Synthesis of trifluoromethyl-substituted salicylates by cyclocondensation of 1,3-bis(silyloxy)-1,3-butadienes with 4,4-dimethylthio-1,1,1-trifluorobut-3- en-2-one

Article abstract of DOI:10.1016/j.jfluchem.2011.04.011

A formal [3+3] cyclocondensation of 1,3-bis(silyl enol ethers) with the little-known 4,4-dimethylthio-1,1,1-trifluorobut-3-en-2-one was studied. In contrast to 4,4-dimethoxy-1,1,1-trifluorobut-3-en-2-one, this α-oxoketene dithioacetal reacts with 1,3-bis(

Full text of DOI:10.1016/j.jfluchem.2011.04.011

Journal of Fluorine Chemistry 132 (2011) 441–449
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Synthesis of trifluoromethyl-substituted salicylates by cyclocondensation of
1,3-bis(silyloxy)-1,3-butadienes with 4,4-dimethylthio-1,1,
1-trifluorobut-3-en-2-one
Viktor O. Iaroshenko a,b, , Alina Bunescu a,c, Lutz Domke a, Anke Spannenberg c, Dmitri V. Sevenard d,
*
Alexander Villinger a, Vyacheslav Ya. Sosnovskikh e, Peter Langer a,c,
*
a Institut fu¨r Chemie, Universita¨t Rostock, Albert-Einstein-Str. 3a, 18059 Rostock, Germany
b National Taras Shevchenko University, 62 Volodymyrska St., Kyiv-33 01033, Ukraine
c
¨
Leibniz-Institut fu¨r Katalyse e. V. an der Universitat Rostock, Albert-Einstein-Str. 29a, 18059 Rostock, Germany
d Hansa Fine Chemicals GmbH, BITZ, Fahrenheitstrasse 1, 28359 Bremen, Germany
e Department of Chemistry, Ural State University, 51 Lenina Ave., 620083 Ekaterinburg, Russian Federation
A R T I C L E I N F O
A B S T R A C T
Article history:
A formal [3+3] cyclocondensation of 1,3-bis(silyl enol ethers) with the little-known 4,4-dimethylthio-
1,1,1-trifluorobut-3-en-2-one was studied. In contrast to 4,4-dimethoxy-1,1,1-trifluorobut-3-en-2-one,
Received 16 February 2011
Received in revised form 15 April 2011
Accepted 19 April 2011
this
a-oxoketene dithioacetal reacts with 1,3-bis(trimethylsilyloxy)-1,3-butadienes in the presence of
TiCl4 to give mainly 6-methylthio-4-(trifluoromethyl)salicylates via 1,2-addition. The scope and
limitations of the reaction are discussed.
Available online 27 April 2011
ß 2011 Elsevier B.V. All rights reserved.
Keywords:
1,3-Bis(silyl enol ethers)
4,4-Dimethylthio-1,1,1-trifluorobut-3-en-
2-on
Cyclocondensation
Trifluoromethyl-substituted salicylates
Regioselectivity
1. Introduction
Chan and co-workers developed [3] a convenient synthesis of
salicylates by cyclocondensation of 1,3-bis(silyl enol ethers) [4]
Polysubstituted aromatic compounds are useful intermediates
in organic syntheses. However, their preparation by classical
synthetic methods is restrained by the customary long synthetic
routes and the difficult separation of positional isomers which are
often formed. Besides, it has not been possible so far to introduce a
perfluoroalkyl group using Friedel–Crafts type electrophilic
substitution reactions. At the same time, fluorinated arenes
represent important molecules in organic and medicinal chemistry
[1]. In fact, undesirable metabolic transformations are often
avoided, due to the high chemical and biological stability of the
fluoro group. Thus, the preparation of specific positional isomers of
polysubstituted trifluoromethylated arenes is of considerable
current interest [1,2].
with 3-silyloxy-2-en-1-ones. In recent years, we have extended
the scope of this chemistry and studied its application to the
synthesis of a variety of functionalized arenes [5]. For example,
formal [3+3] cyclocondensations of 1,3-bis(trimethylsilyloxy)-
1,3-butadienes
1 with 3-alkoxy-1-alkyl-2-en-1-ones [6], 3-
alkoxy-1-trifluoromethyl-2-en-1-ones [7], and related enones
[8], in particular with 4,4-dimethoxy-1,1,1-trifluorobut-3-en-2-
one
2 [9], to afford new aromatic compounds has been
described. In most reactions developed so far, the products
– functionalized salicylates – contain CF3 group located at C-6 as
in compounds 3. 3,3-Bis(methylthio)propenones 4 have also
been successfully applied in reactions with 1 and salicylates 5
have been prepared [10]. In this case, the regioselectivity
(initial 1,2-addition) is opposite to the one observed for
cyclocondensations of 1,3-bis(silyl enol ethers) 1 with 3-alkoxy-
and 3-silyloxypropenones (initial 1,4-addition). In keeping with
* Corresponding authors at: Institut fu¨r Chemie, Universita¨t Rostock, Albert-
Einstein-Str. 3a, 18059 Rostock, Germany. Tel.: +49 381 4986410;
fax: +49 381 49864112.
the greater ability of
a-oxoketene dithioacetals to afford
products of 1,2-addition with C-nucleophiles (for example,
Junjappa–Ila annulation [11]), we envisaged that the reaction of
4,4-dimethylthio-1,1,1-trifluorobut-3-en-2-one 6 with 1 would
E-mail addresses: viktor.iaroshenko@uni-rostock.de (V.O. Iaroshenko),
peter.langer@uni-rostock.de (P. Langer).
0022-1139/$ – see front matter ß 2011 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2011.04.011

442
V.O. Iaroshenko et al. / Journal of Fluorine Chemistry 132 (2011) 441–449
OH
O
OH
O
MeO
MeO
O
OR
OR2
SMe
CF3
2
MeO
Ar
CF3
F3C
3
7a-g
OH
O
MeS
MeS
O
O
TiCl4,
CH2Cl2
R1 = H
Me3SiO
OSiMe3
OR
OR
Ar
4
6
SMe
Me3SiO
R1
OSiMe3
OR2
MeS
MeS
O
1
5
+
CF3
MeS
MeS
OH
O
6
1a-r
CF3
OR
SMe
TiCl4,
CH2Cl2
R1 = Alk
F3C
7
OH
O
OH
O
Scheme 1.
R1
R1
MeS
OR2
OR2
CF3
+
produce the corresponding 4-trifluoromethyl-substituted
salicylates 7. Indeed, we found that 6-methylthio-4-(trifluor-
omethyl)salicylates 7 can be obtained by reaction of 1,3-bis(silyl
enol ethers) 1, prepared according to the literature from the
F3C
SMe
7h-r
8h-r
Scheme 2.
corresponding
dimethylthio-1,1,1-trifluorobut-3-en-2-one 6. The latter was
synthesized, following known procedure [13], by base-
b-ketoesters in two steps [3,12], with 4,4-
a
similar in their reactivities with ammonia and primary amines
[14], however, their reaction with 1,3-bis(silyl enol ethers) 1
gave completely different products. The reaction of 1 with
dithioacetal 6 gave 4-(trifluoromethyl)salicylates 7, while the
reaction of 1 with acetal 2 afforded 6-(trifluoromethyl)salicy-
lates 3 [9].
Having established that the 1,2-addition is the major mecha-
nistic pathway for the reaction of dithioketeneacetal 6 with 1a–g, it
was interesting to study the reaction of 6 with 1,3-bis(silyloxy)-
mediated reaction of 1,1,1-trifluoroacetone with carbon
disulfide and methyl iodide (Scheme 1).
The easy accessibility and high electrophilicity make dithioa-
cetal 6 an attractive candidate for further synthetic elaboration.
However, little effort has been devoted to trifluoroacetylketene
dithioacetals, especially with respect to C-nucleophiles. To the best
of our knowledge, there are only two reports on the reactions of 6
with amines, which proceed via nucleophilic 1,4-addition,
followed by elimination [13,14].
1,3-butadienes 1h–r containing
a terminal substituent. As
expected, the regioselectivity of the nucleophilic attack depends
on the steric effects of the substituents. In fact, the regioselectivity
dropped, however, the 1,2-attack is still dominant. The reaction of
dienes 1h–r with enone 6, in the presence of TiCl4, afforded
mixtures of two regioisomeric products. The expected 6-
methylthio-4-(trifluoromethyl)salicylates 7h–r were formed by
1,2-addition, and the 4-methylthio-6-(trifluoromethyl)salicylates
8h–r were formed by 1,4-addition in variable proportions and
yields (23–69%) (Scheme 2, Table 2).
It is noteworthy that the regioselectivity decreased with
increasing steric hindrance of the 1,3-bis(silyl enol ether). This
fact suggests that the steric effect of the R1 group located at the
carbon atom C-4 of the diene influences the course of the
annulation reaction. The moderate yields can be explained by
hydrolysis and TiCl4-mediated oxidative dimerization of dienes
1. This type of process has been previously reported [15]. Note
2. Results and discussion
It is evident from the reactions of 1,3-bis(trimethylsilyloxy)-
1,3-butadienes
1 with a number of electrophiles that the
nucleophilic site at C-4 is more reactive than that at C-2 [3–
6]. On the other hand, it is known that the allyl and heteroallyl
anions add to the
a-oxoketene dithioacetals mainly by 1,2-
addition [11a,b] (the electron-donating sulfur atoms increase
the negative charge of C-4 atom compared with that of electron-
withdrawing oxygen atom, which rationalizes their 1,2-addition
preference [11c]). In accordance with this, we found that the
TiCl4-mediated cyclocondensation of 6 with 1a–g derived from
unsubstituted alkyl acetoacetates afforded the products of 1,2-
addition, namely 6-methylthio-4-(trifluoromethyl)salicylates
7a–g, in 49–56% yields (Scheme 2). The reaction conditions
have been optimized for the synthesis of derivative 7d (Table 1),
the structure of which was elucidated by 2D NMR spectroscopic
methods (NOESY and COSY). During the optimization, the
concentration and the stoichiometry play an important role.
The best yield is obtained when the solution is slowly warmed
from À78 to 20 8C, when the reaction is carried out in a highly
concentrated solution, and when an excess (2.0 equiv.) of 1 is
employed. Products 7a–g, containing the CF3 group located para
to the ester group, are formed with excellent regioselectivity.
The formation of the other regioisomer, containing the CF3
group located ortho to the ester group, is not observed in these
examples. It should be emphasized that acetals 2 and 6 are quite
Table 1
Optimization of the synthesis of 7d.
Ratio of 6:1d (mmol)
CH2Cl2 (mL)
Yielda of 7d (%)
1:2
1:1
1:2
1:3
1:2
1:2
0
1
1
1
2
5
26
33
56
21
38
39
a
Yields of the isolated product.

V.O. Iaroshenko et al. / Journal of Fluorine Chemistry 132 (2011) 441–449
443
Table 2
Synthesis of salicylates 7 and 8.
Bissilyl 1
R1
R2
Arenes
Ratio of
Yielda
(%)
7, 8
7:8
a
b
c
H
Me
Et
7a
52
51
51
56
49
56
55
69
54
39
50
30
36
34
50
44
54
23
H
7b
H
Bn
7c
d
e
f
H
i-Pr
i-Bu
i-Pent
n-Oct
Me
Me
Me
Et
7d
H
7e
H
7f
g
h
i
H
7g
Me
7h + 8h
7i + 8i
7j + 8j
7k + 8k
7l + 8l
7m + 8m
7n + 8n
7o + 8o
7p + 8p
7q + 8q
7r + 8r
1:0.1
1:0.1
1:0.1
1:0.4
1:0.5
1:0.7
1:0.7
1:0.7
1:0.5
1:0.4
1:1
Et
j
n-Pr
i-Pr
n-Bu
n-Pent
n-Hept
n-Oct
Allyl
(CH2)3Cl
(CH2)3Ph
k
l
Et
m
n
o
p
q
r
Et
Et
Fig. 1. Molecular structure of compound 7a.
Me
Me
Me
Et
crystal structure analyses [16] (Figs. 1 and 2). Thus, we have shown
that, while the addition of 1,3-bis(silyl enol ethers) to -alkoxy-
-unsaturated fluorinated ketones proceeds by a 1,4-pathway,
additions to -oxoketene dithioacetals occur by preferential 1,2-
b
a
Yields of isolated products.
a,b
a
addition. Obviously, the change in the regioselectivity is a result of
the replacement of the methoxy groups by methylthio groups in
the 1,1,1-trifluorobut-3-en-2-one. Taking into account that the
methylthio substituent can easily be removed by desulfurization
[17], this is also a method for preparing 4-CF3-substituted
derivatives of salicylic acid. Given the actual interest in fluoroar-
enes as pharmaceutical intermediates [1,2], this simple entry to
novel fluorinated arenes is useful and complements the published
synthetic methods.
When the reaction of 6 with 1a,b was catalyzed by AlCl3 (1.0
equiv.), salicylates 7a,b were isolated in high yield (75–80%),
however the other bis-silyls gave no results with AlCl3. The
terminal substituted diene 1h under AlCl3 conditions gave the
stable cyclohexenone 9h in 52% yield. Similar compounds have
been observed earlier [9]. The X-ray crystal structure analysis of
9h allows to unambiguously prove the relative configuration of
this molecule [16]. The hydroxyl and the ester group are located
cis to each other and an intramolecular hydrogen bond O–
HÁ Á ÁO55C is present (Fig. 3). In this case, there is a preference for
1,4-addition, followed by elimination of methanethiol (the
conjugative position is more reactive than the carbonyl function).
This might be explained by the steric influence of the methyl
group, which results in a change of the reaction route with regard
that regioisomers 7 and 8 could be easily distinguished by the
chemical shift of the phenolic proton in a CDCl3 solution. For
7j,m,o, this signal is observed as a singlet at
d 11.77–11.86 ppm,
whereas for 8j,m,o the protons are more shielded (
d 11.17–
11.31 ppm).
In an analogous manner the less reactive benzoylacetone-
derived diene 1s gave, by initial 1,2-addition, the benzophenone 7s
as the only isolated product in 39% yield (Scheme 3). This result
clearly shows that the present methodology could be applicable to
various types of 1,3-bis(silyl enol ethers), providing a rapid route to
the synthesis of a great variety of CF3-containing arenes. The
structures of 7a and 7s are independently confirmed by X-ray
OH
O
OH
O
OR2
Ph
F3C
SMe
F3C
SMe
7a,b (75-80%)
7s (39%)
R1 = H AlCl3
TiCl4
Me3SiO
R1
OSiMe3
OR2
Me3SiO
OSiMe3
Ph
6
+
+
1a,b,f-h,t
1s
TMSOTf
R1 = Me
AlCl3
R1 = H
O
O
O
O
Me
OR2
SMe
OMe
HO
F3C
OH
MeS
CF3
9h (52%)
10a,f,g,t (32-52%)
Scheme 3.
Fig. 2. Molecular structure of compound 7s.

444
V.O. Iaroshenko et al. / Journal of Fluorine Chemistry 132 (2011) 441–449
O
SMe
Me3SiO
OSiMe3
+
CH2Cl2 TiCl4
Cl
OR2
4
2
4
3
R1
1
F3C
SMe
3
2
6
1
Cl3TiO
SMe
+
CF3
SMe
A
-TMSCl
R1 = H
1
R1 = Alk
Me3SiO
O
Me3SiO
R1
O
Fig. 3. Molecular structure of compound 9h.
OR2
SMe
OR2
OTiCl3
CF3
Cl3TiO
F3C
MeS
SMe
MeS
B
D
to unsubstituted dienes 1a–g. Attempts to synthesize other
derivatives 9 in the presence of AlCl3/DCM as well as arenes 7
using BF3/DCM or ZnCl2/THF failed.
-TMSOTiCl3
-TMSSMe
Next, we have made efforts to increase the yield of salicylates
7 by changing the catalyst to Me3SiOTf (1.0 equiv.). Starting with
dienes 1a,f,g,t, which do not contain a substituent located at
carbon C-4 (R1 = H), the trifluoromethylated cyclohexenones
10a,f,g,t, which are regioisomeric to 9h, were obtained in 32–
52% yields. The formation of these products proceeds by 1,2-
addition of the diene to the enone 6 with subsequent ring
closure (Scheme 3). In contrast to the formation of salicylates 7,
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 the
intermediate containing a titanium alkoxide moiety readily
undergoes an elimination of TiCl3OH and aromatization, while
the analogous intermediate containing a silanolate moiety is
more stable and no elimination occurs. The aromatization of 10
by elimination of water is difficult because of the destabilisation
of a carbocationic intermediate by the electron-withdrawing CF3
group. The regiochemistry of 10a is independently confirmed by
X-ray crystal structure analysis (Fig. 4) [16]. The structures of
cyclohexenones 10f,g,t were firmly established by comparison
of their spectra with the spectra of 10a.
O
O
O
O
R1
OR2
OTiCl3
CF3
OR2
SMe
SMe
MeS
F3C
C
E
-MeSH H2O
H2O -TiCl3OH
7
8
O
O
O
O
R1
OR2
SMe
OR2
HO
F3C
OH
MeS
CF3
10
9
Scheme 4.
The formation of product 7 can be explained by reaction of 6
with a Lewis acid, for example TiCl4, to give cation A containing
an allylic carbon unit. The attack of the terminal carbon atom of
1
onto the activated carbonyl group of A (1,2-addition,
intermediate B), cyclization (intermediate C), and subsequent
aromatization by extrusion of methanethiol give 4-CF3-substi-
tuted salicylates 7. The formation of the other regioisomer 8,
containing the CF3 group located ortho to the ester group,
proceeds by attack of the substituted terminal carbon atom of 1
onto the
b-carbon atom of A to give intermediate D; the
elimination of Me3SiSMe and subsequent cyclization afforded
intermediate E (l,4-addition–elimination sequence). The elimi-
nation of titanium hydroxide (before or during the aqueous
workup) and aromatization results in the formation of product
8. It is evident that compounds 9 (AlCl3 conditions) and 10
(Me3SiOTf conditions) are formed by the sequence of reactions
shown in Scheme 4.
Derivatives of ortho-acylated phenols and thiophenols have
recently been used for the synthesis of various benzofurans and
benzothiophenes [18]. We therefore investigated the synthesis of a
benzofuran derivative starting from arene 7a. First, 7a was
alkylated by 2-bromoacetophenone, 2-(bromomethyl)oxirane or
methyl bromoacetate as representative examples to give com-
pounds 11–13 in 31–99% yields. When 13 was heated in methanol
in the presence of sodium methoxide for 6h, cyclization took place
Fig. 4. Molecular structure of compound 10a.

V.O. Iaroshenko et al. / Journal of Fluorine Chemistry 132 (2011) 441–449
445
Ph
filtrate was concentrated in vacuo. The residue was purified by
chromatography.
O
O
O
O
O
O
OMe
SMe
11 (31%)
OMe
4.1.1. Methyl 6-methylthio-4-(trifluoromethyl)salicylate (7a)
F3C
F3C
SMe
Starting with
6 (0.216 g, 1.0 mmol) and 1-methoxy-1,3-
bis(trimethylsilyloxy)-1,3-butadiene 1a (0.521 g, 2.0 mmol), prod-
uct 7a was isolated as a colorless solid. Yield 0.138 g (52%), mp
12 (99%)
91 8C; 1H NMR (300 MHz, CDCl3)
d
2.47 (s, 3H, SMe), 4.04 (s, 3H,
OMe), 6.86 (br s, 1H, CH), 6.99 (d, 4J = 1.1 Hz, 1H, CH), 11.46 (s, 1H,
OH); 13C NMR (63 MHz, CDCl3)
16.4 (SMe), 52.4 (OMe), 110.7 (q,
PhCOCH2Br
CH2Br
O
d
OH
O
JC,F = 3.8 Hz, C-3), 111.3 (q, JC,F = 3.8 Hz, C-5), 112.5 (C-1), 123.1 (q,
JC,F = 273.4 Hz, CF3), 135.4 (q, JC,F = 32.8 Hz, C-4), 146.0, 163.4 (C),
OMe
SMe
170.2 (C55O); 19F NMR (282 MHz, CDCl3)
d
À64.2 (CF3); IR (ATR,
cmÀ1
) n 3041 (w), 2960 (w), 2922 (w), 1667 (w), 1610 (w), 1575
F3C
(w), 1557 (w), 1441 (w), 1416 (w), 1351 (w), 1338 (w), 1292 (w),
1107 (m), 929 (m), 799 (m), 744 (m), 699 (m); GC–MS (EI, 70 eV) m/
z (%) 266 (M+, 52), 236 (11), 235 (18), 234 (100), 206 (47), 191 (39),
163 (7); HRMS (EI, 70 eV): calcd for C10H9F3O3S (M+) 266.02190,
found 266.021597. Anal. Calcd. for C10H9F3O3S: C, 45.11; H, 3.41.
Found: C, 45.30; H, 3.09.
7a
BrCH2CO2Me
MeO
SMe
O
O
OH
O
O
MeONa
OMe
SMe
13 (71%)
4.1.2. Ethyl 6-methylthio-4-(trifluoromethyl)salicylate (7b)
OMe
O
Starting with 6 (0.216 g, 1.0 mmol) and 1-ethoxy-1,3-bis(tri-
methylsilyloxy)-1,3-butadiene 1b (0.549 g, 2.0 mmol), product 7b
was isolated as a colorless solid. Yield 0.143 g (51%), mp 65–66 8C;
F3C
F3C
14 (31%)
1H NMR (300 MHz, CDCl3) 1.49 (t, 3J = 7.1 Hz, 3H, Me), 2.46 (s, 3H,
d
Scheme 5.
SMe), 4.52 (q, 3J = 7.2 Hz, 2H, OCH2), 6.85 (br s, 1H, CH), 6.98 (d,
4J = 1.1 Hz, 1H, CH), 11.57 (s, 1H, OH); 13C NMR (63 MHz, CDCl3)
d
to give the previously unknown benzofuran 14 in 31% yield
(Scheme 5).
14.1 (Me), 16.4 (SMe), 62.8 (CH2), 110.7 (q, JC,F = 3.8 Hz, C-3), 111.2
(q, JC,F = 3.8 Hz, C-5), 112.7 (C-1), 123.2 (q, JC,F = 273.3 Hz, CF3),
135.3 (q, JC,F = 32.7 Hz, C-4), 146.2, 163.4 (C), 169.8 (C55O); 19F NMR
(282 MHz, CDCl3)
d
À64.1 (CF3); IR (ATR, cmÀ1
) n 3000 (w), 2925
3. Conclusion
(w), 1661 (w), 1607 (w), 1576 (w), 1466 (w), 1450 (w), 1412 (w),
1374 (w), 1349 (m), 1289 (m), 1221 (m), 1014 (w), 956 (m), 801
(m), 773 (w), 698 (m); GC–MS (EI, 70 eV) m/z (%) 280 (M+, 40), 235
(21), 234 (100), 206 (42), 191 (29); HRMS (EI, 70 eV): calcd for
In conclusion, we reported a convenient and short synthesis of
functionalized 6-methylthio-4-(trifluoromethyl)salicylates by the
formal [3+3] cyclocondensation of 1,3-bis(silyl enol ethers) with
4,4-dimethylthio-1,1,1-trifluorobut-3-en-2-one. The products
C
C
11H11F3O3S (M+) 280.03755, found 280.03832. Anal. Calcd. for
11H11F3O3S: C, 47.14; H, 3.96. Found: C, 47.08; H, 3.33.
constitute an important structural subunit of
a variety of
biologically active compounds, which are not readily available
by other methods. They could serve as versatile and useful building
blocks in the construction of functionalized heterocycles bearing a
trifluoromethyl group.
4.1.3. Benzyl 6-methylthio-4-(trifluoromethyl)salicylate (7c)
Starting with 6 (0.216 g, 1.0 mmol) and 1-benzyloxy-1,3-
bis(trimethylsilyloxy)-1,3-butadiene 1c (0.673 g, 2.0 mmol), prod-
uct 7c was isolated as a slight yellow solid. Yield 0.175 g (51%), mp
82–84 8C; 1H NMR (300 MHz, CDCl3)
CH2), 6.85 (br s, 1H, CH), 6.98 (d, 4J = 0.9 Hz, 1H, CH), 7.36–7.53 (m,
5H, Ph), 11.48 (s, 1H, OH); 13C NMR (75 MHz, CDCl3)
16.5 (SMe),
d 2.44 (s, 3H, SMe), 5.50 (s, 2H,
4. Experimental
NMR spectra were recorded on a Brucker AVANCE 250 II,
Brucker AV 300 and Brucker AV 400. IR spectra were recorded on a
Perkin Elmer FT IR 1600 spectrometer (ATR). Mass spectra were
obtained on a Hewlett-Packard HPGC/MS 5890/5972 instrument
(EI, 70 eV) by GC inlet or on a MX-1321 instrument (EI, 70 eV) by
direct inlet. Column chromatography was performed on silica gel
(63–200 mesh, Merck). Silica gel Merck 60F254 plates were used for
TLC. All solvents were purified and dried by standard methods. The
d
68.0 (OCH2), 110.7 (q, JC,F = 3.9 Hz, C-3), 111.2 (q, JC,F = 3.9 Hz, C-5),
112.5 (C-1), 123.1 (q, JC,F = 273.4 Hz, CF3), 128.5, 128.7, 128.7 (CH),
134.4 (C), 135.4 (q, JC,F = 32.8 Hz, C-4), 146.3, 163.5 (C), 169.6
(C55O); 19F NMR (282 MHz, CDCl3)
d
À64.2 (CF3); IR (ATR, cmÀ1
) n
3031 (w), 2988 (w), 2956 (w), 2925 (w), 1731 (w), 1698 (w), 1663
(m), 1611 (w), 1600 (w), 1577 (m), 1496 (m), 1455 (w), 1428 (m),
1412 (m), 1387 (m), 1342 (m), 1289 (s), 1218 (s), 1182 (s), 1116 (s),
964 (s), 909 (s), 860 (s), 846 (s), 799 (s), 762 (m), 746 (s), 695 (s);
GC–MS (EI, 70 eV): m/z (%) = 342 (M+, 33), 92 (9), 91 (100); HRMS
(EI, 70 eV): calcd for C16H13F3O3S (M+) 342.05320, found
342.05339.
starting 4,4-dimethylthio-1,1,1-trifluorobut-3-en-2-one
prepared according to described procedure [13].
6 was
4.1. General procedure for the synthesis of salicylates 7 and 8
To a solution of 1,1,1-trifluoro-4,4-bis(methylthio)but-3-en-
2-one 6 (1.0 mmol) in CH2Cl2 (1 mL) was added bissilyl 1
(2.0 mmol) and, subsequently, TiCl4 (0.11 mL, 1.0 mmol) at
À78 8C. The temperature of the solution was allowed to warm
to 20 8C during 12–14 h with stirring. To the solution was added
HCl (10%, 15 mL), and the organic and the aqueous layer were
separated. The latter was extracted with CH2Cl2 (3 Â 15 mL). The
combined organic layers were dried (Na2SO4), filtered, and the
4.1.4. Isopropyl 6-methylthio-4-(trifluoromethyl)salicylate (7d)
Starting with 6 (0.216 g, 1.0 mmol) and 1-isopropyloxy-1,3-
bis(trimethylsilyloxy)-1,3-butadiene 1d (0.577 g, 2.0 mmol), prod-
uct 7d was isolated as a colorless oil. Yield 0.164 g (42%); 1H NMR
(300 MHz, CDCl3)
5.31–5.44 (m, 1H, OCH), 6.85 (br s, 1H, CH), 6.97 (d, 3J = 1.1 Hz, 1H,
CH), 11.65 (s, 1H, OH); 13C NMR (75 MHz, CDCl3)
16.5 (SMe), 22.1
(Me), 71.8 (CH), 110.6 (q, JC,F = 3.9 Hz, C-3), 111.2 (q, JC,F = 3.9 Hz, C-
d
1.48 (d, 3J = 6.2 Hz, 6H, 2 Me), 2.45 (s, 3H, SMe),
d

446
V.O. Iaroshenko et al. / Journal of Fluorine Chemistry 132 (2011) 441–449
5), 113.0 (C-1), 123.2 (q, JC,F = 273.4 Hz, CF3), 135.1 (q, JC,F = 32.6 Hz,
(M+, 17), 252 (11), 235 (28), 234 (100), 206 (11); HRMS (EI, 70 eV):
calcd for C17H23F3O3S (M+) 364.13145, found 364.13071. Anal.
Calcd. for C17H23F3O3S: C, 56.03; H, 6.36. Found: C, 56.20; H, 6.39.
C-4), 146.2, 163.4 (C), 169.4 (C55O); 19F NMR (282 MHz, CDCl3)
d
À64.1 (CF3); IR (ATR, cmÀ1
) n 2985 (w), 2925 (w), 1724 (w), 1660
(m), 1609 (m), 1575 (m), 1468 (w), 1455 (w), 1412 (s), 1373 (m),
1342 (s), 1289 (s), 1276 (m), 1221 (s), 1190 (s), 1123 (s), 1097 (s),
959 (s), 907 (m), 805 (m), 758 (m), 699 (s); GC–MS (EI, 70 eV) m/z
(%) 294 (M+, 24), 252 (17), 235 (22), 234 (100), 206 (27), 191 (16);
HRMS (EI, 70 eV): calcd for C12H13F3O3S (M+) 294.05320, found
294.053170. Anal. Calcd. for C12H13F3O3S: C, 48.97; H, 4.45. Found:
C, 48.99; H, 4.32.
4.1.8. Methyl 6-methylthio-3-propyl-4-(trifluoromethyl)salicylate
(7j) and methyl 4-methylthio-3-propyl-6-(trifluoromethyl)salicylate
(8j)
Starting with 6 (0.216 g, 1.0 mmol) and 1-methoxy-1,3-
bis(trimethylsilyloxy)-1,3-heptadiene 1j (0.605 g, 2.0 mmol), a
mixture of regioisomers 7j and 8j (1:0.2) was isolated as a
colorless oil. Yield 0.119 g (39%); 1H NMR (300 MHz, CDCl3) for
4.1.5. Isobutyl 6-methylthio-4-(trifluoromethyl)salicylate (7e)
Starting with 6 (0.216 g, 1.0 mmol) and 1-isobutyloxy-1,3-
bis(trimethylsilyloxy)-1,3-butadiene 1e (0.605 g, 2.0 mmol), prod-
uct 7e was isolated as a colorless solid. Yield 0.150 g (49%), mp 49–
7j
3H, SMe), 2.70 (t, 3J = 8.0 Hz, 2H, CH2), 4.03 (s, 3H, OMe), 6.90,
(br s, 1H, Ar), 11.78 (s, 1H, OH), for 8j
1.00, (t, 3J = 7.4 Hz, 3H,
d
1.01 (t, 3J = 7.4 Hz, 3H, Me), 1.51–1.65 (m, 2H, CH2), 2.45, (s,
d
Me), 1.51–1.65 (m, 2H, CH2), 2.51 (s, 3H, SMe), 2.76 (t,
50 8C; 1H NMR (300 MHz, CDCl3)
d
1.08 (d, 3J = 6.8 Hz, 6H, 2 Me),
3J = 7.9 Hz, 2H, CH2), 3.96, (s, 3H, OMe), 7.07 (br s, 1H, Ar),
2.12–2.25 (m, 1H, CH), 2.47 (s, 3H, SMe), 4.25 (d, 3J = 6.4 Hz, 2H,
OCH2), 6.86 (br s, 1H, CH), 6.98 (d, 4J = 1.1 Hz, 1H, CH), 11.69 (s, 1H,
11.18, (s, 1H, OH); 13C NMR (63 MHz, CDCl3) for 7j
d 14.5 (Me),
16.2 (SMe), 22.7, 28.6 ((CH2)2), 52.4, (OMe), 112.1, 111.5 (q,
JC,F = 6.4 Hz, CHAr), 123.8 (q, JC,F = 275.1 Hz, CF3), 126.3 (q,
JC,F = 31.9 Hz, CCF3), 133.1 (q, JC,F = 29.3 Hz, CCF3), 141.4, 162.3
OH); 13C NMR (75 MHz, CDCl3)
d 16.5 (SMe), 19.3 (Me), 27.6 (CH),
73.1 (CH2), 110.7 (q, JC,F = 3.9 Hz, C-3), 111.1 (q, JC,F = 3.9 Hz, C-5),
112.7 (C-1), 123.2 (q, JC,F = 273.4 Hz, CF3), 135.3 (q, JC,F = 32.6 Hz, C-
(C), 170.8 (C55O), for 8j
d 14.3 (Me), 14.8 (SMe), 20.9, 29.1
4), 146.1, 163.3 (C), 170.1 (C55O); 19F NMR (282 MHz, CDCl3)
d
((CH2)2), 52.7 (OMe), 106.5, 113.9 (q, JC,F = 7.2 Hz), 123.5 (q,
JC,F = 273.3 Hz, CF3), 131.9, 127.8 (q, JC,F = 31.9 Hz, CCF3), 145.6,
À64.1 (CF3); IR (ATR, cmÀ1
) n 3067 (w), 2967 (w), 2924 (w), 2873
(w), 1666 (s), 1610 (w), 1571 (m), 1465 (w), 1414 (m), 1381 (m),
1369 (m), 1342 (s), 1222 (m), 1184 (s), 1114 (s), 956 (m), 938 (s),
776 (m), 697 (s); GC–MS (EI, 70 eV) m/z (%) 308 (M+, 27), 252 (11),
235 (25), 234 (100), 206 (20), 191 (12); HRMS (EI, 70 eV): calcd for
159.3 (C), 170.2 (C55O); 19F NMR (282 MHz, CDCl3) for 7j
d
À60.5
(CF3), for 8j
d
À58.7 (CF3).
4.1.9. Ethyl 6-methylthio-3-pentyl-4-(trifluoromethyl)salicylate
(7m) and ethyl 4-methylthio-3-pentyl-6-(trifluoromethyl)salicylate
(8m)
C
C
13H15F3O3S (M+) 308.06885, found 308.06864. Anal. Calcd. for
13H15F3O3S: C, 50.64; H, 4.90. Found: C, 49.96; H, 4.77.
Starting with 6 (0.216 g, 1.0 mmol) and 1-ethoxy-1,3-bis(tri-
methylsilyloxy)-1,3-nonadiene 1m (0.689 g, 2.0 mmol), a mix-
ture of regioisomers 7m and 8m (1:1) was isolated as a colorless
4.1.6. Isopentyl 6-methylthio-4-(trifluoromethyl)salicylate (7f)
Starting with 6 (0.216 g, 1.0 mmol) and 1-isopentyloxy-1,3-
bis(trimethylsilyloxy)-1,3-butadiene 1f (0.633 g, 2.0 mmol), prod-
uct 7f was isolated as a colorless solid. Yield 0.180 g (56%), mp 32–
oil. Yield 0.127 g (36%); 1H NMR (300 MHz, CDCl3) for 7m
d 0.91 (t,
3J = 7.1 Hz, 3H, Me), 1.36–1.59 (m, 9H, Me(CH2)3), 2.44 (s, 3H,
SMe), 2.71 (t, 3J = 7.8 Hz, 2H, CH2), 4.52 (q, 3J = 7.2 Hz, 2H, OCH2),
6.90 (br s, 1H, Ar), 11.86 (s, 1H, OH), for 8m d
0.91 (t, 3J = 7.1 Hz, 3H,
33 8C; 1H NMR (300 MHz, CDCl3)
1.71–1.93 (m, 3H, CH2CH), 2.46 (s, 3H, SMe), 4.49 (t, 3J = 6.8 Hz, 2H,
OCH2), 6.85 (br s, 1H, CH), 6.98 (br s, 1H, CH), 11.63 (s, 1H, OH); 13
NMR (75 MHz, CDCl3) 16.5 (SMe), 22.4 (Me), 25.0 (CH), 37.1
d
0.98 (d, 3J = 6.4 Hz, 6H, 2 Me),
C
Me), 1.36–1.59 (m, 9H, Me(CH2)3), 2.51 (s, 3H, SMe), 2.77 (t,
d
3J = 7.8 Hz, 2H, CH2), 4.42 (q, 3J = 7.2 Hz, 2H, OCH2), 7.07 (br s, 1H,
(CH2), 65.5 (OCH2), 110.7 (q, JC,F = 3.9 Hz, C-3), 111.2 (q,
JC,F = 3.9 Hz, C-5), 112.7 (C-1), 123.2 (q, JC,F = 273.4 Hz, CF3),
135.3 (q, JC,F = 32.6 Hz, C-4), 146.1, 163.5 (C), 170.0 (C55O); 19F
Ar), 11.31, (s, 1H, OH); 13C NMR (63 MHz, CDCl3) for 7m
d 14.0,
14.2 (2 Me), 16.3 (SMe), 22.4, 26.6, 29.1, 32.3 ((CH2)4), 62.7
(OCH2), 112.3 (CAr), 111.4 (q, JC,F = 6.3 Hz, CHAr), 123.9 (q,
JC,F = 275.1 Hz, CF3), 126.5 (CAr), 132.9 (q, JC,F = 29.3 Hz, CCF3),
NMR (282 MHz, CDCl3)
d
À64.1 (CF3); IR (ATR, cmÀ1
) n 2959 (w),
2929 (w), 2872 (w), 1726 (w), 1665 (m), 1608 (w), 1575 (m), 1464
(w), 1412 (s), 1349 (s), 1289 (s), 1220 (s), 1189 (s), 1118 (s), 963
(m), 934 (m), 803 (m), 758 (m), 699 (s); GC–MS (EI, 70 eV) m/z (%)
322 (M+, 28), 252 (11), 235 (32), 234 (100), 206 (18), 191 (11);
HRMS (EI, 70 eV): calcd for C14H17F3O3S (M+) 322.08450, found
322.08462. Anal. Calcd. for C14H17F3O3S: C, 52.16; H, 5.32. Found:
C, 52.25; H, 5.30.
141.5, 162.3 (CAr), 170.4 (C55O), for 8m d 13.5, 14.0 (2Me), 14.8
(SMe), 22.5, 27.1, 27.2, 32.0 ((CH2)4), 62.3 (OCH2), 106.7 (CAr),
113.9 (q, JC,F = 7.3 Hz, CHAr), 123.5 (q, JC,F = 273.3 Hz, CF3), 132.1,
(CAr), 127.7 (q, JC,F = 31.6 Hz, CCF3), 145.2, 159.4 (CAr), 169.8
(C55O); 19F NMR (282 MHz, CDCl3) for 7m
À57.9 (CF3).
d
À0.4 (CF3), for 8m
d
4.1.10. Methyl 6-methylthio-3-octyl-4-(trifluoromethyl)salicylate
(7o) and methyl 4-methylthio-3-octyl-6-(trifluoromethyl)salicylate
(8o)
4.1.7. Octyl 6-methylthio-4-(trifluoromethyl)salicylate (7g)
Starting with
6 (0.216 g, 1.0 mmol) and 1-octyloxy-1,3-
bis(trimethylsilyloxy)-1,3-butadiene 1g (0.717 g, 2.0 mmol), prod-
uct 7g was isolated as a colorless solid. Yield 0.200 g (55%), mp 49–
Starting with 6 (0.216 g, 1.0 mmol) and 1-methoxy-1,3-
bis(trimethylsilyloxy)-1,3-dodecadiene 1o (0.745 g, 2.0 mmol), a
mixture of regioisomers 7o and 8o (1: 0.7) was isolated as a
50 8C; 1H NMR (300 MHz, CDCl3)
d
0.89 (t, 3J = 6.7 Hz, 3H, Me),
1.26–1.54 (m, 11H, (CH2)5), 1.54–1.80 (m, 2H, CH2), 2.46 (s, 3H,
colorless oil. Yield 0.190 g (50%); 1H NMR (300 MHz, CDCl3) for 7o
d
SMe), 4.45 (t, 3J = 6.6 Hz, 2H, OCH2), 6.86 (br s, 1H, CH), 6.98 (d,
0.89 (t, 3J = 6.7 Hz, 3H, Me), 1.28–1.58 (m, 12H, (CH2)6), 2.44 (s, 3H,
SMe), 2.77 (t, 3J = 7.8 Hz, 2H, CH2), 4.03 (s, 3H, OMe), 6.90 (br s, 1H,
4J = 1.1 Hz, 1H, CH), 11.63 (s, 1H, OH); 13C NMR (63 MHz, CDCl3)
d
14.1 (Me), 16.5 (SMe), 22.6, 26.0, 28.4, 29.1, 29.1, 31.7 (CH2)6, 67.0
(OCH2), 110.7 (q, JC,F = 3.8 Hz, C-3), 111.2 (q, JC,F = 3.8 Hz, C-5),
112.7 (C-1), 123.2 (q, JC,F = 273.4 Hz, CF3), 135.2 (q, JC,F = 32.7 Hz, C-
Ar), 11.77 (s, 1H, OH), for 7o d
0.88 (t, 3J = 6.7 Hz, 3H, Me), 1.28–1.58
(m, 12H, (CH2)6), 2.51 (s, 3H, SMe), 2.71 (t, 3J = 8.0 Hz, 2H, CH2),
3.96 (s, 3H, OMe), 7.07 (br s, 1H, Ar), 11.17 (s, 1H, OH); 13C NMR
4), 146.1, 163.5 (C), 170.0 (C55O); 19F NMR (282 MHz, CDCl3)
d
(63 MHz, CDCl3) for 7o d 14.1 (Me), 16.2 (SMe), 22.7, 26.5, 29.2,
29.3, 29.4, 30.1, 31.9 ((CH2)7), 52.4 (OMe), 112.1 (CAr), 111.5 (q,
JC,F = 6.4 Hz, CHAr), 123.8 (q, JC,F = 275.1 Hz, CF3), 126.5 (CAr), 132.0
À64.1 (CF3); IR (ATR, cmÀ1
)
n
2956 (w), 2924 (m), 2855 (w), 2158
(w), 1976 (w), 1665 (m), 1636 (w), 1608 (w), 1575 (m), 1457 (w),
1412 (m), 1346 (s), 1289 (s), 1220 (s), 1189 (s), 1118 (s), 961 (m),
938 (m), 804 (m), 756 (m), 699 (s); GC–MS (EI, 70 eV) m/z (%) 364
(q, JC,F = 29.6 Hz, CCF3), 141.3, 162.3 (CAr), 170.8 (C55O), for 8o
d
14.1 (Me), 14.8 (SMe), 22.7, 27.2, 27.5, 29.2, 29.4, 29.9, 31.9

V.O. Iaroshenko et al. / Journal of Fluorine Chemistry 132 (2011) 441–449
447
((CH2)7), 52.7 (OMe), 106.5 (CAr), 113.9 (q, JC,F = 7.2 Hz, CHAr), 123.5
(q, JC,F = 273.3 Hz, CF3), 131.9 (CAr), 127.8 (q, JC,F = 31.7 Hz, (CCF3),
145.6, 159.4 (CAr), 170.2 (C55O); 19F NMR (282 MHz, CDCl3) for 7o
À60.5 (CF3), for 8o À58.7 (CF3).
4.2.1. Methyl 4-hydroxy-2-methylthio-6-oxo-4-
(trifluoromethyl)cyclohex-1-enecarboxylate (10a)
d
Starting with 6 (0.216 g, 1.0 mmol) and 1-methoxy-1,3-
d
bis(trimethylsilyloxy)-1,3-butadiene 1a (0.520 g, 2.0 mmol),
product 10a was isolated as a colorless solid. Yield 0.110 g
4.1.11. 2-Hydroxy-6-methylthio-4-(trifluoromethyl)benzophenone
(39%), mp 142–143 8C; 1H NMR (400 MHz, (CD3)2CO)
d
2.53 (s,
3H, SMe), 2.60–2.88 (m, 2H, CH2), 3.07–3.23 (m, 2H, CH2), 3.74
(s, 3H, OMe), 5.69 (s, 1H, OH); 13C NMR (100 MHz, (CD3)2CO)
(7s)
Starting with 6 (0.216 g, 1.0 mmol) and 1-phenyl-1,3-bis(tri-
methylsilyloxy)-1,3-butadiene 1s (0.613 g, 2.0 mmol), product 7s
was isolated as a brown solid. Yield 0.120 g (38%), mp 133 8C; 1H
d
14.1 (SMe), 34.6, 42.0 (CH2), 52.1 (OMe), 73.7 (q, JC,F = 29.5 Hz,
C-4), 126.2 (q, JC,F = 283.0 Hz, CF3), 129.1, 159.7, 166.3 (C), 187.5
NMR (300 MHz, CDCl3)
1H, CH), 7.45–7.50 (m, 2H, Ph), 7.59–7.65 (m, 1H, Ph), 7.75–7.79
(m, 2H, Ph), 8.13 (br s, 1H, OH); 13C NMR (63 MHz, CDCl3)
17.5
d
2.36 (s, 3H, SMe), 7.07 (s, 1H, CH), 7.08 (s,
(C55O); 19F NMR (282 MHz, (CD3)2CO)
cmÀ1
d
À83.7 (CF3); IR (ATR,
)
n 3429 (m), 3252 (w), 3011 (w), 2957 (w), 2930 (w), 2850
d
(w), 1721 (s), 1640 (s), 1549 (s), 1431 (m), 1403 (m), 1164 (s),
1044 (s), 813 (m), 552 (m); HRMS (ESI-TOF/MS): calcd for
(SMe), 111.6 (q, JC,F = 3.8 Hz, C-3), 115.5 (q, JC,F = 4.0 Hz, C-5), 123.2
(q, JC,F = 273.1 Hz, CF3), 126.3 (C-1), 128.8, 129.5, 133.9 (CH), 134.1
(q, JC,F = 33.0 Hz, C-4), 137.6, 141.5, 157.0 (C), 197.9 (C55O); 19F
C
C
10H12F3O4S ([M+H]+) 285.0402, found 285.0400; calcd. for
10H11F3NaO4S ([M+Na]+) 307.0222, found 307.0221. Anal.
NMR (282 MHz, CDCl3)
d
À63.5 (CF3); IR (ATR, cmÀ1
)
n
3331 (w),
Calcd. for C10H11F3O4S: C, 42.25; H, 3.90; S, 11.28. Found: C,
42.45; H, 4.26; S, 11.16.
3081 (w), 3064 (w), 2928 (w), 1679 (w), 1653 (m), 1594 (w), 1579
(w), 1484 (m), 1448 (m), 1416 (w), 1345 (w), 1324 (w), 1309 (w),
1284 (w), 1265 (w), 1244 (w), 1128 (m), 1087 (m), 954 (m), 924
(m), 856 (m), 713 (m), 683 (m), 626 (w); GC–MS (EI, 70 eV) m/z (%)
312 (M+, 14), 311 (10), 297 (21), 295 (18), 294 (72), 293 (100), 235
(14), 105 (22), 77 (39), 51 (10), 32 (20), 91 (100); HRMS (EI, 70 eV):
calcd for C15H11F3O2S (M+) 312.04264, found 312.042315. Anal.
Calcd. for C15H11F3O2S: C, 57.69; H, 3.55. Found: C, 57.51; H, 3.57.
4.2.2. Isopentyl 4-hydroxy-2-methylthio-6-oxo-4-
(trifluoromethyl)cyclohex-1-enecarboxylate (10f)
Starting with 6 (0.216 g, 1.0 mmol) and 1-isopentyloxy-1,3-
bis(trimethylsilyloxy)-1,3-butadiene 1f (0.633 g, 2.0 mmol),
product 10f was isolated as a colorless solid. Yield 0.110 g
(32%), mp 130–132 8C; 1H NMR (300 MHz, (CD3)2CO)
d 0.91 (s, 3H,
Me), 0.94 (s, 3H, Me), 1.53–1.59 (m, 2H, CH2), 1.72–1.81 (m, 1H,
CH), 2.53 (s, 3H, SMe), 2.58–2.88 (m, 2H, CH2), 3.05–3.24 (m, 2H,
CH2), 4.21 (t, 3J = 6.7 Hz, 2H, OCH2), 5.69 (s, 1H, OH); 13C NMR
4.1.12. Methyl 6-hydroxy-3-methyl-4-methylthio-2-oxo-6-
(trifluoromethyl)cyclohex-3-enecarboxylate (9h)
To a solution of 6 (0.216 g, 1.0 mmol) in CH2Cl2 (10 mL) was
added 1-methoxy-1,3-bis(trimethylsilyloxy)-1,3-pentadiene 1h
(0.549 g, 2.0 mmol) and, subsequently, AlCl3 (0.134 g, 1.0 mmol)
at À78 8C. The temperature of the solution was allowed to warm to
20 8C during 12–14 h with stirring. To the solution was added HCl
(10%, 15 mL), and the organic and the aqueous layer were
separated. The latter was extracted with CH2Cl2 (3 Â 15 mL).
The combined organic layers were dried (Na2SO4), filtered, and the
filtrate was concentrated in vacuo. The residue was purified by
chromatography to give 9h as a colorless solid. Yield 0.154 g (52%),
(75 MHz, (CD3)2CO) d 14.1 (SMe), 22.6 (Me), 25.5 (CH), 34.4, 38.0,
42.0, 64.1 (OCH2), 73.7 (q, JC,F = 29.0 Hz, C-4), 126.2 (q,
JC,F = 282.9 Hz, CF3), 129.3, 159.3, 165.9 (C), 187.6 (C55O); 19F
NMR (282 MHz, (CD3)2CO)
d
À83.7 (CF3); IR (ATR, cmÀ1
) n 3312
(m), 2946 (w), 2811 (w), 1720 (s), 1643 (s), 1547 (s), 1430 (m),
1403 (m), 1267 (s), 1043 (s), 786 (m), 533 (m); HRMS (ESI-TOF/
MS): calcd for C14H20F3O4S ([M+H]+) 341.1029, found 341.1029;
calcd for C14 H19F3NaO4S ([M+Na]+) 363.0848, found 363.0857.
Anal. Calcd. for C14H19F3O4S: C, 49.40; H, 5.63; S, 9.42. Found: C,
50.05; H, 5.88; S, 9.45.
mp 93 8C; 1H NMR (300 MHz, CDCl3)
d
1.88 (s, 3H, Me), 2.44 (s, 3H,
4
SMe), 2.80 (dq, 2J = 17.8 Hz, JH,F = 2.1 Hz, 1H, H-5a), 2.97 (br d,
4.2.3. Octyl 4-hydroxy-2-methylthio-6-oxo-4-
2J = 17.8 Hz, 1H, H-5b), 3.72 (s, 1H, CH), 3.87 (s, 3H, OMe), 5.35 (s,
(trifluoromethyl)cyclohex-1-enecarboxylate (10g)
1H, OH); 13C NMR (75 MHz, CDCl3)
d
11.6 (Me), 14.0 (SMe), 33.1
Starting with 6 (0.216 g, 1.0 mmol) and 1-octyloxy-1,3-
(CH2), 53.1 (CH), 53.3 (OMe), 74.7 (q, JC,F = 28.8 Hz, C-6), 124.4 (q,
JC,F = 287.0 Hz, CF3), 127.0, 154.0, 171.0 (C), 184.8 (C55O); 19F NMR
bis(trimethylsilyloxy)-1,3-butadiene 1g (0.717 g, 2.0 mmol),
product 10g was isolated as a colorless solid. Yield 0.130 g
(282 MHz, CDCl3)
d
À81.6 (CF3); IR (ATR, cmÀ1
)
n
3431 (w), 3285
(34%), mp 98–99 8C; 1H NMR (400 MHz, (CD3)2CO)
d 0.88 (t,
(w), 3024 (w), 2962 (w), 2935 (w), 2919 (w), 2858 (w), 2635 (w),
1737 (m), 1651 (m), 1574 (m), 1441 (w), 1414 (w), 1372 (w), 1356
(w), 1333 (m), 1301 (m), 1267 (m) 1222 (w), 1200 (m), 1162 (m),
1129 (m), 1068 (m), 1003 (m), 630 (m), 569 (m); GC–MS (EI, 70 eV)
m/z (%) 298 (M+, 13), 281 (13), 280 (100), 265 (30), 248 (16), 223
(27), 221 (49), 197 (24), 193 (22), 175 (16), 85 (16), 81 (22), 69 (33),
59 (19), 53 (18); HRMS (EI, 70 eV): calcd for C11H13F3O4S (M+)
298.04812, found 298.048772. Anal. Calcd. for C11H13F3O4S: C,
44.29; H, 4.39. Found: C, 44.34; H, 4.67.
3J = 6.8 Hz, 3H, Me), 1.28–1.45 (m, 10H, (CH2)5), 1.64–1.71 (m,
2H, CH2), 2.53 (s, 3H, SMe), 2.60–2.87 (m, 2H, CH2), 3.07–3.23
(m, 2H, CH2), 4.18 (t, 3J = 6.4 Hz, 2H, OCH2), 5.68 (s, 1H, OH); 13C
NMR (75 MHz, (CD3)2CO)
d 14.1 (SMe), 14.3 (Me), 23.2, 26.6,
29.8, 29.9, 32.5, 34.4, 42.0, 65.6 (OCH2), 73.7 (q, JC,F = 29.2 Hz, C-
4), 126.2 (q, JC,F = 282.9 Hz, CF3), 129.3, 159.1, 165.8 (C), 187.5
(C55O); 19F NMR (282 MHz, (CD3)2CO)
cmÀ1
d
À83.6 (CF3); IR (ATR,
)
n 3348 (m), 2935 (m), 2855 (w), 1712 (s), 1653 (s), 1564
(s), 1464 (w), 1437 (w), 1318 (s), 1159 (s), 1045 (s), 938 (m), 544
(m), 488 (m); HRMS (ESI-TOF/MS): calcd for C17H26F3O4S
([M+H]+) 383.1498, found 383.1503; calcd. for C17H25F3NaO4S
([M+Na]+) 405.1318, found 405.1324. Anal. Calcd. for
4.2. General procedure for the synthesis of compounds 10
To a solution of 6 (0.216 g, 1.0 mmol) in CH2Cl2 (10 mL) was
C17H25F3O4S: C, 53.39; H, 6.59; S, 8.38. Found: C, 54.26; H,
added
1
(2.0 mmol) and, subsequently, Me3SiOTf (0.18 mL,
6.53; S, 9.20.
1 mmol) at À78 8C. The temperature of the solution was allowed
to warm to 20 8C during 12–14 h with stirring. To the solution was
added HCl (10%, 15 mL), and the organic and the aqueous layer
were separated. The latter was extracted with CH2Cl2 (3 Â 15 mL),
the combined organic layers were dried (Na2SO4), filtered, and the
filtrate was concentrated in vacuo. The residue was purified by
chromatography.
4.2.4. Butyl 4-hydroxy-2-methylthio-6-oxo-4-
(trifluoromethyl)cyclohex-1-enecarboxylate (10t)
Starting with
6 (0.216 g, 1.0 mmol), 1-butoxy-1,3-bis(tri-
methylsilyloxy)-1,3-butadiene 1t (0.605 g, 2.0 mmol), product
10t was isolated as a colorless solid. Yield 0.170 g (52%), mp
d
137–138 8C; 1H NMR (300 MHz, (CD3)2CO) 0.93 (t, 3J = 7.5 Hz, 3H,

448
V.O. Iaroshenko et al. / Journal of Fluorine Chemistry 132 (2011) 441–449
Me), 1.36–1.49 (m, 2H, CH2), 1.60–1.70 (m, 2H, CH2), 2.53 (s, 3H,
SMe), 2.59–2.88 (m, 2H, CH2), 3.05–3.24 (m, 2H, CH2), 4.41 (t,
3J = 6.6 Hz, 2H, CH2), 5.68 (s, 1H, OH); 13C NMR (75 MHz, (CD3)2CO)
4.3.3. Methyl 2-(2-methoxy-2-oxoethoxy)-6-methylthio-4-
(trifluoromethyl)benzoate (13)
Starting with 7a (0.400 g, 1.5 mmol), methyl bromoacetate
(0.549 g, 2.0 mmol) and K2CO3 (0.249 g, 1.8 mmol) in acetone
(3.0 mL), product 13 was isolated as a yellow solid. Yield 0.362 g
d
13.9 (Me), 14.1 (SMe), 19.7, 31.3, 34.5, 42.0, 65.3 (OCH2), 73.7 (q,
JC,F = 29.2 Hz, C-4), 126.2 (q, JC,F = 283.1 Hz, CF3), 129.4, 159.1,
165.8 (C), 187.5 (C55O); 19F NMR (282 MHz, (CD3)2CO)
À83.7
(CF3); IR (ATR, cmÀ1
3294 (m), 2963 (w), 2934 (w), 2874 (w),
d
(71%), mp 64 8C; 1H NMR (300 MHz, CDCl3)
d
2.50 (s, 3H, SMe),
3.79, 3.96 (both s, 3H, OMe), 4.68 (s, 2H, CH2), 6.83 (br s, 1H, CH),
7.19 (br s, 1H, CH); 13C NMR (75 MHz, CDCl3)
16.7 (SMe), 52.4,
)
n
1707 (s), 1648 (s), 1558 (m), 1470 (w), 1405 (m), 1180 (s), 1043 (s),
946 (m), 540 (m); HRMS (ESI-TOF/MS): calcd. for C13H18F3O4S
([M+H]+) 327.0872, found 327.0869; calcd for C13H17F3NaO4S
([M+Na]+) 349.0692, found 349.0694.
d
52.7 (OMe), 66.2 (OCH2), 106.6 (q, JC,F = 3.7 Hz, C-3), 117.2 (q,
JC,F = 3.9 Hz, C-5), 123.2 (q, JC,F = 273.1 Hz, CF3), 127.3 (C), 135.9
(q, JC,F = 32.8 Hz, C-4), 139.8, 155.1 (C), 165.8 (OC = O), 168.0
(C55O); 19F NMR (282 MHz, CDCl3)
d
À63.1 (CF3); IR (ATR, cmÀ1
) n
4.3. General procedure for the synthesis of compounds 11, 12 and 13
3457 (w), 3188 (w), 3098 (w), 3010 (w), 2961 (w), 2915 (w), 2860
(w), 1733 (m), 1698 (w), 1605 (w), 1580 (w), 1557 (w), 1471 (w),
1449 (w), 1417 (m), 1389 (w), 1330 (w), 1303 (m), 1249 (m),
1206 (w), 1161 (m), 1120 (m), 1078 (m), 1066 (m), 1018 (m), 935
(m), 864 (m), 705 (m); GC–MS (EI, 70 eV) m/z (%) 338 (M+, 47),
319 (17), 307 (51), 279 (27), 249 (19), 248 (16), 247 (100), 246
(31), 219 (14), 218 (37), 191 (22), 189 (12), 45 (92); HRMS (ESI-
TOF/MS): calcd for C13H14F3O5S ([M+H]+) 339.0509, found
339.0508; calcd for C13H13F3NaO5S ([M+Na]+) 361.0328, found
361.0329. Anal. Calcd. for C13H13F3O5S: C, 46.15; H, 3.87. Found:
C, 46.27; H, 3.77.
To a solution of methyl 6-methylthio-4-(trifluoromethyl)sali-
cylate 7a (0.275 g, 1.1 mmol) in acetone (2–3 mL) was added
K2CO3 (0.172 g, 1.3 mmol) and 2-bromoacetophenone, 2-(bromo-
methyl)oxirane or methyl bromoacetate (1.3 mmol). The mixture
was then heated to 55 8C for 8 h and the resulting suspension was
filtered and washed with diethyl ether. The ether solution was
washed with Brine (4 Â 15 mL), dried (Na2SO4), filtered, and the
filtrate was concentrated in vacuo. The residue was purified by
chromatography.
4.3.1. Methyl 2-methylthio-6-phenacyloxy-4-
4.3.4. Methyl 3-hydroxy-4-methylthio-6-
(trifluoromethyl)benzoate (11)
(trifluoromethyl)benzofuran-2-carboxylate (14)
Starting with 7a (0.275 g, 1.1 mmol) and 2-bromoacetophe-
none (0.247 g, 1.3 mmol), product 11 was isolated as a colorless
To a solution of 13 (0.160 g, 0.5 mmol) in MeOH/CH2Cl2 (1:1,
3.0 mL) was added MeONa (0.065 g, 0.6 mmol). The reaction
mixture was then heated to 50 8C for 6 h. To the solution was
added HCl (10%, 15 mL), and the organic and the aqueous layer
were separated. The latter was extracted with CH2Cl2
(3 Â 15 mL). The combined organic layers were dried (Na2SO4),
filtered, and the filtrate was concentrated in vacuo. The residue
was purified by chromatography to give 14 as an yellow solid.
solid. Yield 0.121 g (32%), mp 82 8C; 1H NMR (300 MHz, CDCl3)
d
2.50 (s, 3H, SMe), 3.89 (s, 3H, OMe), 5.31 (s, 2H, CH2), 6.87 (br s, 1H,
CH), 7.18 (br s, 1H, CH), 7.47–7.52 (m, 2H, Ph), 7.60–7.65 (m, 1H,
Ph), 7.94–7.97 (m, 2H, Ph); 13C NMR (63 MHz, CDCl3)
d 16.7 (SMe),
52.6 (OMe), 71.7 (CH2), 106.6 (q, JC,F = 3.7 Hz, C-5), 117.0 (q,
JC,F = 3.8 Hz, C-3), 123.2 (q, JC,F = 273.1 Hz, CF3), 128.2, 128.8, 128.9,
132.8 (q, JC,F = 32.8 Hz, C-4), 134.1 (CH), 134.1, 139.7, 155.3 (C),
Yield 0.045 g (31%), mp 179 8C; 1H NMR (300 MHz, CDCl3)
(s, 3H, SMe), 4.02 (s, 3H, OMe), 7.16 (br s, 1H, CH), 7.44 (s, 1H, CH),
8.26 (br s, 1H, OH); 13C NMR (63 MHz, CDCl3)
14.9 (SMe), 52.3
d 2.61
165.9 (OC55O), 192.9 (C55O); 19F NMR (282 MHz, CDCl3)
(CF3); IR (ATR, cmÀ1
d
À63.0
)
n
3084 (w), 3009 (w), 2959 (w), 2925 (w),
d
2908 (w), 2841 (w), 1710 (m), 1597 (w), 1579 (w), 1468 (w), 1448
(w), 1421 (m), 1325 (m), 1278 (w), 1255 (m), 1224 (m), 1180 (w),
1159 (m), 1122 (m), 1093 (m), 1074 (m), 984 (m), 760 (m), 670 (m);
GC–MS (EI, 70 eV) m/z (%) 384 (M+, 22), 353 (13), 106 (8), 105 (100),
91 (11), 77 (24), 45 (9); HRMS (EI, 70 eV): calcd for C18H15F3O4S
(M+) 384.06377, found 384.06394.
(OMe), 106.4 (q, JC,F = 4.4 Hz, C-7), 114.6 (q, JC,F = 3.7 Hz, C-5),
116.8 (q, JC,F = 275 Hz), 136.1, 138.9 (q, JC,F = 33.5 Hz), 142.2,
145.3, 150.9, 152.5, 162.4 (C55O); 19F NMR (282 MHz, CDCl3)
d
À62.2 (CF3); IR (ATR, cmÀ1
) n 3331 (w), 3087 (w), 3003 (w), 2959
(w), 2930 (w), 2864 (w), 1688 (w), 1604 (w), 1575 (w), 1499 (w),
1455 (w), 1377 (w), 1335 (m), 1258 (w), 1216 (m), 1198 (m),
1148 (m), 1115 (m), 1074 (m), 966 (m), 849 (m), 658 (m); GC–MS
(EI, 70 eV) m/z (%) 306 (M+, 100), 275 (15), 274 (49), 273 (15), 247
(17), 246 (65), 217 (21), 190 (17), 189 (33), 143 (15), 121 (15);
HRMS (EI, 70 eV): calcd for C12H9F3O4S (M+) 306.01682, found
306.01591.
4.3.2. Methyl 2-methylthio-6-(oxiran-2-ylmethoxy)-4-
(trifluoromethyl)benzoate (12)
Starting with 7a (0.275 g, 1.1 mmol) and 2-(bromomethyl)
oxirane (0.170 g, 1.3 mmol), product 12 was isolated as a colorless
solid. Yield 0.330 g (99%), mp 45 8C; 1H NMR (300 MHz, CDCl3)
d
2.49 (s, 3H, SMe), 2.73 (dd, 2J = 4.9 Hz, 3J = 2.6 Hz, 1H, OCHH), 2.87
(dd, 2J = 4.9 Hz, 3J = 4.2 Hz, 1H, OCHH), 3.28–3.33 (m, 1H, CH), 3.94
(s, 3H, OMe), 4.02 (dd, 2J = 11.1 Hz, 3J = 5.5 Hz, 1H, OCHH), 4.33 (dd,
2J = 11.3 Hz, 3J = 2.6 Hz, 1H, OCHH), 6.99 (br s, 1H, CH), 7.16 (br s,
Acknowledgement
Funding for Dr. V.O.I. by the German Ministry of Education and
Research (BMBF) is gratefully acknowledged (grant No.
03IS2081A).
1H, CH); 13C NMR (63 MHz, CDCl3)
d 16.7 (SMe), 44.2 (OCH2), 49.7
(CH), 52.6 (OMe), 69.8 (OCH2), 106.9 (q, JC,F = 3.7 Hz, C-5), 116.6 (q,
JC,F = 4.0 Hz, C-3), 123.3 (q, JC,F = 273.0 Hz, CF3), 127.1 (C), 132.9 (q,
JC,F = 32.7 Hz, C-4), 139.3, 155.7 (C), 166.0 (C55O); 19F NMR
Appendix A. Supplementary data
(282 MHz, CDCl3)
d
À63.1 (CF3); IR (ATR, cmÀ1
) n 3078 (w),
3003 (w), 2960 (w), 2930 (w), 2854 (w), 1714 (m), 1605 (w), 1573
(w), 1464 (w), 1432 (w), 1425 (w), 1387 (m), 1322 (m), 1283 (m),
1250 (m), 1201 (m), 1169 (m), 1120 (s), 1086 (m), 1074 (m), 1024
(m), 993 (m), 842 (s), 704 (m); GC–MS (EI, 70 eV) m/z (%) 322 (M+,
100), 303 (21), 291 (60), 235 (42), 234 (85), 206 (38), 191 (44), 163
(12), 57 (49) 45 (54), 31 (23), 29 (45); HRMS (EI, 70 eV): calcd for
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.jfluchem.2011.04.011.
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V.O. Iaroshenko et al. / Journal of Fluorine Chemistry 132 (2011) 441–449
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