First synthesis of functionalized 5-aryl-3-(trifluoromethyl)phenols by regioselective [3+3] cyclocondensations of 1,3-bis(silyloxy)-1,3-butadienes with 3-aryl-3-silyloxy-1-trifluoromethyl-2-en-1-ones

Article abstract of DOI:10.1016/j.tet.2008.12.076

A variety of functionalized 5-aryl-3-(trifluoromethyl)phenols were prepared by the first TiCl₄-mediated [3+3] cyclocondensation of 1,3-bis(trimethylsilyloxy)-1,3-butadienes with 3-aryl-3-trimethylsilyloxy-1-trifluoromethyl-2-en-1-ones.

Full text of DOI:10.1016/j.tet.2008.12.076

Tetrahedron 65 (2009) 2124–2135
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
First synthesis of functionalized 5-aryl-3-(trifluoromethyl)phenols by
regioselective [3þ3] cyclocondensations of 1,3-bis(silyloxy)-1,3-butadienes
with 3-aryl-3-silyloxy-1-trifluoromethyl-2-en-1-ones
,
Stefan Bu¨ttner a, Abdolmajid Riahi a b, Ibrar Hussain a, Mirza A. Yawer a, Mathias Lubbe a,
,b,
Alexander Villinger a, Helmut Reinke a, Christine Fischer b, Peter Langer a
*
a
¨
Institut fu¨r Chemie, Universitat Rostock, Albert-Einstein-Str. 3a, 18059 Rostock, Germany
b Leibniz-Institut fu¨r Katalyse e. V. an der Universita¨t 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:
A variety of functionalized 5-aryl-3-(trifluoromethyl)phenols were prepared by the first TiCl4-mediated
[3þ3] cyclocondensation of 1,3-bis(trimethylsilyloxy)-1,3-butadienes with 3-aryl-3-trimethylsilyloxy-1-
trifluoromethyl-2-en-1-ones.
Received 14 November 2008
Accepted 17 December 2008
Available online 3 January 2009
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
aromatic compound or by transformation of a CX3 into a CF3
group.6,7 An important method relies on the reaction of aryl ha-
The trifluoromethyl group possesses unique stereoelectronic
properties and is, therefore, of great importance in organic and
medicinal chemistry.1 The CF3 and the methyl group are of similar
size. However, the high electron-withdrawing effect of the CF3
group results in a great difference in the physical properties and in
the chemical reactivity of CF3- and CH3-substituted molecules. This
effect plays an important role in drug–receptor interactions. It is
worth to be noted that the lipophilicity of CF3-substituted mole-
cules is often higher than the lipophilicity of their methyl-
substituted analogues, which often results in an improvement of
their in vivo transport. In addition, undesirable metabolic trans-
formations are often avoided, due to the high chemical and bi-
ological stability of the CF3 group. Therefore, CF3-substituted arenes
and heterocycles play an increasingly important role in drug dis-
covery.1 Trifluoromethyl- and perfluoroalkyl-substituted molecules
show an excellent solubility in fluorophilic solvents. Therefore, CF3-
substituted molecules have been used as ligands2 in catalytic
processes in fluorous biphasic systems and supercritical carbon
dioxide.3 It is worth to be mentioned that CF3-substituted arenes
are present in many organocatalysts (e. g. in CF3-substituted N,N0-
diarylthioureas).4,5
lides with trifluoromethylcopper. Despite its great utility, this
reaction is often restricted to specific substrates as trifluoro-
methylcopper is relatively unstable and easily decomposes when
the reaction with ‘difficult’ substrates is slow. In addition, the
synthesis of more complex starting materials, functionalized and
highly substituted aryl halides, can be a tedious and difficult
task (due to the formation of regioisomers in electrophilic
substitutions, low reactivity, etc.).
An interesting alternative and supplement for direct fluorina-
tion methods relies on the application of a ‘building block strategy’
based on cyclization reactions of suitable CF3-substituted mole-
cules.8 This strategy has been applied, for example, to the synthesis
of (trifluoromethyl)phenols.9–11 Kostyuk et al. reported the syn-
thesis of 3,5-bis(trifluoromethyl)anilines by cyclization of
1,1,1,5,5,5-hexafluoroacetylacetone with enamines.12 Various CF3-
substituted heterocycles have been prepared based on cyclization
reactions of
a,b
-unsaturated trifluoromethylketones.13,14 The
NaH-mediated cyclization of acetylacetone with 4-ethoxy-1,1,1-
trifluorobut-3-en-2-one has been reported to give 2-acetyl-5-(tri-
fluoromethyl)phenol.15 However, this protocol is limited to the
synthesis of only one specific example. Recently, we have
reported16 the synthesis of 3-(trifluoromethyl)phenols by cyclo-
condensation17,18 of 1,3-bis(silyloxy)-1,3-butadienes19 with 4-eth-
oxy-1,1,1-trifluoroalk-3-en-2-ones. Herein, we report what are, to
the best of our knowledge, the first formal [3þ3] cyclizations of 1,3-
bis(silyloxy)-1,3-butadienes with 3-aryl-3-trimethylsilyloxy-1-tri-
fluoromethyl-2-en-1-ones. These reactions allow for a convenient
Most of the methods reported so far for the synthesis of tri-
fluoromethyl-substituted arenes rely on the functionalization of
arenes by direct introduction of the CF3 group into a suitable
* Corresponding author. Fax: þ49 381 4986412.
E-mail address: peter.langer@uni-rostock.de (P. Langer).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.12.076

S. Bu¨ttner et al. / Tetrahedron 65 (2009) 2124–2135
2125
synthesis of
a
variety of functionalized 5-aryl-3-(tri-
Me3SiO
OSiMe3
OMe
O
fluoromethyl)phenols, which can be regarded as 3-trifluoromethyl-
biaryls.
OH
Me3SiO
Ph
O
_
4a
OMe
CF3
CF3
i
Ph
2. Results and discussion
3a
5a
_
TiCl3OH
1,3-Bis(silyloxy)-1,3-butadienes 4a–i were prepared from the
corresponding 1,3-dicarbonyl compounds in one or two steps.19 3-
Aryl-1,3-diones 2a–c are commercially available. Derivatives 2d–i
were prepared by LDA-mediated condensation of ketones 1d–i
with ethyl trifluoroacetate (Scheme 1, Table 1). The silylation of 2a–c
was carried out under standard conditions (Me3SiCl, NEt3,
benzene or toluene) to give 3-aryl-3-trimethylsilyloxy-1-tri-
fluoromethyl-2-en-1-ones 3a–c. Silyl enol ethers 3d–j were
prepared by reaction of an Et2O solution of 2d–j with trime-
thylsilyl-trifluoromethanesulfonate (Me3SiOTf) in the presence of
NEt3.
O
O
TiCl4
CF3
Me3SiO
Ph
O
OMe
+
OTiCl3
Ph
CF3
A
D
Me3SiCl
4a
Me3SiCl
O
O
Me3SiO
Ph
Me3SiO
OMe
OMe
+
Me3SiCl
CF3
OTiCl3
O
O
Ph
O
TiCl4
CF3
O
(Me3Si)2O
O
i
OSiMe3
+
CF3
Ar
CF3
EtO
Ar
B
C
2a-j
1d-j
Scheme 2. Possible mechanism of the cyclization of 4a with 3a: conditions: (i) TiCl4,
CH2Cl2, ꢁ78/20 ꢀC, 20 h.
ii
O
OSiMe3
CF3
Ar
phenyl is located next to the ester group. Obviously, the change of
the regioselectivity is a result of the replacement of the CH3 by a CF3
group in the 3-silyloxy-2-en-1-one.
3a-j
Scheme 1. Synthesis of 3a–j: conditions: (i) NaOMe, MeOH, 0/20 ꢀC, 20 h; (ii) Me3
SiOTf (0.95 equiv), NEt3 (1.0 equiv), Et2O, 0 ꢀC, 30 min, 20 ꢀC, 3 days; the configuration
-
of 3a–j has not been unambiguously determined.
Me3SiO
MeO
OSiMe3
The TiCl4-mediated [3þ3] cyclization of 4a with 3a afforded 4-
phenyl-6-(trifluoromethyl)salicylate 5a in up to 48% yield (Scheme
2). The product may be regarded also as a functionalized 5-aryl-3-
(trifluoromethyl)phenol or as a 3-trifluoromethyl-biaryl (note the
different numbering systems). During the optimization of this re-
action, the (high) concentration and the temperature played an
important role. The moderate yield can be explained by hydrolysis
and TiCl4-mediated oxidative dimerization of diene 4a. The re-
action proceeded with excellent regioselectivity. Only the forma-
tion of the regioisomer containing the phenyl group located on the
opposite site of the ester group was observed. The cyclo-
condensation and the regioselectivity can be explained by forma-
tion of intermediate A, attack of the terminal carbon atom of 4a
onto the carbon located next to the phenyl group to give in-
termediate B, cyclization by an SN mechanism with displacement
of the Cl3TiO group (intermediates C and D) and subsequent
aromatization.
It has been previously reported that the reaction of 4a with 3-
silyloxy-2-en-1-one 6, available from benzoylacetone, resulted in
formation of 4-methyl-6-phenylsalicylate 7 (Scheme 3).17,18a In-
terestingly, the cyclization of 4a with 3-silyloxy-2-en-1-ones 6 and
3a proceeded with opposite regioselectivities. In the case of 7, the
O
OH
Me3SiO
Ph
O
4a
MeO
Ph
Me
ref. 18a
i
Me
6
7
Scheme 3. Cyclization of 4a with 6: conditions: (i) TiCl4, CH2Cl2, ꢁ78/20 ꢀC.
_
OH
TiCl4
CF3
CO2Me
CF3
Me3SiO
Ph
O
4a
+
Ph
A2, major
5a
0
TiCl4
3a
OH
_
TiCl4
MeO2C
Ph
Me3SiO
Ph
O
4a
+ CF3
CF3
iso-5a
A1, minor
Table 1
Synthesis of 3a–j
_
OH
TiCl4
MeO2C
Ph
Me3SiO
Ph
O
4a
a
a
2,3
Ar
%
(2)
% (3)
+ CH3
db
db
db
41
87
35
63
43
72
56
CH3
a
b
c
d
e
f
g
h
i
Ph
2-Naph
4-ClC6H4
4-FC6H4
4-BrC6H4
4-(O2N)C6H4
4-(F3C)C6H4
4-(MeO)C6H4
4-MeC6H4
4-PhC6H4
E1, major
7
95
98
88
84
82
95
90
90
85
TiCl4
6
_
OH
TiCl4
4a
CO2Me
CH3
Me3SiO
O
Ph
+
CH3
Ph
iso-7
E2, minor
j
a
Isolated yields.
Commercially available.
Scheme 4. Possible explanation of the different regioselectivity of the cyclization of 4a
with 3a and 6.
b

2126
S. Bu¨ttner et al. / Tetrahedron 65 (2009) 2124–2135
Me3SiO
R1
OSiMe3
R2
O
OH
R1
Ar
Me3SiO
Ar
O
R2
CF3
4a-k
CF3
i
3a-j
5a-ao
Scheme 5. Synthesis of 5a–ao: conditions: (i) TiCl4, CH2Cl2, ꢁ78/20 ꢀC.
The different regioselectivities might be rationalized by com-
parison of the resonance structures of the cations formed by re-
action of TiCl4 with 3-silyloxy-2-en-1-ones 3a and 6 (Scheme 4). In
the case of the CH3-substituted substrate 6, it can be expected that
resonance structure E1 is more stable than E2, due to the
s-do-
Figure 1. Ortep plot of 5b (50% probability level).
nating effect of the methyl group. The phenyl group is expected to
be twisted out of plane. In contrast, A2 is expected to have a higher
impact than A1, due to the cation-destabilizing effect of the CF3
group. The reactions presumably proceed, under kinetic reaction
control, by attack of the terminal carbon atom of 4a onto the cat-
ionic intermediate, which is predominantly present.
The TiCl4-mediated formal [3þ3] cyclization of 3-aryl-3-trime-
thylsilyloxy-1-trifluoromethyl-2-en-1-ones 3a–j with 1,3-bis(sily-
loxy)-1,3-butadienes 4a–k afforded 5-aryl-3-(trifluoromethyl)-
phenols 5a–ao (Scheme 5, Table 2). Some trends are observed
related to the influence of the substitution pattern of the starting
materials on the yields. Dienes 4a,f,h are derived from simple
methyl, isopropyl and ethyl acetoacetate, respectively. Dienes 4b–
e,i are prepared from higher b-ketoester homologues. 1,3-Bis(silyl
enol ether) 4g contains a methoxy group located at carbon C-4 of
the diene. 1,3-Bis(silyloxy)-1,3-butadienes 4j,k are derived from
1,3-diketones and are generally less reactive than dienes 4a–i de-
rived from b-ketoesters. The yields of cyclization products derived
from diene 4a are often higher than the yields of products derived
from 4b–e. In addition, the yields of the products prepared from 4a
are often higher than those of products derived from 4j (however,
for 5n and 5r the opposite case is true). There is no significant
difference between the yields of the products derived from dienes
4b and 4k, both containing a methyl group attached to carbon atom
C-4 of the diene. The aryl group attached to the enone also has
some influence on the yields. The yields of products 5n–r and 5w–
ad, prepared from enones containing electron-poor aryl groups, are
in several cases higher than the yields of those products, which
are derived from the other enones. The yields of products 5f,g,
derived from naphthyl-substituted enone 3b, are relatively
low.
Table 2
Synthesis of 5a–ao
a
3
4
5
Ar
R1
R3
%
(5)
a
a
a
a
a
b
b
c
c
c
c
c
c
d
d
d
d
d
e
e
e
e
f
a
b
c
d
e
a
f
a
b
c
d
e
g
b
h
b
i
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
p
q
r
s
t
u
v
w
x
y
z
aa
ab
ac
ad
ae
af
ag
ah
ai
aj
ak
al
am
an
ao
Ph
Ph
Ph
Ph
Ph
2-Naph
2-Naph
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-FC6H4
4-FC6H4
4-FC6H4
4-FC6H4
4-FC6H4
4-BrC6H4
4-BrC6H4
4-BrC6H4
4-BrC6H4
4-(O2N)C6H4
4-(O2N)C6H4
4-(O2N)C6H4
4-(F3C)C6H4
4-(F3C)C6H4
4-(F3C)C6H4
4-(F3C)C6H4
4-(F3C)C6H4
4-(MeO)C6H4
4-(MeO)C6H4
4-(MeO)C6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-PhC6H4
4-PhC6H4
4-PhC6H4
H
Me
Et
OMe
OMe
OEt
OMe
OMe
OMe
OiPr
OMe
OMe
OEt
OMe
OMe
OMe
OMe
OEt
OMe
OMe
Me
48
51
37
56
60
30
30
36
52
38
40
45
37
53
32
61
55
68
65
31
68
61
71
51
64
69
72
63
54
70
66
51
67
52
42
44
49
32
70
41
42
nHex
nOct
H
H
H
Me
Et
The 1H NMR spectra of products 5a–ao show a sharp signal
between 9 and 12 ppm, which can be assigned to the proton in-
volved in a hydrogen bond O–H/O. In the 19F NMR spectra, the
signals of the CF3 group of acetophenone and propiophenone de-
rivatives (derived from 4j,k) appear in the range of ꢁ53 to
ꢁ56 ppm and in the range of ꢁ58 to ꢁ59 ppm for salicylate de-
rivatives (derived from 4a–i). The CF3 groups attached to the
simple benzene moiety (products 4z–ad) usually appear at ca.
ꢁ63 ppm, which is in agreement with the literature.20 In contrast,
CF3 signals located next to a carbonyl group appear at ca. ꢁ70 ppm.
The structures of 5b and 5h were independently confirmed by
X-ray crystal structure analyses (Figs. 1 and 2).21
nHex
nOct
OMe
H
H
Me
Et
j
H
b
g
j
k
a
b
j
a
b
i
Me
OMe
H
Me
H
Me
H
H
Me
Et
H
Me
H
Me
OMe
H
OMe
OMe
Me
Et
OMe
OMe
Me
OMe
OMe
OMe
Me
f
f
g
g
g
g
g
h
h
h
i
i
i
i
i
j
k
a
b
g
a
b
g
j
Et
OMe
OMe
OMe
OMe
OMe
OMe
Me
Me
OMe
H
Me
Me
Et
k
b
i
Et
j
j
j
OMe
OMe
OMe
g
OMe
a
Isolated yields.
Figure 2. Ortep plot of 5h (50% probability level).

S. Bu¨ttner et al. / Tetrahedron 65 (2009) 2124–2135
2127
In conclusion, a variety of sterically encumbered and function-
3.2.4. 4,4,4-Trifluoro-1-(4-trifluoromethylphenyl)butane-1,3-dione
(2g)
alized 5-aryl-3-(trifluoromethyl)phenols were prepared by the first
TiCl4-mediated [3þ3] cyclocondensations of 1,3-bis(trimethyl-
silyloxy)-1,3-butadienes with 3-aryl-3-trimethylsilyloxy-1-trifluo-
romethyl-2-en-1-ones. The products are not readily available by
other methods.
Starting with 1-(4-trifluoromethylphenyl)ethanone (4.704 g,
25.0 mmol), 2g was isolated as a colourless liquid (4.507 g, 63%),
bp¼90–92 ꢀC/2.9 mmHg; 1H NMR (250 MHz, CDCl3):
¼6.60 (s, 1H,
d
COCHCOH), 7.78 (d, 3J¼8.2 Hz, 2H, ArH), 8.06 (d, 3J¼8.2 Hz, 2H,
ArH), 14.85 (s, 1H, OH). 19F NMR (235 MHz, CDCl3):
d
¼ꢁ76.7 (CF3),
ꢁ63.3 (CF3). 13C NMR (75 MHz, CDCl3):
d
¼92.9 (q, 3J¼1.8 Hz,
3. Experimental section
3.1. General comments
COCHCOH), 116.9 (q, 1J¼284 Hz, CF3), 123.4 (q, 1J¼273 Hz, CF3),
126.0 (q, 3J¼3.7 Hz, CF3CCHCH), 127.9 (CF3CCHCH), 135.2 (q,
2J¼33.0 Hz, CF3CCH), 136.0 (Cq), 178.5 (q, 2J¼36.7 Hz, COH), 183.9
(CO).
All solvents were dried by standard methods and all reactions
were carried out under an inert atmosphere. For 1H and 13C NMR
spectra the deuterated solvents indicated were used. Mass spec-
trometric data (MS) were obtained by electron ionization (EI,
70 eV), chemical ionization (CI, H2O) or electrospray ionization
(ESI). For preparative scale chromatography, silica gel (60–200
mesh) was used. Melting points are uncorrected. Compounds 2a–c
are commercially available.
3.2.5. 1-(4-Methoxyphenyl)-4,4,4-trifluorobutane-1,3-dione (2h)
Starting with 1-(4-methoxyphenyl)ethanone (3.755 g, 25.0 mmol),
2h was isolated as a colourless solid (2.641 g, 41%), mp¼59–
60 ꢀC; 1H NMR (250 MHz, CDCl3):
d
¼3.90 (s, 3H, OCH3), 6.51 (s,
1H, COCHCOH), 6.99 (d, 3J¼9.1 Hz, 2H, ArH), 7.94 (d, 3J¼9.1 Hz,
2H, ArH), 15.43 (s, 1H, OH). 19F NMR (235 MHz, CDCl3):
d
¼ꢁ76.3
(CF3). 13C NMR (75 MHz, CDCl3):
d
¼55.6 (OCH3), 91.5 (COCH-
COH), 114.4 (CH), 117.4 (q, 1J¼282.7 Hz, CF3), 125.4 (Cq), 130.0
(CH), 164.6 (Cq), 175.8 (q, 2J¼36.0 Hz, COH), 186.2 (CO).
3.2. General procedure for the synthesis of 3-aryl-1-
trifluoromethyl-2-en-1-ones 2d–i
3.2.6. 1-(p-Tolyl)-4,4,4-trifluorobutane-1,3-dione (2i)
Sodium (1.2 equiv) was added to methanol (10.0 equiv) at 0 ꢀC
and the mixture was stirred for 30 min. Ethyl trifluoroacetate
(1.0 equiv) was added and the solution was stirred for further
30 min. To the solution was added acetophenone 1 (1.0 equiv). The
temperature of the reaction mixture was allowed to rise to 20 ꢀC in
the period of 3 h and the solution was stirred for 16 h at 20 ꢀC. To
the solution was added sulfuric acid (10%, 0.35 mL per 1.0 mmol of
1) and the mixture was extracted with diethyl ether. The combined
organic layers were dried (Na2SO4), filtered and the filtrate was
concentrated under reduced pressure. The residue was purified by
column chromatography (silica gel, heptanes/EtOAc/heptanes¼1:10).
Starting with 1-(4-methylphenyl)ethanone (3.355 g, 25.0 mmol),
2i was isolated as a colourless solid (4.131 g, 72%), mp¼45–
46 ꢀC. 1H NMR (250 MHz, CDCl3):
d
¼2.45 (s, 3H, CH3), 6.55 (s,
1H, COCHCOH), 7.31 (d, 3J¼8.3 Hz, 2H, ArH), 7.85 (d, 3J¼8.3 Hz,
2H, ArH), 15.24 (s, 1H, OH). 19F NMR (235 MHz, CDCl3):
d
¼ꢁ76.4
(CF3). 13C NMR (75 MHz, CDCl3):
d
¼21.8 (CH3), 92.0 (COCHCOH),
117.2 (q, 1J¼283.1 Hz, CF3), 127.7 (CH), 129.8 (CH), 130.2 (Cq),
145.4 (Cq), 176.8 (q, 2J¼36.1 Hz, COH), 186.4 (CO).
3.2.7. 1-(4-Phenylphenyl)-4,4,4-trifluorobutane-1,3-dione (2j)
Starting with 1-(4-phenylphenyl)ethanone (3.533 g,18.0 mmol),
2j was isolated as a pale red solid (2.947 g, 56%), mp¼104 ꢀC. 1H
3.2.1. 1-(4-Fluorophenyl)-4,4,4-trifluorobutane-1,3-dione (2d)
Starting with 1-(4-fluorophenyl)ethanone (3.454 g, 25.0 mmol),
2d was isolated as a colourless solid (2.423 g, 41%), mp¼40–41 ꢀC.
NMR (250 MHz, CDCl3):
d
¼6.63 (s, 1H, COCHCOH), 7.40–7.55 (m,
3H, ArH), 7.65 (d, 3J¼7.9 Hz, 2H, ArH), 7.74 (d, 3J¼8.6 Hz, 2H,
ArH), 8.03 (d, 3J¼8.6 Hz, 2H, ArH), 15.24 (s, 1H, OH). 19F NMR
1H NMR (250 MHz, CDCl3):
d
¼6.53 (s, 1H, COCHCOH), 7.20 (dd,
(235 MHz, CDCl3):
d
d
¼ꢁ76.4 (CF3). 13C NMR (75 MHz, CDCl3):
3JH,H¼9.0 Hz, JH,F¼8.3 Hz, 2H, CFCH), 7.99 (dd, JH,H¼9.1 Hz,
¼92.2 (COCHCOH), 117.2 (q, 1J¼283.5 Hz, CF3), 127.2 (CH), 127.5
3
3
4JH,F¼5.3 Hz, 2H, CFCHCH), 15.14 (s, 1H, OH). 19F NMR (235 MHz,
(CH), 128.2 (CH), 128.6 (CH), 129.0 (CH), 131.5 (Cq), 139.4 (Cq),
146.9 (Cq), 177.3 (q, 2J¼36.2 Hz, COH), 185.6 (CO).
CDCl3):
d
¼ꢁ76.4 (CF3), ꢁ102.9 (CF). 13C NMR (75 MHz, CDCl3):
d
¼92.2 (q, 3J¼2.1 Hz, COCHCOH), 116.4 (d, 2J¼22.2 Hz, CFCH), 117.2
(q, 1J¼283.2 Hz, CF3), 129.3 (d, 4J¼2.9 Hz, CFCHCHC), 130.3 (d,
3J¼9.5 Hz, CFCHCH), 166.4 (d, 1J¼256.8 Hz, CF), 176.6 (q, 2J¼36.4 Hz,
COH), 185.3 (CO).
3.3. General procedure for the synthesis of 3-aryl-3-silyloxy-
1-trifluoromethyl-2-en-1-ones 3a–c
To a stirred benzene solution (2.5 mL per 1.0 mmol of 2a–c) of
2a–c (1.0 equiv) was added triethylamine (1.6 equiv). After stirring
the solution for 2 h, trimethylchlorosilane (1.8 equiv) was added.
The solution was stirred for 72 h and, subsequently, the solvent was
removed in vacuo and hexane (1.5 mL per 1.0 mmol of starting
material) was added to the residue to give a suspension. The latter
was filtered under argon atmosphere. The filtrate was concentrated
in vacuo to give silyl enol ethers 3a–c, which were used without
further purification. Due to the unstable nature of the products, MS
and analytical data could not be obtained. All products were
obtained as mixtures of E/Z-isomers.
3.2.2. 1-(4-Bromophenyl)-4,4,4-trifluorobutane-1,3-dione (2e)
Starting with 1-(4-bromophenyl)ethanone (4.976 g, 25.0 mmol),
2e was isolated as a pale yellow solid (6.410 g, 87%), mp¼60 ꢀC. 1H
NMR (300 MHz, CDCl3):
d
¼6.54 (s, 1H, COCHCOH), 7.66 (d,
3J¼8.8 Hz, 2H, ArH), 7.81 (d, 3J¼8.8 Hz, 2H, ArH), 15.02 (s, 1H,
OH). 19F NMR (282 MHz, CDCl3):
d
¼ꢁ76.5 (CF3). 13C NMR
(75 MHz, CDCl3):
d
¼92.3 (COCHCOH), 117.0 (q, 1J¼283.4 Hz, CF3),
129.0 (CH), 129.3 (Cq), 131.7 (Cq), 132.4 (CH), 177.5 (q,
2J¼36.5 Hz, COH), 184.9 (CO).
3.2.3. 1-(4-Nitrophenyl)-4,4,4-trifluorobutane-1,3-dione (2f)
Starting with 1-(4-nitrophenyl)ethanone (4.129 g, 25.0 mmol),
2f was isolated as a pale yellow solid (2.172 g, 35%), mp¼99–100 ꢀC.
3.3.1. 1,1,1-Trifluoro-4-phenyl-4-[(trimethylsilyl)oxy]-3-buten-2-
one (3a)
1H NMR (250 MHz, CDCl3):
d
¼6.62 (s, 1H, COCHCOH), 8.12 (d,
Starting with benzene (60.0 mL), 2a (5.00 g, 24.6 mmol), tri-
ethylamine (3.927 g, 38.8 mmol) and trimethylchlorosilane
(2.917 g, 27.0 mmol), 3a was isolated as a reddish oil (5.729 g, 82%).
3J¼9.1 Hz, 2H, ArH), 8.36 (d, 3J¼9.1 Hz, 2H, ArH),14.70 (s,1H, OH).19
F
NMR (235 MHz, CDCl3):
d
¼ꢁ76.7 (CF3). 13C NMR (75 MHz, CDCl3):
d
¼93.4 (COCHCOH), 116.7 (q, 1J¼283.9 Hz, CF3), 124.1 (CH), 128.6
1H NMR (300 MHz, CDCl3):
CH), 7.29–7.34 (m, 3H, CHAr), 7.77–7.80 (m, 2H, CHAr).
d
¼0.20 (m, 9H, Si(CH3)3), 6.56 (s, 1H,
(CH), 138.1 (Cq), 150.7 (Cq), 179.2 (q, 2J¼37.0 Hz, COH), 182.2 (CO).

2128
S. Bu¨ttner et al. / Tetrahedron 65 (2009) 2124–2135
3.3.2. 4-(Naphth-2-yl)-1,1,1-trifluoro-4-(trimethylsilyloxy)but-3-
en-2-one (3b)
(CHPh), 123.3 (d, 1J¼269.7 Hz, CF3), 127.1 (2CHPh), 129.0 (2CHPh),
130.7 (q, 2J¼31.6 Hz, CCF3Ar), 138.2 (CPh), 146.7 (CAr), 162.2 (COHAr),
169.5 (CO). IR (neat, cmꢁ1):
n
¼ 1660 ðsÞ, 1619 (m), 1452 (s), 1343
~
Starting with benzene (37.5 mL), 2b (3.993 g, 15.0 mmol), tri-
ethylamine (2.428 g, 24.0 mmol), and trimethylchlorosilane
(2.933 g, 27.0 mmol), 3b was isolated as a yellowish solid (4.82 g,
(s),1219 (m), 1136 (s), 966 (m), 882 (m), 694 (m). GC–MS (EI, 70 eV):
m/z (%)¼296 ([Mþ], 49), 265 (27), 264 (100), 263 (22), 236 (43), 208
(8), 188 (18), 139 (13), 118 (6). HRMS (EI) calcd for C15H11F3O3:
296.06548, found: 296.06510.
95%), mp¼130–132 ꢀC. 1H NMR (250 MHz, CDCl3):
¼0.22 [s, 9H,
d
Si(CH3)3], 6.75 (s, 1H, CH), 7.46–7.57 (m, 2H, CH), 7.79–7.86 (m, 2H,
CHNaph), 7.89–7.94 (m, 2H, CHNaph), 8.35 (m, 1H, CHNaph). 19F NMR
(235 MHz, CDCl3):
CDCl3):
d
¼ꢁ73.72, ꢁ76.39, ꢁ78.44. 13C NMR (75 MHz,
3.5.2. Methyl 3-hydroxy-2-methyl-5-(trifluoromethyl)[1,10-
biphenyl]-4-carboxylate (5b)
Starting with 3a (0.361 g, 1.5 mmol), 4b (0.426 g, 1.6 mmol) and
TiCl4 (0.18 mL, 1.6 mmol), 5b was isolated as yellowish solid (0.237 g,
d
¼0.37 [Si(CH3)3], 106.4 (CH), 122.9, 124.0, 127.0, 128.0,
128.7, 129.7, 130.1 (CHNaph), 130.9 (d, 1JC,F¼257.5 Hz, CF3), 171.8 (CO),
188.7 (COSi).
51%).1H NMR (300 MHz, CDCl3):
7.15 (m, 1H, CHPh), 7.19 (m, 1H, CHAr), 7.22 (m, 1H, CHPh), 7.34 (m, 2H,
CHPh), 7.36 (m, 1H, CHPh), 11.09 (s,1H, OH). 13C NMR (75 MHz, CDCl3):
d
¼2.13(s,3H, CH3),3.91(s,3H, OCH3),
3.3.3. 4-(4-Chlorophenyl)-1,1,1-trifluoro-4-(trimethylsilyloxy)-but-
3-en-2-one (3c)
Starting with benzene (30 mL), 2c (3.000 g, 12.0 mmol), tri-
ethylamine (1.938 g, 19.2 mmol) and trimethylchlorosilane
(2.340 g, 21.5 mmol), 3c was isolated as a yellowish oil (3.80 g, 98%).
d
¼13.6 (CH3), 52.8 (OCH3), 108.6 (CCOOCH3Ar), 120.2 (q, 3JF, C¼6.8 Hz,
CHAr), 123.5 (d, 1J¼269.0 Hz, CF3), 127.4 (q, 2J¼31.6 Hz, CCF3Ar), 127.9
(CHPh), 128.3 (2CHPh), 128.8 (2CHPh), 130.0 (CPh), 139.7, 146.9 (CAr),
1H NMR (250 MHz, CDCl3):
d
¼0.13 [s, 9H, Si(CH3)3], 6.74 (s, 1H, CH),
160.6 (COHAr), 170.2 (CO). 19F NMR (235 MHz, CDCl3):
d¼ꢁ58.0 (CF3).
7.29 (d, 3J¼8.3 Hz, 2H, CHClph), 7.70 (d, 3J¼8.3 Hz, 2H, CHClph). 19F
IR (neat, cmꢁ1):
n
¼ 2995 ðwÞ,1681 (m),1609(w),1439 (m),1335 (m),
~
NMR (235 MHz, CDCl3):
d
¼ꢁ73.91. 13C NMR (75 MHz, CDCl3):
d¼0.2
1274 (s), 1122 (s), 1017 (s), 886 (s), 700 (s). GC–MS (EI, 70 eV): m/z
(%)¼310 ([Mþ], 68), 279(27), 278 (80), 277 (100), 257 (9), 250(36), 231
(7), 201 (24), 181 (57), 152 (24), 152 (24), 115 (5). HRMS (EI) calcd for
C16H13F3O3: 310.08113, found: 310.08062.
[Si(CH3)3], 105.8 (CH), 119.7 (d, 1JC,F¼276.8 Hz, CF3), 129.0 (2CHClph),
129.6 (2CHClph), 136.2, 139.8 (2CClph), 185.0 (CO), 187.4 (COSi).
3.4. General procedure for the synthesis of 3-silyloxy-1-
(trifluoromethyl)prop-2-en-1-ones 3d–j
3.5.3. Ethyl 2-ethyl-3-hydroxy-5-(trifluoromethyl)[1,10-biphenyl]-
4-carboxylate (5c)
To a stirred diethyl ether solution (2 mL per 1.0 mmol of 2) of
2d–j (1.0 equiv) were added triethylamine (1.0 equiv) and TMSOTf
(0.95 equiv) at 0 ꢀC under an argon atmosphere. The solution was
stirred for 30 min at 0 ꢀC. The temperature of the reaction mixture
was allowed to rise to 20 ꢀC and the stirring was continued for 3
days. A liquid salt layer separated at the bottom of the flask. The
upper layer (ether solution containing the product) was transferred
to a dry flask by syringe under an argon atmosphere. Diethyl ether
(1.5 mL per 1.0 mmol of 2) was added to the liquid salt layer, the
mixture was stirred for 2 min and the layers were allowed to
separate in the period of 2 h. The ether solutions were combined
and concentrated in vacuo to give silyl enol ethers 3d–j, which were
not further purified. Due to their unstable nature, products 3d–j
were immediately used for the synthesis of phenols 5 (without
detailed spectroscopic characterization).
Starting with 3a (0.360 g, 1.5 mmol), 4c (0.495 g, 1.6 mmol) and
TiCl4 (0.18 mL,1.6 mmol), 5c was isolated as a red viscous oil (0.187 g,
37%). 1H NMR (250 MHz, CDCl3):
d
¼1.00 (t, 3J¼7.4 Hz, 3H, CH2CH3),
1.32 (t, 3J¼7.1 Hz, 3H, OCH2CH3), 2.54 (q, 3J¼7.4 Hz, 2H, CH2CH3), 4.36
(q, 3J¼7.2 Hz, 2H, OCH2CH3), 7.09 (br s, 1H, CHAr), 7.15 (m, 1H, CHPh),
7.16–7.19 (m, 2H, CHPh), 7.30–7.33 (m, 2H, CHPh), 11.13 (s, 1H, OH). 19
F
NMR (235 MHz, CDCl3):
d
¼ꢁ57.8 (CF3). 13C NMR (75 MHz, CDCl3):
d
¼12.4 (CH2CH3), 12.6 (OCH2CH3), 19.8 (CH2CH3), 62.2 (OCH2CH3),
3
108.3 (CCOOCH2CH3Ar), 119.5 (q, JF,C¼6.6 Hz, CHAr), 122.5 (d,
1JF,C¼269.0 Hz, CF3), 125.4 (q, 2J¼31.6 Hz, CCF3Ar), 126.7 (CHPh), 127.2
(2CHPh), 127.5 (2CHPh), 134.2 (CPh), 139.0, 145.7 (CAr), 159.1 (COHAr),
168.7 (CO). GC–MS (EI, 70 eV): m/z (%)¼338 ([Mþ], 59), 293 (26), 292
(79), 291 (100), 264 (46), 249 (24), 223 (5),195 (21),165 (15). HRMS (EI)
calcd for C18H17F3O3: 338.11243, found: 338.11274.
3.5.4. Methyl 2-hexyl-3-hydroxy-5-(trifluoromethyl)[1,10-
biphenyl]-4-carboxylate (5d)
Starting with 3a (0.360 g, 1.5 mmol), 4d (0.563 g, 1.6 mmol) and
TiCl4 (0.18 mL, 1.6 mmol), 5d was isolated as a red viscous oil
3.5. General procedure for the synthesis of 5-aryl-3-
(trifluoromethyl)phenols 5a–ao
To a stirred dichloromethane solution (2 mL per 1.0 mmol of 3)
of enone 3 (1.0 equiv) and 1,3-bis(silyl enol ether) 4 (1.1 equiv) was
added TiCl4 (1.1 equiv) at ꢁ78 ꢀC under an argon atmosphere. The
temperature of the reaction mixture was allowed to rise to 20 ꢀC in
the period of 16 h. To the solution was added hydrochloric acid
(10%, 3 mL per 1.0 mmol of 3) and the mixture was extracted with
dichloromethane (3ꢂ15 mL). The combined organic layers were
dried (Na2SO4), filtered and the filtrate was concentrated under
reduced pressure. The residue was purified by column chroma-
tography (silica gel, heptanes/EtOAc/heptanes¼1:10).
(0.319 g, 56%). 1H NMR (250 MHz, CDCl3):
d
¼0.64 (br t, 3J¼7.0 Hz,
3H, CH2(CH2)4CH3), 0.99–1.34 (m, 8H, CH2(CH2)4CH3), 2.44 (t,
3J¼8.0 Hz, 2H, CH2(CH2)4CH3), 3.81 (s, 3H, OCH3), 7.01 (m,1H, CHAr),
7.08 (m, 1H, CHPh), 7.11 (m, 1H, CHPh), 7.23 (m, 2H, CHPh), 7.25 (m,
1H, CHPh), 10.91 (s, 1H, OH). 19F NMR (235 MHz, CDCl3):
d¼ꢁ57.8
(CF3). 13C NMR (62 MHz, CDCl3):
d
¼13.9 (CH3), 22.4, 27.3, 29.0, 29.3,
3
31.3 (CH2), 52.7 (OCH3), 109.0 (CCOOCH3Ar), 120.5 (q, JF,C¼6.5 Hz,
CHAr), 123.5 (d, 1JF,C¼269.0 Hz, CF3), 127.4 (q, 2JF,C¼31.6 Hz, CCF3Ar),
127.8 (CHPh), 128.2 (2CHPh), 128.6(2CHPh), 134.2 (CPh), 140.0, 147.0
~
(CAr),160.4 (COHAr),170.2 (CO). IR (neat, cmꢁ1):
n
¼ 2927 ðwÞ, 2856
(w), 1671 (m), 1610 (w), 1439 (m), 1336 (m), 1280 (s), 1200 (m), 1177
(s), 1030 (w), 947 (m), 885 (m), 770 (m), 701 (s). GC–MS (EI, 70 eV):
m/z (%)¼380 ([Mþ], 55), 349 (31), 348 (100), 347 (49), 331 (13), 278
(40), 277 (62), 250 (28), 229 (5), 201 (23), 181 (28), 152 (16). HRMS
(EI) calcd for C21H23O3F3: 380.15938, found: 380.15976.
3.5.1. Methyl 3-hydroxy-5-(trifluoromethyl)[1,10-biphenyl]-4-
carboxylate (5a)
Starting with 3a (0.361 g, 1.5 mmol), 4a (0.426 g, 1.6 mmol) and
TiCl4 (0.18 mL, 1.6 mmol), 5a was isolated as a colourless solid
(0.213 g, 48%). 1H NMR (300 MHz, CDCl3):
d
¼3.82 (s, 3H, OCH3), 7.24
(m, 1H, CHPh), 7.27 (m, 2H, CHPh), 7.32 (m, 1H, CHAr), 7.37 (m, 1H,
3.5.5. Methyl 3-hydroxy-2-octyl-5-(trifluoromethyl)[1,10-biphenyl]-
4-carboxylate (5e)
Starting with 3a (0.360 g, 1.5 mmol), 4e (0.563 g, 1.6 mmol) and
TiCl4 (0.18 mL, 1.6 mmol), 5e was isolated as a red viscous oil
CHAr), 7.42–7.44 (m, 2H, CHPh),10.55 (s,1H, OH). 19F NMR (235 MHz,
CDCl3):
d
¼ꢁ58.8 (CF3). 13C NMR (75 MHz, CDCl3):
d¼52.8 (OCH3),
3
109.5 (CCOOCH3Ar), 118.0 (q, JF,C¼6.8 Hz, CHAr), 116.7 (CHAr), 119.7

S. Bu¨ttner et al. / Tetrahedron 65 (2009) 2124–2135
2129
(0.367 g, 60%). 1H NMR (250 MHz, CDCl3):
d
¼0.77 (br t, 3J¼6.9 Hz,
3J¼8.8 Hz, 2H, CHClph), 7.37 (d, 3J¼8.4 Hz, 2H, CHClph), 10.73 (s, 1H,
3H, CH2(CH2)6CH3), 1.08–1.39 (m, 12H, CH2(CH2)6CH3), 2.25 (t,
3J¼7.8 Hz, 2H, CH2(CH2)6CH3), 3.90 (s, 3H, OCH3), 7.10 (m, 1H, CHAr),
7.16 (m, 1H, CHPh), 7.19 (m, 1H, CHPh), 7.32 (m, 2H, CHPh), 7.25 (m,
OH). 19F NMR (235 MHz, CDCl3):
d
¼ꢁ58.84. 13C NMR (75 MHz,
3
CDCl3):
d
¼53.1 (OCH3), 109.9 (CCOOMe), 117.9 (q, JC,F¼6.6 Hz,
1
CHAr), 119.8 (CHAr), 123.3 (d, JC,F¼228.3 Hz, CF3), 128.5 (2CHClph),
1H, CHPh), 10.99 (s, 1H, OH). 19F NMR (235 MHz, CDCl3):
d
¼ꢁ58.6
129.4 (2CClph), 131.1 (d, JF,C¼33.1 Hz, CAr), 135.5, 136.8 (2CClph),
2
(CF3). 13C NMR (62 MHz, CDCl3):
d
¼13.0 (CH3), 21.6, 26.3 (CH2), 28.0
145.5 (CAr), 162.4 (COHAr), 169.5 (CO). IR (KBr, cmꢁ1):
¼ 3072 ðwÞ,
~
n
(3CH2), 28.6, 30.8 (CH2), 51.7 (OCH3), 108.0 (CCOOCH3Ar), 119.5 (q,
3033 (w), 2954 (w), 2923 (w), 1671 (m), 1619 (w), 1594 (w), 1556
(w), 1503 (w), 1486 (w), 1438 (m), 1337 (m), 1309 (m), 1289 (s), 1246
(m), 1203 (m), 1162 (m), 1130 (s), 1089 (s), 1055 (m), 1012 (m), 967
(m), 931 (m), 883 (m), 861 (w), 826 (s), 802 (m), 726 (m), 711 (m),
696 (m), 637 (w), 622 (w), 569 (w), 543 (w). GC–MS (EI, 70 eV): m/z
(%)¼332 ([Mþ], 37Cl, 17), 330 ([Mþ], 35Cl, 49), 300 (37Cl, 37), 299
3JF,C¼6.8 Hz, CHAr), 122.4 (d, JF,C¼269.0 Hz, CF3), 125.8 (q,
1
2JF,C¼31.6 Hz, CCF3Ar), 126.7, 126.9, 127.0, 127.2, 127.5 (CHPh), 133.2
(CPh), 139.0 (CAr), 146.0 (CAr), 159.4 (COHAr), 169.2 (CO). IR (neat,
cmꢁ1):
n
¼ 2961 ðwÞ, 2854 (w), 1672 (w), 1374 (w), 1257 (s), 1087
~
(m), 1012 (s), 791 (s). GC–MS (EI, 70 eV): m/z (%)¼408 ([Mþ], 43),
377 (32), 37 (100), 359 (12), 333 (7), 278 (41), 277 (59), 250 (25),
229 (5), 201 (19), 181 (18), 152 (13). HRMS (EI) calcd for C23H27O3F3:
408.19068, found: 408.19180.
(
37Cl, 34), 298 (35Cl, 100), 297 (35Cl, 15), 272 (37Cl, 14), 270 (35Cl, 40),
207 (24), 188 (15), 135 (12), 94 (5). HRMS (EI) calcd for C15H10ClO3F3
([M]þ, 35Cl): 330.02651, found: 330.026277.
3.5.6. Methyl 2-hydroxy-4-(naphth-2-yl)-6-(trifluoromethyl)-
benzoate (5f)
3.5.9. Methyl 40-chloro-3-hydroxy-2-methyl-5-(trifluoromethyl)-
biphenyl-4-carboxylate (5i)
Starting with 3b (0.338 g, 1.0 mmol), 4a (0.286 g, 1.1 mmol) and
TiCl4 (0.12 mL, 1.1 mmol), 5f was isolated as a yellow viscous oil
Starting with 3c (0.483 g,1.5 mmol), 4b (0.452 g,1.65 mmol) and
TiCl4 (0.18 mL, 1.65 mmol), 5i was isolated as a slightly yellow vis-
(0.098 g, 30%). 1H NMR (250 MHz, CDCl3):
d
¼3.93 (s, 3H, OCH3),
cous oil (0.270 g, 52%). 1H NMR (250 MHz, CDCl3):
d
¼2.03 (s, 3H,
7.41–7.48 (m, 3H, CH), 7.59–7.64 (m, 2H, CH), 7.75–7.87 (m, 3H, CH),
CH3), 3.84 (s, 3H, OCH3), 7.02 (s, 1H, CHAr), 7.07 (d, 3J¼8.3 Hz, 2H,
7.98 (m, 1H, CHNaph), 10.80 (s, 1H, OH). 19F NMR (235 MHz, CDCl3):
CHclph), 7.26 (d, 3J¼8.7 Hz, 2H, CHClph), 11.03 (s, 1H, OH). 19F NMR
d
¼ꢁ58.72. 13C NMR (75 MHz, CDCl3):
d
¼53.0 (OCH3), 109.6
(235 MHz, CDCl3):
d
¼ꢁ58.66. 13C NMR (75 MHz, CDCl3):
d¼12.8
3
3
(CCOOMe), 118.4 (q, JC,F¼7.5 Hz, CHAr), 120.1 (CHAr), 123.4 (d,
1JC,F¼123.4 Hz, CF3), 124.7, 126.7, 126.9, 127.0, 127.8, 128.6, 129.1
(CHNaph), 131.0 (q, 2JC,F¼30 Hz, CAr), 133.5, 133.7, 135.6 (CNaph), 146.7
~
(CH3), 52.0 (OCH3), 108.0 (CCOOMe), 119.1 (q, JC,F¼7.7 Hz, CHAr),
1
2
122.5 (d, JC,F¼274.2 Hz, CF3), 126.3 (d, JF,C¼33.2 Hz, CAr), 127.7
(2CHClph), 128.5 (CAr), 129.3 (2CHClph), 133.3, 137.2 (CClph), 144.7
(CAr), 162.4 (COH), 169.7 (CO). IR (KBr, cmꢁ1):
n
¼ 3057 ðwÞ, 2982
(CAr), 159.7 (COH), 169.3 (CO). IR (KBr, cmꢁ1):
¼ 3008 ðwÞ, 2956
~
n
(w), 2923 (w), 2855 (w), 1660 (m), 1615 (w), 1600 (w), 1568 (w),
1511 (w), 1465 (w), 1442 (w), 1406 (w), 1362 (m), 1335 (m), 1323
(m), 1292 (s), 1272 (m), 1240 (m), 1209 (m), 1177 (m), 1148 (m), 1135
(s), 1100 (s), 1053 (m), 1020 (w), 973 (m), 949 (w), 914 (w), 874(w),
855 (m), 815 (m), 786 (w), 747 (m), 705 (m), 658 (w), 607 (w), 591
(w), 555 (w). GC–MS (EI, 70 eV): m/z (%)¼347 ([Mþ], 18), 346 (88),
315 (29), 314 (100), 313 (15), 286 (37), 258 (12), 238 (19), 189 (30),
157 (9), 143 (12), 133 (10), 119 (10), 94 (9). HRMS (EI) calcd for
C19H13O3F3 ([M]þ): 346.08113, found: 346.081463.
(w), 2926 (w), 2855 (w), 1671 (w), 1610 (w), 1575 (w), 1559 (w),
1493 (w), 1439 (w), 1405 (w), 1336 (m), 1309 (m), 1281 (s), 1245 (w),
1203 (m), 1133 (s), 1090 (m), 1015 (m), 987 (w), 937 (w), 905 (m),
889 (w), 833 (m), 808 (w), 773 (w), 729 (s), 681 (w), 652 (w), 642
(w), 601 (w), 537 (w). GC–MS (EI, 70 eV): m/z (%)¼346 ([Mþ], 37Cl,
20), 344 ([Mþ], 35Cl, 61), 314 (37Cl, 23), 313 (37Cl, 56), 312 (35Cl, 65),
311 (35Cl, 100), 278 (15), 277 (94), 257 (24), 249 (29), 219 (9), 201
(35), 170 (6), 152 (21), 138 (11), 114 (11), 100 (8), 75 (7). HRMS (EI)
calcd for C16H12ClO3F3 ([M]þ, 35Cl): 344.04216, found: 344.041922.
3.5.7. Isopropyl 2-hydroxy-4-(naphth-2-yl)-6-(trifluoromethyl)-
benzoate (5g)
3.5.10. Ethyl 40-chloro-2-ethyl-3-hydroxy-5-(trifluoromethyl)-
biphenyl-4-carboxylate (5j)
Starting with 3b (0.507 g, 1.5 mmol), 4f (0.476 g, 1.65 mmol) and
TiCl4 (0.18 mL, 1.65 mmol), 5g was isolated as a red viscous oil
Starting with 3c (0.483 g, 1.5 mmol), 4c (0.495 g, 1.65 mmol) and
TiCl4 (0.18 mL, 1.65 mmol), 5j was isolated as a yellowish viscous oil
(0.162 g, 30%). 1H NMR (250 MHz, CDCl3):
d
¼1.33 (s, 3H, CH3), 1.36
(0.210 g, 38%). 1H NMR (250 MHz, CDCl3):
d
¼0.99 (t, 3J¼7.5 Hz, 3H,
(s, 3H, CH3), 5.28 (q, 3J¼6.7 Hz, 1H, OCH), 7.42–7.50 (m, 3H, CH),
CH2CH3), 1.33 (t, 3J¼7.0 Hz, 3H, OCH2CH3), 2.52 (q, 3J¼7.5 Hz, 2H,
CH2CH3), 4.37 (q, 3J¼7.0 Hz, 2H, OCH2CH3), 7.04 (s, 1H, CHAr), 7.12 (d,
3J¼8.5 Hz, 2H, CHClph), 7.32 (d, 3J¼8.5 Hz, 2H, CHClph), 11.14 (s, 1H,
7.60–7.66 (m, 2H, CH), 7.77–7.88 (m, 3H, CH), 8.05 (m, 1H, CHNaph),
11.05 (s, 1H, OH). 19F NMR (235 MHz, CDCl3):
d
¼ꢁ57.52. 13C NMR
(75 MHz, CDCl3):
d
¼21.4 (2CH3), 71.1 [OCH(CH3)2], 110.3 (CCOOiPr),
OH). 19F NMR (235 MHz, CDCl3):
d
¼ꢁ57.94. 13C NMR (75 MHz,
3
1
118.3 (q, JC,F¼6.2 Hz, CHAr), 120.1 (CHAr), 123.5 (d, JC,F¼271 Hz,
CF3), 124.7, 126.7, 126.9, 127.0, 127.8, 128.6, 129.0 (CHNaph), 130.9 (q,
2JC,F¼31.4 Hz, CAr), 133.4, 133.5, 135.7 (CNaph), 146.5 (CAr), 162.6
~
CDCl3):
d
¼12.6, 12.8 (2CH3), 19.9 (CH2), 61.7 (OCH2), 109.1 (CAr
-
COOMe), 119.5 (q, 3JF,C¼7.5 Hz, CHAr), 122.8 (d, 1JF,C¼240.8 Hz, CF3),
2
126.2 (d, JF,C¼34.7 Hz, CAr), 127.8 (2CHClph), 129.1 (2CHClph), 133.2
(COH), 168.8 (CO). IR (KBr, cmꢁ1):
n
¼ 3058 ðwÞ, 2983 (w), 2921
(CAr), 134.4, 137.5 (2CClph), 144.5 (CAr), 159.6 (COH), 168.8 (CO). IR
(KBr, cmꢁ1):
¼ 2982 ðwÞ, 2966 (w), 2932 (w), 2876 (w), 2855 (w),
~
n
(m), 2852 (w), 1660 (m), 1618 (w), 1583 (w), 1511 (w), 1465 (w),
1406 (w), 1363 (s), 1335 (m), 1294 (s), 1274 (m), 1242 (m), 1209 (m),
1178 (m), 1149 (m), 1135 (s), 1100 (s), 1055 (m), 1020 (w), 972 (m),
948 (w), 913 (m), 887(w), 854 (m), 814 (m), 785 (w), 745 (m), 705
(m), 658 (w), 606 (w), 591 (w), 554 (w). GC–MS (EI, 70 eV): m/z
(%)¼375 ([Mþ], 12), 374 (50), 332 (42), 315 (31), 314 (100), 313 (11),
287 (8), 286 (25), 258 (8), 238 (16), 189 (23), 133 (6), 43 (6). HRMS
(EI) calcd for C21H17O3F3 ([M]þ): 374.11243, found: 374.111760.
1668 (w), 1610 (w), 1493 (w), 1464 (w), 1399 (w), 1372 (m), 1331
(w), 1290 (s), 1261 (w), 1230 (w), 1201 (w), 1136 (s), 1091 (w), 1061
(w), 1018 (w), 986 (w), 942 (w), 906 (w), 888 (w), 867 (w), 833 (w),
815 (w), 729 (m), 651 (w), 639 (w), 597 (w), 538 (w). GC–MS (EI,
70 eV): m/z (%)¼374 ([Mþ], 37Cl, 12), 372 ([Mþ], 35Cl, 36), 328 (37Cl,
10), 327 (37Cl, 28), 326 (35Cl, 26), 325 (35Cl, 46), 298 (15), 292 (19),
291 (100), 263 (7), 243 (7), 201 (7), 165 (10). HRMS (EI) calcd for
C18H16ClO3F3 ([M]þ, 35Cl): 372.07346, found: 372.073126.
3.5.8. Methyl 40-chloro-3-hydroxy-5-(trifluoromethyl)biphenyl-4-
carboxylate (5h)
3.5.11. Methyl 40-chloro-2-hexyl-3-hydroxy-5-(trifluoromethyl)-
biphenyl-4-carboxylate (5k)
Starting with 3c (0.483 g, 1.5 mmol), 4a (0.426 g, 1.6 mmol) and
TiCl4 (0.18 mL, 1.65 mmol), 5h was isolated as a yellow solid
Starting with 3c (0.483 g, 1.5 mmol), 4d (0.568 g, 1.65 mmol)
and TiCl4 (0.18 mL, 1.6 mmol), 5k was isolated as a slightly yellow
(0.175 g, 36%), mp¼87–88 ꢀC. 1H NMR (250 MHz, CDCl3):
¼3.89 (s,
d
3H, OCH3), 7.26–7.27 (m, 1H, CHAr), 7.30–7.32 (m, 1H, CHAr), 7.43 (d,
viscous oil (0.251 g, 40%). 1H NMR (250 MHz, CDCl3):
d¼0.73 (t,

2130
S. Bu¨ttner et al. / Tetrahedron 65 (2009) 2124–2135
3J¼6.3 Hz, 3H, CH3), 1.03–1.16 (m, 6H, CH2), 1.30–1.42 (m, 2H,
CH2), 2.49 (t, 3J¼7.6 Hz, 2H, CH2), 3.90 (s, 3H, OCH3), 7.04 (s, 1H,
CHAr), 7.11 (d, 3J¼8.4 Hz, 2H, CHClph), 7.32 (d, 3J¼8.4 Hz, 2H,
(21), 121 (10). HRMS (EI) calcd for C16H12ClO3F3 ([M]þ, 35Cl):
360.03707, found: 360.036271.
CHClph), 11.0 (s, 1H, OH). 19F NMR (235 MHz, CDCl3):
d
¼ꢁ57.94. 13
C
3.5.14. 40-Fluoro-3-hydroxy-5-trifluoromethyl-biphenyl-4-
carboxylic acid methyl ester (5n)
NMR (75 MHz, CDCl3):
d
¼14.1 (CH3), 22.6, 27.5, 29.1, 29.5, 31.5 (5
3
CH2), 53.0 (OCH3), 109.1 (CCOOMe), 120.4 (q, JC,F¼6.4 Hz, CHAr),
Starting with 3d (0.433 g, 1.41 mmol), 4a (0.430 g, 1.65 mmol)
and TiCl4 (0.18 mL,1.65 mmol), 5n was isolated as a pale yellow solid
1
2
123.5 (d, JC,F¼269.9 Hz, CF3), 127.2 (d, JC,F¼33.2 Hz, CAr), 128.7
(2CHClph), 130.1 (2CHClph), 134.1 (CAr), 134.4, 138.5 (2CClph), 145.8
(0.234 g, 53%), mp¼69–71 ꢀC. 1H NMR (250 MHz, CDCl3):
¼4.01 (s,
d
(CAr), 160.5 (COH), 170.3 (CO). IR (KBr, cmꢁ1):
¼ 2955 ðwÞ, 2926
3H, OCH3), 7.17 (dd, 3JH,H¼3JH,F¼8.7 Hz, 2H, CFCH), 7.37 (d, 4J¼1.7 Hz,
~
n
3
(w), 2856 (w), 1674 (w), 1611 (w), 1493 (w), 1440 (w), 1403 (w),
1339 (w), 1298 (w), 1283 (m), 1237 (w), 1202 (w), 1143 (m), 1092
(w), 1016 (w), 949 (w), 908 (w), 888 (w), 833 (w), 814 (w), 730
(w), 687 (w), 651 (w), 598 (w). GC–MS (EI, 70 eV): m/z (%)¼416
([Mþ], 37Cl, 18), 414 ([Mþ], 35Cl, 52), 384 (37Cl, 19), 383 (37Cl, 29),
382 (35Cl, 46), 381 (35Cl, 30), 367 (37Cl, 10), 365 (35Cl, 14), 354 (12),
348 (22), 347 (100), 325 (9), 314 (11), 313 (27), 312 (31), 311 (62),
291 (14), 289 (9), 257 (10), 256 (12), 249 (19), 248 (8), 243 (10),
201 (16). HRMS (EI) calcd for C21H22ClO3F3 ([M]þ, 35Cl): 414.12041,
found: 414.119859.
1H, ArH), 7.50 (d, 4J¼1.6 Hz, 1H, ArH), 7.58 (dd, JH,H¼8.9 Hz,
4JH,F¼5.2 Hz, 2H, CFCHCH), 10.86 (s, 1H, OH). 19F NMR (235 MHz,
CDCl3):
d
¼ꢁ112.5 (CF), ꢁ58.8 (CF3). 13C NMR (75 MHz, CDCl3):
d
¼52.9 (OCH3), 109.6 (Cq), 116.1 (d, 2J¼21.9 Hz, CFCH), 117.9 (q,
3J¼6.8 Hz, CHCCF3), 119.6 (CH), 123.3 (q, 1J¼273.6 Hz, CF3), 128.9 (d,
3J¼8.4 Hz, CFCHCH), 131.0 (q, 2J¼32.0 Hz, CCF3), 134.4 (d, 4J¼3.3 Hz,
CFCHCHC), 145.7 (Cq), 162.3 (COH), 163.4 (d, 1J¼249.4 Hz, CF), 169.5
~
(CO). IR (ATR, cmꢁ1):
n
¼ 3016 ðwÞ, 2958 (w), 2925 (w), 2854 (w),
1661 (m),1600 (m),1516 (m),1438 (m),1371 (m),1347 (m),1322 (m),
1293 (m), 1240 (m), 1221 (m), 1202 (m), 1174 (m), 1136 (s), 1056 (m).
MS (EI, 70 eV): m/z (%)¼314 (Mþ, 52), 282 (100), 254 (517), 235 (10),
226 (15), 206 (22), 157 (22). HRMS (EI, 70 eV) calcd for C15H10F4O3
(Mþ): 314.05606, found: 314.05584. Anal. Calcd for C15H10F4O3
(314.23): C, 57.33; H, 3.21. Found: C, 57.43; H, 3.14.
3.5.12. Methyl 40-chloro-3-hydroxy-2-octyl-5-(trifluoromethyl)-
biphenyl-4-carboxylate (5l)
Starting with 3c (0.483 g, 1.5 mmol), 4e (0.614 g, 1.65 mmol) and
TiCl4 (0.18 mL, 1.65 mmol), 5l was isolated as a yellowish viscous oil
(0.300 g, 45%). 1H NMR (250 MHz, CDCl3):
d
¼0.74 (t, 3J¼6.2 Hz, 3H,
3.5.15. 40-Fluoro-3-hydroxy-5-trifluoromethyl-biphenyl-4-
carboxylic acid ethyl ester (5o)
CH3CH2), 1.04–1.20 (m, 10H, CH2), 1.30–1.41 (m, 2H, CH2), 2.48 (t,
3J¼7.7 Hz, 2H, CH2), 3.90 (s, 3H, OCH3), 7.04 (s, 1H, CHAr), 7.11 (d,
3J¼8.7 Hz, 2H, CHClph), 7.32 (d, 3J¼8.5 Hz, 2H, CHClph), 11.0 (s, 1H,
Starting with 3d (2.426 g, 7.92 mmol), 4h (2.391 g, 8.71 mmol)
and TiCl4 (0.96 mL, 8.71 mmol), 5o was isolated as a yellow solid
OH). 19F NMR (235 MHz, CDCl3):
d
¼ꢁ58.66. 13C NMR (75 MHz,
(0.840 g, 32%), mp¼44–45 ꢀC. 1H NMR (250 MHz, CDCl3):
¼1.43 (t,
d
CDCl3):
d
¼14.2 (CH3), 22.8, 27.4, 29.2, 29.3,29.4, 29.8, 31.9 (5CH2),
3J¼7.2 Hz, 3H, CH2CH3), 4.47 (q, 3J¼7.2 Hz, 2H, CH2CH3), 7.12–7.22
(m, 2H, ArH), 7.37 (d, 4J¼1.7 Hz, 1H, ArH), 7.49 (d, 4J¼1.7 Hz, 1H,
ArH), 7.54–7.64 (m, 2H, ArH), 10.99 (s, 1H, OH). 19F NMR (235 MHz,
53.0 (OCH3), 109.6 (CCOOMe), 120.4 (q, 3JC,F¼7.0 Hz, CHAr), 123.5 (d,
1JC,F¼272.3 Hz, CF3), 127.2 (d, JC,F¼32.1 Hz, CAr), 128.7 (2CHClph),
2
130.1 (2CHClph), 134.1 (CAr), 134.4, 138.5 (CClph), 145.8 (CAr), 160.5
CDCl3):
d
d
¼ꢁ112.6 (CF), ꢁ58.1 (CF3). 13C NMR (63 MHz, CDCl3):
(COH), 170.3 (CO). IR (KBr, cmꢁ1):
¼ 2954 ðwÞ, 2924 (w), 2853
¼13.5 (CH2CH3), 62.4 (CH2CH3), 109.8 (d, 5J¼1.4 Hz, CFCHCHCC),
~
n
(w), 1672 (m), 1610 (w), 1572 (w), 1492 (w), 1439 (m), 1403 (w),
1336 (m), 1282 (s), 1229 (w), 1200 (s), 1133 (s), 1089 (m), 1015 (m),
994 (w), 955 (w), 907 (w), 887 (w), 832 (s), 813 (w), 758 (w), 728
(m), 685 (w), 655 (w), 643 (w), 598 (w), 537 (w). GC–MS (EI, 70 eV):
m/z (%)¼444 ([Mþ], 37Cl, 16), 442 ([Mþ], 35Cl, 45), 412 (37Cl, 19), 411
116.1 (d, 2J¼21.7 Hz, CFCH), 117.9 (q, 3J¼6.9 Hz, CHCCF3), 119.6 (CH),
123.3 (q, 1J¼273.6 Hz, CF3), 128.9 (d, 3J¼8.4 Hz, CFCHCH), 130.9 (q,
2J¼31.9 Hz, CCF3), 134.5 (d, 4J¼3.4 Hz, CFCHCHC), 145.5 (Cq), 162.4
(COH), 163.4 (d, 1J¼249.4 Hz, CF), 169.1 (CO). IR (ATR, cmꢁ1):
~
n
¼ 3012 ðwÞ, 2987 (w), 2943 (w), 2871 (w), 1665 (m), 1599 (m),
(
37Cl, 31), 410 (35Cl, 49), 409 (35Cl, 29), 393 (16), 376 (24), 375 (100),
1568 (w), 1512 (m), 1468 (w), 1431 (w), 1400 (m), 1366 (m), 1331
(m), 1303 (m), 1288 (m), 1240 (m), 1216 (m), 1137 (s), 1101 (m), 1058
(m). MS (EI, 70 eV): m/z (%)¼328 (Mþ, 43), 282 (100), 254 (42), 226
(11), 206 (19), 157 (18). HRMS (EI, 70 eV) calcd for C16H12F4O3 (Mþ):
328.07171, found: 328.07164. Anal. Calcd for C16H12F4O3 (328.26):
C, 58.54; H, 3.68. Found: C, 58.69; H, 3.57.
325 (10), 314 (12), 313 (29), 312 (37), 311 (70), 299 (12), 297 (16),
291 (17), 289 (13), 278 (10), 277 (59), 257 (12), 256 (14), 249 (20),
248 (10), 243 (12), 220 (12), 219 (12), 201 (15), 43 (13), 41 (15).
HRMS (EI) calcd for C23H26ClO3F3 ([M]þ, 35Cl): 442.15171, found:
442.151120.
3.5.13. Methyl 40-chloro-3-hydroxy-2-methoxy-5-
(trifluoromethyl)-biphenyl-4-carboxylate (5m)
3.5.16. 1-(40-Fluoro-3-hydroxy-2-methyl-5-trifluoromethyl-
biphenyl-4-yl)-propan-1-one (5p)
Starting with 3c (0.483 g,1.5 mmol), 4g (0.360 g,1.65 mmol) and
TiCl4 (0.18 mL, 1.65 mmol), 5m was isolated as a colourless viscous
Starting with 3d (0.430 g, 1.40 mmol), 4b (0.453 g, 1.65 mmol)
and TiCl4 (0.18 mL, 1.65 mmol), 5p was isolated as a colourless solid
oil (0.200 g, 37%). 1H NMR (250 MHz, CDCl3):
d
¼3.59 (s, 3H, OMe),
(0.279 g, 61%), mp¼96–97 ꢀC. 1H NMR (250 MHz, CDCl3):
¼2.20 (s,
d
3.93 (s, 3H, COOMe), 7.19 (s, 1H, CHAr), 7.35 (d, 3J¼9 Hz, 2H, CHClph),
7.42 (d, 3J¼8.7 Hz, 2H, CHClph), 10.01 (s, 1H, OH). 19F NMR (235 MHz,
3H, ArCH3), 4.01 (s, 3H, OCH3), 7.10–7.19 (m, 2H, ArH), 7.20 (s, 1H,
ArH), 7.24–7.32 (m, 2H, ArH), 11.18 (s, 1H, OH). 19F NMR (235 MHz,
CDCl3):
d
¼ꢁ58.72. 13C NMR (75 MHz, CDCl3):
d
¼53.0, 60.7 (OMe),
CDCl3):
d
¼ꢁ113.9 (CF), ꢁ58.7 (CF3). 13C NMR (75 MHz, CDCl3):
3
112.8 (C COOMe), 120.1 (q, JC,F¼12.7 Hz, CHAr), 123.1 (d,
d
¼13.7 (ArCH3), 52.9 (OCH3), 108.8 (Cq), 115.4 (d, 2J¼21.5 Hz, CFCH),
1JC,F¼260.9 Hz, CF3), 124.7 (d, JC,F¼42.9 Hz, CAr) 128.8 (2CHClph),
120.2 (q, 3J¼6.7 Hz, CHCCF3), 123.4 (q, 1J¼272.8 Hz, CF3), 127.1 (q,
2J¼32.1 Hz, CCF3), 129.5 (Cq), 130.6 (d, 3J¼8.2 Hz, CFCHCH), 135.7 (d,
4J¼3.5 Hz, CFCHCHC), 145.9 (Cq), 160.7 (COH), 162.5 (d, 1J¼247.7 Hz,
~
2
130.2 (2CHClph), 134.4 (CAr), 134.6, 136.7 (CClph), 148.3 (CArOMe),
154.4 (COH), 168.7 (CO). IR (KBr, cmꢁ1):
¼ 3399 ðwÞ, 3006 (w),
~
n
2954 (w), 2930 (w), 2852 (w), 1741 (w), 1673 (w), 1609 (w), 1492
(w), 1442 (w), 1415 (w), 1388 (m), 1371 (m), 1321 (m), 1281 (s), 1265
(s), 1247 (s), 1200 (w), 1138 (s), 1090 (m), 1027 (m), 1016 (w), 978
(w), 950 (m), 904 (m), 833 (m), 811 (w), 789 (w), 728 (s), 665 (w),
649 (w), 636 (w), 534 (w). GC–MS (EI, 70 eV): m/z (%)¼362 ([Mþ],
37Cl, 18), 360 ([Mþ], 35Cl, 51), 330 (37Cl, 29), 329 (37Cl, 57), 328 (35Cl,
80), 327 (35Cl, 100), 309 (37Cl, 11), 307 (35Cl, 16), 300 (11), 299 (10),
293 (39), 282 (14), 273 (15), 265 (14), 250 (10), 229 (13), 175 (9), 146
CF), 170.2 (CO). IR (ATR, cmꢁ1):
n
¼ 3074 ðwÞ, 3052 (w), 3011 (w),
2958 (w), 1661 (m), 1614 (w), 1573 (w), 1506 (w), 1438 (m), 1387
(w), 1366 (w), 1338 (m), 1282 (m), 1248 (m), 1208 (m), 1197 (m),
1161 (m), 1131 (s), 1095 (m), 1024 (m). MS (EI, 70 eV): m/z (%)¼328
(Mþ, 37), 295 (100), 268 (9), 219 (15), 199 (18), 170 (14); HRMS (EI,
70 eV) calcd for C16H12F4O3 (Mþ): 328.07171, found: 328.07160.
Anal. Calcd for C16H12F4O3 (328.26): C, 58.54; H, 3.68. Found: C,
58.41; H, 3.83.

S. Bu¨ttner et al. / Tetrahedron 65 (2009) 2124–2135
2131
3.5.17. 2-Ethyl-40-fluoro-3-hydroxy-5-trifluoromethyl-biphenyl-4-
carboxylic acid methyl ester (5q)
Starting with 3d (0.469 g, 1.53 mmol), 4i (0.476 g, 1.65 mmol)
and TiCl4 (0.18 mL, 1.65 mmol), 5q was isolated as a colourless solid
(0.248 g, 31%), mp¼80–83 ꢀC. 1H NMR (250 MHz, CDCl3):
d
¼3.68 (s,
3H, OCH3), 4.01 (s, 3H, OCH3), 7.27 (s, 1H, ArH), 7.44 (d, 3J¼8.6 Hz,
2H, ArH), 7.60 (d, 3J¼8.6 Hz, 2H, ArH), 8.78 (s, 1H, OH). 19F NMR
(235 MHz, CDCl3):
d
¼ꢁ58.7 (CF3). 13C NMR (75 MHz, CDCl3):
¼53.0
d
(0.289 g, 55%), mp¼72–74 ꢀC. 1H NMR (250 MHz, CDCl3):
d
¼1.10 (t,
(OCH3), 60.7 (OCH3), 112.9 (Cq), 120.1 (q, 3J¼6.5 Hz, CHCCF3), 122.9
(Cq), 123.2 (q, 1J¼273.1 Hz, CF3), 124.7 (q, 2J¼32.3 Hz, CCF3), 128.6
(CH), 130.6 (CH), 134.9 (Cq), 136.7 (Cq), 148.3 (Cq), 154.4 (COH), 168.7
~
3J¼7.4 Hz, 3H, CH2CH3), 2.63 (q, 3J¼7.4 Hz, 2H, CH2CH3), 4.01 (s, 3H,
OCH3), 7.09–7.19 (m, 3H, ArH), 7.21–7.31 (m, 2H, ArH), 11.14 (s, 1H,
OH). 19F NMR (235 MHz, CDCl3):
d
¼ꢁ114.1 (CF), ꢁ58.7 (CF3). 13C
(CO). IR (ATR, cmꢁ1):
n
¼ 2922 ðwÞ, 2850 (w), 1665 (m), 1634 (w),
NMR (75 MHz, CDCl3):
d
¼13.6 (CH2CH3), 20.8 (CH2), 52.9 (OCH3),
1491 (w), 1446 (m), 1415 (m), 1386 (m), 1341 (m), 1288 (s), 1269 (s),
1255 (s), 1200 (m), 1160 (m), 1120 (s), 1071 (m), 1029 (m), 1008 (m).
MS (EI, 70 eV): m/z (%)¼406 (81Br, Mþ, 51), 404 (79Br, Mþ, 52), 373
109.3 (Cq), 115.4 (d, 2J¼21.5 Hz, CHCF), 120.5 (q, 3J¼6.7 Hz, CHCCF3),
123.4 (q, 1J¼273.2 Hz, CF3), 127.1 (q, 3J¼32.0 Hz, CCF3), 130.3 (d,
3J¼8.1 Hz, CHCHCF), 135.5 (Cq), 135.9 (d, 4J¼3.5 Hz, CCHCHCF),145.8
(Cq), 160.4 (COH), 162.5 (d, 1J¼247.2 Hz, CF), 170.2 (CO). IR (ATR,
~
(100), 371 (78), 293 (42), 273 (30), 250 (39), 146 (18). HRMS (EI,
79
70 eV) calcd for C16
H
BrF3O4 (Mþ): 403.98656, found: 403.98622;
12
81
cmꢁ1):
n
¼ 2988 ðwÞ, 2966 (w), 2939 (w), 2876 (w), 1678 (m), 1602
calcd for C16H
BrF3O4 (Mþ): 405.98451, found: 405.98440.
12
(w), 1512 (m), 1440 (m), 1365 (m), 1336 (m), 1293 (m), 1261 (m),
1225 (m), 1199 (m), 1142 (s), 1124 (s), 1094 (s), 1060 (m). MS (EI,
70 eV): m/z (%)¼342 (Mþ, 44), 309 (100), 282 (27), 267 (14), 219
(13), 183 (12). HRMS (EI, 70 eV) calcd for C17H14F4O3 (Mþ):
342.08736, found: 342.08706.
3.5.21. 1-(40-Bromo-3-hydroxy-5-trifluoromethyl-biphenyl-4-yl)-
ethanone (5u)
Starting with 3e (0.867 g, 2.36 mmol), 4j (0.660 g, 2.70 mmol)
and TiCl4 (0.30 mL, 2.70 mmol), 5u was isolated as a pale yellow
solid (0.575 g, 68%), mp¼130–133 ꢀC. 1H NMR (250 MHz, CDCl3):
3.5.18. 1-(40-Fluoro-3-hydroxy-5-trifluoromethyl-biphenyl-4-yl)-
ethanone (5r)
d
¼2.67 (q, 6J¼1.8 Hz, 3H, CH3), 7.34 (d, 4J¼1.8 Hz, 1H, ArH), 7.42–
7.49 (m, 3H, ArH), 7.58–7.64 (m, 2H, ArH), 9.92 (s, 1H, OH). 19F NMR
Starting with 3d (0.448 g, 1.46 mmol), 4j (0.403 g, 1.65 mmol)
and TiCl4 (0.18 mL, 1.65 mmol), 5r was isolated as a pale red solid
(235 MHz, CDCl3):
d
¼ꢁ55.7 (CF3). 13C NMR (63 MHz, CDCl3):
¼31.5
d
(q, 5J¼5.3 Hz, CH3), 117.3 (q, 3J¼5.8 Hz, CHCCF3), 119.8 (CH), 120.8
(Cq), 123.5 (Cq), 123.7 (q, 1J¼273.3 Hz, CF3), 128.6 (CH), 129.5 (q,
2J¼31.7 Hz, CCF3), 132.3 (CH), 137.1 (Cq), 144.6 (Cq), 158.6 (COH),
~
(0.296 g, 68%), mp¼125–128 ꢀC. 1H NMR (250 MHz, CDCl3):
¼1.10
d
(t, 3J¼7.4 Hz, 3H, CH2CH3), 2.63 (q, 3J¼7.4 Hz, 2H, CH2CH3), 4.01 (s,
3H, OCH3), 7.09–7.19 (m, 3H, ArH), 7.21–7.31 (m, 2H, ArH), 11.14 (s,
204.6 (CO). IR (ATR, cmꢁ1):
n
¼ 3171 ðwÞ, 3072 (w), 2926 (w), 2851
1H, OH). 19F NMR (235 MHz, CDCl3):
d
¼ꢁ114.1 (CF), ꢁ58.7 (CF3). 13
C
(w), 1683 (m), 1612 (m), 1588 (m), 1563 (w), 1488 (m), 1431 (m),
1391 (m), 1338 (m), 1290 (m), 1246 (m), 1153 (m), 1129 (s), 1108 (m),
1075 (m), 1011 (m). MS (EI, 70 eV): m/z (%)¼360 (Mþ, 81Br, 38), 358
NMR (75 MHz, CDCl3):
d
¼13.6 (CH2CH3), 20.8 (CH2), 52.9 (OCH3),
109.3 (Cq), 115.4 (d, 2J¼21.5 Hz, CHCF), 120.5 (q, 3J¼6.7 Hz, CHCCF3),
123.4 (q, 1J¼273.2 Hz, CF3), 127.1 (q, 3J¼32.0 Hz, CCF3), 130.3 (d,
3J¼8.1 Hz, CHCHCF), 135.5 (Cq), 135.9 (d, 4J¼3.5 Hz, CCHCHCF),145.8
(Cq), 160.4 (COH), 162.5 (d, 1J¼247.2 Hz, CF), 170.2 (CO). IR (ATR,
~
(Mþ, 79Br, 38), 345 (98), 343 (100), 297 (20), 295 (23), 188 (30), 139
79
(10). HRMS (EI, 70 eV) calcd for C15
found: 357.98198; calcd for C15
H
10
BrF3O2 (Mþ): 357.98108,
81
H
BrF3O2 (Mþ): 359.97903, found:
10
cmꢁ1):
n
¼ 2988 ðwÞ, 2966 (w), 2939 (w), 2876 (w), 1678 (m), 1602
359.97903. Anal. Calcd for C15H10BrF3O2 (359.14): C, 50.16; H, 2.81;
Br, 22.25. Found: C, 50.04; H, 2.75; Br, 22.21.
(w), 1512 (m), 1440 (m), 1365 (m), 1336 (m), 1293 (m), 1261 (m),
1225 (m), 1199 (m), 1142 (s), 1124 (s), 1094 (s), 1060 (m). MS (EI,
70 eV): m/z (%)¼342 (Mþ, 44), 309 (100), 282 (27), 267 (14), 219
(13), 183 (12). HRMS (EI, 70 eV) calcd for C17H14F4O3 (Mþ):
342.08736, found: 342.08706.
3.5.22. 1-(40-Bromo-3-hydroxy-2-methyl-5-trifluoromethyl-
biphenyl-4-yl)-propan-1-one (5v)
Starting with 3e (0.769 g, 2.09 mmol), 1,3-bis-silyl enol ether 4k
(0.600 g, 2.20 mmol) and TiCl4 (0.24 mL, 2.20 mmol), 5v was iso-
lated as a pale yellow solid (0.497 g, 61%), mp¼110–114 ꢀC. 1H NMR
3.5.19. 1-40-Bromo-3-hydroxy-2-methyl-5-trifluoromethyl-
biphenyl-4-carboxylic acid methyl ester (5s)
Starting with 3e (0.817 g, 2.22 mmol), 4b (0.686 g, 2.50 mmol)
and TiCl4 (0.28 mL, 2.50 mmol), 5s was isolated as a colourless solid
(250 MHz, CDCl3):
d
¼1.22 (t, 3J¼7.2 Hz, 3H, CH2CH3), 2.19 (s, 3H,
ArCH3), 2.94 (q, 3J¼7.3 Hz, 2H, CH2CH3), 7.13 (s, 1H, ArH), 7.17 (d,
3J¼8.5 Hz, 2H, ArH), 7.59 (d, 3J¼8.5 Hz, 2H, ArH), 8.98 (s, 1H, OH). 19
F
(0.559 g, 65%), mp¼85–86 ꢀC. 1H NMR (250 MHz, CDCl3):
d
¼2.20 (s,
NMR (235 MHz, CDCl3):
d
¼ꢁ55.7 (CF3). 13C NMR (63 MHz, CDCl3):
3H, ArCH3), 4.01 (s, 3H, OCH3), 7.16 (s, 1H, ArH), 7.19 (d, 3J¼8.5 Hz,
d
¼8.8 (CH3), 13.6 (CH3), 37.2 (q, 5J¼4.4 Hz, CH2), 119.7 (q, 3J¼5.4 Hz,
2H, ArH), 7.59 (d, 3J¼8.5 Hz, 2H, ArH), 11.18 (s, 1H, OH). 19F NMR
CHCCF3), 121.1 (Cq), 122.3 (Cq), 123.9 (q, 1J¼273.9 Hz, CF3), 126.8 (q,
(235 MHz, CDCl3):
d
¼ꢁ58.7 (CF3). 13C NMR (75 MHz, CDCl3):
d
¼13.7
2J¼31.8 Hz, CCF3), 128.9 (Cq), 130.5 (CH), 131.7 (CH), 138.5 (Cq), 144.4
(ArCH3), 52.9 (OCH3), 109.0 (Cq), 119.9 (q, 3J¼6.8 Hz, CHCCF3), 122.3
(Cq), 123.4 (q, 1J¼273.1 Hz, CF3), 127.2 (q, 2J¼32.1 Hz, CCF3), 129.3
(Cq), 130.5 (CH), 131.6 (CH), 138.6 (Cq), 145.6 (Cq), 160.7 (COH), 170.1
~
(Cq), 155.2 (COH), 208.6 (CO). IR (ATR, cmꢁ1):
¼ 3435 ðwÞ, 2997
~
n
(w), 2979 (w), 2943 (w), 2919 (w), 1678 (m), 1610 (w), 1591 (w),
1556 (w), 1480 (m), 1415 (w), 1352 (m), 1313 (m), 1257 (s), 1198 (m),
1173 (m), 1144 (m), 1110 (s), 1099 (s), 1072 (m), 1045 (m). MS (EI,
70 eV): m/z (%)¼388 (Mþ, 81Br, 15), 386 (Mþ, 79Br, 14), 359 (95), 357
(CO). IR (ATR, cmꢁ1):
n
¼ 3400 ðwÞ, 3011 (w), 2972 (w), 2958 (w),
1694 (m), 1607 (w), 1589 (m), 1502 (w), 1483 (w), 1439 (m), 1410
(w), 1357 (m), 1318 (m), 1279 (m), 1260 (m), 1200 (m), 1131 (s), 1106
(s), 1072 (m), 1018 (m), 1009 (m). MS (EI, 70 eV): m/z (%)¼390 (Mþ,
81Br, 50), 388 (Mþ, 79Br, 51), 358 (61), 357 (76), 356 (62), 355 (59),
(100), 311 (15), 309 (15), 201 (19); HRMS (EI, 70 eV) calcd for
79
C17
C17
H
H
BrF3O2 (Mþ): 386.01238, found: 386.01156, calcd for
BrF3O2 (Mþ): 388.01033, found: 388.01127. Anal. Calcd for
14
81
14
277 (100), 257 (36), 201 (57), 152 (30). HRMS (EI, 70 eV) calcd for
C17H14BrF3O2 (388.19): C, 52.73; H, 3.64; Br, 20.64. Found: C, 52.78;
H, 3.52; Br, 20.66.
BrF3O3 (Mþ): 387.99164, found: 387.99125; calcd for
BrF3O3 (Mþ): 389.98960, found: 389.98956. Anal. Calcd for
79
C16
C16
H
H
12
81
12
C16H12BrF3O3 (389.16): C, 49.38; H, 3.11; Br, 20.53. Found: C, 49.53;
H, 3.05; Br, 20.35.
3.5.23. 5-Hydroxy-40-nitro-3-trifluoromethyl-biphenyl-4-
carboxylic acid methyl ester (5w)
Starting with 3f (0.516 g,1.55 mmol), 4a (0.430 g,1.65 mmol) and
TiCl4 (0.18 mL, 1.65 mmol), 5w was isolated as a pale yellow solid
3.5.20. 40-Bromo-3-hydroxy-2-methoxy-5-trifluoromethyl-
biphenyl-4-carboxylic acid methyl ester (5t)
Starting with 3e (0.734 g, 1.97 mmol), 4g (0.639 g, 2.20 mmol)
and TiCl4 (0.24 mL, 2.20 mmol), 5t was isolated as a pale red solid
(0.377 g, 71%), mp¼135–137 ꢀC. 1H NMR (250 MHz, CDCl3):
¼4.03
d
(s, 3H, OCH3), 7.45 (d, 4J¼1.6 Hz,1H, ArH), 7.54 (d, 4J¼1.6 Hz,1H, ArH),
7.77 (d, 3J¼8.9 Hz, 2H, ArH), 8.34 (d, 3J¼8.9 Hz, 2H, ArH),10.83 (s,1H,

2132
S. Bu¨ttner et al. / Tetrahedron 65 (2009) 2124–2135
OH). 19F NMR (235 MHz, CDCl3):
d
¼ꢁ58.9 (CF3). 13C NMR (75 MHz,
3.5.27. 3-Hydroxy-2-methyl-5,40-bis(trifluoromethyl)-biphenyl-4-
carboxylic acid methyl ester (5aa)
CDCl3):
d
¼53.2 (OCH3),111.0 (Cq),118.0 (q, 3J¼6.8 Hz, CHCCF3),120.5
(CHCOH), 123.0 (q, 1J¼274.1 Hz, CF3), 124.3 (CH), 128.1 (CH), 131.4 (q,
Starting with silyl enol ether 3g (0.659 g, 1.85 mmol), 1,3-bis-
silyl enol ether 4b (0.604 g, 2.20 mmol) and TiCl4 (0.24 mL,
2.20 mmol), 5aa was isolated as a colourless solid (0.501 g, 72%),
2J¼32.3 Hz, CCF3),144.1 (Cq),144.5 (Cq),148.1 (Cq),162.2 (COH),169.2
(CO). IR (ATR, cmꢁ1):
n
¼ 3113 ðwÞ, 3083 (w), 2958 (w), 2862 (w),
~
1668 (m),1596 (w),1520 (m),1443 (m),1344 (m),1293 (m),1210 (m),
1138 (s), 1105 (m), 1060 (m). MS (EI, 70 eV): m/z (%)¼341 (Mþ, 35),
309 (100), 281 (17), 251 (14), 206 (13). HRMS (EI, 70 eV) calcd for
C15H10F3NO5 (Mþ): 341.05056, found: 341.05088.
mp¼90–91 ꢀC. 1H NMR (250 MHz, CDCl3):
¼2.20 (s, 3H, ArCH3),
d
4.02 (s, 3H, OCH3), 7.20 (s, 1H, ArH), 7.43 (d, 3J¼8.1 Hz, 2H, ArH), 7.73
(d, 3J¼8.1 Hz, 2H, ArH), 11.20 (s, 1H, OH). 19F NMR (235 MHz, CDCl3):
d
¼ꢁ62.7 (CF3), ꢁ58.7 (CF3). 13C NMR (75 MHz, CDCl3):
d
¼13.7
(ArCH3), 53.0 (OCH3), 109.3 (Cq), 119.8 (q, 3J¼6.8 Hz, CHCCF3), 123.3
(q, 1J¼273.2 Hz, CF3), 124.0 (q, 1J¼272.6 Hz, CF3), 125.5 (q, 3J¼3.8 Hz,
CF3CCHCH), 127.4 (q, 2J¼32.2 Hz, CCF3), 129.3 (CF3CCHCH), 129.5
(Cq), 130.2 (q, 2J¼32.7 Hz, CCF3), 143.4 (Cq), 145.3 (Cq), 160.7 (COH),
~
3.5.24. 3-Hydroxy-2-methyl-40-nitro-5-trifluoromethyl-biphenyl-
4-carboxylic acid methyl ester (5x)
Starting with 3f (0.500 g, 1.50 mmol), 4b (0.453 g, 1.65 mmol)
and TiCl4 (0.18 mL, 1.65 mmol), 5x was isolated as a pale yellow
solid (0.274 g, 51%), mp¼199–201 ꢀC. 1H NMR (250 MHz, CDCl3):
170.1 (CO). IR (ATR, cmꢁ1):
n
¼ 3392 ðwÞ, 3083 (w), 2961 (w), 2856
(w), 1695 (m), 1610 (w), 1440 (m), 1359 (m), 1323 (s), 1200 (m), 1136
(s), 1108 (s), 1066 (s), 1014 (s). MS (EI, 70 eV): m/z (%)¼378 (Mþ, 52),
347 (29), 346 (65), 345 (100), 277 (86), 249 (22), 201 (24). Anal.
Calcd for C17H12F6O3 (378.27): C, 53.98; H, 3.20. Found: C, 53.81; H,
3.32.
d
¼2.20 (s, 3H, ArCH3), 4.02 (s, 3H, OCH3), 7.19 (s, 1H, ArH), 7.49 (d,
3J¼8.8 Hz, 2H, ArH), 8.33 (d, 3J¼8.8 Hz, 2H, ArH), 11.21 (s, 1H, OH).
19F NMR (235 MHz, CDCl3):
d
¼ꢁ58.7 (CF3). 13C NMR (75 MHz,
CDCl3):
d
¼13.7 (ArCH3), 53.1 (OCH3), 109.7 (Cq), 119.5 (q, 3J¼6.8 Hz,
CHCCF3), 123.2 (q, 1J¼273.0 Hz, CF3), 123.7 (CH), 127.6 (q,
2J¼32.3 Hz, CCF3), 129.5 (Cq), 129.9 (CH), 144.4 (Cq), 146.3 (Cq), 147.6
3.5.28. 2-Ethyl-3-hydroxy-5,40-bis(trifluoromethyl)-biphenyl-4-
carboxylic acid methyl ester (5ab)
(Cq), 160.7 (COH), 169.9 (CO). IR (ATR, cmꢁ1): ¼ 3111 ðwÞ, 3083
~
n
(w), 3013 (w), 2960 (w), 2929 (w), 2855 (w), 1665 (m), 1596 (w),
1567 (w), 1516 (m), 1441 (w), 1410 (w), 1334 (m), 1285 (m), 1247
(m), 1205 (m), 1132 (s), 1013 (m). MS (EI, 70 eV): m/z (%)¼355 (Mþ,
61), 323 (93), 306 (84), 276 (100), 257 (13), 201 (38),152 (20). HRMS
(EI, 70 eV) calcd for C16H12F3NO5 (Mþ): 355.06621, found:
355.06610. Anal. Calcd for C16H12F3NO5 (355.27): C, 54.09; H, 3.40;
N, 3.94. Found: C, 54.34; H, 3.37; N, 3.56.
Starting with 3g (0.734 g, 2.06 mmol), 4i (0.635 g, 2.20 mmol)
and TiCl4 (0.24 mL, 2.20 mmol), 5ab was isolated as a pale red solid
(0.508 g, 63%), mp¼78–80 ꢀC. 1H NMR (250 MHz, CDCl3):
¼1.10 (t,
d
3J¼7.4 Hz, 3H, CH2CH3), 2.61 (q, 3J¼7.4 Hz, 2H, CH2CH3), 4.02 (s, 3H,
OCH3), 7.15 (s, 1H, ArH), 7.42 (d, 3J¼8.0 Hz, 2H, ArH), 7.72 (d,
3J¼8.1 Hz, 2H, ArH), 11.14 (s, 1H, OH). 19F NMR (235 MHz, CDCl3):
d
¼ꢁ62.6 (CF3), ꢁ58.7 (CF3). 13C NMR (75 MHz, CDCl3):
d
¼13.7
(CH2CH3), 20.9 (CH2), 53.0 (OCH3), 109.8 (Cq), 120.1 (q, 3J¼6.7 Hz,
CHCCF3), 125.4 (q, 3J¼3.7 Hz, CF3CCH), 127.3 (q, 2J¼32.3 Hz, CCF3),
129.0 (CH), 130.2 (q, 2J¼32.8 Hz, CCF3), 135.4 (Cq), 143.5 (Cq), 145.2
~
3.5.25. 1-(5-Hydroxy-40-nitro-3-trifluoromethyl-biphenyl-4-yl)-
ethanone (5y)
Starting with 3f (0.482 g,1.45 mmol), 4j (0.403 g,1.65 mmol) and
TiCl4 (0.18 mL, 1.65 mmol), 5y was isolated as a pale red solid
(0.303 g, 64%), mp¼167–169 ꢀC. 1H NMR (250 MHz, (CD3)2CO):
(Cq), 160.4 (COH), 170.1 (CO). IR (ATR, cmꢁ1):
n
¼ 2980 ðwÞ, 2959
(w), 2946 (w), 2883 (w), 1681 (m), 1607 (w), 1563 (w), 1485 (w),
1443 (m), 1411 (w), 1365 (m), 1321 (s), 1292 (s), 1264 (s), 1227 (m),
1198 (m), 1164 (s), 1126 (s), 1117 (s), 1101 (s), 1070 (s), 1058 (s), 1018
(m). MS (EI, 70 eV): m/z (%)¼392 (Mþ, 44), 359 (66), 317 (11), 291
(100), 263 (12). HRMS (EI, 70 eV) calcd for C18H14F6O3 (Mþ):
392.08417, found: 392.08409.
d
¼2.61 (s, 3H, CH3), 7.61 (s, 1H, ArH), 7.63 (s, 1H, ArH), 8.03 (d,
3J¼8.9 Hz, 2H, ArH), 8.40 (d, 3J¼8.9 Hz, 2H, ArH), 9.87 (s,1H, OH). 19
F
NMR (235 MHz, (CD3)2CO):
d
¼ꢁ53.8 (CF3). 13C NMR (75 MHz,
(CD3)2CO):
d
¼31.8 (CH3),117.1 (q, 3J¼5.0 Hz, CHCCF3),119.3 (CHCOH),
124.6 (q, 1J¼273.5 Hz, CF3), 125.0 (CH), 128.8 (q, 2J¼31.9 Hz, CCF3),
129.2 (CH), 129.7 (Cq), 141.9 (Cq), 146.0 (Cq), 148.8 (Cq), 155.7 (COH),
3.5.29. 1-(3-Hydroxy-5,40-bis(trifluoromethyl)-biphenyl-4-yl)-
ethanone (5ac)
Starting with 3g (0.696 g, 1.95 mmol), 4j (0.538 g, 2.20 mmol)
and TiCl4 (0.24 mL, 2.20 mmol), 5ac was isolated as a colourless
solid (0.365 g, 54%), mp¼141–143 ꢀC. 1H NMR (250 MHz, CDCl3):
201.4 (CO). IR (ATR, cmꢁ1):
¼ 3457 ðwÞ, 3084 (w), 3012 (w), 2923
~
n
(w), 2852 (w),1696 (m),1615 (w),1597 (w),1582 (w),1519 (m),1438
(m), 1348 (s), 1323 (m), 1247 (m), 1144 (m), 1126 (s), 1115 (s). MS (EI,
70 eV): m/z (%)¼325 (Mþ, 22), 310 (100), 264 (21),188 (7). HRMS (EI,
70 eV) calcd for C15H10F3NO4 (Mþ): 325.05564, found: 325.05522.
d
¼2.68 (q, 6J¼1.7 Hz, 3H, CH3), 7.39 (d, 4J¼1.5 Hz, 1H, ArH), 7.48 (d,
4J¼1.2 Hz, 1H, ArH), 7.66–7.78 (m, 4H, ArH), 9.78 (s, 1H, OH). 19F
3.5.26. 3-Hydroxy-5,40-bis(trifluoromethyl)-biphenyl-4-carboxylic
acid methyl ester (5z)
NMR (235 MHz, CDCl3):
d
¼ꢁ62.7 (CF3), ꢁ55.8 (CF3). 13C NMR
(63 MHz, CDCl3):
d
¼31.6 (q, 5J¼5.1 Hz, CH3), 117.6 (q, 3J¼5.6 Hz,
Starting with 3g (0.718 g, 2.01 mmol), 4a (0.573 g, 2.20 mmol)
and TiCl4 (0.24 mL, 2.20 mmol), 5z was isolated as a pale yellowsolid
CHCCF3), 120.3 (CHCOH), 121.4 (Cq), 126.1 (q, 3J¼3.8 Hz, CF3CCH),
129.6 (q, 2J¼31.7 Hz, CCF3), 131.0 (q, 2J¼32.8 Hz, CCF3), 141.7 (Cq),
(0.510 g, 69%), mp¼70–72 ꢀC. 1H NMR (250 MHz, CDCl3):
d¼4.02 (s,
144.3 (Cq), 158.4 (COH), 204.5 (CO). IR (ATR, cmꢁ1):
¼ 3176 ðwÞ,
~
n
3H, OCH3), 7.43 (d, 4J¼1.8 Hz, 1H, ArH), 7.54 (d, 4J¼1.7 Hz, 1H, ArH),
1688 (m), 1651 (w), 1615 (w), 1594 (w), 1574 (w), 1440 (w), 1399
(m), 1364 (m), 1321 (s), 1292 (m), 1271 (m), 1246 (m), 1155 (m), 1113
(s), 1070 (s), 1047 (m), 1016 (m). MS (EI, 70 eV): m/z (%)¼348 (Mþ,
28), 333 (100), 285 (26), 237 (6), 188 (10). HRMS (EI, 70 eV) calcd for
C16H10F6O2 (Mþ): 348.05795, found: 348.05739. Anal. Calcd for
C16H10F6O2 (348.24): C, 55.18; H, 2.89. Found: C, 54.89; H, 3.18.
7.67–7.78 (m, 4H, ArH),10.83 (s,1H, OH). 19F NMR (235 MHz, CDCl3):
d
¼ꢁ62.7 (CF3), ꢁ58.9 (CF3). 13C NMR (75 MHz, CDCl3):
d
¼53.1
(OCH3),110.5 (Cq),118.0 (q, 3J¼6.8 Hz, CHCCF3),120.2 (CHCOH),123.2
(q, 1J¼273.5 Hz, CF3), 123.9 (q, 1J¼272.0 Hz, CF3), 126.1 (q, 3J¼3.8 Hz,
CF3CCHCH), 127.6 (CH), 131.1 (q, 2J¼32.7 Hz, CCF3), 131.2 (q,
2J¼32.2 Hz, CCF3), 141.8 (Cq), 145.1 (Cq), 162.2 (COH), 169.4 (CO). IR
~
(ATR, cmꢁ1):
n
¼ 3233 ðwÞ, 3071 (w), 2961 (w), 2901 (w), 1682 (m),
3.5.30. 1-(3-Hydroxy-2-methyl-5,40-bis(trifluoromethyl)-biphenyl-
4-yl)-propan-1-one (5ad)
1617 (m), 1563 (w), 1485 (w), 1360 (m), 1348 (m), 1322 (s), 1294 (s),
1274 (s),1205 (m),1172 (m),1139 (s),1108 (s),1070 (s),1054 (s),1014
(m). MS (EI, 70 eV): m/z (%)¼364 (Mþ, 38), 332 (100), 304 (56), 285
(10), 207 (20), 188 (11). HRMS (EI, 70 eV) calcd for C16H10F3O3 (Mþ):
364.05286, found: 364.05252. Anal. Calcd for C16H10F6O3 (364.24):
C, 52.76; H, 2.77. Found: C, 52.35; H, 2.91.
Starting with 3g (0.698 g, 1.96 mmol), 4k (0.600 g, 2.20 mmol)
and TiCl4 (0.24 mL, 2.20 mmol), 5ad was isolated as a pale yellow
solid (0.516 g, 70%), mp 111–112 ꢀC. 1H NMR (250 MHz, CDCl3):
d
¼1.23 (t, 3J¼7.2 Hz, 3H, CH2CH3), 2.19 (s, 3H, ArCH3), 2.95 (q,
3J¼7.2 Hz, 2H, CH2CH3), 7.15 (s, 1H, ArH), 7.43 (d, 3J¼8.0 Hz, 2H,

S. Bu¨ttner et al. / Tetrahedron 65 (2009) 2124–2135
2133
ArH), 7.72 (d, 3J¼8.0 Hz, 2H, ArH), 8.95 (s, 1H, OH). 19F NMR
154.2 (COCH3), 159.8 (COH), 168.8 (CO). IR (ATR, cmꢁ1):
(235 MHz, CDCl3):
d
¼ꢁ62.7 (CF3), ꢁ55.7 (CF3). 13C NMR (75 MHz,
¼ 2962 ðwÞ, 2932 (w), 2839 (w), 1738 (w), 1689 (m), 1668 (m),
~
n
CDCl3):
d
¼8.7 (CH3), 13.6 (CH3), 37.3 (CH2), 119.7 (q, 3J¼5.4 Hz,
1608 (m), 1556 (w), 1515 (m), 1448 (m), 1440 (m), 1424 (m), 1397
(m), 1325 (m), 1306 (m), 1276 (s), 1249 (s), 1202 (m), 1177 (m), 1159
(s), 1109 (s), 1037 (m), 1024 (m). MS (EI, 70 eV): m/z (%)¼356 (Mþ,
100), 323 (66), 293 (54), 281 (32), 253 (15), 225 (15). HRMS (EI,
70 eV) calcd for C17H15F3O5 (Mþ): 356.08661, found: 356.08573.
Anal. Calcd for C17H15F3O5 (356.29): C, 57.31; H, 4.24. Found: C,
57.46; H, 4.41.
CHCCF3), 121.5 (Cq), 123.8 (q, 1J¼273.3 Hz, CF3), 124.0 (q,
1J¼272.1 Hz, CF3), 125.5 (q, 3J¼3.8 Hz, CHCCF3), 125.6 (q, 2J¼31.9 Hz,
CCF3), 129.0 (Cq), 129.3 (CH), 130.2 (q, 2J¼32.6 Hz, CCF3), 143.3 (Cq),
~
144.2 (Cq), 155.1 (COH), 208.6 (CO). IR (ATR, cmꢁ1):
n
¼ 3252 ðwÞ,
2981 (w), 2945 (w), 2885 (w), 1691 (m), 1618 (w), 1605 (w), 1581
(w), 1405 (w), 1363 (m), 1324 (s), 1302 (m), 1259 (m), 1232 (m), 1170
(m), 1160 (m), 1140 (m), 1101 (s), 1065 (s), 1045 (m). MS (EI, 70 eV):
m/z (%)¼376 (Mþ, 22), 357 (12), 347 (100), 299 (46), 201 (14). HRMS
(EI, 70 eV) calcd for C18H14F6O2 (Mþ): 376.08925, found: 376.08879.
Anal. Calcd for C18H14F6O2 (376.29): C, 57.45; H, 3.75. Found: C,
57.46; H, 3.79.
3.5.34. 3-Hydroxy-40-methyl-5-trifluoromethyl-biphenyl-4-
carboxylic acid methyl ester (5ah)
Starting with 3i (0.612 g, 2.02 mmol), 4a (0.573 g, 2.20 mmol)
and TiCl4 (0.24 mL, 2.20 mmol), 5ah was isolated as a pale red solid
(0.328 g, 52%), mp¼83–85 ꢀC. 1H NMR (250 MHz, CDCl3):
¼2.41 (s,
d
3.5.31. 3-Hydroxy-40-methoxy-5-trifluoromethyl-biphenyl-4-
carboxylic acid methyl ester (5ae)
Starting with 3h (0.439 g, 1.38 mmol), 4a (0.430 g, 1.65 mmol)
and TiCl4 (0.18 mL, 1.65 mmol), 5ae was isolated as a pale red solid
3H, ArCH3), 4.00 (s, 3H, OCH3), 7.28 (d, 3J¼7.9 Hz, 2H, ArH), 7.41 (d,
4J¼1.7 Hz, 1H, ArH), 7.48–7.56 (m, 3H, ArH), 9.76 (s, 1H, OH). 19F
NMR (235 MHz, CDCl3):
d
¼ꢁ58.8 (CF3). 13C NMR (75 MHz, CDCl3):
d
¼21.2 (ArCH3), 52.8 (OCH3),109.4 (Cq), 117.8 (q, 3J¼6.7 Hz, CHCCF3),
(0.295 g, 66%), mp¼91–93 ꢀC. 1H NMR (250 MHz, CDCl3):
d
¼3.87 (s,
119.4 (CHCOH), 123.4 (q, 1J¼273.6 Hz, CF3), 127.0 (CH), 129.8 (CH),
3H, OCH3), 4.00 (s, 3H, OCH3), 7.00 (d, 3J¼8.8 Hz, 2H, ArH), 7.37 (d,
4J¼1.7 Hz, 1H, ArH), 7.52 (d, 4J¼1.8 Hz, 1H, ArH), 7.57 (d, 3J¼8.8 Hz,
130.7 (q, 2J¼31.9 Hz, CCF3), 135.4 (Cq), 139.2 (Cq), 146.6 (Cq), 162.1
(COH), 169.6 (CO). IR (ATR, cmꢁ1): ¼ 3338 ðwÞ, 3021 (w), 2986
~
n
2H, ArH), 10.88 (s, 1H, OH). 19F NMR (235 MHz, CDCl3):
d
¼ꢁ58.8
(w), 2959 (w), 2860 (w), 1692 (m), 1668 (m), 1613 (m), 1519 (w),
1480 (w),1440 (m),1345 (m),1286 (s),1247 (m),1208 (m),1189 (m),
1158 (s), 1131 (s), 1153 (m), 1017 (m). MS (EI, 70 eV): m/z (%)¼310
(Mþ, 62), 278 (100), 263 (28), 250 (38), 153 (12). HRMS (EI, 70 eV)
calcd for C16H10F3O3 (Mþ): 310.08113, found: 310.08057.
(CF3). 13C NMR (75 MHz, CDCl3):
d
¼52.8 (OCH3), 55.4 (OCH3), 108.8
(Cq), 114.5 (CH), 117.6 (q, 3J¼6.9 Hz, CHCCF3), 118.9 (CHCOH), 123.4
(q, 1J¼273.7 Hz, CF3), 128.3 (CH), 130.5 (Cq), 130.7 (q, 2J¼31.8 Hz,
CCF3), 146.3 (Cq), 160.5 (COCH3), 162.3 (COH), 169.6 (CO). IR (ATR,
~
cmꢁ1):
n
¼ 3063 ðwÞ, 3019 (w), 2954 (w), 2932 (w), 2840 (w), 1667
(m), 1606 (m), 1584 (m), 1514 (m), 1440 (m), 1372 (m), 1342 (m),
1311 (m), 1285 (s), 1246 (s), 1215 (m), 1200 (m), 1170 (s), 1133 (s),
1113 (s), 1057 (m), 1031 (s). MS (EI, 70 eV): m/z (%)¼326 (Mþ, 87),
294 (100), 266 (40), 251 (25), 223 (14). HRMS (EI, 70 eV) calcd for
C16H13F3O4 (Mþ): 326.07604, found: 326.07580.
3.5.35. 3-Hydroxy-2,40-dimethyl-5-trifluoromethyl-biphenyl-4-
carboxylic acid methyl ester (5ai)
Starting with 3i (0.615 g, 2.03 mmol), 4b (0.604 g, 2.20 mmol)
and TiCl4 (0.24 mL, 2.20 mmol), 5ai was isolated as a yellow oil
(0.274 g, 42%). 1H NMR (250 MHz, CDCl3):
2.42 (s, 3H, ArCH3), 4.01 (s, 3H, OCH3), 7.17–7.32 (m, 5H, ArH), 11.19
d¼2.23 (s, 3H, ArCH3),
3.5.32. 1-(3-Hydroxy-40-methoxy-2-methyl-5-trifluoromethyl-
biphenyl-4-yl)-propan-1-one (5af)
Starting with 3h (0.478 g, 1.43 mmol), 4b (0.453 g, 1.65 mmol)
and TiCl4 (0.18 mL, 1.65 mmol), 5af was isolated as a pale yellow
solid (0.248 g, 51%), mp¼49–51 ꢀC. 1H NMR (250 MHz, CDCl3):
(s, 1H, OH). 19F NMR (235 MHz, CDCl3):
(75 MHz, CDCl3):
d
¼ꢁ58.6 (CF3). 13C NMR
d
¼13.7 (ArCH3), 21.3 (ArCH3), 52.8 (OCH3), 108.4
(Cq), 120.4 (q, 3J¼6.8 Hz, CHCCF3), 123.5 (q, 1J¼273.0 Hz, CF3), 126.9
(q, 2J¼31.9 Hz, CCF3), 128.8 (CH), 129.1 (CH), 129.3 (Cq), 136.9 (Cq),
137.8 (Cq), 147.0 (Cq), 160.7 (COH), 170.3 (CO). IR (ATR, cmꢁ1):
~
d
¼2.23 (s, 3H, ArCH3), 3.87 (s, 3H, OCH3), 4.00 (s, 3H, OCH3), 6.98 (d,
n
¼ 3027 ðwÞ, 2955 (w), 2924 (w), 2862 (w), 1669 (m), 1609 (w),
3J¼8.8 Hz, 2H, ArH), 7.21–7.28 (m, 3H, ArH), 11.20 (s, 1H, OH). 19F
1563 (w), 1516 (w), 1439 (m), 1387 (m), 1360 (m), 1334 (s), 1280 (s),
1243 (m), 1201 (s), 1128 (s), 1018 (m). MS (EI, 70 eV): m/z (%)¼324
(Mþ, 44), 292 (25), 277 (100), 201 (10), 165 (8). HRMS (EI, 70 eV)
calcd for C17H15F3O3 (Mþ): 324.09678, found: 324.09653.
NMR (235 MHz, CDCl3):
d
¼ꢁ58.6 (CF3). 13C NMR (75 MHz, CDCl3):
d
¼13.7 (ArCH3), 52.8 (OCH3), 55.3 (OCH3), 108.3 (Cq), 113.8 (CH),
120.4 (q, 3J¼6.8 Hz, CHCCF3), 123.5 (q, 1J¼272.8 Hz, CF3), 126.9 (q,
2J¼31.9 Hz, CCF3), 129.3 (Cq), 130.1 (CH), 132.1 (Cq), 146.7 (Cq), 159.4
(COCH3), 160.7 (COH), 170.3 (CO). IR (ATR, cmꢁ1):
¼ 3036 ðwÞ,
3.5.36. 3-Hydroxy-2-methoxy-40-methyl-5-trifluoromethyl-
biphenyl-4-carboxylic acid methyl ester (5aj)
~
n
3018 (w), 2961 (w), 2936 (w), 2841 (w), 1678 (m), 1612 (m), 1559
(w), 1515 (m), 1456 (w), 1439 (m), 1415 (m), 1392 (m), 1361 (m),
1305 (m), 1275 (s), 1246 (s), 1195 (m), 1179 (s), 1165 (m), 1133 (s),
1115 (s), 1019 (s). MS (EI, 70 eV): m/z (%)¼340 (Mþ, 100), 307 (53),
280 (77), 277 (67), 265 (24), 237 (12), 211 (13). HRMS (EI, 70 eV)
calcd for C17H15F3O4 (Mþ): 340.09170, found: 340.09182. Anal.
Calcd for C17H15F3O4 (340.29): C, 60.00; H, 4.44. Found: C, 60.10; H,
4.71.
Starting with 3i (0.641 g, 2.12 mmol), 4g (0.639 g, 2.20 mmol)
and TiCl4 (0.24 mL, 2.20 mmol), 5aj was isolated as a pale red solid
(0.321 g, 44%), mp¼60–61 ꢀC. 1H NMR (300 MHz, CDCl3):
¼2.42 (s,
d
3H, ArCH3), 3.66 (s, 3H, OCH3), 4.00 (s, 3H, OCH3), 7.24–7.31 (m, 3H,
ArH), 7.46 (d, 3J¼8.2 Hz, 2H, ArH), 9.84 (s, 1H, OH). 19F NMR
(282 MHz, CDCl3):
d
¼ꢁ58.7 (CF3). 13C NMR (75 MHz, CDCl3):
¼21.2
d
(ArCH3), 52.9 (OCH3), 60.6 (OCH3), 112.5 (Cq), 120.5 (q, 3J¼6.4 Hz,
CHCCF3), 123.3 (q, 1J¼273.2 Hz, CF3), 124.3 (q, 2J¼32.3 Hz, CCF3),
128.7 (CH), 129.3 (CH), 133.2 (Cq), 137.8 (Cq), 138.5 (Cq), 148.3 (Cq),
~
3.5.33. 3-Hydroxy-2,40-dimethoxy-5-trifluoromethyl-biphenyl-4-
carboxylic acid methyl ester (5ag)
154.0 (COH), 168.7 (CO). IR (ATR, cmꢁ1):
n
¼ 3030 ðwÞ, 2925 (w),
Starting with 3h (0.509 g, 1.60 mmol), 4g (0.479 g, 1.65 mmol)
and TiCl4 (0.18 mL, 1.65 mmol), 5ag was isolated as a pale red solid
2852 (w),1740 (w),1681 (m),1604 (w),1518 (w),1446 (w),1418 (w),
1394 (w),1368 (m),1326 (m),1285 (m),1268 (m),1249 (m),1199 (m),
1187 (m),1149 (m),1140 (m),1121 (s),1027 (m),1018 (m). Anal. Calcd
for C17H15F3O4 (340.29): C, 60.00; H, 4.44. Found: C, 60.37; H, 4.51.
(0.383 g, 67%), mp¼59–60 ꢀC. 1H NMR (250 MHz, CDCl3):
¼3.66 (s,
d
3H, OCH3), 3.87 (s, 3H, OCH3), 4.00 (s, 3H, OCH3), 6.99 (d, 3J¼8.9 Hz,
2H, ArH), 7.29 (s, 1H, ArH), 7.53 (d, 3J¼8.9 Hz, 2H, ArH), 9.98 (s, 1H,
OH). 19F NMR (235 MHz, CDCl3):
d
¼ꢁ58.7 (CF3). 13C NMR (75 MHz,
3.5.37. 1-(3-Hydroxy-40-methyl-5-trifluoromethyl-biphenyl-4-yl)-
ethanone (5ak)
Starting with 3i (0.608 g, 2.01 mmol), 4j (0.538 g, 2.20 mmol)
and TiCl4 (0.24 mL, 2.20 mmol), 5ak was isolated as a slightly
CDCl3):
d
¼52.9 (OCH3), 55.3 (OCH3), 60.4 (OCH3), 112.1 (Cq), 114.0
(CH), 120.3 (q, 3J¼6.4 Hz, CHCCF3), 123.3 (q, 1J¼272.9 Hz, CF3), 124.4
(q, 2J¼32.3 Hz, CCF3), 128.3 (Cq), 130.2 (CH), 137.5 (Cq), 148.2 (Cq),

2134
S. Bu¨ttner et al. / Tetrahedron 65 (2009) 2124–2135
brownish solid (0.287 g, 49%), mp¼148–151 ꢀC. 1H NMR (250 MHz,
(m), 1603 (w), 1568 (w), 1521 (w), 1486 (w), 1440 (m), 1407 (w),
1366 (m), 1284 (m), 1258 (m), 1199 (m), 1130 (s), 1059 (m). MS (EI,
70 eV): m/z (%)¼400 (Mþ, 100), 367 (35), 340 (69), 325 (15), 291
(26). HRMS (EI, 70 eV) calcd for C23H19F3O3 (Mþ): 400.12808,
found: 400.12753.
CDCl3):
d
¼2.42 (s, 3H, ArCH3), 2.67 (q, 6J¼1.8 Hz, 3H, CH3), 7.29 (d,
3J¼8.0 Hz, 2H, ArH), 7.37 (s, 1H, ArH), 7.47–7.54 (m, 3H, ArH), 10.09
(s, 1H, OH). 19F NMR (235 MHz, CDCl3):
d
¼ꢁ55.5 (CF3). 13C NMR
(63 MHz, CDCl3):
d
¼21.2 (ArCH3), 31.5 (q, 5J¼5.5 Hz, CH3), 117.5 (q,
3J¼5.9 Hz, CHCCF3), 119.6 (CH), 119.9 (Cq), 123.8 (q, 1J¼273.9 Hz,
CF3), 126.9 (CH), 129.3 (q, 2J¼31.5 Hz, CCF3), 129.8 (CH), 135.2 (Cq),
139.4 (Cq), 146.0 (Cq), 158.9 (COH), 204.6 (CO). IR (ATR, cmꢁ1):
~
3.5.41. 300-Hydroxy-200-methoxy-500-trifluoromethyl-
[1,10;40,100]terphenyl-400-carboxylic acid methyl ester (5ao)
Starting with 3j (0.530 g, 1.45 mmol), 4g (0.479 g, 1.65 mmol)
and TiCl4 (0.18 mL, 1.65 mmol), 5ao was isolated as a pale red solid
n
¼ 3192 ðwÞ, 2925 (w), 1666 (m), 1611 (m), 1590 (m), 1567 (m),
1525 (w), 1505 (w), 1430 (m), 1400 (w), 1338 (m), 1279 (m), 1252
(m), 1191 (m), 1130 (s), 1049 (m). MS (EI, 70 eV): m/z (%)¼294 (Mþ,
43), 279 (100), 231 (21), 188 (8). HRMS (EI, 70 eV) calcd for
C16H13F3O2 (Mþ): 294.08622, found: 294.08637.
(0.246 g, 42%), mp¼142–143 ꢀC. 1H NMR (300 MHz, CDCl3):
¼3.64
d
(s, 3H, OCH3), 3.94 (s, 3H, OCH3), 7.29 (s, 1H, ArH), 7.35–7.44 (m, 3H,
ArH), 7.55–7.65 (m, 6H, ArH). 19F NMR (282 MHz, CDCl3):
d¼ꢁ58.7
(CF3). 13C NMR (75 MHz, CDCl3):
d
¼53.0 (OCH3), 60.7 (OCH3), 112.7
3.5.38. 1-(3-Hydroxy-2,40-dimethyl-5-trifluoromethyl-biphenyl-4-
yl)-propan-1-one (5al)
Starting with 3i (0.602 g, 1.99 mmol), 4k (0.600 g, 2.20 mmol)
and TiCl4 (0.24 mL, 2.20 mmol), 5al was isolated as a pale red
solid (0.205 g, 32%), mp¼110–113 ꢀC. 1H NMR (250 MHz, CDCl3):
(Cq), 120.4 (q, 3J¼6.4 Hz, CHCCF3), 123.3 (q, 1J¼272.9 Hz, CF3), 124.5
(q, 2J¼32.0 Hz, CCF3), 127.1 (CH), 127.2 (CH), 127.6 (CH), 128.9 (CH),
129.3 (CH), 135.0 (Cq), 137.4 (Cq), 140.3 (Cq), 141.3 (Cq), 148.4 (Cq),
~
154.2 (COH), 168.7 (CO). IR (ATR, cmꢁ1):
n
¼ 3033 ðwÞ, 2956 (w),
2853 (w), 1668 (m), 1602 (m), 1557 (w), 1486 (w), 1446 (m), 1415
(w),1393 (w),1336 (m),1286 (m),1251 (m),1199 (m),1184 (m),1157
(m), 1120 (s), 1036 (m). MS (EI, 70 eV): m/z (%)¼402 (Mþ, 100), 369
(71), 346 (27), 341 (29), 207 (65), 175 (33). HRMS (EI, 70 eV) calcd
for C22H17F3O7 (Mþ): 402.10735, found: 402.10692.
d
¼1.22 (t, 3J¼7.2 Hz, 3H, CH2CH3), 2.21 (s, 3H, ArCH3), 2.42 (s, 3H,
ArCH3), 2.94 (q, 3J¼7.2 Hz, 2H, CH2CH3), 7.15–7.30 (m, 5H, ArH),
8.23 (s, 1H, OH). 19F NMR (235 MHz, CDCl3):
NMR (75 MHz, CDCl3):
d
¼ꢁ55.8 (CF3). 13C
d
¼8.7 (CH3), 13.7 (CH3), 21.2 (CH3), 37.3
(CH2), 119.9 (q, 3J¼5.4 Hz, CHCCF3), 121.2 (Cq), 124.0 (q,
1J¼273.3 Hz, CF3), 125.1 (q, 2J¼31.2 Hz, CCF3), 128.8 (CH), 129.0
(Cq), 129.1 (CH), 136.8 (Cq), 137.7 (Cq), 145.7 (Cq), 155.0 (COH),
~
Acknowledgements
208.8 (CO). IR (ATR, cmꢁ1):
n
¼ 3316 ðwÞ, 2979 (w), 2943 (w),
Financial support by the state of Pakistan (HEC scholarships for
I.H. and for M.A.Y.) is gratefully acknowledged.
2882 (w), 1690 (m), 1607 (m), 1564 (w), 1518 (m), 1456 (w), 1408
(w), 1361 (m), 1300 (m), 1262 (m), 1218 (m), 1184 (m), 1125 (s),
1098 (s), 1046 (m). MS (EI, 70 eV): m/z (%)¼322 (Mþ, 18), 293
(100), 245 (20), 201 (8). HRMS (EI, 70 eV) calcd for C18H17F3O2
(Mþ): 322.11752, found: 322.11690.
References and notes
1. While the size of the methyl and trifluoromethyl group is comparable, the latter
possesses a strong electron-withdrawing effect. Therefore, the replacement of
a CH3 group by a CF3 group in a molecule results in a great change of its
electronic properties and reactivity. The trifluoromethyl group of drugs plays an
important role in drug–receptor interactions and in the in vivo transport. In
addition, the high chemical and biological stability of the CF3 group allows to
avoid unwanted metabolic transformations. For reviews, see: (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, NY, 1979;
Chapter 6; (c) Hudlicky, M. Chemistry of Organic Compounds; Ellis Horwood:
Chichester, UK, 1992; See also: (d) Ryckmanns, T.; Balancon, L.; Berton, O.;
Genicot, C.; Lamberty, Y.; Lallemand, B.; Passau, P.; Pirlot, N.; Que´re´, L.; Talaga, P.
Bioorg. Med. Chem. Lett. 2002, 12, 261; (e) Malamas, M. S.; Sredy, J.; Moxham, C.;
Katz, A.; Xu, W.; McDevitt, R.; Adebayo, F. O.; Sawicki, D. R.; Seestaller, L.;
Sullivan, D.; Taylor, J. R. J. Med. Chem. 2000, 43, 1293; (f) Ciha, A. J.; Ruminski, P.
G. J. Agric. Food Chem. 1991, 39, 2072.
3.5.39. 300-Hydroxy-200-methyl-500-trifluoromethyl-
[1,10;40,100]terphenyl-400-carboxylic acid methyl ester (5am)
Starting with 3j (0.523 g, 1.44 mmol), 4b (0.453 g, 1.65 mmol)
and TiCl4 (0.18 mL, 1.65 mmol), 5am was isolated as a colourless
solid (0.386 g, 70%), mp¼156–157 ꢀC. 1H NMR (300 MHz, CDCl3):
d
¼2.29 (s, 3H, ArCH3), 4.02 (s, 3H, OCH3), 7.30 (s, 1H, ArH), 7.36–7.43
(m, 3H, ArH), 7.45–7.52 (m, 2H, ArH), 7.63–7.72 (m, 4H, ArH), 11.22
(s, 1H, OH). 19F NMR (282 MHz, CDCl3):
(75 MHz, CDCl3):
d
¼ꢁ58.6 (CF3). 13C NMR
d
¼13.8 (ArCH3), 52.9 (OCH3), 108.6 (Cq), 120.3 (q,
3J¼6.8 Hz, CHCCF3), 123.5 (q, 1J¼272.6 Hz, CF3), 127.1 (q, 2J¼32.1 Hz,
CCF3), 127.1 (CH), 127.6 (CH), 128.9 (CH), 129.3 (CH), 129.4 (Cq), 138.7
(Cq), 140.4 (Cq), 140.9 (Cq), 146.6 (Cq), 160.7 (COH), 170.2 (CO). IR
~
(ATR, cmꢁ1):
n
¼ 3034 ðwÞ, 2960 (w), 2923 (w), 2859 (w), 1668
2. (a) Schmidbaur, H.; Kumberger, O. Chem. Ber. 1993, 126, 3; (b) Dinger, M. B.;
Henderson, W. J. Organomet. Chem. 1998, 560, 233; (c) Liedtke, J.; Loss, S.;
Widauer, C.; Gru¨ tzmacher, H. Tetrahedron 2000, 56, 143.
(m), 1603 (w), 1569 (w), 1548 (w), 1525 (w), 1487 (w), 1442 (m),
1408 (w), 1385 (w), 1336 (m), 1286 (m), 1242 (m), 1201 (m), 1155
(m), 1127 (s). MS (EI, 70 eV): m/z (%)¼386 (Mþ, 100), 353 (66), 326
(50), 277 (46), 257 (39), 228 (14), 177 (10). HRMS (EI, 70 eV) calcd
for C22H17F3O3 (Mþ): 386.11243, found: 386.11185.
3. See for example: (a) Schneider, S.; Tzschucke, C. C.; Bannwarth, W. In Multi-
phase Homogeneous Catalysis; Cornils, B., Herrmann, W. A., Horvath, I. T., Leit-
ner, W., Mecking, S., Olivier-Booubigou, H., Vogt, D., Eds.; Wiley VCH: 2005;
Chapter 4, p 346; (b) Clarke, D.; Ali, M. A.; Clifford, A. A.; Parratt, A.; Rose, P.;
Schwinn, D.; Bannwarth, W.; Rayner, C. M. Curr. Top. Med. Chem. 2004, 7, 729.
4. (a) Wittkopp, A.; Schreiner, P. R. The chemistry of dienes and polyenes; John
Wiley & Sons: New York, NY, 2000; Vol. 2; (b) Schreiner, P. R. Chem. Soc. Rev.
2003, 32, 289; (c) Wittkopp, A.; Schreiner, P. R. Chem.dEur. J. 2003, 9, 407; (d)
Kleiner, C. M.; Schreiner, P. R. Chem. Commun. 2006, 4315; (e) Kotke, M.;
Schreiner, P. R. Synthesis 2007, 779; (f) Okino, T.; Hoashi, Y.; Takemoto, Y. J. Am.
Chem. Soc. 2003, 125, 12672.
3.5.40. 200-Ethyl-300-hydroxy-500-trifluoromethyl-
[1,10;40,100]terphenyl-400-carboxylic acid methyl ester (5an)
Starting with 3j (0.524 g, 1.44 mmol), 4i (0.476 g, 1.65 mmol)
and TiCl4 (0.18 mL, 1.65 mmol), 5an was isolated as a pale red solid
(0.234 g, 41%), mp¼173–174 ꢀC. 1H NMR (300 MHz, CDCl3):
¼1.16
d
5. Review: Tsogoeva, S. B. Eur. J. Org. Chem. 2007, 1701.
6. Review: McClinton, M. A.; McClinton, D. A. Tetrahedron 1992, 48, 6555.
7. (a) Paratian, J. M.; Sibille, S.; Pe´richon, J. J. Chem. Soc., Chem. Commun. 1992, 53;
(b) Tordeux, M.; Langlois, B.; Wakselman, C. J. Chem. Soc., Perkin Trans. 1 1990,
2293.
(t, 3J¼7.4 Hz, 3H, CH2CH3), 2.71 (q, 3J¼7.4 Hz, 2H, CH2CH3), 4.02 (s,
3H, OCH3), 7.25 (s, 1H, ArH), 7.35–7.42 (m, 3H, ArH), 7.45–7.52 (m,
2H, ArH), 7.63–7.71 (m, 4H, ArH), 11.13 (s, 1H, OH). 19F NMR
(282 MHz, CDCl3):
d
¼ꢁ58.6 (CF3). 13C NMR (75 MHz, CDCl3):
¼13.8
d
8. Ding, W.; Pu, J.; Zhang, C. Synthesis 1992, 635.
9. For cyclocondensations, see: (a) Guan, H.-P.; Hu, C.-M. Synthesis 1996, 1363; (b)
Guan, H.-P.; Hu, C.-M. J. Fluorine Chem. 1996, 78, 101; (c) Guan, H.-P.; Hu, Q.-S.;
Hu, C.-M. Chin. J. Chem. 1996, 14, 87.
10. For the metalation of (trifluoromethyl)arenes and subsequent coupling with
electrophiles, see: (a) Marzi, E.; Mongin, F.; Spitaleri, A.; Schlosser, M. Eur. J. Org.
Chem. 2001, 2911; (b) Dmowski, W.; Piasecka-Maciejewska, K. J. Fluorine Chem.
1996, 78, 59.
(CH2CH3), 20.9 (CH2), 52.8 (OCH3), 109.1 (Cq), 120.6 (q, 3J¼6.7 Hz,
CHCCF3), 123.5 (q, 1J¼272.7 Hz, CF3), 127.0 (q, 2J¼32.1 Hz, CCF3),
127.0 (CH), 127.1 (CH), 127.6 (CH), 128.9 (CH), 129.0 (CH), 135.4 (Cq),
138.9 (Cq), 140.4 (Cq), 140.8 (Cq), 146.5 (Cq), 160.5 (COH), 170.2 (CO).
~
IR (ATR, cmꢁ1):
n
¼ 3032 ðwÞ, 2957 (w), 2941 (w), 2879 (w), 1668

S. Bu¨ttner et al. / Tetrahedron 65 (2009) 2124–2135
2135
11. For Diels–Alder reactions, see: (a) Abubakar, A. B.; Booth, B. L.; Suliman, N. N. E.;
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21. CCDC-715404 and 700728 contain the supplementary crystallographic data for
this paper. These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.