Regioselective synthesis of 2-acetyl- and 2-alkoxycarbonyl-3- (trifluoromethyl)phenols by [3+3] cyclization of 1,3-bis-silyl enol ethers with 4-ethoxy- and 4-silyloxy-1,1,1-trifluoroalk-3-en-2-ones

Article abstract of DOI:10.1016/j.tetlet.2006.01.111

2-Acetyl- and 2-alkoxycarbonyl-3-(trifluoromethyl)phenols were prepared by [3+3] cyclization of 1,3-bis-silyl enol ethers with 4-ethoxy- and 4-silyloxy-1,1,1-trifluoroalk-3-en-2-ones.

Full text of DOI:10.1016/j.tetlet.2006.01.111

Tetrahedron Letters 47 (2006) 2183–2185
Regioselective synthesis of 2-acetyl- and
2-alkoxycarbonyl-3-(trifluoromethyl)phenols by [3+3]
cyclization of 1,3-bis-silyl enol ethers with 4-ethoxy- and
4-silyloxy-1,1,1-trifluoroalk-3-en-2-ones
Constantin Mamat,a Thomas Pundt,a Andreas Schmidta and Peter Langera,b,
*
aInstitut fu¨r Chemie, Universita¨t Rostock, Albert-Einstein-Str. 3a, 18059 Rostock, Germany
bLeibniz-Institut fu¨r Katalyse e. V. an der Universita¨t Rostock, Albert-Einstein-Str. 29a, 18059 Rostock, Germany
Received 18 November 2005; revised 19 January 2006; accepted 23 January 2006
Dedicated to Professor Ralf Miethchen on the occasion of his 65th birthday
Abstract—2-Acetyl- and 2-alkoxycarbonyl-3-(trifluoromethyl)phenols were prepared by [3+3] cyclization of 1,3-bis-silyl enol ethers
with 4-ethoxy- and 4-silyloxy-1,1,1-trifluoroalk-3-en-2-ones.
ꢀ 2006 Elsevier Ltd. All rights reserved.
(Trifluoromethyl)benzenes are present in a great variety
of pharmaceuticals,1,2 pesticides and ligands.3 The trifluo-
romethyl group strongly increases the lipophilicity of
arenes and heterocycles.1 In fact, functionalized (trifluo-
romethyl)benzenes represent important building blocks
for the development of novel lead structures in medicinal
chemistry. They have been prepared mainly by trifluo-
romethylation of aromatic compounds4 or by reactions
of appropriate fluorine-containing building blocks.5
However, these reactions often suffer from low regio-
selectivities. Therefore, the development of new strate-
gies for the synthesis of functionalized benzenes with a
trifluoromethyl group located at a specific position is
of considerable current interest. Some years ago, Chan
and co-workers reported6 an elegant approach to salicy-
lates based on cyclization of 1,3-bis-silyl enol ethers
(d4-synthons)7 with 3-(silyloxy)alk-2-en-1-ones.8 Very
recently, Kostyuk and co-workers reported the synthesis
of 3,5-bis(trifluoromethyl)anilines by cyclization of
enamines with 1,1,1,5,5,5-hexafluoroacetylacetone.9
Herein, we report a new synthesis of 2-acetyl- and 2-alk-
oxycarbonyl-3-(trifluoromethyl)phenols based on [3+3]
cyclizations of 1,3-bis-silyl enol ethers with 4-ethoxy-
and 4-silyloxy-1,1,1-trifluoroalk-3-en-2-ones. From a
preparative viewpoint, these transformations offer a
O
O
Me SiO
O
3
Me SiCl
3
CF
CF
3
3
C H
6
6
1a
2a
°
20 C
TiCl
4
Me SiO
OSiMe
3
3
CH Cl
2
2
_
°
20 C
78
_
OMe
3a
Me SiCl
3
Me SiO
O
3
OH O
OMe
OMe
Me SiO
3
CF
O
3
CF
3
Keywords: Arenes; Cyclizations; Organic fluorine compounds; Silyl
enol ethers.
Cl Ti
4a (76%)
A
3
*
Corresponding author. Tel.: +49 381 4986410; fax: +49 381
4986412; e-mail: peter.langer@uni-rostock.de
Scheme 1. Possible mechanism of the formation of 4a.
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.01.111

2184
C. Mamat et al. / Tetrahedron Letters 47 (2006) 2183–2185
convenient and regioselective approach to functional-
ized (trifluoromethyl)phenols, which are not readily
available by other methods. The starting materials—3-
alkoxyalk-2-en-1-ones—are readily available by acyla-
tion of enol ethers.
O
O
Me SiO
3
O
i
1
1
CF
R
CF
3
R
3
1a,b
2a,b
ii
1,1,1-Trifluoro-4-silyloxypent-3-en-2-one (2a) and 1,1,1,
5,5,5-hexafluoro-4-silyloxypent-3-en-2-one (2b) were
prepared by silylation of the corresponding 1,3-di-
ketones according to a literature procedure.9 The TiCl4
mediated cyclization of 2a with 1,3-bis-silyl enol ethers
3a—prepared from methyl acetoacetate—afforded the
desired 2-ethoxycarbonyl-3-(trifluoromethyl)phenol 4a
(Scheme 1). The regioselective formation of the product
can be explained—following general observations by
Chan et al.6—by conjugate addition of the terminal
carbon atom of 3a onto 2a and subsequent cyclization
by attack of the central carbon atom of the bis-silyl enol
ether onto the carbonyl group (Mukaiyama aldol
reaction).
Me SiO
OSiMe
3
3
OH O
2
2
R
3
R
3
R
R
3a-e
1
CF
R
3
1
R = Me, CF
3
4a-f
2
3
R , R : see Table 1
Scheme 2. Synthesis of 4a–f. Reagents and conditions: (i) Me3SiCl,
NEt3, C6H6, 20 ꢁC, 3 d; (ii) TiCl4, CH2Cl2, ꢀ78!20 ꢁC, 20 h.
Table 1. Products and yields
2
3
4
R1
R2
R3
Yield (%)a
a
a
a
a
a
b
a
b
c
d
e
c
a
b
c
d
e
f
Me
Me
Me
Me
Me
CF3
H
H
H
Me
Et
H
OMe
OEt
Me
OEt
OEt
Me
76
40
61
75
72
35
The TiCl4 mediated cyclization of 2a with 1,3-bis-silyl
enol ethers 3b–e—prepared from ethyl acetoacetate,
acetylacetone, ethyl 3-oxopentanoate and ethyl 3-oxo-
hexanoate—afforded the desired 2-alkoxycarbonyl-3-
(trifluoromethyl)phenols 4b,d,e and the 2-acetyl-3-(tri-
fluoromethyl)phenol 4c (Scheme 2, Table 1). The cycli-
zation of 1,3-bis-silyl enol ether 3c with 2b afforded
2-acetyl-3,5-bis(trifluoromethyl)phenol (4f). The forma-
tion of regioisomeric products was not observed. How-
ever, the concentration of the starting materials proved
to be an important parameter during the optimization.
a Isolated yields.
(Scheme 3, Table 2).à All products were formed with
very good regioselectivity. The reactions proceeded by
regioselective attack of the terminal carbon atom of
the 1,3-bis-silyl enol ether onto the carbon atom at-
tached to the ethoxy group of the enone and subsequent
cyclization by attack of the central carbon atom of 3
onto the carbonyl group.11 During the optimization of
the cyclization reaction, the concentration of the starting
materials and the use of an excess of 3 (2.0 equiv) played
an important role. Only moderate yields were obtained
in some cases, since non-dehydrated cyclic products
The 4-ethoxy-1,1,1-trifluorobut-3-en-2-ones 6a–c were
prepared by reaction of enol ethers with trifluoroacetic
anhydride according to a literature procedure.10 The
TiCl4 mediated cyclization of 6a–c with 1,3-bis-silyl enol
ethers 3a–e afforded the 3-(trifluoromethyl)phenols 7a–g
General procedure for the synthesis of 4a–f: To a CH2Cl2 solution
(5 mL) of 1,3-bis-silyl enol ether 3 (2.4 mmol) and 4-(silyloxy)alk-3-
en-2-one 2a,b (2.2 mmol) was added TiCl4 (2.4 mmol) at ꢀ78 ꢁC
under argon atmosphere. The temperature of the reaction mixture
was allowed to rise to 20 ꢁC during 14 h and, subsequently, a
saturated aqueous solution of NaHCO3 (20 mL) was added. The
organic layer was separated and extracted with diethyl ether
(3 · 20 mL). The combined organic layers were dried (Na2SO4),
filtered and the filtrate was concentrated in vacuo. The residue was
purified by column chromatography (silica gel, n-heptane/
EtOAc = 20:1).
2-(Ethoxycarbonyl)-5-methyl-3-(trifluoromethyl)phenol (4b). Starting
with 2a and 3b, 4b was isolated as a yellow solid (220 mg, 40%),
mp = 28 ꢁC; Rf = 0.48 (n-heptane/EtOAc = 2:1). 1H NMR
(250 MHz, CDCl3): d = 10.90 (s, 1H, OH), 7.13 (s, 1H, H-4), 7.01
(s, 1H, H-6), 4.43 (q, 2H, 3J = 7.2 Hz, OCH2CH3), 2.38 (s, 3H, CH3),
1.41 (t, 3H, 3J = 7.2 Hz, OCH2CH3). 13C NMR (63 MHz, CDCl3):
d = 169.3 (C@O), 162.1 (C-1), 145.0 (C-5), 130.1 (q, JC,F = 34 Hz, C-
3), 123.2 (q, JC,F = 275 Hz, CF3), 122.0 (C-6), 120.4 (q, JC,F = 7 Hz,
C-4), 108.6 (C-2), 62.3 (CH2), 21.5 (CH3), 13.4 (CH2CH3). 19F NMR
(235 MHz, CDCl3): d = ꢀ58.0 (s, CF3). Anal. Calcd for C11H11F3O3:
C, 53.23; H, 4.47. Found: C, 52.85; H, 4.69. All new compounds gave
correct spectroscopic and analytical and/or high resolution mass
data.
à General procedure for the synthesis of 7a–g: To a CH2Cl2 solution
(10 mL) of 1,3-bis-silyl enol ether 3 (7.7 mmol) and 6 (3.8 mmol) was
added TiCl4 (3.8 mmol) at ꢀ78 ꢁC under argon atmosphere. The
temperature of the reaction mixture was allowed to rise to 20 ꢁC
during 14 h and, subsequently, an aqueous solution of HCl (20 mL,
10%) was added. The organic layer was separated and extracted with
CH2Cl2 (3 · 20 mL). The combined organic layers were dried
(Na2SO4), filtered and the filtrate was concentrated in vacuo. The
residue was purified by column chromatography (silica gel,
n-heptane/EtOAc = 10:1).
Methyl 5-ethyl-6-(trifluoromethyl)salicylate (7f). Starting with 6c
(750 mg, 3.8 mmol), 3b (2.00 g, 7.7 mmol) and TiCl4 (1.2 mL,
3.8 mmol), 7f was isolated as a colourless solid (670 mg, 71%),
mp = 84 ꢁC; Rf = 0.46 (n-heptane/EtOAc = 2:3). IR (Nujol):
~m ¼ 3663 ðwÞ, 1710 (s) cmꢀ1
.
1H NMR (250 MHz, CDCl3): d = 8.14
(br, 1H, OH), 7.32 (d, 1H, 3J = 8.5 Hz, H-6), 7.09 (d, 1H,
3J = 8.5 Hz, H-5), 3.93 (s, 3H, OMe), 2.75 (m, 2H, 3J = 7.3 Hz,
CH2CH3), 1.23 (t, 3H, 3J = 7.3 Hz, CH2CH3). 13C NMR (62 MHz,
CDCl3): d = 169.6 (C@O), 155.2 (C-1), 136.5 (C-4), 135.4 (C-5), 127.2
(q, JC,F = 31 Hz, C-3), 124.1 (q, JC,F = 276 Hz, CF3), 120.8 (C-6),
115.2 (C-2), 53.1 (OMe), 26.6 (CH2CH3), 16.1 (CH2CH3). 19F NMR
(235 MHz, CDCl3): d = ꢀ54.4 (CF3). MS (EI, 70 eV): m/z (%) = 248
(27) [M+], 217 (29) [M+ꢀOMe], 216 (100) [M+ꢀHOMe]. HRMS
(EI): calcd for C11H11F3O3: 248.0655; found: 248.0651.

C. Mamat et al. / Tetrahedron Letters 47 (2006) 2183–2185
2185
1
esforschungsschwerpunkt ‘Neue Wirkstoffe und Screen-
ingverfahren’) is gratefully acknowledged.
R
O
EtO
i
5a-c
EtO
CF
3
O
O
1
R
+
F C
3
References and notes
O
CF
3
6a-c
ii
1. (a) Fluorine in Bioorganic Chemistry; Filler, R., Kobayasi,
Y., Yagupolskii, L. M., Eds.; Elsevier: Amsterdam, 1993;
(b) Filler, R. Fluorine Containing Drugs in Organofluorine
Chemicals and Their Industrial Application; Pergamon:
New York, 1979; Chapter 6; (c) Hudlicky, M. Chemistry
of Organic Fluorine Compounds; Ellis Horwood: Chiches-
ter, 1992.
Me SiO
OSiMe
3
3
OH O
2
2
R
3
R
3
R
R
3a-e
CF
3
1
1
2
R
R , R = H, Me, Et
2. (a) Ryckmans, T.; Balancon, L.; Berton, O.; Genicot, C.;
Lamberty, Y.; Lallemand, B.; Pasau, P.; Pirlot, N.; Quere,
L.; Talaga, P. Bioorg. Med. Chem. Lett. 2002, 12, 261; (b)
Malamas, M. S.; Sredy, J.; Gunawan, I.; Mihan, B.;
Sawicki, D. R.; Seestaller, L.; Sullivan, D.; Flam, B. R. J.
Med. Chem. 2000, 43, 3995.
3
R = OMe, OEt, Me
7a-g
Scheme 3. Synthesis of 7a–g. Reagents and conditions: (i) CH2Cl2,
pyridine, 0 ꢁC; (ii) TiCl4, CH2Cl2, ꢀ78!20 ꢁC, 20 h.
3. Liedtke, J.; Loss, S.; Widauer, C.; Grutzmacher, H.
¨
Table 2. Products and yields
Tetrahedron 2000, 56, 143.
3
6
7
R1
R2
R3
Yield (7) (%)a
4. (a) Paratian, J. M.; Sibille, S.; Perichon, J. J. Chem. Soc.,
Chem. Commun. 1992, 53; (b) Tordeux, M.; Langlois, B.;
Wakselman, C. J. Chem. Soc., Perkin Trans. 1 1990, 2293.
5. Ding, W. Y.; Pu, J. Q.; Zhang, C. M. Synthesis 1992, 635.
6. Chan, T.-H.; Brownbridge, P. J. Am. Chem. Soc. 1980,
102, 3534.
b
d
e
a
c
a
c
a
a
a
b
b
c
a
b
c
d
e
f
H
H
H
Me
Me
Et
Et
H
OEt
OEt
OEt
OMe
Me
30
20
26
45
60
71
40
Me
Et
H
H
H
7. For a review of 1,3-bis-silyl enol ethers, see: Langer, P.
Synthesis 2002, 441.
OMe
Me
c
g
H
8. For [3+3] cyclizations from our laboratory, see: (a) Bose,
G.; Nguyen, V. T. H.; Ullah, E.; Lahiri, S.; Go¨rls, H.;
Langer, P. J. Org. Chem. 2004, 69, 9128; (b) Nguyen, V. T.
H.; Langer, P. Tetrahedron Lett. 2005, 46, 815; (c)
Nguyen, V. T. H.; Langer, P. Tetrahedron Lett. 2005, 46,
1013; (d) Nguyen, V. T. H; Bellur, E.; Appel, B.; Langer,
P. Synthesis, in press.
9. (a) Volochnyuk, D. M.; Kostyuk, A. N.; Sibgatulin, D. A.;
Chernega, A. N.; Pinchuk, A. M.; Tolmachev, A. A.
Tetrahedron 2004, 60, 2361; (b) Volochnyuk, D. M.;
Kostyuk, A. N.; Sibgatulin, D. A.; Chernega, A. N.
Tetrahedron 2005, 61, 2839.
10. (a) Hojo, M.; Masuda, R.; Sakaguchi, S.; Takagawa, M.
Synthesis 1986, 1016; (b) Colla, A.; Martins, M. A. P.;
Clar, G.; Krimmer, S.; Fischer, P. Synthesis 1991, 483; (c)
Hojo, M.; Masuda, R.; Kokuryo, Y.; Shioda, H.; Matsuo,
S. Chem. Lett. 1976, 499.
11. The opposite regioselectivity was observed for the reaction
of 6a with the monoanion of acetylacetone (a d2-synthon):
Zanatta, N.; Barichello, R.; Bonacorso, H. G.; Martins,
M. A. P. Synthesis 1999, 5, 765.
a Isolated yields.
were formed as side products. The latter could not be
transformed into the desired phenols by treatment with
acid.
In conclusion, we have reported a new approach to
2-acetyl- and 2-alkoxycarbonyl-3-(trifluoromethyl)-
phenols based on [3+3] cyclizations of 1,3-bis-silyl
enol ethers with 4-ethoxy- and 4-silyloxy-1,1,1-trifluoro-
alk-3-en-2-ones.
Acknowledgements
Financial support by the state of Mecklenburg-
Vorpommern (scholarship for A.S. and Land-