One-pot synthesis of functionalized 3-(trifluoromethyl)phenols by [3+3] cyclization of 1,3-bis(silyl enol ethers) with α,β-unsaturated trifluoromethyl ketones

Article abstract of DOI:10.1002/ejoc.200700801

Functionalized 3-(trifluoromethyl)phenols were prepared by formal [3+3] cyclization of 1,3-bis(silyl enol ethers) with readily available open-chained and cyclic α,β-unsaturated trifluoromethyl ketones. The reaction of 3,4-dihydro-5-(trifluoroacetyl)-2H-pyran with 1,3-bis(silyl enol ethers) resulted in a domino process to give new functionalized dihydropyrans. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejoc.200700801

FULL PAPER
DOI: 10.1002/ejoc.200700801
One-Pot Synthesis of Functionalized 3-(Trifluoromethyl)phenols by [3+3]
Cyclization of 1,3-Bis(silyl enol ethers) with α,β-Unsaturated Trifluoromethyl
Ketones
Constantin Mamat,[a] Thomas Pundt,[a] T. H. Tam Dang,[a,b] Renske Klassen,[a]
Helmut Reinke,[a] Martin Köckerling,[a] and Peter Langer*[a,b]
Dedicated to Professor Dr. Ralf Miethchen
Keywords: Arenes / Cyclizations / Organic fluoro compounds / Silyl enol ethers / Regioselectivity
Functionalized 3-(trifluoromethyl)phenols were prepared by
formal [3+3] cyclization of 1,3-bis(silyl enol ethers) with read-
ily available open-chained and cyclic α,β-unsaturated trifluo-
romethyl ketones. The reaction of 3,4-dihydro-5-(trifluo-
roacetyl)-2H-pyran with 1,3-bis(silyl enol ethers) resulted in
a domino process to give new functionalized dihydropyrans.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
transformation of carboxylic acids into CF3 groups, and the
transformation of CX3 into CF3 groups. However, these re-
actions are often applicable only to specific substrates. (Tri-
fluoromethyl)copper is rather unstable and rapidly un-
dergoes decomposition in reactions with “difficult” sub-
strates. In addition, it has to be taken into consideration
that the synthesis of complex aromatic starting materials is
often a difficult task. An important alternative for the syn-
thesis of CF3-substituted arenes relies on synthetic transfor-
mations of CF3-containing building blocks.[8] This strategy
is a good supplement for direct fluorination methods, and
is gaining considerable importance. For example, (trifluoro-
methyl)phenols have been prepared based on cycloconden-
sation reactions,[9] metalation of (trifluoromethyl)arenes
and subsequent addition of electrophiles,[10] and Diels–
Alder reactions.[11] 3,5-Bis(trifluoromethyl)anilines were
prepared by cyclization of enamines with 1,1,1,5,5,5-hexa-
fluoroacetylacetone.[12] α,β-Unsaturated trifluoromethyl
ketones, readily available by condensation of enol ethers
with trifluoroacetic anhydride,[13] have been widely used for
the synthesis of CF3-substituted heterocycles.[14] The syn-
thesis of CF3-substituted benzene derivatives by this
method has, despite the pharmacological and synthetic im-
portance of these compounds, only scarcely been reported
to date. 2-Acetyl-5-(trifluoromethyl)phenol was prepared by
sodium hydride mediated cyclization of acetylacetone with
4-ethoxy-1,1,1-trifluorobut-3-en-2-one.[15] However, this
protocol proved not to be general, and is restricted to the
synthesis of only one specific example. Recently, we have
reported[16] the synthesis of 2-acetyl- and 2-(alkoxycar-
bonyl)-3-(trifluoromethyl)phenols by formal [3+3] cycliza-
tions[17,18] of 1,3-bis(silyl enol ethers) Ϫ electroneutral
Introduction
The trifluoromethyl group represents, due to its unique
stereoelectronic properties, a very important substituent in
organic and medicinal chemistry.[1] While the size of the
CF3 group is comparable to the methyl group, its high elec-
tronegativity results in a much different electronic situation
and a change of the reactivity. This plays an important role
in drug–receptor interactions. In addition, the increased li-
pophilicity of CF3-substituted molecules improves their in
vivo transport. Undesirable metabolic transformations are
often avoided, due to the high chemical and biological sta-
bility of the CF3 group. Therefore, the synthesis of CF3-
substituted arenes and hetarenes plays an important role in
drug discovery.[1] Trifluoromethyl-substituted compounds
also play an increasingly important role as ligands[2] for
catalytic reactions in fluorous biphase systems and super-
critical carbon dioxide.[3] This takes advantage of the excel-
lent solubility of trifluoromethyl- and perfluoroalkyl-substi-
tuted molecules in fluorophilic solvents. It is noteworthy
that CF3-substituted arenes also represent important sub-
structures of various organocatalysts (such as CF3-substi-
tuted N,NЈ-diarylthioureas).[4,5]
Trifluoromethyl-substituted arenes and hetarenes are
available by trifluoromethylation of appropriate starting
materials.[6,7] This includes, for example, the reaction of aryl
halides with (trifluoromethyl)copper, the SF4-mediated
[a] Institut für Chemie der Universität Rostock,
Albert-Einstein-Straße 3a, 18059 Rostock
Fax: +49-381-498-6411
E-mail: peter.langer@uni-rostock.de
[b] Leibniz-Institut für Katalyse e.V. an der Universität Rostock,
Albert-Einstein-Straße 29a, 18059 Rostock
492
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 492–502

Functionalized 3-(Trifluoromethyl)phenols
equivalents of 1,3-dicarbonyl dianions (masked dianions)[19] product 5 was isolated as a side product in 21% yield. The
Ϫ with 4-ethoxy-1,1,1-trifluoroalk-3-en-2-ones. These reac- formation of this type of side product could be explained
tions offer a convenient and regioselective approach to by hydrolysis of intermediate C, as not all of the material
functionalized CF3-substituted phenols which are not read- underwent the final aromatization (Scheme 2). The rela-
ily available by other methods. Herein we wish to report tively low yields of some phenols 4 can be explained by the
full details of these studies. With regard to our preliminary formation of side products such as 5.
communication,[16] the preparative scope was significantly
extended. In addition, we report a new domino reaction of
1,3-bis(silyl enol ethers) with 3,4-dihydro-5-(trifluoroace-
tyl)-2H-pyran.
Results and Discussion
Reactions of electron-rich olefins such as vinyl ethers or
vinyl sulfides with trifluoroacetic anhydride give the corre-
sponding trifluoroacetylated compounds in high yields. Fol-
lowing the procedure of Hojo[13b,13c] and Colla,[13d] the syn-
thesis of substituted enol ethers 1a–c with trifluoroacetic
anhydride afforded the α,β-unsaturated trifluoromethyl
ketones 2a–c in good yields (Scheme 1, Table 1). This reac-
tion is known to proceed by an addition–elimination
mechanism.[20–22]
Scheme 1. Synthesis of α,β-unsaturated trifluoromethyl ketones 2a–c.
Table 1. Synthesis of α,β-unsaturated trifluoromethyl ketones 2a–c.
Scheme 2. Possible mechanism of the formation of 3-(trifluoro-
methyl)phenols 4a–m.
2
R1
% Yield[a]
a
b
c
H
Me
Et
93[13e]
64[13d]
86
Table 2. Synthesis of 3-(trifluoromethyl)phenols 4a–m.
3
2
4
R1
R2
R3
%
Yield[a]
[a] Isolated yield.
a
b
c
d
e
a
d
e
f
a
a
a
b
b
c
c
c
c
c
a
b
c
d
e
f
H
H
H
Me
Me
Et
Et
Et
Et
H
Me
Et
H
H
H
H
H
nBu
OEt
OEt
OEt
OMe
Me
OEt
OMe
Me
30
20
26
The TiCl4-mediated cyclization of enone 2a with 1,3-
bis(silyl enol ether) 3a afforded 3-(trifluoromethyl)phenol
4a (Scheme 2, Table 2). The reaction presumably proceeds
by regioselective attack of the terminal carbon atom of 3a
onto the carbon attached to the ethoxy group of enone 2a,
cyclization by attack of the central carbon atom of 3a onto
the carbonyl group, and aromatization by elimination
(either before or during the aqueous work-up). The high
concentration of the reaction mixture and the employment
of an excess of 3a (2.0 equiv.) proved to be important pa-
rameters during the optimization of this reaction. The cycli-
zation of enones 2a–c with 1,3-bis(silyl enol ethers) 3a–j af-
forded, following our optimized protocol, the 3-(trifluoro-
methyl)phenols 4a–m in 20 to 88% yield. The best yields
were generally obtained for those phenols derived from the
methyl- and ethyl-substituted enones 2b and 2c (except for
products 4j and 4m). The mechanism proposed for the for-
mation of phenols 4a–m is supported by the following ob-
servation: during the formation of 4f, the non-aromatized
45
58
71[b]
71
g
h
i
40
77
20
OMe
g
j
Et H2C=CH(CH2) OMe
2
h
i
j
c
c
c
k
l
m
Et
Et
Et
Cl(CH2)6
n-C7H15
PhCH2
OMe
OMe
OMe
88
53
24
[a] Isolated yields. [b] Compound 5 was also isolated in 21% yield
(see structure).
Eur. J. Org. Chem. 2008, 492–502
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493

P. Langer et al.
FULL PAPER
1
The H NMR spectra of products 4a–m show a sharp
signal between δ = 10 and 12 ppm which can be assigned
to the proton involved in a hydrogen bond: O–H···O=C.
The CF3 group appears (19F NMR) at about –63 ppm for
acetophenone derivatives (4e,h) and in the range of –52 ppm
for salicylate derivatives (4a–d, f–g, i–m). For comparison,
CF3 groups attached to a simple benzene moiety usually
give rise to a signal at δ = –64 ppm[23] and CF3 groups
located next to a carbonyl group resonate at about
–70 ppm. The structure of 4g was independently confirmed
by an X-ray single-crystal structure analysis (Figure 1).[24]
The structure of 5 was elucidated by NMR, MS and IR
spectroscopy. The resonance (19F NMR) of the CF3 group
(δ = –80 ppm) suggests that the latter is attached to an al-
1
kene rather than to an arene moiety. In the H NMR spec-
trum, no signals are observed in the aromatic region. For
proton 4-H, a doublet is observed at δ = 5.73 ppm and a
double doublet for 3a/b-H at δ = 2.88–3.13 ppm.
Scheme 3. Synthesis of annulated 3-(trifluoromethyl)phenols 9a–g.
rived 1,3-bis(silyl enol ether) 3e, were lower than those of
phenols 9a,f which were prepared from β-keto-ester-derived
1,3-bis(silyl enol ethers) 3a,d. This can be explained by the
lower reactivity of 3e compared to 3a,d. The structures of
products 9a–g were established by spectroscopic methods.
The resonances of the CF3 groups (19F NMR) were ob-
served in the expected range of δ = –51 ppm (ester deriva-
tives) and –63 ppm (keto derivatives). In addition the struc-
ture of 9c was independently confirmed by an X-ray single-
crystal diffraction analysis (Figure 2).[24] The unit cell hosts
two symmetric independent molecules of 9a, which are in-
terconnected by hydrogen bonds.
Figure 1. Molecular structure of 4g in the crystal (ORTEP plot,
50% probability level, one of the two symmetry-independent mole-
cules is shown).
The known cyclic α,β-unsaturated trifluoromethyl
ketones 8a–d were prepared, following a known pro-
cedure,[25,26] by reaction of trifluoroacetic anhydride with
ketals 7a–d (Scheme 3). The latter are available from cyclo-
alkanones 6a–d.[27] Notably, enol ethers 8a–d were formed,
in contrast to the corresponding silyl enol ethers,[28] with
definite regioselectivity. This is an important issue for the
regioselectivity of the [3+3] cyclizations, since the employ-
ment of a mixture of regioisomeric enol ethers usually re-
sults in the formation of a mixture of regioisomeric phenols.
Besides, it is known that the silyl group of 3-(silyloxy)alk-
2-en-1-ones can undergo a TiCl4-mediated rearrangement
from one oxygen atom to the other, which may also result
in the formation of regioisomeric mixtures of phenols (de-
pending on the substitution pattern).[17,18] In fact, this type
Table 3. Synthesis of annulated 3-(trifluoromethyl)phenols 9a–g.
3
8
9
n
R
% Yield[a]
d
e
d
e
e
a
e
a
a
b
b
c
d
d
a
b
c
d
e
f
1
1
2
2
3
4
4
OMe
Me
OMe
Me
Me
OEt
Me
68
14
30
37
40
84
40
g
[a] Isolated yields.
The reaction of hexane-2,5-dione (10) with trimethyl or-
of rearrangement is not observed for 3-alkoxyalk-2-en-1- thoformate in the presence of p-toluenesulfonic acid
ones.
(pTsOH) afforded the known bis(ketal) 11.[29] The latter was
The TiCl4-mediated cyclization of enones 8a–d with 1,3- transformed into bis(enone) 12 by treatment with trifluoro-
bis(silyl enol ethers) 3a,d,e afforded the annulated 3-(tri- acetic anhydride (Scheme 4).[30] The TiCl4-mediated cycliza-
fluoromethyl)phenols 9a–g in moderate to good yields (ex- tion of 12 with 1,3-bis(silyl enol ether) 3a afforded bis[4-
cept for 9b) and with excellent regioselectivity (Table 3). (trifluoromethyl)salicylate] 13.
The formation of the other regioisomer was not observed.
The aryl-substituted α,β-unsaturated trifluoromethyl
The products are presumably formed by the mechanism ketones 16a–c were prepared by reaction of trifluoroacetic
proposed for the formation of 4a–m. In most cases, the anhydride with ketals 15a–c, which are available from aceto-
yields of phenols 9b,d,e,g, prepared from acetylacetone-de- phenones 14a–c.[31] In the TiCl4-mediated cyclization of 16a
494
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Functionalized 3-(Trifluoromethyl)phenols
Figure 2. Molecular structure of 9c in the crystal (ORTEP plot,
50% probability level).
Scheme 5. Synthesis of biaryls 17a–d.
Table 4. Products and yields of 17a–d.
3
16
17
R1
R2
% Yield[a]
d
d
e
a
b
a
c
a
b
c
Cl
Br
Cl
H
OMe
OMe
Me
25
20
40
28
k
d
Ph
[a] Isolated yields.
Scheme 4. Synthesis of bis[4-(trifluoromethyl)salicylate] 13.
and 16b with 1,3-bis(silyl enol ether) 3d, the appropriate
CF3-substituted biaryls 17a and 17b were obtained
(Scheme 5, Table 4). The cyclization of 1,3-bis(silyl enol
ethers) 3e and 3k with 16a and 16c afforded the biaryls 17c
and 17d, respectively. It is noteworthy that different re-
gioisomers were obtained for the reactions of β-keto-ester-
and 1,3-diketone-derived 1,3-bis(silyl enol ethers), as evi-
denced by X-ray structural analysis (Figures 3 and 4).[24]
Both compounds 17b and 17d were independently charac-
terized by this method. Any formation of the opposite re-
gioisomer could not be detected. This can be explained
Figure 3. Molecular structure of 17b in the crystal (ORTEP plot,
50% probability level, one out of the four symmetry-independent
molecules is shown).
based on the different reactivities of the starting materials oxygen atom onto the carbonyl group gave intermediate C,
3d,e,k. and subsequent elimination afforded the products 20a–d.
Treatment of 3,4-dihydro-2H-pyran (18) with trifluoro- The structure was independently confirmed by an X-ray
acetic anhydride afforded the known[13d,22] cyclic enone 19. crystal structure analysis (Figure 5).[24] In solution (CDCl3),
The TiCl4-mediated reaction of 19 with 1,3-bis(silyl enol the β-keto-ester-derived product 20a exists as a tautomeric
ethers) 3a,e,l,k afforded the 2-(trifluoroalkylated) 5,6-dihy- mixture (ketone/enol ratio 2:1), which is supported by
dro-4H-pyran derivatives 20a–d (Scheme 6, Table 5). The NMR spectroscopic observations. All 1,3-diketone-derived
formation of the products can be explained by a domino products 20b–d exclusively exist in their enol tautomeric
reaction: the TiCl4-mediated conjugate addition of the ter- form. In case of the synthesis of 20b, side product 21 was
minal carbon atom of the 1,3-bis(silyl enol ether) to 19 gave isolated in 40% yield. The formation of 21 can be explained
intermediate A. Ring opening of the pyran ring by a retro- by attack of the terminal carbon atom of the 1,3-bis(silyl
Michael reaction afforded intermediate B. Attack of the enol ether) onto carbon atom C-6 of the 3,4-dihydro-2H-
Eur. J. Org. Chem. 2008, 492–502
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495

P. Langer et al.
FULL PAPER
Michael reaction is a good nucleophile and can compete
easily (6-exo-trig ring closure) with the enol ether [6-(enol-
endo)-exo-trig ring closure].
Table 5. Synthesis of dihydropyrans 20a–d.
3
20
R
Ketone/enol
% Yield[a]
a
e
k
l
a
b
c
OEt
Me
Ph
2:1
0:1
0:1
0:1
24
53[b]
29
d
CF3
26
[a] Isolated yields. [b] Compound 21 was also isolated in 40% yield
(see structure).
Figure 4. Molecular structure of 17d in the crystal (ORTEP plot,
50% probability level, only one of the two disorderd orientations
of the CF3 group is shown).
pyran 19, ring opening, and subsequent re-cyclization via
the central carbon atom of the 1,3-dicarbonyl moiety. Re-
lated transformations were reported for the reaction of cy-
clic enol ethers, such as 19, with carbon,[32] nitrogen,[33] and
oxygen nucleophiles.[13c] The formation of products 20a–d
is not unexpected, since the alcohol released by the retro-
Figure 5. Molecular structure of 20a in the crystal (ORTEP plot,
50% probability level, one out of the four symmetry independent
molecules is shown).
Conclusions
In conclusion, we have reported a new and versatile ap-
proach to functionalized 3-(trifluoromethyl)phenols based
on [3+3] cyclizations of 1,3-bis(silyl enol ethers) with open-
chain and cyclic α,β-unsaturated trifluoromethyl ketones.
These products are not readily available by other synthetic
strategies. The reaction of 3,4-dihydro-5-(trifluoroacetyl)-
2H-pyran with different 1,3-bis(silyl enol ethers) resulted in
an unexpected domino process to give new 2-(trifluoroalky-
lated) 5,6-dihydro-4H-pyrans.
Experimental Section
General: Chemical shifts of the 1H and 13C NMR spectra were
reported in parts per million (ppm) using the solvent as internal
standard (chloroform, δ = 7.26 and 77.0 ppm, respectively). Infra-
red spectra were recorded with an FTIR spectrometer. Mass spec-
trometric data (MS) were obtained by electron ionization (EI,
70 eV), chemical ionization (CI, isobutane) or electrospray ioniza-
tion (ESI). Melting points are uncorrected. The solvent CH2Cl2
(anhydrous, 99.8%) was purchased directly from ACROS, and was
used without further purification. TiCl4 was purchased from Ald-
rich and freshly distilled prior to use. Analytical thin-layer
chromatography was performed on 0.20 mm 60-Å silica gel plates.
Column chromatography was performed using 60-Å silica gel (60–
200 mesh). All cyclization reactions were carried out in Schlenk
tubes under an argon atmosphere. The α,β-unsaturated ketones and
bis(silyl enol ethers) were prepared as described in the literature.
Crystallographic data were collected with a Bruker-Nonius Apex-
X8 CCD-diffractometer with Mo-Kα radiation (λ = 0.71073 Å).
The structures were solved by direct methods using SHELXS-97
Scheme 6. Reaction of enone 19 with 1,3-bis(silyl enol ethers)
3a,e,l,k.
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Functionalized 3-(Trifluoromethyl)phenols
2
and refined against F2 on all data by full-matrix least-squares with
SHELXL-97.[34] All non-hydrogen atoms were refined anisotropi-
cally; all hydrogen atoms were placed on geometrically calculated
positions and refined by using a riding model.
137.5 (C-3), 132.3 (C-4), 127.7 (q, JC,F = 32.0 Hz, C-6), 123.6 (q,
1JC,F = 273.0 Hz, CF3), 118.4 (q, 3JC,F = 7.0 Hz, C-5), 110.6 (C-1),
62.5 (OCH2CH3), 23.2 (CH2CH3), 13.5 (OCH2CH3), 13.2
(CH2CH3) ppm. 19F NMR (235 MHz, CDCl3): δ = –57.7 (CF3)
ppm. IR (Nujol): ν = 3200 (OH), 1672 (C=O) cm–1. MS (EI,
˜
4-Ethoxy-3-ethyl-1,1,1-trifluorobuten-2-one (2c): To a mixture of 1-
butenyl ethyl ether (1c) (5.00 g, 50.0 mmol) and pyridine (3.7 mL,
45.0 mmol) in CH2Cl2 (20 mL) was added trifluoroacetic anhydride
(7.0 mL, 45.0 mmol) at 0 °C, and the temperature of the reaction
mixture was allowed to rise to 20 °C during 14 h. The pyridinium
salt was filtered off and washed with CH2Cl2, and the solvent of
the filtrate was removed in vacuo. After distillation in vacuo, 2c
(8.42 g, 86%) was obtained as a colourless liquid; b.p. 68 °C
(10 mbar). 1H NMR (250 MHz, CDCl3): δ = 7.48 (q, JH,F = 1.2 Hz,
1 H, 4-H), 4.20 (q, 3J = 7.0 Hz, 2 H, OCH2CH3), 2.32 (q, 3J =
70 eV): m/z (%) = 262 (29) [M+], 216 (55) [M+ – OCH2CH3].
HRMS (EI): calcd. for C13H15F3O3 262.0811; found 262.0804
[M+].
Methyl 5-Methyl-6-(trifluoromethyl)salicylate (4d): Following the
general procedure, 2b (500 mg, 2.75 mmol), 3d (1.43 g, 5.49 mmol)
and TiCl4 (0.30 mL, 2.75 mmol) yielded 4d as a colourless solid
(289 mg, 45%); m.p. 83 °C; Rf = 0.53 (n-heptane/EtOAc = 3:1). 1H
3
NMR (250 MHz, CDCl3): δ = 8.21 (s, 1 H, OH), 7.26 (d, J3,4
=
3
8.7 Hz, 1 H, 3-H), 7.04 (d, J3,4 = 8.7 Hz, 1 H, 4-H), 3.94 (s, 3 H,
3
OCH3), 2.43 (q, JH,F = 2.9 Hz, 3 H, CH3) ppm. 13C NMR
5
7.6 Hz, 2 H, CH2CH3), 1.38 (t, J = 7.0 Hz, 3 H, OCH2CH3), 0.96
3
(t, J = 7.6 Hz, 3 H, CH2CH3) ppm. 13C NMR (63 MHz, CDCl3):
(76 MHz, CDCl3): δ = 169.4 (C=O), 155.2 (C-2), 136.5 (C-5), 129.8
2
3
3
2
δ = 179.7 (q, JC,F = 33.4 Hz, C=O), 164.3 (q, JC,F = 4.8 Hz, C-
(q, JC,F = 2.0 Hz, C-4), 127.7 (q, JC,F = 31.0 Hz, C-6), 123.8 (q,
1
1JC,F = 276.0 Hz, CF3), 120.3 (C-3), 115.2 (q, 3JC,F = 3.0 Hz, C-1),
4), 118.5 (C-3), 117.1 (q, JC,F = 293 Hz, CF3), 71.8 (OCH2CH3),
16.6 (CH2CH3), 15.4 (OCH2CH3), 12.8 (CH2CH3) ppm. 19F NMR
53.0 (OCH3), 20.2 (q, JC,F = 4 Hz, CH3) ppm. 19F NMR
4
(235 MHz, CDCl ): δ = –68.8 (CF ) ppm. IR (neat): ν = 1626
˜
(235 MHz, CDCl ): δ = –55.7 (CF ) ppm. IR (Nujol): ν = 3283
˜
3
3
3
3
(OH), 1683 (C=O) cm–1. MS (EI, 70 eV): m/z (%) = 196 (16) [M+],
127 (63) [M+ – CF3], 99 (100) [M+ – COCF3]. HRMS (EI): calcd.
for C8H11F3O2 196.0706; found 196.0704 [M+].
(OH), 1705 (C=O) cm–1. MS (EI, 70 eV): m/z (%) = 234 (24) [M+],
202 (100) [M+ – OCH3]. HRMS (EI): calcd. for C10H9F3O3
234.0498; found 234.0502 [M+].
General Procedure for the Synthesis of 4a–m, 5 and 17a–d: To a
solution of 1,3-bis(silyl enol ether) 3a–k (2.0 equiv.) and the respec-
tive enone 2a–c, 16a–c (1.0 equiv.) in CH2Cl2 (5 mL) was added
TiCl4 (1.0 equiv.) at –78 °C under argon. The temperature of the
reaction mixture was allowed to rise to 20 °C during 14 h, and an
aqueous HCl solution (10%, 20 mL) was added. The organic layer
was separated, and the aqueous layer was extracted with CH2Cl2
(3ϫ20 mL). The combined organic layers were dried (Na2SO4),
filtered, and concentrated in vacuo. The residue was purified by
column chromatography (silica gel, n-heptane/EtOAc = 20:1).
2-Acetyl-4-methyl-3-(trifluoromethyl)phenol (4e): Following the ge-
neral procedure, 2b (500 mg, 2.75 mmol), 3e (1.34 g, 5.49 mmol)
and TiCl4 (0.30 mL, 2.75 mmol) yielded 4e as a colourless solid
(346 mg, 58%); m.p. 96 °C; Rf = 0.56 (n-heptane/EtOAc = 3:1). 1H
3
NMR (250 MHz, CDCl3): δ = 7.20 (d, J5,6 = 8.5 Hz, 1 H, 6-H),
6.98 (d, 3J5,6 = 8.5 Hz, 1 H, 5-H), 2.51 (q, 6JH,F = 1.7 Hz, 3 H, C(O)-
CH3), 2.42 (q, 5JH,F = 2.5 Hz, 3 H, CH3) ppm. 13C NMR (63 MHz,
3
CDCl3): δ = 205.5 (C=O), 151.2 (C-1), 134.3 (C-4), 129.2 (q, JC,F
3
2
= 2.0 Hz, C-5), 127.1 (q, JC,F = 3.0 Hz, C-2), 125.5 (q, JC,F
=
1
30.0 Hz, C-3), 124.1 (q, JC,F = 276.0 Hz, CF3), 120.0 (C-6), 32.1
3
3
(q, JC,F = 3.0 Hz, C(O)CH3), 19.3 (q, JC,F = 3.0 Hz, CH3) ppm.
Ethyl 6-(Trifluoromethyl)salicylate (4a): Following the general pro-
cedure, 2a (500 mg, 2.97 mmol), 3a (5.95 mmol) and TiCl4
(0.33 mL, 2.97 mmol) yielded 4a as a colourless syrup (208 mg,
30%). The spectroscopic data were identical with those report-
ed.[11b]
19F NMR (235 MHz, CDCl ): δ = –54.9 (CF ) ppm. IR (Nujol): ν
˜
3
3
= 3275 (OH), 1697 (C=O) cm–1. MS (EI, 70 eV): m/z (%) = 218
(25) [M+], 203 (100) [M+ – CH3]. HRMS (EI: calcd. for C10H9F3O2
218.0549; found 218.0546 [M+].
Ethyl 5-Ethyl-6-(trifluoromethyl)salicylate (4f): Following the gene-
ral procedure, 2c (750 mg, 3.8 mmol), 3a (2.00 g, 7.7 mmol) and
TiCl4 (0.42 mL, 3.8 mmol) yielded 4f as a colourless solid (670 mg,
Ethyl 3-Methyl-6-(trifluoromethyl)salicylate (4b): Following the ge-
neral procedure, 2a (500 mg, 2.97 mmol), 3b (1.07 g, 5.95 mmol)
and TiCl4 (0.33 mL, 2.97 mmol) yielded 4b as a colourless syrup
(150 mg, 20%); Rf = 0.56 (n-heptane/EtOAc = 3:1). 1H NMR
71%); m.p. 84 °C; Rf = 0.55 (n-heptane/EtOAc = 2:3). 1H NMR
3
3
(250 MHz, CDCl3): δ = 8.37 (br. s, 1 H, OH), 7.31 (d, J3,4
=
(250 MHz, CDCl3): δ = 11.00 (s, 1 H, OH), 7.33 (d, J4,5 = 8.0 Hz,
3
3
3
3
8.5 Hz, 1 H, 3-H), 7.09 (d, J3,4 = 8.5 Hz, 1 H, 4-H), 4.39 (q, J =
7.1 Hz, 2 H, OCH2CH3), 2.68–2.80 (m, 3J = 7.4 Hz, 2 H,
CH2CH3), 1.38 (t, 3J = 7.1 Hz, 3 H, OCH2CH3), 1.29 (t, 3J =
7.4 Hz, 3 H, CH2CH3) ppm. 13C NMR (63 MHz, CDCl3): δ =
169.2 (C=O), 155.4 (C-2), 136.4 (C-5), 135.4 (C-4), 126.4 (q, JC,F
= 33.0 Hz, C-6), 124.3 (q, JC,F = 274.0 Hz, CF3), 120.8 (C-3),
1 H, 5-H), 7.20 (d, J4,5 = 8.0 Hz, 1 H, 4-H), 4.44 (q, J = 7.3 Hz,
2 H, OCH2CH3), 2.30 (s, 3 H, CH3), 1.41 (t, 3J = 7.3 Hz, 3 H,
OCH2CH3) ppm. 13C NMR (63 MHz, CDCl3): δ = 169.6 (C=O),
2
160.1 (C-2), 133.9 (C-4), 131.9 (C-3), 127.8 (q, JC,F = 33.0 Hz, C-
2
1
3
6), 123.5 (q, JC,F = 273.0 Hz, CF3), 118.3 (q, JC,F = 7.0 Hz, C-
5), 110.5 (C-1), 62.5 (OCH2CH3), 16.3 (CH3), 13.5 (OCH2CH3)
ppm. 19F NMR (235 MHz, CDCl3): δ = –57.6 (CF3) ppm. IR (Nu-
1
117.6 (C-1), 62.7 (OCH2CH3), 26.7 (CH2CH3), 16.1 (OCH2CH3),
13.8 (CH2CH3) ppm. 19F NMR (235 MHz, CDCl3): δ = –53.8
jol): ν = 3203 (OH), 1672 (C=O) cm–1. MS (EI, 70 eV): m/z (%) =
˜
(CF ) ppm. IR (Nujol): ν = 3288 (OH), 1700 (C=O) cm–1. MS (EI,
248 (25) [M+], 202 (54) [M+ – OCH2CH3]. C11H11F3O3 (248.20):
˜
3
70 eV): m/z (%) = 262 (19) [M+], 217 (31) [M+ – OCH2CH3], 216
(100) [M+ – HOCH2CH3]. C12H13F3O3 (262.22): calcd. C 54.96, H
5.00; found C 55.07, H 5.06.
calcd. C 53.23, H 4.47; found C 53.34, H 4.93.
Ethyl 3-Ethyl-6-(trifluoromethyl)salicylate (4c): Following the gene-
ral procedure, 2a (500 mg, 2.97 mmol), 3c (1.80 g, 5.95 mmol) and
TiCl4 (0.33 mL, 2.97 mmol) yielded 4c as a colourless syrup
During the synthesis of 4f, compound 5 was isolated as a side prod-
(150 mg, 20%); Rf = 0.62 (n-heptane/EtOAc = 3:1). 1H NMR uct. The reaction of 2c (750 mg, 3.8 mmol), 3a (2.00 g, 7.7 mmol)
3
(250 MHz, CDCl3): δ = 10.96 (s, 1 H, OH), 7.34 (d, J4,5 = 7.9 Hz,
and TiCl4 (0.42 mL, 3.8 mmol) yielded 5 as a colourless syrup
3
3
1 H, 5-H), 7.24 (d, J4,5 = 7.9 Hz, 1 H, 4-H), 4.44 (q, J = 7.2 Hz,
(223 mg, 21%); Rf = 0.76 (n-heptane/EtOAc = 2:3). 1H NMR
3
3
3
2 H, OCH2CH3), 2.72 (q, J = 7.5 Hz, 2 H, CH2CH3), 1.41 (t, J (250 MHz, CDCl3): δ = 5.73 (d, J3a,4 = 1.9 Hz, 1 H, 4-H), 5.40
3
= 7.2 Hz, 3 H, OCH2CH3), 1.41 (t, 3J = 7.5 Hz, 3 H, CH2CH3) (br. s, 1 H, OH), 4.42 (q, J = 7.2 Hz, 2 H, OCH2CH3), 2.88–3.13
ppm. 13C NMR (63 MHz, CDCl3): δ = 169.7 (C=O), 159.7 (C-2), (dd, 2J3a,3b = 17.0 Hz, 3J4,3a = 1.9 Hz, 2 H, 3a-H, 3b-H), 2.17–2.52
Eur. J. Org. Chem. 2008, 492–502
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
497

P. Langer et al.
FULL PAPER
(m, J7a,7b = 16.0 Hz, J = 7.4 Hz, 2 H, 7a-H, 7b-H), 1.39 (t, J =
2
3
3
1
less syrup (137 mg, 20%); Rf = 0.75 (n-heptane/EtOAc = 1:1). H
7.2 Hz, 3 H, OCH2CH3), 1.09 (t, J = 7.4 Hz, 3 H, 8-H) ppm. 13C NMR (300 MHz, CDCl3): δ = 8.49 (s, 1 H, OH), 7.16 (s, 1 H, 4-
3
NMR (76 MHz, CDCl3): δ = 177.6 (C=O), 170.9 (C-2), 139.0 (C- H), 5.85 (ddd, 3J = 6.8 Hz, 3J = 10.2 Hz, 1 H, HC=), 4.95–5.03
1
3
1), 126.4 (q, JC,F = 290.0 Hz, CF3), 119.5 (C-4), 96.1 (C-5), 74.0
(m, 2 H, H2C=), 3.92 (s, 3 H, OCH3), 2.74 (dd, J = 7.2 Hz, 2 H,
(q, JC,F = 30.0 Hz, C-6), 62.2 (OCH2CH3), 31.8 (C-3), 22.4 (C-7), ArCH2), 2.71 (dd, 5JH,F = 1.9 Hz, 3J = 7.4 Hz, 2 H, CH2CH3), 2.37
2
14.2 (OCH2CH3), 13.0 (C-8) ppm. 19F NMR (235 MHz, CDCl3):
(dd, 3J = 7.2 Hz, 2 H, ArCH2CH2), 1.22 (t, 3J = 7.4 Hz, 3 H,
CH2CH3) ppm. 13C NMR (76 MHz, CDCl3): δ = 170.3 (C=O),
153.6 (C-2), 137.8 (H2C=), 135.8 (C-5), 135.7 (C-4), 124.6 (q, 2JC,F
δ = –79.9 (CF ) ppm. IR (Nujol): ν = 3529, 3353 (OH), 1689 cm–1
˜
3
(C=O). MS (EI, 70 eV): m/z (%) = 262 (17) [M+ – H2O], 216 (100)
[M+ – H2O – EtOH]. C12H15F3O4 (280.24): calcd. C 51.43, H 4.06;
found C 50.97, H 4.12.
1
= 29.6 Hz, C-6), 124.3 (q, JC,F = 275.9 Hz, CF3), 123.1 (C-3),
115.5 (HC=), 114.4 (C-1), 53.1 (OCH3), 33.2, 29.8 (CH2), 26.8
(CH2CH3), 16.2 (CH2CH3) ppm. 19F NMR (235 MHz, CDCl3): δ
Methyl 5-Ethyl-6-(trifluoromethyl)salicylate (4g): Following the ge-
neral procedure, 2c (750 mg, 3.8 mmol), 3d (2.00 g, 7.7 mmol) and
TiCl4 (0.42 mL, 3.8 mmol) yielded 4g as a colourless solid (670 mg,
= –53.9 (CF ) ppm. IR (neat): ν = 3420 (OH), 1716 cm–1 (C=O).
˜
3
MS (EI, 70 eV): m/z (%) = 302 (25) [M+], 270 (22) [M+ – CH3OH].
HRMS (EI): calcd. for C15H17F3O3 302.11243; found 302.112124
[M+].
71%); m.p. 84 °C; Rf = 0.45 (n-heptane/EtOAc = 2:3). 1H NMR
3
(250 MHz, CDCl3): δ = 8.14 (br. s, 1 H, OH), 7.32 (d, J3,4
=
3
8.5 Hz, 1 H, 3-H), 7.09 (d, J3,4 = 8.5 Hz, 1 H, 4-H), 3.93 (s, 3 H,
Methyl 3-(6-Chlorohexyl)-5-ethyl-6-(trifluoromethyl)salicylate (4k):
Following the general procedure, 2c (388 mg, 1.98 mmol), 3h
(1.50 g, 3.96 mmol) and TiCl4 (0.22 mL, 1.98 mmol) yielded 4k as
a colourless syrup (636 mg, 88%); Rf = 0.74 (n-heptane/EtOAc =
OCH3), 2.75 (dq, 3J = 7.3 Hz, 5JH,F = 2.4 Hz, 2 H, CH2CH3), 1.23
3
(t, J = 7.3 Hz, 3 H, CH2CH3) ppm. 13C NMR (63 MHz, CDCl3):
δ = 169.6 (C=O), 155.2 (C-2), 136.5 (C-5), 135.4 (C-4), 127.2 (q,
2JC,F = 31.0 Hz, C-6), 124.1 (q, JC,F = 276.0 Hz, CF3), 120.8 (C-
1
1
1:1). H NMR (300 MHz, CDCl3): δ = 8.47 (s, 1 H, OH), 7.15 (s,
4
3
3), 115.2 (C-1), 53.1 (OCH3), 26.6 (q, JC,F = 2.9 Hz, CH2CH3),
1 H, 4-H), 3.92 (s, 3 H, OCH3), 3.53 (t, J = 7.5 Hz, 2 H, CH2Cl),
16.1 (CH2CH3) ppm. 19F NMR (235 MHz, CDCl3): δ = –54.4
3
3
2.71 (dq, JH,F = 2.3 Hz, J = 7.5 Hz, 2 H, CH2CH3), 2.65 (t, J =
7.4 Hz, 2 H, CH2(CH2)5Cl), 1.32–1.82 (m, 8 H, CH2(CH2)4CH2Cl),
1.22 (t, 3J = 7.5 Hz, 3 H, CH2CH3) ppm. 13C NMR (76 MHz,
CDCl3): δ = 170.2 (C=O), 153.5 (C-2), 135.8 (C-5), 135.5 (C-4),
(CF ) ppm. IR (Nujol): ν = 3663 (OH), 1710 (C=O) cm–1. MS (EI,
˜
3
70 eV): m/z (%) = 248 (27) [M+], 217 (29) [M+ – OCH3], 216 (100)
[M+ – HOCH3]. C11H11F3O3 (248.20): calcd. C 53.23, H 4.47;
found C 53.59, H 4.93.
2
1
124.7 (q, JC,F = 31.0 Hz, C-6), 124.3 (q, JC,F = 274.3 Hz, CF3),
114.3 (C-1), 53.1 (OCH3), 45.2 (CH2Cl), 32.6, 30.1, 29.1, 28.8, 27.1,
26.8 (CH2), 16.3 (CH2CH3). 19F NMR (235 MHz, CDCl3): δ =
2-Acetyl-4-ethyl-3-(trifluoromethyl)phenol (4h): Following the gene-
ral procedure, 2c (800 mg, 4.1 mmol), 3e (2.00 g, 8.2 mmol) and
TiCl4 (0.45 mL, 4.1 mmol) yielded 4h as a colourless solid (376 mg,
–53.8 (CF ) ppm. IR (neat): ν = 3420 (OH), 1748 (C=O) cm–1. MS
˜
3
(EI, 70 eV): m/z (%) = 368 (3) [M+, 37Cl], 366 (17) [M+, 35Cl], 334
(16) [M+ – CH3OH]. HRMS (EI): calcd. for C17H22ClF3O3
366.12041; found 366.120050 [M+].
40%); m.p. 83 °C; Rf = 0.4 (n-heptane/EtOAc = 1:1). 1H NMR
3
(250 MHz, CDCl3): δ = 7.78 (br. s, 1 H, OH), 7.14 (d, J5,6
8.2 Hz, 1 H, 6-H), 6.94 (d, J5,6 = 8.2 Hz, 1 H, 5-H), 2.70 (q, J =
=
3
3
3
7.6 Hz, 2 H, CH2CH3), 2.52 (s, 3 H, COCH3), 1.18 (t, J = 7.6 Hz,
Ethyl 5-Ethyl-3-heptyl-6-(trifluoromethyl)salicylate (4l): Following
the general procedure, 2c (410 mg, 2.09 mmol), 3i (1.50 g,
4.18 mmol) and TiCl4 (0.45 mL, 4.1 mmol) yielded 4l as a colour-
3 H, CH2CH3) ppm. 13C NMR (63 MHz, CDCl3): δ = 206.0
3
(C=O), 151.2 (C-1), 135.8 (C-4), 133.3 (C-5), 126.8 (q, JC,F
=
=
2
1
2.8 Hz, C-2), 125.1 (q, JC,F = 30.0 Hz, C-3), 124.8 (q, JC,F
1
less syrup (387 mg, 53%); Rf = 0.75 (n-heptane/EtOAc = 1:1). H
275.6 Hz, CF3), 120.5 (C-6), 32.2 (q, 5JC,F = 2.8 Hz, COCH3), 25.8
NMR (250 MHz, CDCl3): δ = 8.43 (br. s, 1 H, OH), 7.15 (s, 1 H,
4
(q, JC,F = 2.0 Hz, CH2CH3), 16.2 (CH2CH3) ppm. 19F NMR
3
5
4-H), 3.92 (s, 3 H, OCH3), 2.71 (dq, J = 7.5 Hz, JH,F = 1.8 Hz,
(235 MHz, CDCl ): δ = –53.3 (CF ) ppm. IR (Nujol): ν = 3419
˜
3
3
3
2 H, CH2CH3), 2.63 (t, J = 7.9 Hz, 2 H, ArCH2), 1.54–1.65 (m,
(OH), 1702 (C=O) cm–1. MS (EI, 70 eV): m/z (%) = 232 (29) [M+],
217 (100) [M+ – CH2CH3]. HRMS (EI): calcd. for C11H11F3O2
232.0706; found 232.0707 [M+].
3J = 7.9 Hz, 2 H, ArCH2CH2), 1.24–1.39 (m, 8 H, Ar(CH2)2(CH2)
3
3
4CH3), 1.22 (t, J = 7.5 Hz, 3 H, CH2CH3), 0.88 (t, J = 7.3 Hz, 3
H, Ar(CH2)6CH3) ppm. 13C NMR (76 MHz, CDCl3): δ = 170.3
2
(C=O), 153.2 (C-2), 135.5 (C-5), 135.5 (C-4), 124.7 (q, JC,F
=
Methyl 3-Butyl-5-ethyl-6-(trifluoromethyl)salicylate (4i): Following
the general procedure, 2c (465 mg, 2.37 mmol), 3f (1.50 g,
4.74 mmol) and TiCl4 (0.26 mL, 2.4 mmol) yielded 4i as a colour-
less syrup (555 mg, 77%); Rf = 0.65 (n-heptane/EtOAc = 1:1). H
NMR (300 MHz, CDCl3): δ = 8.43 (s, 1 H, OH), 7.16 (s, 1 H, 4-
1
30.9 Hz, C-6), 124.4 (q, JC,F = 274.2 Hz, CF3), 122.5 (C-3), 114.3
3
(q, JC,F = 2.5 Hz, C-1), 53.0 (OCH3), 31.9, 30.2, 29.3, 29.2, 26.7
(Ar(CH2)6CH3), 26.7 (q, 4JC,F = 3.4 Hz, CH2CH3), 22.8 (Ar(CH2)6-
1
CH3), 16.2 (CH2CH3), 14.2 (Ar(CH2)6CH3) ppm. 19F NMR
5
3
(235 MHz, CDCl ): δ = –53.8 (CF ) ppm. IR (neat): ν = 3415
˜
H), 3.92 (s, 3 H, OCH3), 2.72 (dq, JH,F = 1.7 Hz, J = 7.4 Hz, 2
H, CH2CH3), 2.65 (t, 3J = 7.1 Hz, 2 H, CH2(CH2)2CH3), 1.53–1.64
(m, 2 H, CH2CH2CH2CH3), 1.31–1.44 (m, 2 H, (CH2)2CH2CH3),
1.22 (t, 3J = 7.4, 3 H, CH2CH3), 0.94 (t, 3J = 7.4 Hz, 3 H, (CH2)3-
3
3
(OH), 1746 (C=O) cm–1. MS (EI, 70 eV): m/z (%) = 346 (31) [M+],
314 (32) [M+ – CH3OH], 285 (49) [M+ – HC(O)OCH3].
Methyl 3-Benzyl-5-ethyl-6-(trifluoromethyl)salicylate (4m): Follow-
ing the general procedure, 2c (420 mg, 2.14 mmol), 3j (1.50 g,
4.28 mmol) and TiCl4 (0.26 mL, 2.1 mmol) yielded 4m as a colour-
CH3) ppm. 13C NMR (76 MHz, CDCl3): δ = 170.3 (C=O), 153.5
2
(C-2), 135.8 (C-5), 135.5 (C-4), 135.1 (C-3), 124.6 (q, JC,F
=
=
1
3
31.0 Hz, C-6), 124.3 (q, JC,F = 275.0 Hz, CF3), 114.4 (q, JC,F
1
less syrup (175 mg, 24%); Rf = 0.65 (n-heptane/EtOAc = 1:1). H
3.5 Hz, C-1), 53.0 (OCH3), 31.5, 30.0 (CH2), 26.7 (CH2CH3), 22.7
NMR (250 MHz, CDCl3): δ = 8.36 (s, 1 H, OH), 7.15–7.44 (m, 5
(CH2), 16.2, 14.1 (CH3) ppm. 19F NMR (282 MHz, CDCl3): δ =
H, Ph), 7.03 (s, 1 H, 4-H), 3.91 (s, 2 H, CH2), 3.82 (s, 3 H, OCH3),
–53.8 ppm. IR (neat): ν = 3427 (OH), 1746 (C=O) cm–1. MS (EI,
˜
5
3
3
2.59 (dq, JH,F = 1.9 Hz, J = 7.5 Hz, 2 H, CH2CH3), 1.09 (t, J =
7.5 Hz, 3 H, CH3CH3) ppm. 13C NMR (76 MHz, CDCl3): δ =
170.1 (C=O), 153.4 (C-2), 141.5 (CPh), 136.1 (C-5), 134.8 (C-4),
133.4 (C-3), 129.0, 128.7, 126.6 (CHPh), 123.7 (q, 1JC,F = 273.0 Hz,
CF3), 114.8 (q, 3JC,F = 3.5 Hz, C-1), 53.1 (OCH3), 36.0 (CH2), 26.6
(CH2CH3), 16.2 (CH2CH3) ppm. 19F NMR (235 MHz, CDCl3): δ
70 eV): m/z (%) = 304 (31) [M+], 273 (18) [M+ – OCH3]. HRMS
(EI): calcd. for C15H19F3O3 304.1281; found 304.1275 [M+].
Methyl 3-(But-3-enyl)-5-ethyl-6-(trifluoromethyl)salicylate (4j): Fol-
lowing the general procedure, 2c (468 mg, 2.38 mmol), 3g (1.50 g,
4.77 mmol) and TiCl4 (0.26 mL, 2.4 mmol) yielded 4j as a colour-
498
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 492–502

Functionalized 3-(Trifluoromethyl)phenols
= –53.9 (CF ) ppm. IR (neat): ν = 3625 (OH), 1741 (C=O) cm–1.
2-Acetyl-3-hydroxy-1-(trifluoromethyl)-5,6,7,8-tetrahydronaphtha-
˜
3
MS (EI, 70 eV): m/z (%) = 338 (47) [M+], 306 (40) [M+ – CH3OH], lene (9d): Following the general procedure, 8b (815 mg, 3.67 mmol),
278 (31) [M+ – HC(O)OCH3]. HRMS (EI): calcd. for C18H17F3O3 3e (1.8 g, 7.34 mmol) and TiCl4 (0.40 mL, 3.67 mmol) yielded 9d
338.11243; found 338.111978 [M+].
as a colourless solid (350 mg, 37%); m.p. 134 °C; Rf = 0.48 (n-
1
heptane/EtOAc = 1:1). H NMR (250 MHz, CDCl3): δ = 7.12 (s,
General Procedure for the Synthesis of 9a–g: To a solution of the
1,3-bis(silyl enol ether) 3a,d,e (2.0 equiv.) and the respective enone
8a–d (1 equiv.) in CH2Cl2 (5 mL) was added TiCl4 (1 equiv.) at
–78 °C under argon. The temperature of the reaction mixture was
allowed to rise to 20 °C during 14 h, and then an aqueous HCl
solution (10%, 20 mL) was added. The organic layer was separated
and the aqueous layer was extracted with CH2Cl2 (3ϫ20 mL). The
combined organic layers were dried (Na2SO4), filtered, and concen-
trated in vacuo. The residue was purified by column chromatog-
raphy (silica gel, n-heptane/EtOAc = 20:1).
1 H, 4-H), 2.80–2.94 (m, 4 H, 5-H, 8-H), 2.63 (s, 3 H, Me) 1.70–
1.87 (m, 4 H, 6-H, 7-H) ppm. 13C NMR (76 MHz, CDCl3): δ =
2
206.6 (C=O), 155.3 (C-3), 139.1 (C-4a), 132.9 (q, JC,F = 29.9 Hz,
1
C-1), 127.6 (C-8a), 127.3 (C-2), 123.8 (q, JC,F = 273.7 Hz, CF3),
3
4
114.2 (q, JC,F = 3.0 Hz, C-4), 33.1 (Me), 30.1 (C-6), 25.1 (q, JC,F
= 2.6 Hz, C-8), 22.2, 22.0 (C-6, C-7) ppm. 19F NMR (235 MHz,
CDCl ): δ = –61.9 (CF ) ppm. IR (Nujol): ν = 3256 (OH), 1684
˜
3
3
(C=O) cm–1. MS (EI, 70 eV): m/z (%) = 258 (64) [M+], 243 (100)
[M+ – Me], 215 (9) [M+ – COCH3]. C13H13F3O2 (258.24): calcd. C
60.46, H 5.07; found C 60.77, H 5.51.
Methyl 6-Hydroxy-4-(trifluoromethyl)indan-5-carboxylate (9a): Fol-
lowing the general procedure, 8a (500 mg, 2.4 mmol), 3d (1.30 g,
4.8 mmol) and TiCl4 (0.26 mL, 2.4 mmol) yielded 9a as a colourless
solid (423 mg, 68%); m.p. 76 °C; Rf = 0.47 (n-heptane/EtOAc =
2-Acetyl-3-hydroxy-1-(trifluoromethyl)-6,7,8,9-tetrahydro-5H-benzo-
cyclohept-2-ene (9e): Following the general procedure, 8c (500 mg,
2.12 mmol), 3e (1.03 g, 4.2 mmol) and TiCl4 (0.23 mL, 2.12 mmol)
yielded 9e as a colourless solid (231 mg, 40%); m.p. 152 °C; Rf =
0.42 (n-heptane/EtOAc = 1:1). 1H NMR (250 MHz, CDCl3): δ =
8.16 (s, 1 H, OH), 6.88 (s, 1 H, 4-H), 2.50–2.90 (m, 4 H, 5-H, 9-
H), 2.48 (s, 3 H, COCH3), 1.57–1.85 (m, 6 H, 6-H, 7-H, 8-H) ppm.
13C NMR (76 MHz, CDCl3): δ = 204.6 (C=O), 152.4 (C-3), 150.2
1
1:1). H NMR (250 MHz, CDCl3): δ = 9.33 (s, 1 H, OH), 7.03 (s,
1 H, 7-H), 3.93 (s, 3 H, OCH3), 2.98–3.09 (m, 2 H, 3-H), 2.89 (t,
3
3J1,2 = 7.6 Hz, 2 H, 3-H), 2.04 (quint, J1,2 = 7.6 Hz, 2 H, 2-H)
ppm. 13C NMR (76 MHz, CDCl3): δ = 170.8 (C=O), 158.5 (C-6),
3
2
2
(C-4a), 135.9 (q, 3JC,F = 1.9 Hz, C-9a), 126.4 (C-2), 125.7 (q, JC,F
152.7 (C-7a), 135.9 (q, JC,F = 2.3 Hz, C-3a), 125.5 (q, JC,F
=
1
1
5
32.3 Hz, C-4), 124.1 (q, JC,F = 274.7 Hz, CF3), 116.8 (C-7), 110.8
= 29.0 Hz, C-1), 124.5 (q, JC,F = 273.8 Hz, CF3), 122.2 (q, JC,F
4
4
(C-5), 52.9 (OCH3), 33.0 (C-1), 32.8 (q, JC,F = 3.3 Hz, C-3), 25.2
= 2.7 Hz, C-4), 36.1 (C-5), 32.1 (q, JC,F = 4.6 Hz, C-9), 31.4
(C-2) ppm. 19F NMR (235 MHz, CDCl3): δ = –56.1 (CF3) ppm.
(COCH3), 29.8 (q, 5JC,F = 2.8 Hz, C-8), 27.7, 27.2 (C-6, C-7) ppm.
IR (Nujol): ν = 3273 (OH), 1707 (C=O) cm–1. MS (EI, 70 eV): m/z
19F NMR (235 MHz, CDCl ): δ = –51.1 (CF ) ppm. IR (Nujol): ν
˜
˜
3
3
(%) = 260 (17) [M+], 228 (100) [M+ – CH3OH], 200 (3) [M+
–
= 3253 (OH), 1700 cm–1 (C=O). MS (EI, 70 eV): m/z (%) = 272
(29) [M+]; 257 (100) [M+ – CH3]. C14H15F3O2 (272.26): calcd. C
61.76, H 5.55; found C 61.64, H 5.63.
HCOOCH3]. C12H11F3O3 (260.21): calcd. C 55.39, H 4.26; found
C 55.19, H 4.28.
5-Acetyl-6-hydroxy-4-(trifluoromethyl)indane (9b): Following the
general procedure, 8a (770 mg, 3.7 mmol), 3e (1.80 g, 7.4 mmol)
and TiCl4 (0.41 mL, 3.7 mmol) yielded 9b as a colourless solid
(130 mg, 14%); m.p. 68 °C; Rf = 0.51 (n-heptane/EtOAc = 1:1). 1H
NMR (250 MHz, CDCl3): δ = 12.56 (s, 1 H, OH), 7.10 (s, 1 H, 7-
Ethyl 3-Hydroxy-1-(trifluoromethyl)-5,6,7,8,9,10-hexahydrobenzo-
cyclooctene-2-carboxylate (9f): Following the general procedure, 8d
(400 mg, 1.6 mmol), 3a (922 mg, 3.2 mmol) and TiCl4 (0.18 mL,
1.6 mmol) yielded 9f as a colourless solid (400 mg, 79%); m.p.
105 °C; Rf = 0.5 (n-heptane/EtOAc = 1:1). 1H NMR (250 MHz,
CDCl3): δ = 8.08 (s, 1 H, OH), 6.95 (s, 1 H, 4-H), 4.37 (q, 3J =
7.1 Hz, 2 H, OCH2CH3), 2.84–3.92 (m, 2 H, 10-H), 2.73–2.80 (m,
2 H, 5-H), 1.65–1.78 (m, 4 H, 6-H, 9-H), 1.36 (t, 3J = 7.1 Hz, 3 H,
OCH2CH3), 1.34–1.43 (m, 4 H, 7-H, 8-H) ppm. 13C NMR
(76 MHz, CDCl3): δ = 169.3 (C=O), 154.7 (C-3), 149.4 (C-4a),
3
3
H), 3.24 (t, J1,3 = 7.5 Hz, 2 H, 3-H), 3.01 (t, J1,2 = 7.5 Hz, 2 H,
3
3
1-H), 2.68 (s, 3 H, COCH3), 1.18 (t, J1,2 = J2,3 = 7.5 Hz, 2 H, 2-
H) ppm. 13C NMR (76 MHz, CDCl3): δ = 205.4 (C=O), 161.9 (C-
3
2
6), 147.8 (C-7a), 132.9 (q, JC,F = 1.9 Hz, C-3a), 132.3 (q, JC,F
=
1
32.3 Hz, C-4), 123.4 (q, JC,F = 273.4 Hz, CF3), 120.5 (C-5), 114.5
(C-7), 36.3 (C-1), 32.6 (COCH3), 30.5 (C-3), 25.4 (C-2) ppm. 19F
3
2
133.6 (q, JC,F = 2.9 Hz, C-10a), 127.7 (q, JC,F = 29.9 Hz, C-1),
1
3
NMR (235 MHz, CDCl ): δ = –63.9 (CF ) ppm. IR (Nujol): ν =
˜
124.5 (q, JC,F = 275.8 Hz, CF3), 121.1 (C-4), 114.6 (q, JC,F
=
3
3
3214 (OH), 1731 (C=O) cm–1. MS (EI, 70 eV): m/z (%) = 244 (38)
[M+], 229 (100) [M+ – CH3], 201 (4) [M+ – COCH3]. C12H11F3O2
(244.21): calcd. C 59.02, H 4.54; found C 58.78, H 4.70.
2.9 Hz, C-2), 62.5 (OCH2CH3), 32.6, 32.0 (C-5, C-10), 31.6, 27.9
(C-6, C-9), 26.2, 26.1 (C-7, C-8), 13.8 (OCH2CH3) ppm. 19F NMR
(235 MHz, CDCl ): δ = –52.7 (CF ) ppm. IR (Nujol): ν = 3317
˜
3
3
(OH), 1714 (C=O) cm–1. MS (EI, 70 eV): m/z (%) = 316 (19) [M+],
271 (26) [M+ – OCH2CH3], 270 (100) [M+ – HOCH2CH3].
C16H19F3O3 (316.32): calcd. C 60.75, H 6.05; found C 60.52, H
6.19.
Methyl 3-Hydroxy-1-(trifluoromethyl)-5,6,7,8-tetrahydronaphtha-
lene-2-carboxylate (9c): Following the general procedure, 8b
(500 mg, 2.25 mmol), 3d (1.17 g, 4.5 mmol) and TiCl4 (0.25 mL,
2.25 mmol) yielded 9c as a colourless solid (300 mg, 48%); m.p.
1
153 °C; Rf = 0.34 (n-heptane/EtOAc = 1:1). H NMR (250 MHz, 2-Acetyl-3-hydroxy-1-(trifluoromethyl)-5,6,7,8,9,10-hexahydrobenzo-
CDCl3): δ = 8.04 (br. s, 1 H, OH), 6.85 (s, 1 H, 4-H), 3.91 (s, 3 H,
cyclooctene (9g): Following the general procedure, 8d (400 mg,
OCH3), 2.72–2.89 (m, 4 H, 5-H, 8-H), 1.68–1.83 (m, 4 H, 6-H, 7- 1.6 mmol), 3e (782 mg, 3.2 mmol) and TiCl4 (0.18 mL, 1.6 mmol)
H) ppm. 13C NMR (76 MHz, CDCl3): δ = 169.7 (C=O), 154.1 (C-
yielded 9g as a colourless solid (138 mg, 40%); m.p. 105 °C; Rf =
0.38 (n-heptane/EtOAc = 1:1). 1H NMR (250 MHz, CDCl3): δ =
7.50 (br. s, 1 H, OH), 6.85 (s, 1 H, 4-H), 2.82–2.90 (m, 2 H, 10-H),
2.68–2.75 (m, 2 H, 5-H), 2.49 (s, 3 H, COCH3), 1.62–1.74 (m, 4 H,
3
2
3), 144.4 (C-4a), 130.2 (q, JC,F = 1.6 Hz, C-8a), 127.7 (q, JC,F
30.2 Hz, C-1), 124.2 (q, JC,F = 276.9 Hz, CF3), 120.6 (C-4), 114.0
=
1
3
4
(q, JC,F = 3.0 Hz, C-2), 53.0 (OCH3), 30.3 (C-6), 26.7 (q, JC,F
=
3.8 Hz, C-8), 22.8, 22.0 (C-6, C-7) ppm. 19F NMR (235 MHz, 6-H, 9-H), 1.32–1.39 (m, 4 H, 7-H, 8-H) ppm. 13C NMR (76 MHz,
CDCl ): δ = –55.0 (CF ) ppm. IR (Nujol): ν = 3343 (OH),
CDCl3): δ = 205.5 (C=O), 151.4 (C-3), 147.9 (C-4a), 133.0 (q, 3JC,F
˜
3
3
1712 cm–1 (C=O). MS (EI, 70 eV): m/z (%) = 274 (17) [M+], 243
(100) [M+ – HOCH3], 214 (10) [M+ – HCOOCH3]. C13H13F3O3
(274.23): calcd. C 56.94, H 4.78; found C 57.33, H 4.67.
= 1.7 Hz, C-10a), 125.8 (q, JC,F = 29.4 Hz, C-1), 124.8 (q, 1JC,F
=
2
3
276.2 Hz, CF3), 125.1 (q, JC,F = 3.0 Hz, C-2), 121.3 (C-4), 32.6
4
5
(C-5), 32.4 (q, JC,F = 3.7 Hz, C-10), 32.0 (C-6), 31.6 (q, JC,F
=
Eur. J. Org. Chem. 2008, 492–502
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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499

P. Langer et al.
FULL PAPER
1.5 Hz, C-9), 27.4 (q, JC,F = 2.1 Hz, COCH3), 26.3, 26.1 (C-7, C-
5
2-Acetyl-4Ј-chloro-3-hydroxy-5-(trifluoromethyl)biphenyl (17c): Fol-
8) ppm. 19F NMR (235 MHz, CDCl3): δ = –51.6 (CF3) ppm. IR lowing the general procedure given for the synthesis of 4a–m, 16a
(Nujol): ν = 3317 (OH), 1714 (C=O) cm–1. MS (EI, 70 eV): m/z
(500 mg, 1.89 mmol), 3e (968 mg, 3.96 mmol) and TiCl4 (0.21 mL,
1.89 mmol) yielded 17c as a yellow solid (234 mg, 39 %); m.p.
117 °C; Rf = 0.4 (n-heptane/EtOAc = 1:1). 1H NMR (250 MHz,
˜
(%) = 286 (30) [M+], 271 (100) [M+ – CH3], 243 (4) [M+ – COCH3].
C15H17F3O2 (286.29): calcd. C 62.93, H 5.99; found C 62.73, H
6.08.
3
CDCl3): δ = 11.39 (s, 1 H, OH), 7.47 (d, J3Ј,5Ј = 8.6 Hz, 2 H, 3Ј-
3
4
H, 5Ј-H), 7.30 (d, J2Ј,6Ј = 8.6 Hz, 2 H, 2Ј-H, 6Ј-H), 7.27 (d, J4,6
Ethyl 6,6Ј-(1,2-Ethanediyl)-4,4Ј-bis(trifluoromethyl)salicylate (13):
To a solution of 3a (1.48 g, 5.39 mmol) and 12 (600 mg, 1.8 mmol)
in CH2Cl2 (5 mL) was added TiCl4 (0.40 mL, 3.6 mmol) at –78 °C
under argon. The temperature of the reaction mixture was allowed
to rise to 20 °C during 14 h, and then an aqueous HCl solution
(10%, 20 mL) was added. The organic layer was separated and the
aqueous layer was extracted with CH2Cl2 (3ϫ20 mL). The com-
bined organic layers were dried (Na2SO4), filtered and concentrated
in vacuo. Purification by column chromatography (silica gel, n-hep-
tane/EtOAc = 20:1) yielded 13 as a colourless solid (350 mg, 37%);
m.p. 139 °C; Rf = 0.5 (n-heptane/EtOAc = 1:1). 1H NMR
4
= 1.9 Hz, 1 H, 6-H), 7.05 (d, J4,6 = 1.9 Hz, 1 H, 4-H), 1.92 (s, 3
H, CH3) ppm. 13C NMR (76 MHz, CDCl3): δ = 206.5 (C=O),
2
161.0 (C-3), 144.3, 139.2 (C-1, C-1Ј), 135.5 (C-4Ј), 135.3 (q, JC,F
= 32.7 Hz, C-5), 130.3 (C-3Ј, C-5Ј), 129.5 (C-2Ј, C-6Ј), 123.5 (C-2),
1
3
123.1 (q, JC,F = 273.7 Hz, CF3), 118.5 (q, JC,F = 3.8 Hz, C-6),
115.1 (q, JC,F = 3.8 Hz, C-4), 32.0 (CH3) ppm. 19F NMR
3
(235 MHz, CDCl ): δ = –63.8 (CF ) ppm. IR (Nujol): ν = 1678
˜
3
3
(C=O) cm–1. MS (EI, 70 eV): m/z (%) = 316 (25) [M+, 37Cl], 314
(72) [M+, 35Cl], 299 (91) [M+ – CH3], 279 (100) [M+ 35Cl].
–
C15H10ClF3O2 (314.69): calcd. C 57.25, H 3.20; found C 57.44, H
3.48.
4
(250 MHz, CDCl3): δ = 11.20 (s, 2 H, OH), 7.14 (d, J = 1.8 Hz, 2
4
3
H, 3-H, 3Ј-H), 6.80 (d, J = 1.8 Hz, 2 H, 5-H, 5Ј-H), 4.50 (q, J =
1-Hydroxy-6-phenyl-3-(trifluoromethyl)benzophenone (17d): Follow-
ing the general procedure given for the synthesis of 4a–m, 16c
(500 mg, 2.0 mmol), 3k (1.30 g, 4.1 mmol) and TiCl4 (0.22 mL,
2.0 mmol) yielded 17d as a yellow solid (193 mg, 28 %); m.p.
117 °C; Rf = 0.4 (n-heptane/EtOAc = 1:1). 1H NMR (250 MHz,
CDCl3): δ = 9.13 (br. s, 1 H, OH), 7.00–7.60 (m, 12 H, Ph) ppm.
13C NMR (76 MHz, CDCl3): δ = 200.4 (C=O), 158.6 (C-2), 144.9,
3
7.2 Hz, 4 H, OCH2CH3), 3.28 (s, 4 H, CH2), 1.43 (t, J = 7.2 Hz,
6 H, OCH2CH3) ppm. 13C NMR (76 MHz, CDCl3): δ = 170.4
2
(C=O), 162.8 (C-2, C-2Ј), 145.3 (C-1, C-1Ј), 135.4 (q, JC,F
=
1
33.4 Hz, C-4, C-4Ј), 127.6 (C-6, C-6Ј), 123.4 (q, JC,F = 254.6 Hz,
CF3), 118.4 (q, 3JC,F = 2.8 Hz, C-3, C-3Ј), 113.7 (q, 3JC,F = 3.0 Hz,
C-5, C-5Ј), 62.7 (OCH2CH3), 37.8 (CH2), 14.2 (OCH2CH3) ppm.
19F NMR (235 MHz, CDCl ): δ = –64.1 (CF ) ppm. IR (Nujol): ν
˜
2
3
3
139.5, 138.1 (CPh), 134.5 (q, JC,F = 32.9 Hz, C-4), 132.9, 129.5,
= 1662 (C=O) cm–1. MS (EI, 70 eV): m/z (%) = 494 (34) [M+], 448
(60) [M+ – CH2CH3OH], 402 (100) [M+ – 2CH2CH3OH]. HRMS
(EI): calcd. for C22H20F6O6 494.1159; found 494.1161 [M+].
1
129.0, 128.5, 128.2, 128.0, 127.2, 124.6 (CHPh), 123.4 (q, JC,F
=
=
3
3
272.9 Hz, CF3), 118.4 (q, JC,F = 3.5 Hz, C-5), 113.6 (q, JC,F
3.5 Hz, C-3) ppm. 19F NMR (235 MHz, CDCl3): δ = –63.2 (CF3)
ppm. IR (Nujol): ν = 3342 (OH), 1663 (C=O) cm–1. MS (EI,
Methyl 4Ј-Chloro-3-hydroxy-5-(trifluoromethyl)biphenyl-4-carboxy-
late (17a): Following the general procedure given for the synthesis
of 4a–m, 16a (557 mg, 2.0 mmol), 3d (1.04 g, 4.0 mmol) and TiCl4
(0.22 mL, 2.0 mmol) yielded 17a as a pale yellow solid (170 mg,
˜
70 eV): m/z (%) = 342 (69) [M+], 273 (3) [M+ – CF3], 265 (28) [M+ –
Ph]. C20H13F3O2 (342.31): calcd. C 70.17, H 3.83; found C 69.85,
H 4.05.
1
25%); m.p. 84–85 °C; Rf = 0.4 (n-heptane/EtOAc = 1:1). H NMR
General Procedure for the Synthesis of 20a–d and 21: To a solution
of 1,3-bis(silyl enol ether) 3a,e,k,l (2.0 equiv.) and 19 (1.0 equiv.) in
CH2Cl2 (5 mL) was added TiCl4 (1.0 equiv.) at –78 °C under argon.
The temperature of the reaction mixture was allowed to rise to
20 °C during 14 h, and then an aqueous HCl solution (10 %,
20 mL) was added. The organic layer was separated and the aque-
ous layer was extracted with CH2Cl2 (3ϫ20 mL). The combined
organic layers were dried (Na2SO4), filtered and concentrated in
vacuo. The residue was purified by column chromatography (silica
gel, n-heptane/EtOAc = 20:1).
3
(250 MHz, CDCl3): δ = 10.83 (s, 1 H, OH), 7.55 (d, J = 8.8 Hz, 2
4
H, 3Ј-H, 5Ј-H), 7.50 (d, J2,6 = 1.8 Hz, 1 H, 2-H), 7.45 (d, 3J =
4
8.8 Hz, 2 H, 2Ј-H, 6Ј-H), 7.38 (d, J2,6 = 1.8 Hz, 1 H, 6-H), 4.01
(s, 3 H, OCH3) ppm. 13C NMR (76 MHz, CDCl3): δ = 169.6
(C=O), 162.4 (C-3), 145.5, 136.8 (C-1, C-1Ј), 135.5 (C-4Ј), 131.2 (q,
2JC,F = 31.5 Hz, C-5), 129.5, 128.5 (C-2Ј/C-6Ј, C-3Ј/C-5Ј), 123.4 (q,
1JC,F = 273.6 Hz, CF3), 119.8, 117.9 (C-2, C-6), 109.9 (C-4), 53.1
(CH3) ppm. 19F NMR (235 MHz, CDCl3): δ = –58.5 (CF3) ppm.
IR (Nujol): ν = 1678 (C=O) cm–1. MS (EI, 70 eV): m/z (%) = 332
˜
(16) [M+, 37Cl], 330 (48) [M+, 35Cl], 298 (100) [M+ – CH3OH], 270
(41) [M+ – HCOOCH3]. C15H10ClF3O3 (330.69): calcd. C 54.48, H
3.05; found C 54.91, H 3.42.
Keto-Enol Mixture of Ethyl (E)-3-Oxo-5-[2-(trifluoromethyl)-5,6-di-
hydro-4H-pyran-3-yl]pent-4-enoate and Ethyl (2Z,4E)-3-Hydroxy-5-
[2-(trifluoromethyl)-5,6-dihydro-4H-pyran-3-yl]penta-2,4-dienoate
(20a): Following the general procedure, 19 (660 mg, 3.66 mmol), 3a
(2.01 g, 7.33 mmol) and TiCl4 (0.40 mL, 3.66 mmol) yielded 20a as
a colourless solid (245 mg, 24%); m.p. 52 °C; Rf = 0.32 (n-heptane/
Methyl 4Ј-Bromo-3-hydroxy-5-(trifluoromethyl)biphenyl-4-carboxy-
late (17b): Following the general procedure given for the synthesis
of 4a–m, 16b (500 mg, 1.55 mmol), 3d (807 mg, 3.1 mmol) and
TiCl4 (0.17 mL, 1.55 mmol) yielded 17b as a yellow solid (110 mg,
20%); m.p. 103 °C; Rf = 0.4 (n-heptane/EtOAc = 1:1). 1H NMR
1
EtOAc = 1:1). H NMR (250 MHz, CDCl3, ketone:enol = 2:1): δ
3
3
(250 MHz, CDCl3): δ = 10.83 (s, 1 H, OH), 7.61 (d, J = 8.5 Hz, 2
= 11.91 (s, 1 H, OHenol), 7.65 (d, J4,5 = 15.8 Hz, 1 H, 4-Hketo),
4
3
3
H, 3Ј-H, 5Ј-H), 7.50 (d, J2,6 = 1.5 Hz, 1 H, 2-H), 7.47 (d, 3J = 7.49 (d, J4,5 = 15.6 Hz, 1 H, 4-Henol), 6.21 (d, J4,5 = 15.8 Hz, 1
4
3
8.5 Hz, 2 H, 6Ј-H, 2Ј-H), 7.38 (d, J2,6 = 1.5 Hz, 1 H, 6-H), 4.00 H, 5-Hketo), 5.87 (d, J4,5 = 15.6 Hz, 1 H, 5-Henol), 5.06 (s, 1 H, 2-
(s, 3 H, OCH3) ppm. 13C NMR (76 MHz, CDCl3): δ = 169.6
Henol), 4.11–4.26 (m, 8 H, OCH2CH3, 6Ј-Hketo, 6Ј-Henol), 3.61 (s, 2
(C=O), 162.4 (C-3), 145.6, 137.3 (C-1, C-1Ј), 132.5 (C-4Ј), 131.2 (q, H, 2-Hketo), 2.29–2.40 (m, 4 H, 5Ј-Hketo, 5Ј-Henol), 1.93–2.05 (m, 4
2JC,F = 32.2 Hz, C-5), 128.8, 123.8 (C-2Ј/C-6Ј, C-3Ј/C-5Ј), 123.3 (q, H, 4Ј-Hketo, 4Ј-Henol), 1.30 (t, 3J = 7.1 Hz, 3 H, OCH2CH3,enol),
1JC,F = 273.4 Hz, CF3), 119.8, 117.9 (C-2, C-6), 110.0 (C-4), 53.1
1.27 (t, 3J = 7.0 Hz, 3 H, OCH2CH3,keto) ppm. 13C NMR (63 MHz,
(CH3) ppm. 19F NMR (235 MHz, CDCl3): δ = –58.5 (CF3) ppm. CDCl3): δ = 191.9 (C-3keto), 172.9 (C-3enol), 169.3 (C-1enol), 167.6
IR (Nujol): ν = 1678 (C=O) cm–1. MS (EI, 70 eV): m/z (%) = 332
(C-1keto), 147.4 (q, JC,F = 34.8 Hz, C-2Јenol), 144.6 q, JC,F =
2
2
˜
(16) [M+, 37Cl], 330 (48) [M+, 35Cl], 298 (100) [M+ – CH3OH], 270
(41) [M+ – HCOOCH3]. C15H10ClF3O3 (330.69): calcd. C 54.48, H
3.05; found C 54.91, H 3.42.
33.9 Hz, C-2Јketo), 138.8 (q, 4JC,F = 2.8 Hz, C-5keto), 130.9 (q, 4JC,F
= 2.8 Hz, C-5enol), 124.8 (C-4keto), 121.2 (C-4enol), 120.5 (q, 1JC,F
=
1
275.8 Hz, CF3,enol), 120.1 (q, JC,F = 275.8 Hz, CF3,keto), 113.3,
500
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 492–502

Functionalized 3-(Trifluoromethyl)phenols
112.6 (C-3Јketo, C-3Јenol), 91.6 (C-2enol), 67.7 (C-6Јketo), 67.2 (C- (1.00 g, 4.11 mmol) and TiCl4 (0.23 mL, 2.05 mmol), 21 was iso-
6Јenol), 61.6 (OCH2CH3,keto), 60.3 (OCH2CH3,enol), 47.3 (C-2keto),
21.2 (C-4Јenol), 21.0 (C-5Јenol), 20.9 (C-4Јketo, C-5Јketo), 14.4 (OCH2-
lated as a colourless syrup (230 mg, 40%); Rf = 0.76 (n-heptane/
EtOAc = 2:3). 1H NMR (250 MHz, CDCl3): δ = 6.81 (dd, 3J =
3
CH3,enol), 14.2 (OCH2CH3,keto). 19F NMR (235 MHz, CDCl3): δ = 15.6 Hz, 1 H, 3-H), 5.86 (d, J = 15.6 Hz, 1 H, 2-H), 5.53 (s, 1 H,
–62.6 (CF3,keto), –62.9 (CF3,enol). IR (Nujol): ν = 3419 (OH), 1738
OH), 3.80–4.00 (m, 2 H, 3Ј-H), 2.58–2.71 (m, 1 H, 4-H), 2.12 (s, 3
˜
(C=O) cm–1. MS (EI, 70 eV): m/z (%) = 292 (19) [M+], 246 (6)
H, COCH3), 1.59–1.81 (m, 4 H, 1Ј-H, 2Ј-H) ppm. 13C NMR
[M+ – CH2CH3OH], 223 (100) [M+ – CF3]. C13H15F3O4 (292.25): (76 MHz, CDCl3): δ = 197.9, 177.3 (C=O), 141.9 (C-3), 126.9 (C-
calcd. C 53.43, H 5.17; found C 53.29, H 5.59.
1
2
2), 122.8 (q, JC,F = 287.5 Hz, CF3), 100.4 (C-6), 94.8 (q, JC,F =
30.5 Hz, C-5), 61.4 (C-3Ј), 42.2 (C-4), 27.0 (COCH3), 25.7, 24.1 (C-
(3Z,5E)-4-Hydroxy-6-[2-(trifluoromethyl)-5,6-dihydro-4H-pyran-3-
yl]hexa-3,5-dien-2-one (20b): Following the general procedure, 19
(370 mg, 2.05 mmol), 3e (1.00 g, 4.11 mmol) and TiCl4 (0.23 mL,
2.05 mmol) yielded 20b as a colourless solid (617 mg, 53%); m.p.
62 °C; Rf = 0.32 (n-heptane/EtOAc = 1:1). 1H NMR (250 MHz,
1Ј, C-2Ј) ppm. 19F NMR (235 MHz, CDCl3): δ = –67.4 (CF3) ppm.
IR (Nujol): ν = 3240 (OH), 1658 (C=O) cm–1. MS (EI, 70 eV): m/z
˜
(%) = 280 (33) [M+], 262 (6) [M+ – H2O], 193 (22) [M+ – H2O –
CF3]. HRMS (EI): calcd. for C12H15F3O4 280.0917; found
280.0915 [M+].
3
3
CDCl3): δ = 7.64 (d, J5,6 = 15.4 Hz, 1 H, 6-H), 5.89 (d, J5,6
=
15.4 Hz, 1 H, 5-H), 5.56 (s, 1 H, 3-H), 4.16 (m, 2 H, 6Ј-H), 2.31–
2.39 (m, 2 H, 4Ј-H), 2.13 (s, 3 H, 1-H), 1.93–2.04 (m, 2 H, 5Ј-H)
ppm. 13C NMR (63 MHz, CDCl3): δ = 197.6 (C-4), 177.3 (C-2),
Acknowledgments
2
4
145.6 (q, JC,F = 34.0 Hz, C-2Ј), 133.8 (q, JC,F = 2.9 Hz, C-6),
1
3
Financial support by the State of Mecklenburg-Vorpommern
(Landesforschungs-Schwerpunkt “Neue Wirkstoffe und Screening-
Verfahren”) is gratefully acknowledged.
122.1 (C-5), 120.5 (q, JC,F = 275.0 Hz, CF3), 113.2 (q, JC,F
=
1.8 Hz, C-3Ј), 100.8 (C-3), 67.3 (C-6Ј), 27.1 (C-1), 21.1, 21.0 (C-4Ј,
C-5Ј) ppm. 19F NMR (235 MHz, CDCl3): δ = –62.6 (CF3) ppm.
IR (Nujol): ν = 1628 (C=O) cm–1. MS (EI, 70 eV): m/z (%) = 262
˜
(64) [M+], 247 (5) [M+ – Me], 219 (10) [M+ – COCH3], 193 (100)
[M+ – CF3]. HRMS (EI): calcd. for C12H13F3O3 262.08168; found
262.08188 [M+].
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(2Z,4E)-3-Hydroxy-1-phenyl-5-[2-(trifluoromethyl)-5,6-dihydro-4H-
pyran-3-yl]penta-2,4-dien-1-one (20c): Following the general pro-
cedure, 19 (500 mg, 2.78 mmol), 3k (1.70 g, 5.55 mmol) and TiCl4
(0.31 mL, 2.78 mmol) yielded 20c as a yellow solid (260 mg, 30%);
m.p. 90 °C; Rf = 0.28 (n-heptane/EtOAc = 1:1). 1H NMR
3
(250 MHz, CDCl3): δ = 7.78–7.85 (m, 2 H, Ph), 7.65 (d, J4,5
=
15.3 Hz, 1 H, 4-H), 7.31–7.47 (m, 3 H, Ph), 6.14 (s, 1 H, 2-H), 5.98
3
3
(d, J4,5 = 15.3 Hz, 1 H, 5-H), 4.07 (t, J5Ј,6Ј = 5.2 Hz, 2 H, 6Ј-H),
3
2.24–2.35 (m, 2 H, 4Ј-H), 1.86–1.95 (m, J5Ј,6Ј = 5.2 Hz, 2 H, 5Ј-
H) ppm. 13C NMR (63 MHz, CDCl3): δ = 189.1 (C-3), 179.7 (C-
2
4
1), 145.8 (q, JC,F = 34.0 Hz, C-2Ј), 136.4 (CPh), 134.1 (q, JC,F
=
2.5 Hz, C-5), 132.6, 128.7, 127.4 (CHPh), 122.7 (C-4), 120.5 (q,
3
1JC,F = 275.8 Hz, CF3), 113.3 (q, JC,F = 2.0 Hz, C-3Ј), 97.4 (C-
2), 67.4 (C-6Ј), 21.2, 21.1 (C-4Ј, C-5Ј) ppm. 19F NMR (235 MHz,
CDCl3): δ = –62.5 (CF3) ppm. MS (EI, 70 eV): m/z (%) = 324 (16)
[M+], 255 (71) [M+ – CF3], 227 (10) [M+ – COCF3]. C17H15F3O3
(324.29): calcd. C 62.96, H 4.66; found C 62.56, H 4.67.
(3Z,5E)-1,1,1-Trifluoro-4-hydroxy-6-[2-(trifluoromethyl)-5,6-dihy-
dro-4H-pyran-3-yl]hexa-3,5-dien-2-one (20d): Following the general
procedure, 19 (450 mg, 2.5 mmol), 3l (1.49 g, 5.0 mmol) and TiCl4
(0.28 mL, 2.5 mmol) yielded 20d as a colourless solid (205 mg,
43%); m.p. 53 °C; Rf = 0.18 (n-heptane/EtOAc = 1:1). 1H NMR
3
(250 MHz, CDCl3): δ = 7.84 (d, J5,6 = 15.3 Hz, 1 H, 6-H), 6.00
3
3
(d, J5,6 = 15.3 Hz, 1 H, 5-H), 5.93 (s, 1 H, 3-H), 4.21 (“t”, J5Ј,6Ј
= 5.2 Hz, 2 H, 6Ј-H), 2.32–2.42 (m, 2 H, 4Ј-H), 1.96–2.07 (m, 3J5Ј,6Ј
= 5.2 Hz, 2 H, 5Ј-H) ppm. 13C NMR (63 MHz, CDCl3): δ = 181.1
2
2
(C-4), 180.4 (q, JC,F = 35.8 Hz, C-2), 147.8 (q, JC,F = 34.0 Hz,
C-2Ј), 137.7 (q, JC,F = 2.7 Hz, C-6), 120.2 (q, JC,F = 276.4 Hz,
3
1
1
3
CF3), 120.1 (C-5), 116.9 (q, JC,F = 283.3 Hz, C-1), 112.8 (q, JC,F
= 2.1 Hz, C-3Ј), 95.5 (C-3), 67.7 (C-6Ј), 20.9, 20.8 (C-4Ј, C-5Ј) ppm.
19F NMR (235 MHz, CDCl3): δ = –76.8 (C-1), –62.5 (CF3) ppm.
IR (Nujol): ν = 1628 (C=O) cm–1. MS (EI, 70 eV): m/z (%) = 316
˜
(11) [M+], 247 (100) [M+ – CF3], 219 (24) [M+ – COCF3]. HRMS
(EI): calcd. for C12H10F6O3 316.0529; found 316.0523 [M+].
6-Acetyl-5-hydroxy-4-(3-hydroxypropyl)-5-(trifluoromethyl)cyclo-
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
501

P. Langer et al.
FULL PAPER
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www.ccdc.cam.ac.uk/data_request/cif.
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Received: August 29, 2007
Published Online: November 15, 2007
502
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 492–502