Regioselective synthesis of 5-ethoxycarbonyl-, 5-acetyl- and 5-trifluoroacetyl-6-trifluoromethylsalicylates by one-pot cyclizations of 1,3-bis(trimethylsilyloxy)-1,3-butadienes with 3-alkoxy-2-alken-1-ones

Article abstract of DOI:10.1016/j.jfluchem.2012.02.002

5-Ethoxycarbonyl-, 5-trifluoroacetyl-, and 5-acetyl-6- trifluoromethylsalicylates were prepared by one-pot cyclizations of 1,3-bis(trimethylsilyloxy)-1,3-butadienes with 3-alkoxy-2-alken-1-ones. The reactions proceeded with very good regioselectivity by c

Full text of DOI:10.1016/j.jfluchem.2012.02.002

Journal of Fluorine Chemistry 136 (2012) 38–42
Contents lists available at SciVerse ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Regioselective synthesis of 5-ethoxycarbonyl-, 5-acetyl- and 5-trifluoroacetyl-6-
trifluoromethylsalicylates by one-pot cyclizations of 1,3-bis(trimethylsilyloxy)-
1,3-butadienes with 3-alkoxy-2-alken-1-ones
Simone Ladzik a, Mathias Lubbe a, Nazken K. Kelzhanova a,b, Zharylkasyn A. Abilov b,
Holger Feist a, Peter Langer a,c,
*
a Institut fu¨r Chemie, Universita¨t Rostock, Albert-Einstein-Str. 3a, 18059 Rostock, Germany
b Al-Farabi Kazakh National University, Al-Farabi ave. 71, 050040 Almaty, Kazakhstan
c
¨
Leibniz-Institut fu¨r Katalyse e. V. an der Universitat Rostock, Albert-Einstein-Str. 29a, 18059 Rostock, Germany
A R T I C L E I N F O
A B S T R A C T
Article history:
5-Ethoxycarbonyl-, 5-trifluoroacetyl-, and 5-acetyl-6-trifluoromethylsalicylates were prepared by one-
pot cyclizations of 1,3-bis(trimethylsilyloxy)-1,3-butadienes with 3-alkoxy-2-alken-1-ones. The
reactions proceeded with very good regioselectivity by conjugate addition of the terminal carbon
atom of the diene to the enone and subsequent cyclization. The cyclization proceeded in most cases via
the trifluoroacetyl group.
Received 20 April 2011
Received in revised form 30 January 2012
Accepted 3 February 2012
Available online 11 February 2012
ß 2012 Elsevier B.V. All rights reserved.
Keywords:
Organofluorine compounds
Cyclizations
Silyl enol ethers
Regioselectivity
1. Introduction
fluorination. These drawbacks can be circumvented when
fluorine-containing substrates are employed in cyclization reac-
Organofluorine compounds play an important role in medicinal
and agricultural chemistry. Due to the stereoelectronic properties
of the carbon–fluorine bond, organofluorine compounds show an
excellent solubility, bioavailability and metabolic stability [1]. A
number of fluorinated molecules are clinically used. For example,
5-fluorouracil exhibits antineoplastic activity [2] and ciprofloxacin
and flurithromycin are important antibiotics. Fluoxetine (prozac)
shows antidepressant activity, while faslodex and efavirenz
exhibit antitumor and antiviral activity, respectively [3,4].
Amphiphilic and liquid crystalline properties have been reported
for a number of perfluoroalkyl-substituted compounds [5]. Last but
not the least, fluoroalkylated compounds are also used as ligands
[6] in catalytic reactions, as organocatalysts [7], and as substrates
in palladium catalyzed reactions [8].
tions (building block strategy). Aryl fluorides have been prepared
by [4 + 2] cycloaddition reactions of fluorinated dienes [9]. The
synthesis of fluorophenols by annulation reactions of 2,2-
difluoro-1,5-diketones has been developed by Portella and
coworkers [10]. In recent years, we have studied [11,12] the
synthesis of fluorinated arenes based on cyclocondensation
reactions of 1,3-bis(trimethylsilyloxy)-1,3-butadienes [13]. Here-
in, we report what are, to the best of our knowledge, the first
regioselective syntheses of 5-ethoxycarbonyl-, 5-acetyl- and 5-
trifluoroacetyl-6-trifluoromethylsalicylates by one-pot cycliza-
tions of 1,3-bis(trimethylsilyloxy)-1,3-butadienes with 3-alkoxy-
2-alken-1-ones. Salicylates containing a trifluoromethyl function
located at the aromatic ring have been reported in the literature.
[14] Some of these derivatives show interesting biological
activities like inhibition of protein syntheses [15], inhibition of
Two principal strategies for the synthesis of fluorinated
molecules are possible. Firstly, direct fluorination reactions
and, secondly, the application of a building block strategy.
Fluorination reactions of arenes and heteroarenes are often
limited by their low chemo- and regioselectivity and by multiple
nuclear factor
kB (NF-kB) activity [16] and antithrombotic
activity [17]. In case of the known trifluoromethylsalicylates,
besides the three characteristic groups (carboxylate, hydroxy, and
trifluoromethyl), at maximum one further functional group is
present. The highly substituted trifluoromethylated derivatives
reported the present manuscript have not been prepared so far.
Due to the high degree of functionalization and substitution of
these molecules, it can be anticipated that they are not readily
available by other methods.
* Corresponding author at: Institut fu¨r Chemie, Universita¨t Rostock, Albert-
Einstein-Str. 3a, 18059 Rostock, Germany. Fax: +49 381 4986412.
E-mail address: peter.langer@uni-rostock.de (P. Langer).
0022-1139/$ – see front matter ß 2012 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2012.02.002

S. Ladzik et al. / Journal of Fluorine Chemistry 136 (2012) 38–42
39
Me3SiO
OSiMe3
2. Results and discussion
O
OH
TiCl4
CH2Cl2
OMe
Enones 1a–c were synthesized by known procedures [18–20]
(Scheme 1).
2a
OMe
CF3
EtO
O
_
The TiCl4-mediated cyclization of enone 1a with 1,3-bis(sily-
loxy)-1,3-butadiene 2a (Chan’s diene) [21] afforded 5-ethoxycar-
bonyl-6-trifluoromethyl-salicylate 3a (Scheme 2). The formation
of 3a can be explained by reaction of 1a with TiCl4 to give
intermediate A, regioselective attack of the terminal carbon atom
of 2a to A to give intermediates B and C, cyclization (to give
intermediate D) and aromatization (before or during the aqueous
work-up). Product 3a was formed with excellent regioselectivity.
Only the isomer containing the CF3 group located ortho to the ester
group was formed (inspection of the crude product). The formation
of the other regioisomer, containing the CF3 group located para to
the ester group, was not observed. The regioselectivity can be
explained by steric and electronic effects.
78 to 20 °C
14 h
+
CF3
CO2Et
CO2Et
3a (65%)
1a
TiCl4
H2O
O
_
O
TiCl4
EtO
O
OMe
+
OTiCl3
CF3
CO2Et
CF3
CO2Et
The TiCl4-mediated cyclization of enones 1a,b with 1,3-
bis(silyloxy)-1,3-butadienes 2a–u, prepared from the correspond-
ing 1,3-dicarbonyl compounds in one or two steps [21,22], afforded
the 5-ethoxycarbonyl-6-trifluoromethyl-salicylates 3a–r and the
5-trifluoroacetyl-6-trifluoromethyl-salicylates 3s–ai (Scheme 3,
Table 1). The best yields for compounds 3 were obtained when the
reactions were carried out in highly concentrated solutions. For
3a,b,s,t a 1.0/2.0/1.0 ratio of 1/2/TiCl4 gave the best yields. In case
of 3c–r and 3u–ai, the best yields were obtained using a 1.0/1.5/1.0
ratio. The yields decreased when the stoichiometric ratio was 1.0/
1.0/1.0. The reason for the change remains unclear at present. The
temperature had to slowly warm from ꢀ78 to 20 8C.
A
D
2a
Me3SiCl
Me3SiCl
O
O
Me3SiO
EtO
OMe
TiCl3
Me3SiO
OMe
TiCl4
Me3SiCl
O
O
CF3
CF3
Me3SiOEt
CO2Et
CO2Et
B
C
Products 3a–r were isolated in 30–79% yield. The best yields
were obtained for 3a and 3b. Salicylates 3s–ai were isolated in 32–
69% yields. No clear trend was observed for the yields. All reactions
proceeded with excellent regioselectivity by initial attack of the
terminal carbon atom of the diene to the double bond. A first attack
to the carbonyl group was not observed. The cyclization step
proceeded by attack of the central carbon atom of the diene to the
CF3CO group. The moderate yields of all products can be explained
by practical problems during the chromatographic purification.
The formation of regioisomers as a reason for the moderate yields
can be excluded because the crude product mixtures (before
chromatographic purification) were analyzed by 1H NMR and no
Scheme 2. Possible mechanism of the formation of 3a.
Table 1
Synthesis of 3a–ai.
1
2
3
R1
R2
R3
% (3)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
b
b
b
b
b
b
b
b
b
b
b
a
b
c
d
e
f
a
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
H
OMe
OMe
OEt
65
79
36
67
33
40
37
30
35
30
30
36
52
45
51
52
43
50
60
40
40
52
61
35
43
32
44
50
30
33
52
46
69
62
44
b
Me
c
iPr
d
(CH2)2CH(Me)2
nBu
OMe
OEt
e
f
nPent
nHex
OEt
g
h
i
g
OEt
h
i
nHept
nOct
OEt
OMe
OMe
OEt
j
j
nNon
O
EtO
O
k
l
k
nDec
HC(OEt)3
l
nDodec
nHexadec
nOctadec
Allyl
OMe
OMe
OEt
CF3
CF3
CO2Et
1a (65%)
m
n
o
p
q
r
m
n
o
CO2Et
i
OMe
OMe
OMe
OMe
Me
p
Cl(CH2)4
Cl(CH2)3
Ph(CH2)2
H
q
OnBu
nBuO
O
r
s
s
+
O
O
t
t
H
OEt
CF3
CF3
1b (70%)
u
c
d
f
u
v
H
OiPr
OEt
ii
F3C
O
CF3
iPr
O
w
x
(CH2)2CH(Me)2
nPent
nHex
OMe
OEt
g
h
i
y
OEt
EtO
O
z
nHept
nOct
OEt
O
aa
ab
ac
ad
ae
af
ag
ah
ai
OMe
OMe
OEt
HC(OEt)3
CF3
Me
1c (70%)
j
nNon
CF3
k
l
nDec
i
O
nDodec
nHexadec
Allyl
OMe
OMe
OMe
OMe
OMe
OMe
O
Me
m
o
p
q
r
Cl(CH2)4
Cl(CH2)3
Ph(CH2)2
Scheme 1. Synthesis of 1a-c: Reagents and conditions: i: CF3CO–CH2–CO2Et (1.0
equiv.), HC(OEt)3 (1.5 equiv.), Ac2O (3.0 equiv.), 120 8C, 2 h, then 140 8C, 5 h; ii:
H2C = CH(OnBu) (1.0 equiv.), pyridine (3.0 equiv.), CHCl3, (F3CCO)2O (3.0 equiv.),
50 8C, 20 h.
aYields of isolated products.

40
S. Ladzik et al. / Journal of Fluorine Chemistry 136 (2012) 38–42
Table 2
Me3SiO OSiMe3
R2
Synthesis of 4a–e.
O
OH
TiCl4
R3
R2
R1
R2
% (4)a
CH2Cl2
2
4
2a-u
R3
CF3
s
a
b
c
H
Me
55
47
48
56
62
RO
O
_
v
w
a
x
OMe
H
OMe
Ph
78 to 20 °C
12 h
+
CF3
O
R1
3a-ai
d
e
H
OMe
OEt
Et
O
R1
aYields of isolated products.
1a (R = Et, R1 = OEt)
1b (R = nBu, R1 = CF3)
OH
O
R1
R2
Scheme 3. Synthesis of 3a–ai.
Me3SiO
R1
OSiMe3
CF3
R2
regioisomers were observed. However, hydrolysis of the 1,3-
bis(silyloxy)-1,3-butadienes (to give 3-oxoalkanoates) and TiCl4-
mediated oxidative dimerization of the dienes (to give 3,6-
dioxooctane-1,8-dioates) were observed as side reactions. Such
products were found in the crude mixture in small amounts.
The structures of the products were established by spectro-
scopic methods (2D NMR, HMBC, NOESY, analysis of the C–F
coupling constants). For example, the structure of 3a was easily
proven by inspection of the 1H NMR spectrum which exhibits two
characteristic doublets for the aromatic protons (J = 8.7 Hz).
Analysis of the 13C NMR shows quartets for the carbon atoms
attached to the ester groups, due to carbon–fluorine coupling
(3JC,F = 2 and 3 Hz). For the other regioisomer, a singlet would be
expected. In the 13C NMR spectra of isophthalates 3a,b, a typical
quartet (J = 275 Hz) is observed at approx. 123 ppm for the CF3
group attached to the benzene moiety. A singlet at approx.
ꢀ54 ppm is observed in the 19F NMR spectrum. For the 5-
2a,s,v,w,x
O
O
Me
+
i
4a-c
OEt O
OH
O
R1
CF3
Me
R2
Me
CF3
O
1c
4d,e
Scheme 4. Synthesis von 4a–e: i: TiCl4, CH2Cl2, ꢀ78 ! 20 8C, 14 h.
yields can again be explained by practical problems during the
chromatographic purification. As side-reactions, hydrolysis and
oxidative dimerization of the diene was observed.
In all reactions, the first step proceeds by conjugate addition of
the terminal carbon atom of the diene to the enone. The
regioselectivity of the subsequent cyclization step seems to
depend on the substitution pattern of the diene. The nucleophilic-
ity of dienes 2s,v,w is lower than the nucleophilicity of 2a and 2x.
This is a result of the fact that dienes 2s and 2w are derived from
trifluoroacetyl-6-trifluoromethyl-salicylates 3s,t two quartets (13
C
NMR) and singlets (19F NMR) are observed. The CF3 group located
at the benzene ring appears at ꢀ52 ppm while the CF3 group
located at the carbonyl group appears at approx. ꢀ75 ppm. The
structures of all other derivatives were established by similar
observations. In addition, NOESY and HMBC experiments were
carried out for specific derivatives which further support the
structures. The structure of 3m was independently confirmed by
X-ray crystal structure analysis (Fig. 1) [23].
1,3-diketones, while dienes 2a and 2x are derived from
ketoesters (which possess an additional -donating alkoxy group
b-
p
located at carbon atom C-1 of the diene). The decreased
nucleophilicity of diene 2v can be explained by the electron-
withdrawing effect of the methoxy group located at carbon C-4 of
the diene. The cyclizations of the less reactive dienes proceed via
the more reactive trifluorocarbonyl group, while the cyclizations of
the more reactive dienes proceed via the less reactive acetyl group.
The exact reason for this change of the regioselectivity remains
unclear at present. Obviously, steric effects (presence of
substituent R1) do not play a role.
In conclusion, we have reported the synthesis of 5-ethoxy-
carbonyl-, 5-acetyl- and 5-trifluoroacetyl-6-trifluorosalicylates by
regioselective one-pot cyclizations of 1,3-bis(trimethylsilyloxy)-
1,3-butadienes with 3-alkoxy-2-alken-1-ones. The use of enones
The TiCl4-mediated cyclization of 1,3-bis(silyloxy)-1,3-buta-
dienes 2s, 2v and 2w with enone 1c afforded the 5-acetyl-6-
trifluoromethyl-salicylates 4a–c, respectively (Scheme 4, Table 2).
The formation of the regioisomeric 5-triluoroacetyl-6-methyl-
salicylates was not observed. Interestingly, the cyclization of 1c
with dienes 2a and 2x resulted in a complete change of the
regioselectivity and formation of the 5-trifluoroacetyl-6-methyl-
salicylates 4d,e, respectively. Inspection of the crude products
showed that a small amount (less than 10%) of the other
regioisomer was present which could be separated. The moderate
a
Fig. 1. Crystal structure of 3m.

S. Ladzik et al. / Journal of Fluorine Chemistry 136 (2012) 38–42
41
derived from 1,1,1-trifluoroacetylacetone resulted, depending on
the substitution pattern of the diene, in the formation of two
different regioisomers. The products are not readily available by
other methods.
128.1 (q, JC,F = 33 Hz, C-2), 128.0 (q, JC,F = 2 Hz, C), 124.2 (q,
JC,F = 2 Hz, C), 120.0 (CH), 119.5 (q, JC,F = 291 Hz, COCF3), 118.8 (q,
JC,F = 275 Hz, ArCF3), 31.8 (q, JC,F = 3 Hz, CH3). 19F NMR (CDCl3, 235
˜
MHz):
d
= ꢀ51.5 (ArCF3), ꢀ74.0 (COCF3). IR (KBr, cmꢀ1):
n
= 3391
(w), 1699 (m), 1591 (m), 1134 (w), 1001 (s), 968 (s). MS (EI, 70 eV):
m/z (%) = 300 (M+, 20), 265 (58), 231 (100), 215 (22), 191 (40). Anal.
Calcd. for C11H6F6O3 (300.15): C, 44.02; H, 2.01. Found: C, 43.93; H,
2.36.
3. Experimental
General comments: All solvents were dried by standard methods
and all reactions were carried out under an inert atmosphere.
Melting points were determined with a Micro heating table HMK
67/1825 Kuestner (Bu¨chi Apparatus), Leitz Labolux 12 Pol with
3-Acetyl-4-hydroxy-2-trifluoromethyl-acetophenone (4a). Start-
ing with 1c (420 mg, 2.0 mmol), 2s (489 mg, 2.0 mmol) and TiCl4
(379 mg, 2.0 mmol) in CH2Cl2 (4 mL), 4a was isolated as a
colourless solid (270 mg, 55%); Rf 0.11 (n-heptane/EtOAc = 1:1).
heating table Mettler FP 90. Melting points are uncorrected. 1H, 13
C
and 19F NMR spectra were recorded with a Bruker ARX 300
spectrometer (300.1 MHz, 75.5 MHz, and 235 MHz, respectively).
For 1H, 13C and and 19F NMR spectra the deuterated solvents
indicated were used. Mass spectra were recorded with Varian MAT
CH 7, MAT 731 (EI, 70 eV) and Intecta AMD 402 (EI, 70 eV and CI).
For 19F NMR, CFCl3 was used as external standard (0.0 ppm). Mass
spectrometric data (MS) were obtained by electron ionization (EI,
70 eV), chemical ionization (CI, H2O) or electrospray ionization
(ESI). For HRMS Varian MAT 311 and Intecta AMD 402 were used.
IR spectra were detected with Nicolet 205 FT-IR and Nicolet
1H NMR (CDCl3, 300 MHz):
1H, CH), 7.11 (d, 3J = 8.6 Hz, 1H, CH), 2.59 (s, 3H, CH3), 2.56 (s, 3H,
CH3). 13C NMR (CDCl3, 75 MHz):
= 204.2 (C55O), 202.3 (C55O),
d
= 8.38 (s, 1H, OH), 7.36 (d, 3J = 8.6 Hz,
d
155.3 (C-4), 133.2 (q, JC,F = 3 Hz, C), 129.7 (CH), 127.6 (q, JC,F = 3 Hz,
C), 125.0 (q, JC,F = 32 Hz, C-2), 123.1 (q, JC,F = 276 Hz, CF3), 119.8
(CH), 31.7, 30.6 (CH3). 19F NMR (CDCl3, 235 MHz):
d
= ꢀ51.9 (CF3).
˜
IR (KBr, cmꢀ1):
n
= 3362 (s), 1709 (s), 1676 (s), 1585 (s). MS (EI,
70 eV): m/z (%) = 246 (M+, 39), 231 (100), 211 (73), 191 (48), 43
(55). Anal. Calcd. for C11H9F3O3 (246.18): C, 53.67; H, 3.68; found:
C, 53.82; H, 3.73.
´
Protege 460 FT-IR. Elemental analyses were performed with a LECO
CHNS-932, Thermoquest Flash EA 1112. X-ray data collections
were performed with a Bruker X8Apex diffractometer with CCD
Acknowledgement
camera (Mo
˚
K
radiation and graphite monochromator,
Financial support from the State of Mecklenburg-Vorpommern
is gratefully acknowledged.
a
l
= 0.71073 A). The space group is determined by the XPREP
program and the structures were solved via the SHELX-97 program
package. Refinements were carried out according to the minimum
square error method. For preparative scale chromatography, silica
gel (60–200 mesh) was used. The synthesis of enones 1a, [14] 1b,
[15] and 1c [16] and of dienes 2 [17,18] were carried out following
known procedures.
Appendix A. Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.jfluchem.2012.02.002.
General procedure for the synthesis of 3a–ai and 4a–4e.
Compound 1a, 1b or 1c was solved in 3 mL of dry CH2Cl2 under
inert atmosphere. To the solution was added diene 2. The solution
was cooled to ꢀ78 8C and TiCl4 was added. The mixture was
allowed to warm to room temperature during 14 h with stirring.
The solution was poured into an aqueous solution of hydrochloric
acid (10%, 50 mL) and the mixture was extracted with CH2Cl2 three
times. The combined organic layers were dried with Na2SO4,
filtered and the filtrate was concentrated in vacuo. The residue was
purified by chromatography (silica gel) to give products 3a–ai.
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(e) D. Clarke, M.A. Ali, A.A. Clifford, A. Parratt, P. Rose, D.W. Schwinn, C. Bann-
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MHz):
d = 168.9, 167.1 (C55O), 160.1 (C–O), 134.0 (CH), 129.5 (q,
JC,F = 33 Hz, C-2), 126.1 (q, JC,F = 3 Hz C-1), 122.7 (q, JC,F = 275 Hz,
CF3), 120.9 (CH), 114.4 (q, JC,F = 2 Hz, C-3), 62.2 (CH2), 53.3 (OCH3),
13.8 (CH2CH3). 19F NMR (CDCl3, 235 MHz):
d
= ꢀ54.3 (CF3). IR (ATR,
˜
cmꢀ1):
n
= 3350 (br m), 2986 (m), 2958 (w), 2910 (m), 1725 (s),
1597 (s), 1446 (s), 1369 (m). MS (EI, 70 eV): m/z (%) = 292 (M+, 36),
260 (47), 232 (28), 227 (42), 212 (100). Anal. Calcd. for C12H11F3O5
(292.21): C, 49.32; H, 3.79. Found: C, 49.48; H, 4.05.
1-(3-Acetyl-4-hydroxy-2-trifluoromethylphenyl)-2,2,2-trifluor-
oethanone (3s): Starting with 1b (292 mg, 1.0 mmol), 2s (489 mg,
2.0 mmol) and TiCl4 (190 mg, 1.0 mmol) in 3 mL of CH2Cl2, 3s was
isolated as a red oil (179 mg, 60%); Rf 0.36 (n-heptane/EtOAc 1:1).
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1H NMR (CDCl3, 300 MHz):
1H, CH), 7.22 (d, 3J = 9.0 Hz, 1H, CH), 2.63 (q, JH,F = 1.4 Hz, 3H, CH3).
13C NMR (CDCl3, 75 MHz):
= 203.7 (H3C–C55O), 183.0 (q,
JC,F = 37 Hz, F3C–C55O), 157.2 (C–O), 130.7 (q, JC,F = 2 Hz, CH),
d
= 8.45 (s, 1H, OH), 7.59 (d, 3J = 9.0 Hz,
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d
(f) S.B. Tsogoeva, Eur. J. Org. Chem. (2007) 1701.

42
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