,
functionalized benzene derivatives, are not readily available.
An alternative strategy for the synthesis of halogenated arenes
relies on the application of a building block strategy. In recent
years, we have studied various cyclization reactions of 1,3-
bis(silyloxy)-1,3-butadienes with electrophiles and found that
the type of Lewis acid can have an important influence on the
regioselectivity of cyclization [19–22]. Recently, the synthesis of 1-
chloro-1,1-difluoro-4,4-dimethoxybut-3-en-2-one [23] and its
diethoxy derivative [24] and their reactions with a primary amine
R1
O
MeO
R1
1a R1 = CF2Cl
1b R1 = CF2H
2a R1 = CF2Cl (42%)
2b R1 = CF2H (45%)
Scheme 1. Synthesis of 2a,b: i, pyridine, CH2Cl2, 0 ! 20 8C, 18 h.
reaction of chlorodifluoroacetic anhydride 1a or difluoro acetic
anhydride (1b) with 1,1,1-trimethoxyethane (Scheme 1) [23,26].
1,3-Bis(silyloxy)-1,3-butadienes 3a-x were prepared according to
the literature from the corresponding
[20,27,28].
The reaction of 2a,b with 1,3-bis(silyloxy)-1,3-butadienes 3a-v,
carried out in the presence of TiCl4, afforded the salicylates 4a–aa,
with excellent regioselectivity in moderate to good yields (Scheme
2, Table 1). The CF2Cl and the CF2H groups were located ortho to the
ester moiety. The formation of the para regioisomer was not
observed.
b-ketoester in two steps
´
have been studied. Furthermore Gree et al. described the synthesis
of pyrimidine derivatives containing a difluoromethyl side chain
starting with easily accessible propargylic fluoride building blocks
[25].
Herein, we report the first cyclocondensation reactions of 1,3-
The yields depend on the type of diene employed. It is
noteworthy that the presence of long alkyl groups located at the
terminal carbon atom of the diene afforded the expected
salicylates (4m,n,q), albeit, in lower yields. The moderate yields
can be explained by steric hindrance and competing TiCl4-
mediated oxidative dimerization of the diene as a side-reaction.
This type of process has been previously reported [29]. In some
bis(silyloxy)-1,3-butadienes
with
1-chloro-1,1-difluoro-4,4-
dimethoxybut-3-en-2-one and 1,1-difluoro-4,4-dimethoxybut-3-
en-2-one. These reactions provide a convenient approach to CF2Cl
and CF2H salicylates and pyran-4-ones which are not readily
available by other methods. The products, fluorinated salicylates
and pyran-4-ones, are of general interest as potentially biologically
relevant analogues of natural products and drugs.
reactions, the formation of a small amount of b-ketoester, formed
by hydrolysis of the diene, was observed. Its chromatographic
separation from the product was difficult in some cases. Therefore,
practical problems during the chromatographic purification also
influenced the yields. The synthesis of C-3-substituted CF2H-
salicylates (R3 ¼ H) was not possible.
1. Results and discussion
1-Chloro-1,1-difluoro-4,4-dimethoxybut-3-en-2-one 2a and
1,1-difluoro-4,4-dimethoxybut-3-en-2-one 2b were prepared by
O
R2
O
O
R3
O
R3
R2
O
or
OH
MeO
CF2Cl
CF2Cl
Me3SiOTf
i
5a-e R2 = OAlkyl
3 = H
6a-k R2 = OAlkyl
OMe
O
R3 = Alkyl
R
OH
O
MeO
CF2Cl
R3
2a
R2
CF2Cl
TiCl4
i
MeO
4a-u R2 = OAlkyl
R3 = H, Alkyl
Bu3SnH
Me3SiO
R3
OSiMe3
R2
ii
AIBN
OH
O
R3
3
R2
TiCl4
i
MeO
CF2H
4v-aa R2 = OAlkyl
R
3 = H
OMe
O
O
MeO
CF2H
R2
i
2b
R3
O
O
Me3SiOTf
CF2H
5f-m R2 = OAlkyl
R3 = H, Alkyl
Scheme 2. Synthesis of 4, 5 and 6: i, CH2Cl2, ꢀ78 ! 20 8C, 12–14 h; ii, benzene, 90 8C, 20 h.

30
S. Reimann et al. / Journal of Fluorine Chemistry 139 (2012) 28–45
Table 1
OH
2
O
Synthesis of 4a–aa.
R3
3
4
1
6
R2
a
2
3
4
R1
R2
R3
%
[4]
5
R1
a
a
a
a
a
a
a
a
a
a
a
a
a
a
a
a
a
a
a
a
a
b
b
b
b
b
b
a
b
c
d
e
f
a
b
c
CF2Cl
CF2Cl
CF2Cl
CF2Cl
CF2Cl
CF2Cl
CF2Cl
CF2Cl
CF2Cl
CF2Cl
CF2Cl
CF2Cl
CF2Cl
CF2Cl
CF2Cl
CF2Cl
CF2Cl
CF2Cl
CF2Cl
CF2Cl
CF2Cl
CF2H
CF2H
CF2H
CF2H
CF2H
CF2H
OMe
OEt
H
86
50
50
56
50
48
68
89
69
62
42
57
30
31
55
42
30
40
35
36
42
35
33
30
58
30
37
MeO
H
OiPr
H
Fig. 1. Numbering of salicylates 4a–aa.
d
e
f
OiBu
OBn
H
H
O(CH2)2OMe
OMe
OMe
OMe
OMe
OEt
H
g
h
i
g
h
i
Me
Et
iPr
j
j
nPr
k
l
k
l
Et
OEt
nPent
nHex
nHept
nOct
nDodec
nHexadec
BnCH2
Cl(CH2)4
Cl(CH2)3
MeO
H
m
n
o
p
q
r
m
n
o
p
q
r
OMe
OEt
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OEt
s
s
t
t
u
a
b
e
c
f
u
v
w
x
y
z
Fig. 2. Ortep drawing of 4v.
H
OBn
H
OiPr
H
O(CH2)2OMe
OnBu
H
assigned to the C55O stretch vibration of the ester group and of the
C–O stretch vibration of the OH group. The signals indicate that
both groups are involved in an intramolecular hydrogen bond.
The structure of product 4v was independently confirmed by
X-ray structure analysis (Fig. 2).[30]
v
aa
H
a
Yields of isolated products.
The reaction conditions were optimized for the synthesis of
salicylates 4a and 4y (Table 2). It is obvious that the temperature
and the stoichiometry play an important role. The best yield was
obtained when the solution was slowly warmed from ꢀ78 to 20 8C.
The reaction was carried out in a concentrated solution using an
excess (2.0 equiv.) of the diene.
The reaction of 2a with 1,3-bis(silyloxy)-1,3-butadienes 3,
carried out in the presence of Me3SiOTf, resulted in the formation
of CF2H-substituted 4H-pyran-4-ones 5a–m and CF2Cl-substituted
cyclohexenones 6a–k (Scheme 1, Table 3). On the other hand, the
reaction of 2b with 1,3-bis(silyloxy)-1,3-butadienes 3, carried out
in the presence of Me3SiOTf, yielded the CF2H-substituted 4H-
pyran-4-ones 5f–m (Scheme 1, Table 3). The formation of
cyclohexenones was not observed.
The structures were confirmed by spectroscopic methods. The
hydroxyl proton of salicylates 4a–aa showed low field resonances
(
d
ꢁ 11.00 ppm, 1H NMR) which indicates that the protons are
involved in an intramolecular hydrogen bond O–Hꢂ ꢂ ꢂO. The carbon
atoms were unambigiously assigned by analysis of the C–F
coupling constants (JC–F) in the 13C NMR-spectra and by 2D
NMR experiments. The absence of any JC–F coupling at C-3 (Fig. 1)
prooves that the CF2Cl group is located ortho to the ester group.
Besides routine IR spectroscopy, RAMAN experiments were
carried out for derivatives 4g and 4r. Broad signals were observed
in the region of ca. 150 cmꢀ1 which are diagnostic for intermolec-
ular hydrogen bonds. Strong signals are observed at 1300 cmꢀ1
(C–F stretch vibrations) and 1450 cmꢀ1 (C–Cl stretch vibrations).
As expected from the 2:1 ratio of fluorine and chlorine atoms
present in the CF2Cl group, the intensity of the C–F signal is two
times higher than the C–Cl signal. These signals are much more
pronounced in RAMAN compared to IR spectra. Two signals were
detected, during IR experiments, in the region of 1650 cmꢀ1
It is obvious that the reactions of 2a with 4-unsubstituted
dienes (R3 = H) afforded pyran-4-ones 5a–e, while the reaction
Table 3
Synthesis of 5a–m and 6a–k.
a
2
3
5/6
R1
R2
R3
%
5
6
a
a
a
a
a
b
b
b
b
b
b
b
b
a
a
a
a
a
a
a
a
a
a
a
a
b
c
5a
5b
5c
5d
5e
5f
CF2Cl
CF2Cl
CF2Cl
CF2Cl
CF2Cl
CF2H
CF2H
CF2H
CF2H
CF2H
CF2H
CF2H
CF2H
CF2Cl
CF2Cl
CF2Cl
CF2Cl
CF2Cl
CF2Cl
CF2Cl
CF2Cl
CF2Cl
CF2Cl
CF2Cl
OMe
OEt
H
32
44
51
43
50
60
57
52
31
45
31
32
26
–
–
H
–
OiPr
H
–
d
f
OiBu
O(CH2)2OMe
OEt
H
–
H
–
b
c
H
–
5g
5h
5i
OiPr
H
–
d
g
h
k
j
OiBu
OMe
OMe
OEt
H
–
Me
–
5j
Et
–
5k
5l
Et
–
Table 2
OMe
OMe
OMe
OMe
OEt
nPr
nNon
Me
–
Optimization of the synthesis of 4a and 4y.
w
g
h
l
5m
6a
6b
6c
6d
6e
6f
–
32
56
57
57
58
57
46
64
80
80
52
Ratio of 2:3 [mmol]
V (CH2Cl2) [mL]
Yield (4) [%]a
Et
–
4a
4y
1:2
1:2
1:3
1:1
1:2
1:2
1:2
1:1
1:3
2
5
86
72
82
48
48
58
55
38
42
nPent
nHex
nHept
nOct
nNon
nDodec
nHexadec
iBu
Cl
–
x
n
o
w
p
q
y
z
OEt
–
2
OEt
–
2
OMe
OMe
OMe
OMe
OMe
OMe
–
2
6g
6h
6i
–
5
–
10
5
–
6j
–
5
6k
–
a
a
Yields of isolated products.
Yields of isolated products.

S. Reimann et al. / Journal of Fluorine Chemistry 139 (2012) 28–45
31
Table 4
Optimization of the synthesis of 5c, 5f and 6a.
Ratio of 2:3 [mmol]
V (CH2Cl2) [mL]
Yield (5) [%]a
5c
1:2
1:2
1:2
1:3
1:1
1:2
1:2
1:2
1:2
1:2
1:2
10
5
51
41
36
49
22
34
60
55
32
23
30
15
10
10
5
5f
10
15
10
5
6a
15
a
Yields of isolated products.
with dienes containing an alkyl or a chloride group located at
carbon C-4 (R3 ¼ H) of the diene afforded cyclohexenones 6a–k. In
contrast, the reaction of substrate 2b led only to the formation of
pyran-4-ones 5f–m. All products were obtained in moderate to
good yields and the cyclohexenones were formed with very good
1,2-diastereoselectivity (vide infra).
Fig. 4. Ortep drawing of 6b.
The Me3SiOTf-mediated reaction was optimized for products
5c, 5f and 6a (Table 4). The best yield was obtained when an excess
of diene 3 was employed. In contrast to the TiCl4-mediated
reaction, which is carried out in a highly concentrated solution
(c(2) = 0.5 M), the yield of 5 and 6 can be improved when the
reaction is carried out in a more dilute solution (c(2) = 0.1 M).
However, the change of the solvent from dichloromethane to
acetone and tetrahydrofuran failed.
The structures of all products were confirmed by spectroscopic
methods. The CF2Cl-substituted cyclohexenones 6a–k show
interesting spectroscopic properties. The two fluorine atoms of
the CF2Cl-group are diastereotopic (Fig. 3). Therefore, two signals
titanium hydroxide (before or during the aqueous work-up) and
aromatization resulted in the formation of product 4 (Scheme 4).
The formation of 5 and 6 presumably proceeds by formation of
allylic cation E. The attack of the terminal carbon atom of 3 onto E
provides intermediate F. We consider two pathways which either
lead to pyran-4-one 5 or to cyclohehexenone 6. Pathway I: The
rotation of the C3–C4-bond of the diene (intermediate F) followed
by elimination of Me3SiOMe (intermediate G) and subsequent
cyclization via the oxygen rather than the carbon atom provides
intermediate H. The elimination of silanol (before or during the
aqueous work-up) results in the formation of pyran-4-ones 5.
Pathway II: The formation of product 6 can be explained by a
mechanism which is similar to the one leading to salicylates 4. The
cyclization of intermediate I proceeds via the central carbon atom
of the diene moiety. In contrast to the formation of salicylates 4, no
elimination of the hydroxyl group and aromatization occurs. This
result is surprising since the aromatization should be a facile
process. It might be explained by the assumption that intermediate
are observed in the 19F NMR spectra at
d
d
ꢃ ꢀ64 ppm and
ꢃ ꢀ66 ppm. The 1H NMR spectra of 6a–k show two characteristic
doublets in the range of
d = 2.80–3.10 ppm for protons H-5
(2J ꢃ 17.7 Hz). The proton of the OH group appears as a singlet
at
d
ꢃ 5.66 ppm. The chemical shift suggests that the latter is not
involved in an intramolecular hydrogen bond in the solution.
The structures of 6b,e,k were independently confirmed by X-
ray crystal structure analysis (Figs. 4–6) [30]. The crystal structures
unambiguously prove the relative configuration of these mole-
cules. The hydroxyl and the ester group are located cis to each
other. In the solid state an intramolecular hydrogen bond O–Hꢂ ꢂ ꢂO
is present. In solution, beside the major isomer, a small amount of
the minor isomer is detected.
Under the conditions of mass spectrometry (EI, electron
ionization), elimination of water from cyclohexenones
6 is
observed and only the molecular ions of the aromatized products
can be detected. The correct molecular ions are observed when the
measurements are carried out using the milder ESI technique
(electrospray ionization).
The formation of 4 can be explained by reaction of 2 with TiCl4
to give A containing an allylic carbon unit. The attack of the
terminal carbon atom of the diene 3 onto A afforded intermediate
B. The elimination of Me3SiOMe (intermediate C) and subsequent
cyclization gave intermediate D (Scheme 3). The elimination of
O
2
O
R3
3
4
1
6
OR2
OH
Cl
F
MeO
5
F
Fig. 3. Numbering scheme of cyclohexenones 6 and diastereotopic nature of the
fluorine atoms.
Fig. 5. Ortep drawing of 6e.

32
S. Reimann et al. / Journal of Fluorine Chemistry 139 (2012) 28–45
OMe
O
MeO
CH2Cl2
R1
2a,b
Me3SiOTf
OMe OSiMe3
Me3SiO
R3
OSiMe3
R2
OTf
MeO
R1
3
E
-Me3SiOTf
Me3SiO
O
R3
MeO
R2
SiMe3
O
R1
MeO
F
-Me3SiOMe
Pathway II
Fig. 6. Ortep drawing of 6k.
Pathway I
R2
Me3SiO
OSiMe3
Me3SiO
R3
O
O
OH
O
TiCl4
OR2
CH2Cl2
OR2
OTf
SiMe3
R3
MeO
R2
OTf
SiMe3
OSiMe3
O
R1
3
O
R1
+
-78 to 20 °C
18 h
MeO
R1
MeO
O
MeO
I
4
MeO
R1
G
2a,b
-Me3SiOTf
-Me3SiOTf
TiCl4
_
H2O
O
O
O
O
O
R2
R3
TiCl4
OR2
OTiCl3
R1
R2
MeO
O
R3
O
+
OSiMe3
R1
O
MeO
R1
MeO
OSiMe3
R1
MeO
D
A
J
H
3
Me3SiCl
H2O
Me3SiCl
H2O
O
O
O
Me3SiO
OR2
Me3SiO
MeO
OR2
Me3SiCl
O
O
TiCl3
TiCl4
R2
R1
O
O
R3
R2
R3
MeO
MeO
R1
R1
OH
R1
O
Me SiOMe
3
MeO
B
C
O
6
5
Scheme 3. Possible mechanism of the formation of 4.
Scheme 4. Possible mechanism of the formation of 5 and 6.
D, containing a titanium alkoxide moiety, readily undergoes an
elimination of TiCl3OH and aromatization before the aqueous work
up (vide supra). In contrast, intermediate J, containing a silanolate
moiety, is more stable and no elimination occurs. The addition of
hydrochloric acid (10%) (aqueous work up) results in cleavage of
Si–O bond, but no elimination and aromatization occurs. The
stability of compounds 6 might be explained by the presence of the
electron-withdrawing CF2Cl group. The rate of the acid-mediated
elimination of water is decreased because a cation located next to
the CF2Cl group is expected to be unstable and an elimination
requires more drastic conditions.
substituted salicylates with tributyltin hydride in the presence of
AIBN (Scheme 5, Table 5) [21,22]. Both C-3-substituted and C-3-
unsubstituted CF2H-salicylates were successfully prepared in
moderate to good yields.
In addition, CF2Cl-substituted salicylates 4a,c,i,j,o were trans-
formed, by reaction with allyltributyltin and AIBN, to the
corresponding CF2H-substituted salicylates 7a–e in good to very
good yields (Scheme 6, Table 6).
Using the Density Functional Theory (DFT) B3LYP method with
a 6-31g* basis set and the Natural Bond Orbital (NBO) analysis [31],
we calculated the atomic charges of the electrophilic and
nuceleophilic centers of enones 2a,b and 1,3-bis(silyloxy)-1,3-
butadienes 3a,b,g,h, respectively (Scheme 7, Table 7). The terminal
carbon atom C-4 of dienes 3a,b exhibits the highest nucleophilici-
ty, while carbon atom C-3 of the enones 2a,b represents the most
electrophilic center. The difference in the substitution pattern of
As mentioned before, the TiCl4-mediated reactions of 2b with
1,3-bis(silyloxy)-1,3-butadienes 3, containing an alkyl or
a
chloride group located at carbon C-4 of the diene moiety
(R3 ¼ H), did not result in the formation of 3-substituted CF2H-
salicylates (vide supra). A successful alternative is the preparation
of these salicylates by radical reactions of the respective CF2Cl-

S. Reimann et al. / Journal of Fluorine Chemistry 139 (2012) 28–45
33
OH
O
Me3SiO
R3
OSiMe3
R2
OMe
O
R3
R2
i
MeO
CF2Cl
MeO
CF2Cl
2a
3
R3 = H, Alkyl
4a,b,c,i,o
ii
OH
O
i
Me3SiO
R3
OSiMe3
R2
OMe
O
R3
R2
MeO
CF2H
3
R3 = Alkyl
2b
MeO
CF2H
4v,w,y,ab,ac
Scheme 5. Attempted synthesis of 3-substituted CF2H-salicylates: i, TiCl4, CH2Cl2, ꢀ78 ! 20 8C; synthesis of CF2H-substituted salicylates 4v,w,y,ab,ac by reduction of CF2Cl-
salicylates: i, AIBN, Bu3SnH, benzene, 90 8C, 20 h.
the butenone (CF2Cl vs. CF2H) influences the electronic situation of
these molecules. The change of the CF2Cl group to the CF2H group
decreases the NPA atomic charge on the carbon atom C-3 from
0.749 to 0.718, due to the stronger electron withdrawing effect of
the CF2Cl group compared to the CF2H group. The substitution of
carbon atom C-4 (R3 ¼ H) lowers the nucleophilicity of diene 3. The
decrease of the electrophilicity at carbon atom C-3 of the CF2H-
substituted enone and the decrease of the nucleophilicity at carbon
atom C-4 of 4-substituted dienes (3g,h) might be the reason why
the formation of 3-substituted (R3 ¼ H) CF2H-salicylates could not
be achieved.
In addition, we calculated the geometric structures of CF2Cl-
and CF2H-substituted salicylates along with their electrostatic
potential maps in the ground state and the dipole moments (Table
8) (Density Functional B3LYP method (DFT) with 6-31g* basis set).
The mapped electrostatic potential (MEP) of compounds 4a and 4v
show a high negative potential in the area of the CF2Cl/CF2H group
while 6-unsubstituted salicylates (R = H) and 6-methylsalicylates
show a more neutral area. This may have an effect on further
chemical, physical and biological properties (e.g. interactions
between substrate and receptor).
one and 1,1-difluoro-4,4-dimethoxybut-3-en-2-one which
afforded a variety of functionalized CF2Cl- and CF2H-salicylates
with very good regioselectivities. The Me3SiOTf-mediated cycliza-
tion of 1,3-bis(silyloxy)-1,3-butadienes, containing no substituent
R3 located at carbon atom C-4 of the diene (R3 = H), resulted in the
formation of CF2Cl-substituted pyran-4-ones. CF2Cl-substituted
cyclohexenones were formed when dienes were employed which
contain a substituent R3 located at carbon C-4 (R3 ¼ H). In contrast,
independently from the substitution pattern of the diene (R3 = H
and R3¼H), the reaction of dienes with 1,1-difluoro-4,4-dimethox-
ybut-3-en-2-one resulted in the formation of pyran-4-ones
when Me3SiOTf was employed as the Lewis acid. The synthesis
of 3-substituted difluoromethylsalicylates was possible by reac-
tion of 3-substituted chlorodifluoromethyl-salicylates with tribu-
tyltin hydride and AIBN.[12] In addition, CF2Cl-substituted
salicylates could be transformed to 6-difluorobutenyl-salicylates
in the presence of allyltributyltin and AIBN.[32]
OH
O
OH
O
R3
R3
R2
R2
CF2Cl
i
Conclusions. In conclusion, we reported the TiCl4-mediated
formal [3+3]-cyclocondensation reactions of 1,3-bis(silyloxy)-1,3-
butadienes with 1-chloro-1,1-difluoro-4,4-dimethoxybut-3-en-2-
MeO
C
MeO
F2
7a-e
4a,c,i,j,o
Scheme 6. Synthesis of 7a–e: i, AIBN, Bu3SnCH2CHCH2, benzene, 90 8C, 20 h.
Table 5
Synthesis of 4v,w,y,ab,ac.
a
4 (CF2Cl)
4 (CF2H)
R2
R3
% (4, CF2H)b
OMe
O
1
Me3SiO
R1
OSiMe3
a
b
c
i
v
Me
Et
H
88
87
48
46
51
3
w
y
H
3
1
MeO
2
R1
4
2
R2
iPr
Me
Me
H
ab
ac
iPr
2a R1 = CF2Cl
3a,b,g,h
o
nOctyl
2b R1 = CF2H
a
CF2Cl-substituted salicylate;
Yields of isolated products.
b
Scheme 7. Numbering scheme of enones 2a,b and of 1,3-bis(silyloxy)-1,3-
butadienes 3a,b,g,h.
Table 7
Table 6
Atomic charges calculated by NBO-analysis.
Synthesis of 7a–e.
NPA C1
NPA C2
NPA C3
NPA C4
a
4
7
R1
R2
%
[7]
Compound
2a
2b
3a
3b
3g
3h
0.441
0.451
0.689
0.693
0.673
0.675
ꢀ0.557
ꢀ0.525
ꢀ0.452
ꢀ0.451
ꢀ0.452
ꢀ0.453
0.749
0.718
0.344
0.334
0.302
0.308
–
a
c
i
a
b
c
Me
iPr
H
72
96
89
85
77
–
H
ꢀ0.562
ꢀ0.563
ꢀ0.288
ꢀ0.291
Me
Me
Me
nPr
iPr
j
d
e
o
nOctyl
a
Yields of isolated products.

34
S. Reimann et al. / Journal of Fluorine Chemistry 139 (2012) 28–45
Table 8
Calculated geometric structure, MEP, dipole moments of 4a and 4v and of 6 methyl- and 6-unsubstituted salicylates.
OH
O
OH
O
OH
O
OH
O
OMe
CF2H
OMe
CH3
OMe
OMe
CF2Cl
Numbering scheme and structure
MeO
MeO
MeO
MeO
Geometric structure
Electrostatic potential maps
mcalc [D]
6.9850
6.6991
5.5748
5.9910
2. Experimental
40 mmol), 2b was isolated as a white solid (1.54 g, 45%); mp = 49–
51 8C, 1H NMR (300 MHz, CDCl3):
= 3.90 (s, 3H, OCH3), 3.94 (s, 3H,
OCH3), 4.99 (t, 4J = 1.3 Hz, 1H, CH), 5.76 (t, 2J = 55.0 Hz, 1H, CF2H).
d
General Comments. All solvents were dried by standard methods
and all reactions were carried out under an inert atmosphere. For
1H and 13C NMR spectra the deuterated solvents indicated were
used. Mass spectrometric data (MS) were obtained by electron
ionization (EI, 70 eV), chemical ionization (CI, isobutane) or
electrospray ionization (ESI). X-ray crystal structure analysis of
4 v: Data were collected on a Bruker APEX II CCD diffractometer
using graphite-monochromated Mo K
structure analysis of 6b, 6e and 6k: Data were collected on a STOE
IPDS II diffractometer using graphite-monochromated Mo K
radiation. For preparative scale chromatography silica gel 60
(0.063–0.200 mm, 70–230 mesh) was used. 1,3-bis(trimethylsily-
loxy)-1,3-butadienes 3a–x were prepared according to the
literature from the corresponding
[20,29,30].
13C NMR (75 MHz, CDCl3):
d = 55.4, 57.5 (OCH3), 73.3 (CH), 110.8
(q, JC–F = 252.0 Hz, CF2H), 171.4 (C), 184.0 (t, JC–F = 23.3 Hz, CO). 19
F
2
NMR (282 MHz, CDCl3):
d
= ꢀ124.5 (2F, d, JF–H = 54.6 Hz, CF2H).
General procedure (I) for the synthesis of 4a–aa: To a CH2Cl2
solution (2 mL/1 mmol of 2) of 2 (1 mmol) was added 3 (2 mmol)
and, subsequently, TiCl4 (0.1 mL, 1 mmol) at ꢀ78 8C. The tempera-
ture of the solution was allowed to warm up to 20 8C during a 12–
14 h period with stirring. Hydrochloric acid (10%, 15 mL) was
added to the solution and the organic and aqueous layers were
separated. The latter was extracted with CH2Cl2 (3 ꢄ 10 mL). The
combined organic layers were dried (Na2SO4), filtered and the
filtrate was concentrated in vacuo. The residue was purified by a
column chromatography.
a radiation. X-ray crystal
a
b-ketoesters into two steps
Methyl
2-hydroxy-4-methoxy-6-(chlorodifluoromethyl)-
General procedure for the synthesis of 2a,b: To a stirred
solution of methyl orthoacetate (20 mmol) and pyridine
(40 mmol) in dry dichloromethane (20 mL), 1 (40 mmol) is added
drop wise (ice cooling) and the mixture is stirred for 24 h at 20–
25 8C. It is then washed two times with 10% sodium carbonate
(20 mL), one time with ice cold dist. water and dried with sodium
sulfate. The solvent and pyridine are removed in vacuo to give 2 as
a white solid. It is used without further purification and can be
stored at ꢀ20 8C.
benzoate (4a): Starting with 2a (1.0 mmol, 200 mg), 3a (2.0 mmol,
0.521 g) and TiCl4 (1.0 mmol, 0.11 mL) in 2 mL of CH2Cl2, 4a was
isolated (228 mg, 86%) by chromatography (silica gel, heptanes/
EtOAc = 100:0 ! 15:1) as a slightly yellow solid; mp 50–51 8C; 1H
NMR (250 MHz, CDCl3):
d = 3.85 (s, 3H, OCH3), 3.95 (s, 3H, OCH3),
6.59 (d, 1H, 4J = 2.5 Hz, H3), 6.85 (d, 1H, 4J = 2.5 Hz, H5), 11.13 (s,
1H, OH); 13C NMR (126 MHz, CDCl3):
d = 52.3 (OCH3), 55.8 (OCH3),
103.1 (C1), 103.3 (C3), 107.9 (t, 3J = 9.5 Hz, C5), 124.8 (t,
1J = 290.5 Hz, CClF2), 137.7 (t, 2J = 26.4 Hz, C6), 163.4 (C4), 164.4
1-Chloro-1,1-difluoro-4,4-dimethoxybut-3-en-2-one (2a):
This compound has been previously described [23]. Starting with
methyl orthoacetate (2.56 mL, 20 mmol) and pyridine (3.22 mL,
40 mmol) and chlorodifluoro acetic acid anhydride (9.70 g,
(C2), 169.8 (CO); 19F NMR (235 MHz, CDCl3)
d
= ꢀ45.8 (s, CF2Cl). IR
˜
(ATR, cmꢀ1):
n
= 3120 (w), 3093 (w), 3032 (w), 3015 (w), 2974 (w),
2958 (w), 2945 (w), 2847 (w), 1674 (s), 1615 (s); MS (EI, 70 eV): m/
z = 266 (M+, 35), 236 (35), 235 (23), 234 (100), 171 (71); HRMS (EI,
70 eV): calcd. for C10H9O4ClF2 (M+) 266.014859, found: m/
z = 266.01519.
40 mmol), 2a was isolated as
mp = 48–50 8C, [lit. [23] 48–49 8C]. 1H NMR (400 MHz, CDCl3)
= 3.92, 3.97 (s, 3H, OCH3), 4.96 (s, 1H, CH).13C NMR (100 MHz,
CDCl3)
= 55.5, 57.6 (OCH3), 70.9 (CH), 121.1 (t, 1J = 307.2 Hz,
CF2Cl), 172.4 (C4), 177.5 (t, 2J = 27.2 Hz, C-2). 19F NMR (282 MHz,
CDCl3)
a white solid (1.68 g, 42%);
d
Ethyl
2-hydroxy-4-methoxy-6-(chlorodifluoromethyl)-
d
benzoate (4b): Starting with 2a (0.200 g, 1 mmol), 1-ethoxy-
1,3-bis(trimethylsilyloxy)-1,3-butadiene (3b) (0.549 g, 2 mmol)
and TiCl4 (0.1 mL, 1 mmol) in CH2Cl2 (2 mL), product 4b was
isolated as a colorless solid (0.139 g, 50%); mp = 33–35 8C; RF = 0.47
d
= ꢀ65.51 (s, CF2Cl).
1,1-Difluoro-4,4-dimethoxybut-3-en-2-one (2b): Starting
with methyl orthoacetate (2.56 mL, 20 mmol) and pyridine
(3.22 mL, 40 mmol) and difluoro-acetic acid anhydride (6.96 g,
(n-hexane/CH2Cl2 = 3:2). 1H NMR (400 MHz, CDCl3):
d
= 1.43 (t,
3J = 6.8 Hz, 3H, CH3), 3.85 (s, 3H, OCH3), 4.51 (q, 3J = 6.8 Hz, 2H,

S. Reimann et al. / Journal of Fluorine Chemistry 139 (2012) 28–45
35
CH2), 6.58 (d, 4J = 2.4 Hz, 1H, CH), 6.84 (d, 4J = 2.4 Hz, 1H, CH), 11.26
(s, 1H, OH). 13C NMR (100 MHz, CDCl3):
= 13.6 (CH3), 55.8 (OCH3),
2-Methoxyethyl 2-hydroxy-4-methoxy-6-(chlorodifluoro-
methyl)benzoate (4f): Starting with 2a (0.200 g, 1 mmol), 1-(2-
d
62.3 (CH2), 103.2 (C-1), 103.2 (C-3), 107.8 (t, JC–F = 9.0 Hz, C-5),
124.9 (t, JC–F = 289.0 Hz, CF2Cl), 137.7 (t, JC–F = 26.0 Hz, C-6), 163.3
methoxyethoxy)-1,3-bis(trimethylsilyloxy)-1,3-butadiene
(3f)
(0.610 g, 2 mmol) and TiCl4 (0.1 mL, 1 mmol) in CH2Cl2 (2 mL),
product 4f was isolated as a slight yellow oil (0.147 g, 48%);
RF = 0.47 (n-hexane/EtOAc = 3:2). 1H NMR (400 MHz, CDCl3):
(C-2), 164.6 (C-4), 169.4 (CO). 19F NMR (282 MHz, CDCl3):
˜
d
= ꢀ44.8 (s, CF2Cl). IR (ATR, cmꢀ1):
n
= 3091 (w), 3014 (w),
2990 (w), 2944 (w), 2906 (w), 2784 (w), 2744 (w), 2712 (w), 2656
(w), 2570 (w), 1645 (s), 1595 (s), 1485 (w), 1368 (s), 1331 (s), 1266
(s), 1230 (m), 1210 (s), 1106 (s), 1043 (m), 991 (s), 954 (s), 805 (s),
703 (m). GC–MS (EI, 70 eV): m/z (%): 280 (M+, 28), 236 (36), 234
(100), 197 (13), 171 (50), 149 (7). Anal. calcd. for C11H11ClF2O4
(280.65): C, 47.08; H, 3.95. Found: C, 47.02; H, 4.072.
d
= 3.47 (s, 3H, OCH3), 3.75 (t, 3J = 4.8 Hz, 2H, CH2), 3.85 (s, 3H,
OCH3), 4.51 (t, 3J = 4.8 Hz, 2H, CH2), 6.58 (d, 4J = 2.8 Hz, 1H, CH),
6.84 (d, 4J = 2.8 Hz, 1H, CH), 10.84 (s, 1H, OH). 13C NMR (100 MHz,
CDCl3):
d = 55.8, 58.9 (OCH3), 64.7, 69.5 (CH2), 103.4 (C-1), 103.5
(C-3), 107.8 (t, JC–F = 10.0 Hz, C-5), 124.9 (t, JC–F = 289.0 Hz, CF2Cl),
137.6 (t, JC–F = 26.0 Hz, C-6), 163.3 (C-2), 164.0 (C-4), 168.9 (CO).
Isopropyl 2-hydroxy-4-methoxy-6-(chlorodifluoromethyl)-
benzoate (4c): Starting with 2a (0.200 g, 1 mmol), 1-isopropy-
19F NMR (282 MHz, CDCl3):
d
= ꢀ45.1 (s, CF2Cl). IR (ATR, cmꢀ1):
˜
n
= 3092 (w), 2941 (w), 2895 (w), 2848 (w), 2823 (w), 1659 (s),
loxy-1,3-bis(trimethylsilyloxy)-1,3-butadiene
(3c)
(0.577 g,
1614 (s), 1440 (w), 1372 (w), 1262 (s), 1206 (m), 1107 (s), 1041 (s),
952 (s), 795 (s), 702 (w). GC–MS (EI, 70 eV): m/z (%): 310 (M+, 19),
275 (16), 237 (11), 236 (36), 235 (30), 234 (100), 171 (32), 157 (9),
59 (8). Anal. calcd. for C12H13ClF2O4 (310.86): C, 46.39; H, 4.22.
Found: C, 46.42; H, 4.50.
Methyl 2-hydroxy-4-methoxy-3-methyl-6-(chlorodifluoro-
methyl)benzoate (4g): Starting with 2a (0.200 g, 1 mmol), 1-
methoxy-1,3-bis(trimethylsilyloxy)-1,3-pentadiene (3g) (0.549 g,
2 mmol) and TiCl4 (0.1 mL, 1 mmol) in CH2Cl2 (2 mL), product 4g
was isolated as a white solid (0.191 g, 68%); mp = 56–57 8C;
RF = 0.63 (n-hexane/CH2Cl2 = 3:2). 1H NMR (300 MHz, CDCl3):
2 mmol) and TiCl4 (0.1 mL, 1 mmol) in CH2Cl2 (2 mL), product
4c was isolated as a white solid (0.147 g, 50%); mp = 35–36 8C;
RF = 0.54 (n-hexane/CH2Cl2 = 3:2). 1H NMR (300 MHz, CDCl3):
d
= 1.40 (s, 3H, CH3), 1.42 (s, 3H, CH3), 3.84 (s, 3H, OCH3), 5.28–
5.36 (m, 1H, CH), 6.58 (d, 4J = 2.4 Hz, 1H, CH), 6.83 (d, 4J = 2.7 Hz,
1H, CH), 11.41 (s, 1H, OH). 13C NMR (100 MHz, CDCl3):
= 21.4
d
(CH3), 55.7 (OCH3), 70.8 (CH), 103.3 (C-3), 103.6 (C-1), 107.8 (t, JC–
F = 10.0 Hz, C-5), 124.9 (t, JC–F = 288.0 Hz, CF2Cl), 137.6 (t, JC–
F = 26.0 Hz, C-6), 163.2, 164.6 (C), 169.0 (CO). 19F NMR (282 MHz,
˜
CDCl3):
d
= ꢀ44.5 (s, CF2Cl). IR (ATR, cmꢀ1):
n
= 3232 (w), 3122 (w),
3091 (w), 3028 (w), 2980 (m), 2940 (w), 2846 (w), 1672 (s), 1616
(s), 1359 (s), 1094 (s), 996 (s), 948 (s), 839 (s), 794 (s), 841 (s), 794
(s). GC–MS (EI, 70 eV): m/z (%): 294 (M+, 16), 252 (14), 236 (35), 235
(24), 234 (100), 171 (35). Anal. calcd. for C12H13ClF2O4 (294.68): C,
48.10; H, 4.45; Cl, 12.03. Found: C, 48.03; H, 4.539; Cl, 11.93.
Isobutyl 2-hydroxy-4-methoxy-6-(chlorodifluoromethyl)-
benzoate (4d): Starting with 2a (0.200 g, 1 mmol), 1-isobuty-
loxy-1,3-bis(trimethylsilyloxy)-1,3-butadiene (3d) (0.604 g,
2 mmol) and TiCl4 (0.1 mL, 1 mmol) in CH2Cl2 (2 mL), product
4d was isolated as a colorless oil (0.174 g, 56%); RF = 0.44 (n-
d
= 2.14 (s, 3H, CH3), 3.91 (s, 3H, OCH3), 3.95 (s, 3H, OCH3), 6.82
(s, 1H, H-5), 10.86 (s, 1-H, OH). 13C NMR (75 MHz, CDCl3):
d
= 8.4
(CH3), 52.3, 55.8 (OCH3), 101.3 (t, JC–F = 9.4 Hz, C-5), 104.0 (t, JC–
F = 1.5 Hz, C-1), 117.3 (C-3), 125.3 (t, JC–F = 288.0 Hz, CF2Cl), 134.8
(t, JC–F = 25.9 Hz, C-6), 160.5, 160.6 (C), 170.2 (CO). 19F NMR
˜
(282 MHz, CDCl3):
d
= ꢀ44.5 (s, CF2Cl). IR (ATR, cmꢀ1):
n
= 3019
(w), 2976 (w), 2923 (w), 2851 (m), 1671 (s), 1605 (s), 1510 (s), 1437
(s), 1238 (s), 1194 (s), 1168 (s), 1108 (s), 1003 (s), 973 (s), 884 (s),
841 (s), 794 (s), 766 (s). GC–MS (EI, 70 eV): m/z (%): 280 (M+, 60),
250 (27), 249 (30), 248 (76), 245 (16), 230 (32), 229 (14), 228 (80),
225 (15), 213 (13), 212 (100), 201 (10), 198 (11), 190 (12), 185 (21),
182 (11), 162 (18), 142 (12). Anal. calcd. for C11H11ClF2O4 (280.65):
C, 47.08; H, 3.95. Found: C, 47.25; H, 4.156.
hexane/CH2Cl2 = 3:2). 1H NMR (400 MHz, CDCl3):
d = 1.00, 1.02
(s, 3H, CH3), 2.09–2.20 (m, 1H, CH), 3.85 (s, 3H, OCH3), 4.16 (d,
3J = 6.8 Hz, CH2), 6.59 (d, 4J = 2.4 Hz, 1H, CH), 6.85 (d, 4J = 2.8 Hz,
1H, CH), 11.24 (s, 1H, OH). 13C NMR (100 MHz, CDCl3):
d
= 19.3
Methyl
3-ethyl-2-hydroxy-4-methoxy-6-(chlorodifluoro-
(CH3), 27.4 (CH), 55.8 (OCH3), 72.8 (CH2), 103.3 (C-3), 103.4 (C-
1), 107.8 (t, JC–F = 9.0 Hz, C-5), 124.9 (t, JC–F = 288.0 Hz, CF2Cl),
137.6 (t, JC–F = 26.0 Hz, C-6), 163.2, 164.5 (C), 169.7 (CO). 19F
methyl)benzoate (4h): Starting with 2a (0.200 g, 1 mmol), 1-
methoxy-1,3-bis(trimethylsilyloxy)-hexa-1,3-diene (3 h) (0.577 g,
2 mmol) and TiCl4 (0.11 mL, 1 mmol) in CH2Cl2 (2 mL), product 4 h
was isolated as a white solid (0.257 g, 89%); mp = 39–40 8C;
RF = 0.54 (n-hexane/CH2Cl2 = 3:2). 1H NMR (300 MHz, CDCl3):
NMR (282 MHz, CDCl3):
d
= ꢀ44.9 (s, CF2Cl). IR (ATR, cmꢀ1):
˜
n
= 3098 (w), 3012 (w), 2964 (w), 2914 (w), 2876 (w), 2850 (w),
1656 (m), 1614 (m), 1581 (m), 1377 (m), 1260 (s), 1146 (m),
1042 (s), 996 (s), 954 (s), 794 (s). GC–MS (EI, 70 eV): m/z (%): 308
(M+, 14), 252 (10), 236 (35), 235 (23), 234 (100), 171 (21). Anal.
calcd. for C13H15ClF2O4 (308.71): C, 50.58; H, 4.90. Found: C,
50.56; H, 4.90.
d
= 1.09 (t, 3J = 7.5 Hz, 3H, CH3), 2.70 (q, 3J = 7.5 Hz, 2H, CH2),
3.90 (s, 3H, OCH3), 3.95 (s, 3H, OCH3), 6.81 (s, 1H, H-5), 10.78 (s, 1-
H, OH). 13C NMR (75 MHz, CDCl3):
= 12.8 (CH3), 16.5 (CH2), 52.3,
d
55.8 (OCH3), 101.5 (t, JC–F = 9.5 Hz, C-5), 104.2 (t, JC–F = 1.8 Hz, C-1),
123.2 (C-3), 125.3 (t, JC–F = 289.8 Hz, CF2Cl), 134.9 (t, JC–F = 26.0 Hz,
C-6), 160.2, 160.3 (C), 170.2 (CO). 19F NMR (282 MHz, CDCl3):
Benzyl
2-hydroxy-4-methoxy-6-(chlorodifluoromethyl)-
˜
benzoate (4e): Starting with 2a (0.200 g, 1 mmol), 1-benzyloxy-
1,3-bis(trimethylsilyloxy)-1,3-butadiene (3e) (0.673 g, 2 mmol)
and TiCl4 (0.1 mL, 1 mmol) in CH2Cl2 (2 mL), product 4e was
isolated as a slightly yellow oil (0.170 g, 50%); RF = 0.42 (n-hexane/
d
= ꢀ44.5 (s, CF2Cl). IR (ATR, cmꢀ1):
n
= 3005 (w), 2968 (w), 2939
(w), 2877 (w), 2852 (w), 1667 (m), 1603 (m), 1579 (m), 1509 (w),
1438 (m), 1290 (s), 1235 (s), 1132 (s), 1105 (s), 980 (s), 802 (s). GC–
MS (EI, 70 eV): m/z (%): 294 (M+, 24), 262 (16), 242 (11), 227 (12),
226 (100). Anal. calcd. for C12H13ClF2O4 (294.68): C, 48.91; H, 4.45.
Found: C, 48.93; H, 4.663.
CH2Cl2 = 3:2). 1H NMR (300 MHz, CDCl3):
d = 3.83 (s, 3H, OCH3),
5.39 (s, 2H, CH2), 6.57 (d, 4J = 2.7 Hz, 1H, CH), 6.83 (d, 4J = 2.7 Hz,
1H, CH), 7.34–7.47 (m, 5H, Ph), 11.17 (s, 1H, OH). 13C NMR
Methyl 3-isopropyl-2-hydroxy-4-methoxy-6-(chlorodifluor-
omethyl)benzoate (4i): Starting with 2a (0.200 g, 1 mmol), 1-
methoxy-1,3-bis(trimethylsilyloxy)-5-methyl-hexa-1,3-diene (3i)
(0.605 g, 2 mmol) and TiCl4 (0.11 mL, 1 mmol) in CH2Cl2 (2 mL),
product 4i was isolated as a slight yellow oil (0.211 g, 69%);
RF = 0.51 (n-hexane/CH2Cl2 = 3:2). 1H NMR (300 MHz, CDCl3):
(75 MHz, CDCl3): d = 55.8 (OCH3), 68.2 (CH2), 103.1 (C-1), 103.3 (C-
3), 107.9 (t, JC–F = 6.75 Hz, C-5), 124.8 (t, JC–F = 216.0 Hz, CF2Cl),
128.5, 128.7, 129.3, 134.5 (Ph), 137.7 (t, JC–F = 19.5 Hz, C-6), 163.4
(C-2), 164.6 (C-4), 169.2 (CO). 19F NMR (282 MHz, CDCl3):
˜
d
= ꢀ44.8 (s, CF2Cl). IR (ATR, cmꢀ1):
n
= 3092 (w), 3067 (w),
3034 (w), 2934 (w), 2849 (w), 1657 (s), 1615 (s), 1376 (s), 1260 (s),
1146 (s), 1041 (s), 952 (s), 793 (s), 695 (s). GC–MS (EI, 70 eV): m/z
(%): 342 (M+, 15), 92 (9), 91 (100), 65 (7). Anal. calcd. for
C16H13ClF2O4 (342.72): C, 56.07; H, 3.82. Found: C, 56.26; H, 4.093.
d
= 1.10 (s, 3H, CH3), 1.13 (s, 3H, CH3), 2.26 (m, 3J = 6.7 Hz, 1H,
CH), 3.71 (s, 3H, OCH3), 3.77 (s, 3H, OCH3), 6.63 (s, 1H, H-5), 10.62
(s, 1H, OH). 13C NMR (300 MHz, CDCl3):
= 21.0 (CH), 23.6, 24.0
(CH3), 53.1, 56.91 (OCH3), 103.1 (t, 3JC–F = 36.0 Hz, C-5), 105.7 (C-1),
d

36
S. Reimann et al. / Journal of Fluorine Chemistry 139 (2012) 28–45
2
129.5 (CF2Cl), 127.5 (C-3), 136.1 (t, JC–F = 26.6 Hz, C-6), 161.8 (C-
Methyl
3-hexyl-2-hydroxy-4-methoxy-6-(chlorodifluoro-
2), 169.6 (C-4), 171.5 (CO). 19F NMR (300 MHz, CDCl3):
d
= ꢀ45.0 (s,
methyl)benzoate (4m): Starting with 2a (0.200 g, 1 mmol), 1-
methoxy-1,3-bis(trimethylsilyloxy)-1,3-decadiene (3m) (0.689 g,
2 mmol) and TiCl4 (0.1 mL, 1 mmol) in CH2Cl2 (2 mL), product 4m
was isolated as a colorless oil (0.105 g, 30%); RF = 0.41 (n-hexane/
˜
CF2Cl). IR (ATR, cmꢀ1):
n
= 2958 (w), 2903 (w), 2873 (w), 1702 (m),
1602 (w), 1437 (w), 1312 (w), 1235 (m), 1098 (s), 983 (m), 839 (m),
802 (w), 696 (w), 627 (m). GC–MS (EI, 70 eV): m/z (%): 308 (M+, 45),
275 (28), 237 (14), 236 (33), 235 (44), 171 (31), 157 (15). HRMS (EI,
70 eV): calcd. for C13H14ClO4F2 ([M+H]ꢀ) 307.0554, found
307.0561.
CH2Cl2 = 3:2). 1H NMR (300 MHz, CDCl3): = 0.92 (t, 3J = 6.8 Hz, 3H,
d
CH3), 1.28–1.51 (m, 8H, (CH2)4), 2.66 (t, 3J = 7.8 Hz, 2H, CH2Ar), 3.89
(s, 3H, OCH3), 3.95(s, 3H, OCH3), 6.81 (s, 1H, H-5), 10.77 (s, 1H, OH).
13C NMR (75 MHz, CDCl3):
d = 14.1 (CH3), 22.7, 23.1, 28.3, 29.5, 31.7
Methyl 3-npropyl-2-hydroxy-4-methoxy-6-(chlorodifluoro-
methyl)benzoate (4j): Starting with 2a (0.200 g, 1 mmol), 1-
methoxy-1,3-bis(trimethylsilyloxy)-hepta-1,3-diene (3j) (0.605 g,
2 mmol) and TiCl4 (0.11 mL, 1 mmol) in CH2Cl2 (2 mL), product 4j
was isolated as a slight yellow oil (0.198 g, 62%); RF = 0.59 (n-
(CH2), 52.3, 55.8 (OCH3), 101.4 (t, JC–F = 9.0 Hz, C-5), 104.2 (C-1),
122.1 (C-3), 125.3 (t, JC–F = 288.0 Hz, CF2Cl), 134.8 (t, JC–F = 25.5 Hz,
C-6), 160.4 (C-2), 160.5 (C-4), 170.2 (CO). 19F NMR (282 MHz,
˜
CDCl3):
d
= ꢀ44.5 (s, CF2Cl). IR (ATR, cmꢀ1):
n
= 3006 (w), 2955 (w),
hexane/CH2Cl2 = 3:2). 1H NMR (300 MHz, CDCl3):
d
= 0.75 (t,
2929 (w), 2857 (w), 1669 (s), 1604 (m), 1579 (w), 1510 (w), 1438
(s), 1402 (m), 1298 (s), 1236 (s), 979 (s), 801 (s), 693 (w). GC–MS
(EI, 70 eV): m/z (%): 350 (M+, 44), 319 (16), 315 (18), 301 (16), 289
(30), 288 (12), 287 (78), 283 (18), 282 (69), 261 (10), 250 (34), 249
(43), 248 (100), 247 (97), 230 (22), 228 (49), 213 (12), 212 (61), 209
(23), 197 (14), 181 (33). Anal. calcd. for C16H21ClF2O4 (350.79): C,
54.78; H, 6.03. Found: C, 54.75; H, 6.17.
3J = 7.2 Hz, 1H, 3H, CH3), 1.89 (m, 3J = 7.6 Hz, 2H, CH2), 2.48 (t,
3J = 7.8 Hz, 2H, CH2), 3.72 (s, 3H, OCH3), 3.77 (s, 3H, OCH3), 6.64 (s,
1H, H-5), 10.58 (s, 1H, OH). 13C NMR (300 MHz, CDCl3):
d = 15.3
(CH3), 21.7, 22.8 (CH2), 53.0, 57.0 (OCH3), 102.65 (t, 3JC–F = 36.0 Hz,
2
C-5), 105.4 (C-1), 126.5 (CF2Cl), 130.3 (C-3), 135.7 (t, JC–
F = 26.6 Hz, C-6), 161.6 (C-2), 169.67 (C-4), 171.4 (CO). 19F NMR
˜
(300 MHz, CDCl3):
d
= ꢀ44.9 (s, CF2Cl). IR (ATR, cmꢀ1):
n
= 2957
Ethyl
3-heptyl-2-hydroxy-4-methoxy-6-(chlorodifluoro-
(w), 2934 (w), 2873 (w), 1934 (m), 1604 (w), 1510 (w), 1437 (w),
1402 (m), 1288 (s), 1236 (m), 1135 (m), 1110 (w), 983 (m), 902 (s),
840 (w), 800 (m), 694 (w). GC–MS (EI, 70 eV): m/z (%): 308 (M+, 41),
276 (21), 237 (10), 236 (30), 235 (40), 171 (38), 157 (8). HRMS (EI,
70 eV): calcd. for C13H14ClO4F2 ([M+H]ꢀ) 307.0554, found 307.0561.
methyl)benzoate (4n): Starting with 2a (0.200 g, 1 mmol), 1-
ethoxy-1,3-bis(trimethylsilyloxy)-1,3-undecadiene (3n) (0.747 g,
2 mmol) and TiCl4 (0.1 mL, 1 mmol) in CH2Cl2 (2 mL), product 4n
was isolated as a colorless oil (0.110 g, 31%); RF = 0.69 (n-hexane/
CH2Cl2 = 3:2). 1H NMR (300 MHz, CDCl3): = 0.88 (t, 3J = 6.9 Hz, 3H,
d
Ethyl
3-ethyl-2-hydroxy-4-methoxy-6-(chlorodifluoro-
CH3), 1.26–1.55 (m, 13H, CH3, (CH2)5), 2.66 (t, 3J = 7.8 Hz, 2H, CH2),
3.89 (s, 3H, OCH3), 4.43 (q, 3J = 7.2 Hz, 2H, OCH2), 6.80 (s, 1H, H-5),
methyl)benzoate (4k): Starting with 2a (0.200 g, 1 mmol), 1-
ethoxy-1,3-bis(trimethylsilyloxy)-1,3-hexadiene (3k) (0.533 g,
2 mmol) and TiCl4 (0.1 mL, 1 mmol) in CH2Cl2 (2 mL), product
4k was isolated as a slight yellow oil (0.129 g, 42%); RF = 0.69 (n-
10.90 (s, 1H, OH). 13C NMR (75 MHz, CDCl3):
d = 13.7, 14.1 (CH3),
22.7, 23.1, 28.4, 29.2, 29.8, 31.9 (CH2), 55.8 (OCH3), 62.3 (OCH2),
101.4 (t, JC–F = 9.8 Hz, C-5), 104.4 (C-1), 121.5 (C-3), 125.3 (t, JC–
F = 288.0 Hz, CF2Cl), 134.8 (t, JC–F = 26.3 Hz, C-6), 160.4 (C-2), 160.5
(C-4), 169.9 (CO). 19F NMR (282 MHz, CDCl3):
(ATR, cmꢀ1):
1501 (w), 1396 (m), 1288 (s), 1235 (s), 1150 (w), 1111 (w), 1023
(m), 986 (s), 845 (w), 801 (m), 723 (w), 694 (m). GC–MS (EI, 70 eV):
m/z (%): 378 (M+, 36), 333 (18), 315 (20), 303 (31), 302 (13), 301
(84), 297 (16), 296 (76), 295 (17), 293 (10), 250 (34), 249 (38), 248
(100), 247 (80), 230 (22), 229 (14), 228 (48), 213 (13), 212 (58), 209
(11), 197 (10), 181 (29), 29 (9). Anal. calcd. for C18H25Cl1F2 O4
(378.81): C, 57.07; H, 6.65. Found: C, 57.26; H, 6.764.
Methyl
methyl)benzoate (4o): Starting with 2a (0.200 g, 1 mmol) and
1-methoxy-1,3-bis(trimethylsilyloxy)-dodeca-1,3-diene (3o)
heptane/EtOAc = 3:2). 1H NMR (300 MHz, CDCl3):
d = 1.10 (t,
3J = 7.5 Hz, 3H, CH3), 1.43 (t, 3J = 7.2 Hz, 3H, CH3), 2.70 (q,
3J = 7.2 Hz, 2H, CH2), 3.90 (s, CH3, OCH3), 4.43 (q, 3J = 7.2 Hz,
CH2), 6.81 (s, 1H, H-5), 10.91 (s, 1H, OH). 13C NMR (100 MHz,
d
= ꢀ44.1 (CF2Cl). IR
˜
n
= 2957 (w), 2926 (w), 2856 (w), 1664 (m), 1604 (w),
CDCl3):
d = 12.8, 13.7 (CH3), 16.5 (CH2), 55.8 (OCH3), 62.3 (CH2),
101.5 (t, JC–F = 9.0 Hz, C-5), 104.5 (C-1), 123.2 (C-3), 125.4 (t, JC–
F = 288.0 Hz, CF2Cl), 134.8 (t, JC–F = 26.0 Hz, C-6), 160.2 (C-2), 160.3
(C-4), 169.8 (CO). 19F NMR (282 MHz, CDCl3):
d
= ꢀ43.7 (s, CF2Cl).
˜
IR (ATR, cmꢀ1):
n
= 2970 (w), 2939 (w), 2908 (w), 2877 (w), 2849
(w), 1662 (s), 1603 (m), 1579 (m), 1508 (w), 1462 (m), 1396 (m),
1287 (s), 1235 (s), 1107 (s), 1057 (m), 973 (m), 897 (w), 804 (s), 659
(w). GC–MS (EI, 70 eV): m/z (%): 308 (M+, 21), 263 (10), 262 (18),
242 (11), 227 (13), 226 (100), 198 (7). Anal. calcd. for C13H15ClF2O4
(308.71): C, 50.58; H, 4.90. Found: C, 50.58; H, 5.049.
3-octyl-2-hydroxy-4-methoxy-6-(chlorodifluoro-
(0.745 g, 2 mmol) and TiCl4 (0.1 mL, 1 mmol) in CH2Cl2 (2 mL),
Ethyl
3-pentyl-2-hydroxy-4-methoxy-6-(chlorodifluoro-
product 4o was isolated as a colorless oil (0.207 g, 55%); RF = 0.60
methyl)benzoate (4l): Starting with 2a (0.200 g, 1 mmol), 1-
ethoxy-1,3-bis(trimethylsilyloxy)-1,3-nonadiene (3l) (0.717 g,
2 mmol) and TiCl4 (0.1 mL, 1 mmol) in CH2Cl2 (2 mL), product 4l
was isolated as a slight yellow oil (0.199 g, 57%); RF = 0.61 (n-
(n-hexane/CH2Cl2 = 3:2). 1H NMR (300 MHz, CDCl3):
d = 0.88 (t,
3J = 6.6 Hz, 3H, CH3), 1.27–1.30 (m, 10H, (CH2)5CH3), 1.43–1.51 (m,
2H, CH2), 2.66 (t, 3J = 7.6 Hz, 2H, CH2Ar), 3.89 (s, 3H, OCH3), 3.95 (s,
3H, OCH3), 6.81 (s, 1H, H-5), 10.78 (s, 1-H, OH). 13C NMR (75 MHz,
heptane/EtOAc = 3:2). 1H NMR (400 MHz, CDCl3):
d
= 0.89 (t,
CDCl3): d = 14.1 (CH3), 22.7, 23.1, 28.4, 29.3, 29.4, 29.5, 29.8, 31.9
3J = 6.9 Hz, 3H, CH3), 1.32–1.51 (m, 9H, CH3, (CH2)3), 2.66 (t,
3J = 7.8 Hz, 2H, CH2), 3.89 (s, 3H, OCH3), 4.43 (q, 3J = 7.2 Hz, 2H,
OCH2), 6.80 (s, 1H, H-5), 10.89 (s, 1H, OH). 13C NMR (100 MHz,
(CH2), 52.3, 55.8 (OCH3), 101.5 (t, JC–F = 9.4 Hz, C-5), 104.2 (t, JC–
F = 1.9 Hz, C-1), 122.1 (C-3), 125.3 (t, JC–F = 287.9 Hz, CF2Cl), 134.8
(t, JC–F = 25.7 Hz, C-6), 160.4, 160.5 (C), 170.2 (CO). 19F NMR
˜
CDCl3):
d
= 13.7, 14.0 (CH3), 22.5, 23.0, 28.1, 31.1, 31.9 (CH2), 55.8
(282 MHz, CDCl3):
d
= ꢀ44.5 (s, CF2Cl). IR (ATR, cmꢀ1):
n
= 3006
(OCH3), 62.3 (OCH2), 101.4 (t, JC–F = 10.0 Hz, C-5), 104.4 (C-1), 122.1
(C-3), 125.4 (t, JC–F = 288.0 Hz, CF2Cl), 134.8 (t, JC–F = 26.3 Hz, C-6),
(w), 2954 (w), 2925 (w), 2854 (w), 1668 (m), 1604 (m), 1579 (m),
1509 (w), 1438 (m), 1288 (s), 1235 (s), 1167 (m), 1146 (s), 1111 (s),
1092 (s), 982 (s), 801 (s). GC–MS (EI, 70 eV): m/z (%): 380 (12), 378
(M+, 35), 347 (14), 343 (17), 329 (15), 317 (27), 316 (13), 315 (77),
311 (28), 310 (78), 261 (11), 250 (35), 249 (43), 248 (100), 247 (96),
230 (20), 228 (48), 224 (11), 213 (12), 212 (59), 209 (23), 197 (13),
181 (29). Anal. calcd. for C18H25ClF2O4 (378.84): C, 57.07; H, 6.65.
Found: C, 57.24; H, 6.55.
160.4 (C-2), 160.5 (C-4), 169.9 (CO). 19F NMR (282 MHz, CDCl3):
˜
d
= ꢀ43.9 (s, CF2Cl). IR (ATR, cmꢀ1):
n
= 2957 (w), 2929 (w), 2859
(w), 1663 (m), 1604 (w), 1509 (w), 1465 (w), 1396 (m), 1287 (s),
1235 (m), 1150 (m), 1109 (w), 1023 (m), 988 (s), 844 (w), 801 (m),
726 (w), 694 (m). GC–MS (EI, 70 eV): m/z (%): 350 (M+, 36), 305
(17), 287 (24), 275 (43), 274 (16), 273 (100), 268 (57), 267 (16), 250
(31), 249 (36), 248 (91), 247 (78), 230 (22), 229 (13), 228 (47), 213
(12), 212 (59), 197 (11), 181 (28). Anal. calcd. for C16H21ClF2O4
(350.79): C, 54.78; H, 6.03. Found: C, 55.14; H, 6.422.
Methyl 3-dodecyl-2-hydroxy-4-methoxy-6-(chlorodifluoro-
methyl)benzoate (4p): Starting with 2a (0.200 g, 1 mmol),
1-methoxy-1,3-bis(trimethylsilyloxy)-hexadeca-1,3-diene
(3p)

S. Reimann et al. / Journal of Fluorine Chemistry 139 (2012) 28–45
37
(0.857 g, 2 mmol) and TiCl4 (0.1 mL, 1 mmol) in CH2Cl2 (2 mL),
product 4p was isolated as a colorless solid (0.179 g, 41%); mp = 47–
48 8C; RF = 0.73 (n-hexane/DCM = 3:2). 1H NMR (400 MHz, CDCl3):
CDCl3):
(t, 3J = 7.2 Hz, 2H, CH2), 3.57 (t, 3J = 6.9 Hz, 2H, CH2), 3.91 (s, 3H,
OCH3), 3.96 (s, 3H, OCH3), 6.80 (s, 1H, H-5), 10.84 (s, 1H, OH). 13
NMR (75 MHz, CDCl3): = 22.1, 25.6, 32.4, 45.0 (CH2), 52.4, 55.8
d = 1.61–1.71 (m, 2H, CH2), 1.76–1.86 (m, 2H, CH2), 2.71
C
d
= 0.88(t,3J = 6.9 Hz,3H,CH3),1.25–1.35(m,18H,(CH2)9CH3),1.44–
d
1.49 (m, 2H, CH2), 2.66 (t, 3J = 7.7 Hz, 2H, CH2Ar), 3.89 (s, 3H, OCH3),
(OCH3), 101.4 (t, JC–F = 9.8 Hz, C-5), 104.2 (C-1), 120.9 (C-3), 125.2
(t, JC–F = 288.0 Hz, CF2Cl), 135.2 (t, JC–F = 26.3 Hz, C-6), 160.5 (C-2),
3.95 (s, 3H, OCH3), 6.81 (s, 1H, H-5), 10.75 (s, 1-H, OH). 13C NMR
(100 MHz, CDCl3):
d
= 14.1 (CH3), 22.7, 23.1, 28.4, 29.4, 29.5, 29.6,
160.5 (C-4), 170.1 (CO). 19F NMR (282 MHz, CDCl3):
d
= ꢀ44.7 (s,
˜
29.7, 29.7, 29.831.9(CH2),52.3, 55.8(OCH3),101.5(t,JC–F = 9.3 Hz, C-
5), 104.2 (t, JC–F = 1.9 Hz, C-1), 122.1 (C-3), 125.3 (t, JC–F = 288.0 Hz,
CF2Cl). IR (ATR, cmꢀ1):
n
= 3011 (w), 2954 (w), 2865 (w), 1667 (m),
1604 (w), 1438 (m), 1284 (s), 1235 (s), 1144 (s), 1100 (s), 981 (s),
801 (s), 693 (w). GC–MS (EI, 70 eV): m/z (%): 357 (M+, 2), 356 (11),
291 (34), 290 (16), 289 (100), 249 (12), 247 (32). Anal. calcd. for
CF2Cl), 134.8 (t, JC–F = 25.5 Hz, C-6), 160.4, 160.5 (C), 170.2 (CO). 19
F
˜
NMR(282 MHz, CDCl3):
d
= ꢀ44.5(s, CF2Cl).IR(ATR,cmꢀ1):
n
= 3024
(w), 2953 (w), 2914 (s), 2849 (s), 1655 (m), 1606 (m), 1582 (m), 1499
(w), 1466 (m), 1438 (m), 1301 (s), 1242 (s), 1138 (s), 977 (s), 803 (m),
784 (m). GC–MS (EI, 70 eV): m/z (%): 434 (M+, 26), 403 (12), 399 (15),
385 (12), 373 (26), 372 (17), 371 (69), 367 (37), 366 (29), 261 (11),
250 (32), 249 (43), 248 (100), 247 (93), 230 (20), 228 (43), 224 (11),
213 (13), 212 (54), 209 (22), 197 (13), 182 (24), 43 (15), 41 (11). Anal.
Calcd.forC22H33ClF2O4 (434.94):C,60.75;H,7.65.Found:C,60.73;H,
7.56.
C
14H16Cl2F2O4 (357.18): C, 47.08; H, 4.52. Found: C, 47.02; H,
4.901.
Methyl
(chloro-difluoromethyl)benzoate (4t): Starting with 2a
(0.200 g, 1 mmol), 1-methoxy-1,3-bis(trimethylsilyloxy)-7-
2-hydroxy-4-methoxy-3-(4-chloropropyl)-6-
chloro-1,3-heptadiene (3t) (0.674 g, 2 mmol) and TiCl4 (0.1 mL,
1 mmol) in CH2Cl2 (2 mL), product 4t was isolated as a colorless oil
(0.122 g, 36%); RF = 0.50 (n-hexane/CH2Cl2 = 3:2). 1H NMR
Methyl
3-hexadecyl-2-hydroxy-4-methoxy-6-(chlorodi-
(300 MHz, CDCl3): d
= 1.95–2.05 (m, 2H, CH2), 2.82 (t, 3J = 7.8 Hz,
fluoromethyl)benzoate (4q): Starting with 2a (0.300 g,
1.5 mmol), 1-methoxy-1,3-bis(trimethylsilyloxy)-icosa-1,3-diene
(3q) (1.41 g, 3 mmol) and TiCl4 (0.16 mL, 1.5 mmol) in CH2Cl2
(3 mL), product 4q was isolated as a colorless solid (0.160 g, 30%);
mp = 63–64 8C; RF = 0.76 (n-hexane/CH2Cl2 = 3:2). 1H NMR
2H, CH2), 3.55 (t, 3J = 6.9 Hz, 2H, CH2), 3.91 (s, 3H, OCH3), 3.96 (s,
3H, OCH3), 6.80 (s, 1H, H-5), 10.87 (s, 1H, OH). 13C NMR (75 MHz,
CDCl3):
d = 20.7, 31.4, 44.9 (CH2), 52.4, 55.9 (OCH3), 101.4 (t, JC–
F = 9.8 Hz, C-5), 104.2 (C-1), 120.0 (C-3), 125.2 (t, JC–F = 288.0 Hz,
CF2Cl), 135.5 (t, JC–F = 26.3 Hz, C-6), 160.5 (C-2), 160.6 (C-4), 170.1
(300 MHz, CDCl3):
d
= 0.88 (t, 3J = 6.7 Hz, 3H, CH3), 1.25–1.31 (m,
(CO). 19F NMR (282 MHz, CDCl3):
d
= ꢀ44.7 (s, CF2Cl). IR (ATR,
˜
26H, (CH2)13CH3), 1.43–1.52 (m, 2H, CH2), 2.65 (t, 3J = 7.6 Hz, 2H,
cmꢀ1):
n
= 3007 (w), 2955 (w), 2851 (w), 1667 (m), 1605 (w), 1438
CH2Ar), 3.89 (s, 3H, OCH3), 3.95 (s, 3H, OCH3), 6.81 (s, 1H, H-5),
(m), 1291 (s), 1235 (s), 1144 (s), 1098 (s), 982 (s), 800 (s), 693 (w).
GC–MS (EI, 70 eV): m/z (%): 343 (M+, 1), 342 (11), 306 (17), 277
(34), 276 (14), 275 (100), 271 (12), 248 (16), 247 (18), 212 (11).
Anal. calcd. for C13H14Cl2F2O4 (343.15): C, 45.50; H, 4.11. Found: C,
45.59; H, 4.264.
10.77 (s, 1-H, OH). 13C NMR (75 MHz, CDCl3):
d = 14.1 (CH3), 22.7,
23.1, 28.4, 29.4, 29.5, 29.6, 29.7, 29.7, 29.8 31.9 (CH2), 52.3, 55.8
(OCH3), 101.5 (t, JC–F = 9.4 Hz, C-5), 104.2 (t, JC–F = 1.8 Hz, C-1),
122.1 (C-3), 125.3 (t, JC–F = 288.0 Hz, CF2Cl), 134.8 (t, JC–F = 25.8 Hz,
C-6), 160.4, 160.5 (C), 170.2 (CO). 19F NMR (282 MHz, CDCl3):
Methyl
2-hydroxy-3,4-dimethoxy-6-(chlorodifluoro-
˜
d
= ꢀ44.5 (s, CF2Cl). IR (ATR, cmꢀ1):
n
= 3022 (w), 2953 (w), 2913
methyl)benzoate (4u): Starting with 2a (0.200 g, 1 mmol), 1,4-
dimethoxy-1,3-bis(trimethylsilyloxy)-1,3-butadiene (3u) (0.581 g,
2 mmol) and TiCl4 (0.1 mL, 1 mmol) in CH2Cl2 (2 mL), product 4u
was isolated as a slightly yellow oil (0.126 g, 42%); RF = 0.64 (n-
(s), 2849 (s), 1655 (m), 1606 (m), 1582 (m), 1498 (w), 1466 (m),
1438 (m), 1304 (s), 1282 (s), 1138 (s), 985 (m), 975 (s), 803 (m), 784
(m). GC–MS (EI, 70 eV): m/z (%): 491 (M+, 5), 490 (18), 427 (26), 423
(10), 250 (30), 249 (32), 248 (100), 247 (67), 228 (21), 212 (28), 209
(13), 57 (15), 55 (15), 43 (31), 41 (17). Anal. calcd. for C26H41ClF2O4
(491,05): C, 63.59; H, 8.42. Found: C, 63.51; H, 8.427.
heptane/EtOAc = 3:2). 1H NMR (300 MHz, CDCl3):
OCH3), 3.95 (s, 3H, OCH3), 3.96 (s, 3H, OCH3), 6.84 (s, 1H, H-5), 9.20
(s, 1H, OH). 13C NMR (100 MHz, CDCl3):
= 52.6, 56.3, 60.9 (OCH3),
d = 3.94 (s, 3H,
d
Methyl
fluoromethyl)benzoate (4r): Starting with 2a (0.200 g, 1 mmol),
1- methoxy-1,3-bis(trimethylsilyloxy)-6-phenyl-1,3-hexadiene
2-hydroxy-4-methoxy-3-phenethyl-6-(chlorodi-
102.6 (t, JC–F = 8.0 Hz, C-5), 107.9 (C-1), 125.1 (t, JC–F = 288.0 Hz,
CF2Cl), 130.8 (t, JC–F = 27.0 Hz, C-6), 138.4 (C-3), 152.9, 154.3 (C),
168.3 (CO). 19F NMR (282 MHz, CDCl3):
d
= ꢀ45.1 (s, CF2Cl). IR (ATR,
˜
(3r) (0.577 g, 2 mmol) and TiCl4 (0.1 mL, 1 mmol) in CH2Cl2
(2 mL), product 4r was isolated as a colorless solid (0.144 g, 39%);
mp = 52–53 8C; RF = 0.62 (n-hexane/CH2Cl2 = 3:2). 1H NMR
cmꢀ1):
n
= 3333 (m), 3096 (w), 3008 (w), 2957 (w), 2853 (w), 1732
(s), 1612 (m), 1513 (w), 1431 (m), 1353 (m), 1278 (s), 1104 (m),
1023 (s), 982 (s), 874 (m), 808 (s), 739 (m), 689 (w). GC–MS (EI,
70 eV): m/z (%): 296 (M+, 45), 267 (11), 266 (28), 265 (34), 264 (79),
261 (11), 245 (14), 241 (24), 237 (11), 236 (26), 235 (23), 229 (21),
228 (100), 223 (11), 221 (31), 204 (12), 193 (9), 183 (11), 178 (23),
157 (12) 115 (11), 93 (14). Anal. calcd. for C11H11ClF2O4 (296.65): C,
44.54; H, 3.74. Found: C, 44.65; H, 4.050.
(300 MHz, CDCl3):
d
= 2.79 (t, 3J = 5.1 Hz, 2H, CH2), 2.97 (t,
3J = 5.1 Hz, 2H, CH2), 3.83 (s, 3H, OCH3), 3.96 (s, 3H, OCH3), 6.80
(s, 1H, H-5), 7.15–7.31 (m, 5H, Ph), 10.87 (s, 1H, OH). 13C NMR
(75 MHz, CDCl3): d = 25.3, 34.4 (CH2), 52.4, 55.8 (OCH3), 101.5 (t, JC–
F = 9.8 Hz, C-5), 104.2 (C-1), 120.9 (C-3), 125.3 (t, JC–F = 288.0 Hz,
CF2Cl), 128.2, 128.5, 129.1 (Ph), 135.2 (t, JC–F = 26.3 Hz, C-6), 160.5
(C-2), 160.5 (C-4), 169.9 (CO). 19F NMR (282 MHz, CDCl3):
Methyl 2-(difluoromethyl)-6-hydroxy-4-methoxybenzoate
(4v): Starting with 2b (0.166 g, 1.0 mmol), 1-methoxy-1,3-
bis(trimethylsilyloxy)-1,3-butadiene (3a) (0.521 g, 2.0 mmol)
and TiCl4 (0.1 mL, 1 mmol) in CH2Cl2 (5 mL), the product 4v was
isolated as a white solid (0.081 g, 35%); mp = 72–73 8C; RF = 0.70
˜
d
= ꢀ44.6 (s, CF2Cl). IR (ATR, cmꢀ1):
n
= 3087 (w), 3065 (w),
3028 (w), 3004 (w), 2960 (w), 2942 (w), 2849 (w), 1668 (s), 1579
(w), 1497 (w), 1440 (m), 1405 (m), 1297 (s), 1237 (m), 1099 (s),
1072 (m), 1013 (m), 973 (s), 892 (m), 841 (m), 799 (s), 749 (s), 698
(s). GC–MS (EI, 70 eV): m/z (%): 370 (M+, 12), 279 (21), 249 (33), 248
(11), 247 (100), 181 (12), 91 (19). Anal. calcd. for C18H17ClF2O4
(370.77): C, 58.31; H, 4.62. Found: C, 58.28; H, 4.657.
(heptane/EtOAc = 1:1). 1H NMR (250 MHz, CDCl3):
3H, OCH3), 6.55, 6.88 (d, 4J = 2.4 Hz, 1H, CH), 7.24 (t, 2J = 55.6 Hz,
1H, CF2H), 11.60 (s, 1H, OH). 13C NMR (63 MHz, CDCl3):
= 52.5,
d = 3.85, 3.97 (s,
d
55.7 (OCH3), 102.7 (t, JC–F = 1.6 Hz, C-3), 102.8 (bs, C-1), 106.7 (t, JC–
F = 10.5 Hz, C-5), 111.9 (t, JC–F = 237.7 Hz, CF2H), 136.9 (t, JC–
Methyl 2-hydroxy-4-methoxy-3-(4-chlorobutyl)-6-(chlor-
odi- fluoromethyl)benzoate (4s): Starting with 2a (0.200 g,
F = 21.4 Hz, C-6), 164.5, 165.4, 170.2 (C). 19F NMR (282 MHz,
2
1 mmol),
1-methoxy-1,3-bis(trimethylsilyloxy)-8-chloro-1,3-
CDCl3):
d
= ꢀ113.3 (2F, d, JF–H = 56.4 Hz, CF2H). IR (ATR, cmꢀ1):
˜
octadiene (3s) (0.702 g, 2 mmol) and TiCl4 (0.1 mL, 1 mmol) in
CH2Cl2 (2 mL), product 4s was isolated as a colorless oil (0.122 g,
35%); RF = 0.52 (n-hexane/CH2Cl2 = 3:2). 1H NMR (300 MHz,
n = 3097 (w), 2950 (w), 2923 (w), 2848 (w), 1652 (s), 1620 (s), 1583
(s), 1519 (w), 1436 (s) 1259 (s), 999,6 (s), 752 (s). MS (EI, 70 eV): m/
z (%): 232 (M+, 41), 201 (21), 200 (100), 172 (34), 157 (21). HRMS

38
S. Reimann et al. / Journal of Fluorine Chemistry 139 (2012) 28–45
(EI, 70 eV): calcd. for C10H10F2O4 (M+) 232.05417, found
232.05483.
58.9 (OCH3), 64.5, 69.8 (CH2), 102.6 (bs, C-3), 103.0 (t, JC–F = 4.5 Hz,
C-1), 106.7 (t, JC–F = 10.5 Hz, C-5), 112.0 (t, JC–F = 237.5 Hz, CF2H),
137.3 (t, JC–F = 21.5 Hz, C-6), 164.5, 165.3, 169.4 (C). 19F NMR
Ethyl
2-(difluoromethyl)-6-hydroxy-4-methoxybenzoate
(4w): Starting with 2b (0.166 g, 1.0 mmol), 1-ethoxy-1,3-bis(tri-
methylsilyloxy)-1,3-butadiene (3b) (0.549 g, 2.0 mmol) and TiCl4
(0.1 mL, 1.0 mmol) in CH2Cl2 (5 mL), the product 4b was isolated as
a white solid (0.082 g, 33%); mp = 71–72 8C; RF = 0.60 (n-heptane/
(282 MHz, CDCl3):
d
= ꢀ113.1 (2F, d, 2JF–H = 56.4 Hz, CF2H). IR (ATR,
˜
cmꢀ1):
n = 3339 (w), 3095 (w), 2995 (w), 2922 (w), 2852 (w), 2820
(w), 1649 (s), 1613 (s), 1590 (s), 1488 (w), 1436 (s), 1372 (s), 1258
(s), 1205 (s), 1107 (s), 1024 (s), 995 (s), 755 (s), 543 (s). GC–MS (EI,
70 eV): m/z (%): 276 (M+, 27), 218 (12), 201 (41), 200 (100), 172
(18). HRMS (EI, 70 eV): calcd. for C12H14F2O5 (M+) 276.08038,
found 276.08054.
EtOAc = 3:2). 1H NMR (300 MHz, CDCl3): = 1.43 (t, 3J = 7.0 Hz, 3H,
d
CH3), 3.85 (s, 3H, OCH3), 4.44 (q, 3J = 7.2 Hz, 2H, CH2), 6.55, 6.88 (d,
4J = 2.7 Hz, 1H, CH), 7.28 (t, 2J = 55.5 Hz, 1H, CF2H), 11.71 (s, 1H,
OH). 13C NMR (75 MHz, CDCl3):
d
= 13.9 (CH3), 55.6 (OCH3), 62.0
n-Butyl 2-(difluoromethyl)-6-hydroxy-4-methoxybenzoate
(4aa): Starting with 2b (0.166 g, 1.0 mmol), 1-butoxy-1,3-bis(-
trimethylsilyloxy)-1,3-butadiene (3v) (0.605 g, 2.0 mmol) and
TiCl4 (0.1 mL, 1.0 mmol) in CH2Cl2 (5 mL), the product 4aa was
isolated as a white solid (0.101 g, 37%); mp = 43 8C. 1H NMR
(CH2), 102.7 (t, JC–F = 1.5 Hz, C-3), 103.1 (t, JC–F = 4.4 Hz, C-1), 106.6
(t, JC–F = 10.5 Hz, C-5), 111.9 (t, JC–F = 237.7 Hz, CF2H), 136.9 (t, JC–
F = 21.3 Hz, C-6), 164.4, 165.5, 169.7 (C). 19F NMR (282 MHz,
2
CDCl3):
n
d
= ꢀ113.2 (2F, d, JF–H = 56.4 Hz, CF2H). IR (ATR, cmꢀ1):
˜
= 3094 (w), 2983 (w), 2925 (w), 2854 (w), 1649 (m), 1617 (m),
(250 MHz, CDCl3): d
= 0.99 (t, 3J = 7.3 Hz, 3H, CH3), 1.40–1.54 (m,
1589 (m), 1527 (w), 1445 (m), 1370 (s), 1255 (s), 996 (s), 862 (s),
624 (s), 411 (s). GC–MS (EI, 70 eV): m/z (%): 246 (M+, 31), 201 (22),
200 (100), 172 (31), 157 (15). HRMS (EI, 70 eV): calcd. for
2H, CH2), 1.73–1.84 (m, 2H, CH2), 3.85 (s, 3H, OCH3), 4.39 (t,
3J = 6.7 Hz, 2H, OCH2), 6.55 (d, 4J = 2.7 Hz, 1H, CH), 6.88 (d,
4J = 2.7 Hz, 1H, CH), 7.26 (t, 2J = 55.6 Hz, 1H, CF2H) 11.74 (s, 1H,
OH). 13C NMR (63 MHz, CDCl3):
d = 13.6 (CH3), 19.2, 30.4 (CH2),
C
11H12F2O4 (M+) 246.06982, found 246.07028.
Benzyl 2-(difluoromethyl)-6-hydroxy-4-methoxybenzoate
55.6 (OCH3), 66.0 (OCH2), 102.8 (C-3), 103.1 (t, JC–F = 4.3 Hz, C-1),
106.6 (t, JC–F = 10.8 Hz, C-5), 111.9 (t, JC–F = 239.2 Hz, CF2H), 136.9
(4x): Starting with 2b (0.166 g, 1.0 mmol), 1-benzyloxy-1,3-
bis(trimethylsilyloxy)-1,3-butadiene (2e) (0.673 g, 2.0 mmol)
and TiCl4 (0.1 mL, 1.0 mmol) in CH2Cl2 (5 mL), the product 4x
was isolated as a yellow oil (0.091 g, 30%); RF = 0.62 (n-heptane/
(t, JC–F = 21.5 Hz, C-6), 164.4, 165.5, 169.9 (C). 19F NMR (282 MHz,
2
CDCl3):
n
d
= ꢀ113.4 (2F, d, JF–H = 56.4 Hz, CF2H). IR (ATR, cmꢀ1):
˜
= 2962 (w), 2937 (w), 2875 (w), 1724 (w), 1658 (s), 1618 (s), 1582
EtOAc = 3:2). 1H NMR (300 MHz, CDCl3):
d
= 3.84 (s, 3H, OCH3),
(m), 1504 (w), 1463 (m), 1444 (m), 1433 (m), 1396 (m), 1372 (s),
1330 (s), 1249 (s), 1205 (s), 1162 (s), 1108 (s), 1051 (m), 1032 (s),
1002 (s), 954 (s), 843 (m), 757 (s). GC–MS (EI, 70 eV): m/z (%): 274
(M+, 21), 201 (20), 200 (100), 172 (18), 157 (8), 153 (8). Anal. calcd.
for C13H16F2O4 (274.26): C, 56.93; H, 5.88. Found: C, 57.19; H, 5.95.
General procedure (II) for the synthesis of 4 v,w,y,ab,ac: The
reaction was carried out in a pressure tube. To a benzene
suspension (10 mL/1 mmol of 4) of 4 (1 mmol) was added Bu3SnH
(1.2 mmol) and AIBN (azobisisobutyronitrile) (0.12 mmol) and the
resultant solution was degassed by bubbling argon through the
solution for 5 min. The mixture was heated up to 90 8C under
Argon atmosphere for 20 h with stirring. The temperature of the
solution was allowed to warm to room temperature. The pressure
tube was rinsed with benzene and the organic solution was
concentrated in vacuo. The residue was purified by a column
chromatography (n-heptane/EtOAc).
5.40 (s, 2H, CH2), 6.55 (d, 4J = 2.7 Hz, 1H, CH), 6.84 (d, 4J = 2.7 Hz,
1H, CH), 7.20 (t, 2J = 57.0 Hz, 1H, CF2H), 7.37–7.47 (m, 5H, Ph),
11.65 (s, 1H, OH). 13C NMR (100 MHz, CDCl3):
d = 55.6 (OCH3), 67.9
(CH2), 102.7 (bs, C-3), 102.8 (t, JC–F = 4.0 Hz, C-1), 106.8 (t, JC–
F = 11.0 Hz, C-5), 111.7 (t, JC–F = 237.5 Hz, CF2H), 128.6, 128.8, 134.5
(Ph), 137.0 (t, JC–F = 21.5 Hz, C-6), 164.5, 165.6, 169.5 (C). 19F NMR
(282 MHz, CDCl3):
d
= ꢀ113.0 (2F, d, 2JF–H = 56.4 Hz, CF2H). IR (ATR,
˜
cmꢀ1):
n = 3066 (w), 3033 (w), 2959 (w), 2852 (w), 1655 (s), 1618
(s), 1581 (m), 1498 (w), 1441 (w), 1373 (s), 1248 (s), 1161 (s), 1030
(s), 951 (s), 749 (s), 695 (s). GC–MS (EI, 70 eV): m/z (%): 308 (M+,
18), 91 (100). HRMS (EI, 70 eV): calcd. for C16H14F2O4 (M+)
308.08547, found 308.08601.
Isopropyl 2-(difluoromethyl)-6-hydroxy-4-methoxybenzo-
ate (4y): Starting with 2b (0.166 g, 1.0 mmol), 1-isopropyloxy-
1,3-bis(trimethylsilyloxy)-1,3-butadiene (3c) (0.577 g, 2.0 mmol)
and TiCl4 (0.1 mL, 1.0 mmol) in CH2Cl2 (5 mL), the product 4y was
isolated as a yellow oil (0.151 g, 58%); RF = 0.57 (n-heptane/
Methyl 2-(difluoromethyl)-6-hydroxy-4-methoxybenzoate
(4v): Starting with 4a (0.266 g, 1.0 mmol), Bu3SnH (0.349 g,
1.2 mmol), AIBN (0.020 g, 0.12 mmol), the product 4v was isolated
as a white solid (0.204 g, 88%); mp = 72–73 8C; RF = 0.60 (heptane/
EtOAc = 3:2). Product 4v was analytically characterized.
EtOAc = 3:2). 1H NMR (300 MHz, CDCl3):
d = 1.40 (s, 3H, CH3), 1.42
(s, 3H, CH3), 3.84 (s, 3H, OCH3), 5.26 ꢀ 5.38 (m, 1H, CH), 6.54 (d,
4J = 2.7 Hz, 1H, CH), 6.84 (d, 4J = 2.7 Hz, 1H, CH), 7.28 (t, 2J = 55.5 Hz,
1H, CF2H), 11.79 (s, 1H, OH). 13C NMR (75 MHz, CDCl3):
d
= 21.7
Ethyl
2-(difluoromethyl)-6-hydroxy-4-methoxybenzoate
(CH3), 55.6 (OCH3), 70.4 (CH), 102.7 (bs, C-3), 103.5 (t, JC–F = 4.1 Hz,
C-1), 106.5 (t, JC–F = 10.5 Hz, C-5), 111.8 (t, JC–F = 237.7 Hz, CF2H),
137.0 (t, JC–F = 21.3 Hz, C-6), 164.3, 165.5, 169.3 (C). 19F NMR
(4w): Starting with 4b (0.246 g, 1.0 mmol), Bu3SnH (0.349 g,
1.2 mmol), AIBN (0.020 g, 0.12 mmol), the product 4w was isolated
as a white solid (0.214 g, 87%); mp = 71–72 8C; RF = 0.62 (heptane/
EtOAc = 3:2). Product 4w was analytically characterized.
Isopropyl 2-(difluoromethyl)-6-hydroxy-4-methoxybenzo-
ate (4y): Starting with 4c (0.294 g, 1.0 mmol), Bu3SnH (0.349 g,
1.2 mmol), AIBN (0.020 g, 0.12 mmol), the product 4y was isolated
as a colorless oil (0.126 g, 48%); RF = 0.67 (heptane/EtOAc = 3:2).
Product 4y was analytically characterized.
(282 MHz, CDCl3):
d
= ꢀ113.1 (2F, d, 2JF–H = 56.4 Hz, CF2H). IR (ATR,
˜
cmꢀ1):
n
= 3062 (w), 2983 (w), 2935 (w), 2853 (w), 1654 (s), 1617
(s), 1583 (m), 1444 (w), 1360 (s), 1254 (s), 1098 (s), 1032 (s), 954
(s), 757 (s). GC–MS (EI, 70 eV): m/z (%): 260 (M+, 17), 218 (17), 201
(20), 200 (100), 172 (22). Anal. calcd. for C12H14F2O4 (260.23): C,
55.38; H, 5.42. Found: C, 55.77; H, 5.74.
2-Methoxyethyl 2-(difluoromethyl)-6-hydroxy-4-methoxy-
benzoate (4z): Starting with 2b (0.166 g, 1.0 mmol), 1-(2-
Methyl 2-(difluoromethyl)-6-hydroxy-4-methoxy-3-propyl-
benz oate (4ab): Starting with 4i (0.308 g, 1.0 mmol), Bu3SnH
(0.349 g, 1.2 mmol), AIBN (0.020 g, 0.12 mmol), the product 4ab
was isolated as a colorless oil (0.126 g, 46%); RF = 0.61 (heptane/
methoxyethoxy)-1,3-bis(trimethylsilyloxy)-1,3-butadiene
(3f)
(0.609 g, 2.0 mmol) and TiCl4 (0.1 mL, 1.0 mmol) in CH2Cl2
(5 mL), the product 4z was isolated as a white solid (0.082 g,
30%); mp = 63–64 8C; RF = 0.61 (n-heptane/EtOAc = 3:2). 1H NMR
EtOAc = 3:2). 1H NMR (300 MHz, CDCl3):
(s, 3H, CH3), 3.57 (t, 3J = 7.0 Hz, 1H, CH), 3.81 (s, 3H, OCH3), 3.83 (s,
3H, OCH3), 6.78 (s, 1H, H-5), 11.59 (s, 1H, OH), 12.56 (s, 1H, CF2). 13
NMR (300 MHz, CDCl3): = 14.1 (CH3), 22.7, 23.1, 28.4, 29.5, 29.8,
d = 1.22 (s, 3H, CH3), 1.25
(300 MHz, CDCl3):
d
= 3.43 (s, 3H, OCH3), 3.72 (t, 3J = 4.8 Hz, 2H,
C
CH2), 3.85 (s, 3H, OCH3), 4.50 (t, 3J = 4.8 Hz, 2H, CH2), 6.54 (d,
4J = 2.7 Hz, 1H, CH), 6.89 (d, 4J = 2.7 Hz, 1H, CH), 7.31 (t, 2J = 55.3 Hz,
d
3
31.9 (CH2), 52.3, 55.8 (OCH3), 101.5 (t, JC–F = 36.0 Hz, C-5), 104.2
(C-1), 121.5 (CF2), 125.3 (C-3), 134.8 (t, 2JC–F = 102.0 Hz, C-6), 160.4
1H, CF2H), 11.47 (s, 1H, OH). 13C NMR (75 MHz, CDCl3):
d = 55.6,

S. Reimann et al. / Journal of Fluorine Chemistry 139 (2012) 28–45
39
(C-2), 160.5 (C-4), 170.19 (CO). 19F NMR (282 MHz, CDCl3):
70 eV): m/z (%): 266 (M+, 64), 221 (25), 203 (36), 196 (31), 195 (12),
194 (100), 165 (30), 157 (10), 109 (20), 69 (42), 52 (11), 29 (55).
Anal. calcd. for C10H9ClF2O4 (266.63): C, 45.05; H, 3.40. Found: C,
44.96; H, 3.88.
Isopropyl 2-(4-oxo-6-(chlorodifluoromethyl)-4H-pyran-2-
yl)acetate (5c): Starting with 2a (0.200 g, 1 mmol), 1-isopropy-
˜
2
d
= ꢀ112.5 (2F, d, JF–H = 56.4 Hz, CF2H). IR (ATR, cmꢀ1):
n
= 2960
(w), 2904(w), 2874 (w), 1699 (m), 1604 (w), 1308 (w), 1234 (m),
1095 (s), 840 (m), 802 (w), 696 (w), 626 (m). GC–MS (EI, 70 eV): m/
z (%): 274 (M+, 22), 201 (20), 200 (98), 170 (24), 157 (10). HRMS (EI,
70 eV): calcd. for C13H16F2O4 (M+) 274.10167, found 274.10162.
Methyl 2-(difluoromethyl)-6-hydroxy-4-methoxy-3-octyl-
benzoate (4ac): Starting with 4o (0.308 g, 1.0 mmol), Bu3SnH
(0.349 g, 1.2 mmol), AIBN (0.020 g, 0.12 mmol), the product 4ac
was isolated as a colorless oil (0.175 g, 51%); RF = 0.67 (heptane/
loxy-1,3-bis(trimethylsilyloxy)-1,3-butadiene
(3c)
(0.577 g,
2 mmol) and Me3SiOTf (0.181 mL, 1 mmol) in CH2Cl2 (10 mL),
product 5c was isolated as a slightly yellow oil (0.142 g, 51%);
RF = 0.35 (n-heptane/EtOAc = 3:2). 1H NMR (400 MHz, CDCl3):
EtOAc = 3:2). 1H NMR (300 MHz, CDCl3):
d
= 0.80 (t, 3J = 7,14 Hz,
d
= 1.26, 1.27 (s, 3H, CH3), 3.59 (s, 2H, CH2), 5.06–5.12 (m, 1H, CH),
6.35 (d, 4J = 2.4 Hz, 1H, CH), 6.63 (d, 4J = 2.4 Hz, 1H, CH). 13C NMR
(75 MHz, CDCl3): = 21.6, 21.7 (CH3), 39.7 (CH2), 70.0 (OCH), 112.6
3H, CH3), 1.14–1.44 (m, 12H, (CH2)6), 2.47 (t, 3J = 7.5 Hz, 2H, CH2),
2.62 (t, 3J = 7.7 Hz, 2H, CH2), 3.82 (s, 3H, OCH3), 3.87 (s, 3H, OCH3),
6.74 (s, 1H, H-5), 10.68 (s, 1H, OH), 11.64 (s, 1H, CF2). 13C NMR
d
(t, JC–F = 3.0 Hz, C-5), 117.2 (C-3), 120.1 (t, JC–F = 288.8 Hz, CF2Cl),
156.4 (t, JC–F = 33.8 Hz, C-6), 161.7, 166.0, 177.9 (C). 19F NMR
(75 MHz, CDCl3):
d
= 14.1 (CH3), 22.67, 23.1, 28.4, 29.5, 29.8, 31.9
˜
(CH2), 52.3, 55.8 (OCH3), 101.5 (t, 3JC–F = 36.0 Hz, C-5), 104.2 (C-1),
121.5 (CF2), 125.3 (C-3), 134.8 (t, 2JC–F = 102.0 Hz, C-6), 160.4 (C-2),
(282 MHz, CDCl3):
d
= ꢀ59.8 (s, CF2Cl). IR (ATR, cmꢀ1):
n
= 3367
(w), 3085 (w), 2983 (w), 2940 (w), 2881 (w), 1734 (m), 1668 (s),
1617 (m), 1232 (m), 1159 (m), 1102 (s), 1082 (s), 928 (s), 813 (m).
GC–MS (EI, 70 eV): m/z (%): 280 (M+, 19), 223 (16), 221 (47), 217
(19), 196 (18), 194 (54), 193 (11), 167 (10), 165 (31), 69 (21), 43
(100), 41 (19). Anal. calcd. for C11H11ClF2O4 (280.65): C, 47.08; H,
3.95. Found: C, 47.26; H, 4.305.
160.5 (C-4), 170.2 (CO). 19F NMR (282 MHz, CDCl3):
d
= ꢀ112.5 (2F,
˜
2
d, JF–H = 56.4 Hz, CF2H). IR (ATR, cm ꢀ 1):
n
= 2959 (w), 2903(w),
2874 (w), 1700 (m), 1612 (w), 1608 (w), 1234 (m), 1180 (m), 1144
(m), 1130 (m), 1109 (m), 1099 (m), 1082 (s), 840 (m), 802 (w), 693
(w), 627 (m). GC–MS (EI, 70 eV): m/z (%): 344 (M+, 33), 322 (33),
298 (12), 256 (13), 223(22), 201 (20), 200 (98), 170 (24), 157 (10).
HRMS (EI, 70 eV): calcd. for C13H16F2O4 (M+) 344.17992, found
344.17986.
Isobutyl
yl)acetate (5d): Starting with 2a (0.200 g, 1 mmol), 1-isobuty-
loxy-1,3-bis(trimethylsilyloxy)-1,3-butadiene (3d) (0.605 g,
2-(4-oxo-6-(chlorodifluoromethyl)-4H-pyran-2-
General procedure for the synthesis of 5a–m and 6a–k: To a
CH2Cl2 solution (10 mL/1 mmol of 2) of 2 (1 mmol) was added 3
(2 mmol) and, subsequently, Me3SiOTf (0.18 mL, 1 mmol) at
ꢀ78 8C. The temperature of the solution was allowed to warm
up to 20 8C during 12–14 h with stirring. To the solution was added
hydrochloric acid (10%, 20 mL) and the organic and the aqueous
layer were separated. The latter was extracted with CH2Cl2
(3 ꢄ 15 mL). The combined organic layers were dried (Na2SO4),
filtered and the filtrate was concentrated in vacuo. The residue was
purified by chromatography.
2 mmol) and Me3SiOTf (0.181 mL, 1 mmol) in CH2Cl2 (10 mL),
product 5d was isolated as a slightly yellow oil (0.126 g, 43%);
RF = 0.44 (n-heptane/EtOAc = 3:2). 1H NMR (300 MHz, CDCl3):
d
= 0.91, 0.94 (s, 3H, CH3), 1.88–1.99 (m, 1H, CH), 3.64 (s, 2H, CH2),
3.97 (d, 3J = 6.6, 2H, CH2), 6.36 (d, 4J = 2.1 Hz, 1H, CH), 6.64 (d,
4J = 2.1 Hz, 1H, CH). 13C NMR (75 MHz, CDCl3):
= 18.9, 19.2 (CH3),
d
27.6 (CH), 39.3 (CH2), 72.1 (OCH2), 112.6 (t, JC–F = 3.0 Hz, C-5),
117.3 (C-3), 120.1 (t, JC–F = 288.8 Hz, CF2Cl), 156.4 (t, JC–F = 33.8 Hz,
C-6), 161.5, 166.5, 177.8 (C). 19F NMR (282 MHz, CDCl3):
d
= ꢀ59.7
˜
(s, CF2Cl). IR (ATR, cmꢀ1):
n
= 3078 (w), 2959 (w), 2921 (w), 2875
Methyl 2-(4-oxo-6-(chlorodifluoromethyl)-4H-pyran-2-yl)a-
cetate (5a): Starting with 2a (0.200 g, 1 mmol), 1-methoxy-1,3-
bis(trimethylsilyloxy)-1,3-butadiene (3a) (0.520 g, 2 mmol) and
Me3SiOTf (0.181 mL, 1 mmol) in CH2Cl2 (10 mL), product 5a was
isolated as a yellow oil (0.079 g, 32%); RF = 0.23 (n-heptane/
(w), 2851 (w), 1739 (m), 1672 (s), 1641 (m), 1618 (m), 1397 (m),
1233 (m), 1152 (s), 1082 (s), 991 (s), 963 (s), 929 (s), 876 (s), 824 (s),
720 (w). GC–MS (EI, 70 eV): m/z (%): 294 (M+, 7), 241 (35), 240 (11),
239 (100), 231 (20), 221 (21), 196 (20), 194 (60), 167 (12), 130 (12),
69 (27), 57 (70), 56 (16), 43 (10), 41 (48), 39 (13), 29 (18). HRMS (EI,
70 eV): calcd. for C12H13ClF2O4 (M+): 294.04649. Found:
294.046922.
EtOAc = 3:2). 1H NMR (300 MHz, CDCl3):
(s, 3H, OCH3), 6.36 (d, 4J = 2.1 Hz, 1H, CH), 6.65 (d, 4J = 2.1 Hz, 1H,
CH). 13C NMR (75 MHz, CDCl3):
= 39.0 (CH2), 52.9 (OCH3), 112.6
d = 3.65 (s, 2H, CH2), 3.79
d
2-Methoxyethyl 2-(4-oxo-6-(chlorodifluoromethyl)-4H-py-
ran-2-yl)acetate (5e)
(t, JC–F = 3.0 Hz, C-5), 116.2 (C-3), 120.0 (t, JC–F = 288.8 Hz, CF2Cl),
156.4 (t, JC–F = 33.8 Hz, C-6), 161.3, 166.9, 177.8 (C). 19F NMR
Starting with 2a (0.200 g, 1 mmol), 1-(2-methoxyethyl)-1,3-
bis(trimethylsilyloxy)-1,3-butadiene (3f) (0.609 g, 2 mmol) and
Me3SiOTf (0.181 mL, 1 mmol) in CH2Cl2 (10 mL), product 5e was
isolated as a yellow oil (0.148 g, 50%); RF = 0.15 (n-heptane/
˜
(282 MHz, CDCl3):
d
= ꢀ59.9 (s, CF2Cl). IR (ATR, cmꢀ1):
n
= 3082
(w), 2957 (w), 2921 (w), 2850 (w), 1743 (s), 1668 (s), 1639 (m),
1615 (m), 1400 (m), 1233 (m), 1152 (s), 1081 (s), 927 (s), 876 (m),
823 (s), 749 (w). GC–MS (EI, 70 eV): m/z (%): 252 (M+, 100), 210
(14), 208 (40), 189 (47), 165 (29), 147 (16), 130 (25), 123 (27), 101
(10), 95 (19), 80 (11), 69 (39), 59 (72). Anal. calcd. for C9H7ClF2O4
(252.60): C, 42.79; H, 2.79. Found: C, 42.79; H, 2.974.
EtOAc = 3:2). 1H NMR (300 MHz, CDCl3):
d = 3.38 (s, 2H, CH2), 3.61
(t, 3J = 4.8, 2H, CH2), 3.68 (s, 3H, OCH3), 4.34 (t, 3J = 4.5, 2H, OCH2),
6.37 (d, 4J = 2.4 Hz, 1H, CH), 6.64 (d, 4J = 2.4 Hz, 1H, CH). 13C NMR
(75 MHz, CDCl3):
d = 39.0 (CH2), 59.0 (OCH3), 64.9 (CH2, OCH2),
Ethyl 2-(4-oxo-6-(chlorodifluoromethyl)-4H-pyran-2-yl)a-
cetate (5b): Starting with 2a (0.200 g, 1 mmol), 1-ethoxy-1,3-
bis(trimethylsilyloxy)-1,3-butadiene (3b) (0.548 g, 2 mmol) and
Me3SiOTf (0.181 mL, 1 mmol) in CH2Cl2 (10 mL), product 5b was
isolated as a yellow oil (0.118 g, 44%); RF = 0.27 (n-heptane/
70.0 (CH2, CH2OCH3), 112.6 (t, JC–F = 3.0 Hz, C-5), 117.4 (C-3), 120.1
(t, JC–F = 288.8 Hz, CF2Cl), 156.4 (t, JC–F = 33.8 Hz, C-6), 161.2, 166.6,
177.8 (C). 19F NMR (282 MHz, CDCl3):
d
= ꢀ59.8 (s, CF2Cl). IR (ATR,
˜
cmꢀ1):
n
= 3081 (w), 2952 (w), 2920 (w), 2850 (w), 1741 (m), 1669
(s), 1639 (m), 1399 (m), 1236 (m), 1155 (m), 1080 (s), 990 (s), 927
(s), 876 (m), 821 (m), 668 (m). GC–MS (EI, 70 eV): m/z (%): 296 (M+,
29), 238 (11), 230 (15), 196 (27), 194 (81), 167 (13), 165 (39), 161
(36), 157 (10), 130 (16), 99 (10), 69 (32), 59 (15), 58 (42), 45 (100),
43 (12), 31 (10), 29 (18). Anal. calcd. for C11H11ClF2O5 (296.65): C,
44.54; H, 3.74. Found: C, 44.97; H, 3.945.
EtOAc = 3:2). 1H NMR (300 MHz, CDCl3):
d
= 1.29 (t, 3J = 6.9, 3H,
CH3), 3.62 (s, 2H, CH2), 4.24 (q, 3J = 7.2, 3H, OCH2), 6.35 (d,
4J = 2.1 Hz, 1H, CH), 6.64 (d, 4J = 2.1 Hz, 1H, CH). 13C NMR (75 MHz,
CDCl3):
d = 14.1 (CH3), 39.3 (CH2), 62.2 (OCH2), 112.6 (t, JC–
F = 2.3 Hz, C-5), 117.3 (C-3), 120.1 (t, JC–F = 288.8 Hz, CF2Cl), 156.4
(t, JC–F = 33.8 Hz, C-6), 161.5, 166.5, 177.8 (C). 19F NMR (282 MHz,
Ethyl
2-(6-(difluoromethyl)-4-oxo-4H-pyran-2-yl)acetate
˜
CDCl3):
d
= ꢀ59.9 (s, CF2Cl). IR (ATR, cmꢀ1):
n
= 3080 (w), 2948 (w),
(5f): Starting with 2b (0.166 g, 1.0 mmol), 1-ethoxy-1,3-bis(tri-
methylsilyloxy)-1,3-butadiene (3b) (0.549 g, 2.0 mmol) and
Me3SiOTf (0.18 mL, 1 mmol) in CH2Cl2 (10 mL), product 5f was
2936 (w), 2853 (w), 1739 (m), 1669 (s), 1616 (m), 1398 (m), 1233
(m), 1153 (s), 1081 (s), 1027 (m), 928 (s), 823 (m). GC–MS (EI,

40
S. Reimann et al. / Journal of Fluorine Chemistry 139 (2012) 28–45
isolated as a orange solid (0.140 g, 60%); mp = 49–51 8C; RF = 0.17
51 (14). HRMS (EI, 70 eV): calcd. for C10H10F2O4 (M+) 232.05417,
found 232.054580. Anal. calcd. for C10H10F2O4 (232.181): C, 51.73;
H, 4.34. Found: C, 51.78; H, 4.507.
(n-heptane/EtOAc = 3:2). 1H NMR (300 MHz, CDCl3):
d = 1.29 (t,
3J = 6.0 Hz, 3H, CH3), 3.59 (s, 2H, CH2), 4.23 (q, 3J = 7.1 Hz, 2H, CH2),
6.32 (d, 4J = 3.0 Hz, 1H, CH), 6.36 (t, 2J = 52.5 Hz, 1H, CF2H), 6.56 (d,
Methyl
yl)acetate (5j): Starting with 2b (0.166 g, 1.0 mmol), 1-meth-
oxy-1,3-bis(trimethylsilyloxy)-1,3-hexadiene (3h) (0.577 g,
2-(6-(difluoromethyl)-4-oxo-3-ethyl-4H-pyran-2-
4J = 3.0 Hz, 1H, CH). 13C NMR (75 MHz, CDCl3):
d = 14.0 (CH3), 39.3
(CH2), 62.0 (CH2), 108.7 (t, JC–F = 241.1 Hz, CF2H), 114.1 (t, JC–
F = 3.7 Hz, C-5),117.3 (C-3), 157.5 (t, JC–F = 27.3 Hz, C-6), 161.4,
2.0 mmol) and Me3SiOTf (0.18 mL, 1 mmol) in CH2Cl2 (10 mL),
product 5j was isolated as a slight yellow oil (0.125 g, 52%);
RF = 0.46 (n-heptane/EtOAc = 1:1). 1H NMR (300 MHz, CDCl3):
166.7, 178.1 (C). 19F NMR (282 MHz, CDCl3):
d
= ꢀ123.3 (2F, d, 2JF–
˜
H = 56.4 Hz, CF2H). IR (ATR, cmꢀ1):
n
= 3233 (w), 3055 (w), 2987
(w), 2973 (w), 2934 (w), 2855 (w), 1724 (s), 1668 (s), 1622 (s), 1416
(m), 1371 (s), 1337 (s), 1223 (s), 1114 (s), 1026 (s), 905 (s). GC–MS
(EI, 70 eV): m/z (%): 232 (M+, 63), 187 (24), 160 (100), 131 (42), 121
(17), 109 (28), 69 (45), 29 (62). Anal. calcd. for C10H10F2O4 (232.18):
C, 51.73; H, 4.34. Found: C, 51.14; H, 4.58.
d
= 1.08 (t, 3J = 7.5 Hz, 3H, CH3), 2.45 (q, 3J = 7.5 Hz, 2H, CH2), 3.69
(s, 2H, CH2), 3.77 (s, 3H, OCH3), 6.31 (t, 2J = 53.6 Hz, 1H, CF2H), 6.51
(s, 1H, CH). 13C NMR (75 MHz, CDCl3):
= 12.7 (CH3), 18.2, 36.9
d
(CH2), 52.9 (OCH3), 108.8 (t, JC–F = 242.2 Hz, CF2H), 112.9 (t, JC–
F = 3.9 Hz, C-5), 130.5 (C-3), 156.7 (t, JC–F = 27.8 Hz, C-6), 157.1,
Isopropyl 2-(6-(difluoromethyl)-4-oxo-4H-pyran-2-yl)ace-
tate (5g): Starting with 2b (0.166 g, 1.0 mmol), 1-isopropyloxy-
1,3-bis(trimethylsilyloxy)-1,3-butadiene (3c) (0.577 g, 2.0 mmol)
and Me3SiOTf (0.18 mL, 1 mmol) in CH2Cl2 (10 mL), product 5 g
was isolated as a orange oil (0.139 g, 57%); RF = 0.31 (n-heptane/
167.9, 178.0 (C). 19F NMR (282 MHz, CDCl3):
d
= ꢀ123.4 (2F, d, 2JF–
˜
H = 56.4 Hz, CF2H). IR (ATR, cmꢀ1):
n
= 2959 (s), 1741 (s), 1667 (s),
1609 (s), 1434 (s), 1382 (s), 1056 (s), 797 (m), 564 (w). GC–MS (EI,
70 eV): m/z (%): 260 (M+, 100), 215 (71), 199 (17), 188 (43), 187
(83), 186 (11), 185 (28), 173 (12), 121 (11), 69 (11), 67 (18). HRMS
(EI, 70 eV): calcd. for C11H12F2O4 (M+) 246.06982, found
246.069858. Anal. calcd. for C11H12F2O4 (246.07): C, 53.66; H,
4.91. Found: C, 54.15; H, 5.26.
EtOAc = 1:1). 1H NMR (300 MHz, CDCl3): = 1.16 (d, 3J = 6.3 Hz, 6H,
d
CH3), 3.46 (s, 2H, CH2), 4.91–5.04 (m, 1H, CH), 6.24 (d, 4J = 2.4 Hz,
1H, CH), 6.25 (t, 2J = 53.4 Hz, 1H, CF2H), 6.56 (d, 4J = 9.0 Hz, 1H, CH).
13C NMR (75 MHz, CDCl3):
d
= 21.7, 21.8 (CH3), 39.6 (CH2), 70.0
Ethyl 2-(6-(difluoromethyl)-4-oxo-3-ethyl-4H-pyran-2-yl)a-
cetate (5k): Starting with 2b (0.166 g, 1.0 mmol), 1-ethoxy-1,3-
bis(trimethylsilyloxy)-1,3-hexadiene (3k) (0.605 g, 2.0 mmol) and
Me3SiOTf (0.18 mL, 1 mmol) in CH2Cl2 (10 mL), product 5k was
isolated as a yellow oil (0.081 g, 31%); RF = 0.28 (n-heptane/
(OCH), 108.7 (t, JC–F = 242.0 Hz, CF2H), 114.2 (t, JC–F = 3.8 Hz, C-
5),117.3 (C-3), 157.5 (t, JC–F = 27.3 Hz, C-6), 161.8, 166.3, 178.4 (C).
2
19F NMR (282 MHz, CDCl3):
d
= ꢀ123.3 (2F, d, JF–H = 56.4 Hz,
˜
CF2H). IR (ATR, cmꢀ1):
n
= 2985 (w), 1731 (s), 1670 (s), 1616 (s),
1467 (s), 1467 (w), 1376 (s), 1261 (s), 1101 (s), 926 (s), 876 (s), 905
(s). GC–MS (EI, 70 eV): m/z (%): 246 (M+, 38), 187 (63), 160 (76), 159
(17), 131 (54), 83 (12), 81 (10), 69 (25), 43 (100), 41 (20), 39 (11).
HRMS (EI, 70 eV): calcd. for C11H12F2O4 (M+) 246.069117, found
246.06982. Anal. calcd. for C11H12F2O4 (246.21): C, 53.66; H, 4.91.
Found: C, 53.34; H, 4.87.
Isobutyl 2-(6-(difluoromethyl)-4-oxo-4H-pyran-2-yl)acetate
(5h): Starting with 2b (0.166 g, 1.0 mmol), 1-isobutyloxy-1,3-
bis(trimethylsilyloxy)-1,3-butadiene (3d) (0.605 g, 2.0 mmol) and
Me3SiOTf (0.18 mL, 1 mmol) in CH2Cl2 (10 mL), product 5 h was
isolated as a slight yellow oil (0.125 g, 52%); RF = 0.37 (n-heptane/
EtOAc = 1:1). 1H NMR (300 MHz, CDCl3): = 0.91 (t, 3J = 7.8 Hz, 3H,
d
CH3), 1.12 (t, 3J = 6.9 Hz, 3H, CH3), 2.28 (q, 3J = 6.9 Hz, 2H, CH2), 3.50
(s, 2H, CH2), 4.05 (q, 3J = 6.9 Hz, 2H, OCH2), 6.16 (t, 2J = 53.6 Hz, 1H,
CF2H), 6.41 (s, 1H, CH). 13C NMR (75 MHz, CDCl3):
d = 12.7, 14.1
(CH3), 18.2, 37.2 (CH2), 62.1 (OCH2), 108.8 (t, JC–F = 242.1 Hz, CF2H),
112.9 (t, JC–F = 3.8 Hz, C-5), 130.4 (C-3), 156.7 (t, JC–F = 27.8 Hz, C-6),
157.4, 167.4, 178.1 (C). 19F NMR (282 MHz, CDCl3):
d
= ꢀ123.2 (2F,
˜
2
d, JF–H = 56.4 Hz, CF2H). IR (ATR, cmꢀ1):
n
= 2979 (m), 1736 (s),
1607 (s), 1423 (m), 1328 (m), 1056 (s), 795 (m), 564 (w). GC–MS
(EI, 70 eV): m/z (%): 260 (M+, 44), 215 (31), 189 (12), 187 (83), 187
(77), 185 (19), 173 (9), 69 (11), 67 (22), 29 (13). ESI-MS: calcd. for
EtOAc = 1:1). 1H NMR (300 MHz, CDCl3):
d
= 0.77 (d, 3J = 6.9 Hz, 6H,
C
C
12H15F2O4 (M+H+) 261.0933, found 261.0933; calcd. for
12H14F2NaO4 (M+Na+) 283.0752, found 283.0753. Anal. calcd.
CH3), 1.73–1.84 (m,1H, CH), 3.46 (s, 2H, CH2), 3.80 (d, 3J = 6.6 Hz,
2H, OCH2), 6.18 (d, 4J = 2.3 Hz, 1H, CH), 6.21 (t, 2J = 53.3 Hz, 1H,
CF2H), 6.42 (d, 4J = 8.6 Hz, 1H, CH). 13C NMR (75 MHz, CDCl3):
for C12H14F2O4 (260.23): C, 55.38; H, 5.42. Found: C, 55.31; H,
5.525.
d
= 18.9 (6H, CH3), 27.6 (CH), 39.4 (CH2), 72.0 (OCH2), 108.7 (t, JC–
Methyl 2-(6-(difluoromethyl)-4-oxo-3-propyl-4H-pyran-2-
yl)acetate (5l): Starting with 2b (0.166 g, 1.0 mmol), 1-meth-
F = 241.9 Hz, CF2H), 114.2 (t, JC–F = 3.9 Hz, C-5),117.4 (C-3), 157.6 (t,
JC–F = 27.4 Hz, C-6), 161.6, 166.8, 178.2 (C). 19F NMR (282 MHz,
oxy-1,3-bis(trimethylsilyloxy)-1,3-heptadiene
(3j)
(0.605 g,
2
CDCl3):
d
= ꢀ123.2 (2F, d, JF–H = 56.4 Hz, CF2H). IR (ATR, cmꢀ1):
2.0 mmol) and Me3SiOTf (0.18 mL, 1 mmol) in CH2Cl2 (10 mL),
˜
n
= 2961 (w), 2922 (w), 2852 (w), 1737 (s), 1671 (s), 1632 (s), 1470
product 5l was isolated as a orange oil (0.082 g, 32%). 1H NMR
(w), 1378 (m), 1259 (s), 1056 (s), 925 (s), 876 (s). GC–MS (EI,
70 eV): m/z (%): 260 (M+, 12), 205 (100), 187 (25), 160 (70), 159
(17), 131 (44), 69 (16), 57 (41), 41 (26), 39 (11). HRMS (EI, 70 eV):
calcd. for C12H14F2O4 (M+) 260.08547, found 260.086103.
(300 MHz, CDCl3): d
= 0.94 (t, 3J = 7.4 Hz, 3H, CH3), 1.41–1.53 (m,
2H, CH2), 2.38 (t, 3J = 7.8 Hz, 2H, CH2), 3.67 (s, 2H, CH2), 3.76 (s, 3H,
OCH3), 6.31 (t, 2J = 53.7 Hz, 1H, CF2H), 6.54 (s, 1H, CH). 13C NMR
(75 MHz, CDCl3): d = 14.0 (CH3), 21.5, 26.5, 37.0 (CH2), 52.7 (OCH3),
Methyl 2-(6-(difluoromethyl)-4-oxo-3-methyl-4H-pyran-2-
yl)acetate (5i): Starting with 2b (0.166 g, 1.0 mmol), 1-meth-
108.8 (t, JC–F = 242.4 Hz, CF2H), 112.8 (t, JC–F = 3.9 Hz, C-5), 129.1
(C-3), 156.6 (t, JC–F = 27.8 Hz, C-6), 157.3, 167.8, 178.1 (C). 19F NMR
oxy-1,3-bis(trimethylsilyloxy)-1,3-pentadiene
(3g)
(0.549 g,
(282 MHz, CDCl3):
d
= ꢀ123.7 (2F, d, 2JF–H = 56.4 Hz, CF2H). IR (ATR,
˜
2.0 mmol) and Me3SiOTf (0.18 mL, 1 mmol) in CH2Cl2 (10 mL),
cmꢀ1):
n = 3083 (w), 2961 (w), 2936 (w), 2874 (w), 1741 (s), 1668
product 5i was isolated as a colorless oil (0.071 g, 31%); RF = 0.28
(s), 1631 (m), 1609 (s), 1456 (w), 1434 (m), 1420 (m), 1380 (m),
1338 (m), 1309 (m), 1262 (m), 1195 (m), 1177 (m), 1158 (m), 1136
(s), 1092 (s), 1051 (s), 1011 (m), 873 (m), 801 (m), 649 (w). GC–MS
(EI, 70 eV): m/z (%): 260 (M+, 24), 259 (10), 246 (11), 245 (100), 232
(50), 229 (17), 228 (24), 213 (14), 201 (41), 200 (12), 199 (25), 187
(63), 185 (31), 174 (44), 173 (22), 121 (13), 79 (16), 77 (11), 69 (18),
59 (18), 53 (14), 51 (14). Anal. calcd. for C12H14F2O4 (260.23): C,
55.38; H, 5.42. Found: C, 55.16; H, 5.44.
(n-heptane/EtOAc = 1:1). 1H NMR (300 MHz, CDCl3):
d
= 1.82 (s,
3H, CH3), 3.54 (s, 2H, CH2), 3.61 (s, 3H, OCH3), 6.18 (t, 2J = 54.0 Hz,
1H, CF2H), 6.40 (s, 1H, CH). 13C NMR (75 MHz, CDCl3):
= 9.9 (CH3),
d
37.4 (CH2), 52.9 (OCH3), 108.8 (t, JC–F = 242.2 Hz, CF2H), 112.5 (t, JC–
F = 3.9 Hz, C-5), 125.2 (C-3), 156.7 (t, JC–F = 27.8 Hz, C-6), 157.0,
167.6, 178.4 (C). 19F NMR (282 MHz, CDCl3):
d
= ꢀ123.1 (2F, d, 2JF–
˜
H = 56.4 Hz, CF2H). IR (ATR, cmꢀ1):
n
= 3466 (w), 2957 (m), 1739 (s),
1667 (s), 1610 (s), 1434 (m), 1329 (m), 1082 (s), 794 (m), 562 (w).
GC–MS (EI, 70 eV): m/z (%): 232 (M+, 100), 201 (89), 175 (10), 174
(78), 173 (51), 145 (48), 121 (23), 69 (20), 59 (23), 53 (23), 52 (12),
Methyl 2-(6-(difluoromethyl)-4-oxo-3-nonyl-4H-pyran-2-
yl)acetate (5m): Starting with 2b (0.166 g, 1.0 mmol), 1-meth-
oxy-1,3-bis(trimethylsilyloxy)-1,3-tridecadiene (3w) (0.773 g,

S. Reimann et al. / Journal of Fluorine Chemistry 139 (2012) 28–45
41
2.0 mmol) and Me3SiOTf (0.18 mL, 1 mmol) in CH2Cl2 (10 mL),
product 5 m was isolated as a slight yellow solid (0.071 g, 31%);
mp = 41–42 8C; RF = 0.38 (n-heptane/EtOAc = 1:1). 1H NMR
diene (3l) (0.577 g, 2 mmol) and Me3SiOTf (0.181 mL, 1 mmol) in
CH2Cl2 (10 mL), product 6c was isolated as a yellow solid (0.208 g,
56%); mp = 55–57 8C, RF = 0.57 (n-heptane/EtOAc = 3:2). 1H NMR
(300 MHz, CDCl3):
16H, CH2), 3.59 (s, 2H, CH2), 3.67 (s, 3H, OCH3), 6.23 (t, 2J = 54.2 Hz,
1H, CF2H), 6.41 (s, 1H, CH). 13C NMR (75 MHz, CDCl3):
= 14.1
d
= 0.78 (t, 3J = 6.9 Hz, 3H, CH3), 1.62–1.22 (m,
(300 MHz, CDCl3): d
= 0.86 (t, 3J = 7.2 Hz, 3H, CH3), 1.25–1.38 (m,
9H,CH3(CH2)4), CH3), 2.22–2.34 (m, 2H, CH2), 2.84 (d, 2J = 17.1 Hz,
1H, H-5a), 2.99 (d, 2J = 17.4 Hz, 1H, H-5b), 3.76 (s, 0.5H, H-1a), 3.76
(s, 0.5H, H-1b), 3.88 (s, 3H, OCH3), 4.35 (q, 3J = 6.6 Hz, CH2, OCH2),
5.76 (s, 0.5H, OH-a), 5.77 (s, 0.5H, OH-b). 13C NMR (75 MHz, CDCl3):
d
(CH3), 22.4, 24.7, 28.3, 29.3, 29.4, 29.5, 29.7, 31.9 (CH2), 52.8
(OCH3), 108.8 (t, JC–F = 242.5 Hz, CF2H), 112.8 (t, JC–F = 3.7 Hz, C-5),
129.4 (C-3), 156.6 (t, JC–F = 27.8 Hz, C-6), 157.3, 167.9, 178.2 (C). 19
F
d = 13.9, 14.1 (CH3), 22.2, 22.5, 28.0, 31.8 (CH2), 31.5 (C-5), 53.3 (C-
NMR (282 MHz, CDCl3):
d
= ꢀ123.3 (2F, d, 2JF–H = 56.4 Hz, CF2H). IR
1), 55.7 (OCH3), 62.5 (OCH2), 78.0 (t, JC–F = 24.0 Hz, C-6), 118.2 (C-
˜
(ATR, cmꢀ1):
n
= 2952 (w), 2916 (m), 2850 (w), 1730 (m), 1669 (s),
3), 130.3 (t, JC–F = 299.3 Hz, CF2Cl), 166.7, 171.3, 188.7 (C). 19F NMR
2
1636 (s), 1424 (m), 1382 (m), 1067 (s), 790 (m), 573 (w). GC–MS
(EI, 70 eV): m/z (%): 344 (M+, 3), 312 (14), 272 (20), 271 (100), 259
(26), 245 (24), 232 (40), 201 (18), 199 (17), 185 (11), 174 (22).
HRMS (EI, 70 eV): calcd. for C18H26F2O4 (M+) 344.17937, found
344.179242. Anal. calcd. for C18H26F2O4 (344.39): C, 62.77; H, 7.61.
Found: C, 62.68; H, 7.498.
(282 MHz, CDCl3):
d
= ꢀ64.0 (d, JF–F = 166.4, 1F, CF2Cl), ꢀ66.5 (d,
˜
2JF–F = 166.4 Hz, 1F, CF2Cl). IR (ATR, cmꢀ1):
n = 3435 (w), 3014 (w),
2964 (w), 2924 (w), 2874 (w), 2858 (w), 1732 (s), 1651 (s), 1615 (s),
1374 (m), 1336 (m), 1255 (s), 1164 (s), 1074 (s), 1024 (s), 933 (m),
879 (m), 814 (m), 788 (m), 708 (w), 675 (w). GC–MS (EI, 70 eV): m/z
(%): 368 (M+, 1), 350 (8), 330 (10), 314 (23), 283 (31), 265 (15), 249
(21), 248 (19), 247 (20), 237 (30), 223 (35), 221 (100), 211 (21), 153
(29), 69 (21), 29 (16). ESI-MS: calcd. for C16H24ClF2O5 (M+H+)
369.12748, found 369.12795; calcd. for C16H23ClF2NaO5 (M+Na+)
391.10943, found 391.10963. Anal. calcd. for C16H23ClF2O5
(368.80): C, 52.11; H, 6.29. Found: C, 52.13; H, 6.359.
Methyl 6-(chlorodifluoromethyl)-6-hydroxy-4-methoxy-3-
methyl-2-oxocyclohex-3-ene-carboxylate (6a): Starting with
2a (0.200 g, 1 mmol), 1-methoxy-1,3-bis(trimethylsilyloxy)-1,3-
pentadiene (3 g) (0.549 g, 2 mmol) and Me3SiOTf (0.181 mL,
1 mmol) in CH2Cl2 (10 mL), product 6a was isolated as a yellow
solid (0.094 g, 32%); mp = 73–75 8C, RF = 0.51 (n-heptane/
Ethyl
6-(chlorodifluoromethyl)-6-hydroxy-4-methoxy-3-
EtOAc = 3:2). 1H NMR (300 MHz, CDCl3):
d
= 1.72–1.74 (m, 3H,
hexyl-2-oxocyclohex-3-ene-carboxylate (6d): Starting with 1
(0.200 g, 1 mmol), 1-ethoxy-1,3-bis(trimethylsilyloxy)-1,3-deca-
diene (3x) (0.740 g, 2 mmol) and Me3SiOTf (0.181 mL, 1 mmol) in
CH2Cl2 (10 mL), product 6d was isolated as a yellow solid (0.218 g,
57%); mp = 64–66 8C, RF = 0.61 (n-heptane/EtOAc = 3:2). 1H NMR
CH3), 2.84 (brd, 2J = 17.7 Hz, 1H, H-5a), 2.99 (d, 2J = 17.1 Hz, 1H, H-
5b), 3.81 (s, 0.5H, H-1a), 3.81 (s, 0.5H, H-1b), 3.88 (s, 3H, OCH3),
3.90 (s, 3H, OCH3), 5.65 (s, 0.5H, OH-a), 5.66 (s, 0.5H, OH-b). 13C
NMR (75 MHz, CDCl3):
d = 7.4 (CH3), 31.5 (C-5), 53.2 (C-1), 53.2,
55.8 (OCH3), 78.0 (t, JC–F = 24.8 Hz, C-6), 113.3 (C-3), 130.2 (t, JC–
(300 MHz, CDCl3): d
= 0.87 (t, 3J = 6.9 Hz, 3H, CH3), 1.22–1.29 (m,
F = 299.3 Hz, CF2Cl), 166.8, 171.6, 188.7 (C). 19F NMR (282 MHz,
8H, CH3(CH2)5), 1.35 (t, 3J = 7.2 Hz, 3H, CH3), 2.22–2.32 (m, 2H,
CH2), 2.84 (d, 2J = 17.4 Hz, 1H, H-5a), 2.98 (d, 2J = 17.4 Hz, 1H, H-
5b), 3.76 (s, 0.5H, H-1a), 3.76 (s, 0.5H, H-1b), 3.88 (s, 3H, OCH3),
4.34 (q, 3J = 7.2 Hz, CH2, OCH2), 5.75 (s, 0.5H, OH-a), 5.76 (s, 0.5H,
2
2
CDCl3):
d
= ꢀ64.0 (d, JF–F = 166.4, 1F, CF2Cl), ꢀ66.5 (d, JF–
˜
F = 166.4 Hz, 1F, CF2Cl). IR (ATR, cmꢀ1):
n
= 3428 (w), 3009 (w),
2965 (w), 2932 (w), 2865 (w), 1748 (s), 1666 (m), 1601 (s), 1434
(w), 1256 (m), 1096 (s), 1020 (s), 948 (s), 706 (s). GC–MS (EI,
70 eV): m/z (%): 298 (M+, 1), 280 (61), 223 (17), 213 (31), 212 (17),
201 (100), 187 (23), 181 (72), 137 (15), 83 (17), 69 (32), 59 (15).
ESI-MS: calcd. for C11H14ClF2O5 (M+H+) 299.04923, found
299.04978; calcd. for C11H13ClF2NaO5 (M+Na+) 321.03118, found
321.03204.
OH-b). 13C NMR (75 MHz, CDCl3):
d = 14.0, 14.1 (CH3), 22.3, 22.7,
28.3, 29.3, 31.7 (CH2), 31.6 (C-5), 53.3 (C-1), 55.7 (OCH3), 62.5
(OCH2), 78.0 (t, JC–F = 24.0 Hz, C-6), 118.3 (C-3), 130.4 (t, JC–
F = 299.3 Hz, CF2Cl), 166.7, 171.3, 188.7 (C). 19F NMR (282 MHz,
2
2
CDCl3):
d
= ꢀ64.0 (d, JF–F = 166.4, 1F, CF2Cl), ꢀ66.5 (d, JF–
˜
F = 166.4 Hz, 1F, CF2Cl). IR (ATR, cmꢀ1):
n
= 3419 (w), 2955 (w),
Methyl 6-(chlorodifluoromethyl)-6-hydroxy-4-methoxy-3-
ethyl-2-oxocyclohex-3-ene-carboxylate (6b): Starting with 2b
(0.200 g, 1 mmol), 1-methoxy-1,3-bis(trimethylsilyloxy)-1,3-hex-
adiene (3 h) (0.577 g, 2 mmol) and Me3SiOTf (0.181 mL, 1 mmol) in
CH2Cl2 (10 mL), product 6b was isolated as a yellow solid (0.176 g,
56%); mp = 100–102 8C, RF = 0.42 (n-heptane/EtOAc = 3:2). 1H
2931 (w), 2851 (w), 1721 (m), 1637 (w), 1604 (s), 1374 (s), 1333
(m), 1254 (m), 1091 (s), 1021 (s), 954 (m), 901 (m), 799 (m), 668
(m). GC–MS (EI, 70 eV): m/z (%): 382 (M+, 1), 364 (13), 344 (11), 328
(32), 297 (34), 287 (23), 282 (20), 255 (16), 251 (31), 249 (25), 248
(30), 247 (25), 225 (19), 223 (41), 221 (100), 212 (19), 186 (15), 153
(30), 69 (21), 43 (22), 29 (22). Anal. calcd. for C17H27ClF2O5
(384.84): C, 53.06; H, 7.07. Found: C, 53.02; H, 6.848.
NMR (300 MHz, CDCl3):
d
= 0.93 (t, 3J = 7.5 Hz, 3H, CH3), 2.28–
2.32 (m, 2H, CH2), (brd, 2J = 17.7 Hz, 1H, H-5a), 2.99 (d, 2J = 17.7 Hz,
1H, H-5b), 3.78 (s, 0.5H, H-1a), 3.78 (s, 0.5H, H-1b), 3.88 (s, 3H,
OCH3), 3.90 (s, 3H, OCH3), 5.66 (s, 0.5H, OH-a), 5.67 (s, 0.5H, OH-b).
Ethyl
6-(chlorodifluoromethyl)-6-hydroxy-4-methoxy-3-
heptyl-2-oxocyclohex-3-ene-carboxylate (6e): Starting with 2a
(0.200 g, 1 mmol), 1-ethoxy-1,3-bis(trimethylsilyloxy)-1,3-unde-
cadiene (3n) (0.745 g, 2 mmol) and Me3SiOTf (0.181 mL, 1 mmol)
in CH2Cl2 (10 mL), product 6e was isolated as a yellow solid
(0.231 g, 58%); mp = 65–67 8C, RF = 0.60 (n-heptane/EtOAc = 3:2).
13C NMR (75 MHz, CDCl3):
d = 12.8 (CH3), 15.7 (CH2), 31.5 (C-5),
53.2 (C-1), 53.3, 55.7 (OCH3), 78.0 (t, JC–F = 24.0 Hz, C-6), 119.5 (C-
3), 130.3 (t, JC–F = 298.5 Hz, CF2Cl), 166.6, 171.7, 188.3 (C). 19F NMR
2
(282 MHz, CDCl3):
d
= ꢀ64.0 (d, JF–F = 166.4, 1F, CF2Cl), ꢀ66.5 (d,
1H NMR (300 MHz, CDCl3): = 0.88 (t, 3J = 6.5 Hz, 3H, CH3), 1.23–
d
˜
2JF–F = 166.4 Hz, 1F, CF2Cl). IR (ATR, cmꢀ1):
n
= 3413 (w), 3024 (w),
1.29 (m, 10H, CH3(CH2)6), 1.36 (t, 3J = 7.2 Hz, 3H, CH3), 2.24–2.30
(m, 2H, CH2), 2.83 (d, 2J = 17.7 Hz, 1H, H-5a), 2.98 (d, 2J = 17.4 Hz,
1H, H-5b), 3.76 (s, 0.5H, H-1a), 3.76 (s, 0.5H, H-1b), 3.88 (s, 3H,
OCH3), 4.35 (q, 3J = 7.0 Hz, CH2, OCH2), 5.76 (s, 0.5H, OH-a), 5.76 (s,
2997 (w), 2964 (w), 2957 (w), 2934 (w), 2871 (w), 1714 (s), 1653
(m), 1619 (s), 1442 (m), 1409 (m), 1355 (m), 1246 (s), 1206 (s),
1172 (s), 1079 (s), 1026 (s), 997 (s), 964 (s), 887 (m), 802 (m), 699
(s). GC–MS (EI, 70 eV): m/z (%): 312 (M+, 1), 294 (43), 274 (15), 258
(21), 237 (47), 235 (97), 227 (46), 226 (33), 195 (100), 170 (20), 155
(17), 83 (27), 69 (45), 59 (15). ESI-MS: calcd. for C12H16ClF2O5
(M+H+) 313.06488, found 313.06457; calcd. for C12H15ClF2NaO5
(M+Na+) 335.04683, found 335.04684. Anal. calcd. for
0.5H, OH-b). 13C NMR (75 MHz, CDCl3):
d = 14.0, 14.1 (CH3), 22.3,
22.7, 28.3, 29.2, 29.6, 31.9 (CH2), 31.5 (C-5), 53.3 (C-1), 55.7 (OCH3),
62.5 (OCH2), 78.0 (t, JC–F = 24.8 Hz, C-6), 118.3 (C-3), 130.3 (t, JC–
F = 298.5 Hz, CF2Cl), 166.6, 171.3, 188.7 (C). 19F NMR (282 MHz,
2
2
CDCl3):
d
= ꢀ64.0 (d, JF–F = 166.4, 1F, CF2Cl), ꢀ66.5 (d, JF–
˜
C12H15ClF2O5 (312.69): C, 46.09; H, 4.84. Found: C, 46.15; H, 4.82.
F = 166.4 Hz, 1F, CF2Cl). IR (ATR, cmꢀ1):
n = 3424 (w), 3036 (w),
Ethyl 6-(chlorodifluoromethyl)-6-hydroxy-4-methoxy-3-
pentyl-2-oxocyclohex-3-ene-carboxylate (6c): Starting with 2a
(0.200 g, 1 mmol), 1-ethoxy-1,3-bis(trimethylsilyloxy)-1,3-nona-
2960 (w), 2928 (w), 2856 (w), 1722 (s), 1638 (s), 1604 (s), 1445 (m),
1374 (m), 1334 (s), 1255 (s), 1162 (s), 1089 (s), 1022 (s), 976 (m),
800 (m), 669 (w). GC–MS (EI, 70 eV): m/z (%): 396 (M+, 1), 378 (15),

42
S. Reimann et al. / Journal of Fluorine Chemistry 139 (2012) 28–45
358 (11), 342 (32), 311 (35), 301 (31), 296 (28), 293 (20), 269 (15),
265 (25), 249 (24), 248 (39), 247 (34), 239 (18), 228 (17), 223 (37),
221 (100), 212 (22), 153 (26), 69 (15), 29 (15). ESI-MS: calcd. for
C
C
CH3), 1.25–1.32 (m, 20H, CH3(CH2)11), 2.22–2.31 (m, 2H, CH2), 2.84
(brd, 2J = 17.7 Hz, 1H, H-5a), 2.99 (d, 2J = 17.7 Hz, 1H, H-5b), 3.80 (s,
0.5H, H-1a), 3.80 (s, 0.5H, H-1b), 3.88, 3.88 (s, 3H, OCH3), 5.66 (s,
0.5H, OH-a), 5.67 (s, 0.5H, OH-b). 13C NMR (75 MHz, CDCl3):
18H28ClF2O5 (M+H+) 397.15878, found 397.15921; calcd. for
18H27ClF2NaO5 (M+Na+) 419.14073, found 419.14074. Anal. calcd.
d
= 14.1 (CH3), 22.3, 22.7, 28.3, 29.4, 29.5, 29.6, 29.7, 29.7, 29.7, 32.0
for C18H27ClF2O5 (396.85): C, 54.48; H, 6.86. Found: C, 54.57; H,
6.807.
(CH2), 31.5 (C-5), 53.2 (OCH3), 53.3 (C-1), 55.7 (OCH3), 78.0 (t, JC–
F = 24.0 Hz, C-6), 118.3 (C-3), 130.2 (t, JC–F = 299.3 Hz, CF2Cl), 166.7,
2
Methyl 6-(chlorodifluoromethyl)-6-hydroxy-4-methoxy-3-
octyl-2-oxocyclohex-3-ene-carboxylate (6f): Starting with 2a
(0.200 g, 1 mmol), 1-methoxy-1,3-bis(trimethylsilyloxy)-1,3-
dodecadiene (3n) (0.745 g, 2 mmol) and Me3SiOTf (0.181 mL,
1 mmol) in CH2Cl2 (10 mL), product 6f was isolated as a slight
yellow solid (0.225 g, 58%); mp = 59–61 8C, RF = 0.50 (n-heptane/
171.7, 188.5 (C). 19F NMR (282 MHz, CDCl3):
d
= ꢀ64.0 (d, JF–
2
F = 166.4, 1F, CF2Cl), ꢀ66.5 (d, JF–F = 166.4 Hz, 1F, CF2Cl). IR (ATR,
˜
cmꢀ1):
n = 3420 (w), 3014 (w), 2956 (w), 2914 (m), 2850 (m), 1717
(m), 1652 (m), 1610 (s), 1382 (m), 1346 (m), 1255 (s), 1167 (s),
1081 (s), 1025 (w), 986 (s), 956 (m), 833 (w), 799 (w), 715 (m), 673
(w). GC–MS (EI, 70 eV): m/z (%): 452 (M+, 1), 434 (22), 414 (26), 399
(26), 398 (52), 373 (35), 371 (42), 368 (17), 367 (76), 366 (19), 349
(56), 335 (48), 250 (19), 249 (25), 248 (63), 247 (57), 244 (21), 235
(21), 228 (19), 223 (45), 221 (100), 216 (19), 212 (28), 209 (19), 181
(20), 153 (20), 69 (23), 43 (32), 41 (21), 29 (15). ESI-MS: calcd. for
EtOAc = 3:2). 1H NMR (300 MHz, CDCl3): = 0.87 (t, 3J = 7.2 Hz, 3H,
d
CH3), 1.25–1.29 (m, 12H, CH3(CH2)7), 2.24–2.29 (m, 2H, CH2), 2.84
(d, 2J = 17.7 Hz, 1H, H-5a), 2.99 (d, 2J = 17.7 Hz, 1H, H-5b), 3.80 (s,
0.5H, H-1a), 3.80 (s, 0.5H, H-1b), 3.88, 3.90 (s, 3H, OCH3), 5.66 (s,
0.5H, OH-a), 5.67 (s, 0.5H, OH-b). 13C NMR (75 MHz, CDCl3):
C
22H36ClF2O5 (M+H+) 453.22138, found 453.22163; calcd. for
d
= 14.1 (CH3), 22.3, 22.7, 28.3, 29.3, 29.4, 29.6, 31.9 (CH2), 31.5 (C-
C22H35ClF2NaO5 (M+Na+) 475.20333, found 475.20363. Anal. calcd.
for C22H35ClF2O5 (452.96): C, 58.34; H, 7.79. Found: C, 58.26; H,
7.680.
5), 53.2 (OCH3), 53.3 (C-1), 55.7 (OCH3), 78.0 (t, JC–F = 24.0 Hz, C-6),
118.3 (C-3), 130.3 (t, JC–F = 298.5 Hz, CF2Cl), 166.7, 171.7, 188.5 (C).
19F NMR (282 MHz, CDCl3):
d
= ꢀ64.0 (d, JF–F = 166.4, 1F, CF2Cl),
Methyl 6-(chlorodifluoromethyl)-6-hydroxy-4-methoxy-3-
hexadecyl-2-oxocyclohex-3-ene-carboxylate (6i): Starting with
2a (0.200 g, 1 mmol), 1-methoxy-1,3-bis(trimethylsilyloxy)-1,3-
icosandiene (3q) (0.969 g, 2 mmol) and Me3SiOTf (0.181 mL,
1 mmol) in CH2Cl2 (10 mL), product 6i was isolated as a slightly
yellow solid (0.409 g, 80%); mp = 58–59 8C, RF = 0.62 (n-heptane/
2
˜
ꢀ66.5 (d, 2JF–F = 166.4 Hz, 1F, CF2Cl). IR (ATR, cmꢀ1):
n = 3400 (w),
3008 (w), 2955 (w), 2925 (w), 2855 (w), 1721 (m), 1658 (m), 1619
(s), 1459 (m), 1379 (s), 1348 (s), 1250 (s), 1167 (s), 1114 (s), 1024
(s), 988 (s), 943 (m), 795 (w), 666 (w). GC–MS (EI, 70 eV): m/z (%):
396 (M+, 1), 378 (26), 358 (23), 343 (24), 342 (61), 317 (19), 315
(50), 311 (86), 310 (47), 293 (57), 283 (32), 279 (100), 250 (22), 249
(31), 248 (64), 247 (62), 235 (20), 228 (28), 223 (37), 221 (99), 212
(32), 209 (18), 181 (23), 153 (29), 69 (36), 59 (18), 55 (16). ESI-MS:
calcd. for C18H28ClF2O5 (M+H+) 397.15878, found 397.15943;
calcd. for C18H27ClF2NaO5 (M+Na+) 419.14073, found 419.1409.
Anal. calcd. for C18H27ClF2O5 (396.85): C, 54.48; H, 6.86. Found: C,
54.22; H, 6.783.
EtOAc = 3:2). 1H NMR (300 MHz, CDCl3): = 0.88 (t, 3J = 6.9 Hz, 3H,
d
CH3), 1.24–1.33 (m, 28H, CH3(CH2)15), 2.22–2.31 (m, 2H, CH2), 2.84
(brd, 2J = 17.7 Hz, 1H, H-5a), 2.99 (d, 2J = 17.7 Hz, 1H, H-5b), 3.80 (s,
0.5H, H-1a), 3.80 (s, 0.5H, H-1b), 3.88, 3.88 (s, 3H, OCH3), 5.66 (s,
0.5H, OH-a), 5.67 (s, 0.5H, OH-b). 13C NMR (75 MHz, CDCl3):
d
= 14.1 (CH3), 22.3, 22.7, 28.2, 28.3, 29.4, 29.5, 29.5, 29.6, 29.6,
29.7, 29.7, 29.7, 31.9, 32.0 (CH2), 31.5 (C-5), 53.2 (OCH3), 53.3 (C-1),
55.7 (OCH3), 78.0 (t, JC–F = 24.0 Hz, C-6), 118.3 (C-3), 130.3 (t, JC–
F = 299.3 Hz, CF2Cl), 166.7, 171.7, 188.5 (C). 19F NMR (282 MHz,
Methyl 6-(chlorodifluoromethyl)-6-hydroxy-4-methoxy-3-
nonyl-2-oxocyclohex-3-ene-carboxylate (6g): Starting with 2a
(0.200 g, 1 mmol), 1-methoxy-1,3-bis(trimethylsilyloxy)-1,3-tri-
decadiene (3w) (0.773 g, 2 mmol) and Me3SiOTf (0.181 mL,
1 mmol) in CH2Cl2 (10 mL), 6 g was isolated as a slightly yellow
solid (0.189 g, 46%); mp = 52–54 8C, RF = 0.58 (n-heptane/
2
2
CDCl3):
d
= ꢀ64.0 (d, JF–F = 166.4, 1F, CF2Cl), ꢀ66.5 (d, JF–
˜
F = 166.4 Hz, 1F, CF2Cl). IR (ATR, cmꢀ1):
n
= 3382 (w), 3015 (w),
2954 (w), 2915 (s), 2849 (s), 1744 (m), 1715 (w), 1653 (w), 1614
(s), 1385 (m), 1249 (s), 1165 (s), 1082 (s), 1021 (s), 985 (s),955 (m),
940 (m), 837 (w), 718 (m), 665 (w). GC–MS (EI, 70 eV): m/z (%): 508
(M+, 1), 590 (22), 470 (15), 455 (21), 454 (45), 429 (15), 427 (38),
424 (22), 423 (75), 422 (19), 405 (29), 391 (30), 279 (18), 250 (33),
249 (40), 248 (100), 247 (69), 245 (21), 244 (27), 235 (19), 230 (20),
228 (34), 223 (40), 221 (98), 214 (29), 213 (46), 212 (41), 211 (19),
209 (24), 195 (20), 187 (33), 181 (27), 153 (22), 97 (20), 83 (28), 71
(25), 69 (51), 67 (18), 59 (19), 57 (52), 55 (58), 44 (49), 43 (79), 41
(52). ESI-MS: calcd. for C26H44ClF2O5 (M+H+) 509.28399, found
509.28398; calcd. for C26H43ClF2NaO5 (M+Na+) 531.26593, found
531.26622. Anal. calcd. for C26H43ClF2O5 (509.07): C, 61.34; H,
8.51. Found: C, 61.38; H, 8.478.
EtOAc = 3:2). 1H NMR (300 MHz, CDCl3):
d
= 0.88 (t, 3J = 7.2 Hz,
3H, CH3), 1.25–1.32 (m, 14H, CH3(CH2)8), 2.24–2.27 (m, 2H, CH2),
2.84 (brd, 2J = 17.7 Hz, 1H, H-5a), 2.99 (d, 2J = 17.7 Hz, 1H, H-5b),
3.80 (s, 0.5H, H-1a), 3.80 (s, 0.5H, H-1b), 3.87, 3.88 (s, 3H, OCH3),
5.66 (s, 0.5H, OH-a), 5.67 (s, 0.5H, OH-b). 13C NMR (75 MHz, CDCl3):
d
= 14.2 (CH3), 22.2, 22.7, 28.3, 29.4, 29.5, 29.5, 29.6, 31.9 (CH2),
31.5 (C-5), 53.2 (OCH3), 53.3 (C-1), 55.7 (OCH3), 78.0 (t, JC–
F = 24.0 Hz, C-6), 118.3 (C-3), 130.3 (t, JC–F = 299.3 Hz, CF2Cl), 166.7,
171.7, 188.5 (C). 19F NMR (282 MHz, CDCl3):
2
d
= ꢀ64.0 (d, JF–
2
F = 166.4, 1F, CF2Cl), ꢀ66.5 (d, JF–F = 166.4 Hz, 1F, CF2Cl). IR (ATR,
˜
cmꢀ1):
n = 3447 (w), 3025 (w), 2958 (w), 2923 (w), 2855 (w), 1741
(s), 1651 (m), 1614 (s), 1393 (m), 1258 (s), 1167 (s), 1127 (s), 1023
(s), 983 (s), 945 (s), 918 (m), 815 (w), 664 (w). GC–MS (EI, 70 eV):
m/z (%): 410 (M+, 1), 392 (8), 372 (10), 356 (29), 326 (15), 325 (100),
307 (25), 293 (90), 248 (20), 221 (45), 153 (12),69 (15). ESI-MS:
calcd. for C19H30ClF2O5 (M+H+) 411.17443, found 411.1748; calcd.
for C19H29ClF2NaO5 (M+Na+) 433.16638, found 433.15629. Anal.
calcd. for C19H29ClF2O5 (410.88): C, 55.54; H, 7.11. Found: C, 55.63;
H, 7.187.
Methyl 6-(chlorodifluoromethyl)-6-hydroxy-4-methoxy-3-
isobutyl-2-oxocyclohex-3-ene-carboxylate (6j): Starting with
2a (0.200 g, 1 mmol), 1-methoxy-1,3-bis(trimethylsilyloxy)-6-
methyl-1,3-heptadiene (3y) (0.661 g, 2 mmol) and Me3SiOTf
(0.181 mL, 1 mmol) in CH2Cl2 (10 mL), product 6j was isolated
as a slightly yellow solid (0.271 g, 80%); mp = 85–87 8C, RF = 0.53
(n-heptane/EtOAc = 3:2). 1H NMR (300 MHz, CDCl3):
d = 0.88, 088
(d, 3J = 6.6 Hz, 3H, CH3), 1.19–1.26 (m, 2H, CH2), 1.45–1.54 (m, 1H,
CH), 2.22–2.32 (m, 2H, CH2), 2.84 (brd, 2J = 17.7 Hz, 1H, H-5a), 2.99
(d, 2J = 17.7 Hz, 1H, H-5b), 3.79 (s, 0.5H, H-1a), 3.80 (s, 0.5H, H-1b),
3.88, 3.89 (s, 3H, OCH3), 5.66 (s, 0.5H, OH-a), 5.67 (s, 0.5H, OH-b).
Methyl 6-(chlorodifluoromethyl)-6-hydroxy-4-methoxy-3-
dodecyl-2-oxocyclohex-3-ene-carboxylate (6h): Starting with
2a (0.200 g, 1 mmol), 1-methoxy-1,3-bis(trimethylsilyloxy)-1,3-
pentadecadiene (3p) (0.857 g, 2 mmol) and Me3SiOTf (0.181 mL,
1 mmol) in CH2Cl2 (10 mL), product 6h was isolated as slightly
yellow solid (0.291 g, 64%); mp = 45–46 8C, RF = 0.63 (n-heptane/
13C NMR (75 MHz, CDCl3):
d = 20.3 (CH2), 22.4, 22.5 (CH3), 28.2
(CH), 31.5 (C-5), 37.3 (CH2), 53.2 (OCH3), 53.3 (C-1), 55.7 (OCH3),
78.0 (t, JC–F = 24.0 Hz, C-6), 118.4 (C-3), 130.2 (t, JC–F = 299.3 Hz,
CF2Cl), 166.6, 171.7, 188.5 (C). 19F NMR (282 MHz, CDCl3):
EtOAc = 3:2). 1H NMR (300 MHz, CDCl3): = 0.88 (t, 3J = 6.9 Hz, 3H,
d

S. Reimann et al. / Journal of Fluorine Chemistry 139 (2012) 28–45
43
d
= ꢀ64.0 (d, 2JF–F = 166.4, 1F, CF2Cl), ꢀ66.5 (d, 2JF–F = 166.4 Hz, 1F,
192 (33), 177 (10), 171 (25), 168 (11), 149 (34), 133 (28), 121 (14),
101 (13), 69 (15). HRMS (EI, 70 eV): calcd. for C13H14F2O4 (M+)
272.08547, found 272.085365. Anal. calcd. for C13H14F2O4
(232.181): C, 57.35; H, 5.18. Found: C, 56.98; H, 4.907.
Isopropyl 2-(1,1-difluorobut-3-enyl)-6-hydroxy-4-methoxy-
benzoate (7b): Starting with 4c (0.294 g, 1 mmol),
Bu3SnCH2CH55CH2 (1.65 g, 5.0 mmol), AIBN (0.020 g, 0.12 mmol),
the product 7b was isolated as a slight yellow oil (0.289 g, 96%);
RF = 0.69 (heptane/EtOAc = 3:2). 1H NMR (300 MHz, CDCl3):
˜
CF2Cl). IR (ATR, cmꢀ1):
n
= 3431 (w), 3018 (w), 2962 (w), 2905 (w),
2871 (w), 2849 (w), 1740 (s), 1652 (s), 1615 (s), 1439 (m), 1341
(m), 1253 (s), 1167 (s), 1132 (s), 1093 (s), 986 (s), 972 (s), 943 (s),
918 (s), 817 (s), 795 (m), 709 (w), 664 (m). GC–MS (EI, 70 eV): m/z
(%): 354 (M+, 1), 336 (35), 316 (18), 300 (51), 279 (34), 269 (64), 261
(16), 260 (30), 251 (87), 249 (30), 248 (86), 247 (49), 244 (39), 241
(22), 238 (19), 237 (91), 235 (20), 228 (30), 223 (43), 221 (100), 216
(30), 212 (39), 209 (27), 199 (20), 181 (28), 155 (20), 153 (41), 83
(16), 69 (53), 59 (26), 55 (16), 53 (18), 43 (28), 41 (26). ESI-MS:
calcd. for C15H22ClF2O5 (M+H+) 355.11183, found 355.11211;
calcd. for C15H21ClF2NaO5 (M+Na+) 377.09378, found 377.09392.
Anal. calcd. for C15H21ClF2O5 (354.77): C, 50.78; H, 5.97. Found: C,
51.03; H, 5.987.
3
3
d
= 1.38, 1.40 (s, 6H, CH3), 3.16 (dt, JHH = 7.1 Hz, JHF = 17.1 Hz,
2H, CH2), 3.82 (s, 3H, OCH3), 5.17 (d, 3Jtrans = 1.8 Hz, 1H, CH55CH2),
5.22 (d, Jcis = 1.6 Hz, 1H, CH55CH2), 5.28–5.37 (m, 1H, CH), 5.82–
3
5.93 (m, 1H, CH55CH2), 6.52 (s, 1H, H-3), 6.63 (s, 1H, H-5), 10.70 (s,
1H, OH). 13C NMR (75 MHz, CDCl3):
d
= 21.6, 21.6 (CH3), 43.1 (t, 2JC–
3
Methyl 6-(chlorodifluoromethyl)-6-hydroxy-4-methoxy-3-
chloro-2-oxocyclohex-3-ene-carboxylate (6k): Starting with 2a
(0.200 g,
F = 27 Hz, CH), 55.6 (OCH3), 70.3 (CH), 101.9 (CH), 105.0 (t, JC–
F = 2.25 Hz, C-5), 108.4 (t, 3JC–F = 10.5 Hz, C-6), 120.3 (CH2), 121.9 (t,
3
3
1 mmol),
1-methoxy-1,3-bis(trimethylsilyloxy)-4-
1JC–F = 243.75 Hz, CF2), 129.3 (t, JC–F = 4.5 Hz, CH), 139.4 (t, JC–
chloro-1,3-butadiene (3z) (0.589 g, 2 mmol) and Me3SiOTf
(0.181 mL, 1 mmol) in CH2Cl2 (10 mL), product 6k was isolated
as a yellow solid (0.165 g, 52%); mp = 98–100 8C, RF = 0.32 (n-
F = 26.25 Hz, C-6), 163.0 (C–OH), 163.2 (C–OMe), 169.5 (CO). 19F
˜
NMR (282 MHz, CDCl3):
d
= ꢀ87.85 (CF2). IR (ATR, cmꢀ1):
n
= 2984
(w), 1655 (m), 1580 (s), 1466 (m), 1426 (w), 1356 (m),1261 (s),
1204 (m), 1099 (s), 1024 (m), 979 (m), 842 (m), 620 (s), 591 (w),
476 (w), 429 (w). GC–MS (EI, 70 eV): m/z (%): 300 (M+, 46), 258
(18), 241 (30), 240 (67), 221 (16), 220 (32), 214 (22), 213 (30), 212
(28), 198 (15), 197 (28), 194 (18), 193 (100), 192 (26), 177 (23), 171
(11), 163 (10), 162 (11), 150(13), 149 (35), 69 (12), 43 (22), 41 (16).
HRMS (EI, 70 eV): calcd. for C15H18F2O4 (M+) 300.11677, found
300.116729. Anal. calcd. for C13H14F2O4 (300.30): C, 59.99; H, 6.04.
Found: C, 59.72; H, 6.031.
heptane/EtOAc = 3:2). 1H NMR (300 MHz, CDCl3):
d = 3.01 (brd,
2J = 17.7 Hz, 1H, H-5a), 3.13 (d, 2J = 17.7 Hz, 1H, H-5b), 3.89 (s, 3H,
OCH3), 3.93 (s, 0.5H, H-1a), 3.94 (s, 0.5H, H-1b), 4.05 (s, 3H, OCH3),
5.66 (s, 0.5H, OH-a), 5.67 (s, 0.5H, OH-b). 13C NMR (75 MHz, CDCl3):
d
= 31.5 (C-5), 53.5 (C-1), 53.9 (OCH3), 57.2 (OCH3), 77.7 (t, JC–
F = 24.0 Hz, C-6), 109.5 (C-3), 129.7 (t, JC–F = 299.3 Hz, CF2Cl), 166.3,
170.4, 182.2 (C). 19F NMR (282 MHz, CDCl3):
2
d
= ꢀ64.1 (d, JF–
2
F = 166.4 Hz, 1F, CF2Cl), ꢀ66.4 (d, JF–F = 166.4 Hz, 1F, CF2Cl). IR
˜
(ATR, cmꢀ1):
n
= 3404 (w), 3005 (w), 2958 (w), 2857 (w), 1726 (w),
Methyl 2-(1,1-difluorobut-3-enyl)-6-hydroxy-4-methoxy-5-
npropylbenzoate (7c): Starting with 4i (0.314 g, 1 mmol),
Bu3SnCH2CH55CH2 (1.65 g, 5.0 mmol), AIBN (0.020 g, 0.12 mmol),
the product 7c was isolated as a colorless oil (0.281 g, 89%);
RF = 0.61 (heptane/EtOAc = 3:2). 1H NMR (300 MHz, CDCl3):
1669 (m), 1595 (s), 1375 (m), 1347 (m), 1261 (s), 1169 (s), 1090
(m), 1041 (s), 1008 (m), 947 (s), 797 (m), 662 (m). GC–MS (EI,
70 eV): m/z (%): 318 (M+, 1), 300 (22), 233 (33), 223 (35), 221 (100),
207 (21), 174 (41), 103 (12), 69 (35), 59 (25). ESI-MS: calcd. for
C
C
calcd. for C10H10Cl2F2O5 (319.09): C, 37.64; H, 3.16. Found: C,
37.86; H, 3.452.
General procedure for the synthesis of 7a–e: The reaction was
carried out in a pressure tube. To a benzene suspension (10 mL/
10H11Cl2F2O5 (M+H+) 318.99461, found 318.99511; calcd. for
10H10Cl2F2NaO5 (M+Na+) 340.97656, found 340.97701. Anal.
d
= 0.77 (t, 3J = 7.4 Hz, 3H, CH3), 1.35 (m, 3J = 7.5 Hz, 2H, CH2),
2.46 (t, 3J = 7.7 Hz, 2H, CH2), 2.96 (dt, JHH = 7.1 Hz, JHF = 17.1 Hz,
2H, CH2), 3.68 (s, 3H, OCH3), 3.74 (s, 3H, OCH3), 5.03 (d,
3Jtrans = 16.9 Hz, 1H, CH55CH2), 5.06 (d, 3Jcis = 8.7 Hz, 1H, CH55CH2),
3
3
3
4
3
CH2), 5.72 (dt, JH–H = 7.1 Hz, JH–F = 27.3 Hz, dd, Jcis = 7.0 Hz,
3Jtrans = 12,7 Hz, 1H, CH55CH2), 6.44 (s, 1H, H-5), 9.96 (s, 1H, OH).
1 mmol of 4) of
4
(1 mmol) was added Bu3SnCH2CH55CH2
13C NMR (75 MHz, CDCl3):
41.10 (t, JC–F = 27.0 Hz, CH2), 50.01 (OCH3), 53.36 (OCH3), 100.14
d
= 11.31 (CH3), 19.48, 20.97 (CH2),
2
(5.0 mmol) and AIBN (azobisisobutyronitrile) (0.12 mmol) and
the resultant solution was degassed by bubbling argon through the
solution for 5 min. The mixture was heated up to 90 8C under
Argon atmosphere for 20 h with stirring. The temperature of the
solution was allowed to warm to room temperature. The pressure
tube was rinsed with benzene and the organic solution was
concentrated in vacuo. The residue was purified by a column
chromatography (n-heptane/EtOAc).
Methyl 2-(1,1-difluorobut-3-enyl)-6-hydroxy-4-methoxy-
benzoate (7a): Starting with 4a (0.266 g, 1 mmol),
Bu3SnCH2CH55CH2 (1.65 g, 5.0 mmol), AIBN (0.020 g, 0.12 mmol),
the product 7a was isolated as a colorless oil (0.196 g, 72%);
RF = 0.45 (heptane/EtOAc = 3:2). 1H NMR (300 MHz, CDCl3):
3
(t, JC–F = 2.25 Hz, C-5), 103.01 (C-1), 117.58 (C-3), 117.86 (CH2),
1
3
119.87 (t, JC–F = 243.75 Hz, CF2), 127.25 (t, JC–F = 4.5 Hz, CH),
134.40 (t, 2JC–F = 26.25 Hz, C-6), 156.97 (C-2), 158.29 (C-4), 168.41
(CO). 19F NMR (282 MHz, CDCl3):
d
= ꢀ88.80 (CF2). IR (ATR, cmꢀ1):
˜
n
= 2956 (w), 2936 (w), 2873 (w), 1935 (m), 1655 (m), 1611 (w),
1509 (w), 1395 (m), 1288 (s), 1167 (m), 1132 (m), 1109 (w), 985
(m), 906 (s), 839 (w), 784 (m), 695 (w). GC–MS (EI, 70 eV): m/z (%):
314 (M+, 92), 288 (45), 245 (22), 241 (22), 240 (70), 231 (16), 221
(9), 220 (20), 212 (30), 211 (32), 201 (10), 198 (13), 194 (18), 193
(100), 192 (33), 177 (10), 171 (25), 168 (11), 149 (38), 133 (18), 121
(14), 102 (15), 69 (8). HRMS (ESI): calcd. for C16H20O4F2 (M+Na]+)
337.1222, found 337.1231.
3
3
d
= 3.16 (dt, JHH = 7.1 Hz, JHF = 17.1 Hz, 2H, CH2), 3.82, 3.92 (s,
Methyl 2-(1,1-difluorobut-3-enyl)-6-hydroxy-4-methoxy-5-
isopropylbenzoate (7d): Starting with 4j (0.314 g, 1 mmol),
Bu3SnCH2CH55CH2 (1.65 g, 5.0 mmol), AIBN (0.020 g, 0.12 mmol),
the product 7d was isolated as a slight yellow oil (0.267 g, 85%);
3
3H, OCH3), 5.16 (d, Jtrans = 1.5 Hz, 1H, CH55CH2), 5.21 (d,
3Jcis = 1.5 Hz, 1H, CH55CH2), 5.80–5.94 (m, 1H, CH55CH2), 6.52 (s,
1H, H-3), 6.65 (s, 1H, H-5), 10.50 (s, 1H, OH). 13C NMR (75 MHz,
CDCl3):
d
= 43.1 (t, 2JC–F = 27 Hz, CH), 52.4, 55.6 (OCH3), 101.9 (CH),
RF = 0.57 (heptane/EtOAc = 3:2). 1H NMR (300 MHz, CDCl3):
3
3
3
104.3 (t, JC–F = 2.25 Hz, C-5), 108.5 (t, JC–F = 10.5 Hz, C-6), 120.3
(CH2), 121.8 (t, 1JC–F = 243.75 Hz, CF2), 129.4 (t, 3JC–F = 4.5 Hz, CH),
139.6 (t, 3JC–F = 26.25 Hz, C-6), 163.2 (C–OH), 163.3 (C–OMe), 170.2
d
= 1.20 (s, 3H, CH3), 1.23 (s, 3H, CH3), 3.05 (dt, JHH = 7.1 Hz,
3JHF = 17.1 Hz, 2H, CH2), 3.54 (m, 3J = 7.1 Hz, 1H, CH), 3.78 (s, 3H,
OCH3), 3.84 (s, 3H, OCH3), 5.13 (d, Jtrans = 12.1 Hz, 1H, CH55CH2),
5.18 (d, Jcis = 4.5 Hz, 1H, CH55CH2), 5.83 (dt, JH–H = 7.1 Hz, JH–
F = 27.4 Hz, dd, Jcis = 7.0 Hz, Jtrans = 13.65 Hz, 1H, CH55CH2), 6.52
(s, 1H, H-5), 10.09 (s, 1H, OH). 13C NMR (75 MHz, CDCl3):
3
(CO). 19F NMR (282 MHz, CDCl3):
d
= ꢀ88.67 (CF2). IR (ATR, cmꢀ1):
3
3
4
˜
3
3
n
= 2982 (w), 1653 (m), 1614 (s), 1426 (m), 1356 (m), 1260 (s),
1098 (s), 978 (s), 730 (m), 620 (m), 538 (m), 429 (w). GC–MS (EI,
70 eV): m/z (%): 272 (M+, 92), 241 (22), 240 (74), 231 (16), 221 (15),
220 (26), 212 (28), 211 (32), 201 (12), 198 (13), 194 (13), 193 (100),
d
= 19.9
2
(CH3), 24.2 (CH), 43.4 (t, JC–F = 27.0 Hz, CH2), 52.3, 55.6 (OCH3),
102.9 (t, JC–F = 2.4 Hz, C-5), 105.6 (C-1), 120.2 (t, JC–F = 243.7 Hz,
3
1

44
S. Reimann et al. / Journal of Fluorine Chemistry 139 (2012) 28–45
CF2), 122.1 (CH2), 124.4 (C-3), 129.5 (t, 3JC–F = 4.5 Hz, CH), 136.6 (t,
(e) S. Anjaiah, S. Chandrasekhar, R. Gree, Advanced Synthesis and Catalysis 346
(2004) 1329;
(f) M.A. Iorio, R.T. Paszkowska, V. Frigeni, Journal of Medicinal Chemistry 30
(1987) 1906.
2JC–F = 26.25 Hz, C-6), 159.3 (C-2), 160.7 (C-4), 170.8 (CO). 19F NMR
˜
(282 MHz, CDCl3):
d
= ꢀ88.96 (CF2). IR (ATR, cmꢀ1):
n
= 2958 (w),
[5] (a) J.L. Popp, L.L. Musza, C.J. Barrow, P.J. Rudewicz, D.R. Houck, Journal of Anti-
biotics 47 (1994) 411;
2903 (w), 2869 (w), 1697 (m), 1655 (m), 1602 (w), 1438 (w), 1310
(w), 1234 (m), 1148 (m), 1103 (w), 1095 (s), 842 (m), 804 (w), 702
(w), 626 (m). GC–MS (EI, 70 eV): m/z (%): 314 (M+, 92), (M+, 92), 288
(40), 243 (22), 240 (20), 241 (75), 231 (10), 221 (13), 212 (33), 210
(35), 194 (14), 191 (100), 192 (30), 177 (15), 171 (12), 168 (10), 133
(16), 121 (12), 102 (10), 69 (13). HRMS (EI, 70 eV): calcd. for
(b) T.S. Chen, B. Petuch, J. MacConnell, R. White, G. Dezeny, Journal of Antibiotics
47 (1994) 1290;
(c) K.S. Lam, D.R. Schroeder, J.M. Veitch, K.L. Colson, J.A. Matson, W.C. Rose, T.W.
Doyle, S. Forenza, Journal of Antibiotics 54 (2001) 1.
[6] (a) H. Schmidbaur, O. Kumberger, Chemische Berichte 126 (1993) 3;
(b) M.B. Dinger, W.J. Henderson, Organometallic Chemistry 560 (1998) 233;
(c) J. Liedtke, S. Loss, C. Widauer, H. Gru¨ tzmacher, Tetrahedron 56 (2000) 143;
(d) S. Schneider, C.C. Tzschucke, W. Bannwarth, in: B. Cornils, W.A. Herrmann,
I.T. Horvath, W. Leitner, S. Mecking, H. Olivier-Booubigou, D. Vogt (Eds.),
Multiphase Homogeneous Catalysis, Wiley VCH, Weinheim, 2005 , p. 346
(Chapter 4);
(e) D. Clarke, M.A. Ali, A.A. Clifford, A. Parratt, P. Rose, D. Schwinn, W. Bann-
warth, C.M. Rayner, Current Topics in Medicinal Chemistry 7 (2004) 729.
[7] (a) Reviews: A. Wittkopp, P.R. Schreiner, The Chemistry of Diens and Polyenes,
second ed., John Wiley & Sons Ltd., 2000;
C
16H20O4F2 (M+) 314.13242, found 314.132385.
Methyl 2-(1,1-difluorobut-3-enyl)-6-hydroxy-4-methoxy-5-
octylbenzoate (7e): Starting with 4o (0.384 g, 1 mmol),
Bu3SnCH2CH55CH2 (1.65 g, 5.0 mmol), AIBN (0.020 g, 0.12 mmol),
the product 7e was isolated as a colorless oil (0.296 g, 77%);
RF = 0.59 (heptane/EtOAc = 3:2). 1H NMR (300 MHz, CDCl3):
d
= 0.70 (t, 3J = 7,0 Hz, 3H, CH3) 1.00–1.35 (m, 12H, (CH2)6), 2.47
3
3
(t, 3J = 7,5 Hz, 2H, CH2), 2.96 (dt, JHH = 7.1 Hz, JHF = 17.0 Hz, 2H,
(b) See also: P.R. Schreiner, Chemical Society Reviews, 32 (2003) 289;
(c) A. Wittkopp, P.R. Schreiner, Chemistry – A European Journal 9 (2003) 407;
(d) C.M. Kleiner, P.R. Schreiner, Chemical Communications (2006) 4315;
(e) M. Kotke, P.R. Schreiner, Synthesis 5 (2007) 779;
CH2), 3.68 (s, 3H, OCH3), 3.74 (s, 3H, OCH3), 5.02 (d, 3Jtrans = 12.2 Hz,
1H, CH55CH2), 5.07 (d, Jcis = 4.7 Hz, 1H, CH55CH2), 5.72 (dt, JH–
H = 7.0 Hz, JH–F = 27.3 Hz, dd, Jcis = 7.2 Hz, Jtrans = 13.65 Hz, 1H,
CH55CH2), 6.44 (s, 1H, H-5), 9.96 (s, 1H, OH). 13C NMR (75 MHz,
3
3
4
3
3
(f) S.B. Tsogoeva, European Journal of Organic Chemistry (2007) 1701.
[8] (a) A. Olah, G.K. Surya Prakash, R.D. Chambers, Synthetic Fluorine Chemistry,
Wiley & Sons, New York, 1992;
CDCl3):
d = 14.1 (CH3), 22.7, 22.9, 28.5, 29.4, 29.7, 31.9 (CH2), 43.3
(b) M.R.C. Gerstenberger, A. Haas, Angewandte Chemie International Edition in
English 20 (1981) 647–667;
(c) A. Kamal, T.B. Pratap, K. Venkata Ramana, A.V. Ramana, A. Hari Babu, Tetra-
hedron Letters 43 (2002) 7353.
(t, 2JC–F = 27.0 Hz, CH2), 52.2, 55.6 (OCH3), 102.4 (t, 3JC–F = 2.25 Hz,
C-5), 105.3 (C-1), 120.1 (CF2), 122.1 (CH2), 126.0 (C-3), 129.5 (t, 3JC–
F = 4.5 Hz, CH), 136.5 (t, 2JC–F = 26.25 Hz, C-6), 159.2 (C-2), 160.4 (C-
[9] Review: T. Furuya, A.S. Kamlet, T. Ritter, Nature, 473 (2011) 470.
[10] (a) X. Wang, T.-S. Mei, J.-Q. Yu, Journal of the American Chemical Society 131
(2009) 7520;
4), 170.65 (CO). 19F NMR (282 MHz, CDCl3):
(ATR, cmꢀ1):
d
= ꢀ88.79 (CF2). IR
˜
n
= 2959 (w), 2903(w), 2874 (w), 1700 (m), 1612 (w),
(b) P. Anbarasan, H. Neumann, M. Beller, Angewandte Chemie International
Edition 49 (2010) 2219;
1608 (w), 1234 (m), 1180 (m), 1144 (m), 1130 (m), 1109 (m), 1099
(m), 1082 (s), 840 (m), 802 (w), 693 (w), 627 (m). GC–MS (EI,
70 eV): m/z (%): 384 (M+, 88), 354 (12), 323 (22), 301 (34), 288 (42),
243 (21), 240 (13), 241 (66), 231 (10), 221 (13), 212 (33), 191 (100),
192 (22), 177 (13), 171 (10), 168 (22), 133 (11), 121 (11), 102 (10),
69 (10). HRMS (EI): calcd. for C21H30O4F2 (M+) 384.21122, found
384.21119.
´
(c) D.A. Watson, M. Su, G. Teverovskiy, Y. Zhang, J. Garcıa-Fortanet, T. Kinzel, S.L.
Buchwald, Science 325 (2009) 1661;
(d) P. Tang, T. Furuya, T. Ritter, Journal of the American Chemical Society 132
(2010) 12150–12154;
(e) M. Oishi, H. Kondo, H. Amii, Chemical Communications (2009) 1909;
(f) E.J. Cho, Science 328 (2010) 1679;
(g) X. Wang, L. Truesdale, J.-Q. Yu, Journal of the American Chemical Society 132
(2010) 3648;
(h) D.A. Nagib, M.E. Scott, D.W.C. MacMillan, Journal of the American Chemical
Society 131 (2009) 10875–10877;
(i) X.-F. Wu, P. Anbarasan, H. Neumann, M. Beller, Angewandte Chemie Interna-
tional Edition 49 (2010) 9047.
Acknowledgments
Financial support by the University of Rostock (scholarship of
the Interdisciplinary Faculty of the University of Rostock for S.R.)
and by the State of Mecklenburg-Vorpommern is gratefully
acknowledged.
[11] E.L. Piatnitski, M.A.J. Duncton, A.S. Kiselyov, R. Katoch-Rouse, D. Sherman, D.L.
Milligan, C. Balagtas, W.C. Wong, J. Kawakami, J.F. Doody, Bioorganic and Medici-
nal Chemistry Letters 15 (2005) 4696.
[12] M. Yoshida, Y. Morinaga, M. Iyoda, Journal of Fluorine Chemistry 68 (1994) 33.
[13] (a) G.A. Olah, M.B. Comisarow, Journal of the American Chemical Society 91
(1969) 2955;
References
(b) W.A. Sheppard, Tetrahedron 27 (1971) 945;
(c) J. He, C.U. Pittman, Synthetic Communications 29 (1999) 855.
[14] S. Rozen, E. Mishani, Journal of the Chemical Society Chemical Communications
18 (1994) 2081.
[1] (a) R. Filler, Y. Kobayasi, L.M. Yagupolskii, Fluorine in Bioorganic Chemistry,
Elsevier, Amsterdam, 1993;
[15] (a) L. Saint-Jalmes, Journal of Fluorine Chemistry 127 (2006) 85;
(b) S. Anguille, M. Garayt, V. Schanen, R. Gree, Advanced Synthesis and Catalysis
348 (2006) 1149.
[16] (a) G.A. Boswell, W.C. Ripka, R.M. Schribner, C.W. Tullock, Organic Reactions 21
(1974) 1;
(b) C.L. Wang, Journal of Organic Reactions 34 (1985) 319;
(c) W. Domowski, Journal of Fluorine Chemistry 32 (1986) 2555.
[17] T. Umemoto, R.P. Singh, Y. Xu, N. Saito, Journal of the American Chemical Society
132 (2010) 18199.
(b) R. Filler, Fluorine Containing Drugs in Organofluorine Chemicals and their
Industrial Application, Pergamon, New York, 1979, chapter 6;
(c) M. Hudlicky, Chemistry of Organic Compounds, Ellis Horwood, Chichester,
1992;
(d) P. Kirsch, Modern Fluoroorganic Chemistry, VCH, Weinheim, 2004;
(e) R.D. Chambers, Fluorine in Organic Chemistry, Blackwell Publishing CRC
Press, 2004.
[2] (a) T. Ryckmanns, L. Balancon, O. Berton, C. Genicot, Y. Lamberty, B. Lallemand, P.
´
´
Passau, N. Pirlot, L. Quere, P. Talaga, Bioorganic and Medicinal Chemistry Letters
[18] M. Hudlicky, Organic Reactions 35 (1988) 515.
[19] (a) V. Karapetyan, S. Mkrtchyan, G. Ghazaryan, A. Villinger, C. Fischer, P. Langer,
Tetrahedron 65 (2009) 9271;
12 (2002) 261;
(b) M.S. Malamas, J. Sredy, C. Moxham, A. Katz, W. Xu, R. McDevitt, F.O. Adebayo,
D.R. Sawicki, L. Seestaller, D. Sullivan, J.R. Taylor, Journal of Medicinal Chemistry
43 (2000) 1293;
(c) A.J. Ciha, P.G. Ruminski, Agricultural Journal of Food Chemistry 39 (1991)
2072;
(b) C. Mamat, T. Pundt, A. Schmidt, P. Langer, Tetrahedron Letters 47 (2006) 2183;
(c) C. Mamat, T. Pundt, T. Dang, R. Klassen, H. Reinke, M. Ko¨ckerling, P. Langer,
European Journal of Organic Chemistry (2008) 492–502;
(d) M. Lubbe, A. Bunescu, A. Villinger, P. Langer, Synlett (2008) 1862;
(e) A. Bunescu, S. Reimann, M. Lubbe, A. Spannenberg, P. Langer, Journal of
Organic Chemistry 74 (2009) 5002;
(d) S. Purser, P.R. Moore, Chemical Society Reviews 37 (2008) 320–330.
[3] K. Mu¨ller, C. Faeh, F. Diedrich, Science 317 (2007) 1881–1886.
[4] (a) H.A. Albrecht, G. Beskid, N.H. Georgopapadakou, D.D. Keith, F.M. Konzelmann,
D.L. Pruess, P.L. Rossman, C.C. Wei, J.G. Christenson, Journal of Medicinal Chem-
istry 34 (1991) 2857;
(f) M. Lubbe, C. Mamat, P. Langer, Synlett (2008) 1684.
[20] T.H. Chan, P. Brownbridge, Journal of the American Chemical Society 102 (1980)
3534.
[21] For a review of [3+3] cyclizations of 1,3-bis(silyloxy)-1,3-butadienes, see: H. Feist,
P. Langer, Synthesis, (2007) 327.
(b) H.A. Albrecht, G. Beskid, J.G. Christenson, K.H. Deitcher, N.H. Georgopapada-
kou, D.D. Keith, F.M. Konzelmann, D.L. Pruess, C.C. Wie, Journal of Medicinal
Chemistry 37 (1994) 400;
[22] For a review of the chemistry of 1,3-bis(silyl enol ethers) in general, see: P. Langer,
Synthesis, (2002) 441.
(c) C.W. Song, K.Y. Lee, C.D. Kim, T.-M. Chang, W.Y. Chey, Journal of Pharmacology
and Experimental Therapeutics 281 (1997) 1312;
[23] M. Medebielle, S. Hohn, E. Okada, H. Myoken, D. Shibata, Tetrahedron Letters 46
(2005) 7817.
(d) J.J. De Voss, Z. Sui, D.L. DeCamp, R. Salto, L.M. Babe, C.S. Craik, P.R. Ortiz de
Montellano, Journal of Medicinal Chemistry 37 (1994) 665;

S. Reimann et al. / Journal of Fluorine Chemistry 139 (2012) 28–45
45
[24] F. Fenain, M. Medebielle, M. Rocher, O. Onomura, E. Okada, D. Shibata, Journal of
Fluorine Chemistry 128 (2007) 1286.
[25] (a) P. Bannwarth, A. Valleix, D. Gre´e, R. Gre´e, Journal of Organic Chemistry 74
(2009) 4646;
(b) D. Gre´e, R. Gre´e, Tetrahedron Letters 48 (2007) 5435;
(c) S.A. Pujari, K.P. Kaliappan, A. Valleix, D. Gre´e, R. Gre´e, Synlett (2008) 2503.
[26] E. Sawicki, Journal of Organic Chemistry 21 (1956) 376.
[27] G.A. Molander, K.O. Cameron, Journal of the American Chemical Society 115
(1993) 830.
[28] V.T.H. Nguyen, E. Bellur, B. Appel, Synthesis (2006) 2865.
[29] (a) P. Brownbridge, T.-H. Chan, M.A. Brook, G.J. Kang, Canadian Journal of Chem-
istry 61 (1983) 688;
(b) K. Hirai, I. Ojima, Tetrahedron Letters 24 (1983) 785.
[30] CCDC 869951–869954 contain all crystallographic details of this publication and
is available free of charge at www.ccdc.cam.ac.uk/conts/retrieving.html or can be
ordered from the following address: Cambridge Crystallographic Data Centre, 12
Union Road, GB-Cambridge CB21EZ; Fax: (+44) 1223-336-033; or deposit@ccdc.
cam.ac.uk.
[31] (a) M.J. Frisch, G.W. Trucks, H.B. Schlegel, G.E. Scuseria, M.A. Robb, J.R. Cheese-
man, J.A. Montgomery Jr., T. Vreven, K.N. Kudin, J.C. Burant, J.M. Millam, S.S.
Iyengar, J. Tomasi, V. Barone, B. Mennucci, M. Cossi, G. Scalmani, N. Rega, G.A.
Petersson, H. Nakatsuji, M. Hada, M. Ehara, K. Toyota, R. Fukuda, J. Hasegawa, M.
Ishida, T. Nakajima, Y. Honda, O. Kitao, H. Nakai, M. Klene, X. Li, J.E. Knox, H.P.
Hratchian, J.B. Cross, V. Bakken, C. Adamo, J. Jaramillo, R. Gomperts, R.E. Strat-
mann, O. Yazyev, A.J. Austin, R. Cammi, C. Pomelli, J.W. Ochterski, P.Y. Ayala, K.
Morokuma, G.A. Voth, P. Salvador, J.J. Dannenberg, V.G. Zakrzewski, S. Dapprich,
A.D. Daniels, M.C. Strain, O. Farkas, D.K. Malick, A.D. Rabuck, K. Raghavachari, J.B.
Foresman, J.V. Ortiz, Q. Cui, A.G. Baboul, S. Clifford, J. Cioslowski, B.B. Stefanov, G.
Liu, A. Liashenko, P. Piskorz, I. Komaromi, R.L. Martin, D.J. Fox, T. Keith, M.A. Al-
Laham, C.Y. Peng, A. Nanayakkara, M. Challacombe, P.M.W. Gill, B. Johnson, W.
Chen, M.W. Wong, C. Gonzalez, J.A. Pople, Gaussian 03, Revision C.02, Gaussian
Inc., Wallingford CT, 2004;
(b) A.-D. Becke, Journal of Chemical Physics 98 (1993) 5648;
(c) C. Lee, W. Yang, R.G. Parr, Phys. Rev. B 37 (1988) 785;
(d) E.D. Glendening, A.E. Reed, J.E. Carpenter, F. Weinhold, NBO Version 3.1.
[32] A. Arnone, P. Bravo, G. Cavicchio, M. Frigeria, F. Viani, Tetrahedron 48 (1992) 8523.